Science, Faculty of
Chemistry, Department of
DSpace
UBCV
He, Qiuyu
Doctor of Philosophy - PhD
University of British Columbia
This dissertation presents research work on hetero-Diels-Alder reactions using 2-diphenylphosphoryloxy-1,3-butadienes and imines for the construction of six-membered nitrogen heterocycles. Chapter 1 provides an overview of hetero-Diels-Alder reactions that primarily focuses on imines and enol-based dienes. Chapter 2 describes hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines under the promotion of iron(III) chloride. Twelve examples of 2-diphenylphosphoryloxy-1,3-butadienes were synthesized, and eighteen cycloaddition products were constructed in 30–91% isolated yields. Relative configurations of products formed in diastereomeric mixtures were analyzed by 2-dimensional NMR spectroscopy, and the diastereomeric ratios ranged from 2:1 to >20:1. The utility of the enol phosphate functionality was demonstrated in manipulations of the cycloaddition products in transition metal catalyzed cross-coupling reactions. Chapter 3 describes the multicomponent hetero-Diels-Alder reactions using dienes from Chapter 2, amines, and aldehydes through in situ generation of iminium species under the promotion of boron trifluoride diethyl etherate. The reactions were carried in non-distilled dichloromethane without the use of inert atmosphere. Thirty-one examples of cycloaddition products were presented with a diverse scope of aromatic aldehydes, aliphatic aldehydes, N-sulfonyl amines, and N-carbamoyl amines. Chapter 4 describes a sequence of cycloaddition–cross-coupling–oxidation reactions to construct functionalized pyridines. The N-Fmoc substituted cycloaddition products were subjected to Pd(0)-catalyzed Kumada coupling reactions with varied Grignard coupling partners. The Fmoc protecting group in the cross-coupling products was deprotected using piperidine. A subsequent addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidized the heterocyclic ring to an aromatic pyridine structure. Twenty examples of disubstituted pyridines and one example of trisubstituted pyridine were constructed in 17–88% yields over two synthetic steps. Twelve examples of fluorescent 4-biphenylpyridines were constructed and could potentially be applied in light-luminating materials. Their wavelengths of maximum emission lied in the range of 349–389 nm.
CONSTRUCTION OF FUNCTIONALIZED NITROGEN HETEROCYCLES USING 2-(DIPHENYLPHOSPHORYL)OXYGEN-1,3-BUTADIENES IN MULTICOMPONENT [4+2] CYCLOADDITION REACTIONS by Qiuyu He B. Sc. (Hons.), The University of Toronto, 2019 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) August 2023 © Qiuyu He, 2023 ii The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Construction of Functionalized Nitrogen Heterocycles Using 2-(Diphenylphosphoryl)oxygen-1,3-Butadienes in Multicomponent [4+2] Cycloaddition Reactions submitted by Qiuyu He in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Chemistry Examining Committee: Gregory Dake, Associate Professor, Chemistry, UBC Supervisor Jason Hein, Associate Professor, Chemistry, UBC Supervisory Committee Member Michael Wolf, Professor & Head, Chemistry, UBC University Examiner Abby Collier, Professor, Pharmaceutical Sciences, UBC University Examiner Additional Supervisory Committee Members: Glenn Sammis, Professor, Chemistry, UBC Supervisory Committee Member Eva Nichols, Assistant Professor, Chemistry, UBC Supervisory Committee Member iii Abstract This dissertation presents research work on hetero-Diels-Alder reactions using 2-diphenylphosphoryloxy-1,3-butadienes and imines for the construction of six-membered nitrogen heterocycles. Chapter 1 provides an overview of hetero-Diels-Alder reactions that primarily focuses on imines and enol-based dienes. Chapter 2 describes hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines under the promotion of iron(III) chloride. Twelve examples of 2-diphenylphosphoryloxy-1,3-butadienes were synthesized, and eighteen cycloaddition products were constructed in 30–91% isolated yields. Relative configurations of products formed in diastereomeric mixtures were analyzed by 2-dimensional NMR spectroscopy, and the diastereomeric ratios ranged from 2:1 to >20:1. The utility of the enol phosphate functionality was demonstrated in manipulations of the cycloaddition products in transition metal catalyzed cross-coupling reactions. Chapter 3 describes the multicomponent hetero-Diels-Alder reactions using dienes from Chapter 2, amines, and aldehydes through in situ generation of iminium species under the promotion of boron trifluoride diethyl etherate. The reactions were carried in non-distilled dichloromethane without the use of inert atmosphere. Thirty-one examples of cycloaddition products were presented with a diverse scope of aromatic aldehydes, aliphatic aldehydes, N-sulfonyl amines, and N-carbamoyl amines. Chapter 4 describes a sequence of cycloaddition–cross-coupling–oxidation reactions to construct functionalized pyridines. The N-Fmoc substituted cycloaddition products were subjected to Pd(0)-catalyzed Kumada coupling reactions with varied Grignard coupling partners. The Fmoc protecting group in the cross-coupling products was deprotected using piperidine. A subsequent iv addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone oxidized the heterocyclic ring to an aromatic pyridine structure. Twenty examples of disubstituted pyridines and one example of trisubstituted pyridine were constructed in 17–88% yields over two synthetic steps. Twelve examples of fluorescent 4-biphenylpyridines were constructed and could potentially be applied in light-luminating materials. Their wavelengths of maximum emission lied in the range of 349–389 nm. v Lay Summary Six-membered nitrogen heterocycles are core motifs in nature products and active pharmaceutical ingredients. They are also useful in material science and particularly in light-luminating materials. Methods to construct six-membered nitrogen heterocycles have been extensively studied in synthetic organic chemistry. A hetero-Diels-Alder reaction is one of the synthetic transformations that build a six-membered heterocyclic ring in a two-bond forming process. The goal of this research work is to apply a type of diene that has notable bench stability in the hetero-Diels-Alder reaction with imines. Using this type of diene, a protocol that has advantages of good atom economy, ease of execution and broad substrate scopes can be established to construct functionalized non-aromatic and aromatic six-membered nitrogen heterocycles. vi Preface The research in Chapter 2 was based on preliminary work by Yiran Wei, a MSc student in Dake lab and Lirong Cao, an undergraduate summer student in Dake lab. All five N-sulfonyl imines (2.5a-e), two of the N-carbamoyl imines (2.15c, 2.15d) and two of the cycloaddition products (2.8b, 2.8e) were synthesized by Yiran Wei. The rest of the compounds were all synthesized by me. Characterizations of diene 2.1a and cycloaddition product 2.8a was done by Yiran and me together. Spectral analysis on relative configurations of 2.18a and 2.18b were done by me. The NOESY experiment of product 2.18a was performed by UBC NMR lab technician Maria Ezhova. The research material in Chapter 3 was published in 2022: Qiuyu He, Lirong Cao, Yiran Wei, Gregory R. Dake. “Utility of 2-Diphenylphosphoryloxy-1,3-Dienes in Multicomponent Hetero-Diels-Alder Reactions to Construct Functionalized Six-membered Nitrogen Heterocycles.” Chem. Eur. J. 2022, 28, e202201328. Lirong Cao and Yiran Wei synthesized the diene 2.1a and performed some initial studies on the reactivities of the diene under the direction of Prof. Dake. The design of the multicomponent hetero-Diels-Alder approach was done by Prof. Dake and me. All the multicomponent hetero-Diels-Alder reactions and characterization of cycloaddition products were performed by me. The research in Chapter 4 was all done by me including the design of the work, synthesis of compounds, characterizations, and other experimental work. The fluorescence spectroscopy experiments were performed with the help of UBC Shared Instrument Facility technician Ben Herring. A manuscript was in preparation during the time of thesis writing. vii Table of Contents Abstract ......................................................................................................................................... iii Lay Summary ................................................................................................................................ v Preface ........................................................................................................................................... vi Table of Contents ........................................................................................................................ vii List of Tables ............................................................................................................................... xii List of Figures ............................................................................................................................. xiv List of Schemes .......................................................................................................................... xvii List of Equations ....................................................................................................................... xxii List of Abbreviation and Symbols .......................................................................................... xxiii Acknowledgements ................................................................................................................. xxvii Chapter 1: Nitrogen Heterocycles, Hetero-Diels-Alder Reactions and Enol-based Functionality: Background .......................................................................................................... 1 1.1 Synthetic organic chemistry ............................................................................................ 1 1.2 An outline of the background survey .............................................................................. 2 1.3 Nitrogen heterocycles: nomenclature ............................................................................. 3 1.4 Importance of six-membered nitrogen heterocycles in industry ..................................... 5 1.4.1 Applications of six-membered nitrogen heterocycles in pharmaceuticals ............. 5 1.4.2 Applications of six-membered nitrogen heterocycles in fluorescent materials ...... 6 1.5 Six-membered nitrogen heterocycles: synthesis ............................................................. 8 viii 1.6 Diels-Alder reaction: background ................................................................................. 12 1.7 Hetero-Diels-Alder reaction: background ..................................................................... 17 1.7.1 Inverse-electron-demand hetero-Diels-Alder reaction ......................................... 18 1.7.2 Normal-electron-demand hetero-Diels-Alder reaction ......................................... 20 1.8 Enol-based functional groups: preparation and reactivities .......................................... 26 1.8.1 Enol-based dienes ................................................................................................. 32 1.8.2 Enol phosphate as a synthetically useful functionality ......................................... 43 1.9 Conclusion .................................................................................................................... 49 Chapter 2: Hetero-Diels-Alder Reactions of 2-Diphenylphosphoryloxy-1,3-Butadienes and Imines ....................................................................................................................................51 2.1 Introduction ................................................................................................................... 51 2.2 Synthesis of 2-diphenylphosphoryloxy-1,3-diene and characterization ....................... 52 2.3 The hetero-Diels-Alder reaction between 2-diphenylphosphoryloxy-1,3-butadiene and N-(p-toluenesulfonyl)benzaldimine .......................................................................................... 55 2.3.1 Characterization of the hetero-Diels-Alder product ............................................. 57 2.3.2 Optimization of the reaction btween 2-diphenylphosphoryloxy-1,3-butadiene and N-(p-toluenesulfonyl)benzaldimine ...................................................................................... 61 2.4 Substrate scope for the hetero-Diel-Alder reaction ...................................................... 63 2.4.1 Synthesis of derivatives of N-(p-toluenesulfonyl)benzaldimine ........................... 63 2.4.2 Scope of imines for the hetero-Diels-Alder reaction with 2-diphenylphosphoryloxy-1,3-butadienes ................................................................................ 64 ix 2.4.3 Synthesis of derivatives of 2-diphenylphosphoryloxy-1,3-butadiene .................. 66 2.4.4 Hetero-Diels-Alder reactions of two 4-substituted 2-diphenylphosphoryloxy-1,3-butadienes and diastereoselectivity studies ........................................................................... 69 2.4.5 Scope of dienes for the hetero-Diels-Alder reaction ............................................. 78 2.4.6 Observation on challenges in expanding the scope of imines .............................. 81 2.5 Cross-coupling reactions of hetero-Diels-Alder products ............................................ 82 2.6 Conclusions ................................................................................................................... 85 2.7 Experimental ................................................................................................................. 85 Chapter 3: Multicomponent Hetero-Diels-Alder Reactions of Dienes, Aldehydes and Amines ........................................................................................................................................125 3.1 Introduction ................................................................................................................. 125 3.2 Optimization of the multicomponent hetero-Diels-Alder reaction ............................. 128 3.3 Substrate scope for the multicomponent hetero-Diels-Alder reaction ........................ 131 3.3.1 Aldehyde scope for the multicomponent hetero-Diels-Alder reaction ............... 131 3.3.2 Diene scope for the multicomponent hetero-Diels-Alder reaction ..................... 138 3.3.3 Amine scope for the multicomponent hetero-Diels-Alder reaction .................... 139 3.4 The scope of 2-diethylphosphoryloxy-1,3-butadiene in multicomponent hetero-Diels-Alder reactions ........................................................................................................................ 142 3.5 Manipulation of a multicomponent hetero-Diels-Alder product ................................ 145 3.6 Conclusions ................................................................................................................. 146 x 3.7 Experimental ............................................................................................................... 146 Chapter 4: A Cycloaddition–Cross-Coupling–Oxidation Sequence to Build Fluorescent Arylpyridines .............................................................................................................................176 4.1 Introduction ................................................................................................................. 176 4.2 Synthesis of substituted pyridines ............................................................................... 179 4.2.1 Optimization of the Kumada coupling reaction on enol phosphate .................... 181 4.2.2 Scope of Grignard reagents for the Kumada coupling reaction .......................... 183 4.2.3 Kumada coupling reactions with alkyl Grignard reagents .................................. 185 4.2.4 Deprotection and oxidation of tetrahydropyridines to form pyridines ............... 187 4.3 Synthesis of derivatives of fluorescent pyridines ....................................................... 192 4.3.1 Scope of aldehydes for the multicomponent hetero-Diels-Alder reaction using N-Fmoc amine ......................................................................................................................... 195 4.3.2 Synthesis of fluorescent 4-biphenyl pyridine derivatives ................................... 197 4.4 UV-vis and fluorescence spectroscopy analysis on 4-biphenylpyridines ................... 199 4.4.1 Absorption and emission wavelengths of the 4-biphenylpyridine derivatives ... 199 4.4.2 Measuring quantum yields of the 4-biphenylpyridine derivatives ..................... 203 4.5 Manipulations of 4-biphenyl-2-phenylpyridines ........................................................ 207 4.6 Conclusions ................................................................................................................. 211 4.7 Experimental information ........................................................................................... 212 Chapter 5: Conclusion ......................................................................................................... 253 xi References .................................................................................................................................. 257 Appendix: Selected Spectra Data ............................................................................................ 293 xii List of Tables Table 1.1 Hydrolysis of silyl enol ether (1.52) at neutral and acidic conditions ......................... 30 Table 1.2 Hydrolysis of four examples of silyl enol ethers 1.54 at acidic conditions ................. 31 Table 2.1 Diagnostic 1H and 13C NMR assignments of alkenyl protons of 2.1a ......................... 53 Table 2.2 Carbon and proton assignments of the heterocyclic ring in 2.8a ................................. 58 Table 2.3 Hydrolysis of the product 2.8a in neutral and acidic aqueous media .......................... 60 Table 2.4 Screening equivalents of BF3•OEt2 and diene 2.1a for the hetero-Diels-Alder reactiona....................................................................................................................................................... 61 Table 2.5 Screening equivalents of FeCl3 and diene 2.1a for the hetero-Diels-Alder reactiona .. 62 Table 2.6 Assignment of carbons and protons on the heterocyclic ring of the major diastereomer of 2.18a and some correlations in 1H-1H COSY ........................................................................... 70 Table 2.7 Assignments of carbons and protons on the heterocyclic ring of the minor diastereomer of 2.18a ......................................................................................................................................... 72 Table 2.8 Assignments of carbons and protons on the heterocyclic ring of the major diastereomer of 2.18b ......................................................................................................................................... 74 Table 2.9 Assignment of carbons and protons on the heterocyclic ring of the minor diastereomer of 2.18b ......................................................................................................................................... 74 Table 3.1 Screening of solvents for the multicomponent hetero-Diels-Alder reactiona ............ 130 Table 4.1 Condition screen for the Kumada coupling reaction on 4.1aa ................................... 182 Table 4.2 Kumada coupling reactions on enol phosphates with alkyl Grignard reagents ......... 187 Table 4.3 Screen of solvents for the deprotection and oxidation of 4.2aa ................................. 188 Table 4.4 Wavelengths of maximum absorption and emission of 4-biphenyl pyridine derivativesa..................................................................................................................................................... 200 xiii Table 4.5 Quantum yields of 4-biphenyl pyridine derivativesa ................................................. 206 xiv List of Figures Figure 1.1 Graphical representation of synthesis and methodology in organic chemistry ............ 1 Figure 1.2 Graphical representation of the methods in this thesis ................................................. 2 Figure 1.3 Common nitrogen heterocycles .................................................................................... 4 Figure 1.4 Distribution of six-membered nitrogen heterocycles in FDA approved small molecule drugs before 2014 ........................................................................................................................... 5 Figure 1.5 Examples of small-molecule drugs that contain piperidine and pyridine substructures.......................................................................................................................................................... 6 Figure 1.6 Simplified Jablonski diagram and examples of pyridine-containing fluorescent compounds ...................................................................................................................................... 7 Figure 1.7 Electronic states of p-electron systems of a 1,3-butadiene and an alkene ................. 13 Figure 1.8 Substituent perturbation in normal-electron-demand and inverse-electron-demand Diels-Alder reactions .................................................................................................................... 14 Figure 1.9 Resonance structures of (E)-1-methoxybuta-1,3-diene and acrolein ......................... 16 Figure 1.10 Common enol-based functional groups .................................................................... 27 Figure 1.11 Examples of enol-based dienes ................................................................................. 32 Figure 1.12 Diels-Alder reactions of 2-phosphoryloxy-1,3-butadienes with maleic anhydride .. 41 Figure 1.13 General mechanism of the palladium catalyzed cross-coupling reaction on enol phosphate ...................................................................................................................................... 44 Figure 2.1 Percentage degradation of 2.1a and 2.4 when they were stored as 1 M solutions in CH2Cl2 at 5 °C .............................................................................................................................. 54 Figure 2.2 Proton and phosphorus assignments of enol phosphate 2.9 ....................................... 59 Figure 2.3 Expected COSY correlations in the two regioisomers of product 2.8a ...................... 59 xv Figure 2.4 Synthesis of N-(p-toluenesulfonyl)benzaldimine and derivativesa ............................ 63 Figure 2.5 Two-step synthesis of N-carbamoyl imine derivativesa ............................................. 64 Figure 2.6 Scope of imines for the hetero-Diels-Alder reactiona ................................................ 65 Figure 2.7 Synthesis of 2-diphenylphosphoryloxy-1,3-diene derivativesa .................................. 67 Figure 2.8 1H NMR spectra on heterocyclic rings of 2.8a and the major diastereomer of 2.18a 70 Figure 2.9 Diagnostic NOE to identify the relative configuration of the major diastereomer of product 2.18a ................................................................................................................................ 71 Figure 2.10 1H NMR spectra on heterocyclic rings of 2.8a and the minor diastereomer of 2.18a....................................................................................................................................................... 72 Figure 2.11 The 1H NMR spectrum of heterocyclic rings of both diastereomers of 2.18b ......... 75 Figure 2.12 Proposed transition states of the cycloaddition processes under the promotion of two different Lewis acids ..................................................................................................................... 77 Figure 2.13 Scope of dienes for the hetero-Diels-Alder reactiona ............................................... 79 Figure 3.1 The hetero-Diels-Alder product between diene 2.1a and benzaldehyde .................. 129 Figure 3.2 Scope of aromatic aldehydes for the multicomponent hetero-Diels-Alder reactiona 132 Figure 3.3 Side products 3.16d and 3.16i in hetero-Diels-Alder reactions and their diagnostic NMR signals ............................................................................................................................... 133 Figure 3.4 Scope of aliphatic aldehydes for the multicomponent hetero-Diels-Alder reactiona 135 Figure 3.5 Unsuccessful aldehyde substrates in the multicomponent hetero-Diels-Alder reactionsa..................................................................................................................................................... 136 Figure 3.6 Side products 3.16t and 3.16u in hetero-Diels-Alder reactions and their diagnostic NMR signals ............................................................................................................................... 137 Figure 3.7 Scope of dienes for the multicomponent hetero-Diels-Alder reactiona .................... 138 xvi Figure 3.8 Scope of amines for the multicomponent hetero-Diels-Alder reactions .................. 140 Figure 3.9 Diagnostic signals in 1H and 31P NMR spectra of the hetero-Diels-Alder products 3.22-3.24.............................................................................................................................................. 143 Figure 4.1 Scope of Grignard reagents for the Kumada coupling reaction of 4.1aa .................. 183 Figure 4.2 TLC plates of the reaction mixture in the processes of deprotection and oxidation in DMF and CH2Cl2a ....................................................................................................................... 189 Figure 4.3 Synthesis of 2,4-disubstituted pyridinea ................................................................... 190 Figure 4.4 The effect of p conjugation length on the fluorescence of compounds .................... 195 Figure 4.5 Scope of aldehydes for the multicomponent hetero-Diels-Alder reactiona .............. 196 Figure 4.6 Synthesis of 4-biphenylpyridine derivatives from 4.1a ............................................ 198 Figure 4.7 Fluorescence spectra of 4-biphenylpyridine derivatives with methoxy-, cyano-, naphthyl, and cyclohexyl groups ................................................................................................ 201 Figure 4.8 Fluorescence spectra of 4-biphenyl pyridines with halogen and sulfonate groups .. 202 Figure 4.9 Fluorescence spectra of compound 4.15 under different excitation wavelengths .... 209 Figure 4.10 Schematic representation of ESIPT of 4.15 ............................................................ 210 xvii List of Schemes Scheme 1.1 Examples of synthetic approaches to pyridines (see text for references) ................... 9 Scheme 1.2 Examples of synthetic approaches to 1,2,3,6-tetrahydropyridines via reduction and cyclization (see text for references) .............................................................................................. 10 Scheme 1.3 Examples of synthetic approaches to 1,2,3,6-tetrahydropyridines via cycloaddition....................................................................................................................................................... 11 Scheme 1.4 Retrosynthetic analysis on pyridines and tetrahydropyridines ................................. 12 Scheme 1.5 Regioselectivity of Diels-Alder reactions of C-1- and C-2 substituted dienes ......... 15 Scheme 1.6 Stereoselectivity of a Diels-Alder reaction via secondary orbital interaction .......... 16 Scheme 1.7 Retrosynthesis of tetrahydropyridines in hetero-Diels-Alder reactions ................... 18 Scheme 1.8 Examples of inverse-electron-demand hetero-Diels-Alder reactions as approaches to pyridines ........................................................................................................................................ 19 Scheme 1.9 First report of the hetero-Diels-Alder reaction between dimethyl (E)-2-(phenylimino)succinate (1.23) and 1,3-butadienes by Alder. ....................................................... 20 Scheme 1.10 Early examples of hetero-Diels-Alder reactions of imines with 2,3-dimethylbuta-1,3-diene. ............................................................................................................................................. 21 Scheme 1.11 Mechanisms of the reactions between 1,3-butadiene and formaldimine under thermal, Lewis acid, and Bronsted acid activations. ................................................................................... 22 Scheme 1.12 Examples of hetero-Diels-Alder reactions of imines forming diastereomer mixtures....................................................................................................................................................... 24 Scheme 1.13 Reaction pathways towards the two regioisomers of the hetero-Diels-Alder reaction....................................................................................................................................................... 25 Scheme 1.14 A general pathway of the synthesis of enols from ketones ..................................... 27 xviii Scheme 1.15 Examples of synthetic approaches to alkyl enol ethers .......................................... 28 Scheme 1.16 Reactivities of enol ethers towards electrophiles .................................................... 29 Scheme 1.17 Two possible mechanisms of hydrolysis of alkyl enol ethers and silyl enol ethers........................................................................................................................................................ 29 Scheme 1.18 Examples of synthetic approaches to 2-alkoxy-1,3-butadienes .............................. 33 Scheme 1.19 2-Alkoxy-1,3-butadienes in hetero-Diels-Alder reactions ...................................... 34 Scheme 1.20 Early examples of preparations and reactions of 2-trimethylsiloxy-1,3-butadienes....................................................................................................................................................... 35 Scheme 1.21 First preparation and reaction of Danishefsky’s diene. .......................................... 36 Scheme 1.22 Examples of 2-trimethylsiloxy-1,3-butadiene in hetero-Diels-Alder reactions ...... 37 Scheme 1.23 Site-selectivity issue on derivatization of a substituted cyclohexanone ................. 38 Scheme 1.24 Examples of approaches to 2-sulfonyloxy-1,3-butadienes ..................................... 39 Scheme 1.25 Synthesis and intramolecular Diels-Alder reaction of 2-methanesulfonyloxy-1,3-butadiene ....................................................................................................................................... 40 Scheme 1.26 Synthesis of 2-phosphoryloxy-1,3-butadienes by Wiemer and Calogeropoulou ... 41 Scheme 1.27 Diels-Alder reactions of 2-phosphoryloxy-1,3-butadienes with other dienophiles 42 Scheme 1.28 Examples of reductions of enol phosphates ............................................................ 45 Scheme 1.29 Examples of transition metal catalyzed alkylations on enol phosphates ................ 46 Scheme 1.30 Examples of transition metal catalyzed cross-coupling reactions enol phosphates with aryl- or vinyl organometallic reagents .................................................................................. 47 Scheme 1.31 Examples of cross-coupling reactions on enol phosphates from simple ketones ... 48 Scheme 2.1 The proposed hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines ................................................................................................................... 51 xix Scheme 2.2 Synthesis of 2-diphenylphosphoryloxy-1,3-butadiene 2.1a ..................................... 52 Scheme 2.3 Synthesis of N-(p-toluenesulfonyl)benzaldimine (2.5a) ........................................... 55 Scheme 2.4 the thermal cycloaddition between 2.1a and 2.5a was not successful ...................... 56 Scheme 2.5 Lewis acid catalyzed hetero-Diels-Alder reaction between 2.1a and 2.5a to form the expected product ........................................................................................................................... 56 Scheme 2.6 Synthesis of enol phosphate 2.9 from N-Boc-4-piperidone (2.10) ........................... 59 Scheme 2.7 Synthesis of substituted enones using wittig reactions on aldehydes ....................... 68 Scheme 2.8 The hetero-Diels-Alder reaction of 4-isopropyl-2-diphenylphosphoryloxy-1,3-butadiene ....................................................................................................................................... 69 Scheme 2.9 The hetero-Diels-Alder reaction of 4-n-heptyl-2-diphenylphosphoryloxy-1,3-butadiene ....................................................................................................................................... 73 Scheme 2.10 Diastereoselective ratios of products 2.18a and 2.18b under different Lewis acids....................................................................................................................................................... 76 Scheme 2.11 Diastereoselectivity of a hetero-Diels-Alder reaction of 2-trimethylsiloxy-1,3-diene using different Lewis acids. .......................................................................................................... 78 Scheme 2.12 Manipulations of the hetero-Diels-Alder product 2.8a ........................................... 83 Scheme 2.13 Palladium-catalyzed reduction of hetero-Diels-Alder products. ............................ 84 Scheme 3.1 An example of the hetero-Diels-Alder reaction in Chapter 2 and the proposed multicomponent hetero-Diels-Alder reactions ............................................................................ 125 Scheme 3.2 Multicomponent hetero-Diels-Alder reactions to construct six-membered nitrogen heterocycles ................................................................................................................................. 126 Scheme 3.3 The multicomponent hetero-Diels-Alder reactions conducted at rt and 40 °C ...... 128 Scheme 3.4 Overall yields of 3.15a-c using the experimental techniques from chapter 2. ....... 134 xx Scheme 3.5 Synthesis and application of 2-(dimethoxymethyl)pyridine in hetero-Diels-Alder reaction ........................................................................................................................................ 136 Scheme 3.6 Synthesis of 2-diethylphosphoryloxy-1,3-butadiene .............................................. 142 Scheme 3.7 Multicomponent hetero-Diels-Alder reactions of diene 3.19 ................................. 143 Scheme 3.8 Comparing the reactivities of diene 2.1a and 3.19 in the multicomponent hetero-Diels-Alder reactions with Fmoc-NH2 ................................................................................................. 144 Scheme 3.9 Deprotection and alkylation of 3.18i. ..................................................................... 145 Scheme 4.1 The hetero-Diels-Alder reaction and cross-coupling reactions on enol phosphates presented in Chapter 2 and plausible mechanisms of N-tosyl deprotection ............................... 176 Scheme 4.2 The multicomponent Diels-Alder reaction and deprotection of the Fmoc group presented in Chapter 3 and a plausible mechanism of N-Fmoc deprotection ............................. 177 Scheme 4.3 Proposed synthesis of a substituted pyridine from the cycloaddition product 4.1a 178 Scheme 4.4 The Kumada cross-coupling reaction of 4.1a with phenylmagnesium bromidea ... 179 Scheme 4.5 Deprotection and oxidation of 4.2a to form 2,4-diphenylpyridine (4.3a)a ............. 180 Scheme 4.6 Catalyst screen for the Kumada coupling reaction with pentylmagnesium chloride..................................................................................................................................................... 185 Scheme 4.7 The Kumada coupling reaction on enol diethylphosphate with pentylmagnesium bromide ....................................................................................................................................... 186 Scheme 4.8 The construction of a 2,4,6-trisubstituted pyridine ................................................. 191 Scheme 4.9 Synthesis of 4-biphenyl-2-phenylpyridine 4.3h in the patent in 2008 ................... 193 Scheme 4.10 A plausible mechanism of the protodeboronation of a polyfluorophenylboronic acid..................................................................................................................................................... 194 Scheme 4.11 The hetero-Diels-Alder reaction of 4-(9H-carbazol-9-yl)benzaldehyde .............. 207 xxi Scheme 4.12 Cross-coupling reactions of 4.12g with carbazole ................................................ 208 Scheme 4.13 Nucleophilic aromatic substitution on 4.12c ........................................................ 208 Scheme 5.1 A summary of methods described in Chapter 2, 3, and 4 to construct non-aromatic or aromatic six-membered nitrogen heterocycles ........................................................................... 254 xxii List of Equations Equation 4.1 Calculating the relative quantum yields of compounds 4.12a-k in reference to 4.3h..................................................................................................................................................... 204 Equation 4.2 Calculating absorption factors from absorbance .................................................. 204 Equation 4.3 Calculating the quantum yield of 4.3h from the known quantum yield of a standard p-terphenyl .................................................................................................................................. 205 xxiii List of Abbreviation and Symbols d chemical shift F quantum yield l wavelength 2D 2 dimensional Å angstrom Ac acetyl API active pharmaceutical ingredient acac acetylacetonate aq aqueous Bn benzyl Boc tert-butoxycarbonyl bp boiling point br broad Bu butyl Bz benzoyl °C degrees Celsius calcd calculated Cbz carboxylbenzyl cm-1 wavenumber COSY correlation spectroscopy d doublet DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane dd doublet of doublets ddd doublet of doublets of doublets dddd doublet of doublets of doublets of doubles DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone DME 1,2-dimethoxyethane DMF N,N-dimethylformamide xxiv DMSO dimethylsulfoxide dppf 1,1′-bis(diphenylphosphino)ferrocene dr diastereomeric ratio dt doublet of triplets EDG electron-donating group ee enantiomeric excess equiv equivalent ESI electrospray ionization ESIPT excited-state intramolecular proton transfer Et ethyl EWG electron-withdrawing group FDA Food and Drug Administration Fmoc 9-fluorenylmethoxycarbonyl g gram(s) GC gas chromatography GSIPT ground-state intramolecular proton transfer h hour(s) HRMS high resolution mass spectroscopy HSQC heteronuclear single quantum coherence HOMO highest occupied molecular orbital Hz hertz i-Pr isopropyl IR infrared J coupling constant J joule(s) KHMDS potassium bis(trimethylsilyl)amide L liter(s) LDA lithium diisopropylamide LRMS low resolution mass spectroscopy LUMO lowest unoccupied molecular orbital xxv m milli; multiplet M molar; mega Me methyl min minute(s) µW microwave mol mole(s) mp melting point Ms methylsulfonyl m/z mass to charge ratio n nano NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY Nuclear Overhauser effect spectroscopy Ns 4-nitrophenylsulfonyl OLED organic light-emitting diodes PG protecting group Ph phenyl ppm parts per million q quartet rt room temperature s singlet SN2 bimolecular nucleophilic substitution SNAr nucleophilic aromatic substitution t triplet td triplet of doubles TEA triethylamine TMEDA N,N,N’,N’-tetramethylethylenediamine temp temperature Tf trifluoromethanesulfonyl THF tetrahydrofuran xxvi TLC thin layer chromatography TMB 1,3,5-trimethoxybenzene TMS trimethylsilyl TOF time-of-flight Ts para-toluenesulfonyl (not the element Tennessine) UBC University of British Columbia UV-vis ultraviolet-visible xxvii Acknowledgements First and foremost, I would like to thank my research supervisor Prof. Gregory Dake for his guidance, encouragement and support during my four-year PhD study. He did an amazing job to demonstrate the creativeness and precision of synthetic organic chemistry. In particular, I am thankful to his effort to improve my writing and logic in the preparation of this thesis. I would like to thank Prof. Jason Hein and Prof. Glenn Sammis to read my thesis. Their suggestions and edits were very much appreciated. Any errors that remain are my responsibilty. I would also like to thank all the current and past Dake group members: Ardalan Nabi, Chris Voth, Yiran Wei, Katerina Schwab and Melody Shen for their warm help and support for my study and life. My appreciation also gives to Sammis group members: Jiayi Mo, Wei Zhang, Cayo Lee, Trevor Bolduc, Brodie Thomson, Joey Lai and Willam Chappell who shared the PhD experience with me and often invitated me to their activities. I gained great support from Trevor Bolduc who wrote his thesis at the same with me. I also want to thank my friends from other groups: Zaile Zhuang from Tanner lab and Xianzhe Yin from Chen lab who joined with me to explore fantastic food and view in Vancouver, and Zhen Xu from MacLachlan lab for sharing his knowledge in fluorescent molecules. I would like to thank my parents, Moxiang He and Yan Xiao, for their endless love and support. There is no word that can express my gratitude to them. Last but not least, I would like to thank all the technicians of the NMR lab, Mass Spectrometry lab and Shared Instrucment Facility. I am grateful to the help from Maria Ezhova with 2-dimensional NMR experiments and Ben Herring with fluorescence spectroscopy experiments. xxviii A poem written by Xueqin Cao in his book “A Dream of The Red Mansions” Calligraphy, Qiuyu He, 2023 1 Chapter 1: Nitrogen Heterocycles, Hetero-Diels-Alder Reactions and Enol-based Functionality: Background 1.1 Synthetic organic chemistry Organic chemistry is a field of science focused on the study of the properties, reactivities and preparation of carbon-containing compounds.1 Like artists that use pens and pigments to paint pieces of fine art, synthetic organic chemists use flasks and reagents to build molecules with desired functionalities and appropriate stereochemical features. Every new discovery in organic chemistry embodies the beauty of science, including preciseness, creativeness, and usefulness. Organic chemists are intrigued by the ongoing exploration in organic chemistry that can induce great impact on not only the field itself but also other fields of science. Wide applications of organic chemistry are found in the pharmaceutical, agrochemical and material industries.2 Figure 1.1 Graphical representation of synthesis and methodology in organic chemistry Synthetic organic chemistry can be divided into two major fields: synthesis and methodology (Figure 1.1). Synthesis refers to the process of the multistep construction of a relatively complex molecule from structurally simpler commercially available starting materials.3 synthesismethodologynatural product Active Pharmaceutical Ingredientmaterial 2 Within academia, these complex molecules are usually natural products that have interesting bioactive properties. Alternatively, the target molecules in industry can be pharmaceutical ingredients (API) or light-luminating materials. A multistep synthesis involves the utilization of existing methods and requires the development of new protocols when confronted with challenging synthetic problems. This is where methodology makes its most impactful contributions. Methodology studies focus on the development of reaction methods that have improved efficiency when compared with existing transformations. Efficient reaction methods can be characterized using factors including a) improved atom economy4, b) lower energy consumption5, c) utilization of catalysis6, d) minimization of solvents,6 d) elimination of isolation/purification steps, e) high yields and selectivity7, and f) more widely applicable substrate scope.88 1.2 An outline of the background survey The central project presented in this thesis lies in the field of synthetic organic methodology. The project is composed of three components that are all related to the development of hetero-Diels-Alder reactions using storable dienes and imines or iminium species as an approach to functionalized six-membered nitrogen heterocycles. Figure 1.2 Graphical representation of the methods in this thesis A general scheme of the method presented in this thesis is shown in Figure 1.2. This chapter will survey background materials related to this project and discuss the significance of the thesis work, including: N N N N 3 a) a brief introduction to nitrogen heterocycles (Chapter 1.3). b) applications of six-membered nitrogen heterocycles in pharmaceuticals and fluorescent molecules to show the importance of the motifs (Chapter 1.4). c) previous synthetic approaches to two related six-membered nitrogen heterocyclic structures: 1,2,3,6-tetrahydropyridines and pyridines (Chapter 1.5). d) a background introduction to the Diels-Alder reaction (Chapter 1.6). The mechanistic aspects of Diels-Alder reactions are crucial to the analysis of cycloaddition products in this method. e) a background introduction to the hetero-Diels-Alder reaction (Chapter 1.7). Inverse-electron-demand hetero-Diels-Alder reactions are briefly touched because some methods are related to the construction of pyridines. Normal-electron-demand hetero-Diels-Alder reactions— particularly reactions of imines—will be discussed in detail. f) discussion of enol-based functionality (Chapter 1.8). Enol-based functional groups are incorporated in both the diene starting materials and cycloaddition products in the method presented in this thesis. A comparison of the synthesis and reactivities of some major types of enol-based functionalities will be provided. g) a summary of the synthetic goal of this thesis work (Chapter 1.9). 1.3 Nitrogen heterocycles: nomenclature Heterocycles are cyclic compounds that contain at least one atom on the main ring that is different from carbon, most prevalently oxygen, nitrogen, and sulfur in organic chemistry.9 Nitrogen heterocycles are heterocycles that contain at least one nitrogen atom on the ring. Nitrogen heterocycles can be classified by ring size, degree of unsaturation and aromaticity. Aromatic nitrogen heterocycles satisfy Huckel’s rule of being cyclic and planar with 4n+2 p electrons.10,11,12 4 Figure 1.3 Common nitrogen heterocycles Common nitrogen heterocycles are presented in Figure 1.3 including three-to-six-membered and fused nitrogen heterocycles. This thesis focuses on the study of methods to build six-membered nitrogen heterocycles. Piperidine (1.1) is the saturated six-membered nitrogen heterocycle with one nitrogen atom on the ring. Pyridine (1.2) is an aromatized ring structure. Adding hydrogens to a pyridine reduces the degree of unsaturation of the heterocycle. Adding two hydrogens forms a dihydropyridine (1.3) with two double bonds on the ring. Adding four hydrogens forms three regioisomers of tetrahydropyridines (1.4-1.6). The importance of six-membered nitrogen heterocycles can be reflected by their wide applications in industry and Saturated Unsaturated Three- to five and fused nitrogen heterocycles Six-membered nitrogen heterocycles HNaziridineNHazetidineHNpyrrolidineNazirineNHβ-lactamOHNpyrroleNHNimidazoleNNHNtriazoleindoleHNquinolineNcarbazoleHNN1-azetineHNpiperidine 1.1NHHNpiperazineHN1,2,3,6-tetrahydropyridine1.4HNdihydropyridine 1.3Npyridine 1.2NNpyrimidineNNpyrazineN NNtriazineHN1,2,3,4-tetrahydropyridine1.5N2,3,4,5-tetrahydropyridine1.6 5 witnessed by a great number of methods that have been established to build these structures in synthetic organic chemistry. 1.4 Importance of six-membered nitrogen heterocycles in industry 1.4.1 Applications of six-membered nitrogen heterocycles in pharmaceuticals Nitrogen heterocycles exist throughout Nature.13 The significant applications of these structures in bioactive molecules come from their impact on physicochemical properties including metabolic stability, permeability and specificity.14,15 Consequently, nitrogen heterocycles are incorporated in enormous amounts of pharmaceutical drugs.9,16 Vitaku and coworkers reported that 59% of the U.S. Food and Drug Administration (FDA) approved small molecule drugs before 2014 contained nitrogen heterocycles.17 Figure 1.4 Distribution of six-membered nitrogen heterocycles in FDA approved small molecule drugs before 2014 Among a total number of 640 nitrogen heterocycle-containing small molecule drugs before 2014, the most prevalent structure is piperidine (11%, Figure 1.4). Pyridine and piperazine account 72, 11%62, 10%59, 9%16, 2%10, 2%160, 25%261, 41%piperidinepyridinepiperazinepyrimidinedihydropyridineother six-membered 6 for the second- and third-most abundant structures. Two other common six-membered nitrogen heterocycles in small-molecule drugs are pyrimidine and dihydropyridine. A more recent report in 2022 found that the numbers of pyridine- and piperidine-containing small molecule drugs increased to 86 and 76, respectively, before January 2020.18 Some examples of piperidine- and pyridine-containing small-molecule drugs are presented in Figure 1.5. Figure 1.5 Examples of small-molecule drugs that contain piperidine and pyridine substructures. 1.4.2 Applications of six-membered nitrogen heterocycles in fluorescent materials Fluorescent molecules are compounds that excite upon absorbing electromagnetic radiation and relax via emitting photons.19 An energy gap between the singlet excited state (S1) and ground state (S0) that lies in the energy range of UV-visible light is the basic requirement for a molecule to be fluorescent. Normally, emission occurs at a longer wavelength than absorption NOHN NH2isoniazid (treating tuberculosis)NNONperampanel (anticonvulsant)NHNClO OHclonixin (anti-inflammatory)NOOHOFOH OHcerivastatin (lower cholesterol)Ncyproheptadine(antihistamine drug)NNOfentanyl(anesthesia)OO OHNFparoxetine (antidepression)NHNOropivacaine (anesthesia) 7 due to vibrational relaxation at the singlet excited state (S1), as explained by the Jablonski diagram (Figure 1.6).20 An excited molecule can also relax to the ground state via non-radiative relaxation without emitting photons. The ratio of number of photons emitted vs absorbed defined the efficiency of fluorescence that is referred as the quantum yield (F).21 Nitrogen heterocycles, especially aromatic structures like pyridines, are important fluorophores in fluorescent compounds. It was claimed in an article by Schramm and Weib that aromatic heterocyclic structures are suitable for creating fluorescent molecules in high efficiency due to their extended p-conjugation and molecular rigidity introduced by the participation of heteroatoms in conjugation.22 Figure 1.6 Simplified Jablonski diagram and examples of pyridine-containing fluorescent compounds Fluorescent molecules have practical applications in many fields. In material science, applications of fluorescent compounds in organic light-emitting diodes (OLEDs) have received considerable attention in recent years. OLEDs are becoming popularized as replacement of inorganic luminous materials.23 Small-molecule luminescent compounds are also widely utilized in bioanalytical applications.24 They can be used in bio-imaging for studies on cell activities and assist in diagnosis of diseases.25 Three examples of pyridine-containing fluorescent compounds are presented in Figure 1.6. (Z)-3-Methyl-2-phenyl-5-(pyridin-4-ylmethylene)-3,5-dihydro-4H-S001234S1absorption fluorescencenonradiative relaxation01234NNNOPhNNNOHBDI derivative 1.7 Py-BDI 1.8N N N OHPvP 1.9 8 imidazol-4-one (HBDI derivative, 1.7) and (Z)-4-(pyridin-4-ylmethylene)-1H-imidazo[1,2-a]pyridin-5(4H)-one (Py-BDI, 1.8) were reported by Ermakova and coworkers in 2018 and 2019. They were used for fluorescent labelling to visualize partial fractions of endoplasmic reticulum and mitochondria, respectively.26,27 2-(Pyridine-2-yl)vinyl pyridine (PvP, 1.9) was synthesized and characterized as a thermosensitive fluorescent compound by Witkowska and coworkers in 2019.28 This compound is useful as a removable fluorescent labelling of oligonucleotides. 1.5 Six-membered nitrogen heterocycles: synthesis In synthetic organic chemistry, a considerable number of methods have been established to build six-membered nitrogen heterocycles with different substitution patterns. As this field is very large, readers are directed to reviews for more comprehensive description of the topic.29,30,31,32 Some examples of important approaches to two six-membered nitrogen heterocycles: pyridines (1.2) and 1,2,3,6-tetrahydropyridines (1.4), are presented in Scheme 1.1-1.3. 9 Scheme 1.1 Examples of synthetic approaches to pyridines (see text for references) Condensation reactions between amines and carbonyl compounds form the basis of numerous synthetic approaches to pyridines (path a-g, Scheme 1.1).33,34,35,36,37,38,39 These reactions a) are relatively easy to execute, b) use readily available starting materials, and c) involve kinetically and thermodynamically feasible cyclization reactions that form six-membered rings and aromatic products.40 Other synthetic methods incorporate either FMO-controlled processes N R2R3R4R5R6[O]NH R1R2R3R4R5OEtO2C CO2EtONH3OHHMe OMeO O OCO2MePhPh CO2MeN2 N ONH4OAcRh2(OAc)4O R2EWGR5 NH2EtO OEtOEtMeH2NCO2EtH2NCO2EtOROOPhMeOPhMeNH4OAcNaOH, rtN NNN NClNH4OAca) LDAb)c) HCl, MeOHONC CNPhOPh NC CNOOHEt rtCp2ZrNBuEtTMSPh MeTMS BuEtCNCp2ZrEt2NiCl2(PPh3)2PhNPhOCH2OC6F5B n-BuHOOH NPhn-BuPhCu(OAc)2NNN NNNNNa)c)d)e)then 120 °Cf)b)g)h)i)j)k)100 °C95 °C80 °C110 °CNHOPhOPhHN85 °C60 °C45 °C50 °C40 —> 150 °C50 °C1.2 10 (e.g. cycloadditions, rearrangement, or cycloisomerizations) or transition metal catalysis/mediation or both are available to create pyridines that have different substitution patterns compared to those formed by condensation. Four such examples that form pyridines are presented (path h-k, Scheme 1.1).41,42,43,44 Scheme 1.2 Examples of synthetic approaches to 1,2,3,6-tetrahydropyridines via reduction and cyclization (see text for references) NHP OEtOOEtPh OHNHP OEtOOEtPhTfOH110 °CNNNPhOEtOH, 0 °C, 4 hNaBH4N-C6 cyclicationR3 = PhNOOPh C3-C4 cyclizationR6 =OONTsI PhC4-C5 cyclizationR3 = PhPhOHNHOEtON-C2 cyclicationR2 = Ph, R6 = MePdCl2(MeCN)2, 40 °CGrubbs-I, rtPdCl2(dppf), 110 °CPd(OAc)2, 60 °CC4-C5 cyclizationNTsIn-BuPhR3 = Ph, R5 = n-BuIb)c)d)e)f)HNPhONa)1.11, 86%1.10N R2R3R4R5R6R11.4 11 Scheme 1.3 Examples of synthetic approaches to 1,2,3,6-tetrahydropyridines via cycloaddition 1,2,3,6-Tetrahydropyridines can be constructed in transformations that involve zero-bond formation, one-bond formation, and two bond formation on the cyclic rings (Scheme 1.2-1.3). The redox relationship between pyridines and tetrahydropyridines obviously indicates that one structural class is available by oxidation or reduction of the other. As an example, sodium borohydride reduces the heterocyclic ring of a pyridinium ylide 1.10 to give 1,2,3,6-tetrahydropyridine 1.11 in 86% yield (Scheme 1.2a).45 The ease of these transformations will be dependent on substitution patterns, reagent strength and functional group compatibility as they might give mixtures of dihydropyridines, tetrahydropyridines and piperidines30,46,45,47 In contrast, cyclization of acyclic starting materials that have the double bond located at the desired position can be used to form 1,2,3,6-tetrahydropyridines selectively (Scheme 1.2b-f).48,49,50,51,52 Cycloaddition processes can be used to construct tetrahydropyridines in good regiocontrol when compared with the reduction methods, and in ease of execution from readily accessible starting materials when compared with the cyclization reactions. For example, a Rhodium catalyzed construction of a dihydropyridine from the cycloaddition between an vinylogous amide and an alkyne can be followed by a reduction by sodium cyanoborohydride to afford 1,2,3,6-tetrahydropyridine 1.12 in 79% yield and >95% dr (path a, Scheme 1.3).53 An example of a hetero-NBnMeMePhEtEtNBnEtMeMePhEt NaBH(OAc)3MeNPhBnEt EtMeRhLn(cat.)100 °CN PhPhBF3•OEt2CO2MeOBn-30 °C —> rtPhBnONMeO2CPha)b)Masanaw et al. 2015Corey et al. 19890 °C —> rt1.12, 79%, dr > 95%1.13, 95%, dr > 95% 12 Diels-Alder reaction to form 1,2,3,6-tetrahydropyridine 1.13 in 95% yield and >95% dr is presented (path b, Scheme 1.3).54 The goal of this research work is to design a method that can construct tetrahydropyridines or pyridines with substitution variability at every carbon position on the heterocyclic ring (Scheme 1.4). The hetero-Diels-Alder reaction has caught our attention because it is highly efficient in terms of atom economy, mild conditions, and control on regioselectivity and stereoselectivity. The tetrahydropyridine product from a hetero-Diels-Alder reaction can be readily oxidized to a pyridine motif. A detailed introduction on the Diels-Alder reaction and hetero-Diels-Alder reaction will be provided in the next two sections. Scheme 1.4 Retrosynthetic analysis on pyridines and tetrahydropyridines 1.6 Diels-Alder reaction: background A Diels-Alder reaction is a [4+2] cycloaddition process between a conjugated 1,3-butadiene with 4 p-electrons and a dienophile with 2 p-electrons.55 This reaction was discovered by Otto Diels and Kurt Alder in 1928.56 The Diels-Alder reaction is a highly efficient process because a) all atoms in starting materials are incorporated in the product,57 b) it is driven by the formation of 2 new s bonds,58 and c) it builds up to 4 stereocenters in the product.59 The high predictability and synthetic effectiveness of Diels-Alder reactions make them become significantly powerful transformations in synthesis.60 N R2R3R4R5R61.2N R2R3R4R5R6PG1.4[O]NR2R3R4R5R6PG[4+2] 13 Figure 1.7 Electronic states of p-electron systems of a 1,3-butadiene and an alkene The mechanism of the Diels-Alder reaction can be analyzed by evaluating the frontier MO’s in the process (Figure 1.7).61 The electronic orbitals of p electrons on the diene and dienophile interact in a suprafacial manner in a Diels-Alder reaction that occurs through a concerted pericyclic process via a single transition state.62,63,64 Synchronous transition states are generally expected for Diels-Alder processes between symmetrical dienes and dienophiles, whereas substitutions on either dienes or dienophiles could induce asynchronicity in transition states.65 Two possible interactions are thermally allowed according to orbital symmetry considerations.66 The highest occupied molecular orbital (HOMO) of the diene and the lowest unoccupied molecular orbital (LUMO) of the dienophile interact in a normal-electron-demand Diels-Alder reaction. In an inverse-electron-demand Diels-Alder reaction, the primary bonding occurs between the LUMO of the diene and the HOMO of the dienophile. HOMOLUMOHOMOLUMO 14 Figure 1.8 Substituent perturbation in normal-electron-demand and inverse-electron-demand Diels-Alder reactions The energy gap between the two interacting frontier orbitals controls the rate of the Diels-Alder process (Figure 1.8).67,68 Perturbation theory argues that an electron-donating substituent raises the energy of molecular orbitals of a p-electron system by induction or resonance effect, while an electron-withdrawing substituent lowers the energy of molecular orbitals.66 A diene with an electron-donating group and a dienophile with an electron-withdrawing group have a smaller HOMO-LUMO energy gap than a neutral diene and dienophile, thus react at a higher rate in a normal-electron-demand Diels-Alder reaction. In an inverse-electron-demand Diels-Alder reaction, the reaction is faster between a diene with an electron-withdrawing group and a dienophile with electron-donating group than those without substituents. Since the methods presented in this thesis belong to the normal-electron-demand Diels-Alder reactions, a more detailed mechanistic interpretation on the regio- and stereoselectivity of this type of reactions will be provided. HOMOLUMOHOMOLUMOHOMOLUMOHOMOLUMOEDG EWG EWG EDGnormal-electron-demand inverse-electron-demandHOMOLUMOHOMOLUMOneutral 15 Scheme 1.5 Regioselectivity of Diels-Alder reactions of C-1- and C-2 substituted dienes The regioselectivity of a Diels-Alder reaction is argued to arise from a frontier interaction between the orbitals that have the highest coefficient magnitudes in the diene and dienophile (Scheme 1.5).69 The coefficient magnitudes of orbitals in dienes and dienophiles are affected by substituents according to perturbation theory.70 For instance, the orbitals of a diene with an electron-donating group at C-1 position have larger coefficient magnitudes at C-2 and C-4 positions. An electron-withdrawing group of a dienophile increases the coefficient magnitude of the orbital at C-2 position. Bond connections only occur at terminal positions of the diene and dienophile. Thus, the frontier interaction between orbitals at C-4 position of the diene and C-2 position of the dienophile affords the major 1,2-disubstituted product (Scheme 1.5b). If the diene has an electron-donating group at C-2 position, the Diels-Alder reaction will afford the 1,4-product (Scheme 1.5b). Reactions between dienes with stronger electron-donating groups and dienophiles with stronger electron-withdrawing groups give larger ratios of the major and minor regioisomers of products.71,72 EDGEWG123 412EDG123 4EWG12= EWGEDG1,2-productmajorEDG1,3-productminorEWG123 412123 4EWG12=1,4-productmajor1,3-productminorEDGEDGEWGEDGEWGEDG EWGa)b) 16 Figure 1.9 Resonance structures of (E)-1-methoxybuta-1,3-diene and acrolein An analogous method to rationalize the regioselectivity of the normal-electron-demand Diels-Alder reaction is by identifying the most nucleophilic position in a diene and the most electrophilic position in a dienophile.72 For instance, The resonance structures of (E)-1-methoxybuta-1,3-diene (1.14) indicate that C-2 and C-4 are the most nucleophilic positions on the diene due to an electron-donating (resonance) effect of the methoxy group (Figure 1.9). Acrolein (1.15) is most electrophilic at C-2 position due to an electron-withdrawing (resonance) character of the carbonyl group. The major 1,2-disubstituted product is formed from the bond connection between C-4 position of methoxybuta-1,3-diene (1.14) and C-2 position of acrolein (1.15) that is the same as the prediction from perturbation theory. Scheme 1.6 Stereoselectivity of a Diels-Alder reaction via secondary orbital interaction OMe OMeOMeOMeδ+δ-δ+δ-123 4OHOHOH12δ-δ+1.141.15OMe1.14OMeCHOOH1.151,2 productmajorOMe OHOMeOsyn productmajorHHOMeCHO1.14 1.15 17 The stereoselectivity of a Diels-Alder reaction can sometimes be explained by secondary orbital interaction that favors an endo geometry within the transition state.73 The secondary orbital interaction involves the interaction between p orbitals that are not at the active centre of new bond formation.74 For instance, a Diels-Alder reaction between (E)-1-methoxybuta-1,3-diene (1.14) and acrolein (1.15) forms the syn product as the major diastereomer (Scheme 1.6). In the transition state, the aldehyde group lies under the plane of the diene due to a favorable secondary orbital interaction between p systems of the carbonyl group in acrolein and the diene. In modern theoretical chemistry, many arguments have been made on the existence of secondary orbital interaction.75 The stereoselectivity of Diels-Alder reactions was argued to arise from a combination of many factors including steric hindrance between substituents, solvents and catalysts that are utilized in the reactions.73,76,77 As a result, prediction of forming the major diastereomer from an endo transition state is not always reliable. 1.7 Hetero-Diels-Alder reaction: background A hetero-Diels-Alder reaction involves a diene or dienophile that contains a heteroatom.78 These variations have the same useful attributes as the carbon-based cycloaddition reactions. Unsurprisingly, the high predictability and ease of execution of hetero-Diels-Alder reactions make them considerably applied in protocols that construct non-aromatic and aromatic six-membered heterocycles.79,80 This thesis focuses on the hetero-Diels-Alder reaction involving nitrogen atom, which is also referred as an aza-Diels-Alder reaction.81 18 Scheme 1.7 Retrosynthesis of tetrahydropyridines in hetero-Diels-Alder reactions As mentioned in Chapter 1.5, an advantage of a cycloaddition process is the regiocontrol of the double bond in the construction of tetrahydropyridines compared to the reduction methods.79 Retrosynthesis of the three tetrahydropyridine isomers demonstrate the corresponding dienes and dienophiles in [4+2] cycloaddition reactions (Scheme 1.7). Both 2,3,4,5-tetrahydropyridines and 1,2,3,4-tetrahydropyridines are constructed from nitrogen-containing dienes and carbon-based dienophiles via inverse-electron-demand hetero-Diels-Alder reactions (Scheme 1.7a and b). The normal-electron-demand hetero-Diels-Alder reaction between a carbon-based diene and an imine affords 1,2,3,6-tetrahydropyridine, which is of interest in this thesis (Scheme 1.7c). 1.7.1 Inverse-electron-demand hetero-Diels-Alder reaction The inverse-electron-demand hetero-Diels-Alder reaction is a hetero-Diels-Alder reaction between an electron-deficient diene and an electron-rich dienophile.82 Synthetic approaches to six-membered heterocycles using inverse-electron-demand hetero-Diels-Alder reactions have attracted past and ongoing attention because they provide solutions to challenging bioactive compound synthesis.83 Since the products of these protocols are not all structurally related to this thesis, a few examples will be displayed and some references are provided.84,85,86,87 The NNHNHNNHHNa)b)c) 19 construction of pyridines via inverse-electron-demand hetero-Diels-Alder reactions will be introduced briefly. The first example was reported by Boger in 1982 and it was presented in path j in Scheme 1.2. Scheme 1.8 Examples of inverse-electron-demand hetero-Diels-Alder reactions as approaches to pyridines Inverse-electron-demand hetero-Diels-Alder reactions are incorporated as important steps for the construction of substituted pyridines in the synthesis of bioactive molecules. Two examples are presented in Scheme 1.8. In 1984, Boger and coworkers reported a total synthesis of Lavindamycin that incorporated a step of a cycloaddition-retro-cycloaddiiton between triethyl 1,2,4-triazine-3,5,6-tricarboxylate (1.16) and an enamine 1.17 to form a tetrasubstituted pyridine 1.18 in 50% yield (Scheme 1.7a).88 In 2005, Schnermann and Boger reported an approach to a functionalized pyridine via the inverse-electron-demand hetero-Diels-Alder reaction of 1-aza-1,3-butadiene (Scheme 1.7b).89 The cycloaddition between ethyl (Z)-3-methyl-2-((phenylsulfonyl)imino)but-3-enoate (1.19) and 1,1,2,2-tetramethoxyethene (1.20) formed a NSO2PhEtO2CMeMeO OMeOMeMeO50 °C, 18 htoluene NEtO2CMeOMeOMeOMeOMeSO2PhBF3•OEt2 NEtO2CMe OMeOMe1.19 1.20 1.21, 62% 1.22, 88%b)NN NCO2EtCO2EtMeN 25 °CNMeCO2Et1.16 1.17 1.18, 50%CO2EtBrEtO2CEtO2CBrCHCl3a)Boger et al. 1984Schnermann et al. 2005 20 1,2,3,4-tetrahydropyridine 1.21 in 62% yield. A Lewis acid promoted elimination of 1.21 afforded a tetrasubstituted pyridine 1.22 in 88% yield. 1.7.2 Normal-electron-demand hetero-Diels-Alder reaction The normal-electron-demand hetero-Diels-Alder reaction is a hetero-Diels-Alder reaction between an electron-rich diene and an electron-deficient dienophile. Many protocols have been established using heteroatom-containing dienophiles including carbonyls, imines, nitriles, thiocarbonyls.78,81,90,91,92 This section will focus on the application of imines in hetero-Diels-Alder reactions as an approach to six-membered nitrogen heterocycles. Scheme 1.9 First report of the hetero-Diels-Alder reaction between dimethyl (E)-2-(phenylimino)succinate (1.23) and 1,3-butadienes by Alder. The history of using an imine as the dienophile in hetero-Diels-Alder reactions went back to 1943. It was discovered by Alder in an unexpected formation of tetrahydropyridine from an amino diester (Scheme 1.9).93 He was intent on investigating the reactivity of dimethyl 2-(phenylamino)fumarate (1.24) in Diels-Alder reactions with carbon-based 1,3-butadienes, but the desired carbocycloaddition products were not observed. Instead, tetrahydropyridines (1.25) were obtained from cycloaddition reactions between 1,3-butadienes and the imine tautomer of 1.24. NHPhMeO2CCO2MeNPhMeO2CCO2MeR NPhCO2MeCO2MeR1.24 1.25Alder et al. 19431.23 21 Scheme 1.10 Early examples of hetero-Diels-Alder reactions of imines with 2,3-dimethylbuta-1,3-diene. There was no other report on this type of hetero-Diels-Alder reaction after its discovery by Alder in 1940s until twenty years later when Merten and coworkers described a cycloaddition reaction between 1,3-butadiene and an iminium species (Scheme 1.10a).94 Under the promotion of a Lewis acid BF3•OEt2, elimination of a carbamate group in diethyl (phenylmethylene)dicarbamate (1.26) generated a N-acyl iminium species 1.27 in situ. The iminium species underwent a cycloaddition reaction with 2,3-dimethyl-1,3-butadiene (1.28) to form the 1,2,3,6-tetrahdyropyridine product 1.29 in 65% yield. Another method was reported in 1960s by Kresze and coworkers that used pre-constructed N-sulfonyl imines in hetero-Diels-Alder reactions.95 The reactions between 2,3-dimethyl-1,3-butadiene (1.28) and two derivatives of N-sulfonyl imines (1.30) were conducted at 80 °C to afford the tetrahydropyridine products 1.31a and 1.31b in 94% and 96% yield, respectively (Scheme 1.10b). In 1985, Larsen and coworkers reported the first example of the hetero-Diels-Alder reaction between 2,3-dimethyl-1,3-butadiene (1.28) and a N-NTsCR380 °CC6H6NCR3Ts1.28 1.30, R = Cl, F 1.31a: R = Cl, 94%1.31b: R = F,. 96%b)PhNHCO2EtNHCO2EtBF3•OEt2 N CO2EtPhNPhCO2Eta)1.26 1.27 1.28 Kresze et al. 1964Merten et al. 1962F3B1.29, 65%HCHOBnNH2•HClH2O, 35 °C, 48 hN Bn1.28c)Larsen et al. 19851.32, 64% 22 alkyl imine under aqueous acidic condition (Scheme 1.10c).96 The iminium species was formed in situ from formaldehyde and benzyl amine hydrochloride. The cycloaddition reaction of the iminium species with 2,3-dimethyl-1,3-butadiene (1.28) in water formed the product 1.32 in 64% yield. Scheme 1.11 Mechanisms of the reactions between 1,3-butadiene and formaldimine under thermal, Lewis acid, and Bronsted acid activations. In the three examples presented in Scheme 1.10, the hetero-Diels-Alder reactions of imines were promoted under Lewis acid activation, thermal activation, and Bronsted acid activation, respectively. Studies on the mechanistic pathways of hetero-Diels-Alder reactions of imines under these three conditions were performed using theoretical calculations in 1990s (Scheme 1.11). In 1992, MaCarrick and coworkers reported calculations on the transition state of a hetero-Diels-Alder reaction between 1,3-butadiene (1.33) and methanimine (formaldimine, 1.34) under thermal condition where a concerted nonsynchronous mechanism was presumed (Scheme 1.11a).97 The NH1.33 1.34NHNH a)1.33 1.34NHN HNH b)1.33 1.34NHL.A.NHHHANHHc)BH3H3B6543N H2NH6543 2NH6543 2 23 activation energy of the transition state with an exo geometry of the lone pair on nitrogen is lower than that with an endo geometry by 5.3 kcal/mol. The bond established between N-C6 (1.93 Å) is shorter than C2-C3 by 0.435 Å in the exo transition state. In 1993, MaCarrick and coworkers also reported calculations on the transition state of the reaction between 1,3-butadiene (1.33) and methanimine (formaldimine, 1.34) under the promotion of BH3 (Scheme 1.11b).98 The energy of the transition state was decreased by 2.5 kcal/mol compared to the reaction without a Lewis acid. A shorter bond connection is established between C2-C3 in the transition state. The reaction favors an exo position of BH3 by 3.8 kcal/mol. When the hetero-Diels-Alder reaction was conducted in the presence of a Bronsted acid, whether the iminium salt react with a diene in a concerted or stepwise mechanism still remained controversial.99,100,101 An example of calculations on the pathway of the reaction between 1,3-butadiene (1.33) and protonated formaldimine was reported by Mayr in 2000.102 The calculations found that C2-C3 and N-C6 in the transition state had a bond length of 1.919 Å and 3.058 Å, respectively. The long bond length of N-C6 supported the formation of an allyl cation intermediate. 24 Scheme 1.12 Examples of hetero-Diels-Alder reactions of imines forming diastereomer mixtures Although the theoretical calculations found a general preference of the transition state with an exo geometry of the lone pair or Lewis acid by 4 – 5 kcal/mol, experimental results on the hetero-Diels-Alder reactions of imines only gave moderate ratios of diastereomeric mixtures (Scheme 1.12). In Scheme 1.12a and b, hetero-Diels-Alder reactions of two iminium species (1.35 and 1.36) with cyclohexadiene (1.37) under the promotion of BF3•OEt2 afforded exo products (1.38a and 1.39a) as the major diastereomers.103,104 The diastereomeric ratios of products 1.38 and 1.39 were reported to be 70:30 and 1.5:1, respectively. The Bronsted acid catalyzed hetero-Diels-Alder reactions of imines 1.40 with cyclopentadiene (1.41) were reported by Grieco and coworkers in 1986 (Scheme 1.12c).105 The diastereoselectivity of this hetero-Diels-Alder reaction was altered by the substituent on the nitrogen atom of imines. When an unprotected imine was reacted with cyclopentadiene, the endo product (1.42b) was formed as the major diastereomer in a EtO2CNHCO2EtNHCO2EtBF3•OEt2 N CO2EtEtO2Cb)1.36 1.37NCO2EtHCO2Et NCO2EtHCO2EtBF3•OEt2 NF3Ba)1.35 1.37 1.38a (exo) 1.38b (endo) 73%, dr = 1.5 : 1NEtHTs NEtHTsOHTs N S OMgSO4F3BTsNPhOR HClH2O, rtR = H: 1.42a (exo) 1.42b (endo)89%, dr = 1 : 2R = Bn: 1.43a (exo) 1.43b (endo)88%, dr = 3 : 2NHR NHRPhOPhO1.40, R = H, Bn 1.41c)1.39a (exo) 1.39b (endo) dr = 70 : 30Sisko et al. 1989Krow et al. 1985Grieco et al. 1986 25 diastereomeric ratio of 1:2. In contrast, the reaction of a N-benzyl imine afforded the exo product 1.43a as the major diastereomer (dr = 1:2). The ambiguity in stereoselectivity when N- or C-substituted imines are applied in hetero-Diels-Alder reactions is argued to arise from several aspects.106 Under thermal condition, the prediction of the lone pair occupying the exo position might not be followed due to the existence of substituents on the nitrogen and carbon atom.107 The secondary orbital interaction between substituents and the p system of the diene as well as a combination of steric effect, solvent effect and electrostatic forces affect the stereoselectivity of the hetero-Diels-Alder reaction.108 Introduction of a Lewis acid also complicates the prediction on stereoselectivity of the reaction. The Lewis acid can compete with the substituents for the endo- or exo position in the transition. Another factor that leads to ambiguity of stereoselectivity is the facile isomerization of imines in hetero-Diels-Alder reactions. It cannot be assured whether the imine reacts in an E- or Z geometry in the hetero-Diels-Alder reaction.109 Some hetero-Diels-Alder reactions of imines do not proceed through concerted mechanisms. The endo- and exo orientations are no longer meaningful in stepwise mechanisms through acyclic intermediates.110,111 Therefore, identification of the relative configuration of a hetero-Diels-Alder product typically requires spectral analysis. Scheme 1.13 Reaction pathways towards the two regioisomers of the hetero-Diels-Alder reaction δ+δ-432 1Nδ-δ+R1R2EDGδ+δ-432 1Nδ-δ+R1R2EDGNEDG R2R1NEDG R1R2NEDG R2R1a)b) 26 When an imine is treated with an unsymmetrical diene, regioselectivity of the hetero-Diels-Alder reaction is another factor that requires analysis.93 Scheme 1.13 presents the two theoretical pathways of the hetero-Diels-Alder reaction between an imine and 2-substituted 1,3-butadiene.112 The transition state in Scheme 1.13a has a lower energy because the nitrogen atom is capable of stabilizing a partial negative charge.72 Thus, the regioisomer that is formed from the bond connection between C-1 on the diene and the carbon of the imine is typically the more favorable product. Incorporation of a Lewis acid can effectively improve the regioselectivity of a hetero-Diels-Alder reaction by further stabilization of the negative charge on nitrogen.60 A special case is when R2 on the imine is a very electron-withdrawing substituent that can stabilize a negative charge on the carbon where the second regioisomer can be formed as the major product (Scheme 1.13b).106 The substituents on dienes can also induce significant effect on hetero-Diels-Alder reactions with imines.60 Generally, a strong electron-donating group on the diene can effectively increase the rate of the hetero-Diels-Alder reaction and unambiguously dictate regioselectivity of the product according to perturbation theory.70 Many interesting dienes activated by electron-donating groups were developed, of which enol-based dienes were shown to be particularly effective for cycloaddition processes.71 An introduction to enol-based functionality, especially its application in hetero-Diels-Alder reactions will be presented in the next section. 1.8 Enol-based functional groups: preparation and reactivities Enols are the typically less stable tautomers of the carbonyl functional groups.113 Common enol derivatives where the oxygens are connected to carbon-based groups, phosphorus-based groups, silicon-based groups, and sulfur-based groups are presented in Figure 1.10.114 27 Figure 1.10 Common enol-based functional groups Scheme 1.14 A general pathway of the synthesis of enols from ketones An enol derivative is synthesized by treating an enolate with an electrophile that preferentially reacts at the oxygen atom (Scheme 1.14).115 Enol derivatives like silyl enol ethers, enol sulfonates and enol phosphates are typically synthesized using this method. Selection of the base is subjected to the desired regioselectivity of the enolate formation from an unsymmetrical ketone.116,117 Strong and bulky bases like lithium diisopropylamide (LDA) and lithium bis(trimethylsilyl)amide (LiHMDS) are effective for kinetic enolate formation, while weak bases like alkoxides and amines are suitable for thermodynamic enolates. R1OR2R2enol triflateSF3CO OR1OR2R2enol mesylateSMeO OR1OR2R2enol tosylateSO OR1OMeR2R2methyl enol etherR1OR2R2enol acetateOR1OR2R2enol carbamateONR1OR2R2enol phosphatePOROROR1OR2R2enol phosphinatePORRR1OR2R2silyl enol etherSiRRRO a) base b) R Cl OROOR = Si, S(VI), P(V) 28 Scheme 1.15 Examples of synthetic approaches to alkyl enol ethers Alkyl enol ethers are not synthesized by alkylation of enolates because alkyl electrophiles can potentially react at both of the oxygen and carbon positions.118,119 Many other methods have been established for the synthesis of alkyl enol ethers and some examples are presented in Scheme 1.15.113 In 1982, Miller and coworkers reported an approach to methyl enol ethers via elimination of TMSI promoted ketals (1.44, Scheme 1.15a).120 When an unsymmetrical ketal starting material 1.45 was applied to the method, two regioisomers of the products 1.46 were formed in a ratio of 67:33. Another method was reported by Charbonnier and coworkers using methyl 2-cyclohexylacetate (1.47) to form an alkoxy enol phosphate 1.48. A reduction of 1.48 formed a methyl enol ether 1.49 in 50% yield and 10:1 Z/E selectivity (Scheme 1.15b).121 A recent protocol to synthesize an alkyl enol ether in excellent E/Z selectivity (94:6) was reported by Veenboer and coworkers in 2015 using an Au-catalyzed hydroalkoxylation on an alkyne (Scheme 1.15c).122 MeOOa) LDA, -78 °Cb) ClPO(OEt)2MeOO HPOEtO OEtPd(PPh3)4Al(Et)3MeOHPh MeMeO OMe TMSIPh MeMeO OMeTMS IHMDSPhOMePh Ph [Au(NHC)(CH3CN)][BF4]OPhPhH1.49, 52%, E/Z = 10:181%a)b)c)1.47 1.48, 94%86%, E/Z = 94:6NHC = N-heterocyclic carbeneMiller et al. 1982Charbonnier et al. 1987 Veenboer et al. 2015rt, 20 hMeO OMe TMSIHMDSOMe OMe1.45 1.46, 67:33rt, 15 hrt, 30 minPhOH80 °C, 2 h Ph1.44 29 Scheme 1.16 Reactivities of enol ethers towards electrophiles Analogous to enamines, enol derivatives can react as nucleophiles where the alkenes are activated by the electron-donating effect of oxygen atoms (Scheme 1.16).123 Removal of the alkyl or silyl groups generates carbonyls with substituents at the a position. Thus, enol derivatives are often used as the reactive equivalents of ketones or aldehydes.113 The first step of forming the oxonium intermediate is the rate-determining step.124 The oxonium intermediate can be destabilized by an electron-withdrawing R group like sulfonate or phosphate group. Thus, enol phosphates and enol sulfonates would be expected to be less reactive when reacting with electrophiles.125 Scheme 1.17 Two possible mechanisms of hydrolysis of alkyl enol ethers and silyl enol ethers. Enol derivatives are also prone to hydrolysis in acidic aqueous conditions.126 Two mechanistic paths for the acid-catalyzed hydrolysis of enol ethers are reasonable (Scheme 1.17). OR E+ OEOROREER = alkyl, silylOR O RH3OH2ORO OH2 P.T. O OHHR OHH2OOb)a)OR O RH3OOH2OR OH2HO RH3OR O R1.501.50R = SiMe3R = SiMe3, CH3 1.51 30 Water attacks the carbonyl carbon of the oxonium intermediate 1.50 to form a protonated hemiacetal 1.51 that decomposes as expected to ketone (path a, Scheme 1.17). Alternatively, a direct attack of water on the trimethylsilyl group of the intermediate 1.50 forms ketone and an ether byproduct (path b, Scheme 1.17). Table 1.1 Hydrolysis of silyl enol ether (1.52) at neutral and acidic conditions entry condition temp (°C) time % of 1.53 1 methanol 25 24 h 95% 2 methanol/HOAc 25 2 h 95% 3 KF•2H2O 25 5 h 95% The stability of silyl enol ethers in different media was evaluated by Jung and McCombs in 1976 (Table 1.1).127 In a neutral condition, the silyl enol ether was hydrolyzed by 95% after 24 h at rt (Entry 1). Adding acetic acid in hydrolysis of the silyl enol ether shortened the time to 2 h (Entry 2). A fluoride source KF accelerated the rate of hydrolysis where the fluoride presumably attacked silicon and formed a stable Si-F bond (540 kJ/mol). This paper did not report a comparison experiment on hydrolysis of a silyl enol ether and an alkyl enol ether. They referred to a literature report in which an ethyl enol ether derivative was hydrolyzed at a harsher condition of concentrated hydrochloric acid for 24 h.128 Jung and McCombs proposed that hydrolysis of alkyl enol ethers generally proceeded through the mechanistic path b in Scheme 1.17. In contrast, silyl enol ethers could be hydrolyzed in both pathways, thus made them more prone to hydrolysis than alkyl enol ethers. Me3SiOCO2MeCO2MeconditionOCO2MeCO2Me1.52 1.53 31 Table 1.2 Hydrolysis of four examples of silyl enol ethers 1.54 at acidic conditions entry compound R condition temp (°C) time % of 1.55 1 1.54a R = Me A 25 6 h 100% 2 B 25 15 min 100% 3 1.54b R = t-butyl A 25 6 h 0% 4 B 25 15 min 80% 5 B 25 1 h 100% 6 1.54c R = t-butyloxy A 25 6 h 0% 7 B 25 15 min 70% 8 B 25 1 h 90% 9 B 25 2 h 100% 10 1.54d R = 2,4,6-tri-t-butylphenyl A 25 6 h 0% 11 B 25 12 min 10% 12 B 25 1 h 70% 13 B 25 2 h 100% Another literature report by Fataftah and coworkers in 2015 focused on comparing the rates of hydrolysis of different silyl enol ethers in acidic conditions (Table 1.2).129 Trimethylsilyl enol ether (1.54a) is most easily hydrolyzed among the four compounds as six hours in aqueous acetic acid (HOAc/THF/H2O, 1:10:1) or 15 minutes in aqueous hydrochloric acid (THF/1 M HCl, 20:1) were sufficient for complete hydrolysis of 1.54a (entry 1 and 2). As expected, an increase in steric bulk of the R group significantly decreased the rate of hydrolysis. For compound 1.54d where R = 2,4,6-tri-t-butylphenyl, only 10% was hydrolyzed after 12 min in aqueous acetic acid, and complete hydrolysis occurred after 2 h in aqueous hydrochloric acid (entry 11 and 13). An increase Ocondition A: HOAc/THF/H2O: 1:10:1condition B: THF/1 M HCl: 20:1O1.54 1.55SiR 32 in steric bulk of the R group also increased the difficulty of its preparation. The authors found general stability of these structures in basic conditions. All four compounds (1.54a-d) were degraded by less than 5% after 1 h in THF/1 M NaOH, 20:1. Enol-based functionalities have been used in many protocols within organic synthesis. Two of them that are of interest in this thesis are cycloaddition and cross-coupling reactions. Enol-based dienophiles are electron-rich and react in inverse-electron-demand hetero-Diels-Alder reactions (Scheme 1.8b). Enol-based dienes can be used in normal-electron-demand hetero-Diels-Alder reactions. In transition metal catalyzed cross-coupling reactions, enol-based functionality can react as the electrophilic partner and be coupled with organometallic reagents. 1.8.1 Enol-based dienes Enol-based dienes refer to 1,3-butadienes that have oxy substituents at any carbon positions. Some examples of enol-based dienes including alkoxy-1,3-butadienes, phosphoryloxy-1,3-butadienes, siloxy-1,3-butadienes, and sulfonyloxy-1,3-butadienes are displayed in Figure 1.11. Enol-based dienes have advantages of enhanced reactivity and improved regiocontrol in Diels-Alder and hetero-Diels-Alder reactions.70,71,130 Figure 1.11 Examples of enol-based dienes MeO2-methoxy-1,3-butadieneO2-trimethylsiloxy-1,3-butadieneSiO2-diphenylphosphoryloxy-1,3-butadienePPhOOOPhO2-trifluoromethanesulfonyloxy-1,3-butadieneSF3CO OO1-methoxy-1-trimethylsiloxy-1,3-butadiene(Danishefsky’ diene)SiOMeO2-diethylphosphoryloxy-1,3-butadienePEtOOOEt 33 Scheme 1.18 Examples of synthetic approaches to 2-alkoxy-1,3-butadienes Alkoxy-1,3-butadienes are one of the earliest enol-based dienes applied in Diels-Alder reactions.131 The traditional approach to 2-methoxy-1,3-butadiene was established using elimination of 1,3,3-trimethoxybutane (1.56, Scheme 1.18a).132 A reaction mixture of methyl vinyl ketone (1.57) and methyl orthoformate was stirred for at rt for 12 days to give 78% of 1,3,3-trimethoxybutane (1.56) that underwent elimination to form 2-methoxy-1,3-butadiene (1.58) in 45% yield. The product 1.58 was purified by distillation at 150 °C, washed carefully with water several times, and stored over 4 Å molecular sieves. Twenty years later, some more practical methods were developed under transition metal catalyzed conditions. In 1989, Andersson and coworkers reported a protocol of using Pd-catalyzed cross-coupling reactions between cyclohex-1-en-1-yl trifluoromethanesulfonate (1.59) and alkyl enol ethers (1.60) to form 2-alkoxy-1,3-butadienes (1.61, Scheme 1.18b).133 The authors reported that trace amounts of ketones were detected in GC-MS from hydrolysis of 2-alkoxy-1,3-butadienes in the reaction processes. Prolonged reaction time and higher temperature promoted decomposition of the products. In 1995, Petasis reported a protocol of methylenations on esters and amides using a dimethyl titanocene O CH(OMe)3methanolMeO OMeOMep-TsOH 1.56, 78%KHSO4150 °COMe1.58, 45%1.57a)OTfORR = Et, n-BuPd(OAc)2NEt3DMSO, 60 °C, 3 hRO1.59 1.61, R = n-Bu, 87% R = Et, 82%MeOOPhTiMeMeTHF, 65 °C MeO Ph1.62 1.63, 67%b)c)rt, 12 daysDolby et al. 1969Andersson et al. 1989Petasis et al. 19951.60 34 reagent (Scheme 1.18c).134 The methylenation on methyl cinnamate (1.62) formed 4-phenyl-2-methoxy-1,3-butadiene (1.63) in 67% yield. Scheme 1.19 2-Alkoxy-1,3-butadienes in hetero-Diels-Alder reactions Although many examples of 2-alkoxy-1,3-butadienes in Diels-Alder reactions with carbon-based dienophiles can be found in literature, their applications in hetero-Diels-Alder reactions are not as well established.131 Three examples of 2-alkoxy-1,3-butadienes in hetero-Diels-Alder reactions, including two examples with imine dienophiles and one example with a nitroso dienophile, are presented in Scheme 1.19. In 1972, Rijsenbrij and coworkers reported a cycloaddition reaction between 2-methoxy-1,3-butadiene (1.58) and (E)-4-methyl-N-(2,2,2-trichloroethylidene)benzenesulfonamide (1.30) to form a tetrahydropyridine product 1.64 (Scheme 1.19a).135 However, no details on reaction conditions or isolated yield were provided. A similar reaction using a more functionalized 2-methoxy-1,3-butadiene derivative (1.65) in the hetero-MeONTsCCl3NMeO CCl3TsRijsenbrij et al. 1972MeONTsCCl3NMeO CCl3TsMeO MeO80%, dr = 1:1Loven et al. 1975C6H6rt, 23 hMeONOMeOTaylor et al. 1984NOCO2Me CO2MeCHCl30 °C —> rt1 h1.58 1.30 1.64a)b)1.65 1.301.58 1.66 1.67, 76%c)15% HClrt, 48 h NOOCO2Me84%NO CCl3TsMeOHBr/HOAc/CHCl3rta) H2/Ptb) EtOH, NEt3NEtO CHCl2TsEtO 35 Diels-Alder reaction was reported by Loven and coworkers in 1975 (Scheme 1.19b).136 A reaction between 2-methoxy-1,3-butadiene (1.58) and methyl 4-nitrosobenzoate (1.66) to form a substituted oxazine (1.67) was established by Taylor and coworkers in 1984 (Scheme 1.19c).137 In all three methods, the methyl enol ether products were hydrolyzed in acidic conditions to ketones for further manipulations because the subsequent reactions were not successful in the presence of the methyl enol ether functionality. Scheme 1.20 Early examples of preparations and reactions of 2-trimethylsiloxy-1,3-butadienes Preparations of siloxy-1,3-butadienes are more straightforward than alkoxy-1,3-butadienes because silicon electrophiles preferentially react with the oxygen atom of an enolate intermediate.138 First synthesis of 2-trimethylsiloxy-1,3-butadiene was reported by Girard and coworkers in 1974 (Scheme 1.20a).139 Methyl vinyl ketone (1.57) was treated with triethylamine and trimethylsilyl chloride in DMF to afford 2-trimethylsiloxy-1,3-butadiene (1.68) in 50% yield. When 1-penten-3-one (1.69) was applied to the reaction, the product 1-methyl-2-trimethylsiloxy-1,3-butadiene (1.70) was formed in an 83:17 ratio of the Z and E isomers. 2-Siloxy-1,3-butadienes were synthesized for applications of cyclopropanation reactions in these examples. The first use of 2-trimethylsiloxy-1,3-butadiene (1.68) in a Diels-Alder reaction was performed by Jung and ONEt3TMSClDMF TMSO1.57 1.68, 50%a)OLDATMSClTHF TMSOMeO2CCO2Metolueneheat, 18 h TMSOCO2MeCO2Me1.57 1.68, 60% 1.71 1.52, 71%b)Girard et al. 1974Jung et al. 1976ONEt3TMSClDMF TMSO1.69 1.70, 65%, Z/E: 83:17 36 McCombs in 1976 (Scheme 1.19b).127 2-Trimethylsiloxy-1,3-butadiene (1.68) was obtained in a higher yield (60%) by treating methyl vinyl ketone (1.57) with lithium diisopropylamide (LDA) and trimethylsilyl chloride in THF. 2-Trimethylsiloxy-1,3-butadiene (1.68) successfully reacted with dimethyl fumarate (1.71) at enhanced temperature (not specified in the report) to afford the Diels-Alder product 1.52 in 71% yield. As presented in Table 1.1, the silyl enol ether functionality in Diels-Alder product 1.52 was hydrolyzed to ketone by 95% after the compound was stirred in methanol 24 h at rt. Scheme 1.21 First preparation and reaction of Danishefsky’s diene. At the same time period, another highly reactive siloxy-1,3-butadiene was developed by Danishefsky and coworkers (Scheme 1.21).140 (E)-1-Methoxy-3-trimethylsiloxy-1,3-butadiene (1.72), named as Danishefsky’s diene, was synthesized from (E)-4-methoxybutene-2-one (1.73) with triethylamine-zinc chloride and trimethylsilyl chloride and purified by distillation. A Diels-Alder reaction between 1.72 and 2-methylcyclohexanone (1.74) was conducted at 195 °C for 50 h. The reaction mixture was then treated with dilute HCl at rt to form the hydrolyzed cycloaddition product 1.75 in 53% yield. ONEt3, ZnCl2TMSOxylene1.73 1.72, 68% 1.74 1.75, 53%OMe OMeTMSClDanishefsky et al. 1974O195 °C, 50 hOOMea)b) 4:1 THF/0.005 N HClrt, 1 h 37 Scheme 1.22 Examples of 2-trimethylsiloxy-1,3-butadiene in hetero-Diels-Alder reactions Siloxy-1,3-butadienes has been widely applied in hetero-Diels-Alder reactions as approaches to six-membered nitrogen heterocycles (Scheme 1.22).141,142,143,144 The dienes are typically not bench-stable. They were prepared and used directly in cycloaddition reactions.138 The silyl enol ether functional groups in cycloaddition products were readily hydrolyzed to ketones in post-reaction work up processes. N TsMeO2CNCO2MeTsTMSOOa) C6H6, rt, 3 hb) 0.005 M HCl/THFrt, 1 h57%ONTMSOa) TfOH, BF3•OEt2rt, 30 minb) methanol, 1 h ONO91%Ryan et al. 1987Holmes et al. 1985N NHPivTMSOPhCH2Cl2, reflux, 24 hNMeSiO PhClPhMe N NHPivO Ph78%, 87% eeTambar et al. 2010NXTMSOa) Yb(OTf)3 toluene, rt, 1 hb) 1 N HCl, rt, 30 minNXOX = H: 75% = O: 72%Brambilla et al. 2021a)b)c)d)X = H, O 38 Scheme 1.23 Site-selectivity issue on derivatization of a substituted cyclohexanone Conversion of the cycloaddition product featuring a ketone functional group to a substituted alkene would be an obstacle because of a site-selectivity issue, as shown in an example in Scheme 1.23.127 When the author applied the enol silyl ether (1.52) after careful work up of the cycloaddition process into a bromination reaction, only one regioisomer of the product was formed (Scheme 1.23a). However, when the hydrolyzed cyclohexanone (1.53) was applied to the same reaction conditions, two inseparable regioisomers of the products were obtained (Scheme 1.23b). It was envisioned that an enol functionality that persists in a cycloaddition product can be used directly in further manipulations and solve the obstacle of site-selectivity issue of derivatizing a cyclohexanone. Enol triflate and enol phosphate are two functional groups that could be useful in the transformations to substituted alkenes through transition metal catalyzed cross-coupling reactions125,145 OCO2MeCO2MeBr2, CCl4OCO2MeCO2MeBrOCO2MeCO2MeBrJung et al. 1976CO2MeCO2MeTMSO1.531.52Br2, CCl4OCO2MeCO2MeBrrt, 1 h70%a)b)TMSOCO2MeCO2Memethanol, rt, 24 h1.52 39 Scheme 1.24 Examples of approaches to 2-sulfonyloxy-1,3-butadienes Approaches to 2-trifluoromethanesulfonyloxy-1,3-butadiene (Figure 1.11) featuring an enol triflate functionality were found in a few literature reports (Scheme 1.24). In 1992, Comins and coworkers reported an approach to enol triflates using N-(5-chloropyridin-2-yl)-1,1,1-trifluoro-N-((trifluoromethyl)sulfonyl)methanesulfonamide (Comins’ reagent, 1.76).146 One substrate reported in this protocol was a cyclic diene with a triflate group (1.77, Scheme 1.24a). In 1995, Luan and coworkers reported an addition of trifluoroacetic acid to 2-methylbut-1-en-3-yne (1.78) that formed 3-methyl-2-trifluoromethansulfonyloxy-1,3-butadiene (1.79) in 34% yield (Scheme 1.24b).147 It was mentioned in the paper that this diene degraded to a dark viscous oil even when stored at 3 °C under Argon. In 2005, Ogasawara and coworkers reported a two-step protocol to synthesize 1,3-dien-2-yl triflates (Scheme 1.24c).148 An O-silylation of 4-ethylhex-3-TfOH, CH2Cl2-40 °C —> rt, 3 hOTfb)1.79, 34%1.78Luan et al. 1995LDA, THF-78 °C, 2 h1.77, 86%ON NClTfTfOTfComins et al. 1992a)O Me3SiCl, NEt3, NaICH3CN, 80 °C, 12 h TMSO1.81, 57%1.80EtEtEtEt MeLi, THF0 °C —> rt, 30 minb)1.761.76-78 °C —> rt, 2 ha)TfO1.82, 70%EtEt c)Ogasawara et al. 2005O Nf-40 °C —> rt, 16 h TfOF(i-Pr)2NH, THF1.83, 7%McCammant et al. 2016d) 40 en-2-one (1.80) formed 2-trimethylsiloxy-1,3-butadiene (1.81) that was treated with methyl lithium and Comins’ regent (1.76) to afford the product 4-ethylhexa-1,3-dien-2-yl trifluoromethanesulfonate (1.82) in 70% yield. The product was applied in a Pd-catalyzed allene formation reaction. In 2016, McCammant and workers reported the synthesis of 4-methylpenta-1,3-dien-2-yl trifluoromethanesulfonate (1.83) that was subsequently used in a Pd-catalyzed cross-coupling reaction (Scheme 1.24d).149 They mentioned that this diene decomposed rapidly after purification through silica gel chromatography and was used immediately. Due to challenges in preparation and storage of this type of dienes, their reactivities in cycloaddition reactions remain largely unknown. Scheme 1.25 Synthesis and intramolecular Diels-Alder reaction of 2-methanesulfonyloxy-1,3-butadiene 2-Methanesulfonyloxy-1,3-butadiene that contains an enol mesylate group is slightly more stable than 2-trifluoromethanesulfonyloxy-1,3-butadiene and has been applied in an intramolecular Diels-Alder reaction (Scheme 1.25).150,151 The 2-methanesulfonyloxy-1,3-butadiene derivative (1.84) was formed in situ from [3,3]-sigmatropic rearrangement of an α-allenic methanesulfonate (1.85). An intramolecular Diels-Alder reaction of 1.84 formed a cis-decalin 1.86 in 47% yield. OHMeMeSO2ClOOOMsMeHHMeOOMsNEt31.84 1.86, 47%, dr = 85:15toluene, 190 °CAlcaide et al. 2005OMsMeO1.85 41 Scheme 1.26 Synthesis of 2-phosphoryloxy-1,3-butadienes by Wiemer and Calogeropoulou 2-Phosphoryloxy-1,3-butadienes that contain the enol phosphate functionality are the research interest of this thesis. They were first synthesized by Wiemer and Calogeropoulou in 1987.152 Methyl vinyl ketone (1.57) was treated with lithium diisopropylamide (LDA) and phosphoryl chlorides to afford six examples of 2-phosphoryloxy-1,3-butadienes (1.87) in 45 – 89% yields (Scheme 1.26). Figure 1.12 Diels-Alder reactions of 2-phosphoryloxy-1,3-butadienes with maleic anhydride Wiemer and Calogeropoulou predicted that the phosphoryloxy group in dienes would be relatively electron-withdrawing and deactivating when compared with the analogous trimethylsiloxy group.152 As a result, 2-phosphoryloxy-1,3-butadiene might have a weaker ability to dictate regioselectivity of Diels-Alder reactions. Nevertheless, they reported that these dienes O OPROR1.87, 45 – 89%1.57LDA, -78 °Cb) OP ClR R-78 °C -> rta)R = EtO, n-PrO, ArylO, Me2NOPROOOOrt1 – 16 hOPRO OOO1.87 1.88 1.89, 89 – 95%R ROPEtOO OOOOEt1.89a, 89%OPn-PrOO OOOn-PrO1.89b, 90%OPPhOO OOOOPh1.89c, 90%1.89d, 92%OPMe2NO OOONMe21.89f, 89%OPOO2MeMeOOO1.89e, 95%OPOO2OMeOMeOOO 42 reacted with maleic anhydride (1.88) in neat and formed bicyclic products 1.89a-f in 89 – 95% yields (Figure 1.12). Scheme 1.27 Diels-Alder reactions of 2-phosphoryloxy-1,3-butadienes with other dienophiles Reactivities of 2-phosphoryloxy-1,3-butadienes with other carbon-based dienophiles were assessed (Scheme 1.27). Wiemer and Calogeropoulou attempted the Diels-Alder reaction of 2-bis(2,6-dimethoxyphenyl)phosphoryloxy-1,3-butadiene (1.87e) with a relatively weak dienophile cyclohexanone (1.90). Only trace amount of the product was obtained when the reaction was heated at 110 °C in toluene. Under the promotion of a Lewis acid AlCl3, diene 1.87e reacted with cyclohexenone (1.90) and afforded 40% of the cycloaddition product 1.91 (Scheme 1.27a). Liu and coworkers investigated the reactivities of 2-diethylphosphoryloxy-1,3-butadiene (1.87a) with OPOO2OMeOMe110 °C16 – 24 h OPOO2OMeOMe1.87e 1.90 1.91: 40%O AlCl3PhCH3Oa)Wiemer et al. 1987Liu et al. 1994OOPEtOO1.87aOEt1.57SnCl4CH2Cl2, 0 °C, 1.5 h OPEtOOOEtO1.92, >99%OOPEtOO1.87aOEt1.93SnCl4CH2Cl2, 0 °C, 18 h OPEtOOOEtO81%, 8:1OPEtOOOEt OOPEtOO1.87aOEt1.94SnCl4CH2Cl2, 0 °C, 65 h OPEtOOOEtO23%, 9:2OPEtOOOEt OOCO2MeMeO2CH MeO2CHb)c)d) 43 several acyclic and cyclic dienophiles under the promotion of SnCl4 (Scheme 1.27b-c).153 The Diels-Alder reaction of 1.87a with methyl vinyl ketone (1.57) was conducted at 0 °C for 1.5 h. The product 1.92 was obtained in an almost quantitative yield (Scheme 1.26b). However, regioisomeric mixtures were obtained when diene 1.87a was reacted with 3-butyn-2-one (1.93) and methyl 3,3-dimethyl-6-oxocyclohexa-1,4-diene-1-carboxylate (1.94). This result supported the prediction by Wiemer and Calogeropoulou on a relatively deactivating property of the phosphoryloxy group in a Diels-Alder reaction. A noticeable property of this type of 2-phosphoryloxy-1,3-butadiene was the unusual bench stability compared with analogous 2-siloxy-1,3-butadienes.153,154 The properties of 2-phosphoryloxy-1,3-butadiene to be stable in storage while retaining good synthetic versatility make it synthetically useful in organic synthesis. The reactivities of 2-phosphoryloxy-1,3-dienes with some carbon-based dienophiles have been reported, but they have never been applied in hetero-Diels-Alder reactions. It would be a very interesting topic to investigate an approach to functionalized six-membered heterocycles via hetero-Diels-Alder reactions of 2-phosphoryloxy-1,3-dienes. The enol phosphate functionality was found to persist in the cycloaddition processes of 2-phosphoryloxy-1,3-dienes with or without Lewis acids. Manipulations could be performed directly on the enol phosphate functionality in the cycloaddition product.153,155 Synthetic usefulness of an enol phosphate especially as an electrophilic partner in the transition-metal catalyzed cross-coupling reaction will be presented in the next section. 1.8.2 Enol phosphate as a synthetically useful functionality The enol-based functionality has been widely applied in transition metal catalyzed cross-coupling reactions as an approach to substituted olefins.114,156 The easy accessibility of an enol 44 derivative from a ketone makes it a very useful alternative to vinyl halide.157 A large number of methods have been established on cross-coupling reactions of enol acetates, enol sulfonates and enol phosphates that can be found in several review papers.114,158,159 In this section, I will focus on demonstrating the synthetic utility of enol phosphates.115 Transition metal catalzyed transformations on enol phosphates described in this section are categorized into three types of bond formations: a) C-H bond formation: reduction, b) C(sp2)-C(sp3) bond formation: alkylation, and c) C(sp2)-C(sp2) bond formation: vinylation and arylation.115 Figure 1.13 General mechanism of the palladium catalyzed cross-coupling reaction on enol phosphate A Pd-catalyzed cross-coupling reaction on an enol phosphate generally proceeds through a three-step pathway: oxidative addition, transmetallation and reductive elimination (Figure 1.13). Oxidative insertion of Pd(0) into the vinyl phosphate bond (blue) to form the desired cross-coupling product competes with a side process of insertion into the aryl phosphate bond (red). Pd(0)L2OPOOOPd(II) OP OPhOOPhR [M]OP OPhOOPh[M]Pd(II) RRLLPd(II) OP OPhOOPhLLLLPd(II) RLLoxidative additiontransmetallationreductive eliminationPhPh 45 Insertion into an aryl phosphate bond is typically slower than a vinyl phosphate bond that can be dependent on the catalyst, the ligand, and the substitution pattern on the enol phosphate.160. Scheme 1.28 Examples of reductions of enol phosphates The first example of a reduction of enol phosphate was reported by Ireland and coworkers in 1969 (Scheme 1.28a).161 The enol phosphate functionality in 1.95 was reduced by lithium in ethyl amine and t-butyl alcohol to form the product 1.96 in 91% yield. In 1981, Sato and coworkers reported a method of treating an enol phosphate with triethyl aluminium under the catalysis of tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4). The reaction afforded a 2:1 ratio of the hydrogenated product 1.97a and the alkylated product 1.97b (Scheme 1.28b).162 Some recent O OOa) Li, NH3, etherb) (EtO)2POCl, etherO OOPEtOOOEt H1.95, 56%O OHLi, EtNH2, t-BuOH1.96, 91%a)Ireland et al. 1969PhO SEtHPOPhOPhO Pd(PPh3)4AlEt3CH2ClCH2Cl83 °CPhH SEtHPhEt SEtH1.97a:1.97b = 2:1Sato et al. 1981b)NBocOO P OPhOOPhHCOOH, NEt3Pd(OAc)2, PPh3DME, 85 °C NBocO67%Buon et al. 2000c)NOPhO2C POPhOPhOMe2PhSiH, Pd(PPh3)4DMF, 60 °C NPhO2C68%Fuwa et al. 2007d) 46 methods of reducing enol phosphates through palladium(0)-catalzyed hydride transfer were examplified in Scheme 1.28c and d.163,164 Scheme 1.29 Examples of transition metal catalyzed alkylations on enol phosphates The first example of a transition metal catalzyed alkylation on an enol phosphate was reported by Blaszczak and coworkers in 1976 (Scheme 1.29a).165 4-(tert-Butyl)cyclohex-1-en-1-yl diphenyl phosphate (1.98) was treated with di(n-butyl)cuprate at -30 °C for 12 h to form the product 4-(tert-butyl)-1-butylcyclohex-1-ene (1.99) in 59% isolated yield. An alkylation of the enol phosphate (1.98) by trimethyl aluminum under the catalysis of OPOPhOPhO (n-Bu)2CuLiTHF, -30 °C, 12 h1.98 1.99, 59%a)OPOPhOPhO Pd(PPh3)4, AlMe325 °C, 5 h1.98 72%b)Blaszczak et al. 1976Takai et al. 1980Pd2dba3, dppf, LiClTHF, 70 °C, 18 h1.100 1.101, 50%c)Hansen et al. 2007O P OPhOOPhn-BuZnBrFe(acac)3THF, 20 °C1.102 1.103, 92%d)Cahiez et al. 2008O P OEtOOEtn-OctMgCln-oct 47 tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) was reported by Takai and coworkers in 1980 (Scheme 1.29b).157 This method has been widely used in organic synthesis to convert a ketone to a methyl substituted olefin.166,167 Some modern cross-coupling methods have been developed to couple enol phosphates with alkyl organometallic reagents. A palladium-catalyzed Negishi coupling on an enol phosphate 1.100 with n-butylzinc bromide formed the product 1.101 in 50% yield (Scheme 1.29c).168 An iron catalyzed Kumada coupling on an enol phosphate 1.102 with n-octylmagnesium chloride formed (E)-dodeca-1,3-diene (1.103) in 92% yield (Scheme 1.29d).169 Scheme 1.30 Examples of transition metal catalyzed cross-coupling reactions enol phosphates with aryl- or vinyl organometallic reagents Transition metal catalyzed alkenylations and arylations on enol phosphates account for the most common processes among cross-coupling reactions of enol phosphates. The first example OOOOPOPhO OPhHHPhSn(Bu)3Pd(PPh3)4, LiClTHF, 70 °C, 2 hOOOHHPh1.104 1.105, 96%a)Nicolaou et al. 1997NBoc O POPhOPhOPhZnClPd(PPh3)4THF, 50 °C, 1 h NBoc Ph1.106 87%Nicolaou et al. 1998b)O O P OPhOOPhB(OH)2O2NPd(PPh3)4, K3PO4DMF, 50 °CO NO2Pedzisa et al. 20081.107 88%c)1.108 48 was reported by Nicolaou and coworkers in 1997 (Scheme 1.30a).170 An enol phosphate 1.104 derived from a lactone was coupled with tributyl(vinyl)tin in a Stille coupling reaction to form the product 1.105 in 96% yield. Nicolaou and coworkers also reported a palladium-catalyzed Negishi coupling of an enol phosphate 1.106 derived from a lactam in 1998 (Scheme 1.30b).171 An example of Suzuki coupling of an enol phosphate 1.107 with (3-nitrophenyl)boronic acid (1.108) was reported by Pedzisa in 2008 (Scheme 1.30c).172 Scheme 1.31 Examples of cross-coupling reactions on enol phosphates from simple ketones NBocO P OPhOOPhPhB(OH)2Pd(OAc)2, KF, ligandH2O/DME, 150 °C, 5 minNBocPhligand = P(t-Bu)21.112 1.114, 48%Larsen et al. 2005NBocO P OPhOOPhPhMgClPdCl2(PPh3)2, TMEDATHF, 40 °C, 1 hNBocPh1.112 1.114, 93%TMEDA = N NO P OPhOOPhMgBrPdCl2THF, rt, 7 h1.115 1.116, 79%b)c)d)Gauhier et al. 20091.113PdCl22 * RMgBr Pd(0) R RO P OPhOOPh MeOB(OH)2NiCl2(dppf), K3PO4toluene, 90 °C, 24 hOMe1.109 1.111, 82%Nan et al. 1999a)1.110R = p-tolyl 49 Enol phosphates shown in Scheme 1.30 that are derived from lactones or lactams are generally very good substrates for cross-coupling reactions.115,173 In contrast, the cross-coupling reactions of enol phosphates from simple ketones were found to be more challenging.115 In 1999, Nan and coworkers reported a Nickel catalyzed Suzuki coupling on an enol phosphate derived from cyclohexanone (Scheme 1.31a).174 The enol phosphate 1.109 was heated with (4-methoxyphenyl)boronic acid (1.110) and [1,1′-Bis(diphenylphosphino)ferrocene]dichloronickel(II) (NiCl2(dppf)) at 90 °C in toluene for 24 h to form the product 1.111 in 82% yield. In 2005, Larsen and coworkers reported a method of cross-coupling reactions on enol phosphate esters of N-Boc-4-piperidone (Scheme 1.31b and c).175 The Suzuki coupling of 1.112 required the addition of a phosphorus ligand 2-(di-tert-butylphosphino)biphenyl (1.113). The reaction was conducted at 150 °C to afford the product 1.114 in 48% isolated yield. Cross-coupling reactions with Grignard reagents are more efficient for enol phosphates from simple ketones. The same product 1.114 was formed in a much higher yield (93%) from a Kumada coupling reaction of 1.112 with phenylmagneisum chloride. In 2009, Gauhier reported a protocol of ligand-free Kumada coupling reactions on enol phosphates (Scheme 1.31d).176 The reaction of an enol phosphate 1.115 with p-tolylmagnesium bromide was conducted at rt for 7 h using a pre-catalyst palladium(II) chloride, and the product 1.116 was formed in 79% yield. The active palladium(0) catalyst was formed in situ from palladium(II) chloride and two equivalents of the Grignard reagent. 1.9 Conclusion Six-membered nitrogen heterocycles have significant applications in bioactive molecules and fluorescent molecules. It results in ongoing interest in the development of synthetic approaches 50 to functionalized six-membered nitrogen heterocycles in organic chemistry. Hetero-Diels-Alder reactions have been considered as very efficient methods for the construction of six-membered heterocycles beucause they can be conducted at mild conditions and form the products in high atom economy and selectivity. In this thesis, we are invesigating the application of an underexplored enol-based diene: 2-diphenylphosphoryloxy-1,3-butadiene in the hetero-Diel-Alder reaction. This diene is more stable in storage than the analogous 2-trimethylsiloxy-1,3-butadiene. The enol phosphate functionality in the cycloaddtion product can be directly utilized in subsequent manipulation in a transition metal catalyzed cross-coupling reaction. The following three chapters will describe the methods that are developed for the construction of two six-membered nitrogen heteocycles: 1,2,3,6-tetrahydropyridines and pyridines. The content in chapter 2 focuses on the establishement of hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and N-(p-toluenesulfonyl)benzaldimine and related derivatives. Chapter 3 introduces a method that improves the efficacy of the hetero-Diels-Alder reaction through a multicomponent condensation/cycloaddition process. This method allows for the construction of more variously substituted 1,2,3,6-tetrahydropyridines. Chapter 4 introduces the manipulation of hetero-Diels-Alder products to functionalized pyridines. Fluorescent properties of light-luminating pyridine substrates will be presented. 51 Chapter 2: Hetero-Diels-Alder Reactions of 2-Diphenylphosphoryloxy-1,3-Butadienes and Imines 2.1 Introduction Hetero-Diels-Alder reactions are important transformations to construct six-membered heterocycles.78,80,93 They have advantages of good atom economy and high selectivity. An enol-based butadiene in the hetero-Diels-Alder reaction is particularly effective in terms of high reaction rates and regioselectivity, and provides a functionality that is useful for further manipulations of the cycloaddition product.71,130 Scheme 2.1 The proposed hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines Our research group has had long interest in constructions of heterocycles. We are intrigued by the potential application of 2-diphenylphosphoryloxy-1,3-butadienes in hetero-Diels-Alder reactions, especially the reactions between dienes and imines. It was proposed that 2-diphenylphosphoryloxy-1,3-butadienes could react with imines to generate substituted six-membered nitrogen heterocycles, with or without the promotion of a Lewis acid (Scheme 2.1). The cycloaddition product contained an enol phosphate functionality if it persisted in the process of the hetero-Diels-Alder reaction. The synthetic utility of enol phosphate functionality especially in transition metal catalyzed cross-coupling reactions should allow further derivatization to other substituents. OPPhOOOPPhOO NNR1R2R1R2Lewis acid? R3-[M]Pd or NiN R1R2R3OPh OPhR R R 52 This chapter is divided into four sections. The first section presents the synthesis of 2-diphenylphosphoryloxy-1,3-butadiene and its spectral analysis. The second section presents the initial attempt of the hetero-Diels-Alder reaction between 2- diphenylphosoryloxy-1,3-butadiene and N-(p-toluenesulfonyl)benzaldimine. Spectral analysis of the cycloaddition products and condition screen of the hetero-Diels-Alder reactions are included in this section. The third section presents the scope of imines and dienes in hetero-Diels-Alder reactions. Application of hetero-Diels-Alder products in cross-coupling reactions for the synthesis of substituted tetrahydropyridines will be described in the last section. 2.2 Synthesis of 2-diphenylphosphoryloxy-1,3-diene and characterization 2-Diphenylphosphoryloxy-1,3-butadiene (2.1a) was chosen as the parent diene in this project because it could be readily constructed from the commercially available 3-butene-2-one (2.2a) and diphenylphosphoryl chloride (2.3). The synthesis of diene 2.1a was conducted using the procedure outlined by Wiemer and Calogeropoulou in 1987 (Scheme 2.2).152 Distilled 3-butene-2-one (2.2a) was added slowly to a solution of lithium diisopropylamide (LDA) in distilled THF at –78 °C followed by a quench using non-distilled diphenylphosphoryl chloride (2.3). Scheme 2.2 Synthesis of 2-diphenylphosphoryloxy-1,3-butadiene 2.1a 2-Diphenylphosphoryloxy-1,3-butadiene (2.1a) was prepared on a 10-gram scale and purified using silica gel chromatography. It decomposed after a week through polymerization if it O OPPhOOOPh2.1a, 67%2.2ai-Pr2NHnBuLi THF -78 °C, 30 minb) OP ClPhO OPh-78 °C -> rt, 3 ha)2.3 53 was stored neat at rt. Fortunately, a ~ 1 M solution (CH2Cl2) of 2.1a could be stored at rt or 5 °C for several months. Either distilled or non-distilled CH2Cl2 could be used as no significant difference was found between those two solvent systems. Table 2.1 Diagnostic 1H and 13C NMR assignments of alkenyl protons of 2.1a entry carbon δ (ppm) 13C-31P Splitting proton δ (ppm) splitting 1 C1 102.4 d (J = 3.5 Hz) Hc/He 5.22–5.19 m 2 C1 102.4 d (J = 3.5 Hz) Hc/He 4.85 dd (J = 2.3, 2.3 (1H-31P) Hz) 3 C2 151.3 d (J = 8.2 Hz) - - - 4 C3 130.7 d (J = 6.9 Hz) Ha 6.19 ddd (J = 17.0, 10.9, 2.9 (1H-31P) Hz) 5 C4 125.7 d (J = 1.5 Hz) Hb 5.45 d (J = 17.0 Hz) 6 C4 125.7 d (J = 1.5 Hz) Hd 5.18 d (J = 10.9 Hz) Diagnostic spectroscopic assignments for 2-diphenylphosphoryloxy-1,3-butadiene (2.1a) are presented in Table 2.1. In the 1H NMR spectrum, signals in the range of 5 – 7 ppm corresponded to the chemical shifts of hydrogens attached to sp2-hybridized carbon atoms of the 1,3-butadiene fragment. Four-bond 1H-31P couplings were observed at signals of Ha (6.19 ppm) and Hc/He (4.85 ppm) with coupling constants of 2.9 and 2.3 Hz, respectively. 13C-31P Couplings were found in the 13C NMR spectrum of 2.1a, where 2JC-P was around 8 Hz, 3JC-P was 3.5 – 7 Hz and 4JC-P was around 1.5 Hz. The lower chemical shift at C-1 of the diene (102.4 ppm) than C2-4 is consistent with an increased electron density on that carbon due to the electron-donating (resonance) effect of the OPPhOOOPhHdHbHeHcHa123 4 54 oxygen substituent. 2-Diphenylphosphoryloxy-1,3-butadiene (2.1a) had a diagnostic 31P NMR signal at -17.3 ppm. This resonance was used to identify the enol phosphate in other diene derivatives. A HRMS-ESI experiment of the compound found [M+H]+ = 303.0782 which was consistent with our calculation for C16H15O4P ([M+H]+ = 303.0786). Condition: 2.1a/2.4 (2 mmol) and 0.015 g TMB are dissolved in 2 mL of CH2Cl2 and stored at 5 °C. Integration ratio of Ha (6.19/6.21 ppm) of 2.1a/2.4 and TMB (6.10 ppm) on the same day after synthesis was measured (I0). After n days, integration ratio of the same signals was measured (In). Percentage of degradation was calculated using the formula: !!"!"!" × 100%. Figure 2.1 Percentage degradation of 2.1a and 2.4 when they were stored as 1 M solutions in CH2Cl2 at 5 °C One of the potential advantages of 2-diphenylphosphoryloxy-1,3-butadiene (2.1a) is its purported stability relative to other 2-oxy-substituted dienes. Its relative stability was assessed by OPPhOOOPh OSi2.1a 2.4Ha Haδ 6.22 (ddd, J = 17.0, 10.9, 2.9 Hz) δ 6.21 (dd, J = 16.9, 10.5 Hz)0, 0% 1, 0%8, 3.80% 11, 4.40%0, 0%6, 43%8, 57%12, 76%0%10%20%30%40%50%60%70%80%0 2 4 6 8 10 12 14PERCENTAGE OF DEGRADATIONDAYSRate of degradation of two 2-oxy-substituted dienes2.1a 2.4 55 evaluating the rate of degradation of diene 2.1a under its storage condition compared to 2-trimethylsiloxy-1,3-butadiene (2.4), a well established diene in Diels-Alder chemistry. 1,3,5-Trimethoxybenzene (TMB, 6.10 ppm) was used as an internal NMR standard for a 1.0 M butadiene solution in CH2Cl2 (undistilled) at 5 °C (refrigerator). The degradation of each diene was measured by the change in integration ratios of signals of Ha relative to the internal standard. A plot of percentage degradation of dienes 2.1a and 2.4 with respect to time is presented in Figure 2.1. 2-Trimethylsiloxy-1,3-butadiene (2.4) degraded by 76% after twelve days, while diene 2.1a degraded by less than 5% in the same time period. The stability of diene 2.1a in storage is much higher than the analogous 2-trimethylsiloxy-1,3-butadiene (2.4). Diene 2.1a has the advantage of being synthesized and stored as a solution in the refrigerator for its utilization in reactions, whereas 2-trimethylsiloxy-1,3-butadiene (2.4) is only accesible immediately after its synthesis. 2.3 The hetero-Diels-Alder reaction between 2-diphenylphosphoryloxy-1,3-butadiene and N-(p-toluenesulfonyl)benzaldimine N-(p-Toluenesulfonyl)benzaldimine (2.5a) was selected as the test imine of the hetero-Diels-Alder reaction, because a) its synthesis is known from literature, b) it could be stored on bench-top, and c) its reactivity in hetero-Diels-Alder reactions has been reported in literature.177,178,179 Scheme 2.3 Synthesis of N-(p-toluenesulfonyl)benzaldimine (2.5a) H2N TsOPhH PhCH3130 °C, 16 hBF3•OEt2 NHPhTs2.5a, 89%2.6 2.7δ 9.05 ppm 56 N-(p-Toluenesulfonyl)benzaldimine (2.5a) was synthesized using the conditions outlined by Liu K and his coworkers in 2009 (Scheme 2.3).180 A mixture of 1.5 equivalents of benzaldehyde (2.6), 1 equivalent of p-toluenesulfonamide (2.7) and 10 mol% of BF3OEt2 were heated at 130 °C in toluene for 16 h using a Dean-Stark apparatus. Recrystallization of crude products from ethyl acetate/hexane gave white crystals of 2.5a in 89% yield. This imine was stored at rt for one to two months without problems of hydrolysis. Keeping it at 5 °C allowed storage for longer time. Imine 2.5a had a diagnostic signal in 1H NMR spectrum at 9.05 ppm, corresponding to the imine C-H proton. Scheme 2.4 the thermal cycloaddition between 2.1a and 2.5a was not successful Yiran Wei was the first student in the Dake group to attempt a hetero-Diels-Alder reaction between 2-diphenylphosphoryloxy-1,3-butadiene (2.1a) and N-(p-toluenesulfonyl)benzaldimine (2.5a). The reaction was conducted using a 1:1 ratio of 2.1a and 2.5a at 110 °C in dry toluene, but no product was observed (Scheme 2.4). It was observed that diene 2.1a had low solubility in toluene, resulting in the formation of an oily suspension. Scheme 2.5 Lewis acid catalyzed hetero-Diels-Alder reaction between 2.1a and 2.5a to form the expected product OPPhOOOPhNHPhTs NPhOTsPPhOOOPhtoluene110 °C, 24 h2.1a (1.0 equiv) 2.5a (1.0 equiv)OPPhOOOPhNHPhTs NPhOTsPPhOOOPh2.8a, 27%DCM, rt, 24 hBF3•OEt2 (1.0 equiv)2.1a (1.0 equiv) 2.5a (1.0 equiv) 57 Yiran modified the conditions of the hetero-Diels-Alder reaction by a) adding a Lewis acid BF3•OEt2 to activate the imine dienophile and b) switching the solvent to CH2Cl2 to improve solubility of diene 2.1a (Scheme 2.5). The imine N-(p-toluenesulfonyl)benzaldimine (2.5a) was not entirely soluble in distilled CH2Cl2 as evidenced by persisting precipitates. Boron trifluoride diethyl etherate was added and the mixture was stirred at rt for 15 – 30 min to obtain a clear solution. 2-Diphenylphosphoryloxy-1,3-butadiene (2.1a) was added as a 0.8 M solution in distilled CH2Cl2. A new spot was observed on the TLC plate (25% EtOAc in hexanes) after the reaction mixture was stirred for ~ 24 hours. After quenching the reaction with saturated aqueous sodium bicarbonate, a quick NMR analysis on the unpurified reaction mixture was performed. The 1H NMR spectrum showed consumption of the diene and appearance of new signals. The 31P NMR spectrum had a signal at -17.4 ppm that is consistent with an enol phosphate functionality. The product was purified by silica gel chromatography and isolated in 27% yield as a light yellow oil. 2.3.1 Characterization of the hetero-Diels-Alder product Although Yiran performed the initial experiment to generate the product, the characterization of the product is relevant to my research. I will go into details on more elaborate structural analysis that was performed by Yiran and I cooperatively. 58 Table 2.2 Carbon and proton assignments of the heterocyclic ring in 2.8a entry carbon δ (ppm) 13C-31P Splitting proton δ (ppm) splitting 1 C1 39.6 - Hc/Hd 4.29–4.17 m 2 C1 39.6 - Hc/Hd 3.48–3.33 m 3 C2 108.6 d (J = 5.5 Hz) Ha 5.54 ddd (J = 4.9, 1.7, 1.7 (1H-31P) Hz) 4 C3 144.8 d (J = 9.2 Hz) - - - 5 C4 29.1 d (J = 4.3 Hz) He+Hf 2.66–2.58 m 6 C5 53.5 - Hb 5.38 dd (J = 3.8, 3.8 Hz) Diagnostic spectroscopic assignments for the hetero-Diels-Alder product 2.8a are presented in Table 2.2. The correlations of carbons and protons were identified by a complementary analysis of 1H-13C Heteronuclear Single Quantum Coherence (HSQC). The 1H NMR spectrum of the product showed signals in the range of 2 – 4 ppm. Compared with the 1H NMR spectrum of diene 2.1a that only contained aromatic and alkenyl protons, the appearance of signals at 2 – 4 ppm indicated that the material had protons connecting to sp3-hybridized carbons. The signal of Ha (5.54 ppm) of the product 2.8a was also splitted by a four-bond 1H-31P coupling with a coupling constant of 1.7 Hz. A HRMS-ESI experiment of the product found [M+H]+ = 562.1451 is consistent with C30H29NO6PS ([M+H]+ = 562.1453). NPhOTsPPhOOOPhHaHe HfHd HcHb123 45 59 Scheme 2.6 Synthesis of enol phosphate 2.9 from N-Boc-4-piperidone (2.10) Figure 2.2 Proton and phosphorus assignments of enol phosphate 2.9 A literature known enol phosphate compound 2.9 that was derived from N-Boc-4-piperidone (2.10) has a similar heterocyclic structure to 2.8a (Scheme 2.6).175 The chemical shifts and splitting patterns of protons on the heterocycle of 2.9 (Figure 2.2) provided a reference to the spectral analysis of 2.8a. Figure 2.3 Expected COSY correlations in the two regioisomers of product 2.8a Only one signal at -17.4 ppm in the 31P NMR spectrum of the unpurified product after quenching suggested formation of a single regioisomer. The expected regioselectivity of the hetero-Diels-Alder reaction between 2.1a and 2.5a was supported by results of ¹H-¹H Correlation i-Pr2NHnBuLi THF -78 °C, 30 minb) OP ClPhO OPh-78 °C -> rt, 3 ha)2.102.3NOBocPPhOOOPh 2.9, 44%N BocONHcOBocPPhOOOPhHaHg HfHd HeHbδ 4.00-3.88 (m)δ 3.57 (dd, J = 5.80, 5.79 Hz)δ 2.43-2.17 (m)δ 5.60-5.49 (m)δ -17.1 ppmNPhOTsPPhOOOPhHaHe HfHd HcHb12345 NOPPhOOOPhHH HH H12345 TsHPh(not observed)(observed) 60 Spectroscopy (COSY) experiments. The COSY spectrum of 2.8a showed correlations between Ha and Hc/Hd, and Hb and He/Hf (Figure 2.3). Table 2.3 Hydrolysis of the product 2.8a in neutral and acidic aqueous media entry condition temp (°C) time % of 2.11 1 A 25 24 h 0% 2 B 25 24 h 0% 3 C 25 24 h 0% Formation of the expected cycloaddition product conveyed that the enol phosphate functionality persisted in the Lewis acid promoted hetero-Diels-Alder reaction and the aqueous base work up process. The product 2.8a could be stored in neat on the bench top for several months without degradation. The relative stability of the enol phosphate functionality in the product 2.8a in neutral and aqueous acidic conditions was assessed (Table 2.3), in comparison with the analogous silyl enol ethers (Table 1.1 and 1.3, Chapter 1.8). The product 2.8a was dissolved in methanol, aqueous acetic acid (HOAc/THF/H2O: 1:10:1), and aqueous hydrochloric acid (THF/1 M HCl: 20:1), respectively. After stirring compound 2.8a in each condition for 24 h, 1H NMR spectroscopy spectrum of each reaction mixture showed no signal of the hydrolyzed product (2.11, Table 2.3).181 The enol phosphate functionality in the hetero-Diels-Alder product was not hydrolyzed or decomposed at any of the three conditions within 24 h. The enol phosphate NOTsPPhOOOPhconditon A: methanolcondition B: HOAc/THF/H2O: 1:10:1condition C: THF/1 M HCl: 20:1NOTs2.8a 2.11 61 functionality can be compatible in various conditions in manipulations of the cycloaddition product. 2.3.2 Optimization of the reaction btween 2-diphenylphosphoryloxy-1,3-butadiene and N-(p-toluenesulfonyl)benzaldimine I performed a condition screen for the hetero-Diels-Alder reaction by varying the equivalents of BF3•OEt2 and diene 2.1a. The results are shown in Table 2.4. Generally, conversions increased as the number of equivalents of 2.1a and BF3•OEt2 increased. Table 2.4 Screening equivalents of BF3•OEt2 and diene 2.1a for the hetero-Diels-Alder reactiona entry BF3•OEt2 (equiv) diene 2.1a (equiv) reaction time (h) conversion by NMR (%)b 1 1.0 1.0 ~ 24 27 2 1.0 2.0 ~ 24 61 3 1.0 3.0 ~ 24 61 4 1.0 3.0 ~ 48 66 5 1.0 4.0 ~ 48 73 6 1.5 4.0 ~ 48 76 7 2.0 4.0 ~ 48 80 a reaction condition: 2.5a (0.2 mmol), 2.1a (0.8 M solution in DCM), DCM (1 mL). b conversions determined by integrations of Ha (5.57-5.50 ppm) and the internal standard TMB in 1H NMR spectra in quenched reaction mixtures. Each condition was repeated, and the higher number of conversions was reported because the numbers were within experimental errors. OPPhOOOPhNHPhTs BF3•OEt2DCMNPhOTsPPhOOOPh2.5art, 24 h – 48 h2.8a2.1a 62 Yiran Wei attempted different Lewis acid promotions including FeCl3, Yb(OTf)3, TMSOTf and Cu(OAc)2 in the hetero-Diels-Alder reaction. Her experimental results showed that under the promotion of FeCl3, the reactions also gave high yields of the product. I performed further optimization of the reaction conditions using FeCl3 (Table 2.5). Table 2.5 Screening equivalents of FeCl3 and diene 2.1a for the hetero-Diels-Alder reactiona entry FeCl3 (equiv) diene 2.1a (equiv) reaction time (h) conversion by NMR (%)b 1 0.1 2.0 ~ 48 38 2 0.2 2.0 ~ 48 62 3 0.4 2.0 ~ 48 56 4 0.2 3.0 ~ 48 67 5 0.2 3.0 ~ 24 72 6 0.2 4.0 ~ 24 80 a reaction condition: 2.5a (0.2 mmol), 2.1a (0.8 M solution in DCM), DCM (1 mL). b conversions determined by integrations of Ha (5.57-5.50 ppm) and the internal standard TMB in 1H NMR spectra of quenched reaction mixtures. Each condition was repeated, and the higher number of conversions was reported because the numbers were within experimental errors. An 80% conversion by NMR was achieved using 20 mol% of FeCl3 and 4.0 equivalents of diene 2.1a (entry 6). The reaction could be finished within 24 h. Less than stoichiometric ratio of FeCl3 was required for this reaction. This is presumably because that iron(III) is a d5 centre and forms a coordinate complex with several ligands in an octahedral geometry.182 In contrast, BF3 could only coordinate to one Lewis base due to lack of d orbitals in boron.183,184 When the catalytic loading of FeCl3 was increased to 40 mol%, the yield was slightly decreased from 62% to 56% OPPhOOOPhNHPhTsFeCl3DCMNPhOTsPPhOOOPhrt, 24 h – 48 h2.5a 2.8a2.1a 63 (entry 2 and 3), perhaps because that iron(III) could also coordinate to the phosphate group on diene 2.1a and deactivate it. However, the hetero-Diels-Alder reaction under the promotion of FeCl3 was more sensitive to moisture. When non-distilled CH2Cl2 was used in the reaction, product 2.8a could still be obtained in 44% conversion using BF3•OEt2, whereas no product was observed using FeCl3. 2.4 Substrate scope for the hetero-Diel-Alder reaction 2.4.1 Synthesis of derivatives of N-(p-toluenesulfonyl)benzaldimine Yiran Wei synthesized N-sulfonyl imine derivatives 2.5b-2.5f and purified them by recrystallization (Figure 2.4). Each imine was identified by the signal of the imine C-H proton in the range of 8.95 – 9.25 ppm in its 1H NMR spectrum. a Reaction condition: 2.12 (5 mmol), 2.13 (7.5 mmol), BF3•OEt2 (0.5 mmol), toluene (25 mL), 130 °C, 16 h. Isolated yields reported. Figure 2.4 Synthesis of N-(p-toluenesulfonyl)benzaldimine and derivativesa H2N SO2R1OR2H PhCH3130 °C, 16 hBF3•OEt2 NHR2NHSO OClNHSO ONO2NHSO OOMeNHSO ONHSO O2.5b, 60% 2.5c, 50%2.5d, 85% 2.5e, 40% Cl2.5f, 36%NHSO O2.5a, 89%2.12 2.13 2.5SO2R1δ 9.05 ppm δ 8.99 ppm δ 9.25 ppmδ 8.94 ppm δ 9.07 ppm δ 9.02 ppm 64 N-Carbamoyl imines could not be synthesized using the condensation method for N-sulfonyl imines 2.5.185 A two-step protocol reported by Huang and coworkers in 2011 was used to synthesize N-carbamoyl imines (Figure 2.5).186 The first dehydration step formed stable salts 2.15 which then underwent elimination to form imines 2.16 in neat. This method is easy to scale-up to a 5-gram scale. Four examples of N-carbamoyl imines were synthesized using this protocol. I synthesized 2.16a and 2.16b, and Yiran Wei synthesized 2.16c and 2.16d. a Reaction condition: 2.14 (20 mmol), 2.12 (40 mmol), PhSO2Na (50 mmol), HCOOH (40 mmol), methanol (20 mL), water (40 mL), rt, 16 h; 2.15 (4 mmol), K2CO3 (88 mmol, 63 mL water), DCM (63 mL). Isolated yields reported. Figure 2.5 Two-step synthesis of N-carbamoyl imine derivativesa 2.4.2 Scope of imines for the hetero-Diels-Alder reaction with 2-diphenylphosphoryloxy-1,3-butadienes The functionalized imines 2.5/2.15 were subjected to the hetero-Diels-Alder reaction with 2-diphenylphosphoryloxy-1,3-butadienes (2.1a) following the optimized conditions using 20mol% OHPhSO2NaHCOOHMeOH/H2OHNPhO2SK2CO3 (aq)DCM, rt, 4 hrt, 16 hNH2.14 2.12R2 R2 R2NHOO2.15a, 78%; 2.16a, 98%NHOO2.15b, 48%; 2.16b, 71%NHOO2.15c, 31%; 2.16c, 72%ClNHOO2.15d, 21%; 2.16d, 52%NHOO2.15e, 0 %2.15 2.16Brδ 8.87 ppm δ 8.95 ppm δ 8.92 ppmδ 8.85 ppmOOH2NR1OO R1OO R1 65 of FeCl3 (Figure 6, chapter 2.3.2). Two of the products (2.8b and 2.8e) were synthesized by Yiran Wei and the rest were synthesized by me. All the cycloaddition products had diagnostic signals at around -17.3 ppm in the 31P NMR spectra, showing that the enol phosphate functionality persisted in the reaction processes. a Reaction condition: 2.5/2.15 (0.2 mmol), 2.1a (0.8 mmol, 1 mL DCM), FeCl3 (0.04 mmol), 1 mL DCM, rt, 24 – 48 h. Isolated yields reported. b Reaction carried as in a using 0.08 mmol of FeCl3. Figure 2.6 Scope of imines for the hetero-Diels-Alder reactiona Cycloaddition products 2.8a-g were constructed from diene 2.1a in yields consistent with our expectation. When imines with a chloro- and a nitro- substituent on the phenyl ring were reacted with diene 2.1a, products 2.8b and 2.8c were formed in higher yields (62% and 67%, respectively) than the imine with an methoxy group (2.8d, 30%). The yield of 2.8b became higher (62%) when 40 mol% of FeCl3 was applied than 20 mol% (45%). The cycloaddition of 2.1a with OPPhOOOPhNR2HR1 FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNR2OR1PPhOOOPhNOTsPPhOOOPhClNOTsPPhOOOPhNO2NOTsPPhOOOPhOMeNOSO2PhPPhOOOPhNOSO2PhPPhOOOPhClNOTsPPhOOOPh2.8a, 78%31P δ -17.4 ppm2.8b, 45% (62%b)31P δ -17.2 ppm2.8c, 67%31P δ -17.1 ppm2.8d, 30%31P δ -17.3 ppm2.8e, 65%31P δ -17.3 ppm2.8f, 51%b31P δ -17.2 ppm2.1a 2.5, 2.15 2.8NOCbzPPhOOOPh2.8g, 44%31P δ -17.1 ppmNOBocPPhOOOPh2.8h, 0% 66 N-carbamoyl imine 2.15b formed the product 2.8g in a lower yield (44%) than those products from N-sulfonyl imines, presumably because that imine 2.15b was less stable in an acidic medium. Formation of 2.8h was not observed: the Boc protecting group on the imine 2.15a might be removed first in the presence of a Lewis acid and the imine decomposed. The variation in functionalization of products 2.8a-g was not high in this substrate scope and the reasons will be discussed later. 2.4.3 Synthesis of derivatives of 2-diphenylphosphoryloxy-1,3-butadiene A variety of substituted 2-diphenylphosphoryloxy-1,3-butadienes were made from enones using LDA and diphenylphosphoryl chloride as described for 2-diphenylphosphoryloxy-1,3-butadiene (2.1a). A scope of substituted 2-diphenylphosphoryloxy-1,3-butadienes is shown in Figure 2.7 and they were all syntheized by me. Each diene has a diagnostic signal at around -17.3 ppm in its 31P NMR spectrum. For convenience, they were stored as 0.8 M solutions in distilled CH2Cl2 at 5 °C. 67 a Reaction condition: 2.2 (10 mmol), i-Pr2NH (11 mmol), nBuLi (11 mmol, 1.6 M solution in hexane), 2.3 (12 mmol), THF (7 mL), -78 °C à rt, 3 h. Isolated yields reported. b Product synthesized on a 10 g scale. Figure 2.7 Synthesis of 2-diphenylphosphoryloxy-1,3-diene derivativesa Six examples of 4-substiuted 2-diphenylphosphoryloxy-1,3-butadienes (2.1b-g) were synthesized because the enone starting materials were accessible from commercial sources or can be easily synthesized from Wittig reactions on aldehydes. Aldehydes were treated with (acetylmethylene)triphenyl-phosphorane (2.17) to afford enones 2.17b-c in >20:1 E/Z ratios (Scheme 2.7). This approach allowed for the incorporation of varied substituents at the C-4 position of dienes. Diene 2.1d is analogous to (E)-1-methoxy-3-trimethylsilyloxy-buta-1,3-diene (Danishefsky’s diene) which is commonly used in hetero-Diels-Alder reactions. However, it OPPhOOOPh OPPhOOOPh OPPhOOOPhC7H15OPPhOOOPhOPPhOOOPhOBnOPPhOOOPh2.1a, 67%b31P δ -17.3 ppm2.1b, 53%31P δ -17.3 ppm2.1e, 71%31P δ -17.3 ppm2.1h, 68%31P δ -17.3 ppm2.1j, 90%31P δ -17.1 ppm2.1f, 69%31P δ -17.3 ppmOPPhOOOPhOPPhOOOPhPhO OPPhOOOPhR2R1 R1R2R3R3OPPhOOOPhOPPhOOOPhOMe2.1m, 0%OPPhOOOPhN2.1i-Pr2NHnBuLi THF -78 °C, 30 minb) OP ClPhO OPh-78 °C -> rt, 3 ha)2.3OPPhOOOPhPh2.1c, 65%31P δ -17.4 ppm2.1d, 51%31P δ -17.4 ppm2.1k, 72%31P δ -17.2 ppm2.1g, 78%31P δ -17.4 ppm2.1i, 28%31P δ -17.3 ppmOPPhOOOPh2.1l, 20%, Z/E = 4.5:131P(Z) δ -17.3 ppm31P(E) δ -17.0 ppm2.2 68 decomposed much more rapidly compared to other dienes. It became a dark black gel after four days at 5 °C as a 0.8 M solution in distilled CH2Cl2. The formation of diene 2.1f demonstrated the compatibility of an -OBn functional group in the process of diene synthesis. Diene 2.1l with an amino group at C-4 position was detected on the 31P NMR spetrum of the crude reaction mixture by a signal of -17.1 ppm, but this diene degraded on silica gel chromatography and could not be isolated. Scheme 2.7 Synthesis of substituted enones using wittig reactions on aldehydes A diene with substitution at C-3 position is expected to be more reactive in Diels-Alder reactions compared to 4-substituted dienes because the substitution does not introduce sterics strain in a cycloaddition process. Diene 2.1h with a methyl substituent at C-3 position was sucessfully constructed from 3-methylbut-3-en-2-one in 68% yield. The diene with a phenyl substituent at C-3 position (2.1i) was isolated in a very low yield of 28%. This was presumably due to an enhanced steric strain between the the phenyl ring and the adjacent phosphate group, compared with diene 2.1e with a methyl group. Dienes that have substitutents at other carbon positions were attempted to be synthesized (2.1j-l) because they can potentially be used to construct nitrogen heterocycles with different substitution patterns. The cyclic diene 2.1k was constructed from cyclohexenone with an isolated yield of 72%. Diene 2.1l was formed from pent-1-en-3-one in an inseparable mixture of Z and E isomers (ratio = 4.5:1). The formation of a Z/E mixture of an analogous 1-methyl-2-PPh3OORHTHF70 °C, 16 h2.2e R = C7H15, 80%2.2f R = C3H6OBn, 91%2.2g R = c-propyl, 66%OR2.17 69 trimethylsiloxy-1,3-butadiene in a similar ratio (83:17) was reported by Girard and coworkers in 1974 (Scheme 1.20a, Chapter 1.8.1). 2.4.4 Hetero-Diels-Alder reactions of two 4-substituted 2-diphenylphosphoryloxy-1,3-butadienes and diastereoselectivity studies The reaction of a 4-substituted 2-diphenylphosphoryloxy-1,3-butadiene 2.1b with N-(p-toluenesulfonyl)benzaldimine (2.5a) was conducted and two diastereomers of the product were generated as expected (Scheme 2.8). The 1H NMR spectrum of unpurified reaction mixture after quenching showed a 5:1 ratio of the two diastereomers. The product was purified by silica gel chromatography to give an isolated yield of 52%. The two diastereomers were separated using a gradient solvent system for the silica gel chromatography (15-25% EtOAc in hexanes). Scheme 2.8 The hetero-Diels-Alder reaction of 4-isopropyl-2-diphenylphosphoryloxy-1,3-butadiene OPPhOOOPhNPhHTs FeCl3 (0.2 equiv)DCMrt, 24 hNPhOTsPPhOOOPh2.1b 2.5a 2.18a52%, dr = 5:1 70 Table 2.6 Assignment of carbons and protons on the heterocyclic ring of the major diastereomer of 2.18a and some correlations in 1H-1H COSY entry carbon δ (ppm) 13C-31P Splitting proton δ (ppm) splitting 1 C1 61.3 - Hc 4.55–4.43 m 2 C2 112.8 d (J = 5.6 Hz) Ha 5.98–5.88 m 3 C3 146.6 d (J = 9.2 Hz) - - - 4 C4 30.8 d (J = 4.5 Hz) Hd 3.42–3.28 m 5 C4 30.8 d (J = 4.5 Hz) He 2.47 ddd (J = 16.8, 4.1, 1.4 (1H-31P) Hz) 6 C5 55.7 - Hb 4.67 dd (J = 11.4, 4.0 Hz) Figure 2.8 1H NMR spectra on heterocyclic rings of 2.8a and the major diastereomer of 2.18a NOTsPPhOOOPhHcHbHe HdHa 123 45δ -17.3 ppmHfCOSYCOSYNPhOTsPPhOOOPhHaHe HfHd HcHb2.8aNOTsPPhOOOPhHcPhHbHe HdHa2.18a major 71 Carbons and protons on the heterocyclic ring of the major diastereomer of 2.18a (Table 2.6) were assigned based on the analysis of 2D NMR spectra. The COSY correlations between Ha and Hc, and Hb and Hd/He also supported the formation of the expected regioisomer. Comparing with the parent cycloaddition product 2.8a (Table 2.2), Hb shifted upfield by ~ 0.6 ppm and Hd shifted downfield by ~ 0.6 ppm (Figure 2.8). Figure 2.9 Diagnostic NOE to identify the relative configuration of the major diastereomer of product 2.18a The relative configuration of the major diastereomer was identified by analyzing its Nuclear Overhauser effect spectrum (NOESY) (Figure 2.9). The signal of ortho-protons on the phenyl substituent (Hh) was distinguished by its NOE correlation with Hd/He. The detected NOE correlation between Hh and Hc indicated that the phenyl substituent was likely on the same face with Hc. NOTsPPhOOOPhHcHbHhHe HdNOENOEHa 72 Table 2.7 Assignments of carbons and protons on the heterocyclic ring of the minor diastereomer of 2.18a entry carbon δ (ppm) 13C-31P Splitting proton δ (ppm) splitting 1 C1 60.2 - Hc 4.24–4.10 m 2 C2 112.0 d (J = 5.6 Hz) Ha 5.81 ddd (J = 4.4, 2.2, 2.2 (1H-31P) Hz) 3 C3 143.9 d (J = 9.2 Hz) - - - 4 C4 26.2 d (J = 4.1 Hz) Hd 2.55 d (J = 17.9 Hz) 5 C4 26.2 d (J = 4.1 Hz) He 2.13–1.95 m 6 C5 52.4 - Hb 5.31 d (J = 7.5 Hz) Figure 2.10 1H NMR spectra on heterocyclic rings of 2.8a and the minor diastereomer of 2.18a NOTsPPhOOOPhHcHbHe HdHa 123 45δ -17.2 ppmNPhOTsPPhOOOPhHaHe HfHd HcHb2.8aNOTsPPhOOOPhHcPhHbHe HdHa2.18a minor 73 Assignments of carbons and protons on the heterocyclic ring of the minor diastereomer of 2.18a were presented in Table 2.7. The chemical shifts and splitting patterns of the minor diastereomer resembled those of the cycloaddition product 2.5a (Figure 2.10). The 31P NMR signal of the minor diastereomer shifted downfield by ~ 0.1 ppm compared with the signal of the major diastereomer. There is no obvious difference in signals in 13C NMR spectra of the two diastereomers. The chemical shifts and splitting patterns of signals of the major and minor diastereomers of 2.18a can provide reference to the spectra analysis of other products. Scheme 2.9 The hetero-Diels-Alder reaction of 4-n-heptyl-2-diphenylphosphoryloxy-1,3-butadiene A second 4-substituted 2-diphenylphosphoryloxy-1,3-butadiene was applied to the hetero-Diels-Alder reaction to investigate consistency in diastereoselectivity and NMR signals of the two diastereomers. 4-n-Heptyl-2-diphenylphosphoryloxy-1,3-butadiene (2.1e) was reacted with N-(p-toluenesulfonyl)benzaldimine (2.5a) to give 60% of the product 2.18b and a diastereomeric ratio of 2:1 (Scheme 2.9). OPPhOOOPhNPhHTs FeCl3 (0.2 equiv)DCMrt, 24 hNPhOTsPPhOOOPh2.1e 2.5a 2.18b60%, dr = 2:15 5 74 Table 2.8 Assignments of carbons and protons on the heterocyclic ring of the major diastereomer of 2.18b entry carbon δ (ppm) 13C-31P Splitting proton δ (ppm) splitting 1 C1 61.3 - Hc 4.88–4.78 m 2 C2 112.8 d (J = 5.6 Hz) Ha 5.84–5.75 m 3 C3 146.6 d (J = 9.2 Hz) - - - 4 C4 30.8 d (J = 4.5 Hz) Hd 3.38–3.24 m 5 C4 30.8 d (J = 4.5 Hz) He 2.49 ddd (J = 16.9, 4.0, 1.5 (1H-31P) Hz) 6 C5 55.7 - Hb 4.70 dd (J = 10.9, 4.0 Hz) Table 2.9 Assignment of carbons and protons on the heterocyclic ring of the minor diastereomer of 2.18b entry carbon δ (ppm) 13C-31P Splitting proton δ (ppm) splitting 1 C1 54.1 - Hc 4.57–4.42 m 2 C2 112.9 d (J = 5.5 Hz) Ha 5.59 ddd (J = 4.3, 2.3, 2.3 (1H-31P) Hz) 3 C3 143.6 d (J = 8.4 Hz) - - - 4 C4 26.6 d (J = 3.6 Hz) Hd 2.63 d (J = 17.7 Hz) 5 C4 26.6 d (J = 3.6 Hz) He 2.26–2.10 m 6 C5 52.2 - Hb 5.36 d (J = 7.2 Hz) NOTsPPhOOOPhHcHbHe HdHa 123 45δ -17.4 ppm5NOTsPPhOOOPhHcHbHe HdHa 123 45δ -17.3 ppm5 75 Figure 2.11 The 1H NMR spectrum of heterocyclic rings of both diastereomers of 2.18b The assignments of carbons and protons on the heterocyclic rings of the major and minor diastereomers of 2.18b are presented in Table 2.8 and 2.9, respectively. The chemical shifts and splitting patterns of proton signals for each diastereomer of 2.18b (Figure 2.11) were almost identical to the corresponding diastereomer of 2.18a. The 31P NMR signal of the minor diastereomer of 2.18b was also ~ 0.1 ppm more downfield than the major diastereomer. Thus, we can use this consistency in chemical shifts and splitting patterns in signals of 1H NMR and 31P NMR spectra to assign the major diastereomers of the following cycloaddition products in chapter 2.4.5 without performing 2D NMR analysis. NOTsPPhOOOPhHcHbHe HdHa5NOTsPPhOOOPhHcHbHe HdHa52.18b, major 2.18b, minor 76 Scheme 2.10 Diastereoselective ratios of products 2.18a and 2.18b under different Lewis acids Two different Lewis acids FeCl3 and BF3•OEt2 were applied to the hetero-Diels-Alder reactions of dienes 2.1b and 2.1e to see their impact on the diastereomeric ratios. Each diastereomeric ratio was determined by the integration of Ha of each diastereomer in the 1H NMR spectrum of the crude product mixture. Reversed diastereoselectivity was observed for both products 2.18a and 2.18b when the reaction was promoted by BF3•OEt2 (Scheme 2.10a and b). The mixture of the exo- and endo diasteromers of product 2.18b were subjected to BF3•OEt2 in CH2Cl2 for 16 h and an almost complete conversion of the exo diasteromer to the endo diastereomer was observed (Scheme 2.10c). This result suggested a reversible mechanistic pathway of the reaction under the promotion of BF3•OEt2 and the endo product is formed as the OPPhOOOPhNPhHTs Lewis acidDCMrt, 24 hNPhOTsPPhOOOPh2.1b 2.5a 2.18a(exo)OPPhOOOPhNPhHTs NPhOTsPPhOOOPhC7H152.1e 2.5a 2.18b(exo)C7H15NPhOTsPPhOOOPh2.18a(endo)FeCl3 (0.2 equiv)BF3•OEt2 (1.5 equiv)5 : 11 : 1.5Lewis acidDCMrt, 24 hNPhOTsPPhOOOPhC7H152.18b(endo)FeCl3 (0.2 equiv)BF3•OEt2 (1.5 equiv)2 : 11 : 5a)b)NPhOTsPPhOOOPhC7H152.18b(exo)NPhOTsPPhOOOPhC7H152.18b(endo)DCM, rt, 16 hNPhOTsPPhOOOPhC7H152.18b(exo)NPhOTsPPhOOOPhC7H152.18b(endo)c)exo:endo = 2:1Lewis acidFeCl3 (0.2 equiv)BF3•OEt2 (1.5 equiv)2 : 1< 1 : 20 77 thermodynamically favorable diastereomer. For comparison, resubjection of 2.18b (2:1 mix) to iron chloride for an extended time gave no change to the product ratio. Figure 2.12 Proposed transition states of the cycloaddition processes under the promotion of two different Lewis acids The transition states of the cycloaddition processes under the promotion of these two Lewis acids could give a viable conjecture to the reverse in diastereoselectivity (Figure 2.12). An assumption was made in Figure 2.12 that the N-(p-toluenesulfonyl)benzaldimine (N-tosyl group, 2.5a) and phenyl group in the imine are oriented in a trans-geometry during the reaction. The coordinated iron chloride is in an exo orientation due to steric bulk, and thus the cycloaddition through an exo orientation (iPr vs Ph) is the lower energy transition state. Two observations with boron trifluoride may be made: a) this Lewis acid may be less sterically hindered and can reside in an endo orientation in a transition state that also could have secondary orbital interactions between the diene and the Ph group of the dienophile, and b) the cycloaddition is reversible so the more stable cis-isomer is formed over an extended reaction time. Other mechanistic pathways including stepwise addition/cyclization or radical cyclization induced by electron transfer from iron are also plausible for the formal hetero-Diels-Alder processes that might lead to different explanation for the reverse in diastereoselectivity. It could be an interesting topic to optimize the diastereomeric ratio of this hetero-Diels-Alder reaction. We decided to not study this topic in greater depth because the purpose of this research is for the [P]ONPh TsF3B[P]ONPhTs FeCl3exo orientation endo orientationδ+ δ+ 78 synthesis of pyridines and both diastereomers would be converted into the same compound after oxidation. Scheme 2.11 Diastereoselectivity of a hetero-Diels-Alder reaction of 2-trimethylsiloxy-1,3-diene using different Lewis acids. A similar result of reversed diastereoselectivity of a hetero-Diels-Alder reaction under the promotion of different Lewis acid was reported by Nogue and coworkers in 1992.187 A 2-trimethylsiloxy-1,3-diene derivative (2.19) was reacted with N,1-diphenylmethanimine (2.20) to form the exo product (2.21a) under the promotion of t-butyldimethylsilyl triflate (TfOSitBDM). The endo product (2.21b) was formed as the major diastereomer when AlCl3 was used (Scheme 2.11). 2.4.5 Scope of dienes for the hetero-Diels-Alder reaction The functionalized dienes 2.1 were reacted with imines 2.5/2.15 under the optimized conditions using 20 mol% of FeCl3 (Figure 2.13). OTMSNPhPhLewis acidNOTMSPhPhH NOTMSPhPhHAlCl3 5 : 95TfOSitBDM 54 : 282.19 2.20 2.21a 2.21brtNogue et al. 1992 79 a Reaction condition: 2.5/2.15 (0.2 mmol), 2.1 (0.8 mmol, 1 mL DCM), FeCl3 (0.04 mmol), 1 mL DCM, rt, 24 – 48 h. Isolated yields reported. Diastereomeric ratios determined by integration of specific signals in 1H NMR spectra of the crude product mixture. b Reaction carried as in a using 0.08 mmol of FeCl3. Figure 2.13 Scope of dienes for the hetero-Diels-Alder reactiona When the imine 2.5a was reacted with 4-substituted dienes, the increase in steric strain resulted in lower yields of cycloaddition products 2.18a-c (52 – 60%) compared with the parent product 2.8a. A lower yield of 2.18a than 2.18b and 2.18c was expected because a branched OPPhOOOPhNR5HR4 FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNR5OR4PPhOOOPhR2R1R3R1R3R2NPhOTsPPhOOOPhNPhOTsPPhOOOPhC7H15NPhOPPhOOOPhTsNOPPhOOOPhTsPh(CH2)3OBnOPPhOOOPhNPhTs NPhOCbzPPhOOOPhPh NOPPhOOOPhCbzBrPhNOPPhOOOPhCbzPhClNOTsPPhOOOPhClNPhOSO2PhPPhOOOPhNPhOTsPPhOOOPh2.18a, 52%, dr = 5:131P(major) δ -17.3 ppm31P(minor) δ -17.2 ppm2.18b, 60%, dr = 2:131P(major) δ -17.4 ppm31P(minor) δ -17.3 ppm2.18d, 92%, dr = 2:131P(major) δ -16.7 ppm31P(minor) δ -16.6 ppm2.18c, 60%, dr = 2:131P(major) δ -17.5 ppm31P(minor) δ -17.3 ppm2.18e, 61%, dr = 6:131P(major) δ -17.6 ppm31P(minor) δ -18.3 ppm2.18i, 72%31P δ -16.7 ppm2.18f, 70%, dr > 20:131P δ -17.7 ppm2.18g, 82%, dr > 20:131P δ -17.6 ppm2.18h, 51%b, dr = 6:131P(major) δ -17.6 ppm31P(minor) δ -17.1 ppm2.18k, 71%31P δ -16.7 ppm2.18j, 69%b31P δ -16.6 ppm2.1 2.5, 2.15 2.18NPhOTsPPhOOOPhOMe2.18l, 0%NPhOTsPPhOOOPh2.18m, 0%NPhOTsPPhOOOPh2.18n, 0%Ph 80 isopropyl substituent has a larger steric strain than the linear substituents. Adding carbon-based substituents at C-3 position enhanced reactivities of dienes due to the electron-donating (induction) effect by alkyl groups. Dienes 2.1h and 2.1j effectively reacted with several imines derivatives and give products 2.18d and 2.18i-k in very high yields (69 – 91%). The diene with a phenyl group at C-4 position (2.1c) did not react with N-sulfonyl imines, but effectively reacted with N-carbamoyl imines 2.15 to give products 2.18f-h in good yields (51 – 82%). Compounds 2.18l and 2.18m were not successfully constructed due to low stability of the corresponding dienes. The TLC plates of crude reaction mixtures showed no spot of new products and degradation of dienes. Formation of 2.18n from diene 2.1l was also not observed. The steric strain between the phosphate group and phenyl ring could make the diene non-planar or preferentially adopt a s-trans conformation, thus prohibited the reactivity of the diene in a cycloaddition process. Products from 4-substituted dienes were formed in diastereomeric mixtures and their relative configurations were analyzed by comparing their 1H NMR spectra to the spectral data of 2.18a and 2.18b (chapter 2.4.4). 31P NMR signals of the minor diastereomers of products were always more downfield by less than 1 ppm than the major diastereomer, except for the product 2.18e. The diastereoselective ratios of products 2.18a-h were determined by integration ratios of signals in 1H NMR spectra of unpurified reaction mixtures after quenching. All dienes with un-branched substituents at C-4 position formed cycloaddition products with dr = 2:1 (2.18b-d). The diastereoselective ratio of the product 2.18a with a branched substituent increased to 5:1. Cycloaddition products (2.18f-g) from 4-phenyl-2-diphenylphosphoryloxy-1,3-butadiene (2.1e) had much higher drs than other products. It was suggested that the diastereomeric ratios of the 81 hetero-Diels-Alder reactions was affected by the steric strain of substituents at C-4 position on dienes. 2.4.6 Observation on challenges in expanding the scope of imines A challenge with expanding the scope of hetero-Diels-Alder reactions of 2-diphenylphosphoryloxy-1,3-butadienes was the limited variation in imine derivatives. Even though synthesis of imines was mostly performed by Yiran Wei, I want to provide some observations on problems associated with the imine synthesis. The method of condensation at 130 °C in toluene was suitable for the synthesis of imines from N-sulfonyl amines and some substituted benzaldehydes. Six examples of N-sulfonyl imines were successfully synthesized using this protocol as presented in Figure 2.4. High yield loss due to recrystallization was observed to 2.5c, 2.5e and 2.5f (yields ≤ 50%). Some other aldehyde derivatives were observed to be not soluble in toluene. In some cases, the produced imine became an oily suspension in the solvent system and could not be purified by recrystallization. These problems could be solved by changing the solvent system of condensation and optimizing the purification conditions, but these are not the focus of this project. The two-step protocol successfully afforded four examples of N-carbamoyl imines that were difficult to be synthesized using the condensation method. The effectiveness of this protocol is highly dependent on solubilities of amines, aldehydes, and intermediates in the specific solvent system of each step. Synthesis of N-Boc imine 2.15a was the most efficient, but the yields dropped significantly for N-Cbz imines 2.15b-d, especially those from substituted benzaldehydes. (9H-Fluoren-9-yl)methyl carbamate (Fmoc-NH2) was not applicable to this protocol because it was not soluble in methanol/water with formic acid. Moreover, N-carbamoyl imines were less stable in 82 storage. A 1H NMR spectrum of benzyl benzylidenecarbamate (2.15b) after a week on bench top showed a substantial decrease of the signal at 8.95 ppm and appearance of a signal at 10.01 ppm corresponding to benzaldehyde. The challenge of synthesizing and storing imines needs to be overcome to improve the efficiency of this hetero-Diels-Alder reaction. When we looked at the conditions of imine formations and hetero-Diels-Alder reactions, each step requires implementation of a Lewis acid. It was envisioned that, using a Lewis acid, the dehydration and hetero-Diels-Alder reaction could occur in a one-pot condition. The investigation on this multicomponent hetero-Diels-Alder reaction will be presented in Chapter 3. This is the reason why I didn’t make a greater effort to optimize conditions for the synthesis of imine derivatives. 2.5 Cross-coupling reactions of hetero-Diels-Alder products The enol phosphate functionality in hetero-Diels-Alder products should act as an electrophilic partner in transition metal catalyzed cross-coupling reactions.115 Manipulations of the cycloaddition product 2.8a were performed to install substituents on the heterocyclic ring (Scheme 2.12). 83 Scheme 2.12 Manipulations of the hetero-Diels-Alder product 2.8a A palladium-catalyzed Suzuki-hiyama coupling reaction on 2.8a was attempted using the conditions outlined by Campbell and coworkers in 2004 (Scheme 2.12a).154 Three equivalents of the organometallic reagents were added because the two phenyl rings on the phosphate group could also participate in the cross-coupling reaction. A palladium-catalyzed alkylation with organoalunimum performed well to form 4-methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (2.23) in 66% yield (Scheme 2.12b).157 Kumada coupling reactions on 2.8a were also conducted using various commercially available Grignard reagents.188 A nickel-catalyzed coupling with (trimethylsilyl)methylmagnesium chloride formed an allylsilane 2.24 in 41% yield (Scheme 2.12c). A palladium-catalyzed Kumada coupling reaction of 2.8a with isopropenylmagnesium bromide formed 2.25 in 51% yield (Scheme 2.12d).176 NPh PhTsPh-B(OH)2 (4.0 equiv)Pd(PPh3)4 (5 mol%)Na2CO3 (4.0 equiv)DME/EtOH/H2O (2.5:1:1)90 °C, 16 – 20 h 2.22, 55%NMe PhNOTsPhTsAlMe3 (3.0 equiv)Pd(PPh3)4 (10 mol%)(CH2Cl)2, 80 °C, 4 h2.23, 66%TMS MgClNi(acac)2 (10 mol%)THF, rt, 24 hNPhTs2.24, 41%TMS(3.0 equiv)PPhOOOPh 2.8aa)b)c)PdCl2 (10 mol%)THF, rt, 24 hNPhTs2.25, 51%d)isopropenylMgBr (3.0 equiv) 84 Scheme 2.13 Palladium-catalyzed reduction of hetero-Diels-Alder products. When the Kumada coupling reaction was conducted using isopropylmagnesium bromide, an expected reduction of the enol phosphate functionality was achieved (Scheme 2.13).189 2-Phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (2.26) was formed in 65% yield from the reduction of the cycloaddition product 2.8a with isopropylmagnesium bromide (Scheme 2.13a). The hydride source came from a b-hydride elimination when the isopropyl group was transmetallated to palladium. This reduction of enol phosphate led to a noteworthy protocol when it was applied to the cycloaddition product 2.18i (Scheme 2.13b). This process formed a product 2.27 that is the opposite regioisomer to the Diels-Alder reaction between isoprene and imines (Scheme 2.13c and d).178,179 As a result of the regiocontrol of isoprene and imines, this type of product of 2.27 has rarely been reported in literature before. This protocol provided a potentially useful pathway for the synthesis of cycloadducts with reversed regioselectivity. N Tsi-PrMgBr (3.0 equiv)PdCl2 (10 mol%)THF, rt, 24 h Ph2.27, 54%opposite regioisomer to isoprene + imineHNOTsPhPPhOOOPh 2.18ib)N Tsi-PrMgBr (3.0 equiv)PdCl2 (10 mol%)THF, rt, 24 h Ph2.26, 65%HNOTsPhPPhOOOPh 2.8aa)N Tstoluene, rt, 2 h Ph2.23, 71%c)Wakabayashi et al. 20122.28 2.5a[Co(TPP)]SbF6 (1 mol%)N SCHCl3, 50 °C, 140 h Ph2.30, 68%d)NHPh2.28 2.29catalyst (10 mol%)N TsPh HSO O O OCoNNNNPhPhPhPhSbF6[Co(TPP)]SbF6F3C ArF3C ArOOP ONHTfAr = 2,4,6-(i-Pr)3Phcatalyst for d)Hatanaka et al. 2017 85 2.6 Conclusions Hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadiene and N-(p-toluenesulfonyl)benzaldimine and their derivatives were established under the promotion of either FeCl3 or BF3•OEt2. This type of diene had an advantage of being more stable in storage in preference to analogous siloxy dienes. Eighteen examples of the cycloaddition products were synthesized from various dienes and imines in 30 – 91% isolated yields. The reaction formed only one regioisomer of each cycloaddition product because the enol phosphate group was able to dictate regioselectivity by electron-donating (resonance) effect. Diastereomer mixtures were obtained when 4-substituted dienes were reacted with imines. The diastereomeric ratios ranged from 2:1 to >20:1. The relative configuration of each diastereomer was analyzed by NMR spectroscopy. The enol phosphate functionality of dienes persisted in the cycloaddition products and was synthetically useful as an electrophilic partner in transition metal catalyzed cross-coupling reactions. The cycloaddition products were applied to Suzuki and Kumada coupling reactions to form substituted tetrahydropyridines. 2.7 Experimental General Information The preparation of dienes, hetero-Diels-Alder reactions and Kumada coupling reactions were all performed under nitrogen atmosphere using flame-dried glassware or oven-dried glassware. Tetrahydrofuran (THF) was distilled over sodium metal and benzophenone. Diisopropylamine and dichloromethane were distilled over calcium hydride. All dried solvents were stored over 3 Å 86 molecular sieves. Reagents were used as received from commercial appliers, unless otherwise noted. But-3-en-2-one was purified by distillation before used. Thin layer chromatography (TLC) was performed on aluminum backed plates coated with silica (silica gel 60 F254) and visualized by either ultraviolet light (254 nm) or potassium permanganate. Flash chromatography was performed on silica gel (SiliaFlashâ, F60, 40-63 µm, 60 Å). All synthesized dienes were stored as a 1.0 M solution in distilled DCM in the fridge. Instruments: 1H NMR, 13C NMR{H}, 19F NMR{H} and 31P NMR{H} experiments of products were carried at room temperature using a Bruker Advance III AV 300 Spectrometer and a Bruker Advance 400dir Spectrometer. 1H NMR and 13C{1H} NMR were obtained in reference to chloroform. 19F{1H} NMR were obtained in reference to CFCl3. 31P{1H} NMR were obtained in reference to H3PO4. Spectra analysis was performed using MESTRELAB MestReNova software. Chemical shifts were reported in parts per million (ppm) and coupling constants were reported in Hertz (Hz). Infrared spectroscopy analysis of the products was performed using a PerkinElmer Frontier Transfer-Infrared Spectroscopy (FT-IR). High resolution mass spectra were recorded on Waters/Micromass LCT time-of-flight (TOF) mass spectrometer with electrospray ionization method. Melting points were determined using a MEL-TEMPS II capillary melting point apparatus (lab device USA). Preparation of 4-(benzyloxy)butanal190 Butane-1,4-diol (5.41 g, 60 mmol, 3 equiv) was dissolved in THF (21 mL) and sodium hydride (1.2 g, 30 mmol, 1.5 equiv, 60% in mineral) was added slowly at rt. Benzyl bromide (3.42 g, 20 H OO(COCl)2DMSOHO OHOOH THFrt, 6 hNaHBnBrEt3N-78 °C -> 0 °C, 1 h 87 mmol, 1 equiv) was added dropwise at rt. The reaction mixture was stirred at rt for 6 h. Aqueous ammonium chloride (20 mL, 38 M) was added, and the aqueous layer was extracted with EtOAc (´ 3). The combined organic extracts were washed with brine and dried over sodium sulfate. The extracts were concentrated in vacuo. The resultant oil was purified by column chromatography over silica gel (30% EtOAc/hexanes) to give 3.57 g (99%) of 4-(benzyloxy)butan-1-ol as a colorless oil. Spectroscopy data match a literature report.190 1H NMR (300 MHz, Chloroform-d) δ 7.34 – 7.14 (m, 5H), 4.45 (s, 2H), 3.57 (t, J = 5.9 Hz, 2H), 3.45 (t, J = 5.8 Hz, 2H), 2.17 (d, J = 2.5 Hz, 1H), 1.75 – 1.46 (m, 4H) ppm. Oxalyl chloride (1.02 g, 8 mmol, 1.6 equiv) was dissolved in DCM (15 mL) and cooled to -78 °C. DMSO (1.17 g, 15 mmol, 3 equiv) was added at -78 °C and stirred for 10 min. A solution of 4-(benzyloxy)butan-1-ol (0.90 g, 5 mmol, 1 equiv) in DCM (10 mL) was added to the reaction mixture dropwise over 15 min at -78 °C. The reaction mixture was stirred at -78 °C for 30 min. Triethylamine (2.23 g, 25 mmol, 5 equiv) was added dropwise at -78 °C. The reaction mixture was warmed to rt over a period of 1 h. Aqueous ammonium chloride (20 mL, 38 M) was added, and the aqueous layer was extracted with DCM (´ 3). The combined organic extracts were washed with brine and dried over sodium sulfate. Concentration of extracts in vacuo gave a yellow oil. The crude residue was purified by column chromatography over silica gel (20% EtOAc in hexanes) to give 0.63 g (72%) of 4-(benzyloxy)butanal as a colorless oil. Spectroscopy data match a literature report.190 1H NMR (300 MHz, Chloroform-d) δ 9.78 (t, J = 1.6 Hz, 1H), 7.40 – 7.24 (m, 5H), 4.49 (s, 2H), 3.51 (t, J = 6.1 Hz, 2H), 2.55 (td, J = 7.1, 1.6 Hz, 2H), 2.03 – 1.87 (m, 2H) ppm. 88 Representative procedure for the synthesis of Enones191 (E)-undec-3-en-2-one (2.17b) (Acetylmethylene)triphenyl-phosphorane(1.59 g, 5.0 mmol, 1.0 equiv) was dissolved in THF (10 mL) and heated to 70 °C. Octanal (0.80 g, 6.25 mmol, 1.25 equiv) was added. The reaction mixture was heated at 70 °C for 16 h. The reaction mixture was cooled to rt and concentrated in vacuo to give a yellow oil residue. Hexanes (10 mL) was added and the resultant solids were separated by vacuum filtration. The filtrate was concentrated in vacuo. The resultant oil was purified by column chromatography over silica gel (10% EtOAc/hexanes) to give 0.50 g (60%) of the (E)-undec-3-en-2-one as a colorless oil. 1H NMR (300 MHz, Chloroform-d) δ 6.80 (dt, J = 16.0, 6.9 Hz, 1H), 6.06 (dt, J = 15.9, 1.5Hz, 1H), 2.24 (s, 3H), 1.54 – 1.39 (m, 2H), 1.37 – 1.17 (m, 10H), 0.88 (t, J = 6.9 Hz, 3H) ppm. (E)-7-(benzyloxy)hept-3-en-2-one (2.17c) (E)-7-(Benzyloxy)hept-3-en-2-one was constructed from 4-(benzyloxy)butanal (0.80 g, 2.5 mmol) using the analogous procedure as described for (E)-undec-3-en-2-one. Column condition: 20% EtOAc in hexanes. Yield: 91%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.38 – 7.27 (m, 5H), 6.80 (dt, J = 16.0, 6.9 Hz, 1H), 6.07 (dt, J = 15.9, 1.5 Hz, 1H), 4.50 (s, 2H), 3.50 (t, J = 6.2 Hz, 2H), 2.40 – 2.28 (m, 2H), 2.22 (s, 3H), 1.86 – 1.70 (m, 2H) ppm. PPh3OC7H15HTHF70 °C, 16 hOC7H15OOO 89 (E)-4-Cyclopropylbut-3-en-2-one (2.17d): (E)-4-Cyclopropylbut-3-en-2-one was constructed from cyclopropanecarbaldehyde (1.59 g, 5 mmol) using the analogous procedure as described for (E)-undec-3-en-2-one. Column condition: 10% EtOAc in hexanes. Yield: 66%. Colorless oil. Spectroscopy data match a literature report.192 1H NMR (300 MHz, Chloroform-d) δ 6.34 – 6.11 (m, 2H), 2.18 (s, 3H), 1.65 – 1.47 (m, 1H), 1.04 – 0.90 (m, 2H), 0.73 – 0.51 (m, 2H) ppm. Preparation of 3-phenylbut-3-en-2-one193 2-Phenylacetic acid (1.36 g, 10 mmol, 1 equiv) and acetic anhydride (4.7 mL, 50 mmol, 5 equiv) were placed in a three-neck round bottom flask and purged with N2 using a needle for 5 min. 1-Methylimidazole (0.8 mL, 10 mmol, 1 equiv) was added at rt. The reaction mixture was stirred at rt for 16 h when N2 was continuously purged using a needle. Water (5 mL) was added, and the aqueous layer was extracted with EtOAc (5 mL ´ 3). The combined organic layer was washed with aqueous sodium bicarbonate (5 mL, 1.1 M) and brine, and dried over sodium sulfate. The extracts were concentrated in vacuo and purified by column chromatography over silica gel (10% OCOOH Ac2ONNrt, 16 hONHHCHOAcOHDMF90 °C, 2 hO 90 EtOAc/hexanes) to give 0.63 g (47%) of 1-phenylpropan-2-one as a colorless oil. Spectroscopy data match a literature report.194 1H NMR (300 MHz, Chloroform-d) δ 7.40 – 7.14 (m, 5H), 3.70 (s, 2H), 2.15 (s, 3H) ppm. Formaldehyde (0.75 g, 25 mmol, 5 equiv), 1-phenylpropan-2-one (0.67 g, 5 mmol, 1 equiv), and piperidine (0.06 mL, 0.65 mmol, 0.13 equiv) were dissolved in N,N-dimethylformamide (5 mL). Acetic acid (0.06 mL, 1.1 mmol, 0.22 equiv) was added dropwise at 0 °C. The reaction mixture was heated at 90 °C for 2 h. The reaction mixture was cooled down to rt and diluted with aqueous ammonia chloride (5 mL, 38 M). The aqueous layer was extracted with EtOAc (5 mL ´ 3). The combined organic extracts were washed with brine and dried over sodium sulfate. The extracts were concentrated in vacuo and purified by column chromatography over silica gel (10% EtOAc/hexanes) to give 0.28 g (38%) of 3-phenylbut-3-en-2-one as a light-yellow oil. Spectroscopy data match a literature report.195 1H NMR (300 MHz, Chloroform-d) δ 7.44 – 7.25 (m, 5H), 6.18 (s, 1H), 5.97 (s, 1H), 2.44 (s, 3H) ppm. Representative procedure for the synthesis of 2-diphenylphosphoryloxy-1,3-butadiene152 Buta-1,3-dien-2-yl diphenyl phosphate (2.1a) OLDA THF -78 °C, 30 minb) OP ClPhO OPh-78 °C -> rt, 3 hOPPhOOOPha) 91 Diisopropylamine (3.34 g, 33 mmol, 1.1 equiv) was dissolved in distilled THF (21 mL). The mixture was cooled to -78 °C and 21 mL of nBuLi (33 mmol, 1.1 equiv, 1.6 M in hexane) was added slowly. The solution was stirred at -78 °C for 10 min. But-3-en-2-one (2.10 g, 30 mmol, 1.0 equiv) was added dropwise at -78 °C. The solution was stirred at -78 °C for 30 min. Diphenylphosphoryl chloride (9.67 g, 36 mmol, 1.2 equiv) was added at -78 °C. The mixture was warmed to rt over a period of 3 h. Water (0 °C, 21 mL) was added, and the aqueous layer was extracted using a mixture of 1:1 diethyl ether and hexane (´ 2). The combined organic extracts were washed with brine and dried over sodium sulfate. The extracts were concentrated in vacuo and purified by column chromatography over silica gel (20% EtOAc/hexanes) to give 6.05 g (67%) of buta-1,3-dien-2-yl diphenyl phosphate (2.1a) as a colorless oil. Spectroscopy data match a literature report.152 1H NMR (300 MHz, Chloroform-d) δ 7.40 – 7.17 (m, 10H), 6.19 (ddd, J = 17.0, 10.9, 2.9, 1H), 5.45 (d, J = 17.0 Hz, 1H), 5.22 – 5.19 (m, 1H), 5.18 (d, J = 10.9 Hz, 1H), 4.85 (dd, J = 2.3, 2.3 Hz, 1H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 151.3 (d, J = 8.2 Hz), 150.6 (d, J = 7.4 Hz), 130.7 (d, J = 6.9 Hz), 130.0, 125.7 (d, J = 1.5 Hz), 120.3 (d, J = 5.0 Hz), 117.0, 102.4 (d, J = 3.5 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1590, 1487, 1298, 1184 cm-1. HRMS-ESI (m/z) calcd for C16H16O4P ([M+H]+): 303.0786, found: 303.0782. 92 (E)-5-Methylhexa-1,3-dien-2-yl diphenyl phosphate (2.1b) Diene 2.1b was constructed using an analogous procedure as described for 2.1a from (E)-5-methylhex-3-en-2-one (0.84 g, 7.5 mmol). Column condition: 10-15% EtOAc in hexanes. Yield: 53%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.38 – 7.13 (m, 10H), 5.84 – 5.79 (m, 2H), 5.03 (t, J = 2.2 Hz, 1H), 4.71 (t, J = 2.5 Hz, 1H), 2.36 – 2.18 (m, 1H), 0.92 (d, J = 6.7 Hz, 6H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 151.6 (d, J = 8.4 Hz), 150.7 (d, J = 7.4 Hz), 141.0, 129.9, 125.6 (d, J = 1.4 Hz), 121.1 (d, J = 6.7 Hz), 120.3 (d, J = 4.9 Hz), 99.9 (d, J = 3.5 Hz), 30.8, 22.0 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 2960, 1590, 1489, 1299, 1187cm-1. HRMS-ESI (m/z) calcd for C19H22O4P ([M+H]+): 345.1256, found: 345.1251. (E)-Diphenyl (4-phenylbuta-1,3-dien-2-yl) phosphate (2.1c) Diene 2.1c was constructed using an analogous procedure as described for 2.1a from 4-phenyl-3-butene-2-one (0.66 g, 4.5 mmol, a solution in 3 mL of THF). Column condition: 15% EtOAc in hexanes. Yield: 65%. Light yellow oil. OPPhOOOPhOPPhOOOPh 93 1H NMR (300 MHz, Chloroform-d) δ 7.43 – 7.18 (m, 15H), 6.67 (d, J = 15.8 Hz, 1H), 6.55 (dd, J = 15.8, 2.6 Hz, 1H), 5.26 (t, J = 2.4 Hz, 1H), 4.95 (t, J = 2.5 Hz, 1H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 151.5 (d, J = 8.1 Hz), 150.7 (d, J = 7.5 Hz), 135.9, 131.3, 130.0, 128.8, 128.5, 127.1, 125.8 (d, J = 1.5 Hz), 122.0 (d, J = 6.9 Hz), 120.4 (d, J = 4.9 Hz), 102.3 (d, J = 3.5 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. IR (neat): 1589, 1487, 1258, 1184 cm-1. HRMS-ESI (m/z) calcd for C22H20O4P ([M+H]+): 379.1099, found: 379.1093. (E)-4-methoxybuta-1,3-dien-2-yl diphenyl phosphate (2.1d) Diene 2.1d was constructed using an analogous procedure as described for 2.1a from distilled (E)-4-methoxybut-3-en-2-one (0.70 mL, 7 mmol). Column condition: 25% EtOAc in hexanes. Yield: 51%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.63 – 7.08 (m, 10H), 6.68 (d, J = 12.4 Hz, 1H), 5.36 (dd, J = 12.4, 2.5 Hz, 1H), 4.97 – 4.84 (m, 1H), 4.61 (td, J = 2.5, 0.6 Hz, 1H), 3.56 (s, 3H) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. (E)-Diphenyl undeca-1,3-dien-2-yl phosphate (2.1e) OPPhOOOPhOMeOPPhOOOPhC7H15 94 Diene 2.1e was constructed using an analogous procedure as described for 2.1a from (E)-undec-3-en-2-one (0.50 g, 3 mmol). Column condition: 15% EtOAc in hexanes. Yield: 71%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.42 – 7.14 (m, 10H), 5.91 – 5.83 (m, 2H), 5.03 (t, J = 2.3 Hz, 1H), 4.70 (t, J = 2.5 Hz, 1H), 2.08 – 1.98 (m, 2H), 1.38 – 1.17 (m, 10H), 0.87 (t, J = 6.7 Hz, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 151.4 (d, J = 8.5 Hz), 150.7 (d, J = 7.4 Hz), 134.6, 129.9, 125.6 (d, J = 1.4 Hz), 123.7 (d, J = 6.6 Hz), 120.3 (d, J = 4.9 Hz), 99.7 (d, J = 3.6 Hz), 32.3, 31.9, 29.3, 29.2, 28.9, 22.8, 14.2 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 2927, 1593, 1490, 1268, 1187 cm-1. HRMS-ESI (m/z) calcd for C23H30O4P ([M+H]+): 401.1882, found: 401.1877. (E)-7-(benzyloxy)hepta-1,3-dien-2-yl diphenyl phosphate (2.1f) Diene 2.1f was constructed using an analogous procedure as described for 2.1a from (E)-7-(benzyloxy)hept-3-en-2-one (0.44 g, 2 mmol). Column condition: 20% EtOAc in hexanes. Yield: 69%. Colorless oil. OPPhOOOPhO 95 1H NMR (300 MHz, Chloroform-d) δ 7.57 – 6.89 (m, 15H), 6.15 – 5.65 (m, 2H), 5.05 (t, J = 2.3 Hz, 1H), 4.72 (t, J = 2.5 Hz, 1H), 4.47 (s, 2H), 3.42 (t, J = 6.4 Hz, 2H), 2.28 – 2.04 (m, 2H), 1.65 (p, J = 6.8 Hz, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 151.2 (d, J = 8.3 Hz), 150.6 (d, J = 7.5 Hz), 138.6, 133.6, 129.9, 128.5, 127.7, 127.7, 125.6 (d, J = 1.4 Hz), 124.2 (d, J = 6.6 Hz), 120.3 (d, J = 4.9 Hz), 100.0 (d, J = 3.6 Hz), 73.0, 69.5, 28.9, 28.9 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1590, 1488, 1300, 1186 cm-1. HRMS-ESI (m/z) calcd for C26H27O5PNa ([M+Na]+): 473.1494, found: 473.1493. (E)-4-cyclopropylbuta-1,3-dien-2-yl diphenyl phosphate (2.1g) Diene 2.1g was constructed using an analogous procedure as described for 2.1a from (E)-4-cyclopropylbut-3-en-2-one (0.44 g, 4 mmol). Column condition: 20% EtOAc in hexanes. Yield: 78%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.56 – 6.93 (m, 10H), 5.95 (dd, J = 15.3, 2.8 Hz, 1H), 5.26 (dd, J = 15.3, 9.5 Hz, 1H), 4.99 (t, J = 2.3 Hz, 1H), 4.67 (t, J = 2.5 Hz, 1H), 1.46 – 1.28 (m, 1H), 0.81 – 0.66 (m, 2H), 0.36 – 0.23 (m, 2H) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. OPPhOOOPh 96 3-Methylbuta-1,3-dien-2-yl diphenyl phosphate (2.1h) Diene 2.1h was constructed using an analogous procedure as described for 2.1a from 3-methylbut-3-en-2-one (0.42 g, 5 mmol). Column condition: 15% EtOAc in hexanes. Yield: 68%. Colorless oil. 1H NMR (300 MHz, Chloroform-d) δ 7.49 – 6.91 (m, 10H), 5.36 – 5.29 (m, 1H), 5.23 – 5.16 (m, 1H), 5.06 – 5.00 (m, 1H), 4.95 (t, J = 2.8 Hz, 1H), 1.92 – 1.83 (m, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 153.0 (d, J = 8.4 Hz), 150.6 (d, J = 7.5 Hz), 136.2 (d, J = 6.1 Hz), 129.9, 125.6 (d, J = 1.4 Hz), 120.3 (d, J = 4.9 Hz), 115.6, 99.7 (d, J = 3.5 Hz), 19.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1590, 1487, 1295, 1186 cm-1. HRMS-ESI (m/z) calcd for C17H18O4P ([M+H]+): 317.0943, found: 317.0939. Diphenyl (3-phenylbuta-1,3-dien-2-yl) phosphate (2.1i) Diene 2.1i was constructed using an analogous procedure as described for 2.1a from 3-phenylbut-3-en-2-one (0.26 g, 1.75 mmol). Column condition: 20% EtOAc in hexanes. Yield: 28%. Colorless oil. 1H NMR (300 MHz, Chloroform-d) δ 7.42 – 7.14 (m, 15H), 5.64 – 5.50 (m, 1H), 5.36 – 5.32 (m, 1H), 5.25 – 5.20 (m, 1H), 4.88 – 4.79 (m, 1H) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. OPPhOOOPhOPPhOOOPhPh 97 1-(Cyclohex-1-en-1-yl)vinyl diphenyl phosphate (2.1j) Diene 2.1j was constructed using an analogous procedure as described for 2.1a from 1-acetylcyclohexene (0.51 g, 4 mmol). Column condition: 15% EtOAc in hexanes. Yield: 90%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.39 – 7.15 (m, 10H), 6.10 (td, J = 4.0, 1.9 Hz, 1H), 5.02 (ddd, J = 3.1, 2.2, 0.9 Hz, 1H), 4.82 – 4.77 (m, 1H), 2.16 – 1.97 (m, 4H), 1.70 – 1.47 (m, 4H). 13C NMR (75 MHz, Chloroform-d) δ 153.4 (d, J = 8.7 Hz), 150.7 (d, J = 7.3 Hz), 129.8, 127.7, 125.5 (d, J = 1.3 Hz), 120.3 (d, J = 5.0 Hz), 96.4 (d, J = 3.5 Hz), 25.4, 24.7, 22.4, 21.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 2931, 1590, 1488, 1297, 1186 cm-1. HRMS-ESI (m/z) calcd for C20H22O4P ([M+H]+): 357.1256, found: 357.1252. Cyclohexa-1,5-dien-1-yl diphenyl phosphate (2.1k) Diene 2.1k was constructed using an analogous procedure as described for 2.1a from 2-cyclohexen-1-one (0.19 g, 2 mmol). Column condition: 20% EtOAc in hexanes. Yield: 72%. Light yellow oil. OPPhOOOPhOPPhOOOPh 98 1H NMR (300 MHz, Chloroform-d) δ 7.59 – 6.93 (m, 10H), 5.99 – 5.88 (m, 1H), 5.87 – 5.76 (m, 1H), 5.62 – 5.45 (m, 1H), 2.38 – 2.05 (m, 4H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.6 (d, J = 7.3 Hz), 145.3 (d, J = 8.7 Hz), 130.5, 129.9, 125.5 (d, J = 1.3 Hz), 122.6 (d, J = 5.9 Hz), 120.2 (d, J = 4.9 Hz), 108.9 (d, J = 5.7 Hz), 21.9, 21.5 (d, J = 1.4 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 2939, 1590, 1488, 1298, 1186 cm-1. HRMS-ESI (m/z) calcd for C18H18O4P ([M+H]+): 329.0943, found: 329.0937. Penta-1,3-dien-3-yl diphenyl phosphate (2.1l) Diene 2.1l was constructed using an analogous procedure as described for 2.1a from pent-1-en-3-one (0.3 mL, 3 mmol). Column condition: 20% EtOAc in hexanes. Yield: 20% (Z/E = 4.5:1). Light yellow oil. (E)-disastereomer: 1H NMR (300 MHz, Chloroform-d) δ 7.35 – 7.00 (m, 10H), 6.14 (dd, J = 17.2, 11.1 Hz, 1H), 5.37 (dt, J = 17.2, 0.8 Hz, 1H), 5.26 (dd, J = 7.1, 2.2 Hz, 1H), 5.05 – 4.96 (m, 1H), 1.68 (dd, J = 7.1, 3.0 Hz, 3H) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. (Z)-diastereomer: OPPhOOOPh 99 1H NMR (300 MHz, Chloroform-d) δ 7.39 – 7.00 (m, 10H), 6.41 (ddd, J = 16.9, 11.1, 2.1 Hz, 1H), 5.64 – 5.50 (m, 1H), 5.35 (d, J = 17.0 Hz, 1H), 5.10 (d, J = 11.1 Hz, 1H), 1.62 (dd, J = 8.8, 6.2 Hz, 3H) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.0 ppm. Representative procedure for the synthesis of N-sulfonyl imines180 (E)-N-benzylidene-4-methylbenzenesulfonamide (2.5a) p-Toluenesulfonamide (0.86 g, 5 mmol, 1.0 equiv) and benzaldehyde (0.80 g, 7.5 mmol, 1.5 equiv) were dissolved in toluene (25 mL). Boron trifluoride diethyl etherate (0.071 g, 0.5 mmol, 0.1 equiv) was added at rt. The reaction mixture with heated at 130 °C for 16 h with Dean-Stark Trap. The reaction mixture was cooled down to rt and concentrated under vacuum to give a light yellow solid. The resultant solid was purified by recrystallization in hot EtOAc/hexanes to give 0.12 g (89%) of 2.5a as a white crystal. mp 103 – 105 °C. Spectroscopy data match a literature report.196 1H NMR (300 MHz, Chloroform-d) δ 9.05 (s, 1H), 7.95 – 7.93 (m, 2H), 7.92 – 7.90 (m, 1H), 7.65 – 7.61 (m, 1H), 7.52 – 7.48 (m, 2H), 7.35 (d, J = 6.03 Hz, 2H), 2.45 (s, 3H) ppm. 13C NMR (100 MHz, Chloroform-d) δ 170.2, 144.6, 135.1, 135.0, 132.4, 131.3, 129.8, 129.2, 128.1, 21.7 ppm. H2N TsOPhH PhCH3130 °C, 16 hBF3•OEt2 NPhHTs 100 (E)-N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide (2.5b) Imine 2.5b was constructed using an analogous procedure as described for 2.5a from 4-chlorobenzaldehyde and p-toluenesulfonamide. Yield: 60%. White crystal. mp 167 – 169 °C. Spectroscopy data match a literature report.196 1H NMR (300 MHz, Chloroform-d) δ 8.99 (s, 1H), 7.92 – 7.83 (m, 4H), 7.50 – 7.44 (m, 2H), 7.38 – 7.33 (m, 2H), 2.44 (s, 3H) ppm. (E)-N-(4-nitrobenzylidene)-4-methylbenzenesulfonamide (2.5c) Imine 2.5c was constructed using an analogous procedure as described for 2.5a from 4-nitrobenzaldehyde and p-toluenesulfonamide. Yield: 50%. Light yellow crystal. White crystals. mp 201 – 203 °C. Spectroscopy data match a literature report.196 1H NMR (300 MHz, Acetone-d6) δ 9.25 (s, 1H), 8.44 – 8.30 (m, 4H), 7.93 – 7.87 (m, 2H), 7.52 – 7.46 (m, 2H), 2.46 (s, 3H) ppm. NHSO OClNHSO ONO2 101 (E)-N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide (2.5d) Imine 2.5d was constructed using an analogous procedure as described for 2.5a from p-anisaldehyde and p-toluenesulfonamide. Yield: 85%. White crystal. mp 118 – 120 °C. Spectroscopy data match a literature report.196 1H NMR (300 MHz, Chloroform-d) δ 8.94 (s, 1H), 7.92 – 7.84 (m, 4H), 7.37 – 7.29 (m, 2H), 7.00 – 7.94 (m, 2H), 3.88 (s, 3H), 2.43 (s, 3H) ppm. (E)-N-benzylidenebenzenesulfonamide (2.5e) Imine 2.5e was constructed using an analogous procedure as described for 2.5a from benzaldehyde and benzenesulfonamide. Yield: 40%. White crystal. mp 65 – 71 °C. Spectroscopy data match a literature report.197 1H NMR (300 MHz, Chloroform-d) δ 9.07 (s, 1H), 8.07 – 7.90 (m, 4H), 7.68 – 7.44 (m, 6H) ppm. (E)-N-(4-chlorobenzylidene)benzenesulfonamide (2.5f) NHSO OOMeNHSO ONHSO OCl 102 Imine 2.5f was constructed using an analogous procedure as described for 2.5a from 4-chlorobenzaldehyde and benzenesulfonamide. Yield: 36%. Light yellow crystal. mp 176 – 184 °C. Spectroscopy data match a literature report.198 1H NMR (300 MHz, Chloroform-d) δ 9.02 (s, 1H), 8.04 – 7.82 (m, 4H), 7.70 – 7.42 (m, 5H) ppm. Representative procedure for the synthesis of N-carbamoyl imines186 (E)-N-Benzylidiene-2-phenylacetamide (2.15b) Benzyl carbamate (3.02 g, 20 mmol, 1.0 equiv), benzaldehyde (4.24 g, 40 mmol, 2.0 equiv), benzenesulfinic acid sodium salts (8.21 g, 50 mmol, 2.5 equiv) and formic acid (1.84 g, 40 mmol, 2.0 equiv) were dissolved in a mixture of methanol/water (20 mL/40 mL). The reaction mixture was stirred at rt for 16 h. The precipitates were separated by vacuum filtration and rinsed with diethyl ether to give 3.69 g (48%) of benzyl (phenyl(phenylsulfonyl)methyl)carbamate as a white solid. Benzyl (phenyl(phenylsulfonyl)methyl)carbamate (1.53g, 4 mmol, 1.0 equiv) was dissolved in DCM (63 mL) and mixed with a solution of potassium carbonate in water (12.2 g, 88 mmol, 22 equiv, 1.4 M). The reaction mixture was stirred vigorously at rt for 4 h. The organic layer was concentrated in vacuo to give 0.68 g (71%) of 2.15b as a white solid. Spectroscopy data match a literature report.199 1H NMR (300 MHz, Chloroform-d) δ 8.95 (s, 1H), 7.95 – 7.89 (m, 2H), 7.63 – 7.31 (m, 8H), 5.32 (s, 2H) ppm. H2N CbzOPhHPhSO2NaHCOOHMeOH/H2OHNSO2PhPhCbz K2CO3 (aq)DCM, rt, 4hrt, 16 hNHPhCbz 103 tert-Butyl (E)-Benzylidenecarbamate (2.15a) Imine 2.15a was constructed using an analogous procedure as described for 2.15b from benzaldehyde and t-butyl carbamate. Yield: 78%, 98%. White solid. Spectroscopy data match a literature report.186 1H NMR (300 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.98 – 7.85 (m, 2H), 7.60 – 7.52 (m, 1H), 7.52 – 7.42 (m, 2H), 1.59 (s, 9H) ppm. Benzyl (E)-(4-chlorobenzylidene)carbamate (2.15c) Imine 2.15c was constructed using an analogous procedure as described for 2.15b from 2-bromobenzaldehyde and benzyl carbamate. Yield: 31%, 72%. White solid. 1H NMR (300 MHz, Acetone-d6) δ 8.92 (s, 1H), 8.06 – 7.91 (m, 2H), 7.66 – 7.55 (m, 2H), 7.52 – 7.29 (m, 5H), 5.29 (s, 2H) ppm. Benzyl (E)-(2-bromobenzylidene)carbamate (2.15d) NHOONHOOClNHOOBr 104 Imine 2.15d was constructed using an analogous procedure as described for 2.15b from 2-bromobenzaldehyde and benzyl carbamate. Yield: 21%, 52%. White solid. 1H NMR (300 MHz, Chloroform-d) δ 8.85 (s, 1H), 8.11 (t, J = 1.8 Hz, 1H), 7.81 (dt, J = 7.7, 1.3 Hz, 1H), 7.70 (ddd, J = 8.0, 2.0, 1.1 Hz, 1H), 7.50 – 7.29 (m, 6H), 5.32 (s, 2H) ppm. Representative procedure for the hetero-Diels-Alder reaction Diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (2.8a) Iron(III) chloride (0.0065 g, 0.04 mmol, 0.2 equiv) and (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol, 1.0 equiv) were dissolved in distilled DCM (1 mL) and stirred at rt for 30 min. A solution of buta-1,3-dien-2-yl diphenyl phosphate (0.24 g, 0.8 mmol, 4.0 equiv) in distilled DCM (1 mL) was added to the reaction mixture at rt. The reaction mixture was stirred at rt for 24 – 48 h. The mixture was flushed through a short plug of silica gel (1:1 EtOAc/hexanes). The resultant oil was purified by column chromatography with silica gel (25% EtOAc/hexanes) to give 0.088 g (78%) of 2.8a as a light-yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.75 – 7.66 (m, 2H), 7.41 – 7.11 (m, 17H), 5.54 (dt, J = 4.9, 1.7 Hz, 1H), 5.38 (dd, J = 3.84, 3.75 Hz, 1H), 4.29 – 4.17 (m, 1H), 3.48 – 3.33 (m, 1H), 2.66 – 2.58 (m, 2H), 2.36 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.4 (dd, J = 7.3, 2.4 Hz), 144.8 (d, J = 9.2 Hz), 143.7, 137.9, 137.5, 130.0, 129.9, 128.8, 128.0, 127.3, 127.1, 125.8 (d, J = 1.4 Hz), 120.1 (d, J = 5.1 Hz), 108.6 (d, J = 5.5 Hz), 53.5, 39.6, 29.1 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. OPPhOOOPhNPhHTs FeCl3DCMrt, 24 h - 48 hNPhOTsPPhOOOPh 105 IR (neat): 1591, 1488, 1298, 1185, 1160, 1132, 1091 cm-1. HRMS-ESI (m/z) calcd for C30H29NO6PS ([M+H]+): 562.1453, found: 562.1451. 2-(4-Chlorophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.8b) Heterocycle 2.8b was constructed using an analogous procedure as described for 2.8a from (E)-N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide (0.059 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 62%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.33 – 7.06 (m, 16H), 5.49 – 5.43 (m, 1H), 5.28 (t, J = 4.0 Hz, 1H), 4.24 – 4.10 (m, 1H), 3.40 – 3.26 (m, 1H), 2.56 – 2.48 (m, 2H), 2.31 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.3 (dd, J = 7.4, 3.8 Hz), 144.5 (d, J = 9.0 Hz), 143.8, 137.2, 136.4, 133.9, 130.0, 130.0, 128.9, 128.8, 127.0, 125.8, 120.0 (d, J = 5.0 Hz), 108.7 (d, J = 5.7 Hz), 52.9, 39.5, 29.1 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 1590, 1489, 1301, 1184, 1160, 1133, 1091 cm-1. HRMS-ESI (m/z) calcd for C30H27ClNO6PSNa ([M+Na]+): 618.0883, found: 618.0882. 2-(4-Nitrophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.8c) NOPPhOOOPhTsClNOPPhOOOPhTsNO2 106 Heterocycle 2.8c was constructed using an analogous procedure as described for 2.8a from (E)-N-(4-nitrobenzylidene)-4-methylbenzenesulfonamide (0.061 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 67%. Bright yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 8.14 – 8.06 (m, 2H), 7.74 – 7.67 (m, 2H), 7.60 – 7.52 (m, 2H), 7.40 – 7.10 (m, 12H), 5.56 – 5.49 (m, 1H), 5.44 (t, J = 3.9 Hz, 1H), 4.27 (ddd, J = 18.4, 4.7, 2.7 Hz, 1H), 3.47 – 3.30 (m, 1H), 2.70 – 2.58 (m, 2H), 2.38 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.3 (dd, J = 7.4, 5.4 Hz), 147.6, 145.2, 144.2, 144.2 (d, J = 8.7 Hz), 137.0, 130.1, 130.1, 128.4, 127.0, 126.0, 123.9, 120.0 (dd, J = 4.8, 1.6 Hz), 108.9 (d, J = 5.8 Hz), 53.1, 39.8, 29.0 (d, J = 4.0 Hz), 21.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1594, 1518, 1488, 1342, 1296, 1186, 1160, 1132, 1093 cm-1. HRMS-ESI (m/z) calcd for C30H28N2O8PS ([M+H]+): 607.1304, found: 607.1300. 2-(4-Methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.8d) Heterocycle 2.8d was constructed using an analogous procedure as described for 2.8a from (E)-N-(4-methoxybenzylidene)-4-methylbenzenesulfonamide (0.058 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 30%. Bright yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.74-7.66 (m, 2H), 7.40-7.11 (m, 14H), 6.83 – 6.75 (m, 2H), 5.56 – 5.50 (m, 1H), 5.36 – 5.31 (t, J = 4.0 Hz, 1H), 4.27 – 4.15 (m, 1H), 3.77 (s, 3H), 3.45 – 3.32 (m, 1H), 2.61 – 2.54 (m, 2H), 2.36 (s, 3H) ppm. NOTsPPhOOOPhOMe 107 13C NMR (101 MHz, Chloroform-d) δ 159.3, 150.4 (d, J = 7.4 Hz), 145.0 (d, J = 9.2 Hz), 143.6, 137.6, 130.0, 129.9, 129.9, 128.6, 127.1, 125.8, 120.1 (d, J = 5.0 Hz), 114.0, 108.7 (d, J = 5.5 Hz), 55.4, 53.0, 39.4, 29.3 (d, J = 4.4 Hz), 21.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1590, 1513, 1489, 1301, 1185, 1162, 1133, 1092 cm-1. HRMS-ESI (m/z) calcd for C31H31NO7PS ([M+H]+): 592.1559, found: 592.1553. Diphenyl (2-phenyl-1-(phenylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl) phosphate (2.8e) Heterocycle 2.8e was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidenebenzenesulfonamide (0.049 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 65%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.82 – 7.76 (m, 2H), 7.48 – 7.10 (m, 17H), 5.55 – 5.46 (m, 1H), 5.36 (dd, J = 5.4, 2.8 Hz, 1H), 4.29 – 4.16 (m, 1H), 3.46 – 3.32 (m, 1H), 2.60 – 2.54 (m, 2H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.4 (dd, J = 7.4, 2.3 Hz), 144.8 (d, J = 9.2 Hz), 143.6, 137.9, 137.4, 130.0, 129.9, 128.7, 128.0, 127.2, 127.1, 125.8, 120.1 (d, J = 5.0 Hz), 108.6 (d, J = 5.5 Hz), 55.4, 39.5, 29.1 (d, J = 4.4 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1590, 1488, 1298, 1185, 1161, 1133, 1092 cm-1. HRMS-ESI (m/z) calcd for C29H26NO6PSNa ([M+Na]+): 570.1116, found: 570.1113. NPhOPPhOOOPhSO2Ph 108 2-(4-Chlorophenyl)-1-(phenylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.8f) Heterocycle 2.8f was constructed using an analogous procedure as described for 2.8a from (E)-N-(4-chlorobenzylidene)benzenesulfonamide (0.056 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 51%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.74 – 7.67 (m, 2H), 7.46 – 6.99 (m, 17H), 5.44 – 5.38 (m, 1H), 5.24 (t, J = 4.0 Hz, 1H), 4.22 – 4.05 (m, 1H), 3.37 – 3.21 (m, 1H), 2.51 – 2.40 (m, 2H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.3 (dd, J = 7.3, 4.2 Hz), 144.5 (d, J = 8.9 Hz), 140.2, 136.3, 134.0, 133.0, 130.0, 129.4, 128.9, 128.8, 127.0, 125.9 (t, J = 1.7 Hz), 120.1 (d, J = 5.0 Hz), 108.6 (d, J = 5.8 Hz), 53.0, 39.6, 29.1 (d, J = 4.2 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 1589, 1489, 1300, 1184, 1160, 1134, 1092 cm-1. HRMS-ESI (m/z) calcd for C29H25ClNO6PSNa ([M+Na]+): 604.0726, found: 604.0725. Benzyl 4-((diphenoxyphosphoryl)oxy)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (2.8g) NOPPhOOOPhSO2PhClNOPPhOOOPh PhCbz 109 Heterocycle 2.8g was constructed using an analogous procedure as described for 2.8a from benzaldehyde, benzyl carbamate (0.031 g, 0.2 mmol) and Buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 44%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.38 – 7.15 (m, 20H), 5.79 – 5.59 (m, 1H), 5.57 – 5.48 (m, 1H), 5.28 – 5.08 (m, 2H), 4.51 – 4.31 (m, 1H), 3.48 – 3.18 (m, 1H), 3.02 – 2.84 (m, 1H), 2.76 – 2.61 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.4, 150.5 (d, J = 7.2 Hz), 139.1, 136.5, 130.0, 128.8, 128.7, 128.3, 128.2, 127.7, 126.8, 125.8, 120.2 (d, J = 5.0 Hz), 108.8, 67.8, 51.7, 38.9, 30.3 ppm. 31P NMR (120 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1703, 1591, 1489, 1299, 1188, 1125 cm-1. HRMS-ESI (m/z) calcd for C31H28NO6PNa ([M+Na]+): 564.1552, found: 564.1544. 6-Isopropyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.18a) Heterocycle 2.18a was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol) and (E)-5-methylhexa-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 52% (dr = 5:1). Light yellow oil. Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.42 – 7.05 (m, 17H), 6.99 – 6.93 (m, 2H), 5.98 – 5.88 (m, 1H), 4.67 (dd, J = 11.4, 4.0 Hz, 1H), 4.52 – 4.39 (m, 1H), 3.42 – 3.28 (m, 1H), 2.47 (ddd, J = 16.8, NPhOPPhOOOPhTs 110 4.1, 1.4 Hz, 1H), 2.30 (s, 3H), 2.12 – 1.97 (m, 1H), 1.07 (d, J = 6.6 Hz, 3H), 1.01 (d, J = 6.6 Hz, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.5 (t, J = 7.8 Hz), 146.6 (d, J = 9.2 Hz), 142.4, 139.3, 136.4, 130.0, 129.1, 128.8, 128.0, 127.8, 127.2, 125.7 (d, J = 1.8 Hz), 120.2 (dd, J = 4.9, 2.5 Hz), 112.8 (d, J = 5.6 Hz), 61.3, 55.7, 33.2 (d, J = 1.6 Hz), 30.8 (d, J = 4.5 Hz), 21.5, 21.1, 19.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 2964, 1591, 1490, 1300, 1188, 1159, 1134, 1089 cm-1. HRMS-ESI (m/z) calcd for C33H35NO6PS ([M+H]+): 604.1923, found: 604.1921. Diastereomer B (minor): 1H NMR (300 MHz, Chloroform-d) δ 7.80 – 7.69 (m, 2H), 7.54 – 7.44 (m, 2H), 7.42 – 7.31 (m, 5H), 7.33 – 7.06 (m, 10H), 5.81 (dt, J = 4.4, 2.2 Hz, 1H), 5.31 (d, J = 7.5 Hz, 1H), 4.24 – 4.10 (m, 1H), 2.55 (d, J = 17.9 Hz, 1H), 2.35 (s, 3H), 2.13 – 1.95 (m, 1H), 1.04 (dd, J = 18.9, 6.6 Hz, 1H), 0.78 (d, J = 2.3 Hz, 3H), 0.67 (d, J = 1.7 Hz, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.5 (d, J = 7.2 Hz), 143.9 (d, J = 9.2 Hz), 143.7, 139.1, 137.8, 130.0, 130.0, 128.3, 128.2, 128.0, 127.2, 125.8, 120.1 (dd, J = 5.1, 2.1 Hz), 112.0 (d, J = 5.6 Hz), 60.2, 52.4, 32.5, 26.2 (d, J = 4.1 Hz), 21.6, 21.1, 20.1 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. 6-Heptyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.18b) Heterocycle 2.18b was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol) and (E)-diphenyl undeca-1,3-NOPPhOOOPhTsPhC7H15 111 dien-2-yl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 60% (dr = 2:1). Light yellow oil. Diastereomer A (major): 1H NMR (400 MHz, Chloroform-d) δ 7.42 – 7.08 (m, 17H), 7.01 – 6.94 (m, 2H), 5.84 – 5.75 (m, 1H), 4.88 – 4.78 (m, 1H), 4.70 (dd, J = 10.9, 4.0 Hz, 1H), 3.39 – 3.23 (m, 1H), 2.49 (ddd, J = 16.9, 4.0, 1.5 Hz, 1H), 2.31 (s, 3H), 1.80 – 1.66 (m, 2H), 1.42 – 1.10 (m, 10H), 0.96 – 0.79 (m, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.6 (dd, J = 8.6, 7.6 Hz), 146.3 (d, J = 9.2 Hz), 142.4, 139.5, 136.4, 130.0, 129.0, 128.9, 128.0, 127.8, 127.1, 125.7, 120.3 (d, J = 4.9 Hz), 114.0 (d, J = 5.4 Hz), 55.3, 54.9, 34.8, 31.9, 31.2 (d, J = 4.6 Hz), 29.4, 29.3, 26.6, 22.8, 21.5, 14.2 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. IR (neat): 2926, 1590, 1489, 1301, 1187, 1157, 1133, 1090 cm-1. HRMS-ESI (m/z) calcd for C37H43NO6PS ([M+H]+): 660.2549, found: 660.2544. Diastereomer B (minor): 1H NMR (300 MHz, Chloroform-d) δ 7.79 – 7.69 (m, 2H), 7.53 – 7.43 (m, 2H), 7.41 – 7.10 (m, 15H), 5.59 (dt, J = 4.3, 2.3 Hz, 1H), 5.36 (d, J = 7.2 Hz, 1H), 4.56 – 4.43 (m, 1H), 2.63 (d, J = 17.7 Hz, 1H), 2.35 (s, 3H), 2.26 – 2.10 (m, 1H), 1.35 – 0.74 (m, 15H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.2 Hz), 143.6, 143.5, 139.5, 137.9, 130.0, 130.0, 128.4, 127.9, 127.8, 127.0, 125.8, 120.1 (d, J = 4.9 Hz), 112.9 (d, J = 5.5 Hz), 54.1, 52.2, 35.4, 31.8, 29.2, 29.0, 26.6, 22.7, 21.6, 14.2 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. 112 6-(3-(Benzyloxy)propyl)-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.18c) Heterocycle 2.18c was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol) and (E)-7-(benzyloxy)hepta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 60% (dr = 2:1). Light yellow oil. Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.42 – 7.05 (m, 22H), 7.01 – 6.91 (m, 2H), 5.89 – 5.69 (m, 1H), 4.92 – 4.80 (m, 1H), 4.70 (dd, J = 10.9, 4.0 Hz, 1H), 4.51 (s, 2H), 3.52 (t, J = 5.9 Hz, 2H), 3.39 – 3.21 (m, 1H), 2.55 – 2.41 (m, 1H), 2.30 (s, 3H), 1.93 – 1.67 (m, 4H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.5 (t, J = 6.8 Hz), 146.4 (d, J = 9.3 Hz), 142.5, 139.3, 138.6, 136.3, 130.0, 129.1, 129.0, 128.5, 128.0, 127.8, 127.8, 127.1, 125.7, 120.3 (d, J = 4.9 Hz), 113.7 (d, J = 5.5 Hz), 73.1, 69.7, 55.2, 54.7, 31.6, 31.1 (d, J = 4.6 Hz), 26.8, 21.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.5 ppm. IR (neat): 2923, 1591, 1490, 1301, 1187, 1164, 1132, 1091 cm-1. HRMS-ESI (m/z) calcd for C40H40NO7PSNa ([M+Na]+): 732.2161, found: 732.2160. Diastereomer B (minor): 1H NMR (300 MHz, Chloroform-d) δ 7.77 – 7.68 (m, 2H), 7.51 – 7.43 (m, 2H), 7.40 – 7.13 (m, 18H), 5.59 (dt, J = 4.4, 2.3 Hz, 1H), 5.35 (d, J = 7.2 Hz, 1H), 4.63 – 4.48 (m, 1H), 4.36 (s, 2H), NOPPhOOOPhTsPhOBn 113 3.27 (dt, J = 9.4, 5.9 Hz, 1H), 3.07 (dt, J = 9.5, 6.5 Hz, 1H), 2.62 (d, J = 17.8 Hz, 1H), 2.34 (s, 3H), 2.25 – 2.06 (m, 1H), 1.69 – 1.42 (m, 3H), 1.17 – 0.98 (m, 1H), 0.85 – 0.64 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.2 Hz), 143.8 (d, J = 9.2 Hz), 143.7, 139.4, 138.8, 137.8, 130.0, 128.5, 128.4, 127.9, 127.6, 127.5, 127.0, 125.8, 120.1 (d, J = 5.1 Hz), 112.9 (d, J = 5.7 Hz), 72.7, 69.9, 53.9, 52.2, 32.0, 26.8, 26.5 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. Diphenyl (2-phenyl-1-tosyl-1,2,3,5,6,7,8,8a-octahydroquinolin-4-yl) phosphate (2.18d) Heterocycle 2.18d was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol) and 1-(Cyclohex-1-en-1-yl)vinyl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 92% (dr = 2:1). Light yellow oil. Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.38 – 7.12 (m, 17H), 7.05 (d, J = 8.1 Hz, 2H), 5.00 (dd, J = 7.7, 4.3 Hz, 1H), 4.53 – 4.37 (m, 1H), 3.30 – 3.14 (m, 1H), 2.93 – 2.73 (m, 2H), 2.34 (s, 3H), 1.91 – 1.08 (m, 7H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.6 (t, J = 6.9 Hz), 142.5, 140.1, 137.4, 136.9 (d, J = 8.9 Hz), 130.0, 129.9, 129.2, 128.6, 128.0, 127.6, 126.7, 125.6 (d, J = 4.3 Hz), 120.2 (dd, J = 8.8, 4.9 Hz), 57.2, 56.9, 34.3 (d, J = 1.9 Hz), 32.6, 26.9, 26.5, 25.4, 21.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.7 ppm. IR (neat): 2933, 1590, 1488, 1295, 1187, 1150, 1130, 1091 cm-1. NPhOPPhOOOPhTs 114 HRMS-ESI (m/z) calcd for C34H35NO6PS ([M+H]+): 616.1923, found: 616.1922. Diastereomer B (minor): 1H NMR (300 MHz, Chloroform-d) δ 7.78 – 7.69 (m, 2H), 7.60 – 7.51 (m, 2H), 7.40 – 7.11 (m, 15H), 5.33 (d, J = 6.7 Hz, 1H), 4.29 – 4.16 (m, 1H), 2.82 (d, J = 17.2 Hz, 1H), 2.51 – 2.38 (m, 1H), 2.34 (s, 3H), 1.75 – 1.45 (m, 6H), 0.99 – 0.78 (m, 1H), 0.57 (qd, J = 12.6, 3.7 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.5 (d, J = 6.8 Hz), 143.6, 139.9, 138.0, 135.4 (d, J = 9.0 Hz), 130.1, 130.0, 128.4, 128.2, 127.7, 126.8, 125.7, 123.6 (d, J = 8.1 Hz), 120.1 (d, J = 5.1 Hz), 56.5, 52.6, 34.9, 27.5, 27.1, 25.9, 25.7, 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.6 ppm. Diphenyl (3-phenyl-2-tosyl-2-azabicyclo[2,2,2]oct-5-en-5-yl) phosphate (2.18e) Heterocycle 2.18e was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol) and Cyclohexa-1,5-dien-1-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 56% (dr = 6:1). White solids. mp 131 – 135 °C Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.66 – 7.59 (m, 2H), 7.41 – 7.10 (m, 17H), 5.57 (dt, J = 6.3, 2.2 Hz, 1H), 4.74 (dt, J = 6.0, 2.9 Hz, 1H), 4.62 – 4.58 (m, 1H), 2.74 (p, J = 2.7 Hz, 1H), 2.25 (s, 3H), 1.65 – 1.39 (m, 4H) ppm. OPPhOOOPhNPhTs 115 13C NMR (75 MHz, Chloroform-d) δ 151.7 (d, J = 9.2 Hz), 150.3 (d, J = 7.7 Hz), 143.8, 139.7, 135.3, 130.1, 129.7, 128.4, 128.2, 127.4, 126.5, 125.9, 120.1 (d, J = 5.1 Hz), 112.0 (d, J = 5.8 Hz), 62.7, 51.5, 42.7 (d, J = 4.9 Hz), 29.8, 27.4, 21.6, 16.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.6 ppm. IR (neat): 2925, 1656, 1591, 1489, 1295, 1192, 1151, 1092 cm-1. HRMS-ESI (m/z) calcd for C32H30NO6PSNa ([M+Na]+): 610.1429, found: 610.1429. Benzyl 4-((diphenoxyphosphoryl)oxy)-2,6-diphenyl-3,6-dihydropyridine-1(2H)-carboxylate (2.18f) Heterocycle 2.18f was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidiene-2-phenylacetamide (0.096 g, 0.4 mmol) and (E)-diphenyl (4-phenylbuta-1,3-dien-2-yl) phosphate. Column condition: 20% EtOAc in hexanes. Yield: 70% (dr > 20:1). Light yellow solids. mp 108 – 112 °C. 1H NMR (400 MHz, Chloroform-d) δ 7.29 – 7.03 (m, 19H), 6.91 – 6.83 (m, 4H), 6.72 (d, J = 6.7 Hz, 2H), 5.81 – 5.72 (m, 1H), 5.61 – 5.37 (m, 2H), 4.89 (d, J = 12.3 Hz, 1H), 4.77 (d, J = 12.4 Hz, 1H), 3.20 – 3.10 (m, 1H), 2.61 (dd, J = 16.8, 3.2 Hz, 1H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 156.0, 150.3 (dd, J = 7.5, 2.8 Hz), 143.4 (d, J = 9.4 Hz), 136.1, 129.9, 128.9, 128.6 128.3, 127.9, 127.8, 127.4, 127.3, 126.1, 125.6 (d, J = 5.0 Hz), 120.1 (dd, J = 7.2, 4.9 Hz), 113.5 (d, J = 5.3 Hz), 67.5, 57.8, 55.7, 33.8 (d, J = 4.7 Hz) ppm. NOPPhOOOPhOO 116 31P NMR (121 MHz, Chloroform-d) δ -17.7 ppm. IR (neat): 1700, 1588, 1488, 1298, 1182, 1132 cm-1. HRMS-ESI (m/z) calcd for C37H33NO6P ([M+H]+): 618.2046, found: 618.2043. Benzyl 2-(2-bromophenyl)-4-((diphenoxyphosphoryl)oxy)-6-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (2.18g) Heterocycle 2.18g was constructed using an analogous procedure as described for 2.8a from benzyl (E)-(2-bromobenzylidene)carbamate (0.13 g, 0.4 mmol) and (E)-diphenyl (4-phenylbuta-1,3-dien-2-yl) phosphate. Column condition: 25% EtOAc in hexanes. Yield: 82% (dr > 20:1). Light yellow solids. mp 101 – 104 °C. 1H NMR (300 MHz, Chloroform-d) δ 7.43 – 7.06 (m, 17H), 7.05 – 6.91 (m, 4H), 6.82 (dd, J = 7.4, 2.0 Hz, 2H), 5.96 – 5.78 (m, 1H), 5.73 – 5.56 (m, 1H), 5.54 – 5.38 (m, 1H), 4.98 (d, J = 12.3 Hz, 1H), 4.86 (d, J = 12.3 Hz, 1H), 3.32 – 3.09 (m, 1H), 2.63 (dd, J = 16.8, 3.3 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.8, 150.2 (dd, J = 7.4, 2.4 Hz), 145.0, 143.2 (d, J = 9.2 Hz), 135.8, 130.5, 130.2, 129.9, 129.1, 128.9, 128.4, 128.0, 127.8, 127.5, 126.3, 125.7 (d, J = 3.9 Hz), 124.7, 122.8, 120.0 (t, J = 5.6 Hz), 113.5 (d, J = 5.6 Hz), 67.7, 57.6, 55.2, 33.6 (d, J = 4.7 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.6 ppm. IR (neat): 1705, 1590, 1489, 1298, 1186, 1135 cm-1. NOPPhOOOPhOOBr 117 HRMS-ESI (m/z) calcd for C37H31BrNO6PNa ([M+Na]+): 718.0970, found: 718.0966. Benzyl 2-(4-chlorophenyl)-4-((diphenoxyphosphoryl)oxy)-6-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (2.18h) Heterocycle 2.18h was constructed using an analogous procedure as described for 2.8a from benzyl (E)-(4-chlorobenzylidene)carbamate (0.11 g, 0.4 mmol) and (E)-diphenyl (4-phenylbuta-1,3-dien-2-yl) phosphate. Column condition: 25% EtOAc in hexanes. Yield: 51% (dr = 6:1). Light yellow solids. mp 109 – 114 °C. 1H NMR (300 MHz, Chloroform-d) δ 7.35 – 7.02 (m, 18H), 6.95 – 6.86 (m, 4H), 6.78 – 6.71 (m, 2H), 5.81 (dt, J = 5.2, 2.4 Hz, 1H), 5.63 – 5.52 (m, 1H), 5.48 – 5.34 (m, 1H), 4.91 (d, J = 12.3 Hz, 1H), 4.78 (d, J = 12.3 Hz, 1H), 3.20 – 3.05 (m, 1H), 2.58 (dd, J = 16.7, 3.4 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.9, 150.2 (d, J = 7.5 Hz), 144.1, 143.3 (d, J = 9.0 Hz), 141.0, 135.9, 133.1, 129.9, 129.0, 128.8, 128.4, 128.0, 127.9, 127.5, 127.5, 126.3, 125.7 (d, J = 3.4 Hz), 120.0 (dd, J = 6.8, 5.0 Hz), 113.6 (d, J = 5.7 Hz), 67.7, 57.6, 55.2, 33.7 (d, J = 4.7 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.6 ppm. IR (neat): 1706, 1590, 1490, 1299, 1186, 1136 cm-1. HRMS-ESI (m/z) calcd for C37H31ClNO6PNa ([M+Na]+): 674.1475, found: 674.1472. NOPPhOOOPhOOCl 118 5-Methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.18i) Heterocycle 2.18i was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidene-4-methylbenzenesulfonamide (0.052 g, 0.2 mmol) and 3-methylbuta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 76%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.69 – 7.62 (m, 2H), 7.38 – 7.08 (m, 17H), 5.34 – 5.28 (m, 1H), 4.06 – 3.94 (m, 1H), 3.36 – 3.21 (m, 1H), 2.80 – 2.55 (m, 2H), 2.32 (s, 3H), 1.52 – 1.46 (m, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.5 (dd, J = 7.4, 2.0 Hz), 143.6, 138.5 (d, J = 8.8 Hz), 138.1, 137.4, 129.9, 129.9, 128.7, 127.9, 127.3, 127.0, 125.7 (dd, J = 2.9, 1.3 Hz), 120.1 (dd, J = 5.0, 2.7 Hz), 117.0 (d, J = 8.2 Hz), 54.0, 44.1, 29.0, 21.6, 13.4 (d, J = 1.5 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ –16.7 ppm. IR (neat): 1591, 1489, 1289, 1185, 1160, 1123, 1088 cm-1. HRMS-ESI (m/z) calcd for C31H31NO6PS ([M+H]+): 576.1610, found: 576.1607. 2-(4-Chlorophenyl)-5-methyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.18j) Heterocycle 2.18j was constructed using an analogous procedure as described for 2.8a from (E)-N-(4-chlorobenzylidene)-4-methylbenzenesulfonamide (0.059 g, 0.2 mmol) and 3-methylbuta-NPhOTsPPhOOOPhNOTsPPhOOOPhCl 119 1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 69%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.71 – 7.65 (m, 2H), 7.39 – 7.09 (m, 16H), 5.33 – 5.26 (m, 1H), 4.09 – 3.97 (m, 1H), 3.36 – 3.22 (m, 1H), 2.80 – 2.56 (m, 2H), 2.37 (s, 3H), 1.57 – 1.49 (m, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.4 (dd, J = 7.4, 3.5 Hz), 143.8, 138.2 (d, J = 8.6 Hz), 137.3, 136.6, 133.8, 130.0, 129.9, 128.9, 128.8, 127.0, 125.8, 120.1 (t, J = 5.4 Hz), 117.1 (d, J = 8.2 Hz), 53.5, 44.1, 28.9, 21.6, 13.4 (d, J = 1.2 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ –16.6 ppm. IR (neat): 1590, 1489, 1291, 1184, 1160, 1123, 1088 cm-1. HRMS-ESI (m/z) calcd for C31H30ClNO6PS ([M+H]+): 610.1220, found: 610.1217. 5-Methyl-2-phenyl-1-(phenylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (2.18k) Heterocycle 2.18k was constructed using an analogous procedure as described for 2.8a from (E)-N-benzylidenebenzenesulfonamide (0.049 g, 0.2 mmol) and 3-methylbuta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 71%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.85 – 7.77 (m, 2H), 7.57 – 7.10 (m, 18H), 5.38 – 5.31 (m, 1H), 4.13 – 3.97 (m, 1H), 3.41 – 3.25 (m, 1H), 2.85 – 2.55 (m, 2H), 1.57 – 1.49 (m, 3H) ppm. NPhOSO2PhPPhOOOPh 120 13C NMR (101 MHz, Chloroform-d) δ 150.5 (dd, J = 7.3, 1.9 Hz), 140.4, 138.5 (d, J = 8.6 Hz), 138.0, 132.8, 130.0, 129.3, 128.8, 128.0, 127.3, 127.0, 125.7 (d, J = 2.9 Hz), 120.2 (dd, J = 5.0, 3.1 Hz), 117.0 (d, J = 8.2 Hz), 54.1, 44.2, 29.1, 13.4 (d, J = 1.5 Hz). 31P NMR (121 MHz, Chloroform-d) δ –16.7 ppm. IR (neat): 1590, 1489, 1298, 1187, 1162, 1125, 1089 cm-1. HRMS-ESI (m/z) calcd for C30H29NO6PS ([M+H]+): 562.1453, found: 562.1447. Representative procedure for Suzuki coupling reaction154 2,4-Diphenyl-1-tosyl-1,2,3,6-tetrahydropyridine (2.22) The mixture of diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (2.8a, 0.096 g, 0.17 mmol, 1.0 equiv), phenylboronic acid (0.083 g, 0.68 mmol, 4.0 equiv) and sodium carbonate (0.072 g, 0.68 mmol, 4.0 equiv) in DME(0.85 mL)/EtOH(0.34 mL)/H2O(0.35 mL) were degassed with nitrogen for 30 min. Tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.0085 mmol, 0.05 equiv) was added and the reaction mixture was heated at 90 °C for 16 – 20 h. The mixture was diluted with EtOAc and flushed through a short plug of silica gel. After concentration in vacuo, the resultant oil was purified by column chromatography over silica gel (10% EtOAc/hexanes) to give 0.0358 g (55%) of heterocycle 2.22 as a light-yellow oil. Spectroscopy data match a literature report.177 1H NMR (300 MHz, Chloroform-d) δ 7.78 – 7.69 (m, 2H), 7.45 – 7.29 (m, 12H), 5.94 – 5.87 (m, 1H), 5.46 (d, J = 6.2 Hz, 1H), 4.38 – 4.26 (m, 1H), 3.64 – 3.48 (m, 1H), 2.83 – 2.76 (m, 1H), 2.75 – 2.62 (m, 1H), 2.38 (s, 3H). N TsNOPPhOOOPhTsB(OH)2Pd(PPh3)4Na2CO3DME/EtOH/H2O90 °C, 16 – 20 h 121 13C NMR (75 MHz, Chloroform-d) δ 143.4, 140.5, 139.1, 137.8, 134.4, 129.7, 128.7, 128.6, 127.8, 127.7, 127.5, 127.2, 125.2, 120.3, 53.4, 41.5, 28.7, 21.6 ppm. HRMS-ESI (m/z) calcd for C24H23NO2S ([M+H]+): 412.1347, found: 412.1345. Representative procedure for the cross-coupling alkylation reaction157 4-Methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (2.23) The solution of diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (0.056 g, 0.1 mmol, 1.0 equiv) in 1,2-dichloroethane (1 mL) was degassed with nitrogen for 10 min. Tetrakis(triphenylphosphine)palladium(0) (0.012 g, 0.01 mmol, 0.1 equiv) and trimethylaluminum (0.3 mmol, 3.0 equiv, 2.0 M in toluene) were added at rt. The reaction mixture was heated at 80 °C for 4 h. The reaction mixture was diluted with diethyl ether (1 mL) and washed with 1 M HCl (2 mL). The organic layer was washed with brine and dried over sodium sulfate. The resultant oil after concentration in vacuo was purified by column chromatography over silica gel (15% EtOAc in hexanes) to give 0.022 g (66%) of heterocycle 2.23 as a colorless oil. Spectroscopy data match a literature report.178 1H NMR (300 MHz, Chloroform-d) δ 7.74 – 7.57 (m, 2H), 7.34 – 7.13 (m, 7H), 5.33 – 5.25 (m, 2H), 4.15 – 3.99 (m, 1H), 3.43 – 3.23 (m, 1H), 2.41 (s, 3H), 2.36 – 2.16 (m, 2H), 1.66 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 143.1, 139.6, 137.9, 131.6, 129.6, 128.5, 127.6, 127.4, 127.2, 117.6, 53.3, 41.0, 31.4, 23.4, 21.6 ppm. HRMS-ESI (m/z) calcd for C19H22NO2S ([M+H]+): 328.1371, found: 354.1366. NPhTsNPhOPPhOOOPhTs AlMe3Pd(PPh3)480 °C, 4 h(CH2Cl)2 122 Representative procedure for the Kumada coupling reaction188 2-Phenyl-4-(prop-1-en-2-yl)-1-tosyl-1,2,3,6-tetrahydropyridine (2.25) Diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (0.11 g, 0.2 mmol, 1.0 equiv) was dissolved in distilled THF (2.0 mL). Palladium(II) chloride (0.0036 g, 0.02 mmol, 0.1 equiv) was added. Isopropenylmagnesium bromide (0.6 mmol, 3.0 equiv, 0.5 M in THF) was added in six portions (0.1 mmol for each portion). The addition process was repeated every 1 h over a period of 6 h. The reaction mixture was stirred at rt for 14 – 18 h. The mixture was diluted with EtOAc and flushed through a short plug of silica gel. The resultant oil after concentration in vacuo was purified by column chromatography over silica gel (15% EtOAc in hexanes) to give 0.036 g (51%) of heterocycle 2.25 as a light-yellow oil. 1H NMR δ 7.69 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 10.6 Hz, 7H), 5.75 – 5.60 (m, 1H), 5.38 (d, J = 6.6 Hz, 1H), 4.95 (d, J = 14.5 Hz, 2H), 4.32 – 4.10 (m, 1H), 3.61 – 3.40 (m, 1H), 2.74 (d, J = 17.1 Hz, 1H), 2.49 – 2.42 (m, 1H), 2.40 (s, 3H), 1.85 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 143.3, 142.0, 139.2, 137.7, 134.1, 129.7, 128.5, 127.6, 127.5, 127.2, 120.0, 111.6, 53.2, 41.4, 26.7, 21.6, 20.5 ppm. IR (neat): 1599, 1451, 1344, 1161 cm-1. HRMS-ESI (m/z) calcd for C21H24NO2S ([M+Na]+): 354.1528, found: 354.1523. 2-Phenyl-1-tosyl-4-((trimethylsilyl)methyl)-1,2,3,6-tetrahydropyridine (2.24) NPhTsNPhOPPhOOOPhTsPdCl2THF, rt, 20 – 24 KIsoprenylMgBrNPhTsTMS 123 Heterocycle 2.24 was constructed using an analogous procedure as described for 2.25 from diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (0.056 g, 0.1 mmol), (trimethylsilyl)methylmagnesium chloride (1.0 M in Et2O) and Nickel(II) bis(acetylacetonate) (0.0026 g, 0.01 mmol). Column condition: 20% EtOAc in hexanes. Yield: 41%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.69 (d, J = 8.0 Hz, 2H), 7.48 – 7.04 (m, 7H), 5.41 – 5.22 (m, 1H), 5.14 – 5.04 (m, 1H), 4.23 – 4.02 (m, 1H), 3.54 – 3.34 (m, 1H), 2.51 – 2.30 (m, 4H), 2.28 – 2.09 (m, 1H), 1.56 (d, J = 12.6 Hz, 1H), 1.39 (d, J = 13.8 Hz, 1H), -0.12 (s, 9H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 143.1, 139.8, 138.0, 133.0, 129.7, 128.4, 127.5, 127.1, 115.0, 53.5, 41.4, 32.5, 28.7, 21.6, -1.3 ppm. IR (neat): 1478, 1399, 1162, 1092 cm-1. HRMS-ESI (m/z) calcd for C22H29NO2SSi ([M+Na]+): 422.1586, found: 422.1580. 2-Phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (2.26) Heterocycle 2.26 was constructed using an analogous procedure as described for 2.25 from diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (0.056 g, 0.1 mmol) and isopropylmagnesium chloride (2.0 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 65%. Light yellow oil. Spectroscopy data match a literature report.200 1H NMR (300 MHz, Chloroform-d) δ 7.7 – 7.6 (m, 2H), 7.4 – 7.2 (m, 7H), 5.8 (ddd, J = 10.3, 4.8, 2.4 Hz, 1H), 5.6 (ddd, J = 10.3, 4.3, 2.2 Hz, 1H), 5.3 (dd, J = 5.7, 2.3 Hz, 1H), 4.2 – 4.0 (m, 1H), 3.5 – 3.3 (m, 1H), 2.5 – 2.3 (m, 5H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 143.2, 139.3, 137.9, 129.8, 129.7, 128.5, 127.5, 127.2, 124.1, 123.9, 53.0, 41.0, 26.6, 21.7 ppm. NPhTs 124 HRMS-ESI (m/z) calcd for C18H20NO2S ([M+H]+): 314.1215, found: 314.1212. 5-Methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridine (2.27) Heterocycle 2.27 was constructed using an analogous procedure as described for 2.25 from 5-methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (0.0 g, 0.1 mmol) and isopropylmagnesium chloride (2.0 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 54%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.71 – 7.63 (m, 2H), 7.37 – 7.17 (m, 7H), 5.49 – 5.38 (m, 1H), 5.24 (d, J = 4.7 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.32 – 3.17 (m, 1H), 2.41 (s, 3H), 2.39 – 2.32 (m, 2H), 1.58 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 143.2, 139.5, 137.9, 130.7, 129.6, 128.5, 127.5, 127.1, 118.2, 52.7, 44.4, 26.6, 21.7, 20.6 ppm. IR (neat): 1595, 1472, 1221, 1151 cm-1. HRMS-ESI (m/z) calcd for C19H22NO2S ([M+H]+): 328.1371, found: 328.1365. N Ts 125 Chapter 3: Multicomponent Hetero-Diels-Alder Reactions of Dienes, Aldehydes and Amines 3.1 Introduction Chapter 2 presented a protocol of hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines that was developed to construct functionalized nitrogen heterocycles (Scheme 3.1a). A narrow scope of imines were explored because of difficulties in synthesizing and storing some imine derivatives. In an attempt to expand the imine scope in the protocol, I envisioned a multicomponent process where Lewis acid promoted imine formation in situ would take place with the cycloaddition process with 2-diphenylphosphoryloxy-1,3-butadienes (Scheme 3.1b). Scheme 3.1 An example of the hetero-Diels-Alder reaction in Chapter 2 and the proposed multicomponent hetero-Diels-Alder reactions OPPhOOOPhOR2HNR2OR1PPhOOOPhH2N R1BF3•OEt2 NR1R2BF3OPPhOOOPhNPhHTs FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNPhOTsPPhOOOPh78%Chapter 2Chapter 3a)b)OR2HH2N R1BF3 OR2HBF3H2NR1HOR2HBF3HNR1NR1R2BF3H2ORR 126 A multicomponent reaction is a process in which three or more starting materials form one single product through a series of bimolecular elementary reactions.201 A synthetic usefulness of the multicomponent reaction is to avoid the necessity of isolating and purifying some intermediates. Simple reaction conditions and high atom economy make this method widely applied in natural product and drug-like molecule synthesis.202,203 Scheme 3.2 Multicomponent hetero-Diels-Alder reactions to construct six-membered nitrogen heterocycles Hetero-Diels-Alder reactions in multicomponent processes are well established in literature.204,205 The reactions proceed through cycloadditions between dienes and iminium species BnNH2ŎHClHCHO b)H2ONBn HClrt, 3 hNBn3.7, 99%BnNH2ŎHClHCHOH2O, rt, 70 hN Bn3.9, 59%Larsen et al. 1985N SCHCl3, rt, 70 h3.12, 46%52% eec)3.10 3.11catalyst (10 mol%)O OF3C ArF3C ArOOP ONHTfAr = 2,4,6-(i-Pr)3PhcatalystHatanaka et al. 2017OHPh3.5 3.83.2PhNHCO2EtNHCO2EtBF3•OEt2 N CO2EtPhNPhCO2Et a)F3BMerten et al. 19623.4, 65%3.2 3.33.13.6H2NSO O 127 that are formed in situ from aldehydes and amines, typically under the promotion of Lewis acids or Bronsted acids (Scheme 3.2). The first example of using an iminium species in a multicomponent hetero-Diels-Alder reaction was reported by Merten and coworkers in 1962 (Scheme 3.2a).94 The iminium species (3.1) that was generated from BF3•OEt2 promoted elimination of diethyl (phenylmethylene)dicarbamate (3.2) was reacted with 2,3-dimethyl-1,3-butadiene (3.3) to form the product 3.4 in 65% yield. The first example of Bronsted acid catalyzed multicomponent hetero-Diels-Alder reaction was reported by Larsen and Grieco in 1985 (Scheme 3.2b).96 The iminium salt (3.5) was formed in situ from the reaction between benzylamine hydrochloride (3.6) and formaldehyde in water. The cycloaddition between 3.5 and cyclopentadiene formed a bicyclic product 3.7 in a near quantitative yield within 3 h. When the iminium salt was treated with a less reactive isoprene (3.8), the product 3.9 was formed in 59% yield after 70 h at rt. A recent method of a multicomponent hetero-Diels-Alder reaction was reported by Hatanaka and coworkers in 2017 (Scheme 3.2d).179 Under a chiral catalyst, a mixture of 3-phenylpropanal (3.10), naphthalene-2-sulfonamide (3.11) and 2,3-dimethyl-1,3-butadiene (3.2) was stirred at rt in CHCl3 for 70 h to form a tetrahydropyridine 3.12 in 46% isolated yield and 52% ee. An observation in these examples is a long reaction time, perhaps due to a low rate of iminium formation at rt. The rest of this chapter will be divided into three sections. The first section presents the condition screen of the multicomponent hetero-Diels-Alder reaction. The scope of the multicomponent hetero-Diels-Alder reaction using a variety of aldehydes, dienes and amines will be presented in the second part. Manipulations of a multicomponent hetero-Diels-Alder product will be described in the last section. 128 3.2 Optimization of the multicomponent hetero-Diels-Alder reaction The multicomponent hetero-Diels-Alder reaction was attempted using a 1:1:1 ratio of 2-diphenylphosphoryloxy-1,3-butadiene (2.1a), benzaldehyde and p-toluenesulfonamide (Scheme 3.3a). The solvent, CH2Cl2, was not distilled beforehand as the imine formation generates water. One equivalent of BF3•OEt2 was added to promote the imine formation and cycloaddition reaction. All the reaction components were mixed in a glassware under open air atmosphere. The reaction mixture was stirred at rt for three days, and the product 3.15a was isolated in 29% yield. The structure of the isolated product was confirmed by its 1H NMR and 31P NMR spectra. Scheme 3.3 The multicomponent hetero-Diels-Alder reactions conducted at rt and 40 °C A modest survey of the conditions of the multicomponent hetero-Diels-Alder reactions was performed to optimize the yield (Scheme 3.3b-c). When 3.0 equivalents of diene 2.1a, 1.0 OPPhOOOPhOPhHNPhOTsPPhOOOPhH2N TsBF3•OEt2 (1.0 equiv)rt, 72 hDCM3.15a, 29%3.13 (1.0 equiv) 3.14 (1.0 equiv)2.1a (1.0 equiv)OPPhOOOPhOPhHNPhOTsPPhOOOPhH2N TsBF3•OEt2 (1.5 equiv)rt, 72 hDCM3.15a, 38%3.13 (1.0 equiv) 3.14 (1.5 equiv)2.1a (3.0 equiv)a)b)OPhHNPhOTsPPhOOOPhH2N Tsa) BF3•OEt2 (1.5 equiv)DCM, 2 hb)OPPhOOOPhDCM, 14 h3.11 (1.0 equiv)3.12 (1.5 equiv)2.1a (3.0 equiv)3.15a, 65%OPPhOOOPhOPhHNPhOTsPPhOOOPhH2N TsBF3•OEt2 (1.5 equiv)40 °C, 24 hDCM3.15a, 55%3.11 (1.0 equiv) 3.12 (1.5 equiv)2.1a (3.0 equiv)c)OPhOPPhOOOPh3.16a, (16%)OPhOPPhOOOPh3.16a, (15%)d) 129 equivalent of p-toluenesulfonamide (3.13), 1.5 equivalents of benzaldehyde and 1.5 equivalents of BF3•OEt2 were used in the reaction, the product was formed in a slightly higher yield (38%, Scheme 3.3b). The long reaction time may be attributed to the low rate of N-(p-toluenesulfonyl)benzaldimine (2.13a) formation at rt. The same imine was synthesized by heating p-toluenesulfonamide and benzaldehyde at 130 °C in toluene (chapter 2.4.1). The multicomponent hetero-Diels-Alder reaction was then conducted at 40 °C, and 55% of the product was isolated after 24 h (Scheme 3.3c). When a mixture of p-toluenesulfonamide (1.0 equiv), benzaldehyde (1.5 equiv) and BF3•OEt2 (1.5 equiv) was stirred at 40 °C for 2 h before addition of the diene, the yield was increased to 65% (Scheme 3.3d). Figure 3.1 The hetero-Diels-Alder product between diene 2.1a and benzaldehyde A side product (3.16a) was formed in a cycloaddition process between diene 2.1a and benzaldehyde when the multicomponent hetero-Diels-Alder reaction was conducted at 40 °C (Scheme 3.3c and d). This side product was detected on 1H NMR spectra by a signal of Ha’ at 5.82-5.54 ppm and a signal of Hb’ at 4.53 ppm (dd, J = 10.1, 3.7 Hz, Figure 3.1). It also had a diagnostic 31P NMR signal at -17.1 ppm. The integration ratios of signals of Hb’ in the 1H NMR spectra of unpurified reaction mixtures were used to calculate the conversions of this product with respect to in internal NMR standard 1,3,5-trimethoxybenzene (TMB, 6.10 ppm). OPhOPPhOOOPhHa’δ 5.82-5.74 (m)3.16a31P δ -17.1 ppmLCMS [M+Na]+ = 431.0Hb’ δ 4.53 (dd, J = 10.1, 3.7 Hz) 130 Table 3.1 Screening of solvents for the multicomponent hetero-Diels-Alder reactiona entry solvent A temp of a) (°C) solvent B temp of b) (°C) conversion by NMR (%)b 1 acetonitrile 60 DCM 40 <10 2 methanol 40 DCM 40 <10 3 THF 40 THF 40 <10 4 toluene 110 DCM 40 <10 5 chloroform 60 chloroform 40 45 6 chloroform 60 DCM 40 50 7 DCM 40 DCM 40 65 a reaction condition: 3.13 (0.2 mmol), 3.14 (0.3 mmol) in solvent B (0.5 mL), 2.1a (1 M solution in solvent A). b conversions determined by integration ratios of Ha (5.57-5.50 ppm) of 3.15a and the internal standard TMB (6.10 ppm) in 1H NMR spectra of crude reaction mixture after quenching. A solvent screen was performed to the multicomponent hetero-Diels-Alder reaction (Table 3.1). The reactions only worked well in chloroform and CH2Cl2 (entry 5-7). Other Lewis acids were also applied in this multicomponent hetero-Diels-Alder reaction but no increase in product yields was observed. For example, using 20 mol% of Sc(OTf)3 and FeCl3 gave 11% and 32% conversions to the product, respectively. Dehydrating reagents were then assessed for their ability to promote the imine formation step. However, utilizing 3 Å molecular sieves or sodium sulfate under the conditions of entry 7 in Table 3.1 decreased the yields to 35 – 40%. Presumably, the multicomponent hetero-Diels-Alder reaction worked less efficiently if it is conducted in a heterogenous reaction mixture. OPhHNPhOTsPPhOOOPhH2N Tsa) BF3•OEt2 (1.5 equiv)solvent A, 2 hb)OPPhOOOPhsolvent B, 14 h3.13 (1.0 equiv)3.14 (1.5 equiv)2.1a (3.0 equiv)3.15a 131 A significant advantage of this one-pot imine formation/hetero-Diels-Alder reaction was the ease of execution compared to the hetero-Diels-Alder reaction described in Chapter 2. The reaction was performed in an open flask without the use of inert atmosphere or distilled solvent. All the reagents were transferred into the reaction vessel either as a solid or via syringe and stirred as a homogeneous mixture. The in-situ generation of imines from aldehydes and amines in the presence of a Lewis acid circumvented the problems associated with their isolation and purification. It was expected that a wider variety of aldehydes and amines would be applicable in the scope of this reaction. 3.3 Substrate scope for the multicomponent hetero-Diels-Alder reaction 3.3.1 Aldehyde scope for the multicomponent hetero-Diels-Alder reaction With the optimized conditions for the multicomponent hetero-Diels-Alder reaction in hand, a substrate screen was performed using a variety of aldehydes, dienes, and amines. The scopes of aromatic aldehydes and aliphatic aldehydes are presented in Figure 3.2 and Figure 3.3, respectively. 132 a Reaction condition: p-toluenesulfonamide (0.2 mmol), aldehyde (0.3 mmol), 2.1a (0.6 mmol, 0.6 mL CH2Cl2), BF3•OEt2 (0.3 mmol), CH2Cl2 (0.5 mL), 40 °C, 16 h. Isolated yields reported. b Reaction carried as in a using 0.2 mmol of aldehyde and BF3•OEt2. Figure 3.2 Scope of aromatic aldehydes for the multicomponent hetero-Diels-Alder reactiona Several para-substituted aromatic aldehydes with electron donating groups (-OMe) and electron withdrawing groups (-Cl, -CN, and -CO2Me) were chosen to be attempted in the multi-component hetero-Diels-Alder reactions. All substituents were compatible in the reaction conditions. Products 3.15b-3.15d were isolated in 40 – 56% yields. A general trend was observed that aldehydes with electron withdrawing groups reacted more effectively than aldehydes with electron donating groups, but with less significant difference compared to the hetero-Diels-Alder reactions in Chapter 2 (Figure 2.6). Aromatic aldehydes with different substituent patterns like 2-bromobenzaldehyde, 2,5-difluorobenzaldehyde and 3-methoxybenzaldehyde were also applied in the reactions to form products 3.15f-3.15h in 45 – 54% isolated yields. Cinnamaldehyde has both aldehyde and alkene functionalities, so there may be a competition between either the alkene or NOTsPPhOOOPhFFNOTsPPhOOOPhCO2MeNOPPhOOOPhTsCNNOPPhOOOPhTsBrNOTsPPhOOOPhOMeNOPPhOOOPhTsNOTsPPhOOOPhClNOTsPPhOOOPhOMeNPhOTsPPhOOOPh3.15a, 65% 3.15b, 56% 3.15c, 40%3.15g, 51%3.15e, 55%3.15d, 42% (48%b) 3.15f, 53%3.15h, 45% 3.15i, 51%b 2.1a, (3-4 equiv)H2N-Ts (1 equiv)aldehyde (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOTsROPPhOOOPhPPhOOOPharomatic aldehyde3.15 133 iminium species acting as the dienophile. Formation of the desired product 3.15i in 51% yield suggested a higher rate of the hetero-Diels-Alder process of diene 2.1a with the iminium species than a 4p+2p Diels-Alder process with the alkene. Figure 3.3 Side products 3.16d and 3.16i in hetero-Diels-Alder reactions and their diagnostic NMR signals A surprisingly low yield of 3.15d (42%) from 4-cyanobenzaldehyde was obtained compared with other products from electron-deficient aromatic aldehydes. An analysis on the 1H NMR spectrum of unpurified reaction mixtures found that the side product pyran (3.16d, Figure 3.3) was formed in a conversion of 20%. The pyran side product coeluted with the desired product 3.15d on silica gel chromatography. A small amount of product was lost in isolation because the coeluted portion was not collected. A modification on conditions of the reaction was made using 1.0 equivalent of 4-cyanobenzaldehyde to minimize the formation of the compound 3.16d. The side product (3.16i) of diene 2.1a reacting with the alkene functional group in cinnamaldehyde was formed in a 17% conversion (Figure 3.3). The side product also coeluted with the desired product 3.15i on silica gel chromatography. The same modification of conditions using 1.0 equivalent of cinnamaldehyde was made. OOPPhOOOPhHa’δ 5.76-5.66 (m)3.16d31P δ -17.1 ppmLCMS [M+Na]+ = 456.1CNPhOPPhOOOPhHa’δ 5.76-5.65 (m)3.16i31P δ -17.3 ppmLCMS [M+Na]+ = 457.0HOδ 9.46 (d)Hb’δ 4.62-4.50 (m)Hb’δ 3.27 (ddd, J = 9.7, 8.4, 6.4 Hz) 134 Scheme 3.4 Overall yields of 3.15a-c using the experimental techniques from chapter 2. Cycloadducts 3.15a-c were also constructed for the purpose of comparing the yields of the multicomponent hetero-Diels-Alder reactions with the experimental techniques in Chapter 2 (Scheme 3.4). The overall yield of 3.15a from the two-step protocol of imine formation and hetero-Diels-Alder reaction was calculated to be 69% (Scheme 3.4a), that is close to the isolated yield from the multicomponent hetero-Diels-Alder reaction (65%). Nevertheless, the multicomponent hetero-Diels-Alder reaction was completed in a shorter reaction time of 16 h. Products 3.15b and 3.15c were both obtained in much higher yields from the multicomponent hetero-Diels-Alder reactions (56% and 40%, respectively, Figure 3.2) than the two-step methods (37% and 26%, respectively, Scheme 3.4b and c). H2N TsOPhH PhCH3130 °C, 16 hBF3OEt2 NHPhTs89%FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNPhOTsPPhOOOPhOPPhOOOPh (4 equiv)2.8a/3.15a, 78% overall 69%a)H2N TsOH PhCH3130 °C, 16 hBF3OEt2 NHTs60%FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNOTsPPhOOOPhOPPhOOOPh (4 equiv)2.8b/3.15b, 62% overall 37%b)Cl Cl ClH2N TsOH PhCH3130 °C, 16 hBF3OEt2 NHTs85%FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNOTsPPhOOOPhOPPhOOOPh (4 equiv)2.8d/3.15c, 30% overall 26%c)OMe MeO OMeChapter 2 135 a Reaction condition: p-toluenesulfonamide (0.2 mmol), aldehyde (0.3 mmol), 2.1a (0.6 mmol, 0.6 mL DCM), BF3•OEt2 (0.3 mmol), DCM (0.5 mL), 40 °C, 16 h. Isolated yields reported. b reaction was carried as in a using chloroacetaldehyde dimethyl acetal. Figure 3.4 Scope of aliphatic aldehydes for the multicomponent hetero-Diels-Alder reactiona Aliphatic aldehydes are interesting substrates (Figure 3.4), as competitive aldol condensation processes could be expected to occur due to tautomerization of aliphatic imines to enamines. It is reasonable to choose branched aliphatic aldehydes like isobutyraldehyde, cyclohexanecarbaldehyde and cyclopropanecarbaldehyde because they are less likely to undergo aldol condensation reactions. The cycloaddition products 3.15j-l were successfully obtained in 50%, 64% and 55% isolated yields, respectively. Sterically hindered aliphatic aldehydes like isovaleraldehyde also reacted smoothly with diene 2.1a to form 3.15m in 57% isolated yield. The reaction of a linear aliphatic aldehyde like hexanal unsurprisingly formed the product 3.15n in a lower yield of 33%. The in-situ generation of an iminium species was also expected to occur from an acetal starting material that is more bench stable than an aldehyde. Product 3.15o was successfully synthesized from chloroacetaldehyde dimethyl acetal in 62% isolated yield. In comparison to the hetero-Diels-Alder process described in Chapter 2, the construction of 2.1a, (3-4 equiv)H2N-Ts (1 equiv)aldehyde (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOTsROPPhOOOPhPPhOOOPh3.15NOTsPPhOOOPhNOPPhOOOPhTsNOPPhOOOPhTsNOTsPPhOOOPhClNOPPhOOOPhTs3.15j, 50%3.15m, 57%3.15k, 64% 3.15l, 55%3.15o, 62%bNC5H11OTsPPhOOOPh3.15n, 33%aliphatic aldehyde 136 cycloaddition products from aliphatic aldehydes is a significant improvement in the substrate scope. An aliphatic imine is typically not isolable or not stable in storage due to tautomerization.185,206 a Reaction condition: p-toluenesulfonamide (0.2 mmol), aldehyde (0.3 mmol), 2.1a (0.6 mmol, 0.6 mL DCM), BF3•OEt2 (0.3 mmol), DCM (0.5 mL), 40 °C, 16 h. Isolated yields reported. Yields in parathesis are conversions determined by integration of Ha of products and the internal standard TMB in 1H NMR spectra of unpurified reaction mixtures after quenching. b reaction was carried as in a using 2-(dimethoxymethyl)pyridine. Figure 3.5 Unsuccessful aldehyde substrates in the multicomponent hetero-Diels-Alder reactionsa Scheme 3.5 Synthesis and application of 2-(dimethoxymethyl)pyridine in hetero-Diels-Alder reaction Limitation of the multicomponent hetero-Diels-Alder process was reflected by the unsuccessful formation of cycloaddition products 3.15p and 3.15q from aldehydes with NOTsPPhOOOPhFFFFFNCO2EtOTsPPhOOOPh3.15u, 0%NOTsPPhOOOPh3.15p, 0%O3.15t, (24%)NOTsPPhOOOPh3.15q, 0% (8%b)NNOTsPPhOOOPh3.15s, (12%)OHunsuccessful substrateNOTsPPhOOOPhSNO23.15r, (32%) 2.1a, (3-4 equiv)H2N-Ts (1 equiv)aldehyde (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOTsROPPhOOOPhPPhOOOPh3.15NOp-TsOH•H2OMeOH70 °C, 16 hNOOH80%H2N-Ts (1 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOTsOPPhOOOPhPPhOOOPh(3 equiv)N3.15q, (8%) 137 heterocycles (Figure 3.5). A plausible reason was that the heteroatoms on aldehydes could interact with the Lewis acid. A dimethyl acetal of aldehyde might be a more effective substrate for the hetero-Diels-Alder reaction. 2-(Dimethoxymethyl)pyridine was synthesized by heating 2-pyridinecarboxaldehyde with p-toluenesulfonic acid in methanol at 70 °C for 16 h (Scheme 3.5).207 When 2-(dimethoxymethyl)pyridine was applied in the multicomponent hetero-Diels-Alder reaction, the conversion of the product 3.15q was only raised slightly to 8% based on the 1H NMR spectrum of the quenched reaction mixture. Cycloaddition product 3.15r was successfully formed in the multicomponent hetero-Diels-Alder reaction because of a weaker competitive binding between the sulfur-heterocycle and the Lewis acid. However, this product degraded to a dark viscous oil after stored for a week on the bench top. The reaction was also not compatible with 4-hydroxybenzaldehyde and aldehydes with very strong electron withdrawing groups (Figure 3.5). It was later found that protected 4-hydroxylbenzaldehyde was applicable to the multicomponent hetero-Diels-Alder reactions. Some substrates will be shown in Chapter 4. Aldehydes with very strong electron withdrawing groups such as pentafluorobenzaldehyde and ethyl glyoxalate reacted with diene 2.1a to form pyrans as the major products (3.16t and 3.16u, Figure 3.6). Figure 3.6 Side products 3.16t and 3.16u in hetero-Diels-Alder reactions and their diagnostic NMR signals OOPPhOOOPhHa’δ 5.75-5.67 (m)3.16t31P δ -17.3 ppmLCMS [M+Na]+ = 520.9FFFFOCO2EtOPPhOOOPhHa’δ 5.69-5.62 (m)3.16u31P δ -17.0 ppmLCMS [M+Na]+ = 427.1Hb’Fδ 4.88 (dd, J = 10.8, 3.6 Hz)Hb’δ 5.62-5.55 (m) 138 3.3.2 Diene scope for the multicomponent hetero-Diels-Alder reaction The scope of dienes for the multicomponent hetero-Diels-Alder reaction is presented in Figure 3.7. a Reaction condition: p-toluenesulfonamide (0.2 mmol), benzaldehyde (0.3 mmol), 2.1 (0.6 mmol, 0.6 mL DCM), BF3•OEt2 (0.3 mmol), DCM (0.5 mL), 40 °C, 16 h. Isolated yields reported. Diastereomeric ratios determined by integration ratios of signals in 1H NMR spectra of the unpurified product mixtures after quenching. Figure 3.7 Scope of dienes for the multicomponent hetero-Diels-Alder reactiona Most of the dienes from chapter 2.4.3 participated smoothly in the reactions, affording cycloaddition products 3.17a-3.17e in 29 – 88% isolated yields. The lower yield of 3.17c compared to 3.17a and 3.17b was expected because of the increase in steric strain of a branched substituent at C-4 position of the diene. Dienes with alkyl groups at C-3 positions formed the cycloaddition products in very high yields (88% of 3.17d and 72% of 3.17e). The cyclic diene did not react in this multicomponent hetero-Diels-Alder process to form the bicyclic product 3.17f, presumably due to the high steric strain of substituents at both the C-1 and C-4 positions of the diene. NPhOTsPPhOOOPhNPhOTsPPhOOOPhNPhOPPhOOOPhTsNOPPhOOOPhTsPhOBnNPhOTsPPhOOOPhC7H153.17c, 29%, dr = 3:13.17a, 55%, dr = 8:13.17e, 72%3.17d, 88%, dr = 1.2:13.17b, 57%, dr > 20:1 2.1 (3-4 equiv)H2N-Ts (1 equiv)PhCHO (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOTsPhOPPhOOOPhPPhOOOPhR1R2R1R2OPPhOOOPhNPhTs3.17f, 0%3.17 139 The relative configuration of each major diastereomer in Figure 3.7 was assigned according to the analysis on chemical shifts and splitting patterns of NMR signals of two diastereomer mixtures in Chapter 2.4.4. Each of the major diastereomers of products 3.17a-c was formed from an endo orientation of the phenyl group in the transition state. The endo-favored stereocontrol under the promotion of BF3•OEt2 is consistent with the results of diastereoselectivity studies in chapter 2.4.4. One exception was the cycloadduct 3.17d that was formed in a 1.2:1 ratio of the exo- and endo products. 3.3.3 Amine scope for the multicomponent hetero-Diels-Alder reaction The multicomponent hetero-Diels-Alder reactions were tolerant of a variety of amines to form cycloaddition products 3.18a-n (Figure 3.8). 140 a Reaction condition: amine (0.2 mmol), aldehyde (0.3 mmol), 2.1 (0.6 mmol, 0.6 mL DCM), BF3•OEt2 (0.3 mmol), DCM (0.5 mL), 40 °C, 16 h. Isolated yields reported. b reaction carried as in a using 1 mL DCM. c Fmoc-NH2 (1.0 mmol), benzaldehyde (1.5 mmol), BF3•OEt2 (1.5 mmol), 2.1a (2.0 mmol, 2.0 mL DCM), DCM (8 mL). Figure 3.8 Scope of amines for the multicomponent hetero-Diels-Alder reactions N-Sulfonyl and N-carbamoyl amines were attempted in the reactions because these two types of substituents were widely used in multicomponent hetero-Diels-Alder reactions in literature (Scheme 3.2). In the reactions with diene 2.1a, two examples of N-sulfonyl amines successfully afforded nitrogen heterocycles featuring phenylsulfonamide and methanesulfonamide (3.18a-c) in 54 – 59% isolated yields. Three examples of carbamates including ethyl carbamate, benzyl carbamate (Cbz-NH2) and (9H-fluoren-9-yl)methyl carbamate (Fmoc-NH2) were applied NPhOMsPPhOOOPhNPhOCbzPPhOOOPhNOCbzPPhOOOPhClNPhOMsPPhOOOPhNPhOFmocPPhOOOPhNPhOCO2EtPPhOOOPhNPhOCbzPPhOOOPhNOCbzPPhOOOPhNOFmocPPhOOOPhNPhOPPhOOOPhSO2PhNPhOFmocPPhOOOPh3.18a, 59% 3.18c, 54%3.18i, 68%b (60%c)3.18d, 50% 3.18e, 41%3.18h, 55%3.18k, 51%b3.18g, 51%3.18b, 58%3.18f, 60%3.18j, 86%b 2.1 (3-4 equiv)H2N-R2 (1 equiv)aldehyde (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOR2R3OPPhOOOPhPPhOOOPhR1 R1NPhOPPhOOOPhPhO3.18l, 0% 3.18m, 0%NPhOPhPPhOOOPh3.18n, 0%NPhOPPhOOOPh3.18sulfonamidecarbamateunsuccessful substrate 141 to the multicomponent hetero-Diels-Alder reactions to form products 3.18d-3.18k in 41 – 68% yields. The formation of N-carbamoyl substituted cycloaddition products is a significant improvement in the scope of multicomponent hetero-Diels-Alder reactions because a) carbamoyl protecting groups are typically removed under milder conditions than sulfonyl groups,185 and b) (9H-fluoren-9-yl)methyl (E)-benzylidenecarbamate (N-Fmoc imine) cannot be synthesized using either the condensation method due to rapid hydrolysis of the imine or the two-step addition/elimination method due to a low solubility of 9-fluorenylmethyl carbamate (Fmoc-NH2) in methanol, as discussed in Chapter 2.4.1. The product 3.18i is a significantly useful substrate for further manipulations due to ease of deprotection of the Fmoc protecting group. It can be removed by a weak base like piperidine.208 Due to a lack of an efficient method for the synthesis of N-Fmoc imines, cycloaddition products in the type of 3.18i were rarely reported in literature. A multicomponent hetero-Diels-Alder reaction of N-Fmoc amine, benzaldehyde, and diene 2.1a was conducted at a larger scale (1.0 mmol), and 0.38 g of the product 3.18i was isolated (60%). Applications of benzamide, aniline and butylamine were not successful in the multicomponent hetero-Diels-Alder reactions (3.18l-n). Benzamide and aniline might be less reactive in the imine formation process because the lone pairs on nitrogen are delocalized into the adjacent carbonyl or arene moiety via resonance.206,209 An alkyl amine could be more reactive in the process of nucleophilic addition to aldehydes, but the electron-donating (induction) effect of an alkyl group hindered the subsequent hetero-Diels-Alder process. In general, this multicomponent hetero-Diels-Alder process favored amines with functional groups that are nucleophilic enough for the initial of imine formation yet electron-withdrawing enough for the 142 cycloaddition at the same time. N-Sulfonyl amines and N-carbonyl amines are most suitable for these two requirements. 3.4 The scope of 2-diethylphosphoryloxy-1,3-butadiene in multicomponent hetero-Diels-Alder reactions Another diene derivative, 2-diethylphosphoryloxy-1,3-butadiene, that is analogous to diene 2.1a is also accessible from methyl vinyl ketone and can be potentially applied in a multicomponent hetero-Diels-Alder reaction. It would be interesting to compare the reactivities of these two dienes. Scheme 3.6 Synthesis of 2-diethylphosphoryloxy-1,3-butadiene 2-Diethylphosphoryloxy-1,3-butadiene (3.19) was synthesized using the same conditions as for 2.1a by treating methyl vinyl ketone (3.20) with LDA and diethylphosphoryl chloride (3.21, Scheme 3.6). The diene 3.19 can be synthesized on a 2-gram scale and conveniently stored as a 1.0 M solution in CH2Cl2 at 5 °C for several months without degradation. It has a signal at -6.4 ppm in its 31P NMR spectrum that is more downfield than the signal of diene 2.1a (-17.3 ppm). O OPEtOOOEt3.20 3.19, 66%i-Pr2NHnBuLi THF -78 °C, 30 minb) OP ClEtO OEt-78 °C -> rt, 3 ha)3.21δ -6.4 ppm 143 Scheme 3.7 Multicomponent hetero-Diels-Alder reactions of diene 3.19 Figure 3.9 Diagnostic signals in 1H and 31P NMR spectra of the hetero-Diels-Alder products 3.22-3.24 2-Diethylphosphoryloxy-1,3-butadiene (3.19) was reacted with two representative amines, p-toluenesulfonamide and (9H-fluoren-9-yl)methyl carbamate, in the multicomponent hetero-Diels-Alder reactions (Scheme 3.7). When diene 3.19 was treated with p-toluenesulfonamide, the product 3.22 was only isolated in 36% yield (Scheme 3.7a). A 1H NMR spectrum of quenched reaction mixture found a 2:1 ratio of the product 3.22 and the side product pyran 3.23. This ratio is higher than that of the multicomponent hetero-Diels-Alder reactions of diene 2.1a (~ 4:1, OPEtOOOEtNPhOTsPEtOOOEt 3.22, 36% ratio = 2:1 3.233.19 (3 equiv)OPhOPEtOOOEtOPEtOOOEtNPhOFmocPEtOOOEt3.19 (3 equiv)OPhOPEtOOOEt 3.24, 64% ratio = 10:0.6 3.23a)b)H2N-Ts (1 equiv)PhCHO (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hH2N-Fmoc (1 equiv)PhCHO (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNPhOTsPEtOOOEtNPhOFmocPEtOOOEtOPhOPEtOOOEt3.2231P δ -6.5 ppm3.2431P δ -6.2 ppm3.2331P δ -6.3 ppmHaHbHaHbHaHbδ 5.36 (ddd, J = 4.9, 1.7, 1.7 Hz)δ 5.31 (dd, J = 4.1, 4.1 Hz)δ 5.55 (ddd, J = 4.2, 2.1, 2.1 Hz)δ 4.55 (dd, J = 10.0, 3.8 Hz)δ 5.47 (m)δ 5.39 (m) 144 Chapter 3.2). The reaction of diene 3.19 with 9-fluorenylmethyl carbamate (Fmoc-NH2) gave a much higher yield of the product 3.24 (64%) and a much lower ratio of the side product 3.23 (10:0.6, Scheme 3.7b). Signals in 1H NMR spectra that were utilized to calculate ratios of 3.22, 3.23 and 3.24 as well as their diagnostic signals in 31P NMR spectra are presented in Figure 3.9. Scheme 3.8 Comparing the reactivities of diene 2.1a and 3.19 in the multicomponent hetero-Diels-Alder reactions with Fmoc-NH2 A competitive multicomponent hetero-Diels-Alder reaction was set up to evaluate the relative reactivities of diene 2.1a and 3.19 (Scheme 3.8). The mixture of 9-fluorenylmethyl carbamate (Fmoc-NH2, 1 equiv), benzaldehyde (1.5 equiv) and BF3•OEt2 (1.5 equiv) was stirred at rt in 1 mL of CH2Cl2 then heated to 40 °C. Solutions of diene 2.1a (1.5 equiv, 1 M in CH2Cl2) and diene 3.19 (1.5 equiv, 1 M in CH2Cl2) were added together into the reaction mixture. After quenching the reaction with aqueous sodium bicarbonate, the products were isolated by silica gel chromatography using a gradient solvent condition of 30 – 50% EtOAc in hexanes. The cycloaddition products 3.18i and 3.24 were isolated in 19% and 53% yields, respectively. Diene 3.19 reacted in the multicomponent hetero-Diels-Alder reaction with Fmoc-NH2 at a higher rate than diene 2.2a. Nevertheless, when the two dienes were separately reacted in the multicomponent Diels-Alder reactions, the yields of products were similar (68% for 3.18i, Figure 3.8, and 65% for 3.24, Scheme 3.7b), presumably because that the reaction mixtures were stirred for long enough time. OPPhOOOPhOPEtOOOEt2.1a (1.5 equiv) 3.19 (1.5 equiv)H2N-Fmoc (1 equiv)PhCHO (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNPhOFmocPPhOOOPhNPhOFmocPEtOOOEt3.18i, 19% 3.24, 53% 145 2-Diethylphosphoryloxy-1,3-butadiene was successfully applied to the multicomponent hetero-Diels-Alder reaction especially with 9-fluorenylmethyl carbamate (Fmoc-NH2). Even though there was no significant increase in the isolated yield of the product, the enol diethylphosphate functionality makes the product a potentially useful substrate in transition metal catalyzed cross-coupling reactions, to be discussed in Chapter 4. 3.5 Manipulation of a multicomponent hetero-Diels-Alder product The successful formation of the cycloaddition product 3.18i enabled further manipulations due to facile deprotection of the Fmoc group (Scheme 3.9). Compound 3.18i was treated with 1.2 equivalents of piperidine in N,N-dimethylformamide (DMF) to achieve a complete deprotection of the Fmoc group in two hours at rt. A subsequent addition of benzyl bromide to the reaction mixture afforded the SN2 product 3.25a in 80% yield. Product 3.25b was generated from allyl bromide in 78% yield. Derivatization of the cycloaddition product 3.18i to form 3.25a and 3.25b alleviated the challenges of applying aliphatic amines in the multicomponent Diels-Alder reactions (Figure 3.8). This reaction also demonstrated that the enol phosphate functional group was stable in a weakly basic reaction condition in non-distilled solvent system. Scheme 3.9 Deprotection and alkylation of 3.18i. a) piperidine (1.2 equiv)DMF, rt, 2 hb) R-Br (2.0 equiv)rt, 16 – 20 h3.25a, R = Bn, 80%3.25b, R = allyl, 78%NPhOFmocPPhOOOPh3.18iNPhORPPhOOOPh 146 3.6 Conclusions A protocol of multicomponent hetero-Diels-Alder reactions of 2-phenylphosphoryloxy-1,3-dienes, aldehydes, and amine derivatives under the promotion of BF3•OEt2 were established for the construction of functionalized nitrogen heterocycles. The reaction conditions have the advantage of ease of set-up in open-air and non-distilled solvents. The one-pot condition obviated the challenging isolation and purification of unstable imines intermediates, thus expanded the scope of aldehydes and amines applicable to the reactions. The significant improvement of the substrate scope in this protocol was reflected by the successful generation of more diverse and functionally complex cycloaddition products. Formation of a N-Fmoc substituted cycloaddition product was synthetically significant due to ease of deprotection of a Fmoc group compared to N-sulfonyl protecting groups. The cycloaddition products from N-Fmoc amines could potentially be manipulated in cross-coupling reactions on enol phosphate functionality and subsequent deprotection of the Fmoc group and oxidation of the heterocycles to synthesize substituted pyridines. This protocol allowed access to synthetically complex substituted pyridine motifs, derived from the corresponding dienes and aldehydes. An investigation on this protocol will be presented in chapter 4. 3.7 Experimental General information: Refer to Experimental in Chapter 2. The multicomponent hetero-Diels-Alder reactions were conducted in non-distilled DCM. 147 Preparation of (9H-fluoren-9-yl)methyl carbamate210 A 30% aqueous solution of ammonia in excess (8 mL) was cooled to 0 °C. (9H-fluoren-9-yl)methyl chloroformate (1.03 g, 4 mmol) was dissolved in DCM (3 mL) and added dropwise to aqueous ammonia at 0 °C. The reaction mixture was warmed up to rt over a period of 20 min. The precipitates were separated by vacuum filtration and rinsed with ice-cold water to give 0.90 g (95%) of (9H-fluoren-9-yl)methyl carbamate as a white solid. mp 191 – 194 °C. Spectroscopy data match a literature report.208 1H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J = 7.5 Hz, 2H), 7.60 (d, J = 7.4 Hz, 2H), 7.41 (t, J = 7.3 Hz, 2H), 7.32 (td, J = 7.4, 1.2 Hz, 2H), 4.65 (br s, 2H), 4.42 (d, J = 7.0 Hz, 2H), 4.24 (t, J = 6.9 Hz, 1H) ppm. Preparation of Buta-1,3-dien-2-yl diethyl phosphate (3.19)152 Diisopropylamine (1.11 g, 10 mmol, 1.1 equiv) was dissolved in distilled THF (7 mL). The mixture was cooled to -78 °C and 6.9 mL of nBuLi (11 mmol, 1.1 equiv, 1.6 M in hexane) was added slowly. The solution was stirred at -78 °C for 10 min. But-3-en-2-one (0.70 g, 10 mmol, 1.0 equiv) was added dropwise at -78 °C. The solution was stirred at -78 °C for 15 min. Diethylphosphoryl NH4OH0 °C -> rtH2N OOCl OOOLDA THF -78 °C, 30 minb) OP ClEtO OEt-78 °C -> rt, 3 hOPEtOOOEta) 148 chloride (2.07 g, 12 mmol, 1.2 equiv) was added at -78 °C. The mixture was warmed to rt over a period of 3 h. Water (0 °C, 10 mL) was added, and the aqueous layer was extracted with diethyl ether (´ 2). The combined organic extracts were washed with brine and dried over sodium sulfate. The extracts were concentrated in vacuo and purified by column chromatography over silica gel (30% EtOAc/hexanes) to give 1.2 g (66%) of buta-1,3-dien-2-yl diethyl phosphate (3.19) as a colorless oil. Spectroscopy data match a literature report.152 1H NMR (300 MHz, Chloroform-d) δ 6.16 (ddd, J = 17.0, 10.8, 2.8 Hz, 1H), 5.55 (dd, J = 17.0, 1.2 Hz, 1H), 5.24 – 5.13 (m, 1H), 5.11 – 5.01 (m, 1H), 4.72 (t, J = 2.3 Hz, 1H), 4.24 – 4.08 (m, 4H), 1.33 (td, J = 7.1, 1.1 Hz, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 151.3 (d, J = 7.7 Hz), 131.4 (d, J = 6.9 Hz), 116.1, 101.4 (d, J = 3.4 Hz), 64.5 (d, J = 6.0 Hz), 16.2 (d, J = 6.8 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -6.4 ppm. IR (neat): 1593, 1266, 1027 cm-1. HRMS-ESI (m/z) calcd for C8H16O4P ([M+H]+): 207.0786, found: 207.0783. Representative procedure for the multicomponent hetero-Diels-Alder reaction Diphenyl (2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (3.15a) Benzaldehyde (0.032 g, 0.3 mmol, 1.5 equiv), p-toluenesulfonamide (0.034 g, 0.2 mmol, 1.0 equiv) and boron trifluoride diethyl etherate (0.043 g, 0.3 mmol, 1.5 equiv) were dissolved in DCM (0.5 OPhHNPhOTsPPhOOOPhH2N Tsb)OPPhOOOPh40°C, 14 hBF3•OEt2DCM40 °C, 2 ha) 149 mL). The reaction mixture was heated at 40 °C for 2 h. A solution of buta-1,3-dien-2-yl diphenyl phosphate (0.18 g, 0.6 mmol, 3.0 equiv) in DCM (0.6 mL) was added. The reaction mixture was heated at 40 °C for 14 h. A solution of aqueous sodium bicarbonate (1 mL, 1.1 M) was added, and the aqueous layer was extracted with EtOAc (´ 3). The combined organic layer was washed with brine and dried over sodium sulfate. The crude products were purified by column chromatography over silica gel (30% EtOAc/hexanes) to give 0.073 g (65%) of heterocycle 3.15a as a light-yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.75 – 7.66 (m, 2H), 7.41 – 7.11 (m, 17H), 5.57 – 5.50 (m, 1H), 5.38 (dd, J = 3.84, 3.75 Hz, 1H), 4.29 – 4.17 (m, 1H), 3.48 – 3.33 (m, 1H), 2.66 – 2.58 (m, 2H), 2.36 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.4 (dd, J = 7.3, 2.4 Hz), 144.8 (d, J = 9.2 Hz), 143.7, 137.9, 137.5, 130.0, 129.9, 128.8, 128.0, 127.3, 127.1, 125.8 (d, J = 1.4 Hz), 120.1 (d, J = 5.1 Hz), 108.6 (d, J = 5.5 Hz), 53.5, 39.6, 29.1 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1591, 1488, 1298, 1185, 1160, 1132, 1091 cm-1. HRMS-ESI (m/z) calcd for C30H29NO6PS ([M+H]+): 562.1453, found: 562.1451. 2-(4-Chlorophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15b) Heterocycle 3.15b was constructed using an analogous procedure as described for 3.15a from 4-chlorobenzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 56%. Light yellow oil. NOPPhOOOPhTsCl 150 1H NMR (300 MHz, Chloroform-d) δ 7.66 – 7.60 (m, 2H), 7.33 – 7.06 (m, 16H), 5.49 – 5.43 (m, 1H), 5.28 (t, J = 4.0 Hz, 1H), 4.24 – 4.10 (m, 1H), 3.40 – 3.26 (m, 1H), 2.56 – 2.48 (m, 2H), 2.31 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.3 (dd, J = 7.4, 3.8 Hz), 144.5 (d, J = 9.0 Hz), 143.8, 137.2, 136.4, 133.9, 130.0, 130.0, 128.9, 128.8, 127.0, 125.8, 120.0 (d, J = 5.0 Hz), 108.7 (d, J = 5.7 Hz), 52.9, 39.5, 29.1 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 1590, 1489, 1301, 1184, 1160, 1133, 1091 cm-1. HRMS-ESI (m/z) calcd for C30H27ClNO6PSNa ([M+Na]+): 618.0883, found: 618.0882. 2-(4-Methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15c) Heterocycle 3.15c was constructed using an analogous procedure as described for 3.15a from 4-methoxybenzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 40% EtOAc in hexanes. Yield: 40%. Bright yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.74-7.66 (m, 2H), 7.40-7.11 (m, 14H), 6.83 – 6.75 (m, 2H), 5.56 – 5.50 (m, 1H), 5.36 – 5.31 (t, J = 4.0 Hz, 1H), 4.27 – 4.15 (m, 1H), 3.77 (s, 3H), 3.45 – 3.32 (m, 1H), 2.61 – 2.54 (m, 2H), 2.36 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 159.3, 150.4 (d, J = 7.4 Hz), 145.0 (d, J = 9.2 Hz), 143.6, 137.6, 130.0, 129.9, 129.9, 128.6, 127.1, 125.8, 120.1 (d, J = 5.0 Hz), 114.0, 108.7 (d, J = 5.5 Hz), 55.4, 53.0, 39.4, 29.3 (d, J = 4.4 Hz), 21.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. NOTsPPhOOOPhOMe 151 IR (neat): 1590, 1513, 1489, 1301, 1185, 1162, 1133, 1092 cm-1. HRMS-ESI (m/z) calcd for C31H31NO7PS ([M+H]+): 592.1559, found: 592.1553. 2-(4-Cyanophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15d) Heterocycle 3.15d was constructed using an analogous procedure as described for 3.15a from 4-cyanobenzaldehyde (0.026, 0.2 mmol), p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 48%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.74 – 7.66 (m, 2H), 7.60 – 7.45 (m, 4H), 7.39 – 7.30 (m, 4H), 7.30 – 7.10 (m, 8H), 5.56 – 5.48 (m, 1H), 5.40 (t, J = 4.0 Hz, 1H), 4.33 – 4.19 (m, 1H), 3.46 – 3.26 (m, 1H), 2.67 – 2.49 (m, 2H), 2.39 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.3 (dd, J = 7.2, 4.0 Hz), 144.2 (d, J = 9.0 Hz), 144.1, 143.3, 137.0, 132.6, 130.1, 128.2, 127.1, 126.0, 120.0 (d, J = 4.9 Hz), 118.6, 112.0, 108.9 (d, J = 5.9 Hz), 53.2, 39.7, 29.8, 28.8 (d, J = 3.8 Hz), 21.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. IR (neat): 2230, 1590, 1489, 1300, 1187, 1162, 1136, 1093 cm-1. HRMS-ESI (m/z) calcd for C31H28N2O6PSNa ([M+H]+): 587.1406, found: 587.1408. NOPPhOOOPhTsCN 152 Methyl 4-(4-((diphenoxyphosphoryl)oxy)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) benzoate (3.15e) Heterocycle 3.15e was constructed using an analogous procedure as described for 3.15a from methyl 4-formylbenzoate, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 55%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.97 – 7.91 (m, 2H), 7.73 – 7.66 (m, 2H), 7.45 – 7.12 (m, 14H), 5.55 – 5.48 (m, 1H), 5.41 (t, J = 4.1 Hz, 1H), 4.33 – 4.17 (m, 1H), 3.91 (s, 3H), 3.45 – 3.32 (m, 1H), 2.66 – 2.57 (m, 2H), 2.37 (s, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 166.8, 150.4 (dd, J = 7.4, 3.0 Hz), 144.5 (d, J = 9.0 Hz), 143.9, 143.0, 137.3, 130.1, 130.1, 130.0, 129.9, 127.4, 127.1, 125.9, 120.1 (d, J = 4.9 Hz), 108.7 (d, J = 5.6 Hz), 53.3, 52.3, 39.7, 29.1 (d, J = 4.3 Hz), 21.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1721, 1591, 1489, 1282, 1187, 1163, 1136, 1093 cm-1. HRMS-ESI (m/z) calcd for C32H31NO8PS ([M+H]+): 620.1508, found: 620.1503. 2-(2-Bromophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15f) NOTsPPhOOOPhCO2MeNOPPhOOOPhTsBr 153 Heterocycle 3.15f was constructed using an analogous procedure as described for 3.15a from 2-bromobenzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 53%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.67 – 7.58 (m, 2H), 7.57 – 7.48 (m, 1H), 7.39 – 6.98 (m, 15H), 5.78 (dd, J = 7.5, 1.5 Hz, 1H), 5.74 – 5.68 (m, 1H), 4.30 – 4.14 (m, 1H), 3.82 – 3.66 (m, 1H), 2.98 – 2.82 (m, 1H), 2.52 – 2.38 (m, 1H), 2.34 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (dd, J = 7.5, 3.3 Hz), 144.5 (d, J = 9.2 Hz), 143.7, 139.0, 136.3, 133.6, 130.0 (d, J = 2.2 Hz), 129.6, 129.4, 128.0, 127.6, 127.5, 125.8, 123.8, 120.1 (t, J = 4.9 Hz), 108.1 (d, J = 5.2 Hz), 54.0, 41.4, 31.9 (d, J = 4.7 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. IR (neat): 1592, 1490, 1293, 1187, 1162, 1139, 1026 cm-1. HRMS-ESI (m/z) calcd for C30H28BrNO6PS ([M+H]+): 640.0558, found: 640.0555. 2-(2,5-Difluorophenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15g) Heterocycle 3.15g was constructed using an analogous procedure as described for 3.15a from 2,5-difluorobenzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 51%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.70 – 7.62 (m, 2H), 7.39 – 7.28 (m, 4H), 7.25 – 7.11 (m, 8H), 7.06 – 6.85 (m, 3H), 5.73 – 5.62 (m, 2H), 4.35 – 4.19 (m, 1H), 3.67 – 3.51 (m, 1H), 2.90 – 2.74 (m, 1H), 2.49 – 2.41 (m, 1H), 2.36 (s, 3H) ppm. NOPPhOOOPhTsFF 154 13C NMR (101 MHz, Chloroform-d) δ 158.6 (dd, J = 242.8, 2.3 Hz), 156.1 (dd, J = 244.9, 2.6 Hz), 150.3 (dd, J = 7.4, 4.5 Hz), 144.5 (d, J = 9.1 Hz), 143.9, 136.5, 130.0, 129.8, 128.1 (dd, J = 15.4, 7.2 Hz), 127.3, 125.9, 120.1 (dd, J = 5.0, 2.8 Hz), 117.0 (dd, J = 25.2, 8.6 Hz), 116.2 (dd, J = 24.0, 8.8 Hz), 114.8 (dd, J = 25.3, 3.5 Hz), 108.3 (d, J = 5.4 Hz), 47.9 (d, J = 2.6 Hz), 40.4, 31.0 (d, J = 3.7 Hz), 21.6 ppm. 19F NMR (282 MHz, Chloroform-d) δ -118.1 (d, J = 17.7 Hz), -121.0 (d, J = 17.5 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1592, 1491, 1301, 1187, 1163, 1143, 1092 cm-1. HRMS-ESI (m/z) calcd for C30H27F2NO6PS ([M+H]+): 598.1265, found: 598.1263. 2-(3-Methoxyphenyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15h) Heterocycle 3.15h was constructed using an analogous procedure as described for 3.15a from m-anisaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 43%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 – 7.65 (m, 2H), 7.40 – 7.11 (m, 13H), 6.97 – 6.89 (m, 2H), 6.83 – 6.75 (m, 1H), 5.59 – 5.45 (m, 1H), 5.35 (t, J = 4.1 Hz, 1H), 4.33 – 4.16 (m, 1H), 3.73 (s, 3H), 3.52 – 3.37 (m, 1H), 2.66 – 2.52 (m, 2H), 2.36 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 160.0, 150.4 (d, J = 7.4 Hz), 144.9 (d, J = 9.2 Hz), 143.7, 139.6, 137.5, 130.0, 129.9, 129.7, 127.1, 125.8, 120.1 (d, J = 4.9 Hz), 119.4, 113.7, 112.9, 108.6 (d, J = 5.7 Hz), 55.3, 53.5, 39.7, 29.3 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. NOTsPPhOOOPhOMe 155 31P NMR (121 MHz, Chloroform-d) δ -16.9 ppm. IR (neat): 2921, 1589, 1489, 1297, 1160, 1133, 1092 cm-1. IR (neat): 1589, 1489, 1297, 1186, 1160, 1133, 1092 cm-1. HRMS-ESI (m/z) calcd for C31H30NO7PSNa ([M+Na]+): 614.1378, found: 614.1376. (E)-Diphenyl (2-styryl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl) phosphate (3.15i) Heterocycle 3.15i was constructed using an analogous procedure as described for 3.15a from cinnamaldehyde (0.026 g, 0.2 mmol), p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 51%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.75 – 7.64 (m, 2H), 7.40 – 7.05 (m, 17H), 6.51 (dd, J = 16.0, 1.4 Hz, 1H), 5.89 (dd, J = 16.0, 6.4 Hz, 1H), 5.67 – 5.43 (m, 1H), 4.92 (t, J = 6.3 Hz, 1H), 4.37 – 4.12 (m, 1H), 3.74 – 3.51 (m, 1H), 2.86 – 2.62 (m, 1H), 2.37 – 2.21 (m, 4H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (dd, J = 7.3, 3.2 Hz), 144.4 (d, J = 9.1 Hz), 143.8, 136.7, 136.1, 133.5, 130.0, 129.8, 128.6, 128.1, 127.5, 126.7, 125.8, 124.5, 120.1 (d, J = 5.0 Hz), 107.8 (d, J = 5.7 Hz), 52.8, 40.0, 32.5 (d, J = 4.0 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 1590, 1488, 1299, 1186, 1161, 1134, 1091 cm-1. HRMS-ESI (m/z) calcd for C32H30NO6PSNa ([M+Na]+): 610.1429, found: 610.1429. NOPPhOOOPhTs 156 2-Isopropyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15j) Heterocycle 3.15j was constructed using an analogous procedure as described for 3.15a from isobutyraldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 50%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.69 – 7.63 (m, 2H), 7.38 – 7.11 (m, 12H), 5.53 – 5.46 (m, 1H), 4.36 – 4.22 (m, 1H), 3.75 – 3.57 (m, 2H), 2.33 (s, 3H), 2.20 – 2.13 (m, 2H), 1.84 – 1.71 (m, 1H), 0.95 (d, J = 6.7 Hz, 3H), 0.90 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.4 (dd, J = 7.4, 2.1 Hz), 144.8 (d, J = 9.2 Hz), 143.4, 137.9, 130.0, 129.8, 126.9, 125.7 (d, J = 1.3 Hz), 120.1 (d, J = 5.0 Hz), 107.5 (d, J = 5.5 Hz), 57.7, 39.6, 28.4, 28.2 (d, J = 4.1 Hz), 21.6, 20.4, 19.9. ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.9 ppm. IR (neat): 2966, 1591, 1488, 1301, 1186, 1160, 1133, 1025 cm-1. HRMS-ESI (m/z) calcd for C27H30NO6PSNa ([M+Na]+): 550.1429, found: 550.1428. 2-Cyclohexyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15k) Heterocycle 3.15k was constructed using an analogous procedure as described for 3.15a from cyclohexanecarboxaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 64%. Yellow oil. NOPPhOOOPhTsNOPPhOOOPhTs 157 1H NMR (300 MHz, Chloroform-d) δ 7.72 – 7.61 (m, 2H), 7.37 – 7.28 (m, 4H), 7.24 – 7.09 (m, 8H), 5.53 – 5.47 (m, 1H), 4.34 – 4.19 (m, 1H), 3.78 (ddd, J = 10.5, 5.8, 1.8 Hz, 1H), 3.72 – 3.56 (m, 1H), 2.33 (s, 3H), 2.21 – 2.11 (m, 2H), 2.00 – 1.56 (m, 6H), 1.53 – 1.36 (m, 1H), 1.33 – 1.21 (m, 1H), 1.20 – 1.06 (m, 2H), 1.07 – 0.82 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 8.0 Hz), 144.8 (d, J = 9.3 Hz), 143.4, 138.0, 130.0, 129.8, 126.9, 125.7, 120.1 (d, J = 5.0 Hz), 107.5 (d, J = 5.5 Hz), 56.5, 39.7, 37.3, 30.8, 30.1, 27.6 (d, J = 4.3 Hz), 26.3, 26.1, 26.0, 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.5 ppm. IR (neat): 2928, 1592, 1490, 1302, 1188, 1162, 1136, 1092 cm-1. HRMS-ESI (m/z) calcd for C30H34NO6PSNa ([M+Na]+): 590.1742, found: 590.1742. 2-Cyclopropyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15l): Heterocycle 3.15l was constructed using an analogous procedure as described for 3.15a from cyclopropanecarboxaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 55%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.70 – 7.61 (m, 2H), 7.39 – 7.29 (m, 4H), 7.25 – 7.14 (m, 8H), 5.65 – 5.51 (m, 1H), 4.33 – 4.13 (m, 1H), 3.99 – 3.82 (m, 1H), 3.37 (dd, J = 9.6, 6.4 Hz, 1H), 2.47 – 2.37 (m, 1H), 2.35 (s, 3H), 2.23 – 2.10 (m, 1H), 1.15 – 0.98 (m, 1H), 0.60 – 0.21 (m, 4H) ppm. NOPPhOOOPhTs 158 13C NMR (75 MHz, Chloroform-d) δ 150.5 (d, J = 7.4 Hz), 145.0 (d, J = 9.2 Hz), 143.4, 137.7, 130.0, 129.8, 127.1, 125.8, 120.1 (d, J = 5.1 Hz), 107.5 (d, J = 5.5 Hz), 56.7, 39.8, 32.0 (d, J = 4.3 Hz), 21.6, 13.6, 5.0, 4.4 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. IR (neat): 2925, 1590, 1488, 1300, 1186, 1160, 1132, 1092 cm-1. HRMS-ESI (m/z) calcd for C27H29NO6PS ([M+H]+): 526.1453, found: 526.1452. 2-Isobutyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl-diphenyl phosphate (3.15m) Heterocycle 3.15m was constructed using an analogous procedure as described for 3.15a from isovaleradehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 57%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 – 7.60 (m, 2H), 7.39 – 7.30 (m, 4H), 7.25 – 7.12 (m, 8H), 5.55 – 5.47 (m, 1H), 4.35 – 4.17 (m, 2H), 3.70 – 3.55 (m, 1H), 2.48 – 2.36 (m, 1H), 2.34 (s, 3H), 1.87 (dd, J = 17.2, 2.3 Hz, 1H), 1.65 – 1.51 (m, 1H), 1.39 (ddd, J = 14.2, 8.4, 5.9 Hz, 1H), 1.27 – 1.12 (m, 1H), 0.88 (d, J = 6.6 Hz, 6H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.5 (dd, J = 7.3, 2.7 Hz), 144.9 (d, J = 9.3 Hz), 143.5, 137.6, 130.0, 129.9, 127.1, 125.8, 120.1 (d, J = 5.1 Hz), 107.3 (d, J = 5.6 Hz), 49.4, 40.4, 39.2, 31.2 (d, J = 4.3 Hz), 24.7, 22.9, 22.3, 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.5 ppm. IR (neat): 2956, 1591, 1489, 1301, 1186, 1160, 1135, 1091 cm-1. HRMS-ESI (m/z) calcd for C28H33NO6PS ([M+H]+): 542.1766, found:542.1765. NOPPhOOOPhTs 159 2-(Chloromethyl)-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.15o) Heterocycle 3.15o was constructed using an analogous procedure as described for 3.15a from chloroacetaldehyde dimethyl acetal, p-toluenesulfonamide (0.034 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 62%. Light yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.72 – 7.66 (m, 2H), 7.39 – 7.15 (m, 12H), 5.61 – 5.55 (m, 1H), 4.45 – 4.37 (m, 1H), 4.29 – 4.20 (m, 1H), 3.68 – 3.58 (m, 1H), 3.46 – 3.41 (m, 2H), 2.52 – 2.41 (m, 2H), 2.39 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.8 Hz), 144.1, 144.0 (d, J = 9.0 Hz), 136.8, 130.1, 127.2, 125.9, 120.1 (d, J = 4.9 Hz), 107.2 (d, J = 5.4 Hz), 52.5, 42.8, 39.6, 28.8 (d, J = 4.6 Hz), 21.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 1590, 1488, 1295, 1186, 1161, 1093 cm-1. HRMS-ESI (m/z) calcd for C25H26ClNO6PS ([M+H]+): 534.0907, found: 534.0903. 6-Heptyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.17a) Heterocycle 3.17a was constructed using an analogous procedure as described for 3.15a from benzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and (E)-diphenyl undeca-1,3-dien-2-yl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 55% (dr = 8:1). Light yellow oil. NOPPhOOOPhTsClNOPPhOOOPhTsPhC7H15 160 Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.79 – 7.69 (m, 2H), 7.53 – 7.43 (m, 2H), 7.41 – 7.10 (m, 15H), 5.59 (dt, J = 4.3, 2.3 Hz, 1H), 5.36 (d, J = 7.2 Hz, 1H), 4.56 – 4.43 (m, 1H), 2.63 (d, J = 17.7 Hz, 1H), 2.35 (s, 3H), 2.26 – 2.10 (m, 1H), 1.35 – 0.74 (m, 15H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.2 Hz), 143.6, 143.5, 139.5, 137.9, 130.0, 130.0, 128.4, 127.9, 127.8, 127.0, 125.8, 120.1 (d, J = 4.9 Hz), 112.9 (d, J = 5.5 Hz), 54.1, 52.2, 35.4, 31.8, 29.2, 29.0, 26.6, 22.7, 21.6, 14.2 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 2926, 1590, 1489, 1301, 1187, 1157, 1133, 1090 cm-1. HRMS-ESI (m/z) calcd for C37H43NO6PS ([M+H]+): 660.2549, found: 660.2544. 6-(3-(Benzyloxy)propyl)-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.17b) Heterocycle 3.17b was constructed using an analogous procedure as described for 3.15a from benzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and (E)-7-(benzyloxy)hepta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 57% (dr > 20:1). Light yellow oil. Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.77 – 7.68 (m, 2H), 7.51 – 7.43 (m, 2H), 7.40 – 7.13 (m, 18H), 5.59 (dt, J = 4.4, 2.3 Hz, 1H), 5.35 (d, J = 7.2 Hz, 1H), 4.63 – 4.48 (m, 1H), 4.36 (s, 2H), NOPPhOOOPhTsPhOBn 161 3.27 (dt, J = 9.4, 5.9 Hz, 1H), 3.07 (dt, J = 9.5, 6.5 Hz, 1H), 2.62 (d, J = 17.8 Hz, 1H), 2.34 (s, 3H), 2.25 – 2.06 (m, 1H), 1.69 – 1.42 (m, 3H), 1.17 – 0.98 (m, 1H), 0.85 – 0.64 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.2 Hz), 143.8 (d, J = 9.2 Hz), 143.7, 139.4, 138.8, 137.8, 130.0, 128.5, 128.4, 127.9, 127.6, 127.5, 127.0, 125.8, 120.1 (d, J = 5.1 Hz), 112.9 (d, J = 5.7 Hz), 72.7, 69.9, 53.9, 52.2, 32.0, 26.8, 26.5 (d, J = 4.3 Hz), 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 3032, 2923, 2854, 1591, 1490, 1454, 1301, 1187, 1164, 1132, 1091 cm-1. IR (neat): 2923, 1591, 1490, 1301, 1187, 1164, 1132, 1091 cm-1. HRMS-ESI (m/z) calcd for C40H40NO7PSNa ([M+Na]+): 732.2161, found: 732.2160. 6-Isopropyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.17c) Heterocycle 3.17c was constructed using an analogous procedure as described for 3.15a from benzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and (E)-5-methylhexa-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 29 % (dr = 3:1). Light yellow oil. Diastereomer A (major): 1H NMR (300 MHz, Chloroform-d) δ 7.80 – 7.69 (m, 2H), 7.54 – 7.44 (m, 2H), 7.42 – 7.31 (m, 5H), 7.33 – 7.06 (m, 10H), 5.81 (dt, J = 4.4, 2.2 Hz, 1H), 5.31 (d, J = 7.5 Hz, 1H), 4.24 – 4.10 (m, 1H), 2.55 (d, J = 17.9 Hz, 1H), 2.35 (s, 3H), 2.12 – 1.95 (m, 2H), 0.78 (d, J = 2.3 Hz, 3H), 0.67 (d, J = 1.7 Hz, 3H) ppm. NPhOPPhOOOPhTs 162 13C NMR (75 MHz, Chloroform-d) δ 150.5 (d, J = 7.2 Hz), 143.9 (d, J = 9.2 Hz), 143.7, 139.1, 137.8, 130.0, 130.0, 128.3, 128.2, 128.0, 127.2, 125.8, 120.1 (dd, J = 5.1, 2.1 Hz), 112.0 (d, J = 5.6 Hz), 60.2, 52.4, 32.5, 26.2 (d, J = 4.1 Hz), 21.6, 21.1, 20.1 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 2964, 1591, 1490, 1300, 1188, 1159, 1134, 1089 cm-1. HRMS-ESI (m/z) calcd for C33H35NO6PS ([M+H]+): 604.1923, found: 604.1921. Diastereomer B (minor): 1H NMR (300 MHz, Chloroform-d) δ 7.45 – 6.93 (m, 19H), 5.96 (dd, J = 4.6, 2.1 Hz, 1H), 4.68 (dd, J = 11.4, 4.0 Hz, 1H), 4.53 – 4.43 (m, 1H), 3.45 – 3.30 (m, 1H), 2.53 – 2.42 (m, 1H), 2.31 (s, 3H), 2.14 – 1.96 (m, 1H), 1.09 (d, J = 6.6 Hz, 3H), 1.02 (d, J = 6.6 Hz, 3H). 13C NMR (101 MHz, Chloroform-d) δ 150.5 (t, J = 7.8 Hz), 146.6 (d, J = 9.2 Hz), 142.4, 139.3, 136.4, 130.0, 129.1, 128.8, 128.0, 127.8, 127.2, 125.7 (d, J = 1.8 Hz), 120.2 (dd, J = 4.9, 2.5 Hz), 112.8 (d, J = 5.6 Hz), 61.3, 55.7, 33.2 (d, J = 1.6 Hz), 30.8 (d, J = 4.5 Hz), 21.5, 21.1, 19.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. Diphenyl (2-phenyl-1-tosyl-1,2,3,5,6,7,8,8a-octahydroquinolin-4-yl) phosphate (3.17d) Heterocycle 3.17d was constructed using an analogous procedure as described for 3.15a benzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and 1-(Cyclohex-1-en-1-yl)vinyl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 88% (dr = 1.5:1). Light yellow oil. Diastereomer A (major): NPhOPPhOOOPhTs 163 1H NMR (300 MHz, Chloroform-d) δ 7.38 – 7.12 (m, 17H), 7.05 (d, J = 8.1 Hz, 2H), 5.00 (dd, J = 7.7, 4.3 Hz, 1H), 4.53 – 4.37 (m, 1H), 3.30 – 3.14 (m, 1H), 2.93 – 2.73 (m, 2H), 2.34 (s, 3H), 1.91 – 1.08 (m, 7H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.6 (t, J = 6.9 Hz), 142.5, 140.1, 137.4, 136.9 (d, J = 8.9 Hz), 130.0, 129.9, 129.2, 128.6, 128.0, 127.6, 126.7, 125.6 (d, J = 4.3 Hz), 120.2 (dd, J = 8.8, 4.9 Hz), 57.2, 56.9, 34.3 (d, J = 1.9 Hz), 32.6, 26.9, 26.5, 25.4, 21.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.7 ppm. IR (neat): 2933, 1590, 1488, 1295, 1187, 1150, 1130, 1091 cm-1. HRMS-ESI (m/z) calcd for C34H35NO6PS ([M+H]+): 616.1923, found: 616.1922. Diastereomer B (minor): 1H NMR (300 MHz, Chloroform-d) δ 7.78 – 7.69 (m, 2H), 7.60 – 7.51 (m, 2H), 7.40 – 7.11 (m, 15H), 5.33 (d, J = 6.7 Hz, 1H), 4.29 – 4.16 (m, 1H), 2.82 (d, J = 17.2 Hz, 1H), 2.51 – 2.38 (m, 1H), 2.34 (s, 3H), 1.75 – 1.45 (m, 6H), 0.99 – 0.78 (m, 1H), 0.57 (qd, J = 12.6, 3.7 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.5 (d, J = 6.8 Hz), 143.6, 139.9, 138.0, 135.4 (d, J = 9.0 Hz), 130.1, 130.0, 128.4, 128.2, 127.7, 126.8, 125.7, 123.6 (d, J = 8.1 Hz), 120.1 (d, J = 5.1 Hz), 56.5, 52.6, 34.9, 27.5, 27.1, 25.9, 25.7, 21.6 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.6 ppm. 5-Methyl-2-phenyl-1-tosyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.17e) NPhOTsPPhOOOPh 164 Heterocycle 3.17e was constructed using an analogous procedure as described for 3.15a from benzaldehyde, p-toluenesulfonamide (0.034 g, 0.2 mmol) and 3-methylbuta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 72%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.69 – 7.62 (m, 2H), 7.38 – 7.08 (m, 17H), 5.34 – 5.28 (m, 1H), 4.06 – 3.94 (m, 1H), 3.36 – 3.21 (m, 1H), 2.80 – 2.55 (m, 2H), 2.32 (s, 3H), 1.52 – 1.46 (m, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.5 (dd, J = 7.4, 2.0 Hz), 143.6, 138.5 (d, J = 8.8 Hz), 138.1, 137.4, 129.9, 129.9, 128.7, 127.9, 127.3, 127.0, 125.7 (dd, J = 2.9, 1.3 Hz), 120.1 (dd, J = 5.0, 2.7 Hz), 117.0 (d, J = 8.2 Hz), 54.0, 44.1, 29.0, 21.6, 13.4 (d, J = 1.5 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ –16.7 ppm. IR (neat): 1591, 1489, 1289, 1185, 1160, 1123, 1088 cm-1. HRMS-ESI (m/z) calcd for C31H31NO6PS ([M+H]+): 576.1610, found: 576.1607. 1-(Methylsulfonyl)-2-phenyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.18a) Heterocycle 3.18a was constructed using an analogous procedure as described for 3.15a from benzaldehyde, methanesulfonamide (0.019 g, 0.2 mmol) and Buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 59%. Bright yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.48 – 7.14 (m, 15H), 5.71 – 5.63 (m, 1H), 5.37 (d, J = 7.2 Hz, 1H), 4.20 – 4.04 (m, 1H), 3.49 – 3.35 (m, 1H), 3.07 – 2.91 (m, 1H), 2.77 (s, 3H), 2.75 – 2.66 (m, 1H) ppm. NPhOMsPPhOOOPh 165 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.4 Hz), 145.2 (d, J = 9.0 Hz), 137.9, 130.1, 129.0, 128.4, 127.4, 125.9, 120.1 (dd, J = 5.0, 1.8 Hz), 108.8 (d, J = 5.5 Hz), 53.8, 39.4, 39.3, 30.4 (d, J = 4.2 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.9 ppm. IR (neat): 1589, 1488, 1296, 1186, 1160, 1124 cm-1. HRMS-ESI (m/z) calcd for C24H25NO6PS ([M+H]+): 486.1140, found: 486.1134. 5-Methyl-1-(methylsulfonyl)-2-phenyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.18b) Heterocycle 3.18b was constructed using an analogous procedure as described for 3.15a from benzaldehyde, methanesulfonamide (0.019 g, 0.2 mmol) and 3-methylbuta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 58%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.63 – 7.09 (m, 15H), 5.33 (d, J = 7.1 Hz, 1H), 3.91 (dt, J = 17.0, 2.9 Hz, 1H), 3.41 – 3.25 (m, 1H), 3.17 – 2.98 (m, 1H), 2.88 – 2.81 (m, 1H), 2.79 (s, 3H), 1.75 – 1.42 (m, 3H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.5 (d, J = 7.3 Hz), 138.9 (d, J = 8.6 Hz), 138.0, 130.0, 129.0, 128.3, 127.4, 125.8, 120.2 (t, J = 4.5 Hz), 117.4 (d, J = 8.1 Hz), 54.3, 43.9, 39.4, 30.2, 13.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.2 ppm. IR (neat): 1590, 1488, 1293, 1186, 1155, 1117 cm-1. HRMS-ESI (m/z) calcd for C25H27NO6PS ([M+H]+): 500.1297, found: 500.1295. NPhOMsPPhOOOPh 166 Diphenyl (2-phenyl-1-(phenylsulfonyl)-1,2,3,6-tetrahydropyridin-4-yl) phosphate (3.18c) Heterocycle 3.18c was constructed using an analogous procedure as described for 3.15a from benzaldehyde, benzenesulfonamide (0.31 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 54%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.82 – 7.76 (m, 2H), 7.48 – 7.10 (m, 17H), 5.55 – 5.46 (m, 1H), 5.36 (dd, J = 5.4, 2.8 Hz, 1H), 4.29 – 4.16 (m, 1H), 3.46 – 3.32 (m, 1H), 2.60 – 2.54 (m, 2H) ppm. 13C NMR (101 MHz, Chloroform-d) δ 150.4 (dd, J = 7.4, 2.3 Hz), 144.8 (d, J = 9.2 Hz), 143.6, 137.9, 137.4, 130.0, 129.9, 128.7, 128.0, 127.2, 127.1, 125.8, 120.1 (d, J = 5.0 Hz), 108.6 (d, J = 5.5 Hz), 55.4, 39.5, 29.1 (d, J = 4.4 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.3 ppm. IR (neat): 3063, 2993, 2855, 1590, 1488, 1298, 1185, 1161, 1133, 1092 cm-1. IR (neat): 1590, 1488, 1298, 1185, 1161, 1133, 1092 cm-1. HRMS-ESI (m/z) calcd for C29H26NO6PSNa ([M+Na]+): 570.1116, found: 570.1113. Ethyl 4-((diphenoxyphosphoryl)oxy)2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (3.18d) NPhOPPhOOOPhSO2PhNOPPhOOOPh PhOO 167 Heterocycle 3.18d was constructed using an analogous procedure as described for 3.15a from benzaldehyde, ethyl carbamate (0.018 g, 0.2 mmol) and Buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 50%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.41 – 7.11 (m, 15H), 5.78 – 5.61 (m, 1H), 5.60 – 5.49 (m, 1H), 4.41 (d, J = 17.9 Hz, 1H), 4.27 – 4.16 (m, 2H), 3.43 – 3.25 (m, 1H), 3.04 – 2.86 (m, 1H), 2.72 (d, J = 17.4 Hz, 1H), 1.29 (t, J = 7.1 Hz, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.6, 150.5 (d, J = 7.5 Hz), 139.3, 130.0, 129.8, 128.8, 127.7, 126.8, 125.8, 120.2 (d, J = 4.9 Hz), 108.9, 62.0, 51.4, 38.8, 30.3, 14.8 ppm. 31P NMR (120 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1693, 1590, 1488, 1298, 1187, 1125 cm-1. HRMS-ESI (m/z) calcd for C26H27NO6P ([M+H]+): 480.1576, found: 480.1574. Benzyl 4-((diphenoxyphosphoryl)oxy)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (3.18e) Heterocycle 3.18e was constructed using an analogous procedure as described for 3.18a from benzaldehyde, benzyl carbamate (0.031 g, 0.2 mmol) and Buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 41%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.38 – 7.15 (m, 20H), 5.79 – 5.59 (m, 1H), 5.57 – 5.48 (m, 1H), 5.28 – 5.08 (m, 2H), 4.51 – 4.31 (m, 1H), 3.48 – 3.18 (m, 1H), 3.02 – 2.84 (m, 1H), 2.76 – 2.61 (m, 1H) ppm. NOPPhOOOPh PhCbz 168 13C NMR (75 MHz, Chloroform-d) δ 155.4, 150.5 (d, J = 7.2 Hz), 139.1, 136.5, 130.0, 128.8, 128.7, 128.3, 128.2, 127.7, 126.8, 125.8, 120.2 (d, J = 5.0 Hz), 108.8, 67.8, 51.7, 38.9, 30.3 ppm. 31P NMR (120 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1703, 1591, 1489, 1299, 1188, 1125 cm-1. HRMS-ESI (m/z) calcd for C31H28NO6PNa ([M+Na]+): 564.1552, found: 564.1544. Benzyl 4-((diphenoxyphosphoryl)oxy)-5-methyl-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (3.18f) Heterocycle 3.18f was constructed using an analogous procedure as described for 3.15a from benzaldehyde, benzyl carbamate (0.031 g, 0.2 mmol) and 3-methylbuta-1,3-dien-2-yl diphenyl phosphate. Column condition: 25% EtOAc in hexanes. Yield: 60%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.40 – 7.17 (m, 20H), 5.86 – 5.50 (m, 1H), 5.27 – 5.17 (m, 2H), 4.35 – 4.12 (m, 1H), 3.35 – 3.19 (m, 1H), 3.12 – 2.97 (m, 1H), 2.93 – 2.78 (m, 1H), 1.59 – 1.48 (m, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.3, 150.6 (d, J = 7.5 Hz), 139.3, 136.6, 130.0, 129.9, 128.8, 128.7, 128.3, 128.2, 127.6, 126.8, 125.7, 120.2 (d, J = 4.9 Hz), 67.7, 52.2, 43.6, 30.3, 13.5 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.4 ppm. IR (neat): 1696, 1590, 1488, 1295, 1187, 1112 cm-1. HRMS-ESI (m/z) calcd for C32H30NO6PNa ([M+Na]+): 578.1708, found: 578.1707. NPhOCbzPPhOOOPh 169 Benzyl 2-(4-chlorophenyl)-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.18g) Heterocycle 3.18g was constructed using an analogous procedure as described for 3.15a from 4-chlorobenzaldehyde, benzyl carbamate (0.031 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 51%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.39 – 7.31 (m, 9H), 7.25 – 7.18 (m, 10H), 5.77 – 5.61 (m, 1H), 5.58 – 5.49 (m, 1H), 5.26 – 5.12 (m, 2H), 4.51 – 4.34 (m, 1H), 3.41 – 3.27 (m, 1H), 3.03 – 2.85 (m, 1H), 2.73 – 2.60 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.4, 150.5 (d, J = 7.2 Hz), 137.7, 136.4, 133.6, 130.1, 128.9, 128.7, 128.4, 128.3, 128.2, 125.8, 120.1 (d, J = 5.0 Hz), 108.9, 67.9, 51.2, 38.9, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1699, 1590, 1489, 1296, 1186, 1126 cm-1. HRMS-ESI (m/z) calcd for C31H27ClNO6PNa ([M+Na]+): 598.1162, found: 598.1155. Benzyl (E)-4-((diphenoxyphosphoryl)oxy)-2-styryl-3.6-dihydropyridine-1(2H)-carboxylate (3.18h) NOCbzPPhOOOPhClNOCbzPPhOOOPh 170 Heterocycle 3.18h was constructed using an analogous procedure as described for 3.15a from cinnamaldehyde, benzyl carbamate (0.031 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 55%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.41 – 7.16 (m, 20H), 6.69 – 6.41 (m, 1H), 6.16 (dd, J = 16.0, 6.0 Hz, 1H), 5.67 – 5.51 (m, 1H), 5.33 – 5.06 (m, 3H), 4.50 – 4.29 (m, 1H), 3.83 – 3.57 (m, 1H), 2.99 – 2.72 (m, 1H), 2.36 (d, J = 16.9 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.3, 150.5 (d, J = 7.3 Hz), 136.5 (d, J = 11.4 Hz), 132.4, 130.0, 128.7, 128.3, 128.1, 128.0, 126.7, 126.4, 125.8, 120.2 (d, J = 5.1 Hz), 108.4, 67.7, 50.7, 39.3, 32.1, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.0 ppm. IR (neat): 1703, 1590, 1489, 1299, 1188, 1130 cm-1. HRMS-ESI (m/z) calcd for C33H31NO6P ([M+H]+): 568.1889, found: 568.1889. (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)2-phenyl-3,6-dihyropyridine-1(2H)-carboxylate (3.18i) Heterocycle 3.18i was constructed using an analogous procedure as described for 3.15a from benzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and Buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 68%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.47 – 7.04 (m, 19H), 5.60 – 5.53 (m, 2H), 4.70 – 4.47 (m, 2H), 4.47 – 4.16 (m, 2H), 3.51 – 3.21 (m, 1H), 3.02 – 2.77 (m, 1H), 2.70 (d, J = 17.3 Hz, 1H) ppm. NOFmocPPhOOOPh Ph 171 13C NMR (75 MHz, Chloroform-d) δ 155.3, 150.5 (d, J = 7.4 Hz), 144.0 (d, J = 2.5 Hz), 141.5, 139.1, 130.0, 128.8, 127.8, 127.7, 127.2, 126.8, 125.8, 125.0, 120.2 (d, J = 4.8 Hz), 108.6, 67.6, 51.6, 47.5, 38.9, 30.4 ppm. 31P NMR (120 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1699, 1590, 1488, 1418, 1298, 1186, 1124 cm-1. HRMS-ESI (m/z) calcd for C38H32NO6PNa ([M+Na]+): 652.1865, found: 652.1861. (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphory)oxy)-5-methyl-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (3.18j) Heterocycle 3.18j was constructed using an analogous procedure as described for 3.15a from benzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and 3-methylbuta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 86%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.66 (d, J = 7.5 Hz, 2H), 7.53 – 7.38 (m, 2H), 7.38 – 6.88 (m, 19H), 5.93 – 4.92 (m, 1H), 4.48 (d, J = 6.2 Hz, 2H), 4.33 – 3.86 (m, 2H), 3.14 (d, J = 17.5 Hz, 1H), 3.01 – 2.57 (m, 2H), 1.47 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.1, 150.5 (d, J = 7.5 Hz), 144.0, 143.9, 141.5 (d, J = 2.2 Hz), 139.2, 130.0, 128.7, 127.9, 127.8, 127.8, 127.6, 127.2, 126.8, 125.7, 125.0, 120.2 (d, J = 4.9 Hz), 120.1 (d, J = 3.1 Hz), 67.5, 52.1, 47.4, 43.5, 30.3, 13.4 ppm. 31P NMR (121 MHz, Chloroform-d) δ -15.9 ppm. IR (neat): 1699, 1590, 1489, 1297, 1188, 1117 cm-1. NPhOFmocPPhOOOPh 172 HRMS-ESI (m/z) calcd for C39H35NO6S ([M+H]+): 644.2202, found: 644.2198. (9H-Fluoren-9-yl)methyl 2-cyclopropyl-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (3.18k) Heterocycle 3.18k was constructed using an analogous procedure as described for 3.15a from cyclopropanecarboxaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and Buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 51%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.60 – 7.49 (m, 2H), 7.45 – 7.15 (m, 14H), 5.60 (dd, J = 4.8, 2.5 Hz, 1H), 4.65 – 4.14 (m, 4H), 3.92 – 3.54 (m, 1H), 2.79 – 2.40 (m, 2H), 2.36 – 2.15 (m, 1H), 1.18 – 0.92 (m, 1H), 0.69 – 0.17 (m, 4H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.2, 150.5 (d, J = 7.3 Hz), 144.1, 141.5, 130.0, 127.8, 127.8, 127.2, 127.2, 125.7, 124.9, 120.1 (d, J = 4.9 Hz), 107.7, 67.3, 54.7, 47.4, 39.0, 32.5, 13.5, 4.6, 3.2 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.2 ppm. IR (neat): 1700, 1591, 1488, 1301, 1188, 1124 cm-1. HRMS-ESI (m/z) calcd for C35H32NO6PNa ([M+Na]+): 616.1865, found: 616.1862. NOFmocPPhOOOPh 173 (9H-Fluoren-9-yl)methyl 4-((diethoxyphosphoryl)oxy)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (3.24) Heterocycle 3.24 was constructed using an analogous procedure as described for 3.15a from benzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diethyl phosphate. Column condition: 50% EtOAc in hexanes. Yield: 64%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.4 Hz, 2H), 7.46 – 7.20 (m, 9H), 5.82 – 5.26 (m, 2H), 4.60 – 4.49 (m, 2H), 4.43 – 4.30 (m, 1H), 4.27 (t, J = 6.3 Hz, 1H), 4.23 – 4.07 (m, 4H), 3.44 – 3.23 (m, 1H), 3.00 – 2.79 (m, 1H), 2.77 – 2.60 (m, 1H), 1.42 – 1.30 (m, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.4, 144.0 (d, J = 3.3 Hz), 141.5, 139.4, 128.7, 127.8, 127.8, 127.6, 127.2, 126.8, 125.0, 120.1 (d, J = 4.1 Hz), 107.3, 67.6, 64.6 (d, J = 6.2 Hz), 51.7, 47.5, 39.0, 29.8, 16.2 (d, J = 6.7 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -6.2 ppm. IR (neat): 1699, 1420, 1265, 1145, 1029 cm-1. HRMS-ESI (m/z) calcd for C30H33NO6P ([M+H]+): 534.2045, found: 534.2044. Representative procedure for the deprotection and alkylation of Fmoc-protected tetrahydropyridines 1-Benzyl-2-phenyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.19a) NOPEtOOOEtFmocNOPPhOOOPhPhPhNOFmocPPhOOOPh Pha) piperidineb) BnBrDMF, rt, 2 hrt, 16 – 20 h 174 Heterocycle 3.18i (0.076 g, 0.12 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (DMF, 1 mL). Piperidine (0.0123 g, 0.144 mmol, 1.2 equiv, 2% solution in DMF) was added. The reaction mixture was stirred at rt for 2 h. Benzyl bromide (0.041 g, 0.24 mmol, 2.0 equiv) was added slowly. The reaction mixture was stirred at rt for 16 – 20 h. Water (2 mL) was added, and the aqueous layer was extracted with DCM (´ 3). The combined organic extracts were washed with water (´ 1) and brine, then dried over sodium sulfate. The resultant oil after concentrated in vacuo was purified by column chromatography over silica gel (25% EtOAc in hexanes) to give 0.048 g (80%) of heterocycle 3.19 as a light-yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.50 – 7.10 (m, 20H), 5.68 – 5.44 (m, 1H), 3.85 – 3.60 (m, 2H), 3.26 (d, J = 16.6 Hz, 1H), 3.06 (d, J = 13.1 Hz, 1H), 2.94 (d, J = 16.9 Hz, 1H), 2.78 – 2.46 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.6 (d, J = 7.6 Hz), 145.2 (d, J = 9.4 Hz), 130.0, 128.9, 128.4, 128.0, 127.8, 127.2, 125.6, 120.2 (d, J = 5.1 Hz), 109.3, 63.4, 57.9, 49.4, 35.7 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.0 ppm. IR (neat): 1590, 1489, 1298, 1188, 1115 cm-1. HRMS-ESI (m/z) calcd for C30H29NO4P ([M+H]+): 498.1834, found: 498.1831. 1-Allyl-2-phenyl-1,2,3,6-tetrahydropyridin-4-yl diphenyl phosphate (3.19b) Heterocycle 3.19b was constructed using an analogous procedure as described for 3.19a from 3.18i (0.063 g, 0.1 mmol) and allyl bromide. Column condition: 30% EtOAc in hexanes. Yield: 78%. Light yellow oil. NPhOPPhOOOPh 175 1H NMR (300 MHz, Chloroform-d) δ 7.43 – 7.11 (m, 15H), 5.80 (dddd, J = 19.3, 9.7, 7.4, 5.6 Hz, 1H), 5.70 – 5.61 (m, 1H), 5.17 – 5.03 (m, 2H), 3.69 (dd, J = 8.2, 5.0 Hz, 1H), 3.42 (d, J = 16.8 Hz, 1H), 3.13 (dd, J = 13.7, 5.6 Hz, 1H), 3.05 (d, J = 17.1 Hz, 1H), 2.78 – 2.43 (m, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.6 (d, J = 8.1 Hz), 145.3 (d, J = 9.3 Hz), 130.0, 128.8, 128.1, 127.9, 125.6, 120.2 (d, J = 4.9 Hz), 109.2, 63.1, 56.6, 49.2, 35.8, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 2924, 1590, 1488, 1296, 1187, 1115 cm-1. HRMS-ESI (m/z) calcd for C26H27NO4P ([M+H]+): 448.1678, found: 448.1678. 176 Chapter 4: A Cycloaddition–Cross-Coupling–Oxidation Sequence to Build Fluorescent Arylpyridines 4.1 Introduction The hetero-Diels-Alder reactions described in Chapters 2 and 3 enabled access to N-sulfonyl and N-carbamoyl heterocyclic products featuring an enol phosphate functionality. It was envisioned that this protocol could be used to construct substituted pyridines. Scheme 4.1 The hetero-Diels-Alder reaction and cross-coupling reactions on enol phosphates presented in Chapter 2 and plausible mechanisms of N-tosyl deprotection As described in Chapter 2, 2-diphenylphosphoryloxy-1,3-butadiene reacted smoothly in a [4+2] cycloaddition reaction with N-(p-toluenesulfonyl)benzaldimine and related compounds (Scheme 4.1). The enol phosphate functionality in the cycloaddition product can be used in Group 10 Metal (e.g. Pd(0))-catalyzed cross-couplings such as Suzuki coupling or Kumada coupling Chapter 2:OPPhOOOPhNPhHTs FeCl3 (0.2 equiv)DCMrt, 24 h – 48 hNPhOTsPPhOOOPh78%NPh PhTsPh-B(OH)2 (4.0 equiv)Pd(PPh3)4 (5 mol%)Na2CO3 (4.0 equiv)DME/EtOH/H2O (2.5:1:1)90 °C, 16 – 20 h 55%Pd or Ni catalyst(10 mol%)THF, rt, 24 hNR PhTsRMgBr (3.0 equiv)R = TMSCH2, 41%R = isopropenyl, 51%NR PhTs concentrated acidor sodium/naphthalene? NR PhHNR PhSO OHA NR PhSO OHA NR PhHNR PhSO ONa0 NR PhSO ONR PhSO2 Na NR PhHharsh conditionsthen H2O 177 (Chapter 2.5). The removal of the p-toluenesulfonyl group on the nitrogen atom in the products was expected to be challenging. Literature conditions for the deprotection of the p-toluenesulfonyl substituent on nitrogen are typically harsh, such as reactions using concentrated hydrochloric acid at 150 °C or the use of single electron reductive cleavage with sodium metal with naphthalene, each for extended time.211,212,213 The literature record has many instances where these reactions simply fail due to the robustness of the p-toluenesulfonyl group.211 Scheme 4.2 The multicomponent Diels-Alder reaction and deprotection of the Fmoc group presented in Chapter 3 and a plausible mechanism of N-Fmoc deprotection In Chapter 3, 2-diphenylphosphoryloxy-1,3-butadiene reacted with imine or iminium type species formed in situ from electron-deficient amine derivatives and aldehydes in a multicomponent process (Scheme 4.2). The formation of a N-Fmoc substituted cycloaddition product from 9-fluorenylethyl carbamate (Fmoc-NH2) was demonstrated in Chapter 3.3.3. This is a notable achievement as this N-substituent was not accessible using the experimental techniques in Chapter 2. The N-Fmoc substituted imine was not isolable. The Fmoc protecting group simplifies the deprotection of the nitrogen atom in the cycloaddition product. Standard conditions H2N-Fmoc (1 equiv)PhCHO (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hNOFmocPhOPPhOOOPhPPhOOOPh 68%a) piperidine (1.2 equiv)DMF, rt, 2 hb) R-Br (2.0 equiv)rt, 16 – 20 hR = Bn, 80%R = allyl, 78%NPhORPPhOOOPhChapter 3:NO PhPPhOOOPhOO HHNNO PhPPhOOOPhOO NHO PhPPhOOOPhCO2 178 use piperidine in DMF to deprotect the Fmoc group. This reaction was demonstrated using two examples in Chapter 3.5 in a deprotection process that was followed by N-alkylation. The enol phosphate functionality was stable to these reaction conditions in these two examples. Scheme 4.3 Proposed synthesis of a substituted pyridine from the cycloaddition product 4.1a With these results established, it was a straightforward consideration to apply this pathway to the synthesis of substituted pyridines (Scheme 4.3). A Suzuki cross-coupling process might not be viable because the Fmoc group may be incompatible in protonic basic conditions at 90 °C. A Kumada cross-coupling reaction was expected to convert the enol phosphate functionality to a desired molecular fragment assuming that the Fmoc deprotection by a non-protonic base like the Grignard reagent would be much slower than the cross-coupling process. Deprotection and oxidation of the tetrahydropyridine would generate a functionalized pyridine. This approach should allow for the construction of pyridines with different substitution patterns. This chapter is divided into three parts. The first section describes the optimization of the cross-coupling step and a solvent screen for the deprotection and oxidation step. A scope of the Grignard reagents within the Kumada coupling to synthesize variously functionalized tetrahydropyridines and pyridines will be presented. The second section focuses on the synthesis of fluorescent 4-biphenylpyridines. The aldehyde scope for the multi-component hetero-Diels-Alder reaction using Fmoc-NH2 that was developed in Chapter 3 was broadened. The third section describes an analysis of the fluorescence spectroscopy of 4-biphenylpyridines. R2Nb) [O]a) piperidineR1R2MgBrPdCl2 (cat.) NR1R2FmocNR1OFmocPPhOOOPhOPOPhOPhOR H2N-FmocR1CHOBF3•OEt2R R R 179 4.2 Synthesis of substituted pyridines The Kumada coupling reaction of the cycloaddition product 4.1a was conducted using a ligand-free palladium-catalyzed process outlined by Gauthier and coworkers in 2009.176 The cycloaddition product 4.1a was treated with three equivalents of phenylmagnesium bromide (commercially available from Sigma-Aldrich) and 10 mol% of palladium(II) chloride in distilled THF under nitrogen atmosphere (Scheme 4.4a). The desired heterocycle 4.2a was isolated in 60% yield after purification by silica gel chromatography (20% EtOAc in hexanes). a reaction condition: 4.1a (0.2 mmol), phenylmagnesium bromide (0.6 mmol, 3.0 M in Et2O), THF (2 mL). b solvent condition for TLC plates: 20% EtOAc in hexanes. R = unquenched reaction mixture Scheme 4.4 The Kumada cross-coupling reaction of 4.1a with phenylmagnesium bromidea The reaction progress was monitored by thin layer chromatography (TLC) and the products were analyzed by NMR spectroscopy (Scheme 4.4). A TLC plate of the unquenched reaction mixture showed two new spots with higher Rf values than the starting material. A 1H NMR spectrum of the product with a Rf value of 0.40 showed signals at 4.57 (d, J = 6.3 Hz) and 4.30 (t, J = 6.5 Hz) ppm that corresponded to protons at a- and b carbon positions to carbamate in the PhMgBr (3.0 equiv)PdCl2 (10 mol%)THF, rt, 20 h4.2a, 60%, Rf = 0.40NPhOPPhOOOPh4.1aOONPhPhOO H H Hδ 4.57 (d, J = 6.3 Hz)δ 4.30 (t, J = 6.5 Hz)δ 4.58 (d, J = 6.2 Hz)δ 4.27 (t, J = 6.3 Hz)H H HRf = 0.08Rf = 0.40Rf = 0.724.1a RbPdCl22 * PhMgBr Pd(0)Rf = 0.72orNPhOFmocPPhOOOPhPhMgBrPd(0)Rf = 0.72a)b)c) 180 Fmoc group. These two signals of the product indicated that the Fmoc group persisted in the Kumada coupling process. A HRMS-ESI experiment found [M+H]+ = 458.2118 which was consistent with our calculation for C32H28NO2 ([M+H]+ = 458.2120). The byproduct with a Rf value of 0.72 was characterized to be 1,1'-biphenyl that could be formed in the process of reducing palladium(II) chloride to palladium(0) species with two equivalents of phenylmagnesium bromide (Scheme 4.4b) and the coupling between phenylmagnesium bromide and the phenyl group in the enol phosphate functionality (Scheme 4.4c). a reaction condition: 4.2a (0.1 mmol), piperidine (0.12 mmol, 2% in 0.64 mL of DMF), DDQ (0.2 mmol), DMF (1 mL). b solvent condition for TLC plates: 20% EtOAc in hexanes. R = unquenched reaction mixture Scheme 4.5 Deprotection and oxidation of 4.2a to form 2,4-diphenylpyridine (4.3a)a The deprotection of 4.2a was conducted at the same condition as described in Scheme 3.10 (Chapter 3.5) using 1.2 equivalents of piperidine in non-distilled DMF. The mixture of 4.2a and piperidine was stirred at rt for 2 h. Subsequently, a solution of 2 equivalents of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in DMF (1 mL) was added to the reaction mixture. DDQ was chosen as the oxidant because it is commonly utilized for aromatizing heterocycles.44,214,215 A TLC plate of the reaction mixture showed two spots with a Rf value of 0.42 and 0.70, respectively. The spot at Rf = 0.42 was identified to be the desired product 2,4-diphenylpyridine (4.3a) because its spectroscopy data are consistent with literature reports. It was isolated in 60% yield. The 2,4-disubstituted pyridine has a diagnostic signal in its 1H NMR spectrum at 8.75 (dd, J = 5.2, 0.8 Hz) PhN4.3a, 61%b) DDQ (2.0 equiv)DMF, rt, 16 ha) piperidine (1.2 equiv)DMF, rt, 2 hPhNPhPhFmoc4.2a, Rf = 0.404.4, Rf = 0.7Rf = 0.40 Rf = 0.42Rf = 0.704.2a RbHδ 8.75 (dd, J = 5.2, 0.8 Hz)Hδ 7.94 (dd, J = 1.7, 0.8 Hz) 181 ppm that corresponds to the proton adjacent to the nitrogen atom. This proton is more deshielded than most protons on a benzene ring, thus can be used to identify the formation of a pyridine product in the following experimental section. The product with a Rf value of 0.70 was characterized to be the by product 9-methylene-9H-fluorene (4.4). The protocol of a Kumada cross-coupling reaction on the cycloaddition product (4.1a) that was followed by a deprotection/oxidation process successfully generated 2,4-diphenypyridine (4.3) in moderate yields. Although the cross-coupling, deprotection and oxidation reactions were conducted at conditions outlined in reference papers, a modest survey of conditions is still necessary for each step to optimize the yield. 4.2.1 Optimization of the Kumada coupling reaction on enol phosphate The conditions of the Pd-catalyzed Kumada coupling reaction on 4.1a with phenylmagnesium bromide were screened to minimize the amount of catalytic loading, equivalents of the Grignard reagent and reaction time (Table 4.1). 182 Table 4.1 Condition screen for the Kumada coupling reaction on 4.1aa entry X catalyst Y time yield (%)b 1 3 PdCl2 10 16 – 20 h 60 2 3 PdCl2 + TMEDAc 10 16 – 20 h <10 3 3 PdCl2 10 3 h 59 4 3 PdCl2(PPh3)2 10 3 h 58 5 1.5 PdCl2 5 3 h 35 6 2 PdCl2 5 3 h 57 a reaction condition: 4.1a (0.1 mmol), THF (1.0 mL). b isolated yields reported. Each condition was repeated, and the higher yield was reported because the numbers were within experimental errors. c TMEDA = N,N,N’,N’-tetramethylethylenediamine The yields of the product remained around 60% when the reaction time was shortened to 3 h (59%, entry 3) or when the equivalents of the Grignard reagent was lowered to 2 and the catalytic loading of PdCl2 was lowered to 5 mol% (57%, entry 6). When 1.5 equivalents of the Grignard regent were used, the yield decreased to 35% (entry 5). In a report by Larsen and coworkers in 2005, a combination of PdCl2(PPh3)3 and a ligand N,N,N’,N’-tetramethylethylenediamine (TMEDA) was required to effectively couple the enol phosphate ester of N-Boc-4-piperidone with phenylmagnesium chloride in 93% yield (Scheme 1.29, Chapter 1.8.2).175 However, when this condition was applied to the Kumada coupling of 4.1a, the product was afforded in a very low yield (<10%, entry 2). The reaction was also conducted using the pre-catalyst PdCl2(PPh3)3 without addition of the ligand, and a similar yield of 4.2a was obtained compared with PdCl2 (58%, entry 3). NPhOFmoc Ph-MgBr (X equiv)catalyst (Y mol%)THF, rt, timeNPhPhFmocPPhOOOPh 4.1a 4.2a 183 4.2.2 Scope of Grignard reagents for the Kumada coupling reaction The cycloaddition product 4.1a was treated with various Grignard reagents at the optimized condition from Table 4.1 using 2 equivalents of the Grignard reagents and 5 mol% of PdCl2 (Figure 4.1). a Reaction condition: 4.3a (0.2 mmol), RMgX (X = Br or Cl, 0.4 mmol), PdCl2 (0.01 mmol), THF (2 mL), rt, 3 h. Isolated yields reported. b Reaction carried as in a using isopropylmagnesium chloride (0.4 mmol). Figure 4.1 Scope of Grignard reagents for the Kumada coupling reaction of 4.1aa Four commercially available Grignard reagents were applied to the Kumada coupling reactions to form products 4.2b-4.2e in 51 – 77% isolated yields. The reduced product 4.2c was obtained in 73% isolated yield from the cross-coupling reaction of 4.1a with isopropylmagnesium RMgX (2.0 equiv)PdCl2 (5 mol%)THF, rt, 3 – 8 hNPhRFmocNPhFmoc NPhFmoc NPhFmocFNPhFmocOMeNPhFmocNPhFmocNPhFmocPhNPhFmocMeON FmocNPhFmoc4.2b, 58%4.24.2c, 73%b 4.2d, 51%4.2e, 77%4.2i, 80% 4.2j, 85%4.2g, 60%4.2f, 28%4.2h, 81%4.2k, 0%NPhOFmocPPhOOOPh 4.1aN Fmoc4.2l, 0%N Fmoc4.2m, 0%N 184 chloride. The hydride source that reduced the enol phosphate functionality was formed from b-H elimination of the isopropyl group after it was transmetallated to palladium. The same reduced product (4.2c) was obtained from pentylmagnesium chloride in the Pd-catalyzed Kumada coupling reaction. The desired cross-coupling product with a pentyl substituent (4.2k) could not be constructed using this method. Different transition metal catalysts were screened for the cross-coupling reaction with an alkyl Grignard reagent, to be discussed in the next section. The Kumada coupling reaction of 4.1a with 4-fluorophenylmagnesium bromide afforded the product 4.2d in a lower yield of 51% than 4.2a. It suggested that a Grignard reagent with electron-withdrawing substituent was less reactive in the reactions. The product 4.2e from the cross-coupling reaction of 4.1a with p-tolylmagnesium bromide was formed in a high yield of 77%. It suggested that an aryl Grignard reagent with an alkyl substituent can be effectively coupled with the enol phosphate functionality. According to the results from commercially available Grignard reagents, some other electron-rich Grignard reagents that contain methoxy substituents and alkyl substituents should be attempted. Each Grignard reagent was synthesized by heating the corresponding aryl bromide with Mg metal in distilled THF at 70 °C. Five synthesized Grignard reagents were applied to the Kumada coupling reactions with 4.1a to form products 4.2f-j in 28 – 85% yields. Products 4.2h-j from 2-naphthylmagnesium bromide, 3,5-dimethylphenylmagnesium bromide and 4-biphenylmagnesium bromide were formed in very high yields of 81%, 80% and 85%, respectively. The Kumada coupling reactions on 4.1a were less effective for sterically hindered Grignard reagents. The cross-coupling reaction of 4.1a with 2-methoxyphenylmagnesium bromide formed the product 4.2f in a very low yield of 28%. No product (4.2l) was observed from the coupling with 2-mesitylmagnesium bromide. 185 The Kumada coupling reaction was not compatible with 2-pyridylmagnesium bromide (4.2m). Application of pyridyl derivatives as nucleophilic partners is known to be a challenge in traditional cross-coupling methods.216,217 It could be an interesting future direction to screen different catalysts and ligands to solve the challenge of cross-coupling reactions between pyridyl Grignard reagents and the enol phosphate functionality. 4.2.3 Kumada coupling reactions with alkyl Grignard reagents Palladium-catalyzed Kumada coupling reactions on the enol phosphate functionality with alkyl Grignard reagents formed the reduced product instead of the desired products with alkyl substituents. Some other metal catalysts were screened to diminish the b-H elimination of alkyl organometallic reagents.175,188,169 Scheme 4.6 Catalyst screen for the Kumada coupling reaction with pentylmagnesium chloride The desired product 4.2k was formed using first row transition metal catalysts in the Kumada coupling reaction of the cycloaddition product 4.1a with pentylmagnesium chloride (Scheme 4.4). When the pre-catalyst Ni(acac)2 was used in the reaction, the reduced compound (4.2c) was still formed as the major product (Scheme 4.4b). A 1H NMR spectrum of the quenched reaction mixture gave a 1:1.5 ratio of 4.2k and 4.2c. When Fe(acac)3 was applied to the reaction, NPhOFmoccatalyst (5 mol%)THF, rt, 3 hNPhFmocPPhOOOPh 4.1a 4.2kMgCl (2 equiv) NPhFmoc4.2cPdCl2: < 1 : 20Ni(acac)2: 1 : 1.5Fe(acac)3: 1.6 (20%) : 1a)b)c)Ha Haδ 5.79-5.51 (m)δ 5.47-5.32 (m) 186 the desired product 4.2k was successfully afforded as the major product in a 1.6:1 ratio of the two compounds in the product mixture, and it was isolated in a 20% yield (Scheme 4.4c). The signals of Ha of products 4.2k and 4.2c that were used to calculate their ratios in 1H NMR spectra were shown in Scheme 4.4. Scheme 4.7 The Kumada coupling reaction on enol diethylphosphate with pentylmagnesium bromide A protocol of Fe-catalyzed cross-coupling reactions with alkyl Grignard reagents that was established on enol diethylphosphate functionality was presented in the report by Cahiez and coworkers in 2008.169 It was envisioned that the cycloaddition product 4.5 featuring an enol diethylphosphate functional group could be a useful substrate in the Kumada coupling reaction with pentylmagnesium bromide (Scheme 4.7). The desired product 4.2k was obtained in 50% isolated yield. A higher ratio of 4.2k and 4.2c (3:1) was found in the 1H NMR spectrum of quenched reaction mixture. NPhOFmocPEtOOOEt4.5Fe(acac)3 (5 mol%)THF, rt, 3 hMgCl (2 equiv) NPhFmocNPhFmoc4.2k, 50%, ratio = 3 : 1 4.2c 187 Table 4.2 Kumada coupling reactions on enol phosphates with alkyl Grignard reagents entry R1 R product yield (%) ratio of 4.5:4.2c 1 n-Pr Ph 4.6a 24 1.5:1 2 Et 51 6:1 3 i-Pr Ph/Et 4.6c <10% <20:1 4 Et Ph/Et 4.6d <10% <20:1 Some other alkyl Grignard reagents were coupled with the enol diphenylphosphate cycloaddition product 4.1a and the enol diethylphosphate cycloaddition product 4.5 (Table 4.2). n-Propylmagnesium chloride was also applicable to the reaction. The product 4.6a was obtained from 4.5 in a higher yield (51%) and a higher ratio (6:1) than from 4.1a (entry 1 and 2). However, the Fe-catalyzed cross-coupling reactions with ethymagnesium chloride and isopropylmagnesium chloride still afforded the reduced product 4.2c as the major product. 4.2.4 Deprotection and oxidation of tetrahydropyridines to form pyridines The deprotection of the Fmoc group is typically conducted using piperidine in DMF.218 However, DMF is non-volatile (bp 153 °C) and miscible with both polar and nonpolar solvents, and removing it can be challenging. The deprotection and oxidation reaction that was conducted in DMF was quenched by adding water and extracting the aqueous layer with CH2Cl2. This process caused yield loss because the pyridine product is soluble in DMF. A quick solvent screen NPhOFmocFe(acac)3 (5 mol%)THF, rt, 3 hNPhR1FmocPROOOR 4.1a: R = Ph4.5: R = Et4.6R1 MgBr/Cl (2 equiv) NPhFmoc4.2c 188 established CH2Cl2 as a superior solvent for the deprotection and oxidation of 4.2a (entry 5, Table 4.3). Table 4.3 Screen of solvents for the deprotection and oxidation of 4.2aa entry solvent dielectric constant yield (%)b 1 DMSO 46.7 <10 2 CH3CN 37.5 71 3 DMF 36.7 61 4 DCM 8.93 97 5 THF 7.58 80 6 toluene 2.38 low solubility of 4.2a 7 hexanes 1.88 low solubility of 4.2a a reaction condition: 4.2a (0.1 mmol), piperidine (0.12 mmol, 0.64 mL in solvent), DDQ (0.2 mmol), solvent (1 mL). b isolated yields reported. Each condition was repeated, and the higher yield was reported because the numbers were within experimental errors. PhNb) DDQ (2.0 equiv)rt, 20 ha) piperidine (1.2 equiv)solvent, rt, 2 hPhNPhPhFmoc4.2a 4.3a 189 a reaction condition: 4.2a (0.1 mmol), piperidine (0.12 mmol, 0.64 mL in DCM), DDQ (0.2 mmol), solvent (1 mL). solvent condition for TLC plates: 20% EtOAc in hexanes. R = unquenched reaction mixture Figure 4.2 TLC plates of the reaction mixture in the processes of deprotection and oxidation in DMF and CH2Cl2a The reaction progress of the deprotection and oxidation of 4.2a was monitored using TLC (Figure 4.2). When the reaction was conducted in DMF, the Fmoc group was completely deprotected from the nitrogen atom after 2 h at rt (Figure 4.2a). The TLC plate showed consumption of 4.2a (Rf = 0.4) and formation of the unprotected tetrahydropyridine product 4.7 (Rf = 0.33) and the byproduct 4.4. Addition of DDQ resulted in oxidation of 4.7 to 2,4-diphenylpyridine (4.3a, Rf = 0.42). When the reaction was conducted in CH2Cl2, 4.2a was not fully deprotected after 2 h at rt (Figure 4.2b). The oxidant DDQ was still added to the reaction mixture, and the starting material 4.2a was completely converted to the pyridine product 4.3a after 20 h at Rf = 0.40 Rf = 0.402% piperidine in DMFrt, 2 h Rf = 0.40 Rf = 0.33Rf = 0.70DDQ, DMFrt, 20 h Rf = 0.40 Rf = 0.42Rf = 0.704.2a 4.2a 4.2aPhNH b) DDQ (2.0 equiv)rt, 20 ha) piperidine (1.2 equiv)solvent, rt, 2 hPhNPhPhFmoc4.2a, Rf = 0.4 4.7, Rf = 0.33PhNPh4.3a, Rf = 0.424.4, Rf = 0.7Rf = 0.40 Rf = 0.402% piperidine in DCMrt, 2 h Rf = 0.40 Rf = 0.33Rf = 0.40Rf = 0.70DDQ, DMFrt, 20 h Rf = 0.40 Rf = 0.42Rf = 0.704.2a 4.2a 4.2aR R RR R Ra)b) 190 rt. It suggested that the Fmoc group was deprotected at a higher rate in DMF than CH2Cl2. The deprotection and oxidation processes occurred in a one-pot condition in CH2Cl2. The higher overall yield of the pyridine product in CH2Cl2 might be attributed to a faster oxidation in CH2Cl2 or the ease of work up in CH2Cl2 where the solvent was directly concentrated in vacuo. a Reaction condition: 4.2 (0.1 mmol), piperidine (0.12 mmol, 0.6 mL in DCM), DDQ (0.2 mmol), DCM (1 mL), rt, 16 – 20 h. Isolated yields reported. Figure 4.3 Synthesis of 2,4-disubstituted pyridinea The tetrahydropyridines 4.2 obtained from the Kumada coupling reactions were treated with 1.2 equivalents of 2% piperidine in CH2Cl2 and 2 equivalents of DDQ to generate substituted RNb) DDQ (2.0 equiv)rt, 16 – 20 ha) piperidine (1.2 equiv)DCM, rt, 2 hPhNPhRFmocNPhNPhNPhPhNPhOMeNPhMeONPhFNPhNPh4.3c, 91%4.3g, 96%4.3h, 94%4.3f, 90%4.3e, 67%4.3d, 61%4.3b, 88%4.3i, 82%4.2 4.3NPh4.3j, 65%Hδ 8.75 (d, J = 5.2 Hz)Hδ 8.73 (d, J = 5.2 Hz)Hδ 8.71 (d, J = 5.2 Hz)H H Hδ 8.72 (d, J = 5.2 Hz) δ 8.85 (d, J = 5.5 Hz) δ 8.72 (dd, J = 5.2, 0.8 Hz)H H Hδ 8.67 (d, J = 5.2 Hz) δ 8.60 (d, J = 5.1 Hz) δ 8.60 (d, J = 5.2 Hz) 191 pyridines (Figure 4.3). Each product was identified by the diagnostic signal of the proton adjacent to the nitrogen atom that has a chemical shift in the range of 8.60 – 8.85 ppm in its 1H NMR spectrum. Products 4.3b-j with aryl and alkyl substituents at the C-4 position were isolated in 61 – 96% isolated yields. The construction of 2,4-disubstituted pyridines was shown to be efficient using the protocol of cycloaddition, cross-coupling, deprotection and oxidation reactions. It would be synthetically interesting to generate a pyridine derivative that has a different substitution pattern. Scheme 4.8 The construction of a 2,4,6-trisubstituted pyridine An attempt to construct a 2,4,6-trisubstituted pyridine was performed using 4-isopropyl-2-diphenylphosphoryloxy-1,3-butadiene 2.1b from Chapter 2 (Scheme 4.8). The hetero-Diels-Alder reaction of diene 2.1b with Fmoc-NH2 and benzaldehyde afforded two diastereomers of the product 4.8a in 62% isolated yield. The two diastereomers were not separated on silica gel chromatography because they were converted to the same pyridine product. A Pd-catalyzed cross-coupling reaction between 4.8 and p-tolylmagnesium bromide afforded two diastereomers of the 2.1b (3 equiv)H2N-Fmoc (1 equiv)PhCHO (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °CKNOFmocPhOPPhOOOPhPPhOOOPh1)MgBrPdCl2 (5 mol%)THF, rt, 8 h2) piperidine (1.2 equiv) DCM, rt, 2 hthen DDQ (2.0 equiv)DCM, rt, 16 – 20 h(2 equiv)NPh4.8 4.3ka)NOFmocPhPPhOOOPh1)MgBrPdCl2 (5 mol%)THF, rt, 8 h2) piperidine (1.2 equiv) DMF, rt, 8 hthen DDQ (2.0 equiv)DCM, rt, 16 – 20 h(2 equiv)NPh4.84.3k, 54% over two stepsb) 192 tetrahydropyridine product that was confirmed by the 1H NMR spectrum of the crude reaction mixture after quenching. The crude reaction mixture was directly applied to the deprotection and oxidation step in CH2Cl2, but no desired pyridine product was observed (Scheme 4.6a). A plausible reason was that the isopropyl group introduced a large steric strain that lowered the rate of the deprotection or oxidation process. Since the deprotection step proceeds at a higher rate in DMF as shown in Figure 4.2, the crude reaction mixture of 4.8 was subjected to a deprotection reaction in DMF and the reaction progress was monitored by TLC plates. After 8 h of the reaction at rt, the TLC plate showed a complete deprotection of the Fmoc group. Subsequent addition of DDQ in CH2Cl2 successfully converted the unprotected tetrahydropyridine to 2-isopropyl-6-phenyl-4-(p-tolyl)pyridine (4.3k) in 54% isolated yield over two steps (Scheme 4.6b). 4.3 Synthesis of derivatives of fluorescent pyridines An interesting product 4-biphenyl-2-phenylpyridine (4.3h) was synthesized in 94% isolated yield from the tetrahydropyridine 4.2j (Figure 4.3). This product was visualized as a bright blue spot on the TLC plate under both long-wave and short-wave UV light. The bright blue spot suggested that it is a fluorescent molecule. This pyridine 4.3h was found in two patents in 2015 and 2018,219,220 but it has not been reported in any manuscripts before. The 2018 patent presented the invention of using 4-aryl-2-arylpyridines as bidentate ligands in Ir(III) or Pt(II) complexes to construct phosphorescent emitters with improved emission efficiency. The patent suggested in a future aspect that a layer comprised of the ligand or the complex could serve as a light emitter in OLEDs. 193 Scheme 4.9 Synthesis of 4-biphenyl-2-phenylpyridine 4.3h in the patent in 2008 The method to construct 4-biphenyl-2-phenylpyridine (4.3h) in the patent in 2008 is presented in Scheme 4.9. A Pd-catalyzed Suzuki coupling of 2,4-dibromopyridine (4.8) with phenylboronic acid was conducted at 100 °C for 2 days. The C-2 position on the pyridine was selectively coupled to form 4-bromo-2-phenylpyridine 4.9 in 66% yield. A byproduct 2,4-diphenylpyridine (4.3a) was also obtained in 13% yield. A subsequent Suzuki coupling of 4.9 with biphenylboronic acid afforded 4.3h in 50% yield. Some drawbacks of this protocol include a) utilization of an expensive starting material (CA$107 for 1 g of 4.8 on Sigma-Aldrich), b) long reaction time at temperature above 100 °C, c) loss of compound 4.9 due to a second coupling with phenylboronic acid, and d) requirement of a degass process via three cycles of freeze-pump-thaw for each step. A protocol to construct 4-biphenyl-2-phenylpyridine (4.3h) with ease of execution could be significant to improve the applicability of this compound in material science. A derivative of 4-biphenyl-2-phenylpyridine with substituents on the phenyl ring was stated to be particularly useful in light-luminating materials in the patent. The authors proposed that substitution of the phenyl ring might twist the conjugated plane of the molecule, thus tune the band gap of the material. For example, introduction of fluorine substituents on the phenyl ring NBr BrB(OH)2Pd(PPh3)4Na2CO3DME/H2O100 °C, 48 hNBr4.9, CA$107/g 4.10, 66%N4.3a, 13%B(OH)2Pd(PPh3)4Na2CO3PhCH3/EtOH/H2O110 °C, 24 hN4.3h, 50% 194 could have blueshift effect on the fluorescence of the molecule. However, the patent did not report any results on the construction of fluorinated or other substituted 4-biphenylpyridine derivatives. A plausible reason is that coupling an arylbromide with polyfluorophenylboronic acid can be challenging.221,222,223 Polyfluorophenylboronic acid can decompose rapidly in a protodeboronation process (Scheme 4.8).224,225 According to the mechanism, using any arylboronic acids that contain strong electron-withdrawing groups could suffer from the problem of protodeboronation.226 Some special boronic esters were developed to solve the problem of protodeboronation, but the reactions proceeded in the presence of strictly chosen catalysts, ligands, bases, and solvents.227,228,229,230 Scheme 4.10 A plausible mechanism of the protodeboronation of a polyfluorophenylboronic acid I was intrigued by the potential applicability of the protocol that is presented in this Chapter to construct variously substituted 4-biphenyl-2-phenylpyridines. Substitution on the phenyl ring of 4-biphenyl-2-phenylpyridine derivatives can be introduced by using substituted benzaldehydes in the multicomponent hetero-Diels-Alder step. Substituted benzaldehydes are much more easily accessed and stable than the corresponding boronic acids. The synthesis of 4-biphenylpyridine derivatives will be presented in this section and their fluorescent properties will be examined in the next section. B(OH)2F H2O B(OH)3F H2O HFH3O B(OH)3 195 4.3.1 Scope of aldehydes for the multicomponent hetero-Diels-Alder reaction using N-Fmoc amine According to principles of fluorescence, a molecule that has higher extent of conjugation in p electrons has smaller band gap between the ground state and the excited state, thus absorbs and emits at a longer wavelength.231 An increase in extent of conjugation can be achieved from more conjugated p bonds or the incorporation of substituents that have resonance effect (Figure 4.4).232 Figure 4.4 The effect of p conjugation length on the fluorescence of compounds The scope of aldehydes for the multicomponent hetero-Diels-Alder reaction with diene 2.1a and N-Fmoc amine were broadened to incorporate substitutions that might have redshift or blueshift effect on fluorescence (Figure 4.5). Heteroatom-substituted benzaldehydes and two naphthaldehydes were applied in the multicomponent hetero-Diels-Alder reactions to examine their redshift effect. Cyclohexanecarboxaldehyde was used to make a comparison with products of naphthaldehydes. 4-Hydroxybenzaldehyde that was not applicable to the multicomponent hetero-Diels-Alder reaction (Figure 3.2, Chapter 3) was sulfonated by treating with mesyl-, tosyl- S001234S1λabs λem01234S001234S1λabs λem01234OHS001234S1λabs λem01234 287 291 320 Wavelength (nm) emission Fluorescence spectra 196 and nosyl chloride. Some di- and trifluoro substituted benzaldehydes were applied to the hetero-Diels-Alder reactions because the corresponding fluorinated 4-biphenyl-2-phenylpyridine products were difficult to be synthesized using Suzuki coupling reactions, as discussed before. Similarly, some other benzaldehydes with electron-withdrawing groups like chloro- and cyano groups were applied to the multicomponent hetero-Diels-Alder reactions. a Reaction condition: H2N-Fmoc (0.2 mmol), aldehyde (0.3 mmol), 2.1a (0.6 mmol, 0.6 mL DCM), BF3•OEt2 (0.3 mmol), DCM (1.0 mL), 40 °C, 16 h. Isolated yields reported. Figure 4.5 Scope of aldehydes for the multicomponent hetero-Diels-Alder reactiona 2.1a (3 equiv)H2N-Fmoc (1 equiv)aldehyde (1.5 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °CKNOFmocROPPhOOOPhPPhOOOPhNOFmocPPhOOOPhOMeNOFmocPPhOOOPhFFNOFmocPPhOOOPhFFNOFmocPPhOOOPhNOFmocPPhOOOPhOMeNOFmocPPhOOOPhFFF NOFmocPPhOOOPhCN4.14.1n, 67%4.1b, 58% 4.1c, 52% 4.1d, 50%4.1e, 62% 4.1f, 62% 4.1g, 43%NOFmocPPhOOOPhCl4.1h, 56%NOFmocPPhOOOPh4.1i, 58%NOFmocPPhOOOPh4.1l, 56% OTsNOFmocPPhOOOPh4.1k, 52% OMsNOFmocPPhOOOPh4.1m, 56% ONsNOFmocPPhOOOPh4.1j, 57% 197 Both electron-rich and electron-deficient aldehydes participated smoothly in the multicomponent hetero-Diels-Alder reactions with N-Fmoc amine and diene 2.1a to form products 4.1b-n in 43 – 67% isolated yields. Three products (4.1d, 4.1e, and 4.1f) from polyfluorobenzaldehyde were isolated in 50%, 62%, and 62%, respectively. Three sulfonates derived from 4-hydroxylbenzaldehyde reacted in the multicomponent hetero-Diels-Alder reactions to form products 4.1j, 4.1k and, 4.1l in 52%, 56%, and 56% yields, respectively. 4.3.2 Synthesis of fluorescent 4-biphenyl pyridine derivatives 4-Biphenylpyridine derivatives were constructed through derivatization of the cycloaddition products 4.1b-n in cross-coupling reactions and deprotection/oxidation reactions (Figure 4.6). Compounds 4.1 were treated with 2 equivalents of biphenylmagnesium bromide in the presence of 5 mol% of PdCl2 to afford crude mixtures of tetrahydropyridines 4.11. Subsequently, the crude mixtures of 4.11 were treated with 1.2 equivalents of piperidine and 2 equivalents of DDQ in CH2Cl2 to generate 4-biphenylpyridine derivatives. Each product was visualized as a bright blue spot on the TLC plate under long-wave or short-wave UV light. 198 a Reaction condition: 4.1 (0.1 mmol), biphenylMgBr (0.2 mmol), PdCl2 (0.005 mmol), THF (1 mL), rt, 3 h; piperidine (0.12 mmol, 0.64 mL in DCM), DDQ (0.2 mmol), DCM (2 mL), rt, 16 – 20 h. Isolated yields reported. Yields in paratheses are average yields per step. Figure 4.6 Synthesis of 4-biphenylpyridine derivatives from 4.1a The 4-biphenylpyridine products 4.12a-k were isolated in 39% to 88% overall yields that gave the average yields per step in the range of 62% to 94%. Three examples of fluorinated 4-biphenylpyridine derivatives (4.12c-e) were successfully synthesized in 56%, 53%, and 70% overall yields, respectively. A cyano substituent on the phenyl ring survived in the condition of a Kumada coupling reaction where pyridine 4.12f was obtained in 58% overall yield. The successful NOFmocRPPhOOOPhpiperidine (1.2 equiv) DCM, rt, 2 hthen DDQ (2.0 equiv) rt, 16 – 20 hNRPhPhMgBrPdCl2 (5 mol%)THF, rt, 3 h(2.0 eqiuv) NRPhFmocNPhNPhOMeOMeNPhFFNPhFFNPhFFFNPh4.1 4.11 4.124.12a, 65% (81%) 4.12b, 50% (71%) 4.12c, 56% (75%)4.12d, 53% (73%) 4.12e, 70% (84%)4.12i, 52% (72%)NPh CN4.12f, 58% (76%)NPh Cl4.12g, 39% (62%)NPh4.12h, 77% (88%)NPh OTs4.12k, 88% (94%)NPh OMs4.12j, 60% (77%)a)b)NPh ONs4.12l, 0%NPh4.12m, 0% 199 formation of products 4.12g, 4.12j and 4.12k featuring an aryl chloride, aryl mesylate and aryl tosylate group, respectively, suggested a superior selectivity of the enol phosphate functionality in the Kumada coupling reactions. The pyridine product (4.12l) with a nosyl group was not obtained, perhaps because that the aryl nosyl group competes with the enol phosphate group in the cross-coupling process. Formation of pyridine (4.12m) was not observed that might be due to a large steric strain between the 1-napthyl group and the pyridine ring. 4.4 UV-vis and fluorescence spectroscopy analysis on 4-biphenylpyridines 4.4.1 Absorption and emission wavelengths of the 4-biphenylpyridine derivatives The absorption and emission profiles of the 4-biphenylpyridine derivatives were obtained from UV-vis spectroscopy and fluorescence spectroscopy. Each compound was dissolved in CH2Cl2, that has a cut-off wavelength at 235 nm.233 A dilute solution of each compound was made such that the maximum absorbance in its UV-vis spectrum was lower than 0.5. The wavelength of maximum absorption for each compound captured by UV-vis spectroscopy was used as the excitation wavelength in fluorescence spectroscopy. The wavelengths of maximum absorption and emission for all 4-biphenylpyridine derivatives are presented in Table 4.4. 200 Table 4.4 Wavelengths of maximum absorption and emission of 4-biphenyl pyridine derivativesa pyridine R max UV absorption (nm) max emission (nm) Stokes shift (cm-1) 4.3h Ph 283 355 7167 4.12a 4-MeOPh 276 389 10525 4.12b 3-MeOPh 286 363 7417 4.12c 2,5-difluoroPh 285 365 7690 4.12d 3,4-difluoroPh 282 359 7606 4.12e 2,3,6-trifluoroPh 283 361 7635 4.12f 4-cyanoPh 268 370 10286 4.12g 4-chloroPh 267 355 9284 4.12h 2-naphthyl 259 369 11510 4.12i c-hexyl 282 349 6808 4.12j 4-TsOPh 267 359 9598 4.12k 4-MsOPh 267 358 9520 a Samples were dissolved in CH2Cl2 for measurements in both UV-vis spectroscopy and fluorescence spectroscopy. The wavelength of maximum absorption for each compound was set as the excitation wavelength in fluorescence spectroscopy. The wavelengths of maximum absorption of 4-biphenylpyridine derivatives lied in the range of 260 – 285 nm, and the wavelengths of maximum fluorescence were around 350 nm to 390 nm. The difference between wavenumbers of the maximum absorption and fluorescence gives the Stokes shift of a compound. A fluorophore with a larger Stokes shift is beneficial to its application in imaging because it can minimize self-absorption of the molecule.234 The Stokes shift is not directly related to the HOMO-LUMO band gap, thus is less predictable than the shift in wavelengths of fluorescence.235 In these examples of 4-biphenylpyridine derivatives, compounds NRPh 201 4.12a (R = 4-MeOPh), 4.12f (R = 4-CNPh) and 4.12h (R = 2-naphthyl) had Stokes shifts higher than 1´104 cm-1. All three compounds have increased extent in conjugation of p electrons. Figure 4.7 Fluorescence spectra of 4-biphenylpyridine derivatives with methoxy-, cyano-, naphthyl, and cyclohexyl groups As expected, 4-biphenylpyridine derivatives that had increase in conjugation of p electrons had significant redshift in fluorescence wavelengths (Figure 4.7). 4-Biphenyl-2-(4-methoxyphenyl)pyridine (4.12a) had the highest wavelength of maximum fluorescence at 389 nm among all examples. The wavelength lies in the region of violet visible light in electromagnetic wave. In contrast, when the methoxy group was at meta-position (4.12b), less redshift was observed because the electron-donating (resonance) effect of the methoxy group could only be induced on the phenyl ring but not on the entire molecule. Incorporating a naphthyl group (4.12h) NRPh35538936337036934900.20.40.60.811.2300 320 340 360 380 400 420 440 460 480 500relative intensitywavelength (nm)Fluorescence spectroscopy #14.3h, R = Ph4.12a, R = 4-MeOPh4.12b, R = 3-MeOPh4.12f, R = 4-CNPh4.12h, R = 2-naphthyl4.12i, R = c-hexyl 202 increased the extent of conjugation of the p system, thus induced an observable redshift effect (lem = 370 nm). The cyclohexyl group led to a blueshift (lem = 349 nm) in fluorescence. Figure 4.8 Fluorescence spectra of 4-biphenyl pyridines with halogen and sulfonate groups Substituents that withdraw electrons by induction effect, including fluoro- and chloro-groups in products 4.12c-e and 4.12g, had little effect on the wavelengths of maximum fluorescence compared to 4.3h. Compounds 4.12j and 4.12k with sulfonate groups on the phenyl ring had no obvious change in emission wavelengths either. Even though the oxygen atom located at the para-position of the phenyl ring in each compound, the electron-withdrawing character of a sulfonyl group reduces the electron-donating (resonance) effect of the oxygen. Fluorescence spectra of products with halogen groups and sulfonate groups were plotted in Figure 4.8, and the curves were all overlapped with very slight change in wavelengths of fluorescence. NPhR00.20.40.60.811.2300 320 340 360 380 400 420 440 460 480 500relative intensitywavelength (nm)Fluorescence spectroscopy #24.3h, R = H4.12c, R = 2,5-difluoro4.12d, R = 3,4-difluoro4.12e, R = 2,3,6-difluoro4.12g, R = 4-Cl4.12j, R = 4-TsO4.12k, R = 4-MsO 203 The fluorescence spectroscopy analysis on 4-biphenylpyridine derivatives found that fluorine substituents had little effect on the wavelengths of emission that is not consistent with the statement in the patent. Nevertheless, it was envisioned that the substituents might have effects on the efficiency of emission of the compounds, to be presented in the next section. 4.4.2 Measuring quantum yields of the 4-biphenylpyridine derivatives Quantum yield (F) is an indication of the efficiency of emission for a photoluminescent compound.236 Quantum yield is defined as the number of photons emitted vs the number of photons absorbed.237 However, these two quantities are difficult to be measured directly. The quantum yield of a photoluminescent compound is typically obtained via a relative measurement in reference to a standard compound that has a literature value of quantum yield.238 In this section, the relative quantum yields of compounds 4.12a-k were measured in reference to the parent compound 4-biphenyl-2-phenylpyridine (4.3h). The absolute quantum yield of 4.3h was determined in a relative measurement with a standard compound p-terphenyl. In the measurement of relative quantum yields of compounds 4.12a-k, the solution of each compound in CH2Cl2 was diluted such that the maximum absorbance was around 0.1. A low concentration of the sample is important to ensure uniform emission from the entire volume of the cuvette. The excitation wavelength was set at 275 nm for measurements of 4.3h and 4.12a-k in fluorescence spectroscopy. The emission spectrum of each compound was obtained in a scan range of 300 nm to 500 nm. The relative quantum yield of each compound can be calculated using the following equations, and the numbers will be presented in Table 4.5. 204 !#$!#% × 100% = "$×$%×%$&"%×$$×%%& Equation 4.1 Calculating the relative quantum yields of compounds 4.12a-k in reference to 4.3h 𝑓& = 1 − 10'(& Equation 4.2 Calculating absorption factors from absorbance In Equation 4.1, !#$!#% × 100% refers to the relative quantum yield of a sample in percentage with respect to the reference compound 4.3h. Symbols 𝐹) and 𝐹* are the integrated intensities of fluorescence of the reference and the sample. Symbols 𝑓) and 𝑓* are the absorption factors of the reference and the sample, where absorption factors are calculated from absorbance (A) using Equation 4.2. Symbols 𝑛) and 𝑛* are the refractive indices of the solvents for the reference and the sample. In this case, the reference compound 4.3h and samples were all dissolved in CH2Cl2 that has a refractive index of 1.4241. Area = Fr Area = Fi Wavelength (nm) 275 absorbance Absorption spectrum of sample Ai Wavelength (nm) absorbance Absorption spectrum of reference Wavelength (nm) 275 emission Fluorescence spectrum of reference Ar Wavelength (nm) emission Fluorescence spectrum of sample 205 The absolute quantum yield of the compound 4.3h was measured using a standard compound p-terphenyl (4.13). p-Terphenyl was selected as the standard because it has similar absorption and emission profiles (labs = 276 nm and lem = 337 nm) with 4.3h. The quantum yield of p-terphenyl was reported to be 0.93 in cyclohexane (refractive index = 1.4262) by Berlman in 1971.239 Excitation wavelength was set at 290 nm for the fluorescence spectroscopy because this is the wavelength used in the reference paper. The fluorescence spectrum of p-terphenyl was scanned from 300 nm to 500 nm, and the quantum yield of 4.3h in CH2Cl2 can be calculated using Equation 4.3. Φ$* = "$×$'×%$&"'×$$×%'& ×Φ$+ Equation 4.3 Calculating the quantum yield of 4.3h from the known quantum yield of a standard p-terphenyl s =4.13 206 Table 4.5 Quantum yields of 4-biphenyl pyridine derivativesa pyridine R Relative quantum yield Quantum yield 4.3h Ph 100% 0.32 4.12a 4-MeOPh 202% 0.64 4.12b 3-MeOPh 148% 0.47 4.12c 2,5-difluoroPh 147% 0.46 4.12d 3,4-difluoroPh 233% 0.74 4.12e 2,3,6-trifluoroPh 90.8% 0.29 4.12f 4-cyanoPh 128% 0.40 4.12g 4-chloroPh 107% 0.34 4.12h 2-naphthyl 166% 0.52 4.12i c-hexyl 83.8% 0.26 4.12j 4-TsOPh 197% 0.62 4.12k 4-MsOPh 134% 0.42 a Samples were dissolved in CH2Cl2 for measurements in both UV-vis spectroscopy and fluorescence spectroscopy. The reference standard p-terphenyl was dissolved in cyclohexane. The excitation wavelength was 275 nm for all fluorescence measurements. Fluorescence spectra were scanned from 300 nm to 500 nm. The absolute quantum yield of 4.3h in CH2Cl2 was determined to be 0.32 in reference to p-terphenyl, and the absolute quantum yields of other products 4.12a-k were calculated from their relative quantum yields (Table 4.5). Significantly higher quantum yields were obtained for compounds 4.12a (R = 4-MeOPh, F = 0.64) and 4.12h (R = 2-naphthyl, F = 0.52), that might be attributed to an increase in extent of conjugation of p electrons. A longer p-conjugation length could likely decrease the dipole length when the molecule is excited from S0 to S1, thus lowers the rate of nonradiative decay due to electron transfer in the dipole and increases the quantum yield.240 NRPh 207 The efficiency of emission of compound 4.12j (R = 4-TsOPh, F = 0.62) was significantly higher than the parent compound 4.3h, perhaps due to the incorporation of another phenyl ring in the p-toluenesulfonate group. Introducing two fluorine atoms at varied positions on the phenyl ring significantly increased the quantum yields of 4.12c (F = 0.46) and 4.12d (F = 0.74), whereas three fluorine atoms lowered the quantum yield of 4.12e (F = 0.29) compared to the parent compound 4.3h. This result is not surprising because several similar examples of fluorinated fluorophores that have higher quantum yields than the parent compound were found in literature, and all the reports mentioned that the positions and numbers of fluorine atoms can have great effects on the quantum yields.241,242,243,244 4.5 Manipulations of 4-biphenyl-2-phenylpyridines The functionalization of 4-biphenyl-2-phenylpyridine derivatives should allow further manipulations of the compounds. It was intent on coupling the phenyl ring of 4-biphenyl-2-phenylpyridine derivatives with some chromophores like carbazole to construct highly fluorescent compounds. The resulted compound could not be directly obtained from the protocol developed in this Chapter because the corresponding aldehyde was not applicable to the multicomponent hetero-Diels-Alder reactions (Scheme 4.11). Scheme 4.11 The hetero-Diels-Alder reaction of 4-(9H-carbazol-9-yl)benzaldehyde BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °CKNOFmocPPhOOOPhOPPhOOOPhOHH2N Fmoc(1.0 equiv)(1.5 equiv)2.1a (3.0 equiv)N Npdt not observed 208 Scheme 4.12 Cross-coupling reactions of 4.12g with carbazole The aryl chloride functionality in compound 4.12g was used as an electrophilic partner in transition metal catalyzed cross-coupling reactions with carbazole. Two examples were attempted using a Pd-catalyzed Buchwald-Hartwig reaction245 and a Cu-catalyzed Ullman-type reaction,246 but neither of them afforded the desired product 4.13 (Scheme 4.12). Scheme 4.13 Nucleophilic aromatic substitution on 4.12c The compound 4.12c with 2,5-difluorophenyl functional group is a good substrate for nucleophilic aromatic substitution (SNAr). A SNAr of 4.12c with carbazole was conducted using a condition outlined by Muhammad and coworkers in 2019.247 Compound 4.12c was treated with NPhHNSPhos (10 mol%) NPh4.13, product not observed4.12gKtBuO (1.5 equiv)toluene, 110 °C, 16 hCl(1.2 equiv)Pd2(dba)3 (10 mol%)Na)NPhHNCuI (5 mol%)NPh4.13, product not observed4.12gCs2CO3 (1.5 equiv)DMF, 150 °C, 16 hCl(1.5 equiv)Nb)NPhFFHNKOH (1.5 equiv)NPhN4.14, desired product, not observedNPhOHF4.12c 4.15, 90%FDMSO, 110 °C, 16 h(1.5 equiv)123456 209 1.5 equivalents of carbazole and potassium hydroxide at 110 °C in DMSO for 16 h (Scheme 4.13). Substitution at C-2 position was expected due to the electron-withdrawing effect of the pyridine. Formation of product 4.14 was not observed, perhaps due to high steric strain of the tricyclic ring in carbazole. Instead, SNAr of 4.12c by hydroxide formed 2-(4-([1,1'-biphenyl]-4-yl)pyridin-2-yl)-4-fluorophenol (4.15) in 90% isolated yield. The 19F NMR spectrum of the product found one signal at -125.3 ppm. A HRMS-ESI experiment of the product found [M+H]+ = 342.1293 that was consistent with our calculation for C23H17FNO ([M+H]+ = 342.1294). The product was visualized as a bright green spot on the TLC plate under short-wave UV light. The spot was at a much higher Rf value of 0.7 (20% EtOAc in hexanes) compared to the starting material 4.12c (Rf = 0.42) that suggested an intramolecular hydrogen bonding in the compound. Figure 4.9 Fluorescence spectra of compound 4.15 under different excitation wavelengths A fluorescence spectroscopy analysis on 4.15 in CH2Cl2 found that its emission profile was affected by the excitation wavelength (Figure 4.9). When the sample was excited by photons at 240 nm, the wavelength of maximum fluorescence was at 356 nm that was close to the parent 356392413.02999880100200300400500600300 320 340 360 380 400 420 440 460 480intensitywavelengthFluorescence Spectra of 4.15 under Different Excitation Wavelengths240 nm250 nm256 nm260 nm270 nm 210 compound 4.3h. When the excitation wavelengths were in the range of 250 nm to 260 nm, the intensities of peaks at 392 nm and 413 nm increased in the emission spectra. This property was not observed for any of the compounds 4.3h and 4.12a-k, where changing the excitation wavelengths by around 20 nm did not have large effect on their emission spectra. The peaks at 392 nm and 413 nm might come from an excited-state intramolecular proton transfer (ESIPT) that is shown in a simplified schematic representation in Figure 4.10.248 Figure 4.10 Schematic representation of ESIPT of 4.15 The compound 4.15 has a hydrogen donor (-OH) and a hydrogen acceptor (-N=) near each other, that makes it a good substrate for intramolecular hydrogen transfer. When 4.15 is excited to its singlet excited state, it can either relax back to the ground state via fluorescence at lE or transfer to the excited state of its tautomer 4.16 via ESIPT. Emission from the excited state of 4.16 to the ground state occurred at a wavelength lK that is normally larger than lE. The relative intensities of the emission of a ESIPT fluorophore can be largely affected by the surrounding media including solvents, temperature, and excitation wavelengths. The tunable fluorescent properties of ESIPT S0S1absorption emission (λE)ESIPTS0S1emission (λK)GSIPTNPhOFHNPhOFH4.15 4.16δ-δ+ 211 fluorophores by changing the surrounding media make them significantly useful in optical emitters in material science.249 4.6 Conclusions A protocol of multicomponent hetero-Diels-Alder reactions, cross-coupling reactions, deprotection and oxidation reactions was established for the construction of di- and trisubstituted pyridines. The Pd-catalyzed cross-coupling reactions of N-Fmoc cycloaddition products with various Grignard reagents afforded 12 examples of tetrahydropyridine products in 28 – 85% yields. The tetrahydropyridine products were treated with piperidine and DDQ in DCM to afford 10 examples of 2,4-disubstituted pyridines in 61 – 97% yields. One example of 2,4,6-trisubstituted pyridine was constructed from a cycloaddition product in 54% yield over two steps. When the enol phosphate functionality was converted to a biphenyl substituent, the pyridine product showed strong fluorescence. Hetero-Diels-Alder products from various aldehydes were applied in the protocol to construct 11 examples of 4-biphenylpyridine derivatives in 39 – 88% isolated yields over two steps. The absorption and emission profiles of all 4-biphenylpyridine derivatives were obtained from UV-vis and fluorescence spectroscopy. The wavelengths of maximum emission of 4-biphenylpyridine derivatives ranged from 349 nm to 389 nm. Their quantum yields were measured to be 0.26 – 0.74 in reference to a standard compound p-terphenyl. There is a general trend that pyridine derivatives with increase in extent of conjugation have higher wavelengths of emission and higher quantum yields. Fluorinated pyridine derivatives had no observable change in wavelengths of emission but had significant enhancement in quantum yields. 212 4.7 Experimental information General information: Referred to Experimental in Chapter 2. The multicomponent hetero-Diels-Alder reactions were conducted in non-distilled DCM. UV-vis spectroscopy was performed using a Cary 5000 UV-Vis NIR Spectrophotometer. Fluorescence spectroscopy was performed using an Agilent Cary Eclipse Fluorescence Spectrophotometer. Representative procedure for sulfonation of 4-hydroxybenzaldehyde250 4-Formylphenyl methanesulfonate A solution of 4-hydroxybenzaldehyde (0.37 g, 3 mmol, 1.0 equiv) in EtOAc (10 mL) was cooled to 0 °C. Triethylamine (0.41 g, 3.6 mmol, 1.2 equiv) and methanesulfonyl chloride (0.61 g, 6 mmol, 2.0 equiv) were added in sequence at 0 °C. The reaction mixture was warmed to rt and stirred for 10 min. Water (10 mL) was added and the aqueous layer was extracted with EtOAc (´2). The combined extracts were washed with water (5 mL) and brine (10 mL) and dried over sodium sulfate. The extracts were concentrated in vacuo and gave 0.55 g (95%) of the product as a light-yellow solid. The material was used without further purification. mp 56 – 57 °C. Spectroscopy data match a literature report.250 1H NMR (300 MHz, Chloroform-d) δ 10.02 (s, 1H), 8.13 – 7.76 (m, 2H), 7.68 – 7.36 (m, 2H), 3.21 (s, 3H) ppm. HOOHSO OClEt3NEtOAc0 °C -> rt, 10 minHOOMs 213 4-Formylphenyl 4-methylbenzenesulfonate 4-formylphenyl 4-methylbenzenesulfonate was constructed using an analogous procedure as described for 4-formylphenyl methanesulfonate from 4-hydroxybenzaldehyde (0.37 g, 3 mmol), and 4-toluenesulfonyl chloride (0.69 g, 3.6 mmol) in DCM (10mL). The resultant solids after concentration in vacuo was purified by column chromatography over silica gel (25% EtOAc/hexanes). Yield: 90%. Light pink solid. mp 68 – 69 °C. Spectroscopy data match a literature report.250 1H NMR (300 MHz, Chloroform-d) δ 9.97 (s, 1H), 7.86 – 7.79 (m, 2H), 7.78 – 7.66 (m, 2H), 7.37 – 7.28 (m, 2H), 7.22 – 7.11 (m, 2H), 2.46 (s, 3H) ppm. 4-Formylphenyl 4-nitrobenzenesulfonate 4-formylphenyl 4-nitrobenzenesulfonate was constructed using an analogous procedure as described for 4-formylphenyl methanesulfonate from 4-hydroxybenzaldehyde (0.37 g, 3 mmol), and 4-nitrobenzenesulfonyl chloride (0.80 g, 3.6 mmol) in DCM (10mL). The resultant solids after concentration in vacuo was purified by column chromatography over silica gel (40% EtOAc/hexanes). Yield: 88%. Light yellow solid. mp 139 – 140 °C. Spectroscopy data match a literature report.251 HOOTsHOONs 214 1H NMR (300 MHz, Chloroform-d) δ 10.00 (s, 1H), 8.50 – 8.30 (m, 2H), 8.21 – 7.99 (m, 2H), 7.96 – 7.76 (m, 2H), 7.25 – 7.18 (m, 2H) ppm. Representative procedure for the multicomponent hetero-Diels-Alder reaction (9H-fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.1a) Benzaldehyde (0.032 g, 0.3 mmol, 1.5 equiv), (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol, 1.0 equiv) and boron trifluoride diethyl etherate (0.043 g, 0.3 mmol, 1.5 equiv) were dissolved in DCM (1 mL) and heated at 40 °C for 1 h. A solution of buta-1,3-dien-2-yl diphenyl phosphate (2.1a, 0.18 g, 0.6 mmol, 3.0 equiv) in DCM (0.6 mL) was added. The reaction mixture was heated at 40 °C for 14 h. Aqueous sodium bicarbonate (1 mL, 1.1 M) was added, and the aqueous layer was extracted with EtOAc (´ 3). The combined extracts were washed with brine and dried over sodium sulfate. The resultant oil after concentration in vacuo was purified by column chromatography over silica gel (30% EtOAc/hexanes) to give 0.086 g (68%) of heterocycle 4.1a as a light-yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.5 Hz, 2H), 7.47 – 7.04 (m, 19H), 5.60 – 5.53 (m, 2H), 4.70 – 4.47 (m, 2H), 4.47 – 4.16 (m, 2H), 3.51 – 3.21 (m, 1H), 3.02 – 2.77 (m, 1H), 2.70 (d, J = 17.3 Hz, 1H) ppm. OPhHNPhOFmocPPhOOOPhH2N Fmocb)OPPhOOOPh40°C, 14 hBF3•OEt2DCM40 °C, 2 ha) 215 13C NMR (75 MHz, Chloroform-d) δ 155.3, 150.5 (d, J = 7.4 Hz), 144.0 (d, J = 2.5 Hz), 141.5, 139.1, 130.0, 128.8, 127.9, 127.8, 127.7, 127.2, 126.8, 125.8, 125.0, 120.2 (d, J = 4.8 Hz), 108.6, 67.6, 51.6, 47.5, 38.9, 30.4 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1699, 1590, 1488, 1418, 1298, 1186, 1124 cm-1. HRMS-ESI (m/z) calcd for C38H32NO6PNa ([M+Na]+): 652.1865, found: 652.1861. (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(4-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1b) Heterocycle 4.1b was constructed using an analogous procedure as described for 4.1a from p-anisaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 58%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.71 – 7.60 (m, 2H), 7.50 – 7.41 (m, 2H), 7.35 – 7.06 (m, 13H), 6.90 – 6.79 (m, 1H), 6.68 (d, J = 8.2 Hz, 2H), 5.75 – 5.52 (m, 1H), 5.49 – 5.40 (m, 1H), 4.46 (m, 2H), 4.33 – 4.19 (m, 1H), 4.16 (t, J = 6.3 Hz, 1H), 3.67 (s, 3H), 3.28 – 3.11 (m, 1H), 2.89 – 2.64 (m, 1H), 2.62 – 2.44 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 159.0, 155.3, 150.5 (d, J = 7.3 Hz), 144.0, 141.5, 131.1, 130.0, 128.0, 127.9, 127.8, 127.2, 125.8, 125.0, 120.2 (d, J = 4.9 Hz), 114.0, 108.7, 67.5, 55.4, 51.1, 47.5, 38.7, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.5 ppm. IR (neat): 3066, 1700, 1599, 1511, 1489, 1298, 1250 cm-1. NOFmocPPhOOOPhOMe 216 HRMS-ESI (m/z) calcd for C39H34NO7PNa ([M+Na]+): 682.1971, found: 682.1963. (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(3-methoxyphenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1c) Heterocycle 4.1c was constructed using an analogous procedure as described for 4.1a from m-anisaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 52%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.67 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.39 – 7.03 (m, 16H), 6.81 – 6.65 (m, 2H), 5.75 – 5.20 (m, 2H), 4.45 (d, J = 6.5 Hz, 2H), 4.36 – 4.24 (m, 1H), 4.19 (t, J = 6.6 Hz, 1H), 3.65 (s, 3H), 3.47 – 3.19 (m, 1H), 2.94 – 2.69 (m, 1H), 2.71 – 2.51 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 160.0, 150.5 (d, J = 7.0 Hz), 144.0, 141.5, 140.9, 130.0, 129.8, 127.9, 127.2, 125.8, 125.0, 120.2 (d, J = 5.0 Hz), 119.1, 113.0, 112.7, 108.7, 67.8, 55.3, 51.7, 47.5, 39.1, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.1 ppm IR (neat): 1698, 1587, 1488, 1289, 1186 cm -1. HRMS-ESI (m/z) calcd for C39H35NO7P ([M+H]+): 660.2151, found: 660.2145. NOFmocPPhOOOPhOMe 217 (9H-Fluoren-9-yl)methyl 2-(2,5-difluorophenyl)-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (4.1d) Heterocycle (4.1d) was constructed using an analogous procedure as described for 4.1a from 2,5-difluorobenzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 50%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.80 – 7.66 (m, 2H), 7.56 – 7.41 (m, 2H), 7.44 – 7.10 (m, 14H), 7.03 – 6.86 (m, 3H), 5.94 – 5.70 (m, 1H), 5.72 – 5.56 (m, 1H), 4.50 (d, J = 6.9 Hz, 2H), 4.45 – 4.29 (m, 1H), 4.22 (t, J = 6.7 Hz, 1H), 3.74 – 3.46 (m, 1H), 3.05 – 2.83 (m, 1H), 2.54 (d, J = 17.4 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 158.7 (dd, J = 243.0, 1.7 Hz), 156.3 (d, J = 240.0 Hz), 154.9, 150.4 (d, J = 7.3 Hz), 143.9 (d, J = 2.1 Hz), 141.4 (d, J = 2.3 Hz), 136.4, 130.0, 127.9, 127.2, 125.8, 125.0, 120.1 (d, J = 3.9 Hz), 116.9 (dd, J = 25.0, 8.7 Hz), 115.8 (dd, J = 23.9, 8.8 Hz), 114.5 (dd, J = 25.1, 3.6 Hz), 108.4, 67.9, 47.4, 40.2, 31.2, 29.8 ppm. 19F NMR (282 MHz, Chloroform-d) δ -117.6 – -119.2 (m), -121.0 – -122.8 (m) ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.6 ppm. IR (neat): 1705, 1590, 1489, 1296, 1186, 1126 cm-1. HRMS-ESI (m/z) calcd for C38H34F2N2O6P ([M+NH4]+): 683.2123, found: 683.2118. NOFmocPPhOOOPhFF 218 (9H-Fluoren-9-yl)methyl 2-(3,4-difluorophenyl)-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (4.1e) Heterocycle 4.1e was constructed using an analogous procedure as described for 4.1a from 3,4-difluorobenzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 62%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.59 (d, J = 7.4 Hz, 2H), 7.38 (d, J = 7.4 Hz, 2H), 7.31 – 6.91 (m, 17H), 5.61 – 5.43 (m, 1H), 5.44 – 5.27 (m, 1H), 4.60 – 4.34 (m, 2H), 4.28 – 4.13 (m, 1H), 4.09 (t, J = 5.9 Hz, 1H), 3.25 – 3.00 (m, 1H), 2.80 – 2.27 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.7 (dd, J = 246.9, 12.5 Hz), 150.4 (d, J = 7.2 Hz), 148.1 (dd, J = 247.4, 12.4 Hz), 143.8, 141.5, 136.2 (dd, J = 4.3, 4.3 Hz), 130.1, 127.9 (d, J = 2.4 Hz), 127.3, 125.9, 124.8, 123.0, 120.2, 120.1 (d, J = 4.9 Hz), 117.4 (d, J = 17.2 Hz), 116.1 (d, J = 15.7 Hz), 108.7, 67.5, 50.9, 47.5, 38.8, 29.8 ppm. 19F NMR (282 MHz, Chloroform-d) δ -138.96, -139.04 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.6 ppm. IR (neat): 1591, 1528, 1489, 1281, 1187, 1116 cm-1. HRMS-ESI (m/z) calcd for C38H30F2NO6PNa ([M+Na]+): 688.1677, found: 688.1672. NOFmocPPhOOOPhFF 219 (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(2,3,6-trifluorophenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1f) Heterocycle 4.1f was constructed using an analogous procedure as described for 4.1a from 2,3,6-trifluorobenzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 62%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.80 – 7.69 (m, 3H), 7.60 – 7.44 (m, 2H), 7.44 – 7.11 (m, 12H), 7.08 – 6.94 (m, 1H), 6.90 – 6.65 (m, 1H), 5.96 – 5.64 (m, 2H), 4.48 (d, J = 6.4 Hz, 2H), 4.43 – 4.25 (m, 1H), 4.21 (t, J = 6.5 Hz, 1H), 3.93 – 3.72 (m, 1H), 3.37 – 3.09 (m, 1H), 3.04 – 2.81 (m, 1H), 2.53 (d, J = 17.1 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.0, 150.4 (d, J = 7.6 Hz), 143.9, 141.4 (d, J = 2.3 Hz), 136.0, 130.0, 127.8, 127.2, 125.8, 125.2, 124.9, 120.1, 116.1 (dd, J = 19.5, 10.7 Hz), 111.3 (ddd, J = 26.0, 4.0, 4.0 Hz), 108.3 (d, J = 5.7 Hz), 67.9, 47.3, 46.7, 41.2, 32.2 ppm. 19F NMR (282 MHz, Chloroform-d) δ -119.4 (d, J = 15.0 Hz), -137.2 (d, J = 20.6 Hz), -141.4 (d, J = 17.0 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.0 ppm. IR (neat): 3067, 1704, 1590, 1489, 1293, 1241, 1186, 1128 cm-1. HRMS-ESI (m/z) calcd for C38H29F3NO6PNa ([M+Na]+): 706.1582, found: 706.1579. NOFmocPPhOOOPhFFF 220 (9H-Fluoren-9-yl)methyl 2-(4-cyanophenyl)-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (4.1g) Heterocycle 4.1g was constructed using an analogous procedure as described for 4.1a from 4-cyanobenzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 43%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.66 (d, J = 7.5 Hz, 2H), 7.51 – 7.39 (m, 3H), 7.37 – 7.17 (m, 10H), 7.20 – 7.07 (m, 7H), 5.78 – 5.50 (m, 1H), 5.52 – 5.36 (m, 1H), 4.70 – 4.39 (m, 2H), 4.37 – 4.17 (m, 1H), 4.16 (t, J = 5.6 Hz, 1H), 3.26 – 3.00 (m, 1H), 2.95 – 2.37 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.3 (dd, J = 7.4, 3.2 Hz), 144.4, 143.8, 141.5, 132.5, 130.1, 127.9, 127.9, 127.6, 127.2, 125.9, 124.8, 120.2 (d, J = 4.8 Hz), 120.1 (d, J = 4.9 Hz), 118.7, 111.6, 108.8, 67.5, 51.4, 47.5, 39.0, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.4 ppm. IR (neat): 2227, 1700, 1590, 1488, 1297 cm-1 HRMS-ESI (m/z) calcd for C39H31N2O6PNa ([M+Na]+): 677.1817, found: 677.1815. (9H-Fluoren-9-yl)methyl 2-(4-chlorophenyl)-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (4.1h) NOFmocPPhOOOPhCNNOFmocPPhOOOPhCl 221 Heterocycle 4.1h was constructed using an analogous procedure as described for 4.1a from 4-chlorobenzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 56%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.75 (d, J = 7.6 Hz, 2H), 7.54 (d, J = 7.4 Hz, 2H), 7.46 – 7.00 (m, 18H), 5.78 – 5.58 (m, 1H), 5.60 – 5.43 (m, 1H), 4.57 (d, J = 7.2 Hz, 2H), 4.42 – 4.29 (m, 1H), 4.25 (t, J = 6.0 Hz, 1H), 3.36 – 3.17 (m, 1H), 2.98 – 2.45 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (d, J = 7.9 Hz), 143.9, 141.5, 137.7, 133.5, 130.1, 128.9, 128.2, 127.9, 127.9, 127.3, 125.8, 124.9, 120.1 (d, J = 4.8 Hz), 108.7, 67.5, 51.1, 47.5, 38.8, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.5 ppm. IR (neat): 1699, 1590, 1489, 1297 cm-1 HRMS-ESI (m/z) calcd for C38H31ClNO6PNa ([M+Na]+): 664.1656, found: 664.1658. (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(naphthalen-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1i) Heterocycle 4.1i was constructed using an analogous procedure as described for 4.1a from 2-naphthylaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 58%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.87 – 7.67 (m, 6H), 7.63 – 7.53 (m, 2H), 7.52 – 7.44 (m, 2H), 7.45 – 7.16 (m, 15H), 6.11 – 5.73 (m, 1H), 5.85 – 5.36 (m, 1H), 4.82 – 4.48 (m, 2H), 4.51 – 4.35 (m, 1H), 4.31 (t, J = 6.3 Hz, 1H), 3.53 – 3.28 (m, 1H), 3.14 – 2.70 (m, 2H) ppm. NOFmocPPhOOOPh 222 13C NMR (75 MHz, Chloroform-d) δ 155.3 (d, J = 8.4 Hz), 150.5 (dd, J = 7.4, 2.1 Hz), 143.9, 141.5, 136.4, 133.2, 132.8, 130.0, 128.6, 128.4, 127.9, 127.8, 127.5, 127.2, 126.3, 126.2, 125.8, 125.0, 120.2 (d, J = 3.1 Hz), 120.1 (d, J = 2.1 Hz), 109.0, 67.7, 51.8, 47.4, 39.0, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.9 ppm. IR (neat): 3062, 1699, 1488, 1297, 1187, 1117 cm-1 HRMS-ESI (m/z) calcd for C42H35NO6P ([M+H]+): 680.2202, found: 680.2200. (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(naphthalen-1-yl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1j) Heterocycle 4.1j was constructed using an analogous procedure as described for 4.1a from 1-naphthylaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 57%. Yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.99 – 6.93 (m, 25H), 6.47 – 5.71 (m, 1H), 5.75 – 5.31 (m, 1H), 4.47 (d, J = 8.1 Hz, 2H), 4.37 – 4.21 (m, 1H), 4.14 (t, J = 6.6 Hz, 1H), 3.39 – 2.14 (m, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.0, 150.5 (d, J = 7.5 Hz), 143.9 (d, J = 4.5 Hz), 141.4, 134.1, 130.0, 128.9, 127.8, 127.8, 127.2, 126.8, 125.9, 125.8, 125.1, 124.9, 120.1 (d, J = 4.9 Hz), 120.1, 109.2 (d, J = 5.5 Hz), 67.8, 50.5, 47.4, 38.8, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.5 ppm. HRMS-ESI (m/z) calcd for C42H34NO6PNa ([M+Na]+): 702.2021, found: 702.2018. NOFmocPPhOOOPh 223 (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(4-((methylsulfonyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1k) Heterocycle 4.1k was constructed using an analogous procedure as described for 4.1a from 4-formylphenyl methanesulfonate, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 40% EtOAc in hexanes. Yield: 52%. Colorless oil. 1H NMR (300 MHz, Chloroform-d) δ 7.67 (d, J = 7.5 Hz, 2H), 7.46 (d, J = 7.5 Hz, 2H), 7.38 – 6.99 (m, 18H), 5.79 – 5.51 (m, 1H), 5.53 – 5.39 (m, 1H), 4.67 – 4.44 (m, 2H), 4.38 – 4.25 (m, 1H), 4.17 (t, J = 5.9 Hz, 1H), 3.29 – 3.11 (m, 1H), 3.04 (s, 3H), 2.92 – 2.43 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.4 (dd, J = 7.4, 2.4 Hz), 148.5, 143.8 (d, J = 4.1 Hz), 141.5 (d, J = 2.2 Hz), 138.5, 130.0, 128.6, 127.9, 127.9, 127.2, 125.8 (t, J = 1.3 Hz), 124.8, 122.2, 120.1 (t, J = 4.8 Hz), 110.2, 67.5, 51.0, 47.4, 38.8, 37.5, 29.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.5 ppm. IR (neat): 1702, 1488, 1418, 1368, 1295, 1183, 1150, 1122 cm-1. HRMS-ESI (m/z) calcd for C39H34NO9PSNa ([M+Na]+): 746.1590, found: 746.1586. NOFmocPPhOOOPhOMs 224 (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(4-(tosyloxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1l) Heterocycle 4.1l was constructed using an analogous procedure as described for 4.1a from 4-formylphenyl 4-methylbenzenesulfonate, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 56%. Colorless oil. 1H NMR (300 MHz, Chloroform-d) δ 7.74 – 7.56 (m, 4H), 7.45 (d, J = 7.4 Hz, 2H), 7.37 – 7.06 (m, 18H), 6.86 – 6.74 (m, 2H), 5.75 – 5.51 (m, 1H), 5.55 – 5.34 (m, 1H), 4.65 – 4.44 (m, 2H), 4.39 – 4.20 (m, 1H), 4.17 (t, J = 5.9 Hz, 1H), 3.27 – 3.01 (m, 1H), 2.91 – 2.63 (m, 1H), 2.63 – 2.41 (m, 1H), 2.37 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.1, 150.4 (dd, J = 7.3, 2.1 Hz), 148.9, 145.5, 143.8 (d, J = 3.9 Hz), 141.5, 138.0, 132.6, 130.0, 129.9, 128.6, 128.2, 127.9, 127.2, 125.8, 124.8, 122.6, 120.1 (t, J = 4.6 Hz), 108.7, 67.4, 51.0, 47.4, 38.7, 29.8, 21.8 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.1 ppm. IR (neat): 1704, 1488, 1372, 1295, 1179, 1155, 1119cm-1. HRMS-ESI (m/z) calcd for C45H38NO9PSNa ([M+Na]+): 822.1903, found: 822.1900. NOFmocPPhOOOPhOTs 225 (9H-Fluoren-9-yl)methyl 4-((diphenoxyphosphoryl)oxy)-2-(4-(((4-nitrophenyl)sulfonyl)oxy)phenyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.1m) Heterocycle 4.1m was constructed using an analogous procedure as described for 4.1a from 4-formylphenyl 4-nitrobenzenesulfonate, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 35% EtOAc in hexanes. Yield: 56%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 8.41 – 8.28 (m, 2H), 8.07 – 7.96 (m, 2H), 7.74 (d, J = 7.5 Hz, 2H), 7.52 (d, J = 7.4 Hz, 2H), 7.45 – 7.16 (m, 14H), 6.96 – 6.78 (m, 2H), 5.83 – 5.59 (m, 1H), 5.59 – 5.42 (m, 1H), 4.73 – 4.48 (m, 2H), 4.45 – 4.26 (m, 1H), 4.24 (t, J = 5.8 Hz, 1H), 3.36 – 3.14 (m, 1H), 2.99 – 2.40 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 151.1, 150.4 (dd, J = 7.4, 3.3 Hz), 148.4, 143.8 (d, J = 4.6 Hz), 141.5 (d, J = 2.3 Hz), 141.0, 136.8, 135.0, 134.1, 132.0, 130.0, 129.9, 128.5, 127.9, 127.2, 125.9, 124.8, 124.5, 122.2, 120.1 (dd, J = 6.8, 4.4 Hz), 108.7, 67.4, 51.0, 47.4, 38.8, 30.3 ppm. 31P NMR (121 MHz, Chloroform-d) δ -17.4 ppm. IR (neat): 1699, 1533, 1382, 1488, 1349, 1294, 1184, 1124 cm-1. HRMS-ESI (m/z) calcd for C44H35N2O11PSNa ([M+Na]+): 853.1597, found: 853.1594. NOFmocPPhOOOPhONs 226 (9H-Fluoren-9-yl)methyl 2-cyclohexyl-4-((diphenoxyphosphoryl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate (4.1n) Heterocycle 4.1n was constructed using an analogous procedure as described for 4.1a from cyclohexanecarboxaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diphenyl phosphate. Column condition: 30% EtOAc in hexanes. Yield: 67%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.57 (d, J = 7.4 Hz, 2H), 7.47 – 6.94 (m, 14H), 5.61 – 5.43 (m, 1H), 4.68 – 4.08 (m, 4H), 3.62 (dd, J = 10.6, 6.2 Hz, 1H), 3.56 – 3.28 (m, 1H), 2.62 – 2.16 (m, 2H), 1.84 – 0.83 (m, 11H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.5, 150.5 (d, J = 7.2 Hz), 144.1, 141.5, 130.0, 127.8, 127.2, 125.7, 125.1, 124.8, 120.1 (d, J = 5.2 Hz), 108.1, 107.5, 67.4, 66.8, 54.6, 54.3, 47.5, 38.9, 37.3, 37.2, 30.9, 29.0, 26.0 ppm. 31P NMR (121 MHz, Chloroform-d) δ -16.6 ppm. IR (neat): 2928, 2852, 1703, 1591, 1489, 1299, 1189 cm-1. HRMS-ESI (m/z) calcd for C38H38NO6PNa ([M+Na]+): 658.2334, found: 658.2329. (9H-Fluoren-9-yl)methyl 4-((diethoxyphosphoryl)oxy)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.5) NOFmocPPhOOOPhNOPEtOOOEtFmoc 227 Heterocycle 4.5 was constructed using an analogous procedure as described for 4.1a from benzaldehyde, (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol) and buta-1,3-dien-2-yl diethyl phosphate. Column condition: 50% EtOAc in hexanes. Yield: 64%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.54 (d, J = 7.4 Hz, 2H), 7.46 – 7.20 (m, 9H), 5.82 – 5.26 (m, 2H), 4.60 – 4.49 (m, 2H), 4.43 – 4.30 (m, 1H), 4.27 (t, J = 6.3 Hz, 1H), 4.23 – 4.07 (m, 4H), 3.44 – 3.23 (m, 1H), 3.00 – 2.79 (m, 1H), 2.77 – 2.60 (m, 1H), 1.42 – 1.30 (m, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.4, 144.0 (d, J = 3.3 Hz), 141.5, 139.4, 128.7, 127.8, 127.8, 127.6, 127.2, 126.8, 125.0, 120.1 (d, J = 4.1 Hz), 107.3, 67.6, 64.6 (d, J = 6.2 Hz), 51.7, 47.5, 39.0, 29.8, 16.2 (d, J = 6.7 Hz) ppm. 31P NMR (121 MHz, Chloroform-d) δ -6.2 ppm. IR (neat): 2916, 1699, 1420, 1265, 1145, 1029 cm-1. HRMS-ESI (m/z) calcd for C30H33NO6P ([M+H]+): 534.2045, found: 534.2044. Representative procedure for the synthesis of Grignard reagents252 3,5-Dimethylphenylmagnesium bromide A three-neck round bottom flask was equipped with a condenser, sealed with septum, flame dried and purged under N2. Magnesium metal (0.18 g, 7.5 mmol, 1.5 equiv) and I2 (0.0125 g, 0.05 mmol, 0.01 equiv) were added to the flask. The flask was heated by a heat gun to generate I2 gas. Distilled THF (10 mL) was added and heated to reflux by a heat gun. 1-Bromo-3,5-dimethylbenzene (0.62 g, 5 mmol, 1.0 equiv) was added dropwise and the mixture was heated to reflux by a heat gun to BrMg, I2THFrefluxMgBr 228 initiate the reaction. When a colorless solution was obtained, the rest of 1-bromo-3,5-dimethylbenzene was added and the reaction mixture was heated to reflux by a heat gun for 10 min. The solution of Grignard reagent was titrated with 0.0056 g of I2 in distilled THF. The end point of a colorless solution was obtained after adding 0.06 mL of the Grignard reagent in distilled THF. The concentration of the Grignard reagent was calculated to be 0.37 M in THF. 𝐶𝑜𝑛𝑐𝑒𝑛𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑜𝑓 𝐺𝑟𝑖𝑔𝑛𝑎𝑟𝑑 𝑖𝑛 𝑇𝐻𝐹 (𝑀) = 0.0056 𝑔 ÷ 253.808𝑔/𝑚𝑜𝑙0.06 𝑚𝐿 Representative procedure for the Kumada coupling reaction on enol phosphate (9H-Fluoren-9-yl)methyl 2,4-diphenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2a) Palladium(II) chloride (0.0009 g, 0.005 mmol, 0.05 equiv) was added to the solution of 4.1a (0.063 g, 0.1 mmol, 1.0 equiv) in distilled THF (1.0 mL). Phenylmagnesium bromide (0.2 mmol, 2 equiv, 3.0 M in Et2O) was added dropwise over 30 min. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc and flushed through a short plug of silica gel. The resultant oil after concentration in vacuo were purified by column chromatography over silica gel (20% EtOAc in hexanes) to give 0.026 g (57%) of heterocycle 4.2a as a light-yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J = 7.5 Hz, 2H), 7.58 (dd, J = 10.6, 4.3 Hz, 2H), 7.49 – 7.10 (m, 12H), 6.99 – 6.68 (m, 2H), 6.10 – 5.93 (m, 1H), 5.91 – 5.45 (m, 1H), 4.57 (d, J = 6.3 Hz, 2H), 4.53 – 4.38 (m, 1H), 4.30 (t, J = 6.5 Hz, 1H), 3.57 (dd, J = 18.9, 3.4 Hz, 1H), 3.13 – 2.79 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.9, 144.0, 141.5, 140.6, 129.7, 128.7, 128.6, 127.8, 127.7, 127.4, 127.2, 125.2, 125.1, 120.7, 120.2, 120.1, 115.4, 67.6, 51.7, 47.5, 41.1, 29.8 ppm. NPhFmocNPhOPPhOOOPhFmocPdCl2THF, rt, 3 h PhPhMgBr 229 IR (neat): 3042, 1670, 1594, 1471, 1428, 1222 cm-1. HRMS-ESI (m/z) calcd for C32H28NO2 ([M+H]+): 458.2118, found: 458.2120. (9H-Fluoren-9-yl)methyl 2-phenyl-4-(prop-1-en-2-yl)-3,6-dihydropyridine-1(2H)- carboxylate (4.2b) Heterocycle 4.2b was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and isopropenylmagnesium bromide (0.5 M in THF). Column condition: 15% EtOAc in hexanes. Yield: 58%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.62 – 7.49 (m, 2H), 7.46 – 7.35 (m, 2H), 7.36 – 7.17 (m, 7H), 5.86 – 5.29 (m, 2H), 5.06 (d, J = 31.9 Hz, 2H), 4.56 (d, J = 6.6 Hz, 2H), 4.46 – 4.33 (m, 1H), 4.29 (t, J = 6.5 Hz, 1H), 3.59 – 3.40 (m, 1H), 2.98 – 2.81 (m, 1H), 2.79 – 2.58 (m, 1H), 1.94 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.9, 144.1, 142.2, 141.5, 140.4, 129.8, 128.5, 127.8, 127.3, 126.9, 125.1, 120.1, 120.1, 115.4, 111.5, 67.5, 51.4, 47.5, 40.9, 29.8, 20.5 ppm. IR (neat): 2925, 1673, 1594, 1451, 1315, 1241, 1117 cm-1. HRMS-ESI (m/z) calcd for C29H28NO2 ([M+H]+): 422.2120, found: 422.2119. (9H-Fluoren-9-yl)methyl 2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2c) N FmocN Fmoc 230 Heterocycle 4.2c was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and isopropylmagnesium chloride (2.0 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 73%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.73 (d, J = 7.5 Hz, 2H), 7.61 – 7.46 (m, 2H), 7.45 – 7.13 (m, 7H), 5.98 – 5.75 (m, 1H), 5.79 – 5.51 (m, 1H), 5.47 – 5.30 (m, 1H), 4.50 (d, J = 6.5 Hz, 2H), 4.28 (t, J = 6.8 Hz, 1H), 3.55 – 3.19 (m, 1H), 2.85 – 2.27 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.9, 144.1, 141.5, 140.8, 129.7, 128.5, 127.8 (d, J = 2.1 Hz), 127.3, 127.2, 125.1, 120.1, 120.1, 115.4, 67.5, 51.3, 47.5, 40.7, 29.8 ppm. IR (neat): 3039, 1698, 1450, 1418 cm-1. HRMS-ESI (m/z) calcd for C26H24NO2 ([M+H]+): 382.1807, found: 382.1806. (9H-Fluoren-9-yl)methyl 4-(4-fluorophenyl)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2d) Heterocycle 4.2d was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and 4-fluorophenylmagnesium bromide (1 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 51%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J = 7.5 Hz, 2H), 7.58 (d, J = 10.6 Hz, 2H), 7.48 – 7.18 (m, 11H), 7.06 (t, J = 8.6 Hz, 2H), 6.15 – 5.75 (m, 2H), 4.59 (d, J = 6.2 Hz, 2H), 4.50 – 4.37 (m, 1H), 4.30 (t, J = 6.4 Hz, 1H), 3.57 (dd, J = 18.8, 3.4 Hz, 1H), 3.12 – 2.68 (m, 2H) ppm. N FmocF 231 13C NMR (75 MHz, Chloroform-d) δ 162.4 (d, J = 246.7 Hz), 152.2, 144.0, 141.5, 140.3, 136.7, 136.7, 128.5, 127.8, 127.8, 127.4, 127.2, 126.8, 126.7, 125.1, 120.1 (d, J = 3.8 Hz), 115.5 (d, J = 21.4 Hz), 67.6, 51.4, 47.5, 41.0, 29.8 ppm. 19F NMR (282 MHz, Chloroform-d) δ -114.8 ppm. IR (neat): 3065, 1699, 1510, 1450, 1422, 1223 cm-1. HRMS-ESI (m/z) calcd for C32H27FNO2 ([M+H]+): 476.2026, found: 476.2017. (9H-Fluoren-9-yl)methyl 2-phenyl-4-(p-tolyl)-3,6-dihydropyridine-1(2H)-carboxylate (4.2e) Heterocycle 4.2e was constructed using an analogous procedure as described for 4.2a from 4.1a (0.13 g, 0.2 mmol) and p-tolylmagnesium bromide (1.0 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 77%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.78 (d, J = 7.5 Hz, 2H), 7.67 – 7.50 (m, 2H), 7.49 – 7.10 (m, 13H), 6.08 – 5.84 (m, 1H), 5.92 – 5.43 (m, 1H), 4.59 (d, J = 6.3 Hz, 2H), 4.53 – 4.38 (m, 1H), 4.31 (t, J = 6.5 Hz, 1H), 3.72 – 3.43 (m, 1H), 3.23 – 2.73 (m, 2H), 2.38 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 153.7, 144.1, 141.5, 137.7, 137.4, 130.1, 129.7, 129.4, 128.6, 127.8, 127.3, 127.2, 125.1, 125.0, 120.2, 120.1, 115.5, 67.5, 51.6, 47.5, 41.1, 29.8, 21.2 ppm. IR (neat): 2923, 2853, 1699, 1452, 1424, 1241 cm-1. HRMS-ESI (m/z) calcd for C33H30NO2 ([M+H]+): 472.2277, found: 472.2274 N Fmoc 232 (9H-Fluoren-9-yl)methyl 4-(2-methoxyphenyl)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2f) Heterocycle 4.2f was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and 2-methoxyphenylmagnesium bromide (1.4 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 28%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.76 (d, J = 7.5 Hz, 2H), 7.59 (d, J = 14.8 Hz, 2H), 7.52 – 7.05 (m, 10H), 7.01 – 6.70 (m, 3H), 5.84 – 5.57 (m, 2H), 4.59 – 4.48 (m, 2H), 4.51 – 4.36 (m, 1H), 4.37 – 4.23 (m, 1H), 3.95 – 3.69 (m, 4H), 3.64 – 3.51 (m, 1H), 3.03 – 2.81 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.8, 144.1, 141.5, 129.8, 129.6, 128.8, 128.4, 127.8, 127.2, 125.2, 124.3, 120.9, 120.8, 120.1, 115.9, 115.4, 114.3, 67.6, 56.3, 55.4, 47.5, 32.1, 29.5 ppm. IR (neat): 1700, 1595, 1451, 1248 cm-1. HRMS-ESI (m/z) calcd for C33H29NO3Na ([M+Na]+): 510.2045, found: 510.2044. (9H-Fluoren-9-yl)methyl 4-(4-methoxyphenyl)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2g) Heterocycle 4.2g was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and 4-methoxyphenylmagnesium bromide (0.34 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 60%. Light yellow oil. N FmocOMeNPhFmocMeO 233 1H NMR (300 MHz, Chloroform-d) δ 7.70 (d, J = 7.5 Hz, 2H), 7.56 – 7.43 (m, 2H), 7.39 – 7.09 (m, 7H), 6.84 (d, J = 8.4 Hz, 2H), 6.71 (s, 4H), 5.89 – 5.80 (m, 1H), 5.78 – 5.34 (m, 1H), 4.51 (d, J = 6.3 Hz, 2H), 4.44 – 4.29 (m, 1H), 4.23 (t, J = 6.5 Hz, 1H), 3.76 (s, 3H), 3.56 – 3.41 (m, 1H), 2.99 – 2.78 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 159.3, 153.8, 149.8, 144.1, 141.5, 133.2, 128.6, 127.8, 127.3, 127.2, 126.3, 125.1, 120.2, 120.1, 116.2, 114.9, 114.0, 67.5, 55.9, 55.5, 47.5, 41.0, 29.5 ppm. IR (neat): 2923, 1698, 1511, 1451, 1236 cm-1. HRMS-ESI (m/z) calcd for C33H30NO3 ([M+H]+): 488,2226, found: 488.2218. (9H-Fluoren-9-yl)methyl 4-(naphthalen-2-yl)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2h) Heterocycle 4.2h was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and naphthalen-2-ylmagnesium bromide (0.22 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 81%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 8.20 (d, J = 1.8 Hz, 1H), 8.03 – 7.29 (m, 19H), 6.25 – 6.10 (m, 1H), 5.98 – 5.65 (m, 1H), 4.63 (d, J = 6.2 Hz, 2H), 4.61 – 4.43 (m, 1H), 4.32 (t, J = 6.4 Hz, 1H), 3.82 – 3.46 (m, 1H), 3.27 – 2.94 (m, 2H) ppm. HRMS-ESI (m/z) calcd for C36H29NO2Na ([M+Na]+): 530.2096, found: 530.2085. N Fmoc 234 (9H-Fluoren-9-yl)methyl 4-(3,5-dimethylphenyl)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2i) Heterocycle 4.2i was constructed using an analogous procedure as described for 4.2a from 4.1a and 3,5-dimethylphenylmagnesium bromide (0.4 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 80%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.77 (d, J = 7.5 Hz, 2H), 7.66 – 7.48 (m, 2H), 7.48 – 7.35 (m, 2H), 7.36 – 7.19 (m, 5H), 7.05 – 6.77 (m, 3H), 6.64 – 6.41 (m, 2H), 6.07 – 5.84 (m, 1H), 5.88 – 5.57 (m, 1H), 4.64 – 4.42 (m, 2H), 4.50 – 4.37 (m, 1H), 4.30 (t, J = 6.5 Hz, 1H), 3.75 – 3.42 (m, 1H), 3.19 – 2.72 (m, 2H), 2.34 (s, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.7, 144.1, 141.5, 140.6, 140.4, 139.6, 138.2, 129.8, 129.3, 128.6, 127.8, 127.3, 127.2, 125.1, 123.1, 120.2, 120.1, 115.4, 113.1, 67.6, 51.8, 47.5, 41.1, 29.8, 21.5 ppm. IR (neat): 2922, 1699, 1597, 1451 cm-1. HRMS-ESI (m/z) calcd for C34H32NO2 ([M+H]+): 486.2433, found: 486.2428. (9H-Fluoren-9-yl)methyl 4-([1,1'-biphenyl]-4-yl)-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2j): NPhFmocNPhFmoc 235 Heterocycle 4.2j was constructed using an analogous procedure as described for 4.2a from 4.1a (0.063 g, 0.1 mmol) and 4-biphenylmagnesium bromide (0.4 M in THF). Column condition: 20% EtOAc in hexanes. Yield: 85%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.67 (d, J = 7.5 Hz, 2H), 7.59 – 7.01 (m, 20H), 6.03 – 5.90 (m, 1H), 5.76 – 5.34 (m, 1H), 4.50 (d, J = 6.2 Hz, 2H), 4.46 – 4.29 (m, 1H), 4.21 (t, J = 6.5 Hz, 1H), 3.50 (dd, J = 19.0, 3.1 Hz, 1H), 3.05 – 2.77 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.6, 144.1, 141.5, 140.7, 140.5, 139.4, 129.0, 128.8, 128.6, 128.5, 127.8, 127.5, 127.4, 127.4, 127.2, 127.1, 126.8, 125.5, 125.1, 120.1, 115.8, 67.6, 51.7, 47.6, 41.2, 29.8 ppm. IR (neat): 3032, 1695, 1522, 1488, 1450cm-1. HRMS-ESI (m/z) calcd for C38H32NO2 ([M+H]+): 534.2433, found: 534.2433. (9H-Fluoren-9-yl)methyl 4-pentyl-2-phenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2k) Heterocycle 4.2k was constructed using an analogous procedure as described for 4.2a from 4.5 (0.053 g, 0.1 mmol), Fe(acac)3 (5 mol%) and pentylmagnesium chloride (1.0 M in THF). Column condition: 10% EtOAc in hexanes. Yield: 50%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.68 (d, J = 7.6 Hz, 2H), 7.56 – 7.38 (m, 2H), 7.38 – 7.25 (m, 2H), 7.27 – 7.03 (m, 7H), 5.75 – 4.93 (m, 2H), 4.42 (d, J = 6.6 Hz, 2H), 4.32 – 3.97 (m, 2H), 3.57 – 3.21 (m, 1H), 2.73 – 2.45 (m, 1H), 2.46 – 2.23 (m, 1H), 2.11 – 1.76 (m, 2H), 1.65 – 1.00 (m, 6H), 0.80 (t, J = 6.9 Hz, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 144.2, 141.5, 128.5, 127.8, 127.2, 125.1, 120.1, 120.1, 67.4, 51.6, 47.5, 40.8, 37.4, 31.6, 29.9, 26.9, 22.7, 14.2 ppm. NPhFmoc 236 IR (neat): 2927, 1702, 1450, 1417 cm-1. HRMS-ESI (m/z) calcd for C31H33NO2Na ([M+Na]+): 474.2409, found: 474.2405. (9H-Fluoren-9-yl)methyl 2-phenyl-4-propyl-3,6-dihydropyridine-1(2H)-carboxylate (4.6a) Heterocycle 4.6a was constructed using an analogous procedure as described for 4.1a from 4.5 (0.053 g, 0.1 mmol), Fe(acac)3 (5 mol%) and propylmagnesium chloride (2.0 M in THF). Column condition: 10% EtOAc in hexanes. Yield: 51%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 7.68 (d, J = 7.6 Hz, 2H), 7.56 – 7.39 (m, 2H), 7.40 – 7.09 (m, 9H), 5.68 – 5.10 (m, 2H), 4.43 (d, J = 6.5 Hz, 2H), 4.33 – 4.03 (m, 2H), 3.51 – 3.18 (m, 1H), 2.64 – 2.43 (m, 1H), 2.38 – 2.28 (m, 1H), 2.24 (t, J = 7.5 Hz, 1H), 1.60 – 1.30 (m, 2H), 0.81 (t, J = 6.6 Hz, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 144.2, 141.5, 129.8, 128.5, 127.8, 127.2, 126.8, 125.1, 120.1, 120.1, 115.4, 67.5, 47.5, 39.6, 32.1, 25.0, 22.8, 20.5, 14.3 ppm. IR (neat): 3064, 2926, 1701, 1450, 1417 cm-1. HRMS-ESI (m/z) calcd for C29H29NO2Na ([M+Na]+): 446.2096, found: 446.2098. Representative procedure for the deprotection and oxidation of tetrahydropyridine: 2,4-diphenylpyridine (4.3a) NPhFmocNNFmoc a) piperidineb) DDQ, rt, 20 hDCM, rt, 2 h 237 (9H-Fluoren-9-yl)methyl 2,4-diphenyl-3,6-dihydropyridine-1(2H)-carboxylate (4.2a, 0.046 g, 0.1 mmol, 1.0 equiv) was dissolved in DCM (1 mL). Piperidine (0.010 g, 0.12 mmol, 1.2 equiv, 2% solution in DCM) was added. The reaction mixture was stirred at rt for 2 h. 2,3-Dichloro-5,6-dicyano-1,4-benzoquino (0.045 g, 0.20 mmol, 2.0 equiv) was dissolved in DCM (1 mL) and added slowly to the reaction mixture. The reaction mixture was stirred at rt for 20 h. The reaction mixture was directly concentrated in vacuo and the resultant oil was purified by column chromatography over silica gel (15% EtOAc in hexanes) to give 0.022 g (97%) of heterocycle 4.3a as a white solid. Spectroscopy data match a literature report.253 1H NMR (300 MHz, Chloroform-d) δ 8.75 (dd, J = 5.2, 0.8 Hz, 1H), 8.13 – 8.00 (m, 2H), 7.94 (dd, J = 1.7, 0.8 Hz, 1H), 7.77 – 7.65 (m, 2H), 7.59 – 7.38 (m, 7H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 158.1, 150.1, 138.6, 129.3, 129.3, 129.0, 127.3, 127.2, 120.5, 119.0 ppm. HRMS-ESI (m/z) calcd for C17H14N ([M+H]+): 232.1126, found: 232.1123. 4-(4-Fluorophenyl)-2-phenylpyridine (4.3b) Heterocycle 4.3b was constructed using an analogous procedure as described for 4.3a from 4.2d (0.038, 0.08 mmol). Column condition: 20% EtOAc in hexanes. Yield: 88%. Light yellow oil. Spectroscopy data match a literature report.254 1H NMR (300 MHz, Chloroform-d) δ 8.75 (d, J = 5.2 Hz, 1H), 8.04 (dt, J = 6.0, 1.5 Hz, 2H), 7.95 – 7.85 (m, 1H), 7.75 – 7.58 (m, 2H), 7.58 – 7.37 (m, 4H), 7.25 – 7.14 (m, 2H) ppm. NF 238 13C NMR (75 MHz, Chloroform-d) δ 163.9 (d, J = 245.0 Hz), 158.5, 149.4, 148.9, 138.1, 134.1, 130.0, 129.3, 129.2, 127.5, 120.5, 119.3, 116.5 (d, J = 21.8 Hz) ppm. 19F NMR (282 MHz, Chloroform-d) δ -112.3 ppm. HRMS-ESI (m/z) calcd for C17H13FN ([M+H]+): 250.1032, found: 250.1032. 2-Phenyl-4-(p-tolyl)pyridine (4.3c) Heterocycle 4.3c was constructed using an analogous procedure as described for 4.3a from 4.2e (0.038 g, 0.08 mmol). Column condition: 20% EtOAc in hexanes. Yield: 91%. White solid. Spectroscopy data match a literature report.255 1H NMR (300 MHz, Chloroform-d) δ 8.73 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 7.5 Hz, 2H), 7.93 (s, 1H), 7.62 (d, J = 7.8 Hz, 2H), 7.55 – 7.42 (m, 4H), 7.33 (d, J = 7.7 Hz, 2H), 2.45 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 158.7, 150.8, 149.4, 139.8, 135.4, 130.1, 129.5, 129.3, 129.0, 127.3, 127.1, 120.3, 119.0, 21.4 ppm. HRMS-ESI (m/z) calcd for C18H16N ([M+H]+): 246.1283, found: 247.1271. 4-(2-Methoxyphenyl)-2-phenylpyridine (4.3d) Heterocycle 4.3d was constructed using an analogous procedure as described for 4.3a from 4.2f. Column condition: 20% EtOAc in hexanes. Yield: 61%. Light yellow oil. Spectroscopy data match a literature report.256 NNOMe 239 1H NMR (300 MHz, Chloroform-d) δ 8.71 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 7.4 Hz, 2H), 7.90 (s, 1H), 7.74 – 7.59 (m, 2H), 7.46 – 7.37 (m, 4H), 7.16 – 6.99 (m, 1H), 3.86 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 158.1, 157.2, 148.9, 147.4, 140.3, 130.7, 130.0, 128.7, 128.3, 128.2, 127.9, 124.5, 121.5, 120.4, 111.8, 55.4 ppm. HRMS-ESI (m/z) calcd for C18H16NO ([M+H]+): 262.1232, found: 262.1228. 4-(4-Methoxyphenyl)-2-phenylpyridine (4.3e) Heterocycle 4.3e was constructed using an analogous procedure as described for 4.3a from 4.2g (0.029 g, 0.06 mmol). Column condition: 20% EtOAc in hexanes. Yield: 67%. White solids. Spectroscopy data match a literature report.257 1H NMR (300 MHz, Chloroform-d) δ 8.72 (d, J = 5.2 Hz, 1H), 8.16 – 7.99 (m, 2H), 7.91 (d, J = 1.7 Hz, 1H), 7.72 – 7.62 (m, 2H), 7.58 – 7.38 (m, 4H), 7.12 – 6.98 (m, 2H), 3.89 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 160.9, 157.7, 149.4, 148.3, 130.0, 129.5, 129.0, 128.5, 127.3, 120.0, 118.6, 114.8, 55.6 ppm. HRMS-ESI (m/z) calcd for C18H16NO ([M+H]+): 262.1232, found: 262.1227. 4-(Naphthalen-2-yl)-2-phenylpyridine (4.3f) NMeON 240 Heterocycle 4.3f was constructed using an analogous procedure as described for 4.3a from 4.2h (0.041g, 0.08 mmol). Column condition: 20% EtOAc in hexanes. Yield: 90%. Light yellow oil. Spectroscopy data match a literature report.258 1H NMR (300 MHz, Chloroform-d) δ 8.85 (d, J = 5.5 Hz, 1H), 8.22 (s, 1H), 8.19 – 8.10 (m, 3H), 8.02 (d, J = 8.6 Hz, 1H), 7.99 – 7.87 (m, 1H), 7.83 (dd, J = 8.6, 1.9 Hz, 1H), 7.76 (d, J = 17.6 Hz, 1H), 7.66 – 7.31 (m, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 157.1, 151.1, 140.7, 139.4, 135.7, 134.9, 133.7, 129.6, 129.5, 128.8, 128.2, 128.0, 127.8, 127.5, 127.3, 124.4, 121.2 ppm. HRMS-ESI (m/z) calcd for C21H16N ([M+H]+): 282.1283, found: 282.1280. 4-(3,5-Dimethylphenyl)-2-phenylpyridine (4.3g) Heterocycle 4.3g was constructed using an analogous procedure as described for 4.3a from 4.2i (0.039 g, 0.08 mmol). Column condition: 20% EtOAc in hexanes. Yield: 96%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 8.72 (dd, J = 5.2, 0.8 Hz, 1H), 8.12 – 8.00 (m, 2H), 7.91 (dd, J = 1.7, 0.9 Hz, 1H), 7.58 – 7.39 (m, 4H), 7.31 (s, 2H), 7.11 (s, 1H), 2.42 (s, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 158.0, 150.0, 138.9, 138.6, 130.9, 129.2, 128.9, 127.2, 125.1, 120.5, 119.1, 21.5 ppm. IR (neat): 3032, 2922, 1596, 1449 cm-1. HRMS-ESI (m/z) calcd for C19H18N ([M+H]+): 260.1439, found: 260.1436. N 241 4-([1,1'-Biphenyl]-4-yl)-2-phenylpyridine (4.3h) Heterocycle 4.3h was constructed using an analogous procedure as described for 4.3a from 4.2j (0.037 g, 0.07 mmol). Column condition: 20% EtOAc in hexanes. Yield: 93%. White solids. mp 146 – 149 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.67 (d, J = 5.2 Hz, 1H), 8.05 – 7.95 (m, 2H), 7.90 (s, 1H), 7.75 – 7.54 (m, 9H), 7.42 (d, J = 7.3 Hz, 4H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 158.1, 150.0, 142.3, 140.4, 137.3, 130.0, 129.4, 129.1, 129.0, 128.0, 127.9, 127.7, 127.3, 124.5, 120.4, 120.3, 118.9 ppm. IR (neat): 3029, 1597, 1488, 1449 cm-1. HRMS-ESI (m/z) calcd for C23H18N ([M+H]+): 308.1439, found: 308.1436. 4-Pentyl-2-phenylpyridine (4.3i) Heterocycle 4.3i was constructed using an analogous procedure as described for 4.3a from 4.2k (0.036 g, 0.08 mmol). Column condition: 15% EtOAc in hexanes. Yield: 82%. Light yellow oil. Spectroscopy data match a literature report.259 1H NMR (300 MHz, Chloroform-d) δ 8.62 (d, J = 5.2 Hz, 1H), 8.14 – 7.86 (m, 2H), 7.58 (s, 1H), 7.55 – 7.38 (m, 3H), 7.13 (d, J = 5.2 Hz, 1H), 2.70 (t, J = 7.8 Hz, 2H), 2.31 (t, J = 7.8 Hz, 2H), 1.72 – 1.56 (m, 4H), 0.88 (t, J = 8.2 Hz, 3H) ppm. NN 242 13C NMR (75 MHz, Chloroform-d) δ 159.4, 152.6, 148.0, 141.1, 129.8, 129.1, 127.4, 123.0, 121.7, 35.8, 32.1, 31.5, 22.8, 14.3 ppm. HRMS-ESI (m/z) calcd for C16H20N ([M+H]+): 226.1596, found: 226.1590. Representative procedure for the synthesis of trisubstituted pyridines 2-Isopropyl-6-phenyl-4-(p-tolyl)pyridine (4.3k) Benzaldehyde (0.032 g, 0.3 mmol, 1.5 equiv), (9H-fluoren-9-yl)methyl carbamate (0.048 g, 0.2 mmol, 1.0 equiv) and boron trifluoride diethyl etherate (0.043 g, 0.3 mmol, 1.5 equiv) were dissolved in DCM (1 mL) and heated at 40 °C for 1 h. A solution of (E)-5-methylhexa-1,3-dien-2-yl diphenyl phosphate (2.1b, 0.18 g, 0.6 mmol, 3.0 equiv) in DCM (0.6 mL) was added. The reaction mixture was heated at 40 °C for 14 h. Aqueous sodium bicarbonate (1 mL, 1.1 M) was added, and the aqueous layer was extracted with EtOAc (´ 3). The combined extracts were washed with brine and dried over sodium sulfate. The resultant oil after concentration in vacuo was purified by column chromatography over silica gel (25% EtOAc/hexanes) to give 0.083 g (62%) of heterocycle 4.8 as a light-yellow oil. Heterocycle 4.8 (0.083 g, 0.12 mmol) was dissolved in distilled THF (1 mL). Palladium(II) chloride (0.00011 g, 0.006 mmol, 0.05 equiv) was added to the solution. p-Tolylmagnesium bromide (0.24 mmol, 2 equiv, 1 M in THF) was added dropwise over 30 min. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc and flushed through a short NOFmocPhPPhOOOPh1)MgBrPdCl2 THF, rt, 8 h2) piperidine DMF, rt, 8 hthen DDQ DCM, rt, 16 – 20 hNPhH2N-Fmoc PhCHO BF3•OEt2CH2Cl2, 40 °CKOPPhOOOPh 243 plug of silica gel. The resultant oil after concentration in vacuo were dissolved in DMF (8 mL). Piperidine (0.012 g, 0.144 mmol, 1.2 equiv, 4% solution in DMF) was added. The reaction mixture was stirred at rt for 2 h. 2,3-Dichloro-5,6-dicyano-1,4-benzoquino (0.054 g, 0.24 mmol, 2.0 equiv) was dissolved in DCM (1 mL) and added slowly to the reaction mixture. The reaction mixture was stirred at rt for 20 h. Water (1 mL) was added, and the aqueous layer was extracted with DCM (´2). The combined extracts were washed with brine, dried over sodium sulfate. After concentrate in vacuo, the resultant oil was purified by column chromatography over silica gel (5% EtOAc in hexanes) to give 0.019 g (54%) of heterocycle 4.3k as a white solid. 1H NMR (300 MHz, Chloroform-d) δ 8.06 – 7.94 (m, 2H), 7.70 – 7.47 (m, 9H), 3.03 – 2.93 (m, 1H), 2.34 (s, 3H), 1.33 (d, J = 6.9 Hz, 6H) ppm. HRMS-ESI (m/z) calcd for C21H22N ([M+H]+): 288.1752, found: 288.1751. Representative procedure for the synthesis of 4-biphenyl pyridine derivatives: 4-([1,1'-Biphenyl]-4-yl)-2-(4-methoxyphenyl)pyridine (4.12a) Palladium(II) chloride (0.0009 g, 0.005 mmol, 0.05 equiv) was added to the solution of 4.1b (0.066 g, 0.1 mmol, 1.0 equiv) in distilled THF (1.0 mL). Biphenylmagnesium bromide (0.2 mmol, 2 equiv) was added dropwise over a period of 30 min. The reaction mixture was stirred at rt for 3 h. The reaction mixture was diluted with EtOAc and flushed through a short plug of silica gel. The crude mixture was concentrated in vacuo and dissolved in DCM (1 mL). Piperidine (0.010 g, 0.12 NOFmocPPhOOOPh piperidine (1.2 equiv) DCM, rt, 2 hthen DDQ (2.0 equiv) rt, 20 hNPhPhMgBrPdCl2 (5 mol%)THF, rt, 3 h(2.0 eqiuv)OMe OMe1)2) 244 mmol, 1.2 equiv, 2% solution in DCM) was added. The reaction mixture was stirred at rt for 2 h. 2,3-Dichloro-5,6-dicyano-1,4-benzoquino (0.045 g, 0.20 mmol, 2.0 equiv) was dissolved in DCM (1 mL) and added slowly to the reaction mixture. The reaction mixture was stirred at rt for 20 h. The reaction mixture was directly concentrated in vacuo, and the resultant oil was purified by column chromatography over silica gel (20% EtOAc in hexanes) to give 0.022 g (overall 65%) of heterocycle 4.12a as a white solid. mp 124 – 126 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.74 (d, J = 5.3 Hz, 1H), 8.17 – 7.98 (m, 2H), 7.95 (d, J = 1.7 Hz, 1H), 7.86 – 7.70 (m, 4H), 7.71 – 7.59 (m, 2H), 7.57 – 7.37 (m, 4H), 7.18 – 6.98 (m, 2H), 3.89 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 161.1, 157.2, 150.0, 149.0, 142.5, 140.3, 137.1, 129.1, 128.7, 128.0, 128.0, 127.7, 127.3, 119.7, 118.3, 114.5, 55.6 ppm. IR (neat): 2924, 1599, 1515, 1468, 1248 cm-1. HRMS-ESI (m/z) calcd for C24H20NO ([M+H]+): 338.1545, found: 338.1544. 4-([1,1'-Biphenyl]-4-yl)-2-(3-methoxyphenyl)pyridine (4.12b) Heterocycle 4.12b was constructed using an analogous procedure as described for 4.12a from 4.1c (0.066 g, 0.1 mmol). Column condition: 20% EtOAc in hexanes. Overall yield: 71%. White solids. mp 114 – 115 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.76 (dd, J = 5.2, 0.8 Hz, 1H), 7.98 (dd, J = 1.7, 0.8 Hz, 1H), 7.84 – 7.70 (m, 4H), 7.71 – 7.58 (m, 4H), 7.56 – 7.36 (m, 5H), 7.01 (ddd, J = 8.2, 2.7, 1.0 Hz, 1H), 3.92 (s, 3H) ppm. NOMePh 245 13C NMR (75 MHz, Chloroform-d) δ 160.3, 158.0, 150.0, 149.2, 142.3, 140.4, 137.3, 130.0, 129.1, 128.0, 127.9, 127.7, 127.3, 120.4, 119.6, 119.0, 115.8, 115.5, 112.4, 55.6 ppm. IR (neat): 2918, 1597, 1467 cm-1. HRMS-ESI (m/z) calcd for C24H20NO ([M+H]+): 338.1545, found: 338.1544. 4-([1,1'-Biphenyl]-4-yl)-2-(2,5-difluorophenyl)pyridine (4.12c) Heterocycle 4.12c was constructed using an analogous procedure as described for 4.12a from 4.1d (0.060 g, 0.09 mmol). Column condition: 15% EtOAc in hexanes. Overall yield: 56%. White solids. mp 142 – 144 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.79 (d, J = 5.2 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.83 – 7.70 (m, 5H), 7.71 – 7.62 (m, 2H), 7.56 (dd, J = 5.2, 1.8 Hz, 1H), 7.55 – 7.43 (m, 2H), 7.45 – 7.34 (m, 2H), 7.20 – 7.06 (m, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 159.5 (d, J = 199.2 Hz), 156.6 (d, J = 244.1 Hz), 150.3, 148.9, 142.3, 140.4, 137.0, 129.1, 128.0, 127.9, 127.7, 127.3, 122.6, 112.5, 121.0, 117.7 (dd, J = 17.5, 8.8 Hz), 117.6 – 117.3 (m), 117.1 (dd, J = 24.3, 9.0 Hz) ppm. 19F NMR (282 MHz, Chloroform-d) δ -118.5 (d, J = 18.1 Hz), -122.7 (d, J = 18.1 Hz). IR (neat): 1598, 1487, 1463, 1170 cm-1. HRMS-ESI (m/z) calcd for C23H16F2N ([M+H]+): 344.1251, found: 344.1248. NPhFF 246 4-([1,1'-Biphenyl]-4-yl)-2-(3,4-difluorophenyl)pyridine (4.12d) Heterocycle 4.12d was constructed using an analogous procedure as described for 4.12a from 4.1e (0.080 g, 0.12 mmol). Column condition: 20% EtOAc in hexanes. Overall yield: 53%. White solids. mp 153 – 154 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.74 (d, J = 5.1 Hz, 1H), 8.01 – 7.89 (m, 2H), 7.86 – 7.70 (m, 5H), 7.71 – 7.63 (m, 2H), 7.57 – 7.46 (m, 3H), 7.44 – 7.29 (m, 2H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 156.0, 154.1 (dd, J = 243.9, 11.6 Hz), 151.3 (dd, 251.3, 12.3 Hz), 150.3, 149.4, 142.4, 140.3, 137.1, 129.1, 128.1, 128.0, 127.6, 127.3, 123.5 (dd, J = 5.3, 4,1 Hz), 120.7, 118.4, 117.7 (dd, J = 16.7, 1.3 Hz), 116.3 (dd, J = 16.6, 2.6 Hz), 115.4 ppm. 19F NMR (282 MHz, Chloroform-d) δ -137.2 (d, J = 21.2 Hz), -137.3 (d, J = 21.3 Hz) ppm. IR (neat): 1598, 1520, 1487, 1272 cm-1. HRMS-ESI (m/z) calcd for C23H16F2N ([M+H]+): 344.1251, found: 344.1245. 4-([1,1'-Biphenyl]-4-yl)-2-(2,3,6-trifluorophenyl)pyridine (4.12e) Heterocycle 4.12e was constructed using an analogous procedure as described for 4.12a from 4.1f (0.041 g, 0.06 mmol). Column condition: 20% EtOAc in hexanes. Overall yield: 70%. Light yellow solids. NPh FFNPhFFF 247 1H NMR (300 MHz, Chloroform-d) δ 8.83 (d, J = 5.2 Hz, 1H), 7.82 – 7.69 (m, 5H), 7.64 (ddd, J = 9.1, 6.2, 1.7 Hz, 3H), 7.55 – 7.43 (m, 2H), 7.45 – 7.34 (m, 1H), 7.20 (dt, J = 9.1, 4.5 Hz, 1H), 6.99 (tdd, J = 9.1, 3.8, 2.2 Hz, 1H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 159.5 (d, J = 188.4 Hz), 156.6 (d, J = 233.7 Hz), 150.3, 148.9, 142.3, 140.4, 137.0, 129.1, 128.8, 128.0, 127.9, 127.7, 127.3, 127.1, 127.0, 122.5 (d, J = 9.9 Hz), 121.0, 117.7 (dd, J = 17.5, 8.8 Hz), 117.1 (dd, J = 27.0, 8.2 Hz) ppm. 19F NMR (282 MHz, Chloroform-d) δ -119.6 (d, J = 15.2 Hz), -137.4 (d, J = 21.1 Hz), -141.7 (dd, J = 21.2, 15.2 Hz) ppm. IR (neat): 1597, 1495 cm-1. HRMS-ESI (m/z) calcd for C23H15F3N ([M+H]+): 362.1157, found: 362.1155. 4-(4-([1,1'-Biphenyl]-4-yl)pyridin-2-yl)benzonitrile (4.12f) Heterocycle 4.12f was constructed using an analogous procedure as described for 4.12a from 4.1g (0.052 mmol, 0.08). Column condition: 20% EtOAc in hexanes. Overall yield: 58%. Light yellow solids. mp 209 – 212 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.80 (d, J = 5.1 Hz, 1H), 8.20 (d, J = 8.0 Hz, 2H), 8.01 (s, 1H), 7.86 – 7.72 (m, 4H), 7.71 – 7.57 (m, 4H), 7.45 (dt, J = 26.5, 7.3 Hz, 4H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 143.6, 141.7, 137.0, 133.2, 133.0, 129.1, 128.4, 128.2, 127.8, 127.6, 127.2, 127.1, 124.7, 121.7, 112.7 ppm. IR (neat): 2227, 1600, 1488 cm-1. HRMS-ESI (m/z) calcd for C24H17N2 ([M+H]+): 333.1392, found: 333.1389. NPh CN 248 4-([1,1'-Biphenyl]-4-yl)-2-(4-chlorophenyl)pyridine (4.12g) Heterocycle 4.12g was constructed using an analogous procedure as described for 4.12a from 4.1h (0.073 g, 0.11 mmol). Column condition: 20% EtOAc in hexanes. Overall yield: 39%. White solids. mp 96 – 97 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.75 (d, J = 5.2 Hz, 1H), 8.08 – 7.97 (m, 2H), 7.95 (d, J = 1.7 Hz, 1H), 7.83 – 7.73 (m, 4H), 7.71 – 7.62 (m, 2H), 7.55 – 7.44 (m, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 149.8, 147.1, 142.5, 140.9, 140.3, 140.0, 137.0, 129.2, 129.1, 128.9, 128.6, 127.7, 127.2, 127.1, 126.4, 120.6, 118.7 ppm. IR (neat): 3031, 1600, 1487 cm-1. HRMS-ESI (m/z) calcd for C23H17ClN ([M+H]+): 342.1050, found: 342.1047. 4-([1,1'-Biphenyl]-4-yl)-2-(naphthalen-2-yl)pyridine (4.12h) Heterocycle 4.12h was constructed using an analogous procedure as described for 4.12a from 4.1i (0.068 g, 0.1 mmol). Column condition: 20% EtOAc in hexanes. Overall yield: 77%. White solids. mp 69 – 70 °C. NPh ClNPh 249 1H NMR (300 MHz, Chloroform-d) δ 8.82 (dd, J = 5.2, 0.8 Hz, 1H), 8.57 (d, J = 1.8 Hz, 1H), 8.22 (dd, J = 8.6, 1.8 Hz, 1H), 8.14 (dd, J = 1.8, 0.8 Hz, 1H), 8.04 – 7.95 (m, 2H), 7.90 (dd, J = 6.1, 3.4 Hz, 1H), 7.87 – 7.72 (m, 4H), 7.71 – 7.64 (m, 2H), 7.60 – 7.37 (m, 6H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 150.0, 142.4, 140.4, 137.3, 133.9, 133.7, 129.1, 129.0, 128.9, 128.8, 128.5, 128.1, 128.0, 127.9, 127.7, 127.3, 126.9, 126.6, 124.8, 120.4, 119.2, 115.8 ppm. IR (neat): 3031, 1602, 1486 cm-1. HRMS-ESI (m/z) calcd for C27H20N ([M+H]+): 358.1596, found: 358.1592. 4-([1,1'-Biphenyl]-4-yl)-2-cyclohexylpyridine (4.12i) Heterocycle 4.12i was constructed using an analogous procedure as described for 4.12a from 4.1n (0.095 g, 0.15 mmol). Column condition: 20% EtOAc in hexanes. Overall yield: 52%. White solids. mp 48 – 49 °C. 1H NMR (300 MHz, Chloroform-d) δ 8.53 (d, J = 5.3 Hz, 1H), 7.66 (s, 4H), 7.61 – 7.55 (m, 2H), 7.52 – 7.30 (m, 5H), 2.82 (t, J = 12.2 Hz, 1H), 2.19 – 1.27 (m, 10H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 155.6, 149.1, 145.1, 137.4, 136.1, 134.0, 129.1, 128.5, 127.9, 127.7, 127.3, 119.4, 115.8, 33.1, 31.7, 26.7, 22.8 ppm. IR (neat): 3021, 2926, 1604, 1486 cm-1. HRMS-ESI (m/z) calcd for C23H24N ([M+H]+): 314.1909, found: 314.1904. NPh 250 4-(4-([1,1'-Biphenyl]-4-yl)pyridin-2-yl)phenyl methanesulfonate (4.12j) Heterocycle 4.12j was constructed using an analogous procedure as described for 4.12a from 4.1k (0.074 g, 0.1 mmol). Column condition: 40% EtOAc in hexanes. Overall yield: 60%. Light yellow oil. 1H NMR (300 MHz, Chloroform-d) δ 8.77 (d, J = 5.2 Hz, 1H), 8.20 – 8.08 (m, 2H), 7.98 (d, J = 1.7 Hz, 1H), 7.85 – 7.71 (m, 4H), 7.71 – 7.61 (dt, J = 6.1, 1.4 Hz, 2H), 7.61 – 7.39 (m, 6H), 3.19 (s, 3H) ppm. IR (neat): 2923, 2849, 1599, 1489, 1369, 1150 cm-1. 13C NMR (75 MHz, Chloroform-d) δ 156.2, 150.3, 149.5, 143.9, 142.7, 140.2, 137.8, 136.7, 130.1, 129.1, 128.1, 127.7, 127.3, 122.6, 120.8, 120.2, 119.1, 37.7 ppm. HRMS-ESI (m/z) calcd for C24H20NO3S ([M+H]+): 402.1164, found: 402.1162. 4-(4-([1,1'-Biphenyl]-4-yl)pyridin-2-yl)phenyl 4-methylbenzenesulfonate (4.12k) Heterocycle 4.12k was constructed using an analogous procedure as described for 4.12a from 4.1l (0.080 g, 0.1 mmol). Column condition: 25% EtOAc in hexanes. Overall yield: 88%. White solids. mp 145 – 146 °C. NPh OMsNPh OTs 251 1H NMR (300 MHz, Chloroform-d) δ 8.73 (d, J = 5.1 Hz, 1H), 8.03 – 7.95 (m, 2H), 7.92 (s, 1H), 7.81 – 7.70 (m, 6H), 7.71 – 7.62 (m, 2H), 7.54 – 7.44 (m, 3H), 7.44 – 7.38 (m, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.16 – 7.06 (m, 2H), 2.45 (s, 3H) ppm. 13C NMR (75 MHz, Chloroform-d) δ 156.8, 150.5, 150.2, 149.4, 145.6, 142.4, 140.3, 138.3, 137.1, 132.4, 130.0, 129.1, 128.8, 128.5, 128.0, 128.0, 127.6, 127.3, 122.9, 120.6, 118.8, 21.9 ppm. IR (neat): 2925, 1598, 1373, 1177, 1155 cm-1. HRMS-ESI (m/z) calcd for C30H24NO3S ([M+H]+): 478.1477, found: 478.1474. Representative procedure for the nucleophilic aromatic substitution247 2-(4-([1,1'-Biphenyl]-4-yl)pyridin-2-yl)-4-fluorophenol (4.15) A mixture of 4-([1,1'-Biphenyl]-4-yl)-2-(2,5-difluorophenyl)pyridine (0.017 g, 0.05 mmol, 1 equiv) and potassium hydroxide (0.0042 g, 0.075 mmol, 1.5 equiv) in DMSO (1.5 mL) was heated at 110 °C for 16 h. The reaction mixture was cooled to rt. Water (1.5 mL) was added, and the aqueous layer was extracted with EtOAc (´ 3). The combined extracts were washed with brine and dried over sodium sulfate. The resultant oil after concentration under vacuo was purified by chromatography over silica gel (5% EtOAc in hexanes) to give 0.015 g (90%) of 2-(4-([1,1'-biphenyl]-4-yl)pyridin-2-yl)-4-fluorophenol (4.15) as a light yellow solid. mp 45 – 46 °C. NPhFFKOHNPhOHFDMSO, 110 °C, 16 h 252 1H NMR (300 MHz, Chloroform-d) δ 8.53 (d, J = 5.3 Hz, 1H), 8.01 (s, 1H), 7.72 (s, 4H), 7.60 (d, J = 7.5 Hz, 2H), 7.50 (d, J = 5.5 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.38 – 7.30 (m, 2H), 7.01 – 6.94 (m, 2H) ppm. 19F NMR (282 MHz, Chloroform-d) δ -125.3 ppm. IR (neat): 1604, 1486, 1262, 1173 cm-1. HRMS-ESI (m/z) calcd for C23H17FNO ([M+H]+): 342.1294, found: 342.1293. 253 Chapter 5: Conclusion This thesis presents three parts of the research work on the hetero-Diels-Alder reactions of 2-diphenylphosphoryloxy-1,3-butadienes to construct functionalized six-membered nitrogen heterocycles (Scheme 5.1). Constructions of products with high variation in functionality at C-2, C-4, and C-6 positions and moderate variation in functionality at C-3 position of the nitrogen heterocyclic rings were achieved. A limitation in functionality at C-5 position was resulted from the formation of Z/E isomers of the diene derivatives and the enhanced steric strain between the R5 and R6 in the cycloaddition processes. This research work disclosed the synthesis of 237 compounds, of which 167 are unknown, resulting from a total number of 921 experiments over the course of my graduate study. 254 Scheme 5.1 A summary of methods described in Chapter 2, 3, and 4 to construct non-aromatic or aromatic six-membered nitrogen heterocycles Chapter 2 describes the hetero-Diels-Alder reactions between 2-diphenylphosphoryloxy-1,3-butadienes and imines under the promotion of a Lewis acid FeCl3. An important advantage of this type of diene is its bench stability. With the goal of constructing substituted heterocycles in mind, I synthesized twelve examples of dienes with substituents at varied carbon positions. Eighteen examples of the cycloaddition products were synthesized from various dienes and imines in 30 – 91% isolated yields. Another advantage of the method is that the enol phosphate functionality was retained in the cycloaddition products and was synthetically useful in transition O OPPhOOOPhR3R2 R2R3R5R5i-Pr2NHnBuLi THF -78 °C, 30 minb) OP ClPhO OPh-78 °C -> rt, 3 ha)12 examples, 20 – 78%R2 = H, alkyl, Ph, OMeR3 = H, alkyl, PhR5 = H, alkylNR6HPGFeCl3 (0.2 equiv)DCM, rt24 — 48 hNR6[P]OPG18 examples, 30 – 92%, dr = 2:1 to >20:1R2R3R5R2 = H, alkyl, PhR3, R5 = H, alkylR6 = arylPG = Ts, SO2Ph, CbzChapter 2(~ 3 equiv)BF3•OEt2 (1.5 equiv)CH2Cl2, 40 °C, 16 hOR3PPhOOOPhN[P]OPGR6R3R2 R231 examples, 29 – 88%NH2 PG(1.0 equiv)OR6(1.5 equiv)Chapter 3R2, R3= H, alkylR6 = aryl, alkylPG = Ts, SO2Ph, Ms, Cbz, CO2Et, Fmoc(~ 3 equiv)BF3•OEt2 (1.5 equiv)Fmoc-NH2 (1.0 equiv)R2CHO (1.5 equiv)CH2Cl2, 40 °C, 16 hOPPhOOOPhN[P]OFmocR6R215 examples, 43 – 67%Chapter 4R2R2 = H, alkylR6 = aryl, alkyl1) R4MgBr/Cl (2 equiv) PdCl2 or Fe(acac)3 (5 mol%)THF, 2 — 8 h, rt2) piperidine (1.2 equiv)DCM or DMF, 2 — 8 h, rt then DDQ (2.0 equiv)DCM, rt, 16 — 20 hNR4 R621 examples, 17 – 88% (over two steps)R2R2 = H, alkylR4, R6 = aryl, alkylR4 = biphenyl: 12 examples of fluorescent pyrdines, λem = 349 – 389 nm 255 metal catalyzed cross-coupling reactions. Suzuki and Kumada coupling reactions were attempted to convert the enol phosphate functional groups to varied substituents on the heterocyclic rings. A limitation in the protocol was the small variation in functionality of imines due to challenging purification and isolation of various imine derivatives. This challenge was overcome by the multicomponent process in Chapter 3. Chapter 3 presents a protocol of multicomponent hetero-Diels-Alder reactions using dienes from chapter 2, amines, and aldehydes under the promotion of BF3•OEt2. The in-situ generation of iminium species in the multicomponent process avoids isolation and purification of the imine. The scope of amines and aldehydes are significantly broadened in the multicomponent hetero-Diels-Alder reaction. Thirty-one examples of cycloaddition products were obtained in 29 – 88% isolated yields. The reactions also have the advantage of ease of execution because they didn’t require accommodation of inert atmosphere or distilled solvent. This multicomponent method allowed for the construction of a N-Fmoc substituted cycloaddition product that could not be obtained using the experimental techniques in Chapter 2. The ease of deprotection of the Fmoc group made this cycloaddition product significantly useful in further manipulations to synthesize functionalized pyridines. In Chapter 4, a variety of di- and tri-substituted pyridines were built from the N-Fmoc substituted cycloaddition products in a sequence of Kumada coupling reactions, Fmoc deprotection and oxidation reactions. In the screening of Grignard reagents, a fluorescent compound, 4-biphenyl-2-phenylpyridine, was obtained that could potentially be applied in OLEDs materials. I envisioned that the protocol developed in this research work can be used to introduce substitutions on the phenyl ring of 4-biphenyl-2-phenylpyridine that have redshift or blueshift effect on fluorescence. The substituents can be varied from using different aldehyde starting 256 materials in the hetero-Diels-Alder step. Twelve examples of 4-biphenylpyridine derivatives were constructed, and their wavelengths of emission and quantum yields were obtained. A general trend was found that 4-biphenylpyridine derivatives with higher extent of conjugation had redshift in fluorescence and fluorinated 4-biphenylpyridine derivatives had significantly enhanced efficiency of fluorescence. For the future work, hetero-Diels-Alder reactions of 2-diphenylphosphoryloxy-1,3-butadienes with other dienophiles including nitriles, oximes and hydrazones could be investigated. A chiral catalyst might be developed for an enantioselective hetero-Diels-Alder reaction of this type of diene. 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Soc. 2020, 142 (26), 11370–11375. https://doi.org/10.1021/jacs.0c04499. 293 Appendix: Selected Spectra Data 2.1a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) OPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-100010020030040050060070080090010001100120013001400150016001.012.011.081.0010.26A (m)7.28B (ddd)6.19C (d)5.45D (m)5.20E (d)5.18F (dd)4.854.846254.854074.861845.166345.197815.200695.203625.421465.478416.142566.151826.178586.188166.199206.208466.235386.244997.178527.182487.186407.190387.209047.226997.230547.235727.240567.245077.251677.25939CDCl37.266007.270157.275097.330117.338257.353987.358897.375557.38240-100102030405060708090100110120130140150160170180190200210220230f1 (ppm)0500100015002000250030003500A (d)151.3B (d)150.6C (d)130.7D (d)125.7E (d)120.3F (d)102.476.84275CDCl377.16014CDCl377.47792CDCl3102.38213102.41735116.95805120.26753120.29038120.31693125.70973125.72471129.97247130.68184130.75038150.58749150.66120151.30779151.38907 294 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)0500010000150002000025000-17.28237 295 2.1b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) OPPhOOOPh-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)050001000015000200002500030000350006.041.031.001.001.8210.82A (m)7.27B (m)5.81C (t)5.03D (t)4.71E (m)2.27F (d)0.920.913780.936222.260792.267772.283742.289304.698714.706964.715185.021365.028835.036355.803625.805765.809905.813427.158037.161747.175687.182447.185297.188387.191717.201897.205967.210037.213717.222547.226557.230707.233917.238547.243927.251757.256037.26058CDCl37.303807.306547.312497.314907.327457.330227.333657.336617.350467.352927.356897.35944-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000280003000032000340003600038000A (d)151.6B (d)150.7C (d)125.6D (d)121.1E (d)120.3F (d)99.922.0103530.8322076.84224CDCl377.15987CDCl377.47806CDCl399.9065599.94157120.32062120.36973121.01993121.08629125.64076125.65490129.93326141.00552150.66214150.73578151.55899151.64260 296 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-50050100150200250300350400450500550600-17.34938 297 2.1c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) OPPhOOOPh-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)-2000020004000600080001000012000140001600018000200002200024000260001.011.001.000.9815.93A (m)7.31B (d)6.67C (dd)6.55D (t)5.26E (t)4.954.945684.954434.962515.251875.259665.267666.519546.528146.572346.580966.647746.700467.204267.208197.212887.221677.228517.231427.234717.238657.247487.251707.256027.25970CDCl37.269967.276777.284637.288677.293037.296237.304687.313777.317667.322957.328107.344357.351937.358707.360747.368307.372757.375477.378717.381967.395817.398107.402857.40506-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000280003000032000A (d)151.5B (d)150.7C (d)125.8D (d)122.0E (d)120.4F (d)102.376.84255CDCl377.15994CDCl377.47705CDCl3102.32192102.35671120.34243120.39138121.97762122.04652125.77000125.78461127.06643128.53390128.78853130.01649131.30285135.91367150.64070150.71572151.47314151.55347 298 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-1000010002000300040005000600070008000900010000110001200013000-17.35315 299 2.1e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) OPPhOOOPhC7H15-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)-100001000200030004000500060007000800090001000011000120001300014000150003.6910.602.201.011.001.8311.08A (m)7.28B (m)5.87C (t)5.03D (t)4.71E (dt)2.04F (m)1.26G (m)0.870.856900.880410.902041.218711.237451.243911.249971.259431.272311.294781.320102.024422.031392.045442.049704.700854.709174.717535.026175.033785.041335.864825.870135.877655.881297.176647.201047.203957.224577.228637.235277.239247.243257.246737.250227.25974CDCl37.264577.268597.273167.318157.322187.324907.331167.345817.348547.352007.354977.37771-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000020004000600080001000012000140001600018000200002200024000A (d)151.4B (d)150.7C (d)125.6D (d)123.7E (d)120.3F (d)99.714.2292022.7855128.9236729.2131929.2518231.9104632.3106976.84243CDCl377.16076CDCl377.47812CDCl399.7003799.73658120.30475120.35300123.65881123.72444125.62937125.64293129.92250134.64314150.65179150.72558151.40550151.48949 300 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-5000500100015002000250030003500400045005000550060006500700075008000-17.31507 301 2.1f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) OPPhOOOPhOBn0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007502.242.052.072.061.041.001.9515.01A (m)7.29B (m)5.88C (t)5.05D (t)4.72E (s)4.47F (t)3.42G (m)2.15H (p)1.651.603431.626491.649901.673731.696052.126732.140902.152802.167292.190103.402593.423793.445024.473524.706824.715304.723775.044635.052285.060005.866355.875795.880665.891317.175637.199977.223027.234317.26092CDCl37.297657.304557.320217.327947.346627.37274-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000140000150000160000A (d)151.2B (d)150.6C (d)125.6D (d)124.2E (d)120.3F (d)100.028.8759128.9439669.5003072.9887776.73614CDCl377.15978CDCl377.58286CDCl3100.01305100.06098120.24895120.31368124.19197124.27946125.63087125.64918127.65782127.71636128.47742129.91299133.56833138.62265150.57825150.67708151.18662151.29681 302 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-500050010001500200025003000350040004500500055006000-17.28986 303 2.1h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) OPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-10001002003004005006007008009001000110012002.981.021.021.011.0010.90A (m)7.27B (m)5.32C (m)5.20D (m)5.03E (t)4.95F (m)1.891.884931.889444.942204.951684.961095.023585.028405.032965.037225.041625.183625.191235.199275.207045.323057.166307.170237.174317.192797.200037.210277.214097.218187.221967.227057.231077.235097.239107.250257.256167.26039CDCl37.265197.316297.323587.340137.345537.361617.36868-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000140000150000160000170000A (d)153.0B (d)150.6C (d)136.2D (d)125.6E (d)120.3F (d)99.719.5125576.73679CDCl377.16033CDCl377.58391CDCl399.6973099.74365115.55686120.23610120.30084125.62793125.64604129.92055136.12188136.20258150.58838150.68729152.95915153.07002 304 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-2000020004000600080001000012000140001600018000200002200024000260002800030000-17.30046 305 2.1j 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) OPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507004.354.291.081.071.0010.24A (m)7.28B (m)6.12C (t)5.03D (t)4.81E (m)2.08F (m)1.601.522301.533021.540731.552941.560031.638951.645641.658211.665651.676832.034492.040072.046992.053332.059772.067412.082772.088302.095832.103372.109572.116512.123932.130594.800514.809844.819085.024475.033145.041846.115737.192607.214067.218177.222077.238827.242727.247837.25992CDCl37.267787.272147.277087.319197.326447.343117.348577.364007.37159-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-20000-100000100002000030000400005000060000700008000090000100000110000120000130000140000150000160000170000180000190000200000210000220000230000A (d)153.4B (d)150.7C (d)125.5D (d)120.3E (d)96.421.7731122.3633124.7164725.4018676.73745CDCl377.16010CDCl377.58446CDCl396.3802996.42713120.24104120.30682125.51167125.52948127.70939129.84362150.63255150.72964153.31436153.42996 306 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)0500010000150002000025000300003500040000-17.14776 307 2.1k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) OPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-1000100200300400500600700800900100011004.180.960.981.0010.57A (m)7.28B (m)5.92C (m)5.81D (m)5.55E (m)2.222.158362.164552.172062.179062.185662.191622.198092.204782.210322.237352.242792.246872.252212.257332.261642.267882.278842.284742.295095.533025.540945.548865.556405.563775.794485.801215.827955.834525.841195.906935.920495.924847.166917.171187.193817.217547.230337.235317.248497.255807.25995CDCl37.265157.320507.327747.344157.349387.365707.37303-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-20000020000400006000080000100000120000140000160000180000200000220000240000A (d)150.6B (d)145.3C (d)125.5D (d)122.6E (d)120.2F (d)108.9G (d)21.521.4517121.4703821.9192176.73634CDCl377.15996CDCl377.58546CDCl3108.84296108.91913120.16712120.23265122.52790122.60566125.53111125.54790129.87678130.50125145.22948145.34495150.58515150.68213 308 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250 f1 (ppm)010002000300040005000600070008000900010000-17.23003 309 2.8a, 3.15a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NPhOPPhOOOPhTs-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)-10000100020003000400050006000700080009000100001100012000130001400015000160003.012.081.011.070.991.0017.712.04A (m)7.70B (m)7.26D (dd)5.38E (m)4.24F (m)3.41G (m)2.61H (s)2.36C (dt)5.542.362542.593482.599552.604872.609962.615232.621032.626942.632593.374973.380133.428053.435153.440393.447294.203454.211574.271295.369785.383445.397195.521725.527485.532815.538075.543785.549457.144937.148817.169327.212757.220097.237807.241247.248197.25975CDCl37.266057.275917.283917.316757.342017.347857.368487.380817.689697.695817.711237.71727-100102030405060708090100110120130140150160170180190200210220230f1 (ppm)-5000500100015002000250030003500400045005000550060006500A (dd)150.4B (d)144.8C (d)125.8D (d)120.1E (d)108.6F (d)29.121.6424029.1033229.1459939.5925553.4668576.84187CDCl377.15959CDCl377.47746CDCl3108.58517108.63997120.09166120.14282125.81021125.82431127.12597127.29975128.03712128.78047129.91218130.03105137.46686137.93826143.68241144.79320144.88485150.38076150.40436150.45350150.47765 310 31P{1H} NMR (121 MHz, CDCl3) 1H-1H COSY (CDCl3) -100-50050100150200250f1 (ppm)05001000150020002500-17.363191.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f2 (ppm)1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm) 311 1H-13C Heteronuclear Single Quantum Coherence (HSQC) 1.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f2 (ppm)102030405060708090100110120130140150160170180190f1 (ppm) 312 2.8b, 3.15b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhTsCl-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000021000220003.082.041.031.020.991.0017.692.06A (m)7.63B (m)7.17C (m)5.46D (t)5.28E (m)4.17F (m)3.32G (m)2.52H (s)2.312.313532.498152.503902.510082.515762.521002.526092.531452.537803.286153.293133.298683.305633.346603.353603.359163.365904.138974.146664.155124.199984.206674.210094.216625.269595.283045.296325.448515.454095.460105.465425.470315.475957.076597.079667.102087.107387.160197.172317.182157.189157.200627.229407.25985CDCl37.284357.287737.619377.64700-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000A (dd)150.3B (d)144.5C (d)120.0D (d)108.7E (d)29.121.6200429.0388829.0813739.5478752.9221976.84225CDCl377.16028CDCl377.47801CDCl3108.65562108.71214120.02478120.07417125.84929127.04540128.75222128.89342129.95208130.02422133.89414136.42951137.24881143.84346144.47949144.56852150.27916150.31738150.35301150.39058 313 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)010002000300040005000600070008000900010000-17.24241 314 2.8c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhTsNO20.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)010020030040050060070080090010003.011.981.001.011.001.0012.622.092.052.00A (m)8.11B (m)7.70C (m)7.56D (m)7.24E (m)5.53F (t)5.44G (ddd)4.27H (m)3.38I (m)2.64J (s)2.382.384232.624472.631082.637032.642222.647062.653135.431925.444585.457765.515595.522555.530605.537037.127547.131407.134897.138197.142737.152007.156217.162097.167117.193007.196297.199707.221407.244847.253517.25998CDCl37.281317.318987.343767.346907.369407.372407.543217.550047.564697.572237.690527.696697.712147.718188.095378.101828.117958.12467-100102030405060708090100110120130140150160170180190200210220230f1 (ppm)0100020003000400050006000700080009000A (dd)150.3B (d)144.2C (dd)120.0D (d)108.9E (d)29.021.6540028.9684629.0083139.7520253.0750076.84249CDCl377.16029CDCl377.47808CDCl3108.82443108.88207119.98956120.00616120.03844120.05357123.94502125.95183127.04443128.38789130.06624130.08864130.09116136.95245144.12544144.18445144.21280145.22291147.59385150.20727150.26046150.28043150.33470 315 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-100001000200030004000500060007000800090001000011000120001300014000150001600017000-17.12829 316 2.8d, 3.15c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOTsPPhOOOPhOMe-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-1000010002000300040005000600070008000900010000110001200013000140003.041.961.003.111.001.001.021.9914.252.00A (m)7.70B (m)7.25C (m)6.79D (m)5.53E (t)5.33F (m)4.21G (s)3.77H (m)3.39I (m)2.58J (s)2.362.363982.565472.570002.574292.578142.582332.586883.772135.330465.521485.526205.530455.533836.782056.787376.798676.803997.151467.154417.157267.170207.173077.176247.179657.213537.215887.222377.224297.229107.231427.233997.236597.238917.243747.26047CDCl37.272857.274557.295257.296977.323937.343507.345757.362777.364167.688097.692747.704587.70891-100102030405060708090100110120130140150160170180190200210220230f1 (ppm)050010001500200025003000350040004500B (d)145.0C (d)120.1D (d)108.7A (d)150.4E (d)29.321.6518229.3204129.3639839.4361152.9928755.4014976.84251CDCl377.16004CDCl377.47772CDCl3108.66321108.71817114.04713120.10857120.15831125.81813127.13127128.60961129.90050129.93884130.03576137.57891143.62791144.90551144.99693150.39707150.47016159.28338 317 31P{1H} NMR (121 MHz, CDCl3) -350-300-250-200-150-100-50050100150200250300350f1 (ppm)-1000100200300400500600700800900-17.26195 318 2.8e, 3.18c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NPhOPPhOOOPhSO2Ph-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)010020030040050060070080090010001.981.031.060.991.0014.803.181.98A (m)7.82B (m)7.32C (m)5.54D (dd)5.39E (m)4.26F (m)3.42G (m)2.602.591682.597582.602352.606472.610792.616303.390493.395563.444153.450933.455763.462734.225954.233614.238154.286574.293825.378885.388235.397125.406025.526385.532095.536385.542365.548355.553557.141397.170137.188637.212047.237827.25940CDCl37.274527.281787.295197.318657.342217.367577.418907.441827.467497.493497.517317.805887.811677.834697.83870-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000A (dd)150.4B (d)144.9C (d)120.1D (d)108.6E (d)29.229.2028629.2470439.6669953.5862076.84242CDCl377.15917CDCl377.47829CDCl3108.52317108.57909120.10542120.15487125.81997127.06859127.29665128.09763128.80976129.31034130.03024132.85222137.84694140.44541144.81945144.90960150.39074150.41686150.46299150.49081 319 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-5000500100015002000250030003500400045005000550060006500700075008000-17.22681 320 2.8f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhSO2PhCl0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)0501001502002503003504004505001.961.031.031.001.0217.461.99A (m)7.70B (m)7.15C (m)5.41D (t)5.24E (m)4.15F (m)3.29G (m)2.452.438242.445432.452202.458362.464512.470553.254763.260263.307653.315203.320633.327524.107854.113314.119114.172884.178945.227495.240885.254305.405285.413505.420577.017887.022267.026577.041527.046487.051327.107667.129307.136287.148557.168317.197207.207937.234407.26007CDCl37.343387.349427.369457.399437.423487.685867.691557.709277.714667.71854-100102030405060708090100110120130140150160170180190200210220230f1 (ppm)-200-100010020030040050060070080090010001100120013001400150016001700180019002000210022002300A (dd)150.3B (d)144.5C (t)125.9D (d)120.1E (d)108.6F (d)29.129.0895129.1313239.6195853.0199376.84179CDCl377.15931CDCl377.47747CDCl3108.61658108.67394120.05196120.10137125.85777125.87396125.89202126.99992128.75786128.94494129.37671130.04410132.98843133.98844136.32002140.23130144.50482144.59323150.28074150.32277150.35366150.39571 321 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-5000500100015002000250030003500400045005000550060006500700075008000-17.22681 322 2.8g, 3.18e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPh PhCbz0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508001.071.060.950.892.061.031.0021.10B (m)5.74C (dq)5.55D (m)5.19E (m)4.44F (m)3.38G (m)2.97H (m)2.74A (m)7.312.694832.698942.702992.707312.752822.757052.761102.765582.924912.935192.944352.948312.993203.350983.358093.402833.410383.417613.423434.412925.158945.199945.219855.250235.260895.278835.541695.549455.557245.564935.572685.728757.186527.190227.211727.237287.26006CDCl37.267287.290667.325077.334907.341657.347617.352257.364107.371977.377067.38143-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000A (d)150.5B (d)120.230.3460538.9260951.6565467.7525876.73633CDCl377.16052CDCl377.58326CDCl3108.76495120.13641120.20299125.77398126.83603127.73845128.15099128.30733128.69038128.77796130.02007136.50378139.14636150.45064150.54611155.40434 323 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-1000100200300400500600700800900100011001200130014001500160017001800-17.09492 324 2.18a, 3.17a (diastereomer A) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NPhOPPhOOOPhTs-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-10001002003004005006007008009001000110012001300140015003.042.961.113.041.021.001.011.021.002.0318.67A (m)7.21B (m)6.96D (dd)4.67G (ddd)2.47H (s)2.30I (m)2.04J (d)1.07K (d)1.01F (m)3.36C (m)5.95E (m)4.460.996681.018661.059101.081192.031362.062432.303922.433912.442952.447492.484992.489672.498622.503314.445924.453824.461614.469434.642624.655914.680714.693965.930315.935385.940335.946285.952015.957036.948346.975217.088327.116117.142147.153987.172787.182447.188047.191717.195647.214367.243187.26013CDCl37.268297.339927.361927.365417.368847.39178-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000050000100000150000200000250000300000350000400000450000500000550000600000650000A (t)150.5B (d)146.6C (d)125.7D (dd)120.2E (d)112.8F (d)33.2G (d)30.819.4531221.1053221.4723830.8198930.8645133.1996833.2154155.6841361.2563776.84226CDCl377.15988CDCl377.47719CDCl3112.81440112.86971120.20316120.22843120.25295120.27698125.68423125.70243125.71994127.18593127.83125127.96928127.97687128.83017129.05088129.98191136.43381139.27392142.43486146.54788146.63959150.44739150.52392150.60280 325 31P{1H} NMR (121 MHz, CDCl3) 1H-1H COSY (CDCl3) -250-200-150-100-50050100150f1 (ppm)-40-20020406080100120140160180200220240260280300320340360380400-17.31451-0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f2 (ppm)012345678f1 (ppm) 326 NOESY (CDCl3) -0.50.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f2 (ppm)0123456789f1 (ppm) 327 2.18a, 3.17c (diastereomer B) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOPPhOOOPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004505002.833.351.441.432.941.051.061.081.0510.995.462.282.00A (m)7.75B (m)7.48C (m)7.36D (m)7.22E (dt)5.81F (d)5.31G (m)4.19H (d)2.55I (s)2.35J (m)2.04K (dd)1.04L (d)0.78M (d)0.670.671050.676780.773070.780840.998521.020551.061581.083662.053142.062362.078512.087612.346482.519782.579474.175285.292575.317695.797015.804295.811615.819045.826457.156217.175587.202617.229607.241317.248817.25960CDCl37.266257.274447.279767.290297.295137.336697.342227.363537.389217.461267.467647.479847.485107.493297.738537.744417.759517.76609-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000A (d)150.5B (d)143.9C (dd)120.1D (d)112.0E (d)26.220.0958021.1207121.6325426.1482226.2019232.4578152.3685260.2002576.73750CDCl377.16054CDCl377.58319CDCl3111.92609112.00067120.01550120.04286120.08289120.11045125.80702127.16533127.97066128.18008128.34762130.00563130.03822137.82990139.11964143.71071143.87167143.99411150.40486150.50054 328 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)05001000150020002500-17.19923 329 2.18b, 3.17a (mixture of diastereomers) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhTsPhC7H15-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-5005010015020025030035040045050055060065070075080085029.251.970.652.991.411.160.470.990.471.080.990.450.451.002.0827.580.940.88A (m)7.74B (m)7.48C (m)7.22D (d)6.97F (dt)5.59G (d)5.35H (m)4.83I (dd)4.70J (m)4.50L (d)2.62N (s)2.35O (s)2.31P (m)2.19Q (m)1.72R (m)1.26S (m)0.88E (m)5.80K (m)3.31M (ddd)2.490.825200.849300.866730.872050.879850.903080.924151.149531.173141.190651.212581.236161.260101.275971.304431.322622.308592.345776.958166.985197.114177.121277.128887.143247.149477.157737.161897.166317.180507.186037.190907.195657.212287.221017.230977.236027.243547.249047.25938CDCl37.326247.333177.338767.355207.362267.379017.385197.727767.75535-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0100002000030000400005000060000700008000090000C (d)146.3D (d)130.0E (d)120.3F (d)120.1G (d)114.0H (d)112.9I (d)31.2J (d)29.4A (dd)150.6B (d)150.414.1805914.2438021.4922021.6215922.7157122.7913326.5862029.0310329.1932729.3217029.3816031.2188131.2643631.8387131.8796034.8318952.1852954.8604155.2622876.84292CDCl377.15977CDCl377.47768CDCl3113.97048114.02403120.07576120.12562120.25226120.30058125.72771125.80267127.02025127.09217127.79588127.83170127.94801127.95204128.40823128.90230129.03695130.00358130.02200136.42247139.47452139.49395142.44332143.64661146.22941146.32080 330 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150 f1 (ppm)-2000-1000010002000300040005000600070008000900010000110001200013000140001500016000170001800019000200002100022000-17.39305-17.26376 331 2.18b, 3.17b (Diastereomer B) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTsPhC7H150.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-5005010015020025030035040045050055018.051.053.071.051.021.001.0017.702.052.13A (m)7.74B (m)7.48C (m)7.26D (dt)5.59E (d)5.36F (m)4.50G (d)2.63H (s)2.35I (m)2.19J (m)1.060.804150.826220.850290.873231.045531.068141.087281.104311.113801.126001.149581.173781.192001.213601.232721.238651.258061.263342.345082.596072.655075.345035.368955.585605.592555.599527.130547.164047.188367.193387.221687.231027.244527.248917.25959CDCl37.270307.327857.353717.379527.464287.470087.477987.488717.496607.729807.735817.751087.75727-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000A (d)150.4B (d)120.1C (d)112.9D (d)29.1E (d)26.614.1698421.6051922.6991226.5637826.6108529.0123929.1765331.8197735.3593952.1670154.1473976.73597CDCl377.16083CDCl377.58349CDCl3112.85762112.93049120.05091120.11648125.78958126.99999127.81527127.91765128.39245130.00967137.86061139.47786143.52439143.63610150.40219150.49738 332 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000280003000032000-17.26376 333 2.18c, 3.17b (diastereomer A) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTsPhOBn0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005.133.151.151.212.112.041.000.981.002.1126.75A (m)7.26B (m)6.95C (m)5.80D (m)4.86E (dd)4.70F (s)4.51G (t)3.52H (m)3.28I (m)2.49J (s)2.30K (m)1.821.727251.746521.769621.832751.838921.854181.862261.876702.295973.496503.515353.535924.513575.792495.803886.940386.967357.105617.113067.125217.140667.148697.156077.162747.178087.182297.185917.189757.208887.224487.228317.231987.235157.250067.254007.25993CDCl37.280057.285777.291577.299577.305967.314847.329347.339887.352487.356887.375457.38235-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000A (t)150.5B (d)146.4C (d)120.3D (d)113.7E (d)31.121.5080726.8388731.1060231.1664031.5516054.6979455.2458569.6916973.0888776.73566CDCl377.16038CDCl377.58361CDCl3113.70803113.78038120.23538120.30074125.74257127.10815127.75062127.83845127.96280128.52907128.97696129.07596130.02344136.31062138.57755139.28391142.52480146.37704146.49981150.44220150.53220150.62331 334 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-1000100200300400500600700800900100011001200130014001500-17.46664 335 2.18c, 3.17b (diastereomer B) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTsPhOBn0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504001.081.112.181.073.090.980.991.021.991.061.011.0022.372.111.98A (m)7.72B (m)7.48C (m)7.25D (dt)5.59E (d)5.35F (m)4.55H (dt)3.27I (dt)3.07J (d)2.62K (s)2.34L (m)2.16N (m)1.08O (m)0.75M (m)1.54G (s)4.361.476971.494971.509481.515711.528851.538481.549532.340922.593512.652663.059583.068733.090813.252783.264183.272653.284204.355224.538754.550334.561775.341395.365375.575195.582745.589795.596795.604347.157167.184297.193547.219387.245367.253457.26082CDCl37.279117.284907.299177.304887.323367.348827.374967.464717.487197.493477.709707.730947.73705-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000A (d)150.4B (d)143.8C (d)120.1D (d)112.9E (d)26.521.6324926.4496326.5067126.7776031.9835152.2145153.8674169.8567972.6735876.73733CDCl377.15999CDCl377.58264CDCl3112.85069112.92584120.06638120.13373125.82256127.00792127.51079127.64075127.89123128.40419128.46130130.04715137.75593138.76212139.41229143.70290143.72625143.82543150.39874150.49465 336 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-200-100010020030040050060070080090010001100120013001400150016001700180019002000210022002300-17.31729 337 2.18d, 3.17d (diastereomer A) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NPhOPPhOOOPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506007.563.452.381.041.011.001.9621.54A (m)7.24B (d)7.05C (dd)5.00D (m)4.46E (m)3.22F (ddd)2.84G (s)2.34H (m)1.511.150791.163801.193011.263151.459701.490561.529131.571131.614891.644551.692011.797221.804691.811031.820511.829742.336072.806692.814732.822122.828772.853182.860272.867302.873603.187483.206534.433554.453064.468264.470144.983064.997365.008865.023207.034737.061727.142997.159697.178187.207567.228017.25949CDCl37.278957.307237.316807.340507.36204-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000650007000075000A (t)150.6B (d)136.9C (d)125.6D (dd)120.2E (d)34.321.5063025.4231926.4554226.8549032.6434834.2739034.2924856.8581857.2248076.84183CDCl377.15944CDCl377.47745CDCl3120.13198120.18126120.21983120.26855125.61439125.65697126.67654127.59274127.98898128.56197129.16788129.92536129.95705136.84909136.93786137.43618140.10497142.50258150.48440150.55320150.62168 338 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)050010001500200025003000350040004500-16.73793 339 2.18d, 3.17d (diastereomer B) 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOPPhOOOPhTs-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)01002003004005006007008009000.981.248.073.301.381.741.031.0021.092.032.03A (m)7.74B (m)7.56C (m)7.28D (d)5.33E (m)4.22F (d)2.82G (m)2.44I (m)1.56J (m)0.88K (qd)0.57H (s)2.340.546100.558250.588040.600340.837620.881461.470201.483701.519821.562081.635091.660261.675031.686251.716881.729262.343292.408722.418802.453702.464762.476092.487562.792852.850134.198964.202404.218824.232444.244205.323035.345437.143327.168427.207607.219977.232697.240607.25967CDCl37.268177.293857.315567.341807.367797.547327.567197.723677.75126-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000A (d)150.5B (d)135.4D (d)120.1C (d)123.621.6344925.7339125.8740327.0997027.5026034.8815352.6426956.4859976.73636CDCl377.15978CDCl377.58458CDCl3120.06836120.13610123.58892123.69633125.72214126.78830127.73552128.16352128.40050129.99258130.09598135.32138135.44036137.97916139.90762143.56102150.49108150.58108 340 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100010020030040050060070080090010001100120013001400150016001700-16.63373 341 2.18e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) OPPhOOOPhNPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004.203.150.990.990.991.0022.282.08A (m)7.63B (m)7.26C (dt)5.57D (dt)4.74E (m)4.60F (p)2.74G (s)2.25H (m)1.481.458621.469921.492181.501901.513992.248702.730382.739502.748644.592704.599654.607124.730314.740874.751385.551395.558695.566015.572485.579717.118527.130437.133627.137857.158087.162137.167397.195797.205287.208987.229787.250847.254337.25992CDCl37.269027.274637.309057.335257.357257.360877.366367.372427.388007.394597.617287.623397.638807.64483-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0500010000150002000025000300003500040000A (d)151.7B (d)150.3C (d)120.1D (d)112.0E (d)42.716.4823521.5658227.4428829.8372642.6436442.7081851.5306662.7184276.73754CDCl377.16037CDCl377.58303CDCl3111.97810112.05478120.05521120.12280125.92198126.51878127.41861128.19880128.44646129.72204130.06917135.25841139.65831143.75090150.28122150.38370151.68112151.80297 342 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-10001002003004005006007008009001000-18.28451-17.62197 343 2.18f 1H NMR (400 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhCbzPhPh-0.50.51.52.53.54.55.56.57.58.59.510.511.512.5f1 (ppm)-1000100200300400500600700800900100011001200130014001.001.030.980.991.911.021.973.9020.74A (m)7.15B (dd)6.87C (d)6.72D (dd)5.77F (d)4.89G (d)4.77H (m)3.15I (dd)2.61E (d)5.522.587292.595232.629212.637153.117503.123263.132903.138623.165063.174874.756414.787344.871874.902675.558355.763415.770965.777545.783396.706886.723616.854766.865756.875306.886537.048897.053387.069977.084207.089017.100947.105087.108987.122517.131897.139277.152517.159797.174377.178387.188707.203477.206937.213327.216787.224657.248957.25995CDCl3-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000065000A (dd)150.3B (d)143.4C (d)125.6D (dd)120.1E (d)113.5F (d)33.833.8011833.8477855.6698457.7517767.5449676.84195CDCl377.15981CDCl377.47735CDCl3113.49824113.55070120.01719120.06623120.08850120.13761125.62077125.67014126.06411127.30455127.42424127.79188127.86685128.31346128.64808128.90814129.90685136.06021143.36055143.45367150.24557150.27369150.32014150.34724156.04709 344 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-20-100102030405060708090100110120130140150160170-17.65214 345 2.18g 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhCbzPhBr0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504001.011.011.011.010.941.021.002.023.9618.03A (m)7.23B (m)6.98C (dd)6.82D (m)5.89E (m)5.65F (m)5.47G (d)4.98H (d)4.86I (m)3.20J (dd)2.632.596502.607442.652402.663353.169803.182953.190444.839894.880834.961565.002565.645585.660365.668645.870975.878745.887785.896915.904676.808046.815496.833496.839606.962146.967176.971856.986636.990886.995696.999887.004827.120697.137927.158287.165287.183057.201457.207847.230707.239697.25969CDCl37.267557.283157.292537.330517.352837.368627.37540-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000A (dd)150.2B (d)143.2C (d)125.7D (t)120.0E (d)113.5F (d)33.633.6114433.6734555.2075957.5781667.6843976.73553CDCl377.16064CDCl377.58399CDCl3113.50727113.58106119.93100120.00464120.07859122.77773124.68409125.65880125.71056126.26487127.50738127.80391127.97526128.36976128.91576129.12551129.90856130.19127130.46608135.80239143.09537143.21753144.95596150.13835150.17035150.23651150.26812155.80354 346 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)0500100015002000250030003500400045005000-17.60633 347 2.18h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhPhClCbz0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004500.991.131.000.990.860.951.071.934.078.679.83A (m)7.32B (m)7.20C (m)6.97D (m)6.81E (dt)5.87F (m)5.63G (m)5.47H (d)4.97I (d)4.85J (m)3.20K (dd)2.642.611242.622342.666842.678133.156193.163903.170043.176644.825334.866204.950184.991135.630065.855415.862895.871595.880596.791976.798186.818226.823586.940286.943846.953566.967656.972056.978016.982736.987737.157197.162727.170587.177277.180567.185587.189687.195307.204857.210457.218427.227527.234127.283377.310777.314457.324697.340747.34141-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000A (d)150.2B (d)143.3C (d)125.7D (dd)120.0E (d)113.6F (d)33.733.6481833.7104455.1583357.5996267.6874076.73749CDCl377.16099CDCl377.58364CDCl3113.53017113.60544119.94492120.01167120.03526120.10057125.70552125.75023126.33292127.47765127.53854127.92161128.02121128.35657128.76684128.95134129.14769129.94731133.09629135.86809141.04299143.28573143.40512144.05108150.19991150.29878155.92004 348 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-200-10001002003004005006007008009001000110012001300140015001600170018001900-17.64793-17.11476 349 2.18i, 3.17e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NPhOTsPPhOOOPh-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)-2000-100001000200030004000500060007000800090001000011000120001300014000150001600017000180001900020000210002200023000240003.002.952.091.011.000.9718.512.06A (m)7.65B (m)7.22C (m)5.31D (m)4.00E (m)3.29F (m)2.69G (s)2.32H (m)1.491.487651.494621.500392.319052.649402.659602.669332.705322.713353.310563.314453.318363.964393.972953.981364.031885.297305.318517.107127.111047.115127.118567.123137.135887.141477.147047.163537.171517.186687.213367.222287.227247.234007.242127.248397.25948CDCl37.267787.278027.294597.305167.320737.330807.355507.363177.642677.649047.664017.67016-100102030405060708090100110120130140150160170180190200210220230f1 (ppm)-500050010001500200025003000350040004500A (dd)150.5B (d)138.5C (dd)125.7D (dd)120.1E (d)117.0F (d)13.413.3807513.3953221.5871328.9519944.1374953.9868476.84227CDCl377.16077CDCl377.47817CDCl3116.97088117.05206120.06937120.09632120.11918120.14547125.67205125.68384125.69945125.71413126.99313127.27275127.88181128.70843129.85532129.94220137.43706138.07322138.44127138.52915143.60004150.40704150.42760150.48158150.50046 350 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-100001000200030004000500060007000800090001000011000120001300014000-16.69774 351 2.18j 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOTsPPhOOOPhCl-1.5-0.50.51.52.53.54.55.56.57.58.59.510.511.5f1 (ppm)-2000-1000010002000300040005000600070008000900010000110001200013000140001500016000170001800019000200002100022000230002.993.082.001.011.101.0017.682.03A (m)7.68B (m)7.24C (m)5.30D (m)4.03E (m)3.30F (m)2.69G (s)2.37H (m)1.531.521931.528871.535692.369722.627622.636972.647162.657112.667422.700832.758513.249493.254953.262403.271563.281773.303573.312263.318203.322513.326013.331523.340614.003304.061624.074225.284945.305277.123957.128367.148437.152927.168637.172957.177937.217367.234737.239257.247057.26021CDCl37.307247.317197.335187.345247.666417.672557.687797.69404-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000065000700007500080000A (dd)150.4B (d)138.2C (d)125.8D (t)120.1E (d)117.1F (d)13.413.3746413.3867721.6133728.9219644.1261153.4951176.84225CDCl377.15924CDCl377.47807CDCl3117.06689117.14828120.04238120.09656120.14952125.75052125.79624126.97354128.78046128.86046128.87048129.92986129.97943133.77106136.59454137.29821138.17838138.26373143.79458150.35500150.38961150.42804150.46268 352 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000-16.56824 353 2.18k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOSO2PhPPhOOOPh0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)0501001502002503003504004505003.072.071.031.031.0018.622.06A (m)7.81B (m)7.31C (d)5.35D (m)4.04E (m)3.34F (m)2.70G (q)1.531.518121.524101.530291.537252.737765.337375.358997.141587.145567.149297.166457.170527.174237.200547.208567.222727.226827.231077.234967.239187.256077.26005CDCl37.281267.304107.313637.330347.340317.349327.355937.366507.374207.381737.415747.422007.444587.451587.464637.470167.482627.488017.493147.511297.791257.797197.804467.813967.819547.82390-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000650007000075000A (dd)150.5B (d)138.5C (d)125.7D (dd)120.2E (d)117.0F (d)13.413.4270113.4416029.0681544.2245754.1251576.84282CDCl377.16009CDCl377.47719CDCl3116.98176117.06290120.14064120.17093120.19018120.22054125.73495125.76371126.98026127.31491127.98527128.77859129.29344129.98200132.82579137.99429138.50046138.58613140.43585150.44109150.46006150.51347150.53304 354 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000-16.67874 355 2.22 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Ts0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-10001002003004005006007008009001000110012003.161.081.051.041.081.031.0015.952.22A (m)7.72B (m)7.29C (m)5.91D (d)5.46E (m)4.32F (m)3.55G (d)2.82H (m)2.71I (s)2.392.386532.724182.733662.745792.795583.514013.521203.527143.578193.589744.280324.292594.356235.451565.472075.895085.902905.910705.918375.926177.223537.232867.238137.245317.250227.26041CDCl37.265507.270867.286667.290667.301107.304847.310517.315467.323137.329327.336437.340557.344057.349617.356737.363347.367867.705137.713447.719727.734917.74104-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000021000220002300021.6326028.7288841.5051553.3754876.73622CDCl377.15926CDCl377.58364CDCl3120.25980125.19115127.20677127.48120127.71499127.76297128.59196128.65027129.73917134.42647137.77462139.14803140.49596143.38397 356 2.23 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)01002003004005006007008009003.011.892.970.981.001.927.231.93A (m)7.67B (m)7.25C (m)5.29D (m)4.06E (m)3.33F (s)2.41G (m)2.28H (s)1.661.57136HDO1.656072.194162.252522.281432.284242.287942.292102.296362.300572.304802.309342.313572.317902.322042.327152.405623.284583.292713.299743.305033.312503.320373.344753.352993.359743.364983.372433.380664.035534.049954.098335.284055.302697.215927.225117.242767.253617.26006CDCl37.269337.278147.284047.658377.664687.680017.68597-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)05000100001500020000250003000035000400004500021.6473723.3930431.4311240.9846753.3193976.73623CDCl377.15939CDCl377.58408CDCl3117.63676127.21143127.44621127.58208128.50145129.58108131.58157137.86653139.58117143.12896 357 2.24 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhTsTMS0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505008.971.191.561.364.531.111.091.001.259.832.31A (d)7.69B (m)7.28C (m)5.31D (m)5.10E (m)4.12F (m)3.44G (m)2.41H (m)2.19I (d)1.56J (d)1.39K (s)-0.12-0.120281.367951.413841.534861.576792.159722.190732.217242.345432.405253.412523.473064.088714.149885.100195.296045.318047.225577.251827.25947CDCl37.279897.286707.311357.675387.70203-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100001000200030004000500060007000800090001000011000-1.2727921.5849228.6995732.5397141.3583753.4805876.73583CDCl377.16043CDCl377.58356CDCl3115.02239127.07265127.46051128.43696129.74681133.00663137.98730139.77121143.08234 358 2.25 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Ts0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508003.313.440.871.111.041.142.031.140.947.322.00A (d)7.69B (s)7.22C (m)5.66D (d)5.38E (d)4.95F (m)4.22G (m)3.50H (d)2.74I (s)2.40J (s)1.85K (m)2.441.845282.400552.420812.434292.451152.461012.710552.767533.456823.466883.523143.533864.178034.190104.201764.242334.254774.266604.927464.975665.370745.392665.647745.655275.662945.671595.680057.224707.248617.25985CDCl37.276537.677427.70409-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000650007000075000800008500020.4512521.6488526.7235241.3728053.2300276.73685CDCl377.15982CDCl377.58416CDCl3111.62130119.98685127.15890127.45056127.59466128.50216129.69056134.13929137.72638139.22722141.98737143.29649 359 2.26 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-1000100200300400500600700800900100011006.631.081.281.311.061.007.732.43A (m)7.69B (m)7.29C (ddd)5.79D (ddd)5.59E (dd)5.30F (m)4.12G (m)3.40H (m)2.422.311912.388832.398052.410612.423302.429352.437393.363563.425304.076364.087124.136634.141425.289405.297625.308815.316035.601355.608275.764355.772077.216537.223527.229537.240267.245097.252487.26017CDCl37.269537.279027.285967.294767.299077.305657.309097.314157.330867.340217.345027.351437.358987.366257.373197.668747.675997.682337.697627.70357-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-100001000200030004000500060007000800090001000011000120001300014000150001600017000180001900020000210002200021.6614326.5822629.8511440.9525452.9646476.73688CDCl377.15995CDCl377.58446CDCl3115.42540120.87983123.88754124.05296127.18022127.52833128.50063129.66985129.79239137.89799139.34225143.22157 360 2.27 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Ts0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508003.192.273.111.051.041.071.009.282.17A (m)7.66B (m)7.27C (m)5.44E (m)3.94F (m)3.25G (s)2.41H (m)2.36I (s)1.58D (d)5.241.578242.345232.349982.356032.361022.366612.371682.377502.407273.221073.281173.906583.966635.231035.242975.257275.418515.426825.433035.438985.445055.451027.203197.209547.219737.226067.239617.246867.253897.26053CDCl37.271757.274587.284247.292167.298087.306067.310887.317087.325197.331477.338937.643147.650457.656797.664567.672077.677987.68579-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-1000010002000300040005000600070008000900010000110001200013000140001500016000170001800019000200002100022000230002400020.6420721.6602326.6445344.4417852.6881576.73674CDCl377.16146CDCl377.58412CDCl3118.18291127.11866127.52755128.47478129.62413130.66112137.87250139.53243143.16436 361 3.19 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) OPEtOOOEt0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-200-10001002003004005006007008009001000110012001300140015001600170018001900200021002200230024006.264.171.051.051.051.041.00A (ddd)6.16B (dd)5.55C (m)5.18D (m)5.07E (t)4.72F (m)4.16G (td)1.331.305451.309111.328971.332681.352601.356304.114624.116434.138004.140464.143604.161424.164574.167464.184874.188504.191214.212224.214924.716494.724294.732085.064145.070475.076835.083095.159245.163025.166615.170575.195185.199015.202635.206505.521515.525425.578265.582116.108726.117906.135516.144636.153886.165496.174676.201406.210587.25953CDCl3-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000140000A (d)151.3B (d)131.4C (d)101.4D (d)64.5E (d)16.216.1220816.2116964.4828264.5623776.73616CDCl377.16096CDCl377.58417CDCl3101.37839101.42371116.12678131.36737131.45895151.21391151.31528 362 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)0100020003000400050006000700080009000-6.35150 363 3.15d 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTsCN0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004503.122.080.980.990.971.009.414.273.922.01A (m)7.70B (m)7.53C (m)7.35D (m)7.19E (m)5.52F (t)5.40G (m)4.23H (m)3.36I (m)2.61J (s)2.392.388022.592372.599042.605002.610532.615662.620942.627003.333073.383923.394143.403074.205854.218604.279475.389165.402225.415785.504865.510765.518795.526765.532727.122167.133477.146537.150797.156907.162177.204067.226657.251227.26023CDCl37.278697.321897.347747.365947.373707.486937.514577.550367.558157.572547.578647.682567.688987.704067.71013-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000020004000600080001000012000140001600018000200002200024000A (dd)150.31K (d)120.05N (d)108.86R (d)28.84B (d)144.2421.6818028.8123128.8628729.8341139.7406253.2249076.7372077.1601877.58284108.81890108.89747112.03828118.56200120.01573120.08072125.96545127.07168128.18488130.08688132.60810137.03266143.28873144.14053144.18172144.30158150.23473150.28966150.33106150.38320 364 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100010020030040050060070080090010001100120013001400150016001700-17.14967 365 3.15e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOTsPPhOOOPhCO2Me0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)01002003004005006007008009003.011.941.023.051.001.001.0014.612.172.05A (m)7.94B (m)7.70C (m)7.26D (m)5.52E (t)5.41F (m)4.25G (s)3.91H (m)3.38I (m)2.63J (s)2.372.370542.611822.623902.630872.636993.343993.354833.364283.404963.415363.424923.906134.222204.282235.398065.411545.425125.509075.515375.523745.531025.536887.133937.138747.158547.162607.166207.170307.216277.232457.239727.26021CDCl37.316667.342547.368767.413667.441277.686477.692777.707987.714097.925847.931877.95379-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000B (d)144.5C (d)120.1D (d)108.7E (d)29.1A (dd)150.421.6577029.0717529.1148239.7346252.3064853.3321476.84268CDCl377.16010CDCl377.47817CDCl3108.62465108.67999120.06819120.11721125.88415127.10357127.36206129.89923130.01045130.06047130.06940137.26467143.01399143.92866144.48663144.57643150.33423150.36369150.40677150.43668166.75831 366 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100001000200030004000500060007000800090001000011000-17.34089 367 3.15f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTsBr0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506002.961.331.141.071.050.991.0017.781.042.13A (m)7.63B (m)7.52C (m)7.20D (dd)5.78E (m)5.72F (m)4.22G (m)3.74H (m)2.90I (m)2.44J (s)2.342.339582.419622.436012.477915.705285.712855.719865.760505.765615.785325.790457.059287.067477.074917.082537.091077.107907.115417.119707.124327.134207.142527.158717.163067.168427.172007.182737.191327.200437.205047.214117.225487.229067.25972CDCl37.275527.301307.307447.313957.328347.334517.359937.506947.521917.537937.617067.622747.638627.64479-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)050001000015000200002500030000350004000045000A (dd)150.4B (d)144.5C (d)130.0D (t)120.1E (d)108.1F (d)31.921.6006031.8702431.9331341.4329254.0057676.73673CDCl377.15970CDCl377.58412CDCl3108.09304108.16228120.02641120.09114120.15587123.81889125.80072127.54405127.62541127.98453129.42004129.59139129.98853130.01712133.56760136.27773138.99741143.66532144.44528144.56702150.29268150.33735150.39292150.43555 368 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100010020030040050060070080090010001100120013001400-17.39589 369 3.15g 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhTsFF-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)010020030040050060070080090010002.941.161.151.001.001.943.188.114.242.14A (d)7.66B (m)6.95C (m)7.17D (dd)7.32E (m)5.67F (m)4.26G (m)3.60H (ddt)2.83I (m)2.43J (s)2.362.361112.398762.409572.424672.431432.454132.462022.796512.808013.567743.619473.627603.635564.231934.239154.247934.293054.306395.645125.652735.660315.667875.675425.684395.708486.918376.925376.941586.955186.971537.002817.140997.144757.149057.152977.157217.169687.177927.181937.198257.224677.25998CDCl37.302827.317037.329447.343547.650097.67787-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000010000020000030000040000050000060000070000080000090000010000001100000120000013000001400000C (dd)150.3D (d)144.5F (dd)120.1G (dd)117.0H (dd)116.2I (dd)114.8J (d)108.3K (d)47.9L (d)31.0A (dd)158.6B (dd)156.1E (dd)128.121.6131130.9774531.0144640.3680847.9354747.9613476.84220CDCl377.16067CDCl377.47784CDCl3108.28057108.33462114.62539114.66047114.87650114.91189116.04268116.13015116.28168116.36868116.79899116.88411117.04948117.13507120.05810120.08565120.10795120.13513125.85431127.30371127.94119128.01273128.09470128.16615129.77811130.02904136.54722143.88927144.44191144.53264150.28929150.33337150.36238150.40772157.39122157.41371159.80388159.82740 370 19F{1H} NMR (282 MHz, CDCl3) 31P{1H} NMR (121 MHz, CDCl3) -200-180-160-140-120-100-80-60-40-200204060f1 (ppm)-50050100150200250300350400450500550600650700750800A (d)-118.1B (d)-121.0-121.05442-120.99238-118.15189-118.08938-250-200-150-100-50050100150f1 (ppm)0500100015002000250030003500400045005000-17.25744 371 3.15h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOTsPPhOOOPhOMe0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)01002003004005006007008009003.071.961.003.140.970.971.001.062.0513.872.00A (m)7.71B (m)7.23C (m)6.93D (m)6.79E (m)5.53F (t)5.35G (m)4.24H (s)3.73I (m)3.45J (m)2.61K (s)2.362.361642.601822.608622.614622.620522.626453.725855.349355.523806.807176.814036.904736.911236.920526.926376.949016.952056.955127.143397.147247.150737.157677.168667.172517.175897.179457.184107.203497.206587.210047.222227.228847.232277.235867.248347.250727.25982CDCl37.311817.334027.337137.340097.356427.362257.366017.690507.696777.712367.71809-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000A (d)150.44B (d)144.85C (d)120.13D (d)108.61E (d)29.3121.6211629.2808029.3379239.6557653.5016755.3217576.73633CDCl377.15899CDCl377.58250CDCl3108.56881108.64497112.90744113.69399119.44036120.09466120.15949125.78846127.12474129.73369129.89686129.99944137.47844139.57996143.66450144.78926144.91110150.38687150.48449159.98436 372 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-2000200400600800100012001400160018002000220024002600280030003200340036003800-17.34698 373 3.15i 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004.101.101.081.111.011.040.981.0020.432.03A (m)7.70B (m)7.23C (dd)6.51D (dd)5.89E (m)5.58F (t)4.92G (m)4.25H (m)3.63I (m)2.74J (m)2.332.264442.331692.355772.709133.604413.654173.661283.668354.208404.216344.224484.896914.918044.939215.572015.579685.587575.595305.853865.875065.907255.928506.480596.485226.534056.538667.123767.129737.147107.155647.163717.186237.192657.205887.212717.216937.233437.25998CDCl37.286027.292087.312347.337987.355547.680977.687517.702507.708547.71981-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0500010000150002000025000300003500040000A (dd)150.4B (d)144.4C (d)120.1D (d)107.8E (d)32.521.5695232.4550432.5075139.9706352.8200176.73791CDCl377.16095CDCl377.58396CDCl3107.79448107.86977120.10014120.16655124.47521125.79436126.66083127.50036128.13347128.62339129.82883130.02429133.52995136.11260136.65748143.76060144.37480144.49593150.37567150.41983150.47370150.51492 374 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-1000100200300400500600700800900100011001200-17.22904 375 3.15j 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhTs0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.010.511.011.512.0f1 (ppm)-500501001502002503003504004505005506006507003.203.201.102.113.072.031.001.0013.802.12A (m)7.66B (m)7.22C (m)5.50D (m)4.29E (m)3.68F (s)2.33G (m)2.17H (m)1.78I (d)0.95J (d)0.900.893790.915550.941800.964051.758471.771481.780461.793562.148272.153662.159802.165742.172062.179182.186042.329853.621913.627123.669273.682423.695043.704903.716894.254184.261784.316845.482705.488815.496515.503845.509727.126117.130217.134447.154677.159287.173307.177557.196477.200437.224057.26035CDCl37.307737.333967.352327.359807.650687.67833-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)050001000015000200002500030000A (dd)150.4B (d)144.8C (d)125.7D (d)120.1E (d)107.5F (d)28.219.9446820.3920621.5683728.1832828.2241828.4202539.5893557.6900176.84323CDCl377.16012CDCl377.47776CDCl3107.46765107.52243120.02741120.07749125.74162125.75488126.88121129.83262129.97493137.93638143.38060144.73309144.82489150.35463150.37563150.42864150.44856 376 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-2000020004000600080001000012000140001600018000200002200024000-16.85341 377 3.15k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508001.872.681.412.336.602.023.281.031.061.131.008.014.252.11A (m)7.66B (m)7.33C (m)7.16D (m)5.50E (m)4.26F (ddd)3.78G (m)3.65H (s)2.33I (d)2.17J (m)1.75K (m)1.43L (m)1.26M (m)1.12N (m)0.971.089821.104121.129821.158041.252091.261101.408831.420591.434181.444771.455891.617971.636871.678781.728471.742011.754201.805721.852782.162962.170952.178222.325503.674003.760525.491785.499075.506755.513997.119617.124057.128647.136827.148467.153197.157567.176227.191487.199537.219267.26011CDCl37.306617.332887.358727.645837.651977.667347.67346-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000065000A (d)150.4B (d)144.8C (d)120.1D (d)107.5E (d)27.621.5804226.0214826.0964526.2842527.5889927.6457930.0577530.8114537.2991939.7165556.4781176.73607CDCl377.16060CDCl377.58426CDCl3107.44322107.51669120.03366120.10014125.74913126.87510129.83835129.98013138.00585143.35010144.76028144.88400150.37631150.48292 378 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-5000500100015002000250030003500400045005000-17.45090 379 3.15l 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508008504.381.081.101.440.981.001.071.0513.601.98A (m)7.65C (m)5.58D (m)4.23E (m)3.90F (dd)3.37G (m)2.42H (s)2.35I (m)2.16J (m)1.07K (m)0.43B (m)7.34L (m)7.190.256970.272590.285480.383010.399570.415880.468170.484210.495060.510430.521620.529500.536762.126692.135242.181562.189022.350112.384082.388502.396812.407592.429202.441203.345213.366523.377183.398843.933314.202265.570985.578635.586525.594137.160397.180667.185157.189177.206327.235687.26040CDCl37.313457.338967.365327.643637.649797.664967.67117-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000A (d)150.5B (d)145.0C (d)120.1D (d)107.5E (d)32.04.425814.9626113.5728421.5842031.9515832.0089339.8490256.7356676.73534CDCl377.16079CDCl377.58345CDCl3107.50746107.58061120.05201120.11940125.75111127.06087129.79053129.99212137.73831143.42452144.91902145.04089150.40977150.50828 380 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)0500100015002000250030003500-17.41931 381 3.15m 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NOPPhOOOPhTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006506.101.221.181.120.953.171.111.022.001.008.054.272.07A (m)7.68B (m)7.34C (m)7.19D (dq)5.51E (m)4.25F (dtt)3.63G (m)2.42H (s)2.34I (dd)1.87J (m)1.58K (ddd)1.39L (m)1.19M (d)0.880.865940.887861.175511.178721.197931.202341.224671.254281.360071.368571.387781.891541.899422.344564.224834.234454.244364.250765.502905.510495.518325.525877.134917.138667.142467.146427.163367.167297.171357.176047.180437.204367.213297.225717.229037.232747.240427.26010CDCl37.313567.335587.338897.341867.358877.365577.662987.669337.684707.69059-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000A (dd)150.5B (d)144.9C (d)120.1D (d)107.3E (d)31.221.5980522.2876522.9367524.7431331.1850731.2278439.2266740.4337649.4297176.84272CDCl377.16025CDCl377.47853CDCl3107.25015107.30597120.07199120.12265125.76043127.11489129.85329129.99705137.59150143.53194144.88273144.97489150.41777150.44309150.48853150.51751 382 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000021000-17.46000 383 3.15o 1H NMR (400 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhTsCl-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)050001000015000200002500030000350004000045000500003.092.061.981.091.010.970.9915.282.00A (m)7.69B (m)7.24C (m)5.58D (m)4.41E (m)4.24G (m)3.43H (m)2.46I (s)2.39F (m)3.632.388942.430312.439442.446412.454033.419073.422073.436093.442743.654754.394604.398474.415695.570895.576515.582205.587817.164227.166997.169777.173267.176217.179227.185407.188767.192057.194987.197947.201307.211307.213887.216267.231397.234017.236527.239137.26005CDCl37.266217.286667.329907.347247.349717.351957.368987.686357.691117.702697.70715-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000A (d)150.4B (d)144.0C (d)120.1D (d)107.2E (d)28.821.6727328.7236528.7845739.6213242.8274252.5104376.73622CDCl377.16067CDCl377.58422CDCl3107.14861107.22052120.05504120.12020125.88466127.17458130.06565136.79763143.90316144.02286144.08021150.32527150.42887 384 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000140000150000160000170000-17.89948 385 3.18a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOMsPPhOOOPh-1.00.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-10001002003004005006007008009001000110012001300140015001600170018001.163.031.121.051.031.031.0017.35A (m)7.33B (m)5.67C (d)5.37D (m)4.12E (m)3.42F (m)2.99G (s)2.77H (m)2.692.669592.677402.735912.747732.774122.963473.395043.446703.454174.087824.091844.095894.100005.356335.380335.657205.664935.673495.681227.194197.198047.202117.206107.216897.221097.225087.229187.247357.252557.25971CDCl37.312847.317077.319777.326647.336357.341307.344267.352837.359897.368437.371827.389467.397647.408357.414047.416047.433417.44069-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000A (d)150.4B (d)145.2C (dd)120.1D (d)108.8E (d)30.430.3350030.3911039.3234239.3686353.8317876.73745CDCl377.16018CDCl377.58284CDCl3108.76721108.84035120.08214120.10737120.14926120.17211125.91866127.39449128.41961129.03504130.10372137.86274145.16974145.28943150.36888150.46677 386 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)05001000150020002500300035004000-16.91880 387 3.18b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (101 MHz, CDCl3) NPhOMsPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-100010020030040050060070080090010003.034.041.081.031.021.0016.24A (m)7.34B (d)5.33C (dt)3.91D (m)3.33E (m)3.07F (m)2.85G (s)2.79H (m)1.631.623371.627271.631931.635822.792052.842382.850653.041643.350153.354083.358183.362163.365923.876693.885613.894523.942885.319285.342937.189577.193157.196567.199847.216077.219847.224557.228987.232817.236567.26083CDCl37.293737.297007.305917.310307.317637.331867.337967.344517.359077.362177.367077.383997.390557.412367.417507.422197.437827.44447-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000140000150000160000170000A (d)150.5B (d)138.9C (t)120.2D (d)117.413.5046930.1968339.4005543.9279954.2854076.84282CDCl377.16032CDCl377.47746CDCl3117.31228117.39264120.13546120.17971120.22408125.84071127.39645128.28598128.97939130.04727137.98200138.81927138.90500150.45288150.52538 388 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-2000200400600800100012001400160018002000220024002600280030003200340036003800-16.16413 389 3.18d 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPh PhOO0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506003.170.950.890.822.121.001.001.0018.03A (m)7.27B (m)5.70C (m)5.55D (d)4.41E (m)4.21F (m)3.34G (m)2.95H (d)2.72I (t)1.291.270711.294411.318032.694812.752712.915502.926122.936812.948703.296733.302253.309413.316603.356093.361593.369073.376463.382094.172454.184054.196154.207794.219764.231634.243384.254954.377764.437425.530895.538755.546655.554455.562215.569865.689815.711977.186187.211887.237187.25975CDCl37.269417.278037.295827.307847.313627.327007.352167.37963-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000A (d)150.5B (d)120.214.8106930.3046338.7577551.4439662.0004476.73552CDCl377.15891CDCl377.58352CDCl3108.91232120.15107120.21580125.77698126.84262127.68708128.76219129.80846130.02817139.29399150.46395150.56400155.63590 390 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250 f1 (ppm)-100010020030040050060070080090010001100120013001400-17.09083 391 3.18f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOCbzPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508002.941.000.950.971.052.060.8521.68A (m)7.30B (m)5.69C (m)5.21D (m)4.25F (m)3.03E (m)3.27G (m)2.86H (m)1.551.544121.553692.829842.886702.990523.000773.011123.021723.032173.057823.068043.236603.278473.295114.228214.229604.250984.274534.287134.297085.204295.212085.691267.206027.232647.254987.26016CDCl37.269747.285087.303697.323337.341717.349187.36418-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-20000200040006000800010000120001400016000180002000022000240002600028000A (d)150.6B (d)120.213.4579230.2988143.6208452.1595767.7160576.73652CDCl377.15999CDCl377.58300CDCl3120.21407120.27866125.71414126.82767127.62457128.18006128.29545128.69277128.75769129.89131129.98951136.56472139.27011150.51934150.61815155.27573 392 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-1000100200300400500600700800900100011001200130014001500160017001800-16.39855 393 3.18g 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOCbzPPhOOOPhCl0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506000.970.980.911.142.090.981.0010.419.91A (m)7.36B (m)7.22C (m)5.70D (dq)5.54E (m)5.18F (m)4.40G (dtt)3.35H (ddq)2.94I (dq)2.672.635182.639472.643612.648022.693022.697782.701882.706282.910762.921062.931523.319603.371813.379353.386634.381924.386184.393814.406925.141735.182565.206945.248055.528285.536015.543745.551347.185437.188447.192727.197117.209317.216597.221637.226107.230797.237347.241917.26020CDCl37.313407.324807.327347.332457.348477.356617.367247.371697.37948-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000280003000032000A (d)150.5B (d)120.129.8305738.9249351.1817767.8709876.73572CDCl377.15987CDCl377.58315CDCl3108.85498120.11071120.17753125.84759128.20502128.32603128.40428128.72785128.92403130.05369133.57831136.36422137.68158150.40509150.50063155.35034 394 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100010020030040050060070080090010001100-17.03614 395 3.18h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhCbz0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004501.171.220.991.003.111.060.970.8825.06A (m)7.27B (m)6.56C (dd)6.16D (m)5.59E (m)5.17F (m)4.43G (m)3.72H (m)2.84I (d)2.362.327982.384442.802192.812782.823842.858682.870332.879143.678583.685933.693433.732343.738683.745993.753314.391235.134265.175185.197785.234285.239045.576825.585395.592485.599846.125616.145456.178916.198767.193977.202407.212987.218577.230807.238197.242467.25968CDCl37.283527.294157.300927.318117.324287.331047.337057.347187.362677.371857.37772-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000021000A (d)150.5B (d)136.5C (d)120.229.8437332.0632639.2976050.7136067.6622576.73659CDCl377.15957CDCl377.58428CDCl3108.40984120.14471120.21218125.76443126.42819126.67768128.00787128.14717128.30351128.69601130.02466132.42352136.41768136.56838150.47183150.56856155.32310 396 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100010020030040050060070080090010001100-17.01087 397 3.18i, 4.1a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPh Ph0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005501.020.991.002.061.961.9519.272.102.04A (d)7.76B (d)7.55C (m)7.32E (m)4.58F (m)4.27G (m)3.35H (m)2.87I (d)2.70D (m)5.572.671722.729392.858672.875023.299123.307203.312793.319913.327593.332843.340313.358453.366493.371913.379253.386743.392164.253874.274884.295814.363324.565574.586165.553505.561245.568895.576587.200797.223407.248867.26014CDCl37.267387.281197.304707.308837.330067.338597.362247.367787.380737.392367.404587.418997.428667.540447.565337.748827.77386-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000C (d)150.5D (d)144.0O (d)120.230.4280538.8799647.4766651.6336567.5810776.73718CDCl377.15983CDCl377.58317CDCl3108.63937120.12607120.19013124.96567125.77213126.77005127.22745127.69359127.83761127.86320128.77061130.01856139.12147141.49525143.93748143.96996150.44782150.54588155.29111 398 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-2000200400600800100012001400160018002000220024002600280030003200-17.12566 399 3.18j 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOFmocPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-40-200204060801001201401601802002202402602803003203403603804002.951.991.002.071.921.1819.461.952.12A (d)7.66B (m)7.46C (m)7.22D (m)5.51E (d)4.48F (m)4.19G (d)3.14H (m)2.79I (s)1.471.467762.722332.778932.854112.916433.106473.164853.929133.949544.011214.030964.051614.071664.093794.117374.139694.164544.185714.206844.296884.320044.464724.485495.288835.595595.694057.060257.082327.101337.125357.150057.163187.178767.207217.229047.236457.246107.26080CDCl37.269797.289637.297757.305757.320257.329987.444627.469527.651217.67629-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000650007000075000A (d)150.55B (d)141.48C (d)120.22D (d)120.1213.4367930.2844443.5296047.4498952.1240067.5467276.73622CDCl377.16119CDCl377.58385CDCl3120.10153120.14305120.18531120.25078124.96635125.70191126.75529127.20268127.57890127.81386127.84126128.73850129.97071139.20078141.46337141.49250143.94467143.98274150.49774150.59674155.11530 400 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-20002004006008001000120014001600180020002200240026002800-15.86129 401 3.18k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005503.571.072.791.224.081.0016.322.082.15A (m)7.76B (m)7.55C (m)7.32D (dd)5.60E (m)4.33F (m)3.75G (m)2.59H (m)2.23I (m)1.06J (m)0.470.465941.006931.056732.183332.204622.230312.255342.593413.750254.209094.229064.248354.357954.371384.383714.410894.415624.446904.467945.592345.600965.608475.616597.191387.215977.228827.240637.26007CDCl37.282127.287627.292157.305477.312017.316707.336917.360757.365587.376597.390307.397807.402537.422967.538237.561787.749047.77399-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0500010000150002000025000300003500040000A (d)150.55B (d)120.153.176784.5515213.4697132.5079038.9922847.4415254.7071067.3157476.73646CDCl377.16079CDCl377.58345CDCl3107.74959120.11560120.18022124.92693125.73515127.18321127.23603127.81289127.84526130.01185141.49184144.07968150.49735150.59417155.22968 402 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-1000100200300400500600700800900100011001200130014001500160017001800-17.15635 403 3.24 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPEtOOOEtFmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006506.391.061.321.054.341.191.001.962.199.241.962.00A (d)7.76B (d)7.54C (m)7.33D (m)5.47E (m)4.55F (m)4.36G (t)4.27H (m)4.17I (m)3.35J (m)2.89K (m)2.67L (m)1.351.325621.348971.370271.373832.695033.315593.326613.337523.374653.385643.396634.106264.114204.137454.147154.162494.171674.187824.197604.212094.247084.268494.289354.545855.454165.461895.469425.476945.484517.25950CDCl37.275047.275387.298367.302367.322947.327017.364747.373137.377867.391057.401117.415357.423237.427147.531247.556067.744807.76981-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000065000700007500080000A (d)143.99B (d)120.14C (d)64.61D (d)16.2316.1860216.2748629.8196038.9666547.4558351.6675464.5707764.6531867.5804876.73627CDCl377.15984CDCl377.58313CDCl3107.28893120.11315120.16704124.99210126.81156127.21202127.63804127.82054127.84720128.69572139.43285141.48465143.96697144.01064155.35315 404 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)050010001500200025003000350040004500-6.21330 405 3.25a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOPPhOOOPhPhPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506002.061.070.921.091.971.0020.81A (m)7.30B (m)5.59C (m)3.74D (d)3.26E (d)3.06F (d)2.94G (m)2.592.536862.591952.652122.675712.730892.915412.971823.036313.079803.236013.291233.704293.748353.768883.787195.574145.582275.590675.598547.179637.204077.228647.240967.25964CDCl37.265737.270477.289397.304327.328127.337657.351977.357167.365287.380467.388487.430627.45564-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000065000700007500080000A (d)150.6B (d)145.2C (d)120.235.6789149.3768957.8631163.4236876.73744CDCl377.16022CDCl377.58287CDCl3109.34459120.18383120.25123125.64047127.19235127.84379128.02365128.41203128.85787129.95569145.12532145.24974150.57703150.67735 406 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-400-20002004006008001000120014001600180020002200240026002800300032003400360038004000-17.03304 407 3.25b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhOPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004503.042.051.010.961.981.011.0016.22A (m)7.28B (dddd)5.80C (m)5.65D (m)5.09E (dd)3.69F (d)3.42G (dd)3.13H (d)3.05I (m)2.622.539362.619432.669012.692602.714953.078753.095903.117483.144493.393513.666663.688903.710685.064875.071055.085715.123035.638885.647125.655365.662925.788215.805887.165767.170257.174597.191177.197087.217387.222757.228037.233367.242197.246367.253207.25961CDCl37.274817.287947.293117.304007.314757.322097.331357.338367.345537.351207.367267.37465-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0500010000150002000025000300003500040000A (d)150.6B (d)145.3C (d)120.229.8361135.8087849.2086956.6328163.0729376.73629CDCl377.15931CDCl377.58377CDCl3109.20789120.18932120.25407125.64844127.90757128.10683128.82437129.96449145.24962145.37267150.56815150.67485 408 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-200-1000100200300400500600700800900100011001200130014001500160017001800190020002100-17.13770 409 4.2a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Fmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004502.131.111.151.162.190.711.0020.092.692.31A (d)7.77B (dd)7.58C (m)7.34E (m)6.00F (m)5.72G (d)4.57H (m)4.45I (t)4.30J (dd)3.57K (m)3.002.959662.999243.531223.542483.594313.605414.276144.298064.319754.425674.439514.491934.562184.583205.574575.807625.862236.002347.220427.244367.26109CDCl37.287787.290637.295017.305657.317127.328237.343247.369167.378447.401377.426717.555027.575627.596617.604697.754237.77930-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000600006500029.8399841.1322547.5216051.6715867.6139476.73818CDCl377.16083CDCl377.58349CDCl3115.44858120.11800120.16367120.68459125.07487125.18009127.23159127.38984127.65106127.83475128.61582128.67855129.74892140.58591141.51295144.04193155.88530 410 4.2b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Fmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505003.111.051.000.991.190.962.112.022.217.172.292.032.13A (d)7.76B (m)7.56C (m)7.40D (m)7.27F (m)5.57G (d)5.06H (d)4.56I (m)4.38J (t)4.29K (m)3.50L (m)2.90M (m)2.69N (s)1.941.61986HDO1.935172.721352.867292.923413.458563.468403.514373.522893.532154.263894.285664.307404.362504.362664.429514.545274.567205.002425.108655.743797.211547.218567.225987.236267.240107.245077.25996CDCl37.275567.280297.301207.305347.319297.325907.330007.370897.376447.381377.396067.401587.406287.420597.427607.549437.574557.600157.752277.77732-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500020.5108429.8340040.9123147.5417251.3753167.4855976.73640CDCl377.15976CDCl377.58362CDCl3111.53518115.44444120.11035120.14692125.09353126.89463127.28425127.81436128.53396129.75026140.41586141.50654142.19830144.11581155.90881 411 4.2c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Fmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504002.031.002.052.062.161.0011.002.082.06A (d)7.73B (m)7.51C (m)7.29D (m)5.87E (m)5.65F (m)5.35G (d)4.50I (m)3.40J (m)2.57H (t)4.252.502692.559562.638603.348623.357923.368713.377763.385953.417793.425183.431563.438973.447224.223054.245204.267804.485854.507525.350065.358255.617195.626205.653745.663865.868126.796436.822966.886137.128347.168987.177997.183787.206777.226717.238297.26070CDCl37.285467.334937.343757.360287.368777.384677.393267.508777.717537.74267-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000029.8458640.6855447.5136551.2544367.4942876.73784CDCl377.16050CDCl377.58426CDCl3115.44392120.10389120.14064125.10237127.19101127.26615127.77921127.80684128.52604129.74724140.75186141.49181144.13552155.91802 412 4.2d 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N FmocF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508001.880.971.101.041.800.821.002.3111.092.232.12A (d)7.77B (d)7.58C (m)7.35D (t)7.06E (m)5.94F (d)4.59G (m)4.45H (t)4.30I (dd)3.57J (m)2.952.954833.530713.541673.593203.604594.279744.301034.322624.403134.421364.480894.584364.605165.819365.940657.027717.056597.085147.237887.242597.26006CDCl37.283227.290227.311237.315197.335807.340017.348007.353557.359657.365787.384807.388927.410207.414497.436217.762177.78722-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000A (d)162.42B (d)120.14C (d)115.5129.8336741.0418547.5193451.4435667.5679176.73688CDCl377.16003CDCl377.58324CDCl3115.36769115.65171120.11876120.16861120.58226125.05562126.70649126.81174127.21954127.42613127.82116127.84781128.64064136.70388136.74644140.26857141.51369144.04582152.17026160.79022164.05893 413 4.2e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Fmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508008509002.981.941.001.041.081.981.191.0014.102.062.01A (d)7.78B (m)7.58D (m)5.98E (m)5.63F (d)4.59G (m)4.46H (t)4.31I (m)3.57J (m)2.99K (s)2.38C (m)7.312.380642.992423.523623.533443.543423.553213.586853.596653.606383.616044.288034.309644.331254.431484.495864.580414.601465.634355.979667.178757.205267.218837.243387.247207.251187.25956CDCl37.271167.290687.294687.314007.319087.340047.344197.388477.393257.413407.418027.438547.572117.597717.765907.79088-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000600006500070000750008000021.2245729.8379641.0747047.5389551.6112367.5332676.73717CDCl377.16032CDCl377.58502CDCl3115.45713120.10635120.15309125.02819125.08956127.21535127.33510127.82530128.57246129.35339129.72844130.13586137.44286137.73606141.50950144.09875153.70049 414 4.2j 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhFmocPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004501.820.911.101.062.051.201.0027.742.17A (d)7.67B (m)7.34C (m)5.97E (d)4.50F (m)4.42G (t)4.21H (dd)3.50I (m)2.93D (m)5.622.933134.187694.209134.230694.493764.514575.966347.111827.118057.136347.145627.156637.164677.176647.191117.201697.214657.226857.236517.240767.252227.25990CDCl37.267327.283557.288447.309167.314357.332387.337947.356817.363207.376947.384247.400917.415377.431017.448957.455487.460737.470537.479417.494597.504557.522697.529587.534977.661807.68690-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000029.8414641.1662347.5555751.7161867.5840976.73788CDCl377.16054CDCl377.58433CDCl3115.83423120.12989125.08782125.53372126.82073127.10317127.23577127.36342127.40384127.50912127.84132128.45364128.63458128.82988128.94885128.95404139.41841140.48323140.71507141.53080144.08544155.64131 415 4.2k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N Fmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505003.568.482.271.201.000.801.851.761.140.607.032.192.051.82A (d)7.68B (m)7.46C (m)7.32D (m)7.19E (m)5.29F (d)4.42G (m)4.19H (m)3.38I (m)2.55J (m)2.32K (m)1.95L (m)1.21M (t)0.800.781550.805750.827341.142431.184581.213321.236411.262211.320601.350891.527201.938921.967951.994852.287582.346412.527112.533402.589433.348483.408374.162234.188234.211854.412204.434055.052495.222625.292245.340707.153167.183217.202977.227497.290237.315307.340147.442287.468727.666937.69211-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000014.1971622.6959726.9259829.8517231.5858637.4280140.8179647.4992151.5501567.4482576.73678CDCl377.16150CDCl377.58416CDCl3120.07916120.12392125.14230127.17295127.77136128.48947141.47049144.16805 416 4.6a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhFmoc0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006504.383.422.221.100.912.131.862.269.072.072.00A (d)7.68B (m)7.45C (m)7.23D (m)5.26E (d)4.43F (m)4.20G (m)3.37H (m)2.53I (m)2.34J (t)2.24K (m)1.45L (t)0.810.785390.808590.829501.366101.533612.214462.239282.264362.343182.527733.342283.402234.164114.192104.212914.236094.415634.437325.193895.223645.294795.553327.138647.182967.204947.230217.291557.316277.341287.451707.667837.69310-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000600006500070000750008000014.2652920.4588122.8409925.0204529.8562332.0768239.6127747.5392667.4612276.73680CDCl377.16009CDCl377.58297CDCl3115.43459120.08341120.12569125.14422126.78307127.18139127.77957128.50326129.77824141.49441144.17140 417 4.3a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)01002003004005006007008009006.952.071.012.051.00A (dd)8.75B (m)8.05C (dd)7.94D (m)7.70E (m)7.507.25959CDCl37.442967.459997.465967.471477.476577.483747.489487.498197.503947.509227.511697.516907.522947.525707.532107.538337.544967.689797.694497.700077.709227.715957.722067.938867.941537.944527.947348.039108.043388.048768.065868.071698.740848.743568.758008.76076-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000076.73700CDCl377.15965CDCl377.58309CDCl3119.02927120.45916127.23776127.26377128.96359129.28117129.30244138.62918150.06301158.14486 418 4.3b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007502.043.952.000.992.001.00A (d)8.75B (dt)8.04C (d)7.89D (m)7.68E (m)7.46F (d)7.197.180507.186997.209327.26008CDCl37.414937.420747.432257.437947.449147.466717.471737.477037.487077.492067.504857.512407.534507.540737.657757.663797.675787.686627.697207.704287.888557.893277.897368.029298.033828.039338.049448.056028.061808.736558.75389-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-200002000400060008000100001200014000160001800020000220002400026000280003000032000A (d)163.9B (d)116.576.73634CDCl377.16108CDCl377.58373CDCl3116.38912116.67752119.32787120.51370127.47093129.19347129.29628129.98929134.13623138.08507148.93892149.35917158.50509162.27525165.52230 419 19F{1H} NMR (282 MHz, CDCl3) -200-180-160-140-120-100-80-60-40-200204060f1 (ppm)-15-10-505101520253035404550-112.28833 420 4.3c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007503.002.194.062.120.992.041.00A (d)8.73B (m)8.05C (s)7.94D (m)7.61E (m)7.48G (s)2.44F (d)7.332.438317.26043CDCl37.313677.333657.340297.443997.455077.461817.466977.472797.478617.485017.490537.503257.510447.526747.532787.538967.599977.606307.620827.627177.935148.037608.041978.047378.057848.064408.070138.723248.74055-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000021000220002300021.4264676.73700CDCl377.15965CDCl377.58336CDCl3119.00377120.32238127.14153127.34314129.04500129.28864129.53777130.09448135.36444139.77057149.44378150.82470158.69994 421 4.3d 13C{1H} NMR (75 MHz, CDCl3) NOMe0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003503.661.816.753.000.932.081.00A (d)8.71B (d)8.02C (s)7.90D (m)7.67E (m)7.42F (m)7.07G (s)3.863.860367.025227.054507.085737.111257.25592CDCl37.259977.390857.420187.443307.644047.668967.693817.902498.006298.031108.702278.71960-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100001000200030004000500060007000800090001000055.3561876.73702CDCl377.15974CDCl377.58454CDCl3111.82302120.41482121.53550124.50418127.86609128.18525128.29638128.72756129.98127130.68738140.31789147.39178148.91200157.18401158.08752 422 4.3e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NMeO0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-10001002003004005006007008009001000110012003.661.954.022.111.052.071.00A (d)8.72B (m)8.05C (d)7.91D (m)7.67E (m)7.47F (m)7.04G (s)3.893.886177.026887.033967.049357.056067.25961CDCl37.438647.444537.455837.462447.467977.473257.485237.490877.503757.510657.533147.655797.662987.678237.685027.908287.913938.032818.037198.042638.052608.059378.065268.708348.72579-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000055.6001976.73680CDCl377.15996CDCl377.58289CDCl3114.78728118.61352119.95032127.31466128.49886129.01290129.45506129.99593148.25529149.42059157.68418160.91870 423 4.3f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007.481.481.851.871.433.101.021.00A (d)8.85B (s)8.22C (m)8.14D (d)8.02E (m)7.95F (dd)7.83G (d)7.76H (m)7.567.26035CDCl37.354167.382347.396307.422637.446667.510737.533347.544147.570347.581917.591567.602427.728737.756437.787307.808757.815137.837347.843647.909497.921167.929927.940857.958577.969977.990538.003988.032748.123918.134778.149798.216978.222058.844418.86260-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)05000100001500020000250003000076.73600CDCl377.16092CDCl377.58512CDCl3121.18749121.37344124.38313127.31979127.51287127.82391127.99706128.20522128.60129128.83762129.48415129.59876133.69258134.85825135.70687139.38094140.69596151.05958157.11302 424 4.3g 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-10001002003004005006007008009001000110012006.120.992.063.971.002.021.00A (dd)8.72B (m)8.05C (dd)7.91D (m)7.47E (s)7.31F (s)7.11G (s)2.422.419307.106237.25966CDCl37.305627.426587.433087.443737.450117.457457.462607.478377.483957.497557.504197.526657.532467.909697.912487.915437.918328.027268.035648.039918.045378.055938.062458.068158.706768.709328.723978.72670-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000650007000021.5407276.73633CDCl377.16105CDCl377.58412CDCl3119.05680120.51162125.10939127.23082128.92648129.19062130.88068138.62278138.91348149.94807158.03387 425 4.3h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506.112.974.190.962.051.00A (d)8.76B (m)8.07C (t)7.99D (m)7.77E (m)7.67F (m)7.487.26006CDCl37.448617.456527.463337.467717.472147.477217.483807.490277.497717.504147.512617.517627.648097.652077.657117.668717.675037.680647.732217.752297.760417.782427.790457.810687.981417.985127.989678.051328.055528.060878.078088.083748.753198.77038-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)05000100001500020000250003000035000400004500076.73600CDCl377.15950CDCl377.58276CDCl3118.87520120.27845120.40040124.49757127.27334127.66035127.93451128.01828128.99379129.08444129.35859129.96533137.32052140.37544142.27435149.99804158.13798 426 4.3i 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007507.294.372.512.301.153.481.132.081.00A (d)8.62B (m)8.00C (s)7.58D (m)7.47E (d)7.13F (t)2.70G (t)2.31H (m)1.65I (t)0.880.855690.880450.910371.599371.636581.676811.692362.284692.310552.336692.670432.696512.722177.121027.138357.26024CDCl37.429787.452187.467617.492557.514547.520847.576067.985078.007078.013068.609978.62713-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000600006500014.2683622.8426229.8493731.5232132.0765035.8264376.73790CDCl377.16011CDCl377.58398CDCl3121.73045122.97103127.42427129.09933129.76602141.07087147.99119152.64313159.38379 427 4.1b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhOMe0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007500.930.980.963.191.120.851.941.452.1015.832.042.00A (d)7.76B (dd)7.55C (m)7.32D (d)6.78E (m)5.55F (m)4.56G (m)4.34H (t)4.27I (s)3.78J (m)3.31K (m)2.86L (m)2.652.617522.675392.841842.855553.281483.341163.780234.246554.267514.288484.315654.322034.336444.560985.534915.542525.550265.558035.565645.573236.767846.795197.197797.221497.246927.26025CDCl37.279157.284407.289477.304537.308867.314807.329057.336537.346667.360577.366367.378537.390207.403177.417087.427627.534707.542867.559157.567317.745957.77105-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0100002000030000400005000060000700008000090000A (d)150.5B (d)120.229.8216738.6592147.4551851.0534755.3523867.5161976.73650CDCl377.16041CDCl377.58355CDCl3108.66746114.00378120.12539120.19012124.97050125.78079127.22296127.83042127.85504128.03781130.02228131.13458141.47865143.95945150.42205150.51895155.28644158.97147 428 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)-50050100150200250300350400450500550600650700750800850-16.64622 429 4.1c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhOMe0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006500.920.990.932.951.010.871.991.861.9615.622.162.00A (d)7.67B (d)7.46C (m)7.22D (m)6.74E (m)5.51F (d)4.45G (m)4.30H (t)4.19I (s)3.65J (m)3.33K (m)2.82L (m)2.622.586652.644452.782872.834372.855653.303263.362993.651274.164184.186214.208104.295504.320294.439394.461165.335515.469655.477725.485035.492295.566885.632586.708266.736356.775637.086057.112207.134197.158497.180197.209197.233117.248887.275857.304827.332827.445807.470757.659977.68500-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000A (d)150.5B (d)120.229.8407639.0587247.4571151.7109555.3440367.7750676.73651CDCl377.16108CDCl377.58373CDCl3108.68491112.65459113.01048119.13350120.16919120.23553125.02921125.78687127.24538127.87604129.81794130.02659140.85699141.48834143.96880150.46591150.55933159.99407 430 31P{1H} NMR (121 MHz, CDCl3) -250-200-150-100-50050100150f1 (ppm)0100200300400500600700800900-17.07267 431 4.1d 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhFF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504001.000.990.981.121.301.921.051.033.1515.672.032.37A (m)7.65B (m)7.41C (m)7.20D (m)6.88E (m)5.77F (m)5.57G (d)4.43H (m)4.29I (t)4.15J (m)3.54K (m)2.86L (m)2.462.431972.489874.126434.149024.170774.416484.438785.574546.843026.858926.863786.869506.880236.884526.889426.896136.911707.089907.093657.098137.103767.118457.122647.127607.133067.149317.152937.158237.173377.184597.190187.195127.200317.210877.216367.235487.242047.250087.26086CDCl37.267177.272307.288437.294987.317247.408997.634827.642887.66700-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000C (d)150.4D (d)143.9E (d)141.4G (dd)116.9H (dd)115.8I (dd)114.5F (d)120.1A (dd)158.7B (d)157.929.8305531.2477840.2411747.4072567.9169976.73608CDCl377.16058CDCl377.58386CDCl3108.38707114.32030114.36849114.65286114.70026115.57432115.69173115.89120116.00793116.68618116.80041117.01746117.13260120.09599120.14795124.95490125.83386127.18973127.85039130.02840141.42939141.46037143.87155143.89990150.35778150.45450154.89728 432 19F{1H} NMR (282 MHz, CDCl3) 31P{1H} NMR (121 MHz, CDCl3) -200-180-160-140-120-100-80-60-40-200204060f1 (ppm)-50005001000150020002500300035004000450050005500A (m)-121.8B (m)-118.2-122.33417-122.29088-122.24912-122.20063-121.62804-121.58163-121.55356-121.51260-121.47639-121.43477-121.37958-118.39483-118.33850-118.27047-118.11891-118.03764-117.99729-100-50050100150200250f1 (ppm)05001000150020002500300035004000-16.59061 433 4.1e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhFF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504001.281.061.001.410.852.041.100.4116.282.202.32A (d)7.69B (d)7.48C (m)7.23D (m)5.61E (m)5.47F (m)4.54G (m)4.25I (m)3.20J (m)2.77K (m)2.47H (t)4.193.161023.167013.174213.181613.187463.220693.226573.233983.241203.247204.166914.186454.206094.229214.519464.542855.451865.459565.467225.474845.482555.490397.140237.162407.171147.185167.196997.206377.220277.224017.230057.234077.244847.248777.255067.25959CDCl37.273017.300397.314357.327027.337387.352117.358147.363477.462967.487617.673097.69851-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000650007000075000F (d)120.1C (dd)148.1B (d)150.4A (dd)150.7D (dd)136.2E (d)127.9G (d)117.4H (d)116.129.8241338.7820447.4757350.8691767.4867276.73765CDCl377.16031CDCl377.58339CDCl3108.73146115.95604116.16360117.33168117.56014120.09227120.15663120.19889122.96438124.83657125.87971127.25839127.91217127.94377130.06205136.19139136.24960136.30632141.52208143.83662148.03031148.19407148.61114148.78158150.36967150.46453151.32250152.07325 434 19F{1H} NMR (282 MHz, CDCl3) 31P{1H} NMR (121 MHz, CDCl3) -200-180-160-140-120-100-80-60-40-200204060f1 (ppm)-200-1000100200300400500600700800900100011001200130014001500160017001800190020002100-139.03782-138.96256-100-50050100150200250f1 (ppm)-5000500100015002000250030003500400045005000-16.45991 435 4.1f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhFFF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506001.001.160.521.021.612.282.331.671.6516.961.630.913.11A (m)7.74B (m)7.53C (m)7.26D (m)7.02E (m)6.80F (m)5.81G (d)4.48H (m)4.35I (t)4.21J (m)3.83K (m)3.22L (m)2.97M (d)2.532.556964.208484.466464.487895.732575.738095.745195.752247.012987.026677.043057.164997.169197.173817.178237.184307.197567.202677.206567.227547.231517.241097.25994CDCl37.266657.280667.286937.291687.296977.315167.321387.339657.344787.353007.358427.367237.379207.382957.390347.394457.407047.464587.486217.490667.716397.727927.741797.753067.76706-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000A (d)150.4C (dd)116.1D (ddd)111.3E (d)108.3B (d)141.432.1716641.2144946.6677047.3471167.8821076.73672CDCl377.16110CDCl377.58416CDCl3108.25796108.33295111.06310111.09965111.14866111.42332111.43932111.49679115.88878116.02744116.14325116.28913120.06300120.12012124.89630125.15325125.77647127.17018127.83454129.99519136.04778141.40904141.43950143.85840150.39500150.49576155.04601 436 19F{1H} NMR (282 MHz, CDCl3) 31P{1H} NMR (121 MHz, CDCl3) -240-220-200-180-160-140-120-100-80-60-40-20020406080100f1 (ppm)-50050100150200250300350400A (d)-119.4B (d)-137.2C (d)-141.4-141.39611-141.33578-137.25820-137.18538-119.41490-119.36170-250-200-150-100-50050100150f1 (ppm)-50050100150200250300350400450500-16.96813 437 4.1g 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhCN0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005502.270.982.101.950.940.517.019.533.072.00A (d)7.66B (m)7.46E (m)5.60F (m)5.43G (m)4.55H (m)4.28I (m)3.13J (m)2.67C (m)7.27D (m)7.14K (t)4.162.559632.778672.779722.806543.093663.099293.106853.114663.120193.145513.153413.159093.166863.174273.180144.136504.155424.174064.525844.544894.561034.579535.412485.420235.427965.435635.443425.451247.101147.118377.128727.143697.171897.199347.205417.223657.247957.274057.297787.317557.342157.356647.384577.434157.459007.481317.644627.66963-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)0100002000030000400005000060000700008000090000A (dd)150.3B (d)120.2C (d)120.129.8025638.9516047.4603351.4029367.5465376.73682CDCl377.16006CDCl377.58523CDCl3108.81473111.57360118.66284120.02981120.09454120.13262120.19688124.77865125.90199127.24330127.55979127.89417127.92700130.05552132.53814141.50878143.77183144.44499150.27415150.31738150.37347150.41536 438 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250 f1 (ppm)-500050010001500200025003000350040004500500055006000-16.44394 439 4.1h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhCl0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005502.041.092.272.131.000.3319.982.312.43A (d)7.75B (d)7.54C (m)7.32D (m)5.67E (m)5.53F (d)4.57G (m)4.32H (t)4.25I (m)3.27J (m)2.732.617782.841992.905903.223903.231773.237783.244923.252313.258193.265973.283703.291413.297173.304623.311843.317784.231664.251534.271744.314574.328964.561334.585354.613745.513845.521645.529315.536895.544535.552277.197997.224187.248967.25988CDCl37.284077.304857.308907.334357.359917.367417.380197.384927.390777.405527.523577.548297.739667.76485-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-500005000100001500020000250003000035000400004500050000550006000065000A (d)150.4B (d)120.129.8357038.8430047.4958051.1312567.4906076.73684CDCl377.16124CDCl377.58435CDCl3108.72771120.10673120.17023124.88278125.84767127.25216127.88461127.91472128.24691128.89922130.05561133.50972137.65894141.52819143.88839150.39163150.49671 440 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-100010020030040050060070080090010001100120013001400150016001700-16.51116 441 4.1i 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007501.961.001.080.831.981.290.6614.822.091.936.02A (m)7.80B (m)7.58C (m)7.49D (m)7.30E (m)5.92F (m)5.59G (m)4.62H (m)4.43I (t)4.31J (m)3.38K (m)2.942.916522.971293.337203.347433.357623.395983.407323.418104.287224.308384.329534.618275.571075.578595.586205.593775.601375.608997.201437.226837.249237.26056CDCl37.274427.303307.327717.352587.378047.393497.404097.417527.428617.460857.468777.481267.493387.501707.518167.553947.567307.591417.733637.747907.772627.814767.825707.836967.845357.85866-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000A (d)155.3B (dd)150.5C (d)120.2D (d)120.129.7995439.0080847.4494651.7502867.6681876.73676CDCl377.16104CDCl377.58369CDCl3109.00312120.10061120.12838120.15392120.19518124.95457125.76268126.24068126.26911127.20200127.54089127.82259127.85312128.36335128.63029130.00113132.79934133.23053136.35847141.46569143.91656150.43620150.50672 442 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-10000000100000020000003000000400000050000006000000700000080000009000000100000001100000012000000130000001400000015000000-16.90529 443 4.1k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhOMs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507002.673.571.001.301.232.171.050.5021.362.302.45A (d)7.67B (d)7.46C (m)7.20D (m)5.64E (dq)5.46F (m)4.53G (m)4.30H (t)4.17I (m)3.20J (s)3.04K (m)2.662.591522.610613.036733.165073.173493.180623.222293.233684.153444.173174.192844.282214.307834.512924.528114.546234.559365.444575.452195.459905.467595.475167.064347.088687.127147.146207.153877.159247.168787.180607.189747.204717.210997.216397.229767.234247.239717.25958CDCl37.286807.312967.323227.337117.346457.451187.476077.491847.659647.68449-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-1000010002000300040005000600070008000900010000110001200013000A (dd)150.4B (d)143.8C (d)141.5D (t)125.8E (t)120.129.7761637.3874737.5086038.7587947.4285751.0145367.5335576.73670CDCl377.15971CDCl377.58373CDCl3110.24041120.04666120.11209120.17406122.23143124.81986125.81895125.83635125.85312127.22423127.85591127.88456128.54674130.03829138.51553141.45897141.48835143.78249143.83743148.46872150.31322150.34543150.41152150.44272 444 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)05001000150020002500300035004000-16.45962 445 4.1l 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhOTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005503.420.970.941.001.330.922.181.040.372.2319.622.144.43A (m)7.64B (d)7.45C (m)7.21D (m)6.80E (m)5.62F (m)5.44G (m)4.50H (m)4.25J (m)3.14K (m)2.75L (m)2.54M (s)2.37I (t)4.172.350692.369172.537442.747163.106173.166064.146194.165914.185804.212594.226974.252234.266654.287614.473094.488334.505284.518095.422915.430425.438125.445795.453355.460776.799046.799437.123797.149977.174197.187397.206047.213357.216817.241787.26014CDCl37.267007.285167.307127.311857.334447.442177.466897.617337.623547.639027.645097.655627.68065-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000120000130000140000A (dd)150.4B (d)143.8C (t)120.11.1346721.8238929.8012638.6766147.4482050.9854867.4141676.73587CDCl377.16086CDCl377.58404CDCl3108.66957120.05146120.11665120.17331122.56836124.83776125.84056127.22519127.87459128.15427128.55453129.90740130.04348132.56021138.03529141.47986143.79354143.84586145.51856148.94508150.36047150.42939150.45665 446 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-2000000-1000000010000002000000300000040000005000000600000070000008000000900000010000000110000001200000013000000140000001500000016000000170000001800000019000000200000002100000022000000-17.07809 447 4.1m 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPhONs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508008502.130.981.250.932.061.000.412.1915.252.102.082.232.25A (m)8.35B (m)8.01C (d)7.74D (d)7.52E (m)7.30F (m)6.88G (m)5.71H (m)5.52I (m)4.58J (m)4.33K (t)4.24L (m)3.24M (m)2.634.215764.235154.254684.557524.571534.586844.602215.508125.515795.523425.530966.870316.896187.193977.216077.222747.244487.248617.26012CDCl37.266187.279937.287037.291007.303337.311707.315847.333567.359487.385257.409547.511787.536497.729047.754067.988757.997068.004138.012078.019728.026618.034928.320918.328998.336218.344488.351978.358578.36712-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-100000100002000030000400005000060000700008000090000100000110000A (dd)150.4B (d)143.8C (d)141.5D (dd)120.130.3152238.7651247.4112350.9756967.3956376.73571CDCl377.16093CDCl377.58389CDCl3108.68352120.02194120.08558120.11736120.16935122.23693124.47421124.80532125.85024127.20219127.86951128.52725129.89965130.03531138.91037141.04323141.44304141.47350143.74354143.80504148.42314150.37733151.06308 448 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-5000500100015002000250030003500400045005000-17.40727 449 4.1n 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOFmocPPhOOOPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-5005010015020025030035040045012.612.461.534.291.0014.892.152.14A (d)7.76B (d)7.57C (m)7.32D (m)5.52F (dd)3.62G (m)3.44H (m)2.35I (m)1.34E (m)4.410.978011.013121.037191.114221.260571.274761.285681.301371.304271.316621.327701.456051.532811.563281.604361.678191.708552.240092.340634.216434.235144.258714.434414.453844.553044.571105.520537.186417.209207.231497.250047.26035CDCl37.280437.284397.304947.308987.329337.334227.353717.362587.368417.381097.392457.417397.555147.579697.748607.77349-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)050001000015000200002500030000350004000045000A (d)150.5B (d)120.126.0100828.9961030.8644237.1919437.3290138.9162447.5417454.3084854.5827866.8367567.4220276.73884CDCl377.16150CDCl377.58416CDCl3107.45832108.07015120.11265120.18134124.82573125.05376125.73259127.19117127.81976130.00235141.54612144.08881150.48415150.57979155.52600 450 31P{1H} NMR (121 MHz, CDCl3) -100-50050100150200250f1 (ppm)-1000100200300400500600700800900100011001200-16.60754 451 4.12a 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh OMe0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-100010020030040050060070080090010001100120013003.552.114.652.274.381.072.111.00A (d)8.74B (m)8.05C (d)7.95D (m)7.78E (m)7.66F (m)7.48G (m)7.04H (s)3.893.887427.032207.038727.054507.061577.25974CDCl37.399767.423607.428217.464497.469457.480287.484987.490267.497727.503857.513607.517707.646607.650117.655107.673447.678787.733157.761577.779077.807247.944767.950378.042768.049548.065198.072108.726488.74403-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-50000500010000150002000025000300003500040000450005000055000600006500055.5602176.73773CDCl377.16169CDCl377.58435CDCl3114.48851118.33970119.71031127.26358127.69385127.97873128.03018128.72968129.08969137.08662140.28790142.45635149.02679149.95020157.19220161.09130 452 4.12b 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOMePh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005503.071.235.344.254.271.041.00A (d)8.76B (d)7.97C (m)7.78D (m)7.65E (m)7.47F (dd)7.01G (s)3.923.923596.996117.014697.023537.26051CDCl37.395237.420247.446227.462827.467677.482817.489047.498777.505147.511827.516267.522147.612007.616447.638817.649937.656557.663827.673987.679327.730417.736327.750407.759327.777867.805987.971597.977368.748878.76605-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)05000100001500020000250003000035000400004500055.6055876.73661CDCl377.15952CDCl377.58473CDCl3112.39232115.49416115.83533119.02164119.64092120.41770127.27066127.65616127.93144128.01408129.08241129.95983137.29278140.37011142.26995149.23918149.95032157.95317160.29207 453 4.12c 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhFF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005501.282.232.471.142.335.071.000.93A (d)8.79B (d)8.09C (m)7.75D (m)7.66E (dd)7.56F (m)7.49G (m)7.39H (m)7.137.089947.102297.126207.141387.159437.174537.25997CDCl37.365797.370957.389097.395917.419027.462007.467367.487277.510737.515037.545517.551307.562827.568747.645857.651857.669767.675027.726827.756117.771187.792837.801928.081108.087818.094488.776658.79381-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-5000050001000015000200002500030000350004000045000500005500060000A (d)159.5B (d)156.6E (dd)117.1C (dd)117.6D (m)117.476.73851CDCl377.16146CDCl377.58412CDCl3116.89138117.01192117.21768117.26146117.33557117.35850117.47475117.55539117.59737117.71237117.82403120.95397122.45786122.58901127.27006127.70225127.94470128.03351129.08344136.99309140.35046142.34189148.90790150.28197152.85239158.11901160.77447 454 19F{1H} NMR (282 MHz, CDCl3) -200-180-160-140-120-100-80-60-40-200204060f1 (ppm)-20020406080100120140160180200220240A (d)-118.5B (d)-122.7-122.78033-122.71610-118.52100-118.45692 455 4.12d 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh FF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506002.623.462.165.292.141.00A (d)8.74B (m)7.94C (m)7.78D (m)7.66E (m)7.51F (m)7.397.241197.26079CDCl37.267747.273007.301067.330647.388357.401857.408847.420917.425467.429937.466767.471277.486227.492677.514917.519847.531527.537007.649797.655737.667107.673617.678907.762847.769647.788447.795067.799267.910107.916287.945998.731278.74841-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-20000200040006000800010000120001400016000180002000022000240002600028000C (dd)123.2E (dd)116.3D (dd)117.7A (dd)154.3B (dd)149.776.73731CDCl377.16127CDCl377.58392CDCl3115.44154116.22187116.25530116.44039116.47612117.57033117.58776117.80797117.81029118.41022120.69818123.09741123.17546123.23066127.27389127.63129127.98753128.05897129.10629137.07645140.30791142.39672149.37706149.55038149.71440150.29616155.97050 456 19F{1H} NMR (282 MHz, CDCl3) -240-220-200-180-160-140-120-100-80-60-40-20020406080100f1 (ppm)-50050100150200250300350400450500550600650700750A (d)-137.2B (d)-137.3-137.36801-137.29273-137.22673-137.15182 457 4.12e 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPhFFF0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006500.991.031.332.293.165.181.00A (d)8.83B (m)7.76C (ddd)7.64D (m)7.49E (m)7.40F (dt)7.20G (tdd)6.996.976596.983836.989046.996477.013787.019107.201837.218117.231707.25969CDCl37.365227.369587.374187.385197.393917.401737.413477.418057.422687.458207.463627.478167.484107.501227.507437.511627.610757.616767.628437.633947.637267.641137.646197.657457.664097.669557.721737.725087.730527.741607.751337.760027.768167.780237.786387.789548.821588.83887-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-20000200040006000800010000120001400016000180002000022000240002600028000300003200034000360003800076.73800CDCl377.16065CDCl377.58331CDCl3111.24950117.30598117.44598121.36128123.94370127.27698127.70355127.99358128.07739129.09405136.54386140.27730142.50945148.97370149.12649150.36622 458 19F{1H} NMR (282 MHz, CDCl3) -200-180-160-140-120-100-80-60-40-200204060f1 (ppm)-20-100102030405060708090100110120A (d)-119.6B (d)-137.4C (dd)-141.7-141.76656-141.71295-141.69159-141.63763-137.48007-137.40521-119.58838-119.53457 459 4.12f 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh CN0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)0501001502002503003504004504.384.864.381.232.011.00A (d)8.80B (d)8.20C (s)8.01D (m)7.79E (m)7.63F (dt)7.457.25971CDCl37.264297.382957.407037.430847.471117.494957.519537.587547.607517.634457.650527.676067.743607.771257.777977.792057.818488.012098.186018.212698.791808.80882-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-10000100020003000400050006000700080009000100001100012000130001400015000160001700018000190002000021000220002300076.73619CDCl377.15947CDCl377.58267CDCl3112.81375121.87256124.85169127.24889127.31144127.75664127.92710128.39171128.52558129.21388133.10849133.31668137.10266141.82209149.68846150.63834158.63509 460 4.12g 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh Cl0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507007508008506.652.904.160.962.000.94A (d)8.75B (m)8.02C (d)7.95D (m)7.77E (m)7.67F (m)7.507.25987CDCl37.469397.485577.491137.498027.515347.521547.648687.655297.672747.678477.725937.762337.774077.794547.802637.951407.957008.001538.010658.017078.032278.039168.048448.743898.76118-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)05000100001500020000250003000035000400004500076.73750CDCl377.16015CDCl377.58411CDCl3118.73656120.58086126.43779127.10211127.21253127.67095128.58461128.89609129.10116129.22374136.95647140.03149140.26156140.86318142.48907147.11163149.76486 461 4.12h 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-1000100200300400500600700800900100011006.402.124.331.072.081.001.041.011.00A (dd)8.82B (d)8.57C (dd)8.22D (dd)8.14E (m)7.99F (dd)7.90G (m)7.81H (m)7.67I (m)7.527.26005CDCl37.458967.472637.478027.487717.492827.498517.517247.521687.526827.537677.542597.549077.554287.560027.660757.664397.669397.687487.692887.755727.761517.776637.783847.789697.824587.831667.846197.852577.885087.895937.973437.992418.003018.135558.138298.141438.144218.200388.206438.229108.235198.566458.572438.810698.813298.827888.83047-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-2000-1000010002000300040005000600070008000900010000110001200013000140001500016000170001800019000200002100076.73691CDCl377.16008CDCl377.58499CDCl3115.81456119.18642120.37239124.77030126.57896126.86518127.29100127.72508127.85833127.96637128.06144128.51423128.76686128.85873128.95385129.10347133.66511133.93350137.27123140.36733142.37191149.95894 462 4.12i 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) N0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-5005010015020025030035040045050055020.581.141.7720.164.281.00A (d)8.60B (s)7.72D (m)6.92E (t)2.82F (m)1.66C (m)7.511.431901.444041.476241.518211.550151.559681.590691.602391.631731.642261.677361.759651.862571.874151.912892.784082.824522.863326.903536.909966.924496.932077.26045CDCl37.387977.410187.436687.455237.464447.479997.485707.493297.504897.513647.528847.552707.558097.568927.578187.592657.598427.605637.636297.659937.665497.723558.590018.60743-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-20000200040006000800010000120001400016000180002000022000240002600028000300003200034000360003800022.8059626.7168831.7354433.1425476.73813CDCl377.16146CDCl377.58412CDCl3115.84021119.38900127.25832127.65174127.93731128.51228129.06950133.96442136.13680137.40224145.13877149.14520155.55191 463 4.12j 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NOMs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)01002003004005006007008009002.796.732.064.541.001.790.90A (d)8.77B (m)8.14C (d)7.98D (m)7.79E (m)7.66F (m)7.49G (s)3.193.189157.26062CDCl37.404587.430817.436747.452847.460067.468627.473697.494587.517107.521987.552237.566617.571607.584107.591367.648307.652037.657007.668537.675257.680657.743977.763187.773517.783157.812247.975907.981618.130758.136468.160108.762918.78036-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)-4000-2000020004000600080001000012000140001600018000200002200024000260002800030000320003400036000380004000037.6632676.73823CDCl377.16088CDCl377.58354CDCl3119.09444120.18035120.80158122.57928127.27039127.70447128.12151129.13109130.09263136.68160137.83851140.18914142.68324143.89562149.49601150.32734156.16394 464 4.12k 1H NMR (300 MHz, CDCl3) 13C{1H} NMR (75 MHz, CDCl3) NPh OTs0.01.02.03.04.05.06.07.08.09.010.011.012.0f1 (ppm)-500501001502002503003504004505005506006507003.192.022.241.033.222.136.241.042.151.00A (d)8.73B (m)7.98C (s)7.92D (m)7.75E (m)7.66F (m)7.50G (m)7.42H (d)7.32I (m)7.11J (s)2.452.451047.092787.102277.108977.124487.131397.141167.25970CDCl37.303817.330767.398837.406537.418427.422907.427437.463487.483707.489327.501717.507187.512717.518537.524647.634417.641727.645477.650557.662207.668587.674037.723867.730057.752707.758617.768877.778717.784987.788527.919077.962337.963157.972687.979537.995018.001748.011498.718528.73563-20-100102030405060708090100110120130140150160170180190200210220f1 (ppm)05000100001500020000250003000035000400004500021.8818976.73625CDCl377.15922CDCl377.58343CDCl3118.77296120.56357122.91194127.26035127.61827127.98440128.04472128.52505128.75118129.09873129.97265132.40106137.06521138.27050140.28654142.38456145.60210149.36251150.15376150.53984156.76799
Thesis/Dissertation
eng
Chemistry
Vancouver : University of British Columbia Library
Attribution-NonCommercial-NoDerivatives 4.0 International
Graduate
Dake, Gregory
Construction of functionalized nitrogen heterocycles using 2-(diphenylphosphoryl)oxygen-1,3-butadienes in multicomponent [4+2] cycloaddition reactions
Text