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Catalyst and methodology development for regioselective C-N and C-C bond formation Lee, Alison Victoria 2007

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C A T A L Y S T A N D M E T H O D O L O G Y D E V E L O P M E N T FOR REGIOSELECTIVE C - N A N D C - C BOND FORMATION by ALISON VICTORIA L E E B.Sc. (Honours), Queen's University, 2002 A THESIS SUBMITTED IN PARTIAL F U L F I L L M E N T OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE F A C U L T Y OF G R A D U A T E STUDIES (Chemistry) THE UNIVERSITY OF BRITISH C O L U M B I A June 2007 © Alison Victoria Lee, 2007 A B S T R A C T The related investigations of catalytic hydroamination as a key step in synthetic methodology development and the synthesis of new hydroamination catalysts are reported in this thesis. The first section focuses on methodology development for the application of a bis(amidate)bis(amido) titanium hydroamination precatalyst towards the synthesis of functionalized small molecules via a tandem C - N , C - C bond forming reaction sequence. The development of two tandem sequential reactions will be described, as well as their applications in the synthesis of a-cyanoamines, a-amino acid derivatives, P-amino alcohols, diamines, imidazolidinones, and P-amino acid derivatives. These tandem reactions show an expanded substrate scope and increase synthetic flexibility by allowing for alternative starting materials in the preparation of highly functionalized small molecules. The second section describes progress towards the development of an asymmetric tandem reaction sequence, including investigations into the mode of activation for the tandem reaction. It has been established that a nucleophilic activation mode is required to generate an active species for the C - C bond forming step. Furthermore, it is postulated that the coordination environment and steric congestion about the activator impacts reaction efficiency and stereoselectivity. This information will be valuable in the design of future generations of activators. The final section reports the development of two novel group 4 metal complexes for catalytic hydroamination. The synthesis and full characterization of these complexes wil l be described, as well as the results of the catalytic investigations. Through this investigation it has been postulated that while a change in the electronic nature of the i i metal complex does enhance catalytic reactivity, the degree of orbital overlap between the ligand and the metal center is also an important consideration in the design of electrophilic hydroamination precatalysts. Hydroamination catalysis is currently an attractive area of intense research. The work in this thesis has demonstrated the use of hydroamination catalysis in the synthesis of highly functionalized small molecules, and has furthered the fundamental understanding of the hydroamination reaction. This increase in understanding can then be applied towards the rational design of more powerful hydroamination catalysts and further their application in the synthesis of functionalized N-containing compounds. i i i TABLE OF CONTENTS Abstract i i Table of Contents iv List of Tables ix List of Figures xi List of Schemes xv List of Abbreviations xvi Acknowledgements xx Foreword xxi CHAPTER ONE: INTRODUCTION TO C A T A L Y S T A N D M E T H O D O L O G Y D E V E L O P M E N T FOR REGIOSELECTIVE C - N A N D C - C BOND F O R M A T I O N 1 1.1 Catalyst development 1 1.2 Amidates as a modular ligand set 3 1.2.1 Monodentate binding of amidates 4 1.2.2 Bridging binding modes of amidates 6 1.2.3 Chelating binding modes of amidates 8 1.2.4 Amidates as an auxiliary ligand set 12 1.2.4.1 Proligand synthesis 12 1.2.4.2 Group 4 coordination complexes with amidate 13 1.3 Hydroamination 16 1.3.1 Hydroamination with Cp-based ligand sets 19 1.3.2 Hydroamination with non-Cp-based ligand sets 21 1.3.3 Hydroamination with the amidate ligand set 24 1.4 Scope of thesis 30 iv 1.5 References 34 C H A P T E R T W O : S Y N T H E T I C A P P L I C A T I O N S O F T A N D E M C - N , C - C B O N D F O R M I N G R E A C T I O N S 40 2.1 Introduction 40 2.1.1 Hydroamination 40 2.1.2 Tandem reaction sequences 42 2.1.3 Scope of project 46 2.2 Tandem sequential reactions using hydroamination and the Strecker reaction 47 2.2.1 Synthesis of a-cyanoamines 47 2.2.1.1 Introduction 47 2.2.1.1.1 The Strecker reaction 47 2.2.1.1.2 Alternative literature methods for the synthesis of a-cyanoamines 56 2.2.1.1.3 Reported uses of a-cyanoamines 58 2.2.1.1.4 Development of a hydroamination tandem sequential reaction 61 2.2.1.2 Results and discussion 65 2.2.1.2.1 a-Cyanoamines via hydroamination tandem reaction sequence 65 2.2.1.3 Summary of a-cyanoamines 73 2.2.2 Synthesis of a-amino acid derivatives 74 2.2.2.1 Introduction 74 2.2.2.1.1 Reported uses of a-amino acid derivatives 74 2.2.2.1.2 Literature methods for the synthesis of a-amino acid derivatives 76 2.2.2.2 Results and discussion 80 2.2.2.2.1 a-Amino acid derivatives via hydroamination tandem reaction sequence 80 2.2.2.3 Summary of a-amino acid derivatives 89 2.2.3 Synthesis of P-amino alcohols 90 v 2.2.3.1 Introduction 90 2.2.3.1.1 Reported uses of P-amino alcohols 90 2.2.3.1.2 Literature methods for the synthesis of P-amino alcohols 91 2.2.3.2 Results and discussion 94 2.2.3.2.1 P-Amino alcohols via hydroamination tandem reaction sequence 94 2.2.3.3 Summary of P-amino alcohols 96 2.2.4 Synthesis of diamines 97 2.2.4.1 Introduction 97 2.2.4.1.1 Reported uses of diamines 97 2.2.4.1.2 Literature methods for the synthesis of diamines 98 2.2.4.2 Results and discussion 100 2.2.4.2.1 Diamines via hydroamination tandem reaction sequence 100 2.2.4.3 Summary of diamines 106 2.2.5 Overall summary 106 2.3 Tandem sequential reactions with hydroamination and the Mannich reaction 107 2.3.1 Introduction 107 2.3.1.1 The Mannich reaction 107 2.3.1.2 Tandem reaction sequence 110 2.3.1.3 Reported uses of P-amino acid derivatives I l l 2.3.1.4 Literature methods for the synthesis of P-amino acid derivatives 112 2.3.2 Results and discussion 113 2.3.2.1 P-Amino acid derivatives via hydroamination tandem reaction sequence 113 2.3.3 Summary of P-amino acid derivatives 118 2.4 Conclusions and applications 119 2.5 Experimental 122 2.6 References 162 vi C H A P T E R T H R E E : P R O B I N G M O D E O F A C T I V A T I O N I N T A N D E M C - N , C - C B O N D F O R M I N G R E A C T I O N S E Q U E N C E 169 3.1 Introduction 169 3.1.1 Tandem reaction sequence 169 3.1.2 Mechanism for catalytic hydroamination 170 3.1.3 Possible modes of activation for the Strecker reaction 172 3.1.4 Scope of project 177 3.2 Results and discussion 178 3.2.1 Mode of activation 178 3.2.2 Nature of the nucleophilic activation 183 3.2.3 Practical synthetic applications of nucleophilic activation 190 3.2.4 Progress towards asymmetric synthesis of chiral a-cyanoamines 194 3.2.4.1 Introduction 194 3.2.4.2 Diastereoselectivity 196 3.2.4.3 Enantioselectivity 216 3.3 Summary and conclusions 234 3.4 Experimental 236 3.5 References 255 C H A P T E R F O U R : C A T A L Y S T D E V E L O P M E N T F O R G R O U P 4 M E D I A T E D H Y D R O A M I N A T I O N 257 4.1 Introduction 257 4.1.1 Hydroamination 257 4.1.2 Scope of project 262 4.2 Results and discussion 262 4.2.1 Ligand design and synthesis 262 4.2.2 Metal complex synthesis 264 4.2.3 Applications in catalysis 270 4.2.3.1 Hydroamination of terminal alkynes with aryl amines 270 4.2.3.2 Hydroamination of terminal alkynes with alkyl amines 274 4.2.3.3 Hydroamination of internal alkynes 277 4.2.3.4 Hydroamination of aminoalkenes 281 4.2.3.5 Hydroamination summary 285 4.3 Summary and conclusions 286 4.4 Experimental 288 4.5 References 293 C H A P T E R F I V E : C O N C L U S I O N S A N D F U T U R E W O R K 298 5.1 Summary and conclusions 298 5.2 Future work 300 5.2.1 Preliminary investigations 300 5.2.1.1 Hydroamination tandem reaction sequences 300 5.2.1.2 Catalyst design 303 5.2.2 New avenues of research 306 5.2.2.1 Hydroamination tandem reaction sequences 306 5.2.2.2 Asymmetric tandem hydroamination and Strecker reaction sequence 309 5.3 Summary 312 5.4 References 314 Appendix 1 315 Appendix II 322 Appendix III 330 Appendix IV 352 Appendix V 363 L I S T O F T A B L E S Table 2.1: Yields of TMS-protected a-cyanoamines synthesized via the combination of hydroamination and the Strecker reaction in eq. 2.17 68 Table 2.2: Yields of a-amino amides that are purified via precipitation 82 Table 2.3: Yields of a-amino esters synthesized from terminal alkynes 88 Table 2.4: Yields of P-amino alcohols synthesized from terminal alkynes 95 Table 2.5: Yields of diamines synthesized from terminal alkynes 102 Table 2.6: Yields of imidazolidinones synthesized from diamines 104 Table 2.7: Screening of reaction conditions for tandem hydroamination and the Mannich reaction sequence 115 Table 3.1: Yields of TFA-protected a-cyanoamines after column chromatography with a variety of activators 182 Table 3.2: Yields of TFA-protected a-cyanoamines after column chromatography with novel activators 193 Table 3.3: Effect of solvent polarity on diastereoselectivity 203 Table 3.4: Effects of temperature and concentration on diastereoselectivity 204 Table 3.5: Effect of other activators on the diastereoselectivity of the reaction 206 Table 3.6: Effect of the amount of primary amine on the amount of elimination product formed 209 Table 3.7: Effects of the addition of inorganic bases on the formation of the elimination product 210 Table 3.8: Effect of activators on the enantioselectivity of the reaction 219 Table 3.9: Enantioselectivities obtained using a stoichiometric amount of P-amino alcohols as chiral activators 222 Table 3.10: Enantioselectivities obtained using chiral diamines as catalytic activators 225 Table 3.11: Enantioselectivities obtained using a stoichiometric amount of a-amino methyl esters as activators 227 Table 3.12: Enantioselectivities obtained using a-amino ^-butyl esters as activators 229 Table 4.1: Selected bond lengths (distance, A) and angles (angle, °) for 4.9 266 Table 4.2: Selected bond lengths (distance, A) and angles (angle, °) for complex 4.13 269 ix Table 4.3: Catalytic hydroamination of terminal alkynes with 4.9 and aryl amines 271 Table 4.4: Catalytic hydroamination of terminal alkynes with 4.10 and aryl amines 271 Table 4.5: Catalytic hydroamination of terminal alkynes with alkyl amines using 4.9 274 Table 4.6: Hydroamination of 1-phenyl-1-propyne and alkyl amines using complex 4.9 278 Table 4.7: Hydroamination of symmetrical alkynes with aryl and alkyl amines using 4.9 279 Table 4.8: Hydroamination of diphenyl-substituted aminoalkene with various precatalysts 282 Table 4.9: Intramolecular hydroamination of aminoalkenes with 4.10 283 x L I S T O F FIGURES Figure 1.1: Variety of amidate ligands and group 4 complexes that have been synthesized in the Schafer group 2 Figure 1.2: Examples of possible binding modes of amidate ligands 4 Figure 1.3: Examples of complexes that are bond through the amide oxygen (1.1) and the amidate nitrogen (1.2) without further donation from another atom in the same ligand 5 Figure 1.4: Examples of constrained diamidate ligands that bind the metal through both the amidate nitrogen and other atoms in the molecule 5 Figure 1.5: Examples of structurally investigated bridging amidate complexes 7 Figure 1.6: Examples of bridging amidates that have been investigated for stoichiometric and catalytic reactivity 8 Figure 1.7: Amidate complex resulting from reactions with isocyanates 9 Figure 1.8: Example of a chelating lactamide on titanium 10 Figure 1.9: Chelating amidate complexes synthesized by Stahl and co-workers 10 Figure 1.10: Chelating diamide pro ligand 1.16 and bimetallic bis(amidate) complex 1.17 11 Figure 1.11: Resonance structures for deprotonated amides {E conformation) 12 Figure 1.12: Possible coordination isomers of bis(amidate) complexes. L = chloro, alkyl, amido. R = alkyl, aryl 13 Figure 1.13: ORTEP depictions of bis(amidate)bis(amido) titanium complexes containing ligands with varying degrees of steric bulk on the nitrogen. Hydrogen atoms have been omitted for clarity, (a) Amidate ligand contains 2,6-diisopropylphenyl substituent on the nitrogen, (b) amidate ligand contains f-butyl substituent on the nitrogen 15 Figure 1.14: Examples of Cp-based catalysts for catalytic hydroamination 19 Figure 1.15: Examples of hydroamination precatalysts containing non-Cp ligands 22 Figure 1.16: Amide pro ligands with varying electronic properties 24 Figure 1.17: Hydroamination precatalysts with varying steric properties 25 Figure 1.18: Proposed mechanism for catalytic hydroamination involving insertion into the Ln-N bond., 27 Figure 1.19: Proposed mechanism for catalytic hydroamination involving a metal-imido species 28 Figure 2.1: Literature examples of catalysts used to promote the Strecker reaction... 51 xi Figure 2.2: Catalysts designed by Corey and co-workers for the Strecker reaction .. .52 Figure 2.3: Tripeptide ligands investigated for Ti-catalyzed Strecker reaction by Hoveyda and Snapper 53 Figure 2.4: Chiral Zr catalyst used for the Strecker reaction by Kobayashi and co-workers 54 Figure 2.5: Metal based systems used for the Strecker reaction by Jacobsen and co-workers 55 Figure 2.6: Organocatalysts used for the Strecker reaction by Jacobsen and co-workers 56 Figure 2.7: Literature examples of a natural product and synthetic analogue containing the a-cyanoamine functionality 59 Figure 2.8: Potential synthetic transformations of a-cyanoamines 60 Figure 2.9: Classes of highly functionalized small molecules that can be synthesized using this tandem sequential reaction sequence 63 Figure 2.10: The only two examples of alkyl a-amino acid derivatives discussed in reports on current Strecker reaction research 64 Figure 2.11: 300 MHz lH N M R spectrum of an aldimine in CeD 6 showing diagnostic triplet at 7.4 ppm 67 Figure 2.12: a-Cyanoamines that have been synthesized through tandem catalytic hydroamination and the Strecker reaction sequence 69 Figure 2.13: 300 MHz *H N M R spectrum of crude 2.29 in C 6 D 6 with contamination from pro ligand 2.18 70 Figure 2.14: Additional a-cyanoamines that could only be synthesized using the K C N methodology 71 Figure 2.15: Examples of a-cyanoamines synthesized with increased functionality... .73 Figure 2.16: Literature examples of a-amino acid derivatives in pharmaceutically relevant compounds and natural products 75 Figure 2.17: Total synthesis reported in the literature of (+)-P-erythroidine where an a-amino ester is a key intermediate 76 Figure 2.18: Chiral phase-transfer catalysts that have been used in the synthesis of a-amino acids by Maruoka and co-workers 77 Figure 2.19: Examples of a-amino amides synthesized using tandem C - N , C - C bond forming methodology followed by hydrolysis 81 Figure 2.20: 300 MHz ' H N M R spectrum of a-amino amide 2.48 in C D 3 O D 83 Figure 2.21: Examples of a-amino acid salts synthesized using tandem C - N , C - C bond forming methodology 84 xii Figure 2.22: 400 MHz ! H N M R spectrum of a-amino acid 2.54 in C D 3 O D 85 Figure 2.23: Reaction of an a-amino acid salt with a base yields the zwitterionic a-amino acid 87 Figure 2.24: Literature examples of p-amino alcohols in natural products 90 Figure 2.25: Literature examples where p-amino alcohols have been used in medicinal chemistry applications as either the target (2.70) or as an advanced intermediate (2.71) 95 Figure 2.26: Literature examples of diamines in natural products and pharmacologically relevant compounds 97 Figure 2.27: Literature examples of imidazolidinones in compounds that are investigated for pharmaceutical applications 103 Figure 2.28: Asymmetric catalysts and ligands for the Mannich reaction reported in the literature 109 Figure 2.29 Literature examples of natural products that contain p-amino acid derivatives I l l Figure 2.30: Literature examples of P-amino acids in pharmacologically relevant compounds 112 Figure 2.31: P-Amino esters that are synthesized in good yields from the tandem hydroamination and the Mannich reaction sequence 116 Figure 2.32: P-Amino esters that are synthesized in poor yields by the combination of hydroamination and the Mannich reaction 117 Figure 3.1: Proposed mechanism for the catalytic hydroamination of terminal alkynes with primary amines using precatalyst 3.1. L = amidate ligand 171 Figure 3.2: Catalyst systems where the mode of activation for the Strecker reaction has been proposed to be imine activation 173 Figure 3.3: Possible species for the reaction between carbenes and T M S C N 175 Figure 3.4: Proposed catalytic cycle for Strecker reaction with bicyclic guanidine catalyst 3.12 176 Figure 3.5: Proposed catalytic cycle of bifunctional Al-catalyst for the Strecker reaction 177 Figure 3.6: Possible modes of activation for the Strecker reaction 179 Figure 3.7: Three possibilities for the species formed from the reaction between benzylamine and T M S C N 183 Figure 3.8: 300 M H z : H N M R spectrum of the equilibrium in eq. 3.5 in CeD 6 185 Figure 3.9: 75 M H z 1 3 C N M R spectrum of the equilibrium in eq. 3.5 in C 6 D 6 186 Figure 3.10: Proposed mechanism for imine metathesis. L = amidate ligand 192 Figure 3.11: G C trace showing the retention times of the two diastereomers formed during the test reaction in Scheme 3.4 198 Figure 3.12: Typical G C trace of crude reaction mixture using alternate chiral activators showing common extra peak at 15.4 minutes 205 Figure 3.13: Chiral H P L C trace showing the resolution of the two TFA-protected a-cyanoamine enantiomers 218 Figure 3.14: 0-Amino alcohols that are used as activators in tandem reaction sequence 221 Figure 3.15: Chiral diamines that are used as catalytic activators in the tandem reaction sequence 223 Figure 3.16: a-Amino methyl esters used as activators in enantioselective tandem reaction sequence 226 Figure 3.17: Examples of possible geometric isomers that could be formed for the proposed hexacoordinate silicon adduct 231 Figure 4.1: Sterically hindered proligands used by Beller and co-workers 259 Figure 4.2: Selected aryloxide complexes investigated by Rothwell and co-workers 263 Figure 4.3: O R T E P depiction of complex 4.9. Hydrogen atoms are omitted for clarity. Thermal ellipsoids are set to 50% probability 266 Figure 4.4: Related bis(phenoxide)bis(amido) titanium complexes reported in the literature 267 Figure 4.5: Two views of the O R T E P representation of complex 4.13. Hydrogen atoms are omitted for clarity in both, (a) Fu l l view, (b) the core of the molecule where the r-butyl and methyl groups from the pyrimidinoxide ligand are removed. Thermal ellipsoids are set to 50% probability 269 Figure 5.1: A x i a l l y chiral proligand (5.4) used successfully by the Schafer group. Proposed proligand (5.5) with an electron-withdrawing substituent attached to the carbonyl carbon atom 305 Figure 5.2: A x i a l l y chiral molecules that could be potential activators 310 Figure 5.3: Chiral amines attached to solid support that could potentially act as activators for the Strecker reaction 311 Figure 5.4: Use of ort/jo-substituted aniline to affect the enantioselectivities of the tandem reaction sequence 312 x iv LIST OF SCHEMES Scheme 2.1: Tandem hydroamination C - H activation reaction sequence 45 Scheme 2.2: Synthesis of a stable TFA-protected a-cyanoamine 72 Scheme 2.3: Methodology for synthesizing a-amino acids and a-amino esters reported by Walsh and co-workers 78 Scheme 2.4: Synthesis of (3-amino alcohols via a Ti-enolate reported in the literature 92 Scheme 2.5: Synthesis of unsymmetrical diamines from the reductive cross coupling of nitrones and A^-rerZ-butanesulfmyl imines reported by Xu and co-workers 99 Scheme 2.6: Literature report of the synthesis of substituted unsymmetrical diamines 100 Scheme 2.7: Synthesis of diamines from terminal alkynes via the tandem hydroamination and Strecker reaction sequence 101 Scheme 2.8: Synthesis of (3-amino esters through tandem C - N , C - C bond forming reaction sequence 114 Scheme 3.1: Proposed mechanism for Strecker reaction with catalyst 3.9 174 Scheme 3.2: Separation of the imine from the titanium precatalyst before the Strecker reaction 181 Scheme 3.3: Synthesis of a-cyanoamines using isopropylamine as an activator 191 Scheme 3.4: Test reaction used in development of diastereoselective version of tandem reaction sequence 196 Scheme 3.5: Reaction of chiral amine with titanium precatalyst to determine whether any racemization is occurring 200 Scheme 3.6: Possible pathways for the formation of the elimination product 208 Scheme 3.7: Enantioselective test reaction used to optimize chiral activators 217 Scheme 4.1: Synthesis of substituted pyrimidinol 4.8 264 xv L I S T O F A B B R E V I A T I O N S 2-D 2-Dimensional AcOH Acetic acid APCI-MS Atmospheric pressure chemical ionization mass spectrometry APT Attached proton test Ar Aryl Ar* 2,6-Dimethylaniline Bn Benzyl BOC tert-Butoxycarbonyl br Broad, in N M R spectroscopy cat. Catalyst CDI N, 7V-carbonyldiimadazole CDRD Center for Drug Research and Design CFI Canada Foundation for Innovation cm"1 Wavenumber, in IR spectroscopy cone. Concentrated COSY Correlation spectroscopy Cp Cyclopentadienyl Cp ' Pentamethylcyclopentadienyl d Doublet, in N M R spectroscopy d o f d Doublet of doublets, in N M R spectroscopy dba dibenzylideneacetone D C A 9,10-dicyanoanthracene DCC Dicyclohexylcarbodiimide D C M Dichloromethane DDI Drug Development Institute de Diastereomeric excess DFT Density functional theory Di iPEA Diisopropylethylamine xvi D M A P Dimethylaminopyridine DRI Drug Research Institute E + Electrophile E A Elemental analysis ee Enantiomeric excess EI-MS Electron-impact mass spectrometry eq. Equation ESI-MS Electrospray ionization mass spectrometry Et Ethyl Equiv. Equivalent Flu Fluorenyl FT-IR Fourier-transform infrared GC-MS Gas chromatography-mass spectrometry HPLC High performance liquid chromatography HR-MS High resolution-mass spectrometry Hz Hertz h Planck's constant, 6.626 x 10"34 J-s i Iso Ind Indenyl 'Pr Isopropyl IR Infrared J Coupling constant, in N M R spectroscopy Kcal/mol Kilocalories per mole K H M D S Potassium hexamethyldisilazane L A H Lithium aluminum hydride Ln Lanthanide atom L R - M S Low-resolution mass spectrometry M i) metal atom ii) central atom or parent peak in MS iii) concentration, in molarity MS Mass spectrometry xvii m Multiplet, in N M R spectroscopy Me Methyl M H z Megahertz mmol Millimole mol Mole N Normality "Bu n-Butyl N H C A/-heterocyclic carbene N M R Nuclear magnetic resonance OAc acetate ORTEP Oak Ridge Thermal Ellipsoid Plot OTf Triflouromethylsulfonate Ph Phenyl ppm Parts per million, in N M R spectroscopy R Alky l group r.t. Room temperature s Singlet, in N M R spectroscopy SAR Structure-activity relationship sat. Saturated sept Septet, in N M R spectroscopy t Triplet, in N M R spectroscopy T Temperature, °C t tert 'Bu f-butyl T B A F Tetrabutylammonium flouride TFA Trifluoroacetyl T F A A Trifluoroacetic anhydride THF Tetrahydrofuran TLC Thin layer chromatography TMS Trimethylsilyl TMS-allyl Allyltrimethylsilane T M S C F 3 Trifluoromethyltrimethylsilane T M S C N Cyanotrimethylsilane Tol Toluene TM Trademark © Copyright A Change in 5 Chemical shift in N M R spectroscopy, in ppm I Wavelength, in cm"1 VJ Frequency in Hz or s"1 71 Pi, as in 7t-bond a Sigma, as in a-bond xix Acknowledgments First and foremost, I would like to thank my supervisor, Dr. Laurel Schafer, for all her help and patience with my research projects and the writing of this thesis. I would also like to thank her for all the encouragement she has given me over the years, both personally and professionally. I would also like to thank the members of the Schafer group, both past and present, for their help in the lab and their distractions outside of the lab. I have really enjoyed being a member of this group. I would like to thank the various shops and services in the chemistry department at U B C , including the mech shop, the electronics shop, the glassblower, the IT department, the N M R staff, and the analytical services staff. In particular I would like to thank Ken Love and Brian Snapkauskas in the mech shop for their patience and assistance with the gloveboxes, as well as the speed at which they have helped me out of an equipment crisis. I would also like to thank Brian Patrick and Rob Thomson for assistance with X-ray crystallography. I would like to thank the chemistry department and NSERC for funding throughout my time at U B C . Finally, I would like to thank my parents for continually supporting me over the years and my sister for providing a welcomed distraction. I would also like to thank Chuck and Carli for all their love and support and for never letting me quit. xx F O R E W O R D The work that is reported in this thesis covers two related areas of catalysis research: the applications of a previously reported hydroamination precatalyst in methodology development for the synthesis of functionalized small molecules and the design and synthesis of novel hydroamination precatalysts. The theme of this thesis is catalytic hydroamination, and as this is a manuscript based thesis, each chapter is meant to be a stand-alone document. Therefore, one wil l find that there is some repetition in the introductory information between the chapters. Furthermore, some compounds are used in more than one chapter, however, as each chapter is intended to be a discrete document, compound numbering is consistent within each chapter and thus some compounds will be associated with more than one number in this thesis. A l l work completed during this course of study were new projects within the Schafer group. In order to produce a document that would be useful to the research group in the coming years, a comprehensive review of the literature has been performed for each chapter. In general each chapter is organized with an introduction, results and discussion, and summary and conclusions section. However, in some sections of this thesis, especially in chapter two, individual subchapters have been assembled for each class of target compounds and once again there is an introduction, results and discussion, and summary section for each subchapter. Titles of subchapter sections clearly delineate introductory literature reviews from the original results presented here. xxi C H A P T E R O N E : INTRODUCTION T O C A T A L Y S T AND M E T H O D O L O G Y D E V E L O P M E N T FOR R E G I O S E L E C T I V E C - N A N D C-C B O N D F O R M A T I O N 1.1 Catalyst development Catalysts are very important in chemistry and generally increase the synthetic utility of reactions that otherwise would not occur. Without catalysts, reactions such as olefin metathesis, polymerizations, and C - C bond coupling, among others, would not be as generally applicable. Catalysts can also enable reactions to proceed in less time and at lower temperatures, important considerations in both laboratory and industrial processes. Furthermore, the use of catalysts can increase the efficiency of a reaction, and reduce the amount of stoichiometric reagents that are needed, which both contribute to greener chemistry.1 By their very nature, catalysts can also be reused after a reaction, presuming that they can be easily recovered, which can lead to a reduction in chemical waste, especially when compared to the use of stoichiometric amounts of reagents. Overall, catalysis is very important in chemistry, and hence catalyst development is an active research area. When designing new catalyst systems, there are several factors to consider. First, it is economically desirable to choose a metal that is relatively inexpensive. Second, the ligands should be easy to synthesize and easy to modify. The facile modification of ligands is particularly important as that allows the chemist to investigate structure/activity relationships (SARs) and modify the catalyst structure accordingly to tune catalytic reactivity. Third, ideally a catalyst should form discrete molecular complexes so that © A version of this chapter has been published. Lee, A . V . ; Schafer, L . L . Eur. J. Inorg. Chem. 2007, 2243. Copyright W i l e y - V C H Verlag G m b H & Co. K G a A . Reproduced with permission. 1 information about bonding can be gained through examination of the solid state molecular structure. This solid state information also assists in making rational changes to the catalytic design. Fourth, the catalysts should be stable enough that they are easy to work with and can be stored for a period of time without consequence. Finally, in regards to the particular reaction that the catalyst promotes, the catalyst should be chemoselective, regioselective and stereoselective, in cases in which more than one product can be formed. The Schafer group is very interested in designing group 4 metal complexes and investigating them for catalytic reactivity. Group 4 metals are ideal for catalyst development as they are relatively inexpensive and non-toxic. Furthermore, there are a number of group 4 starting materials that are commercially available, including alkyl, chloro, and amido species. This allows for the ready synthesis of a number of organometallic and coordination compounds. Organic amides have been identified as a highly modular proligand set for the synthesis of group 4 metal complexes, and have been used extensively by the Schafer group (Figure 1.1). Figure 1.1: Variety of amidate ligands and group 4 complexes that have been synthesized in the Schafer group. R = aryl, alkyl R2 = aryl, alkyl L = chloro, alkyl, amido M = Ti,Zr, Hf 2 Once deprotonated, the amidates form stable complexes with a variety of group 4 metal-containing starting materials, and often lead to structures that can be studied using X-ray crystallography. This, in combination with the easily synthesized ligand set, facilitates SAR investigations and promotes greater understanding of a particular catalyzed reaction. This understanding can then be used in the design of more effective catalysts. 1.2 Amidates as a modular ligand set The use of amidates as a ligand set follows a recent trend to move away from ligands based on cyclopentadienyl (Cp). Although investigations involving the Cp ligand set have been widespread and the subject of several reviews,2 there are a number of drawbacks associated with Cp-based ligands. Primarily, extensive modification of the Cp backbone is very difficult, and thus tuning of the catalytic activity is limited. This has led to research into non-Cp based ligand sets in which modifications are more easily accomplished.3,4 Examples of these classes of ligands have included, but are not restricted to, amidinates,5"9 troponiminates,10'11 guanidinates,12"14 sulfonamides,15'16 nitrogen-based ligands1 7"1 9 and chelating nitrogen and oxygen ligand sets.20"22 However, amidates were not among the investigated ligand sets, and seemed to have been overlooked prior to the Schafer group's research. Amides are readily synthesized from starting materials that are widely available. Furthermore, both their steric and electronic properties are easily varied. These are very desirable factors in building a new, tunable ligand set. There are however, some potential drawbacks to using amidate ligands. Among these, it has been shown that amidates can bind to a metal in a number of fashions as illustrated in Figure 1.2. Possibly it is the 3 numerous potential coordination isomers that has kept amidates from being fully exploited as auxiliary ligands. monodentate bridging chelating M M M M M iii F i g u r e 1 .2 : Examples of possible binding modes of amidate ligands. A review of the literature shows that most examples of amidates binding to metal centers fall into one of four categories: i) monodentate, O-bound, ii) monodentate, N-bound, iii) bridging and iv) chelating. There are examples of amidates in complexes that are used for bioinorganic2 3"2 5 and lanthanide coordination chemistry,2 6'2 7 but these are outside the scope of this thesis. Furthermore, with one exception, examples of the coordination of * 23 28 29 neutral amides ' ' will not be addressed. Generally, the discussion will focus on amidates that have been used as ligands to form catalytically relevant metal complexes. 1.2.1 M o n o d e n t a t e b i n d i n g o f a m i d a t e s There are several examples of amidate ligands coordinating to a metal center in a monomeric fashion through either the oxygen ( i ) or the nitrogen ( i i ) atoms. In general, coordination occurs via the more basic oxygen atom with "hard" metals ( l . l ) , 3 0 but via the nitrogen atom to'"soft" metals (1 .2 ) (Figure 1.3).31'32 Most examples are reported as either type i or type i i , without reference to isomerism between the two. Typically, i f the 4 amide is in its neutral form, then the ligand coordinates through the oxygen atom to the metal center (eg. 1.1). H N M e 2 C I * ' | ^ N H 3 N / , , H 3 N O K ,NH '| N H }\ Bu Bu CI o 1.1 1.2 N = phenan th rene Figure 1.3: Examples of complexes that are bound through the amide oxygen (1.1) and the amidate nitrogen (1.2) without further donation from another atom in the same ligand. Typically, ligands that bind to a metal center through only the amidate nitrogen atom (and not the amidate oxygen atom) have a constrained geometry such that donation through the carbonyl oxygen is unfavorable. For example, the diamidate chelating ligands in 1.3 and 1.4 in Figure 1.4 both have other donor atoms in their backbone that restrict the coordination environment. Complexes 1.3 and 1.4 have been investigated as models for the interaction between metalloenzymes and amides of peptides in biological chemistry24 and in medicinal inorganic chemistry,3 3 , 3 4 respectively. Figure 1.4: Examples of constrained diamidate ligands that bind the metal through both the amidate nitrogen and other atoms in the molecule. 1.3 1.4 5 Variations of 1.4 have been made with Cu(II), Ni(II), Zn(II), Cr(III), Fe(III), and Bi(III) metal centers and were used for catalytic investigations into the selective liquid-phase hydroxylation of phenol. 3 5 ' 3 6 While many examples in coordination chemistry investigations have monodentate binding modes of amidates, few examples of well characterized complexes for catalytic applications have been reported. The few examples included here illustrate several aspects of ligand design which must be considered in preparing well-defined complexes with discrete binding modes for use in further applications. 1.2.2 Bridging binding modes of amidates One of the most common bonding motifs observed with amidates is bonding type iii in which the amidate ligand bridges two metal centers. Many of these examples use very simple amidate ligands to form complexes that have been investigated for their interesting structural features (Figure 1.5) and stoichiometric reactivity (Figure 1.6). For example, in 1979 the first Cr (1.5) and Mo complexes containing metal-metal bonds and bridging amidates were reported. Interestingly, complex 1.5 displays a very short Cr-Cr bond (1.873 A). 6 F i g u r e 1 .5 : Examples of structurally investigated bridging amidate complexes. Another example of type i i i bonding is seen in complex 1.6. These heterotrimetallic complexes contain two platinum atoms and a Cu, Co, Mn, Cd, In, or N i atom and have been formed with various amidate ligands in which the amidate ligands bridge two metal IS? centers ( 1 . 6 ) . Finally, structurally interesting tetranuclear complexes with bridging amidate ligands have been reported with both M o 3 9 (1 .7 ) and Re 4 0 metal centers. While the aforementioned examples have been used for structural chemistry studies, similar complexes have also been used to probe stoichiometric and catalytic reactivity (Figure 1.6). For example, bridging amidate complexes involving Pt, as seen in 1.8 and 1.9 have been reported,32'41"43 and their reactivity has been investigated,44"46 including their application in catalytic olefin functionalization 4 7 7 '''C02Me F i g u r e 1 .6 : Examples of bridging amidates that have been investigated for stoichiometric and catalytic reactivity. Also, the group of Doyle and co-workers have made a series of dirhodium(II) carboxamidates of the type shown in complex 1 .10 . These compounds have shown important reactivity in a wide variety of metal carbene transformations48'49 and as catalysts for enantioselective hetero-Diels-Alder reactions.50 1.2.3 C h e l a t i n g b i n d i n g m o d e s o f a m i d a t e s Of particular interest to the Schafer group are examples of amidates that chelate through both the nitrogen atom and the oxygen atom to a single metal center (bonding type i v ) , which have been more rarely reported in the literature. One example with simple amidates, such as N-f-butylbenzamidate and substituted derivatives, has been investigated in conjunction with organoaluminum compounds, such as AlMe3, and used for the synthesis of aluminum diketiminates. Futhermore, tris(amidate) alummum(III) compounds, 1 . 1 1 , have been synthesized and identified as the catalyst resting state in Al(III) catalyzed transamidation of carboxamides.51 8 [ R —D A I ( I I I ) R " C 6 H 1 3 , R 1 = B n , - C H 2 C H ( C 2 H 5 ) C 4 H 9 R l / 3 1.11 Many of the examples of amidates that chelate metal centers have resulted from organometallic compounds reacting with isocyanates. For example, complexes of the type M(Me)3Cl2 (M = Nb, Ta) readily insert phenyl or methyl isocyanates to form chelating amidate complexes as shown in eq. 1.1.52 M(Me) 3CI 2 R N C ° . M(Me)CI 2 (RNC (0 )Me) 2 (1.1) M = Nb, Ta R = Ph, Me Analogous reactions occur with Cp 2 ZrMe 2 5 3 and Cp 2 TiR 5 2 complexes and various isocyanates to give complexes of the type 1.12 (Figure 1.7). Me i Me Ar * 1.12 1.13 M = Zr, Ti R = "hexyl = polymer chain Figure 1.7: Amidate complexes resulting from reactions with isocyanates. With respect to polymerization catalysis, complexes like 1.12 are relevant to more recent examples using T i C l 3 O C H 2 C F 3 and CpTiCl 2 L (L= -OCH 2 CF 3 , -N(CH 3 ) 2 , -CH 3 ) as catalysts for the living polymerization of isocyanates.54 It has been proposed, based on ER 9 spectroscopic analysis, that the propagating endgroup during chain growth is a T i -amidate complex, 1.13, with a chelating bonding motif.5 4 There have only been a few reports of titanium amidate chelates that have not been formed as intermediates in organometallic reactions. One example includes the use of caprolactam as a precursor to form the titanium complex 1.14, which was postulated to be an intermediate in the ring-opening polymerization of lactams to form polyamides.55 Cp 2 T i 1.14 Figure 1.8: Example of a chelating lactamide on titanium. Another example of a sterically congested Cp*-Ti complex has been synthesized by Stahl and coworkers, 1.15, during investigations of Ti(IV) catalyzed transamidation.56 i P h CI ' . . . . | i . . . . iN / N T V>NPh 1.15 Figure 1.9: Chelating amidate complex synthesized by Stahl and co-workers. 10 Finally, an example of a Ti complex with chelating amidates without any Cp ligands was described in 2001 by the Arnold group.57 They employ the diamide proligand 1.16, which reacts cleanly with a homoleptic titanium amide to generate a crystalline bimetallic complex 1.17 (Figure 1.10) that maintains the chelating bonding motif. M e 2 N N M e 2 0—1V""0 ATAN N.^S\r 1.16 A r ~ ~ ~ - N N - ^ - A r / \ M e 2 N N M e 2 1.17 Figure 1.10: Chelating diamide proligand 1.16 and bimetallic bis(amidate) complex, 1.17. The two reactive N R 2 groups on each Ti are cis to one another, and bond lengths indicate derealization of the amidate double bond. This compound has been screened and show modest activity for the polymerization of ethylene with methylalumoxane activation.57 While a large variety of amidate structures using different metal centers and bonding motifs have been reported in the literature, it is clear that little work has been disclosed using neutral amides as easily synthesized and readily modified precursors to amidate auxiliary ligands. In particular, the variation of electronic and steric effects within the amidate backbone and the impact on the structural properties of early 11 transition metal complexes had not been investigated, previous to the work done by the Schafer group in this area. 1.2.4 A m i d a t e s as a n a u x i l i a r y l i g a n d se t 1.2.4.1 P r o l i g a n d s y n t h e s i s Amides are easily synthesized with a variety of steric and electronic properties as the starting materials, acid chlorides and amines, are inexpensive and commercially available (eq. 1.2). O O .A + N H 2 R 2 ^ - , 1 , + HNEt 3 GI (1.2) R 1 Cl n u m ( H h R 1 ^ N H R 2 3 ( } CH 2CI 2 /r . t . /1h Once deprotonated, the monoanionic amidate ligand can adopt a conformation to bind the metal in a chelating fashion, where the anion is delocalized throughout the N , C, O backbone (Figure 1.11). O X -R N - R 1 ^ N R 2 F i g u r e 1 . 1 1 : Resonance structures for deprotonated amides (E conformation). The major contributing resonance structure is the one representing charge localization on the oxygen atom, and the double bond between carbon and nitrogen atoms. The lone pairs of electrons on N and O can then interact very strongly with the electropositive metal centers. The hard nature of both the donor atoms and the resonance stabilization of the 12 negative charge, in combination with early transition metals, suggest that the bonding in these complexes will be largely ionic in character. The steric nature of both the groups on the carbon atom of the carbonyl (R 1) and bulk, the greater the possibility of synthesizing dimers and oligomers. Consequently, to minimize this possibility, a certain degree of steric bulk must be maintained in the ligand design. There are five possible geometric isomers that can result from the formation of monomelic bis(amidate) metal complexes, as shown in Figure 1.12. This large number of potential isomers complicates spectral assignments and could be a reason why amidates have been largely overlooked as auxiliary ligands. alkyl, amido. R = alkyl, aryl. 1.2.4.2 Group 4 coordination complexes with amidates Amidates have been used as ligands in the Schafer group to synthesize group 4 chloro and alkyl complexes.58 However, the most widely synthesized and studied metal complexes in the Schafer laboratories are bis(amidate)bis(amido) titanium and zirconium complexes. These complexes are both precursors to other organometallic compounds and catalytically active species for synthetic transformations such as hydroamination. on the nitrogen atom (R 2) affects the metal complex as the smaller the degree of steric Figure 1.12: Possible coordination isomers of bis(amidate) complexes. L = chloro, 13 Bis(amidate)bis(amido) complexes of titanium and zirconium are easily synthesized in high yields via a protonolysis reaction as shown in eq. 1.3. O ether 3 h R . R2 + M ( N R 2 ) 4 H - 2 equiv. H N R 2 , N R 2 ~NR 2 (1.3) M = Ti, Zr R = Et, Me A wide variety of amides have been used for making these bis(amidate)bis(amido) complexes.59 In general, amides containing alkyl groups on both the carbonyl carbon atom and the nitrogen atom yield metal complexes that are oily and difficult to purify. Incorporation of a phenyl group on either the nitrogen atom or the carbonyl carbon atom yields crystalline metal complexes suitable for X-ray analysis. In addition the steric properties of the proligand affect the geometric isomer observed in the solid state. Very bulky substituents on the nitrogen atom, such as 2,6-diisopropylphenyl, ensure that the nitrogen atoms are oriented trans to one another.60 Less bulky substituents on the nitrogen atom, such as £-butyl, lead to an orientation where the nitrogen atoms are cis to one another, as seen by X-ray crystallography61 (Figure 1.13). 14 Figure 1.13: ORTEP depictions of bis(amidate)bis(amido) titanium complexes containing ligands with varying degrees of steric bulk on the nitrogen. Hydrogen atoms have been omitted for clarity, (a) Amidate ligand contains 2,6-diisopropylphenyl substituent on the nitrogen,60 (b) amidate ligand contains ^-butyl substituent on the nitrogen.61 DFT calculations have shown that in both cases the lowest calculated energy matches that observed in the solid state.61 Most importantly for catalytic applications, in both cases the reactive dialkyl amido ligands are oriented cis to one another. Amidates are a modular ligand set; the substituents on both the nitrogen and the carbonyl carbon can be varied between aryl and alkyl groups with different degrees of steric bulk. They have been used in the synthesis of a wide variety of complexes with metal centers such as Ti , Zr, and Hf, and reactive ligands such as chloro, alkyl, and amido groups. The ease with which both the proligand and the metal complexes are synthesized makes this family of complexes very desirable for catalytic investigations. As both the steric and the electronic properties of the system can be readily varied, there is enormous potential for tuning of catalytic reactivity. While group 4 metal complexes are often applied to the catalytic polymerization of alkenes, the most investigated catalytic reaction 15 with these amidate complexes in the Schafer laboratories is hydroamination. In this regard, the bis(amidate)bis(amido) complexes described above have shown interesting and unprecedented reactivity. 1.3 Hydroamination Hydroamination is the addition of nitrogen and hydrogen atoms across a carbon-carbon multiple bond (eq. 1.4) such as an alkyne (shown), allene, or alkene. 3 ,H catalyst "N—H N R 1 = R 2 + R3~K • / = < • R 1 j l (1.4) R' R^ v R When an alkyne is used in hydroamination, the products of the reactions are enamines, which generally tautomerize to the more stable imine when a primary amine is used. This imine can then be reduced to form a substituted amine. The hydroamination of alkenes, on the other hand, leads to the direct synthesis of amines without the required reduction step. The production of amines is industrially very important; worldwide several million tons of amines are synthesized every year.62 Amines are often synthesized from compounds such as alcohols, aldehydes, ketones, nitro-compounds, halides and nitriles. In turn, these starting materials are often synthesized from alkenes and 62 63 alkynes. ' Therefore, it is much more efficient to synthesize amines directly from alkynes and alkenes via hydroamination. Enamines and imines, along with amines, appear in natural products,64'65 and are also useful compounds as building blocks in pharmaceuticals,66"68 detergents and dyes.69"72 Furthermore, as can be seen in eq. 1.4, hydroamination is an atom-economical reaction.73 There are no byproducts formed, and 16 hence hydroamination is very well suited to use in tandem reaction sequences with the hydroamination products acting as in situ intermediates. Thermodynamically, the addition of an amine to an alkene is slightly exothermic, or approximately thermoneutral.72'74 While there is no corresponding data available for the addition of an amine to an alkyne, it has been estimated that this addition is 15 kcal/mol more exothermic then the analogous addition to ethylene.75 However, hydroamination is hindered by two factors. The first is the high activation barrier that results from the electrostatic interaction between the lone pair of electrons on the nitrogen atom and the electrons in the carbon-carbon multiple bond. The second is the negative entropy (AS) of the reaction. This negative value for AS means that heat can not simply be added to the hydroamination reaction to get over the high activation barrier; this only results in the reversion to starting materials. Therefore, with the exception of some very reactive starting materials, such as electron-deficient C - C multiple bonds or benzyne,76"79 the hydroamination reaction always requires the use of a catalyst. There have been reports of hydroamination catalysts using metal centers that span the periodic table. For example, hydroamination reactions can occur with alkali 8 0 and R I Q S Sift Qf\ I I S alkaline metals, late transition metals, " mercury, lanthanides, " and actinides. 7 5 ' 1 1 6 , 1 1 7 There have also been a number of group 4 metal complexes disclosed for catalytic hydroamination, and this amount has been steadily increasing within the last few years. As well, there have been a number of reviews on the subject in the literature. 6 3 , 1 1 8" 1 2 2 For the scope of this thesis, the discussion on hydroamination is limited to group 4 complexes. 17 There are a number of different types of hydroamination reactions. It can occur intramolecularly or intermolecularly. The intermolecular hydroamination of alkynes can use internal alkynes that are either symmetrically or unsymmetrically substituted, with aryl or alkyl substituents, or aryl or alkyl substituted terminal alkynes. When either internal, unsymmetrical alkynes or terminal alkynes are used, the regioselectivity of the process must be considered (eq. 1.5). N R 1 N R 1 R = H + R 1 N H 2 C A A Y S • + R ^ ^ H (1-5) Markovnikov anf/-Markovnikov Two products can now be formed in this reaction, the Markovnikov product and the anti-Markovnikov product. This can challenge a catalyst system even more. The choice of amines for hydroamination includes aryl amines and alkyl amines, with a wide degree of steric bulk present in both. In 1990 Rothwell and co-workers made note of a bis(phenoxide)bis(amido) titanium complex carrying out the hydroamination reaction of 3-hexyne with aniline. 1 2 3 Since that initial report, research into hydroamination catalysis began with Cp-based catalyst systems and then evolved to non-Cp based catalysts. Contributions in both of these areas will be highlighted, and in all cases the type of hydroamination reaction that has been performed will be noted. Amidate complexes of group 4 metals have also been found to be a class of non-Cp based catalysts that are very reactive and regioselective for hydroamination reactions. Investigations to further the understanding of the hydroamination reaction and tune catalyst reactivity have been carried out in the form of SAR's , mechanistic studies, and 18 evaluation of the solid state molecular structures of the complexes. The results of these studies wil l also be presented. 1.3.1 H y d r o a m i n a t i o n w i t h C p - b a s e d l i g a n d se ts The first report of a Cp-based catalyst for hydroamination was reported in 1992 by Bergman and co-workers.124 Shown in Figure 1.14, the zirconocene complex 1 .18 (where R = 2,6-dimethylphenyl, ^-butyl) has been found to catalyze the hydroamination of symmetrically substituted internal alkynes with the very bulky 2,6-dimethylaniline. C P \ C \ C P \ C P \ ' n d \ c o / S i M e 3 Zr-^ 'NHR M - " M e T i ^ ' M e T i ^ ' M e T i - ^ 'Me V . ^ f Cp" NHR C | / ^ M e C p / ^ M e C p V ^ M e | n ( j - ^ M e T.^l l Cp R 1.18 1.19 1.20 1.21 1.22 1.23 F i g u r e 1 . 1 4 : Examples of Cp-based catalysts for catalytic hydroamination. Also in 1992, Livinghouse and co-workers reported 1 . 19 , where M = Ti , Zr for the intramolecular hydroamination of alkynes.1 2 5 Precatalyst 1 .20 , 1 . 21 , and 1 .22 have all been reported by Doye and co-workers some years later. Precatalyst 1 .20 can catalyze the hydroamination reaction between symmetrically substituted internal alkynes with both aryl and alkyl amines.1 2 6 It has also been shown that unsymmetrical internal alkynes are favorable for this reaction, but that terminal alkynes lead to low yields of products. This precatalyst has also been used with benzhydrylamine and internal alkynes;1 2 7 this has a synthetic advantage as the benzhydryl group can be removed via hydrogenolysis. It has also been shown that these hydroamination reactions can be greatly accelerated by using microwave radiation.1 2 8 Precatalyst 1 . 2 1 , containing the more bulky Cp* ligands, 19 was later reported to catalyze the hydroamination of internal, symmetrical alkynes with a variety of both aryl and alkyl amines. Again, terminal alkynes are not compatible with this precatalyst. The indenyl precatalyst 1.22 has been found to be more generally applicable to hydroamination reactions than its predecessors.130 Precatalyst 1 .22 can catalyze the reaction between internal, symmetrical alkynes with both aryl and alkyl amines. Furthermore, this precatalyst is also compatible with terminal alkynes, however the observed regioselectivity is not very high and is highly dependent upon the substrates used. For example, when aryl amines are used, regioselectivity for the Markovnikov product is observed with alkyl terminal alkynes, and regioselectivity for the anti-Markovnikov product is observed with aryl terminal alkynes. In general, this precatalyst is poor at catalyzing hydroamination with unhindered primary amines, though slow addition of the unhindered amine to the reaction does lead to the formation of some product. A later report with precatalyst 1 .22 demonstrates that gaseous primary amines, such as methyl- and ethylamine, are suitable substrates with both internal and terminal alkynes.1 3 1 No regioselectivity is observed with the terminal alkynes. Finally, Beller and co-workers have reported precatalyst 1 .23 for catalytic hydroamination (where R = SiMe3, Ph). 1 3 2 This precatalyst is again active in the hydroamination of internal alkynes with both aryl and bulky alkyl amines. Likewise, the hydroamination of terminal alkynes with f-butylamine shows good regioselectivity for the fl«ri-Markovnikov product; as the steric bulk in the primary amine decreases, the regioselectivity of the product decreases. The hydroamination of terminal alkynes with aniline, on the other hand, is regioselective for the Markovnikov product. It was also 20 later reported that as the steric bulk in the aryl amine increases, the selectivity for the Markovnikov product increases.133 A l l these reported precatalysts with Cp ligands share some characteristics. They all generally require high temperatures for the reactions to proceed (average 100 °C) and lengthy reaction times (24-72 h). Likewise, most Cp-based precatalysts are compatible with internal alkynes, but display much lower reactivity with terminal alkynes. With terminal alkynes, when they could be used with these precatalysts, the regioselectivity is dependent on the steric bulk of the primary amine. While some success has been realized in hydroamination with Cp based complexes, these limitations, along with the fact that modification of the Cp-backbone is non-trivial, prompted the investigation of non-Cp based ligand sets for catalytic hydroamination. 1.3.2 H y d r o a m i n a t i o n w i t h n o n - C p b a s e d l i g a n d se ts Precatalysts containing ligands other then Cp have been widely reported in the literature for catalytic hydroamination (Figure 1.15). In 2001, Odom and co-workers reported that the commercially available compound Ti(NMe2)4, 1 .24 , is active for the hydroamination of both internal and terminal alkynes with aniline and f-butylamine.134 In all cases, the regioselectivity favours the formation of the Markovnikov imine. Benzylamine also gives the Markovnikov product, but in low yields. In the same year, Odom and co-workers reported 1 .25 for the catalytic hydroamination of terminal and internal alkynes. With both aniline and cyclohexylamine, the selectivity has been found to favour the Markovnikov product.135 It is generally noted that the hydroamination of the internal alkynes with alkyl amines is slow. Benzylamine leads to a higher yield of 21 product with this precatalyst (relative to 1.24) and it is again noted to be Markovnikov selective. T i ( N M e 2 ) 4 1.24 Ti(NMe 2)2(dpma) , N . ^ ^ . N . op™=\_f N \ J 1.25 Ts i N \ i Ts 1.26 MeoN ' P r - N , i.r ,T i (NMe 2 ) 2 ' P r - N T i = N A r 'Pr M e 2 N r r Ar = 2,6-dimethylphenyl 1.27 T i (NMe 2 ) 2 (dap) 2 H N M e 2 dap = M \\ ll 1.28 Ti(NMe 2 ) 2 (dmpm) R , R H dmp'm: 1.29 P h H N . T i = N P h P h H N 1.30 / V0 - W i ( N M e 2 ) 2 1.31 Figure 1.15: Examples of hydroamination precatalysts containing non-Cp ligands. Bergman and co-workers reported in 2002 the non-Cp precatalyst (1.26) containing a bis(sulfonamido) ligand for intramolecular hydroamination of both alkynes and allenes.1 3 6 Also in 2002, the guanidinate imido complex 1.27 was reported by Richeson and co-workers.12 The substrate scope in this report is limited, though this catalyst is capable of promoting the hydroamination of terminal alkynes with bulky aryl amines; the regioselectivity depends on the terminal alkyne used. For example, 1.27 yields the anti-Markovnikov product when phenylacetylene is used, but the Markovnikov product when 1-hexyne is used. Odom and co-workers have been interested in using hydrazines as opposed to primary amines for hydroamination, and found that a new catalyst is required 22 for that transformation.137 Precatalyst 1 .28 has been shown to be successful in the hydroamination of terminal and unsymmetrical internal alkynes with hydrazines. When aryl hydrazines are used, Fischer cyclization could then occur in a one-pot process. Internal alkynes on the other hand are not very reactive substrates for this reaction. Odom and co-workers also reported another precatalyst similar to 1 .25 , but with a slightly different ligand set, 1 .29 (R = Me, Pr) . 1 3 8 Precatalyst 1 .29 has been found to have a similar substrate scope to 1 .25 , but the reactions occur faster. In 2004 Lorber and co-workers reported the titanium imido precatalyst 1 .30 for the hydroamination of 1-hexyne and aniline. 1 3 9 This catalyst shows Markovnikov selectivity for the above reaction. It is also successful for the hydroamination of internal alkynes, but it is noted that the terminal alkynes proceed faster. There is no reaction between 1-hexyne and benzylamine. Beller and co-workers reported a series of precatalysts of the type 1 . 3 1 , where there is variation in the R groups of the ligands. Initially it was reported that when R is a bulky r-butyl group, 1.31 is an active precatalyst for the hydroamination of terminal alkynes with both aryl and alkyl amines.1 4 0 There is a high regioselectivity for the Markovnikov imine, even when benzylamine is used as a substrate. Later it was reported that by simply switching the R group on the proligand to the slightly less bulky isopropylamine, the regioselectivity of the reaction changes to be selective for the anti-Markovnikov imine. 1 4 1 ' 1 4 2 This regioselectivity is again observed with benzylamine. The use of non-Cp ligand sets to synthesize group 4 metal complexes for catalytic hydroamination has expanded the scope of this reaction. In contrast to the Cp-based catalysts, the non-Cp based catalysts are generally more active for the hydroamination of terminal alkynes, and occasionally display very good regioselectivities. However, as is 23 evident from the summary presented above, regioselectivity is typically very dependant on the substrates used and generalized reactivity remains a challenge for this reaction. 1.3.3 Hydroamination with the amidate ligand set Previous work in the Schafer group showed the advantages of using the highly modular and easily synthesized amidate ligand set in the initial investigations into catalytic hydroamination.59 For example, when the three proligands 1.32, 1.33, and 1.34 shown in Figure 1.16 are used to synthesize bis(amidate)bis(amido) titanium complexes, the complex containing the more electron-withdrawing proligand (1.34) leads to a very active precatalyst for the intramolecular hydroamination reaction shown in eq. 1.6.59 F 1.32 1.33 1.34 Figure 1.16: Amide proligands with varying electronic properties. 5 mol% N 2 catalyst^ P h ^ N ^ "> C 6 D 6 ™ ( 1 . 6 ) This complex can perform the cyclization at room temperature in less than 15 minutes; Ti(NMe 2 )4 (1.24) performs this cyclization in 0.5 h at room temperature,136 and Cp2TiMe2 (1.20) requires 4 h at 110 °C. 1 4 3 Further advantages to this easily synthesized, highly tunable ligand set have been realized through an investigation that modified the steric bulk of the nitrogen-substituent of the proligand.60 Five bis(amidate)bis(amido) 24 titanium complexes were synthesized (Figure 1.17) with pro ligands of varying steric bulk. 1.37 L38 1.39 Figure 1.17: Hydroamination precatalysts with varying steric properties. These complexes were screened for activity in the more challenging intermolecular hydroamination reaction (eq. 1.7). Markovnikov ant/'-Markovnikov Complex 1.35 can not perform the intermolecular hydroamination reaction shown in eq. 1.7. However, as the steric bulk of the ligand increases, the activity of the metal complexes increases, and the time of the reaction decreases. Furthermore, the regioselectivity for the anri-Markovnikov imine drastically increases from 5:1 for 1.36 to > 99:1 for 1.39 while the yield of the reaction increases to 82%. 6 0 Hence, titanium 25 complex 1 .39 has been structurally characterized, and fully investigated for its abilities to catalyze other hydroamination reactions.144 In particular, 1 .39 has been found to be extremely regioselective for the awft'-Markovnikov imine when performing the hydroamination of terminal alkynes with primary amines, regardless of the steric bulk that is present in the primary amine substrate. Furthermore, it has been found to be active and regioselective with benzylamine, a notoriously difficult hydroamination substrate.126 This is advantageous for synthetic applications as the benzyl group can be removed via hydrogenolysis. Moreover, 1 .39 can tolerate protected alcohol and amine functionalities, silicon groups, carbonyls, esters, and amides, making this precatalyst attractive for use in organic synthesis.144 To date, this catalyst system remains the only example that displays this degree of regioselectivity and functional group tolerance. While precatalyst 1 .39 is very reactive with terminal alkynes, the reactivity decreases with both symmetrical and unsymmetrical internal alkynes. This is a common phenomenon observed in hydroamination catalysis. Catalysts that are effective for one type of hydroamination are often less effective for another. Likewise, 1 .39 is unable to catalyze the hydroamination with secondary amines. While synthetically this can be a weakness, this observation has implications for the reaction mechanism. There are two different mechanisms by which hydroamination has been shown to occur. The first is shown in Figure 1.18. This mechanism is often invoked for catalytic hydroamination of alkynes with lanthanide and group 3 complexes. 9 7' 1 0 2 26 LLnCH(TMS) 2 f - H 2 N R Figure 1.18: Proposed mechanism for catalytic hydroamination involving insertion into the Ln-N bond. The first step of this mechanism is reaction of the precatalyst with the primary amine to release the alkyl substituent (CH2(TMS)2) and generate the catalytically active lanthanide amide, 1.40. After coordination of the alkyne, there is insertion of the alkyne into the Ln-N bond to yield the lanthanide alkyl complex 1.41. Protonation of the Ln-C bond leads to the formation of the enamine and regenerates the lanthanide amide 1.40. The enamine will generally isomerize to the imine product. The second mechanism for catalytic hydroamination was first reported in the early 1990's when Bergman and co-workers published their initial work on catalytic hydroamination with Cp-based group 4 complexes.124 Doye and co-workers also did some mechanistic investigations into this reaction,145 and the general mechanism is shown in Figure 1.19. 27 Cp 2 T iMe 2 N R 1.46 c H 2 N R L2 L 1 Ti—(NHR )2 1.45 2 C H 4 / L 2 L 1 T i = N R 1.42 L\ L 2 = Cp, NHR NHR L 2 L 1 T i—NR 1 H 2 N R - ^ F i g u r e 1 . 1 9 : Proposed mechanism for catalytic hydroamination involving a metal-imido species. Reaction of the precatalyst with the primary amine generates the titanium imido species 1 .42 . After the alkyne coordinates to the metal center, it can undergo a [2+2] cycloaddition to form the metallocycle 1 .43 . Reaction of 1 .43 with a second equivalent of primary amine yields the mixed bis(amido) species 1 .44 . A final proton transfer generates the enamine (which can isomerize to the imine) and regenerates the catalytically active species 1 .42 . There are also several side reactions that can occur. One is the equilibrium between the titanium imido species 1 .42 and the bis(amido) species 1 . 4 5 , and the other is the equilibrium between the titanium imido species 1.42 and the dimer species 1 .46. The formation of both of these two species has been used to explain the low reactivity that is observed with the Cp complexes and non-bulky amines. 28 While the a-bond insertion mechanism (Figure 1.18) can utilize both primary and secondary amines as substrates, the metal-imido mechanism (Figure 1.19) can only be accomplished with primary amines since secondary amines are unable to form the requisite metal-imido bond. Due to the fact that 1.39 is unable to catalyze the hydroamination of any substrates with secondary amines, it is proposed that this catalyst system also follows the metal-imido mechanism. Furthermore, bis(amidate)imido titanium complexes have been synthesized in the Schafer laboratory as a result of the reaction between a bis(amidate)bis(amido) titanium complex with a stoichiometric amount of Mjutylamine.1 4 4 These bis(amidate)imido titanium complexes have also been shown to be very active for the hydroamination reaction. Precatalyst 1.39 has also been investigated for the hydroamination of different substrates, namely allenes and alkenes. Allene hydroamination is generally regarded to be more difficult than alkyne hydroamination, but more facile than alkene hydroamination. Precatalyst 1.39 has been found to be active in the intermolecular hydroamination of allenes with primary amines (aryl and alkyl). 1 4 6 The reactions require higher temperatures than the reactions with alkynes but are compatible with primary amines of varying steric bulk Likewise, the regioselectivity in these reactions is high. As alkene hydroamination is more difficult then both alkyne and allene hydroamination, initial investigations into this reaction have been focused on the intramolecular version (eq. 1.8). R R H 5 mol% cat. (1.8) R 29 This is a very desirable reaction, as nitrogen containing heterocycles are synthesized. There have been numerous examples of lanthanide complexes 96,101,104,107,109,113,147-151 ^ late transition metal complexes8 7'1 5 2"1 5 7 for aminoalkene hydroamination, and more recently, group 4 metal catalyzed aminoalkene hydroamination has been reported. There have been several reports of cationic group 4 complexes for this transformation158'159 as well as neutral group 4 complexes,160"164 including reports from the Schafer group. 1 6 5" 1 6 7 Presently, this is an on-going area of intense investigation. Overall, bis(amidate)bis(amido) complexes of group 4 metals have been shown to be very successful catalysts for the hydroamination of a number of substrates. In particular, bis(amidate)bis(amido) titanium complex 1.39 is a very active, very regioselective catalyst for the intermolecular hydroamination of terminal alkynes. Further applications of this precatalyst have been found in allene and alkene hydroamination, and modifications to the complex have led to active catalysts in alkene and asymmetric alkene hydroamination. The easily synthesized amidate ligand set allows for rational modifications to the catalyst design in order to maximize catalytic reactivity. 1.4 Scope of thesis The research in this thesis has been investigating two different areas in synthetic chemistry: the first has been methodology development, and the second has been catalyst development. As was mentioned above, precatalyst 1.39 has been shown to be extremely regioselective in the hydroamination of terminal alkynes, yielding only the anti-Markovnikov imine. Furthermore, the functional group tolerance of this catalyst greatly exceeds that which is normally attributed to group 4 metal complexes. With these two 30 factors in mind, the applications of 1.39 towards organic synthesis have been probed, namely by using the hydroamination generated imines as in situ intermediates. As this work represents the first Ph.D. project in the Schafer group to focus on organic synthesis and methodology development, the project began as a general screen of different possible synthetic applications of imines. The focus then became the development of tandem sequential C - N , C - C bond forming reaction sequences using hydroamination to synthesize the aldimine intermediates. This step could be combined with either the Strecker reaction or the Mannich reaction to lead to one-pot syntheses of a variety of nitrogen-containing functionalized small molecules. The combination of catalytic hydroamination with the Strecker reaction has led to a tandem sequential reaction sequence that can be used to synthesize alkyl oc-cyanoamines, a-amino acids and a-amino acid derivatives, P-amino alcohols, diamines, and imidazolidinones. As the typical Strecker reaction focuses on using aryl imines as substrates, the molecules synthesized via the tandem reaction sequence, which are all derived from alkyl imines, have generally not been reported in the literature. The development of the synthetic methodology for each class of molecules will be discussed. Furthermore, the combination of catalytic hydroamination with the Mannich reaction has led to a tandem sequential reaction sequence that can be used to synthesize p-amino acid derivatives, and the development of this methodology will also be presented. Again, this route has also led to the synthesis of a class of molecules that is typically not reported in the literature. Both of these tandem sequential reaction sequences utilize 1.39 to catalyze the hydroamination step in situ, and the simple change of the nucleophile directs the products that can be obtained. Likewise, the development of both tandem reaction 31 sequences has led to an increase in synthetic flexibility as the products of these reactions are now accessed from terminal alkynes, and importantly, carbonyl-containing molecules are not required. The mode of activation of the Strecker reaction in the tandem reaction sequence has been investigated in more detail. The insight that has been gained from the mechanistic investigations has been applied towards the development of both diastereoselective and enantioselective variations of this novel tandem reaction sequence. Since all the synthetic applications of the tandem hydroamination and the Strecker reaction have resulted in the formation of racemic products, it is desirable to develop an asymmetric version of this methodology. Furthermore, typical asymmetric Strecker reactions are often more limited in generality when alkyl imines are the substrates, and also use the dangerous and toxic HCN as the cyanide reagent. The development of the asymmetric version of this tandem reaction sequence addresses both of these concerns, as alkyl imines are the only substrates used, and TMSCN (a liquid) is the cyanide delivery reagent. While precatalyst 1.39 has shown some remarkable catalytic traits, there are still some drawbacks. This precatalyst is not a general precatalyst for all types of hydroamination reactions since the reactivity decreases with internal alkynes. It is also a very air and moisture sensitive complex, and hence precautions must be taken to prevent exposure of this precatalyst to the atmosphere. In addition to these drawbacks, it is also poorly understood why the use of 1.39 leads to such high reactivity and regioselectivity in the hydroamination of terminal alkynes or why there is such good functional group tolerance. In order to address some of these issues, two novel group 4 metal complexes 32 have been investigated using substituted pyrirriidinol proligands. Through investigations into catalytic reactivity for hydroamination, the effects of changing the electronics of the metal complex could be studied. The results of these investigations will be presented. Overall this thesis brings together two aspects involved in catalysis research: developing new methodology, and furthering the fundamental understanding of the hydroamination reaction. The applications of a previously synthesized precatalyst in organic synthesis have been probed and have resulted in the development of alternate methodologies for the synthesis of a number of highly functionalized, synthetically important small molecules. Likewise, the fundamental understanding of catalytic hydroamination has been furthered through the design and synthesis of two novel hydroamination precatalysts, and investigations into both their solid state molecular structures and their catalytic applications. 33 1.5 R e f e r e n c e s (1) Clark, J. H . Pure Appl. Chem. 2 0 0 1 , 73, 103. 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A. ; Schafer, L. L. Organometallics 2006, 25, 4069. Wood, M . C ; Leitch, D. C ; Yeung, C. S.; Kozak, J. A. ; Schafer, L. L. Angew. Chem., Int. Ed. 2007, 46, 354. 39 C H A P T E R T W O : S Y N T H E T I C APPLICATIONS O F T A N D E M C - N , C - C B O N D F O R M I N G R E A C T I O N S 2.1 Introduction 2.1.1 Hydroamination Hydroamination is the addition of nitrogen and hydrogen atoms across a carbon-carbon multiple bond. It is an atom economical reaction, as there are no byproducts that are formed. 1 In particular, the hydroamination of terminal alkynes (eq. 2.1) yields the synthesis of two isomeric products, the Markovnikov imine and the a«ft'-Markovnikov imine. R " = - H + H 2 N R 1 + R J ^ > (2.1) Markovnikov - ant/-Markovnikov Imines are very common and useful intermediates in organic synthesis. Typically these molecules are formed through a Schiff-base condensation reaction of aldehydes or ketones with amines, forming water as a byproduct (eq. 2.2). O N R 1 0 + H 2 N R ' U + H 2 0 (2.2) R H R H The resulting imines require isolation and purification before use in further synthetic steps i f water-sensitive reagents are to be used. Isolation and purification in the presence of atmospheric moisture can be problematic, especially with alkyl imines. Therefore, © Reprinted with permission from: Lee, A. V. ; Schafer, L . L . Synlett 2006, 2973. Copyright 2006 Georg Thieme Verlag Stuttgart-New York. 40 synthesizing these molecules directly via hydroamination is a desirable process, as no byproducts are formed during the reaction and the isolation of these moisture sensitive and often unstable intermediates is not required before use in further synthetic steps. However, the hydroamination reaction almost always requires the use of a catalyst; consequently research into new catalysts for this reaction is very active. Since the early 1990's, there have been numerous reports of group 4 metal complexes that are able to perform hydroamination reactions. These include complexes that contain Cp-based ligands,2"7 as well as those that do not contain Cp-based ligands.8"15 The Schafer group is very interested in designing non-Cp based ligand sets and applying them to group 4 catalyzed hydroamination reactions.16 In particular, titanium complex 2.1 is a very active and very regioselective hydroamination precatalyst.17 Only the an ^ '-Markovnikov imine is formed when performing the hydroamination of terminal alkynes with primary amines, regardless of the steric bulk that is present in the primary amine substrate. Moreover, 2.1 can tolerate protected alcohol and amine functionalities, silicon groups, carbonyls, esters and amides, all which make this precatalyst attractive for use in organic synthesis.18 To date, this catalyst system remains the only example that displays this degree of regioselectivity and functional group tolerance. 2.1 41 2.1.2 Tandem reaction sequences Due to the fact that there are no byproducts formed in the hydroamination reaction and the resulting imines are suitable for use in subsequent reactions without isolation, these hydroamination products may be used as reactive intermediates prepared in situ. This is particularly advantageous when synthesizing alkyl imines, as these molecules tend to be more hydrolytically unstable (relative to their aryl counterparts) and more difficult to isolate.1 9'2 0 Furthermore, since 2.1 is highly regioselective for the anti-Markovnikov imine, it is proposed that this transformation wil l be very well suited to synthesize more highly functionalized small molecules via a tandem reaction sequence. A tandem reaction sequence can be defined in different ways. First, a tandem * 01 reaction can refer to two reactions that follow one another. However, such a definition encompasses all reaction sequences in chemistry. Second, and more specifically, a tandem reaction sequence can be defined as one that links several transformations together in a single step, or reactions that are carried out in a single reaction vessel without the necessity of purification at each step.23 Third, and even more specific, is defining a tandem reaction sequence as one where the initial reaction produces an intermediate that then undergoes further transformations (for example intramolecularly, intermolecularly, or with the addition of reagents).22 Different authors define tandem reactions in slightly different ways depending on their particular reaction sequences.24 For the purposes of this thesis, tandem reactions are defined as a series of one-pot reactions where the first reaction step yields an intermediate that is required for the second reaction step. This second reaction step in turn requires the addition of other reagents. These can also be referred to as tandem sequential reactions. Tandem 42 sequential reactions are desirable in organic chemistry as they increase the synthetic efficiency by decreasing the number of laboratory operations. They also lead to a decrease in the quantities of chemicals and solvents that are required. In this age of green chemistry and environmental concern, this is a very important consideration in synthesis.22 There are numerous examples of tandem reaction sequences with many different types of reactions in the literature, and several reviews have been written on the topic. 2 1 ' 2 2 ' 2 4 ' 2 5 Examples include tandem ring-closing metathesis-olefin isomerization,23 tandem transannular Diels-Alder reactions,26 tandem Stille-Suzuki-Miyaura coupling reactions,27 tandem Pd catalyzed alkylation-direct arylation reactions,28 tandem Wolff-Cope rearrangements,29 and tandem cross metathesis-ring closing metathesis reactions.30 Furthermore, there have been several examples of using group 4 catalyzed hydroamination in tandem reaction sequences. For example, hydroamination of internal alkynes has been used to synthesize imines followed by the nucleophilic addition of diethyl or dimethyl phosphate with a catalytic amount of Me2AlCl (eq. 2.3).31 The intramolecular version of this reaction has also been performed, leading to the synthesis of both cyclic and acyclic a,a-disubstituted a-amino phosphonates. Alkyl lithium reagents have also been added to hydroamination generated imines (eq. 2.4). This transformation results in the synthesis of branched secondary amines.32 ,2 + (2.3) 43 (2.4) cat. = Cp 2 T i (Me 3 Si = S iMe 3 ) Tryptamine and their homologues have been synthesized using a tandem hydroamination-[3,3] sigmatropic rearrangement reaction sequence as shown in eq. 2.5. 3 3 (2.5) The hydroamination of the chloroalkyne with an aryl hydrazine leads to the formation of TV-aryl-A^-chloro-alkylhydrazone. A [3,3] sigmatropic rearrangement forms the indole, and nucleophilic substitution of the halide by the liberated ammonia completes the sequence. Furthermore, a very similar reaction sequence with only a slight change in starting materials has been used by the same research group to synthesize tryptophols and their homologues.34 Group 4 catalyzed hydroamination has also been combined with C -H insertion reactions, such as the one shown in Scheme 2.1. 3 5 In this sequence, the hydroamination of enynes leads to the formation of a,P-unsaturated imines. From that point, a C - H activation-alkyne insertion reaction is performed followed by a 6-electron electrocyclization to synthesize the dihydropyridine. 44 V - = + H 2 N P h NPh 1 ) 5 0 m o l % H 2 O 2) E t - -Et 2 mol% RhCI(PPh 3 ) 3 \NMe2 Me, - ' E t w / E t /—L NPh CM 6 Tt e- electrocyclization olefin isomerization Scheme 2.1: Tandem hydroamination C - H activation reaction sequence. Other nitrogen containing heterocycles such as indoles have been formed through the tandem hydroamination-Heck cyclization reaction sequence in eq. 2.6. 3 6 Cl N H , + Ph- -Et 1 )T iC I 4 / 'BuNH 2 2) 5 mol% Pd(dba) 2 5 mol% NHC-HCI/KO'Bu Ph 4, -Et (2.6) Finally, secondary amines have been synthesized directly from the hydroamination of internal alkynes. Typically, this transformation is carried out using a reducing agent such as NaCNBH3 with a Lewis acid such as ZnCL. after the imines are formed via hydroamination. In the reaction sequence shown in eq. 2.7, a Ti(IV) metal complex is used to synthesize the imine; a Ti(III) species is then proposed to be formed in situ from the initial Cp2TiMe2, and this is used to catalyze the hydrosilylation portion of this reaction.37 The secondary amines are formed from the aqueous workup of the TMS-protected amines. 4 5 R Cp2~nMe2 N R 3 PhSiHs/piperidine N H R3 H 2 N R 3 + MeOH (2.7) Catalytic hydroamination is an ideal reaction for incorporation into tandem reaction sequences as is demonstrated in the aforementioned examples. Hydroamination is still a relatively new area of research, new catalysts continue to be developed, and consequently their application in tandem reaction sequences remains a rich area of investigation. The application of the new family of bis(amidate)bis(amido) complexes for hydroamination in tandem reaction sequences results in quantitative conversions to products, unprecedented regioselectivity, and reliable access to reactive aldimine (anti-Markovnikov) intermediates. Furthermore, to increase the synthetic applicability, these hydroamination precatalysts have been shown to be very tolerant of different functional groups. There are a number of different reactions using imines as intermediates that are appropriate for combination with catalytic hydroamination. By simply changing the nucleophile, a variety of tandem sequential C - N , C - C bond forming reactions can be developed. In particular, after initial screening, the Strecker reaction and the Mannich reaction have been targeted for the development of tandem sequential C - N , C - C bond forming reaction sequences utilizing hydroamination to generate the imines. These two methodologies result in the synthesis of a-amino acid derivatives and P-amino acid derivatives respectively, along with other highly functionalized small molecules 2.1.3 Scope of project This project is the first investigation in the Schafer group into the applications of catalysis in organic synthesis and methodology development. While a number of 46 different reactions have been surveyed for combination with catalytic hydroamination, this chapter addresses the development of reliable and general methodologies for the Strecker reaction and the Mannich reaction. The combination of hydroamination with the Strecker reaction gives a-cyanoamines that are then used to synthesize highly functionalized small molecules, including a-amino acid derivatives, P-amino alcohols, diamines, and nitrogen-containing heterocycles. Furthermore, by simply utilizing a different nucleophile, catalytic hydroamination has been combined with the Mannich reaction to synthesize P-amino acid derivatives. Both of these tandem methodologies have increased the substrate scope of the respective reactions, relative to what is currently reported in the literature. Furthermore, these preparative routes represent alternative synthetic approaches towards these nitrogen-containing small molecules by using terminal alkynes rather than carbonyl-containing starting materials. Therefore, this chapter presents the development of the synthetic methodologies for two tandem C - N , C - C bond forming reaction sequences using hydroamination with either the Strecker reaction or the Mannich reaction. 2 .2 T a n d e m s e q u e n t i a l r e a c t i o n s u s i n g h y d r o a m i n a t i o n a n d t h e S t r e c k e r r e a c t i o n 2 .2 .1 S y n t h e s i s o f a - c y a n o a m i n e s 2 .2 .1 .1 I n t r o d u c t i o n 2 .2 .1 .1 .1 T h e S t r e c k e r r e a c t i o n The Strecker reaction (eq. 2.8) was first reported in 1850 when the observation was made that the combination of an aldehyde, ammonia, and hydrogen cyanide leads to the formation of a new product, an a-cyanoamine.38 47 (2.8) Since that time, the Strecker reaction has been a very active area of research. A number of different reagents have been found to deliver the cyanide moiety in addition to H C N 3 9 such as T M S C N , 4 0 diethyl phosphocyanidate,41 K C N , 4 2 and E t 2 A l C N 4 3 Likewise, a number of different reagents have been added to the reactions in order to promote cyanide addition to the imine, most notably Lewis acids. Examples of the many Lewis acids that can be used in the Strecker reaction include AICI3 4 0 L1CI3,42 polymeric scandium triflamide,44 NiCl2,45 and Yb(OTf)3. 4 6 It has also been shown that by using acetonitrile as a solvent, no Lewis acid is required for the Strecker reaction.47 Variations of the imines that are used for this transformation have been explored, and include the use of sulfinimines,48 sulfonylimines,49 a-amide sulfones,50 and a,p-unsaturated imines.5 1 More complex catalyst systems have been explored for the Strecker reaction, including titanium catalysts with amino alcohol ligands,52 and titanium and vanadium complexes with salen ligands.53 Many of these reports only use aryl imines generated from carbonyl-containing compounds for their investigations and so tend to have a limited substrate scope. When alkyl imines are used in the Strecker reaction, they typically do not contain a-protons. Even more rarely reported is the use of alkyl imines that contain an a-methylene unit; the occurrence of this functionality wil l be highlighted in the upcoming sections. A variation on the Strecker reaction has been reported in the literature that also uses carbonyl-containing molecules as starting materials, and leads to the formation of a-48 cyanoamines. Using bis(dialkylamino)cyanoboranes as a starting material, ct-cyanoamines are synthesized from aldehydes (eq. 2.9). R1 R1 1 • , O N' R1\ ,R1 R ^ H + N O ' S ' * * X (2-9) R 1 F T X N This specialized bis(dialkylamino)cyanoborane reagent transfers both the amino and the cyano groups to the aldehyde starting material. The a-cyanoamines are synthesized in excellent yields and initial investigations show good substrate scope,54 including some alkyl examples with a-protons. Furthermore this methodology has been extended to the synthesis of a-cyanoamines with a wide variety of functional groups, including protected alcohols, amines, and ferrocene units.55 It should be noted that all products that are synthesized using this methodology contain a tertiary nitrogen atom. Since a new stereocenter can be formed in the Strecker reaction, there is a lot of interest in the development of asymmetric catalysts that can synthesize a-cyanoamines in enantiopure form. A number of these catalyst systems will be presented in the following section. Again, the substrates are generally restricted to aryl imines, and hence the less common use of alkyl imines as substrates will be highlighted. It should be noted that in all of these reports, the imines are synthesized from carbonyl-containing compounds and are isolated and purified prior to their use in the Strecker reaction. Furthermore, most of these developed catalytic systems are restricted to the use of H C N as the cyanide source. In 1996, the first asymmetric catalyst (2.2) was reported by Lipton and co-workers for the Strecker reaction.39 49 H 2.2 This cyclic dipetide organocatalyst is used in combination with H C N to synthesize a-cyanoamines from preformed aryl imines with good yields (71-98%) and enantiomeric excesses (ee's) (< 10 to 99%). There are few examples of this catalyst with alkyl imines (results had ee's < 20%) and notably there are no examples of imines with a-methylene protons. Following this initial publication, other catalysts have been reported for the asymmetric Strecker reaction (Figure 2.1) by various research groups. Complex 2.3 was the first asymmetric catalyst for the Strecker reaction that utilized T M S C N instead of the more dangerous H C N as the source of the nucleophile. This catalyst system is compatible with both aryl and alkyl imines that contain the relatively bulky fluorenyl protecting group on the nitrogen. The reported ee's (79-95%) and yields (> 90%) are excellent for the aryl systems though these decrease to ee's of 70-80% for alkyl systems that contain a-methylene protons (yields 80-84%). Alkyl examples that do not contain an a-methylene unit result in ee's from 72-96% and yields from 66-97%. 5 6 50 X X = P ( 0 ) P h 2 , C H 2 P h 2.3 2.4 2.5 2.6 Figure 2.1: Literature examples of catalysts used to promote the Strecker reaction. Chiral AyV-dioxide complexes, such as 2.4, promote the Strecker reaction with high yields (30-96%) and ee's (12-99%), but only the aryl imine substrates with bulky benzhydryl groups on the nitrogen have been reported.57 Various thiourea derivatives (2.5) have been investigated for the asymmetric Strecker reaction of aryl imines and while high conversions are sometimes obtained (0-100%), the ee's of the reactions are generally low (2-68%).5 8 Finally, more recently, phase transfer catalysts, such as 2.6, have been used with K C N as the nucleophile in combination with a number of alkyl 51 imines. Alkyl examples where there is not an a-methylene unit display good yields (85-98%) and ee's (93-98%); the two alkyl examples that do contain an a-methylene unit show slightly lower yields (81-82%) and ee's (88-90%).59 Several research groups have been very active in the literature reporting a number of different catalyst systems for the Strecker reaction. This includes the research groups of Corey, Hoveyda and Snapper, Kobayashi, and Jacobsen; the contributions of each of these research groups to this area will be discussed in turn. Corey and co-workers have designed two different organocatalysts for the Strecker reaction, both of which are shown in Figure 2.2. The chiral, bicyclic guanidine complex 2.7 has been used in the Strecker reaction of aryl imines with benzhydryl substituents with H C N . 6 0 Figure 2.2: Catalysts designed by Corey and co-workers for the Strecker reaction. This catalyst gives high yields of the products (80-99%) and ee's in the range of 50-88%. However, only aryl imines have been investigated, and the ee's decrease when the benzhydryl substituent on the nitrogen atom is absent. The Strecker reaction of aryl imines with allyl substituents on the nitrogen proceeds with high yields (88-96%) and 2.7 2.8 52 ee's (79 to > 99%) with catalyst 2.8.61 However, the substrate scope is limited to that particular substrate combination. The research groups of Hoveyda and Snapper have studied tripeptide Schiff base complexes for the in situ generation of Ti complexes to catalyze the Strecker reaction (Figure 2.3). Ligand 2.9 is combined with Ti(0'Pr) 4, T M S C N , and a protic additive (such as isopropyl alcohol) and results in the addition of cyanide to a number of aryl imines, all of which contain a benzhydryl substituent on the nitrogen atom (yields 80-97%, ee's 85 to > 99%). A variation of this ligand structure, 2.10, gives a complex that is effective for the Strecker reaction of a,|3-unsaturated imines with benzhydryl nitrogen substituents (yields 61-93%, ee's 76-97%).6 3 The substrate scope of the investigation is limited, though the importance of the structural features in the ligand backbone have been probed through detailed mechanistic investigations.64 2.9 2.10 Figure 2.3: Tripeptide ligands investigated for Ti-catalyzed Strecker reaction by Hoveyda and Snapper. Kobayashi and co-workers have also been very active in investigating the Strecker reaction. For example, they found that Sc(OTf)3 will promote the Strecker reaction with BuaSnCN in aqueous media using both aryl and alkyl imines with a benzhydryl substituent on the nitrogen.65 Likewise, it has been shown that Yb(OTf) 3 will 53 perform the Strecker reaction of imines preferentially in the presence of aldehydes.66 Examples in this report include both aryl and alkyl imines, some of which contained a-protons. Furthermore, the chiral binuclear zirconium complex, 2.11 (L = N-methylimidazole) (Figure 2.4) has been synthesized, characterized, and investigated for its proficiency at catalyzing the Strecker reaction. L = N-methylimidazole 2.11 Figure 2.4: Chiral Zr catalyst used for the Strecker reaction by Kobayashi and co-workers. In combination with Bu 3 SnCN, 2.11 is able to catalyze the Strecker reaction of both aryl and alkyl imines, some containing a-protons.67 The yields of this reaction are good (79-98%) and the ee's range from 83-92% for the aryl examples and alkyl examples that do not contain an a-methylene unit. The two examples utilizing imines with an a-methylene unit have lower yields of 55% and 72% and lower ee's of 83% and 74%, respectively. A l l the imines used have an aryl group on the nitrogen with a hydroxyl group in the ortho position. This hydroxyl group has been found to be essential for the obtained ee's and yields of the reactions. Importantly, 2.11 can be used in a three-component reaction with the aldehyde, amine, and H C N with a similar substrate scope.69 Jacobsen and co-workers have also been very active in investigating catalysts to promote the asymmetric Strecker reaction. Two of the metal based catalysts that have 54 been developed are shown in Figure 2.5. The chiral (salen)Al(III) complex, 2.12, has been shown to perform the Strecker reaction with aryl imines in good yields (91-99%) and ee's (37-95%) using H C N as the cyanide source.70 Some alkyl imines are also reported (without a-methylene protons), with lower yields (69-77%) and low ee's (37-57%). Compound 2.13 has been used as a ligand with ErCb and was found to carry out the Strecker reaction with hydrazones and H C N . 7 1 Once again the scope of this reaction is limited to mostly aryl hydrazones, and the alkyl hydrazones give lower ee's. Figure 2.5: Metal based systems used for the Strecker reaction by Jacobsen and co-workers. This research group also has a number of organocatalysts that they have investigated for the Strecker reaction. Compound 2.14 in Figure 2.6 has been identified after using a parallel library combinatorial approach.72 Optimization of the reaction conditions resulted in an increase in ee's from 19% to 91%, though this is with a limited number of examples. Further optimization led to the synthesis of organocatalyst 2.15 that can be used in solution, or as a solid-phase catalyst.73 There are many examples of the formation of a-cyanoamines with these catalysts in combination with H C N , including both aryl and alkyl imines with both benzyl and allyl substituents on the nitrogen (yields 65-99%; ee's 2.12 2.13 55 77-97%). However, there are only two examples that contained a-methylene protons in the substrate (yields 69-85%; ee's 78-90%). 2.14 2.15 F i g u r e 2 . 6 : Organocatalysts used for the Strecker reaction by Jacobsen and co-workers. There have been some very successful catalyst systems developed for the Strecker reaction that achieve high yields and ee's when using aryl imines as the starting materials. While there are also some examples of alkyl imines for this reaction, they are by far the minority of the substrates that are presented, and tend to display a decrease in yields and/or ee's. Furthermore, all of the methodologies illustrated in the above section utilize carbonyl-containing compounds as a common starting material. The imines that are then synthesized from these carbonyl-containing compounds require isolation and rigorous purification before use in the Strecker reaction sequence. Thus, the use of terminal alkynes as precursors to imines that do not require isolation simplifies the Strecker reaction sequence. 2 . 2 . 1 . 1 . 2 A l t e r n a t i v e l i t e r a t u r e m e t h o d s f o r t h e s y n t h e s i s o f a - c y a n o a m i n e s While the Strecker reaction is the most common method for the synthesis of a-cyanoamines, there have been several other methods reported in the literature for the 56 synthesis of this class of molecules. The notable difference between the methodologies described in the upcoming section and those in the preceding section are the starting materials. A l l of the following examples utilize non-carbonyl containing starting materials. a-Cyanoamines containing an unprotected indole functionality, as shown in eq. 2.10, can be synthesized from 2,3,5,6-tetrahydropyridines.74,75 (2.10) 2-Cyano-2,3,5,6-tetrahydropyridines are synthesized by the 9,10-dicyanoanthracene (DC A)-sensitized photo-oxygenation of the starting material by irradiation with hv in the presence of both oxygen and TMSCN. The T M S C N acts as a trapping agent in this reaction to yield the final a-cyanoamine. Anodic oxidation has also been used to synthesize a-cyanoamines as shown in eq. 2.11. In this reaction, 6-membered a-silylamines undergo an electrochemical reaction in the presence of NaCN to yield the a-cyanoamine.76 (2.11) 57 This reaction methodology lacks generality, and is confined to TV-benzyl substituted cyclic six-membered rings with a trimethylsilyl group alpha to the nitrogen. a-Cyanoamines can also be synthesized through the oxidation of tertiary amines, as shown in eq. 2 . 1 2 . 7 7 R 1 R 1 R 2 ^ N ^ R 3 + NaCN R ^ C l 3 . R 2 , N ^ R 3 (2.12) C N This reaction methodology is very similar to the Strecker reaction in that there is nucleophilic addition of the cyanide to an iminium ion. The initial step is aerobic oxidation of the tertiary amine to an iminium ion by a catalytic amount of R .UCI3 and oxygen, followed by addition of the cyanide nucleophile (in the form of NaCN) to this iminium ion to yield the a-cyanoamine. While the reaction conditions are relatively mild, the substrate scope is limited. These aforementioned examples all lead to the synthesis of a-cyanoamines without using carbonyl-containing molecules as starting materials. However, the generality of these methodologies is limited, and typically only very specific a-cyanoamines can be synthesized. In comparison, the Strecker reaction is by far the most general and widely applicable method for the synthesis of a-cyanoamines. 2.2.1.1.3 Reported uses of a-cyanoamines The products of the Strecker reaction after addition of the cyanide functionality to the imine are a-cyanoamines, which are also known as a-amino nitriles. a-Cyanoamines are present in natural products and natural product analogues, and they are synthetically 58 important as they can be transformed into other useful functionalities that are often employed in synthesis. In 1999 Martinez and Corey synthesized two complex molecules containing the a-cyanoamine unit.7 8 Shown in Figure 2.7 is the natural product saframycin A and a synthetic analogue, phthalascidin.78 Both these compounds have been shown to have anti-tumor activity, where phthalascidin is more active than saframycin A. saframycin A phthalascidin Figure 2.7: Literature examples of a natural product and synthetic analogue containing the a-cyanoamine functionality. From a synthetic standpoint, a-cyanoamines are stable precursors to iminium ions (Figure 2.8a); cyanide loss can occur by treatment with silver or copper salts, Bronsted or Lewis acids, or thermolysis.79 Furthermore, a-cyanoamines can be hydrolyzed to a-amino acids (Figure 2.8b), reduced to diamines (Figure 2.8c), or deprotonated to form nucleophiles (Figure 2.8d). 59 E + = electrophile Figure 2.8: Potential synthetic transformations of a-cyanoamines. The versatility of the a-cyanoamine functionality has been exploited in a number of synthetic strategies.80"83 A three component [1+2+3] annulation strategy has been reported in the literature that takes advantage of the dual ability of a-cyanoamines to act both as nucleophiles and as masked iminium ions (eq. 2.13).84 The first step of this synthetic sequence involves a deprotonated a-cyanoamine acting as a nucleophile in a Michael addition to the a,P-unsaturated lactone. Treatment of the resultant a-cyanoamine with AgOTf leads to the formation of the iminium ion, which then undergoes cyclization with the neighbouring nucleophilic allyl silane moiety to form 60 the final product. This strategy is limited to using aryl cyanoamines; reliable access to alkyl cyanoamines would expand the classes of compounds that could be formed. Overall, a-cyanoamines are an important class of molecules. The functionality appears in natural products and pharmaceutically relevant compounds. Furthermore, the synthetic versatility exhibited by a-cyanoamines has been shown to be very useful in a number of synthetic strategies towards the synthesis of other key classes of molecules. Therefore, increasing the scope of a-cyanoamines that can be reliably synthesized is a valuable contribution. 2.2.1.1.4 Development of a hydroamination tandem sequential reaction Despite all the successes of the asymmetric Strecker reaction discussed above, a significant challenge is the notable lack of substrate scope. As was identified earlier, the majority of the work that has been done with the Strecker reaction is done with aryl imines that are synthesized and isolated from carbonyl-containing compounds. The hydrolytic instability of alkyl imines makes this isolation step more challenging. In fact, it has been noted in a review on Strecker chemistry that it is advantageous to directly access Strecker products without the isolation of the preformed imines.1 9 The combination of catalytic hydroamination and the Strecker reaction accomplishes this goal. There are no byproducts after the initial hydroamination reaction, thus the imines do not require isolation. Therefore, access to alkyl imines is facilitated, and the scope of the Strecker reaction is readily expanded to include these products. It has been noted that while reactions using alkyl imines are limited in general, they are even more limited when there are a-protons in the substrate.20 This was also 61 observed while surveying the literature on the Strecker reaction. By combining catalytic hydroamination with the Strecker reaction a tandem reaction sequence is formed leading to the synthesis of alkyl a-cyanoamines containing a methylene unit alpha to the newly formed stereocenter (eq. 2.14). Overall, this tandem sequential strategy contributes to expanding the substrate scope of the Strecker reaction. Along with an increase in substrate scope, there are other advantages resulting from this tandem reaction sequence. In contrast to all the Strecker reaction methodologies discussed above (that use carbonyl-containing compounds as starting materials), the imines can now be formed from terminal alkynes and the need for carbonyl-containing molecules is eliminated. This leads to an alternate synthetic strategy where terminal alkynes are now acting as masked carbonyl-containing molecules. This would be most advantageous in longer reaction sequences in which carrying carbonyl groups through multiple synthetic steps can be problematic due to the need to protect and deprotect the carbonyl unit. It will also provide the chemist with more flexibility in choosing the starting materials for a reaction. In examining the reaction conditions that are used in the asymmetric Strecker reactions described earlier, the vast majority of the examples utilize H C N as the cyanide source. H C N is a dangerous and toxic gaseous reagent, and while it is widely used industrially, it is not an ideal reagent for bench-top laboratory research, especially with small scale reactions. Therefore, T M S C N has been targeted as the cyanide delivery H H + (2.14) C N 62 reagent for the tandem sequential reaction sequence developed here. Furthermore, although the initial developments of the tandem sequential reaction sequence have resulted in the formation of racemic products, a stereoselective version of this methodology using T M S C N is also desirable, and progress toward this synthetic achievement will be presented in the following chapter of this thesis. This hydroamination tandem reaction sequence can readily lead to the synthesis of other highly functionalized nitrogen-containing small molecules (Figure 2.9) that were previously not accessible through other methodologies. For example, the alkyl a-amino acid derivatives, P-amino alcohols, vicinal diamines, and heterocycles that can be accessed through this tandem reaction sequence all exhibit an increased substrate scope, and all contain at least one methylene spacer between the functionality in the backbone (R) and the stereocenter. Likewise, the same synthetic flexibility discussed above is also afforded to these classes of molecules as they are all synthesized from terminal alkynes. R -+ H 2 N R 1 tandem reaction sequence N H R 1 C N a-cyanoamines N H R R 2 = N H 2 , O H , O C H 3 a-amino acid derivatives N H R * N H 2 diamines ^ R ^ N H R ^ O H P-amino alcohols R 1 N H imidazolidinones Figure 2.9: Classes of highly functionalized small molecules that can be synthesized using this tandem sequential reaction sequence. 63 While this type of functional group transformation is possible with all Strecker reactions that have been reported, it is rarely carried out, and when it is, it is generally involving one example of an aryl a-cyanoamine used to synthesize an a-amino acid derivative. A survey of the literature reveals that few examples of the synthesis of alkyl a-cyanoamines have been reported, and even fewer of these molecules have been utilized in further transformations. For example, in all the reports on Strecker methodology discussed above, only two alkyl a-amino acid derivatives have been synthesized using previously established methodologies (Figure 2.10). 2.16 2.17 Figure 2.10: The only two examples of alkyl a-amino acid derivatives discussed in reports on current Strecker reaction research. Compound 2.16 has been reported by Jacobsen and co-workers73 and compound 2.17 has been reported by Kobayashi and coworkers.67 Notably, only compound 2.17 contains a methylene unit alpha to the stereocenter. It is hypothesized that i f the tandem reaction sequence resulting from catalytic hydroamination and the Strecker reaction is successful, then this approach could be readily extended to synthesize other highly functionalized small molecules that are presently unreported, resulting in a broadly applicable methodology. 64 2 . 2 . 1 . 2 R e s u l t s a n d d i s c u s s i o n 2 .2 .1 .2 .1 a - C y a n o a m i n e s v i a h y d r o a m i n a t i o n t a n d e m r e a c t i o n s e q u e n c e In order to begin investigations into tandem C - N , C - C bond forming reactions utilizing catalytic hydroamination, the proligand ( 2 . 18 ) and hydroamination precatalyst (2 .1 ) are first synthesized. The amide proligand is synthesized on multi-gram scale in a one-step addition reaction of 2,6-diisopropylaniline to benzoyl chloride in the presence of triethylamine (eq. 2.15). JL + H 2 N ^ > „ n r j j + H N E t 3 C I ( 2 . 1 5 ) CH 2CI 2/r.t./1 h The synthesis of the bis(amidate)bis(amido) titanium precatalyst 2 .1 is shown in eq. 2.16. T i ( N R 2 ) 4 ^ _ ( p h - < 0 > i ( N R 2 ) 2 + 2 H N R 2 (2.16) -78 ° C t o r.t . /3 h \ I N U i 8  ./   | 7 / 2 R = Me, Et J k J 2.18 2.1 A protonolysis reaction between two equivalents of 2 . 1 8 and one equivalent of tetrakis(dialkylamido) titanium(IV) forms complex 2 . 1 . The formation of 2.1 is marked by a dramatic colour change from pale yellow to deep red. After 3 h at room temperature, the ether is removed under reduced pressure on a vacuum line, and the reaction mixture is brought into the nitrogen-filled glovebox. The crude solid is 65 redissolved in hexanes, filtered through Celite™, and then concentrated to a red solid. No further purification is required before using 2.1 as a hydroamination precatalyst.17 In developing a tandem C - N , C - C bond forming reaction sequence from hydroamination and the Strecker reaction, T M S C N is targeted to deliver the cyanide functionality. The initial reaction that is used to screen for reactivity is shown in eq. 2.17. In order to form the required imines, a terminal alkyne is combined with a primary amine and 5 mol% of 2.1 in deuterated benzene. The solution is then heated to 65 °C for 12 h in a J. Young N M R tube. There is quantitative conversion of the alkyne starting material to the aldimine product, as evidenced by the diagnostic triplet for the aldimine peak at approximately 7.4 ppm in the ! H N M R spectrum (Figure 2.11). R = H + 2H2NR •, 1)5 mol% 2.1/C6D6/65 °C/12 h TMS-. .R N (2.17) 2.19-2.24 66 i j jTrT, „ t .. m .! ,n , t t ..^ ^vJTtH n WBMJ ^ W»tBftia«J faaal Ctofrtcaisitaaym) Figure 2.11: 300 MHz ! H N M R spectrum of an aldimine in C6D6 showing diagnostic triplet at 7.4 ppm. At this stage, imine formation can also be confirmed by 1 3 C N M R spectroscopy, where the aldimine carbon is observed between 156 and 165 ppm, depending on the substrate combination. Then, T M S C N is added directly to the J. Young N M R tube containing the in situ formed aldimine at room temperature via syringe, and the reaction progress is monitored by *H N M R spectroscopy. This reaction is very rapid, as there is never any spectroscopic evidence of aldimine in the N M R tube after the addition of T M S C N , regardless of how quickly N M R spectroscopy is performed. Furthermore, the 1 3 C N M R spectrum reveals a diagnostic peak at 120 ppm, attributed to the nitrile carbon of the TMS-protected a-cyanoamine, which is shifted from 126 ppm for the nitrile in the T M S C N reagent. There is a 100% conversion of aldimine as confirmed by the lH N M R spectrum, and a number of these reactions are performed in the presence of an internal standard (1,3,5-trimethoxybenzene) to quantify the yield of the reaction (Table 2.1). 67 T a b l e 2 . 1 : Yields of TMS-protected a-cyanoamines synthesized via the combination of hydroamination and the Strecker reaction in eq. 2.17. E n t r y C o m p o u n d T M S - p r o t e c t e d a-C y a n o a m i n e R 1 % Y i e l d 1 2 . 1 9 TMS ^ \ ^ N . , Bn 90" 2 2 . 2 0 o n ; 'Pr 89" 3 2 .21 TMS. R1 Bn quant.6 4 2 . 2 2 'Pr quant.6 5 2 . 2 3 TMS R 1 N Bn 98" 6 2 . 2 4 'Pr 86° "Yield calculated by H N M R spectroscopy of the formation of TMS-cyanoamine using 1,3,5-trimethoxybenzene as an internal standard. ^Conversion of imine calculated from *H N M R spectroscopy based on disappearance of signal. Three different alkynes are targeted for these investigations, including aryl substituted alkyl alkynes and long-chain alkyl alkynes. Likewise, three different primary amines are chosen, of varying steric bulk. However, very little reaction between the aldimine and the T M S C N is observed when R 1 is equal to ?-butyl; presumably this is due to prohibitive steric hindrance between the bulky f-butyl group and the bulky trimethylsilyl group. Even when heat is applied to the reaction, the reactions with ^-butylamine never proceed to completion. In general, with the other substrate combinations, it is observed that this reaction is very high yielding over two steps. In certain cases, namely entries 3 and 4, the *H N M R spectra are too complicated to confidently assign the product peak required to determine the yield by ' H N M R spectroscopy. These promising initial screening reactions performed on an N M R tube reaction scale support further investigation of these reactions on preparatory scale. For these larger scale reactions (100 mg of alkyne starting 68 material), after formation of the TMS-protected a-cyanoamines, the reaction is quenched with saturated ammonium chloride to form a-cyanoamines (eq. 2.18). " H 1 ) 5 m o l % 2 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h ™ S ^ N ' R 3) NH 4CI (sat.) H?NR 2) TMSCN/r.t./3 h HN . R 1 R ^ ' ^ C N 2.19-2.24 C N 2.25 - 2.30 (2.18) The isolated racemic a-cyanoamines (2.25 to 2.30) resulting from quenching of the TMS-protected a-cyanoamines (2.19 to 2.24) are shown below in Figure 2.12. CN 2.25 ,Ph c o - ; 2.26 2.28 HN Ph C N 2.29 H N ' CN 2.30 Figure 2.12: a-Cyanoamines that have been synthesized quantitatively through tandem catalytic hydroamination and the Strecker reaction sequence. The *H N M R spectra of 2.25-2.30 do not show the presence of any side products from the reaction. However, the reaction mixture still contains the amide proligand 2.18 from the initial hydroamination step (example shown in Figure 2.13) in approximately 9-13% of the total isolated reaction mixture. 69 F i g u r e 2 . 1 3 : 300 M H z lH N M R spectrum of crude 2 . 2 9 in CeD6 with contamination from proligand 2 . 1 8 . Purification of compounds 2 . 2 5 - 2 . 3 0 to separate the a-cyanoamines from 2 . 1 8 is problematic. Column chromatography with numerous solvent systems leads only to decomposition of the products, which is consistent with a previous literature report.85 Attempts to selectively remove one compound through washing with various organic solvents have been unsuccessful. However, without purification, by both *H and 1 3 C N M R spectroscopy of the crude product there is only the additional presence of 2 . 1 8 , and no indication of any side products. Therefore, characterization of 2 . 2 5 - 2 . 3 0 is carried out in the presence of 2 . 1 8 , and the formation of 2 . 2 5 - 2 . 3 0 is further confirmed by l 3 C N M R spectroscopy, low-resolution mass spectrometry (LR-MS) and high-resolution mass spectrometry (HR-MS). 70 Since steric bulk appears to be limiting the reactions with ^-butylamine when T M S C N is used as a reagent, K C N is investigated to add the cyanide functionality to the imine formed from hydroamination (eq. 2.19). 1)5mol%2.1/C 6 H 6 /65°C/12h h n - r 1 R - ^ H + H 2 NR 1 2 ) K C N / E t 0 H / r , . / 3 h * R J ^ C N ( 2 ' 1 9 ) 3) N H 4 C I (sat.) This reaction is successful and compounds 2.25-2.30 presented above can also be formed through this methodology, as can the additional r-butyl substituted compounds 2.31-2.33 shown in Figure 2.14 that are not readily accessible with T M S C N . 2.31 2.32 2.33 Figure 2.14: Additional a-cyanoamines that could only be synthesized using the K C N methodology. While this route using K C N does lead to the formation of the desired products, there are also some side-products observed in both the ' H and the 1 3 C N M R spectra. Mass spectrometry suggests that these side-products are cyanohydrins. Cyanohydrins can be formed via the hydrolysis of the imine in the alcoholic solution required for K C N addition. In contrast, the tandem sequential reaction sequence utilizing T M S C N does not show the formation of any side-products; this is desirable as a-cyanoamines are most commonly used as intermediates in the formation of other molecules. Therefore, since 71 side-products are formed when K C N is used, methodology with this reagent has not been further developed. To determine the overall isolated yield of the tandem reaction sequence, a representative a-cyanoamine example is derivatized and isolated as the trifluoroacetate (TFA)-protected a-cyanoamine simply by quenching the reaction mixture with trifluoroacetic anhydride ( T F A A ) 7 0 instead of ammonium chloride (Scheme 2.2). " H T M S . ^ 1 ) 5 m o l % 2 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h ' " ^ P h 3 ) T F A A / r , . / 1 5 m i n H 2 N Ph 2) TMSCN/r . t . /3 h Scheme 2.2: Synthesis of a stable TFA-protected a-cyanoamine. Compound 2.34 can be purified via column chromatography and isolated in 93% yield over 3 steps (calculated from terminal alkyne). Furthermore, this product is fully characterized by lH and 1 3 C N M R spectroscopy, LR-MS and HR-MS, and elemental analysis (EA). The isolation of 2.34 complements the ' H N M R spectroscopic yields in Table 2.1 and indicates that this tandem reaction sequence is high yielding over the three reaction steps. One of the most important features of the hydroamination precatalyst 2.1 is that it 18 is remarkably compatible with a number of different functional groups. To demonstrate 72 this compatibility with the tandem hydroamination and the Strecker reaction sequence, several novel a-cyanoamines are synthesized (2.35-2.41) as shown in Figure 2.15. 2.35 2.36 2.37 2.38 2.39 2.40 2.41 Figure 2.15: Examples of a-cyanoamines synthesized with increased functionality. Compounds 2.35-2.37 all contain an allyl amine, compounds 2.38 and 2.39 have an additional olefin in the backbone, and 2.40 and 2.41 have a protected alcohol functionality. Notably, these compounds are Cleanly formed and characterized by *H and 1 3 C N M R spectroscopy, LR-MS, and HR-MS. The primary synthetic use of a-cyanoamines is as intermediates in the synthesis of more complex molecules (vide supra). While purification is not possible at this stage without derivitization, the small amount of 2.18 that is present in the a-cyanoamine sample has been shown to be benign, and does not hinder further transformations (vide infra). 2.2.1.3 Summary of a-cyanoamines The combination of catalytic hydroamination of terminal alkynes with the Strecker reaction has been successful and a number of a-cyanoamines have been 73 synthesized using this methodology. Furthermore, the majority of the a-cyanoamines reported here are novel compounds. This illustrates how this tandem methodology can expand upon current synthetic approaches to increase the scope of molecules that can be reliably prepared. This methodology also demonstrates an increase in synthetic flexibility as a-cyanoamines can now be accessed from terminal alkynes instead of carbonyl-containing compounds. Likewise, the a-cyanoamines all contain a methylene group alpha to the stereocenter, a motif that is rarely reported in the literature. Since the synthetic utility of a-cyanoamines is as intermediates in other reactions, an extension of this methodology has been explored to utilize this tandem reaction sequence in the synthesis of other highly functionalized small molecules. 2.2.2 Synthesis of a-amino acid derivatives 2.2.2.1 Introduction 2.2.2.1.1 Reported uses of a-amino acid derivatives As was mentioned earlier, the Strecker reaction is most commonly used for the synthesis of a-amino acid derivatives, such as a-amino amides and a-amino esters, a-Amino acids and their derivatives are extremely important molecules; aside from being the building blocks of peptides and proteins, they are also used as food additives, agrochemicals, detergents, and metal-chelating agents. In fact, amino acids are so important that a journal from Springer-Verlag has been dedicated to these molecules since 1994.87 a-Amino acid derivatives also appear in a number of natural products, and are often key intermediates in total syntheses. 74 The a-amino acid motif appears in numerous natural products and important drug targets, as shown in Figure 2.16. For example, the a-amino amide, 2.42, has been approved as an add-on treatment for refractory partial onset seizures in adults, and further structural modifications to the pyrrolidone backbone has led to the synthesis of even more active compounds.88 2.44 Figure 2.16: Literature examples of a-amino acid derivatives in pharmaceutically relevant compounds and natural products. The a-amino acid functionality appears in natural products such as criamides, 2.43, themselves members of a family of cytotoxic and antimitotic tripeptides that are present 89 m marine sponges. Likewise, the a-amino ester functionality is observed in a group of compounds (2.44) that have been isolated from the aerial parts of Croton ciliatoglandulifer?0 In addition to appearing in natural products and as final synthetic 75 targets, a-amino acid derivatives are often used as synthetic intermediates in total syntheses. For example, in Figure 2.17, the a-amino ester is a key intermediate in the total synthesis of (+)-P-eiythroidine.91 (+)-p-Erythroidine F i g u r e 2 . 1 7 : Total synthesis reported in the literature of (+)-P-eiythroidine where an a-amino ester is a key intermediate. 2 . 2 . 2 . 1 . 2 L i t e r a t u r e m e t h o d s f o r t h e s y n t h e s i s o f a - a m i n o a c i d d e r i v a t i v e s Given the commonality and importance of the a-amino acid motif, it is not surprising that the synthesis of these types of molecules is an area of active research. The Strecker reaction is not the only method available for synthesizing a-amino acids and a-amino acid derivatives. Other methods, of varying complexity and generality, include those derived from aminoalkylations,92 a-alkylations of iminoacetic acid esters,93 or reductive animations.94 Additional methodologies to obtain enantiopure a-amino acid derivatives include kinetic resolutions95 or the use of chiral auxiliaries,9 6'9 7 often based on glycine derivatives.9 8'9 9 Myers and co-workers have reported a general synthetic methodology for the synthesis of both D- and L-a-amino acids using pseudoephedrin glycinamide as a chiral auxiliary (eq.2.20).1 0 0 76 O H A ^ N H 2 O 1) nBuLi 2) RX 1) NaOH 2) B O C 2 0 HO' H ^ B O C ( 2 ' 2 0 ) R Reaction of the chiral auxiliary with a strong base, followed by addition of an alkyl halide leads to the asymmetric alkylation of the pseudoephedrin glycinamide. The chiral auxiliary is removed under aqueous alkaline conditions and the primary amino group is protected with BOC-anhydride. This methodology results in a wide range of a-amino acid products with excellent yields and ee's. The products include R groups that are alkyl, with and without a-methylene protons (yields 70-97%; ee's 96 to > 99%). However, several drawbacks that are noted include the vigilance required in titration of the nBuLi base prior to use and in the drying of several reagents, without which the reactions proceed poorly. In 2002, another approach to the asymmetric synthesis of a-amino acid derivatives was reported by Maruoka and co-workers using chiral phase-transfer catalysts (Figure 2.18). 1 0 1 Figure 2.18: Chiral phase-transfer catalysts that have been used in the synthesis of a-amino acids by Maruoka and co-workers. These catalysts are used to promote the alkylation of various glycine ester benzophenone Schiff bases with alkyl bromides (eq. 2.21), yielding a variety of alkyl a-amino acid A r 77 derivatives in good yields (10-91%) and excellent ee's (82-99%). The drawback to this methodology is the number of synthetic steps required to synthesize the phase-transfer catalysts (8-12 steps). P h 2 C = N ^ X O A l k + R B r cat. P h 2 C = N so lvent - a q u e o u s b a s e O A l k (2.21) R H In 2002 Walsh and co-workers reported another enantioselective method for the synthesis of both D- and L-a-amino acids from terminal alkynes as shown in Scheme 102 2.3, a methodology that is directly comparable to the hydroamination tandem reaction sequence as it utilizes a common starting material. -H 1) C y 2 B H 2) M e 2 Z n MeZn 3) M IB /PhCHO O H P h ' Ph MIB : O O H o o C I 3 C T " N H R u C I 3 . x H 2 0 H N ^ C C l 3 0 NalO„ 0 3 / N a O H / M e O H H 3 C O 0 x HN C C I 3 R ~R 1) cat. KH/CI3CCN 2) reflux Scheme 2.3: Methodology for synthesizing a-amino acids and a-amino esters reported by Walsh and co-workers. The first step of this sequence is the enantioselective synthesis of allylic alcohols. This is accomplished through the reduction of the alkyne to a vinyl group, transmetallation of the 78 product to form the vinylzinc reagent and asymmetric addition to an aldehyde in the presence of a chiral ligand, MIB. The allylic amine is then synthesized via Overman's [3,3] sigmatropic rearrangement of trichloroacetimidates. Oxidative cleavage of the protected allylic amines yields either the alkyl a-amino acid or the a-amino ester depending on the choice of the reagent. This reaction methodology also shows good substrate scope, good yields, and excellent ee's (> 95%) for the synthesis of alkyl a-amino acid derivatives. However, only one of these alkyl a-amino esters contains an a-methylene unit. The formation of this molecule requires six synthetic steps, 3 purifications via column chromatography, and results in 46% overall yield of product from the terminal alkyne starting material. The methods mentioned above are not an exhaustive report of the many routes that are available to synthesize a-amino acids. They do show, however, the variety of methods that can be used to synthesize these molecules in sequences that range from one step to many steps. The procedures that have fewer steps (< 4), while more synthetically attractive, require synthetic prudence and are not very atom economical, or utilize catalysts that require many steps to synthesize. Hence, using alkyl a-cyanoamines that are previously synthesized via the tandem hydroamination and the Strecker reaction sequence to make the alkyl a-amino acid derivatives is very attractive. The reagents are all inexpensive, the multiple reactions can be performed in one pot without isolating intermediates, and most importantly, the products obtained from this reaction sequence are often very different from those commonly reported in the literature. 79 2 . 2 . 2 . 2 R e s u l t s a n d d i s c u s s i o n 2 .2 .2 .2 .1 a - A m i n o a c i d d e r i v a t i v e s v i a h y d r o a m i n a t i o n t a n d e m r e a c t i o n s e q u e n c e The alkyl a-cyanoamines that are synthesized using the tandem hydroamination and Strecker reaction sequence have been used as starting materials in the synthesis of a number of a-amino acid derivatives, namely a-amino amides, a-amino acids (as HC1 salts and zwitterions), and a-amino esters. Each of these classes of molecules wil l be discussed in turn. Literature reports cite that aryl a-amino acids are synthesized by heating an aryl a-cyanoamine to 60 °C in concentrated hydrochloric acid. 3 9 With alkyl a-cyanoamines however, this methodology leads to the formation of a-amino amides, not a-amino acids (eq. 2.22). The disappearance of the a-cyanoamine and the appearance of the a-amino amide can be monitored by ESI-MS. Over an extended period of time with heating the reaction will continue towards the slow formation of a-amino acids. R = H 1) 5 mol% 2 .1 /C 6 H 6 /65 °C/12 h + *-u M D 1 2) TMSCN/r.t . /3 h 3) NH 4 CI (sat.) Concentration of the acidic solution gives the crude a-amino amides 2 . 4 5 - 2 . 5 0 as shown in Figure 2 . 1 9 . This hydrolysis is very clean, proceeding without the formation of side products; the only other compound that is spectroscopically present is the amide proligand 2 . 1 8 . Compounds 2 . 4 5 , 2 . 4 6 , 2 . 4 9 , and 2 . 5 0 are all novel. H v M ' R u _ , C I N H 2 R 1 N 4 ) c o n c . H C , R , ^ R ^ ^ C N 6 0 ° C / 1 2 h ^ C O N H 2 2.45 - 2.50 80 CIH 2 N Ph x CIH 2 N H 2CI Ph C O N H 2 C O N H 2 2.45 2.46 2.47 Y CIH 2 N Ph CIH 2 N C O N H 2 NH 2 CI C O N H 2 C O N H 2 2.48 2.49 2.50 Figure 2.19: Examples of a-amino amides synthesized quantitatively using tandem C -N , C - C bond forming methodology followed by hydrolysis. Purification of a-amino amides 2.45-2.50 is difficult as recrystallization with a number of different solvent combinations generally leads to only partial recrystallization of 2.18 or co-recrystallization of the desired a-amino amide and 2.18. However, for the a-amino amides shown in Table 2.2, separation from 2.18 is accomplished by dissolving the residue in methanol, heating the resulting solution to reflux, and quickly adding cold diethyl ether to precipitate the corresponding a-amino amides as white solids. The yields obtained through this precipitation sequence are calculated from the terminal alkyne starting material and should be considered unoptimized. 81 T a b l e 2 . 2 : Yields of a-amino amides that are purified via precipitation. E n t r y C o m p o u n d a - A m i n o a m i d e R 1 % Y i e l d " 1 2 . 4 7 H2CI \^f> CONH 2 Bn 38 2 2 . 4 8 'Pr 30 3 2 . 4 9 CIH2N r J ^ j ^ - ^ ^ C O N H 2 Bn 33 4 2 . 5 0 'Pr 66 "Overall isolated yield calculated from terminal alkyne The notably enhanced yield of a-amino amide 2 . 5 0 is due to the fact that this reaction is performed on much larger scale (15 mmol, 1.7 g of 3-phenyl-1-propyne starting material) relative to the other a-amino amides (1 mmol, 100 mg of alkyne starting material), and illustrates that improved isolated yields can be easily attained. Likewise, the synthesis of 2 . 5 0 also illustrates that the tandem sequential reaction sequence can be carried out on gram scale. A ' H N M R spectrum of compound 2 . 4 8 in Figure 2.20 clearly indicates that the a-amino amide can be cleanly isolated from 2 . 1 8 through precipitation. Unfortunately, a-amino amides 2 . 4 5 and 2 . 4 6 can not be purified via this precipitation sequence because of co-precipitation with amide 2 . 1 8 . 82 r , T , , , n i „ , , , , , , i | M i , M . | . M . T t . , . n . r i l t . n T . r T M T M . r r , l l , i l . i I M i i n i i M i | » i T H i T i | i H > n H H m H m H T T n i u M | M i i | i i u j i M M i V M H M ; ! T T r r r H ^ 9s i.s ?.$ r.a e.o 5.5 S.D *,o a s-.o 2.* 23 ».« ii- 2.; Figure 2.20: 300 M H z ! H N M R spectrum of a-amino amide 2.48 in CD 3 OD. The tandem hydroamination and Strecker reaction sequence is also successful in the synthesis of a-amino acid salts (eq. 2.23) when the precursor a-cyanoamine is hydrolyzed in refluxing HC1 for 12 h (compounds 2.51-2.56, Figure 2.21). The disappearance of the initial a-cyanoamine and the intermediate a-amino amide, as well as the appearance of the a-amino acid can be monitored by ESI-MS. R — H 1) 5 mol% 2.1/C 6H 6/65 °C/12 h hk . R 1 « „ , , • „ 1 + ! „ N 4) cone. HCI C INH 2 R , 2 )TMSCN/r . t . /3h R ^ C N reflux/12 h ' R ^ X C 0 2 H ^ " 2 n 3) NH4CI (sat.) 2.51 -2.56 83 2.54 2.55 2.56 Figure 2.21: Examples of a-amino acid salts synthesized using tandem C - N , C - C bond forming methodology. Again, this hydrolysis shows no evidence of decomposition, as can be seen in the ' H N M R spectrum shown in Figure 2.22. For compounds 2.53-2.56, the corresponding a-amino amide is synthesized first (as per eq. 2.22) and 2.18 is separated during the aforementioned precipitation sequence. The a-amino amide can then be re-exposed to refluxing concentrated HC1 to form the corresponding a-amino acid free from 2.18. 84 , N H , C H , 1 Jk_ " i ' ' • • i " " T " " i i " " , r ' i " i ' i i i " ' i ' i " " 4.3 7.5 7.5 «.S 5.3 Figure 2.22: 400 MHz *H NMR spectrum of a-amino acid 2.54 in CD 3 OD. The 'H NMR spectrum of a-amino acid 2.54 (Figure 2.22) is very similar to the spectrum in Figure 2.20 for a-amino amide 2.48. This is expected given the structural similarities of these two classes of molecules and such a similarity is also observed in the 1 3 C NMR spectra, as the peaks are only slightly shifted from one another (approximately 0.4 ppm). However, the most diagnostic characterization tool is mass spectrometry because the one amu mass difference between these classes of molecules can be reliably observed. It is also predicted that the differences between the a-amino amides and the a-amino acids would be dramatic in the IR spectrum. Primary amides generally exhibit two sharp stretches in the region around 3300 cm"1 and a carbonyl stretching frequency around 1690 cm"1. Carboxylic acids on the other hand typically have a very broad peak around 3000 cm"1 and a carbonyl stretch at a higher frequency (around 1710 cm"1). 85 Indeed, the a-amino amide 2.48 does exhibit a carbonyl stretch at 1694 cm"1 and the a-amino acid 2.54 displays a carbonyl stretching frequency of 1726 cm"1. However, the region around 3000 cm"1 is not very diagnostic, as it is quite broad in both samples. This is attributed to the large amount of hydrogen bonding that is present in these hygroscopic HCl-salts. Furthermore, as these are amino amides and amino acids, there are also amine stretching frequencies in this region to further complicate interpretation of spectra. Though the differences in the IR spectra between the a-amino amides and the a-amino acids are not as pronounced as might be predicted, this characterization method did further support the selective formation of these two classes of compounds, with only a modification of reaction temperature during the hydrolysis. A key synthetic consideration of this tandem reaction sequence is the fact that the a-cyanoamine intermediate does not require acidic workup before hydrolysis with concentrated HCI. Both the a-amino amide and the a-amino acid can be formed directly from the TMS-protected a-cyanoamine simply by removing the benzene solvent, adding the concentrated HCI to the reaction mixture and heating as mentioned previously. Combining this step together with the tandem reaction sequence represents a one-pot synthesis of a-amino amides and a-amino acids from terminal alkynes. a-Amino acids can be difficult molecules to work with when they are not in their protonated forms. In their neutral form, a-amino acids exists as zwitterions. These neutral molecules are obtained by reacting the a-amino acid salt with a base (Figure 2.23). The neutral form will often exhibit good solubility in water as does the precursor salt, and this presents a challenge for isolation. 86 H 2CI ^ ^ / - \ ^ N Ph Base H 2 o x — - c o r Protonated form Neutral form Figure 2.23: Reaction of an a-amino acid salt with a base yields the zwitterionic a-amino acid. Furthermore, if the neutral amino acid (as a zwitterion) is obtained using an inorganic base, then excess salts exist in the water layer along with the zwitterionic a-amino acid. One solution to this problem is to use an organic proton scavenger, such as propylene oxide, to react with the HC1 salt of the a-amino acid (eq. 2.24).103 (2.24) 1)5 mol% 2 .1 /C 6 H 6 / 65 °C/12 h — H 2) TMSCN/r. t . /3 h + 3) NH4CI (sat.) 2 H 2 N ^ P h 4) cone. HCI/reflux/12 h 5) propylene ox ide/EtOH/H 2 0 After the a-amino acid salt reacts with the propylene oxide, the 2-chloro-propanol will be extracted into the organic layer, and the free a-amino acid can be precipitated from the aqueous layer. As a representative example, compound 2.57 can be synthesized via this methodology, and while it is isolated in low yields (< 30%), it can be rigorously characterized, including by elemental analysis. This isolation and characterization demonstrates the applicability of the tandem reaction sequence to the synthesis of purified free alkyl a-amino acids. a-Amino esters on the other hand, are not zwitterionic molecules, and since they have more desirable solubility properties, the purification of these molecules is 87 facilitated. The a-amino esters are formed by extending the methodology from eq. 2.23 as per eq. 2.25. Acidic methanol is formed by adding freshly distilled thionyl chloride to methanol. A solution of a-amino acid and acidic methanol is heated at reflux for 12 h until the a-amino acid has disappeared as observed by ESI-MS. Removal of the solvent under reduced pressure leaves the crude a-amino ester as an HCI salt. Treatment of this compound with a base gives the free a-amino ester which is amenable to purification by column chromatography. 1)5mol%2.1 /C 6 H 6 / R H 6 5 ° C / 1 2 h + 2)TMSCN/r.t. /12 h H 2 N R 1 3) NH 4CI (sat.) R C | N H , R 1 5) SOCI 2 /MeOH/ reflux/12 h NHR R 4) cone. HCI/reflux/12 h C ° 2 H 6) NaHC-03 (sat.) " C 0 2 C H 3 2.58 - 2.63 (2.25) Six a-amino esters (2.60-2.63 are novel compounds) are formed using this methodology, isolated in high yields over six reaction steps, and are fully characterized. 2-D N M R spectroscopic experiments are used when necessary to fully assign all spectra (Table 2.3). Table 2.3: Yields of a-amino esters synthesized from terminal alkynes. "Overal Entry Compound a-Amino ester R 1 % Yield" 1 2.58 ( P T ^ Y N H R 1 Bn 58 2 2.59 C 0 2 C H 3 'Pr 54 3 2.60 NHR 1 Bn 58 4 2.61 ^ ^ ^ ^ ^ ^ C O z C H 3 'Pr 61 5 2.62 NHR1 Bn 58 6 2.63 (j^^J X 0 2 C H 3 'Pr 69 isolated yield calculated from terminal alkyne. 88 The good yields of the a-amino ester formation over the six synthetic steps supports the assertion that the tandem hydroamination and Strecker reaction sequence is a high yielding reaction methodology for the preparation of this class of a-methylene substituted a-amino acid derivatives. Again, these reactions can be performed in one pot. In comparison to the methodology presented earlier in this section that also utilized terminal alkynes as starting materials (Scheme 2.3), these isolated yields are higher, are also over six synthetic steps, require only one purification by column chromatography and can be completed within 35 h. As a further comparison to traditional Strecker methodology, compound 2.60 has been prepared from the corresponding aldehyde starting material, using a traditional Schiff-base condensation to form the imine, and following a literature method to form the racemic a-cyanoamine.64 The reaction is performed on the same scale as the tandem reaction sequence in eq. 2.25 and the optimized purification method developed above is used to isolate 2.60 prepared from the aldehyde starting material. After 56 h, only 19% of the a-amino methyl ester is isolated after column chromatography. This is significantly less than the 58% of 2.60 that is isolated after the tandem reaction sequence, and is a further demonstration of the efficiency of using in situ generated imines via hydroamination. 2.2.2.3 Summary of a-amino acid derivatives The tandem sequential C - N , C - C bond forming reaction sequence from the combination of catalytic hydroamination with the Strecker reaction is useful in the synthesis of various classes of a-amino acid derivatives, many of which are novel 89 compounds.1"4 Both the a-amino amides and the a-amino acids are isolated as HC1 salts that are amenable to purification by precipitation. The a-amino esters are synthesized in high yields and can be purified by column chromatography. Furthermore, this tandem reaction sequence furthers existing Strecker methodology, since all molecules contain a methylene group alpha to the formed stereocenter. Finally, and most importantly, these a-amino acid derivatives can be synthesized in a one-pot procedure starting from terminal alkynes, a methodology demonstrating enhanced synthetic flexibility. 2 . 2 . 3 S y n t h e s i s o f P - a m i n o a l c o h o l s 2 .2 .3 .1 I n t r o d u c t i o n 2 . 2 . 3 . 1 . 1 R e p o r t e d u s e s o f P - a m i n o a l c o h o l s a-Amino acids are common precursors to P-amino alcohols, which are a very important class of molecules.1 0 5 They are also often referred to as vicinal amino alcohols, or 1,2-amino alcohols, though in this thesis they wil l be called p-amino alcohols. As shown in Figure 2.24, P-amino alcohols appear in a number of natural products, such as bestatin106 and sphingosine,107 as well as pharmacologically active molecules such as saquinavir (a HIV protease inhibitor).1 0 8 bestatin sphingosine saquinavir F i g u r e 2 . 2 4 : Literature examples of P-amino alcohols in natural products. 90 In addition, P-amino alcohols can be used as ligands for metal complexes, such as in the catalysis of both hydroamination109 and the Strecker reaction,52 and as chiral auxiliaries.1 0 5 As this is such a useful functionality, there are numerous methods available for their syntheses. 2.2.3.1.2 Literature methods for the synthesis of P-amino alcohols There are many synthetic routes available to synthesize P-amino alcohols including the addition of nucleophiles to an a-amino carbonyl, 1 1 0 , 1 1 1 the reduction of an 112 113 a-amino carbonyl, the addition of nucleophiles to a-hydroxy imines, the ring opening reactions of epoxides with nitrogen-nucleophiles,114 the ring opening reactions of aziridines with oxygen-nucleophiles,115 and the reduction of oxazolidinones.116 Furthermore, p-amino alcohols can be synthesized by the reduction of a-amino acids (eq. 2.26). T 2 H t- n h 2 R ^ Y O H J^IU R^I^oh (2-26) o This reduction leads to the formation of P-amino alcohols with a methylene group alpha to the hydroxyl group, regardless of the amino acid that is used. Furthermore, when the initial a-amino acid contains an a-methylene unit, such as the ones synthesized by the hydroamination tandem reaction sequence, the P-amino alcohol will now contain two a-methylene groups. There are many methods for synthesizing p-amino alcohols in addition to those listed above. For the purposes of this thesis, the discussion of methodology will be limited to those that lead to the synthesis of p-amino alcohols that 91 contain the methylene group alpha to the hydroxyl group. Since this motif will be common to all examples, it will not be explicitly mentioned. Any time an a-methylene unit is highlighted it will be referring to the a-methylene group derived from the terminal alkyne substrate, ie, the one that is alpha to the R group in eq. 2.26. In 1998 Takacs and co-workers used /V-acyloxazolidinones as precursors to Ti-enolates that are added to formaldehyde, as shown in Scheme 2.4. 1 1 7 Scheme 2.4: Synthesis of p-amino alcohols via a Ti-enolate reported in the literature. The P-hydroxy-7V-acyloxazolidinone formed after the initial addition is hydrolyzed, and a Curtius rearrangement via the acyl azide is performed. Hydrolysis of the final crude oxazolidinone yields a number of P-amino alcohols in good yields and ee's. The R 1 functionality is generally limited to aryl groups (yields 72-87%; ee's 72-84%); however, there are two alkyl examples (yields 76-79%; ee's 92%), neither of which contained an a-methylene unit. The direct a-amination of aldehydes has also been reported in the literature to synthesize a number of P-amino alcohols (eq. 2.27).1 1 8 92 o , C 0 2 R2 1)L-proline O Q A N . N H C 0 2 R 2 (2.27) \__y H + R 2 0 2 C ' N N II 2) N a B H 4 3) 0.5 N NaOH R R L-Proline was used as a catalyst to facilitate the a-amination of a wide variety of aldehydes with azodicarboxylates. The P-amino alcohol products are converted to oxazolidinones for ease of isolation and characterization. A variety of alkyl P-amino alcohols are synthesized using this procedure (yields 67-92%; ee's 91-95%), including some examples containing methylene protons alpha to the stereocenter; however these molecules display lower yields (68-77%) and ee's (89-95%). More recently, this methodology has been extended towards the formation of disubstituted P-amino alcohols.1 1 9 P-Amino alcohols are a very important motif that appears in a number of natural products and pharmacologically important molecules. They can be synthesized by a variety of different routes. Given the ease with which novel a-amino acids can be accessed through the combination of catalytic hydroamination and the Strecker reaction, this methodology is further applied to the synthesis of a number of novel p-amino alcohols. While it is common to use the Strecker reaction to synthesize a-amino acids, it is more rarely reported in current literature on Strecker methodology to extend this route to P-amino alcohols. In addition, in these reports there are no examples of alkyl P-amino alcohols synthesized using this method. 93 2 . 2 . 3 . 2 R e s u l t s a n d d i s c u s s i o n 2 .2 .3 .2 .1 P - A m i n o a l c o h o l s v i a h y d r o a m i n a t i o n t a n d e m r e a c t i o n s e q u e n c e Following the four-step sequence to yield the alkyl a-amino acid salt, two different routes for the reduction of this compound are investigated. The first route used N a B H 4 with H2SO4 in a solvent mixture of THF and ether at room temperature;120 there is never any evidence of P-amino alcohol product formation under these reaction 121 conditions. The second reduction route employed N a B H 4 and I 2 in refluxing THF; this methodology cleanly yielded the p-amino alcohols after 12 h (eq. 2.28). 1) 5 mol% 2 .1 /C 6 H 6 / 65 °C/12 h R H 2 )TMSCN/r . t . /12h C I N H 2 R 1 5) NaBH 4 / l 2 / THF / N H R 1 + ~ R JL — — R X D H ( 2 - 2 8 ) H 2 N R 1 3) NH4CI (sat.) ^^C02r\ reflux/12 h K ^ V u n 4) cone. HCI/reflux/12 h 2 .64 -2 .69 A number of P-aminoalcohols are synthesized using this methodology in good yields over 5 steps, and the results are summarized in Table 2.4. These molecules contain aryl substituted alkyl chains, and long alkyl chains in the backbone, as well as substituents with varying steric bulk on the nitrogen. Purification is accomplished by flash column chromatography with a solvent gradient, and the P-amino alcohols are separated from the amide proligand 2 . 1 8 for full characterization. The yields of the reaction are calculated from the terminal alkyne starting material. Four of these compounds are novel ( 2 . 6 4 , 2 . 6 5 , 2 . 6 8 , and 2 . 6 9 ) and are fully characterized. When necessary, 2-D N M R techniques are performed to fully assign the N M R spectra. 94 Table 2.4: Yields of P-amino alcohols synthesized from terminal alkynes. Entry Compound P-Amino alcohol R 1 % Yield 0 1 2.64 NHR 1 Bn 53 2 2.65 'Pr 37 3 2.66 Bn 52 4 2.67 U L 'Pr 67 5 2.68 NHR1 Bn 40 6 2.69 'Pr 54 "Overall yield calculated from terminal alkyne. The use of the hydroamination tandem reaction methodology to synthesize alkyl substituted P-amino alcohols can be compared with methodologies reported in the literature to synthesize similar molecules. Shown in Figure 2.25, compound 2.70 has been investigated for activity against the parasitic disease leichmaniasis,122 and compound 2.71 is an advanced intermediate in the synthesis of lysine sulfonamides that have been investigated as novel HlV-protease inhibitors. 1 2 3 ' 1 2 4 N R 1 R 2 . O H R = (CH 2)i2CH3 R 1 = Me, Et, n-Bu, n-Hex, n-Dec 2.70 2 H 2.71 Figure 2.25: Literature examples where P-amino alcohols have been used in medicinal chemistry applications as either the target (2.70) or as an advanced intermediate (2.71). The literature reported method for the racemic synthesis of 2.70 consists of 9-10 synthetic steps, an undisclosed amount of purification via column chromatography, and no reported overall yield. On the other hand, 2.70 could theoretically be synthesized by 95 the tandem hydroamination and the Strecker reaction sequence in a four-step sequence that could be carried out in one pot, with one final purification via column chromatography. It should be noted that a recent contribution disclosed a shorter methodology for synthesizing some of these types of P-amino alcohols that remains step-wise, but does provide comparable yields. 1 2 5 The advanced intermediate 2.71 is synthesized in a four-step, four-pot reaction sequence from chiral starting materials with no mention of the purification required or the overall yield. The hydroamination reaction sequence could be used to make this intermediate beginning from the protected terminal alkyne in 5 steps that could be carried out in one pot with one final purification step. While at present, the hydroamination and Strecker reaction sequence results in the racemic synthesis of P-amino alcohols, asymmetric versions of this methodology are being developed, and the approaches under investigation would not add any steps to the reaction sequence (vide infra). The asymmetric versions of the hydroamination reaction sequence will be addressed in the next chapter in this thesis. In the absence of new methodology, the desired stereoisomers could be isolated by well established diastereomer formation and resolution approaches (nitrogen-derivitization). These two examples illustrate how the tandem sequential C - N , C - C bond forming reaction sequence developed here has potential applications in the synthesis of desirable small-molecule target compounds. 2.2.3.3 Summary of p-amino alcohols The combination of hydroamination with the Strecker reaction has been successful in the synthesis of a number of novel P-amino alcohols from terminal alkynes. 96 Many of the alkyl P-amino alcohols are novel compounds, and all contain an a-methylene group and are isolated in high yields over five reaction steps. This methodology represents an important addition to existing methodologies and provides an alternate route into these functionalized small molecules. 2.2.4 Synthesis of diamines -2.2.4.1 Introduction 2.2.4.1.1 Reported uses of diamines Another class of molecules that can be accessed from a-cyanoamines are diamines. Vic ina l diamines, or 1,2-diamines, are a very common structural motif, as there are numerous occurrences of this functionality in natural products and pharmacologically active compounds. Moreover, diamines are useful in organic • 126 synthesis, and have been invoked in a number of transformations and reactions. For the remainder of this thesis, the term diamines wi l l be used to specifically refer to vicinal diamines. There are many natural products and pharmacologically relevant compounds that contain diamines and a selection is shown in Figure 2.26. 2.72 2.73 2.74 Figure 2.26: Literature examples of diamines in natural products and pharmacologically relevant compounds. 97 The natural products 2 . 7 2 are compounds that inhibit the oxidation of long-chain fatty • 127 acids. Diamines are also present as ligands in coordination complexes ( 2 . 7 3 ) , such as analogues of the well known anti-tumor agent cisplatin.128 Other pharmacologically relevant compounds containing diamines include K-agonists such as 2 . 7 4 . 1 2 9 ' 1 3 0 A K -receptor is an opioid receptor type, and hence agonists of this receptor could lead to the synthesis of analgesics without the potential for abuse and side effects associated with analgesics like morphine. Not only are diamines a common and useful structural motif, they are also very useful in synthetic organic chemistry. Examples include diamines as intermediates in forming heterocycles,131 as agents for the resolution of enantiomers,132 as chiral auxiliaries,133 and as ligands in numerous reactions.131 Due to the high occurrence of this functionality and the abundance of potential uses for this motif, much research has been dedicated to the synthesis of diamines. 2 . 2 . 4 . 1 . 2 L i t e r a t u r e m e t h o d s f o r t h e s y n t h e s i s o f d i a m i n e s One method for the synthesis of diamines, as was mentioned in the introduction, is the reduction of a-cyanoamines. Other methods include addition of two nitrogen atoms across an alkene,134 and nucleophilic substitution of oxygen by a nitrogen nucleophile on a P-amino alcohol.1 3 5 Furthermore, diamines can also be accessed from diols, 1 3 6 a-amino acids,1 3 7 and from the reductive amination of a-amino carbonyls.138 Many available methodologies for synthesizing diamines yield symmetrically substituted diamines. For the scope of this thesis, only the syntheses of diamines that are not symmetrically substituted will be highlighted. 98 X u and co-workers have reported a cross coupling methodology that gave unsymmetrical diamines (Scheme 2.5). 1 3 9 9 Q 0+ Bn A Q m l .OH | . 1)Cu(OAc) 2 /Zn/AcOH N N ^ > C S m ' 2 , BnN H N ^ ^ jl + l| | N * R " ^ R 2 / ^ H f B u 0 H R 1 ' V 3) H 2 /Pd(OH) 2 /C 2) HCI/MeOH H 2 N v N H 2 ) \ 2 • 2 H C I R 1 R 2 Scheme 2.5: Synthesis of unsymmetrical diamines from the reductive cross coupling of nitrones and Af-ferr-butanesulfinyl imines reported by Xu and co-workers. A number of unsymmetrical diamines are synthesized from the reductive cross coupling of nitrones with TV-tert-butanesulfmyl imines, after deoxygenation and removal of the sulfinyl and benzyl groups. R 1 displays good substrate scope and good diastereoselectivity is obtained for the reaction sequence. However, the R 2 substituent is limited to aryl groups. It is possible to use a-cyanoamines as precursors to diamines without reduction of the cyano functional group (Scheme 2.6). 1 4 0 99 C N KHMDS N H R ' N R" NHR N n C R 2 ' " ^ N H R 1 1 R 3 ^ H NR R' N H R ' NHR R' R J NHR R J N a C N B H 3 AcOH/EtOH NHR R' NR NC r 3 NHR R' NHR R J S c h e m e 2 . 6 : Literature report of the synthesis of substituted unsymmetrical diamines. In this example, an aryl a-cyanoamine is deprotonated with a strong base to form a ketene iminate, before nucleophilic addition to an imine. Intramolecular elimination of the cyano group results in the formation of a-aminoimine/enediamine tautomers that are finally reduced to the corresponding diamines. This methodology leads to the formation of a number of highly substituted diamines in reasonable yields. But it is severely limited by the nature of the R-groups, since all the R substituents, with the exception of R 1, must be aryl groups. 2 . 2 . 4 . 2 R e s u l t s a n d d i s c u s s i o n 2 .2 .4 .2 .1 D i a m i n e s v i a h y d r o a m i n a t i o n t a n d e m r e a c t i o n s e q u e n c e The synthesis of asymmetrically substituted diamines is notably more difficult then the synthesis of symmetrically substituted diamines.126 The types of diamines that are accessed from the reduction of a Strecker product (eq. 2.29) are often not synthesized using other methods, in that a primary and a secondary amine are both present in the product. 100 R / - x ^ N H R 1 r e d u c t i o n ^ R / ^ N H R 1 C N L. <2-29> N H , As the tandem hydroamination and Strecker reaction sequence gives facile access to a wide variety of a-cyanoamines in a high yielding, one-pot reaction, these molecules are attractive precursors for the synthesis of asymmetrically substituted diamines containing a variety of functional groups. This extension of the methodology is an important addition to existing synthetic routes, as it increases the synthetic flexibility, and leads to the synthesis of a number of novel, asymmetrically substituted diamines. Literature reports show that a-cyanoamines can undergo decyananation upon treatment with a strong reducing agent, such as lithium aluminum hydride (LAH). 1 4 1 However, the alkyl a-cyanoamines synthesized using the tandem reaction sequence are easily reduced with LAH with little evidence of decomposition (Scheme 2.7) R — H H R 1 + 1 )5mo l%2.1 /C 6 H 6 / 65 °C /12h V N " 4) LiAIH4/ether/r.t./12 h H 2 N R 1 2) TMSCN/r.t . /3 h R ^ ^ C N 5) oxalic acid/acetone ' 3) NH 4 CI (sat.) N H R 1 j? R\z-X N H 2 * H O ^ Y ° H O 2.75 - 2.82 Scheme 2.7: Synthesis of diamines from terminal alkynes via the tandem hydroamination and Strecker reaction sequence. Following reduction, the free diamines obtained are often unstable with respect to column chromatography, and are susceptible to decomposition when stored at ambient temperatures in the laboratory (days). Decomposition is avoided by isolating the 101 diamines as their corresponding oxalate salts. A number of diamines are synthesized using this method in high yields (over the five synthetic steps) shown in Table 2.5. The synthesized diamines contain various functionalities in the backbone including long alkyl chains, aryl substituents, and cyclic alkyl substituents. The nitrogen substituents include the bulky isopropyl group, a benzyl functionality that can be removed, and an allyl group that could lead to further functionalization or undergo deprotection of the amine. It should be noted that these diamines, with the exception of 2.78 and 2.79, are novel compounds and have not been previously reported in the literature, a testament to the usefulness of this methodology. Table 2.5: Yields of diamines synthesized from terminal alkynes. Entry Compound Diamine R 1 % Yield" 1 2.75 NHR1 0 / \ ^ \ / k ^ N H 2 . HCrV° H Bn 65 2 2.76 'Pr 69 3 2.77 n 0 allyl 59 4 2.78 Bn 55 5 2.79 (XX -HOVH 'Pr 54 6 2.80 NH2 o allyl 60 7 2.81 O X ; * V Bn 56 8 2.82 allyl 50 "Overall isolated yield calculated from terminal alkyne. After reduction, the diamines are extracted from the organic layer with I M HCI. The aqueous layer is then repeatedly washed with organic solvents to remove any proligand (2.18) present, before the solution is made basic with 5 M NaOH. The final extraction of the aqueous layer with dichloromethane yields only the free diamines in good yields. A 102 solution of the diamine in acetone is treated with oxalic acid, also in acetone, to form the stable diamine-oxalate salt as a white precipitate. Entries 3, 6, and 8 all contain a small amount of contamination in the product, which can be reduced with recrystallizations of the oxalate salt, but never fully eliminated. The ! H and 1 3 C (APT) N M R spectra indicate that this contamination is a second diamine resulting from the additional reduction of the allyl amine substituent. Mass spectrometry also supports this assignment. As mentioned earlier, diamines are useful starting materials for the synthesis of various heterocycles such as imidazolidinones. The imidazolidinone functionality has been investigated by other researchers in a number of compounds for pharmaceutical applications (Figure 2.27). 2.83 2.84 Figure 2.27: Literature examples of imidazolidinones in compounds that are investigated for pharmaceutical applications. Compound 2.83 has been examined for potential potency against influenza virus A , 1 4 2 and compound 2.84 has been found to be a potent N K i selective antagonist.143 Furthermore, imidazolidinones have been found to be potent, non-peptide HIV-protease inhibitors,1 4 4 have been utilized as synthetic intermediates in the synthesis of streptolidine lactam precursors (molecules that form the core of streptothricin antibiotics),145 and have been employed as both ligands 1 4 6 and chiral auxiliaries.1 4 7 103 Several novel imidazolidinones are synthesized from the diamines presented in Table 2.5. This is accomplished through the reaction of the diamine-oxalate salts with a base to obtain the free diamines, followed by reaction with JV,./V-carbonyldiimadazole (CDI) in refluxing THF (eq. 2.30). NHR 1 O 1)NaHC0 3(sat.) ^ O N H 2 - H O - J L Y O H 2)CDI/THF/reflux/12h T ^ N H ( 2 " 3 0 ) O R, 2.85 - 2.87 This leads to the formation of the corresponding imidazolidinones in high yields after column chromatography (Table 2.6). T a b l e 2 . 6 : Yields of imidazolidinones synthesized from diamines. E n t r y C o m p o u n d I m i d a z o l i d i n o n e % Y i e l d " r N H 1 2 . 8 5 82 (53)* r H 2 2 . 8 6 75 (41)6 r" H 4 2 . 8 7 85 (48)6 "Isolated yield after column chromatography calculated from diamine. 6 Yield calculated from terminal alkyne. 104 Imidazolidinones with long alkyl chains, aryl substituted alkyl chains, and cyclic alkyl groups are all synthesized with a benzyl substituent on the nitrogen. Notably, all the products contain a methylene spacer in the backbone alpha to the stereocenter. The ' H and 1 3 C N M R spectra of the imidazolidinones products suggest that there is a mixture of tautomers present in solution (eq. 2.31). For example, in the ! H N M R spectrum of 2 . 8 5 there is a second, small set of diastereotopic benzylic protons observed. Likewise, in the 1 3 C N M R spectrum of 2 . 8 5 there are two peaks in the carbonyl region, at 154 ppm and 151 ppm, which are attributed to the two tautomers shown above. COSY and 1 3 C APT spectroscopic experiments support this assertion, as do variable temperature N M R experiments. The imidazolidinones are not cleanly formed when there is the more bulky isopropyl subsitutent on the nitrogen, as a number of unidentified byproducts are formed. As the synthesis of imidazolidinones is often accomplished through the reaction with triphosgene, this method has also been investigated. This reaction shows limited success; for example, 2 . 8 5 is only formed in 42% yield and there are often large quantities of byproducts that are isolated. Therefore it has been determined that the methodology using CDI is the more reliable method for the synthesis of this class of compounds. The synthesis of these novel imidazolidinones demonstrates the further synthetic utility of this tandem reaction sequence. The diamines that are readily synthesized from the easily accessible a-cyanoamines are precursors in the synthesis of imidazolidinones. (2.31) 105 These imidazolidinones contain varying functionality and represent a valuable extension of this methodology. 2.2.4.3 Summary of diamines The tandem reaction sequence that is the result of combining hydroamination and the Strecker reaction is successful in the synthesis of a number of novel diamines. These diamines are isolated and characterized as their corresponding stable oxalate salts. Furthermore, the diamines are then utilized as precursors in the synthesis of novel heterocycles, such as imidazolidinones. 2.2.5 Overall summary Overall, the tandem sequential reaction sequence of hydroamination and the Strecker reaction has been successfully developed. This methodology has been demonstrated to be applicable in the synthesis of various classes of highly functionalized small molecules not accessible through other routes. In particular, alkyl a-cyanoamines, a-amino acids and a-amino acid derivatives, P-amino alcohols, diamines, and imidazolidinones are all synthesized in good yields, starting from terminal alkynes. Furthermore, in a direct comparison to traditional Strecker methodology, the yield of the product obtained from the tandem reaction sequence is much greater than that obtained from using an aldehyde starting material. A l l of these molecules contain the a-methylene group, a motif which is rarely reported in the literature, and many of these molecules can be synthesized in a one pot procedure. Furthermore, using terminal alkynes as the starting material leads to an increase in synthetic flexibility, as the use of carbonyl-106 containing compounds can be completely avoided and there is no need to isolate unstable intermediates. 2 .3 T a n d e m s e q u e n t i a l r e a c t i o n s w i t h h y d r o a m i n a t i o n a n d t h e M a n n i c h r e a c t i o n 2 .3 .1 I n t r o d u c t i o n 2 .3 .1 .1 T h e M a n n i c h r e a c t i o n Similar to the Strecker reaction, the Mannich reaction (eq. 2.32) is also a commonly used organic reaction that has the potential to be combined with catalytic hydroamination in a tandem reaction sequence. The Mannich reaction involves the addition of an enolate to an imine to form P-amino ketones, P-amino esters, or P-amino thio esters. In general, the Mannich reaction requires the use of a catalyst, such as a Lewis acid. Lanthanide triflates have been shown to be effective catalysts for this reaction. 1 4 8 For example, Kobayashi and coworkers reported a Mannich reaction where the imines are formed in situ from aldehydes and amines and Yb(OTf)3 is used to promote the enolate addition. The majority of the examples utilize aryl imines though there are several alkyl imines that contain a-protons (with slightly lower yields) . 1 4 8 Yb(OTf)3 is also shown to selectively promote the reactions with aldimines in the presence of aldehydes in enolate additions. 6 6 ' 1 4 9 Zn(OTf)2 w i l l promote the Mannich reaction, but only with aryl imines + (2.32) X = Li, Na, T M S Y = Me, Ph , O M e , S P h 1 0 7 and when aryl substituents are present on the nitrogen.150 Salts, such as NaOTf and Nal in the presence of water, also catalyze the Mannich reaction.151 Other Mannich-type reactions however, avoid the use of imines all together (citing their instability). These reactions favour benzotriazoles152 and acylhydrazones153 as N-containing starting materials. The Mannich reaction can lead to the formation of a new stereocenter in the product, and hence much research is dedicated to asymmetric versions of this reaction. Not only is it possible to use chiral auxiliaries154"156 to accomplish this goal, but reports of asymmetric catalysts (Figure 2.28) are prevalent in the literature. In 1997 complex 2.88 was the first catalyst reported for the enantioselective version of the Mannich reaction by behaving as a chiral Lewis acid. 1 5 7 ' 1 5 8 This catalyst promotes the reaction of imines containing an ort/zo-hydroxy phenyl substituent on the nitrogen with good yields and ee's, but is generally limited to aryl imines. The one alkyl example lacks a-methylene protons. 108 Br-Br X = O, S 2.88 2.89 Ph Ph NH HN + Cu(OTf)2 P P h 2 + "OMe AgOAc 2.90 2.91 Figure 2.28: Asymmetric catalysts and ligands for the Mannich reaction reported in the literature. The urea organocatalyst, 2.89, not only promotes the Strecker reaction, but also catalyzes the Mannich reaction with good yields and ee's; however only BOC-protected aryl imines are reported as substrates.159 Another example uses Cu(OTf)2 along with 2.90 as a chiral ligand to promote the Mannich reaction of ./V-acylimino esters with good yields and ee's.1 6 0 When 2.91 is used as a ligand with AgOAc, a wide variety of aryl imines are shown to be successful in the Mannich reaction giving moderate to good yields (46-97%) and ee's (76-98%).1 6 1 Unsaturated imines are also utilized in this report, as are several examples of alkyl imines (41-53% yield, 94% ee), one containing an a-methylene group (60% yield, 92% ee). There are also examples of direct Mannich reactions in the literature. These are reactions in which rather than preforming the enolate, the aldehyde is simply used. (S)-109 Proline has found widespread applications as an asymmetric catalyst for this reaction. There are several examples utilizing aryl imines for the direct Mannich reaction, as well as one example where an alkyl imine is used for this transformation (without a-methylene protons).163 2.3.1.2 Tandem reaction sequence Though there have been a number of successful systems for asymmetric versions ' of the Mannich reaction, there is still a dramatic lack of substrate scope, even more so than what is observed with the Strecker reaction. The use of alkyl imines as substrates for the Mannich reaction is rarely reported, and imines containing a-methylene groups seldom appear in the literature. Thus, by combining catalytic hydroamination with the Mannich reaction (eq. 2.33), a tandem reaction methodology for the synthesis of alkyl Mannich products can be developed. This tandem sequential hydroamination and Mannich reaction sequence also leads to products containing a methylene spacer between the stereocenter and the substituent (R). These types of products are very rarely reported with the Mannich reaction. Furthermore, this methodology will provide the chemist with an increase in synthetic flexibility, as terminal alkynes are now acting as masked carbonyl-containing molecules. Finally, as a tandem reaction sequence, the efficiency of this reaction is increased as the isolation and purification of the intermediate imines is not required. (2.33) Y 110 The general premise of this proposed tandem reaction sequence is the same as the aforementioned tandem reaction sequence with the Strecker reaction. Catalytic hydroamination is used to generate the aldimines and simply by selecting a different nucleophile, in this case, an enolate, a different class of molecules is synthesized. For the development of this tandem reaction sequence, |3-amino acid derivatives are targeted as the desired product, as these are closely related to the a-amino acid derivatives that are synthesized in the tandem hydroamination and the Strecker reaction sequence. Thus, by judicious selection of the nucleophile two different classes of amino acid derivatives can be accessed. 2.3.1.3 Reported uses of P-amino acid derivatives P-Amino acid derivatives are one possible product from the Mannich reaction. These molecules are an important class of compounds because they are building blocks for the synthesis of P-lactams164 and P-peptides,165 both of which are found in a variety of pharmaceutically relevant compounds.166 Furthermore, this functionality is prevalent in many complex natural products, such as the ones shown in Figure 2.29. majusculamide C amastatin Figure 2.29: Literature examples of natural products that contain P-amino acid derivatives. I l l Majusculamide C is a cyclic depsipeptide containing P-amino acid derivatives, that has been isolated from Lyngbya majuscula}61 and amastatin is an aminopeptidase 168 inhibitor. Furthermore, P-amino acids are present in a number of molecules that show pharmacological properties (Figure 2.30). ADDA cispentacin Figure 2.30: Literature examples of P-amino acids in pharmacologically relevant compounds. For example, A D D A is present in several antibiotics and cispentacin is an antifungal antibiotic.1 6 9 Given the importance of this class of molecules, research is active into methodologies for their syntheses. 2.3.1.4 Literature methods for the synthesis of P-amino acid derivatives The Mannich reaction is one of the most common methods for synthesizing P-amino acid derivatives, though it is by no means the only method. Research into synthesizing P-amino acid derivatives is very active for the reasons cited above, and the subject of several reviews. 1 6 9 ' 1 7 0 For example, the synthesis of a number of different P-amino esters have been reported using the asymmetric hydrogenation of P-aryl-substituted P-(acylamino)acrylates with ruthenium catalysts as per eq. 2.34. 1 7 1 112 A % H 0 o-BINAPO A c s I 11 [(p-Cymene)RuCI2]2 ¥ H 9 (2.34) A r ^ V " • A A A ) R O-BINAPO = ^ V ^ O P A r 2 R Though good ee's are reported, this route is limited to the synthesis of aryl substituted (3-amino esters. Also, the conjugate addition of amine nucleophiles to a,P-unsaturated carbonyls is another common method in the literature for synthesizing P-amino acid derivatives. 1 7 2 ' 1 7 3 For example, the reaction shown in eq. 2.35 utilizes the chiral TMS-protected pyrrolidine as a catalyst to promote the aza-Michael reaction between the amine and the a,P-unsaturated carbonyl. 1 7 4 p i r 2 « 9 ^ R 1 V R 2 0 H R H (20mol%) R - ^ ^ H The synthesized P-amino aldehydes are then oxidized to the corresponding P-amino acids. The yield and ee's of this reaction are good and a variety of R groups could be incorporated (including alkyl derivatives) into the products. When the R group contains an a-methylene unit, the yields range from 59-86% and ee's from 93-98%. 2.3.2 Results and discussion 2.3.2.1 P-Amino acid derivatives via hydroamination tandem reaction sequence The proposed tandem sequential reaction sequence for the combination of catalytic hydroamination and the Mannich reaction is shown in Scheme 2.8. After the 113 aldimines are synthesized in situ, an enolate can be added to yield the P-amino ester products. R R Scheme 2.8: Synthesis of P-amino esters through tandem C - N , C - C bond forming reaction sequence. Unlike the tandem sequential reaction sequence using hydroamination and the Strecker reaction, the initial reactions with the hydroamination and the Mannich reaction sequence were unsuccessful. As discussed above, the Mannich reaction generally requires the use of a catalyst. Since the titanium hydroamination catalyst (2.1) can behave as a Lewis acid and it is present in solution after the hydroamination, it is postulated that 2.1 can also catalyze this transformation. However, no product formation is observed after addition of a lithium enolate to the in situ generated imine in either benzene or THF after 12 h. However, when Yb(OTf)3 is used as a Lewis acid with the lithium enolate, a trace amount of product is observed. Since the silyl ketene acetal can be synthesized on larger scale and stored for a period of time, the dimethyl substituted silyl ketene acetal (R = Me, X = TMS in Scheme 2.8) is chosen for the further screening that is carried out in order to increase the amount of product formed. Yb(OTf>3 is used in 114 catalytic amounts with dichloromethane as a solvent and the reaction conditions are varied (eq. 2.36). The results of this investigation are summarized in Table 2.7 in which the yield of the product after isolation by column chromatography is calculated from the terminal alkyne. H 2 N Ph Ph 1) 5 mol% 2.1/C6H.6/65 °C/12 h "I NH O 2) OTMS^ "OMe M e ^ o . , „ / Y b ( 0 T f ) 3 / C H 2 C I 2 OMe (2.36) Me 2.92 Table 2.7: Screening of reaction conditions for tandem hydroamination and the Mannich reaction sequence. Entry Temp. (°C) Time (h) % Yield" 1 23 12 14 2 23 4 36 3 0 4 25 4 -78 4 31 5 -78 0 4 39 6 -78 0 4 50" "Isolated yield measured from terminal alkyne after column chromatography. "Used three-fold increase of dichloromethane. As can be seen in Table 2.7, there is a variation in the yield of the reaction with both time and temperature. At room temperature for 12 h, only 14% yield of the product (entry 1) is obtained. It is possible to increase the yield of the reaction by lowering the reaction time from 12 h to 4 h. In addition, as the temperature decreases, there is an increase in the product yield. Optimal temperature is obtained when the enolate addition and the resulting solution are kept at -78 °C for one hour, followed by 3 h at 0 °C, and quenching the reaction at the same temperature. Also of note is the significant difference in the 115 yield of the reaction relative to the concentration shown in entries 5 and 6. When the reaction is performed under dilute conditions, the highest yield is obtained. It has been reported that alkyl imines with a-protons are difficult substrates for 20 many reactions, and this is much more apparent in the tandem hydroamination and Mannich reaction then in the tandem hydroamination and Strecker reaction. Indeed, the amount of optimization required, and the care necessary for this reaction to give even 50% yield of product in the test reaction is much greater than that which is required in the tandem hydroamination and Strecker reaction sequence presented earlier. Even so, the tandem sequential reaction, with the optimized conditions shown in eq. 2.37, leads to the synthesis of several different P-amino esters. 1)5mol%2.1 /C 6 H 6 /65°C/12h R 1 NH O R ^ ^ ~ H + H 2NR 1 0 T M S ' R, 1 II <2-37) 2) Yb(OTf)3/CH2CI2/ Y " V I ° ^ X OMe N ^ O M e -78 °C to 0 °C/4 h 1 In some cases, the reaction is successful (Figure 2.31). Examples include compounds 2.93 and 2.94, both of which contain bulky isopropyl substituents, which are synthesized and isolated in good yields over two steps after column chromatography. O ^ N H O Pru 2.93 2.94 52% yield 59% yield Figure 2.31: P-Amino esters that are synthesized in good yields from the tandem hydroamination and the Mannich reaction sequence. 116 In other cases, such as the examples shown in Figure 2.32, the reaction conditions are sufficient to yield the formation of product. But, the yields are low, < 30% in all cases after column chromatography. Furthermore, along with the low yields, the products are isolated as a mixture of compounds, as determined by TLC analysis. LK N M R spectroscopy leads to the estimate that the desired compounds are present in 85-90% in the mixtures, and hence characterization of the major product is still possible. The identity of the compounds shown in Figure 2.32 is confirmed by ' H and 1 3 C N M R spectroscopy, LR-MS, and HR-MS. 2.95 2.96 2.97 2.98 Figure 2.32: P-Amino esters that are synthesized in poor yields by the combination of hydroamination and the Mannich reaction. The common structural feature between the two compounds (2.93 and 2.94) that are successfully isolated in good yields is the isopropyl substituent on the nitrogen. It could be predicted then, that 2.95 would also be isolated in high yields, as it contains the isopropyl substituent on the nitrogen as well as the n-pentyl backbone present in the test compound 2.92. However, this is not observed as compound 2.95 is isolated in low yields under the same reaction conditions. Likewise, the low yield of 2.96 is also surprising as the reaction conditions have been optimized with 2.92, a compound that also contains a benzyl substituent on the nitrogen. Furthermore, 2.96 shares a common benzyl backbone to 2.93, a compound that is successfully synthesized. To probe the 117 effect of the nitrogen substituent further, compound 2.97 is synthesized with the unhindered w-butylamine, and again isolated in low yields. This suggests that with the benzyl backbone, a degree of steric bulk around the nitrogen atom is necessary for high yields of product under these reaction conditions. There is a limit to this steric bulk, as the r-butyl substituted compound 2.98 is also isolated in low yields. However, imines that are substituted with /-butyl groups on the nitrogen, such as the starting material for 2.98, are difficult substrates in these tandem reactions, as this particular combination is also unsuccessful in the tandem hydroamination and Strecker reaction sequence. Overall these results emphasize the challenge in using alkyl imines as substrates and show how small structural changes in the molecule dramatically affect the outcome of the reaction. Progress has been made in the development of a tandem sequential hydroamination and Mannich reaction, and this sequence has been applied in the synthesis of P-amino esters. After optimization of the reaction conditions for one test substrate, these reaction conditions have been found to be applicable in the synthesis of two additional Mannich products. However, it is clear that the same reaction conditions are not amenable to all substrate combinations as seen by lower yields of products. These results can become the basis upon which further development of the tandem hydroamination and the Mannich reaction sequence can be built. 2.3.3 Summary of p-amino acid derivatives The combination'of catalytic hydroamination with the Mannich reaction has been moderately successful. After optimization, three novel P-amino esters are synthesized in good yields over the two reaction steps and characterized. A further four novel P-amino 118 esters are also synthesized and characterized by this methodology, though the yields of these reactions are low. This initial investigation has increased the substrate scope of the Mannich reaction by providing in situ access to alkyl imines that do not require isolation and purification before use. This methodology also provides an increase in synthetic flexibility as all the P-amino esters are synthesized from terminal alkynes and not from carbonyl-containing molecules. 2.4 Conclusions and applications The catalytic hydroamination of terminal alkynes with the bis(amidate)bis(amido) titanium precatalyst 2.1 has been used successfully in two tandem sequential C-N, C-C bond forming reaction sequences: a tandem hydroamination and Strecker reaction and a tandem hydroamination and Mannich reaction. Both of these tandem sequential reaction sequences share several characteristics. First, by using imines that are synthesized in situ, the need to isolate and purify the imines before use in either the Strecker reaction or the Mannich reaction is eliminated. This is an improvement over current methodologies that do often require the isolation of the imine prior to the second step of the reaction sequence. Second, alkyl imines are often not used in traditional Strecker and Mannich reactions as the isolation of these hydrolytically unstable imines can be problematic. As there is no need to isolate the imine products of hydroamination, alkyl imines can easily be used in both reactions and this has increased the scope of the products that can be formed from these two reactions respectively. Finally, the tandem sequential hydroamination reaction sequences increase the synthetic flexibility afforded to the 119 chemist. The terminal alkyne acts as a masked carbonyl allowing for a choice in starting materials for both the Strecker reaction and the Mannich reaction. The combination of hydroamination with the Strecker reaction has led to the one-pot synthesis of alkyl a-cyanoamines in excellent yields. Furthermore, this tandem reaction sequence has been extended to the synthesis of a-amino acids, a-amino acid derivatives, P-amino alcohols, diamines, and imidazolidinones, all of which are also synthesized in good overall yields. Likewise it has been shown that there is an improvement in the yield obtained using the tandem reaction sequence, over traditional methodologies using aldehyde starting materials. Since the imines that are synthesized via hydroamination are all alkyl imines, this leads to an increase in substrate scope relative to current state of the art with the Strecker reaction. All the compounds that have been synthesized contain a methylene unit alpha to the newly formed stereocenter, a motif that is rarely reported in the literature. Progress towards the combination of catalytic hydroamination and the Mannich reaction has also been successful. This reaction sequence has been used to synthesize several alkyl P-amino esters, products that are complimentary to the a-amino esters synthesized via the tandem hydroamination and Strecker reaction sequence. All the p-amino esters that have been synthesized contain a methylene spacer alpha to the stereocenter, which is rarely seen in the literature. By making the simple change of the nucleophile that is used in the tandem reaction sequence, a different class of functionalized small molecules has been synthesized. Very recently, a Center for Drug Research and Design (CDRD) has been initiated at the University of British Columbia (www.cdrd.ca). Funding for this institute is being 120 provided by a number of sources including the Province of BC, the Western Economic Diversification Canada, the University of British Columbia, Simon Fraser University, Canadian Institute for Health Research, and the Michael Smith Foundation for Health Research, as well as support from the Canadian Foundation for Innovation (CFI). The CDRD is divided into two sections, the Drug Research Institute (DRI) and the Drug Development Inc. (DDI). The DRI focuses on drug discovery and development whereas the DDI facilitates the commercialization of the drugs discovered. Part of the process of the drug research institute is the search for molecules that are candidates in the treatment of a variety of diseases including cancers and microbial diseases. Thirty of the compounds synthesized during this work including 2.34, 2.47, 2.48, 2.49, 2.50, 2.54, 2.55, 2.56, 2.60, 2.61, 2.62, 2.63, 2.64, 2.65, 2.68, 2.69, 2.75, 2.76, 2.77, 2.78, 2.79, 2.80, 2.81, 2.82, 2.85, 2.86, 2.87, 2.92, 2.93, and 2.94 will be submitted as a small molecule library to this institute, and will be screened for activity in the treatment of the above diseases in a number of biological assays. 121 2.5 Experimental General experimental: Except where otherwise noted, all reactions and manipulations were carried out at room temperature without precautions to exclude atmospheric moisture. A l l solvents for work up procedures were used as received from Aldrich or Sigma. Dry benzene, diethyl ether and THF were purified on an Alumina column and stored under a nitrogen atmosphere. Dry dichloromethane was distilled from CaH 2 under nitrogen. Ti(NEt2)4 and Ti(NMe 2)4 was purchased from Strem or Aldrich and used as received. 1-Hexyne, phenylacetylene and 1 -ethynylcyclohexene were purchased from Aldrich. A l l alkynes were dried over 4 A molecular sieves for 12 h before they were distilled, and degassed using the freeze-pump-thaw method. The alkynes were then transferred into the nitrogen-filled glovebox and further dried over 4 A molecular sieves for an additional 12 h before use. A l l primary amines were purchased from Aldrich and were dried over CaH 2 for 12 h before they were distilled and degassed using the freeze-pump-thaw method. The amines were then stored in the nitrogen-filled glovebox and further dried over 4 A molecular sieves for an additional 12 h before use. 1,3,5-Trimethoxybenzene was purchased from Aldrich, and was ground to a fine powder, and dried under high vacuum with mild heating for 12 h before transfer and storage in the nitrogen glovebox. Deuterated benzene was degassed using the freeze-pump-thaw method and stored over 4 A molecular sieves for 12 h before use. A l l other chemicals were reagent grade and used as received from Aldrich. A l l N M R spectra were acquired in deuterated solvents (purchased from Cambridge Isotope Labs) at room temperature in the UBC Chemistry N M R facility on a Bruker Avance 300 spectrometer (300 M H z [ !H] and 75 M H z [ 1 3C]), a 122 Bruker Avance 400 spectrometer (400 MHz [*H] and 100 MHz [ l 3C]) or a Bruker Avance 600 spectrometer (600 MHz ['H] and 150 MHz [ 1 3C]) and chemical shifts are given relative to residual solvent. ! H N M R spectral assignments are indicated by italicized H's (H). Infrared spectra were recorded on a Nicolet 4700 FT-IR (Fourier transform infrared) spectrophotometer in transmission mode as K B r discs between 400 and 4000 cm"1 at a resolution of ±4 cm' 1. LR-MS were obtained using ESI-MS (electrospray ionization mass spectrometry), and APCI-MS (atmospheric pressure chemical ionization mass spectrometry) in the U B C Chemistry Mass Spectrometry facility on the open access MS. EI-MS (electron impact mass spectrometry), HR-MS (high resolution mass spectrometry), and E A (elemental analysis) were performed by the U B C Chemistry Mass Spectrometry facility. Plates used for TLC (thin layer chromatography) (0.2 mm silica gel 60 F254 on alumina) and silica gel used for column chromatography (70-230 and 230-400 mesh) were purchased from Silicycle (Montreal, PQ). TLC spots were visualized under a UVG-54 Mineralight® short-wave U V lamp (k = 254 nm). P-Amino alcohols were visualized using a ninhydrin stain (1.4 g of ninhydrin in 100 mL of ethanol) followed by heating with a heat gun. Selected ! H and 1 3 C N M R spectra of the compounds synthesized in this chapter can be found in Appendix III. The following compounds were synthesized from literature procedures: A^^-diisopropylphenyl benzamide (2.18) 17 123 b i s ( 7 V - 2 , 6 - d i i s o p r o p y I p h e n y l b e n z a m i d a t e ) b i s ( d i e t h y l a m i d o ) t i t a n i u m ( 2 . 1 ) 1 7 3 - p h e n y I - l - p r o p y n e 1 TBDMSO' l - ( t e r t - b u t y l d i m e t h y l s i I y l o x y ) - 4 - p e n t y n e 1 7 6 O T M S O M e ( l - m e t h o x y - 2 - m e t h y p r o p e n y l o x y ) t r i m e t h y l s i l a n e 1 X>Li OMe m e t h y l i s o b u t y r a t e l i t h i u m s a l t 1 7 8 I m i n e s R e p r e s e n t a t i v e p r o c e d u r e : A small vial is charged with 5 mg (0.006 mmol) of 2 . 1 , 0.12 mmol of terminal alkyne, 0.24 mmol of primary amine and 0.5 g of deuterated benzene 124 within a nitrogen-filled glovebox. The solution is transferred to an oven-dried J. Young N M R tube, removed from the glovebox and heated at 65 °C for 12 h before cooling to room temperature. N M R spectroscopy was then performed, and the imine signals could be assigned. The spectral data matches that which has been observed in the Schafer group and in the literature,17'18 and can be found in Appendix I. TMS-a-Cyanoamines Representative procedure: A small vial was charged with 5 mg (0.006 mmol) of 2.1, 0.12 mmol of terminal alkyne, 0.24 mmol of primary amine, 0.02 g (0.12 mmol) of 1,3,5-trimethoxybenzene and 0.5 g of deuterated benzene within a nitrogen-filled glovebox. The exact weights to four decimal places of all components were noted. The solution was transferred to an oven-dried J. Young tube, removed from the glovebox, and heated at 65 °C for 12 h. The N M R tube was cooled to room temperature and transferred back into the glovebox where 0.016 mL (0.12 mmol) of T M S C N was added to the tube via microsyringe. The N M R tube was removed from the glovebox and sat at room temperature for 12 h. ' H N M R spectroscopy was used to determine the yield of the a-cyanoamine relative to the internal standard using well-defined product peaks and a correction factor based on the exact masses of the alkyne and the internal standard used. The experiments were repeated three times, and the yields that are listed are an average of the three runs. In situ characterization data of these compounds is reported in Appendix I. 125 a - C y a n o a m i n e s R e p r e s e n t a t i v e p r o c e d u r e : An oven-dried 110 mL tube Schlenk flask was brought into the glovebox and was charged with 1.7 mmol of alkyne, 3.4 mmol of primary amine, 0.06 g (0.09 mmol) of 2 .1 and 2 mL of benzene. The Schlenk flask was sealed with a greased glass stopper and sidearm stopcock, and removed from the glovebox. The solution was stirred at 65 °C for 12 h before it was cooled to room temperature. The solution was then frozen using liquid nitrogen, and the headspace of the flask was evacuated under vacuum. The flask was warmed to room temperature, and taped with electrical tape before bringing brought back into the glovebox where 0.23 mL (1.7 mmol) of T M S C N was added via syringe. The flask was again sealed and removed from the glovebox where it stirred for 3 h within a fume hood. The solution was then open to the atmosphere, diluted with 20 mL of dichloromethane, and quenched with saturated ammonium chloride (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (1 x 20mL), dried over MgSCU, filtered and concentrated under reduced pressure to give the a-cyanoamine as an oily compound. A l l characterization was performed in the presence of the amide proligand 2 . 1 8 , which is present in the samples from 9-13 % of the reaction mixture. The signals in the N M R spectra from the 2 . 1 8 1 7 are not listed. complete spectral data. *H N M R (300 MHz, C 6 D 6 , 6): 0.91 (br s, Ntf, 1H), 2.47-2.50 (m, H 2 - ( b e n z y l a m i n o ) - 3 - p h e n y l p r o p a n e n i t r i l e ( 2 . 2 5 ) This previously reported uncharacterized compound 179-183 is presented here with 126 PhC# 2 , 2H), 3.12-3.19 (m, CH, 1H), 3.45 (d, 2J = 13 Hz, NC# 2 Ph, 1H), 3.61 (d, 2J = 13 Hz, NC/ / 2 Ph , 1H) 6.99-7.20 (m, Ar H, 10H); B C N M R (C 6 D 6 , 75 MHz): 5 39.4, 50.6, 51.4, 119.4, 127.5, 127.6, 128.5, 128.7, 128.8, 129.8, 135.8, 138.9; ESI m/z (relative intensity, ion): 237.3 (50%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 6 H i 7 N 2 , 237.1392; found 237.1393. H 2 - ( i s o p r o p y I a m i n o ) - 3 - p h e n y I p r o p a n e n i t r i l e ( 2 . 2 6 ) ' H N M R (300 MHz, C 6 D 6 , 5): 0.68-0.71 (m, CH(C/7 3) 2 , N#, 7H), 2.48-2.62 (m, ?hCH2, 2H), 2.80 (sept, 3J= 6.1 Hz, C#(CH 3 ) 2 , 1H), 3.32 (t, 3J= 6.3 Hz, CH, 1H), 7.05-7.12 (m, AxH, 5H); 1 3 C N M R (C 6 D 6 , 75 MHz): 5 21.3, 23.4, 39.9, 46.9, 49.3, 119.8, 127.5, 128.8, 129.8, 135.9; ESI m/z (relative intensity, ion): 189.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 2 H , 7 N 2 , 189.1392; found 189.1396. H N ^ P h 2 - ( b e n z y l a m i n o ) h e p t a n e n i t r i l e ( 2 . 2 7 ) This previously reported uncharacterized compound 4 7 ' 1 8 4 is present here with full spectral data. ' H N M R (300 MHz, C 6 D 6 , 5): 0.79 (t, 3J= 7.2Hz, CH3, 3H), 0.87-0.97 (m, CH2, 2H), 1.17-1.23 (m, (CH2)2, 4H), 2.93 (t, 3 J = 6.4 Hz, CH, 1H), 3.54 (d, 2J = 13 Hz, NC# 2 Ph, 1H), 3.72 (d, 2J = 13 Hz, NC/ / 2 Ph, 1H), 7.07-7.22 (m, Ar H, 5H); 1 3 C N M R (C 6 D 6 , 75 MHz): 5 14.1, 22.6, 25.4, 31.4, 33.6, 49.6, 51.7, 120.0, 126.9, 128.6, 128.7, 139.2; ESI m/z (relative intensity, ion): 217.2 (50%, M + H) 190.3 (100%, M - CN); HRMS (ESI) m/z: [M + H ] + calcd for C i 4 H 2 1 N 2 , 217.1705; found 217.1705. 127 HN C N 2 - ( i s o p r o p y l a m i n o ) h e p t a n e n i t r i I e ( 2 . 2 8 ) l H N M R (300 MHz, C 6 D 6 , 5): 0.62 (br s, NJ/ , 1H), 0.77-0.83 (m, CH(C/7 3) 2 , CH3, 9H), 1.02-1.30 (m, (C// 2 ) 4 , 8H), 2.91 (sept, V = 6.2 Hz, C/ / (CH 3 ) 2 , 1H), 3.09 (t, 3J= 6.0 Hz, CH, 1H); 1 3 C N M R (C 6 D 6 , 75 MHz): 8 14.1, 21.4, 22.7, 23.7, 25.6, 31.5, 34.2, 46.9, 48.1, 120.5; ESI m/z (relative intensity, ion): 169.2 (100%, M + H), 142.3 (90%, M - CN); HRMS (ESI) m/z: [M + H ] + calcd for C i 0 H 2 i N 2 , 169.1705; found 169.1701. 2 - ( b e n z y l a m i n o ) - 4 - p h e n y l b u t a n e n i t r i l e (2 .29 ) *H N M R (300 MHz, C 6 D 6 , 8): 0.64 (br s, \SH, 1H), 1.49-1.57 (m, PhCH 2CrY 2 , 2H), 2.42 (t, 3J= 7.5 Hz, PhCJ72, 2H), 2.91 (t, V = 7.7 Hz, CH, 1H), 3.42 (d, 2 J = 13 Hz, NC/ / 2 Ph , 1H), 3.66 (d, 2J= 13 Hz, NCi7 2Ph, 1H), 6.88-6.90 (m, Ar H, 2H) 7.01-7.13 (m, Ar H, 8H); 1 3 C N M R (C 6 D 6 , 75 MHz): 8 31.8, 35.2, 48.8, 51.6, 119.8, 126.5, 127.7, 128.6, 128.6, 128.8, 131.5, 139.1, 140.5; ESI m/z (relative intensity, ion): 251.3 (80%, M + H), 224.3 (30%, M - CN); HRMS (APCI) m/z: [M + H ] + calcd for C i 7 H i 9 N 2 , 251.1548; found 251.1544. Ph 128 2-(isopropylamino)-4-phenylbutanenitrile (2.30) ! H N M R (300 MHz, C 6 D 6 , 5): 0.69 (d, V = 6.1 Hz, CH(C/ / 3 ) 2 , 3H), 0.79 (d, V = 6.3 Hz, CH(C/ / 3 ) 2 , 3H), 1.56-1.62 (m, PhCH 2 C/ / 2 , 2H), 2.52 (t, 3J = 7.6 Hz, PhCH 2 , 2H) 2.81-2.90 (m, C/ / (CH 3 ) 2 , 1H), 3.03-3.07 (m, C H 2 C / / , 1H), 6.96-7.12 (m, Ar H, 5H); 1 3 C N M R (C 6 D 6 , 75 MHz): 8 21.4, 23.7, 31.9, 35.7, 47.0, 47.3, 120.4, 126.5, 128.7, 128.8, 140.6; ESI m/z (relative intensity, ion): 203.1 (100%, M + H); HRMS (APCI) m/z: [M + H ] + calcd for C , 3 H i 9 N 2 , 203.1548; found 203.1550. 2-(allylamino)heptanenitrile (2.35) *H N M R (400 MHz, CDC1 3, 8): 0.91 (t, V = 6.8 Hz, CH3, 3H), 1.32-1.42 (m, (CH2)2, 4H), 1.50-1.52 (m, CH2, 2H), 1.70-1.77 (m, CH2, 2H), 3.30-3.32 (m, NCH2, 1H), 3.50-3.56 (m, NC/Y 2 , NCH, 3H), 5.17 (d, 3J= 10 Hz, 2J= 0.6 Hz, HCC/7 2 , 1H), 5.28 (d, 3 J = 17 Hz, ZJ = 1.4 Hz, NCC/fe, 1H), 5.82-5.89 (m, HCCR2, 1H); 1 3 C N M R (CDC1 3, 100 MHz): 8 15.4, 22.5, 25.4, 31.3, 33.6, 49.9, 50.3, 117.6, 120.4, 135.2; APCI m/z (relative intensity, ion): 167.3 (100%, M + H); HRMS (APCI) m/z: [M + H ] + calcd for C 1 0 H 1 9 N 2 , 167.1548; found 167.1542. 129 H 2 - ( a I l y l a m i n o ) - 3 - p h e n y I p r o p a n e n i t r i l e ( 2 . 3 6 ) ' H N M R (400 MHz, CDCI3, 5): 1.63 (br s, N i / , 1H), 3.00-3.20 (m, ?hCH2, 2H), 3.29 (d of d, 2J = 12 Hz, V = 6.4 Hz, NHC# 2 , 1H), 3.52 (d of d, 2J = 13 Hz, V = 5 Hz, NHGtf 2 , 1H), 3.80 (t, 3J= 6.6 Hz, PhCH 2 C#, 1H), 5.17 (d, V = 10 Hz, 2J= 0.8 Hz, H C C / / 2 , 1H), 5.26 (d, 37= 16 Hz, 2J = 1.2 Hz, HCC7/ 2 , 1H), 5.78-5.88 (m, i / C C H 2 , 1H), 7.20-7.42 (m, Ar H, 5H); I 3 C N M R (CDCI3, 100 MHz): 8 39.6, 50.3, 51.0, 117.8, 119.7, 127.7, 128.9, 129.7, 135.0, 146.6; APCI m/z (relative intensity, ion): 187.3 (100%, M + H); HRMS (EI) m/z: [M] + calcd for C i 2 H , 4 N 2 , 186.11570; found 186.11579. 2 - ( a l l y l a m i n o ) - 4 - p h e n y l b u t a n e n i t r i l e ( 2 . 3 7 ) ' H N M R (400 MHz, CDC1 3, 5): 1.46 (br s, NT/, 1H), 2.07-2.17 (m, CH2, 2H), 2.79-2.93 (m, CH2, 2H), 3.25-3.31 (m, NC# 2 , 1H), 3.48-3.55 (m, NC# 2 , N C H , 2H), 5.16 (d, 3 J = 10 Hz, HCC/fc, 1H), 5.27 (d, 3J = 16 Hz, HCC# 2 , 1H), 5.81-5.91 (m, HCCE2, 1H), 7.08-7.37 (m, Ar H, 5H); I 3 C N M R ( C D C 1 3 , 100 MHz): 8 31.8, 35.1, 49.1, 50.2, 117.5, 120.2, 126.5, 128.5, 128.7, 135.0, 140.0; APCI m/z (relative intensity, ion): 201.3 (100%, M + H) 174.3 (100%, M - CN); HRMS (APCI) m/z: [M + H ] + calcd for C i 3 H 1 7 N 2 , 201.1392; found 201.1388. 130 H 2 - ( b e n z y I a m i n o ) - 3 - c y c I o h e x - l - e n - l - y l p r o p a n e n i t r i l e ( 2 . 3 8 ) j H N M R (400 MHz, CDC1 3 , 8): 1.53-1.63 (m, (CH2)2, 4H), 1.83-2.03 (m, (CH2)2, 4H), 2.51-2.54 (m, CH2, 2H), 3.60 (t, 3J = 7.2 Hz, CH, 1H), 3.82 (d, V = 13 Hz, NC/ / 2 Ph , 1H), 4.09 (d, 2J= 13 Hz, NC/ / 2 Ph, 1H), 5.60-5.62 (m, C/ / , 1H), 7.22-7.59 (m, Ar 5H); 1 3 C N M R (CDCI3, 100 MHz): 8 22.2, 22.9, 25.4, 28.4, 42.0, 43.4, 51.7, 120.4, 126.8, 127.7, 128.2, 129.0, 131.9, 138.6; APCI m/z (relative intensity, ion): 241.4 (70%, M + H) 214.4 (40%, M - CN); HRMS (EI) m/z: [M] + calcd for C i 6 H 2 0 N 2 , 240.16265; found 240.16152. H 3 - c y c l o h e x - l - e n - l - y l - 2 - ( i s o p r o p y l a m i n o ) p r o p a n e n i t r i l e ( 2 . 3 9 ) ] H N M R (400 MHz, CDCI3, 5): 1.04 (d, 3J = 6.4 Hz, CH(C/ / 3 ) 2 , 3H), 1.12 (d, V = 6.4 Hz, CH(C/ / 3 ) 2 , 3H), 1.53-1.73 (m, (CH2)2, 4H), 1.97-2.04 (m, (CH2)2, 4H), 2.23-2.43 (m, CH2, 2H), 3.11 (sept, 3J = 6.0 Hz, C/ / (CH 3 ) 2 , 1H), 3.68 (t, 3J = 6.4 Hz, CH, 1H), 5.61-5.63 (m, CH, 1H); 1 3 C N M R (CDC1 3, 100 MHz): 8 21.5, 22,2, 22.9, 23.9, 25.4, 28.5, 42.4, 47.1, 47.3, 120.7, 126.7, 131.9; APCI m/z (relative intensity, ion):193.4 (100%, M + H); HRMS (EI) m/z: [M] + calcd for C i 2 H 2 0 N 2 , 192.16265; found 192.16277. 131 TBDMSO' l - ( r - b u t y l d i m e t h y l s i l y l o x y ) - 5 - ( i s o p r o p y l a m i n o ) h e x a n e n i t r i l e ( 2 . 4 0 ) ' H N M R (400 MHz, CDCI3, 8): 0.05 (s, Si(C// 3 ) 2 , 6H), 0.90 (s, SiC(Cr7 3) 3, 9H), 1.03 (d, V= 6.0 Hz, CH(C/ / 3 ) 2 , 3H), 1.12 (d, V= 6.4 Hz, CH(C/ / 3 ) 2 , 3H), 1.52-1.56 (m, (CH2)2, 4H), 1.76- (m, CH2, 2H), 3.10 (sept, V= 6.0 Hz, C/ / (CH 3 ) 2 , 1H), 3.56 (t, V= 6.8 Hz, CH, 1H), 3.61-3.65 (m, OCH2, 2H); 1 3 C N M R (CDC1 3, 100 MHz): 8 -5.1, 18.5, 21.5, 22.3, 23.8, 25.8, 32.3, 34.0, 47.1, 48.3, 62.8, 120.7; APCI m/z (relative intensity, ion): 285.3 (70%, M + H) 258.4 (100%, M - CN); HRMS (EI) m/z: [M] + calcd for C i 5 H 3 2 N 2 O S i , 284.22839; found 284.22825. Ph ; HN TBDMSO'^^ / X^ vCN l - ( ^ - b u t y l d i m e t h y l s i l y l o x y ) - 5 - ( b e n z y l a m i n o ) h e x a n e n i t r i l e ( 2 . 4 1 ) ' H N M R (400 MHz, CDC1 3 , 8): 0.06 (s, Si(C// 3 ) 2 , 6H), 0.91 (s, SiC(C// 3 ) 3 , 9H), 1.49-1.60 (m, (Cr72)2, 4H), 1.78-1.83 (m, CH2, 2H), 3.51 (t, V= 6.8 Hz, CH, 1H), 3.62 (t, 3 J = 5.6 Hz, OCH2, 2H), 3.84 (d, 2J= 13 Hz, NC/ / 2 Ph , 1H), 4.08 (d, V= 13 Hz, NC/ / 2 Ph , 1H), 7.24-7.36 (m, Ar H, 5H); 1 3 C N M R (CDC1 3, 100 MHz): 8 -5.2, 18.5, 22.4, 26.1, 32.3, 33.5, 50.0, 51.8, 62.8, 120.4, 127.7, 128.5, 128.7, 138.6; APCI m/z (relative intensity, ion): 333.3 (100%, M + H); HRMS (EI) m/z: [M] + calcd for C i 9 H 3 2 N 2 O S i , 332.22839; found 332.22828. 132 T F A - P r o t e c t e d a - C y a n o a m i n e s O A r - b e n z y I - A r - ( l - c y a n o h e x y l ) - 2 , 2 , 2 - t r i f l u o r o a c e t a m i d e ( 2 . 3 4 ) R e p r e s e n t a t i v e p r o c e d u r e : An oven-dried 40 mL tube Schlenk flask was charged with 0.16 g (2.0 mmol) of 1-hexyne, 0.42 g (3.9 mmol) of benzylamine, 0.07 g (0.10 mmol) of 2 . 1 9 and 4 mL of benzene in the glovebox. The Schlenk flask was sealed with a greased glass stopper and sidearm stopcock, and removed from the glovebox. The solution was stirred at 65 °C for 12 h before it was cooled to room temperature. The solution was then frozen using liquid nitrogen, and the headspace of the flask was evacuated. The flask was warmed to room temperature, and taped with electrical tape before being brought back into the glovebox where 0.26 mL (2.0 mmol) of T M S C N was added via syringe. The flask was again sealed and removed from the glovebox where it stirred for 3 h within a fume hood. The flask was opened to the atmosphere and 0.68 mL (4.9 mmol) of trifluoroacetic anhydride was added. After stirring for 5 minutes, 10 mL of diethyl ether was added, and the organic phase was washed with a saturated sodium bicarbonate solution (4x10 mL). The organic portion was separated, dried over magnesium sulfate, and concentrated to a dark red-brown oil. It was purified by silica gel column chromatography (3:2 hexanes:ether) and concentrated to yield the title compound (0.57 g, 93% yield): ' H N M R (400 MHz, CDC1 3 , 5): 0.82 (t, V= 7.2 Hz, CH3, 3H), 1.13-1.22 (m, (CH2)2, 4H), 1.32-1.41 (m, CH2, 2H), 1.51-1.60 (m, CH2, 1H), 1.69-1.82 (m, CH2, IK), 4.64 (d, 2J= 16 Hz, NC# 2 Ph, 1H), 4.73 (t, V= 6.0 Hz, CH, 1H), 4.85 (d, 2 J = 16 Hz, NC# 2 Ph, 1H), 7.24-7.39 (m, Ar H, 5H); 1 3 C N M R (CDC13,100 MHz): 5 13.9, 22.3, 25.6, 133 30.8, 31.1,48.9, 51.3, 116.1, 116.3 (q, 17=286Hz), 128.0, 129.2, 129.4, 133.7, 157.2 (q, 2J= 37Hz); ESI m/z (relative intensity, ion): 335.2 (40%, M + Na); HRMS (ESI) m/z: [M + Na] + calcd for CieH.gFjN^ONa, 335.1347; found 335.1346; Anal. Calcd. for C16H19N2OF3: C, 61.53; N , 8.97; H , 6.13. Found: C, 61.93; N , 9.10, H , 6.35. a-Amino Amides Representative procedure: To a 250 mL round bottom flask containing a Teflon coated stirbar and 0.98 mmol of a-cyanoamine (synthesized via above procedure) was added 20 mL of concentrated HCI and the solution was stirred at 60 °C for 12 h. The reaction progress was monitored by ESI mass spectrometry, and when there was no a-cyanoamine the aqueous HCI was removed under reduced pressure to yield the a-amino amide HCI salt. The a-amino amide salt was transferred to a 100 mL round bottom flask equipped with a stir bar and a condenser. Enough methanol was added to wet the salt, and the solution was heated at reflux. More methanol was added until the solid was completely dissolved. Diethyl ether was then quickly added through the condenser until a white precipitate was formed. The precipitate was filtered, washed with hexanes, and dried under high vacuum. a-Amino amides that could not be separated from 2.18 through this method were characterized in the presence of the proligand, and will be noted individually. Percent yields are calculated from initial terminal alkyne used in the hydroamination step. However, it should be noted that these compounds are hygroscopic, and excess water could lead to an overestimation of the yield. 134 2-(benzylamino)heptanamide • HC1 (2.45) This compound could not be separated from 2.18 via precipitation. J H N M R (400 MHz, CD 3 OD, 5): 6 0.84-0.87 (m, CH3, 3H), 1.22-1.39 (m, (CH2)3, 6H), 1.83-1.99 (m, (CH2), 2H), 3.89 (t, 3J= 6.4 Hz, CH, 1H), 4.18 (s, NC7/ 2Ph, 2H), 7.43-7.55 (m, ArH, 5H); 1 3 C N M R (CD3OD, 100 MHz): 8 14.4, 24.0, 25.6, 32.6, 33.7, 51.5, 61.3, 130.2, 130.9, 132.0, 133.1, 171.4; ESI m/z (relative intensity, ion): 257.3 (50%, M + Na), 235.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C14H23N2O, 235.1810; found 235.1812. 2-(isopropylamino)heptanamide • HC1 (2.46) This compound could not be separated from 2.18 via precipitation. ] H N M R (400 MHz, CD3OD, 8): 0.91-0.94 (m, CH3, 3H), 1.29-1.45 (m, CR(CH3)2, (CH2)3, 12H), 1.83-1.90 (m, CH2, 2H), 3.31-3.37 (m, C/ / (CH 3 ) 2 , 1H), 3.95 (t, V = 6.4 Hz, CH, 1H); 1 3 C N M R (CD3OD, 100 MHz): 8 14.4, 18.8, 20.2, 23.5, 25.7, 32.0, 32.7, 51.4, 59.2, 171.5; ESI m/z (relative intensity, ion): 187.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i o H 2 3 N 2 0 , 187.1810; found 187.1809. 135 H 2 CI C O N H 2 2 - ( b e n z y l a m i n o ) - 3 - p h e n y l p r o p a n a m i d e • H C I (2.47) 38% yield. ! H N M R (300 MHz, CD 3 OD, 5): 3.14-3.25 (m, PhCtf2, 2H), 4.04 (t, V = 7.3 Hz, CH, 1H), 4.08-4.23 (m, NC/ / 2 Ph, 2H) 7.27-7.38 (m, Ar H, 10H); 1 3 C N M R (CD3OD, 75 MHz): 8 37.9, 51.5, 62.4, 129.0, 130.2, 130.5, 130.7, 131.0, 131.3, 132.2, 135.6, 170.7; ESI m/z (relative intensity, ion): 255.3 (100%, M + H), 210.3 (100%, M -CONH2); HRMS (ESI) m/z: [M + H ] + calcd for C i 6 H 1 9 N 2 0 , 255.1497; found 255.1495. 2 - ( i s o p r o p y I a m i n o ) - 3 - p h e n y l p r o p a n a m i d e • H C I (2.48) 30% yield. ' H N M R (300 MHz, CD3OD, 5): 1.36-1.39 (m, C H ( C # » ) 2 , 6H), 3.08-3.27 (m, PhCf72, 2H), 3.33-3.39 (m, CH, 1H), 4.11-4.16 (m, CH, 1H), 7.30-7.37 (m, Ar H, 5H); 1 3 C N M R (CD3OD, 100 MHz): 5 18.9, 20.2, 38.2, 51.4, 60.4, 129.0, 130.1, 130.7, 135.6, 170.7; IR (KBr) v m a x : 1694 ( C O ) , 2823, 3002, 3155, 3378 (N-H) cm"1; ESI m/z (relative intensity, ion): 207.3 (100%, M + H), 162.2 (100%, M - CONH 2 ) ; H R M S (ESI) m/z: [M + H ] + calcd for C2H19N2O, 207.1497; found 207.1495. C I H g N ^ P h 2 - ( b e n z y l a m i n o ) - 4 - p h e n y l b u t a n a m i d e • H C I (2.49) 33% yield. ' H N M R (400 MHz, CD3OD, 5): 2.13-2.19 (m, PhCH 2 C# 2 , 2H), 2.67-2.73 (m, PhC# 2 , 2H), 3.92 (t,  2 J = 6.5 Hz, C H 2 C / / , 1H), 4.15-4.25 (m, NC/ / 2 Ph , 2H), 7.19-136 7.28 (m, Ar H, 5H), 7.46-7.51 (m, Ar H, 5H); 1 3 C N M R (CD3OD, 100 MHz): 5 32.1, 33.8, 51.7, 61.1, 127.7, 129.4, 129.9, 130.5, 131.0, 131.5, 132.2, 141.5, 171.0; ESI m/z (relative intensity, ion): 269.3 (100%, M + H), 224.3 (100%, M - CONH 2 ) ; HRMS (ESI) m/z: [M + H ] + calcd for C i 7 H 2 i N 2 0 , 269.1654; found 269.1657. 2 - ( i s o p r o p y l a m i n o ) - 4 - p h e n y I b u t a n a m i d e • H C 1 ( 2 . 50 ) 66% yield. ' H N M R (400 MHz, CD 3 OD, 5): 1.36 (d, 3 J = 6.5 Hz, CH(C/ / 3 ) 2 , 6H), 2.13-2.18 (m, PhCH 2 C/ / 2 , 2H), 2.72 (t, 3J= 8.5 Hz, PhGf/2, 2H) 3.33-3.37 (m, Cr7(CH 3) 2 1H), 4.04 (t, 3 J = 6.6 Hz, CH, 1H), 7.18-7.30 (m, Ar H, 5H); 1 3 C N M R (CD3OD, 100 MHz): 8 18.9, 20.2, 32.2, 34.1, 51.6, 59.0, 127.7, 129.4, 129.9, 141.6, 171.2; ESI m/z (relative intensity, ion): 221.3 (100%, M + H), 176.3 (100%, M - CONH 2 ) ; HRMS (ESI) m/z: [M + H ] + calcd for C i 3 H 2 i N 2 0 , 221.1654; found 221.1653. a - A m i n o A c i d s R e p r e s e n t a t i v e p r o c e d u r e : A 100 mL flask was charged with a Teflon coated stir bar, 0.98 mmol of a-cyanoamine (synthesized using earlier method), 20 mL of concentrated HC1 and a condenser. The solution was heated after reflux for 12 h. After complete consumption of the a-cyanoamine and the intermediate a-amino amide (as monitored by ESI mass spectrometry) the solution was cooled to room temperature, and the aqueous HC1 was removed under reduced pressure to yield the a-amino acid as an HC1 salt. Purification was not performed so characterization was performed in the presence of the 137 2.18. Alternately, a-amino amides that were purified via precipitation (as discussed above) were then converted to the corresponding a-amino acid by re-heating the a-amino amide in refluxing concentrated HCI followed by removed of the aqueous acid under reduced pressure. In all cases there was no spectroscopic evidence of any side product formation, and the yields are considered to be quantitative from terminal alkyne. However, these compounds are hygroscopic, which could lead to an overestimation of the yield. C I H 2 N ^ P r i 2-(benzylamino)heptanoic acid • HCI (2.51) *H N M R (300 MHz, CD 3 OD, 5): 0.76-0.81 (m, CH3, 3H), 1.17-1.47 (m, (Ctf 2) 3, 6H), 1.82-1.95 (m, CH2, 2H), 3.87 (t, V = 5.1 Hz, CH, 1H), 4.19 (s, NC# 2 Ph, 2H), 7.27-7.49 (m, Ar H, 5H); , 3 C N M R (CD 3 OD, 75 MHz): 5 12.8, 21.8, 24.1, 29.2, 30.9, 50.1, 59.2, 128.7, 129.3, 130.0, 132.9, 169.7; ESI m/z (relative intensity, ion): 258.3 (20%, M + Na), 236.3 (60%, M + H); H R M S (ESI) m/z: [ M + H ] + calcd for C i 4 H 2 2 N 0 2 > 236.1651; found 236.1653. ' H N M R (300 MHz, CD 3 OD, 5): 0.21 (t, CH3, V = 6.6 Hz, 3H), 0.61-0.69 (m, CH(C# 3 ) 2 , (CH2)3, 12H), 1.20-1.31 (m, CH2, 2H) 2.69-2.76 (m, CH, 1H), 3.31-3.35 (m, 2-(isopropylamino)heptanoic acid • HCI (2.52) 138 CH, 1H); 1 3 C N M R (CD 3 OD, 100 MHz): 5 14.3, 18.9, 19.9, 23.5, 25.6, 31.1, 32.6, 51.8, 59.8, 171.5; ESI m/z (relative intensity, ion): 188.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 0 H 2 2 NO 2 ,188.1651; found 188.1650. C 0 2 H 2 - ( b e n z y l a m i n o ) - 3 - p h e n y l p r o p a n o i c a c i d • HC1 ( 2 . 5 3 ) This previously reported uncharacterized compound 1 8 5 ' 1 8 6 is presented here with full spectral data. I H N M R (300 MHz, CD 3 OD, 5): 3.22 (d of d, 2J= 14 Hz, 3J = 7.8 Hz, PhC# 2 , 1H), 3.36 (d of d, 2J = 14 Hz, 3J = 5.8 Hz, ?hCH2, 1H), 4.20-4.23 (m, CH, NCH2, 3H), 7.26-7.35 (m, Ar H, 5H), 7.41-7.46 (m, Ar H, 5H); 1 3 C N M R (CD3OD, 100 MHz): 5 36.9, 51.8, 61.9, 129.0, 130.2, 130.5, 130.6, 131.0, 131.5, 132.1, 135.6, 170.7; ESI m/z (relative intensity, ion): 278.2 (10 %, M + Na), 256.2 (100%, M + H); H R M S (ESI) m/z: [M + H ] + calcd for C i 6 H 1 7 N 0 2 , 256.1338; found 256.1336. 2 - ( i s o p r o p y I a m i n o ) - 3 - p h e n y l p r o p a n o i c a c i d • HC1 ( 2 . 5 4 ) ' H N M R (300 MHz, CD3OD, 5): 1.31 (d, 3J= 6.4 Hz, CH(C//3)2, 6H), 3.14-3.33 (m, PhC/7 2, 2H), 3.42 (sept, 3J= 6.6 Hz, C#(CH 3 ) 2 , 1H), 4.26 (t, 3J= 6.6 Hz, CH, 1H), 7.26-7.34 (m, Ar H, 5H); 1 3 C N M R (CD 3 OD, 100 MHz): 8 19.0, 19.8, 37.2, 51.8, 60.1, 128.9, 130.1, 130.6, 135.6, 170.8; IR (KBr) v m a x : 1726 (C=0), 3200-2400 (O-H, N-H) cm"1; ESI m/z (relative intensity, ion): 208.2 (100%, M + H); H R M S (ESI) m/z: [M + H ] + calcd for C i 2 H i 8 N 0 2 , 208.1338; found 208.1335. 139 Ph C 0 2 H 2 - ( b e n z y I a m i n o ) - 4 - p h e n y l b u t a n o i c a c i d • HC1 ( 2 . 55 ) ' H N M R (300 MHz, CD 3 OD, 5): 2.16-2.32 (m, PhCH 2 C/ / 2 , 2H), 2.62-2.86 (m, PhC// 2 , 2H), 3.95 (t, V = 5.5 Hz, CH, 1H), 4.23 (s, NC/f 2 Ph, 2H), 7.17-7.27 (m, Ar H, 5H), 7.40-7.49 (m, Ar H, 5H); 1 3 C N M R (CD 3 OD, 100 MHz): 5 32.3, 32.9, 51.7, 60.4, 127.7, 129.6, 129.9, 130.4, 131.0, 131.5, 132.2, 141.3, 171.2; ESI m/z (relative intensity, ion): 292.2 (20%, M + Na), 270.2 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 7 H 2 0 N O 2 , 270.1494; found 270.1498. 2 - ( i s o p r o p y l a m i n o ) - 4 - p h e n y l b u t a n o i c a c i d • HC1 ( 2 . 5 6 ) ] H N M R (400 MHz, CD3OD, 5): 1.35 (d, 3 J = 6.4 Hz, CH(Cr7 3) 2, 6H), 2.22-2.30 (m, PhCH 2 C/ / 2 , 2H), 2.72-2.91 (m, PhC// 2 , 2H), 3.48 (sept, 3J = 6.4 Hz, C/ / (CH 3 ) 2 , 1H), 4.06 (t, 3J = 6.2 Hz, CH, 1H) 7.21-7.34 (m, Ar H, 5H); 1 3 C N M R (CD3OD, 100 MHz): 5 18.9, 19.8, 31.1, 33.1, 51.7, 58.1, 127.8, 129.6, 129.9, 141.3, 171.3; ESI m/z (relative intensity, ion): 244.2 (50%, M + Na), 222.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 3 H 2 0 N O 2 , 222.1494; found 222.1496. 140 F r e e a - A m i n o A c i d s + "Ph co2 2 - ( b e n z y l a m i n o ) h e p t a n o i c a c i d ( 2 . 5 7 ) R e p r e s e n t a t i v e p r o c e d u r e : A 50 mL round bottom flask was charged with 0.46 g (1.7 mmol) of amino acid salt. 8 mL each of water, propylene oxide, and ethanol was then added to the solid and the solution stirred for 1 h. 10 mL of hexanes was added, and the phases were separated. The aqueous phase was concentrated until the solution was cloudy. The precipitate was filtered, and dried under vacuum to yield the free amino acid: ! H N M R (300 MHz, CD 3 OD, 6): 0.93 (t, 3 J = 6.6 Hz, CH3, 3H), 1.30-1.39 (m, (CH2)3, 6H), 1.84 (m, CH2, 2H), 3.50 (t, V = 6.0 Hz, CH, 1H), 4.12 (d, 2J = 13 Hz, NCY72Ph, 1H), 4.24 (d, 2J = 13 Hz, NC# 2 Ph, 1H), 7.45-7.50 (m, Ar H, 5H); , 3 C N M R (CD 3 OD, 75 MHz): 5 14.3, 23.4, 25.9, 31.6, 32.7, 51.7, 63.5, 130.2, 130.6, 131.2, 132.8, 173.3; ESI m/z (relative intensity, ion): 236.1 (100%, M + H), 190.1 (10%, M - C 0 2 H ) ; Anal. Calcd. for C i 4 H 2 i N 0 2 : C, 71.46; N , 5.95; H , 8.99. Found: C, 71.66; N , 9.18; H , 6.19. a - A m i n o M e t h y l E s t e r s R e p r e s e n t a t i v e p r o c e d u r e : Acidic methanol was formed by the addition of 25 mL of thionyl chloride dropwise to 125 mL of methanol at 0 °C to a 250 mL round bottom flask equipped with a Teflon coated stirbar. The solution warmed to room temperature and 5.1 mmol of a-amino acid salt (synthesized by procedure described above) was added. The solution was heated at reflux for 12 h while monitoring by ESI mass spectrometry to 141 ensure complete conversion of starting material. The solution was cooled to room temperature and was concentrated under vacuum to yield the crude a-amino methyl ester as an HCI salt. 40 mL of diethyl ether was added to the salt, along with 40 mL of saturated sodium bicarbonate. The organic portion was washed with saturated sodium bicarbonate (4 x 30 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure to yield the crude a-amino methyl ester. It was purified via silica gel column chromatography (column conditions specified in each case) and concentrated to the a-amino methyl ester as an oil in all cases. Percent yields are calculated from terminal alkyne used in the hydroamination step. C O 2 C H 3 m e t h y l 2 - ( b e n z y l a m i n o ) - 3 - p h e n y l p r o p a n o a t e ( 2 . 5 8 ) 58% yield. 1:15:1 ethyl acetate:hexanes:triethylamine. Spectra compared with literature data.187 m e t h y l 2 - ( i s o p r o p y l a m i n o ) - 3 - p h e n y l p r o p a n o a t e ( 2 . 5 9 ) 54% yield. 1:17:1 ethyl acetate:hexanes:triethylamine. Spectra compared with literature H data. 187 142 C 0 2 C H 3 Ph m e t h y l 2 - ( b e n z y l a m i n o ) h e p t a n o a t e ( 2 .60 ) 58% yield, 1:17:1 ethyl acetate:hexanes:triethylamine. J H N M R (400 MHz, CDC1 3 , 5): 0.86 (t, V= 6.8 Hz, CH3, 3H), 1.21-1.36 (m, (C// 2 ) 3 , 6H), 1.57-1.62 (m, CH2, 2H), 1.82 (br s, N/7, 1H), 3.25 (t, 3J = 6.8 Hz, CH, IK), 3.61 (d, 2J= 13 Hz, N C / / 2 , 1H), 3.70 (s, O C / / 3 , 3H), 3.79 (d, 2J= 13 Hz, N C / / 2 , 1H), 7.25-7.31 (m, Ar / / , 5H); 1 3 C N M R (CDC1 3, 100 MHz): 5 14.2, 22.6, 25.6, 31.8, 33.7, 51.7, 52.4, 60.9, 127.2, 128.4, 128.5, 140.1, 176.3; ESI m/z (relative intensity, ion): 272.3 (100%, M + Na), 250.3 (100%, M + H); HRMS (EI) m/z: [M] + calcd for C i 5 H 2 3 N 0 2 , 249.17288; found 249.17325; Anal. Calcd. for C i 5 H 2 3 N 0 2 : C, 72.25; N , 5.62; H , 9.30. Found: C, 72.30; N , 6.00; H , 9.00. ' v v C 0 2 C H 3 m e t h y l 2 - ( i s o p r o p y l a m i n o ) h e p t a n o a t e ( 2 . 6 1 ) 61% yield, 1:16:1 ethyl acetate:hexanes:triethylamine. ! H N M R (400 MHz, CDC1 3 , 8): 0.83 (t, V= 6.4 Hz, CH3, 3H), 0.95 (d, 3J= 6.0 Hz, CH(C// 3 ) , 3H), 0.99 (d, V= 6.0 Hz, CH(C// 3 ) , 3H), 1.22-1.30 (m, (CH2)3, 6H), 1.50-1.58 (m, CH2, 2H), 2.64 (sept, 3 J = 6.0 Hz, C7/(CH) 3, 1H), 3.27 (t, 3 J = 6.8 Hz, C / / C 0 2 C H 3 , 1H), 3.66 (s, O C / / 3 , 3H); 1 3 C N M R (CDCI3, 100 MHz): 8 14.2, 22.2, 22.6, 24.0, 25.6, 31.8, 34.2, 47.2, 51.7, 59.2, 176.8; ESI m/z (relative intensity, ion): 202.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C11H24NO2, 202.1807; found 202.1809; Anal. Calcd. for C i i H 2 3 N O 2 0 . 5 H 2 O : C, 62.82; N , 6.66, H , 11.50. Found: C, 62.89; N , 7.08; H , 11.27. 143 C 0 2 C H 3 Ph methyl 2-(benzylamino)-4-phenylbutanoate (2.62) 58% yield, 1:10:1 ethyl acetate:hexanes:triethylamine. *H N M R (400 MHz, CDC1 3 , 8): 1.97 (br s, NH, 1H), 1.99-2.11 (m, PhCH 2Gr7 2, 2H), 2.77-2^88 (m, PhGr72, 2H), 3.37 (t, V= 6.6 Hz, PhCH 2 CH 2 C/ / , 1H), 3.71 (d, 2J= 13 Hz, NCH2, 1H), 3.76 (s, OCH3, 3H), 3.91 (d, 2J = 13 Hz, NCH2, 1H), 7.23-7.44 (m, Ar H, 10H); 1 3 C N M R (CDC1 3, 100 MHz): 5 32.0, 35.0, 51.6, 52.1, 60.0, 125.9, 127.0, 128.3, 128.4, 128.5, 139.4, 141.4, 175.7; ESI m/z (relative intensity, ion): 306.1 (100%, M + Na), 284.2 (40%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 8 H 2 2 N 0 2 , 284.1651; found 284.1649; Anal. Calcd. for C i 8 H 2 1 N 0 2 : C, 76.29; N , 4.94; H , 7.47. Found: C, 76.43; N , 5.00; H , 7.56. 69% yield, 1:10:1 ethyl acetate:hexanes:triethylamine. l H N M R (400 MHz, CDC1 3, 8): 0.96 (d, 3J= 6.0 Hz, CH(C// 3 ) , 3H), 1.02 (d, 3J= 6.4 Hz, CH(C// 3 ) , 3H), 1.55 (br s, NH, 1H), 1.81-1.95 (m, PhCH 2 C/ / 2 , 2H), 2.63-2.71 (m, ?hCH2, N C i / ( C H 3 ) 2 , 3H), 3.30 (t, V = 6.8 Hz, CK2CH, 1H), 3.65 (s, OCH2, 3H), 7.11-7.25 (m, Ar H, 5H); 1 3 C N M R (CDC1 3, 100 MHz): 8 22.1, 23.8, 32.0, 35.5, 47.0, 51.5, 58.3, 125.9, 128.3, 128.4, 141.4, 176.4; ESI m/z (relative intensity, ion): 258.3 (80%, M + Na), 236.3 (90%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 4 H 2 2 N 0 2 , 236.1651; found 236.1651; Anal. Calcd. For C 1 4 H 2 1 N 0 2 : C, 71.46; N , 5.95; H , 8.99. Found: C, 71.47; N , 6.00; H , 9.00. methyl 2-(isopropylamino)-4-phenylbutanoate (2.63) 144 a-Amino methyl esters from aldehyde starting materials: A n oven-dried 100 mL round bottom flask containing a Teflon coated stirbar was cooled under a nitrogen atmosphere before being charged with 0.51 mL (4.2 mmol) of hexanal, 0.45 mL (4.2 mmol) of benzylamine, 0.2 g of anhydrous MgSCM, and 8 mL of dry toluene under nitrogen. The solution stirred for 12 h before filtration. The filtrate is then added to an oven dried 110 mL Schlenk flask containing a Teflon coated stirbar, 1.1 mL (8.3 mmol) of T M S C N and 8 mL of dry toluene under nitrogen. A solution of 0.50 g (8.3 mmol) of isopropyl alcohol in 1 mL of toluene is added to the Schlenk flask, and the resulting solution is stirred for a further 12 h. The reaction was quenched upon addition of 25 mL of saturated NH4CI and the aqueous layer was extracted with dichloromethane (3 x 30 mL). The combined organic fractions were dried over MgSC>4, filtered, and concentrated under reduced pressure to yield an oil. 150 mL of concentrated HCI was then added to the oil, and the resulting mixture was heated at reflux for 12 h. The concentrated HCI was removed under reduced pressure to leave a white solid. Acidic methanol was formed by the slow addition of 22 mL of thionyl chloride to 110 mL of methanol at 0 °C and was added to the solid formed above. The resulting solution was refluxed for an additional 12 h before it was cooled to room temperature and the solvent was removed under reduced pressure to yield an oily solid. 20 mL of saturated NaHCCh was added to the reaction flask, and the aqueous layer was extracted with dichloromethane (3 x 20 mL), dried over MgSC^, filtered and concentrated under reduced pressure. Purification was then accomplished using column chromatography (1:16:1 ethyl acetate:hexanes:triethylamine) and 2.60 was isolated in 19% overall yield. 145 P- Amino Alcohols Representative procedure: To an oven-dried 100 mL round bottom flask was added 0.21 g (6.0 mmol) of NaBH 4 , 5 mL of dry THF and a Teflon coated stirbar. It was cooled to 0 °C, and 0.86 mmol of a-amino acid salt was added. A separate small vial was charged with 0.87 g (3.4 mmol) of I 2 that was dissolved in 3 mL of dry THF and added dropwise to the above solution. The dark-red solution was then warmed to first room temperature and then heated to reflux whereupon the solution turned cloudy and colourless. After 12 h at reflux the solution was cooled to room temperature and methanol was added slowly until the solution was clear. It was concentrated under reduced pressure and 3 mL of 6 M NaOH was added to the round bottom flask. The solution stirred for 3 h before the aqueous layer was extracted with dichloromethane (3 x 10 mL). The organic layer was dried with MgS04, filtered, and concentrated under reduced pressure to the a-amino alcohol. The a-amino alcohols were purified via flash column chromatography on silica gel. As a-amino alcohols remain on the stationary phase, all byproducts were separated first using 10:1 hexanes:ethyl acetate as eluent followed by 4:1 hexanes:ethyl acetate, 1:1 hexanes:ethyl acetate, and 100% ethyl acetate eluents. The a-amino alcohols were then removed from the column with an eluent of 5% methanol in dichloromethane that steadily increased to 50% methanol in dichloromethane, and were concentrated in all cases to a white solid. Percent yields are calculated from the initial terminal alkyne. 146 Ph . O H 2-(benzylamino)heptan-l-ol (2.64) 53% yield. ! H N M R ((400 MHz, CDC1 3 , 5): 0.90 (t, 3J = 6.3 Hz, CH3, 3H), 1.14-1.63 (m, (CH2)4, 8H), 2.41 (br s, N / / , Oi7, 2H, deuterium exchangeable), 2.63-2.70 (m, N C / / C H 2 , 1H), 3.33 (d of d, 2J= 10.6 Hz, V - 6.3 Hz, CHOH 1H), 3.65 (d of d, 2J= 10.7 Hz, V = 3.8 Hz, C/fOH, 1H), 3.72-3.83 (m, N C / / 2 , 2H), 7.22-7.32 (m, Ar tf, 5H); 1 3 C N M R (CDC1 3, 75 MHz): 5 14.2, 22.7, 25.9, 31.7, 32.1, 51.2, 58.5, 63.1, 127.2, 128.3, 128.6, 140.4; ESI m/z (relative intensity, ion): 244.3 (5%, M + Na), 222.3 (100%, M + H); H R M S (ESI) m/z: [M + H ] + calcd for C i 4 H 2 4 N O , 222.1858; found 222.1857. Anal. Calcd. for C 1 4 H 2 3 N O : C, 75.97; N , 6.33; H , 10.47. Found: C, 75.60; N , 6.25; H , 10.76. 2-(isopropylamino)heptan-l-ol (2.65) 37% yield. ] H N M R (400 MHz, CDC1 3, 5): 0.90 (t, 3J = 6.4 Hz, CH3, 3H), 1.08 (d, 3J = 6.2 Hz, CH(Gr7 3) 2, 3H), 1.13 (d, 3J= 6.2 Hz, CH(C/ / 3 ) 2 , 3H), 1.26-1.50 (m, (C// 2 ) 4 , 8H), 2.27 (br s, N # , OH, 2H), 2.69-2.74 (m, NCr7CH 2 , 1H), 2.97 (sept, 3J = 6.2 Hz, C/ / (CH 3 ) 2 , 1H), 3.24 (d of d, 2J = 10.6 Hz, 3J = 6.8 Hz, CHOH, 1H), 3.62 (d of d, 2J = 10.6 Hz, 3J= 4.0 Hz, CHOH, 1H); 1 3 C N M R (CDC1 3, 100 MHz): 5 14.2, 22.8, 23.2, 23.7, 26.0, 32.2, 32.4, 46.6, 56.5, 63.5; ESI m/z (relative intensity, ion): 174.4 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 0 H 2 3 N O , 174.1858; found 174.1853. Anal. Calcd. for Ci 0 H 2 3 NO(0.1 H 2 0) : C, 68.60; N , 8.00; H , 13.35. Found: C, 68.39; N , 7.76; H , 13.48. 147 H 2 - ( b e n z y I a m i n o ) - 3 - p h e n y I p r o p a n - l - o l ( 2 . 6 6 ) 52% yield. Spectra compared with literature data.1 H 2 - ( i s o p r o p y l a m i n o ) - 3 - p h e n y l p r o p a n - l - o l ( 2 . 67 ) 67% yield. Spectra compared with literature data.1 Ph 2 - ( b e n z y l a m i n o ) - 4 - p h e n y l b u t a n - l - o l ( 2 . 68 ) 40% yield. ] H N M R (400 MHz, CDC1 3, 5): 1.77-1.90 (m, PhCH 2Cf7 2 , 2H), 2.11 (br s, N#, OH, 2 H), 2.63-2.73 (m, PhC// 2 , 2H), 2.74-2.79 (m, CH 2Gf7, 1H), 3.41 (d of d, 2J = 10.7 Hz, 3J= 6.1 Hz, CHOH, 1H), 3.72 (d of d, V = 10.7 Hz, V = 3.9 Hz, CHOH, 1H), 3.75-3.84 (m, NCtf 2 , 2H), 7.16-7.22 (m, Ar H, 2H), 7.27-7.36 (m, Ar H, 6H); 1 3 C N M R (CDCI3, 100 MHz): 6 32.6, 33.4, 51.0, 58.0, 63.0, 126.2, 127.5, 128.4, 128.5, 128.7, 128.8, 140.0, 141.9; ESI m/z (relative intensity, ion): 256.4 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C n H 2 2 N O , 256.1701; found 256.1699. Anal. Calcd. for C n H 2 1 N O : C, 79.96; N , 5.49; H , 8.29. Found: C, 80.34; N , 5.70; H , 8.52. 148 2 - ( i s o p r o p y l a m i n o ) - 4 - p h e n y l b u t a n - l - o l ( 2 . 6 9 ) 54% yield. *H N M R (400 MHz, CDC1 3, 5): 1.05 (d, 3J= 6.2 Hz, CH(C/ / 3 ) 2 , 3H), 1.11 (d, 3J = 6.3 Hz, CH(C# 3 ) 2 , 3H), 1.76-1.84 (m, PhCH 2 C/ / 2 , 2H), 2.06 (br s, NT/, OH, 2H), 2.59-2.71 (m, ?hCH2, 2H), 2.76-2.80 (m, CH 2Gtf, 1H), 2.98 (sept, V = 6.3 Hz, CH(C/ / 3 ) 2 , 1H), 3.36 (d of d, 2J= 10.7 Hz, 3J = 6.6 Hz, CHOH, 1H), 3.70 (d of d, 2J = 10.8 Hz, V = 3.9 Hz, C/ /OH, 1H), 7.18-7.22 (m, Ar H, 2H), 7.27-7.31 (m, Ar H, 3H); 1 3 C N M R (CDC1 3, 100 MHz): 5 23.3, 23.7, 32.6, 34.1, 46.4, 55.9, 63.5, 126.2, 128.5, 128.7, 141.9; ESI m/z (relative intensity, ion): 230.3 (5%, M + Na), 208.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 3 H 2 2 N O , 208.1701; found 208.1702. Anal. Calcd. for C i 3 H 2 1 N O : C, 75.32; N , 6.76; H , 10.21. Found: C, 75.01; N , 6.37; H , 10.49. D i a m i n e s R e p r e s e n t a t i v e p r o c e d u r e : An oven-dried 110 mL Schlenk flask was charged with 4.9 mmol of alkyne, 5.4 mmol of primary amine, 0.18 g (0.24 mmol) of precatalyst 2 .1 and 6 mL of benzene. The Schlenk flask was sealed with a greased glass stopper and sidearm stopcock, and removed from the glovebox. The solution was stirred at 65 °C for 12 h before it was cooled to room temperature. The solution was then frozen using liquid nitrogen, and the headspace of the flask was evacuated under vacuum. The flask was warmed to room temperature, and taped with electrical tape before bringing brought back into the glovebox where 0.65 mL (4.9 mmol) of T M S C N was added via syringe. After 149 stirring for an additional 3 h it was diluted with 30 mL of dichloromethane, quenched with saturated ammonium chloride (30 mL), extracted with dichloromethane (3x30 mL), washed with brine (1 x 30 mL), dried over MgS04, filtered and concentrated under reduced pressure to give the a-cyanoamine. Then 10 mL of anhydrous diethyl ether was added to the a-cyanoamine and the solution was transferred to an oven dried round bottom flask that was charged with a Teflon coated stirbar, and covered with a nitrogen atmosphere. 0.37 g (9.8 mmol) of L i A l H 4 was added to the solution in small portions over 20 minutes. The slurry stirred at room temperature for 12 h. After, 0.37 mL of water was added slowly to the solution, followed by 0.37 mL of 1 M NaOH, and a further 1.11 mL of water. The solution was stirred until a white precipitate was formed, and there was no grey solid left in the reaction flask. It was then filtered into a separatory funnel and the white solid was washed with an addition 20 mL of ether. The organic layer was extracted with 1 M HC1 (3 x 30 mL). The combined aqueous layers were washed with dichloromethane (2 x 90 mL) and hexanes (1 x 90 mL). Aqueous 5 M NaOH was added to the acidic aqueous layer until it was basic by pH paper. The aqueous layer was then extracted with dichloromethane (3 x 100 mL), dried over anhydrous M g S 0 4 , filtered, and concentrated under reduced pressure. The resultant oil was dissolved in a minimum amount of acetone and transferred to a small round bottom flask. A solution of 0.44 g (4.9 mmol) of oxalic acid was prepared in a minimal amount of acetone and added dropwise to the solution containing the diamine in acetone. A white precipitate was immediately obvious. After complete addition of the oxalic acid, the precipitate was filtered, washed with diethyl ether, and dried under high vacuum. Generally the recovered precipitate did not require any further purification, though 150 recrystallization could be performed from ethanol/methanol and water mixtures i f necessary. The hygroscopic nature of these compounds along with the diprotic nature of the oxalic acid rendered elemental analysis unsuccessful as a characterization technique. /V2-benzylheptane-l,2-diamine • oxalic acid (2.75) 65% yield. ' H N M R (400 MHz, D 2 0 , 5): 0.86-0.88 (m, CH3, 3H), 1.31-1.40 (m, (CH2)3, 6H), 1.84-1.90 (m, CH2, 2H), 3.42 (d, V = 5.7 Hz, CHC7/ 2 NH 2 , 2H), 3.61-3.65 (m, CH, 1H), 4.32 (d, 2J= 13 Hz, NC/ / 2 Ph, 1H), 4.38 (d, 2J= 13 Hz, N C / / 2 P h 1H), 7.49-7.51 (m, AiH, 5H); 1 3 C N M R (D 2 0, 100 MHz): 8 14.1, 22.6, 24.5, 28.6, 31.5, 40.0, 50.0, 56.6, 130.4, 130.7, 130.9, 131.1, 166.8; ESI m/z (relative intensity, ion): 221.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C ] 4 H 2 5 N 2 , 221.2018; found 221.2017. 69% yield. ' H N M R (300 MHz, D 2 0 , 6): 0.87-0.90 (m, CH3, 3H), 1.29-1.37 (m, CH(C/f 3 ) 2 , (CH2)3, 12H), 1.76-1.81 (m, CH2, 2H), 3.37 (d, 3J = 5.7 Hz, C H C / / 2 N H 2 , 2H), 3.58-3.65 (m, C/7(CH 3) 2, CH, 2H); 1 3 C N M R (D 2 0, 75 MHz): 8 13.2, 18.0, 18.4, 21.8, 23.4, 27.8, 30.7, 39.0, 49.1, 52.8, 165.2; ESI m/z (relative intensity, ion): 173.3 (70%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 0 H 2 5 N 2 , 173.2018; found 173.2012. Ph O O 151 o A ^ - a l l y l h e p t a n e - l ^ - d i a m i n e • o x a l i c a c i d ( 2 . 7 7 ) 59% yield. ' H N M R (300 MHz, D 2 0 , 5): 0.87-0.91 (m, CH3, 3H), 1.32-1.45 (m, (C// 2 ) 3 , 6H), 1.80-1.86 (m, CH2, 2H), 3.40-3.43 (m, C / / 2 N H 2 , 2H), 3.59-3.65 (m, CU2CH, 1H), 3.77-3.82 (m, N C H 2 , 2H), 5.53-5.61 (m, KCCH2, 2H), 5.87-6.00 (m, HCCH2, 1H); 1 3 C N M R (D 2 0, 100 MHz): 5 14.1, 22.6, 24.4, 28.6, 31.5, 39.7, 48.5, 56.1, 125.3, 127.8, 167.2; ESI m/z (relative intensity, ion): 171.3 (100%, M + H); HRMS (ESI) m/z: [M + H] + calcd for C l 0 H 2 3 N 2 , 171.1861; found 171.1863. A ^ - b e n z y l - S - p h e n y l p r o p a n e - l ^ - d i a m i n e • o x a l i c a c i d ( 2 . 7 8 ) 55% yield. *H N M R (300 MHz, D 2 0 , §): 3.13-3.20 (m, PhC// 2 , 1H), 3.28-3.36 (m, PhC/J 2 , 1H), 3.40-3.52 (m, C / / 2 N H 2 , 2H), 3.92-3.98 (m, CR2CH, 1H), 4.38 (s, NC/ / 2 Ph , 2H), 7.34-7.48 (m, Ar H, 10H); 1 3 C N M R (D 2 0, 100 MHz): 5 35.4, 40.3, 50.1, 57.5, 129.1, 130.2, 130.3, 130.4, 130.6, 130.8, 131.1, 134.9, 169.4; ESI m/z (relative intensity, ion): 241.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 6 H 2 1 N 2 , 241.1705; found 241.1700. 152 A ^ - i s o p r o p y l - S - p h e n y l p r o p a n e - l ^ - d i a m i n e • o x a l i c a c i d ( 2 . 7 9 ) 54% yield. ! H N M R (400 MHz, D 2 0 , 5): 1.34 (d, V= 4.4 Hz, CH(C# 3) 2 , 6H), 3.11-3.16 (m, PhCr72, 1H), 3.24-3.29 (m, PhGf/2, 1H), 3.35-3.46 (m, CH2NH2, 2H), 3.59-3.65 (m, Ctf(CH 3 ) 2 , 1H), 3.95-3.98 (m, CH 2 Ctf, 1H), 7.39-7.50 (m, Ar H, 5H); 1 3 C N M R (D 2 0, 100 MHz): 5 18.7, 19.4, 35.4, 40.4, 50.3, 54.9, 129.1, 130.3, 130.4, 134.8, 167.7; ESI m/z (relative intensity, ion): 193.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 2 H 2 1 N 2 , 193.1705; found 193.1710. 7 V 2 - a I l y l - 3 - p h e n y l p r o p a n e - l , 2 - d i a m i n e • o x a l i c a c i d ( 2 . 8 0 ) 60% yield. ] H N M R (300 MHz, D 2 0 , 5): 3.09-3.14 (m, PhC// 2 , 1H), 3.24-3.29 (m, PhC# 2 , 1H), 3.34-3.39 (m, C# 2 NH 2 , 1H), 3.44-3.50 (m, C7/ 2 NH 2 , 1H), 3.73-3.83 (m, NC# 2 , 2H), 3.92-3.95 (m, CH 2 Ctf, 1H), 5.49-5.53 (m, HCC# 2 , 2H), 5.82-5.89 (m, # C C H 2 , 1H), 7.37-7.48 (m, Ar H, 5H); I 3 C N M R (D 2 0, 100 MHz): 8 35.3, 40.1, 48.6, 57.2, 125.4, 127.8, 129.1, 130.3, 130.4, 134.9, 168.8; ESI m/z (relative intensity, ion): 191.3 (100%, M + H) 174.3 ( M - NH 2 ) ; HRMS (ESI) m/z: [M + H ] + calcd for C 1 2 H 1 9 N 2 , 191.1548; found 191.1544. 153 H N Ph 0 • HO' O H O A^-benzyl-S-cyclohex-l-en-l-ylpropane-l^-diamine • oxalic acid (2.81) 56% yield. ' H N M R (400 MHz, D 2 0 , 8): 1.51-1.69 (m, (CH2)2, 4H), 1.83-2.03 (m, (CH2)2, 4H), 2.46-2.58 (m, CH2CR, 2H), 3.33-3.51 (m, C / / 2 N H 2 , 2H), 3.68-3.71 (m, CK2CH, 1H), 4.37 (s, NC7/ 2Ph, 2H), 5.75 (s, CH, 1H), 7.47-7.50 (m, Ar H, 5H); 1 3 C N M R (D 2 0, 150 MHz): 8 20.8, 21.5, 24.3, 26.5, 36.9, 38.8, 48.4, 52.1, 128.3, 128.9, 129.3, 129.5, 130.1, 165.2; ESI m/z (relative intensity, ion): 245.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 6 H 2 5 N 2 , 245.2018; found 245.2020. Af2-allyl-3-cycIohex-l-en-l-ylpropane-l,2-diamine • oxalic acid (2.82) 50% yield. *H N M R (300 MHz, D 2 0 , 8): 1.46-1.56 (m, (CH2)2, 4H), 1.86-1.94 (m, (CH2)2, 4H), 2.35-2.42 (m, CH2CR, 2H), 3.27-3.33 (m, C / / 2 N H 2 , 2H), 3.62-3.73 (m, CH2CH, 3H), 5.43-5.46 (m, KCCH2, 2H), 5.49 (br s, HCC, 1H), 5.71-5.90 (m, HCCK2, 1H); I 3 C N M R (D 2 0, 100 MHz): 8 22.4, 23.1, 25.8, 28.2, 38.2, 40.4, 48.4, 53.7, 125.5, 127.8, 129.6, 131.7, 169.0; ESI m/z (relative intensity, ion): 195.3 (50%, M + H) 178.2 ( M - N H 2 ) ; HRMS (ESI) m/z: [M + H ] + calcd for C 1 2 H 2 3 N 2 , 195.1861; found 195.1857. Imidazolidinones Representative procedure: Approximately 0.40 g of diamine as the oxalate salt (synthesized using the route described above) was dissolved in 30 mL of sat. N a H C 0 3 solution. The pH of the solution was measured to ensure that it was basic, otherwise sat. 154 NaHCC>3 solution was added 1 mL at a time until the solution was basic. The aqueous layer was extracted with dichloromethane (3 x 30 mL) and the combined organic layers were dried with MgS04, filtered, and concentrated under reduced pressure. The diamine was then further dried on a high vacuum line. To a flask containing 1.1 mmol of free diamine (for example) was added 2 mL of dry THF, and 0.20 g (1.2 mmol) of CDI. The solution was then heated at reflux for 12 h before cooling to room temperature. The solvent was removed under reduced pressure to yield the crude imidazolidinone which was purified by column chromatography with an eluent of 5% methanol in dichloromethane solution. The yields are calculated from the diamine starting material. 82% yield. *H N M R (400 MHz, CDC1 3, 5): 0.86 (t, 3J= 6.8 Hz, CH3, 3H), 1.19-1.26 (m, (CH2h, 6H), 1.36-1.44 (m, CRCH2, 1H), 1.61-1.63 (m, C H C / / 2 , 1H), 3.06-3.11 (m, CH, 1H), 3.41-3.52 (m, NHC/7 2 , 2H), 4.03 (d, 2J= 15 Hz, PhC// 2 , 1H), 4.75 (d, 2 J = 15 Hz, ThCH2, 1H), 5.31 (s, N / / , 1H), 7.21-7.35 (m, Ar H, 5H); 1 3 C N M R (CDC1 3, 100 MHz): 5 14.1, 22.7, 24.3, 31.8, 31.8, 45.6, 47.1, 51.8, 127.8, 128.2, 128.9, 136.7, 154.5; ESI m/z (relative intensity, ion): 269.2 (100%, M + Na), 247.3 (10%, M + H); HRMS (ESI) m/z: [M + Na] + calcd for C ] 5 H 2 2 N 2 O N a , 269.1630; found 269.1624. P h N H l-benzyl-5-pentylimidazolidin-2-one (2.85) 155 cnrv H 1, 5 - d i b e n z y l i m i d a z o l i d i n - 2 - o n e ( 2 . 8 6 ) 75% yield. *H N M R (300 MHz, CDC1 3, 5): 2.59-2.65 (m, ?hCH2, 1H), 3.05-3.11 (m, PhC// 2 , NHC# 2 , 2H), 3.22-3.26 (m, N H C / / 2 , 1H), 3.69-3.75 (m, CH 2 C/7, 1H), 4.07 (d, 2J = 15 Hz, NC# 2 Ph, 1H), 4.69 (br s, N / / , 1H), 4.86 (d, 2J= 15 Hz, NC# 2 Ph, 1H), 7.10-7.37 (m, Ar H, 5H); 1 3 C N M R (CDC1 3, 100 MHz): 5 38.8, 43.8, 45.5, 56.3, 127.0, 127.7, 128.4, 128.8, 128.9, 129.3, 136.9, 137.2, 162.4; ESI m/z (relative intensity, ion): 289.2 (100%, M + Na), 267.2 (30%, M + H); HRMS (ESI) m/z: [M + Na] + calcd for C 1 7 H i 8 N 2 O N a 289.1317; found 289.1308. H l - b e n z y I - 5 - ( c y c l o h e x - l - e n - l - y l m e t h y I ) i m i d a z o l i d i n - 2 - o n e ( 2 . 8 7 ) 85% yield. ! H N M R (400 MHz, CDCI3, 5): 1.50-1.52 (m, CH2, 4H), 1.71-1.73 (m, CH2, 2H), 1.94-1.99 (m, CH2, CCH2, 3H), 2.38 (d, V = 12 Hz, CCH2, 1H), 3.07 (t, V = 7.8 Hz, NHCtf 2 , 1H), 3.35 (t, 3J= 8.6 Hz, NHC# 2 , 1H), 3.54-3.57 (m, CH, 1H), 4.06 (d, 2J = 15 Hz, PhCH2, 1H), 4.77 (d, 2J= 15 Hz, ?hCH2, 1H), 4.95 (s, NH, 1H), 5.39 (s, HCC, 1H), 7.25-7.42 (m, Ar H, 5H); 1 3 C N M R (CDCI3, 100 MHz): 5 22.4, 22.9, 25.4, 28.7, 41.3, 44.1, 45.2, 53.5, 124.9, 127.5, 128.2, 128.7, 133.1, 137.6, 162.8; ESI m/z (relative intensity, ion): 293.2 (100%, M + Na), 271.2 (60%, M + H); HRMS (ESI) m/z: [M + Na] + calcd for C n H 2 2 N 2 O N a , 293.1630; found 293.1625. P h 156 P-Amino Methyl Esters Representative procedure: An 40 mL oven-dried tube Schlenk flask was charged with - 1.0 mmol of alkyne, 1.0 mmol of amine, 0.04 g (0.05 mmol) of 2 . 1 , 2 mL of benzene and a Teflon coated stirbar within the glovebox. The Schlenk flask was sealed with a greased stopper and stopcocks before being removed from the glovebox. The solution was heated at 65 °C for 12 h before being cooled to room temperature. The benzene was removed under vacuum and 6 mL of dry dichloromethane was added to the solution under nitrogen. In a separate, oven-dried 110 mL tube Schlenk flask was added 0.17 g (0.31 mmol) of either Yb(OTf) 3 or Y(OTf) 3 and 5 mL of dry dichloromethane under nitrogen. This solution was cooled to -78 °C and stirred for 15 minutes. The initial solution of imine in dichloromethane was then added dropwise to the cooled solution and it stirred for a further 15 minutes. A small vial was charged with 0.20 g (1.2 mmol) of the ketene silyl acetal that was dissolved in 4 mL of dry dichloromethane and was added to the above combined solutions at -78 °C. The solution stirred at -78 °C for 1 h before warming to 0 °C where it stirred for a further 2 h. The Schlenk flask was opened to the atmosphere and 20 mL of water was added to the organic solution at 0 °C before the mixture was transferred to a separatory funnel. The organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The organic portions were combined and washed with brine (1 x 40 mL), dried over anhydrous MgSC»4, and concentrated under reduced pressure. The resultant (3-amino methyl esters were purified by silica gel column chromatography with an eluent mixture of 1:18:1 ethyl acetate:hexanes:triethylamine. The compounds where the yield is specified were isolated as one fraction by TLC. The compounds where the yield is listed as trace were isolated 157 in < 30% yield and were not found to be pure by tic (greater then 2 spots). However, the desired product was the major component (85-90%) in the isolated mixture and thus the N M R spectroscopic data could be confidently assigned. m e t h y l 3 - ( b e n z y l a m i n o ) - 2 , 2 - d i m e t h y l o c t a n o a t e ( 2 . 9 2 ) 50% yield. ' H N M R (300 MHz, CDC1 3, 5): 0.90 (t, V = 6.3 Hz, CH3, 3H), 1.14 (s, CCH3, 3H), 1.19 (s, CC# 3 , 3H), 1.23-1.36 (m, (CH2)3, 6H), 1.42-1.47 (m, CH2, 2H), 2.77-2.81 (m, N C / / , 1H), 3.65 (s, OCH3, 3H), 3.77 (d, 2J= 12 Hz, N C / / 2 , 1H), 3.91 (d, 2J = 12 Hz, N C / / 2 , 1H), 7.23-7.35 (m, Ar H, 5H) 1 3 C N M R (CDC1 3, 100 MHz): 8 14.3, 21.7, 21.7, 22.8, 27.6, 32.3, 33.0, 48.5, 51.7, 55.3, 64.0, 127.1, 128.3, 128.5, 141.5, 178.7; ESI m/z (relative intensity, ion): 292.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C i 8 H 3 0 N O 2 , 292.2277; found 292.2278. m e t h y l 3 - ( i s o p r d p y l a m i n o ) - 2 , 2 - d i m e t h y l - 4 - p h e n y l b u t a n o a t e ( 2 . 9 3 ) 52% yield. *H N M R (400 MHz, CDC1 3, 5): 0.58 (d, 3 J = 6.4 Hz, CH(C/7 3) 2 , 3H), 0.81 (d, V = 6.4 Hz, CH(C/7 3) 2, 3H), 1.17 (s, CCH3, 3H), 1.22 (s, CCH3, 3H), 2.26 (sept, 3 J = 6.4 Hz, C/ / (CH 3 ) 2 , 1H), 2.31-2.37 (m, N C / / , 1H), 2.81 (d of d, 2J= 8.4 Hz, V = 3.6 Hz, PhC/7 2, 1H), 3.04 (d of d, 2J = 6.4 Hz, V = 3.6 Hz, PhC/Y 2, 1H), 3.64 (s, OCH3, 3H), 7.18-7.29 (m, Ar H, 5H); 1 3 C N M R (CDC1 3, 100 MHz): 8 20.9, 22.8, 23.5, 23.6, 40.1, 47.9, 48.3, 51.7, 63.2, 126.3, 128.4, 129.5, 140.6, 178.5; ESI m/z (relative intensity, ion): P h HN O 158 264.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for Ci6H 26N0 2, 264.1964; found 264.1960. 59% yield. [ H N M R (400 MHz, CDC1 3, 8): 0.76 (br s, Ni/, 1H), 1.01 (d, 3J= 6.0 Hz, CH(Ci / 3 ) 2 , 3H), 1.07 (d, V = 6.0 Hz, CH(Ci / 3 ) 2 , 3H), 1.14 (s, CCH3, 3H), 1.19 (s, C C / / 3 , 3H), 1.43-1.53 (m, P h C H 2 C i / 2 , 1H), 1.74-1.82 (m, PhCH 2 C/ / 2 , 1H), 2.58-2.66 (m, C H 2 C i / , 1H), 2.80-2.93 (m, C//(CH 3 ) 2 , PhC// 2 , 3H), 3.65 (s, OCH3, 3H), 7.19-7.32 (m, A r / / , 5H); 1 3 C N M R (CDC1 3, 100 MHz): 5 21.5, 22.4, 23.8, 24.4, 34.5,36.1,48.1,48.1, 51.7, 60.9, 125.9, 128.4, 128.5, 142.7, 178.6; ESI m/z (relative intensity, ion): 278.3 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 7 H 2 8 N 0 2 , 278.2120; found 278.2127; Anal. Calcd. for Ci 7 H 2 7 NO 2 -0.25H 2 O: C, 72.43; N , 4.97, H , 9.83. Found: C, 72.46; N , 5.38; H , 9.50. m e t h y l 3 - ( i s o p r o p y l a m i n o ) - 2 , 2 - d i m e t h y l o c t a n o a t e ( 2 . 9 5 ) trace. *H N M R (400 MHz, CDC1 3, 8): 0.87 (t, 3 J = 6.4 Hz, C / / 3 , 3H), 0.96 (d, V = 6.4 Hz, CH(C/ / 3 ) 2 , 3H), 0.99 (d, 3 / = 6.0 Hz, CH(C/ / 3 ) 2 , 3H), 1.08 (s, C C i / 3 , 3H), 1.14 (s, C C / / 3 , 3H), 1.25-1.47 (m, (C/ / 2 ) 4 ) 8H), 2.66-2.69 (m, N C / / , 1H), 2.81 (sept, 3 J = 6 Hz, C/ / (CH 3 ) 2 , 1H), 3.63 (s, O C / / 3 , 3H); 1 3 C N M R (CDC1 3, 100 MHz): 8 14.3, 21.2, 22.5, 22.8, 23.8, 24.3, 27.7, 32.4, 34.0, 48.2, 48.3, 51.6, 61.1, 178.9; ESI m/z (relative intensity, m e t h y l 3 - ( i s o p r o p y l a m i n o ) - 2 , 2 - d i m e t h y l - 5 - p h e n y l p e n t a n o a t e ( 2 . 9 4 ) 159 ion): 266.3 (20%; M + Na), 244.4 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C14H30NO2, 244.2277; found 244.2269. m e t h y l 3 - ( b e n z y l a m i n o ) - 2 , 2 - d i m e t h y I - 4 - p h e n y l b u t a n o a t e ( 2 . 9 6 ) trace. ' H N M R (300 MHz, CDCI3, 5): 1.24 (s, C C / / 3 , 3H), 1.28 (s, C C / / 3 , 3H), 1.89 (br s, Nif, 1H), 2.39-2.47 (m, N C / / , 1H), 2.89-2.94 (m, PhC// 2 , 1H), 3.14-3.19 (m, PhC// 2 , N C / / 2 , 2H), 3.43 (d, 2J = 12 Hz, NC/7 2 , 1H), 3.66 (s, O C / / 3 , 3H), 7.01-7.36 (m, Ar H, 10H); 1 3 C N M R (CDCI3, 100 MHz): 5 38.9, 48.4, 51.9, 54.8, 65.8, 126.5, 127.1, 128.2, 128.3, 128.5, 128.7, 129.5, 140.2, 178.2; APCI m/z (relative intensity, ion): 312.2 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 2 0 H 2 6 N O 2 , 312.1964; found 312.1953. m e t h y l 3 - ( b u t y l a m i n o ) - 2 , 2 - d i m e t h y I - 4 - p h e n y l b u t a n o a t e ( 2 . 9 7 ) trace. ' H N M R (400 MHz, CDCI3, 8): 0.73 (t, V = 4.8 Hz, N(CH 2 ) 3 C/7 3 , 1.05-1.12 (m, NCH 2 (C / / 2 ) 2 > 4H), 1.19 (s, C C / / 3 , 3H), 1.23 (s, CC/7 3 , 3H), 2.09-2.16 (m, NC/7 2 , 1H), 2.24-2.29 (m, NC/7 2 , 1H), 2.33-2.39 (m, N C / / , 1H), 2.82 (d of d, 2J= 8.8 Hz, V = 3.6 Hz, ?hCH2, 1H), 2.98 (d of d, 2J= 6.8 Hz, 3 J - 3.6 Hz, PhC/7 2, 1H), 3.66 (s, O C / / 3 , 3H), 7.18-7.31 (m, Ar H, 5H); 1 3 C N M R (CDCI3, 100 MHz): 8 14.1, 20.3, 21.4, 22.1, 32.9, 39.2, 48.4, 50.5, 51.7, 66.3, 126.3, 128.5, 129.4, 140.4, 178.5; ESI m/z (relative intensity, ion): 278.2 (100%, M + H); HRMS (ESI) m/z: [M + H ] + calcd for C 1 7 H 2 8 N 0 2 , 278.2120; found 278.2110. Ph HN J O 160 ^ NH 0 m e t h y l 3 - ( t e r t - b u t y l a m i n o ) - 2 , 2 - d i m e t h y l - 4 - p h e n y l b u t a n o a t e ( 2 . 9 8 ) trace. ' H N M R (400 M H z , CDC1 3 , 5): 0.94 (s, C(C/ / 3 ) 3 , 9 H ) , 1.10 (s, C C / / 3 , 3H), 1.19 (s, C C / / 3 , 3H), 2.61 (d of d,2J= 10'Hz ,V= 5.8 Hz, ?hCH2, 1H), 2.81 (d of d, 2J = 10 Hz, V = 6.3 Hz, PhC/7 2,1H), 3.32 (t, V = 6.1 Hz, N C / / , 1H), 3.40 (s, O C / / 3 , 3H), 7.23-7.29 (m, A r / / , 5H); 1 3 C N M R (CDC1 3, 100 MHz): 8 20.1, 24.6, 30.9, 42.5, 48.3, 50.9, 51.5, 58.7, 126.2, 128.3, 129.7, 140.5, 178.6; ESI m/z (relative intensity, ion): 278.3 (100%, M + H); HRMS (ESI) m/z: [M + Na] + calcd for Ci 7 H 2 7N0 2 Na, 300.1939; found 300.1928. 161 2 . 6 R e f e r e n c e s (1) Trost, B. M . Angew. Chem. Int. Ed, Engl. 1 9 9 5 , 34, 259. (2) Walsh, P. J.; Baranger, A . M . ; Bergman, R. G. J. Am. Chem. Soc. 1 9 9 2 , 114, 1708. (3) Baranger, A . M . ; Walsh, P. J.; Bergman, R. G. J. Am. Chem. Soc. 1 9 9 3 , 115, 2753. (4) McGrane, P. L. ; Jensen, M . ; Livinghouse, T. J. Am. Chem. Soc. 1992 ,1 1 4 , 5459. (5) Heutling, A . ; Pohlki, F.; Doye, S. Chem. Eur. 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[180) Lee, K. -D. ; Suh, J.-M.; Park, J.-H.; Ha, H.-J.; Choi, H . G.; Park, C. S.; Chang, J. W.; Lee, W. K. ; Dong, Y . ; Yun, H . Tetrahedron 2 0 0 1 , 57, 8267. [181) Ha, H.-J.; Ahn, Y . - G . ; Lee, G. S. Tetrahedron Asymmetry 1999 , 1 0 , 2327. [182) Hassan, N . A . ; Bayer, E.; Jochims, J. C. J. Chem. Soc. Perkin Trans. 1 1 9 9 8 , 22, 3747. [183) Sassaman, M . B. Tetrahedron 1 9 9 6 , 52, 10835. [184) Vachal, P.; Jacobsen, E. N . J. Am. Chem. Soc. 2002 , 1 2 4 , 10012. [185) Kost, A . N . ; Koronelli, T. V. ; Sagitullin, R. S.; Puchkov, V . A. ; Denisov, Y . V . ; Vul'fson, N . S. Tetrahedron 1 9 6 9 , 25, 3067. [186) Baker, J. K . ; Little, T. L. J. Med. Chem. 1 9 8 5 , 28, 46. [187) Verardo, G.; Geatti, P.; Pol, E.; Giumanini, A . G. Can. J. Chem. 2 0 0 2 , 80, 779. [188) Garner, P.; Kaniskan, H. U . Tetrahedron Lett. 2 0 0 5 , 46, 5181. [189) Ho, C. K. ; Schuler, A . D.; Yoo, C. B.; Herron, S. R.; Kantardjieff, K . A. ; Johnson, A . R. Inorg. Chim. Acta 2 0 0 2 , 431, 71. 168 C H A P T E R T H R E E : P R O B I N G M O D E O F A C T I V A T I O N IN T A N D E M C - N , C - C B O N D F O R M I N G R E A C T I O N S E Q U E N C E 3.1 I n t r o d u c t i o n 3 .1 .1 T a n d e m r e a c t i o n s e q u e n c e The catalytic hydroamination of alkynes is an atom economical method for generating imines, as there are no byproducts formed in the reaction (eq. 3.1).1 A catalyst N R 1 N R 1 R = H + H 2 N R - — - JT + R ll^  (3.1) R H Markovnikov anf/-Markovnikov The Schafer group is very active in developing new group 4 metal complexes such as 3.1 to promote this transformation.2 [Ph—i J^Ti(NEt 2) 2 N 3.1 Complex 3 .1 has been found to be very active in the regioselective hydroamination of terminal alkynes with primary amines, yielding almost exclusively the arcfr'-Markovnikov imine, regardless of the substrate combinations. Furthermore, 3.1 is very tolerant of different functional groups, such as protected alcohols and amines, silyl groups, carbonyls, esters, and amides.2,3 Combining these two observations, along with the fact that there are no byproducts formed in hydroamination reactions, indicates that 3.1 is 169 very suitable for use in tandem reaction sequences. In these tandem reaction sequences, catalysis of the hydroamination reaction with 3.1 (to generate the aldimines in situ) followed by the addition of a variety of nucleophiles, results in a one-pot synthesis of functionalized small molecules. The combination of catalytic hydroamination with the Strecker reaction results in a tandem reaction sequence for the synthesis of a-cyanoamines as shown in eq. 3.2. After the hydroamination reaction, T M S C N is used to deliver the cyanide moiety in a Strecker-type reaction. The result of this tandem sequential C - N , C - C bond forming reaction is the one-pot synthesis of a number of alkyl a-cyanoamines. These a-cyanoamines have been used as intermediates in the racemic synthesis of a number of other functionalized small molecules, including a-amino acids, a-amino acid derivatives, P-amino alcohols, diamines, and imidazolidinones. A long term goal of this research program is the asymmetric synthesis of a-cyanoamines. The rational development of an asymmetric variant of this methodology first requires a basic mechanistic understanding of this synthetic transformation. 3 . 1 . 2 M e c h a n i s m f o r c a t a l y t i c h y d r o a m i n a t i o n There are two steps to the tandem reaction sequence shown in eq. 3.2, and thus two different reaction mechanisms to consider. In the early 1990's, Bergman and co-workers extensively investigated the mechanism for group 4 catalyzed hydroamination of R 170 alkynes.4 This mechanism invoked a titanium imido species (3.2) as the active catalyst (Figure 3.1). Initial investigations into hydroamination with complex 3.1 have shown that there is no reaction when secondary amines are used, suggesting that this system also follows the same mechanism.3 L 2 T i ( N R 2 ) 2 3.1 H 2 N R 1 ^ 2 H N R 2 I 1 H 2 N R ^ F i g u r e 3.1: Proposed mechanism for the catalytic hydroamination of terminal alkynes with primary amines using precatalyst 3.1. L = amidate ligand. The first step in this reaction is the generation of the titanium imido complex, 3.2, through the reaction of the precatalyst 3.1 with one equivalent of the primary amine. The metallocycle 3.3 is formed through the [2+2] cycloaddition between 3.2 and the terminal alkyne. A second equivalent of primary amine can protonate the metallocycle to form the mixed bis(amido) species 3.4. A final proton transfer results in the formation of the 171 enamine 3.5 and regenerates the titanium-imido complex 3.2. Generally with precatalyst 3.1 quantitative tautomerization of the enamine 3.5 to the imine 3.6 is observed. 3.1.3 P o s s i b l e m o d e s o f a c t i v a t i o n f o r t h e S t r e c k e r r e a c t i o n While the mechanism for the catalytic hydroamination portion of the tandem reaction sequence is well established, there are several possible modes of activation for the Strecker reaction portion of the reaction sequence. In the literature there are three commonly reported modes of activation for the Strecker reaction: electrophilic activation of the imine, nucleophilic activation o f the cyanide reagent, and Lewis acid/Lewis base bifunctional catalysis. Previously reported examples of each of these modes of activation w i l l be presented in turn. The first mode of activation for the Strecker reaction involves electrophilic activation of the imine substrate. When compared with aldehydes, imines are less reactive to nucleophilic addition due to the differences in electronegativity between oxygen and nitrogen atoms.5 Therefore, many reactions with imines require a catalyst, such as a Lewis acid, to make the imine more electrophilic. Examples o f Lewis acids that have been used to catalyze the Strecker reaction include AICI3, 6 InCb , 7 polymeric scandium triflamide, 8 N i C h , 9 and Yb(OTf )3 . 1 0 There have also been more complex catalyst systems developed for the asymmetric Strecker reaction (Figure 3.2), and these systems have also been proposed to proceed via imine activation, either through hydrogen bonding (3.7) or Lewis acid activation (3.8). 172 R H N t ? o O C H 3 0 C H 3 O H O + R = polystyrene, Ph Ti(0'Pr)4 3.7 3.8 Figure 3.2: Catalyst systems where the mode of activation for the Strecker reaction has been proposed to be imine activation. For example, catalyst 3.7 has been used in combination with H C N by Jacobsen and co-workers successfully in the Strecker reaction, and preliminary kinetic investigations are consistent with the reversible binding of the imine to 3.7.11 The in situ generated complex 3.8 has been used by the research groups of Hoveyda and Snapper for the asymmetric Strecker reaction. This reaction uses T M S C N as the cyanide source, though the addition of isopropyl alcohol is required for optimum yields and enantiomeric excesses (ee's). It has been determined that the active nucleophile is actually H C N and not T M S C N . Initially the mode of activation was proposed to be simple electrophilic activation of the imine by the Ti-metal center, though later observations determined that the mode of activation is actually one of bifunctional catalysis. This mechanism will be discussed later on in this section. The second mode of activation proposed for the Strecker reaction is generally only applicable i f T M S C N is the cyanide delivery reagent. This mode of activation involves Lewis base coordination of the electropositive silicon to enhance the nucleophilicity of the cyanide. For example, compound 3.9 has been found to react with T M S C N to form a hexacoordinate silicon species. 1 7 3 3.9 This complex has then been shown to be active for the asymmetric Strecker reaction, though the scope of this reaction is limited to aryl imines containing a benzhydryl substituent on the nitrogen.13 The ee's of this reaction range from 12-99% and the average ee is 76%. The proposed reaction mechanism is shown in Scheme 3.1. Scheme 3 . 1 : Proposed mechanism for Strecker reaction with catalyst 3 . 9 . After the formation of the hexacoordinate silicon compound, the nucleophilically-enhanced cyanide can then attack the imine on the Re face to yield the product with the observed stereochemistry. Si N M R spectroscopic experiments support the formation of a hexacoordinate silicon compound, and it is also proposed that the cyanoamine remains coordinated to the silicon center after cyanide addition. This mechanism has also been recently supported using computational methods.14 In addition, there has been a recent report of 7V-heterocyclic carbenes as catalysts for a racemic version of the Strecker reaction.15 In this investigation, observations of ' H and 1 3 C N M R spectroscopy indicate that the catalytically active species is either 3 . 1 0 or 3 .11 (Figure 3.3), resulting from the reaction between the carbene and the T M S C N . 174 C N /=\ + 3.10 3.11 F i g u r e 3 . 3 : Possible species for the reaction between carbenes and TMSCN. The third mode of activation that is reported for the Strecker reaction is a bifunctional type mechanism. In this mechanism, the catalyst activates both the imine and the cyanide nucleophile simultaneously. The in situ generated complex 3 .8 (vide supra) was initially reported by Hoveyda and Snapper to catalyze the Strecker reaction via electrophilic activation of the imine. However, a later report proposes that while the titanium center does activate the imine, one of the carbonyls of the amide in the ligand backbone also activates the H C N through hydrogen bonding to enhance the cyanide nucleophilicity. The mechanism has been probed in these investigations using kinetic experiments and molecular modeling and calculations.16 Corey and co-workers also propose a bifunctional type mechanism for the Strecker reaction using a bicyclic guanidine catalyst (Figure 3.4).17 175 Ph Figure 3.4: Proposed catalytic cycle for Strecker reaction with bicyclic guanidine catalyst 3.12. In this reaction, H C N is the reagent for delivering the cyanide, and this molecule initially forms a hydrogen bonding interaction with the catalyst. The imine can then form a hydrogen bond adjacent to the cyanide, bringing it into closer proximity to the cyanide for addition. Protonation of the a-cyanoamine yields the product and regenerates the catalyst. Notably, the substrate scope of this reaction fs limited to aryl imines. Another example of bifunctional catalysis has been reported by Shibasaki arid co-workers for the asymmetric Strecker reaction using T M S C N . 1 8 Shown in Figure 3.5, the aluminum-based catalyst 3.13 is proposed to electrophilically activate the imine, while the oxygen of the phosphine oxide activates the silicon. 176 Flu = fluorenyl Figure 3.5: Proposed catalytic cycle of bifunctional Al-catalyst for the Strecker reaction. After nucleophilic attack by the cyanide and elimination of the TMS-protected a-cyanoamine, the catalyst is regenerated. Furthermore, while the reaction does require the slow addition of phenol for optimum yields and ee's, it has been determined that the active species is still the T M S C N , and that the alcohol and the generated H C N are only acting as a proton source. This proton source is required to protonate the TMS-protected a-cyanoamine, yielding the desired product. 3.1.4 Scope of project As the mechanism for catalytic hydroamination is already well understood, mechanistic investigations included here focus on the Strecker reaction portion of the 177 tandem reaction sequence. The insight that is gained by investigating the mode of activation of this reaction is then applied towards the development of modified reaction conditions to use easily recoverable activators to facilitate product recovery as well as the design of both diastereoselective and enantioselective versions of the tandem C - N , C - C bond forming reaction sequence. 3 .2 R e s u l t s a n d d i s c u s s i o n 3 .2 .1 M o d e o f a c t i v a t i o n As was discussed in the introduction, there are three common modes of activation for the Strecker reaction, activation of the imine, activation of the cyanide, and bifunctional activation of both. In the case of the tandem reaction sequence, the electrophilic imine activation could occur by the Lewis Acidic titanium precatalyst 3 .1 (Figure 3.6). Since the hydroamination occurs in the same pot as the Strecker reaction, 3.1 is not removed from the mixture and thus it could also catalyze the Strecker reaction. Ideally, i f 3.1 catalyzes the Strecker portion of this tandem reaction sequence, asymmetric catalyst systems that have been developed in the Schafer group1 9 could be applied towards the asymmetric version of the tandem reaction sequence. Alternatively imine activation could also occur through a hydrogen bonding interaction between the primary amine and the imine. There is an extra equivalent of primary amine in the reaction mixture, as two equivalents are commonly used in the hydroamination reaction, though only one equivalent is consumed in the formation of the aldimine product. In contrast to imine activation, under these reaction conditions the excess primary amine could activate the cyanide through a nucleophilic interaction with the T M S C N . 178 Nucleophilic activation could also occur through the reaction between the imine and the TMSCN, which would serve to enhance the electrophilicity of the imine and effectively "deliver" the cyanide nucleophile in the C - C bond forming step. 8+ ' . f 8-R 2 H 2 N . : — - S i - C N NC. H imine activation cyanide activation Figure 3.6: Possible modes of activation for the Strecker reaction. The bifunctional mechanism is unlikely because the titanium catalyst 3.1 does not have any functionality present to activate the silicon. However, there is the small possibility that one of the chelating ligands could shift to a monodentate binding mode (through the oxygen atom) thus allowing for nucleophilic activation of the T M S C N by the nitrogen atom. Due to the steric bulk of the N-substituent on the ligand, this interaction with T M S C N should be sterically unfavourable. Thus, a bifunctional mechanism is not probable in the developed tandem sequential reaction. In order to establish the mode of activation in the Strecker portion of the tandem sequential reaction, multiple control experiments have been performed. For this tandem reaction sequence the results of these experiments indicate that the mode of activation is nucleophilic activation of the T M S C N by the excess primary amine. Evidence supporting this particular mode of activation, along with evidence refuting the other possible modes of activation, will be presented. 179 A key control experiment provides valuable insight into the mode of activation in the Strecker portion of the tandem reaction sequence. Since activation can occur in four possible ways for the tandem reaction sequence as developed in chapter two: 1) imine activation by 3 . 1 , 2) imine activation by excess primary amine, 3) nucleophilic activation of T M S C N by excess primary amine or 4) nucleophilic activation of T M S C N by imine, a control experiment that eliminates the excess primary amine is performed (eq. 3.3). In this reaction, the hydroamination is carried out with only one equivalent of primary amine, which is completely consumed in the hydroamination step. After the imine is formed (as observed by ' H N M R spectroscopy) the T M S C N is then added to the reaction as before. However, by *H N M R spectroscopy, no reaction is observed under these conditions. 1) 5 mol% 3 .1 /C 6 D 6 /65 °C/12 h / ~ ^ ^ ^ ^ H 2) TMSCN/r.t. /12 h + ( 3 " 3 ) T M S C N The outcome of this experiment shows that 3.1 is not an effective Lewis Acid activator for the Strecker reaction in this tandem reaction sequence. This result also indicates that the imine product itself is not an efficient Lewis base activator of the T M S C N reagent. This reaction does suggest that the excess primary amine is an efficient activator for the tandem reaction sequence. For further confirmation that 3 .1 is not required for the tandem reaction sequence, the reaction using two equivalents of primary amine (Scheme 3.2) is performed. In this 180 reaction, the imine is separated from 3.1 by vacuum transfer of the entire reaction mixture before the addition of TMSCN. In this case the TMS-protected ct-cyanoamine is readily formed in 100% conversion, based on disappearance of terminal alkyne. H-+ 1)5 mol% 3.1/C6D6/65 °C/12 h 2 equiv. 2) Vacuum transfer H,N' 3)TMSCN/r.t./12h 100% conversion Scheme 3.2: Separation of the imine from the titanium precatalyst before the Strecker reaction. From these experiments, it can be concluded that the mode of activation requires the primary amine and that the titanium precatalyst 3.1 is not necessary for the Strecker reaction to occur. While it is clear that the excess primary amine is essential for the success of the Strecker reaction in this tandem reaction sequence, the role of the primary amine is not clear. To gain more insight to the activation of this reaction by amines, secondary and tertiary amines are investigated. With the tertiary amines in particular, activation of the imine through hydrogen bonding can not occur. After the hydroamination reaction with one equivalent of primary amine, a second equivalent of amine (secondary or tertiary) is added along with T M S C N (eq. 3.4). The reaction is then quenched with trifluoroacetic 181 anhydride (TFAA) and the trifluoroacetate (TFA)-protected a-cyanoamines are isolated via column chromatography. H2N Ph 1) 5 mol% 3.1/C6H6/65 °C/12 h 2) activator/TMSCN/r.t./3 h 3) TFAA (3.4) Each experiment is repeated twice and the yields are the average of the two experiments. These results are summarized in Table 3.1. Table 3 .1: Yields of TFA-protected a-cyanoamines after column chromatography with a variety of activators. Entry Activator % Yield" 1 P h ^ N H 2 93 2 0 H 82 3 k 91 "Isolated yield after column chromatography calculated from terminal alkyne; average yield of two experiments. As can be seen in Table 3.1, the secondary and tertiary amines also lead to the formation of products in yields comparable to those observed when benzylamine is the activator. While is it possible that the primary and secondary amines are promoting this reaction by hydrogen bonding with the imine (vide supra), the success of the aprotic tertiary amine suggests that nucleophilic activation of the T M S C N by the amine is sufficient to promote the addition of cyanide to the aldimine. Further characterization of this nucleophilically-182 activated silicon species would provide valuable insight into the mode of activation for the tandem sequential reaction. 3 . 2 . 2 N a t u r e o f t h e n u c l e o p h i l i c a c t i v a t i o n There are three possible species that can be formed through the reaction of an amine (such as benzylamine) and TMSCN, and these are shown in Figure 3.7. Ph N - S i — C N H H 1 reactive species #1 PIT N - S L H H C N „Si> Ph N H + HCN reactive species #2 reactive species #3 F i g u r e 3 . 7 : Three possibilities for the species formed from the reaction between benzylamine and TMSCN. The first candidate is a pentacoordinate silicon adduct (reactive species #1), the second is a tetracoordinate silicon salt (reactive species #2), and the third candidate is the combination of silylated amine and H C N gas (reactive species #3). Under the typical reaction conditions utilized for the tandem sequential reaction, all three reactive species must be considered. In this case, spectroscopic characterization of solution phase species generated using representative reaction conditions assists in differentiation of these three reactive species. It has been determined that reactive species #1 is most likely the adduct that is formed. Evidence against the formation of the other two candidates in Figure 3.7, as well as support for reactive species #1, will be presented. The characterization of silicon complexes by 2 9 S i N M R spectroscopy has been reported in the literature. For example, the formation of pentacoordinate silicon species, such as reactive species #1, is generally characterized by a large change in the chemical 183 shift in the 2 y S i N M R spectrum (10-95 ppm) from the starting tetracoordinate silicon 20 compound. On the other hand, the formation of a tetracoordinate silicon salt, such as reactive species #2, shows a much smaller change in the chemical shift (4-20 ppm) from the initial tetracoordinate silicon starting material.21 Therefore, spectroscopy should be useful in distinguishing between these compounds. Furthermore, i f the acidic H C N is being formed under these reaction conditions (reactive species #3) the addition of a base to the reaction mixture should result in no product formation. In investigating the nature of the species formed through the nucleophilic activation of the silicon by the primary amine, it is necessary to determine whether the interaction between the primary amine and the T M S C N can be observed spectroscopically. For these experiments, one equivalent of benzylamine is combined with one equivalent of T M S C N in CeD6 in an N M R tube (eq. 3.5). H 2 N " > h C 6 D 6 + . "reactive species" (3.5) T M S C N The *H N M R spectrum of this reaction is shown below in Figure 3.8. Both the free T M S C N and the free benzylamine signals are observed. In addition, the two additional peaks in this spectrum are attributed to the methyl and methylene signals of a reactive species that is formed between T M S C N and benzylamine. 184 TMSCN Benzyl amine i UL M i m i i H u i i n u u i m i 70 CS CO '4 '4U' Figure 3 . 8 : 300 MHz *H N M R spectrum of the equilibrium in eq. 3.5 in CeD 6. This indicates that the primary amine is interacting with the T M S C N and is consistent with the formation of a reactive species three of which are shown in Figure 3.7. The 1 3 C N M R spectrum of the reaction in eq. 3.5 is shown in Figure 3.9. Again, it is observed that there is an extra set of signals, in addition to the signals from the benzylamine and the T M S C N , indicating the formation of a reactive species. It should be noted that while only one new species is observed by N M R spectroscopy, there is also the possibility of the formation of other products, for example, hexacoordinate silicon adducts,22"24 that are in rapid equilibrium and are not apparent on the N M R timescale, but could be catalytically active. Likewise, the observed reactive species is not necessarily the species that is responsible for the cyanide addition. 185 tt it "^"""'s r ' i" '"""Ji" Figure 3 . 9 : 75 M H z 1 3 C N M R spectrum of the equilibrium in eq. 3.5 in C 6 D 6 . As there is still starting material present in the reaction mixture, two additional reactions are then performed, one with a five-fold excess of TMSCN, and the other with a five-fold excess of benzylamine, in an attempt to completely shift the equilibrium to the reactive species. However, in both these experiments there are still substantial amounts of free benzylamine and free T M S C N observed respectively, indicating that a complete shift of the equilibrium under these conditions is not obtained. Only when the *H N M R data is collected at very low temperature is a dramatic shift in equilibrium observed. For example, at -70 °C, the peak due to the methylene group on the benzylamine has almost completely disappeared, and the second methylene peak of the product has increased in strength, indicating that the equilibrium is now favouring the formation of the "reactive species". 186 Reactive species #3 can be quickly ruled out through a combination of literature precedence and experimental results. In 1986 there was a report in the literature of attempts to form the silylated amine and liberate H C N , as shown in eq. 3.6.25 N H + T M S C N N - S i M e 3 + H C N (3.6) This transformation has been completed in good yields of the silylated amine (88%), but notably the reaction is slow, and elevated temperatures (70 °C) and neat reaction conditions are required. The tandem reaction sequence here is carried out at room temperature and is observed to occur very rapidly (vide supra), which makes the formation of H C N unlikely. Although the literature on the Strecker reaction often invokes the in situ formation of H C N , this is generally achieved with a protic additive such as isopropyl alcohol and this reaction has been noted to fail under strictly anhydrous conditions.26 The hydroamination tandem reaction sequence here is performed under strictly anhydrous conditions, which is required for the air- and moisture-sensitive titanium precatalyst. It is qualitatively very obvious when the titanium precatalyst is exposed to air or moisture in that the insoluble titanium dioxide is formed as a white precipitate; this solid has never been observed with these reactions. Therefore, based on literature reports, it is very unlikely that the formation of free H C N is occurring in the tandem hydroamination and Strecker reaction sequence. To experimentally rule out H C N formation (reactive species #3), the results of two experiments are considered. First, it was shown in section 3.2.1 that the use of aprotic triethylamine in the tandem reaction sequence leads to the successful formation of products. Reactive species #3 can not be formed with triethylamine. Second, in the 187 reaction shown in eq. 3.7, the tandem reaction sequence is equally successful when a stoichiometric quantity of the bulky pyridine (2,6-di-te^butyl-4-methylpyridine) is introduced into the reaction before the T M S C N is added. 2,6-Di-tert-butyl-4-methylpyridine is commonly used as a proton scavenger to rule out proton mediated reaction pathways in mechanistic studies.27'28 This substituted pyridine is too sterically hindered to interact with either the metal center or the silicon. However, it should react with the H C N i f it is indeed being produced. Ph — H T M S . ^ + 1) 5 mol% 3.1/C 6 H 6 /65 °C/12 h JI 2 equiv. 2) , , P h ^ A C N (3.7) 2) H 2 N ^ P h >^y< /TMSCN/r.t./3 h 100% conversion Therefore, both literature precedence and the success of the reaction in the presence of aprotic exogenous base rule out reactive species #3 as being the mode of activation in the tandem reaction sequence. To discern between reactive species #1 and reactive species #2 for the tandem reaction sequence, literature precedence is again considered in combination with experimental evidence. There have been a number of very detailed investigations in the literature studying the formation of both pentacoordinate organosilicon adducts (such as reactive species #1) and tetracoordinate organosilicon salts (such as reactive species #2) with various organosilicon species. ' " Though T M S C N has never been the subject of these investigations, some very clear trends have emerged that provide insight into the identity of the adduct formed between the amine and the T M S C N . Tetracoordinate silicon salts are only formed when there is a highly electronegative group or good leaving 188 group attached to the silicon. Examples of such groups include CIO4, OSO2CF3, Br, and I. On the other hand, i f a C l is attached to the organosilicon, then only adduct formation is observed.20'21 Since cyanide is not a typical leaving group it is postulated that reactive species #2 is not being formed. Furthermore, 2 9 S i N M R spectroscopy can provide information as to the nature of the species involved in this reaction. The Si signal that is measured for TMSOTf is 48 ppm. 2 0 The 2 9 S i signal for T M S C N on the other hand is found to be -12 ppm. This lower frequency signal indicates that there is much more shielding of the silicon; it also shows the great difference in electronegativity between triflate and cyanide. Since the electronegativity of the group attached to the silicon affects whether or not a salt wil l be formed, it is unlikely that T M S C N wil l form a tetracoordinate salt (reactive species #2), but should form a pentacoordinate adduct (reactive species #1). Since the interaction between the amine and the T M S C N can be observed spectroscopically, further evidence supporting the formation of reactive species #1 and refuting the formation of reactive species #2 is found through N M R spectroscopic experiments. It has been reported in the literature that there is not a large difference in chemical shift observed between the organosilicon starting material and the 9 0 9 1 9 0 • tetracoordinate silicon salt in the Si N M R spectrum (between 4 and 20 ppm). The Si N M R spectrum of a 1:1 mixture of T M S C N and benzylamine in toluene shows two signals. One is at -12 ppm, which is due to the T M S C N , and the other is at -99 ppm, which is due to the reactive species. This is a very large change in chemical shift, and is not consistent with the formation of reactive species #2. This large change in chemical shift is consistent with literature vales for pentatcoordinate silicon adducts where the 189 range is between 10 and 95 ppm, and is further support for the formation of reactive species #1.20 Finally, it has also been noted in the literature that many organosilicon species will first form the pentacoordinate adduct, but that when the amount of base (i.e., • * 20 benzylamine) is increased to two equivalents, the tetracoordinate salt is also formed. This observation has not been made with this system. When the T M S C N is combined with five equivalents of benzylamine in CeD6 (vide supra), there is no change observed in the ' H N M R spectra, relative to what is observed in the 1:1 reaction mixture. This suggests that the tetracoordinate salt (reactive species #2) is not formed under these conditions. The combination of literature precedence and experimental evidence strongly disfavors the formation both reactive species #3 and reactive species #2 in the solvents used for the tandem hydroamination and Strecker reaction sequence developed here. These investigations strongly support the formation of the pentacoordinate silicon adduct, reactive species #1. Additional evidence supporting the formation of a silicon adduct will be presented later in this chapter in the section discussing asymmetric versions of this tandem reaction sequence. 3.2.3 Practical synthetic applications of nucleophilic activation a-Cyanoamines are challenging molecules to purify. With the insight into the nucleophilic activation gained in the previous section, it is postulated that the purification of this class of molecules can be simplified through judicious choice of activator. It is proposed that i f the initial hydroamination is carried out with a primary amine with a high 190 boiling point, such as benzylamine, then the activation of the T M S C N could be carried out with a more volatile amine, such as isopropylamine. The isopropylamine could then be easily removed under vacuum upon completion of the reaction to simplify the purification. This approach to the tandem sequential reaction is shown in Scheme 3.3. -H p h + 1)5 mol% 3 .1 /C 6 H 6 /65 °C/12 h H 2 N Ph 2) isopropylamine/TMSCN/r.t./12 h N ^ P h P h ^ ^ ^ ^ H HN Ph 3) sat. NH 4 CI Ph" ^ C N P I T v " C N Scheme 3 .3 : Synthesis of a-cyanoamines using isopropylamine as an activator. After forming the initial imine containing the benzyl substituent on the nitrogen, the isopropylamine is added to the reaction mixture, along with T M S C N . After quenching the reaction with saturated NH 4C1, the ' H N M R spectrum indicates the formation of two a-cyanoamines, one with the benzyl substituent on the nitrogen, and a second one with the isopropyl substituent on the nitrogen, in approximately equal amounts. The formation of these two a-cyanoamines can be explained through imine metathesis at the catalytically active titanium center. Imine metathesis has been reported in the literature,33 and a proposed reaction mechanism is shown in Figure 3.10. 191 Figure 3.10: Proposed mechanism for imine metathesis. L = amidate ligand. In the mechanism for catalytic hydroamination discussed in the introduction, the bis(amidate)imido titanium complex, 3.14, is proposed to be the catalytically active species. Upon addition of an alternative primary amine, such as isopropylamine, a proton transfer reaction leads to the formation of a bis(amidate) mixed bis(amido) titanium complex, 3.15. A second proton transfer reaction leads to the formation of a second bis(amidate)imido titanium complex, 3.16. This complex can then react with the initially formed imine (the one containing the benzyl substituent on the nitrogen) to form the metallacyclic intermediate, 3.17. Compound 3.17 can then form a second imine, one containing the isopropyl substituent on the nitrogen, and regenerate 3.14. Finally, this second imine can also react with the TMSCN, leading to the formation of two different o> cyanoamines. 192 While the addition of the second, more volatile, primary amine in the tandem reaction sequence is intended to simplify purification of the products, the occurrence of the imine metathesis side reaction is deleterious to reaction success. Clearly, primary amines cannot be used to simplify work-up conditions. While secondary and tertiary amines (as activators) do avoid unwanted side reactions, such as imine metathesis, their high boiling points and reactivities with T F A A do not simplify the work-up protocol. However, commercially available amines on solid support34 would enhance purification efficiency. Entries 2 and 3 in Table 3.2 show that amines mounted on a polystyrene bead are effective at promoting the Strecker reaction, although they result in slightly reduced yields. These beads are added to the reaction mixture after the hydroamination reaction and before the addition of T M S C N . After the reaction is complete, the reaction mixture is simply filtered to separate the solid-supported activators before quenching the TMS-protected a-cyanoamines with TFAA. Table 3.2: Yields of TFA-protected a-cyanoamines after column chromatography with novel activators. H-+ 1 equiv. HzN^Ph 1) 5 mol% 3.1/C6H6/65 °C/12 h 2) activator/TMSCN/r.t./3 h 3) TFAA Entry Activator % Yield" 1 ^ N H 2 . N C 6 2 87 3 77 (3.8) "Isolated yield after column chromatography calculated from terminal alkyne; average yield of two experiments. ^Not calculated due to imine metathesis. PS = polystyrene. 193 The use of the solid-supported activators facilitates straight forward purification of this class of molecules. Furthermore, the amine substituted polystyrene beads can be recovered after the reaction, washed with hexanes, dried under high vacuum, and then re-used in another tandem reaction sequence with no reduction in product yield. Although using different primary amines as activators leads to an undesirable side reaction, a number of different activators have been shown to be successful in promoting the Strecker reaction portion of the tandem C - N , C - C bond forming reaction sequence. These include primary, secondary, and tertiary amines, as well as amines on solid support. With the success of nucleophilic activation demonstrated, it is hypothesized that the nucleophilic activation of T M S C N with chiral molecules could be used in the development of an asymmetric version of the tandem reaction methodology. Since all products contain a stereocenter alpha to the nitrogen, it remains a longstanding goal of this project to do this transformation in an asymmetric fashion. 3.2.4 P r o g r e s s t o w a r d s a s y m m e t r i c s y n t h e s i s o f c h i r a l a - c y a n o a m i n e s 3.2.4.1 I n t r o d u c t i o n Previously reported examples of the asymmetric Strecker reaction typically use H C N as the cyanide source, either directly as a gas, or through its in situ generation from T M S C N . H C N is a very toxic and dangerous chemical, and hence it would be desirable to have a protocol that avoids its use all together. The one example of the asymmetric Strecker reaction that utilizes T M S C N has only been demonstrated with aryl imines containing the bulky benzhydryl substituent on the nitrogen as substrates.13 There have been no asymmetric methodologies found that use nucleophilic activation of T M S C N 194 with alkyl imines. Therefore, the development of an asymmetric version of the tandem hydroamination and the Strecker reaction sequence would be a very valuable contribution to this area of research. Furthermore, it is often noted that when alkyl imines are used in the Strecker reaction, the resulting ee's are lower then their aryl counterparts. This could possibly be due to the decrease in steric bulk of an alkyl imine compared to an aryl imine. It is also common that very bulky groups are used on the nitrogen in order to get good ee's, such as benzhydryl groups or fluorenyl groups. It is postulated that i f an asymmetric methodology could be developed with non-bulky alkyl imines, such as the ones synthesized via hydroamination, then this should be a general methodology that could be extended to other alkyl imines with varying degrees of steric bulk. It would be anticipated that as steric bulk is enhanced, asymmetric induction should also improve. The mechanistic information regarding the mode of activation for the Strecker reaction portion of the tandem sequential reaction can be used advantageously for the extension to an asymmetric methodology. There are many readily available chiral molecules that could be suitable to activate the T M S C N to form a chiral nucleophile. This could then result in the asymmetric formation of a-cyanoamines from terminal alkynes via the tandem hydroamination and the Strecker reaction sequence. This project is the first project in the Schafer group to look at asymmetric methodology development. The parallel synthetic unit contained within a glovebox in the Schafer group is ideal for this sort of investigation. Numerous reactions can be performed at one time under inert atmosphere, without the need for large amounts of glassware. This is very useful in the screening reactions that are generally required to find a suitable activator. However, when this project began there were no developed 195 methods for the screening of stereoselectivity within the Schafer group. Using the GC-MS, methods can be optimized to determine the diastereomeric excesses (de's) of the reaction, without the need for extra equipment or reagents. Therefore, the initial investigations into an asymmetric version of the tandem reaction sequence have focused on a diastereoselective version. In terms of the tandem sequential reaction, a diastereoselective version is one where the imine contains a pre-set stereocenter before the addition of the cyanide. This first stereocenter could help direct the chiral nucleophile in forming the second stereocenter, and should help diastereoselectivity in the nucleophilic addition step. 3 .2 .4 .2 D i a s t e r e o s e l e c t i v i t y To begin investigations into a diastereoselective version of the tandem C - N , C - C bond forming reaction sequence, the test reaction shown in Scheme 3.4 using 1-hexyne and (/?)-a-methylbenzylamine is chosen. H-+ 1) 5 mol% 3 .1 /C 6H 6 /65 °C/12 h N Ph ! 2 equiv. *" + H 2 N ^ P h H 2 N ^ P h 2)TMSCN/r.t./3 h 3) T F A A S c h e m e 3 . 4 : Test reaction used in development of diastereoselective version of tandem reaction sequence. 196 This particular reaction is selected for a number of reasons. First, the long chain alkyl substituent on the imine backbone is unhindered, which while it may make the optimization of the de's more challenging, it could also result in a widely applicable methodology, as selectivities should improve as steric bulk is increased. Second, the primary amine, (i?)-a-methylbenzylamine, is a relatively inexpensive chiral amine. Third, because this primary amine is a benzylamine, the benzyl group can be removed via hydrogenolysis, which makes this route synthetically attractive for the potential preparation of primary amines. Finally, the separation of the two diastereomers formed via this reaction sequence can be accomplished using GC-MS and/or column chromatography. As seen in Figure 3.11, the two diastereomers are nicely resolved with retention times of 16.7 and 16.8 minutes respectively. 197 16.7 min. ! 16.8 min. . ! . . . 1 1 n.. i . — . . i T 1111, i . 1 1 ! . I | i C f f l • ! • • . . • Y u r i • i m • i • • . i . • . .Cte >»• • i • • " I " i • 'I • ! . . ... t I • . r r r T T T i i i i |  i . i ! i . . | tan •  . . f i - , * . . . . . . i i , . I. T .JT,^ i |  . | i . . . . . . ^ s mi i i I I i i | . i i • ') 11.00 11S0 12.00 1 2 » U.C0 1 « » . » , » . U M 1S.00 1!^......1&0p..,.J.Si».„....t7,pB 1T50. « . » M » 1900 1 W » 20.00 2pi Figure 3.11: GC trace showing the retention times of the two diastereomers formed during the test reaction in Scheme 3.4. This makes screening of reaction conditions and activators for this reaction straightforward. It should be noted that GC-MS is not used in these experiments to determine the yields of the reactions. It has been the experience in the Schafer group that yield determinations in this manner are inconsistent with what is observed in the N M R spectra. The GC-MS is used for fast determination of the relative amounts of the two diastereomers and to ensure that there are no side products being formed under the reaction conditions. Before the screening of reaction conditions for the diastereoselective reaction sequence began, the control experiment shown in eq. 3.9 is carried out. In this experiment, the chiral imine is formed using hydroamination, but the T M S C N is never added. T F A A is simply added to the reaction mixture, and the solution is concentrated. 198 When the GC-MS is run there is only one peak observed, with a retention time of 15.4 minutes and a mass of 299 amu. This product is consistent with the TFA-protected enamine shown in eq. 3.9. The difference in retention time from the diastereomeric a-cyanoamine products ensures that there will not be any overlap of these peaks with the product peaks. It should be reiterated that the Strecker reaction portion of the tandem reaction sequence has always been observed to occur very rapidly, and with complete consumption of imine. The only example where there has not been complete formation of product has been when the imine is substituted with the bulky /-butyl substituent on the nitrogen. Presumably in this case, the steric interference between the T M S C N and the /-butyl group is jUst too great. There are two ways that asymmetry can be induced in this reaction giving diastereomeric products: the first is through a chiral auxiliary effect on the imine electrophile and the second is through the formation of a chiral nucleophile. Since the chiral amine is used to form the imine, this could induce diastereoselectivity in the subsequent cyanide addition. However, it has been shown that many titanium hydroamination precatalysts will actually racemize this particular primary amine, including Ti(NEt2)4, the starting material in the synthesis of 3 . 1 . 3 6 To determine whether or not this would be the case with 3 . 1 , two control experiments are performed, the first of which is shown in Scheme 3.5. In this reaction, the chiral amine is heated in the presence + 1)5mol%3.1/ N Ph 2) TFAA 199 of a catalytic amount of 3.1 to mimic the relevant reaction conditions. After 12 h, the titanium precatalyst is purposefully decomposed, and the amine is re-isolated. O + MeC\ f 1 ) 5 m o l % 3 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h ? H 2 N ^ P h 2 ) H + H 2 N ^ P h X "Cl Phs C F 3 O N E t 3 / D C M / Q ° C t o r . t . / 1 2 h M e 0 II = Pfr C F 3 H Scheme 3.5: Reaction of chiral amine with titanium precatalyst to determine whether any racemization is occurring. A small amount of this amine is then reacted with Mosher's acid chloride (1.1 equivalents), in the presence of triethylamine, and the Mosher's amide is isolated. In comparison to a sample of Mosher's amide synthesized from racemic a-methylbenzylamine, both the ' H and the 1 9 F N M R spectra indicate that there is only one diastereomer present. This indicates that the chiral amine is not epimerized under catalytic conditions. A second control experiment (eq. 3.10) is performed with an alkyne present in the solution to determine whether racemization could occur during imine formation. 1 ) 5 m o l % 3 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h 9 + (3-10) } 2 ) S I 0 2 / H + ^ \ / \ / ^ H H 2 N Ph H o N ^ P h After the imine is formed, it is hydrolyzed with a small amount of acid and silica to form the aldehyde and the amine. The amine is then isolated via flash column 200 chromatography, and a Mosher's amide is synthesized as before. Again, both the *H and 1 9 F N M R spectra indicate that no racemization has occurred. As the catalyst systems reported in the literature that racemize this particular chiral amine are often lacking steric bulk around the metal center,36 it is not unreasonable that 3.1 does not racemize the chiral amine. This racemization is postulated to occur via a C - H bond activation alpha to the nitrogen (the mechanism of C - H bond activation remains unclear). There is a significant amount of steric bulk surrounding the titanium center in 3 . 1 , 2 and possibly it is this steric bulk that is preventing the racemization from occurring. To first probe the chiral auxiliary effect of the chiral imine, a reaction is run using the achiral primary amine on polystyrene beads as an activator (eq. 3.11). In this reaction, all the diastereoselectivity observed in the product should be a result of the chiral electrophile. 0 = O = + 1 )5mo l%3.1 /C 6 H 6 / 65 °C /12h F 3 C ^ N ^ P h + F 3 C ^ N ^ > h r 2)beads/TMSCN/r . t . /12h ^ ^ A ^ ' " H ^ ^ ^ A ' C N H 2 N ^ P h 3) T F A A C N H H — ^ beads = (ps ) - ^N l - l 2 After the imine is formed, the beads and the T M S C N are added to the reaction mixture, which after 12 h is followed by filtration to separate the beads and subsequent quenching with T F A A . By GC-MS there are no side products formed but unfortunately the diastereoselectivity is low (de = 14%). This indicates that the chiral electrophile has little effect on the diastereoselective addition of the cyanide. In an earlier section it has been postulated that a silicon adduct (reactive species #1, Figure 3.7) is the active compound for introducing the cyanide. This postulate would 201 be further supported i f diastereoselectivity is observed in the reactions with the chiral activator. Furthermore, i f active species #2, the tetracoordinate salt, or active species #3 (with the production of HCN) is occurring, no improved diastereoselectivity should be observed. The effects of the chiral primary amine to form both a chiral nucleophile and a chiral electrophile are probed (eq. 3.12). Using two equivalents of the chiral primary amine, the imine is formed in benzene, followed by addition of the T M S C N (where the excess chiral primary amine is also the activator) and quenching of the reaction with TFAA. + 1)5mol%3.1/C6H6/65 °C/12 h 2 equiv. _ 2) TMSCN/solvent/temp./12 h X 3) T F A A H2N Ph When the reaction is run in benzene the de increases to 30%. This increase in de supports the formation of a chiral silicon adduct as the nucleophile. Unfortunately this diastereoselectivity is not very high. Possibly this could be due to the relatively small chiral activator that is used; this particular amine has been used previously in an effort to induce enantioselectivity in reactions reported in the literature with limited success.37 The effects of different solvents on the diastereoselectivity of this reaction are then investigated. It is predicted that the more non-polar solvents will lead to the highest de's as the adduct should be the only species formed and its reactivity should be enhanced. As the polarity of the solvent increases, the reactive species could be further stabilized and possess decreased reactivity. This should impact de's for this reaction. Furthermore, 202 i f the solvent molecules contain any lone pairs of electrons that are capable of directly activating the TMSCN, there would also be a decrease in the observed de. The benzene solvent for the hydroamination is removed under vacuum before the second step of the reaction, when a second solvent is added. A l l of these reactions are performed at room temperature with 2 mL of the selected solvent, and the de's are measured using GC-MS. The results are summarized in Table 3.3. Table 3.3: Effect of solvent polarity on diastereoselectivity. Entry Solvent % dea 1 benzene 30 2 toluene 27 3 hexanes 28 4 dichloromethane 26 5 acetonitrile 0 6 THF 5 7 diethyl ether 20 "Determined by GC-MS. The best diastereoselectivity is observed when benzene is the solvent (entry 1). Other non-coordinating non-polar solvents (entries 2-4) give similar de's. The use of polar solvents results in the predicted decrease in de's with acetonitrile (entry 5) and THF (entry 6) being the most notable. Since benzene is the best solvent for the reactions, the effects of temperature and concentration with benzene as a solvent are further investigated (Table 3.4). 203 T a b l e 3.4: Effects of temperature and concentration on diastereoselectivity. E n t r y T e m p e r a t u r e ( ° Q m L o f b e n z e n e u s e d % d e " 1 0 2 40 2 23 0.5 26 3 23 6 22 "Determined by GC-MS. When the temperature of the reaction for the T M S C N addition is reduced to approximately 0 °C, the best de's are observed (entry 1). Furthermore, as can be seen in entries 2 and 3, the concentration of the solution has little effect on diastereoselectivity. Both concentrated and dilute solutions give relatively similar de's, with results lower than that observed with 2 mL of benzene. This indicates that the catalytically active species is likely not an aggregate. In an effort to increase the observed diastereoselectivities, different chiral activators are then examined for this reaction. Although other chiral primary amines could not be used because of the metathesis side reaction, it is shown above that various other donating molecules wil l promote this reaction and thus could be potential chiral activators. The test reaction (eq. 3.13) now only utilizes one equivalent of chiral primary amine for the initial hydroamination, and requires the addition of a second activator before the T M S C N . The activators chosen include a catalytic amount of the chiral (R)-a-methylbenzylamine, Ar,Ar-dimethyl-(5)-a-methylbenzylamine, the sodium salt of (R)-2-phenylglycine and achiral triethylamine. The de's are measured by GC-MS after the reaction is quenched with T F A A . It is observed in all the GC-traces for these reactions that there is an extra peak present at 15.4 minutes that has not been observed previously in these tandem sequential reactions (Figure 3.12). 204 16.7 min, 15.4 min. 16.8 min. 17.6 min. 11.6 min. Figure 3.12: Typical GC trace of crude reaction mixture using alternate chiral activators showing common extra peak at 15.4 minutes. However, this is the same peak that has been observed earlier during the control experiment between the imine and the T F A A , and could possibly indicate that the 17.6 minutes are the products of the reaction between (i?)-a-methylbenzylamine and the amide proligand with T F A A , respectively. Isolation of the compound with retention time of 15.4 minutes has been accomplished using column chromatography, and the identity of this compound (3.18) is confirmed using ' H and 1 3 C N M R spectroscopy, low-resolution mass spectrometry (LR-MS), high resolution mass spectrometry (HR-MS), and GC-MS. T M S C N addition reactions are not going to completion. The peaks at 11.6 minutes and Ph 3.18 205 The amount of 3.18 that is formed relative to the amount of desired product formed is noted for these reactions in Table 3.5, along with the de's. Table 3.5: Effect of other activators on the diastereoselectivity of the reaction. + 1) 5 mol% 3.1/C 6H 6/65 °C/12 h 1 equiv. 2 ) a c t i v a t o r / T M scN / r . t . / 1 2 h ? 3) TFAA H , N ^ P h (3.13) Entry Activator % 3.18 Amount % de" 1 P h ^ N H 2 49-81* 10mol% 24-88" 2 P h ^ N ^ 1 74 stoichiometric 69 3 P h ^ N ^ 1 76 10mol% 59 4 NH, I P i T X 0 2 N a 11-75 c stoichiometric 52 to> 95 c 5 k 100 stoichiometric NR r f 6 100 10 mol% NR r f In entry 1, the chiral primary amine is used as an activator, though only in catalytic amounts. There is both a dramatic increase and a dramatic variation in the de's that are observed upon repetition of the experiments. Likewise, 3.18 is present in high amounts; this has not been observed when a stoichiometric amount of this activator is used. The chiral tertiary amine in entries 2 and 3 also give good de's, with a decrease in de's observed with a decreasing amount of activator. Entry 4 uses the sodium salt of (R)-2-phenylglyCine as an activator. This compound has been used successfully as a catalyst in 206 the enantioselective formation of cyanohydrins,38 and shows good de's for the formation of the TFA-protected a-cyanoamines, though again with a large range of de's. Again, both these activators also result in the formation of 3 . 1 8 . It is hypothesized that the triethylamine as an activator would give the same results as are observed with the amines on solid support; surprisingly, the GC-MS trace indicates that there is no product formed at all in these reactions. This is concerning, as triethylamine is shown above to be an excellent activator for the achiral system. Instead, all that is observed is 3 . 1 8 . Along with the unprecedented side product formation, the reproducibility of these experiments is concerning. Reproducibility is vital for a methodology to be synthetically useful. Many factors have been investigated as to the cause of this variation including age of reagents, purity of reagents, dryness of solvent, atmosphere under which the reactions are performed, use of Schlenk flasks versus parallel synthetic unit, time of reaction, and addition time for TFAA. No correlation between any of these factors and the de's has been found and the cause of the variation remains unknown. There are several different possible pathways for the formation of 3 . 1 8 (Scheme 3.6). It has been shown earlier that the reaction between the imine and T F A A will form this compound. However, this pathway is considered unlikely in this reaction as it has always been observed in previous experiments that the cyanide addition is rapid and quantitative. Other possibilities are H C N elimination from the TMS-protected a-cyanoamine or from the TFA-protected a-cyanoamine. 207 o 3.18 3.18 Scheme 3.6: Possible pathways for the formation of the elimination product. The elimination of H C N from either diastereomer, regardless of the pathway in which the elimination occurs, could lead to the formation of this elimination product; therefore the de's that are reported in Table 3.5 are not necessarily indicative of diastereoselective nucleophilic addition. Since there is such a large increase in the de's relative to the experiments done with the chiral primary amine (in stoichiometric quantities) even though some of the activators in Table 3.5 are structurally very similar (entries 2 and 3), it is likely that one diastereomer is preferentially undergoing elimination over the other diastereomer. This could account for the large observed de's. Likewise, 3.18 is observed with the triethylamine activator, so much so that no product formation is observed. Until this set of experiments, 3.18 has never been observed in this tandem reaction sequence. Several reactions are performed to understand why 3.18 is being formed under these circumstances and how it can be prevented. The most notable example of the formation of 3.18 is when the chiral primary amine is acting as the activator. When there is one full equivalent of primary amine in 208 solution after the initial hydroamination, 3.18 is not observed. When there is only 0.1 equivalent of primary amine in solution, 3.18 is formed in varying amounts from 49-81%, relative to the amount of product formed. In order to better understand this reaction, a series of experiments is performed in which the amount of chiral primary amine is varied, and the results are summarized in Table 3.6. Table 3.6: Effect of the amount of primary amine on the amount of elimination product formed. H,N Ph 1) 5 mol% 3 .1 /C 6 H 6 /65 °C/12 h 2) TMSCN/r . t . /12 h 3) T F A A (3.14) "Determined by GC-MS 3.18 Entry Equivalents of amine as activator % 3.18" % de" 1 0.1 49-81" 24-88* 2 0.2 36 92 3 0.4 10 37 4 0.5 6 33 5 0.6 0 64 6 1.0 0 30-77 c The amount of 3.18 observed decreases until there are 0.6 equivalents of the chiral primary amine in solution, at which point there is no elimination product observed at all. Likewise, the de's generally decrease as the % elimination product decreases. Unfortunately, again the reproducibility of these experiments is poor, as there is a wide range of de's observed when the experiments are repeated. 209 With the observation that the amount of 3 . 1 8 formed increases as the amount of primary amine that is present in solution decreases, it is hypothesized that an acid catalyzed elimination could be occurring. Furthermore, when isolation of the TFA-protected a-cyanoamine diastereomers is attempted by column chromatography (with the slightly acidic silica gel), it is observed that 3 . 1 8 forms even when none had been present before chromatography. However, a series of experiments carried out in the presence of inorganic bases show that this elimination is not an acid catalyzed process (Table 3.7). T a b l e 3 . 7 : Effects of the addition of inorganic bases on the formation of the elimination product. H- — 1)5mol%3.1/C6H6/65°C/12h 1 1 equiv. 2) base/TMSCN/r.t./12 h r 3) TFAA H 2 N^Ph O F 3 (r N Ph F3CT N Ph y// C N (3.15) H 3.18 E n t r y I n o r g a n i c B a s e A m o u n t ( m o l . e q u i v a l e n t ) % 3 . 1 8 " % d e " 1 K 2 C 0 3 1.0 16-64" 57-80" 2 K 2 C 0 3 2.0 51 63 3 K2CO3 0.5 81 79 4 K2CO3 2.0C 40 70 5 K2CO3 1.0" 61 80 6 N a 2 C 0 3 1.0 59 51 "Determined by GC-MS. "Three trials. cAdded to TMSCN. "Added to T F A A . The hydroamination and activation of T M S C N is accomplished with 1.1 equivalents of the chiral primary amine, and the inorganic base is added to the reaction mixture before the addition of the T M S C N . When the amount of base added is increased from 1 210 equivalent to 2 equivalents (entries 1 and 2), the amount of 3 . 1 8 increases, relative to the amount of product that is formed. However, when the amount of base is decreased to 0.5 equivalents (entry 3) the percentage of 3 . 1 8 observed is still high. In entry 4 the K2CO3 is added to the T M S C N , rather then to the imine, but this has no effect on the amount of 3 . 1 8 that is formed. Likewise, in entry 5 the K2CO3 is added to the TFAA, but 3 . 1 8 is still observed. Substitution of Na2CC>3 for K.2C03 (entry 6) has no change on the formation of 3 . 1 8 . Finally, there is a large variation in the amount of 3 . 1 8 observed even when the same amount of K2CO3 is added (entry 1). Since the addition of the inorganic base has no remarkable effect on decreasing the formation of 3 . 1 8 , the elimination seen is not likely an acid catalyzed process. A second hypothesis regarding the origin of the H C N elimination to form 3 . 1 8 is that it is base catalyzed. This hypothesis accounts for the observations that the tertiary amines, in both catalytic and stoichiometric amounts, promote the elimination reaction. After the imine is formed, the triethylamine could activate the T M S C N for the cyanide addition. After the TMS-protected a-cyanoamine is formed, the same stoichiometric amount of triethylamine could then act as a base, to deprotonate the TMS-protected a-cyanoamine leading to the overall elimination of H C N . If there is only a catalytic amount of triethylamine present, it is possible that this elimination could occur faster then the cyanide addition. Hence the triethylamine could quickly be removed from the system as the H C N salt. At this point, there would be no activators left in solution for the cyanide addition, and just the imine would be quenched with the TFAA. As has been shown before, this will also lead to the formation of 3 . 1 8 . However, a base catalyzed process is 211 not consistent with earlier observations that no elimination occurs i f greater the 0.6 equivalents of primary amine is present in solution. After ruling out both acid and base catalyzed elimination, the possibility that unreacted imine is leading to the formation of 3 . 1 8 must be considered. Possibly, the reactions are not going to completion when the activation is occurring with less then 1 equivalent of primary amine, or with tertiary amine, before the quench with T F A A . Therefore, there is unreacted imine in the reaction mixture that leads to the formation of the 3 . 1 8 . In order to investigate this possibility further, the reaction in eq. 3.16 was monitored by N M R spectroscopy. 1.1 equiv. H 2 N^Ph The *H N M R spectrum is not very helpful in determining whether or not this reaction has gone to completion. The imine that is formed with the (i?)-a-methylbenzylamine does not cleanly display the diagnostic aldimine triplet at approximately 7.4 ppm as it overlaps with the aryl proton signals, and thus it is not apparent when this triplet has disappeared. Furthermore, the presence of diastereomers after the TMS-protected a-cyanoamine forms complicates the alkyl region of the *H N M R spectrum. What is clear is that 3 . 1 8 has not yet been formed. However, the 1 3 C N M R spectrum is very helpful in determining whether the reaction is complete. The aldimine carbon signal (in the starting imine) appears at 163 ppm, and the nitrile (in the product) signal appears at 120 ppm. In this particular experiment, there is a nitrile signal in the 1 3 C N M R spectra, but there is also the presence of the aldimine signal. This indicates that while some product is being formed, 1) 5 mol%3.1/ C6H6/65°C/12 h ' 2) TMSCN/r.t./12h TMS (3.16) 212 the reaction is not going to completion. Quenching of this reaction under these circumstances would lead to the observation of 3 . 1 8 . A second experiment is monitored by N M R spectroscopy to determine what is occurring when triethylamine is used as an activator (eq. 3.17). 1 equiv. 1)5 mol% 3.1/ H — = — + C 6 H 6 / 6 5 ° C / 1 2 h N H 2 N Ph 2 ) NEtyTMSCN/ r.t./12h Again, the ' H N M R spectra is not helpful in determining whether or not product is formed under these conditions. The 1 3 C N M R spectrum, on the other hand, very clearly shows the aldimine carbon peak at 163 ppm and the absence of a signal at 120 ppm. This indicates that the reaction does not proceed at all, which is why 3 . 1 8 is observed. These results indicate that the origin of 3 . 1 8 is from incomplete formation of the desired TMS-protected a-cyanoamine when performing the reaction with the chiral primary amine. This was not originally considered, as similar observations have not been observed with the achiral case. For example, when the analogous reaction is carried out with benzylamine, (eq. 3.18) only a very tiny amount (1.5%) of elimination product is observed by GC-MS. 1 — 1 ) 5 m o l % 3 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h + 2)TMSCN/r.t./12 h F 3 C " N ' "Ph (3.18) 1.1 equiv. 3) TFAA H 2 N ^ P h Likewise, as was discussed earlier, triethylamine is a very efficient activator for this achiral reaction, and leads to the formation of the product in high isolated yields. The 213 only difference between the achiral system and the chiral system is the additional presence of the methyl group in the benzylic position. Perhaps this increase in sterics leads to incomplete product formation, mirroring the steric effects observed in the t-butylamine case. The effects of steric bulk about the nitrogen are investigated using the sterically bulky, but achiral, isopropyl substituent on the nitrogen (eq. 3.19). Using only 1.1 equivalents of isopropylamine, the TFA-protected a-cyanoamine is formed. + 1) 5 mol% 3.1/C 6H 6/65 °C/12.h 2) TMSCN/r.t./12h r 3 ° 7 (3-19) 1.1 equiv. 3) TFAA GC-MS analysis shows that the analogous elimination product is also formed in this case in 8% relative to the product formation. This is more elimination product then what is observed with the benzylamine case. This reaction is also repeated using triethylamine as an activator (eq. 3.20). 1) 5 mol% 3.1/C 6H 6/65 °C/12 h 2) NEt3/TMSCN/r.t./12h r 3 ° "j" ( 3 - 2 0 ) 3) TFAA While product is formed in this case (relative to the example with the chiral amine where no product is observed), there is also an increase in elimination product observed by GC-MS to 44%. This indicates that the steric bulk around the nitrogen does affect the formation of the elimination product. This also indicates that the activator used affects 214 the outcome of the reaction as the steric bulk around the nitrogen and the T M S C N adduct increases. The results of this investigation have contributed more to the mechanistic knowledge for the Strecker reaction portion of the tandem reaction sequence. While a wide variety of activators are suitable for cyanide addition to substrates without a lot of steric bulk around the nitrogen, as this bulk increases the ability for the activator to effectively react with the T M S C N must also increase. With sterically hindered substrates, the more sterically hindered activators, such as tertiary amines, are not sufficient to realize complete addition of the cyanide to the imine. It also has to be considered that the primary amine can further assist in these reactions through a'hydrogen bonding interaction with the imine, which may contribute to the difference in reactivity observed relative to the amount of primary amine used. While the (i?)-a-methylbenzylamine is not racemized under the hydroamination conditions, this chiral amine is found to be both a poor chiral auxiliary and a poor chiral activator for the diastereoselective version of the tandem C - N , C - C bond forming reaction sequence. Optimization of the reaction conditions with this chiral nucleophile led to a maximum de of 40%, though the reproducibility of the de's is not good. Other chiral activators have been investigated; however, it has been discovered that this test reaction with the increased steric bulk around the nitrogen atom is very sensitive to the activator that is used. In particular, tertiary amines do not activate the T M S C N enough to overcome the steric bulk present around the nitrogen in the imine and hence the reactions do not proceed to completion. These experiments also provide further insight into the details of the mode of activation of the tandem sequential reaction sequence. As there 215 has been some diastereoselectivity observed, this supports the formation of a silicon adduct as the nucleophile. While the nature of the activator that is used must be carefully chosen when the steric bulk about the nitrogen is increased, i f a less bulky nitrogen substituent is chosen as a test reaction, further development of a diastereoselective version of the tandem reaction sequence could be accomplished. However, since (i?)-a-methylbenzylamine is too sterically hindered for the development of a reliable diastereoselective reaction sequence, and it is a relatively small chiral amine, there are no obvious options available to decrease this bulk and maintain chirality in the electrophile. The results of this investigation are disappointing; generally an increase in steric bulk should help promote diastereoselectivity, however, in this case it appears that this steric bulk is what is hindering the reaction. 3 . 2 . 4 . 3 E n a n t i o s e l e c t i v i t y In developing a second test reaction for investigations into the stereoselective tandem C - N , C - C bond forming reaction, it is desirable to use a test substrate with less steric bulk around the nitrogen. Likewise, while the diastereoselective reaction sequence has the added advantage of using a chiral electrophile, it is more synthetically attractive to develop an enantioselective methodology that does not require a chiral auxiliary. There is also more substrate choice in an enantioselective methodology as one is not limited by the availability of suitable chiral amines. A t the onset o f this investigation there were no facilities in the Schafer lab for the facile determination o f ee's. However, with the purchase of a chiral H P L C column, protocols have been developed to determine the ee's of the TFA-protected a-cyanoamine products. Furthermore, as more research in 216 the Schafer group is being performed in the area of asymmetric catalysis, the protocols that have been developed here are being extended to those areas. The enantioselective test reaction using 1-hexyne and benzylamine is chosen to begin investigations into an asymmetric tandem reaction sequence (Scheme 3.7). + 1 ) 5 m o l % 3 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h * \ \ ^ P h H 2 N Ph u 0 2) activator/TMSCN/r.t./3 h p „ r . ^ w ^ D h A ^ Scheme 3.7: Enantioselective test reaction used to optimize chiral activators. This test reaction is chosen for a number of reasons. First, it is very similar to the diastereoselective test reaction used, but it has reduced steric bulk around the nitrogen atom, and hence a wider variety of chiral activators should be tolerated. Second, the benzylamine substituent is synthetically attractive as the benzyl group can be removed via hydrogenolysis. Third, this molecule is resolved from the other components in the reaction nicely by G C - M S ; more importantly, the two enantiomers in the product can be cleanly resolved using chiral H P L C allowing for facile determination of enantiomeric excesses (ee's) (Figure 3.13). CN H 217 4.03 min. 4.30 min. Figure 3.13: Chiral HPLC trace showing the resolution of the two TFA-protected a-cyanoamine enantiomers. Likewise, the retention times of the two enantiomers are low at 4.03 and 4.30 minutes respectively, meaning that a number of reactions can be screened in a relatively short amount of time. Finally, alkyl substrates such as the one shown in Scheme 3.7 are rarely used in asymmetric Strecker reactions, and will often display lower yield's and ee's. 3 9 ' 4 0 More importantly, there have been no reported instances of asymmetric nucleophilic activation of T M S C N for cyanide addition to alkyl imines. Therefore, the development of an enantioselective Strecker reaction using T M S C N would be very useful and the use of terminal alkynes as the starting material would increase the synthetic flexibility. The focus of this investigation is on small, commercially available or readily synthesized chiral activators. Along with the chiral 7V,Af-dimethyl-(£)-a-methylbenzylamine and the (i?)-2-phenylglycine sodium salt investigated in the 218 diastereomeric reactions, several other classes of molecules are targeted. These include chiral P-amino alcohols, diamines, and a-amino esters. The results of each of these investigations will be discussed in turn. To ensure that analogous side reactions to the diastereomeric case are not occurring in the enantiomeric test reaction, the A^^V-dimethyl-(5)-a-methylbenzylamine and the (i?)-2-phenylglycine sodium salt are the first activators that are investigated. Using the test reaction in eq. 3.21, a stoichiometric amount of the chiral activator is added to the reaction before addition of the TMSCN. The results are summarized in Table 3.8. Table 3.8: Effect of activators on the enantioselectivity of the reaction. H = + 1 ) 5 m o l % 3 . 1 / C 6 H 6 / 6 5 ° C / 1 2 h 2) activator/TMSCN/r.t./3 h H 2 N ^ P h 3) T F A A "Isolated by column chromatography. Determined by chiral TMSCN and cooled to -78 °C. (3.21) Entry Activator Solvent Amount of activator % Yield" % ee* 1 1 benzene stoichiometric 89 4 2 P h - ^ N ^ 1 benzene 10mol% 44 3 3 N H , I P i r X 0 2 N a benzene stoichiometric 83 19 4 N H 2 I Ph C 0 2 N a DCM stoichiometric 92 19 5 N H 2 I P h ^ C 0 2 N a THF stoichiometric 93 22 6 N H 2 I p r r x o 2 N a THFC stoichiometric 95 24 HPLC. cAdded activator to 219 The product is isolated by column chromatography to ensure that the reactions are proceeding in high yields, and the ee's are determined by chiral HPLC. GC-MS is also performed to ensure that there is no elimination product formed. When the chiral tertiary amine is used in this reaction, high yields are obtained when the amine is present in stoichiometric amounts (entry 1), though a decrease in yield is observed when there is only a catalytic amount of activator (entry 2). There is however, no variation in the ee's; in both cases the ee's are low. However, it is notable that the chiral tertiary amine is able to activate the T M S C N enough to get product formation in this test substrate, in contrast to what has been observed in the diastereoselective test reaction. Since the (R)-2-phenylglycine sodium salt is not very soluble in organic solvents, a number of solvent systems are investigated. In benzene (entry 3), the yield of the reaction is lower, but the ee's are higher, relative to the chiral tertiary amine activator. An increase in yield is obtained when dichloromethane is the solvent, but the ee's stay the same (entry 4). A slight increase in ee is observed when THF is the solvent; this is probably due to a greater amount of the salt in solution acting as an activator. The highest ee's (24%) occur when the (i?)-2-phenylglycine sodium salt is premixed with T M S C N and heated for an hour at 40 °C, before being cooled to -78 °C for addition of the imine (entry 6). The yields of these reactions are also high. These initial investigations show that the enantiomeric test reaction does not have the same problems with side reactions as the diastereomeric test reaction. The isolated yields of the reactions are all very high (when the activator is present in stoichiometric amounts), though the ee's are lower. As it is known that the asymmetric additions to alkyl imines are more difficult and result in lower ee's relative to aryl imines, 3 9 ' 4 0 it is desirable to optimize as many 220 contributing factors as possible. One probable cause of the low ee's in this system is the speed of the reaction. The T M S C N addition to the imines is rapid at room temperature with unhindered substrates. So fast, in fact, that by the time that ' H N M R spectroscopy can be performed on these systems, the reaction is already complete. In an effort to slow down the reaction, and optimize the ee's, all the remaining investigations into chiral activators are performed at -78 °C in toluene. Toluene is chosen as a solvent based on the results obtained in the diastereomeric investigations with the (i?)-a-methylbenzylamine where the highest de's are observed with non-coordinating solvents. The non-polar nature of toluene has also been shown to promote the formation of the pentacoordinate silicon adduct, and should suppress the formation of the tetracoordinate silicon salt, i f it is being formed at all. Toluene is also preferable over benzene as it can be cooled to lower temperatures without freezing. Furthermore, as this particular test substrate has been shown on numerous occasions to be high yielding in the formation of the TFA-protected a-cyanoaimines, a rapid screen of different activators is carried out using the crude reaction material for analysis and the TFA-protected a-cyanoamines are not isolated. The first class of commercially available chiral activators for investigation is P-amino alcohols (Figure 3.14). H 2 N ? h P hA/OH H 2 N ^ ° H ^ ^ O H Ph H 2 N (R)-2-phenyl glycinol (1R,2R)-2-amino-1,2-diphenyl D-2-amino-butanol ethanol Figure 3.14: P-Amino alcohols that are used as activators in tandem reaction sequence. It is postulated that the P-amino alcohols could act as bifunctional activators for the Strecker reaction portion of the tandem reaction sequence. The amine functionality could 221 activate the silicon, and the alcohol functionality could form a hydrogen bond with the imine to hold the substrate in position. However, the presence of the alcoholic hydrogen atom could also lead to the formation of H C N , which in turn would result in low ee's. After the imine is formed in toluene, one equivalent of the P-amino alcohol is added to the imine and the resulting solution' is then added dropwise to a solution of T M S C N in toluene at -78 °C. After quenching of the reaction mixture, GC-MS is run to ensure that there is no elimination product formed; there is never any elimination product observed with these activators. Furthermore, as imine metathesis has been shown in the past to be a problem with primary amines, ESI-MS is performed on all products to rule out this possibility. Imine metathesis is not observed with the use of any of the P-amino alcohol activators. Possibly the P-amino alcohols are reacting with the titanium center leading.to the formation of an amido alkoxide species that is unable to catalyze imine metathesis. The results of this investigation are summarized in Table 3.9. Table 3.9: Enantioselectivities obtained using a stoichiometric amount of p-amino alcohols as chiral activators. + 1)5 mol% 3.1/C 7H 8/65 °C/12 h 1 equiv. 2) activator/TMSCN/ H 2 N ^ P h -78 °C to r.t./3h 3) TFAA Entry Activator % ee" 1 NH 2 P h A / O H 3 2 Ph H 2 N ^ V 0 H Ph 7 3 NH 2 6 "Determined by chiral HPLC. 222 Very low ee's are found for this class of activators, and there are several possible reasons for this observation. The presence of the alcohol functionality, as another activator for the T M S C N , could increase the rate of reaction even more, and hence further decrease the ee's. As well, the acidic alcohol functionality could react with the T M S C N to form H C N which would then add to the imine with very little asymmetric direction. While chiral P-amino alcohols can promote the tandem reaction sequence, they do not induce appreciable enantioselectivity into the products formed. The second class of chiral molecules that are used as activators for the tandem hydroamination and the Strecker reaction sequence are chiral diamines (Figure 3.15). a. N H 2 P n - A T (1 R,2R)-1,2-diamino- (1 S,2S)-1,2-diphenylethylene cyclohexane diamine (-)-dimetnylbiphenyldiamine Figure 3.15: Chiral diamines that are used as catalytic activators in the tandem reaction sequence. Both the (l^,2i?)-l,2-diaminocyclohexane and the (l£,2S)-l,2-diphenylethylenediamine can be purchased in enantiopure form. The (-)-dimethylbiphenyldiamine is a very expensive reagent, and so it is more economical to synthesize and resolve this compound from less expensive starting materials; however, this is a commonly used diamine in the Schafer group and hence it is readily available. Since the diamines do not have the acidic functionality like the P-amino alcohols, it is hoped this would translate into an increase in ee's, since the potential formation of H C N would be eliminated. These diamines are 223 more costly then the P-amino alcohols and so the reactions are performed with only a catalytic amount of activator. While it has been shown with the diastereoselective test reaction that decreasing the amount of activator decreases the de, control experiments have been done that show that using a catalytic amount of activator instead of a stoichiometric amount of activator has no effect on the enantioselectivity with this test system (vide supra). The reaction time is also increased to 12 h for the cyanide addition to ensure that the reactions go to completion. Again, GC-MS is run on the crude reaction mixture to identify any elimination product. In these experiments, a very small amount of elimination product is observed, though it is less then 3% in all cases. This is comparable to what is observed when a catalytic amount of benzylamine is utilized to perform the tandem reaction sequence. Also, ESI-MS is run on the crude reaction mixture to check for metathesis product formation; none is observed. Chiral HPLC is used to determine the ee's and the results of this investigation are summarized in Table 3.10. 224 Table 3.10: Enantioselectivities obtained using chiral diamines as catalytic activators. + 1)5mol%3.1/C7H8/65°C/12h 1 equiv. 2) 10 mol% activator/TMSCN/ H 2 N^Ph -78 °C to r.t./12 h 3) TFAA (3.23) Entry Activator % eefl 1 1 2 Ph Ph 9 3 21 "Determined by chiral HPLC. The use of (li?,2i?)-l,2-diaminocyclohexane as an activator results in no enantioselectivity. While the (l£,2S)-l,2-diphenylethylenediamine shows only a modest increase in ee's, the axially chiral (-)-dimethylbiphenyldiamine did show a larger increase in ee, up to 21% (entry 3). This is an interesting result as it provides more insight into the mechanism for the enantioselective addition. Both entries 1 and 2 use relatively flexible diamines that could potentially form pentacoordinate silicon adducts and/or hexacoordinate silicon adducts with the T M S C N . The rigidity of the axially chiral (-)-dimethylbiphenyldiamine suggests that the hexacoordinate silicon adduct is more likely formed, similar to the proposed active structure with catalyst 3.9 (vide supra). The resulting increase in ee suggests that this hexacoordinate silicon adduct is better at inducing enantioselectivites then the pentacoordinate silicon adduct. Furthermore, the ee's in entry 3 are similar to the ee's obtained with the (i?)-2-phenylglycine sodium salt, 225 an activator that could also potentially form a hexacoordinate silicon species. Thus a chelating activator has potential advantages. This leads to the third class of chiral activators to be investigated: potentially chelating a-amino methyl esters derived from naturally occurring a-amino acids, a-Amino methyl esters are purchased as H C I salts, though in their free form they are an oil. The a-amino methyl esters wil l have enhanced solubility in the preferred non-coordinating organic solvents, relative to that of the a-amino acid sodium salt. This solubility effect may impact the reactivity and enantioselectivity. It is also shown in the above investigations with diamines that the more rigid diamine resulted in an increased ee (possibly by forming a hexacoordinate adduct); it is also thought that the carbonyl of the a-amino ester could have . a similar effect, especially when considering the oxophilicity of silicon. Four a-amino methyl esters, derived from naturally occurring a-amino acids are targeted (Figure 3.16). N H z NH2 NH2 N C02Me P h ^ C 0 2 M e P h - ^ C 0 2 M e ^ r ^ C 0 2 M e L-proline (R)-2-phenylglycine (R)-phenylalanine L-valine methyl ester methyl ester methyl ester methyl ester Figure 3.16: a-Amino methyl esters used as activators in enantioselective tandem reaction sequence. L-proline derivatives have found many applications as organocatalysts. The use of (R)-2-phenylglycine methyl ester allows for direct comparison with the (i?)-2-phenylglycine sodium salt that has been previously used. To investigate the effects of substitution in the side chain, the aryl substituted (K)-phenylalanine methyl ester and the more bulky 226 isopropyl substituted valine methyl ester are used. These reactions are performed in toluene at -78 °C as described previously, and the obtained ee's are summarized in Table 3.11. The GC-MS traces of these reactions show no unidentified extra peaks, and there is never any evidence of elimination product being formed. Likewise, the ESI-MS show that no imine metathesis is occurring. Again, this side reaction is probably suppressed through the reaction of the a-amino methyl esters with the titanium metal center. Table 3.11: Enantioselectivities obtained using a stoichiometric amount of a-amino methyl esters as activators. H-+ 1)5mol%3.1/C7H8/65°C/12h 1 equiv. 2) activator/TMSCN/ H 2 N^Ph -78 °C to r.t./3 h 3) TFAA F,CT N "Ph Entry Activator % eefl 1 ^ N ^ C O o M e H 5 2 N H 2 1 Ph^ e 0 2 Me 0 3 N H 2 P h ^ A c 0 2 M e 15 4 N H 2 22 Determined by chiral HPLC. F , C N "Ph (3.24) Disappointingly, the L-proline methyl ester as a chiral activator gives very low ee's. Surprisingly, the use of (i?)-2-phenylglycine methyl ester results in no enantioselectivity (entry 2). However, with the addition of an alkyl group alpha to the stereocenter, the ee's increase (entries 3 and 4). The highest ee's are obtained with L-valine methyl ester, and these ee's are the same as what is obtained with the chiral (-)-dimethylbiphenyldiamine. 227 L-Valine methyl ester has the distinct advantage over the biphenyldiamine in that it is commercially available at low cost whereas the chiral biphenyl requires several synthetic steps, as well as an enantiomeric resolution before use. These ee's are also approximately the same as the highest ee's obtained with the (i?)-2-phenylglycine sodium salt (24% ee). With these promising initial results in hand, sterically enhanced activators are accessed by using a-amino J-butyl esters. These molecules are generally not commercially available, though they can be readily synthesized from a-amino acids.41 To compare the effectiveness of the a-amino ?-butyl esters with that of the a-amino methyl esters, (i?)-2-phenylglycine r-butyl ester, (K)-phenylalanine f-butyl ester and L-valine t-butyl ester are all synthesized. After using these compounds as activators in the asymmetric reaction sequence, the GC-MS traces of the crude reaction mixture strongly resemble those that are observed with the a-amino methyl ester activators as there are no extra, unidentified signals. The ESI-MS does not indicate any metathesis product. The results of these investigations are summarized in Table 3.12. 228 Table 3.12: Enantioselectivities obtained using a-amino f-butyl esters as activators. + 1)5 mol% 3.1/C7H8/65 °C/12 h 1 equiv. 2) activator/TMSCN/ H 2 N ^ P h -78 °C to r.t./3 h 3) TFAA Entry Activator % ee" 1 H2N 4 2 NH 2 P h - ^ C 0 2 ' B u 3 3 NH 2 1 P h ^ C 0 2 ' B u 32 "Determined by chiral HPLC. The trend with the r-butyl esters is generally opposite to that which is observed with the methyl esters. The enantioselectivities of both the L-valine J-butyl ester and the (R)-phenylalanine ?-butyl ester both dramatically decrease. The (i?)-2-phenylglycine f-butyl ester, on the other hand, shows a dramatic increase in ee, up to 32% (entry 3). This is the highest observed ee of all the small, readily available, chiral activators that have been investigated. While.there is no clear trend between structure of the activator and enantioselectivity in the tandem C - N , C - C bond forming reaction sequence, as has been noted often, simple structural modifications make a big difference in the observed ee's. In the investigations into the diastereoselective tandem reaction sequence, it was noted that reproducibility was a problem. In this enantioselective version, however, a number of these reactions have been repeated and the same results have been obtained. This is true when the reactions are performed with the same supply of chemicals as the initial reactions, as well as when the reactions are performed with a newly synthesized or 229 purified supply of chemicals. This is very encouraging, as the development of reliable and generally applicable synthetic methodology is a key focus of this work. Through these investigations into chiral small molecule activators for the enantioselective tandem hydroamination and the Strecker reaction sequence, several key insights are gained into the mechanism. Small, tertiary chiral amines are not very successful at inducing stereoselectivity. Furthermore, the alcohol functionality leads to low ee's, likely due to H C N mediated reactivity. However, there is an increase in ee's observed when the alcohol functionality is replaced with the less acidic amine functionality. The ee's are increased further when the diamines are held in a rigid conformation that favours chelation of a single silicon centre. Interestingly, comparable ee's can be attained with commercially available alkyl a-amino methyl esters and easily accessed a-amino /-butyl esters. The most promising results using chelating activators suggest that different silicon adducts are being formed in this reaction sequence. Namely, with the tertiary amines and flexible diamines a pentacoordinate silicon adduct, possibly in equilibrium with a hexacoordinate adduct, is formed resulting in lower ee's. However, an increase in ee's is observed when there is the possibility of forming a monomelic hexacoordinate silicon adduct. As described earlier, a silicon adduct with benzylamine and T M S C N has been characterized by ! H , 1 3 C , and 2 9 S i N M R spectroscopy, at both room temperature and low temperature. To determine whether there are any differences in the adduct that is formed during the chelate investigations, the reaction shown in eq. 3.26 is carried out. Using the most successful chiral activator, one equivalent of (/v)-2-phenylglycine /-butyl ester is combined with one equivalent of T M S C N . 230 H,N I Pri C02(Bu + TMSCN C 7 D 8 "reactive species" (3.26) ] H N M R spectroscopy of this reaction indicates the presence of both starting materials and a reactive species, much the same way that it is when benzylamine is combined with T M S C N . The methine proton alpha to the NH2 is present for the starting (R)-2-phenylglycine /-butyl ester, and there are two other singlets in the same region that presumably correspond to the reactive species. The integrations for these three signals are the same, indicating that they are all present in approximately the same amounts. The presence of two additional methine proton signals indicates that not only is a hexacoordinate silicon adduct being forming, but potentially geometric isomers, such as the ones shown in Figure 3.17, could also be formed. P h^p-N„.,. 1 Si« *CN H H 2 P h x p N ' " . . U C N Figure 3.17: Examples of possible geometric isomers that could be formed for the proposed hexacoordinate silicon adduct. Further conformation of the presence of geometric isomers is observed in the methyl region of the ' H N M R spectra. The signal for the /-butyl substituent is broad and the integration indicates that it accounts for 2 separate /-butyl substituents. The same observation is made for the methyl signals on the silicon center. The 1 3 C N M R spectrum of this reaction further supports the formation of the hexacoordinate silicon adduct. The 231 presence of geometric isomers in solution could lead to an erosion of the ee's, and is a possible reason why observed ee's are relatively low. Most importantly, Si N M R spectroscopy has been particularly helpful in assigning the pentacoordinate silicon species that is formed from the reaction between the benzylamine and the T M S C N . While there is a lot of literature on hexacoordinate silicon complexes,22"24 direct analogies to the adduct formed here are more difficult as the ligand coordination environment is very different in these reports. There have been reports of the formation of a pentacoordinate silicon salt from a hexacoordinate silicon complex, but it was noted that this will not occur in toluene,42 and hence this is not a concern for this system. While there has not been as much research done on the formation of hexacoordinate silicon adducts, the 2 9 S i N M R chemical shifts for two very comparable systems have been reported in the literature. The 2 9 S i N M R spectrum for the reaction of (i?)-2-phenylglycine sodium salt and T M S C N has been published.38 While the calibration of the spectrum is ill-defined, the adduct that is formed is shown to give a signal that is approximately 18 ppm downfield from the T M S C N 2 9 S i signal. In this report, T M S C N is reported to give rise to a signal at -18 ppm, and the adduct at -0.5 ppm. The 2 9 S i N M R spectral data is also reported for the proposed hexacoordinate silicon adduct formed from the chiral A^iV-dioxide 3.9 and T M S C N . 1 3 This report lists the chemical shift for T M S C N to be -12 ppm, and the chemical shift for the adduct to be at 7 ppm. Again it is observed that the chemical shift of the adduct is shifted downfield relative to TMSCN. This is the opposite observation to the upfield chemical shift that is found with the pentacoordinate silicon adducts (adduct observed at -99 ppm). When 2 9 S i N M R spectroscopy is performed on the reaction in eq. 3.26, the T M S C N chemical shift is 232 found to be -12 ppm, and the chemical shift for the reactive species is 3 ppm. The presence of the nitrogen atom in this system is likely responsible for the smaller downfield shift relative to the system formed with 3.9. This data further supports the formation of a hexacoordinate silicon adduct as the catalytically active species for the asymmetric Strecker reaction portion of this tandem reaction sequence. While it has been postulated that a pentacoordinate silicon adduct is the active species in the diastereomeric tandem reaction sequence, it is also possible that a hexacoordinate silicon adduct could be the active species (though there is no spectroscopic evidence of this occurrence). When a full equivalent of chiral primary amine is present in solution, there is no side-product (3.18) formation observed. Possibly under these circumstances a hexacoordinate adduct is formed that is promoting the reaction. Then, as the amount of primary amine decreases, the amount of hexacoordinate adduct formed decreases, the cyanide addition does not occur as readily, and the amount of 3.18 increases after quenching of the reaction mixture with T F A A . Furthermore, with the more sterically bulky tertiary amines, the hexacoordinate adduct would be disfavoured, and this could possibly be why the reactions do not proceed to completion (vide supra). To investigate this possibility, the chelating (i?)-phenylglycine /-butyl ester is used to activate the T M S C N for addition to the chiral imine electrophile that is used in the diastereomeric tandem reaction sequence. Unfortunately, 3.18 is still formed during this reaction, in 2 0 % relative to the product formation, but this is significantly less than what is observed when tertiary amines are used in this reaction ( 7 4 % and 100%, Table 3.5). This suggests that while the adduct formed with the chelating activator is more 233 reactive, the reactivity is still not enough to overcome the increased steric bulk at the nitrogen center for this test reaction. Through this investigation into the asymmetric version of the tandem C - N , C - C bond forming reaction sequence using small, readily available chiral activators, a number of key insights have been gained. First, while tertiary chiral amines do promote this reaction, they are not very effective at inducing enantioselectivity. Second, even compounds that contain two possible activating groups are not effective at promoting enantioselectivity unless the groups are rigidly held in place, and preferably contain an oxygen atom, so that formation of the hexacoordinate silicon adduct can be facilitated. Finally, even with the formation of the hexacoordinate silicon adduct, small structural changes to the chiral activators can have a large effect on the resulting enantioselectivity. 3.3 Summary and conclusions The mode of activation for the Strecker reaction portion of the tandem C - N , C - C bond forming reaction sequence has been investigated and found to be nucleophilic activation of silicon. This activation can occur with primary, secondary, and tertiary amines, as well as amines on solid support, to yield alkyl TFA-protected a-cyanoamines in good isolated yields. Furthermore, the mechanistic insight that has been gained led to the development of asymmetric versions of the tandem reaction sequence. With the use of a chiral auxiliary in conjunction with a chiral activator, the alkyl TFA-protected a-cyanoamine has been synthesized in 40% de. Unfortunately, the diastereomeric version of the tandem reaction sequence is complicated by side reactions and hence this version is unreasonably limited in its applicability. With the use of small, readily available chiral 234 molecules, a number of systems for the enantiomeric version of the tandem reaction sequence have been investigated. Axially chiral diamines, along with various a-amino acid derivatives imparted some enantioselectivity to this reaction, with a maximum ee of 32%. It has been determined that small structural changes to the a-amino acid derivatives have a large effect on the ee's of the reaction, and that greater enantioselectivities are obtained when a hexacoordinate silicon adduct can be formed. Furthermore, it is postulated that the formation of a hexacoordinate silicon species could be responsible for the success (however limited) realized in the diastereomeric tandem sequence. To date, there are no known examples in the literature of nucleophilic activation of T M S C N for the asymmetric Strecker reaction with alkyl imines, and thus this work represents important progress towards attaining that research goal. 235 3.4 Experimental General experimental: Except where otherwise noted, all reactions and manipulations were carried out at room temperature without precautions to exclude atmospheric moisture. A l l solvents for work up procedures were used as received from Aldrich or Sigma. Dry benzene and toluene were purified on an Alumina column and stored under a nitrogen atmosphere. Ti(NEt2)4 and T i ( N M e 2 ) 4 were purchased from Strem or Aldrich and used as received. A l l terminal alkynes were purchased from Aldrich, with the exception of 3-phenyl-1-propyne,43 which was synthesized according to a literature procedure. A l l alkynes were dried over 4A molecular sieves for 12 h before distillation, and degassing using the freeze-pump-thaw method. The alkynes were then transferred into the nitrogen-filled glovebox and further dried over 4A molecular sieves for an additional 12 h before use. A l l primary amines were purchased from Aldrich and were dried over CaH 2 for 12 h before distillation and degassing using the freeze-pump-thaw method. The amines were then stored in the nitrogen-filled glovebox and further dried over 4A molecular sieves for an additional 12 h before use. Deuterated benzene and toluene was degassed using the freeze-pump-thaw method and stored over 4A molecular sieves for 12 h before use. Solid activators for stereoselectivity experiments were dried on a high vacuum line for 24 h before transferal to the glovebox. Liquid activators for stereoselectivity experiments were degassed using the freeze-pump-thaw method, transferred to the glovebox and dried over 4 A molecular sieves for 48 h before use. Solid-supported amines were dried under high vacuum for 24 h before transferal and storage in the glovebox. A l l other chemicals were reagent grade and used as received from Aldrich. A l l N M R spectra were acquired 236 in deuterated solvents (purchased from Cambridge Isotope Labs) at room temperature in the U B C Chemistry N M R facility on a Bruker Avance 300 spectrometer (300 M H z [ lH], 282 MHz [ 1 9F], and 75 M H z [ 1 3C]), or a Bruker Avance 400 spectrometer (400 MHz ['H] and 100 MHz [ l 3C]). 2 9 S i N M R spectroscopy was performed using a 2 9 S i DEPT experiment on a Bruker Avance 400 spectrometer (79 MHz). ! H N M R assignments are indicated by italicized H's (H). LR-MS (low mass spectrometry) were obtained using ESI-MS (electrospray ionization mass spectrometry), and APCI-MS (atmospheric pressure chemical ionization mass spectrometry) in the UBC Chemistry Mass Spectrometry facility on the open access MS. HR-MS (high resolution mass spectrometry) and E A (elemental analysis) were performed by the U B C Chemistry Mass Spectrometry facility. GC-MS was performed on an Agilent series 6890 GC system with a 5973 Mass Selective Detector. The solutions were made up in dichloromethane with a concentration of approximately 3 mg/mL and an injection volume of 2 pL was used for analysis. Chiral H P L C was performed on a Varian 3800 L C with a 325 UV-Detector equipped with a Chiralpak A S - H column. The flow rate was 1 mL/minute with a solvent mixture of 90:10 hexanes:isopropyl alcohol (HPLC grade), and the products were detected using a UV-detector at X = 210 nm. The solutions were made up in 90:10 hexanes:isopropyl alcohol with a concentration of approximately 1 mg/mL and an injection volume of 5 pL was used for analysis. Note that a racemic mixture resulted in an ee of 1-2%. Plates used for TLC (thin layer chromatography) (0.2 mm silica gel 60 F254 on alumina) and silica gel used for column chromatography (70-230 and 230-400 mesh) were purchased from Silicycle (Montreal, PQ). T L C spots were visualized under a 237 1 13 UVG-54 Mineralight® short-wave U V lamp (k = 254 nm). Representative H and C N M R spectra can be found in Appendix III. The following compounds were synthesized following literature procedures: f P n^f^>Ti(NEt 2) 2 2 B i s t j V - l ^ - d i i s o p r o p y l p h e n y l b e n z a m i d a t e ) b i s ( d i e t h y l a m i d o ) t i t a n i u m (3 .1 ) 3 - p h e n y l - l - p r o p y n e 4 3 N H 2 I P r T X 0 2 N a S o d i u m ( 2 2 ? ) - a m i n o ( p h e n y I ) a c e t a t e NH Ph ( i f ) - P h e n y l g l y c i n e f - b u t y l e s t e r 4 1 N H , A Y o ,41 (R)-Valine f - b u t y l e s t e r 238 ( ^ - P h e n y l a l a n i n e r - b u t y l e s t e r 4 1 P r o c e d u r e f o r p r e p a r a t i o n o f a - a m i n o m e t h y l e s t e r s : The a-amino methyl esters were purchased from Aldrich as an HC1 salt. Approximately 1 g of the HC1 salt was combined with 50 mL of sat. NaHC03. The aqueous solution was extracted with dichloromethane (4 x 50 mL) and the combined organic fractions were dried over MgSC^, filtered, and concentrated under reduced pressure. The resultant oils were transferred to a tube Schlenk flask, where they were degassed using the freeze-pump-thaw method, and transferred into the glovebox. The oils were dried over 4 A molecular sieves for 48 h before use. I m i n e f o r m a t i o n : R e p r e s e n t a t i v e p r o c e d u r e : A small vial is charged with 5 mg (0.006 mmol) of 3.1, 0.12 mmol of terminal alkyne, 0.24 mmol of primary amine, and 0.5 g of deuterated benzene within a nitrogen-filled glovebox. The solution is transferred to an oven-dried J. Young N M R tube, removed from the glovebox and heated at 65 °C for 12 h before cooling to room temperature. N M R spectroscopy was used to confirm the in situ formation of the imines. Spectral data for the imines synthesized in this work can be found in Appendix II. 239 T M S - p r o t e c t e d - a - c y a n o a m i n e f o r m a t i o n : R e p r e s e n t a t i v e p r o c e d u r e : A small vial was charged with 5 mg (0.006 mmol) of 3 . 1 , 0.12 mmol of terminal alkyne, 0.24 mmol of primary amine, and 0.5 g of deuterated benzene within a nitrogen-filled glovebox. The solution was transferred to an oven-dried J. Young tube, removed from the glovebox, and heated at 65 °C for 12 h. The N M R tube was cooled to room temperature and transferred back into the glovebox where 0.016 mL (0.12 mmol) of T M S C N was added to the tube via microsyringe. The N M R tube was re-sealed, removed from the glovebox and stored at room temperature for 12 h, before analysis by N M R spectroscopy. Spectral data of the TMS-protected-a-cyanoamines synthesized during this work can be found in Appendix II. a - C y a n o a m i n e f o r m a t i o n : R e p r e s e n t a t i v e p r o c e d u r e : An oven dried 110 mL tube Schlenk flask containing a Teflon coated stirbar was brought into the glovebox and was charged with 1.7 mmol of alkyne, 3.4 mmol of primary amine, 0.06 g (0.09 mmol) of 3 . 1 , and 2 mL of benzene. The Schlenk flask was sealed with a greased glass stopper and sidearm stopcock, and removed from the glovebox. The solution was stirred at 65 °C for 12 h before it was cooled to room temperature. The solution was then frozen using liquid nitrogen, and the headspace of the flask was evacuated. The flask was warmed to room temperature, and taped with electrical tape before bringing brought back into the glovebox where 0.23 mL (1.7 mmol) of T M S C N was added via syringe. The flask was again sealed and removed from the glovebox where it stirred for 3 h within a fume hood. The solution was then open to the atmosphere, diluted with 20 mL of dichloromethane, and quenched with sat. 240 NH4CI (20 mL). The two-phase solution was transferred to a separatory funnel, the organic layer was separated and the aqueous layer was extracted with dichloromethane (2 x 20 mL). The combined organic layers were washed with brine (1 x 20 mL), dried over MgS04, filtered, and concentrated under reduced pressure to give the a-cyanoamine as an oily compound. H N ^ P h 2-(benzylamino)heptanenitrile This previously reported uncharacterized compound 4 4 , 4 5 is present here with full spectral data. ' H N M R (300 M H z , C 6 D 6 , 8): 0.79 (t, V = 7.2Hz, C773, 3H), 0.87-0.97 (m, CH2, 2H), 1.17-1.23 (m, (CH2)2, 4H), 2.93 (t, V = 6.4 Hz, CH, 1H), 3.54 (d, 2J = 13 Hz, NCtf 2Ph, 1H), 3.72 (d, 2J = 13 Hz, NC# 2 Ph, 1H), 7.07-7.22 (m, Ar H, 5H); 1 3 C N M R (C6D6, 75 MHz): 8 14.1, 22.6, 25.4, 31.4, 33.6, 49.6, 51.7, 120.0, 126.9, 128.6, 128.7, 139.2; ESI m/z (relative intensity, ion): 217.2 (50%, M + H) 190.3 (100%, M - CN); HRMS (ESI) m/z: [M + H ] + calcd for C 1 4 H 2 i N 2 , 217.1705; found 217.1705. ! H N M R (300 MHz, C 6 D 6 , 8): 0.64 (br s, NH, 1H), 1.49-1.57 (m, PhCH 2 C# 2 , 2H), 2.42 (t, 3J= 7.5 Hz, PhCifc, 2H), 2.91 (t, 3 J = 7.7 Hz, CH, 1H), 3.42 (d, 2 J = 13 Hz, NC# 2 Ph, 1H), 3.66 (d, 2J= 13 Hz, NC# 2Ph, 1H), 6.88-6.90 (m, Ar H, 2H) 7.01-7.13 (m, Ar H, 8H); 1 3 C N M R (C 6 D 6 , 75 MHz): 8 31.8, 35.2, 48.9, 51.6, 119.8, 126.5, 127.7, 128.6, 128.6, 128.8, 131.5, 139.1, 140.5; ESI m/z (relative intensity, ion): 251.3 (80%, M + H), Ph 2-(benzylamino)-4-phenylbutanenitrile 241 224.3 (30%, M - C N ) ; H R M S (APCI) m/z: [M + H ] + calcd for C i 7 H i 9 N 2 , 251.1548; found 251.1544. H N C N 2 - ( i s o p r o p y l a m i n o ) - 4 - p h e n y l b u t a n e n i t r i l e ' H N M R (300 MHz, C 6 D 6 , 5): 0.69 (d, V = 6.1 Hz, CH(C/7 3) 2, 3H), 0.79 (d, 3 J = 6.3 Hz, CH(C/7 3) 2 , 3H), 1.56-1.62 (m, PhCH 2 C/ / 2 , 2H), 2.52 (t, 3J= 7.6 Hz, PhC// 2 , 2H) 2.81-2.90 (m, GrY(CH 3) 2, 1H), 3.03-3.07 (m, CH 2Cr7, 1H), 6.96-7.12 (m, Ar H, 5H); 1 3 C N M R (C 6 D 6 , 75 MHz): 5 21.4, 23.7, 31.9, 35.7, 47.0, 47.3, 120.4, 126.5, 128.7, 128.8, 140.6; ESI m/z (relative intensity, ion): 203.1 (100%, M + H); HRMS (APCI) m/z: [M + H ] + calcd for d 3 H 1 9 N 2 , 203.1548; found 203.1550. T F A - p r o t e c t e d - a - c y a n o a m i n e f o r m a t i o n : A / - b e n z y l - A ^ - ( l - c y a n o h e x y l ) - 2 , 2 , 2 - t r i f l u o r o a c e t a m i d e R e p r e s e n t a t i v e p r o c e d u r e : An oven-dried 40 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.16 g (2.0 mmol) of 1-hexyne, 0.42 g (3.9 mmol) of benzylamine, 0.07 g (0.10 mmol) of 3.1 and 4 mL of benzene in the glovebox. The Schlenk flask was sealed with a greased glass stopper and sidearm stopcock, and removed from the glovebox. The solution was stirred at 65 °C for 12 h before it was cooled to room temperature. The solution was then frozen using liquid nitrogen, and the headspace of the flask was evacuated. The flask was warmed to room temperature, and O C N Ph 242 taped with electrical tape before bringing brought back into the glovebox where 0.26 mL (2.0 mmol) of T M S C N was added via syringe. The flask was again sealed and removed from the glovebox where it stirred for 3 h within a fume hood. The flask was opened to the atmosphere and 0.68 mL (4.9 mmol) of T F A A was added. After stirring for 5 minutes, the solution was diluted with 10 mL of diethyl ether, transferred to a separatory funnel, and the organic phase was washed with a sat. NaHC03 solution (4x10 mL). The organic portion was separated, dried over MgS04, filtered, and concentrated to a dark red-brown oil under reduced pressure. It was purified by silica gel column chromatography (3:2 hexanes:ether) and concentrated to yield the title compound (0.57 g, 93% yield): ' H N M R (400 MHz, CDC1 3, 5): 0.82 (t, 3 J = 7.2 Hz, CH3, 3H), 1.13-1.22 (m, (CH2)2, 4H), 1.32-1.41 (m, CH2, 2H), 1.51-1.60 (m, CH2, 1H), 1.69-1.82 (m, CH2, 1H), 4.64 (d, 2J = 16 Hz, NCtf 2 Ph, 1H), 4.73 (t, 3 J = 6.0 Hz, CH, 1H), 4.85 (d, 2J= 16 Hz, NC/ / 2 Ph , 1H), 7.24-7.39 (m, Ar H, 5H); , 3 C N M R (CDC13,100 MHz): 5 13.9, 22.3, 25.6, 30.8,31.1,48.9,51.3, 116.1, 116.3 (q, '7=286 Hz), 128.0, 129.2, 129.4, 133.7, 157.2 (q, 2J= 37 Hz); ESI m/z (relative intensity, ion): 335.2 (40%, M + Na); HRMS (ESI) m/z: [M + Na] + calcd for C ] 6 H i 9 F 3 N 2 O N a , 335.1347; found 335.1346; Anal. Calcd. for C i 6 H 1 9 N 2 O F 3 : C, 61.53; N , 8.97; H , 6.13. Found: C, 61.93; N , 9.10, H , 6.35. Chiral HPLC tr = 4.03 min.; tr = 4.30 min. Achiral activator experiments: A n oven-dried 110 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.16g (2.0 mmol) of 1-hexyne, 0.21g (2.0 mmol) of benzylamine, 0.07g (0.09 mmol) of 3.1 and 4 mL of dry benzene within the glovebox. The flask was sealed, 243 removed from the glovebox, and heated at 65 °C for 12 h. After cooling the flask to room temperature, the solution was frozen with liquid nitrogen, and the headspace of the flask was evacuated on a vacuum line. The flask was sealed with electrical tape, and brought back into the glovebox where 2.0 mmol of activator, and 0.26 mL (2.0 mmol) of T M S C N was added via syringe. The solution was removed from the glovebox, and stirred in the fumehood for 12 h. The flask was opened to the atmosphere and 0.68 mL (4.9 mmol) of T F A A was added, followed by 15 minutes of stirring and then concentration on a vacuum line. The red-brown oil was purified via column chromatography using a 3:2 hexanes:diethyl ether eluent and concentrated to a pale yellow oil. The spectroscopic data matches that which is reported above. This was repeated two times for each activator and the reported yield is the average (in all cases the two yields were within ± 5% of each other). When the polystyrene beads were used as an activator, the mixture was diluted with dichloromethane and filtered before the addition of the T F A A . C h i r a l T F A - p r o t e c t e d - a - c y a n o a m i n e f o r m a t i o n : A r - ( l - c y a n o h e x y l ) - 2 , 2 , 2 - t r i f l u o r o - A L [ ( l / i ) - l - p h e n y l e t h y l ] a c e t a m i d e R e p r e s e n t a t i v e p r o c e d u r e : A n oven-dried 40 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.07 g (0.90 mmol) of 1-hexyne, 0.10 g (0.90 mmol) of (i?)-a-methylbenzylamine, 0.03 g (0.04 mmol) of 3.1 and 2 mL of benzene in the glovebox. The Schlenk flask was sealed with a greased glass stopper and sidearm stopcock, and removed from the glovebox. The solution was stirred at 65 °C for 12 h CN Ph 244 before it was cooled to room temperature. The solution was then frozen using liquid nitrogen, and the headspace of the flask was evacuated. The flask was warmed to room temperature, and taped with electrical tape before bringing brought back into the glovebox where 0.11 mL (0.9 mmol) of T M S C N was added via syringe. The flask was again sealed and removed from the glovebox where it stirred for 3 h within a fume hood. The flask was opened to the atmosphere and 0.24 mL (1.7 mmol) of T F A A was added. After stirring for 5 minutes, 10 mL of diethyl ether was added, the solution was transferred to a separatory funnel, and the organic phase was washed with a sat. NaF£C03 solution (4x10 mL). The organic portion was separated, dried over MgSC>4, filtered, and concentrated to a dark red-brown oil under reduced pressure. ' H N M R spectrum was complicated. GC-MS m/z (tr, ion): 326 (16.7 min., M+), 326 (16.8 min. M+). R a c e m i z a t i o n e x p e r i m e n t s : E x p e r i m e n t # 1 : A n oven-dried 40 mL Schlenk flask, outfitted with a Teflon coated stirbar and a greased sidearm was charged with 0.21 g (1.7 mmol) of (R)-a-methylbenzylamine, 0.06 g (0.08 mmol) of 3.1 and 2 mL of benzene within a nitrogen filled glovebox. The flask was sealed with a greased stopcock, removed from the glovebox, and heated at 65 °C for 12 h. The solution was cooled to room temperature, and opened to the atmosphere. Both dichloromethane (10 mL) and water (10 mL) were added to the flask, and the two-phase mixture was stirred for 2 h, before being transferred to a separatory funnel. After separation of the two phases, the organic phase was extracted with 1 M HCI (2 x 10 mL). The aqueous phase was washed with dichloromethane ( 2 x 1 0 mL) before the solution was made basic with 1 M NaOH. The 245 aqueous phase was extracted with dichloromethane (3 x 20 mL) and the combined organic fractions were dried over MgS04, filtered, and concentrated under reduced pressure. ! H N M R spectroscopy confirmed that only the (i?)-a-methylbenzylamine was present. A 25 mL round bottom flask equipped with a Teflon coated stirbar was then charged with 0.07 g (0.60 mmol) of the (i?)-a-methylbenzylamine that was isolated above, 0.1 mL (0.63 mmol) of triethylamine, 0.16 g (0.63 mmol) of (5)-(+)-methoxy-a-(trifluoromethyl)phenyl acetic acid chloride and 2 mL of dichloromethane. After the solution stirred for 12 h, it was diluted with 5 mL of dichloromethane and washed with 1 M HC1 ( 1 x 5 mL), 1 M NaOH ( 1 x 5 mL) and brine ( 1 x 5 mL). The organic phase was dried over MgS04, filtered, and concentrated under reduced pressure. ] H and 1 9 F N M R spectroscopy indicated that there was only 1 diastereomer present. *H N M R (400 MHz, CDCI3, 8): 1.52 (d, 3J= 7.2 Hz, C/7 3, 3H), 3.37 (s, OC773, 3H), 5.19-5.23 (m, CH, IK), 6.99-7.02 (m, Ar H, 1H), 7.05-7.50 (m, AxH, IK), 7.52-7.54 (m, ArH, 2H); 1 9 F N M R (300 MHz, C 6 D 6 , 8): 7.93 (s, CF 3 ) . Experiment #2: A.oven-dried 40 mL Schlenk flask, outfitted with a greased sidearm and a Teflon coated stirbar, was charged with 0.07 g (0.90 mmol) of 1-hexyne, 0.21g (1.7 mmol) of (i?)-a-methylbenzylamine, 0.03g (0.04 mmol) of 3.1 and 2 mL of dry benzene within the glovebox. The flask was sealed with a greased stopcock, removed from the glovebox, and heated at 65 °C for 12 h. After cooling to room temperature, the flask was opened to the atmosphere, and diluted with 5 mL of dichloromethane. A small amount of silica gel was added to the flask, along with several drops of 3 M HC1. The mixture stirred for 12 h before 50 mL of dichloromethane was added and the solution was filtered through a ground glass frit. The silica residue was washed with 50 mL of a 5% methanol 246 in dichloromethane solution and the organic solvent was removed under reduced pressure. l H N M R spectroscopy confirmed that only the (i?)-a-methylbenzylamine was present. A 25 mL round bottom flask containing a Teflon coated stirbar was then charged with 0.04 g (0.30 mmol) of the (i?)-a-methylbenzylamine that was isolated above, 0.05 mL (0.40 mmol) of triethylamine, 0.09 g (0.40 mmol) of (5>(+)-methoxy-a-(trifluoromethyl)phenyl acetic acid chloride and 1 mL of dichloromethane. The solution stirred for 12 h, was diluted with 5 mL of dichloromethane and transferred into a separatory funnel. The solution was washed with 1 M HC1 ( 1 x 5 mL), 1 M NaOH (1x5 mL) and brine ( 1 x 5 mL). The organic phase was removed, dried over MgSO,*, filtered, and concentrated under reduced pressure. ' H and 1 9 F N M R spectroscopy indicated that there was only 1 diastereomer present, and the spectroscopic data matches that which was reported above in experiment #1. Diastereoselectivity experiments: An oven-dried 40 mL tube Schlenk flask complete with a Teflon coated stirbar and a greased sidearm, was charged with 0.07g (0.86 mmol) of 1-hexyne, 0.10g (0.86 mmol) of (i?)-a-methylbenzylamine, 0.03g (0.04 mmol) of 3.1 and 2 mL of dry benzene within a glovebox. The flask was sealed, removed from the glovebox, and stirred at 65 °C for 12 h. After cooling to room temperature, the solution was frozen with liquid nitrogen, the headspace of the flask was evacuated on a vacuum line, and the flask was sealed with electrical tape before being transferred back into the glovebox. The desired amount of activator and 0.11 mL (0.86 mmol) of T M S C N was added to the flask, which was then resealed, removed from the glovebox, and stirred in a fumehood for 12 h. The 247 flask was opened to the atmosphere and 0.24 mL (1.7 mmol) of T F A A was added. After stirring for 15 minutes, the solution was concentrated on a vacuum line. A sample of approximately 3 mg/mL of dichloromethane was used for GC-MS analysis with an injection volume of 2 uL. When the (i?)-a-methylbenzylamine was used as an activator, the entire amount of amine was added at the time of the initial hydroamination. When the polystyrene beads were used as an activator, the solution was diluted with dichloromethane and filtered before addition of T F A A . When the (J?)-2-phenylglycine sodium salt was used as an activator the solution was filtered through Celite™ before GC-MS analysis. E l i m i n a t i o n p r o d u c t : 2 , 2 , 2 - t r i f l u o r o - A / - [ ( l Z ) - h e x - l - e n - l - y l ] - / V - [ ( l i f ) - l - p h e n y l e t h y l ] a c e t a m i d e ( 3 . 1 8 ) An oven dried 110 mL tube Schlenk flask was charged with a Teflon coated stirbar, 0.14g (1.7 mmol) of 1-hexyne, 0.20g (1.7 mmol) of (R)-a-methylbenzylamine, 0.06g (0.08 mmol) of 3 . 1 , and 3 mL of benzene within the glovebox. The flask was sealed, removed from the glovebox and heated at 65 °C for 12 h. After cooling to room temperature, the solution was frozen with liquid nitrogen, the headspace of the flask was evacuated on a vacuum line, and the flask was sealed with electrical tape before being transferred back into the glovebox. Using a syringe, 0.03 mL (0.17 mmol) of (S)-NJV-dimethyl-a-methylbenzylamine and 0.23 mL (1.7 mmol) of T M S C N were added to the flask, which was resealed, removed from the glovebox, and placed in a fumehood with P h 248 stirring for 12 h. The flask was opened to the atmosphere, and 0.48 mL (3.4 mmol) of T F A A was added. After stirring for 15 minutes the solution was concentrated on a vacuum line. Column chromatography using an eluent of 3:2 hexanes:dichloromethane was performed, and the title compound was isolated as an oil. ' H N M R (400 MHz , C D C 1 3 , 5): 0.84 (t, V= 6.8 Hz, CH3, 3H) , 1.17-1.27 (m, (C /7 2) 2 , 4H ) , 1.52 (d, 3J= 7.2 Hz, CH(C/7 3), 3H) , 1.94-1.99 (m, CH2, 2H) , 5.39-5.46 (m, C H 2 C / 7 C H , 1H) 5.63 (d, 3 J = 14 Hz, C H 2 C H G r 7 , 1H), 5.82 (q, 3J= 7.2 Hz, C/7(CH 3), 1H), 7.23-7.34 (m, Ar H, 5H) ; 1 3 C N M R ( C D C 1 3 , 1 0 0 MHz): 5 13.9, 16.2, 22.2, 29.6, 30.9, 54.283 116.8 (q, XJ = 286 Hz), 121.2, 127.9, 128.2, 128.7, 138.0, 139.0, 156.8 (q, 2J = 34 Hz); ESI m/z (relative intensity, ion): 322.2 (50%, M + Na) 300.2 (30%, M + H); HRMS (ESI) m/z: [M + Na] + calcd for C i 6 H 2 0 F 3 N O N a , 322.1395; found 322.1396; GC-MS m/z (tr, ion): 299 (15.4 min., M+). G e n e r a l p r o c e d u r e s f o r e x p e r i m e n t s p e r f o r m e d i n p a r a l l e l s y n t h e t i c u n i t : An oven-dried parallel synthetic unit tube, charged with a Teflon coated stirbar, 0.07 g (0.86 mmol) of 1-hexyne, 0.10 g (0.86 mmol) of (i?)-a-methylbenzylamine, 0.03 g (0.04 mmol) of 3.1, and 2 mL of benzene was sealed and placed in a parallel synthetic unit within the glovebox. The temperature was set to 65 °C and the solution stirred for 12 h. The solution was transferred to a 25 mL Teflon sealed vial containing a stirbar, and the desired amount of activator and 0.11 mL (0.86 mmol) of T M S C N was added to the vial. The vial was sealed, removed from the glovebox and stirred in a fumehood for 12 h. The vial was opened to the atmosphere, and 0.24 mL (1.7 mmol) of T F A A was added. After 15 minutes the solution was concentrated and the diastereoselectivity in the 249 products was determined by GC-MS. If any salts were present in the solution, the solution was filtered through Celite™ before analysis by GC-MS. Enantioselective experiments: Chiral tertiary amine/a-amino acid salt as activators: A n oven-dried 40 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.16 g (2.0 mmol) of 1-hexyne, 0.21 g (2.0 mmol) of benzylamine, 0.07 g (0.09 mmol) of 3.1, and 2 mL of benzene within the glovebox. The flask was sealed, removed from the glovebox and heated at 65 °C for 12 h. After cooling to room temperature, the solution was frozen with liquid nitrogen, the headspace of the flask was evacuated on a vacuum line, and the flask was sealed with electrical tape. After transferal of the flask back into the glovebox, the required amount of activator was added, followed by 0.26 mL (2.0 mmol) of TMSCN. The solution stirred at room temperature for 3 h before the flask was opened to the atmosphere and 0.68 mL (4.9 mmol) of T F A A was added. After a further 15 minutes of stirring, the solution was concentrated on a vacuum line, and the product was isolated by column chromatography using a 3:2 hexanes:diethyl ether eluent, and concentrated to an oil. GC-MS was run to ensure purity of the product, and chiral HPLC was run to determine the enantiomeric excess. GC-MS was run on a solution of approximately 3 mg/mL in dichloromethane with an injection volume of 2 pL. HPLC was run on a solution of approximately 1 mg/mL in 90:10 hexanes:isopropyl alcohol with an injection volume of 5 pL. Amino alcohols/a-amino methyl esters as activators: A n oven-dried 40 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.16 g (2.0 mmol) of 1-hexyne, 0.21 g (2.0 mmol) of benzylamine, 0.07 g 250 (0.09 mmol) of 3.1, and 2 mL of toluene within the glovebox. The flask was sealed, removed from the glovebox and heated at 65 °C for 12 h. After cooling to room temperature, the solution was frozen with liquid nitrogen, the headspace of the flask was evacuated on a vacuum line, and the flask was sealed with electrical tape. The flask was transferred to the glovebox, along with a second 110 mL tube Schlenk flask. The original Schlenk flask is charged with 2.0 mmol of the activator along with 4 mL of toluene. The second Schlenk flask was charged with 0.26 mL (2.0 mmol) of T M S C N and 2 mL of toluene. Both flasks were sealed with rubber septas, and removed from the glovebox. The flask containing the T M S C N was cooled to -78 °C and the contents of the first Schlenk tube were added dropwise via syringe. The solution stirred at -78 °C for 15 minutes, and then at room temperature for 3 h. The flask was opened to the atmosphere and 0.95 mL (6.9 mmol) of T F A A was added. After 15 minutes the solution was concentrated. GC-MS analysis of the crude compound was performed to ensure that there was no elimination product present, and was not found in any case. ESI-MS of the crude product was performed to determine whether any imine metathesis had occurred, and again was not observed in any cases. Chiral HPLC was performed to determine the enantiomeric excess of the product. a-Amino-*-butylesters as activators: A n oven-dried 40 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.04 g (0.49 mmol) of 1-hexyne, 0.05 g (0.49 mmol) of benzylamine, 0.017 g (0.02 mmol) of 3.1, and 1 mL of toluene within the glovebox. The flask was sealed, removed from the glovebox and heated at 65 °C for 12 h. After cooling to room temperature, the solution was frozen with liquid nitrogen, the headspace of the flask was 251 evacuated on a vacuum line, and the flask was sealed with electrical tape. The flask was transferred to the glovebox, along with a second 40 mL tube Schlenk flask. The original Schlenk flask is charged with 0.49 mmol of the activator, along with 0.5 mL of toluene. The second Schlenk flask was charged with 0.06 mL (0.49 mmol) of T M S C N and 0.5 mL of toluene. Both flasks were sealed with rubber septas, and removed from the glovebox. The flask containing the T M S C N was cooled to -78 °C and the contents of the first Schlenk tube were added dropwise via syringe. The solution stirred at -78 °C for 15 minutes, and then at room temperature for 3 h. The flask was opened to the atmosphere and 0.24 mL (1.7 mmol) of T F A A was added. After 15 minutes the solution was concentrated. GC-MS analysis of the crude compound was performed to ensure that there was no elimination product present, and was not found in any case. ESI-MS was of the crude product was performed to determine whether any imine metathesis had occurred, and again was not observed in any cases. Chiral HPLC was performed to determine the enantiomeric excess of the product. Chiral diamines as activators: A n oven-dried 40 mL tube Schlenk flask containing a Teflon coated stirbar was charged with 0.07 g (0.94 mmol) of 1-hexyne, 0.10 g (0.94 mmol) of benzylamine, 0.03 g (0.05 mmol) of 3.1, and 2 mL of toluene within the glovebox. The flask was sealed, removed from the glovebox and heated at 65 °C for 12 h. After cooling to room temperature, the solution was frozen with liquid nitrogen, the headspace of the flask was evacuated on a vacuum line, and the flask was sealed with electrical tape. The flask was transferred to the glovebox, along with a second 40 mL tube Schlenk flask. The original Schlenk flask is charged with 0.05 mmol of the diamine activator. The second Schlenk 252 flask was charged with 0.13 mL (0.94 mmol) of T M S C N and 2 mL of toluene. Both flasks were sealed with rubber septas, and removed from the glovebox. The flask containing the T M S C N was cooled to -78 °C and the contents of the first Schlenk tube were added dropwise via syringe. The solution stirred at -78 °C for 15 minutes, and then at room temperature for 12 h. The flask was opened to the atmosphere and 0.46 mL (3.3 mmol) of T F A A was added. After 15 minutes the solution was concentrated. GC-MS analysis of the crude compound was performed to determined how much elimination product was present (<3% in all cases). ESI-MS of the crude product was performed to determine whether any imine metathesis had occurred, which was not observed in any cases. Chiral HPLC was performed to determine the enantiomeric excess of the product. Characterization of adduct between benzylamine and T M S C N : A small vial, within a nitrogen filled glovebox, is charged with 0.20 g (1.9 mmol) of benzylamine and 0.5 g of C7D8 before being transferred into a J. Young N M R tube. Using a syringe, 0.25 mL (1.9 mmol) of T M S C N was added directly to the N M R tube and the tube was sealed and removed from the glovebox. N M R spectroscopy was performed within 0.5 h of preparing the sample. As the reaction forms an equilibrium, at room temperature there is evidence of both the adduct and the starting materials (amine and TMSCN). Solution characterization data is presented with the signals from the adduct listed first, followed by the amine and the T M S C N . Copies of the N M R spectra can be found in Appendix II. ' H N M R (400 MHz, C 7 D 8 , 8): (adduct) 0.04 (s, Si(C// 3 ) 3 , 9H), 3.76 (s, CH2, 2H), 7.05-7.19 (m, Ar H, 5H); (amine) 3.48 (s, CH2, 2H), 7.05-7.19 (m, Ar H, 5H); (TMSCN) -0.03 (s, Si(C# 3) 3, 9H); 1 3 C N M R (C 6 D 6 , 100 MHz): 8 253 (adduct) 0.1, 46.5, 109.0, 127.2, 127.3, 128.4, 144.7; (amine) 46.1, 126.8, 127.2, 128.5, 143.9; (TMSCN) -2.42, 126.6; 2 9 S i N M R (C 7 D 8 , 79 MHz): 5 (adduct) -99.42; (TMSCN) -12.31. Characterization of adduct between (if)-phenylglycine /-butyl ester: A small vial, within a nitrogen filled glovebox, is charged with 0.07 g (0.31 mmol) of (i?)-phenylglycine /-butyl ester and 0.5 g of C 7 D 8 before' being transferred into a J. Young N M R tube. Using a syringe, 0.04 mL (0.31 mmol) of T M S C N was added directly to the N M R tube and the tube was sealed and removed from the glovebox. N M R spectroscopy was performed within 0.5 h of preparing the sample. As the reaction forms an equilibrium, at room temperature there is evidence of both the adduct and the starting materials (ester and TMSCN). Solution characterization data is presented with the signals from the adduct listed first, followed by the ester and the T M S C N . Copies of the N M R spectra can be found in Appendix II. *H N M R (400 MHz, C 7 D 8 , 6): (adduct) -0.03 (s, Si(C// 3 ) 3 , 18H), 1.25 (s, C(CH3)h 18H), 4.53 (s, CH, 1H), 4.56 (s, CH, 1H) 6.97-7.36 (m, Ar H, 10H); (ester) 1.23 (s, C(C/ / 3 ) 3 , 9H), 4.23 (s, CH, 1H), 6.97-7.36 (m, Ar H, 5H); (TMSCN) -0.06 (s, Si(C# 3) 3, 9H); 1 3 C N M R (C 7 D 8 , 100 MHz): 8 (adduct) 0.3, 28.2, 60.4, 81.1, 109.2, 127.4, 128.0, 128.9, 143.5, 173.7; (ester) 28.16, 59.97, 81.07, 127.5, 127.9, 128.9, 142.3, 173.6; (TMSCN) -1.66, 126.8; 2 9 S i N M R (C 7 D 8 , 79 MHz): 8 (adduct) -3.79; (TMSCN) -12.54. 254 3 .5 R e f e r e n c e s (1) Trost, B . M . Angew. Chem. Int. Ed, Engl. 1 9 9 5 , 34, 259. (2) Zhang, Z.; Schafer, L. L. Org. Lett. 2 0 0 3 , J , 4733. (3) Zhang, Z.; Leitch, D. C ; Lu, M . ; Patrick, B. O.; Schafer, L. L. Chem. Eur. J. 2 0 0 7 , 1 3 , 2012. (4) Walsh, P. J.; Baranger, A . M . ; Bergman, R. G. J. Am. Chem. Soc. 1 9 9 2 , 114, 1708. (5) Yamaguchi, M . ; In Comprehensive Organic Synthesis, Trost, B. M . , Ed.; Pergamon Press: New York, 1991; Vol . 1, Chapter 1.11. (6) Ojima, I.; Inaba, S.; Nakatsugawa, K. Chem. Lett. 1 9 7 5 , 331. (7) Rami, B. C ; Dey, S. S.; Hajra, A . Tetrahedron 2 0 0 2 , 58, 2529. (8) Kobayashi, S.; Nagayama, S.; Busujima, T. Tetrahedron Lett. 1 9 9 6 , 37, 9221. (9) De, S. K . J. Mol. Catal. A: Chem. 2 0 0 5 , 225, 169. (10) Sakurai, R.; Suzuki, S.; Hashimoto, J.; Baba, M . ; Itoh, O.; Uchida, A . ; Hattori, T.; Miyano, S.; Yamaura, M . Org. Lett. 2 0 0 4 , 6, 2241. (11) Sigman, M . S.; Vachal, P.; Jacobsen, E. N . Angew. Chem., Int. Ed. 2 0 0 0 , 39, 1279. (12) Krueger, C. A. ; Kuntz, K . W.; Dzierba, C. D.; Wirschun, W. G.; Gleason, J. D.; Snapper, M . L.; Hoveyda, A . H. J. Am. Chem. Soc. 1 9 9 9 , 1 2 1 , 4284. (13) Jiao, Z.; Feng, X . ; Liu, B. ; Chen, F.; Zhang, G.; Jiang, Y . Eur. J. Org. Chem. 2003 ,3818 . (14) Su, Z.; Hu, C ; Qin, S.; Feng, X . Tetrahedron 2 0 0 6 , 62, 4071. (15) Fukuda, Y . ; Maeda, Y . ; Kondo, K. ; Aoyama, T. Synthesis 2 0 0 6 , 1 2 , 1937. (16) Josephsohn, N . S.; Kuntz, K. W.; Snapper, M . L.; Hoveyda, A . H . J. Am. Chem. Soc. 2001 ,1 2 3 , 11594. (17) Corey, E. J.; Grogan, M . J. Org. Lett. 1 9 9 9 , 1 , 157. (18) Takamura, M . ; Hamashima, Y . ; Usuda, H. ; Kanai, M . ; Shibasaki, M . Angew. Chem., Int. Ed. 2 0 0 0 , 39, 1650. ( 1 9 ) Wood, M . C ; Leitch, D. C ; Yeung, C. S.; Kozak, J. A. ; Schafer, L . L . Angew. Chem., Int. Ed. 2 0 0 7 , 46, 354. (20) Margolis, L. A. ; D., S. J. C ; Yoder, C. H . Synthesis and reactivity in inorganic and metal-organic chemistry 2 0 0 3 , 33, 359. (21) Bassindale, A . R.; Stout, T. Tetrahedron Lett. 1 9 8 5 , 26, 3403. (22) Chult, C ; Corriu, R. J. P.; Reye, C ; Young, J. C. Chem. Rev. 1 9 9 3 , 93, 1371. (23) Corriu, R. J. P.; Dabosi, G.; Martineau, M . J. Organomet. Chem. 1 9 7 8 , 154, 33. (24) Wagler, J.; Bohme, U . ; Brendler, E.; Thomas, B.; Goutal, S.; Mayr, H . ; Kempf, B. ; Remennikov, G. Y. ; Roewer, G. Inorg. Chim. Acta 2 0 0 5 , 358, 4270. (25) . Mai, K . ; Patil, G. J. Org. Chem. 1 9 8 6 , 51, 3545. (26) Sigman, M . S.; Jacobsen, E. N . J. Am. Chem. Soc. 1998 ,120 , 5315. (27) Anderson, L . L. ; Arnold, J.; Bergman, R. G. J. Am. Chem. Soc. 2005 ,1 2 7 , 14542. 255 (28) Thomson, R. K. ; Bexrud, J. A. ; Schafer, L. L. Organometallics 2006, 25, 4069. Holmes, R. H . Chem. Rev. 1996, 96, 927. Chojnowski, J.; Cypryk, M . ; Michalski, J. J. Organomet. Chem. 1978, 767, C31. Corriu, R. J. P.; Dabosi, G.; Martineau, M . J. Organomet. Chem. 1980, 186, 25. Bassindale, A . R.; Stout, T. J. Organomet. Chem. 1982, 238, C41. Zuckerman, R. L.; Krska, S. W.; Bergman, R. G. J. Am. Chem. Soc. 2000, 122, 751. The solid supported amines were purchased from Aldrich. Poly(styrene-co-divinylbenzene)amino methylated, 0.5 mmol N/g; Diethylamine, polymer bound, 1 mmol N/g. Lee, A . 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Soc. 2002,124, 10012. 256 CHAPTER FOUR: CATALYST DEVELOPMENT FOR GROUP 4 MEDIATED HYDROAMINATION 4.1 I n t r o d u c t i o n 4 .1 .1 H y d r o a m i n a t i o n The most efficient method for synthesizing imines and amines is through hydroamination, the addition of nitrogen and hydrogen atoms across a carbon-carbon multiple bond (eq. 4.1). 1 - 6 The initially formed enamine generally isomerizes to the imine when primary amines are used. Many different substrates can be used in the hydroamination reaction. For example, alkynes, allenes, and alkenes can be used to provide the carbon-carbon unsaturated bond, while primary amines, secondary amines, and hydrazines can be used as the nitrogen source to yield a wide range of imine and/or amine containing products. With a few exceptions of extremely reactive starting materials,7"11 hydroamination always requires the use of a catalyst. A number of metal-containing catalyst systems 12 25 have been designed for the hydroamination reaction including late transition metals, lanthanides,26"44 actinides,45"47 alkali and alkaline earth metals,4 8'4 9 and early transition metals.50"60 As early transition metals are relatively inexpensive and non-toxic, they are extremely attractive for catalyst development. © Reproduced in part with permission from Lee, A. V.; Schafer, L. L. Organometallics, 2006, R (4.1) 25, 5249. Copyright 2006 American Chemical Society. 257 The Schafer group is very interested in investigating organic amides as a class of non-Cp proligands that are easily prepared, and are known to form stable complexes with group 4 metals.61 These complexes have been extensively investigated for activity in catalytic hydroamination. For example, the bis(amidate)bis(amido) titanium complex, 4.1, is a very active, very regioselective hydroamination precatalyst.62'63 Regardless of the steric bulk in the alkyl primary amine or the terminal alkyne used, 4.1 under 24 h (unoptimized). Furthermore, complex 4.1 exhibits a very high tolerance of many different functional groups, including carbonyls, esters, amides, protected alcohols and amines, and silyl groups. This type of tolerance, reactivity, and regioselectivity has not been observed previously with any other group 4 catalytic systems. Clearly, the amidate ligand set imposes some, interesting effects on the metal center. The hard, chelating nature of the amidate ligands results in enhanced ionic bonding, giving a very electropositive metal center. The amidate ligands also provides poor orbital overlap with the metal center.64 For reasons that are not fully understood at this point, this leads to high reactivity and regioselectivity in the catalytic hydroamination of terminal alkynes that has not been seen before. Given the importance of regioselectivity for the applications of catalysis in organic synthesis, this in an area of on-going research. 4.1 always produces high yields of the anfr'-Markovnikov product, the aldimine, at 65 °C in 258 The general mechanism for group 4 catalyzed hydroamination of alkynes has been investigated by a number of groups over the past twenty years. 5 0 ' 5 2 ' 6 5 ' 6 6 Depending on the catalytic system used, the symmetry of the alkyne that is used in this reaction can affect the regioselectivity,67 as can the type of primary amine.68 Furthermore, it appears that the use of aryl amines generally tends to lead to the formation of the Markovnikov product, whereas the use of alkyl amines has been shown to form either or both the Markovnikov product and the anft'-Markovnikov product. Further investigations into this observation have been made in terms of isolating intermediates69 and theoretical studies.70'71 However, the regioselectivity of this reaction also varies depending on the catalytic system, and to date there is not a clear, general understanding of this phenomenon. In 2004, Beller and co-workers reported interesting work regarding the regioselectivity of terminal alkyne hydroamination using non-Cp proligands.72 A variety of sterically hindered phenols were studied as proligands on titanium and a dramatic change in regioselectivity is observed between proligands 4.2 and 4.3 (Figure 4.1). 4.2 4.3 Figure 4.1: Sterically hindered proligands used by Beller and co-workers. For example, when two equivalents of 4.2 are combined in situ with Ti(NMe2)4 and used in the hydroamination of terminal alkynes, very high regioselectivity for the Markovnikov product is observed. On the other hand, the same reaction conditions with 259 4.3 results in high regioselectivity for the an/z'-Markovnikov product. This seemingly small change in sterics results in a complete change in regioselectivity and this result is observed regardless of the steric nature of the primary amine used. The initial investigation has been followed up with calculations to try and understand the dramatic change in regioselectivity.71 It is proposed that the change in sterics of the ligand affects the stability of the 7t-complex that is formed during the hydroamination reaction. Calculations have shown that the n-complex resulting from the Markovnikov orientation with proligand 4.2 is lower in energy than the rc-complex that results from the anti-Markovnikov orientation. In contrast, the calculations show the opposite to be true with 4.3. While these computational results support observed product yields, no experimental mechanistic work has been done to further substantiate this hypothesis. Another interesting observation has been noted by Beller and co-workers during these investigations. Complex 4.4 is reported to be stable in air for short periods of Generally, group 4 metal complexes are very sensitive to both air and moisture, and hence precautions need to be taken for their use in synthesis. This sensitivity can limit the use of a precatalyst in organic synthesis as well as in industry. Therefore, the design of air-stable group 4 complexes would be very useful and is an attractive research goal. time. 73 4.4 2 6 0 When looking at the regioselective hydroamination of alkynes, it appears that many different factors affect the outcome of the reaction. For example, it has been observed for titanium complex 4.1 that the ionic nature of the chelating amidate ligands and the poor orbital overlap affects the regioselectivity, yielding a very a«/z'-Markovnikov selective precatalyst. Likewise, it has been demonstrated that slight changes in the sterics of phenolic proligands 4.2 and 4.3 can shift the regioselectivity from the Markovnikov product to the awfr'-Markovnikov product. The combination of these factors has lead to investigations with pyrimidinols, 4.5. Pyrimidinols, like phenols, are aromatic alcohols. However, the presence of the two nitrogen atoms in the aromatic ring leads to a decrease in the p K a of the hydroxy substituent. For example, the pK a of a pyrimidinol is approximately 7 , 7 4 which is approximately three orders of magnitude smaller than the average p K a of a phenol.7 5 Therefore, i f a pyrimidinol is used as a proligand for the synthesis of a group 4 complex, this decrease in pK a wil l lead to bonding that is even more ionic in nature, and promote even greater electropositive character at the metal center, relative to the phenoxide ligands. It is also predicted that the orbital overlap between the pyrimidinoxide ligand and the metal center would be much greater than that which is observed with the amidate complex 4.1. Insight into the importance of orbital overlap and the effects of this electronic change could then be probed through catalytic reactivity. The application of R 4.5 261 pyrimidinols as proligands for transition metal complexes has not been explored previous to this work and it is postulated that the use of this proligand may lead to a metal complexes with enhanced air stability. Furthermore, while both 4 .1 and 4 . 4 are highly regioselective precatalysts, neither are completely general precatalysts in terms of reactivity with all types of alkynes (internal and terminal) and all types of amines (aryl and alkyl). Therefore, continual development of new hydroamination precatalysts is a worthy research goal. 4 . 1 . 2 S c o p e o f p r o j e c t The purpose of this investigation is to synthesize and structurally characterize group 4 metal complexes containing pyrimidinoxide ligands. These complexes are surveyed for reactivity and regioselectivity in catalytic hydroamination of alkynes and alkenes. It is proposed that the change in the electronic nature of the metal complexes could lead to more active hydroamination precatalysts. Furthermore, it is hypothesized that the complexes may also exhibit enhanced stability to air and moisture. Comparing and contrasting the experimental results with related phenoxide systems and the amidate catalysts developed in the Schafer group would, provide valuable insights to further the understanding of regioselectivity and reactivity in catalytic hydroamination. 4 . 2 R e s u l t s a n d d i s c u s s i o n 4 .2 .1 L i g a n d d e s i g n a n d s y n t h e s i s Group 4 metals are oxophilic, and therefore it is often difficult to form complexes in a controlled manner with oxygen-donating ligands. Phenols, however, have been used 2 6 2 successfully as proligands previously on both Ti and Zr. " Rothwell and co-workers extensively investigated the coordination chemistry of many substituted phenols on early transition metals,5 1'8 3"8 7 with a few select examples shown in Figure 4.2. 8 8" 9 0 Figure 4.2: Selected aryloxide complexes investigated by Rothwell and co-workers. Likewise, as discussed in the introduction, Beller and coworkers have investigated Ti complexes of substituted phenols and their activity in the regioselective hydroamination of terminal alkynes.71"73 Through these investigations it has been noted that phenols lacking steric bulk in the 2 and 6 position lead to the formation of catalytically inactive tris and tetrakis phenoxide titanium complexes. Catalytically active complexes have been successfully formed when there is sufficient steric bulk in the 2,6-positions of the phenol. With this in mind, a pyrimidinol that is substituted in the 2,6-positions with bulky /-butyl groups is targeted as a potential proligand. A suitable pyrimidinol had been reported in the literature.91 This compound has been used in physical organic chemistry studies where it is utilized as a radical scavenger. The reported pyrimidinol synthetic procedure is slightly modified as shown in Scheme 4.1, and pyrimidinol 4.8 is synthesized in 3 steps.91 263 Scheme 4.1: Synthesis of substituted pyrimidinol 4.8. Bromination of commercially available diketone is easily accomplished and compound 4.6 is recrystallized in high yield. Compound 4.6 is then heated in boiling acetic acid in the presence of ammonium acetate for at least 27 h. The resulting acyloxazole 4.7 is purified via column chromatography. Finally, heating 4.7 in ammonium hydroxide to 180 °C within a Parr Bomb for 36 h yields the /-butyl substituted pyrimidinol, 4.8. Compound 4.8 is isolated as a stable, crystalline white solid that is purified via column chromatography and dried by vacuum sublimation. The 'Ff and 1 3 C N M R spectra and mass spectrum are in agreement with literature data.91 4.2.2 Metal complex synthesis Bis(pyrimidinoxide)bis(amido) titanium (4.9) and zirconium (4.10) complexes are synthesized via a protonolysis reaction between proligand 4.8 and tetrakis(dimethylamido) titanium or zirconium (eq. 4.2) in toluene at room temperature under a nitrogen atmosphere in a glovebox. 264 (4.2) 4.8 4.9 M = Ti 4.10 M = Zr This reaction proceeds very quickly at room temperature for the formation of both complexes. The synthesis of 4.9 is marked by a colour change from light to dark orange. After removal of the solvent, the dark orange solid is redissolved in hexanes, filtered through Celite™, and concentrated. The ' H N M R spectrum of 4.9 shows a downfield shift of the /-butyl peaks from 1.36 ppm (in the *H N M R spectrum of 4.8) to 1.51 ppm, a smaller downfield shift for the methyl peaks from 2.65 ppm to 2.67 ppm, and the disappearance of the O-H peak at 4.31 ppm. There is no evidence in either the ' H or 1 3 C N M R spectra of any non-volatile byproducts being formed in this reaction. Mass spectrometry and elemental analysis also confirm the formation of 4.9. There is no colour change associated with the synthesis of 4.10, which is formed as a white solid. The ' H N M R spectrum shows a shift in the /-butyl resonances from 1.36 ppm to 1.50 ppm. The methyl resonances also shift from 2.65 ppm to 2.67 ppm, and the O-H peak at 4.31 ppm disappears. The successful synthesis of 4.10 is further supported by 1 3 C N M R spectroscopy, mass spectrometry and elemental analysis. X-Ray quality crystals of 4.9 are obtained following recrystallization from toluene, and an ORTEP depiction of the solid-state molecular structure of 4.9 is shown in Figure 4.3, with selected bond lengths and bond angles summarized in Table 4.1. 265 Figure 4.3: ORTEP depiction of the solid state molecular structure of complex 4.9. Hydrogen atoms are omitted for clarity. Thermal ellipsoids are set to 50% probability. Table 4.1: Selected bond lengths (distance, A) and angles (angles, °) for 4.9. Distance Angle Ti -O( l ) 1.8408(13) 0(1)-Ti-N(5) 100.97(7) Ti-0(2) 1.8421(14) 0(1)-Ti-N(6) 121.69(7) Ti-N(5) 1.8965(17) 0(2)-Ti-N(5) 121.91(7) Ti-N(6) 1.9065(17) 0(2)-Ti-N(6) 101.89(7) 0(1)-C(1) 1.351(2) 0(l)-Ti-0(2) 112.36(7) 0(2)-C(14) 1.356(2) N(5)-Ti-N(6) 98.70(8) Ti-0(2)-C(14) 176.76(14) Ti-0(1)-C(l) 172.17(13) Ti-N(5)-C(29) 123.92(14) Ti-N(5)-C(30) 125.29(15) C(29)-N(5)-C(30) 110.75(18) Ti-N(6)-C(27) 123.07(16) Ti-N(6)-C(28) 126.28(16) C(27)-N(6>-C(28) 110.6(2) The coordination geometry about the Ti atom is a distorted tetrahedron, which is expected given the steric bulk around the pyrimidinol ligand. Furthermore, the N(5)-Ti-N(6) angle of 98.70(8)° is much smaller then any of the other three angles around the Ti center. A similar observation has been made in the isosteric solid state structures reported by Jones and co-workers76 ( 4 . 11 ) and Rothwell and coworkers77 ( 4 . 1 2 ) shown as simplified ChemDraw pictures in Figure 4 . 4 . F i g u r e 4 . 4 : Related bis(phenoxide)bis(amido) titanium complexes reported in the literature. The T i - 0 bond lengths in 4 . 9 are very similar in length, which is in contrast to 4 . 1 1 in which one of the T i - 0 bonds is substantially longer then the other (1.860(3) versus 1.813(4) A). The discrepancy in the bond lengths in 4 . 1 1 has been attributed to crystal packing. Furthermore, the T i - 0 bond lengths in 4 . 9 are longer then the shortest bond in 4 .11 and both of the T i - 0 bonds in 4 . 1 2 (1.808(2) and 1.828(2) A). This is in agreement with the electronic nature of proligand 4 . 8 , and is indicative of bonding that is more ionic in nature. The observed bond length is still significantly shorter then the calculated T i - 0 single covalent bond length of 2.01 A and indicates a high degree of 7i-bonding. The T i -O-C bond angles of 176.76(14)° and 172.17(13)° are also consistent with 7t-bonding and sp hybridization of the oxygen. These do not differ significantly from the bond angles measured in 4 . 1 2 (these angles are similar to one reported for 4 . 1 1 , but not to the other given the difference in the bonding of the two phenoxide ligands in that molecule). 4.11 4.12 267 The lengths of the T i - N bonds are both shorter then a T i - N single bond (1.96 A) indicating some degree of 7i-bonding. These are not remarkably different from either of the T i - N bond lengths reported for 4 .11 and 4 . 1 2 . Furthermore, the T i - N - C bond angles indicate that the nitrogen atoms are planar, consistent with sp2 hybridization. Both 4 . 9 and 4 . 1 0 are thermally stable in solution, as there is no obvious decomposition after prolonged heating at 1.10 °C for ten days. Both are also stable for months in the solid state when stored at -35 °C under inert atmosphere. Some decomposition is evident after time (weeks) at room temperature under inert atmosphere. It is hoped that the use of these bulky, highly acidic proligands will lead to Ti and Zr complexes that exhibit enhanced resistance to hydrolysis than is normally attributed to group 4 metal complexes. Indeed, both 4 . 9 and 4 . 1 0 can be handled in the open laboratory for short periods of time (minutes) without consequence. In comparison, the bis(amidate)bis(amido) titanium complex 4 .1 can not be exposed to any atmospheric moisture for any length of time without decomposition. However, long term exposure of bis(pyrimidinoxide)bis(amido) complexes to atmospheric moisture results in their obvious decomposition, with one crystalline example of a decomposition product of complex 4 . 1 0 , the oxo-bridged complex 4 . 1 3 , being shown in Figure 4.5. Selected bond lengths and angles are summarized in Table 4.2. 268 (a) (b) Figure 4.5: Two views of the ORTEP representation of complex 4.13. Hydrogen atoms are omitted for clarity in both, (a) Full view, (b) the core of the molecule where the t-butyl and methyl groups from the pyrimidinoxide ligand are removed. Thermal ellipsoids are set to 50% probability. Table 4.2: Selected bond lengths (distance, A) and angles (angle, °) for complex 4.13. Distance Angle Zr(l)-0(5) 1.956(5) Zr(l)-0(5)-Zr(2) 164.1(3) Zr(2)-0(5) 1.960(6) 0(l)-Zr(l)-0(2) 113.3(2) Zr(l)-0(1) 1.961(6) 0(3)-Zr(2}-0(4) 113.5(2) Zr(l)-0(2) 1.938(5) 0(1)-Zr(l)-N(5) 108.8(3) Zr(2)-0(3) 1.959(5) 0(2)-Zr(l)-N(5) 101.9(3) Zr(2)-0(4) 1.965(5) O(3)-Zr(2)-N(10) 101.7(3) Zr(l)-N(5) 2.009(7) O(4)-Zr(2)-N(10) 109.8(3) Zr(2)-N(10) 2.001(7) 0(l)-Zr(l)-0(5) 107.8(2) 0(1)-C(1) 1.361(10) 0(2)-Zr(l)-0(5) 119.6(2) 0(2)-C(14) 1.366(10) 0(3)-Zr(2)-0(5) 119.1(2) 0(3)-C(29) 1.350(10) 0(4)-Zr(2)-0(5) 107.9(2) 0(4)-C(42) 1.345(10) Oxo-bridged species, such as complex 4.13, are not uncommon, and a similar structure, 4.14, of which a ChemDraw depiction is shown, has been reported.92 269 (Me 3 Si ) 2 N N(S iMe 3 ) 2 ( M e 3 S i ) 2 N v / Me \ , / N ( S i M e 3 ) 2 Me 4.14 Complex 4 . 1 3 retains both the bis(pyrimidinoxide) ligands and one of the amido ligands on each Zr metal center. In the solid state, the remaining amido ligands are eclipsed and have Tt-bonding character, as evidenced by the planar, sp2 hybridization of the nitrogen atoms. The Z r - 0 bond lengths of the pyrimidinoxide ligands are typical for these types of structures and the Zr-O-Zr bond angle of 164.1(3)° is intermediate for previously reported Zr u-0 species (range 142° to 180°). 9 3 ' 9 4 4 . 2 . 3 A p p l i c a t i o n s i n c a t a l y s i s 4 .2 .3 .1 H y d r o a m i n a t i o n o f t e r m i n a l a l k y n e s w i t h a r y l a m i n e s After synthesizing and characterizing 4 . 9 and 4 . 1 0 , these complexes are tested for reactivity in hydroamination catalysis. Initial investigations focus on the reactions between terminal alkynes and primary amines. Terminal alkynes are chosen as these substrates allow for investigations into regioselectivity and a direct comparison with the bis(amidate)bis(amido) complex 4 . 1 . High regioselectivity is an imperative trait for a catalyst i f it is going to be utilized for more complex organic syntheses. Furthermore, several early hydroamination catalysts, especially those containing Cp ligands, are unable to efficiently catalyze hydroamination reactions with terminal alkynes, 5 3 , 9 5 or give low yields of products.54 Aniline and 2,6-dimethylaniline are utilized to investigate the reactivity of aryl amines with varying steric properties. The results of these tests with precatalysts 4 . 9 and 4 . 1 0 are summarized in Tables 4.3 and 4.4, respectively. 270 T a b l e 4.3: Catalytic hydroamination of terminal alkynes with 4.9 and aryl amines. R = H 2 H 2 NAr 5 mol% cat. C 7 D 8 N , A r N .A r R R H (M) (AM) (4.3) E n t r y R A r T i m e (h ) T e m p ( ° C ) % Y i e l d " R a t i o ( M : A M ) " 1 Ph Ph 16 110 87 4:1 2 Bn Ph 16 110 67 7:3 3 "Bu Ph 16 110 72 4:1 4 Ph Ar* 16 110 78 3:2 5 Bn Ar* 16 110 78 >20:1 6 "Bu Ph 24 100 99" 4:1° 7 Ph Ph 24 23 83 c >49: l c with 1,3,5-trimethyoxybenzene as an internal standard. Ar* = 2,6-dimethylphenyl. *10 mol% 4.4, determined by GC-analysis.7 3 c5 mol% 4.1, isolated yield after reduction of imines, ratio determined by ' H N M R spectroscopy.96 T a b l e 4.4: Catalytic hydroamination of terminal alkynes with 4.10 and aryl amines. E n t r y R A r T i m e (h ) T e m p ( ° C ) % Y i e l d " R a t i o ( M : A M ) " 1 Ph Ph 16 110 53 > 20:1 2 Ph Ph 64 110 89 >20:1 3 Bn Ph 16 110 22 >20:1 4 Bn Ph 64 110 48 >20:1 5 "Bu Ph 16 110 11 >20:1 6 "Bu Ph 64 110 52 >20:1 7 Ph Ar* 16 110 no reaction — 8 Ph Ar* 64 110 no reaction ~ 9 Bn Ar* 16 110 no reaction — 10 Bn Ar* 64 110 no reaction — "Determined by H N M R spectroscopy by appearance of product with 1,3,5-trimethyoxybenzene as an internal standard. Ar = 2,6-dimethylphenyl. Both 4.9 and 4.10 are able to catalyze the hydroamination reaction between terminal alkynes and aniline. Although 4.9 can perform this reaction with both phenylacetylene and 1-hexyne at 65 °C, it is very sluggish, and the reactions are incomplete after 5 days. 271 Therefore the rest of the reactions are carried out at 110 °C. Elevated temperatures are often required for hydroamination reactions, and it is not uncommon to see temperatures greater than 100 °C. 4 Complex 4 . 9 is also a more efficient precatalyst than 4 . 1 0 . In all cases with 4 . 9 , the reactions proceed to 100% conversion after 16 h at 110 °C. With 4 . 1 0 on the other hand, the reactions with aniline never proceed to complete conversion, even after reaction times of up to 64 h. There is also no reaction observed with the more bulky 2,6-dimethyl aniline. There is some evidence with precatalyst 4 . 1 0 that C - H activation of the terminal alkyne is occurring. If the alkyne is added to 4 . 1 0 , followed by the primary amine, ! H N M R spectroscopy shows that the methine proton signal has disappeared, but no imine product is formed. Hence, the yields of the imines shown in Table 4.4 are calculated after sequentially adding the amine to 4 . 1 0 , followed by the alkyne. This trend, in which the Ti congener is more reactive than the Zr congener, in alkyne hydroamination has been observed before by us 6 1 and others.65 In all cases, the regioselectivity favors the formation of the Markovnikov product, with some examples of excellent regioselectivity (Table 4.3 entry 5 and Table 4.4 entries 1-6). Precatalyst 4 . 1 0 is particularly regioselective as no arcft'-Markovnikov product is observed at all. This is the same regioselectivity that has been observed by Beller and co-workers with the bis(phenoxide)bis(amido) titanium complex, 4 . 4 (Table 4.3 entry 6), and has been noted with many other Ti precatalysts.56"58'97 ,98 However, there have also been reports of regioselectivity for the an/z'-Markovnikov product with some related systems. 5 5 ' 6 0 ' 9 9 ' 1 0 0 The bis(amidate)bis(amido) titanium precatalyst 4 .1 is particularly active for this reaction (Table 4.3 entry 7). After 24 h at room temperature, 83% of the flwft'-Markovnikov product is isolated as the secondary amine.96 272 It is also interesting to note that while precatalyst 4.9 leads to complete conversion of the starting material (terminal alkyne), the yields of the reactions are often lower (67-87%). This decrease in yield could be due to unidentified side reactions resulting from uncontrolled reactivity, such as alkyne oligomerization. Such side products in the hydroamination of terminal alkynes are often noted in the literature. 5 3 ' 5 6 ' 5 8 ' 7 1" 7 3 ' 9 8 Furthermore, in entries 2 and 3 of Table 4.3 there is evidence of a small amount of enamine formation in the ' H N M R spectrum, which is not accounted for in the reported yield of the reaction. In the literature, yields for these types of hydroamination reactions are often measured using GC-MS. There have also been a number of corrections in the literature resulting from the inaccuracy of yield determination by G C - M S . 1 0 1 ' 1 0 2 It has been found through the course of these investigations and through other investigations within the Schafer group that the yields and ratios determined in this manner are inconsistent with what is observed in the ' H N M R spectra. Therefore, even though ' H N M R spectroscopy leads to an underestimation of the yield of the reaction in some cases, it has been selected as the most accurate assessment of reaction progress. Both complexes 4.9 and 4.10 can catalyze the hydroamination of terminal alkynes with aniline but 4.9 is more reactive. Both precatalysts are regioselective for the Markovnikov product and though the reactivity is decreased, 4.10 is very regioselective as the aw/z'-Markovnikov product is not observed at all. Of the two complexes investigated, only 4.9 can catalyze the hydroamination of terminal alkynes with the more bulky 2,6-dimethylaniline. 273 4 . 2 . 3 . 2 H y d r o a m i n a t i o n o f t e r m i n a l a l k y n e s w i t h a l k y l a m i n e s The hydroamination of terminal alkynes with a variety of alkyl amines is investigated with both precatalysts 4 . 9 and 4 . 1 0 . Zirconium complex 4 . 1 0 is unable to catalyze any of these reactions, even after lengthy reaction times and elevated temperatures. Precatalyst 4 . 9 is able to catalyze these reactions showing 100% conversion of the starting material (terminal alkyne) after 16 h with primary amines of varying steric bulk (eq. 4.4), and these results are summarized in Table 4.5. T a b l e 4 . 5 : Catalytic hydroamination of terminal alkynes with alkyl amines using 4 . 9 . R- -H +2 H 2 N R 1 5 mol% 4.9 C7D8/16 h N . R 1 (M) N . R 1 + R H (AM) (4.4) E n t r y R R 1 T e m p CO % Y i e l d " R a t i o ( M : A M ) ° 1 Ph 'Bu 65 no reaction — 2 Ph 'Bu 110 82 1:2 3 Ph 'Pr 110 83 2:3 4 Ph Bn 110 61 3:2 5 Bn 'Bu 110 >95 1:4 6 Bn 'Pr 110 >95 2:3 7 Bn Bn 110 82 1:1 8 "Bu 'Bu 65 no reaction — 9 "Bu 'Bu 110 >95" — 10 "Bu 'Pr 110 >95" — 11 "Bu Bn 110 80(62)c 3:2 12 "Hex 'Bu 100 50" 1:3" 13 "Hex Bn 100 99" 4:1" 14 Ph 'Bu 65 74e — 15 "Bu Bn 65 88e appearance 1,3,5-trimethyoxybenzene as an internal standard. Conversion based on disappearance of terminal alkyne starting material. Isolated yield after reduction with NaBH 3 CN/ZnCl 2 and column chromatography. 10 mol% 4 . 4 , 24 h, determined by GC-analysis. e5 mol% 4 . 1 , 24 h, isolated yield of antf-Markovnikov product after reduction of imine. 6 2 274 At 65 °C (entries 1 and 8) there is no reaction observed after 16 h, though the reactions are complete in the same amount of time at 110 °C (entries 2 and 9). In some cases (entries 9, 10) the reactions exhibited complete conversion of starting material as determined by ' H N M R spectroscopy, though the N M R spectra are too complicated to assign the isomers. Again, it is noted that in all cases the reaction goes to complete conversion, though the yields are often more moderate. However, these yields are generally an improvement over what is observed with the majority of the aryl amines. As is noted earlier, the reactions with aryl amines will proceed at 65 °C whereas the alkyl amines will not. This relative decrease in reactivity with the alkyl amines can lead to an increase in the yield of the desired product as the reactivity is more controlled and there are fewer side reactions. Interestingly, the use of bis(phenoxide)bis(amido) precatalyst 4.4, in reactions with r-butylamine and 1-octyne (structurally similar to 1-hexyne) have been reported to go to only 50% conversion (entry 12).71 An increase in reactivity is noted with precatalyst 4.9 by comparison, as all examples with /-butylamine (entries 2, 5, 9) show 100% conversion of starting materials and yields greater then 80%. As shown in entries 14 and 15, 4.1 is extremely efficient at these reactions, showing high isolated yields of the a«z7-Markovnikov product. This regioselectivity is seen with both the bulky /-butylamine and the sterically unencumbered benzylamine.63 In general, lower regioselectivity is observed in the catalysis with the alkyl amines than with aryl amines, and both display regioselectivities that are less than what is reported in the literature for other catalyst systems. An increase in regioselectivity for the arcrz'-Markovnikov imine is observed when using the bulky J-butylamine (Table 4.5 entries 2, 5), and this regioselectivity decreases as the steric bulk of the amine decreases. 275 With the use of benzylamine (Table 4.5 entries 4, 7, 11) the Markovnikov product is generally favoured though the regioselectivity is not high. Benzylamine is regarded as a difficult substrate in hydroamination,54'55 and many complexes display little or no product formation with its use.56 In contrast, precatalyst 4.4 exhibits high regioselectivity for the Markovnikov product (Table 4.5 entry 13) with both benzylamine and other alkyl amines (with the exception of /-butylamine),73 and there are other catalyst systems that are also Markovnikov selective under similar conditions.5 6'5 8 Conversely, precatalyst 4.1 is very regioselective for the an ^ '-Markovnikov product with all of these reactions (Table 4.5 entries 14 and 15).62 In order to isolate the product of this reaction, entry 11 in Table 4.5 is scaled up to preparatory scale, and the formed imines are reduced with NaBHaCN and ZnCh in methanol (eq. 4.5) to yield the corresponding secondary amines. (4.5) The secondary amines are purified via column chromatography and isolated in a combined 62% yield. GC-MS show that both isomers are isolated and the ' H N M R spectrum matches what is reported in the literature.103 Only precatalyst 4 . 9 , and not 4 . 1 0 , is able to catalyze the hydroamination of terminal alkynes with alkyl amines. The yields of the reactions are generally higher then what is observed with the aryl amines and this is attributed to the reduced unwanted side reactions. However, the regioselectivities are lower than with aryl amines. The 276 regioselectivity depends on the steric bulk of the amine and is lower than the reported regioselectivities with 4.4. There is, however, an increase in reactivity relative to 4.4 in the hydroamination reactions with /-butylamine. This may be attributed to steric bulk, as while these complexes are isosteric, the electronic nature o f the pyrimidinol proligand results in the steric bulk being slightly more removed from the metal center. 4.2.3.3 Hydroamination of internal alkynes To further investigate the regioselectivity of precatalyst 4.9, another unsymmetrical internal alkyne, 1-phenyl-1-propyne, is probed in the hydroamination reaction with aryl amines (eq. 4.6). 5mol%4.9 P h " P h Ph — + 2 H 2 NAr " + Tj (4.6) C 7D8/110°C , N ^ A r N , 40 h "Ar (A) (B) When aniline is the primary amine used, the two isomeric products are formed in 71% combined yield with A being the preferred product ( A : B 9:1). When the more sterically hindered 2,6-dimethylaniline is used, only compound A is formed in 31% yield after 40 h. There are many T i precatalysts that are very proficient at this reaction, completing the transformation in less than 40 h. This regioselectivity for isomer A is the same that is observed for both T i complexes containing Cp l igands 5 3 " 5 5 ' 6 7 ' 1 0 0 and T i complexes that have non-Cp l igands. 5 8 ' 7 1 ' 9 7 Furthermore, 4.1 has been shown to form isomer A in > 98% isolated yield of the reduced product after 24 h at 110 °C. The ratio of A to B was determined to be > 49:1 9 6 277 The reaction between 1-phenyl-1-propyne and alkyl amines is very sluggish (eq. 4.7), and though the isomers could not be confidently assigned, the conversions are measured and summarized in Table 4.6. Table 4.6: Hydroamination of 1-phenyl-1-propyne and alkyl amines using complex 4.9. + Ti (4.7) N R (B) Entry R Time (h) % Conversion" 1 'Bu 16 trace 2 'Bu 40 9 3 'Pr 16 46 4 'Pr 40 79 5 Bn 16 20 6 Bn 40 54 7 Bn 24 99" "Determined by *H NMR spectroscopy with 1,3,5-trimethyoxybenzene as an internal standard based on disappearance of terminal alkyne. *10 mol% 4.4, 120 °C, determined by GC-analysis.71 Even after 40 h, the conversion ranged from a low of 9% with the very hindered t-butylamine (entry 2), to a high of 79% with isopropylamine (entry 4). By comparison, precatalyst 4.4 can perform these reactions in high yields after 24 h at 120 °C (entry 7). The regioselectivity in that case favors isomer A (A:B 94:6).71 Furthermore, there are other catalyst systems that are much more effective for this transformation than 4.9.5 3'7 1 After looking at unsymmetrical alkynes for intermolecular hydroamination, the reaction between symmetric internal alkynes and various primary amines is surveyed using 4.9 (eq. 4.8). While there is no regioselectivity associated with these reactions, they are undertaken to probe the general reactivity of this precatalyst. Typically „ . ^ O U M D 5mol%4.9 P n Ph — — + 2 H 2 N R *- N C 7 D 8 / 1 1 0 ° C • (A) 278 hydroamination precatalysts are not very general in terms of the substrates that can be used. For example, many catalysts are very active with internal alkynes but inactive with terminal alkynes, or vice versa. The realization of a general catalyst system is a very attractive research goal. The results of these investigations are summarized in Table 4.7. Table 4.7: Hydroamination of symmetrical alkynes with aryl and alkyl amines using 4.9. .R R — R + 2H 2 N R 1 5 mol% 4 .9 C 7 D 8 / 110°C (4.8) Entry R R 1 Time (h) % Yield" 1 Ph Ph 16 28 2 Ph Ph 40 52 3 Ph Ar* 5 days no reaction 4 Ph 'Bu 7 days no reaction 5 CH3CH2 Ph 16 28 6 C H 3 C H 2 Ph • 40 42 7 CH3CH2 Ar* 5 days no reaction 8 CH3CH2 'Bu 16 no reaction 9 CH3CH2 'Pr 16 no reaction 10 CH3CH2 Bn 16 no reaction "Determined by H NMR spectroscopy by appearance of product with 1,3,5-trimethyoxybenzene as an internal standard. Ar* = 2,6-dimethylphenyl. Two different internal alkynes were targeted for these reactions, containing either aryl or alkyl substituents. These reactions are sluggish with aniline, proceeding to 42-52% yield after 40 h, and do not occur at all with 2,6-dimethylaniline or any alkyl amines. Likewise, there is no reaction observed at all with any of these combinations and zirconium complex 4.10. In general, Ti precatalysts that contain Cp, or Cp-based ligand sets, are very effective for this reaction.50'53"55'57'100 Those that have non-Cp based ligands are often less successful at catalyzing this transformation.58'60'98 For example, 4.1 requires 279 elevated temperatures (110 °C) and 10 mol% catalyst loading to perform the reaction of internal alkynes with p-methoxyaniline.96 Precatalyst 4.9 is not as reactive for the hydroamination reactions with internal alkynes as it is with terminal alkynes. However, the reactions do proceed slowly, with select substrates, where aniline is generally the most reactive. Precatalyst 4.10, on the other hand, is completely inactive for all these reactions with internal alkynes, regardless of the amine substrate. Although the bis(pyrimidinoxide)bis(amido) complex 4.9 shares the same substitution pattern as the bis(phenoxide)bis(amido) complex 4.4, the electronic nature of the pyrimidinol proligand results in this steric bulk being more removed from the metal center. This results in an increase in observed reactivity with 4.9 in the hydroamination of hindered substrates, such as f-butylamine, than with 4.4. It is much more difficult to compare the steric effects between 4.9 and the bis(amidate)bis(amido) complex 4.1. Complex 4.9 is a tetracoordinate metal complex whereas complex 4.1 is a hexacoordinate metal complex with chelating ligands. Both complexes contain bulky substituents that are relatively close to the metal center. The differences in observed reactivity between these