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Early and late transition metal complexes featuring 1,3-N,O-chelates : development of homogenous catalysts… Brandt, Jason W. 2018

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EARLY AND LATE TRANSITION METAL COMPLEXES FEATURING 1,3-N,O-CHELATES: DEVELOPMENT OF HOMOGENOUS CATALYSTS FOR THE α-ALKYLATION OF AMINES VIA HYDROAMINOALKYLATION  by  Jason W. Brandt  B.Sc. Honors, University of Alberta, 2012  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)  April 2018  © Jason W. Brandt, 2018 ii  The following individuals certify that they have read, and recommend to the Faculty of Graduate and Postdoctoral Studies for acceptance, the dissertation entitled: Early and Late Transition Metal Complexes Featuring 1,3-N,O-Chelates: Development of Homogenous Catalysts for the α-Alkylation of Amines via Hydroaminoalkylation submitted by Jason W. Brandt  in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Chemistry  Examining Committee:  Prof. Laurel Schafer (Chemistry) Supervisor  Prof. Glenn Sammis (Chemistry) Supervisory Committee Member  Prof. Parisa Mehrkhodavandi (Chemsitry) University Examiner Prof. Mark Martinez (Chemical and Biological Engineering) University Examiner Prof. Roland Roesler (Chemistry, University of Calgary) External Examiner Additional Supervisory Committee Members: Prof. Mike Fryzuk (Chemistry) Supervisory Committee Member Prof. Alex Wang (Chemistry) Supervisory Committee Member  iii  Abstract This thesis details the development of transition-metal complexes that are utilized as precatalysts for catalytic hydroaminoalkylation chemistry. Hydroaminoalkylation is the activation of an α-C(sp3)–H of an amine, and subsequent addition across a C–C unsaturation. This results in α-alkylated amines in a 100% atom-economical reaction, while avoiding amine protection/deprotection strategies. A series of 2-pyridonate chloro tris(dimethylamido) tantalum complexes have been synthesized and tested for the hydroaminoalkylation of alkenes with secondary amines. These complexes were found to exhibit high reactivity for a broad range of internal alkene substrates and represent the first, general hydroaminoalkylation of cyclic and linear internal alkenes that occurs without isomerization of the C=C double bond. Further study supports the assertion that minimized steric parameters of the 2-pyridonate and chloro ligands allow for reactivity with sterically demanding internal alkenes. Kinetic studies and deuterium labeling experiments reveal a complex kinetic profile and provide evidence for off-cycle equilibria that dominate catalytic activity. Complementary to this work, an alternative 1,3-N,O-chelating phosphoramidate ligand framework was explored to synthesize Nb complexes for hydroaminoalkylation. A variety of monophosphoramidate tetrakis(dimethylamido) Nb complexes were synthesized, as well as bis(phosphoramidate) niobaziridines, which are proposed as intermediates for the hydroaminoalkylation mechanism. The optimal precatalyst system was found to be an in situ preparation of 2:1 phosphoramide:Nb(NMe2)5. This offers comparable results to analogous phosphoramidate Ta complexes, but with a significantly different phosphoramidate ligand set. iv  New cationic complexes of Ru, Rh, and Ir were synthesized featuring a bidentate κ2- P,N-phosphino-2-pyridonate ligand. These complexes were not viable precatalysts for hydroaminoalkylation, but were found to promote the stoichiometric dehydrogenation of amines to generate cationic metal hydrides. Analogous cationic complexes of 1,3-N,O-chelating 2-pyridonate complexes were prepared in situ and were found to catalyzed the reaction of dibenzylamine to tribenzylamine. A 2-pyridonate Ru complex was found to catalyze the dehydrogenation of benzylamine to the corresponding imine in the presence of isoprene, which acted as the hydrogen acceptor. Attempted hydroaminoalkylation reactions with non-arene supported 2-pyridonate complexes did not result in catalysis. These results provide insight into the use of late-transition metal complexes in amine activation and reactivity.    v  Lay Summary Amines are compounds that contain a nitrogen atom, and play a crucial role in biological systems. The development of new reactions that can efficiently synthesize amines are therefore of academic, pharmaceutical, agrochemical, and other industrial importance. These developments can improve our general understanding of how amine containing molecules chemically react, which can spur further developments in chemistry, biology, etc. A transition-metal complex can be defined as a metal ion chemically bound to molecules termed ligands. This thesis describes the development of new transition-metal complexes that function as catalysts in the efficient chemical transformation of simple amines into more complex amines that may be useful in synthesis of biologically active molecules or materials.  vi  Preface In collaboration and consultation with my supervisor Prof. Dr. Laurel Schafer, I designed and conducted all of the experiments described herein, except for specific instances described below. I have written the text of this document entirely with input and suggestions from my supervisor Prof. Dr. Laurel Schafer, except for specific instances described below. A version of the data contained in Chapter 2.2.1 has been published: Chong, E.; Brandt, J. W.; Schafer, L. L. J. Am. Chem. Soc. 2014, 136, 10898-10901. This work (experimental and otherwise) was done in collaboration with former Schafer group colleague Dr. Eugene Chong. Dr. Chong was responsible for the discovery and synthesis of complexes 2.12 and 2.13, and the initial reactivity as presented in Scheme 2.10. Catalyst optimization, and evaluation of substrate scope was performed collaboratively. Dr. Chong performed the final isolation and characterization of substrates presented in Scheme 2.12 and Scheme 2.13 after optimization.  A version of Chapters 2.2.2, 2.2.3, and 2.2.4 have been published: Brandt, J. W.; Chong, E.; Schafer, L. L. ACS Catal. 2017, 7, 6323-6330. This work was inspired by the work discussed above. Dr. Chong contributed the reaction found in Scheme 2.20. I wrote the text of this publication entirely, with input and suggestions from Prof. Schafer.         vii  Table of Contents Abstract ......................................................................................................................................... iii	Lay Summary .................................................................................................................................v	Preface ........................................................................................................................................... vi	Table of Contents ........................................................................................................................ vii	List of Schemes ............................................................................................................................. xi	List of Tables .............................................................................................................................. xvi	List of Figures ............................................................................................................................ xvii	List of Abbreviations ................................................................................................................. xix	List of Symbols ...........................................................................................................................xxv	Acknowledgements .................................................................................................................. xxvi	Dedication ................................................................................................................................ xxvii	Chapter 1: Introduction ................................................................................................................1	1.1	 Scope of Thesis ............................................................................................................... 2	1.2	 2-Pyridones as Ligands for Transition-Metal-Catalyzed Reactions ............................... 3	1.2.1	 Group 4 – 7 Transition-Metal Precatalysts with 2-Pyridone Ligands .................... 4	1.2.2	 Group 8 Transition-Metal Precatalysts with 2-Pyridone Ligands .......................... 6	1.2.2.1	 Transfer Hydrogenation and Hydrogenation of Ketones .................................... 6	1.2.2.2	 Additional Reactions with Group 8 Complexes ............................................... 11	1.2.2.3	 Bio-Inspired Complexes ................................................................................... 17	1.2.3	 Group 9 Transition-Metal Precatalysts with 2-Pyridone Ligands ........................ 18	1.2.3.1	 Reactions Involving Acceptorless Dehydrogenation ........................................ 18	1.2.3.2	 Hydrogenation of Carbon Dioxide and Dehydrogenation of Formic Acid ...... 26	viii  1.2.3.3	 Additional Catalytic Reactions ......................................................................... 34	1.2.4	 Group 10 – 12 Transition-Metal Precatalysts with 2-Pyridone Ligands .............. 37	1.2.5	 Conclusion ............................................................................................................ 40	Chapter 2: 2-Pyridonate Tantalum Complexes for the Hydroaminoalkylation of Unactivated Internal Alkenes with Unprotected Secondary Amines – Synthetic Development and Mechanistic Insights .....................................................................................42	2.1	 Introduction ................................................................................................................... 42	2.1.1	 Early-Transition-Metal Hydroaminoalkylation .................................................... 45	2.1.2	 Late-Transition-Metal Hydroaminoalkylation ...................................................... 51	2.1.3	 Scope of Chapter ................................................................................................... 53	2.2	 Results and Discussion ................................................................................................. 54	2.2.1	 Development of a Novel 2-Pyridonate Precatalyst for the Hydroaminoalkylation of Internal Alkenes ................................................................................................................ 54	2.2.2	 Exploration of 2-Pyridonate Ligand Effects on Hydroaminoalkylation Catalysis 59	2.2.3	 Mechanistic Interpretation .................................................................................... 65	2.2.4	 Investigations into Precatalyst Activation and Off-Cycle Equilibria ................... 67	2.3	 Conclusions ................................................................................................................... 76	2.4	 Experimental Details ..................................................................................................... 77	2.4.1	 General Considerations ......................................................................................... 77	2.4.2	 Instrumentation ..................................................................................................... 78	2.4.3	 Materials ............................................................................................................... 78	2.4.4	 Synthesis and Characterization of Compounds .................................................... 79	2.4.5	 Reaction and Experimental Details: ...................................................................... 85	ix  Chapter 3: Phosphoramidate Niobium Complexes for the Hydroaminoalkylation of Alkenes with Secondary Amines – Synthesis of Novel Niobium Complexes and Catalytic Reactivity ......................................................................................................................................91	3.1	 Introduction ................................................................................................................... 91	3.1.1	 Niobium Catalyzed Hydroaminoalkylation .......................................................... 91	3.1.2	 Phosphoramidate Ancillary Ligands for Early-Transition-Metal-Catalyzed Hydroaminoalkylation .......................................................................................................... 93	3.2	 Scope of Chapter ........................................................................................................... 94	3.3	 Results and Discussion ................................................................................................. 95	3.3.1	 Synthesis of Phosphoramidate Nb Complexes ..................................................... 95	3.3.2	 Catalytic Hydroaminoalkylation Reactivity of Phosphoramidate Nb Complexes 101	3.4	 Conclusions ................................................................................................................. 108	3.5	 Experimental Details ................................................................................................... 109	3.5.1	 Materials ............................................................................................................. 110	3.5.2	 Synthetic and Experimental Details .................................................................... 110	Chapter 4: 6-Substituted-2-Pyridonate and 2-Pyridonate Ligated Ru, Rh, and Ir Complexes for the Activation of Unprotected Amines – Efforts Towards Hydroaminoalkylation Catalysis for the α-Functionalization of Amines .............................118	4.1	 Introduction ................................................................................................................. 118	4.1.1	 Alkylation of Amines through Hydrogen-Borrowing Catalysis ......................... 118	4.1.2	 Acceptorless Dehydrogenation of Amines ......................................................... 121	4.2	 Scope of Chapter ......................................................................................................... 123	x  4.3	 Results and Discussion ............................................................................................... 126	4.3.1	 Arene Supported Ru, Rh, and Ir Complexes and Reactivity .............................. 126	4.3.2	 Initial Investigations into Non-Arene Ligated Late-Transition-Metal Complexes for Hydroaminoalkylation ................................................................................................... 138	4.4	 Conclusions ................................................................................................................. 142	4.5	 Experimental Details ................................................................................................... 143	4.5.1	 Materials ............................................................................................................. 143	4.5.2	 Synthetic and Experimental Details .................................................................... 144	Chapter 5: Conclusion ...............................................................................................................159	5.1	 Summary ..................................................................................................................... 159	5.2	 Future Directions ........................................................................................................ 161	5.2.1	 Early-Transition Metal Catalyzed Hydroaminoalkylation .................................. 161	5.2.2	 Late-Transition Metal Catalyzed Hydroaminoalkylation ................................... 163	5.3	 Concluding Remarks ................................................................................................... 165	References ...................................................................................................................................166	Appendices ..................................................................................................................................176	Appendix A NMR Spectra ...................................................................................................... 176	Appendix B Solid State Molecular Structures and X-ray Data: ............................................. 227	  xi  List of Schemes Scheme 1.1 2-Pyridonate Ti complexes for polymerization reactions ........................................... 4	Scheme 1.2 Hydroamination and hydroaminoalkylation reactions ................................................ 5	Scheme 1.3 Mn complexes for hydrogenative chemistry ............................................................... 6	Scheme 1.4 Ru complexes 1.17 – 1.30 for transfer hydrogenations and hydrogenations .............. 7	Scheme 1.5 Comparative study of Ru complexes 1.22, 1.31-1.38 for transfer hydrogenation ...... 9	Scheme 1.6 Ru complexes 1.38-1.44 for transfer hydrogenation ................................................. 10	Scheme 1.7 Os Complex 1.45 (right) and Ru catalyzed hydroesterification of ethylene (left) .... 11	Scheme 1.8 2-Pyridonate Ru paddlewheel complexes ................................................................. 13	Scheme 1.9 Ru catalyzed terpenylation of piperidines ................................................................. 14	Scheme 1.10 Ru catalyzed hydroboration of nitriles .................................................................... 14	Scheme 1.11 Ru catalyzed hydrogen borrowing catalysis ............................................................ 15	Scheme 1.12 Ru complexes 1.72-1.75 uses in catalytic reactions ................................................ 16	Scheme 1.13 [Fe]-hydrogenase active site Fe-GP cofactor and synthetic derivatives ................. 16	Scheme 1.14 [Fe]-hydrogenase inspired Fe and Co complexes ................................................... 17	Scheme 1.15 Dehydrogenative formation of aldehydes with complexes 1.87-1.91 ..................... 22	Scheme 1.16 Dehydrogenative formation of carboxylic acids with 1.96 ..................................... 22	Scheme 1.17 Formation of aldehydes from alcohols using a hydrogen acceptor ......................... 22	Scheme 1.18 Use of complex 1.88 in dehydrogenative catalysis ................................................. 23	Scheme 1.19 2,2'-Bipyridine derived ligands on Ir precatalysts for dehydrogenative reactions .. 24	Scheme 1.20 Ir catalyzed acetal formation with bi- and tri-dentate phosphine-2-pyridone ligands....................................................................................................................................................... 24	Scheme 1.21 Ir catalyzed dehydrogenation/hydrogenation of N-heterocycles ............................. 25	xii  Scheme 1.22 Ir complex 1.88 used in the catalytic synthesis of unsaturated N-heterocycles ...... 26	Scheme 1.23 Square planar Rh(I) complexes 1.139-1.140 ligated with 2,2'-bipyridine derivatives....................................................................................................................................................... 34	Scheme 1.24 Ir complexes for hydrogen borrowing catalysis ...................................................... 35	Scheme 1.25 Transfer hydrogenation of ketones with Ir complexes ............................................ 35	Scheme 1.26 Ir complexes for the transfer hydrogenation/hydrogenation of 5-hydroxymethylfurfural and catalytic formation of pyrrolidinones ............................................... 36	Scheme 1.27 Ni 2-pyridonate complex 1.158 and bimetallic Pd/Cu 2-pyridonate complex used in catalysis ......................................................................................................................................... 37	Scheme 1.28 Pd complexes 1.160-1.165 and their activity in catalytic reactions ........................ 38	Scheme 1.29 Cu 2-pyridonate systems for catalytic reactivity ..................................................... 39	Scheme 2.1 Catalytic synthesis of amines by hydroaminomethylation, hydroamination, and Buchwald-Hartwig amination. ...................................................................................................... 43	Scheme 2.2 Examples of metal-catalyzed α-C–H functionalization of amines ............................ 44	Scheme 2.3 Use of steric control for selective C–H functionalization ......................................... 45	Scheme 2.4 Inter- and intra-molecular variants of hydroaminoalkylation ................................... 46	Scheme 2.5 Intramolecular hydroaminoalkylation reactions ........................................................ 47	Scheme 2.6 Sc catalyzed hydroaminoalkylation of trialkyl amines ............................................. 49	Scheme 2.7 Ru and Ir catalyzed hydroaminoalkylation utilizing N-pyridyl directing groups ..... 51	Scheme 2.8 Late-transition-metal catalyzed hydroaminoalkylation without a directing group ... 53	Scheme 2.9 Synthesis of 2-pyridonate Ta complexes .................................................................. 54	Scheme 2.10 Complementary catalytic reactivity of 2.12 and 2.13 with cyclohexene and 1-octene....................................................................................................................................................... 55	xiii  Scheme 2.11 Hydroaminoalkylation of cyclohexene with known precatalyst under our conditions....................................................................................................................................................... 56	Scheme 2.12 Alkene substrate scope for the hydroaminoalkylation catalyzed by 2.12 ............... 57	Scheme 2.13 Amine substrate scope for hydroaminoalkylation catalyzed by 2.12 ...................... 58	Scheme 2.14 Substrate scope limitations for hydroaminoalkylation catalyzed by 2.12 ............... 59	Scheme 2.15 Synthesis of new Ta complexes 2.14-2.20 .............................................................. 60	Scheme 2.16 Hydroaminoalkylation activity of new precatalyst complexes with cyclohexene substrate ........................................................................................................................................ 62	Scheme 2.17 Hydroaminoalkylation activity of new precatalyst complexes with 1-octene substrate ........................................................................................................................................ 63	Scheme 2.18 Comparative hydroaminoalkylation reactivity of 2.15 and 2.17 ............................. 65	Scheme 2.19 Deuterium Scrambling Experiment ......................................................................... 68	Scheme 2.20 Isolation of dialkylated byproduct ........................................................................... 69	Scheme 2.21 Stoichiometric experiments with variable equivalents of alkene to determine relative amounts of product and byproduct formation. ................................................................. 70	Scheme 2.22 Ortho-deuteration off-pathway equilibrium ............................................................ 73	Scheme 2.23 Analysis of Deuterium Incorporation into Product and Byproduct Aniline after Partial Catalytic Conversion with Variably Deuterated Aniline Substrates ................................. 75	Scheme 3.1 Comparative hydroaminoalkylation reactivity of Nb and Ta precatalysts ................ 92	Scheme 3.2 Deuterium scrambling experiments with complexes 3.7 and 3.8 ............................. 93	Scheme 3.3 Hydroaminoalkylation reactivity of phosphoramidate ligated Ta complexes .......... 93	Scheme 3.4 Synthesis of phosphoramidate Nb complexes 3.13 – 3.17 ........................................ 96	Scheme 3.5 Synthesis of niobaziridine complex 3.18 .................................................................. 97	xiv  Scheme 3.6 Reaction of Nb(NMe2)5 with two equivalents of phosphoramide ............................. 99	Scheme 3.7 Synthesis of niobaziridine 3.20 ............................................................................... 100	Scheme 3.8 Synthesis of phosphoramidate imido Nb complex 3.21 .......................................... 101	Scheme 3.9 Substrate combinations that are not reactive for hydroaminoalkylation with a phosphoramidate Nb catalytic system ........................................................................................ 108	Scheme 4.1 N-alkylation of amines with alkylamines via hydrogen-borrwing catalysis ........... 119	Scheme 4.2 N-alkylation of amines with alcohols via hydrogen borrowing catalysis ............... 119	Scheme 4.3 α-Alkylation of cyclic amines with alkenes ............................................................ 121	Scheme 4.4 Ru-catalyzed synthesis of α-alkylated amines ........................................................ 121	Scheme 4.5 Acceptorless dehydrogenation of N-heterocycles by 2-pyridonate Ir complexes ... 122	Scheme 4.6 Mechanism for the acceptorless dehydrogenation of 1,2,3,4-tetrahydroquinoline proposed by DFT calculations .................................................................................................... 123	Scheme 4.7 Stoichiometric dehydrogenation of pyrrolidine by a 1,3-N,O-chelated phosphoramidate Ir complex ....................................................................................................... 124	Scheme 4.8 Proposed catalytic cycle for the late-transition metal catalyzed hydroaminoalkylation of amines ..................................................................................................................................... 125	Scheme 4.9 Synthesis of bidentate phosphine-2-pyridone ligands ............................................. 127	Scheme 4.10 Synthesis of Rh, Ir and Ru complexes 4.25, 4.26, and 4.27 .................................. 128	Scheme 4.11 Synthesis of small-bite-angle complexes 4.28 and 4.29 ....................................... 129	Scheme 4.12 Attempted hydroaminoalkylation of isoprene with pyrrolidine ............................ 130	Scheme 4.13 Reaction of 4.25, 4.26, and 4.27 with 5 equivalents of pyrrolidine ...................... 131	Scheme 4.14 Reaction of 4.28 and 4.29 with 5 equivalents of pyrrolidine ................................ 132	Scheme 4.15 Synthesis and isolation of 4.31 and 4.31•pyrrolidine ............................................ 133	xv  Scheme 4.16 Attempted hydroaminoalkylation of isoprene with dibenzylamine ...................... 135	Scheme 4.17 Generation of tribenzylamine from dibenzylamine .............................................. 135	Scheme 4.18 Attempted catalytic acceptorless dehydrogenation of dibenzylamine .................. 137	Scheme 4.19 Attempted catalytic reactions between dibenzylamine and C–C unsaturations .... 138	Scheme 4.20 Synthesis and reactivity of 4.41 ............................................................................ 139	Scheme 4.21 (a) Synthesis of Rh(I) and Ir(I) complexes 4.45 and 4.46; (b) attempted use of M(I) as precatalysts for hydroaminoalkylation ................................................................................... 140	Scheme 4.22 Attempted synthesis of phosphino-2-pyridonate ligated Ru–H complexes .......... 141	Scheme 4.23 Attempted hydroaminoalkylation of 2,3-dimethyl-1,3-butadiene with piperidine in situ generated Ru catalysts .......................................................................................................... 142	Scheme 4.24 Attempted hydroaminoalkylation of isoprene with pyrrolidine using Ru complexes 4.43 and 4.44 ............................................................................................................................... 142	Scheme 5.1 Synthesis of Ta alkyl complexes analogous to 2.12 ................................................ 162	Scheme 5.2 Potential tethered diphosphoramide protio-ligands for use in Nb catalyzed hydroaminoalkylation ................................................................................................................. 163	xvi  List of Tables Table 1.1 Dehydrogenation of 1-phenylethanol to acetophenone ................................................ 20	Table 1.2 Compiled results of catalytic hydrogenation of CO2 ................................................... 30	Table 1.3 Compiled results of catalytic dehydrogenation of formic acid ..................................... 31	Table 2.1 Comparison of key bond lengths and angles of the solid state molecular structures of 2.12, 2.15, 2.16, and 2.18 .............................................................................................................. 61	Table 3.1 Evaluation of monophosphoramidate Nb complexes as precatalysts for hydroaminoalkylation ................................................................................................................. 103	Table 3.2 Evaluation of diphosphoramidate and imido Nb complexes as precatalyst for hydroaminoalkylation ................................................................................................................. 105	Table 3.3 Evaluation of substrate scope of Nb catalyzed hydroaminoalkylation ....................... 107	Table B.1 Single crystal X-ray diffraction data for complexes 2.15, 2.16, and 2.18 ................. 229	Table B.2 Single crystal X-ray diffraction data for complexes 3.13, 3.18, 3.20, 3.21 ............... 230	Table B.3 Single crystal X-ray diffraction data for complexes 4.25, 4.26, and 4.41 ................. 232	 xvii  List of Figures Figure 1.1 Nomenclature and binding modes of 2-pyridone derived ligands ................................. 3	Figure 1.2 Complexes 1.81-1.100 used for catalysis discussed in this section ............................ 20	Figure 1.3 Complexes 1.117-1.138 utilized in catalytic hydrogenation/dehydrogenation of CO2/HCOOH ................................................................................................................................ 27	Figure 1.4 Ir complexes studied for catalytic water oxidation ...................................................... 36	Figure 1.5 Cu complexes 1.167-1.175 tested as catalyst in electrochemical water oxidation ...... 39	Figure 2.1 Early-transition-metal catalysts used for the intermolecular hydroaminoalkylation of secondary amines .......................................................................................................................... 48	Figure 2.2 Proposed mechanism for early-transition-metal catalyzed hydroaminoalkylation ..... 50	Figure 2.3 Proposed mechanism for directed, late-transition-metal catalyzed hydroaminoalkylation ................................................................................................................... 52	Figure 2.4 ORTEP representations of 2.15 (top-left), 2.16 (top-right), and 2.18 (bottom) .......... 62	Figure 2.5 Hydroaminoalkylation Reaction Monitoring with 5, 8, and 12 mol % of [Ta] Precatalyst 2.15 ............................................................................................................................. 71	Figure 2.6 Graphical representation of resting state equilibria ..................................................... 73	Figure 2.7 Plot of reaction monitoring experiments with 5, 8, and 12 mol% 2.15 as precatalyst for the hydroaminoalkylation reaction between N-methylaniline and 1-octene. Overlay of both experiments. .................................................................................................................................. 89	Figure 2.8 Plot of reaction monitoring experiments with 12 mol% 2.15 as precatalyst for the hydroaminoalkylation reaction between N-methylaniline (variably deuterated) and 1-octene. Overlay of both experiments. ........................................................................................................ 90	Figure 3.1 Nb complexes reported for hydroaminoalkylation and their direct Ta analogues ...... 91	xviii  Figure 3.2 ORTEP representation of 3.13 with select bond lengths and angles ........................... 96	Figure 3.3 ORTEP representation of 3.18 and select bond lengths and angles ............................ 98	Figure 3.4 ORTEP representations of 3.20 (left) and 3.21 (right) with select bond lengths and angles .......................................................................................................................................... 100	Figure 4.1 Transition-metal complexes reported to catalyze the acceptorless dehydrogenation of amines ......................................................................................................................................... 124	Figure 4.2 ORTEP representations of the solid-state molecular structures of 4.25 and 4.26 ..... 128	Figure 4.3 ORTEP represenation of the solid-state molecular structure of 4.41 ........................ 139	Figure 5.1 Examples of alternative ligand sets for future work toward late-transition-metal catalyzed hydroaminoalkylation chemistry ................................................................................ 165	 xix  List of Abbreviations Abbreviation  Description  1D   1-dimensional  2D   2-dimensional  Ac    acetylAd    adamantyl    Anal.    analysisaq    aqueous [B(ArF)4]–  tetrakis(3,5-trifluoromethylphenyl)borate BINAP  (1,1′-binaphthalene-2,2′-diyl)bis(diphenylphosphine) BINOL   1,1`-bi-2-naphtholbipy    2,2`-bipyridinebr    broad (spectral) Bn    benzylBu    butyl 13C{1H}  13C with 1H broadband decoupling NMR experimentCalc’d    calculatedcat.   catalyst CL   caprolactoneCp    cyclopentadienylCp*    η5-1,2,3,4,5-pentamethylcyclopentadienyl  xx  Abbreviation  Description  COD   1,5-cyclooctadiene COSY   correlation spectroscopy Cy   cyclohexyld    doublet (spectral) dap   2,9-disubstituted-1,10-phenanthrolineDCM    dichloromethane dCypm  bis(dicyclohexylphosphino)methane dCypp   bis(dicyclohexylphosphino)propane dd    doublet of doublets (spectral)Dipp    2,6-diisopropylphenylDFT    density functional theoryDMAP   4-dimethylaminopyridine DMF   dimethylformamide DMSO   dimethylsulfoxide dppe   bis(diphenylphosphino)ethane dppp   bis(diphenylphosphino)propane dtbbpy   4,4′-bis(tert-butyl)-2,2′-bipyridine E/Z    entgegen (“opposite”) / zusammen (“together”) (isomers) EA   elemental analysis  EI    electron impactESI    electrospray ionization  xxi  Abbreviation  Description  equiv.    equivalentsEt    ethyl Fc    ferrocene Fe-GP   Fe-guanylylpyridinolg    gramG    Gibb’s free energyGC    gas chromatography GMP   guanosine monophosphateH    enthalpy HA   hydroaminationHAA   hydroaminoalkylation HMDS   bis(trimethylsilyl)amide H4MPT+  tetrahydromethyanopterinh    hour(s)hex    hexylHz    Hertz    iPr    isopropylInd    indenyl  K    kelvinkJ    kilojoule xxii  Abbreviation  Description  kcal   kilocalorieL    liter LA   lactideLAH    lithium aluminum hydride LED   light emitting diodeM    molaritym    multiplet (spectral)  m    meta Me    methyl mg    milligrammL    millilitermmol    millimoleMS    mass spectrometry MOF   metal-organic frameworkmol    molem/z    mass-to-charge ration   normal ND    not determined NHC   N-heterocycliccarbenenM    nanomolar  xxiii  Abbreviation  Description  NMR    nuclear magnetic resonanceo    ortho OAc   acetate OPiv   trimethylacetate, 2,2-dimethylpropionate ORTEP   Oakridge thermal ellipsoid plot     p    para  p-cymene  1-isopropyl-4-methylbenzene, 4-isopropyltoluene PE    petroleum etherPh    phenyl  pH    potential of hydrogen ppm    parts per million  PMP    para-methoxyphenyl  pyr    pyridine q    quartet (spectral)  quint    quintet (spectral)  R    ideal gas constant RT   room temperature  rac    racemic  red    reductionROMP   ring-opening metathesis polymerization  s    singlet (spectral)  xxiv  Abbreviation  Description  S    entropysec    secondsept    septet (spectral)  t    triplet (spectral)  t-    tertiary tert-   tertiary temp   temperature t-amyl   1,1-dimethyl propyl, –C(CH3)2CH2CH3TBA    tetrabutyl ammoniumTBDMS   tert-butyldimethylsilyl Tf   trifluoromethylsulfonylTHF    tetrahydrofuranTMS    tetramethylsilane (molecule) TMS-   trimethylsilyl (group) Tol   toluene (molecule) Tol-   tolyl (group) tol-BINAP  2,2′-bis(di-p-tolylphosphino)-1,1′-binaphthyl VT    variable temperature    xxv  List of Symbols Symbol   Description  °    degree °C    degrees CelsiusÅ    angstromδ    chemical shift in ppmΔ    thermal heat; change Đ   polydispersity (polymers) ηx    eta, denotes hapticity of x atomsnJAB    n-bond coupling constant between atoms A and B (spectral) kobs    observed rate constantκx    kappa, denotes denticity of x atoms Keq   equilibrium constant µx   mu, denotes bridging of ligand to x metal centers   xxvi  Acknowledgements I would like to sincerely express my thanks and gratitude to the many people and organizations that made this thesis possible. First and foremost, I would like to thank my supervisor Prof. Laurel Schafer. The time, patience, and effort required to teach, develop, and encourage a student through completion of a Ph.D. is immense. Many thanks go to my current and former colleagues of the Schafer group, who have been continually insightful and supportive. Thank you to Erica Lui, whose editing has made this document appear to be written in English. Thank you to Prof. Glenn Sammis and Prof. Jen Love for offering their time and insight towards the assembly of this document. Their comments and suggestions have greatly improved the quality of this thesis.  I would also like to thank the many members of the UBC Chemistry department who maintain and make our lab equipment and instruments. Without them, this research would not be possible. Thank you to UBC (4YF) and NSERC (CGS-M, PGS-D) for financial support throughout my graduate studies. Finally, I would not be where I am today without the support of my parents, Bill and Jane, my sister, Rebecca, and my girlfriend, Erica. I will be forever indebted to them for their love, support, encouragement, and for putting up with my nonsense for all these years. xxvii  Dedication  I dedicate this thesis to my parents and my sister,   and to Erica.   1  Chapter 1: Introduction Organic molecules containing amine functional groups are ubiquitous throughout the chemical industries and often play significant roles in the function of many useful products.1-3 Specific examples of amine utilization include pharmaceuticals,4-5 the development of novel polymers, electronic and other advanced materials,6-10 and industrially used chemicals, such as compounds for the sequestration of CO2.11 Fundamental research into the general reactivity and synthesis of amines provides the foundational concepts and chemical space for this class of molecules. In turn, this allows for advances in biochemistry, chemical biology, pharmacology, and industry. Catalytic syntheses can offer multiple advantages over their stoichiometric counterparts. Catalysis offers the ability to alter the reaction pathway for a given set of starting materials and products.12 This can allow for novel reactivity of traditionally unreactive bonds, and provide alternative and/or improved chemo-, regio-, and stereo-selectivity of the product. Ultimately, catalysis allows for alternate disconnection strategies in the synthesis of molecules, significantly broadening the available chemical space, in turn leading to new developments. Catalysis can also significantly reduce the associated synthetic cost by reducing the number steps in a synthetic pathway, gaining step- and atom-efficiencies, and by reducing, or eliminating, the byproducts associated with a stoichiometric synthesis.13 A general theme of research into catalysis is to develop novel reactions while undertaking studies to understand the general reactivity properties of a catalyst, thereby leading to improved catalyst development. One way to catalytically synthesize amine containing molecules is through the use of homogenous transition-metal complexes as catalysts. Amines can serve many chemical functions, such as acting as an acid or base, a hydrogen bond donor or acceptor, or as a 2  nucleophile. While this diverse reactivity can be exploited for a variety of applications, this reactivity often makes the synthesis of amine-containing molecules difficult as unintended side-reactions often occur. With specific reference to transition-metal based catalysis, the high Lewis basicity of amines causes them to often be good ligands themselves. As a base and/or nucleophile, amines can also react with the ligand of the transition-metal catalyst. Additionally, the oxidation potential of amines often overlaps with the reduction potential of the transition-metal complex, causing reduction of the metal center. Together, these effects lead to catalyst deactivation. Often, conversion of the free amine into a deactivated or protected form (e.g. amide, carbamate, sulfonamide, etc.) is required to avoid catalyst deactivation. However, requiring stoichiometric protection/deprotection strategies adds complexity and inefficiency to a synthetic pathway. A desirable catalytic transformation would be able to avoid the use of protection/deprotection steps. To promote the desired reactivity of a transition-metal catalyst, significant effort must be made toward ligand and complex design. Choice of ligands will affect the electron density at the metal center and the steric environment about the metal center. Choice of the transition-metal ion and oxidation state will also bring about drastic changes in reactivity of the complex towards organic molecules, and, in the case of this thesis, amines. 1.1 Scope of Thesis   The focus of this thesis will be on the use of transition-metal complexes containing 1,3-N,O-chelating ligands as precatalysts towards the transformation of simple amine substrates into complex amine products. A central goal of this thesis is to present novel conclusions on how the design of specific 1,3-N,O-chelating ligands can affect the reactivity of transition-metal complexes with amines and catalytic transformation of amines. 3  Significant research has been devoted to the use of 2-pyridonate and 2-pyridone ligated transition-metal complexes in catalytic reactions. The remainder of Chapter 1 will review this topic and highlight the significance of ligand design in the reactivity of transition metal complexes. Chapter 2 will present the development of a novel 2-pyridonate tantalum precatalyst for the hydroaminoalkylation of alkenes with amines. Chapter 2 will also provide an introduction to the hydroaminoalkylation reaction and other catalytic α-C(sp3)–H functionalization of amines.  Chapter 3 will present the development of alternative 1,3-N,O-chealting systems, phosphoramidate niobium precatalysts, for the hydroaminoalkylation reaction. In addition, it will introduce Nb precatalysts and phosphoramidates as ancillary ligands for the hydroaminoalkylation reaction. Chapter 4 will present efforts to develop phosphine-tethered 2-pyridonate Ru, Rh, and Ir precatalysts towards the hydroaminoalkylation reaction and the acceptorless dehydrogenation of amines. Further, Chapter 4 introduces the concept of alkylation of amines via a dehydrogenative/hydrogen-borrowing approach. Chapter 5 will offer concluding remarks and future outlooks on the chemistry presented in the thesis. 1.2 2-Pyridones as Ligands for Transition-Metal-Catalyzed Reactions 2-Pyridones (or 2-hydroxypyridines) are found in equilibrium between the two tautomeric forms, where the equilibrium can depend on substitution and the solvent (Figure 1.1).14-16 As will be discussed in the following sections, ligation of the 2-pyridone can result in multiple binding modes, with various naming conventions, as detailed in Figure 1.1 for reference.  Figure 1.1 Nomenclature and binding modes of 2-pyridone derived ligands NOHNHO2-pyridone 2-hydroxypyridineNO [M]κ2-N,O-2-pyridonateNO[M]μ2-κ1-N-κ1-O-2-pyridonate[M]NO[M]κ1-N-2-pyridonateNOH[M]κ1-N-2-hydroxypyridineNOκ1-O-2-pyridonate[M]4  1.2.1 Group 4 – 7 Transition-Metal Precatalysts with 2-Pyridone Ligands Examples of 2-pyridonate complexes of early-transition metals (groups 4-6) utilized for catalysis are limited to Ti,17-21 Zr,22-23 and Ta.24-26 2-Pyridonate Ti complexes have been utilized in multiple polymerization reactions (Scheme 1.1). In ring opening polymerization (Scheme 1.1a), the 2-pyridonate ligand is found to have significantly lower activity than other pyridine derivatives.17 Isolated Ti complex 1.1 is active for ethylene polymerization but has significantly worse reactivity compared to thiopyridinate complex 1.2 (Scheme 1.1b).18 Complexes 1.3, 1.4, and 1.5 demonstrate structural variety that is possible with 2-pyridonate ligands and are active precatalysts for the ring opening polymerization of ϵ-caprolactone and lactide (Scheme 1.1c).20-21 While multiple derivatives of the 2-pyridonate motif were utilized in polymerization, Schafer Scheme 1.1 2-Pyridonate Ti complexes for polymerization reactions nn50:1 Monomer:[Ti]TiCl4:L:MeLi 1:2:2Toluene27 °C, 6 hN NNHOLActivity(g/mol Ti • h) 95.9 1031.1 1097.4NOPh NOPhTiNMe2NMe2NSAr NSArMNMe2NMe2R = H, Me, ArM = Ti, Zr1.2 M = TiR = 3,5-dimethylphenyln n1 atm1000:1 MMAO/MAO:[M]Toluene–40 to 80 °C1.11.160 °C9.3 kg/mol•h•atm1.260 °C1200 kg/mol•h•atmNONOTiR2R2R1R1R1 =6-Me3-Me3-PhOOOOmrac-LAO OOOmn OOOO nn OOCLOOOOm+ OO nO OOOmrandom copolymerization56-83%CL:LA incorporation23:77 to 50:50Đ 1.29-1.79R2 =NMe2 OiPrOEtOBnMonomer:[Ti]300:1Melt Phase130 °C, 24 hMonomer:[Ti]300:1Melt Phase130 °C, 24 h79-98%Đ 1.16-1.35 82-96%Đ 1.16-1.44CL:LA:[Ti]300:300:1Melt Phase130 °C, 24 hNONOTiNONMe2NONOTiNOOiPr1.31.4 1.5(a)(b)(c)5  and co-workers did not determine a direct structure-activity relationship with respect to the 2-pyridonate ligand.    Zr complex 1.6 (Scheme 1.2a) has been demonstrated to show substrate dependent intramolecular hydroamination (HA) and hydroaminoalkylation (HAA) reactivity.22-23 A series of structurally varied 2-pyridonate Ti complexes 1.7 – 1.10 were evaluated for selective hydroaminoalkylation over hydroamination (Scheme 1.2b).19 Interestingly, it was shown that 3-phenyl-2-pyridonate 1.7 provided superior yield and selectivity for hydroaminoalkylation with only minor structural change to the 2-pyridonate ligand. This suggests that modification of the pyridonate can have a significant effect on activity and selectivity. This is also shown in Ta catalyzed hydroaminoalkylation (Scheme 1.2c).24-26 Complexes of the type 1.11 are the first reported complexes active for hydroaminoalkylation of internal alkenes without isomerization (see Chapter 2).  R1HN+10 mol% [Ta]145 °C, 24 hR2 R1HNR2R3R4R3R4NOtBu NOtBuZrNMe2NMe2PhPh1.6R1 NH2R2 R2NHR2R2R1nnR = aryl, alkyl10 mol% [Zr]110 °C – 145 °Cup to 98%NH2R RR = aryl, alkylRRNH210 mol% [Zr]145 °Cup to 91%NONOTiNMe2NMe2H2NPhPh+HNPhPhH2NPhPh20 mol% [Ti]110 °CCat. – Yield (HAA:HA)1.7 – 76% (14:1)1.8 – 9% (8:1) 1.9 – 45% (4.6:1)1.10 – 16% (1:1)RR1.7 R = Ph1.8 R = H1.9 R = Me1.10 R = MesTaNONNNClR6R51.118 ExamplesR5, R6 = H, aryl, alkylup to 92% yieldR = H, aryl, alkyl(c)(b)(a)Scheme 1.2 Hydroamination and hydroaminoalkylation reactions 6  A single report on Mn bipyridine complexes highlights the high reactivity of complex 1.12 in the hydrogenation of CO2 (Scheme 1.3).27 Compared to analogues 1.13 – 1.16, the presence of the 2-hydroxypyridine motif is required for the high activity observed. Khusnutdinova and co-workers here propose the ability of the 2-hydroxypyridine motif to act as an intramolecular proton shuttle that is positioned in close proximity to the reactive site as key to the reactivity. This concept reappears significantly in the following late-transition metal discussions (Chapter 1.2.2, 1.2.3, and 1.2.4). Complex 1.12 highlights the κ1-N-2-hydroxypyridine binding mode (with respect to a single pyridyl ring).  1.2.2 Group 8 Transition-Metal Precatalysts with 2-Pyridone Ligands 1.2.2.1 Transfer Hydrogenation and Hydrogenation of Ketones Many examples of group 8 metals featuring 2-hydroxypyridine ligands have been synthesized and tested for hydrogenation and dehydrogenation reactions. Additionally, many have also been compared against analogues that have the 2-hydroxy functionality removed, blocked, or transferred to another position of the pyridine ring. This effectively isolates the hydroxyl functionality from the reactive site to determine if cooperative action of the hydroxyl group is required for the reported activity.NNRRMnCOCOBrCO1.12 R = OH1.13 R = H1.14 R = OMe1.15 R = NH2NNMnCOCOBrCOHOHOCO2 +5 μmol [Mn]6.5 mmol DBU65-80 °C, 24 h3 MPaH23 MPa H O-O+ DBUH+[Mn] – TON (yield) 1.12 – 1313 (96%)1.13 – 17 (< 2%)1.14 – 18 (< 2%)1.15 –  20 (7%)1.16 –  121 (10%)H NO+ NHCO2 +2 MPaH25 MPa72%2.5 μmol 1.1280 °C, 24 h1.16Scheme 1.3 Mn complexes for hydrogenative chemistry 7  NN NRuN OOH2N O1.17R1 R2O 0.5 mol% 1.17NaOHiPrOHReflux, 30-180 min.R1 R2OHR = aryl, alkyl > 95%5 examples70-408 av. TO/hFor acetophenone408 av. TO/hRuCliPrNN OHOHRuCliPrNN OORuCliPrNN1.181.19 1.21PhO1 mol% [Ru]NaO2CH10/90 MeOH/H2O90 °CPhOH1.18 – 95%, 18 h, 5 TO/h1.19 – 50%, 21 h1.20 – 22%, 20 h1.21 – 22%, 24 h6 other examples ofacetophenone derivativesRu ClNN OHOH1.20NN NOHOHRuPPh3PPh3Cl1.22R1 R2O 0.5 mol% 1.17tBuOKiPrOH80 °CR1 R2OHR = aryl, alkyl up to quant. yields11 examplesFor acetophenone82 TO/h1.23R1 R2O 1 mol% 1.23NaOHiPrOH82 °CR1 R2OHR = aryl, alkyl up to > 95%16 examplesFor acetophenone25 TO/hNNOHOHRu2 PF6–2+NNNNRuNPOHClPhPhiPrRuCliPrNHPh2PORuCliPrNPh2PO1.241.251.26PhO1 mol% [Ru]DABCO MeOH50 °C, 15 hPhOH1.24 – 90%, 6 TO/h1.25 – 64%1.26 – 65%+ H250 barRuCliPrNN OH1.27ORuCliPrNN OH1.28RuCliPrNN1.29ORuCliPrNN1.30OArO1 mol% [Ru]NaOHiPrOH82 °CArOHquant. conversion7 examplesAr = Ph1.27 – 96%, 192 TO/h1.28 – 97%, 291 TO/h1.29 – 95%, 190 TO/h1.30 – 96%, 128 TO/h+ +++++++ +++Scheme 1.4 Ru complexes 1.17 – 1.30 for transfer hydrogenations and hydrogenations  8  An early report, in 2000, detailed the transfer hydrogenation of ketones by 1.17 achieving promising turnovers per hour (TO/h) (Scheme 1.4).28 This catalyst has recently been stabilized on colloidal Fe nanoparticles as a reusable transfer hydrogenation catalyst.29 Not until 2011 was interest renewed in 2-hydroxypyridine complexes of Ru for these reaction types. This coincides with interest in similar Ir complexes for hydrogenation/dehydrogenation reactions (See Chapter 1.2.3).  A comparative study of complexes 1.18 – 1.21 demonstrates the ability of this type of complex to perform transfer hydrogenations in water (Scheme 1.4).30 The 6,6’-dihydroxy-2,2’-bipyridine complex 1.18 significantly outperformed 6,6’-dimethoxy-2,2’bipyridine complex 1.20 and 2,2’-bipyridine complex 1.21, highlighting the importance of the 2-hydroxypyridine motif. Complex 1.22 is effective for the transfer hydrogenation of ketones.31 For ketone substrates that incorporate alkenes (α,β-unsaturated ketones not reported), 1.22 was found to be selective for the reduction of ketones. The dicationic complex 1.23 was also active for this reaction and includes high yields with 16 ketone examples and comparable turnover rates.32  Complexes 1.24 – 1.26 incorporate a phosphine tether to create a P,N (1.24) or P,O (1.25, 1.26) type chelate. These were found to be active for the hydrogenation of acetophenone with 50 bar H2(g). Notably, a base additive was required to achieve high reactivity, as the anionic 2-pyridonate was proposed to be involved in the splitting of H2 to form the active [Ru–H] species.33 The 4,5-diazafluorene motif has also been utilized on arene supported complexes and tested for the transfer hydrogenation of acetophenone derivatives. Of the seven new complexes reported, 1.27 – 1.30 directly compare the effect of including a 3-hydroxy group (forming the 2-hydroxypyridine sub-motif) to those precatalysts without this functionality (Scheme 1.4).34 While 1.28 provided the highest turnover per hour (TO/h), the other complexes were also highly 9  effective for this reaction. The comparative hydrogenation activities leave ambiguity as to the significance of the 2-hydroxypyridine motif in transfer hydrogenation with Ru complexes chelated with bidentate 4,5-diazafluorene derived ligands.  A recent report by Szymczak and co-workers has built upon the success of complex 1.22, and has investigated the analogous complexes 1.31 – 1.37.35 Scheme 1.5 illustrates the complexes and their reported turnover numbers (TON) at 2 h. Complex 1.35 proves to be most active. However, 1.37 is also comparable to most of the other complexes. In basic reaction conditions, the deprotonated hydroxyl functionality may serve to create a more electron rich metal center enhancing the reactivity in both 1.35 and 1.37 over 1.36. Additionally, this report details reaction kinetics, as well as identified a strong cation effect that significantly affected the rate of the reaction. Transfer hydrogenation of 5-hexen-2-one to 5-hexen-2-ol with complex 1.35 results in 96% conversion in 3 h with complete selectivity for reduction of the ketone. Complexes 1.36 and 1.37 produce only 13% and 12% conversion with a mixture of alkene and double reduction products. The authors suggest a concerted hydrogenation mechanism that involves the 2-hydroxypyridine motif acting as a proton source during the hydrogenation. NN NOHOHRuPPh3LClNN NOHOHRuPPh3PPh3Cl1.22NN NOHOHRuPPh3ClCl1.31NN NOHOHRuPR3PR3Cl1.32 R = Me1.33 R = OPh1.34L = 4-methoxypyridine1.35 L = CONN NRuPPh3COClHOOH1.37NN NRuPPh3COCl1.36ArO0.5 mol% [Ru]KOtBuiPrOH80 °CArOH1.22 — 1591.31 — 1241.32 — 161.33 — 1061.34 — 1381.35 — 107++++ + 1.35 — 191*1.36 — 34*1.37 — 104**Verdake’s base, KB(C6F5)4,no KOtBu[Ru] — TON at 2 hScheme 1.5 Comparative study of Ru complexes 1.22, 1.31-1.38 for transfer hydrogenation 10  The addition of a single methylene linker in 1.38, as a modification to the terpyridine derivatives, resulted in an order of magnitude increase in turnover rate at 1160 turnover per hour for acetophenone reduction (Scheme 1.6).36 Complex 1.39 also offered significant improvements with turnover frequency of 2400/h for acetophenone reduction (Scheme 1.6).37 The methoxy-derivative, complex 1.40, is also active for this transfer hydrogenation. However, the significantly reduced 640 turnovers per hour for acetophenone reduction demonstrates the role of the 2-hydroxy group for improved rate. A more complete follow up examination of derivatives of 1.38 has also been reported (Scheme 1.6).38 Among the 11 complexes reported, the most relevant to this discussion are the illustrated 1.42 and 1.43. Ru complex 1.43 demonstrates high activity, although reduced compared to 1.38. Complex 1.39, featuring two 2-hydroxypyridine motifs, resulted in a significant decrease in reaction rate. Optimization found that an axial carbon NNN OHRuPPh3ClCl1.38R1 R2O 0.5 mol% 1.38KOiPriPrOH82 °CR1 R2OHR = aryl, alkyl up to > 90% yield19 examplesFor acetophenone1160 TO/hNNN OHRu ClPPh3PPh3NNN OMeRu ClPPh3PPh31.39 1.40R1 R2O 0.1 mol% 1.39KOtBuiPrOH80 °CR1 R2OHR = aryl, alkyl up to > 90% yield25 examplesFor acetophenone1.39 – 2400 TO/h1.40 – 640 TO/hNNNRuPPh3ClCl1.41OHNN NN OHRuPPh3ClCl1.44NNN OHRuPPh3ClCl1.38NNNRuPPh3ClCl1.42OHOHNNNRuCOClO1.43OHMeO0.5 mol% [Ru]KOiPriPrOH82 °C, 2h or 4hOHa+Ob+OHc• Reduced activity• Highly selectivefor reduction of5-hexen-2-oneto 5-hexen-2-olR1 R2O0.5 mol% [Ru]KOiPriPrOH82 °CR1 R2OHR = aryl, alkylwith acetophenonet = 15 min1.38 – 98% (1160 TO/h)1.41 – 96% (768 TO/h)1.42 – 28%1.43 – 67%1.44 – 96% (1440 TO/h)**0.2 mol%, 20 minwith 1.41up to > 90% yield22 examplesConversion (a:b:c)1.38 – 93% (45:27:21) (2 h)1.41 – 94% (50:12:32)1.43 – 95% (93:0:2)+ +Scheme 1.6 Ru complexes 1.38-1.44 for transfer hydrogenation 11  monoxide ligand (1.43) significantly improves selectivity over phosphine ligated complexes 1.38 and 1.39, while reducing activity.36,38 Additional N,N,N-chelates have been reported with 1.44 exhibiting the highest activity.39 This increased activity decreases selectivity for the reduction of 5-hexen-one consistent with the reports on these tridentate derivatives.  A 2-pyridonate Os complex 1.45 has been tested for the hydrogenation of 1-hexene. While the reactivity was middling, further study demonstrates the strained chelate improves reactivity relative to other, derivative Os catalysts, but did not comment on the role of the 2-pyridonate ligand (Scheme 1.7).40    1.2.2.2 Additional Reactions with Group 8 Complexes One of the earliest reports utilizing 2-pyridonate ligands was of a tri-ruthenium system (Scheme 1.7).41 However, reactivity for hydroesterification of ethylene was poor compared to a chloro tri-ruthenium complex.  Multiple examples of di-ruthenium paddlewheel-type complexes bearing 2-pyridonate ligands have been reported for multiple reactions. Complexes of the types 1.46 – 1.49 have been demonstrated to be active catalysts for cyclopropanation reactions with diazo compounds (Scheme 1.8). However, pyridonate derivatives exhibit poor reactivity and selectivity compared to their acetate analogues.42 Complex 1.49-Cl has been utilized in the synthesis of γ-lactams along with a large variety of Ru complexes (Scheme 1.8).43-44 Ru complex 1.49-Cl is a competent precatalysts with some of the best reactivity and selectivity for the synthesis of γ-lactams. Related complex 1.50 was found to be highly successful for Scheme 1.7 Os Complex 1.45 (right) and Ru catalyzed hydroesterification of ethylene (left) 0.3 mol% [Ru]DMF160 °C, 12 hH OO+OO20 atm[PPN][Ru3(μ-Cl)(CO)10] – Quant Conversion[PPN][Ru3(μ-OPy)(CO)10] – 58% Conversion (88% selectivity)OPy = 2-pyridonatePMe3Me3P NOsPMe3HO1.4512  intramolecular allylic C–H amination (Scheme 1.8).45 Complex 1.50 provided significant enhancement to both reactivity and selectivity compared to acetate derivatives in screening, and provided high selectivity with eight substrates. Compound 1.50 was also utilized in a similar C–H amination of aliphatic substrates (Scheme 1.8).46 Reactivity and selectivity both suffered in comparison to a variety of Ag catalysts also screened for this reaction. It should be noted that the paddlewheel complexes demonstrate varied binding modes for 2-pyridonate ligands such as µ3-κ2-N,O-κ1-O binding (1.46, 1.47) and µ2-κ2-N,O binding in others (1.48, 1.49).  13  Complex 1.51 was examined for an interesting C–C bond forming terpenylation of N-heterocycles (Scheme 1.9).47 While 1.51 demonstrated similar reactivity and selectivity to the optimal precatalyst candidate 1.52, substrate scope was examined only with 1.52. While the mechanism is not discussed, a transfer hydrogenation utilizing formic acid as the hydrogen source was also exploited in the reaction.  NO RCON ORuRuRCOLCON ORuRuRN ORCO COCO2OC OCLCON ORuRuRN ORCO COCOLNO RCON ORuRuRCOOC OCn1.47R = Cl, Br1.48R = Cl, BrL = MeOH, PPh3(4 cmpds)1.49R = Cl, BrL = MeCNR3R2R1R4OON2 + R1R3R2R4CO2Me1 mol% [Ru2]neatRT10up to 95%8 examples1.46NO ClCON ORuRuClCOLOC OCL1.49-ClL = MeCNON2NOBuBu NNOPr BuO+BuOOEt3 mol% 1.49-ClDCM40 °C, 1 h0% 99%N ON ON ORuRuN OCl1.50OSH2NOOOSHNOON OSHO O+2.5 mol% [Ru2]PhI(O2CtBu)2DCM40 °C a b1.50 – 68% 8:1 (a:b)7 additional examples with1.50 as catalystOCySNH2OSHN + O NHSOOO O O O2.5 mol% 1.50PhI(O2CtBu)2DCM40 °C a bYield (a:b)n = 0, 65% (1:1)n = 1, 88% (1:3.3)n = 2, 78 (2.1:1)nnScheme 1.8 2-Pyridonate Ru paddlewheel complexes 14  Tridentate complexes 1.53 – 1.57 (and 1.58 as a control) were examined for the hydroboration of arylcyanides to benzylamines (after acidic workup) (Scheme 1.10).48 The anionic complex 1.53 is highly successful for this reaction and 13 examples are provided. These complexes highlight interesting aspects of coordination for the 2-pyridonate fragments. The addition of one equivalent of an acid to 1.53 resulted in protonation of one 2-pyridonate fragments to form 1.54. A second equivalent of acid, interestingly, did not protonate the second 2-pyridonate fragment, and rather protonated a backbone nitrogen atom to generate 1.55.  Many Ru complexes are reported for hydrogen-borrowing catalysis. Ru complexes 1.59 – 1.62 are compared for their reactivity in the Geurbet reaction, the coupling of two alcohols resulting in the α-alkylated alcohol product (Scheme 1.11).49 These derivatives demonstrate that the 2-hydroxypyridine fragment in 1.59 plays a crucial role to improving the reactivity and the selectivity of the reaction. Related complex 1.63 was found to be an active precatalyst for the mono- and di-methylation of ketones utilizing methanol as the C1-source. Additionally, 1.63 was RuCliPrN OON N+UndesiredOver-reductionProductsSPOOORuCliPrPhnBu1.51 1.521) 3 mol% [Ru]150 °C, 16 h2) HCO2H150 °C, 3 h1.51 – 83% (90% selective)1.52 – 91% (90% selective)10 examples using 1.52Scheme 1.9 Ru catalyzed terpenylation of piperidines Ph CN + HBPin Ph NBPin24.5NNNNNRuPPh3PPh3-OO-5 mol% [Ru]Benzene, 25 °CComplexInitial TOF (s-1)NNNNNRuPPh3PPh3H O-Substrate Scope with 1.5313 Examples up to 94%(isolated as hydrolyzed amine salt)NNNNNRuPPh3O-O-PPh3NNNNNRuPPh3OO HPPh3NNHNNNRuPPh3OOPPh3H1.531.19 x 10-21.542.7 x 10-41.55no reaction1.562.6 x 10-51.572.5 x 10-51.581.3 x 10-4Scheme 1.10 Ru catalyzed hydroboration of nitriles 15  exploited for a multicomponent alkylation-methylation of ketones (Scheme 1.11).50 A study of the Geurbet reaction involving a variety of bipyridine Ru complexes included the use of the 6,6’-dihydroxy-2,2’-bipyridine complexes 1.66 and 1.69 (Scheme 1.11).51 As illustrated, their findings demonstrated the 2-hydroxypyridine fragment was important to selectivity and reactivity in this reaction.  A series of 2-hydroxy-6-phosphinomethyl-pyridine Ru complexes 1.72 – 1.74 were reported for the dehydrogenation reactions of alcohols to form acetals or esters, and the hydrogenation of CO2 with H2 to form formic acid (Scheme 1.12).52 Interestingly, the addition of base significantly altered reactivity. With base, ester formation was favoured, with 1.73 providing the highest activity and complete selectivity. In the absence of base, the acetal product was formed, with 1.73 as the best performing precatalyst. Complex 1.73 was also reported for NNN OHRu ClPPh3PPh3NNN OMeRu ClPPh3PPh3NNNRu ClPPh3PPh3NNNRu ClPPh3PPh3NNRRRuClClPPh3PPh3NNOHOHRuHCOPPh3PPh3NNN OHRu ClNCMeNCMe1.59 1.601.61 1.62R1OH+ R2 OHR1OHR2R1 = Ar, AlkylR2 = Ar, Alkyl0.1 mol% 1.59NaOHTolueneReflux, 90 minPhOH+ Ph OHPhOHPh+PhOPh0.1 mol% [Ru]NaOHTolueneReflux, 60 minR1OR2+a b29 examplesup to 99%up to 99:1 (a:b)ArArOH dialkylation ofcyclopentanol with 1.596 examples63-75% yielda bConversion (a:b)1.59 – 73% (93:7)1.60 – 22% (77:23)1.61 – 27% (79:21)1.62 – 23% (78:22)1.63ArO+ MeOH0.5 mol% 1.63KOtBu85 °C, 24 hR1 ArOR1 If R1 = H then double methylation20 examples84-97%ArO+ MeOH R OH+0.5 mol% 1.63KOtBu85 °C, 24 h ArORR = Ar,alkyl 16 examples54-86%PhOH+ Ph OHPhOHPh+PhOPh0.1 mol% [Ru]KOtBuTolueneReflux, 45 min a bConversion (a:b)1.64 – 52% (86:14)1.65 – 54% (58:42)1.66 – 11% (92:8)1.67 – 48% (86:14)1.68 – 49% (86:14)1.69 – 94% (90:10)1.70 – 45% (76:24)1.71 – 29% (58:42)1.64 R = H1.65 R = OMe1.66 R = OH1.67 R = H1.68 R = OMe1.69 R = OHRuHCl(CO)(PPh3)31.70RuCl2(PPh3)31.71Substrate Scope26 examples with 1.6955-100%up to 99:1 selectivity++ ++++Scheme 1.11 Ru catalyzed hydrogen borrowing catalysis 16  the cross coupling of secondary alcohols with primary alcohols to generate α-alkylated ketones.53 This is similar to the Geurbet reaction, however, H2 loss occurs instead of hydrogenation of the ketone to generate an alcohol. A one-pot two step procedure was also explored to synthesize the α,α’-dialkylated ketone product. A similar reaction generated amides from the cross coupling of primary alcohols and amines. Ru complex 1.75, featuring by O,N,S-tridentate ligand, catalyzed this reaction in high yields with 15 examples (Scheme 1.12).54 Scheme 1.12 Ru complexes 1.72-1.75 uses in catalytic reactions Scheme 1.13 [Fe]-hydrogenase active site Fe-GP cofactor and synthetic derivatives R1OHNPh2POHRuCl ClNPPh2HO1.72RuPh3P ClClNHOPNOHPh1.73RuPh3P ClNHOPNOHtBu1.74OHOOBnBn + +OO BnOHCO2 + H2H OHOAr OH +R NH2RuCOPPh3PPh3NHONNNH2S1 mol% [Ru]10 mol% NaOHToluene150 °C, 16 h a b cConversion (a:b:c)1.72 – 94% (0:50:50)1.73 – 100% (0:100:0)1.74 – 75% (0:98:2)Without NaOH, in THFConversion (a:b:c)1.72 – 71% (92:0:8)1.73 – 75% (88:0:12)1.74 – 56% (96:0:4)Substrate scope with 1.73for ester formation11 examples, 63-94%10 atm 50 atm6 μmol [Ru]DMSO50 °C, 16 hTurnover Numbers1.72 – 115-1311.73 – 33-401.74 – 310.5 mol% 1.7310 mol% NaOHToluene150 °C, 16-24 h+ R2 OHR1OR2+R1OHR2Undesired AlcoholGeurbet Product11 examples65-89%(3-15% alcohol)1.75orHNAr NHOR0.2 mol% 1.75KOtBuToluene120 °C, 12 h Ar NOor15 examples82-99%++HNN NHNNOH2NH + H2HNN NHNNOH2NH+ H+Hmethenyl-H4MPT+COFeCON ROOO1.76 R = OH; high activity1.77 R = OMe; trace reactivityCOFeCON OHOOOO GMPExtracted cofactorGMP = guanosine monophosphateCOFeCON OHO?SO GMPCys176Fe-GP cofactorin wild-type enzyme? = unresolved incrystal structure[Fe]-hydrogenase17  1.2.2.3 Bio-Inspired Complexes [Fe]-hydrogenase containing an Fe cofactor has been demonstrated to reversibly hydrogenate methenyl-H4MPT+ (methenyl tetrahydromethyanopterin) (Scheme 1.13).55-57 The crystal structure of the enzyme reveals an Fe-guanylylpyridinol (Fe-GP) cofactor (Scheme 1.13).57-58 Recently, a series of synthetic cofactors, 1.76 and 1.77, have been reconstituted into enzymes to form semisynthetic [Fe]-hydrogenases (Scheme 1.13).59 Interestingly, enzymes reconstituted with 1.76 showed high activity while those with 1.77 showed low activity for both the forward and reverse hydrogenation reaction. This demonstrated a critical importance of the 2-hydroxypyridine in the [Fe]-hydrogenase to modulate proton transfer. DFT calculations suggest the deprotonated hydroxyl group functions as an base to promote H2 heterolysis.59 Additional DFT calculations have been made on both Fe and Co synthetic models 1.78 and 1.79 towards the proposed hydrogenation of CO2 with H2 (Scheme 1.14).60-61 These calculations suggest H2 heterolysis is facile and this reaction theoretically attainable. The 2-methoxy pyridine derivative 1.80 has been synthesized. However, without the surrounding enzyme, exposure to H2 leads to decomposition of the complex (Scheme 1.14).62 Scheme 1.14 [Fe]-hydrogenase inspired Fe and Co complexes CO2 + H2H OHONOOFePNPHiPr iPriPr iPrNOOCoPNPiPr iPriPr iPrH1.78 1.79[M] cat.FeN OMeOCOIPEt2Et2P N+ H2NH OMe+1.80FeIICOOCPEt2Et2P N> 95%40%18  1.2.3 Group 9 Transition-Metal Precatalysts with 2-Pyridone Ligands 1.2.3.1 Reactions Involving Acceptorless Dehydrogenation A significant amount of research has been undertaken on the group 9 catalyzed acceptorless dehydrogenation of alcohols by pentamethylcyclopentadienyl (Cp* Ir(III) complexes ligated with the 2-hydroxypyridine (or anionic 2-pyridonate) ligands and ligand derivatives. Additionally, Cp*Co(III) andCp*Rh(III) analogues have also been explored. These reactions are of particular interest as they provide the synthetically useful transformation of readily obtained alcohols into the corresponding ketone or aldehyde with the benign, or even desired, byproduct of H2 gas.  Figure 1.2 represents the many precatalysts that have been tested, including many of which that do not incorporate the 2-hydroxypyridine/2-pyridonate motif. These direct comparisons help to elucidate the significance (or lack thereof) of incorporating this ligand design feature, and help discover additional ligand properties that enhance reactivity. Table 1.1 presents the data for the dehydrogenation of 1-phenylethanol to acetophenone that serves as a standard benchmark reaction. Substrate scope is highlighted for a given precatalyst. An initial report compared complexes 1.81 – 1.83 (entries 1-4) and highlights a significant improvement in rate at for complex 1.82 featuring the 2-hydroxypyridine ligand.63 Inspired by the [Fe]-hydrogenase cofactor (vide supra), 1.85 (entry 5) mimics the bidentate ligand found there with a bidentate O,N-bidentate ligand. Complex 1.85 (entry 6) removed the 2-hydroxy group and resulted in approximately a three-fold decrease in activity. 19   Entry Precatalyst Conditions Yield% Turnovers/h (TO/h) (calculated if not reported) Substrate Scope Ref 1 1.81 0.1 mol%, Toluene, Reflux, 20 h 9 4.5  63 2 1.82 0.1 mol%, Toluene, Reflux, 20 h 70 35 15 ketone products, up to 95% yield 63 3 1.83 0.1 mol%, Toluene, Reflux, 20 h 10 5  63 4 1.84 0.1 mol%, Toluene, Reflux, 20 h 13 6.5  63 5 1.85 0.1 mol%, neat, 130 °C, 24 h 19.2 8  64 6 1.86 0.1 mol%, neat, 130 °C, 24 h 6.5 2.7  64 7 1.87 0.1 mol%, p-Xylene, Reflux, 20 h 96 48 9 ketone and 23 aldehyde products, up to 100% yield 65 8 1.89 1.0 mol%, H2O, 20 h 92 4.6 11 ketone and 9 aldehyde products, up to 98% yield 66 9 1.92 0.5 mol%, Pentane, Reflux, 5 h 100 40  67 10 1.92 0.0002 mol%, p-Xylene, Reflux, 48 h 55 5729 (exhaustive) 12 ketone (up to 275,000 TON) and 7 aldehyde (up to 47,500 TON) products, up to 95% yield, 67 11 1.93 0.5 mol%, Pentane, Reflux, 5 h 36 14.4  67 12 1.92 0.5 mol%, Benzene, Reflux, 20 h 100 10  68 13 1.94 0.5 mol%, Benzene, Reflux, 20 h 95 9.5  68 14 1.95 0.5 mol%, Benzene, Reflux, 20 h 97 9.7  68 15 1.92 0.5 mol%, H2O, Reflux, 1h 15 30  69 16 1.96 0.5 mol%, H2O, Reflux, 1h 46 92 15 ketone and 7 carboxylic acid products, up to 95% yield 69 PhOHPhO+ H220   Entry Precatalyst Conditions Yield% Turnovers/h (TO/h) (calculated if not reported) Substrate Scope Ref 17 1.97 0.5 mol%, H2O, Reflux, 1h 4 8  69 18 1.98 0.5 mol%, H2O, Reflux, 1h 4 8  69 19 1.99 0.5 mol%, H2O, Reflux, 1h 8 16  69 Table 1.1 Dehydrogenation of 1-phenylethanol to acetophenone PhOHPhO+ H2IrClNOHCl IrClNCl IrClNClOH HO1.821.83 1.84[Cp*IrCl2]21.81IrClN OHOO1.85IrClNOO1.86IrClN OH1.87IrOH2NN OHOH IrOH2NN OHIrOH2NNIrOH2NNHOHO2+2+2+2+1.88 1.891.90 1.91IrOH2NN OOIrOH2NN OO1.92 1.93RhOH2NN OO RuNN OOOH21.94 1.95IrOH2NN N OH2+IrOH2NN OH22+1.96IrOHNN N2+NOOIr1.97 1.981.99RhClN O1.100Figure 1.2 Complexes 1.81-1.100 used for catalysis discussed in this section 21  The use of an ortho-metallated tethered phenyl group in 1.87 (entry 7) not only allowed for the formation of ketones but allowed for the efficient synthesis of aldehydes while avoiding the common alcohol coupling reaction resulting in ester formation (Scheme 1.15).65 Complexes 1.89 – 1.91 were also competent for the formation of aldehydes (Scheme 1.15) and ketones (entry 8).66 Interestingly, these complexes allowed for water to be used as the reaction solvent, and for significant reusability, with a drop in yield from 98% to 94% by the eighth consecutive reaction. Ligand design accounts for the effects of the 2-hydroxypyridine moiety, and was consistent with the increased rates associated with the 2-hydroxy group being present. Complex 1.92 (entries 9 and 10) was demonstrated to significantly outperform 1.93 (entry 11).67 It was also found that 1.92 offered extremely high turnover numbers of 275,000 (formation of acetophenone) and 47,500 (formation of benzaldehyde). The derivative Rh (1.94) and Ru (1.95) complexes were predicted by DFT computation and have been demonstrated experimentally to be effective for the acceptorless dehydrogenation reaction (entries 13 and 14).68  Complex 1.96 tethers the 2-hydroxypyridine fragment to an N-heterocycliccarbene (NHC) to form a N,C-bidentate ligand. Complex 1.96 was active for this reaction in water (entry 16) and performed better than 1.92 under the same conditions (entry 15).69 Ir complexes 1.97 and 1.98 both functioned as control reactions, and were consistent with demonstrating the requirement of the 2-hydroxypyridine functionality for increased activity (compare entries 16-18). The use of benzylalcohol (and 6 derivatives) in water resulted in the formation of the corresponding carboxylic acids in good yields (Scheme 1.16). While competent for the dehydrogenation of 1-phenylethanol, and the hydrogenation of acetophenone, Rh complex 1.100 was demonstrated to undergo formation of nanoparticles and behave as a heterogeneous catalyst for both reactions.70 22  Scheme 1.15 Dehydrogenative formation of aldehydes with complexes 1.87-1.91 Scheme 1.16 Dehydrogenative formation of carboxylic acids with 1.96 A series of 2-pyridonate Ir complexes, 1.101 – 1.106, were explored for the dehydrogenation of alcohols to aldehydes using a hydrogen acceptor (Scheme 1.17).71 Interestingly, this report also demonstrated that the substitution pattern of the 2-pyridonate ring can affect the activity of this reaction.  Cp*Ir 2-pyridonate complexes have been exploited as precatalysts for other dehydrogenative reactions (Scheme 1.18). Complex 1.88 was found to be superior to derivatives with the 2-hydroxy functionality remove as a precatalyst for the dehydrogenative lactonization of diols (Scheme 1.18a).72 This same Ir complex was found to be effective for the acceptorless dehydrogenation of allyl alcohols under mild conditions (Scheme 1.18b).73 Additionally, 1.88 was also used for the hydrogenation of variety of ketones and aldehydes with only 1 atm of H2 at 40 °C (Scheme 1.18c). Complexes 1.88 and 1.92 catalyzed the reaction of methanol and water to OHR+OH222-5 mol% 1.96H2OReflux, 20 hOHR + H2O7 Examples60-88%R OHRO+ H22.0 mol% 1.875.0 mol% NaOMeTolueneReflux, 20 h23 Examples34-95%Ar OHArO+ H20.5 mol% [Ir]WaterReflux, 20 hAr = Ph1.88 – 62%1.89 – 51%1.90 – 25%1.91 – 23%9 examples77-94% yieldHHIrClN OR1.101 R = H1.102 R = 5-CF31.103 R = 5-Me1.104 R = 4-Me1.105 R = 3-Me1.106 R = 3-OMeR OH +2.0 mol% [Ir]TolueneReflux, 20 hOO R O+ +OHO19 Exampleswith 1.10552-96%R = (CH2)6CH31.101 – 63%1.102 – 48%1.103 – 73% (3 mol%, 80%)1.104 – 61%1.105 – 73% (3 mol%, 94%)1.106 – 71%HScheme 1.17 Formation of aldehydes from alcohols using a hydrogen acceptor 23  produce H2 and CO2 (Scheme 1.19a).74 The 2-hydroxy functionality was crucial to reactivity, with only trace gas production with 1.90 and 1.91. This report also detailed the reversible protonation and deprotonation of 1.88 to 1.92 to 1.107, dependent on pH of the solution. Complex 1.92 was attempted for a tandem, one-pot dehydrogenation–deoxygenation reaction, but served as a poor catalyst (Scheme 1.19b).75 Scheme 1.19c demonstrates the use of 1.92 for the dehydrogenative coupling of ortho-aminobenzamides and methanol to form quinazolinones in high yields.76 Complex 1.82 was found to show some catalytic activity, but the absence of the 2-hydroxy functionality in 1.90 results in no product formation.  OHOH + 2 H2OOR2O+ H2R12 mol% 1.889:1 H2O:tBuOH40 °C, 24 h1.0 mol% [Ir]H2OReflux, 6 h1.88 – 98%1.90 – 3%1.91 – 41%1.82 – 0%22 examples with 1.8852-97%R2OHR1R1 = alkyl,R2 = alkyl, H7 examples, 9-92%No reaction withnon-allyl alcoholsat these mild conditionsR2R1O+ H22 mol% 1.889:1 H2O:tBuOH25 °C, 24 h1 atmR2R1OH8 examples70-98%R1 = alkyl, allylR2 = alkyl, H(b) (c)(a)Scheme 1.18 Use of complex 1.88 in dehydrogenative catalysis 24  Recently, phosphino-2-hydroxypyridine ligands were utilized as ligands for the Ir-catalyzed dehydrogenative homo-coupling of alcohols to generate acetals.77 Here, in situ preparation of the catalyst system was employed utilizing [Cp*IrCl2]2 and ligands 1.108 – 1.111 (Scheme 1.20). A Ir complex incorporating ligand 1.109 was found to be highly active and highly selective for acetal formation. Ligand 1.108 would likely form a similar complex to 1.82, and while exhibiting high activity is non-selective, producing only trace acetal. Complexation of Ph OH + N2H4•H2O Ph HNH2ONH2+ MeOHRNHONRCH3OH + H2O0.5 mol% [Ir]2 mol% NaOHH2OReflux, 20 h3 H2 + CO21.88 – 61%1.92 – 60% (w/ 1 mol% NaOH)1.90 – < 1%1.91 – < 1%IrOH2NN OHOH2+1.88pH < 2.7IrOH2NN OO1.92pH 6.5-6.8–IrOHNN OO1.107pH > 123 mol% [M]tBuOKtBuOH80 °C, 9 h1.92 – 9%[Ru(p-cymene)Cl2]2 – 53%(optimized to 95%)1 mol% [Ir]CsCO3MeOH150 °C, 12 hR = H1.92 – 70%1.82 – 26%1.90 – no reactionOptimized with 1.92μwave, 130 °C, 2 h14 examples66-91%(a)(b)(c)Scheme 1.19 2,2'-Bipyridine derived ligands on Ir precatalysts for dehydrogenative reactions Scheme 1.20 Ir catalyzed acetal formation with bi- and tri-dentate phosphine-2-pyridone ligands R OH O + R O+ R OOIrClPN OH+HNOPNNOHOHD2OPhIr2+PNNOOPhIrtBuOKNHOPh2PNHOPNHOR1.109 R = Ph1.110 R = tBuNHO1.1081.111a b c0.5 mol%[Cp*IrCl2]21 mol% ligandTHF150 °C, 24 hR RR = aryl,aklylRRR = PhLigand – Conversion (a:b:c)No L – 51% (49:50:1)1.108 – 96% (41:58:1)1.109 – 95% (6:7:87)1.110 – 20% (6:66:28)1.111 – 45% (2:27:71)With 1.10912 examples61-94%1.112 1.113 1.114PhH25  1.109 reveals an equilibrium between Ir complexes 1.112 and 1.113, with the addition of base leading to 1.114.   Complexes of this type have also been reported for the acceptorless dehydrogenation of cyclic amines. Scheme 1.19 illustrates that 1.101 – 1.104 and 1.106 were all found to catalyze the dehydrogenation of 1,2,3,4-tetraquinoline with 1.102 bearing an electron withdrawing CF3 group providing the highest activity (Scheme 1.21a).78 Complex 1.102 was also found to catalyze the reverse reaction, and through 5 dehydrogenation/hydrogenation cycles conversion only dropped from 100% to 98%. Ir complex 1.92, its electronically varied derivatives 1.115 and 1.116, and 1.93 have been explored for the dehydrogenation and hydrogenation of N-heterocycles (Scheme 1.21b,c).79-80 Contrasting with 1.102 above, the electron withdrawing character of 1.115 significantly reduced activity, and the electron donating character of 1.116 also reduced activity compared to 1.102. Importantly, no decrease in reactivity with 1.102 was found over 4 dehydrogenation/hydrogenation cycles.  NHN+ 2 H2IrOH2NN OOF3CF3CIrOH2NN OOtButBuNN+ H2NHHNIrClN OR1.101 R = H1.102 R = 5-CF31.103 R = 5-Me1.104 R = 4-Me1.106 R = 3-OMeR R2 mol% 1.102p-xyleneReflux, 20 hN+ H2R1 atm NHRR = H, alkyl5 examples73-100%4-5 mol% 1.102p-xylene110 °C, 20 hR = H, alkyl5 examples13-100%1.1151.11615 atm0.25 mol% [Ir]p-xylene110 °C, 20 h1.92 – 89%1.115 – 53%1.116 – 77%2.0 mol% 1.102p-xylene, Reflux, 20 h100%+ H270 atm5.0 mol% 1.93p-xylene130 °C, 20 h85%5.0 mol% 1.93p-xylene, Reflux, 20 h97%NNHNNH(a)(b)(c)Scheme 1.21 Ir catalyzed dehydrogenation/hydrogenation of N-heterocycles 26  Two reports have combined these dehydrogenation reactions to form unsaturated N-heterocycles (Scheme 1.22). While numerous Ir complexes and one Rh complex were screened, 1.88 was found to significantly outperform all others for the cyclization of ortho-aminobenzylalcohol with ketones.81 Similarly, 1.88 also results in significantly higher yields than other reported complexes for the cyclization of ortho-aminobenzylamines with aldehydes.82 1.2.3.2 Hydrogenation of Carbon Dioxide and Dehydrogenation of Formic Acid A compilation of complexes utilized for this reaction, in addition to those already presented, can be found in Figure 1.3. Compiled results for the hydrogenation reaction can be seen in Table 1.2, and for dehydrogenation in Table 1.3. The initial reports for 2-hydroxypyridine derivatives and their use in the hydrogenation of carbon dioxide to formate (under basic conditions) and the reverse dehydrogenation reaction involve complexes 1.117 and 1.118 and are compared to reported results for 4-hydroxypyridine containing derivative 1.91.83-84 Complex 1.117 provided a significant improvement over 1.118 and 1.91 based on turnover number (Table 1.2, entries 1-4).84 This is again born out in the dehydrogenation of formic acid (Table 1.3, entries 1-4).   Scheme 1.22 Ir complex 1.88 used in the catalytic synthesis of unsaturated N-heterocycles NH2NH2 R2 O+R1NNR1R2+ 2 H2 + H2ONH2OH+R1OR2NR2R1+ H2 + H2O21 mol% 1.88KOHH2O100 °C, 12 hR1 = aryl, alkylR2 = H, alkyl26 examples61-91%2 mol% 1.88H2O130 °C, 12 hR1 = halide, OMe,alkyl, CN, CF3R2 = H, alkyl20 examples52-83%H27   IrOH2NN RR1.88 R = OH1.119 R = OMe1.120 R = Me2+IrClNNNN RRIrClRR2+1.117 R = OH1.118 R = HIrOH2N NNN OHOHHOHO2+1.121CoLNNHOHOn+CoLNN OHOHn+CoLNNn+1.123 1.1241.125IrOH2NN OHOHHOHO2+1.122IrClNNN OMe1.126+IrOH2NNN OH1.1272+IrOH2NNNN OH1.1282+HOIrOH2NNNN OH1.1292+HOIrOH2HNNNN OH1.1302+HOIrOH2HNNNN OH1.1312+HOIrOH2HNNN1.133 R = OMe1.134 R = OH2+RIrOH2HNNNN OMe1.1322+MeOIrOH2HNNN1.135 R = OMe1.136 R = OH2+RIrOH2HNNN1.137 R = OMe1.138 R = OH2+RRFigure 1.3 Complexes 1.117-1.138 utilized in catalytic hydrogenation/dehydrogenation of CO2/HCOOH 28  Entry Precatalyst Conditions Precatalyst Concentration (µM) Initial Turnover Frequency (h-1) Turnover Number Ref 1 1.117 1:1 H2:CO2 at 0.1 MPa, 1 M NaHCO3, 25 °C, 336 h 50 64 7,200 84 2 1.118 1:1 H2:CO2 at 0.1 MPa, 1 M NaHCO3, 25 °C, 25 h 50 0 0 84 3 1.91 1:1 H2:CO2 at 0.1 MPa, 1 M NaHCO3, 25 °C, 24 h 50 7 92 83-84 4 1.117 1:1 H2:CO2 at 4 MPa, 1 M NaHCO3, 80 °C, 2 h 10 53,800 79,000 (up to 153,000 other cond.) 84 5 1.91 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 50 °C, 30 h 20 790 7,700 85 6 1.117 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 50 °C, 8 h 20 4,200 24,000 85 7 1.88 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 50 °C, 9 h 20 1,650 5,150 85 8 1.119 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 80 °C, 8 h 20 565 410 85 9 1.12 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 80 °C, 8 h 200 30 50 85 29  Entry Precatalyst Conditions Precatalyst Concentration (µM) Initial Turnover Frequency (h-1) Turnover Number Ref 10 1.88 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 120 °C, 8 h 10 25,200 12,500 85 11 1.121 1:1 H2:CO2 at 1 MPa, 1 M NaHCO3, 50 °C, 24 h 20 3,060 28,000 86 12 1.123 1:1 H2:CO2 at 4 MPa, 1 M NaHCO3, 100 °C, 1 h 400 39 (total) 39 87 13 1.124 1:1 H2:CO2 at 4 MPa, 1 M NaHCO3, 50 °C, 1 h 400 1.3 (total) 1.3 87 14 1.125 1:1 H2:CO2 at 4 MPa, 1 M NaHCO3, 60 °C, 3 h 1000 0.22 0.66 87 15 1.132 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 532 – 88 16 1.131 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 1,500 – 88 17 1.133 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 402 – 88 18 1.134 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 1,090 – 88 19 1.135 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 441 – 88 20 1.136 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 1,600 – 88 21 1.137 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 550 – 88 30  Entry Precatalyst Conditions Precatalyst Concentration (µM) Initial Turnover Frequency (h-1) Turnover Number Ref 22 1.138 1:1 H2:CO2 at 1 MPa, 2 M KHCO3, 50 °C 20 2,600 – 88 23 1.138 1:1 H2:CO2 at 0.1 MPa, 1 M NaHCO3, 25 °C, 336 h 25 98 7,280 88 Table 1.2 Compiled results of catalytic hydrogenation of CO2  Entry Precatalyst Conditions Precatalyst Concentration (µM) Initial Turnover Frequency Turnover Number Ref 1 1.117 1 M HCO2H/HCO2Na (1:1), 60 °C, 18 h 50 31,600 16,800 84 2 1.118 2 M HCO2H/HCO2Na (1:1), 60 °C, 1.5 h 50 32,000 10,000 84 3 1.91 3 M HCO2H/HCO2Na (1:1), 60 °C, 4 h 200 2,400 5,000 83-84 4 1.117 1 M HCO2H/HCO2Na (1:1), 90 °C, 7 h 3.1 228,000 165,000 (up to 308,000 other cond.) 84 5 1.88 1 M HCO2H/HCO2Na (1:1), 60 °C, 4.5 h 100 5,440 5,300 89 6 1.88 1 M HCO2H/HCO2Na (1:1), 90 °C, 4.5 h 33.3 19,800 30,000 89 7 1.119 1 M HCO2H/HCO2Na (1:1), 60 °C, 8 h 200 910 2,500 89 8 1.120 1 M HCO2H/HCO2Na (1:1), 60 °C, 9 h 4000 6 25 89 31  Entry Precatalyst Conditions Precatalyst Concentration (µM) Initial Turnover Frequency Turnover Number Ref 9 1.121 1 M HCO2H/HCO2Na (1:1), 60 °C, 6 h 100 12,200 6,340 89 10 1.122 1 M HCO2H/HCO2Na (1:1), 60 °C, 6 h 100 3,300 4,800 89 11 1.126 1 M HCO2H/HCO2Na (1:1), 60 °C, 5 h 100 160 430 90 12 1.127 1 M HCO2H/HCO2Na (1:1), 60 °C, 7 h 100 3,620 5,000 90 13 1.128 1 M HCO2H/HCO2Na (1:1), 60 °C, 1 h 100 11,400 5,500 90 14 1.1.29 1 M HCO2H/HCO2Na (1:1), 60 °C, 1.5 h 100 10,800 7,640 90 15 1.130 1 M HCO2H/HCO2Na (1:1), 60 °C, 1 h 100 5,520 10,000 90 16 1.131 1 M HCO2H/HCO2Na (1:1), 60 °C, 0.5 h 100 32,500 7,850 90 17 1.128 4 M HCO2H/HCO2Na (49:1), 100 °C, 6 h 20 269,000 196,000 90 18 1.131 4 M HCO2H/HCO2Na (2:1), 100 °C, 0.5 h 40 322,000 68,000 90 19 1.134 1 M HCO2H/HCO2Na (1:1), 60 °C, 6 h 25 14,500 28,000 88 20 1.136 1 M HCO2H/HCO2Na (1:1), 60 °C, 5.5 h 25 16,000 27,900 88 21 1.137 1 M HCO2H/HCO2Na (1:1), 60 °C, 5 h 25 16,500 28,900 88 22 1.138 1 M HCO2H/HCO2Na (1:1), 60 °C, 1 h 25 56,900 29,000 88 Table 1.3 Compiled results of catalytic dehydrogenation of formic acid32  Catalysis with complex 1.117 resulted in some of the highest activity and turnover numbers reported for both of hydrogenation and dehydrogenation reactions using mild conditions (25 °C, atmospheric pressures). Further investigations have explored the catalytic activity of 1.88 and closely related derivatives 1.119 and 1.120 in an effort to examine the role of the 2-hydroxy functional group for the hydrogenation of carbon dioxide.85 A comparison of 1.117, 1.88, 1.119, and 1.120 demonstrated that 1.117 was multiple times more active than 1.88 (Table 1.2, entries 5-10). Importantly, 1.88 demonstrated the necessity for the 2-hydroxy functional group with 1.119 and 1.120 performing poorly for the hydrogenation of carbon dioxide. An additional report Himeda and co-workers adds complex 1.121 to the list of competent precatalysts for hydrogenation of carbon dioxide.86 Complex 1.121 was found to be comparable to the high performing complex 1.117 (Table 1.2, entry 11). Additional kinetic details including kinetic isotope effects of both H2/D2 and KHCO3(H2O)/KDCO3(D2O) have been reported along with DFT computational details. In a separate report, these complexes along with 1.122 were evaluated for their reactivity for the dehydrogenation of formic acid, (Table 1.3, entries 5-10) and a series of kinetic investigations were  carried out.89 Compared to 1.88, complex 1.91  performed poorly, while 1.121 and 1.122 offer comparable results. This study offers additional confirmation of the significant importance of the 2-hydroxypyridine motif as 1.119 and 1.120 showed poor reactivity comparatively. A series of related bipyridine Co complexes, 1.123 – 1.125, were synthesized and tested for the hydrogenation of carbon dioxide (Table 1.2, entries 12-14).87 These system required significantly higher catalyst loading, temperature, and pressures to achieve limited activity. Interestingly, unlike the Ir complexes studied, the Co complex ligated by the 6,6’-33  dihydroxybipyridine ligand (1.124) was significantly less effective than the 4,4’-dihydroxybipyridine complex (1.123) suggesting a departure in this trend with Co catalysts.  A series of Ir compounds feature modified N,N-chelating ligands (1.126 – 1.131) have also been tested for the dehydrogenation of formic acid reactions (Table 1.3, entries 11-16).90 While all proved to be quite active, 1.128 (Table 1.3, entry 17) was found to have turnover numbers of up to 196,000 and 1.131 (Table 1.3, entry 18) was found to have initial turnover frequency of up to 320,000, with high reaction temperatures at 100°C. These results are comparable to that of the high perform Ir complex 1.117 (Table 1.3, entries 1, 4). Due to the promising reactivity of 1.131, derivatives 1.132 – 1.138 were explored for both hydrogenation of carbon dioxide (Table 1.2, entries 15-23) and dehydrogenation of formic acid (Table 1.3, entries 19-22) in an effort to further understand the ligand requirements for these reactions.88 For hydrogenation of carbon dioxide, the methoxy substituted pyridine or pyrimidine ligands all performed poorly, highlighting the requirement of the deprotonated hydroxyl group for high reactivity, under basic conditions. Of these, complex 1.138 had the highest initial turnover frequency (Table 1.2, entry 22), and outperformed the benchmark complex 1.117 under ambient conditions (Table 1.2, compare entry 1 and 23). Given this success, the hydroxyl variants (1.131, 1.134, 1.136, 1.138) and a single methoxy substituted variant (1.137) were tested for the dehydrogenation of formic acid (Table 1.3, entries 19-22). Again, complex 1.138 has the highest initial turnover frequency (Table 1.3, entry 22) and, under similar conditions, outperformed previously reported complexes 1.131 (Table 1.3, entry 16) and 1.117 (Table 1.3, entry 1). Interestingly, unlike the poor performance for hydrogenation, methoxy substituted 1.137 (Table 1.3, entry 21) performed comparably to 1.131 (Table 1.3, entry 16), 1.134 (Table 1.3, entry 19), 34  and 1.136 (Table 1.3, entry 20). This makes it unclear as to the effect of the 2-hydroxyl substituent under the acidic conditions used for formic acid dehydrogenation. 1.2.3.3 Additional Catalytic Reactions Rh(I) complexes with 6,6’-functionalized bipyridine derivatives (1.139 – 1.143), including 6,6’-dihydroxy-2,2’-bipyridine (1.140) were evaluated for the carbonylation of methylacetate (Scheme 1.23).91-92 Only small differences in reactivity were observed and these complexes were slightly less active than [RhCl(CO)2]2. Additionally, 2,2’-bipyridine derivatives, including 1.88 and 1.90, were tested for an aldehyde water shift (AWS) reaction. Complex 1.88, and the Cp*Rh and ArRu analogues, provided trace activity for the AWS reaction with mainly aldehyde disproportionation observed. [(p-Cymene)Ru(bipy)(OH2)][OTf] provided the highest selectivity with only trace disproportionation observed.93 Many Cp*Ir complexes bearing the 2-hydroxypyridine ligand motif have been utilized in various hydrogen borrowing catalysis. Complex 1.88 allowed for the alkylation of sulfonamides with alcohols, where complex 1.90 gave no yield (Scheme 1.24a).94 Recently, 2,2’-bibenzimidazole Cp*Ir complexes have been shown to be active for the same reaction with comparable reactivity to 1.88.95 Complex 1.87 was found to be highly active for the Guerbet reaction of ethanol into n-butanol when combined with specific sterically demanding [LnCu-OH] or [LnNi-OH] bases (Scheme 1.24b). Importantly, 1.87 was found to be highly selective for this reaction with minimal oligomer or ketone formation. Complex 1.92 was found to be highly NNRRRhCOCO1.139 R = H1.140 R = OH1.141 R = NH21.142 R = COOEt1.143 R = P(O)(OEt)2OO+ COOHO+~0.01 mol% [Rh]0.45 eq. MeIAcOH/H2O130 °C, 16 h30 barConversion1.139 – 41%1.140 – 39%1.141 – 35%1.142 – 43%1.143 – 47%[RhCl(CO)2]2 – 49%Scheme 1.23 Square planar Rh(I) complexes 1.139-1.140 ligated with 2,2'-bipyridine derivatives 35  active for the coupling of alcohols to form α-alkylated ketones in a two-step procedure: 1) oxidation of alcohol to the ketone, then 2) addition of second alcohol and base (Scheme 1.24c).96 The transfer hydrogenation of ketones with formic acid (Scheme 1.25a),97 and the transfer hydrogenation of aldehydes by NADH (under biological conditions, Scheme 1.25b) were used  to compare complexes containing the 2-hydroxypyridine motif to many other complexes.98 Interestingly, it was found that the 2-hydroxypyridine containing complexes did not achieve the best performance, highlighting the complexity involved with evaluating trends in ligand design to design an optimal organometallic catalyst.  Many Cp*Ir complexes containing 2-hydroxypyridine ligand derivative have been tested for the transfer hydrogenation (and hydrogenation) of 5-hydroxymethylfurfural, a renewable feedstock chemical that is known to be transformed into a wide range of chemicals.99-101 Activity and selectivity of this reactions were shown to be both precatalyst and pH dependent. However, Ar S NH2+ R2 OHO OOH2 OH0.2 mol% 1.87[LnCu-OH] or [LnNi-OH]150 °C, 24 h1 mol% 1.88Cs2CO3H2O120 °CAr S NHO OR229 examples78-94%R1OH+ R3 OH(1) 1 mol% 1.92t-amyl alcohol, Reflux, 6 h(2) Cs2CO3t-amyl alcohol, Reflux, 6 hStep (1)Added inStep (2)R1OR2R2R331 examples79-90%(a)(b)(c)Scheme 1.24 Ir complexes for hydrogen borrowing catalysis O+H OHO OHOH + NADHOHH0.05 mol% [Ir]HCOOH/HCOONapH 2.6, Aqueous Sol.40 °C, 8 h[Ir] – initial TOF – TOF at 8 h (h-1)1.88 – 740 – 8701.91 – 1200 – 18002 mol% [Ir]tBuOH/phosphatebuffered saline (1:4)37 °C, 24 h 1.90 – 0%1.88 – 20%1.117 – 14%1.144 – 89%IrNON+Ph1.144(b)(a)Scheme 1.25 Transfer hydrogenation of ketones with Ir complexes 36  the 2-hydroxypyridine fragment appeared to be beneficial, especially with complex 1.150 (Scheme 1.26a).100 Complex 1.150 has additionally been exploited for the reductive amination of levulinic acid with hydrogen to pyrrolidinones (Scheme 1.26b).102 Multiple Cp*Ir(III) complexes of this type have also been compared for catalytic water oxidation (Figure 1.4).103-105 Interestingly, complexes containing a hydroxypyridine fragment were found to have excellent activity that was demonstrated to be significantly affected by pH, creating pH-switchable catalysts. However, the position of the hydroxy group on the pyridine ring did not play a significant role in altering activity. IrOH2NNRR2+1.91 R = H1.145 R = OMe1.146 R = NH21.147 R = COOHOOHOOOHHO +HOOOIrOH2NN OH2+OHOO+ RNH2 + H2 N ROpH sensitive reactivityand selectivityHCOOH or H2RIrOH2NN RR1.88 R = OH1.90 R = H1.119 R = OMe2+1.89 R = H1.148 R = 5’-CF31.149 R = 4’-Me1.150 R = 4’-NMe2Complexes evaluated for this reaction:0.05 mol% 1.150H2O80 °C, 7-24 h20 barR = aryl, alkyl10 examples63-95%(a)(b)Scheme 1.26 Ir complexes for the transfer hydrogenation/hydrogenation of 5-hydroxymethylfurfural and catalytic formation of pyrrolidinones Figure 1.4 Ir complexes studied for catalytic water oxidation IrClNNRR+1.91 R = OH1.145 R = OMeIrOH2NN OHOH2+1.88IrOH2N NNN OHOHHOHO2+1.121IrOH2NNNN OHOHIrH2OHOHO4+1.151IrOH2N NNN2+1.152IrOH2NN2+1.90IrONO2NOOR1.153 R = H1.154 R = 3-OH1.155 R = 4-OH1.156 R = 5-OH1.157 R = 6-OH37  1.2.4 Group 10 – 12 Transition-Metal Precatalysts with 2-Pyridone Ligands To date, only a few complexes of groups 10 – 12 have been reported for their activity in catalytic reactions. However, despite the small number of complexes, group 10 – 12 complexes demonstrate a wide variety of coordination modes for the 2-pyridone ligand motif. A Ni complex 1.158 exploits a 2-hydroxyquinoline ligand for the acceptorless dehydrogenation of alcohols and the hydrogenation of ketones with H2 (Scheme 1.27a).106 The bimetallic Pd/Cu complex 1.159 has been shown to be a competent catalyst for the one-pot synthesis of 2-phenylindole,107 and provided complete selectivity for C3-alkenylation of indole (Scheme 1.27b).108  Multiple other Pd complexes feature a 2-hydroxypyridine or 2-pyridonate motif have been synthesized, and evaluated for their catalytic reactivity in a number of organic transformations (Scheme 1.28).109-111 Interestingly, in the study of conjugate addition chemistry with 1.160 – 1.163, complex 1.163, featuring the 2-hydroxypyridine motif, severely diminished reactivity for this reaction (Scheme 1.28a).109 H BN NN NN NN CF3ONiINH2+ Ph NHPhN OPd CuN OClN O2OCuNH+ CO2nBuNHCO2nBu1.158R1 R2OH 5 mol% 1.158TolueneReflux, 24-120 hR1 = aryl, alkylR2 = alkyl, HR1 R2OorR1 OOif R2 = HR1 14 examples74-95%For R1 = Ph, R2 = H, MeH2 (12 atm)THF, 120 °C, 72 h100% Conversion1.1592 mol% 1.159DMF/H2O100 °C, 3h100% by GC74% isolated10 mol% 1.159DMF/DMSO70 °C, 20 h65%no C2 product observed(a)(b)Scheme 1.27 Ni 2-pyridonate complex 1.158 and bimetallic Pd/Cu 2-pyridonate complex used in catalysis 38  A Cu(I)/Na-2-pyridonate system was found to be highly efficient for the synthesis of biazoles by aerobic oxidative homocoupling (Scheme 1.29a).112 While many bipyridine derivatives were tested, the 2-pyridonate functionality proved crucial for reactivity. A prepared bimetallic Cu complex 1.166 served as a competent precatalyst for the homocoupling of boronic acids and alkynes (Scheme 1.29b).113-114 Multiple Cu species with 6,6’-dihydroxy-2,2’-bipyridine ligands and their derivatives have been reported for their use in electrocatalytic catalytic water oxidation (Figure 1.5).115-116 These studies have demonstrated high activity at low over potential is due to the 6,6’-dihydroxy groups. Altering these group or moving the placement of the hydroxy functionality was shown to significantly decreases activity. N NOHHOPdCl Cl1.160 3,3’-(OH)21.161 4,4’-(OH)21.162 5,5’-(OH)21.163 6,6’-(OH)2O+ PhB(OH)2OPh+OPhONNOPdClPdCl PPh3Ph3PRXNNH+X = Cl, BrR = CN, COOH,NO2, CF3RNNN OONNOOPdCl Cl NPd1.165PhRROOPhPh Ph O+ Ph +OHPhO1.1645 mol% [Pd]H2O80 °Ca b[Pd] – yield (a:b), time1.160 – 99% (98:1), 1h1.161 – 99% (24:1), 24h1.162 – 99% (12:1), 5h1.163 – 13% (6:1), 24h1.164K2CO3DMAc120 °C, 24-28 h7 examples78-89%5 examples65-90%R = H, alkyl,OMe, Cl3 mol% 1.16510 mol% CuCl2O2 (1 atm)H2O/dioxane85 °C, 20 h4 mol% [Pd]8 mol% CuCl2O2 (1 atm)H2O/2-propanol50 °C, 16 h a b c[Pd] – Yield a:b:c (%)1.165 – 75:0:25PdCl2 – 47:0:15dppePdCl2 – 9:0:10(c)(d)(b)(a)Scheme 1.28 Pd complexes 1.160-1.165 and their activity in catalytic reactions 39  There are also examples where the 2-hydroxypyridine motif has been exploited in supramolecular chemistry. These have been tested as catalyst for a variety of common organic transformations as proof-of-concept that these structures are catalytically active and with significant focus on their catalytic reusability. A 2,4,6-trioxotetrahydropyrimidinylidene was used to form Zn and Cd coordination polymers that were tested as precatalysts for the Knoevenagel condensation of benzaldehyde with malononitrile.117 2-Pyrimidonate is used as a ligand to form a Pd(II) metal-organic-framework (MOF) that has been shown to be effective in Suzuki cross coupling,118 oxidation of allyl alcohols with O2 at the terminal oxidant,118 and the hydrogenation of alkenes with H2.118-121 The 2-pyrimidonate ligand also forms a Cu(II) MOF.122 It has been shown as an effective precatalyst for benzylic C–H oxidation with O2,123-124 azide-NXR1R2 NXR1R2 XNR1R2X = NR3, O, SB(OH)22 R R RNNOCuNNOCuR2 R R1 mol% CuCl2 mol% Na-3-methyl-2-pyridonateair, p-xylenereflux, 20 h19 examples63-98%1.1660.5 mol% 1.166air, DMFRT, 20 h 14 examples10-98%5 mol% 1.1665 mol% TBABair, H2ORT, 5-10 h 14 examples90-96%(a)(b)Scheme 1.29 Cu 2-pyridonate systems for catalytic reactivity NNOHOHCuNNHOHOL2+NNM NN2+HOHOOHOH1.168NNOMeOMeNNMeOMeOCuONO2 +OO NNMeOMeOCuOMeHSOONNCuOHOHNNCuOHOHOHOHRR1.172 R = H1.173 R = OH1.174 R = OMe1.175 R = COOH1.167 1.169 1.1701.171Figure 1.5 Cu complexes 1.167-1.175 tested as catalyst in electrochemical water oxidation 40  alkyne “click” coupling,125 alkynylation of imines,126 hydroxylation and nitration of aryl halides, 127 and the oxidative C–O coupling of alcohols with formamides, aldehydes, and ethers by direct C–H activation.128 1.2.5 Conclusion The 2-pyridone/2-pyridonate ligand motif has been shown to be a highly versatile ligand framework for complexes across the transition metals. This review has highlighted the use of complexes featuring this motif in a wide range of catalysis, and highlighted the diverse range of coordination modes these ligands can support. In early-transition metal complexes, 2-pyridonate ligands have been utilized as ancillary ligands. Substitution of the 2-pyridonate has been utilized to optimize catalytic performance for polymerization, hydroamination, and hydroaminoalkylation reactions. As ligands in late-transition metal complexes, the 2-pyridonate motif has been invoked as an internal base, in effect, storing a proton equivalent from a substrate in the 2-hydroxypyridine form. Significant research has demonstrated this effect in Ru and Ir complexes for simple hydrogenation and dehydrogenation reactions of ketones/alcohols and CO2/HCOOH. Additionally, more complex synthetic reactions have been developed exploiting the ability of Cp*M 2-pyridonate complexes to readily promote hydrogen transfer reactions. While many reactions are demonstrated to require the 2-hydroxypyridine substitution, placing the hydroxyl group in close proximity to the metal center, some late-transition metal complexes remain highly active for a variety of reactions with 6-hydroxypyridine substation. In these situations, the low pKa of coordinated pyridine is exploited under mild, basic conditions to create a more electron rich metal center through donation of anionic 2-pyridonate or 6-pyridonate donor. The 2-41  pyridonate ligand motif has also been incorporated as an ancillary ligand in late-transition metal complexes, such as in paddlewheel complexes or in MOFs.  42  Chapter 2: 2-Pyridonate Tantalum Complexes for the Hydroaminoalkylation of Unactivated Internal Alkenes with Unprotected Secondary Amines – Synthetic Development and Mechanistic Insights 2.1  Introduction  As discussed in Chapter 1, amines are broadly important across multiple industries. While there is a significant volume of work on the use of stoichiometric reagents to achieve amine containing products,1-3 the development of novel catalytic syntheses of amines is a significant challenge. Multiple catalytic reactions for the synthesis of amines are known, and have become reliable and highly used in laboratory settings. Some examples include Buchwald-Hartwig amination,129-130 hydroamination,131 and hydroaminomethylation reactions (Scheme 2.1).132 While these three examples offer unique disconnection strategies, hydroamination and hydroaminomethylation reactions are both 100% atom-economic reactions – where each atom in the reactants are found in the products – and utilize readily available substrates – avoiding additional steps that may be needed to functionalize or activate the substrate to achieve the desired reactivity in other catalytic methods. From an end-user/industrial context, methodologies that employ these strategies are economically efficient by avoiding waste products and reducing the number required steps.      43  Scheme 2.1 Catalytic synthesis of amines by hydroaminomethylation, hydroamination, and Buchwald-Hartwig amination. One strategy that has garnered significant recent interest, is the transition-metal-catalyzed C(sp3)–H activation of amine substrates and subsequent functionalization to create new C–C or C–heteroatom bonds. These synthetic methodologies are of interest as they are able to generate complex amine products from simple amine starting materials. Importantly, these methodologies provide new disconnection strategies, where the starting amine substrate is not required to be pre-activated or pre-functionalized at the to-be-functionalized carbon. Of these examples, a simple way to categorize these examples is by the position of C–H functionalization relative to the amine.  The majority of examples focus on the α-C(sp3)–H functionalization of amines. Pioneering examples include amine alkyl group exchange via C–H activation,133 carbonylation of tertiary N-pyridyl amines (Scheme 2.2a),134 and oxidative functionalization of tertiary amines with cyanide,135 alkenes,136-137 alkynes,138-139 and acidic carbon nucleophiles in a cross-dehydrogenative-coupling (Scheme 2.2b).140-142 Other examples include Fe-catalyzed oxidative coupling of tertiary methyl amines with heteroarenes,143 and Ru-catalyzed arylation of tertiary N-pyridyl amines.144 An important contribution of a Rh-catalyzed carbenoid insertion into an α-C–H bond of a tertiary amine has been reported as a late stage functionalization of brucine (a R1R1 CHO R1 N R2R1 NHR2[LM] catalystH2/CO(syngas)H2NR2H2/CO H2/COH2NR2– H2O(syngas)H2NR2R1[M] catalystfdjkasl;fR1HNR2and/orHNR2R1R2BrR1[Pd] catalystfdjksfl;aNR3R1NHR3R2HydroaminomethylationHydroaminationBuchwald-Hartwig Amination44  cytotoxic alkaloid).145 Recently, significant advances have been made in this chemistry by utilizing photo-redox catalysis and photo-redox dual-catalysis.146 This strategy has allowed for diverse α-functionalization of tertiary amines allowing for functionalization with nitromethanes (Scheme 2.2c),147 cyanoaromatics,148 aryl halides,149-150 anhydrides (Scheme 2.2d),151 and an oxidative cyclization via combined α-C(sp3)–H and β-C(sp2)–H activations of N,N-dialkyl anilines  (Scheme 2.2e).152 Others have developed intriguing examples that functionalize amine C–H bonds at positions further away from the amine. Reactions that functionalize the β-C–H bond of amines include Pt-catalyzed cyclization of amino acids,153 and Pd-catalyzed aziridination, β-lactonization, and arylation of sterically constrained aliphatic amines lacking α-C–H bonds (Scheme 2.3a).154-156 Others have developed late-transition-metal catalyzed reactions that Scheme 2.2 Examples of metal-catalyzed α-C–H functionalization of amines NN+ CO +4 mol% [Rh(cod)Cl]2iPrOH, 160 °C NNOMurai, S.; et al.N Ar+OOOO RR1.2 eq tBuOOH5 mol% CuBrDecaneRoom Temp.N ArOOOORRLi, C.–J.; et al.N Ar+ Me NO2N ArNO21 mol% [Ir(ppy)2(dtbbpy)][PF6]Visible LightNeatRoom TempStephenson, C. R. J.; et al.1 mol% [Ir(ppy)2(dtbbpy)][PF6]5 mol% [Ni(cod)2]7.5 mol% dtbbpy1.5 eq. quinuclidineDMF, 25 °C34 W blue LEDsR1 NR2Ph1.2 +EtOEtOO R1 NR2PhOEtODoyle, A. G.; et al.NOO+N2.05 mol% [Cu(dap)2][Cl]2 eq. TFADMF, room temp, airgreen LEDsNNOOR1 R2R2R1HHBissember, A. C.; et al.(a)(b)(c)(d)(e)45  perform terminal selective activation such as the Ir-catalyzed α-, β-, or γ-C–H borylation of tertiary amines,157 and Pd-catalyzed β-, γ-, and δ-hydroxylation of aliphatic amines.158 Additional examples of selective functionalization include the γ-acetylation of 4-ethyloxazolidines,159 and γ-arylation of tertiary piperidines and 3-methyl-3-azabicyclo[3.1.0]hexanes (Scheme 2.3b).160 A different approach involves the conversion of a free amine into an intermediate product containing a directing group in the reaction mixture, using a catalytic amount of the directing group precursor. Both examples are Pd-catalyzed and generate an imine in situ allowing for the δ-arylation of primary aliphatic amines from aryl iodides,161 or diaryliodonium salts.162 Notably many of these selective examples utilize designed steric constraints to effectively direct the selectivity of the metal-mediated C–H activation event. Scheme 2.3 Use of steric control for selective C–H functionalization  2.1.1 Early-Transition-Metal Hydroaminoalkylation Absent from the above discussions are C(sp3)–H activation and functionalization with alkenes to form alkylation products. As this reaction is the focus of this chapter and the next, a detailed discussion is necessary. ONN(p-CF3C6F4)H 10 mol% Pd(OAc)23 eq. CsOPivt-AmylOH130 °C+ Ar IONN(p-CF3C6F4)Ar[Pd]NONp-CF3C6F4 ‡viaSanford, M. S.; et al.Gaunt, M. J.; et al.5 mol% Pd(OAc)2PhI(OAc)2, Ac2OToluene80°CONHOCH3R1R3 R2ONOR1R3 R2ONOR1R3 R210 mol% Pd(OAc)210 mol% Cu(OAc)2CO/airToluene, 120 °COR1 = MeN [Pd]OOHvia‡(b)(a)46  The catalytic α-C(sp3)–H activation of amines and subsequent α-alkylation with an alkene is commonly referred to as hydroaminoalkylation. This atom-economical approach involves the direct activation of an α-C(sp3)−H bond and its subsequent addition across an alkene unsaturation in an intra- or intermolecular fashion (Scheme 2.4). This method of C–H activation produces complementary products to the examples previously discussed. Importantly, this reaction is 100% atom-economical, and therefore does not produce stoichiometric waste byproducts. Scheme 2.4 Inter- and intra-molecular variants of hydroaminoalkylation First noted in the early 1980’s using homoleptic early-transition-metal amido complexes of the type Zr(NMe2)4, Nb(NMe2)5, Ta(NMe2)5, and W2(NMe2)6/W(NMe2)6, these reactions produced only single digit turnovers for the alkylation of dimethylamine with 1-pentene or 1-hexene.163-164 Since then significant developments have occurred, with the majority of research focused on early-transition-metal catalysts for both the inter- and intra-molecular variants of this reaction.  NHR1HR3R4R2+NHR1R2R3R4NHR1R2R4R3CatalystblankNH2R1NH2R1NH2R1HHNR1 HNR1CatalystblankHydroaminoalkylationProductsCompetingHydroaminationProductsTwo Possible RegioisomersIntermolecular HAA of Secondary AminesIntramolecular HAA of Primary AminesIf R4 = HBranchedIsomerLinearIsomer47  The intramolecular hydroaminoalkylation reaction has been focused on Ti and Zr based catalysts.165 Initially reported as a competing reaction pathway in hydroamination reactions with primary amino-alkene substrates,166-168 ligand modifications and reaction conditions have been improved to be able to selectively access the C–H functionalization of hydroaminoalkylation over the N–H functionalization of hydroamination (Scheme 2.5).19,169 However, these reactions are limited to the formation of the kinetically favoured 5- and 6-membered hydroaminoalkylation cyclization products over the 6- and 7-membered hydroamination cyclization products, respectively. NOPh NOPhTiNMe2NMe2H2NPhPh+HNPhPh2.1H2NPhPh20 mol% 2.1Toluene110 °CHAA:HA14:1Schafer, L. L.; et al.NNNNTiNMe2NMe22.2NHRNHR 5 mol% 2.2n-hexane140 °CR = Ar, CH2CH2PhDoye, S.; et al.Scheme 2.5 Intramolecular hydroaminoalkylation reactions 48  The intermolecular variant of this reaction with secondary amines has seen significantly more development. Practical turn-over numbers (15-20) were originally achieved with the realization that N-methyl anilines were effective hydroaminoalkylation substrates with a variety of terminal alkenes and norbornene.170 Numerous Ti, Nb, and Ta metal complexes have since been developed for this reaction utilizing a variety of ligand substitutions and motifs (Figure 2.1).170-176 The use of Ti(NMe2)4 and TiBn4 initially focused on the use of N-methylaniline derivatives and terminal alkenes. However, these Ti catalysts suffered from poor selectivity between the branched and linear regioisomers (Figure 2.1).167-168 Significant improvement in regioselectivity for the branched hydroaminoalkylation product was found by using Ti(Ind)2Me2 and 2.3 as catalysts.177-178 The use of ligands with increased steric bulk is proposed to be the reason for the improved selectivity toward the branched product. By comparison, in situ generation of 2.1 results in large substrate scope but poor selectivity, generally favouring the linear isomer. Figure 2.1 Early-transition-metal catalysts used for the intermolecular hydroaminoalkylation of secondary amines Ti MeMeTi(NMe2)4 Ti(Bn)4TiNNNNPhNHPhNNPh HN PhONTaNMe2NMe2NMe2NMe2TaPhMeNPhMeN ClClClClTa NMePhNMePhClClOOSiPh2MeSiPh2MeMNMe2NMe2NMe2NHMe2EtONPOTaEtOMeClMe MeTaMe3Cl2Ta(NMe2)5NOArN OArTaNMe2NMe2NMe2Ar = Mes2.8TaNMe2NMe2NMe2NArOONArTi(Ind)2Me22.32.52.6Ar = Dipp2.7M = Nb, Ta2.92.102.11NN DippDippTiNNN2.449   Group 5, in particular Ta, has seen significant advances from the first synthetically useful report utilizing Ta(NMe2)5.170 Generally, group 5 catalysts provide almost exclusively the branched regioisomer, with some exceptions for styrenes and vinyltrimethylsilane as the alkene substrates.175 The use of 2.5 expands the substrate scope to include dialkylamines; to date, utilizing 2.5 provides broadest scope for dialkylamines.171 Notably, 1,3-N,O-chelating ligands (as either amidates or phosphoramidates) provide highly active hydroaminoalkylation catalysts. Of note, 2.6 exhibits remarkable stability, allowing for increased reaction temperatures and extended reaction time for challenging substrates. Complex 2.6 is the only catalyst reported for the hydroaminoalkylation of cyclic secondary amines such as piperidine, piperazine, morpholine, etc.172,179 While 2.6, 2.7, and other chiral biaryl-bisamidate Ta complexes provide good enantioselectivies,173,180-181 the BINOLate complexes 2.9 and 2.10 provide good to excellent enantioselectivities (up to 98 %ee for certain substrates) for hydroaminoalkylation of N-methylaniline derivatives with a broad scope of alkene coupling partners.174,182 Notably, 2.10 is the only reported catalyst that exhibits room temperature hydroaminoalkylation reactivity.   Additionally, a cationic Sc complex has recently been reported for the hydroaminoalkylation of trialkyl tertiary amines with a variety of terminal alkenes. This system exclusively provides for the branched regioisomer with all alkene substrates except styrene derivatives and allyltrimethylsilane, which give the linear regioisomer selectively (Scheme 2.6).183-184 NR2R1R3+[Sc(CH2C6H4-o-NMe2)3] 5 mol%[Ph3C][B(C6F5)4] 5 mol%Toluene70 °CNR2R1R3or NR2R1R3R1, R2 = alkyl when R3 = Ar, SiMe3Scheme 2.6 Sc catalyzed hydroaminoalkylation of trialkyl amines 50  The proposed mechanism for early-transition-metal catalyzed hydroaminoalkylation is has been adopted for all group 4 and 5 catalyst systems. Figure 2.2 shows a simplified proposed mechanism for intermolecular hydroaminoalkylation with secondary amines (relevant to the results presented within this thesis).164,174,185 Entry into the active catalytic cycle occurs via ligand exchange to ligate the substrate amine to the metal center, followed by C–H activation via hydrogen abstraction by an adjacent amido ligand to give tantalaziridine A. Insertion of the alkene into the reactive Ta-C bond forms metallacycle B. Subsequent protonolysis of the Ta–C bond with incoming amine substrate generates C. Another C–H activation event allows for release of the significantly larger product amine, releasing steric strain around the metal center, and regenerating the reactive tantalaziridine moiety. In this proposed mechanism, there is no change in oxidation state of the metal center. This contrasts with the proposed mechanism for the many late-transition-metal-catalyzed hydroaminoalkylation reactions (Figure 2.3).   [M] CH2NR[M]NRR'BA[M]NNRR'CH3R CR'NHRH3CProtonolysisInsertionC-H Activation andProduct ReleaseRHN R'C–H Activation[M]NMe2N CH3R[M]NMe2NMe2HNMe2HNMe2HNRMeProductiveCatalytic CycleAmido LigandExchangeFigure 2.2 Proposed mechanism for early-transition-metal catalyzed hydroaminoalkylation 51  2.1.2 Late-Transition-Metal Hydroaminoalkylation  Significant advances in hydroaminoalkylation chemistry have also been made with late-transition metal catalysts.137,186-197 With few exceptions, development of this methodology has occurred utilizing Ru and Ir catalyst systems, with the majority of examples requiring the use of N-pyridyl secondary and tertiary amines (Scheme 2.7).137,186-190,193-194 The pyridyl group in these examples acts as a directing group, and encourages coordination and activation of the substrate by placing the α-C(sp3)–H bond in the proper orientation for the C–H activation event.  These examples are proposed to proceed through a mechanism involving 2e– oxidative and reductive processes at the metal center (Figure 2.3).186-188 In this mechanism, coordination of the substrate via the pyridyl moiety occurs. C–H activation via oxidative addition occurs to generate the 5-membered metallaacycle (A to B). The alkene then inserts into the M–H bond. Importantly, if internal, alkyl functionalized alkenes are utilized, chain walking will occur until the M–C bond is at the terminal carbon. This is followed by a reductive elimination (C to D), product de-coordination, and regeneration of the metal catalyst. Due to the chain-walking N N HPh+ R1R2Ru3(CO)12 10 mol%Toluene, 130 °CN N HPhR2R1Jun, C.–H.; et al.N N H + Ar[Ir(cod)2][BF4] 10 mol%(S)-tolBINAP 10 mol%DME75-85 °CN N H*ArShibata, T.; et al.up to 90 %eeN N N N+ RR = alkyl, Ar,Cl, Br, OMe, OTs[RuCl2(PPh3)3 5 mol%BINAP 6 mol%AgOTf (12 mol%)i-BuOH80-120 °C RAckermann, L.; et al.Scheme 2.7 Ru and Ir catalyzed hydroaminoalkylation utilizing N-pyridyl directing groups 52  mechanism, this mechanism is consistent with the observed linear products. This is in direct contrast to the early-transition-metal catalyst that can selectively result in the branched regioisomer.  Interestingly, a Ru-catalyzed reaction of 4-aminobutanol with dienes results in 2-allyl pyrrolidine hydroaminoalkylation products (Scheme 2.8a). This communication also provides one example where pyrrolidine undergoes direct C(sp3)–H functionalization with dienes. Another recent report utilizes dienes as the unsaturated coupling partner.195 Alternatively, photo-redox dual-catalysis (Ir photo-catalyst, Co-catalyst system), allows for the hydroaminoalkylation of dienes with tertiary amines with broad substrate scope (Scheme 2.8b).197 It should be noted that these examples follow a different mechanism than presented in Figure 2.3.    While the focus of this thesis is the catalytic transformation of amines, it is also important to mention other late-transition-metal-catalyzed reactions of other nitrogen functional groups (e.g. amides, ureas, sulfonamides, etc.), upon stoichiometric deprotection, can result in alkylated N N HR1[M]HN N HR1[M]AR2N N HR1[M][Ir(I)] or [Ru(0)] + N N HR1NNHR1[M]R2 BCDCoordinationC–H ActivationR2InsertionC–C Bond FormationProduct De-coordinationN N HR1R2Figure 2.3 Proposed mechanism for directed, late-transition-metal catalyzed hydroaminoalkylation 53  amine products. Of direct relevance to this discussion is the Ru-catalyzed hydroalkylation of hydantoin with dienes,192 Pd-catalyzed β-alkylation of protected amino-amides (from unnatural amino acids) with alkenes,198 Ir-catalyzed α-alkylation of N-alkoxythiocarbonyl functionalized aza-heterocycles,199 and the β-alkylation (α to N) of ureas with alkenes.200 These reactions avoid the inherent basicity and reducing potential of free amines that can negatively impact transition-metal-catalyzed reactions. 2.1.3 Scope of Chapter Complex 2.5, and the related [Ta(NEt2)2Cl3], are both reported to exhibit similar reactivity.171 These complexes are interesting as they exhibit high reactivity for dialkyl amine substrates. Most catalyst systems reported to date struggle with these non-aniline derivatives. Additionally, 2.5 exhibits good reactivity at lower temperatures with N-methylaniline as a substrate, which is only equaled by the exceptional 25 °C reactivity of 2.11.175 Notably, 2.11 also utilizes a chloro ligand. While the role of the chloro ligand is not fully understood, its inclusion appears to be important for broad substrate scope and high activity. 2-Pyridonate ligands have been utilized as ligands on Ti and Zr precatalysts,19,166 but have not been explored on Ta precatalysts for hydroaminoalkylation. We desired to explore the R1R2R1, R2 = alkyl+ NH2OHRuHCl(CO)(PPh3)3 5 mol%dCypp 5 mol%Toluene110 °CTosylationR1R2up to >20:1 drTsNR12 ExamplesR1 = H, MeRuH2(CO)(PPh3)(dppp) 5 mol%FcCOOH 5 mol%Toluene130 °CTosylation+ HNR1R2TsNR1 = H, 8:1 drR1 = Me, 5:1 dr(a)CoBr2 10 mol%dppp 10 mol%[Ir[(dF-CF3ppy)2(dtbbpy)][PF6] 0.5 mol%CsOPivMeCNBlue LEDsNR1R2R3OR4O+ OR4ONR3R1R2(b)Scheme 2.8 Late-transition-metal catalyzed hydroaminoalkylation without a directing group 54  use of 2-pyridonate as ancillary ligands on Ta complexes for hydroaminoalkylation. Additionally, we wished to create complexes that did and did not contain chloro ligand(s) in an attempt to determine the role of the chloro ligand in hydroaminoalkylation precatalysts. Thermal robustness also appears to be important for broad substrate scope, so complexes with amido ligands are targeted.  This chapter reports the synthesis and catalytic studies of a variety of 2-pyridonate Ta complexes that are the only reported complexes that exhibit broad substrate scope for the hydroaminoalkylation of internal alkenes that occurs without isomerization of the alkenes. These complexes revealed a substrate/precatalyst dependence for optimal activity. Kinetic and deuterium labelling investigations reveal that off-cycle equilibria limit the activity of the discovered precatalysts. 2.2 Results and Discussion 2.2.1 Development of a Novel 2-Pyridonate Precatalyst for the Hydroaminoalkylation of Internal Alkenes Scheme 2.9 Synthesis of 2-pyridonate Ta complexes TaNOPhNNNNTaNOPhNNNCl[Ta(NMe2)3Cl2]2 +0.5 NOPhNa TolueneRT, 12 hTa(NMe2)5 + NHOPh TolueneRT, 12 h(a)(b)2.1270%2.1382%Dr. Eugene Chong developed the synthesis of 2.12 and 2.1355  Dr. Eugene Chong discovered a route for the selective synthesis of 3-phenyl-2-pyridonate complexes of Ta (Scheme 2.9). Intriguingly, complexes 2.12 and 2.13 show complementary reactivity toward terminal and internal alkenes (Scheme 2.10). Complex 2.12 shows high reactivity with cyclohexene, while complex 2.13 shows better reactivity with 1-octene.   To date, few complexes have been demonstrated to be active catalysts for the hydroaminoalkylation of secondary amines with unactivated internal alkenes (multiple complexes have been reported to catalyzed the hydroaminoalkylation with highly strained norbornene as a substrate). Complex 2.6 is reported to undergo hydroaminoalkylation of N-methylaniline with 1,5-cyclooctadiene (83%, 96 h, 165 °C).172 TaMe3Cl2 is reported to undergo the hydroaminoalkylation of N-methylaniline with cyclooctene (73%, 102 h, 110 °C), cycloheptene (83%, 30 h, 110 °C), cyclohexene (88%, 47 h, 145 °C), and Z-3-hexene (65%, 36 h, 145 °C).176 As reported in an initial communication, Ti complex 2.4 is reported to undergo hydroaminoalkylation of cyclopentene with N-methylaniline (75%, 96 h, 180 °C), cyclohexene (72%, 96 h, 180 °C), 1,4-cyclohexadiene (93%, 96 h, 180 °C), and E-2-octene (16% mixture of isomers, 96 h, 180 °C). Notably, 2.12 demonstrates significantly increased the turnover frequency compared to known examples.  Scheme 2.10 Complementary catalytic reactivity of 2.12 and 2.13 with cyclohexene and 1-octene HN HN1.5Precatalyst5 mol% [Ta]d8-toluene110 °C, 24 h+HN HN1.5Precatalyst5 mol% [Ta]d8-toluene145 °C, 20 h+2.12 – 40%2.13 – >95%2.12 – >95%2.13 – 10%αα ααββHH(a)(b)Dr. Eugene Chong performed the catalysis in this scheme56  To ensure our results were a product of 2.12 and not due to reaction conditions, we attempted the reaction of N-methylaniline and cyclohexene with known for hydroaminoalkylation precatalysts (Scheme 2.11). To our surprise, only a few complexes produced any conversion at our catalyst loading (5 mol%) under our reaction conditions (sealed vessel, 20 h, 145 °C) highlighting the efficacy of 2.12.  Scheme 2.11 Hydroaminoalkylation of cyclohexene with known precatalyst under our conditions   We next turned to elucidating the substrate scope of 2.12 as a precatalyst. To explore the alkene scope, we utilized N-methylaniline as the amine substrate (Scheme 2.12). Gratifyingly, 2.12 is able to catalyze the hydroaminoalkylation of a wide variety of internal alkenes. Cyclo-pentene, -hexadiene, -heptene, -octene, and –dodecene are all tolerated in good to excellent yields. Both E- and Z-3-hexene react giving the desired products in 79% and 69% yields, respectively, while requiring longer reaction times of 44 h than their cyclic counterparts. Here Z-3-hexene is less reactive, producing a lower yield. These linear alkenes, represent the first examples of hydroaminoalkylation of these substrates that produce the β-branched products, and avoid chain-walking to produce the linear coupled products. Unsymmetrical alkenes 2-silylether-Z-4-hexene, cis-β-methylstyrene, and trans-anethole react in good to excellent yields albeit with Precatalyst5 mol% [Ta]d8-toluene145 °C, 5 hHN + 1.5HNTa(NMe2)5n.r.[Ta(NEt2)2Cl3]2n.r. 6%[Ta(NMe2)3Cl2]2 TaMe3Cl23%ONTaNMe2NMe2NMe2NMe22.6EtONPOTaEtOMeClMe Me2.11NOPh NOPhTiNMe2NMe22.1n.r.n.r. 4%NNH + Ti(NMe2)4in situ prepartion(1:1) n.r.(2:1) n.r.Reaction conditions: N-methylaniline (0.5 mmol), cyclohexene (0.75 mmol), [Ta] precatalyst (0.025 mmol), d8-toluene (0.5 mL). Conversion was determined by 1H NMR spectroscopy.I synthesized the above complexes and performed the catalysis in this scheme.57  limited regioselectivity. Here, silyl ether functionality is tolerated, and the first examples of β-styrenes to undergo hydroaminoalkylation are presented. 1,1-Disubstitued alkenes are also tolerated with complete regioselectivity. In particular, (1S)-β-pinene undergoes hydroaminoalkylation with high diastereoselectivity. Scheme 2.12 Alkene substrate scope for the hydroaminoalkylation catalyzed by 2.12  Scope in amine substrate was explored using E-3-hexene (Scheme 2.13). Increasing the precatalyst loading to 10 mol% allows for 91% yield in 24 h reaction time with N-methylaniline. Multiple N-methylaniline derivatives are tolerated in excellent yields. Notably, sterically encumbering 2-methyl substituents are tolerated in good yields. 4-Fluoro, -chloro, -methoxy, and -trifluoromethoxy result in high yields. 4-Bromo-, and 3,4-dimethoxy-N-methylanilines are tolerated but in low yields. Tetrahydroquinoline results in an excellent yield and produces a TaNOPhNNNClHN+HNR1R2Catalyst5 mol% [Ta]d8-toluene145 °C, time1.5R1R22.12PhHN PhHN PhHN44 h73%3.0 eq diene20 h72%20 h93%HNPhfrom E/Z mixture44 h88%cis or transPhHN PhHNfrom E44 h79%from Z44 h69%PhHN OTBSfrom Z44 h70%a(2.3:1)b4PhHN Phfrom Z20 h92%a(4.4:1)bPhHN130 °C20 h93%PhHN PMPfrom Z44 h76%a(2.0:1)bPhHN110 °C20 h91%54 h55%c(15.9:1 d.r.)dPhHNReaction conditions: N-methylaniline (0.5 mmol), cyclohexene (0.75 mmol), [Ta] precatalyst (0.025 mmol), d8-toluene (0.5 mL). Isolated Yields. (a) Major regioisomer represented. (b) Regioselectivity determined by GC analysis. (c) Major diastereomer represented. (d) diastereomeric ratio (d.r.) determined by GC analysis.Initial preparation of substrates and initial reactivity was a collaborative effort between Dr. Eugene Chong and myself. Dr. Eugene Chong performed the final isolation of the compounds.58  single diastereomer. Dialkyl N-methylcyclohexylamine, and N-methyl-N-butylamine result in 88% and 64% yields, respectively, but requires extended reaction times and 165 °C reaction temperature for the latter. Scheme 2.13 Amine substrate scope for hydroaminoalkylation catalyzed by 2.12  Unfortunately, we did observe some substrate scope limitations. Reactivity was tested with 5 mol% 2.12 using N-methylaniline for alkene substrates and E-3-hexene for amine substrates (Scheme 2.14). The trisubstituted alkene, 2-methyl-2-butene, as well as a vinylether were both unreactive to hydroaminoalkylation. Multiple amines were also unreactive. N-methyl-tert-butyl amine, and heterocycles pyrrolidine, piperidine, and azetidine also did not react. Catalytic hydroaminoalkylation with 2-methyl-2-butene or N-methyl-tert-butyl amine have not been reported in the literature. We propose that steric hindrance prevents reactivity with these two substrates. N-heterocycles have successfully been used as substrates in Ta catalyzed hydroaminoalkylation.172,179 At this time, we do not have an explanation for the lack of activity TaNOPhNNNClR1HN +Catalyst10 mol% [Ta]d8-toluene145 °C, 24 h1.52.12R2 R1HNR2HNHNFHNCl92 h70 %84% 78%HNMeO 81%HNF3CO 62%HNMeO31%MeOHN(+/-)H82%HN44 h88%HN92 h165 °C64%HN91%HN92%HNBr 24%Reaction conditions: N-methylaniline (0.5 mmol), cyclohexene (0.75 mmol), [Ta] precatalyst (0.025 mmol), d8-toluene (0.5 mL). Isolated Yields.Initial preparation of substrates and initial reactivity was a collaborative effort between Dr. Eugene Chong and myself. Dr. Eugene Chong performed the final isolation of the compounds.59  with 2.12. Amines with benzylic methylenes were also unproductive substrates. However, we did observe that exposing catalytic amounts of N-methylbenzylamine to 2.12 results in decomposition of 2.12 and formation of new organotransition metal species. Attempts to isolate these species were unsuccessful. A catechol protected aniline derivative, 1,4-di-(N-methylamino)benzene, and 4-N-methylaminopyridine did not result in productive catalysis, but significant decomposition of these amine starting materials was observed. Scheme 2.14 Substrate scope limitations for hydroaminoalkylation catalyzed by 2.12  2.2.2 Exploration of 2-Pyridonate Ligand Effects on Hydroaminoalkylation Catalysis In an effort to better understand the effect of the pyridonate ligand, a systematic investigation of the steric and electronic properties of 2-pyridonate ligands was undertaken. Given the high reactivity of 2.12 with internal alkenes, we synthesized a variety of (2-pyridonate)Ta(NMe2)3Cl complexes (2.14 – 2.19, Scheme 2.15a). Previous work on 2-pyridonate Ti complexes have shown that substituent effects at the 3 and 6 positions on the pyridonate ligand can dramatically affect intramolecular hydroaminoalkylation.19 In an effort to explore the role of the chloride ligand we also synthesized complex 2.20, featuring an axial triflato ligand.  HNOONNHHNNHONHHNNHNHTaNOPhNNNClR1HN +Catalyst5 mol% [Ta]d8-toluene145 °C, 24 h1.5R52.12R4R3R2Amine scope uses E-3-hexeneAlkene scope uses N-Me anilineHNxx = 1-3No DesiredProductReaction conditions: N-methylaniline (0.5 mmol), cyclohexene (0.75 mmol), [Ta] precatalyst (0.025 mmol), d8-toluene (0.5 mL).I performed the attempted catalysis in this scheme.60  Scheme 2.15 Synthesis of new Ta complexes 2.14-2.20 Complexes 2.14 – 2.19 can be prepared via salt metathesis in the same manner as 2.12. To prepare complex 9, complex 1 can be reacted with silver triflate in dichloromethane to produce the desired tantalum triflato analogue (Scheme 2.15b). All resultant complexes were prepared in good yield and were fully characterized by 1H and 13C NMR spectroscopy, EI-MS, and EA. In the solution phase, the three inequivalent dimethylamido ligands in all complexes give rise to a single, broad resonance in both the 1H and 13C NMR spectra. This is due to rapid isomerization of the dimethylamido ligands.        TaNOMesNNNClTaNOMeNNNClTaNONNNClPhTaNONNNClMe2.1866%2.1976%2.1484%2.1580%TaNOF3CNNNCl2.1676%2.1784%TaNONNNClHHTaNOPhNNNOTf2.2061%[Ta(NMe2)3Cl2]2 + NOR1R2Na TolueneRT, 12 h0.5Recrystalized YieldTaNONNNClR2R1TaNOPhNNNCl2.12+ AgOTfDCMRT, 12 h(a)(b)61  Complex 2.12 2.15 2.16 2.18 Ta–N1 (Å) 2.288(4) 2.307(1) 2.295(3) 2.301(1) Ta–O1 (Å) 2.129(2) 2.122(1) 2.155(2) 2.191(2) N1–Ta–O1 (°) 59.30(9) 59.76(5) 59.4(1) 59.13(6) Ta–Cl (Å) 2.4959(8) 2.4931(5) 2.476(1) 2.4643(6) Av. Ta–NMe2 (Å) 1.962(8) 1.97(1) 1.97(1) 1.97(1) C1–N1 (Å) 1.344(4) 1.364(2) 1.349(4) 1.360(3) C1–O1 (Å) 1.298(4) 1.315(2) 1.304(5) 1.302(2) Table 2.1 Comparison of key bond lengths and angles of the solid state molecular structures of 2.12, 2.15, 2.16, and 2.18 Crystals suitable for single crystal X-ray diffraction of complexes 2.15, 2.16, and 2.18 were obtained (Figure 2.4). Each complex adopts a distorted octahedral geometry and shares similarity with the previously complex 2.12. The facial arrangement of the dimethylamido ligands can be attributed to p-bonding effects, as the p-donating amido ligands are all trans to ligands with minimal p-donating ability. A comparison of key bond lengths and angles (Table 2.1), shows that any substituent induced variance in the binding of the pyridonate, chloride, or amido is small in the solid state. Of note, is the extended Ta–O1 bond lengths in complex 2.16 and 2.18 and concomitant shortening of the Ta–Cl bond lengths. Due to the fact that that 2.16 has an electron withdrawing trifluoromethyl group in the 3-position while 2.18 has an electron withdrawing phenyl group in the 6-position, we suggest this distortion is caused by electron withdrawing character coupled with steric effects in 2.18. However, these changes are subtle and we are unable to rule out the possibility that crystal packing effects dominate the observed metrics. We were unable to obtain crystallographic data for all complexes and have assigned the geometries of the remaining complexes by analogy.   62  Figure 2.4 ORTEP representations of 2.15 (top-left), 2.16 (top-right), and 2.18 (bottom) The catalytic activity of these complexes was assessed with the preferred benchmark reactions of N-methylaniline with cyclohexene (Scheme 2.16) and 1-octene (Scheme 2.17). Complex 2.12 has been shown to promote the reaction with cyclohexene in >95% conversion (145 °C, 20 h), and with 1-octene in 40% conversion (110 °C, 24 h). Reaction times of 5 h (Scheme 2.16) and 24 h (Scheme 2.17) were selected to give conversions that would allow for ready comparison of the ligand environments. Thus, the reported conversions do not represent optimized yields. Turnover frequencies (TOF) were calculated based on the given reaction times and do not represent exhaustive study. Turnover numbers were not determined. Scheme 2.16 Hydroaminoalkylation activity of new precatalyst complexes with cyclohexene substrate  Precatalyst5 mol% [Ta]d8-toluene145 °C, 5 hHN + 1.5HN[Ta] ComplexConversionTOF2.1232%1.32.1436%1.42.1539%1.62.1613%0.52.1733%1.32.185%0.22.1915%0.62.208%0.3Reaction conditions: N-methylaniline (0.5 mmol), cyclohexene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol), d8-toluene (0.5 mL). Conversion determined by 1H NMR spectroscopy. Average of two experiments, see experimental section. TOF (h-1) = turnover frequency = turnovers/time. TOF presented here is non-exhaustive.Thermal ellipsoids are shown at 50%. H-atoms omitted for clarity.  63  Scheme 2.17 Hydroaminoalkylation activity of new precatalyst complexes with 1-octene substrate Results with cyclohexene reveal that altering the steric parameters at the 3-position (2.12, 3-phenyl; 2.14, 3-mesityl; 2.15, 3-methyl; 2.17, 3-hydro) of the pyridonate ring result in only minor differences in reactivity. Surprisingly, 2.16 (3-trifluoromethyl) results in low conversion. Analysis of the 19F NMR spectrum after the reaction showed various signals in the region of 50-100 ppm. This suggests the formation of Ta–F complexes,201 via catalyst decomposition. Altering the 6-position (2.18, 6-phenyl; 2.19, 3-methyl) of the pyridonate results in a significant decrease in reactivity. This detrimental effect on catalytic performance is proposed to be due to the added steric congestion at the metal center, thereby hindering reactivity with the sterically demanding internal alkene substrate. The use of 2.20 results in poor conversion. In this case, no Ta–F complexes could be observed by 19F NMR spectroscopy at the end of the catalytic reaction.   Using a terminal alkene, 1-octene, as a substrate provides significantly different results (Scheme 2.17). A marked increased in conversion occurs where the steric parameter is reduced in the 3-position of the pyridonate (2.15 and 2.17). Intriguingly, increasing the steric parameter of the pyridonate in the 6-position (2.18 and 2.19) also provides high conversion with this less sterically demanding terminal alkene substrate. As with the cyclohexene substrate, the triflato complex 2.20 provided disappointing reactivity with 1-octene. Complexes 2.15 and 2.17 are the first examples of highly active catalysts for both internal and terminal alkenes. These complexes offer a minimal increase over our previously reported complex 1 for reactivity with cyclohexene. [Ta] ComplexConversionTOF2.1240%1.62.1592%3.72.17>95%3.82.18>95%3.82.19>95%3.82.2020%0.82.13>95%3.8HN + 1.5HNPrecatalyst5 mol% [Ta]d8-toluene110 °C, 24 h55Reaction conditions: N-methylaniline (0.5 mmol), cyclohexene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol), d8-toluene (0.5 mL). Conversion determined by 1H NMR spectroscopy. Average of two experiments, see experimental section. TOF (h-1) = turnover frequency = turnovers/time. TOF presented here is non-exhaustive.64  However, 2.15 and 2.17 are comparable to 2.13 and are significantly better than 2.12 for reactions with 1-octene. An attractive advantage to 2.15 and 2.17 is the fact that the 2-pyridone proligands are commercially available and inexpensive.  To further elucidate the general reactivity of 2.15 and 2.17, additional reactions with various alkene substrates were completed (Scheme 2.18). By reducing the reaction time to 20 hours with 1-octene (entry 1), the difference in reactivity between 2.15 and 2.17 could be better observed. Gratifyingly, 2.17 produces 86% yield (>95% conversion), while complex 2.15 is slightly less active (63% yield). Reactivity with different internal alkenes (entries 2-6) shows that complex 2.15 is more broadly useful than 2.17. With cyclohexene (entry 2) and cycloheptene (entry 3), 2.15 provides yields of 81% and 93% respectively, in 4 hours less than it takes 2.12 to provide comparable yields (88% and 95% respectively). Complex 2.15 provides slightly less conversion in 24 h than 2.12 (83% vs. 92%) with Z-methylstyrene substrate (entry 5), but more significantly, reduced yields with E-3-hexene (entry 4) and (1S)-b-pinene (entry 6); a 21% and 23% reduction in yield respectively. Both complexes 2.15 and 2.17 offer comparable regioselectively with Z-methylstyrene (entry 5) and diastereoselectivity with (1S)-b-pinene (entry 6), compared to reported complex 2.12.       65  Scheme 2.18 Comparative hydroaminoalkylation reactivity of 2.15 and 2.17 Complex 2.15 is a readily accessible, broadly reactive HAA pre-catalyst, and is the first catalyst system offering excellent reactivity profiles with both internal and terminal alkenes.  However, efforts to optimize reaction yields for specific amine/alkene substrate combinations demanded empirical screening and few reliable reactivity trends could be determined. To improve our predictive ability to select and design optimized catalyst systems, mechanistic investigations were undertaken. 2.2.3 Mechanistic Interpretation We, and others, have proposed a simplified catalytic cycle for hydroaminoalkylation as presented in Figure 2.2. Kinetic mechanistic research by Hultzsch and co-workers on a tantalum BINOLate complex concluded that the rate determining step(s) for their system is either a TaNOMeNNNClTaNONNNClHH2.15 2.17Catalyst5 mol% [Ta]d8-toluenetemp, timeHN + 1.5 HNR2R1R2R1PhHN 63% 86%PhHN 81% 44%PhHN 58% 31%from E-3-hexenePhHN 83% (3.0:1)a,b 29% (3.7:1)a,bfrom Z-methylstyrenePhHNPh32% (20:1)c,d 14% (>20:1)c,dProductsPhHN 93% 95%110 °C20 h145 °C16 h130 °C16 h145 °C44 h145 °C24 h145 °C54 hConds.5123456EntryReaction conditions: N-methylaniline (0.5 mmol), alkene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol), ferrocene (0.05 – 0.11 mmol), d8-toluene (0.5 mL). Yield determined by 1H NMR spectroscopy with Cp2Fe internal standard. a) Major regioisomer shown. b) Ratio determined by 1H NMR analysis. c) Major diastereomer shown. d) Ratio determined by UHPLC analysis. Average of two experiments, see experimental section.66  combined rate constant for conversion of A to C, or amido exchange with C to release product (Figure 2.2).174 Their work also shows that the rate determining step is influenced by substrate.  We propose that the introduction of the planar pyridonate and the chloro ligands (complex 2.12) reduce the steric constraints for the insertion step (A to B), or protonolysis step (B to C) allowing for productive catalysis with sterically demanding internal alkenes. These two steps both involve high steric congestion of the metal center, where complexes of the type [(2-pyridonate)Ta(NMe2)3Cl], provide the necessary steric relief for catalytic turnover. The decreased reactivity shown by 6-phenyl (2.18) and 6-methyl (2.19) with cyclohexene can be explained by the increased steric constraints imparted by 6-substituted-2-pyridonates on the metal center. When utilizing the less sterically demanding terminal alkene substrate, 1-octene, complex 2.12 shows markedly reduced reactivity when compared to 2.13. We proposed that the overall steric congestion at the metal center in 2.13 (effected by the replacement of the chloro ligand with an amido ligand) is required for effective catalytic turnover when employing sterically less demanding terminal alkenes. Unlike the simple picture employed in Figure 2.2, we suggest the equilibrium between off-cycle and on-cycle tantalum species lies heavily towards the off-cycle species. This has the effect of lowering the reaction rate as the concentration of on-cycle species is low at any time during the reaction. Additionally, these off-cycle species are involved in multiple equilibria with rapid exchange of all amines present in solution. The increased congestion at the metal center in 2.13, as well as in 6-substituted-2-pyridone complexes 2.18 and 2.19, encourages product amine to be released from the metal center, resulting in a higher concentration of substrate amine bound as an amido ligand. We posit that this higher concentration of active species results in the observed increase in reactivity.  67  Intriguingly, the most sterically accessible pyridonate complexes 2.15 (3-methyl) and 2.17 (3,6-dihydro) provide high reactivity for both internal alkenes and 1-octene. In the context of the above rationalizations, the reactivity of 2.15 and 2.17 is unexpected. With internal alkenes, complex 2.12 and 2.15 provide similar reactivity (with modest improvements over 2.17) with substrate dependent variations in reactivity. This suggests the 3-substition of the 2-pyridonate ligand has limited effects with sterically demanding substrates. A major departure occurs with 1-octene substrate. Complex 2.17 exhibits higher reactivity than 2.15, and both demonstrate comparable reactivity to 2.13, despite lacking substituents that would impart increased steric crowding at the metal center. Both 2.15 and 2.17 offer improved conversion over that of complex 2.12. Most likely, complex 2.15 and 2.17 alter the turnover limiting step(s) in a more complex way than is rationalized above. 2.2.4 Investigations into Precatalyst Activation and Off-Cycle Equilibria  Initial investigations focused on probing the amine exchange reaction during the precatalyst activation. To observe precatalyst activation, including amido ligand exchange and the C-H activation reactions, we heated a mixture of 2.15 with N-methylaniline at the catalytically relevant temperature of 110 °C (Scheme 2.19a). We expected to observe the formation of a complex with one or more anilido ligands and concomitant release of dimethylamine. This may have also resulted in the formation of N-phenyl tantalaziridine in situ. Interestingly, not only is there no evidence of tantalaziridine formation, there is no decomposition of 2.15, no consumption of N-methylaniline, and no release of dimethylamine when observations are made at elevated temperatures in the NMR spectrometer with in situ monitoring. This shows that the sterically less demanding dimethylamido ligands (compared to N-methylanilido) are favoured as ligands for this tantalum complex. 68  Scheme 2.19 Deuterium Scrambling Experiment  Previous reports from our group demonstrated that tantalaziridine formation could be promoted by increased steric demand at the metal center, in one case by the addition of a second N,O–chelated, amidate ligand.172 Further, Hultzsch et al. propose that C–H activation is facile and reversible in sterically encumbered BINOLate tantalum catalysts.174 We were curious to see if we could observe facile C–H activation in our systems despite having significantly decreased steric bulk at the metal center. A mixture of complex 2.15 with an excess of d-N-methylaniline was heated at 110 °C for 2 hours (Scheme 2.19b). Here the deuterium of the amine group washes into the methyl groups of the pre-catalyst dimethylamido ligands and into the methyl group of the N-methylaniline substrate as observed by 2H NMR at 3.51 and 2.30 ppm respectively. Furthermore, a mixture of complex 2.15 with N-(methyl-d3)aniline heated to 110 °C for 2 hours results in hydrogen being incorporated into the methyl group of the previously deuterated N-(methyl-d3)aniline (Scheme 2.19c). These results reveal that amido ligand exchange and C–H activation pathways are rapid d8-toluene1) 110 °C, 2 h2) cooled to 25 °C3) 1H NMR Spec.HN CD3+ TaNOMeNNNCl+ N CD325% HD/HNo change(c)6% D1d8-toluene1) 110 °C, 2 h2) cooled to 25 °C3) 1H NMR Spec.TaNOMeNNNCl+ N20% DD/H6% Dd8-toluene1) 105 °C, 2 h2) 1H NMR Spec.at 105 °CTaNOMeNNNCl+HN2.15N+(b) 1DHN+(a) 102.152.152.15–d2.152.15–dDeuterium incorporation determined by 1H NMR spectroscopy and deuteration confirmed by 2H NMR spectroscopy.69  and reversible at catalytically relevant temperatures. Additionally, the experiments presented in Scheme 2.19 conclusively show that an equilibrium is present between 2.15 (precatalyst) and N-methylaniline, and this equilibrium strongly favors 2.15 (to the limit of detection of 1H NMR spectroscopy). All the reactions in Scheme 2.19 have been carried out in the absence of alkene substrate. Previous work from our group has shown that the dimethylamido ligands of the precatalyst are not innocent during catalytic reactions, as they also undergo alkylation via hydroaminoalkylation.176,185 Furthermore, complex 2.15 in the presence of excess 3-hexene and no exogenous amine results in high yields of dialkylated dimethylamine (Scheme 2.20).202 Given the aforementioned facile and reversible amido ligand exchange and C-H activation reactions with 2.15, we questioned how dimethyl amido ligands/free dimethyl amine may affect the desired catalytic alkylation of N-methylaniline. To this end, we set up a series of stoichiometric reactions with complex 2.15, N-methylaniline and increasing amounts of either cyclohexene or 1-octene (Scheme 2.21). These experiments were then heated to 145 °C (cyclohexene) or 110 °C (1-octene) for 3 hours. Scheme 2.20 Isolation of dialkylated byproduct  2.15+24 h, 145 °C30 equivalentsNH75% Isolated YieldTaNOPhNNNClYield relative to 1, which contains 3 equivalents of dimethylamine.70  Scheme 2.21 Stoichiometric experiments with variable equivalents of alkene to determine relative amounts of product and byproduct formation. ++HN 3 h, 145 °CHN R +a (equiv.)0.881.644.19b (% yield) 131932c (% yield)3726NHRRand/orNHR2.15 +RemainingStartingMaterialsa b c++HN 3 h, 145 °CHN R +a (equiv.)1.745.407.02b (% yield)242218c (% yield)79161154NHRRand/orNHR2.15 +RemainingStartingMaterialsa b c5Equivalents for a values, and yields for b and c values (reported relative to initial amount of N-methylaniline) are calculated by 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard. A convoluted alkyl region of 1H NMR spectra prevents direct identification of the dimethylamine functionalized byproducts; they are calculated as such: functionalized byproducts = (alkene remaining) – (aniline product).71  Generally, we observe, a mixture of both products, suggesting the rate of functionalization of N-methylaniline and dimethylamine are comparable, and are in competition with each other for activation in the catalytic cycle. Furthermore, substrate dependent equilibria appear to dominate, as reactions with 1-octene yield significantly more alkylated dimethylamine byproducts than reactions with cyclohexene substrates. We also observe that as alkene equivalents increase, the amount of byproduct formation increases relative to the amounts of product. These experiments show that complex equilibria are at play in these catalytic reactions and amido ligand exchange allows for significant amounts of both product and byproduct formation at initial stages of the HAA reaction.  HN + 1.5HNPrecatalystx mol% 2.15d8-toluene105 °CReaction conditions: N-methylaniline (0.5 mmol), 1-octene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol, 0.04 mmol, or 0.06 mmol), 1,3,5-trimethoxybenzene (0.17 mmol), d8-toluene (0.5 mL). See experimental section for details. Plot of average of two runs. See experimental section for plot of non-averaged data.Figure 2.5 Hydroaminoalkylation Reaction Monitoring with 5, 8, and 12 mol % of [Ta] Precatalyst 2.15 00.10.20.30.40.50.60.70.80.910 50 100 150 200 250 300 350 400 450 500Normalizaed	Concentration	of	PhN(H)Me	and	Product(C/Co)Time	(minutes)Product,	 5	mol%	[Ta] PhN(H)Me,	 5	mol%	[Ta] Product,	 8	mol%	[Ta]PhN(H)Me,	 8	mol%	[Ta] Product,	 12	mol%	[Ta] PhN(H)Me,	 12	mol%	[Ta] 72  Further evidence of such equilibria is presented in Figure 2.5. The catalytic reaction of N-methylaniline and 1-octene with 2.15 can be monitored by 1H NMR spectroscopy at 105 °C. Multiple attempts to monitor the reaction at 145 °C using the internal olefin cyclohexene, were unsuccessful. This included attempts to alter the reaction conditions by scale or by vessel for the purpose of real-time sampling, but resulted in inconsistent and poor yields (ca. <10%). Attempts to use d10-orthoxylenes and monitor the reaction at 140 °C by 1H NMR spectroscopy resulted in poor yields (ca. <10%) for similar reaction times. We believe these results are due to unquantified pressure effects.  Product formation could be observed by the appearance of the diagnostic ortho-H proton signal at 6.41 ppm, with the concomitant consumption of starting N-methylaniline, as observed by the disappearance of the peak at 6.33 ppm. Due to the long reaction times, the reaction monitoring was limited to the first approximately 20% conversion with 5, 8, and 12 mol% pre-catalyst 2.15 (Figure 2.5). Notably, this system displays an increasing rate with time, resulting in curved profiles observed for both product formation and starting material consumption. The observed profile is present in reactions with 5, 8, and 12 mol% pre-catalyst loading suggesting that increased catalyst loading does not alter this behaviour. This profile is consistent with an extended induction period. Induction periods are associated with the activation of precatalyst and are ideally short-lived. In this system, there is a period of increasing rate that continues to evolve up to 20% conversion. Unfortunately, these changing rates prevent quantitative kinetic assessments. However, the assembly of the data presented in Schemes 7 through 10 lead us to propose that the observed extended induction period is the result of extensive off-cycle equilibria between various tantalum amido species (Figure 2.6). The equilibrium studies between complex 2.15 and N-methylaniline define that the equilibrium lies heavily toward a combination of amido ligands that 73  minimizes steric crowding of the metal center. The slowly increasing rates are consistent with the alkylation of dimethylamido ligands, resulting in the formation of more sterically demanding amine by-products. These sterically demanding products in turn favor the formation of less sterically demanding N-methylanilido tantalum species. Thus, there is an observable increase in the rate of HAA of N-methylaniline. The equilibria between numerous and variable resting state species limits the formation of catalytically active tantalaziridine. We propose that these complicated and evolving equilibria result in the low observed turnover frequency of catalysis. Finally, other reports of HAA have observed reversible sp2 hybridized C-H bond activation using deuterium labelling experiments.170,174,185 This is proposed to proceed via the formation of a cyclometalated intermediate shown in Scheme 2.22. To determine if sp2 TaNOH3CNNNCl2.15(precatalyst)Equilibrium ofTa–Amido Complexes– multiple amines present in reaction solution– multiple geometric and coordination isomers – mixed Ta-amido species in rapid equilibrium[Ta]NNN R2R1R1R2R1 R2Catalyst Resting Statesmultiple equilibriaprocessesRHNprecatalyst activationvia amido exchange aminesubstrateProductiveCatalytic Cycle(see Figure 2.5)C–H activationentry into productive catalysisRHN R'alkylated amine(product orbyproducts)R'alkenesubstrateR1, R2 = aryl, alkylFigure 2.6 Graphical representation of resting state equilibria [Ta]NNRR'R2R1NR'[Ta]off pathwayortho-metallation ofalkylated aniline– HNR1R2+ HNR1R2C(from Figure 2.4,catalytic cycle)Scheme 2.22 Ortho-deuteration off-pathway equilibrium 74  hybridized C-H activation is occurring with precatalyst 2.15, we have also monitored the reaction with variably deuterated aniline substrates using 12 mol% precatalyst at 105 °C by 1H NMR spectroscopy until ~26% conversion of starting N-methylaniline (see experimental section for plot of results).  After monitoring, one reaction of each type was quenched and subjected to column chromatography. Both the starting N-methylaniline and the alkylation aniline product were isolated. Deuterium incorporation was confirmed by 2D NMR spectroscopy and quantified with 1H NMR spectroscopy. The results of deuterium quantification are summarized in Scheme 2.23. The results of this experiment are also consistent with many off-cycle equilibria, as there are significant deviations in deuterium incorporation from the expected results based upon the mechanistic proposal presented in Figure 2.2. The observation of deuterium in the ortho-position of the phenyl ring of the final product confirms that both sp3 and sp2 C-H bond activation is occurring, however, productive catalysis only proceeds via the tantalaziridine reactive intermediate. 75  Our analysis of starting N-methylaniline represents the first report of analysis of this starting material after being subjected to catalytic HAA conditions. Interestingly, the unreacted starting N-methylaniline does not reversibly incorporate deuterium in the ortho position. This demonstrates that sp3 hybridized C–H (or C–D) activation is more favorable than sp2 C–H activation.  However, once the methyl group of the starting material is converted to the methylene group in the product, subsequent sp3 hybridized C–H (or C–D) activation is hindered, allowing for C–H activation of the ortho-position to become energetically relevant. The observation that methyl C(sp3)–H activation is favoured over methylene C(sp3)–H activation is consistent with previous examples in the literature. Multiple examples of HAA from our group %D IncorporationObserved (Expected)5+DN CD3 5HNHN +0%(0%)23%(100%) 15%(0%)60%(100%)9%(33%)12 mol% [Ta]105 °C, 8 h(~26% conversion)5+HN CD3 5HNHN +0%(0%)62%(100%) 10%(0%)48%(100%)3%(0%)12 mol% [Ta]105 °C, 8 h(~26% conversion)5+DN CH3 5HNHN +0%(0%)23%(0%) 2%(0%)13%(0%)5%(33%)12 mol% [Ta]105 °C, 8 h(~26% conversion)Reaction conditions: N-methylaniline (0.5 mmol), 1-octene (0.75 mmol), [Ta] precatalyst (0.06 mmol), 1,3,5-trimethoxybenzene (0.17 mmol), d8-toluene (0.5 mL). See experimental section for additional details. Deuterium incorporation determined by 1H NMR spectroscopy and deuteration confirmed by 2H NMR spectroscopy.Scheme 2.23 Analysis of Deuterium Incorporation into Product and Byproduct Aniline after Partial Catalytic Conversion with Variably Deuterated Aniline Substrates 76  and others have observed decreased catalytic activity with non N-methyl substrates. Substrates of this type remain a challenge and have been rarely reported.171-172,179,203 Also of note, Hultzsch et al., report scrambling of PhN(H)CD2CD3 when heating alone with 2 mol% of a binolate tantalum catalyst.174 In their report they observe significant deuterium incorporation into the ortho-position of the aryl ring, and loss of deuterium from the methylene (a to the amine) position, consistent with our results presented here. 2.3 Conclusions In summary, we have developed the first precatalyst, 2.12, that is able to perform the hydroaminoalkylation reaction with broad substrate scope for internal alkenes. Additionally, 2.12 is the only precatalyst able to catalyze the hydroaminoalkylation reaction with sterically demanding E- and Z- internal alkenes to result in the β-branched products, avoiding the chain-walking that can occur with late-transition-metal catalysts. We have demonstrated that new substrate compatibilities have been made available through the combination of a 2-pyridonate-chloro ligated tantalum complex. We postulate that this combination of a planar 2-pyridonate and chloro ligand significant reduced that steric congestion at the metal center allowing for improved reactivity with sterically demanding internal alkene substrates.  Complexes 2.15 and 2.17 are the first examples of hydroaminoalkylation catalysts that offer promising reactivity with both internal and terminal alkene substrates. Efforts to understand how ligand substitution affects catalyst activity resulted in the identification of complicating off-cycle equilibria that include (1) readily reversible trans-amination and C−H activation reactions in precatalyst activation, (2) unwanted byproduct formation resulting from alkylation of the dimethylamido ligands of the precatalyst, (3) complex mixtures of catalyst resting states resulting from the generation of multiple Ta amido complexes in situ, and (4) the observation 77  that C−H activation can occur at both sp3- and sp2-hybridized C−H bonds. Considered together, these factors play a significant role in limiting the generation of on-cycle tantalum species, thereby severely limiting catalytic turnover. Ongoing work is focused on new ligand environments that avoid the use of dimethylamido ligands to both increase the concentration of productive on-cycle tantalum species and increase the efficiency of catalytic hydroaminoalkylation. 2.4 Experimental Details 2.4.1 General Considerations All air and moisture sensitive reactions were performed using standard inert atmosphere techniques using a Schlenk double manifold with N2 gas and high vacuum (10-2 mbar), or using a Mbraun LABmaster glovebox filled with a N2 atmosphere. All pieces of glassware were dried for at least 4 hours in a 160 °C oven, or dried over a propane flame before being used on the Schlenk manifold or being transferred into the glovebox. Toluene and hexanes were dried by passing through columns of activated alumina under N2 gas, collected into a Teflon sealed Strauss flask (or other appropriate Teflon sealed bomb type Schenk flask), and sparged with N2 gas for at least 30 minutes to remove dissolved O2 gas. Diethyl ether was dried over Na/benzophenone under N2 and distilled, once a deep purple colour was maintained, into a Teflon sealed Strauss flask. J. Young NMR tubes used for catalytic experiments had Teflon screw-type caps and were 8” x 5 mm tubes. Thin layer chromatography (TLC) was performed on EMD silica get 60 F254 plates. Visualization was achieved under a 254 nm UV light source and/or by staining with iodine or KMnO4 solution. Flash chromatography was performed using Silicycle SiliaFlash F60 silica gel (230-400 mesh), glass columns, and ACS grade solvents. 78  2.4.2 Instrumentation 1H, 13C, 19F, and 31P NMR spectra were recorded on a Bruker 300 MHz, 400 MHz, or 600 MHz Avance spectrometer at ambient temperature. Chemical shifts are given relative to the corresponding residual protio solvent for 1H spectra and to the carbon signal of the solvent for 13C spectra. Chemical shifts for 19F are externally referenced to neat CFCl3. Chemical shifts for 31P are externally references to 85% H3PO4. Chemical shifts, δ, are reported in parts per million (ppm) and coupling constants J are given in Hertz (Hz). The following abbreviations are used to indicate signal multiplicity: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. For quantitative experiments, T1 relaxation times for peaks of interest were estimated utilizing a spin-echo pulse sequence, and relaxation delays were appropriately extended when collecting 1H NMR spectra. Mass spectra (MS) and elemental analyses (EA) were measured by the mass spectrometry and microanalysis service at the Department of Chemistry, University of British Columbia. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 eV) source. Fragment signals are given in mass per charge number (m/z). GCMS analyses. Elemental analyses were performed using a Thermo Flash 2000 Elemental Analyzer. The content of the specified element is expressed in percent (%). UHPLC analysis was conducted on an Agilent 1290 Series UHPLC with a multi wavelength UV detector and 6150 Series Quadrapole ESI/MS, using an Agilent Poroshell 120 column (SB-C18, 2.7 µm, 2.1 x 50 mm) with a water:acetonitrile (0.1% TFA in acetonitrile) solvent system (gradient 80:20 to 0:100). 2.4.3 Materials All chemicals were purchased from commercial sources and used as received unless otherwise specified. Chemicals from commercial sources that were not dried and shipped under inert 79  atmosphere, were appropriately dried and degassed of O2 before being transferred to the glovebox or for use on the Schlenk manifold. All amines and alkenes were dried under N2 atmosphere with CaH2, distilled, and degassed by the freeze-pump-thaw method. 2-pyridones were sublimed under vacuum on a Schlenk manifold at 80 – 100 °C with water cooling, before being transferred into the glovebox. Compounds 2.1,19 2.2,204 2.6,172 2.11,175 2.12,24 2.13,24  [Ta(NMe2)3Cl2]2,205 [Ta(NEt2)2Cl3]2,206 TaMe3Cl2,207 3-phenyl-2-pyridone,19 3-mesityl-2-pyridone,19 6-phenyl-2-pyridone,208 and N-(methyl-d3)aniline209  were synthesized according to literature procedures. Final isolation of amines presented in Scheme 2.12 and Scheme 2.13, as discussed in the preface, were performed by Dr. Eugene Chong. Data and NMR spectra of these compounds can be obtained within these references.24,202 2.4.4 Synthesis and Characterization of Compounds Synthesis of sodium-pyridonates. In a glovebox, equimolar amounts of 2-pyridone (ca. 2.00 mmol) and NaHMDS (ca. 2.00 mmol) were slurried with ~ 6 mL toluene in a 20 mL scintillation vial, and stirred at ambient temperature for 12 hours. The volatiles were removed in vacuo to reveal a sticky white salt. ~2 mL of hexanes was added to form a slurry, and the volatiles were removed in vacuo. This was repeating one to two additional times and the resulting white to off-white powder was thoroughly in vacuo. These products were used without further purification or characterization. General procedure for the synthesis of complexes 2.14 – 2.19. In a glovebox, a white suspension of the sodium pyridonate salt in toluene (~ 3 mL) was added to a stirring suspension of yellow [Ta(NMe2)3Cl2]2 in toluene (~ 3 mL) at ambient temperature. The resulting suspension was stirred for 12 hours at ambient temperature, and then filtered through a plug a celite. The resulting clear yellow solution was concentrated in vacuo. The resulting sticky, pale yellow solid 80  was dissolved in minimal warm toluene (~ 1.5 mL), and cooled first to ambient temperature, and then cooled for 10 minutes at -35 °C. This dark yellow solution was then layered with hexanes (~ 3 mL) and stored in the freezer at -35 °C to promote crystallization. Products generally recrystallized within 24 hours. After thoroughly drying the crushed, recrystallized product in vacuo, samples were used for characterization. Chlorotris(dimethylamido)(k2-N,O-3-(2,4,6-trimethylphenyl)-2-pyridonato)tantalum(V) (2.14). Using the general procedure described above, sodium 3-(2,4,6-trimethylphenyl)-2-pyridonate salt (0.045 g, 0.19 mmol) was added to [Ta(NMe2)3Cl2]2 (0.074 g, 0.01 mmol). A single recrystallization resulted in 0.090 g (84% yield) of yellow crystals. 1H-NMR and 13C-NMR spectra reveal fluctional behavior for the 2,6-dimethyl groups of the 2,4,6-trimethyphenyl group as exhibited by additional resonances in both spectrum (one sharp and one broad). The 4-methyl group of the same aryl ring also exhibits this behavior but results in a single broad resonance. 1H-NMR (400 MHz, C6D6): δ  7.71 (dd, J = 5.4, 1.9 Hz, 1H), 7.11 (dd, J = 7.3, 1.9 Hz, 1H), 6.82 (br. s, 2H), 6.38 (dd, J = 7.3, 5.4 Hz, 1H), 3.50 (br. s, 18H), 2.37 (br. s, 3H), 2.14/2.11 (s/br. s., 6H). 13C{1H}-NMR (101 MHz, C6D6): δ  168.1, 141.4, 140.4, 138.2 (br. s), 137.2, 135.8 (br. s), 132.6, 129.0, 125.6, 113.0, 46.8, 21.2, 21.0 (br. s), 20.8 (br. s). MS (EI): m/z 560 [M+], 516 [M+–NMe2] EA: Calc’d for C20H32ClN4OTa: C 42.83, H 5.75, N 9.99; Found: C 43.12, H 5.80, N 9.80. Chlorotris(dimethylamido)(k2-N,O-3-methyl-2-pyridonato)tantalum(V) (2.15). Using the general procedure described above, sodium 3-methyl-2-pyridonate salt (0.026 g, 0.20 mmol) was added to [Ta(NMe2)3Cl2]2 (0.076 g, 0.10 mmol). A single recrystallization resulted in 0.073 g (80% yield) of yellow crystals.  81  1H-NMR (400 MHz, C6D6): δ  7.60-7.58 (m, 1H), 6.94-6.91 (m, 1H), 6.23 (dd, J = 7.2, 5.5 Hz, 1H), 3.55 (br. s, 18H), 2.02 (s, 3H). 13C{1H}-NMR (101 MHz, C6D6): δ  169.5, 140.0, 138.7, 122.1, 112.8, 46.7, 14.6. MS (EI): m/z 456 [M+], 412 [M+–NMe2] EA: Calc’d for C12H24ClN4OTa: C 31.56, H 5.30, N 12.27; Found: C 31.64, H 5.58, N 12.24. Chlorotris(dimethylamido)(k2-N,O-3-trifluoromethyl-2-pyridonato)tantalum(V) (2.16). Using the general procedure described above, sodium 3-trifluoromethyl-2-pyridonate salt (0.037 g, 0.19 mmol) was added to [Ta(NMe2)3Cl2]2 (0.076 g, 0.10 mmol). A single recrystallization resulted in 0.078 g (76% yield) of yellow crystals.  1H-NMR (600 MHz, C6D6): δ  7.55-7.53 (m, 1H), 7.30-7.29 (m, 1H), 5.94-5.92 (m, 1H), 3.45 (br. s, 18H). 13C{1H}-NMR (151 MHz, C6D6): δ  145.1, 133.0 (q, 2JCF = 4.5 Hz), 128.4, 111.5, 46.7. Could not locate CF3 or C(O)N carbons. 19F-NMR (282 MHz, C6D6): δ  -62.93. MS (EI): m/z 510 [M+], 466 [M+–NMe2] EA: Calc’d for C12H21N4ClF3OTa: C 28.22, H 4.14, N 10.97; Found: C 27.98, H 4.06, N 10.44. Chlorotris(dimethylamido)(k2-N,O-2-pyridonato)tantalum(V) (2.17). Using the general procedure described above, sodium 2-pyridonate salt (0.025 g, 0.21 mmol) was added to [Ta(NMe2)3Cl2]2 (0.082 g, 0.11 mmol). A single recrystallization resulted in 0.080 g (84% yield) of yellow crystals.  1H-NMR (400 MHz, C6D6): δ  7.63 (ddd, J = 5.5, 1.8, 0.9 Hz, 1H), 6.96 (ddd, J = 8.6, 7.1, 1.8 Hz, 1H), 6.32 (ddd, J = 8.6, 0.9, 0.9 Hz, 1H), 6.18 (ddd, J = 7.1, 5.5, 0.9 Hz, 1H), 3.54 (br. s, 18H). 13C{1H}-NMR (101 MHz, C6D6): δ  170.5, 141.4, 140.7, 112.7, 112.6, 46.6. MS (EI): m/z 442 [M+], 398 [M+–NMe2] EA: Calc’d for C11H22ClN4OTa: C 29.84, H 5.01, N 12.66; Found: C 29.72, H 5.03, N 12.25. 82  Chlorotris(dimethylamido)(k2-N,O-6-phenyl-2-pyridonato)tantalum(V) (2.18). Using the general procedure described above, sodium 6-phenyl-2-pyridonate salt (0.035 g, 0.18 mmol) was added to [Ta(NMe2)3Cl2]2 (0.070 g, 0.09 mmol). A single recrystallization resulted in 0.062 g (66% yield) of yellow crystals. 1H-NMR (300 MHz, C6D6): δ  7.89-7.85 (m, 2H), 7.24-7.18 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 7.03 (dd, J = 8.5, 7.4 Hz, 1H), 6.50 (dd, J = 7.4, 0.8 Hz, 1H), 6.34 (dd, J = 8.5, 0.8 Hz, 1H), 3.51 (br. s, 18H). 13C{1H}-NMR (75 MHz, C6D6): δ  170.8, 153.5, 140.9, 139.4, 128.9, 128.6, 128.5, 111.5, 111.4, 48.29. MS (EI): m/z 474 [M+–NMe2] Satisfactory elemental analysis could not be obtained for this product. EA: Calc’d for C17H26ClN4OTa: C 39.36, H 5.05, N 10.80; Found: C 38.70, H 5.23, N 10.35. Chlorotris(dimethylamido)(k2-N,O-6-methyl-2-pyridonato)tantalum(V) (2.19). Using the general procedure described above, sodium 6-methyl-2-pyridonate salt (0.025 g, 0.19 mmol) was added to [Ta(NMe2)3Cl2]2 (0.073 g, 0.09 mmol). A single recrystallization resulted in 0.066 g (76% yield) of yellow crystals. 1H-NMR (400 MHz, C6D6): δ  6.95 (dd, J = 8.5, 7.3 Hz, 1H), 6.20 (m, 1H), 6.08 (m, 1H), 3.60 (br. s, 18H), 2.10 (s, 3H). 13C{1H}-NMR (101 MHz, C6D6): δ  170.9, 151.9, 141.1, 111.9, 109.7, 47.3, 21.8. MS (EI): m/z 412 [M+–NMe2] EA: Calc’d for C12H24ClN4OTa: C 31.56, H 5.30, N 12.27; Found: C 31.91, H 5.37, N 12.47. Tris(dimethylamido)triflato(k2-N,O-3-phenyl-2-pyridonato)tantalum(V) (2.20). In a glovebox, a 10 mL Schlenk tube was charged with 1 (0.071 g, 0.14 mmol) and AgOTf (0.035 g, 0.14 mmol). The flask was moved to the Schlenk line, charged with 3 mL dichloromethane to create a cloudy yellow solution, and stirred at ambient temperature for 12 h. Volatiles were removed in vacuo and the flask returned to the glovebox. The yellow white solid was extracted 83  with 10 mL toluene and filtered through a celite plug. The resulting clear yellow solution was concentrated in vacuo. The resulting sticky, pale yellow solid was dissolved in minimal warm toluene (~ 1.5 mL), and cooled first to ambient temperature, and then cooled for 10 minutes at -35 °C. This dark yellow solution was then layered with hexanes (~ 3 mL) and stored in the freezer at -35 °C to promote recrystallization. Products generally recrystallized within 24 hours. After thoroughly drying the crushed, recrystallized product in vacuo, samples were used for characterization. A single recrystallization resulted in 0.053 g (61% yield) of yellow crystals. 1H-NMR (300 MHz; C6D6): δ  7.86-7.82 (m, 2H), 7.64 (dd, J = 5.5, 1.8 Hz, 1H), 7.37 (dd, J = 7.5, 1.8 Hz, 1H), 7.25-7.20 (m, 2H), 7.11-7.06 (m, 1H), 6.37 (dd, J = 7.5, 5.5 Hz, 1H), 3.43 (br. s, 18H). 13C{1H}-NMR (101 MHz; C6D6): δ  169.0, 140.9, 140.8, 135.3, 128.9, 128.8, 128.1, 125.4, 122.2, 119.1, 114.5, 46.3. 19F-NMR (282 MHz; C6D6): δ  -78.2 MS (EI): m/z 632 [M+], 588 [M+–NMe2], 483 [M+–OTf] EA: Calc’d for C18H26F3N3O4STa: C 34.19, H 4.14, N 8.86; Found: C 33.88, H 4.05, N 8.50. N-deutero aniline derivatives. The requirement of dry substrates for these catalytic reactions does not allow for standard preparation of N-deutero substrates by exchange (with MeOD or DCl/D2O), as drying with CaH2 would be required. To avoid possible loss of deuteration during drying, this procedure was developed to maintain dry substrate for catalysis. N-d-N-methylaniline. All manipulations were conducted in a glovebox or on a Schlenk manifold under N2 with proper Schlenk technique. In a glovebox, a 50 mL pear-shaped Schlenk flask was charged with dried and degassed N-methylaniline (2.290 g, 27.2 mmol), 15 mL diethyl ether, and a stir bar. The mixture was stirred to ensure a homogenous mixture. The flask was attached to the Schlenk line and cooled to 0 °C. With stirring, 17.2 mL of nBuLi solution (27.5 mmol, 1.6 M in hexanes) was added dropwise via syringe and stainless steel needle. The reaction 84  was allowed to slowly warm to ambient temperature and stirred for 2 h. Separately, a small Schlenk flask was charged with D2O, and sparged with N2 for 30 min. After the 2 h stir period, 0.97 equivalents of D2O (0.529 g, 0.48 mL, 26.4 mmol), was added dropwise via syringe and stainless steel needle. The reaction was allowed to stir for 2 h. After the 2 h stir period, a short-path distillation apparatus with a Teflon sealed Schlenk flask connected for collection of the product, was attached to the reaction flask. Vacuum was applied slowly, through the distillation apparatus, and the hexanes and diethyl ether were allowed to evaporate. Once complete, the product was distilled under dynamic vacuum (30 °C, 10-2 mbar), the receiving flask placed under N2 gas, sealed, transferred into the glovebox, and the product transferred to a 20 mL scintillation vial. 1H NMR spectrum revealed trace amounts of hexanes and diethyl ether, which can be removed in vacuo with stirring, inside the glovebox, to yield 1.733 g (59% yield) of the product. 1H NMR spectroscopy reveals >98% deuteration with no evidence for N-H protons. 2D NMR spectroscopy confirms N-deutero incorporation. 1H-NMR (400 MHz; C6D6): δ  7.21-7.16 (m, 2H), 6.78-6.74 (m, 1H), 6.42-6.39 (m, 2H), 2.30 (s, 3H). 2H-NMR (61 MHz; C6H6): δ  2.84 (s, 1D) N-d-N-(methyl-d3)aniline. All manipulations were conducted in a glovebox or on a Schlenk manifold under N2 with proper Schlenk technique. In a glovebox, a 50 mL pear-shaped Schlenk flask was charged with dried and degassed N-(methyl-d3)aniline (2.337 g, 21.2 mmol), 15 mL diethyl ether, and a stir bar. The mixture was stirred to ensure homogeneity. The flask was attached to the Schlenk line and cooled to 0 °C. With stirring, 13.5 mL of nBuLi solution (21.6 mmol, 1.6 M in hexanes) was added dropwise via syringe and stainless steel needle. The reaction was allowed to slowly warm to ambient temperature and stirred for 2 h. Separately, a small Schlenk flask was charged with ~ 1-2 mL of D2O, and sparged with N2 for 30 min. After the 2 h 85  stir period, 0.98 equivalents of D2O (0.416 g, 0.37 mL, 20.8 mmol), was added dropwise via syringe and stainless steel needle. The reaction was allowed to stir for 2 h. After the 2 h stir period, a short-path distillation apparatus with a Teflon sealed Schlenk flask connected for collection of the product, was attached to the reaction flask. Vacuum was applied slowly, through the distillation apparatus, and the hexanes and diethyl ether were allowed to evaporate. Once complete, the product was distilled under dynamic vacuum (30 °C, 10-2 mbar), the receiving flask placed under N2 gas, sealed, transferred into the glovebox, and the product transferred to a 20 mL scintillation vial. 1H NMR spectrum revealed trace amounts of hexanes and diethyl ether, which were removed in vacuo with stirring, inside the glovebox, to yield 2.012 g (87% yield) of the product. 1H NMR spectroscopy indicates >98% deuteration with no evidence for N-H protons. 2D NMR spectroscopy confirms N-deutero incorporation. 1H-NMR (400 MHz; d8-Tol): δ  7.14-7.09 (m, 2H), 6.71-6.67 (m, 1H), 6.35-6.32 (m, 2H) 2H-NMR (61 MHz; Tol): δ  2.81 (s, 1D), 2.33 (s, 3D) 2.4.5 Reaction and Experimental Details: Catalytic Screening Reactions (Scheme 2.16 and Scheme 2.17): In a glovebox, the pre-catalyst (0.025 mmol) was dissolved in d8-toluene (500 µL, 0.477 mg) in a 5 mL scintillation vial. N-methylaniline (0.50 mmol) and alkene (0.75 mmol) were weighed into a separate 5 mL scintillation vial. Using a glass disposable pipette, the solution of pre-catalyst was transferred between the two vials multiple times to ensure a complete dissolution and creation of a homogeneous mixture. The resulting solution was transferred to a J. Young NMR tube and the tube closed with a screw-type Teflon cap. The 1H NMR spectrum was recorded, and the J. Young NMR tube was placed in a preheated oil bath at the specified temperature for the specified time. After the specified time, the tube was removed, allowed to cool to ambient 86  temperature, and a 1H NMR spectrum was recorded. Conversion was determined from this spectrum by integration of the ortho-proton signal of N-methylaniline centered at δ 6.33, and the appearance of product ortho-proton signals of product centered at δ 6.41.  Substrate Scope Investigations (Scheme 2.18): In a glovebox, the pre-catalyst (0.025 mmol) was dissolved in d8-toluene (500 µL, 477 mg) in a 5 mL scintillation vial. Cp2Fe (0.05-0.10 mmol) was weighed into a separate 5 mL scintillation vial and the mass recorded (used to calculated yield after the reaction was completed). N-methylaniline (0.50 mmol) and alkene (0.75 mmol) were weighed into the same 5 mL scintillation vial as the Cp2Fe. Using a glass disposable pipette, the solution of pre-catalyst was transferred between the two vials multiple times to ensure a complete dissolution and creation of a homogeneous mixture. The resulting solution was transferred to a J. Young NMR tube and the tube closed with a screw-type Teflon cap. The 1H NMR spectrum was recorded, and the J. Young NMR tube was placed in a preheated oil bath at the specified temperature for the specified time. After the specified time, the tube was removed, allowed to cool to ambient temperature, and a 1H NMR spectrum was recorded. Yield was determined by 1H NMR spectroscopy by calculating the moles of N-methylaniline (ortho-protons at δ 6.33) in the t = 0 h spectrum relative to the known moles of Cp2Fe (singlet at δ 3.99) and by calculating the moles of product (ortho-protons at δ 6.41) at the end of the reaction relative to the known moles of Cp2Fe. Deuterium Scrambling Experiments (Scheme 2.19): In a glovebox, 2.15 (15.0 mg, 0.033 mmol), N-methylaniline (or isotopically labelled variant) (0.033 mmol), and 1,3,5-trimethoxybenzene (5.5 mg, 0.033 mmol) were dissolved in d8-toluene (500 µL, 477 mg) in a 5 mL scintillation vial. The homogenous solution was transferred into a J. Young NMR tube and sealed with a Teflon screw-type cap. The 1H NMR spectrum was collected, and the tube place in 87  a preheated 110 °C oil bath for 2 h. After the time, the tube was removed, cooled, and a 1H NMR spectrum was collected. Experiments c) and d) were repeated in the same manner but in toluene, so that 2H NMR spectra could be obtained. In a), no change was observed in the integration of 2.15 or N-methylaniline relative to the 1,3,5-trimethoxybenzene internal standard. In b), the experiment was set up as described but with 10 equivalents of N-methylaniline (35.2 mg, 0.328 mmol). Instead of being place into a pre-heated oil bath, the tube was placed into an NMR spectrometer, heated to 105 °C and allowed to stabilize for 15 minutes once the probe temperature was stable. A 1H NMR spectrum was collected every 30 minutes for 2 h. As in a), no change was observed in the integration of 2.15 or N-methylaniline relative to the 1,3,5-trimethoxybenzene internal standard. In c) and d), deuterium incorporation was determined by 1H NMR spectroscopy. 2H NMR spectra confirm the presence of deuterium in the dimethylamido ligands of 4 (deuterium signal at δ 3.51), the presence of an aniline N-d (deuterium signal at δ 2.82), and the presence of deuterium incorporated at methyl position of the aniline (deuterium signal at δ 2.30).  Stoichiometric Experiments with Variable Alkene Equivalents (Scheme 2.21): In a glovebox, 2.15 (12.5 mg, 0.027 mmol), N-methylaniline (2.9 mg, 0.027 mmol), variable amounts of either cyclohexene or 1-octene (~1–7 equivalents), and 1,3,5-trimethoxybeneze (1.5 mg, 0.009 mmol) were dissolved in d8-toluene (500 µL, 477 mg) in a 5 mL scintillation vial. The homogeneous solution was transferred into a J. Young NMR tube and sealed with a Teflon screw-type cap. The 1H NMR spectrum was collected, and the tube was placed in a preheated oil bath for 3 h (with cyclohexene at 145 °C; with 1-octene at 110 °C). After 3 h, the tube was removed and a 1H NMR spectrum was collected. Initial alkene equivalents (proton signal at δ 5.66 for cyclohexene and at δ 5.76 ppm for 1-octene) were calculated from the t = 0 h spectrum 88  relative to the known amount of 1,3,5-trimethoxybenzene internal standard (proton signal at δ 6.14). Product (ortho-protons signal at δ 6.14) and remaining alkene were calculated from the t = 3 h spectrum relative to the known amount of 1,3,5-trimethoxybenzene. A convoluted alkyl region of 1H NMR spectra prevents direct identification of the dimethylamine functionalized byproducts; they are calculated as such: functionalized byproducts = (alkene remaining) – (aniline product). Reaction Monitoring (Scheme 10 and 12): In a glovebox, pre-catalyst 2.15 (5 mol%: 11.4 mg, 0.025 mmol; 8 mol%: 18.3 mg, 0.040 mmol; 12 mol%: 27.4 mg, 0.060 mmol) was dissolved in d8-toluene (500 µL, 477 mg) in a 5 mL scintillation vial. 1,3,5-trimethoxybenzene (28.0 mg, 0.167 mmol) was weighed into a separate 5 mL scintillation vial (used to calculated yields after the reaction was completed). N-methylaniline, or isotopically labelled variant, (0.50 mmol) and 1-octene (84.2 mg, 0.75 mmol) were weighed into the same 5 mL scintillation vial as the 1,3,5-trimethoxybenzene. Using a glass disposable pipette, the solution of pre-catalyst was transferred between the two vials multiple times to ensure a complete dissolution and creation of a homogeneous mixture. These samples were consistently measured to have a volume of 0.55 mL by 1.0 mL syringe. The resulting solution was transferred to a J. Young NMR tube and the tube closed with a screw-type Teflon cap. The tube was then placed into the NMR spectrometer that was already pre-heated to 105 °C. This time point was taken to be t = 0 min. The sample was allowed ~ 10 minutes to reach equilibrium, followed by shimming of the magnet, and tuning and matching of the instrument. An 1H NMR spectrum was collected every 17.6 minutes with the first 1H NMR spectrum recorded at 17.4 minutes. Yield of N-methylaniline (ortho-protons at δ 6.33) and product (ortho-protons at δ 6.41) was determined by integration relative to the known amount of 1,3,5-trimethoxy benzene internal standard (aryl-protons at δ 6.04). Due to deuterium 89  scrambling into the ortho-position of the product, only the yield of the starting material aniline is reported when using deuterated aniline substrates. Each kinetic monitoring experiment was repeated to confirm the reaction profile.  Figure 2.7 Plot of reaction monitoring experiments with 5, 8, and 12 mol% 2.15 as precatalyst for the hydroaminoalkylation reaction between N-methylaniline and 1-octene. Overlay of both experiments.   00.10.20.30.40.50.60.70.80.910 100 200 300 400 500Normalized	Concentration	of	PhN(H)Me	and	Product(C/Co)Time	(minutes)Product,	5	mol%	[Ta] PhN(H)Me,	5	mol%	[Ta] Product,	8	mol%	[Ta] PhN(H)Me,	8	mol%	[Ta] Product,	12	mol%	[Ta] PhN(H)Me,	12	mol%	[Ta] 90    Figure 2.8 Plot of reaction monitoring experiments with 12 mol% 2.15 as precatalyst for the hydroaminoalkylation reaction between N-methylaniline (variably deuterated) and 1-octene. Overlay of both experiments.  Analysis of Deuterium Incorporation (Scheme 2.23): After collecting kinetic data, the reactions with the deuterated substrates were quenched with 2 mL methanol, transferred to 20 mL scintillation vial, and the solvents removed on a rotorary evaporator. The product aniline and the N-methylaniline starting material were isolated by column chromatography (10% EtOAc in hexanes, silica). Deuterium incorporation was determined by 1H NMR spectroscopy and deuteration confirmed by 2H NMR spectroscopy. 0.60.650.70.750.80.850.90.9510 100 200 300 400Normalized	Concentration(C/Co)Time	(minutes)PhN(D)CD3 PhN(H)CD3 PhN(D)CH391  Chapter 3: Phosphoramidate Niobium Complexes for the Hydroaminoalkylation of Alkenes with Secondary Amines – Synthesis of Novel Niobium Complexes and Catalytic Reactivity 3.1 Introduction As discussed in detail in Chapter 2, the hydroaminoalkylation reaction offers a powerful tool for the α-alkylation of simple secondary amine substrates. Additionally, our research into 2-pyridonate tantalum complexes demonstrates that ligand effects can result in significant changes in catalytic activity. While there has been significant development on Ta complexes as precatalysts for hydroaminoalkylation, there are only few reports of niobium complexes as precatalysts for this reaction (Figure 3.1).173-174,181-182,185 3.1.1 Niobium Catalyzed Hydroaminoalkylation Early reports of Nb precatalysts for hydroaminoalkylation have studied chiral, tethered-biaryl-diamidate ligands,173,181 and chiral BINOLate ligands for the enantioselective hydroaminoalkylation.174,182 Complexes 3.1, 3.3, and 3.5 were reported to not be reactive for hydroaminoalkylation, whereas the direct Ta analogues 3.2, 3.4, 3.6 are active and achieve good NOArN OArMNMe2NMe2NMe2Ar = Mes3.1 M = Nb3.2 M = TaOOSiPh2MeSiPh2MeMNMe2NMe2NMe2NHMe23.7 M = Nb3.8 M = TaONMNMe2NMe2NMe2NMe2MNMe2NMe2NMe2NArOONArNOArN OArMNMe2NMe2NMe2Ar = Mes3.3 M = Nb3.4 M = TaAr = Mes3.5 M = Nb3.6 M = Ta3.9 M = Nb3.10 M = TaFigure 3.1 Nb complexes reported for hydroaminoalkylation and their direct Ta analogues 92  enantioselectivities (Scheme 3.1a). In contrast, Nb and Ta BINOLate complexes 3.7 and 3.8 are both active for catalytic hydroaminoalkylation (Scheme 3.1b). Here it was found that Nb complex 3.7 achieved similarly high yields to Ta complex 3.8 while requiring approximately half the reaction time. Recently, an amidate ligated Nb complex 3.9 was reported and compared with its direct Ta analogue 3.10 for hydroaminoalkylation reactivity (Scheme 3.1b).185 Compared to 3.9, Ta complex 3.10 achieves a higher yield with a slightly increased rate.   Scheme 3.1 Comparative hydroaminoalkylation reactivity of Nb and Ta precatalysts Complexes 3.7 and 3.8 were further investigated in an attempt to understand the origin of the increased rate observed with a Nb precatalyst over the Ta precatalyst. Through deuterium labelling experiments, it was observed that significantly less deuterium scrambling occurs with Nb complex 3.7 compared with Ta complex 3.8 (Scheme 3.2). Here, it is proposed that the deuterium scrambling is the result of off-cycle equilibria, similar to those detailed in Chapter 2. These off-cycle pathways may contribute to the reduced observed reaction rate for Ta complex 3.8.   HN +5 mol% [M]Toluene-d8160 °C, 48hHN3.1 no reaction3.2 88%, 85 %ee3.3 no reaction3.4 85%, 91 %ee3.5 no reaction3.6 85%, 77 %eeHN HN+5 mol% [M]SolventTemp, Time3.7(solvent C6D6)150 °C, 7 h140 °C, 11 h        100 °C, 105 h85%, 72 %ee85%, 73 %ee92%, 81 %ee3.8(solvent C6D6)150 °C, 14 h140 °C, 27 h88%, 72 %ee85%, 73 %ee3.93.10(solvent Tol-d8)110 °C, 66 h110 °C, 64 h83%96%(a)(b)93  3.1.2 Phosphoramidate Ancillary Ligands for Early-Transition-Metal-Catalyzed Hydroaminoalkylation To date there has only been a single report of phosphoramidate complexes for hydroaminoalkylation.175 Importantly, phosphoramidate ligated Ta complex 3.11 (and its ligand derivatives) are the only complexes reported for room temperature hydroaminoalkylation. Ta complex 3.12 is also active for hydroaminoalkylation, but with limited reactivity at 90 °C (Scheme 3.3). This reduced reactivity may be attributed to the equilibria detailed in Chapter 2. Complex 3.11 is a significant departure from the amido complexes, and the use of methyl ligands are proposed to allow for room temperature reaction. This dramatic shift in reactivity, simply through the use of an alternate precatalyst that ultimately leads to the same catalytically active intermediates, calls into question whether 3.11 promotes the reaction by the same mechanism (see Chapter 2.1). However, 3.12 demonstrates reactivity at 90 °C, which is at the lower HNCD3 + Cy1 mol% [M]C6D6150 °C, 30 h> 95% conversionN CyCH2DPresented as %Deuterium Incorporatedwith 3.70% 95%96%H/DN CyCH2Dwith 3.845% 66%33%H/DScheme 3.2 Deuterium scrambling experiments with complexes 3.7 and 3.8 HN HN+5 mol% [Ta]Toluene-d8Temp, 20 hMeO MeOEtONPOTaEtOMeClMe MeEtONPOEtOTaNMe2NMe2NMe2NMe23.1290 °C16%3.1122 °C37%Scheme 3.3 Hydroaminoalkylation reactivity of phosphoramidate ligated Ta complexes 94  temperature range for early-transition-metal-catalyzed hydroaminoalkylation with precatalysts containing amido ligands.26,165,185  3.2 Scope of Chapter While the achievement of room temperature reactivity with 3.11 is impressive, this complex suffers greatly from decomposition under catalytic conditions. More specifically, only gentle heating is tolerated (up to 70 °C), which limits substrate scope significantly.175 Additionally, this is in contrast to many of the Ta amido complexes that can be heated at high temperatures (greater than 150 °C), for long reaction times, to achieve high yields with substrates that exhibit slow rates such as piperidine.172,179  To overcome this drawback, a precatalyst with the correct coordination mode of a phosphoramidate ancillary ligand(s) with the remaining ligands as amido ligands, may achieve an increased rate at a given temperature while resisting catalyst death under catalytic conditions over longer reaction times. Additionally, the improved activity and significant reduction in deuterium scrambling with Nb precatalyst 3.7 over Ta precatalyst 3.8 suggests Nb may be well suited for hydroaminoalkylation chemistry. Similar structural features are found between Nb complex 3.9 and Ta complex 3.10, where the ancillary 1,3-N,O-chelating amidate ligand has a planar N-C-O fragment when bound to Nb or Ta. The phosphoramidate ligands can impart a significantly different steric environment about the metal center due to the tetrahedral geometry about the phosphorous atom, which has been postulated to improve catalytic performance.175,185 This chapter details efforts toward the synthesis of highly active phosphoramidate Nb complexes for the hydroaminoalkylation of alkenes with secondary amines. A desirable precatalyst would have an improve rate over known precatalysts with established substrate combinations, and would also have improved yields and rate with challenging substrates such as 95  N-containing saturated heterocycles, highly nucleophilic dialkyl amines, and sterically demanding amine and alkene substrates.24,165,171-172 Presented herein are the synthesis of a variety of phosphoramidate Nb complexes, and their subsequent catalytic reactivity for the hydroaminoalkylation reaction. 3.3 Results and Discussion 3.3.1 Synthesis of Phosphoramidate Nb Complexes A protonolysis reaction was used to synthesize phosphoramidate ligated Nb complexes 3.13 – 3.17 (Scheme 3.4).165,172-173,181,185 Here, phosphoramide protio-ligand is reacted with Nb(NMe2)5 to create the phosphoramidate ligated Nb complex and an equivalent of dimethylamine. Complex 3.13 could be recrystallized and a solid-state molecular structure was obtained (Figure 3.2). The solid-state molecular structure of 3.13 reveals a pseudo-octahedral structure. The phosphoramidate ligand binds as a κ2-1,3-N,O-chelate in a similar manner to the solid-state structure of phosphoramidate Ta complex 3.11, and amidate Nb and Ta complexes 3.9 and 3.10. Notably, N1 is almost perfectly planar suggesting sp2 hybridization. This is consistent with the coordination of both phosphoramidate and amidate ligands on Nb and Ta. All amido ligands are nearly perfectly planar about nitrogen suggesting sp2 hybridization. These provide both σ- and π-bonding interactions, and act as highly donating ligands. A comparison with complex 3.11 shows that complex 3.13 has longer Nb–O1 (2.3237(8) vs. 2.190(2) Å) and Nb–N1 bonds (2.2282(9) vs. 2.135(2) Å). This lengthening is likely caused by 3.13 being more electron rich due to the highly donating amido ligands. Consequently, 3.13 exhibits a slightly tighter bite angle (64.55(3)° vs. 66.68(9)°), and slightly shorter P1–O1 (1.5005(8) vs. 1.516(2) Å) and P1–N1 (1.6062(9) vs. 1.616(2)) bond lengths. When compared to the binding of the amidate ligand in 3.9, the phosphoramidate ligand in 3.11 adopts a more symmetric binding mode with Nb–O1 96  and Nb–N1 (2.3237(8) and 2.2283(9) Å) being closer in distance than the amidate ligand with Nb–O1 and Nb–N1 (2.1133(8) and 2.4653(9) Å). This suggests that the oxygen of the phosphoramidate ligand is, comparatively, less donating likely owing to the high P–O bond strength. The 31P{1H} NMR spectrum of 3.13 reveals a single signal at 4.4 ppm, as expected based on the solid-state structure. The 1H NMR spectrum is also consistent with the solid-state structure. A single broad resonance at 3.36 ppm is observed for the dimethylamido ligands suggesting fluxional behavior due to facile exchange of the amido ligands. In contrast, 3.14 – 3.17 were obtained as sticky solids that were resistant to recrystallization and complete purification. 31P{1H} NMR spectroscopy reveals only a single resonance and the absence of the starting material phosphoramide. Complexes 3.14 – 3.16 demonstrate trace baseline impurities in their 1H and 13C{1H} spectra, while 3.17 has Figure 3.2 ORTEP representation of 3.13 with select bond lengths and angles Thermal ellipsoids are shown at 50%. H-atoms omitted.  Select Bond Lengths (Å) and Angles (°) Nb–O1  2.3237(8) Nb–N1  2.2283(9) P1–O1  1.5005(8) P1–N1  1.6062(9) O1–Nb–N1 64.55(3) O1–P1–N1 102.98(4) Σ	N1  359  Scheme 3.4 Synthesis of phosphoramidate Nb complexes 3.13 – 3.17 R2NPOR2R1NbNMe2NMe2NMe2NMe2Nb(NMe2)5TolueneRT, 12 h+OP NHR1R2R23.13   R1= Ph 3.14   R1= 2-Me-C6H43.15   R1= iPr3.16   R1= Ph3.17   R1= iPrR2= OEtR2= OEtR2= OEtR2= iPrR2= NMe297  unidentified impurities in both the 1H and 31C{1H} NMR spectra. The NMR spectra for these complexes is analogous to that of 3.13 and their structure is presumed to be similar to that of 3.13. Curiously, attempts to synthesize the analogous complex with a phosphoramide ligand containing a more sterically demanding N-2,6-diisopropylphenyl group produces a different product than expected. A 1:1 reaction of phosphoramide:Nb(NMe2)5 resulted in the formation of a new bis-ligated complex, and 0.5 equivalents of Nb(NMe2)5 remaining. A reaction of 2:1 ligand to Nb results in the expected consumption of all Nb(NMe2)5 and the same new complex (Scheme 3.5). Fortunately, complex 3.18 can be recrystallized and the solid-state molecular structure obtained to determine the structure of the complex. The molecular structure reveals that 3.18 is a diphosphoramidate niobaziridine that results from two protonolysis reactions from ligation of the phosphoramidate ligands and a sterically driven hydrogen-atom abstraction event forming the niobaziridine fragment (Scheme 3.5).  Complex 3.18 is 7-coordinate in the solid-state with a pseudo pentagonal bipyramidal geometry (Figure 3.3). The niobaziridine moiety contains a C1–N3 bond length of 1.403(2) Å indicating some multiple bond character. While this binding might also be described as a Nb(III)–η2-imine, assignment of a Nb(V) complex is the best interpretation, as the Nb–C1 and Nb–N3 bond lengths, and angles of the 3-membered metallaacycle are in complete agreement with reported Ta(V) tantalaziridines supported by amidate ligands.172,185,210 Additionally, N3 is Scheme 3.5 Synthesis of niobaziridine complex 3.18 NbNMe2NMe2NMe2P NOP ONDippDippEtOEtOEtOEtO– HNMe2 NbNMe2NP NOP ONDippDippEtOEtOEtOEtONb(NMe2)5 +OP NHDippEtOEtO2.0– 2 HNMe23.18Proposed Intermediate98  planar and sp2 hybridized, and likely a 4e– donor to create a 18e– complex. Each phosphoramidate ligand contains significant differences in binding as evidenced by the Nb–O bond lengths (Nb–O1 of 2.180(1) Å and Nb–O2 2.313(2) Å) and Nb–N bond lengths (Nb–N1 of 2.316(2) Å and Nb–N2 2.179(1) Å). Given the high steric constraints about the metal center, these changes in bond lengths likely arise due to steric interactions over significant changes in binding enthalpy of Nb–O or Nb–N bonds. 1H and 31P{1H} NMR spectra confirm this structure in the solution state. While both spectra reveal two separate phosphoramidate ligand environments at 25 °C, 1H 2D-NOESY experiment at 25 °C reveals chemical exchange peaks for the inequivalent phosphoramidate ligands indicating the complex is fluxional and ligand interconversion occurs on the NMR time scale.  Consumption of 2 equivalents of ligand to Nb center also occurs with a N-2,6-dimethylphenyl phosphoramide ligand (Scheme 3.6). The crude material results in a 31P{1H} spectrum with two major signals at 8.1 and –0.5 with 1:1 integration values. The 1H NMR spectrum is complex, and exhibits broad peaks suggestive of fluxional behavior. Unfortunately, variable temperature NMR experiments (–75 °C to 90 °C) did not result in simplification of the Figure 3.3 ORTEP representation of 3.18 and select bond lengths and angles Select Bond Lengths (Å) and Angles (°) Nb–O1  2.180(1) Nb–O2  2.313(2) Nb–N1  2.316(2) Nb–N2  2.179(1) O1–Nb–N1 65.28(5) O1–Nb–N2 65.38(5) Nb–C1  2.180(2) Nb–N3  1.927(2) N3–C1  1.403(2)  N3–C2  1.451(2) Nb–N3–C2 155.5(1) C1–N3–C2 124.0(1)  Thermal ellipsoids are shown at 50%. H-atoms and OCH2CH3 omitted.   99  1H NMR spectrum. Although this complex could be recrystallized, no crystals suitable for resolved X-ray diffraction could be obtained. However, based on analogy to 3.18, niobaziridine 3.19 is proposed. This assignment is based on the two 31P NMR signals at similar chemical shifts to the fully characterized niobaziridine 3.18. Without further information regarding chemical structure, the assignment is tentative. To ensure accurate concentrations of niobium, catalytic reactions were prepared in situ using 2:1 pro-ligand:Nb(NMe2)5 for catalytic screening (vide infra).  In an attempt to synthesize an additional niobaziridine, two equivalents of a N-phenyl phosphoramide and one equivalent of Nb(NMe2)5 results in a complicated and broad 1H NMR spectrum, and a 31P{1H} spectrum with multiple broad signals between 10 – 0 ppm. VT 1H and 31P{1H} NMR experiments were attempted but no conclusions regarding structure could be made. As above, in situ preparations of 2:1 pro-ligand:Nb(NMe2)5 were used for catalytic screening (vide infra). Scheme 3.7 shows the synthesis of an additional niobaziridine 3.20 where the ethoxy substituents of the phosphoramide have been substituted with dimethylamido groups. The solid-state molecular structure, as well as solution state NMR spectra, reveal an analogous structure to 3.18 (Figure 3.4). The N1–P1–O1 and N2–P2–O2 angles are smaller by ~2° compared to 3.18 due to the increased steric parameter of dimethylamido backbone (vs. ethoxy backbone in 3.18). Scheme 3.6 Reaction of Nb(NMe2)5 with two equivalents of phosphoramide Nb(NMe2)5 +OP NHArEtOEtO2.0Ar = 2,6-dimethylphenylNbNMe2NP NOP ONArArEtOEtOEtOEtO3.19Proposed100  Scheme 3.7 Synthesis of niobaziridine 3.20 The relative thermal stability of niobaziridine 3.18 is notable in comparison to that of mono(phosphoramidate) niobium complex 3.13. In a sealed J. Young NMR tube in Tol-d8, the niobaziridine species is not observed to decompose over 48 hours at 165 °C and less than 10% is observed to decompose over 72 hours of heating at the same temperature, as observed by 31P{1H} spectroscopy. On the other hand, complex 3.13 completely decomposes after only 12 hours at 110 °C, as observed by the formation of a complex 31P{1H} NMR spectrum and a disappearance of the signal for 3.13. Figure 3.4 ORTEP representations of 3.20 (left) and 3.21 (right) with select bond lengths and angles 3.20 Select Bond Lengths (Å) and Angles (°)  Nb–O1  2.2211(9) Nb–O2  2.2545(9) Nb–N1  2.2411(9) Nb–N2  2.1755(8) Nb–C1  2.180(2) Nb–N3  1.940(1) N3–C1  1.404(1)  N3–C2  1.439(2) Nb–N3–C2 153.36(8) C1–N3–C2 126.3(1)  3.21 Select Bond Lengths (Å) and Angles (°) Nb–O1  2.278(1) Nb–N1  2.206(1) P1–O1  1.507(1) P1–N1  1.611(1) Nb–N2  1.790(1) Nb–N3  2.005(1) Nb–N4  1.978(1) Nb–N2–C11 167.3(1)  Thermal ellipsoids are shown at 50%. H-atoms omitted for both. N(CH3)2 omitted for 3.20 (left).  Nb(NMe2)5 +OP NHiPrMe2NMe2N2.0– 3 HNMe2 NbNMe2NP NOP ONiPriPrMe2NMe2NMe2NMe2N3.20101  To date, there are no reports of imido complexes used as precatalysts for hydroaminoalkylation. Incorporation of an imido ligand may provide additional thermal robustness to the precatalyst complex, potentially increasing turnover number or allowing for improved substrate scope with increased reaction temperatures. Phosphoramidate imido complex 3.21 can be prepared from the reaction between 2,6-dimethylaniline and 3.13 (Scheme 3.8). The solid-state molecular structure reveals a pseudo trigonal bipyramidal structure with the multiply bonded imido (N2) and O2 of the phosphoramidate in the axial positions (Figure 3.4). The phosphoramidate ligand binds in a similar manner to those previously discussed with only minor changes from the binding in 3.13 suggesting the amido ligand has limited impact on the electronic character of the metal center. The Nb–N2–C11 bond angle is 167.30° implying N2 has significant sp-hybrid character, and that the imido ligand acts 6e– donor to access an 18e– complex. Both amido ligands are planar at nitrogen, consistent with previous structures.  Scheme 3.8 Synthesis of phosphoramidate imido Nb complex 3.21 3.3.2 Catalytic Hydroaminoalkylation Reactivity of Phosphoramidate Nb Complexes The synthesized mono phosphoramidate Nb complexes were tested for their reactivity as precatalysts in a hydroaminoalkylation reaction between N-methyl-para-methoxyaniline and 1-octene (Table 3.1).165,175,203 Reactivity was assessed at 5 mol% [Nb] loading at various temperatures. The precursor Nb(NMe2)5 was tested in a control reaction (entry 6). Previous work from the Schafer group has demonstrated phosphoramidate Ta complexes are also active precatalysts for hydroaminoalkylation.211 Entry 7 provides the direct comparison to entry 1, while entry 8 represents Ta precatalyst with the highest reported activity. Conversion was determined EtONPOEtOPhNbNMe2NMe2NMe2NMe23.13+– 2 HNMe2NH2NbNMe2NMe23.21NNPOPhEtOEtO102  by 1H NMR spectroscopy as a ratio between starting amine and product amine. Reports of conversions and isolated yields with Group 5 precatalysts have established that conversions are valuable indicators of catalytic activity for catalyst screening purposes.24-25,171-172,175,203  Entry 1 demonstrates good reactivity with 3.13 at 130 °C with decreasing reactivity down to 90 °C. A control reaction exhibits 33% conversion at 130 °C and no reactivity at 110 °C, confirming the ligand plays a significant role in the catalysis (entry 6). Modification of the N-functionality of the phosphoramidate ligand to increase the steric parameter decreases reactivity (entry 2, o-tolyl; entry 3, isopropyl). Modification of the ligand backbone substituents to increased steric parameters of isopropyl (entry 4) and to a significantly more electron donating dimethylamido backbone (entry 5), results in limited reactivity. Nb complex 3.13 (entry 1) demonstrates a marked improvement in activity compared to directly analogous Ta complex (entry 7). Additionally, this complex provides comparable activity at 90 °C to the best reported Ta complex (entry 8). However, a comparison at 100 °C reveals a significant decrease in active of the Nb complex.   103   Entry Precatalyst T (°C) Conversion (%)a 1  130 82 110 71 100 46 90 31 2  110 57 90 13 3  110 38 90 9 4  110 45 90 21 5  110 16 6 Nb(NMe2)5 130 33 110 n.r.c 7b  110 60 90 9 8b  100 98 90 37 Reaction conditions: N-methylaniline (0.5 mmol), 1-octene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol, 5 mol%), d8-toluene (0.5 mL). See experimental section for details. aDetermined by 1H NMR spectroscopy. bResults from the Schafer group.211 cn.r. = no reaction.   Table 3.1 Evaluation of monophosphoramidate Nb complexes as precatalysts for hydroaminoalkylation   EtONPOEtOTaNMe2NMe2NMe2NMe2EtONPOEtONbNMe2NMe2NMe2NMe23.14HN HN+5 mol% [M]20 h, TempMeO MeOEtONPOEtOPhNbNMe2NMe2NMe2NMe23.13EtONPOEtOiPrNbNMe2NMe2NMe2NMe23.15ONPOOPhNbNMe2NMe2NMe2NMe23.16iPriPrMe2NNPOMe2NiPrNbNMe2NMe2NMe2NMe23.17EtONPOEtOTaNMe2NMe2NMe2NMe2104  Next, the diphosphoramide complexes and the phosphoramide imido complex were access for reactivity (Table 3.2). Entry 1 and 2 evaluate the catalytic activity of the isolated niobaziridine complexes. Both provide limited reactivity with 3.20 exhibiting diminished reactivity compared to 3.18, consistent with the comparison between 3.13 and 3.17 (Table 3.1, entries 1 and 5). Notably, these niobaziridines are proposed to be active species in the catalytic cycle (see Chapter 2.1). While their reactivity is poor, the observation that niobaziridine species are active precatalysts suggests that these phosphoramidate Nb complexes follow the same generalized mechanism that has been proposed for Ta precatalysts. The phosphoramidate imido species 3.21 (entry 5) is not reactive for the hydroaminoalkylation reaction. One proposal for the lack of observed reactivity with 3.21 is that there is not sufficient steric congestion at the metal center to encourage appreciable niobaziridine formation as the single, multiple bonded imido ligand has replaced two dimethylamido ligands. Interestingly, the in situ preparations with two equivalents of phosphoramide to Nb, provide moderate (entry 3) and excellent (entry 4) yields at 90 °C. Given the exact nature of these precatalyst structures is unknown, it is difficult to assess the structure-activity relationship. We propose that the second equivalent of phosphoramidate enhances reactivity by creating a more electrophilic metal center by means of replacing a highly donating dimethylamido ligand. This has been demonstrated to enhance reactivity by utilization of chloro ligands in Ta complexes.24,171,175 Entry 4 also creates an optimal steric environment about the metal center, where increasing the steric parameter of the N-substituent (N-2,6-dimethylphenyl, entry 3; N-Dipp, entry 1) favours a highly stabilized niobaziridine structures that are kinetically inert due to the increased steric parameters of the phosphoramide ligands. The in situ preparation with N-phenyl phosphoramide (Table 3.2, entry 1) provides the highest reactivity at 90 °C, and offers a 105  significant improvement in activity compared the best reported Ta phosphoramidate complex (Table 3.1, entry 8).  Entry Precatalyst T (°C) Conversion (%)a 1  110 61 90 17 2  110 <5 3b  110 75 90 37 4b  110 >98 90 78  5  110 n.r.c Reaction conditions: N-methylaniline (0.5 mmol), 1-octene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol, 5 mol%), d8-toluene (0.5 mL). See experimental section for details. aDetermined by 1H NMR spectroscopy. bPrepared in situ at 5% for Nb, 10 mol% phosphoramide; see experimental for details. cn.r. = no reaction.  Table 3.2 Evaluation of diphosphoramidate and imido Nb complexes as precatalyst for hydroaminoalkylation  To further assess these Nb precatalysts, 3.13, 3.18, and the system generated in situ from entry 9, various substrates were examined (Table 3.3). As in the initial screening, the in situ generated system provides the highest reactivity across the evaluated substrate scope. Moving from the para-methoxyaniline derivative to aniline (entry 2) decreases reactivity. This trend has Nb(NMe2)5+OP NHPhEtOEtO2.0Prepared in situNb(NMe2)5+OP NHArEtOEtO2.0Ar = 2,6-dimethylphenylPrepared in situHN HN+5 mol% [M]20 h, TempMeO MeONbNMe2NP NOP ONDippDippEtOEtOEtOEtO3.18NbNMe2NMe23.21NNPOPhEtOEtONbNMe2NP NOP ONiPriPrMe2NMe2NMe2NMe2N3.20106  been observed for the reactivity of known phosphoramidate Ta complex 3.11.175 Dialkylamine substrates, known to be difficult for hydroaminoalkylation, only exhibit trace reactivity at elevated temperatures (entry 3 and 4). It should be noted that the lack of efficient reactivity here could be caused by catalyst design, or by catalyst death at elevated temperatures. For context, using piperidine as a substrate requires 134 h at 165 °C to produce 74% yield using amidate Ta complex 3.10.172 While reactivity with the strained norbornene is excellent (entry 6), reactivity with styrene (entry 7), and cyclohexene (entry 8) are poor.   107   Entry Product Temp (°C) Conversiona    1  110 71 61 >98 2  110 43 36 67 3  110 26 10 29 4  165 n.a.c <10 <10 5  165 n.a.c <10 <10 6  110 71 57 90 7  110 <10 <10 18 8  165 n.a.c <10 16 Reaction conditions: N-methylaniline (0.5 mmol), 1-octene (0.75 mmol), [Ta] pre-catalyst (0.025 mmol, 5 mol%), d8-toluene (0.5 mL). See experimental section for details. aDetermined by 1H NMR spectroscopy. bPrepared in situ at 5 mol% for Nb, 10 mol% phosphoramide; see experimental for details. cn.a. = not attempted. Table 3.3 Evaluation of substrate scope of Nb catalyzed hydroaminoalkylation   HNMeOHNHNHNHNNHMeO(+/–)HNMeOHNMeONb(NMe2)5+OP NHPhEtOEtO2.0Prepared in situbNH R NHR+5 mol% [Nb]Toluene-d8Temp, 20hEtONPOEtOPhNbNMe2NMe2NMe2NMe23.13NbNMe2NP NOP ONDippDippEtOEtOEtOEtO3.18108  A number of limitations in substrate scope were identified utilizing the in situ prepared Nb precatalyst system that has been demonstrated in Table 3.2 as the most active system (Scheme 3.9). It was found that alkynes, unknown as a hydroaminoalkylation substrate, were unreactive to generate the desired allylamines (Scheme 3.9a). In an attempt to observe chirality transfer, N-methyl-methylbenzyl amine was attempted but unsuccessful (Scheme 3.9b). Additionally, N-silylbenzylamine and a secondary amino-alkene substrate were both unreactive for hydroaminoalkylation (Scheme 3.9 c and d). 3.4 Conclusions We have demonstrated that a number of phosphoramidate Nb complexes can be synthesized and isolated. Interestingly, increasing the steric bulk of the N-substituent of the phosphoramide pro-ligand from phenyl to 2,6-dimethylphenyl or 2,6-diisopropylphenyl HNMeOHNNHPhTBDMS+ or++(c)(b)(a)HNPhPh(d)Nb(NMe2)5 +OP NHPhEtOEtOPrepared in situ[Nb] = 5 mol% 10 mol%in situ [Nb]Toluene-d8110 °C, 20 hin situ [Nb]Toluene-d8110 °C or 130 °C20 hXXin situ [Nb]Toluene-d8110 °C, 20 hXin situ [Nb]Toluene-d8110 °C, 20 hXScheme 3.9 Substrate combinations that are not reactive for hydroaminoalkylation with a phosphoramidate Nb catalytic system 109  drastically alters the protonolysis reaction in that two equivalents of ligand coordinate to each equivalent of metal center, even with excess Nb(NMe2)5 present in solution. One of these species (3.18) was identified to be a diphosphoramidate niobaziridine, a proposed intermediate in the catalytic cycle for hydroaminoalkylation.  Rewardingly, these complexes were active towards hydroaminoalkylation. An in situ preparation of 2:1 phosphoramide:Nb was found to be a highly active precatalyst system. Direct determination of the structure of the precatalyst has not yet been possible, but variable temperature NMR experiments reveal a highly fluxional system. Additionally, this system provides high reactivity for multiple substrates at 90 °C. However, challenging substrates such as dialkyl amines or internal alkenes give only trace reactivity even at elevated temperatures. At this time, it is unclear whether or not, or to what extent catalyst decomposition plays a significant role at the temperatures required for challenging substrate. These results also demonstrate that these Nb precatalysts are more active than their Ta analogues, and suggests that Nb analogues of known Ta catalytic systems could be exploited for improved reactivity.165 Many efforts on Ta suggest a mono-ligated 1,3-N,O-chelated complexes provide for best reactivity, while a bis-ligated 1,3-N,O-chelated complex provides significantly reduced activity.24-25,172,175,185 In contrast, the most active phosphoramidate Nb system discussed here requires 2 equivalents of phosphoramide ligand. This demonstrates that ligand design for Nb complexes can significantly from that of Ta complexes for hydroaminoalkylation and direct analogy between the reactivity of Nb and Ta complexes should not be assumed. 3.5 Experimental Details General considerations and instrumentation details can be found in Chapter 2.4.1 and 2.4.2, respectively. 110  3.5.1 Materials All chemicals were purchased from commercial sources and used as received unless otherwise specified. Chemicals from commercial sources that were not dried and shipped under inert atmosphere, were appropriately dried and degassed of O2 before being transferred to the glovebox or for use on the Schlenk manifold. All amines and alkenes were dried under N2 atmosphere with CaH2, distilled, and degassed by the freeze-pump-thaw method. Solid phosphoramides were sublimed under vacuum on a Schlenk manifold at 80 – 100 °C with water cooling, and liquid phosphoramides were distilled from CaH2 and degassed before being transferred into the glovebox. N-2,6-diisopropylphenyl diethyl phosphoramide decomposed during attempts to sublime the compound and was instead dried over 48 h under vacuum (10-2 mbar) at ambient temperature. Phosphoramides were synthesized according to literature procedures.175 Note: attempts to obtain air sensitive EI-MS of these compounds were not successful as they were found to lose dimethylamido ligands and the parent ion could not be detected. However, for purified complexes, solid-state molecular structures obtained from single crystal X-ray diffraction and elemental analysis confirm structure and purity. 3.5.2 Synthetic and Experimental Details Synthesis of (N-phenyl-O,O’-diethylphosphoramidato)tetrakis(dimethylamido)Nb(V) (3.13). In a glovebox, a solution of N-phenyl-O,O’-diethylphosphoramide (0.066 g, 0.287 mmol) in toluene (~ 4 mL) was added to a stirring solution of deep brown Nb(NMe2)5 (0.090 g, 0.287 mmol) in toluene (~ 6 mL). The resulting solution was stirred for 12 hours. The solution was then concentrated in vacuo. The sticky semi-solid was dissolved in a minimal amount of toluene at ambient temperature and stored in the freezer at -35 °C to promote recrystallization. After 24 h, the product could be recovered as red crystals (0.104 g, 0.210 mmol, 73%). 111   1H-NMR (600 MHz, C6D6): δ  7.33-7.31 (m, 2H), 7.20 (dd, J = 7.6, 0.6 Hz, 2H), 6.88 (tt, J = 7.3, 1.1 Hz, 1H), 4.04-3.93 (m, 4H), 3.36 (s, 24H), 1.08 (td, J = 7.1, 0.6 Hz, 6H). 13C{1H}-NMR (151 MHz, C6D6): δ  147.6 (d, JCP = 2.4 Hz), 129.6 (d, JCP = 1.5 Hz), 120.8 (d, JCP = 16.4 Hz), 119.4, 62.80 (d, JCP = 6.6 Hz), 49.1 (br. s), 16.5 (d, JCP = 6.7 Hz). 31P{1H}-NMR (122 MHz, C6D6): δ  5.0 (s). EA: Calc’d for C18H39N5NbO3P: C 43.46, H 7.90, N 14.08; Found: C 43.83, H 8.10, N 14.43. General procedure for the synthesis of complexes 3.14 – 3.17. In a glovebox, a solution of the corresponding phosphoramide (0.096 mmol) in toluene (~ 2 mL) was added to a stirring solution of deep brown Nb(NMe2)5 (0.030 g, 0.096 mmol) in toluene (~ 3 mL). The resulting red-orange solution was stirred for 12 hours. The solution was then concentrated in vacuo. Hexanes (~ 3 mL) was added and the solution concentrated in vacuo. This was repeated three times in an attempt to dissolve residual solvent in an effort to create a solid compound. Attempts at recrystallization from toluene or toluene/hexanes mixtures at ambient temperature or -35 °C were unsuccessful. Crude yields are reported, however, due to residual solvent or small impurities, crude yields are over 100%. (N-(2-methylphenyl)-O,O’-diethylphosphoramidato)tetrakis(dimethylamido)Nb(V) (3.14). Using the general procedure above, N-(2-methylphenyl)-O,O’-diethylphosphoramidate (0.023 g, 0.096) was added to Nb(NMe2)5 (0.030 g, 0.096 mmol) resulting in a red-orange semi-solid (crude yield of 0.047 g, 96%). 1H-NMR (400 MHz, C6D6): δ  7.31-7.28 (m, 1H), 7.20-7.18 (m, 2H), 6.90-6.88 (m, 1H), 4.02 (qd, apt. quintet, JHH = 7.1, JHP = 7.1 Hz, 4H), 3.183 (br. s, 12H), 3.179 (br. s, 12H), 2.62 (s, 4H), 1.14 (td, JHH = 7.1, JHP = 0.7 Hz, 6H). 13C{1H}-NMR (101 MHz, C6D6): δ  149.4 (s), 131.5 (d, JCP = 19.9 Hz), 130.6 (s), 126.4 (d, JCP = 13.0 Hz), 123.7 (d, JCP = 9.2 Hz), 118.3 (s), 62.1 (d, JCP 112  = 7.1 Hz), 47.6 (s), 47.0 (s), 19.9 (d, JCP = 8.3 Hz), 16.7 (d, JCP = 7.6 Hz). 31P{1H}-NMR (162 MHz, C6D6): δ  1.25 (s). (N-phenyl-O,O’-diisopropylphosphoramidato)tetrakis(dimethylamido)Nb(V) (3.15). Using the general procedure above, N-phenyl-O,O’-diisopropylphosphoramidate (0.025 g, 0.096 mmol) was added to Nb(NMe2)5 (0.030 g, 0.096 mmol) resulting in a red-orange semi-solid (crude yield of 0.055 g, 123%). 1H-NMR (400 MHz, C6D6): δ  7.33-7.29 (m, 2H), 7.19-7.15 (m, 2H), 6.88-6.84 (m, 1H), 4.67-4.59 (m, 2H), 3.35 (br. s, 18H), 1.25 (d, J = 6.1 Hz, 6H), 1.17 (d, J = 6.2 Hz, 6H). 13C{1H}-NMR (101 MHz, C6D6): δ  147.7 (d, JCP = 3.1 Hz), 129.5 (s, 4C), 120.8 (d, JCP = 16.9 Hz), 119.3 (s, 2C), 71.0 (d, JCP = 6.9 Hz), 49.1 (br. s), 24.2 (d, JCP = 6.1 Hz), 24.0 (d, JCP = 3.0 Hz). 31P{1H}-NMR (162 MHz, C6D6): δ  3.55 (s). (N-isopropyl-O,O’-diethylphosphoramidato)tetrakis(dimethylamido)Nb(V) (3.16). Using the general procedure above, N-isopropyl-O,O’-diethylphosphoramidate (0.019 g, 0.096 mmol) was added to Nb(NMe2)5 (0.030 g, 0.096 mmol) resulting in a red-orange semi-solid (crude yield of 0.051 g, 115%). 1H -NMR (400 MHz, C6D6): δ  4.01-3.91 (m, 4H), 3.78-3.64 (m, 1H), 3.40 (s, 18H), 1.45 (d, JHH = 6.6 Hz, 6H), 1.11 (td, JHH = 7.1, JHP = 0.4 Hz, 6H). 13C{1H}-NMR (101 MHz, C6D6): δ  62.4 (d, JCP = 7.4 Hz), 52.5 (d, JCP = 9.2 Hz), 49.2 (br. s), 48.1 (br. s), 26.7 (d, JCP = 6.0 Hz), 16.4 (d, JCP = 7.8 Hz). 31P{1H}-NMR (162 MHz, C6D6): δ  56.9 (s). (N-isopropylbis(dimethylamino)phosphoramidato)tetrakis(dimethylamido)Nb(V) (3.17). Using the general procedure above, N-isopropylbis(dimethylamino)phosphoramidate (0.019 g, 0.096 mmol) was added to Nb(NMe2)5 (0.019 g, 0.096) resulting in a red-orange semi-solid (crude yield of 0.059 g, 133%). 113  We observe some unknown significant impurities in the 1H NMR and 31C spectra as well as small baseline impurities. 1H-NMR (400 MHz, C6D6): δ  3.67 (sept, J = 6.5 Hz), 3.42 (br. s, 18H), 3.19 (d, J = 8.4 Hz, 3H, unknown assignment), 2.44 (d, J = 9.2 Hz, 12H), 1.28 (dd, JHH = 6.5, JPH = 0.4 Hz, 6H). 13C{1H}-NMR (101 MHz, C6D6): δ  (101 MHz, C6H6): δ  48.5 , 48.4 (br. s), 47.7 (d, JCP = 3.1 Hz), 47.0, 37.5 (d, JCP = 4.5 Hz), 32.0, 27.1 (d, JCP = 10.7 Hz), 23.1, 14.4. 31P{1H}-NMR (162 MHz, C6D6): δ  26.33 (s). Synthesis of bis(N-(2,6-diisopropyllphenyl)-O,O’-diethylphosphoramidato)dimethylamido-N-methylniobaziridine (3.18). In a glovebox, a solution of N-(2,6-diisopropylphenyl)-O,O’--diethylphosphoramide (0.540 g, 1.724 mmol) in toluene (~ 10 mL) was added to a stirring solution of deep brown Nb(NMe2)5 (0.270 g, 0.862 mmol) in toluene (~ 1 mL). The resulting solution was stirred for 12 hours. The solution was then concentrated in vacuo. The sticky semi-solid was dissolved in a minimal amount of toluene at ambient temperature and then cooled for 10 minutes at -35 °C. The yellow solution was then layered with a small amount of hexanes (~ 0.5 mL) and stored in the freezer at -35 °C to promote recrystallization. The product recrystallized over 24 h to yield pale yellow crystals (0.483 g, 69%). 1H-NMR (600 MHz, C6D6): δ  7.32-7.28 (m, 3H), 7.24-7.20 (m, 2H), 7.19-7.17 (m, 1H), 4.76-4.55 (m, 3H), 4.16-4.10 (m, 1H), 4.08-4.00 (m, J = 6.7 Hz, 1H), 3.97-3.93 (m, 1H), 3.89-3.70 (m, 5H), 3.58-3.54 (m, 1H), 3.11 (s, 3H), 2.86 (s, 6H), 2.59 (d, J = 5.2 Hz, 1H), 2.35 (d, J = 5.2 Hz, 1H), 1.57 (d, J = 6.6 Hz, 3H), 1.48-1.46 (m, 6H), 1.38-1.36 (m, 6H), 1.31 (d, J = 6.9 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H), 1.24 (t, J = 7.0 Hz, 3H), 1.21 (d, J = 6.7 Hz, 3H), 1.16 (t, J = 7.0 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.1 Hz, 3H). 13C{1H}-NMR (151 MHz, C6D6): δ  147.62 (d, JCP = 7.0 Hz), 147.43 (d, JCP = 6.3 Hz), 147.29 (d, JCP = 7.3 Hz), 145.50 (d, JCP = 6.0 Hz), 141.37 (d, JCP = 6.7 Hz), 140.28 (d, JCP = 7.2 Hz), 125.50 (d, JCP = 3.6 Hz), 124.73 (d, JCP = 3.2 Hz), 124.23 (m), 114  124.15 (d, JCP = 4.1 Hz), 123.80 (m), 123.62 (d, JCP = 3.3 Hz), 63.36 (d, JCP = 8.3 Hz), 63.12 (d, JCP = 6.6 Hz), 62.94 (t, JCP = 3.4 Hz), 62.92 (t, JCP = 4.5 Hz), 54.00 (s), 46.80 (s), 27.48 (d, JCP = 1.0 Hz), 27.35 (s), 27.18 (s), 26.99 (s), 25.85 (s), 25.71 (d, JCP = 1.0 Hz), 25.52 (s), 25.40 (s), 25.36 (s), 24.91 (d, JCP = 1.6 Hz), 24.86 (s), 16.78 (d, JCP = 4.8 Hz), 16.67 (d, JCP = 3.9 Hz), 16.24 (d, JCP = 6.8 Hz), 16.09 (d, JCP = 6.7 Hz). 31P{1H}-NMR (162 MHz, C6D6): δ  9.0, -0.2. EA: Calc’d for C36H65N4NbO6P2: C 53.73, H 8.14, N 6.96; Found: C 53.94, H 8.44, N 6.76. Synthesis of bis(N-isopropylbis(dimethylamino)phosphoramidato)dimethylamido-N-methylniobaziridine (3.20). In a glovebox, a solution of N-(N-isopropylbis(dimethylamino)phosphoramide (0.185 g, 0.958 mmol) in toluene (~ 4 mL) was added to a stirring solution of deep brown Nb(NMe2)5 (0.150 g, 0.479 mmol) in toluene (~ 1 mL). The resulting solution was stirred for 12 hours. The solution was then concentrated in vacuo. The sticky semi-solid was dissolved in a minimal amount of toluene at ambient temperature and then cooled for 10 minutes at -35 °C. The yellow solution was then layered with a small amount of hexanes (~ 0.5 mL) and stored in the freezer at -35 °C to promote recrystallization. The product recrystallized over 24 h to yield pale yellow crystals (0.176 g, 65%). 1H-NMR (600 MHz, C6D6): δ  4.08 (s, 3H), 3.90 (br. s, 1H), 3.63 (br. s, 1H), 3.40 (br. s, 6H), 2.65 (d, J = 8.8 Hz, 6H), 2.62 (d, J = 9.4 Hz, 6H), 2.54 (d, J = 9.4 Hz, 6H), 2.41 (d, J = 8.8 Hz, 6H), 1.38-1.31 (m, 12H). 13C{1H}-NMR (151 MHz, C6D6): δ  52.8 (s), 49.6 (s), 48.7 (s), 47.7 (s), 37.67 (t, JCP = 3.3 Hz), 37.65 (t, J CP = 3.3 Hz), 37.5 (d, J CP = 4.9 Hz), 37.3 (d, J CP = 4.4 Hz), 28.4 (d, J CP = 5.0 Hz), 26.7 (d, JCP = 11.2 Hz), 26.1 (d, JCP = 7.5 Hz), 25.8 (d, JCP = 3.5 Hz). 31P{1H}-NMR (121 MHz, C6D6): δ  34.6 (br. s), 24.6 (br. s). EA: Calc’d for C18H49N8NbO2P2: C 38.30, H 8.75, N 19.85; Found: C 38.45, H 8.79, N 19.86.  115  Synthesis of (N-phenyl-O,O’-diethylphosphoramidato)bis(dimethylamido)2,6-dimethylphenylimidoNb(V) (3.21). In the glovebox, a Schlenk flask was charged with a solution of 3.13 (0.115 g, 0.231 mmol) in 5 mL toluene. While stirring, a solution of 2,6-dimethylaniline (0.028 g, 0.231 mmol) in 5 mL toluene was added dropwise over 15 minutes. The Schenk flask was then sealed with a greased stopper and greased key, secured with elastics, removed from the box, and heated (while sealed) at 50 °C for 12 hours. The Schlenk flask was then returned to room temperature, attached to the Schenk manifold, and concentrated in vacuo to a yellow solid. The evacuated Schlenk flask was then returned to the glovebox. The crude solid was dissolved in minimal amount of toluene at ambient temperature and then cooled for 10 minutes at -35 °C. The yellow solution was then layered with a small amount of hexanes (~ 0.5 mL) and stored in the freezer at -35 °C to promote recrystallization. The product recrystallized over 24 h to yield pale yellow crystals (0.030 g, 25%). 1H-NMR (300 MHz, Tol-d8): δ  7.36-7.32 (m, 2H), 6.98-6.96 (m, 2H), 6.92-6.89 (m, 2H), 6.75-6.69 (m, 2H), 3.94-3.76 (m, 4H), 3.53 (s, 12H), 2.47 (s, 6H), 0.99 (td, JHH = 7.1, JHP = 0.6 Hz, 6H). 13C{1H}-NMR (75 MHz, Tol-d8): δ  133.8, 122.9, 122.6, 122.4, 121.9, 63.08 (d, JCP = 4.8 Hz) , 49.65, 19.46, 15.96 (d, JCP = 6.2 Hz). (aryl peaks hidden by solvent, solvent used due to solubility). 31P{1H}-NMR (121 MHz, Tol-d8): δ  11.92. EA: Calc’d for C22H36N4NbO3P: C 50.00, H 6.87, N 10.60; Found: C 50.55, H 6.73, N 9.98.  General procedure for catalytic hydroaminoalkylation reactions with isolated niobium complexes. In the glovebox at room temperature, 0.025 mmol (5 mol%) of metal pre-catalyst was dissolved in 0.30 g toluene-d8 in 1-dram vial. In a separate 1-dram vial, 0.5 mmol of amine substrate was dissolved in 0.30 g toluene-d8. In a third 1-dram vial, 0.75 mmol of alkene (or 116  alkyne) was weighed. The solution of amine was then added to the alkene (or alkyne) and mixed thoroughly to ensure a homogenous mixture. The substrate solution was then added to the pre-catalysts solution, and mixed thoroughly to ensure a homogeneous mixture. The reaction mixture was then transfer to a J. Young NMR tube and sealed with a Teflon screw-type cap. A 1H NMR spectrum was then recorded for reference, as t = 0 h. The NMR tube was placed in a thermostated oil bath on a hot plate, preset for the desired reaction temperature. After the desired reaction time, the J. Young NMR tube was removed from the hot oil bath and a 1H NMR spectrum was recorded. Conversion was determined by integration of peak(s) of desire product to peak(s) of substrate amine, and reported as conversion with respect to the amine substrate (conversion = normalized integration of product amine / sum of normalized integration of product and substrate amines). Chemical shifts of products were obtained from literature values.9,10,22,23  In situations where the pre-catalyst complex is not defined, in situ preparation was used to insure the concentration of metal species was accurately defined. In the glovebox at room temperature, 0.025 mmol of Nb(NMe2)5 was dissolved in 0.30 g toluene-d8. In a second 1-dram vial, 0.050 mmol of phosphoramide ligand was dissolved in 0.30 g toluene-d8. The protioligand solution was then added to and thoroughly mixed with the solution of Nb(NMe2)5. The solution was then added to a J. Young NMR tube and sealed with a Teflon screw-type cap. The NMR tube was shaken vigorously for ~3 minutes, after which 1H and 31P{1H} NMR spectra were recorded to confirm the absence of starting reagents. Utilizing this procedure, in no instances were starting reagents observed in the NMR spectra. The J. Young NMR tube was then taken back into the glovebox. In separate 1-dram vials, the amine substrate and alkene (or alkyne) substrate were 117  weighed. Following this, the contents of the NMR tube was first added to the amine substrate, and mixed thoroughly to ensure a homogenous mixture. This mixture was then added to the alkene (or alkyne) substrate, and mixed thoroughly to ensure a homogenous mixture. This mixture was then charged to the same J. Young NMR tube. From here the procedure recorded above for reactions with isolated niobium complexes was followed.  118  Chapter 4: 6-Substituted-2-Pyridonate and 2-Pyridonate Ligated Ru, Rh, and Ir Complexes for the Activation of Unprotected Amines – Efforts Towards Hydroaminoalkylation Catalysis for the α-Functionalization of Amines 4.1  Introduction 4.1.1 Alkylation of Amines through Hydrogen-Borrowing Catalysis Recently, hydrogen-borrowing catalysis, also termed hydrogen auto-catalysis or hydrogen auto-transfer, has garnered significant interest in the literature for the N-alkylation of amines with alcohols (Scheme 4.2).212-217 This chemistry has been reported for a variety of late transition metal homogeneous and heterogeneous catalysts, including those utilizing 2-hydroxypyridine ligands (or ligands containing the 2-hydroxypryidine fragment) as detailed in Chapter 1. Here, the alcohol is converted to a carbonyl by deprotonation and α-C–H activation resulting in the effective loss of one equivalent of H2 in the form of a proton and a metal hydride species (Scheme 4.2). The mechanism of this step likely depends on the complex and ligand design. For 2-pyridonate Ir species, DFT calculations suggest a concerted mechanism (often more specifically referred to as metal-ligand cooperativity or a bifunctional ligand-assisted mechanism) over a step-wise, β-H elimination mechanism. Subsequently, the amine and carbonyl undergo condensation to produce an imine and water, and, finally, the imine species is reduced by the ‘H2’ equivalent to the N-alkylated amine product. 119  Interestingly, specific complexes were also found to be able to perform the N-alkylation of amines utilizing a sacrificial amine as the alkylation reagent (Scheme 4.1).218-223 These reactions require higher temperatures (100-155 °C) as the C–H activation of amines to produce the an intermediate imine product is more challenging than the alcohol to carbonyl conversion.224 The precatalyst systems 4.1 – 4.5 in (Scheme 4.1) all produce N-alkylation of anilines to the secondary N- alkylaniline utilizing primary, secondary, or tertiary amines as the alkyl source. Precatalyst 4.5 provides the only examples of alkylation of benzylamines, where they utilize diisopropylamine. Substrate scope is (almost exclusively) limited to the formation of non-nucleophilic and sterically hindered N-alkylanilines as these do not appear to readily form the intermediate iminium cation necessary to produce the tertiary N,N-dialkylaniline product. While R1NH2 +[LnM] catalystR2 OH R1HN R2 + H2OMLBHMLBB = basic group(may or may notbe incorporatedinto ligand design)H+R3O– H2OMLBHH+ R1N R2H+ and H– (H2)equivalent storedas conjugated acidand metal hydrideScheme 4.2 N-alkylation of amines with alcohols via hydrogen borrowing catalysis RuPhPhPhPhORuPhPhPhPhOHHCO COOCOCAr NH2 +NHAralkyl + NH3alkyl NH2catalystRepresentative reaction:[Cp*IrCl2]2+ AgOTf[Cp*IrI2]2O NIrClP(nBu)3+ AgNTf2IrClOMeNMeO4.1• alkylation of anilineswith 1° aminesat 150 °C4.2• alkylation of anilineswith 1° aminesat 150 °C4.3• alkylation of anilines,with 1°, 2°, 3° aminesat 155 °C• alkylation of benzylamineswith diisopropylamine 4.4• alkylation of anilineswith triethylamineat 155 °C4.5• alkylation of anilineswith diisopropyl amineat 100 °CScheme 4.1 N-alkylation of amines with alkylamines via hydrogen-borrwing catalysis 120  not necessarily a practical synthetic route, unlike the same reaction with alcohols, the effective dehydrogenation of an amine to produce a metal hydride and proton equivalent is of interest as these types of intermediates can be utilized in other catalytic processes, such as hydroaminoalkylation. The Krische group has exploited and advanced the hydrogen-borrowing approach to produce α-alkylated N-heterocycles from amino-alcohols and dienes (Scheme 4.4).195 The products here are the same as would result from a hydroaminoalkylation reaction between the N-heterocycle and the diene. This Ru catalyzed reaction occurs via a modified hydrogen-borrowing mechanism: first, dehydrogenation of the alcohol produces an aldehyde and a Ru–H; second, cyclization to the cyclic imine occurs; third, insertion of the diene into the Ru–H bond generates a Ru-allyl species; fourth, C–C coupling occurs generating a Ru–amido complex; fifth, protonation of the Ru–amido species regenerates the catalyst and releases the product. A single example is provided where pyrrolidine is functionalized directly (Scheme 4.4b). This concept has also been expanded to a similar system where N-arylmethanimines (generated in situ from N-aryltriazene) are α-functionalized by dienes using 2-propanol as the reducing agent in a related transfer hydrogenation (Scheme 4.4c).196 This produces products that can conceptually be derived from hydroaminoalkylation (from N-methylaniline and diene) or hydroaminomethylation (from aniline, diene, CO, and H2).  Another report from the Yi group demonstrates the possibility of hydroaminoalkylation through this approach with the α-alkylation of amines with alkenes (Scheme 4.3).137 This is presumed to occur through a similar mechanism as described above. Here, the major product is the α-alkylated imine, with the desired α-alkylated amine as the byproduct. Presumably, the 121  imine product results from a dehydrogenation of the amine product, likely using the large excess of alkene (6 – 10 equivalents to amine) as the hydrogen acceptor.  4.1.2 Acceptorless Dehydrogenation of Amines A metal-hydride intermediate generated from the dehydrogenation of an amine can also be intercepted by a C-C unsaturation (such as an alkene) leading to the catalytic transfer dehydrogenation and subsequent hydrogenation of the unsaturation.224 Recently, multiple examples have been discovered where the metal-hydride can be intercepted by an appropriately acidic proton to generate H2; when done catalytically, this reaction is termed the acceptorless dehydrogenation of amines.78-80,225-234 While thermodynamically unfavorable, the release of gaseous hydrogen drives the reaction forward and avoids the use of an acceptor or stoichiometric oxidant to generate an imine. R1R2R1, R2 = alkyl+ NH2OH5 mol% RuHCl(CO)(PPh3)3 5 mol% dCyppToluene110 °CTosylationR1R26 examplesup to >20:1 drTsNR12 ExamplesR1 = H, Me 5 mol% RuH2(CO)(PPh3)(dppp) 5 mol% FcCOOHToluene130 °CTosylation+ HNR1 TsNR1 = H, 8:1 drR1 = Me, 5:1 dr(a)(b)N NNArArArR+(c)5 mol% RuHCl(CO)(PPh3)35 mol% dCypm2-propanolXylene140 °C, 24 hRNHAr15 examplesup to >20:1 (a:b)RNHAr+a bScheme 4.4 Ru-catalyzed synthesis of α-alkylated amines HN tBu+N tBu HN tBu+29%55:45 (imine:amine)HNxs+ xsN HN87%60:40 (imine:amine)+10 mol% RuHCl(CO)(PCy3)2THF120 °C, 24 h15 mol% RuHCl(CO)(PCy3)2THF80 °C, 24 hScheme 4.3 α-Alkylation of cyclic amines with alkenes 122  2-Hydroxypyridine/2-pyridonate ligands have been used in Ir complexes for both the acceptorless dehydrogenation, and the reverse hydrogenation reaction under hydrogen atmosphere (Scheme 4.5). Notably, complete dehydrogenation occurs utilizing these catalyst systems. DFT calculations based on complex 4.6 propose a concerted dehydrogenation step (vs. β-hydrogen elimination steps), followed by isomerization of the N-heterocycle to allow for another α-C–H activation (vs. C–H activation at other positions) (Scheme 4.6).235 The interconversion of 2,6-dimethylpyrazine and 2,6-dimethylpiperazine (Scheme 4.5b) is proposed for use in H2 storage systems as the reaction can be performed under neat conditions in both directions, and 2,6-dimethylpiperazine has a high gravimetric H2 capacity of 5.3 weight percent.80 NHN+ 2 H2IrClN OR 4.6 R = 5-CF3R R2 mol% 4.6p-xyleneReflux, 20 hN+ H2R1 atm NHRR = H, alkyl5 examples73-100%4-5 mol% 4.6p-xylene110 °C, 20 hR = H, alkyl5 examples13-100%IrOH2NN OO NN+ H2NHHN4.815 atm0.25 mol% 4.8p-xylene110 °C, 20 h89%2.0 mol% 4.8p-xylene, Reflux, 20 h100%IrOH2NN OO4.7+ H270 atm5.0 mol% 4.7p-xylene130 °C, 20 h85%5.0 mol% 4.7p-xylene, Reflux, 20 h97%NNHNNH(a)(b)(c)Scheme 4.5 Acceptorless dehydrogenation of N-heterocycles by 2-pyridonate Ir complexes 123  A variety of additional complexes are also utilized for the acceptorless dehydrogenation of amines (Figure 4.1). Complexes 4.1, and 4.9 – 4.11 have been reported for the acceptorless dehydrogenation N-heterocycles.228,230-232 Complex 4.11 has also been reported for the reverse, hydrogenation reaction. Notably, complex 4.9 is reported to dehydrogenate primary amines to the nitrile product in good to high yields with high selectivity.230 Complexes 4.12 – 4.14 have been reported for the dehydrogenation of primary amines, however, newly formed imine and amine condense to form the N-substituted imine and releasing an equivalent of ammonia.225-226,229 With the exception of complex 4.15, all other complexes catalyze acceptorless dehydrogenative reactions at >110 °C. Rh complex 4.15 operates at room temperature but under photolytic conditions (450 W Hg lamp).227 Arene supported Ru complexes 4.16 and 4.17 were studied comparatively to see if tethered amine groups (4.16) could play a significant role in acceptorless dehydrogenation. Catalytic reactions with benzylamine reveal a mixture of nitrile, imine, and dibenzylamine products with similar ratios and rates for both 4.16 and 4.17.233 Complex 4.18 was found to dehydrogenate benzylamine to mixtures of imine, dibenzylamine, and small amounts of tribenzylamine.234 4.2 Scope of Chapter IrClN O+HNIr ClNONHHIr ClNOH HNHNRe-enterscatalytic cycle+– H2Scheme 4.6 Mechanism for the acceptorless dehydrogenation of 1,2,3,4-tetrahydroquinoline proposed by DFT calculations 124  Recently, our group has reported the stoichiometric dehydrogenation of pyrrolidine and piperidine using a 1,3-N,O-chelated phosphoramidate Ir(III) complex 4.19 to produce Ir–H complex 4.20 and one equivalent of phosphoramide (Scheme 4.7).236 Notably, this reaction occurs at room temperature. This result, combined with the significant use of the 2-pyridonate motif used for dehydrogenation/hydrogenation chemistry (outlined above and in Chapter 1), lead us to propose that 2-pyridonate or tethered-2-pyridonate ligands may be effective ligands on Ru, Rh, or Ir complexes for use in the hydroaminoalkylation of unprotected amines utilizing a synthetic strategy similar to that described above for the Ru-catalyzed reactions (vide supra).  RuPhPhPhPhORuPhPhPhPhOHHCO COOCOC4.1FeNPiPr2COHPiPr2RuCliPrNN BuBu Cl4.12NNtBu2P RuNHPtBu2H COCoNPiPr2PiPr2HSiMe3NNNNNRuPPh3PPh3H4.9 4.10 4.114.13NNN ArAr AlH 4.14H BNONONO NCMeRhHH4.15NRuNCMePP+PhPhNBnBnRuNCMePP+PhPhPhPh4.164.17NN N NN IrOH2+4.18Figure 4.1 Transition-metal complexes reported to catalyze the acceptorless dehydrogenation of amines Ir+4.19PN OEtO OEt+ 2HN DCMRTIr+HN H4.20N+OP NHEtOEtO ArScheme 4.7 Stoichiometric dehydrogenation of pyrrolidine by a 1,3-N,O-chelated phosphoramidate Ir complex 125  Multiple steps must be achieved, and multiple side reactions must be suppressed to realize a general catalytic methodology for this reaction. A ligand and complex design approach was adopted to work toward this goal. Scheme 4.8 outlines the catalytic cycle for the hydrogen-borrowing approach to hydroaminoalkylation using a secondary amine and alkene. The first step in the catalytic cycle could potentially be addressed by extending the chemistry realized with 4.19 (Scheme 4.8) but with 2-pyridonate ligands as they have improved donor properties in the 2-hydroxypyridine form to allow for coordination to the metal center. Acceptorless dehydrogenation from the release of H2 is a potential off-cycle pathway. After insertion of the alkene into the M–H, protonation of the M–C bond, resulting in a transfer hydrogenation of the alkene, could occur. The basic functionality (B, Scheme 4.8) must be designed such that its conjugate acid (BH, Scheme 4.8) is not acidic enough to protonate the M–H or M–C bond. Alternatively, the basic functionality may be chosen to have poor binding affinity for the metal complex thereby creating an alternative thermodynamic preference to avoid the undesired side-reactions. The desired catalytic metal complex must then provide the correct environment to [M]LBHNR2+[M]LBHHR1NR2R1[M]LB+ H2Metal CatalystB = basic functionality(may or may notbe incorporateinto ligand)Avoid acceptorlessdehydrogenationof amineR3[M]LBHR3[M]LB[M]LBHNNR2R1+ R3Avoid transfer hydrogenationof C-C unsaturationR2R1R3HNR2R1R3Desired productScheme 4.8 Proposed catalytic cycle for the late-transition metal catalyzed hydroaminoalkylation of amines 126  accommodate insertion of the imine into the M–C bond to achieve C–C bond formation. Finally, protonation of the amide ligand provides the α-alkylated, hydroaminoalkylation product.  To this end, this chapter details the synthesis of 6-phosphinomethyl- and 6-phosphino-2-pyridone ligands and their use in the subsequent synthesis of Ru, Rh, and Ir complexes. These complexes as well as known 2-pyridonate complexes are explored for their reactivity toward secondary amines specifically targeting the catalytic α-alkylation with dienes and acceptorless dehydrogenation chemistry. 4.3 Results and Discussion 4.3.1 Arene Supported Ru, Rh, and Ir Complexes and Reactivity The efforts of Krische and co-workers,195-196 and Yi and co-workers, 137 to achieve hydroaminoalkylation chemistry make use of electron-rich phosphine ligands (e.g. bis(dicyclohexylphosphino)propane, bis(dicyclohexylphosphino)methane, tricyclohexylphosphine). Taking inspiration from their work, we endeavored to synthesize bidentate ligands incorporating both an electron-rich phosphine tethered to a 2-pyridone fragments. Additionally, we wanted to explore ligand derivatives that could provide us with variation in the chelate ring size to explore how that may affect complex synthesis and/or reactivity. Literature procedures for the synthesis of diphenylphosphino-2-pyridone ligands were adapted to synthesize the new variants 4.21 and 4.23 that incorporate more electron rich diisopropylphosphine moiety (Scheme 4.9).33,237 It was found that these ligands could be easily deprotonated with NaH to generate the sodium-2-pyridonate derivatives (4.23 and 4.24) for use in salt metathesis reactions. Reactions of the Na salt 4.23 with [Cp*RhCl2]2, [Cp*IrCl2]2, and [(p-cymene)RuCl2]2 starting materials, followed by the one-pot addition of NaB(ArF)4 (ArF = 3,5-triflu 127  oromethylphenyl), results in the formation of new cationic complexes 4.25, 4.26, and 4.27 (Scheme 4.10). Single crystals of the Rh complex 4.25 suitable for single crystal X-ray diffraction were obtained with the tetraphenylborate anion, which recrystallizes as a dimeric structure. X-ray diffraction data obtained for 4.25 and 4.26 reveal three-legged piano-stool complexes, instead of the expected two-legged piano-stool, unsaturated complex (Figure 4.2). Both structures reveal coordination of one Na ion per metal center, supported by the carbonyl oxygen of the 2-pyridonate ligand, the chloride, and solvent molecules. Analysis of the solid-state molecular structures reveals an anionic κ2-P,N-2-pyridonate binding mode and similar bonding metrics for both Rh and Ir. The 2-pyridonate fragment is found to be in a conjugated amide structure, with a C1–O1 bond length (1.260(4) Å for 4.25, 1.246(8) Å for 4.26) representative of a carbonyl functional group. While the solid-state molecular structure of complex 4.25 was obtained with a different anion (–BPh4 vs. –B(ArF)4), elemental analysis of the products [4.25][B(ArF)4] and  [4.26][B(ArF)4] confirms the molecular formulas as illustrated in Scheme 4.10. The incorporation of the Na ion suggests a highly Lewis basic oxygen in the 2-pyridonate moiety, potentially suitable for deprotonation, as proposed. NPiPr2OH4.21NPiPr2O4.22NOHi) 2 eq nBuLi-78 °C to 0 °Cii) 1 eq iPr2PCl0 °C to RTNaHNPiPr2ONa4.23proposedstructureNBrOtBui) 1 eq nBuLi0 °Cii) 1 eq iPr2PCl0 °C to RTNPiPr2OtBuHCOOHRT, 48 hNPiPr2OHNaHNa4.24proposedstructure(a)(b)Scheme 4.9 Synthesis of bidentate phosphine-2-pyridone ligands 128  1H NMR spectroscopy of 4.25 and 4.26 confirms the solid-state structures are present in solution as the isopropyl groups of the phosphine are inequivalent as expected. If an unsaturated, two-legged piano stool complex was formed in solution, the isopropyl group may be expected to present as equivalent. 1H and 31P{1H} NMR spectroscopy of 4.25 exhibit significant broadening of the signals indicative of a fluxional species. In particular, 31P{1H} NMR signal has poor intensity and suffers from significant broadening, but does present as the doublet expected from Rh coupling (1JPRh = 129.3 Hz). Signals for Et2O in the 1H NMR spectrum appear sharp, suggesting the solvent (THF-d8) replaces the Na coordinated Et2O in the structure in solution. + 2.0[Cp*MCl2]2 + NaB(ArF)44.25 M = Rh4.26 M = IrTHF or DCMRecrystalizedfrom Et2O/hexanes2.0ArF = 3,5-trifluoromethylphenylMNPOCliPriPrNaOEt2OEt2NPiPr2ONa4.23proposedstructure+–B(ArF)42.0RuNPOCliPriPriPrNaTHFTHF[(p-cymene)RuCl2]2THF+ 2.0 + NaB(ArF)42.0ArF = 3,5-trifluoromethylphenylNPiPr2ONa4.23proposedstructure+–B(ArF)44.27Scheme 4.10 Synthesis of Rh, Ir and Ru complexes 4.25, 4.26, and 4.27 [4.26][B(ArF)4] Et2O, H-atoms, and B(ArF)4 removed for clarity. Thermal ellipsoids are shown at 50%.  Select bond lengths (Å). Ir–P 2.306(2) C1–O1 1.246(8) Ir–N 2.137(4) C1–N1 1.390(9) Ir–Cl 2.421(1) [4.25][BPh4] THF, H-atoms, and BPh4 removed for clarity. Thermal ellipsoids are shown at 50%.   Select bond lengths (Å) Rh–P 2.315(1) C1–O1 1.260(4) Rh–N 2.129(3) C1–N1 1.384(4) Rh–Cl 2.4122(9) Figure 4.2 ORTEP representations of the solid-state molecular structures of 4.25 and 4.26 129  While the Ru complex 4.27 proved resistant to recrystallization, 1H and 31P{1H} NMR spectroscopy revealed a single product of high purity with spectroscopic signatures of the ligand environment almost identical to that in 4.26. The structure of 4.27 is thus assigned based on analogy to the Rh and Ir analogues. In the case of Ru, significant amounts of THF (the solvent used for synthesis) that are observed and are likely coordinated to the Na ion. Arene-supported complexes derived from ligand 4.22 would likely form a small-bite-angle 4-membered chelate upon complexation. The strain introduced in a small bite angle chelate may allow for different reactivity from the complexes prepared from 4.23. In particular, this could allow for the ligand to more readily adopt a κ1-P binding mode upon formation of the neutral 2-pyridone, allowing for an open coordination site at the metal center. The same synthetic pathway as above was employed utilizing ligand salt 4.24 to generate complexes 4.28 and 4.29 (Scheme 4.11). Unfortunately, these complexes were resistant to recrystallization. Fortunately, the 1H and 31P{1H} spectra for both complexes exhibit a single complex in high purity, consistent with the representation in Scheme 4.11. The 1H NMR spectra reveal asymmetric complexes with independent isopropyl groups, analogous to that found in structurally characterized complexes 4.25 and 4.26. 31P{1H} spectroscopy confirms a small bite angle with IrClNaTHFTHFRuCliPrNaTHFTHFTHFNOPiPriPrNOPiPriPr+–B(ArF)4+–B(ArF)4+ 2.0[Cp*IrCl2]2 NPiPr2ONa4.24proposedstructure+ NaB(ArF)42.0THF+ 2.0 NPiPr2ONa4.24proposedstructure+ NaB(ArF)42.0[(p-cymene)RuCl2]24.284.29Scheme 4.11 Synthesis of small-bite-angle complexes 4.28 and 4.29 130  both complexes having a significantly upfield and negative chemical shift (4.28, δ -27.8; 4.29, δ -6.3). The negative 31P{1H} NMR resonance is consistent with and indicative of a κ2-P,N binding mode.238 As the Krische group has seen success with pyrrolidine and dienes,195 the hydroaminoalkylation of isoprene with pyrrolidine was attempted with complexes 4.25 – 4.29 (Scheme 4.12). No coupling of pyrrolidine and isoprene was observed by 1H NMR spectroscopy or detected by HPLC/ESI-MS. Interestingly, a small depletion of pyrrolidine was observed and formation of signals consistent with a metal hydride was observed in the 1H NMR spectrum. The dehydrogenation of pyrrolidine was further evaluated by reacting each complex with 5 equivalents of pyrrolidine (Scheme 4.13). The Rh and Ir complexes were completely converted to their corresponding metal hydride species (4.30 and 4.31) with a concomitant loss of 1 equivalent of pyrrolidine as determined by 1H and 31P NMR spectroscopy. The 1H NMR spectra reveal a phosphine coupled doublet of doublets for the Rh complex (4.30, δ -11.97, 1JRhP = 19.7 Hz, 2JPH = 37.6 Hz), and doublet for the Ir complex (4.31, δ -14.90, 2JPH = 30.3 Hz) for the hydride signals. The same reaction can also be performed in toluene-d8. Heating for an additional 48 h at 110 °C brings about no change in the reaction mixture, with no further depletion of amine, indicating a highly stable hydride species. The same reaction with the Ru complex 4.27 (THF-d8, 70 °C, 18 h) results in only trace hydride formation as well as other unidentified species. Interestingly, in excess pyrrolidine the expected –OH resonance is not observed in the HN +10 mol% [M]Toluene-d8110 °C, 24 hNo product formationPartial depletion of pyrrolidineM–H observed by 1H NMR spec.[M] = 4.25, 4.26, 4.27, 4.28, or 4.29Scheme 4.12 Attempted hydroaminoalkylation of isoprene with pyrrolidine 131  1H NMR spectra. This could potentially be due to hydrogen bonding interactions with free pyrrolidine in solution. However, this can be observed in an isolated sample of 4.31 (vide infra). Reactivity of 4.28 and 4.29 show different reactivity due to their small-bite-angle. Both complexes were dissolved in THF-d8 with 5 equivalents of pyrrolidine in a sealed J. Young NMR tube then heated for 18 h at 70 °C, followed by additional heating for 18 h at 110 °C (Scheme 4.14). Complex 4.28 is first transformed into Ir–H 4.33 (31P{1H} δ -11.4), with the loss of one equivalent of pyrrolidine. Additional heating at 110 °C results in a mixture of 4.33 and κ1-P bound 4.34, where the binding mode is suggested based on the significantly downfield shift of the 31P{1H} NMR resonance (31P{1H} δ 53.4, Scheme 4.14a). The Ru complex 4.29 results in formation of κ1-P bound 4.35 (assigned by the upfield shift of the signal in the 31P{1H} NMR spectrum) in a 1.6:1 ratio of 4.35 to 4.29 (Scheme 4.14b). Interestingly, no Ru–H species with a κ2-P,N binding mode is observed. Further heating at 110 °C results in decomposition of the Ru complexes, as evidenced by baseline signals only being observable in the 31P{1H} NMR spectrum. No further conversion of the pyrrolidine is apparent by 1H NMR spectroscopy. Both of the proposed κ1-P complexes [4.34] and [4.35] are assigned a neutral donor, L, based on general electron counting rules (to create an 18 e– complex). However, the number of signals in the 1H NMR spectra prevents further assignment of complexation. These results demonstrate the small-+HN MNPOHHiPriPrTHF–d870 °C, 18 h+N1H NMR, !4.30 -11.97 (d, 1JRhP = 19.7 Hz, 2JPH = 37.6 Hz) 4.31 -14.90 (d, 2JPH = 30.3 Hz)31P{1H} NMR, !4.30 76.5 (d, 1JRhP = 140.8 Hz)4.31 40.1 (s)5.04.30 M = Rh4.31 M = Ir4.25 or4.26+HN4.0++HN THF–d870 °C, 18 h5.04.27decomposition of 4.27trace Ru–H detectedScheme 4.13 Reaction of 4.25, 4.26, and 4.27 with 5 equivalents of pyrrolidine 132  bite-angle derivatives offer hemi-labile coordination/de-coordination. Additionally, the Ir variant requires a higher activation energy than the Ru example to access de-coordination of the pyridine fragment. Similar to the large-bite-angle complexes, no acceptorless dehydrogenation is observed in these reactions. With precedence for 2-pyridonate Ir complexes to be active catalysts for acceptorless dehydrogenation (see Chapter 4.2.1), we further explored 4.26 toward this reaction. A frozen solution of 4.26 in a sealed J. Young NMR tube was backfilled with ~ 1 atm of H2. Heating to 110 °C over 24 h resulted in no reaction. This demonstrates that if H2 release was occurring in the above stoichiometric dehydrogenations, it is not reversible. We also found that a reaction of 4.25 with excess piperidine and diethylamine resulted in the same Ir–H 4.31 (THF-d8, 80 °C, 18 h). Curiously, N-methylaniline only produces 30% of hydride 4.31 under the same reaction conditions. This slow reaction rate could be due to an induction period required to break apart the Na-Cl complex or, alternatively, could indicate a requirement for an electron rich amine in the dehydrogenation step. In all cases, no catalytic acceptorless dehydrogenation or additional conversion of the amine was observed. 4.28 +HN5.0THF–d870 °C, 18 hIrHNOHPiPriPr++N+HN4.0THF–d8110 °C, 18 hIrH+NPOHiPriPrL4.34L = imine oramine4.33(a)4.29 +HN5.0THF–d870 °C, 18 h(b)NPOHiPriPr Ru HiPrL+4.35L = imine oramine+4.334.33 : 4.341 : 9.64.29 +4.29 : 4.351 : 1.7THF–d8110 °C, 18 hdecomposition of Ru–H31P{1H} NMR, !4.28 -27.84.33 -11.44.34 53.431P{1H} NMR, !4.29 -6.34.35 21.2Scheme 4.14 Reaction of 4.28 and 4.29 with 5 equivalents of pyrrolidine 133  To explore the reactivity of 4.31 in the absence of excess pyrrolidine, 4.31 can be isolated from the reaction of 4.26 and excess ethanol, followed by recrystallization (Scheme 4.15a). An attempt to isolate 4.31 from a reaction of 1 equivalent of 4.26 and 1 equivalent of pyrrolidine resulted in only 50% conversion to the hydride species 4.31. Addition of one additional equivalent results in full conversion to 4.31. After workup (removal of volatiles, washing with hexanes, and removal of trace volatiles again), the 1H NMR spectra reveals a remaining equivalent of pyrrolidine, with a downfield shift of the α-methylene proton signals compared to free pyrrolidine (Scheme 4.15b). Further, a 1D 1H NOE experiment, with irradiation of the Cp* protons, results in an NOE signal for the α-protons of the pyrrolidine (in addition to NOE signals of the phosphine/2-pyridone ligand). Comparing isolated 4.31 and 4.31•pyrrolidine, 1H and 31P{1H} spectroscopy reveal very similar chemical shifts for both complexes, however, 4.31•pyrrolidine exhibits broadened peaks, that is particularly evident in the 31P{1H} resonance. Additionally, the OH resonance for 4.31 can be found in the 1H NMR spectrum at 7.78 ppm (CDCl3).  Comparatively, the OH resonance cannot be located in the 1H NMR spectrum of 4.31•pyrrolidine, due to exchange of the hydrogen bonding interaction causing extreme broadening of the signal. The changes in the NMR spectra suggest a similar binding mode in +HN IrNPOHiPriPrTHF–d870 °C, 2 h2.04.26+HNobserved NOE signal(excite methyl of Cp*)+ 4.04.26 OHTHF–d870 °C, 12 h4.31•pyrrolidineIrNPOHHiPriPr4.31+H(b)(a)Scheme 4.15 Synthesis and isolation of 4.31 and 4.31•pyrrolidine 134  each, with the pyrrolidine involved in a hydrogen bonding interaction with the hydroxy functionality (Scheme 4.15b). Isolated complex 4.31 was tested in a variant of refluxing solvents to evaluate if H2 release or other decomposition is possible. However, reactions in THF-d8, D2O, toluene-d8, 2,2,2-trifluoroethanol, and o-xylene-d10 in a J. Young NMR tube reveal no decomposition of complex 4.31 by 31P{1H} NMR spectroscopy. Also, 4.31 showed no reaction with 3 equivalents of t-butylsulfinimide (THF-d8, 70 °C, 24 h). These results suggest the Ir–H complex does not have the required basicity to release H2 or allow for hydrogenation of an unsaturation by 4.31.  While these complexes proved inactive for the desired catalytic hydroaminoalkylation, or the acceptorless dehydrogenation of amines, these results suggest cationic complexes are highly active for stoichiometric dehydrogenation of secondary amines and ethanol. Given the lack of reactivity, we postulated that the bidentate ligands may have suppressed reactivity by not providing an open coordination site, or if the use of a phosphine donor created highly stable metal hydride that is unreactive. Curiously, the known complex 4.36 is reactive for the acceptorless dehydrogenation of N-heterocycles, but is not reported for reactivity with additional amines.78 To this end, catalytic reactions were attempted with complexes 4.36 – 4.40 with one equivalent NaB(ArF)4 to generate a cationic complex in situ. Dibenzylamine was chosen as the amine source due to its NMR spectral simplicity, allowing for ease of analysis of the products. Catalytic reactions between dibenzylamine and isoprene were attempted with 5 mol% 4.36 – 4.38 with 5 mol% NaB(ArF)4 in a J. Young NMR tube at 100 °C for 24 h, and following 1H NMR experiment at ambient temperature, was heated for an additional 72 h at 130 °C (Scheme 4.16). Interestingly, Ir complex 4.36 generates only tribenzylamine product in a final conversion of 72% (by 1H NMR analysis; product presence confirmed by GC/MS). The 135  tribenzylamine product likely results from  a series of steps: 1) generation of N-benzylbenzaldimine and a M–H; 2) attack by an equivalent of dibenzylamine to form N,N-dibenzyl-benzaldiminium cation; 3) the N,N-dibenzyl-benzaldiminium cation is then sufficiently activated to be hydrogenated by the M–H and protonation results in tribenzylamine; 4) released benzylamine can attack an equivalent of N-benzylbenaldimine producing the N,N-dibenzylbenzaldiminium cation and releasing an equivalent of ammonia to result in only Net Reaction: Ph NHPh3.0[M] catalyst Ph N PhPh2.0 + 1.0 NH3Ph NHPh + NO[M]+ Ph N PhNOH[M]+H+Ph N Ph + Ph NHPh Ph N PhPh+ NHPhPh N PhPh+ NHPhNOH[M]+H+ + NO[M]+Ph N PhPh+ NH2PhPh N Ph+ Ph NH2Ph N PhPh+ H2N(1)(2)(3)NOH[M]+H+ + NO[M]+Ph N PhPh+ NH3(4)Scheme 4.17 Generation of tribenzylamine from dibenzylamine IrClNNNNRuCliPrIrClN O4.36RuCliPrNO4.38 4.394.40RhClN O4.37+ 4.05 mol% [M]5 mol% Na(BArF)44:1 Tol-d8:THF-d8Bn2NHBn2NH + Bn3N + N PhBna b c100 °C, 24 h[M] – a:b:c (%)4.36 – 55 : 42 : 04.37 – 96 : 0 : 04.38 – 82 : 5 : 12additional 130 °C, 72 h[M] – a:b:c (%)4.36 – 16 : 72 : 04.37 – 73 : 7 : 04.38 – 18 : 13 : 56130 °C, 24 hw/ 5 eq isoprene[M] – a:b:c (%)4.38 – 12 : 9 : 784.39 – 39 : 12 : 27PhScheme 4.16 Attempted hydroaminoalkylation of isoprene with dibenzylamine 136  formation of the tribenzylamine (Scheme 4.17).   The Rh complex 4.37 only demonstrates trace reactivity for this transformation, and further experimentation with Rh was abandoned. The Ru complex 4.38 provides significant conversion of dibenzylamine to give tribenzylamine (13%), and the imine product (56%). The formation of the imine product is likely the result of dehydrogenation of the amine with concomitant transfer hydrogenation to the isoprene. At this time, the fate of the isoprene has yet not been determined. Reactions with 4.38 in the absence of an acceptor unsaturation result in only the formation of benzylamine confirming the transfer hydrogenation (vide infra, Scheme 4.18a). Unfortunately, in all these reactions, the desired α-alkylation product was not observed by 1H NMR spectroscopy or by GC/MS. We hypothesized that the 2-pyridone ligand was overly acidic, resulting in protonation of the generated Ru–allyl species (from insertion of isoprene into the generated Ru–H). To avoid this, Ru complex 4.39 was prepared and subjected to slightly modified conditions (along with 4.38). However, no α-alkylation product was observed and it was found that 4.39 performed worse for the dehydrogenation of dibenzylamine than 4.38 (Scheme 4.16).  While not successful for hydroaminoalkylation chemistry, we wondered if the chemistry could be adapted to achieve acceptorless dehydrogenation of amines. Reactivity of dibenzylamine was explored, in the absence of isoprene, with these Ir and Ru complexes as well as complex 4.40, a new derivative adapted from previous 2-aminopyridinate complexes of Ir (Scheme 4.18a).239 The complex 4.40 was included as a more basic derivative to potentially avoid the hydrogen bonding observed in 4.31•pyrrolidine, which may hinder hydrogen release in a catalytic acceptorless dehydrogenation. These reactions were conducted in degassed and evacuated J. Young NMR tubes to allow for significant head-space to facilitate H2 release. In the 137  absence of NaB(ArF)4 no reaction with 4.36 or 4.38 and only minor loss of dibenzylamine is observed with no new product formation. Upon addition of 1 equivalent of NaB(ArF)4, it was found that both Ir complexes, 4.36 and 4.40, were most effective in producing tribenzylamine, with quantitative conversion. To encourage H2 release, a solvent mixture of toluene-d8 and tert-butanol (1:1 v:v) was used with the hope that the alcohol could serve as a proton source. This resulted in no change in reactivity. In all cases no imine product was observed. While degassed and evacuated, our closed system could allow for the potentially released H2 to react with our metal species. Complexes 4.36 and 4.26 were revisited, in a reaction of dibenzylamine in an open system under dynamic N2 (Scheme 4.18b). GC/MS analysis revealed full conversion of dibenzylamine into tribenzylamine in both cases. This observation provides strong evidence that H2 is not being produced under either set of conditions. In the reaction with 4.26, there is presumed formation of 4.31, indicating that the Ir–H can hydrogenate iminium cations. Hydrogenation of iminium cations has previously been observed by analogous Cp*Rh and Cp*Ir hydrides.240-241 2 mol% [M]x mol% Na(BArF)4degassed, evacuated (10-1 mbar)J. Young NMR tube130 °C, 24 hsolventBn2NHBn2NH + Bn3N + N PhBna b c4:1 Tol-d8:THF-d80 mol% NaB(ArF)4[M] – a:b:c (%)4.36 – 92 : 0 : 04.38 – 87 : 0 : 04:1 Tol-d8:THF-d82 mol% NaB(ArF)4[M] – a:b:c (%)4.36 – 0 : > 95 : 04.38 – 88 : 15 : 04.39 – 83 : 17: 04.40 – 0: > 95 : 01:1 Tol-d8:tBuOH2 mol% NaB(ArF)4[M] – a:b:c (%)4.36 – 0 : > 95 : 04.38 – 77 : 14 : 02 mol% [4.36 + NaB(ArF)4]or2 mol% 4.26 xylenes, 135 °Copen system under dynamic N2Bn2NH3 Bn3N2 Only amine detectedby GC/MS(a)(b)Scheme 4.18 Attempted catalytic acceptorless dehydrogenation of dibenzylamine 138   Ru complex 4.38 was additionally tested with dibenzylamine and other unsaturations under catalytic conditions (Scheme 4.19). With allyl acetate, quantitative conversion to the N-allyl tertiary amine is formed as determined by 1H NMR spectroscopy and GC/MS analysis. Reaction with styrene or 1-phenylpropyne result in only minimal conversion of dibenzylamine, minimal amounts of tribenzylamine, no imine product, and no α-alkylation products.  4.3.2 Initial Investigations into Non-Arene Ligated Late-Transition-Metal Complexes for Hydroaminoalkylation  The cationic complexes described above have demonstrated facile stoichiometric dehydrogenation of amines, catalytic conversion of dibenzylamine to tribenzylamine, and catalytic dehydrogenation of amine to imine using a diene hydrogen acceptor. This reactivity can be attributed to the use of the 2-pyridonate ligand framework to assist in the dehydrogenation. As cationic complexes, they are inherently electron deficient. Unfortunately, this seems to limit the hydricity of the generated M–H, making them unsuitable for the desired hydroaminoalkylation of amines. Based on the reported successes of non-arene supported Ru phosphine complexes to demonstrate reactivity for the hydroaminoalkylation reaction (see Chapter 4.1.1).195,242 we endeavored to synthesize similar Ru complexes using ligand 4.21 or its sodium salt 4.23. Refluxing 2 equivalents of 4.21 with polymeric [RuCl2(COD)]x in toluene results in complex 4.41 (Scheme 4.20). This complex was could be recrystallized and the solid-state molecular structure was obtained by single crystal X-ray diffraction (Figure 4.3). This complex Bn2NH + 2OOPhPhNPh Phquant. conversionby 1H NMR spec. and GC/MSBn2NH + Bn3N75% 8%Bn2NH + Bn3N93% 3%2 mol% [4.36 + NaB(ArF)4]4:1 Tol-d8:THF-d8130 °C, 24 hScheme 4.19 Attempted catalytic reactions between dibenzylamine and C–C unsaturations 139  recrystallizes in a pseudo-octahedral geometry with axial chloride ligands, and a cis-phosphine arrangement of the phosphino-2-hydroxypyridine ligands. Compared to the 2-pyridonate fragment in 4.25 and 4.26, we observe a lengthened C1–O1 bond at 1.352(7) Å (C13–O2 is 1.351(7) Å) compared to 1.260(4) Å and 1.246(8) Å respectively. Furthermore, 4.41 has a shortened C1–N1 bond of 1.341(7) Å and C13–N2 bond of 1.335(7) Å (1.138(4) Å in 4.25; 1.390(9) Å in 4.26). Both of these results are consistent with the assignment of a κ1-N-2-hydroxypyridine fragments. Complex 4.41 was found to react with 2 equivalents of NaHMDS to produce the proposed complex 4.42 (Scheme 4.20a). This complex could not be purified as it was found to decompose upon removal of solvent and was resistant to recrystallization. The structure of 4.42 [RuCl2(COD)]x + 2/xToluene12 h, reflux4.21 NPHONPOHRuClCliPriPriPriPrTHF-d8in situ2.0 NaHMDS+NPHONPORuNiPriPriPriPrTMS TMSProposed Complex 4.42Decomposes upon removing solvent in vacuoTHF-d870 °C, 15 h+HN5.04.414.42prepared in situ(a)(b)Scheme 4.20 Synthesis and reactivity of 4.41 H-atoms removed. Thermal ellipsoids are shown at 50%.  Select bond lengths reported as averages (Å): Ru–P 2.287 Ru–N 2.224 Ru–Cl 2.427 C(2-position)–N 1.338 C(2-position)–O 1.351 Figure 4.3 ORTEP represenation of the solid-state molecular structure of 4.41 140  is proposed on the basis of the NMR spectra. The 31P{1H} spectrum reveals two coupled doublets, and the 1H NMR spectrum reveals a downfield singlet at 14.59 ppm (integration of 1H, THF-d8), indicative of a 2-hydroxypyridine proton (9.73 ppm in 4.41, THF-d8). The 1H NMR spectrum also indicates two inequivalent phosphino-2-hydroxypyridine ligand environments. A reaction of in situ prepared 4.42 produces no reaction with excess pyrrolidine, and was not further evaluated (Scheme 4.20b). Rh(I) and Ir(I) complexes 4.43 and 4.44 were synthesize by salt metathesis of 2 equivalents of 4.23 and the corresponding [M(COD)Cl2]2 dimer (COD = 1,5-cyclooctadiene) (Scheme 4.21a). Unfortunately, these complexes could not be recrystallized. 1H and 31P{1H} spectra show a single product of high purity that is consistent with the square-planar structure shown. Unlike the previous complexes where Na-Cl is coordinated, there is no significant THF (reaction solvent) signals in the 1H NMR spectrum that would likely be required to support coordination of a Na ion. These complexes were not active precatalysts for the hydroaminoalkylation of isoprene with pyrrolidine (Scheme 4.21b). The attempted salt metathesis reactions with known Ru complex and 4.23 results in mixtures of unidentifiable complexes (Scheme 4.22). However, free PPh3 and no free 4.21 or 4.23 is detected in the 31P{1H} NMR spectra of these attempted reactions, indicating [M(COD)μ2-Cl]2 + 2.0 4.23NPMOiPriPrTHFRT4.45 M = Rh4.46 M = IrHN + 4.0HNDesired product5 mol% 4.45 or 4.46Tol-d8130 °C, 24 h(a)(b)Scheme 4.21 (a) Synthesis of Rh(I) and Ir(I) complexes 4.45 and 4.46; (b) attempted use of M(I) as precatalysts for hydroaminoalkylation 141  complexation of the phosphino-2-pyridonate ligand does occur. As discussed previously, work by Krische and co-workers did not rely on preformed complexes, but instead in situ generation of the active catalyst system.195-196 Due to our lack of success in isolating Ru complexes, we instead turned to attempted α-alkylation reactions between piperidine and 2,3-dimethyl-1,3-butadiene with in situ generation of these systems (Scheme 4.23). Here, 5 mol% of known Ru(CO)HH(PPh3)3 was combined with 5 mol% of one of ligands 4.21, 4.22, or 4.45 – 4.47. Developments from Krische and co-workers have found the use of diphosphinopropane ligands to be successful, and the same series of reactions were attempted with the addition of 5 mol% dppp (dppp = 1,3-bis(diphenylphosphino)propane) added as well. To test whether the carbonyl ligand significantly altered catalytic activity, 5 mol% of the known RuHCl(PPh3)3 with addition of 5 mol% of one of the sodium-2-pyridonate salts (4.23, 4.24, or 4.48) were also tested as a catalyst system. To our disappointment though, these reactions were all unsuccessful. By 1H NMR spectroscopy or HPLC/ESI analysis, no hydroaminoalkylation product formation was observed, nor was any significant consumption of the starting materials apparent. Starting from isolated complexes would remove significant amounts of PPh3 from the reaction. Excess phosphine could be hindering the reactivity by out-competing the amine substrate for coordination/interaction with the metal center. Known Ru complexes 4.49 and 4.50 Ru(CO)HCl(PPh3)3RuHCl(PPh3)3 + 4.23+4.23• unknown complexation• multiple hydride 1H NMR signals• no free 4.21, 4.23, or starting [Ru]• unknown equiv. free PPh3NP[RuHLn]OiPriPrPPh3THFTHFi) 4.21 ii) tBuOKor +NP[RuHLn]OiPriPrPPh3+Scheme 4.22 Attempted synthesis of phosphino-2-pyridonate ligated Ru–H complexes 142  were synthesized and tested as catalyst for the reaction between pyrrolidine and isoprene (Scheme 4.24). However, no α-alkylation products or notable conversion of the starting materials were observed.  4.4 Conclusions In summary, we have successful synthesized a variety of κ2-P,N-bidentate phosphino-2-pyridonate arene supported cationic complexes. Interestingly, the oxygen of the 2-pyridonate ligand fragment proves to be highly Lewis basic, stabilizing a Na-Cl adduct within the solid-state molecular structure. These complexes were demonstrated to stoichiometrically to generate metal +HNHNNPiPr2OH4.21 4.22NPiPr2OHNOHNNHEtOPNHOPhEtONPiPr2ONPiPr2ONa4.23proposedstructureNa4.24proposedstructureNONaDesired product5 mol% [Ru]Tol-d818 h, 110 °CL1 =[Ru] = 5 mol% Ru(CO)HH(PPh3)3 + 5 mol% L1or[Ru] = 5 mol% Ru(CO)HH(PPh3)3 + 5 mol% dppp+ 5 mol% L1[Ru] = 5 mol% RuHCl(PPh3)3 + 5 mol% L2L2 =4.45 4.46 4.474.48Scheme 4.23 Attempted hydroaminoalkylation of 2,3-dimethyl-1,3-butadiene with piperidine in situ generated Ru catalysts NO RuH(CO)(PPh3)24.495 mol% 4.49 or 4.50THF-d8110 °C, 18 hHN +NHN RuH(CO)(PPh3)24.505 mol% 4.49 or 4.505 mol% LTol-d8110 °C, 20 hHN + 4.0 L = rac-BINAP, dppe,tBu3P, CyJohnPhosHNHNDesired productDesired productScheme 4.24 Attempted hydroaminoalkylation of isoprene with pyrrolidine using Ru complexes 4.43 and 4.44 143  hydride complexes. Unfortunately, the generated metal hydrides are not reactive and did not allow for catalytic hydroaminoalkylation of amines, or the catalytic acceptorless dehydrogenation of amines. To test the effect of removing the phosphine donor, cationic complexes were derived in situ from Ru, Rh, and Ir 2-pyridonate and 2-aminopyridinate complexes and sodium tetraarylborate. These in situ systems were tested for as precatalyst for the catalytic hydroaminoalkylation, and catalytic acceptorless dehydrogenation of amines. Attempts at the catalytic acceptorless dehydrogenation of dibenzylamine resulted in formation of tribenzylamine. Reactions of dibenzylamine and diene with catalytic Ir also resulted in formation of tribenzylamine. In contrast, using catalytic Ru resulted in formation of N-benzylbenzaldimine, via transfer hydrogenation of the diene.  Finally, initial investigations were undertaken to synthesize alternative complexes using ligand 4.21. While complexation with Ru occurs, isolation of the products proved difficult. Instead, numerous in situ derived catalytic systems were tested for the hydroaminoalkylation of amines with dienes, but attempts have been unsuccessful to date. Square planar Rh(I) and Ir(I) complexes were synthesized bearing a phosphino-2-pyridonate ligand. These complexes were also not active precatalysts for the hydroaminoalkylation reaction. 4.5 Experimental Details General considerations and instrumentation details can be found in Chapter 2.4.1 and 2.4.2, respectively. 4.5.1 Materials All chemicals were purchased from commercial sources and used as received unless otherwise specified. Chemicals from commercial sources that were not dried and shipped under inert 144  atmosphere, were appropriately dried and degassed of O2 before being transferred to the glovebox or for use on the Schlenk manifold. All amines and alkenes were dried under N2 atmosphere with CaH2, distilled, and degassed by the freeze-pump-thaw method. Commercially available 2-pyridones were sublimed under vacuum on a Schlenk manifold at 80 – 100 °C with water cooling. N-2,6-diisopropylphenyl diethyl phosphoramide decomposed during attempts to sublime the compound and was instead dried over 48 h under vacuum (10-2 mbar) at ambient temperature. NaB(ArF)4 was generously provided by Prof. Hein’s research group (UBC Vancouver). [Cp*RhCl2]2 was generously donated by Prof. Legzdins’ research group (UBC Vancouver). N-(2,4,6-trimethylphenyl)-2-amino-6-(2,4,6-trimethylphenyl)pyridine,243 2-bromo-6-tert-butoxypyridine,244 N-(rac-2-methylpropane-2-sulfinyl)benzaldimine,245 4.36,78 4.37,70 4.38,246 4.49,247 4.50,247 1,2,3,4,5-pentamethylcyclopentadiene (Cp*H),248 [RuCl2(COD)]n,249 [Cp*IrCl2]2,250 [Ir(COD)Cl2]2,251 [Rh(COD)Cl2]2,252 Ru(CO)HH(PPh3)3,253 Ru(dppp)(CO)H(PPh3),254 Ru(CO)HCl(PPh3)3,255 and RuHCl(PPh3)3,256 were synthesized according to literature procedures.  4.5.2 Synthetic and Experimental Details Synthesis of 6-(diisopropylphosphino)methyl-2-pyridone, 4.21.33 Using a Schlenk double manifold and standard technique, a dried 100 mL Schlenk flask was placed under N2 atmosphere. Under positive N2 flow, 6-methyl-2-pyridone (2.000 g, 18.32 mmol) was added to the flask, 20 mL THF was then added, the slurry stirred vigorously, and cooled to -78 °C. A solution of nBuLi (23.2 mL, 37.11 mmol, 1.6 M in hexanes) was added dropwise over 10-15 minutes to produce an orange solution. Upon addition, the solution was warmed to 0 °C and stirred for ~ 3h until all 6-methyl-2-pyridone had dissolved. The solution was then cooled back to -78 °C. In the glovebox, chlorodiisopropylphosphine (2.867 g, 18.78 mmol) was added to a 30 mL Schlenk flask with 10-145  15 mL THF to create a clear solution. This flask was then removed from the glovebox and connected to the Schlenk manifold. The solution of chlorodiisopropylphosphine was then added to the stirred solution of deprotonated 2-pyridone (at -78 °C) dropwise by cannula over 30 minutes. The solution was allowed to stir and warm to room temperature slowly over 12 h to produce a pale-yellow solution. The reaction was quenched with 0.5 mL of NH4Cl(aq) (sparged with N2 for 30 min) to produce a cloudy white solution. The solution was concentrated in vacuo to result in a sticky yellow solid, to which 15 mL H2O (sparged with N2 for 30 min) was added resulting in a partially cloudy yellow solution. Under N2 atmosphere, the phosphine was extracted with EtOAc (2 x 40 mL, sparged for 30 min), dried over sodium sulfate. This was filtered via cannula filtration (oven dried glass-fiber filter), and the sodium sulfate washed with an additional 10 mL portion of EtOAc. The combined EtOAc was concentrated to an off-white solid in vacuo. The Schlenk flask was then transferred into the glovebox, where the solid was transferred to a 20 mL vial. The product was recrystallized from THF/hexanes at -35 °C in two crops resulting in 2.392 g (58%) of a white solid. 1H-NMR (300 MHz, CDCl3): δ  12.92 (s, 1H), 7.30 (dd, J = 9.1, 7.0 Hz, 1H), 6.32 (d, J = 9.0 Hz, 1H), 6.20 (d, J = 7.0 Hz, 1H), 2.72 (d, J = 1.1 Hz, 2H), 1.77 (quintd, J = 7.1, 1.5 Hz, 2H), 1.03 (m, 12H). 13C{1H}-NMR (75 MHz, CDCl3): δ  165.7, 148.8 (d, J = 10.5 Hz), 141.6, 116.4 (d, J = 1.7 Hz), 106.3 (d, J = 9.9 Hz), 26.7 (d, J = 23.8 Hz), 23.6 (d, J = 14.2 Hz), 19.6 (d, J = 14.4 Hz), 19.01 (d, J = 10.7 Hz). 31P{1H}-NMR (121 MHz, CDCl3): δ  11.4. MS (ESI): m/z 242.1 [MOH+]. EA: Calc’d for C12H20NOP: C 63.98, H 8.95, N 6.22; Found: C 62.76, H 9.41, N 6.05. Synthesis of 6-diisopropylphosphinyl-2-pyridone, 4.22.33,237  Using a Schlenk double manifold and standard technique, a dried 100 mL Schlenk flask was placed under N2 atmosphere. Under positive N2 flow, 2-bromo-6-tert-butoxypyridine (2.400 g, 10.43 mmol) was added to the flask, 146  and 50 mL Et2O was then added, the slurry stirred vigorously, and cooled to -0 °C. A solution of nBuLi (6.84 mL, 10.95 mmol, 1.6 M in hexanes) was added dropwise over 10-15 minutes to produce an orange/red solution. The solution was then stirred for 1 h at 0 °C. In the glovebox, chlorodiisopropylphosphine (1.671 g, 10.95 mmol) was added to a 30 mL Schlenk flask with 5-10 mL Et2O to create a clear solution. This flask was then removed from the glovebox and connected to the Schlenk manifold. The solution of chlorodiisopropylphosphine was then added to the stirred solution of lithiated pyridine (at 0 °C) dropwise by cannula over 30 minutes. The solution was allowed to stir and warm to room temperature slowly over 12 h to produce a pale-yellow solution. The reaction was quenched with 0.30 mL methanol (sparged for 30 min) to produce a colorless solution. All volatiles were removed in vacuo. The solid was extracted with 50 mL hexanes and filtered via cannula filtration (oven dried glass-fiber filter). The solvent was again removed in vacuo to give a white solid. To the flask, 20 mL formic acid solution (88%, sparged for 30 min) was added and stirred for 48 h. The formic acid solution was then distilled off at 40 °C in vacuo to leave a sticky yellow solid. The flask was allowed to remain under vacuum at ambient temperature overnight. The Schlenk flask was then transferred into the glovebox, the solid transferred to a water-cooled sublimation glassware, and sublimed in vacuo on the Schlenk manifold at 85 °C overnight to produce 1.40 g of the product as a bright-yellow, waxy solid (64%). 1H-NMR (300 MHz, CDCl3): δ  12.14 (s, 1H), 7.28 (ddd, J  = 9.2, 6.7, 1.3 Hz, 1H), 6.49 (ddd, J = 9.2, 5.7, 1.1 Hz, 1H), 6.34 (ddd, J = 6.7, 5.7, 1.0 Hz, 1H), 2.23 (quintd, J = 7.0, 3.1 Hz, 2H), 1.06 (dd, J = 15.9, 6.9 Hz, 6H), 0.89 (dd, J = 12.1, 6.9 Hz, 6H). 13C{1H}-NMR (75 MHz, CDCl3): δ  165.4 (d, J = 2.2 Hz), 146.6 (d, J  = 33.2 Hz), 139.8 (d, J  = 7.8 Hz), 120.9 , 114.6 (d, J = 21.0 Hz), 22.9 (d, J  = 11.5 Hz), 20.0 (d, J = 19.8 Hz), 19.4 (d, J  = 9.3 Hz). 147  31P{1H}-NMR (121 MHz, CDCl3): δ  11.8. MS (ESI): m/z 228.1 [MOH+]. EA: Calc’d for C11H18NOP: C 62.54, H 8.59, N 6.63; Found: C 62.63, H 8.70, N 6.52.  Synthesis of sodium-2-pyridonate, 4.23, and 4.24. In a glovebox, a THF (~ 3 mL) solution of 2-pyridone, 4.21, or 4.23 (~ 1 mmol scale) was added dropwise to a vigorously stirring suspension of NaH (1.1 equivalents) in THF (~ 10 mL). The suspension was stirred for 12 h, and then filtered through celite. The volatiles were removed from the clear solution in vacuo to reveal a sticky white salt. ~2 mL of hexanes was added to form a slurry, and the volatiles were removed in vacuo. This was repeating three additional times and the resulting white powder was dried thoroughly in vacuo. These products were used without further purification. Synthesis of [κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate-η5-(1,2,3,4,5-pentamethylcyclopentadienyl)Rh(III)•NaCl(Et2O)2][tetrakis(3,5-trifluoromethylphenyl)borate] 4.25. In a glovebox, a solution of 4.23 (0.028 g, 0.113 mmol) in THF (~ 3 mL) was added to a stirring suspension deep red [Cp*RhCl2]2 (0.035 g, 0.057 mmol) in THF (~ 3 mL) at ambient temperature. The resulting suspension was stirred for 2 hours at ambient temperature resulting in a deep red solution. Then, a solution of NaB(ArF)4 (0.100 g, 0.133 mmol) in THF (~ 2 mL) was added and the solution stirred for 12 h. The resulting dark orange solution was concentrated in vacuo. The resulting orange-brown solid was dissolved in minimal Et2O (~ 2 mL), and filtered through celite. The solution was then cooled for 10 minutes at -35 °C. This dark orange-brown solution was then layered with hexanes (~ 7 mL) and stored in the freezer at -35 °C to promote recrystallization. This yielded an orange-brown powder of 0.048 g (27%). It was found that a similar in situ procedure at smaller scale (~ 0.008 mmol Rh) in total volume ~0.7 mL THF-d8 was found to of high purity by 1H and 31P NMR and behaved the same as isolated 4.25. Crystals suitable for single crystal X-ray diffraction were synthesized in the 148  same manner but with NaBPh4 (instead of Na(B(ArF)4). This required two recrystallizations from Et2O layered with hexanes at -35 °C. Significant fluxional behavior is observed, making assignment of peaks difficult. Spectra are further complicated by the presence of significant amounts of Et2O. Fluxionality of the complex can further be observed by the significant depletion in signal integration of the [Rh]+ compared to the signals for Et2O or [B(ArF)4]–. Compare to Ir complex 4.26. 1H-NMR (300 MHz, THF-d8): δ  7.79 (s, 8H), 7.58 (s, 4H), 7.17 (br. s, 1H), 6.35 (d, J = 5.7 Hz, 1H), 6.23 (br. s, 1H), 3.75-3.65 (m, 1H), 3.35-3.27 (m, 1H), 2.77-2.66 (m, 1H), 2.47-2.39 (m, 1H), 1.67 (d, J = 2.7 Hz, 15H), 1.53 (dd, J = 15.8, 7.4 Hz, 3H), 1.42 (dd, J = 12.8, 7.0 Hz, 3H), 1.24-1.15 (m, 6H). 13C{1H}-NMR (75 MHz, THF-d8): δ  163.4 (q, 1JCB = 49.8 Hz, B(ArF4)), 136.2 (br. s, B(ArF4)), 130.7 (qq, 2JCF = 31.5, 2JCB =  2.9 Hz B(ArF4)), 126.1 (q, 1JCF = 272.2 Hz, B(ArF4)), 118.8 (m B(ArF4)), 101.3, 37.7, 36.13, 36.09, 33.2, 30.6, 27.0, 24.1, 21.6, 16.3, 15.0, 12.4, 10.37, 10.35, 9.9 (note: fluxional behavior creates significant difficulties in locating all carbon signals). 31P{1H}-NMR (121 MHz, THF-d8): δ  56.31 (d, JPRh = 129.3 Hz). 19F{1H}-NMR (282 MHz, THF-d8): δ  -65.23. MS (EI): Unable to obtain data, decomposition of sample observed upon collection. EA: Calc’d for C62H66BClF24NNaO3PRh: C 48.60, H 4.34, N 0.91; Found: C 49.54, H 4.25, N 0.91. Synthesis of [κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate-η5-(1,2,3,4,5-pentamethylcyclopentadienyl)Ir(III)•NaCl(Et2O)2][tetrakis(3,5-trifluoromethylphenyl)borate] 4.26. In a glovebox, a solution of 4.23 (0.019 g, 0.075 mmol) in THF (~ 3 mL) was added to a stirring suspension of orange [Cp*IrCl2]2 (0.030 g, 0.038 mmol) in THF (~ 3 mL) at ambient temperature. The resulting suspension was stirred for 2 hours at ambient temperature resulting in an orange solution. Then, a solution of NaB(ArF)4 (0.067 g, 0.075 mmol) in THF (~ 2 mL) was added and the solution stirred for 12 h. The resulting yellow 149  solution was concentrated in vacuo. The resulting yellow solid was dissolved in minimal Et2O (~ 2 mL), and filtered through celite. The solution was then cooled for 10 minutes at -35 °C. This dark orange-brown solution was then layered with hexanes (~ 7 mL) and stored in the freezer at -35 °C to promote recrystallization. This yielded a yellow powder of 0.045 g (37%). It was found that a similar in situ procedure at smaller scale (~ 0.008 mmol Ir) in total volume ~0.7 mL THF-d8 was found to of high purity by 1H and 31P NMR and behaved the same as isolated 4.25. Crystals suitable for single crystal X-ray diffraction could be grown by utilizing a more dilute Et2O solution layered with hexanes at -35 °C. 1H-NMR (400 MHz, THF-d8): δ  7.79 (s, 8H), 7.57 (s, 4H), 7.08 (dd, J = 8.5, 6.8 Hz, 1H), 6.31 (d, J = 6.8 Hz, 1H), 6.09 (d, J = 8.5 Hz, 1H), 3.82 (dd, J = 15.9, 12.4 Hz, 1H), 3.38 (q, J = 7.0 Hz, 4H), 3.17 (dd, J = 15.8, 8.7 Hz, 1H), 2.62 (m, 2H), 1.68 (d, J = 1.9 Hz, 15H), 1.48 (dd, J = 15.8, 7.3 Hz, 3H), 1.40 (dd, J = 13.5, 7.1 Hz, 3H), 1.23 (dd, J = 14.6, 7.2 Hz, 3H), 1.15 (dd, J = 12.7, 7.2 Hz, 3H), 1.12 (t, J = 7.0 Hz, 6H). 13C{1H}-NMR (101 MHz, THF-d8): δ  172.0, 163.4 (q, 1JCB = 49.8 Hz, B(ArF4)), 158.1, 139.1, 136.2 (br. s, B(ArF4)), 130.7 (qq, 2JCF = 31.5, 2JCB =  2.9 Hz B(ArF4)), 126.1 (q, 1JCF = 272.2 Hz, B(ArF4)), 118.8 (m B(ArF4)), 116.1, 94.6 (d, J = 2.60), 66.9, 41.9 (d, J = 32.5 Hz), 28.2 (d, J = 30.2 Hz), 27.0 (d, J = 25.1 Hz), 20.6 (d, J = 30.8 Hz), 20.4 (d, J = 16.0 Hz), 19.5 (d, J = 6.5 Hz), 16.3, 10.1. 31P{1H}-NMR (162 MHz, THF-d8): δ  23.3. MS (EI): m/z 552 [M+]. EA: Calc’d for C62H66BClF24NNaO3PIr: C 45.92, H 4.10, N 0.86; Found: C 45.71, H 3.89, N 0.81. Synthesis of [κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate-η6-(p-cymene)Ru(II)•NaCl(THF)2][tetrakis(3,5-trifluoromethylphenyl)borate] 4.27. In a glovebox, a solution of 4.23 (0.014 g, 0.056 mmol) in THF (~ 3 mL) and a suspension of deep red [(p-cymene)RuCl2]2 (0.017 g, 0.028 mmol) in THF (~ 3 mL) where both chilled to -35 °C in the freezer. The cold solution of ligand salt was then added, dropwise, to the stirring, cold 150  suspension of Ru. After the addition, the suspension was returned to the freezer for 15 min. The solution was then stirred for 5 h, until the Ru had completely dissolved to form a red solution. Then, a solution of NaB(ArF)4 (0.049 g, 0.056 mmol) in THF (~ 2 mL) was added and the solution stirred for 12 h. The resulting orange-red solution was filtered through celite and concentrated to an orange-red powder in vacuo, resulting in a crude yield of 0.085 g (100%). 1H-NMR (400 MHz, THF-d8): δ  7.79 (s, 8H), 7.57 (s, 4H), 7.08 (ddd, J = 8.5, 6.8, 0.7 Hz, 1H), 6.28 (d, J = 6.3 Hz, 1H), 6.21 (d, J = 6.8 Hz, 1H), 6.12 (d, J = 8.5 Hz, 1H), 5.98 (d, J = 5.3 Hz, 1H), 5.92 (d, J = 6.3 Hz, 1H), 5.55 (d, J = 5.3 Hz, 1H), 3.65-3.61 (m, 1H), 3.08 (dd, J = 15.9, 8.6 Hz, 1H), 2.91-2.82 (m, 1H), 2.72-2.65 (m, 1H), 2.44-2.34 (m, J = 7.2 Hz, 1H), 1.76 (s, 3H), 1.68 (dd, J = 15.3, 7.4 Hz, 3H), 1.49 (dd, J = 13.2, 7.1 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H), 1.19 (dd, J = 14.5, 7.1 Hz, 3H), 1.15 (d, J = 6.9 Hz, 3H), 1.05 (dd, J = 15.2, 7.2 Hz, 3H). 31P{1H}-NMR (121 MHz, THF-d8): δ  57.6. 19F-NMR (377 MHz, THF-d8): δ  -63.42. Synthesis of [κ2-P,N-6-diisopropylphosphinyl-2-pyridonate-η5-(1,2,3,4,5-pentamethylcyclopentadienyl)Ir(III)•NaCl(THF)2][tetrakis(3,5-trifluoromethylphenyl)borate] 4.28. In a glovebox, a solution of 4.24 (0.021 g, 0.088 mmol) in THF (~ 3 mL) was added to a stirring suspension of orange [Cp*IrCl2]2 (0.035 g, 0.044 mmol) in THF (~ 3 mL) at ambient temperature. The resulting suspension was stirred for 2 hours at ambient temperature resulting in an orange solution. Then, a solution of NaB(ArF)4 (0.078 g, 0.088 mmol) in THF (~ 2 mL) was added and the solution stirred for 12 h. The resulting yellow solution was filtered through celite and concentrated in vacuo. This resulted in a yellow solid in crude yield of 0.156 g (111%). 1H-NMR (400 MHz, THF-d8): δ  7.79 (s, 8H), 7.57 (s, 4H), 7.27 (ddd, J = 9.0, 6.4, 4.0 Hz, 1H), 6.33 (d, J = 9.0 Hz, 1H), 6.08 (dd, J = 6.4, 4.6 Hz, 1H), 3.11 (ddt, J = 14.7, 11.5, 7.3 Hz, 1H), 2.71 (ddt, J = 14.2, 8.9, 7.1 Hz, 1H), 1.90 (d, J = 2.5 Hz, 15H), 1.45-151  1.31 (m, 12H). 31P{1H}-NMR (162 MHz, THF-d8): δ  -25.87. 19F-NMR (377 MHz, THF-d8): δ  -63.08. Synthesis of [κ2-P,N-6-diisopropylphosphinyl-2-pyridonate-η6-(p-cymene)Ru(II)•NaCl(THF)2][tetrakis(3,5-trifluoromethylphenyl)borate] 4.29. In a glovebox, a solution of 4.24 (0.013 g, 0.056 mmol) in THF (~ 3 mL) and a suspension of deep red [(p-cymene)RuCl2]2 (0.017 g, 0.018 mmol) in THF (~ 3 mL) where both chilled to -35 °C in the freezer. The cold solution of ligand salt was then added, dropwise, to the stirring, cold suspension of Ru. After the addition, the suspension was returned to the freezer for 15 min. The solution was then stirred for 5 h, until the Ru had completely dissolved to form a red solution. Then, a solution of NaB(ArF)4 (0.049 g, 0.056 mmol) in THF (~ 2 mL) was added and the solution stirred for 12 h. The resulting orange-red solution was filtered through celite and concentrated to an orange-red powder in vacuo, resulting in a crude yield of 0.088 g (105%). 1H-NMR (400 MHz, THF-d8): δ  7.79 (s, 8H), 7.57 (s, 4H), 7.22 (ddd, J = 8.7, 6.2, 3.7 Hz, 1H), 6.58 (d, J = 6.3 Hz, 1H), 6.34 (d, J = 8.7 Hz, 1H), 6.20 (d, J = 5.9 Hz, 1H), 6.10 (t, J = 6.2 Hz, 1H), 5.69 (d, J = 6.3 Hz, 1H), 5.62 (d, J = 5.9 Hz, 1H), 2.88-2.78 (m, 2H), 2.68-2.58 (m, 1H), 2.07 (s, 3H), 1.53 (dd, J = 15.2, 7.0 Hz, 3H), 1.41 (dd, J = 15.5, 7.1 Hz, 3H), 1.36 (dd, J = 17.0, 7.2 Hz, 3H), 1.31 (dd, J = 17.6, 7.4 Hz, 3H), 1.21 (d, J = 6.9 Hz, 3H), 1.16 (d, J = 7.0 Hz, 3H). 31P{1H}-NMR (162 MHz, THF-d8): δ  -4.39. 19F-NMR (377 MHz, THF-d8): δ  -63.42. Synthesis of [κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate-η5-(1,2,3,4,5-pentamethylcyclopentadienyl)hydridoIr(III)][tetrakis(3,5-trifluoromethylphenyl)borate] 4.31. Complex 4.26 was prepared in situ as above using 4.23 (0.016 g, 0.065 mmol), [Cp*IrCl2]2 (0.026 g, 0.032 mmol), and NaB(ArF)4 (0.057 g, 0.065 mmol) in THF (total volume 1.0 mL). This solution was placed in a J. Young NMR tube and 2 µL EtOH (0.015 g, 0.324 mmol, dry and 152  degassed), the tube sealed, and heated for 12 h in a 70 °C oil bath. The reaction can be monitored by 31P{1H} NMR spectroscopy to confirm completion. Once complete, the tube was taken into a glovebox, transferred to a vial, filtered through celite, and the volatiles were removed in vacuo. The pale yellow solid was dissolved in a minimal amount of THF (~ 1 mL), layered with hexanes (~ 3 mL), and placed in the freezer at -35 °C to encourage crystallization. This resulted in 0.069 mg (75%) of pale yellow crystals. 1H-NMR (400 MHz, CDCl3): δ  7.78 (s, 1H), 7.70 (s, 8H), 7.52 (s, 4H), 7.48 (dd, J = 8.2, 7.3 Hz, 1H), 6.94 (d, J = 7.3 Hz, 1H), 6.82 (d, J = 8.2 Hz, 1H), 3.68-3.61 (m, 1H), 3.25 (dd, J = 16.9, 8.5 Hz, 1H), 2.56-2.47 (m, 1H), 1.99-1.95 (m, 1H), 1.91 (s, 16H), 1.31 (dd, J = 15.5, 7.1 Hz, 3H), 1.27 (dd, J = 16.7, 7.2 Hz, 3H), 0.87 (dd, J = 17.8, 6.7 Hz, 3H), 0.39 (dd, J = 15.8, 6.9 Hz, 3H), -13.77 (d, J = 27.5 Hz, 1H). 13C-NMR (101 MHz, CDCl3): δ  163.4 (d, J = 2.7 Hz), 161.8 (q, J = 49.8 Hz, B(ArF4)), 159.1 (d, J = 2.3 Hz), 141.7, 134.9, 129.1 (qq, J = 31.54, 2.7 Hz, B(ArF4)), 124.7 (q, J = 272.5 Hz, B(ArF4)), 117.6 (m, B(ArF4)), 114.6 (d, J = 7.9 Hz, 1C), 107.7, 94.5, 41.3 (d, J = 29.1 Hz), 24.7 (d, J = 21.8 Hz), 24.4 (d, J = 20.7 Hz), 19.0 (d, J = 2.2 Hz), 18.6 (s), 18.4 (d, J = 4.4 Hz), 17.2 (d, J = 1.7 Hz), 10.2. 31P{1H}-NMR (162 MHz, CDCl3): δ  38.32. MS (EI): unable to obtain data as complex decomposed upon addition to the instrument. EA: Calc’d for C54H48BF24NOPIr: C 45.77, H 3.41, N 0.99; Found: C 45.67, H 3.51, N 0.86. Synthesis of [κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate-η5-(1,2,3,4,5-pentamethylcyclopentadienyl)hydridoIr(III)•pyrrolidine][tetrakis(3,5-trifluoromethylphenyl)borate] 4.31•pyrrolidine. The reaction was prepared in the same manner as 4.31 except that 7 uL pyrrolidine (0.012 g, 0.150 mmol) and was heated for 2 h at 70 °C. The reaction can be monitored by 31P{1H} NMR spectroscopy. Once complete, the tube was taken into a glovebox, transferred to a vial, filtered through celite, and the volatiles were 153  removed in vacuo. The solid was washed with hexanes (3 x 1.5 mL) and thoroughly dried in vacuo resulting in a pale yellow solid in quantitative yield. 1H-NMR (300 MHz, THF-d8): δ  7.79 (s, 8H), 7.57 (s, 4H), 7.10 (dd, J = 8.1, 7.0 Hz, 1H), 6.44 (d, J = 7.0 Hz, 1H), 6.11 (d, J = 8.1 Hz, 1H), 3.48 (dd, J = 16.9, 10.1 Hz, 1H), 3.30 (dd, J = 16.8, 11.1 Hz, 1H), 3.22-3.17 (m, 4H), 2.52-2.40 (m, 1H), 2.19-2.11 (m, 1H), 2.03 (dd, J = 1.8, 0.9 Hz, 15H), 1.95-1.90 (m, 4H), 1.25 (m, J = 15.4, 7.1 Hz, 3H), 1.19 (m, J = 14.2, 7.0 Hz, 3H), 1.01 (dd, J = 17.0, 6.9 Hz, 3H), 0.82 (dd, J = 14.9, 6.8 Hz, 3H), -14.93 (d, J = 30.3 Hz, 1H). 31P{1H}-NMR (121 MHz, THF-d8): δ  41.25. Synthesis of sodium-[N-(2,4,6-trimethylphenyl)-6-(2,4,6-trimethylphenyl)-2-aminopyridinate]. In a glovebox, a THF (~ 3 mL) yellow solution of N-(2,4,6-trimethylphenyl)-6-(2,4,6-trimethylphenyl)-2-aminopyridine (~ 1 mmol scale) was to a suspension of NaH (1.1 equivalents) in THF (~ 5 mL) in a 15 mL Teflon sealed Schlenk bomb. The Schlenk bomb was sealed, removed from the glovebox, and stirred for 12 h at 70 °C. The bomb was returned to the glovebox and the suspension filtered through celite to produce a clear yellow solution. The volatiles were removed in vacuo to reveal a sticky yellow salt. ~2 mL of hexanes was added to form a slurry, and the volatiles were removed in vacuo. This was repeating three additional times and the resulting yellow powder was dried thoroughly in vacuo. This product was used without further purification. 1H NMR spectroscopy revealed 0.32 eq. THF incorporated into the powder that cannot be removed in vacuo. Synthesis of chloro(κ2-N,N’-N-(2,4,6-trimethylphenyl)-6-(2,4,6-trimethylphenyl)-2-aminopyridinato)-η6-(p-cymene)Ru(II) 4.39. In a glovebox, a solution of sodium-[N-(2,4,6-trimethylphenyl)-6-(2,4,6-trimethylphenyl)-2-aminopyridinate] (0.061 g, 0.163 mmol) in THF (~ 5 mL) and a suspension of deep red [(p-cymene)RuCl2]2 (0.050 g, 0.082 mmol) in THF (~ 5 mL) 154  where both chilled to -35 °C in the freezer. The cold solution of ligand salt was then added, dropwise, to the stirring, cold suspension of Ru. After the addition, the suspension was returned to the freezer for 15 min. The solution was then stirred for 12 h at ambient temperature. The resulting orange-red solution was filtered through celite, concentrated 4 mL, and 8 mL of hexanes were slowly added causing partial precipitation of an orange powder. The solution was stored at -35 °C overnight resulting in the formation of more orange powder. The solution was decanted, the product washed with hexanes (2 x 3 mL), and dried in vacuo resulting in 0.064 g (65%) of bright orange product. 1H-NMR (400 MHz, THF-d8): δ  7.02-6.98 (m, 2H), 6.96 (br. s, 1H), 6.82 (br. d, J = 2.5 Hz, 2H), 5.76 (dd, J = 7.0, 1.0 Hz, 1H), 5.39 (d, J = 6.0 Hz, 1H), 5.24 (dd, J = 8.6, 1.0 Hz, 1H), 5.14 (d, J = 5.5 Hz, 1H), 4.80 (d, J = 5.5 Hz, 1H), 4.68 (d, J = 6.0 Hz, 1H), 2.36 (s, 3H), 2.28 (s, 3H), 2.25 (s, 6H), 2.22 (s, 3H), 2.18 (s, 3H), 1.78-1.73 (m, 1H), 1.55 (s, 3H), 1.16 (d, J = 6.9 Hz, 3H), 0.78 (d, J = 7.0 Hz, 3H). 13C{1H}-NMR (101 MHz, THF-d8): δ  171.4, 157.4, 141.8, 138.4, 138.2, 136.8, 136.5, 135.8, 134.4, 132.4, 130.1, 129.20, 129.13, 127.7, 106.7, 105.5, 102.1, 97.5, 85.4, 79.1, 78.5, 76.2, 30.9, 24.0, 21.66, 21.59, 21.43, 21.0, 20.8, 20.35, 20.20, 17.7. MS (EI): m/z 600 [M+–H], 565 [M+–H–Cl]. EA: Calc’d for C33H39ClN2Ru: C 66.04, H 6.55, N 4.67; Found: C 65.88, H 6.49, N 4.61. Synthesis of chloro(κ2-N,N’-N-(2,4,6-trimethylphenyl)-6-(2,4,6-trimethylphenyl)-2-aminopyridinato)-η5-(1,2,3,4,5-pentamethylcyclopentadienyl)Ir(III) 4.40.239 In a glovebox, a solution of sodium-[N-(2,4,6-trimethylphenyl)-6-(2,4,6-trimethylphenyl)-2-aminopyridinate] (0.055 g, 0.138 mmol) in THF (~ 5 mL) and a suspension of orange [Cp*IrCl2]2 (0.055 g, 0.069 mmol) in THF (~ 5 mL) where both chilled to -35 °C in the freezer. The cold solution of ligand salt was then added, dropwise, to the stirring, cold suspension of Ru. After the addition, the suspension was returned to the freezer for 15 min. The solution was then stirred for 12 h at 155  ambient temperature. The resulting yellow-orange solution was filtered through celite, concentrated to 4 mL, and 8 mL of hexanes were slowly added causing partial precipitation of an yellow powder. The solution was stored at -35 °C overnight resulting in the formation of more yellow powder. The solution was decanted, the product washed with hexanes (2 x 3 mL), and dried in vacuo resulting in 0.079 g (82%) of bright yellow product. 1H-NMR (400 MHz, C6D6): δ  6.95 (br. s, 1H), 6.91 (br. s, 1H), 6.85 (br. s, 1H), 6.79-6.75 (m, 2H), 5.76 (dd, J = 7.0, 1.0 Hz, 1H), 5.43 (dd, J = 8.6, 1.0 Hz, 1H), 2.75 (s, 3H), 2.67 (s, 3H), 2.27 (s, 3H), 2.23 (s, 3H), 2.19 (s, 3H), 2.12 (s, 3H), 1.08 (s, 15H). 13C{1H}-NMR (101 MHz, C6D6): δ  173.1, 155.9, 138.69, 138.50, 137.60, 137.46, 136.82, 136.74, 136.62, 134.8, 132.9, 130.0, 128.9, 128.7, 127.6, 107.8, 107.5, 83.6, 22.1, 21.34, 21.18, 21.08, 20.5, 19.7, 8.8. MS (EI): m/z 692 [M+], 654 [M+–H–Cl]. EA: Calc’d for C33H40ClN2Ir: C 57.25, H 5.82, N 4.05; Found: C 55.69, H 5.78, N 3.93. Synthesis of trans-dichloro-cis-bis(κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate)Ru(II) 4.41. In the glovebox [RuCl2(COD)]n (0.110 g, 0.392 mmol) and 4.21 (0.177 g, 0.785 mmol) were charged to a 10 mL Schlenk flask with 3 mL toluene to create a dark brown slurry. The flask was sealed, removed from the glovebox, and stirred at 110 °C for 12 h resulting in an orange-brown suspension. The flask was connected to a Schlenk manifold and the volatiles were removed in vacuo to leave an orange-brown solid. The flask was returned to the glovebox where is was washed with Et2O (2 x 1.5 mL) and then hexanes (2 x 1.5 mL) to give 0.191 g of the orange-brown product (78%). Single crystals suitable to X-ray diffraction were grown from a saturated toluene solution layered with hexanes at -35 °C over several days. 1H-NMR (300 MHz, THF-d8): δ  9.73 (s, 2H), 7.60 (dd, J = 8.2, 7.5 Hz, 2H), 7.10 (d, J = 7.5 Hz, 2H), 6.50 (d, J = 8.2 Hz, 2H), 4.40-4.32 (m, 2H), 3.53-3.43 (m, 2H), 2.71-2.59 (m, J = 6.8 Hz, 2H), 2.51-2.38 (m, 2H), 1.42 (dd, J = 12.2, 7.2 Hz, 6H), 1.39 (dd, J = 12.2, 7.2 Hz, 6H), 1.10 (dd, J = 14.1, 7.1 Hz, 156  6H), 0.94 (dd, J = 12.4, 7.1 Hz, 6H). 13C{1H}-NMR (75 MHz, THF-d8): δ  169.1, 162.2, 140.4, 115.6 (t, J = 4.8 Hz), 109.1 (t, J = 1.1 Hz), 37.8-37.4 (m), 28.4 (dd, J = 8.8, 8.7 Hz), 27.8 (dd, J = 9.9, 9.8 Hz), 20.7, 19.5, 19.3 (t, J = 1.4 Hz), 18.9. 31P{1H}-NMR (121 MHz, THF-d8): δ  68.0. MS (EI): m/z 622 [M+], 586 [M+–H–Cl]. EA: Calc’d for C24H40Cl2N2O2P2Ru: C 46.31, H 6.48, N 4.50; Found: C 45.48, H 6.42, N 4.47. In situ preparation of proposed complex [4.42]. In the glove box, complex 4.41 (0.010 g, 0.0161 mmol) was dissolved in 0.3 mL THF-d8 in a 5 mL vial. In another vial, NaHMDS (0.006 g, 0.0322 mmol) was dissolved in 0.3 ml THF-d8. Using a pipette, the solution of NaHMDS was added and thoroughly mixed with the solution of 4.41 for 2-3 minutes. This solution was added to a J. Young NMR tube and NMR analysis taken. NMR spectroscopy revealed complete conversion of 4.41 into a new product proposed as [4.42]. Attempts (up to 5x larger scale) to isolate the complex found the removal of the volatiles in vacuo decomposes the product, as evidenced by NMR spectroscopy after dissolving the resulting solid in THF-d8. 1H-NMR (300 MHz, THF-d8): δ  14.59 (s, 1H), 6.72 (dd, J = 8.4, 6.5 Hz, 1H), 6.44 (dd, J = 8.9, 6.7 Hz, 1H), 6.23 (d, J = 6.5 Hz, 1H), 6.13 (d, J = 6.7 Hz, 1H), 5.42 (d, J = 8.9 Hz, 1H), 5.24 (d, J = 8.4 Hz, 1H), 3.29-3.20 (m, 1H), 3.02-2.92 (m, 3H), 2.13 (d, J = 26.5 Hz, 1H), 1.96 (d, J = 29.6 Hz, 1H), 1.68-1.58 (m, 3H), 1.42-1.23 (m, 15H), 1.03 (dd, J = 13.3, 7.2 Hz, 3H), 0.88 (dd, J = 14.2, 7.3 Hz, 3H), 0.04 (s, 32H). Significant broadening in the spectrum is observed obscuring integrations. 31P{1H}-NMR (121 MHz, THF-d8): δ  79.9 (d, J = 36.3 Hz), 67.9 (d, J = 36.2 Hz). Synthesis of η2-η2-(1,5-cyclooctadiene)-(κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate)Rh(I) 4.45. In a glovebox, a solution of 4.23 (0.026 g, 0.104 mmol) in THF (~ 3 mL) was added to a stirring suspension of deep red [Cp*RhCl2]2 (0.026 g, 0.052 mmol) in THF (~ 3 mL) at ambient temperature. The resulting suspension was stirred for 2 hours at ambient 157  temperature resulting in an orange solution. The resulting orange solution was filtered through celite and concentrated in vacuo. This resulted in an orange solid in crude yield of 0.051 g (113%). 1H-NMR (400 MHz, THF-d8): δ  6.82-6.80 (m, 1H), 6.77 (m, 2H), 5.83 (d, J = 8.6 Hz, 1H), 5.77 (d, J = 6.4 Hz, 1H), 3.79 (m, 2H), 3.12 (d, J = 10.7 Hz, 2H), 2.35-2.10 (m, 8H), 2.08-2.01 (m, 2H), 1.23 (dd, J = 15.1, 7.1 Hz, 6H), 1.12 (dd, J = 13.6, 7.0 Hz, 6H). 31P{1H}-NMR (162 MHz, THF-d8): δ  54.3 (d, J = 154.6 Hz). Synthesis of η2-η2-(1,5-cyclooctadiene)-(κ2-P,N-6-diisopropylphosphinomethyl-2-pyridonate)Ir(I) 4.46. In a glovebox, a solution of 4.23 (0.026 g, 0.104 mmol) in THF (~ 3 mL) was added to a stirring suspension of orange [Cp*IrCl2]2 (0.035 g, 0.052 mmol) in THF (~ 3 mL) at ambient temperature. The resulting suspension was stirred for 2 hours at ambient temperature resulting in a yellow-orange solution. The resulting yellow-orange solution was filtered through celite and concentrated in vacuo. This resulted in a yellow-orange solid in crude yield of 0.058 g (105%). 1H-NMR (400 MHz, THF-d8): δ  6.86 (ddd, J = 8.8, 6.4, 0.6 Hz, 1H), 6.45 (m, 2H), 5.95 (d, J = 8.8 Hz, 1H), 5.92 (d, J = 6.4 Hz, 1H), 3.34-3.32 (m, 2H), 3.19 (d, J = 10.4 Hz, 2H), 2.34-2.21 (m, J = 7.3, 6.9 Hz, 2H), 2.14-2.04 (m, 4H), 1.95-1.84 (m, 4H), 1.22 (dd, J = 15.3, 7.1 Hz, 6H), 1.11 (dd, J = 14.0, 7.0 Hz, 6H). 31P{1H}-NMR (162 MHz, THF-d8): δ  38.9.   Attempted Catalytic Reactions: Reactions were prepared in a glovebox and conducted in a J. Young NMR tube at ~ 0.07 mmol scale for metal complex (~ 0.005 – 0.010 g) in ~ 0.5-0.6 mL of the indicated solvent(s) with 1,3,5-trimethoxybenzene as a standard. Metal complexes, [M], substrate, and reaction solvent were first mixed in a 5 mL vial. Liquid substrates were measured using a gas-tight 50 uL syringe. The resulting solution/suspension was then transferred to the J. Young tube, sealed, and removed from the glovebox. Upon removal, NMR spectrum were obtained for reference (t = 0 h), then the reaction placed into a temperature regulated oil bath for 158  the designated time. Reactions from Scheme 4.16, Scheme 4.18, and Scheme 4.19 first had the [M] precursor thoroughly mixed with NaB(ArF)4 in the reaction solvent for ~ 3 minutes by pipette to create a homogenous suspension before adding the substrate(s). Reactions from Scheme 4.24 and Scheme 4.23 were conducted in 5 mL vials sealed with Teflon lined, screw-type caps. The [M] precursor and ligand(s) were thoroughly stirred in the reaction solvent for ~10 minutes before adding the substrates, sealing the reaction vial, and heating in a temperature regulated aluminum block outside the glovebox. After the reactions were complete, a combination of NMR spectroscopy, UHPLC/ESI, and/or GC/MS analyses were performed.   159  Chapter 5: Conclusion 5.1 Summary This thesis has focused on the development of organotransition metal complexes featuring 1,3-N,O-chelating ligands. These complexes were tested as precatalysts in the homogenous catalytic α-alkylation of amines with C-C unsaturations, termed hydroaminoalkylation. Chapter 1 reviewed transition-metal complexes that feature 2-pyridone/2-pyridonate ligands. The review highlights complexes that are used in catalytic reactions. Chapter 2 utilized 2-pyridonate ancillary ligands as a catalyst design feature to develop novel catalytic systems expanding the scope of Ta catalyzed hydroaminoalkylation to include sterically demanding internal alkenes. Further investigations have revealed that the functionalization of the 2-pyridonate ligand can significantly impact reactivity, and that off-cycle equilibria limit the rate of catalysis. Chapter 3 explored new phosphoramidate ligated Nb complexes for hydroaminoalkylation catalysis. Chapter 4 investigates Ru, Rh, and Ir complexes featuring both phosphino-2-pyridonate and 2-pyridonate ligands for their reactivity towards amines and initial efforts to realize a general late-transition-metal hydroaminoalkylation catalyst system. In collaboration with Dr. Eugene Chong, a former Schafer group member, we explored the hydroaminoalkylation reactivity of a 6-phenyl-2-pyridonate chloro tri(amido) tantalum complex 2.12. This complex was found to provide excellent reactivity and broad substrate for the hydroaminoalkylation of internal alkenes with unprotected secondary amines. This reactivity represents the first hydroaminoalkylation catalyst that allows for general reactivity with internal alkenes, without isomerization of the alkene, to produce β-branched amine products. A direct comparison with 2-pyridonate tetra(amido) tantalum complex 2.13 was made. It was found that 2.13 reacts poorly with internal alkenes, but has excellent reactivity with terminal alkenes. Based 160  on this, we propose that the steric accessibility created by the planar 2-pyridonate, and chloro ligands are key features for reactivity with sterically demanding internal alkene substrates. Derivatives of 2.12 were synthesized with modification of the 3- and 6-position of the 2-pyridonate ligand. It was found that commercially available 3-methyl-2-pyridonate and 2-pyridonate maintained high reactivity with cyclohexene while improving reactivity with 1-octene compared to 2.12. Complexes with 2-pyridonate ligands with 6-substitution had significantly hindered reactivity with cyclohexene, while offering high reactivity with 1-octene, which is consistent with our steric proposal. The 6-position of the 2-pyridonate ligand is positioned close to the metal center and could readily impart significant steric bulk about the Ta active site. A series of experiments, including reaction monitoring and deuterium labelling studies, were used to gain mechanistic insight for this new type of precatalyst. It was demonstrated that off-cycle species dominate the tantalum speciation. Deuterium labelling also demonstrates facile C–H activation through scrambling of the deuterium label. Further, significant competition between the amine substrate and the amido ligands of the precatalyst was observed. Reaction monitoring confirmed this, as a significant induction period was observed.  Chapter 3 explored the use of an alternative 1,3-N,O-chelating phosphoramidate ancillary ligand on Nb complexes. A series of complexes was synthesized by protonolysis and activity for catalytic hydroaminoalkylation was tested. It was found that the highest activity was observed with an in situ prepared catalyst system of 2 equivalents phosphoramide ligand to 1 equivalent Nb(NMe2)5. These Nb precatalysts show a slight improvement in activity when compared to analogous Ta complexes. Additionally, diphosphoramidate niobaziridine complexes could be synthesized, and proved to be active for hydroaminoalkylation. The activity of these niobaziridines, while poor, supports that phosphoramidate amido Nb complexes likely follow the 161  same proposed mechanism for that of other early-transition-metal hydroaminoalkylation catalysts. Chapter 4 detailed my initial investigations into the synthesis and reactivity of tethered phosphino-2-pyridonate and 2-pyridonate late-transition metal complexes toward their use in hydroaminoalkylation chemistry. New P,N-chelated cationic Cp*Rh, Cp*Ir, and (p-cymene)Ru complexes were found to react with pyrrolidine to produce M–H complexes. However, these complexes were not active for catalytic hydroaminoalkylation or catalytic acceptorless dehydrogenation of amines. The use of 2-pyridonate and 2-aminopyridinate cationic complexes, generated in situ, were found to catalyze the reaction of dibenzylamine into tribenzylamine. While no hydroaminoalkylation chemistry was observed in the presence of diene, the Ru variant was found to catalyze the dehydrogenation of dibenzylamine to the imine, transferring the ‘H2’ equivalent to the diene. Attempts to synthesize non-arene supported complexes was met with limited success but resulted in a bis(phosphino-2-pyridone)Ru(II) complex, and phosphino-2-pyridonate Rh(I) and Ir(I) complexes. Unfortunately, attempts to utilize these complexes, as well as in situ generated Ru complexes with these ligands sets, did not result in catalytic hydroaminoalkylation. 5.2 Future Directions 5.2.1 Early-Transition Metal Catalyzed Hydroaminoalkylation The discovery of the 2-pyridonate chloro tris(amido) tantalum ligand environment allowed for expansion of hydroaminoalkylation substrate scope to include internal alkenes. This advance should help guide new precatalyst development. The amido ligands have been found to significantly compete for hydroaminoalkylation reactivity, and require the use of excess amounts alkene to ensure complete functionalization of the desired substrate amine, as well as the amido 162  ligands. This could be avoided through the replacement of amido ligands with alkyl ligands in the precatalyst. TaMe3Cl2 and complex 2.11 have both been found to catalyze hydroaminoalkylation.175-176 However, both complexes are thermally and light sensitive potentially limiting their synthetic utility. Fortunately, previously reported TaCl2R3 (R = CH2C(CH3)3, CH2Si(CH3)3, CH2Ph) complexes are stable at ambient temperatures and stable to light.257-259 Complexes analogous to our reported 2.12 could potentially be synthesized using these precursors (Scheme 5.1). Additionally, TaCl3R2 complexes are also readily available, offering the possibility to explore complexes with two chloro ligands.257-259 Upon reaction with substrate amine, these complexes would undergo protonolysis releasing unreactive alkane.   Scheme 5.1 Synthesis of Ta alkyl complexes analogous to 2.12 A logical extension to the use of 2-pyridonate ligands, is the use of 2-aminopyridinate ligands. As outlined in Chapter 2, 2-aminopyridinate Ti complexes have been utilized for hydroaminoalkylation.169,204,260 Compared to 2-pyridonates, the modular synthesis of 2-aminopyridines allows for the N-substitution and the 6-substitution to be readily modified to further control the steric and/or electronic parameters.243,261 The results and conclusions presented in Chapter 3 demonstrate that a Nb metal center ligated by two phosphoramide ligands with minimal steric parameters is a highly effective catalytic system for hydroaminoalkylation. This is in direct contrast to tethered, diamidate complexes of Nb that were found to be unreactive for hydroaminoalkylation,181 as well as results on diamidate complexes of Ta that have been found to exhibit poor activity as precatalysts for hydroaminoalkylation.172,185 TaCl2R3 + NO NaTaNORRRCl+HN3R = CH2C(CH3)3, CH2Si(CH3)3, CH2PhSubstrateamineTaNOPhNNNClPhPhPh+ 3 RH163  The results from Chapter 3 suggest that tethered diphosphoramidate Nb complexes could be highly active catalyst (Scheme 5.2). Previous work on Zr complexes with tethered diureates for hydroamination demonstrate the potential use of these types of motifs in early-transition-metal catalysis.262 A similar N,N-tethered ligand set would allow for significant variation in tether length and flexibility that would in turn allow for precise control over the steric environment and bite angle to optimize reactivity. For example, incorporation of a silyl group in the tether would allow for increased flexibility, while incorporation of an aryl group would provide a more rigid tether structure. A tethered ligand should also offer potential improvements in catalyst stability. The incorporation of a chiral linkage could allow for enantioselective reactivity. For example, biaryl motifs have been successfully utilized in enantioselective hydroaminoalkylation as diamidates and as BINOLate Ta complexes.172-174,181-182 However, these examples suffer from high reaction temperatures resulting in moderate enantioselectivities for all but a few substrates. The 90 °C reactivity provided by phosphoramidate Nb complexes may allow for significant improvement to enantioselectivities. Scheme 5.2 Potential tethered diphosphoramide protio-ligands for use in Nb catalyzed hydroaminoalkylation 5.2.2 Late-Transition Metal Catalyzed Hydroaminoalkylation Unfortunately, our efforts in Chapter 4 to realize a late-transition-metal catalyzed hydroaminoalkylation were unsuccessful. It was demonstrated that facile stoichiometric dehydrogenation of amines could be facilitated by ligands incorporating the 2-pyridonate motif combined with electron-deficient cationic metal complexes. Efforts to move away from arene-NHNHPPOOROROROROnn = 1, 2, 3, …NHNHPPOOROROROROSiNHNHPPOORORORORONHP OORRONHP OORRO164  supported complexes were met with little success. A significant drawback was the inability to produce isolable and characterized non-arene complexes based on the bidentate phosphino-2-pyridone ligands employed. Well-defined complexes could have guided future ligand and catalyst design through additional stoichiometric studies to probe the fundamental steps involved in hydroaminoalkylation. Future work could focus on multi-dentate ligand incorporating the 2-pyridone functionality. Additionally, a ligand framework that could also be modified to incorporate the analogous 2-aminopyridine functionality is desirable. A 2-amino group could be sterically and electronically modified to potentially modulate reactivity. Complexes that incorporate tridentate N,N,N-chelates, such as complexes 1.22, 1.31, 1.38, 1.39, 1.41, or 1.42 detailed in Chapter 1,31,35-36,38 have already been explored for their reactivity in hydrogenation/dehydrogenation chemistry with alcohols/carbonyls. However, their reactivity with amines has not been reported. A related N-mesityl-2-aminopyridine derivative has also been synthesized (Figure 5.1, 5.1).263 These complexes could be starting points to investigate their potential for catalytic hydroaminoalkylation. Additionally, these ligand sets could be expanded to synthesize their Rh and Ir analogues. These derivatives all coordinate in a meridinal geometry about the metal center. As an alternative, the trispyridylamine ligand set has been expanded to include 2-hydroxypyridines and 2-aminopyridines. Complexes of Fe, Cu (Figure 5.1, 5.2), and Ru (Figure 5.1, 5.3) have already been reported,264-266 while trispyridylamine Rh and Ir complexes are also reported.267 Intriguingly, the trispyridylamine ligand has been shown to be hemi-labile, where a pyridyl arm can become uncoordinated from the metal center allowing for an open coordination site.267 While our results demonstrate that cationic complexes can readily facilitate the stoichiometric dehydrogenation of amines, the resulting metal hydride does not have the required 165  hydricity to realize the desired hydroaminoalkylation chemistry. The use of these hard nitrogen donors may provide for non-cationic complexes that are electron poor to accommodate the dehydrogenation step, but have increased hydricity over cationic complexes to effect hydroaminoalkylation chemistry.  Figure 5.1 Examples of alternative ligand sets for future work toward late-transition-metal catalyzed hydroaminoalkylation chemistry 5.3 Concluding Remarks This thesis has demonstrated how a combination of ligand and complex design can significantly alter reactivity. Further, this thesis demonstrates that 1,3-N,O-chelating 2-pyridonate and phosphoramidate ligands are well-suited as ancillary ligands for Ta and Nb catalyzed hydroaminoalkylation of alkenes with secondary amines. In contrast, phosphino-2-pyridonate and 2-pyridonate ligands have been shown to act as a coordinated base when coordinated to late-transition metal complexes, allowing for interesting reactivity with amines.   NOHNNOHHOCuNFNNRNNNRRNRuNOCl5.3R = H, tBuCH2NH, tBuC(O)NHNN NOHOHRuPPh3PPh3Cl1.22NN NOHOHRuPPh3ClCl1.31+NNN OHRu ClPPh3PPh31.39NNNRuPPh3ClCl1.41OHNNN OHRuPPh3ClCl1.38NNNRuPPh3ClCl1.42OHOH+NN NNHNHRuPPh3ClClMesMes5.1Mes = 2,4,6-trimethylphenyl5.2166  References (1) Lawrence, S. 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Crystallogr. 2006, 39, 453-457.    176  Appendices Appendix A  NMR Spectra  5.85.82.72.717.617.61.01.01.91.91.01.01.01.0ppm0 02244668810-13.9752.1122.1352.3743.4986.3606.3746.3786.3926.8197.0947.0987.1127.1167.1607.7047.7097.7187.723TaNOMesNNNClComplex 2.14 ppm0 05050100100150150200200-249.66420.75021.03921.14746.777112.958125.560127.819128.060128.302128.972132.585135.787137.156138.237140.417141.438168.0901H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 177                     3.13.117.817.81.01.01.01.01.01.0ppm0 02244668810-13.982.023.556.226.236.236.256.916.926.926.926.926.926.936.936.946.946.946.947.167.587.587.587.587.597.597.597.60ppm0 05050100100150150200200-249.6614.6146.67112.78122.06127.82128.06128.30138.67140.01169.52TaNOMeNNNClComplex 2.15 1H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 178                       ppm0 05050100100150150200200-249.0946.66111.50127.90128.06128.22128.35137.91137.94137.97138.00145.0518.918.91.01.01.01.01.01.0ppm0 02244668810-13.983.455.925.925.935.935.935.947.297.297.297.297.307.307.307.537.537.547.547.55TaNOF3CNNNClComplex 2.16 1H NMR 600 MHz C6D6 13C{1H} NMR 151 MHz C6D6 179     ppm-200 -200-150-150-100-100-50-50-0-05050100-349.47-62.9319F NMR 282 MHz C6D6 180     18.018.00.90.90.80.81.01.01.01.0ppm0 02244668810-13.983.546.176.176.186.186.186.196.206.206.306.316.316.336.336.336.946.946.966.966.976.986.987.167.627.627.627.627.637.637.647.64ppm0 05050100100150150200200-249.6646.57112.64112.70127.82128.06128.30140.68141.44170.50TaNONNNClHHComplex 2.17 1H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 181     ppm0 05050100100150150200200-240.0248.29111.43111.45127.74128.06128.38128.46128.57128.87139.38140.86153.47170.7918.018.00.80.80.90.91.11.11.01.01.91.91.91.9ppm0 02244668810-14.003.516.336.336.366.366.486.486.516.517.007.037.037.067.187.197.197.207.217.227.237.247.247.857.867.867.877.887.897.89TaNONNNClPhComplex 2.18 1H NMR 300 MHz C6D6 13C{1H} NMR 75 MHz C6D6 182   3.43.418.318.31.01.00.90.91.11.1ppm0 02244668810-13.9752.1053.5986.0696.0716.0736.0876.0896.0916.1906.1926.1946.2116.2136.2156.9286.9466.9496.9677.160ppm0 05050100100150150200200-249.66421.80347.296109.667111.938127.818128.060128.302141.104151.871170.865TaNONNNClMeComplex 2.19 1H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 183    18.018.01.01.01.01.02.12.11.01.01.01.01.91.9ppm0 011223344556677889-14.003.436.356.366.376.397.067.067.067.087.087.097.107.117.117.167.207.207.227.227.257.357.367.387.397.637.647.657.657.827.837.847.857.86ppm0 05050100100150150200200-249.6646.27114.54119.08122.24125.42127.82128.06128.14128.30128.75128.90135.27140.79140.88168.98TaNOPhNNNOTfComplex 2.20 1H NMR 300 MHz C6D6 13C{1H} NMR 101 MHz C6D6 184     ppm-200 -200-150-150-100-100-50-50-0-05050100-349.47-78.1819F NMR 282 MHz C6D6 185   ppm0 0112233445566778-19.952.847.16331.551.50.7290.7291.451.45ppm1 12233445566778-13.982.306.396.396.416.426.746.746.746.766.766.766.776.786.787.167.187.187.20NDN-d-N-methylaniline 1H NMR 400 MHz C6D6 2H NMR 61 MHz C6D6 186    221.091.092.632.63ppm0 0112233445566778-13.980.272.082.082.092.102.106.336.336.336.346.356.356.676.686.686.696.696.706.716.716.716.986.986.987.027.107.117.127.14N CD3D331.161.16ppm0 011223344556677889-19.952.332.81N-d-N-(methyl-d3)aniline 1H NMR 400 MHz Tol-d8 2H NMR 61 MHz Tol-d8 187       6623.923.93.983.980.9130.9132.132.131.961.96ppm0 01122334455667788-9.471.061.061.081.081.091.093.363.933.943.943.943.953.953.963.963.963.963.973.973.983.983.983.993.994.004.004.014.024.024.034.046.866.866.876.876.886.886.896.896.897.167.197.197.217.217.317.317.317.327.327.337.337.337.33EtONPOEtOPhNbNMe2NMe2NMe2NMe23.13ppm0 05050100100150150200200-220.8616.4616.5049.1462.7762.82119.41120.72120.83129.61129.62147.63147.641H NMR 600 MHz C6D6 13C{1H} NMR 151 MHz C6D6 188     ppm-100 -100-50-50-0-05050100100150150200200250250-400.504.9931P{1H} NMR 122 MHz C6D6 189         5.915.913.773.7717174.134.131.131.131.931.9311ppm0 0112233445566778899-13.981.121.121.131.141.151.152.152.623.183.183.994.014.024.044.066.886.886.906.906.907.167.187.187.207.287.287.297.297.307.31EtONPOEtOArNbNMe2NMe2NMe2NMe2Ar = 2-Me-C6H53.14ppm0 05050100100150150200200-249.6616.6916.7619.8219.9046.9747.5862.0862.15118.29123.62123.71126.32126.45127.82128.06128.30130.60131.39131.59149.371H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 190     ppm-100 -100-50-50-0-05050100100150150200200250250-400.811.2531P{1H} NMR 162 MHz C6D6 191        5.855.856.146.1423.123.11.481.484.054.05ppm0 0112233445566778899-13.981.101.101.111.111.131.131.451.463.403.643.663.673.733.753.763.783.913.923.933.933.933.943.953.953.963.973.973.973.993.993.994.004.014.017.161.071.071.121.120.5430.5431.551.550.6290.62911ppm0 05050100100150150200-249.6616.3216.4026.6226.6848.0649.1652.4052.4962.3462.41127.82128.06128.30EtONPOEtOiPrNbNMe2NMe2NMe2NMe23.151H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 192     ppm-100 -100-50-50-0-05050100100150150200200250250-400.8156.8931P{1H} NMR 162 MHz C6D6 193       6.116.116.036.0321.421.42.032.03112.072.072.182.18ppm0 0112233445566778899-13.981.171.181.251.263.354.594.604.614.624.624.634.644.654.654.676.846.866.866.866.887.167.187.187.197.297.307.317.317.327.33ONPOOPhNbNMe2NMe2NMe2NMe23.16iPriPrppm0 05050100100150150200200-249.6623.9824.0124.1524.2149.1470.9471.01119.26120.70120.86127.82128.06128.30129.52147.73147.761H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 194      ppm-100 -100-50-50-0-05050100100150150200200250250-400.813.5531P{1H} NMR 162 MHz C6D6 195          6611.111.2.892.8920.720.71.331.33ppm0 0112233445566778899-13.981.271.271.291.292.432.453.173.203.623.633.653.673.683.703.727.16Me2NNPOMe2NiPrNbNMe2NMe2NMe2NMe23.170.5820.5820.6530.6532.232.230.7670.7674.384.380.7260.7261.371.37.792.791ppm0 02020404060608080100100120120140140160160-249.6614.3923.0927.0027.1132.0037.4637.5046.9847.7047.7348.3548.54127.82128.06128.301H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 196     ppm-100 -100-50-50-0-05050100100150150200200250250-400.8126.3331P{1H} NMR 162 MHz C6D6 197     2.82.83.03.03.03.02.92.93.3.32.92.93.03.06.16.15.95.92.82.81.01.00.90.95.85.83.03.01.11.15.15.11.11.11.11.11.11.13.03.01.01.03.03.0ppm0 01122334455667788-13.980.930.940.951.001.011.021.141.161.171.201.211.221.241.251.281.291.311.321.361.371.381.461.471.481.561.572.352.362.592.602.863.113.543.553.563.573.583.583.703.713.713.723.723.733.733.733.733.743.743.753.753.763.763.773.773.783.783.793.793.803.813.813.823.833.833.833.843.843.843.853.853.863.863.863.873.883.883.893.933.943.953.963.974.004.024.024.034.034.044.044.054.054.064.074.084.104.114.114.124.124.134.134.144.144.154.154.164.554.564.574.584.584.584.594.594.604.604.614.624.634.644.654.714.724.744.754.767.167.177.177.197.207.217.217.227.237.237.247.247.287.287.287.297.307.317.3218.918.920.520.521211 121.119.219.219.219.28.478.4725 125.119.419.417.417.435.735.7.17.9202020.820.-37.2-37.2-34.7-34.723.223.224.724.716.616.615.115.112.512.510.610.612.212.2.310.310.410.48.38.3-2.07-2.070.4490.4490.3180.3180.5590.5592.672.6711ppm0 02020404060608080100100120120140140160160180180200200-249.0916.0716.1216.2116.2616.6616.6916.7616.7924.8624.9124.9225.3625.4025.5225.8526.9927.1827.3527.4727.4846.8054.0062.8862.9262.9462.9763.0963.1463.3363.38123.61123.64123.80124.13124.16124.23124.72124.74125.49125.51127.90128.06128.22128.35140.25140.30141.34141.39145.49145.53147.26147.31147.41147.45147.59147.64NbNMe2NP NOP ONDippDippEtOEtOEtOEtO3.181H NMR 600 MHz C6D6 13C{1H} NMR 151 MHz C6D6 198     ppm-40 -40-30-30-20-20-10-10-0-01010202030304040-98.94-0.158.9931P{1H} NMR 162 MHz C6D6 199     12.312.36.356.356.216.215.735.73726.72661.111.10.9860.9863.243.24ppm0 01122334455667788-8.981.311.321.341.371.382.402.422.532.552.612.632.642.663.403.633.904.087.160.3380.3380.3660.3660.3950.3950.360.3660.6590.6596710.6710.9610.96110.3670.3670.3580.3580.3110.3110.3660.366ppm0 02020404060608080100100120120140140160160180180-200.7914.2922.7325.7725.8026.0626.1126.6626.7328.3428.3734.4437.2537.2837.4937.5237.6237.6537.6737.6947.7048.6749.6252.84127.90128.06128.22NbNMe2NP NOP ONiPriPrMe2NMe2NMe2NMe2N3.201H NMR 600 MHz C6D6 13C{1H} NMR 151 MHz C6D6 200     ppm-100 -100-50-50-0-05050100100150150200200250250-400.5024.5534.6331P{1H} NMR 121 MHz C6D6 201      5.495.495.935.9311.611.64.044.01.941.941.791.791.781.781.861.86ppm0 0112233445566778899-14.000.960.960.980.991.011.012.072.072.082.092.092.473.533.763.783.783.793.803.813.813.823.833.833.843.843.863.863.873.883.883.893.893.903.913.913.923.933.943.946.696.696.706.716.726.736.736.746.756.896.926.926.956.966.976.976.986.987.007.007.097.327.327.337.337.357.357.36ppm0 02020404060608080100100120120140140160160180180-240.0215.9316.0119.4649.6563.0463.11121.87122.42122.58122.85133.79NbNMe2NMe23.21NNPOPhEtOEtO1H NMR 300 MHz Tol-d8 13C{1H} NMR 75 MHz Tol-d8 202      ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4911.9231P{1H} NMR 121 MHz Tol-d8 203     121222220.9680.9680.9230.9230.9870.9870.9540.954ppm0 02244668810101212-14.000.991.011.021.031.041.051.061.071.701.701.721.731.751.751.771.781.791.801.821.821.841.852.712.726.196.216.306.337.287.307.317.3312.92NPiPr2OH4.21ppm0 05050100100150150200200-240.0218.9419.0819.5119.7023.5123.7026.5326.8576.7477.1677.58106.28106.41116.40116.43141.55148.71148.85165.661H NMR 300 MHz CDCl3 13C{1H} NMR 75 MHz CDCl3 204     ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4911.4431P{1H} NMR 121 MHz CDCl3 205   6.446.446.426.422.122.121.051.051.011.011.151.1511ppm0 02244668810101212-14.000.860.880.900.921.021.041.071.102.162.172.182.192.212.222.232.242.252.262.282.292.302.316.326.326.346.346.346.366.366.486.486.486.516.516.517.267.267.287.287.297.297.317.3112.144.22NPiPr2OHppm0 05050100100150150200200-240.0219.3719.5019.9120.1822.8222.9876.7477.1677.58114.48114.76120.91139.76139.86146.39146.83165.39165.421H NMR 300 MHz CDCl3 13C{1H} NMR 75 MHz CDCl3 206     ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4911.8231P{1H} NMR 121 MHz CDCl3 207    7.517.513.813.814.784.7816.816.81.311.311.171.170.7720.7720.9940.9940.8920.8921.051.051.141.147.097.0914.314.3ppm0 011223344556677889910-14.001.091.111.131.141.151.171.181.191.201.211.241.391.411.431.461.491.511.541.571.661.671.731.751.761.771.781.792.392.392.412.432.432.432.442.452.452.472.662.682.702.732.752.773.273.303.323.353.373.403.423.583.623.653.703.756.236.346.357.177.587.79ppm0 02020404060608080100100120120140140160160180-240.029.8610.3510.3712.3515.0416.3021.6024.1427.0030.5633.1536.0936.1337.7467.4467.7468.0368.3268.62101.31118.80118.81120.73124.33127.94129.96130.01130.04130.08130.38130.42130.46130.50130.80130.84130.88130.92131.22131.25131.29131.34131.55136.20136.21136.22136.23162.44163.10163.76164.42RhNPOCliPriPrNaOEt2OEt2+–B(ArF)44.251H NMR 300 MHz THF-d8 13C{1H} NMR 75 MHz THF-d8 208     ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4955.7256.68ppm-200 -200-150-150-100-100-50-50-0-05050100-349.47-65.2331P{1H} NMR 121 MHz THF-d8 19F{1H} NMR 282 MHz THF-d8 209     6.376.375.15.13.613.613.273.273.613.6115.115.12.162.161.131.13441.121. 20.8970.8970.980.98113.93.98.828.82ppm0 011223344556677889910-12.471.101.111.131.131.141.161.181.201.221.241.251.381.391.411.431.451.471.491.501.681.691.732.552.572.592.602.632.652.662.683.143.173.183.213.363.383.393.413.583.783.813.823.856.086.106.306.317.067.087.087.107.577.79IrNPOCliPriPrNaOEt2OEt2+–B(ArF)44.26ppm0 05050100100150150200200-238.3210.0716.3119.4419.5020.3120.4420.4720.7525.9526.9027.1527.9928.2941.7342.0666.9468.0394.5394.56116.10139.14158.06171.961H NMR 400 MHz THF-d8 13C{1H} NMR 101 MHz THF-d8 210     ppm-100 -100-50-50-0-05050100100150150200200250250-400.8723.3031P{1H} NMR 162 MHz THF-d8 211       ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4957.623.093.092.582.585.175.173 13.513.333.332.992.99.183.1810.8980.891.151.151. 31.030.2840.2840.8330.8330.790.790.8230.8230.6640.6640.770.770.7490.7490.7390.7392.482.488.058.05ppm-1 -1001122334455667788991010-20.481.021.041.061.071.141.161.171.181.201.211.221.231.471.491.501.521.651.671.691.712.342.352.372.382.392.402.422.442.652.672.682.702.722.822.832.852.872.892.913.053.073.093.113.583.613.623.623.655.545.555.915.935.975.996.116.136.216.226.286.297.067.067.077.087.087.087.097.107.577.79RuNPOCliPriPriPrNaTHFTHF+–B(ArF)44.271H NMR 400 MHz THF-d8 31P{1H} NMR 121 MHz THF-d8 212      ppm-150 -150-100-100-50-50-0-05050-237.12-63.4219F NMR 377 MHz THF-d8 213     12124.694.6912.912.91.181.181.171.174.244.240.9730.9730.9250.9250.970.973.573.577.797.79ppm0 011223344556677889910-12.491.311.311.331.331.351.351.351.371.391.391.411.431.451.731.771.901.902.662.682.692.702.702.722.722.742.742.763.053.073.083.093.103.113.123.133.143.163.583.626.076.086.086.106.326.357.247.257.267.267.277.277.287.297.577.79ppm-200 -200-150-150-100-100-50-50-0-05050100100-395.71-25.87IrClNaTHFTHFNOPiPriPr+–B(ArF)44.281H NMR 400 MHz THF-d8 31P{1H} NMR 162 MHz THF-d8 214     ppm-150 -150-100-100-50-50-0-05050-237.12-63.0819F NMR 377 MHz THF-d8 215     2.72.72.72.72.362.365.15.172.452.453.43.42.432.431.171.171.851.850.9250.9250.9760.9760.960.9690.9170.9171.061.060.9480.9480.8690.869448.78.70.05680.0568ppm0 01122334455667788991010-12.491.151.171.201.211.281.301.321.331.341.351.371.381.391.401.421.441.511.521.541.562.072.582.602.622.632.642.652.672.682.782.802.822.832.832.842.852.862.872.885.615.625.685.706.086.106.116.196.216.336.356.576.597.197.207.217.217.227.227.237.247.577.577.79ppm-200 -200-150-150-100-100-50-50-0-05050100100-395.71-4.39RuCliPrNaTHFTHFNOPiPriPr+–B(ArF)44.291H NMR 400 MHz THF-d8 31P{1H} NMR 162 MHz THF-d8 216     ppm-150 -150-100-100-50-50-0-05050-237.12-63.4219F NMR 377 MHz THF-d8 217     1.11.13.273.273.453.45.183.184.034.0316.116.11.561.561.31.31. 61.161.181.180.990.91.051.05830.9834.874.8710.510.51.261.26ppm-20 -20-15-15-10-10-5-5-0-055101015-40.05-13.80-13.730.360.380.400.420.840.850.880.901.241.261.291.301.321.341.841.901.951.992.472.492.512.522.542.563.223.243.273.293.613.643.653.683.706.816.836.936.957.477.497.527.707.78IrNPOHHiPriPr4.31+–B(ArF)4ppm0 05050100100150150200200-249.6610.2417.1517.1718.3518.4018.5818.9819.0024.2524.4624.5724.7925.6041.1941.4868.3776.8477.1677.4894.52107.65114.51114.59117.54117.58117.61117.65117.70120.62123.33126.04128.55128.58128.61128.64128.74128.86128.89128.92128.95129.18129.21129.23129.26129.51129.52129.54129.56129.57134.93141.74159.11159.14161.08161.58162.07162.57163.41163.441H NMR 400 MHz CDCl3 13C{1H} NMR 101 MHz CDCl3 218     ppm-100 -100-50-50-0-05050100100150150200200250250-400.8138.3231P{1H} NMR 162 MHz CDCl3 219     0.9540.9543.263.263.193.193.043.04343.343.513.5114.714.70.9920.9920.950.953.483.48920.9921.01.03110.9270.9270.9920.9923.753.758.198.19ppm-20 -20-15-15-10-10-5-5-0-055101015-40.05-14.98-14.880.780.810.830.860.971.001.031.051.161.181.201.211.231.231.261.291.901.921.931.941.952.022.022.032.032.112.142.152.162.172.192.402.422.452.472.492.523.173.183.193.223.263.293.313.353.433.473.493.523.586.096.126.436.457.077.107.107.127.577.797.79ppm-200 -200-150-150-100-100-50-50-0-05050100100150150200-403.4741.25IrNPOHiPriPr+HN4.31•pyrrolidineH1H NMR 300 MHz THF-d8 31P{1H} NMR 121 MHz THF-d8 220     3.093.093.143.143.053.050.8860.8863.013.012.992.995.915.9122.922.952.950.9730.9730.9980.9980.9910.9910.940.949110.9480.9481.951.950.9760.9761.971.97ppm-1 -100112233445566778899-20.020.770.791.151.171.551.731.741.761.782.182.222.252.282.363.584.684.694.794.805.145.155.225.235.255.255.385.405.755.755.765.776.826.826.966.987.007.007.02ppm0 05050100100150150200200-249.6617.7120.2020.3520.8221.0421.4321.5921.6624.7424.9425.1425.3425.5430.9466.7766.9967.4367.6576.2078.4679.0585.4197.49102.12105.51106.70127.66129.13129.20130.06132.42134.36135.76136.52136.76138.16138.41141.77157.43171.44NNRuCliPr4.391H NMR 400 MHz THF-d8 13C{1H} NMR 101 MHz THF-d8 221     15.315.33.413.413.093.093.093.09.163.163.043.043.043.040.9980.998112.082.081.021.021. 21.021.091.09ppm0 011223344556677889910-13.981.082.122.192.232.272.672.755.425.425.445.445.755.755.775.776.756.766.776.776.796.856.916.957.16IrClNN4.40ppm0 02020404060608080100100120120140140160160180180-249.668.8319.7420.5221.0821.1821.3422.1283.61107.49107.77127.61127.82128.06128.30128.68128.94129.99132.92134.84136.62136.74136.82137.46137.60138.50138.69155.88173.091H NMR 400 MHz C6D6 13C{1H} NMR 101 MHz C6D6 222        6.636.637.527.528.278.27.897.892.422.422.122.122.182.182.122.12222.062.062.062.061.831.83ppm0 01122334455667788991010-20.020.110.900.930.950.971.071.091.111.141.361.391.411.411.431.451.732.382.412.422.432.442.452.462.482.492.512.592.622.642.642.662.672.682.713.433.473.483.533.584.324.334.354.354.384.404.404.406.496.527.097.117.577.607.639.73NPHONPOHRuClCliPriPriPriPr4.41ppm0 05050100100150150200-240.0218.8719.2419.2619.2819.5220.7124.7825.0425.3125.5825.8427.6227.7827.9428.2628.3728.4937.4237.5837.6137.7766.8067.0967.3867.6867.97109.07109.09109.10115.51115.58115.64140.40162.19169.511H NMR 300 MHz THF-d8 13C{1H} NMR 75 MHz THF-d8 223     ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4967.9731P{1H} NMR 121 MHz THF-d8 224       36.236.24.54.54.264.2621.821.83.153.150.6280.6280.7560.7562.582.580.6930.6930.9720.9720.9320.9321.381.380.9960.9960.9440.9440.9440.94411ppm0 02244668810101212141416-40.050.840.860.890.910.991.021.041.061.231.241.251.261.391.421.731.731.731.912.012.092.182.913.023.203.293.585.235.265.405.436.116.146.226.246.416.446.476.696.726.7414.591.421.4211ppm-250 -250-200-200-150-150-100-100-50-50-0-05050100100150-403.4967.7568.0579.7880.08NPHONPORuNiPriPriPriPrTMS TMSProposed Complex 4.421H NMR 300 MHz THF-d8 31P{1H} NMR 121 MHz THF-d8 225     7.197.197.537.533.353.358.78.72.222.222.22.2110.9160.9161.961.960.9560.956ppm0 0112233445566778899-12.491.733.113.143.583.795.765.785.825.846.776.786.806.806.82NPRhOiPriPr4.45ppm-200 -200-150-150-100-100-50-50-0-05050100100-395.7153.8254.771H NMR 400 MHz THF-d8 31P{1H} NMR 162 MHz THF-d8 226     6.926.927.247.244.744.744.754.752.492.492.232.232.162.160.990.990.9820.9822.192.191.021.02ppm0 0112233445566778899-12.490.111.091.101.121.141.201.211.231.251.732.212.232.242.252.262.272.282.282.302.302.322.343.323.333.333.343.585.915.935.945.966.456.846.846.866.866.866.876.886.88NPIrOiPriPr4.46ppm-200 -200-150-150-100-100-50-50-0-05050100100-395.7138.881H NMR 400 MHz THF-d8 31P{1H} NMR 162 MHz THF-d8 227  Appendix B  Solid State Molecular Structures and X-ray Data: Single crystal X-ray structure determinations were performed at the X-ray crystallography lab at the Department of Chemistry, University of British Columbia on either a Bruker X8 APEX or Bruker APEX DUO diffractometer using graphite-monochromated Mo Kα radiation (λ=0.71073 Å). Collection of data, integration, and absorption correction were performed by Dr. Jacky Yim, Scott Ryken, Damon Gilmour, or Sam Griffin. Unless otherwise noted, data integration was performed using Bruker SAINT (v.8.34A), absorption correction was performed using Bruker SADABS (2014/5), structures were solved using direct methods using SIR2004,268 and refinement (including modelling of disorder) was performed using SHELXL (2014/7) using the OLEX2 interface.269-270 ORTEP representations were produced using CCDC’s Mercury software.271 Compound 2.16: Crystals were found to be twinned. Both twin domains were integrated using Bruker TWINABS (2012/1), the structure was solved and refined using a dataset consisting of reflections only from the major twin domain.    2.15 2.16 2.18 formula C12H24ClN4OTa C12H21ClF3N4OTa C17H26ClN4OTa Fw 456.75 510.73 518.82 crystal size (mm) 0.25 x 0.19 x 0.17 0.16 x 0.12 x 0.07 0.36 x 0.28 x 0.21 color, habit yellow, plate yellow, plate yellow, prism crystal system Monoclinic Triclinic orthorhombic 228   2.15 2.16 2.18 space group P21/c P-1 Pbca T (K) 100 100 90 a (Å) 8.6755(12) 7.9749(8) 9.6112(4) b (Å) 12.7009(19) 8.4714(8) 14.3447(6) c (Å) 15.100(2) 14.7644(15) 28.6697(12) a (Å) 90 89.788 90 b (Å) 97.197(3) 86.448 90 g (Å) 90 61.895 90 V (Å3) 1650.7(4) 877.79(15) 3952.7(3) Z 4 2 8 rcalcd (g cm-3) 1.838 1.932 1.744 F(000) 888.0 492.0 2032.0 µ (MoKa) (mm-1) 6.819 6.447 5.708 2qmax (°) 60.084 60.05 60.096 total no. of reflns 20011 5107 30947 no. of unique reflns 4839 5107 5797 R1 (F2, all data) 0.0152 0.0377 0.0230 wR2 (F2, all data) 0.0316 0.0556 0.0394 R1 (F, I > 2s(I)) 0.0132 0.0292 0.0194 wR2 (F, I > 2s(I)) 0.0310 0.0551 0.0384 229   2.15 2.16 2.18 goodness of fit 1.037 1.069 1.097     3.13 3.18 3.20 3.21 formula C18H39N5NbO3P C36H65N4NbO6P2 C18H49N8NbO2P2 C22H37N4NbO3P Fw 497.42 804.77 564.50 529.43 crystal size (mm) 0.41 x 0.23 x 0.22 0.25 x 0.24 x 0.20 0.47 x 0.46 x 0.39 0.37 x 0.37 x 0.24 color, habit red, plate yellow, plate yellow, plate yellow, prism crystal system Monoclinic Triclinic monoclinic monoclinic space group P21/c P-1 P21/c P21/c T (K) 90 90 90 90 a (Å) 12.5545(13) 11.3648(10) 9.7447(17) 13.800(2) b (Å) 12.9294(13) 14.2901(12) 14.759(3) 9.1504(15) c (Å) 14.2200(14) 15.4990(13) 19.720(4) 20.890(4) a (Å) 90 94.786(2) 90 90 b (Å) 92.210(2) 111.422(2) 100.356(4) 106.875(3) g (Å) 90 113.251(2) 90 90 V (Å3) 2306.5(4) 2075.3(3) 2789.9(9) 2524.3(7) Z 4 2 4 4 Table B.1 Single crystal X-ray diffraction data for complexes 2.15, 2.16, and 2.18 230   3.13 3.18 3.20 3.21 rcalcd (g cm-3) 1.432 1.288 1.3438 1.393 F(000) 1048.0 856.0 1192.6 1108.0 µ (MoKa) (mm-1) 0.619 0.412 0.575 0.569 2qmax (°) 59.7 61.232 59.94 60.456 total no. of reflns 43833 101321 32074 28595 no. of unique reflns 6564 12472 8065 7422 R1 (F2, all data) 0.0230 0.0371 0.0213 0.0366 wR2 (F2, all data) 0.0549 0.0911 0.0902 0.0760 R1 (F, I > 2s(I)) 0.0187 0.0295 0.0192 0.0292 wR2 (F, I > 2s(I)) 0.0501 0.0777 0.0845 0.0718 goodness of fit 1.091 1.130 0.797 1.046    Table B.2 Single crystal X-ray diffraction data for complexes 3.13, 3.18, 3.20, 3.21 231   4.25 4.26 4.41 formula C29H38.5B0.5Cl0.5N0.5Na0.5 O2P0.5Rh0.5 C31H32.5B0.5Cl0.5F12Ir0.5 N0.5Na0.5O1.5P0.5 C24H40Cl2N2O2P2Ru Fw 527.67 810.28 622.49 crystal size (mm) 0.58 x 0.20 x 0.08 0.201 x 0.056 x 0.026 0.213 x 0.187 x 0.158 color, habit orange, blade yellow, prism Brown-red, prism crystal system triclinic triclinic monoclinic space group P-1 P-1 P21/c T (K) 100 100 100 a (Å) 11.661(2) 12.2496(12) 10.6280(9) b (Å) 14.185(3) 15.9609(15) 13.8180(11) c (Å) 17.002(3) 18.9485(18) 18.6807(16) a (Å) 93.391(4) 114.073(3) 90 b (Å) 102.357(4) 91.081(2) 91.454(2) g (Å) 96.662(4) 94.196(2) 90 V (Å3) 2718.4(9) 3368.4(6) 2742.5(4) Z 4 4 4 rcalcd (g cm-3) 1.289 1.598 1.508 F(000) 1114.0 1618.0 1288.0 µ (MoKa) (mm-1) 0.446 2.162 0.907 2qmax (°) 53.006 54.46 54.294 total no. of reflns 40899 52907 24002 232   4.25 4.26 4.41 no. of unique reflns 11190 14939 6051 R1 (F2, all data) 0.0783 0.0712 0.0655 wR2 (F2, all data) 0.1767 0.1179 0.1247 R1 (F, I > 2s(I)) 0.0561 0.0494 0.0540 wR2 (F, I > 2s(I)) 0.1570 0.1096 0.1197 goodness of fit 1.269 1.038 1.110  Table B.3 Single crystal X-ray diffraction data for complexes 4.25, 4.26, and 4.41 

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