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Development of practical in-situ methods for the early transition metal-catalyzed synthesis of amines Edwards, Peter 2019

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DEVELOPMENT OF PRACTICAL IN-SITU METHODS FOR THE EARLY TRANSITION METAL-CATALYZED SYNTHESIS OF AMINES by  Peter Edwards  B.Sc., Northeastern University, 2013  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  January 2019  © Peter Edwards, 2019   ii  The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled:  Development of Practical In-Situ Methods for the Early Transition Metal-Catalyzed Synthesis of Amines  submitted by Peter Edwards  in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry  Examining Committee: Laurel Schafer, Chemistry Supervisor  Glenn Sammis, Chemistry Supervisory Committee Member   Supervisory Committee Member Harry Brumer, Chemistry University Examiner Scott Renneckar, Forestry University Examiner   Additional Supervisory Committee Members: Jen Love, Chemistry Supervisory Committee Member David Perrin, Chemistry Supervisory Committee Member iii  Abstract  The research presented in this thesis focuses on the development of practical methods for the early transition metal-catalyzed synthesis of amines. The primary focus of this thesis is the development of in-situ generated tantalum catalyst systems for the intermolecular hydroaminoalkylation of alkenes with amines. The intramolecular hydroamination of aminoalkynes followed by asymmetric transfer hydrogenation for the synthesis of chiral 1,4-benzoxazines was also developed. The substrate scope and synthetic utility of these reactions is presented herein. Initial efforts to expand the synthetic utility of hydroaminoalkylation focused on the use of a previously reported phosphoramidate tantalum methyl complex as a catalyst for the hydroaminoalkylation of norbornadiene to produce amine-containing monomers. The optimization of this reaction demonstrated key challenges in the use of hydroaminoalkylation as a synthetic tool. To address these challenges, methods for the in-situ generation of hydroaminoalkylation catalysts were developed. The generation of a pyridonate tantalum dimethylamido catalyst in-situ allowed for a robust catalyst that exhibited an unprecedented substrate scope. Attempts to further probe the reaction through modifying the electronic properties of the pyridonate ligand were unsuccessful. Products accessible from this catalyst system were further reacted to generate poly-methylated piperidines that would be difficult to synthesize through traditional methods. A second in-situ method utilizes tantalum pentafluoride, which is more robust than previously utilized tantalum precursors, to generate a hydroaminoalkylation catalyst in-situ. The substrate scope of this system was explored, and further reactions allowed for the synthesis of iv  1,2,3,4-tetrahydroquinolines. The generation of this catalyst was studied through NMR spectroscopy. The stability of tantalum pentafluoride towards storage in ambient conditions was also studied, showing that while it could not be stored in a non-inert atmosphere, it could be handled in ambient conditions without significant loss of reactivity. Chiral 1,4-benzoxazines are an important class of compounds that form the core of many industrially relevant compounds. By utilizing a previously reported method for the asymmetric synthesis of morpholines through sequential hydroamination/asymmetric transfer hydrogenation, a variety of chiral 1,4-benzoxazines can be synthesized from readily accessible 2-aminophenyl propargyl ethers. While the synthesis suffers from poor yields, the method achieves moderate to good enantiomeric excesses and demonstrates improved step-efficiency. v  Lay Summary  Amines are a class of nitrogen-containing chemicals that have important applications in a large number of industries, such as the pharmaceutical, agrochemical, and plastics industries. However, the production of amines often involves the generation of a significant amount of waste. Hydroaminoalkylation and hydroamination are methods that have been developed for reducing the amount of waste produced by using inexpensive metals, such as titanium or tantalum, as catalysts. However, such methods are often challenging or impractical to use. Described in this thesis is the development of practical methods for the synthesis of amines, using these inexpensive metals, from readily available starting materials while reducing the overall waste of production. vi  Preface  A version of Chapter 1 has been published. Peter Edwards and Laurel Schafer. (2018) Early Transition Metal-Catalyzed C-H Alkylation: Hydroaminoalkylation for Csp3-Csp3 Bond Formation in the Synthesis of Selectively Substituted Amines. P. M. Edwards and L. L. Schafer, Chemistry Communications. 2018, DOI: 10.1039/c8cc06445h. Laurel Schafer provided advice regarding the structure of the manuscript as well as editing prior to submission. I performed the literature search, the analysis of the data from the literature search, and wrote the manuscript.  Chapter 2 is partially based on work done in collaboration with Dr. Mitchell Perry and Dr. Erin Morgan. I was responsible for the work reported, except for the initial synthesis and characterization of 2.10. Part of Chapter 2 has been published. Mitchell Perry, Tannaz Ebrahimi, Erin Morgan, Peter Edwards, Savvas Hatzikiriakos, and Laurel Schafer. (2016) Catalytic Synthesis of Secondary Amine-Containing Polymers: Variable Hydrogen Bonding for Tunable Rheological Properties. Macromolecules, 49, 4423-4430. Mitchell Perry developed the polymerization reaction, produced some of the polymers used for the rheological studies, and wrote part of the manuscript. Tannaz Ebrahimi performed the rheological studies and wrote part of the manuscript. Erin Morgan performed the initial synthesis and characterization of some of the monomers, and synthesized some of the polymers for rheological studies. Savvas Hatzikiriakos provided advice on the rheological studies and edited the manuscript prior to submission. Laurel Schafer provided advice on the synthesis of the polymers and edited the manuscript prior to submission. I performed the initial synthesis and characterization of some of the monomers.  vii  Part of Chapter 3 has been published. Peter Edwards and Laurel Schafer. (2017) In Situ Generation of a Regio- and Diastereoselective Hydroaminoalkylation Catalyst Using Commercially Available Starting Materials. Organic Letters, 19, 5720-5723. Laurel Schafer provided advice on the direction of the research and edited the manuscript prior to submission. I performed all of the experiments, worked up all the data, and wrote the manuscript. Chapter 3 section 3.2.4 was done in collaboration with CHEM 449 student Thomas Horton and summer student Weizhe Dong. I designed the experiments, advised on the synthesis and characterization of the complexes, and advised on the analysis and interpretations of the data. Part of Chapter 3 section 3.2.4 has been published as an undergraduate honors thesis. Thomas Horton. Investigation of the Electronic Effects of Pyridonate Ligands in Hydroaminoalkylation Catalysts. University of British Columbia.  Chapter 4 consists of currently unpublished work. I was the lead investigator for the project where I was responsible for the idea of the project, project design, experimental work, and data analysis.  Chapter 5 consists of currently unpublished work, performed with the assistance of summer student Weizhe Dong and visiting scholar Jan Wilhelm Cremers. I was the lead investigator for the project and responsible for the development of the alkyl bromide-based synthesis of the benzoxazine precursors, the development of the iron-mediated reduction, benzoxazine synthesis, %ee determination, characterization of all final products, and analysis of the data. %ee determination of 5.13 was done with the assistance of graduate student Ryan Chung in the research lab of Prof. Jason Hein. viii  Table of Contents  Abstract ......................................................................................................................................... iii Lay Summary .................................................................................................................................v Preface ........................................................................................................................................... vi Table of Contents ....................................................................................................................... viii List of Tables ................................................................................................................................xv List of Figures ............................................................................................................................ xvii List of Schemes .............................................................................................................................xx List of Abbreviations ............................................................................................................... xxix Acknowledgements ................................................................................................................ xxxiii Dedication .................................................................................................................................xxxv Chapter 1: Early Transition Metal-Catalyzed Hydroaminoalkylation for Csp3 – Csp3 Bond Formation in the Synthesis of Selectively Substituted Amines ..................................................1 1.1 Synthesis of Amines ....................................................................................................... 1 1.2 Hydroaminoalkylation for the Synthesis of Structurally Diverse Amines ..................... 8 1.2.1 Synthesis of Unbranched Amines ............................................................................... 8 1.2.1.1 Synthesis of Unbranched Secondary Amines ................................................... 10 1.2.1.2 Synthesis of Unbranched Tertiary Amines ....................................................... 13 1.2.2 Synthesis of α-Branched Amines .............................................................................. 14 1.2.3 Synthesis of β-Methylated Amines ........................................................................... 16 1.2.3.1 Synthesis of β-Methylated Amines Using Group 4 Catalysts .......................... 18 1.2.3.2 Synthesis of β-Methylated Amines Using Group 5 Catalysts .......................... 23 ix  1.2.3.2.1 Asymmetric Synthesis of β-Methylated Amines ........................................ 28 1.2.3.3 Synthesis of β-Methylated Tertiary Amines ..................................................... 29 1.2.4 Synthesis of α-Branched-β-Methylated Amines ....................................................... 30 1.2.4.1 Intermolecular Hydroaminoalkylation on Secondary Carbons ......................... 31 1.2.4.2 Intramolecular Hydroaminoalkylation .............................................................. 32 1.2.5 Synthesis of β-Alkylated and β-Quaternary Center Amines .................................... 36 1.2.5.1 Titanium Catalysts ............................................................................................ 38 1.2.5.2 Tantalum Catalysts............................................................................................ 39 1.2.6 Synthesis of N-Heterocycles via Sequential Procedures .......................................... 42 1.3 Scope of Thesis ............................................................................................................. 44 Chapter 2: Tantalum Phosphoramidate-Catalyzed Hydroaminoalkylation for the Synthesis of Amine-Substituted Norbornenes ............................................................................................47 2.1 Introduction ................................................................................................................... 47 2.1.1 Amine-Containing Polymers .................................................................................... 47 2.1.2 Synthesis of Amine-Substituted Norbornenes .......................................................... 49 2.1.3 Scope of Chapter ....................................................................................................... 52 2.2 Results and Discussion ................................................................................................. 52 2.2.1 Expansion of Tantalum Phosphoramidate Precatalyst Substrate Scope ................... 52 2.2.2 Optimization of Monomer Synthesis ........................................................................ 55 2.3 Conclusions ................................................................................................................... 59 2.4 Experimental ................................................................................................................. 60 2.4.1 Materials and Methods .............................................................................................. 60 2.4.2 Synthesis and Characterization of Compounds ........................................................ 62 x  2.4.2.1 Experimental Procedures .................................................................................. 62 2.4.2.2 Compound Characterization ............................................................................. 64 2.4.2.2.1 Non-Methyl Hydroaminoalkylation Substrates .......................................... 64 2.4.2.2.2 (N-Substituted-Aminomethyl)-5-Norbornene Derivatives ......................... 65 Chapter 3: Development of an In-situ Generated Tantalum Pyridonate Hydroaminoalkylation Catalyst .................................................................................................68 3.1 Introduction ................................................................................................................... 68 3.1.1 Practical Limitations of Hydroaminoalkylation ........................................................ 68 3.1.2 Substituted 2-Pyridonates as Ligands for Hydroaminoalkylation ............................ 69 3.1.3 Scope of Chapter ....................................................................................................... 72 3.2 Results and Discussion ................................................................................................. 73 3.2.1 In-situ Screening and Optimization of Hydroaminoalkylation Catalysts ................. 73 3.2.2 Substrate Scope ......................................................................................................... 77 3.2.3 Optimization of Hydroaminoalkylation Reaction with 3.80..................................... 84 3.2.4 Determination of Ligand Substituent Effects on Reaction Rate ............................... 87 3.2.4.1 Solid State Molecular Structures of Complexes ............................................... 87 3.2.4.2 Kinetic Screening .............................................................................................. 94 3.2.5 Synthesis of Poly-Substituted Piperidines ................................................................ 99 3.3 Conclusions ................................................................................................................. 101 3.4 Experimental ............................................................................................................... 102 3.4.1 Materials and Methods ............................................................................................ 102 3.4.2 Synthesis and Characterization of Compounds ...................................................... 104 3.4.2.1 Experimental Procedures ................................................................................ 104 xi  3.4.2.2 Synthesis of N-methyl-4-(phenylethynyl)aniline ........................................... 106 3.4.2.3 Synthesis of 2-hydroxy-4-trifluoromethylpyridine ......................................... 108 3.4.2.4 Compound Characterization ........................................................................... 109 3.4.2.4.1 Substrate Scope ......................................................................................... 109 3.4.2.4.2 Tantalum Complexes................................................................................. 123 3.4.2.4.3 Polysubstituted Piperidines ....................................................................... 127 Chapter 4: Development of an In-situ Generated Hydroaminoalkylation Catalyst Utilizing Tantalum Pentafluoride ............................................................................................................131 4.1 Introduction ................................................................................................................. 131 4.1.1 Sacrificial Ligands on Hydroaminoalkylation Precatalysts .................................... 132 4.1.2 Tantalum Pentafluoride as a Tantalum Source ....................................................... 135 4.1.3 Scope of Chapter ..................................................................................................... 137 4.2 Results and Discussion ............................................................................................... 137 4.2.1 Initial Results and Controls ..................................................................................... 137 4.2.2 Optimization of Reaction ........................................................................................ 138 4.2.3 Substrate Scope ....................................................................................................... 142 4.2.4 NMR Studies of In-situ Catalyst Generation .......................................................... 145 4.2.5 Determination of the Bench Stability of Tantalum Pentafluoride .......................... 153 4.3 Conclusions ................................................................................................................. 155 4.4 Experimental ............................................................................................................... 155 4.4.1 General Procedures ................................................................................................. 155 4.4.2 Synthesis and Characterization of Compounds ...................................................... 157 xii  4.4.2.1 Typical Procedure for Tantalum Fluoride-Catalyzed Hydroaminoalkylation Setup in a Glovebox (Method A) .................................................................................... 157 4.4.2.2 Procedure for Tantalum Fluoride-Catalyzed Hydroaminoalkylation Setup on Schlenk Line (Method B)................................................................................................ 158 4.4.2.3 Synthesis of N-phenyl-3-methyl-1,2,3,4-tetrahydroquinoline (Method C) .... 158 4.4.2.4 TaF5 Stability Study Procedure ....................................................................... 158 4.4.2.5 Compound Characterization ........................................................................... 159 Chapter 5: Industrially-Relevant Syntheses of Enantioenriched Morpholines via Hydroamination .........................................................................................................................167 5.1 Introduction ................................................................................................................. 167 5.1.1 Group 4-Catalyzed Hydroamination of Alkynes as a Synthetic Tool .................... 167 5.1.2 Synthesis of Heterocycles via Hydroamination ...................................................... 172 5.1.3 Enantioselective Synthesis of Benzoxazines .......................................................... 178 5.1.4 Scope of Chapter ..................................................................................................... 184 5.2 Results and Discussion ............................................................................................... 185 5.2.1 Synthesis of 3-Substituted-3,4-dihydro-2H-1,4-Benzoxazines .............................. 185 5.3 Conclusions ................................................................................................................. 193 5.4 Experimental ............................................................................................................... 193 5.4.1 General Procedures ................................................................................................. 193 5.4.2 Synthesis and Characterization of Compounds ...................................................... 195 5.4.2.1 General Procedure A for Alkylation of Substituted o-Nitrophenols with Propargyl Bromide .......................................................................................................... 195 xiii  5.4.2.2 General Procedure B for the Alkylation of o-Nitrophenol with Substituted Propargyl Alcohols ......................................................................................................... 196 5.4.2.3 General Procedure C for the Nitro Group Reduction ..................................... 196 5.4.2.4 General Procedure D for Tandem Hydroamination/Racemic Reduction ....... 197 5.4.2.5 General Procedure E for Tandem Hydroamination/Asymmetric Transfer Hydrogenation................................................................................................................. 197 5.4.2.6 Compound Characterization ........................................................................... 198 Chapter 6: Conclusion ...............................................................................................................215 6.1 Summary ..................................................................................................................... 215 6.1.1 Chapter 2 ................................................................................................................. 215 6.1.2 Chapter 3 ................................................................................................................. 216 6.1.3 Chapter 4 ................................................................................................................. 219 6.1.4 Chapter 5 ................................................................................................................. 221 6.2 Future Work ................................................................................................................ 222 6.2.1 Chapter 2 ................................................................................................................. 222 6.2.2 Chapter 3 ................................................................................................................. 223 6.2.3 Chapter 4 ................................................................................................................. 227 6.2.4 Chapter 5 ................................................................................................................. 231 6.3 Concluding Remarks ................................................................................................... 233 Bibliography ...............................................................................................................................234 Appendices ..................................................................................................................................241 Appendix A NMR Spectra ...................................................................................................... 241 A.1 Chapter 2 Substrate Synthesis NMR Spectra.......................................................... 241 xiv  A.2 Chapter 2 Substrate Scope NMR Spectra ............................................................... 244 A.3 Chapter 3 Substrate Synthesis NMR Spectra.......................................................... 248 A.4 Chapter 3 Substrate Scope NMR Spectra ............................................................... 249 A.5 Chapter 3 4-CF3 Synthesis NMR Spectra .............................................................. 272 A.6 Chapter 3 Complex Synthesis NMR Spectra .......................................................... 273 A.7 Chapter 3 Polysubstituted Piperidine Synthesis NMR Spectra .............................. 283 A.8 Chapter 4 Substrate Scope ...................................................................................... 286 A.9 Chapter 4 NMR Study ............................................................................................ 299 A.10 Chapter 5 Substrate Synthesis and Scope ............................................................... 310 Appendix B X-Ray Diffractometry Crystal Data ................................................................... 340 B.1 N-(3-methylnonan-2-yl)aniline Oxalate.................................................................. 340 B.2 Tetrakis(dimethylamido) 3-methyl-2-pyridonate tantalum (V) .............................. 342 B.3 Tetrakis(dimethylamido) 5-trifluoromethyl-2-pyridonate tantalum (V) ................ 344 B.4 Tetrakis(dimethylamido) 4-methyl-2-pyridonate tantalum (V) .............................. 345 B.5 Tetrakis(dimethylamido) 4-trifluoromethyl-2-pyridonate tantalum (V) ................ 347 B.6 Tetrakis(dimethylamido) 4-bromo-2-pyridonate tantalum (V) .............................. 349 B.7 1-(4-methoxyphenyl)-2,3,6-trimethylpiperidine HCl ............................................. 351 Appendix C Kinetic Analysis ................................................................................................. 353 C.1 GC/FID Method Parameters ................................................................................... 353 C.2 Kinetic Analysis Raw Data ..................................................................................... 363 Appendix D Characterization of Side Product 5.15................................................................ 370 Appendix E Chiral Chromatograms ........................................................................................ 378  xv  List of Tables  Table 2.1 Substrate scope of hydroaminoalkylation of norbornadiene with various amines using 2.7.................................................................................................................................................. 54 Table 2.2 Optimization of the hydroaminoalkylation of norbornadiene with N-methylaniline ... 58 Table 2.3 Optimization of the solvent-free hydroaminoalkylation of norbornadiene with N-methylaniline................................................................................................................................. 59 Table 3.1 In-situ catalyst screening and optimization .................................................................. 75 Table 3.2 Amine substrate scope .................................................................................................. 78 Table 3.3 Alkene substrate scope.................................................................................................. 82 Table 3.4 Optimization of hydroaminoalkylation reaction with N-ethylaniline ........................... 85 Table 3.5 Ligand screen for hydroaminoalkylation with N-ethylaniline ...................................... 86 Table 3.6 Synthesis of 4- and 5-substituted pyridonate tantalum complexes ............................... 88 Table 3.7 ORTEP representations of 4- and 5-substituted pyridonate tantalum complexes with selected bond lengths and angles .................................................................................................. 89 Table 3.8 Initial rates of consumption of N-methylaniline for each 4- and 5-substituted pyridonate catalyst ........................................................................................................................ 97 Table 4.1 Control experiments for tantalum fluoride-catalyzed hydroaminoalkylation reaction138 Table 4.2 Optimization of hydroaminoalkylation reaction ......................................................... 139 Table 4.3 Optimization of base for catalyst activation ............................................................... 141 Table 4.4 Bond dissociation energies of selected metal-fluoride bonds124, 128 ........................... 141 Table 4.5 Substrate scope of tantalum fluoride catalyst system ................................................. 144 Table 5.1 Exploration of asymmetric transfer hydrogenation conditions ................................... 187 xvi  Table 5.2 Scope of alkylation of substituted o-nitrophenols ...................................................... 188 Table 5.3 Scope of reduction of o-nitrophenyl ethers to 2-aminophenyl propargyl ethers ........ 189 Table 5.4 Scope of one-pot hydroamination/asymmetric transfer hydrogenation with catalysts 5.1 and 5.2 ......................................................................................................................................... 190  xvii  List of Figures  Figure 1.1 N,O-chelating ligands used in hydroaminoalkylation catalysts .................................. 24 Figure 2.1 Six predominant synthetic polymers used commercially ............................................ 47 Figure 2.2 Examples of Backbone and Pendent Amine-Containing Polymers ............................ 48 Figure 3.1 Reactivity Trend for Tantalum Hydroaminoalkylation Catalysts ............................... 70 Figure 3.2 Ligands used during catalyst screening ....................................................................... 74 Figure 3.3 ORTEP representation of 3.26 oxalate salt X-ray crystallographic structure. Ellipsoids plotted at 50% probability, non-tertiary hydrogens omitted for clarity ........................................ 79 Figure 3.4 Mechanistic rational for observed diastereoselectivity ............................................... 80 Figure 3.5 Amine substrates that exhibit trace or no reactivity .................................................... 81 Figure 3.6 Alkene substrates that exhibited trace or no reactivity ................................................ 83 Figure 3.7 Plot of bond lengths in relation to Hammett σ values, position relative to the oxygen and nitrogen atoms on pyridonate ................................................................................................. 93 Figure 3.8 Plots of initial rates for the 5-substituted (A) and 4-substituted (B) pyridonate catalysts ......................................................................................................................................... 95 Figure 3.9 Hammett analyses for 4- and 5-substituted pyridonate tantalum catalysts, referenced both to the oxygen (A) and nitrogen (B) atoms of the pyridonates .............................................. 98 Figure 3.10 Hydroaminoalkylation catalytic cycle with example on- and off-cycle equilibria ... 99 Figure 3.11 ORTEP Representation of the HCl salt of the major diastereomer of 3.89, ellipsoids are set to 50% probability, hydrogens attached to non-tertiary carbons excluded for clarity .... 101 Figure 4.1 Generalized early transition metal hydroaminoalkylation pre-catalyst ..................... 131 Figure 4.2 Protonolysis of sacrificial ligands with substrate to form metallaziridine ................ 132 xviii  Figure 4.3 Early transition metal hydroaminoalkylation catalysts with alkyl sacrificial ligands 134 Figure 4.4 Hydrolysis of TaF5 and NbF5 in 40 °C water 122 ....................................................... 136 Figure 4.5 Initial hydroaminoalkylation reaction using TaF5 ..................................................... 138 Figure 4.6 Solid-state structure of tantalum pentafluoride ......................................................... 147 Figure 4.7 1H NMR (d8-toluene, rt, 300 MHz) spectrum of N-methylaniline and TaF5, as compared to the spectrum of N-methylaniline alone .................................................................. 147 Figure 4.8 1H NMR spectrum (d8-toluene, rt, 300 MHz) of TaF5 with N-methylaniline and 4.10, as compared to N-methylaniline and 4.10 separately ................................................................. 148 Figure 4.9 31P NMR spectrum (d8-toluene, rt, 300 MHz) of TaF5 with N-methylaniline and 4.10, as compared to the spectra of TaF5 and 4.10 and 4.10 alone ...................................................... 149 Figure 4.10 1H NMR (d8-toluene, rt, 300 MHz) spectrum of the mixture of TaF5, N-methylaniline, and 4.10, with and without methyl lithium. The spectrum with methyl lithium contains 5 equivalents of N-methylaniline instead of 2 equivalents ........................................... 151 Figure 4.11 31P NMR spectrum (d8-toluene, rt, 300 MHz) of the mixture of TaF5, N-methylaniline, and 4.10, with and without methyl lithium ......................................................... 151 Figure 4.12 19F NMR spectrum (d8-toluene, rt, 300 MHz) of the mixture of TaF5, N-methylaniline, and 4.10, with and without methyl lithium ......................................................... 152 Figure 4.13 Yield of the hydroaminoalkylation reaction as a function of time of the tantalum pentafluoride stored outside of an inert atmosphere glovebox ................................................... 154 Figure 5.1 General [2+2] cycloaddition mechanism for group 4-catalyzed hydroamination ..... 169 Figure 5.2 Known bioactive molecules containing a 1,4-benzoxazine core............................... 179 Figure 5.3 GC/MS of 5.38 side products after column chromatography.................................... 192 xix  Figure 6.1 Mechanism of ruthenium-catalyzed H/D exchange and proposed heterogenous-catalyzed hydroaminoalkylation ................................................................................................. 230  xx  List of Schemes Scheme 1.1 Common methods for the synthesis of amines via C-N bond formation .................... 2 Scheme 1.2 Amine directed C-C bond formation through C-H activation ..................................... 3 Scheme 1.3 Amine-directed C-C bond formation through hydroaminoalkylation......................... 3 Scheme 1.4 Different alkylation modes possible through hydroaminoalkylation .......................... 4 Scheme 1.5 Initially reported hydroaminoalkylation reaction by Maspero .................................... 5 Scheme 1.6 Mechanism of late metal-catalyzed hydroaminoalkylation ........................................ 6 Scheme 1.7 Late transition metal-catalyzed hydroaminoalkylation ............................................... 6 Scheme 1.8 Generalized mechanism for group 4 and 5-catalyzed hydroaminoalkylation ............. 7 Scheme 1.9 Hydroaminoalkylation for the synthesis of unbranched amines ................................. 8 Scheme 1.10 Origin of branched regioselectivity for most early transition metal hydroaminoalkylation catalysts ...................................................................................................... 8 Scheme 1.11 Trend of unbranched vs. branched product formation across different metals ....... 10 Scheme 1.12 Hydroaminoalkylation using titanium aminopyridonate catalyst 1.2 to synthesize unbranched amines........................................................................................................................ 11 Scheme 1.13 Hydroaminoalkylation of styrenes and 1,3-butadienes with titanium aminopyridonate catalyst 1.3 ........................................................................................................ 11 Scheme 1.14 Hydroaminoalkylation of 1,4-butadienes with N-methylbenzylamine using titanium formamidinate catalyst 1.4 ............................................................................................................ 12 Scheme 1.15 Hydroaminoalkylation of trimethylvinylsilane using tantalum phosphoramidate catalyst 1.5 .................................................................................................................................... 13 Scheme 1.16 Hydroaminoalkylation of styrenes and trimethylvinylsilane with N-methylpiperidine using scandium catalyst 1.1 .............................................................................. 14 xxi  Scheme 1.17 Synthesis of α-alkylated amines using various titanium catalysts .......................... 15 Scheme 1.18 Synthesis of α-alkylated amines using titanium aminopyridonate catalyst 1.2 ...... 15 Scheme 1.19 Development of Ta(NMe2)5 as a catalyst by Hartwig and Doye ............................ 17 Scheme 1.20 Synthesis of β-methylated amines using scandium catalyst 1.1 ............................. 18 Scheme 1.21 Hydroaminoalkylation with homoleptic titanium catalysts .................................... 18 Scheme 1.22 Synthesis of β-alkylated amines using a titanium indenyl catalyst ......................... 19 Scheme 1.23 Hydroaminoalkylation using the dinuclear titanium sulfamide catalyst 1.7 ........... 20 Scheme 1.24 Hydroaminoalkylation using titanium diaminopyridonate catalyst 1.8 .................. 21 Scheme 1.25 Synthesis of β-methylated amines using titanium formamidinate catalyst 1.4 ....... 22 Scheme 1.26 Hydroaminoalkylation with dimethylamine using titanium formamidinate catalyst 1.4.................................................................................................................................................. 22 Scheme 1.27 Hydroaminoalkylation of 1-octene with N-methylaniline using different dimethyl(indentylethylamido) titanium catalysts ......................................................................... 22 Scheme 1.28 Hydroaminoalkylation of propene with dimethylamine using silica-supported Zr(NMe2)4 ..................................................................................................................................... 23 Scheme 1.29 Hydroaminoalkylation of 1-octene with trichlorotantalum catalysts 1.10 and 1.11 24 Scheme 1.30 Synthesis of β-methylated amines using tantalum amidate catalyst 1.12 ............... 25 Scheme 1.31 Hydroaminoalkylation using tantalum pyridonate catalyst 1.13 ............................. 25 Scheme 1.32 Hydroaminoalkylation with TaMe3Cl2 as a catalyst ............................................... 26 Scheme 1.33 Synthesis of β-methylated amines using tantalum phosphoramidate catalyst 1.5, which is the only early transition metal catalyst active at room temperature ............................... 26 Scheme 1.34 Synthesis of β-alkylated amines using an in-situ generated tantalum ureate catalyst....................................................................................................................................................... 27 xxii  Scheme 1.35 Hydroaminoalkylation of 1-octene using silica-supported Ta(NMe2)5. Basset and co-workers report 3 separate catalysts, each with similar catalytic activities ............................... 28 Scheme 1.36 Asymmetric hydroaminoalkylation through the use of axially chiral diamidate and binaphtholate ligands on tantalum and niobium ........................................................................... 29 Scheme 1.37 Hydroaminoalkylation with tertiary anilines using scandium NacNac catalyst 1.6 30 Scheme 1.38 Rational for observed diastereoselectivity for the synthesis of α-alkylated-β-methylated amines ........................................................................................................................ 31 Scheme 1.39 Synthesis of α-branched-β-methylated amines from N-benzylaniline using homoleptic titanium catalysts ....................................................................................................... 32 Scheme 1.40 Synthesis of α-branched-β-methylated amines through hydroaminoalkylation with unsaturated N-heterocycles using tantalum catalyst 1.12 ............................................................. 32 Scheme 1.41 Intramolecular hydroaminoalkylation of aminoalkenes. The corresponding hydroamination reaction is a common side reaction ..................................................................... 33 Scheme 1.42 Intramolecular hydroaminoalkylation with homoleptic titanium catalysts ............. 33 Scheme 1.43 Intramolecular hydroaminoalkylation with titanium aminopyridonate catalyst 1.2 34 Scheme 1.44 Intramolecular hydroaminoalkylation with dimethyl(indenylethylamido) titanium catalysts ......................................................................................................................................... 34 Scheme 1.45 Intramolecular hydroaminoalkylation with titanium pyridonate catalyst 1.17 can give a quaternary β-carbon............................................................................................................ 35 Scheme 1.46 Intramolecular hydroaminoalkylation with zirconium pyridonate catalyst 1.18 can form a quaternary α-carbon ........................................................................................................... 36 Scheme 1.47 Synthesis of β-alkylated and β-quaternary center amines though hydroaminoalkylation ................................................................................................................... 37 xxiii  Scheme 1.48 Hydroaminoalkylation of norbornene with trialkylamines using scandium hydroaminoalkylation catalyst 1.1 ................................................................................................ 38 Scheme 1.49 Synthesis of β-alkylated and β-quaternary center amines using titanium formamidinate catalyst 1.4 ............................................................................................................ 39 Scheme 1.50 Hydroaminoalkylation of 2,2-disubstituted and cyclic alkenes with various tantalum catalysts .......................................................................................................................... 40 Scheme 1.51 Synthesis of β-alkylated amines, β-quaternary center amines, and the only instance of β,β-dialkylated amines though TaMe3Cl2-catalyzed hydroaminoalkylation ............................ 41 Scheme 1.52 Synthesis of β-alkylated and β-quaternary center amines though the use of tantalum pyridonate catalyst 1.13-Cl ........................................................................................................... 41 Scheme 1.53 Synthesis of β-alkylated amines using in-situ generated tantalum ureate catalyst system 1.19 ................................................................................................................................... 42 Scheme 1.54 Synthesis of 3-methyl-N-phenylindoline through a one-pot hydroaminoalkylation/Buchwald-Hartwig amination .................................................................. 43 Scheme 1.55 Synthesis of 1,5-benzodiazepines, 1,5-benzoazasilepines, and 1,4-benzoazasilines through one-pot hydroaminoalkylation/Buchwald-Hartwig aminations ...................................... 43 Scheme 1.56 Synthesis of β-methylated unsaturated N-heterocycles through hydroaminoalkylation of silyl-protected alcohol-functionalized alkenes and subsequent one-pot deprotection/cyclization ................................................................................................................ 44 Scheme 2.1 Synthesis of poly(norbornene)s through ROMP ....................................................... 49 Scheme 2.2 Synthesis of 2.2 through ROMP of 2.1 ..................................................................... 49 Scheme 2.3 Traditional methods for synthesizing amine-substituted norbornenes ...................... 50 xxiv  Scheme 2.4 Synthesis of aminomethyl-substituted norbornenes through a Diels-Alder cycloaddition to synthesize norbornene carboxaldehyde followed by a reductive amination ...... 51 Scheme 2.5 Synthesis of amine-substituted norbornenes through hydroaminoalkylation with 2.7....................................................................................................................................................... 52 Scheme 2.6 Failed hydroaminoalkylation with non-methylated amines ...................................... 55 Scheme 2.7 Effect of amine electronic environment on the hydroaminoalkylation of norbornadiene ............................................................................................................................... 55 Scheme 2.8 Observed side reactions ............................................................................................. 56 Scheme 3.1 In-situ hydroaminoalkylation using a 2-methylaminopyridinate titanium catalyst system ........................................................................................................................................... 68 Scheme 3.2 Pyridonate ligands in early transition metal hydroaminoalkylation.......................... 71 Scheme 3.3 Analysis of the effect of steric bulk on pyridonate ligands on hydroaminoalkylation....................................................................................................................................................... 72 Scheme 3.4 Formation of dimethylamine byproduct .................................................................... 76 Scheme 3.5 Gram-scale synthesis of 3.59 using modified conditions .......................................... 83 Scheme 3.6 Hydroaminoalkylation of 1-octene with N-methylaniline for kinetic analysis, using 1,3,5-trimethoxybenzene as an internal standard .......................................................................... 94 Scheme 3.7 Synthesis of poly-substituted piperidines ................................................................ 100 Scheme 4.1 Hydroaminoalkylation of liberated dimethylamine to produce di-alkylated dimethylamine byproducts. ......................................................................................................... 133 Scheme 4.2 Formation and use of Hartwig’s activated hydroaminoalkylation catalyst ............. 135 Scheme 4.3 Proposed generation of tantalum hydroaminoalkylation catalyst in situ from tantalum pentafluoride ............................................................................................................................... 137 xxv  Scheme 4.4 Tantalum-fluoride catalyzed hydroaminoalkylation using non-rigorously dried materials ...................................................................................................................................... 142 Scheme 4.5 Synthesis of tetrahydroquinoline 4.27 from hydroaminoalkylation product 4.26 .. 145 Scheme 4.6 Sequential addition of catalyst system reagents and substrate for NMR study ...... 146 Scheme 4.7 Disruption of the tetrameric structure of tantalum pentafluoride to generate the mononuclear complex 4.28 ......................................................................................................... 147 Scheme 4.8 Formation of tantalum phosphoramide 4.29 through displacement of N-methylaniline in 4.28 .................................................................................................................. 149 Scheme 4.9 Formation of a mixture of catalytically active species from 4.29, N-methylaniline, and methyl lithium ...................................................................................................................... 153 Scheme 4.10 Hydroaminoalkylation of 1-octene with N-methylaniline, used to test the benchtop stability of tantalum pentafluoride .............................................................................................. 154 Scheme 5.1 Generalized hydroamination reaction ..................................................................... 167 Scheme 5.2 First group 4 hydroamination catalyst by Bergman and co-workers ...................... 168 Scheme 5.3 First hydroamination catalyst with high selectivity for the anti-Markovnikov product..................................................................................................................................................... 168 Scheme 5.4 Select examples of the synthesis of amines through tandem alkyne hydroamination/imine reduction ................................................................................................. 171 Scheme 5.5 Synthesis of β-amino-α,β-unsaturated imines through a 1-pot hydroamination/isonitrile insertion ............................................................................................. 172 Scheme 5.6 Synthesis of N-substituted amino acids via a 1-pot hydroamination/cyanosilylation/acid hydrolysis ........................................................................ 172 xxvi  Scheme 5.7 Generalized intramolecular hydroamination of aminoalkynes to form 1,2-unsaturated N-heterocycles............................................................................................................................. 173 Scheme 5.8 Synthesis of indoles via sequential 1-pot hydroamination/Fischer indole synthesis..................................................................................................................................................... 173 Scheme 5.9 Synthesis of indoles via sequential 1-pot hydroamination/Buchwald-Hartwig Amination ................................................................................................................................... 173 Scheme 5.10 Synthesis of pyrroles through 1-pot hydroamination/cyclizations ........................ 174 Scheme 5.11 Synthesis of imidazolidinones through tandem hydroamination/cyanosilylation followed by reduction and cyclization with CDI ........................................................................ 175 Scheme 5.12 Synthesis of 1,2,5-trisubstituted piperidines through a sequential 1-pot hydroamination/cyanosilylation/alkylation followed by reduction and a second hydroamination..................................................................................................................................................... 175 Scheme 5.13 Synthesis of pyrrolidines via a sequential 1-pot hydroamination/cyclopropylimine rearrangement/reduction ............................................................................................................. 176 Scheme 5.14 Synthesis of α-functionalized saturated N-heterocycles through tandem hydroamination/functionalization reactions ................................................................................ 176 Scheme 5.15 Total synthesis of S-(-)-laudanosine and S-(-)-xylopinine using hydroamination followed by asymmetric transfer hydrogenation as late-stage transformations .......................... 177 Scheme 5.16 Synthesis of morpholines and other saturated N-heterocycles through sequential 1-pot hydroamination/asymmetric transfer hydrogenation. ........................................................... 178 Scheme 5.17 Initial synthesis of optically active benzoxazine (-)-5.5 ....................................... 180 Scheme 5.18 Subsequent syntheses of optically active benzoxazine intermediates ................... 181 xxvii  Scheme 5.19 Chiral resolution of (-)-5.5 through enantioselective hydrolysis using a strain of Bacillus sp. .................................................................................................................................. 182 Scheme 5.20 Asymmetric synthesis of (-)-5.5 through both an ADH-catalyzed asymmetric reduction and through a lipase-catalyzed chiral resolution to set the stereocenter ..................... 182 Scheme 5.21 Asymmetric synthesis of (-)-5.5 through the formation of a chiral cyclic sulfamidate .................................................................................................................................. 183 Scheme 5.22 Asymmetric synthesis of (-)-5.5 through a sequential ring-opening alkylation/Ullman-type amination of a chiral N-tosyl aziridine ................................................. 183 Scheme 5.23 Synthesis of 1,4-quinaxolines, 1,4-benzoxazines, and a 1,4-benzothiazine using ruthenabicycle 5.10 as a hydrogenation catalyst ......................................................................... 184 Scheme 5.24 Proposed asymmetric synthesis of 1,4-benzoxazines through a 1-pot sequential hydroamination/asymmetric transfer hydrogenation .................................................................. 184 Scheme 5.25 Synthesis of aminoalkyne 5.12.............................................................................. 185 Scheme 5.26 Initial optimization of hydroamination ................................................................. 186 Scheme 5.27 Formation of byproduct 5.38 from the asymmetric transfer hydrogenation reaction..................................................................................................................................................... 191 Scheme 6.1 Optimized conditions for the hydroaminoalkylation of norbornadiene with N-methylaniline using catalyst 2.7 .................................................................................................. 216 Scheme 6.2 Hydroaminoalkylation catalyzed through the in-situ generated Ta(NMe2)5/3.18 catalyst system ............................................................................................................................ 217 Scheme 6.3 Synthesis of poly-substituted piperidines ................................................................ 219 Scheme 6.4 Hydroaminoalkylation catalyzed by an in-situ generated catalyst based on tantalum pentafluoride ............................................................................................................................... 220 xxviii  Scheme 6.5 Synthesis of tetrahydroquinoline 4.27 from hydroaminoalkylation product 4.26 .. 220 Scheme 6.6 One-pot hydroamination/asymmetric transfer hydrogenation for the asymmetric synthesis of 1,4-benzoxazines ..................................................................................................... 221 Scheme 6.7 Synthesis of phosphoramidate catalyst 2.7 ............................................................. 222 Scheme 6.8 Ozonolysis of 2.9 to synthesize 6.1 ......................................................................... 223 Scheme 6.9 Hydroaminoalkylation of an unstrained internal alkene using an in-situ generated tantalum chloro pyridonate catalyst ............................................................................................ 224 Scheme 6.10 Mechanism of early transition metal catalyzed hydroaminoalkylation with off-cycle equilibria ..................................................................................................................................... 226 Scheme 6.11 Proposed syntheses of highly functional polysubstituted piperidines from hydroaminoalkylation products .................................................................................................. 227 Scheme 6.12 H/D exchange through the use of heterogeneous ruthenium catalysts .................. 229 Scheme 6.13 Dihydroaminoalkylation using a dinuclear titanium sulfonamide catalyst ........... 231 Scheme 6.14 Dihydroaminoalkylation observed using the TaF5 catalyst system with 3-methyl-2-pyridone as a ligand .................................................................................................................... 231 Scheme 6.15 Sequential intermolecular alkyne hydroamination/Strecker reaction to yield racemic α-amino acids .............................................................................................................................. 232 Scheme 6.16 Proposed sequential alkyne hydroamination/asymmetric Strecker reaction to yield enantioenriched α-amino acids ................................................................................................... 232  xxix  List of Abbreviations Å  Angstroms δ  Chemical shift °C  Degrees Celcius σ  Hammett parameter %ee  % enantiomeric excess ADH-A Alcohol dehydrogenase A Ar  Aryl ATR  Attenuated total reflectance br  Broad CDI  Carbonyldiimidazole Conc.  Concentration Conv.  Conversion Cp  Cyclopentadienyl d  Doublet D°298  Bond dissociation energy dba  Dibenzylideneacetone  DBU  1,8-Diazabicylco(5.4.0)undec-7-ene DCM  Dichloromethane DEAD  Diethyl azodicarboxylate DG  Directing Group DI  Deionized Dipp  2,6-Diisopropylphenyl xxx  DMF  Dimethylformamide eqv.  Equivalents g  Grams GC/MS Gas Chromatography/Mass Spectrometry gem  Geminal HCl  Hydrogen Chloride Hex  Hexyl IC50  Half maximal inhibitory concentration IR  Infrared Ind  Indenyl kJ  Kilojoules L  Ligand LDA  Lithium diisopropylamide LFER  Linear Free Energy Relationship TMSCN Trimethylsilyl cyanide m  Multiplet M  Molar Me  Methyl MeLi  Methyl Lithium Mes  Mesityl mg  Milligrams mL  Milliliters mmol  Millimoles xxxi  MTBE  Methyl tert-butyl ether N.D.  Not detected NADH  Nicotinamide adenine dinucleotide NaHMDS Sodium Hexamethyldisilylazide NBD  Norbornadiene NMA  N-methylaniline NMR  Nuclear Magnetic Resonance NP@PVP Nanoparticles on polyvinylpyrrolidone ORTEP Oak Ridge Thermal Ellipsoid Plot Ph  Phenyl PMP  Para-methoxyphenyl ppm  Parts-per-million PTFE  Polytetrafluoroethylene q  Quartet RML IM Rhizomucor miehei lipase, immobilized ROMP  Ring opening metathesis polymerization rt  Room Temperature s  Singlet sp.  Species t  Triplet Ta  Tantalum TaF5  Tantalum pentafluoride Temp.  Temperature xxxii  TRIS HCl Tris(hydroxymethyl)aminomethane hydrochloride Trt  Trityl t-Bu  Tert-butyl U/B  Unbranched/Branched  xxxiii  Acknowledgements This thesis, and the work presented within, would not have been possible without the support from the following individuals. First, I would like to thank my advisor, Professor Laurel Schafer. Her support, guidance, and insight has been instrumental in not only producing the work for this thesis, but also in shaping me into the scientist that I am today. I will be eternally grateful for the opportunities that she has provided me. I would also like to thank Dr. Alex Mandel, my supervisor during my co-op at the Centre for Drug Research and Development. Not only did he help me develop many of my skills as a synthetic organic chemist, but he also taught me the work ethic of a professional chemist. His guidance and mentorship not only helped me through my time at the Centre for Drug Research and Development, but also laid the foundation for the remainder of my graduate studies. I would like to express my gratitude towards the support staff in the UBC Chemistry department for their tireless efforts in ensuring that research in the department goes as smoothly as possible. I especially would like to thank Adana Thorne for her management of the CREATE Sustainable Synthesis program, and David Tonkin for his assistance in setting up and maintaining the GC/MS. Thank you to Ryan Chung for assistance with the chiral HPLC, and Professor Scott Rychnovsky and Alexander Burtea at the University of California Irvine for the collaboration for Chapter 5. I have worked alongside a number of amazing chemists during my time at UBC and the Centre for Drug Research and Development. Thank you to all past and present Schafer group members for laying the foundations of this work and assisting me along the way with material support and exceptional insight. I would particularly like to thank my undergraduate mentees, xxxiv  Thomas Horton and Weizhe Dong, as well as visiting student Jan Cremers, who not only performed a portion of the research presented in this thesis, but also helped me learn how to be an effective mentor. I would also like to thank Damon Gilmour for assistance with X-ray crystallography and Joseph Clarkson for sharing his significant knowledge in inorganic chemistry. I would like to thank Nirmalendu Kuanr, Damon Gilmour, Sorin-Claudiu Roşca, Joseph Clarkson, Samuel Griffin, Dawson Beattie, Prof. Glenn Sammis, and Prof. David Perrin for reading drafts of this thesis and providing valuable feedback. I would like to extend a special thanks to Dr. James Jacquith at the Centre for Drug Research and Development for his insight and advice. Finally, I would like to thank everyone outside of the lab who has helped me through my time at UBC. Special thanks to Cameron Kellett, Erin Conroy, and Eric Bowes for their support and friendship. Thanks to Maestro Devon Boorman, Provosts Roland Cooper, Matheus Olmedo, Griffin Knight, and all my friends and training partners at Academie Duello for not only providing me the opportunity to learn new skills outside the lab, but for accepting me into your community and supporting me during the most challenging times of my graduate career. Lastly, but most importantly, I would like to thank my parents, Mark and Cindy Edwards, for supporting a crazy idea that I had as an undergraduate student.  Over 3,000 miles, 5 years, and plenty of blood, sweat and tears later, this is the result of that idea. xxxv  Dedication           To those who came before, and to those who follow.  1  Chapter 1: Early Transition Metal-Catalyzed Hydroaminoalkylation for Csp3 – Csp3 Bond Formation in the Synthesis of Selectively Substituted Amines  1.1 Synthesis of Amines Amines are a highly important class of compounds, with uses ranging from industrial gas treatment, to materials, to pharmaceuticals, and agrochemicals.1-4 As such, methods for the efficient synthesis of selectively substituted amines is an intense area of interest, requiring improved methods that are both economical and environmentally friendly. Traditional synthetic routes, including nucleophilic substitution and reductive amination, have found wide use in both lab-scale and industrial-scale synthesis due to their robust nature. However, they can suffer from the requirement of stoichiometric reagents and the generation of stoichiometric byproducts (Scheme 1.1a).5-6 Catalytic cross-coupling methods for C-N bond formation, such as the Buchwald-Hartwig amination, the Chan-Lam coupling, hydroamination, hydroaminomethylation, and others have risen in prominence in recent decades (Scheme 1.1b).7-9 2   Scheme 1.1 Common methods for the synthesis of amines via C-N bond formation A complementary method for the synthesis of substituted amines is amine-directed C-C bond formation by selective C-H activation (Scheme 1.2). Such strategies include C-H alkylation/arylation through catalytic cross-coupling reactions, which feature late transition metals for C-H activation α to an amine. Directing groups are typically required on the nitrogen of the amine, and pre-functionalized aryl or alkyl halide coupling partners are also required. 10-20 More recently, photocatalytic methods have been shown to generate not only alkylated amines, but also allylic amines and acylated amines.21-26 Such reactions are proposed to proceed through either the photocatalytic generation of an iminium cation followed by nucleophilic addition, or through the photocatalytic generation of an α-amino radical followed by alkylation or further catalysis. 3   Scheme 1.2 Amine directed C-C bond formation through C-H activation A third, and often overlooked, strategy for the synthesis of Csp3-Csp3 bonds through C-H activation of amines is hydroaminoalkylation (Scheme 1.3).  This catalytic reaction generates Csp3-Csp3 bonds by hydrofunctionalization of an alkene with a C-H bond. Hydroaminoalkylation has the benefit of both being atom economic and avoiding pre-functionalized coupling partners, as readily available alkene feedstocks are used. The use of alkenes as coupling partners offers the extra synthetic benefit of allowing for complementary alkylation regioselectivies. This provides the opportunity to generate two different amine products from the same starting materials. Ideally, and in many cases (vide infra), one product is selectively obtained via catalyst control.  Thus, a wide variety of selectively substituted amine products can be accessed by careful selection of starting amine, alkene, and catalyst (Scheme 1.4).  Scheme 1.3 Amine-directed C-C bond formation through hydroaminoalkylation 4   Scheme 1.4 Different alkylation modes possible through hydroaminoalkylation The catalytic hydroaminoalkylation reaction was first reported with homoleptic dimethylamido metal complexes of niobium, tantalum, and zirconium as catalysts in 1980 (Scheme 1.5).27 These early reactions exhibited low yields (10-38%) with few substrates and required long, harsh conditions. The first instance of this reaction catalyzed by late transition metals was reported by Jun et al. in 1998, where they report the use of Ru3(CO)12 for the directing group-assisted alkylation of benzylamine derivatives.28 This was then expanded upon by Chatani et al. for the alkylation of various directing group-functionalized unsaturated N-heterocycles.29 5   Scheme 1.5 Initially reported hydroaminoalkylation reaction by Maspero This transformation largely laid dormant in the literature for over two decades, until it was revisited by Herzon and Hartwig in 2007.30 Since then, this reaction has been reported with both late and early transition metal catalysts. Late transition metal catalyzed hydroaminoalkylation uses primarily ruthenium or iridium catalysts, going through a metal-hydride insertion mechanism (Scheme 1.6).29 Late transition metal hydroaminoalkylation, like the complementary cross-coupling methods, often requires the use of directing or protecting groups on the nitrogen (Scheme 1.7), thereby lowering the atom and step economy associated with the reaction.31 Alternatively, a recent report discloses the use of a cobalt catalyst coupled with an iridium photocatalyst to selectively alkylate tertiary amines with dienes.32 One benefit of the late transition metal catalysts is the predominance of the metal hydride insertion mechanism, which allows for selectivity for the synthesis of α-alkylated amine products, even when internal alkenes are used as substrates (via a chain walking mechanism).28-29, 31-37 6   Scheme 1.6 Mechanism of late metal-catalyzed hydroaminoalkylation  Scheme 1.7 Late transition metal-catalyzed hydroaminoalkylation In contrast to late transition metal catalysts, early transition metals systems, utilizing scandium, titanium, zirconium, niobium, and tantalum have several economic, environmental, and chemical advantages. Early transition metals are more abundant, generally exhibit low toxicity and, most importantly, they catalyze the reaction through an alternative mechanism, allowing for complementary regioselectivity to that seen in late-metal catalysis.38-41 Instead of a metal hydride insertion process, the reaction proceeds through a metallaaziridine mechanism, first proposed by Nugent in 1983 (Scheme 1.8).42-43 Binding of the amine followed by C-H activation yields metallaaziridine A. Insertion of the alkene into the M-C bond can occur in a 1,2 or 2,1-insertion 7  pattern to give a 5-membered metallacycle B. A second equivalent of amine subsequently reacts with the catalyst to generate C, and a second C-H activation liberates the product to reform A. This mechanism is generally applicable through all early transition metal hydroaminoalkylation catalysts.  Scheme 1.8 Generalized mechanism for group 4 and 5-catalyzed hydroaminoalkylation Since Herzon and Hartwig revisited this reaction using early transition metals, significant effort has been applied toward the development of new, more reactive catalysts. This effort has resulted in new catalysts that can access a broad range of selectively substituted amines. Herein is summarized the selection of catalysts that can access different classes of selectively substituted amines.  8  1.2 Hydroaminoalkylation for the Synthesis of Structurally Diverse Amines 1.2.1 Synthesis of Unbranched Amines Unbranched amines are one of the most common amine motifs in both pharmaceuticals and natural products.4 While classical methods such as reductive amination or nucleophilic substitution are most commonly utilized for the synthesis of unbranched amines, recent advances in catalysis have realized the use of alkenes as substrates for hydroaminomethylation and hydroaminoalkylation (Scheme 1.9).44 While such amines are attractive synthetic targets, they are rarely produced via early transition metal hydroaminoalkylation catalysts due to the electronic properties of the catalytic metallaziridine intermediate A (Scheme 1.10). It has been shown through computational methods that the branched regioselectivity is often preferred due to the nucleophilic terminal carbon of alkyl-substituted terminal alkenes interacting with the electrophilic d0 metal of the metallaziridine during the alkene insertion.45 While steric effects also influence branched selectivity, these calculations indicate that stability of the alkene insertion transition states can be significantly affected by electronic properties.   Scheme 1.9 Hydroaminoalkylation for the synthesis of unbranched amines  Scheme 1.10 Origin of branched regioselectivity for most early transition metal hydroaminoalkylation catalysts 9  The synthesis of unbranched amines through hydroaminoalkylation is largely limited at this time to the use of styrenes and vinyl silanes as coupling partners. Hou and co-workers have shown that these substrates favor linear selectivity due to their increased negative charge localization at the substituted carbon of the alkene, as determined through Mulliken atomic charge distribution calculations.45 However, there is an interesting trend that emerges when one looks at the hydroaminoalkylation of styrene (Scheme 1.11).  In moving across the periodic table from group three to group five, the catalysts generate increased amounts of the branched product. Thus the scandium alkyl catalyst 1.1 reacts with styrene to give complete regioselectivity for the linear product while titanium catalysts exhibit some catalyst dependent selectivity, with some favoring the unbranched product. Meanwhile, tantalum catalysts, such as 1.13 produce almost entirely β-methylated products, the branched product, with only one catalyst being reported to give unbranched selectivity with vinyl trimethylsilane.46 While the charge distribution hypothesis does explain why substrates like styrene and vinyl trimethylsilane can favour the formation of linear products, notably groups 4 and 5 catalysts have higher-coordination numbers and branched products often result, presumably due to the increased congestion about the metal center.  These observations suggest that steric factors dominate regioselectivity in these catalyst systems.  More research is needed to develop improved catalyst control for the synthesis of the linear regioisomer.   10   Scheme 1.11 Trend of unbranched vs. branched product formation across different metals 1.2.1.1 Synthesis of Unbranched Secondary Amines Titanium catalysts were the first to exhibit selectivity for the unbranched hydroaminoalkylation product.  The first catalyst reported for this transformation was by Doye and co-workers, consisting of an in situ generated titanium catalyst using Ti(NMe2)4 with 1-2 equivalents of 2-(methylamino)pyridine to make 1.2.47 By utilizing styrene as a substrate, the authors were able to alkylate a variety of amines, including more challenging dialkylamines (Scheme 1.12), utilizing high reaction temperatures and long reaction times. The initial reaction conditions offered low selectivity, with many substrates exhibiting only 2:1 unbranched/branched (U/B) ratios. However, the selectivity could be raised for certain substrates by using two equivalents of ligand per metal center.  Unfortunately, this also involves a decrease in yield.  11   Scheme 1.12 Hydroaminoalkylation using titanium aminopyridonate catalyst 1.2 to synthesize unbranched amines While attempting to optimize the 2-aminopyridinate ligand of 1.2, Doye and co-workers developed catalyst 1.3, which is significantly more selective for unbranched products under the same reaction conditions (Scheme 1.13).47 Exhibiting a slightly expanded substrate scope, 1.3 shows far greater selectivity for the unbranched product with styrenes (U/B ratios from 6:1 to 99:1). 1-Aryl-substituted 1,3-dienes, which are challenging substrates for hydroaminoalkylation due to high temperature dimerization, exhibit complete linear product selectivity (Scheme 1.13).48-49  Scheme 1.13 Hydroaminoalkylation of styrenes and 1,3-butadienes with titanium aminopyridonate catalyst 1.3 12  Aminopyridonato titanium catalysts are not the only class of titanium catalysts capable of the selective synthesis of unbranched amines. Catalyst 1.4 (Scheme 1.14) is capable of alkylating N-methylbenzylamine with 1-aryl-substituted 1,3-dienes with great selectivity for the thermodynamically favored benzyl position, in moderate to good yields.50  There is no reported alkene isomerization byproduct. However, when the amine coupling partner is changed to N-methylaniline, the selectivity drops to nearly a 1:1 U/B ratio.   Scheme 1.14 Hydroaminoalkylation of 1,4-butadienes with N-methylbenzylamine using titanium formamidinate catalyst 1.4 Linear regioselectivity using group 5 catalysts has been rarely observed.  Vinyl trimethylsilane can be used in combination with a tantalum phosphoramidate catalyst 1.5 to access the linear hydroaminoalkylation product of vinyl trimethylsilane (7:1 U/B ratio) (Scheme 1.15).46 The authors hypothesized that this selectivity is observed due to the electronic effects of the β-silicon group, which stabilizes a transient positive charge at the terminal carbon of the alkene. While this is the only substrate that has been shown to exhibit a preference for the unbranched product with group 5 catalysts, 1.5 also showed decreased selectivity for the branched product with electronically varied styrenes. Indeed, there is an observed trend such that electron donating p-methoxystyrene gives the branched product preferentially, while substituents with increasing 13  electron-withdrawing character decrease the regioselectivity of the reaction to the point where p-trifluoromethylstyrene only offers a unbranched/branched ratio of 1.8:1.46   Scheme 1.15 Hydroaminoalkylation of trimethylvinylsilane using tantalum phosphoramidate catalyst 1.5 1.2.1.2 Synthesis of Unbranched Tertiary Amines The first reported scandium hydroaminoalkylation catalyst, 1.1, exhibits excellent regioselectivity for unbranched products  with styrene derivatives or vinyl trimethylsilane (Scheme 1.16).51  Notably this catalyst is not limited to secondary amine substrates but can catalyze this reaction with N-methylpiperidine with complete linear regioselectivity and in good to excellent yields. However, this regioselectivity reverses when alkyl olefins, such as 1-hexene or allyl benzene, are used (See Chapter 1, Section 1.2.3.3).  14   Scheme 1.16 Hydroaminoalkylation of styrenes and trimethylvinylsilane with N-methylpiperidine using scandium catalyst 1.1 1.2.2 Synthesis of α-Branched Amines The synthesis of α-branched amines by linear regioselective hydroaminoalkylation of an alkene with a secondary carbon α to the amine remains a challenge for early transition metal-catalyzed hydroaminoalkylation. Only titanium catalysts have been shown to give these products reliably, and to date the substrate scope for this reaction is very limited (Scheme 1.17). Ti(NMe2)4 has been shown to catalyze the reaction between N-benzylaniline and aliphatic alkenes in good yield, albeit with no regioselectivity.52 Complex 1.3 is capable of catalyzing the reaction of styrene with N-benzylaniline in similar good yields, but a linear selectivity of 19:1 gives the α-arylated product.48 Complex 1.3 is also capable of utilizing N-ethylaniline, N-methylbenzylamine, and tetrahydroquinoline as substrates, yielding the α-substituted products in poor to moderate yields but with very good selectivity for the α-substituted product.48 Changing the catalyst to titanium formamidinate 1.4 allows for the reaction of substituted 1-phenylbutadienes with N-methylbenzylamine to synthesize a variety of 1,5-diphenyl-1-amino-4-pentenes in moderate yields and ~ 10:1 selectivity for the α-substituted product.50 15   Scheme 1.17 Synthesis of α-alkylated amines using various titanium catalysts The most successful early transition metal catalyst for the synthesis of α-substituted amines has been titanium catalyst 1.2 (Scheme 1.18).47 This catalyst is capable of utilizing not only N-ethylaniline and N-methylbenzylamine, but also N-benzylaniline, diethylamine, and pyrrolidine. While the yields for these reactions is highly variable and only styrene has been reported as the coupling partner for these substrates, the selectivity for the α-substituted  product can be high.   Scheme 1.18 Synthesis of α-alkylated amines using titanium aminopyridonate catalyst 1.2 The synthesis of α-branched amines is a particular strength of late transition metal hydroaminoalkylation catalysts.28-29, 31, 33-34, 37 Utilizing various ruthenium or iridium catalysts, a variety of protected alkylamines, including unsaturated N-heterocycles, can be alkylated with terminal aliphatic alkenes and styrenes to produce α-substituted amines and heterocycles. These reactions usually require the presence of a directing/protecting group on the amine, which can be avoided with early transition metal catalysed hydroaminoalkylation. 16  1.2.3 Synthesis of β-Methylated Amines β-methylated amines are the most common amine product that can be synthesized using early transition metal catalyzed hydroaminoalkylation. These products are prepared from the branched regioselective hydroaminoalkylation of a terminal alkene with an N-methylated amine or aniline.  Such products can be accessed in a single, atom-economic catalytic step from readily available starting materials. The β-methylated isomer is not known for late transition metal catalysts.28, 32-34 The regioselective synthesis of β-methylated amines is possible with groups 3, 4, or 5 hydroaminoalkylation catalysts and, depending on the catalyst, can be done with outstanding regioselectivity using both alkyl- and aryl-substituted alkenes. In 2007, Herzon and Hartwig showed that one of the complexes reported by Maspero and co-workers for the hydroaminoalkylation reaction, Ta(NMe2)5, could be used as an effective catalyst when the amine coupling partner was N-methylaniline (Scheme 1.19).30 While the reaction conditions were no less harsh than initially reported by Maspero, the change in amine substrate led to greatly increased yields (up to 96%) and the substrate scope was increased, including the only example of intramolecular hydroaminoalkylation with  a tantalum catalyst.27 Notably, while the reaction of N-methylaniline and vinyl trimethylsilane was not reported to yield any linear product, the analogous reaction with vinyl phenyldimethylsilane yielded product with a unbranched/branched ratio of 1:2.30 Later, Dörfler and Doye built upon this work, using milder reaction conditions with longer reaction times to include more substrates, all with very high to complete branched regioselectivity. Both Hartwig and Doye reported that gem-disubstituted alkenes were active substrates but unstrained internal alkenes were not observed to react.30,53 17   Scheme 1.19 Development of Ta(NMe2)5 as a catalyst by Hartwig and Doye There have also been reports for both homoleptic scandium and titanium catalysts for the synthesis of β-methylated amines. Scandium cationic catalyst 1.1, was reported to exclusively afford branched products with 8 different alkyl-substituted alkenes when using tertiary amine N-methylpiperidine (Scheme 1.20), exhibiting the opposite regioselectivity seen when styrenes are the alkene reactant.51 This catalyst is also one of only two reported early transition metal catalysts reported for the hydroaminoalkylation reaction using tertiary amines.  Most importantly, excellent selectivity for alkylation on the kinetically favoured methyl group is observed.   18   Scheme 1.20 Synthesis of β-methylated amines using scandium catalyst 1.1 Ti(NMe2)4 gives moderate to good yields for the β-methylated amines, albeit with a limited substrate scope (Scheme 1.21).52 Doye and co-workers later demonstrated that TiBn4 was a more reactive catalyst for the synthesis of β-methylated amines, exhibiting significantly higher yields but with similar modest unbranched/branched selectivities.54 However, both Ti catalysts require high temperatures and long reaction times (160 °C for 4 days), and neither are as active nor as selective for the branched product as Ta(NMe2)5, which only requires one day to yield exclusively the branched product.   Scheme 1.21 Hydroaminoalkylation with homoleptic titanium catalysts  1.2.3.1 Synthesis of β-Methylated Amines Using Group 4 Catalysts Over the past decade, the Doye group has disclosed the synthesis, development, and use of several titanium catalysts. The advances in catalyst design have led to expanded amine and alkene 19  substrate scope, generating products that are not yet accessible through group 3 and 5 catalysis. To date, high catalyst loadings and/or multi-day reaction times are required, regardless of the catalyst system. The first reported titanium catalyst for the preferential synthesis of β-methylated amines was Ind2TiMe2 (Scheme 1.22).55 While it displays modest catalytic activity for hydroaminoalkylation, requiring four days for the majority of substrates, it also requires the lowest reaction temperature for a titanium hydroaminoalkylation catalyst (105 °C). The initial report by Doye and co-workers disclosed the reaction of 5 substituted N-methylanilines with 9 terminal alkene substrates, including 6 styrene derivatives with preferred regioselectivity for the β-methylated product. Aliphatic amines, non-methyl N-anilines, and internal alkenes were not tolerated. A later report expanded upon the substrate scope to include the challenging 1-aryl substituted 1,3-butadienes, which afford complete regioselectivity for the terminal alkene vs. the internal alkene of the diene.49 However the regioselectivity for the β-methylated product over the linear product is only modest (1:3, U/B).   Scheme 1.22 Synthesis of β-alkylated amines using a titanium indenyl catalyst In 2012 Doye and co-workers reported a dinuclear titanium catalyst with a bridging sulfamide ligand, 1.7, that is competent as a hydroaminoalkylation catalyst for the synthesis of β-methylated amines (Scheme 1.23).56 This catalyst is one of the few catalysts reported for the 20  dialkylation of amines, and the first titanium catalyst to show activity toward aliphatic amines. However, only 2 amines and 3 terminal alkenes were disclosed in the substrate scope.   Scheme 1.23 Hydroaminoalkylation using the dinuclear titanium sulfamide catalyst 1.7 More recently, Doye and co-workers developed 1.8, with a diaminopyridine ligand similar to catalysts for the synthesis of unbranched amines (Scheme 1.24).57 Notably, the bulky trityl substituents on the ligand led to a monoligated complex, and this led to a corresponding change in the regioselectivity of the catalyst; 1.8 shows an unbranched/branched product ratio of 1:9, as opposed to 2:1 and 16:1 for 1.2 and 1.3, respectively. Furthermore, 1.8 can catalyze intramolecular C-N bond forming reactions by hydroamination. Even vinyl silanes furnish the β- methylated product, including o-bromophenyldimethyl vinyl silane, which the authors then used to develop a one-pot synthesis of 1,4-benzoazasilines using a subsequent Buchwald-Hartwig amination (vide infra).58 21   Scheme 1.24 Hydroaminoalkylation using titanium diaminopyridonate catalyst 1.8 These results should be contrasted with titanium complex, 1.4, which can be used with gem-disubstituted alkenes and 1,3-dienes.50 In addition to its previously mentioned ability to synthesize unbranched amines with N-methylbenzylamine (page 12, scheme 1.14), the authors reported the use of 1.4 for the synthesis of β-methylated amines from 1,3-dienes in moderate to good yields (Scheme 1.25). However, this reaction suffered from poor selectivity, with most substrates exhibiting a unbranched/branched ratio of near 1:1. Allyl silanes were also reported as being active with this catalyst, with high yields and complete regioselectivity for the β-methylated product.59 This catalyst has also been reported for mono- and di-hydroaminoalkylation of dimethylamine (Scheme 1.26) with selectivity depending on the equivalents of dimethylamine used relative to alkene.60 Regioselectivity is substrate dependent, with the β-methylated product being produced exclusively with aliphatic alkenes, but styrenes giving a mixture of linear and β-methylated products. The reaction exhibits no significant diastereoselectivity for the chiral or meso products. 22   Scheme 1.25 Synthesis of β-methylated amines using titanium formamidinate catalyst 1.4  Scheme 1.26 Hydroaminoalkylation with dimethylamine using titanium formamidinate catalyst 1.4 Recently, Doye and co-workers reported a class of dimethyl(indenylethylamido) titanium catalysts for the hydroaminoalkylation of 1-octene with N-methylaniline (Scheme 1.27). By varying the steric and electronic factors on the tethered amido ligand, the authors were able to reach up to 77% yield, with unbranched/branched ratios ranging from 1:9 to 1:32.61  Scheme 1.27 Hydroaminoalkylation of 1-octene with N-methylaniline using different dimethyl(indentylethylamido) titanium catalysts 23  There has been one report to date utilizing zirconium for intermolecular hydroaminoalkylation.62 As part of their studies towards silica-supported catalysts, Basset and co-workers developed a silica-supported zirconium catalyst 1.9, which they showed to be competent towards the hydroaminoalkylation of dimethylamine with propene, albeit in low yields (Scheme 1.28).63  Scheme 1.28 Hydroaminoalkylation of propene with dimethylamine using silica-supported Zr(NMe2)4 1.2.3.2 Synthesis of β-Methylated Amines Using Group 5 Catalysts The first hydroaminoalkylation catalysts developed by Maspero were completely selective for the β-methylated products and in that report the highest yielding catalyst was Ta(NMe2)5.27 Since then, tantalum has typically yielded catalysts for the selective synthesis of β-alkylated amines, as only a very few tantalum catalysts will produce the unbranched product in trace amounts. Herzon and Hartwig explored a broad range of ligands in combination with tantalum and showed that 1.10, which includes chlorides as electron-withdrawing ligands, gives increased reactivity.64 This was proposed to be due to the increased electrophilicity of the tantalum metal center facilitating the reaction. With this catalyst dialkylamines could be used with excellent yields and complete regioselectivity for the β-methylated product, albeit with high reaction temperatures (150 °C) (Scheme 1.29). They also demonstrated that by beginning with catalyst 1.11, prepared by reacting 1.10 with the amine substrate, a much more reactive catalyst could be obtained and lower reaction temperatures were required. This indicates that the presence of the dimethylamido 24  ligands, either on the metal or as free dimethylamine in the reaction mixture, act to inhibit catalyst activity.   Scheme 1.29 Hydroaminoalkylation of 1-octene with trichlorotantalum catalysts 1.10 and 1.11 The Schafer group has explored highly tunable and electron withdrawing 1,3-N,O chelate ligands such as amidates, pyridonates, ureates, and phosphoramidates as ligands for  tantalum (Figure 1.1). Using this flexible approach, some of the most highly active hydroaminoalkylation catalysts have been developed. In 2009, tantalum amidate catalyst 1.12 was reported as being active for the synthesis of β-methylated amines (Scheme 1.30).65-66 The substrate scope encompasses a broad variety of amine and alkene substrates, including silyl protected alcohols and dienes.   Figure 1.1 N,O-chelating ligands used in hydroaminoalkylation catalysts 25   Scheme 1.30 Synthesis of β-methylated amines using tantalum amidate catalyst 1.12 To test the aforementioned theory proposed by Herzon et al. that electrophilic complexes are more active for hydroaminoalkylation, Schafer and co-workers developed 1.13, containing an electron-withdrawing 2-pyridonate ligand. This catalyst is capable of catalyzing the reaction between N-methylaniline and 1-octene under milder conditions (110 °C for 24 hours) (Scheme 1.31).67-68  Scheme 1.31 Hydroaminoalkylation using tantalum pyridonate catalyst 1.13 As mentioned previously, catalysts with dimethylamido ligands suffer from reduced catalyst activity through the formation of inhibiting by-products (dialkylation of dimethylamine with two equivalents of the alkene substrate). To bypass this issue, tantalum complexes that have alkyl ligands instead of dimethylamido ligands can be used as catalysts.69 Thus, a TaMe3Cl2 hydroaminoalkylation catalyst eliminates unreactive methane upon catalyst activation, and offers enhancement of reactivity due to the electron withdrawing halide ligands.70 TaMe3Cl2 can catalyze 26  the hydroaminoalkylation of 1-octene with N-methylaniline at 110 °C (Scheme 1.32). Using this catalyst, a variety of aromatic and aliphatic amines, and terminal alkenes gave products in moderate to excellent yields and excellent selectivity for the β-methylated product.   Scheme 1.32 Hydroaminoalkylation with TaMe3Cl2 as a catalyst TaMe3Cl2 can be combined with electron-withdrawing N,O-chelates to further enhance the reactivity of tantalum hydroaminoalkylation catalysts. Steric bulk is an important factor in ligand design for hydroaminoalkylation catalysis.65  Schafer and coworkers showed that a bulky, electron-withdrawing phosphoramidate ligand could replace a chloride of TaMe3Cl2 to give 1.5, which exhibits higher reactivity than TaMe3Cl2, and is the only catalyst with room temperature reactivity (Scheme 1.33).46 It is not only active towards anilines with alkyl-substituted olefins, but dialkylamines and styrene substrates can also be used.   Scheme 1.33 Synthesis of β-methylated amines using tantalum phosphoramidate catalyst 1.5, which is the only early transition metal catalyst active at room temperature 27  Unfortunately, tantalum phosphoramidate 1.5 is susceptible to thermal and photochemical degredation.71 Therefore, the identification of an alternative reactive alkyl ligand was desirable for the development of improved precatalysts. To this goal, the catalyst system 1.14 was developed, using the more robust Ta(CH2SiMe3)3Cl2 in combination with the electron withdrawing ureate ligand (Scheme 1.34).72 While 1.14 is not catalytically active at room temperature, it catalyzes the reaction at 110 °C, with good to excellent yields for aryl amines, terminal aliphatic alkenes, and terminal styrene substrates.  Catalyst system 1.14 is assembled in situ and requires only 2 hours at 110 °C to realize full conversion with terminal alkene substrates.   Scheme 1.34 Synthesis of β-alkylated amines using an in-situ generated tantalum ureate catalyst While the vast majority of research into tantalum-catalyzed hydroaminoalkylation has been on homogeneous catalysis, there has been an effort to develop heterogeneous tantalum catalysts, specifically through the use of silica-supported tantalum dimethylamido complexes. Bassett and co-workers have reported the synthesis of three different silica-supported tantalum complexes, including two with observable tantallaziridines, and demonstrated their catalytic activity for the hydroaminoalkylation of 1-octene with 6 different amines (Scheme 1.35).73 28   Scheme 1.35 Hydroaminoalkylation of 1-octene using silica-supported Ta(NMe2)5. Basset and co-workers report 3 separate catalysts, each with similar catalytic activities 1.2.3.2.1 Asymmetric Synthesis of β-Methylated Amines  The use of hydroaminoalkylation for the synthesis of β-methylated amines typically involves the generation of a stereocenter at the β-position. Thus, asymmetric catalysis is an important objective in hydroaminoalkylation catalyst development. Given the potential value for the asymmetric synthesis of complex alkylated amines, this is an underdeveloped field, with only 2 classes of asymmetric catalysts reported in the literature (Scheme 1.36). The first report of asymmetric hydroaminoalkylation used the axially chiral diamidate catalyst 1.15 to prepare chiral amines with good to excellent yields and moderate ee’s.65 This was then expanded upon by Zi and co-workers with two reports on related axially chiral diamidate tantalum catalysts that exhibit improved ee’s for select alkene and amine.74-75 29   Scheme 1.36 Asymmetric hydroaminoalkylation through the use of axially chiral diamidate and binaphtholate ligands on tantalum and niobium  The most successful asymmetric hydroaminoalkylation catalyst reported to date is the niobium binaphtholate 1.16 by Hultzsch and co-workers (Scheme 1.36).43, 76 This catalyst produces chiral amines with very good yields and ee’s with a variety of amine substrates and terminal alkene substrates, including the more difficult N-methylbenzylamine. The authors also report the chiral binaphtholate ligand system with tantalum.  Interestingly, binaphtholate niobium catalysts display increased reactivity in comparison to tantalum, which is contrary to the observations by Lauzon et al. that tantalum amidate catalysts exhibit higher reactivity than the corresponding niobium amidate catalysts.66 1.2.3.3 Synthesis of β-Methylated Tertiary Amines In addition to the reports by Hou and co-workers regarding the homoleptic scandium hydroaminoalkylation catalyst 1.1, there has been a report by Xu and co-workers disclosing complex 1.6 as a hydroaminoalkylation catalyst.51, 77 Similar to 1.1, 1.6 is competent for the hydroaminoalkylation of tertiary amines, albeit using substituted N,N-dimethylanilines instead of 30  N-methylated unsaturated heterocycles (Scheme 1.37). The authors demonstrated a substrate scope of 13 N,N-dimethylanilines with 8 alkyl-substituted alkenes to give product in moderate to excellent yields, exhibiting complete regioselectivity for the branched product. Secondary amines such as N-methylaniline proved to be unreactive with this catalyst, and the use of styrene as the alkene coupling partner with this catalyst was unsuccessful due to competing styrene polymerization.77  Scheme 1.37 Hydroaminoalkylation with tertiary anilines using scandium NacNac catalyst 1.6 1.2.4 Synthesis of α-Branched-β-Methylated Amines The synthesis of α,β-disubstituted amines via hydroaminoalkylation is a challenging transformation. The difficulty in promoting this reaction is primarily attributed to increased steric bulk inhibiting the insertion of the alkene into the metal-carbon bond of the metallaziridine. However, the formation of the metallaziridine is also more challenging due to the increased steric congestion, as well as the electronic instability of what can be viewed as a secondary carbanion after C-H activation. Although rare, there have been reports of catalysts capable of promoting this transformation.69, 78 These examples are highly diastereoselective, whic can be rationalized by the steric interactions that control alkene insertion into the metallaziridine. Insertion to form a cis-31  disubstituted metallaazacyclopentane is sterically disfavored compared to the insertion process that forms the trans-disubstituted metallacycle (Scheme 1.38). This leads to the anti alkylation selectivity observed for most catalysts capable of this reaction.   Scheme 1.38 Rational for observed diastereoselectivity for the synthesis of α-alkylated-β-methylated amines 1.2.4.1 Intermolecular Hydroaminoalkylation on Secondary Carbons Examples of intermolecular hydroaminoalkylation with alkylated amines beyond methyl substituents are limited. Examples include diethylamine, di-n-butylamine, and tetrahydroquinoline.27, 46, 53, 64, 67, 69-70 However, other amine substrates, such as N-ethylaniline and N-benzylaniline, are even more rarely reported. Both Ti(NMe2)4 and TiBn4 can mediate reactivity with N-ethyl- and N-benzylaniline, although the α-branched-β-methylated product is the minor product (Scheme 1.39).52, 54 The only catalyst that has been demonstrated to have a broad substrate scope for the synthesis of such α,β-disubstituted amines is tantalum amidate catalyst 1.12, which can synthesize a number of different 6- and 7-membered alkylated N-heterocycles, including 4-substituted piperazines, with good to excellent diastereoselectivity (Scheme 1.40).65-66, 78 32   Scheme 1.39 Synthesis of α-branched-β-methylated amines from N-benzylaniline using homoleptic titanium catalysts  Scheme 1.40 Synthesis of α-branched-β-methylated amines through hydroaminoalkylation with unsaturated N-heterocycles using tantalum catalyst 1.12  1.2.4.2 Intramolecular Hydroaminoalkylation There have been few investigations into the synthesis of 2-alkyl-aminocycloalkanes by the intramolecular hydroaminoalkylation of aminoalkenes. One major reason for this is the difficulty of obtaining selectivity for the hydroaminoalkylation product over the corresponding hydroamination product (Scheme 1.41).79 Indeed, many reports of new catalysts for intermolecular hydroaminoalkylation note that the hydroamination product is seen exclusively when aminoalkenes are utilized as substrates. 56-57, 75-76  33   Scheme 1.41 Intramolecular hydroaminoalkylation of aminoalkenes. The corresponding hydroamination reaction is a common side reaction The first group 4 catalysts for intramolecular hydroaminoalkylation was reported by Doye and co-workers as part of their report on the use of T(NMe2)4 as a hydroaminoalkylation catalyst (Scheme 1.42).52, 54 Aminocyclohexanes were accessed due to the unfavored synthesis of the corresponding strained 7-membered ring through hydroamination. While these catalysts do show good chemoselectivity for hydroaminoalkylation with this class of substrate, the substrate scope was limited to four aminocyclohexanes.  Scheme 1.42 Intramolecular hydroaminoalkylation with homoleptic titanium catalysts While the homoleptic titanium catalysts are capable of cyclizing primary aminoalkenes, secondary aminoalkenes are often unreactive.52, 54 However, 1.2 can cyclize these substrates, producing N-aryl and N-alkyl substituted 2-methylcycloalkylamines in up to 95% yield (Scheme 1.43).80 Unfortunately, the diastereoselectivities for these reactions are low.  34   Scheme 1.43 Intramolecular hydroaminoalkylation with titanium aminopyridonate catalyst 1.2 In addition to being able to catalyze the hydroaminoalkylation of 1-octene with N-methylaniline, the class of dimethyl(indenylethylamido) titanium catalysts developed by Doye and co-workers has the ability to catalyze the intramolecular hydroaminoalkylation of 2,2-dimethyl-6-hepten-1-amine to generate an aminocyclohexane in up to 56% yield with a cis/trans ratio of 1:4 (Scheme 1.44).61 This reaction goes with complete selectivity for the hydroaminoalkylation product; the corresponding 7-membered ring formed through hydroamination is not observed.   Scheme 1.44 Intramolecular hydroaminoalkylation with dimethyl(indenylethylamido) titanium catalysts When varying the ancillary ligands on the titanium complex across a number of chelates, the selectivity for hydroaminoalkylation over hydroamination can be tuned through the use of less sterically demanding 3-substituted pyridonates. Catalyst 1.17 was found to offer improved 35  reactivity and chemoselectivity for hydroaminoalkylation over hydroamination (20 mol% catalyst loading at 110 °C) along with substrate dependent diastereoselectivity (Scheme 1.45).79 An example of an aminoalkene with a geminally disubstituted alkene was also demonstrated, resulting in the formation of a quaternary center at the β-position relative to the amine.   Scheme 1.45 Intramolecular hydroaminoalkylation with titanium pyridonate catalyst 1.17 can give a quaternary β-carbon Zirconium catalysts for this transformation have been reported by the Schafer group. The first catalyst, 1.18 (Scheme 1.46), was demonstrated to catalyze a broader range of substrates, yielding both 5- and 6-membered rings in fair to excellent yields, albeit with low diastereoselectivity.81 This catalyst also suffers from low catalytic efficiency, requiring up to 40 mol% catalyst loading at 145 °C for certain substrates. However, the authors reported the formation of a quaternary center α to amine by using an α-arylated aminoalkene substrate. This is the only report for the synthesis of this class of compounds.  36   Scheme 1.46 Intramolecular hydroaminoalkylation with zirconium pyridonate catalyst 1.18 can form a quaternary α-carbon Notably, although there have been many tantalum hydroaminoalkylation catalysts reported, there has been only one report of a tantalum catalyst for intramolecular hydroaminoalkylation. In their first report, Herzon and Hartwig demonstrated that Ta(NMe2)5 is capable of cyclizing a secondary aminoalkene into the corresponding phenylamino-2-methylcyclohexane as a mixture of diastereomers.30 1.2.5 Synthesis of β-Alkylated and β-Quaternary Center Amines Similar to the synthesis of α-branched-β-methylated amines, the synthesis of β-alkylated and β-quaternary center amines through hydroaminoalkylation of 2,2-disubstituted and 1,2-disubstituted alkenes (Scheme 1.47) remains a significant challenge.  While most catalysts are reported using N-methylaniline as the amine substrate, there are two common alkene substrates that are used for this reaction, methylenecyclohexane and norbornene. Methylene-cyclohexane has been reported to react with a variety of group 4 and group 5 hydroaminoalkylation catalysts; Ta(NMe2)5, TaMe3Cl2 and 1.16 can all catalyze this reaction to give products in good yields, while titanium catalysts 1.1 and TiBn4 give modest yields.30, 43, 47, 54, 70 Norbornene, containing a highly strained internal alkene, reacts with catalysts that are otherwise unreactive with internal alkenes.  37  Catalysts reported to be active with this substrate generally give the alkylated product in good to excellent yields and the one catalyst reported to give a poor yield, the sulfamide bridged titanium complex 1.7, gives a 2:1 mixture of mono- and di-alkylated amine. 30, 43, 46-47, 52, 54, 56, 65, 69, 72, 74-75, 78  Scheme 1.47 Synthesis of β-alkylated and β-quaternary center amines though hydroaminoalkylation One catalyst to note for the hydroaminoalkylation of norbornene is scandium catalyst 1.1. This catalyst has been demonstrated to catalyze the hydroaminoalkylation of norbornene with a variety of trialkylamines with very good to excellent yields (Scheme 1.48).51 Dicyclopentadiene, a norbornene analogue, was also shown to react, with complete selectivity for the strained tricyclic alkene over the monocyclic alkene. Interestingly, hydroaminoalkylation of norbornene with N,N-dimethyladamantylamine not only  led to alkylation at one of the methyl groups, but also resulted in alkylation at a β-carbon of the adamantyl group.  38   Scheme 1.48 Hydroaminoalkylation of norbornene with trialkylamines using scandium hydroaminoalkylation catalyst 1.1 1.2.5.1 Titanium Catalysts Beyond the catalysts reported to be active with methylenecyclohexane and norbornadiene, complex 1.4 is capable of utilizing a variety of internal and gem-disubstituted alkenes, including α- and β-methylstyrenes, indene, and non-strained cyclic alkenes.50 The authors also demonstrate reactivity of both α- and β-methylstyrene with a variety of amines, exhibiting excellent regioselectivity but with highly variable yields (Scheme 1.49). Unfortunately, this catalyst is sensitive to steric bulk, requiring the alkene to either be cyclic or have one substituent as a methyl group in order for the reaction to proceed. In addition, high reaction temperatures and long reaction times (180 °C for 4 days) are required for most substrates.  39   Scheme 1.49 Synthesis of β-alkylated and β-quaternary center amines using titanium formamidinate catalyst 1.4 1.2.5.2 Tantalum Catalysts Compared to titanium, more success has been achieved for the synthesis of β-alkylated and β-quaternary center amines through the use of tantalum hydroaminoalkylation catalysts. A few catalysts have been demonstrated to work with a limited selection of internal and gem-disubstituted alkenes, beyond the privileged methylenecyclohexane and norbornene (Scheme 1.50). Tantalum amidate catalyst 1.12 is capable of reacting 1,5-cyclooctadiene, to give the monoalkylated product with good yields albeit with high temperatures and long reaction times.65-66 In contrast, 1.5 is capable of alkylating para-substituted N-methylanilines and N-methylcyclohexylamine with norbornadiene to give the exo-product selectively.46 Such aniline products are suitable monomers for the synthesis of amine-containing polymers utilizing Grubbs’ second-generation catalyst.3, 46 Ta(NMe2)5 was initially reported by Herzon and Hartwig for the alkylation of N-methylaniline with 2-methyl-1-hexene, and Doye and co-workers later demonstrated the same reaction with p,α-40  dimethylstyrene. Both reactions were completed with high yields and regioselectivities for branched product.30, 53  Scheme 1.50 Hydroaminoalkylation of 2,2-disubstituted and cyclic alkenes with various tantalum catalysts Notably, all tantalum catalysts capable of synthesizing β-alkylated products from unstrained internal alkenes include a halide ancillary ligand. As mentioned previously, halide-containing tantalum catalysts exhibit improved reactivity (Scheme 1.51). Using TaMe3Cl2, these reactions require long reaction times (1-6 days) with variable yields.70 Notably, this is the only catalyst to be reported for reactivity with a tri-substituted alkene; N-methylaniline reacts with 2-methyl-2-butene in 16% yield.  41   Scheme 1.51 Synthesis of β-alkylated amines, β-quaternary center amines, and the only instance of β,β-dialkylated amines though TaMe3Cl2-catalyzed hydroaminoalkylation  Building upon the reactivity of chloride-containing tantalum catalysts, Schafer and co-workers developed 1.13-Cl, an analogue of 1.13 that is capable of alkylating N-methylamines with a variety of cyclic and acyclic internal alkenes in good to excellent yields without any observed C=C bond migration or isomerization (Scheme 1.52).28-29 E-alkenes are more reactive with this catalyst than Z-alkenes, but this trend reverses with β-methylstyrenes. Unfortunately, this catalyst requires high reaction temperatures and long reaction times. When unsymmetrically-substituted internal alkenes are used, regioselectivity remains a challenge.67  Scheme 1.52 Synthesis of β-alkylated and β-quaternary center amines though the use of tantalum pyridonate catalyst 1.13-Cl  While developing the highly active 1.14 catalyst, Schafer and co-workers discovered that by making a minor change to the ureate ligand, the resulting catalyst system, 1.19, shows good 42  activity towards cyclic and acyclic internal alkenes (Scheme 1.53).72 However, while this catalyst can be used under less forcing conditions than 1.13-Cl, it has a narrower substrate scope in terms of both amine and alkene substrates.   Scheme 1.53 Synthesis of β-alkylated amines using in-situ generated tantalum ureate catalyst system 1.19 1.2.6 Synthesis of N-Heterocycles via Sequential Procedures N-heterocycles are very common motifs found in natural products, pharmaceuticals, and other high-value chemicals.82 As most hydroaminoalkylation catalysts produce secondary amines, subsequent cyclizations via C-N bond formation can produce selectively substituted N-heterocycles. The first of these procedures, hydroaminoalkylation/Buchwald-Hartwig amination, was reported by Schafer and co-workers for the synthesis of 3-methylindolines (Scheme 1.54).70 By coupling N-methylaniline with 2-bromostyrene using TaMe3Cl2, the authors produced an intermediate which can be cyclized via a Buchwald-Hartwig amination, yielding 3-methyl-N-phenylindoline in a one-pot procedure in good overall yield. This process has since been expanded upon by the Doye group, with multiple reports using titanium catalysts 1.4 or 1.8 to synthesize a variety of 6- and 7-membered N-heterocycles such as 1,4-benzoazasilines, 1,5-benzoazasilepines, and 1,5-benzodiazepines in moderate to good yields (Scheme 1.55). 43   Scheme 1.54 Synthesis of 3-methyl-N-phenylindoline through a one-pot hydroaminoalkylation/Buchwald-Hartwig amination  Scheme 1.55 Synthesis of 1,5-benzodiazepines, 1,5-benzoazasilepines, and 1,4-benzoazasilines through one-pot hydroaminoalkylation/Buchwald-Hartwig aminations Fully saturated N-heterocycles have also been synthesized through sequential hydroaminoalkylation/cyclization reactions. Schafer and co-workers reported that tantalum amidate catalyst 1.12 can be used to synthesize silyl-protected aminoalcohols.78 These products can be deprotected, converted into amino tosylates, and cyclized to the corresponding β-methyl-N-heterocycles in a single step using tosyl fluoride. The authors demonstrated this reaction sequence as a single pot-synthesis, achieving moderate to good yields for all steps (Scheme 1.56).  44   Scheme 1.56 Synthesis of β-methylated unsaturated N-heterocycles through hydroaminoalkylation of silyl-protected alcohol-functionalized alkenes and subsequent one-pot deprotection/cyclization 1.3 Scope of Thesis The research presented in this thesis is focused on the development of early transition metal catalysis as a set of tools for use in the atom economic synthesis of amines. This involves two major themes that are present throughout the thesis: development of practical methods and synthesis of value-added chemicals. These themes are presented through the development and use of synthetic methods for tantalum-catalyzed hydroaminoalkylation (Chapters 2-4) and for titanium-catalyzed hydroamination (Chapter 5). In each of these chapters, early transition metal catalysts are utilized for the synthesis of reactive intermediates, which can then be further reacted to form new materials (Chapter 2) or heterocycles (Chapters 3-5), which can be further utilized as building blocks for commercially relevant molecules. Chapter 2 is work that was part of an ongoing project in the Schafer research group to utilize hydroaminoalkylation and ring opening metathesis polymerization to generate amine containing polymers. A variety of (aminomethyl)norbornenes were synthesized, with specific focus on modulating the electronic environment of the amine substrate. A brief study of the effects of the steric environment of the amine substrate was also performed. The hydroaminoalkylation reaction was then optimized to facilitate the gram scale synthesis of the (aminomethyl)norbornenes, taking into account different side reactions that occurred and inhibited the reaction yields. 45   Inspired by the difficulty in synthesizing and handling the hydroaminoalkylation catalyst in chapter 2, an in-situ generated tantalum pyridonate hydroaminoalkylation catalyst was developed in chapter 3. This catalyst system utilizes stock solutions of commercially available starting materials and can be utilized outside of an inert atmosphere glovebox using syringe techniques. The substrate scope of the catalyst was explored, and optimization the reaction and catalyst for challenging substrates was attempted. The effect of changing the electronic environment of the pyridonate ligand on the catalyst activity was then explored. Finally, this new method was used for the synthesis of poly-substituted piperidines, which could be utilized as building blocks for pharmaceutically relevant compounds. By considering the catalyst activation in the initial steps of a hydroaminoalkylation reaction, a new catalytic method for this reaction was developed in chapter 4. This method utilizes tantalum pentafluoride as the tantalum precursor and forms the active catalyst through addition of methyl lithium. This method can also be utilized outside of an inert atmosphere glovebox and can be used to synthesize a precursor to tetrahydroquinolines, a class of N-heterocycles that had not been previously accessed through hydroaminoalkylation. An NMR study of the catalyst formation was performed, and the stability of tantalum pentafluoride towards storage outside of an inert atmosphere was probed. Hydroaminoalkylation is not the only atom economic method for the synthesis of structurally diverse amines. In chapter 5, a method for the asymmetric synthesis of 1,4-benzoxazines via hydroamination, the addition of an N-H bond across a C-C unsaturation, followed by asymmetric transfer hydrogenation. This method is a one-pot sequential process to yield pharmaceutically relevant compounds from readily accessible starting materials. A major 46  byproduct of this reaction was isolated and characterized, but a rigorous structural determination was unsuccessful. This thesis explores the development of practical methods for using early transition metal catalysts for the atom economic synthesis of amines. All major research findings are summarized in chapter 6, and ideas for further research in these projects are proposed. 47  Chapter 2: Tantalum Phosphoramidate-Catalyzed Hydroaminoalkylation for the Synthesis of Amine-Substituted Norbornenes 2.1 Introduction 2.1.1 Amine-Containing Polymers While being commonly found in pharmaceuticals, agrochemicals, and other industrial uses, amines are not often incorporated into synthetic polymers due to the difficulty of synthesizing these materials.83 Indeed, the six most common polymers used commercially do not include amine functional groups (Figure 2.1).84 Polymers that incorporate amine functional groups generally are used in specialized applications, such as gas scrubbing, antimicrobial materials, and plastic compatibilizers.85-87   Figure 2.1 Six predominant synthetic polymers used commercially Amine-containing polymers can be broadly classified into two different types: backbone amine-containing polymers and pendent amine-containing polymers (Figure 2.2). Backbone amine-containing polymers, such as polyethylenimine, polyaniline, and various epoxy resins, are polymers that contain amine functional groups in the polymer backbone and are generally used for industrial applications, such as gas scrubbing and adhesives.85, 88-89 Pendent amine-containing 48  polymers are more specialized materials that contain amine functional groups as part of pendent groups, and have been used as antimicrobial materials, plastic compatibilizers, and heterogeneous organocatalysts.86-87, 90-92  Figure 2.2 Examples of Backbone and Pendent Amine-Containing Polymers One important class of pendent amine-containing polymers is poly(norbornene)-based pendant amine-containing polymers. Produced through the ring opening metathesis polymerization (ROMP, scheme 2.1) of amine-substituted norbornenes (Scheme 2.2), these polymers have been studied for use as antimicrobial and cell adhesive materials.86, 93-94 However, the synthesis of these polymers is often synthetically challenging, often requiring either the use of protecting groups and post-polymerization modifications that are difficult to control in order to prevent amine-mediated catalyst degradation, or the use of highly air and moisture sensitive molybdenum ROMP catalysts.86, 95-96 In 2013, Dr. Mitch Perry demonstrated the ability of Grubbs’ 2nd Generation olefin metathesis catalyst to polymerize 2.1 without the need for protecting groups or post-polymerization modification (Scheme 2.2). This represented a new class of arylamine-containing polymers. Given the potential applications of such polymers, an efficient method for synthesizing the monomers was required.3 49   Scheme 2.1 Synthesis of poly(norbornene)s through ROMP  Scheme 2.2 Synthesis of 2.2 through ROMP of 2.1 2.1.2 Synthesis of Amine-Substituted Norbornenes Amine-substituted norbornenes have found use as not only monomers, but for use in the synthesis of molecules with various biological applications.97-99 One of the earlier methods utilized for accessing amine-functionalized norbornenes was through a Diels-Alder cycloaddition between cyclopentadiene and a protected amine-containing dienophile, such as 2.3, to generate protected amine-substituted norbornenes endo-2.4 and exo-2.4, which had to be subsequently deprotected to yield the free aminonorbornene (Scheme 2.3).100-102 While this method is a reliable route towards the synthesis of amine-substituted norbornenes, the requirement of the use of protected amines in order to generate a suitable dienophile adds additional synthetic steps and lowers the atom efficiency of the process. The other predominant method that has been used for the synthesis of amine-substituted norbornenes is coupling with prefunctionalized norbornenes, such as the 50  synthesis of 2.6 using benzylamine and ketone 2.5, but this often requires multi-step syntheses, as the norbornene starting material may not always commercially available.103-104  Scheme 2.3 Traditional methods for synthesizing amine-substituted norbornenes The Diels-Alder cycloaddition approach to the synthesis of aminomethyl-substituted norbornenes, such as 2.1, is possible through the cycloaddition of cyclopentadiene with acrolein to generate norbornene carboxaldehyde, followed by a subsequent reductive amination with 4-methoxyaniline to generate the product 2.1 (Scheme 2.4). Indeed, this method has been utilized for the synthesis of aminomethyl-substituted norbornenes using commercially available norbornene carboxaldehyde.105 This method suffers from poor selectivity for the endo vs. exo products, as commercially available norbornene carboxaldehyde is primarily sold as a mixture of isomers. 51   Scheme 2.4 Synthesis of aminomethyl-substituted norbornenes through a Diels-Alder cycloaddition to synthesize norbornene carboxaldehyde followed by a reductive amination An alternative method for the synthesis of amine-functionalized norbornenes was published by Garcia et al. in 2013.46 Mono-hydroaminoalkylation of commercially available norbornadiene with 4-methoxy-N-methylaniline using the tantalum phosphoramidate catalyst 2.7 allows for the atom economic and exo-selective synthesis of 2.1 (Scheme 2.5), which can then be polymerized using Grubbs’ 2nd Generation olefin metathesis catalyst as noted above (Scheme 2.2).3 The unprecedented room temperature activity of this catalyst presents the opportunity to easily produce a wide array of amine-substituted norbornenes, which could then be polymerized to produce different amine-containing poly(norbornenes). However, the substrate scope of amine-substituted norbornenes reported by Garcia et al. was restricted to the single, unoptimized example of 2.1. To access a wide array of amine-substituted norbornenes, a better understanding of the amine substrate scope for this catalytic transformation was required. 52   Scheme 2.5 Synthesis of amine-substituted norbornenes through hydroaminoalkylation with 2.7 2.1.3 Scope of Chapter This chapter explores the expansion of the substrate scope of known catalyst 2.7, as well as the optimization of the hydroaminoalkylation of norbornadiene with N-methylaniline. Para-substituted-5-aminomethylnorbornenes were synthesized through the hydroaminoalkylation of norbornadiene with a variety of 4-substituted-N-methylanilines, as well as N-methylcyclohexylamine to show that 2.7 exhibits high sensitivity to the electronic environment of the amine. The catalytic hydroaminoalkylation of 1-octene with 2.7 was attempted using various 4-methoxy-N-alkylanilines. Finally, the hydroaminoalkylation of norbornadiene with N-methylaniline, catalyzed by catalyst 2.7, was optimized. 2.2 Results and Discussion 2.2.1 Expansion of Tantalum Phosphoramidate Precatalyst Substrate Scope While the room temperature reactivity of 2.7 allows it to be used for the hydroaminoalkylation of temperature sensitive substrates, the initial reported substrate scope was limited in the scope of amines, utilizing primarily electron-rich N-methylanilines.46 Given the potential usefulness of products that can be accessed from this reaction, it was deemed necessary 53  to explore the scope of amines that are compatible with this catalyst. To this end, a variety of 4-substituted-N-methylanilines were tested for reactivity with 2.7 and norbornadiene (Table 2.1). While all substrates tested are useful substrates, there are some notable trends. Catalyst activity appears to be strongly influenced by the electronic nature of the amine substrate: electron-rich 4-methoxy-N-methylaniline and N-methylcyclohexylamine exhibit the highest reactivity and can react at room temperature, while more electron-deficient substrates require elevated temperatures to observe significant conversion. However, in all cases the reaction gave only moderate to poor yields, with significant amounts of the amine starting material remaining. It was hypothesized that the low conversions were simply due to quenching the reaction before they were finished, but running the reaction for five days showed no increase in yield. This indicates that the low yields were due to catalyst deactivation prior to reaction completion.  54  Table 2.1 Substrate scope of hydroaminoalkylation of norbornadiene with various amines using 2.7  While the original report on precatalyst 2.7 shows activity with a number of methyl-substituted aliphatic and aromatic amines, it also demonstrates activity with di-n-butylamine to yield α-alkylated-β-methylated amines, albeit with low conversion.46 Given the importance of selectively substituted amines, exploring the scope of such substrates was also targeted. Three different N-alkylated-4-methoxyaniline substrates were synthesized and tested with 1-octene as the coupling partner (Scheme 2.6), but none of them were competent substrates for use with 2.7 These observations are consistent with the conclusion of Garcia et al. that limited steric bulk on amine is tolerated.46 55   Scheme 2.6 Failed hydroaminoalkylation with non-methylated amines 2.2.2 Optimization of Monomer Synthesis While a number of different N-substituted 5-aminomethylnorbornenes can be synthesized through hydroaminoalkylation catalyzed by 2.7, the conditions utilized by Garcia et al. were not optimized for the use of norbornadiene as a substrate.46 As such, the hydroaminoalkylation of norbornadiene with 4-methoxy-N-methylaniline using this catalyst was only reported to proceed up to 50% isolated yield with complete selectivity for the exo-product, and the use of less activated amines gave lower yields (Scheme 2.7). Given the utility of these compounds for the synthesis of amine containing polymers, it was necessary to develop optimized conditions for these reactions.  Scheme 2.7 Effect of amine electronic environment on the hydroaminoalkylation of norbornadiene Two side reactions that result in lower yields were immediately identified: dialkylation of norbornadiene and formation of poly(norbornadiene) (Scheme 2.8). N-Substituted-5-aminomethylnorbornenes, due to the strained internal alkene of the norbornene moiety, are competent substrates for hydroaminoalkylation. As the concentration of aminomethyl-norbornene 56  product 2.9 increases as the reaction progresses, the rate of the unwanted second hydroaminoalkylation reaction increases, producing 2.12 and decreasing the yield of the desired mono-hydroaminoalkylated product. In addition, 2.7 is a competent initiator for the polymerization of norbornadiene at higher temperatures, leading to a significant decrease in norbornadiene concentration as the reaction progresses, and the formation of an intractable gel that hampers product isolation.106-107   Scheme 2.8 Observed side reactions With this in mind, efforts were made towards the optimization of this reaction (Table 2.2). Reactions were monitored by 1H NMR spectroscopy. Yield of 2.9 was calculated through the integration of the olefinic peak at 5.96 ppm relative to the 1,3,5-trimethoxybenzene internal standard. The yield of 2.12 was calculated through subtracting the yield of 2.9 from the integration of the ortho-proton peak of both 2.9 and 2.12 (the peaks overlap at 6.44 ppm). Remaining N-methylaniline was calculated through the integration of the ortho-proton peak at 6.35 ppm relative to the internal standard. As expected, increasing the reaction temperature led to an increase in conversion (Entries 1-5). However, the yield of the desired product 2.9 was maximized at 52% yield at 50 °C (Entry 3), with higher reaction temperatures exhibiting increased yields of 2.12 (Entries 4-5). 60 °C was picked for further experiments, as isolation of 2.9 from remaining N-57  methylaniline proved to be more challenging than separating 2.9 from 2.12. Decreasing the concentration of the reaction led to an overall decrease in conversion (Entries 6-8). While decreasing the equivalents of norbornadiene still allowed for full conversion of N-methylaniline (Entry 9), it also led to a slight decrease in the yield of 2.9, possibly due to incorporation of 2.9 into the poly(norbornadiene) formed in the reaction. Increasing the equivalents of norbornadiene les to a significant increase in the formation of poly(norbornadiene) (Entries 10-11) and gave a solid reaction mixture at the end of 20 hours as an intractable gel. When the equivalents of norbornadiene were high enough (Entry 11), yields of both 2.9 and 2.12 were suppressed. Varying of the reaction time was not explored, as previous experiments had shown that, at room temperature, maximum yield was achieved by 20 hours and continuing the reaction beyond that point did not lead to increased yields.         58  Table 2.2 Optimization of the hydroaminoalkylation of norbornadiene with N-methylaniline  Entry Temp. (°C) Conc. (M)a Equiv. Norbornadiene Unreacted Aniline (%).b Yield of 2.9 (%)c Yield of 2.12 (%)d 1 30 1 1.5 56 17 5 2 40 1 1.5 36 22 7 3 50 1 1.5 10 52 15 4 60 1 1.5 N.D. 45 (44) 27 5 70 1 1.5 N.D. 45 18 6 60 0.5 1.5 10 36 18 7 60 0.1 1.5 65 17 3 8 60 0.05 1.5 59 8 3 9 60 1 1.1 N.D. 39 (34) 25 10 60 1 2.0 N.D. 50 (45) 17 11 60 1 5.0 N.D. 28 5 aConcentration relative to N-methylaniline bCalculated through NMR spectroscopy, using 1,3,5-trimethoxybenzene as an internal standard. N.D. = not detected. cParentheses indicate isolated yields, others obtained through NMR spectroscopy relative to 1,3,5-trimethoxybenzene as an internal standard. dCalculated through NMR spectroscopy  Previous studies had indicated that omission of an external solvent leads to a suppression of the yield of 2.12.108 As such, a few reaction conditions were examined without an external solvent (Table 2.3). At room temperature, the reaction exhibits minimal increases in yields for increasing equivalents of norbornadiene (Entries 1-2). At 60 °C (Entries 3-5), the reaction mixture solidifies after 20 hours due to formation of poly(norbornadiene), but the yield of 2.9 increases significantly, with a maximum yield of 75% obtained using five equivalents of norbornadiene 59  (Entry 5). As further increasing the equivalents of norbornadiene was considered undesirable due to increasing waste and difficulty in isolating 2.9 from the poly(norbornadiene) gel, five equivalents of norbornadiene with no external solvent at 60 °C were the optimized conditions. Table 2.3 Optimization of the solvent-free hydroaminoalkylation of norbornadiene with N-methylaniline  Entry Temp. (°C) Equiv. Norbornadiene Unreacted Aniline (%).a Yield of 2.9 (%)b Yield of 2.12 (%)c 1 rt 2.0 52 23 6 2 rt 5.0 56 20 5 3 60 1.5 N.D. 42 13 4 60 2.0 N.D. 59 20 5 60 5.0 N.D. 75 12 aCalculated through NMR spectroscopy, using 1,3,5-trimethoxybenzene as an internal standard. N.D. = not detected. bYields obtained through NMR spectroscopy relative to 1,3,5-trimethoxybenzene as an internal standard. cCalculated through NMR spectroscopy  2.3 Conclusions The substrate scope of 2.7 has been further explored, with both the steric and electronic environments of the amine probed. While 2.7 is not suitable for substrates with steric bulk at the reactive carbon, it can tolerate more electron-withdrawing substrates on the amine. These substrates require more forcing conditions. The optimization of the hydroaminoalkylation of norbornadiene with N-methylaniline was also performed. While 100% yield was not obtained due to competing side reactions, optimized conditions of five equivalents of norbornadiene at 60 °C with no added solvent gave the highest yield of 75%. This work lead to an expansion of the scope 60  of pendent amine-containing polynorbornenes synthesized by other members of the Schafer research group.3 2.4 Experimental 2.4.1 Materials and Methods General Experimental. All air and moisture sensitive reactions were setup in a MBraun LABMaster glovebox under N2 atmosphere or on a Schlenk double manifold with N2 and high-vacuum (10-3 mbar). Glassware was heated in an oven to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Stirring was done with appropriately sized stir bars, heated to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Toluene was passed over activated alumina columns into Teflon-sealed Straus flasks, degassed via 3 freeze-pump-thaw cycles, brought into the glovebox, and stored over 4 Å molecular sieves. d8-toluene was refluxed in a sodium still overnight, degassed through 3 freeze-pump-thaw cycles and stored in a Teflon sealed bomb. Dryness of the toluene and d8-toluene was confirmed through the addition of 2 drops of benzophenone ketyl in THF. Reactions that were monitored via NMR were performed in J-Young NMR tubes (8” x 5mm or 9” x 5mm) with Teflon caps. Flash chromatography was performed on a Biotage Isolera Flash Chromatography system using 10g columns, with both hexanes and ethyl acetate spiked with 0.1% (v/v) triethylamine. Reverse-phase flash chromatography was performed on a Biotage Isolera One Flash Chromatography system with a 30g Biotage KP-C18-HS SNAP column and mobile phase of 0.1% v/v formic acid in deionized water and 0.1% v/v formic acid in acetonitrile Materials Precatalyst 2.7 was synthesized according to literature procedures and stored in an inert atmosphere glovebox freezer in a foil-lined vial.46 All methylated substrates for hydroaminoalkylation were purchased from commercial sources and either distilled over calcium 61  hydride and degassed or sublimed prior to use. Norbornadiene and 1-octene were purchased from commercial sources and distilled over calcium hydride prior to use. 1,3,5-trimethoxybenzene was purchased from commercial sources and sublimed prior to use. Instrumentation. Flash chromatography was performed on a Biotage Isolera Flash Purification system, using repacked 10g flash chromatography columns. 1H and 13C NMR spectra were obtained on either a Bruker 300 MHz Avance or a Bruker 400 MHz Avance spectrometer at ambient temperature. Chemical shifts are given relative to the corresponding residual proteo solvent, and are reported in parts per million. Coupling constants are reported in Hertz. Abbreviations used to indicate signal multiplicity are as follows: s = single, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, br = broad. Infrared (IR) spectra were obtained from neat samples using a PerkinElmer Frontier FT-IR spectrometer with an ATR sampling accessory. High-resolution mass spectra were measured by the University of British Columbia, Department of Chemistry Mass Spectrometry and Microanalysis Service on a Waters Micromass LCT, utilizing electrospray ionization. GC/MS analyses were conducted on an Agilent 7890B GC with an Agilent 5977 inert CI mass detector, utilizing methane as the ionization gas Safety Considerations. Precatalyst 2.7 and the TaMe3Cl2 precursor, is light sensitive, O2 sensitive, moisture sensitive, and highly pyrophoric. Synthesis, handling, and use of these complexes should be done under inert atmosphere. All hydroaminoalkylation reactions in this chapter were performed in sealed reaction vessels; reactions performed at elevated temperatures should be performed in glassware designed for use with elevated pressures and behind appropriately-rated blast shields. Toxicological profiles of many of the starting materials and products are not known, and appropriate precautions should be taken during the handling of these compounds. 62  2.4.2 Synthesis and Characterization of Compounds 2.4.2.1 Experimental Procedures Method A: Synthesis of Non-Methyl Hydroaminoalkylation Substrates To a solution of freshly sublimed p-anisidine (2 g, 1.62 mmol, 1.0 equiv.) in methanol (64 mL was added the corresponding aldehyde or ketone (16.2 mmol, 1.0 equiv.), and the solution was stirred for 3 hours or until full conversion to the Schiff base was observed through GC/MS. Sodium borohydride (25.6 mmol, 1.6 eqv.) was then added portionwise before stirring at room temperature for 15 minutes. The reaction was then quenched with 1M KOH (100 mL) and extracted 3 times with 50 mL diethyl ether. The combined organic phases were then washed 3 times with 100 mL brine, dried over MgSO4, and concentrated in vacuo to yield a crude solid. Recrystallization with hot MeOH/H2O yielded pure product. Method B: Room Temperature Hydroaminoalkylation To a vial containing 2.7 (25.8 mg, 0.05 mmol) in an inert-atmosphere glovebox and a darkened room was added toluene (0.5 mL, excluded for solvent-free reactions), amine (0.5 mmol), and alkene (0.75 mmol), and the solution was capped and left to stir at room temperature for 20 hours with the light being turned on after reaction setup. Upon reaction completion, the reaction was removed from the glovebox, diluted with 10 mL hexanes, washed with 10 mL each saturated sodium bicarbonate solution, DI water, and brine. The organic phase was then dried over MgSO4 and concentrated. Crude products were purified either through normal phase flash chromatography or reverse phase flash chromatography followed by basification with 1M NaOH extraction with ethyl acetate, and concentration of the organic phase to yield the given product. Method C: High Temperature Hydroaminoalkylation 63  To a J-young tube containing 2.7 (25.8 mg, 0.05 mmol) in an inert-atmosphere glovebox and a darkened room was added a given volume of toluene (excluded for solvent-free reactions), amine (0.5 mmol), and norbornadiene (69.1 mg, 0.75 mmol), and reaction was sealed, removed from the glovebox, and heated at the given temperature for 20 hours, with the light being turned on after reaction setup. Upon reaction completion, the reaction was diluted with 10 mL hexanes, washed with 10 mL each saturated sodium bicarbonate solution, DI water, and brine. The organic phase was then dried over MgSO4 and concentrated. Crude products were purified either through normal phase flash chromatography or reverse phase flash chromatography followed by basification with 1M NaOH extraction with ethyl acetate, and concentration of the organic phase to yield the given product. Method D: Hydroaminoalkylation Optimization To a J-young tube containing 2.7 (25.8 mg, 0.05 mmol) in an inert-atmosphere glovebox and a darkened room was added a given volume of d8-toluene (excluded for solvent-free reactions), N-methylaniline (53.6 mg, 0.5 mmol), norbornadiene (69.1 mg, 0.75 mmol), and 1,3,5-trimethoxybenzene (84.1 mg, 0.5 mmol), and reaction was sealed, removed from the glovebox, and heated at the given temperature for 20 hours, with the light being turned on after reaction setup. Upon reaction completion, solvent-free reactions were diluted with d8-toluene (0.5 mL), and the reactions were analyzed with 1H NMR spectroscopy. Yield of 2.9 was determined through the integration of the olefinic peak (5.96 ppm) relative to the 1,3,5-methoxybenzene internal standard, % aniline remaining was determined through the integration of the ortho-proton peak of N-methylaniline (6.35 ppm), and yield of 2.12 was determined through integration of the ortho-proton peak of the products (2.9 and both regioisomers of 2.12, 6.44 ppm) relative to the internal standard and subtraction of the yield of 2.9. 64  2.4.2.2 Compound Characterization 2.4.2.2.1 Non-Methyl Hydroaminoalkylation Substrates  4-Methoxy-N-cyclohexylaniline Synthesized via Method A using cyclohexanone (1.68 mL, 16.2 mmol). Isolated as a white solid (2.21 g, 10.9 mmol, 67% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.04 - 1.44 (m, 5 H) 1.65 (dt, J=11.82, 4.03 Hz, 1 H) 1.76 (dt, J=12.79, 3.43 Hz, 2 H) 1.98 - 2.12 (m, 2 H) 3.10 - 3.23 (m, 1 H) 3.75 (s, 3 H) 6.56 - 6.63 (m, 2 H) 6.74 - 6.81 (m, 2 H); 13C NMR (75.48 MHz, CHLOROFORM-d), δ ppm 25.3, 26.2, 33.8, 53.1, 56.0, 115.08, 115.14, 141.6, 152.1  4-Methoxy-N-isopropylaniline Synthesized via Method A using acetone (1.29 mL, 16.2 mmol). Isolated as a white solid (1.62 g, 10.2 mmol, 63% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ1.19 (d, J=6.3 Hz, 6H), 3.54 (m, 1H), 3.75 (s, 3H), 6.58 (d, J=9.1 Hz, 2H), 6.77 (d, J=9.1Hz, 2H); 13C NMR (75.48 MHz, CHLOROFORM-d) δ ppm 23.0, 45.9, 55.9, 115.0, 115.6, 141.2, 152.5 65   4-Methoxy-N-benzylaniline Synthesized via Method A using benzaldehyde (1.65 mL, 16.2 mmol). Isolated as a white solid (2.58 g, 12.3 mmol, 76% yield), characterization data matches known literature values. 1H NMR (300 MHz, CDCl3) δ ppm 3.76 (s, 3 H) 4.31 (s, 2 H) 6.64 (dt, J=1.00 Hz, 2 H) 6.80 (dt, J=1.00 Hz, 2 H) 7.28 - 7.42 (m, 5 H); 13C NMR (75.48 MHz, CHLOROFORM-d), δ ppm 49.4, 55.9, 114.3, 115.0, 127.3, 127.7, 128.8, 139.7, 142.5, 152.4.   2.4.2.2.2 (N-Substituted-Aminomethyl)-5-Norbornene Derivatives   N-(bicyclo[2.2.1]hept-5-en-2-yl)methyl)-4-methoxyaniline (2.1) Synthesized via Method B using 4-methoxy-N-methylaniline (68.6 mg, 0.5 mmol) and norbornadiene (69.1 mg, 0.75 mmol) without toluene solvent. Isolated through flash chromatography as a colorless oil (53.8 mg, 0.25 mmol, 50% yield), characterization data matches known literature values. 1H NMR (300 MHz, CDCl3) δ ppm 1.17 - 1.45 (m, 4 H) 1.68 (dd, J=7.77, 4.34 Hz, 1 H) 2.73 (br. s., 1 H) 2.86 (br. s., 1 H) 3.09 (qd, J=11.84, 7.65 Hz, 2 H) 3.76 (s, 3 H) 6.06 - 6.14 (m, 2 H) 6.57 - 6.64 (m, 2 H) 6.76 - 66  6.84 (m, 2 H); 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 31.4, 39.2, 41.8, 44.6, 45.4, 50.8, 56.0, 114.1, 115.1, 136.6, 136.9, 143.0, 152.1.   N-((bicyclo[2.2.1]hept-5-en-2-yl)methyl)cyclohexanamine (2.8) Synthesized via Method B using N-methylcyclohexylamine (56.6 mg, 0.5 mmol) and norbornadiene (69.1 mg, 0.75 mmol) without toluene solvent. Isolated through flash chromatography as a colorless oil (63.7 mg, 0.31 mmol, 62% yield). 1H NMR (300 MHz, CDCl3) δ ppm 0.96 - 1.33 (m, 10 H) 1.44 - 1.54 (m, 1 H) 1.54 - 1.64 (m, 1 H) 1.65 - 1.76 (m, 2 H) 1.80 - 1.91 (m, 2 H) 2.38 (tt, J=10.36, 3.68 Hz, 1 H) 2.55 - 2.71 (m, 3 H) 2.77 (br. s., 1 H) 5.98 - 6.09 (m, 2 H) 13C NMR (75 MHz, CHLOROFORM-d), δ ppm 25.3, 26.4, 31.7, 33.8, 33.9, 39.7, 41.8, 44.8, 45.4, 53.1, 57.3, 136.6, 136.9. IR(1/CM): 3059, 2926, 2853, 1449; High-Res MS: Calculated: 206.1909 (M+1), Found: 206.1907 (M+1, C14H24N)   N-((bicyclo[2.2.1]hept-5-en-2-yl)methyl)aniline (2.9) Synthesized via Method C using N-methylaniline (53.6 mg, 0.5 mmol) and norbornadiene (69.1 mg, 0.75 mmol) at 70 °C in toluene (0.5 mL). Isolated through reverse phase flash chromatography as a colorless oil (42.8 mg, 0.21 mmol, 43% yield). 1H NMR (300 MHz, CDCl3) δ ppm 1.21 - 1.29 (m, 1 H) 1.30 - 1.43 (m, 3 H) 1.66 - 1.78 (m, 2 H) 2.77 (d, J=1.37 Hz, 1 H) 2.86 (br. s.,1 H) 3.09 - 3.25 (m, 2 H) 6.04 - 6.10 (m, 2 H) 6.80 - 6.88 (m, 3 H) 7.19 - 7.26 (m, 2 H); 13C NMR (75 MHz, CHLOROFORM-d), δ ppm 67  31.4, 39.1, 41.8, 44.6, 45.4, 49.7, 112.8, 117.3, 129.4, 136.6, 136.9, 148.5; IR(1/cm): 3416, 3054, 2961, 1601, 1504; High-Res MS: Calculated: 200.1439 (M+1), Found: 200.1441 (M+1, C14H18N)   N-((bicyclo[2.2.1]hept-5-en-2-yl)methyl)-4-bromoaniline (2.11) Synthesized via Method C using 4-bromo-N-methylaniline (93.0 mg, 0.5 mmol) and norbornadiene (69.1 mg, 0.75 mmol) at 70 °C in toluene (0.5 mL). Isolated through reverse phase flash chromatography as a light brown oil (27.8 mg, 0.10 mmol, 20% yield) 1H NMR (300 MHz, CDCl3) δ ppm 1.17 - 1.29 (m, 1 H) 1.31 - 1.44 (m, 3 H) 1.57 (br. s., 1 H) 1.61 - 1.73 (m, 1 H) 2.71 (s, 1 H) 2.87 (br. s., 1 H) 3.00 - 3.18 (m, 2 H) 3.75 (br. s., 1 H) 6.06 - 6.14 (m, 1 H) 6.46 - 6.53 (m, 2 H) 7.21 - 7.29 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d), δ ppm 31.2, 38.9, 41.7, 44.4, 45.2, 49.5, 108.6, 114.2, 131.9, 136.3, 136.8, 147.4.; IR(1/cm): 3417, 3343, 2964, 1595, 1497; High-Res MS: Calculated: 278.0544 (M+1), Found: 278.0544 m/z (M+1, C14H17BrN)   68  Chapter 3: Development of an In-situ Generated Tantalum Pyridonate Hydroaminoalkylation Catalyst 3.1 Introduction 3.1.1 Practical Limitations of Hydroaminoalkylation While early transition metal-catalyzed hydroaminoalkylation is a potentially powerful tool for the synthesis of structurally diverse amines, it suffers from a number of practical challenges that limit its utility. The first of these challenges is that, except for one report by Doye and co-workers (Scheme 3.1), all of the reports utilize isolated catalysts.47 These catalysts, in general, exhibit high sensitivity to oxygen and moisture, and utilizing them as isolated materials necessitates the use of Schlenk or glove-box techniques. In addition, the synthesis, isolation, and storage of these catalysts requires appropriate equipment and techniques. Also, catalyst synthesis adds additional steps to the overall pathway towards a target molecule. These limitations present barriers for exploratory synthetic pathways that propose the use of hydroaminoalkylation.  Scheme 3.1 In-situ hydroaminoalkylation using a 2-methylaminopyridinate titanium catalyst system The second practical challenge is that most early transition metal hydroaminoalkylation catalysts require the use of materials that may not be commercially available. While the M(NMe2)x starting materials can be obtained from a number of vendors, other reported metal starting materials, such as Me3TaCl2, must be synthesize prior to use.46, 51, 70, 72, 77 Most ligands utilized as 69  hydroaminoalkylation catalysts are similarly not commercially available, and can require up to 4 steps to synthesize.67 As the reactivity and substrate scope of hydroaminoalkylation catalysts can be highly dependent on the ligand environment around the metal center, ligand synthesis can present a barrier against utilization of these catalysts for those without a pre-made ligand library. Given the potential value of hydroaminoalkylation as a synthetic methodology, the development of a catalyst system that could be generated in situ utilizing commercially available starting materials was targeted as a strategy for making this reaction more accessible to the wider synthetic community. 3.1.2 Substituted 2-Pyridonates as Ligands for Hydroaminoalkylation Early work by Hartwig et. al. suggested that the use of electron-withdrawing ligands, such as halides, lead to increased activity of the resulting metal catalyst, which they demonstrated through the comparison of 3.1 with the more active 3.4 (Figure 3.1).64 Since this report, the Schafer research group has supported this hypothesis through the use 1,3-N,O-chelating ligands; not only does replacement of amido ligands with halides or alkyl ligands lead to increased catalytic activity, but moving from the amidate ligand in 3.2 to a more electron-withdrawing phosphoramidate ligand in 3.5 also leads to an increase in catalytic activity, as measured by the temperature required to achieve catalysis.46, 64, 70 70   Figure 3.1 Reactivity Trend for Tantalum Hydroaminoalkylation Catalysts 2-Pyridonates are a logical step in the development of early transition metal catalysts, due to their increased electron-deficient nature relative to phosphoramidates.109 First used as ligands for the zirconium-catalyzed intramolecular hydroaminoalkylation catalyst 3.6 in 2009, they have since been shown to not only favor hydroaminoalkylation over hydroamination in intramolecular titanium catalysis, but also greatly improve the reactivity of intermolecular tantalum hydroaminoalkylation catalysts with unprecedented reactivity towards internal alkenes. (Scheme 3.2).67, 79, 81 A detailed mechanistic analysis of complexes with this class of ligand was performed by Dr. Jason Brandt, showing that variation of the substituents in the 3-position (3.8, 3.10, 3.11) allows for tuning of the reactivity for the hydroaminoalkylation of 1-octene with N-methylaniline, with less bulky ligands giving greater yields. Increasing the steric bulk at the 6-position (3.12, 3.13) also leads to an increase in reactivity (Scheme 3.3).68 However, an analysis of the effect of tuning the electronic environment of the pyridonate ligand was not performed, nor were the catalysts explored in extensive substrate scope.  71   Scheme 3.2 Pyridonate ligands in early transition metal hydroaminoalkylation 72   Scheme 3.3 Analysis of the effect of steric bulk on pyridonate ligands on hydroaminoalkylation 3.1.3 Scope of Chapter This chapter explores the development of an in-situ method for the generation and subsequent reaction of 2-pyridonate tantalum hydroaminoalkylation catalysts. A variety of N,O-chelate ligands have been screened with 3.2 for in-situ reactivity, and the identified reaction with 3-methyl-2-pyridone (3.21) as a ligand was optimized. The substrate scope of the catalyst system was then explored. The reaction with N-ethylaniline was optimized, both for reaction conditions and catalysts. The effect of electronically varied substituents on the 4 and 5 positions of the pyridonate ligands on the rate of the hydroaminoalkylation reaction were then determined. Finally, the novel reactivity of the catalyst system was utilized for the efficient synthesis of poly-methylated piperidines. 73  3.2 Results and Discussion 3.2.1 In-situ Screening and Optimization of Hydroaminoalkylation Catalysts As the use of isolated precatalysts has been identified as a limitation of previously reported catalyst systems for hydroaminoalkylation, a number of known catalytic systems were tested for in-situ reactivity towards the hydroaminoalkylation of 1-octene with N-methylaniline. As the eventual goal was to be able to perform the reaction outside of a glovebox via the utilization of separate stock solutions of the tantalum sources and the ligands, the reactions were set-up through addition of solutions of the catalyst precursors in toluene to reaction vessels containing N-methylaniline and 1-octene. The reaction conditions were limited to 110 °C in toluene and 24-hour reaction times in order to afford reaction conditions that would be both reasonable and practical for a chemist that did not have the materials required to safely superheat a reaction vessel.  Complexes 3.1 or 3.3 with no additional ligands do not perform the hydroaminoalkylation of 1-octene with N-methylaniline with great efficiency, only achieving 16% and 33% conversion respectively (Table 3.1, Entries 1,4). Amidate 3.16 (Figure 3.2) with 3.1 proved to be more active, achieving 87% conversion (Entries 2-3). However, the reaction suffered from the poor solubility of 3.16 in toluene, which complicated the reaction setup and was determined to be unsuitable for further development for this reason. 2-Pyridonate ligands 3.17 and 3.18 with 3.1 both proved to be suitable for this method (Entries 4-6), as they both achieved full conversion in 24 hours as well as being sufficiently soluble in toluene to make a usable stock solution. Phosphoramidate 3.19 with 3.1 did not show any conversion (Entry 8), likely due to the thermal instability of 3.19. The sodium salt of 3.19 was shown to be active with 3.3 (Entry 9), achieving 85% yield at room temperature, however TaMe3Cl2 (3.3) is particularly difficult to handle due to its sensitivity to air, moisture, and light, as well as being highly pyrophoric. This, combined with it not being commercially available 74  and the sodium salt of 3.19 being insoluble in toluene, made this system unsuitable for further development. As both the combination of 3.18 and 3.1 were highly active for the reaction and both catalyst precursors were commercially available, this system was chosen for optimization.  Figure 3.2 Ligands used during catalyst screening             75  Table 3.1 In-situ catalyst screening and optimization  Entrya [Ta] ligand temp (°C) time (h) conv (%)b yield (%)c 1 3.1 None 110 24 16 N/A 2 3.1 3.16d 110 74 87 N/A 3 3.1 3.16 110 24 87 N/A 4 3.1 3.17d 110 24 100 93 5 3.1 3.17 110 24 100 N/A 6 3.1 3.18 110 24 100 95 7 3.3 None 110 24 33 N/A 8 3.1 3.19 110 24 0 N/A 9 3.3 3.19d rt 24 85 N/A 10 3.1 3.18 100 24 95 90 11 3.1 3.18 90 24 26 21 12 3.1 3.18 110 24e 41 35 13 3.1 3.18 110 20 31 20 14 3.1 3.18 110 16 13 7 15 3.1 3.18 110 16f 87 82 16 3.1 3.18 110 16f,g 100 96 17 3.1 3.18 110 16h 96 91 aReaction performed in a J-Young tube unless stated otherwise. bDetermined by 1H NMR spectroscopy through relative integration of ortho-aniline peaks. cIsolated yield. dIsolated catalyst used. e2.5 mol% catalyst. fLigand and [Ta] allowed to stir for 15 minutes prior to addition of substrates. gReaction performed in a 20 mL vial with a PTFE cap. hReaction performed on 1 g scale with 0.0825 M stock solution of catalyst in a three-necked flask     With the catalyst precursors chosen, the reaction was then optimized (Table 3.1). Lowering the temperature of the reaction below 110 °C leads to incomplete conversion (entries 10-11), as does lowering the catalyst loading to 2.5%. Attempts to reduce the reaction time from 24 hours to 16 hours yielded inconsistent results, with only 13% conversion at 16 hours and 31% conversion at 20 hours (Entries 13-14). It was hypothesized that this was due to the method of setting up the reaction; separate stock solutions of 3.18 in toluene and 3.1 in toluene were added sequentially to 76  vials containing N-methylaniline and 1-octene in toluene, which were then transferred into J. Young NMR tube for heating. This order of addition was hypothesized to prevent the precatalyst from forming in a facile manner due to the excess amine present, and the resulting catalytic mixture would be less active. When the two catalyst precursors are mixed for 15 minutes prior to addition of amine and alkene, the reaction proceeds smoothly to 87% conversion in 16 hours (Entry 15). A common byproduct of the hydroaminoalkylation reaction involving tantalum dimethylamido precatalysts is 3.20, which is the product of the liberated dimethylamine reacting with the catalyst and alkene twice (the monoalkylation product has not been observed with tantalum catalysts) (Scheme 3.4).66 While it would be assumed that the high volatility of the dimethylamine liberated from the precatalyst would allow it to escape the reaction solution at the standard reaction temperatures, these reactions are most often done in a sealed reaction flask, trapping the dimethylamine in the headspace of the reaction and allowing it to re-enter the solution phase to react. It was hypothesized that increasing the ratio of reaction flask headspace to reaction volume would lead to a subsequent decrease in 3.20. Indeed, it was noted that when J. Young NMR tubes of different length were utilized for the same reaction, the amount of 3.20 observed by GC/MS would decrease as the tube length increased. When the reactions were set-up in 20 mL scintillation vials with PTFE-lined caps, the formation of 3.20 is avoided and the reaction proceeds to 100% conversion (Table 3.1, Entry 16).   Scheme 3.4 Formation of dimethylamine byproduct  The hydroaminoalkylation of 1-octene with N-methylaniline using 3.1 and 3.18 was also demonstrated outside of an inert-atmosphere glovebox: a 1-gram scale reaction was set-up using 77  syringe techniques, using N-methylaniline and 1-octene that had not been rigorously dried and a 0.0825 M stock solution of the catalyst system stored in a PTFE-sealed side-arm vessel. A steady stream of nitrogen was blown through the reaction vessel and out of an oil bubbler attached to the top of the reflux condenser to remove free dimethylamine and prevent the formation of 3.20. The reaction proceeds cleanly, with 96% conversion after 16 hours and only a short silica plug is required for purification of the final product. 3.2.2 Substrate Scope With optimized conditions in hand, a wide variety of amines were tested for activity with the catalytic system (Table 3.2). In all cases where reactivity was observed, the only product observed was the branched isomer. The catalyst system tolerated both electron donating and electron withdrawing substituents (3.21, 3.22, 3.24), but strongly electron withdrawing substituents (3.25) led to decreased reactivity. Ortho substituents (3.23) led to a decrease in reactivity due to increased steric encumbrance around the nitrogen. Interestingly, an alkynyl amine (3.28) were tolerated but the reaction was limited to 3 turnovers, even when using more forcing reaction conditions. Dialkylamines (3.29) can undergo the reaction, but require more forcing conditions then anilines. Unexpectedly, N-ethylaniline (3.26) and tetrahydroquinoline (3.27) are both competent substrates, albeit requiring forcing conditions (vide infra). While tetrahydroquinoline is known in the literature for this reaction,53, 67, 70, 78 this is the first report of a tantalum complex being a competent catalyst for hydroaminoalkylation with N-ethylaniline, and the first report of the reaction to yield the branched product 3.26. The only previous reports to utilize N-ethylaniline as a substrate have been with titanium catalysts from the Doye group, and these catalysts only form the α-alkylated product.47 78  Table 3.2 Amine substrate scope  The reaction with N-ethylaniline not only exhibits complete regioselectivity for the α-β-dimethylated product, but also exhibits complete diastereoselectivity for the anti-dimethylated product versus the syn-dimethylated product, with the relative configuration determined through X-ray crystallography of the oxalate salt of 3.26 (Figure 3.3). The diastereoselectivity can be rationalized through the reaction mechanism proposed by Nugent (Figure 3.4): insertion of the alkene into tantallaziridine 3.30 leads to the formation of a 5-membered metallacycle.42 When the reaction involves the alkylation of a secondary carbon on the amine, the 5-membered metallacycle 79  can have either a cis (3.32) or trans (3.31) configuration of the substituents. A cis configuration would not only be a higher energy intermediate due to steric strain, but the transition state for the insertion would also be higher in energy than the transition state to yield the trans configuration.   Figure 3.3 ORTEP representation of 3.26 oxalate salt X-ray crystallographic structure. Ellipsoids plotted at 50% probability, non-tertiary hydrogens omitted for clarity  80   Figure 3.4 Mechanistic rational for observed diastereoselectivity While there are several amines that were found to be active with the 3.18 catalyst system, several amines tested proved to be minimally to completely non-reactive (Figure 3.5). Amines with highly polar functional groups, such as nitro groups (3.35) or any groups with sp2 hybridized oxygens (3.33, 3.34) are non-reactive, likely due to the oxygen coordinating to the oxophilic tantalum center and poisoning the catalyst. Challenging cyclic amine substrates, such as 3.38, 3.39, 3.44, and 3.45, are unreactive, and anilines with sterically encumbered alkyl (3.40, 3.42) or benzyl (3.36, 3.41, 3.43) substituents are too sterically congested to undergo the reaction to any conversion higher than 10%. Primary amines (3.46) did not exhibit any reactivity, which is unsurprising as primary amines are known to react with early transition metal amido complexes to form imido ligands, leading to catalyst death.110-111  81   Figure 3.5 Amine substrates that exhibit trace or no reactivity Various alkenes were also tested for activity with the 3.18 catalyst system (Table 3.3). Styrenes (3.47), including ortho and para substituted styrenes (3.55, 3.56), proved to be competent substrates for the reaction, with a slight formation of the linear product observed in the reaction with styrene. The catalyst was able to react with norbornene (3.49) with high yields and good diastereoselectivity, but norbornadiene initially appeared to be too challenging of a substrate, with significant formation of both dialkylated norbornane and polynorbornadiene observed under standard reaction conditions. However, later work by Nirmalendu Kuanr and undergraduate Edward Hsaing showed that, under forcing conditions and with reduced reaction times, the 3.18 catalyst system can be used for gram-scale production of 3.59 (Scheme 3.5). Vinylsilanes (3.54) proved to be reactive but with low regioselectivity, supporting a hypothesis by Garcia et. al. which proposes that the increased formation of the linear product is due to a buildup of transient positive charge on the alkene substrate, which is stabilized through the β-silicon effect.46 Most notable was that the catalyst is able to tolerate protected oxygen functional groups, namely acetals (3.50), ketals 82  (3.51), and silyl-protected alcohols (3.52, 3.53), as these functional groups can be deprotected and utilized in further reactions. While there are reports of silyl-protected alcohols in the literature, this is the first report of an early transition metal hydroaminoalkylation catalyst capable of reacting with acetal and ketal-functionalized substrates.78 Table 3.3 Alkene substrate scope  83   Scheme 3.5 Gram-scale synthesis of 3.59 using modified conditions As with the amine substrate scope, there were several alkenes tested that did not exhibit reactivity (Figure 3.6). Highly polar substrates, such as acrylate derivatives (3.60, 3.61), show no reactivity, likely due to catalyst poisoning. While longer-chain protected alcohols (3.52, 3.53) are well tolerated, protected allyl alcohols (3.64, 3.65) are not reactive. Sterically encumbered alkenes, such as gem-disubstituted (3.67) and internal alkenes (3.68, 3.69) are also unreactive. The reaction with 3.70 does not yield product, as the Diels-Alder dimerization side reaction occurs too quickly at the reaction temperature. Allenes (3.71, 3.72) and alkynes (3.73, 3.74) are not competent substrates, although the reason for this has not yet been elucidated.  Figure 3.6 Alkene substrates that exhibited trace or no reactivity 84  3.2.3 Optimization of Hydroaminoalkylation Reaction with 3.80 While the result of the hydroaminoalkylation reaction with N-ethylaniline was exciting due to both the novelty of the reaction and the difficulty of synthesizing such products through alternative routes, the yield with the initial optimized reaction conditions were somewhat disappointing (11% yield). Attempts to increase the yield by increasing reaction temperatures were met with limited success, as temperatures higher than 130 °C leads to degradation of the catalyst and a subsequent decrease in yield (Table 3.4, Entries 1-4). It was hypothesized that having a 2:1 ligand/Ta ratio would increase the thermal stability of the catalyst and therefore increase the yield. However, this is not the case, with the conversion not significantly different (Entry 5). Increasing the catalyst loading leads to an increase in conversion (Entry 6), albeit lower than one would expect assuming catalyst turnover remained constant. The reason for this decrease in turnover is unknown but may be due to a catalyst decomposition pathway that is higher-order in catalyst.         85  Table 3.4 Optimization of hydroaminoalkylation reaction with N-ethylaniline   Entrya Mol% Catalyst Ligand:Ta Ratio temp (°C) conv (%)b yield (%)c 1 5 1:1 110 15 11 2 5 1:1 120 23 13 3 5 1:1 130 31 20 4 5 1:1 145 20 17 5 5 2:1 145 18 11 6 10 1:1 130 45 33 7d 10 1:1 130 N/A 13 aReaction performed in a J-Young tube unless stated otherwise. bDetermined by 1H NMR spectroscopy through relative integration of ortho-aniline peaks. cIsolated yield. dReaction performed in a 20 mL vial with a PTFE cap.   One key issue that arose with the increase in reaction temperature is that the reaction conditions are no longer suitable for being run under high headspace/reaction volume ratios. One reason for this is the practical issue of the reaction temperature being high enough to deform the PTFE-lined cap, leading to a significantly increased risk of failure of the reaction vessel. However, the more significant issue is that 1-octene has a boiling point of 121 °C, and having a large reaction flask headspace with higher temperatures leads to significant accumulation of 1-octene in the vapor phase, decreasing the overall conversion of the reaction. As such, the reactions performed under the more forcing conditions must be run in J. Young NMR tubes or appropriately sized PTFE sealed Schlenk tubes, and the formation of the aforementioned dimethylamine byproduct 3.20 is then unavoidable 86  Having exhausted most options for optimizing the conversion of N-ethylaniline using the 3.18/3.1 catalyst system, it was hoped that changing the ligand would lead to an increase in reactivity (Table 3.5). As expected, 3.17 did not significantly differ in activity from 3.18, and use of both 3.16 and 3.19 led to little to no conversion, indicating that the less sterically demanding pyridonate ligands are essential for reactivity. With the trend that more electron withdrawing ligands gave higher catalytic activity, the more electron-deficient pyridone analogues 3.75, 3.76, and 3.77 were tested for catalytic activity in-situ. However, 3.75 proved to give a lower conversion, 3.76 was not an effective ligand, and 3.77 was too insoluble in toluene to form a catalyst, even at elevated temperatures. Table 3.5 Ligand screen for hydroaminoalkylation with N-ethylaniline  87  3.2.4 Determination of Ligand Substituent Effects on Reaction Rate While attempting to optimize the hydroaminoalkylation of 1-octene with N-ethylaniline, it was noted that 3.75, containing an electron-withdrawing bromine instead of an electron-donating methyl group, led to a decrease in conversion. It was hypothesized that fine-tuning the electronic environment of the pyridonate ligand through the use of electron donating or withdrawing substituents would allow for optimization of catalytic activity. Thus I designed a related project that was performed by 449 student Thomas Horton. He synthesized, characterized, and performed kinetic experiments on complexes containing various 5-substituted-2-pyridonate ligands. Additional experiments were completed by by summer student Weizhe Dong under my supervision. He synthesized, characterized, and performed kinetic experiments on complexes containing various 4-substituted-2-pyridonates. 3.2.4.1 Solid State Molecular Structures of Complexes To test the aforementioned hypotheses, a variety of LTa(NMe2)4 complexes containing different 4- and 5-substituted-2-pyridonate ligands were synthesized through the protonolysis of 3.1 with one equivalent of the corresponding proteo-ligand (Table 3.6).  88  Table 3.6 Synthesis of 4- and 5-substituted pyridonate tantalum complexes  X-ray diffractometry was run on complexes where suitable crystals could be grown, and the resulting structures with important bond lengths and angles are shown below with the structure of the 3.18 tantalum complex (3.87) shown as a reference (Table 3.7). 89  Table 3.7 ORTEP representations of 4- and 5-substituted pyridonate tantalum complexes with selected bond lengths and angles  3.79 Important Bond Lengths Atom Atom Length Ta1 O1 2.108(3) Ta1 N1 2.382(4) O1 C1 1.313(5) N1 C1 1.349(6) Ta1 Neq(avg) 1.979 Ta1 Nax(avg) 2.029 Important Bond Angles  Atom Atom Atom Angle O1 Ta1 N1 58.48(12) O1 C1 N1 111.9(4) N2 Ta1 N3 106.03(16) N4 Ta1 N5 166.54(16)   3.80 Important Bond Lengths Atom Atom Length Ta1 O1 2.148(3) Ta1 N1 2.289(3) O1 C1 1.316(5) N1 C1 1.334(5) Ta1 Nax(avg) 2.041 Ta1 Neq(avg) 1.983 Important Bond Angles  Atom Atom Atom Angle O1 Ta1 N1 58.39(11) O1 C1 N1 113.4(4) N2 Ta1 N3 165.39(14) N4 Ta1 N5 106.52(15)         90   3.82 Important Bond Lengths Atom Atom Length Ta1 O1 2.138(3) Ta1 N1 2.361(3) O1 C1 1.315(5) N1 C1 1.352(5) Ta1 Nax(avg) 2.042 Ta1 Neq(avg) 1.992 Important Bond Angles  Atom Atom Atom Angle O1 Ta1 N1 58.93(11) O1 C1 N1 112.8(3) N4 Ta1 N5 167.18(15) N2 Ta1 N3 105.90(15)   3.84 Important Bond Lengths  Atom Atom Length  Ta1 N1 2.394(3)  Ta1 O1 2.145(2)  O1 C1 1.303(4)  N1 C1 1.345(4)  Ta1 Nax(avg) 2.038 Ta1 Neq(avg) 1.974 Important Bond Angles  Atom Atom Atom Angle  O1 Ta1 N1 85.92(9) O1 C1 N1 113.6(3) N2 Ta1 N3 165.52(10) N4 Ta1 N5 106.41(11)          91   3.87 Important Bond Lengths Atom Atom Length (Å) Ta1 O1 2.145(6) Ta1 N1 2.3558) O1 C1 1.347(10) N1 C1 1.328(11) Ta1 Nax(avg) 2.04 Ta1 Neq(avg) 1.985 Important Bond Angles  Atom Atom Atom Angle O1 Ta1 N1 58.8(2) O1 C1 N1 112.0(6) N2 Ta1 N3 168.4(2) N4 Ta1 N5 107.8(3)   Each pyridonate tantalum dimethylamido complex exhibits pseudo-trigonal bipyramidal geometry (considering the N,O-chelating ligand as a occupying a single coordination site, centered on the C1 atom), with the pyridonate ligands bound in the equatorial plane of the tantalum complex. The O1-C1 bond lengths all range from 1.30 – 1.34 Å, with the O1-C1 bond length of 3.87 being longest likely due to steric bulk from the substitution at the 3-position, and the N1-C1 bond lengths ranging from 1.32 – 1.35 Å. While the N1-C1 bonds are slightly longer than those found in the corresponding tantalum amidate complexes (1.29 – 1.32 Å), the O1-C1 bonds are of 92  similar length to the corresponding tantalum amidates.66 Minimal variation in the bond lengths of the Ta-Naxial and Ta-Nequatorial was observed, indicating a minimal effect on the electronic environment and the binding of the reactive dimethylamido ligands. It was hypothesized that changing the electronic nature of the pyridonate ligand would lead to noticeable changes in the solid state molecular structure of the complexes, and that these changes could then be correlated to known electronic LFERs (Linear Free Energy Relationship). However, no strong correlation between observed Ta-O1, Ta-N1, O1-C1, and N1-C1 bond lengths and Hammett σ values of the substitutions on the pyridonate ligands was found, indicating little impact of the electronic environment of the pyridonate ligand on the bonding of the complex (Figure 3.6).112 Analyses of other bond lengths, angles, and electronic LFERs, including isolated field and resonance parameters, were performed with no correlations observed.  93    Figure 3.7 Plot of bond lengths in relation to Hammett σ values, position relative to the oxygen and nitrogen atoms on pyridonate R² = 0.0644R² = 0.0014R² = 0.6663R² = 0.00141.251.451.651.852.052.252.45-0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6Bond Length (Angstoms)Hammet ParameterBond Lengths vs. σ Values (Position Relative to Oxygen)Ta-OTa-N1O-C1N-C1Linear (Ta-O)Linear (Ta-N1)Linear (O-C1)Linear (N-C1)R² = 0.3839R² = 0.1601R² = 0.2102R² = 0.05521.251.451.651.852.052.252.45-0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6Bond Length (Angstroms)Hammet ParameterBond Lengths vs. σ Values (Postion Relative to Nitrogen)Ta-OTa-N1O-C1N-C1Linear (Ta-O)Linear (Ta-N1)Linear (O-C1)Linear (N-C1)94   3.2.4.2 Kinetic Screening To determine the effect of the substituents on the pyridonate ligands on the catalytic activity of the formed complexes, kinetic analysis of the activity of the above synthesized complexes was done via GC/FID, using a method initially developed by graduate student Damon Gilmour and modified by CHEM 449 student Thomas Horton. Identical hydroaminoalkylation reactions of 1-octene with N-methylaniline using 1,3,5-trimethoxybenzene as an internal standard (Scheme 3.6) were performed and quenched at 10-minute intervals, up to one hour, with all reactions being performed in triplicate. The absolute concentration of N-methylaniline for each reaction was determined with a calibration curve, and initial rate plots were generated for each catalyst using the T0, T10, and T20 data points (Figure 3.8). Complex 3.86 exhibited an induction period for the first ten minutes of the reaction, and therefore the initial rates were determined between T10 and T30. Raw data can be found in Appendix C.  Scheme 3.6 Hydroaminoalkylation of 1-octene with N-methylaniline for kinetic analysis, using 1,3,5-trimethoxybenzene as an internal standard  95    Figure 3.8 Plots of initial rates for the 5-substituted (A) and 4-substituted (B) pyridonate catalysts y = -0.0032x + 0.1843y = -0.0028x + 0.2124y = -0.0011x + 0.2175y = -0.0016x + 0.1924y = -0.0016x + 0.21520.00000.05000.10000.15000.20000.25000 5 10 15 20 25 30 35[N-methylaniline] (M)Reaction Time (min)A3.783.833.843.853.86Linear (3.78)Linear (3.83)Linear (3.84)Linear (3.85)Linear (3.86)y = -0.002x + 0.2142y = -0.0053x + 0.2465y = -0.0018x + 0.2181y = -0.0031x + 0.2174y = -0.0032x + 0.21750.00000.05000.10000.15000.20000.25000.30000 5 10 15 20 25[N-methylaniline] (M)Reaction Time (min)B3.783.793.803.813.82Linear (3.78)Linear (3.79)Linear (3.80)Linear (3.81)Linear (3.82)96    After determination of the initial rates for each catalyst (Table 3.8), the rate constants were calculated, normalized to 3.78, and compared to the Hammett σp and σm parameters for each respective functional references (Figure 3.9).112 A limitation of the data must be mentioned: the kinetic data for the 4-substituted pyridonates cannot be directly compared with the kinetic data for the 5-substituted pyridonates. This is due to non-obvious error between the experimenters’ methods that has led to the two data sets having irreconcilable rates for 3.78. While it is possible that the irreconcilable rates for 3.78 for the data sets obtained by Thomas Horton and Weizhe Dong are due to experimenter error, it is also possible that this could be due to variations in the induction periods for each run of the kinetic analysis. This has been observed in previous attempts to perform kinetic analysis on tantalum dimethylamido-based catalysts and cannot be ruled out in this analysis.113 As such, while each catalyst can be compared within it’s own data set, they cannot be compared between data sets. 97  Table 3.8 Initial rates of consumption of N-methylaniline for each 4- and 5-substituted pyridonate catalyst  98   Figure 3.9 Hammett analyses for 4- and 5-substituted pyridonate tantalum catalysts, referenced both to the oxygen (A) and nitrogen (B) atoms of the pyridonates Unfortunately, no strong correlation between the observed rates and reported Hammett σ values or other electronic LFERs could be found. This, coupled with the lack of correlation 3.793.783.81 3.823.803.833.843.863.85R² = 0.2284R² = 0.0417-0.6-0.4-0.200.20.40.60.8-0.4 -0.2 0 0.2 0.4 0.6 0.8log(k/kH)Hammett Parameter (σ)A4-SubstitutedPyridonates5-SubstitutedPyridonatesLinear (4-SubstitutedPyridonates)Linear (5-SubstitutedPyridonates)3.793.783.81 3.823.803.833.853.863.84R² = 0.3889R² = 0.4659-0.6-0.4-0.200.20.40.60.8-0.4 -0.2 0 0.2 0.4 0.6 0.8log(k/kH)Hammett Parameter (σ)B4-SubstitutedPyridonates5-SubstitutedPyridonatesLinear (4-SubstitutedPyridonates)Linear (5-SubstitutedPyridonates)99  between bond lengths and LFERs, indicates that, while the electronic environment of the ligand does affect reactivity, it also affects a myriad of non-catalytic equilibria, such as ortho-metallation, product-tantalum binding, and formation of non-productive geometric isomers, that have been observed in these catalytic systems in an unpredictable manner (Figure 3.10).68 This effectively prevents the use of these types of LFER analyses on these catalytic systems until these off-cycle equilibria are better understood.   Figure 3.10 Hydroaminoalkylation catalytic cycle with example on- and off-cycle equilibria  3.2.5 Synthesis of Poly-Substituted Piperidines The ability for the 3.18/3.1 catalyst system to synthesize α,β-dimethylated amines diastereoselectively, as well as the use of silyl protected alcohol- and ketal-containing substrates, 100  provided an opportunity to synthesize poly-substituted piperidines (Scheme 3.7). Conversion of silyl ether 3.58 to the corresponding tosylate followed by intramolecular cyclization occurs in the presence of tosyl fluoride and DBU to produce the 2,3-cis-dimethylated piperidine 3.88 with excellent yield and no loss of diastereomeric purity. Acidic deprotection of aminoketal 3.57 produces a cyclic iminium cation, which can subsequently be reduced with sodium cyanoborohydride to yield a 2,3,6-trimethylated piperidine 3.89. This reaction exhibits diastereomeric ratio of 1.4:1 with the 2,6-trans configuration being the major product, as determined through X-ray crystallography on the corresponding HCl salt (Figure 3.11). These heterocycles are precursors to free piperidine building blocks, which can be accessed through oxidative cleavage of the para-methoxyphenyl group.  Scheme 3.7 Synthesis of poly-substituted piperidines 101   Figure 3.11 ORTEP Representation of the HCl salt of the major diastereomer of 3.89, ellipsoids are set to 50% probability, hydrogens attached to non-tertiary carbons excluded for clarity  3.3 Conclusions A method for the in-situ generation of a tantalum pyridonate hydroaminoalkylation catalyst was developed. This catalyst system can be performed outside of a glovebox using premade stock solutions of the catalyst, and exhibits unprecedented reactivity towards wide variety of substrates, including N-ethylanilines, with moderate to excellent yields. Attempts at optimizing the reaction and the catalyst for hydroaminoalkylation of N-ethylaniline were unsuccessful at achieving high conversion. The effect of changing the electronic environment of the pyridonate ligand was then tested, but no observable trend was found with known LFERs due to the effects of equilibria that have yet to be quantified. Finally, products of the hydroaminoalkylation of protected functionalized alkenes with N-ethyl-4-methoxyaniline were further reacted to synthesize polysubstituted piperidines, which could be used as building blocks for value-added materials. This in-situ generated catalyst system presents a facile method for the synthesis of structurally diverse amines using commercially available starting materials without the isolation and air- or 102  moisture-sensitive organometallic complexes, as well as providing a platform for the further development of user-friendly early transition metal hydroaminoalkylation catalysts. 3.4 Experimental 3.4.1 Materials and Methods General Experimental. All air and moisture sensitive reactions were setup in a MBraun LABMaster glovebox under N2 atmosphere or on a Schlenk double manifold with N2 and high-vacuum (10-3 mbar). Glassware was heated in an oven to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Stirring was done with appropriately sized stir bars, which were heated to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Toluene was passed over activated alumina columns into Teflon-sealed Straus flasks, degassed via 3 freeze-pump-thaw cycles, brought into the glovebox, and stored over 4 Å molecular sieves. d8-toluene was refluxed in a sodium still overnight, degassed through 3 freeze-pump-thaw cycles and stored in a Teflon sealed bomb. Dryness of the toluene and d8-toluene was confirmed through the addition of 2 drops of benzophenone ketyl in THF. Reactions that were monitored via NMR were performed in J-Young NMR tubes (8” x 5mm or 9” x 5mm) with Teflon caps. Flash chromatography was performed on a Biotage Isolera Flash Chromatography system using 10 g columns, with both hexanes and ethyl acetate spiked with 0.1% (v/v) triethylamine. Materials. Ta(NMe2)5 was purchased from Strem and used as received. Liquid amines and alkenes were purchased from commercial sources, dried over CaH2, distilled, and degassed via freeze-pump-thaw prior to use. Solid amines, 3.18, pyridone ligands for catalysts 3.78, 3.79, 3.81, 3.83, 3.84, 3.85, and 3.86, were purchased from commercial sources and sublimed prior to use. Alkene substrates for compounds  3.50,114 3.51,115 3.52,78 and 3.53,78 as well as the pyridone ligand for complex 3.82,116 were synthesized according to literature procedures. Separate stock solutions of 103  3.1 (0.165 M), 3.18 (0.165 M), N-methylaniline with 1.5 equivalents of 1-octene and 1 equivalent of 1,3,5-trimethoxybenzene (0.5 M with respect to N-methylaniline), and 5- or 4-substituted pyridonate tantalum precatalysts in toluene (0.025 M) were prepared in an inert atmosphere glovebox using volumetric glassware. Catalyst solutions for use outside of the glovebox were made by mixing equal volumes of 0.165 M stock solutions of Ta(NMe2)5 and 3-methyl-2-pyridone at room temperature and stored in PTFE-sealed ampules.  Instrumentation. Flash chromatography was performed on a Biotage Isolera Flash Purification system, using repacked 10 g flash chromatography columns. 1H and 13C NMR spectra were obtained on a Bruker 300 MHz Avance spectrometer at ambient temperature. Chemical shifts are given relative to the corresponding residual proteo solvent, and are reported in parts per million. Coupling constants are reported in Hertz. Abbreviations used to indicate signal multiplicity are as follows: s = single, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, br = broad. Infrared (IR) spectra were obtained from neat samples using a PerkinElmer Frontier FT-IR spectrometer with an ATR sampling accessory. High-resolution mass spectra were measured by the University of British Columbia, Department of Chemistry Mass Spectrometry and Microanalysis Service on a Waters Micromass LCT, utilizing electrospray ionization. GC/MS analyses were conducted on an Agilent 7890B GC with an Agilent 5977 inert CI mass detector, utilizing methane as the ionization gas. Single-crystal X-ray structure determination was performed on a Bruker x8 APEX II diffractometer at the Department of Chemistry, University of British Columbia, by Damon Gilmour and Sam Griffin. Safety Considerations. Complex 3.1 is O2 sensitive and moisture sensitive. Complex 3.3 is light sensitive, O2 sensitive, moisture sensitive, and highly pyrophoric. Handling and use of these complexes should be done under inert atmosphere. All hydroaminoalkylation reactions in this 104  chapter were performed in sealed reaction vessels unless otherwise noted; reactions performed at elevated temperatures should be performed in glassware designed for use with elevated pressures and behind appropriately-rated blast shields. Toxicological profiles of many of the starting materials and products are not known, and appropriate precautions should be taken during the handling of these compounds. Basification of the reaction during the synthesis of 3.89 should be performed, and the pH of the resulting aqueous phase checked using pH paper, in order to prevent the formation of hydrogen cyanide upon addition of sodium cyanoborohydride. Aqueous waste from this reaction should be kept at a high pH and disposed of properly.  3.4.2 Synthesis and Characterization of Compounds 3.4.2.1 Experimental Procedures Method A: Hydroaminoalkylation Reactions in J-Young NMR Tubes In a glovebox, the required amounts of Ta(NMe2)5 and 3-methyl-2-pyridone were added to a 1-dram vial, and dissolved in 300 µL of d8-toluene, and the solution was left to stand at room temperature for 15 minutes. Amine (0.5 mmol) and alkene (0.75 mmol) was then added, and the solution was transferred into a J-Young NMR tube. The 1 dram vial was rinsed with 2 x 100 µL d8-toluene, and the tube was capped, removed from the glovebox, and heated to the stated temperature for 24 hours. After 24 hours, the reaction was cooled and transferred into a scintillation vial. 5 mL of hexanes was added to the reaction, and air was blown into the vial to facilitate quenching and precipitation of the catalyst. The quenched mixture was then filtered through diatomaceous earth, concentrated in vacuo, and purified via flash chromatography (Silica gel stationary phase, Ethyl acetate/Hexanes mobile phase with 0.1% triethylamine) to yield the given product. 105  Method B: Hydroaminoalkylation Reactions in Scintillation Vials In a glovebox, 150 µL of a 0.165 M solution of 3-methyl-2-pyridone in toluene was added to 150 µL of a 0.165 M solution of Ta(NMe2)5 in toluene, and the solution was left to sit at RT for 15 minutes. The solution was then added to a 20 mL scintillation vial containing amine (0.5 mmol), alkene (0.75 mmol), and toluene (200 µL). A stir bar was then added to the vial, and the vial was sealed with a Teflon cap, removed from the glovebox, and heated to 110 °C for 16 hours. After 16 hours, the reaction was cooled, 5 mL of hexanes was added to the reaction, and air was blown into the vial to facilitate quenching and precipitation of the catalyst. The quenched mixture was then filtered through diatomaceous earth, concentrated in vacuo, and purified via flash chromatography (Silica gel stationary phase, Ethyl acetate/Hexanes mobile phase with 0.1% (v/v) triethylamine) to yield the given product. Method C: Hydroaminoalkylation Reaction Outside of Glovebox To an oven-dried, nitrogen filled 25 mL 3-neck flask with attached glass stopper, reflux condenser attached to a Schlenk line, and septum was added N-methylaniline (1.00 g, 1.02 mL, 9.33 mmol), 1-octene (1.57 g, 2.20 mL, 14.00 mmol) and toluene (4.4 mL). To this solution was added 3-methyl-2-pyridone and Ta(NMe2)5 as a premade solution (5.6 mL, 0.0825M of ligand and Ta(NMe2)5, 0.47 mmol), the septum was replaced with a glass stopper, and the reaction was refluxed for 16 hours. After 16 hours, the reaction was cooled, diluted with hexanes (50 mL), and quenched by bubbling air through the solution. The solution was then filtered through diatomaceous earth and concentrated to a clear, yellow oil. Purification through elution through a silica plug (3cm x 4.5cm diameter, 250 mL 98:2 hexanes/ethyl acetate with 0.1% v/v triethylamine mobile phase) and concentration in vacuo yielded pure 3a as a yellow oil (1.87 g, 8.52 mmol, 91% yield). 106   Method D: Synthesis of Precatalyst for Kinetic Screens In a glovebox, a suspension of the ligand (1 mmol) and Ta(NMe2)5 (0.401g, 1mmol) was stirred in hexanes (~6ml) in a 20ml vial at ambient temperature overnight. Solvent was then removed in vacuo and the resulting crude complex were recrystallized from hot hexanes.   Method E: Kinetic Analysis In a glovebox, In a glovebox, 1.4 mL of a 0.025 M solution of 5- or 4-substituted pyridonate tantalum precatalyst in toluene was added to 1.4 mL of 0.5 M solution of N-methylaniline (1 equivalent), 1-octene (1.5 equivalents), and 1,3,5-trimethoxybenzene (1 equivalent) (2.0 M with respect to N-methylaniline) The combined solution was diluted with 0.7 mL toluene, split into seven 0.5 mL aliquots in separate 20 mL scintillation vials with PTFE sealed caps, and removed from the glovebox. The T0 sample was immediately quenched with DCM (10 mL) and filtered through diatomaceous earth. The remaining six samples were stirred and heated to 110 ºC, removing one sample every 10 minutes and quenching as above. GC/FID analysis was then performed on each sample, using the instrument method described in Appendix C1. Each catalyst was tested in triplicate. 3.4.2.2 Synthesis of N-methyl-4-(phenylethynyl)aniline  107  1-Bromo-4-(phenylethynyl)benzene (3.90). To a solution of 4-bromo-1-iodobenzene (4.00 g, 14.1 mmol) in THF (40 mL) was added phenylacetylene (1.44 g 14.1 mmol), bis(triphenylphosphine)palladium(II) dichloride (496 mg, 0.707 mmol), copper(I) iodide (135 mg, 0.707 mmol), and triethylamine (9.8 mL, 70.7 mmol), and left to stir overnight at room temperature. Upon reaction completion, as determined through GC/MS, the solution was concentrated in vacuo, dissolved in hexanes (100 mL), washed with 100 mL each 2M HCl, 2M NaOH, water, and brine, dried over anhydrous MgSO4, and concentrated in vacuo to a brown solid. Recrystallization from hot methanol yielded yellow crystals (2.57 g, 71% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 7.37 (dd, J=6.97, 3.54 Hz, 1 H) 7.40 - 7.43 (m, 2 H) 7.46 - 7.50 (m, 2 H) 7.50 - 7.57 (m, 4 H), matches with literature data.117   N-methyl-4-(phenylethynyl)aniline (3.91). To a solution of 3.90 (2.57 g, 10.0 mmol) in DMF (5.4 mL) in a Teflon sealed glass ampule was added copper powder (762 mg, 12 mmol) and aqueous methylamine (5.4, 30% w/v in water), and ampule was sealed, and heated to 100 °C for 16 hours. The reaction solution was then diluted with ethyl acetate (50 mL), washed with 50 mL each 2M NaOH, water, and brine, dried over anhydrous MgSO4, and concentrated in vacuo to a brown oil. Purification through flash chromatography (100g silica flash column, Hexanes/EtOAc, 0% -> 30% EtOAc over 10 column volumes) yielded the product as a white solid (691 mg, 33% 108  yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.87 (s, 3 H) 3.91 (br. s., 1 H) 6.57 (dt, J=9.00, 2.40 Hz, 2 H) 7.28 - 7.42 (m, 5 H) 7.48 - 7.54 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 30.6, 87.3, 90.6, 111.2, 112.1, 124.2, 127.6, 128.4, 131.4, 133.1, 149.4. IR(1/cm): 3430, 3050, 2982, 2925, 2885, 2818, 2207, 1592. High Res. MS: Calculated: 208.1126 (M+1) Found: 208.1129 (M+1, C15H14N)    3.4.2.3 Synthesis of 2-hydroxy-4-trifluoromethylpyridine  2-hydroxy-4-trifluoromethylpyridine (3.92) To a solution of 2-chloro-4-trifluoromethylpyridine (1.05 g, 5.5 mmol) in glacial acetic acid (26 mL) was added sodium acetate (918 mg, 11.0 mmol), and the solution was transferred to a Teflon-sealed ampule and heated to 150 ºC for 24 hours. Upon reaction completion, the solution was concentrated in vacuo, and the residue was dissolved in ethyl acetate (100 mL), washed with 25 mL each saturated sodium bicarbonate solution, water, and brine, dried over magnesium sulfate, and concentrated in vacuo to yield the product as a pure, white powder (852 mg, 5.2 mmol, 95% yield), characterization matches literature values118 1H NMR (300 MHz, CHLOROFORM-d)  ppm 6.47 (dd, J=6.62, 1.60 Hz, 1 H) 6.87 (s, 1 H) 7.53 (d, J=6.62 Hz, 1 H); 19F NMR (282 MHz, CHLOROFORM-d)  ppm -66.9  109  3.4.2.4 Compound Characterization 3.4.2.4.1 Substrate Scope  N-(2-methyloctyl)aniline (3.15). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (105.3 mg, 0.48 mmol, 96% yield). Also synthesized via Method C utilizing N-methylaniline (1.00 g, 1.02 mL, 9.33 mmol) and 1-octene (1.57 g, 2.20 mL, 14.00 mmol). Isolated as a yellow oil (1.87 g, 8.52 mmol, 91% yield, Method C). Characterization data matches known literature values.30 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.84 - 0.94 (m, 3 H) 0.98 (d, J=6.62 Hz, 3 H) 1.11 - 1.50 (m, 11 H) 1.74 (dt, J=11.94, 6.02 Hz, 1 H) 2.89 (dd, J=12.22, 7.20 Hz, 1 H) 3.01 - 3.11 (dd, J= 12.22, 7.20 Hz, 1 H) 6.61 (dd, J=8.57, 1.03 Hz, 2 H) 6.68 (t, J=7.31 Hz, 1 H) 7.13 - 7.23 (m, 2 H) 13C NMR (75 MHz, CHLOROFORM-d)  ppm 14.3, 18.2, 22.8, 27.1, 29.8, 32.0, 33.1, 34.9, 50.5, 112.7, 117.1, 129.3, 148.7. IR(1/cm): 3422, 3053, 2956, 2924, 2854, 1602, 1506.   4-methoxy-N-(2-methyloctyl)aniline (3.21). Synthesized via Method B utilizing N-methy-4-methoxylaniline (68.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (119.7 mg, 0.48 mmol, 96% yield), characterization data matches known literature values.30 110  1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.82 - 0.94 (m, 3 H) 0.97 (d, J=6.62 Hz, 3 H) 1.08 - 1.51 (m, 11 H) 1.73 (m, 1 H) 2.84 (dd, J=11.99, 7.20 Hz, 1 H) 3.02 (dd, J=11.99, 5.82 Hz, 1 H) 3.76 (s, 3 H) 6.54 - 6.64 (m, 2 H) 6.75 - 6.83 (m, 2 H).13C NMR (75 MHz, CHLOROFORM-d)  ppm 14.2, 18.2, 22.8, 27.1, 29.7, 32.0, 33.0, 34.9, 51.6, 55.9, 114.1, 115.0, 143.0, 152.0. IR(1/cm): 3409, 2955, 2925, 2854, 1619, 1511.   4-bromo-N-(2-methyloctyl)aniline (3.22). Synthesized via Method B utilizing N-methyl-4-bromoaniline (93.0 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (137.2 mg, 0.46 mmol, 92% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.82 - 1.02 (m, 6 H) 1.07 - 1.49 (m, 10 H) 1.73 (m, 1 H) 2.82 - 2.90 (dd, J=12.19, 5.90 Hz, 1 H) 2.97 – 3.06 (dd, J=12.19, 5.90 Hz, 1 H) 6.45 - 6.54 (m, 2 H) 7.21 - 7.26 (m, 2 H) 13C NMR (75 MHz, CHLOROFORM-d)  ppm 14.3, 18.1, 22.8, 27.0, 29.7, 32.0, 33.0, 34.9, 50.5, 108.5, 114.3, 132.0, 147.7. IR(1/cm): 3426, 2955, 2924, 2854, 1859, 1595, 1497, High Res. MS: Calculated: 298.1170 (M+1), Found: 298.1167 (M+1, C15H25NBr)   111  4-methoxy-2-methyl-N-(2-methyloctyl)aniline (3.23). Synthesized via Method B utilizing 4-methoxy-N,2-dimethylaniline (75.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (39.5 mg, 0.15 mmol, 30% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.86 - 0.95 (m, 3 H) 1.01 (d, J=6.62 Hz, 3 H) 1.17 - 1.53 (m, 10 H) 1.79 (m, 1 H) 2.16 (s, 3 H) 2.84 - 2.95 (dd, J=11.90, 7.30 Hz, 1 H) 3.02 – 3.12 (dd, J=11.90, 7.30 Hz, 1 H) 3.76 (s, 3 H) 6.52 - 6.59 (m, 1 H) 6.67 - 6.76 (m, 2 H) 13C NMR (75 MHz, CHLOROFORM-d)  ppm 14.3, 17.8, 18.3, 22.8, 27.1, 32.0, 32.1, 33.0, 35.1, 51.4, 56.0, 111.0, 111.8, 117.1, 123.8, 140.8, 151.6. IR(1/cm): 3435, 2955, 2924, 2854, 2832, 1509. High-Res MS: Calculated: 264.2327 (M+1), Found: 264.2327 (M+1, C17H30NO)   N-(2-methyloctyl)benzo[d][1,3]dioxol-5-amine (3.24). Synthesized via Method B utilizing N-methyl-3-benzodioxol-5-amine (74.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (111.9 mg, 0.42 mmol, 85% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.79 - 1.01 (m, 6 H) 1.06 - 1.49 (m, 10 H) 1.65 - 1.82 (m, 1 H) 2.76 - 2.88 (dd, J=12.00, 7.20 Hz, 1 H) 2.93 – 3.04 (dd, J=12.56, 6.40 Hz, 1 H) 5.86 (s, 2 H) 6.11 (d, J=7.77 Hz, 1 H) 6.30 (s, 1 H) 6.66 (d, J=8.22 Hz, 1 H), 13C NMR (75 MHz, CHLOROFORM-d)  ppm 14.2, 18.1, 22.8, 27.0, 29.7, 32.0, 33.0, 34.9, 51.5, 95.9, 100.5, 104.3, 108.7, 139.4, 144.5, 148.4. IR(1/cm): 3417, 2955, 2924, 2854, 1634, 1613, 1503, 1488 High-Res MS: Calculated: 264.1964 (M+1), Found: 264.1960 (M+1, C16H26NO2) 112       N-(2-methyloctyl)-4-(trifluoromethoxy)aniline (3.25). Synthesized via Method B utilizing N-methyl-4-trifluoromethoxyaniline (95.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (74.6 mg, 0.25 mmol, 49% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.84 - 0.93 (m, 3 H) 0.98 (d, J=6.85 Hz, 3 H) 1.13 - 1.50 (m, 10 H) 1.67 - 1.81 (m, 1 H) 2.81 – 2.92 (dd, J= 12.00, 7.2 Hz, 1 H) 2.97 - 3.08 (dd, J= 12.11, 5.71 Hz, 1 H) 3.84 (br. s., 1 H) 6.50 - 6.59 (m, 2 H) 7.03 (d, J=8.91 Hz, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 14.3, 18.2, 22.8, 27.1, 29.8, 32.0, 33.0, 34.9, 50.8, 113.0, 119.2, 122.5, 140.4, 147.4. 19F NMR (282 MHz, CHLOROFORM-d)  ppm -58.5 IR(1/cm): 3432, 2958, 2927, 2857, 1613, 1515. High-Res MS: Calculated: 304.1888 (M+1), Found: 304.1885(M+1, C16H25NOF3)   113  N-(3-methylnonan-2-yl)aniline (3.26). Synthesized via Method A utilizing 3-methyl-2-pyridone (5.46 mg, 0.05 mmol), Ta(NMe2)5 (20.1 mg, 0.05 mmol), N-ethylaniline (60.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol) at 130 °C. Isolated as a yellow oil (33.8 mg, 0.17 mmol, 33% yield). 1H NMR (400 MHz, CHLOROFORM-d)  ppm 0.84 - 0.92 (t, J=6.7 Hz, 3 H) 0.96 (d, J=7.01 Hz, 3 H) 1.08 - 1.14 (m, 3 H) 1.15 - 1.49 (m, 9 H) 1.66 (m, 1 H) 3.43 (qd, J=6.50, 4.26 Hz, 1 H) 6.60 (d, J=7.92 Hz, 2 H) 6.66 (t, J=7.16 Hz, 1 H) 7.12 - 7.21 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  14.2, 15.6, 17.2, 22.8, 27.6, 29.8, 32.0, 32.3, 37.5, 52.6, 113.1, 116.7, 129.4, 148.0. IR(1/cm): 3412, 3052, 3019, 2958, 2925, 2855, 2872, 1600, 1503, High Res. MS: Calculated: 234.2222 (M+1) Found: 234.2225 (M+1, C16H28N)    2-(octan-2-yl)-1,2,3,4-tetrahydroquinoline (3.27). Synthesized via Method A utilizing 3-methyl-2-pyridone (5.46 mg, 0.05 mmol), Ta(NMe2)5 (20.1 mg, 0.05 mmol), 1,2,3,4-tetrahydroquinoline (66.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol) at 130 °C. Isolated as a yellow oil (110.4 mg, 0.45 mmol, 90% yield), characterization data matches known literature values.30 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.88 - 1.03 (m, 6 H) 1.11 - 1.64 (m, 12 H) 1.65 - 1.82 (m, 1 H) 1.83 - 1.94 (m, 1 H) 2.69 - 2.93 (m, 2 H) 3.16 - 3.25 (m, 1 H) 3.71 (br. s., 1 H) 6.51 (d, J=7.99 Hz, 1 H) 6.61 (t, J=7.31 Hz, 1 H) 6.93 - 7.03 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  14.3, 15.3, 22.8, 25.1, 27.1, 27.7, 29.8, 32.0, 32.8, 37.8, 56.3, 114.2, 116.9, 114  121.6, 126.8, 129.3, 145.3. IR(1/cm): 3417, 3052, 3015, 2955, 2924, 2854, 1586, 1607, 1483. High Res. MS: Calculated: 246.2222 (M+1) Found: 246.2220 (M+1, C17H28N)   N-(2-methyloctyl)-4-(phenylethynyl)aniline (3.28). Synthesized via Method A utilizing 3-methyl-2-pyridone (5.46 mg, 0.05 mmol), Ta(NMe2)5 (20.1 mg, 0.05 mmol), 3.97 (60.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol) at 130 °C. Isolated as a colorless, crystalline solid (48.0 mg, 0.15 mmol, 33% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.77 - 1.01 (m, 6 H) 1.03 - 1.50 (m, 12 H) 1.62 - 1.84 (m, 1 H) 2.81 – 2.94 (dd, J=12.11, 7.08 Hz, 1 H) 2.98 – 3.10 (dd, J=12.33, 5.94 Hz, 1 H) 6.52 (d, J=8.45 Hz, 2 H) 7.27 (m, 5 H) 7.39 - 7.56 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d) d ppm 14.3, 18.2, 22.8, 27.1, 29.7, 32.0, 33.1, 34.9, 50.1, 87.2, 80.7, 110.9, 112.4, 124.3, 127.6, 128.4, 131.4, 133.1, 148.7. IR(1/cm): 3421, 3055, 2955, 2924, 2853, 2209, 1609, 1594, 1519. High-Res MS: Calculated: 320.2378 (M+1), Found: 320.2375 (M+1, C23H30N)   115  N-(2-methyloctyl)cyclohexanamine (3.29). Synthesized via Method A utilizing 3-methyl-2-pyridone (5.46 mg, 0.05 mmol), Ta(NMe2)5 (20.1 mg, 0.05 mmol), N-methylcyclohexylamine (56.6 mg, 0.50 mmol) and allylbenzene (88.6 mg, 0.75 mmol). Isolated as a colorless oil (91.3 mg, 0.40 mmol, 79% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.89 (d, J=6.62 Hz, 3 H) 0.96 - 1.15 (m, 2 H) 1.15 - 1.34 (m, 4 H) 1.56 - 1.66 (m, 1 H) 1.67 - 1.78 (m, 2 H) 1.78 - 1.99 (m, 3 H) 2.30 - 2.52 (m, 3 H) 2.55 - 2.64 (m, 1 H) 2.73 (dd, J=13.36, 6.05 Hz, 1 H) 7.13 - 7.23 (m, 3 H) 7.24 - 7.33 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 18.3, 25.3, 26.4, 33.8, 35.7, 41.8, 53.3, 57.0, 125.9, 128.3, 129.3, 141.1. IR(1/cm): 3085, 3062, 3026, 2924, 2852, 1603, 1496, 1451. High-Res MS: Calculated: 232.2065 (M+1), Found: 232.2057 (M+1, C16H26N)   N-(2-phenylpropyl)aniline (3.47). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and styrene (78.1 mg, 0.75 mmol). Isolated as a yellow oil (97.2 mg, 0.46 mmol, 92% yield), characterization data matches known literature values.70 1H NMR (300 MHz, CHLOROFORM-d)  ppm 1.35 (d, J=6.85 Hz, 3 H) 1.56 (br. s., 1 H) 3.01 - 3.15 (sxt, J=7 Hz, 1 H) 3.20 - 3.30 (dd, J=12.33, 8.22 Hz, 1 H) 3.32 - 3.40 (dd, J=12.33, 6.40 Hz, 1 H) 6.57 - 6.65 (m, 2 H) 6.72 (t, J=7.31 Hz, 1 H) 7.13 - 7.26 (m, 5 H) 7.30 - 7.38 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 19.9, 39.3, 51.0, 77.2, 113.1, 117.4, 126.7, 128.8, 129.4, 144.6, 148.2. IR(1/cm): 3413, 3053, 3025, 2961, 2928, 2871, 1600, 1504, 1494. 116      N-(2-methyl-3-phenylpropyl)aniline (3.48). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and allylbenzene (88.6 mg, 0.75 mmol). Isolated as a yellow oil (112.7 mg, 0.50 mmol, 100% yield), characterization data matches known literature values.65 1H NMR (300 MHz, CHLOROFORM-d)  ppm 1.06 (d, J=6.62 Hz, 3 H) 1.47 - 1.61 (m, 1 H) 1.74 - 1.88 (m, 2 H) 2.56 - 2.80 (m, 2 H) 2.91 - 3.00 (m, 1 H) 3.06 - 3.15 (m, 1 H) 3.68 - 4.05 (br. s., 1 H) 6.61 (dd, J=8.57, 1.03 Hz, 2 H) 6.67 - 6.73 (m, 1 H) 7.12 - 7.24 (m, 5 H) 7.28 - 7.34 (m, 2 H), 13C NMR (75 MHz, CHLOROFORM-d)  18.2, 35.2, 41.5, 50.0, 112.8, 117.2, 126.1, 128.4, 129.2, 129.3, 140.6, 148.5. IR(1/cm): 3419, 3053, 3025, 2955, 2923, 2869, 1601, 1505.   Diastereomers not seperable N-(bicyclo[2.2.1]heptan-2-ylmethyl)aniline (3.49). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 2-norbornene (70.6 mg, 0.75 mmol). Isolated as a yellow oil (89.5 mg, 0.45 mmol, 89% yield), characterization data matches known literature values.65 1H NMR (300 MHz, CHLOROFORM-d)  ppm 1.07 - 1.26 (m, 4 H) 1.35 (dt, J=9.82, 1.83 Hz, 1 H) 1.43 - 1.62 (m, 3 H) 1.67 - 1.79 (m, 1 H) 2.16 (br. s., 1 H) 2.26 (br. s., 1 H) 2.78 - 2.99 (m, 2 117  H) 3.73 (br. s., 1 H) 6.59 - 6.65 (m, 2 H) 6.66 - 6.74 (m, 1 H) 7.13 - 7.23 (m, 2 H), 13C NMR (75 MHz, CHLOROFORM-d) 29.0, 30.0, 35.5, 36.0, 36.4, 39.4, 42.2, 49.4, 112.7, 117.1, 129.3, 148.7. IR(1/cm): 3419, 3049, 3019, 2944, 2909, 2870, 1605, 1505, High Res. MS: Calculated: 202.1596 (M+1) Found: 202.1594 (M+1, C14H20N),    N-(5,5-diethoxy-2-methylpentyl)aniline (3.50). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 5,5-diethoxy-1-pentene (118.7 mg, 0.75 mmol). Isolated as a yellow oil (87.5 mg, 0.33 mmol, 66% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.99 (d, J=6.62 Hz, 3 H) 1.22 (t, J=7.08 Hz, 6 H) 1.25 - 1.34 (m, 1 H) 1.47 - 1.85 (m, 5 H) 2.88 - 2.96 (dd, J=12.33, 7.08 Hz, 1 H) 3.01 - 3.11 (dd, J=12.33, 6.17 Hz, 1 H) 3.50 (dq, J=9.39, 7.07 Hz, 2 H) 3.65 (dq, J=9.37, 7.08 Hz, 2 H) 4.48 (t, J=5.60 Hz, 1 H) 6.61 (d, J=7.77 Hz, 2 H) 6.69 (t, J=7.31 Hz, 1 H) 7.12 - 7.22 (m, 2 H) 13C NMR (75 MHz, CHLOROFORM-d)  ppm 15.5, 18.1, 29.7, 32.1, 32.8, 50.3, 61.1, 103.2, 112.8, 117.1, 129.3, 148.6. IR(1/cm): 3397, 352, 2973, 2928, 2872, 1602, 1506. High-Res MS: Calculated: 266.2120 (M+1), Found: 266.2117 (M+1, C16H28NO2)   118  N-(2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butyl) (3.51). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 2-(3-buten-1-yl)-2-methyl-1,3-dioxolane (106.7 mg, 0.75 mmol). Isolated as a yellow oil (109.7 mg, 0.44 mmol, 88% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 1.00 (d, J=6.62 Hz, 3 H) 1.23 - 1.37 (m, 4 H) 1.52 - 1.83 (m, 4 H) 2.88 – 2.98 (dd, J=12.33, 7.08 Hz, 1 H) 3.02– 3.12 (dd, J=12.33, 5.94Hz, 1 H) 3.72 (br. s., 1 H) 3.89 - 4.01 (m, 4 H) 6.58 - 6.64 (m, 2 H) 6.65 - 6.73 (m, 1 H) 7.14 - 7.22 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 18.1, 24.0, 28.9, 33.1, 36.6, 50.3, 64.8, 110.2, 112.8, 117.1, 129.3, 148.7. IR(1/cm): 3404, 3055, 3021, 2979, 2949, 2924, 2873, 1602, 1507. High-Res MS: Calculated: 250.1807 (M+1), Found: 250.1803 (M+1, C15H24NO2)   N-(5-((tert-butyldimethylsilyl)oxy)-2-methylpentyl)aniline (3.52). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and t-butyldimethyl(4-penten-1-yloxy)silane (150.3 mg, 0.75 mmol). Isolated as a yellow oil (153.7 mg, 0.50 mmol, 100% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.10 (s, 6 H) 0.95 (s, 9 H) 1.02 (d, J=6.62 Hz, 3 H) 1.17 - 1.34 (m, 1 H) 1.46 - 1.73 (m, 3 H) 1.73 - 1.87 (m, 1 H) 2.87 – 2.97 (dd. J=12.33, 7.08 Hz, 1 H) 3.03 – 3.12 (dd. J=12.33, 5.94 Hz, 1 H) 3.64 (t, J=6.3 Hz, 2 H) 3.71 (br. s. 1H) 6.63 (dd, J=8.57, 1.03 Hz, 2 H) 6.71 (d, J=0.91 Hz, 1 H) 6.70 (t, J=7.30 Hz, 2 H) 7.19 (ddt, J=8.45, 7.21, 2.30 Hz, 2H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm -5.1, 18.2, 18.5, 26.1, 30.3, 31.0, 32.9, 50.4, 63.5, 112.8, 118.1, 129.3, 148.7 IR(1/cm): 3422, 3053, 2953, 2928, 2885, 2856, 1602, 1506. High-Res MS: Calculated: 308.2410 (M+1), Found: 308.2404 (M+1, C18H34NOSi) 119    N-(4-((tert-butyldimethylsilyl)oxy)-2-methylbutyl)aniline (3.53). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and t-butyldimethyl(3-buten-1-yloxy)silane (150.3 mg, 0.75 mmol). Isolated as a yellow oil (133.4 mg, 0.46 mmol, 91% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.07 (s, 6 H) 0.87 - 0.93 (s, 9 H) 1.00 (d, J=6.62 Hz, 3 H) 1.37 - 1.51 (m, 1 H) 1.60 - 1.74 (m, 1 H) 1.95 (dq, J=12.1, 6.7 Hz, 1 H) 2.88 - 3.12 (m, 2 H) 3.61 - 3.80 (m, 2 H) 3.85 (br. s., 1H) 6.61 (d, J=8.68 Hz, 2 H) 6.68 (t, J=7.3 Hz, 1 H) 7.17 (t, J=7.3 Hz). 13C NMR (75 MHz, CHLOROFORM-d)  ppm -5.1, 1.5, 26.1, 30.0, 37.9, 50.4, 61.2, 112.8, 117.0, 129.3, 148.7.4 IR(1/cm): 3421, 3058, 3020, 2954, 2928, 2857, 1603, 1506. High-Res MS: Calculated: 294.2253 (M+1), Found: 294.2254 (M+1, C17H32NOSi)   Regioisomer not separable N-(2-(dimethyl(phenyl)silyl)propyl)aniline (3.54). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and phenyldimethylvinylsilane (121.7 mg, 0.75 mmol). Isolated as a yellow oil (76.8 mg, 0.29 mmol, 57% yield), characterization data matches known literature values.30 120  1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.35 - 0.40 (s, 6 H) 1.10 (d, J=7.31 Hz, 3 H) 1.25 - 1.40 (m, 1 H) 2.99 (dd, J=12.11, 9.14 Hz, 1 H) 3.28 (dd, J=12.11, 5.03 Hz, 1 H) 3.57 (br. s., 1H) 6.49 (dd, J=8.57, 1.03 Hz, 2 H) 6.66 - 6.73 (m, 1 H) 7.17 (dd, J=8.45, 7.31 Hz, 2 H) 7.34 - 7.45 (m, 4 H) 7.53 - 7.61 (m, 2 H), 13C NMR (75 MHz, CHLOROFORM-d)  ppm -5.1, -4.32, 13.26, 46.8, 112.8, 117.1, 128.0, 129.3, 133.7, 134.1, 138.0, 148.4. IR(1/cm): 3416, 3071, 3050, 3021, 2954, 2866, 1602, 1505.   Regioisomer not separable N-(2-(2-bromophenyl)propyl)aniline (3.55). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 2-bromostyrene (137.3 mg, 0.75 mmol). Isolated as a yellow oil (87.0 mg, 0.30 mmol, 60% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 1.35 (d, J=6.85 Hz, 3 H) 3.24 - 3.44 (m, 2 H) 3.64 (dq, J=13.96, 7.00 Hz, 1 H) 6.64 (dd, J=8.57, 1.03 Hz, 2 H) 6.67 - 6.75 (m, 1 H) 7.06 - 7.36 (m, 5 H) 7.60 (dd, J=8.34, 0.80 Hz, 1 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 19.1, 38.1, 50.1, 113.0, 117.5, 125.2, 127.5, 128.0, 128.1, 129.3, 133.2, 143.5, 148.1. IR(1/cm): 3412, 3052, 3020, 2964, 2926, 2870, 1601, 1504, 1470. High-Res MS: Calculated: 290.0544 (M+1), Found: 290.0541 (M+1, C15H17NBr)   121   Regioisomer not separable N-(2-(4-bromophenyl)propyl)aniline (3.56). Synthesized via Method B utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 4-bromostyrene (137.3 mg, 0.75 mmol). Isolated as a yellow oil (107.4 mg, 0.37 mmol, 74% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 1.33 (d, J=7.08 Hz, 3 H) 3.00 - 3.10 (m, 1 H) 3.17 - 3.41 (m, 2 H) 3.57 (br. s., 1 H) 6.59 (dd, J=8.57, 1.03 Hz, 2 H) 6.65 - 6.80 (m, 1 H) 7.03 - 7.24 (m, 4 H) 7.34 - 7.54 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 19.7, 38.9, 50.9, 113.1, 117.7, 120.5, 129.2, 129.4, 131.9, 143.4, 148.0 IR(1/cm): 3412, 3050, 3021, 2960, 2926, 2871, 1601, 1504, 1488. High-Res MS: Calculated: 290.0544 (M+1), Found: 290.0548 (M+1, C15H17NBr)   4-methoxy-N-(3-methyl-5-(2-methyl-1,3-dioxolan-2-yl)pentan-2-yl)aniline (3.57). Synthesized via Method A utilizing 3-methyl-2-pyridone (5.46 mg, 0.05 mmol), Ta(NMe2)5 (20.1 mg, 0.05 mmol), N-ethyl-4-methoxyaniline (66.6 mg, 0.50 mmol) and 2-(3-buten-1-yl)-2-methyl-122  1,3-dioxolane (106.7 mg, 0.75 mmol) at 130 °C. Isolated as a yellow oil (66.0 mg, 0.23 mmol, 45% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.96 (d, J=6.85 Hz, 3 H) 1.10 (d, J=6.62 Hz, 3 H) 1.13 - 1.28 (m, 1 H) 1.30 (s, 3 H) 1.50 - 1.79 (m, 4 H) 3.35 (qd, J=6.40, 4.11 Hz, 1 H) 3.75 (s, 3 H) 3.84 - 3.98 (m, 4 H) 6.51 - 6.60 (m, 2 H) 6.73 - 6.81 (m, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 15.9, 17.2, 23.8, 26.4, 37.1, 37.5, 53.8, 55.9, 64.7, 110.3, 114.7, 115.0, 142.2, 151.8. IR(1/cm): 3384, 2957, 2877, 230, 1618, 1509. High-Res MS: Calculated: 294.2069 (M+1), Found: 294.2070 (M+1, C17H28NO3)   N-(6-((tert-butyldimethylsilyl)oxy)-3-methylhexan-2-yl)-4-methoxyaniline (3.58). Synthesized via Method A utilizing 3-methyl-2-pyridone (5.46 mg, 0.05 mmol), Ta(NMe2)5 (20.1 mg, 0.05 mmol), N-ethyl-4-methoxyaniline (66.6 mg, 0.50 mmol) and t-butyldimethyl(4-penten-1-yloxy)silane (150.3 mg, 0.75 mmol) at 130 °C. Isolated as a yellow oil (84.4 mg, 0.24 mmol, 48% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.02 - 0.07 (s, 6 H) 0.87 - 0.92 (s, 9 H) 0.96 (d, J=6.85 Hz, 3 H) 1.10 (d, J=6.62 Hz, 3 H) 1.13 - 1.23 (m, 1 H) 1.37 - 1.73 (m, 4 H) 3.18 (br. s, 1 H) 3.35 (qd, J=6.17, 4.34 Hz, 1 H) 3.59 (t, J=6.28 Hz, 2 H) 3.75 (s, 3 H) 6.51 - 6.59 (m, 2 H) 6.74 - 6.80 (m, 2H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm -5.1, 16.0, 17.3, 18.5, 26.1, 28.3, 123  30.9, 37.3, 53.8, 56.0, 63.6, 114.7, 115.1, 142.3, 151.8. IR(1/cm): 3409, 2955, 2930, 2856, 1510. High-Res MS: Calculated: 352.2672 (M+1), Found: 352.2667 (M+1, C20H38NO2Si)  3.4.2.4.2 Tantalum Complexes  Tetra(dimethylamido)(κ2-N,O-2-pyridonato)tantalum(V) (3.78) Synthesized via Method D utilizing 2-hydroxypyridine (95 mg, 1 mmol). Attempts at recrystallization were unsuccessful, complex was used as a crude, orange oil (315 mg, 0.70 mmol, 70% yield) 1H NMR (400 MHz, Tol) δ ppm 3.30 - 3.37 (m, 24 H) 3.58 (s, 2 H) 6.20 - 6.27 (m, 1 H) 6.37 (s, 1 H) 7.59 - 7.67 (m, 1 H); 13C NMR (101 MHz, Tol) δ ppm 45.97, 46.44, 111.58, 139.10, 142.46, 169.81; Low Res. Mass Spec: m/Z =  451 (M), 407 (M – 44, loss of dimethylamido ligand)  Tetrakis(dimethylamido)(κ2-N,O-4-methyl-2-pyridonato)tantalum(V) (3.79) Synthesized via Method D utilizing 2-hydroxy-4-methylpyridine (109 mg, 1 mmol). Recrystallization from hot hexanes yielded X-ray crystallography-quality crystals as red prisms (292 mg, 0.63 mmol, 63% yield) 1H NMR (400 MHz, Tol) δ ppm 1.82 (s, 3 H) 3.37 (s, 24 H) 6.15 (d, J=5.48 Hz, 1 H) 6.25 (s, 1 H) 7.59 (d, J=5.48 Hz, 1 H); 13C NMR (101 MHz, Tol) δ ppm 21.2, 46.0, 112.0, 113.5, 141.9, 150.6, 170.1; Low Res. Mass Spec: m/z = 465 (M), 421 (M – 44, loss of dimethylamido ligand),   124   Tetrakis(dimethylamido)(κ2-N,O-4-trifluoromethyl-2-pyridonato)tantalum(V) (3.80) Synthesized via Method D utilizing 3.98 (163 mg, 1 mmol). Recrystallization in hot hexanes yielded X-ray crystallography-quality crystals of product as yellow prisms (92 mg, 0.18 mmol, 18% yield). 1H NMR (400 MHz, Tol) δ ppm 3.26 (s, 24 H) 6.47 (d, J=5.48 Hz, 1 H) 6.70 (s, 1 H) 7.55 (d, J=5.79 Hz, 1 H); 13C NMR (101 MHz, Tol) δ ppm 45.9, 107.2 (q, J3C-F=3 Hz), 108.1 (q, J3C-F=3 Hz), 123.7 (q, JC-F=274 Hz), 141.1 (q, J2C-F=32 Hz), 144.0, 169.6; 19F NMR (377 MHz, Tol) δ ppm -64.7; Low Res. Mass Spec: 519 (M), 475 (M – 44, loss of dimethylamido ligand)    Tetrakis(dimethylamido)(κ2-N,O-4-benzyloxy-2-pyridonato)tantalum(V) (3.81) Synthesized via Method D utilizing 2-hydroxy-5-benzyloxypyridine (199 mg, 1 mmol). All attempts at purification were unsuccessful, product was isolated as a dark yellow oil. (467 mg, 0.84 mmol, 84% yield). 1H NMR (400 MHz, Tol) δ ppm 3.41 (s, 24 H) 4.44 (s, 2 H) 6.00 (d, J=2.13 Hz, 1 H) 6.13 - 6.17 (m, 1 H) 7.04 - 7.12 (m, 5 H) 7.50 (d, J=6.09 Hz, 1 H); 13C NMR (101 MHz, Tol) δ ppm 46.0, 69.7, 95.1, 103.0, 127.9, 128.2, 128.3, 129.2, 143.2, 168.1. Low Res. Mass Spec: m/z = 557 (M), 513 (M – 44, loss of dimethylamido ligand), 466 (M-91, loss of benzyl fragment), 91 (benzyl fragment)  125   Tetrakis(dimethylamido)(κ2-N,O-4-bromo-2-pyridonato)tantalum(V) (3.82) Synthesized via Method D utilizing 2-hydroxy-5-bromopyridine (174 mg, 1 mmol). Recrystallization from hot hexanes yielded X-ray crystallography-quality crystals of product as yellow prisms (146 mg, 0.25 mmol, 25% yield) 1H NMR (400 MHz, Tol) δ ppm 3.28 (s, 24 H) 6.46 (dd, J=5.79, 1.52 Hz, 1 H) 6.67 (d, J=1.83 Hz, 1 H) 7.28 (d, J=5.79 Hz, 1 H); 13C NMR (101 MHz, Tol) δ ppm 45.9, 115.1, 115.5, 135.0, 143.0, 169.7; Low Res. Mass Spec: m/z = 529 & 531 (M), 485 & 487 (M – 44, loss of dimethylamido ligand).    Tetrakis(dimethylamido)(κ2-N,O-5-methyl-2-pyridonato)tantalum(V) (3.83) Synthesized via Method D utilizing 2-hydroxy-5-methylpyridine (109 mg, 1 mmol). Attempts at recrystallization were unsuccessful, complex was used as a crude, orange oil (377 mg, 0.81 mmol, 81% yield) 1H NMR (400 MHz, Tol) δ ppm 1.85 (s, 3 H) 3.37 (s, 24 H) 6.34 (d, J=8.54 Hz, 1 H) 6.92 (dd, J=8.54, 2.44 Hz, 3 H) 7.62 (dd, J=1.53, 0.92 Hz, 1 H); 13C NMR (101 MHz, Tol) δ ppm 17.52, 46.03, 111.29, 120.34, 140.57, 141.71, 168.06; Low Res. Mass Spec: m/Z =  465 (M), 485 & 487 (M – 44, loss of dimethylamido ligand)  126   Tetrakis(dimethylamido)(κ2-N,O-5-trifluoromethyl-2-pyridonato)tantalum(V) (3.84) Synthesized via Method D utilizing 2-hydroxy-5-trifluoromethylpyridine (163 mg, 1 mmol). Recrystallization in hot hexanes yielded X-ray crystallography-quality crystals as yellow prisms (467 mg, 0.90 mmol, 90% yield) 1H NMR (400 MHz, Tol) δ ppm 3.24 (s, 24 H) 6.21 (d, J=8.85 Hz, 1 H) 7.24 (dd, J=8.85, 2.75 Hz, 1 H) 8.15 - 8.19 (m, 1 H); 13C NMR (101 MHz, Tol) δ ppm 45.79, 111.99, 114.71, 115.16, 136.24 (d, J=3.07 Hz,), 140.73 (d, J=4.60 Hz),171.30; 19F NMR (377 MHz, Tol) δ ppm -60.40; Low Res. Mass Spec: m/z =  519 (M), 475 (M – 44, loss of dimethylamido ligand)   Tetrakis(dimethylamido)(κ2-N,O-5-benzyloxy-2-pyridonato)tantalum(V) (3.85) Synthesized via Method D utilizing 2-hydroxy-5-benzyloxypyridine (199 mg, 1 mmol). Recrystallization from hot hexanes yielded product as a yellow powder (356 mg, 0.64 mmol, 64% yield) 1H NMR (400 MHz, Tol) δ ppm 3.41 (s, 24 H) 4.42 (s, 2 H) 5.99 - 6.01 (m, 1 H) 6.15 (dd, J=6.24, 2.28 Hz, 1 H) 7.08 - 7.11 (m, 5 H) 7.50 (d, J=6.09 Hz, 1 H); 13C NMR (101 MHz, Tol) δ ppm 46.00, 69.69, 95.12, 102.95, 136.42, 143.14, 168.09, 171.82; Low Res. Mass Spec: m/z = 557 (M), 127  513 (M – 44, loss of dimethylamido ligand), 466 (M – 91, loss of benzyl fragment), 91 (benzyl fragment)   Tetrakis(dimethylamido)(κ2-N,O-5-bromo-2-pyridonato)tantalum(V) (3.86)  Synthesized via Method D utilizing 2-hydroxy-5-bromopyridine (174 mg, 1 mmol). Recrystallization from hot hexanes yielded product as a yellow prism (360 mg, 0.68 mmol, 68% yield) 1H NMR (400 MHz, Tol) δ ppm 3.26 (s, 24 H) 6.11 (dd, J=8.85, 0.61 Hz, 1 H) 7.09 (dd, J=8.85, 2.75 Hz, 1 H) 7.88 - 7.91 (m, 1 H); 13C NMR (101 MHz, Tol) δ ppm 45.88, 105.58, 113.53, 141.97, 143.28, 168.15; Low Res. Mass Spec: m/Z =  529 & 531 (M), 485 & 487 (M – 44, loss of dimethylamido ligand)  3.4.2.4.3 Polysubstituted Piperidines  1-(4-methoxyphenyl)-2,3-dimethylpiperidine (3.88). To a solution of 3.58 (97.0 mg, 0.28 mmol) in acetonitrile (1 mL) was added tosyl fluoride (144.16 mg, 0.83 mmol) and DBU (126.0 mg, 123.7 128  μL, 0.83 mmol), and the solution was stirred at reflux for 16 hours. After 16 hours, the solution was cooled and diluted with 1M NaOH (5 mL). The solution was stirred at RT for 1 hour, then diluted with ethyl acetate (10 mL). The organic phase was then washed with 5 mL each water and brine, dried over MgSO4, concentrated in vacuo, and purified via flash chromatography (Silica gel stationary phase, Ethyl acetate/Hexanes mobile phase with 0.1% (v/v) triethylamine). Concentration of the fractions in vacuo yielded pure 3.88 as a colorless solid (55.6 mg, 0.25 mmol 94% yield). 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.80 (d, J=6.62 Hz, 3 H) 0.92 (d, J=6.85 Hz, 3 H) 1.23 - 1.41 (m, 1 H) 1.47 - 1.82 (m, 3 H) 1.98 - 2.13 (m, 1 H) 2.86 (td, J=11.82, 3.54 Hz, 1 H) 3.06 - 3.18 (m, 1 H) 3.77 (s, 3 H) 6.78 - 6.92 (m, 4 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 6.4, 19.2, 25.8, 26.7, 34.8, 42.5, 55.7, 58.1, 114.5, 118.6, 145.6, 152.9. IR(1/cm): 3061, 3044, 2956, 2929, 2876, 2860, 2830, 1509, High-Res MS: Calculated: 219.1623, Found: 219.1620 (C14H21NO)   1-(4-methoxyphenyl)-2,3,6-trimethylpiperidine (3.89). To a solution of 3.57 (66.0 mg, 0.22 mmol) in THF (1.5 mL) was added 1M HCl (1.5 mL), and the solution was stirred for 3 hours at room temperature. To the reaction mixture was then added NaOH (63.0 mg, 1.57 mmol), and the solution was stirred for 5 minutes, during which partitioning of the THF and water was observed. 129  CAUTION! Failure to fully neutralize the HCl and basify the reaction solution could lead to the generation of hydrogen cyanide! After full dissolution of the NaOH, the aqueous phase was removed, sodium cyanoborohydride (28.3 mg, 0.45 mmol) was added to the organic phase, and the solution was stirred at RT for 16 hours. The solution was then diluted with ethyl acetate (10 mL), and the organic phase was washed with 5 mL each 2M NaOH, water, and brine, dried over MgSO4, concentrated in vacuo, and purified via flash chromatography (Silica gel stationary phase, Ethyl acetate/Hexanes mobile phase with 0.1% (v/v) triethylamine). Concentration of the fractions in vacuo yielded pure 3.89-d1 (13.0 mg, 0.06 mmol, 25% yield) and pure 3.89-d2 (14.0 mg, 0.06 mmol, 27% yield), each as colorless solids.   Minor Product 3.89-d1. 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.71 (d, J=6.62 Hz, 3 H) 0.79 (d, J=6.17 Hz, 3 H) 1.03 (d, J=6.85 Hz, 3 H) 1.50 - 1.72 (m, 5 H) 1.72 - 1.85 (m, 1 H) 2.99 - 3.19 (m, 2 H) 3.79 (s, 3 H) 6.82 (d, J=9.14 Hz, 2 H) 6.98 (d, J=9.14 Hz, 2 H), 13C NMR (75 MHz, CHLOROFORM-d)  ppm 13.9, 18.5, 21.3, 30.5, 30.6, 34.7, 55.6, 55.9, 58.6, 113.9, 125.1, 143.9, 155.6 IR(1/cm): 3032, 2961, 2928, 2877, 2856, 2835, 1607, 1583, 1508. High-Res MS: Calculated: 234.1858 (M+1), Found: 234.1855 (M+1, C15H24NO) 130   Major Product 3.89-d2. 1H NMR (300 MHz, CHLOROFORM-d)  ppm 0.73 (d, J=6.85 Hz, 3 H) 0.88 (d, J=6.85 Hz, 3 H) 0.95 (d, J=5.94 Hz, 3 H) 1.25 - 1.54 (m, 3 H)1.79 (dt, J=5.88, 2.88 Hz, 1 H) 2.13 (br. s., 1 H) 3.19 - 3.32 (m, 2 H) 3.79 (s, 3 H) 6.83 (d, J=9.14 Hz, 2 H) 6.98 (d, J=8.91 Hz, 2 H). 13C NMR (75 MHz, CHLOROFORM-d)  ppm 5.3, 19.4, 21.7, 27.1, 35.7, 35.8, 45.5, 55.5, 62.7, 113.6, 127.1, 144.3, 155.1. IR(1/cm): 3036, 2958, 2923, 2833, 1507. High-Res MS: Calculated: 234.1858 (M+1), Found: 234.1857 (M+1, C15H24NO) 131  Chapter 4: Development of an In-situ Generated Hydroaminoalkylation Catalyst Utilizing Tantalum Pentafluoride 4.1 Introduction While many catalysts consist of a single molecule or complex that facilitates the catalyzed reaction, they generally consist of a combination of various components, each of which performs an important role in the catalysis. For early transition metal hydroaminoalkylation catalysis, the precatalysts can be broken into three major components: the metal center, the ancillary ligands, and the sacrificial ligands (Figure 4.1). The metal center for early transition metal catalyzed hydroaminoalkylation, which has so far been limited to tantalum, niobium, titanium, zirconium, and scandium, is the component where the catalysis occurs.46, 49, 51, 55, 57, 65, 67, 76-77, 81 Ancillary ligands, such as the N,O-chelating ligands used by the Schafer research group, fine-tune the electronic and steric environment of the metal center to facilitate the catalysis.47, 64-65, 68 Finally, sacrificial ligands are ligands that are installed on the precatalyst to form a stable species, but must be replaced by the substrate before the productive hydroaminoalkylation reaction begins.42, 70, 72  Figure 4.1 Generalized early transition metal hydroaminoalkylation pre-catalyst The clear majority of catalyst development for early transition metal catalyzed hydroaminoalkylation has centered on the metal center and the ancillary ligands, as these components are not only more impactful on the catalysis itself, but also are much easier to control, as the metal precursors are often readily available through commercial vendors and ancillary ligands are often either commercially available or can be synthesized. However, as the sacrificial 132  ligands are generally already installed upon the metal center when purchased, altering the sacrificial ligand often requires the synthesis of new metal precursors. As the synthesis of these reactive precursors requires rigorous exclusion of both air and moisture, the use of such catalysts is often challenging 4.1.1 Sacrificial Ligands on Hydroaminoalkylation Precatalysts Sacrificial ligands are necessary for both the generation of stable precatalysts and the activation of metal-bound substrates to form the initial metallaziridine through protonolysis (Figure 4.2, for a more detailed discussion of the mechanism see Chapter 1.1).42 Ideal sacrificial ligands do not interact with either the starting materials, catalytic intermediates, or products after catalysis has begun. The sacrificial ligand must be sufficiently basic as to be able to deprotonate the nitrogen of the coordinated amine substrate to form the metal-substrate complex that is a precursor to the metallaziridine.  Figure 4.2 Protonolysis of sacrificial ligands with substrate to form metallaziridine The most prevalent sacrificial ligands used for early transition metal catalyzed hydroaminoalkylation are dimethylamido ligands. First used as part of Maspero’s initial report on hydroaminoalkylation, dimethylamido ligands have been favored due to their high basicity, thermal stability, and the commercial availability of homoleptic dimethylamido metal complexes.27, 30, 52-53 However, they suffer a major drawback. The dimethylamine that is liberated 133  during catalyst activation is a competent substrate for hydroaminoalkylation. If it is not vented from the reaction vessel, dialkylated dimethylamine byproducts can form. This slows the reaction and complicates product isolation (Scheme 4.1).66, 69 While this side reaction was the product of the initial report by Maspero, and has since been expanded upon by Doye et al. to selectively generate mono- and dialkylated dimethylamine-based hydroaminoalkylation products, this is a common challenge for dimethylamido-based hydroaminoalkylation catalysts.27, 60  Scheme 4.1 Hydroaminoalkylation of liberated dimethylamine to produce di-alkylated dimethylamine byproducts. To avoid the formation of the dialkylated dimethylamine byproduct, early transition metal hydroaminoalkylation catalysts using alkyl ligands as the sacrificial ligands have been developed (Figure 4.3). The first instance of the use of alkyl ligands as reactive ligands was in 2009, when Doye et. al. utilized 4.1 as a hydroaminoalkylation precatalyst, which exhibited modestly higher activity over the corresponding dimethylamido titanium precatalyst.54 This was then expanded upon a year later with the development of precatalyst 4.2, which exhibited higher reactivity and selectivity.49, 55 The first example of a tantalum alkyl hydroaminoalkylation precatalyst was reported in 2013 by the Schafer Group, utilizing 4.3 as a precatalyst.70 This was expanded upon later that year in the report of the first room-temperature early transition metal hydroaminoalkylation precatalyst, 4.4.46 Recently, the Schafer Group has reported the development of an alkyl tantalum ureate precatalyst 4.5, which can catalyze the hydroaminoalkylation of 1-octene with N-methylaniline at an unprecedented rate.72 Both of the scandium precatalysts 4.6 and 4.7 reported by Hou and co-workers and Xu and co-workers use 134  alkyl sacrificial ligands as well.51, 77 However, drawbacks of these metal alkyl precatalysts include  challenging syntheses, often requiring the use of highly pyrophoric dialkyl zinc reagents for synthesis.70, 72 In addition, these complexes are often even more air and moisture sensitive than the corresponding dimethylamido complexes. Tantalum methyl complexes are also light sensitive.  Figure 4.3 Early transition metal hydroaminoalkylation catalysts with alkyl sacrificial ligands A common problem for all of the currently utilized sacrificial ligands is that the ligands used are incredibly basic, rendering the resulting precatalysts highly susceptible to hydrolysis. This limits the practicality of these precatalysts, as they either must be used entirely within a inert atmosphere glovebox or as premade solutions stored in specialized glassware. However, a potential solution to this problem can be found in the work of Herzon and Hartwig. In their second report, Herzon and Hartwig describe the formation and use of the pre-activated catalyst 4.8, which has been synthesized through sequential transmetallation/salt metathesis and is capable of catalyzing the hydroaminoalkylation of 1-octene with N-methylaniline at a lower temperature than 135  Ta(NMe2)5 (Scheme 4.2).64 While the formation of unique, pre-activated catalysts would be impractical for general use due to the requirement for the synthesis of a new catalyst for each amine substrate used, it suggests an alternative route using tantalum halide salts as precursors in the formation of activated early transition metal hydroaminoalkylation catalysts.  Scheme 4.2 Formation and use of Hartwig’s activated hydroaminoalkylation catalyst 4.1.2 Tantalum Pentafluoride as a Tantalum Source One of the key challenges in the development of practical hydroaminoalkylation catalysts is that the precatalysts, or the metal precursors to the precatalysts, cannot be handled in ambient conditions due to high air and moisture sensitivity. While the storage and use of stock solutions of air and moisture sensitive reagents is a common skill in organic synthesis labs, the creation of these solutions can often be challenging if a inert atmosphere glovebox is not available, and solutions of the metal precursors are currently not commercially available. As such, the identification of a suitable, air stable metal precursor is necessary for the development of a practical early transition metal catalyzed hydroaminoalkylation method. Tantalum pentafluoride exhibits potential for use as an air stable tantalum precursor for hydroaminoalkylation catalysis. While its main use is as an intermediate in the separation of tantalum from niobium, it has also been utilized as a catalyst for reactions such as the alkylation of anilines with benzyl alcohols and polymerization of β-pinene.119-121 Tantalum pentafluoride has 136  also been shown to be more stable to hydrolysis than other tantalum complexes (Figure 4.4), which can be attributed to both the high tantalum-fluoride bond strength and tetrameric structure in the solid state.122-125  Figure 4.4 Hydrolysis of TaF5 and NbF5 in 40 °C water 122 Given this increased stability compared to other tantalum precursors, it was hypothesized that tantalum pentafluoride could be utilized as a tantalum source for hydroaminoalkylation. Addition of an ancillary proteo-ligand and the amine and alkene substrates to tantalum pentafluoride, followed by addition of a strong base to deprotonate the ligand and amine to form the corresponding ligand and amido salts, would allow for the generation of the catalyst in situ through salt metathesis (Scheme 4.3). 137   Scheme 4.3 Proposed generation of tantalum hydroaminoalkylation catalyst in situ from tantalum pentafluoride 4.1.3 Scope of Chapter This chapter explores the development of early transition metal catalyzed hydroaminoalkylation using a catalyst generated in situ from TaF5.  The generation of the catalyst system was developed and, after optimization, a substrate scope was explored with one substrate being further reacted to synthesize a substituted tetrahydroquinoline. The formation of the catalyst system was studied through NMR spectroscopy. Finally, a glovebox-free procedure was then developed and the bench stability of TaF5 was studied to determine the feasibility of using and storing this reagent outside of a glovebox. 4.2 Results and Discussion 4.2.1 Initial Results and Controls Initial results indicated that it was indeed possible to utilize TaF5 as a catalyst precursor, with the hydroaminoalkylation of 1-octene with N-methylaniline reaching 84% yield after 44 hours at 70 °C with 0.5 equivalents of methyl lithium and utilizing 4.10 as a ligand (Table 4.1, entry 1). As α-alkylation of amines through ortho-lithiation is a known reaction, several controls were performed (Table 4.1, entries 2-7).126 Excluding methyl lithium from the reaction conditions lead 138  to a complete suppression of the yield (Entry 2). Notably, exclusion of TaF5 from the reaction conditions produced the same effect (Entry 3), indicating that this reaction is not proceeding through an ortho-lithiation pathway. The reaction does occur when an external ligand is not present but results in reduced yield (Entry 4). Control reactions with only one component of the catalyst mixture were performed, but none exhibited any conversion (Entries 5-7).  Figure 4.5 Initial hydroaminoalkylation reaction using TaF5 Table 4.1 Control experiments for tantalum fluoride-catalyzed hydroaminoalkylation reaction Entry Ta Source Ligand MeLi equiv. Yield (%) 1 TaF5 4.10 0.5 84 2 TaF5 4.10 0 0 3 - 4.10 0.5 0 4 TaF5 - 0.5 66 5 - - 0.5 0 6 TaF5 - 0 0 7 - 4.10 0 0  4.2.2 Optimization of Reaction Having established initial conditions for the reaction and performed necessary control experiments, the reaction conditions were optimized (Table 4.2). Increasing the equivalents of methyl lithium leads to a decrease in yield (Entries 2-4), indicating that the presence of N-H bonds in the reaction mixture is necessary to achieve catalyst turnover. Changing the ligand led to 139  decrease in yields (Entries 5-10), with no reactivity observed with amidate ligand 4.15 (Entry 9) or pyridonate ligand 4.16 (Entry 10) at 70 °C. Potassium heptafluorotantalate, a water-stable intermediate in the production of tantalum metal, was tested (Entry 17), but no reactivity was observed.127 Table 4.2 Optimization of hydroaminoalkylation reaction  Entry Ta Source Ligand MeLi equiv. Yield (%) 1 TaF5 4.10 0.5 84 2 TaF5 4.10 1.0 25 3 TaF5 4.10 1.5 8 4 TaF5 4.10 2.0 1 5 TaF5 4.11 0.5 11 6 TaF5 4.12 0.5 49 7 TaF5 4.13 0.5 11 8 TaF5 4.14 0.5 8 9 TaF5 4.15 0.5 0 10 TaF5 4.16 0.5 0 11 K2TaF7 4.10 0.5 0  140  Next, a variety of bases were tested for the reaction (Table 4.3). Interestingly, only alkyl lithium bases proved to be active (Entries 1,2). Use of dibutyl magnesium (Entry 3) and Grignard reagents (Entries 4-6) did not lead to any yield. This can be explained through the thermodynamics of the catalyst formation. Tantalum-fluoride bonds are incredibly strong, with D°298 = 537-657 kJ/mol in the gas phase (Table 4.4).124 Of a variety of common strong bases, only lithium bases have a favorable enough bond formation energy to allow for formation of the catalytically active tantalum species.128 As such, NaHMDS and NaH (Table 4.3, Entry 7,8), both weaker bases and lacking the benefit of the lithium fluoride bond formation, were not active. While LDA (Entry 9) is a strong lithium base, it did not allow for catalytic activity, likely due to the resulting diisopropylamine produced that could compete with the substrates for binding to the tantalum. Tetramethylsilane was also investigated as an activating reagent, attempting to utilize the strength of silicon-fluoride bond formation to drive forward catalyst synthesis in situ, however this was unsuccessful.       141  Table 4.3 Optimization of base for catalyst activation  Entry Base Yield 1 Methyl lithium 84% 2 n-Butyl lithium 80% 3 Dibutyl magnesium 0% 4 TMSCH2MgBr 0% 5 MeMgBr 0% 6 BnMgBr 0% 7 NaHMDS 0% 8 NaH 0% 9 LDA 0% 10 Me4Si 0%  Table 4.4 Bond dissociation energies of selected metal-fluoride bonds124, 128 Bond D°298 (kJ/mol) Ta – F 573 FTa – F 657 F2Ta – F 537 F3Ta – F 544 F4Ta – F 577 Li – F 577 Na – F 481 Mg – F  462  A goal to be realized with this in situ catalyst system is its utilization outside of an inert atmosphere glovebox. Towards this, a procedure for the use of this catalyst system using syringe techniques was developed. While the TaF5 was stored and handled in an inert atmosphere glovebox, the remainder of the reaction was set-up on a Schlenk line, using ligand and substrates that had not been rigorously dried, anhydrous toluene from a commercial source with no further 142  drying, and methyl lithium in diethyl ether from a Sure-Seal bottle (Scheme 4.4). The reaction time was also increased to 48 hours. Using this procedure, a yield of 84% of 4.9 was obtained, indicating that this reaction was capable of being used in conditions more akin to what would be used in a typical synthetic route-scouting process.  Scheme 4.4 Tantalum-fluoride catalyzed hydroaminoalkylation using non-rigorously dried materials Unfortunately, as reproducibility was evaluated, inconsistent results were obtained. Different batches of substrates and ligand gave very different results, e.g. small levels of impurity in an older batch of ligand, as detected through 31P NMR spectroscopy and caused through degradation, was enough to significantly suppress reactivity. In addition, it was showed that while the amine and alkene substrates are not required to be rigorously dried, they are required to be of high purity 4.2.3 Substrate Scope With optimized conditions in hand, a variety of substrates were tested for activity with this catalyst system (Table 4.5). Both electron withdrawing (4.17) and donating (4.19) groups are tolerated, but the highly withdrawing trifluoromethoxy group (4.21) suppresses reactivity. While the presence of electron withdrawing groups such as a bromide leads to decreased yield similar to that of 4.4, whether the very low yield of the trifluoromethoxy-substituted aniline is due to electronic effects or due to potential C-F activation by the tantalum catalyst is unknown. 143  Dialkylamines (4.18) are also competent substrates, but steric bulk at the amine from ortho-substituents (4.20) leads to a sharp drop in yield. Silyl-protected alcohols (4.22) exhibit much lower reactivity compared to other catalyst systems, likely due to the fluoride in solution deprotecting the alcohol, which can subsequently bind to the catalyst and quench reactivity.69, 78 Ketals are tolerated (4.23), allowing for the synthesis of precursors to various saturated N-heterocycles.69 Styrene (4.24) exhibits low yield due to the formation of polystyrene in the reaction mixture. Notably, allyl benzenes (4.25, 4.26) react with good yields, with no base-catalyzed isomerization to β-methyl styrene observed. 144  Table 4.5 Substrate scope of tantalum fluoride catalyst system  The ability to utilize 2-bromoallylbenzene to synthesize 4.26 opens a path to making a new class of N-heterocycles, tetrahydroquinolines. By utilizing Buchwald-Hartwig conditions, 4.26 can be cyclized to synthesize 4.27 with very good yield (Scheme 4.5). Such heterocycles are often found in pharmaceutically relevant molecules, and the ability to synthesize them through simple two step coupling procedures may open more efficient routes towards the synthesis of such molecules.129 145   Scheme 4.5 Synthesis of tetrahydroquinoline 4.27 from hydroaminoalkylation product 4.26 4.2.4 NMR Studies of In-situ Catalyst Generation One observation made during the reaction set-ups was that various color changes would occur during different additions. TaF5 is a white powder that is insoluble in toluene but, after the addition of N-methylaniline, TaF5 would dissolve and the reaction mixture exhibited a bright yellow color. This color would then be quenched upon the addition of phosphoramidate ligand 4.10 to generate a colorless solution, which would persist during the addition of alkene and toluene until the addition of methyl lithium, at which point the solution would turn a deep yellow-orange that is often observed with tantalum-catalyzed hydroaminoalkylation. Given the complex nature of the catalyst system, an NMR study was undertaken to try to identify what occurs during the catalyst formation and provide insight into potential future optimization of the system.  1H, 19F, and 31P NMR spectra in d8-toluene were taken of the catalyst system after key steps during the reaction set-up (Scheme 4.6). Two different order of additions were investigated: TaF5 → amine → ligand → methyl lithium, and TaF5 → ligand → amine → methyl lithium. Investigation of the effect of adding alkene or toluene at different points in the reaction set-up was not performed, as it was considered unlikely that either would have significant impact on the tantalum species formed prior to methyl lithium addition and heating. To prevent the 1H NMR spectra being overwhelmed by N-methylaniline or diethyl ether signals, the amount of N-methylaniline was reduced from 10 equivalents (relative to TaF5) to 2 equivalents, with 5 146  equivalents used with spectra containing methyl lithium, and methyl lithium was used as a solid instead of in solution with diethyl ether.  Scheme 4.6 Sequential addition of catalyst system reagents and substrate for NMR study  As TaF5 is insoluble in toluene, it was not possible to record an initial 19F NMR spectrum of it. However, it is known that TaF5 exists as a tetramer in the solid state, with each tantalum ion exhibiting octahedral geometry and bound to each other through bridging fluorides (Figure 4.6).125 Upon addition of N-methylaniline (NMA), the color changes from a colorless white powder to bright yellow. As this also occurs upon the addition of a solid amine, such as 4-methoxy-N-methylaniline, to TaF5, it is unlikely that this color change is simply due to solvation. Indeed, the 1H NMR spectrum shows significant broadening of the N-methylaniline signals and downfield shifts for both the methyl peak and the N-H peak (Figure 4.7), suggesting that the N-methylaniline has bound to the TaF5. This likely involves the disruption of the tetrameric structure of the TaF5 to generate a mononuclear amine-bound NMA•TaF5 4.28 (Scheme 4.7), which is known in the reaction of group 5 pentahalides with oxygen, sulfur, and nitrogen Lewis bases.130 The 19F NMR spectrum further supports this, with a single, sharp peak at 68.1 ppm that is similar to related LTaF5 complexes (See Appendix A.8 for all individual 1H, 19F, and 31P NMR spectra).131-132 Only one major peak is observed, as opposed to two fluorine peaks (4 fluorine ions cis to the amine, one trans to the amine), indicating that the fluorine ions are fluxional. 147   Figure 4.6 Solid-state structure of tantalum pentafluoride PME4-113.001.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity12NMA onlyTaF5 + NMATolTol Figure 4.7 1H NMR (d8-toluene, rt, 300 MHz) spectrum of N-methylaniline and TaF5, as compared to the spectrum of N-methylaniline alone  Scheme 4.7 Disruption of the tetrameric structure of tantalum pentafluoride to generate the mononuclear complex 4.28 Upon the addition of 4.10 to the solution, the deep yellow color of 4.28 disappears and the resulting solution is colorless. This is accompanied by a change in the 1H NMR spectrum (Figure 4.8), where the N-methylaniline signals that had previously been broadened and shifted downfield 148  in the presence of TaF5 have reverted to being identical to N-methylaniline alone, and the new peaks for 4.10 are upfield compared to pure 4.10. In addition, the 31P NMR spectrum is also identical to that of 4.10 added to TaF5 and exhibiting a slight upfield shift of the peak (3.2 ppm) to that of pure 4.10 (5.6 ppm) (Figure 4.9). As such, it is proposed that the hard-donor sp2 oxygen of the phosphoramide has displaced the softer-donor N-methylaniline of 4.28 to yield 4.29, with the phosphoramide proposed to be bound κ-1 through the oxygen (Scheme 4.8), which is known to occur for secondary amide adducts of tantalum pentahalides.133 PME4-113.007.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)-0.15-0.10-0.0500.050.100.150.200.250.300.350.40Normalized Intensity123TaF5 + NMA + 4.10NMA4.10 Figure 4.8 1H NMR spectrum (d8-toluene, rt, 300 MHz) of TaF5 with N-methylaniline and 4.10, as compared to N-methylaniline and 4.10 separately 149  PME4-113.006.esp80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120Chemical Shift (ppm)-0.4-0.3-0.2-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity123TaF5 + NMA + 4.10TaF5 + 4.104.10 Figure 4.9 31P NMR spectrum (d8-toluene, rt, 300 MHz) of TaF5 with N-methylaniline and 4.10, as compared to the spectra of TaF5 and 4.10 and 4.10 alone  Scheme 4.8 Formation of tantalum phosphoramide 4.29 through displacement of N-methylaniline in 4.28 It must be noted that, while the 1H and the 31P NMR spectra are readily interpreted for determining the species present in solution, the 19F NMR spectrum for the TaF5 + N-methylaniline + 4.10 is less clear. While the major peak has shifted upfield from 68.2 to 63.1 ppm as compared to 4.28, it also has significantly broadened and a number of other minor peaks have appeared (See Appendix A.8). This could potentially be due to the N-H of the N-methylaniline in solution hydrogen bonding to the fluorides of 4.29, as this is not observed in the 19F spectrum of 4.29 without N-methylaniline present. 150  Upon addition of methyl lithium, the reaction mixture changes from being colorless after the addition of the ligand to being a deep yellow-orange color, which is a common color for hydroaminoalkylation reactions catalyzed by tantalum complexes. However, the NMR spectra are significantly more complicated and inconclusive as to what species are present in the mixture. The peaks at 0.8 and 3.8 ppm, corresponding to the ethoxy groups of the phosphoramidate ligand of 4.29, in the 1H NMR spectrum shifted as expected, but are joined by multiple new signals, indicating that instead of cleanly forming a single complex, multiple tantalum phosphoramidate complexes were formed (Figure 4.10). This is corroborated by the 31P NMR spectrum (Figure 4.11), which shows ten new peaks, as compared to the single, clean peak for the mixture prior to the addition of methyl lithium. The 19F NMR also increased in complexity, with the very broad peak at 63.1 ppm disappearing and being replaced by a number of new, smaller peaks (Figure 4.12). It is likely that not all of the fluorine-containing species after the addition of methyl lithium are visible in the 19F NMR spectrum as, without the coordinating diethyl ether solvent usually present with the methyl lithium, formation of a significant amount of a white precipitate is observed, which likely corresponds to both lithium N-methylanilide and lithium fluoride. 151  PME4-113.018.esp7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)-0.0500.050.100.150.200.250.300.350.400.45Normalized Intensity12TaF5 + NMA + 4.10 + MeLiTaF5 + NMA + 4.10 Figure 4.10 1H NMR (d8-toluene, rt, 300 MHz) spectrum of the mixture of TaF5, N-methylaniline, and 4.10, with and without methyl lithium. The spectrum with methyl lithium contains 5 equivalents of N-methylaniline instead of 2 equivalents PME4-113.020.esp18 16 14 12 10 8 6 4 2 0 -2 -4 -6 -8 -10 -12 -14 -16 -18 -20Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.8Normalized Intensity12TaF5 + NMA + 4.10TaF5 + NMA + 4.10 + MeLi Figure 4.11 31P NMR spectrum (d8-toluene, rt, 300 MHz) of the mixture of TaF5, N-methylaniline, and 4.10, with and without methyl lithium 152  PME4-113.019.esp95 90 85 80 75 70 65 60 55 50 45 40 35Chemical Shift (ppm)-0.2-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity12TaF5 + NMA + 4.10 + MeLiTaF5 + NMA + 4.10 Figure 4.12 19F NMR spectrum (d8-toluene, rt, 300 MHz) of the mixture of TaF5, N-methylaniline, and 4.10, with and without methyl lithium  Given the complexity of the 1H NMR spectra after the addition of methyl lithium, it is difficult to determine exactly what is present in the reaction mixture. Given the strength of tantalum-fluoride bonds, it is unlikely that all of the fluorides bound to tantalum are displaced by amide ligands during the early stages of the reaction. More likely is that a mixture of amido tantalum fluorides exist in equilibrium in the reaction mixture (Scheme 4.9). It should be noted that it is possible that each complex can contribute to the catalytic activity of the system, and the results presented here are attributed to the ensemble of catalytically active species formed using this method. 153   Scheme 4.9 Formation of a mixture of catalytically active species from 4.29, N-methylaniline, and methyl lithium 4.2.5 Determination of the Bench Stability of Tantalum Pentafluoride A goal of the development of a TaF5-based hydroaminoalkylation procedure was to avoid the use of an inert atmosphere glovebox. Thus, the stability of tantalum pentafluoride in non-inert atmosphere conditions required investigation. Previous reports in 40 °C water had indicated that, while susceptible to hydrolysis, TaF5 hydrolyzed more slowly than NbF5.122 The effect of storing solid TaF5 outside of an inert atmosphere was unreported. Therefore a stability study was undertaken to determine the bench stability of this compound. The bench stability of TaF5 was tested as a function of the yield of the hydroaminoalkylation of 1-octene with N-methylaniline using the TaF5 catalyst system vs. time stored outside of an inert atmosphere glovebox (Scheme 4.10). TaF5, 4.10, N-methylaniline, and 1-octene were stored in a desiccator and handled outside of an inert atmosphere glovebox. Toluene was dried and degassed using the same method as with the reaction optimization and substrate scope. Methyl lithium was stored at 4 °C in a Sure-Seal bottle and titrated prior to use. The reactions were set-up every week, and the reactions were allowed to run for 48 hours each. Work-up and isolation of the product was done in such a way to minimize loss, and the yield of the purified product was plotted against the time that the TaF5 had been stored outside of the glovebox (Figure 4.13) 154   Scheme 4.10 Hydroaminoalkylation of 1-octene with N-methylaniline, used to test the benchtop stability of tantalum pentafluoride  Figure 4.13 Yield of the hydroaminoalkylation reaction as a function of time of the tantalum pentafluoride stored outside of an inert atmosphere glovebox The T0 reaction produced a similar yield (84% yield) to a similarly set-up reaction where the TaF5 was not exposed to ambient atmosphere prior to the reaction, indicating that TaF5 is stable enough to be utilized outside of a glovebox. However, after one week of being stored in a desiccator, the reaction yield dropped to 51%, and after the second week the reaction only reached 17% yield. In addition to the drop in yield, significant discoloration of the TaF5, normally a fine, white powder, was observed, giving further indication that decomposition had occurred. This drop in yield in only two weeks indicated that, while TaF5 may be stable enough to be handled in ambient atmosphere, it must be stored under rigorously inert atmosphere. 84%51%17% 15%10%0%10%20%30%40%50%60%70%80%90%0 1 2 3 4Hydroaminoalkylation Yield (%)Time (Weeks)Hydroaminoalkylation Yield vs. Tantalum Pentafluoride Storage Time155  4.3 Conclusions  A method for the in-situ generation of a tantalum hydroaminoalkylation catalyst from tantalum pentafluoride was developed. This catalyst system can be utilized outside of the glovebox without the need for non-commercial reagent stock solutions and can be utilized to synthesize a variety of amines, including precursors to tetrahydroquinolines. The nature of the catalyst formation was studied through 1H, 19F, and 31P NMR spectroscopy but it is clear that, upon addition of methyl lithium, a number of different complexes are formed. The precise structure of these species and their individual contributions to the catalytic activity of the system is unknown. Finally, the stability of tantalum pentafluoride was studied, and it was discovered that, while it is not stable enough to be stored outside of an inert atmosphere, tantalum pentafluoride is stable enough to be handled under ambient atmosphere during reaction setup without a significant impact on the reaction yield. 4.4 Experimental 4.4.1 General Procedures General Experimental. All air and moisture sensitive reactions were setup in a MBraun LABMaster glovebox under N2 atmosphere or on a Schlenk double manifold with N2 and high-vacuum (10-3 mbar). Glassware was heated in an oven to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Stirring was done with appropriately sized stir bars, heated to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Toluene was passed over activated alumina columns into Teflon-sealed Straus flasks and sparged with dry N2 gas,. Dryness of the toluene and d8-toluene was confirmed through the addition of 2 drops of benzophenone ketyl in THF. Flash chromatography was performed on a 156  Biotage Isolera Flash Chromatography system using 10g columns, with both hexanes and ethyl acetate spiked with 0.1% (v/v) triethylamine. Materials. Tantalum Pentafluoride was purchased from Strem and used as received. Liquid amines and alkenes were purchased from commercial sources, dried over CaH2, distilled, and degassed via freeze-pump-thaw prior to use. Alkene substrates for products 4.22,115 4.23,114 and 2.26134 were synthesized according to literature procedures. Methyl lithium was purchased from Sigma-Aldrich as a 1.6 M solution in diethyl ether and used as is, titrating with diphenylacetic acid before use. Ligands 4.10-4.14,46 and 4.1565 were synthesized according to literature procedures and sublimed prior to use. 4.16 was purchased from commercial sources and sublimed prior to use. Instrumentation. Flash chromatography was performed on a Biotage Isolera Flash Purification system, using repacked 10g flash chromatography columns. 1H and 13C NMR spectra were obtained on a Bruker 300 MHz Avance or a Bruker 400 MHz Avance spectrometer at ambient temperature. Chemical shifts are given relative to the corresponding residual proteo solvent and are reported in parts per million. Coupling constants are reported in Hertz. Abbreviations used to indicate signal multiplicity are as follows: s = single, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, br = broad. Infrared (IR) spectra were obtained from neat samples using a PerkinElmer Frontier FT-IR spectrometer with an ATR sampling accessory. High-resolution mass spectra were measured by the University of British Columbia, Department of Chemistry Mass Spectrometry and Microanalysis Service on a Waters Micromass LCT, utilizing electrospray ionization. GC/MS analyses were conducted on an Agilent 7890B GC with an Agilent 5977 inert CI mass detector, utilizing methane as the ionization gas. Safety Considerations. Generation of hydrogen fluoride is possible upon the exposure of tantalum pentafluoride with insufficiently basified water. Care should be made to limit exposure of tantalum 157  pentafluoride to moisture, and aqueous workups of the hydroaminoalkylation reactions should be done with basified water. All hydroaminoalkylation reactions described in this chapter were performed in sealed reaction vessels; reactions in sealed vessels at elevated temperatures should be performed in glassware designed for elevated pressures and behind appropriately-rated blast shields. Tantalum pentafluoride has the potential to etch and weaken glassware due to release of fluoride ions; glassware should be thoroughly cleaned and inspected before and after use. Toxicological profiles of many of the starting materials and products are not known, and appropriate precautions should be taken during the handling of these compounds. 4.4.2 Synthesis and Characterization of Compounds 4.4.2.1 Typical Procedure for Tantalum Fluoride-Catalyzed Hydroaminoalkylation Setup in a Glovebox (Method A) In an inert-atmosphere glovebox, tantalum pentafluoride (13.8 mg, 0.05 mmol) and N-methylaniline (1a, 53.6 mg, 0.5 mmol) were mixed in a 20 mL scintillation vial. To this was added diethyl (2,6-dimethylphenyl)phosphoramidate (12.9 mg, 0.05 mmol), 1-octene (2a, 84.2 mg, 0.75 mmol), and toluene (1 mL). The reaction mixture was then cooled to -30 ºC, and methyl lithium in diethyl ether (156 μL, 1.6 M, 0.25 mmol) was added. A stir bar was then added to the vial, and the vial was sealed with a Teflon cap, removed from the glovebox, and heated to 70 °C for 48 hours. After 48 hours, the reaction was cooled, 10 mL of hexanes was added to the reaction, and air was blown into the vial to facilitate quenching and precipitation of the catalyst. The quenched mixture was then filtered through diatomaceous earth, concentrated in vacuo, and purified via flash chromatography (Silica gel stationary phase, Ethyl acetate/Hexanes mobile phase with 0.1% (v/v) triethylamine) to yield N-(2-methyloctyl)aniline (4.9) as a yellow oil (97.0 mg, 0.44 mmol, 89% yield). 158   4.4.2.2 Procedure for Tantalum Fluoride-Catalyzed Hydroaminoalkylation Setup on Schlenk Line (Method B) To a dry Schlenk ampule under N2 gas was added tantalum pentafluoride (55.2 mg, 0.2 mmol), N-methylaniline (0.22 mL, 2.0 mmol), 4.10 (51.5.0 mg, 0.2 mmol), and 1-octene (0.47 mL, 3.0 mmol). The resulting mixture was then dissolved in toluene (2 mL), and the solution was cooled to 0 °C. Methyllithium (0.625 mL, 1.0 mmol, 1.6 M in diethyl ether) was then added dropwise with stirring, and the ampule was sealed and heated to 70 °C for 48 hours. The reaction was then diluted with hexanes (25 mL), washed with 5 mL each 2M NaOH, DI water, and brine, dried over MgSO4, and concentrated in vacuo. Purification via silica plug (2 cm x 0.6 cm diameter, 9:1 hexanes/ethyl acetate (40 mL)) yielded product as a yellow oil (368 mg, 1.68 mmol, 84% yield). 4.4.2.3 Synthesis of N-phenyl-3-methyl-1,2,3,4-tetrahydroquinoline (Method C) To a solution of 4.26 (100 mg, 0.33 mmol) in toluene (2.5 mL) was added potassium carbonate (90.9 mg, 0.66 mmol), sodium tert-butoxide (63.2 mg, 0.66 mmol), and tetrakis(triphenylphosphine) palladium(0) (19.0 mg, 0.016 mmol). The solution was sparged with N2 gas for 5 minutes, then refluxed for 16 hours. Upon reaction completion, the solution was filtered through a 3 cm silica pipette plug, which was then washed with 5 mL DCM and the filtrate concentrated to a yellow oil. Flash chromatography of the crude material (6:1 hexanes/ethyl acetate) yielded pure product as a yellow oil (59.1 mg, 0.26 mmol, 80% yield) 4.4.2.4 TaF5 Stability Study Procedure TaF5 was stored in a 20 mL scintillation vial in a desiccator. 4.10 was sublimed and stored in a desiccator. N-methylaniline and 1-octene were distilled and stored in a desiccator. Methyl lithium 159  was stored a 4 °C in a Sure-Seal bottle and titrated prior to use. Toluene was dried on an SPS and degassed prior to use. Reaction tests were performed once a week for a period of 1 month.  To a dry Schlenk ampule under N2 gas was added tantalum pentafluoride (55.2 mg, 0.2 mmol), N-methylaniline (0.22 mL, 2.0 mmol), 4.10 (51.5 mg, 0.2 mmol), and 1-octene (0.47 mL, 3.0 mmol). The resulting mixture was then dissolved in toluene (2 mL), and the solution was cooled to 0 °C. Methyllithium (0.625 mL, 1.0 mmol, 1.6 M in diethyl ether) was then added dropwise with stirring, and the ampule was sealed and heated to 70 °C for 48 hours. The reaction was then diluted with hexanes (25 mL), quenched by bubbling moist air through the solution until colorless, and filtered through diatomaceous earth. The solution was then concentrated in vacuo, and the resulting yellow oil was further concentrated on high vacuum until all unreacted N-methylaniline was removed, as confirmed through GC/MS analysis.   4.4.2.5 Compound Characterization  N-(2-methyloctyl)aniline (4.9) Synthesized via Method A utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol) and via Method B utilizing N-methylaniline (0.22 mL, 2.0 mmol) and 1-octene (0.47 mL, 3.0 mmol). Isolated as a yellow oil (Method A: 97.0 mg, 0.44 mmol, 89% yield; Method B: 368 mg, 1.68 mmol, 84% yield), characterization data matches known literature values. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.93 (t, J=6.50 Hz, 3 H) 1.00 (d, J=6.49 Hz, 3 H) 1.13 - 1.54 (m, 10 H) 1.70 - 1.85 (m, 1 H) 3.00 (ddd, J=67.93, 12.29, 5.80 Hz, 2 H) 3.69 (br. s., 1 H) 6.63 (dd, J=8.53, 1.02 Hz, 2 H) 6.71 (t, J=7.17 Hz, 1 H) 7.16 - 7.24 (m, 160  2 H), 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 14.3, 18.2, 22.8, 27.1, 29.8, 32.0, 33.1, 35.0, 50.5, 112.8, 117.0, 129.3, 148.8.   4-bromo-N-(2-methyloctyl)aniline (4.17) Synthesized via Method A utilizing N-methyl-4-bromoaniline (93.0 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (96.8 mg, 0.32 mmol, 65% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.91 (t, J=6.40 Hz, 3 H) 0.97 (d, J=6.85 Hz, 3 H) 1.09 - 1.50 (m, 10 H) 1.63 - 1.82 (m, 1 H) 2.94 (ddd, J=47.97, 12.56, 7.08 Hz, 2 H) 3.71 (br. s., 1 H) 6.48 (d, J=8.91 Hz, 2 H) 7.24 (d, J=9.14 Hz, 2 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 14.3, 18.2, 22.8, 27.1, 29.7, 32.0, 33.0, 34.9, 50.5, 108.5, 114.3, 132.0, 147.8.   N-(2-methyl-3-phenylpropyl)cyclohexanamine (4.18) Synthesized via Method A utilizing N-methylcyclohexylamine (56.6 mg, 0.50 mmol) and allylbenzene (88.6 mg, 0.75 mmol). Isolated as a colorless oil (71.5 mg, 0.31 mmol, 62% yield), characterization data matches known literature values1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.89 (d, J=6.62 Hz, 3 H) 0.98 - 1.15 (m, 2 H) 1.15 - 1.34 (m, 4 H) 1.56 - 1.66 (m, 1 H) 1.66 - 1.78 (m, 2 H) 1.78 - 2.00 (m, 3 H) 2.31 - 2.51 (m, 3 H) 2.60 (dd, J=11.65, 6.17 Hz, 1 H) 2.73 (dd, J=13.36, 6.05 Hz, 1 H) 7.13 - 7.23 (m, 3 H) 161  7.28 (m, J=3.65 Hz, 2 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 18.3, 25.2, 25.3, 26.3, 33.7, 35.7, 41.8, 53.3, 57.0, 125.6, 128.27, 128.33, 129.3, 141.1.   4-methoxy-N-(2-methyloctyl)aniline (4.19) Synthesized via Method A utilizing N-methy-4-methoxylaniline (68.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a yellow oil (106.1 mg, 0.42 mmol, 85% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.91 (t, J=7.30 Hz, 3 H) 0.98 (d, J=6.62 Hz, 3 H) 1.05 - 1.51 (m, 10 H) 1.65 - 1.83 (m, 1 H) 2.94 (ddd, J=51.62, 11.65, 5.71 Hz, 2 H) 3.32 (br. s, 1 H) 3.77 (s, 3 H) 6.59 (d, J=8.45 Hz, 2 H) 6.79 (d, J=9.14 Hz, 2 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 14.3, 18.2, 22.8, 27.1, 29.8, 32.0, 33.1, 35.0, 51.5, 56.0, 117.0, 115.1, 143.1, 152.0.   2-methyl-N-(2-methyloctyl)aniline (4.20) Synthesized via Method A utilizing N-methyl-o-toluidine (60.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a colorless oil (13.5 mg, 0.06 mmol, 12% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.90 (t, J=6.40 Hz, 3 H) 1.00 (d, J=6.62 Hz, 3 H) 1.15 - 1.54 (m, 11 H) 1.73 - 1.89 (m, 1 H) 2.16 (s, 3 H) 3.03 (ddd, J=52.31, 11.88, 5.94 Hz, 2 H) 3.55 (br. s., 1 H) 6.57 - 6.71 (m, 2 H) 7.06 (d, J=7.31 Hz, 1 162  H) 7.13 (td, J=7.80, 1.37 Hz, 1 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 14.3, 17.6, 18.3, 22.8, 27.1, 29.8, 32.0, 33.0, 35.1, 50.4, 109.7, 116.6, 121.7, 127.3, 130.1, 146.6; IR(1/cm): 3441, 3075, 3060, 3018, 2956, 2924, 1607, 1587, 1513; High-Res Mass Spec: Calculated: 234.2222 (M+1), Found: 234.2224 (M+1, C16H28N).     4-trifluoromethoxy-N-(2-methyloctyl)aniline (4.21) Synthesized via Method A utilizing N-methyl-4-trifluoromethoxyaniline (95.6 mg, 0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol). Isolated as a colorless oil (14.3 mg, 0.04 mmol, 9% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.90 (t, J=6.40 Hz, 3 H) 0.98 (d, J=6.85 Hz, 3 H) 1.08 - 1.50 (m, 10 H) 1.65 - 1.81 (m, 1 H) 2.95 (ddd, J=48.43, 12.33, 5.94 Hz, 2 H) 3.75 (br. s., 1 H) 6.55 (d, J=8.91 Hz, 2 H) 7.02 (dd, J=8.91, 0.91 Hz, 2 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 14.3, 16.2, 22.8, 27.1, 29.7, 32.0, 33.0, 34.9, 50.9 113.2, 122.5, 124.2 (q, JC-F= 257 Hz), 140.5, 147.2, 19F NMR (282 MHz, CHLOROFORM-d) δ ppm -58.5   163  N-(5-((tert-butyldimethylsilyl)oxy)-2-methylpentyl)aniline (4.22) Synthesized via Method A utilizing N-methylaniline (53.6 mg, 0.50 mmol) and t-butyldimethyl(4-penten-1-yloxy)silane (150.3 mg, 0.75 mmol). Isolated as a yellow oil (43 mg, 0.14 mmol, 28% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.02 - 0.10 (m, 6 H) 0.88 - 0.95 (m, 9 H) 0.99 (d, J=6.62 Hz, 3 H) 1.09 - 1.38 (m, 1 H) 1.44 - 1.70 (m, 3 H) 1.70 - 1.87 (m, 1 H) 2.99 (ddd, J=45.46, 12.33, 5.94 Hz, 2 H) 3.62 (t, J=6.40 Hz, 2 H) 3.70 (br. s., 1 H) 6.60 (dd, J=8.68, 1.14 Hz, 2 H) 6.68 (tt, J=7.30, 1.10 Hz, 1 H) 7.18 (dd, J=8.45, 7.31 Hz, 2 H), 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm -5.1, 18.2, 18.5, 26.1, 30.4, 31.0, 23.9, 50.4, 63.5, 112.8, 117.1, 129.4, 148.7.   N-(2-methyl-4-(2-methyl-1,3-dioxolan-2-yl)butyl)aniline (4.23) Synthesized via Method A utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 2-(3-buten-1-yl)-2-methyl-1,3-dioxolane (106.7 mg, 0.75 mmol). Isolated as a yellow oil (61.9 mg, 0.25 mmol, 50% yield), characterization data matches known literature values. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J=6.83 Hz, 3 H) 1.25 - 1.33 (m, 1 H) 1.34 (s, 3 H) 1.54 - 1.83 (m, 4 H) 3.00 (ddd, J=58.71, 12.29, 6.14 Hz, 2 H) 3.74 (br. s., 1 H) 3.91 - 4.01 (m, 4 H) 6.61 (dd, J=8.53, 1.02 Hz, 2 H) 6.69 (t, J=7.34 Hz, 1 H) 7.15 - 7.22 (m, 2 H), 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 18.1, 23.9, 28.9, 33.1, 36.6, 50.3, 64.7, 64.8, 110.2, 112.7, 117.1, 129.3, 148.7.  164   N-(2-phenylpropyl)aniline (4.24) Synthesized via Method A utilizing N-methylaniline (53.6 mg, 0.50 mmol) and styrene (78.1 mg, 0.75 mmol). Isolated as a yellow oil (25.7 mg, 0.12 mmol, 24% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (d, J=7.08 Hz, 3 H) 3.09 (sxt, J=6.99 Hz, 1 H) 3.27 (dd, J=12.11, 7.99 Hz, 1 H) 3.38 (dd, J=11.88, 6.17 Hz, 1 H) 3.61 (br. s., 1 H) 6.61 (dd, J=8.68, 1.14 Hz, 2 H) 6.72 (t, J=7.30 Hz, 1 H) 7.15 - 7.23 (m, 2 H) 7.24 - 7.31 (m, 3 H) 7.33 - 7.41 (m, 2 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 19.9, 39.4, 51.0, 113.1, 117.5, 126.8, 127.4, 128.9, 129.4, 144.6, 128.2.   N-(2-methyl-3-phenylpropyl)aniline (4.25) Synthesized via Method A utilizing N-methylaniline (53.6 mg, 0.50 mmol) and allylbenzene (88.6 mg, 0.75 mmol). Isolated as a yellow oil (95.3 mg, 0.42 mmol, 85a% yield), characterization data matches known literature values. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.00 (d, J=6.85 Hz, 3 H) 2.10 (dq, J=13.73, 6.77 Hz, 1 H) 2.52 (dd, J=13.48, 7.77 Hz, 1 H) 2.78 (dd, J=13.48, 6.40 Hz, 1 H) 2.97 (dd, J=12.45, 6.97 Hz, 1 H) 3.11 (dd, J=12.45, 6.05 Hz, 1 H) 3.68 (br. s., 1 H) 6.56 (d, J=7.54 Hz, 2 H) 6.70 (t, J=7.31 Hz, 1 H) 7.13 - 7.26 (m, 5 H) 7.28 - 7.35 (m, 2 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 18.3, 35.2, 41.5, 50.0, 112.8, 117.2, 126.1, 128.4, 129.3, 129.5, 140.7, 148.5. 165   N-(3-(2-bromophenyl)-2-methylpropyl)aniline (4.26) Synthesized via Method A utilizing N-methylaniline (53.6 mg, 0.50 mmol) and 2-bromoallylbenzene (84.2 mg, 0.75 mmol). Isolated as a colorless oil (114.2 mg, 0.38 mmol, 75% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.02 (d, J=6.62 Hz, 3 H) 2.12 - 2.30 (m, 1 H) 2.58 (dd, J=13.48, 8.22 Hz, 1 H) 2.92 - 3.08 (m, 2 H) 3.11 - 3.20 (m, 1 H) 3.59 - 4.30 (m, 1 H) 6.56 - 6.62 (m, 2 H) 6.70 (tt, J=7.31, 1.03 Hz, 1 H) 7.05 - 7.12 (m, 1 H) 7.13 - 7.26 (m, 4 H) 7.56 (dd, J=7.88, 1.03 Hz, 1 H); 13C NMR (75.5 MHz, CHLOROFORM-d) δ ppm 18.1, 33.8, 41.5, 50.0, 112.9, 117.2, 125.0, 127.4, 127.9, 129.4, 131.6, 133.1, 140.2, 148.5; IR(1/cm): 3418, 3020, 2956, 2925, 2869, 1602, 1566, 1506; High-Res Mass Spec: Calculated: 304.0701 (M+1), Found: 304.0703 (M+1, C16H19NBr)   3-methyl-1-phenyl-1,2,3,4-tetrahydroquinoline (4.27) Synthesized via Method C. Isolated as a yellow oil (59.1 mg, 0.26 mmol, 80% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.08 (d, J=6.62 Hz, 3 H) 2.14 - 2.31 (m, 1 H) 2.54 (dd, J=15.99, 10.28 Hz, 1 H) 2.91 (ddd, J=16.05, 4.85, 1.48 Hz, 1 H) 3.24 (dd, J=11.42, 9.59 Hz, 1 H) 3.65 (ddd, J=11.42, 3.88, 1.83 Hz, 1 H) 6.66 - 6.80 (m, 2 H) 6.89 - 7.00 (m, 1 H) 7.01 - 7.16 (m, 2 H) 7.25 (m, J=4.34 Hz, 1 H) 7.32 - 7.41 (m, 2 H); (100.6 MHz, CHLOROFORM-d) δ ppm 19.1, 27.8, 36.3, 57.8, 115.3, 118.3, 124.0, 125.0, 166  126.4, 129.5, 129.7, 144.1, 148.4; IR(1/cm): 3061, 3028, 2955, 2916, 2834, 1574, 1592; High-Res Mass Spec: Calculated: 224.1439 (M+1), Found: 224.1436 (M+1, C16H18N)  167  Chapter 5: Industrially-Relevant Syntheses of Enantioenriched Morpholines via Hydroamination 5.1 Introduction While hydroaminoalkylation has great potential as a synthetic tool, the translational research to make it broadly applicable in organic synthesis is ongoing. However, hydroaminoalkylation is not the only atom economic reaction for the synthesis of amines. An orthogonal method for the synthesis of amines is hydroamination. A method of forming C-N bonds instead of C-C bond, hydroamination has been developed over the past 30+ years and utilized for the synthesis of a wide variety of amine products. 5.1.1 Group 4-Catalyzed Hydroamination of Alkynes as a Synthetic Tool Hydroamination is the addition of an N-H bond across an alkene or an alkyne (Scheme 5.1). First reported by B. Howk et al. in 1954 using alkali metals as catalysts, this reaction has since been reported to be catalyzed by early transition metals, late transition metals, lanthanide and actinides, Brønsted acid catalysis, and base catalysis.135-137 One key area of interest in hydroamination catalyst development has been the use of group 4 metals as hydroamination catalysts, as these metals are non-toxic and earth abundant.38, 41  Scheme 5.1 Generalized hydroamination reaction Group 4 metals, namely titanium and zirconium, have been used as hydroamination catalysts since the first report by Bergman and co-workers in 1992, using zirconium bis(amide) complexes for stoichiometric and catalytic hydroamination of alkynes and allenes (Scheme 5.2).138 This was followed by the first titanium hydroamination catalyst, dimethyltitanocene, reported by 168  Doye and co-workers in 1999 for the hydroamination of alkynes.139 Since then, there have been multiple reports on a variety of group 4 hydroamination catalysts from the Schafer group, the Doye group, the Odom group, and others.9, 140-145 One notable example is from the Schafer group: the titanium bis(amidate) complex 5.1 was the first early transition metal hydroamination catalyst to give exclusive selectivity for the anti-Markovnikov product (Scheme 5.3).9, 140  Scheme 5.2 First group 4 hydroamination catalyst by Bergman and co-workers  Scheme 5.3 First hydroamination catalyst with high selectivity for the anti-Markovnikov product The mechanism for the group 4-catalyzed hydroamination of alkynes, first proposed by Bergman and co-workers in their initial report and supported in later mechanistic work by the Doye group and the Schafer group, is shown in Figure 5.1.138, 146-147 Displacement of the sacrificial ligands of the catalyst by one equivalent of the primary amine substrate yields the metal-imido complex A. This complex undergoes a [2+2] cycloaddition with the alkyne substrate to form the 169  azametallacyclobutene B. Protonolysis of this intermediate with another equivalent of amine followed by elimination of the product regenerates metal-imido complex A.  Figure 5.1 General [2+2] cycloaddition mechanism for group 4-catalyzed hydroamination As the product of the hydroamination of alkynes is a reactive imine after tautomerization, there has been a number of reports that further functionalize the hydroamination product as part of a sequential series of reactions. One of the most common of these sequential methods is the use of borohydride reagents to reduce the imine hydroamination product to the corresponding amine (Scheme 5.4).9, 141, 148-150 Alternatives to the use of borohydride reagents have included catalytic hydrogenation with hydrogen gas, hydrosilylation, and homogeneous transfer hydrogenation.150-168 Alternatively, functionalizations to produce more structurally complex products have been 170  reported. By adding an isonitrile to the reaction mixture, Odom and co-workers have demonstrated the ability to generate α,β-unsaturated β-iminoamines through insertion of the isonitrile into the Ti-C bond of the azatitanacyclobutene hydroamination intermediate (Scheme 5.5).169-173 The imine hydroamination product has also been used for the synthesis of N-substituted α-cyanoamines through cyanosilylation of the imine hydroamination product (Scheme 5.6).174-176 Such products can be further functionalized through acid hydrolysis to generate unnatural N-substituted amino acids. 171   Scheme 5.4 Select examples of the synthesis of amines through tandem alkyne hydroamination/imine reduction 172   Scheme 5.5 Synthesis of β-amino-α,β-unsaturated imines through a 1-pot hydroamination/isonitrile insertion  Scheme 5.6 Synthesis of N-substituted amino acids via a 1-pot hydroamination/cyanosilylation/acid hydrolysis 5.1.2 Synthesis of Heterocycles via Hydroamination  One of the key uses of hydroamination has been as a step for the synthesis of saturated and unsaturated N-heterocycles from acyclic starting materials. The simplest and earliest examples of this are the syntheses of 1,2-unsaturated-N-heterocycles from the intramolecular hydroamination of aminoalkynes (Scheme 5.7). This reaction has been demonstrated by a wide variety of hydroamination catalysts.177 As the development of new catalysts for both intramolecular and intermolecular hydroamination progressed, the use of hydroamination for the synthesis of diverse N-heterocycles became more prevalent. One of the more common of these methods is the tandem hydroamination/Fischer indole synthesis, where the hydrazone formed from the hydroamination of an alkyne with a disubstituted hydrazine further reacts with the Lewis-acidic hydroamination catalyst to generate an indole (Scheme 5.8).9, 178-180 An alternative method for the synthesis of indoles was reported by Doye and co-workers, where the hydroamination of various substituted 2-173  chloroethynylbenzenes with a primary amine is followed by an intramolecular Buchwald-Hartwig amination in a 1-pot sequential synthesis (Scheme 5.9).142  Scheme 5.7 Generalized intramolecular hydroamination of aminoalkynes to form 1,2-unsaturated N-heterocycles  Scheme 5.8 Synthesis of indoles via sequential 1-pot hydroamination/Fischer indole synthesis  Scheme 5.9 Synthesis of indoles via sequential 1-pot hydroamination/Buchwald-Hartwig Amination  The ability to perform both intermolecular and intramolecular hydroamination with alkynes has allowed for the facile synthesis of N-heterocycles. By reacting a primary amine with 1,4- or 1,5-diynes using a titanium hydroamination catalyst, Odom and co-workers demonstrated the synthesis of N,2,5-trisubstituted pyrroles through the hydroamination of one alkyne, followed by a 5-endo dig or 5-exo dig cyclization (Scheme 5.10).181 174   Scheme 5.10 Synthesis of pyrroles through 1-pot hydroamination/cyclizations  Another strategy for the formation of N-heterocycles through hydroamination is by using the reactivity of the imine product to install another reactive functional group and forming the heterocycle through cyclization of the resulting functionalized amine. One example of this is the synthesis of imidazolidinones from an amine and alkyne reported by Schafer and co-workers (Scheme 5.11). Intermolecular hydroamination of an alkyne followed by cyanosilylation and reduction of the nitrile forms a vicinal diamine. Cyclization of this diamine using carbonyl diimidazole (CDI) yields the imidazolidinone.182 A similar route was later reported by the Schafer group for the synthesis of 1,2,5-trisubstituted piperidines (Scheme 5.12). Hydroamination of an alkyne with allylamine followed by cyanosilylation and alkylation of the resulting amine was performed as a 1-pot method. Reduction of the α-cyanoamine followed by a second, diastereoselective intramolecular hydroamination of the aminoalkene yields the piperidine product. These piperidines were found to be potent calcium channel blockers, inhibiting channel activity with single digit micromolar IC50 values.183 175   Scheme 5.11 Synthesis of imidazolidinones through tandem hydroamination/cyanosilylation followed by reduction and cyclization with CDI  Scheme 5.12 Synthesis of 1,2,5-trisubstituted piperidines through a sequential 1-pot hydroamination/cyanosilylation/alkylation followed by reduction and a second hydroamination  Many strategies for the synthesis of N-heterocycles using hydroamination involve the use of pre-functionalized amines or alkynes that can undergo further reactions without requiring additional deprotection or additive steps. This type of strategy includes the hydroamination/Buchwald-Hartwig indole synthesis (vide supra), as well as a strategy reported by Doye and co-workers for the synthesis of pyrrolidines (Scheme 5.13). Hydroamination of an internal cyclopropyl alkyne yields an α-cyclopropyl imine. A subsequent cyclopropyl 176  rearrangement followed by reduction with sodium cyanoborohydride yields the substituted pyrrolidine in a 1-pot method.184   Scheme 5.13 Synthesis of pyrrolidines via a sequential 1-pot hydroamination/cyclopropylimine rearrangement/reduction While the intramolecular hydroamination of aminoalkynes has been primarily used for the synthesis of 1,2-unsaturated N-heterocycles, it has also been used for the synthesis of more structurally complex heterocycles through sequential hydroamination/functionalization reactions. The Hammond group has reported the sequential intramolecular hydroamination/functionalization of aminoalkynes to generate a wide variety of α-substituted saturated N-heterocycles, installing alkynes, nitriles, trifluoromethyl groups, and phosphonates (Scheme 5.14).176, 185-187  Scheme 5.14 Synthesis of α-functionalized saturated N-heterocycles through tandem hydroamination/functionalization reactions The formation of cyclic imines through intramolecular hydroamination of aminoalkynes presents the opportunity to synthesize chiral N-heterocycles through sequential intramolecular hydroamination/asymmetric transfer hydrogenation of achiral aminoalkynes. Doye and co-workers used this strategy for the synthesis of (+)-(S)-laudanosine and (-)-(S)-xylopinine, where the cyclic imine 5.3 was formed through an intermolecular hydroamination and a subsequent asymmetric transfer hydrogenation using Noyori’s asymmetric transfer hydrogenation catalyst 177  generated 5.4 with 93 % ee (Scheme 5.15). This chiral tetrahydroisoquinoline is a precursor for both (+)-(S)-laudanosine and (-)-(S)-xylopinine, and both were synthesized with the longest linear step count of 8 steps and total yields of 46% and 39%, respectively.188  Scheme 5.15 Total synthesis of S-(-)-laudanosine and S-(-)-xylopinine using hydroamination followed by asymmetric transfer hydrogenation as late-stage transformations The intramolecular hydroamination/asymmetric transfer hydrogenation strategy has also been utilized for the synthesis of chiral morpholines. In 2016, Lau et al. reported the synthesis of 12 different morpholines in a 1-pot sequential hydroamination/asymmetric transfer hydrogenation using 5.1 and Noyori’s asymmetric transfer hydrogenation catalyst 5.2, achieving moderate to great yields and excellent %ees (Scheme 5.16). The authors also demonstrate this reaction for the synthesis of piperidines, thiomorpholines, and piperazines, but with reduced %ees.189 As morpholines are an important and common structural feature in pharmaceutically-relevant compounds, the expansion of this methodology is required.190 178   Scheme 5.16 Synthesis of morpholines and other saturated N-heterocycles through sequential 1-pot hydroamination/asymmetric transfer hydrogenation. 5.1.3 Enantioselective Synthesis of Benzoxazines One key N-heterocyclic structural motif found in pharmaceutically-relevant molecules is the 1,4-benzoxazine. A key structural feature in the antibiotics orfloxacin and levofloxacin, it has also been incorporated in integrin receptor antagonists, mineralocorticoid antagonists, and can be found in the naturally occurring pesticide DIMBOA (Figure 5.3).191-194 The benzoxazine core of levofloxacin is of particular interest, as it contains a stereocenter that is key to the increased antimicrobial activity and decreased toxicity as compared to orfloxacin, which is the racemic form of levofloxacin.195 179   Figure 5.2 Known bioactive molecules containing a 1,4-benzoxazine core The asymmetric synthesis of the benzoxazine core of levofloxacin has been of particular interest in the synthesis of N-heterocycles due to its original method of synthesis. The first synthesis of the optically active benzoxazine intermediate was done by the researchers at Daiichi Seiyaku Co. Ltd. through the acylation of the racemic benzoxazine (+)-5.5 with N-tosyl-proline to form a mixture of diastereomers 5.6 and 5.7(Scheme 5.17).196 Fractional recrystallization was used to separate the diastereomers, and hydrolysis of the proline amide regenerated the optically active benzoxazine 5.6. Subsequent synthetic routes explored for manufacturing included chiral resolution through the enzymatic hydrolysis of amino ester 5.8, and the asymmetric reduction of imine 5.9. using a proline-based sodium triacyloxyborohydride reagent (Scheme 5.18).197-199 180   Scheme 5.17 Initial synthesis of optically active benzoxazine (-)-5.5 181   Scheme 5.18 Subsequent syntheses of optically active benzoxazine intermediates  Since the initial investigations on the asymmetric synthesis of 5.5 by the scientists at Daiichi Sankyo Co. Ltd., this benzoxazine has been a common substrate in new reaction methodologies for the asymmetric synthesis of 1,4-benzoxazines. There have been three strategies for the synthesis of 1,4-benzoxazines: biological/chemoezymatic synthesis, alkylation with chiral starting materials, and intramolecular cyclization/asymmetric hydrogenations. In 1999, Imura and co-workers reported an alternative route for the chiral resolution of (+)-5.5 through acylation with acetic anhydride followed by enantioselective hydrolysis using the DSC 1012 strain of the microorganism Bacillus subtilis (Scheme 5.19).200 A later report by Gotor-Fernández and co-182  workers demonstrated both a lipase-catalyzed chiral resolution method and an ADH-catalyzed asymmetric reduction method for the synthesis of various 1,4-benzoxazines, including (-)-5.5 (Scheme 5.20).201  Scheme 5.19 Chiral resolution of (-)-5.5 through enantioselective hydrolysis using a strain of Bacillus sp.   Scheme 5.20 Asymmetric synthesis of (-)-5.5 through both an ADH-catalyzed asymmetric reduction and through a lipase-catalyzed chiral resolution to set the stereocenter  In 2007, Gallagher and co-workers reported a method for the asymmetric synthesis of 1,4-benzoxazines using chiral 1,2-cyclic sulfamidates. Derived from the respective amino alcohols, nucleophilic attack with 2-bromophenol followed by acidic workup and an intramolecular Buchwald/Hartwig amination yields the 1,4-benzoxazine in a 4-step process (Scheme 5.21).202 The 183  use of chiral alkylating agents was expanded upon later by Ghorai and co-workers, utilizing chiral aziridines synthesized from corresponding amino alcohols in a two step process. A Lewis-acid catalyzed ring-opening alkylation followed by an intramolecular Ullman-type amination yields the tosylated benzoxazine with excellent %ees (Scheme 5.22).203  Scheme 5.21 Asymmetric synthesis of (-)-5.5 through the formation of a chiral cyclic sulfamidate  Scheme 5.22 Asymmetric synthesis of (-)-5.5 through a sequential ring-opening alkylation/Ullman-type amination of a chiral N-tosyl aziridine  To date, there has only been one instance of a cyclization/metal-catalyzed asymmetric imine hydrogenation for the synthesis of 1,4-benzoxazines. In 2013, Ohkuma and co-workers utilized the ruthenabicyclic complex 5.10 to synthesize 1,4-benzoxazines, 1,4-quinoxalines, and a 1,4-benzothiazine (Scheme 5.23), starting from an imine precursor derived from the corresponding amino ketone.204 It was postulated that asymmetric 1,4-benzoxazines could be synthesized in an 184  facile, atom economic fashion using the 1-pot intramolecular hydroamination/transfer hydrogenation with 5.1 and 5.2 developed by Lau et al. (Scheme 5.24).189 This proposed synthetic route also benefits from high step economy, accessing the asymmetric benzoxazine in only three isolated steps from commercially available starting materials as opposed to five isolated steps using the original reductive amination synthetic route.198  Scheme 5.23 Synthesis of 1,4-quinaxolines, 1,4-benzoxazines, and a 1,4-benzothiazine using ruthenabicycle 5.10 as a hydrogenation catalyst   Scheme 5.24 Proposed asymmetric synthesis of 1,4-benzoxazines through a 1-pot sequential hydroamination/asymmetric transfer hydrogenation 5.1.4 Scope of Chapter This chapter explores the expansion of the asymmetric synthesis of morpholines developed by Lau et al. to the asymmetric synthesis of 1,4-benzoxazines. The conditions of the hydroamination reaction were optimized, and alternative conditions for the asymmetric transfer 185  hydrogenation were explored. The conditions were tested across a variety of 2-aminophenyl propargyl ethers, which were synthesized through a simple 2-step pathway. 5.2 Results and Discussion 5.2.1 Synthesis of 3-Substituted-3,4-dihydro-2H-1,4-Benzoxazines To test the use of the sequential hydroamination/asymmetric transfer hydrogenation reaction developed by Lau et al. for the synthesis of 1,4-benzoxazines, aminoalkyne 5.12 was synthesized through the alkylation of o-nitrophenol with propargyl bromide, followed by selective reduction of the nitro group with iron and ammonium chloride (Scheme 5.25). Initial tests of the hydroamination reaction showed that using titanium hydroamination catalyst 5.1 the reaction conditions developed by Lau et al. led to full conversion, but with the formation of a side product with a molecular weight suggestive of dimerized 5.12 (Scheme 5.26).189 Reduction of the loading of 5.1 to 5 mol% suppressed this byproduct formation, but further lowering of the loading of 5.1 led to incomplete conversion.   Scheme 5.25 Synthesis of aminoalkyne 5.12 186   Scheme 5.26 Initial optimization of hydroamination Attention was next directed at the asymmetric transfer hydrogenation. The initial conditions reported by Lau et al., using Noyori’s asymmetric transfer hydrogenation catalyst 5.2 in a one-pot reaction with the preceding hydroamination reaction, proved competent for achieving full conversion of the imine to the amine at room temperature in 24 hours, achieving 80 %ee (Table 5.1).189 Attempts to improve the enantiomeric excess were unsuccessful, as decreasing the reaction temperature to 0 °C or changing the catalyst to 5.14 both led to incomplete conversion. As such the enantiomeric excesses of these reactions were not obtained. 187  Table 5.1 Exploration of asymmetric transfer hydrogenation conditions  Entry [Ru] temp (°C) conv (%)a ee (%)b 1 5.2 rt 100 80 2 5.2 0 81 N/A 3 5.14 rt 26 N/A 4 5.14 0 22 N/A a % Conversion determined by GC/MS through relative peak area of the imine hydroamination product as compared to 1,3,5-trimethoxybenzene as an internal standard. b %ee determined through chiral HPLC.  With conditions for the one-pot hydroamination/transfer hydrogenation in hand, a variety of substrates were synthesized to test the scope of the process. Alkylation with either propargyl bromide or 3-substituted propargyl mesylates proceeded in moderate to excellent yields, often not requiring column chromatography to produce pure product (Table 5.2). The subsequent reduction of the nitro group produced mixed results: o-nitrophenyl ethers 5.11, 5.15-5.17, and 5.19-5.21 reduced to the corresponding anilines cleanly in moderate to excellent yields with no observed reduction of the alkyne (Table 5.3), but reduction of o-nitrophenyl ethers 5.18 and 5.22-5.26 lead to the formation of significant quantities of inseparable isomers of the product, as observed through GC/MS. Attempts to identify alternative reduction procedures for these substrates were 188  unsuccessful, resulting in either lack of reaction, the aforementioned isomerization, or unacceptable amounts of the over-reduced aminoalkene formed. Table 5.2 Scope of alkylation of substituted o-nitrophenols  189  Table 5.3 Scope of reduction of o-nitrophenyl ethers to 2-aminophenyl propargyl ethers  Next, the aminoalkynes were subjected to the hydroamination/asymmetric transfer hydrogenation conditions that were identified earlier (Table 5.4). Catalyst 5.1 proved to be a competent hydroamination catalyst for each substrate, achieving full conversion with each substrate as determined through GC/MS. Catalyst 5.1 also exhibits the added benefits of being able to be used as a stock solution and exhibiting higher levels of air and moisture stability compared to other early transition metal catalysts, thus allowing it to be used outside of an inert atmosphere glovebox without requiring rigorous drying of the aminoalkyne substrates. Notably, catalyst 5.1 is not only able to tolerate trifluoromethyl and t-butyl ester groups, but it is capable of cyclizing 5.29 to form the imine intermediate to the levofloxacin precursor 5.5.  190  Table 5.4 Scope of one-pot hydroamination/asymmetric transfer hydrogenation with catalysts 5.1 and 5.2  However, the subsequent asymmetric transfer hydrogenation generally suffered from significant formation of a dimer side product (vide infra), suppressing the overall yield. In addition, purification of these substrates proved to be a significant challenge, as the ligand from hydroamination catalyst 5.1 often coelutes with 1,4-benzoxazine product. As such, the purification of these compounds is a multi-step process of forming the HCl salt of the product, washing the ligand out with diethyl ether, reformation of the neutral 1,4-benzoxazine, and column chromatography to remove the dimer side products. This purification process, combined with the dimer side products, is likely the cause of the low yields of this one-pot procedure. As observed previously with the asymmetric synthesis of morpholines, the use of the (R,R) enantiomer of the asymmetric transfer hydrogenation catalyst 5.2 yielded the R enantiomer, as determined through 191  the optical rotation of (+)-5.5.189, 197 While the % ee’s observed for these substrates is lower than then what is observed for the asymmetric synthesis of morpholines, the asymmetric transfer hydrogenation still gives good % ee’s. One key aspect of the reaction that was observed with the asymmetric transfer hydrogenation was the formation of the side products 5.38 (Scheme 5.27). These byproducts were first observed during the optimization of the hydroamination reaction, but the formation of these side products was originally suppressed in the optimized reaction conditions, and such products are not observed with the sodium borohydride reductions. Isolation of the byproducts from the reaction mixture is possible through column chromatography, but GC/MS analysis shows that it is a mixture of products with identical masses, with the molecular ion (m/z = 297.1) indicative of dimerization of the starting material (molecular weight = 148 amu) followed by a single hydrogenation reaction (Figure 5.3). Similar byproducts were observed during the asymmetric transfer hydrogenation of aminoalkynes 5.27 - 5.32. Attempts to further separate the side products were unsuccessful, as were attempts to determine the structure of the compounds through 1D and 2D NMR spectroscopy experiments and IR spectroscopy (See Appendix D).  Scheme 5.27 Formation of byproduct 5.38 from the asymmetric transfer hydrogenation reaction 192   Figure 5.3 GC/MS of 5.38 side products after column chromatography It was hypothesized that the side product was macrocyclic, potentially forming a crown ether-like structure. As such, attempts at growing X-ray diffractometry-quality crystals of 5.38 as a lithium triflate adduct was attempted, but the resulting crystals decomposed prior to the analysis. 193  As these side products are hypothesized to be dimers of the aminoalkyne starting material 5.12, attempts were made to prevent their formation, including rigorous exclusion of air and moisture from the asymmetric transfer hydrogenation reaction and increasing the volume of solvent in the asymmetric transfer hydrogenation reaction. However, all attempts to suppress the formation were unsuccessful. 5.3 Conclusions The asymmetric synthesis of morpholines through intramolecular hydroamination/transfer hydrogenation of aminoalkynes developed by Lau et al. has been expanded for the synthesis of 1,4-benzoxazines. By using catalysts 5.1 for hydroamination and 5.2 for the asymmetric transfer hydrogenation, cyclization of various substituted 2-aminophenyl propargyl ethers to the corresponding cyclic imine and subsequent asymmetric hydrogenation, a variety of 1,4-benxozines can be synthesized in poor-to-good yields and good %ee’s One key complication of this process is the formation of isomeric side products, hypothesized to be the result of dimerization of the aminoalkyne starting material. This method, combined with a simple, two-step synthesis of the aminoalkyne intermediate, represents a step-efficient method to reaching enantioenriched 1,4-benzoxazines, including the 5.5, an intermediate to the antibiotic levofloxacin. 5.4 Experimental 5.4.1 General Procedures General Experimental. All air and moisture sensitive reactions were setup in a MBraun LABMaster glovebox under N2 atmosphere or on a Schlenk double manifold with N2 and high-vacuum (10-3 mbar). Glassware was heated in an oven to 180 °C overnight prior to being transferred to the glovebox or used on the Schlenk line. Stirring was done with appropriately sized stir bars, heated to 180 °C overnight prior to being transferred to the glovebox or used on the 194  Schlenk line. Toluene was passed over activated alumina columns into Teflon-sealed Straus flasks, degassed via 3 freeze-pump-thaw cycles, brought into the glovebox, and stored over 4 Å molecular sieves. Dryness of the toluene was confirmed through the addition of 2 drops of benzophenone ketyl in THF. Flash chromatography was performed on a Biotage Isolera Flash Chromatography system using 10g columns, with both hexanes and ethyl acetate spiked with 0.1% (v/v) triethylamine. Chiral HPLC was performed on an Agilent HPLC at 0.5 mL/min using Daicel CHIRALCEL OJ-RH or AS-RH columns and UV-Vis and ESI mass spec for detection. Optical rotation measurements were taken on a Jasco P-2000 polarimeter with a pathlength of 1 dm.  Materials. Catalyst 5.1 was synthesized using reported literature procedures and used as a 0.05 M solution in dry toluene.9 Catalysts 5.2 and 5.13 were purchased from Strem and used as recieved. O-nitrophenol and other starting materials were purchased from Oakwood chemicals and used as received. O-nitrophenol precursors to 5.16192 and 5.22205were synthesized according to literature procedures Instrumentation. Flash chromatography was performed on a Biotage Isolera Flash Purification system, using repacked 10g flash chromatography columns. 1H and 13C NMR spectra were obtained on a Bruker 300 MHz Avance spectrometer at ambient temperature. Chemical shifts are given relative to the corresponding residual proteo solvent and are reported in parts per million. Coupling constants are reported in Hertz. Abbreviations used to indicate signal multiplicity are as follows: s = single, d = doublet, dd = doublet of doublets, t = triplet, q = quartet, m = multiplet, br = broad. Infrared (IR) spectra were obtained from neat samples using a PerkinElmer Frontier FT-IR spectrometer with an ATR sampling accessory. High-resolution mass spectra were measured by the University of British Columbia, Department of Chemistry Mass Spectrometry and Microanalysis Service on a Waters Micromass LCT, utilizing electrospray ionization. GC/MS 195  analyses were conducted on an Agilent 7890B GC with an Agilent 5977 inert CI mass detector, utilizing methane as the ionization gas.  Safety Considerations. Precatalyst 5.1 is O2 and moisture sensitive. Synthesis, handling, and use of this complex should be done under an inert atmosphere. All hydroamination reactions were performed in sealed reaction vessels; reactions in sealed vessels at elevated temperatures should be performed in glassware designed for use with elevated pressures and behind an appropriately-rated blast shield. Toxicological profiles of many of the starting materials and products are not known; appropriate precautions should be taken during the handling of these compounds.  5.4.2 Synthesis and Characterization of Compounds 5.4.2.1 General Procedure A for Alkylation of Substituted o-Nitrophenols with Propargyl Bromide     To a solution of substituted o-nitrophenol (18.0 mmol) in acetone (100 mL) was added cesium carbonate (6.45 g, 19.8 mmol) and propargyl bromide (2.40 mL, 21.6 mmol, 80% w/w in toluene), and the solution was refluxed overnight. The reaction was then concentrated in vacuo, and the residue was dissolved in 150 mL ethyl acetate, washed with 50 mL each saturated sodium bicarbonate solution, DI water, and brine, dried over magnesium sulfate, and concentrated to a yellow solid. Products were purified through recrystallization or flash chromatography 196  5.4.2.2 General Procedure B for the Alkylation of o-Nitrophenol with Substituted Propargyl Alcohols  To a 0 °C solution of 3-substituted propargyl alcohol (14 mmol) and triethylamine (2.3 mL, 16.8 mmol) in dry DCM (17.5 mL) was added dropwise methanesulfonyl chloride (1.3 mL, 16.8 mmol), and the solution was stirred for 3 hours, warming to room temperature. Upon reaction completion, as determined through GC/MS, the solution was diluted with DCM (50 mL), washed with water (2 x 25 mL), dried over MgSO4, and concentrated in vacuo to a brown oil, which was used without further purification. 2-nitrophenol (2.34 g, 16.8 mmol) and cesium carbonate (5.48 g, 16.8 mmol) were suspended in acetone (70 mL) and stirred at room temperature for 15 minutes. To this suspension was then added the crude 3-substituted propargyl mesylate, and the reaction was stirred at reflux overnight. Upon reaction completion, as determined through GC/MS, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (200 mL). The solution was then washed with 2 M KOH (50 mL), water (50 mL), and brine (50 mL), dried over MgSO4, and concentrated in vacuo to yield a crude product, which was purified through flash chromatography or recrystallization. 5.4.2.3 General Procedure C for the Nitro Group Reduction  197  To a solution of 2-nitro-(propynyloxy)benzene (7 mmol) in 4:1 ethanol/water (25 mL) was added iron powder (1.17 g, 21 mmol) and ammonium chloride (1.87 g, 35 mmol), and the suspension was refluxed overnight. The reaction was then filtered through Celite, diluted with DCM (75 mL), washed with 50 mL each 2M NaOH, DI water, and brine, dried over magnesium sulfate, and concentrated to a crude dark red oil. Products were purified through vacuum distillation. 5.4.2.4 General Procedure D for Tandem Hydroamination/Racemic Reduction  To a solution of aminoalkyne (0.5 mmol) in toluene (0.5 mL) in a nitrogen-filled 10 mL PTFE-sealed ampule was added 5.1 (0.5 mL, 0.025 mmol), and the solution was stirred at 110 °C overnight. The reaction solution was then cooled to RT and diluted with methanol (8 mL) and sodium borohydride (35.8 mg, 1.0 mmol) was added. The reaction was stirred for 30 min, then the solution was concentrated in vacuo. The residue was dissolved in ethyl acetate (5 mL) and washed with 5 mL each sat. bicarbonate, water, and brine. The organic phase was then dried over magnesium sulfate and concentrated to yield crude product. Products were purified via precipitation of the HCl salt from ether, reforming the neutral amine with sat. bicarbonate, and purification through flash column chromatography. 5.4.2.5 General Procedure E for Tandem Hydroamination/Asymmetric Transfer Hydrogenation     198  To a solution of aminoalkyne (0.5 mmol) in toluene (0.5 mL) in a nitrogen-filled10 mL PTFE-sealed ampule was added 5.1 (0.5 mL, 0.025 mmol), and the solution was stirred at 110 °C overnight. The reaction solution was then cooled to RT, then 5.2 (3.2 mg, 0.005 mmol) in DMF (0.1 mL) and 5:2 formic acid/triethylamine (0.1 mL) was added. The reaction was stirred for 24 hours, then the reaction was diluted with ethyl acetate (5 mL) and washed with 5 mL each sat. bicarbonate, water, and brine. The organic phase was then dried over magnesium sulfate and concentrated to yield crude product. Products were purified via precipitation of the HCl salt from ether, reforming the neutral amine with sat. bicarbonate, and purification through flash column chromatography.   5.4.2.6 Compound Characterization  1-nitro-2-(prop-2-yn-1-yloxy)benzene (5.11) Synthesized via general procedure A using o-nitrophenol (2.50 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Recrystallization in hot ethyl acetate/hexanes yielded large tan crystals (3.10 g, 97% yield). Characterization matches literature data. 206 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.60 (t, J=2.40 Hz, 1 H) 4.86 (d, J=2.28 Hz, 2 H) 7.11 (td, J=8.50, 1.37 Hz, 1 H) 7.27 (dd, J=8.45, 0.91 Hz, 1 H) 7.57 (td, J=7.30, 1.80 Hz, 1 H) 7.86 (dd, J=8.11, 1.71 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 57.3, 77.1, 77.2, 115.6, 121.5, 125.8, 134.1, 150.8; IR(1/cm): 3255, 3079, 2927, 2874, 2131, 1978, 1604, 1585.  199   2-nitro-1-(prop-2-yn-1-yloxy)-4-(trifluoromethyl)benzene (5.15) Synthesized via general procedure A using 2-nitro-4-trifluoromethylphenol (3.73 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Purification via flash chromatography yielded product as a bright yellow oil (4.36 g, 98% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.64 (t, J=2.40 Hz, 1 H) 4.93 (d, J=2.51 Hz, 2 H) 7.39 (d, J=8.68 Hz, 1 H) 7.79 - 7.86 (m, 1 H) 8.15 (d, J=1.83 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 57.5, 76.3, 78.1, 115.7, 123.6 (q, 3JCF=4.60 Hz), 124.0 (q, 2JCF=34.48 Hz), 126.7 (q, 1JCF=272.42 Hz), 130.8 (q, 3JCF=4.60 Hz), 140.0, 153.1; 19F NMR (282 MHz, CHLOROFORM-d) δ ppm -62.1; IR(1/cm): 3295, 3086, 2129, 1627, 1586, 1538; HRMS: Calculated: 268.0197 (M+23), Found: 268.0199 (M+23, C10H6F3NO3Na)  tert-butyl 3-nitro-4-(prop-2-yn-1-yloxy)benzoate (5.16) Synthesized via general procedure A using t-butyl 4-hydroxy-3-nitrobenzoic acid (4.31 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene. Purification via recrystallization in hot ethyl acetate/hexanes yielded product as yellow crystals (4.49 g, 90 % yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.60 (s, 9 H) 2.61 (t, J=2.40 Hz, 1 H) 4.91 (d, J=2.28 Hz, 2 H) 7.27 (d, J=8.68 Hz, 1 H) 8.18 (dd, J=8.79, 2.17 Hz, 1 H) 8.43 (d, J=2.06 Hz, 1 H). 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 28.3, 57.4, 76.6, 77.8, 82.3, 114.5, 125.5, 127.1, 134.9, 139.9, 153.5, 163.5. IR(1/cm): 200  3312, 3063, 2994, 2969, 2140, 1707, 1611, 1535. High-Res MS: Calculated: 300.0848 (M+23), Found: 300.0846 (M+23, C14H15NO5Na)   1,2-difluoro-4-nitro-3-(prop-2-yn-1-yloxy)benzene (5.17) Synthesized via general procedure A using 6-nitro-2,3-difluorophenol (3.15 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Purification via flash chromatography yielded product as a bright yellow oil (3.34 g, 87% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.58 (t, J=2.40 Hz, 1 H) 4.93 (d, J=2.28 Hz, 2 H) 7.09 (td, J=9.08, 7.20 Hz, 1 H) 7.73 (ddd, J=9.42, 5.20, 2.28 Hz, 1 H). 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 62.53 (d, nOeJCF=5.75 Hz), 76.7, 77.6, 112.29 (d, 2JCF=19.54 Hz) 120.49 (dd, 2JCF=9.20, 3JCF=3.45 Hz) 141.79 (dd, 2JCF=11.50, 3JCF=3.40 Hz, 1 C) 145.43 (dd, 1JCF=254.03, 2JCF=13.79 Hz) 153.98 (dd, 1JCF=259.77, 2JCF=11.50 Hz); 19F{1H} NMR (282 MHz, CHLOROFORM-d) δ ppm -147.55 (d, J=19.57 Hz, 1 F) -125.68 (d, J=19.57 Hz, 1 F); IR(1/cm): 3296, 3103, 2957, 2884, 2128, 1625, 1595, 1534, 1493. High-Res MS: Calculated: 236.0135 (M+23), Found: 236.0134 (M+23, C9H5F2NO3Na)   1-methyl-3-nitro-2-(prop-2-yn-1-yloxy)benzene (5.18) Synthesized via general procedure A using 2-methyl-6-nitrophenol (2.76 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Crude product was isolated as a yellow solid, recrystallization in ethyl 201  acetate/hexanes yielded pure product as light tan needles (2.80 g, 81% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.43 (s, 3 H) 2.55 (t, J=2.51 Hz, 1 H) 4.72 (d, J=2.51 Hz, 2 H) 7.11 - 7.20 (m, 1 H) 7.45 (ddd, J=7.54, 1.60, 0.69 Hz, 1 H) 7.69 (dd, J=7.99, 1.14 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 16.7, 61.9, 76.7, 78.0, 123.2, 124.6, 135.4, 135.9, 144.6, 150.0; IR(1/cm): 3279, 3085, 2945, 2125, 1605, 1678, 1522; High-Res MS: Calculated: 214.0480 (M+23), Found: 214.0482 (M+23, C10H9NO3Na)   4-methyl-1-nitro-2-(prop-2-yn-1-yloxy)benzene (5.19) Synthesized via general procedure A using 5-methyl-2-nitrophenol (2.76 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Crude product was isolated as a yellow solid, recrystallization in ethyl acetate/hexanes yielded pure product as yellow crystals (3.19 g, 93% yield) 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.43 (s, 3 H) 2.59 (t, J=2.40 Hz, 1 H) 4.83 (d, J=2.28 Hz, 2 H) 6.88 (d, J=8.45 Hz, 1 H) 7.03 (s, 1 H) 7.80 (d, J=8.22 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 22.1, 57.3, 77.0, 77.4, 116.1, 122.2, 126.1, 138.1, 145.9, 151.1; IR(1/cm): 3279, 3120, 3075, 2986, 2923, 2131, 1608, 1589, 1507; High-Res MS: Calculated: 214.0480 (M+23), Found: 214.0482 (M+23, C10H9NO3Na)   202  4-methyl-2-nitro-1-(prop-2-yn-1-yloxy)benzene (5.20) Synthesized via general procedure A using 4-methyl-2-nitrophenol (2.76 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Product was isolated as a dark yellow oil that crystallized as tan crystals upon standing and was then washed with hexanes and dried in vacuo (2.99 g, 87% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.35 (s, 3 H) 2.57 (t, J=2.40 Hz, 1 H) 4.81 (d, J=2.28 Hz, 2 H) 7.15 (d, J=8.68 Hz, 1 H) 7.35 (ddd, J=8.45, 2.28, 0.70 Hz, 1 H) 7.66 (d, J=1.60 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 20.6, 57.7, 77.7, 77.8, 116.1 126.2, 131.9, 134.9, 140.4, 149.0; IR(1/cm): 3285, 3277, 3053, 2995, 2934, 2123, 1621, 1575, 1529; High-Res MS: Calculated: 214.048 (M+23), Found: 214.0488 (M+23, C10H9NO3Na)     1-methyl-2-nitro-3-(prop-2-yn-1-yloxy)benzene (5.21) Synthesized via general procedure A using 3-methyl-2-nitrophenol (2.76 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Crude product was isolated as a yellow solid, recrystallization in ethyl acetate/hexanes yielded pure product as colorless needles (2.19 g, 64% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.31 (s, 3 H) 2.56 (t, J=2.40 Hz, 1 H) 4.76 (d, J=2.28 Hz, 2 H) 6.91 (d, J=7.77 Hz, 1 H) 7.04 (d, J=8.22 Hz, 1 H) 7.28 - 7.36 (m, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 17.1, 57.1, 76.9, 77.4, 111.9, 123.7, 130.6, 131.3, 142.6, 148.8; IR(1/cm): 3289, 2973, 2934, 2122, 1934, 1618, 1582, 1520; High-Res MS: Calculated: 214.0480 (M+23), Found: 214.0483 (M+23, C10H9NO3Na) 203    3-nitro-4-(prop-2-yn-1-yloxy)-1,1'-biphenyl (5.22) Synthesized via general procedure A using 3-nitro-[1,1’-biphenyl]-4-ol ( g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Crude product was isolated as an orange solid, purification via column chromatography yielded product as an orange solid, (2.32 g , 51% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.62 (t, J=2.40 Hz, 1 H) 4.90 (d, J=2.28 Hz, 2 H) 7.31 - 7.51 (m, 4 H) 7.53 - 7.59 (m, 2 H) 7.78 (dd, J=8.79, 2.40 Hz, 1 H) 8.09 (d, J=2.28 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 57.5, 62.4, 77.3, 116.0, 124.1, 126.9, 128.1, 129.2, 132.3, 135.1, 138.3 140.6, 150.1; IR(1/cm): 3287, 3063, 3033, 2928, 2873, 2125, 1618, 1529; High-Res MS: Calculated: 276.0637 (M+23), Found: 276.0640 (M+23, C15H11NO3Na)   3-bromo-1-nitro-2-(prop-2-yn-1-yloxy)benzene (5.23) Synthesized via general procedure A using 2-bromo-6-nitrophenol (3.92 g, 18.0 mmol) and propargyl bromide (2.4 mL, 21.6 mmol, 80% w/w in toluene). Product was isolated as a tan solid, no further purification required (3.43 g, 13.5 mmol, 75% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.57 (t, J=2.51 Hz, 4 H) 4.90 (d, J=2.51 Hz, 2 H) 7.19 (t, J=8.11 Hz, 10 H) 7.81 (dd, J=4.80, 1.60 Hz, 1 H) 7.84 (dd, J=4.34, 1.60 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 62.2, 77.2, 77.4, 120.4, 124.5, 204  126.0, 138.0, 146.0, 148.3; IR(1/cm): 3293, 3078, 2131, 1588, 1524. HRMS: Calculated: 277.9423 (M+23), Found: 277.9429 (M+23, C9H6BrNO3Na)   1-(but-2-yn-1-yloxy)-2-nitrobenzene (5.24) Synthesized via general procedure B using 2-butyn-1-ol (981.3 mg, 1.0 mL, 14.0 mmol). Crude product was isolated as a brown oil, purification through column chromatography yielded pure product as a yellow oil (1.59 g, 59% yield). Characterization matches literature data.206 1H NMR (300 MHz, CHLOROFORM-d) d ppm 1.85 (t, J=2.40 Hz, 3 H) 4.81 (q, J=2.30 Hz, 2 H) 7.06 (ddd, J=8.17, 7.25, 1.03 Hz, 1 H) 7.25 (dd, J=8.45, 0.91 Hz, 1 H) 7.54 (ddd, J=8.68, 7.54, 1.80 Hz, 1 H) 7.84 (dd, J=8.11, 1.71 Hz, 1 H), 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 3.8, 58.0, 72.9, 85.5, 115.6, 121.0, 125.7, 134.0, 140.3, 151.2; IR(1/cm): 3081, 2926, 2875, 1308, 2232, 1719, 1606, 1584, 1520   1-nitro-2-((3-phenylprop-2-yn-1-yl)oxy)benzene (5.25) Synthesized via general procedure B using 3-phenylprop-2-yn-1-ol (1.85 g, 14.0 mmol). Crude product was isolated as a brown solid, recrystallization in hot ethyl acetate/hexanes yielded product as colorless prisms (2.55 g, 72% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 5.09 (s, 2 H) 7.06 - 7.13 (m, 1 H) 7.28 - 7.39 (m, 4 H) 7.39 - 7.47 (m, 2 H) 7.58 (ddd, J=8.57, 7.31, 1.71 Hz, 1 H) 7.88 (dd, J=8.22, 1.60 205  Hz, 1 H) 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 58.3, 82.6, 88.7, 115.8, 121.4, 121.9, 125.9, 128.5, 129.1, 131.9, 134.1, 140.6, 151.2; IR(1/cm): 3106, 3079, 3046, 2923, 2863, 2258, 2236, 1605, 1582, 1516; Calculated: 276.0637 (M+23), Found: 276.0638 (M+23, C15H11NO3Na)   tert-butyldimethyl((4-(2-nitrophenoxy)but-2-yn-1-yl)oxy)silane (5.26) Synthesized via general procedure B using 4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-ol (2.80 g, 14.0 mmol). Crude product was isolated as a waxy, tan solid, with no further purification performed. (3.01 g, 67% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 0.06 - 0.10 (m, 6 H) 0.86 - 0.90 (m, 9 H) 4.34 (t, J=1.83 Hz, 2 H) 4.89 (t, J=1.71 Hz, 2 H) 7.03 - 7.12 (m, 1 H) 7.25 (dd, J=8.45, 1.14 Hz, 1 H) 7.54 (ddd, J=8.45, 7.54, 1.83 Hz, 1 H) 7.85 (dd, J=8.11, 1.71 Hz, 1 H), 13C NMR (75 MHz, CHLOROFORM-d) δ ppm -5.1, 18.4, 25.9, 51.7, 57.6, 78.3, 87.7, 115.6, 121.3, 125.8, 134.0, 140.5, 151.0; IR(1/cm): 3110, 3050, 2953, 2926, 2882, 2856, 1932, 1816, 1605, 1587, 1525; High-Res MS: Calculated: 344.1294 (M+23), Found: 344.1297 (M+23, C16H23NO4NaSi)    2-(prop-2-yn-1-yloxy)aniline (5.12) Synthesized through General Procedure C using 5.11 (1.24 g, 7 mmol). Purification though flash column chromatography yielded product as a colorless oil (814 mg, 79% yield). Characterization matches literature data.206 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.53 (t, J=2.40 Hz, 1 H) 3.71 (br. s., 2 H) 4.70 - 4.77 (m, 2 H) 6.70 - 206  6.79 (m, 2 H) 6.83 - 6.89 (m, 1 H) 6.90 - 6.97 (m, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 56.5, 75.6, 79.0, 112.8, 115.6, 118.4, 122.4, 136.8, 145.4; IR(1/cm): 3456, 3369, 3284, 3062, 3035, 2921, 2866, 2120, 1614, 1501.   2-(prop-2-yn-1-yloxy)-5-(trifluoromethyl)aniline (5.27) Synthesized through General Procedure C using 5.15 (1.72 g, 7 mmol). Purification though flash column chromatography yielded product as a yellow oil (1.01 g, 67% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.56 (t, J=2.40 Hz, 1 H) 3.99 (br. s., 2 H) 4.78 (d, J=2.28 Hz, 2 H) 6.90 - 7.04 (m, 3 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 56.4, 76.2, 78.1, 111.67, 11.70 (q, J3C-F=4.6 Hz), 115.4 (q, J3C-F=4.6), 124.4 (q, J2C-F=32.2 Hz), 124.5 (q, JC-F=270.1 Hz), 137.0, 147.3; 19F{1H} NMR (282 MHz, CHLOROFORM-d) δ ppm -61.8; IR(1/cm): 3478, 2287, 3304, 2929, 2875, 2125, 1622, 1517; High-Res MS: Calculated: 216.0636 (M+1), Found: 216.0638 (M+1, C10H9NOF3)   tert-butyl 3-amino-4-(prop-2-yn-1-yloxy)benzoate (5.28) Synthesized through General Procedure C using 5.16 (1.94 g, 7 mmol). Purification though flash column chromatography yielded product as an orange solid (1.26 g, 73% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.57 (s, 9 H) 2.54 (t, J=2.40 Hz, 1 H) 3.79 (br. s, 2 H) 4.77 (d, J=2.28 Hz, 2 H) 6.89 (d, J=8.45 Hz, 1 H) 7.36 (d, J=2.06 Hz, 1 H) 7.41 (dd, J=8.45, 2.06 Hz, 1 H); 13C NMR (75 MHz, 207  CHLOROFORM-d) δ ppm 28.3, 56.3, 76.1, 78.2, 80.6, 111.2, 116.2, 120.5, 125.8, 136.3, 148.5, 165.8; IR(1/cm): 3439, 3352, 3301, 33075, 2990, 2965, 2933, 1687, 1617, 1593, 1515; High-Res MS: Calculated: 248.1287 (M+1), Found: 248.1285 (M+1, C14H18NO3)   3,4-difluoro-2-(prop-2-yn-1-yloxy)aniline (5.29) Synthesized through General Procedure C using 5.17 (1.49 g, 7 mmol). Purification though flash column chromatography yielded product as a red oil (577 mg, 45% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.54 (t, J=2.40 Hz, 1 H) 3.82 (br. s., 2 H) 4.76 (d, J=2.51 Hz, 2 H) 6.41 (ddd, J=9.14, 4.80, 2.28 Hz, 1 H) 6.75 (ddd, J=9.88, 9.08, 8.22 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 60.7 (d, nOeJC-F=5.75 Hz), 76.2, 786. 109.2 (dd, 2,3JC-F=6.90, 3.45 Hz), 112.0 (d, 2JC-F=17.24 Hz), 133.9 (dd, 2,3JC-F=10.34, 2.30 Hz), 137.4 - 137.5 (m) 144.2 (dd, 1,2JC-F=240.23, 11.49 Hz), 145 (dd, 1,2JC-F=245.98, 14.94 Hz, 5 C); 19F{1H} NMR (282 MHz, CHLOROFORM-d) d ppm -153.74 (d, J=20.65 Hz) -149.88 (d, J=20.65 Hz), IR(1/cm): 3462, 3377, 3299, 3031, 2939, 2878, 2125, 1635; High-Res MS: Calculated: 184.0574 (M+1), Found: 184.0573 (M+1, C9H8NOF2)   4-methyl-2-(prop-2-yn-1-yloxy)aniline (5.30) Synthesized through General Procedure C using 5.19 (1.34 g, 7 mmol). Purification though flash column chromatography yielded product as a red oil (1.05 g, 93% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.28 (s, 3 H) 2.54 (t, 208  J=2.56 Hz, 1 H) 3.66 (br. s., 2 H) 4.71 (d, J=2.39 Hz, 2 H) 6.66 (s, 2 H) 6.75 (s, 1 H); 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 21.0, 56.5, 75.5, 79.0, 113.8, 115.7, 122.6, 128.1, 134.1, 145.5; IR(1/cm): 3449, 3365, 3285, 3029, 2919, 2864, 2121, 1623, 1591, 1516; High-Res MS: Calculated: 162.0919 (M+1), Found: 162.0918 (M+1, C10H12NO)   5-methyl-2-(prop-2-yn-1-yloxy)aniline (5.31) Synthesized through General Procedure C using 5.20 (1.34 g, 7 mmol). Purification though flash column chromatography followed by recrystallization in ethanol/hexanes yielded product as white, crystalline fibers. (602 mg, 53% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 2.24 (s, 3 H) 2.52 (t, J=2.40 Hz, 1 H) 3.77 (br. s., 2 H) 4.69 (d, J=2.28 Hz, 2 H) 6.50 - 6.61 (m, 2 H) 6.82 (d, J=7.99 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 20.9, 56.8, 75.4, 79.1, 113.1, 116.5, 118.7, 132.0, 136.7, 143.4; IR(1/cm): 3456, 3368, 3284, 3021, 2919, 2865, 2122, 1615, 1512; High-Res MS: Calculated: 162.0919 (M+1), Found: 162.0918 (M+1, C10H12NO)   2-methyl-6-(prop-2-yn-1-yloxy)aniline (5.32) Synthesized through General Procedure C using 5.21 (1.34 g, 7 mmol). Purification though flash column chromatography yielded product as a yellow oil (961 mg, 85% yield). 1H NMR (300 MHz, CHLOROFORM-d) d ppm 2.21 (s, 3 H) 2.54 (t, J=2.40 Hz, 1 H) 3.80 (br. s., 2 H) 4.74 (d, J=2.51 Hz, 2 H) 6.69 (t, J=7.80 Hz, 1 H) 6.79 (dq, 209  J=7.54, 0.50 Hz, 1 H) 6.84 (dd, J=7.77, 0.91 Hz, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 17.3, 56.5, 75.4, 79.1, 110.3, 117.4, 123.2, 123.8, 134.9, 145.0; IR(1/cm): 3459, 3376, 3284, 3043, 2923, 2857, 2120, 1617, 1599, 1580; High-Res MS: Calculated: 162.0919 (M+1), Found: 162.0921 (M+1, C10H12NO)   (R)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.13) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.12 (73.6 mg, 0.5 mmol). Purification through flash chromatography yielded product as a colorless oil (42.8 mg 56% yield, 80% ee). Chiral separation was on a Chiralcel OJ-RH column using 40% MeCN in water (retention times = 5.353 min and 5.660 min).  Characterization matches literature data.203 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.20 (d, J=6.40 Hz, 3 H) 3.55 (dqd, J=7.99, 6.40, 2.70 Hz, 1 H) 3.79 (dd, J=10.51, 8.22 Hz, 1 H) 4.20 (dd, J=10.51, 2.74 Hz, 1 H) 6.62 (td, J=7.31, 1.60 Hz, 1 H) 6.68 (dd, J=7.54, 1.60 Hz, 1 H) 6.73 - 6.83 (m, 2 H), 13C NMR (100 MHz, CHLOROFORM-d) δ 17.9, 45.2, 70.8, 115.5, 116.6, 118.9, 121.4, 133.6, 143.8.   (R)-3-methyl-6-(trifluoromethyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.33) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.27 (107.6 mg, 0.5 mmol). Purification through flash chromatography yielded product as a yellow powder (Racemic: 61.9 210  mg, 0.253 mmol, 57% yield; Asymmetric: 35.7 mg, 0.165 mmol 33% yield, 78% ee). Chiral separation was on a Chiralcel OJ-RH column using 55% MeCN in water (retention times = 11.356 min and 11.966 min). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=6.40 Hz, 3 H) 3.56 (dqd, J=7.99, 6.40, 2.74 Hz, 1 H) 3.80 (dd, J=10.51, 7.99 Hz, 1 H) 3.83 (br. s, 1 H) 4.23 (dd, J=10.51, 2.74 Hz, 1 H) 6.79 - 6.87 (m, 2 H) 6.87 - 6.95 (m, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 17.8, 45.0, 70.9, 112.1 (q, 3JC-F=3.4 Hz,), 115.8 (q, 3JC-F=4.6 Hz), 123.6 (q, 2JC-F=32.2 Hz), 124.6 (q, JC-F=271.3 Hz), 133.7, 146.2; 19F{1H} NMR (282 MHz, CHLOROFORM-d) δ ppm -61.7; IR(1/cm): 3391, 2977, 2930, 2879, 1616, 1599; High-Res MS: Calculated: 218.0793 (M+1), Found: 218.0791 (M+1, C10H11NOF3)    tert-butyl (R)-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylate (5.34) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.28 (123.6 mg, 0.5 mmol). Purification through flash chromatography followed by precipitation of the HCl salt from ether yielded product as a yellow powder (Racemic: 30 mg, 0.253 mmol, 24% yield; Asymmetric: 35 mg, 0.165 mmol 28% yield, 78% ee). Chiral separation was on a Chiralcel AS-RH column using 25% MeCN in water (retention times = 11.925 min and 12.791 min).  1H NMR (300 MHz, DMSO-d6) δ ppm 1.14 (d, J=6.40 Hz, 3 H) 1.50 (s, 9 H) 3.40 - 3.52 (m, 1 H) 3.78 (dd, J=10.74, 7.99 Hz, 1 H) 4.25 (dd, J=10.74, 2.97 Hz, 1 H) 6.76 - 6.81 (m, 1 H) 7.22 (dd, J=8.45, 2.06 Hz, 1 H) 7.30 (d, J=2.06 Hz, 1 H); 13C NMR (75 MHz, DMSO-d6) δ ppm 16.3, 27.9, 44.5, 211  69.7, 79.1, 115.9, 117.3, 120.9, 123.5, 124.1, 147.6, 164.8; IR(1/cm): 2976, 2933, 2561, 2464, 2374, 1700, 1618, 1600, 1555, 1512;  High-Res MS: Calculated: 250.1443 (M+1), Found: 250.1445 (M+1, C14H20NO3)   (R)-7,8-difluoro-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine ((+)-5.5) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.29 (123.6 mg, 0.5 mmol). Purification by precipitation of the HCl salt from ether followed by freebasing into ether yielded product as a brown oil (Racemic: 30 mg, 0.253 mmol, 24% yield; Asymmetric: 35 mg, 0.165 mmol 28% yield, 50% ee). [α]D24 1.6 (c = 2.8, CHCl3), lit. [α]D23 7.8 (c = 6.8, CHCl3).197 Characterization  matches known literature values.200 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.21 (d, J=6.40 Hz, 3 H) 3.44 - 3.58 (m, 1 H) 3.80 (dd, J=10.39, 8.11 Hz, 1 H) 4.29 (dd, J=10.51, 2.74 Hz, 1 H) 6.27 (ddd, J=9.02, 4.68, 2.28 Hz, 1 H) 6.48 - 6.62 (m, 1 H); 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 17.6, 45.0, 71.1, 107.91 (d, J=18.39 Hz, 1 C) 108.65 (dd, J=8.05, 4.60 Hz, 1 C) 131.00 (dd, J=4.60, 2.30 Hz, 1 C) 133.46 (dd, J=10.34, 4.60 Hz, 1 C) 140.77 (dd, J=243.68, 16.09 Hz, 1 C) 144.64 (dd, J=236.78, 10.34 Hz, 1 C), 19F{1H} NMR (282 MHz, CHLOROFORM-d) δ ppm -160.82 (d, J=20.65 Hz, 1 F) -149.88 (d, J=20.65 Hz, 1 F)   212  (R)-3,7-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.35) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.30 (80.6 mg, 0.5 mmol). Purification through precipitation of the HCl salt from ether followed by washing 3 x 5 mL ether, freebasing with 2M NaOH (5 mL), extracting with 3 x 5 mL diethyl ether, washing the combined organic phases with brine (5 mL), drying over MgSO4, and concentration in vacuo yielded product as a red oil (Racemic: 42.4 mg, 0.26 mmol, 52% yield; Asymmetric: 23 mg, 0.014 mmol, 28% yield, 75% ee). Chiral separation was on a Chiralcel OJ-RH column using 35% MeCN in water (retention times = 16.511 min and 21.725 min).  1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.18 (d, J=6.49 Hz, 3 H) 2.23 (s, 3 H) 3.45 - 3.58 (m, 1 H) 3.77 (dd, J=10.58, 8.19 Hz, 1 H) 4.18 (dd, J=10.24, 2.73 Hz, 1 H) 6.50 - 6.54 (m, 1 H) 6.57 - 6.61 (m, 1 H) 6.64 (d, J=1.37 Hz, 1 H), 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 17.9, 20.7, 45.4, 71.0, 115.7, 117.1, 121.9, 128.8, 130.9, 143.8;IR(1/cm): 3363, 3025, 2962, 2921, 2868, 1623, 1589, 1515; High-Res MS: Calculated: 164.1075 (M+1), Found: 164.1073 (M+1, C10H14NO)   (R)-3,6-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.36) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.31 (80.6 mg, 0.5 mmol). Purification through precipitation of the HCl salt from ether followed by washing 3 x 5 mL ether, freebasing with 2M NaOH (5 mL), extracting with 3 x 5 mL diethyl ether, washing the combined organic phases with brine (5 mL), drying over MgSO4, and concentration in vacuo yielded product as a red oil (Racemic: 51 mg, 0.315 mmol, 63% yield; Asymmetric: 14.2 mg, 0.085 mmol 17% yield, 86% ee). Chiral separation was on a Chiralcel OJ-RH column using 35% MeCN in water (retention 213  times = 24.829 min and 30.787 min).  1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.19 (d, J=6.40 Hz, 3 H) 2.21 (s, 3 H) 3.46 - 3.61 (m, 1 H) 3.76 (dd, J=10.51, 7.99 Hz, 1 H) 4.17 (dd, J=10.51, 2.74 Hz, 1 H) 6.40 - 6.52 (m, 2 H) 6.69 (d, J=7.99 Hz, 1 H); 13C NMR (100 MHz, CHLOROFORM-d) δ ppm 17.9, 20.9, 26.0, 45.4, 70.8, 116.2, 116.3, 120.0, 130.9, 141.7;  IR(1/cm): 3368, 2968, 2923, 2873, 1615, 1595, 1515; High-Res MS: Calculated: 164.1075 (M+1), Found: 164.1072 (M+1, C10H14NO)     (R)-3,5-dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine (5.37) Synthesized through General Procedures D (racemic) and E (asymmetric) using 5.32 (80.6 mg, 0.5 mmol). Purification through precipitation of the HCl salt from ether followed by washing 3 x 5 mL ether, freebasing with 2M NaOH (5 mL), extracting with 3 x 5 mL diethyl ether, washing the combined organic phases with brine (5 mL), drying over MgSO4, and concentration in vacuo yielded product as a red oil (Racemic: 51 mg, 0.315 mmol, 63% yield; Asymmetric: 35 mg, 0.165 mmol 28% yield, 69% ee) Chiral separation was on a Chiralcel OJ-RH column using 30% MeCN in water (retention times = 16.805 min and 17.762 min). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.24 (d, J=6.40 Hz, 3 H) 2.14 (s, 3 H) 3.52 - 3.64 (m, 1 H) 3.77 (dd, J=10.39, 8.11 Hz, 1 H) 4.19 (dd, J=10.51, 2.74 Hz, 1 H) 6.55 - 6.65 (m, 1 H) 6.66 - 6.75 (m, 2 H), 13C NMR (75 MHz, CHLOROFORM-d) δ ppm 16.9, 18.1, 45.5, 70.5, 114.5, 118.1, 122.8, 123.2, 131.6, 143.5; IR(1/cm): 3392, 3046, 2969, 2929, 214  2869, 1608, 1590; High-Res MS: Calculated: 164.1075 (M+1), Found: 164.1076 (M+1, C10H14NO) 215  Chapter 6: Conclusion 6.1 Summary The research presented in this thesis is focused on the development of practical methods for the use of early transition metal catalysts for the synthesis of amines. These methods allow for the synthesis of a structurally diverse set of amines, including α-alkylated, β-methylated, and α,β-dialkylated amines through hydroaminoalkylation and hydroamination. This allows new, atom-economic routes to compounds with potential relevancy to the pharmaceutical, agrochemical, and materials industries. 6.1.1 Chapter 2 Chapter 2 focused on the expanded development of trimethyl tantalum phosphoramidate complex 2.7 for use as a precatalyst for hydroaminoalkylation. This precatalyst had been previously reported by the Schafer group and has been used for the 1-step synthesis of aminomethyl-substituted norbornenes, which can be further used for the synthesis of amine-containing polynorbornenes.3, 46 However, previous studies of this precatalyst had been primarily limited to the use of electron-rich N-methylamines, with none of the amine substrates reported containing electron-deficient amines and only one instance of a substrate with a reactive secondary carbon. In addition, only one amine substrate, 4-methoxy-N-methylaniline, was reported for the hydroaminoalkylation of norbornadiene to form the aminomethyl norbornene monomer. To expand this scope, a variety of amines were tested for activity with the precatalyst. N-methylanilines with electron donating and electron withdrawing substituents, as well as N-methylcyclohexylamine, were tested for the hydroaminoalkylation of norbornadiene. Multiple N-substituted-4-methoxyanilines were also tested for hydroaminoalkylation with 1-octene. The trends in reactivity observed indicate that, while 2.7 is highly active towards electron-rich amines, 216  it is significantly less active toward anilines without electron-donating substituents, requiring elevated reaction temperatures to achieve poor yields. The precatalyst is also highly sensitive to steric bulk around the amine, with none of the N-substituted-4-methoxyanilines tested exhibiting reactivity. Given the use of the aminomethyl-substituted norbornenes for the synthesis of amine-containing polymers, the moderate to poor yields of the hydroaminoalkylation reactions to form these monomers required optimization. Working to achieve full conversion of the amine to avoid a challenging purification while simultaneously attempting to mitigate the formation of dialkylated norbornane and poly(norbornadiene) byproducts, the hydroaminoalkylation of norbornadiene with N-methylaniline using 2.7 was optimized. It was discovered that, by utilizing 5 equivalents of norbornadiene with no external solvent at 70 °C, a maximum of 75% yield by NMR spectroscopy can be obtained (Scheme 6.1).  Scheme 6.1 Optimized conditions for the hydroaminoalkylation of norbornadiene with N-methylaniline using catalyst 2.7 6.1.2 Chapter 3 Chapter 3 explores the development of a new hydroaminoalkylation catalyst system, utilizing Ta(NMe2)5 with the commercially available pyridonate ligand 3.18. This system was 217  developed as a method to avoid the use of isolated precatalysts, many of which are highly air and moisture sensitive or require synthetically intensive procedures to isolate. By utilizing the tantalum precursor and the ligand in separate stock solutions, this catalyst system can be used for the overnight hydroaminoalkylation of a variety of alkenes with different amines, with isolated yields up to 100% (Scheme 6.2). The substrate scope for this catalyst system is also wider than many other tantalum hydroaminoalkylation catalysts, with the ability to not only tolerate a wider array of functional groups, such as acetals, ketals, and internal alkynes, but also the ability to utilize N-ethylaniline as a substrate. Notably, the use of stock solutions of catalyst precursors for this catalyst system allows it to be used outside of an inert atmosphere glovebox using syringe techniques, allowing for its use by labs that are not as well equipped for highly air- and moisture-sensitive organometallic chemistry. A procedure for avoiding the formation of a common byproduct of dimethylamide-based hydroaminoalkylation catalysis was also developed, simply requiring either a large reaction headspace or the sparging of the headspace with nitrogen during the course of the reaction in order to prevent the liberated dimethylamine from catalyst activation returning to the reaction solution and causing byproduct formation.  Scheme 6.2 Hydroaminoalkylation catalyzed through the in-situ generated Ta(NMe2)5/3.18 catalyst system 218  The ability to use N-ethylaniline as a substrate to synthesize α-methylated-β-alkylated amines has the potential to prove a facile route to new classes of compounds, but the initial yield of this reaction proved to be very low, achieving only 11% yields using the initial optimized conditions. Further optimization of the reaction conditions allowed for yields of up to 33%. In an attempt to further increase the yield of this reaction, a number of different catalyst ligands were tested, but only catalysts with pyridonate ligands were capable of utilizing this substrate. As part of the ligand screen for the N-ethylaniline reaction optimization, it was noted that, while changing the steric environment of the ligand did not result in a change in the overall yield, changing the electronic environment had a small impact. It was hypothesized that, by fine-tuning the electronic environment of the pyridonate ligand, the catalytic activity of the resulting catalyst could be optimized. A series of tantalum complexes containing 4- and 5-substituted pyridonate ligands were synthesized and characterized. The catalytic activity of each complex was determined through the initial rates for each catalyst with the hydroaminoalkylation reaction of 1-octene with N-methylaniline. However, no correlation was observed between complex structure or catalyst rate with known linear free energy relationship values, likely due to a variety of off-cycle equilibria that are also affected by changing the electronic environment of the ligand. The combination of the functional group tolerance and activity towards N-ethylaniline with the Ta(NMe2)5/pyridone catalyst system allows for the synthesis of polysubstituted piperidines that would be otherwise very difficult to synthesize. The protected aminoalcohols and keto-amines that can be synthesized through the hydroaminoalkylation of the corresponding protected hydroxy alkenes and keto-alkene can be deprotected and cyclized in single-pot reactions to form polysubstituted piperidines in poor to excellent yields (Scheme 6.3). 219   Scheme 6.3 Synthesis of poly-substituted piperidines 6.1.3 Chapter 4 Chapter 4 explores the use of tantalum pentafluoride as a precursor to an in-situ generated hydroaminoalkylation catalyst. Generation of the catalytically active species occurs through the addition of methyl lithium to a mixture of tantalum pentafluoride, ligand, amine and alkene substrates, and toluene. While this reaction is slower than other tantalum-catalyzed hydroaminoalkylation reactions, requiring two days to reach maximum conversion, it requires a lower reaction temperature of 70 °C, as opposed to 110+ °C required by most other tantalum catalysts (Scheme 6.4). This method can also be set-up outside of an inert atmosphere glovebox without the need for non-commercially available stock solutions. However, the substrate scope is somewhat restricted, but ketals, aryl halides, and dialkyl amines are tolerated. The functional group tolerance also includes the use of 2-bromoallyl benzene as a substrate, the product of which can 220  be cyclized via Buchwald-Hartwig amination to produce 4.27, the first tetrahydroquinoline synthesized through a hydroaminoalkylation/cyclization sequence (Scheme 6.5).  Scheme 6.4 Hydroaminoalkylation catalyzed by an in-situ generated catalyst based on tantalum pentafluoride  Scheme 6.5 Synthesis of tetrahydroquinoline 4.27 from hydroaminoalkylation product 4.26 In an attempt to understand the nature of the catalyst formation, an NMR study was performed on select steps of the reaction. When exposed to Lewis bases, such as N-methylaniline or proligand 4.10, the tetrameric structure of tantalum pentafluoride is disrupted, forming the corresponding LTaF5 complexes. When both N-methylaniline and 4.10 are present, the harder oxygen donor of 4.10 outcompetes the softer nitrogen donor of N-methylaniline to bind to the hard tantalum Lewis acid. However, upon addition of methyl lithium, a variety of complexes are formed, resulting in an undefined catalytic mixture. Given that the overall goal of this method was to be able to set up the reaction without the use of an inert atmosphere glovebox, the stability of tantalum pentafluoride to storage in air was 221  studied. It was determined that, while tantalum pentafluoride is stable enough to be used outside of a glovebox, it is not stable to storage in a non-inert atmosphere, with yields for the hydroaminoalkylation of 1-octene with N-methylaniline dropping to less than 20% in just 2 weeks. 6.1.4 Chapter 5 Chapter 5 explores the expansion of a method for the asymmetric synthesis of morpholines developed by Lau et al. for the asymmetric synthesis of 1,4-benzoxazines using titanium hydroamination catalyst 5.1 and Noyori’s asymmetric transfer hydrogenation catalyst 5.2 (Scheme 6.6).189 A variety of substituted 2-aminophenyl propargyl ethers were then synthesized through a simple, two-step procedure, and then cyclized to form a variety of substituted 1,4-benzoxazines, including a key intermediate in the synthesis of the antibiotic levofloxacin, in poor-to-good yields and good % ee’s. The reduced yields of this procedure can be attributed to the formation of dimeric side products of the asymmetric transfer hydrogenation reaction as well as challenging purification methods required to remove both the ligand of 5.1 and the side products. Optimization of the hydroamination reaction allowed for the avoidance of a dimer side product formed during this step, but similar side products were consistently observed during the asymmetric transfer hydrogenation and attempts to prevent their formation were unsuccessful.  Scheme 6.6 One-pot hydroamination/asymmetric transfer hydrogenation for the asymmetric synthesis of 1,4-benzoxazines 222  6.2 Future Work 6.2.1 Chapter 2 While the low temperature reactivity of phosphoramidate catalyst 2.7 makes it potentially useful as catalyst for the hydroaminoalkylation of thermally sensitive substrates, it suffers some major drawbacks that prevent it from being broadly relevant as a synthetic tool. The high air, moisture, and light sensitivity, as well as its pyrophoric nature, make it challenging to store and handle. TaMe3Cl2, the tantalum precursor to catalyst 2.7, is similarly sensitive and pyrophoric, and has to be synthesized from TaCl5 and ZnMe2 (Scheme 6.7). Such challenges makes catalyst 2.7 unsuitable as a general use catalyst and potentially dangerous for large-scale syntheses, such as the synthesis of monomer 2.9 on scales relevant for the production of amine-containing poly(norbornenes). Indeed, the use of 2.7 as a hydroaminoalkylation catalyst for the production of (aminomethyl)norbornene monomers has since been supplanted by the Ta(NMe2)5/3.18 catalyst system, which achieves higher yields without the challenge of using 2.7.  Scheme 6.7 Synthesis of phosphoramidate catalyst 2.7 The (aminomethyl)norbornenes synthesized as part of chapter 2 are currently in development as monomers for the formation of amine-containing polymers. However, there are potential alternative uses that could lead to new, value-added compounds. In particular, the highly-strained alkene in the norbornene moiety provides a site for further reactivity. One potential use of 223  this reactive site would be for the synthesis of fused-bicyclic N-heterocycles, such as 6.1 (Scheme 6.8). Such heterocycles are challenging to synthesize through classical techniques and could be used as building blocks for more complex molecules.  Scheme 6.8 Ozonolysis of 2.9 to synthesize 6.1 6.2.2 Chapter 3 While the Ta(NMe2)5/3.18 catalyst system exhibits unprecedented reactivity towards challenging substrates such as N-ethylaniline, it lacks the ability to utilize key classes of substrates, such as unstrained internal alkenes, that can be utilized by other catalysts. One of the key features of catalysts that perform the hydroaminoalkylation of unstrained internal alkenes is the presence of a halide ancillary ligand.67 The catalyst 3.10, which differs from the Ta(NMe2)5/3.18 primarily through both its use as an isolated complex and the replacement of one of the dimethylamido ligands with a chloride ligand, is competent for the hydroaminoalkylation of unstrained internal alkenes.68 While attempts to form this catalyst in situ through salt metathesis of Ta(NMe2)3Cl2 with the sodium salt of 3.18 were unsuccessful in replicating the reactivity of 3.10, an alternative method to generate this catalyst in situ can be imagined. By introducing one catalyst equivalent of an HCl source, such as a lutidine HCl, to the catalyst solution prior to addition of the amine and alkene substrates, the resulting catalyst system can be used for the hydroaminoalkylation of unstrained internal alkenes (Scheme 6.9). While preliminary results show a low conversion of only 12%, this is likely partly due to the low solubility of lutidine HCl during the catalyst formation. 224  Optimization of the HCl source has the potential to lead to an increase in conversion, generating a new method to utilize internal alkenes as hydroaminoalkylation substrates using commercially available starting materials.  Scheme 6.9 Hydroaminoalkylation of an unstrained internal alkene using an in-situ generated tantalum chloro pyridonate catalyst  The ability for the Ta(NMe2)5/3.18 catalyst system to be able to utilize N-ethylaniline as a substrate is a major advance in the substrate scope of early transition metal hydroaminoalkylation catalysts. However, the yield of this reaction, 33%, is still much lower than is ideal for preparative-scale use. Efforts to optimize the ligand for this reaction showed that the decreased steric profile of the pyridonate catalysts is important for achieving any conversion, but the use of 4-hydroxypyrimidine lead to no conversion. Further attempts to optimize this reaction could look at ligands such as the 2-aminopyridine ligands used by Doye and co-workers, 2-hydroxypyrroles, or other sterically unencumbering planar N,O-chelates.47 With further optimization of this reaction, the reactivity of amines with larger substituents, such as N-propyl and N-benzyl, can potentially be realized, greatly expanding the scope and utility of hydroaminoalkylation as a synthetic tool. Despite the fact that hydroaminoalkylation has been known in the literature since 1980, and has seen continuous research effort for over ten years, there are many aspects of the mechanism that are still not well understood.27, 30, 42 Much of this is due to a plethora of off-cycle equilibria, 225  including dimethylamine binding and metallaziridine formation, product binding, and ortho-metalation of the amine, that have been identified through deuterium labeling studies but have yet to be fully elucidated (Scheme 6.10).43, 66, 68 These equilibria constitute a major obstacle towards kinetic analysis of the reaction and comparison between different catalysts, as these equilibria shift in as-of-yet unquantified fashions in response to changes in catalyst, substrates, reaction temperature, reaction concentration, and even reaction vessels. One potential method for dealing with some of these equilibria, especially the dimethylamine equilibria, is in the utilization of metal-alkyl based catalysts, such as catalysts made from Ta(CH2SiMe3)3Cl2.72 Recently reported by the Schafer research group, these catalysts do not utilize dimethylamido sacrificial ligands and therefore do not suffer from the dimethylamine-based equilibria. Given that these equilibria have significant impact on the required reaction time (See Chapter 3, Table 3.1 entries 15 and 16), these catalysts are much more suitable for kinetic analysis. This leads to the possibility of performing Hammett analyses on not only the ligand, but also on the amine and alkene substrates. This, in turn, will allow for a better understanding of how the electronic environment of each aspect of the reaction can affect the overall rate, and lead to the development of more active catalysts. 226   Scheme 6.10 Mechanism of early transition metal catalyzed hydroaminoalkylation with off-cycle equilibria Piperidines are one of the most frequently used heterocycles in medicinal chemistry.207 As such, the synthesis of substituted piperidines, both for use as chemical building blocks and for the synthesis of natural product cores, is an area of ongoing research.208 Piperidine synthesis through sequential hydroaminoalkylation/silyl-deprotection/cyclization has been previously reported by the Schafer group, but such heterocycles were limited to N-substituted-3-methyl substitution patterns. The Ta(NMe2)5/3.18 catalyst system, by allowing for the utilization of both ketal functional groups and N-ethylaniline as a substrate, has expanded this scope to allow substitution at the 2 and 6 positions. While the piperidines formed through this were limited to methyl substituents, a variety of other substituents could be achieved through careful selection of alkene 227  substrate, amine substrate, and catalyst (Scheme 6.11). In addition, the hydroaminoalkylation of a diene followed by an intramolecular hydroamination has the potential to access these compounds in an atom-economic fashion.79 After cyclization, oxidative removal of the p-methyoxyphenyl group can yield the free piperidine, which can be utilized as a building block for the synthesis of new pharmaceuticals.209  Scheme 6.11 Proposed syntheses of highly functional polysubstituted piperidines from hydroaminoalkylation products 6.2.3 Chapter 4 The development of the TaF5 catalyst system in chapter 4 represents a proof-of-concept for the in-situ generation of hydroaminoalkylation catalysts from more robust metal halide starting materials. While TaF5 proved to be less air- and moisture-stable than initially hoped, it still can be handled outside of an inert atmosphere glovebox for the time required to set-up a reaction. One direction that can be explored for the improvement of this reaction is through the use of K2TaF7, a stable, hepta-coordinate tantalum compound that is an intermediate in the purification of tantalum 228  metal from tantalum ores and is known to be water stable.127 An initial test of using K2TaF7 using the reaction conditions developed for the TaF5 was unsuccessful (See Chapter 4, Table 4.1, entry 17), which was hypothesized to be due to the lack of solubility of K2TaF7 in toluene. Changing the solvent to a more polar solvent, such as THF, may overcome this obstacle, allowing for the development of an in-situ generated hydroaminoalkylation catalyst from highly robust tantalum starting materials. While the NMR study performed on the formation of the tantalum catalyst gave some insights into the catalyst formation process, a rigorous attempt to isolate and characterize the catalyst intermediates and fully formed catalyst has not been attempted. Such a study would lead to a better understanding of the catalyst system, and potentially give insight into how to increase the activity and robustness of the catalyst system. The use of heterogeneous catalysts for hydroaminoalkylation is significantly underdeveloped. There have been only two reports of heterogeneous hydroaminoalkylation catalysts, and both are based on the reaction of the corresponding homoleptic dimethylamido complexes with silica to generate silica-bound complexes.63, 73 Given both the ease of use and ease of recycling for heterogeneous catalysts, the development of a heterogeneous, recyclable hydroaminoalkylation catalyst would be of great value. One potential heterogeneous catalyst is suggested by the ruthenium-catalyzed α-deuteration of amines literature. In 2015, Taglang et al. reported the enantiospecific activation of C-H bonds α to amines and alcohols through the use of ruthenium nanoparticles, and the use of such activation for H/D exchange reactions (Scheme 6.12).210 A later report by Michelotti et al. demonstrate this reaction using ruthenium on carbon (Ru/C), with the ability of the catalyst to be recycled with minimal loss of deuterium incorporation.211 Notably, the mechanism proposed by Taglang et al. through computational 229  results involves coordination of the amine to a ruthenium atom on the nano-particle surface, followed by C-H activation on an adjacent ruthenium atom (Figure 6.1). This mechanism is similar to the proposed mechanism for ruthenium-catalyzed hydroaminoalkylation. Addition of an alkene to the reaction mixture could potentially lead to Ru/C-catalyzed hydroaminoalkylation through the insertion of the alkene into the Ru-H bond, followed by elimination of the alkylated amine product. As Ru/C is air- and moisture-stable, and the addition of a strong base would be unnecessary, this method could allow for the hydroaminoalkylation of substrates under ambient atmosphere using substrates, such as amino acids, that are currently not usable in early transition metal-catalyzed hydroaminoalkylation.211  Scheme 6.12 H/D exchange through the use of heterogeneous ruthenium catalysts 230   Figure 6.1 Mechanism of ruthenium-catalyzed H/D exchange and proposed heterogenous-catalyzed hydroaminoalkylation  While there are many catalysts that are capable of alkylating N-methylaniline with one equivalent of alkene, there has only been two reports of a dialkylation on the same reactive site. In their report on the use of TiBn4 as a hydroaminoalkylation catalyst, Doye and co-workers report the formation of a side product consisting of the dialkylation of N-methylaniline with two equivalents of styrene.54 In 2012, Doye and co-workers reported a dinuclear titanium complex with a sulfonamide ligand that is able to catalyze a second hydroaminoalkylation on the same carbon of the product as the initial hydroaminoalkylation, with two examples (Scheme 6.13).56 During the reaction optimization for the TaF5 catalyst system it was observed that, when 3-methyl-2-pyridone is used as a ligand and the reaction is heated to 110 °C, two separate dialkylated products can be observed through GC/MS (Scheme 6.14). These products were never isolated in high enough yield 231  to determine the regioselectivity of the second alkylation. Through optimization of the reaction, a method for the dihydroaminoalkylation of N-methylamines could be determined. Such a method would also likely be capable of utilizing amines with more steric bulk on the reactive carbon, such as N-benzylaniline.  Scheme 6.13 Dihydroaminoalkylation using a dinuclear titanium sulfonamide catalyst  Scheme 6.14 Dihydroaminoalkylation observed using the TaF5 catalyst system with 3-methyl-2-pyridone as a ligand 6.2.4 Chapter 5 While the hydroamination/transfer hydrogenation method developed by Lau et al. for the asymmetric synthesis of morpholines does work for the synthesis of 1,4-benzoxazines, it suffers from low yields and the formation of as-of-yet uncharacterized side products that are hypothesized to be the aminoalkynes that have been dimerized. Full characterization of the side products may help identify the cause of its formation and provide insight into how to prevent it from forming. This would subsequently increase the yield of the reaction and simplify the purification, increasing the utility of the synthesis. In addition, identification of suitable conditions for the clean reduction 232  of the remaining o-nitrophenyl propargyl ethers would allow for further expansion of the substrate scope for this method. While asymmetric hydrogenations and racemic reductions are common second-step reactions after the hydroamination of an alkyne, they are not the only reactions possible. One particular reaction that has been utilized for the further functionalization of the imine product of alkyne hydroamination is the Strecker reaction to yield α-amino acids (Scheme 6.15).174However, this reaction was only reported for a limited number of substrates. There has been a wide variety of methods developed for the asymmetric Strecker synthesis, and coupling these with alkyne hydroamination would allow for the synthesis of enantioenriched unnatural α-amino acids (Scheme 6.16).212 In particular, an intramolecular alkyne hydroamination/asymmetric Strecker method would allow for the synthesis of a wide variety of α-substituted proline analogues that could be used as building blocks for the development of new peptide-based pharmaceuticals.213  Scheme 6.15 Sequential intermolecular alkyne hydroamination/Strecker reaction to yield racemic α-amino acids  Scheme 6.16 Proposed sequential alkyne hydroamination/asymmetric Strecker reaction to yield enantioenriched α-amino acids 233  6.3 Concluding Remarks In this thesis, the development of practical methods for the early transition metal-catalyzed synthesis of amines is presented. By utilizing N,O-chelated tantalum hydroaminoalkylation catalysts, some of which can be readily assembled in-situ from commercially available starting materials, a variety of structurally diverse amines were synthesized with excellent yields, regioselectivity, and in some cases, diastereoselectivity. These amines have the potential to be important intermediates in the synthesis of value-added chemicals, as demonstrated through further reactions to synthesize a variety of substituted N-heterocycles. Other N-heterocycles were accessed through the use of titanium-catalyzed hydroamination/ruthenium-catalyzed asymmetric transfer hydrogenation of readily synthesized aminoalkynes. Many of these methods do not require the use of a rigorously maintained inert atmosphere glovebox and, as such, are more accessible to the broader synthetic organic community. 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Chem. 2018, 61, 1382-1414. 241  Appendices  Appendix A  NMR Spectra A.1 Chapter 2 Substrate Synthesis NMR Spectra OCH3NHPME1-81-1.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.001.051.891.921.052.681.781.77M03(s)M02(m)M01(m)M07(dt)M06(dt)M04(m) M05(m)M08(m)1.111.121.151.201.241.341.381.731.741.751.782.032.042.072.083.143.153.163.173.193.213.756.586.616.756.766.79 1H NMR spectrum of 4-methoxy-N-cyclohexylaniline NHOCH3PME1-81-1 13C.001.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity25.2526.1533.7653.0956.0076.7677.1977.61115.08115.14141.61152.12 13C NMR spectrum of 4-methoxy-N-cyclohexylaniline  242  NHOPME7-072.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity6.071.383.001.951.94M01(s)M04(m)M03(d)M05(m)M02(spt)1.191.213.493.513.543.563.583.603.766.576.596.596.616.766.786.806.827.27 1H NMR spectrum of 4-methoxy-N-isopropylaniline NHOPME7-072.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity23.0445.8855.9277.16115.04115.61141.20152.45 13C NMR spectrum of 4-methoxy-N-isopropylaniline 243  NHOPME1-85-1.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.212.182.142.085.00CDCl3M01(s)M02(s)M03(dt)M04(dt)M05(m)3.764.316.616.626.656.776.796.827.297.317.337.357.367.387.417.42 1H NMR spectrum of 4-methoxy-N-benzylaniline NHOPME1-85-1 13C.001.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity49.4155.9377.16114.29115.04127.32127.70128.72139.74142.49152.37 13C NMR spectrum of 4-methoxy-N-benzylaniline 244  A.2 Chapter 2 Substrate Scope NMR Spectra NHOPME1-032.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.413.141.031.031.082.513.001.922.021.95M01(s)M07(br. s.)M06(br. s.)M04(m)M03(m)M02(m)M10(m)M09(m)M08(qd)M05(m)1.221.241.251.261.361.391.671.681.681.701.701.722.732.863.033.053.063.083.113.133.143.163.766.086.096.096.106.116.126.126.136.596.626.786.796.817.27 1H NMR spectrum of 2.1 NHOPME1-032.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.1431.4139.1741.8044.6445.3950.7855.9977.16114.09115.06136.58136.85143.00152.09 13C NMR spectrum of 2.1 245  NHPME1-84-1.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity9.002.682.051.901.012.550.801.61M04(br. s.)M08(m)M01(d)M02(tt)M05(m)M03(m)M06(m)M07(m)1.031.061.081.101.141.201.321.331.491.511.531.551.581.711.721.771.871.912.372.382.402.422.462.592.632.652.682.692.816.036.046.056.066.086.096.106.11 1H NMR spectrum of 2.8 NHPME1-92-1 13C.001.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity25.2826.3831.7133.8733.9039.6641.7944.7745.3553.0657.2676.8177.2377.66136.60136.78 13C NMR spectrum of 2.8 246  NHPME1-135-1.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.423.481.711.071.062.262.003.042.02M03(m)M05(br. s.)M06(d)M01(m)M09(m)M08(m)M02(m)M07(m)M04(m)1.221.231.241.261.271.361.381.701.711.731.741.751.762.772.772.863.103.133.143.173.173.203.213.246.056.066.076.086.096.826.846.856.867.207.217.237.27 1H NMR spectrum of 2.9 NHPME-NBDNMA.002.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity31.4039.1041.8144.6245.3849.7377.16112.81117.27129.37136.54136.89148.55 13C NMR spectrum of 2.9 247  NHBrPME1-137 1H.001.esp12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.283.330.991.041.042.170.982.002.101.97M03(m)M06(br. s.)M07(s)M02(m)M01(s)M10(m)M08(dd)M09(m)M04(br. s.) M05(m)1.221.231.351.361.381.391.391.651.661.692.712.873.053.083.103.123.143.756.106.476.486.516.527.227.237.267.27 1H NMR spectrum of 2.11 NHBrPME1-EM-BrAn 13C.001.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity31.2138.8741.6744.4245.2249.54108.56114.16131.87136.30136.82147.39 13C NMR spectrum of 2.11 248  A.3 Chapter 3 Substrate Synthesis NMR Spectra NHPME3-139.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.000.972.034.821.91CHCl3AcetoneWaterM01(s)M04(m) M03(dt)M05(m)M02(br. s.)7.527.527.507.407.377.317.276.596.586.556.553.912.872.181.55 1H NMR spectrum of 3.90 NHPME3-139.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3149.36133.05131.44 128.38127.63124.23112.14111.2090.6487.2977.1630.56 13C NMR spectrum of 3.90  249  A.4 Chapter 3 Substrate Scope NMR Spectra CH3CH3NHPME2-126.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.103.0010.521.361.041.031.920.951.89CDCl3M01(d)M08(dd)M07(t)M09(m)M06(m)M02(m)M05(dd)M04(dt)M03(m)0.870.900.970.991.171.191.291.411.441.451.741.761.772.852.882.902.923.033.053.073.096.606.626.636.686.717.147.157.177.187.27 1H NMR spectrum of 3.15 NHCH3CH3PME2-129.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCDCl314.2518.1922.8127.0929.7532.0134.9450.4877.16112.75117.05129.32148.74 13C NMR spectrum of 3.15 250  NHOPME2-130.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.032.9410.431.251.031.033.001.901.86CDCl3M08(d)M03(m)M02(m)M04(dd)M05(dd)M09(m)M01(s)M06(dd)M07(m)0.870.900.960.981.161.191.291.411.431.441.721.741.762.812.842.852.882.993.013.033.053.766.586.616.626.776.807.27 1H NMR spectrum of 3.21  NHOPME2-132.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCDCl314.2218.1922.7927.0729.7431.9933.0334.9451.5955.9377.16114.12115.02142.95152.01 13C NMR spectrum of 3.21 251  NHBrPME2-141.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.539.591.022.001.711.60CHCl3H2OM06(m)M05(m)M02(dd)M04(m)M01(m)M03(m)0.870.900.950.981.161.181.291.341.391.431.461.721.741.762.822.852.862.892.993.013.033.056.476.486.517.227.237.267.27 1H NMR spectrum of 3.22   NHBrPME2-141.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3147.67131.95114.29108.4777.1650.4634.8732.9531.9929.7227.0422.7918.1314.25 13C NMR spectrum of 3.22 252  NHOPME4-019.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.032.9710.330.993.002.442.900.981.92CHCl3M04(s)M02(s)M05(d)M08(m)M09(m)M06(m)M03(d)M01(m)M07(m)0.890.910.991.021.221.231.311.441.461.781.802.162.862.892.902.933.043.063.083.103.766.556.586.706.716.726.736.737.27 1H NMR spectrum of 3.23  NHOPME4-019.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl314.2517.8418.3422.8127.0929.7532.0132.9635.0851.3655.9676.7377.1677.59111.01111.78117.11123.75140.82151.57 13C NMR spectrum of 3.23 253  OONHPME3-104.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.8810.331.212.001.800.870.890.91CHCl3H2OM04(br. s.)M02(s)M03(d)M05(d)M06(m)M07(m)M01(m)M08(m)0.870.890.960.981.181.281.391.721.741.762.802.822.842.862.972.993.013.035.866.106.136.306.656.687.27 1H NMR spectrum of 3.24  OONHPME3-068.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity14.1918.1322.7627.0329.7131.9632.9834.9051.5095.86100.54104.30108.68139.36144.53148.40 13C NMR spectrum of 3.24 254  FNHOFFPME3-101.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.152.8910.300.982.000.701.881.79CHCl3EtOAcM04(d)M05(m)M07(m)M06(d)M02(m)M01(m)M08(br. s.)M03(m)0.880.900.970.991.171.201.291.351.391.411.481.691.731.751.772.842.862.882.913.013.033.053.073.846.546.576.587.027.05 1H NMR spectrum of 3.25  FNHOFFPME3-101.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl314.2518.1822.8127.0729.7432.0133.0034.9050.77113.02119.19122.53140.35147.37 13C NMR spectrum of 3.25 255  NHOCF3PME3-102.002.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized Intensity-58.48 19F{1H} NMR spectrum of 3.25 NHPME2-074.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3Si GreaseM04(d)M09(t)M03(m)M08(d)M01(qd)M05(t)M07(m)M02(m)M06(m)7.197.187.167.167.147.14 6.686.666.616.593.463.453.453.443.433.423.413.401.681.671.671.661.621.451.311.30 1.291.271.261.131.111.100.960.950.880.87(+/-) 1H NMR spectrum of 3.26  256  NHPME4-013.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3147.96129.35116.68113.1252.6137.4632.2629.7827.5922.7917.2815.8614.23(+/-) 13C NMR spectrum of 3.26  NH HPME3-133.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity6.3912.011.141.042.061.000.780.980.961.93CHCl3M09(d)M08(t)M01(m)M07(m)M03(m)M06(m)M04(m)M02(m)M10(m)M05(m)0.900.930.981.001.211.251.321.441.541.571.581.661.761.861.871.881.892.712.732.742.762.782.782.802.852.872.893.193.193.213.223.223.236.506.536.616.646.966.987.017.27(+/-) 1H NMR spectrum of 3.27  257  NH HPME3-133.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl314.2615.2522.8225.0527.1327.6629.7832.0432.7537.7356.25114.20116.86121.64126.81129.29145.28(+/-) 13C NMR spectrum of 3.27  NHPME3-090.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity6.3712.251.172.001.844.931.80CHCl3GreaseM02(d)M04(m)M05(m)M07(m)M03(s)M01(m)M06(m)0.850.870.940.961.141.171.241.261.361.371.691.701.722.852.872.892.913.023.043.063.086.516.537.277.457.467.48 1H NMR spectrum of 3.28  258  NHPME3-090.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3Grease1.1814.2618.1822.8127.0729.7432.0133.0734.8850.1476.7377.1677.5987.2190.73110.86112.39124.28127.58128.36131.42133.07148.71 13C NMR spectrum of 3.28  NHPME5-056.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(d)M03(m)M11(m)M10(m)M07(m)M02(dd)M06(m)M08(m)M09(m)M05(m)M04(m)0.090.880.901.001.071.171.201.231.271.281.311.601.641.701.861.882.322.352.362.392.402.432.472.502.572.592.612.632.692.717.167.187.197.267.287.31 1H NMR spectrum of 3.29  259  NHPME5-056.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity18.2825.2626.3633.7635.6941.8453.3157.0477.16125.85128.27129.27141.14 13C NMR spectrum of 3.29  NHPME3-114.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.001.062.311.930.941.952.901.86CHCl3M07(m)M04(m)M06(s)M08(m)M01(d)M05(m)M02(sxt)M03(m)1.433.083.103.133.153.283.323.393.413.433.456.636.646.666.676.776.807.277.307.307.327.327.397.417.427.447.44 1H NMR spectrum of 3.47  260  NHPME3-114.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl319.8739.3251.0377.16113.09117.44126.73127.37128.79129.35144.64148.19 13C NMR spectrum of 3.47 NHPME3-118.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.001.011.001.022.061.890.934.951.92CHCl3HexaneHexaneM06(d)M01(d)M09(s)M07(t)M04(dd)M03(m)M08(m)M02(m)M05(m)0.960.992.022.062.092.112.132.472.492.512.542.722.752.772.792.962.983.063.083.106.536.566.696.717.217.27 1H NMR spectrum of 3.48  261  NHPME3-118.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3Hexane18.1935.1641.5149.9577.16112.83117.20126.09128.41129.26129.32140.62148.51 13C NMR spectrum of 3.48 NHPME4-003.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.961.203.341.140.971.062.000.090.791.890.941.94CHCl3M08(m)M03(br. s.)M09(m)M06(dt)M02(br. s.)M10(m)M04(m)M07(m)M05(m)M01(m)M11(br. s.)7.277.187.187.167.156.736.726.706.636.636.616.606.593.732.982.962.942.922.862.842.822.802.26 2.161.781.76 1.731.581.561.551.531.521.511.471.341.331.331.201.191.181.171.16 1.141.131.131.111.101.08 1H NMR spectrum of 3.49  262  NHPME4-002.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl314.2622.7828.9629.9835.3435.4536.4236.9239.4142.1546.6949.4476.7377.1677.57112.72117.09129.29148.65 13C NMR spectrum of 3.49 NH OEtOEtPME3-108.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.967.004.132.002.122.200.971.910.931.88CHCl3M03(t)M07(d)M08(dd)M09(t)M10(m)M01(dq)M02(dq)M06(m)M04(m)M05(m)0.991.011.211.231.251.641.661.681.711.731.741.751.762.902.922.942.963.043.063.083.463.483.513.523.543.643.663.673.693.724.484.494.516.606.626.636.696.727.157.167.187.187.217.27 1H NMR spectrum of 3.50  263  NH OEtOEtPME3-108.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl315.4818.1029.6831.1432.8350.3061.09103.22112.77117.11129.32148.59 13C NMR spectrum of 3.50 NHOOPME4-075.001.esp12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.834.004.091.920.663.791.840.891.81M02(d)M06(m)M07(m)M08(m)M05(m)M01(m)M04(m)M09(m)M03(m)0.981.011.281.341.651.691.741.761.782.892.932.963.043.063.083.923.933.943.943.963.963.973.984.006.606.626.636.696.717.157.187.187.21 1H NMR spectrum of 3.51  264  NHOOPME4-075.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl318.1323.9528.9033.0736.6250.3164.7677.16110.22112.75117.06129.32148.65 13C NMR spectrum of 3.51 NH OSiPME3-100.003.esp12 11 10 9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM09(d)M02(t)M10(dd)M12(s)M11(dd)M03(m)M08(m)M04(m)M06(m)M01(m)M05(m)M07(m)7.277.217.197.197.166.706.636.636.603.66 3.643.623.073.052.962.931.020.930.920.090.080.07 1H NMR spectrum of 3.52  265  PME3-100.004.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)-0.0500.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00Normalized Intensity-5.1118.2118.5126.1430.3630.9532.8750.4263.5177.16112.75117.08129.35148.71NH OSi 13C NMR spectrum of 3.52 NHOSiPME3-117.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.829.223.001.131.280.992.022.871.960.931.92CHCl3H2OM09(d)M01(d)M03(m)M02(m)M10(t)M11(m)M05(m)M04(m)M06(dq)M08(m)M12(br. s)M07(m)7.277.207.177.156.706.686.66 6.626.593.753.733.713.713.693.673.103.083.063.042.982.962.942.921.981.961.941.921.681.671.641.481.451.431.411.020.920.910.080.070.06 1H NMR spectrum of 3.53  266  PME3-117.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3-5.1418.4726.1129.9937.9450.4861.2376.7377.1677.59112.78117.05129.34148.66NHOSi 13C NMR spectrum of 3.53 NHSiPME3-127.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.166.000.493.041.110.551.030.441.041.071.980.421.132.343.722.35CHCl3M01(m)M02(d)M06(dd)M07(m)M10(m)M04(dd)M08(dd)M05(dd)M09(m)M03(m)0.360.370.381.081.112.962.993.003.033.253.273.293.316.476.476.506.506.706.727.177.177.197.417.417.427.437.557.567.577.58 1H NMR spectrum of 3.54 Extra peaks are the unbranched product  267  NHSiPME3-127.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3-5.09-4.32-2.9611.2913.2620.3424.1346.7947.22112.80112.86117.06117.20127.89127.93128.01129.26129.34133.66134.03134.07137.97139.11148.42 13C NMR spectrum of 3.54 NHBrPME3-092.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.002.041.122.915.060.93CHCl3M07(dd)M05(m)M04(dd)M03(dq)M01(d)M02(m)M06(m)7.61 7.61 7.597.357.357.33 7.327.317.307.187.167.147.117.106.71 6.656.656.626.623.703.683.653.633.583.433.393.373.313.293.273.251.361.34 1H NMR spectrum of 3.55  268  NHBrPME3-092.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3148.14143.54133.23129.34128.13128.01127.51125.18117.52113.0250.0538.1019.11 13C NMR spectrum of 3.55 NHBrPME3-091.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.791.283.772.601.325.252.57CHCl3M05(dd)M03(d)M07(m)M04(m)M01(m)M02(m)M06(m)M08(br. s.)7.497.487.467.457.417.277.227.197.197.147.117.086.756.726.606.586.573.573.393.373.35 3.333.233.213.193.073.043.021.34 1.32 1H NMR spectrum of 3.56  269  NHBrPME3-091.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3147.98143.68131.86129.41129.17120.46117.65113.1077.5977.1676.7350.9238.8719.72 13C NMR spectrum of 3.56 NHOOOPME4-085.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized Intensity(+/-) 1H NMR spectrum of 3.57  270  NHOOOPME4-083.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity15.8917.2023.8426.3937.1437.5253.8455.9364.6776.7377.1677.59110.30114.73115.02142.17151.78(+/-) 13C NMR spectrum of 3.57 NHOOSiPME4-083.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.979.352.973.111.004.400.871.062.053.002.031.98M06(d)M08(m)M01(s)M09(m)M07(d)M11(m)M10(m)M03(m)M02(t)M12(m)M04(br. s)M05(m)0.050.060.890.900.971.113.573.593.613.756.536.546.566.566.756.787.27(+/-) 1H NMR spectrum of 3.58 271  PME4-091.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)-0.0500.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00Normalized IntensityCHCl3151.78142.27115.08114.7263.6255.9853.8037.3030.9428.2726.1318.5017.2916.01-5.11ONH OSi(+/-) 13C NMR spectrum of 3.58                  272  A.5 Chapter 3 4-CF3 Synthesis NMR Spectra  NOHFFFWD005.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityGreaseWaterAcetoneM02(s)M01(dd)M03(d)6.466.466.486.486.877.277.517.54 1H NMR spectrum of 3.92 NOHFFFWD005.002.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-66.69 19F{1H} NMR spectrum of 3.92  273  A.6 Chapter 3 Complex Synthesis NMR Spectra NOTa(NMe2)4Proton.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M05(s)M03(m)M04(m)M02(s)M01(m)2.093.353.363.586.377.117.64 1H NMR spectrum of 3.78  NOTa(NMe2)413 C NMR.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M04(m)M05(s)M06(s)M03(s)M02(s)M01(s)20.4045.9746.44111.64111.78139.10142.46169.81 13C NMR spectrum of 3.78 274  NOTa(NMe2)4Proton.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M03(s)M04(dd) M01(d)M06(s)M05(dd) 1.852.093.376.336.356.916.916.936.947.617.62 1H NMR spectrum of 3.83NOTa(NMe2)4carbon.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M07(s)M08(s)M01(s)M05(s)M06(s)M04(s)M02(s)17.5220.4046.03111.29120.34140.57141.71168.06 13C NMR spectrum of 3.83 275  NCF3OTa(NMe2)4Proton.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.050.100.150.200.250.300.350.400.450.500.55Normalized IntensityTOLUENE-d8M01(m) M03(d)M02(dd)M04(s)2.093.246.196.227.237.237.257.268.18 1H NMR spectrum of 3.84  NOTa(NMe2)4CF3TH-043.004.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM03(q)M04(q)M01(q)M02(q)20.4045.79111.99114.83115.16115.48121.27123.95126.64129.32136.21136.24140.69140.73171.30 13C NMR spectrum of 3.84 276  NCF3OTa(NMe2)4fluorine.esp120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 -30 -40 -50 -60 -70 -80 -90 -100 -110 -120Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(s)-60.40 19F{1H} NMR spectrum of 3.84  NOTa(NMe2)4OProton.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M04(s)M05(s)M03(m)M06(m)M01(d)M02(dd)2.093.414.426.146.156.166.167.087.087.107.497.51 1H NMR spectrum of 3.85  277  NOTa(NMe2)4OCarbon.esp220 200 180 160 140 120 100 80 60 40 20 0 -20Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M08(s)M05(s)M04(s)M02(s)M01(s)M06(s)M03(s)M07(s)20.4046.0069.6995.12102.95136.42143.14168.09171.82 13C NMR spectrum of 3.85 NBrOTa(NMe2)4Proton.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M08(s)M02(m) M04(dd)M01(dd)2.093.266.106.127.087.097.107.117.897.90 1H NMR spectrum of 3.86 278  NBrOTa(NMe2)4Carbon.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityTOLUENE-d8M02(s)M06(s)M05(s)M01(s)M03(s)M04(s)20.4045.88105.58113.53141.97143.28168.15 13C NMR spectrum of 3.86  NOTa(NMe2)4WD19-1.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM04(s)M02(s)M03(d)M05(d)M01(s)1.822.093.376.146.156.257.587.60 1H NMR spectrum of 3.79 279  NOTa(NMe2)4WD19_1.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity20.4021.1946.02111.98113.47141.92150.56170.05 13C NMR spectrum of 3.79 NOTa(NMe2)4CF3WD25.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM02(d)M03(s)M04(d)M01(s)2.093.266.466.486.707.547.55 1H NMR spectrum of 3.80 280  NCF3OTa(NMe2)4PME6-128.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(q)M02(q)M04(q)M03(q)20.4045.87107.14107.18108.10108.15119.64122.37125.10127.79140.58140.92141.25141.57143.96169.63 13C NMR spectrum of 3.80 NOCF3Ta(NMe2)4PME6-128.003.esp96 88 80 72 64 56 48 40 32 24 16 8 0 -8 -16 -24 -32 -40 -48 -56 -64 -72 -80 -88 -96Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized Intensity-64.74 19F{1H} NMR spectrum of 3.80  281  NOOTa(NMe2)4WD19-2x.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM03(d)M02(s)M04(m)M06(d)M05(m)M01(s)2.093.414.446.006.007.067.087.107.107.497.51 1H NMR spectrum of 3.81 NOTa(NMe2)4OPME6-129.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity20.4046.0269.6995.14102.97127.90128.18128.24129.17143.16168.10 13C NMR spectrum of 3.81 282   1H NMR spectrum of 3.82 13C NMR spectrum of 3.82 283   A.7 Chapter 3 Polysubstituted Piperidine Synthesis NMR Spectra  NOPME4-118.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3M08(d)M07(d)M01(m)M02(m)M03(td)M09(m)M04(m) M06(m)M05(m)7.276.896.86 6.846.836.82 6.813.773.143.123.113.092.902.89 2.862.852.822.812.062.051.751.741.721.681.641.631.511.501.351.330.930.81 0.79(+/-) 1H NMR spectrum of 3.88 ONPME4-117.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCDCl3Grease6.4019.3026.0026.7134.8742.3655.7057.7777.16114.46118.66145.62152.90(+/-) 13C NMR spectrum of 3.88 284  NOPME4-109-d1.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(s)M05(d)M04(d)M06(d)M03(d)M02(m)M08(m)M07(m)M09(m)0.700.720.780.801.021.041.561.571.581.581.611.631.641.651.773.043.063.123.133.143.153.796.806.836.966.977.007.27(+/-) 1H NMR spectrum of 3.89-d1 NOPME4-109-d1.004.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityCDCl3Si Grease1.1613.9118.5221.2930.4530.6334.6655.5758.6476.8477.46113.93125.13143.91155.555b-d1  13C NMR spectrum of 3.89-d1  285  NOPME4-143 d2.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityCHCl3Si GreaseM01(s)M07(d)M06(d)M08(d)M09(d)M04(dt)M10(d)M02(m)M03(m)M05(m)7.276.99 6.966.846.813.793.283.263.263.243.221.811.791.781.771.511.501.401.391.391.370.960.890.860.740.72(+/-) 1H NMR spectrum of 3.89-d2 NOPME4-109-d2.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity155.17144.28127.10113.5762.6555.5245.4635.8435.7227.0521.7319.42 5.26(+/-) 13C NMR spectrum of 3.89-d2     286  A.8 Chapter 4 Substrate Scope  NHPME4-124.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.042.9010.310.982.000.951.890.951.89M07(dd)M05(d)M08(t)M09(m)M06(t)M03(m)M02(br. s.)M01(ddd)M04(m)0.910.931.001.011.201.221.321.321.451.461.481.751.761.781.792.892.912.922.943.063.083.093.113.696.626.626.646.716.737.187.187.207.227.27 1H NMR spectrum of 4.9 NHPME4-124.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity14.2518.2122.8127.1029.7632.0233.0734.9650.4877.16112.76117.04129.34148.79 13C NMR spectrum of 4.9 287  NHPME6-090.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.091.021.021.050.982.001.032.123.351.96J(M06)=6.17 HzJ(M07)=7.99 HzJ(M06)=11.88 HzJ(M07)=12.11 HzM01(dd)M02(t)M04(m)M03(m)M05(m)M10(d)M07(dd)M06(dd)M08(sxt)M09(br. s.)1.361.393.063.083.113.243.263.283.303.353.373.413.616.596.596.626.626.726.757.167.177.197.207.277.287.347.377.377.397.40 1H NMR spectrum of 4.24  NHPME6-090.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.9039.3651.0476.7377.1677.59113.09117.46126.76128.80129.37144.67148.24 13C NMR spectrum of 4.24  288  NHPME6-091.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.861.000.950.990.971.000.981.790.934.781.85M08(d)M11(m)M09(t)M05(dd)M04(dd)M01(d)M03(dd)M06(dd)M10(m)M02(dq)M07(br. s.)0.981.012.042.062.082.112.132.152.492.512.532.562.742.772.792.983.003.083.103.123.143.686.556.576.706.727.147.157.187.207.317.33 1H NMR spectrum of 4.25  NHPME6-091.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity18.2235.1741.5249.9877.16112.84117.21126.11128.42129.27129.34140.65148.52 13C NMR spectrum of 4.25 289  NHOOPME5-004.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.940.943.114.082.000.913.891.900.951.90M05(s)M08(dd)M09(t)M07(d)M10(m)M06(m)M02(m)M03(br. s.)M01(ddd)M04(m)0.991.011.291.321.341.661.671.691.741.751.771.782.912.922.942.953.053.073.093.103.743.913.933.933.943.943.953.963.963.973.984.006.616.626.696.717.167.167.187.187.207.27 1H NMR spectrum of 4.23 NHOOPME5-004.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity18.1223.9428.9133.0736.6250.3164.7564.7977.16110.23112.74117.06129.33148.67 13C NMR spectrum of 4.23 290  NH OSiPME5-012-TaF5.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.8Normalized Intensity5.929.002.551.373.190.901.892.871.630.911.65J(M04)=5.94 HzJ(M04)=12.33 HzM02(m)M01(d)M09(dd)M08(tt)M06(t)M03(m)M07(dd) M05(br. s.)J(M04)=45.46 HzM10(m)M11(m)M12(m)M04(ddd)0.060.070.900.911.002.882.902.922.943.043.063.083.103.603.623.643.706.596.596.626.626.687.157.177.187.207.27 1H NMR spectrum of 4.22  NH OSiPME5-012-TaF5.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-5.0918.2218.5326.1430.3630.9732.8950.4363.5377.16112.78117.11129.37148.71 13C NMR spectrum of 4.22 291  NHOMePME5-082-TaF5.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.232.8010.420.922.000.902.861.831.83J(M01)=5.71 HzJ(M08)=8.45 HzJ(M09)=9.14 HzJ(M01)=11.65 HzM07(s)M05(d)M08(d)M09(d)M06(t)J(M01)=51.62 HzM03(m)M01(ddd)M02(br. s)M04(m)0.890.910.970.991.201.301.361.422.822.842.862.883.003.013.043.063.763.776.576.606.776.786.817.27 1H NMR spectrum of 4.19  NHOMePME5-082-TaF5.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity14.2518.2222.8227.1029.7732.0233.0934.9751.5355.9977.16114.03115.05143.13151.95 13C NMR spectrum of 4.19 292  BrNHPME5-009-TaF5.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.882.819.940.922.000.901.801.65J(M08)=9.14 HzM08(d)M03(d)M04(t)M07(d)M02(m)M06(br. s.)M01(ddd)M05(m)0.880.910.960.981.171.191.301.351.391.401.651.681.741.761.781.812.822.852.862.892.993.013.033.053.716.456.466.496.507.227.237.26 1H NMR spectrum of 4.17  PME5-009-TaF5.003.esp180 160 140 120 100 80 60 40 20 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity147.72131.99114.27108.4777.1650.4634.8832.96 31.9929.7427.0622.8118.1614.25BrNH 13C NMR spectrum of 4.17 293  NHPME5-115-TaF5.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.002.463.721.255.223.571.010.952.942.19J(M08)=11.65 HzM01(d)M11(m)M09(dd)M08(dd)M10(m)M04(m)M05(m)M02(m)M03(m)M07(m)M06(m)0.880.901.031.041.201.231.281.281.301.301.581.601.641.701.711.741.851.861.891.982.362.412.432.572.592.702.712.742.767.167.187.197.267.277.287.317.31 1H NMR spectrum of 4.18  NHPME5-115-TaF5.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity18.2725.2326.3433.7135.6641.8453.2857.0477.16125.85128.27129.27141.12 13C NMR spectrum of 4.18 294  NHPME5-081-TaF5.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.072.9010.761.022.812.000.891.880.890.97J(M09)=1.37 HzJ(M01)=5.94 HzJ(M01)=11.88 HzM10(d)M02(s)M05(d)M06(t)M09(td)M08(m)M07(br. s.)M03(m)J(M01)=52.31 HzM01(ddd)M04(m)0.880.910.991.021.231.241.271.301.351.441.461.481.791.811.832.162.912.932.952.973.083.103.123.143.556.606.626.646.657.057.077.137.167.27 1H NMR spectrum of 4.20  NHPME5-081-TaF5.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity14.2617.6018.3322.8227.0929.7732.9635.0550.4077.16109.64116.57121.74127.26130.14146.59 13C NMR spectrum of 4.20 295  NHOCF3PME5-083-TaF5.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.032.9210.220.972.000.931.871.80J(M08)=0.91 HzJ(M07)=8.91 HzJ(M08)=8.91 HzM04(d)M08(dd)M05(t)M07(d)M02(m)M06(br. s.)M01(ddd)M03(m)0.880.900.970.991.191.231.291.351.391.411.431.741.772.842.862.882.903.003.023.043.063.756.526.536.566.577.007.007.027.047.047.27 1H NMR spectrum of 4.21  NHOCF3PME5-083-TaF5.004.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(q)14.2518.1822.8127.0629.7231.9932.9534.8850.8976.7377.57113.19119.16122.51125.92129.34140.45147.15 13C NMR spectrum of 4.21 296  NHOCF3PME5-083-TaF5.003.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-58.48 19F{1H} NMR spectrum of 4.21  NHBrPME7-078.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.911.000.971.971.041.021.850.970.953.800.90M10(dd)M06(m)M05(d)M08(m)M07(tt)M03(m)M02(dd)M09(m)M04(m)M01(m)M11(m)1.011.032.172.202.202.222.252.272.552.572.592.622.942.962.993.033.053.123.143.163.186.576.586.616.616.706.737.097.127.157.177.187.227.277.557.557.577.58 1H NMR spectrum of 4.26 297  NHBrPME6-155.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensitySi Grease1.1818.0633.8041.4650.0477.16112.84117.24124.95127.36129.35131.56133.08140.15148.51 13C NMR spectrum of 4.26 NPME7-087.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.001.071.141.061.031.022.041.002.052.532.12J(M03)=10.28 HzJ(M03)=15.99 HzM10(m)M01(d)M11(m)M08(m)M06(ddd)M04(ddd)M05(dd)M09(m)M07(m)M02(m)M03(dd)1.071.092.212.212.232.262.502.532.552.592.872.872.882.892.943.213.243.253.283.623.623.633.643.663.663.676.696.716.716.776.947.047.117.247.277.367.367.397.39 1H NMR spectrum of 4.27 298  NPME7-087.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity19.0727.8436.2657.7877.16115.32118.29124.01124.97126.43129.51129.65144.06148.44 13C NMR spectrum of 4.27  299  A.9 Chapter 4 NMR Study Order of compounds in the labels indicates the order of addition for each sample. Proton NMR Spectra PME4-113.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.000.750.711.281.202.78TolTolTolTol2.092.382.473.293.746.416.737.07TaF5 + NMA TaF5 + N-methylaniline PME4-113.003.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity6.005.784.020.952.97TolTolTol2.09TaF5 + 4.10 TaF5 + 4.10 300  PME4-113.007.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.050.100.150.200.25Normalized Intensity5.975.637.652.584.000.874.191.813.213.99TolTolTol 2.09TaF5 + N-methylaniline + 4.10 TaF5 + N-methylaniline + 4.10 PME4-113.027.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.050.100.150.200.250.300.350.400.45Normalized Intensity5.976.056.022.034.000.823.271.492.913.210.850.870.892.082.092.102.122.142.353.323.813.823.833.843.863.873.883.894.356.346.366.386.386.666.666.686.786.816.817.077.097.107.12TaF5 + 4.10 + N-methylaniline TaF5 + 4.10 + N-methylaniline 301  PME4-113.013.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.340.110.070.083.250.141.050.180.040.030.290.412.001.131.253.10MethaneEtherEtherTol\TolTol0.951.191.232.092.532.793.053.093.223.336.336.356.676.696.776.826.857.077.107.117.14TaF5 + N-methylaniline + MeLi TaF5 + N-methylaniline + methyl lithium PME4-113.015.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.70Normalized Intensity5.745.993.512.071.152.421.852.150.540.19MethaneEtherEtherTolTolTol2.09TaF5 + 4.10 + MeLi TaF5 + 4.10 + methyl lithium 302  PME4-113.018.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.001.670.912.22EtherEtherMethane2.09TaF5 + N-methylaniline + 4.10 + MeLi TaF5 + N-methylaniline + 4.10 + MeLi 19F{1H} NMR Spectra PME4-113.002.esp160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.700.085.000.3442.4449.4968.1383.75TaF5 + N-methylaniline TaF5 + N-methylaniline 303  PME4-113.004.esp160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-0.070.09-0.035.000.98101.6262.3747.4942.11-131.18TaF5  + 4.10 TaF5 + 4.10 PME4-113.008.esp160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.36-0.16-0.025.0041.5950.8254.8663.08TaF5 + N-methylaniline + 4.10 TaF5 + N-methylaniline + 4.10 304  PME4-113.028.esp160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.030.875.00-82.6141.5462.74TaF5 + 4.10 + N-methylaniline TaF5 + 4.10 + N-methylaniline PME4-113.016.esp160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180Chemical Shift (ppm)00.250.500.751.00Normalized Intensity53.9333.4424.99J(M03)=13.55 HzJ(M03)=13.55 HzJ(M02)=27.10 HzM02(d)M01(d)M03(t)7.4450.7550.8053.5963.9666.1366.1967.4571.11TaF5 + 4.10 + MeLi TaF5 + 4.10 + methyl lithium 305  PME4-113.019.esp160 140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.873.662.955.00J(M02)=27.10 HzM01(d)M02(d)M03(t)50.3850.4453.3953.4966.2267.1068.2989.99TaF5 + N-methylaniline + 4.10 + MeLi TaF5 + N-methylaniline + 4.10 + methyl lithium PME4-113.031.esp260 240 220 200 180 160 140 120 100 80 60 40 20 0 -20 -40 -60 -80Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity4.252.612.155.00J(M02)=25.60 HzM01(d)M02(d)M03(br. s.)M04(quin)50.4753.4653.5566.3466.3890.06Ta5F + 4.10 + N-methylaniline + MeLi TaF5 + 4.10 + N-methylaniline + methyl lithium No peaks were observed for TaF5 + N-methylaniline + methyl lithium, potentially due to solubility issues  306  31P{1H} NMR Spectra PME4-113.010.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.604.10 4.10 PME4-113.025.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.51N-methylaniline + 4.10 N-methylaniline + 4.10 307  PME4-113.005.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.18TaF5 + 4.10 TaF5 + 4.10 PME4-113.017.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity15.10M01(d)7.909.19TaF5 + 4.10 + MeLi TaF5 + 4.10 + methyl lithium 308  PME4-113.006.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.15TaF5 + N-methylaniline + 4.10  TaF5 + N-methylaniline + 4.10 PME4-113.020.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-15.679.3411.12TaF5 + N-methylaniline + 4.10 + MeLi TaF5 + N-methylaniline + 4.10 + methyl lithium 309  PME4-113.026.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.22TaF5 + 4.10 + N-methylaniline TaF5 + 4.10 + N-methylaniline PME4-113.029.esp140 120 100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity-15.723.426.849.2912.45TaF5 + 4.10 + N-methylaniline + MeLi TaF5 + 4.10 + N-methylaniline + methyl lithium 310  A.10 Chapter 5 Substrate Synthesis and Scope ON+ O-OPME4-136-pure.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityM02(t)M01(d)M06(dd)M04(dd)M03(td)M05(td)7.887.877.857.847.58 7.577.577.557.297.267.267.147.117.087.084.87 4.862.612.602.59 1H NMR spectrum of 5.11 ON+ O-OPME4-136-pure.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity150.84134.06125.82121.54115.6177.5977.1676.7557.32 13C NMR spectrum of 5.11 311  ONO2CF3PME6-001.003.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.872.000.960.960.89M05(d)M02(t)M03(d)M01(d)M04(m)8.158.147.857.847.827.817.817.417.387.274.944.932.652.642.641.59 1H NMR spectrum of 5.15 ONO2CF3PME6-001.004.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.250.500.751.00Normalized Intensity12.58J(M01)=4.60 HzJ(M02)=4.60 HzM01(q)M02(q)J(M04)=34.48 HzJ(M04)=34.48 HzM04(q)J(M03)=272.42 HzJ(M03)=272.42 HzJ(M03)=272.42 HzM03(q)153.12139.95130.92 130.81123.64123.58 123.53121.28117.67115.7478.0977.5977.1676.7376.3557.51 13C NMR spectrum of 5.15 312  ONO2CF3PME6-001.005.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized Intensity-62.13 19F{1H} NMR spectrum of 5.15 NO2OOOPME6-016.003.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity9.000.831.951.100.970.88M02(t)J(M04)=8.68 HzM03(d)M01(s)M04(d)M06(d)M05(dd)8.438.438.208.198.178.16 7.297.27 7.264.924.912.62 2.612.611.60 1H NMR spectrum of 5.16 313  NO2OOOPME6-016.004.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity163.51153.53139.90134.91127.14125.54114.6782.2877.7577.1676.6057.3857.3328.26 13C NMR spectrum of 5.16  N+OFFO-OPME6-026.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.962.131.021.00EtOAcEtOAcEtOAcM02(t)M01(d)M04(ddd)M03(td) 2.572.582.594.924.937.057.087.087.117.117.147.277.707.707.717.727.737.747.75 1H NMR spectrum of 5.17 314  NO2OFFPME6-026.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity5.020.60EtOAc EtOAcEtOAcJ(M01)=3.45 HzJ(M01)=9.20 HzM06(d)J(M04)=13.79 HzM01(dd)M05(dd)J(M04)=254.03 HzM04(dd)M03(dd)155.77155.62152.35152.19147.20147.02 143.83143.65141.84141.69140.85120.58120.41112.42112.1677.8577.1676.7376.6762.4960.4220.9914.19 13C NMR spectrum of 5.17  NO2OFFPME6-026.005.esp100 80 60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.021.00M01(d)M02(d)-125.65-125.71-147.52 19F{1H} NMR spectrum of 5.17 315  ONO2PME6-050.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.010.922.000.990.990.96J(M05)=0.69 HzJ(M05)=1.60 HzJ(M05)=7.54 HzM03(s)M02(t)M01(d)M05(ddd)M06(dd)M04(m)2.432.552.554.724.737.137.167.187.277.447.467.467.677.687.707.70 1H NMR spectrum of 5.18 ONO2PME6-050.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity16.7261.9376.6777.1678.03123.15124.64135.43135.95144.56149.51 13C NMR spectrum of 5.18 316  NO2OPME6-048.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.950.872.000.950.950.91J(M04)=8.45 HzM02(t)M05(s)M03(s)M01(d)M06(d)M04(d)2.432.582.592.604.834.846.876.876.896.907.037.277.787.81 1H NMR spectrum of 5.19  ONO2PME6-048.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity22.0557.2777.0277.1677.42116.10122.24126.05138.05145.87151.05 13C NMR spectrum of 5.19   317  NO2OPME6-045.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.000.892.030.970.970.91J(M05)=2.28 HzM02(t)M01(s)M06(d)M03(d)M05(ddd)M04(d)2.352.562.572.574.814.817.137.167.277.347.347.377.657.66 1H NMR spectrum of 5.20  NO2OPME6-045.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity20.5557.7477.1677.80116.10126.15131.92134.86140.42148.97 13C NMR spectrum of 5.20 318  NO2OPME6-047.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.960.882.000.960.960.97M02(t)M03(s)M01(d)M05(d)M04(m) M06(d)2.312.552.562.564.764.776.906.927.037.057.277.297.327.35 1H NMR spectrum of 5.21  ONO2PME6-047.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity17.1157.1376.9077.1677.40111.85123.73130.60131.33142.55148.84 13C NMR spectrum of 5.21 319  ONO2PME6-078.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.872.004.492.061.040.91M03(d)M05(m)M01(t)M04(dd)M02(d)M06(m)2.622.622.634.894.907.277.327.357.477.557.577.587.767.777.808.098.09 1H NMR spectrum of 5.22 ONO2PME6-078.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity 57.4762.4276.7377.1677.3077.59116.04124.14126.85129.18132.29135.05138.28140.61150.05 13C NMR spectrum of 5.22 320  ON+BrO-OPME6-002.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.902.000.980.970.92WaterCHCl3M03(dd)M01(d)M04(dd)M05(t)M02(t)1.572.572.572.584.894.897.167.197.277.807.807.817.847.85 1H NMR spectrum of 5.23 ON+BrO-OPME6-002.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity62.2076.7377.4277.57120.43124.52126.00137.99146.00148.34 13C NMR spectrum of 5.23  321  ONO2PME6-067.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.000.953.831.840.970.91M02(m)M05(m)M01(s)M03(dd)M04(ddd)M06(m)5.097.077.077.107.127.307.317.337.347.417.427.447.457.617.867.877.897.89 1H NMR spectrum of 5.25 ONO2PME6-067.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity58.2676.7377.1677.5982.5788.72115.83121.37121.90125.86128.47129.11131.92134.07140.56151.17 13C NMR spectrum of 5.25 322  ONO2OSiPME6-069.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity6.009.182.252.261.121.061.061.04J(M07)=1.83 HzJ(M07)=7.54 HzJ(M07)=8.45 HzM03(m)M04(m)M02(t)M06(dd)M01(t)M05(m)M07(ddd)M08(dd)0.070.080.120.130.870.880.910.914.334.344.344.884.894.897.087.087.107.237.237.267.267.277.537.547.847.847.867.87 1H NMR spectrum of 5.26  ONO2OSiPME6-069.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-5.12-5.0318.3825.8751.7457.5977.1678.3387.70115.61121.28125.82134.00140.48151.01 13C NMR spectrum of 5.26  323  ONO2PME6-053.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.062.000.971.040.980.93J(M05)=7.54 HzJ(M05)=8.68 HzM02(t)M04(dd)M06(dd)M01(q)M03(ddd)M05(ddd)1.821.841.851.851.874.794.804.814.827.067.067.067.237.247.267.547.547.557.577.827.837.857.86 1H NMR spectrum of 5.24 ONO2PME6-053.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityDCM3.7953.5156.5757.9672.9177.1685.49115.55121.01125.73134.01140.35151.22 13C NMR spectrum of 5.24 324  ONH2PME6-060.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.882.122.001.910.950.97M03(t)M05(m)M06(m)M01(m)M04(m)M02(br. s.)2.532.532.543.714.734.744.756.716.726.746.746.776.846.916.946.957.27 1H NMR spectrum of 5.12  ONH2PME6-060.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity56.5175.5577.1678.96112.78115.63118.43122.41136.84145.40 13C NMR spectrum of 5.12 325  ONH2CF3PME6-075.003.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.881.932.002.87M02(t)M01(d)M04(m)M03(br. s.)2.552.562.573.994.774.786.936.956.956.966.986.997.017.027.27 1H NMR spectrum of 5.27  CF3ONH2PME6-075.008.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized IntensityM04(q)M01(q)M02(q)56.3976.2377.1678.07111.67111.73115.29115.36115.46122.70123.70124.14124.57126.30129.90137.01147.32 13C NMR spectrum of 5.27 326  ONH2CF3PME6-075.004.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized Intensity-61.83 19F{1H} NMR spectrum of 5.27  OONH2OPME6-019.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity9.000.781.561.800.900.840.89M06(d)M07(dd)M01(t)M03(d)M05(d)M04(s)M02(br. s)7.437.427.40 7.377.366.916.884.774.762.55 2.542.531.57 1H NMR spectrum of 5.28 327  OONH2OPME6-019.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity165.86 148.45136.28125.85120.50116.15111.2180.5678.2177.1676.06 56.3028.33 13C NMR spectrum of 5.28 ONH2FFPME6-079.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity0.961.892.001.010.98EtherEtherM02(t)M01(d)M03(ddd)M04(ddd)M05(br. s.)2.532.542.553.824.764.776.406.416.426.436.446.706.736.746.766.776.797.27 1H NMR spectrum of 5.29 328  ONH2FFPME6-079.004.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.01M03(m)M07(d)M06(dd)M04(dd)M05(d)M02(dd)M01(dd)60.6760.7476.1577.1678.58109.10109.14109.23111.93112.16133.77133.90133.93137.51142.49142.65143.26145.66146.51146.71 13C NMR spectrum of 5.29  ONH2FFPME6-079.003.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)0.10.20.30.40.50.60.70.80.91.0Normalized IntensityJ(M02)=20.65 HzJ(M01)=20.65 HzM02(d)M01(d)-153.70-149.92-149.84 19F{1H} NMR spectrum of 5.29 329  ONH2PME7-029.003.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.010.902.072.001.890.98M03(t)M06(s)M04(s)M05(s) M01(d)M02(br. s.)2.282.532.542.543.664.714.716.666.757.27 1H NMR spectrum of 5.30 ONH2PME7-029.004.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity21.0256.5375.4577.1679.02113.77115.70122.64128.12134.13145.45 13C NMR spectrum of 5.30 330  NH2OPME7-034.003.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.010.891.982.001.910.98M01(d)M03(t)M04(s)M05(d)M06(m)M02(br. s.)2.242.512.522.533.774.694.706.526.546.556.556.586.586.816.837.27 1H NMR spectrum of 5.31 ONH2PME7-034.004.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity20.8956.7775.3877.1679.12113.07116.50118.74132.02136.68143.38 13C NMR spectrum of 5.31 331  NH2OPME7-035.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.010.891.952.000.960.950.94J(M07)=0.91 HzJ(M07)=7.77 HzM06(dq)M07(dd)M01(d)M03(t)M04(s)M05(t)M02(br. s.)2.212.532.542.553.804.734.746.666.696.716.786.786.826.826.857.27 1H NMR spectrum of 5.32 ONH2PME7-035.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity17.3456.5475.4277.1679.06110.31117.44123.15123.79134.89145.04 13C NMR spectrum of 5.32 332  NHOPME6-012.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.001.091.081.031.060.751.83J(M06)=1.60 HzJ(M06)=7.31 HzJ(M06)=7.31 HzM05(dd)M06(td)M01(d)M07(m)M03(dd)M04(dd)M02(dqd)1.191.213.513.553.553.563.573.583.763.793.824.184.194.214.226.596.596.616.626.676.786.796.796.816.827.27 1H NMR spectrum of 5.13 ONHPME6-012.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity17.8945.2370.8177.16115.50116.57118.87121.43133.59143.77 13C NMR spectrum of 5.13 333  CF3 NHOPME7-006.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.000.981.840.991.820.94J(M01)=6.40 HzM01(d)M07(m)M06(m)M05(dd)M02(dqd)M04(br. s)M03(dd)1.201.223.563.563.573.583.593.773.803.813.834.214.224.254.266.816.826.856.896.906.907.27 1H NMR spectrum of 5.33 NHOCF3PME7-006.004.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityM01(q)M02(q)M03(q)M04(q)17.7845.0370.8677.16112.00112.05112.16115.78116.60122.77123.43123.85126.37129.96133.68146.16 13C NMR spectrum of 5.33    334  CF3 NHOPME7-006.002.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity-61.67 19F{1H} NMR spectrum of 5.33 NHOOOPME7-017.002.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.289.001.261.251.261.461.081.13M02(d)M08(d)DMSOM06(m)M07(dd)M01(s)M05(dd) M04(dd)M03(m)1.131.151.503.753.783.793.824.234.244.264.276.776.807.207.217.237.247.307.30 1H NMR spectrum of 5.34 335  NHOOOPME7-017.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity16.2927.8639.5144.4969.6579.91115.92117.30123.48124.11147.64164.79 13C NMR spectrum of 5.34 NHOFFPME7-020.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.971.091.041.000.970.98M04(d)M01(dd) M02(dd)M05(ddd)M03(m)M06(m)1.201.223.503.513.513.523.543.543.773.793.803.834.264.274.304.316.276.286.286.526.546.546.556.576.576.587.27 1H NMR spectrum of 5.5 336  NHOFFPME7-020.003.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityJ(M02)=2.30 HzJ(M03)=4.60 HzJ(M06)=4.60 HzJ(M02)=4.60 HzJ(M06)=8.05 HzJ(M04)=10.34 HzJ(M03)=10.34 HzM02(dd)J(M05)=16.09 HzM06(dd)M03(dd)M01(d)J(M04)=236.78 HzJ(M05)=243.68 HzM04(dd)M05(dd)17.6345.0471.1077.16107.79108.03108.62108.73130.95130.98133.55139.05139.25142.28142.49143.00143.15146.15146.29 13C NMR spectrum of 5.5 NHOFFPME7-020.002.esp60 40 20 0 -20 -40 -60 -80 -100 -120 -140 -160 -180 -200Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity1.061.00J(M01)=20.65 HzJ(M02)=20.65 HzM02(d)M01(d)-160.85-160.78-149.92-149.84 19F{1H} NMR spectrum of 5.5 337  NHOPME7-040.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.993.001.041.021.000.940.940.91Si GreaseLigandM08(d)M06(m)M07(m)M02(d)M01(s)M05(dd)M04(dd)M03(m)1.181.192.233.503.513.513.523.533.533.753.773.773.794.174.174.194.206.516.536.637.27 1H NMR spectrum of 5.35 NHOPME7-040.002.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity17.8820.7045.4070.9977.16115.67117.13121.87128.76130.91143.77 13C NMR spectrum of 5.35 338  NHOPME7-042.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity2.992.791.051.031.001.780.90M04(d)M06(s)M07(d)M01(dd)M05(m)M02(dd)M03(m)1.181.202.213.543.543.543.563.733.753.763.794.154.164.184.196.436.496.686.707.27 1H NMR spectrum of 5.36 NHOPME7-042.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensitySi Grease1.1617.9220.8525.9745.4270.8476.8477.46116.16116.34119.59130.93141.70 13C NMR spectrum of 5.36  339  NHOPME7-063.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity3.233.001.081.071.041.011.93M01(s)M02(d)M05(dd)M07(m)M06(m)M04(dd)M03(m)1.231.252.143.563.583.593.603.613.743.773.804.174.184.214.226.586.606.636.696.706.726.727.27 1H NMR spectrum of 5.37  NHOPME7-063.002.esp190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized Intensity16.9018.1045.5370.5277.16114.52118.11122.76123.21131.57143.47 13C NMR spectrum of 5.37   340  Appendix B  X-Ray Diffractometry Crystal Data B.1 N-(3-methylnonan-2-yl)aniline Oxalate  Identification code  mo_ls686_0m_a  Empirical formula  C18H29NO4  Formula weight  323.42  Temperature/K  100(2)  Crystal system  triclinic  Space group  P-1  a/Å  10.0478(18)  b/Å  10.1851(17)  c/Å  10.8815(19)  α/°  95.641(4)  β/°  114.147(4)  γ/°  108.576(4)  341  Volume/Å3  929.0(3)  Z  2  ρcalcmg/mm3  1.156  m/mm-1  0.081  F(000)  352.0  Crystal size/mm3  0.205 × 0.154 × 0.110  Radiation  MoKα (λ = 0.71073)  2Θ range for data collection  4.254 to 54.374°  Index ranges  -12 ≤ h ≤ 12, -12 ≤ k ≤ 13, -13 ≤ l ≤ 13  Reflections collected  14990  Independent reflections  4055 [Rint = 0.0461, Rsigma = 0.0494]  Data/restraints/parameters  4055/29/212  Goodness-of-fit on F2  1.049  Final R indexes [I>=2σ (I)]  R1 = 0.0908, wR2 = 0.2194  Final R indexes [all data]  R1 = 0.1292, wR2 = 0.2460  Largest diff. peak/hole / e Å-3  1.33/-0.45   342  B.2 Tetrakis(dimethylamido) 3-methyl-2-pyridonate tantalum (V)  Identification code  ls664_a  Empirical formula  C14H30N5OTa  Formula weight  465.38  Temperature/K  100(2)  Crystal system  orthorhombic  Space group  P212121  a/Å  13.3997(11)  b/Å  16.0777(13)  c/Å  17.5502(15)  α/°  90  β/°  90  γ/°  90  Volume/Å3  3781.0(5)  Z  8  343  ρcalcg/cm3  1.635  μ/mm-1  5.821  F(000)  1840.0  Crystal size/mm3  0.368 × 0.186 × 0.149  Radiation  MoKα (λ = 0.71073)  2Θ range for data collection/°  3.436 to 54.352  Index ranges  -10 ≤ h ≤ 17, -16 ≤ k ≤ 20, -21 ≤ l ≤ 22  Reflections collected  32485  Independent reflections  8345 [Rint = 0.0480, Rsigma = 0.0474]  Data/restraints/parameters  8345/390/397  Goodness-of-fit on F2  1.057  Final R indexes [I>=2σ (I)]  R1 = 0.0300, wR2 = 0.0605  Final R indexes [all data]  R1 = 0.0355, wR2 = 0.0622  Largest diff. peak/hole / e Å-3  2.07/-0.90  Flack parameter 0.365(8)  344  B.3 Tetrakis(dimethylamido) 5-trifluoromethyl-2-pyridonate tantalum (V)  Identification code  ls706_a  Empirical formula  C14H27F3N5OTa  Formula weight  519.35  Temperature/K  100(2)  Crystal system  orthorhombic  Space group  Pbca  a/Å  15.1527(5)  b/Å  9.0598(3)  c/Å  27.8633(10)  α/°  90  β/°  90  γ/°  90  Volume/Å3  3825.1(2)  Z  8  ρcalcg/cm3  1.804  345  μ/mm-1  5.786  F(000)  2032.0  Crystal size/mm3  0.240 × 0.192 × 0.148  Radiation  MoKα (λ = 0.71073)  2Θ range for data collection/°  2.924 to 54.26  Index ranges  -11 ≤ h ≤ 19, -9 ≤ k ≤ 11, -35 ≤ l ≤ 35  Reflections collected  17872  Independent reflections  4237 [Rint = 0.0360, Rsigma = 0.0340]  Data/restraints/parameters  4237/0/225  Goodness-of-fit on F2  1.032  Final R indexes [I>=2σ (I)]  R1 = 0.0239, wR2 = 0.0413  Final R indexes [all data]  R1 = 0.0360, wR2 = 0.0441  Largest diff. peak/hole / e Å-3  0.63/-1.12   B.4 Tetrakis(dimethylamido) 4-methyl-2-pyridonate tantalum (V)  346  Identification code  ls720_a  Empirical formula  C14H30N5OTa  Formula weight  465.38  Temperature/K  100  Crystal system  monoclinic  Space group  C2/c  a/Å  11.518(3)  b/Å  12.768(3)  c/Å  25.181(6)  α/°  90  β/°  102.438(12)  γ/°  90  Volume/Å3  3616.1(15)  Z  8  ρcalcmg/mm3  1.7095  m/mm-1  6.086  F(000)  1836.1  Crystal size/mm3  0.136 × 0.095 × 0.088  Radiation  Mo Kα (λ = 0.71073)  2Θ range for data collection  3.32 to 54.56°  Index ranges  -13 ≤ h ≤ 14, -13 ≤ k ≤ 16, -25 ≤ l ≤ 32  347  Reflections collected  9819  Independent reflections  3995 [Rint = 0.0498, Rsigma = 0.0657]  Data/restraints/parameters  3995/0/198  Goodness-of-fit on F2  0.983  Final R indexes [I>=2σ (I)]  R1 = 0.0339, wR2 = 0.0688  Final R indexes [all data]  R1 = 0.0437, wR2 = 0.0737  Largest diff. peak/hole / e Å-3  1.59/-1.93   B.5 Tetrakis(dimethylamido) 4-trifluoromethyl-2-pyridonate tantalum (V)  Identification code  ls729_a  Empirical formula  C14H27F3N5OTa  Formula weight  519.35  Temperature/K  100(2)  Crystal system  triclinic  Space group  P-1  348  a/Å  12.415(4)  b/Å  12.679(4)  c/Å  13.345(4)  α/°  105.410(6)  β/°  99.699(6)  γ/°  91.646(6)  Volume/Å3  1990.1(11)  Z  4  ρcalcmg/mm3  1.733  m/mm-1  5.560  F(000)  1016.0  Crystal size/mm3  ? × ? × ?  Radiation  MoKα (λ = 0.71073)  2Θ range for data collection  3.342 to 61.04°  Index ranges  -17 ≤ h ≤ 17, -18 ≤ k ≤ 18, -19 ≤ l ≤ 18  Reflections collected  27765  Independent reflections  11467 [Rint = 0.0414, Rsigma = 0.0600]  Data/restraints/parameters  11467/0/449  Goodness-of-fit on F2  1.033  Final R indexes [I>=2σ (I)]  R1 = 0.0329, wR2 = 0.0783  Final R indexes [all data]  R1 = 0.0536, wR2 = 0.0845  349  Largest diff. peak/hole / e Å-3  1.58/-1.18   B.6 Tetrakis(dimethylamido) 4-bromo-2-pyridonate tantalum (V)  Identification code  ls725_a  Empirical formula  C13H27BrN5OTa  Formula weight  530.25  Temperature/K  100  Crystal system  monoclinic  Space group  P21/c  a/Å  15.7339(18)  b/Å  8.7192(10)  c/Å  14.0958(16)  α/°  90  β/°  101.112(6)  γ/°  90  350  Volume/Å3  1897.5(4)  Z  4  ρcalcmg/mm3  1.856  m/mm-1  7.904  F(000)  1024.0  Crystal size/mm3  0.4 × 0.3 × 0.23  Radiation  MoKα (λ = 0.71073)  2Θ range for data collection  5.366 to 61.174°  Index ranges  -22 ≤ h ≤ 22, 0 ≤ k ≤ 12, 0 ≤ l ≤ 20  Reflections collected  6513  Independent reflections  6513 [Rint = ?, Rsigma = 0.0448]  Data/restraints/parameters  6513/0/191  Goodness-of-fit on F2  1.091  Final R indexes [I>=2σ (I)]  R1 = 0.0318, wR2 = 0.0879  Final R indexes [all data]  R1 = 0.0382, wR2 = 0.0907  Largest diff. peak/hole / e Å-3  2.52/-0.92   351  B.7 1-(4-methoxyphenyl)-2,3,6-trimethylpiperidine HCl  Identification code  ls709_0m_a  Empirical formula  C120H192Cl8N8O8  Formula weight  2158.40  Temperature/K  100  Crystal system  orthorhombic  Space group  Pna21  a/Å  21.142(4)  b/Å  9.442(2)  c/Å  14.826(3)  α/°  90.00(3)  β/°  90.00(3)  γ/°  90.00(3)  Volume/Å3  2959.7(10)  Z  1  352  ρcalcmg/mm3  1.211  m/mm-1  0.248  F(000)  1168.0  Crystal size/mm3  0.17 × 0.047 × 0.035  Radiation  MoKα (λ = 0.71073)  2Θ range for data collection  4.724 to 39.828°  Index ranges  -20 ≤ h ≤ 19, -9 ≤ k ≤ 8, -14 ≤ l ≤ 11  Reflections collected  5300  Independent reflections  2220 [Rint = 0.0597, Rsigma = 0.0703]  Data/restraints/parameters  2220/3/333  Goodness-of-fit on F2  0.982  Final R indexes [I>=2σ (I)]  R1 = 0.0354, wR2 = 0.0676  Final R indexes [all data]  R1 = 0.0498, wR2 = 0.0730  Largest diff. peak/hole / e Å-3  0.16/-0.16  Flack parameter -0.02(9)    353  Appendix C  Kinetic Analysis C.1 GC/FID Method Parameters D:\MassHunter\GCMS\1\methods\FID DGii.M Mon Oct 17 14:20:04 2016  Control Information ------- -----------  Sample Inlet:   GC Injection Source: GC ALS Injection Location: Front Mass Spectrometer: Disabled  No Sample Prep method has been assigned to this method.  GC GC Summary Run Time    13.667 min Post Run Time   0 min  Oven Temperature Setpoint    On 354  (Initial)    100 °C Hold Time    1 min Post Run    50 °C Program #1 Rate    30 °C/min #1 Value    300 °C #1 Hold Time    6 min  Equilibration Time   0.05 min Max Temperature   325 °C Maximum Temperature Override Disabled Slow Fan    Disabled  ALS Front Injector Syringe Size    10 μL Injection Volume   0.2 μL Solvent A Washes (PreInj)  3 Solvent A Washes (PostInj)  3 Solvent A Volume   8 μL Solvent B Washes (PreInj)  3 Solvent B Washes (PostInj)  3 Solvent B Volume   8 μL 355  Sample Washes   1 Sample Wash Volume  8 μL Sample Pumps   3 Dwell Time (PreInj)   0 min Dwell Time (PostInj)   0 min Solvent Wash Draw Speed  300 μL/min Solvent Wash Dispense Speed 3000 μL/min Sample Wash Draw Speed  300 μL/min Sample Wash Dispense Speed 3000 μL/min Injection Dispense Speed  6000 μL/min Viscosity Delay   0 sec Sample Depth    Disabled Injection Type    Standard L1 Airgap    0.2 μL Solvent Wash Mode   A, B  Sample Overlap Mode     Sample overlap is not enabled  ALS Errors    Pause for user interaction  Front MM Inlet He Temperature 356  Setpoint    On (Initial)    300 °C Post Run    250 °C  Mode     Split Pressure    On 16.596 psi Total Flow    On 10.2 mL/min Septum Purge Flow   On 3 mL/min Gas Saver    Off Split Ratio    5 :1 Split Flow    6 mL/min Cryo     Off Cryo Type    CO2  Back SS Inlet He Mode     Split Heater     On 250 °C Pressure    On 12.93 psi Total Flow    On 16.2 mL/min Septum Purge Flow   On 3 mL/min Gas Saver    Off Split Ratio    10 :1 Split Flow    12 mL/min 357   Thermal Aux 2 (MSD Transfer Line) Temperature Setpoint    On (Initial)    300 °C Post Run    0 °C  Column Column #1 Flow Setpoint    On (Initial)    1.2 mL/min Post Run    2 mL/min  0 °C—325 °C (325 °C): 30 m x 250 μm x 0.25 μm Column lock    Unlocked In     Front MM Inlet He Out     Front Detector FID (Initial)    100 °C Pressure    16.596 psi Flow     1.2 mL/min Average Velocity   31.36 cm/sec Holdup Time    1.5944 min 358   Column #2 Flow Setpoint    On (Initial)    1.2 mL/min Post Run    1.0452 mL/min  0 °C—325 °C (325 °C): 30 m x 250 μm x 0.25 μm Column lock    Unlocked In     Back SS Inlet He Out     MSD  (Initial)    100 °C Pressure    12.93 psi Flow     1.2 mL/min Average Velocity   40.853 cm/sec Holdup Time    1.2239 min  Column Outlet Pressure  0 psi  Front Detector FID Makeup    He Signal is modified by Column Compensation Curve #2 Heater     On 300 °C 359  H2 Flow    On 30 mL/min Air Flow    On 300 mL/min Makeup Flow    On 25 mL/min Carrier Gas Flow Correction  Does not affect Makeup or Fuel Flow Flame     On Electrometer    On  Signals Signal #1:  Front Signal Description    Front Signal Details     Front Signal (FID) Save     On Data Rate    50 Hz Dual Injection Assignment  Front Sample  Signal #2:  Description    None  Signal #3:  Description    None  Signal #4:  Description    None 360   MS Information -- -----------  General Information ------- -----------  Acquisition Mode:   Scan Solvent Delay (minutes):  3 Tune file:    D:\MassHunter\GCMS\1\5977\pcich4.u EM Setting mode Gain:  1.000000  Normal or Fast Scanning:  Normal Scanning Trace Ion Detection:   Off Run Time (if MS only):  10 minutes   [Scan Parameters] Start Time:    3 Low Mass:    50 High Mass:    550 Threshold:    150 A/D Samples:    4  361  [MSZones]  MS Source:    300 C maximum 300 C MS Quad:    150 C maximum 200 C  Timed Events ----- ------ Number Events= 0 END OF MS ACQUISTION PARAMETERS  TUNE PARAMETERS for SN: US1620N005 ---------------------------------  Trace Ion Detection is OFF.  240.108 :EMISSION      49.989  :ENERGY        2.594  :REPELLER      154.879 :IONFOCUS      0.000  :ENTRANCE_LENS 738.143 :EMVOLTS       738.1  :Actual EMV  0.06  :GAIN FACTOR  362  1852.000 :AMUGAIN       133.438 :AMUOFFSET     1.000  :FILAMENT      0.000  :DCPOLARITY    27.961  :ENTLENSOFFSET 0.000  :Ion_Body      0.000  :EXTLENS       -178.000 :MASSGAIN         -24.828 :MASSOFFSET       CI Flow Rate: 16 CI A/B Gas: 1  END OF TUNE PARAMETERS ----------------------  END OF INSTRUMENT CONTROL PARAMETERS ------------------------------------   363  C.2 Kinetic Analysis Raw Data All rates given as R = -[NMA]/min Tetrakis(dimethylamido)(κ2-N,O-2-pyridonato)tantalum(V): Tom Horton’s Data: TH-H1   R = TH-H2   R = Time Rel. Area [NMA] 0.0034 Time Rel. Area [NMA] 0.0023 0 0.8808 0.1887  0 0.8305 0.1772  10 0.7491 0.1586  10 0.7231 0.1527  20 0.5870 0.1215  20 0.6300 0.1314  30 0.4773 0.0964  30 0.4985 0.1013  40 0.4020 0.0792  40 0.4128 0.0817  50 0.2711 0.0493  50 0.2854 0.0525  60 0.2122 0.0358  60 0.3145 0.0592  TH-H3   R = TH-H Avg   Rate = 0.0032 Time Rel. Area [NMA] 0.0039 Time [NMA] Std. Dev. Rate Error = 0.0007 0 0.8730 0.1870  0 0.1843 0.0799   10 0.6953 0.1463  10 0.1525 0.0662   20 0.5304 0.1086  20 0.1205 0.0528   30 0.4904 0.0994  30 0.0991 0.0429   40 0.3373 0.0644  40 0.0751 0.0332   50 0.2861 0.0527  50 0.0515 0.0223   60 0.3280 0.0623  60 0.0524 0.0249    Weizhe Dong’s Data R = H        WD1H   R =  WD2H   R =  Time Rel. Area [NMA] 0.0014 Time Rel. Area [NMA] 0.0022 0 0.9890 0.2133  0 1.0061 0.2170  10 0.9361 0.2019  10 0.8907 0.1921  20 0.8559 0.1846  20 0.8047 0.1736  30 0.7817 0.1686  30 0.6875 0.1483  40 0.6891 0.1486  40 0.6056 0.1306  50 0.5233 0.1129  50 0.4926 0.1063  364  60 0.4853 0.1047  60 0.4682 0.1010  WD3H   R =  Avg H   Rate =  0.0020  Rel. Area [NMA] 0.0024 Time [NMA] St. Dev Rate Error =  0.0004 Time 0.9893 0.2134  0 0.2146 0.0017   10 0.8635 0.1862  10 0.1934 0.0065   20 0.7657 0.1652  20 0.1744 0.0080   30 0.6265 0.1351  30 0.1507 0.0138   40 0.4928 0.1063  40 0.1285 0.0173   50 0.5707 0.1231  50 0.1141 0.0069   60 0.2399 0.0517  60 0.0858 0.0241    Tetrakis(dimethylamido)(κ2-N,O-5-methyl-2-pyridonato)tantalum(V): R = Me        TH-Me1   R = TH-Me2   R = Time Rel. Area [NMA] 0.0027 Time Rel. Area [NMA] 0.0027 0 1.0005 0.2161  0 0.9706 0.2093  10 0.8837 0.1894  10 0.8581 0.1835  20 0.7668 0.1626  20 0.7379 0.1560  30 0.6428 0.1343  30 0.6257 0.1304  40 0.5788 0.1197  40 0.5483 0.1127  50 0.4267 0.0849  50 0.4303 0.0857  60 0.3779 0.0737  60 0.3621 0.0701  TH-Me3   R = TH-Me-Avg   Rate = 0.0028 Time Rel. Area [NMA] 0.0031 Time [NMA] Std. Dev. Rate Error = 0.0002 0 0.9858 0.2128  0 0.2127 0.0921   10 0.8319 0.1775  10 0.1835 0.0796   20 0.7105 0.1498  20 0.1562 0.0678   30 0.6190 0.1288  30 0.1312 0.0568   40 0.4649 0.0936  40 0.1087 0.0480   50 0.3362 0.0642  50 0.0782 0.0350   60 0.6175 0.1285  60 0.0908 0.0456      365  Tetrakis(dimethylamido)(κ2-N,O-5-trifluoromethyl-2-pyridonato)tantalum(V): R = CF3        TH-CF3-1   R = TH-CF3-2   R = Time Rel. Area [NMA] 0.0021 Time Rel. Area [NMA] 0.0025 0 0.9967 0.2152  0 0.9948 0.2148  10 0.9869 0.2130  10 0.9700 0.2091  20 0.9259 0.1990  20 0.8855 0.1898  30 0.8464 0.1809  30 0.7508 0.1590  40 0.7297 0.1542  40 0.6384 0.1333  50 0.6658 0.1396  50 0.5203 0.1063  60 0.5508 0.1133  60 0.4039 0.0796  TH-CF3-3   R = TH-CF3-Avg   Rate = 0.0022 Time Rel. Area [NMA] 0.0022 Time [NMA] Std. Dev. Rate Error = 0.0002 0 1.0084 0.2179  0 0.2160 0.0935   10 0.9641 0.2078  10 0.2100 0.0909   20 0.9108 0.1956  20 0.1948 0.0844   30 0.7693 0.1632  30 0.1677 0.0731   40 0.6751 0.1417  40 0.1430 0.0624   50 0.5068 0.1032  50 0.1163 0.0524   60 0.5019 0.1021  60 0.0983 0.0443     Tetrakis(dimethylamido)(κ2-N,O-5-benzyloxy-2-pyridonato)tantalum(V): R = OBn        TH-OBn-1   R = TH-OBn-2   R = Time Rel. Area [NMA] 0.0015 Time Rel. Area [NMA] 0.0019 0 0.8564 0.1831  0 0.8593 0.1838  10 0.7934 0.1687  10 0.7923 0.1685  20 0.7242 0.1529  20 0.6945 0.1461  30 0.6226 0.1297  30 0.5205 0.1063  40 0.5585 0.1150  40 0.4782 0.0967  50 0.4631 0.0932  50 0.3355 0.0640  60 0.3825 0.0748  60 0.3293 0.0626  366  TH-OBn-3   R =    Rate = 0.0016 Time Rel. Area [NMA] 0.0015 Time [NMA] Std. Dev. Rate Error = 0.0002 0 0.9660 0.2082  0 0.1917 0.0836   10 0.9104 0.1955  10 0.1776 0.0777   20 0.8357 0.1784  20 0.1592 0.0700   30 0.7688 0.1631  30 0.1330 0.0610   40 0.7047 0.1485  40 0.1200 0.0552   50 0.5865 0.1214  50 0.0929 0.0451   60 0.5415 0.1111  60 0.0828 0.0401    Tetrakis(dimethylamido)(κ2-N,O-5-bromo-2-pyridonato)tantalum(V): R = Br        TH-Br-1   R = TH-Br-2   R = Time Rel. Area [NMA] 0.0013 Time Rel. Area [NMA] 0.0011 0 0.9517 0.2050  0 0.9802 0.2115  10 0.9192 0.1975  10 0.9520 0.2050  20 0.8360 0.1785  20 N/A        N/A  30 0.7873 0.1673  30 0.8352 0.1783  40 0.7178 0.1514  40 0.8027 0.1709  50 0.6649 0.1394  50 0.7639 0.1620  60 0.6322 0.1319  60 0.7051 0.1485  TH-Br-3   R =    Rate = 0.0014 Time Rel. Area [NMA] 0.0013 Time [NMA] Std. Dev. Rate Error = 0.0001 0 0.9695 0.2090  0 0.2085 0.0903   10 0.9384 0.2019  10 0.2015 0.0873   20 0.8527 0.1823  20 0.1804 0.0851   30 0.7793 0.1655  30 0.1704 0.0739   40 0.7000 0.1474  40 0.1566 0.0684   50 0.6355 0.1326  50 0.1447 0.0636   60 0.5917 0.1226  60 0.1343 0.0589       367  Tetrakis(dimethylamido)(κ2-N,O-4-methyl-2-pyridonato)tantalum(V): R = Me        WD1Me   R =  WD2Me   R =  Time Rel. Area [NMA] 0.0036 Time Rel. Area [NMA] 0.0101 0 1.0413 0.2246  0 1.6487 0.3556  10 0.8886 0.1917  10 0.8795 0.1897  20 0.7081 0.1527  20 0.7128 0.1537  30 0.6377 0.1375  30 0.6098 0.1315  40 0.4729 0.1020  40 N/A N/A  50 0.3912 0.0844  50 0.4262 0.0919  60 0.4677 0.1009  60 0.4966 0.1071  WD3Me   R =  Avg Me   Rate =  0.0053 Time Rel. Area [NMA] 0.0030 Time [NMA] St. Dev Rate Error = 0.0032 0 1.0239 0.2208  0 0.2531 0.0627   10 0.8309 0.1792  10 0.1806 0.0055   20 0.7432 0.1603  20 0.1476 0.0034   30 0.6317 0.1363  30 0.1279 0.0026   40 0.5313 0.1146  40 0.0877 0.0063   50 0.3402 0.0734  50 0.0826 0.0076   60 0.3316 0.0715  60 0.1040 0.0155    Tetrakis(dimethylamido)(κ2-N,O-4-trifluoromethyl-2-pyridonato)tantalum(V): R = CF3        WD1CF3   R =  WD2CF3   R =  Time Rel. Area [NMA] 0.0020 Time Rel. Area [NMA] 0.0015 0 1.0209 0.2202  0 1.0083 0.2175  10 0.9090 0.1961  10 0.9370 0.2021  20 0.8323 0.1795  20 0.8701 0.1877  30 0.6985 0.1507  30 0.7645 0.1649  40 0.6015 0.1297  40 0.6696 0.1444  50 0.4144 0.0894  50 0.5582 0.1204  60 0.5147 0.1110  60 0.5448 0.1175  WD3CF3   R =  Avg CF3    Rate =  0.0018 Time Rel. Area [NMA] 0.0049 Time [NMA] St. Dev Rate error =  0.0015 0 1.1068 0.2387  0 0.2188 0.0014   368  10 0.8795 0.1897  10 0.1991 0.0030   20 N/A N/A  20 0.1836 0.0041   30 0.5616 0.1211  30 0.1578 0.0071   40 0.4356 0.0940  40 0.1371 0.0073   50 1.4225 0.3068  50 0.1049 0.0155   60 N/A N/A  60 0.1143 0.0032    Tetrakis(dimethylamido)(κ2-N,O-4-benzyloxy-2-pyridonato)tantalum(V): R = Bn        WD1Bn   R =  WD2OBn   R =  Time Rel. Area [NMA] 0.0032 Time Rel. Area [NMA] 0.0029 0 1.0182 0.2196  0 0.9965 0.2149  10 0.8920 0.1924  10 0.8844 0.1908  20 0.7173 0.1547  20 0.7249 0.1564  30 0.5325 0.1149  30 0.6209 0.1339  40 0.8257 0.1781  40 0.4858 0.1048  50 0.8413 0.1815  50 0.3628 0.0783  60 0.3064 0.0661  60 0.2626 0.0566  WD3OBn   R =  Avg Obn   Rate =  0.0031 Time Rel. Area [NMA] 0.0032 Time [NMA] St. Dev Rate Error =  0.0001 0 0.9835 0.2121  0 0.2156 0.0031   10 0.8648 0.1865  10 0.1899 0.0025   20 0.6891 0.1486  20 0.1532 0.0033   30 N/A N/A  30 0.1244 0.0095   40 0.5127 0.1106  40 0.1312 0.0333   50 0.6091 0.1314  50 0.1304 0.0421   60 1.5773 0.3402  60 0.1543 0.1315     Tetrakis(dimethylamido)(κ2-N,O-4-bromo-2-pyridonato)tantalum(V):  WD4Br    WD5Br   R = Time Rel. Area [NMA]  Time Rel. Area [NMA] 0.0022 0 N/A N/A  0 0.9609 0.2073  10 0.9554 0.2061  10 0.8781 0.1894  20 0.8261 0.1782  20 0.7547 0.1628  369  30 N/A N/A  30 0.6829 0.1473  40 0.6235 0.1345  40 0.5263 0.1135  50 0.6091 0.1308  50 0.4753 0.1025  60 0.3388 0.0728  60 N/A N/A  WD4Br    Avg Br (4-6)  Rate 0.0032 Time Rel. Area [NMA]  Time Rel. Area St. Dev Rate Error 0.0016 0 N/A N/A  0 0.2156 0.0083   10 0.9554 0.2061  10 0.1894 0.0136   20 0.8261 0.1782  20 0.1520 0.0268   30 N/A N/A  30 0.1473 0.0000   40 0.6235 0.1345  40 0.1089 0.0230   50 0.6091 0.1308  50 0.0973 0.0297   60 0.3388 0.0728  60 0.0514 0.0214      370  Appendix D  Characterization of Side Product 5.15 1H NMR – 600 MHz, d8 Toluene, rt. PME-085-Dimer.001.esp8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0Chemical Shift (ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00Normalized Intensity0.552.002.950.723.391.130.653.160.361.150.230.140.190.172.021.060.740.810.922.210.780.271.081.800.470.730.870.240.670.240.670.250.912.255.115.530.330.743.55TolTolTolTol2.09 Full Spectrum 371  PME-085-Dimer.001.esp2.0 1.5 1.0 0.5Chemical Shift (ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.700.750.800.850.900.951.00Normalized Intensity0.552.002.950.723.391.130.653.160.361.150.230.140.190.17Tol2.09 0 – 2.5 ppm  PME-085-Dimer.001.esp4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 4.0 3.9 3.8 3.7 3.6 3.5 3.4 3.3 3.2 3.1 3.0 2.9 2.8 2.7 2.6 2.5Chemical Shift (ppm)00.050.100.150.200.250.300.350.400.45Normalized Intensity2.021.060.740.810.922.210.780.271.081.800.470.730.870.24 2.5 – 5.0 ppm 372  PME-085-Dimer.001.esp7.9 7.8 7.7 7.6 7.5 7.4 7.3 7.2 7.1 7.0 6.9 6.8 6.7 6.6 6.5 6.4 6.3 6.2 6.1 6.0Chemical Shift (ppm)00.050.100.150.200.250.300.350.400.450.500.550.600.650.70Normalized Intensity0.670.240.670.250.912.255.115.530.330.743.55TolTolTol 6.0 – 8.0 ppm  13C NMR Spectrum – 150 MHz, d8 Toluene, rt  PME-085-Dimer.003.esp192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8Chemical Shift (ppm)00.10.20.30.40.50.60.70.80.91.0Normalized IntensityTolTolTolTol1.7614.5915.3817.1617.2920.4220.5520.6820.8020.9321.0621.1921.3424.5029.6530.8039.2240.3246.2546.8346.9246.9450.2750.4553.0465.2068.9470.1870.2872.3873.3678.8378.8479.49115.79116.77117.36117.53118.89119.36122.43125.35125.51128.18128.34128.50129.25129.41133.03133.91137.65137.86143.76144.02144.18144.37144.75144.89 373  COSY NMR Spectrum – 600, 600 MHz, d8 Toluene, rt  PME-085-Dimer.002.esp8 7 6 5 4 3 2 1 0 -1F2 Chemical Shift (ppm)012345678F1 Chemical Shift (ppm)   374  HSQC NMR Spectrum – 600, 150 MHz, d8 Toluene, rt  PME-085-Dimer.004.esp8 7 6 5 4 3 2 1F2 Chemical Shift (ppm)0102030405060708090100110120130140150F1 Chemical Shift (ppm)   375  HMBC NMR Spectrum – 600, 150 MHz, d8 Toluene, rt  PME-085-Dimer.005.esp8 7 6 5 4 3 2 1 0F2 Chemical Shift (ppm)-20020406080100120140160F1 Chemical Shift (ppm)    376  1H NMR Spectra, 400 MHz, d8 Toluene, Variable Temperature (25 – 95 °C)  PME6-085-pk2 VT Full.001.esp7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5Chemical Shift (ppm)-1.4-1.3-1.2-1.1-1.0-0.9-0.8-0.7-0.6-0.5-0.4-0.3-0.2-0.100.10.20.30.40.50.60.70.80.91.0Normalized Intensity1234567825 oC35 oC45 oC55 oC665 oC75 oC85 oC95 oC   377  IR Spectrum    378  Appendix E  Chiral Chromatograms  Column: Chiralcel OJ-RH, 60:40 H2O/MeCN, Flow Rate: 0.5 mL/min, Column Temp: 35 °C Racemic                379  Asymmetric  Peak # Retention Time (min) Peak Area (mAU*s) 1 5.355 3042.16016 2 5.655 343.11249   Column: Chiralcel OJ-RH, 45:55 H2O/MeCN, Flow Rate: 0.5 mL/min, Column Temp: 35 °C Racemic      380  Asymmetric  Peak # Retention Time (min) Peak Area (mAU*s) 1 11.356 6262.60840 2 11.966 805.22833   Column: Chiralcel AS-RH, 75:25 H2O/MeCN, Flow Rate: 0.5 mL/min, Column Temp: 35 °C Racemic   Asymmetric  Peak # Retention Time (min) Peak Area (mAU*s) 1 11.925 1.10598e5 2 12.791 1.38192e4     381   Column: Chiralcel OJ-RH, 65:35 H2O/MeCN, Flow Rate: 0.5 mL/min, Column Temp: 35 °C Racemic   Asymmetric  Peak # Retention Time (min) Peak Area (mAU*s) 1 16.511 1.16507e4 2 21.725 1631.85876   Column: Chiralcel OJ-RH, 65:35 H2O/MeCN, Flow Rate: 0.5 mL/min, Column Temp: 35 °C Racemic     382  Asymmetric  Peak # Retention Time (min) Peak Area (mAU*s) 1 24.829 8315.89941 2 30.787 647.37506  Column: Chiralcel AS-RH, 70:30 H2O/MeCN, Flow Rate: 0.5 mL/min, Column Temp: 35 °C Racemic   Asymmetric (Appears different because of longer run time)  Peak # Retention Time (min) Peak Area (mAU*s) 1 16.805 9133.55762 2 17.762 1849.57617  

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