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Catalytic synthesis of N-heterocycles and alpha-alkylated amines by hydroamination and hydroaminoalkylation Lau, Ying Yin 2016

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CATALYTIC SYNTHESIS OF N-HETEROCYCLES AND ALPHA-ALKYLATED AMINES BY HYDROAMINATION AND HYDROAMINOALKYLATION by  Ying Yin Lau  B.Sc., The University of British Columbia, 2008 M.Sc., Queen’s University, 2011  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)  December 2016  © Ying Yin Lau, 2016   ii Abstract  The research presented in this thesis emphasizes the versatility and utility of N,O-chelated early transition metals for the catalytic synthesis of α-alkylated amines.  Two major transformations were studied extensively in this work, hydroamination and hydroaminoalkylation.  For both reactions, the synthetic utility and substrate scope has been expanded by the work presented herein.   In the field of hydroamination, N-heterocycles with more than one heteroatom can now be synthesized using early transition metal catalysts from prochiral substrates.  Hydroamination with a bis(amidate)bis(amido) complex of titanium of ether-containing aminoalkyne substrates yield cyclic imines, which are subsequently reduced via asymmetric transfer hydrogenation using the Noyori-Ikariya catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-cymene). 3-Substituted morpholines are synthesized using a one-pot sequential catalysis protocol, in good yields and high enantiomeric excesses.  Substrate scope investigations reveal that high enantioselectivities in the asymmetric transfer hydrogenation reaction arise from key hydrogen bonding interactions between the oxygen heteroatom of the ether-containing cyclic imine and the [(S,S)-Ts-DPEN] ligand of Noyori-Ikariya catalyst.  This mechanistic insight informed the proposal that this synthetic strategy can be extended to other substrates containing functional groups with hydrogen bond acceptors.  As such, 3-substituted piperazines are also prepared with high enantioselectivities using this one-pot protocol. Advances to the hydroaminoalkylation transformation have also been made with the first reported example of room temperature reactivity observed using a phosphoramidate-tantalum complex.  The preparation and characterization of a series of N,O-chelated phosphoramidate-  iii tantalum complexes is described.  These complexes were easily synthesized from either Ta(NMe2)5 by protonolysis or a simple organometallic precursor, TaMe3Cl2, by salt metathesis.  Reactivity towards catalytic hydroaminoalkylation was explored and the results highlight that the choice of tantalum starting material dramatically affects the reaction temperatures required for catalytic turnover.  N,O-chelated phosphoramidate dimethylamido tantalum complexes showed reactivity occurred only at elevated temperatures (≥ 90 °C), whereas phosphoramidate-tantalum complexes derived from TaMe3Cl2 exhibited unprecedented catalytic activity at room temperature.   Preliminary efforts indicate that there is potential for an asymmetric version of hydroaminoalkylation at room temperature.  Chiral phosphoramidate-tantalum complexes were prepared and studied as the first examples of asymmetric hydroaminoalkylation reactions at room temperature.       iv Preface   The research disclosed in this thesis was partially conducted collaboratively with other members of the Schafer research group.  In consultation with my supervisor Dr. Laurel Schafer, I designed and conducted all of the experiments described herein, except for the specific instances described below.    The synthetic route to enantioenriched 3-substituted morpholines was proposed and originally investigated by post-doctoral researcher, Dr. Huimin Zhai.  The compounds in Chapter 2 were prepared by methods outlined by these methods.  The following compounds were originally synthesized and characterized Dr. Zhai:  tert-butyl (2-((3-phenylprop-2-yn-1-yl)oxy)ethyl)carbamate (32), tert-butyl (2-((3-(4-bromophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (33), tert-butyl (2-((3-(perfluorophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (35), tert-butyl (2-((3-(pyridin-2-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate (37), tert-butyl (2-(pent-2-yn-1-yloxy)ethyl)carbamate (28), tert-butyl (2-((5-(benzyloxy)pent-2-yn-1-yl)oxy)ethyl)carbamate (29), tert-butyl (2-((4,4-dimethylpent-2-yn-1-yl)oxy)ethyl)carbamate (30), (R)-3-benzylmorpholine (66), (R)-3-(4-bromobenzyl)morpholine (67), (R)-3-((perfluorophenyl)methyl)morpholine (69), (R)-3-(pyridin-2-ylmethyl)morpholine (71), (R)-3-methylmorpholine (73), (R)-3-propylmorpholine (74), (R)-3-(3-(benzyloxy)propyl)morpholine (75), (R)-3-neopentylmorpholine (76), (R)-3-methyl-1-tosylpiperazine (82), (R)-3-methylthiomorpholine (83), and (S)-2-benzylpiperidine (84). Compounds 54 and 62 were prepared by RLE student Ms. Anisa Maruschak, who worked under my supervision.  NOE-NMR experiments were conducted using a Bruker Avance 600 MHz spectrometer by Dr. Philippa Payne and I preformed the analysis.   Chiral HPLC methods for   v separation of piperazine products 92 and 94 were developed with assistance from Ms. Diana Yu.  A portion of Chapter 2 has been published by Wiley-VCH:  Zhai, H.; Borzenko, A.; Lau, Y.Y.; Ahn, S.H.; Schafer, L.L.  “Catalytic Asymmetric Synthesis of Substituted Morpholines and Piperazines.” Angew. Chem., Int. Ed. 2012, 51, 12219-12223. and a portion been accepted for publication by the American Chemical Society:  Lau, Y.Y.; Zhai, H.; Schafer, L.L.  “The Catalytic Asymmetric Synthesis of Morpholines.  Using Mechanistic Insights to Realize the Enantioselective Synthesis of Piperazines” J. Org. Chem. 2016, 81, 8696.      Post-doctoral researcher, Dr. Pierre Garcia, proposed the phosphoramidate ligand design studied in Chapter 3. The phosphoramidate-Ta complexes screened for catalysis in this section (101-121, except 110 and 111) and related proligands were synthesized and characterized by Dr. Pierre Garcia, while I was responsible for catalytic investigations.  Complexes 110, 111, and 123 were synthesized using procedures outlined by Dr. Garcia.  Dr. Garcia conducted amine substrate scope investigations with complex 123 and I investigated the alkene substrate scope, except for compounds 128 and 134.  This project was also conducted in collaboration with Mr. Mitchell Perry, who preformed the catalysis under neat conditions.  The solid state molecular data presented herein was collected by Jacky Yim, Scott Ryken, or Damon Gilmour while I performed the final refinements.  The final refinement of complex 154 was conducted with assistance from Damon Gilmour.  A portion of Chapter 3 has been published by Wiley-VCH:  Garcia, P.; Lau, Y.Y.; Perry, M.R.; Schafer, L.L.  “Phosphoramidate Tantalum Complexes for Room-Temperature C-H Functionalization:  Hydroaminoalkylation Catalysis” Angew. Chem., Int. Ed. 2013, 52, 9144.      In Chapter 4, compounds 164 and 165 were prepared and characterized in collaboration with visiting student Ms. Katarina Strobl, who worked under my supervision.   The solid state   vi molecular data for complex 171 was collected by Jacky Yim and I performed the final refinements with his assistance.     vii Table of Contents  Abstract .......................................................................................................................................... ii	Preface ........................................................................................................................................... iv	Table of Contents ........................................................................................................................ vii	List of Tables ................................................................................................................................ xi	List of Figures .............................................................................................................................. xii	List of Schemes ........................................................................................................................... xvi	List of Abbreviations ................................................................................................................. xix	Acknowledgements .................................................................................................................. xxiv	Dedication ................................................................................................................................. xxvi	Chapter 1: Introduction ................................................................................................................1	1.1	 Catalytic Synthesis of Amines ........................................................................................... 1	1.2	 Hydroamination ................................................................................................................. 3	1.2.1	 Hydroamination with Late Transition Metal Catalysts ............................................... 5	1.2.2	 Hydroamination with Early Transition Metal Catalysts ............................................. 8	1.2.2.1	 Early Transition Metal Catalysts for Alkyne Anti-Markovnikov Hydroamination. ............................................................................................................... 11	1.2.2.2	 Bis(amidate)bis(amido)-Titanium Complex for Hydroamination ..................... 13	1.3	 Hydroaminoalkylation ..................................................................................................... 17	1.3.1	 Hydroaminoalkylation Catalyzed by Late Transition Metal Complexes ................. 18	1.3.1.1	 Hydroaminoalkylation Catalyzed by Group 5 Complexes ................................ 22	1.3.1.2	 Hydroaminoalkylation Catalyzed by Group 4 Metal Complexes ...................... 26	  viii 1.4	 Scope of Thesis ................................................................................................................ 32	Chapter 2: Catalytic Asymmetric Synthesis of C-Substituted Morpholines and Piperazines.. ..................................................................................................................................35	2.1	 Introduction ...................................................................................................................... 35	2.1.1	 Hydroamination for the Diastereoselective Synthesis of Piperazines and Morpholines .......................................................................................................................... 36	2.1.2	 Synthesis of Enantioenriched C-Substituted Morpholines ....................................... 41	2.1.3	 Scope of Chapter ....................................................................................................... 42	2.2	 Results and Discussion .................................................................................................... 43	2.2.1	 Synthesis of Aminoalkyne Substrates ....................................................................... 43	2.2.2	 Substrate Scope ......................................................................................................... 47	2.2.3	 Probing Mechanism .................................................................................................. 51	2.2.4	 Mechanistic Proposal ................................................................................................ 54	2.2.5	 Enantioselective Synthesis of 3-Substituted Piperazines .......................................... 59	2.2.6	 Diastereoselective Synthesis of Disubstituted Morpholines ..................................... 63	2.3	 Conclusions ...................................................................................................................... 65	2.4	 Experimental .................................................................................................................... 66	2.4.1	 Materials and Methods .............................................................................................. 66	2.4.2	 Synthesis and Characterization of Compounds ........................................................ 69	Chapter 3: Phosphoramidate-Tantalum Complexes for Room Temperature Hydroaminoalkylation .................................................................................................................95	3.1	 Complexes Supported by N,O-Chelating Ligands For Hydroaminoalkylation ............... 96	3.1.1	 Synthesis of Phosphoramidates and Applications in the Literature ........................ 100	  ix 3.1.2	 Scope of Chapter ..................................................................................................... 101	3.2	 Results and Discussion .................................................................................................. 102	3.2.1	 Catalytic Screening of Phosphoramidate-Ta(NMe2)4 Complexes .......................... 102	3.2.2	 Catalyst screening of Tantalum Complexes Containing Other Phosphorus Containing N,O-Chelating Ligands .................................................................................... 114	3.2.3	 Phosphoramidate-TaMe3Cl Complexes for Catalytic Hydroaminoalkylation ........ 115	3.2.4	 Exploration of Hydroaminoalkylation Substrate Scope of 123 .............................. 120	3.2.5	 Temperature Effects on Regioselectivity ................................................................ 126	3.2.6	 Efforts Toward More Thermally Robust Phosphoramidate-Ta Complexes ........... 129	3.2.7	 Probing the Role of Reactive Ligands –NMe2 and –CH3 ....................................... 135	3.3	 Conclusions .................................................................................................................... 142	3.4	 Experimental .................................................................................................................. 145	3.4.1	 Materials and Methods ............................................................................................ 145	3.4.2	 Synthesis and Characterization of Compounds ...................................................... 146	Chapter 4: Enantioenriched Phosphoramidate-Tantalum Complexes for Catalytic Asymmetric Hydroaminoalkylation .........................................................................................162	4.1	 Asymmetric Hydroaminoalkylation ............................................................................... 162	4.1.1	 Scope of Chapter ..................................................................................................... 165	4.2	 Results and Discussion .................................................................................................. 167	4.2.1	 Synthesis of Enantioenriched Phosphoramidate Proligands ................................... 167	4.2.2	 Synthesis of Enantioenriched Phosphoramidate-Ta Complexes ............................ 169	4.2.3	 Screening of Enantioenriched Phosphoramidate-Ta Complexes for Asymmetric Hydroaminoalkylation ........................................................................................................ 173	  x 4.2.4	 Variable-Temperature NMR Spectroscopy ............................................................ 176	4.3	 Conclusions .................................................................................................................... 181	4.4	 Experimental Procedures ............................................................................................... 182	4.4.1	 Materials and Methods ............................................................................................ 182	4.4.2	 Synthesis and Characterization of Compounds ...................................................... 183	Chapter 5: Conclusions and Future Work ..............................................................................196	5.1	 Summary ........................................................................................................................ 196	5.2	 Future Directions ........................................................................................................... 201	5.2.1	 Synthesis of Substituted 1,4-Oxazapanes, 1,4-Oxazocanes, and 1,4-Oxazonanes . 201	5.2.2	 Strategies for Identifying More Thermally Robust Room Temperature Hydroaminoalkylation Catalysts ......................................................................................... 205	5.2.3	 Chiral Tantalum Complexes for Asymmetric Hydroaminoalkylation .................... 207	5.3	 Concluding Remarks ...................................................................................................... 208	Bibliography ...............................................................................................................................210	Appendices ..................................................................................................................................225	Appendix A X-Ray Crystallographic Data ............................................................................. 225	Appendix B Select Examples of Enantiomeric Excess Determination by NMR Spectroscopy, SFC, and chiral HPLC ............................................................................................................ 228	Appendix C Select NMR Spectra ........................................................................................... 238	   xi List of Tables  Table 2.1 Asymmetric transfer hydrogenation to yield 73 in the absence of [Ti] ........................ 53	Table 2.2 Synthesis of substituted N-heterocycles by one-pot sequential hydroamination and asymmetric transfer hydrogenation ............................................................................................... 59	Table 2.3 Reduction of disubstituted cyclic imines to afford disubstituted morpholines ............. 64	Table 3.1 Preliminary substrate scope investigations for complex 102 in comparison to complex 12................................................................................................................................................. 113	Table 3.2 Optimization of reaction conditions with complex 123 .............................................. 120	Table 3.3 Temperature effects on regioselectivity of 135 .......................................................... 127	Table 4.1 Screening of enantioenriched phosphoramidate-Ta complexes for asymmetric hydroaminoalkylation ................................................................................................................. 174	   xii List of Figures  Figure 1.1.  Select examples of biologically active α-chiral amines9-10 ......................................... 1	Figure 1.2 Select recent examples of metal catalyzed amine synthesis33, 42, 101-102 ......................... 3	Figure 1.3 Select examples of Ti complexes utilized for catalytic hydroamination178, 180-185 ...... 12	Figure 1.4 Possible binding modes for N,O-chelating ligands ..................................................... 13	Figure 1.5 Azatitanacyclobutene intermediates leading to different hydroamination regioisomers....................................................................................................................................................... 15	Figure 1.6 Synthetic applications of hydroamination featuring complex 969-70, 75 ........................ 16	Figure 1.7 Select examples of group 5 hydroaminoalkylation precatalysts95, 99-100, 211-214 ............ 23	Figure 1.8 Select examples of group 4 metal-based complexes for catalytic hydroaminoalkylation89, 94, 221, 223-225, 227, 229 .................................................................................. 29	Figure 2.1 Mechanistic rationale for trans diastereoselectivity in piperazine synthesis via Pd-catalyzed hydroamination ............................................................................................................. 37	Figure 2.2 Attempted syntheses of aminoalkyne substrates ......................................................... 46	Figure 2.3 Synthesis of 3-substituted morpholines by tandem hydroamination and asymmetric transfer hydrogenation .................................................................................................................. 48	Figure 2.4 Alternative transition state for asymmetric transfer hydrogenation ............................ 58	Figure 3.1 Examples of complexes bearing N,O-chelating ligands .............................................. 97	Figure 3.2 A comparison of reactivity between complexes 10 and 1295, 211 ................................. 98	Figure 3.3 Examples of important achievements in hydroaminoalkylation using auxiliary ligand supported group 5 complexes95, 100, 214, 216 ..................................................................................... 99	  xiii Figure 3.4 Select examples illustrating the preparation of phosphoramidates383-384, 386-387, 390-391..................................................................................................................................................... 101	Figure 3.5 A comparison of amidate and phosphoramidate ligands ........................................... 102	Figure 3.6  Preparation of phosphoramidate-Ta(NMe2)4 complexes by protonolysis ................ 104	Figure 3.7  ORTEP of the solid state molecular structure of complex 110 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity)...................................................................................................................................................... 106	Figure 3.8 Catalytic screening of phosphoramidate-Ta(NMe2)4 complexes for hydroaminoalkylation ................................................................................................................. 108	Figure 3.9 Catalytic screening of bis(phosphoramidate)-Ta(NMe2)3 complex and tethered phosphoramidate-Ta(NMe2)4 complexes for hydroaminoalkylation .......................................... 111	Figure 3.10 Screening of tantalum complexes containing other phosphorous N,O-chelating ligands for catalytic hydroaminoalkylation ................................................................................ 115	Figure 3.11 ORTEP of the solid state molecular structure of phosphoramidate proligand 122 and Ta complex 123 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity) .................................................................................. 118	Figure 3.12 Alkene substrate scope for complex 123 ................................................................. 122	Figure 3.13 ORTEP representation of the solid state molecular structure of 129 after derivatization with 4-nitrobenzenesulfonyl chloride .................................................................. 123	Figure 3.14 Unreactive alkene, allene, and alkyne substrates for hydroaminoalkylation with 123..................................................................................................................................................... 126	Figure 3.15 Proposed rationale for the preferential formation of the linear regioisomer of product 135............................................................................................................................................... 128	  xiv Figure 3.16 ORTEP of the solid state molecular structure of 154 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms and toluene solvent molecules removed for clarity) .................................................................................................................... 131	Figure 3.17 N,O-Chelated Ta complexes with pendent donor groups (complexes 155-157) ..... 132	Figure 3.18 ORTEP of the solid state molecular structure of 156 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity) ............. 133	Figure 3.19 ORTEP of the solid state molecular structure of 157 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity) ............. 134	Figure 3.20 Consumption of amine as a function of time for the α-alkylation of 4-methoxy-N-methylaniline with 1-octene catalyzed by 111 and 123 .............................................................. 136	Figure 3.21 Consumption of amine as a function of time for the α-alkylation of 4-methoxy-N-methylaniline with 1-octene catalyzed by 123 ............................................................................ 139	Figure 3.22 Hydroaminoalkylation off-catalytic pathways211-212, 214, 367 ..................................... 141	Figure 3.23 Representative 1H-NMR spectrum (300 MHz, toluene-d8) for monitoring hydroaminoalkylation reactions.  Reaction of 4-methoxy-N-methylaniline and 1-octene after 20 h at 90 °C with precatalyst 114. ..................................................................................................... 150	Figure 4.1 Select examples of precatalysts with chiral N,O-chelating ligands for asymmetric intramolecular hydroamination ................................................................................................... 163	Figure 4.2 Asymmetric hydroaminoalkylation catalyzed by group 5 complexes ...................... 164	Figure 4.3 Select examples of asymmetric hydroaminoalkylation products catalyzed by group 5 systems ........................................................................................................................................ 165	Figure 4.4 Select examples of chiral phosphoric acids utilized in asymmetric synthesis452-454 . 166	Figure 4.5 Synthesis of chiral phosphoramidate proligands ....................................................... 168	  xv Figure 4.6 Chiral phosphoramidate-Ta complexes prepared for asymmetric hydroaminoalkylation ................................................................................................................. 170	Figure 4.7 ORTEP of the solid state molecular structure of complex 171 with select bond lengths and bond angles (Thermal ellipsoids set at 50% probability.  All hydrogen atoms and hexane solvent molecule are removed for clarity) .................................................................................. 172	Figure 4.8 1H-NMR spectra of complex 175 at various temperatures ........................................ 177	Figure 4.9 1H-NMR spectrum of complex 175 (bottom) and complex 175 and 2 equivalents of 4-methoxy-N-methylaniline (top) .................................................................................................. 179	Figure 4.10 1H-NMR spectra of 175 with 4-methoxy-N-methylaniline at various temperatures181	Figure 5.1 Oxygen containing N-heterocycles ............................................................................ 201	Figure 5.2 Potential tantalum starting materials for the preparation of thermally robust tantalum hydroaminoalkylation catalysts472-476 .......................................................................................... 206	Figure 5.3 Potential structural motifs for new chiral phosphoramidate proligands .................... 208	            xvi List of Schemes Scheme 1.1 Hydroamination of alkynes and alkenes ..................................................................... 4	Scheme 1.2 Proposed mechanisms for late-transition metal catalyzed hydroamination via nucleophilic attack .......................................................................................................................... 7	Scheme 1.3 Proposed mechanisms for late-transition metal catalyzed hydroamination via oxidative addition of the amine ....................................................................................................... 8	Scheme 1.4 Proposed mechanism for early transition metal catalyzed hydroamination .............. 10	Scheme 1.5 Preparation of Complex 9 ......................................................................................... 14	Scheme 1.6 α-Alkylation of secondary amines with alkenes by catalytic hydroaminoalkylation 17	Scheme 1.7 Proposed mechanism for intermolecular hydroaminoalkylation catalyzed by homoleptic dimethylamido metal complexes201 ........................................................................... 18	Scheme 1.8 Select examples of late transition metal catalyzed hydroaminoalkylation202-203, 207, 209-210................................................................................................................................................... 19	Scheme 1.9 Proposed mechanism for late transition metal catalyzed hydroaminoalkylation via direct oxidative addition of amine ................................................................................................ 20	Scheme 1.10 Alternative mechanisms for C-H bond cleavage by late transition-metal catalysts 21	Scheme 1.11 Late-transition metal catalyzed asymmetric hydroaminoalkylation ....................... 22	Scheme 1.12 First example of Ta catalyzed asymmetric hydroaminoalkylation95 ....................... 25	Scheme 1.13 Accessing Ti-catalyzed intramolecular hydroaminoalkylation through substrate control221 ....................................................................................................................................... 27	Scheme 1.14 Proposed mechanism for intramolecular hydroaminoalkylation with complex 19 . 28	  xvii Scheme 1.15 Ti catalyzed chemoselective intramolecular hydroaminoalkylation89 .................... 30	Scheme 1.16 Ti catalyzed regioselective formation of linear hydroaminoalkylation product227 . 31	Scheme 2.1 Intramolecular Alkyne and Alkene Hydroamination ................................................ 35	Scheme 2.2 Diastereoselective synthesis of piperazines and morpholines by Pd-catalyzed hydroamination253-254 .................................................................................................................... 36	Scheme 2.3 Diastereoselective synthesis of 2,5-disubstituted piperazines by Ti and Zr-catalyzed hydroamination197 ......................................................................................................................... 39	Scheme 2.4 Recent synthetic strategies for preparation of enantiopure 3-substituted morpholines273, 283 ......................................................................................................................... 41	Scheme 2.5 Enantioselective synthesis of substituted morpholines from prochiral substrates .... 42	Scheme 2.6 General synthetic route to aminoalkyne substrates ................................................... 44	Scheme 2.7 Synthesis of (S)-3-benzylmorpholine (78) ................................................................ 49	Scheme 2.8 Gram scale synthesis of (R)-3-benzylmorpholine ..................................................... 50	Scheme 2.9 Synthesis of nitrile containing morpholine product (81) .......................................... 51	Scheme 2.10 Asymmetric transfer hydrogenation of 73 in the absence of [Ti] ........................... 52	Scheme 2.11 Proposed mechanistic rationale for asymmetric transfer hydrogenation invoking the key role of a heteroatom in favourable H-bonding interactions ................................................... 56	Scheme 2.12 Synthesis of aminoalkyne substrate 87 ................................................................... 60	Scheme 2.13 Synthesis of (R)-1-benzyl-3-methylpiperazine (88) ................................................ 61	Scheme 2.14 Synthesis of (R)-3-benzyl-1-(3-phenylprop-2-yn-1-yl)piperazine (90) .................. 62	Scheme 2.15 Enantioselective preparation of benzyl protected piperazines ................................ 63	Scheme 3.1.  Synthesis of α-alkylated amines by catalytic hydroaminoalkylation ...................... 96	Scheme 3.2 Formation of hydroaminoalkylation byproduct from catalyst activation ................ 100	  xviii Scheme 3.3 Preparation of phosphoramidate proligands ............................................................ 103	Scheme 3.4 Proposed catalytic cycle for hydroaminoalkylation with methane elimination ...... 116	Scheme 3.5 Preparation of complex 123 by salt metathesis ....................................................... 117	Scheme 3.6 Preparation of Complex 154 ................................................................................... 130	Scheme 4.1 Intermolecular hydroaminoalkylation leading to the formation of a new stereocenter..................................................................................................................................................... 162	Scheme 5.1 Proposed preparation of enantioenriched 1,4-oxazepanes, 1,4-oxazocanes, and 1,4-oxazonanes by hydroamination and asymmetric transfer hydrogenation ................................... 202	Scheme 5.2 Synthesis of 1,4-oxazocane using hydroamination followed by NaBH4 reduction 203	Scheme 5.3 Preparation of enantioenriched 1,4-oxazonanes through hydroamination and asymmetric transfer hydrogenation ............................................................................................. 204	   xix List of Abbreviations  [α]D   specific rotation observed at 589 nm   Å   Ångström (10-10m) Ac   acetyl Alk   alkyl aq   aqueous Ar   aryl ATH   asymmetric transfer hydrogenation BINAP  2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINOL  1,1'-bi-2-binaphthol Bn   benzyl Boc   tert-butyloxycarbonyl Box   bis(oxazoline) br.   broad iBu, nBu  isobutyl, normal butyl C   Celsius calcd   calculated cat.   catalyst Cbz   carboxylbenzyl CCDC   Cambridge Crystallographic Data Centre c-hex   cyclohexyl   xx Cp   cyclopentyldienyl Cp*   pentamethylcyclopentyldienyl cm-1   wavenumber COD   cyclooctadiene d   doublet d   deuterium dap   2,9-bis-(4-methoxyphenyl)-1,10-phenanthroline δ   chemical shift (NMR) δ+/ δ+   partial positive charge, partial negative charge °   degrees dba   dibenzylideneacetone DCE   1,2-dichloroethane DCM   dichloromethane DFT   density functional theory DG   directing group DME   1,2-dimethoxyethane DMF   dimethylformamide DMSO   dimethyl sulfoxide DPEN   diphenylethylenediamine dr   diastereomeric ratio DTBM-SEGPHOS 5,5′-bis[di(3,5-di-tert-butyl-4-methoxyphenyl)phosphino]-4,4′-bi-1,3-benzodioxole   η   hapticity   xxi EA   elemental analysis ee   enantiomeric excess EI   electron impact ESI   electrospray ionization Et   ethyl GC   gas chromatography h   hours HA   hydroamination HAA   hydroaminoalkylation HFIP   hexafluoroisopropanol HMDS   hexamethyldisilazide HPLC   high-performance liquid chromatography HRMS   high-resolution mass spectrometry Hz   Hertz iPr   isopropyl J   coupling constant κ   denticity  K   kelvin kobs   observed rate constant m   multiplet M   molar concentration M+   molecular ion m/z   mass-to-charge ratio   xxii µ   absorption coefficient (X-ray crystallography) Me   methyl Mes   mesityl mol   mole mol %   mole percent  MHz   megahertz MS   mass spectrometry NAPHOS  2,2'-bis((diphenylphosphanyl)methyl)-1,1'-binaphthalene nbd   norbornadiene NMR   nuclear magnetic resonance Nos   p-nitrobenzenesulfonyl ORTEP  Oak Ridge thermal ellipsoid plot Ph   phenyl ppm   parts per million q   quartet R   organic substituent R2   coefficient of determination (statistics) reflns   reflections r.t.   room temperature s   singlet SFC   supercritical fluid chromatography t   triplet TBDMS  t-butyldimethylsilyl   xxiii Tf   trimethylmethanesulfonyl TFA   trifluoroacetic acid THF   tetrahydrofuran TLC   thin layer chromatography TMS   trimethylsilyl tol   tolyl p-tol   para-toyl Ts   tosyl (p-CH3C6H4SO2) VT   variable temperature    xxiv Acknowledgements  This thesis and the work presented herein could not have happened without the unwavering support from the following individuals. First and foremost, I would like to thank my supervisor Dr. Laurel Schafer for the opportunity to work in the Schafer Group.  Thank you for the mentorship through the years and guidance in chemistry and other pursuits beyond the lab.  She has inspired me as a scientist and an individual. Thank you to Dr. Glenn Sammis for assisting in the editing process during the assembly of this manuscript.  His thoughtful input and suggestions have helped to improve the overall quality of this document. I would like to express my gratitude towards the support staff here in the chemistry department for all their help towards making this research happen.  In particular, I would like to thank Ken Love for assistance with the glove box, David Tonkin for his dedication to helping me fix the SFC, and Marshall Lapawa for his help with mass spectrometry.  I would also like to acknowledge the University of British Columbia and the Walter C. Sumner Foundation for funding.  Thank you to the Sammis group for allowing me to use the SFC machine for my ee determinations and thank you to Diana Yu for helping me with the chiral HPLC. I am grateful to have worked alongside many tremendous coworkers during my time here at UBC.  Thank you to all the past and present Schafer group members for all of your help through this experience and for making work days fun.  In particular, I would like to acknowledge Scott Ryken, Mitchell Perry, Damon Gilmour, and Joseph Clarkson for helping with the early drafts of this thesis.  Thank you Dr. Robby Zhai and Dr. Pierre Garcia for the   xxv opportunity to collaborate with them in research.  Thank you to the undergraduate students who have helped me with the work presented in Chapter 2, Jennifer Moon and Anisa Maruschak.  I would also like to thank visiting student Katarina Strobl for her help with preparing ligands for the work presented in Chapter 4.  Finally, I would like to thank my all of friends outside of the lab for their support.  Special thanks to Andrea Azcona Axen, Katherine Zavaglia and Matthew Twohig for helping me along the way.  Most importantly, I would like to express my extreme gratitude towards my parents, Teck Hock Lau and Geok Chai Lim, and my brother, Ren Wei Lau, for their endless encouragement.   I cannot thank you enough.   xxvi Dedication     This thesis is dedicated to my parents,   Teck Hock Lau and Geok Chai Lim,   and my brother,  Ren Wei Lau.  1 Chapter 1: Introduction  The amine functional group is commonly used in a variety of compounds, most notably in pharmaceuticals.1 The biological relevance of various amines, in particular α-chiral amines, has garnered academic and industrial interest for the development of simple and efficient synthetic procedures for their preparation (Figure 1.1).2-8 Ideal synthetic approaches would provide controlled chemoselectivity, regioselectivity, diastereoselectivity, and enantioselectivity, all while minimizing the generation of stoichiometric amounts of by-products and waste.     Figure 1.1.  Select examples of biologically active α-chiral amines9-10  1.1 Catalytic Synthesis of Amines  Substituted amines may be synthesized through many different strategies.  Traditional methods include, but are not limited to, N-alkylation of amines,11 reductive amination,12-15 ONONRivasigmine(Novartis, Alzheimer's)HNHHONCF3F3CLariam(Roche, malaria)NHHNHOOHSibutramine(Abbott Laboratories, obesity)NClEthambutol(tuberculosis)HNCF3Cinacalcet(Amgen, hyperparathyroidism)(+)-Crispine(GSK, anti-tumor)NHOO  2 Gabriel Synthesis,16 Ullmann cross-coupling,17-18 and nucleophilic addition to imines,13 but these syntheses are restricted by issues such as chemoselectivity, generation of stoichiometric equivalents of byproducts, and high reaction conditions.   Significant progress toward such idealized syntheses of amines has been made through the development and employment of metal-catalyzed reactions (Figure 1.2).1, 19 Buchwald-Hartwig amination,20-26 direct C-H amination,27-34 hydroaminomethylation,35-45 photoredox catalysis,46-55 hydroamination,41, 56-66 and hydroaminoalkylation67-68 are some select notable advances to this synthetic challenge.  Using inexpensive early transition metal catalysts, two atom-economic methods to prepare substituted amines from commercially available substrates have been extensively studied by the Schafer group: hydroamination62, 69-93 and hydroaminoalkylation.67, 89, 94-100 Because the focal point of this thesis is amine synthesis through hydroamination and hydroaminoalkylation, an in depth look at the other catalytic transformations listed above will not be presented.  Instead, interested readers are directed towards the cited references above which include select seminal reports and review articles.         3  Figure 1.2 Select recent examples of metal catalyzed amine synthesis33, 42, 101-102  1.2 Hydroamination    Hydroamination (HA) is the addition of an N-H bond across a C-C unsaturated bond, resulting in the formation of a new C-N bond (Scheme 1.1).41, 56-66 This is an atom-economic reaction that does not generate stoichiometric amounts of waste, when compared to other traditional methods of making C-N bonds such as reductive amination and Gabriel synthesis.  It is a thermodynamically feasible transformation because the direct addition of an amine to an A.  Buchwald-Hartwig Amination:B.  Direct C-H Amination:NHONHR1 +cat. Cu(OAc)2Pyridine80-110 °C, 5-56 hNHONHONNOR1BrOHNR1R2cat. Pd(OAc)2(R)-DTBM-SEGPHOSK3PO4toluene/dioxane80-130 °C, 7-17 hONR1R2Yield:  95-26%ee: up to 77%C.  Hydroaminomethylation:PhPh+R1HN R3cat. [Rh(ndb)2]BF4NAPHOSCO/H2 (2:1, 30 bar)toluene, 125 °C, 60 hPhPhN R2R1D.  Photoredox Catalysis:cat. Cu(dap)2ClAg2CO3, HCF2SO2ClDCE, 70 °C, 18 hvisible lightNHTosR RNHCF2HRR  4 alkyne is slightly exothermic.57, 103-105 However, due to the electrostatic repulsion between the electron rich C-C unsaturation of an alkyne/alkene and the lone pair of the nitrogen atom of the amine, there is a high kinetic barrier to this reaction, which can be circumvented through the use of catalysts.  Alkenes are less reactive in hydroamination than alkynes and the catalytic intermolecular variant of this reaction still remains a persistent challenge in the field.57 These reactivity differences can be attributed to the weakness of a typical alkyne π-bond relative to an alkene π-bond (approximately 70 kJ/mol weaker), as well as reduced steric accessibility to the C-C unsaturation in substituted alkenes compared to alkynes.56      Catalyst development efforts in this field span complexes of early-60, 106 and late-61, 63, 107-112 transition metals, Lanthanides,60, 113 alkali earth metals,114-119 as well as catalysts derived from frustrated Lewis pairs,120-125 and Brønsted acids58, 122, 126 and bases.127-135 With the use of specialized bifunctional reagents such as hydroxyamines or hydrazines, catalyst free hydroamination is also possible.136-139  Scheme 1.1 Hydroamination of alkynes and alkenes     R1 +catalystR1NHR1HN R2+R2Linear(anti-Markovnikov)Branched(Markovnikov)R1 +catalystR3NR1+R3NR2 R2R1Linear(anti-Markovnikov)Branched(Markovnikov)R2NHR3R2NHR3  5  Ongoing research includes the development of new, robust, and more efficient catalysts and the application of existing catalysts to construct small molecules of biological relevance.  Hydroamination of primary amines (R2 = H, Scheme 1.1) with alkenes can lead directly to substituted secondary amines, whereas hydroamination of alkynes affords enamines, which can tautomerize to yield imines; both of which can be used as building blocks for further organic transformations (Scheme 1.1).  In addition, because two regioisomers can be formed in this reaction (commonly referred to as Markovnikov and anti-Markovnikov products in the literature), control over regioselectivity is of utmost importance in catalyst development.  In general, late transition metal catalyzed hydroamination affords predominantly the Markovnikov product, whereas early transition metal catalysts often give the anti-Markovnikov product.57, 62, 140 This discrepancy in selectivity is attributed through these two classes of catalysts operating through different proposed mechanisms (vide infra).  In the case with alkene hydroamination, formation of the α-branched amine product results in a new stereocenter.  Thus, considerable efforts are made in the pursuit of enantioselective catalysts capable of this transformation.58-59, 141-143   1.2.1 Hydroamination with Late Transition Metal Catalysts   A variety of late transition metal catalysts have been found capable of hydroamination, including catalysts derived from nickel,144-147 copper,107, 111, 148-153 silver,154-158 gold,112, 159-166 and zinc.167-174 In particular, d8 or d10 metal complexes that are Lewis acidic display high catalytic activity in this transformation.57 Complexes derived from late-transition metals are generally less oxophilic than their early-transition metal and rare-earth metal counterparts, and thus, display greater functional group tolerance and greater stability with respect to water and oxygen.175    6  Various different mechanisms have been proposed for late transition metal hydroamination.  In general, they can be divided into two general classes:  one, which involves activation of the C-C multiple bond and the other, which involves metal activation of the amine.57 The former can be further divided into three categories, based on the catalytic step in which regioselectivity of the resulting product is established: coordination of alkene or alkyne followed by nucleophilic attack (Scheme 1.2, A), nucleophilic attack on an allylic-metal complex intermediate (Scheme 1.2, B), or insertion of an alkene or alkyne into a metal hydride bond.     7  Scheme 1.2 Proposed mechanisms for late-transition metal catalyzed hydroamination via nucleophilic attack  For metals in low oxidation states, an often-proposed mechanism considers activation of the amine substrate by oxidative addition (Scheme 1.3).  The active catalytic species is generated [M] NH2[M]HHH2N [M] NH2HNH[M]NH2H[M]NHNalkyne coordinationnucleophilicattackprotolyticcleavageproductrelease[M][M]HRHN R[M]R2HNhydrometallationNR2nucleophilicattack[M][M]HHdeprotonationMechansim A:Mechanism B:  8 with reduction to a coordinatively unsaturated 14 or 16 e- species through the dissociation of ligands.  Oxidative addition of the amine substrate yields a hydrido-amido complex.  Insertion of the alkyne or alkene substrate into the M-N or M-H bond occurs, followed by reductive elimination to regenerate the coordinatively unsaturated low-valent complex.  Scheme 1.3 Proposed mechanisms for late-transition metal catalyzed hydroamination via oxidative addition of the amine  1.2.2 Hydroamination with Early Transition Metal Catalysts    Early transition metal catalysts for hydroamination are comparatively more sensitive to water and oxygen than late transition metal complexes, but more robust relative to their [M]LL-2 Loxidativeaddition[M]RHN R[M]NR2HR1[M]HNR2R1reductiveeliminationNR2R1insertion[M]NR2R1or  9 lanthanide counterparts.57, 62 Many examples of titanium 77, 176-185 and zirconium73, 76, 79, 81, 186-189 based catalysts with 2 labile ligands (methyl, dimethylamido, or cyclopropenyl) have been reported to date.  While the oxophilic nature of the catalyst systems may limit their functional group tolerance, they are generally less expensive and toxic than late-transition metal complexes.   Early transition metal catalysts for hydroamination operate through different mechanistic pathways than those presented previously for late-transition-metals.57, 62 For group 4 systems, alkyne, and primary amine substrates, the mechanism depicted in Scheme 1.4 is most commonly cited and has been corroborated through experimental observations, as well as kinetic190 and computational studies.191 A similar catalytic cycle has been proposed for primary aminoalkene cyclization with neutral group 4 catalysts.74, 77, 81, 188, 192-193 Starting from a catalytically active metal-imido intermediate that is generated through the activation of a primary amine, the alkyne is added in a [2+2] fashion to yield an azatitanacyclobutene intermediate.  The enamine product is liberated with two subsequent protonolysis events with an incoming equivalent of the primary amine substrate to regenerate the catalytically active metal-imido species, which have been previously isolated, characterized, and confirmed to be active hydroamination catalysts.194    10  Scheme 1.4 Proposed mechanism for early transition metal catalyzed hydroamination    Because this proposed mechanism goes through a metal-imido intermediate, which cannot be formed through the use of secondary amines, these are not active substrates in this catalytic cycle.62   Catalyst deactivation can occur through dimerization of two metal-imido intermediates, a problem that is more prevalent with zirconium complexes compared to titanium and consequently contributes to more reported examples of titanium-based intermolecular hydroamination catalysts for alkynes.177    [M]NMe2NMe2[M][M][M]alkyne insertionprotonolysis2 HNMe2NRR1NH2R3NR1R2R2 R3R1NH2NNHR1R3R1protonolysisR2 N HR1R3R2R2 NR1R3  11 1.2.2.1 Early Transition Metal Catalysts for Alkyne Anti-Markovnikov Hydroamination   As hydroamination of a C-C unsaturation can yield two regioisomers (vide supra), catalyst development for synthetic applications must consider regioselectivity of the resulting products.57 Late-transition metal catalysts predominantly generate the branched (Markovnikov) product in intermolecular alkyne hydroamination.  In contrast, early-transition metal catalysts are complementary in regioselectivity, favouring the linear (anti-Markovnikov) product, but for some catalyst systems regioselectivity can be substrate-dependent.  Different mechanistic pathways with late-transition metal catalysts and early-transition metal catalysts are attributed to the overall selectivity observed.62     The first report of anti-Markovnikov regioselectivity with a group 4 metal catalyst was reported in 1992 by Bergman and co-workers.186 This Cp2Zr(NMe2)2 complex catalyzes the intermolecular hydroamination of 2,6-dimethylaniline with symmetric internal alkynes and allene.  The reaction of 2,6-dimethylaniline and allene yielded the anti-Markovnikov product N-(2,6-dimethylphenyl)propan-2-imine exclusively, but catalyst was limited only to 2,6-dimethylaniline due to catalyst deactivation through dimerization of the zirconium-imido intermediate with less sterically bulky amines.  Following the work by Bergman and co-workers, the first Ti example of anti-Markovnikov selectivity was disclosed in 1999 from Doye and co-workers.180 Using a known organometallic Ti complex 1 (Figure 1.3), [Cp2TiMe2], the first example of group 4 intermolecular catalyzed hydroamination of a terminal alkyne was presented.  With phenylacetylene and 1-napththylamine, this Ti complex afforded the anti-Markovnikov product exclusively, albeit in low yield (23%).  In addition, the substrate scope is limited to the sterically   12 bulky amines such as 1-napththylamine and benzylhydrylamine, as benzylamine showed low reactivity.   Subsequent reports in the field have investigated the development of a number of Ti catalysts for catalytic hydroamination (Figure 1.3).  While good reactivity was observed for a number of catalysts, regioselectivity with terminal alkynes was still dependent on sterically demanding amines.  For example, reducing the steric bulk from tert-butyl amine to isobutyl amine to aniline with catalyst 1 demonstrated dramatic regioselective switch from predominantly anti-Markovnikov selectivity to Markovnikov selectivity.180     Figure 1.3 Select examples of Ti complexes utilized for catalytic hydroamination178, 180-185  Ti CH3CH3Doye, 1999Ti CH3CH3NNTi CH3CH3S MesOOS MesOOBeller, 2002TiSiMe3SiMe3Bergman, 2003TiNMe2NNMe2NMe2NMe2NOdom, 2002TiNNiPrNiPrNMe2N iPrNMe2N iPrRicheson, 2002TiNN NMe2NMe2Odom, 2003 Doye, 20041 2 3 45 6 7  13 1.2.2.2 Bis(amidate)bis(amido)-Titanium Complex for Hydroamination  In search for a more general hydroamination catalysts to address the regioselectivity issue discussed in the previous section, the Schafer group explored the use of organic amides as potential proligands for early transition metal complexes.69, 76, 80 These proligands are prepared in one-step from commercially available acid chlorides and amines; therefore, the electronic and steric properties are easily modified.  In addition, this ligand scaffold offers flexibility in sterics around the metal center, as they are hemilabile in nature and can adopt a variety of binding modes (Figure 1.4).195   Figure 1.4 Possible binding modes for N,O-chelating ligands    One particular bis(amidate)bis(amido)-Ti complex (9, Scheme 1.5) was identified as an exceptionally regioselective anti-Markovnikov hydroamination catalyst.69 The precatalyst is easily synthesized by the protonolysis reaction between 2 equivalents of the amide proligand (8, Scheme 1.5) and 1 equivalent of Ti(NMe2)4 and can be prepared on multi-gram scale.  More importantly, it demonstrates catalytic activity towards a wide range of substituted alkynes,69-70, 75 allenes,78 and primary amine substrates, including challenging benzylamine and allylamine. 69-70, 75, 78 Good functional group tolerance is observed, even for oxygen containing substrates including protected alcohols, ethers, and esters. Monometallic Binding Bimetallic BindingNR2R1O[M]NR2R1O[M][M] NR2R1O[M][M]NR2R1O[M]NR2R1O[M]  14  Scheme 1.5 Preparation of Complex 9   Complex 9 is proposed to operate through the mechanistic pathway presented in Scheme 1.4 and this is corroborated by experimental observations.70, 75 The analogous titanium-imido complex of 9 has previously been isolated and demonstrates comparable catalytic activity to starting with the precatalyst complex.  In addition, secondary amines are unreactive with this catalyst due to the inability to form the requisite metal-imido species.   The wide substrate scope and anti-Markovnikov regioselectivity of 9 is attributed to the known hemi-labile nature of the amidate ligand providing a flexible steric environment around the metal center.75 The azatitanacyclobutene intermediate leading to the anti-Markovnikov is more sterically encumbered than the Markovnikov variant (Figure 1.5) and it is postulated that the amidate ligand can access alternative binding modes to alleviate the steric congestion around the metal center, as well as allow for coordination of an amino ligand for protonolysis to occur.  Kinetic isotope experiments indicate that the protonolysis of the azatitanacyclobutene is the turnover-limiting step in the catalytic cycle and the [2+2] cycloaddition step is rapid and reversible.  Therefore, the observed regioselectivity of the products attained with complex 9 is defined by the protonolysis step and is proposed to follow the Curtin-Hammett principle.75  NOTi(NMe2)22NHO + Ti(NMe2)42hexanes23 °C, 18 h8 9  15  Figure 1.5 Azatitanacyclobutene intermediates leading to different hydroamination regioisomers   Precatalyst 9 has been utilized to generate reactive intermediates that can be coupled in a one-pot fashion with other reactions to afford more complex synthetic targets without need to isolate the imine (Figure 1.6).62, 195 Previous reports from the Schafer group exploiting the reactivity of hydroamination products include hydrolysis to yield aldehydes,69, 75 Pd-catalyzed hydrogenation to give secondary amines,93 or subsequent acid-catalyzed Pictet-Spengler reaction to yield substituted isoquinolines and benzoquinolizines.69-70, 75 The hydroamination products can be used in a modified Strecker reaction to produce α-aminonitriles through addition of TMSCN, en route to diamines196-198 and α-amino acids.199 Further synthetic manipulation of diamine products have yielded substituted imidazolidinones196 and disubstituted piperazines.197-198 Complex 9 also displays reactivity towards hydrazines to yield hydrazones, which can be used to form substituted indoles under Lewis acid catalyzed reaction conditions.75    Ti NR1R2 HTi NR1H R2Linear Product(anti-Markovnikov)Branched Product(Markovnikov)L2 L2  16  Figure 1.6 Synthetic applications of hydroamination featuring complex 969-70, 75  A. Synthesis of Aldehydes:R1 + R2 NH2i. 5 mol% 9    C6D6,65 °Cii. SiO2, H2O/Et2OR1 HOB. Synthesis of Secondary Amines:R1 + R2 NH2i. 1-10 mol% 9    C6H6, 70 °Cii. 0.5-1 mol% Pd/C    H2 (3 bar), MeOH, r.t.R1HN R2C. Synthesis of Tetrahydroisoquinolines:MeOMeO NH2R1 +i. 5 mol% 9    C6D6, 65 °Cii. TFAMeOMeO NHR1D. Synthesis of Benzoquinolines:MeOMeO NH2+i. 5 mol% 9    C6D6, 65 °C ii. TFAiii.  xylenes, 140 °CMeOMeO NOO OE. Synthesis of α-Aminonitriles:R1 + R2 NH2i. 5 mol% 9    C6H6, 65 °Cii. TMSCN R1HN R2CNF. Synthesis of Indoles:R1 +i. 5 mol% 9    C6H6, 65 °C ii. ZnCl2     toluene, 100 °CR2 N NH2R3NR1R2R3  17 1.3 Hydroaminoalkylation Hydroaminoalkylation (HAA) is the direct formation of a C-C bond α to a nitrogen atom via C-H activation of an sp3-hybridized carbon (Scheme 1.6).68 This is a powerful 100% atom economical reaction that can be realized from commerically available amines and unactivated alkenes.  In 1980, Clerici and Maspero first disclosed the α-alkylation of secondary amines with terminal alkenes using homoleptic dimethylamido complexes of Nb, Ta, Zr as precatalysts to yield the branched HAA product.200 Moderate to low yields where achieved (up to 38%) over 24 hours with high reaction temperatures (160-200 ˚C).   Investigations into the use of analogous complexes of Ti, V, Mo, and Sn afforded only trace amounts of the desired product.   Scheme 1.6 α-Alkylation of secondary amines with alkenes by catalytic hydroaminoalkylation   A few years later, Nugent and coworkers showed homoleptic dimethylamido complexes can undergo reversible cyclometalation to form azametallacyclopropanes under elevated temperatures.201 Addition of a terminal alkene to the strained metallacycle produces the branched α-alkylated product, leading to the proposed mechanism depicted below (Scheme 1.7).  Of the complexes studied, Zr, Nb, Ta, and W demonstrated catalytic activity at 160 ˚C, but no product was observed with Ti, Hf, or Sn.   R3+R1 NHR2catalystR1HN R3R2+ R1HN R3R2Linear Branched  18  Scheme 1.7 Proposed mechanism for intermolecular hydroaminoalkylation catalyzed by homoleptic dimethylamido metal complexes201  1.3.1 Hydroaminoalkylation Catalyzed by Late Transition Metal Complexes  Late transition metal HAA catalysts have been reported with complexes derived from Ru202-205 and Ir206-208 (Scheme 1.8).  The first example of a late transition metal system was published in 1998 by Jun and coworkers.202 Using Ru3(CO)12 as a catalyst and 3-methyl-2-pyridyl-N-substituted benzylamine as a substrate, α-alkylation was achieved with terminal alkenes to yield exclusively the linear isomer, as well as cyclopentene and cyclohexene in moderate to excellent yields (60-95%) after 6 h.  A follow up report by Murai and coworkers [M]NMe2NMe22 HNMe2[M] NR1[M]R2NR1[M]NNR1R1R2R2HN R2R1HNmetallaaziridineformationalkene insertionprotonolysisC-H activationR1R1HNC-H activation  19 discovered that the same catalyst system was capable of α-alkylation of 2-pyridyl-N-heterocycles with a variety of alkenes, including ethylene and cyclohexene.203   Scheme 1.8 Select examples of late transition metal catalyzed hydroaminoalkylation202-203, 207, 209-210  + R10 mol% Ru3(CO)12toluene, 130 °C, 6 hNNR+8 mol% Ru3(CO)12toluene, 140 °C40-60 hNNRNHNPhNHNPhRNHBnNOArO+3 mol% Ru3(CO)1212 mol% PCy3THF, 140 °C48 hNHBnNOArONON + R7 mol% [Ir(cod)2]BF4DME, 140 °C, 1-2 hmicrowave (300 W)NONRn nJun, 1998Murai, 2001Opatz, 2014Krische, 2013NNR+5 mol% [RuCl2(PPh3)3]6 mol% BINAP12 mol% AgOTfiBuOH, 80-120 °C40-60 hNNRAckermann, 2014  20  This transformation was originally proposed by Jun and coworkers to occur by C-H bond cleavage via oxidative addition of the amine substrate to a catalytically active Ru(0) intermediate (Scheme 1.9).202 Metal mediated sp3 C-H bond cleavage is more challenging than sp2 C-H bond cleavage due to thermodynamic instability of a metal-sp3 carbon bonds compared to metal-sp2 carbon bonds; however, sp3 C-H bonds α to a heteroatom, in this case nitrogen, are more reactive than those next to a carbon.202-203   Scheme 1.9 Proposed mechanism for late transition metal catalyzed hydroaminoalkylation via direct oxidative addition of amine    This and other late transition metal catalyzed HAA reactions are based on a chelation-assisted strategy, where directing groups on the substrate are used to form a metallacycle with R2metallacycleintermediate[M]NHNR1N[M]HNHR1oxidative additionN[M]HNHR1R2NHNreductive eliminationR1R2N[M]NHR1R2insertioncoordination  21 the catalyst to mediate subsequent C-H bond activation.  However, the exact mechanism of C-H bond cleavage remains unclear.203 In addition to direct oxidative addition, hydride elimination from a 1,3-diaza-π-allyl Ru complex and hydride abstraction from an iminium intermediate have also been proposed (Scheme 1.10).    Scheme 1.10 Alternative mechanisms for C-H bond cleavage by late transition-metal catalysts   While pyridine-based directing groups are most commonly employed, benzoxazole has also been shown to be a successful directing group for HAA of 1,2,3,4-tetrahydroisoquinolines selectively at the 3-position.207 Only one directing group free example has been reported by Krische and coworkers, which as an example of α-alkylation of hydantoins with isoprene; however, this reaction is proposed to proceed through a different mechanism where the hydantoin is first dehydrogenated by the Ru catalyst to yield an imine prior to oxidative coupling of the isoprene.209  N NHRA.  Formation of π-Allyl Complex:NHNR[M]N[M]HNHR[M]B.  Formation of Iminium Intermediate:NHNR[M]NHNR[M]NNR[M]HHN[M]HNHRN NR[M]H  22  The field of late-transition metal catalyzed HAA has since been broadened by the use of a chiral cationic tolBINAP-Ir system to achieve enantioselective α-C-H alkylation of 2-pyridyl-N-benzylamine in good yields and good ees (Scheme 1.11, 61-90%).206 This remains the only late-transition metal system for asymmetric HAA reported to date.    Scheme 1.11 Late-transition metal catalyzed asymmetric hydroaminoalkylation   Late transition metal catalyzed HAA forms primarily the linear regioisomer, making it a complementary strategy to early transition metal catalyzed HAA, which gives primarily the branched product.  While late transition metal systems offer greater functional group tolerance and less sensitivity to adventitious moisture than the early-transition metal counterparts, the adjacent directing groups required in most cases is a serious drawback.  Group 4 and group 5 HAA catalysts can directly functionalize unprotected secondary amines and do not require the presence of a large excess of alkenes (5-10 equivalents); therefore, catalysis with these systems is comparatively more atom economical, particularly if synthetic steps for installation and removal of the requisite directing groups are considered.       1.3.1.1 Hydroaminoalkylation Catalyzed by Group 5 Complexes Following the initial reports of Maspero and Nugent,200-201 no further improvements on early transition metal catalyzed hydroaminoalkyation were reported for nearly 20 years until Herzon and Hartwig revisited this reaction in 2007.211 Using commercially available Ta(NMe2)5 -+ R10 mol% [Ir(cod)2]BF410 mol% (S)-tolBINAPDME, 75-95 °C, 1-2 daysNHNNHN R  23 (10, Figure 1.7), α-alkylation of N-aryl alkylamines was achieved with a variety of alkenes. The branched product was preferentially afforded in moderate to excellent yields (50-96%) with improved reaction times (27-67 h), but still requiring high reaction temperatures (160-165 ˚C).   A subsequent report in 2008, saw improvement in the substrate scope of this reaction through the incorporation of electron-withdrawing halide ligands.212 By using [TaCl3(NEt2)2]2 (11, Figure 1.7) as a precatalyst in this transformation, challenging dialkylamine substrates were alkylated with terminal alkenes, which was not previously observed using Ta(NMe2)5. Their work revitalized interest in this synthetic methodology and many other examples soon followed giving further insight to catalyst design and development (Figure 1.7).     Figure 1.7 Select examples of group 5 hydroaminoalkylation precatalysts95, 99-100, 211-214  Ta(NMe2)5 [TaCl3(NEt2)2]NOTa(NMe2)4iPr iPr10Hartwig, 200711Hartwig, 200812Schafer, 2009NONOTa(NMe2)3iPriPriPr13Schafer, 2009NNOOTaMesMes(NMe2)3SiPh2MeSiPh2MeOOM(NMe2)3M = Ta, Nb(HNMe2)n14Zi, 201015Hultzsch, 2011TaMe3Cl216Schafer, 2013NOPhTa(NMe2)3Cl17Schafer, 2014  24  In 2009, the Schafer group reported amidate complexes 12 and 13, which demonstrate catalytic activity towards HAA.95   This work was the first use of an auxiliary ligand supported Ta complex for this transformation and highlighted that modification of steric bulk on the ligand can dramatically affect the reactivity of the metal center. 12 displays excellent reactivity and is the most general catalyst system to date with an expanded substrate scope to include challenging substrates such as N-heterocycles and select internal alkenes.95-96 However, the reaction temperatures are still high (130-165 ˚C), thereby limiting the reaction to exclude temperature sensitive substrates. The first asymmetric variant of this transformation was also reported through the use of the axially chiral complex 13 (Scheme 1.12).     25  Scheme 1.12 First example of Ta catalyzed asymmetric hydroaminoalkylation95   Other notable contributions include axially chiral Ta complexes reported by Zi213, 215 (14) and Hultzsch214, 216 (15) for asymmetric HAA.  High ees can be achieved with these catalysts systems (up to 98%); however, there have been no general catalysts reported which exhibit such selectivity across a wide range of substrates.95, 213, 216   Due to the steric demands of internal alkenes, this remains a class of problematic substrates to functionalize for most reported HAA catalysts.  In an effort to extend the substrate scope of this reaction to include challenging internal alkenes, a simple organometallic complex NONOTa(NMe2)3iPriPriPr13R3+R1NHR210 mol% 13d8- toluene130 °C, 24-192 hR1HN R3R2* *HN86%  44%Yield:ee:80%  61%HN92%  43%HN50%  52%HNO50%  57%HN  26 TaMe3Cl2 (16) was reported to functionalize select Z-alkenes, albeit in low yields.99 More recently, a more general catalyst system (17) was disclosed as an answer to this challenge.100 This sterically accessible Ta complex is the only reported system to date that can functionalize a number of E- and Z-alkenes in good to excellent yields (55-95%).  1.3.1.2 Hydroaminoalkylation Catalyzed by Group 4 Metal Complexes  The original works by Maspero200 and Nugent201 cited that HAA was observed with Zr(NMe2)4, but Ti(NMe2)4 was unreactive under the experimental conditions that were studied.  However, following these seminal reports, C-H activation in the α position of amines was noted with Ti complexes in other synthetic pursuits.217-219 In particular, Ti catalyzed intramolecular HAA was detected as a side reaction by Doye during cyclohydroamination of primary aminoalkene substrates when Ti(NMe2)4 (18) or 7 were used.220 Note that, to date, no intramolecular HAA reactivity has been reported for group 5 catalysts.67  Doye and coworkers were first to achieve accessing the hydroaminoalkylation product over the hydroamination product in 2009 with 18.221 In earlier work by the Doye group, complex 18 was used for the synthesis of piperdines from hydroamination of 6-carbon chain aminoalkene substrates.220 In that investigation, the formation of a 5-membered ring byproduct was observed through a competitive HAA reaction pathway.  Taking advantage of this side reaction with 18, a substrate control strategy was used to preferentially form the HAA product over the HA product (Scheme 1.13).  With 7-carbon chain aminoalkene substrates, complex 18 exclusively affords the more favoured 6-membered ring HAA product, while the 7-membered HA product is not observed.    27  Scheme 1.13 Accessing Ti-catalyzed intramolecular hydroaminoalkylation through substrate control221    In the same year, the first bis(amido)bis(pyridonate)zirconium complex (19) for intramolecular HAA was revealed.94 This system displays dual reactivity towards both HAA and hydroamination.  Isolation of a catalytically active bridging titanaziridine HAA intermediate in a related bis(amidate) titanium system led to the proposal that these catalysts operate through a different pathway than group 5 HAA catalysts (Scheme 1.14).  The proposed mechanism is in a competing equilibrium with the hydroamination mechanism through the formation of a common metal-imido intermediate.  It is proposed that formation of bridging imido dimers is the key catalytically active intermediate in the HAA mechanism, where as monomeric metal-imido species leads to hydroamination.   NH2 1. 5 mol% Ti(NMe2)4toluene, 160 °C, 72 h2. TsCl, pyridine0-25 °C, 20 hNHTs HN+HAA HAYield: 46% Not Observed  28  Scheme 1.14 Proposed mechanism for intramolecular hydroaminoalkylation with complex 19    This proposed mechanism has been corroborated experimentally where an increase in catalyst loading increases the ratio of HAA product observed relative to the HA product.  In addition, secondary amines are unreactive with this zirconium system and lends support to a catalytically active metal-imido intermediate, which undergoes C-H activation to yield a bridging metallaziridine.  As mentioned earlier, this catalytically active intermediate has been isolated [M]NMe2NMe24 HNMe2C-H activation2H2N2[M]N[M] 2bridging imido[M]N[M] NH metallaziridine[M]N[M] NHinsertionH2NNH2N[M]monomeric imido for hydroamination2  29 previously, formed from an analogous bis(amidate)Ti complex.  Insertion of the alkene gives an expanded metallocycle and the release of product occurs with an incoming equivalent of the aminoalkene substrate to reform the bridging imido intermediate.  A number of Ti catalysts have since followed and been investigated for HAA (Figure 1.8).221-229    Figure 1.8 Select examples of group 4 metal-based complexes for catalytic hydroaminoalkylation89, 94, 221, 223-225, 227, 229   Unlike the preceding systems discussed above, complex 21 is the first Ti complex to exhibit chemoselectivity for intramolecular HAA over hydroamination and does not rely on substrate control for such selectivity.89 In particular, intramolecular HAA of 6-carbon chain aminoalkene substrates yields the five-membered ring HAA product over the formation of the 6-membered ring HA product (Scheme 1.13).  The substrate scope investigations for this catalyst Ti(NMe2)418Doye, 200919Schafer, 200921Schafer, 201320Doye, 2012NOPhZr(NMe2)22 SOON NTi Ti(NMe2)3(Me2N)3Ph PhNNTi(NMe2)2HNPhPh23Doye, 20147Doye, 2010NNTi(NMe2)22NOPhTi(NMe2)22Me22Doye, 2013NNTi(NMe2)32iPriPriPriPr24Doye, 2015Ti CH3CH3  30 system showed for cyclopentylamine products, diastereoselectivity (up to 10:1) for cis diastereomers were observed.  In contrast, for the formation of cyclohexylamine and 1-aminoindane products, diastereoselectivity for the trans diastereomers was attained (up to 19:1).  No reactivity was observed with secondary aminoalkene substrates, suggesting that a metal-imido intermediate is catalytically active, which is consistent with the mechanism proposed for bis(pyridonate)Zr complex 19.73  Scheme 1.15 Ti catalyzed chemoselective intramolecular hydroaminoalkylation89    While intramolecular HAA of aminoalkene substrates is in competition with hydroamination, intermolecular HAA catalyzed by group 4 metals do not share this challenge.  This is because Ti catalyzed intermolecular hydroamination of alkenes is not yet known.  Complexes 7, 18, 20, and 22-24, as well as TiBn4 are reported intermolecular precatalysts for secondary amines and alkenes.  In general, the branched regioisomer is exclusively formed through Ti catalyzed HAA, but studies with 23 show preferential formation of linear regioisomer with select styrene substrates with up to 2:98 branched: linear regioselectivity (Scheme 1.16).227 2 x 10 mol% 21toluene, 110 °C, 48 h+HAA HAH2NRRH2NRRHNRR  31  Scheme 1.16 Ti catalyzed regioselective formation of linear hydroaminoalkylation product227   As noted above, both group 4 and group 5 metal based systems are effective for this transformation; however, these two classes of catalysts differ in a few ways.67 Features which are exclusive to group 4 metal-based systems include intramolecular HAA89, 94, 221-222, 228 and access to both linear and branched regioisomers, 188-190, 192 albeit with persistent difficulties in controlling regioselectivity. However, in intramolecular catalysis, hydroamination is a competing reaction pathway and exclusive chemoselectivity is a challenge.  While neither intramolecular HAA nor regioselectivity for the linear isomer has been achieved yet with group 5 metal-based systems, the substrate scope for intermolecular HAA has greater breadth.95-96, 100 In addition, progress towards asymmetric HAA has been made, which is a potentially powerful strategy for accessing β-chiral amines.95, 213-216  HN+10 mol% 23n-hexane140 °C, 96 hHN RRHN+ RHN74% [9:91]Yield [branced:linear ratio]:69% [2:98]HNCF3HN81% [6:94]67% [11:89 ]HNOHN77% [6:94]HN42% [33:67]  32  While there have been significant advances in hydroaminoalkylation catalyst development, there are certain limitations with both group 4 and group 5 metal systems that can be improved upon. This reaction is still has a limited substrate scope (mainly terminal alkenes and N-methyl anilines), long reaction times, and high reaction temperatures. Therefore, a general catalyst with an extensive substrate scope that is effective and efficient at lower reaction temperatures is highly preferred.  Also, as the reaction can result in the generation of a stereocenter, a general catalyst that can induce excellent enantioselectivity for a wide range of substrates is also desired.   1.4 Scope of Thesis  The research presented in this thesis is unified by the exploration of N,O-chelating ligands on early transition metals for catalytic amine synthesis.  In particular, all developments presented herein describe the synthesis of α-substituted amines through catalytic hydroamination, coupled with asymmetric transfer hydrogenation, (Chapter 2) and hydroaminoalkylation (Chapters 3 and 4).  Both of these transformations are atom-economic routes into substituted amine compounds, which are biologically relevant.  Aspects of catalyst development are presented herein (Chapters 3 and 4), in addition to the development of synthetic applications of previously studied catalysts in the Schafer group (Chapter 2).  Chapter 2 is focused on the preparation of enantioenriched N-heterocycles through hydroamination and asymmetric transfer hydrogenation.  From aminoalkyne substrates, a bis(amidate)bis(amido)Ti precatalyst previously established in the Schafer group has been used to yield a cyclic imine, which can subsequently reduced using commercially available RuCl [(S,S)-Ts-DPEN] (η6-p-cymene).  The synthetic route outlined in this chapter is, to the best of   33 our knowledge, the only catalytic route into enantioenriched 3-substituted morpholines, starting from prochiral materials.  This one-pot protocol featuring sequential catalysis, generates 3-substituted morpholine products in good yields and excellent enantioselectivities.  Further extension of this method to include other N-heterocycles and disubstituted morpholines is also described. A mechanistic proposal is presented in light of these investigations, which reveals the importance of hydrogen bonding interactions between the substrate and the Ru catalyst in asymmetric transfer hydrogenation for enantioselectivity observed in the N-heterocyclic product.  The research program in the Schafer group is centered around the development of early transition metals with N,O-chelating ligands for catalysis.  However, the ligand systems studied extensively by past group members were N-C-O motifs, including amidates, pyridonates, and ureates.  Chapter 3 describes the extension of this research program through investigations regarding phosphoramidates as potential ligand scaffolds.  Phosphoramidate ligands offer different steric and electronic parameters than previously investigated N,O-chelates in the Schafer group.  Phosphoramidate-Ta complexes were synthesized and examined as potential catalysts in hydroaminoalkylation.  During the course of this research, a highly reactive phosphoramidate-Ta complex was discovered, which displays the only catalytic room temperature reactivity towards hydroaminoalkylation to date.    As an extension of the work presented in Chapter 3, a series of enantioenriched phosphoramidate-Ta complexes were prepared in Chapter 4.  These complexes were studied for catalytic activity towards asymmetric hydroaminoalkylation.  The α-alkylation of amines with alkenes results in the generation of a new stereocenter in the alkylated amine product and good enantiocontrol remains a persistent challenge in the field, with only select examples reported in the literature.  To date there is no system that can deliver consistently high enantioselectivity   34 over a wide range of substrates.  A number of catalytically active enantioenriched phosphoramidate-Ta complexes have been prepared and investigated in hydroaminoalkylation. Their efficacy towards asymmetric induction is presented in this chapter for this new transformation.  This thesis highlights the use of N,O-chelating ligands on Ti and Ta for the catalytic and atom economic synthesis of α-substituted amines.  All major research findings and insights are summarized in Chapter 5, in addition to potential future directions arising from these projects.           35 Chapter 2: Catalytic Asymmetric Synthesis of C-Substituted Morpholines and Piperazines 2.1 Introduction  Substituted N-heterocycles are prevalent structural motifs found in biologically relevant molecules.230-231 A recent report by Njardarson showed that 21% of all U.S. FDA approved small molecule pharmaceuticals contained 6-membered saturated N-heterocycles with an additional heteroatom, such as morpholines and piperazines.232-233 Therefore, new routes to access selectively substituted morpholines and piperazines are of particular interest. However, a persistent challenge is accessing these molecules diastereoselectively or enantioselectively from prochiral substrates.    Scheme 2.1 Intramolecular Alkyne and Alkene Hydroamination  Hydroamination is a powerful atom economic tool for making new C-N bonds through the addition of an N-H bond across a C-C unsaturation (Scheme 2.1).57, 234 A broad range of catalysts, including late and early transition metals, alkali earth and rare earth metals, Brønsted RNH2A. Alkyne Hydroamination:B. Alkene Hydroamination:R NH2catalystNHR +NHRncatalystNHR +NHRnnnnn  36 and Lewis acids, and Brønsted bases, can mediate this reaction.235-251 Hydroamination catalyst development efforts typically access a number of N-heterocycles such as piperidines, pyrrolidines, tetrahydroisoquinolines, indoles, and pyrroles; however, promising catalyst systems have rarely been explored for their potential application in the synthesis of N-heterocycles with an additional heteroatom.252 In this Chapter, the utility of hydroamination as a strategy to construct these privileged structures is described.  2.1.1  Hydroamination for the Diastereoselective Synthesis of Piperazines and Morpholines  In 2008, Cochran and Michael reported the cyclization of an aminoalkene substrate to yield 2,6-disubstituted piperazines in a diastereoselective fashion through the use of Pd precatalyst 25 (Scheme 2.2).253   Scheme 2.2 Diastereoselective synthesis of piperazines and morpholines by Pd-catalyzed hydroamination253-254 ONHCbzNOCbz5 mol% 2510 mol% AgBF4MgSO4CH2Cl2, r.t., 20 hYield: 28-99%up to >20:1 drR1 = H, Me, Et, nBu, c-Hex, Ph, BnR1 R1NNHCbzNNCbz10 mol% AgBF4CH2Cl2, r.t., 20 hR1 R1PdNPPh2PPh2Cl5 mol%R2 R2Yield: 88-98%up to >20:1 drR1 = H, Me,  iPr, iBu, Ph, BnR2 = Ts, 2-Nos, TFACl25  37 These aminoalkene substrates are synthesized from allylic amines and enantiopure aminoalcohols.  The reaction occurs to give the trans diastereomer selectively due to a preferred configuration to reduce steric interactions in the intramolecular cyclization step.    Figure 2.1 Mechanistic rationale for trans diastereoselectivity in piperazine synthesis via Pd-catalyzed hydroamination   The same Pd catalyst was also shown to be effective for the diastereoselective synthesis of 2,5-disubstituted and 2,3,5-trisubstituted morpholines (Scheme 2.2).254 The aminoalkene substrates were accessed via Lewis acid catalyzed ring opening of enantioenriched carbamate protected aziridines by nucleophilic attack with allyl alcohols.  Intramolecular hydroamination using 5 mol% of 25, 10 mol% of AgBF4, and 1 equivalent of MgSO4 yielded the trans disubstituted morpholine products in high yields with excellent diastereoselectivities.  Similarly, the trisubstituted morpholines were also synthesized as a single diastereomer.  Although the trans isomer is not the thermodynamically favoured product, it is selectively formed due to the TsNNHRCbzTsNNHRCbzTsNNRCbz[Pd] [Pd]Me TsNNRCbzMetransFavouredcisDisfavoured  38 reduction of steric interactions for the intramolecular cyclization step, similar to the aforementioned piperazine case.  Following the original work of Cochran and Michael, Dr. Andrey Borzenko, a previous Ph.D. student in the Schafer group, investigated the potential of our early transition metal hydroamination catalysts for the preparation of piperazines and morpholines.197-198 The previous examples highlighted the utility of hydroamination as a strategy in the synthesis of piperazine and morpholines; however, late transition metals are known to be more functional group tolerant than early transition metals and the compatibility of our catalysts with the heteroatoms in the backbone of these substrates was unexplored.  Other desired improvements included the preparation of these targets while minimizing steps and the use of protecting groups, as well as avoiding the use of enantioenriched starting materials. 		Using bis(amidate)bis(amido) titanium complex as a precatalyst (9), the reactive aldimine product formed from the reaction of phenyl acetylene and an aryl substituted primary amine can be treated with TMSCN in a modified Strecker reaction to access amino acid products.197-198 Alternatively, the intermediate α-aminonitrile accessed upon TMSCN addition can be allylated to give TMS-protected α-aminonitriles in one pot (Scheme 2.3, Route A). Subsequent reduction of the nitrile group using LiAlH4 provided access to a primary aminoalkene, which could then be cyclized via intramolecular hydroamination using the Zr-ureate precatalyst 26.71 Gratifyingly, this cyclization step is diastereoselective with 26 and only yields the cis diastereomer, as confirmed by 1H-NMR spectroscopy and GC-MS analysis. From commercially available prochiral starting materials, the 2,5-substituted piperazine products accessed are isolated in 70-82% overall yield, as calculated using the initial alkyne as the limiting reagent.  This is achieved in 5 steps and with 3 purifications, without the need for protecting groups.    39   Scheme 2.3 Diastereoselective synthesis of 2,5-disubstituted piperazines by Ti and Zr-catalyzed hydroamination197   N-Benzylhydryl substituted piperazines are common structural motifs found in medicinal chemistry,230, 255-259 but efforts to extend the substrate scope of our synthetic route to include ZrONNNMe2NMe2NHMe2ONN26Ph +i. 5 mol% 9 C6H6, 65 °C, 8 hii.  TMSCNiii.NaF, 15-crown-523 °C, 48 hNCNPhLiAlH4, Et2O0 °C to 23 °C12 hNArPhH2N10 mol% 26toluene, 110 °CBrNHNArPhArOverall Yield: 70-82%Route A:Ar NH2R + NCNRLiAlH4, Et2O0 °C to 23 °C12 hNPhRH2N10 mol% 26toluene, 110 °CNHNPhRPhR = Ph, nBu, (CH2)3OTBDMSOverall Yield: 70-82%Route B:NH2i. 5 mol% 9 C6H6, 65 °C, 8 hii.  TMSCNiii.  Ph2CHBrNaF, 15-crown-590 °C, 10 hPhPhPh  40 these molecules were unsuccessful.197 In particular, the increased steric bulk of the benzylhydryl substituted amine compared to the benzyl-substituted amine hinders alkylation with allylbromide in the one pot synthesis of the α-aminonitrile intermediate.  To circumvent this challenge, we modified our approach by using allyl amine in place of benzyl amine in the initial hydroamination step (Scheme 2.3, Route B).  Installation of a nitrile group with TMSCN was followed by nucleophilic substitution with benzylhydryl bromide to access the desired N-benzylhydryl substituted α-aminonitrile.   While the overall yields of the resulting piperazine products (23-29%) are lower than in the N-benzyl protected piperazine case due to the benzylhydryl installation step, the intramolecular hydroamination ring closure step is still effective and diastereoselective for the cis product, even with the introduction of the large benzhydryl substituent onto the aminoalkene substrate.  The 2,5-dialkylated piperazines synthesized in the routes described above were subsequently investigated as potential N-type calcium channel blockers in pain management applications.198  Attempts to extend the substrate scope of this method to diastereoselectively access 2,5-substituted morpholines were successful, albeit low yielding, which was attributed to the incompatibility of the oxygen containing substrates with 26.  While this route is limited to the preparation of 2,5-piperazines diastereoselectivity, there are opportunities for further catalyst development to arrive at these compounds enantioselectively, particularly if resolution can occur at the ring closure step of this sequence as Hultzsch and coworkers have achieved with a variety of other N-heterocycles such as pyrrolidines, piperdines, and azapanes.119, 260-261 Other possible avenues of investigation include the use of catalytically prepared substituted allylamines to access other substitutions incorporated into the ring.262-266    41 2.1.2 Synthesis of Enantioenriched C-Substituted Morpholines  The synthesis of enantiopure C-substituted morpholines is of interest in contemporary organic chemistry.231, 267 These structural motifs are prevalent in biologically relevant compounds and are garnering much research effort in the synthetic community as potential pharmaceuticals.   Traditional synthetic approaches to enantiopure, substituted morpholines generally employ a stepwise synthetic strategy from enantioenriched starting materials derived from naturally occurring chiral amino acids (Scheme 2.4).268-279 These syntheses are not catalytic, leading to stoichiometric amounts of byproducts and waste.  In addition, the reliance on enantiopure starting materials poses a limitation on the morpholine products that can be accessed cost-effectively by these routes.268, 280-282   Scheme 2.4 Recent synthetic strategies for preparation of enantiopure 3-substituted morpholines273, 283   OHNH2+1.  K2CO3, THF/H2O,-10 °C, 1 h2.  tBuOK, iPrOH/CH2Cl2, r.t., 1 h3.  LiAlH4, THF, r.t., 16 hNHOTripathi, 2015Langgaard, 2010RClClO RN SS OONOTBS3 stepsN SS OONONHORROHOHSR = Me, Et, vinyl, cyclopropyl, Ph,4-MeO-PhYields = 57-81%LiOH, DMSOr.t., 5-30 minutesR= Me, Et, cyclopentylYields: 72-90%  42  Prochiral substrates can be used to construct C-substituted morpholine products in both a diastereoselective and enantioselective fashion (Scheme 2.5).  In addition to the hydroamination strategies discussed above,197, 254 Bode and co-workers have recently reported the diastereoselective preparation of disubstituted morpholines and piperazines from easily synthesized SnAP reagents and commercially available aldehydes (d.r. 20:1).284 Enantioenriched 2-substituted morpholines with moderate ee values (up to 61%) can also be realized through Pd-catalyzed allylic substitution reactions.285    Scheme 2.5 Enantioselective synthesis of substituted morpholines from prochiral substrates  2.1.3 Scope of Chapter  In this chapter, a synthetic strategy into enantioenriched C-substituted morpholines is described. These structural motifs are accessed in high yield and excellent enantioselectivities through a one-pot procedure employing catalytic hydroamination and asymmetric transfer hydrogenation sequentially.  Synthesis and general substrate scope of the aminoalkyne substrates ONH2SnBu3+O NPhOH 10 mol% Cu(OTf)2 10 mol% (±)-PhBoxHFIP, r.t., 20 h NHOO NBode, 2015OHNHTs+NTsO5 mol% Pd2(dba)3.CHCl310 mol% (R)-BINAPTHF, 40 °C, 14 hPhHayashi, 1993Yield: 72%ee: 61 %Yield: 82%d.r. 20:1OAcAcO  43 used is presented, in addition to control experiments to elucidate mechanistic insights.  Extension of this method to include other N-heterocycles, such as tosyl-protected piperazines, thiomorpholines, and piperdines, led to the development of a mechanistic proposal used to describe the enantioselectivities observed.  In this proposal, the heteroatom in the backbone of the cyclic imine generated from hydroamination plays an important role in the subsequent asymmetric transfer hydrogenation reaction.  This mechanistic understanding informed the rationalization that benzyl-protected piperazines could be synthesized with good enantiomeric excesses, which was corroborated experimentally.  Further investigations utilizing sequential hydroamination and asymmetric transfer hydrogenation for the diastereoselective synthesis of disubstituted morpholines are also presented.  2.2 Results and Discussion 2.2.1 Synthesis of Aminoalkyne Substrates  The aminoalkyne substrates used were easily prepared through a modular three step synthetic route using modified literature procedures (Scheme 2.6).     44   Scheme 2.6 General synthetic route to aminoalkyne substrates    BOC-protected ethanolamine and a propargyl bromide substrate react under modified Williamson ether synthesis conditions to yield the corresponding ether.286 For alkyl substituted propargyl bromides (R = Et, CH2CH2OBn, t-Bu, c-hex), elevated temperatures are required for the reaction to progress; however, when propargyl bromide  (R = H) is used as a reagent, the reaction proceeds smoothly at room temperature to give protected terminal aminoalkyne 27 (yield = 79%) and 28-31 (R = alkyl, yields: 69-81%).  The preparation of aryl substituted aminoalkyne substrates (32-38, yields: 34-91%) was easily achieved using Sonagashira cross-coupling conditions starting from tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (27).287 Protected aminoethers can also undergo BOC deprotection using acidic conditions to give the requisite primary aminoalkyne substrates (39-51, yields: 51%-quantitative). 27, ArX, 5 mol% CuI,1 mol% Pd(PPh3)2Cl2NEt3,18 hX = I       65 °CX = Br     100 °CRO NH2ArO NHBoc1.  TFA or HCl, 23 °C, 16 h2.  NaOH(aq)+KOH, NaI, Bu4NITHF, 23 °C or reflux, 24 h RO NHBoc32-2839-511.  27-31, TFA or HCl   23 °C, 16 h2.  NaOH(aq)27 (R = H),  28-31 (R = alkyl)RBrBocHN OHYields:  69-81%Yields:  37-91%Yields:  51%-quantitative  45 While the preparation of aminoalkyne substrates using the above synthetic route was generally successful, it was met with some challenges.  Attempted synthesis of the propargyl bromide precursor of 52 from the corresponding propargyl alcohol resulted in the loss of the TBDMS group, as determined by GC-MS (Figure 2.2, A).  Sonagashira cross coupling of electron-rich (53-54) or sterically bulky halide coupling partners (55-56) were low yielding and were not pursued for catalysis (Figure 2.2, B).  One of the major issues in substrate preparation was the BOC-deprotection of the aminoalkyne substrates.  For compounds 57-64, deprotection with 4 M HCl in dioxane and TFA resulted in intractable mixtures of products (Figure 2.2, C).  Mild reaction conditions for deprotection (as noted in the literature) were attempted, including strategies mediated by ceric ammonium nitrate,288 fluorinated alcohols,289 and aqueous phosphoric acid,290 but no notable improvements were observed.        46  Figure 2.2 Attempted syntheses of aminoalkyne substrates    HO NHBocArX, 5 mol% CuI1 mol% Pd(PPh3)2Cl2NEt3,18 hX = I       65 °CX = Br     100 °CArO NHBocOOBr53NINHHN OOBr5554Br5627HO OTBDMS4A.PPh3, CBr4DCM, 0 °C, 0.5 hBr OTBDMS4B.C.RO NHBocRO NH21.  TFA or HCl, 23 °C, 16 h2.  NaOH(aq)ArX:57-64NHBocOS57NHBocOONHBocONSO ONHBocO58 5960NHBocOONHBocOtBuOO61 62NHBocO63NHBocO64  47 2.2.2 Substrate Scope  With the aminoalkyne substrates in hand, tandem hydroamination and asymmetric transfer hydrogenation was attempted in efforts to access enantioenriched 3-substituted morpholines.  This work was conducted in collaboration with post-doctoral researcher Dr. Huimin Zhai, who established the synthetic protocol and conducted initial substrate scope investigations (66-67, 69, 71, 73-76, 82-84).   Optimization of reaction conditions demonstrated that this sequence could be executed with 10 mol% of precatalyst 9, followed by 1 mol% of commercially available Noyori’s catalyst, (RuCl [(S,S)-Ts-DPEN] (η6-p-cymene), 65). Acid-base extraction yielded the desired morpholine products with good purity and further purification by column chromatography was generally unnecessary.  Good yields and excellent enantioselectivities were obtained with morpholine products containing variously substituted aromatic ring systems (Figure 2.3, 66-72).  Both Ti and Ru catalysts are tolerant to electron donating substituents (70) and electron withdrawing substituents (67-69) on the aromatic ring.  Arylbromide functionalities are permitted (67) and the product retains an important functional group amenable to further synthetic manipulations such as cross-coupling.291-298 Nitrogen containing heteroaromatic systems such as pyridine (71) are also tolerated.     48  Figure 2.3 Synthesis of 3-substituted morpholines by tandem hydroamination and asymmetric transfer hydrogenation    RO NH2NHORi. 10 mol% 9   toluene, 110 °C, 14 hii. 1 mol% 65, DMF    HCO2H/NEt3 (5:2)     23 °C, 16 h39-51 66-77NHONHONHONHOBr F3C FFFFFNHONHONNHONHOYield:aee:b6678%98%6780%97%O6852%98%6977%98%7057%94%71 7272%93%73NHONHONHONHO7478%97%c75 7674%74% c7751%95%c66%d99%65%c,e97%BnO79%97%Reaction Conditions:  Precatalyst 9 (10 mol %), the aminoalkyne (0.25~0.4 mmol) dissolved in anhydrous toluene (0.5 mL) in a Schlenk tube.  After hydroamination was complete, precatalyst 65 (1 mol %) in dry DMF (0.1 mL) was added followed by a 5:2 mixture of formic acid/triethylamine (0.1 mL).  aIsolated yield. bDetermined by supercritical fluid chromatography. cDetermined by supercritical fluid chromatography after derivitization with tosyl chloride. dIsolated yield after flash chromatography. eIsolated by derivatization into oxalate salt (vide infra).  49 Gratifyingly, good yields and high enantioselectivities were also obtained with aminoalkyne substrates containing alkyl groups (73-77).  Imines with minimal steric bulk, such as those substituted with simple methyl and n-propyl substituents yielding products 73 and 74 are reduced with good enantioselectivities.  Despite the oxophilic nature of Ti, protected alcohols are well tolerated by both Ti and Ru systems, as exemplified by 75.  Notably, the substrate bearing a t-butyl group afforded 76 in 74% yield with only 74% ee. This lowered enantioselectivity is attributed to the increased steric bulk of the t-butyl group interfering with the transfer hydrogenation step of the synthetic sequence (vide infra).  As illustrated in Table 2, the use of commerically available RuCl [(S,S)-Ts-DPEN] (η6-p-cymene) for asymmetric transfer hydrogenation with the cyclic imines generated by hydroamination affords enantioenriched 3-substituted morpholine products.  For product 65, the corresponding (S)-enantiomer (78) can be synthesized through the use of commercially available RuCl [(R,R)-Ts-DPEN] (η6-p-cymene) (79) with comparable yields and enantioselectivies as the   (S,S) Ru catalyst (Scheme 2.7).  The optical rotation of the resulting product matches that which was previously reported in the literature.299    Scheme 2.7 Synthesis of (S)-3-benzylmorpholine (78)  NHO78i.10 mol% 9  toluene, 110 °C, 14 hii. 1 mol% 79, DMF    HCO2H/NEt3 (5:2)     23 °C, 16 hPhO NH232Yield: 80%ee: 98%  50  Furthermore, this synthetic protocol for the enantioselective synthesis of morpholines is also amenable to gram scale synthesis.  Starting from 1 g of aminoalkyne 32, (R)-3-benzylmorpholine (66) can be synthesized.  Purification through simple acid-base extraction yields the desired product in 72% yield with 95% ee, which is comparable to the results obtained on smaller scale as presented in Figure 2.3.  No further purification by column chromatography or recrystallization was required.    Scheme 2.8 Gram scale synthesis of (R)-3-benzylmorpholine   During the exploration of the substrate scope of this method, an aminoalkyne substrate containing a nitrile group was synthesized (80, Scheme 2.9).  Nitrile groups are versatile functionalities that can undergo a variety of further synthetic transformations.300-301 There are many examples of late transition metal hydroamination catalysts that display functional group tolerance towards nitrile groups, but examples of such functional group tolerance with early transition metal catalysts are noticeably lacking in the literature.145, 175, 302-314   PhO NH2NHOYield:  72%ee:  95%32 661 grami.10 mol% 9  toluene, 110 °C, 14 hii. 1 mol% 65, DMF    HCO2H/NEt3 (5:2)     23 °C, 16 h  51  Scheme 2.9 Synthesis of nitrile containing morpholine product (81)   Hydroamination of 80 occurred successfully to yield the corresponding cyclic imine, which was subsequently reduced with sodium borohydride to afford the racemic morpholine product 81 in good yield (78%) and purity.  While the racemic morpholine was successfully isolated, reduction of the cyclic imine with RuCl [(S,S)-Ts-DPEN] (η6-p-cymene) failed to yield the analogous enantiomerically enriched morpholine product.  This demonstrates that the titanium hydroamination catalyst is tolerant to the nitrile functionality and C-N unsaturations; however, the nitrile group interferes with the asymmetric transfer hydrogenation, as an intractable mixture of products is obtained after this step of the sequence.  2.2.3 Probing Mechanism  A wide range of substrates is compatible with our tandem sequential catalysis method to form 3-substituted morpholines with excellent enantioselectivies (Figure 2.3).  Most importantly, this protocol does not demand aromatic substituents or sterically demanding substrates in contrast to all previous reports that require aromatic substituents to access such excellent enantioselectivities.315-317 One hypothesis for the excellent enantioselectivies in our case could be that the residual Lewis acidic titanium species remaining after the hydroamination step has an advantageous effect on the asymmetric transfer hydrogenation (ATH) reaction.  As a control O NH2 i. 10 mol% 9, toluene   110 °C, 14 hii. NaBH4, MeOH, 23 °C, 7 h NHOYield:  78%NCNC80 81  52 experiment, the volatile aminoalkyne 27 was selected to probe the role of the residual titanium catalyst on the subsequent ATH reaction (Scheme 2.10).  The toluene solvent and the intermediate imine formed upon hydroamination could be vacuum transferred into a clean reaction vessel.    Complex 9 and all other reagents for ATH were then added and upon reaction completion 73 was obtained in 90% ee (average over triplicate) in contrast to the one-pot procedure where 73 was yielded with 97% ee  (Table 1, entry 5), indicating that indeed the presence of the titanium catalyst has a subtle, but notable impact.318 Note that the intrinsic error for ee determination from integration of peak areas of supercritical fluid chromatograms is estimated to be <3%.318   Scheme 2.10 Asymmetric transfer hydrogenation of 73 in the absence of [Ti]    Next, the use of additives in the second step of the reaction in Scheme 2.10 was examined, in an effort to restore the enantioselectivity to the 97% ee observed in the one-pot process.  First, the sequence shown in Scheme 2.10 was carried out, followed by addition of titanium complex 9 into the ATH reaction (a step-wise reaction rather than a one-pot reaction).  Interestingly, the observed ee was raised from 90% ee to 94% ee, but was less than the one-pot reaction. To test if this effect was due to the Lewis acidic character of residual [Ti] species, Ti(NMe2)4 was used as an additive and a similar ee value was achieved.  This effect was not limited to titanium, as the addition of Zr(NMe2)4 also increased the enantiomeric excess to 94%.    OH2N10 mol% 9toluene, 110 °C14 h NOvacuum transfer of imine and tolueneNH1 mol% 65, DMFHCO2H/NEt3 (5:2) 23 °C, 16 hO27 73ee:  90%  53       Table 2.1 Asymmetric transfer hydrogenation to yield 73 in the absence of [Ti]   OH2N10 mol% 9toluene, 110 °C14 h NOvacuum transfer of imine and tolueneNH1 mol% 65, DMFHCO2H/NEt3 (5:2) 23 °C, 16 hO27 73+ Additivea Determined by supercritical fluid chromatography after derivitization with tosyl chloride.  b Experiments performed in duplicate and ee value presented are the average of the two runs.Entry Additive mol loading (%) ee (%)a,b1 9 10% 94%2 Ti(NMe2)4 10% 94%3 Zr(NMe2)4 10% 93%4 AgOTf 10% 71%5NHO20% 93%6 HNEt2 20% 95%  54 However, when the late transition metal Lewis acid AgOTf was used, a dramatic decline in ee to 71% was observed, suggesting that perhaps the slight restoration in ee is not a Lewis acid effect, but rather an amine or amide ligand effect arising from use of precatalyst 9.  Interestingly, the addition of 20 mol% of just proligand resulted in an increase in ee to 93%, with the addition of a simple amine additive also raising the ees to 95%.  The compilation of these data highlight that hydrogen bonding interactions alone affect the ees of ATH and the presence of added metal is not required.  However, the combination of the residual Ti catalyst mixture that remains in the reaction mixture during the one-pot protocol cannot be duplicated through the use of precatalyst, proligand, or other Lewis acidic additives alone.  Efforts to characterize the decomposition products present due to the residual Ti catalyst mixture have not been successful.  2.2.4 Mechanistic Proposal  The proposed mechanism of asymmetric transfer hydrogenation of carbonyl substrates postulates a concerted cyclic six-membered transition state, where hydride and proton transfer from the catalyst to the substrate occurs without pre-coordination of the substrate to the metal center.317, 319-326 A more recent DFT investigation concludes that this proposed pericyclic transition state is only applicable to gas-phase calculations, and that in solution the reaction is a two-step process where transfer of the hydride from the Ru catalyst occurs followed by a proton transfer from either the solvent or the TsDPEN ligand.327   Experimental and computational investigations into the mechanism of ATH for imines suggest that these substrates undergo reduction via a different reaction pathway. Acidic activation of the imine by either a Brønsted or Lewis acid is required for these reactions to proceed.328-329 Gas phase calculations by Kačer and co-workers show that the imine substrates   55 are protonated by formic acid that is present under catalytic reaction conditions and the substrate that can interact with the oxygen atoms of the sulfonyl group through hydrogen bonding to stabilize the transition state.317, 330 Other significant effects include C-H/π interactions between the substrate and the η6-arene ring of the Ru catalyst, which can lower the overall energy of the transition state by up to 12.3 kJ/mol.321 This rationalizes how substrates with aromatic rings adjacent to the C=N bond are known to give high ees with the Noyori-Ikariya catalyst.  However, in our studies, excellent enantioselectivities are achieved even with non-sterically demanding alkyl substituted imines that cannot access the crucial C-H/π interactions discussed above.  In the case of morpholine, the presence of O in the ring could engage in critical hydrogen-bonding interactions.   Inspired by the computational work presented by Kačer and co-workers, the mechanistic rationale proposed is shown in Scheme 2.11.     56  Scheme 2.11 Proposed mechanistic rationale for asymmetric transfer hydrogenation invoking the key role of a heteroatom in favourable H-bonding interactions A highly ordered transition state for the hydrogen transfer process is proposed in which two key hydrogen bonding interactions between the substrate and the chiral ligand are imperative for enantioselectivity:  one between the proton of the iminium moiety and the oxygen atoms of the TsDPEN ligand, the second between the oxygen heteroatom of the imine substrate and the hydrogen atoms of the neutrally bound ethylenediamine ligand.  This simplified proposed RuNNPhPh HHStolOOHRuNNPhPhHHHStolOORuNNPhPh HHStolOOON RHOOHCatalytically Active Hydride ComplexHighly Ordered Transition State Due to Hydrogen BondingOHN HR R-enantiomer is formedHOOCO2NOHRNOHRNOHRH(S,S)-Ru catalyst  57 mechanism focuses on the profound effect of the Noyori-Ikariya catalyst and does not consider the more subtle effect of residual Ti species.317, 330    The substrate is thought to enter the catalytic cycle as an iminium ion due to protonation by the formic acid that is present in the reaction medium. The protonated substrate approaches the catalytically active Ru hydride complex from the side opposite to the chiral ligand, facilitating hydride transfer.  The orientation of the imine substrate for reduction is proposed to occur as depicted in Scheme 2.11 to facilitate 2 key hydrogen bonding interactions.  An alternative approach of the substrate could be envisioned in which the O atom is oriented towards the cymene ligand of 65; however, this creates major steric congestion between the entire ring of the substrate and the ligand and yields the opposite enantiomer than that which is observed experimentally (Figure 2.4).  Therefore, Scheme 2.11 illustrates the relatively less sterically demanding substrate trajectory and gives rise to the possibility of hydrogen bonding between the O atom and the ethylene diamine ligand.  The experimental observation that sterically demanding R groups yield products with reduced ees (76, ee =74%) is consistent with this proposal, as the additional steric bulk on the imine substrate perturbs this approach into the catalyst active site.  Moreover, the predicted stereochemical outcome resulting from this proposed mechanism is in agreement with observed experimental results.  In particular, the (S,S)-Ru catalyst affords the R-enantiomeric product and the (R,R) Ru catalyst yields the corresponding S-enantiomer product.  Therefore, high ees can be achieved for the synthesis of a range of alkyl and aryl-CH2 substituted morpholines without the need for CH/π interactions with the substrate.     58  Figure 2.4 Alternative transition state for asymmetric transfer hydrogenation   The necessity for secondary hydrogen bonding interactions between the oxygen in the backbone of the cyclic imine and the TsDPEN ligand for high enantioselectivities is further corroborated by experimental results when this synthetic strategy is applied to the synthesis of other N-heterocycles  (Table 2.2).   For example, as was shown previously,331 piperidines, with no heteroatom to function as a hydrogen bond acceptor, see dramatic reductions in ees (84).  However, when hydrogen bond acceptor, but slightly larger, thiomorpholines (83, with longer C-S bonds  (1.82 Å) vs. (C-O) (1.46 Å))332 are used, the ees are somewhat restored.  Using the tosyl-protected piperazine (82) the observed ee is only 70%.  In this case, the impeding steric bulk and variable hydrogen-bonding character of the tosyl group may reduce the potential for favorable interactions with the N of the ring.  However, this result suggests that the incorporation of a substituent on N that is neither capable of hydrogen bonding nor sterically demanding should permit the favorable hydrogen-bonding interactions with the ethylene diamine ligand.   To test this hypothesis, the non-hydrogen bonding benzyl protected diaminoalkyne was proposed as a suitable substrate to be used in our one-pot enantioselective protocol.   RuNNPhPhHHHStolOONORH  59 Table 2.2 Synthesis of substituted N-heterocycles by one-pot sequential hydroamination and asymmetric transfer hydrogenation   2.2.5 Enantioselective Synthesis of 3-Substituted Piperazines Aminoalkyne 85 was synthesized starting from reductive amination of BOC-protected ethylene diamine and benzaldehyde,333 followed by the installation of the propargylic functional group through base mediated alkylation conditions to yield 86 (Scheme 2.12).  Removal of the BOC protecting group using 4 M HCl in dioxane yielded substrate 87.  Entry X R- Product Yield (%)a ee (%)b1 O HNHO73 65% >99%c2 NTs HNHTsN82 80% 70%3 S HNHS83 71% 66%4 CH2 Ph NHPh 84 87% 24%cRX NH2NHXRi. 10 mol% 9toluene-d8, 110 °C, 14 hii. 1 mol% 65HCO2H/NEt3 (5:2)aIsolated yield. bDetermined by supercritical fluid chromatography. cDetermined by supercritical fluid chromatography after derivitization with tosyl chloride.73, 82-84  60  Scheme 2.12 Synthesis of aminoalkyne substrate 87  Compound 87 was subjected to general reaction conditions for hydroamination, but complete conversion to the cyclic imine was not observed, suggesting catalyst deactivation by this substrate.  Conversion to the desired cyclic imine can be improved through a second addition of 10 mol% 9 and increased reaction time (Scheme 2.13).  The cyclic imine was reduced using standard ATH reaction conditions to yield (R)-1-benzyl-3-methylpiperazine (88) and derivatized with (R)-(-)-(α)–methoxy-(α)-(trifluoromethyl)phenylacetyl chloride for ee determination by in situ 19F-NMR spectroscopy. 81  Gratifyingly, only one diastereomer was observed, indicating ee of >98%. BocHN NH2 HO+BocHNHNBocHN N1.  MeOH, 4 M HCl in dioxane     23 °C, 16 h2.  NaOH(aq)H2NN1.  MeOH, 23 °C, 16 h2.  NaBH4, 24 h858687Propargyl BromideNaI, Et4NI, EtOAc70 °C, 20 h  61  Scheme 2.13 Synthesis of (R)-1-benzyl-3-methylpiperazine (88)  This strategy may be extended for the preparation of other piperazine compounds with high enantioselectivities. The synthesis of (R)-3-benzyl-1-(3-phenylprop-2-yn-1-yl)piperazine (90) from aminoalkyne (89) successfully yielded the desired piperazine product with a high ee of 96% (Scheme 2.14).  This target compound is amenable to further synthetic manipulations through the pendent alkyne functionality; however, the yield for 90 is low (6%) and the desired product could not be purified as it was inseparable from the starting material.  This is again indicative of catalyst deactivation of 9 by the aminoalkyne substrate.  Nevertheless, these data demonstrate that the scope for ATH of imines is no longer limited to substrates containing aromatic groups as a variety of other imines can be reduced with good enantioselectivities, providing that other stabilizing interactions can be accessed.  This is a powerful extension of ATH to include a variety of new compounds that can be synthesized asymmetrically by this strategy.   87 88i. 10 mol% 9   toluene, 110 °C, 24 hii. 10 mol% 9    toluene, 110 °C, 24 hiii. 1 mol% 65     HCO2H/NEt3 (5:2)H2NBnN NHBnNee : >98%  62  Scheme 2.14 Synthesis of (R)-3-benzyl-1-(3-phenylprop-2-yn-1-yl)piperazine (90)    Further extension of the substrate scope of N-benzyl 2-substituted piperazines was explored. Good ees were obtained for piperazine products 92  (87%) and 94 (81%, Scheme 2.15); however, complete conversion to the desired product was not achieved, even with sequential catalyst loadings.  Interestingly, unlike the morpholine case, the asymmetric reduction to yield the desired piperazine products showed greater variation in enantioselectivies with changes to the R group on the cyclic imine.  Even with a minor increase in steric bulk moving from methyl to ethyl significantly impacts the selectivities observed (88 vs. 94).  These inconsistent ees may arise from the presence of unreacted aminoalkyne present during the asymmetric transfer hydrogenation reaction, as these primary amines may be interfering in detrimental H-bonding interactions.  While the ees of the benzyl protected piperazine products are lower than those achieved with the oxygen containing substrates, they are improved from the tosyl protected piperazine (ee: >98% vs. 70% respectively) highlighting that careful consideration in substrate design for asymmetric transfer hydrogenation can have important implications in enantioselectivities achieved.   NH2N NHNi. 10 mol% 9   toluene, 110 °C, 14 hii. 1 mol% 65, DMF   HCO2H/NEt3 (5:2)    23 °C, 16 h ee : 96%89 90  63  Scheme 2.15 Enantioselective preparation of benzyl protected piperazines  2.2.6 Diastereoselective Synthesis of Disubstituted Morpholines  As an extension of the synthetic method described above, preparation of diastereospecific morpholines were pursued, starting from commercially available amino acids.  Aminoalkyne substrates can be prepared in the same manner as described in Scheme 2.4.  Hydroamination of these aminoalkyne substrates afforded cyclic imines, which were reduced using various reducing agents (Table 2.3).         91 92i. 10 mol% 9   toluene, 110 °C, 24 hii. 10 mol% 9    toluene, 110 °C, 24 hiii. 1 mol% 65     HCO2H/NEt3 (5:2)H2NBnN NHBnN93 94i. 10 mol% 9   toluene, 110 °C, 24 hii. 10 mol% 9    toluene, 110 °C, 24 hiii. 1 mol% 65     HCO2H/NEt3 (5:2)H2NBnN NHBnNee : 87%ee : 81%  64 Table 2.3 Reduction of disubstituted cyclic imines to afford disubstituted morpholines   Hydroamination was observed at room temperature.  Reactions with terminal alkynes are complete within minutes (95 and 96) and an internal alkyne is complete in 3.5 h (97). This is in contrast to the hydroamination of aminoalkyne precursors to monosubstituted N-heterocycles, which, under optimized conditions, require heating at 110 ˚C for 14 h.197 Complete conversion to the cyclic imine was determined by 1H- and 13C-NMR spectroscopy and the corresponding enamine product was not detected.  Entry Aminoalkyne Product NaBH4(S,S)-Ru cat.65(R,R)-Ru cat.791 ONH2Ph95NHOPh98 >20:1b >20:1 >20:12 ONH2Bn96NHOBn99 3:2 6:1 2:13c O NH2Ph97NHOPh(+/-)100 10:1 3:2 3:2i.10 mol% precatalyst 9  d8-toluene, 23 °C,   >10 minutesii. ReductionRatio of Diastereomersa(cis:trans)aDetermined by 1H-NMR spectroscopy and GC-MS. bDetermined by 1D-NOESY NMR spectroscopy.  Diastereomeric ratios of 99 and 100 were assigned by analogy. cReaction time 3.5 h.95-97 98-100  65 Reduction with the stoichiometric reducing agent NaBH4 yields mixtures of diastereomers, with substrate-dependent selectivity.  Unlike the experimental results from the synthesis of 3-substituted morpholines, asymmetric hydrogen transfer catalysts RuCl [(S,S)-Ts-DPEN] (η6-p-cymene) and RuCl [(R,R)-Ts-DPEN] (η6-p-cymene) do not dramatically impact selectivity in the reduction of disubstituted cyclic imines.  Reduction of these imines is substrate controlled and asymmetric hydrogen transfer is not a viable approach to modify diastereoselectivity in the synthesis of 3,5- and 2,5-disubstituted morpholines.  Application of the mechanistic rationale described above suggests that the steric bulk of the extra substituent on the cyclic imine impedes hydrogen-bonding interactions between the substrate and the catalyst, thereby reducing the selectivity of the catalyst.  2.3 Conclusions  An efficient and practical one-pot sequential approach to enantioenriched 3-substituted morpholines through the use of Ti catalyzed hydroamination and Ru catalyzed asymmetric transfer hydrogenation was presented in this Chapter.  This is the only catalytic and enantioselective route to 3-substituted morpholines from prochiral starting materials reported to date.  Precatalysts 9 and 65 are tolerant to a wide range of functional groups and yield morpholine products with good yields and ees of >95% in most cases.   Application of the synthetic strategy to other N-heterocycles indicates that the nature of the secondary heteroatom in the heterocycle has an important impact on the selectivity of the asymmetric transfer hydrogenation step of the sequence.  Tosyl protected piperazines, thiomorpholines, and piperidines all show reduced enantioselectivities (70%, 66%, and 24% respectively) relative to morpholine products.  While mechanistic investigations show that the   66 residual Ti catalyst from hydroamination has a minor influence on the enantioselectivity of the asymmetric transfer hydrogenation reaction, the substrate selection remains the key factor to high ees.   From experimental observations, a mechanistic proposal was derived in which key hydrogen bonding interactions between the imine substrates and the catalytically active Ru species give rise to the resulting high enantioselectivities.  This proposal led to substrate scope extension of this method to include benzyl protected 3-subsituted piperazines.  Good ees were achieved with the piperazine products (>81%), highlighting that good to excellent enantioselectivities can be achieved with new asymmetric transfer hydrogenation imine substrates, providing that secondary hydrogen bonding interactions can be accessed.  An extension of the substrate scope of this method to was made to include disubstituted morpholines.  Commercially available amino acids were used to synthesize aminoalkynes which were readily cyclized with a bis(amidate) titanium precatalyst at room temperature.  Reduction of these cyclic imines afforded the desired morpholine products, where the reductions are substrate controlled and mixtures of diastereomers can therefore result.   2.4 Experimental 2.4.1 Materials and Methods General Methods.  Synthesis of metal complexes and subsequent reactions involving these precatalysts were performed under an inert atmosphere of nitrogen using standard Schlenk line or glove box techniques.  Tetrahydrofuran, diethyl ether, hexanes, and toluene were purified by passage over an activated aluminum oxide column and degassed prior to use.  Dichloromethane was dried over CaH2 and distilled. Toluene-d8 and benzene-d6 were distilled from Na, degassed   67 via three cycles of freeze-pump-thaw, and stored over 4 Å molecular sieves in the glove box.  Solvents for chromatography were used as received from commercial sources and were at lease of ACS reagent grade.   All chemicals were purchased from commercial sources and used as received.  Thin layer chromatography (TLC) was performed on Whatman Partisil K6F UV254 pre-coated TLC plates.  Silica gel F60 (230-400 mesh) was used as purchased from Silicycle. Hydroamination precatalyst 9 was prepared using literature procedure.69, 75 The following compounds were synthesized using known literature procedures and the spectra data were in accordance with those previously published: tert-butyl (2-hydroxyethyl)carbamate,286 tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (27),286 tert-butyl (2-aminoethyl)carbamate,334 tert-butyl (2-(benzylamino)ethyl)carbamate (85),335 3-phenylprop-2-yn-1-ol,336 and (3-bromoprop-1-yn-1-yl)benzene.336-338 Synthesis and characterization of the following compounds were synthesized as described in our previously published report:  tert-butyl (2-((3-phenylprop-2-yn-1-yl)oxy)ethyl)carbamate (32), tert-butyl (2-((3-(4-bromophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (33), tert-butyl (2-((3-(perfluorophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (35), tert-butyl (2-((3-(pyridin-2-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate (37), tert-butyl (2-(pent-2-yn-1-yloxy)ethyl)carbamate (28), tert-butyl (2-((5-(benzyloxy)pent-2-yn-1-yl)oxy)ethyl)carbamate (29), tert-butyl (2-((4,4-dimethylpent-2-yn-1-yl)oxy)ethyl)carbamate (30), (R)-3-benzylmorpholine (66), (R)-3-(4-bromobenzyl)morpholine (67), (R)-3-((perfluorophenyl)methyl)morpholine (69), (R)-3-(pyridin-2-ylmethyl)morpholine (71), (R)-3-methylmorpholine (73), (R)-3-propylmorpholine (74), (R)-3-(3-(benzyloxy)propyl)morpholine (75), (R)-3-neopentylmorpholine (76), (R)-3-methyl-1-tosylpiperazine (82), (R)-3-methylthiomorpholine (83), and (S)-2-benzylpiperidine (84).197   68 Instrumentation.  Proton (1H-NMR) and carbon (13C-NMR) spectra were recorded in deuterochloroform using a Bruker AV-300 or AV-400 MHz spectrometer.  Chemical shifts (δ) are reported in parts per million (ppm) and are referenced to the centerline of the solvent residual peak.339 The samples were measured as solutions in the stated solvent at ambient temperature in non-spinning mode.  To specify signal multiplicity, the following abbreviations are used:  s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet.  A broad resonance is denoted by br.  31P{1H}-NMR and 19F-NMR spectra are referenced to 85% H3PO4 in water and CFCl3 in CDCl3 respectively.  Coupling constants are provided in Hertz (Hz).  NOE-NMR experiments were conducted using a Bruker Avance 600 MHz spectrometer by Dr. Philippa Payne.  GC-MS was acquired from an Agilent 7890A GC system.  Low-resolution mass spectra (LRMS), high resolution mass spectra (HRMS), and elemental analysis was preformed by the mass spectrometry and microanalysis service at the University of British Columbia, Vancouver.  LRMS was recorded on a Bruker Esquire-LC spectrometer and HRMS was recorded on a Waters/Micromass LCT spectrometer. Elemental analyses were performed on a Carlo Erba Elemental Analyzer EA 1108. The content of the specified element is expressed in percent (%).  Optical rotations were recorded with a Perkin-Elmer 241 polarimeter.  The enantiomeric excess values were measured by a Thar SFC method station (Model 840, 120 bar, chiral column temperature of 32-33 °C), 19F-NMR after in situ derivatization with (R)-α-methoxy-α-trifluoromethylphenylacetic acid chloride, or using chiral HPLC measured by an Agilent 1260 Infinity system (Chiralcel OJ-RH column, particle size 5 μm, 4.6 mmΦ x 150 mm).  IR samples were collected neat on NaCl disks using a BOMEM Michelson Series MB-100 FTIR spectrophotometer.    69 2.4.2 Synthesis and Characterization of Compounds tert-Butyl (2-((3-cyclohexylprop-2-yn-1-yl)oxy)ethyl)carbamate (31).  4-Cyclohexylbut-2-yn- 1-ol (0.50 g, 3.6 mmol, synthesized using known literature procedure)340 and triphenylphosphine (1.42 g, 5.40 mmol) were dissolved in CH2Cl2 (50 mL) and the solution was cooled to 0 °C. Carbon tetrabromide (1.89 g, 5.70 mmol) in CH2Cl2 (10 mL) was added dropwise over 5 minutes.  After 15 minutes of stirring at 0 °C, the cold solution was diluted with hexanes (30 mL) and filtered through a plug of silica gel. The solvent was removed by rotary evaporation, followed by a second filtration through a short pad of silica gel with 5% of EtOAc in hexanes to provide (3-bromoprop-1-yn-1-yl)cyclohexane as a pale yellow oil (0.667 g, 92%).  (3-Bromoprop-1-yn-1-yl)cyclohexane is a known compound and spectral data are in agreement with those previously reported:  1H-NMR (300 MHz, CDCl3):  δ 3.85 (d, J = 2.4 Hz, 2H), 2.46-2.40 (m, 1H), 1.83-1.64 (m, 4H), 1.55-1.26 (m, 6H).341 tert-Butyl (2-hydroxyethyl)carbamate (0.458 g, 2.80 mmol)286 and  (3-bromoprop-1-yn-1-yl)cyclohexane (0.630 g, 3.10 mmol) were stirred in THF (10 mL).  Tetrabutylammonium iodide (0.103 g, 0.28 mmol) and sodium iodide (0.042 g, 0.28 mmol) were added, followed by portionwise addition of KOH (0.930 g, 5.60 mmol) over 5 minutes.  The reaction was stirred at room temperature for 72 h.  The solvent was removed in vacuo and the residue was dissolved in H2O (30 mL) and extracted with EtOAc (3 x 30 mL).  The organic extracts were combined, washed with 10% metabisulfite solution (30 mL) and brine, before being dried over NaSO4, filtered, and concentrated.  Purification by column chromatography (10% EtOAc in hexanes) yielded 31 as a pale yellow oil (0.573 g, 73%).  1H-NMR (300 MHz, CDCl3):  δ 4.93 (br s, 1 H), 4.15 (d, J = 3 Hz, 2 H), 3.56 (t, J = 4.8 Hz, 2 H), 3.33 (q, J = 5.4 Hz, 2 H), 2.43-2.37 (m, 1H), 1.84-1.65 (m, 4H), 1.52-1.18 (m, 6H), 1.44 (s, 9H); BocHN O31  70 13C{1H}-NMR (75 MHz, CDCl3):  δ 156.0 (C), 91.6 (C), 79.3 (C), 75.6 (C), 68.8 (CH2), 58.9 (CH2), 40.5 (CH2), 32.7 (CH2), 29.2 (CH), 28.5 (CH3), 25.9 (CH2), 25.0 (CH2); IR (NaCl, cm-1): 3382 (N-H stretch), 2992 (C-H asymmetric stretch), 2856 (C-H symmetric stretch), 1692 (C=O stretch), 1519 (N-H bend); HRMS-ESI (m/z) [M+Na]+ calcd for C16H27NO3Na: 304.1889, Found: 304.1892.  General Procedure A:  Sonagashira Cross Coupling    CuI (5 mol%), tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (5~10 mmol, 1 equiv.) and triethylamine (12 mL) were added into a Schlenk flask under N2. ArX (1.1 equiv.) and Pd(PPh3)2Cl2 (1 mol%) were added and the mixture was heated at 60 °C (X = I) or 100 °C (X = Br) for 16 hours. The solvent was diluted with CH2Cl2 (40 mL) and washed with aqueous HCl (1 M, 2 x 20 mL) and brine.  The organic layer was dried over Na2SO4, filtered, and concentrated under vacuum. The dark residue was purified by flash chromatography (eluent:  15% ethyl acetate in hexanes).     HO NHBoc5 mol% CuI,1 mol% Pd(PPh3)2Cl2NEt3,18 hX = I       65 °CX = Br     100 °CArO NHBoc+   ArX  71 tert-Butyl (2-((3-(4-(trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (34).  Following General Procedure A, the reaction of tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (0.500 g, 2.50 mmol) and 4-iodobenzotrifluoride (0.748 g, 2.80 mmol) afforded the title compound 34 (0.723 g, 91%) as a brown oil.  1H-NMR (300 MHz, CDCl3):  δ 7.58-7.51 (m, 4H), 4.94 (br s, 1H), 4.38 (s, 2H), 3.64 (t, J = 5.1 Hz, 2H), 3.37 (q, J = 5.1 Hz, 2H), 1.43 (s, 9H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 155.8 (C), 131.8 (CH), 130.0 (q, J = 32.4 Hz, C), 126.2 (C), 123.7 (q, J = 270 Hz, C), 125.0 (q, J = 3.3 Hz, CH), 87.4 (C), 84.7 (C), 78.9 (C), 69.0 (CH2), 58.5 (CH2), 40.2 (CH2), 28.1 (CH3); 19F-NMR (282 MHz, CDCl3): δ -63.2; IR (NaCl, cm-1): 3357 (N-H stretch), 2975 (C-H asymmetric stretch), 2971 (C-H symmetric stretch), 1713 (C=O stretch); HRMS-ESI (m/z) [M+Na]+ calcd for C17H20NO3F3Na: 366.1293, Found: 366.1288.  tert-Butyl (2-((3-(3-methoxyphenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (36).  Following General Procedure A, the reaction of tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (1.00 g, 5.00 mmol) and 3-bromoanisole (1.03 g, 5.50 mmol) afforded the title compound 36 (0.560 g, 37%) as a brown oil.  1H-NMR (300 MHz, CDCl3):  δ 7.21 (t,  J= 7.8 Hz, 1H), 7.03 (d, J = 7.5 Hz, 1H), 6.97 (t, J =1.2 Hz, 1H), 6.87 (dd, J = 7.8, 2.1 Hz, 1H), 4.95 (br s, 1 H), 4.37 (s, 2 H), 3.79 (s, 3H), 3.64 (t, J = 5.1 Hz, 2 H), 3.37 (q, J = 5.4 Hz, 2 H), 1.43 (s, 9 H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 159.4 (C), 156.1 (C), 129.5(CH), 124.4 (CH), 123.5 (C), 116.7 (CH), 115.3 (CH), 86.5 (C), 84.7 (C), 79.4 (CH2), 69.3 (CH2), 59.1 (CH2), 55.4 (CH3), 40.5 (CH2), 28.5 (CH3); IR (NaCl, cm-1): 3364 (N-H stretch), 2975 (asymmetric C-H stretch), BocHN O34CF3BocHN O36O  72 2931 (symmetric C-H stretch), 1713 (C=O stretch); HRMS-ESI (m/z) [M+Na]+ calcd for C17H23NO4Na: 328.1525, Found: 328.1523.  tert-Butyl (2-((3-(naphthalen-1-yl)prop-2-yn-1-yl)oxy)ethyl)carbamate (38).  Following General Procedure A, the reaction of tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate (0.500 g, 2.50 mmol) and 4-iodonapthalene (0.699 g, 2.80 mmol) afforded the title compound 38 (0.439 g, 54%) as a light brown oil.  1H-NMR (300 MHz, CDCl3):  δ 8.32 (d, J = 4.2 Hz, 1H), 7.84-7.80 (m, 2H), 7.69 (dd, J = 7.2, 1.2 Hz, 1H), 7.54 (m, 2H), 7.40 (dd, J = 8.1, 6.9 Hz, 1H), 5.09 (br s, 1H), 4.52 (s, 2H), 3.73 (t, J = 5.1 Hz, 2H), 3.42 (q, J = 5.1 Hz, 2H), 1.44 (s, 9H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 156.0 (C), 133.3 (C), 133.1 (C), 130.8 (CH), 129.0 (CH), 128.3(CH), 126.8 (CH), 126.4 (CH), 126.0 (CH), 125.1 (CH), 120.1 (C), 89.7 (C), 84.6 (C), 79.3 (C), 69.2 (CH2), 59.2 (CH2), 40.5 (CH2), 28.4 (CH3); IR (NaCl, cm-1): 3359 (N-H stretch), 3059 (aromatic C-H stretch), 2932 (asymmetric C-H stretch), 1714 (C=O stretch); HRMS-ESI (m/z) [M+Na]+ calcd for C20H23NO3Na: 348.1576, Found: 348.1591.  General Procedure B:  Boc-Deprotection     To a solution of the N-Boc protected amine (1~8 mmol, 1 equiv.) in methanol (15 mL) was added HCl in dioxane (4 M, 2~4.0 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 h and then 14 h at room temperature. The solvent was evaporated and diethyl ether (30 RO NHBocRO NH21.  TFA or HCl, 23 °C, 16 h2.  NaOH(aq)BocHN O38  73 mL) was added.   The solids were filtered and washed with diethyl ether (15 mL).  The solids were dissolved in CH2Cl2 and washed with saturated aqueous NaHCO3 (2 x 30 mL). The aqueous layers were combined and extracted with CH2Cl2 (2 x 15 mL).  The organic layers were combined and washed with brine, dried over Na2SO4, filtered, and concentrated.  The oil was dried over CaH2 and distilled under reduced pressure.  The resulting aminoalkyne was degassed by 3 freeze-pump-thaw cycles and stored over 4 Å molecular sieves in a N2 filled glovebox.  2-((3-(4-(Trifluoromethyl)phenyl)prop-2-yn-1-yl)oxy)ethanamine (41).  Following General Procedure B for Boc-deprotection, 34 (0.476 g, 1.60 mmol) was deprotected to yield 41, as a yellow oil (0.497 g, quantitative). 1H-NMR (300 MHz, CDCl3):  δ 7.43-7.37 (m, 4H), 4.26 (s, 2H), 3.74 (t, J = 5.4 Hz, 2H), 2.77 (t, J = 5.1 Hz, 2H), 1.61 (br s, 2H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 131.8 (CH), 129.8 (q, 2JC-F = 32 Hz, C), 126.3 (C), 124.7 (q, 1JC-F = 271 Hz, C), 125.0 (q, 3JC-F = 3.3 Hz, C), 87.6 (C), 84.6 (C), 72.3 (CH2), 58.6 (CH2), 41.5 (CH2); 19F-NMR (282 MHz, CDCl3): δ -63.4; IR (NaCl, cm-1): 3299 (N-H stretch), 2923 (asymmetric C-H stretch), 2854 (symmetric C-H stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H13NOF3: 244.0949, Found: 244.0950.      H2NO41CF3  74 2-((3-(3-Methoxyphenyl)prop-2-yn-1-yl)oxy)ethanamine (43).  Following General Procedure B, 36 (0.476 g, 1.60 mmol) was deprotected to yield 43, as a yellow oil (0.304 g, 95%). 1H-NMR (300 MHz, CDCl3):  δ 7.21 (t, J= 8.1 Hz, 1H), 7.03 (d, J = 7.8 Hz, 1H), 6.97 (t, J =1.2 Hz, 1H), 6.87 (dd, J = 8.4, 2.7 Hz, 1H), 4.39 (s, 2 H), 3.79 (s, 3H), 3.62 (t, J = 5.1 Hz, 2 H), 2.93 (br s, 2 H), 1.8 (br s, 2 H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 159.1 (C), 129.2 (CH), 124.1 (CH), 123.4 (C), 116.5 (CH), 114.9 (CH), 86.1 (C), 84.8 (C), 70.5 (CH2), 69.3 (CH2), 58.8 (CH2), 55.1 (CH3), 40.9 (CH2); IR (NaCl, cm-1): 3369 (N-H stretch), 2937 (asymmetric C-H stretch), 2858 (symmetric C-H stretch), 1158 (C-O stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H16NO2: 206.1181, Found: 206.1179.  2-((3-(Naphthalen-1-yl)prop-2-yn-1-yl)oxy)ethanamine (45).  Following General Procedure B, 38 (0.439 g, 1.40 mmol) was deprotected to yield 45 as a yellow oil (0.287 g, 94%). 1H-NMR (300 MHz, CDCl3):  δ 8.32 (d, J = 8.7 Hz, 1H), 7.76 (t, J = 7.2 Hz, 2H), 7.66 (d, J = 7.2 Hz, 1H), 7.56-7.42 (m, 2H), 7.35 (dd, J = 8.4, 7.5 Hz, 1H), 4.48 (s, 2H), 3.62 (t, J = 5.1 Hz, 2H), 2.87 (t, J = 5.1 Hz, 2H), 1.38 (br s, 2H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 133.1 (C), 132.9 (C), 130.5 (CH), 128.8 (CH), 128.1 (CH), 126.6 (CH), 126.2 (CH), 125.9 (CH), 125.0 (CH), 120.1 (C), 90.0 (C), 84.1 (C), 72.3 (CH2), 59.0 (CH2), 41.7 (CH2); IR (NaCl, cm-1): 3370 (N-H stretch), 2925 (asymmetric C-H stretch), 2858 (symmetric C-H stretch), 1586 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C15H16NO: 226.1232, Found: 226.1228.  H2NO43OH2NO45  75  2-((3-Cyclohexylprop-2-yn-1-yl)oxy)ethanamine (51).  Following General Procedure B, 31  (0.560 g, 2.00 mmol) was deprotected to yield 51, as a yellow oil (0.270 g, 79%). 1H-NMR (300 MHz, CDCl3):  δ 4.16 (d, J = 2.1 Hz, 2H), 3.52 (t, J = 5.4 Hz, 2H), 2.87 (t, J = 5.1 Hz, 2H), 2.42-2.35 (m, 1H), 1.82-1.24 (m, 10H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 91.2 (C), 75.7 (C), 71.9 (CH2), 58.9 (CH2), 41.8 (CH2), 32.6 (CH2), 29.1 (CH), 25.8 (CH2), 25.0 (CH2); IR (NaCl, cm-1): 3370 (N-H stretch), 2929 (asymmetric C-H stretch), 2853 (symmetric C-H stretch), 1449 (C-H bend); HRMS-ESI (m/z) [M+H]+ calcd for C11H20NO: 182.1545, Found: 182.1542.  General Procedure C:  Intramolecular Hydroamination followed by NaBH4  Reduction    In the glove box, a Teflon sealed, J. Young NMR tube was charged with a solution precatalyst (10 mol %) and the aminoalkyne (0.25~0.5 mmol, 1 equiv.), dissolved in anhydrous toluene- d8 (0.5 mL). The tube was sealed and maintained at 110 °C for 14 h. After allowing the reaction mixture to cool to room temperature, the mixture was diluted with MeOH (7 mL). NaBH4 (4.0 equiv.) was added and the reaction mixture was stirred for 2 h at room temperature. After removal of the solvent in vacuo, the residue was diluted with EtOAc (8mL) and washed with aqueous HCl (1 M, 3 x 5 mL). The combined aqueous layer was basified with saturated aqueous NaHCO3 (20 mL) and extracted with EtOAc (3 x 8 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated by rotary evaporation to provide light yellow oil as the corresponding racemic 3-substituted morpholine with above 95% RO NH2NHORi. 10 mol% 9   toluene, 110 °C, 14 hii. NaBH4, MeOH   0-23 °C, 16 hH2NO51  76 purity in most cases.  The racemic 3-morpholine products were used for development of SFC methods for ee determination.  General Procedure D:  Intramolecular Hydroamination followed by Catalytic Asymmetric Transfer Hydrogenation     In the glove box, a 10 mL Schlenk tube equipped with a magnetic stir bar was charged with a solution of precatalyst 9 (10 mol %) and the aminoalkyne (0.25~0.4 mmol), dissolved in anhydrous toluene (0.5 mL). The Schlenk tube was sealed and heated to 110 °C for 14 h. After allowing the reaction mixture to cool to room temperature, RuCl[(S,S)-TsDPEN(p-cymene)] (65, 1 mol %) in dry DMF (0.1 mL) was added followed by a 5:2 mixture of formic acid/triethylamine (0.1 mL).  The reaction mixture was stirred at room temperature for 14 h under nitrogen. The solution was diluted with EtOAc (8 mL) and washed with water (5 mL), then aqueous HCl (1 M, 2 x 5 mL). The combined aqueous layers were washed with EtOAc (5 mL) and then basified with saturated aqueous NaHCO3 (15 mL), prior to extraction with EtOAc (3 x 8 mL). The combined organic layers were washed with water (2 x 5 mL) and brine, dried over Na2SO4, filtered, and concentrated by rotary evaporation to provide a brown oil as the corresponding 3-substituted morpholine with above 95% purity in most cases.   RO NH2NHORi. 10 mol% 9   toluene, 110 °C, 14 hii. 1 mol% 65, DMF    HCO2H/NEt3 (5:2)     23 °C, 16 h  77 (R)-3-(4-(Trifluoromethyl)benzyl)morpholine (68).  Following General Procedure D, the reaction of 41  (0.055 g, 0.23 mmol) afforded the title compound 68 as a light brown oil (0.029 g, 52%, ee = 98%). The enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Thar SFC AD-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 97:3:0.1, flow rate of 1.0 mL/min, UV detection at 229 nm).  [α]D = +4° (c = 0.7, chloroform); 1H-NMR (300 MHz, CDCl3):  δ 7.56 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 3.82-3.75 (m, 2H), 3.57-3.49 (m, 1H), 3.27 (dd, J = 11, 9.6 Hz, 1H), 3.07-2.98 (m, 1H), 2.92-2.82 (m, 2H), 2.71 (dd, J = 14, 5.1 Hz, 1H), 2.55 (dd, J = 14, 8.7 Hz, 1H), 1.89 (br s, 1H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 142.2 (C), 129.6 (CH), 129.1 (q, 2JC-F = 20 Hz, C), 127.9 (q, 1JC-F = 270 Hz, CF3), 125.7 (q, 3JC-F = 3.3 Hz, CH), 72.4 (CH2), 67.6 (CH2), 56.0 (CH), 46.2 (CH2), 38.8 (CH2); 19F-NMR (282 MHz, CDCl3): δ -63.8; IR (NaCl, cm-1): 3426 (N-H stretch), 2922 (asymmetric C-H stretch), 2851 (symmetric C-H stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H15NOF3: 246.1106, Found: 246.1104.   (R)-3-(3-Methoxybenzyl)morpholine (70).  Following General Procedure D, the reaction of 43  (0.050 g, 0.24 mmol) afforded the title compound 70 as a light brown oil (0.043 g, 85%, ee = 94%).  The enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Thar SFC OD-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 98:2:0.1, flow rate of 1.0 mL/min, UV detection at 259 nm). [α]D = +80° (c = 0.9, methanol); 1H-NMR (300 MHz, CDCl3):  δ 7.27 (dd, J = 15, 7.8 Hz, 1H), 6.84-6.78 (m, 3H), 3.88-3.80 (m, 2H), 3.83 (s, 3H), 3.62-3.54 (m, 1H), 3.31 (t, J = 9.6 Hz, 1H), 3.08-3.00 (m, 1H), 2.95-2.84 (m, 2H), NHOF3C68NHO70O  78 2.68 (dd, J = 13, 4.8 Hz, 1H), 2.49 (dd, J = 13, 9.3 Hz, 1H), 1.97 (br s, 1H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 159.1 (C), 139.2 (C), 129.7 (CH), 121.6 (CH), 114.9 (CH), 112.0 (CH), 72.5 (CH2), 67.5 (CH2), 56.2 (CH), 55.3 (CH3), 46.3 (CH2), 39.0 (CH2); IR (NaCl, cm-1): 3321 (N-H stretch), 2952 (asymmetric C-H stretch), 2849 (symmetric C-H stretch), 1599 (aromatic ring stretch), 1105 (C-O stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H18NO2: 208.1339, Found: 208.1338.  (R)-3-(Naphthalen-1-ylmethyl)morpholine (72).  Following General Procedure D, the reaction  of 45 (0.050 g, 0.24 mmol) afforded the title compound 72 as a light brown oil (0.036 g, 72%, ee = 93%). The enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Chiralpak AS-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 97:3:0.1, flow rate of 1.0 mL/min, UV detection at 229 nm). [α]D = +40° (c = 0.2, methanol); 1H-NMR (300 MHz, CDCl3):  δ 8.08-8.01 (m, 1H), 7.90-7.84 (m, 1H), 7.76 (d, 1H), 7.57-7.47 (m, 2H), 7.43-7.34 (m, 2H), 3.90 (dd, J = 11, 2.7 Hz, 1H), 3.78 (dt, J = 11, 2.7 Hz, 1H), 3.65-3.52 (m, 1H), 3.40 (dd, J = 11, 9 Hz, 1H), 3.24-3.16 (m, 2H), 2.95-2.76 (m, 3H), 1.95 (br s, 1H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 134.2 (C), 133.9 (C), 132.1 (C), 129.0 (CH), 127.6 (CH), 126.2 (CH), 125.9 (CH), 125.5 (CH), 123.8 (CH), 72.7 (CH2), 67.5 (CH2), 55.36 (CH2), 46.3 (CH2), 36.0 (CH); IR (NaCl, cm-1): 2922 (asymmetric C-H stretch), 2850 (symmetric C-H stretch), 1453 (aromatic ring stretch), 1105 (C-O stretch); HRMS-ESI (m/z) [M+H]+ calcd for C15H18NO: 228.1388, Found: 228.1384.  NHO72  79 (R)-3-(Cyclohexylmethyl)morpholine (77).  Following General Procedure D, the reaction of 5l  (0.104 g, 0.240 mmol) afforded the title compound 77 as a light brown oil (0.053 g, 85%). The enantiomeric excess value was measured by SFC after tosylation, see characterization data for compound 77-Ts.  [α]D = +92° (c = 1.0, dichloromethane); 1H-NMR (300 MHz, CDCl3):  δ 3.74 (dt, J = 11, 3.0 Hz, 2H), 3.46 (dt, J = 11, 3.0 Hz, 1H), 3.09 (t, J = 9.9 Hz, 1H), 2.97-2.80 (m, 1H), 2.35 (br s, 1H), 1.68-1.59 (m, 4H), 1.33-0.76 (m, 7H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 73.2 (CH2), 67.6 (CH2), 52.2 (CH), 46.3 (CH2), 40.2 (CH2), 34.1 (CH), 33.7 (CH2), 33.3 (CH2), 26.6 (CH2), 26.3 (CH2), 26.2 (CH2); IR (NaCl, cm-1): 3320 (N-H stretch), 2921 (asymmetric C-H stretch), 2850 (symmetric C-H stretch), 1448 (alkyl C-H bend), 1107 (C-O stretch); HRMS-ESI (m/z) [M+H]+ calcd for C11H22NO: 184.1701, Found: 184.1704.  General Procedure E:  Synthesis of N-Tosylated Morpholines     Tosyl chloride (1.1 equiv.) was added to a solution of crude 3-substituted morpholine (1.0 equiv.) and triethylamine (2.0 equiv.) in CH2Cl2 (10 mL) at 0 °C.  The reaction mixture was warmed to room temperature and stirred overnight.  The reaction mixture was washed with aqueous HCl (1 M, 3 mL), saturated aqueous NaHCO3 (3 mL), then and brine, before being dried over Na2SO4, and filtered. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography (eluent:  15% EtOAc in hexanes).  NHORTsCl, NEt3CH2Cl2, 0-23 °C18 hNTsORNHO77  80 (R)-3-(Cyclohexylmethyl)-4-tosylmorpholine (77-Ts).  Following General Procedure E, the reaction of 77 (0.048 g, 0.26 mmol) afforded the title compound 77-Ts as a colourless oil (0.057 g, 85%, ee = 95%).  The enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Chiralpak AS-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 97:3:0.1, flow rate of 1.0 mL/min, UV detection at 240 nm). [α]D = -14° (c = 0.4, chloroform); 1H-NMR (300 MHz, CDCl3):  δ 7.68 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 8.1 Hz, 2H), 3.85 (dt, J = 7.8, 2.4 Hz, 1H), 3.69 (dd, J = 12, 3.3 Hz, 1H), 3.60 (d, J = 11 Hz, 1H), 3.53 (d, J = 13Hz, 1H), 3.43 (dd, J = 12, 3 Hz, 1H), 3.38-3.18 (m, 2H), 2.41 (s, 3H), 1.73-1.36 (m, 7H), 1.21-1.11 (m, 4H), 0.92-0.72 (m, 2H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 143.4 (C), 138.2 (C), 129.8 (CH), 127.2 (CH), 69.0 (CH2), 66.2 (CH2), 51.1 (CH), 40.7 (CH2), 35.5 (CH2), 34.3 (CH), 33.4 (CH2), 33.2 (CH2), 26.2 (CH2), 26.2 (CH2), 21.6 (CH3); IR (NaCl, cm-1): 2923 (asymmetric C-H stretch), 2852 (symmetric C-H stretch), 1449 (alkyl C-H bend), 1347 (S=O stretch); HRMS-ESI (m/z) [M+Na]+ calcd for C18H27NO3SNa: 360.1609, Found: 360.1616.   (S)-3-Benzylmorpholine (78).  Known compound299 synthesized from 32197 (0.047 g, 0.27  mmol) using General Procedure D, except 1 mol%  RuCl[(R,R)-TsDPEN(p-cymene)] catalyst was used.  The title compound 78 was isolated as a light brown oil (0.038 mmol, 80%, 95% ee).  The enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Thar SFC OD-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 98:2:0.1, flow rate of 0.9 mL/min, UV detection at 250 nm). [α]D = -39° (c = 0.056, methanol, lit. [α]D = -38°);299 1H-NMR (300 MHz, CDCl3) δ 7.34-7.18 (m, 5 H), 3.81 (dt, J = 10, 3 Hz, 2H), 3.61-3.52 NHO78NTsO77-Ts  81 (m, 1H), 3.30 (t, J = 10 Hz, 1H), 3.07-2.96 (m, 1H), 2.93-2.83 (m, 2H), 2.65 (dd, J = 13, 4.8 Hz, 1H), 2.49 (dd, J = 13, 9 Hz, 1H), 2.29 (br s, 1H); HRMS-ESI (m/z) [M+H]+ calcd for C11H16NO: 178.1232, Found: 178.1228.  4-(3-(2-Aminoethoxy)prop-1-yn-1-yl)benzonitrile (81).  Following the General Procedure A, the reaction of tert-butyl (2-(prop-2-yn-1-yloxy)ethyl)carbamate1 (0.500 g, 2.50 mmol) and 4-iodobenzonitrile (0.630 g, 2.80 mmol) afforded tert-butyl (2((3-(4-cyanophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (0.776 g, 52%) as a light brown oil.  1H-NMR (300 MHz, CDCl3):  δ 7.50 (d. J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 5.04 (br s, 1H), 4.30 (s, 2H), 3.55 (t, J = 5.1 Hz, 2H), 3.27 (q, J = 5.1 Hz, 2H), 1.33 (s, 9H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 155.8 (C), 132.0 (CH), 131.8 (CH), 127.2 (C), 118.1 (C), 111.7 (C), 89.4 (C), 84.6 (C), 69.2 (CH2), 58.6 (CH2), 40.1 (CH2), 28.2 (CH3); IR (NaCl, cm-1): 3365 (N-H stretch), 2977 (asymmetric ring stretch), 2933 (symmetric ring stretch), 2229 (C-N stretch, nitrile), 1713 (C=O stretch); HRMS-ESI (m/z) [M+Na]+ calcd for C17H20N2O3Na: 323.1372, Found: 323.1372.  Following General Procedure B, tert-butyl (2-((3-(4-cyanophenyl)prop-2-yn-1-yl)oxy)ethyl)carbamate (0.776 g, 2.6 mmol) was deprotected to yield 80, as a light brown oil (0.452 g, 87%). 1H-NMR (300 MHz, CDCl3):  δ 7.59 (d, J = 8.7 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 4.40 (s, 2H), 3.60 (t, J = 5.1 Hz, 2H), 2.91 (t, J = 5.4 Hz, 2H), 1.42 (br s, 2H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 132.4 (CH), 132.1 (CH), 127.6 (C), 118.4 (C), 112.0 (C), 89.9 (C), 84.7 (C), 72.8 (CH2), 59.0 (CH2), 41.9 (CH2); IR (NaCl, cm-1):  3340 (N-H stretch), 2924 (asymmetric C-H stretch), 2856 (symmetric C-H stretch), 2228 (C-N stretch, H2NO80CN  82 nitrile), 1604 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H13N2O: 201.1028, Found: 201.1029.  4-(Morpholin-3-ylmethyl)benzonitrile (81).  Following General Procedure C, the reaction of 80 (0.050 g, 0.25 mmol) afforded 81, as a light brown oil (0.039 g, 78%). 1H-NMR (300 MHz, CDCl3):  δ 7.58 (d, J = 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 2H), 3.76 (dd, J = 11, 2.7 Hz, 2H), 3.53-3.45 (m, 1H), 3.23 (t, J = 9.6 Hz, 1H), 3.05-2.96 (m, 1H), 2.90-2.80 (m, 2H), 2.69 (dd, J = 13, 5.1 Hz, 1H), 2.55 (dd, J = 13, 8.7 Hz, 1H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 143.8 (C), 132.5 (CH), 130.0 (CH), 118.8 (C), 110.7 (C), 72.2 (CH2), 67.5 (C), 55.8 (CH2), 46.1 (CH2), 39.1 (CH2); IR (NaCl, cm-1): 3309 (N-H stretch), 2954 (asymmetric C-H stretch), 2852 (symmetric C-H stretch), 2227 (C-N stretch, nitrile), 1607 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H15N2O: 203.1184, Found: 203.1178.  tert-Butyl (2-(benzyl(prop-2-yn-1-yl)amino)ethyl)carbamate (86).  tert-Butyl (2-    (benzylamino)ethyl)carbamate (3.26 g, 13.0 mmol) was dissolved in EtOAc (100 mL).  NaI (0.300 g, 2.00 mmol), Et4NI (0.300 g, 1.00 mmol), and K2CO3 (3.59 g, 26.0 mmol) were added and the suspension was heated to 70 °C for 20 h.  The reaction was cooled to room temperature and H2O was added (50 mL).  The resulting layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL).  The organic layers were combined and washed with 10% metabisulfite solution (50 mL) and brine (50 mL) before drying over Na2SO4.  The crude reaction mixture was purified by flash chromatography (15% EtOAc in hexanes) to yield NHO81NCBocHN N86  83 the title compound 86 as a pale yellow oil (3.47 g, 93%).  1H-NMR (300 MHz, CDCl3):  δ 7.38-7.23 (m, 5H), 3.64 (s, 2H), 3.31 (d, J = 2.4 Hz, 2H), 3.24 (q, J = 5.1 Hz, 2H), 2.69 (t, J = 6.0 Hz, 2H), 2.24 (t, J = 2.4 Hz, 1H), 1.62 (br s, 1H), 1.45 (s, 9H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 156.0 (C), 138.3 (CH), 129.1 (CH), 128.5 (CH), 127.4 (C), 79.2 (C), 78.2 (C), 73.5 (CH2), 57.6 (CH2), 52.4 (CH2), 41.4 (CH2), 37.9 (C), 28.5 (CH3); IR (NaCl, cm-1): 3426 (N-H stretch), 2976 (asymmetric C-H stretch), 2834 (symmetric C-H stretch), 1712 (C=O stretch), 1495 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C17H25N2O2: 289.1916, Found: 289.1917.  N1-Benzyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine (87).  Following General Procedure B, tert-  butyl (2-(benzyl(prop-2-yn-1-yl)amino)ethyl)carbamate (86, 1.77 g, 4.80 mmol) was deprotected to yield N1-benzyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine (87) as a light brown oil (1.27 g, quantitative).   1H-NMR (400 MHz, CDCl3):  δ 7.35-7.23 (m, 5H), 3.64 (s, 2H), 3.31 (d, J = 1.6 Hz, 2H), 2.77 (t, J = 5.6 Hz, 2H), 2.64 (t, J = 6.0 Hz, 2H), 2.23 (t, J = 2.4 H, 1H), 1.66 (br s, 2H); 13C{1H}-NMR (75 MHz, CDCl3): δ 138.3 (C), 128.7 (CH), 127.9 (CH), 126.8 (C), 78.2 (C), 72.9 (C), 57.5 (CH2), 55.7 (CH2), 41.2 (CH2), 39.0 (CH2); IR (NaCl, cm-1): 3056 (N-H stretch), 2926 (asymmetric C-H stretch), 2822 (symmetric C-H stretch), 1489 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C12H17N2: 189.1392, Found: 189.1396.  (R)-1-Benzyl-3-methylpiperazine (88).  Known compound342-344 synthesized from N1-benzyl-N1-(prop-2-yn-1-yl)ethane-1,2-diamine (87, 0.100 g, 0.530 mmol) using General Procedure D, except after reaction with 1 at 110 °C for 14 h, an additional 10 mol% of H2NN87NTsBnN88  84 1 was added and the reaction was heated to 110 °C for an additional 14 h.  Compound 88 was isolated as a brown oil (0.058 g, 58%, > 98% ee as determined by derivatization with (R)-α-methoxy-α-trifluoromethylphenylacetic acid chloride in situ using previously described experimental procedure),81 19F-NMR (292 MHz, CDCl3): δ -72.1.  Derivatization of the opposite enantiomer synthesized using RuCl[(R,R)-TsDPEN(p-cymene) with (R)-α-methoxy-α-trifluoromethylphenylacetic acid chloride in situ using previously described experimental procedure,81 19F-NMR (292 MHz, CDCl3): δ -73.4).  Following General Procedure E, 87 was isolated as the tosylated piperazine compound as a colourless oil (0.062 g, 60%).  1H-NMR (300 MHz, CDCl3):  δ 7.69 (d, J = 8.0 Hz, 2H), 7.30 (m, 7H), 4.06-4.04 (m, 1H), 3.58 (d, J =13 Hz, 1H), 3.47 (d, J = 13 Hz, 1H), 3.37 (d, J = 13 Hz, 1H), 3.23 (dt, J = 12, 2.8 Hz, 1H), 2.71 (d, J = 10 Hz, 1H), 2.52 (d, J = 11 Hz, 1H), 2.43 (s, 3H), 2.16 (dd, J = 11, 3.6 Hz, 1H), 2.05 (dt, J = 12, 3.6 Hz, 1H), 1.16 (d, J = 6.4 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 143.0 (C), 138.1 (C), 137.9 (C), 129.6 (CH), 128.7 (CH), 128.2 (CH), 127.1 (CH), 62.5 (CH2), 57.8 (CH2), 52.7 (CH), 49.6 (CH2), 40.9 (CH2), 21.5 (CH3), 15.4 (CH3); IR (NaCl, cm-1):  2920 (asymmetric ring stretch), 2849 (symmetric ring stretch), 1463 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C19H25N2O2S: 345.1637, Found: 345.1633.  N1,N1-Bis(3-phenylprop-2-yn-1-yl)ethane-1,2-diamine (89).  DBU (1.1 g, 7.0 mmol, 1.0 mL) was added to (3-bromoprop-1-yn-1-yl)benzene (1.34 g, 7.00 mmol) dissolved in toluene (10 mL), resulting in a dark brown reaction mixture.  A solution of tert-butyl (2-aminoethyl)carbamate (1.12 g, 7.00 mmol) in toluene (10 mL) was added and the reaction was stirred at room temperature for 48 h.  The solvent was removed H2NN89  85 in vacuo and the residue was dissolved in DCM (50 mL), washed with 10% metabisulfite solution (30 mL) and brine before drying over Na2SO4, filtering, and concentrating into brown oil.  The crude material was purified by flash chromatography (15% EtOAc in hexanes) to afford (2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl)carbamate as a yellow oil (0.235 g, 9%).  1H-NMR (300 MHz, CDCl3):  δ 7.44-7.41 (m, 4H), 7.29-7.23 (m, 6H), 5.14 (br s, 1H), 3.70 (s, 4H), 3.30 (q, J = 4.8 Hz, 2H), 2.81 (t, J = 6.0 Hz, 2H), 1.43 (s, 9H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 156.0 (C), 131.8 (CH), 128.3 (CH), 128.2 (CH), 122.9 (C), 85.4 (C), 84.4 (C), 79.1 (C), 52.1 (CH2), 43.3 (CH2), 37.9 (C), 28.4 (CH3); IR (NaCl, cm-1): 3427 (N-H stretch), 2976 (asymmetric C-H stretch), 2930 (symmetric C-H stretch), 1711 (C=O stretch), 1490 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C25H29N2O2: 389.2222, Found: 389.2229.  (2-(bis(3-phenylprop-2-yn-1-yl)amino)ethyl)carbamate (0.230 g, 0.590 mmol) was deprotected using General Procedure B to yield N1,N1-bis(3-phenylprop-2-yn-1-yl)ethane-1,2-diamine as a yellow oil (89, 0.168 g, quantitative).  1H-NMR (300 MHz, CDCl3):  δ 7.46-7.40 (m, 4H), 7.30-7.27 (m, 6H), 3.72 (s, 2H), 2.86 (t, J = 5.7 Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.12 (br s, 2H); 13C{1H}-NMR (75 MHz, CDCl3): δ 131.8 (CH), 128.3 (CH), 128.1 (CH), 123.0 (C), 85.2 (C), 84.7 (C), 55.8 (CH2), 43.5 (CH2), 39.4 (CH2); IR (NaCl, cm-1): 3363 (N-H stretch), 2923 (asymmetric C-H stretch), 2850 (symmetric C-H stretch), 1597 (N-H bend); HRMS-ESI (m/z) [M+H]+ calcd for C20H21N2: 289.1705, Found: 289.1699.  (R)-3-Benzyl-1-(3-phenylprop-2-yn-1-yl)piperazine (90).  Following General Procedure D, 89   (0.073 g, 0.25 mmol) was reacted to yield 15 in a mixture with unreacted 90 as a brown oil (NMR yield: 14%, 96% ee).  The NHN90  86 enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Thar SFC OD-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 98:2:0.1, flow rate of 1.0 mL/min, UV detection at 229 nm). Diagnostic signals:  1H-NMR (300 MHz, CDCl3): δ 7.23-7.20 (m, Ar-H), 4.11 (apparent quartet, 1H), 3.51(s, 2H), 3.08-2.92 (m, 2H), 2.61 (dd, J = 14, 9 Hz, 1H), 2.39 (dt, J = 11, 3 Hz, 1H), 2.13 (t, J = 10 Hz, 1H); HRMS-ESI (m/z) [M+H]+ calcd for C20H23N2: 291.1861, Found: 291.1858.  N1-Benzyl-N1-(3-phenylprop-2-yn-1-yl)ethane-1,2-diamine (91).  Following the General Procedure A, the reaction of tert-butyl (2-(benzyl(prop-2-yn-1-yl)amino)ethyl)carbamate (1.00 g, 3.50 mmol) and iodobenzene (0.79 g, 3.9 mmol, 0.43 mL) afforded tert-butyl (2-(benzyl(3-phenylprop-2-yn-1-yl)amino)ethyl)carbamate (1.16 g, 91% yield) as a brown oil.  1H-NMR (400 MHz, CDCl3):  δ 7.47-7.45 (m, 2H), 7.38-7.28 (m, 8H), 4.99 (br s, 1H), 3.72 (s, 2H), 3.53 (s, 2H), 3.32-3.27 (m, 2H), 2.77 (t, J = 5.6 Hz, 2H), 1.46 (2, 9H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 156.1 (C), 138.5 (C), 131.9 (CH), 129.3 (CH), 128.5 (CH), 128.4 (CH), 128.2 (CH), 127.4 (CH), 123.2 (C), 85.9 (C), 84.1 (C), 79.2 (C), 58.0 (CH2), 52.7 (CH3), 42.3 (CH2), 38.0 (CH2), 28.6 (CH3); IR (NaCl, cm-1): 3426 (N-H stretch), 2976 (asymmetric C-H stretch), 2835 (symmetric C-H stretch), 1712 (C=O stretch), 1485 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C23H29N2O2: 365.2229, Found: 365.2232.  Following General Procedure B, tert-butyl (2-(benzyl(3-phenylprop-2-yn-1-yl)amino)ethyl)carbamate (1.00 g, 2.80 mmol) was deprotected to yield 91 as a brown oil (0.789 g, quantitative).  1H-NMR (400 MHz, CDCl3):  δ 7.48-7.45 (m, 2H), 7.40-7.25 (m, 8H), 3.73 (s, 2H), 3.54 (s, 2H), 2.83 (t, J = 6 HZ, 2H), 2.72 (t, J = 6.4 Hz, 2H), 1.61 (br s, 2H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 138.9 (C), 131.8 (CH), H2NBnN91  87 129.2 (CH), 128.4 (CH), 128.3 (CH), 128.1 (CH), 127.2 (CH), 123.3 (C), 85.6 (C), 84.4 (C), 58.2 (CH2), 56.4 (CH2), 42.5 (CH2), 39.5 (CH2); IR (NaCl, cm-1):  3365 (N-H stretch), 2938 (asymmetric C-H stretch), 2832 (symmetric C-H stretch), 1289 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C18H21N2: 265.1705, Found:  265.1704.   (R)-2,4-Dibenzyl-1-tosylpiperazine (92).  Following General Procedure D, amino alkyne 91  (0.050 g, 0.38 mmol) was reacted; however, after reaction with 9 at 110 °C for 14 h, an additional 10 mol% of 1 was added and the reaction was heated to 110 °C for an additional 14 h.  Subsequent reduction with RuCl[(S,S)-TsDPEN(p-cymene)] yielded crude 92 as a brown oil (0.042 g, 84%).  Following General Procedure E, 92 was isolated as the tosylated piperazine compound (0.005 g, 8%, 87% ee).  The enantiomeric excess value was measured by chiral HPLC.  Separation of enantiomers was achieved by using a Chiralcel OJ-RH column (particle size 5 μm, 4.6 mmΦ x 150 mm, 37% acetonitrile in water, UV detection at 210 nm).   1H-NMR (400 MHz, CDCl3):  δ 7.65 (d, J = 8.4 Hz, 2H), 7.34-7.24 (m, 7H), 7.15-7.13 (m, 3H), 6.98-6.96 (m, 2H), 4.07-4.04 (m, 1H), 3.70 (d, J = 14 Hz, 1H), 3.45 (d, J = 13 Hz, 1H), 3.35-3.28 (m, 2H), 3.17 (dd, J = 13, 11 Hz, 1H), 2.78 (d, J = 12 Hz, 1H), 2.65 (dd, J = 12, 4 Hz, 1H), 2.62 (d, J = 12 Hz, 1H), 2.41 (s, 3H), 2.05 (dt, J =12, 3.2 Hz, 1H), 1.90 (dd, J = 11, 3.2 Hz, 1H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 143.2 (C), 138.8 (C), 138.2 (C), 138.7 (C), 129.8 (CH), 129.5 (CH), 129.4 (CH), 128.5 (CH), 128.4 (CH), 127.4 (CH), 127.2 (CH), 126.4 (CH), 62.9 (CH2), 55.8 (CH2), 53.3 (CH), 52.9 (CH2), 41.5 (CH2), 35.4 (CH2), 29.9 (CH2), 21.7 (CH2); IR (NaCl, cm-1):  2923 (asymmetric C-H stretch), 2853 (symmetric C-H stretch), 1351 (S=O stretch), 1161 (C-O stretch); HRMS-ESI (m/z) [M+H]+ calcd for C25H29N2O2S: 421.1950, Found:  421.1957. NTsBnN92  88  N1-Benzyl-N1-(but-2-yn-1-yl)ethane-1,2-diamine (93).  2-Butyn-1-ol (0.350 g, 5.00 mmol) was stirred in THF (5 mL) and the solution was cooled to 0 °C.  Triethylamine was added (0.550, 5.50 mmol) followed by methanesulfonyl chloride (0.63 g, 5.5 mmol, 0.43 mL) dropwise over 5 minutes.  The resulting reaction mixture was an orange solution with a white precipitate.  The reaction was stirred for 15 minutes before the precipitate was filtered off and the filtrate was concentrated into clear orange oil.  The oil was dissolved in acetonitrile (10 mL) and added to tert-butyl (2-(benzylamino)ethyl)carbamate (1.40 g, 5.50 mmol) and potassium carbonate (2.51 g, 18.0 mmol) in acetonitrile (20 mL).  The reaction was heated to a reflux for 64 h.  The reaction mixture was cooled to room temperature and the solvent was removed in vacuo.  The residue was dissolved in water (50 mL) and the aqueous solution was extracted with ethyl acetate (3 x 50 mL).  The organic fractions were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated into brown oil.  The crude material was purified by flash chromatography (eluent:  5-15% ethyl acetate in hexanes) to yield tert-butyl (2-(benzyl(but-2-yn-1-yl)amino)ethyl)carbamate as a clear, colourless oil (0.514 g, 31%).  1H-NMR (400 MHz, CDCl3):  δ 7.34-7.23 (m, 5H), 5.02 (br s, 1H), 3.62 (s, 2H), 3.26-3.20 (m, 4H), 2.65 (t, J = 6.0 Hz, 2H), 1.86 (s, 3H), 1.45 (s, 9H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 156.0 (C), 138.6 (C), 129.0 (CH), 128.3 (CH), 127.1 (CH), 80.9 (C), 78.9 (C), 73.4 (C), 57.7 (CH2), 52.3 (CH2), 41.7 (CH2), 37.9 (CH2), 28.4 (CH3), 3.43 (CH3); IR (NaCl, cm-1):  3359 (N-H stretch), 2913 (asymmetric C-H stretch), 2849 (symmetric C-H stretch), 1712 (C=O stretch), 1494 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C18H27N2O2: 303.2073,  Found:  303.2066.  Following General Procedure B, tert-butyl (2-(benzyl(but-2-yn-1-yl)amino)ethyl)carbamate was H2NBnN93  89 deprotected to yield N1-benzyl-N1-(but-2-yn-1-yl)ethane-1,2-diamine (94) as a clear, colourless oil.  1H-NMR (400 MHz, CDCl3):  δ 7.33-7.19 (m, 5H), 3.60 (s, 2H), 3.24 (s, 2H), 2.74 (t, J = 5.6 Hz, 2H), 2.58 (t, J = 4.8 Hz, 2H), 1.83 (s, 3H), 1.34 (br s, 2H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 138.6 (C), 129.0 (CH), 128.1 (CH), 126.9 (CH), 80.6 (C), 73.7 (C), 57.9 (CH2), 56.1 (CH2), 41.9 (CH2), 39.5 (CH2), 3.40 (CH3); IR (NaCl, cm-1):  3356 (N-H stretch), 2913 (asymmetric C-H stretch), 2849 (symmetric C-H stretch), 1452 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ calcd for C13H19N2: 203.1548, Found:  203.1545.  (R)-4-Benzyl-2-ethyl-1-tosylpiperazine (94).  Following General Procedure D, amino alkyne 93  (0.100 g, 0.490 mmol) was reacted; however, after reaction with 1 at 110 °C for 14 h, an additional 10 mol% of 9 was added and the reaction was heated to 110 °C for an additional 14 h.  Subsequent reduction with RuCl[(S,S)-TsDPEN(p-cymene)]  yielded crude 94 as a brown oil (0.025 g, 24%).  Following General Procedure E, 94 was isolated as the tosylated piperazine compound (0.004 g, 10%, 81% ee). The enantiomeric excess value was measured by chiral HPLC.  Separation of enantiomers was achieved by using a Chiralcel OJ-RH column (particle size 5 μm, 4.6 mmΦ x 150 mm, 37% acetonitrile in water, UV detection at 230 nm).   1H-NMR (400 MHz, CDCl3):  δ 7.69 (d, J = 11 Hz, 2H), 7.29-7.20 (m, 7H), 3.80-3.75 (m, 1H), 3.66 (d, J = 19 Hz, 1H), 3.43 (d, J = 18 Hz, 1H), 3.30-3.18 (m, 2H), 2.61 (d, J = 15 Hz, 2H), 2.43 (s, 3H), 1.90 (dt, J =16, 4.4 Hz, 2H), 1.70 (sextet, J = 10 Hz, 2H), 0.78 (t, J =10 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3):  δ 143.1 (C), 138.9 (C), 138.2 (C), 129.8 (CH), 128.8 (CH), 128.4 (CH), 127.3 (CH), 127.2 (CH), 62.8 (CH2), 55.7 (CH2), 52.5 (CH), 52.9 (CH2), 41.3 (CH2), 29.9 (CH3), 22.5 (CH2), 11.0 (CH3); IR (NaCl, cm-1):  2923 (asymmetric C-H NTsBnN94  90 stretch), 2850 (symmetric C-H stretch), 1460 (aromatic ring stretch), 1347 (S=O stretch), 1163 (C-O stretch); HRMS-ESI (m/z) [M+H]+ calcd for C20H27N2O2S: 359.1793, Found:  359.1786.  General Procedure F:  Preparation of Substrates for Disubstituted Morpholines   Propargyl bromide (0.655 g, 5.50 mmol, 0.61 mL) was added to a solution of Boc-protected amino alcohol (5.00 mmol) in THF (50 mL).  Sodium iodide (0.091 g, 0.61 mmol) and tetrabutylammonium iodide (0.090 g, 0.24 mmol) was added to afford an orange-brown solution.  Ground KOH (0.280 g, 5.00 mmol) was added portionwise over 5 minutes.  After stirring at room temperature for 20 h, the solvent was removed.  H2O (25 mL) and EtOAc (25 mL) were added and the layers were separated.  The aqueous layer was extracted with EtOAc (2 x 25 mL) and the organic layers were combined and washed with 10% sodium metabisulfite solution and brine.  After drying over sodium sulfate, the mixture was filtered and concentrated into orange oil.  Purification of the crude material by flash chromatography (eluent:  10% EtOAc in hexanes) yielded the desired Boc-protected aminoalkyne.  Deprotection with 4 M HCl in dioxane using General Procedure B yielded the desired primary aminoalkyne substrate, which was dried over sodium hydride and distilled under reduced pressure.      +1. KOH, NaI, Bu4NI    THF, 23 °C, 24 h2. 4 M HCl in dioxane    MeOH, 23 °C, 18 h3.  NaOH(aq)OH2NBrBocHN OHR1R2 R2R1  91 (S)-1-Phenyl-2-(prop-2-yn-1-yloxy)ethanamine (95).  Following General Procedure F, the title compound was isolated as pale yellow oil after distillation (0.147 g, 88%).  1H-NMR (300 MHz, toluene-d8): δ 7.34-7.30 (m, 2H), 7.20-7.01 (m, 3H), 4.03 (dd, J = 9.4, 3.9 Hz, 1H), 3.82 (dd, J = 2.1, 2.0 Hz, 2H), 3.45 (dd, J = 8.7, 3.7 Hz, 1H), 3.29 (dd, J = 9.0, 8.88 Hz, 1H), 2.00 (t, J = 2.4 Hz, 1H), 1.28 (br s, 2H); 13C{1H}-NMR (75 MHz, toluene-d8): δ 142.8 (C), 128.1 (CH), 127.3 (CH), 127.0 (CH) 79.8 (CH), 76.5 (CH), 74.2 (CH2), 57.9 (CH2), 55.5 (CH); IR (NaCl, cm-1): 3297 (N-H stretch), 2862 (symmetric C-H stretch), 1661 (N-H bend), 1093 (C-O stretch); HRMS (m/z) [M+H]+ Calcd for C11H14NO: 176.1075, Found: 176.1077.  (S)-1-Phenyl-3-(prop-2-yn-1-yloxy)propan-2-amine (96).  Following General Procedure F, the title compound was isolated as pale yellow oil after distillation (0.451 g, 86%).  1H-NMR (300 MHz, toluene-d8): δ 7.18-7.04 (m, 5H), 3.85 (d, J = 2.4 Hz, 2H), 3.28 (dd, J = 8.4, 4.2 Hz, 1H), 3.18 (dd, J = 8.7, 6.9 Hz, 1H), 3.10-3.02 (m, 1H), 2.63 (dd, J = 13, 5.4 Hz, 1H), 2.40 (dd, J = 13.2, 8.1 Hz, 1H), 2.12 (t, J = 2.4 Hz, 1H), 1.53 (br s, 2H); 13C{1H}-NMR (75 MHz, toluene-d8):  δ 139.6 (C), 129.7 (CH), 128.6 (CH), 126.6 (CH), 80.4 (C), 75.0 (CH), 74.6 (CH2), 58.3 (CH2), 52.7 (CH), 41.2 (CH2); IR (NaCl, cm-1):  3288 (N-H stretch), 2915 (asymmetric C-H stretch), 2856 (symmetric C-H stretch), 1601 (N-H bend), 1454 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C12H15NO: 190.1232, Found: 190.1232.     O NH2Ph95O NH2Bn96  92 2-(((3-Phenylprop-2-yn-1-yl)oxy)propan-1-amine (97).  Following General Procedure F and General Procedure A, the title compound was isolated as clear, colourless oil after distillation (0.489 g, 82%).  1H-NMR (300 MHz, CDCl3):  δ 7.44-7.40 (m, 2H), 7.35-7.30 (m, 3H), 4.27 (dd, J = 28, 16 Hz, 2H), 3.70-3.64 (m, 1H), 2.80-2.66 (m, 2H), 1.51 (br s, 2H), 1.18 (d, J = 6.2 Hz, 3H); 13C{1H}-NMR (75 MHz, CDCl3): δ 131.7 (CH), 128.4 (CH), 128.2 (CH), 122.6 (C), 85.7 (C), 85.6 (C), 76.2 (CH), 56.8 (CH2), 47.2 (CH2), 16.9 (CH3); IR (NaCl, cm-1):  3354 (N-H stretch) 2972 (asymmetric C-H stretch), 2929 (symmetric C-H stretch), 1664 (N-H bend), 1490 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C12H15NO: 190.1232; Found: 190.1234.              O NH297Ph  93 (3R, 5S)-3-Methyl-5-phenylmorpholine (98).  Following General Procedures C and D, the title compound was isolated as a light brown oil (reduction by NaBH4: 0.055 g, quantitative; reduction by RuCl[(S,S)-Ts-DPEN](p-cymene): 0.036 g, 75%; reduction by RuCl[(R,R)-Ts-DPEN](p-cymene): 0.028 g, 55%).  1H-NMR (CDCl3, 300 MHz): δ 7.43-7.26 (m, 5H), 4.02 (dd, J = 10, 3.0 Hz, 1H), 3.86-3.90 (m, 2H), 3.32 (dd, J = 11, 10 Hz, 1H), 3.22-3.10 (m, 2H), 2.02 (br s, 1H), 1.05 (d, J = 6.4 Hz, 3H); 13C{1H}-NMR (CDCl3, 75 MHz): δ 140.6 (C), 128.6 (CH), 127.9 (CH), 127.4 (CH), 73.2 (CH2), 73.2 (CH2), 60.8 (CH), 51.1 (CH), 17.9 (CH3); IR (NaCl, cm-1):  3306 (N-H stretch) 2963 (asymmetric C-H stretch), 1574 (N-H bend), 1455 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C11H16NO: 178.1228, Found: 178.1232.  The stereochemistry of 99 was assigned on the basis of 1D-NOESY experiments.  The key NOE signals are shown below.  The stereochemistry of 99 and 100 was assigned based on analogy to 99.   3-Benzyl-5-methylmorpholine (99).  Following General Procedures C and D, the title compound was isolated as a light brown oil (reduction by NaBH4:  0.055g, 98%; reduction by RuCl[(S,S)-Ts-DPEN](p-cymene): 0.047 g,  91%; reduction by RuCl[(R,R)-Ts-DPEN](p-cymene): 0.036 g, 75%,) Mixture of diastereomers observed by 1H-NMR spectroscopy. Cis-diastereomer diagnostic signals: 1H-NMR (CDCl3, 300 MHz): δ 7.31-7.17 (m, 5H), 3.81-3.68 (overlapped m, 2H), 3.30-3.02 (m, 3H), 2.94-2.80 (m, NHOHHHH HHNHO98NHOBn99  94 2H), 2.65 (dd, J = 13, 4.8 Hz, 1H), 2.48 (dd, J = 14, 8.7 Hz, 1H), 2.04 (br s., 1H), 0.91 (d, J = 6.3 Hz, 3H); 13C{1H}-NMR (CDCl3, 75 MHz): δ 137.8 (C), 129.2 (CH), 128.7 (CH), 126.6 (CH), 73.2 (CH2), 71.9 (CH2), 56.5 (CH), 50.7 (CH), 38.8 (CH2), 17.6 (CH3); Trans-diastereomer diagnostic signals:  δ 3.68 (overlapped m, 1H), 3.53 (dd, J  = 11, 4.2 Hz, 1H); 13C{1H}-NMR (CDCl3, 75 MHz): δ 137.8 (C), 129.2 (CH), 128.7 (CH), 126.4 (CH), 73.1 (CH2), 70.4 (CH2), 52.6 (CH), 45.1 (CH), 37.5 (CH2), 17.8 (CH3); IR (NaCl, cm-1):  3283 (N-H stretch), 2961 (asymmetric C-H stretch), 2852 (symmetric C-H stretch), 1454 (aromatic ring stretch), 1108 (C-O stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C12H18NO: 192.1388, Found: 192.1386.  5-Benzyl-2-methylmorpholine (100).  Following General Procedures C and D, the title compound was isolated as a light brown oil (reduction by NaBH4: 0.055 g, 99%; reduction by RuCl[(S,S)-Ts-DPEN](p-cymene):  0.045 g, 88%; reduction by RuCl[(R,R)-Ts-DPEN](p-cymene): 0.035 g, 66%).  Mixtures of diastereomers observed 1H-NMR spectroscopy and GC-MS.  Cis-diastereomer diagnostic signals: 1H-NMR (CDCl3, 400 MHz): δ 7.31-7.18 (m, 5H), 3.83 (dd, J = 11, 2.4 Hz 1H), 3.61-3.54 (m, 1H), 3.34 (t, J = 11 Hz, 1H), 3.00-2.95 (m, 1H), 2.87 (d, J = 11 Hz, 1H), 2.72 (br s., 1H), 2.61 (dd, J = 14, 4.8 Hz, 1H), 2.52-2.45 (m, 2H), 1.11 (d, J = 6.4 Hz, 3H); 13C{1H}-NMR (CDCl3, 100 MHz): δ 137.8 (C), 129.2 (CH), 128.7 (CH), 126.7 (CH), 72.4 (CH2), 72.3 (CH2), 55.7 (CH), 52.7 (CH), 38.5 (CH2), 19.0 (CH3); Trans-diastereomer diagnostic signals: 1H-NMR (CDCl3, 400 MHz): δ 0.93 (d, J  = 6.4 Hz, 3H); IR (NaCl, cm-1):  3310 (N-H stretch), 2969 (asymmetric C-H stretch), 2852 (symmetric C-H stretch), 1453 (aromatic ring stretch), 1102 (C-O stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C12H18NO: 192.1388, Found: 192.1383.NHOPh(+/-)100  95 Chapter 3: Phosphoramidate-Tantalum Complexes for Room Temperature Hydroaminoalkylation α-Substituted amines are an important structural motif prevalent in many biologically active molecules.2-8 Synthesis of these compounds in a catalytic manner can be achieved with hydroaminoalkylation (HAA), which is the direct alkylation of a carbon center α to an amine by an alkene leading to two possible regioisomers, a linear isomer and a branched isomer (Scheme 3.1).67-68 Such C-C bond forming transformations can be realized using a variety of different catalysts and several important milestones in this field have been achieved in the Schafer group by utilizing N,O-chelated early transition metal complexes.  While there has been significant progress in the field of HAA catalyst development, this reaction still has a limited substrate scope (mainly terminal alkenes, no alkynes or allenes, and N-methyl anilines), long reaction times (5-192 h), and high reaction temperatures (100-165 °C). Therefore, a general catalyst with an extensive substrate scope that displays reactivity under more mild reaction conditions is highly desired.   96  Scheme 3.1.  Synthesis of α-alkylated amines by catalytic hydroaminoalkylation  3.1 Complexes Supported by N,O-Chelating Ligands For Hydroaminoalkylation  At the crux of the catalyst development strategy in the Schafer group is the use of N,O-chelating ligands to modify reactivity at the metal center.41, 62, 67, 69-76, 78, 80-92, 94-100, 195-199, 345-365 These ligands systems include amidates, pyridonates, and ureates and offer modular control over R2+catalystR1HN R2 +R1HN R2Linear Branched[M]NMe2NMe22 HNMe2[M] NR1[M]R2NR1[M]NNR1R1R2R2HN R2R1HNmetallaaziridineformationalkene insertionprotonolysisC-H ActivationR1R1HNC-H ActivationR1HN  97 steric and electronic properties of the resulting metal complexes (Figure 3.1).  In addition, a variety of different binding modes can be accessed by these potentially hemilabile ligands, which may play important roles in catalysis (Figure 1.4).    Figure 3.1 Examples of complexes bearing N,O-chelating ligands    These ligand motifs have been installed on a number of early transition metals (Y, Hf, Ti, Zr, Ta),69-71, 73, 76, 79-82, 84-85, 87, 89, 91, 94-95, 98, 100, 345-346, 348-349, 354-356 as well as late transition metals (Ru, Ir, Rh).360-361, 365 The resulting complexes have demonstrated catalytic activity towards a variety of transformations including hydroamination of alkenes, alkynes, and allenes,62, 69-93 HAA of alkenes,89, 94-96, 98-100 amidation of amines,353 and ring-opening polymerization.362, 366  Seminal reports of HAA by Herzon and Hartwig found success with Ta-amido complexes, Ta(NMe2)5 (10) and [TaCl3(NEt2)2] (11).211-212 Their work inspired the investigation of an auxiliary ligand supported tantalum catalyst for this transformation.95 By using the N,O-chelating amidate ligand motif, catalyst systems with tunable steric and electronic properties were investigated for the α-alkylation of secondary amines with alkenes.95 Through this exploration, complex 12 was identified as the most reactive, with improved reactivity compared to complex 10 originally reported by Herzon and Hartwig (Figure 3.2).  With the amidate supported tantalum system, reaction times were shortened (20 h vs. 27 h) and reaction NR2R1O[M]AmidateNR2N(R1)2O[M]UreateNO[M]2-pyridonateR1  98 temperatures were reduced (130 °C vs. 160-165 °C).95, 211 In addition, a wide substrate scope, including challenging N-heterocycles, can be achieved with complex 12 and it is still one of the most broadly applicable catalyst systems reported to date.95-96    Figure 3.2 A comparison of reactivity between complexes 10 and 1295, 211   Following the disclosure of complex 12, a number of other auxiliary ligand supported group 5 complexes were described in the literature.100, 213-216 As a result, several important achievements were reached in the field of HAA, highlighting the importance of ligand design on catalytic activity.  Select examples of such milestones include the development of chiral catalysts for asymmetric HAA95, 213-216 and the expansion of the substrate scope of this transformation to include challenging, sterically demanding internal alkenes (Figure 3.3).100 HN+Ta precatalysttoluene, heatHNO OTa(NMe2)5NOTa(NMe2)4iPr iPr10Hartwig, 20074 mol%160-165 °C (27 h)90%12Schafer, 20095 mol%130 °C (20 h)87%Catalyst Loading:Reaction Conditions:Yield:  99  Figure 3.3 Examples of important achievements in hydroaminoalkylation using auxiliary ligand supported group 5 complexes95, 100, 214, 216   While several notable advances have been made in HAA with group 5 complexes, using precatalysts derived from group 5 metal-amido starting materials can result in an unwanted side reaction to generate an undesired dialkylamine by-product (Scheme 3.2).367 The secondary amine released during the precatalyst C-H activation step (Scheme 3.1) can serve as a substrate in the catalytic cycle (Scheme 3.2). This is problematic as it consumes the alkene substrate and can complicate purification steps.  In addition, a survey of the reaction conditions utilized in these reports has illustrated that high reaction temperatures are required for catalysis to proceed (Figures 3.2 and 3.3).95, 100, 211, 214, 216 In general, temperatures of >100 °C are necessary for good to moderate yields; therefore, the identification of a catalyst system which can operate under milder reaction conditions would be an important development for this field and could broaden the scope of this transformation to include thermally sensitive substrates.  NONOTa(NMe2)3iPriPriPr13Schafer, 200910 mol% 130 °C 24-192 hSiPh2MeSiPh2MeOONb(NMe2)3(HNMe2)n15Hultzsch, 20115 mol% 100-140 °C 5-105 hNOPhTa(NMe2)3Cl17Schafer, 20145-10 mol% 145 °C 20-44 hFirst example of asymmetric HAA(ee up to 61%)Highest ee achieved in asymmetric HAA (up to 98%)First example of HAA precatalyst for unactivated, sterically demanding internal alkenesCatalyst Loading:Reaction Conditions:  100   Scheme 3.2 Formation of hydroaminoalkylation byproduct from catalyst activation  3.1.1 Synthesis of Phosphoramidates and Applications in the Literature  Phosphoramidate compounds have been extensively studied in the literature due to their presence in a variety of biologically relevant natural products.368 Various derivatives have demonstrated anti-viral, anti-tumor, anti-bacterial, anti-malarial, and anti-protozoal activities.  Beyond the attractive medicinal chemistry properties, this class of molecules has also been investigated for agricultural applications,369-372 as flame retardant materials,373-380 as well as for applications in analytical chemistry.381-382  Phosphoramidates can easily be prepared from commerically available starting materials through a number of synthetic strategies described in the literature (Figure 3.4).383-391 Modifications are facile and can be made on both the nitrogen and the oxygen heteroatoms to tune the resulting electronic and steric properties about the phosphorous center. Despite the widespread interest in synthesis and applications of phosphoramidates, the use of this structural motif as an auxiliary ligand in organometallic and inorganic chemistry has yet to be widely exploited.  [Ta] [Ta]R HNR RC-H activation +  HNMe2N MeNMe2NMe22  101  Figure 3.4 Select examples illustrating the preparation of phosphoramidates383-384, 386-387, 390-391  3.1.2 Scope of Chapter Although many different N,O-chelating ligands have been explored by the Schafer group, they were all previously limited to N-C-O ligand motifs.  In search of a more general HAA catalyst, a post-doctoral fellow in the Schafer group, Dr. Pierre Garcia, proposed the use of phosphoramidates as proligands.  Amidates are planar in geometry and provide little steric protection about the metal center (Figure 3.5).  In contrast, the phosphoramidate motif is tetrahedral in geometry at the phosphorus center, resulting in a more sterically encumbered POHRORO +R1HN R2CCl4 PONROROR2R1 Atherton-Todd ReactionNH2R + POEtEtO OEt20 mol% Rose Bengalgreen light, airCH3CN, 70 °CP NHEtOEtORios, 2016R1DG+PON3RORO4 mol% [IrCp*Cl2]216 mol% AgSbF650 mol% AgOAcDCM, 60 °CPONHRORODGR1OZhu, 2014POHRORO +R1HN R2PONROROR2R110 mol% I2aq. H2O2DCM, r.t.Prabhu, 2013NH2 i.  NaNO2AcOH/H2O, -15 °Cii.  NaN3 -15 °C to r.t.iii.  P(OR)3, DCMPON HR1OR1OModified Staudinger ReactionRRR  102 ligand system about the metal center.  In addition, they are electronically different from amidate proligands, which is expected to significantly impact the resulting electronic nature of the metal catalyst.392 In addition, access to 31P-NMR spectroscopy could be a useful diagnostic tool for studying various binding modes of these resulting complexes, providing an advantage to phosphoramidate ligands over amidate ligands.  Figure 3.5 A comparison of amidate and phosphoramidate ligands  This chapter explores the use of new N,O-phosphoramidate tantalum complexes for catalytic HAA.  In particular, efforts to identify a catalyst with unprecedented room temperature reactivity will be presented.  Two classes of compounds were studied, phosphoramidate-Ta(NMe2)4 and phosphoramidate-TaMe3Cl, and unique reactivity was observed with each of these two new classes of complexes.    3.2 Results and Discussion 3.2.1 Catalytic Screening of Phosphoramidate-Ta(NMe2)4 Complexes The phosphoramidate proligands and phosphoramidate-Ta complexes screened for catalysis in this section (101-121, except 110 and 111) were originally synthesized and characterized by Dr. Pierre Garcia, while I was responsible for catalytic investigations.   R NOR'MMONR'RP NOR'MMONR'ROROORROAmidate Ligand Phosphoramidate Ligand  103 The phosphoramidate proligands were synthesized using modified literature procedures.  391, 393 N-Alkyl substituted phosphoramidates were prepared from the chlorophosphate precursor,393 whereas N-aryl substituted phosphoramidates were synthesized from a modified Staudinger reaction (Scheme 3.3).391   Scheme 3.3 Preparation of phosphoramidate proligands  Phosphoramidate-Ta(NMe2)4 complexes were synthesized from protonolysis of Ta(NMe2)5 (Figure 3.6).  In general, this is a high yielding route to access these precatalysts for HAA.  A family of tantalum complexes (101-116) with varying substitution on the oxygen (Et, iPr, or Ph) and the nitrogen (alkyl or aryl) of the phosphoramidate ligand was tested by catalytic screening, thereby permitting exploration of electronic and steric effects on the catalytic efficiency of this new class of complexes for HAA.       POClRORO + PONROROR1HNEt3,CH2Cl20 °C to r.t., 18 hH2NR1NH2 i.  NaNO2AcOH/H2O, -15 °Cii.  NaN3 -15 °C to r.t.iii.  P(OR)3, DCMPON HR1OR1ORR  104   Figure 3.6  Preparation of phosphoramidate-Ta(NMe2)4 complexes by protonolysis  Analysis by 31P{1H}-NMR spectroscopy showed that some of these phosphoramidate-Ta(NMe2)4 complexes (104, 111-116) exist as multiple species in solution, possibly due to the NPR1ROOROTa(NMe2)4PONROROR1H + Ta(NMe2)5hexanesr.t., 18 hNPOOO Ta(NMe2)4NPOOOTa(NMe2)4NPOOOTa(NMe2)4NPOOOTa(NMe2)4NPOOOTa(NMe2)4NPOOOTa(NMe2)4CF3NPOOOTa(NMe2)4NPOOOTa(NMe2)4NPOOOTa(NMe2)4101 102107112111110114 116NPPhOOPhOTa(NMe2)4NPOOOTa(NMe2)4NPPhOOPhOTa(NMe2)4NPOOOTa(NMe2)4113106 108109115NPOOOTa(NMe2)4104NPOOOTa(NMe2)4103NPOOOTa(NMe2)410592%91% 72%b quantitativequanitative 74%b 89% quantitative67% 28%b 98% 61%93% 93% 93% 98%Yield:aaIsolated yield after removal of volatiles.  bRecrystallized yield.  105 phosphoramidate ligand adopting different binding modes.  In general, these complexes are oils and are N-aryl substituted phosphoramidate-Ta complexes with ortho substituents on the aryl ring.  In these cases, since the 1H{31P}-NMR spectra show broad signals, 31P{1H}-NMR spectroscopy was particularly useful for determining how many possible species are present (signals typically range from δ 10 to -5 ppm).  Further purification steps to isolate a single species from these mixtures were largely unsuccessful and screening for catalytic activity was performed using the crude mixture. Solid state molecular structures were obtained for select complexes (107, 108, and 110) and show that these tantalum complexes crystallize in a pseudo-trigonal bipyramidal geometry with the κ2(N,O)-chelate occupying one equatorial coordination site (Figure 3.7).  Solid state molecular structures of 107 and 108 were obtained by Dr. Garcia and I obtained the structure for complex 110.  In these cases, only one signal is observed in the 31P{1H}-NMR spectra and the 1H-NMR spectra are consistent with the presence of signal species.  This assignment is made by considering the bond angles in the plane of the phosphoramidate ligand (P1-Ta-N3: 114.20(4)°, N2-Ta-N3:  104.66(5)°, and P1-Ta-N2: 141.12(4)°) which are closer to 120° (trigonal bipyramidal) than 90° (octahedral).  Solid state molecular structures of related monoamidate-Ta(NMe2)4 complexes are also consistent with a distorted trigonal bipyramidal geometry.367   In comparison to previously synthesized monoamidate-Ta(NMe2)4 complexes, the O1-Ta-N1 bite angle is slightly larger in the case of the phosphoramidate ligand (64.70(4)° vs. 56.85(7)-57.66(6)°).367 Also, complex 110 has a shorter Ta-N1 bond than a Ta-O1 bond (2.2399(12) Å vs. 2.2823(11) Å), which is unusual for N,O-chelating ligands on early transition metals when compared to other amidate, ureate, and pyridonate complexes.69, 71, 76, 95 Both complex 110 and analogous monoamidate-Ta(NMe2)4 complexes have dimethylamido ligands with planar nitrogen   106 atoms.367 The sums of the bond angles about the nitrogen atoms total approximately 360° (359.868°), which is consistent with a monoanionic, 4-electron donor; therefore, like the monoamidate-Ta(NMe2)4 systems, these can be considered to be 20-electron complexes. Complex 110 crystallizes in the centrosymmetric space group P21/n; however, an incomplete data set was collected for the same compound exhibiting different crystal morphology.  Interestingly, this second data set showed crystallization of 110 in a non-centrosymmetric space group, P212121, despite being an achiral complex.          	  Figure 3.7  ORTEP of the solid state molecular structure of complex 110 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity).  The test reaction between 4-methoxy-N-methyl aniline and 1-octene was used to screen the prepared phosphoramidate-Ta(NMe2)4 complexes for catalytic activity using previously  Selected Bond Lengths (Å) Selected Bond Angles (°) Ta-N1 2.2399(12)  N1-Ta-O1 64.70(4) Ta-N2 2.0038(13) P1-Ta-N3 114.20(4) Ta-O1 2.2823(11) N2-Ta-N3 104.66(5) P1-N1 1.6140 (13) N4-Ta-N5 171.31(5) P1-O1 1.5021(11) O1-P-N1 101.85(6) O1O2O3P1N1N2N3N4N5Ta1C1  107 published reaction conditions at 130 °C and 110 °C (Figure 3.8).95 Complexes which displayed high reactivity under these screening conditions were studied at the lower reaction temperature of 90 °C in an effort to identify potential systems that show catalytic activity at reaction temperatures below 100 °C.  The reactions were monitored by 1H-NMR spectroscopy (300 MHz, toluene-d8) and yields were determined by monitoring the disappearance of diagnostic signals of the aromatic protons in the ortho position in the starting material (δ 6.48) and the appearance of new aromatic signals associated with the analogous protons in the resulting product (δ 6.63) after 20 h (for a sample spectrum, see Figure 3.23 in Section 3.4).  As with previously reported group 5 HAA systems,95, 200-201, 211-213, 394 only the branched regioisomer was observed by NMR spectroscopy with these phosphoramidate-Ta complexes.  Due to the modular nature of these proligands, the effect of substituents on the nitrogen and the phosphorus atoms could be assessed independently.  Figure 3.8 illustrates the results for the initial complex screening for HAA and exploration of the effect of the nitrogen substituent with respect to catalyst efficiency.     108  Figure 3.8 Catalytic screening of phosphoramidate-Ta(NMe2)4 complexes for hydroaminoalkylation NPOOO Ta(NMe2)4HN+5 mol% Ta precatalysttoluene-d8, 20 hHNO OYielda,b130 °C: 70%110 °C: 27%NPOOOTa(NMe2)4130 °C: 86%110 °C: 11%NPOOOTa(NMe2)4130 °C: 60%110 °C: 9%130 °C: >95%110 °C: >95%  90 °C:   30%               (81% after 40 h)NPOOOTa(NMe2)4NPOOOTa(NMe2)4130 °C: 58%110 °C: 42%NPOOOTa(NMe2)4CF3130 °C: 63%110 °C:   5%NPOOOTa(NMe2)4110 °C: >95%  90 °C:   50%             (>95% after 40 h)NPOOOTa(NMe2)4 90 °C:   38%             (>95% after 40 h)NPOOOTa(NMe2)490 °C: 19%101 102107112111110114 116NPPhOOPhOTa(NMe2)4130 °C: 68%110 °C: 27%NPOOOTa(NMe2)4130 °C: 71%110 °C: 17%NPPhOOPhOTa(NMe2)4130 °C: 24%110 °C:   0%NPOOOTa(NMe2)4 90 °C: 17%113106 108109115aScreening reaction conditions:  0.5 mmol of amine, 0.75 mmol of alkene, 0.025 mmol of Ta catalyst, 1 g of toluene-d8. bYield was determined by 1H-NMR spectroscopy (toluene-d8, 300 MHz, 298 K).NPOOOTa(NMe2)4104NPOOOTa(NMe2)4103NPOOOTa(NMe2)4105130 °C: 65%110 °C: 14%130 °C: 19%110 °C: 4%130 °C: 85%110 °C: 35%  109 Most of the phosphoramidate-Ta(NMe2)4 complexes investigated demonstrated catalytic activity for HAA, particularly at elevated temperatures (≥ 110 °C, Figure 3.8).  In general, N-aryl phosphoramidate-Ta complexes showed improved activity over the N-alkyl complexes.  This is proposed to be a steric effect not an electronic effect, as complexes with similar steric bulk at the nitrogen display similarities in reactivity (yields at 130 °C:  65% for 103 (N-Cy) and 60% for 107 (N-Ph), yields at 110 °C:  14% for 103 and 9% for 107). The addition of electron withdrawing substituents on the N-aryl ring showed no improvement in catalysis.  This is in contrast to literature examples that show that incorporation of electron-withdrawing ligands can be advantageous for catalysis.95, 212 In addition, this result corroborates the hypothesis that the predominant feature of the phosphoramidate ligand influencing catalytic activity are steric properties, not electronic effects. Substitutions at both the 2,6-positions of the N-aryl ring were observed to decrease reactivity (Figure 3.8, 111).  This extra steric bulk on the ligand system appears to also affect the stability of the resulting tantalum complex, as the unwanted formation of a precipitate in the reaction mixture is observed.  This observation is possibly due to catalyst decomposition, and notably the reactions with precipitate show no further conversion to the α-alkylated product, as detected by 1H-NMR spectroscopy, even with prolonged heating.  Interestingly, the ortho monosubstituted N-aryl phosphoramidate-Ta complexes (112-116) demonstrated the highest activity relative to all other complexes studied (Figure 3.8).  At reaction temperatures of 130 ˚C and 110 ˚C, complete conversion to the desired HAA product was observed after 20 h with complex 112.  Catalytic activity was even observed at 90 ˚C (30% yield).  In comparison, to achieve similar reaction progress for the same test reaction, the Ta(NMe2)5 system reported by Hartwig (10) requires reaction temperatures of 160-165 ˚C (90% yield after 27 h)211 and the   110 Schafer amidate system operates at 130 ˚C (complex 12:  87% yield after 20 h).95 Gratifyingly, complete conversion can be achieved with ethyl (114) and n-propyl (116) substitutions on the phenyl ring at temperatures of 90 ˚C, and some reactivity was also observed at 70 ˚C with complex 116, albeit only after an extended period of time (24%, 72 h). It is important that these substituents are linear in configuration, as the isopropyl variant fails to show comparable conversion, once again showing that the test reaction is sensitive to steric bulk about the metal center (Figure 3.8).  With respect to the substituents on the P-oxygen, ethyl, isopropyl, and phenyl were studied (Figure 3.8).  Ethyl substituents on the oxygen performed consistently better than the rest, indicating that an increase in steric bulk at this particular position has no beneficial effect on catalysis, presumably because it is far removed from the metal center.  In some cases, analysis of the Ta residue following catalysis by mass spectrometry indicated loss of the substituents on the P-oxygen atoms (101, 102, and 104).   In addition to the tantalum complexes discussed above, a bis(phosphoramidate)-Ta(NMe2)3 complex (117) was also screened for catalytic activity using the same test reaction conditions described previously (Figure 3.9).  This increase in coordination number and steric bulk around the metal center showed a detrimental effect on catalytic activity relative to monophosphoramidate-Ta complexes.  A phosphoramidate-Ta complex containing a tethered backbone was also investigated (118), in light of the observation that a loss of the substituents on the P-oxygen atoms of the phosphoramidate ligand can occur.   However, the resulting complex did not demonstrate improved reactivity relative to the untethered counterparts, suggesting that the loss of the substituents on the P-oxygen atoms does not impact catalysis.    111  Figure 3.9 Catalytic screening of bis(phosphoramidate)-Ta(NMe2)3 complex and tethered phosphoramidate-Ta(NMe2)4 complexes for hydroaminoalkylation   Overall, while all of the phosphoramidate-Ta(NMe2)4 complexes synthesized were catalytically active towards HAA, many of the catalysts still required reaction temperatures of ≥ 110 °C for yields >50%.  As previously reported group 5 complexes also typically require reaction temperatures of ≥ 110 °C,95, 200-201, 211-213, 215-216 this is not a significant advancement towards the development of a low temperature HAA catalyst. Select complexes were reactive at lower temperatures (112-116, 90-70 °C) and displayed progress towards room temperature reactivity, but there remained room for improvement in this area.   A preliminary investigation of substrate scope was conducted with complex 102, which was one of our most promising catalyst in the early stages of this project, and these results were compared with that obtained with complex 12 (Table 3.1).95 Using 4-methoxy-N-methylaniline as the amine substrate, similar reactivity towards linear alkenes and strained internal alkenes NPO Ta(NMe2)3117NPOOO Ta(NMe2)42110 °C: 12%130 °C: 39%110 °C: 9%118HN+5 mol% Ta precatalysttoluene-d8, 20 hHNO OYielda,baScreening reaction conditions:  0.5 mmol of amine, 0.75 mmol of alkene, 0.025 mmol of Ta catalyst, 1 g of toluene-d8.  bYield was determined by 1H-NMR spectroscopy (toluene-d8, 300 MHz, 298 K).OO  112 such as norobornene (Table 3.1, Entries 1 and 2) was observed with complex 102 and 12.  The reaction of 1-octene and benzylmethylamine also gave comparable results between complex 102 and 12; however, complex 12 required shorter reaction times to achieve similar yield (Table 3.1, Entry 4).  While complex 12 was effective towards substrates such as unstrained internal alkene cyclooctene (Table 3.1, Entry 3) and N-heterocycles (Table 3.1, Entry 5 and 6), complex 102 was not.  These are challenging substrates for HAA that typically require elevated reaction temperatures (>130 °C) and are only reactive with select catalyst systems.95-96, 99-100, 211, 215, 225, 229 While complex 102 demonstrated comparable reactivity to complex 12 for select substrates, in general the amidate-Ta catalyst displays a broader substrate scope than the phosphoramidate-Ta system.                113 Table 3.1 Preliminary substrate scope investigations for complex 102 in comparison to complex 12   +5 mol% Ta precatalysttoluene-d8, 130 °C, 20 h R1HNR2R3R4R3NPOOOTa(NMe2)4102NOTa(NMe2)4iPr iPr 12Entrya Amine Alkene 102NMR Yield  (%)b12 Isolated Yield (%)c1HNO86% 87%2HNO87% 93%3HNO0% 83% (for COD, 96 h)d4 NH 77% (60h) 75% (50 h)5HN 22% 92% (37 h)6HN 0% 74% (134 h)aScreening reaction conditions:  0.5 mmol of amine, 0.75 mmol of alkene, 0.025 mmol of Ta catalyst, 1 g of toluene-d8. bYield was determined by 1H-NMR spectroscopy (toluene-d8, 300 MHz, 298 K).  cIsolated yield after flash chromatography.  dReaction temperature: 165 °C.R1HN R2R4  114 The catalytic screening of the phosphoramidate-Ta(NMe2)4 complexes demonstrated progress towards milder reaction conditions, with reactivity detected at temperatures as low as 70 °C; however, these complexes were not viable candidates for a room temperature HAA reaction.  In addition, no improvement on substrate scope over the amidate-Ta(NMe2)4 system was observed.  Thus, we sought to find a new catalyst with improved reactivity and substrate scope than that observed with these initial phosphoramidate-Ta systems. 		 	3.2.2 Catalyst screening of Tantalum Complexes Containing Other Phosphorus Containing N,O-Chelating Ligands  As an extension of the ligand motif studied in the previous section, other phosphorus containing N,O-ligands were installed onto tantalum and their effects on catalysis were studied (Figure 3.10). Complexes 119-121 were subjected to the same test reaction of 4-methoxy-N-methyl aniline and 1-octene using the same catalytic screening conditions that were described in Section 3.2.2.  The absence of the oxygen atoms in the backbone of the ligand for the phosphinic amidate complex 119 gave poor yield of the desired product (10%) at reaction temperatures of 110 °C.  In comparison, the analogous phosphoramidate complex 109 was relatively more active for the same reaction (27% yield), albeit, the reactivity is still poor.  Replacement of the oxygen atoms in the backbone of the phosphoramidate ligand with nitrogen atoms (120) was proposed to increase steric bulk of the ligand framework relative to the original phosphoramidate motif, due to the incorporation of two methyl groups on each N-atom.  However, no catalyst turnover was observed at the reaction temperature studied.  Finally, the effect of a phosphoramidothiolate ligand was investigated (123).  The sulfur analogue resulted in 15% yield of the desired product at 130 °C in contrast to the phosphoramidate ligand (102) which displayed good reactivity (86%   115 yield) under the same conditions.  The catalytic screening of these alternative phosphorus containing N,O-ligand frameworks demonstrate that these modifications made to the phosphoramidate motif were detrimental to catalytic activity.  Also, these results show the importance of oxygen atoms in the backbone of the ligand scaffold of the N,O-chelate to dramatically modify the reactivity of the resulting Ta complex.   Figure 3.10 Screening of tantalum complexes containing other phosphorous N,O-chelating ligands for catalytic hydroaminoalkylation  3.2.3 Phosphoramidate-TaMe3Cl Complexes for Catalytic Hydroaminoalkylation Previous work in our group demonstrated that a known, simple organometallic complex,395 TaMe3Cl2, was catalytically active for HAA.99 Unlike the Ta(NMe2)5 starting material used for the complexes discussed (vide supra), precatalyst activation results in the liberation of methane (Scheme 3.4), which avoids the formation of the dialkylamine by-product depicted in Scheme 3.2.  In addition to demonstrating that this complex was effective for this NPPhOPhTa(NMe2)4110 °C: 10%NPNONTa(NMe2)4 90 °C: 0%119 120NPOSOTa(NMe2)4130 °C: 15%121HN+5 mol% Ta precatalysttoluene-d8, 20 hHNO OYield:a,baScreening reaction conditions:  0.5 mmol of amine, 0.75 mmol of alkene, 0.025 mmol of Ta catalyst, 1 g of toluene-d8.  bYIeld was determined by 1H-NMR spectroscopy (toluene-d8, 300 MHz, 298 K).  116 transformation, an improved substrate scope and a decrease in reaction temperature (some reactions proceeded even at 90 ˚C) was observed.99   Scheme 3.4 Proposed catalytic cycle for hydroaminoalkylation with methane elimination   Using TaMe3Cl2 as a simple tantalum organometallic starting material, phosphoramidate ligands can be installed using salt metathesis (Scheme 3.5).97 Unlike the phosphoramidate-Ta(NMe2)4 complexes, the resulting phosphoramidate-TaMe3Cl organometallic complexes are [Ta]MeMe2 CH4[Ta] NR1[Ta]R2NR1[Ta]NNR1R1R2R2HN R2R1HNmetallaaziridineformationalkene insertionprotonolysisC-H activationR1R1HNC-H activation  117 light and thermally sensitive, highlighting significant differences in reactivity of these complexes as a result of the tantalum starting materials chosen.      Scheme 3.5 Preparation of complex 123 by salt metathesis   Solid state molecular structures of phosphoramidate proligand 122 and resulting Ta complex 123 were obtained by myself and Dr. Garcia, respectively (Figure 3.11).97 In the solid state, 122 displays a distorted tetrahedral geometry around the phosphorus center with angles ranging from 100.49(4)° to 113.01(5)°.  Like the previously described phosphoramidate-Ta(NMe2)4 complex 114, 123 exhibits a pseudo-trigonal bipyramidal geometry in the solid-state; however, in this case the chloro and the phosphoramidate ligands occupy the axial coordination sites, with the methyl ligands in the equatorial positions.    A comparison of the solid state molecular structures of the phosphoramidate proligand 122 with complex 123 indicates slight changes in the phosphoramidate moiety upon ligation.   The P1-O1 bond is elongated from 1.4727(9) Å to 1.516(2) Å to indicate loss of double bond character in the P1-O1 bond and the P1-N1 bond is slightly shortened upon ligation from 1.6338(10) Å in 122 to 1.616(3) Å in 123. In addition, the O1-P1-N1 bond angle is significantly more acute in the case of the complex (98.68(12)°) than in the proligand (113.01(5)°).  The N1-Ta-O1 bite angle for this complex is 66.68(9)°, which is slightly larger than the bite angle of PONHOO 1. NaHMDS, toluene    18 h, rt2.  TaCl2Me3, hexanes     -30 °C to r.t., 2 hNPOOOTaMe3Cl122 123  118 complex 110 (64.70(4)°), a phosphoramidate-Ta(NMe2)4 complex, and larger than the bite angle observed for amidate-Ta(NMe2)4 complexes (56.85(7)-57.66(6)°)).367  122 123 Selected Bond Lengths (Å) Selected Bond Angles (°) Selected Bond Lengths (Å) Selected Bond Angles (°) P1-O1 1.4727(9) O1-P1-N1 113.01(5) P1-O1 1.516(2) O1-P1-N1 98.68(12) P2-O2 1.5778(9) O1-P1-O2 109.30(5) P1-O2 1.560(2) O1-P1-O2 115.57(13) P1-N1 1.6388(10) O2-P1-O3 100.49(4) P1-N1 1.616(3) O2-P1-O3 102.75(13) N1-C1 1.6488(10)   N1-C1 1.439(4) O1-Ta-N1 66.68(9)     Ta1-N1 2.315(3) C13-Ta-Cl1  82.38(8)     Ta1-O1 2.190(2) Cl1-Ta-P1  164.02(2)       C13-Ta-C14  111.28(13)       C14-Ta-C15  110.34(13)  Figure 3.11 ORTEP of the solid state molecular structure of phosphoramidate proligand 122 and Ta complex 123 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity) Selected Bond Lengths (Å) Selected Bond Angles (°)P1-O1 1.4727(9) O1-P1-N1 113.01(5)P1-O2 1.5778(9) O1-P1-O2 109.30(5)P1-N1 1.6388(10) O2-P1-O3 100.49(4)N1-C1 1.4410(14)Selected Bond Lengths (Å) Selected Bond Angles (°)P1-O1 1.516(2) O1-P1-N1 98.68(12)P1-O2 1.560(2) O1-P1-O2 115.57(13)P1-N1 1.616(3) O2-P1-O3 102.75(13)N1-C1 1.439(4) O1-Ta1-N1 66.68(9)Ta1-N1 2.315(3) Cl1-Ta-C13 82.38(8)Ta1-O1 2.190(2) Cl1-Ta-P1 164.02(2)C13-Ta-C14 111.28(13)Cl1C13C14N1O1O2O3P1C15Ta1O1O2O3N1C1  119 A screening of various phosphoramidate ligands by Dr. Garcia indicated that complex 123 was the most catalytically active complex and impressively showed catalytic turnover even at room temperature.97 High reaction temperatures is a persistent challenge in the field of catalytic HAA; thereby limiting the reaction to exclude thermally sensitive substrates, such as styrenes,396-398 dienes,399-400 and acrylates.401-403 Reactivity with complex 123 is the first and only reported example of room temperature HAA.97  Using the standard test reaction between 4-methoxy-N-methylaniline and 1-octene, the optimization of reaction conditions was conducted (Table 3.2).  Dr. Garcia showed that for the in situ generated catalyst, increasing the catalyst loading from 5 mol% to 10 mol% afforded an increase of conversion to the desired product from 52% to 76% (Table 3.2, Entries 1 and 2).97 Using isolated complex improved the conversion from 76% to 86% (Table 3.2, Entries 1 and 2).97   I was responsible for screening various solvents for the reaction.  The test reaction was studied using toluene-d8, C6D6, hexanes, and THF-d8 as solvents and yields were determined using 1H-NMR spectroscopy after the reaction was stirred at room temperature for 20 h.  Yields of 86%, 73%, 62%, and 26% were obtained respectively, indicating that toluene was the preferred solvent for the reaction (Table 3.2, Entries 3-6).  Further investigations by coworker Mr. Mitchell Perry later showed that this catalyst system is effective even under neat conditions, achieving 96% yield for the same test reaction (Table 3.2, Entry 7).97        120 Table 3.2 Optimization of reaction conditions with complex 123   3.2.4 Exploration of Hydroaminoalkylation Substrate Scope of 123  The amine substrate scope of complex 123 was studied with 1-octene at room temperature as the alkene substrate in HAA by Dr. Garcia (reaction time 20 h).97 These investigations revealed that electron rich N-methylaniline substrates (4-methoxy-N-methylaniline and 4-dimethylamido-N-methylaniline) yielded the desired branched product in good isolated yields (84 and 87%) and alkyl substituted N-methylaniline substrates such as N-methyl-p-toluidine were reacted in moderate yields (43%).  Electron poor substrates showed poor to no reactivity, as did linear dialkylamines (dibutylamine, 15%). N-Heterocycles such as piperdine and tetrahydroquinoline were unreactive as well.  While a few of catalysts have been reported to HN+x mol% 123solvent, 20 hHNO OEntrya 123(mol %) SolventYield(%)1b 5 toluene-d8 52%2b 10 toluene-d8 76%3c 10 toluene-d8 86%4b 10 C6D6 73%5b 10 hexanes 62%6c 10 THF-d8 26%7c 10 none 96%aReaction conditions:  0.5 mmol of amine, 0.75 mmol of alkene, 0.6 g of solvent. Yield was determined by 1H-NMR spectroscopy.bIn situ generated catalyst.  cIsolated complex  121 be reactive with tetrahydroquinoline,211, 215, 227, 404 only the Schafer tantalum amidate complex 12 has shown reactivity towards piperdine.95 As such, electron rich 4-methoxy-N-methylaniline was utilized as the amine substrate in alkene substrate scope investigations.  The electron-rich 4-methoxy-N-methylaniline shows excellent reactivity with a range of terminal alkenes in 20 h (Figure 3.12).  Notably, despite the oxophilic nature of early transition metals, this catalytic system can tolerate silyl-protected alcohols and the desired products are isolated in good yields (125-126).  Phenyl-substituted alkenes are well tolerated and the resulting branched products are recovered in good yields (127-128).      122  Figure 3.12 Alkene substrate scope for complex 123 OHN+10 mol% 123 toluene, r.t., 20 hOHNR1R2OHN12486%Isolated Yield:aR1R2OHN OTBS12588%OHN12778%OHN OTBS12659%OHN12870%OHN129 (+/-)86%OHNOOHNCl OHNCF3 OHN13088% [68:1]b (50 °C)87% (168 h)13193% [99:1]b (168 h)13491% [1.6:1 ]b (50 °C)78% [1.8:1 ]b (168 h)OHN13391% [10:1 ]b (50 °C)93% [10:1 ]b (168 h)SiMe313566% [1:7 ]baReaction conditions:  1.0 mmol of amine, 1.5 mmol of alkene, 0.1 mmol of 123, 1.2 g of toluene. bMajor isomer presented, [branched/linear] ratio determined by GC-MS of the crude material.  Yields refer to the combined regioisomers.  cConverison determined by 1H-NMR spectroscopy.13287% [14:1 ]b (50 °C)93% [26:1]b (168 h)OHNOHN13621%cOHN13710%cOHN1385%cOHN13928%cOHN14029%cO O Ph  123 Good reactivity with strained internal alkenes such as norbornene was observed and a single diastereomer of the product was observed by GC-MS and 1H-NMR spectroscopy (129, Figure 3.12).  After isolation, product 129 reacted with 4-nitrobenzenesulfonyl chloride in the presence of triethylamine to yield the derivatized sulfonamide product.  Crystallization of the sulfonamide from acetonitrile yielded colourless crystals (41% yield) that were subsequently analyzed by single crystal X-ray diffraction studies to confirm the stereochemistry of the product as the exo-diastereomer (Figure 3.13).   Figure 3.13 ORTEP representation of the solid state molecular structure of 129 after derivatization with 4-nitrobenzenesulfonyl chloride  O1O2O3O5O4N2 N1S1  124 Challenging substrates, such as styrene, require longer reaction times to achieve full conversion at room temperature, but reaction times can be accelerated to just 20 h with mild heating (50 °C, 130-134, Figure 3.12).  Although some of these reactions require prolonged reaction times at room temperature, catalyst deactivation is not observed and full conversion is reached with extended reaction times.  Efforts to reduce reaction times through increasing reaction temperatures (>70 °C) resulted in catalyst decomposition.  As expected for group 5 metal-based catalysts, HAA with 123 gives exclusively the branched isomer as seen with products 124-129 and substrate scope investigations with various amines.  However, formation of the linear regioisomer was observed by GC-MS and 1H-NMR spectroscopy when styrene and substituted styrene substrates were employed in the reaction (131-134).  Examples of titanium catalyzed HAA with styrenes also yielded mixtures of regioisomers (complexes 20, 22-24),224, 227-228, 405 but the only other tantalum complexes with reported reactivity towards styrenes (complex 10 and 16) only note the trace formation of the linear product (≥4%).99, 404 Thus, this is a rare example of a group 5 catalyst accessing both linear and branched isomers for a variety of substrates.97 Interestingly, the branched to linear product ratio is dependent on the nature of the p-substituent on the styrene, as the amount of linear product increases in the presence of stronger electron-withdrawing groups.  Almost exclusive branched regioselectivity is observed with 4-methoxystyrene (130, 68:1 branched:linear), but for the first time, up to a 1.8:1 ratio of branched to linear product is observed with the trifluoromethyl substituted styrene in product 134.  While mixtures of regioisomers are observed when various styrenes are employed in HAA with 123, the branched regioisomer is still the major product formed.  However, when vinyltrimethylsilane was used as the alkene substrate, a switch in regioselectivity was observed to yield the linear regioisomer as the major product (135, 1:7 branched:linear, Figure 3.12) in   125 moderate yield (66%, combined yield for both regioisomers).  Further attempts to separate the regioisomers through column chromatography were unsuccessful and the product was isolated as a mixture. Other alkenes were studied and low conversions to the desired HAA products were observed with complex 123 (136-140, Figure 3.12).  Only select systems have been reported in the literature for accessing 137 with a β-quaternary centre and 138, the product of the reaction with a less strained internal alkene,99-100, 211, 214, 229 and there are no reported examples in the literature of HAA leading to aminoether products 139 and 140.  Product 139 has a synthetic handle for further reactivity and 140 could be deprotected to reveal a primary alcohol. A number of other alkenes were investigated as possible substrates, but no conversion was observed in the cases described in Figure 3.14.   Complex 123 was found to be unreactive towards sterically demanding alkene substrates such as 2-methylbut-2-ene (141) and 2,4,6-trimethylstyrene.  The reaction of 4-methoxy-N-methylaniline with ethyl acrylate (143) also failed to yield the desired HAA product, although conversion to the aza-Michael addition product was observed by 1H-NMR spectroscopy (78% by GC-MS).  Unfortunately, compound 123 does not react with dienes 144 and 145 and reactivity with substrates 146-148 containing various functional groups was also not observed. To date, there have been no reported examples of the catalytic α-alkylation of amines with allenes and alkynes, thus reactivity with other C-C unsaturations was also investigated (Figure 3.14).  No reactivity was observed with allenes (149-151) and alkynes (152-153).  While no conversion to product was observed during the reaction of 4-methoxy-N-methylaniline and 1-octyne (152), catalyst decomposition was observed, possibly due to the acidic nature of the terminal alkyne proton.     126  Figure 3.14 Unreactive alkene, allene, and alkyne substrates for hydroaminoalkylation with 123  3.2.5 Temperature Effects on Regioselectivity As noted in Figure 3.12, when vinyltrimethylsilane was used as the alkene substrate with complex 124, a switch in regioselectivity was observed to yield the linear regioisomer as the major product (135, 1:7, branched:linear). In contrast, previous reports of group 5 catalyzed HAAs with vinyltrimethylsilane show exclusive regioselectivity for the branched product, albeit at much higher reaction temperatures (100-165 °C).211, 214 Intrigued by this observation, the HAA 141B142 143147S144148OONo product formation was observed:a145146NOOOOCNPh PhC149O C150OSiMe3C151 152 153OHN+10 mol% 123toluene-d8, r.t., 20 hOHNR1R2R1R2aReaction conditions:  0.5 mmol of amine, 0.75 mmol of alkene, 0.05 mmol of 123, 0.6 g of toluene-d8.  Reactions were monitored by 1H-NMR spectroscopy (300 MHz, 298 K).  127 reaction between vinyltrimethylsilane and 4-methoxy-N-methylaniline was studied at various temperatures (4 °C, 22 °C, and 50 °C) to determine if the room temperature reaction conditions influence the switch in regioselectivity observed (Table 3.3). Changes in reaction temperature over the range studied did not appreciably change the branched:linear ratio of the resulting mixture of 135.  Therefore, the changes in regioselectivity observed with complex 123 when vinyltrimethylsilane is used as an alkene substrate is unrelated to the lower reaction temperature relative to previous reports. 211, 214 Remarkably, complex 123 is still catalytically active at 4 °C with this substrate, despite other reported systems requiring over 90 °C for catalytic turnover.97  Table 3.3 Temperature effects on regioselectivity of 135    In the absence of evidence supporting the hypothesis that reaction temperatures can influence regioselectivity in HAA, the switch in regioselectivity observed in the formation of product 135 with complex 123 is proposed to be a result of the vinyltrimethylsilane substrate itself.  We believe that the regioselectivity observed may be a result of stabilization of transient OHN+ SiMe310 mol% 123toluene, 20 hOHN SiMe3 +OHN SiMe3Temperature (°C) Yield (%) Branched:Linear[a]4 29 1:1622 69 1:750 69 1:10[a] Ratios determined by GC-MS before flash chromatography.135branched 135linear  128 positive charge buildup during the alkene insertion step of the catalytic cycle (Figure 3.15).97  For vinyltrimethylsilane, preferential formation of transient positive charge would occur at the terminal position, or β to the silicon, due to stabilization through hyperconjugation, thus leading to the preferential formation of the linear product.406-407 In contrast, with alkyl and aryl substituted alkenes, formation of transient positive charge would preferentially occur in the internal position, leading to the branched product.408    Figure 3.15 Proposed rationale for the preferential formation of the linear regioisomer of product 135  The proposal that transiently charged species are involved is further corroborated with the experimental observations regarding regioselectivity obtained from HAA using substituted styrenes.97 Electron-donating groups, such as –OMe, at the para-position of the styrene ring result in almost exclusive regioselectivity for the branched product (130, 68:1 branched to linear), but mixtures of linear and branched isomers are observed with the incorporation of electron-withdrawing substituents, such as –CF3 (134, 1.6:1 ratio).  The inductive effect of an [Ta]NArR+[Ta]NArAlk (Ar)[Ta]NAlk (Ar)Ar[Ta]NArMe3Si[Ta]NArMe3SiBranchedProductLinearProductδ+ δ-δ-δ-δ-δ+δ+δ+δ- δ+δ-stabilization of transient positive charge by β-silicon  129 electron-withdrawing groups will result in the destabilization of transient positive charge in the internal position of the alkene;408 therefore, resulting in a competition between the reaction pathways leading to the two different regioisomers and the formation of a mixture of linear and branched product.  3.2.6 Efforts Toward More Thermally Robust Phosphoramidate-Ta Complexes Complex 123 is the only reported precatalyst for room temperature hydroaminoalkylation to date,97 allowing for this transformation to include thermally sensitive substrates that cannot tolerate the high reaction conditions generally required for reactivity.  However, one of the drawbacks of 123 is the thermal sensitivity of this complex.  Catalyst decomposition is observed at reaction temperatures higher than 70 °C, as evidenced by the formation of a precipitate and low conversions of substrate to the HAA product.  This limits the substrate scope of this reaction, as challenging substrates can sometimes be forced to react at elevated reaction temperatures.  In addition, complex 123 is light sensitive making it challenging to store and handle.  Thus, a robust catalyst system that can operate across a wider range of reaction conditions and/or a catalyst system with improved substrate scope relative to 123 is desired. In an effort to identify a new catalyst system with modified reactivity from 123, a bis(phosphoramidate)-TaMe2Cl complex (154) was synthesized.  Starting from 123, the second phosphoramidate ligand was installed through protonolysis (Scheme 3.6).  Removal of the volatiles yielded the crude material as a yellow solid that was crystallized through slow diffusion of pentanes into toluene to obtain yellow prisms suitable for X-ray crystallography (Figure 3.14).    130  Scheme 3.6 Preparation of Complex 154   The solid-state molecular structure of 154 showed a complex with bond angles consistent with a pseudo-trigonal bipyramidal geometry (Figure 3.16).  The phosphoramidate ligands each occupy one coordination site in the equatorial plane with one of the methyl groups (P1-Ta1-C26: 109.54(11)°, P2-Ta1-C26: 110.53(16)°, P1-Ta1-P2: 139.88(11)°), Figure 3.15) while the two remaining ligands occupy the axial positions (C25-Ta-Cl1:  163.6(3)°, C26-Ta-Cl1: 98.22(17)°).   Bond angles are measured using the Ta-P vector and show that the two sterically demanding phosphoramidate groups create deviations from idealized 120° bond angles.              NPOOOTaMe3Cl123NPOOOTaMe2Cl2122, hexanes-30 °C to r.t. 18 h154  131          Figure 3.16 ORTEP of the solid state molecular structure of 154 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms and toluene solvent molecules removed for clarity)   Complex 154 (10 mol%) was used in the test reaction between 4-methoxy-N-methylaniline and 1-octene.  After 20 h at room temperature, 8% yield of the desired product was observed by 1H-NMR spectroscopy.  This poor conversion is attributed to suspected catalyst decomposition as evidenced by the formation of an insoluble precipitate during the reaction.  Thus, the bis(phosphoramidate)-TaMe2Cl structural motif was not explored further in the pursuit of more robust catalyst systems.  Previously, complex 155 was studied for catalytic HAA and showed particularly promising results in catalytic screening (Figure 3.17).98 The in situ prepared catalyst showed full conversions at 110 °C after 20 h when investigated for the test reaction between 1-octene and N-methylaniline or 4-methoxy-N-methylaniline.  This amidate ligand incorporates a pendent donor on the aryl N-substituent that could interact with the metal center to modify reactivity under reaction conditions, potentially stabilizing electrophilic intermediates.  In light of these results,  Selected Bond Lengths (Å) Selected Bond Angles (°) Ta-N1 2.150(3)  N1-Ta-O1 66.38(11) Ta-N2 2.146(3) N2-Ta-O4 66.58(11) Ta-O1 2.189(3) P1-Ta-C26 109.54(11) Ta-O4 2.184(3) P1-Ta-P2 139.88(11) P1-N1 1.6140 (13) P2-Ta-C26 110.53(16) P2-N2 1.592(6) C25-Ta-Cl1 163.6(3) P1-O1 1.510(3) C26-Ta-Cl1 98.22(17) P2-O4 1.447(6) O1-P-N1 99.15(16)   O4-P-N2 100.5(3) O1O2O3O4O6P1 P2N2N1Ta1Cl1C25C26  132 the analogous phosphoramidate proligand was prepared and tantalum complexes were synthesized to examine if these resulting complexes would display improved reactivity and stability due to the pendent donor group.   Figure 3.17 N,O-Chelated Ta complexes with pendent donor groups (complexes 155-157)   Complex 156 was prepared by salt metathesis from TaMe3Cl2 and complex 157 was synthesized from Ta(NMe2)5 via protonolysis.  Both complexes were characterized in the solid state using single crystal X-ray diffraction (Figure 3.18 and Figure 3.19).           NO Ta(NMe2)4ONPOOOTa(NMe2)4O155 157NPOOOTaMe3ClO156Mes  133           Figure 3.18 ORTEP of the solid state molecular structure of 156 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity)   In the solid state, the structure of 156 is similar to that of 123 as they both adopt a pseudo-trigonal bipyramidal geometry with the κ2-N,O-chelating ligand in the equatorial position (Figure 3.18).  However, complex 156 shows the ortho-methoxy substituent of the N-aryl ring is oriented towards Ta and an interaction with the metal center results in a wider bond angle of C13-Ta-C14 (141.2(2)°) relative to 123 (C13-Ta-C14 (111.28(13)°)).  The distance between O4 and Ta is estimated to be 2.746(5) Å, which is within the estimated sum of the Van der Waals radii of O and Ta (3.75 Å).332 This also results in a shortening of the Ta-N1 bond length (2.189(3) Å vs. 2.315(3) Å).      Selected Bond Lengths (Å) Selected Bond Angles (°) Ta-Cl1 2.4089(16)  N1-Ta-O1 65.76(18) Ta-O1 2.198(4) P1-Ta-C13 93.37(16) Ta-N1 2.189(3) P1-Ta-Cl1 173.55(5) Ta-C12 2.165(6) C12-Ta-C13 115.5(2) P1-N1 1.608(5) C13-Ta-C14 141.2(2) P1-O1 1.520(5) C13-Ta-Cl1 80.17(16) Ta-O4 2.746(5) O1-P-N1 97.2(3) O1O2O3O4Ta1Cl1C12C14C13N1C1  134    Figure 3.19 ORTEP of the solid state molecular structure of 157 with select bond lengths and bond angles (thermal ellipsoids set at 50% probability, H-atoms removed for clarity)   Similar to 156, complex 157 also adopts a pseudo-trigonal bipyramidal geometry with the κ2-N,O-chelating ligand in the equatorial position (Figure 3.19).  However, in this case, no interaction is observed between the metal center and the methoxy substituent in the solid state, which is similar to the solid state molecular structure reported for complex 155.98 In comparison to the analogous phosphoramidate and amidate-Ta complexes 155 and 157, the Ta-N1 bond length is slightly shorter (2.261(4) Å vs. 2.351(2) Å) and the bite angle is found to be wider (N1-Ta-O1: 65.76(18)° vs. 57.70(8)).98   Complexes 156 and 157 were subjected to the test reaction between 4-methoxy-N-methylaniline and 1-octene to evaluate their efficacy towards catalytic HAA.  While 155 demonstrated improved reactivity relative to other amidate-Ta(NMe2)4 complexes,98 157 only  Selected Bond Lengths (Å) Selected Bond Angles (°) Ta-O1 2.234(4) N1-Ta-O1 65.76(18) Ta-N1 2.261(4) P1-Ta-N2 115.28(14) Ta-N2 1.986(4) P1-Ta-N3 142.04(14) P1-N1 1.600(4) N4-Ta-N5 169.08(18) P1-O1 1.522(4) P1-Ta-N4 91.24(13)   P1-Ta-N5 82.90(13)   O1-P-N1 101.0(2) O1O2O3O4P1Ta1N1C1N2N3N5N4  135 showed 22% yield (determined by 1H-NMR spectroscopy) after 20 h at 110 °C, whereas 156 showed no conversion to the desired product after 20 h at room temperature.  In addition, 156 showed signs of decomposition when left at room temperature in both the absence and presence of light.  Therefore, ligand modifications leading to 156 and 157 did not improve either reactivity or robustness.    3.2.7 Probing the Role of Reactive Ligands –NMe2 and –CH3  To date, complex 123 remains the only precatalyst reported that is capable of catalytic HAA at room temperature.97 The reactivity differences between the phosphoramidate-Ta(NMe2)4 and the phosphoramidate-TaMe3Cl complexes were especially intriguing because both classes of complexes are hypothesized to operate through the same proposed mechanism and via the same reactive intermediate (see Scheme 3.1 and Scheme 3.4).99, 201, 214 However, the distinguishing feature between the two mechanisms is the catalyst activation step, where 111 liberates dimethylamine and catalyst activation of 123 results in the release of methane.99, 201, 214  To probe the differences in catalytic activity observed, we investigated the reactivity profiles of two analogous Ta precatalysts, 111 and 123, for the first 2 h of the reaction with the test reaction between 4-methoxy-N-methylaniline and 1-octene (Figure 3.20).  The reactions were conducted in duplicate and catalysis with complex 111 was conducted at 130 °C and reactions with 123 were performed at room temperature. The consumption of amine was monitored as a function of time and both complexes showed a zero-order dependence on the amine concentration at these early stages of the reaction, consistent with previous studies using amidate-Ta catalyst, 12.367   From these plots, kobs was determined for catalysis with complex 111 at 130 °C (kobs = 0.239 M/h) and complex 123 at room temperature (25 °C: kobs = 0.116   136 M/h).  In both cases, no induction period was observed.  However, one limitation of this study is that the two catalysts cannot be studied at the same reaction temperature.  Phosphoramidate-Ta(NMe2)4 catalysts will not perform the desired transformation at temperatures lower than 110 °C, but phosphoramidate-TaMe3Cl decompose at temperatures greater than  70 °C.    Reaction conditions:  0.5 mmol of 4 methoxy-N-methylaniline, 0.75 mmol of 1-octene, 0.025 mmol of Ta catalyst, and 0.6 g of toluene-d8.  Consumption of amine was determined by 1H-NMR spectroscopy (300 MHz, 298 K).  Reaction temperature for 111: 130 °C.  Reaction temperature for 123: 23 °C.  Reactions are conducted in duplicate and the average of the two runs are represented.  Error bars represent two standard deviations from the mean.  Solid lines depict the least-squares fit to the data points.  Figure 3.20 Consumption of amine as a function of time for the α-alkylation of 4-methoxy-N-methylaniline with 1-octene catalyzed by 111 and 123   As discussed earlier in this chapter, dimethylamine released during catalyst activation can feed into the catalyst cycle and serve as an amine substrate in HAA.  This poses two possibilities kobs	=	0.239	M/hkobs	=	0.116	M/hkobs	=	0.034	M/hkobs	=	0.099	M/h00.20.40.60.811.20 0.5 1 1.5 2 2.5[amine](t)/[amine]0Time	(h)Complex	111Complex	123Complex	123+diethylamineComplex	123+diisobutylamine  137 in the reactivity differences observed: competitive substrate binding of the dimethylamine to the catalyst and resultant side product formation, and more significant product inhibition of the catalyst.  Two model substrates were used to explore these effects on catalysis with 123:  diethylamine and diisobutylamine.  Diethylamine was chosen as a model substrate for dimethylamine, as dimethylamine is challenging to introduce into the reaction mixture in specific amounts as it is a gas at room temperature.  The effect of diisobutylamine was investigated as a model system for di(octan-2-yl)amine, which is the byproduct arising from dialkylation of dimethylamine with 1-octene.  Both additives were used in sub-stoichiometric amounts (40 mol%). This was chosen to represent the maximum formation of dimethylamine and di(octan-2-yl)amine with phosphoramidate-Ta(NMe2)4 complexes under catalytic conditions for 10 mol% catalyst loading.  Addition of diisobutylamine to the test reaction did not considerably change the initial reaction profile of 123 for the first two hours (25 °C: kobs = 0.099 M/h for the addition of diisobutylamine vs. kobs = 0.116 M/h without, Figure 3.20), but the addition of diethylamine showed that the reaction was proceeding slower than the reaction with no additive (25 °C: kobs = 0.034 M/h, Figure 3.20).   When the reaction times were extended to 12 h for catalysis using complex 123, the consumption of amine as a function of time is first-order with respect to 4-methoxy-N-methylaniline (Figure 3.21), in contrast with the zero-order dependence on amine concentration observed during the first 2 h of the reaction (Figure 3.20).  For the first 2 h, the reaction can be considered to be under pseudo-first order conditions due to the high concentrations of amine relative to catalyst, resulting in an observed zero-order dependence on amine at these early stages of the reaction (Figure 3.20).     138 Addition of diethylamine to the α-alkylation of 4-methoxy-N-methylaniline with 1-octene catalyzed by 123 resulted in the conversion to the desired product was noticeably lower for the reaction containing the additive than without after a period of 12 h (Figure 3.21).  In contrast, the addition of diisobutylamine did not have the same impact on consumption of aniline to yield the desired product, but lower yields of the HAA product were observed.  Furthermore, the addition of 1 equivalent of the product, 4-methoxy-N-(2-methyloctyl)aniline, to the test reaction did not show evidence of product inhibition.              139  Reaction conditions:  0.5 mmol of 4 methoxy-N-methylaniline, 0.75 mmol of 1-octene, 0.025 mmol of Ta catalyst, and 0.6 g of toluene-d8.  Consumption of amine was determined by 1H-NMR spectroscopy (300 MHz, 298 K). Reaction temperature: 23 °C.    Figure 3.21 Consumption of amine as a function of time for the α-alkylation of 4-methoxy-N-methylaniline with 1-octene catalyzed by 123   These investigations highlight that the byproduct that is released during catalyst activation is a contributing factor to the reactivity differences observed between the phosphoramidate-Ta(NMe2)4 and the phosphoramidate-TaMe3Cl complexes beyond precatalyst activation.   Previous work with Ta complexes has indicated that there are different off-catalytic pathways that involve amines, particularly of an amine that can undergo C-H activation (Figure 3.22).211-212, 214, 367 Using deuterium labeling studies with N-(methyl-d3)-aniline, Herzon and Hartwig observed and reported loss of deuterium in the HAA product.211   The washing of 00.10.20.30.40.50.60.70.80.910 2 4 6 8 10 12([amine](t)/[amine]0)Time	(h)Complex	123Complex	123+diethylamineComplex	123+diisobutylamine  140 deuterium into various positions of the product indicates reversible formation of the catalytically active metallaziridine intermediate.  Incorporation of deuterium into the ortho-aryl position is also indicative of reversible activation of the aryl C-H bonds.  These observations were also noted in subsequent investigations using other group 5 metal-based systems.212, 409 In addition, when catalyst 10 was heated with an excess of N-methyl-p-toluidine, amine exchange was observed yielding the mono- and bis(aniline) Ta complex.211 Finally, previous work done in the Schafer group has identified that the liberated dimethylamine can undergo HAA with 2 equivalents of 1-octene to yield the bis(alkylated) product.367      141  Figure 3.22 Hydroaminoalkylation off-catalytic pathways211-212, 214, 367  These off-catalytic pathways involving amines that can undergo C-H activation are potential persistent challenges when using catalytic systems derived from phosphoramidate-Ta(NMe2)4 vs. phosphoramidate-TaMe3Cl.  The dimethylamine liberated during the catalyst activation step can participate in any or all of the proposed pathways presented in Figure 3.22, with detrimental effects on catalysis.  Note that the reaction is proposed to be first order in catalyst concentration and all of the non-productive pathways observed involve catalyst interaction. However, the release of methane during catalyst activation using phosphoramidate-HN CD3 +HN4 mol% 10toluene160-165 °C, 27 hH/DH/DH/DH/DB.  Amine Exchange:+toluene-d8dodecane80 °C, 24 hHNN Ta(NMe2)4+N Ta(NMe2)325 equiv. 37% 39%[Ta] R HNR R+  HNMe2N Me2C. Byproduct Formation:[Ta] [Ta]C-H activationN MeNMe2NMe2A. Reversible Metallaziridine Formation:Demonstrated by deutrium labelling studies:+   HNMe2Ta(NMe2)510  142 TaMe3Cl does not have the same consequences.  When catalysis with 123 was conducted in the presence of diethylamine, the consumption of amine was comparatively slower, potentially due to some or all of these side reactions.  Likewise, when diisobutylamine was used as an additive, there was a negative effect on catalysis, but such an influence was not as substantial.  Diisobutylamine is comparatively more sterically hindered in the α-position than diethylamine and C-H activation by the catalyst would be more challenging, due to the steric demands of the resulting metallaziridine.  Both of these observations highlight that the presence of an amine additive that is not the substrate undergoing productive catalysis can impact the relative efficacy of the catalyst.  Therefore, the observed differences in catalytic activity of Ta(NMe2)4 vs. phosphoramidate-TaMe3Cl is, at least in part, a result of the dialkylamine byproduct released during catalyst activation.  3.3 Conclusions In this chapter, a new group of Ta complexes with chelating phosphoramidate complexes was presented.  This new N,O-chelating ligand motif was installed onto two different Ta starting materials, Ta(NMe2)5 and TaMe3Cl2, leading to two groups of Ta complexes with distinctive reactivity towards catalytic HAA.   A series of phosphoramidate-Ta(NMe2)4 complexes was screened for catalytic HAA.  Due to the modular nature of this ligand motif, modifications to the electronic and steric nature of the ligand were investigated to determine the influence on catalysis.  Changes to the structural motif included varying substituents on the nitrogen (N-aryl and N-alkyl) and the oxygen (-Et, -iPr, -Ph).  In general, the Ta complexes with N-aryl phosphoramidates ligands performed better in catalysis over N-aryl ligands, particularly when steric bulk is incorporated in the N-aryl ortho   143 position.  In select cases, HAA was catalyzed by such Ta complexes at reaction temperatures as low as 70 °C.  While reduced reaction temperatures relative to other reported catalyst systems were achieved with these complexes, no improvement in substrate scope was noted.  Other phosphorous containing N,O-chelating ligands, such as thiophosphoramidates and phosphinic amidates, were also studied, but Ta complexes containing these ligands performed poorly in catalysis.   Following the work with phosphoramidate-Ta(NMe2)4 complexes, phosphoramidate-TaMe3Cl complexes were prepared and studied for catalysis.  One particular system, complex 123, was identified as an effective catalyst for HAA at room temperature.  This achievement was unprecedented at the time and still remains the only reported example of room temperature HAA.97   The alkene substrate scope for 123 shows reactivity towards a variety of unactivated terminal alkenes, including silyl-protected alcohols despite the oxophilic nature of early transition metals.  These reactions are diastereoselective for the branched regioisomer.  While unstrained internal alkenes such as cyclooctene are nearly unreactive with 123, strained internal alkenes such as norborene react to give exclusively the exo-diastereomeric product, as confirmed by X-ray crystallography.  Challenging substrates such as styrenes can be utilized as well, but prolonged reaction times or mild heating (50 °C) are required for improved yields.  Interestingly, the p-substituent on styrene substrates can influence the resulting diastereoselectivity observed in the final product.  Electron-donating groups afford nearly exclusively the branched product, but electron-withdrawing substituents increase the formation of the linear product.  Moreover, a switch in regioselectivity for the linear product is observed when vinyltrimethylsilane is used as the alkene substrate.  In addition to being the first room temperature active catalyst, 123 is the   144 rare example of a group 5 based metal catalyst accessing both branched and linear regioisomers.97 Further investigations reveal that accessing the linear regioisomer is not a function of reduced reaction temperatures relative to other group 5 catalysts, but is proposed to be due to the stabilization of transient positive charge during alkene insertion from the β-silicon effect. The room temperature reactivity of 123 expands the potential synthetic applications of HAA to include substrates that cannot withstand high reaction conditions, but one significant drawback of this system is its thermal sensitivity. While 123 is an attractive candidate for catalysis under mild reaction conditions, a robust catalyst that can operate under a wider range of reaction temperatures is desirable to accommodate more challenging substrates such as internal alkenes and N-heterocycles.  A bis(phosphoramidate)-TaMe2Cl complex, 154, was synthesized in attempts to identify a more stable catalyst system; however, poor catalytic performance was observed.  In addition, phosphoramidate-Ta complexes (156 and 157) with pendent donors were investigated, but both were also poor catalysts under the conditions described and did not display enhanced stability relative to 123.  Mechanistic investigations were conducted to probe reactivity differences between 123 and the analogous dimethylamido complex 111. Complex 123 is catalytically active at room temperature, but 111 requires elevated reaction temperatures for catalysis. Both 123 and 111 are proposed to operate through the same mechanism, but one key difference is the release of methane vs. dimethylamine during the catalyst activation step.  Monitoring of the consumption of amine over time was conducted using 1H-NMR spectroscopy.  Both systems exhibit first order dependence on amine and no induction period was observed. However, the addition of diethylamine to a HAA reaction catalyzed by 123 resulted in decreased conversion to the desired   145 product.  While the addition of diisobutylamine also reduced the conversion of the reaction, the greater deleterious effect was observed with diethylamine. Therefore, the presence of dimethylamine is a contributing factor to the reactivity differences observed between the phosphoramidate-Ta(NMe2)4 and the phosphoramidate-TaMe3Cl complexes, possibly due to non-productive off-catalytic pathways.     3.4 Experimental 3.4.1 Materials and Methods All general materials and methods are outlined in Section 2.4.1 with the following addition: All preparative scale reactions were conducted using oven dried (160 °C) glassware with magnetic stirring. Single X-ray structure determinations were preformed at the Department of Chemistry, University of British Columbia by Dr. Jacky Yim, Mr. Scott Ryken, or Mr. Damon Gilmour using either a Bruker APEX or APEX DUO instrument with a molybdenum radioation source (MoKα, λ = 0.71073 Å) under a continuous flow of nitrogen (T = 90(2) K or 100(2) K).  Complexes 101-121 and related proligands were prepared and provided by post-doctoral researcher Dr. Pierre Garcia for catalytic screening.  Complex 110, 111, and 123 was prepared using procedures outlined by Dr. Garcia.  Liquid reagents were prepared for the glove box by distillation under reduced pressure from CaH2 and degassed by 3 freeze-pump-thaw cycles.  Solid reagents were sublimed under reduced pressure.  Ta(NMe2)5 was used as received.  Dichlorotrimethyltantalum (16),395 4-methoxy-N-methylaniline,410 tert-butyldimethyl(pent-4-en-1-yloxy)silane,411 and (allyloxy)(tert-butyl)dimethylsilane412 were prepared using known literature procedures.  The following compounds are known and spectral data obtained using   146 catalysts developed in this Chapter are in accordance with those previously published: 4-methoxy-N-(2-methyloctyl)aniline (124),211 N-(3-((tert-butyldimethylsilyl)oxy)-2-methylpropyl)-4-methoxyaniline (126).96 Synthesis and characterization data for complex 123 and 4-methoxy-N-(2-(4-(trifluoromethyl)phenyl)propyl)aniline (134) are described in our previous publication.97  3.4.2 Synthesis and Characterization of Compounds General Procedure A: Preparing Phosphoramidate Proligands   Primary alkylamine (23 mmol) and triethylamine (3.3 mL, 25 mmol) was added to anhydrous CH2Cl2 (50 mL) and cooled to 0 °C. Chlorophosphate (3.6 mL, 25 mmol) was added dropwise over 5 minutes. After stirring overnight at room temperature, the mixture was directly purified by flash chromatography to obtain the desired product (eluent:  1% methanol in CH2Cl2).        POClRORO + PONROROR1HNEt3,CH2Cl20 °C to r.t., 18 hH2NR1  147 General Procedure B: Preparing Phosphoramidate Proligands    Adapted from literature.391 To a solution of the starting aniline in a mixture of glacial AcOH /H2O (1:1) at -15 °C, NaNO2 (1.4 equiv.) was added portionwise. After 10 min, NaN3 (1.5 equiv.) was added portionwise and the reaction brought to room temperature. After 45 min, the reaction was extracted with CH2Cl2 and neutralized with saturated aqueous NaHCO3. To the resulting organic layer P(OR)3 (1.5 equiv.) was added and the reaction stirred overnight. Hydrolysis with aqueous 5 M HCl, extraction with CH2Cl2, washing with brine, and drying over MgSO4 afforded crude products after removal of the volatiles under reduced pressure. Sonication in pentane yielded beige solid that was sublimed under reduced pressure to afford a white solid.  Diethyl (2,6-dimethylphenyl)phosphoramidate (122).  Known compound383 synthesized using  General Procedure B from 2,6-dimethylaniline (3.9 g, 32 mmol, 4.0 mL) to afford the title compound as white crystalline material after sublimation (6.31 g, 76%).  Single crystals suitable for X-ray crystallography were obtained after sublimation (CCDC 932204).  1H-NMR (300 MHz, CDCl3): δ 7.04-6.95 (m, 3H), 4.14-4.04 (m, 5H), 2.37 (s, 6H), 1.27 (t, J = 7.3 Hz, 6H); 13C{1H}-NMR (75 MHz, CDCl3): δ 136.0 (2 C), 135.1 (C), 128.6 (2 CH), 126.2 (CH), 63.2 (CH2) 62.1 (CH2), 19.2 (2 CH3), 16.5 (CH3), 16.3 (CH3); 31P{1H}-NMR (122 MHz, CDCl3) δ 4.24; EA: Calculated: C 56.02, H 7.84, N 5.44; O 18.66; Found: C 56.09, H 7.82, N 5.37. NH2 i.  NaNO2AcOH/H2O, -15 °Cii.  NaN3 -15 °C to r.t.iii.  P(OR)3, DCMPON HR1OR1ORRPONHOO122  148 General Procedure C: Synthesis of Phosphoramidate-Ta Complexes via Protonolysis     In the glove box, phosphoramidate proligand was dissolved or suspended in anhydrous hexanes (2.5 g).  Ta(NMe2)5 was dissolved in anhydrous hexanes (2.5 g).  The proligand solution was added dropwise to the Ta(NMe2)5 solution.  The reaction mixture was stirred at room temperature overnight.  Removal of volatiles in vacuo yielded crude phosphoramidate-Ta(NMe2)4 complexes, which were used for catalytic screening without further purification.  (Diethyl (4-(trifluoromethyl)phenyl)phosphoramidate)tetrakis (dimethylamido) tantalum  (110).  Synthesized by protonolysis using General Procedure C from phosphormidate proligand (0.148 g, 0.498 mmol) and Ta(NMe2)5 (0.200 g, 0.498 mmol) to yield the desired compound as a yellow solid (0.318 g, 98%).  The crude material was recrystallized in hexanes to yield yellow crystals (0.088 g, 28%), which were suitable for X-ray crystallography.  1H-NMR (300 MHz, C6D6): δ 7.50 (d, J = 8.4 Hz, 2H), 7.04 (d, J = 8.7 Hz, 2H), 3.96-3.86 (m, 4H), 3.43 (s, 24H), 1.03 (t, J = 6.9 Hz, 6H); 13C{1H}-NMR (100 MHz, C6D6): δ 150.3 (C), 126.9 (q, 3JC-F = 2.5 Hz, CH), 126.0 (q, 1JC-F = 268 Hz, C), 121.1 (q, 2J C-F = 32 Hz, C), 120.6 (CH), 120.5 (CH), 63.5 (CH2), 63.4 (CH2), 47.6 (br s., N(CH3)), 16.4 (CH3), 16.3 (CH3); 31P{1H}-NMR (162 MHz, C6D6):  δ 5.85; 19F-NMR (282 MHz, C6D6):  δ -61.1; HRMS-EI (m/z) [M-NMe2]+ Calcd for C17H32N4O3PTaF3: 609.16443, Found: 609.16413.  NPR1ROOROTa(NMe2)4PONROROR1H + Ta(NMe2)5hexanesr.t., 18 hNPOOOTa(NMe2)4CF3110  149 (Diethyl (2,6-dimethylphenyl)phosphoramidate)tetrakis(dimethylamido)tantalum (111).   Synthesized by protonolysis using General Procedure C from phosphoramidate proligand (122)97 (0.108 g, 0.416 mmol) and Ta(NMe2)5 (0.167 g, 0.416 mmol) to yield an orange solid (0.252 g, 98%).  Analyses of NMR-spectra indicate multiple species in solution.  The isolated crude mixture was used without further purification in catalysis. Mixture:  1H-NMR (300 MHz, C6D6): δ 7.21-7.15 (m, 2H), 7.10 (t, J = 4.8 Hz, 2H), 7.00 (app q, 5.1 Hz, 2H), 4.34-4.26 (m, 1H), 4.11-4.03 (m, 1H), 4.00-3.71 (m, 6H), 3.32 (s, 3H), 3.30 (s, 1H), 3.09 (br s, overlapped), 3.04 (s, overlapped), 2.84 (s, 3H), 2.63 (s, 3H), 2.46 (s, 3H), 2.43 (s, 3H), 1.13 (t, J = 5.4 Hz, 3H), 1.04 (t, J = 5.4 Hz, 3H), 0.96 (t, J = 5.1 Hz, 3H), 0.93 (t, J = 5.1 Hz, 3H); 31P-NMR (121 MHz, C6D6):  δ 9.52, -0.04, -6.38; HRMS-EI (m/z) [M-NMe2]+ Calcd for C18H37N4O3PTa: 569.20834, Found: 569.20850.  General Method D: Screening Hydroaminoalkylation Reactions Using Phosphoramidate-Ta(NMe2)4 Complexes    In the glove box, 4-methoxy-N-methylaniline (0.069, 0.50 mmol) was dissolved in 0.6 g of toluene-d8.  1-octene (0.084 g, 0.75 mmol) was added.  The precatalyst (0.025 mmol) was also dissolved in 0.6 g of toluene-d8.  The precatalyst was combined with the substrates and the mixture was transferred to a Teflon sealed NMR tube.  The tube was heated for at least 20 h before yield was determined by 1H-NMR spectroscopy (300 MHz, 298 K).    Yield was determined by monitoring the disappearance of diagnostic signals of the aromatic protons in the NPOOOTa(NMe2)4111HN+5 mol% Ta precatalysttoluene-d8, 20 hHNO O  150 ortho position in the starting material (δ 6.48) and the appearance of new aromatic signals associated with the analogous protons in the resulting product (δ 6.63).    Yield = !"#$%&'#!(" !" !"#$%&' !"#$%&!"#$%&'#!(" !"#$%&'!!!"#$%&"'(! !"#$"%&' !"#$%&"' ×100%  Figure 3.23 Representative 1H-NMR spectrum (300 MHz, toluene-d8) for monitoring hydroaminoalkylation reactions and determining yield by 1H-NMR spectroscopy.  Reaction of 4-methoxy-N-methylaniline and 1-octene after 20 h at 90 °C with precatalyst 114.      151 General Procedure D: Synthesis of Phosphoramidate-Ta Complexes via Salt Metathesis    Phosphoramidate proligand (5.95 mmol) was dissolved in anhydrous toluene (6 g) in the glove box.  NaHMDS (1.09 g, 5.95 mmol) was suspended in anhydrous toluene (6 g).  The two solutions were mixed together and stirred at room temperature overnight.  The solvent was removed in vacuo and the resulting powder was rinsed with anhydrous hexanes (2 x 6 g).  Removal of solvent afforded an off white solid corresponding to the sodium salt of the proligand.  In the absence of light, the sodium salt of the phosphoramidate proligand (0.340 mmol) was suspended in 3 g of anhydrous hexanes and cooled to -30 ˚C.   TaCl2Me3 (0.100 g, 0.340 mmol) was dissolved in 3 g of anhydrous hexanes and cooled to -30 ˚C.  The suspension of sodium salt was added dropwise to a stirring solution of TaCl2Me3.  The reaction was stirred at room temperature in the dark for 1.5 h prior to filtering through a 0.22 µm syringe filter or a filter pipette.  The solvent was removed in vacuo to yield the desired Ta complex (light sensitive, thermally sensitive complex).       PONHROO1. NaHMDS, toluene    18 h, r.t.2.  TaCl2Me3, hexanes     -30 °C to r.t., 2 hNPROOOTaMe3Cl  152 General Procedure F: Screening Hydroaminoalkylation Reactions Using Phosphoramidate-TaMe3Cl Complexes    In the glove box and in the absence of light, 4-methoxy-N-methylaniline (0.069 g, 0.50 mmol) was dissolved in 0.3 g of toluene-d8.  The alkene (0.75 mmol) was added.  The precatalyst (0.050 mmol) was also dissolved in 0.3 g of toluene-d8.  The precatalyst was combined with the substrates and the mixture was transferred to a 10 mL vial and stirred in the glovebox at room temperature.  In the cases where reactions were conducted at 50 °C, the mixture was transferred into a Teflon sealed NMR tube and heated in an oil bath.  Reaction mixtures are no longer light sensitive after addition of substrates.  After the specified reaction time, conversion was determined by 1H-NMR spectroscopy and an aliquot was taken from the reaction mixture for analysis by GC-MS to determine ratios of regioisomers.   Reactions conducted to obtain isolated yields were preformed as above, but all quantities of solvent, substrate, and precatalyst were doubled.  Toluene was used in place of toluene-d8.  Upon the end of the specified reaction time, the reaction mixture was purified directly by flash chromatography (eluent:  5% EtOAc in hexanes).      OHN+10 mol% 123 toluene, r.t., 20 hOHNR1R2R1R2  153 N-(5-((tert-butyldimethylsilyl)oxy)-2-methylpentyl)-4-methoxyaniline (125).  Synthesized   using General Procedure F from 4-methoxy-N-methylaniline (0.137 g, 1.00 mmol), tert-butyldimethyl(pent-4-en-1-yloxy)silane (0.168 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Purification by flash chromatography yielded a colourless oil (0.299 g, 88%).  1H-NMR (300 MHz, CDCl3): δ 6.83 (d, J = 9.0 Hz, 2H), 6.62 (d, J = 9.0 Hz, 2H), 3.79 (s, 3H), 3.68 (t, J = 6.9 Hz, 2H), 3.41 (br s, 1H), 3.06 (dd, J = 12.3 Hz, 6.4 Hz, 1H), 2.91 (dd, J = 12.5 Hz, 6.9 Hz, 1H), 1.88-1.50 (m, 4H), 1.33-1.18 (m, 1H), 1.03 (d, J = 6.5 Hz, 3H), 0.98 (s, 9H), 0.13 (s, 6H); 13C{1H}-NMR (75 MHz, CDCl3): δ 152.0 (C), 143.1 (C), 115.1 (CH), 114.1 (CH), 63.6 (CH2), 56.0 (CH3), 51.5 (CH2), 33.0 (CH), 31.1 (CH2), 30.4 (CH2), 26.2 (CH3), 18.6 (C), 18.3 (CH3), -5.02 (CH3); IR (NaCl, cm-1) 3409 (N-H stretch), 2930 (C-H asymmetric stretch), 2856 (C-H symmetric stretch), 1513 (aromatic ring stretch), 1197 (Si-O stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C19H36NO2Si:  338.2515, Found: 338.2507.  N-(bicyclo[2.2.1]heptan-2-yl)methyl)-4-methoxyaniline (129). Known compound.95  Synthesized using General Procedure F from 4-methoxy-N-methylaniline (0.137 g, 1.00 mmol), norbornene (0.146 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Purification by flash chromatography yielded yellow oil (0.180 g, 70%).  1H-NMR (300 MHz, CDCl3): δ 7.24-7.39 (m, 5H), 6.85 (d, J = 9.0 Hz, 2H), 6.59 (d, J = 9.0 Hz, 2H), 3.81 (s, 3H), 3.43 (br s, 1H), 3.12 (dd, J = 12, 6.0 Hz, 1H), 2.98 (dd, J = 13, 6.9 Hz, 1H), 2.83 (dd, J = 13, 6.3 Hz, 1H), 2.57 (dd, J = 14, 7.8 Hz, 1H), 2.13 (m, 1H), 1.05 (d, J = 6.6 Hz, 3H); 13C{1H}-NMR (75 MHz, CDCl3): δ 152.0 (C), 142.8 (C), 140.7 (C), 129.2 (CH), 128.4 (CH), 126.0 (CH), 115.0 (CH), 114.1 (CH), 55.9 (CH3), 50.9 OHN129 (+/-)OHN OTBS125  154 (CH2), 41.5 (CH2), 35.1 (CH), 18.2 (CH3); IR (NaCl, cm-1) 3406 (N-H stretch), 2952 (asymmetric C-H stretch), 2926 (symmetric C-H stretch), 1514 (aromatic ring stretch), 1234 (aromatic C-H in-plane bend); HRMS-ESI (m/z) [M+H]+ Calcd for C15H22NO:  255.16231, Found: 255.16253.  N-bicyclo[2.2.1]heptan-2-yl)methyl)-N-(4-methoxyphenyl)-4-nitrobenzenesulfonamide  (129-Nos).  129 (0.052 g, 0.22 mmol) was dissolved in CH2Cl2 (5 mL) and the solution was cooled to 0 °C.  p-Nitrobenzenesulfonyl chloride (0.055 g, 0.25 mmol) was added, followed by triethylamine (0.025 g, 0.25 mmol).  The reaction was warmed to room temperature and stirred overnight.  The reaction mixture was washed with water (50 mL) and brine.  The organic layer was retained and dried over Na2SO4, filtered, and concentrated to yield a brown solid.  Purification by flash chromatography (eluent:  10% EtOAc/hexanes) yielded 129-Nos as a white solid (0.041 g, 46%). Recrystallization from acetonitrile yielded colourless crystals suitable for X-ray diffraction studies.  Mp:  139 °C; 1H-NMR (300 MHz, CDCl3): δ 8.29 (d, J = 8.7 Hz, 2H), 7.75 (d, J = 8.7 Hz, 2H), 6.89 (d, J = 9.0 Hz, 2H), 6.82 (d, J = 9.0 Hz, 2H), 2.80 (s, 3H), 3.40 (dd, J = 13, 8.1 Hz, 1H), 3.19 (dd, J = 13, 7.8 Hz, 1H), 2.23 (br s, 1H), 2.12 (br s, 1H), 1.34-1.45 (m, 4H), 1.12-1.27 (m, 3H), 0.95-1.04 (m, 2H); 13C{1H}-NMR (75 MHz, CDCl3):  δ 159.4 (C), 150.0 (C), 144.5 (C), 130.7 (C), 130.0 (CH), 128.9 (CH), 124.1 (CH), 114.6 (CH), 55.7 (CH2), 55.6 (CH2), 40.2 (CH), 38.8 (CH), 36.6 (CH), 35.5 (CH2), 35.1 (CH2), 29.6 (CH2), 29.9 (CH2); IR (NaCl, cm-1):  2951 (asymmetric C-H stretch), 2869 (symmetric C-H stretch), 1606 (aromatic ring stretch), 1530 (asymmetric N-O stretch), 1350 ON129-Nos (+/-)SNO2O O  155 (symmetric N-O stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C21H24N2O5SNa:  439.1304, Found: 439.1302; CCDC 937356.  4-Methoxy-N-(2-(4-methoxyphenyl)propyl)aniline (130). Synthesized using General   Procedure F from 4-methoxy-N-methylaniline (0.137 g, 1.00 mmol), 4-methoxystyrene (0.239 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Branched to linear ratio (room temperature reaction:  no linear product detected, 50 °C reaction: 68:1) was determined by GC-MS prior to purification by flash chromatography to afford yellow oil (room temperature reaction:  0.236 g, 87%, 50 °C:  0.239 g, 88%).  Branched and linear isomers were inseparable by column chromatography and yields refer to isolated mixtures.  130-branched.  1H-NMR (300 MHz, CDCl3): δ 7.14 (d, J = 8.7 Hz, 2H), 6.87 (d, J = 8.7 Hz, 2H), 6.78 (d, J = 9.0 Hz, 2H), 6.54 (d, J = 9.0 Hz, 2H), 3.77 (s, 3H), 3.72 (s, 3H), 3.27 (dd, J = 12, 6.0 Hz, 2H), 3.14 (dd, J = 12, 8.1 Hz, 1H), 2.93-3.05 (m, 1H), 1.30 (d, J = 6.9 Hz, 3H).  130-linear.  Diagnostic signals:  1H-NMR (300 MHz, CDCl3): δ 4.14 (m); 13C{1H}-NMR (75 MHz, CDCl3): δ 28.8 (CH2), 29.2 (CH2) 34.4 (CH2); Mixture:  IR (NaCl, cm-1) 3399 (N-H stretch), 2958 (C-H asymmetric stretch), 2830 (C-H symmetric stretch), 1513 (aromatic ring stretch), 1236 (aromatic C-H in plane bend); HRMS-ESI (m/z) [M+H]+ Calcd for C17H22NO2: 272.1651, Found: 272.1651.     OHNO130  156 4-Methoxy-N-(2-(p-tolyl)propyl)aniline (131).   Synthesized using General Procedure F from  4-methoxy-N-methylaniline (0.137 g, 1.00 mmol), 4-methylstyrene (0.177 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Branched to linear ratio (50 °C reaction: 99:1) was determined by GC-MS prior to purification by flash chromatography to afford brown oil (0.223 g, 88%). Branched and linear isomers were inseparable by column chromatography and yield refers to mixture.  131-branched. 1H-NMR (300 MHz, CDCl3): δ 7.28 (s, 2H), 6.94 (d, J = 9.0 Hz, 2H), 6.69 (d, J = 9.0 Hz, 2H), 3.88 (s, 3H), 3.47-3.30 (m, 2H), 3.42 (br s, 1H), 3.25 (sextet, J = 7.5 Hz, 1H), 2.50 (s, 3H), 1.47 (d, J = 6.9 Hz, 3H); 13C{1H}-NMR (75 MHz, CDCl3): δ 152.1 (C), 142.5 (C), 141.6 (C), 136.0 (C), 129.3 (CH), 127.1 (CH), 114.9 (CH), 114.3 (CH), 55.7 (CH2), 52.0 (CH3), 38.8 (CH3), 21.0 (CH), 19.9 (CH3); 131-linear.  Diagnostic signals: 1H-NMR (300 MHz, CDCl3): δ 4.32-4.19 (m); IR (NaCl, cm-1): 3396 (N-H stretch), 2957 (asymmetric C-H stretch), 2830 (symmetric C-H stretch), 1514 (aromatic ring stretch); HRMS-ESI (m/z) [M+H]+ Calcd for C17H22NO:  256.1701, Found: 256.1696.    4-Methoxy-N-(2-phenylpropyl)aniline (132).  Synthesized using General Procedure F from 4-   methoxy-N-methylaniline (0.137 g, 1.00 mmol), styrene (0.156 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Branched to linear ratio (room temperature reaction:  26:1, 50 °C reaction:  14:1) was determined by GC-MS prior to purification by flash chromatography to afford yellow oil (room temperature reaction:  0.224 g, 93%, 50 °C reaction:  0.209 g, 87%).  Branched and linear isomers were separable by column chromatography and yields refer to isolated branched regioisomer.  132-branched.  1H-NMR (300 MHz, CDCl3): δ 7.43-7.38 (m, 2H), 7.32-7.28 (m, 131OHN132OHN  157 3H), 6.85 (d, J = 8.4 Hz, 2H), 6.61 (d, J = 8.4 Hz, 2H), 3.80 (s, 3H), 3.40-3.23 (m, 3H), 3.11 (dt, J = 21 Hz, 6.7 Hz, 1H), 1.40 (d, J = 7.0 Hz, 3H); 13C-NMR (75 MHz, CDCl3): δ 152.1 (C), 144.7 (C), 142.4 (C), 128.7 (CH), 127.3 (CH), 126.6 (CH), 114.9 (CH), 114.3 (CH), 55.8 (CH3), 52.0 (CH2), 39.3 (CH), 19.8 (CH3); IR (NaCl, cm-1): 3399 (N-H stretch), 2958 (C-H asymmetric stretch), 2830 (C-H symmetric stretch), 1513 (aromatic ring stretch), 1236 (aromatic C-H in plane bend); HRMS-ESI (m/z) [M+H]+ Calcd for C16H20NO:  242.1545, Found: 242.1550.    N-(2-(4-chlorophenyl)propyl)-4-methoxyaniline (133).  Synthesized using General Procedure   F from 4- methoxy-N-methylaniline (0.137 g, 1.00 mmol), 4-chlorostyrene (0.208 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Branched to linear ratio (room temperature reaction:  10:1, 50 °C reaction:  10:1) was determined by GC-MS prior to purification by flash chromatography to afford yellow oil (room temperature reaction:  0.255 g, 93%, 50 °C reaction:  0.169 g, 58%).  Branched and linear isomers were separable by column chromatography and yields refer to isolated branched regioisomer.  133-branched.  1H-NMR (300 MHz, CDCl3):  δ 7.31 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 8.8 Hz, 2H), 6.56 (d, J = 8.8 Hz, 2H), 3.76 (s, 3H), 3.33-3.14 (m, 3H), 3.10-2.98 (m, 1H), 1.32 (d, J = 6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ 152.3 (C), 143.3 (C), 142.2 (C), 132.3 (C), 128.9 (2 CH), 128.8 (2 CH), 115.0 (2 CH), 114.4 (2 CH), 55.9 (CH3), 52.0 (CH2), 38.8 (CH), 31.7 (CH), 19.8 (CH3); IR (NaCl, cm=1) 3399 (N-H stretch), 2956 (C-H asymmetric stretch), 2830 (C-H symmetric stretch), 1513 (aromatic ring stretch),	 819 (1,4 disubstituted aromatic C-H out-of-plane bend); HRMS-ESI (m/z) [M+H]+ Calcd for C16H19NOCl:  276.1155, Found: 276.1156.    OHNCl133  158 4-methoxy-N-(3-(trimethylsilyl)propyl)aniline (135). Synthesized using General Procedure F   from 4-methoxy-N-methylaniline (0.137 g, 1.00 mmol), vinyltrimethylsilane (0.075 g, 1.50 mmol), and 123 (0.052 g, 0.10 mmol).  Branched to linear ratio (room temperature reaction:  112:88, 50 °C reaction:  1:10) determined by GC-MS prior to purification by flash chromatography to afford yellow oil (room temperature reaction:  0.164 g, 69%, 50 °C reaction:  0.165 g, 69%).  Branched and linear isomers were inseparable by column chromatography and yields refer to isolated mixture of regioisomers.  135 was also prepared at 4 °C using the following modified procedure:  4-methoxy-N-methylaniline and vinyltrimethylsilane were dissolved in toluene (0.6 g).  123 was dissolved in toluene (0.6 g) and both solutions were cooled to -30 °C.  The solutions were combined and the reaction was stirred at 4 °C for 20 h.   Branched to linear ratio (1:16) was determined by GC-MS prior to purification by flash chromatography to afford yellow oil (0.070 g, 29%).  135-branched.  Diagnostic signals:  1H-NMR (300 MHz, CDCl3): δ 6.81 (overlapped), 6.59 (overlapped), 3.77 (overlapped), 3.28-3.37 (m), 2.90-2.97 (m), 1.00-1.07 (m), 0.07 (s, 9H); 13C-NMR (300 MHz, CDCl3): δ 47.7 (CH3), 20.5 (CH), 12.8 (CH3), -3.4 (CH3).  135-linear.  1H-NMR (300 MHz, CDCl3): δ 6.81 (d, J = 8.7 Hz, 2H), 6.59 (d, J = 8.7 Hz, 2H), 3.77 (s, 3H), 3.34 (br s, 1H), 3.08 (t, J = 7.3 Hz, 2H), 1.68-1.57 (m, 2H), 0.57-0.63 (m, 2H), 0.05 (s, 9H); 13C-NMR (75 MHz, CDCl3): δ 152.0 (C), 142.9 (C), 115.0 (CH), 114.1 (CH), 55.8 (CH3), 48.3 (CH2), 24.2 (CH2), 14.1 (CH2), -1.6 (CH3); IR (NaCl, cm-1) 3395 (N-H stretch), 2951 (asymmetric C-H stretch), 2830 (symmetric C-H stretch), 1514 (aromatic ring stretch), 1234 (Si-CH3 deformation); HRMS-ESI (m/z) [M+H]+ Calcd for C13H24NOSi:  238.1627, Found: 238.1625.    OHN SiMe3135  159 Chlorobis(diethyl (2,6-dimethylphenyl)phosphoramidate)dimethyltantalum (154). In the   glove box and in the absence of light, complex 123 (0.100 g, 0.20 mmol) was dissolved in hexanes (3 g) and cooled to -30 °C.  Phosphoramidate proligand 122 (0.051 g, 0.20 mmol) was suspended in hexanes (3 g) and cooled to -30 °C.  The suspension of 122 was added slowly to the solution of 123 and the reaction was stirred at room temperature for 18 h in the dark.  Removal of all volatiles yielded a 154 as a pale yellow powder (0.129 g, 85%).  Single crystals suitable for X-ray diffraction studies were prepared from slow diffusion of pentanes into a solution of 154 dissolved in toluene. 1H{31P}-NMR (300 MHz, C6D6): δ 7.08-7.06 (m, 4H), 6.93 (t, J = 7.5 Hz, 2H), 4.87-4.77 (m, 2H), 4.42-4.31 (m, 2H), 3.83-3.73 (m, 2H), 3.67-3.57 (m, 2H), 2.78 (s, 6H), 2.62 (s, 6H), 1.18 (s, 6H), 0.99 (t, J = 6.9 Hz, 6H), 0.86 (t, J = 7.2 Hz, 6H); 13C{1H}-NMR (100 MHz, C6D6): δ 140.9 (C), 140.8 (C), 138.0 (C), 137.9 (C), 137.4 (C), 137.3 (C), 129.1 (CH), 129.0 (CH), 126.2 (CH), 126.1 (CH), 66.7 (CH2), 66.6 (CH2), 64.9 (CH2), 64.8 (CH2), 21.0 (CH3), 20.9 (CH3), 16.5 (CH3), 16.5 (CH3), 16.0 (CH3), 15.9 (CH3); 31P-NMR (121 MHz, C6D6): δ 14.8;   HRMS-ESI (m/z) [M-Me]+ Calcd for C25H41N2O6P2Ta35Cl:  238.1627, Found: 238.1625.    (2-methoxyphenyl)phosphoramidate (158). Known compound.390 Synthesized using General  Procedure B from o- anisidine (4.0 g, 32 mmol, 3.6 mL) and triethyl phosphite (8.0 g, 48 mmol, 8.1 mL).  The crude product was purified by flash chromatography (eluent:  1% methanol in CH2Cl2) and sublimation to yield white crystals (158, 0.832 g, 10%).  1H-NMR (300 MHz, CDCl3): δ 7.19 (dd, J = 7.2, 1.8 Hz, 1H), 6.94-6.82 (m, 4H), 5.73 (br s, 1H), 4.23-4.02 (m, 4H), 3.85 (s, NPOOOTaMe2Cl2154NHPOOOO158  160 3H), 1.31 (t, J = 6.9 Hz, 6H); 31P-NMR (121 MHz, C6D6): δ 2.85; EA Calcd. For C11H18NO4P:  N, 5.40, C, 50.96, H, 7.00, Found:  N, 5.29, C, 50.77, H, 6.97.  Chloro(diethyl (2-methoxyphenyl)phosphoramidate)trimethyltantalum (156).  56 was  prepared using General Procedure D from diethyl (2-methoxyphenyl)phosphoramidate (0.094 g, 0.34 mmol) and TaMe3Cl2 (0.100 g, 0.340 mmol) to yield a yellow powder (0.141 g, 80 %).  Single crystals suitable for X-ray diffraction studies were prepared by recrystallization from hexanes at -30 °C. 1H-NMR (300 MHz, C6D6): δ 6.92-6.89 (m, 1H), 6.82-6.71 (m, 2H), 6.46-6.43 (m, 1H), 3.92-3.81 (m, 4H), 3.58 (s, 3H), 1.73 (s, 6H), 0.85 (t, J = 6.9 Hz, 6H); 13C{1H}-NMR (100 MHz, C6D6): δ 152.5 (d, 3JC-P = 15 Hz, C), 134.1 (C), 124.2 (CH), 121.9 (CH), 120.2 (d, 3JC-P = 6.6 Hz, CH), 112.7 (CH), 78.9 (d, 3JC-P = 5.5 Hz, CH3), 65.5 (d, 2JC-P = 5.5 Hz, CH2), 54.8 (CH3), 15.9 (CH3), 15.8 (CH3); 31P{1H}-NMR (161 MHz, C6D6):  δ 9.11; EA Calcd. For C26H38N5O3PTa:  N, 2.69, C, 32.35, H, 5.04, Found:  N, 2.79, C, 32.30, H, 5.30.  	(Diethyl (2-methoxyphenyl)phosphoramidate)tetrakis(dimethylamido) tantalum (157).   Synthesized by protonolysis using General Procedure C from phosphoramidate proligand (0.108 g, 0.416 mmol) and Ta(NMe2)5 (0.167 g, 0.416 mmol) using General Procedure C to yield an orange crystalline solid (0.252 g, 98%).  The crude material was recrystallized in hexanes to yield yellow crystals (0.122 g, 48%).  1H-NMR (400 MHz, C6D6): δ 7.27 (dd, J = 8.0, 1.2 Hz, 1H), 7.04 (dt, J = 7.6, 1.2 Hz, 1H), 6.84 (dt, J = 8.0, 1.6 Hz, 1H), 6.69 (dd, J = 8.0, 1.2 Hz, 1H), 4.09-3.96 (m, 4H), 3.51 (s, 24 H), 3.47 (s, 3H), 1.11 (t, J = 6.8 Hz, 6H); 13C{1H}-NMR (100 NPOOOTaMe3ClO156NPOOOTa(NMe2)4O157  161 MHz, C6D6): δ 150.9 (d, J = 9.5 Hz, C), 136.4 (d, J = 5.4 Hz, C), 123.0 (d, J = 2.2 Hz, CH), 121.9 (d, J = 2.7 Hz, CH), 120.2 (CH), 112.4 (CH), 62.8 (d, J = 6.8 Hz, CH2), 55.4 (CH3), 47.8 (br s., N(CH3)), 16.6 (d, J = 7.2 Hz, CH3);  31P{1H}-NMR (161 MHz, C6D6):  δ 6.06; HRMS-EI (m/z) [M-NMe2]+. Calcd for C17H35N4O4PTa:  571.18761, Found: 571.18717.  Procedure for Monitoring Consumption of 4-methoxy-N-methylaniline vs. Time with Complex 111. In the glove box, 4-methoxy-N-methylaniline (0.549 g, 4.00 mmol), 1-octene (0.898 g, 6.00 mmol), and 1,3,5-trimethoxybenzene (0.224 g, 1.33 mmol) were dissolved in toluene-d8 (2.4 mL).  Precatalyst 123 (0.248 g, 0.400 mmol) was dissolved in toluene-d8 (2.4 mL).  The stock solutions were combined and divided by 8 prior to transferring into Teflon sealed NMR tubes.  The reactions were heated to 130 °C.  Reaction progress was monitored every 15 minutes by removing a NMR tube for analysis by 1H-NMR spectroscopy.  Procedure for Monitoring Consumption of 4-methoxy-N-methylaniline vs. Time with Complex 123.    In the glove box and in the absence of light, 4-methoxy-N-methylaniline (0.069 g, 0.50 mmol), 1-octene (0.112 g, 0.750 mmol), and 1,3,5-trimethoxybenzene (0.028 g, 0.17 mmol) were dissolved in toluene-d8 (2.4 mL).  Any amine additive used (diethylamine:  0.015 g, 0.20 mmol or diisobutylamine:  0.026 g, 0.20 mmol) was added to the above solution.  Precatalyst 123 was dissolved in toluene-d8 (2.4 mL).  Both solutions were cooled to -30 °C.  The solutions were mixed and transferred into a Teflon sealed NMR tube and reaction progress was measured by 1H-NMR spectroscopy every 10 minutes.     162 Chapter 4:  Enantioenriched Phosphoramidate-Tantalum Complexes for Catalytic Asymmetric Hydroaminoalkylation  Hydroaminoalkylation (HAA) results in the direct alkylation of a C(sp3)-H bond α to an amine by an unactivated olefin.67-68 Recent progress in this field has identified a number of late-202-206, 208-210, 413 and early-97, 200-201, 211-212, 214, 216, 221-229, 404-405, 414-415	transition metal catalysts that are capable of this transformation.  Recently a scandium-catalyzed HAA reaction has also been reported.416 While the α-alkylation of an amine generates a new stereocenter in the resulting product (Scheme 4.1), to date, there have been few reports of stereoselective HAA reactions reported in the literature.95, 213, 215-216, 409 In all of these examples, axially chiral biaryl ligands have been employed as the source of chirality in tantalum and niobium precatalyst complexes.  Although enantioselectivities of up to 98% ee have been achieved,409 stereoselectivity remains substrate specific and interest for a more broadly applicable catalyst system persists.   Scheme 4.1 Intermolecular hydroaminoalkylation leading to the formation of a new stereocenter  4.1 Asymmetric Hydroaminoalkylation Early transition metal complexes containing chiral N,O-chelates have previously been explored for catalysis, in particular for asymmetric hydroamination (Figure 4.1).81, 85, 87, 91 Bis(amidate)-Ti complexes were investigated for the synthesis of enantioenriched N-heterocycles through intramolecular hydroamination of aminoalkene substrates with enantioselectivities up to R3+R1 NHR2catalystR1HN R3R2+ R1HN R3R2Linear Branched* * *  163 68% ee reported.195, 417 Further investigations with analogous chiral Zr complexes have been more successful than their Ti counterparts, with ees reported of up to 93% and much shorter reaction times (24 h vs. 48 h).81, 85, 87, 91, 188, 418     Figure 4.1 Select examples of precatalysts with chiral N,O-chelating ligands for asymmetric intramolecular hydroamination  Following the success of chiral bis(amidate) ligand motifs in inducing enantioselection for asymmetric hydroamination, the application this ligand motif to asymmetric HAA afforded the first reported example of intermolecular asymmetric HAA in 2009.95 Precatalyst 13 was utilized in the synthesis of a variety of enantioenriched α-chiral amines in moderate to good PRRONZr(NMe2)2NPOR R159Bergman, 2006up to 80% eeNNOOMesMesZr(NMe2)2160Schafer, 2007up to 93% eeR = 3,5-C6H3Me2NNOOZrMesMes(NMe2)2161Zi, 2010up to 93% eeNNSOSOZr(NMe2)2162Zi, 2010up to 37% eeO MesO MesONTi(NMe2)2O163Zi, 2010up to 68% ee  164 yield (50-92%), but moderate enantioselectivities of up to 61% ee (Figure 4.2).  However, long reaction times (24-192 h) and high reaction temperatures (130 °C) are required.  Figure 4.2 Asymmetric hydroaminoalkylation catalyzed by group 5 complexes  Following this seminal report from the Schafer group, Zi and coworkers reported a bis(amidate)-Ta system for asymmetric HAA (14, Figure 4.2).213 The ligand motif employed incorporates a binaphthyl-based backbone and the modification resulted in substrate specific improved enantioselectivies (up to 93% ee, Figure 4.3), but no improvement in reaction temperatures (130-160 °C) or reaction times (48-160 h).  The highest enantioselectivities reported to date are achieved with group 5 binaphtholate complex, 15 (Figure 4.2).214 Up to 98% ee was attained in the α-alkylation of N-methylaniline with vinyltrimethylsilane.  Both niobium and tantalum were investigated with this ligand motif, with the niobium analogue exhibiting better reactivity and enantioselectivities in most cases.  Catalysis with complex 15 can be conducted at lower reaction temperatures (100 °C, 38-105 h), NONOTa(NMe2)3iPriPriPriPrNNOOTaMesMes(NMe2)3SiR3SiR3OONb(NMe2)3R = PhMe2(HNMe2)n13Schafer, 2009up to 61% ee14Zi, 2010up to 93% ee15Hultzsch, 2011up to 98% ee  165 but elevated temperatures can be used to reduce reaction times (140 °C, 5-48 h), often also with a detrimental effect on ees. While high ees have been realized in asymmetric HAA, thus far, this has only been applicable for select substrate and catalyst combinations.  Out of the three examples noted vide supra, no system has been highly enantioselective for a wide range of substrates (Figure 4.3).  In addition, high reaction conditions and long reaction times are required for complexes 13-15.  Therefore, identifying a catalyst system, which is highly enantioselective over a broad range of substrates and catalytically active under mild reaction conditions, remains a challenge in the field.  Figure 4.3 Select examples of asymmetric hydroaminoalkylation products catalyzed by group 5 systems  4.1.1 Scope of Chapter  Our group previously disclosed the first and only reported HAA catalyst active at room temperature.97 This phosphoramidate-TaMe3Cl complex displays good reactivity towards electron-rich arylamines and unactivated terminal alkenes, even under solvent free reaction conditions.  However, no examples of asymmetric HAA conducted at room temperature have ever been reported in the literature.  All previous examples have required high reaction HN1386%  44%Yield:ee:1479%  70%1592%  81%1380%  61%1484%93%1561%  59%HN1392%  43%1487%76%1592%  91%HN  166 conditions (vide supra), thereby limiting the use of this transformation to thermally robust substrates. Chiral phosphoramidates have important applications particularly in the development of therapeutics,419-421 but also as organocatalysts for transformations such as ring-opening polymerization422 and Pictet-Spengler-type reactions.423 Related to chiral phosphoramidates are chiral phosphoric acids which are much more prevalent in the literature for applications in asymmetric synthesis.424-428 A number of transformations have been reported where enantioselectivities in the resulting products are induced by chiral phosphoric acids, including transfer hydrogenation,429-434 Michael additions,435-440 heterocycle synthesis,441-446 and Mannich reactions.447-451 Structural motifs containing axial chirality and planar chirality are some examples observed in the literature (Figure 4.4).   Figure 4.4 Select examples of chiral phosphoric acids utilized in asymmetric synthesis452-454  Inspired by the numerous chiral structural patterns found in phosphoric acids, chiral phosphoramidates were investigated as ligands in asymmetric HAA. This is an extension of the work presented in Chapter 3 regarding room temperature HAA catalyzed by phosphoramidate-OOPOOHRRPhPhOO POOHOOPOOHRROO POOHAntilla, 2009 Marinetti, 2014 Wang, 2012ArAr  167 tantalum complexes.  In this chapter, a family of chiral phosphoramidate-tantalum complexes were prepared and characterized in an effort to identify a highly enantioselective catalyst system for asymmetric HAA at modest reaction temperatures with a broad substrate scope. Synthetic details regarding the preparation of chiral phosphoramidate-Ta complexes and related proligands, in addition catalytic screening results are presented herein.   4.2 Results and Discussion 4.2.1 Synthesis of Enantioenriched Phosphoramidate Proligands A number of enantioenriched phosphoramidate proligands were synthesized using modified literature procedures (Figure 4.5).422, 455 (S)-BINOL derived proligands were prepared in a two-step, one-pot process from enantioenriched starting materials (99%, 164-168, Figure 4.5).  BINOL and substituted varients react with phosphorus(V) oxychloride in the presence of triethylamine in methylene chloride at room temperature for 6 h to yield the chlorophosphate derivative.422 To this intermediate, a solution of primary alkyl amine in methylene chloride was added affording the desired phosphoramidate proligand after 2.5 h at room temperature. Similarly, proligand 169 was synthesized from diethyl chlorophosphate and (S)-methylbenzylamine in the presence of triethylamine in 16 h at room temperature.455 The crude materials were purified by flash chromatography to yield the desired product in low to moderate yields.  Challenges involving these reactions that contribute to the low yields include low solubility of the product, particularly BINOL derived phosphoramidates, resulting in loss of material in the extraction protocol as well as during purification by flash chromatography.  In addition, dimers, which arise from two equivalents of chlorophosphate reacting with the primary amine, are sometimes observed by mass spectrometry.  This reduces conversion to the desired   168 product as well as creating arduous purification steps.  Efforts to purify the phosphoramidate proligands through recrystallization were unsuccessful.  A particularly useful analytical tool to determine successful purification of the proligands was 31P{1H}-NMR spectroscopy.  Single signals with chemical shifts in the range of δ 15-10 ppm is diagnostic for these compounds.    Figure 4.5 Synthesis of chiral phosphoramidate proligands   While previous work described in Chapter 3, identified that N-aryl substituted phosphoramidate-Ta complexes exhibit superior catalytic activity relative to N-alkyl substituted phosphoramidate-Ta complexes, the N-aryl enantioenriched phosphoramidate proligands were synthetically challenging and could only be isolated in poor yields (<10%) due to reduced the nucleophilicity of aniline.  As such, these proligands were not investigated further.   OHOHR1R1i. POCl3, NEt3  CH2Cl2, r.t., 6 hii. R2NH2, r.t., 2.5 hOOPONHR1R1R2164:  R1 = H, R2 = benzyl (Yield: 76%)165:  R1 = H, R2 = isopropyl (Yield: 38%)166:  R1 = H, R2 = (S)-methylbenzyl (Yield: 43%)167:  R1 = TMS, R2 = isopropyl (Yield: 38%)168:  From H8-BINOL,  R1 = H, R2 = benzyl (Yield: 58%)O P ClO+NEt3CH2Cl2, r.t., 16 hO O P NHOONH2169Yield:  30%  169 4.2.2 Synthesis of Enantioenriched Phosphoramidate-Ta Complexes  With the phosphoramidate proligands in hand, Ta complexes were synthesized through protonolysis with Ta(NMe2)5 (170-175) or via salt metathesis from the sodium salt of the phosphoramidate proligand and TaMe3Cl2 (176-181, Figure 4.6).  Chapter 3 illustrated that phosphoramidate-Ta(NMe2)4 complexes show markedly different reactivity compared to phosphoramidate-TaMe3Cl complexes.  The latter exhibit room temperature reactivity, but result in less robust HAA catalysts due to problems with thermal and light sensitivity.  Likewise, while the phosphoramidate-Ta(NMe2)4 complexes require elevated reaction temperatures for catalytic turnover, these complexes are easier to handle and store.  In this study, enantioenriched phosphoramidate proligands were installed on both Ta(NMe2)5 and TaMe3Cl2 materials to compare the enantioselectivities observed in catalytic HAA. Changes in reaction temperatures can have significant effects on stereoselectivity in synthesis.102, 456-460 As these two classes of phosphoramidate-Ta complexes require different reaction temperatures for optimal catalytic activity, but yet, operate through the same proposed reaction mechanism, temperature effects on enantioselectivity can be probed.    These Ta complexes were isolated as crude products (Figure 4.6) and analysis by NMR spectroscopy showed that some of these complexes exist as multiple species in solution, particularly complexes 176-181 synthesized via salt metathesis.  The multiple products may be due to the phosphoramidate ligand adopting different binding modes.  In those cases, since the 1H{31P}-NMR spectra show complex signals, 31P{1H}-NMR spectroscopy was a particularly useful spectroscopic tool for determining how many possible species are present.  Preparation of these complexes at -78 °C instead of room temperature did not afford single species either, as determined by NMR spectroscopy.  Further purification attempts through recrystallization were   170 unsuccessful and screening for catalytic activity was performed using the crude mixture or in situ generated catalyst.   Figure 4.6 Chiral phosphoramidate-Ta complexes prepared for asymmetric hydroaminoalkylation  OOPONTa(NMe2)4OOPONTa(NMe2)4OOPONTa(NMe2)4OOPONTa(NMe2)4OOPONTaMe3ClOOPONTaMe3ClOOPONTaMe3ClOOPONTaMe3ClOOPONTaMe3ClOOPONTa(NMe2)4176 177 178179 180170 171 172173 174OOPONTa(NMe2)4175OOPONTaMe3Cl181A.  Phosphoramidate-Ta(NMe2)4 complexes synthesized by protonolysis:B.  Phosphoramidate-TaMe3Cl synthesized by salt metathesis:TMSTMSTMSTMS  171 Single crystals suitable for X-ray crystallography were obtained for 171 through recrystallization from toluene (Figure 4.7).  The solid state molecular structure shows the complex is C1 symmetric with a geometry that is best described as distorted trigonal bipyramidal, as would be expected.  The complex crystallizes in the P212121 space group, which is a chiral space group.  The phosphoramidate ligand is in a κ2-binding mode through the oxygen and nitrogen atoms and formally occupies a single equatorial coordination site.  The shortened P-O1 and P-N1 bond lengths are consistent with partial double bond character and delocalization of electrons between N1-P-O1.  In the solid state molecular structure, the binapthyl portion of the phosphoramidate ligand can be observed as the (S)-enantiomer, which is consistent with the absolute stereochemistry of the enantiopure starting material, (S)-BINOL.        172 	         Figure 4.7 ORTEP of the solid state molecular structure of complex 171 with select bond lengths and bond angles (Thermal ellipsoids set at 50% probability.  All hydrogen atoms and hexane solvent molecule are removed for clarity)   Selected Bond Lengths (Å) Selected Bond Angles (°) Ta-O1 2.307(3) N1-Ta-O1 64.10(12) Ta-N1 2.262(3) P1-Ta-N2 115.69(12) Ta-N2 1.985(4) P1-Ta-N3 139.52(12) Ta-N4 2.047(4) N4-Ta-N5 172.23(17) P1-N1 1.576(4) P1-Ta-N4 82.79(13) P1-O1 1.497(3) P1-Ta-N5 89.44(11) P1-O2 1.603(3) O1-P1-N1 105.40(10) O1O2O3P1N1C1Ta1N2N3N4N5  173 4.2.3 Screening of Enantioenriched Phosphoramidate-Ta Complexes for Asymmetric Hydroaminoalkylation  The isolated tantalum complexes were screened for catalytic activity in catalytic HAA using the standard test reaction between 4-methoxy-N-methylaniline and 1-octene at 10 mol% precatalyst loading for 20 h.  In the cases where multiple species were observed by 1H{31P}- and 31P{1H}-NMR spectroscopy, the crude mixtures were used in the screen without further purification or alternatively, in situ catalyst was generated, as noted.  Test reactions utilizing phosphoramidate-Ta(NMe2)4 complexes were conducted at 110 °C, while reactions with phosphoramidate-TaMe3Cl precatalysts were conducted at room temperature due to thermal sensitivity of these complexes. Of the precatalysts screened (170-181), all complexes show catalytic activity towards HAA (Table 4.1). Of the phosphoramidate-Ta complexes screened, complex 170 was the most active, resulting in >98% yield.  The same ligand motif also generated the most catalytically active complex when installed onto TaMe3Cl2 (176, 85%).  In light of these results, catalyst turnover appears to be sensitive to steric bulk at the nitrogen of the phosphoramidate ligand, as complexes with α-methyl substitutions on the nitrogen show reduced reactivity (171, 172, 175, 177, 178, and 181).          174 Table 4.1 Screening of enantioenriched phosphoramidate-Ta complexes for asymmetric hydroaminoalkylation    Following catalysis, the HAA product, 4-methoxy-N-(2-methyloctyl)aniline, was isolated through column chromatography after tosylation and analyzed by supercritical fluid HN+10 mol% Ta precatalysttoluene-d8, 20 hHNO OEntrya Precatalyst Temperature (°C) Yield (%)b ee (%)c1 170d 110 98 02 170e 110 >98 03 171d 110 48b(40)f 144 172d 110 47 85 173d 110 86 06 174d 110 80 07 175d 110 28 48 176e 23 85 09 177e 23 41 010 178e 23 13 011 179e 23 25 012 180e 23 74 013 181e 23 16 50aReaction Conditons:  0.5  mmol 4-methoxy-N-methylaniline, 0.75 mmol 1-octene, 0.6 mL of toluene-d8.  Reactions conducted at room temperature were performed in Teflon sealed vials.  Reactions at 110 °C were performed in sealed J-Young NMR tubes.  bDetermined by 1H-NMR spectroscopy (300 MHz, 298 K).  cDetermined by supercritical fluid chromatography after tosylation.  dIsolated complex.  eIn situ generated complex.  fIsolated yield.(+/-)  175 chromatography.  Comparison of these products against a known racemic mixture was used for ee determination.  Unfortunately, although these complexes are competent catalysts for the transformation, enantioselectivities from the screen were poor and racemic product was observed in most cases.  Additional steric bulk in the 3,3'-positions of the binapthyl moiety provided by the installation of trimethylsilyl group (173 and 179) did not improve selectivities and racemic product was obtained.  Incorporation of steric bulk at the nitrogen for BINOL derived phosphoramidates (172 and 178) yielded no appreciable enantiomeric excess, but in the case of 181 50% ee was observed for the isolated product, despite 4% ee for the analogous 175 compound.  The reaction utilizing 181 was conducted at room temperature, whereas that of 175 was heated to 110 °C.  Phosphoramidate-Ta(NMe2)4 and phosphoramidate-TaMe3Cl complexes are hypothesized to operate through the same proposed mechanism for catalytic HAA,99, 201, 214, 461 the differences in the selectivities may be a result of the different reaction temperatures.  Further inspection of the solid-state molecular structure of precatalyst 171 affords some insight into the poor enantioselectivities observed in catalysis with these enantioenriched phosphoramidate-Ta complexes (Figure 4.7).  In this κ2-binding mode, the enantiodetermining portion of the complex, the axially chiral binaphthyl group, is far removed from the metal center at which the reaction occurs.  Even with the inclusion of additional steric bulk in the 3,3'-positions of the binapthyl moiety through the installation of trimethylsilyl groups, the steric bulk may not be close enough to the coordination sites at which catalysis occurs to induce any stereoselectivity on the resulting product.  The catalytic screening results from complexes 173 and 179 are in contrast to the binaphtholate tantalum and niobium complexes previously described by Hultzsch and coworkers.214, 216 While the 3,3'-TMS substituted analogue of 15 was not the most enantioselective precatalyst reported, up to 54% ee was observed with the   176 binaphtholate niobium complex.214, 216 Without the phosphoramidate O-P-N linker to the metal center, in the solid state, the axially chiral binapthyl group is much closer to the metal center in Hultzsch’s complexes than the phosphoramidate-tantalum complexes described vide supra.214, 216 Therefore, stereoselectivity was possible with the binaphtholate complexes unlike these phosphoramidate-Ta complexes.  The poor enantioselectivities obtained with our phosphoramidate-Ta complexes was disappointing.  4.2.4 Variable-Temperature NMR Spectroscopy The lack of any enantioselectivity observed in HAA reactions catalyzed by most of the enantioenriched phosphoramidate-Ta complexes utilized in catalysis may result from a few different factors.  One possibility is that the enantiodetermining moiety of the chiral auxiliary ligand complex is removed from the metal center at which the catalysis occurs.  However, under the reaction temperatures which are required for catalysis with phosphoramidate-Ta(NMe2)4 complexes (170-175), it is not clear if the enantioenriched ligand remains coordinated to the metal center.  Variable-temperature NMR spectroscopy experiments were used to probe changes in ligand coordination under conditions of increasing temperature (Figure 4.8).     177  Figure 4.8 1H-NMR spectra of complex 175 at various temperatures   An NMR sample of complex 175 was studied under various different temperatures (298-363 K).  Overall, the 1H{31P}-NMR spectra of this complex remains unchanged as the temperature is increased in comparison to the room temperature spectrum.  The 31P{1H}-NMR spectra collected over the same range of temperatures also showed no changes in profile with increasing temperatures; only one signal (δ 9.84) was observed from 298-363 K.  The unchanged NMR spectra for complex 175 are consistent with no change in coordination of the phosphoramidate ligand as a result of an increase in temperature.   178  Under catalytic conditions, not only are the phosphoramidate-Ta complexes subjected to high reaction temperatures, but also an excess of amine.  This can result in exchange with any of the labile ligands and potential displacement of the enantiodetermining phosphoramidate ligand.  To probe the effect of excess amine on complex 175, 2 equivalents of 4-methoxy-N-methylaniline was added to a solution of 175 in toluene-d8 and the sample was analyzed by 1H{31P}- and 31P{1H}-NMR spectroscopy (Figure 4.9).      179   Figure 4.9 1H-NMR spectrum of complex 175 (bottom) and complex 175 and 2 equivalents of 4-methoxy-N-methylaniline (top)  In the presence of an excess of amine (2 equivalents of 4-methoxy-N-methylaniline), a spontaneous change to the 1H{31P}-NMR spectrum was observed and signals not associated to the free complex or free 4-methoxy-N-methylaniline appears (Figure 4.9).   Characteristic signals of the phosphoramidate ligand (δ 4.70 ppm, q; 1.64 ppm, d; 1.07 ppm, t; 0.93 ppm, t) are observed in duplicate (δ 4.78 ppm, q; 1.79 ppm, d; 0.95 ppm, t; 0.88 ppm, t) in a 2:3 ratio.  A   180 multitude of signals are observed in the 31P{1H}-NMR spectrum, but two main signals are present in a 1:1 ratio, one corresponding to complex 175 (δ 9.84 ppm) and the other to a new phosphorous containing compound (δ 10.5 ppm).  The absence of the proligand signal in the 31P{1H}-NMR spectrum (δ 8.7 ppm) indicates that displacement of the phosphoramidate ligand has not occurred.  In addition, new signals corresponding to the release of dimethylamine (δ 2.21 ppm, d) are evident.  While spontaneous formation of tantallaaziridines, the proposed catalytically active intermediate, is possible at room temperature, diagnostic signals in the 1H{31P}-NMR spectrum corresponding to the diastereotopic Ta-CH2 protons were not observed in the region of approximately δ 2.5 ppm.95, 351 No diagnostic signals for the tantallaaziridine was present in the 13C{1H}-NMR spectrum either (~δ 60 ppm).95, 351 Therefore, in the absence of any evidence of tantallaaziridine formation at room temperature, the new set of signals observed via NMR spectroscopy is attributed to coordination of aniline to complex 175 at room temperature and the liberation of dimethylamine.   Complex 175 in the presence of excess 4-methoxy-N-methylaniline was studied by variable temperature NMR spectroscopy to determine if any further changes occur at higher temperatures similar to those employed under catalytic conditions.  Ratios of the two phosphoramidate-Ta species change with increasing temperature, but no new signals corresponding to free proligand is observed in both the 1H{31P}- and the 31P{1H}-NMR spectra. Therefore, in the presence of excess amine, which is used to simulate catalytic reaction conditions, disassociation of the phosphoramidate ligand from the metal complex does not seem to occur.  Signals associated with complex 175 become increasingly broadened, possibly due to fluxional behavior in solution at higher temperatures.  This fluxional behavior is likely   181 detrimental for the enantiodetermining step in the HAA, resulting in poor geometrical control over the substrates in the reaction, thus resulting in poor ees.   Figure 4.10 1H-NMR spectra of 175 with 4-methoxy-N-methylaniline at various temperatures   4.3 Conclusions In this Chapter, a new family of enantioenriched phosphoramidate compounds were synthesized and characterized. Axially chiral phosphoramidate proligands (164-168) were prepared and characterized in addition to a phosphoramidate proligand bearing a stereocenter   182 (166 and 169).  These new N,O-chelating ligands were installed onto two different Ta starting materials, Ta(NMe2)5 and TaMe3Cl2 and screened for asymmetric HAA.    These complexes were found to be effective precatalysts for the catalytic HAA towards α-alkylation of 4-methoxy-N-methylaniline with 1-octene at both elevated reaction temperatures (110 °C) and room temperature.  Of the phosphoramidate-Ta(NMe2)4 complexes studied, reactions with precatalyst 170 demonstrated the highest reactivity with >98% conversion after 20 h at 110 °C to afford the branched HAA product.  Amongst phosphoramidate-TaMe3Cl complexes, reactions with precatalyst 176 was identified to be the most catalytically active with 85% conversion after 20 h at room temperature.  Both of these complexes bear the same phosphoramidate ligand (164). In general, catalysis with axially chiral phosphoramidate-Ta complexes did not result in observable asymmetric induction, presumably due to the enantiodetermining moiety of the phosphoramidate ligand being far removed from the metal center.  Variable temperature NMR studies also indicate fluxional behavior of these complexes in solution at elevated temperatures under simulated catalytic conditions in the presence of excess amine.  Such fluxional behavior is likely detrimental towards high enantioselectivities.  However, moderate ee (50%) was achieved at room temperature with complex 175.  This is the first and only example to date of an asymmetric room temperature HAA reaction.    4.4 Experimental Procedures 4.4.1 Materials and Methods  General materials and methods are as outlined in Section 2.4.1 and also include the following additions:     183  (S)-H8-BINOL,462 (S)-3,3'-bis(trimethylsilyl)1,1'-binapththyl-2,2'-diol,463 and diethyl (S)-(1-phenylethyl)phosphoramidate (169)455  were prepared from literature procedures and spectral data for these compounds are consistent with previous reports.   4.4.2 Synthesis and Characterization of Compounds General Procedure A:  Preparation of Enantioenriched Phosphoramidate Proligands.   Adapted from literature.422 In a Schlenk tube under N2, (S)-BINOL (0.300 g, 1.00 mmol) was added to anhydrous CH2Cl2 (1 mL) to form a slurry.  POCl3 was added (1.50 equivalents), followed by anhydrous NEt3 (2.50 equivalents) and evolution of white smoke was observed.  The reaction was stirred at room temperature for 2 h before dilution with anhydrous DCM (20 mL).  Amine (5.00 equivalents) was added dropwise and the reaction was stirred at room temperature for 20 h.  Water (20 mL) was added to quench the reaction and the layers were separated.  The organic layer was washed with 1 M HCl (3 x 20 mL), H2O (2 x 20 mL), and brine (20 mL) before drying over Na2SO4 and filtration.  The filtrate was concentrated in vacuo to yield crude product, which was purified by flash chromatography (50% EtOAc in hexanes).  The proligand was heated to 60 °C under vacuum for 20 h before introduction into a N2 filled glovebox.   OHOHR1R1i. POCl3, NEt3  CH2Cl2, r.t., 6 hii. R2NH2, r.t., 2.5 hOOPONHR1R1R2  184 (S)-1,1'-Binaphthy-2,2'-diyl benzylphosphoramidate (164).  The target compound was synthesized from (S)-BINOL (1.20 g, 4.20 mmol), POCl3 (0.90 g, 4.4 mmol, 0.52 mL), NEt3 (1.0 g, 10 mmol, 1.4 mL), and benzyl amine (2.3 g, 21 mmol, 2.3 mL) using General Procedure A.  Purification by column chromatography (50% EtOAc in hexanes) yielded a white solid (1.41 g, 76%).  Spectral data match previously reported racemic compound.422 [α]D = +438° (c = 0.25, dichloromethane); m.p.:  160-163 °C; 1H{31P}-NMR (300 MHz, CDCl3):  δ 8.03 (d, J = 9.0 Hz, 1H), 7.96 (m, 3H), 7.62 (d, J = 8.7 Hz, 1H), 7.50-7.43 (m, 3H), 7.38-7.25 (m, 9H), 4.13 (dd, J = 7.5, 3.6 Hz, 2H), 3.34 (t, J = 6.9 Hz, 1H); 13C{1H}-NMR (75 MHz, CDCl3): δ 147.4 (d, 2JC-P = 10.7 Hz, C), 146.6 (d, 2JC-P = 8.6 Hz, C), 139.1 (d, 3JC-P = 6.1 Hz, C), 132.4 (d, 3JC-P = 6.9 Hz, C), 131.9 (C), 131.5 (C), 131.3 (CH), 131.1 (CH), 128.8 (CH), 128.6 (d, 3JC-P = 7.7 Hz, CH), 127.8 (CH), 127.6 (CH), 127.2 (CH), 127.0 (CH), 126.8 (CH), 126.7 (CH), 125.7 (d, 3JC-P = 7.4 Hz, CH), 121.9 (C), 121.4 (C), 121.1 (d, 4JC-P = 2.3 Hz, CH), 120.7 (d, 4JC-P = 3.1 Hz, CH), 46.0 (CH2); 31P{1H}-NMR (121 MHz, CDCl3): δ 14.5; IR (NaCl, cm-1): 3382 (N-H stretch), 1590 (aromatic ring stretch), 1464 (aromatic ring stretch); HRMS-ESI (m/z) [M+Na]+: Calcd for C27H20NO3PNa: 460.1079, Found: 460.1078.       OOPO164NH  185 (S)-1,1'-Binaphthy-2,2'-diyl isopropylphosphoramidate (165).  The target compound was  synthesized from (S)-BINOL (1.20 g, 4.20 mmol), POCl3 (0.90 g, 4.4 mmol, 0.52 mL), NEt3 (1.0 g, 10 mmol, 1.4 mL), and benzyl amine (1.2 g, 21 mmol, 1.8 mL) using General Procedure A. Purification by column chromatography (50% EtOAc in hexanes) yielded a white solid (0.614 g, 38%). [α]D = +19° (c = 0.6, dichloromethane); m.p.: 222-224 °C; 1H{31P}-NMR (300 MHz, CDCl3):  δ 8.02 (dd, J = 8.7, 1.8 Hz, 2H), 7.95 (t, J = 7.2 Hz, 2H), 7.60 (d, J = 8.7 Hz, 1H), 7.52-7.41 (m, 4H), 7.35-7.27 (m, 3H), 3.58-3.46 (m, 1H), 2.65 (d, J = 9.9 Hz, 1H), 1.23 (d, J = 6.3 Hz, 3H), 1.18 (d, J = 6.6 Hz, 3H); 13C{1H}-NMR (75 MHz, CDCl3): δ 147.5 (d, 2JC-P = 10.7 Hz, C), 146.6 (d, 2JC-P = 9.1 Hz, C), 132.4 (d, 3JC-P = 10.2 Hz, C), 131.8 (C), 131.5 (C), 131.2 (CH), 130.9 (CH), 128.5 (d, 3JC-P = 4.1 Hz, CH), 127.2 (CH), 127.0 (CH), 126.8 (CH), 126.6 (CH), 125.7 (CH), 125.6 (CH), 121.8 (C), 121.4 (C), 121.1 (d, 4JC-P = 1.9 Hz, CH), 120.8 (d, 4JC-P = 2.7 Hz, CH), 44.9 (CH), 25.7 (d, 4JC-P = 3.8 Hz, CH3), 25.4 (d, 4JC-P = 6.9 Hz, CH3); 31P{1H}-NMR (121 MHz, CDCl3): δ 14.2; IR (NaCl, cm-1): 3210 (N-H stretch), 2972 (aliphatic C-H stretch), 1591 (aromatic ring stretch), 1464 (aromatic ring stretch); HRMS-ESI (m/z) [M+Na]+: Calcd for C23H20NO3PNa: 412.1079, Found: 412.1079.        OOPO165NH  186  (S)-1,1'-Binaphthy-2,2'-diyl (S)-(-)-(α) methylbenzylphosphoramidate (166).  The target  compound was synthesized from (S)-BINOL (0.300 g, 1.00 mmol), POCl3 (0.22 g, 1.5 mmol, 0.13 mL), NEt3 (0.25 g, 2.5 mmol, 0.35 mL), and (S)-(-)-α-methylbenzylamine (0.64 g, 5.3 mmol, 0.68 mL) using General Procedure A.  Purification by column chromatography (50% EtOAc in hexanes) yielded a white solid (0.614 g, 38%).  Spectral data match previously reported racemic compound.422 [α]D = +457° (c = 0.25, dichloromethane); m.p.: 232-234 °C; 1H{31P}-NMR (300 MHz, CDCl3):  δ 8.02 (d, J = 8.7 Hz, 1H), 7.95-7.92 (m, 2H), 7.87 (d, J = 8.7 Hz, 1H), 7.60 (d, J = 9.0 Hz, 1H), 7.52-7.40 (m, 3H), 7.35-7.21 (m, 4H), 4.55-4.56 (m, 1H), 3.33 (d, J = 9.9 Hz, 1H), 1.57 (d, J = 6.6 Hz, 3H); 13C{1H}-NMR (100 MHz, CDCl3): δ 147.5 (d, 2JC-P = 10.9 Hz, C), 146.6 (d, 2JC-P = 9.1 Hz, C), 144.1 (d, 3JC-P = 6.2 Hz, C), 132.4 (d, 3JC-P = 8.3 Hz, C), 131.8 (C), 131.5 (C), 131.3 (CH), 130.9 (CH), 128.7 (CH), 128.5 (d, 3JC-P = 9.8 Hz, CH), 127.1 (CH), 126.8 (d, 3JC-P = 9.1 Hz, CH), 125.9 (CH), 125.7 (d, 3JC-P = 6.9 Hz, CH), 121.7 (CH), 121.4 (CH), 121.2 (CH), 120.9 (CH), 52.0 (CH), 25.7 (d, 4JC-P = 4.4 Hz, CH3); 31P{1H}-NMR (121 MHz, CDCl3): δ 12.8; IR (NaCl, cm-1): 3204 (N-H stretch), 2923 (aliphatic C-H stretch), 1466 (aromatic ring stretch), 1226 (aromatic C-H bend);  HRMS-ESI (m/z) [M-2H+Na]+ Calcd for C28H22NO3PNa: 446.1235, Found: 474.1239.    OOPO166NH  187 (S)-3,3'-Bis(trimethylsilyl)1,1'-binaphthy-2,2'-diyl benzylphosphoramidate (167).  The target  compound was synthesized from (S)-3,3'-bis(trimethylsilyl)1,1'-binapththyl-2,2'-diol463 (0.440 g, 1.00 mmol), POCl3 (0.22 g, 1.5 mmol, 0.13 mL), NEt3 (0.252 g, 2.5 mmol, 0.35 mL), and benzyl amine (0.57 g, 5.3 mmol, 0.58 mL) using General Procedure A.  Purification by column chromatography (50% EtOAc in hexanes) yielded a white solid (0.236 g, 53%). [α]D = +508° (c = 0.25, dichloromethane); m.p.: 162-165 °C; 1H{31P}-NMR (300 MHz, CDCl3):  δ 8.21 (d, J = 11.1 Hz, 2H), 8.03 (d, J = 8.7 Hz, 1H), 7.96 (d, J = 8.1 Hz, 1H), 7.53-7.46 (m, 2H), 7.32-7.12 (m, 9H), 4.53 (br s, 1H), 3.96-3.88 (m, 1H), 3.71-3.63 (m, 1H), 0.63 (s, 9H), 0.57 (s, 9H); 13C{1H}-NMR (75 MHz, CDCl3): δ 151.5 (d, 2JC-P = 10.6 Hz, C), 150.8 (d, 2JC-P = 9.4 Hz, C), 139.0 (d, 3JC-P = 4.7 Hz, C), 137.8 (CH), 133.6 (C), 133.5 (C), 132.2 (d, 3JC-P = 3.5 Hz, C), 132.1 (d, 3JC-P = 3.6 Hz, C), 131.2 (C), 131.1 (C), 128.4 (CH), 127.6 (CH), 127.3 (CH), 127.1 (d, 4JC-P = 4.3 Hz, CH), 126.8 (d, 4JC-P = 4.1 Hz, CH), 125.5 (CH), 125.3 (CH), 120.9 (C), 120.5 (C), 46.5 (CH2), 0.27 (CH3), -0.01 (CH3); 31P{1H}-NMR (121 MHz, CDCl3): δ 10.5; IR (NaCl, cm-1): 3203 (N-H stretch), 2924 (aliphatic C-H stretch), 1454 (aromatic ring stretch), 1217 (aromatic C-H bend);  HRMS-ESI (m/z) [M-2H+Na]+ Calcd for C33H36NO3Si2PNa: 604.1869, Found: 604.1859.     OOPO167NHTMSTMS  188 (S)-H8-1,1'-Binaphthy-2,2'-diyl benzylphosphoramidate (168).  The target compound was  synthesized from (S)-H8-BINOL (1.03 g, 3.50 mmol), POCl3 (0.77 g, 5.3 mmol, 0.46 mL), NEt3 (0.88 g, 8.8 mmol, 1.2 mL), and benzyl amine (2.0 g, 19 mmol, 2.0 mL) using General Procedure A.422 Purification by column chromatography (50% EtOAc in hexanes) yielded a white solid (0.280 g, 85%).  [α]D = +155° (c = 0.25, dichloromethane); m.p.: 148-150 °C; 1H{31P}-NMR (300 MHz, CDCl3):  δ 7.40-7.29 (m, 5H), 7.17 (s, 2H), 7.08 (d, J = 8.4 Hz, 2H), 6.85 (d, J = 8.1 Hz, 2H), 4.15 (d, J = 6.9 Hz, 2H), 3.28 (t, J = 6.9 Hz, 1H), 2.94-2.64 (m, 6H), 2.36-2.26 (m, 2H), 1.9-1.76 (m, 6H), 1.62-1.50 (m, 2H); 13C{1H}-NMR (75 MHz, CDCl3): δ 146.7 (d, 2JC-P = 10.1 Hz, C), 145.6 (d, 2JC-P = 8.9 Hz, C), 139.4 (d, 3JC-P = 5.7 Hz, C), 138.5 (C), 138.3 (C), 135.6 (C), 135.2 (C), 130.0 (CH), 129.7 (CH), 128.6 (CH), 127.6 (CH), 127.5 (CH), 126.5 (C), 125.9 (C), 118.6 (d, 4JC-P = 2.8 Hz, CH), 118.1 (d, 4JC-P = 2.0 Hz, CH), 45.8 (CH2), 29.1 (CH2), 27.9 (CH2), 27.8 (CH2), 22.5 (CH2), 22.4 (CH2), 22.3 (CH2); 31P{1H}-NMR (121 MHz, CDCl3): δ 11.9; IR (NaCl, cm-1): 3213 (N-H stretch), 2927 (aliphatic C-H stretch), 1469 (aromatic ring stretch), 1226 (aromatic C-H bend);  HRMS-ESI (m/z) [M+H]+ Calcd for C27H29NO3P: 446.1885, Found: 446.1889.       OOPO168NH  189 General Method B:  Preparing Enantioenriched Phopshoramidate-Ta Complexes via Protonolysis  In the glove box, phosphoramidate proligand (0.25 mmol) was dissolved or suspended in anhydrous hexanes (1 g).  Ta(NMe2)5 (0.25 mmol) was dissolved in anhydrous hexanes (1.5 g).  The proligand solution was added dropwise to the Ta(NMe2)5 solution.  The reaction mixture was stirred at room temperature overnight.  Removal of volatiles in vacuo yielded crude phosphoramidate-Ta(NMe2)4 complexes.   ((S)-1,1'-Binaphthy-2,2'-diyl benzylphosphoramidate) tetrakis(dimethylamido)tantalum (170).  Synthesized by protonolysis using General Method B from 164 (0.097 g, 0.25 mmol) and Ta(NMe2)5 (0.100 g, 0.250 mmol).  Removal of solvent in vacuo yielded a yellow amorphous solid (0.178 g, 90%).  1H{31P}-NMR (400 MHz, toluene-d8):  δ 7.58-7.57 (m, 2H), 7.50-7.47 (m, 2H), 7.43 (d, J = 8.8 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.26 (t, J = 8.8 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.07 (t, J = 7.2 Hz, 1H), 6.97-6.93 (m, 2H), 4.45 (d, J = 14 Hz, 1H), 4.4.26 (d, J = 14 Hz, 1H), 3.60 (br s, 24 H); 13C{1H}-NMR (100 MHz, toluene-d8):  δ 148.4 (d, 2JC-P = 9.9 Hz, C), 147.9 (d, 2JC-P = 11 Hz, C), 142.1 (d, 3JC-P  = 5.5 Hz, C), 132.7 (d, 3JC-P  = 15 Hz, C), 137.7 (C), 132.0 (C), 131.6 (C), 131.2 (CH), 130.8 (CH), 129.3 (CH), 129.1 (CH), 128.8 (CH), 128.5 (CH), 128.1 (CH), 127.6 (CH), 127.2 (CH), 126.7 (CH), 126.6 (CH), 125.6 (d, 3JC-P  = 6.2 Hz, CH), 125.4 (d, 3JC-P = 8.4 Hz, CH), 121.8 (C), 121.7 NPR1ROOROTa(NMe2)4PONROROR1H + Ta(NMe2)5hexanesr.t., 18 hOOPONTa(NMe2)4170  190 (CH), 121.6 (C), 121.6 (d, 4JC-P = 2.5 Hz, CH), 50.3 (d, 2JC-P  = 5.1 Hz, CH2), 46.9 (br s, (N(CH3)2); 31P{1H}-NMR (121 MHz, C6D6): δ 15.7; HRMS-EI (m/z) [M-NMe2]+ Calcd for C33H37N4O3PTa: 749.20834, Found: 749.20696.  ((S)-1,1'-Binaphthy-2,2'-diyl isopropylphosphoramidate) tetrakis(dimethylamido)tantalum    (171).  Synthesized by protonolysis using General Method B from 165 (0.097 g, 0.25 mmol) and Ta(NMe2)5 (0.100 g, 0.250 mmol).  Removal of solvent in vacuo yielded a pale yellow powder (0.182 g, quantitative).  Analyses of NMR spectra indicate multiple species in solution.  Single crystals suitable for X-ray diffraction studies were obtained through recrystallization in toluene/hexanes.  1H{31P}-NMR (400 MHz, C6D6):  δ 7.68 (d, J = 8.8 Hz, 1H), 7.64-7.60 (m, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.8 Hz, 1H), 7.30 (d, J = 8.0 Hz, 1H), 7.16-7.07 (m, 2H), 6.92-6.85 (m, 2H), 3.76 (quintet, J = 6.8 Hz, 1H), 3.65 (br s, 24H), 1.03 (d, J = 6.4 Hz, 3H), 0.98 (d, J = 6.4 Hz, 3H); 13C{1H}-NMR (100 MHz, C6D6): δ 148.6 (d, 2JC-P = 9.8 Hz, C), 148.2 (d, 2JC-P = 11 Hz, C), 132.9 (d, 3JC-P = 15 Hz, C), 132.1 (C), 131.6 (C), 131.4 (CH), 130.5 (CH), 128.9 (CH), 128.6 (CH), 127.7 (CH), 127.3 (CH), 126.9 (CH), 126.7 (CH), 122.3, 122.1, 121.8, 47.7 (d, 2JC-P = 4.4 Hz, CH), 47.1 (br s, (N(CH3)2), 27.1 (d, 3JC-P = 5.5 Hz, CH3), 26.5 (d, 3JC-P = 14 Hz, CH3); 31P{1H}-NMR (121 MHz, CDCl3): δ 14.1; HRMS-EI (m/z) [M-NMe2]+ Calcd for C29H37N4O3PTa: 701.20834, Found: 701.20740.   OOPONTa(NMe2)4171  191 ((S)-1,1'-Binaphthy-2,2'-diyl (S)-(-)-(α) methylbenzylphosphoramidate) tetrakis(dimethylamido)tantalum (172).  Synthesized by protonolysis using General Method B from 166 (0.112 g, 0.250 mmol) and Ta(NMe2)5 (0.100 g, 0.250 mmol).  Removal of solvent in vacuo yielded yellow solid foam (0.178 g, 90%). 1H{31P}-NMR (400 MHz, C6D6):  δ 7.66-7.61 (m, 2H), 7.53-7.48 (m, 2H), 7.41 (d, J = 8.7 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.28 (d, J = 8.7 Hz, 1H), 7.18-7.05 (m, 6H), 6.96-6.76 (m, 4H), 4.74 (q, J = 6.6 Hz, 1H), 3.62 (br s, 24H), 1.43 (d, J = 6.9 Hz, 3H); 31P{1H}-NMR (121 MHz, CDCl3): δ 14.0; HRMS-EI (m/z) [M-NMe2]+ Calcd for C34H39N4O3PTa: 763.22399; Found: 763.22317.     ((S)-3,3'-Bis(trimethylsilyl)1,1'-binaphthy-2,2'-diyl benzylphosphoramidate) tetrakis(dimethylamido)tantalum (173).  Synthesized by protonolysis using General Method B from 167 (0.145 g, 0.250 mmol) and Ta(NMe2)5 (0.100 g, 0.250 mmol).  Removal of solvent in vacuo yielded pale orange solid foam (0.234 g, quantitative).  Analyses of NMR spectra indicate multiple species in solution.  31P{1H}-NMR (121 MHz, CDCl3): δ 15.9, 15.1, 15.0, 14.2, 11.5, 11.4, 7.24, 0.25, 0.04, HRMS-EI (m/z) [M-NMe2]+ Calcd for C39H53N4O3Si2PTa: 893.28740, Found: 893.28518.   OOPONTa(NMe2)4172OOPONTa(NMe2)4173TMSTMS  192 ((S)-H8-1,1'-Binaphthy-2,2'-diyl benzylphosphoramidate) tetrakis(dimethylamido)tantalum   (174).  Synthesized by protonolysis using General Method B from 169 (0.111 g, 0.250 mmol) and Ta(NMe2)5 (0.100 g, 0.250 mmol).  Removal of solvent in vacuo yielded solid yellow foam (0.145 g, quantitative).  1H-NMR (300 MHz, CDCl3):  δ 7.27 (d, J = 8.4 Hz, 1H), 7.10-7.00 (m, 4H), 6.80 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.61 (d, J = 14.0 Hz, 1H), 4.39 (d, J = 14.0 Hz, 1H), 3.60 (s, 24H), 2.65-2.38 (m, 6H), 2.29-2.23 (m, 1H), 2.12-2.06 (m, 1H), 1.59-1.31 (m, 6H), 1.23-1.16 (m, 2H); 13C-NMR (75 MHz, CDCl3): δ 148.1 (d, 2JC-P = 9.5 Hz, C), 147.2 (d, 2JC-P = 10.9 Hz, C), 142.5 (d, 3JC-P = 5.5 Hz, C), 138.4 (C), 138.1 (C), 135.1 (C), 134.7 (C), 130.3 (CH), 129.9 (CH), 129.3 (CH), 127.0 (C), 126.7 (CH), 126.5 (C), 119.6 (d, 3JC-P = 2.2 Hz, CH), 119.0 (d, 3JC-P = 2.5 Hz, CH), 50.4 (d, 2JC-P = 5.5 Hz, CH2), 46.9 (br s., (N(CH3)2), 46.0 ((N(CH3)2), 29.3 (CH2), 29.3 (CH2), 28.2 (CH2), 28.0 (CH2), 22.9 (CH2), 22.8 (CH2), 22.7 (CH2), 22.6 (CH2); 31P{1H}-NMR (121 MHz, CDCl3): δ 12.9; HRMS-EI (m/z) [M-NMe2]+ Calcd for C33H45N4O3PTa: 757.27025, Found: 757.27063.  Diethyl (S)-(1-phenylethyl)phosphoramidate-Ta(NMe2)4 (175).  Synthesized by protonolysis using General Method B from 170 (0.064 g, 0.250 mmol) and Ta(NMe2)5 (0.100 g, 0.250 mmol).  Removal of solvent in vacuo yielded dark yellow oil (0.145 g, quantitative).  1H{31P}-NMR (300 MHz, CDCl3):  δ 7.46-7.42 (m, 2H), 7.19-7.13 (m, 2H), 7.09-7.05 (m, 1H), 4.68 (q, J = 6.9 Hz, 1H), 3.83-3.66 (m, 4H), 3.50 (s, 24H), 1.61 (d, J = 6.9 Hz, 3H), 1.01 (t, J = 7.2 Hz, 3H), 0.88 (t, J = 7.2 Hz, 3H); 13C{1H}-NMR (75 MHz, C6D6):  δ 127.8 (d, 3JC-P = 4.4 Hz, C), 128.2 (CH) 127.0 (CH), 62.6 (d, 2JC-P = 8.0 Hz, CH2), 62.1 (d, 2JC-P = 6.8 Hz, CH2), 56.7 OOPONTa(NMe2)4174OOPONTa(NMe2)4175  193 (d, 2JC-P = 5.0 Hz, CH), 47.2 (br s., N(CH3)2), 16.0 (d, 3JC-P = 6.8 Hz, CH3), 15.8 (d, 3JC-P = 7.4 Hz, CH3); 31P{1H}-NMR (121 MHz, CDCl3): δ 9.84; HRMS-EI (m/z) [M-NMe2]+ Calcd for C18H37N4O3PTa: 569.20834; Found: 569.20883.  General Method D: Screening of Asymmetric HAA Reactions Using Prepared Phosphoramidate-Ta Complexes  In the glove box, 4-methoxy-N-methylaniline (0.0686, 0.50 mmol) was dissolved in 0.3 g of toluene-d8. 1-octene (0.084 g, 0.75 mmol) was added.  The precatalyst (0.050 mmol) was also dissolved in 0.3 g of toluene-d8.  If the reaction was to be heated, the precatalyst was combined with the substrates and the mixture was transferred to a Teflon sealed NMR tube.  The tube was heated for at least 20 h before yield was determined by 1H-NMR spectroscopy.  For reactions conducted at room temperature, the reaction mixture was stirred in a Teflon sealed vial in the glove box with temperature regulated to 23 °C.  Yield was determined by monitoring the disappearance of diagnostic signals of the aromatic protons in the ortho position in the starting material (δ 6.48, toluene-d8, 300 MHz, 298 K) and the appearance of new aromatic signals associated with the analogous protons in the resulting product (δ 6.63).    !"#$% = !"#$%&'#!(" !" !"#$%&' !"#$%&!"#$%&'#!(" !"#$%&' + !"#$%&'#!(" !"#$"%&' !"#$%&"' ×100%  HN+10 mol% Ta precatalysttoluene-d8, 20 hHNO O (+/-)  194 After 20 h, the reaction was purified by column chromatography (eluent:  5% ethyl acetate/hexanes).  Samples were tosylated for ee determination using the procedure below:  Tosyl chloride (1.1 equiv.) was added to a solution of 4-methoxy-N-(2-methyloctyl)aniline (1.0 equiv.), and triethylamine (2.0 equiv.) in CH2Cl2 (10 mL) at 0 °C.  The reaction mixture was warmed to room temperature and stirred overnight.  The reaction mixture was washed with aqueous HCl (1 M, 3 mL), saturated aqueous NaHCO3 (3 mL), then and brine, before being dried over Na2SO4, and filtered. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography (eluent:  15% EtOAc in hexanes).  General Method E: Screening of Asymmetric Hydroaminoalkylation Reactions Using In Situ Generated Phosphoramidate-Ta Complexes     In the glove box, phosphoramidate proligand (5.95 mmol) was dissolved in anhydrous toluene (6 g) in the glove box.  NaHMDS (1.09 g, 5.95 mmol) was suspended in anhydrous toluene (6 g).  The two solutions were mixed together and stirred at room temperature overnight.  The solvent was removed in vacuo and the resulting powder was rinsed with anhydrous hexanes (2 x 6 g).  Removal of solvent afforded an off white solid corresponding to the sodium salt of the proligand.  The sodium salt of the proligand (0.050 mmol) was suspended in toluene-d8 (0.25 g) and cooled to -30 °C.  In the absence of light, the suspension was added dropwise to a cooled HN+10 mol% ligand salt10 mol% TaMe3Cl2d8-toluene, 20 hHNO O (+/-)  195 solution of TaMe3Cl2 in toluene-d8 (0.25 g, -30 °C).  The resulting solution was added to a mixture containing 4-methoxy-N-methylaniline (0.068 g, 0.50 mmol), 1-octene (0.084 g, 0.75 mmol), and toluene-d8 (0.10 g).  The reaction was stirred in a Teflon sealed vial for 20 h in a temperature regulated glove box (23 °C).  Conversion was determined after 20 h by 1H-NMR spectroscopy and the sample was tosylated for ee determination, as described in General Procedure D.    The enantiomeric excess value was measured by SFC.  Separation of enantiomers was achieved with a Chiralpak AS-H column (0.46 cm  × 25 cm × 5 µm, mobile phase:  liquid CO2/2-propanol/diethylamine, 97:3:0.1, flow rate of 1.0 mL/min, UV detection at 229 nm).    196 Chapter 5: Conclusions and Future Work 5.1 Summary The research presented in this thesis is focused on the exploration of early transition metal catalysts bearing N,O-chelating ligands for the atom-economic synthesis of α-substituted amines.  These structural motifs can be accessed through two different transformations:  hydroamination and HAA.  The sustainable synthesis of molecules with such structural patterns can be achieved through development of new synthetic protocols using existing catalyst systems established in the Schafer group or the design and preparation of new catalysts.  Chapter 2 focused on the preparation of enantioenriched α-substituted N-heterocycles through hydroamination coupled with asymmetric transfer hydrogenation. A bis(amidate)bis(amido)Ti precatalyst 9 previously established in the Schafer group is used to yield a cyclic imine from aminoalkyne substrates, which is subsequently reduced using Noyori-Ikariya’s catalyst, RuCl [(S,S)-Ts-DPEN] (η6-p-cymene) (65) in a sequential, one-pot protocol.  The synthetic strategy described in this chapter is the only published catalytic route to access enantioenriched 3-substituted morpholines starting from prochiral materials and generates 3-substituted morpholine products in moderate to good yields (51-80%) and excellent enantioselectivities (>95% in most cases) for a variety of substrates.  Previous work described in the literature regarding imine reduction with the Noyori-Ikariya catalyst note the requirement for aromatic substituents adjacent to the imine functionality for excellent enantioselectivies;317, 329-330, 464 however, high ees for morpholine synthesis by sequential hydroamination and asymmetric transfer hydrogenation can be achieved for a broad range of substrates containing a variety of functional groups.     197 Expansion of the substrate scope of this method to include other N-heterocycles such as substituted N-tosyl piperazines, thiomorpholines, and piperidines was met with less success with respect to enantioselectivities than those observed for morpholine synthesis. A trend was observed for the resulting ees where substrates containing heteroatoms in the backbone with capacity for hydrogen bonding were reduced with higher selectivity than those without. A mechanistic rationale was proposed based on this experimental observation and highlights the importance of hydrogen bonding interactions between the substrate and the Ru catalyst in asymmetric transfer hydrogenation for high enantioselectivities in the resulting N-heterocyclic product.  In light of this proposal, the substrate scope of this protocol could be extended for the synthesis of substituted benzyl-protected piperazines.  Good ees (>81%) were achieved for these piperazine products, accentuating the importance of substrate design in asymmetric transfer hydrogenation.  However, the overall synthetic yield was low because of incomplete conversion in the hydroamination reaction presumably due to catalyst deactivation by the substrate. Further extension of the hydroamination-asymmetric transfer hydrogenation protocol to disubstituted morpholines was investigated.  For these substrates, hydroamination proceeds to completion more quickly than observed in the synthesis of monosubstituted morpholines.  Reduction of these imine substrates to disubstituted morpholines was attempted with the Noyori-Ikariya catalyst, but a comparison of the results with a reduction using NaBH4 reveal that the reduction step is substrate controlled and consistent stereoselectivity could not be achieved for these disubstituted cyclic imine substrates.  Chapter 3 explores the use of new tantalum complexes with phosphorous containing N,O-chelating ligands for the preparation of α-substituted amines through HAA.  Previous work in the Schafer group has focused on the development of metal complexes for catalysis that contain   198 N,O-chelating ligand motifs such as amidates, pyridonates, and ureates.  Through the use of phosphoramidates, a new collection of ligands was explored for catalyst design and development.  In particular, phosphoramidate-Ta complexes were investigated for catalytic HAA in an effort to identify a catalyst system that operates under mild reaction conditions.   Phosphoramidate-Ta(NMe2)4 complexes were screened as potential precatalysts in HAA and a number of catalytically active systems were identified from these investigations.  The most active were tantalum complexes ligated with N-aryl substituted phosphoramidates that were substituted in the ortho position of the aromatic ring.  Catalytic activity was observed in these cases at reduced reaction temperatures of 90 °C compared to previously reported complexes (110-130 °C).95, 200-201, 211-214, 216   Phosphoramidate-TaMe3Cl complexes were also screened for HAA.  During the course of this research, a highly reactive tantalum complex (123) was discovered that displays incomparable reactivity for HAA at room temperature.  To date, this is the only reported catalyst that operates at room temperature for this transformation.  An investigation of the substrate scope of this reaction with 123 revealed that a variety of unactivated terminal alkenes could be utilized in this reaction including silyl-protected alkyl alcohols, strained internal alkenes, and styrenes with electron-rich aryl amines.  In the case of terminal alkenes, regioselectivity for the branched product is observed.  Interestingly, reactions with para-substituted styrenes yield mixtures of the branched and the linear regioisomers with varying ratios depending on the electronic properties of the para-substituent.  The branched product remains the major observed product in all of these cases, consistent with other reports regarding catalysis conducted using group 5 metal systems.  Substrate scope investigations with complex 123 also revealed a rare example for the preferential formation of the linear product with a group 5 catalyst.  Vinyltrimethylsilane undergoes HAA   199 with 4-methoxy-N-methylaniline as the amine with preferential formation of the linear isomer at room temperature and further investigations confirmed this switch in regioselectivity is not a result of the reaction temperature. Instead, it is proposed to be due to a stabilization of transient positively charged species by the Si containing substrate through the β-silicon effect. While unprecedented room temperature reactivity was achieved with complex 123, one significant challenge with this system is its lack of thermal stability.  In an effort to identify a more thermally robust catalyst system, a bis(phosphoramidate)-TaMe2Cl complex, 154, was synthesized and screened for catalysis; however, poor catalytic activity was observed and the complex still demonstrated light and thermal sensitivity.  In addition, two phosphoramidate-Ta complexes with pendent donors were prepared and investigated (155 and 156), but again, no appreciable improvements with respect to neither catalytic activity nor enhanced stability was noted. The unique room temperature reactivity of complex 123 was particularly noteworthy as the analogous dimethylamido complex, 111, did not display similar activity under the same reaction conditions.  However, both 123 and 111 are hypothesized to operate through the same reaction mechanism.  One key difference is the catalyst activation step, where 123 liberates methane and 111 releases dimethylamine to access the catalytically active tantallaaziridine intermediate.  Mechanistic investigations were conducted to probe reactivity differences between 123 and the analogous dimethylamido complex 111.  Diethylamine was chosen as a model substrate for dimethylamine, as the latter is a gas and challenging to deliver in stoichiometric amounts accurately.  Studying the reaction progress via NMR spectroscopy revealed that the presence of dimethylamine is a contributing factor to the reactivity differences observed between   200 these two complexes due to a number of possible non-productive off cycle pathways involving dimethylamine.  Following the discovery of 123, the first room temperature HAA catalyst system presented in Chapter 3, the synthesis, characterization, and screening of enantioenriched phosphoramidate-Ta complexes for asymmetric HAA was studied in Chapter 4.  Inspired by the plethora of structural motifs reported in asymmetric catalysis with chiral phosphoric acids, a number of chiral phosphoramidate proligands were prepared and installed onto Ta(NMe2)5 and TaMe3Cl2.  All of the prepared complexes were screened for catalytic activity towards HAA and reactivity was observed for all complexes.   Chiral phosphoramidate-Ta(NMe2)4 were reactive at 110 °C and phosphoramidate-TaMe3Cl complexes displayed reactivity at room temperature.  While these complexes were all competent catalysts for HAA, unfortunately most of the α-alkylated amine products were isolated as the racemate.  The lack of an enantioenrichment was investigated by variable-temperature NMR spectroscopy studies to confirm that the ligands remain coordinated to the metal center and the lack of stereoselectivity in these reactions is not largely due to disassociation of the chiral ligand.  In the case of the axially chiral phosphoramidate-Ta complexes studied, the solid state molecular structure of complex 171 affords further insight into this problem.  That is, the proposed enantiodetermining moiety of the complex is too far removed from the metal center for it to have an impact on asymmetric induction.  However, the HAA product obtained from complex 181, with a stereocenter α to a coordinating nitrogen of the phosphoramidate ligand, had a measured ee of 50%.  While this fails to match or better the state-of-the-art ee for this transformation, to the best of our knowledge, this is the first example of a room temperature asymmetric HAA reaction.    201 5.2 Future Directions 5.2.1 Synthesis of Substituted 1,4-Oxazapanes, 1,4-Oxazocanes, and 1,4-Oxazonanes The one-pot sequential catalysis procedure developed in Chapter 2 has afforded the enantioselective synthesis of substituted morpholines.  The mechanistic insights that arose from this work has guided strategic substrate design to extend the substrate scope to include the enantioselective synthesis of N-benzyl protected piperazines.  Further extension of this synthetic approach can be envisioned to achieve enantioselective synthesis of other N-containing heterocycles.  An important class of molecules in medicinal chemistry is substituted 7-, 8-, and 9- membered N-heterocycles such as 1,4-oxazepane, 1,4-oxazocanes, and 1,4-oxazonanes (Figure 5.1).465 Efficient catalytic asymmetric strategies to access these structures remain a persistent challenge.232, 466-468 The preparation of enantioenriched versions of these N-heterocycles typically utilize starting materials derived from amino acids and there are few examples in the literature that utilize easily varied prochiral substrates.469  Figure 5.1 Oxygen containing N-heterocycles   Using the strategy developed in Chapter 2, longer aminoalkyne substrates could be prepared and treated under the same hydroamination/asymmetric transfer hydrogenation NHONHONHO1,4-oxazepane 1,4-oxazocane 1,4-oxazonaneR RR  202 reduction protocol in efforts to access larger enantioenriched N-heterocycles from prochiral starting materials (Scheme 5.1).  Hydroamination can yield two regioisomers of these aminoalkynes, yielding two possible N-heterocyclic products after reduction.     Scheme 5.1 Proposed preparation of enantioenriched 1,4-oxazepanes, 1,4-oxazocanes, and 1,4-oxazonanes by hydroamination and asymmetric transfer hydrogenation   Preliminary investigations were conducted regarding the preparation of aminoalkyne substrate 184, which is an intermediate en route to substituted 1,4-oxazocane 185 (Scheme 5.2).  Synthesis of the BOC-protected aminoalkyne substrate 183 from BOC-protected ethanolamine and 5-bromo-1-pentyne under the modified Williamson ether synthesis conditions described in Chapter 2 failed to yield the desired product.  However, alternative reaction conditions H2NONHOorNHOH2NOR i. 10 mol% 9   toluene, 110 °C ii. 1 mol% 65, DMF    HCO2H/NEt3 (5:2) RRNHORNHORorRi. 10 mol% 9   toluene, 110 °C ii. 1 mol% 65, DMF    HCO2H/NEt3 (5:2)NOTi(NMe2)22 RuN NH2SPhPhOOCl659  203 employing BOC-protected ethanolamine and 182 afforded 183, albeit in low yields.  Further optimization of these reaction conditions is required.  Deprotection of 183 occurs smoothly to yield aminoalkyne 184.    Scheme 5.2 Synthesis of 1,4-oxazocane using hydroamination followed by NaBH4 reduction  Aminoalkyne 184 was subjected to hydroamination catalyzed by precatalyst 9, under reaction conditions previously described in Chapter 2.  The reaction was monitored by 1H- and 13C{1H}-NMR spectroscopy until complete consumption of starting material was observed.  Subsequent reduction using NaBH4 did not afford the expected 1,4-oxazocane product 185.  Preliminary characterization of the resulting product by NMR spectroscopy and mass spectrometry is consistent with the formation of the 1,4-oxazonane product 186.  In synthesis of the 6-membered N-heterocycles described in Chapter 2, the intramolecular hydroamination reaction forms a new C-N bond in the internal position of the aminoalkyne.  However, intermolecular hydroamination reactions with precatalyst 9 gives exquisite regioselectivity for C-BocHN OH MsO+NaH, DMF/THF75 °C, 18 h BocHNOYield:  31%1. 10 mol% 9   toluene-d8, 110 °C, 20 h2. NaBH4, MeOH, 2 hNHOorNHO1. 4 M HCl in dioxane    MeOH, r.t, 18 h2.  NaOH(aq)H2NOYield: Quantitative182 183184185186  204 N bond formation at the least substituted carbon of the alkyne.69, 75 Interestingly, as the 1,4-oxazonine product 186 is preferentially formed over the 1,4-oxazocane product 185, the regioselectivity observed in the hydroamination reaction with substrate 184 mirrors that of the intermolecular reaction instead of the intramolecular reaction.  Thus, this suggests that when the tether between the reactive alkyne and amine functionalities are long enough within an intramolecular hydroamination substrate, the regioselectivity trends observed in intermolecular reactions will be obtained with the use of complex 9.  Further investigations with an aminoalkyne substrate analogous to 184, but one carbon shorter, will be interesting to determine if preferential formation of the 1,4-oxazocane product occurs over the 1,4-oxazepane product. The successful preparation of 186 is promising for future studies regarding the preparation of enantioenriched 1,4-oxazonane products by using asymmetric transfer hydrogenation (Scheme 5.3).  Based on the mechanistic rationale proposed in Chapter 2, the oxygen heteroatom in the imine obtained from hydroamination with substrate 184 may participate in key hydrogen bonding interactions with the Ru catalyst 65 to afford high enantioselectivities.  To date, there are few reported methods in the literature for the preparation of these N-heterocycles and none reported for the synthesis of enantioenriched substituted 1,4-oxazonanes from prochiral substrates.470-471   Scheme 5.3 Preparation of enantioenriched 1,4-oxazonanes through hydroamination and asymmetric transfer hydrogenation H2NO NHORi. 10 mol% 9   toluene, 110 °C ii. 1 mol% 65, DMF    HCO2H/NEt3 (5:2) R  205 5.2.2 Strategies for Identifying More Thermally Robust Room Temperature Hydroaminoalkylation Catalysts The research presented in Chapter 3 focuses on the development of new phosphoramidate-Ta complexes for room temperature HAA.  Investigations with complex 123 revealed unprecedented reactivity at room temperature for this transformation; however, complex 123 is both light and thermally sensitive.  The lack of thermal stability limits the use of this catalyst system for challenging substrate combinations that require forcing conditions to proceed.  Therefore, there remains an opportunity to identify a robust catalyst system that is active for a broader range of reaction conditions. Previous work with phosphoramidate-Ta(NMe2)4 systems displayed some reactivity at lower reaction temperatures (90 °C), but no catalysis was observed at room temperature. However, room temperature HAA was achieved through the use of phosphoramidate-TaMe3Cl complexes.  The simple task of changing the nature of the tantalum starting material used to construct these HAA precatalysts resulted in remarkable changes in reactivity and perhaps, installing the phosphoramidate ligand onto a different organometallic tantalum complex may afford improved properties.  TaMe3Cl2 is a light and thermally sensitive compound and the resulting phosphoramidate-complexes derived from this organometallic starting material displayed similar issues with respect to stability.  A number of other tantalum organometallic complexes have been reported in the literature that may serve as feasible starting materials in search for a highly active phosphoramidate-Ta complex with improved thermal stability.  However, a few important aspects of catalyst design must be considered when selecting potential tantalum starting materials for HAA catalysts.   206 A key step in the proposed HAA mechanism for tantalum and other group 5 catalysts is the requisite formation of a metallaaziridine intermediate.  Therefore, any tantalum starting materials selected must have at least 3 labile ligands, as one gets displaced during the installation of the phosphoramidate ligand, one undergoes transamination was the substrates, and the third is released through β-hydrogen abstraction upon catalyst activation.  Another important consideration in the design of new HAA catalysts is the byproduct released during catalyst activation. In the case of phosphoramidate-Ta(NMe2)4 complexes, dimethylamine is released which is a problematic side product that can participate in a variety of off-catalytic pathways.  Activation of phosphoramidate-TaMe3Cl complexes results in the loss of methane, which is an innocuous byproduct.  Therefore, a desirable characteristic of new tantalum complexes is the formation of a benign side products during catalyst activation. Six examples of known organometallic tantalum complexes are presented in Scheme 5.3 and coordination of phosphoramidate ligands to these starting materials could be used to identify potential room temperature HAA catalysts that are also thermally robust.472-476   Figure 5.2 Potential tantalum starting materials for the preparation of thermally robust tantalum hydroaminoalkylation catalysts472-476 Ta(CH2SiMe3)2Cl3 Ta(CH2SiMe3)3Cl2 TaBn3Cl2Ta(CH2CMe3)3Cl2 CpTaMe2Cl2 CpTa(CH2CMe3)2Cl2187 188 189190 191 192  207 5.2.3 Chiral Tantalum Complexes for Asymmetric Hydroaminoalkylation The chiral phosphoramidate-Ta complexes presented in Chapter 4 exhibited promising reactivity towards catalytic HAA; however, challenges regarding enantioselectives were encountered.  Of the 12 complexes screened for catalysis (170-181), the highest ee achieved was 50% and 10 of the 12 complexes yielded racemic product.  Asymmetric HAA remains a persistent challenge in the field and further optimization of ligand design may advance the selectivities accessed with this transformation. Chapter 4 studied the effects of 6 chiral phosphoramidate ligands on asymmetric induction for HAA, with 5 of the 6 ligands investigated derived from BINOL.  While binaphtholate ligands have demonstrated previous success in this reaction, these BINOL derived phosphoramidates were unsuccessful for asymmetric induction.  The solid-state molecular structure of 171 affords the insight that the enantiodetermining moiety of the ligand is too far removed from the metal center to have an influence on the incoming prochiral substrates; therefore, this axially chiral ligand motif is not ideally suited for this transformation.  However, a number of other structural motifs can be investigated in future studies. Inspired by other patterns observed in chiral phosphoric acids, new phosphoramidate proligands may be synthesized and investigated for asymmetric induction upon coordination to tantalum.  Some examples of such potential ligands are depicted in Figure 5.3 and are derived from related chiral phosphoric acids.  These phosphoramidates can easily be synthesized from the phosphoric acid through known literature procedures.  To date, only axially chiral biaryl ligands have been reported in the literature for asymmetric HAA and the use ligands with planar chirality and spirocyclic ligands remain unexplored.    208  Figure 5.3 Potential structural motifs for new chiral phosphoramidate proligands   Deviating from the N,O-chelating ligands explored in the Schafer group, improved enantioselectivities for HAA may be achieved with chiral phosphoric acids. For N,O-chelating ligands, the potential to access a number of different ligand binding modes may be advantageous for reactivity, but this feature may be detrimental for asymmetric induction. While the solid state molecular structures of these phosphoramidate-tantalum complexes presented in this thesis show a κ2-binding mode of the N,O-chelate, under catalytic conditions, a κ1-binding mode is also possible.  Therefore, the hemilability of this ligand motif may result in the enantiodetermining feature of the phosphoramidate ligand being removed from the metal center and incapable of asymmetric induction of the prochiral substrate.  With chiral phosphoric acids, this hemilability will be unlikely due to the oxophilic nature of the tantalum metal center.  Thus, fixture of the chiral ligand to the catalytically active metal species may be beneficial for stereoselectivity.  5.3  Concluding Remarks The research presented in this thesis emphasizes the versatility and utility of N,O-chelated early transition metals for the catalytic synthesis of α-alkylated amines.  This begins PhPhOO PONHOOPONHR1R1OO PONHRR1R1R2 R2  209 with catalyst development, where facets of ligand design have dramatically impacted reactivity in catalysis.  The simple modification of the ligand from amidates to phosphoramidates, in particular with careful selection of metal precursors, exemplified the impact of ligand design on reactivity with these complexes.  These ligands are tunable and easily modified for optimization of reactivity.  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Chem. 1992, 439, 147.    225 Appendices  Appendix A  X-Ray Crystallographic Data  Compound 110 122 Formula TaPO3N5F3C19H38 TaPO3N5F3C19H38 PO3C12H20 Fw 653.37 653.37 257.27 Crystal size (mm) 0.6 x 0.48 x0.35 0.26 x 0.21 x 0.17 0.61 x 0.15 x 0.13 Color, habit Yellow, prism Yellow, prism Colourless, prism Crystal system Monoclinic Orthorhombic Monoclinic Space group P21/n Pna21 P21/c a (Å) 14.942(2) 12.7064(4) 8.8913(13) b (Å) 11.7915(18) 24.5272(8) 14.918(2) c (Å) 15.339(2) 8.4409(3) 10.2711(16) α (°) 90 90 90 β (°) 110.430(3) 90 103.868(3) γ (°) 90 90 90 V (Å3) 2532.5(7) 2630.63(15) 1322.6(3) Z 4 4 4 ρcalcd (g cm-1) 1.714 1.650 1.2919 Tmeasurement (K) 90(2) 90(2) 90(2) Radiation Mo Kα (λ = 0.71073 Å) Mo Kα (λ = 0.71073 Å) Mo Kα (λ = 0.71073 Å) Crystallization Solvent Hexanes Hexanes None (sublimation) F(000) 1304 1304 552.7 µ (Mo Kα) (mm-1) 4.454 4.288 0.205 θ (°) 3.276-60.172 3.61-54.208 4.72-60 Total number of reflns 55645 13138 27490 Number unique reflns 7173 (Rint = 0.0279) 4404 (Rint = 0.0315) 3304 (Rint = 0.0369) Number reflns  I > 2σ (I) 7439 4851 3858 Number of parameters 328 299 157 wR2 (F2, all data) 0.0353 0.1359 0.0936 R1, wR2 (I > 2σ(I)) 0.0148, 0.0349 0.0450-0.1206 0.0324, 0.0868 Goodness of fit 1.114 0.897 0.989     226 Compound 130 154 156 Formula SO5N2C21H24 TaClP2N2O6C26H44 TaClPNO4C15H21 Fw 416.48 758.88 526.70 Crystal size (mm) 0.13 x 0.11 x 0.09 0.06 x 0.14 x 0.13 0.17 x 0.14 x 0.1 Color, habit Colourless, prism Yellow, prism Yellow, prism Crystal system Monoclinic Monoclinic Monoclinic Space group P21/n P21/n P21/n a (Å) 6.0539(4) 11.628(3) 10.5309(16) b (Å) 12.0285(7) 20.539(5) 16.625(3) c (Å) 27.7928(19) 16.497(4) 10.9179(17) α (°) 90 90 90 β (°) 92.905(3) 91.121(6) 106.562(3) γ (°) 90 90 90 V (Å3) 2021.3(3) 3939.2(16) 1832.2(5) Z 4 4 4 ρcalcd (g cm-1) 1.369 1.513 1.909 Tmeasurement (K) 90(2) 90(2) 90(2) Radiation Mo Kα (λ = 0.71073 Å) Mo Kα (λ = 0.71073 Å) Mo Kα (λ = 0.71073 Å) Crystallization Solvent Acetonitrile Toluene/Hexanes Hexanes F(000) 880.0 1828 1020 µ (Mo Kα) (mm-1) 0.196 2.984 6.249 θ (°) 3.61-54.208 3.166-60.348 4.6-70.24 Total number of reflns 13138 60177 32164 Number unique reflns 4850 (Rint = 0.0254) 9604 (Rint = 0.0254) 6162 (Rint = 0.0429) Number reflns  I > 2σ (I) 5941 11638 8079 Number of parameters 305 567 200 wR2 (F2, all data) 0.1181 0.0887 0.1214 R1, wR2 (I > 2σ(I)) 0.0454, 0.1107 0.0424, 0.0839 0.0564, 0.113 Goodness of fit 1.028 1.120 1.209               227 Compound 157 171 Formula TaPO3N5C19H42 C34H50N5O3PTa Fw 600.41 788.71 Crystal size (mm) 0.13 x 0.11 x 0.09 0.24 x 0.12 x 0.08 Color, habit Yellow, prisms Yellow, prisms Crystal system Orthorhomic Orthorhombic Space group Pbca P212121 a (Å) 14.9937(15) 18.831(3) b (Å) 21.706(2) 18.874(3) c (Å) 47.543(5) 19.778(3) α (°) 90 90 β (°) 90 90 γ (°) 90 90 V (Å3) 15473(3) 7029.2(19) Z 4 8 ρcalcd (g cm-1) 1.584 1.491 Tmeasurement (K) 90(2) 90(2) Radiation Mo Kα (λ = 0.71073 Å) Mo Kα (λ = 0.71073 Å) Crystallization Solvent Hexanes Hexanes F(000) 7432 3208 µ (Mo Kα) (mm-1) 4.356 3.213 θ (°) 3.212-63.056 2.06-60.278 Total number of reflns 138023 61831 Number unique reflns 18123 (Rint = 0.0564) 19871(Rint = 0.0366) Number reflns  I > 2σ (I) 25425 20694 Number of parameters 934 823 wR2 (F2, all data) 0.1075 0.0445 R1, wR2 (I > 2σ(I)) 0.0568, 0.0962 0.0247, 0.0437 Goodness of fit 1.173 0.994               228 Appendix B  Select Examples of Enantiomeric Excess Determination by NMR Spectroscopy, SFC, and chiral HPLC Enantiomeric Excess Determination of 68 by SFC            Thar SFC AD-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 97:3:0.1 (Flow rate 1.0 mL/min, UV 229 nm) NHOF3C68NHOF3Cracemic  229 Enantiomeric Excess Determination 70 by SFC   Thar SFC OD-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 98:2:0.1 (Flow rate 1.0 mL/min, UV 259 nm)  NHO70ONHOracemicO  230 Enantiomeric Excess Determination 72 by SFC  Chiralpak AS-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 97:3:0.1 (Flow rate 1.0 mL/min, UV 229 nm)  NHO72NHOracemic  231 Enantiomeric Excess Determination 77-Ts by SFC  Chiralpak AS-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 97:3:0.1 (Flow rate 1.0 mL/min, UV 240 nm)   NTsO77-TsNTsOracemic  232 Enantiomeric Excess Determination 78 by SFC  Thar SFC OD-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 98:2:0.1 (Flow rate 0.9 mL/min, UV 250 nm)  NHO78NHOracemic  233 Enantiomeric Excess Determination of 88 by 19F-NMR Spectroscopy         NBnNOO CF3Derivatized Enantiomer of 88NBnNOO CF388NBnNOO CF3Derivatized Enantiomer of 88NBnNOO CF3Derivatized 88  234 Enantiomeric Excess Determination of Compound 90  Thar SFC OD-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 98:2:0.1 (Flow rate 0.9 mL/min, UV 229 nm)   NHN90NHNracemic  235 Enantiomeric Excess Determination of Compound 92 by Chiral HPLC      Chiralcel OJ-RH column, particle size 5 μm, 4.6 mmΦ × 150 mm  37% Acetonitrile in Water (UV 210 nm) Area %: 14.455 min (0.600%) 15.749 (8.878%)  NTsBnN92NTsBnNracemic  236 Enantiomeric Excess Determination of Compound 94 by Chiral HPLC  Chiralcel OJ-RH column, particle size 5 μm, 4.6 mmΦ x 150 mm 37% Acetonitrile in Water (UV 230 nm) NTsBnN94Area %: 14.102 min (25.875%) 14.942 min (2.694%) NTsBnNracemic  237 Enantiomeric Excess Determination of Compound 92 by SFC  Chiralpak AS-H column 0.46 cm × 25 cm × 5 µm Mobile phase: liq. CO2/2-propanol/diethylamine, 97:3:0.1 (Flow rate 1.0 mL/min, UV 229 nm)  HNO (+/-)racemicOHNAppendix C  Select NMR Spectra !238(3-bromoprop-1-yn-1-yl)cyclohexaneBr!239BocHN O31 !240BocHN O34CF3 !241BocHN O36O!242BocHN O38!243H2NO41CF3!244H2NO43O!245H2NO45!246H2NO51!247NHOF3C68!248NHO70O!249NHO72!250NHO77!251NTsO77-Ts !252NHO78!253H2NO80CN!254NHO81NC!255H2NN87!2561H-NMRCDCl3400 MHz, 298 K13C{1H}-NMRCDCl3100 MHz, 298 KNTsBnN88!257H2NN89!258NHN90!259H2NBnN91!260NTsBnN92!261H2NBnN93!262NTsBnN94!2634.7 2.2 1.1 1.02.1 1.1 1.2 1.0 1.8ppm1.2761.9932.0012.0092.1072.1152.1222.1292.1373.2563.2863.3163.4263.4383.4553.4673.7573.7653.8043.8103.8173.8243.8693.8774.0144.0274.0444.0577.0117.0147.0507.0727.0767.0817.0907.1007.1097.1197.1247.1297.1497.1557.1627.1697.1757.1817.1917.1987.2037.2997.3107.3267.3337.33900.511.522.533.544.555.566.577.588.59ppmppm19.66719.92020.17620.43220.68520.94221.19455.83158.23774.52176.83980.201124.804125.126125.449127.357127.445127.642127.961128.280128.452128.551128.866129.181137.480143.1970102030405060708090100110120130140150160170ppmO NH2Ph95!264O NH2Bn961.11.1 1.0 0.65.0 1.9 1.1 1.1 2.1ppm1.0832.1122.1192.1272.3662.3932.4102.4372.6032.6212.6472.6653.0223.0383.0453.0493.0553.0623.0713.0773.0813.0873.1043.1553.1773.1833.2063.2623.2773.2913.3053.8513.8593.8667.0407.0537.0677.0777.0897.1257.1337.1387.1447.1487.1537.1687.1737.17700.511.522.533.544.555.566.577.588.5ppmppm19.66819.92120.17720.43020.68620.94321.19541.17152.67958.32374.57774.99580.400124.794125.116125.435126.365127.633127.955128.270128.559128.856129.171129.669137.474139.5650102030405060708090100110120130140150160170ppm!2658.6 2.3 1.1 2.4 4.9 3.0ppm1.1851.2061.5252.6762.6982.7202.7432.7522.7672.7802.8112.8243.6613.6753.6833.6963.7043.7184.3474.4004.4454.4987.2607.2837.2887.2967.3007.3117.3187.4247.4387.4507.45700.511.522.533.544.555.566.577.588.59ppmppm17.05647.32556.88276.36876.73477.16077.35877.57985.71985.871122.689128.370128.522131.7970102030405060708090100110120130140150160170ppmO NH297Ph!2662.12.25.7 1.1 1.1 1.4 0.8 3.0ppm0.1030.9581.0421.0611.2401.2531.2621.2771.2831.3002.0242.0593.0963.1043.1103.1173.1303.1373.1553.1663.1883.2223.2863.3213.3573.7903.8103.8193.8463.8563.9793.9904.0144.0247.2627.2677.2747.2797.2867.2967.3037.3097.3147.3227.3407.3477.3627.3697.3747.3857.3937.4017.4057.4217.4277.4330123456789ppmppm17.87450.99560.77073.10673.20876.73577.16077.581127.282127.795128.542140.5040102030405060708090100110120130140150160170ppmNHO98!2670.8 1.12.4 1.1 3.08.5 3.5 4.9 2.5 1.8ppm0.0850.9140.9350.9991.0191.2271.2501.2662.0612.0662.4652.4932.5092.5382.6342.6502.6792.6952.8152.8192.8402.8602.8832.9052.9172.9613.0403.0533.0753.0983.1103.1253.1393.1603.1943.2283.2473.2553.2683.2853.2963.3203.5263.5403.5643.5773.6993.7083.7163.7273.7343.7443.7543.7653.7863.7933.8203.8287.1937.2057.2197.2277.2457.2557.2657.2797.3027.3277.35000.511.522.533.544.555.566.577.588.5ppmppm1.11817.65117.89331.08237.55738.85745.17950.77952.63956.56970.46571.94873.23073.32276.73577.16077.581126.465126.626128.721129.234133.545137.896138.9540102030405060708090100110120130140150160170ppmNHO99!2681.21.21.72.13.09.23.25.02.72.4ppm0.0860.9130.9341.1131.1331.2181.2281.2391.2501.9852.4202.4482.4652.4802.4842.4942.5192.6392.6552.6652.6752.6842.7002.7152.8172.8282.8362.8452.8542.8682.8742.8872.9092.9252.9372.9392.9552.9722.9822.9882.9983.0163.0433.0553.0823.2943.3303.3653.5283.5363.5493.5573.5613.5693.5823.5903.6593.6693.6803.6893.7033.7103.7193.7413.7493.7623.7713.8003.8093.8333.8423.8703.8807.1927.2147.2267.2347.2537.2587.2737.2807.2927.2977.3177.34000.511.522.533.544.555.566.577.588.5ppmppm18.95138.54138.73852.73755.68972.33876.84377.16077.481126.695128.732129.243137.7600102030405060708090100110120130140150160170ppmNHO100Ph!269ppm15.91915.98947.22463.00963.074120.059120.223120.555120.876121.196124.214125.800126.547126.900127.425127.666127.906129.608149.8950102030405060708090100110120130140150160170180ppmNPOOOTa(NMe2)4CF3110!270ppm15.81415.88716.06216.12316.23316.28718.76619.47319.92520.70944.66146.23659.37962.71762.81662.88963.25363.32263.384123.051123.088124.498127.451127.691127.932128.242128.303135.451135.516136.960137.022137.288142.674143.2500102030405060708090100110120130140150160170ppmNPOOOTa(NMe2)41113.55.36.02.04.01.01.14.99.43.43.65.73.0ppm0.9100.9270.9430.9590.9761.0231.0401.0581.1121.1291.1472.4352.4632.5952.6292.8433.0493.0873.2493.2963.3213.7513.8003.8073.8173.8263.8433.8613.8683.8853.9023.9243.9413.9593.9663.9844.0494.0664.0744.0924.2914.2976.9446.9626.9806.9977.0797.0957.1117.1527.1717.1897.20600.511.522.533.544.555.566.577.588.5ppm!2712.9 4.8 6.1 0.7 6.0ppm1.2621.2861.3101.7122.3944.0604.0634.0844.0874.0994.1114.1334.1564.1597.0027.0057.0187.0257.0407.26000.511.522.533.544.555.566.577.588.5ppmppm16.28716.37819.20363.10363.18776.74177.16077.586126.131128.606135.041136.0380102030405060708090100110120130140150160170ppmPONHOO122!272ppm-4.76818.54818.82226.47530.68631.30333.22251.75756.22763.82677.16077.58678.013114.343115.364143.394152.2880102030405060708090100110120130140150160170ppmOHN OTBS1252.01.01.08.51.23.11.12.02.03.11.05.55.8ppm0.1000.1090.9510.9600.9991.0211.1811.2271.2451.2591.2831.3071.4751.4911.5261.5661.5821.6091.6301.6481.6671.7181.7421.7611.7821.8031.8252.8542.8782.8942.9173.0103.0293.0513.0703.3913.6283.6503.6713.7626.5776.5996.6066.7926.8227.26000.511.522.533.544.555.566.577.588.5ppm!273ppm28.92729.97135.44636.03236.37539.40542.20050.49355.86976.73477.16077.586113.947114.937143.036151.9230102030405060708090100110120130140150160170ppmOHN129 (+/-)0.5 0.5 2.01.0 1.51.0 1.0 1.5 0.5 1.0ppm1.1341.1481.1561.1671.1721.1771.1851.1941.2021.2081.2161.2271.3421.3481.3551.3811.4811.4891.5211.5281.5401.5461.5501.5571.5671.6771.7021.7251.7441.7712.1612.1702.2732.7632.7852.8022.8242.8932.9212.9312.9593.3333.7676.5806.5886.6026.6106.7936.8016.8166.8237.26000.511.522.533.544.555.566.577.588.5ppm!274ppm28.79629.62035.11035.52136.61238.82440.21655.55855.72776.73977.16077.585114.595124.092128.886130.014130.695144.463150.008159.443020406080100120140160180ppm2.23.41.01.91.90.63.82.91.02.24.5ppm0.0650.9780.9891.0001.0081.0161.0241.0401.1181.1501.1791.2031.2301.2451.3361.3651.3801.3891.4081.4261.4491.4651.4762.1162.1232.2303.1543.1793.1963.2223.3683.3963.4113.4383.8036.8056.8126.8276.8356.8686.8786.8846.9006.9087.2607.7367.7417.7587.7658.2758.2818.2978.304012345678910ppmON129-Nos (+/-)SNO2O O!275ppm1.02314.12419.89222.83028.82229.19231.42931.54734.40038.29751.99155.07555.60269.11076.73577.16077.585113.470113.950114.185114.771128.066136.555142.390151.920158.168020406080100120140160180ppm1.12.1 3.12.0 1.9 2.0 6.0 1.9 1.0ppm0.5971.7351.7583.2023.3983.4263.4503.4733.4993.5533.5813.5933.6213.6833.7033.7233.7434.1654.2136.9706.9776.9936.9997.1987.2097.2167.2387.2607.3067.3357.5747.60200.511.522.533.544.555.566.577.588.59ppmOHNO130!276ppm19.86321.00638.82452.01355.70576.73577.16077.585114.302114.892127.113129.333135.984141.617142.467152.063020406080100120140160180ppm131OHN1.1 1.0 3.14.0x 1.02.0 2.0 3.0 2.0 3.0ppm1.4501.4742.4923.0983.1223.1453.1703.1933.2163.2883.3153.3283.3553.3963.4173.4363.4573.8686.6696.6986.9116.9417.2507.27900.511.522.533.544.555.566.577.588.5ppm!2771.12.91.92.02.03.02.93.0ppm1.4061.4293.0733.0943.1183.1443.1673.1903.2493.2763.2903.3173.3543.3753.3953.4163.8156.6106.6406.8526.8827.2607.3027.3087.3217.3287.3447.3477.3957.4197.4247.44500.511.522.533.544.555.566.577.588.5ppm132OHNppm19.80539.25351.98555.77076.74177.16077.586114.336114.915126.611127.296128.690142.404144.696152.090020406080100120140160180ppm!278ppm19.68338.72051.90155.78576.73477.16077.586114.374114.953128.682128.781132.216142.161143.219152.2050102030405060708090100110120130140150160170ppm1.11.13.34.42.02.0x 1.03.01.9ppm1.3261.3502.0843.0023.0263.0493.0743.0973.1183.1593.1863.2003.2283.2733.2913.3123.3323.3513.7603.7756.5626.5926.8046.8347.1687.1967.2607.3177.3407.34500.511.522.533.544.555.566.577.588.5ppmOHNCl133!279OHN SiMe3135ppm-3.017-1.62312.84514.11620.52124.23747.65248.34555.83876.73477.16077.586114.107114.960142.876151.999020406080100120140160180ppm1.71.08.92.02.03.01.81.6ppm0.0340.0450.0690.5690.5880.5980.6110.6261.5731.5971.6131.6261.6391.6541.6773.0533.0773.1013.3383.7686.5906.6206.7996.8287.26000.511.522.533.544.555.566.577.588.5ppm!280ppm1.42515.94916.01516.20816.45616.51420.85520.97964.78864.87665.94066.61066.67277.822126.194127.819128.060128.301128.997129.091137.350137.405137.970138.025140.809140.871020406080100120140160180ppmNPOOOTaMe2Cl2154ppm1.42515.94916.01516.20816.45616.51420.85520.97964.78864.87665.94066.61066.67277.822126.194127.819128.060128.301128.997129.091137.350137.405137.970138.025140.809140.871020406080100120140160180ppm!2811.01.70.9 5.73.3 3.2 9.4ppm0.8510.8690.8820.8861.4491.6882.4533.3603.5953.8193.8373.8453.8553.8633.8823.9003.9083.9183.9276.4616.4656.4816.4846.7386.7446.7596.7626.7816.7996.8026.8176.8906.8956.9096.9127.16000.511.522.533.544.555.566.577.588.5ppmNPOOOTaMe3ClO156ppm15.81415.88016.16116.22354.83465.46665.52477.44678.82078.875112.665120.118120.184121.915124.193127.819128.060128.301134.085152.348152.498020406080100120140160180200ppm!282NPOOOTa(NMe2)4O157!283OOPO164NH!284OOPO165NH!285OOPO166NH!286OOPO167NHTMSTMS!287OOPO168NH!288OOPONTa(NMe2)4170ppm19.85820.04720.24020.43020.62320.81321.00221.37446.97450.24050.291121.246121.639121.742121.833124.854125.095125.335125.419125.547125.609126.614126.717127.249127.609127.690127.930128.050128.167128.451128.543128.597128.834129.064129.268130.751131.189131.582131.990132.625132.778137.436137.738142.046142.101147.801147.914148.333148.432020406080100120140160180ppm!289OOPONTa(NMe2)4171!290OOPONTa(NMe2)4172!291OOPONTa(NMe2)4174!292OOPONTa(NMe2)4175

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