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Sequential intermolecular hydroamination of alkynes and amines towards the synthesis of nitrogen-containing… Lui, Erica Kwei Jen 2018

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SEQUENTIAL INTERMOLECULAR HYDROAMINATION OF ALKYNES WITH AMINES TOWARDS THE SYNTHESIS OF NITROGEN-CONTAINING COMPOUNDS by  Erica Kwei Jen Lui  B.Sc., The University of Toronto, 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)  October 2018  © Erica Kwei Jen Lui, 2018    ii Sequential Intermolecular Hydroamination of Alkynes with Amines Towards the Synthesis of Nitrogen-Containing Componds submitted by Erica Kwei Jen Lui  in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry  Examining Committee:  Prof. Laurel Schafer (Chemistry) Supervisor  Prof. Martin E. Tanner (Chemistry) Supervisory Committee Member  Prof. David M. Perrin (Chemistry) University Examiner Prof. Jörg Bohlmann (Botany and Forestry & Conservation Sciences) University Examiner Prof. Mark Stradiotto (Dalhousie University) External Examiner Additional Supervisory Committee Members: Prof. Chris Orvig (Chemistry) Supervisory Committee Member Prof. Glenn M. Sammis (Chemistry) Supervisory Committee Member    iii Abstract This thesis details the development of sequential intermolecular hydroamination of alkynes with amines followed by other reactions for the synthesis nitrogen-containing compounds, such as amines and heterocycles. The main feature of this thesis is the use of a bis(amidate)bis(amido)titanium complex, also known as the Schafer titanium catalyst, for the catalytic intermolecular hydroamination of terminal and internal alkynes.  The catalytic synthesis of linear secondary amines using the Schafer titanium catalyst was accomplished through an intermolecular hydroamination of terminal alkynes followed by a Pd/C hydrogenation. The clean formation of products allowed for a facile synthesis and isolation of 23 examples of secondary amines in yields of 33-99%. The developed methodology allows for the synthesis of a variety of secondary amines containing aryl or alkyl substituents within a few hours and without the need for column chromatography.  The selective anti-Markovnikov hydroamination of alkynes and ammonia remains a challenge. The first example of a hydroamination reaction with N-silylamine as an ammonia surrogate is disclosed in this thesis. Synthesis of anhydrous N-silylamine was accomplished using gaseous ammonia and tert-butyldimethylchlorosilane, which was then reacted with a variety of terminal and internal alkynes, leading to the synthesis of 25 examples of N-silylenamines in yields of 54-99%. The synthesis of primary amines (9 examples) was also accomplished upon treatment of the reaction mixture with palladium on carbon (Pd/C) and H2. The isolation and characterization of key organometallic titanium-imido complexes was performed to probe the mechanism of the hydroamination reaction. Computational studies were also performed to study the preference of the N-silylenamine over the N-silylimine tautomer.   iv Upon the remark that N-silylenamines were observed exclusively in the majority of cases, it was reasoned that such synthons could be used towards the synthesis of pyridines. Following the reported hydroamination reaction, a large variety of pyridines were formed with the addition of α,β-unsaturated followed by an oxidation event. This methodology allowed for the synthesis of 47 examples of mono-, di-, tri-, tetra-, and penta-substituted pyridines in yields of 11-96%.         v Lay Summary Nitrogen-containing compounds are ubiquitous in all aspects of life. Biologically, for example, both DNA and proteins contain nitrogen in their structures. Furthermore, in the pharmaceutical and chemical companies, nitrogen-containing compounds are also commonly found. In fact 84% of the U.S. Food and Drug Administration approved small molecules by 2014 contained nitrogen in their structure. It is therefore not surprising that efficient and facile methods to make nitrogen-containing compounds are important. This thesis describes the synthesis of amines and pyridines using a titanium metal catalyst. In particular, the amines synthesized in this thesis are structurally similar to a family of neurotransmitters called trace amines, which includes adrenaline and dopamine, for example. A methodology for the synthesis of a pyridine motif, which is found in nicotine, is also disclosed in this thesis.   vi Preface In collaboration and consultation with my supervisor Prof. Dr. Laurel L. Schafer, I designed and conducted all of the experiments described herein, except for specific instances described below. I have written the text of this document entirely with input and suggestions from my supervisor Prof. Dr. Laurel L. Schafer, except for specific instances described below. A version of the data contained in Chapter 2 has been published: Lui, E. K. J.; Schafer, L. L. Adv. Synth. Catal. 2016, 358, 713-718. I performed this work (experimental and otherwise) in its entirety. This publication was written with input and suggestions from Prof. Schafer. A version of Chapter 3 has been published: Lui, E. K. J.; Brandt, J. W.; Schafer, L. L. J. Am. Chem. Soc. 2018, 140, 4973-4976. This work (experimental and otherwise) was done in collaboration with former Schafer group colleague Dr. Jason W. Brandt. Dr. Brandt contributed to the synthesis of the (N-tert-butyldimethylsilyl)amine, to the refinement of the single-crystal molecular structures of titanium complexes 3.1a-c and to the calculations and conclusions reported in Section 3.2.4. I designed and performed all the other reactions reported in Chapter 3. This publication was written with input and suggestions from Dr. Brandt and Prof. Schafer. A version of Chapter 4 has been accepted for publication: Lui, E. K. J.; Hergesell, D.; Schafer, L. L. Org. Lett. 2018, Just Accepted Manuscript (DOI: ol-2018-02703f). This work was done in collaboration with former Schafer group visiting student Daniel Hergesell. While I designed the experiments, Mr. Hergesell contributed experimentally to the screening of reaction conditions listed on Table 4-3 (4.3b) and Table 4-4 (4.4b, 4.4h-l, 4.4p, 4.4r-u) as well as to the synthesis of compounds 4.1a-e, 4.1g-i, 4.1k-o and 4.1q. All other screening reactions and substrate scope was performed by me. This publication was written with input and suggestions from Prof. Schafer.   vii Table of Contents  Abstract ......................................................................................................................................... iii	Lay Summary .................................................................................................................................v	Preface ........................................................................................................................................... vi	Table of Contents ........................................................................................................................ vii	List of Tables ............................................................................................................................... xii	List of Figures ............................................................................................................................. xiii	List of Schemes ........................................................................................................................... xiv	List of Symbols ........................................................................................................................... xxv	List of Abbreviations ............................................................................................................... xxvi	Acknowledgements .................................................................................................................. xxxi	Dedication ............................................................................................................................... xxxiii	Chapter 1: Introduction ................................................................................................................1	1.1	 Efforts Towards Sustainable Chemistry ............................................................................ 2	1.1.1	 Catalysis ...................................................................................................................... 2	1.1.2	 Cascade, Domino, Sequential and Tandem Reactions ................................................ 3	1.2	 Sequential Reactions Involving Catalytic Intermolecular Hydroamination of Alkynes Towards the Synthesis of Nitrogen-Containing Small Molecules and Heterocycles ................. 4	1.2.1	 Amine Synthesis ......................................................................................................... 5	1.2.1.1	 Using Stoichiometric Reductants ......................................................................... 5	1.2.1.2	 Using Catalytic Hydrogenation .......................................................................... 24	1.2.1.3	 Using Transfer Hydrogenation .......................................................................... 27	  viii 1.2.1.4	 Using Nucleophilic Addition ............................................................................. 28	1.2.1.5	 Conclusion ......................................................................................................... 31	1.2.2	 Heterocycle Synthesis ............................................................................................... 32	1.2.2.1	 Formation of 5-Membered N-Heterocycles ....................................................... 32	1.2.2.1.1	 Pyrrolidine and Pyrrole ............................................................................... 32	1.2.2.1.2	 Indole .......................................................................................................... 36	1.2.2.2	 Formation of 5-Membered N,N- or N,O-Heterocycles ...................................... 37	1.2.2.2.1	 Pyrazole and Imidazole ............................................................................... 37	1.2.2.2.2	 Oxazolidine, Oxazole and Others ............................................................... 38	1.2.2.3	 Formation of 6-Membered N-Heterocycles ....................................................... 40	1.2.2.3.1	 Dihydropyridine and Pyridine ..................................................................... 40	1.2.2.3.2	 Dihydroquinoline, Quinoline, Tetrahydroquinoline, Tetrahydroisoquinoline and Naphthyridine ......................................................................................................... 41	1.2.2.4	 Formation of 6-Membered N,N- or N,O-Heterocycles ...................................... 47	1.2.2.4.1	 Tetrahydropyrimidine, Pyrimidine and Quinoxaline .................................. 47	1.2.2.5	 Formation of 7-Membered N,N- or N,O-Heterocycles ...................................... 49	1.2.2.5.1	 Dihydrobenzodiazapine and Benzodiazepine ............................................. 49	1.2.2.6	 Conclusion ......................................................................................................... 50	1.3	 Scope of Thesis ................................................................................................................ 50	Chapter 2: Facile Synthesis and Isolation of Secondary Amines via a Sequential Titanium(IV)-Catalyzed Hydroamination and Palladium-Catalyzed Hydrogenation .........53	2.1	 Introduction ...................................................................................................................... 53	2.1.1	 Amination of Alcohols .............................................................................................. 53	  ix 2.1.2	 C-N Cross-Coupling Reactions ................................................................................. 57	2.1.2.1	 Copper-Mediated or Catalyzed C-N Cross Coupling ........................................ 58	2.1.2.2	 Palladium-Catalyzed C-N Cross Coupling ........................................................ 60	2.1.3	 Hydrofunctionalization Reactions ............................................................................ 62	2.1.3.1	 Hydroaminomethylation .................................................................................... 62	2.1.3.2	 Hydroamination ................................................................................................. 66	2.2	 Results and Discussion .................................................................................................... 68	2.2.1	 Optimization of Reaction Conditions ....................................................................... 69	2.2.2	 Substrate Scope of Sequential Hydroamination/Hydrogenation Transformation Towards Linear Secondary Amines ...................................................................................... 73	2.2.3	 Large Scale and One-Pot Transformations ............................................................... 76	2.3	 Conclusion ....................................................................................................................... 79	Chapter 3: Regio- and Stereoselective Hydroamination of Alkynes Using an Ammonia Surrogate: Synthesis of N-Silylenamines as Reactive Synthons ..............................................81	3.1	 Enamines in Organic Chemistry ...................................................................................... 81	3.1.1	 Synthesis of Enamines .............................................................................................. 81	3.1.2	 Synthesis of N-Silylenamines ................................................................................... 82	3.2	 Results and Discussion .................................................................................................... 85	3.2.1	 Reaction Conditions and Controls ............................................................................ 85	3.2.2	 Stoichiometric Studies .............................................................................................. 86	3.2.3	 Substrate Scope of the Intermolecular Hydroamination of Alkynes and N-Silylamine 89	3.2.4	 Computational Studies – DFT Calculations ............................................................. 91	  x 3.2.5	 Substrate Scope of Sequential Hydroamination/Hydrogenation Transformation To Access Primary Amines ........................................................................................................ 93	3.3	 Conclusion ....................................................................................................................... 95	Chapter 4: N-Silylenamines as Reactive Intermediates. Hydroamination for the Modular Synthesis of Selectively Substituted Pyridines ..........................................................................97	4.1	 Introduction ...................................................................................................................... 97	4.2	 Results and Discussion .................................................................................................... 99	4.2.1	 Optimization of Pyridine Formation Step ................................................................. 99	4.2.2	 Substrate Scope ....................................................................................................... 103	4.2.3	 Proposed Mechanism for the Formation of Pyridines ............................................ 111	4.2.4	 Isolation of 2,4,5-Triphenylpyridin-3-ol By-Product ............................................. 113	4.3	 Conclusion ..................................................................................................................... 114	Chapter 5: Future Directions and Conclusions ......................................................................116	5.1	 Future Directions ........................................................................................................... 116	5.1.1	 Synthesis of Secondary Amines Containing α- and β-Substituents via a Sequential Hydroamination of Alkynes Followed by Reduction ......................................................... 116	5.1.1.1	 Preliminary Results .......................................................................................... 118	5.1.2	 Synthesis of N-Heterocycles Using N-Silylenamine as a Reactive Intermediate ... 120	5.1.2.1	 Reactivity of α-Haloketones with N-Silyenamines .......................................... 120	5.1.2.2	 Synthesis of N-Silyl-1-Amino-1,3-Diene and Reactivity with Dienophiles .... 123	5.2	 Summary ........................................................................................................................ 125	5.3	 Concluding Remarks ...................................................................................................... 127	References ...................................................................................................................................128	  xi Appendices ..................................................................................................................................140	Appendix A ............................................................................................................................. 140	A.1	 General Considerations ............................................................................................. 140	A.2	 Materials .................................................................................................................... 140	A.3	 Instrumentation ......................................................................................................... 141	A.4	 Synthesis and Compound Characterization .............................................................. 141	A.5	 NMR Spectra ............................................................................................................. 158	Appendix B ............................................................................................................................. 175	B.1	 General Considerations ............................................................................................. 175	B.2	 Materials .................................................................................................................... 175	B.3	 Instrumentation .......................................................................................................... 175	B.4	 Synthesis and Compound Characterization ............................................................... 176	B.5	 NMR Spectra ............................................................................................................. 198	B.6	 Solid State Molecular Structures and X-Ray Crystallographic Data ........................ 235	B.7	 Computational Data and Details ............................................................................... 238	Appendix C ............................................................................................................................. 253	C.1	 General considerations .............................................................................................. 253	C.2	 Materials .................................................................................................................... 253	C.3	 Instrumentation .......................................................................................................... 254	C.4	 Synthesis and Compound Characterization ............................................................... 254	C.5	 NMR Spectra ............................................................................................................. 288	C.6	 Solid State Molecular Structures and X-Ray Crystallographic Data ........................ 323	   xii List of Tables Table 2-1 Optimization of the Hydroamination Reactions Using Ethynylbenzene ..................... 70	Table 2-2 Optimization of the Hydroamination Reactions Using Sec-Butylamine ...................... 71	Table 2-3 Optimization of the Sequential Reaction Conditions ................................................... 72	Table 3-1 Ratio of Primary to Secondary Amines After Hydrogenation and Salt Formation Reactions ....................................................................................................................................... 94	Table 4-1 Optimization of Conditions for the Pyridine Formation Steps ................................... 101	Table 4-2 Optimization of Pyridine Synthesis Using 10 mol% Cesium Fluoride ...................... 101	Table 4-3 Optimization of Pyridine Synthesis Using 10 mol% of Other Fluoride Sources and 3Å molecular sieves .......................................................................................................................... 102	Table 4-4 Optimization of Pyridine Synthesis Using 10 mol% of 1M Tetra-Butylammonium Fluoride in THF and 3Å molecular sieves .................................................................................. 103	Table 5-1 Preliminary Results of the Homogeneous Hydrogenation Towards α-Substituted Secondary Amines ...................................................................................................................... 119	Table 5-2 Preliminary Results of Sequential Hydroamination/Addition of α-Haloketone Reactions ..................................................................................................................................... 122	   xiii List of Figures Figure 2.1 1H NMR Spectrum (CDCl3, 400 MHz, 298 K) for the Crude Sequential Hydroamination/Hydrogenation Reaction of Ethynylbenzene and Tert-Butylamine .................. 73	Figure 2.2 1H NMR Spectrum (CDCl3, 400 MHz, 298 K) for the Crude Large-Scale Sequential Hydroamination/Hydrogenation Reaction of Ethynylbenzene and Tert-Butylamine .................. 77	Figure 2.3 1H NMR Spectrum (CDCl3, 400 MHz, 298 K) for the Crude One-Pot Hydroamination/Hydrogenation Reaction of Ethynylbenzene and Tert-Butylamine .................. 79	Figure 3.1 Single-Crystal Molecular Structures of 3.1a (left) and 3.1b (right) ............................ 87	Figure 3.2 Single-Crystal Molecular Structures of 3.1c ............................................................... 89	Figure 3.3 Frontier Molecular Orbital Analysis Based on Natural Bond Order Calculations ...... 93	Figure 4.1 X-ray Crystallography of Pyridine 4.1m ................................................................... 106	Figure 4.2 X-ray Crystallography of Hydroxypyridine 4.4 ........................................................ 114	Figure 5.1 1H NMR Spectra (C6D6, 300 MHz, 298 K) for the Crude Hydroamination Reaction Product Between 1-Ethynylcyclohex-1-ene and N-Tert-Butyldimethylsilylamine (top) and for the Crude Reaction depicted in Scheme 5.7 (bottom) ...................................................................... 125	Figure B.1 Glassware Used for the Synthesis of Tert-Butyldimethylsilanamine ....................... 177	Figure B.2 Single crystal molecular structure of complex 3.1a .................................................. 236	Figure B.3 Single crystal molecular structure of complex 3.1b ................................................. 237	Figure B.4 Single crystal molecular structure of complex 3.1c .................................................. 237	Figure C.1 Single Crystal Molecular Structure of Pyridine 4.1m ............................................... 324	   xiv List of Schemes Scheme 1.1 Importance of Nitrogen-Containing Compounds ........................................................ 1	Scheme 1.2 General Alkene and Alkyne Hydroamination Reactions ............................................ 2	Scheme 1.3 General Sequential Hydroamination/Addition of Hydride Reactions Toward the Synthesis of Amines ....................................................................................................................... 5	Scheme 1.4 Doye (1999) – Dimethyltitanocene-Catalyzed Hydroamination Reaction Toward the Synthesis of Secondary Amines ...................................................................................................... 6	Scheme 1.5 Doye (2001) – Microwave-Assisted Dimethyltitanocene-Catalyzed Hydroamination Reaction Toward the Synthesis of Secondary Amines ................................................................... 6	Scheme 1.6 Doye (2002) – Titanium-Catalyzed Hydroamination Reaction Toward the Synthesis of Secondary Amines ...................................................................................................................... 7	Scheme 1.7 Doye (2002) – Fifteen Titanium Catalysts Studied for the Hydroamination Reaction Toward the Synthesis of Secondary Amines .................................................................................. 8	Scheme 1.8 Doye (2005) – Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ...................................................................................................................... 9	Scheme 1.9 Odom (2001) – Titanium Pyrrolyl Complex-Catalyzed Hydroamination Reaction Towards the Synthesis of a Secondary Amine ............................................................................... 9	Scheme 1.10 Yamamoto (2002) – Palladium-Catalyzed Hydroamination Reaction Towards the Synthesis of a Secondary Amine .................................................................................................. 10	Scheme 1.11 Schafer (2003) – Bis(amidate)bis(amido)titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Linear Secondary Amines .................................................... 10	Scheme 1.12 Beller (2003) – Ayloxotitanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 11	  xv Scheme 1.13 Doye (2004) – Diindenyldimethyltitanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ............................................................................... 11	Scheme 1.14 Liu (2007) – Iridium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................................... 12	Scheme 1.15 Djukic (2012) – Tricarbonylchromium-Bound Iridium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ............................................................... 12	Scheme 1.16 Esteruelas (2006, 2007) – Half-Sandwich Alkyl Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................... 13	Scheme 1.17 Doye (2008) – Neutral Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 14	Scheme 1.18 Gade (2009) – Half-Sandwich Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ............................................................................... 15	Scheme 1.19 Beller (2008) – Zinc Triflate-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 15	Scheme 1.20 Shi (2009) – Gold-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ........................................................................................................................ 16	Scheme 1.21 Schafer (2009) – Bis(ureate)tris(dimethylamido)Zirconium-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines ........................................ 17	Scheme 1.22 Yao (2015) – Cationic Zirconium-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines .................................................................................................. 17	Scheme 1.23 Stradiotto (2010) – Gold-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines ........................................................................................................ 17	  xvi Scheme 1.24 Hartwig (2011) – Copper-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 18	Scheme 1.25 Monnier (2015) – Copper-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines ........................................................................................................ 18	Scheme 1.26 Kawatsura (2016) – Copper-Catalyzed Hydroamination Reaction Towards the Synthesis of β-Trifluoromethyl Substituted Secondary Amines .................................................. 19	Scheme 1.27 Doye (2012) – Zirconium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 20	Scheme 1.28 Leong (2012) – Rhodium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 21	Scheme 1.29 Li (2012) – Gallium Trichloride Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary and Tertiary Amines ............................................................................... 21	Scheme 1.30 Sakai (2014) – Indium Tribromide Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary and Tertiary Amines ......................................................................... 22	Scheme 1.31 Doye (2013) – (Aminopyridiminato)Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ............................................................................... 22	Scheme 1.32 Liu (2015) – Imidazo[1,5-a]pyridine-Containing Pyrrolyl Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................... 23	Scheme 1.33 Cao (2013) – (N-Heterocyclic Carbene)Palladium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines ............................................................... 23	Scheme 1.34 Hammond (2016) – Gold Nanoparticles Supported on Tititanium Oxide Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................... 24	  xvii Scheme 1.35 General Sequential Hydroamination/Hydrogenation Reactions Toward the Synthesis of Amines ..................................................................................................................... 24	Scheme 1.36 Doye (2000) – Dimethyltitanocene-Catalyzed Hydroamination Reaction Toward the Synthesis of Primary Amines .................................................................................................. 25	Scheme 1.37 Esteruelas (2005, 2006, 2007) – Half-Sandwich Alkyl Titanium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines ..................... 25	Scheme 1.38 Beller (2012) – Gold-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Enantioselective Secondary Amines ........................................................................ 26	Scheme 1.39 Yamamoto (2005) – Palladium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Tertiary Amines ........................................................................................ 26	Scheme 1.40 Beller (2008) – Zinc Triflate-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines .................................................................................... 27	Scheme 1.41 Stephan (2013) – Frustrate-Lewis Pair-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Tertiary Amines ................................................................... 27	Scheme 1.42 Che (2009) – Gold-Catalyzed Hydroamination Reaction Towards the Synthesis of Enantioselective Secondary Amines ............................................................................................. 28	Scheme 1.43 General Sequential Hydroamination/Addition of Nucleophile Reactions Toward the Synthesis of Amines ..................................................................................................................... 28	Scheme 1.44 Beller (2001) – Rhodium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines Containing a α-Quaternary Centre ............................ 29	Scheme 1.45 Beller (2003) – Titanium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines .................................................................................... 29	  xviii Scheme 1.46 Schafer (2006, 2009) – Titanium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of α-Cyanoamines and Vicinal Diamines ..................................................... 30	Scheme 1.47 Li (2009) – Copper-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Propargylamines ....................................................................................................... 30	Scheme 1.48 Larsen (2013) – Copper-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Propargylamines Containing a Quaternary Centre ................................... 31	Scheme 1.49 Blechert (2010) –  Zinc-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Propargylamines ....................................................................................................... 31	Scheme 1.50 Doye (2009) – Sequential Titanium-Catalyzed Hydroamination, Cyclopropylimine Rearrangement and Reduction Reactions Towards the Synthesis of Pyrrolidines ....................... 32	Scheme 1.51 Odom (2004) – Sequential Double Titanium-Catalyzed Hydroamination Reactions Towards the Synthesis of Pyrroles ................................................................................................ 33	Scheme 1.52 Ackermann (2009) – Sequential Titanium-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Pyrroles ............................................................................... 33	Scheme 1.53 Odom (2009) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Cyclization Reactions Towards the Synthesis of Pyrroles ..... 34	Scheme 1.54 Skrydstrup (2010) – Sequential Gold-Catalyzed Double Hydroamination Reactions Towards the Synthesis of Pyrroles ................................................................................................ 35	Scheme 1.55 Liu (2015) – Sequential Gold-Catalyzed Hydroamination/Cyclization Reaction Towards the Synthesis of Pyrroles ................................................................................................ 35	Scheme 1.56 Corma (2010) – Sequential Gold-Catalyzed Hydroamination/ Reaction Towards the Synthesis of Cyclobutapyrrolidine ................................................................................................ 36	  xix Scheme 1.57 Ackermann (2008) – Sequential Titanium-Catalyzed Hydroamination/Palladium-Catalyzed Heck Reactions Towards the Synthesis of Indoles ...................................................... 36	Scheme 1.58 Li (2007) – Sequential Gold-Catalyzed Double-Hydroamination Reactions Towards the Synthesis of N-Vinylindoles .................................................................................... 37	Scheme 1.59 Skrydstrup (2009) – Sequential Gold-Catalyzed Hydroamination/Cyclization Towards the Synthesis of an Indole .............................................................................................. 37	Scheme 1.60 Odom (2009) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Hydrazine Addition Reactions Towards the Synthesis of Pyrazoles ....................................................................................................................................... 38	Scheme 1.61 Beller (2011) – Sequential Zinc-Catalyzed Hydroamination/Cyclization/Dehydration Reactions Towards the Synthesis of Imidazoles ....... 38	Scheme 1.62 Yamamoto (2003) – Sequential Ruthenium-Catalyzed Double Hydroamination/C-C Bond Cleavage Reactions Towards the Synthesis of Benzoxazoles ............................................ 39	Scheme 1.63 Corma (2009) – Sequential Gold-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of a Oxazolidine ....................................................................................... 39	Scheme 1.64 Odom (2012) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Hydroxylamine Addition Reactions Towards the Synthesis of Mono- and Di-Substituted Isoxazoles ........................................................................................... 40	Scheme 1.65 Odom (2014) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Dimroth Rearrangement Reactions Towards the Synthesis of 2-Amino-3-Cyanopyridines ............................................................................................................. 40	Scheme 1.66 Odom (2004) – Sequential Titanium-Catalyzed Hydroamination/C-H Activation/Electrocyclization Reactions Towards the Synthesis of a Dihydropyridine ............... 41	  xx Scheme 1.67 Wakatsuki (1999), Che (2007), Li (2011) – Sequential Metal-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Quinolines ............................ 42	Scheme 1.68 Peshkov (2016) – Sequential Copper-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Naphthyridines .................................................................... 42	Scheme 1.69 Schafer (2003) – Sequential Titanium-Catalyzed Hydroamination/Pictet-Spengler Reactions Towards the Synthesis of a Tetrahydroisoquinoline .................................................... 43	Scheme 1.70 Li (2005) – Sequential Silver-Catalyzed Hydroamination/Alkyne Addition/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines ..................... 43	Scheme 1.71 Che (2007) – Sequential Gold-Catalyzed Hydroamination/Alkyne Addition/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines ..................... 44	Scheme 1.72 Blechert (2012) – Sequential Zinc-Catalyzed Hydroamination/Alkyne Addition/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines ..................... 44	Scheme 1.73 Bertrand (2009) – Sequential Gold-Catalyzed Hydroamination/Alkyne Additon/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines ....................... 45	Scheme 1.74 Patil (2010) – Sequential Gold-Catalyzed Hydroamination/Hydroarylation Reactions Towards the Synthesis of Tetrahydroquinolines .......................................................... 45	Scheme 1.75 Verma (2012), Wu (2013) – Sequential Copper-Catalyzed Hydroamination/Arylation Reactions Towards the Synthesis of Multi-Fused Isoquinolines ...... 46	Scheme 1.76 Odom (2009) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Cyclization Reactions Towards the Synthesis of Quinolines . 47	Scheme 1.77 Rossi (2009) – Sequential Titanium-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Pyrimido[1,6-α]Indolones .................................................. 47	  xxi Scheme 1.78 Odom (2010) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Amidine Addition Reactions Towards the Synthesis of Pyrimidines ................................................................................................................................... 48	Scheme 1.79 Patil (2010), Liu (2011) – Sequential Gold-Catalyzed Hydroamination/Hydroarylation Reactions Towards the Synthesis of Fused-Quinoxalines ....... 48	Scheme 1.80 Chen (2011) – Sequential Copper-Catalyzed Hydroamination/Cyclization/Alkyne Additon Reactions Towards the Synthesis of Quinoxalines ......................................................... 49	Scheme 1.81 Xu (2012), Luo (2014) – Sequential Gold-Catalyzed Double Hydroamination/Cyclization Reactions Towards the Synthesis of Dihydrobenzodiazapines ...... 50	Scheme 1.82 Overview of Scope of Thesis .................................................................................. 51	Scheme 2.1 General Amination of Alcohols Towards the Synthesis of Secondary Amines ....... 54	Scheme 2.2 Yamaguchi (2008, 2011) – Iridium-Catalyzed Amination of Alcohols Towards the Synthesis of Secondary Amines .................................................................................................... 55	Scheme 2.3 Kempe (2009) – Iridium-Catalyzed Amination of Alcohols Towards the Synthesis of Secondary Amines ........................................................................................................................ 55	Scheme 2.4 Zhao (2014) – Cooperative Iridium/Chiral-Phosphoric Acid Catalyzed Enantioselective Amination of Alcohols Towards the Synthesis of Secondary Amines ............. 56	Scheme 2.5 Barta (2014) – Iron-Catalyzed Amination of Alcohols Towards the Synthesis of Secondary Amines ........................................................................................................................ 57	Scheme 2.6 Chan (1998) – Copper-Mediated Arylation of Amines Towards the Synthesis of Secondary Amines ........................................................................................................................ 58	Scheme 2.7 Buchwald (2003) – Copper-Catalyzed Arylation of Amines Towards the Synthesis of Secondary Amines .................................................................................................................... 59	  xxii Scheme 2.8 Hartwig (2006) – Sequential Iridium-Catalyzed Borylation/Copper-Catalyzed C-N Cross-Coupling Reactions Towards the Synthesis of Secondary Amines .................................... 60	Scheme 2.9 General Palladium-Catalyzed C-N Cross-Coupling Towards the Synthesis of Secondary Aryl-Amines ................................................................................................................ 60	Scheme 2.10 Buchwald (2018) – Palladium-Catalyzed Arylation of Amines Towards the Synthesis of Secondary Amines .................................................................................................... 62	Scheme 2.11 General Hydroaminomethylation of Alkenes Towards the Synthesis of Secondary Amines .......................................................................................................................................... 63	Scheme 2.12 Eilbracht (1997) – Rhodium-Catalyzed Hydroaminomethylation Reaction Towards the Synthesis of Secondary Amines .............................................................................................. 64	Scheme 2.13 Beller (2005) – Rhodium-Catalyzed Hydroaminomethylation Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 64	Scheme 2.14 Xiao (2015), Han (2017) –Asymmetric Hydroaminomethylation Reaction Towards the Synthesis of Secondary Amines .............................................................................................. 65	Scheme 2.15 Hartwig (2000) – Palladium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines .................................................................................................... 67	Scheme 2.16 Marks (2003) – Neodymium-Catalyzed Hydroamination Reaction Towards the Synthesis of a Secondary Amine .................................................................................................. 68	Scheme 2.17 Effect of Amine Modification on Reaction with Ethynylbenzene .......................... 74	Scheme 2.18 Effect of Alkyne Modification on Reaction with sec-Butylamine .......................... 76	Scheme 2.19 One-Pot Approach Towards the Synthesis of Secondary Amines .......................... 78	Scheme 3.1 General Stork Enamine Alkylation Reaction and Enamine Catalysis ...................... 81	  xxiii Scheme 3.2 Barluenga (2002) – Palladium-Catalyzed Amination of Alkenyl Bromides Towards the Synthesis of Enamines ............................................................................................................ 82	Scheme 3.3 Stoichiometric and Catalytic Syntheses of N-Silylenamines .................................... 83	Scheme 3.4 Bergman (1992) – Catalytic and Stoichiometric Bis(Cyclopentadienyl)Zirconium Chemistry ...................................................................................................................................... 83	Scheme 3.5 Odom (2001, 2005) – Catalytic and Stoichiometric Bis(Pyrrolyl)Titanium Chemistry....................................................................................................................................................... 84	Scheme 3.6 Testing the Importance of Amidate Ligands ............................................................. 86	Scheme 3.7 Proposed Mechanism for the Titanium-Catalyzed Hydroamination of Alkynes ...... 86	Scheme 3.8 Synthesis of N-Silylimido-Titanium Species 3.1a and 3.1b ...................................... 87	Scheme 3.9 Synthesis of N-Silylimido-Titanium Species 3.1c .................................................... 88	Scheme 3.10 Scope of Alkyne Hydroamination Towards the Synthesis of N-Silylenamines ...... 90	Scheme 3.11 Experimental and Calculated Data for Enamine and Imine Tautomerization Experiments .................................................................................................................................. 92	Scheme 3.12 Sequential Catalysis for the Synthesis of Primary Amines from Alkynes and N-Silylamine ..................................................................................................................................... 95	Scheme 4.1 General Hantzsch (top) and Kröhnke (bottom) Pyridine Syntheses ......................... 98	Scheme 4.2 Various α,β-Unsaturated Carbonyl Substrates can be Incorporated into this Sequential Reaction .................................................................................................................... 105	Scheme 4.3 Effect of Alkyne-Substituents on Sequential Reaction for Pyridine Synthesis ...... 108	Scheme 4.4 Importance of 3-Heterocyclic Pyridine Motif ......................................................... 109	Scheme 4.5 Synthesis of Penta-Substituted Pyridines ................................................................ 111	Scheme 4.6 Potential Mechanisms for the Formation of Pyridines ............................................ 113	  xxiv Scheme 4.7 Reaction that Lead to the Isolation of By-Product 4.4 ............................................ 114	Scheme 5.1 Uses of Amphetamine and Derivatives ................................................................... 116	Scheme 5.2 General Asymmetric Hydrogenation of Enamides and Enamines .......................... 117	Scheme 5.3 Sequential Hydroamination/Hydrogenation Towards the Synthesis of N-isopropyl-1-phenylpropan-2-amine ................................................................................................................ 118	Scheme 5.4 Synthesis of N-Heterocycles Using N-Mono-Silylated Enamines .......................... 120	Scheme 5.5 Proposed Sequential Hydroamination/Addition of α-Haloketone Towards the Synthesis of Pyrroles and General Scheme for Experimentally Obtained Results ..................... 121	Scheme 5.6 Dienophiles Attempted Towards the Synthesis of Aminocyclohexenes ................ 124	Scheme 5.7 Sequential Hydroamination/Addition of Acrolein .................................................. 124	   xxv List of Symbols Symbol   Description  °    degree  °C    degrees Celsius  Å    angstrom δ    chemical shift in ppm  Δ    reflux ΔGcalc    calculated change in Gibbs energy ηx    eta, denotes hapticity of x atoms   nJ(A,B)   n-bond coupling constant between atoms A and B (spectral) κx    kappa, denotes denticity of x atoms µx   mu, denotes bridging of ligand to x metal centers     xxvi List of Abbreviations Abbreviation  Description  Ac    acetyl ACS   American Chemical Society Alk   generic alkyl group Ar   generic aryl group atm   standard atmosphere bar   metric unit of pressure Bn    benzyl  BQ   1,4-benzoquinone Bu    butyl Calc’d    calculated  cat.   catalyst CI   chemical ionization Cl-BQ   tetrachloro-1,4-benzoquinone Cp    cyclopentadienyl  Cp*    η5-1,2,3,4,5-pentamethylcyclopentadienyl  cod   1,5-cyclooctadiene Cy   cyclohexyl  d    doublet (spectral) DCM    dichloromethane dd    doublet of doublets (spectral)   xxvii DDQ   2,3-dichloro-5,6-dicyano-1,4-benzoquinone DFT    density functional theory  DMF   dimethylformamide dmpa   di(pyrrolyl-α-methyl)methylamine DMSO   dimethylsulfoxide dppf   1,1’-Ferrocenediyl-bis(diphenylphosphine) (E)-/(Z)-   entgegen (“opposite”) / zusammen (“together”) (isomers) EA   elemental analysis   EI    electron impact  ESI    electrospray ionization  equiv.    equivalents  Et    ethyl et. al   and others FDA   Food and Drug Administration FLP   Frustrated Lewis Pair g    gram  G    Gibbs free energy  GC-MS   gas chromatography mass spectrometry h    hour(s) HMPA   hexamethylphosphoramide HRMS   high resolution mass spectrometry  Hz    Hertz       xxviii iPr    isopropyl  Ind    indenyl  K    kelvin  kcal   kilocalorie  LC   liquid chromatography LED   light emitting diode LP   lone pair LRMS   low resolution mass spectrometry M    molarity  m    multiplet (spectral)  m-    meta mm   millimeter  Me    methyl  mL    milliliter  mmol    millimole  MS    molecular sieves m/z    mass-to-charge ratio  NaBAr4F  sodium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate N.D.   not determined NHC   N-heterocycliccarbene  NMR    nuclear magnetic resonance [O]   oxidation      xxix o-   ortho ORTEP   Oakridge thermal ellipsoid plot OTf   triflate     p-    para  p-cymene  1-isopropyl-4-methylbenzene, 4-isopropyltoluene PET   positron emission tomography  Ph    phenyl Pr    propyl  py   pyridine q    quartet (spectral)  quint    quintet (spectral)  RT   room temperature  rac    racemic  s    singlet (spectral) sec    second  sept    septet (spectral)  t    triplet (spectral) TASF   tris(dimethylamido)sulfonium difluorotrimethylsilicate TBAF    tetrabutylammonium fluoride TBAT    tetrabutylammonium difluorotriphenylsilicate TBDMS   tert-butyldimethylsilyl tBu   tert-butyl   xxx Tf   triflyl THF   tetrahydrofuran tert-   tertiary temp   temperature Tf   trifluoromethylsulfonyl  THF    tetrahydrofuran  TMS-   trimethylsilyl (group) TLC   thin layer chromatography Tol   toluene (molecule) Tol-   tolyl (group) TRIP 3,3’-bis(2,4,6-triisopropylphenyl)-1,1’-binaphthyl-2,2’-diyl hydrogen phosphate   xxxi Acknowledgements I would like to thank my advisor Prof. Dr. Laurel L. Schafer for guiding and supporting me over the years. Graduate school, let alone a Ph.D. degree, would not have been possible without your support, even before I joined the Schafer lab. Thank you for your commitment and dedication in shaping me into becoming the best scientist I could be and for sharing your knowledge and personal experiences with me, which taught me that with perseverance and hard word, I can achieve anything I want. Many thanks to my former and current colleagues of the Schafer group and around the department for their assistance both in chemistry and non-chemistry areas. Special thanks to my collaborators Dr. Jason W. Brandt and Mr. Daniel Hergesell for fast tracking the projects we worked on together. I would also like to thank the Love lab, which has been my go to refuge when needed. Thank you Weiling Chiu for your friendship and for listening to me whenever I needed to talk.  Thank you to the faculty members that have helped me get to the point I am currently. I would like to thank my committee members, Prof. Dr. Chris Orvig, Prof. Dr. Glenn M. Sammis, and Prof. Dr. Martin E. Tanner for their time and patience throughout the years. I am very thankful to Prof. Dr. Jason E. Hein, Prof. Dr. Jennifer A. Love and Prof. Dr. Glenn M. Sammis for all the encouragement and counseling they have given me. I would like to thank the many members of the shops and services at the UBC Chemistry department. In particular, I would like to thank Ken Love for his passion and efficiency in fixing and maintaining the various equipments that were used throughout my Ph.D degree. I would also like to thank Dr. Maria Ezhova for her help with a variety of NMR experiments that were crucial for this thesis to be completed. Thank you to Brian Ditchburn for making the necessary   xxxii glassware to perform the reactions, specially the ones needed for the liquid ammonia reactions and Milan Coschizza for keeping impeccable notes on the gloveboxes, so that problems could be fixed in a timely fashion. Finally, I would not be where I am today without the support of my family and my boyfriend Jason W. Brandt. Special thanks are owed to my parents, in special my dad Lui Pak Kam who has supported me throughout my years of education, both morally and financially. While a Ph.D. degree was not in the original plans, I hope my mom Perng Shwu Yuh Lui (who passed away years ago, but is always, and will forever be, in my heart) is proud of my achievements.     xxxiii Dedication I dedicate this thesis to my parents and my boyfriend Jason.   1 Chapter 1: Introduction Nitrogen-containing compounds play an important role in many aspects of biological and industrial processes (Scheme 1.1). Not only are they found in all living organisms, such as the nucleotides and amino acids, but they are also found in a wide variety of pharmaceutical and agrochemical agents. For example, 84% of unique small-molecules approved by the U.S. Food and Drug Administration (FDA) by 2014 were N-containing drugs.1 Furthermore, 90% of heterocycles synthesized by medicinal chemists contains a nitrogen molecule.2 It is therefore not surprising that continuous research towards more efficient methods of incorporating nitrogen have been reported throughout the years.  Scheme 1.1 Importance of Nitrogen-Containing Compounds In medicinal chemistry, N-substitution or N-arylation of alkyl-/aryl-halides and reductive amination remain preferred methods for the construction of C-N bonds.2 Extensive air and moisture exclusion are usually not necessary for N-substitution or reductive amination reactions and thus the reaction set-up is typically straightforward. However, all three methodologies suffer from the production of by-products and/or stoichiometric amounts of waste.  One of the major drawbacks of the substitution reaction is over-alkylation, which delivers complex reaction mixtures of primary, secondary and tertiary amines as well as quaternary ammonium salts. On the other hand, while the condensation of carbonyl functional groups with Nucleotides: DNA building blocks Amino Acids: protein building blocksBiological Importance Industrial ImportanceNNNNNH2OOHOPHOOOAdenineNH2R OHOPharmaceutical agents Agrochemical agentsNH2OHOIIOIIHOLevothyroxineHNPOOHOHOHOGlyphosate  2 amines could deliver similar products selectively, reductive aminations often involve the use of stoichiometric hydride sources, consequently forming stoichiometric amounts of waste. Furthermore, carbonyl-containing compounds are usually derived from feedstock chemicals, such as alkenes and alkynes. Thus several steps are required to access target amine products.  1.1 Efforts Towards Sustainable Chemistry 1.1.1 Catalysis In efforts to develop more selective and efficient C-N bond formation protocols, extensive advances in transition metal catalysis have been achieved. Palladium-catalyzed C-N cross coupling, for example, has emerged as a powerful tool for the synthesis of aryl amines.3 While exceptionally efficient catalytic conditions have been developed, due to the requirement of a halogen or pseudo-halogen starting materials, the reaction inherently produces stoichiometric amounts of waste.  On the other hand, hydrofunctionalization reactions are atom economical. The direct addition of an N-H bond from an amine across an unsaturated C-C bond, also known as hydroamination, is among the various synthetic approaches developed in the past two decades to minimize waste production (Scheme 1.2).4-5   Scheme 1.2 General Alkene and Alkyne Hydroamination Reactions  Although the intermolecular hydroamination of alkenes deliver amines directly, its substrate scope remains a significant challenge, even with the recent contribution from the R2NHR1R3 R3NR2R1NR2R1R3R2NHR1R3NR2R1NR2R1R3R3Markovnikovproductanti-MarkovnikovproductCatalystCatalyst  3 Knowles research group. Knowles and co-workers reported an intermolecular hydroamination of unactivated alkenes with secondary alkylamines, which delivered 50 examples of tertiary amines with a variety of different substitutents.6 The transformation was accomplished using an iridium catalyst and a thiol additive, under a blue LED light. Mechanistically, the authors propose that an aminium radical cation intermediate is formed via an electron transfer between an excited state photocatalyst and an amine substrate, which then undergoes a C-N bond formation and quenching of the radical to deliver the desired products.6 Alternatively, the intermolecular hydroamination of alkynes has been well developed and a wide range of amines and alkynes can be employed.4-5, 7-9 To date, some highly selective catalysts deliver either the Markovnikov or the anti-Markovnikov product from terminal alkynes. Likewise, the reaction with internal alkynes has also been well studied, although few catalysts are able to perform the intermolecular hydroamination of unsymmetrical alkynes selectively. For the intermolecular hydroamination of alkynes, depending on the starting materials used, the imine/enamine products formed could be moisture sensitive. Thus, instead of a traditional stepwise synthetic approach, the reactions are commonly incorporated into sequential transformations, as well as one-pot methodologies. 1.1.2 Cascade, Domino, Sequential and Tandem Reactions The development of methodologies that elaborate simple precursors into more complex structures in more than one step is highly desirable due to the minimization of waste produced by the absence of work-up/purification between various steps.10-11 While terminology is not used uniformly, there are four major terms used in literature: cascade, domino, sequential and tandem transformations.12-15 In all cases, the process involves two or more bond-forming events and the   4 subsequent reactions can only transpire as a consequence of the functionality formed in the preceding steps.  In cascade/domino and tandem transformations all the reagents or catalysts required are added at the onset of the reaction. Meanwhile, in sequential transformations, addition of other reagents or catalysts is usually necessary for the latter reactions to occur. The intermediates in cascade/domino transformations are generally not isolable, which is in contrast with the products formed in the first step of the tandem or sequential reactions. In fact, in the development of sequential reactions, the individual reactions are usually established separately and then attempted in a sequential fashion.12-15 Among the reactions commonly performed after an intermolecular hydroamination of alkynes are reductions to form higher molecular amines and cyclizations to form N-heterocycles. 1.2 Sequential Reactions Involving Catalytic Intermolecular Hydroamination of Alkynes Towards the Synthesis of Nitrogen-Containing Small Molecules and Heterocycles Reactions using alkoxyamines, amides, carbonates, hydrazine, sulfonamides, and ureas, as well as formal hydroamination reactions, where the nitrogen and hydrogen source comes from different starting materials, will not be discussed in this chapter. The hydroamination of highly activated substrates that could occur through an aza-Michael reaction will also not be included. In the case of intermolecular hydroamination of alkynes, two potential regioisomers are possible, Markovnikov and anti-Markovnikov. The regioselectivity of the reaction is highly dependent on the catalyst as well as the starting materials used. While no regioisomeric ratios will be provided in this section, a single isomer will be drawn for highly selective reactions, while both isomers will be shown for reactions providing a mixture of products. In this section, "Alkx" will be used as an abbreviation for alkyl substituents, while "Arx" will be used as an   5 abbreviation for aryl substituents. In cases where more than one functional group is represented, “Rx” will be used as the abbreviation. 1.2.1 Amine Synthesis The use of intermolecular alkyne hydroamination for the synthesis of secondary amines has been well established, with procedures that deliver high yields and great selectivity.4-5, 7-9 In contrast, the synthesis of primary and tertiary amines has not been studied as extensively due to the limited number of catalysts that are able to catalyzed the hydroamination of alkynes using ammonia or secondary amines. While some sequential hydroamination/reduction reactions implemented stoichiometric amounts of reductant,16-56 in the past decade, groups have shifted their focus to the employment of catalytic reduction routes, such as metal-catalyzed hydrogenation using H2,18, 24, 35-36, 57-61 frustrated Lewis pair hydrogenation,62 and more recently transfer hydrogenation.63 Other nucleophiles, such as organolithium reagents,64-65 trimethylsilyl cyanide,66-67 and metal-acetylides,68-71 have also been added to the hydroamination intermediate products to access more complex amine products. 1.2.1.1 Using Stoichiometric Reductants The ease of using stoichiometric hydride sources to reduce imine/enamine hydroamination intermediates products allowed for the easy isolation of a variety of amines (Scheme 1.3).  Scheme 1.3 General Sequential Hydroamination/Addition of Hydride Reactions Toward the Synthesis of Amines R1R2 R3NH R1R2i) Hydroaminationii) Stoichiometric [H-]R1NR2Nand/orR4R4R4R3 R3  6 In 1999, Doye and co-workers reported the intermolecular hydroamination of diphenylacetylene, which was catalyzed by dimethyltitanocene, followed by reduction with lithium aluminum hydride to synthesize 4 examples of secondary amines (Scheme 1.4).16 A wide variety of 2-arylethylamines were synthesized regioselectively using dimethyltitanocene-catalyzed hydroamination of unsymmetrical aryl/alkyl alkynes. The yields of the secondary amines after reduction using sodium cyano-borohydride varied from 19-87%.17  Scheme 1.4 Doye (1999) – Dimethyltitanocene-Catalyzed Hydroamination Reaction Toward the Synthesis of Secondary Amines A follow-up paper explored the reaction using microwave technology, which significantly reduced the reaction times for the dimethyltitanocene-catalyzed hydroamination reaction (Scheme 1.5).18 In this case, while internal alkynes delivered a single product in moderate to good yields, terminal alkynes delivered a mixture of Markovnikov and anti-Markovnikov products.   Scheme 1.5 Doye (2001) – Microwave-Assisted Dimethyltitanocene-Catalyzed Hydroamination Reaction Toward the Synthesis of Secondary Amines  Heutling and Doye also showed that the hydroamination reaction of internal alkynes and amines was possible with a derivative of dimethyltitanocene, dipentamethylcyclopentadienyl PhHNPh4 examples3-68%PhPh R NH2i) cat. Cp2TiMe2100 °Cii) LiAlH4RR1R2 R3NH2R1 R1HNHN andR3R3i) cat. Cp2TiMe2μWii) NaCNBH35 examples34-87%R2 = HR2 = Alk, ArR1HNR24 examples59-78%R3  7 dimethyl titanium (Scheme 1.6).19 Unfortunately, in the case of unsymmetrical aryl/alkyl alkynes, a mixture of regioisomers was obtained.  Scheme 1.6 Doye (2002) – Titanium-Catalyzed Hydroamination Reaction Toward the Synthesis of Secondary Amines  A variety of titanium-catalysts were used to study two hydroamination reactions (Scheme 1.7).20 Sequence A focused on the reaction between diphenylacetylene and tert-butyl amine, while sequence B focused on the reaction with hex-3-yne. In all cases, the reactivity of the catalyst for one sequence was opposite as that for the other sequence. For example, in the case of dimethyltitanocene, 81% yield was obtained for sequence A, while only 38% was obtained for sequence B. On the other hand, tetrakis(dimethylamido)titanium did not react in sequence A, while 92% yield was obtained for sequence B. R1R2 R3NH2Ph PhHNHN andR3R3i) cat. Cp*2TiMe2114 °Cii) NaCNBH34 examples82-95%R1 = PhR2 = MeR1 = R2 R1HNR17 examples78-97%R3Me Me  8  Scheme 1.7 Doye (2002) – Fifteen Titanium Catalysts Studied for the Hydroamination Reaction Toward the Synthesis of Secondary Amines  Instead of the traditional boron and aluminium-based reductants, Doye also reported that phenylsilane could be used to reduce hydroamination products by hydrosilylation (Scheme 1.8).21  R1R1 R2NH2 R1i) 5 mol% [Ti]105 °Cii) NaCNBH3 R1HNR2Sequence A: R1 = Ph, R2 = tBuSequence B: R1 = Et, R2 = 4-Me(C6H4)Ti MeMeTi MeMeEtEtTi MeMeiPriPrTi MeMetButBuTi MeMeTi NMe2NMe2Me2SiNtBuTi NMe2NMe2Me2SiNPhTi MeMeNPh3P TiNtBupyClTi NtBupySequence A: 81%Sequence B: 38%Ti MeMeTiNMe2NMe2NMe2Me2NSequence A: 87%Sequence B: 30%Sequence A: 91%Sequence B: 29%Sequence A: 93%Sequence B: 20%Sequence A: 96%Sequence B: 9%Sequence A: 84%Sequence B: 59%Sequence A: 55%Sequence B: 17%Sequence A: 62%Sequence B: 15%Ti MeMeMeMeSequence A: 90%Sequence B: 4%Sequence A: 84%Sequence B: 15%Sequence A: 46%Sequence B: 93%Sequence A: 98%Sequence B: 43%Sequence A: -%Sequence B: 92%  9  Scheme 1.8 Doye (2005) – Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines Odom and co-workers published a single example of a Markovnikov selective hydroamination of hex-1-yne and p-toluidine, which was reduced with lithium aluminum hydride to afford the desired secondary amine in 82% yield (Scheme 1.9).22  Scheme 1.9 Odom (2001) – Titanium Pyrrolyl Complex-Catalyzed Hydroamination Reaction Towards the Synthesis of a Secondary Amine Up until the early 2000’s, all of the catalysts reported for the sequential intermolecular hydroamination reactions of alkynes followed by stoichiometric reduction of the imine intermediates were titanium based. However, in 2002, Yamamoto and co-workers reported an example of a palladium-catalyzed hydroamination reaction of dodec-6-yne and ortho-aminophenol, which delivered the reduced product in 62% yield (Scheme 1.10).23  R1R2 R3NH2R1 R1HNHN andR3R3Sequence BR2 = H, MeSequence AR1 = R2R1HNR2R3R2R2i) 10 mol% [Ti]105 °Cii) PhSiH340 mol% piperidine40 mol% MeOH105 °CTi MeMeTi NMe2NMe2Me2SiNtBuSequence A:2 examples31-33%Sequence B:15 examples6-88%Sequence B:3 examples44-99%nBuH MenBu82%i) 2 mol% [Ti]75 °Cii) LiAlH4ΔHNH2NTiNMe2NMe2N NNMe  10  Scheme 1.10 Yamamoto (2002) – Palladium-Catalyzed Hydroamination Reaction Towards the Synthesis of a Secondary Amine A follow-up publication demonstrated that by changing the palladium source to [Pd(dppe)(H2O)2](OTf)2, they were able to perform the reaction using diphenylacetylene and aniline to deliver 48% of the desired secondary amine.24 In both cases, oxygen or water exclusion were not necessary due to the stability of the palladium catalysts, which was in great contrast to the early transition metal work. In 2003, Schafer and co-workers reported an bis(amidate)bis(amido)titanium catalyzed anti-Markovnikov hydroamination of terminal alkyl-alkynes followed by lithium aluminium hydride reduction to deliver 8 examples of linear secondary amines in 72-95% yields (Scheme 1.11).25 In follow-up publications, the substrate scope was increased to include terminal aryl-alkynes as well as symmetrical and unsymmetrical internal alkynes.26-27 The Schafer group also showed that by changing the phenyl group on the amide ligand to a penta-fluorophenyl group, the Markovnikov and anti-Markovnikov selectivity ratios change according to the different substrates used.28  Scheme 1.11 Schafer (2003) – Bis(amidate)bis(amido)titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Linear Secondary Amines PentnnPentNH2i) 15 mol% Pd(NO3)2120 °Cii) NaBH3CN35-50 °C62%PentnnPentNHOHOHAlk1HN8 examples72-95%Alk1HAlk2 NH2i) 5 mol% [Ti]65 °Cii) LiAlH4 Alk2Ar = 2,6-diisopropylphenylTiNONOPhPh ArArNEt2NEt2  11  Using an aryloxotitanium complex, a Markovnikov regioselective hydroamination of terminal alkynes was reported by Beller and co-workers (Scheme 1.12).29 Upon reduction of the reaction mixture using sodium cyano-borohydride, 21 examples of the desired secondary amine were obtained.  Scheme 1.12 Beller (2003) – Ayloxotitanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  Evolving from the dimethyltitanocene work, three separate publications were reported by Doye and co-workers on the diindenyldimethyltitanium-catalyzed hydroamination of alkynes (Scheme 1.13).30-32 Unfortunately, the reaction was not regioselective when unsymmetrical aryl/alkyl alkynes and terminal alkynes were used as substrates. Notably, methyl- and ethyl-amine gases were successfully employed to deliver the respective secondary amines after reduction.32  Scheme 1.13 Doye (2004) – Diindenyldimethyltitanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines R121 examples69-99%R1HR2NH2i) 5 mol% [Ti]100 °Cii) NaCNBH3HN R2TiNMe2OArOArMe2NAr = 2,6-di-tert-butyl-4-methylphenylR1R2 R3NH2 Ph PhHNHN andR3R3i) 5 mol% Ind2TiMe275-105 °Cii) NaCNBH39 examples76-99%R1 = PhR2 = AlkR1 = R2 R1HNR115 examples19-98%R3Alk AlkR2 = H PhPhHNHN andR3R310 examples71-95%  12  The combination of a phosphine-imine iridium complex with sodium tetrakis(3,5-trifluoromethylphenyl)borate was shown to be catalytically active for the Markovniokv intermolecular hydroamination of aryl terminal alkynes with aniline derivatives, which upon hydrosilylation and hydrolysis afforded 8 examples of secondary amines in poor to excellent yields (Scheme 1.14).33  Scheme 1.14 Liu (2007) – Iridium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines It has also been shown that tricarbonylchromium-bound iridacycles can be used as the catalyst for a one-pot tandem hydroamination/hydrosilylation transformation, as reported by the Djukic group (Scheme 1.15).34  Scheme 1.15 Djukic (2012) – Tricarbonylchromium-Bound Iridium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines The Esteruelas group has focused their study on the intermolecular hydroamination of alkynes catalyzed by a variety of half-sandwich alkyl-titanium complexes (Scheme 1.16).35-36 The selectivity that they observe is intrinsically related to the substrates that are used for the reactions. If the amine used is an aromatic amine with ortho-disubstitution, the Markovnikov product is obtained. However, an inversion in the regioselectivity occurs if the amine used is tert-butylamine. Furthermore, using cyclohexylamine leads to a mixture of the two regioisomers. Ar1HAr2 NH2Ar1i) 1 mol% [Ir]10.5 mol% NaBAr4FΔii) Et3SiHiii) H2OHN Ar28 examples12-96%PNIrClHCOPhPhArH Ph NH2Ari) Et3SiH 1 mol% [Ir]r.t.ii) H2OHN Ph5 examples50-90%NIrClCr(CO)3  13  Scheme 1.16 Esteruelas (2006, 2007) – Half-Sandwich Alkyl Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  Doye and co-workers also studied similar complexes to that reported by Esteruelas and co-workers. In their case, the titanium complexes featured the common constrained geometry ligand [η5-(C5H4)-SiMe2-NtBu]2- together with two X ligands (Scheme 1.17).37 Similarly to other Doye hydroamination systems, the reaction with unsymmetrical aryl/alkyl and terminal alkynes leads to a mixture of Markovnikov and anti-Markovnikov products. AlkH R NH2 AlkHN tBui) 5 mol% [Ti]100 °Cii) NaCNBH3quantitativeR = tBuR = 2,6-ArAlkquantitativeHR = Cy AlkAlkHNHN andCyCyquantitativeHN RM PPhPhMe MeMe OMMe MeMe M MeMe MeMeNMMe MeMeMeMe M MeMe MeMMe MeMe  14  Scheme 1.17 Doye (2008) – Neutral Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines Other half-sandwich titanium complexes containing Cp* and 2-aminopyrrolinato ligands were also reported by Gade and co-workers (Scheme 1.18).38 Not surprisingly, their reactions were also not selective when it came to unsymmetrical aryl/alkyl and terminal alkynes. R1R2 R3NH2 Ph PhHNHN andR3R3i) 5 mol% Ind2TiMe2105 °Cii) NaCNBH3Sequence BR1 = PhR2 = MeSequence AR1, R2 = PhPhHNPhR3Me MeSequence CR1 = nHexR2 = HPhPhHNHN andR3R3Ti NMe2NMe2NMe2SitBuTi MeMeNMe2SitBuSequence A:6 examples11-92%Sequence B:R3 = p-Tol91%Sequence C:5 examples31-92%Ti ClClNMe2SitBuSequence A:6 examples58-94%Sequence B:R3 = p-Tol96%Sequence C:5 examples42-99%Sequence A:R3 = nC8H1719%Sequence B:R3 = p-Tol93%Sequence C:5 examples45-90%  15  Scheme 1.18 Gade (2009) – Half-Sandwich Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines Beller and co-workers were able to perform the intermolecular hydroamination of terminal alkynes and aniline derivatives using zinc triflate as the catalyst to afford 16 examples of α-methylated amines in 51-98% yields (Scheme 1.19).39  Scheme 1.19 Beller (2008) – Zinc Triflate-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  A triazole-gold complex was shown by the Shi group to be catalytically active for the hydroamination of alkynes (Scheme 1.20).40 While a mixture of products was obtained with the R1R2 R3NH2 Ph PhHNHN andR3R3i) 5 mol% [Ti]105 °Cii) NaCNBH3Sequence BR1 = PhR2 = MeSequence AR1 = R2R1HNR1R3Me MeSequence CR1 = PhR2 = HPhPhHNHN andR3R3TiMeNNMe TiNH2NNN TiNN NMeMeMeTiNN NiPriPrTiNN NMeMeTiNNNNSequence A:7 examples5-96%Sequence B:4 examples11-92%Sequence C:4 examples5-94%Sequence A:7 examples5-96%Sequence B:4 examples11-99%Sequence C:4 examples5-93%Sequence CR3 = 2,4,6-trimethylphenyl80%Sequence CR3 = 2,6-diisopropyllphenyl4%Sequence CR3 = 2,6-dimethylphenyl86%Sequence CR3 = 4,-methylphenyl94%R1HArH2NR116 examples51-98%i) 5 mol% Zn(OTf)2120 °Cii) NaCNBH3HN Ar  16 use of unsymmetrical aryl/alkyl alkynes, the reactions with terminal alkynes were selective for the Markovnikov product.  Scheme 1.20 Shi (2009) – Gold-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  While titanium complexes have been widely studied for the intermolecular hydroamination of alkynes, zirconium-complexes have not received as much attention, although they have been shown to be catalytically active for the hydroamination reaction if sterically demanding amines are used. In 2009, Schafer and co-workers reported a tethered bis(ureate)tris(dimethylamido)zirconium species that was competent for the hydroamination of terminal alkynes using secondary amines to deliver linear tertiary amines after reduction with sodium cyano-borohydride (Scheme 1.21).41 This was the first neutral group 4 example to show significant reactivity towards secondary amines for the intermolecular hydroamination of alkynes, this would only be possible with a change in mechanism. The authors proposed that the reaction does not go through an imido species followed by a [2+2] cycloddition, but through a nucleophilic attack of the bound secondary amido ligand to a coordinated alkyne substrate. R1R2 R3NH2 Ph PhHNHN andR3R3i) 0.1-10 mol%80 °Cii) BH37 examples85-93%R1 = PhR2 = AlkR1 = R2 R1HNR14 examples83-86%R3Alk AlkR2 = H PhHN R311 examples81-98%N Au PPh3NN  17  Scheme 1.21 Schafer (2009) – Bis(ureate)tris(dimethylamido)Zirconium-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines  In 2015, Yao and co-workers disclosed a cationic zirconium-complex that was competent for the hydroamination of alkynes using secondary amines (Scheme 1.22).42 In their case however, the reaction delivered the Markovnikov product selectively for terminal alkynes. A follow up report by the same authors showed that similar cationic zirconium-complexes also work with primary amines.43  Scheme 1.22 Yao (2015) – Cationic Zirconium-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines  Complementary to the zirconium publications, Stradiotto and co-workers reported a gold catalyst competent for the hydroamination of internal alkynes using secondary amines to deliver 20 examples of tertiary amines in good to excellent yields (Scheme 1.23).44  Scheme 1.23 Stradiotto (2010) – Gold-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines PhH R NH PhAlk4 examples68-82%N AlkRi) 10 mol% [Zr]110 °Cii) NaCNBH3ZrONONNMe2NMe2NMe22iPrN2iPrNR2NHR3R1Hi) 10 mol% [Zr]10 mol% [Ph3C][B(C6F5)4]110 °Cii) LiAlH4R1N R3R221 examples51-93%BnZrOBnNtButBuO tButBuPhPhR1PhNH20 examples72-93%i) 5 mol% [Au]5 mol% AgB(C6F5)4110 °Cii) NaB(OAc3)Hor LiAlH4N R2R1NOP AuAdAd ClR2Ph  18 Robbins and Hartwig demonstrated two examples of Markovnikov selective intermolecular hydroamination of terminal alkynes using copper chloride as the catalyst (Scheme 1.24).45 Moderate yields of the final secondary amine products were obtained by reducing the hydroamination reaction mixture with sodium cyanoborohydride.  Scheme 1.24 Hartwig (2011) – Copper-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines Copper-catalysis was also demonstrated to be successful for the synthesis of tertiary amines (Scheme 1.25).46 Monnier and co-workers reported using copper cyanide as the catalyst for the hydroamination of terminal alkynes with secondary amines, followed by reduction with sodium cyanoborohydride to deliver 21 examples of tertiary amines in 64-90% yields.   Scheme 1.25 Monnier (2015) – Copper-Catalyzed Hydroamination Reaction Towards the Synthesis of Tertiary Amines Furthermore, Kawatsura and co-workers reported a methodology towards the synthesis of β-trifluoromethyl substituted secondary and tertiary amines using catalytic amounts of copper triflate (Scheme 1.26).47 The hydroamination reaction with aryl and trifluoromethyl substituted internal alkynes was accomplished with 10 mol% copper triflate, while the reduction was performed with sodium cyanoborohydride to afford 33 examples of secondary and 3 examples of tertiary amines if moderate to excellent yields. R2 examples55-68%RHNH2i) 25 mol% CuCl100 °Cii) NaCNBH3nBuHNnBuR2NHR3R1Hi) 15 mol% CuCN120 °Cii) NaCNBH3R1N R3R221 examples64-90%  19  Scheme 1.26 Kawatsura (2016) – Copper-Catalyzed Hydroamination Reaction Towards the Synthesis of β-Trifluoromethyl Substituted Secondary Amines In 2012, Born and Doye reported a zirconium-catalyzed intermolecular hydroamination (Scheme 1.27).48 The catalyst used was generated in situ from the combination of tetrakis(dimethylamido)zirconium and a sulfonamide ligand. The type of sulfonamide ligand significantly influenced the regioselectivity of the reactions using unsymmetrical aryl/alkyl and terminal alkynes.  Ar133 examples43-98%Ar1CF3i) 10 mol% Cu(OTf)24Å MS40 °Cii) NaCNBH3HN Ar2Ar2 NH2 CF3  20  Scheme 1.27 Doye (2012) – Zirconium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  The readily available [Cp*RhCl2]2 was shown to be a good catalyst for the Markovnikov hydroamination of terminal aryl-alkynes and aniline derivatives, delivering 20 examples of the reduced product in yields of 55-83% (Scheme 1.28).49 Experimental and computational evidence led to the proposal of a reaction pathway involving cationic intermediates. R1R2 R3NH2 Ph PhHNHN andR3R3i) 5 mol% Zr(NMe2)410 mol% sulfonamide130 °Cii) NaCNBH3Sequence BR1 = PhR2 = MeSequence AR1, R2 = PhPhHNPhR3Me MeSequence CR1 = PhR2 = HPhPhHNHN andR3R3N SHOON SHOON SHOON SHnC6H13OOMeSequence A:4 examples<1-46%Sequence B:2 examples<1%Sequence C:2 examples41-45%Sequence A:4 examples68-93%Sequence B:2 examples46-65%Sequence C:2 examples28-55%Sequence A:3 examples26-70%Sequence B:2 examples<1-48%Sequence A:3 examples65-81%Sequence B:2 examples19-23%Sequence A:3 examples<1-55%Sequence B:2 examples<1-37%no sufonamideN SHOOMeOSequence A:3 examples10-55%Sequence B:2 examples7-33%N SHOOCF3Sequence A:R3 = p-Tol90%N SHOOOMeSequence A:R3 = p-Tol82%  21  Scheme 1.28 Leong (2012) – Rhodium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  Using gallium trichloride as the catalyst allowed for the synthesis of Markovnikov products using both, primary and secondary amines as substrates (Scheme 1.29).50 In their system, however, trace amounts of the anti-Markovnikov products were also observed by GC-MS for some of the substrates attempted.  Scheme 1.29 Li (2012) – Gallium Trichloride Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary and Tertiary Amines  Similarly, indium tribromide was also shown to perform the intermolecular hydroamination of alkynes with primary and secondary amines (Scheme 1.30).51 Upon hydrosilylation, secondary and tertiary amines were synthesized in 38-99% yields. Ar1HAr2H2NAr120 examples55-83%i) 0.5 mol% [Cp*RhCl2]21.5 mol% NH4PF480 °Cii) NaBH4HN Ar2Ar115 examples21-93%i) 10 mol% GaCl360 °Cii) LiAlH460 °CHN Ar2Ph18%N PhMeAr1H R1NHAr1, Ar2 = PhR1 = MeR1 = HAr2  22  Scheme 1.30 Sakai (2014) – Indium Tribromide Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary and Tertiary Amines  Moving away from titanium complexes containing a cyclopentadienyl group, Doye and co-workers reported an (aminopyrimidinato)titanium catalyst that delivered high anti-Markovnikov regioselectivity for unsymmetrical aryl/alkyl and terminal alkynes (Scheme 1.31).52 They also reported an (aminopyridinato)titanium catalyst that was competent for the intermolecular hydroamination of alkynes and amines, although the selectivity of the reaction was highly dependent on the substrates used.53  Scheme 1.31 Doye (2013) – (Aminopyridiminato)Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  Similar titanium complexes containing amino-heteroaromatic ancillary ligands were reported by the Doye group and others. Liu and co-workers, for example, reported a couple of R1i) 10 mol% InBr3Δii) PhMe2SiH60 °CHN Ar19 examples38-99%R2PhN R22 examples52-63%R1R1R2 R3NHR1 = PhR2 = HR3 = ArR4 = HR4R1R2 R3NH2 Ph PhHNHN andR3R3i) 5 mol% 50-120 °Cii) NaCNBH310 examples59-97%R1 = PhR2 = MeR1 = R2 R1HNR13 examples61-95%R3Me MeR2 = HR3 = p-TolPhPhHNHN andp-Tolp-Tol7 examples71-95%TiNMe2NMe2NNNtBuNNNtBu  23 imidazo[1,5-a]pyridine-containing pyrrolyl titanium complexes that were competent for the hydroamination of alkyl-alkynes and aniline derivatives (Scheme 1.32).54 While the Markovnikov selectivity was favoured, the majority of reactions attempted delivered mixtures of two products.   Scheme 1.32 Liu (2015) – Imidazo[1,5-a]pyridine-Containing Pyrrolyl Titanium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  In 2013, Cao and co-workers reported an N-heterocyclic carbene-palladium complex that was selective for the Markovnikov regioisomer (Scheme 1.33).55 While their reaction was limited to aromatic terminal alkynes and aromatic amines, the catalyst used could be recovered through precipitation using diethyl ether and re-used 3 times without loss of reactivity.  Scheme 1.33 Cao (2013) – (N-Heterocyclic Carbene)Palladium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines Commercially available gold nanoparticles supported on titanium oxide was also found to be a recyclable and efficient catalyst for the Markovnikov intermolecular hydroamination of terminal alkynes and aniline derivatives (Scheme 1.34).56 Filtration and washing of the Au/TiO2 with toluene allowed for the catalyst to be reused 5 times with no loss of catalytic activity. AlkH Ar NH2Alk AlkHNHN andArAri) 10 mol% [Ti]120 °Cii) LiAlH4TiNMe2NMe2NNNNNN13 examples22-93%Ar1HNH2Ar2Ar115 examples54-89%i) 0.5- 2 mol% [Pd]1-4 mol% AgOTf100 °Cii) LiAlH4HN Ar2 NPdNBr BrNNNNtButBu  24  Scheme 1.34 Hammond (2016) – Gold Nanoparticles Supported on Tititanium Oxide Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines 1.2.1.2 Using Catalytic Hydrogenation It is undeniable that reduction using hydrogen (H2) gas is the ideal scenario for a truly catalytic and atom-economical synthesis of amines using sequential hydroamination/reduction reactions (Scheme 1.35). Thus, it is not surprising that such approaches have been successfully carried out with both homogeneous and heterogeneous catalyts.   Scheme 1.35 General Sequential Hydroamination/Hydrogenation Reactions Toward the Synthesis of Amines  Notably, the development of methodologies towards the synthesis of primary amines using hydroamination has been limited. To date, only two approaches have been previously explored.57, 72 The first approach, reported by Doye and co-workers, makes use of a titanium-catalyzed hydroamination reaction of alkynes and diphenylmethanamine.57 Upon exposure of the hydroamination product to palladium on carbon (Pd/C) and H2 gas, the imine/enamine double bond was reduced and the C-N bond of diphenylmethanamine underwent hydrogenolysis to deliver 7 examples of the desired primary amines (Scheme 1.36). They also showed a few examples of secondary amines being synthesized using the same hydroamination followed by Pd/C hydrogenation.18 R16 examples77-93%RHi) 0.2 mol% Au/TiO20.1 mol%H3PO4・12 WO380 °Cii) NaBH(OAc)3HN ArAr NH2R1R2 R3NH R1R2i) Hydroaminationii) H2R1NR2Nand/orR4R4R4R3 R3  25  Scheme 1.36 Doye (2000) – Dimethyltitanocene-Catalyzed Hydroamination Reaction Toward the Synthesis of Primary Amines  The second, more challenging, approach was reported by Bertrand and co-workers, in which gaseous ammonia was used as their nitrogen source.72 Although no primary amines were isolated, they report the formation of H-substituted imines, which in theory could be hydrogenated using H2 gas to afford a 100% atom-economical and catalytic synthesis of primary amines from ammonia feedstocks.  Platinum dioxide has also been show to be a good hydrogenation catalyst for the synthesis of secondary amines as reported by Esteruelas and co-workers (Scheme 1.37).35-36, 58-59  Scheme 1.37 Esteruelas (2005, 2006, 2007) – Half-Sandwich Alkyl Titanium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines  In 2012, Beller and co-workers reported an enantioselective synthesis of secondary amines through a sequential hydroamination/hydrogenation reaction (Scheme 1.38).60 The Markovnikov selectivity for the hydroamination reaction was obtained using a gold-phosphine R1R2Ph NH2PhR1NH2R27 examples16-79%i) 3 mol% Cp2TiMe2110-120 °Cii) 1.5-5 mol% Pd/C1 atm H2PhHNR1PhR1 R2NH2i) 3 mol% [Ti]100 °Cii) 3 atm H23 mol% PtO2R2M PPhPhMe MeMeMMeMe MeMMeMe MeM NMeMeMe MeMe M O MeMe MeMeOMMe MeMe MeNMMe MeMe MeMe12 examplesquantitative10 examplesquantitative24 examplesquantitative10 examplesquantitative10 examplesquantitative10 examplesquantitative10 examplesquantitative  26 complex, and the enantioselectivity of the final product was obtained using an iron-catalyst in addition to (R)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate, (R)-TRIP, under 50 bar of H2 gas.  Scheme 1.38 Beller (2012) – Gold-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Enantioselective Secondary Amines Yamamoto and co-workers demonstrated a single example of a palladium-catalyzed hydroamination of alkynes with N-methylaniline, followed by Pd/C hydrogenation to deliver 45% of the desired tertiary amine (Scheme 1.39).24  Scheme 1.39 Yamamoto (2005) – Palladium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Tertiary Amines Beller and co-workers were able to perform the intermolecular hydroamination and the hydrogenation reactions using zinc triflate as the catalyst for both transformations.61 At catalytic loadings of 5 to 10 mol% of zinc, under 80 bar of hydrogen gas, 17 examples of α-methylated secondary amines were synthesized in 34-91% yields (Scheme 1.40). A single example was also reported for the synthesis of N-methyl-N-(1-phenylethyl)aniline, which was accomplished in 69% yield. R117 examples71-96%67-94% eeR1HR2NH2i) 1 mol% [Au]r.t.ii) 50 bar H25 mol%2 mol% (R)-TRIPHN R2BF4P AutButBu+FeOC HCOOHTMSTMSPhPh Ph NHi) 10 mol%[Pd(dppe)(H2O)2](OTf)280 °Cii) 1 atm H2Pd/C45%Ph PhNPh  27  Scheme 1.40 Beller (2008) – Zinc Triflate-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines  Frustrated-Lewis pair (FLP) chemistry with B(C6F5)3 was reported to be catalytically active for the intermolecular hydroamination of aryl terminal alkynes and secondary amines to afford Markovnikov selective products (Scheme 1.41).62 Interestingly, the FLP-catalyst is also capable of performing the hydrogenation step when the reaction solution it is exposed to 4 atm of H2 gas.  Scheme 1.41 Stephan (2013) – Frustrate-Lewis Pair-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Tertiary Amines 1.2.1.3 Using Transfer Hydrogenation To date, only one example of transfer hydrogenation has been applied to the sequential hydroamination of alkyne/reduction to synthesize amines (Scheme 1.42).63 Not only were Che and co-workers able to synthesized racemic secondary amines through a tandem gold-catalyzed hydroamination followed by a transfer hydrogenation using Hantzsch ester, they were also able to synthesize highly enantioselective chiral amines by adding (S)-3,3′-bis(2,4,6-triisopropylphenyl)-1,1′-binaphthyl-2,2′-diyl hydrogenphosphate, (S)-TRIP, to the reaction mixture. RHArH2NR17 examples34-91%5-10 mol% Zn(OTf)2120 °C80 bar H2HN ArAr1H Ar2 NHi) 10 mol% B(C6F5)3ii) 4 atm H280 °C2 examples64-77%Ar1NAr2Ar3 Ar3  28  Scheme 1.42 Che (2009) – Gold-Catalyzed Hydroamination Reaction Towards the Synthesis of Enantioselective Secondary Amines 1.2.1.4 Using Nucleophilic Addition Hydrides are not the only nucleophiles that have been used in sequential hydroamination/reduction reactions. Other carbon- or nitrogen-nucleophiles have also been added to give α-substituted amines (Scheme 1.43).   Scheme 1.43 General Sequential Hydroamination/Addition of Nucleophile Reactions Toward the Synthesis of Amines   The first rhodium-catalyzed intermolecular hydroamination of alkynes was performed with [Rh(cod)2]BF4 and tricyclohexylphosphine (Scheme 1.44).64 Following the Markovnikov selective imine formation, secondary amines were synthesized in a one-pot fashion by the addition of organolithium reagents to the hydroamination product mixtures. Due to the selectivity of the rhodium-catalyst, 5 examples of amines containing α-quaternary centers were synthesized in moderate yields. R10 examples86-95%RH Ar NH22 mol% [Au]2 mol% AgBF460 °C HN Ar P AutButBu ClNHEtOOOEtOR27 examples54-98%83-96 ee%RH Ar NH21-2 mol% [Au]5-10 mol% (S)-TRIP5Å MS, 40 °C HN ArNHEtOOOEtOOTfP AutButBu+R1H R2NH R1 Nuci) Hydroaminationii) Addition of Nuc-R1NNucNand/orR3R3R3R2 R2  29  Scheme 1.44 Beller (2001) – Rhodium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines Containing a α-Quaternary Centre  Beller and co-workers also reported a similar approach to synthesize α-substituted phenethylamines (Scheme 1.45).65 In this case, however, instead of using a rhodium-catalyst in the hydroamination step, Rosenthal’s catalyst was used. Complementary to the previous approach, the change in catalyst led to the formation of anti-Markovnikov products, which upon addition of organolithium reagents delivered 15 examples of amines in 49-78% yields.  Scheme 1.45 Beller (2003) – Titanium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Secondary Amines  Instead of adding organolithium reagents to the hydroamination reaction, Schafer and co-workers showed that trimethylsilyl cyanide could be used as the nucleophilic source (Scheme 1.46).66-67 Since the hydroamination reaction delivers imines, and such intermediates are invoked in the Strecker reaction, by combining these two reactions, a one-pot synthesis of α-cyanoamines was developed. Further transformations could be performed sequentially to afford unsymmetrical vicinal diamines in moderate yields. AlkH Ar NH2 Alki) 1.5 mol% [Rh(cod)2]BF43 mol% PCy3ii) RLi-70 °C to r.t.HN Ar5 examples42-60%RR1H Alk NH2 R1i) 2.5 mol% [Ti] 85 °Cii) R2Li-70 °C to r.t.15 examples49-78%TiSiMe3SiMe3HNR2Alk  30  Scheme 1.46 Schafer (2006, 2009) – Titanium-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of α-Cyanoamines and Vicinal Diamines  Propargylamines can be readily synthesized from a tandem hydroamination and alkyne addition as shown by Li and co-workers (Scheme 1.47).68 Copper bromide was used as the catalyst to perform both the anti-Markovnikov hydroamination reaction as well as the alkyne addition to the formed imine.   Scheme 1.47 Li (2009) – Copper-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Propargylamines  Interestingly, if the reaction is performed under neat conditions and copper triflate was the catalyst used, the Markovnikov imine was formed, thus allowing for the synthesis of quaternary propargyl amines, as shown by Larsen and co-workers (Scheme 1.48).69-70 R1i) 5 mol%  65 °Cii) TMSCN6 examples86%-quantitativeNCNR2TMSR18 examples50-69%HNR2Ar = 2,6-diisopropylphenylTiNONOPhPh ArArNEt2NEt2NH2HOOOOHR1H R2NH2iii) sat. NH4Cliv) LiAlH4v) oxalic acidR1H 5 mol% CuBr100 °C16 examples40-84%4 equiv.R2NHR3N R3R2R1R1  31  Scheme 1.48 Larsen (2013) – Copper-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Propargylamines Containing a Quaternary Centre  Similar products can also be synthesized using a zinc β-diiminate-complex in the presence of a triflate co-catalyst (Scheme 1.49).71   Scheme 1.49 Blechert (2010) –  Zinc-Catalyzed Hydroamination Reaction Towards the Catalytic Synthesis of Propargylamines 1.2.1.5 Conclusion The synthesis of amines through a sequential intermolecular hydroamination of alkynes followed by reduction of the imine/enamine product mixtures has been well established. However, further work is required to increase the scope of primary amines synthesized through this methodology. Currently, in order to obtain good yields of primary amines, the scope is mainly limited to internal alkynes. Although remarkable progress has been made towards the synthesis of secondary amines through sequential hydroamination/reduction transformations, a selective, practical and broad methodology has been underdeveloped. Furthermore, the synthesis of enantiopure amines via the sequential transformations has been limited.  R1HR1 = ArR1 = nBuR3 = HnBu10 mol% Cu(OTf)2110 °CHN R22 examples68-72%nBu2.2 equiv.R2R1NH16 examples60-88%N R3R2R3R1R1HR11-10 mol% [Zn]1-10 mol%[PhNMe2H][OTf]r.t.-80 °CN R37 examples61-87%R1R2NH2.5 equiv.R3R2N NArAr ZnMeAr = 2,6-diisopropylphenyl  32 1.2.2 Heterocycle Synthesis The intermolecular hydroamination of alkynes can also be employed to construct more sophisticated N-containing heterocycles, which includes 5-,73-88 6-,25-26, 89-108 or 7-membered109-110 rings and may contain one or more heteroatoms. 1.2.2.1 Formation of 5-Membered N-Heterocycles 1.2.2.1.1 Pyrrolidine and Pyrrole  Doye and co-workers reported a one-pot methodology for the synthesis of 30 examples of N-substituted-2-(arylmethyl)pyrrolidines through a titanium catalyzed intermolecular hydroamination of alkynes followed by a cyclopropylimine rearrangement and sodium cyano-borohydride reduction (Scheme 1.50).73   Scheme 1.50 Doye (2009) – Sequential Titanium-Catalyzed Hydroamination, Cyclopropylimine Rearrangement and Reduction Reactions Towards the Synthesis of Pyrrolidines Starting from 1,4- and 1,5-diynes, 1,2,5-trisubstituted pyrroles can be accessed via a titanium-catalyzed hydroamination followed by an in situ 5-endo-dig or a 5-exo-dig cyclization (Scheme 1.51).74 Interestingly, the titanium complexes used were chosen depending on the substrates used, for example, if terminal alkynes were present, the tridentate titanium-complex was used, while for internal alkynes, the bidentate titanium-complex was used. ArRH2Ni) 5 mol% Ind2TiMe2105 °Cii) cat. NH4Cl145 °Ciii) NaBH3CNNR30 examples5-95%Ar  33  Scheme 1.51 Odom (2004) – Sequential Double Titanium-Catalyzed Hydroamination Reactions Towards the Synthesis of Pyrroles Pyrroles could also be synthesized in one-pot using (E/Z)-haloenynes (Scheme 1.52).75 In 2009, Ackermann and co-workers reported a regioselective method for the synthesis of mono-substituted pyrroles using 20 mol% of tetrachlorotitanium as the catalyst in the presence of stoichiometric amounts of tert-butylamine. Upon formation of the hydroamination product, an intramolecular nucleophilic substitution occurs to form the pyrrole ring. Fully substituted pyrroles could also be synthesized by the addition of acetyl chloride and excess titanium chloride to the hydroamination reaction mixture to deliver the desired product in 49-81% yields.  Scheme 1.52 Ackermann (2009) – Sequential Titanium-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Pyrroles R2R3H2Ni) 10 mol% [Ti]100 °Cii) 5-endo digcyclizationR1NR3R1R2NTiNMeMeNMe2NMe22 examples35-56%3 examples30-62%R2H2Ni) 10 mol% [Ti]100 °Cii) 5-exo digcyclizationR1NR2R1R1 R1TiNMe2NMe2N NNMeNTiNMeMeNMe2NMe22 examples34-68%1 example90%TiNMe2NMe2N NNMeClR1R2H2N20 mol% TiCl4tBuNH2105 °CNR2R112 examples39-87%R1R3ArH2Ni) 120 mol% TiCl4tBuNH2105 °Cii) AcCl, TiCl40-23 °CNArR39 examples49-81%R2OHR1R2 AcCl  34  The synthesis of 2,3-diaminopyrroles was accomplished from a four-component coupling of 2 equivalents of isonitrile, 1 equivalent of arylamine and 1 equivalent of alkyne using a diindolylbis(dimethylamido)titanium complex (Scheme 1.53).76 The transformation from starting materials to products is proposed to occur through a hydroamination reaction followed by insertion of two isonitriles and finally a nucleophilic attack to form the pyrrole.  Scheme 1.53 Odom (2009) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Cyclization Reactions Towards the Synthesis of Pyrroles By using 1,3-diynes, 2,5-disubstitutedpyrroles could be synthesized using a cationic gold-complex (Scheme 1.54).77 Different substrates demanded different cataysts, for example, 1 mol% of [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold complex was used for the synthesis of 8 examples of 2,5-diaminopyrrole in 90-96% yields, while 5 mol% of (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold hexafluoroantimonate was used for the synthesis of 4 examples of 2,5-disubstituted pyrroles in 24-58% yields. In both cases, product formation occurs through a double hydroamination of the starting materials. R1R2ArH2N5 mol% [Ti]80 °C NArNHtBu11 examples35-82%tBuN R2R1 NHtBuTiMe2NNNMe2N4 equiv.  35  Scheme 1.54 Skrydstrup (2010) – Sequential Gold-Catalyzed Double Hydroamination Reactions Towards the Synthesis of Pyrroles  Liu and co-workers, used the same (acetonitrile)[(2-biphenyl)di-tert-butylphosphine]gold hexafluoroantimonate complex to synthesize 28 examples of pyrroles (Scheme 1.55).78 Starting from an intermolecular hydroamination of alkynes with α-amino ketones, following a cyclization and aromatization events, a variety of di-, tri- and tetra-substituted pyrroles were synthesized in moderate to excellent yields.  Scheme 1.55 Liu (2015) – Sequential Gold-Catalyzed Hydroamination/Cyclization Reaction Towards the Synthesis of Pyrroles Similarly, Corma and co-workers also used a gold-complex to synthesize a single example of a fused cyclobutapyrrolidine compound in 75% yield and greater than 99% diastereoselectivity (Scheme 1.56).79 In this case, hydroamination of two phenylacetylene molecules to p-toluidine formed a bis(enamine) intermediate, which was reacted with dimethylacetylenedicarboxylate to form the final product. NN RTsRTsArH2N NArN1 mol% [Au]30 °CNRTsRTs8 examples90-96%R1R2H2N NR2R1R14 examples24-58%R1SbF6P AutButBu+NCCH3NTf2P AuPhPhPh +5 mol% [Au]80 °CSbF6P AutButBu+NCCH3R1O HNR3 R4R5NR3R1 R5R428 examples40-94%5 mol% [Au]3 equiv. MgO100 °CR2R2  36  Scheme 1.56 Corma (2010) – Sequential Gold-Catalyzed Hydroamination/ Reaction Towards the Synthesis of Cyclobutapyrrolidine 1.2.2.1.2 Indole The intermolecular hydroamination of alkynes and ortho-chloroaniline derivatives was combined with a 5-endo Heck cyclization to afford a variety of indoles regioselectively (Scheme 1.57).80-81 After titanium-catalyzed hydroamination, 10 mol% of palladium acetate and 10 mol% of the N-heterocyclic carbene ligand were added to the reaction mixture to afford 10 examples of indoles in 46-84% yields.80 By changing the ligand for the second step to tricyclohexylphosphine, the scope of the reaction could be improved to allow for further substitution on other positions of the ortho-chloroaniline.81  Scheme 1.57 Ackermann (2008) – Sequential Titanium-Catalyzed Hydroamination/Palladium-Catalyzed Heck Reactions Towards the Synthesis of Indoles The synthesis of N-vinylindoles was performed through a double hydroamination of terminal alkynes with ortho-alkynylanilines to deliver 17 examples of the desired product in varying yields (Scheme 1.58).82 The first hydroamination is an intermolecular reaction between the aniline and the terminal alkyne, while the second hydroamination is an intramolecular reaction between the formed imine and the alkyne. Both reactions are performed in the presence PhH H2Ni) 3 mol% [Au]80 °Cii) aaaaaaaaaaaaa80 °C 75%d.r. >99%MePhCO2Me NPhCO2MeMeO2CPh pTolNTf2P AutButButBu +ClNH2 ArR10 examples46-84%NHArR N NAr ArAr = 2,6-diisopropylphenylCli) 10-20 mol% TiCl4tBuNH2105 °Cii) 10 mol% [Pd]10 mol% LigandKOtBu105 °CNHRArandPd(OAc)2  37 of 5 mol% of gold trichloride and 15 mol% of silver triflate. The Markovnikov regioselectivity is exclusively formed in the first step of the reaction for the majority of cases demonstrated, except in the case where the terminal alkyne used is hex-1-yne.  Scheme 1.58 Li (2007) – Sequential Gold-Catalyzed Double-Hydroamination Reactions Towards the Synthesis of N-Vinylindoles  The hydroamination of methyl 3-phenylpropiolate and p-toluidine was performed with catalytic amounts of [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold complex. The newly formed N-arylenamine was then cyclized to the indole under oxidizing conditions with (diacetoxyiodo)benzene (Scheme 1.59).83  Scheme 1.59 Skrydstrup (2009) – Sequential Gold-Catalyzed Hydroamination/Cyclization Towards the Synthesis of an Indole 1.2.2.2  Formation of 5-Membered N,N- or N,O-Heterocycles 1.2.2.2.1 Pyrazole and Imidazole  Odom and co-workers also reported a four-component synthesis of 17 examples of pyrazoles (Scheme 1.60).84 Through a titanium-catalyzed coupling of 1 equivalent of isonitrile, 1 equivalent of amine and 1 equivalent of alkyne, 1,3-diimines were generated, which underwent an in situ cyclization with hydrazine and derivatives to produce pyrazoles in moderate yields.  NH2R217 examples10-82%NR15 mol% AuCl315 mol% AgOTfr.t.R1R22 equiv.NH2i) 1.5 mol% [Au]60 °Cii) PhI(OAc)260 °C47%MeNHPhMeCO2EtPhCO2EtNTf2P AuPhPhPh +  38  Scheme 1.60 Odom (2009) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Hydrazine Addition Reactions Towards the Synthesis of Pyrazoles Zinc triflate was reported for the catalytic synthesis of 13 examples of imidazoles in moderate to great yields (Scheme 1.61).85 After the zinc-catalyzed intermolecular hydroamination of propargylamides, a cyclization between the formed imine and the amide group occurs, which is followed by a dehydration event to afford the imidazoles. While the majority of examples demonstrated delivers 1,2,5-trisubstituted imidazoles, a single example of a 2,5-disubstituted imidazole was shown using ammonia as the nitrogen source.  Scheme 1.61 Beller (2011) – Sequential Zinc-Catalyzed Hydroamination/Cyclization/Dehydration Reactions Towards the Synthesis of Imidazoles 1.2.2.2.2 Oxazolidine, Oxazole and Others Benzoxazoles can be synthesized from the intermolecular hydroamination of 1,3-diynes and ortho-aminophenol derivatives (Scheme 1.62).86 The reaction mechanism reported by Yamamoto and co-workers starts from a double hydroamination of the diyne, followed by a C-C bond cleavage to form the desired products and ketone by-products. Unfortunately, the transformation reported delivers a mixture of two regioisomers. R1R2R3H2Ni) 10 mol% [Ti]100 °Cii) R4NHNH2Pyridine150 °CNNR4tBu N R2R1 NTiNMeMeNMe2NMe212 examples35-50%5 examples28-38%TiNMe2NMe2N NNMeR2H2N5 mol% Zn(OTf)2140 °C, μWNNR2MeNH R1OR113 examples38-96%  39  Scheme 1.62 Yamamoto (2003) – Sequential Ruthenium-Catalyzed Double Hydroamination/C-C Bond Cleavage Reactions Towards the Synthesis of Benzoxazoles Leyva and Corma demonstrated a single example of an oxazolidine being synthesized through a [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine) gold-complex catalyzed hydroamination of oct-1-yne and 2-aminoethan-1-ol (Scheme 1.63).87 The chemoselectivity of the gold catalyst to perform hydroamination over hydroalkoxylation was crucial for the transformation to deliver a single product after the nucleophilic attack of the hydroxyl group to the newly formed imine.  Scheme 1.63 Corma (2009) – Sequential Gold-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of a Oxazolidine Odom’s four-component strategy could be applied to synthesize 4-substituted isoxazoles from terminal alkynes and 3,4-disubstituted isoxazoles from internal alkynes, albeit the yields were modest (Scheme 1.64).88 The methodology involved a one-pot titanium-catalyzed multicomponent coupling reaction followed by the addition of hydroxylamine. The choice of titanium-catalyst used was dependent on the starting materials used, for example, for all the phenylacetylene derivatives, the tridentate titanium complex was used, while for all the internal alkynes, the bidentate titanium scomplex was used. R2H 1 mol% Ru3(CO)123 mol% NH4PF680 °C14 example58-97%NH2OHR1 R1ONR2 R1ONMeand5H2N OH5 mol% [Au]80 °COHN580%NTf2P AuPhPhPh +  40  Scheme 1.64 Odom (2012) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Hydroxylamine Addition Reactions Towards the Synthesis of Mono- and Di-Substituted Isoxazoles 1.2.2.3 Formation of 6-Membered N-Heterocycles 1.2.2.3.1 Dihydropyridine and Pyridine The strategy of forming 1,3-diimides through intermolecular hydroamination of alkynes followed by iminoamination was also implemented towards the synthesis of 2-amino-3-cyanopyridines in a one-pot procedure in moderate to good yields (Scheme 1.65).89 According to studies performed by the authors, a Dimroth rearrangement occurs upon treatment of the reaction mixture with base and malononitrile to afford a single isomer of the final product and tert-butylamine as a side product.  Scheme 1.65 Odom (2014) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Dimroth Rearrangement Reactions Towards the Synthesis of 2-Amino-3-Cyanopyridines Odom and co-workers also demonstrated an example of a tandem intermolecular hydroamination of 1-ethynylcyclohexene with aniline followed by a C-H activation/insertion and NTiNMeMeNMe2NMe27 examples35-60%3 examples25-35%TiNMe2NMe2N NNMeR1 = PhR2 = AlkR2 = HR1R2R3H2N tBu NNONOR1Ph Alki) 10 mol% [Ti]100 °Cii) NH2OH·HClr.t.-45 °CR1R2R3H2Ni) 10 mol% [Ti]100 °Cii) 2 equiv.0.5 mol% DBU3Å molecular sieves80 °C10 examples35-82%tBu N NR2 NHR1R3N NTiNMeMeNMe2NMe2N N  41 a 6-π electrocyclization to afford a dihydropyridine in 66% yield (Scheme 1.66).90 The authors disclosed that in order for the one-pot reaction to be successful, prior to the addition of Wilkinson’s catalyst, 50 mol% of water had to be added to decompose the titanium catalyst, which was thought to interfere with the second reaction.  Scheme 1.66 Odom (2004) – Sequential Titanium-Catalyzed Hydroamination/C-H Activation/Electrocyclization Reactions Towards the Synthesis of a Dihydropyridine 1.2.2.3.2 Dihydroquinoline, Quinoline, Tetrahydroquinoline, Tetrahydroisoquinoline and Naphthyridine Wakatsuki and co-workers reported that catalytic amounts of triruthenium dodecarbonyl and tetrafluoroboric acid could be used to synthesize 2,4-disubstituted quinolines (Scheme 1.67 – top).91 After the intermolecular hydroamination of alkynes with 2-amino aromatic ketones, a nucleophilic attack on the ketone occurs from the enamine formed, thus forming the bicyclic-core. Upon dehydration, 2 examples of quinolines were synthesized in excellent yields. This transformation has also been shown to be feasible using an NHC-gold complex, which delivered 9 examples of the desired quinoline in moderate to great yields (Scheme 1.67, middle).92 Furthermore, Li and co-workers have demonstrated that silver triflate is also competent towards the synthesis of 2,4,6-trisubstituted quinolines following a similar approach (Scheme 1.67 – bottom).93 In their report, however, aniline was used as a mediator for the reaction to occur. The mechanism proposed by the authors started from the hydroamination of the terminal alkyne with aniline to form a silver enaminyl species. Nucleophilic attack to the ketone functional group, PhH2Ni) 10 mol% [Ti]50 °Cii) 50 mol% H2Oiii) 2 mol% RhCl(PPh3)3150 °C5 equiv.TiNNNMe2NHNMe2NMe266%EtEtNEtPhEtH  42 followed by intramolecular cycloaddition leads to the release of aniline. Finally, aromatization delivered the quinoline product in 55-84% yields. Palladium bromide in the presence of acetic or pivalic acid has also been shown to be a competent catalyst for the synthesis of 2,3,4-trisubstituted quinolines from internal alkynes and 2-amino aromatic ketones.94  Scheme 1.67 Wakatsuki (1999), Che (2007), Li (2011) – Sequential Metal-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Quinolines A similar approach was reported for the synthesis of naphthyridines (Scheme 1.68).95 Peshkov and co-workers used catalytic amounts of copper triflate and stoichiometric amounts of diethylamine to synthesize 13 examples of 1,8-naphthyridines in moderate yields of up to 62%.   Scheme 1.68 Peshkov (2016) – Sequential Copper-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Naphthyridines In 2003, Zhang and Schafer showed the synthesis of a dihydroisoquinoline substrate in 95% yield (Scheme 1.69).25 A hydroamination reaction using a bis(amidate)bis(amido)titanium PhNH22 examples89-99%NRROPhH0.7 mol% Ru3(CO)122.1 mol% HBF4160 °C2 equiv.R2NH29 examples63-94%NR1R1OR2H N NAuClArArAr = 2,6-iPr-C6H25 mol% [Au]/AgOTf15 mol% NH4PF6150 °C, μWOR2NH2R1R3H10 mol% AgOTfPhNH280 °CNR1R2R313 examples55-84%NOHNH2R1R2H5 mol% Cu(OTf)2Et2NH110 °C N NR113 examples22-62%N NR1R2R2  43 catalyst was performed first, followed by the addition of trifluoroacetic acid, which triggered a Pictet-Spengler type reaction to afford the desired product. In a following publication, the substrate scope of the reaction was increased to accommodate aryl alkyne starting materials.26  Scheme 1.69 Schafer (2003) – Sequential Titanium-Catalyzed Hydroamination/Pictet-Spengler Reactions Towards the Synthesis of a Tetrahydroisoquinoline Poly-substituted 1,2-dihydroquinoline derivatives were synthesized in a one-pot domino process in the presence of catalytic amounts of silver tetrafluoroborate, tetrafluoroboric acid and boron trifluoride (Scheme 1.70).96 The transformation occurs through an intermolecular hydroamination, followed by an alkyne addition to the formed imine, intramolecular hydroarylation and then a second intermolecular hydroarylation of a third molecule of alkyne.  Scheme 1.70 Li (2005) – Sequential Silver-Catalyzed Hydroamination/Alkyne Addition/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines A variety of gold-complexes have been used for the tandem hydroamination/alkyne addition/hydroarylation reactions towards the synthesis dihydroquinolines and quinolines (Scheme 1.71).92, 97-98 Che and co-workers showed that in the majority of cases, using aryl amine derivatives and excess terminal alkynes in the presence of catalytic amounts of an NHC-gold complex, a single hydroarylation reaction occurs to deliver 1,2-dihydroquinolines in moderate to 95%C4H9HNH2i) 5 mol% [Ti]65 °Cii) CF3CO2HAr = 2,6-diisopropylphenylTiNONOPhPh ArArNEt2NEt2OMeMeO NHC5H11MeOMeOAr5 mol% AgBF47 mol% HBF48 mol% BF3·Et2O160-190 °C8 example60-88%NH ArArRArNH2R H4 equiv.  44 great yields. However, in 3 examples due to the occurrence of a second hydroarylation reaction, a mixture of products is formed. Additionally, the reaction with a phosphine-based gold complex was also successful using indoline instead of aniline to produce 8 examples of tricyclic N-heterocycles in 58-95% yields. Pentamethylcyclopentadienylrhodium chloride dimer has also been used as a catalyst to synthesize 1,2-dihydroquinolines from terminal alkynes and anilines in yields of 34-89%.99 In the report by Kumaran and Leong, a second intermolecular hydroarylation was not stated.  Scheme 1.71 Che (2007) – Sequential Gold-Catalyzed Hydroamination/Alkyne Addition/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines Catalytic amounts of zinc β-diiminate-complex and N,N-dimethylaniline hydrotrifluoromethyl sulfonate have been identified as a catalyst for the synthesis of 1,2-dihydroquinolines (Scheme 1.72).100  Scheme 1.72 Blechert (2012) – Sequential Zinc-Catalyzed Hydroamination/Alkyne Addition/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines R25 mol% [Au]/AgOTf15 mol% NH4PF6150 °C, μWH5 equiv.16 examples52-89%and/or8 examples58-95%HNR1NH2R1NHR1NHR2R2 R2R2R2RH 5 mol% [Au]/AgSbF6r.tP AutButBu ClNRR5 equiv.N NAuClArArAr = 2,6-iPr-C6H25 mol% [Zn]15 mol%[PhNMe2H][SO3CF3]130 °CR2H3 equiv.18 examples53-98%N NArAr ZnMeAr = 2,6-diisopropylphenylNR2R2MeR1NHR1  45 The scope of 1,2-dihydroquinolines synthesized using a one-pot three-component approach was greatly improved when internal alkynes were reported to be viable starting materials (Scheme 1.73).97 Bertrand and co-workers were able to synthesize 12 examples of 1,2-dihydroquinolines containing a variety of substitutions in 53-83% yield. The reported methodology not only allowed for the use of internal alkynes in the first reaction, but it also allowed for a different alkyne to be used in the second step, thus further increasing the scope of the products synthesized.  Scheme 1.73 Bertrand (2009) – Sequential Gold-Catalyzed Hydroamination/Alkyne Additon/Hydroarylation Reactions Towards the Synthesis of Dihydroquinolines  Patil and co-workers demonstrated that a [bis(trifluoromethanesulfonyl)imidate](triphenylphosphine)gold complex can be used to synthesize fused-tetrahydroquinolines (Scheme 1.74).98 Following the hydroamination reaction, hydroarylation of the ortho-substitutent on the aniline forms the final product.   Scheme 1.74 Patil (2010) – Sequential Gold-Catalyzed Hydroamination/Hydroarylation Reactions Towards the Synthesis of Tetrahydroquinolines NArAuClAr = 2,6-diisopropylphenyl12 examples53-83%R3R4R1NHR1NR5R4R2R2R3i) 5 mol% [Au]5 mol% KB(C6F5)4120 °Cii) aaaaaaaaaa100 °CR5HRR1HNMePhNHRMeR2NHY = IndoleR2NH2HY3 examples90-95%Y = Ar3 examples30-75%R12 mol% 100 °CNTf2P AuPhPhPh +  46  The groups of Verma and Wu disclosed two copper-catalyzed tandem hydroamination/arylation reactions towards the synthesis of multi-fused isoquinolines starting from ortho-bromoarylalkynes and N-heterocyles, such as pyrroles and pyrazoles (Scheme 1.75).101-102 In both cases, copper iodide was used as the metal source and potassium alkoxide/hydroxide were used as the base. However, while Verma and co-workers reported the use of a triazole derivative as their ligand, Wu and co-workers reported the use of an NHC compound. Overall, the substrate scope presented and yields obtained were comparable between the two methodologies. A follow-up publication using microwave technology was also disclosed by Verma and co-workers, although no significant improvement on the yields were observed.103  Scheme 1.75 Verma (2012), Wu (2013) – Sequential Copper-Catalyzed Hydroamination/Arylation Reactions Towards the Synthesis of Multi-Fused Isoquinolines A three-component strategy could be applied to synthesize quinolines from aniline, alkyne and tert-butylisonitrile (Scheme 1.76).104 The methodology involves the synthesis of N-aryl-1,3-diimines through hydroamination/iminoamination followed by a Brönstead acid-catalyzed intramolecular electrophilic attack on the pendant aromatic ring, which triggers the release of tert-butylamine and aromatization of the nitrogen heterocycle. The tridentate pyrrolyl R2R1NHZBrAr5-10 mol% CuI10-20 mol% LKOtBu110 °CZNAr25 examples58-75%R1NNNOHR2Z = C, NBrR2NHN10 mol% CuI10 mol% NHC2,6-diethylanilineKOH110 °CNNR2N NAr ArAr = 2,6-diethylphenylCl15 examples45-83%R1 R3R1R3  47 titanium complex was chosen as the catalyst when terminal alkynes were used, while the bidentate pyrrolyl titanium complex was chosen for internal alkynes.  Scheme 1.76 Odom (2009) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Cyclization Reactions Towards the Synthesis of Quinolines 1.2.2.4 Formation of 6-Membered N,N- or N,O-Heterocycles 1.2.2.4.1 Tetrahydropyrimidine, Pyrimidine and Quinoxaline Through a titanium-catalyzed hydroamination of N-ethoxycarbonyl-2-alkynylindole, followed by the nucleophilic attack of the enamine to the ester functional group, 12 examples of pyrimido[1,6-α]indolones were synthesized in a wide range of yields (Scheme 1.77).105   Scheme 1.77 Rossi (2009) – Sequential Titanium-Catalyzed Hydroamination/Cyclization Reactions Towards the Synthesis of Pyrimido[1,6-α]Indolones Substituted pyrimidines can be accessed via a one-pot procedure through the formation of 1,3-diimides followed by the addition of amidines (Scheme 1.78).106 While the yields obtained were poor, the transformation was reported to be regioselective depending on the titanium catalyst employed. NTiNMeMeNMe2NMe23 examples30-60%13 examples25-71%TiNMe2NMe2N NNMeR2i) 10 mol% [Ti]100 °Cii) removed Toland added AcOH150 °CR3tBu NR1NH2R1N R2R3R1R2H2N20 mol% TiCl4tBuNH2105 °C12 examples13-93%NCO2EtNNO R2R1  48  Scheme 1.78 Odom (2010) – Sequential Titanium-Catalyzed Hydroamination/Iminoamination/Amidine Addition Reactions Towards the Synthesis of Pyrimidines Starting from anilines containing an N-heterocycle on the ortho-position and alkynes, a variety of fused-quinoxalines and fused-quinazolines were reported in two separate publications (Scheme 1.79).98, 107 While both methodologies make use of phophine-bound gold complexes, which have been shown to perform tandem hydroamination/hydroarylation reactions, Patil and co-workers were limited to the use of terminal alkynes.  Scheme 1.79 Patil (2010), Liu (2011) – Sequential Gold-Catalyzed Hydroamination/Hydroarylation Reactions Towards the Synthesis of Fused-Quinoxalines Chen and co-workers reported a copper-catalyzed synthesis of quinoxaline starting from benzene-1,2-diamine and terminal alkyne (Scheme 1.80).108 While a single product was obtained NTiNMeMeNMe2NMe28 examples35-51%8 examples17-43%TiNMe2NMe2N NNMeR1R2R3H2Ni) 10 mol% [Ti]110 °Cii) aaaaaaaaa150 °CtBu NH2NR4NHN NR4R1R2R1R2R3R4MeRNHN16 examples48-97%R2R1R3MeRNHN6 examples70-98%NNHRMeN2 examples80-94%HetRHAmino HeterocyclesNH22 mol% [Au] 100 °CNTf2P AuPhPhPh +N22 examples20-98%1 mol% [Au]80 °CNH2R1R2R3R4NHR1SbF6P AutButBu+NCCH3NR3R4R2  49 with unsubstituted diamines in moderate to great yields, a mixture of regioisomers were obtained with 4-substituted benzene-1,2-diamines. Mechanistically, the authors propose that an intermolecular anti-Markovnikov alkyne hydroamination occurs, followed by a cyclization of the ortho-nitrogen on to the formed enamine. Attack of a second equivalent of alkyne and oxidation leads to the formation of product.   Scheme 1.80 Chen (2011) – Sequential Copper-Catalyzed Hydroamination/Cyclization/Alkyne Additon Reactions Towards the Synthesis of Quinoxalines 1.2.2.5 Formation of 7-Membered N,N- or N,O-Heterocycles 1.2.2.5.1 Dihydrobenzodiazapine and Benzodiazepine The synthesis of dihydrobenzodiazapine from benzene-1,2-diamine and terminal alkynes can be accomplished using gold catalysts (Scheme 1.81).109-110 While the groups of Liu and Xu focused on a phosphine-based gold complex,109 Luo and co-workers showcased their methodology using an NHC-gold complex.110 The main difference between the two methodologies reported was the starting diamine. In the former report, primary benzene-1,2-diamines were used as the starting material and in the latter report, mixed primary/secondary benzene-1,2-diamines were used. Overall the yield of the dihydrobenzodiazapines obtained is comparable in the two systems. The proposed mechanism for both reports begins with double hydroamination of the benzene-1,2-diamine to form an dienamine intermediate, which can 10 mol% Cu(OAc)2·H2ODMAP, Cs2CO370 °CR1 = HR2NH2H4 equiv.R1NH29 examples63-94%NNNNR1 ≠ HR2R2R2R2R1 12 examples30-99%  50 readily tautomerize to an enamine-ketimine intermediate. Then, the 7-membered cycle is formed upon an intramolecular addition of the enamine to the ketimine.   Scheme 1.81 Xu (2012), Luo (2014) – Sequential Gold-Catalyzed Double Hydroamination/Cyclization Reactions Towards the Synthesis of Dihydrobenzodiazapines 1.2.2.6 Conclusion A wide variety of N-heterocycles have been synthesized through sequential hydroamination followed by another reaction. By far, indoles and multi-fused heterocycles have received the greatest amount of attention. The development of new synthons through hydroamination could help increase the targeted heterocyclic compounds. For example, there is currently a single methodology towards the synthesis of pyridines starting from an intermolecular hydroamination of alkynes, even though pyridines were the second most common motif in U.S. FDA nitrogen containing heterocycle approved drugs. 1.3 Scope of Thesis The development of sequential methods featuring the bis(amidate)bis(amido)titanium-catalyzed intermolecular hydroamination of alkynes, followed by other reactions is the focus of this thesis (Scheme 1.82). Among the reactions attempted after the hydroamination reaction were catalytic hydrogenation (Chapter 2 and 3) and N-heterocycle formation (Chapter 4). R2NH2HNH2R12.5 equiv.NHN R2R2R15 mol% [Au]60 °CNTf2P AuCyCy+24 examples46-98%R25 mol% [Au]10 mol% AgOTf15 mol% NH4PF6Δ NNR1R2R2AuClAr = 2,6-iPr-C6H210 examples41-88%R1NH2HN5 equiv.H ArAr  51 Stoichiometric work was also performed towards the isolation of organometallic intermediates (Chapter 3).  Scheme 1.82 Overview of Scope of Thesis Chapter 2 focuses on the catalytic synthesis of secondary amines using a previously reported bis(amidate)bis(amido)titanium complex. While the Schafer group has extensively studied the hydroamination of alkynes using this titanium complex, the formation of amines from the imine intermediates relied heavily on the use of stoichiometric reductants, such as sodium borohydride and lithium aluminum hydride. To access a more sustainable synthesis of amines, the intermolecular hydroamination process was further examined, which led to the reduction of catalyst loading. The minimization of waste produced was also accomplished with the change from stoichiometric hydride sources for the reduction step, to the use of catalytic amounts of palladium on carbon (Pd/C) and hydrogen (H2) gas. Due to the great regioselectivity of the first step and clean hydrogenation of products to the amines, a facile synthesis and isolation of 23 examples of secondary amines was accomplished. The formation of primary amines through an intermolecular hydroamination of alkynes has been reported only once and it made use of diphenylmethanamine as the nitrogen source. An alternative ammonia surrogate that has received some attention in the past 10 years has been N-silylated amines. While the intermolecular hydroamination of alkynes and N-silylamines has been attempted in the past, no successful reports prior to this work had been published. Thus, i) Hydroaminationcatalyzed by 1ii) Other ReactionsR1R3H2N+Ar = 2,6-diisopropylphenylTitanium Complex 1TiNONOPhPh ArArNMe2NMe2R2 Nitrogen ContainingProducts  52 Chapter 3 focuses on the study of this reaction using the same titanium complex as above. Under our reaction conditions, the reaction was successful and allowed for the synthesis of 25 examples of N-silylenamines. Upon treatment of the hydroamination mixture with Pd/C and H2 gas, 9 examples of primary amines were obtained. Stoichiometric work was also performed to isolate a series of relevant organometallic complexes. The tautomerization of the enamine to the imine products formed from the hydroamination reaction was not as readily achieved in the case with silicon substitution on the nitrogen as compared to the case with carbon substitution on the nitrogen. This observation showed that a primary enamine surrogate could be reliably obtained. This new synthon inspired the synthesis of pyridines, which is the focus of Chapter 4. After the hydroamination reaction, in the presence of α,β-unsaturated carbonyls, molecular sieves, catalytic amounts of tetra-butylammonium fluoride, and oxidant, a large variety of pyridines were formed. This methodology allowed for the synthesis of mono-, di-, tri-, tetra-, and penta-substituted pyridines in moderate to good yields. Finally, in Chapter 5, several preliminary results that further exploit the use of our preferred titanium hydroamination catalyst allow for further research projects within the Schafer group. Conclusions to the research presented in this thesis will also be presented.      53 Chapter 2: Facile Synthesis and Isolation of Secondary Amines via a Sequential Titanium(IV)-Catalyzed Hydroamination and Palladium-Catalyzed Hydrogenation  2.1 Introduction The synthesis of secondary amines from primary amines has been the topic of intense investigation. In order to develop selective syntheses, the formation of by-products, such as tertiary amines or quaternary ammonium salts has to be suppressed, either through the implementation of protecting groups or through the modification of starting material and/or product reactivity. In the former case, the introduction of protecting groups adds two steps to the synthesis. Therefore, it is not surprising that efforts have been applied towards the development of methodologies in which unprotected amines can be used. Among the catalytic syntheses developed for the selective formation of secondary amines, this section will focus on the amination of alcohols, C-N cross-coupling, hydroaminomethylation and hydroamination. 2.1.1 Amination of Alcohols Reductive amination is a facile transformation that allows for the synthesis of secondary amines starting from a carbonyl moiety, a primary amine and a hydride source. The synthesis of a carbonyl functional group can be derived from feedstocks through a variety of transformations. For example, aldehydes and ketones can be formed from alkenes through ozonolysis, hydroformylation, or hydration followed by oxidation and from alkynes through hydration followed by tautomerization. The development of methodologies, which use pre-carbonyl starting materials, would be desirable to reduce the synthetic steps required.   54 The reaction between an alcohol and a primary amine in the presence of a catalyst can lead to the synthesis of secondary amines through a hydrogen borrowing strategy (Scheme 2.1).111-112 The amination of alcohols starts from the in situ formation of a carbonyl group by dehydrogenation, which in the presence of a primary amine forms an imine. This imine can then be hydrogenated to deliver the desired secondary amine. Among the advantages of this methodology is the formation of water as the only by-product of the reaction as well as the minimization of side reactions that can occur in reductive amination, such as aldol condensations. On the other hand, the reactions usually require extensive heating at temperatures that are either at or above the boiling point of the solvent, which requires extra caution.  Scheme 2.1 General Amination of Alcohols Towards the Synthesis of Secondary Amines  While heterogeneous catalysts for the amination of alcohols have been known since the early 20th century and are used industrially for the synthesis of lower alkyl amines, the first homogeneous catalysts for this transformation were only reported in the 80s. Simultaneous research by Grigg et. al113 and Watanabe et. al114 was disclosed in 1981. While Grigg’s study included the use of ruthenium, rhodium and iridium as catalysts, and the amination of alcohols was performed with primary and secondary amines,113 Watanabe’s study focused on the dichlorotris(triphenylphosphine)ruthenium catalyzed amination of alcohols with aniline.114 In R1HNR1OH R2R1OH R1NHR2H2N-R2Catalyst[M][MH2]H2NR2 H2OHydrogenationDehydrogenationImine Formation  55 both cases, substrate scope was limited to simple alcohols, such as methanol and ethanol, and the reaction conditions required high temperatures of up to 180 °C.  In recent years, a more diverse substrate scope and milder reaction conditions have been realized. Fujita et. al demonstrated that a catalytic system consisting of di-µ-chloro-bis[chloro(pentamethylcyclopentadienyl)iridium(III)] and sodium bicarbonate could perform the amination reaction with alcohols containing a variety of substituents, which included nitro-, cyano-, and ester-substituents (Scheme 2.2 – top).115 The same research group also showed that the reaction can be accomplished in water in an air atmosphere using a water-soluble iridium catalyst.116  Scheme 2.2 Yamaguchi (2008, 2011) – Iridium-Catalyzed Amination of Alcohols Towards the Synthesis of Secondary Amines In 2009, Kempe and co-workers disclosed a P,N-ligand stabilized iridium complex that showed high reactivity, which allowed for the amination reactions to be accomplished with low catalyst loading of 0.1 mol% and at comparatively mild temperature (70 °C) (Scheme 2.3 – top).117 The same catalyst system was used towards the synthesis of diamines starting from aminoalcohols (Scheme 2.3 – bottom).118  Scheme 2.3 Kempe (2009) – Iridium-Catalyzed Amination of Alcohols Towards the Synthesis of Secondary Amines H2NR31-3 mol% [Cp*IrCl2]2NaHCO3110 °C26 examples71-98%R1 R2OHR1 R2HN R30.1-2 mol% [Ir(cod)]2/LigandKOtBu, 70 °C8 examples71-93%R1OHR1HNH2N NN NPNN  56 Up until Zhao and co-workers disclosed an enantioselective amination of alcohols in 2014, no asymmetric examples had been reported. Using cooperative catalysis between an iridium catalyst and a chiral phosphoric acid, the authors were able to synthesize 26 examples of secondary amines in 64-98% yields and up to 97% of enantiomeric excess (Scheme 2.4).119 Following a similar procedure, Zhao and co-workers also reported a dynamic kinetic asymmetric amination starting from a mixture of four isomers to deliver enantiopure α-branched amines.120 Dual-enzyme catalysis has also been reported to deliver secondary amines from alcohol in up to 96% yield and 99% enantiomeric excess.121  Scheme 2.4 Zhao (2014) – Cooperative Iridium/Chiral-Phosphoric Acid Catalyzed Enantioselective Amination of Alcohols Towards the Synthesis of Secondary Amines Another area of improvement has been the shift towards the implementation of cheaper metals, such as iron.122-126 While Singh and co-workers showed that iron phthalocyanine was able to perform the amination of alcohols, their substrate scope was limited to heterocyclic amines.122 On the other hand, Barta and co-workers reported an iron-catalyzed amination of a wide range of alcohols with aryl and benzyl amines delivering 29 examples of secondary amines.123 H2NAr5 mol% [Ir]10 mol% (S)-TRIP4 Å MStert-Amyl alcohol, Δ26 examples64-98%69-97%  eeR1 R2OHR1 R2HN Ar IrHNNPhPhS OO  57  Scheme 2.5 Barta (2014) – Iron-Catalyzed Amination of Alcohols Towards the Synthesis of Secondary Amines  While improvements have been reported on the amination of alcohols, some goals remain unsolved. The development of more active catalysts could help increase the substrate scope to include a wider range of alcohols and amines as well as decrease the need for heating at or above boiling point temperatures. 2.1.2 C-N Cross-Coupling Reactions Traditional cross-coupling reactions refer to the formation of a C-C bond through a metal catalyzed oxidative addition, transmetallation and reductive elimination steps. The cross-coupling field is of such importance that the 2010 Nobel Prize in Chemistry was awarded to Professors Richard F. Heck, Ei-ichi Negishi and Akira Suzuki for their work in the development of palladium-catalyzed cross coupling reactions.127  Just as significant, is the research on the C-N cross-coupling reaction, which includes the copper-mediated or catalyzed Ullmann-Goldberg reaction and Chan-Evans-Lam reaction as well as the palladium-catalyzed Buchwald-Hartwig coupling.3, 128-129 While the copper reactions are more robust, in the sense that water and oxygen exclusion are not necessary for the reaction to occur, the substrate scope is usually limited. On the other hand, the scope of the palladium-catalyzed reactions is wide, but palladium is comparatively expensive and toxic and usually requires ligands to tune the reactivity.130 In both cases, numerous reports are available and thus R1 R229 examples8-95%5 mol% [Fe]10 mol% Me3NO120-130 °CHN R3FeOC COCOOTMSTMSH2NR3R1 R2OH  58 the focus of this section will be to give a historical perspective while highlighting the important advancements towards the synthesis of secondary amines in particular. 2.1.2.1 Copper-Mediated or Catalyzed C-N Cross Coupling The Ullmann reaction is a copper-mediated nucleophilic aromatic substitution between an aryl amine and an aryl halide.131 The addition of potassium carbonate allows for the reaction to be performed with catalytic amounts of copper, which is known as the Ullmann-Goldberg reaction.132 While the Ullmann-Goldberg reaction has been known since the early 20th century, the requirement for reflux conditions of over 260 °C limited the scope of the reaction and thus the practicality of the transformation. Recent advances in copper catalysis towards the synthesis of C-N bonds include the development of reactive copper-complexes133-136 or the utilization of other coupling agents, which include organoboron,137-139 organosilicon,140 organolead,141-142 organotin143-144 and organobismuth.145-146 In 1998, the groups of Chan,137 and Lam138 independently reported a general protocol for a copper-mediated arylation of a wide variety of nitrogen nucleophiles, which was accomplished at room temperature using boronic acids (Scheme 2.6). While Chan and co-workers were able to use alkyl/aryl amines, amides, imides, ureas, sulfonamides and carbamates as their nitrogen source, Lam and co-workers focused on heterocyclic amines. In both cases, however, sub- or super-stoichiometric amounts of copper ranging from 0.5 to 1.5 equivalents were necessary.   Scheme 2.6 Chan (1998) – Copper-Mediated Arylation of Amines Towards the Synthesis of Secondary Amines H2N R2BOHOHR1HNR2R10.5 equiv. Cu(OAc)2Et3N or pyridine4 examples56-93%  59 Shortly after, the catalytic version of the reaction was accomplished by Collman and Zhong using catalytic amounts of di-µ-hydroxo-bis[(N,N,N′.N′-tetramethylethylenediamine)copper] chloride, albeit the nitrogen source studied was limited to imidazoles.147 A more general copper-catalyzed C-N cross-coupling of aryl boronic acids with simple primary amines to deliver secondary amines was reported by Antilla and Buchwald in 2001 (Scheme 2.7).148 The coupling was accomplished at room temperature under catalytic copper acetate/myristic acid using 2,6-lutidine as the base. Examples of monoaryl and diaryl secondary amines were synthesized in 50-91% yields.  Scheme 2.7 Buchwald (2003) – Copper-Catalyzed Arylation of Amines Towards the Synthesis of Secondary Amines  In 2006, Hartwig and co-workers disclosed a sequential iridium-catalyzed borylation followed by a copper-catalyzed C-N bond formation (Scheme).149 The reported methodology allowed for the synthesis of secondary aryl/alkyl-amines starting from arenes in moderate yields without the isolation of the organo-boron species. While the yields for the synthesized diarylamines was higher, extra steps were required as the boronic ester had to be converted to the boronic acid and isolated prior to the C-N bond formation.  H2N R2BOHOHR1HNR2R15-20 mol% Cu(OAc)210-40 mol% Myristic acid2,6-Lutidineunder airvigorous stirring 20 examples50-91%  60  Scheme 2.8 Hartwig (2006) – Sequential Iridium-Catalyzed Borylation/Copper-Catalyzed C-N Cross-Coupling Reactions Towards the Synthesis of Secondary Amines  The copper-mediated/catalyzed C-N cross-coupling reaction has come a long way since it’s first discovery in 1903. The substrate scope has increased dramatically and the applicability of the transformation has been applied in the synthesis of natural products.150 The overall understanding of the reaction mechanism is still being investigated, as evidenced by the 2017 report from Watson and co-workers on the spectroscopic studies of the Chan-Lam amination.151 2.1.2.2 Palladium-Catalyzed C-N Cross Coupling A few years before the emergence of the Chan-Lam reaction, Buchwald and Hartwig concurrently reported the C-N cross-coupling using phosphine/palladium complexes (Scheme 2.9).152-153 The initial catalyst reported by both groups was a tri-o-tolylphosphine palladium complex, which in the presence of alkali metals, such as sodium tert-butoxide or lithium (bistrimethylsilyl)amide was able to catalyze the C-N bond formation between aryl bromides and amines.  Scheme 2.9 General Palladium-Catalyzed C-N Cross-Coupling Towards the Synthesis of Secondary Aryl-Amines HR213 examples31-67%10 examples70-95%R11) remove solvent2) 2 equiv. H2NAlk1 equiv. KF10 mol% Cu(OAc)2·H2O4Å MS, O2, 80 °C1) 3 equiv. NaIO40.6 equiv. HCl2) isolate boronic acid3) 2 equiv. H2NAr10 mol% Cu(OAc)2·H2O4Å MS, O2, 80 °CBpinR2R10.025 mol%[Ir(COD)(OMe)]20.05 mol% LigandB2pin2, 80 °CNHR2R1AlkNHR2R1ArH2N R2XR1HNR2R1cat. [Pd]alkali base  61  While copper amination reactions traditionally do not require ligands, in palladium catalysis, the presence and type of ligand are crucial to the reactivity of the complex.154 For example, in the initial communications by Buchwald and Hartwig, tri-o-tolylphosphine was used as the ligand and minimal formation of products was observed when primary amines were attempted. However, by changing the ligand from a monodentate phosphine to a bidentate phosphine (DPPE155 or BINAP156-157), the reaction with primary amines delivered the arylated products in yields of up to 98%.  The importance of the ligand on the palladium-complex is not related only to the reactivity of the amine starting materials but also to the coupling reagents used. Currently, the Buchwald-Hartwig amination works with aryl iodides,155, 158 bromides,152-153 chlorides,159-160 triflates,161-162 mesylates,163-164 and tosylates.159 Depending on the ligand used, the reaction can be selective for the synthesis of secondary amines.  For over 30 years, the need for alkali bases was one of the major drawbacks in the product scope of the reaction. In 2018, Buchwald and co-workers were able to perform the reaction in the presence of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), which is a mild soluble organic base (Scheme 2.10). Starting from aryl (pseudo)halides and amines, 16 examples of secondary amines were synthesized in great yields. While the change in base seems like a minor improvement to a well-established transformation, the new methodology allows for the use of functional groups, such as alkyl halides, which were not tolerated with previous reaction conditions.   62  Scheme 2.10 Buchwald (2018) – Palladium-Catalyzed Arylation of Amines Towards the Synthesis of Secondary Amines  The usefulness of the Buchwald-Hartwig amination reaction can be seen in the synthesis of a wide range of heterocycles and natural products.3 Furthermore, the reaction has also been applied in medicinal and process chemistry as well as in material and biological chemistry.3 Despite the improvements and efficiency of both copper- and palladium-catalyzed C-N cross-coupling, the starting materials used in the reaction still require pre-activation and the products formed are largely arylated amines. Thus, the development of other methodologies is required. 2.1.3 Hydrofunctionalization Reactions The functionalization of inexpensive feedstock materials such as alkenes and alkynes represents an advance towards the development of efficient amine syntheses. The minimization of the steps required to manufacture the starting materials required, in addition to the atom-economic nature of hydrofunctionalization reactions make the development of versatile and selective synthetic routes of fundamental importance. Among the different types of hydrofunctionalization reactions, the focus will be on hydroaminomethylation and hydroamination reactions. 2.1.3.1 Hydroaminomethylation Hydroaminomethylation is a one-pot, tandem reaction that involves an alkene, an amine and syngas, which is a gas mixture consisting of carbon monoxide and hydrogen (Scheme H2N RAr X ArHN R0.5 mol% COD(ligand-Pd)22 equiv. DBU60 °CX = OTf, Br, Cl 16 examples71-99%OMeP AdAdiPriPr iPrFFnBuFF  63 2.11).165-167 The reaction starts with the hydroformylation of the alkene, followed by the addition of the amine to the newly formed aldehyde. The imine/enamine mixture is then reduced through hydrogenation to deliver the desired amine.   Scheme 2.11 General Hydroaminomethylation of Alkenes Towards the Synthesis of Secondary Amines In 1949, the first account of this reaction was reported by Reppe and Vetter, who were able to synthesize amine products from acetylene, carbon monoxide, ammonia and water using stoichiometric amounts of pentacarbonyliron.168 Since then, rhodium has become the metal of choice for the hydroaminomethylation transformation,166 although recently, some ruthenium catalysts have been developed. Chemo- and regio-selectivity are among the challenges in the development of this reaction. Due to the presence of hydrogen gas at the onset of the reaction, formation of alkane and alcohol by-products can occur through the hydrogenation of the starting alkene and formed aldehyde. In addition, the hydroformylation reaction can form linear and/or branched aldehydes, thus leading to the formation of two similar amines, which could be difficult to separate. R1CO/H2, H2N-R2CatalystH2NR2 H2OHydrogenationHydroformylationImine FormationOHR1and/orR1OHNHR1and/orR1NHR2R2NHHR1and/or R1NHH R2R2NHHR1and/or R1NHH R2R2  64 The group of Eilbracht was a big contributor to the development of hydroaminomethylation methodologies towards the synthesis of nitrogen containing products.169-185 Eilbracht and co-workers reported the first hydroaminomethylation reaction of styrenes. In the presence of catalytic amounts of [Rh(cod)Cl]2 and syngas, 12 examples of secondary amines were synthesized in high yields (Scheme 2.12).169   Scheme 2.12 Eilbracht (1997) – Rhodium-Catalyzed Hydroaminomethylation Reaction Towards the Synthesis of Secondary Amines Milder reaction conditions (60 °C of heating and 30 bar of pressure) for the hydroaminomethylation of styrenes were obtained by Beller and co-workers using [Rh(cod)2BF4] and 1,1'- bis( diphenylphosphanyl)ferrocene (dppf) ligand.186 In the Beller case, however, the selectivity was favoured towards the branched product with the best ratio between products being 88:12.  Scheme 2.13 Beller (2005) – Rhodium-Catalyzed Hydroaminomethylation Reaction Towards the Synthesis of Secondary Amines H2N R1 mol% [Rh(cod)Cl]2110 bar (4.5:1 CO:H2)110 °CNHR5 examples82-99%up to 16:1 ratioH2N R1 mol% [Rh(cod)Cl]2110 bar (4.5:1 CO:H2)110 °CNHR7 examples71-99%HN R+H2N R20.25 mol% [Rh(cod)2BF4]0.275 mol% dppf10 mol% HBF430 bar (1:5 CO:H2)60 °C 10 examples17-99%up to 88:12 ratio+R1 R1HNR2 R1NHR2  65 Due to the tautomerization between imines and enamines, an asymmetric variant for the synthesis of amines using hydroaminomethylation has not been successfully developed187-189 without the addition of a secondary chiral catalyst (Scheme 2.14).190-191 Both the Xiao and Han reports had similar reaction conditions, which included a rhodium catalyst, phosphine ligand, chiral phosphoric acid, and 1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate. In both cases, the substrate scope was limited to aryl amine derivatives, although in the Han example, the alkene starting material was expanded beyond styrene derivatives to include electron-withdrawing aliphatic alkenes (Scheme 2.14 – bottom).  Scheme 2.14 Xiao (2015), Han (2017) –Asymmetric Hydroaminomethylation Reaction Towards the Synthesis of Secondary Amines The separation of two amine products containing similar physical proprieties is non-trivial. Thus, the development of selective hydroaminomethylation reaction conditions for either the branched or linear amines is crucial. In particular, the selective synthesis of linear amines has been well studied. Beller and co-workers have demonstrated that linear amines can be obtained H2N Ar0.5 mol% [Rh(acac)2(CO)2]0.275 mol% Ligand5 mol% (R)-TRIP11 bar (1:1 CO:H2)4Å MS, 50 °C, 3 d2.4 equiv.16 examples45-87%78-91% eeR1 R1HN ArNHEtOOOEtOH2N Ar2 mol% [Rh(acac)2(CO)2]2.4 mol% Ligand5 mol% Phosphoric acid1 bar (1:1 CO:H2)5Å MS, 25 °C, 3 d1.5 equiv. 23 examples36-99%46-99% eeR1 R1HN ArNHtBuOtBuOPOMeOMeMeOOOPOOHP PPhPhPhPh  66 through the hydroaminomethylation reaction using both internal192 and terminal alkenes.193 Unfortunately, only a handful of secondary amine examples were accomplished in either publication. Hydroaminomethylation is an atom-economic reaction that produces nitrogen-containing products from alkenes. While improvements have been made towards the chemo- and regio-selectivity of this transformation, further advances are required to broaden the scope of the reaction. The substrate scope, for example, is still highly reliant on styrene derivatives and amino-heterocycles. Furthermore, the isomerization of internal alkenes to terminal alkenes under catalytic conditions prevents the development of the selective synthesis of β,γ-branched amines from internal alkenes.  2.1.3.2 Hydroamination Similarly to hydroaminomethylation, hydroamination is a hydrofunctionalization reaction in which nitrogen-containing compounds can be synthesized. The main difference between the two methodologies is the fact that in hydroamination, the C-N bond is formed in a single step. Similarly, however, is the need for regio-selective catalysts in order to obtain the Markovnikov or anti-Markovikov amines selectively. For hydroamination, both alkenes and alkynes can be used, and in fact the latter case is the more established methodology for the synthesis of amines (Scheme 1.2).4-5 Chapter 1 addresses the synthesis of amines through the intermolecular hydroamination of alkynes, thus, this section will focus on the intermolecular hydroamination of alkenes for the synthesis of secondary amines. The first example of hydroamination in the academic literature was reported in 1953 and it demonstrated that alkali metals were able to perform the hydroamination reaction of olefins under high temperature (up to 200 °C) and pressure (800-1000 atm).194 Since then, a wide range   67 of catalysts has been developed to perform the C-N bond formation under milder reaction conditions.  Traditionally, the intermolecular hydroamination of olefins is usually performed with highly activated alkenes, such as styrenes,195 norbornenes,196 allenes,197 and dienes.198 The nitrogen source is also typically performed with heterocyclic amines.199 On the other hand, very few examples use primary amines, thus the formation of secondary amines has not been broadly explored.195, 200 In 2000, Kawatsura and Hartwig reported a palladium catalyzed Markovnikov selective intermolecular hydroamination of styrene derivatives with aryl amines, which delivered 8 examples of secondary amines in 64-99% yields (Scheme 2.15).195 The same publication also attempted the reaction asymmetrically using 4-trifluoromethylstyrene and aniline with 10 mol% [Pd((R)-binap)(OTf)2], which gave products with a yield of 80% in 81% ee.  Scheme 2.15 Hartwig (2000) – Palladium-Catalyzed Hydroamination Reaction Towards the Synthesis of Secondary Amines  In the past 10 years, attempts at performing intermolecular hydroamination with simple alkyl alkenes have been successful using specific heterocyclic amines.201-203 However, a general synthesis of secondary amines by hydroamination of alkenes with primary amines remains a challenge. Marks and co-workers showed one example of a dialkyl amine synthesis using pent-1-ene and propan-1-amine in the presence of a lanthanide-complex (Scheme 2.16).200 H2N ArR1 R1NHAr8 examples64-99%2 mol% Pd(PPh3)420 mol% TfOH100 °Cor2 mol% Pd(TFA)23 mol% dppf20 mol% TfOH100 °C  68  Scheme 2.16 Marks (2003) – Neodymium-Catalyzed Hydroamination Reaction Towards the Synthesis of a Secondary Amine  While the asymmetric synthesis of secondary amines has been tried using an intermolecular hydroamination of alkenes with alkyl amines, the enantiomeric excesses are usually moderate of up to 61%.204 2.2 Results and Discussion In Chapter 1, it was shown that a wide variety of complexes were competent for the intermolecular hydroamination of alkynes with primary amines, which upon reduction of the hydroamination product led to the formation of secondary amines. A synthetic approach to linear secondary amines that minimizes waste generation and reduces the amount of solvent required for product purification is disclosed in this section of Chapter 2. An optimized intermolecular alkyne hydroamination methodology with a reduced catalyst loading of only 1 mol% of pre-catalyst has been developed. Subsequent hydrogenation of the enamine/imine mixture is achieved using easily removed Pd/C catalyst. Finally, a streamlined work-up procedure has been established which features filtration protocols, and avoids purification by column chromatography in most cases. As a demonstration of utility, secondary amines have been prepared and isolated on multigram scale in 5 - 10 h from commercially available terminal alkyne and primary amine starting materials. H2N5 mol% [Nd]60 °CHN90%NdSiMeMeSiSi  69 2.2.1 Optimization of Reaction Conditions To optimize reaction conditions, the hydroamination reaction with 1 was monitored by 1H NMR spectroscopy to determine substrate dependent reaction times (30 min to 6 h) giving TOFs of 1.3 to 200 h-1 at 70 °C (Table 2-2 and Table 2-2). A variety of alkyl and aryl amines and alkynes of different electronic and steric nature were successfully employed in the hydroamination step.   Entry Alkyne Amine Time E:I Ratio TOF (h-1) 2.1a   30 min 91:9 200 2.1b   30 min 83:17 200 2.1c   1h 97:3 100 2.1d   1h 42:58 100 2.1e   1h 74:26 100 2.1f   2h 69:31 50 2.1g   30 min 82:18 200 2.1h   30 min 49:51 200 1 mol% 1C6D6, 70 °CtimePh+ H2N R PhHN RH+ Ph N RH2NH2NH2NH2NH2NH2NH2NH2NCF3  70  Entry Alkyne Amine Time E:I Ratio TOF (h-1) 2.1i   1h 67:33 100 2.1j   1h 57:43 100 2.1k   1h 82:18 100 2.1l   3h 100:0 33 2.1m   5h 54:46 20 2.1n   6h 60:40 17 Table 2-1 Optimization of the Hydroamination Reactions Using Ethynylbenzene  Entry Alkyne Amine Time E:I Ratio TOF (h-1) 2.2a   30 min 69:31 200 2.2b   1h 75:25 100 2.2c   1h 60:40 100 1 mol% 1C6D6, 70 °CtimePh+ H2N R PhHN RH+ Ph N RH2NFH2NOMeH2NClH2NCNH2NH2N OMeOMe1 mol% 1C6D6, 70 °CtimeR+ PhHNH + Ph NH2NF3CH2NFH2NMeH2N  71  Entry Alkyne Amine Time E:I Ratio TOF (h-1) 2.2d   1h 84:16 100 2.2e   1h 64:36 100 2.2f   3h 63:37 33 2.2g   2h 58:42 50 2.2h   3h 7:93 33 2.2ia   6h 1:99 1.7 2.2jb   30 min 55:46 80 2.2kb   1h 31:69 40 a) 10 mol% of the titanium complex was required. b) 2.5 mol% of the titanium complex was required. Table 2-2 Optimization of the Hydroamination Reactions Using Sec-Butylamine Initial studies on the feasibility of performing a sequential hydroamination/hydrogenation reaction were performed using ethynylbenzene and tert-butylamine as model substrates (Table 2-3). The hydroamination reaction was set-up in a scintillation vial in an inert atmosphere glovebox using dried and distilled starting materials. The reaction mixture was removed from the 1 mol% 1C6D6, 70 °CtimeR+ PhHNH + Ph NH2NMeOH2NOMeH2NOMeH2NH2NH2NH2NSi OH2NHNOH2N  72 glovebox and was stirred at 70 °C for 1 h before transferring the reaction mixture by syringe to the Fischer-Porter® tube used for hydrogenation. Reduction of the hydroamination product was first performed at 1 bar of H2 over 3 days, yielding 65% of the desired product (Entry 1). In an attempt to shorten the reaction time, the pressure of H2 was increased to 3 bar resulting in a reaction time of only 3 h and an improved yield (Entry 2). Although different solvents delivered similar yields, methanol was selected as the solvent of choice due to its favorable environmental and health hazard profile.205  Entry Solvent Time (hours) Yield (%)a 2.3ab MeOH 72 65 2.3b MeOH 3 98 2.3c THF 3 96 2.3d iPrOH 3 96 2.3e Benzene 3 92 a) Reported yield percentages refer to obtained yield after work-up conditions. b) Hydrogenation reaction was performed at 1 bar. Table 2-3 Optimization of the Sequential Reaction Conditions  In addition to developing optimized hydrogenation conditions, an easy work-up procedure was established to afford the desired amine (Figure 2.1). Due to the lack of by-products formed in this reaction sequence and the low solubility of the ligand in hexanes, simple filtration of the crude reaction mixture through Celite® removed the titanium and palladium metal residues, while the addition of cold hexanes followed by a second filtration allowed for full recovery of the amide proligand. Using this protocol, no column chromatography was required to i) 1 mol% 1C6H6, 70 °C, 1 hii) 0.5 mol% Pd/CH2 (3 bar)Solvent, r.t., timeH2N+HNAr = 2,6-diisopropylphenylTitanium Complex 1TiNONOPhPh ArArNMe2NMe2H  73 obtain clean products (>95% purity as established by 1H NMR spectroscopy) and thus, all reported yields are crude, unless stated otherwise.  Figure 2.1 1H NMR Spectrum (CDCl3, 400 MHz, 298 K) for the Crude Sequential Hydroamination/Hydrogenation Reaction of Ethynylbenzene and Tert-Butylamine 2.2.2 Substrate Scope of Sequential Hydroamination/Hydrogenation Transformation Towards Linear Secondary Amines In order to investigate the scope and limitations of the sequential procedure, we first examined the reaction of ethynylbenzene with a wide variety of amines (Scheme 2.17). Alkyl amines, both acyclic (2.1a-c) and cyclic (2.1d-f), deliver excellent yields of enamine/imine intermediates in an hour or less. More sterically demanding substituents require longer reaction   74 intermediates in an hour or less. More sterically demanding substituents require longer reaction times (2.1c-f). Aryl amines (2.1g-j), including aryl amines with both electron-withdrawing (eg. 2.1h) and electron-donating substituents (eg. 2.1j) are also compatible with these low catalyst loadings.   Scheme 2.17 Effect of Amine Modification on Reaction with Ethynylbenzene Although the aforementioned work-up procedure was transferrable towards all alkyl amines screened (2.1a-f), aryl amines (2.1g-j) required further purification to remove minor, i) 1 mol% 1C6H6, 70 °C, timeaii) 0.5 mol% Pd/CH2 (3 bar)MeOH, r.t., 3 hRH2N+HN RHNHNHNHN2.1a 91%b2.1b97%b2.1c98%b2.1e 95%bHN2.1j77%c2.1m58%d2.1n33%dHNHNHN2.1g89%c2.1h85%c2.1i81%cHNHNCF3FHN2.1d 98%b2.1f96%bHNOMeOMeOMeHN2.1k0%ClHN2.1l0%CNHa) Refer to Table 2-1 for hydroamination reaction times. b) Reported yield percentages refer to obtained yield after work-up conditions, unless otherwise stated. c) Isolated yield percentages after column chromatography. d) Isolated yield percentages after back-extraction.   75 unidentified impurities. Unfortunately, chloro- (2.1k) and cyano- (2.1l) substituted aniline derivatives were incompatible with the hydrogenation step. In the case of diphenethylamine derivatives (2.1m,n), this protocol affords the desired products quantitatively; however, the insolubility of these amines in hexanes complicates isolation. In these cases column chromatography could not be used effectively to separate impurities from the desired secondary amine products. Thus, to obtain the amine in pure form, the optimized work-up procedure required isolation of the amine-HCl salt product derivative followed by re-basification and extraction.  The reaction of sec-butylamine with a variety of terminal alkynes was also examined (Scheme 2.2). Both electron-withdrawing and -donating para-substituted ethynylbenzenes (2.2a-d) were successfully synthesized in excellent yields. Meta- (2.2e) and ortho-substituted (2.2f) ethynylbenzenes were also tolerated, though the latter was obtained in lower yield, presumably due to steric bulk. Such steric hinderance has not been observed to dramatically impact hydroamination, but could hinder palladium-catalyzed hydrogenation. More importantly, less electronically and sterically biased alkyl alkynes also smoothly reacted in a regioselective manner with the amine in the hydroamination step (2.2g, 2.2h). To the best of our knowledge, catalyst 1 is the only highly regioselective catalyst using such alkyl alkynes and alkyl amines as substrates. In the hydrogenation step of alkyl substituted imines (2.2g-i) a higher catalyst loading of 1 or 5 mol % of Pd/C and slightly prolonged reaction times were necessary to realize full hydrogenation of these unactivated species. In all instances presented in Scheme 3, no further purification was required beyond the established filtration protocol to afford pure products.  We have previously shown25-27 that the hydroamination of alkynes containing protected alcohols, esters, or amides can be tolerated, notably these substrates are not compatible with the   76 low catalyst loading and short reaction times targeted here. However, by increasing the loading of 1, the streamlined one-day process could also be achieved with alkynes containing silylether (2.2j) and amide (2.2k) functionalities.   Scheme 2.18 Effect of Alkyne Modification on Reaction with sec-Butylamine 2.2.3 Large Scale and One-Pot Transformations With the potential synthetic relevance of our methodology in mind, larger-scale reactions of 25 mmol were performed in a 100 mL round bottomed flask. Following the general procedure for the sequential approach and simplified filtration work-up protocol, 4.3g (97% yield) of 2-methyl-N-phenethylpropan-2-amine and 3.3g (83% yield) of N-(sec-butyl)hexan-1-amine was HN2.2hc96%bHN HN2.2gc92%bHNMeOHNOMe OMeHN2.2id,e72%bHN2.2a99%bHN2.2c99%bFHN2.2b99%bF3C Me2.2e98%b2.2f51%b2.2d99%bi) 1 mol% 1C6H6, 70 °C, timeaii) 0.5 mol% Pd/CH2 (3 bar)MeOH, r.t., 3 hRH2N+HNRHN2.2kc,f92%gSi OHN2.2jc,f99%bHNOHa) Refer to Table 2-2 for hydroamination reaction times. b) Reported yield percentages refer to obtained yield after work-up conditions; c) 1 mol% of Pd/C and 5 hours were required. d) 10 mol% of 1 was required. e) 5 mol% of Pd/C and 4 hours were required. f) 2.5 mol% of 1 was required. g) Isolated yield percentages after back-extraction.     77 obtained with the same degree of purity as that obtained for the smaller scale reactions (Figure 2.2).  Figure 2.2 1H NMR Spectrum (CDCl3, 400 MHz, 298 K) for the Crude Large-Scale Sequential Hydroamination/Hydrogenation Reaction of Ethynylbenzene and Tert-Butylamine  With this facile procedure in hand, we next developed a one-pot approach to further simplify our methodology. Experiments confirmed that palladium does not affect the desired hydroamination transformation that is mediated by titanium and a control experiment confirmed that Pd/C does not catalyze the hydroamination reaction itself.  Varied selections of substrates were synthesized using the one-pot approach (Scheme 2.19). In this case, both Ti catalyst 1 and Pd/C were loaded into a scintillation vial in the   78 glovebox. Benzene, amine and alkyne were added before removing the reaction vessel from the glovebox. After stirring and heating the hydroamination reaction mixture for the previously determined optimized reaction times, a hydrogen-filled balloon was attached to the reaction vial. Upon reaction completion our optimized reaction protocol was used to obtain yields comparable to those of the sequential approach. Only minor impurities can be observed in the baseline of the 1H NMR spectra (Figure 2.3).   Scheme 2.19 One-Pot Approach Towards the Synthesis of Secondary Amines  HNHN2.3a 91%2.3b 98%HN2.3ca86%HN2.3da94%i) 1 mol% 10.5-1 mol% Pd/CC6H6, 70 °C30 min - 3 hii) H2 (1 atm)r.t., 40 hR+ R1H2N RHNR1Ha) 1 mol% of palladium on carbon was required. b) Refer to Table 2-1 and Table 2-2 for hydroamination reaction times. c) Reported yield percentages refer to obtained yield after work-up conditions.   79  Figure 2.3 1H NMR Spectrum (CDCl3, 400 MHz, 298 K) for the Crude One-Pot Hydroamination/Hydrogenation Reaction of Ethynylbenzene and Tert-Butylamine 2.3 Conclusion In summary, this chapter describes an alternative to reductive amination for the synthesis of primary and secondary amines, using terminal or internal alkynes and amines as starting materials. Titanium-catalyzed regioselective, intermolecular alkyne hydroamination can be performed quantitatively at low catalyst loading (1 mol %). The resultant intermediate mixtures can then undergo quantitative hydrogenation with a commonly available Pd/C catalyst to give amine products. These products can typically be isolated cleanly using a simple filtration protocol to give a variety of alkyl- and aryl-substituted secondary amine product, or using   80 sublimation to give a variety of primary amine products. This sequential reaction affords clean products that typically avoid the need for column chromatography. Most importantly, we have demonstrated that this protocol can be carried out on multigram scale, and is suitable for general laboratory use. Future directions for this chapter will include expanding the scope of the secondary amines synthesized by using internal alkynes and optimizing the homogenous hydrogenation conditions towards the synthesis of enantiopure amines. Chapter 5 will have a more detailed background and overview of the future directions of this research project.    81 Chapter 3: Regio- and Stereoselective Hydroamination of Alkynes Using an Ammonia Surrogate: Synthesis of N-Silylenamines as Reactive Synthons 3.1 Enamines in Organic Chemistry The first few reports on the reactivity of enamines were published in the late 19th century and the beginning of the 20th century.206-208 However, it was only after Stork and co-workers demonstrated that N-alkylenamines could be used for C-alkylation (Scheme 3.1– left) and C-acylation that great attention was focused on the synthetic applications of enamines.209 Presently, chemistry involving enamines revolves around the topic of organocatalysis, where the enamine is formed catalytically (Scheme 3.1– right).210  Scheme 3.1 General Stork Enamine Alkylation Reaction and Enamine Catalysis 3.1.1 Synthesis of Enamines Traditionally, the synthesis of enamines occurs through the condensation of secondary amines to carbonyls, such as aldehydes or ketones, in the presence of a water scavanger.206-207, 211 The requirement for secondary amines arises from the fact that enamine-imine tautomerization readily occurs for enamines that contain one or two hydrogen substituents.211 O NHN NRORMeOH, 65 ºCR XStork Enamine Alkylation Enamine CatalysisR1R2NR1R2NR3NHR1R2NR3 XR1R2OR3R1R2OH2OH+  82 Catalytically, the synthesis of enamines can be accomplished through the amination of alkenyl (pseudo)halides with secondary or N-heterocycles.212 Barluenga and co-workers reported the first example of a palladium catalyzed amination of alkenyl bromides in 2002 (Scheme 3.2).213 Since then, other similar methodologies have been developed using alkenyl chlorides214 and triflates215. Copper-catalyzed variants have also been studied using alkenyl boronic acids216 and alkenyl bromides.217   Scheme 3.2 Barluenga (2002) – Palladium-Catalyzed Amination of Alkenyl Bromides Towards the Synthesis of Enamines 3.1.2 Synthesis of N-Silylenamines Although N-alkyl substituted enamines are commonly used in synthesis, use218-227 of related N-silylenamines are limited, largely due to their laborious syntheses. The preparation of N-silylenamines is typically achieved by the stoichiometric addition of highly active carbon nucleophiles to aromatic cyanide groups followed by trapping with either silylchloride218-219, 222, 226-229 (Scheme 3.3 – top) or an intramolecular silyl-migration229-235 (Scheme 3.3 – middle). A Rh-catalyzed route was reported by Brookhart and co-workers, which employed intramolecular transfer hydrogenation of vinylaminosilane, to give N-silylenamine in 70% yield (Scheme 3.3 – bottom).236  R2R1BrR31-3 mol% Pd2(dba)3or Pd(OAc)23-9 mol% BINAPNaOtBu90 °CR4NHR5R4N R5R1R2R310 examples45-81%  83  Scheme 3.3 Stoichiometric and Catalytic Syntheses of N-Silylenamines  Over the past 25 years, no example of N-silylenamine synthesis by hydroamination has been reported, even though the reaction has been previously attempted with catalysts that are known to catalyze the hydroamination of alkynes with typical carbon substituted amines.197, 237 For example, Bergman and co-workers showed that bis(cyclopentadienyl)bis(amido)zirconium complexes could be used as catalysts for the generation of enamines with anilines. However when the reaction was performed with N-silylamine, no enamine formation was observed. Furthermore, when isolated zircona-(N-silyl)-azametallacycle was reacted with excess N-silylamine, only the products resulting from cycloreversion, free diphenylacetylene and Cp2Zr-bis(silyl)amide, were recovered (Scheme 3.4).197  Scheme 3.4 Bergman (1992) – Catalytic and Stoichiometric Bis(Cyclopentadienyl)Zirconium Chemistry R11. R2CH2-M-78 ºC → r.t.2. R3SiClNR1HN SiR3R2R1 = Alkyl, arylR2 = H, alkylR = TMS, TBDMSM = Li, MgBrR11. LDA -78 ºC2. R2CN-78 ºC → r.t. R1HN SiR3R2R1 = Aryl, heteroarylR2 = ArylR = TMS, TBDMSSiR3RhSiSiPhHN Si0.5 mol% [Rh]140 ºC, 12 hPhHN SiStoichiometric synthesesCatalytic synthesis70%tBuMe2SiNH225 mol% Cp2Zr(NHSiMe2tBu)2140 °C, 6 dPhPh2,6-dimethylaniline3 mol% Cp2Zr(NHAr)295 °CPhPhHN Ar No ProductObservedZr NSiPhPhtBuMe2SiNH2C6D6, 95 °C, 4 dZr NHNHSiPhPhSi  84  In 2001, Odom and co-workers showed that the catalytic hydroamination reaction of hex-1-yne and aniline was successful using their titanium-pyrrolyl complex.22 A few years after, the hydroamination reaction was attempted using (N-triphenylsilyl)amine as the substrate and no product was observed. The Odom group was able to prepare an (N-triphenylsilyl)imido titanium complex supported by pyrrole ligands (Scheme 3.5).237  Scheme 3.5 Odom (2001, 2005) – Catalytic and Stoichiometric Bis(Pyrrolyl)Titanium Chemistry The Schafer group’s bis(amidate)bis(amido)-Ti(IV) catalyst (1) has high activity and excellent anti-Markovnikov selectivity for the hydroamination of alkynes. Inspired by other transition-metal catalyzed reactions that utilize silylated amines as ammonia surrogates for the generation of primary amines, such as (N-triphenylsilyl)amine in Pd-catalyzed Buchwald-Hartwig cross-coupling,238-247 we envisioned utilizing N-silylamines, H2NSiR3, as ammonia surrogates for the hydroamination of alkynes. In this chapter, we disclose the regioselective hydroamination of a variety of alkynes to give a broad range of (E)-N-silylenamines. The use of these products as reactive enamine intermediates is demonstrated and a mechanistic proposal invoking catalytically active Ti-silylimido is presented.  Ph3SiNH2Ti(NMe2)2dmpaNPhAniline10 mol%Ti(NMe2)2dmpa75 °C, 6 hPh3SiNH2C6H5Cl, 60 °C, 16 hNNtButBuTiNMe2NMe2N NNMeTiNN NNMePh PhPhNNtButBuNo ProductObserved  85 3.2 Results and Discussion 3.2.1 Reaction Conditions and Controls Our studies toward the catalytic hydroamination of alkynes with N-silylamines began by using commercially available (N-triphenylsilyl)amine, ethynylbenzene, and the commercialized Ti catalyst 1. In an NMR tube scale reaction the N-silylenamine product was observed exclusively after 18 hours at 70 °C using 2.5 mol% of 1. The anti-Markovnikov product was assigned as the E-isomer on the basis of the observed 13.7 Hz coupling between the vicinal olefinic hydrogens (δ 6.99, 5.61 ppm). With this successful reaction in hand we also sought to use a trialkylsilylamine variant. Thus, (N-tert-butyldimethylsilyl)amine was prepared in 82% yield from ammonia and tert-butyldimethylchlorosilane. Subsequent hydroamination of ethynylbenzene with the synthesized N-silylamine gave the anti-Markovnikov (E)-N-silylenamine product using only 1 mol% catalyst loading at 70 °C over 6 hours.  Tetrakis(dimethylamido)titanium is known to catalyze the hydroamination of alkynes.248 However, when this complex was tested as a potential catalyst, no N-silylenamine formation could be observed (Scheme 3.6). By adding the amide proligand (L) to the unreacted reaction mixture, catalyst 1 was formed in situ and full conversion to the desired product was achieved. This experiment demonstrates the importance of the bis(amidate) ligand environment to promote hydroamination with silylamine substrates (vide infra).   86  Scheme 3.6 Testing the Importance of Amidate Ligands 3.2.2 Stoichiometric Studies The accepted mechanism for Ti-catalyzed hydroamination invokes the formation of an imido reactive intermediate, thereby limiting reactivity to primary amine substrates (Scheme 3.7).249-251 Consistent with this mechanistic proposal, when the reaction was attempted with bis(trimethylsilylamine), a secondary amine, no product was observed by 1H NMR spectroscopy.   Scheme 3.7 Proposed Mechanism for the Titanium-Catalyzed Hydroamination of Alkynes To further probe the role of intermediate imido complexes, we synthesized and characterized silylimido species from 1. The generation of imido complex 3.1a was obtained by reacting one equivalent of (N-tert-butyldimethylsilyl)amine with one equivalent of Ti complex 1 (Scheme 3.8, Figure 3.1). Recrystallization afforded the desired silylimido species in 55% yield. 10 mol% Ti(NMe2)4C6D6, 70 °C, 6 hH2NSiNo product observed by1H NMR Spectroscopy20 mol% LC6D6, 70 °C, 18 hONHArAr = 2,6-diisopropylphenylL =HN SiProduct observedafter in situpreparation of 1L2Ti NRL2Ti NRHR1R1HNRL2TiNHRL2Ti(NEt2)2H2NR2 HNEt2H2NRR1HNHRR1HNRR1[2+2] CycloadditionLigand dissociationProduct liberationTautomerizationProtonolysis  87 Attempts to remove the neutral dimethyl amine donor under vacuum proved unsuccessful. However, the addition of excess pyridine resulted in ligand exchange to give complex 3.1b in 44% recrystallized yield from complex 1.   Scheme 3.8 Synthesis of N-Silylimido-Titanium Species 3.1a and 3.1b     Figure 3.1 Single-Crystal Molecular Structures of 3.1a (left) and 3.1b (right) Importantly, 3.1a can catalyze the reaction between ethynylbenzene and (N-tert-butyldimethylsilyl)amine at 1 mol% Ti with full conversion of starting materials to the desired enamine product in 6 h at 70 °C. This strongly suggests that catalysis described here follows the previously proposed mechanism involving a Ti–imido species.249-251 Furthermore, we have Ar = 2,6-diisopropylphenyl1TiNONOPhPh ArArNMe2NMe2H2NSiC6D655%TiNONOPhPh ArArNN Sii) aaaaaaaaaaC6D6ii)  1 eq. pyridineC6D644%3.1b3.1aTiNSiONPhAr OPhN ArN HH2NSiThermal ellipsoids are shown at 50% probability. Phenyl and 2,6-diisopropylphenyl groups of the ligand and hydrogen atoms are omitted for clarity.   88 previously proposed the hemi-lability of amidate ligands to play a significant role in the reactivity and selectivity of complex 1.27  Interestingly, complexes 3.1a and 3.1b display different coordination of the ancillary amidate ligand due to change in donor ligand. In 3.1a one of the amidate ligands is bound in a κ1-O fashion, giving in a 5-coordinate pseudo-square based pyramidal complex with an axial N-silylimido ligand. Substitution of the dimethylamine ligand with a pyridine ligand results in a 6-coordinate, distorted octahedral complex 3.1b, with both amidate ligands in a κ2-N,O binding mode. We attribute this coordination variation to the slight steric differences in the dimethylamine and pyridine neutral ligands. The N-sp3 hybridized dimethylamine, with a comparatively shorter Ti–N bond length of 2.1780(18) Å, imparts a greater steric parameter at the Ti center (2a) than the planar, N-sp2 hybridized pyridine, with a comparatively longer bond length of 2.2140(13) Å (3.1b). We additionally attempted the analogous reaction with (N-triphenylsilyl)amine, however, recrystallization was only possible as the pyridine complex resulting in complex 3.1c, in 66% yield (Scheme 3.9, Figure 3.2).  Scheme 3.9 Synthesis of N-Silylimido-Titanium Species 3.1c 3.1cTiNONOPhPh ArArNN Si PhPhPhi) C6D6, r.t., 18 hii) Pyr, r.t., 18 h66%Ar = 2,6-diisopropylphenyl1TiNONOPhPh ArArNMe2NMe2H2NSi PhPhPh  89   Figure 3.2 Single-Crystal Molecular Structures of 3.1c The Ti–N bond lengths and Ti–N–Si bond angles observed in the silylimido ligands observed in 3.1a (1.7030(16) Å, 170.70(9)°), 3.1b (1.7196(12) Å, 168.92(8)°), and 3.1c (1.724(3) Å, 168(2)°) are comparable to the known bis(amidate)tert-butylimidopyridine Ti(IV) complex (1.1711(2) Å, 172.3(2)°),26 and the previously mentioned Ti complex reported by Odom and co-workers (1.718(4) Å, 168.9(3)°).237 3.2.3 Substrate Scope of the Intermolecular Hydroamination of Alkynes and N-Silylamine The scope of the hydroamination reaction was studied with a variety of terminal and internal alkynes (Scheme 3.9). Due to the moisture sensitivity of the products, 1H NMR spectroscopy was used to determine reaction yields in situ using trimethoxybenzene as an internal standard. In all cases, full consumption of starting materials was observed and only the anti-Markovnikov product was formed. The yields obtained for the hydroamination of a range of ethynylbenzene derivatives (3.2a-i) were excellent, independent of the arene substitution pattern. Thermal ellipsoids are shown at 50% probability. Phenyl and 2,6-diisopropylphenyl groups of the ligand and hydrogen atoms are omitted for clarity.   90 Even substrates with sterically demanding and potentially chelating ortho-methoxy substituents (3.2i) could be accomodated. Good yields were also obtained using alkynes with nitrogen and sulfur containing heterocycles (3.2j-p). In all cases where conjugated products result, only the enamine tautomer could be observed. Interestingly, when using alkyl substituted alkynes such as 1-hexyne (3.2q) or 1-ethynylcyclohexane (3.2r) a minor amount of imine tautomer can be observed. Notably, the conjugated 1-ethynylcyclohex-1-ene delivered the enamine product exclusively (3.2s). Other functional groups, such as silylether (3.2t) and amide (3.2u) were also compatible with catalyst 1. Internal alkynes were employed successfully (3.2v-y) to give products regioselectively and in high yield.    Scheme 3.10 Scope of Alkyne Hydroamination Towards the Synthesis of N-Silylenamines  Three examples of N-silylenamines (3.2a, 3.2s, 3.2v) were purified and isolated by vaccum distillation under heat. It is worth noting that for the majority of substrates synthesized, TBDMSOHNtBuOR11-10 mol% 1C6D6 or d8-Tol70-145 °C, 6-72 hH2NSiR2R1HN SiR2R1N SiR2RRH: 96% (82%)b4-F: 99%4-Cl: 99%4-Br: 98%4-CF3: 98%4-Me: 95%4-OMe: 97%3-OMe: 98%2-OMe: >99%3.2a3.2b3.2c3.2d3.2e3.2f3.2g3.2h3.2i3.2s94%(72%)b3.2t76%(7% imine)3.2u>99%R1 = Ph, R2 = Me: 84% (57%)bR1 = Ph, R2 = Et: 74%R1 = Ph, R2 = Pr: 74%3.2v3.2w3.2xHNHNHNHNR2Si+ +SiSiSiHN Si HetHN SiHeterocycles2-pyridine: 85%3-pyridine: 94%4-pyridine: 69%4-pyrazine: 86%1-methyl-4-pyrazole: 85%2-thiophene: 97%3-thiophene: 88%3.2j3.2k3.2l3.2m3.2n3.2o3.2p3.2r77%(9% imine)HN SiR1R1, R2 = Ph: 87%3.2y3.2q54%(4% imine)HN Sia) 1H NMR yields obtained quantitatively by using 1,3,5-trimethoxybenzene as internal standard. b) Reactions were performed on a 5 mmol scale using nondeuterated toluene, and products were purified by vacuum distillation under heat.   91 the (E)-isomer was the sole product obtained. However, a mixture of (E)- and (Z)-isomers were observed in certain cases (3.2j, 3.2m, 3.2u-y). Furthermore, analogous to the initial reaction using (N-triphenylsilyl)amine, it was observed that the enamine tautomer was prevalent and exclusive in all cases, except for the alkyl substituted derivatives (3.2q-r and 3.2t), where minor amounts of the imine tautomer is observed due to the absence of extended conjugation. In the generally accepted mechanism for titanium-catalyzed hydroamination of alkynes, the formation of the more thermodynamically stable imine occurs via the tautomerization of the enamine product. Thus, the preference for the enamine tautomer when the nitrogen is silylated warranted further investigation.  3.2.4 Computational Studies – DFT Calculations The observation of the preferential formation of enamine products when using silylamines is in contrast to reactivity trends observed with primary alkyl amine substrates which furnish imine products upon reaction completion.27 In order to further understand the preference of N-silylenamines over the N-silylimine tautomer, DFT calculations (B3LYP/6-311g(d,p)) were performed by Dr. Jason W. Brandt. These results were evaluated in comparson to experimental results obtained.  Calculated tautomer ratios correlated well with experimentally determined equilibria (Scheme 3.11). For example, the calculated and observed tautomeric ratios for the hydroamination reaction using ethynylcyclohexane showed that when N is alkylated, the observed imine:enamine ratio is 100:0 (DFT calc. 99.7:0.3), yet when N is silylated the observed imine:enamine ratio is reversed at 12:88 (DFT calc. 8:92).    92 The NBO calculations show a change in bond polarity between the N-alkyl and N-silyl cases, such that the electropositive Si affords a more electron rich N. This results in significant stabilization of the N lone pair by donation into the π* of the enamine double bond. Although this interaction exists in both N-alkyl and N-silyl enamines, NBO analysis estimates the NLP to π*C=C stabilization to be ~9 kcal/mol greater in the enamine with N-SiMe2tBu over N-CMe3 (Figure 3.3). These insights highlight the different electronic features accessible in N-silylenamines as readily accessible reactive intermediates.   Scheme 3.11 Experimental and Calculated Data for Enamine and Imine Tautomerization Experiments HN SiN SiHN NExclusive(99.9%) (0.1%)ΔGcalc = 4.33 kcal/mol43%(67.6%)57%(32.4%)ΔGcalc = 0.43 kcal/molExperimental(Calculated)Experimental(Calculated)HN SiN Si88%(92.0%)12%(8.0%)ΔGcalc = 1.45 kcal/molExperimental(Calculated)3.4a 3.4b3.5a 3.5b3.7a 3.7bHN N(0.3%)Exclusive(99.7%)ΔGcalc = –3.46 kcal/molExperimental(Calculated)3.6a 3.6b  93  Figure 3.3 Frontier Molecular Orbital Analysis Based on Natural Bond Order Calculations 3.2.5 Substrate Scope of Sequential Hydroamination/Hydrogenation Transformation To Access Primary Amines As an illustration of the use of N-silylenamines as in situ generated reactive intermediates and a demonstration of the use of N-silylamines as ammonia surrogates for hydroamination, primary amine products were prepared using this sequential catalytic approach. First, the hydroamination reaction was performed and the reactive N-silylenamine intermediate was then exposed to catalytic Pd/C and H2. The salt of the crude amine product could be isolated by filtration following treatment with 1M hydrochloric acid.  In some cases, unwanted secondary amine byproducts were formed during the hydrogenation reaction (Table 3-1). The formation of secondary amines could occur through the exchange of silicon between the starting enamine and the reduced product, leading to the formation of an unsubstituted imine, which could be attacked by another amine. Gratifyingly, the salt of the primary amine product can be isolated by sublimation. Various terminal alkynes and one internal alkyne could be used in this tandem sequential approach (Scheme 3.12).  Cy N SitBu3.7a!∠N = 359°H3.6a!∠N = 345°Cy N HStabilization to molecule (NBO)NLP ➞ π*C=C = ~36 kcal/molNLP ➞ σ*Si-C = ~8 kcal/molStabilization to molecule (NBO)NLP ➞ π*C=C = ~27 kcal/molNLP ➞ σ*C-C = ~9 kcal/mol  94  Compound Number Ratio of Primary to Secondary Amines Combined Yield (%)a 3.3a 95:5 82 3.3b 92:8 71 3.3c >99:1 81 3.3d 95:5 70 3.3e 74:26 84 3.3f >99:1 85 3.3g 96:4 90 3.3h >99:1 70 3.3i >99:1 77 Table 3-1 Ratio of Primary to Secondary Amines After Hydrogenation and Salt Formation Reactions    R1i) 1-10 mol% 1C6D6 or d8-Tol70-145 °C, 6-72 hii) 2.5-5 mol% Pd/CH2 (1 atm)C6D6 or d8-Tolr.t., 40 hiii) 1 M HCl in Et2OEtOAc, r.t., 18 hR1NH2ClH2NSiR2R2R1NR2+R2R1HCl  95   Scheme 3.12 Sequential Catalysis for the Synthesis of Primary Amines from Alkynes and N-Silylamine 3.3 Conclusion In summary, a regio- and stereoselective hydroamination with N-silylamine substrates using bis(amidate)bis(amido)titanium catalyst 1 has been realized. The diverse array of (E)-N-silylenamines accessible represents a high yielding and atom-economic route for the in situ preparation of a useful class of organic synthons, which are otherwise hard to access through alternative methods. To test the [2+2] cycloaddition mechanistic hypothesis for the hydroamination reaction with silylamines, catalytically active silylimido species were isolated. Characterization by X-ray crystallography provided insights regarding the hemi-labile nature of the 1,3-N,O-chelating amidate ligands that support this unique reactivity. As a demonstration of the use of N-silylamine as a viable ammonia surrogate, a tandem sequential catalytic route was R1i) 1-10 mol% 1C6D6 or d8-Tol70-145 °C, 6-72 hii) 2.5-5 mol% Pd/CH2 (1 atm)C6D6 or d8-Tolr.t., 40 hiii) 1 M HCl in Et2OEtOAc, r.t., 18 hR1NH2•HClH2NSiR2R2NH2•HCl3.3h70%aNH2•HCl NH2•HClMeONH2•HClOMe OMeNH2•HCl3.3a75%aNH2•HCl3.3c81%aFNH2•HCl3.3b65%aF3C3.3e59%a3.3f84%a3.3d65%aNH2•HClMe3.3g73%aNH2•HCl3.3i77%aa) Isolated yields after purification by sublimation.   96 used to prepare primary amines from alkynes in good yields. On-going work focuses on the application of selectively prepared (E)-N-silylenamines as reactive intermediates in the preparation of N-heterocycles, which will be further discussed in Chapter 5.   97 Chapter 4: N-Silylenamines as Reactive Intermediates. Hydroamination for the Modular Synthesis of Selectively Substituted Pyridines 4.1 Introduction A wide variety of pyridines, can be found in numerous natural products252 and pharmaceutical agents.1, 253 Thus, significant effort has been employed toward their efficient preparation. In order to access pyridines with selected substitution patterns, two approaches are commonly employed: laborious, stepwise functionalization of the pyridine core,254-256 or formation of the 6-membered aromatic ring through condensation, cycloisomerization or cycloaddition.257-260  Selective functionalization of the pyridine core is an attractive methodology, albeit in the cases of multi-substituted pyridines, it can be material and labour intensive. On the other hand, combining two or more simple molecules via thermal or metal-catalyzed reactions can readily assemble substituted pyridines.258-260 For example, established condensation methods using 1,3- or 1,5-dicarbonyl derivatives are procedurally easy to set up, but offer restricted substitution patterns. For example, the Hantzsch pyridine synthesis reacts 1,3-dicarbonyls, an aldehyde and an ammonia source in one-pot to typically form substituted pyridines with specifically electron-withdrawing substituents in the 3- and/or 5-positions (Scheme 4.1 – top).261 The Kröhnke synthesis, on the other hand, starts with a pyridinium salt and a α,β-unsaturated carbonyl to form a 1,5-dicarbonyl intermediate, which can then react with ammonium acetate to deliver 2,4,6-trisubstituted pyridines selectively (Scheme 4.1 – bottom).262-263 However, yields can be problematic as dicarbonyls are prone to side-reactions, such as intra- or inter-molecular condensations, especially in cases where aldehydes are required to make pyridines without ortho-  98 substituents. Thus, a flexible and selective approach for the rapid assembly of a library of pyridines with diverse substitution patterns would allow for the modular assembly of such important substituted pyridine products and building blocks.  Scheme 4.1 General Hantzsch (top) and Kröhnke (bottom) Pyridine Syntheses Previously, N-silylated enamines had been used to construct select substituted pyridines,221, 264-265 although reported results were limited in substrate scope due to the difficult preparation and handling of moisture sensitive N-silylenamines using traditional stoichiometric approaches. However, as described in Chapter 3, a regioselective catalytic alkyne hydroamination with N-silylamines enables reliable and efficient in situ access to a wide range of mono-silylated enamines.266 Such reactive nucleophilic synthons allow for subsequent reaction with a broad range of α,β-unsaturated carbonyls to access very diverse substitution patterns using a single synthetic protocol. Among these pyridine motifs, we disclose the synthesis of 3-mono-, 2,5-di-, 3,4-di-, 2,3,5-tri-, 2,4,5-tri-, 2,3,4,5-tetra-, 2,3,4,6-tetra- and even 2,3,4,5,6-penta-substituted pyridines. In this chapter, 47 examples of substituted pyridines are disclosed, including 30 examples of 2,4,5-trisubstituted pyridines. This specific substitution pattern is known to be of importance for the development of a new class of NK1 receptor antagonists,267 the preparation of radiolabels for PET imaging,268 and the synthesis of alkaloids, such as flavocarpine and dihydrovincarpine.269 However, there are very few general syntheses of such General Hantzsch Pyridine SynthesisGeneral Kröhnke Pyridine SynthesisR1OOR2OR3 HO"NH3"2 x1) Δ2) [O]NR2OO OOR2R3R1 R1NR1 R3R2R1ON R2OR3NH4OAc/AcOHΔ  99 2,4,5-trisubstituted pyridines,221, 270-275 and even fewer where the substituent at the 5-position is something other than methyl.270-273, 275 Here we highlight how 1) the anti-Markovnikov regioselectivity of our hydroamination reaction with terminal alkynes, followed by 2) 6-membered ring formation via addition to an α,β-unsaturated aldehyde or ketone and (3) oxidation, affords a range of selectively substituted pyridines, including 2,4,5-substituted pyridines with various substituents.  Alkynes and α,β-unsaturated carbonyls, are both commercially available and have been previously used in pyridine syntheses, although not concurrently in the same procedure. The intermolecular synthesis of pyridines using unactivated alkynes is commonly performed using late transition metals with coupling partners such as nitriles,273, 275-280 halovinylimines,281-282 enamides,283-285 α,β-unsaturated imines286 and α,β-unsaturated ketoximes,287-291 which often have to be pre-synthesized. While, α,β-unsaturated carbonyls are readily available, they have been most typically applied toward the synthesis of 2,4,6-trisubstituted pyridines292-296 or pyridines containing electron-withdrawing groups (amide, cyano, ester and ketone groups) at the 3-position,297-302 with few examples that reach beyond these limitations..221, 264, 274, 303-307 Here we show how alkynes and α,β-unsaturated carbonyls can be used together to access a broad range of selectively substituted pyridines in moderate to excellent yields. 4.2 Results and Discussion 4.2.1 Optimization of Pyridine Formation Step Preliminary studies on the feasibility of synthesizing substituted pyridines using a sequential hydroamination followed by addition of an α,β-unsaturated carbonyl approach were performed using ethynylbenzene and (N-tert-butyldimethylsilyl)amine for the hydroamination step to generate the reactive N-silylenamine synthon in situ. Subsequently trans-chalcone was   100 added for the development of optimized conditions for the second step of the reaction (Table 4-1). While the reaction does occur in the absence of additives at 100 °C, the 11% yield was unsatisfactory. The addition of catalytic amounts a fluoride source helped activate the N-Si bond. For example, by adding 0.05 eq. of CsF the yield of the desired product was raised to 43%. Further optimization conditions were attempted with 10 mol% of CsF (Table 4-2). By changing the fluoride source to TBAF, the yield was not improved, however, a 1M solution of TBAF in THF is procedurally easier to handle. Other fluoride sources were also attempted, albeit no improvement on the yield was obtained (Table 4-3). The addition of 3 Å molecular sieves further increased the yield to 62% (Entry 4.1d). Finally, addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant allowed for the isolation of the desired product in 78% yield (Entry 4.1e). Further screening of stoichiometric and catalytic oxidant sources were attempted to no improvements in yield could be obtained (Table 4-4). A slight improvement on the yield was obtained using dimethysulfoxide (DMSO) as the solvent (Entry 6). Furthermore, a 5-mmol scale of the reaction was also performed to synthesize over a gram of the desired pyridine (Entry 4.1f, yield in parenthesis). If desired, the intermediate N-silylenamine can be purified by vacuum distillation. The use of the isolated intermediate affords the same yield as the case using in situ prepared intermediate, suggesting that the titanium and amide ligand present no deleterious effect on pyridine formation (Entry 4.1g). The reaction can also be achieved by using commercially available N-triphenylsilylamine instead of the (N-tert-butyldimethylsilyl)amine although a somewhat diminished yield results (65% , Entry 4.1h).  [F-] SourceAdditives NPhPhPhPhOPhPhHN SiCrude hydroaminationreaction mixture  101  Entry Fluoride Source Additive Yield [%]a 4.1a - - 11b 4.1b 0.05 equiv. CsF - 43c 4.1c 0.1 equiv. TBAF - 43 4.1d 0.1 equiv. TBAF 3 Å MS 62 4.1e 0.1 equiv. TBAF 3 Å MS; 1 equiv. DDQ 78 4.1f 0.1 equiv. TBAF 3 Å MS; 1 equiv. DDQ 85d (74)e 4.1g 0.1 equiv. TBAF 3 Å MS; 1 equiv. DDQ 83f 4.1h 0.1 equiv. TBAF 3 Å MS; 1 equiv. DDQ 65g a) Isolated yields. b) Heated to 100 °C. c) Heated to 50 °C; d DMSO as solvent. e) 5 mmol scale. f) Using isolated N-silylenamine. g) Commercially available Ph3SiNH2. Table 4-1 Optimization of Conditions for the Pyridine Formation Steps  Entry Temp (°C) Oxidant Yield (%) Notes 4.2a 25 - 46  4.2b 25 - 40 25 mol% CsF 4.2c 25 - 51 50 mol% CsF 4.2d 25 - 52 1 equiv. CsF 4.2e 50 - 43 5 mol% CsF 4.2f 50 Air 47  4.2g 50 10 mol% CuCl Under air 24 Solvent was DMSO 4.2h 80  46  4.2i 25 - 40 0.5 equiv. chalcone 4.2j 25 - 38 2 equiv. chalcone 4.2k 25 - 29 3Å molecular sieves Table 4-2 Optimization of Pyridine Synthesis Using 10 mol% Cesium Fluoride H2NSii) 1 mol% 1C6D6, 70 °C, 6 hii) trans-Chalcone10 mol% CsFDMF, Temp., 18 hiii) OxidantDMF, r.t., 1hNPhPhPh  102  Entry [F-] Yield (%) Notes 4.3a 1M TBAF in THF 43  4.3b CuF2 30  4.3c TASF 39  4.3d TBAT 31  Table 4-3 Optimization of Pyridine Synthesis Using 10 mol% of Other Fluoride Sources and 3Å molecular sieves  Entry Temp. (°C) Oxidant Yield (%) Notes 4.4a 50 - 21 5 mol% 1M TBAF no molecular sieves THF was used as solvent 4.4b 25 - 52 2 equiv. chalcone 4.4c 25 - 49 1.2 equiv. N-silylamine 4.4d 25 - 62  4.4e 50 - 71  4.4f 75 - 61  4.4g 100 - 62  4.4h 25 - 57 1 equiv. 1M TBAF 4.4i 25 - 67 1 equiv. 1M TBAF 0.4000g of molecular sieves 4.4j 25 10 mol% Cu(OAc)2 63 Oxidant allowed to react for 18 h 4.4k 25 10 mol% Cu(OAc)2 62 Oxidant added after 3 h and allowed to react for 18 h 4.4l 25 20 mol% Cu(OAc)2 70 Oxidant added after 30 min and allowed to react for 18 h H2NSii) 1 mol% 1C6D6, 70 °C, 6 hii) trans-Chalcone3Å molecular sieves10 mol% [F-]DMF, r.t., 18 hNPhPhPhH2NSii) 1 mol% 1C6D6, 70 °C, 6 hii) trans-Chalcone3Å molecular sieves10 mol% 1M TBAFDMF, Temp., 18 hiii) OxidantDMF, r.t., 1hNPhPhPh  103 Entry Temp. (°C) Oxidant Yield (%) Notes 4.4m 25 1 equiv. MnO2 53 Oxidant added after 3 h and allowed to react for 18 h 4.4n 25 10 equiv. MnO2 53 Oxidant allowed to react for 18 h 4.4o 25 1 equiv. KMnO4 64 Oxidant allowed to react for 18 h 4.4p 25 1 equiv. I2 in MeOH 67  4.4q 25 1 equiv. I2 in MeOH 25 Oxidant added after 3 h and allowed to react for 18 h 4.4r 25 1 equiv. I2 in MeOH 77 Oxidant allowed to react for 18 h 4.4s 25 1 equiv. I2 in MeOH 74 Oxidant allowed to react for 3 h 4.4t 25 10 equiv. activated carbon Under air 56 Oxidant added after 1.5 h and allowed to react for 18 h 4.4u 25 10 equiv. activated carbon 1 atm O2 54 Oxidant added after 3 h and allowed to react for 18 h 4.4v 25 1 equiv. DDQ 74 Oxidant added after 3 h 4.4w 25 1 equiv. BQ 54 Oxidant added after 3 h 4.4x 25 1 equiv. Cl-BQ 63 Oxidant added after 3 h 4.4y 25 1 equiv. DDQ 65 Oxidant added after 1 h 4.4z 25 1 equiv. DDQ 78  4.4aa 25 1 equiv. DDQ 41 0.0 mL DMF was used 4.4ab 25 1 equiv. DDQ 80 0.25 mL DMF was used 4.4ac 25 1 equiv. DDQ 78 1 mL DMF was used 4.4ad 25 1 equiv. DDQ 84 2.5 mL DMF was used 4.4ae 25 1 equiv. DDQ 77 5 mL DMF was used 4.4af 25 1 equiv. DDQ 85 0.25 mL DMSO was used Table 4-4 Optimization of Pyridine Synthesis Using 10 mol% of 1M Tetra-Butylammonium Fluoride in THF and 3Å molecular sieves 4.2.2 Substrate Scope With optimized conditions in hand, the scope and limitations of the sequential procedure were investigated (Scheme 4.2). We first examined the reaction of a terminal alkyne,   104 ethynylbenzene, with a variety of α,β-unsaturated aldehydes and ketones, which were commercially available or easily synthesized through aldol condensation.308-310 By reacting the hydroamination product mixture with prop-2-enal, an example of a mono-substituted pyridine was obtained in 34% yield (4.1a). By using a mono-substituted α,β-unsaturated carbonyl substrate, di-substituted pyridines, with 2,5- or 3,4-substitution patterns were obtained in 40 and 13% yields, respectively (4.1b and 4.1c). The reduced yields observed for the reactions using aldehydes is likely due to ill-defined side reactions of these substrates in the presence of the Lewis acidic titanium catalyst. Regardless, of note is the fact that currently 2,5-diphenylpyridine is commonly prepared via a double Suzuki coupling.311-317 However, the synthesis of 2,5-disubstituted pyridines with different substituents would demand sequential and chemospecific reaction conditions to distinguish between (pseuso)halogens. As for 3,4-diphenylpyridine only 6 procedures have been disclosed, all of which require multi-step procedures.318-323 Meanwhile our approach is completely regioselective and uses a common reaction protocol in all cases.   105   Scheme 4.2 Various α,β-Unsaturated Carbonyl Substrates can be Incorporated into this Sequential Reaction Similarly, disubstituted α,β-unsaturated ketones can be used to access tri-substituted pyridines with excellent regioselectivity for either the 2,3,5- or 2,4,5-positions. These variably substituted products were synthesized in a variety of yields ranging from 11-96% (4.1d-q). In H2NSii) 1 mol% 170 °C, 6 hii)aaaaaaaaaaa3Å MS10 mol% TBAFDMSO, r.t., 18 hiii) 1 eq. DDQDMSO, r.t., 1 hNPhR3R5R4R3OR5R4NPhHHHNPhR3R4R5R44.1r4.1sR5Me: 22%a,cPh: 68%a,cMePhR3MePhR34.1t4.1u4.1v4.1wR5H: 78%a,c4-OMe: 66%a,c4-Me: 68%a,c4-F: 58%a,cH4-CF34-Cl4-Br4.1qR5H: 78%aH: 83%a4.1o4.1pR34.1k4.1l4.1m4.1n4-OMe: 79%a2-OH: 44%aH: 84%aH: 48%aHH4-F 4-F: 83%aNPhR3R5NPhR3R5MeMono-substitutedTetra-substituted4.1a34%a,bNPhHHPh4.1b40%a,bNPhPhHH4.1c13%a,bDi-substitutedNPhR3HR5R34.1f4.1g4.1h4.1iR5Ph: 11%aMe: 23%a,biPr: 49%a,btBu: 96%a,bMePhPhPh4.1j CF3: 68%aPhTri-substituted2,5-substituted 3,4-substitutedNPhHR4R5R44.1d4.1eR5Ph: 47%a,bPh: 70%a,bMePhTri-substituted2,3,5-substituted2,4,5-substituted3-substituted2,3,4,5-substituted4-OMe3,4-OMe4-Cl4-NO2a) Isolated yields. b) One-pot reaction: hydroamination reaction performed under neat conditions followed by addition of α,β-unsaturated carbonyl. c) Second step performed at 80 °C.   106 medicinal chemistry, a trifluoromethyl group can drastically change the physical and biological properties of heterocycles.324 Thus a noteworthy example is pyridine 4.1j, which contains a trifluoromethyl group at the 2-position. This desirable motif was synthesized in 68% yield from 1,1,1-trifluoro-4-phenylbut-3-en-2-one.325 The resulting regioselectivity of pyridine formation was confirmed by X-ray diffraction of crystalline product 4.1m (Figure 4.1).  Figure 4.1 X-ray Crystallography of Pyridine 4.1m Finally, the synthesis of 2,3,4,5-tetrasubstituted pyridines could also be readily accessed using trisubstituted α,β-unsaturated ketones. Notably, this transformation features symmetrical and unsymmetrical α,β-unsaturated ketones in yields of up to 78% (4.1r-w). Notably, 4 of the 5 examples of 2,3,4,5-tetrasubstituted pyridines reported here are new compounds, which suggests that routine methods for these more highly substituted pyridines are underdeveloped.  Compound 4.1s has been recently synthesized by Chen and co-workers.275 In their synthesis, an alkenylation of nitriles with vinyliodonium salts is performed. While the reaction occurs in a single step, the vinyliodonium salts have to be pre-synthesized. Next the effect of different alkyne-substituents on the sequential reaction was examined using 4,4-dimethyl-1-phenylpent-1-en-3-one as a consistent α,β-unsaturated carbonyl substrate   107 (Scheme 4.3). In all cases, full consumption of starting materials in the hydroamination step is observed for the hydroamination reaction and the 1H NMR yields for the synthesized N-silylenamines vary between 69-99%.266 Halogenated para-substituted ethynylbenzenes (4.2a-c) were successfully employed in 81-88% yields. The presence of chloro- and bromo-substituents could allow for further cross-coupling transformations to be performed. Other para-substituted ethynylbenzenes bearing electron-donating and electron-withdrawing substituents were used to give products (4.2d-f) in great yields. The meta- (4.2g) and ortho-substituted (4.2h) ethynylbenzenes were also tolerated with no decrease in pyridine yield.      108   Scheme 4.3 Effect of Alkyne-Substituents on Sequential Reaction for Pyridine Synthesis The synthesis of pyridines containing other heterocycles on the 3- or 5-positions is important, as seen by the presence of such motifs in current commercial pharmaceutical drugs such as Crizotinib, Etoricoxib and Imatinib (Scheme 4.4). Using our developed methodology, alkynes containing various nitrogen- or sulfur-heterocycles (4.2i-o) were also compatible with these reaction conditions and the resultant pyridines could be synthesized and isolated in good yields (60-82%).  R1 H2NSii) 1-10 mol% 170-145 °C, 6-24 hii)aaaaaaaaaaa3Å MS10 mol% TBAFDMSO, r.t., 18 hiii) 1 eq. DDQDMSO, r.t., 1 hNR2PhtBuPhOtBuR2R1NPhtBuR4-F: 81%a4-Cl: 88%a4-Br: 85%a4-CF3: 77%a4-Me: 82%a4-OMe: 85%a3-OMe: 90%a2-OMe: 78%a4.2a4.2b4.2c4.2d4.2e4.2f4.2g4.2hRNR2PhtBuR1R14.2s4.2t4.2u4.2vR2Ph: 79%a,cPh: 72%a,cPh: 67%a,cPh: 64%a,cMeEtPrPhNPhtBu4.2p78%aN tBuPhHON tBuPhNHO4.2q27%a,b4.2r26%a,bTri-substitutedTetra-substituted2,3,4,6-substituted2,4,5-substitutedNHetPhtBuHeterocycles2-pyridine: 70%a3-pyridine: 72%a4-pyridine: 60%a4-pyrazine: 72%a1-methyl-4-pyrazole: 63%a2-thiophene: 82%a3-thiophene: 75%a4.2i4.2j4.2k4.2l4.2m4.2n4.2oa) Isolated yields. b) Second step performed at 50 °C. c) Second step performed at 80 °C.   109  Scheme 4.4 Importance of 3-Heterocyclic Pyridine Motif  Importantly, our reaction conditions are not limited to arylalkyne substrates, as shown with an enyne precursor (4.2p), as well as the use of an alkylamide to give product (4.2q) and silylether to furnish pyridine (4.2r). While these different derivatives were tolerated, the latter two were noted to be lower yielding. The incorporation of alkyl substituents on the 5-position presents a challenge. For example, there are no examples of 2,4,5-trisubstituted pyridines containing a methylene-spaced pivalamide substituent on the 5-position and only a single example containing a propanol substituent on the 5-position.326 Finally, internal alkynes could be used in combination with disubstituted α,β-unsaturated ketones to give 2,3,4,6-tetrasubstituted pyridines in 64-79% yields (4.2s-v). In the case of unsymmetrical aryl-alkyl internal alkynes, the regioselective hydroamination reaction allowed for the selective synthesis of tetra-substituted pyridines containing an alkyl group at the 2-position and an aryl group on the 3-position (4.2s-u). None of these examples have been reported previously. N NH2NN OHNClClFCrizotinibAnti-cancer drugN MeEtoricoxibAnti-inflammatoryNClS MeOONNNHNMeHN ONN MeImatinibAnti-cancer drugCurrently Approved Drugs Containing 3-Heterocyclic Pyridine Motifs  110 The synthesis of penta-substituted pyridines is a synthetic challenge, particularly in cases where the pyridine core contains five-carbon substitutents.272, 286-289, 327-330 However, using the developed sequential methodology, penta-substituted pyridines can be assembled in yields of 23-47% (4.3a-c) using the same 3 step sequential protocol (Scheme 4.5). Unfortunately, when the reaction was attempted with aryl-alkyl alkynes and unsymmetrical α,β-unsaturated ketones, a mixture of 2 regioisomers were obtained in ratios ranging from 65:35 to 78:22 (4.3d-f). Since the hydroamination using 1 is known to be regioselective for the addition of the amine to the alkyl side of the alkyne, the formation of regioisomers could hint to a change in mechanism for the formation of the 6-membered ring.   111   Scheme 4.5 Synthesis of Penta-Substituted Pyridines 4.2.3 Proposed Mechanism for the Formation of Pyridines Analysis of the substitution pattern obtained for product 4.1m provides a hint as to the mechanistic path for the cycloaddition step for pyridine formation (Scheme 4.6). As observed, R3 is located in the 4-position, which would be consistent with a Stork enamine reaction, where the R1 H2NSii) 10 mol% 1110-145 °C, 18-48 hii)aaaaaaaaaaa3Å MS10 mol% TBAFDMSO, 100 °C, 18 hiii) 1 eq. DDQDMSO, r.t., 1 hNR2R3R5R4R3OR5R4R2R1NPhPhPhMeMeNPhPhPhPhPh4.3c23%aPenta-substitutedNPhPhPhMePh4.3b47%a2,3,4,5,6-substituted4.3a46%aNPh MePrNPh MeMe4.3f12%a,bNPh MeEt4.3e14%a,b4.3d32%a,bCF3OMeClMeBrFNPh MeMeOMeCF3NPh MeEtMeClNPh MePrFBra) Isolated yields. b) Combined yields.   112 β-carbon of the enamine attacks the α,β-unsaturated carbonyl in a 1,4-addition fashion. Another pathway that could not be ruled out was the condensation reaction, followed by a cyclization event, which would also deliver the correct regioisomer. After condensation or cyclization and oxidation, the pyridine regioisomer obtained through these mechanisms would be in agreement with the isolated product. An alternative pathway considered was an aza-Michael addition, where the nitrogen of the enamine nucleophilically attacks the β-position of the α,β-unsaturated carbonyl. The product of this mechanism, however, would not furnish the observed regioisomer. Carbon-based enamines are known to react through the β-carbon of the enamine moiety. However, as shown from our previous study on N-silylenamines,266 which were notably resistant to tautomerization, in contrast to their carbon-substituted variants, the reactivity of enamines containing silicon-based substituents can be different from enamines containing carbon-based substituents. Thus, further investigation on the nucleophilicity of mono-silylated enamines is necessary to confirm the mechanistic pathway of this reaction.   113  Scheme 4.6 Potential Mechanisms for the Formation of Pyridines  4.2.4 Isolation of 2,4,5-Triphenylpyridin-3-ol By-Product In the initial stages of the optimization screening for the formation of pyridines, a common spot not corresponding to the product retention factor was observed by TLC. Separation of the unknown spot by column chromatography lead to the isolation of hydroxypyridine 4.4 in 28% yield (Scheme 4.7). The molecular structure of 4.4 was characterized by X-ray diffraction of the crystalline product (Figure 4.2). Preliminary efforts at optimizing the reaction towards the synthesis of 4.4 were attempted, but unsuccessfully. R2R1HN SiRRRR3OR5R4"F-"R2R1HN SiRRR R3OR5R4"F-"Pathway A-11,4-AdditionNHR2R1R4R5OR3R2R1 N R5R4R3R3R4R5NR1R3R4R5NR1R2OxidationCyclizationR2CondensationPathway A-2CondensationObserved regioisomerB. Aza-Michael AdditionA. Stork Enamine Reaction or CondensationR5R4R3NR1R21,4-AdditionCyclizationthen OxidationRegioisomerNot Observed  114  Scheme 4.7 Reaction that Lead to the Isolation of By-Product 4.4  Figure 4.2 X-ray Crystallography of Hydroxypyridine 4.4 4.3 Conclusion In conclusion, a simple, modular method to prepare mono-, di-, tri-, tetra-, and pentasubstituted pyridines has been disclosed in this chapter. The method developed employs a sequential regioselective hydroamination of alkynes with N-silylamine followed by the addition of an α,β-unsaturated carbonyl substrate to give a 6-membered nitrogen-containing ring intermediate that can undergo oxidation to afford pyridines. A broad range of targeted products could be isolated in a wide range of isolated yields. The generality of the transformation is demonstrated by using a wide scope of both alkyne and α,β-unsaturated carbonyl substrates. Notably, both of these starting materials are commercially available and/or easily synthesized. An aza-Michael reaction mechanism for N-silylenamine nucleophilic attack of the α,β-unsaturated carbonyl has been ruled out. A Stork enamine 1,4-addition would furnish the NPhPhPhOHH2NSii) 1 mol% 170 °C, 6 hii)aaaaaaaaaaa5 mol% CsFDMF, 50 °C, 18 h28%PhOPh4.4  115 observed selectively substituted pyridine products. Mechanistic investigations and applications in the synthesis of selectively substituted pharmaceutically relevant pyridine compounds are the natural progression for the continuation of this chapter.   116 Chapter 5: Future Directions and Conclusions 5.1 Future Directions The use of the Schafer, bis(amidate)bis(amido) titanium, complex has been studied extensively.25-27, 66-67, 266, 331-338 However, as clearly demonstrated by the work within this thesis, there are numerous new synthetic opportunities that can be explored using this complex. 5.1.1 Synthesis of Secondary Amines Containing α- and β-Substituents via a Sequential Hydroamination of Alkynes Followed by Reduction For several decades, amphetamine and its derivatives have been used as pharmaceutical agents, both medicinally and illicitly (Scheme 5.1).339-340 As such, the synthesis of such motifs is of significant interest to the pharmacology community. Titanium complex 1 has been shown to be regioselective for the hydroamination of unsymmetrical aryl/alkyl internal alkynes to give the correct regioisomer towards the synthesis of α-alkyl and β-aryl substituted amines. A logical continuation of the work performed in Chapter 2 would be to expand the substrate scope to include internal alkynes.   Scheme 5.1 Uses of Amphetamine and Derivatives Furthermore, there is currently no sequential hydroamination of alkynes followed by asymmetric hydrogenation strategy for the synthesis of enantiopure α-substituted phenethylamines. The only example of an asymmetric reduction after a hydroamination reaction Pharmaceutical Agents Ilicit DrugsAmphetamineTreatment for ADHDFenfluramineFormer treatment for obesityMethamphetamineNH2 HNPrenylamineFormer treatment for angina pectorisHN HNF3C3,4-MethylenedioxymethamphetamineHNOO  117 was accomplished using transfer hydrogenation.63 In the methodology developed by Che and co-workers, however, the hydroamination reaction delivered the Markovnikov regioisomer.  The challenge for the synthesis of enantiopure amines, via alkyne hydroamination, lies within the asymmetric reduction step. The asymmetric hydrogenation of enamides (N-acetyl enamines) using late-transition metal complexes, in particular rhodium,341 has been well studied, with systems delivering high yields and enantiomeric excesses. Consequently, the required N-acyl group is generally not easily cleaved (Scheme 5.2 – top).342-345   Scheme 5.2 General Asymmetric Hydrogenation of Enamides and Enamines On the other hand, the asymmetric hydrogenation of alkyl enamines has only been reported a few times, with a compromise between high enantiomeric excess and broad substrate scope (Scheme 5.2 – bottom).346-357 Furthermore, the asymmetric hydrogenation of unactivated imines has only been successful in cases where the substrate is cyclic, or has an aryl substituent on the nitrogen or on the α-position of the imine.342, 344, 358 The difficulty in the asymmetric hydrogenation of unactivated enamines stems from the fact that these enamines lack the ability to form a stable bis-chelate that the related enamides are proposed to form, which occurs through chelation of the alkene and oxygen of the carbonyl prior to insertion into the metal-hydride. Asymmetric Hydrogenation of EnamidesR3R2R1 NHAcRh*/Ru*/Ir*CatalyzedHydrogenationH2R3R2R1 NHAc*R3R2R1 NTi*/Rh*/Ir*CatalyzedHydrogenationH2R3R2R1 N*R5R4R5R4Asymmetric Hydrogenation of Enamines  118 5.1.1.1 Preliminary Results  The hydroamination of internal alkynes with complex 1 followed by Pd/C hydrogenation was successful with one example. Following the same procedure as developed for terminal alkynes discussed in Chapter 2, prop-1-yn-1-ylbenzene was reacted with iso-propylamine in the presence of 10 mol% of titanium complex 1 and then reacted with Pd/C and H2 gas at 3 bar to deliver 96% yield of N-isopropyl-1-phenylpropan-2-amine (Scheme 5.3).  Scheme 5.3 Sequential Hydroamination/Hydrogenation Towards the Synthesis of N-isopropyl-1-phenylpropan-2-amine  The synthesis of enantiopure secondary amines using homogeneous hydrogenation catalysts were attempted (Table 5-1). The reaction mixtures were analyzed using mass spectrometry, but isolation of the final products have yet to be performed.  Entry [M] Observation by GC-MS 2.4a  Mass corresponding to hydrolyzed starting material observed. LRMS (CI) m/z calc’d for C9H10O [M+H+]: 134.07; found: 135.0. Trace amounts of product observed.    i) 10 mol% 1d8-Tol, 110 ºC24 hii) 5 mol% Pd/CH2 (3 bar)MeOH, r.t., 3 hH2N+ PhHNPh96%MeMei) 10 mol% 1d8-Tol, 100 ºC24 hii) [M]H2 (660 psi)MeOH, r.t., 24 hH2N+ PhHNPhMeMeRhPPFeiPriPriPriPrBF4+1 mol%  119 Entry [M] Observation by GC-MS 2.4b  Mass corresponding to hydrolyzed starting material observed. LRMS (CI) m/z calc’d for C9H10O [M+H+]: 134.07; found: 135.0. Trace amounts of desired product observed. 2.4c  Mass corresponding to product observed. LRMS (CI) m/z calc’d for C13H21N [M+H+]: 191.17; found: 192.0. Yield: N.D. 2.4d  Mass corresponding to product observed. LRMS (CI) m/z calc’d for C13H21N [M+H+]: 191.17; found: 192.0. Yield: N.D. Enantiomeric excess %: N.D. 2.4e  Mass corresponding to product observed. LRMS (CI) m/z calc’d for C13H21N [M+H+]: 191.17; found: 192.0. Yield: N.D. Enantiomeric excess %: N.D. 2.4f  Trace amounts of desired product observed. Table 5-1 Preliminary Results of the Homogeneous Hydrogenation Towards α-Substituted Secondary Amines  By examining the results in hand, it seems that rhodium catalysts are not as reactive as iridium catalysts towards the hydrogenation of the hydroamination reaction mixtures. However, RhPPiPriPriPriPrBF4+1 mol%IrPCy3NPF6+0.5 mol%FePPhPhPPhPh0.5 mol% [Ir(cod)Cl]21 mol%P PMeOOMe0.5 mol% [Ir(cod)Cl]21 mol%P PMeOOMe0.5 mol% [Ir(cod)Cl]21 mol%1 mol% NaBF4  120 other reaction conditions, such as addition of acids, could still be attempted with rhodium catalysts. 5.1.2 Synthesis of N-Heterocycles Using N-Silylenamine as a Reactive Intermediate Mono-silylated enamines have been used in the synthesis of very few N-heterocycles, which range from a single ring to multi-fused systems (Scheme 5.4).219, 223, 225-226 Due to the limited synthetic methodologies available towards the synthesis of N-silylenamines, in all previous cases, an α-substituent was required. In Chapter 3, however, it was demonstrated that linear N-silylenamines could be synthesized through a titanium-catalyzed hydroamination of alkynes with N-silylamines. Furthermore, a modular synthesis of mono-, di-, tri-, tetra- and penta-substituted pyridines using N-silylenamines as a reactive synthon was described in Chapter 4. Thus, the synthesis of other N-heterocycles would be a reasonable extension to showcase the applicability of N-silylenamines.  Scheme 5.4 Synthesis of N-Heterocycles Using N-Mono-Silylated Enamines 5.1.2.1 Reactivity of α-Haloketones with N-Silyenamines Due to the diverse biological activity shown by molecules containing a pyrrole motif, it is not surprising that the syntheses of such compounds have been widely studied.359-361 The synthesis of pyrroles through an intermolecular hydroamination of alkynes has been accomplished four times.74-77 However, in all cases reported to date, no examples of pyrroles NNNR22ArR1Cl13 examples18-95%NN24%NOR1R2 R3R310 examples34-84%N Alk2 examples82-86%PhenanthridineDihydroquinolinone1-Aza-azulenePyrimidineHighlighted in red are the bonds formed between the N-silylenamine and the other starting material.   121 without an N-substituent has been demonstrated. Since the cleavage of an N-Si bond can be be readily achieved, it was envisioned that the synthesis of pyrroles could occur through the addition of an α-haloketone to the N-silylenamine product (Scheme 5.5 – top). However, when the reaction was performed, 3,5-disubstituted pyridines were obtained (Scheme 5.5 – bottom). The pyridine product was unexpected, as both the starting materials are two-carbon fragments, suggesting either the cleavage of a C-C bond or methyl abstraction from the DMSO solvent.  Scheme 5.5 Proposed Sequential Hydroamination/Addition of α-Haloketone Towards the Synthesis of Pyrroles and General Scheme for Experimentally Obtained Results When the reaction was performed with 2-bromo-1-phenylethan-1-one, 3,5-diphenylpyridine was isolated in 20% yield (Table 5-2, Entry 3.2a). By changing the α-haloketone to 1-bromo-3,3-dimethylbutan-2-one, the mass corresponding to 3,5-diphenylpyridine was obtained by GC-MS. On the other hand, by changing the N-silylenamine fragment but maintaining the α-haloketone as 2-bromo-1-phenylethan-1-one, the mass corresponding to 3,5-bis(4-(trifluoromethyl)phenyl)pyridine was obtained by GC-MS.    R2OBrR1i) Hydroaminationii) Addition ofH2NSiNHR1R2and/orNHR1 R2Hi) 1 mol% 1C6D6, 70 °C, 6 hii) aaaaaaaaa10 mol% TBAF3 Å MSDMSO, r.t., 18 hNR1R1R1 H2NSiHR2OBrProposed Synthesis of PyrrolesExperimental Result  122 Entry Reaction (Notes) 3.2a  (20% isolated yield. Product obtained was confirmed by X-ray crystallography.)  3.2b  (Yield: N.D. Mass corresponding to depicted product was observed by GC-MS. LRMS (CI) m/z calc’d for C17H13N [M+H+]: 231.30; found: 232.1.) 3.2c  (Yield: N.D. Mass corresponding to depicted product was observed by GC-MS. LRMS (CI) m/z calc’d for C19H11F6N [M+H+]: 367.08; found: 368.0.) Table 5-2 Preliminary Results of Sequential Hydroamination/Addition of α-Haloketone Reactions Considered together, it is reasonable to propose that 2 equivalents of N-silylenamine and a yet unidentified one-carbon source are reacting to form the observed 3,5-disubstituted pyridines. While we do not have evidence that dimethylsulfoxide is involved in the reaction, it has been previously shown that dimethylsulfoxide can act as a one-carbon source.362-363 In most cases reduction of dimethylsulfoxide to dimethylsulfide is necessary before it can be used as a –CH– source. Other control reactions, which include performing the reaction in the absence of α-i) 1 mol% 1C6D6, 70 °C, 6 hii) aaaaaaaaa10 mol% TBAF3 Å MSDMSO, r.t., 18 hNPhPhH2NSiHPhOBri) 1 mol% 1C6D6, 70 °C, 6 hii) aaaaaaaaa10 mol% TBAF3 Å MSDMSO, r.t., 18 hNPhPhH2NSiHtBuOBri) 1 mol% 1C6D6, 70 °C, 6 hii) aaaaaaaaa10 mol% TBAF3 Å MSDMSO, r.t., 18 hNH2NSiHPhOBrF3CCF3F3C  123 haloketone and performing the reaction in various solvents, are needed to further understand the formation of 3,5-disubstituted pyridines. 5.1.2.2 Synthesis of N-Silyl-1-Amino-1,3-Diene and Reactivity with Dienophiles The syntheses of linear dienes containing a nitrogen group at the 1-position are usually limited to N-acylated,364-366 N-Boc protected367 or secondary amine368-370 containing dienes. Such 1-amino-1,3-dienes are reactive towards dienophiles to give aminocyclohexenes via a Diels-Alder transformation.364, 366, 371-376 Through the methodology developed in Chapter 3, N-silyl-1-amino-1,3-dienes could be easily synthesized in a single step starting from an enyne and a N-silylamine. Furthermore, primary aminocyclohexenes could be targeted. Other than traditional Diels-Alder reactions, aminocyclohexenes can be synthesized through the hydroamination of 1,3-dienes,377 allylic substitution of cyclic allyl carbonates with amines,378 hydrogenation of cyclic enamides,379 and isomerization of ynamides and allenamides.380   After performing the hydroamination of 1-ethynylcyclohex-1-ene with N-silylamine, a variety of dienophiles were added to the reaction mixture (Scheme 5.6). Although the consumption of starting materials was observed by 1H NMR spectroscopy, the isolation of the final desired products remains unsuccessful and thus further work towards the isolation of product would be a priority.   124  Scheme 5.6 Dienophiles Attempted Towards the Synthesis of Aminocyclohexenes  In the case when acrylaldehyde was added to the hydroamination mixture (Scheme 5.7), full consumption of both starting materials (N-silylenamine and acrolein) and appearance of new peaks were observed by 1H NMR spectroscopy (Figure 5.1). However, attempted purification and isolation of the product by column chromatography was not successful. Decomposition of the product appears to occur as evidenced by the appearance of several compounds by TLC.  Scheme 5.7 Sequential Hydroamination/Addition of Acrolein SiH2N+H i) 2.5 mol% 1C6D6, 70 °C, 8 hii) Addition ofDienophilesNH2R2R1OOOHOHOHOCN CNNCCNNCNCCNDienophilesOMeOOMeOSiH2N+H i) 2.5 mol% 1C6D6, 70 °C, 8 hii) Addition of1 equiv. ofAcroleinNHHOHNorHOSi SiHN Si  125  Figure 5.1 1H NMR Spectra (C6D6, 300 MHz, 298 K) for the Crude Hydroamination Reaction Product Between 1-Ethynylcyclohex-1-ene and N-Tert-Butyldimethylsilylamine (top) and for the Crude Reaction depicted in Scheme 5.7 (bottom) 5.2 Summary  This thesis has demonstrated that titanium complex 1 is a useful catalyst towards the synthesis of nitrogen-containing small molecules and heterocycles, including primary and secondary amines, and pyridines. An atom economical and catalytic route for the synthesis of aryl‐ and alkyl‐substituted secondary amines was disclosed in Chapter 2. Using the titanium complex 1, the hydroamination of terminal alkynes with a range of amines resulted in the selective formation of the anti‐  126 Markovnikov hydroamination product. The crude enamine/imine mixtures were effectively hydrogenated using palladium on carbon (Pd/C) and H2 to afford the corresponding secondary amine in excellent yields. Simple work‐up procedures allowed for the isolation of pure compounds while avoiding purification via column chromatography. Further work into the hydroamination of internal alkynes for the synthesis of asymmetric α-substituted amines is required. In Chapter 3, an anti-Markovnikov selective hydroamination of alkynes with N-silylamines to afford N-silylenamines was reported. The reaction was also catalyzed by complex 1 and was compatible with a variety of terminal and internal alkynes. Stoichiometric mechanistic studies and computational calculations were also performed. This method easily afforded interesting N-silylenamine synthons in good to excellent yields and the easily removable silyl protecting group enabled the catalytic synthesis of primary amines after reduction using Pd/C and H2. The applicability of the N-silylenamine synthon still requires further exploration. Finally, a modular and selective synthesis of mono-, di-, tri-, tetra- and penta-substituted pyridines is reported in Chapter 4. Addition of α,β-unsaturated carbonyls to the crude mixtures of hydroamination reactions followed by oxidation affords 47 examples of pyridines in yields of up to 96%. This disclosed synthetic route allows for the synthesis of diverse pyridines containing different substitution patterns in three sequential reactions, which can be carried out using a one-pot protocol. 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Denise, B.; Parlier, A.; Rudler, H.; Vaissermann, J., J. Organomet. Chem. 1995, 494, 43.  140 Appendices Appendix A   This appendix is for the supporting information pertaining the research conducted in Chapter 2. A.1 General Considerations All air and moisture sensitive reactions were performed using a MBraun LABmaster glovebox filled with a N2 atmosphere. All pieces of glassware were dried for at least 4 hours in a 160 °C oven before being transferred into the glovebox. All stirring was done with appropriately sized Teflon coated magnetic stir bars dried for at least 4 hours in a 160 °C oven. Benzene and hexanes were passed over activated alumina columns into Teflon sealed Straus flasks and stored therein until use. d6-Benzene was dried over sodium metal, distilled, degassed, and stored in Teflon sealed Schlenk flasks prior to use. Hydrogenations were performed using a Fischer-Porter tube. Experiments conducted on NMR tube scale were performed in J-Young NMR tubes (8” x 5 mm) sealed with screw-type Teflon caps. Thin layer chromatography (TLC) was set-up on EMD Silica gel 60 F254 plates. Visualization was achieved under a 254 nm UV light source and/or by staining with potassium permanganate or ninhydrin solutions. Flash chromatography was set-up using SiliaFlash F60 silica gel (230-400 mesh) (Silicycle) and glass columns, with ACS grade solvents (Sigma-Aldrich). A.2 Materials Ti(NMe2)4 (Sigma-Aldrich) and 10 wt% Pd/C (Sigma-Aldrich) were used as received. All amines and alkynes were purchased from commercial sources, dried over CaH2 and distilled prior to use. Hydrogen gas (PP 4.5) was purchased from Praxair and used without further purification.  141 A.3 Instrumentation NMR spectra were recorded as dilute solutions in deuterated chloroform or benzene on a Bruker Avance 300, 400 or 600 MHz spectrometer at ambient temperature. 1H chemical shift data are given in units δ relative to the residual protic solvent where δ (CDCl3) = 7.26 ppm and δ (C6D6) = 7.16 ppm, while 13C chemical shift data are given in units δ relative to the solvent where δ (CDCl3) = 77.16 ppm and δ (C6D6) = 128.06 ppm. High-resolution mass spectra were measured by the mass spectrometry and microanalysis service at the Department of Chemistry, University of British Columbia. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 eV) source or a Bruker Esquire LC spectrometer using electrospray ionization source. Fragment signals are given in mass per charge number (m/z). A.4 Synthesis and Compound Characterization N-(2,6-diisopropylphenyl)benzamide  The amide was synthesized following a procedure adapted from literature.381 Benzoyl chloride (5.10 mL, 44 mmol, 1.1 equiv.) was added to a solution of 2,6-diisopropylaniline (7.54 mL, 40 mmol, 1 equiv.) and triethylamine (7.21 mL, 52 mmol, 1.3 equiv.) in dichloromethane (267 mL, 0.15M). The reaction solution was stirred at room temperature overnight. Upon completion, the reaction mixture was washed with 1M HCl (x3), 1M NaOH (x3) and brine (x1). The organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure to afford a pale pink solid. Subsequent re-crystallizations afforded the title compound as white needles in 89% yield. The analytical data was consistent with literature.382 1H NMR (400 MHz; CDCl3): δ 7.95-7.92 (m, 2H), 7.61-7.56 (m, 1H), 7.52 (m, ONH i-Pri-PrEt3NDCM, r.t.onOCl H2Ni-Pri-Pr+ONH i-Pri-Pr 142 2H), 7.34 (m, 1H), 7.30 (s, 1H), 7.23 (m, 2H), 3.15 (7, J = 6.9 Hz, 2H), 1.23 (d, J = 6.9 Hz, 12H). 13C NMR (100 MHz; CDCl3): δ 167.1, 146.5, 134.7, 131.8, 131.3, 128.9, 128.6, 127.3, 123.7, 29.0, 23.8. Bis(N-2,6-diisoprpylphenylbenzamidate)bis(dimethylamido)titanium (IV)  The titanium complex was synthesized following a procedure adapted from literature.25 Inside an inert atmosphere box, tetrakis(dimethylamido)titanium (IV) (0.6728 g, 3 mmol, 1 equiv.) was added to a solution of N-(2,6-diisopropylphenyl)benzamide (1.6871 g, 6 mmol, 2 equiv.) in hexanes. The reaction mixture was stirred at room temperature overnight. Upon completion, the reaction solution was concentrated under reduced pressure to afford the title compound as a red powder in quantitative yield. The crude compound was subsequently used without further purification. 1H NMR (400 MHz; C6H6): δ 7.75-7.73 (m, 4H), 7.20 (s, 6H), 6.95-6.86 (m, 6H), 3.71-3.61 (m, 4H), 3.33 (s, 12H), 1.35 (d, J = 6.8 Hz, 12H), 0.98 (d, J = 6.8 Hz, 12H). 13C NMR (100 MHz; C6D6): δ 177.2, 142.7, 142.5, 133.1, 131.5, 130.3, 128.0, 126.0, 124.1, 47.8, 28.2, 24.7, 24.4. General Procedure for the Time Optimization of the Hydroamination Reaction  Inside an inert atmosphere box, benzene (0.3 mL) was added to the titanium complex (0.01 mmol, 1 mol% Ti) in a 5-dram vial. The solution was then transferred to a J-Young tube. The amine (1 mmol, 1 equiv.) and alkyne (1 mmol, 1 equiv.) were pre-weighed to separate 5-dram ONH i-Pri-PrTi(NMe2)4Hex, r.t.onAr = 2,6-diisopropylphenylTitanium Complex 1TiNONOPhPh ArArNMe2NMe21 mol% 1C6H6, 70 °CTimeR1H2N+ RHNR1RR, R1 = aryl or alkyl+ R N R1Enamine (E) Imine (I)HAr = 2,6-diisopropylphenylTitanium Complex 1TiNONOPhPh ArArNMe2NMe2 143 vials and transferred to the J-Young tube. The remaining benzene (0.7 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction tube. The J-Young tube was sealed, taken out of the inert atmosphere box and a time zero 1H NMR spectrum was obtained. The reaction solution was heated at 70 °C and after every hour of heating, a 1H NMR spectrum was obtained until full consumption of starting materials was observed. For reactions that required more than 1 hour of heating, a second reaction was set-up, in which no hourly stoppages occurred. Other than the time zero 1H NMR spectrum, only the 1H NMR spectrum at the expected completion time was obtained. General Procedure for the Sequential Hydroamination/Hydrogenation Synthesis of Secondary Amines  Inside an inert atmosphere box, benzene (3 mL) was added to the titanium complex (0.05 mmol, 1 mol% Ti) in a 5-dram vial. The solution was then transferred to a scintillation vial. The amine (5 mmol, 1 equiv.) and alkyne (5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the reaction vessel. The remaining benzene (2 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction vessel. The mixture was sealed, taken out of the inert atmosphere box and stirred at 70 °C for 0.5 to 6 hours, depending on the substrate. Half an hour prior to the completion of the hydroamination step, an oven dried Fischer-Porter tube was cooled under N2. Under a N2 flow, palladium on carbon (0.25 mmol, 0.5 mol% Pd or 0.5 mmol, 1 mol% Pd) and methanol (2 mL) were added to the vessel, which was then pressurized and vented with H2 five times. After allowing the hydroamination reaction mixture to cool down, the solution was added to the Fischer-Porter tube using a 5 mL syringe. i) 1-10 mol% [Ti]C6H6, 70 °C30 min - 6 hii) 0.5-1 mol% Pd/CH2 (3 bar)MeOH, r.t., 3-5 hR1H2N+ RHNR1R23 examplesup to 99% yieldR, R1 = aryl or alkylH 144 An additional 3 mL of methanol was used to rinse the vial containing the first step, and this liquid was also added to the Fischer-Porter tube. The tube was then sealed and pressurized to 3 bar. The reaction was allowed to proceed at room temperature for 3 to 5 hours depending on the substrate. The crude compound was concentrated under reduced pressure and filtered through a short plug of Celite using hexanes. The filtrate was concentrated under reduced pressure, affording a mixture of ligand and product. The mixture was chilled in the fridge for at least 30 minutes. Cold hexanes were added to the concentrated oil and the suspension formed was filtered using filter paper and a funnel. Unless otherwise stated, concentration of filtrate under reduced pressure afforded the desired secondary amine in high purity.  N-phenethylpropan-2-amine (2.1a) According to the general procedure, propan-2-amine (0.2956 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 30 minutes. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a pale yellow oil in 91% yield. The analytical data was consistent with literature.383 1H NMR (400 MHz; CDCl3): δ 7.30-7.28 (m, 2H), 7.23-7.19 (m, 3H), 2.91-2.87 (m, 2H), 2.82 (m, 3H), 1.06 (d, J = 6.3 Hz, 6H).13C NMR (101 MHz; CDCl3): δ 140.3, 128.8, 128.6, 126.3, 49.0, 48.7, 36.7, 23.0. N-phenethylbutan-2-amine (2.1b) According to the general procedure, butan-2-amine (0.3657 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 30 minutes. Upon HNHN 145 completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a yellow oil in 97% yield. 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.23-7.19 (m, 3H), 2.95-2.78 (m, 4H), 2.60-2.52 (m, 1H), 1.51-1.43 (m, 1H), 1.33-1.28 (m, 1H), 1.02 (d, J = 6.3 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 140.3, 128.8, 128.6, 126.2, 54.6, 48.8, 36.8, 29.7, 20.0, 10.4. HRMS (ESI+) m/z calc’d for C12H20N [M+H+]: 178.1596; found: 178.1597. 2-methyl-N-phenethylpropan-2-amine (2.1c) According to the general procedure, 2-methyl-propan-2-amine (0.3657 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a yellow oil in 98% yield. The analytical data was consistent with literature.58 1H NMR (400 MHz; CDCl3): δ 7.32-7.27 (m, 2H), 7.23-7.19 (m, 3H), 2.86-2.82 (m, 2H), 2.80-2.76 (m, 2H), 1.08 (s, 9H).13C NMR (101 MHz; CDCl3): δ 140.4, 128.8, 128.5, 126.2, 50.4, 44.3, 37.4, 29.1. N-phenethylcyclopentanamine (2.1d) According to the general procedure, cyclopentanamine (0.4258 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the HNHN 146 title compound as a pale yellow oil in 98%. 1H NMR (400 MHz; CDCl3): δ 7.31-7.28 (m, 2H), 7.22-7.19 (m, 3H), 3.12-3.06 (m, 1H), 2.90-2.80 (m, 4H), 1.88-1.81 (m, 2H), 1.70-1.63 (m, 2H), 1.56-1.49 (m, 2H), 1.36-1.27 (m, 2H). 13C NMR (101 MHz; CDCl3) δ 140.3, 128.8, 128.6, 126.2, 59.9, 50.1, 36.7, 33.3, 24.2. HRMS (ESI+) m/z calc’d for C13H20N [M+H+}: 190.1596; found: 190.1591. N-phenethylcyclohexanamine (2.1e) According to the general procedure, cyclohexanamine (0.4959 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 2 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a pale yellow oil in 95% yield. The analytical data was consistent with literature.58 1H NMR (400 MHz; CDCl3): δ 7.31-7.27 (m, 2H), 7.22-7.18 (m, 3H), 2.92-2.88 (m, 2H), 2.81-2.78 (m, 2H), 2.43 (m, 1H), 1.89-1.83 (m, 2H), 1.74-1.68 (m, 2H), 1.63-1.57 (m, 1H), 1.29-1.20 (m, 2H), 1.18-1.12 (m, 1H), 1.10-1.00 (m, 2H).13C NMR (101 MHz; CDCl3) δ 140.4, 128.8, 128.6, 126.2, 56.9, 48.4, 36.8, 33.7, 26.3, 25.2. N-phenethylcycloheptamine (2.1f) According to the general procedure, cycloheptanamine (0.5660 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 2 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a pale yellow oil in 96% yield. 1H NMR (400 MHz; CDCl3): δ 7.31-7.27 (m, HNHN 147 2H), 7.22-7.18 (m, 3H), 2.90-2.86 (m, 2H), 2.83-2.79 (m, 2H), 2.67-2.62 (m, 1H), 1.85-1.79 (m, 2H), 1.67-1.60 (m, 2H), 1.56-1.47 (m, 4H), 1.44-1.36 (m, 4H).13C NMR (101 MHz; CDCl3) δ 140.4, 128.8, 128.6, 126.2, 59.2, 49.0, 36.7, 35.0, 28.4, 24.6. HRMS (ESI+) m/z calc’d for C15H24N [M+H+}: 218.1909; found: 218.1911. N-phenethylaniline (2.1g) According to the general procedure, aniline (0.0.4656 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 30 min. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Purification by column chromatography (95:5 Hex/Et2O + 0.1% Et3N) afforded the title compound as a yellow oil in 89% yield.384 The analytical data was consistent with literature.x 1H NMR (400 MHz; CDCl3): δ 7.35-7.31 (m, 2H), 7.26-7.22 (m, 3H), 7.21-7.17 (m, 2H), 6.74-6.69 (m, 1H), 6.64-6.61 (m, 2H), 3.67 (s, 1H), 3.41 (t, J = 7.0 Hz, 2H), 2.93 (t, J = 7.0 Hz, 2H).13C NMR (101 MHz; CDCl3): δ 148.1, 139.4, 129.4, 128.9, 128.7, 126.6, 117.6, 113.1, 45.2, 35.7. N-phenethyl-4-(trifluoromethyl)aniline (2.1h) According to the general procedure, 4-(trifluoromethyl)aniline (0.8056 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Purification by column chromatography (95:5 Hex/Et2O + 0.1% Et3N) afforded the title compound as a yellow oil in 85% yield. 1H NMR (400 MHz; CDCl3): δ 7.41 (d, J = 8.4 Hz, 2H), 7.35-7.31 (m, 2H), 7.28-7.21 HNHNCF3 148 (m, 3H), 6.65 (d, J = 8.5 Hz, 2H), 3.44 (t, J = 7.0 Hz, 2H), 2.94 (t, J = 7.0 Hz, 2H). 13C NMR (151 MHz; CDCl3): δ 150.4, 138.9, 128.9, 128.8, 126.8 (q, 3J(C,F) = 3.6Hz),125.1 (q, 1J(C,F) = 270.2Hz), 119.1 (q, 2J(C,F) = 32.7Hz), 112.2, 44.8, 35.3. HRMS (ESI+) m/z calc’d for C15H15NF3 [M+H+}: 266.1157; found: 266.1150. N-phenethyl-4-fluoroaniline (2.1i) According to the general procedure, 4-fluoroaniline (0.5556 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Purification by column chromatography (95:5 Hex/Et2O + 0.1% Et3N) afforded the title compound as a pale yellow oil in 81% yield.384 1H NMR (400 MHz; CDCl3): δ 7.34-7.30 (m, 2H), 7.24-7.20 (m, 3H), 6.93-6.88 (m, 2H), 6.63-6.59 (m, 2H), 3.37 (t, J = 7.1 Hz, 2H), 2.93 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz; CDCl3): δ 156.0 (d, 1J(C,F) = 235.9Hz), 139.3, 128.9, 128.8, 126.6, 115.8 (d, 2J(C,F) = 22.4Hz), 114.1 (d, 3J(C,F) = 6.5Hz), 45.9, 35.5. 4-methoxy-N-phenethylaniline (2.1j) According to the general procedure, 4-metoxyaniline (0.6158 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Purification by column chromatography (9:1 Hex/EtOAc + 0.1% Et3N) afforded the title compound as a yellow oil in 77% yield.384 1H NMR (400 MHz; CDCl3): δ 7.31 (m, 2H), 7.25-7.21 (m, 3H), 6.81-6.79 (m, HNFHNOMe 149 2H), 6.67 (m, 2H), 3.75 (s, 3H), 3.37 (t, J = 7.1 Hz, 2H), 2.93 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz; CDCl3): δ 152.5, 142.1, 139.5, 128.9, 128.7, 126.5, 115.1, 114.7, 55.9, 46.3, 35.7. Diphenethylamine (2.1k) According to the general procedure, 2-phenylethan-1-amine (0.6059 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex in benzene. The reaction mixture was stirred at 70 °C for 5 hours. Upon completion the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Purification by formation and isolation of HCl salt and re-basification to the free amine afforded the title compound as a pale orange solid in 58% yield.385 1H NMR (400 MHz; CDCl3): δ 7.30-7.26 (m, 4H), 7.22-7.16 (m, 6H), 2.96-2.92 (m, 4H), 2.86-2.83 (m, 4H). 13C NMR (101 MHz; CDCl3): δ 139.9, 128.8, 128.6, 126.3, 51.1, 36.3. N-(3,4-dimethoxyphenethyl)-2-phenylethan-1-amine (2.1l) According to the general procedure, 2-(3,4-dimethoxyphenyl)ethan-1-amine (0.9062 g) and ethynylbenzene (0.5107 g) were added to a solution of the titanium complex in benzene. The reaction mixture was stirred at 70 °C for 6 hours. Upon completion the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Purification by formation and isolation of HCl salt and re-basification to the free amine afforded the title compound as a pale yellow solid in 33% yield. 1H NMR (400 MHz; CDCl3): δ 7.29-7.25 (m, 1H), 7.22-7.15 (m, 3H), 6.78-6.76 (m, 1H), 6.70 (m, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.97-2.79 (m, 8H). 13C NMR (101 MHz; CDCl3): δ 149.1, 147.7, 139.1, 131.7, 128.7, 128.6, 126.5, HNHN OMeOMe 150 120.6, 112.0, 111.4, 56.0, 55.9, 50.5, 50.4, 35.3, 34.9. HRMS (ESI+) m/z calc’d for C18H23NO2 [M+H+]: 286.1807; found: 286.1805. N-(4-(trifluoromethyl)phenethyl)butan-2-amine (2.2a) According to the general procedure, butan-2-amine (0.3657 g) and 1-ethynyl-4-(trifluoromethyl)benzene (0.8506 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 30 minutes. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a yellow oil in 99% yield. 1H NMR (400 MHz; CDCl3): δ 7.55 (d, J = 8.2 Hz, 2H), 7.33 (d, J = 8.2 Hz, 2H), 2.95-2.84 (m, 4H), 2.58 (m, 1H), 1.52-1.45 (m, 1H), 1.35-1.28 (m, 1H), 1.03 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (151 MHz; CDCl3): δ 144.3, 129.0, 128.6 (q, 2J(C,F) = 32.4Hz) 125.4 (q, 3J(C,F) = 3.7Hz), 124.3 (q, 1J(C,F) = 271.8Hz), 54.5, 48.2, 36.4, 29.4, 19.7, 10.2. HRMS (ESI+) m/z calc’d for C13H19NF3 [M+H+]: 246.1470; found: 246.1465. N-(4-fluorophenethyl)butan-2-amine (2.2b) According to the general procedure, butan-2-amine (0.3657 g) and 1-ethynyl-4-fluorobenzene (0.6006 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a yellow oil in 99% yield. 1H NMR (400 MHz; CDCl3): δ 7.34-7.30 (m, 2H), 7.24-7.20 (m, 3H), 6.93-6.88 (m, 2H), 6.63-6.59 (m, 2H), 3.37 (t, J = 7.1 Hz, 2H), 2.93 (t, J = 7.1 Hz, 2H). 13C NMR (101 MHz; CDCl3): δ 161.5 (d, 1J(C,F) = 244.0Hz), 135.9, 130.2(d, 3J(C,F) = HNF3CFHN 151 7.6Hz), 115.3 (d, 2J(C,F) = 20.1Hz), 54.6, 48.8, 35.9, 29.6, 19.9, 10.4. HRMS (ESI+) m/z calc’d for C12H19NF [M+H+]: 196.1502; found: 196.1503. N-(4-methylphenethyl)butan-2-amine (2.2c) According to the general procedure, butan-2-amine (0.3657 g) and 1-ethynyl-4-methylbenzene (0.5808 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a pale yellow oil in 99% yield. 1H NMR (400 MHz; CDCl3): δ 7.10 (s, 4H), 2.93-2.75 (m, 4H), 2.57 (m, 1H), 2.32 (s, 3H), 1.53-1.43 (m, 1H), 1.36-1.26 (m, 1H), 1.03 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 137.2, 135.7, 129.2, 128.7, 54.6, 48.9, 36.3, 29.7, 21.1, 19.9, 10.4. HRMS (ESI+) m/z calc’d for C13H22N [M+H+}: 192.1752; found: 192.1747. N-(4-methoxyphenethyl)butan-2-amine (2.2d) According to the general procedure, butan-2-amine (0.3657 g) and 1-ethynyl-4-methoxybenzene (0.6608 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a yellow oil in 99% yield. 1H NMR (400 MHz; CDCl3): δ 7.15-7.11 (m, 2H), 6.86-6.82 (m, 2H), 3.79 (s, 3H), 2.91-2.72 (m, 4H), 2.59-2.51 (m, 1H), 1.50-1.43 (m, 1H), 1.33-1.26 (m, 1H), 1.02 (d, J = 6.3 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 158.1, 132.3, 129.7, 114.0, 77.5, 77.2, 76.8, 55.4, 54.6, HNMeMeOHN 152 48.9, 35.7, 29.6, 19.9, 10.4. HRMS (ESI+) m/z calc’d for C13H22NO [M+H+]: 208.1701; found: 208.1703. N-(3-methoxyphenethyl)butan-2-amine (2.2e) According to the general procedure, butan-2-amine (0.3657 g) and 1-ethynyl-3-methoxybenzene (0.6608 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% of palladium (0.0266 g) in 3 hours. Subsequent filtrations afforded the title compound as a pale yellow oil in 98% yield. 1H NMR (400 MHz; CDCl3): δ 7.21 (td, J = 7.7, 0.7 Hz, 1H), 6.81 (dd, J = 7.5, 1.0 Hz, 1H), 6.78-6.74 (m, 2H), 3.80 (s, 3H), 2.94-2.76 (m, 4H), 2.60-2.52 (m, 1H), 1.51-1.44 (m, 1H), 1.35-1.26 (m, 1H), 1.02 (d, J = 6.3 Hz, 3H), 0.84 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 159.8, 142.0, 129.5, 121.2, 114.5, 111.6, 55.3, 54.6, 48.6, 36.8, 29.7, 19.9, 10.4. HRMS (ESI+) m/z calc’d for C13H22NO [M+H+}: 208.1701; found: 208.1704. N-(2-methoxyphenethyl)butan-2-amine (2.2f) According to the general procedure, butan-2-amine (0.3657 g) and 1-ethynyl-2-methoxybenzene (0.6608 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 3 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 0.5 mol% in 3 hours. Subsequent filtrations afforded the title compound as an orange oil in 51% yield. 1H NMR (400 MHz; CDCl3): δ 7.21-7.15 (m, 2H), 6.91-6.84 (m, 2H), 3.82 (s, 3H), 2.88-2.81 (m, 4H), 2.63-2.55 (m, 1H), 1.51-1.44 (m, 1H), 1.34-1.27 (m, 1H), 1.03 (d, J = 6.3 Hz, 3H), 0.85 (t, J = 7.5 Hz, 3H).13C NMR (101 MHz; CDCl3): δ 157.7, 130.4, 128.8, HNOMeHNOMe 153 127.5, 120.5, 110.5, 55.4, 54.5, 47.3, 31.2, 29.7, 19.9, 10.4. HRMS (ESI+) m/z calc’d for C13H22NO [M+H+}: 208.1701; found: 208.1700. N-(sec-butyl)hexan-1-amine (2.2g) According to the general procedure, butan-2-amine (0.3657 g) and hex-1-yne (0.4108 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 2 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 1 mol% of palladium (0.0532 g) in 5 hours. Subsequent filtrations afforded the title compound as a clear oil in 92% yield. 1H NMR (400 MHz; CDCl3): δ 2.66-2.49 (m, 3H), 1.52-1.42 (m, 3H), 1.30-1.26 (m, 7H), 1.03 (d, J = 6.3 Hz, 3H), 0.88 (t, J = 7.4 Hz, 6H). 13C NMR (101 MHz; CDCl3): δ 77.5, 77.2, 76.8, 54.8, 47.6, 32.0, 30.6, 29.8, 27.3, 22.8, 20.0, 14.2, 10.4. HRMS (ESI+) m/z calc’d for C10H24N [M+H+]: 158.1909; found: 158.1904. N-(2-cyclohexylethyl)butan-2-amine (2.2h) According to the general procedure, butan-2-amine (0.3657 g) and ethynylcyclohexane (0.5409 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction mixture was stirred at 70 °C for 3 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 1 mol% of palladium (0.0532 g) in 5 hours. Subsequent filtrations afforded the title compound as a clear oil in 96% yield. 1H NMR (400 MHz; CDCl3): δ 2.68-2.53 (m, 3H), 1.73-1.60 (m, 5H), 1.56-1.45 (m, 1H), 1.41-1.15 (m, 8H), 1.03 (d, J = 6.3 Hz, 3H), 0.96-0.87 (m, 5H). 13C NMR (101 MHz; CDCl3): δ 77.5, 77.2, 76.8, 54.9, 45.2, 38.3, 36.0, 33.6, 33.6, 29.7, 26.8, 26.5, 20.0, 10.5. HRMS (ESI+) m/z calc’d for C12H26N [M+H+]: 184.2065; found: 184.2062. HNHN 154 N-(sec-butyl)-3,3-dimethylbutan-1-amine (2.2i) According to the general procedure, butan-2-amine (0.3657 g) and 3,3-dimethylbut-1-yne (0.4108 g) were added to a solution of the titanium complex (0.3484 g) in benzene. The reaction mixture was stirred at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 5 mol% of palladium (0.2660 g) in 4 hours. Subsequent filtrations afforded the title compound as a clear oil in 72% yield. 1H NMR (400 MHz; CDCl3): δ 2.64-2.49 (m, 3H), 1.53-1.43 (m, 1H), 1.39-1.34 (m, 2H), 1.32-1.25 (m, 1H), 1.01 (d, J = 6.3 Hz, 3H), 0.89 (s, 9H), 0.86 (d, J = 7.5 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 55.0, 44.6, 43.5, 30.0, 29.8, 20.0, 10.4. HRMS (ESI+) m/z calc’d for C10H24N [M+H+]: 158.1909; found: 158.1908. N-(sec-butyl)-4-((tert-butyldimethylsilyl)oxy)butan-1-amine (2.2j) According to the general procedure, butan-2-amine (0.3657 g) and (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (0.9218 g) were added to a solution of the titanium complex (0.0871 g) in benzene. The reaction mixture was stirred at 70 °C for 30 minutes. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 1 mol% of palladium (0.0532 g) in 5 hours. Subsequent filtrations afforded the title compound as a clear oil in 99% yield. 1H NMR (400 MHz; CDCl3): δ 3.62 (m, 2H), 2.67-2.50 (m, 3H), 1.57-1.45 (m, 5H), 1.30 (m, 1H), 1.02 (d, J = 6.3 Hz, 3H), 0.90-0.86 (m, 13H), 0.04 (s, 6H). 13C NMR (101 MHz; CDCl3): δ 63.3, 54.7, 47.4, 30.9, 29.8, 27.0, 26.1, 20.0, 18.5, 10.4, -5.1. HRMS (ESI+) m/z calc’d for C14H33NOSi [M+H+]: 260.2410; found: 260.2418. N-(3-(sec-butylamino)propyl)pivalamide (2.2k) According to the general procedure, butan-2-amine (0.3657 g) and N-(prop-HNSi OHNHNHNO 155 2-yn-1-yl)pivalamide (0.6960 g) were added to a solution of the titanium complex (0.0871 g) in benzene. The reaction mixture was stirred at 70 °C for 1 hour. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 1 mol% of palladium (0.0532 g) in 5 hours. Purification by formation of HCl salt and re-basification to the free amine afforded the title compound as a yellow oil in 92% yield. 1H NMR (400 MHz; CDCl3): δ 3.41-3.29 (m, 2H), 2.77-2.67 (m, 2H), 2.57-2.49 (m, 1H), 1.68-1.62 (m, 2H), 1.55-1.45 (m, 1H), 1.32 (m, 1H), 1.18 (s, 9H), 1.04 (d, J = 6.3 Hz, 3H), 0.89 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 178.5, 55.0, 46.5, 39.9, 38.7, 29.6, 29.4, 27.8, 20.0, 10.3. HRMS (EI+) m/z calc’d for C12H26N2O [M+H+]: 214.20451; found: 214.20430. General Procedure for the One-Pot Hydroamination/Hydrogenation Synthesis of Secondary Amines Inside an inert atmosphere box, benzene (3 mL) was added to the titanium complex (0.05 mmol, 1 mol% Ti) in a 5-dram vial. The solution was transferred to a scintillation vial containing pre-weighed palladium on carbon (0.25 mmol, 0.5 mol% or 0.5 mmol, 1 mol% Pd). The amine (5 mmol, 1 equiv.) and alkyne (5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the reaction vessel. The remaining benzene (2 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction vessel. The mixture was sealed, taken out of the inert atmosphere box and stirred at 70 °C for 0.5 to 3 hours, depending on the substrate. Upon completion of the hydroamination reaction, the mixture was allowed to cool down and a balloon filled with hydrogen gas was attached to the reaction vessel. The reaction was allowed to proceed at room temperature for 40 hours. The crude compound was concentrated under reduced pressure and filtered through a short plug of Celite using hexanes. The filtrate was concentrated under reduced pressure, affording a mixture of ligand and product.  156 The mixture was chilled in the fridge for at least 30 minutes. Cold hexanes were added to the concentrated oil and the suspension formed was filtered using filter paper and a funnel. Unless otherwise stated, concentration of filtrate under reduced pressure afforded the desired secondary amine in high purity.  General Procedure for the Large Scale Sequential Hydroamination/Hydrogenation Synthesis of Secondary Amines Inside an inert atmosphere box, benzene (20 mL) was added to the titanium complex (0.25 mmol, 1 mol% Ti) in a 5-dram vial. The solution was then transferred to a 100 mL round bottom flask. The amine (25 mmol, 1 equiv.) and alkyne (25 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the reaction vessel. The remaining benzene (5 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction vessel. The mixture was sealed, taken out of the inert atmosphere box and stirred at 70 °C for 1 to 2 hours, depending on the substrate. Half an hour prior to the completion of the hydroamination step, an oven dried Fischer-Porter tube was cooled under N2. Under a N2 flow, palladium on carbon (0.125 mmol, 0.5 mol% Pd or 0.25 mmol, 1 mol% Pd) and methanol (10 mL) were added to the vessel, which was then pressurized and vented with H2 five times. After allowing the hydroamination reaction mixture to cool down, the solution was added to the Fischer-Porter tube using a 10 mL syringe. An additional 15 mL of methanol was used to rinse the vial containing the first step, and this liquid was also added to the Fischer-Porter tube. The tube was then sealed and pressurized to 3 bar. The reaction was allowed to proceed at room temperature for 3 to 5 hours depending on the substrate. The crude compound was concentrated under reduced pressure and filtered through a short plug of Celite using hexanes. The filtrate was concentrated under reduced pressure, affording a mixture of ligand and product. The mixture was  157 chilled in the fridge for a few hours. Cold hexanes were added to the concentrated oil and the suspension formed was filtered using filter paper and a funnel. Unless otherwise stated, concentration of filtrate under reduced pressure afforded the desired secondary amine in high purity. 158 A.5 NMR Spectra Bis(N-2,6-diisoprpylphenylbenzamidate)bis(dimethylamido)titanium (IV) (1)    1H NMR (400 MHz; CDCl3)     Ar = 2,6-diisopropylphenylTitanium Complex 1TiNONOPhPh ArArNMe2NMe213C NMR (101 MHz; CDCl3)     Ar = 2,6-diisopropylphenylTitanium Complex 1TiNONOPhPh ArArNMe2NMe2 159 N-phenethylbutan-2-amine (2.1b)    1H NMR (400 MHz; CDCl3)  2.1b HN13C NMR (101 MHz; CDCl3)  2.1b HN 160 N-phenethylcyclopentanamine (2.1d)    1H NMR (400 MHz; CDCl3)  2.1d HN13C NMR (101 MHz; CDCl3)  2.1d HN 161 N-phenethylcycloheptamine (2.1f)    1H NMR (400 MHz; CDCl3)  2.1f HN13C NMR (101 MHz; CDCl3)  2.1f HN 162 N-phenethyl-4-(trifluoromethyl)aniline (2.1h)    1H NMR (600 MHz; CDCl3)  2.1h HNCF313C NMR (151 MHz; CDCl3)  2.1h HNCF3 163 N-(3,4-dimethoxyphenethyl)-2-phenylethan-1-amine (2.1l)    1H NMR (400 MHz; CDCl3)  2.1l HN OMeOMe13C NMR (101 MHz; CDCl3)  2.1l HN OMeOMe 164 N-(4-(trifluoromethyl)phenethyl)butan-2-amine (2.2a)     1H NMR (600 MHz; CDCl3)  2.2a HNF3C13C NMR (151 MHz; CDCl3)  2.2a HNF3C 165 N-(4-fluorophenethyl)butan-2-amine (2.2b)    13C NMR (151 MHz; CDCl3)  2.2b FHN1H NMR (400 MHz; CDCl3)  2.2b FHN 166 N-(4-methylphenethyl)butan-2-amine (2.2c)    1H NMR (400 MHz; CDCl3)  2.2c HNMe13C NMR (101 MHz; CDCl3)  2.2c HNMe 167 N-(4-methoxyphenethyl)butan-2-amine (2.2d)    1H NMR (400 MHz; CDCl3)  2.2d MeOHN13C NMR (101 MHz; CDCl3)  2.2d MeOHN 168 N-(3-methoxyphenethyl)butan-2-amine (2.2e)    1H NMR (400 MHz; CDCl3)  2.2e HNOMe13C NMR (101 MHz; CDCl3)  2.2e HNOMe 169 N-(3-methoxyphenethyl)butan-2-amine (2.2f)    1H NMR (400 MHz; CDCl3)  2.2f HNOMe13C NMR (101 MHz; CDCl3)  2.2f HNOMe 170 N-(sec-butyl)hexan-1-amine (2.2g)    1H NMR (400 MHz; CDCl3)  2.2g HN13C NMR (101 MHz; CDCl3)  2.2g HN 171 N-(2-cyclohexylethyl)butan-2-amine (2.2h)    1H NMR (400 MHz; CDCl3)  2.2h HN13C NMR (101 MHz; CDCl3)  2.2h HN 172 N-(sec-butyl)-3,3-dimethylbutan-1-amine (2.2i)    1H NMR (400 MHz; CDCl3)  2.2i HN13C NMR (101 MHz; CDCl3)  2.2i HN 173 N-(sec-butyl)-4-((tert-butyldimethylsilyl)oxy)butan-1-amine (2.2j)    1H NMR (400 MHz; CDCl3)  2.2j Si OHN13C NMR (101 MHz; CDCl3)  2.2j Si OHN 174 N-(3-(sec-butylamino)propyl)pivalamide (2.2k)    1H NMR (400 MHz; CDCl3)  2.2k HNHNO1H NMR (400 MHz; CDCl3)  2.2k HNHNO 175 Appendix B   This appendix is for the supporting information pertaining the research conducted in Chapter 3. B.1 General Considerations All air and moisture sensitive reactions were performed using a MBraun LABmaster glovebox filled with a N2 atmosphere. All pieces of glassware were dried for at least 4 hours in a 160 °C oven before being transferred into the glovebox. All stirring was done with appropriately sized Teflon coated magnetic stir bars dried for at least 4 hours in a 160 °C oven. Benzene and hexanes were passed over activated alumina columns into Teflon sealed Straus flasks and stored therein until use. d6-Benzene was dried over sodium metal, distilled, degassed, and stored in Teflon sealed Schlenk flasks prior to use. Hydrogenations were performed using a Radley’s parallel reactor tube. Experiments conducted on NMR tube scale were performed in J-Young NMR tubes (8” x 5 mm) sealed with screw-type Teflon caps. Internal standard used for quantitative 1H NMR experiments was 1,3,5-trimethoxybenzene and the chemical shifts associated with it are the following: 1H NMR (400 MHz; C6D6): δ 6.25 (s, 1H), 3.32 (s, 3H). 13C NMR (101 MHz; C6D6): δ 162.3, 93.5, 54.9. B.2 Materials Ti(NMe2)4 (Sigma-Aldrich) and 10 wt% Pd/C (Sigma-Aldrich) were used as received. All amines and alkynes were purchased from commercial sources, dried over CaH2 and distilled prior to use. Hydrogen gas (PP 4.5) was purchased from Praxair and used without further purification. B.3 Instrumentation NMR spectra were recorded as dilute solutions in deuterated chloroform or benzene on a Bruker Avance 300, 400 or 600 MHz spectrometer at ambient temperature. 1H chemical shift data are  176 given in units δ relative to the residual protic solvent where δ (CDCl3) = 7.26 ppm and δ (C6D6) = 7.16 ppm, while 13C chemical shift data are given in units δ relative to the solvent where δ (CDCl3) = 77.16 ppm and δ (C6D6) = 128.06 ppm. High-resolution mass spectra were measured by the mass spectrometry and microanalysis service at the Department of Chemistry, University of British Columbia. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 eV) source or a Bruker Esquire LC spectrometer using electrospray ionization source. Fragment signals are given in mass per charge number (m/z). B.4 Synthesis and Compound Characterization Tert-butyldimethylsilanamine  The tert-butyldimethylsilanamine was synthesized following a procedure adapted from literature.386 Inside an inert atmosphere box, sublimed tert-butyldimethylchlorosilane (15.072g, 100 mmol, 1 equiv.) was added to the glassware depicted below and diluted with 50 mL of pentane. The glassware was sealed and taken out of the inert atmosphere box. Connection to an Schlenk line occurred through the middle ground-joint (hidden behind the Teflon tap). The tubing was evacuated and refilled with N2 (x3) and then both sides of glassware were cooled to -78 °C. Anhydrous ammonia gas (excess) was introduced to the system and condensed on left side of the glassware prior to the addition of sodium pieces. Upon the ammonia solution turning blue in colour, the system was carefully closed and the ammonia was transferred to the right side of the glassware, which contained the tert-butyldimethylchlorosilane solution. After transfer, the reaction solution was stirred at -78 °C for an hour and then warmed to room temperature with a vent. The salts formed during the reaction were removed via filter cannula to an Schlenk flask Cl Si H2NSiNH3 (l)Pent-78 °C → r.t.82%H2NSi 177 and the pentane was distilled off from the product. Careful evacuation of the remainder of the pentane afforded the desired product as a white solid in 82% yield. 1H NMR (400 MHz; CDCl3): δ 0.90 (s, 9H), -0.01 (s, 6H). 13C NMR (101 MHz; CDCl3): δ 26.2, 17.9, -3.4.  Figure B.1 Glassware Used for the Synthesis of Tert-Butyldimethylsilanamine Bis(N-2,6-diisopropylphenylbenzamidate)(tert-butyldimethylsilylimido)(dimethylamido) titanium (IV) (3.1a)   Ar = 2,6-diisopropylphenyl1TiNONOPhPh ArArNMe2NMe2H2NSiC6D6, r.t., 18 h55%2aTiNSiONPhAr OPhN ArN H 178 Inside an inert atmosphere box, toluene (0.15 mL) was added to the titanium complex 1 (0.3484 g, 0.5 mmol, 1 equiv.) in a 5-dram vial and the solution was transferred to a scintillation vial. The silylamine (0.0656 g, 0.5 mmol, 1 equiv.) was also pre-weighed to a separate 5-dram vial and transferred to the same scintillation vial using the remainder of the solvent (0.35 mL). The reaction flask was sealed and the reaction solution was stirred for 18 h at room temperature. The volatiles were removed under reduced pressure and recrystallization of the solid compound from hexanes afforded complex 3.1a as yellow crystals in 55% yield. 1H NMR (300 MHz; C6D6): δ 8.37 (s, 1H), 7.73-7.63 (m, 2H), 7.31-7.18 (m, 4H), 7.13-7.00 (m, 6H), 6.95-6.83 (m, 4H), 3.97-3.74 (m, 2H), 3.23-3.14 (m, 1H), 2.59 (d, J = 5.9 Hz, 3H), 2.33-2.25 (m, 1H), 1.57 (d, J = 6.7 Hz, 3H), 1.51-1.42 (m, 9H), 1.28 (d, J = 6.7 Hz, 3H), 1.17 (d, J = 6.9 Hz, 3H), 0.94 (s, 9H), 0.80 (d, J = 6.0 Hz, 3H), 0.04 (s, 3H), -0.10 (s, 3H). MS (EI) m/z: calc’d for C46H66N4O2SiTi [M – C9H13N]+: 680; found: 680. Elemental Analysis calc’d for C46H66N4O2SiTi: C 70.56, H 8.50, N 7.16; found: C 70.21, H 8.63, N 6.80. Bis(N-2,6-diisopropylphenylbenzamidate)(tert-butyldimethylsilylimido)(pyridino) titanium (IV) (3.1b)  Titanium complex 3.1b was synthesized following a procedure adapted from literature.1 Inside an inert atmosphere box, hexanes (0.15 mL) were added to the titanium complex 1 (0.3484 g, 0.5 mmol, 1 equiv.) in a 5-dram vial and the solution was transferred to a scintillation vial. The silylamine (0.0656 g, 2bTiNONOPhPh ArArNN Sii) C6D6, r.t., 18 hii) Pyr, r.t., 18 h44%Ar = 2,6-diisopropylphenyl1TiNONOPhPh ArArNMe2NMe2H2NSiTiNSiONPhAr OPhN ArN HAr = 2,6-diisopropylphenyl3.1aTiNONOPhPh ArArNN SiAr = 2,6-diisopropylphenyl3.1b 179 0.5 mmol, 1 equiv.) was also pre-weighed to a separate 5-dram vial and transferred to the same scintillation vial using the remainder of the solvent (0.35 mL). The reaction flask was sealed and the reaction solution was stirred for 18 h at room temperature. The volatiles under reduced pressure and due to the lack of crystallinity, pyridine (0.0395 g, 0.5 mmol, 1 equiv.) was added to the scintillation vial and the reaction mixture was once again stirred for 18 h at room temperature. The volatiles were once again removed under reduced pressure. Recrystallization of the solid compound from toluene and hexanes afforded complex 3.1b as orange crystals in 44% yield. 1H NMR (300 MHz; C6D6): δ 9.31 (d, J = 4.9 Hz, 2H), 7.82-7.79 (m, 4H), 7.18 (s, 5H), 6.92-6.89 (m, 7H), 6.73-6.66 (m, 1H), 6.49-6.44 (m, 2H), 4.29-4.23 (m, 2H), 3.70-3.60 (m, 2H), 1.42-1.38 (m, 12H), 1.23-1.19 (m, 9H), 1.12-1.09 (m, 12H), -0.08 (s, 9H). MS (EI): m/z: calc’d for C49H64N4O2SiTi [M – C9H13N]+: 680; found: 680. Elemental Analysis calc’d for C49H64N4O2SiTi: C 72.03, H 7.90, N 6.86; found: C 72.24, H 7.98, N 6.77. Bis(N-2,6-diisopropylphenylbenzamidate)(triphenylsilylimido)(pyridino) titanium (IV) (3.1c)  Titanium complex 3.1c was synthesized following a procedure adapted from literature.1 Inside an inert atmosphere box, hexanes (0.15 mL) were added to the titanium complex 1 (0.3484 g, 0.5 mmol, 1 equiv.) in a 5-dram vial and the solution was transferred to a scintillation vial. The silylamine (0.1377 g, 0.5 mmol, 1 equiv.) was also pre-weighed to a separate 5-dram vial and transferred to the same scintillation vial using the remainder of the solvent (0.35 mL). The reaction flask was sealed and 2cTiNONOPhPh ArArNN Si PhPhPhi) C6D6, r.t., 18 hii) Pyr, r.t., 18 h66%Ar = 2,6-diisopropylphenyl1TiNONOPhPh ArArNMe2NMe2H2NSi PhPhPhTiNONOPhPh ArArNN Si PhPhPhAr = 2,6-diisopropylphenyl3.1c 180 the reaction solution was stirred for 18 h at room temperature. The volatiles under reduced pressure and due to the lack of crystallinity, pyridine (0.0395 g, 0.5 mmol, 1 equiv.) was added to the scintillation vial and the reaction mixture was once again stirred for 18 h at room temperature. The volatiles were once again removed under reduced pressure. Recrystallization of the solid compound from toluene and hexanes afforded complex 3.1c as yellow crystals in 66% yield. 1H NMR (300 MHz; C6D6): δ 9.08 (d, J = 4.9 Hz, 2H), 7.80-7.75 (m, 9H), 7.14-7.00 (m, 18H), 6.96-6.93 (m, 4H), 6.69-6.63 (m, 1H), 6.36-6.31 (m, 2H), 4.02-3.99 (m, 2H), 3.67-3.63 (m, 2H), 1.29 (d, J = 5.8 Hz, 6H), 1.02-0.95 (m, 12H), 0.73 (d, J = 5.8 Hz, 6H). MS (EI): m/z: calc’d for C61H64N4O2SiTi [M – C5H5N]+: 881; found: 881. Elemental Analysis calc’d for C61H64N4O2SiTi: C 76.23, H 6.71, N 5.83; found: C 75.87, H 7.03, N 5.80. General Procedure for the Hydroamination Reaction  Inside an inert atmosphere box, 1,3,5-trimethoxybenzene solution was added to a J-young tube. Then, d6-benzene (0.15 mL) was added to the titanium complex (0.005-0.05 mmol, 1-10 mol% Ti) in a 5-dram vial and the solution was transferred to a J-Young tube. The amine (0.5 mmol, 1 equiv.) and alkyne (0.5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the J-Young tube. The remaining benzene (0.35 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction tube. The J-Young tube was sealed, taken out of the inert atmosphere box and a time zero 1H NMR spectrum was obtained. The reaction solution was heated at 70-145 °C depending on the starting materials used. A 1H NMR spectrum was obtained after 6-72 hours of heating and full consumption of R11-10 mol% [Ti]C6D6 or d8-Tol70-145 °C, timeH2NSiR2R1HN SiR2R1 N SiR2+ + 181 starting materials was observed. Quantitative 1H NMR yields were obtained by integrating the starting materials and products to the internal standard. (E)-1-tert-butyl-1,1-dimethyl-N-styrylsilanamine (3.2a) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 96%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.21 (m, 4H), 6.99 (m, 1H), 6.69 (dd, J = 13.7, 13.4 Hz, 1H), 5.47 (d, J = 13.7 Hz, 1H), 3.02 (d, J = 13.4 Hz, 1H), 0.81 (s, 9H), -0.03 (s, 6H). 13C NMR (101 MHz; C6D6): δ 139.8, 133.8, 128.9, 124.3, 124.3, 105.3, 26.1, 18.4, -5.3 (E)-1-tert-butyl-N-(4-fluorostyryl)-1,1-dimethylsilanamine (3.2b) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-fluorobenzene (0.0601 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 99%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 6.99-6.95 (m, 2H), 6.86-6.82 (m, 2H), 6.53 (dd, J = 13.8, 13.5 Hz, 1H), 5.35 (d, J = 13.5 Hz, 1H), 3.01 (d, J = 13.8 Hz, 1H), 0.82 (s, 9H), -0.02 (s, 6H). 13C NMR (101 MHz; C6D6): δ 160.9 (d, 1J(C,F) = 274.4Hz), 135.9, 133.6, 125.3 (d, 3J(C,F) = 7.7Hz), 115.6 (d, 2J(C,F) = 21.4Hz), 104.0, 26.1, 18.3, -5.3. 19F NMR (282 MHz; C6D6): δ -119.7. (E)-1-tert-butyl-N-(4-chlorostyryl)-1,1-dimethylsilanamine (3.2c) HN SiHN SiF 182 According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-chloro-4-ethynylbenzene (0.0683 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 99%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.14-7.10 (m, 2H), 6.94-6.91 (m, 2H), 6.57 (dd, J = 14.0, 13.5 Hz, 1H), 5.29 (d, J = 13.5 Hz, 1H), 3.06 (d, J = 14.0 Hz, 1H), 0.80 (s, 9H), -0.03 (s, 6H). 13C NMR (101 MHz; C6D6): δ 138.4, 134.5, 129.2, 128.9, 125.3, 103.9, 26.1, 18.3, -5.3. (E)-1-tert-butyl-N-(4-chlorostyryl)-1,1-dimethylsilanamine (3.2d) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-bromo-4-ethynylbenzene (0.0905 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 98%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.28-7.25 (m, 2H), 6.88-6.85 (m, 2H), 6.58 (dd, J = 14.0, 13.5 Hz, 1H), 5.27 (d, J = 13.5 Hz, 1H), 3.06 (d, J = 14.0 Hz, 1H), 0.80 (s, 9H), -0.04 (s, 6H). 13C NMR (101 MHz; C6D6): δ 138.8, 134.6, 131.8, 125.7, 117.0, 103.9, 26.1, 18.3, -5.3 (E)-1-tert-butyl-1,1-dimethyl-N-(4-(trifluoromethyl)styryl)silanamine (3.2e) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-(trifluoromethyl)benzene (0.0851 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 98%. Characterization was performed in situ - 1H NMR (400 MHz; HN SiClHN SiBrHN SiF3C 183 C6D6): δ 7.37 (d, J = 8.3 Hz, 2H), 7.00 (d, J = 8.3 Hz, 2H), 6.68 (dd, J = 14.2, 13.5 Hz, 1H), 5.28 (d, J = 13.5 Hz, 1H), 3.16 (d, J = 14.2 Hz, 1H), 0.80 (s, 9H), -0.03 (s, 6H). 13C NMR (101 MHz; C6D6): δ 143.7, 136.5, 125.8 (q, 3J(C,F) = 3.8Hz), 125.6 (q, 1J(C,F) = 271.0Hz), 125.5 (q, 2J(C,F) = 32.2Hz), 123.8, 103.7, 25.9, 18.2, -5.5. 19F NMR (282 MHz; C6D6): δ -119.7. (E)-1-tert-butyl-1,1-dimethyl-N-(4-methylstyryl)silanamine (3.2f) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-methylbenzene (0.0581 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 95%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.18 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 6.69 (dd, J = 13.8, 13.6 Hz, 1H), 5.51 (d, J = 13.6 Hz, 1H), 3.01 (d, J = 13.8 Hz, 1H), 2.19 (s, 3H), 0.83 (s, 9H), -0.01 (s, 6H). 13C NMR (101 MHz; C6D6): δ 137.0, 133.3, 133.0, 129.6, 124.3, 105.3, 26.2, 21.2, 18.4, -5.2. (E)-1-tert-butyl-N-(4-methoxystyryl)-1,1-dimethylsilanamine (3.2g) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 97%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.16-7.14 (m, 3H), 6.82-6.80 (m, 2H), 6.61 (dd, J = 13.7, 13.6 Hz, 1H), 5.52 (d, J = 13.6 Hz, 1H), 3.41 (s, 3H), 3.03 (d, J = 13.7 Hz, 1H), 0.85 (s, 9H), 0.01 (s, 6H). 13C NMR (101 MHz; C6D6): δ 157.4, 132.5, 132.1, 125.3, 114.5, 104.9, 54.9, 26.2, 18.4, -5.2.  (E)-1-tert-butyl-N-(3-methoxystyryl)-1,1-dimethylsilanamine (3.2h) HN SiMeHN SiMeO 184 According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-3-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 98%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.12 (m, 1H), 6.91-6.88 (m, 2H), 6.74 (dd, J = 13.5, 13.5 Hz, 1H), 6.57 (m, 1H), 5.48 (d, J = 13.5 Hz, 1H), 3.43 (s, 3H), 3.13 (d, J = 13.5 Hz, 1H), 0.81 (s, 9H), -0.02 (s, 6H). 13C NMR (101 MHz; C6D6): δ 160.7, 141.3, 134.2, 129.7, 117.0, 110.5, 109.5, 105.2, 54.7, 26.1, 18.3, -5.3. (E)-1-tert-butyl-N-(2-methoxystyryl)-1,1-dimethylsilanamine (3.2i) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-2-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was >99%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.34 (dd, J = 7.5, 1.7 Hz, 1H), 6.98 (td, J = 7.9, 1.7 Hz, 1H), 6.94-6.87 (m, 2H), 6.62 (dd, J = 7.9, 1.1 Hz, 1H), 6.01 (d, J = 13.6 Hz, 1H), 3.44 (s, 3H), 3.16 (d, J = 14.0 Hz, 1H), 0.83 (s, 9H), -0.01 (s, 6H). 13C NMR (101 MHz; C6D6): δ 155.7, 134.8, 128.9, 124.8, 121.2, 111.1, 111.0, 100.7, 55.1, 26.2, 18.4, -5.3. (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyridin-2-yl)vinyl)silanamine (3.2j) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 2-ethynylpyridine (0.0516 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 8 hours. Upon full disappearance of starting material, the obtained 1H NMR yield HN SiOMeHN SiOMeNHN Si 185 was 85% (81% of (E)-isomer and 4% of (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; C6D6): δ 8.43 (ddd, J = 4.9, 1.9, 0.8 Hz, 1H), 7.76 (dd, J = 14.8, 12.9 Hz, 1H), 7.11 (ddd, J = 7.9, 7.4, 1.9 Hz, 1H), 6.71 (ddd, J = 7.9, 1.1, 0.8 Hz, 1H), 6.55 (ddd, J = 7.4, 4.8, 1.1 Hz, 1H), 5.64 (d, J = 12.9 Hz, 1H), 3.93 (d, J = 14.8 Hz, 1H), 0.80 (s, 9H), -0.01 (s, 6H). 13C NMR (101 MHz; C6D6): δ 158.7, 149.5, 139.5, 135.8, 119.2, 118.4, 104.7, 26.1, 18.3, -5.3.  (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyridin-3-yl)vinyl)silanamine (3.2k) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 3-ethynylpyridine (0.0516 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 18 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 94%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 8.66 (s, 1H), 8.32 (d, J = 4.2 Hz, 1H), 7.21 (d, J = 7.8 Hz, 1H), 6.78 (dd, J = 7.8, 4.2 Hz, 1H), 6.71 (dd, J = 13.8, 13.6 Hz, 1H), 5.35 (d, J = 13.6 Hz, 1H), 3.87 (d, J = 13.8 Hz, 1H), 0.82 (s, 9H), -0.01 (s, 6H). 13C NMR (101 MHz; C6D6): δ 146.5, 145.3, 136.1, 135.6, 129.6, 123.5, 100.8, 26.1, 18.4, -5.3.  (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyridin-4-yl)vinyl)silanamine (3.2l) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 4-ethynylpyridine (0.0516 g) were added to a solution of the titanium complex (0.0348 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 18 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 69%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 8.41 (s, 2H), 6.96 (dd, J = 13.4, 13.2 Hz, 1H), 6.84 (d, J = 2.7 Hz, 2H), 5.34 (d, J = 13.4 Hz, 1H), 4.50 (d, J = NHN SiNHN Si 186 13.2 Hz, 1H), 0.83 (s, 9H), 0.02 (s, 6H). 13C NMR (101 MHz; C6D6): δ 150.1, 147.5, 139.0, 118.5, 102.1, 26.0, 18.3, -5.4 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyrazin-2-yl)vinyl)silanamine (3.2m) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 2-ethynylpyrazine (0.0521 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 18 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 86% (69% of (E)-isomer and 17% of (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; C6D6): δ 8.21 (s, 1H), 8.05 (s, 1H), 7.92 (s, 1H), 7.70 (dd, J = 14.9, 12.9 Hz, 1H), 5.43 (d, J = 12.9 Hz, 1H), 4.14 (d, J = 14.9 Hz, 1H), 0.87 (s, 3H), 0.78 (s, 9H), 0.03 (s, 2H), -0.03 (s, 6H). 13C NMR (101 MHz; C6D6): δ 154.5, 144.0, 141.7, 139.3, 100.5, 94.8, 26.0, 18.2, -5.4. (E)-1-tert-butyl-1,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)silanamine (3.2n) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 4-ethynyl-1-methyl-1H-pyrazole (0.0531 g) were added to a solution of the titanium complex (0.0087 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 18 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 85%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 7.55 (s, 1H), 6.73 (s, 1H), 6.47 (dd, J = 14.1, 13.7 Hz, 1H), 5.37 (d, J = 13.7 Hz, 1H), 3.33 (s, 3H), 3.25 (d, J = 14.1 Hz, 1H), 0.86 (s, 9H), 0.02 (s, 6H). 13C NMR (101 MHz; C6D6): δ 135.9, 132.3, 124.7, 121.6, 94.8, 38.3, 26.2, 18.5, -5.2.  (E)-1-tert-butyl-1,1-dimethyl-N-(2-(thiophen-2-yl)vinyl)silanamine (3.2o) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) NNHN SiNNHN SiSHN Si 187 and 2-ethynylthiophene (0.0541 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 18 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 97%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 6.77 (dd, J = 5.2, 3.5 Hz, 1H), 6.68-6.61 (m, 3H), 5.61 (d, J = 13.4 Hz, 1H), 2.97 (d, J = 13.6 Hz, 1H), 0.79 (s, 9H), -0.06 (s, 6H). 13C NMR (101 MHz; C6D6): δ 144.4, 134.4, 127.5, 120.1, 119.3, 99.3, 26.1, 18.3, -5.4. (E)-1-tert-butyl-1,1-dimethyl-N-(2-(thiophen-3-yl)vinyl)silanamine (3.2p) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 3-ethynylthiophene (0.0541 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 18 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 88%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 6.95 (d, J = 2.1 Hz, 2H), 6.60 (t, J = 2.1 Hz, 1H), 6.54 (dd, J = 13.7, 13.5 Hz, 1H), 5.48 (d, J = 13.5 Hz, 1H), 2.94 (d, J = 13.7 Hz, 1H), 0.82 (s, 9H), -0.02 (s, 6H). 13C NMR (101 MHz; C6D6): δ 141.1, 133.9, 125.4, 124.7, 114.8, 100.5, 26.2, 18.4, -5.2.  (E)-1-tert-butyl-N-(hex-1-en-1-yl)-1,1-dimethylsilanamine (3.2q) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and hex-1-yne (0.0411 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 24 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 63% (55% of enamine and 8% of imine). Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 5.95-5.88 (ddt, J = 13.2, 12.5, 1.0 Hz, 1H), 4.50 (dt, J = 13.2, 7.0 Hz, 1H), 2.64 (d, J = 12.5 Hz, 1H), 2.02-1.97 (m, 2H), 1.40-1.33 (m, 4H), 1.04-0.94 (m, 3H), 0.85 (s, 9H), -SHN SiHN Si 188 0.01 (s, 6H). 13C NMR (101 MHz; C6D6): δ 132.1, 103.4, 34.1, 30.4, 26.7, 26.3, 22.6, 14.3, -5.1. Note: other isomers could be present in the reaction mixture, which could explain the convoluted 1H NMR and 13C NMR spectra. (E)-1-tert-butyl-N-(2-cyclohexylvinyl)-1,1-dimethylsilanamine (3.2r) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and ethynylcyclohexane (0.0541 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 24 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 77% (68% of enamine and 9% imine). Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 6.02 (ddd, J = 13.3, 13.2, 0.9 Hz, 1H), 4.59 (dd, J = 13.3, 7.3 Hz, 1H), 2.71 (d, J = 13.2 Hz, 1H), 2.03-1.67 (m, 9H), 1.43-1.14 (m, 8H), 0.96 (s, 9H), 0.10 (s, 6H). 13C NMR (101 MHz; C6D6): δ 130.2, 110.3, 39.3, 35.4, 27.0, 26.8, 26.8, 26.8, 26.4, 18.7, -5.1. Note: other isomers could be present in the reaction mixture, which could explain the convoluted 1H NMR and 13C NMR spectra.  (E)-1-tert-butyl-N-(2-(cyclohex-1-en-1-yl)vinyl)-1,1-dimethylsilanamine (3.2s) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynylcyclohex-1-ene (0.0531 g) were added to a solution of the titanium complex (0.0087 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 8 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 94%. Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 6.15 (dd, J = 13.5, 13.4 Hz, 1H), 5.46 (t, J = 3.6 Hz, 1H), 5.37 (d, J = 13.5 Hz, 1H), 2.82 (d, J = 13.4 Hz, 1H), 2.14-2.09 (m, 4H), 1.64-1.53 (m, 4H), 0.84 (s, 9H), -0.00 (s, 6H). 13C NMR (101 MHz; C6D6): δ 135.2, 129.9, 119.3, 110.2, 26.3, 26.2, 25.5, 23.6, 23.4, 18.6, -5.2.  HN SiHN Si 189 (E)-1-tert-butyl-N-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-1,1-dimethylsilanamine (3.2t) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (0.0922 g) were added to a solution of the titanium complex (0.0087 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 8 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 76% (69% of enamine and 7% of imine). Characterization was performed in situ - 1H NMR (400 MHz; C6D6): δ 5.92 (dd, J = 13.3, 13.1 Hz, 1H), 4.48 (dt, J = 13.3, 7.0 Hz, 1H), 3.56 (t, J = 7.0 Hz, 2H), 2.69 (d, J = 13.1 Hz, 1H), 2.24-2.17 (m, 2H), 0.97 (s, 9H), 0.83 (s, 9H), 0.05 (s, 6H), -0.03 (s, 6H). 13C NMR (101 MHz; C6D6): δ 133.7, 99.2, 65.0, 34.5, 26.3, 26.3, 18.6, 18.6, -4.9, -5.1. (E)-N-(3-((tert-butyldimethylsilyl)amino)allyl)pivalamide (3.2u) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and N-(prop-2-yn-1-yl)pivalamide (0.0696 g) were added to a solution of the titanium complex (0.0087 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 3 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was >99% (85% of (E)-isomer and 14% (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; C6D6): δ 6.05 (dd, J = 14.4, 7.7 Hz, 1H), 5.97 (t, J = 5.9 Hz, 1H), 5.27 (d, J = 14.4 Hz, 1H), 4.30 (q, J = 7.7 Hz, 1H), 3.80 (dd, J = 7.7, 5.9 Hz, 2H), 1.06 (s, 9H), 0.94 (s, 9H), 0.06 (s, 6H). 13C NMR (101 MHz; C6D6): δ 178.2, 136.7, 96.5, 38.6, 34.7, 27.8, 26.3, 18.5, -5.1.  (E)-1-tert-butyl-1,1-dimethyl-N-(1-phenylprop-1-en-2-yl)silanamine (3.2v)  According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) TBDMSOHN SiHNtBuOHN SiHNMeSi 190 and prop-1-yn-1-ylbenzene (0.0581 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 110 °C for 6 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 84% (82% of (E)-isomer and 2% (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; C6D6): δ 7.26-7.21 (m, 4H), 7.07-7.03 (m, 1H), 5.75 (s, 1H), 2.49 (s, 1H), 1.81 (s, 3H), 0.94 (s, 9H), 0.20 (s, 6H). 13C NMR (101 MHz; C6D6): δ 142.3, 140.3, 128.8, 128.4, 124.4, 104.0, 26.7, 20.5, 18.2, -3.8. Note: by heating the reaction solution for extended time at 110 °C, the conversion between (E)- and (Z)-isomer occurs and the (Z)-isomer can be characterized. (Z)-isomer: 1H NMR (400 MHz; C6D6): δ 7.39-7.37 (m, 2H), 7.20-7.19 (m, 2H), 7.00-6.96 (m, 1H), 5.24 (s, 1H), 4.46 (s, 1H), 1.86 (s, 3H), 0.83 (s, 9H), 0.06 (s, 6H). 13C NMR (101 MHz; C6D6): δ 141.7, 139.7, 129.1, 128.1, 124.9, 102.3, 26.5, 23.6, 17.7, -2.5. (E)-1-tert-butyl-1,1-dimethyl-N-(1-phenylbut-1-en-2-yl)silanamine (3.2w)  According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and prop-1-yn-1-ylbenzene (0.0651 g) were added to a solution of the titanium complex (0.0348 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 110 °C for 24 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 74% (73% of (E)-isomer and <1% (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; C6D6): δ 7.34-7.28 (m, 4H), 7.15-7.10 (m, 1H), 5.84 (s, 1H), 2.44 (s, 1H), 2.29 (q, J = 7.6 Hz, 2H), 1.11 (t, J = 7.6 Hz, 3H), 1.04 (s, 9H), 0.30 (s, 6H). 13C NMR (101 MHz; C6D6): δ 147.6, 140.1, 131.9, 128.6, 128.5, 124.6, 103.6, 26.8, 18.2, 13.4, -4.0.  (E)-1-tert-butyl-1,1-dimethyl-N-(1-phenylpent-1-en-2-yl)silanamine (3.2x)  According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and pent-1-yn-1-ylbenzene (0.0721 g) were added to a solution of the titanium HNEtSiHNPrSi 191 complex (0.0348 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 110 °C for 24 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 74% (72% of (E)-isomer and 2% (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; C6D6): δ 7.21-7.19 (m, 4H), 7.05-6.99 (m, 1H), 5.77 (s, 1H), 2.39 (s, 1H), 2.21-2.17 (m, 2H), 1.51-1.45 (m, 2H), 0.94 (s, 9H), 0.91-0.88 (m, 3H), 0.21 (s, 6H). 13C NMR (101 MHz; C6D6): δ 146.2, 140.1, 128.8, 128.4, 124.6, 104.1, 35.4, 26.8, 22.1, 18.2, 14.0, -4.0.  (E)-1-tert-butyl-N-(1,2-diphenylvinyl)-1,1-dimethylsilanamine (3.2y)  According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1,2-diphenylethyne (0.0891 g) were added to a solution of the titanium complex (0.0348 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 145 °C for 48 hours. Upon full disappearance of starting material, the obtained 1H NMR yield was 87% (79% of (E)-isomer and 8% (Z)-isomer). Characterization was performed in situ – (E)-isomer: 1H NMR (400 MHz; d8-Tol): δ 7.39-7.37 (m, 2H), 7.08-7.06 (m, 3H), 6.97-6.93 (m, 4H), 6.86-6.83 (m, 1H), 5.97 (s, 1H), 2.83 (s, 1H), 0.93 (s, 9H), 0.19 (s, 6H). 13C NMR (101 MHz; d8-Tol): δ 145.8, 141.3, 131.8, 129.6, 128.7, 128.6, 128.3, 128.0, 124.3, 105.5, 26.6, 18.0, -4.1.  General Procedure for the Sequential Hydroamination/Hydrogenation Synthesis of Primary Amines Inside an inert atmosphere box, d6-benzene (0.15 mL) was added to the titanium complex (0.005-0.05 mmol, 1-10 mol% Ti) in a 5-dram vial and the solution was transferred to a J-Young tube. The amine (0.5 mmol, 1 equiv.) and alkyne (0.5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the J-Young tube. The remaining benzene (0.35 mL) was used to HN Si 192 rinse the vials containing amine and alkyne, which were also transferred to the reaction tube. The J-Young tube was sealed, taken out of the inert atmosphere box and a time zero 1H NMR spectrum was obtained. The reaction solution was heated at 70-145 °C depending on the starting materials used. A 1H NMR spectrum was obtained after 6-72 hours of heating and full consumption of starting materials was observed. The reaction tube was cooled and brought into the inert atmosphere box, where the reaction solution was transferred to a Radley’s parallel reactor tube using d6-benzene (0.5 mL). Pd/C (0.0125 mmol, 2.5 mol% Pd) was added to the reaction tube, which was then sealed with the Radley’s parallel reactor cap. The system was removed from the inert atmosphere box and attached to a Schlenk line. After evacuating and refilling the tubing with N2, H2 was introduced to the reaction flask at 1 atm. The reaction was allowed to proceed at room temperature for 40 hours. The crude compound was filtered through a short plug of Celite using ethyl acetate. To the filtrate was added 1M HCl in ether (1 mmol, 2 equiv.) and the hydrochloride amine salts were filtered using a Büchner funnel. If a mixture of primary to secondary amine were obtained, sublimation under reduced pressure was performed to isolate the primary amine salt. 2-phenylethan-1-amine hydrochloride salt (3.3a) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of palladium (0.0133 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, a mixture of 95:5 of primary to secondary amine was obtained in 82% yield. Purification by sublimation afforded the title NH2•HCl 193 compound as a colourless powder in 75% yield. 1H NMR (400 MHz; D2O): δ 7.46-7.41 (m, 2H), 7.39-7.31 (m, 3H), 3.30 (t, J = 7.3 Hz, 2H), 3.02 (t, J = 7.3 Hz, 2H). 13C NMR (101 MHz; D2O): δ 136.7, 129.1, 128.9, 127.4, 40.6, 32.8. HRMS (ESI+) m/z calc’d for C8H12N [M+H+]: 122.0970; found: 122.0964. 2-(4-fluorophenyl)ethan-1-amine hydrochloride salt (3.3b) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-fluorobenzene (0.0601 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of palladium (0.0133 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, a mixture of 92:8 of primary to secondary amine was obtained in 71% yield. Purification by sublimation afforded the title compound as a colourless powder in 65% yield. 1H NMR (400 MHz; D2O): δ 7.36-7.31 (m, 2H), 7.18-7.12 (m, 2H), 3.28 (t, J = 7.3 Hz, 2H), 3.00 (t, J = 7.3 Hz, 2H). 13C NMR (101 MHz; D2O): δ 1612.0 (d, 1J(C,F) = 242.4 Hz), 132.4 (d, 3J(C,F) = 3.0 Hz), 130.6, 130.5, 115.7 (d, 2J(C,F) = 21.6 Hz), 40.6, 32.0. HRMS (ESI+) m/z calc’d for C8H11NF [M+H+]: 140.0876; found: 140.0881. 2-(4-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride salt (3.3c) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-(trifluoromethyl)benzene (0.0851 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of FNH2•HClNH2•HClF3C 194 palladium (0.0133 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, a mixture of >99:1 of primary to secondary amine was obtained in 81%. Purification by sublimation afforded the title compound as a colourless powder in 81% yield. 1H NMR (400 MHz; D2O): δ 7.72 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 3.33 (t, J = 7.4 Hz, 2H), 3.09 (t, J = 7.4 Hz, 2H). 13C NMR (101 MHz; D2O): δ 141.0, 129.4, 128.8 (q, 2J(C,F) = 32.2Hz), 125.8 (q, 3J(C,F) = 3.7Hz), 124.2 (q, 1J(C,F) = 250.3Hz), 40.2, 32.6. HRMS (ESI+) m/z calc’d for C9H11NF3 [M+H+]: 190.0844; found: 190.0846. 2-(4-methoxyphenyl)ethan-1-amine hydrochloride salt (3.3d) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of palladium (0.0133 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, a mixture of 95:5 of primary to secondary amine was obtained in 70%. Purification by sublimation afforded the title compound as a colourless powder in 65% yield. 1H NMR (400 MHz; D2O): δ 7.29 (d, J = 8.6 Hz, 2H), 7.01 (d, J = 8.6 Hz, 2H), 3.83 (s, 3H), 3.25 (t, J = 7.3 Hz, 2H), 2.95 (t, J = 7.3 Hz, 2H). 13C NMR (101 MHz; D2O): δ 158.0, 130.2, 129.1, 114.5, 55.4, 40.7, 31.9. HRMS (ESI+) m/z calc’d for C9H14NO [M+H+]: 152.1075; found: 152.1081. 2-(3-methoxyphenyl)ethan-1-amine hydrochloride salt (3.3e) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-3-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel MeONH2•HClNH2•HClOMe 195 was heated at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of palladium (0.0133 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, a mixture of 74:26 of primary to secondary amine was obtained in 84% yield. Purification by sublimation afforded the title compound as a colourless powder in 59% yield. 1H NMR (400 MHz; D2O): δ 7.40-7.34 (m, 1H), 6.98-6.94 (m, 3H), 3.84 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H), 2.99 (t, J = 7.3 Hz, 2H). 13C NMR (101 MHz; D2O): δ 159.2, 138.4, 130.3, 121.7, 114.6, 112.8, 55.4, 40.5, 32.8. HRMS (ESI+) m/z calc’d for C9H14NO [M+H+]: 152.1075; found: 152.1071. 2-(2-methoxyphenyl)ethan-1-amine hydrochloride salt (3.3f) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-2-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of palladium (0.0133 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, a mixture of >99:1 of primary to secondary amine was obtained in 85% yield. Purification by sublimation afforded the title compound as a colourless powder in 84% yield. 1H NMR (400 MHz; D2O): δ 7.37 (dd, J = 8.2, 7.5 Hz, 1H), 7.27 (d, J = 7.4 Hz, 1H), 7.09 (dd, J = 8.2 Hz, 1H), 7.03 (t, J = 7.5, 7.4 Hz, 1H), 3.87 (s, 3H), 3.25 (t, J = 7.0 Hz, 2H), 3.00 (t, J = 7.0 Hz, 2H). 13C NMR (101 MHz; D2O): δ 157.5, 130.9, 129.1, 124.8, 121.2, 111.5, 55.4, 39.7, 27.9. HRMS (ESI+) m/z calc’d for C9H14NO [M+H+]: 152.1075; found: 152.1077. 2-(p-tolyl)ethan-1-amine hydrochloride salt (3.3g) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) NH2•HClOMeNH2•HClMe 196 and 1-ethynyl-4-methylbenzene (0.0581 g) were added to a solution of the titanium complex (0.0035 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 6 hours. Upon completion and salt formation using hydrochloric acid, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 2.5 mol% of palladium (0.0133 g) in 40 hours. Upon deprotection, a mixture of 96:4 of primary to secondary amine was obtained in 90% yield. Purification by sublimation afforded the title compound as a colourless powder in 73% yield. 1H NMR (400 MHz; D2O): δ 7.25 (q, J = 6.3 Hz, 4H), 3.26 (t, J = 7.4 Hz, 2H), 2.97 (t, J = 7.4 Hz, 2H), 2.33 (s, 3H). 13C NMR (101 MHz; D2O): δ 137.5, 133.5, 129.7, 128.9, 40.7, 32.4, 20.1. HRMS (ESI+) m/z calc’d for C9H14N [M+H+]: 136.1126; found: 136.1128. 2-cyclohexylethan-1-amine hydrochloride salt (3.3h) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and ethynylcyclohexane (0.0541 g) were added to a solution of the titanium complex (0.0174 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 70 °C for 24 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 5 mol% of palladium (0.0266 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, the title compound was obtained as a colourless powder in 70% yield. 1H NMR (400 MHz; D2O): δ 3.09-3.05 (m, 2H), 1.75-1.57 (m, 7H), 1.44-1.18 (m, 4H), 1.03-0.94 (m, 2H). 13C NMR (101 MHz; D2O): δ 37.7, 34.4, 34.2, 32.4, 26.1, 25.8. HRMS (ESI+) m/z calc’d for C8H11NF [M+H+]: ; found:. 1,2-diphenylethan-1-amine hydrochloride salt (3.3i) According to the general procedure, tert-butyldimethylsilanamine (0.0656 g) and 1,2-diphenylethyne (0.0891 g) were added to a solution of the titanium NH2•HClNH2•HCl 197 complex (0.0348 g) in benzene and transferred to a J-Young tube. The reaction vessel was heated at 145 °C for 48 hours. Upon completion, the hydrogenation was set-up following the general procedure. Fully hydrogenated product was obtained using 5 mol% of palladium (0.0266 g) in 40 hours. Upon deprotection and salt formation using hydrochloric acid, the title compound was obtained as a colourless powder in 77% yield. 1H NMR (400 MHz; D2O): δ 7.46-7.39 (m, 5H), 7.34-7.26 (m, 3H), 7.22-7.19 (m, 2H), 4.65 (dd, J = 8.6, 7.0 Hz, 1H), 3.37 (dd, J = 13.8, 7.0 Hz, 1H), 3.30 (dd, J = 13.8, 8.6 Hz, 1H). 13C NMR (101 MHz; D2O): δ 135.7, 135.6, 129.4, 129.3, 129.2, 128.9, 127.4, 127.3, 56.7, 39.8. HRMS (ESI+) m/z calc’d for C14H16N [M+H+]: 198.1283; found: 198.1281.  198 B.5 NMR Spectra Tert-butyldimethylsilanamine   1H NMR (400 MHz; C6D6)    H2NSi13C NMR (101 MHz; C6D6)    H2NSi 199 Bis(N-2,6-diisopropylphenylbenzamidate)(tert-butyldimethylsilylimido) (dimethylamido)titanium (IV) (3.1a)  Bis(N-2,6-diisopropylphenylbenzamidate)(tert-butyldimethylsilylimido)(pyridino) titanium (IV) (3.1b)  1H NMR (300 MHz; C6D6)         3.1a Ar = 2,6-diisopropylphenyl TiNSiONPhAr OPhN ArN H1H NMR (300 MHz; C6D6)       3.1b Ar = 2,6-diisopropylphenyl TiNONOPhPh ArArNN Si 200 Bis(N-2,6-diisopropylphenylbenzamidate)(triphenylsilylimido)(pyridino) titanium (IV) (3.1c)                         1H NMR (300 MHz; C6D6)       3.1c Ar = 2,6-diisopropylphenyl TiNONOPhPh ArArNN Si PhPhPh 201 (E)-1-tert-butyl-1,1-dimethyl-N-styrylsilanamine (3.2a)    1H NMR (400 MHz; C6D6)     3.2a HN Si13C NMR (101 MHz; C6D6)     3.2a HN Si 202 (E)-1-tert-butyl-N-(4-fluorostyryl)-1,1-dimethylsilanamine (3.2b)    1H NMR (400 MHz; C6D6)     3.2b HN SiF13C NMR (101 MHz; C6D6)     3.2b HN SiF 203 (E)-1-tert-butyl-N-(4-chlorostyryl)-1,1-dimethylsilanamine (3.2c)     13C NMR (101 MHz; C6D6)     3.2c HN SiCl1H NMR (400 MHz; C6D6)     3.2c HN SiCl 204 (E)-1-tert-butyl-N-(4-chlorostyryl)-1,1-dimethylsilanamine (3.2d)     13C NMR (101 MHz; C6D6)     3.2d HN SiBr1H NMR (400 MHz; C6D6)     3.2d HN SiBr 205 (E)-1-tert-butyl-1,1-dimethyl-N-(4-(trifluoromethyl)styryl)silanamine (3.2e)    1H NMR (400 MHz; C6D6)     3.2e HN SiF3C13C NMR (101 MHz; C6D6)     3.2e HN SiF3C 206 (E)-1-tert-butyl-1,1-dimethyl-N-(4-methylstyryl)silanamine (3.2f)     13C NMR (101 MHz; C6D6)     3.2f HN Si1H NMR (400 MHz; C6D6)     3.2f HN Si 207 (E)-1-tert-butyl-N-(4-methoxystyryl)-1,1-dimethylsilanamine (3.2g)     13C NMR (101 MHz; C6D6)     3.2g HN SiMeO1H NMR (400 MHz; C6D6)     3.2g HN SiMeO 208 (E)-1-tert-butyl-N-(3-methoxystyryl)-1,1-dimethylsilanamine (3.2h)    13C NMR (101 MHz; C6D6)      3.2h HN SiOMe1H NMR (400 MHz; C6D6)      3.2h HN SiOMe 209 (E)-1-tert-butyl-N-(2-methoxystyryl)-1,1-dimethylsilanamine (3.2i)    1H NMR (400 MHz; C6D6)     3.2i 13C NMR (101 MHz; C6D6)     3.2i HN SiOMeHN SiOMe 210 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyridin-2-yl)vinyl)silanamine (3.2j)    1H NMR (400 MHz; C6D6)     3.2j NHN Si13C NMR (101 MHz; C6D6)     3.2j NHN Si 211 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyridin-3-yl)vinyl)silanamine (3.2k)    1H NMR (400 MHz; C6D6)     3.2k NHN Si13C NMR (101 MHz; C6D6)     3.2k NHN Si 212 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyridin-4-yl)vinyl)silanamine (3.2l)    1H NMR (400 MHz; C6D6)     3.2l NHN Si1H NMR (400 MHz; C6D6)     3.2l NHN Si 213 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(pyrazin-2-yl)vinyl)silanamine (3.2m)    1H NMR (400 MHz; C6D6)     3.2m NNHN Si13C NMR (101 MHz; C6D6)     3.2m NNHN Si 214 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(1-methyl-1H-pyrazol-4-yl)vinyl)silanamine (3.2n)    1H NMR (400 MHz; C6D6)     3.2n NNHN Si13C NMR (101 MHz; C6D6)     3.2n NNHN Si 215 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(thiophen-2-yl)vinyl)silanamine (3.2o)    1H NMR (400 MHz; C6D6)     3.2o SHN Si13C NMR (101 MHz; C6D6)     3.2o SHN Si 216 (E)-1-tert-butyl-1,1-dimethyl-N-(2-(thiophen-3-yl)vinyl)silanamine (3.2p)   1H NMR (400 MHz; C6D6)     3.2p SHN Si13C NMR (101 MHz; C6D6)     3.2p SHN Si 217 (E)-1-tert-butyl-N-(hex-1-en-1-yl)-1,1-dimethylsilanamine (3.2q)     13C NMR (101 MHz; C6D6)     3.2q HN Si1H NMR (400 MHz; C6D6)     3.2q HN Si 218 (E)-1-tert-butyl-N-(2-cyclohexylvinyl)-1,1-dimethylsilanamine (3.2r)    13C NMR (101 MHz; C6D6)     3.2r HN Si1H NMR (400 MHz; C6D6)     3.2r HN Si 219 (E)-1-tert-butyl-N-(2-(cyclohex-1-en-1-yl)vinyl)-1,1-dimethylsilanamine (3.2s)    1H NMR (400 MHz; C6D6)     3.2s HN Si13C NMR (101 MHz; C6D6)     3.2s HN Si 220 (E)-1-tert-butyl-N-(4-((tert-butyldimethylsilyl)oxy)but-1-en-1-yl)-1,1-dimethylsilanamine (3.2t)   1H NMR (400 MHz; C6D6)     3.2t TBDMSOHN Si13C NMR (101 MHz; C6D6)     3.2t TBDMSOHN Si 221 (E)-N-(3-((tert-butyldimethylsilyl)amino)allyl)pivalamide (3.2u)    1H NMR (400 MHz; C6D6)     3.2u HNtBuOHN Si13C NMR (101 MHz; C6D6)     3.2u HNtBuOHN Si 222 (E)-1-tert-butyl-1,1-dimethyl-N-(1-phenylprop-1-en-2-yl)silanamine (3.2v)    13C NMR (101 MHz; C6D6)     3.2v HNMeSi1H NMR (400 MHz; C6D6)     3.2v HNMeSi 223 (E)-1-tert-butyl-1,1-dimethyl-N-(1-phenylbut-1-en-2-yl)silanamine (3.2w)     13C NMR (101 MHz; C6D6)     3.2w HNEtSi1H NMR (400 MHz; C6D6)     3.2w HNEtSi 224 (E)-1-tert-butyl-1,1-dimethyl-N-(1-phenylpent-1-en-2-yl)silanamine (3.2x)     1H NMR (400 MHz; C6D6)     3.2x HNPrSi13C NMR (101 MHz; C6D6)     3.2x HNPrSi 225 (E)-1-tert-butyl-N-(1,2-diphenylvinyl)-1,1-dimethylsilanamine (3.2y)     13C NMR (101 MHz; d8-Tol)      3.2y HN Si1H NMR (400 MHz; d8-Tol)      3.2y HN Si 226 2-phenylethan-1-amine hydrochloride salt (3.3a)    1H NMR (400 MHz; D2O)     3.3a NH2•HCl13C NMR (101 MHz; D2O)     3.3a NH2•HCl 227 2-(4-fluorophenyl)ethan-1-amine hydrochloride salt (3.3b)    1H NMR (400 MHz; D2O)     3.3b FNH2•HCl13C NMR (101 MHz; D2O)     3.3b FNH2•HCl 228 2-(4-(trifluoromethyl)phenyl)ethan-1-amine hydrochloride salt (3.3c)    13C NMR (101 MHz; D2O)     3.3c NH2•HClF3C1H NMR (400 MHz; D2O)     3.3c NH2•HClF3C 229 2-(4-methoxyphenyl)ethan-1-amine hydrochloride salt (3.3d)    1H NMR (400 MHz; D2O)     3.3d MeONH2•HCl13C NMR (101 MHz; D2O)     3.3d MeONH2•HCl 230 2-(3-methoxyphenyl)ethan-1-amine hydrochloride salt (3.3e)    13C NMR (101 MHz; D2O)     3.3e 1H NMR (400 MHz; D2O)     3.3e NH2•HClOMeNH2•HClOMe 231 2-(2-methoxyphenyl)ethan-1-amine hydrochloride salt (3.3f)    13C NMR (101 MHz; D2O)     3.3f NH2•HClOMe1H NMR (400 MHz; D2O)     3.3f NH2•HClOMe 232 2-(p-tolyl)ethan-1-amine hydrochloride salt (3.3g)    1H NMR (400 MHz; D2O)     3.3g NH2•HClMe13C NMR (101 MHz; D2O)     3.3g NH2•HClMe 233 2-cyclohexylethan-1-amine hydrochloride salt (3.3h)    13C NMR (101 MHz; D2O)     3.3h NH2•HCl1H NMR (400 MHz; D2O)     3.3h NH2•HCl 234 1,2-diphenylethan-1-amine hydrochloride salt (3.3i)    1H NMR (400 MHz; D2O)     3.3i NH2•HCl13C NMR (101 MHz; D2O)     3.3i NH2•HCl 235 B.6 Solid State Molecular Structures and X-Ray Crystallographic Data  Single crystal X-ray structure determinations were performed at the X-ray crystallography lab at the Department of Chemistry, University of British Columbia on either a Bruker X8 APEX or Bruker APEX DUO diffractometer using graphite-monochromated Mo Kα radiation (λ=0.71073 Å). Unless otherwise noted, data integration was performed using Bruker SAINT (v.8.34A),387 absorption correction was performed using Bruker SADABS (2014/5),387 structures were solved using direct methods using SIR2004 or SHELXS,388,389 and refinement (including modelling of disorder) was performed using SHELXL (2014/7)390 using the OLEX2391 interface.  Compound LS590: Disorder was modelled for a single benzamidate benzene ring (of the four present in the asymmetric unit). This group was split into two parts using the SIMU constraint, with each part being assigned a free variable and refined freely. Electron density from disordered solvent molecules was masked using OLEX2.  Complex 3.1a (LS648) Complex 3.2b (LS599) Complex 3.3c (LS590) formula C46H66N4O2SiTi C52H71N4O2SiTi C244H256N16O8Si4Ti4 Fw 783.01 860.11 3844.59 crystal size (mm) 0.58 x 0.51 x 0.46 0.28 x 0.26 x 0.24 0.42 x 0.32 x 0.17 color, habit yellow, prism orange, prism yellow, prism crystal system Monoclinic Monoclinic Triclinic space group P21/n P21/n P-1 T (K) 90 90 100 a (Å) 12.4428(12) 12.8621(10) 812.843 b (Å) 27.623(3) 21.1899(17) 20.558 c (Å) 13.2015(12) 18.8390(15) 23.390 α (Å) 90 90 72.79 β (Å) 92.073(2) 104.842(2) 77.72 γ (Å) 90 90 72.76 V (Å3) 4534.4(7) 877.79(15) 5580.9 Z 4 4 1  236 ρcalcd (g cm-3) 1.147 1.151 1.144 F(000) 1688.0 1852.0 2040.0 µ (MoKα) (mm-1) 0.254 0.238 0.219 2θmax (°) 54.36 60.124 60.126 total no. of reflns 70628 59876 124636 no. of unique reflns 10001 14512 32571 R1 (F2, all data) 0.0470 0.0605 0.0556 wR2 (F2, all data) 0.0939 0.1155 0.1046 R1 (F, I > 2σ(I)) 0.0376 0.0427 0.0396 wR2 (F, I > 2σ(I)) 0.0886 0.1056 0.0965 goodness of fit 1.049 1.012 1.028   Figure B.2 Single crystal molecular structure of complex 3.1a  237  Figure B.3 Single crystal molecular structure of complex 3.1b  Figure B.4 Single crystal molecular structure of complex 3.1c     238 B.7 Computational Data and Details Geometry optimizations and single point frequency calculations were performed with Gaussian 09 (Revision E.01)392 at the B3LYP/6-311g(d,p) level of theory.393-396 NBO calculations were performed with the NBO 6.0 program,397 linked to through the Gaussian software. Frequency calculations showed no negative frequencies for all structures ensuring the calculated structures were at a minimum. Solvation effects were accounted for using the PCM model (solvent = benzene),398 however, these results differed significantly from experiment. The PCM model was not used given the strong agreement with experiment (as shown below) without the model. 239 Optimized geometry for 3.4a  N                  1.93552300   -0.50785900   -0.56611500  H                  2.00346100   -1.50911000   -0.69998000  C                  3.21517300    1.57401100   -0.21758500  H                  2.40732500    2.13006200    0.26377500  H                  4.15703600    1.97936500    0.16026400  H                  3.16490900    1.75501100   -1.29361400  C                  3.12288500   -0.17716500    1.60144200  H                  3.08760000   -1.24825600    1.82086800  H                  4.01708000    0.23724500    2.07631500  H                  2.24653500    0.28716900    2.06087400  C                  0.65566100   -0.07049800   -0.29002800  C                 -0.46301200   -0.82185500   -0.35221400  H                  0.58739600    0.98516700   -0.05157700  H                 -0.35589300   -1.88871900   -0.53988300  C                 -1.83360000   -0.34295200   -0.17719800  C                 -2.86571000   -1.27561100    0.03397500  C                 -2.19261500    1.01843700   -0.20998400  C                 -4.18304700   -0.87234600    0.22335500  H                 -2.62144000   -2.33308000    0.05530900  C                 -3.50754000    1.42125500   -0.01234600  H                 -1.43881600    1.77039700   -0.41501200  C                 -4.51431000    0.48072300    0.20717300  H                 -4.95383200   -1.61848000    0.38475600  H                 -3.75218700    2.47778900   -0.04419000  H                 -5.54041800    0.79828700    0.35278700  C                  3.13699300    0.06726100    0.07872400  C                  4.34487400   -0.63736600   -0.55632500  H                  4.30562600   -1.71724100   -0.37821100  H                  4.36429700   -0.46873000   -1.63559000  H                  5.27814100   -0.26523200   -0.12800600   240 Optimized geometry for 3.4b  N                 -1.71184100   -0.21726300   -0.63169600  C                 -0.72258300   -0.80471300   -0.10750600  H                 -0.65908700   -1.05619100    0.95932900  C                  1.74868900   -0.50573200   -0.44884400  C                  2.73530200   -1.20473200    0.25137500  C                  1.93809600    0.86128000   -0.68458000  C                  3.88568100   -0.55901600    0.70272900  H                  2.60630100   -2.26607000    0.43916100  C                  3.08618300    1.50850800   -0.23764400  H                  1.17775200    1.41712600   -1.22339800  C                  4.06470400    0.79980200    0.45871000  H                  4.64215100   -1.11933300    1.24116400  H                  3.21900900    2.56678000   -0.43412600  H                  4.95989800    1.30344700    0.80575600  C                  0.48418900   -1.19358700   -0.93062000  H                  0.27432700   -0.94138700   -1.97240300  H                  0.61885000   -2.27946000   -0.86754100  C                 -2.89748000    0.17803500    0.15362800  C                 -3.02814100    1.70269000   -0.02350100  H                 -3.04431800    1.95857200   -1.08481400  H                 -3.94788800    2.06869800    0.44149500  H                 -2.18083800    2.21787700    0.43724800  C                 -2.85686600   -0.17063100    1.65057400  H                 -2.77555000   -1.24912100    1.81387200  H                 -2.02088500    0.31779700    2.15925000  H                 -3.77834100    0.16690700    2.13144100  C                 -4.09436300   -0.52504500   -0.51412500  H                 -5.03591700   -0.19947300   -0.06295600  H                 -4.11742300   -0.29663000   -1.58146200  H                 -4.01560900   -1.60984200   -0.40130700   241 Optimized geometry for 3.5a  N                  0.67143500   -0.49708500    0.21620200  H                  0.75131100   -1.49756200    0.34923900  Si                 2.13145100    0.47976900    0.41607700  C                  1.79780900    2.16555800   -0.35532800  H                  1.04817000    2.72480700    0.21182200  H                  2.71056400    2.76853800   -0.35655200  H                  1.44931700    2.08449600   -1.38783000  C                  2.52468900    0.70882400    2.24858000  H                  2.72799500   -0.24327200    2.74696200  H                  3.39206700    1.35795000    2.40176000  H                  1.67245500    1.16803600    2.75857400  C                  3.55559300   -0.45314500   -0.47171100  C                  4.89320300    0.27423800   -0.21431200  H                  5.70730900   -0.23422500   -0.74519500  H                  4.87403900    1.30947200   -0.56924200  H                  5.15600200    0.28814600    0.84732000  C                  3.28982800   -0.49897500   -1.99088000  H                  4.08261300   -1.06268100   -2.49803100  H                  2.33712300   -0.98310600   -2.22284000  H                  3.27028100    0.50231100   -2.43064700  C                  3.66777200   -1.89826300    0.06049700  H                  4.50953900   -2.41286900   -0.41886300  H                  3.84049600   -1.93090600    1.14056300  H                  2.77199600   -2.48835100   -0.15842700  C                 -0.63969600   -0.06467500    0.10232700  C                 -1.73867700   -0.84312400    0.15628900  H                 -0.74046500    1.00531700   -0.04739700  H                 -1.60343600   -1.90677200    0.34484700  C                 -3.12473300   -0.39866800    0.01134900  C                 -4.16583500   -1.29174800    0.32396000  242  C                 -3.49189000    0.88664400   -0.43254300  C                 -5.50175600   -0.91967600    0.21632200  H                 -3.91506800   -2.29227200    0.66225800  C                 -4.82600600    1.25958400   -0.53463200  H                 -2.72674100    1.60029900   -0.71708300  C                 -5.84337800    0.36134700   -0.21015100  H                 -6.27855700   -1.63407400    0.46749400  H                 -5.07555700    2.25737200   -0.88000300  H                 -6.88336000    0.65464700   -0.29581500   243 Optimized geometry for 3.5b  N                  0.51419000   -0.20651300    0.43974900  C                  1.77421100    0.41463600   -2.26213200  H                  0.85385000    0.87971100   -2.62925400  H                  2.60961200    0.93485500   -2.73991800  H                  1.78494800   -0.62016700   -2.61574700  C                  1.86060700    2.36269700    0.11528000  H                  1.84030200    2.48171800    1.20116500  H                  2.73267000    2.89935000   -0.26993300  H                  0.96816500    2.85038900   -0.28825600  C                  3.45381600   -0.34708300    0.28790000  C                  4.71912200    0.22818900   -0.38262700  H                  5.61434500   -0.27090100    0.00905200  H                  4.71427900    0.08064900   -1.46686500  H                  4.83617600    1.29929500   -0.18983600  C                  3.36594900   -1.85778200   -0.01410000  H                  4.25301500   -2.37318700    0.37513700  H                  2.48886500   -2.31229100    0.45485600  H                  3.31880300   -2.06190300   -1.08850800  C                  3.55524200   -0.14971400    1.81533100  H                  4.42582800   -0.69017900    2.20840300  H                  3.67824700    0.90385700    2.08360000  H                  2.66608300   -0.52448100    2.32824400  C                 -0.50075000   -0.72666300   -0.10351800  H                 -0.64723600   -0.77244600   -1.19844900  C                 -2.95831200   -0.62908800    0.38380500  C                 -3.86351700   -1.15221200   -0.54418100  C                 -3.26766600    0.58490200    1.00819300  C                 -5.04998300   -0.48331400   -0.84052900  H                 -3.64237400   -2.09585000   -1.03305400  C                 -4.45330700    1.25346100    0.71713300  244  H                 -2.57273000    1.00485900    1.72795100  C                 -5.34869700    0.72151000   -0.20971300  H                 -5.74228500   -0.90704600   -1.55969900  H                 -4.67994600    2.18972100    1.21524800  H                 -6.27310700    1.24106200   -0.43538800  C                 -1.64712500   -1.32867100    0.68685200  H                 -1.39830200   -1.26273700    1.74770600  H                 -1.73119900   -2.38899900    0.42048200  Si                 1.89036600    0.54393600   -0.37723800   245 Optimized geomtry for 3.6a  C                 -0.92574300    0.32444800    0.04190800  H                 -0.92196400    0.32447900    1.12823100  C                  1.58073800    0.08835300    0.04979300  C                  2.29719700   -1.22707700   -0.33000500  C                  2.49031300    1.29623800   -0.27275500  H                  1.42190200    0.07730600    1.13787600  C                  3.68338100   -1.34977700    0.31863400  H                  2.40307000   -1.26713500   -1.42285000  H                  1.66682400   -2.07667100   -0.04892000  C                  3.87685400    1.17527500    0.37594800  H                  2.60478700    1.36887600   -1.36296200  H                  1.99598500    2.21818100    0.04887200  C                  4.56953900   -0.13972700   -0.00682600  H                  4.16965200   -2.27569800   -0.00627000  H                  3.56570900   -1.42646500    1.40763700  H                  4.50008500    2.02976000    0.09140700  H                  3.76930700    1.22022500    1.46775600  H                  5.53331400   -0.22483100    0.50612100  H                  4.78842300   -0.13235400   -1.08273000  C                  0.23543300    0.19923700   -0.61546200  H                  0.23273800    0.19731100   -1.70628400  N                 -2.17974000    0.54316300   -0.52502900  H                 -2.16946400    0.44735900   -1.53355400  C                 -3.40594700   -0.03916000    0.06628600  C                 -4.57179700    0.41700000   -0.82351600  H                 -4.44988300    0.04692800   -1.84715600  H                 -5.52206700    0.03435400   -0.44375200  H                 -4.62240900    1.50775400   -0.85853000  C                 -3.34440600   -1.58025900    0.10077400  H                 -3.22207900   -1.98394600   -0.90876200  246  H                 -2.49780500   -1.92279000    0.70127900  H                 -4.25850700   -2.00415900    0.52724100  C                 -3.60774500    0.51535300    1.48627300  H                 -3.59969700    1.60755200    1.47286400  H                 -4.56675200    0.17793700    1.88776200  H                 -2.82989300    0.17445800    2.17360800   247 Optimized geometry for 3.6b  N                 -1.91762000   -0.36109400   -0.51688900  C                 -0.98560200   -0.73910600    0.25076300  H                 -1.05731000   -0.69650600    1.34751000  C                  0.30654700   -1.29541500   -0.28356800  H                  0.26169800   -1.28232800   -1.37626700  H                  0.37633500   -2.34647500    0.03017200  C                  1.56322800   -0.55651500    0.21900100  C                  2.84324400   -1.31294700   -0.17923400  C                  1.62253900    0.89753600   -0.28277900  H                  1.52397000   -0.53053400    1.31883800  C                  4.11516100   -0.59364700    0.29167300  H                  2.86752700   -1.41508300   -1.27269000  H                  2.81360900   -2.33045400    0.22648900  C                  2.89008100    1.62236500    0.19227900  H                  1.59664600    0.89082800   -1.38083300  H                  0.73120700    1.44474900    0.03959900  C                  4.16038600    0.85814300   -0.20478400  H                  5.00185300   -1.13917200   -0.04744000  H                  4.14717600   -0.60037600    1.38905200  H                  2.91532100    2.63806500   -0.21567500  H                  2.85903000    1.72764000    1.28476800  H                  5.04787000    1.36540800    0.18741000  H                  4.25613500    0.86242300   -1.29838400  C                 -3.19911500    0.15979700   -0.00339900  C                 -4.28505600   -0.78335000   -0.55567400  H                 -4.18043000   -1.78397100   -0.12730200  H                 -5.28361200   -0.40781500   -0.31459300  H                 -4.19293300   -0.86831500   -1.64021700  C                 -3.32285500    0.25548000    1.52663900  H                 -3.22974200   -0.72346600    2.00562400  248  H                 -2.56635400    0.91999400    1.95406600  H                 -4.30342700    0.65918800    1.79119200  C                 -3.36639300    1.55854000   -0.62673000  H                 -3.25931900    1.50141000   -1.71167800  H                 -4.35052800    1.97268500   -0.38995200  H                 -2.60436900    2.24447800   -0.24659900   249 Optimized geometry for 3.7a  C                 -2.18374600    0.62282900    2.14801200  H                 -1.45749900    1.38533500    2.44431900  H                 -3.12667300    0.87203600    2.64345800  H                 -1.84083200   -0.33717700    2.54125500  C                 -2.81715100    2.33030400   -0.31697900  H                 -2.98222700    2.36904800   -1.39755100  H                 -3.70910400    2.73397900    0.17182000  H                 -1.98324900    3.00188300   -0.09064500  C                 -3.79667000   -0.64076900   -0.25269700  C                 -5.16529900   -0.12751500    0.24402600  H                 -5.95800400   -0.83184200   -0.03703000  H                 -5.19538200   -0.02582100    1.33335100  H                 -5.42259900    0.84241400   -0.19110700  C                 -3.53009400   -2.03501600    0.35159700  H                 -4.29992600   -2.74513200    0.02432000  H                 -2.55850800   -2.43125300    0.04397900  H                 -3.55012000   -2.01443600    1.44525200  C                 -3.84417500   -0.76305600   -1.79141900  H                 -4.65816600   -1.43421200   -2.09246500  H                 -4.02132500    0.20062600   -2.27863000  H                 -2.92017600   -1.18472100   -2.20028500  C                  0.38540400    0.13780400    0.06492900  H                  0.42930000    0.48890700    1.09279800  C                  2.89779700    0.00536600    0.02783800  C                  3.63216200   -1.35254500    0.11436600  C                  3.76721000    1.02493300   -0.74236400  H                  2.77811300    0.38125900    1.05439100  C                  5.04338500   -1.22064400    0.70480900  H                  3.69891500   -1.78094500   -0.89511400  H                  3.03299700   -2.05066100    0.70735600  250  C                  5.17897700    1.15791800   -0.15375300  H                  3.84039000    0.70295900   -1.79024700  H                  3.26366300    1.99674100   -0.75176700  C                  5.88883800   -0.20029100   -0.06909600  H                  5.53957900   -2.19696100    0.71368300  H                  4.96661800   -0.90241500    1.75292900  H                  5.77052100    1.85909700   -0.75204700  H                  5.11095700    1.59086700    0.85302700  H                  6.87191400   -0.08693500    0.39993200  H                  6.06933100   -0.57730400   -1.08442300  C                  1.52789800   -0.13377300   -0.57950100  H                  1.48722700   -0.48715500   -1.61065700  N                 -0.91043100    0.00135200   -0.43402500  H                 -0.93384700   -0.32394400   -1.39189400  Si                -2.41257800    0.58164400    0.27725400   251 Optimized geometry for 3.7b N                 -0.74351300   -0.18512900   -0.28741000  C                 -2.26142800    1.09232900    2.02711400  H                 -1.41186600    1.73074000    2.28956000  H                 -3.17003100    1.64914300    2.27469500  H                 -2.22688700    0.21279600    2.67606400  C                 -2.29375600    2.22497800   -0.83339000  H                 -2.21198900    2.01069400   -1.90160300  H                 -3.22340600    2.77668700   -0.66581300  H                 -1.46416700    2.88599600   -0.56482400  C                 -3.66902400   -0.54617900   -0.25563300  C                 -5.02150100    0.09565300    0.11904200  H                 -5.84552100   -0.57971200   -0.14335600  H                 -5.09828400    0.29872900    1.19154700  H                 -5.19293000    1.03621300   -0.41390400  C                 -3.51116100   -1.87255900    0.51716700  H                 -4.32612400   -2.56033500    0.25847400  H                 -2.56939600   -2.37187300    0.27289100  H                 -3.54440300   -1.72511500    1.60133100  C                 -3.65320500   -0.84723100   -1.76893400  H                 -4.45402400   -1.55428900   -2.02089200  H                 -3.81599700    0.05500500   -2.36606700  H                 -2.70321500   -1.28794400   -2.08074500  C                  0.24221200   -0.48272900    0.44710000  H                  0.28179200   -0.23220600    1.52593300  C                  1.46252800   -1.21835200   -0.04595100  H                  1.36409000   -1.37436200   -1.12395200  H                  1.46350300   -2.20838700    0.43271600  Si                -2.22768400    0.64240300    0.18775700  C                  2.79157500   -0.51544900    0.29355600  C                  3.99469800   -1.43047100    0.00273000  252  C                  2.94601200    0.82437400   -0.44968200  H                  2.79341800   -0.30244700    1.37357600  C                  5.33346100   -0.74909200    0.31952800  H                  3.97461000   -1.71529700   -1.05788900  H                  3.90036300   -2.35972500    0.57555500  C                  4.28179300    1.51151800   -0.13142700  H                  2.88153400    0.63643900   -1.52984000  H                  2.11235300    1.49081800   -0.20585800  C                  5.47480300    0.58944200   -0.41821300  H                  6.16311800   -1.41502600    0.06091300  H                  5.40146000   -0.57357700    1.40107300  H                  4.37140200    2.43848600   -0.70698600  H                  4.29612400    1.80094600    0.92749600  H                  6.41164800    1.08097000   -0.13664700  H                  5.53294600    0.40151100   -1.49821800   253 Appendix C   This appendix is for the supporting information pertaining the research conducted in Chapter 4. C.1 General considerations All air and moisture sensitive reactions were performed using a MBraun LABmaster glovebox filled with a N2 atmosphere. All pieces of glassware were dried for at least 4 hours in a 160 °C oven before being transferred into the glovebox. All stirring was done with appropriately sized Teflon coated magnetic stir bars dried for at least 4 hours in a 160 °C oven. Benzene and hexanes were passed over activated alumina columns into Teflon sealed Straus flasks and stored therein until use. d6-Benzene was dried over sodium metal, distilled, degassed, and stored in Teflon sealed Schlenk flasks prior to use. Experiments conducted on NMR tube scale were performed in J-Young NMR tubes (8” x 5 mm) sealed with screw-type Teflon caps. Thin layer chromatography (TLC) was set-up on EMD Silica gel 60 F254 plates. Visualization was achieved under a 254 nm UV light source and/or by staining with potassium permanganate or ninhydrin solutions. Flash chromatography was set-up using SiliaFlash F60 silica gel (230-400 mesh) (Silicycle) and glass columns, with ACS grade solvents (Sigma-Aldrich). C.2 Materials Commercially available terminal and internal alkynes were dried over CaH2 and distilled or sublimed prior to use. Synthesized terminal and internal alkynes were made following previously reported conditions399 and were also dried prior to use. Commercially available α,β-unsaturated carbonyls were dried over CaH2 and distilled or sublimed prior to use. Synthesized α,β-unsaturated carbonyls were made following previously reported conditions308-310, 325 and were also dried prior to use. The oxidant, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (Combi-Blocks), was used as received.  254 C.3 Instrumentation NMR spectra were recorded as dilute solutions in deuterated chloroform or benzene on a Bruker Avance 400, 400 or 600 MHz spectrometer at ambient temperature. 1H chemical shift data are given in units δ relative to the residual protic solvent where δ (CDCl3) = 7.26 ppm and δ (C6D6) = 7.16 ppm, while 13C chemical shift data are given in units δ relative to the solvent where δ (CDCl3) = 77.16 ppm and δ (C6D6) = 128.06 ppm. High-resolution mass spectra were measured by the mass spectrometry and microanalysis service at the Department of Chemistry, University of British Columbia. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 eV) source or a Bruker Esquire LC spectrometer using electrospray ionization source. Fragment signals are given in mass per charge number (m/z). C.4 Synthesis and Compound Characterization General Procedure for the Optimization of the Pyridine Synthesis  Inside an inert atmosphere box, benzene (0.15 mL) was added to the titanium complex (0.005 mmol, 1 mol% Ti) in a 5-dram vial. The solution was then transferred to a J-Young tube. The amine (0.5 mmol, 1 equiv.) and alkyne (0.5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the J-Young tube. The remaining benzene (0.35 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction tube. The J-Young tube was sealed, taken out of the inert atmosphere box and heated at 70 °C for 6 hours. The reaction vessel was re-introduced into the inert atmosphere box, where the reaction solution was transferred with hexanes (0.5 mL) to a Radley’s parallel reactor tube containing pre-weighed H2NSii) 1 mol% 1C6D6, 70 °C, 6 hii) trans-Chalconex mol% [F-]AdditiveSolvent, Temp, Timeiii) OxidantNPhPhPh 255 trans-chalcone (0.5 mmol, 1 equiv.) and 3Å molecular sieves (0.1000 g). Outside the inert atmosphere box, the Radley’s tube was connected to a Radley’s parallel reactor. The tubing was evacuated and purged with nitrogen gas three times before the solvent inside the reaction mixture was removed under reduced pressure. Under nitrogen, the new solvent (0.5 mL) was introduced using a syringe and needle. If a solid fluoride source (0.05 mmol, 10 mol% F) was used, it was introduced inside the glovebox together with the trans-chalcone, however, if 1M TBAF in THF (0.05 mmol, 10 mol% F) was used, it was added after the addition of new solvent using a syringe and needle. The reaction mixture was allowed to stir at a specific temperature and time. In some cases, oxidants were subsequently added to the reaction mixture. Upon completion, the solvents were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the desired compound as a colourless solid. General Procedure A: Procedure for the Synthesis of Poly-Substituted Pyridines Using High Boiling α,β-Unsaturated Carbonyls Inside an inert atmosphere box, d6-benzene or d8-toluene (0.15 mL) was added to the titanium complex (0.005 mmol, 0.0125 mmol or 0.025 mmol, 1 mol% Ti, 2.5 mol% Ti or 5 mol% Ti) in a 5-dram vial. The solution was then transferred to a J-Young tube. The amine (0.5 mmol, 1 equiv.) and alkyne (0.5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the J-Young tube. The remaining benzene or toluene (0.35 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction tube. The J-Young tube was sealed, taken out of the inert atmosphere box and heated at 70 °C, 110 °C or 145 °C for a specific time. The reaction vessel was re-introduced into the inert atmosphere box, where the reaction solution was transferred with hexanes (0.5 mL) to a Radley’s parallel reactor tube containing pre-weighed α,β-unsaturated carbonyl (0.5 mmol, 1 equiv.) and 3Å molecular  256 sieves (0.1000 g). Outside the inert atmosphere box, the Radley’s tube was connected to a Radley’s parallel reactor. The tubing was evacuated and purged with nitrogen gas three times before the solvent was evacuated under reduced pressure. The DMSO (0.25 mL or 0.50 mL) was introduced using a syringe and needle. After the addition of solvent, 1M TBAF in THF (0.05 mmol 10 mol% F) was also added using a syringe and needle. The reaction mixture was allowed to stir at room temperature, 50 °C, 80 °C or 100 °C for 18 hours. Upon completion, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.5 mmol, 1 equiv.) and more DMSO (0.25 mL or 0.50 mL) were added to the reaction mixture, which was allowed to react for 1 hour. The volatiles were removed under reduced pressure and purification by column chromatography afforded the desired compounds. General Procedure B: Procedure for the Synthesis of Poly-Substituted Pyridines Using Low Boiling α,β-Unsaturated Carbonyls Inside an inert atmosphere box, d6-benzene or d8-toluene (0.15 mL) was added to the titanium complex (0.005 mmol, 1 mol% Ti) in a 5-dram vial. The solution was then transferred to a J-Young tube. The amine (0.5 mmol, 1 equiv.) and alkyne (0.5 mmol, 1 equiv.) were pre-weighed to separate 5-dram vials and transferred to the J-Young tube. The remaining benzene or toluene (0.35 mL) was used to rinse the vials containing amine and alkyne, which were also transferred to the reaction tube. The J-Young tube was sealed, taken out of the inert atmosphere box and heated at 70 °C for a specific time. The reaction vessel was re-introduced into the inert atmosphere box, where the reaction solution was transferred with hexanes (0.5 mL) to a Radley’s parallel reactor tube. The solvent was removed under reduced pressure and then the α,β-unsaturated carbonyl (0.5 mmol, 1 equiv.) and 3Å molecular sieves (0.1000 g) were added to the reaction mixture. Outside the inert atmosphere box, the Radley’s tube was connected to a  257 Radley’s parallel reactor. The tubing was evacuated and purged with nitrogen gas three times before DMSO (0.25 mL) was introduced using a syringe and needle. After the addition of solvent, 1M TBAF in THF (0.05 mmol 10 mol% F) was also added using a syringe and needle. The reaction mixture was allowed to stir at room temperature for 18 hours. Upon cooling, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.5 mmol, 1 equiv.) and more DMSO (0.50 mL) were added to the reaction mixture, which was allowed to react for 1 hour. The volatiles were removed under reduced pressure and purification by column chromatography afforded the desired compounds. General Procedure C: One-Pot Procedure for the Synthesis of Poly-Substituted Pyridines Inside an inert atmosphere box, the titanium complex (0.005 mmol, 1 mol% Ti) was weighed into a Teflon sealed reaction vessel. The amine (0.5 mmol, 1 equiv.) and alkyne (0.5 mmol, 1 equiv.) were also weighed into the reaction vessel. The vessel was sealed, taken out of the inert atmosphere box and heated at 70 °C for 3 hours. The reaction vessel was re-introduced into the inert atmosphere box. The α,β-unsaturated carbonyl (0.5 mmol, 1 equiv.) and 3Å molecular sieves (0.1000 g) were then added to the reaction mixture. Outside the inert atmosphere box, the reaction vessel was evacuated and purged with nitrogen gas three times before DMSO (0.25 mL) was introduced using a syringe and needle. After the addition of solvent, 1M TBAF in THF (0.05 mmol 10 mol% F) was also added using a syringe and needle. The reaction mixture was allowed to stir at room temperature, 80 °C or 100 °C for 18 hours. Upon cooling, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.5 mmol, 1 equiv.) and more DMSO (0.50 mL) were added to the reaction mixture, which was allowed to react for 1 hour. The crude mixture was filtered through a Celite pad and the Celite was rinsed with ethyl acetate. The volatiles were then removed under reduced pressure. Purification by column chromatography afforded the desired compounds.  258 2,4,5-Triphenylpyridine According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, chalcone (0.1041 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 85% yield. The analytical data were consistent with literature.270 1H NMR (400 MHz; CDCl3): δ 8.73 (s, 1H), 8.10-8.07 (m, 2H), 7.79 (s, 1H), 7.53-7.49 (m, 2H), 7.44 (m, 1H), 7.32-7.27 (m, 6H), 7.24-7.18 (m, 4H).13C NMR (101 MHz; CDCl3): δ 156.4, 150.8, 148.8, 139.04, 138.92, 137.6, 134.4, 129.9, 129.4, 129.2, 128.9, 128.43, 128.40, 128.0, 127.4, 127.1, 121.8. 3-phenylpyridine (4.1a) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, prop-2-enal (0.0280 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (85:15 Hex/EtOAc) afforded the title compound as a colourless solid in 34% yield. The analytical data were consistent with literature.400 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.61 (d, J = 2.7 Hz, 1H), 7.94-7.90 (m, NPhN 259 1H), 7.61-7.57 (m, 2H), 7.52-7.46 (m, 2H), 7.45-7.38 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 148.32, 148.21, 137.8, 136.9, 134.7, 129.2, 128.3, 127.3, 123.8. 2,5-diphenylpyridine (4.1b) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 1-phenylprop-2-en-1-one (0.0661 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (75:25 Hex/EtOAc) afforded the title compound as a colourless solid in 40% yield. The analytical data were consistent with literature.401 1H NMR (400 MHz, CDCl3) 8.94 (dd, J = 2.4, 0.8 Hz, 1H), 8.06-8.03 (m, 2H), 7.96 (dd, J = 8.2, 2.4 Hz, 1H), 7.82 (dd, J = 8.2, 0.8 Hz, 1H), 7.66-7.63 (m, 2H), 7.52-7.49 (m, 4H), 7.46-7.40 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 156.3, 148.2, 139.1, 137.8, 135.22, 135.04, 129.24, 129.13, 128.94, 128.2, 127.14, 126.97, 120.5. 3,4-diphenylpyridine (4.1c) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, cinnamaldehyde (0.0661 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (85:15 Hex/EtOAc) NPhNPh 260 afforded the title compound as a colourless solid in 13% yield.319 The analytical data were consistent with literature. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.63 (d, J = 5.0 Hz, 1H), 7.34 (d, J = 5.0 Hz, 1H), 7.28-7.26 (m, 6H), 7.17-7.14 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 150.5, 148.5, 148.2, 138.5, 137.6, 136.2, 129.9, 129.4, 128.5, 128.1, 127.6, 124.9. 3-methyl-2,5-diphenylpyridine (4.1d) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 2-methyl-1-phenylprop-2-en-1-one (0.0731 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 47% yield. The analytical data were consistent with literature.402 1H NMR (400 MHz, CDCl3) δ 8.78 (d, J = 2.1 Hz, 1H), 7.81 (d, J = 1.9 Hz, 1H), 7.65-7.62 (m, 2H), 7.60-7.57 (m, 2H), 7.52-7.46 (m, 4H), 7.44-7.40 (m, 2H), 2.45 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.6, 145.5, 140.5, 137.9, 137.1, 135.1, 130.8, 129.18, 129.13, 128.3, 128.1, 127.2, 20.3.  2,3,5-triphenylpyridine (4.1e) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 1,2-diphenylprop-2-en-1-one (0.1041 g) and molecular sieves (0.1000 g) were added following NPh MeNPh 261 general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 70% yield. The analytical data were consistent with literature.403 1H NMR (400 MHz, CDCl3) δ 8.93 (d, J = 2.3 Hz, 1H), 7.93 (d, J = 2.3 Hz, 1H), 7.70-7.67 (m, 2H), 7.53-7.49 (m, 2H), 7.45-7.38 (m, 3H), 7.32-7.29 (m, 3H), 7.27-7.24 (m, 5H). 13C NMR (101 MHz, CDCl3) δ 156.0, 146.8, 140.01, 139.96, 137.5, 137.0, 136.1, 135.1, 130.0, 129.7, 129.3, 128.5, 128.3, 128.03, 127.93, 127.5, 127.2. 4-methyl-2,5-diphenylpyridine (4.1f) According to general procedure B, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 1-phenylbut-2-en-1-one (0.0731 g) and molecular sieves (0.1000 g) were added following general procedure B. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 11% yield. The analytical data were consistent with literature.401 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 8.04-8.02 (m, 2H), 7.64 (s, 1H), 7.51-7.46 (m, 4H), 7.44-7.36 (m, 4H), 2.38 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.3, 150.0, 145.3, 139.4, 138.0, 136.4, 129.5, 128.96, 128.87, 128.6, 127.7, 127.0, 122.2, 20.3. 2-methyl-4,5-diphenylpyridine (4.1g) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a NPhMeNPhMe 262 sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 4-phenylbut-3-en-2-one (0.0731 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 23% yield. The analytical data were consistent with literature.273 1H NMR (400 MHz, CDCl3) δ 8.53 (s, 1H), 7.27-7.24 (m, 6H), 7.21 (s, 1H), 7.16-7.12 (m, 4H), 2.64 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 157.4, 150.3, 148.2, 138.9, 137.8, 133.2, 129.9, 129.4, 128.3, 128.3, 127.8, 127.2, 124.3, 24.1. 2-isopropyl-4,5-diphenylpyridine (4.1h) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 4-methyl-1-phenylpent-1-en-3-one (0.0871 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 49% yield. The analytical data were consistent with literature.273 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.30-7.27 (m, 6H), 7.20-7.15 (m, 4H), 3.21 (7, J = 6.9 Hz, 1H), 1.42 (d, J = 6.9 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.4, 150.2, 148.4, 139.3, 138.0, 133.4, 129.9, 129.4, 128.3, 128.3, 127.8, 127.2, 121.7, 36.2, 22.8. 2-(tert-butyl)-4,5-diphenylpyridine (4.1i) NPhiPr 263 According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 96% yield. The analytical data were consistent with literature.273 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.37 (s, 1H), 7.28-7.24 (m, 6H), 7.18-7.13 (m, 4H), 1.45 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 168.5, 149.9, 148.0, 139.6, 138.1, 132.9, 130.0, 129.5, 128.34, 128.32, 127.8, 127.1, 120.2, 37.4, 30.4. 4,5-diphenyl-2-(trifluoromethyl)pyridine (4.1j)  According to general procedure B, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 1,1,1-trifluoro-4-phenylbut-3-en-2-one (0.1001 g) and molecular sieves (0.1000 g) were added following general procedure B. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 68% yield. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 7.74 (s, 1H), 7.35-7.27 (m, 6H), 7.18-7.15 (m, 4H). 13C NMR (151 MHz, CDCl3) δ 151.4, 149.4, 147.3 (q, 2J(C,F) = 34.6Hz), 138.7, NPhCF3NPhtBu 264 137.6, 136.5, 129.8, 129.4, 128.68, 128.66, 128.2, 121.83 (q, 1J(C,F) = 274.1Hz), 121.67 (q, 3J(C,F) = 2.7Hz). 19F NMR (282 MHz; CDCl3): δ -67.7. HRMS (ESI+) m/z calc’d for C18H13NF3 [M+H+]: 400.1000; found: 400.1006. 4-(4-methoxyphenyl)-2,5-diphenylpyridine (4.1k) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one (0.1191 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (85:15 Hex/EtOAc) afforded the title compound as a colourless solid in 78% yield. 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.09-8.06 (m, 2H), 7.76 (s, 1H), 7.53-7.48 (m, 2H), 7.46-7.42 (m, 1H), 7.33-7.28 (m, 3H), 7.23-7.20 (m, 2H), 7.17-7.14 (m, 2H), 6.84-6.81 (m, 2H), 3.81 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 159.6, 156.5, 101.0, 148.4, 138.0, 134.4, 131.3, 130.7, 129.9, 129.2, 128.9, 128.5, 127.4, 127.1, 121.7, 113.9, 55.4. HRMS (EI+) m/z calc’d for C24H19NO [M+H+]: 337.14666; found: 337.14624.  4-(3,4-dimethoxyphenyl)-2,5-diphenylpyridine (4.1l) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 3-(3,4-dimethoxyphenyl)-1-phenylprop-2-en-1-one NPhOMeNPhOMeOMe 265 (0.1341 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 83% yield. 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 8.10-8.07 (m, 2H), 7.81 (s, 1H), 7.54-7.49 (m, 2H), 7.47-7.43 (m, 1H), 7.34-7.29 (m, 3H), 7.23-7.21 (m, 2H), 6.94 (dd, J = 8.3, 2.0 Hz, 1H), 6.85 (d, J = 8.3 Hz, 1H), 6.58 (d, J = 2.0 Hz, 1H), 3.89 (s, 3H), 3.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.6, 150.9, 149.0, 148.50, 148.40, 139.1, 138.1, 134.4, 131.4, 129.9, 129.2, 128.9, 128.5, 127.4, 127.1, 121.8, 121.4, 113.1, 111.1, 56.0, 55.7. HRMS (ESI+) m/z calc’d for C25H22NO2 [M+H+]: 368.1651; found: 368.1642. 4-(4-chlorophenyl)-2,5-diphenylpyridine (4.1m) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (0.1214 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5-9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 84% yield. 1H NMR (400 MHz, CDCl3) δ 8.73 (s, 1H), 8.08-8.06 (m, 2H), 7.74 (s, 1H), 7.53-7.49 (m, 2H), 7.47-7.43 (m, 1H), 7.34-7.26 (m, 5H), 7.21-7.14 (m, 4H). 13C NMR (101 MHz, CDCl3) δ 156.7, 101.0, 147.5, 138.8, 137.51, 137.31, 134.33, 134.26, 130.8, NPhCl 266 129.9, 129.3, 129.0, 128.74, 128.59, 127.6, 127.1, 121.4. HRMS (EI+) m/z calc’d for C23H16NCl [M+H+]: 341.09713; found: 341.09671. 4-(4-nitrophenyl)-2,5-diphenylpyridine (4.1n) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 3-(4-nitrophenyl)-1-phenylprop-2-en-1-one (0.1266 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 48% yield. 1H NMR (400 MHz, CDCl3) δ 8.79 (s, 1H), 8.18-8.15 (m, 2H), 8.09-8.07 (m, 2H), 7.76 (s, 1H), 7.54-7.50 (m, 2H), 7.48-7.47 (m, 1H), 7.42-7.38 (m, 2H), 7.34-7.30 (m, 3H), 7.19-7.15 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 157.0, 101.3, 147.5, 146.3, 145.9, 138.6, 136.7, 134.3, 130.4, 129.9, 129.6, 129.1, 128.8, 128.0, 127.1, 123.7, 121.1. HRMS (ESI+) m/z calc’d for C23H17N2O2 [M+H+]: 353.1290; found: 353.1295. 2-(4-methoxyphenyl)-4,5-diphenylpyridine (4.1o) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 1-(4-methoxyphenyl)-3-phenylprop-2-en-1-one (0.1191 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone NPhNO2NPhOMe 267 (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 79% yield. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.06-8.02 (m, 2H), 7.72 (s, 1H), 7.30-7.27 (m, 6H), 7.24-7.17 (m, 4H), 7.04-7.01 (m, 2H), 3.88 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.7, 156.3, 150.9, 148.6, 139.3, 137.9, 133.7, 131.8, 129.9, 129.5, 128.41, 128.37, 128.32, 127.9, 127.3, 120.9, 114.3, 55.5. HRMS (EI+) m/z calc’d for C24H19NO [M+H+]: 337.14666; found: 337.14638. 2-(4,5-diphenylpyridin-2-yl)phenol (4.1p) According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 1-(2-hydroxyphenyl)-3-phenylprop-2-en-1-one (0.1121 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 44% yield. 1H NMR (400 MHz, CDCl3) δ 8.55 (d, J = 0.5 Hz, 1H), 7.94 (s, 1H), 7.87 (dd, J = 8.0, 1.6 Hz, 1H), 7.36-7.27 (m, 7H), 7.25-7.21 (m, 2H), 7.20-7.15 (m, 2H), 7.07 (dd, J = 8.3, 1.2 Hz, 1H), 6.92 (ddd, J = 8.0, 7.2, 1.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 160.2, 156.8, 149.8, 147.1, 138.8, 137.1, 134.2, 131.6, 129.9, 129.4, 128.56, 128.52, 128.33, 127.7, 126.3, 120.2, 119.01, 118.85, 118.78. HRMS (ESI+) m/z calc’d for C23H18NO [M+H+]: 324.1388; found: 324.1379. 2,4-bis(4-fluorophenyl)-5-phenylpyridine (4.1q) NPhHO 268 According to general procedure C, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to a solution of the titanium complex (0.0035 g) in a sealed reaction vessel. The reaction vessel was heated at 70 °C for 3 hours. Upon completion, 1,3-bis(4-fluorophenyl)prop-2-en-1-one (0.1221 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 83% yield. 1H NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.09-8.04 (m, 2H), 7.70 (s, 1H), 7.31-7.30 (m, 3H), 7.21-7.17 (m, 6H), 7.01-6.96 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 163.8 (d, 1J(C,F) = 248.8Hz), 162.6 (d, 1J(C,F) = 248.0Hz), 155.7, 101.1, 147.7, 137.4, 135.19 (d, 4J(C,F) = 3.0Hz), 135.00 (d, 4J(C,F) = 3.6Hz), 134.4, 131.2 (d, 3J(C,F) = 8.1Hz), 129.9, 128.9 (d, 3J(C,F) = 8.5Hz), 128.6, 127.6, 121.2, 115.9 (d, 2J(C,F) = 21.4Hz), 115.6 (d, 2J(C,F) = 21.8Hz). 19F NMR (282 MHz; CDCl3): δ -112.8, -113.6. HRMS (ESI+) m/z calc’d for C23H16NF2 [M+H+]: 344.1251; found: 344.1245. 2,3,4-trimethyl-5-phenylpyridine (4.1r) According to general procedure B, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 3-methylpent-3-en-2-one (0.0491 g) and molecular sieves (0.1000 g) were added following general procedure C. The reaction was heated and stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification NPhMeMeMeNPhFF 269 by column chromatography (6:4 Hex/EtOAc) afforded the title compound as a colourless solid in 22% yield. 1H NMR (400 MHz, CDCl3) δ 8.19 (s, 1H), 7.46-7.42 (m, 2H), 7.40-7.35 (m, 1H), 7.29-7.26 (m, 2H), 2.60 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 155.3, 146.4, 143.0, 139.1, 135.9, 130.3, 129.7, 128.4, 127.4, 23.4, 17.1, 15.4. HRMS (ESI+) m/z calc’d for C14H16N [M+H+]: 198.1283; found: 198.1275. 2,3,4,5-tetraphenylpyridine (4.1s) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 1,2,3-triphenylprop-2-en-1-one (0.1422 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 68% yield. The analytical data were consistent with literature.275 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 7.34-7.30 (m, 2H), 7.23-7.18 (m, 6H), 7.15-7.11 (m, 2H), 7.04-6.97 (m, 6H), 6.89-6.85 (m, 2H), 6.82-6.79 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 157.2, 149.3, 148.4, 140.8, 138.18, 138.09, 137.5, 135.5, 135.1, 131.4, 130.6, 130.06, 129.98, 128.1, 127.74, 127.57, 127.50, 127.46, 127.1, 126.8, 126.5. 3-methyl-2,4,5-triphenylpyridine (4.1t) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon NPhNPh Me 270 completion, 2-methyl-1,3-diphenylprop-2-en-1-one (0.1111 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (85:15 Hex/EtOAc) afforded the title compound as a colourless solid in 78% yield. 1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 0.4 Hz, 1H), 7.62-7.59 (m, 2H), 7.50-7.46 (m, 2H), 7.43-7.39 (m, 1H), 7.31-7.24 (m, 3H), 7.23-7.17 (m, 3H), 7.13-7.07 (m, 4H), 2.13 (d, J = 0.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.6, 149.3, 147.5, 141.3, 138.35, 138.29, 135.3, 130.0, 129.7, 129.3, 129.0, 128.34, 128.28, 128.03, 128.00, 127.4, 127.0, 18.6. HRMS (ESI+) m/z calc’d for C24H20N [M+H+]: 322.1596; found: 322.1600. 2-(4-methoxyphenyl)-3-methyl-5-phenyl-4-(4-(trifluoromethyl)phenyl)pyridine (4.1u) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 1-(4-methoxyphenyl)-2-methyl-3-(4-(trifluoromethyl)phenyl)prop-2-en-1-one (0.1601 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (8:2 to 7:3 Hex/EtOAc) afforded the title compound as a colourless solid in 66% yield. 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.58-7.54 (m, 4H), 7.24-7.19 (m, 5H), 7.08-7.06 (m, 2H), 7.04-7.00 (m, 2H), 3.88 (s, 3H), 2.13 (s, 3H). 13C NMR (151 MHz, CDCl3) δ 159.8, 158.1, 148.3, 147.18, 147.17, 142.2, 137.5, 134.9, 132.7, 130.7, NPh MeCF3OMe 271 130.1, 129.87, 129.70 (q, 2J(C,F) = 32.6Hz), 128.8, 128.3, 127.4, 125.3 (q, 3J(C,F) = 3.7Hz), 124.1 (q, 1J(C,F) = 272.1Hz), 113.9, 55.5, 18.9. 19F NMR (282 MHz; CDCl3): δ -62.6. HRMS (ESI+) m/z calc’d for C26H21NOF3 [M+H+]: 420.1575; found: 420.1583. 4-(4-chlorophenyl)-3-methyl-5-phenyl-2-(p-tolyl)pyridine (4.1v) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 3-(4-chlorophenyl)-2-methyl-1-(p-tolyl)prop-2-en-1-one (0.1354 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 to 9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 68% yield. 1H NMR (400 MHz, CDCl3) 8.58 (d, J = 0.4 Hz, 1H), 7.50-7.47 (m, 2H), 7.30-7.25 (m, 5H), 7.24-7.20 (m, 3H), 7.10-7.08 (m, 2H), 7.05-7.01 (m, 2H), 2.43 (s, 3H), 2.12 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 158.7, 148.0, 147.5, 138.15, 138.01, 137.93, 136.9, 135.1, 133.4, 131.1, 129.9, 129.20, 129.04, 128.78, 128.59, 128.2, 127.2, 21.5, 18.7. HRMS (ESI+) m/z calc’d for C25H21NCl [M+H+]: 370.1363; found: 370.1360. 4-(4-bromophenyl)-2-(4-fluorophenyl)-3-methyl-5-phenylpyridine (4.1w) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and ethynylbenzene (0.0511 g) were added to the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 3-(4-bromophenyl)-1-(4-fluorophenyl)-2-methylprop-2-en-1-one NPh MeClMeNPh MeBrF 272 (0.1596 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 to 9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 58% yield. 1H NMR (400 MHz, CDCl3) δ 8.57 (d, J = 0.3 Hz, 1H), 7.59-7.56 (m, 2H), 7.44-7.41 (m, 2H), 7.25-7.21 (m, 3H), 7.20-7.15 (m, 2H), 7.10-7.07 (m, 2H), 6.98-6.95 (m, 2H), 2.11 (d, J = 0.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.9 (d, 1J(C,F) = 246.7Hz), 157.6, 148.2, 147.6, 137.8, 137.15, 137.05 (d, 4J(C,F) = 3.9Hz), 135.4, 131.6, 131.4, 131.1 (d, 3J(C,F) = 9.1Hz), 129.9, 128.8, 128.3, 127.3, 121.8, 115.4 (d, 2J(C,F) = 21.8Hz), 18.7. 19F NMR (282 MHz; CDCl3): δ -113.8. HRMS (ESI+) m/z calc’d for C24H18NBrF [M+H+]: 418.0607; found: 418.0612. 2-(tert-butyl)-5-(4-fluorophenyl)-4-phenylpyridine (4.2a) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-fluorobenzene (0.0601 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 81% yield. 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 7.37 (s, 1H), 7.30-7.27 (m, 3H), 7.16-7.13 (m, 2H), 7.12-7.08 (m, 2H), 6.97-6.93 (m, 2H), 1.45 (s, 9H). 13C NMR NPhtBuF 273 (101 MHz, CDCl3) δ 168.7, 162.2 (d, 1J(C,F) = 247.0Hz), 149.7, 148.1, 139.4, 134.0, 132.0, 131.5 (d, 3J(C,F) = 7.6Hz), 129.5, 128.5, 127.9, 120.3, 115.4 (d, 2J(C,F) = 21.5Hz), 37.5, 30.4. 19F NMR (282 MHz; CDCl3): δ -115.4. HRMS (ESI+) m/z calc’d for C21H20FN [M+H+]: 306.1658; found: 306.1658. 2-(tert-butyl)-5-(4-chlorophenyl)-4-phenylpyridine (4.2b) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-chloro-4-ethynylbenzene (0.0683 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 88% yield. 1H NMR (400 MHz; CDCl3): 8.56 (s, 1H), 7.37 (s, 1H), 7.32-7.28 (m, 3H), 7.25-7.21 (m, 2H), 7.17-7.14 (m, 2H), 7.08-7.05 (m, 2H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 168.9, 149.7, 148.1, 139.3, 136.5, 133.4, 131.8, 131.2, 129.5, 128.61, 128.52, 128.0, 120.3, 37.5, 30.4. HRMS (ESI+) m/z calc’d for C21H20ClN [M+H+]: 322.1363; found: 322.1371. 2-(tert-butyl)-5-(4-bromophenyl)-4-phenylpyridine (4.2c) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-bromo-4-ethynylbenzene (0.0905 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves NPhtBuClNPhtBuBr 274 (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 85% yield. 1H NMR (400 MHz; CDCl3): δ 8.56 (s, 1H), 7.40-7.37 (m, 2H), 7.37 (s, 1H), 7.32-7.28 (m, 3H), 7.17-7.14 (m, 2H), 7.03-6.99 (m, 2H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3) δ 169.0, 149.6, 148.1, 139.2, 137.0, 131.8, 131.57, 131.53, 129.5, 128.6, 128.0, 121.6, 120.4, 37.5, 30.4. HRMS (ESI+) m/z calc’d for C21H21NBr [M+H+]: 366.0857; found: 366.0859.  2-(tert-butyl)-4-phenyl-5-(4-(trifluoromethyl)phenyl)pyridine (4.2d) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-(trifluoromethyl)benzene (0.0851 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 77% yield. 1H NMR (400 MHz; CDCl3): δ 8.59 (s, 1H), 7.53-7.50 (m, 2H), 7.40 (s, 1H), 7.31-7.25 (m, 5H), 7.15-7.13 (m, 2H), 1.45 (s, 9H). 13C NMR (151 MHz; CDCl3): δ 169.4, 149.6, 148.3, 141.8, 138.9, 131.7, 130.2, 129.45, 129.31 (q, 2J(C,F) = 32.4Hz), 128.6, 128.1, 125.3 (q, 3J(C,F) = 3.7Hz), 124.3 (q, 1J(C,F) = 272.1Hz), 120.5, 37.5, 30.4. 19F NMR NPhtBuF3C 275 (282 MHz; CDCl3): δ -62.5. HRMS (ESI+) m/z calc’d for C22H21NF3 [M+H+]: 356.1626; found: 356.1627.  2-(tert-butyl)-4-phenyl-5-(p-tolyl)pyridine (4.2e) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-methylbenzene (0.0581 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 82% yield. 1H NMR (400 MHz; CDCl3): δ 8.59 (s, 1H), 7.35 (s, 1H), 7.30-7.26 (m, 3H), 7.19-7.16 (m, 2H), 7.07-7.02 (m, 4H), 2.32 (s, 3H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 168.2, 149.9, 147.9, 139.8, 136.8, 135.0, 132.9, 129.8, 129.5, 129.1, 128.3, 127.7, 120.3, 37.4, 30.4, 21.3. HRMS (ESI+) m/z calc’d for C22H24N [M+H+]: 302.1909; found: 302.1913. 2-(tert-butyl)-5-(4-methoxyphenyl)-4-phenylpyridine (4.2f) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-4-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction NPhtBuMeNPhtBuMeO 276 solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 85% yield. 1H NMR (400 MHz; CDCl3): δ 8.58 (s, 1H), 7.35 (s, 1H), 7.30-7.27 (m, 3H), 7.20-7.16 (m, 2H), 7.08-7.04 (m, 2H), 6.81-6.77 (m, 2H), 3.79 (s, 3H), 1.45 (s, 9H).13C NMR (101 MHz; CDCl3) δ 168.1, 158.9, 149.8, 147.9, 139.8, 132.6, 131.0, 130.3, 129.5, 128.4, 127.7, 120.3, 113.9, 55.3, 37.4, 30.4. HRMS (ESI+) m/z calc’d for C22H24NO [M+H+]: 318.1858; found: 318.1862. 2-(tert-butyl)-5-(3-methoxyphenyl)-4-phenylpyridine (4.2g) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-3-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 90% yield. 1H NMR (400 MHz; CDCl3): δ 8.61 (d, J = 0.5 Hz, 1H), 7.37 (d, J = 0.6 Hz, 1H), 7.29-7.27 (m, 3H), 7.20-7.17 (m, 3H), 6.79 (ddd, J = 8.3, 2.5, 0.9 Hz, 1H), 6.75 (ddd, J = 7.6, 1.6, 0.9 Hz, 1H), 6.66 (dd, J = 2.5, 1.6 Hz, 1H), 3.62 (s, 3H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3) δ 168.6, 159.4, 149.8, 148.0, 139.7, 139.4, 132.8, 129.44, 129.32, 128.4, 127.8, 122.4, 120.2, 115.3, 113.3, 55.2, 37.4, 30.4. HRMS (ESI+) m/z calc’d for C22H24NO [M+H+]: 318.1858; found: 318.1853. 2-(tert-butyl)-5-(2-methoxyphenyl)-4-phenylpyridine (4.2h) NPhtBuMeO 277 According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynyl-2-methoxybenzene (0.0661 g) were added to a solution of the titanium complex (0.0035 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (9:1 Hex/EtOAc) afforded the title compound as a colourless solid in 78% yield. 1H NMR (400 MHz; CDCl3): δ 8.55 (s, 1H), 7.38 (s, 1H), 7.27 (ddd, J = 8.2, 7.5, 1.7 Hz, 1H), 7.24-7.22 (m, 3H), 7.20 (dd, J = 7.5, 1.7 Hz, 1H), 7.17-7.13 (m, 2H), 6.96 (td, J = 7.5, 1.0 Hz, 1H), 6.73 (dd, J = 8.2, 0.5 Hz, 1H), 3.32 (s, 3H), 1.46 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 168.4, 156.6, 150.2, 149.1, 140.6, 131.7, 129.8, 129.2, 128.5, 128.0, 127.5, 127.2, 120.8, 119.6, 111.0, 55.0, 37.4, 30.5. HRMS (ESI+) m/z calc’d for C22H24NO [M+H+]: 318.1858; found: 318.1858. 6'-(tert-butyl)-4'-phenyl-2,3'-bipyridine (4.2i) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 2-ethynylpyridine (0.0516 g) were added to a solution of the titanium complex (0.0174 g) in benzene. The reaction J-Young tube was heated at 70 °C for 8 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (6:4 Hex/EtOAc) afforded the title compound as a colourless solid in 70% yield. NPhtBuOMeNPhtBuN 278 1H NMR (400 MHz; CDCl3): δ 8.81 (d, J = 0.6 Hz, 1H), 8.63 (ddd, J = 4.9, 1.8, 1.0 Hz, 1H), 7.47 (td, J = 7.8, 1.8 Hz, 1H), 7.37 (d, J = 0.6 Hz, 1H), 7.31-7.26 (m, 3H), 7.19-7.13 (m, 3H), 6.97 (dt, J = 7.8, 1.0 Hz, 1H), 1.44 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 169.6, 156.8, 150.2, 149.8, 148.2, 139.5, 135.7, 132.0, 129.3, 128.5, 127.9, 125.3, 121.9, 120.0, 37.6, 30.4. HRMS (ESI+) m/z calc’d for C20H21N2 [M+H+]: 289.1705; found: 289.1707. 6-(tert-butyl)-4-phenyl-3,3'-bipyridine (4.2j) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 3-ethynylpyridine (0.0516 g) were added to a solution of the titanium complex (0.0174 g) in benzene. The reaction J-Young tube was heated at 70 °C for 18 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (1:1 Hex/EtOAc) afforded the title compound as a colourless solid in 73% yield. 1H NMR (400 MHz; CDCl3): δ 8.59 (d, J = 0.6 Hz, 1H), 8.50-8.46 (m, 2H), 7.42-7.39 (m, 2H), 7.31-7.28 (m, 3H), 7.19-7.13 (m, 3H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 169.6, 150.4, 149.7, 148.50, 148.39, 138.9, 137.2, 133.9, 129.51, 129.44, 128.6, 128.2, 123.1, 120.4, 37.6, 30.4. HRMS (ESI+) m/z calc’d for C20H21N2 [M+H+]: 289.1705; found: 289.1699. 6-(tert-butyl)-4-phenyl-3,4'-bipyridine (4.2k) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 4-ethynylpyridine (0.0516 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction J-Young tube was heated at 70 °C for 18 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) NPhtBuNNPhtBuN 279 were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (1:1 Hex/EtOAc) afforded the title compound as a colourless solid in 60% yield. 1H NMR (400 MHz; CDCl3): 8.58 (d, J = 0.6 Hz, 1H), 8.49 (dd, J = 4.5, 1.5 Hz, 2H), 7.40 (d, J = 0.6 Hz, 1H), 7.33-7.28 (m, 3H), 7.16-7.13 (m, 2H), 7.07 (dd, J = 4.5, 1.5 Hz, 2H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 170.1, 149.8, 149.4, 148.3, 146.2, 138.7, 130.3, 129.4, 128.7, 128.3, 124.7, 120.5, 37.6, 30.3. HRMS (ESI+) m/z calc’d for C20H21N2 [M+H+]: 289.1705; found: 289.1701. 2-(6-(tert-butyl)-4-phenylpyridin-3-yl)pyrazine (4.2l) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 2-ethynylpyrazine (0.0521 g) were added to a solution of the titanium complex (0.0174 g) in benzene. The reaction J-Young tube was heated at 70 °C for 18 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (7:3 Hex/EtOAc) afforded the title compound as a colourless solid in 78% yield. 1H NMR (400 MHz; CDCl3): δ 8.84 (d, J = 0.5 Hz, 1H), 8.60 (dd, J = 2.5, 1.4 Hz, 1H), 8.41 (d, J = 2.5 Hz, 1H), 8.20 (d, J = 1.4 Hz, 1H), 7.41 (d, J = 0.5 Hz, 1H), 7.34-7.31 (m, 3H), 7.18-7.15 (m, 2H), 1.45 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 170.6, 152.8, 150.3, 148.6, 146.2, 144.4, 142.5, 138.8, 129.2, 128.88, 128.73, 128.4, 120.2, 37.7, 30.3. HRMS (ESI+) m/z calc’d for C19H20N3 [M+H+]: 290.1657; found: 290.1664. NPhtBuNN 280 2-(tert-butyl)-5-(1-methyl-1H-pyrazol-5-yl)-4-phenylpyridine (4.2m) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 4-ethynyl-1-methyl-1H-pyrazole (0.0531 g) were added to a solution of the titanium complex (0.0087 g) in benzene. The reaction J-Young tube was heated at 70 °C for 18 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (1:1 Hex/EtOAc) afforded the title compound as a colourless solid in 63% yield. 1H NMR (400 MHz; CDCl3): δ 8.65 (d, J = 0.6 Hz, 1H), 7.39-7.36 (m, 3H), 7.28-7.25 (m, 3H), 7.21 (d, J = 0.6 Hz, 1H), 6.98 (s, 1H), 3.80 (s, 3H), 1.41 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 167.6, 148.6, 147.5, 140.1, 138.8, 129.04, 128.95, 128.6, 128.1, 124.1, 120.3, 118.6, 39.1, 37.3, 30.4. HRMS (ESI+) m/z calc’d for C19H22N3 [M+H+]: 292.1814; found: 292.1823. 2-(tert-butyl)-4-phenyl-5-(thiophen-2-yl)pyridine (4.2n) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 2-ethynylthiophene (0.0541 g) were added to a solution of the titanium complex (0.0174 g) in benzene. The reaction J-Young tube was heated at 70 °C for 18 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 82% NPhtBuNNMeNPhtBuS 281 yield. 1H NMR (400 MHz; CDCl3): δ 8.72 (d, J = 0.6 Hz, 1H), 7.37-7.33 (m, 3H), 7.31 (d, J = 0.6 Hz, 1H), 7.28-7.26 (m, 1H), 7.26-7.25 (m, 1H), 7.23 (dd, J = 5.1, 1.2 Hz, 1H), 6.92 (dd, J = 5.1, 3.6 Hz, 1H), 6.80 (dd, J = 3.6, 1.2 Hz, 1H), 1.42 (s, 9H) 13C NMR (101 MHz; CDCl3): δ 168.8, 149.7, 148.2, 139.56, 139.51, 129.3, 128.5, 128.1, 127.34, 127.25, 126.38, 126.27, 120.3, 37.5, 30.3. HRMS (ESI+) m/z calc’d for C19H20NS [M+H+]: 294.1315; found: 294.1314. 2-(tert-butyl)-4-phenyl-5-(thiophen-3-yl)pyridine (4.2o) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 3-ethynylthiophene (0.0541 g) were added to a solution of the titanium complex (0.0174 g) in benzene. The reaction J-Young tube was heated at 70 °C for 18 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 75% yield. 1H NMR (400 MHz; CDCl3): δ 8.67 (d, J = 0.6 Hz, 1H), 7.34-7.31 (m, 4H), 7.23-7.20 (m, 2H), 7.17 (dd, J = 5.0, 3.0 Hz, 1H), 7.07 (dd, J = 3.0, 1.3 Hz, 1H), 6.71 (dd, J = 5.0, 1.3 Hz, 1H), 1.43 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 168.5, 149.5, 147.9, 139.8, 138.5, 129.2, 128.9, 128.4, 127.98, 127.95, 125.3, 123.5, 120.2, 37.4, 30.4. HRMS (ESI+) m/z calc’d for C19H20NS [M+H+]: 294.1316; found: 294.1305. 2-(tert-butyl)-5-(cyclohex-1-en-1-yl)-4-phenylpyridine (4.2p) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1-ethynylcyclohex-1-ene (0.0531 g) were added to a solution of the titanium complex (0.0087 g) in benzene. The reaction J-Young tube was heated at 70 °C for 6 hours. NPhtBuSNPhtBu 282 Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 71% yield. 1H NMR (400 MHz; CDCl3): δ 8.40 (s, 1H), 7.46-7.37 (m, 5H), 7.24 (s, 1H), 5.79-5.76 (m, 1H), 2.16-2.11 (m, 2H), 1.76-1.71 (m, 2H), 1.57-1.53 (m, 2H), 1.48-1.44 (m, 2H), 1.41 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 167.8, 148.8, 147.0, 140.4, 136.2, 135.7, 128.8, 128.54, 128.37, 127.9, 119.7, 37.3, 30.4, 29.2, 25.9, 23.0, 22.0. HRMS (ESI+) m/z calc’d for C19H20NS [M+H+]: 294.1316; found: 294.1305. N-((6-(tert-butyl)-4-phenylpyridin-3-yl)methyl)pivalamide (4.2q) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and N-(prop-2-yn-1-yl)pivalamide (0.0696 g) were added to a solution of the titanium complex (0.0087 g) in benzene. The reaction J-Young tube was heated at 70 °C for 3 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (1:1 Hex/EtOAc) afforded the title compound as a colourless solid in 27% yield. 1H NMR (400 MHz; CDCl3): δ 8.56 (s, 1H), 7.49-7.41 (m, 3H), 7.36-7.33 (m, 2H), 7.23 (s, 1H), 5.67 (s, 1H), 4.46 (d, J = 5.4 Hz, 2H), 1.40 (s, 9H), 1.07 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 178.1, 168.9, 149.4, 148.8, 139.0, 128.9, 128.4, 128.0, 120.2, 39.5, 38.7, 37.4, 30.3, 27.5. HRMS (ESI+) m/z calc’d for C21H29N2O [M+H+]: 325.2280; found: 325.2282. NPhtBuNHtBuO 283 2-(6-(tert-butyl)-4-phenylpyridin-3-yl)ethan-1-ol (4.2r) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and (but-3-yn-1-yloxy)(tert-butyl)dimethylsilane (0.0922 g) were added to a solution of the titanium complex (0.0087 g) in benzene. The reaction J-Young tube was heated at 70 °C for 8 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (4:6 Hex/EtOAc) afforded the title compound as a colourless solid in 26% yield. 1H NMR (400 MHz; CDCl3): δ 8.54 (s, 1H), 7.48-7.41 (m, 3H), 7.33-7.31 (m, 2H), 7.20 (s, 1H), 3.69 (t, J = 6.9 Hz, 2H), 2.89 (t, J = 6.9 Hz, 2H), 1.39 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 167.4, 150.3, 150.0, 139.7, 128.71, 128.61, 128.3, 128.0, 120.2, 63.0, 37.2, 33.3, 30.4. HRMS (ESI+) m/z calc’d for C18H23NO2 [M+H+]: 286.1807; found: 286.1805. HRMS (ESI+) m/z calc’d for C17H22NO [M+H+]: 256.1701; found: 256.1703. 6-(tert-butyl)-2-methyl-3,4-diphenylpyridine (4.2s) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and prop-1-yn-1-ylbenzene (0.0581 g) were added to a solution of the titanium complex (0.0174 g) in benzene. The reaction J-Young tube was heated at 110 °C for 6 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. After 1 hour, the volatiles were removed under reduced NPhtBuHONPhtBuMe 284 pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 79% yield. 1H NMR (400 MHz; CDCl3): δ 7.25-7.15 (m, 7H), 7.08-7.04 (m, 4H), 2.40 (s, 3H), 1.43 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 167.4, 155.6, 148.8, 140.5, 139.1, 132.1, 130.5, 129.5, 128.1, 127.9, 127.1, 126.7, 117.6, 37.3, 30.4, 24.5. HRMS (ESI+) m/z calc’d for C22H24N [M+H+]: 302.1909; found: 302.1911. 6-(tert-butyl)-2-ethyl-3,4-diphenylpyridine (4.2t) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and but-1-yn-1-ylbenzene (0.0651 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction J-Young tube was heated at 110 °C for 24 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure.  After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 72% yield. 1H NMR (400 MHz; CDCl3): δ 7.24-7.18 (m, 3H), 7.17-7.15 (m, 4H), 7.08-7.04 (m, 4H), 2.66 (q, J = 7.5 Hz, 2H), 1.43 (s, 9H), 1.19 (t, J = 7.5 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 167.4, 159.9, 148.8, 140.7, 138.8, 131.5, 130.7, 129.5, 127.93, 127.80, 127.0, 126.7, 117.2, 37.5, 30.4, 29.4, 13.8.  HRMS (ESI+) m/z calc’d for C23H26N [M+H+]: 316.2065; found: 316.2069. 6-(tert-butyl)-3,4-diphenyl-2-propylpyridine (4.2u) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and pent-1-yn-1-ylbenzene (0.0721 g) were added to a solution of the titanium NPhtBuEtNPhtBuPr 285 complex (0.0348 g) in benzene. The reaction J-Young tube was heated at 110 °C for 24 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 67% yield. 1H NMR (400 MHz; CDCl3): δ 7.24-7.18 (m, 3H), 7.17-7.14 (m, 4H), 7.07-7.03 (m, 4H), 2.63-2.59 (m, 2H), 1.75-1.66 (m, 2H), 1.43 (s, 9H), 0.85 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz; CDCl3): δ 167.2, 158.8, 148.8, 140.7, 138.9, 131.8, 130.8, 129.5, 127.90, 127.79, 127.0, 126.7, 117.1, 38.1, 37.5, 30.4, 22.6, 14.3. HRMS (ESI+) m/z calc’d for C24H28N [M+H+]: 330.2222; found: 330.2222. 6-(tert-butyl)-2,3,4-triphenylpyridine (4.2v) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1,2-diphenylethyne (0.0891 g) were added to a solution of the titanium complex (0.0348 g) in toluene. The reaction J-Young tube was heated at 145 °C for 48 hours. Upon completion, 4,4-dimethyl-1-phenylpent-1-en-3-one (0.0941 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction mixture was stirred for 18 hours at 80 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (100 Hex to 97:3 Hex/EtOAc) afforded the title compound as a colourless solid in 64% yield. 1H NMR (400 MHz; CDCl3): δ 7.33-7.30 (m, NPhtBu 286 3H), 7.22-7.15 (m, 6H), 7.09-7.01 (m, 5H), 6.89-6.86 (m, 2H), 1.48 (s, 9H). 13C NMR (101 MHz; CDCl3): δ 167.8, 156.4, 149.9, 141.4, 140.5, 138.5, 131.6, 131.2, 130.4, 129.5, 127.92, 127.76, 127.5, 127.21, 127.17, 126.5, 119.1, 37.7, 30.4. HRMS (ESI+) m/z calc’d for C27H26N [M+H+]: 364.2065; found: 364.2071. 2,3,4,5,6-pentaphenylpyridine (4.3a) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1,2-diphenylethyne (0.0891 g) were added to a solution of the titanium complex (0.0348 g) in toluene. The reaction J-Young tube was heated at 145 °C for 48 hours. Upon completion, 1,2,3-triphenylprop-2-en-1-one (0.1422 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 100 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 46% yield. The analytical data were consistent with literature.329 1H NMR (400 MHz; CDCl3): δ 7.44-7.39 (m, 4H), 7.21-7.15 (m, 6H), 7.02-6.97 (m, 6H), 6.95-6.89 (m, 7H), 6.80-6.76 (m, 2H). 13C NMR (101 MHz; CDCl3): δ 156.5, 150.4, 141.0, 138.6, 138.3, 133.8, 131.5, 130.56, 130.37, 127.64, 127.52, 127.47, 127.1, 126.39, 126.32. 3-methyl-2,4,5,6-tetraphenylpyridine (4.3b) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and 1,2-diphenylethyne (0.0891 g) were added to a solution of the titanium complex (0.0348 g) in toluene. The reaction J-Young tube was heated at 145 °C for 48 hours. Upon completion, 2-methyl-1,3-diphenylprop-2-en-1-one (0.1111 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 100 °C. Upon N PhPhPhPhPhN PhMePhPhPh 287 cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (95:5 Hex/EtOAc) afforded the title compound as a colourless solid in 47% yield. The analytical data were consistent with literature.330 1H NMR (400 MHz; CDCl3): δ 7.75-7.72 (m, 2H), 7.53-7.49 (m, 2H), 7.45-7.41 (m, 1H), 7.38-7.34 (m, 2H), 7.27-7.21 (m, 3H), 7.20-7.16 (m, 3H), 7.08-7.05 (m, 2H), 7.04-7.00 (m, 3H), 6.93-6.89 (m, 2H), 2.16 (s, 3H). 13C NMR (101 MHz; CDCl3): δ 158.0, 154.8, 151.3, 141.4, 141.0, 139.1, 138.6, 133.8, 131.3, 130.2, 129.61, 129.51, 128.2, 127.98, 127.83, 127.63, 127.45, 127.2, 126.9, 126.3, 18.8. 2,5-dimethyl-3,4,6-triphenylpyridine (4.3c) According to general procedure A, tert-butyldimethylsilanamine (0.0656 g) and prop-1-yn-1-ylbenzene (0.0581 g) were added to a solution of the titanium complex (0.0348 g) in benzene. The reaction J-Young tube was heated at 110 °C for 6 hours. Upon completion, 2-methyl-1,3-diphenylprop-2-en-1-one (0.1111 g) and molecular sieves (0.1000 g) were added following general procedure A. The reaction was heated and stirred for 18 hours at 100 °C. Upon cooling of the reaction mixture, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.1135 g) was added to the reaction solution. After 1 hour, the volatiles were removed under reduced pressure. Purification by column chromatography (85:15 Hex/EtOAc) afforded the title compound as a colourless solid in 23% yield.404 1H NMR (400 MHz; CDCl3): δ 7.60-7.57 (m, 2H), 7.49-7.44 (m, 2H), 7.41-7.37 (m, 1H), 7.21-7.16 (m, 4H), 7.15-7.10 (m, 2H), 7.03-6.97 (m, 4H), 2.39 (s, 3H), 2.02 (s, 3H). 13C NMR (101 MHz; CDCl3): δ 157.7, 153.4, 150.3, 141.6, 139.08, 139.03, 134.8, 130.1, 129.32, 129.28, 128.3, 127.89, 127.86, 127.83, 126.8, 126.6, 126.2, 24.0, 18.2. N PhMePhPhMe 288 C.5 NMR Spectra 4,5-diphenyl-2-(trifluoromethyl)pyridine (4.1j)    13C NMR (151 MHz; CDCl3)    NPhCF31H NMR (400 MHz; CDCl3)       4.1j NPhCF3 289 4-(4-methoxyphenyl)-2,5-diphenylpyridine (4.1k)    1H NMR (400 MHz; CDCl3)         4.1k NPhOMe13C NMR (101 MHz; CDCl3)         4.1k NPhOMe 290 4-(3,4-dimethoxyphenyl)-2,5-diphenylpyridine (4.1l)    1H NMR (400 MHz; CDCl3)         4.1l NPhOMeOMe13C NMR (101 MHz; CDCl3)         4.1l NPhOMeOMe 291 4-(4-chlorophenyl)-2,5-diphenylpyridine (4.1m)    1H NMR (400 MHz; CDCl3)         4.1m 13C NMR (101 MHz; CDCl3)         4.1m NPhClNPhCl 292 4-(4-nitrophenyl)-2,5-diphenylpyridine (4.1n)    1H NMR (400 MHz; CDCl3)         4.1n 13C NMR (101 MHz; CDCl3)         4.1n NPhNO2NPhNO2 293 2-(4-methoxyphenyl)-4,5-diphenylpyridine (4.1o)    1H NMR (400 MHz; CDCl3)        4.1o NPhOMe13C NMR (101 MHz; CDCl3)        4.1o NPhOMe 294 2-(4,5-diphenylpyridin-2-yl)phenol (4.1p)    1H NMR (400 MHz; CDCl3)        4.1p NPhHO13C NMR (101 MHz; CDCl3)        4.1p NPhHO 295 2,4-bis(4-fluorophenyl)-5-phenylpyridine (4.1q)    1H NMR (400 MHz; CDCl3)         4.1q 13C NMR (101 MHz; CDCl3)         4.1q NPhFFNPhFF 296 2,3,4-trimethyl-5-phenylpyridine (4.1r)    1H NMR (400 MHz; CDCl3)      4.1r NPhMeMeMe13C NMR (101 MHz; CDCl3)      4,1r NPhMeMeMe 297 3-methyl-2,4,5-triphenylpyridine (4.1t)    1H NMR (400 MHz; CDCl3)        4.1t 13C NMR (101 MHz; CDCl3)        4.1t NPh MeNPh Me 298 2-(4-methoxyphenyl)-3-methyl-5-phenyl-4-(4-(trifluoromethyl)phenyl)pyridine (4.1u)    1H NMR (400 MHz; CDCl3)         4.1u NPh MeCF3OMe13C NMR (151 MHz; CDCl3)         4.1u NPh MeCF3OMe 299 4-(4-chlorophenyl)-3-methyl-5-phenyl-2-(p-tolyl)pyridine (4.1v)    1H NMR (400 MHz; CDCl3)         4.1v NPh MeClMe13C NMR (101 MHz; CDCl3)         4.1v NPh MeClMe 300 4-(4-bromophenyl)-2-(4-fluorophenyl)-3-methyl-5-phenylpyridine (4.1w)    1H NMR (400 MHz; CDCl3)         4.1w NPh MeBrF13C NMR (101 MHz; CDCl3)         4.1w NPh MeBrF 301 2-(tert-butyl)-5-(4-fluorophenyl)-4-phenylpyridine (4.2a)    1H NMR (400 MHz; CDCl3)      4.2a NPhtBuF13C NMR (101 MHz; CDCl3)      4.2a NPhtBuF 302 2-(tert-butyl)-5-(4-chlorophenyl)-4-phenylpyridine (4.2b)    1H NMR (400 MHz; CDCl3)      4.2b NPhtBuCl13C NMR (101 MHz; CDCl3)      4.2b NPhtBuCl 303 2-(tert-butyl)-5-(4-bromophenyl)-4-phenylpyridine (4.2c)    1H NMR (400 MHz; CDCl3)      4.2c NPhtBuBr13C NMR (101 MHz; CDCl3)      4.2c NPhtBuBr 304 2-(tert-butyl)-4-phenyl-5-(4-(trifluoromethyl)phenyl)pyridine (4.2d)     1H NMR (400 MHz; CDCl3)      4.2d NPhtBuF3C13C NMR (151 MHz; CDCl3)      4.2d NPhtBuF3C 305 2-(tert-butyl)-4-phenyl-5-(p-tolyl)pyridine (4.2e)    1H NMR (400 MHz; CDCl3)      4.2e NPhtBuMe13C NMR (101 MHz; CDCl3)      4.2e NPhtBuMe 306 2-(tert-butyl)-5-(4-methoxyphenyl)-4-phenylpyridine (4.2f)    1H NMR (400 MHz; CDCl3)      4.2f NPhtBuMeO13C NMR (101 MHz; CDCl3)      4.2f NPhtBuMeO 307 2-(tert-butyl)-5-(3-methoxyphenyl)-4-phenylpyridine (4.2g)    1H NMR (400 MHz; CDCl3)      4.2g NPhtBuMeO13C NMR (101 MHz; CDCl3)      4.2g NPhtBuMeO 308 2-(tert-butyl)-5-(2-methoxyphenyl)-4-phenylpyridine (4.2h)    1H NMR (400 MHz; CDCl3)      4.2h NPhtBuOMe13C NMR (101 MHz; CDCl3)      4.2h NPhtBuOMe 309 6'-(tert-butyl)-4'-phenyl-2,3'-bipyridine (4.2i)    1H NMR (400 MHz; CDCl3)      4.2i NPhtBuN13C NMR (101 MHz; CDCl3)      4.2i NPhtBuN 310 6-(tert-butyl)-4-phenyl-3,3'-bipyridine (4.2j)    1H NMR (400 MHz; CDCl3)      4.2j NPhtBuN13C NMR (101 MHz; CDCl3)      4.2j NPhtBuN 311 6-(tert-butyl)-4-phenyl-3,4'-bipyridine (4.2k)    1H NMR (400 MHz; CDCl3)      4.2k NPhtBuN13C NMR (101 MHz; CDCl3)      4.2k NPhtBuN 312 2-(6-(tert-butyl)-4-phenylpyridin-3-yl)pyrazine (4.2l)    1H NMR (400 MHz; CDCl3)      4.2l NPhtBuNN13C NMR (101 MHz; CDCl3)      4.2l NPhtBuNN 313 2-(tert-butyl)-5-(1-methyl-1H-pyrazol-5-yl)-4-phenylpyridine (4.2m)    1H NMR (400 MHz; CDCl3)      4.2m NPhtBuNNMe13C NMR (101 MHz; CDCl3)      4.2m NPhtBuNNMe 314 2-(tert-butyl)-4-phenyl-5-(thiophen-2-yl)pyridine (4.2n)    1H NMR (400 MHz; CDCl3)      4.2n NPhtBuS13C NMR (101 MHz; CDCl3)      4.2n NPhtBuS 315 2-(tert-butyl)-4-phenyl-5-(thiophen-3-yl)pyridine (4.2o)    1H NMR (400 MHz; CDCl3)      4.2o NPhtBuS13C NMR (101 MHz; CDCl3)      4.2o NPhtBuS 316 2-(tert-butyl)-5-(cyclohex-1-en-1-yl)-4-phenylpyridine (4.2p)    1H NMR (400 MHz; CDCl3)      4.2p NPhtBu13C NMR (101 MHz; CDCl3)      4.2p NPhtBu 317 N-((6-(tert-butyl)-4-phenylpyridin-3-yl)methyl)pivalamide (4.2q)    1H NMR (400 MHz; CDCl3)      4.2q NPhtBuNHtBuO13C NMR (101 MHz; CDCl3)      4.2q NPhtBuNHtBuO 318 2-(6-(tert-butyl)-4-phenylpyridin-3-yl)ethan-1-ol (4.2r)    1H NMR (400 MHz; CDCl3)      4.2r NPhtBuHO13C NMR (101 MHz; CDCl3)      4.2r NPhtBuHO 319 6-(tert-butyl)-2-methyl-3,4-diphenylpyridine (4.2s)    1H NMR (400 MHz; CDCl3)      4.2s NPhtBuMe13C NMR (101 MHz; CDCl3)      4.2s NPhtBuMe 320 6-(tert-butyl)-2-ethyl-3,4-diphenylpyridine (4.2t)    1H NMR (400 MHz; CDCl3)      4.2t NPhtBuEt13C NMR (101 MHz; CDCl3)      4.2t NPhtBuEt 321 6-(tert-butyl)-3,4-diphenyl-2-propylpyridine (4.2u)    1H NMR (400 MHz; CDCl3)      4.2u NPhtBuPr13C NMR (101 MHz; CDCl3)      4.2u NPhtBuPr 322 6-(tert-butyl)-2,3,4-triphenylpyridine (4.2v)    1H NMR (400 MHz; CDCl3)      4.2v NPhtBu13C NMR (101 MHz; CDCl3)      4.2v NPhtBu 323 C.6 Solid State Molecular Structures and X-Ray Crystallographic Data  Single crystal X-ray structure determinations were performed at the X-ray crystallography lab at the Department of Chemistry, University of British Columbia on either a Bruker X8 APEX or Bruker APEX DUO diffractometer using graphite-monochromated Mo Kα radiation (λ=0.71073 Å). Unless otherwise noted, data integration was performed using Bruker SAINT (v.8.34A),387 absorption correction was performed using Bruker SADABS (2014/5),387 structures were solved using direct methods using SIR2004 or SHELXS,388,389 and refinement (including modelling of disorder) was performed using SHELXL (2014/7)390 using the OLEX2391 interface.   Pyridine 2m (LS707) formula C23H16ClN Fw 341.82 crystal size (mm) 0.523 × 0.223 × 0.065 color, habit Colourless, prism crystal system Monoclinic space group P21/c T (K) 100 a (Å) 12.6031(11) b (Å) 5.7258(5) c (Å) 24.106(2) α (Å) 90 β (Å) 103.839(2) γ (Å) 90 V (Å3) 1689.1(3) Z 4 ρcalcd (g cm-3) 1.344 F(000) 712.0 µ (MoKα) (mm-1) 0.230 2θmax (°) 3.328 to 50.782 total no. of reflns 6383 no. of unique reflns 6383 R1 (F2, all data) 0.0700 wR2 (F2, all data) 0.0940  324 R1 (F, I > 2σ(I)) 0.0450 wR2 (F, I > 2σ(I)) 0.0847 goodness of fit 1.015   Figure C.1 Single Crystal Molecular Structure of Pyridine 4.1m                    

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