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Synthetic applications of zirconium and titanium amidate complexes Yim, Jacky Chun-Ho 2015

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SYNTHETIC APPLICATIONS OF ZIRCONIUM AND TITANIUM AMIDATE COMPLEXES by  Jacky Chun-Ho Yim  B. Sc., The University of Western Ontario, 2009  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 2015  © Jacky Chun-Ho Yim, 2015 ii  Abstract  The use of titanium or zirconium amidate complexes as either reagents or catalysts for targeted applications is described herein. The investigation is focused on a novel class of zirconocene amidate hydride complexes primarily used for the hydrozirconation reaction and a previously disclosed bis(amidate) bis(amido) titanium complex for the regioselective alkyne hydroamination reaction.  A novel class of zirconocene amidate hydride complexes is synthesized and characterized. The amidate binding mode is significantly influenced by sterics. A rare example of an equilibrium between the structural isomers where the amidate ligand adopts either the κ1 O-bound or κ2 is shown. Reaction of styrene with these complexes resulted in the formation of the branched insertion products, which is in contrast to the observed regioselectivity when the well-known Schwartz’s reagent is used. Asymmetric insertion was attempted with a complex bearing an amidate ligand with a stereocenter. Reactivity with other alkenes and phenylacetylene were explored. Under harsh reaction conditions, the zirconocene amidate hydride complexes undergo a halide exchange reaction with phenyl halides. A competition experiment suggests two separate mechanistic pathways for styrene insertion and halide exchange. A primary kinetic isotope effect suggests Zr─H cleavage is involved in the rate-determining step. Experimental evidence is consistent with a coordination-insertion mechanistic proposal.  The synthetic utility of a previously reported bis(amidate) bis(amido) titanium complex for the regioselective alkyne hydroamination reaction is further explored. The reactivity and regioselectivity of hydroamination with benchmark substrates using this bis(amidate) titanium complex is directly compared to other titanium based hydroamination catalysts. The substrate iii  scope of this bis(amidate) titanium hydroamination catalyst is extended to include more difficult substrates, such as protected propargyl alcohols. Modifications to the reaction protocol allow for facile bench-top use. The bis(amidate) titanium complex was applied to tandem sequential reactions featuring hydroamination to afford secondary amines, a primary amine and a substituted primary allylamine. This hydroamination catalyst is also used for the oligomerization of alkynylanilines. By tuning the alkynylaniline monomer, a soluble N-containing oligomer was synthesized, which shows a degree of conjugation. This bis(amidate) titanium hydroamination catalyst was employed to assemble a small library of aminoether compounds targeted as T-type calcium channel blockers.   iv  Preface  Parts of the research conducted for this thesis were carried out collaboratively with other members of the Schafer group, Dr. Martin Haehnel under the joint supervision with Prof. Uwe Rosenthal, and Prof. Terrence Snutch and his team at Zalicus Pharmaceuticals Ltd. Unless otherwise noted, all of the experiments described in this thesis were designed by me, in consultation with my supervisor, Prof. Laurel Schafer. I performed all of these experiments except for the following specific instances.  The initial studies with the synthesis and reactivity (insertion of styrene and isomerization of 1-octene) with complexes 2a and b of Chapter 2 were designed and performed by Dr. Martin Haehnel and he performed most characterization of these complexes. I aided by providing starting materials and in the characterization of these complexes by collecting the data for the solid-state molecular structures and performing the final refinements. EXSY, TOCSY and NOESY NMR studies on complex 2d were performed with the aid of Mr. Marcus Drover. DFT calculations were performed by Mr. Jason Brandt.  Compounds 25c-d,f, and 26a,d were synthesized and characterized by Dr. Jason Bexrud. Determination of the kinetic isotope effect was performed by Dr. David Leitch. Initial studies with the polymerization of 37 with precatalyst 20 were performed by Ms. Ellen Pope, an undergraduate researcher, under my supervision. However, the experimental design was solely mine.   All biological data in Chapter 4 were collected by Prof. Terrance Snutch, his academic research group and Zalicus Pharmaceuticals Ltd. Compounds 46d,e and 47d were synthesized and characterized by Mr. David Le, an undergraduate researcher under my supervision. Compounds 47a, 48a and b were synthesized and characterized by Dr. Christine Rogers.  v  All mass spectrometry and elemental analysis data were collected by technicians at the UBC Mass Spectrometry Centre in the chemistry department.  Select data presented in Section 2.2.2 have been reported in Angewandte Chemie International Edition published by Wiley-VCH Verlag and Chemistry ̶ A European Journal published by Wiley-VCH Verlag as: Haehnel, M.; Yim, J. C.-H.; Schafer, L. L.; Rosenthal, U. “Facile Access to Tuneable Schwartz’s Reagents: Oxidative Addition Products from the Reaction of Amide N-H Bonds with Reduced Zirconocene Complexes” Angew. Chem., Int. Ed. 2013, 52, 11415-11419 and Haehnel, M.; Priebe, J. B.; Yim, J. C.-H.; Spannenberg, A.; Brückner, A.; Schafer, L. L.; Rosenthal, U. “Four-Membered Heterometallacyclic d0 and d1 Complexes of Group 4 Metallocenes with Amidato Ligands” Chem. Eur. J. 2014, 20, 7752-7758. I wrote portions of the introductory sections of these papers and participated in the editing process.   Portions of Sections 3.1, 3.2.2 and 3.2.3 have been reported in European Journal of Organic Chemistry published by Wiley-VCH Verlag as: Yim, J. C.-H.; Schafer, L. L. “Efficient Anti-Markovnikov-Selective Catalysts for Intermolecular Alkyne Hydroamination: Recent Advances and Synthetic Applications” Eur. J. Org. Chem. 2014, 2014, 6825-6840.   Portions of Section 3.2.1 have been reported in Journal of Organic Chemistry published by the American Chemical Society as: Yim, J. C.-H.; Bexrud, J. A.; Ayinla, R. O.; Leitch, D. C.; Schafer, L. L. “Bis(amidate)bis(amido) Titanium Complex: A Regioselective Intermolecular Alkyne Hydroamination Catalyst” J. Org. Chem. 2014, 79, 2015-2028.     vi  Table of Contents  Abstract ........................................................................................................................................... ii Preface............................................................................................................................................ iv Table of Contents ........................................................................................................................... vi List of Tables ................................................................................................................................. xi List of Figures .............................................................................................................................. xiii List of Schemes ............................................................................................................................ xvi List of Symbols and Abbreviations.............................................................................................. xxi Compound Numbers of Select Complexes ............................................................................... xxvii Acknowledgements .................................................................................................................. xxviii Dedication .................................................................................................................................. xxix Chapter 1: Introduction ....................................................................................................................1 1.1 Titanium and Zirconium Complexes as Synthetic Tools ................................................ 1 1.2 N,O-Chelates as Ancillary Ligands............................................................................... 11 1.3 Scope of this Thesis ...................................................................................................... 14 Chapter 2: Synthesis and Reactivity of Zirconocene Amidate Hydride Complexes .....................16 2.1 Introduction ................................................................................................................... 16 2.1.1 Scope of this Chapter ................................................................................................ 24 2.2 Results and Discussion ................................................................................................. 25 2.2.1 Synthesis and Structure of Zirconocene Amidate Hydride Complexes .................... 25 2.2.2 Reactivity of Zirconocene Amidate Hydride Complexes ......................................... 44 2.2.2.1 Reaction of Styrene with Zirconocene Amidate Hydride Complexes .............. 44 vii  2.2.2.2 Attempted Asymmetric Hydrozirconation ........................................................ 50 2.2.2.3 Reactivity of Zirconium Amidate Hydride Complexes with Other Alkenes .... 54 2.2.2.4 Insertion of Phenylacetylene ............................................................................. 56 2.2.2.5 Reactivity of Amidate Hydride Complexes with Other Reagents .................... 58 2.2.3 Mechanistic Rationale for the Observed Regioselectivity ........................................ 66 2.3 Conclusions ................................................................................................................... 76 2.4 Experimental ................................................................................................................. 77 2.4.1 Materials and Methods .............................................................................................. 77 2.4.2 Synthesis and Characterization of Proligands and Complexes ................................. 79 2.4.3 Synthesis and Characterization of Zirconocene Amidate Hydride Complexes ........ 81 2.4.4 Synthesis and Characterization of Styrene Insertion Products ................................. 87 2.4.5 Insertion Reaction with Styrene Derivatives ............................................................ 89 2.4.6 Procedures for the Reactivity of Complex 2d with Other Reagents ......................... 90 2.4.7 Comparison of Relative Reactivity of Insertion Reaction with Styrene ................... 93 2.4.8 Variable temperature van’t Hoff study for the Equilibrium of κ1- and κ2-2d ........... 93 2.4.9 Kinetics Experiments ................................................................................................ 94 2.4.10 General Procedure for Electrochemical Analysis ................................................. 95 2.4.11 Crystallographic Structure Determination ............................................................ 96 Chapter 3: Bis(Amidate)Bis(Amido) Titanium Complex as a Versatile Hydroamination Catalyst ..........................................................................................................................................99 3.1 Introduction ................................................................................................................... 99 3.1.1 Scope of this Chapter .............................................................................................. 112 3.2 Results and Discussion ............................................................................................... 113 viii  3.2.1 Bis(amidate)bis(amido) Titanium Complex for Hydroamination .......................... 113 3.2.1.1 Expansion of Substrate Scope ......................................................................... 119 3.2.1.2 Discussion of Mechanism ............................................................................... 130 3.2.1.3 Improved Protocol .......................................................................................... 132 3.2.2 Tandem Sequential Reactions with Hydroamination ............................................. 135 3.2.2.1 Hydroamination/hydrosilylation Reaction Sequence ..................................... 136 3.2.2.2 Hydroamination/Isomerization/Deprotection Sequence ................................. 139 3.2.2.3 Synthesis of Substituted Allylamine via Hydroamination/Alkynlation Reaction Sequence ……………………………………………………………………………….141 3.2.3 Synthesis of Nitrogen Containing Oligomers via Hydroamination ........................ 142 3.2.3.1 Synthesis of Oligomers from Meta-ethynylaniline ......................................... 143 3.2.3.2 Synthesis of Oligomers from Para-1-hexynylaniline ..................................... 145 3.2.3.3 Synthesis of Oligomers from Para-(2-phenylethyn-1-yl)aniline ................... 149 3.3 Conclusions ................................................................................................................. 154 3.4 Experimental ............................................................................................................... 155 3.4.1 Material and Methods ............................................................................................. 155 3.4.2 Synthesis and Characterization of Titanium Complex ........................................... 157 3.4.3 Synthesis and Characterization of Hydroamination Substrates .............................. 158 3.4.4 General Methods for Hydroamination with Complex 20. ...................................... 162 3.4.5 General Methods for Reductions. ........................................................................... 164 3.4.6 Synthesis and Characterization of Hydroamination Products. ............................... 165 3.4.7 Synthesis of Standard Solution of Complex 20 and Hydroamination Reaction with the Solution of Precatalyst .................................................................................................. 176 ix  3.4.8 General Procedure for Hydroamination/Hydrosilylation Reaction Sequence ........ 177 3.4.9 Hydroamination/Isomerization Reaction Sequence: N-hexyl-4-methylbenzenesulfonamide (35). ........................................................................................ 180 3.4.10 Hydroamination/Alkyne Addition: Synthesis of Substituted Allylamine 36. .... 181 3.4.11 Procedure for Oligomerization with Hydroamination ........................................ 183 3.4.12 Crystallographic Structure Determination .......................................................... 184 Chapter 4: Library Synthesis of Aminoethers via Hydroamination as Target for Calcium Ion Channel Blockers .........................................................................................................................186 4.1 Introduction ................................................................................................................. 186 4.1.1 Scope of this Chapter .............................................................................................. 192 4.2 Results and Discussion ............................................................................................... 193 4.2.1 Synthesis of Aminoether Library ............................................................................ 193 4.2.2 Biological Studies ................................................................................................... 199 4.3 Conclusions ................................................................................................................. 208 4.4 Experimental ............................................................................................................... 209 4.4.1 Methods and Materials ............................................................................................ 209 4.4.2 Synthesis and Characterization of Compounds. ..................................................... 210 Chapter 5: Summary, Future Work and Conclusions ..................................................................221 5.1 Summary ..................................................................................................................... 221 5.2 Future Works .............................................................................................................. 226 5.2.1 Use of Zirconium Amidate Hydride Complexes for Hydrosilylation: Preliminary Results and New Directions ................................................................................................ 226 x  5.2.2 Use of Zirconium Amidate Hydride Complexes for Cross-Dehydrocoupling Reactions: Preliminary Results and New Directions .......................................................... 229 5.2.3 Hydroamination to form N-containing Oligomers with Other Alkynylanilines: Preliminary Results and New Directions ............................................................................ 230 5.2.4 Conductivity Measurements of N-containing Oligomers: New Direction ............. 234 5.3 Conclusions ................................................................................................................. 234 5.4 Experimental for Preliminary Results ......................................................................... 235 References ....................................................................................................................................240 Appendices ...................................................................................................................................273 Appendix A Supplementary Figures for Chapter 2 ................................................................ 273 Appendix B NMR Spectra for Select Compounds ................................................................. 279 Appendix C Biological Data ................................................................................................... 325  xi  List of Tables  Table 1-1: Prices of select transition metals in 2011 ...................................................................... 2 Table 2-1: Comparison of selected structural metrics of κ2 bound zirconocene amidate hydride complexes. .................................................................................................................................... 34 Table 2-2: Comparison of selected NMR spectroscopic data of zirconocene amidate  complexes. .................................................................................................................................... 39 Table 2-3: Qualitative comparison of reactivity of hydride complexes 2 with styrene. ............... 71 Table 2-4: Crystal data collection and refinement parameters for zirconium hydride  complexes .................................................................................................................................... 97 Table 2-5: Crystal data collection and refinement parameters for other zirconium complexes ... 98 Table 3-1: Hydroamination of 1-phenyl-1-propyne and aniline (or p-toluidine) catalyzed by selected titanium complexes. ...................................................................................................... 115 Table 3-2: Hydroamination of phenylacetylene and aniline (or p-toluidine) catalyzed by selected titanium complexes. .................................................................................................................... 116 Table 3-3: Hydroamination of 1-hexyne (or 1-octyne) and aniline catalyzed by selected titanium complexes. .................................................................................................................................. 117 Table 3-4: Hydroamination of 1-hexyne (or 1-octyne) and benzylamine catalyzed by selected titanium complexes. .................................................................................................................... 118 Table 3-5: Hydroamination of 1-hexyne and alkylamines by complex 20. ................................ 120 Table 3-6: Hydroamination of benzylamine and terminal alkynes catalyzed by complex 20. ... 123 Table 3-7: Hydroamination of terminal alkynes and arylamines catalyzed by complex 20. ...... 125 Table 3-8: Hydroamination of internal alkynes by complex 20. ................................................ 127 xii  Table 3-9: Comparison of crystalline precatalyst 20 and in situ generated complex 20. ........... 133 Table 3-10: Hydroamination/hydrosilylation reaction sequence in the presence of  complex 20. ................................................................................................................................ 139 Table 3-11: Crystal data collection and refinement parameters for complex 20 and compound 28i. .............................................................................................................................................. 185  xiii  List of Figures  Figure 1-1: Tebbe’s and Petasis reagent commonly used for the olefination of carbonyl  moieties. .......................................................................................................................................... 3 Figure 1-2: Proposed transition state for Sharpless asymmetric epoxidation. ................................ 7 Figure 1-3: Examples of titanium or zirconium hydroaminoalkylation catalysts......................... 10 Figure 1-4: Different bonding motifs adoptable by amidate ligands. ........................................... 12 Figure 2-1: (a, left) Two possible sites for olefin coordination to Schwartz’s reagent. (b, right) Depiction of the LUMO of Cp2ZrH2. ........................................................................................... 19 Figure 2-2: Proposed structure of zirconocene amidate complexes with a terminal hydride  ligand............................................................................................................................................. 22 Figure 2-3: Diagnostic signals for [Cp2Zr(C(SiMe3)CHSiMe3)]2O ............................................. 27 Figure 2-4: Molecular structure of 2a in the solid state. ............................................................... 31 Figure 2-5: Molecular structure of 2b in the solid state.. .............................................................. 32 Figure 2-6: Molecular structure of 2c in the solid state. ............................................................... 33 Figure 2-7: Molecular structure of 2d in the solid state. ............................................................... 34 Figure 2-8: Two possible geometric isomers of zirconocene amidate hydride complexes. ......... 35 Figure 2-9: Molecular orbital surfaces for the HOMO (left) and LUMO (right) calculated for complex 2d.................................................................................................................................... 36 Figure 2-10: Molecular structure of rac-2e in the solid state. ...................................................... 37 Figure 2-11: Left, a) 1H-13C HMBC NMR spectrum of complex 2d at room temperature. Right, b) 1H-13C HMBC NMR spectrum of complex 2d at 65 °C. ......................................................... 41 xiv  Figure 2-12: Partial variable temperature 13C NMR spectra of the cyclopentadienyl region of complex 2d.................................................................................................................................... 41 Figure 2-13: Van’t Hoff plot of the interconversion of the isomers of complex 2d generated from VT quantitative 13C NMR spectroscopic experiments.................................................................. 43 Figure 2-14: Crude 1H NMR spectrum of styrene insertion with complex 2d. ............................ 45 Figure 2-15: Molecular structure of 3b in the solid state. ............................................................. 47 Figure 2-16: Molecular structure of 3c in the solid state .............................................................. 48 Figure 2-17: Molecular structure of 3d in the solid state. ............................................................. 49 Figure 2-18: Molecular structure of (R)-5b in the solid state ....................................................... 52 Figure 2-19: Partial 1H NMR spectra of the reaction between 5a and 5b with styrene. .............. 54 Figure 2-20: Insertion reaction with phenylacetylene with complex 2d. ..................................... 57 Figure 2-21: Molecular structure of 6 in the solid state.. .............................................................. 57 Figure 2-22: Molecular structure of 7a in the solid state .............................................................. 60 Figure 2-23: Cyclic voltammogram of complex 2d (5 × 10-3 M) in THF at 25 °C (scan speed 100 mV/s)............................................................................................................................................. 64 Figure 2-24: Plot showing the rates of reaction between 1 equiv. of complex 2d (2 runs) and d-2d (2 runs) and 10 equiv. of styrene at 25 °C. ................................................................................... 74 Figure 3-1: Rate constants of hydroamination for several titanium catalysts ............................. 107 Figure 3-2: ORTEP diagram of the structure of complex 20 at 50% probability. ...................... 109 Figure 3-3: ORTEP diagram of compound 28i as the DCl salt at 50% probability ................... 129 Figure 3-4: TGA curve of oligomer 42. ...................................................................................... 152 Figure 4-1: Structural formula of Mibefradil (43). ..................................................................... 187 Figure 4-2: The “ball and stick” model of a voltage-gated ion channel. .................................... 188 xv  Figure 4-3: Simplified model of a typical T-type calcium channel blocker. .............................. 189 Figure 4-4: (top) Reported T-type calcium channel blockers with similar potency with improved selectivity than Mibefradil. (bottom) Our class of target compounds. ....................................... 190 Figure 4-5: Pyrrolidine and piperidine derivatives synthesized by Dr. Robbie Zhai. ................ 192 Figure 4-6: Complete library of aminoether (Class I) compounds synthesized for biological screening. .................................................................................................................................... 193 Figure 4-7: Biological data for Mibefradil. ................................................................................. 201 Figure 4-8: Biological data for various aminoethers. ................................................................. 203 Figure 4-9: Schematic changes to the aminoether core to obtain the most potent compound towards blocking CaV3.1. ........................................................................................................... 205 Figure 4-10: The effect on the biological activity of switching the benzhydryl protected oxygen atom to a nitrogen atom or a silyl protecting group. ................................................................... 206 Figure 4-11: The effect on the biological activity of additional substituents to the nitrogen atom to the aminoether core. ................................................................................................................ 206 Figure 4-12: Biological data for a series of N-substituted heterocycles. .................................... 207 Figure 5-1: Insertion-σ-bond metathesis mechanism for hydrosilylation. .................................. 227 Figure 5-2: Partial COSY NMR spectrum of the crude product mixture following hydrosilylation. ........................................................................................................................... 236    xvi  List of Schemes  Scheme 1-1: General reaction scheme of hydrozirconation with Schwartz’s reagent .................... 4 Scheme 1-2: Negishi’s reagent used for the homocoupling of diphenylacetylene. ........................ 5 Scheme 1-3: General reaction scheme of Sharpless asymmetric epoxidation ................................ 6 Scheme 1-4: General reaction scheme of Ziegler-Natta polymerization ........................................ 8 Scheme 1-5: (top) General reaction scheme of hydroamination (bottom) General reaction scheme of hydroaminoalkylation ................................................................................................................. 8 Scheme 1-6: Asymmetric intramolecular hydroamination catalyzed by a chiral bisamidate zirconium complex........................................................................................................................ 13 Scheme 2-1: Synthesis of heteroles with Negishi’s reagent ......................................................... 16 Scheme 2-2: Synthesis of various organic and organometallic products from hydrozirconation with Schwartz’s reagent ................................................................................................................ 17 Scheme 2-3: Styrene insertion with Schwartz's reagent ............................................................... 20 Scheme 2-4: (a, top) C─N bond cleavage of a tertiary amide with Schwartz’s reagent to afford an aldehyde. (b, bottom) C─N bond cleavage of a secondary amide with Schwartz’s reagent to afford an imine. ............................................................................................................................. 23 Scheme 2-5: Oxidative addition of an EH moiety to a Zr(II) species. ......................................... 24 Scheme 2-6: Two synthetic routes to synthesize zirconocene amidate hydride complexes. ........ 25 Scheme 2-7: Proligand synthesis from commercially available acyl chlorides and amines. ........ 26 Scheme 2-8: Synthesis of zirconocene complexes with N,O-chelating ligands using a formal oxidative addition.......................................................................................................................... 27 Scheme 2-9:  Reaction of zirconocene amidate hydride complex with amide proligand. ............ 28 xvii  Scheme 2-10: Synthesis of the zirconocene amidate hydride complexes 2a–e via salt  metathesis. .................................................................................................................................... 29 Scheme 2-11: Equilibrium between the κ2 and κ1 binding motif of the amidate ligand in complex 2d. ................................................................................................................................................. 42 Scheme 2-12: Insertion reaction with styrene to form the branched insertion product. ............... 44 Scheme 2-13: Electrophilic quenching of the insertion product 3d with iodine. ......................... 50 Scheme 2-14: Synthesis of complexes 5a and 5b and their reactivity with styrene. .................... 51 Scheme 2-15: Hydrozirconation of 1-phenylpropene by Schwartz reagent followed by an oxidative quench ........................................................................................................................... 55 Scheme 2-16: Reaction of 2d with halobenzene to form 7a and 7b. ............................................ 59 Scheme 2-17: Reaction of Schwartz’s reagent and iodobenzene. ................................................ 61 Scheme 2-18: Competition experiment with styrene and iodobenzene. (a, top) with complex 2d. (b, bottom) with Schwartz’s reagent. ............................................................................................ 62 Scheme 2-19: Reaction of dibenzyldisulfide with complex 2d. ................................................... 65 Scheme 2-20: Reaction of 2d with radical probe 10 and competition experiment with 10 and styrene. .......................................................................................................................................... 68 Scheme 2-21: β-hydride elimination is observed upon heating for complex 3d. ......................... 72 Scheme 2-22: Synthesis of the deuterated amidate complex d-2d and their insertion reaction with styrene d-3d. ................................................................................................................................. 73 Scheme 2-23: Possible mechanistic pathway for styrene insertion of zirconocene amidate hydride complexes. .................................................................................................................................... 75 Scheme 3-1: General intermolecular hydroamination of terminal alkynes. ............................... 101 Scheme 3-2: General mechanism of titanium catalyzed hydroamination. ................................. 102 xviii  Scheme 3-3: Hydroamination of butylamine and diphenylacetylene in the presence of 11 ....... 104 Scheme 3-4: Hydroamination of hexylamine and 1-phenyl-1-propyne in the presence of 11b . 104 Scheme 3-5: Regioselective hydroamination of benzylamine in the presence of 12 ................. 105 Scheme 3-6: Control of regioselectivity of hydroamination using Cp ligands ........................... 106 Scheme 3-7: Control of regioselectivity of hydroamination using aryloxo ligands ................... 108 Scheme 3-8: Synthesis of bis(amidate)bis(amido)titanium precatalyst 20. ................................ 109 Scheme 3-9: Synthesis of withasomnine using a Ti catalyzed hydroamination as a key step. ... 111 Scheme 3-10: Hydroamination of 1-hexyne and N-benzyl-1,2-ethylenediamine in the presence of complex 20. ................................................................................................................................. 121 Scheme 3-11: Hydroamination of (4-methoxyphenyl)phenylacetylene with aniline catalyzed by complex 20. ................................................................................................................................. 128 Scheme 3-12: Hydroamination of (4-(trifluoromethyl)phenyl)phenylacetylene with para-methoxyaniline catalyzed by complex 20. .................................................................................. 129 Scheme 3-13: General mechanism of bisamido group 4 catalyzed hydroamination. ................. 130 Scheme 3-14: Precatalyst 20 prepared in situ for multigram synthesis and column-free isolation of 24a .......................................................................................................................................... 134 Scheme 3-15: Multigram synthesis of 24a with a premade solution of complex 20. ................. 134 Scheme 3-16: General scheme of titanium catalyzed tandem sequential hydroamination reaction followed by a titanium catalyzed reduction. ............................................................................... 137 Scheme 3-17: Synthesis of primary amine (33) using 20 by a sequential hydroamination/isomerization/deprotection sequence. ............................................................... 140 Scheme 3-18: Synthesis of substituted primary allylamine (36) using 20 by a sequential hydroamination/alkynylation/deprotection sequence. ................................................................ 141 xix  Scheme 3-19: Oligomerization of meta-ethynylaniline in the presence of complex 20. ............ 144 Scheme 3-20: Oligomerization of para-1-hexynylaniline in the presence of complex 20. ........ 146 Scheme 3-21: Infrared spectra of the monomer 39 (top) and of the oligomer 40 (bottom). ...... 147 Scheme 3-22: UV-Vis spectrum of monomer 39 and oligomer 40 in DCM. ............................. 148 Scheme 3-23: Oligomerization of para-(2-phenylethyn-1-yl)aniline in the presence of  complex 20. ................................................................................................................................ 149 Scheme 3-24: Infrared spectrum of monomer 41 and oligomer 42. ........................................... 150 Scheme 3-25: UV-Vis spectra of monomer 41 and oligomer 42 in THF. .................................. 153 Scheme 4-1: Retrosynthetic scheme for the synthesis of aminoether-type compounds. ............ 191 Scheme 4-2: Retrosynthetic scheme for the synthesis of N-heterocyclic compounds with hydroamination. .......................................................................................................................... 192 Scheme 4-3: Hydroamination of an amine and benzhydryl protected propargyl alcohol in the presence of complex 20 to afford aminoether (Class I) compounds. ......................................... 194 Scheme 4-4: Hydroamination of an amine and protected propargyl alcohol in the presence of complex 20 to afford aminoether (Class I) compounds. ............................................................. 195 Scheme 4-5: Hydroamination of an amine and protected homopropargyl alcohol in the presence of complex 20 to afford aminoether (Class I) compounds. ........................................................ 196 Scheme 4-6: Functionalization of compound 24i. ...................................................................... 196 Scheme 4-7: Synthesis of benzhydryl substituted cyclic amines (Class II) with complex 50. ... 197 Scheme 4-8: Functionalization of compound 52a. ..................................................................... 197 Scheme 4-9: Tandem-sequential intramolecular-intermolecular hydroamination using  complex 50. ................................................................................................................................. 199 Scheme 5-1: Hydrosilylation of styrene and phenylsilane catalyzed by complex 2d. ............... 228 xx  Scheme 5-2: General reaction scheme for cross-dehydrocoupling of a silane and amine. ......... 229 Scheme 5-3: Cross-dehydrocoupling of phenylsilane and isopropylamine catalyzed by  complex 2d.................................................................................................................................. 230 Scheme 5-4: Proposed oligomerization of a monomer with methyl substituent to afford an oligomer with higher regioselectivity. ........................................................................................ 231 Scheme 5-5: Synthesis of monomer 56. ..................................................................................... 232 Scheme 5-6: Proposed oligomerization of an N-substituted alkynylaniline. .............................. 233 Scheme 5-7: Synthesis of monomer 57. ..................................................................................... 233   xxi  List of Symbols and Abbreviations  Abbreviation Description  1D 1-dimensional 2D 2-dimensional Å angstrom A ampere Ac acetyl Ad adamantyl Anal. analysis ATR attenuated total reflectance a.u. arbitrary units aq aqueous BINOL 1,1`-bi-2-naphthol bpy 2,2`-bipyridine br broad (spectral) BTMSA bis(trimethylsilyl)acetylene Bn benzyl Bu butyl ° degree °C degrees Celsius 13C{1H} proton-decoupled carbon-13 xxii  ca. circa (approximately) Calcd  calculated cat. catalyst cm-1 wavenumber Cp cyclopentadienyl Cp* η5-C5Me5; 1,2,3,4,5-pentamethylcyclopentadienyl COSY correlation spectroscopy δ chemical shift in ppm Δ heat; change d doublet (spectral) DCM dichloromethane dd doublet of doublets (spectral) DEPT distortionless enhancement of polarization transfer Dipp 2,6-diisopropylphenyl  DFT density functional theory DMAP 4-dimethylaminopyridine  E/Z trans / cis EA elemental analysis EB electrostatic analyzer-magnetic sector EI electron impact  ESI electrospray ionization equiv. equivalents Et ethyl; C2H5 xxiii  eV electron volt EXSY exchange spectroscopy 19F fluorine-19 Fc ferrocene FLIPR Fluorescent Imaging Plate Reader g gram G Gibb’s free energy GC gas chromatography η hapto, denotes ligand hapticity H enthalpy 1H hydrogen, proton 2H deuterium HMBC Heteonuclear multiple-bond correlation spectroscopy HMDS bis(trimethylsilyl)amide HOMO Highest Occupied Molecular Orbital  hr hour hex hexyl; n-C6H13 Hz Hertz FT-IR Fourier transformed infrared I current IC50 half maximal inhibitory concentration iPr isopropyl Ind indenyl xxiv  nJAB n-bond coupling constant between atoms A and B K kelvin kobs observed rate constant  κn kappa; denotes n-number of bound atom(s) kJ kilojoule λ wavelength L liter  LAH lithium aluminum hydride LUMO Lowest Unoccupied Molecular Orbital  M molarity m multiplet (spectral); medium  m meta MALDI matrix assisted laser desorption ionization Me methyl; CH3 mg milligram mL milliliter mmol millimole MS mass spectrum mol mole m/z mass-to-charge ratio  ND not determined nm nanometer  nM nanomolar xxv  NMR nuclear magnetic resonance ν stretching frequency o ortho ORTEP Oakridge Thermal Ellipsoid Plot p para PE petroleum ether Ph phenyl; C6H5 pH power of hydrogen ppm parts per million PMP para-methoxyphenyl  py pyridine q quartet (spectral) quint quintet (spectral) R ideal gas constant rac racemic red reduction Rf retention factor ROMP ring-opening metathesis polymerization  s singlet (spectral); strong S entropy sec second sept septet (spectral) SHE standard hydrogen electrode xxvi  t triplet (spectral) TADDOL α,α,α`,α`-tetraaryl-1,3-dioxolane-4,5-dimethanol TBA tetrabutyl ammonium TBDMS  tert-butyldimethylsilyl tBu tert-butyl TGA thermal gravimetric analysis THF  tetrahydrofuran TMS tetramethylsilane  TOCSY total correlated spectroscopy TOF time-of-flight μ Mu; denotes bridging ligand UV-Vis ultraviolet-visible  V volts VT variable temperature w weak   xxvii  Compound Numbers of Select Complexes     xxviii  Acknowledgements  I would like to sincerely thank all of the people and organizations that have contributed to this body of work. First and foremost, I am greatly indebted to my research supervisor, Prof. Laurel Schafer. She has been unbelievably supportive and helpful through my studies at UBC. The guidance and reassurance she has provided during the course of my time at UBC is invaluable. Thank you for teaching me all the hard lessons that I will surely need in the future.  I am thankful for all of the labmates, both past and present, in the Schafer group. The time spent here would not be the same without all of you. I must especially thank Dr. Desiree Sauer, Ying Lau, Jason Brandt and Scott Ryken for being so helpful with the editing process to put this thesis together. Also, I would like to thank Dr. Christine Rogers and Dr. Patricia Horrillo-Martinez for being such great mentors and showing me the ropes when I first got here.  Thank you to Prof. Mark MacLachlan for being a helpful and insightful reader. Your comments and suggestions greatly improved the quality of this thesis. I would also like to thank all the staff members at the shops and services at UBC, who always provided the needed support. I thank the following agencies for funding: the University of British Columbia, the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. Finally, thanks are owed to my family and my girlfriend, Renee Man, for all the support they have given and continue to give me.  xxix  Dedication  This thesis is the dedicated to my parents, Helen and Imran Afzal, to my sister, Anisa Afzal and to my girlfriend, Renee Man.   1  Chapter 1: Introduction   1.1 Titanium and Zirconium Complexes as Synthetic Tools Titanium and zirconium complexes are widely used as synthetic tools, both as reagents and catalysts.1 As with other transition metal complexes, these group 4 metal complexes are known to be excellent catalysts or reagents to invoke unique reactivity.2 When compared to other transition metals, such as gold or palladium, titanium and zirconium are relatively inexpensive and display lower toxicities in both the metallic and metal oxide states.1 Titanium and zirconium are abundant in the earth’s crust and are therefore relatively inexpensive when compared to other metals often used in catalysis (Table 1-1).3 Although this attribute does not directly apply to all titanium and zirconium complexes, this does impact the cost and availability of homoleptic titanium and zirconium complexes that are commonly used as metal precursors. Titanium is non-toxic even in large doses and is one of the most biocompatible metals; it is even used as pins to set bones.4 On the other hand, although the biological effects of zirconium are not well known, zirconium is not considered as an industrial health hazard and there is no evidence of zirconium being a carcinogen or genotoxin.5 These metals can access the +4, +3, and +2 (Zr: +1) oxidation states, but they are typically found in the +4 oxidation state. Thus, the metal center generally has a d0 electronic configuration. The vacant d-orbitals lead to an electrophilic metal center, which results in high reactivity. Therefore, generally titanium and zirconium metal complexes facilitate a broad range of reactions, with relatively low cost and environmental impact.   2  Table 1-1: Prices of select transition metals in 2011.6  Metal Price (€ mol-1) Metal Price (€ mol-1) Metal Price (€ mol-1) Ti 0.97 Pt 8117 Rh 5436 Zr 58 Pd 1942 Au 6371  The use of many titanium and zirconium reagents and catalysts as common synthetic tools have been highlighted in numerous reviews and books.1-2, 7-19 The wide selection of titanium and zirconium complexes that are commonly used illustrate the general applicability of these complexes in homogeneous reactions. It must be mentioned that these metals also play a large role in heterogeneous catalytic applications. For example, TiO2 is widely used as a photocatalyst20 for solar cells,21-22 hydrogen evolution,23 air and water purification,24-25 and can be used to oxidize amines26-27 and alcohols28-29 under aerobic conditions. Due to the breadth of chemical transformations involving these metals, a brief overview of select examples of the more broadly useful titanium and zirconium complexes in homogenous stoichiometric and catalytic reactions is presented.   Titanium and zirconium complexes are not without drawbacks. One major disadvantage is the highly oxophilic nature of these metals. This typically leads to instability of the metal complexes towards air and moisture. However, the oxophilic nature of titanium can be exploited to invoke desired reactivity. One notable example is the use of titanium complexes as an olefination reagent to transform a carbonyl functionality to afford a terminal olefin.11, 30-31 Two well-known reagents to affect such reactivity are Tebbe (Cp2TiCH2ClAl(CH3)2)32 and Petasis reagents (Cp2Ti(CH3)2).33 The active complex in both reagents is the titanocene methylidene complex (Figure 1-1). In this reaction, the titanium complex is used in at least stoichiometric amounts, where the titanium ultimately forms a stable Ti=O bond. The formation of this bond is thought to 3  be the driving force for this reaction. These reagents can be used as late-stage olefination reagents to complete a total synthesis or they can be used to generate the terminal olefin to be used as a synthetic handle to further build molecular complexity.11    Figure 1-1: Tebbe’s and Petasis reagent commonly used for the olefination of carbonyl moieties.32-33  Zirconocene based complexes are also useful reagents in organic synthesis, examples of these complexes include Schwartz’s reagent and Negishi’s reagent. In the seminal report by Schwartz,34 zirconocene chloro hydride was reacted with an olefin to afford the insertion product (Scheme 1-1). This reaction is known as hydrozirconation.14 The most notable observation was that this reagent typically offered the exclusive formation of the linear product. Because of the excellent regiocontrol, this reagent has been widely used to generate regioselectively the organozirconium complex from terminal and internal carbon-carbon unsaturations (vide infra). These organozirconium complexes can then be used in subsequent reactions, such as carbonyl insertions or act as transmetallating reagents, to afford targeted compounds.34-35 Interestingly, a general complementary reagent to afford the insertion product with the opposite regioisomer is 4  unknown. As this reaction is one of the focal points of this thesis, a more detailed overview of this reagent (and regioselective hydrozirconation) is presented in Chapter 2.   Scheme 1-1: General reaction scheme of hydrozirconation with Schwartz’s reagent.34  Nobel laureate Prof. Ei-ichi Negishi has successfully used zirconocene-type complexes for a wide range of applications including the use of organozirconium complexes as transmetalating reagents in Pd-catalyzed cross-coupling reactions and zirconium-catalyzed asymmetric carboalumination of alkenes.15, 36 In addition, Negishi has also developed [Cp2Zr(n-Bu)2], which is a useful organometallic reagent and often referred to as Negishi’s reagent (Scheme 1-2).36-39 This reagent is an example of a masked reduced zirconium complex, which is a very reactive class of compounds. Hence, Negishi’s reagent is typically generated in situ from the treatment of zirconocene dichloride with 2 equivalents of n-butyl lithium. The resulting complex exists as a mixture of the Zr(IV) complex (directly from the reaction) and the Zr(II) complex (thought to originate from a series of β-H elimination steps). This reagent is known to promote bicyclization of enynes, diynes, and dienes and cross coupling of two alkynes (Scheme 1-2).36 The target organic products can be cleaved from the resulting organozirconium complex via various methods, such as insertion of CO followed by treatment with I2 and an acid to afford a ketone product or by treatment with electrophilic quenching agent to substitute the zirconium moiety with an electrophile.36  5  Complexes analogous to Negishi’s reagent have been prepared by others.36 For example, by replacement of the n-butene ligand with ethylene, the coupling of two different unsymmetrical alkynes can then be achieved with regiocontrol over a broader range of substrates.40 Another noteworthy example is Rosenthal’s reagent, Cp2Zr(TMSCCTMS) and its related titanium variant, which can also be used as the masked Zr(II) and Ti(II) complexes for similar applications.16 The methodology of utilizing Zr(II) complexes for coupling reactions has been widely applied to organic synthesis, included its use in the total or formal syntheses of natural products.19, 41    Scheme 1-2: Negishi’s reagent used for the homocoupling of diphenylacetylene.36    Titanium and zirconium complexes are Lewis acidic and are readily used as Lewis acid catalysts for many reactions. For example, TiCl4 is used for the diastereoselective Aldol reaction,42-44 and ZrCl4 is used for the Friedel-Crafts reaction and in the esterification of primary alcohols with carboxylic acids.45 With the addition of a chiral ligand, asymmetric Lewis acid catalysis can be realized, including examples of the Diels-Alder reaction46-52 and nucleophilic addition reactions to imines and carbonyls.17-18 The chiral catalysts can either be pre-formed or generated in situ from the homoleptic alkoxide metal complex and a chiral ligand.  Chiral ligands that have been frequently used include BINOL derivatives46-52 and TADDOL derivatives.51 These asymmetric 6  Lewis-acid catalyzed reactions are examples of how titanium and zirconium complexes have been used advantageously to generate stereocenters starting from achiral starting materials. Another asymmetric catalytic reaction is the Sharpless asymmetric epoxidation using titanium-tartrate complexes prepared in situ.13 This reaction is an enantioselective method to prepare 2,3-epoxyalcohols from primary and secondary allylic alcohols using tert-butyl hydroperoxide as the oxidixing agent (Scheme 1-3). Epoxidation can be controlled to occur on a selected face of the C=C bond by either using the (R,R)- or (S,S)-tartrate ligand. For example, (S,S)-diethyltartrate would result in the selective epoxidation of the si face of the allylalcohol. Although the exact structure of the transition state is unknown, Figure 1-2 shows a proposed structure53 that accounts for the enantiofacial selectivity and the experimentally determined rate law.54 This reaction can also be used for the kinetic resolution of racemic allylic alcohols.55-56 These chiral epoxides are important synthetic building blocks that are used to construct larger, more complicated compounds, such as the natural products, amphidinolide X,57 and (-)-Nakamurol A.58  Scheme 1-3: General reaction scheme of Sharpless asymmetric epoxidation.13  7   Figure 1-2: Proposed transition state for Sharpless asymmetric epoxidation.53     Titanium and zirconium complexes are also known to be homogeneous Ziegler-Natta catalysts for the polymerization of α-olefins (Scheme 1-4).59 In the seminal report in 1955, Ziegler and coworkers disclosed the use of TiCl4─AlClEt2 for the polymerization of ethylene to polyethylene.60 This work was followed by Natta’s discovery of the stereoselective polymerization of propene.61 Although many materials are known to be Ziegler-Natta catalysts, some of the most well-studied Ziegler-Natta catalysts are group 4 metallocene complexes. As physical properties arise from the structure of the polymer, polymerization with stereocontrol allows for the synthesis of polymers with targeted physical and mechanical characteristics. This important discovery ultimately led to present day industrial scale applications.59 For the work in this area, Ziegler and Natta won the Nobel Prize in chemistry in 1963. Following these early publications, much work was done to determine the mechanism of this polymerization, typically using a titanocene derivative as a catalyst with an alkylaluminum initiator.10, 12, 62  An important discovery was made when it was identified that trace amounts of water present in the reaction resulted in increased polymerization activity.63-64 This led to the identification of methylaluminoxane (MAO) as an excellent initiator.65 Using MAO as the initiator, Cp2ZrCl2 can be efficiently used as a polymerization catalyst. This was followed by a number of studies to improve the stereochemical 8  control of the polymer by using derivatives of titanium and zirconium based metallocenes and ansa-metallocenes to synthesize more stereo-regular polymers.10, 66    Scheme 1-4: General reaction scheme of Ziegler-Natta polymerization.59   More recently, titanium and zirconium complexes have been used for catalytic amine synthesis. There are many examples of these complexes being able to promote the hydroamination reaction, which is the addition of a C─N bond over a C─C bond unsaturation (such as an alkene or alkyne),67-73 and the hydroaminoalkylation reaction, which is the alkylation of a carbon atom adjacent to a nitrogen atom (Scheme 1-5).74-76 Nitrogen-containing organic molecules are ubiquitous in pharmaceuticals and agrochemicals, making efficient synthesis of amines of considerable interest. Both hydroamination and hydroaminoalkylation, where a C─N or a C(sp3) ─C(sp3) bond is constructed, respectively, are 100% atom-economical reactions.     Scheme 1-5: (top) General reaction scheme of hydroamination.67-73 (bottom) General reaction scheme of hydroaminoalkylation.74-76 9  Although many complexes are able to catalyze the hydroamination reaction, group 4 metal complexes offer a balance of complex robustness, ease of handling of the complex, functional group tolerance, inexpensive cost, and regioselectivity.67-73 The mechanism of group 4 metal catalyzed hydroamination has been thoroughly investigated by detailed kinetic, mechanistic, and computational studies, where it is generally believed that a metal imido complex is the catalytically active species.67-73 Hydroamination can be facilitated by many metal complexes, ranging from simple homoleptic complexes, such as Ti(NMe2)477 and Zr(NMe2)4,78 to metallocene derivatives, such as Cp2TiMe2,67 Cp2Ti((SiMe3)CC(SiMe3)),79 and Cp2Zr(NHAr)2.80 More recently the focus has shifted to the development of other ancillary ligands away from cyclopentadienyl derived ligands. Complexes bearing tethered dipyrrolyl,81 alkoxide,64, 82 and amidate auxiliary ligands82-85 have been shown to be efficient hydroamination catalysts. Each catalyst differs from one another by either reactivity towards hydroamination, regioselectivity, chemoselectivity and effective substrate scope. Although some catalysts perform better than others, no one catalyst is broadly applicable for a wide range of substrates. As this reaction is one of the primary focuses of this thesis, a more detailed overview of this reaction is presented in Chapter 3.  Hydroaminoalkylation can be a side reaction that occurs during hydroamination but when optimized, hydroaminoalkylation is a powerful C─C bond forming reaction.74-76 This reaction was first independently reported by Maspero86 and later Nugent87 over 30 years ago, who used a range of simple early-transition metal complexes, including Zr(NMe2)4, to afford very low yields of the alkylated amine product. In 2008, Doye reported the use of Ind2TiMe2 for the hydroaminoalkylation of aminoalkenes, which marked the first example of titanium-catalyzed hydroaminoalkylation.88-92 This work was built upon preliminary results with Ti(NMe2)493-94 and related observation made by Odom during the investigation of titanium mediated transfer of 10  alkenyl groups from alcohols to amines.95 Since then, other examples of titanium and zirconium complexes have been shown to be capable hydroaminoalkylation catalysts (Figure 1-3),96-97 including examples developed by the Schafer group.98-99   Figure 1-3: Examples of titanium or zirconium hydroaminoalkylation catalysts.88, 93-94, 96-99   As highlighted above, titanium and zirconium complexes have many uses as synthetic tools, acting either as reagents or catalysts. Catalytic application of these complexes is intrinsically more beneficial than stoichiometric applications, due to the reduced amounts of the complexes that are needed under catalytic conditions. Ligand design can lead to more efficient catalysts that are able to react faster, afford higher yields or control regio-, chemo- or stereo-selectivity. In addition, judicious ligand design choices can convert stoichiometric reagents to catalysts. For example, titanium mediated hydroaminoalkylation was initially recognized as a byproduct during the study of titanium catalyzed hydroamination.88 By using clever ligand design, such as the use of N,O- and N,N-chelating ligands, the hydroaminoalkylation reaction was optimized to afford synthetically viable yields (typically 55 – 92% yield).96, 98-99 This example also highlights the importance of the 11  exploration of the reactivity of new classes of complexes for related reactivity to harness their synthetic utility.   1.2 N,O-Chelates as Ancillary Ligands N,O-chelating ligands have been used to advantage as ancillary ligands to modulate the reactivity at the metal center to invoke desired reactivity.82, 100 For example, the Schafer group has utilized early-transition metal based complexes with amidate,83-85, 101-108 ureate,102, 109-111 pyridonate,98-99, 101, 112 and phosphoramidate113 ligands towards a wide range of transformations.   In particular amidates, accessed from the deprotonation of amides, are excellent ancillary ligands. The amide proligands can be easily synthesized from commercially available acid chlorides and amines. This facile synthesis allows for the rapid generation of a wide range of proligands, which allows for the electronic and steric properties of these ligands to be tuned in a modular fashion. Amidate ligands can access several binding motifs (Figure 1-4).82 These ligands can adopt either a κ1 O-bound or an N-bound mode to one metal center, act as a bridging ligand between two metal centers or bind to a metal center in a κ2 N,O-chelating fashion. Typically, amidate ligands adopt the κ2 binding geometry towards early-transition metals.82-84, 102-106, 114-115 However, examples where the amidate ligand is κ1 O-bound have also been observed.116-121 On the other hand, late-transition metal complexes with amidate ligands have exhibited κ1 O-bound,122-125 κ1 N-bound,124, 126-129, κ2,124, 130-131 and bridging binding motifs.122-123, 132-133 It is believed that these ligands are hemilabile, which presumably accounts for their ability to modulate the reactivity of the metal center.   12   Figure 1-4: Different bonding motifs adoptable by amidate ligands.   As mentioned above, the Schafer group has used amidate ligands to modulate the reactivity of group 3-5 metal centers to achieve a wide range of transformations. For example, amidate ligands have been used to form yttrium complexes, which were demonstrated to be efficient catalysts for the polymerization of ε-caprolactone,104 catalytic amide formation from aldehydes and amines,107 intramolecular hydroamination,105 and carboxylation of terminal alkynes.134 Furthermore, tantalum amidate complexes have been utilized as intermolecular hydroaminoalkylation catalysts for alkenes and secondary amines to afford synthetically viable yields over a wide range of substrates.114, 135 Focusing on group 4 metals, titanium complexes bearing either amidate or pyridonate ligands have been shown to be able to catalyze the polymerization of rac-lactide and ε-caprolactone to afford random copolymers.101  As mentioned previously, by using titanium and zirconium pyridonate complexes, chemoselectivity can be tuned to favour intramolecular hydroaminoalkylation reactivity over hydroamination reactivity.98-99 Zirconium complexes with amidate ligands have been shown as active catalysts for intramolecular hydroamination.103, 108 In extension, a zirconium complex synthesized with a tethered bis(amidate) using an axially chiral tether was shown to be an asymmetric hydroamination catalyst affording yields up to >98% with 13  ees up to 93% (Scheme 1-6).106 A zirconium complex bearing a tethered bis(ureate) ligand has been shown to be an efficient catalyst for both intramolecular and intermolecular hydroamination.109-110 Using the same tethered bis(ureate) ligand a zirconium complex was found to catalyze the dimerization of alkynes to selectively afford the Z-enyne product.111      Scheme 1-6: Asymmetric intramolecular hydroamination catalyzed by a chiral bisamidate zirconium complex.106    In addition, the Schafer group reported the use of a bis(amidate) bis(amido) titanium complex for the intermolecular hydroamination of primary aminoalkynes and the intermolecular hydroamination of alkynes and primary amines.83 In the following report, a more sterically bulky variant was identified as a broadly applicable and regioselective intermolecular hydroamination catalyst.84-85 While other titanium catalysts are known for this reaction, this bis(amidate) bis(amido) titanium complex is able to tolerate a wide range of substrates and demonstrates excellent regioselectivity. As the titanium complex is able to tolerate such a wide range of substrates, it has been used in tandem sequential reactions to afford tetrahydroisoquinolines,84 α-cyanoamines, diamines, imidazolidinones, α-amino acid derivatives,136-137 chiral morpholines,138 and piperazines.138 As this complex is one of the focuses of this thesis, a more detailed overview is presented in Chapter 3.   14  1.3 Scope of this Thesis In summary, the work in the Schafer group focuses on the development of novel [N,O]-ligated early transition metal complexes, the elucidation of the fundamental chemistry of these compounds, and demonstration of their potential synthetic utility. This thesis discloses the development of a series of zirconium amidate hydride complexes and their applications as Schwartz’s reagent alternatives. Furthermore, the expansion of the synthetic utility of a known titanium amidate complex is presented.    In Chapter 2, the synthesis and structural characterization of a novel class of zirconocene amidate hydride complexes will be discussed. The initial stages of this work were undertaken in collaboration between the Schafer group and the Rosenthal group of the Leibniz Institute for Catalysis at the University of Rostock in Rostock, Germany. These zirconocene amidate hydride complexes resemble the well-known Schwartz reagent. As such, its reactivity was explored and compared and contrasted to that of Schwartz reagent. Finally, the mechanistic rationale for the different reactivity of the zirconium amidate complexes is presented.   In Chapter 3, the extension of the synthetic application of a previously disclosed hydroamination catalyst, bis(amidate) bis(amido) titanium complex,84-85 will be discussed. This complex has been previously shown to be a robust catalyst that is compatible with a range of functional groups. However, there are known challenging substrates for this catalyst. This chapter will show the efforts to overcome these limitations and further expand the substrate scope of this catalyst. Furthermore, a simplified protocol for facile benchtop use will be presented. The application of this catalyst in tandem-sequential reactions is undertaken. Finally, the use of this hydroamination catalyst for synthesis of a novel class of N-containing polymer is investigated. 15   In Chapter 4, the use of our preferred titanium hydroamination catalyst is applied to the synthesis of a library of aminoethers. A lead aminoether compound has been reported for T-type calcium ion channel blocking and is a biological target for the treatment of prostate cancer. However, the exact mechanism by which the chemical structure of the compound promotes ion channel blocking is unclear. The good functional-group tolerance of the titanium catalyst can be taken advantage of to synthesize rapidly a library of these aminoethers for exploration of structure/ channel blocking activity relationships. These compounds were screened for their biological activity by our collaborators Prof. Terrence Snutch and his team at Zalicus. The results from these studies will be presented.   Finally in Chapter 5, the work presented in this thesis will be summarized and conclusions will be presented. Possible future research directions arising from the investigations undertaken as part of this thesis will be also be presented.   16  Chapter 2: Synthesis and Reactivity of Zirconocene Amidate Hydride Complexes  2.1  Introduction The chemistry of zirconocene complexes continues to be of key interest to inorganic and organic chemists due to their unique structure and reactivity.14, 34, 139 During the last 50 years these complexes have been extensively developed and many well-known reagents have emerged as standard synthetic tools. For example, reduced zirconocene species have been widely utilized for coupling reactions, especially of unsaturated hydrocarbons. These reactive species are generated typically either in situ, such as Negishi’s reagent ([Cp2Zr(n-Bu)2]),37-39 or as a masked Zr(II) species, such as Rosenthal’s reagent ([Cp2Zr(BTMSA)],140-142 BTMSA = bis(trimethylsilyl)acetylene). In particular, subsequent “metallacycle transfer” with a heteroatom-containing electrophile offers access to main group heteroles143-147 (Scheme 2-1), which have been investigated for their electric properties and their application toward novel materials.144, 147-150    Scheme 2-1: Synthesis of heteroles with Negishi’s reagent.143-147  Another interesting class of zirconocene complexes often used for its synthetic utility is the family of zirconocene hydride complexes, in particular Schwartz’s reagent. Since the seminal work 17  by Schwartz,34-35 this zirconocene chloro hydride has been utilized as a reducing agent for the synthesis of organic halides and carbonyl compounds, and as a precursor to transmetallating reagents for cross coupling reactions.35, 139, 151 Schwartz’s reagent has the empirical formula [Cp2ZrHCl] and undergoes the so-called hydrozirconation reaction with C─C multiple bonds (Scheme 2-2). This reaction affords an organometallic zirconium complex that can undergo further reactivity. A wide range of subsequent reactions can be performed leading to interesting products, such as electrophilic quenching to access organic halides, CO insertion to form acyl zirconium complexes, or transmetallation for the formation of C─C bonds.35 The key advantage of Schwartz’s reagent over other metal hydrides is the strict regiocontrol of the hydrozirconation. Selective formation of the linear product is typically observed. Even the use of internal olefins results in the terminal linear product through a “chain-walking mechanism” that involves a sequence of insertion and β-hydride elimination events.152   Scheme 2-2: Synthesis of various organic and organometallic products from hydrozirconation with Schwartz’s reagent.139  18  The excellent regioselectivity of Schwartz’s reagent has led to its liberal use by the synthetic organic community. For example, it has been used in the total synthesis of (-)-callystatin A153 and (-)-α-kainic acid.154  Unfortunately, Schwartz’s reagent has an oligomeric structure, which posses bridging hydrides and chlorides,155 and therefore only limited solubility in common organic solvents. Several methods have been developed to overcome this disadvantage, such as the in situ preparation of this reagent in THF.156 Another method to improve its solubility involves the replacement of the chloro ligand. For example, Cp2ZrH(OSO2CF3) has been synthesized, which is more soluble than the Schwartz’s reagent and still undergoes hydrozirconation with terminal acetylenes to afford selectively the linear product.157 Interestingly, due to the affinity of the hydride ligands to bridge two metal centers, the triflate complex forms a dimer in the solid state.157    Despite the low solubility of Schwartz’s reagent, chemists are intrigued by the excellent regiocontrol offered by the insertion reaction. In seminal reports, Schwartz noted that the zirconium moiety is placed at the sterically least hindered position, indicating the importance of steric factors for this reaction.34 The mechanism was proposed to consist of first the coordination of the olefin, followed by a rate-determining insertion event. These steps have been supported by computational studies.158-159 Olefin coordination can occur at two possible reaction sites: one being the internal (between the hydrido and chloro ligands; central) and the other external (between the hydrido and cyclopentadienyl ligands; side-on) (Figure 2-1a).158 DFT calculations have shown that the LUMO of a related complex (Cp2ZrH2) has lobes in both the internal and external positions, where they exist on the plane that bisects the two Cp rings. In the case of Cp2ZrH2, the LUMO and the π bonding orbital of an olefin have better orbital overlap when the olefin if bound in the internal position due to the large probability coefficient of the internal lobe (Figure 2-1b).160 This theory 19  has been extended to Cp2ZrHCl, and it has been concluded from DFT calculations that both ethylene and propylene are most favourably coordination through the internal position rior to insertion, where steric factors dictate the observed regioselectivity.158-159 In contrast, DFT calculations have shown that alkene coordination to cationic zirconium olefin polymerization catalysts occur at the empty coordination site, which in Schwartz’s reagent is spatially occupied by the choro ligand.161 With this mechanistic question addressed, an unsolved challenge in the organometallic community is determining if the selectivity could be reversed to access selectivity for the branched product.    Figure 2-1: (a, left) Two possible sites for olefin coordination to Schwartz’s reagent. (b, right) Depiction of the LUMO of Cp2ZrH2. Copied with permission from Journal of Organometallic Chemistry.160  Aryl olefins are more challenging substrates for Schwartz’s reagent as they afford mixtures of regioisomers.12, 17 For example, the hydrozirconation of styrene followed by oxidative quench with peroxides affords a 93 : 7 mixture of the linear and branched alcohols (Scheme 2-3).162 In a separate study, monitoring the reaction by 1H NMR spectroscopy revealed a product ratio of the direct zirconium insertion product to be 85 : 15 (linear:branched).163  20   Scheme 2-3: Styrene insertion with Schwartz's reagent.162,163    One strategy to reverse the regioselectivity of Schwartz’s reagent is to include a proximal oxygen atom on the substrate together with the use of additives.164-165 Ready and coworkers have shown that by the addition of methyl lithium and zinc dichloride, the hydrozirconation of propargyl alcohols proceeds to afford selectively the branched product. It is proposed that first the lithium alkoxide is formed from the reaction of the propargyl alcohol with MeLi, which subsequently reacts with a mixture formed from Cp2ZrHCl and ZnCl2.164-165 However, the structure and composition of the active complex to selectively afford the branch product is unknown.164-165 In a control experiment, without the metal additives selective linear insertion was observed.164-165 However, this strategy is limited to hydrozirconation of substrates with propargyl alcohol moieties.  Lastly, the structure of the zirconium complex can be altered to achieve different regioselectivities. The reaction of Cp2ZrH(OSO2CF3) (which contains a triflate ligand instead of the chloro ligand) with styrene results in an equilibrium mixture of products. In this case, the branched product is favoured in a ratio of 1.4 : 1.166 The preference of this complex to form the branched product has been proposed to be due to a strong electronic influence from the ancillary ligand, however, no further elaboration has been presented.166-167 Based on this result, Schaper and coworkers have investigated alkoxy zirconocene complexes. Insertion using the in situ generated ZrH complexes with styrene resulted in only the linear insertion product.167 However, isolation of these complexes could not be achieved. Interestingly, Sita has showed that an in situ generated 21  pentamethylcyclopentadienyl zirconium hydrido chloro complex bearing an amidinate ligand facilitated not only the selective branched insertion product but also controlled the stereo-chemical outcome of the product.168 This example shows the potential utility of accessing the branched insertion product, as this method could be used to generate a stereocenter in a controlled manner. Bercaw and Chirik studied the hydrozirconation of olefins using Cp*2ZrH2.169 Insertion of various olefins resulted in selective linear insertion. However, when the steric bulk on the metal center was reduced, by using (t-BuC5H4) instead of Cp*, selective branched insertion was observed. The authors proposed that the steric congestion brought on by the substituted cyclopentadienyl ring was important for the regiocontrol. They further supported this hypothesis by investigating a variety of substituted cyclopentadienyl zirconium dihydride complexes, where various mixtures of regioisomers were obtained.  One persistent challenge in this work is that such zirconium hydride complexes are not trivial to prepare due to the fact that each modified Cp organometallic reagent must be independently prepared. Furthermore in many examples, the hydride species are generated in situ. Therefore, the exact structure of the active hydride species is not well known. Additionally, as in the case of Schwartz’s reagent, the hydride may form bridging structures, leading to oligomeric organometallic products that are insoluble in common organic solvents. Indeed, mononuclear terminal hydride complexes Cp'2Zr(H)R have not been commonly reported and there are only a handful of examples in the literature (Cp' = unsubstituted or substituted Cp, R = alkoxide,170 amide171, alkyl,172-177 aryl,178-179 silyl,180-181 phosphanyl182). General approaches to obtain such complexes typically exploit salt metathesis (starting from Cp'2Zr(H)Cl)171, 175 or protonolysis reactions (starting from Cp'2ZrH2).174  22  Recently, the Rosenthal group showed that 4-membered heterometallacycles containing two phosphines can stabilize zirconocene hydrido complexes,182 although these complexes are limited to special substituents on the cyclic unit. In comparison, amidates can form 4-membered heterometallacycles with the Zr center that are readily tuned by varying the electronic and steric properties of the nitrogen and carbonyl substituents of the amidate ligand.82 Amidate ligands have been exploited in the formation of group 4 metal complexes which show interesting reactivity and can be used efficiently in catalysis.82, 101, 183 The success of these ligands has been partially attributed to their ability to adopt multiple bonding modes (Figure 1-4), where it is surmised that their hemilabile nature helps modulate the coordinative saturation at the metal center.184 However, direct evidence of this hemilabililty is rarely observed. The different bonding motifs of the amidate ligand led us to propose that they may be suitable to stabilize zirconium hydride complexes thus giving access to terminal zirconocene amidate hydride complexes (Figure 2-2). Additionally, the hemilabile nature of the amidate ligand might invoke unique reactivity of these terminal hydride complexes. These complexes could then be studied in terms of their structure and reactivity, and compared and contrasted with Schwartz’s reagent.   Figure 2-2: Proposed structure of zirconocene amidate complexes with a terminal hydride ligand.  The hydridic character of the hydride in Schwartz’s reagent is well known and is illustrated by its ability to facilitate the stoichiometric C─N bond cleavage of tertiary amides to afford selectively 23  aldehydes. This reaction has been utilized in various synthetic applications (Scheme 2-4a).185 The mechanism of this reaction has been studied through computational and experimental methods and is proposed to operate  via first coordination of the carbonyl oxygen to the electron deficient metal centre before insertion of the carbonyl into the Zr─H bond.186 Again, DFT calculations show that coordination of the substrate at the interior position is preferred. Furthermore, the hydride transfer affords a Cp2Zr moiety with a chloro substituent and the reduced substrate bound to the Zr center through the oxygen. Subsequent C─N bond cleavage results in the aldehyde product and presumably a zirconocene byproduct. Alternatively the reaction of secondary amides with Schwartz’s reagent results in the formation of imines and presumably a zirconocene oxide byproduct (Scheme 2-4b).187 The mechanism of this reduction is supposed to proceed via a metalation followed by a hydride transfer. The metalation of the secondary amide is achieved via either a salt metathesis reaction using KH and Schwartz’s reagent or a protonolysis reaction with Cp2ZrH2. The imine is then afforded via the reaction with another equivalent of Schwartz’s reagent. Using either the salt metathesis or protonolysis route, zirconocene amidate complexes are generated and characterized in solution, however, these complexes are then used as reactive intermediates and were not isolated.    Scheme 2-4: (a, top) C─N bond cleavage of a tertiary amide with Schwartz’s reagent to afford an aldehyde. (b, bottom) C─N bond cleavage of a secondary amide with Schwartz’s reagent to afford an imine.  24  Another route to access zirconocene amidate complexes is through the formal oxidative addition of the N─H bond to a masked reduced zirconocene complex.  Oxidative addition of E─H bonds (E = O, N, C, Si) to transiently generated Zr(II) species has been observed in reactivity investigations of a variety of zirconocene complexes (Cp'2ZrX2) (Scheme 2-5).172-173, 178-180  The oxidative addition of Si─H and C─H bonds to reduced zirconocene derivatives yielded selectively mononuclear terminal hydride complexes.178-180   In the case of more polar E─H bonds, such as N─H bonds, only a few reported examples with group 4 metals are known.188  The only structurally characterized product involves the oxidative addition of an N─H bond of aminoborane to yield zirconocene amidoborane complexes.189  While late transition metal complexes are known to promote N─H oxidative addition,190 characterized examples of the oxidative addition of amides are restricted to Pt,191 Ru,192-193 and Ir194-196 examples.    Scheme 2-5: Oxidative addition of an EH moiety to a Zr(II) species.  2.1.1 Scope of this Chapter  This chapter describes the preparation of a series of well-defined zirconocene amidate hydride complexes, demonstrating the broad applicability of our synthetic strategy for the preparation of mononuclear zirconocene complexes with terminal hydrides (Scheme 2-6). An example of an amidate hydride complex that clearly shows both the κ1 and κ2 isomer in solution will be discussed. Structure and reactivity, with a special emphasis on the insertion of styrene, into these hydride complexes are presented. Attempted insertion of other olefins and phenylacetylene are also reported. A mechanistic rational for the observed regioselectivity will be discussed. Additionally, 25  the hydridic character of the H in these complexes was investigated. Finally, unexpected reactivity of these complexes towards phenyl halide will be disclosed.   Scheme 2-6: Two synthetic routes to synthesize zirconocene amidate hydride complexes.  2.2 Results and Discussion 2.2.1 Synthesis and Structure of Zirconocene Amidate Hydride Complexes Amide proligands were synthesized from commercially available acid chlorides and amines under standard conditions (NEt3, DCM) (Scheme 2-7).85 The amine precursor to proligand 1e was synthesized following published procedures.197 In an initial Grignard reaction, using freshly prepared phenyl magnesium bromide and methyl ethyl ketone, the corresponding tertiary alcohol was formed. This alcohol was then converted to a tertiary amine through a modified Ritter reaction.197  The selection of proligands was made based on the increasing steric bulk at the N atom to test its effect on the stability and reactivity of the resulting complex. Additionally, ligands 1b and 1c were designed to have the same N-substituent with different carbonyl substituent for the comparison of their reactivity.   26   Scheme 2-7: Proligand synthesis from commercially available acyl chlorides and amines.   Using a previously reported formal oxidative addition route starting from Rosenthal’s reagent and proligands 1a and b, a past exchange student from Germany, Dr. Martin Haehnel, synthesized complexes 2a and b in 73 and 86% yield, respectively (Scheme 2-8).198 It was found that this insertion occurs through an alkenyl intermediate, which could be detected and characterized by 1H (8.08 ppm) and 13C{1H} NMR spectroscopy (234.5 and 113.8 ppm). This assignment was made in comparison to a structurally fully characterized zirconium alkenyl complex, [Cp2Zr(C(SiMe3)CHSiMe3)]2O (Figure 2-3).199 As illustrated in Figure 2.3, an agostic interaction between the β-hydride has been found by X-ray diffraction analysis where a Zr─H bond distance of 2.72(1) Å and the 1H (8.00 ppm) and 13C{1H} NMR spectroscopy (236.1 and 148.3 ppm) signals are consistent with this assignment.199 Steric hindrance appears to slow this reaction down as complex 2b, with its bulky N-Dipp group, required elevated temperatures of 65 °C, while complex 2a was synthesized at room temperature. With bulky proligand 1d, the attempted synthesis of complex 2d via this route was unsuccessful, revealing its limitations. As proligand 1c is similar to proligand 1b, the synthesis of complex 2c using this route was omitted and is achieved using a more general synthetic route (vide infra).  27   Scheme 2-8: Synthesis of zirconocene complexes with N,O-chelating ligands using a formal oxidative addition.   Figure 2-3: Diagnostic signals for [Cp2Zr(C(SiMe3)CHSiMe3)]2O.199  Dr. Haehnel also found that the addition of a second equivalent of amide proligand (such as 1b) to the zirconium hydride complex (such as 2b) affords a bis(amidate) zirconocene complex with hydrogen as the only by-product.198 However, when proligand 1d and complex 2d was 28  attempted for this reaction, no reaction was observed, even at elevated temperatures (Scheme 2-9). This behavior is attributed to the excess steric bulk of this proligand.    Scheme 2-9:  Reaction of zirconocene amidate hydride complex with amide proligand.  An alternative route to access these complexes is via salt metathesis. The sodium salts of the amides were formed with NaHMDS under inert conditions. Removal of the volatiles components in vacuo afforded the desired salt. The reaction of these salts with Schwartz’s reagent forms the desired complexes (Scheme 2-10). Isolation of the amidate salt is not necessary and the zirconocene amidate complex can be synthesized in a one-pot fashion by generating the amidate salt in situ. Following filtration, removal of volatiles in vacuo, and recrystallization, complexes 2a-e could be isolated in moderate yields (56 – 77%). Using this route, the zirconocene hydride complexes can be prepared on a multigram scale. For example, the synthesis of complex 2d was achieved on a 10 g scale. To ensure proper mixing, THF was utilized as the solvent of choice for the large scale synthesis. However, this leads to excess salt being trapped in the product mixture, 29  resulting in the need for more sequential filtrations through Celite and slightly reduced yields (56%).    Scheme 2-10: Synthesis of the zirconocene amidate hydride complexes 2a–e via salt metathesis.  Complexes 2a-e were fully characterized by 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis. Additionally, their structures in the solid state were analyzed by X-ray diffraction measurements. The solid state molecular structures are shown in Figure 2-4 ─ Figure 2-7 together with selected bond lengths and angles. Complexes 2a-d display similar metal coordination environments with the amidate ligands adopting a κ2-binding mode, while the amidate ligand in 2e adopts an O-bound κ1-binding motif. The distance of the Cp carbon atoms to the Zr center varies between 2.485(1) – 2.556(1) Å and each Cp unit is best described as having a η5 coordination mode. Each complex adopts a typical bent zirconocene geometry, the angle of Cp(centroid)-Zr-Cp(centroid) is between 128.90(4) – 132.117(2)°. In each case, the terminal hydride was located from residual electron density and freely refined. No bridging hydrides were detected, possibly owing to the electronically saturated nature of these formally 18 e- complexes. The amidate ligand adopts an asymmetric κ2 bonding geometry with the bond lengths of C1-O1 30  (1.294(2) – 1.3111(17) Å) and C1-N1 (1.3096(13) – 1.3168(18) Å) being typical for C─O and C─N multiple bonds.106, 108 In general, the metallacyclic unit is planar in nature, as shown by the torsion angle O1-C1-N1-Zr1 in complex 2a being 1.26(8)°. However, increased steric congestion can perturb the planarity, as in 2b with a torsion angle of 7.2(1)°. Although the carbonyl substituent of the amidate ligand differs from an alkyl to an aryl substituent, the puckering of the metallacycle is observed to be driven by the steric bulk of the nitrogen substituent. This is evidenced by the enhanced distortion in 2c (torsion angle: 12.82(7)°), where the carbonyl substituent is the same as in 2a but the N-substituent is the same as the one in 2b. This distortion coincides with a shortening of the Zr1-O1 bond (2a: 2.2595(8) Å vs. 2b: 2.246(1) Å vs 2c: 2.2117(10) Å) and slight elongation of the Zr1-N1 bond (2a: 2.2784(9) Å vs. 2b: 2.315(2) Å vs 2c: 2.3541(10) Å). Further increasing the steric congestion by replacing the Dipp substituent with the even bulkier adamantyl moiety, complex 2d displays the most distorted metallacycle (torsion angle: 18.6(1)°) and the shortest Zr─O bond (2.1991(11) Å). Although the bite angle of the amidate ligand of complex 2d is similar to the other complexes (C1-Zr1-N1 56.98(3) –  57.45(3)°), due to the non-planar metallacycle, the O1-C1-N1 angle is smaller than the others of this series (2d: 111.80(12)° vs. 113.36(9) –  114.39(16)°). A summary of the structural metrics for complexes 2a-e is shown in Table 2-1.   31   Figure 2-4: Molecular structure of 2a in the solid state. H1 was located in electron density maps and refined. Hydrogen atoms except for H1 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.2984(12), C1-N1 1.3096(13), Zr1-O1 2.2595(8), Zr1-N1 2.2784(9); O1-C1-N1 113.51(9), O1-Zr1-N1 57.45(3), Cp-Zr-Cp 131.28(2), O1-C1-N1-Zr1 12.6(8).   32    Figure 2-5: Molecular structure of 2b in the solid state. H1 was located in electron density maps and refined. Hydrogen atoms except for H1 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.294(2), C1-N1 1.314(2); Zr1-O1 2.2463(12), Zr1-N1 2.3155(15); O1-Zr1-N1 57.41(5), O1-C1-N1 114.39(15), Cp-Zr-Cp 128.90(4), O1-C1-N1-Zr1 7.25(16).   33    Figure 2-6: Molecular structure of 2c in the solid state. H1 was located in electron density maps and refined. Hydrogen atoms except for H1 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.2992(11), C1-N1 1.3116(12), Zr1-O1 2.2117(10), Zr1-N1 2.3541(10); O1-C1-N1 113.36(9), O1-Zr1-N1 56.98(3), Cp-Zr-Cp 129.02(1), O1-C1-N1-Zr1 12.82(7).   34    Figure 2-7: Molecular structure of 2d in the solid state. H1 was located in electron density maps and refined. Hydrogen atoms except for H1 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.3111(17), C1-N1 1.3168(18), Zr1-O1 2.1991(11), Zr1-N1 2.3451(13); O1-C1-N1 111.80(12), O1-Zr1-N1 57.11(4), Cp-Zr-Cp 131.49(1), O1-C1-N1-Zr1  ̶ 18.6(1).  Table 2-1: Comparison of selected structural metrics of κ2 bound zirconocene amidate hydride complexes.  2a 2b 2c 2d C1-O1 (Å) 1.2984(12) 1.294(2) 1.2992(11) 1.3111(17) C1-N1 (Å) 1.3096(13) 1.314(2) 1.3116(12) 1.3168(18) Zr1-O1 (Å) 2.2595(8) 2.2463(12) 2.2117(10) 2.1991(11) Zr1-N1 (Å) 2.2784(9) 2.3155(15) 2.3541(10) 2.3451(13) O1-C1-N1-Zr1 (°) 1.26(8) 7.2(1) 12.82(7) 18.6(1)   In each of these complexes (2a-d), the hydride ligand is nearly coplanar with the O and N atoms of the amidate ligand and the zirconium metal center. The amidate ligands are 35  unsymmetrically bound to the metal center with shorter Zr─O bonds vs. Zr─N bonds. The Zr─N bond is susceptible to steric strain imposed by the N-substituent, whereby increased steric bulk on the nitrogen substituent causes lengthening of this bond. Additionally, the nitrogen atom is always in the interior position, flanked by the oxygen and the hydride donors (Figure 2-8a). The other geometric isomer, where the oxygen atom occupies the internal position, is not observed (Figure 2-8b). This isomer is hypothesized to be disfavoured because of unfavourable steric interaction between the bulky N-substituent of the amidate and the Cp ligands. DFT calculations performed by Mr. Jason Brandt have shown that the observed geometry is energetically more favored (~9 kcal mol-1).    Figure 2-8: Two possible geometric isomers of zirconocene amidate hydride complexes.  Previous computational studies on Schwartz’s reagent have shown that the most energetically accessible unoccupied orbital to interact with substrates has a lobe positioned between the Cl and H ligands. For the zirconocene amidate complexes, the nitrogen atom of the amidate ligand coordinates to the lobe positioned between the O and H ligands, this means that this lobe is unavailable for interation with the substrate. The calculated HOMO of complex 2d (Figure 2-9, left) shows significant hydridic character of the hydride ligand. The calculated LUMO of complex 2d (Figure 2-9, right) shows significant character from the bent metallocene moiety 36  where a lobe with a larger probability coefficient is in the exterior position (between the Cp and H ligands).  Figure 2-9: Molecular orbital surfaces for the HOMO (left) and LUMO (right) calculated for complex 2d.  Further increasing the steric bulk at the nitrogen atom and carbonyl carbon as in complex 2e leads to the observation of a κ1-bound amidate ligand in the extreme case (Figure 2-10). The zirconium center is arranged in a distorted tetrahedral coordination environment with two η5-cyclopentadienyl units, the hydride ligand and the amidate ligand, which is κ1 bound through the oxygen atom in a nearly linear fashion (C1-O1-Zr1 174.01(15)°). The C1-O1 and C1-N1 bond distances are 1.340(3) Å and 1.279(3) Å, respectively, while C1 remains trigonal planar in geometry (sum of angles about C1 359.9(3)°), which indicates that the amidate ligand is best described as an alkoxide type ligand116-121 with double bond character localized in the C─N bond, where a cis-imine geometry is adopted and no donation from the N to the metal center is observed. 37  Again, one terminal hydride ligand was found. Complex 2e crystallized in the space group Pna21 and this chiral molecule is present as the racemate.200    Figure 2-10: Molecular structure of rac-2e in the solid state. H1 was located in electron density maps and refined. Hydrogen atoms except for H1 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.340(3), C1-N1 1.279(3), Zr1-O1 1.9871(18); O1-C1-N1 125.7(2), O1-Zr1-H1 102.8(11), C1-O1-Zr1 174.01(15), Cp-Zr-Cp 131.56(5), sum of angles around C1 359.9(3). Flack parameter = -0.026(12).  Moving from the solid-state structural analysis to solution phase spectroscopic characterization, the 1H NMR signal of the hydride ligand of complexes 2a-e appear between 4.90 and 5.75 ppm (Table 2-2), which is within the typical range for zirconocene complexes with terminal hydrides (3.15 – 7.46 ppm).170-182, 201-203 Bridging hydrides are usually found within the chemical shift range of -5.32 to -2.98 ppm.202, 204-205 However, no signals appearing below ~0.5 38  ppm in the 1H NMR spectrum were observed for any of the complexes. Another diagnostic signal in the 1H NMR spectrum is the resonance of the cyclopentadienyl ligands, which is observed between 5.60 – 6.08 ppm. Typically the two Cp ligands are equivalent, so that they are appear as one singlet. However, the presence of a stereocenter in proligand 1e renders the two Cp ligands diastereotopic and they present two distinct singlets. 2D NOESY NMR spectroscopy display a correlation between the hydride and methyl substituent of the N-substituted quaternary carbon, which indicates that the amidate ligand maintains the cis-imine geometry in solution phase. Interestingly, complex 2d displays a more complicated 1H NMR spectrum, with two singlets for the Cp ligands. Furthermore, selective 1D total correlated spectroscopy (TOCSY) NMR spectroscopy was utilized for the assignment of signals attributed to the adamantyl moiety.206 NMR spectroscopy with a high field (600 MHz) magnet was utilized, and two sets of adamantyl signals (2.12 – 1.59 ppm) were detected with d8-toluene as the solvent. Irradiation of the signal at 1.99 ppm resulted in the appearance of signals at 2.12, 1.86 and 1.74 – 1.72 ppm. Irradiation of the signal at 2.04 ppm resulted in the appearance of signals at 2.06, 1.99 and 1.68 – 1.59 ppm. This result suggests the presence of two isomers of 2d in solution. 1H NMR exchange spectroscopy (EXSY) experiments revealed exchange signals of the two cyclopentadienyl, and hydride signals, suggesting chemical exchange between the two isomers in solution. 1H NMR spectra were recorded over a temperature range from 25 to 65 °C in C6D6. Temperature dependent changes in chemical shifts and sharpness of the signals were observed. However, signal coalescence in the 1H NMR spectrum was not observed in that temperature range. Complex 2d is thermally stable as no degradation was observed in this temperature range. In the adamantyl region, as temperature increases, the signal at 1.63 ppm loses intensity while signals at 1.91 and 39  1.76 persist. Concurrently, the signal at 5.26 also disappears. These changes show that the one of the two equilibrating isomers is favored at elevated temperatures. Although the 13C NMR spectrum of 2d is complicated, the carbonyl carbon of the amidate ligand displays two distinct resonances (182.8 ppm and 165.8 ppm). These chemical shifts are very diagnostic for assigning the binding motif of the amidate ligand.114, 117, 207 When the amidate ligand binds in a κ2 fashion (as with complex 2a – c), the carbonyl carbon signal is typically downfield shifted (2a - c: 176.9 – 195.8 ppm (C6D6)) compared to that of the free ligand (1a – e: 166.1 – 176.5 ppm (C6D6)) (Table 2-2). However, in complex 2e, where the amidate ligand adopts a κ1 binding mode, the carbonyl carbon signal (167.3 ppm) is significantly upfield shifted compared to the free ligand (175.7 ppm). The same trend has been observed in other early transition metal amidate complexes before.114, 117, 207  This led to the conclusion that in solution a mixture of isomers of 2d is present, with the amidate ligand adopting either a κ2 geometry (182.8 ppm) or binding in a κ1 O-bound geometry (165.8 ppm).   Table 2-2: Comparison of selected NMR spectroscopic data of zirconocene amidate complexes.  2a 2b 2c 2d 2e δHZrH (ppm, C6D6) 5.54 5.72 5.01 5.75 (κ1)/5.18 (κ2) 5.60 δCC=O Complex (ppm, C6D6) 186.1 176.9 195.8 182.8 (κ2)/165.8 (κ1) 167.3 δCC=O Free Ligand (ppm, C6D6) 176.7 166.1 176.5 176.5 175.7  To further support the presence of isomers of 2d in solution, a series of variable temperature multinuclear NMR spectroscopic studies were undertaken. As shown by a 1H-13C HMBC NMR experiment at room temperature, each carbonyl carbon environment displays a 3JH-C coupling to a distinct tert-butyl resonance (Figure 2-11a). The HMBC NMR spectrum of complex 2d at 65 °C in C6D6 suggests that only the complex with a κ1-bound amidate ligand is present at elevated 40  temperature (Figure 2-11b). The 13C NMR spectrum of complex 2d at room temperature displays two distinct signals attributed to the cyclopentadienyl ligands. At 65 °C, only one of the signals remains in the spectrum. As such, 13C NMR spectra were collected over a temperature range of -15 to 65 °C, specifically tracking the cyclopentadienyl carbon signals (Figure 2-12). As expected, a marked temperature dependence of the ratio of these signals was observed. Quantitative 13C NMR spectroscopy reveals a 1 : 4.1 mixture of κ2-2d to κ1-2d at 25 °C. Complex 2d is a rare example of an amidate complex that displays hemilability and shows the κ1 and κ2 isomers of an amidate complex in solution. Presumably the amidate ligand of κ1-2d adopts a cis-imine geometry, similar to complex 2e and other complexes with κ1-amidate ligands (vide infra). To access the cis-imine geometry from κ2-2d, the amidate ligand would first adopt the trans-imine geometry (Scheme 2-11). These κ1-amidate ligands are most similar to ketimine, where cis-trans-ketimine isomerization is known to be a facile process, either by inversion, rotation or a tautomerism mechanism.208  Like ketimine, the amidate ligands prefer the cis-imine geometry, especially with sterically bulky nitrogen and carbonyl substituents. It is proposed that when the option for the amidate to adopt readily the trans-imine geometry is viable, the κ2-binding motif is observed to form a four-membered metallocycle, such as with complexes 2a-c. Computational studies by Mr. Jason Brandt have shown that κ2-2d is higher in energy than κ1-2d, where ΔG° for this process was found to be 2.3 kcal mol-1. It was also found that this was an entropically favoured process.    41   Figure 2-11: Left, a) 1H-13C HMBC NMR spectrum of complex 2d at room temperature (400 MHz, C6D6). Right, b) 1H-13C HMBC NMR spectrum of complex 2d at 65 °C (400 MHz, C6D6).   Figure 2-12: Partial variable temperature 13C NMR spectra of the cyclopentadienyl region of complex 2d (100 MHz, d8-toluene). 42   Scheme 2-11: Equilibrium between the κ2 and κ1 binding motif of the amidate ligand in complex 2d.   By using variable temperature, quantitative 13C NMR spectroscopy209 on complex 2d with using the two distinct signals from cyclopentadienyl ligands as integration handles, a van’t Hoff plot was obtained (Figure 2-13). The temperature range of -15 – 65 °C was chosen, as below -15 °C multiple cyclopentadienyl signals were observed, possibly due to the hindered rotation of the Cp rings at lower temperature. From this plot, a slope of 670 K and an intercept of -3.7 was obtained, which relates to -ΔH°/R and ΔS°/R respectively.  ΔH° was calculated to be -5.5 ± 0.6 kJ mol-1 (-1.3 ± 0.1 kcal mol-1) and ΔS° -30 ± 2 J K-1 mol-1 (-7.2 ± 0.5 eu), which indicates a near enthalpically neutral, entropy driven process.   43   Figure 2-13: Van’t Hoff plot of the interconversion of the isomers of complex 2d generated from VT quantitative 13C NMR spectroscopic experiments.    In summary, a series of zirconocene amidate hydride complexes (2a-e) was synthesized and characterized by 1H and 13C NMR spectroscopy, mass spectrometry, elemental analysis and their solid state molecular structure was determined by X-ray diffraction crystallography. Each complex was found to be mononuclear bearing a terminal hydride ligand. The solid state molecular structures show the amidate ligands in complexes 2a-d adopt the κ2 binding motif, while in complex 2e the amidate ligand adopts the κ1 O-bound motif in the cis-geometry. Interestingly, in the solution phase, complex 2d displayed an equilibrium between two isomers where the amidate is either bound in κ2 or a κ1 O-bound motif. Experimental evidence showed that the isomer with κ1 O-bound amidate is favoured at higher temperatures.    y = 664.68x - 3.6554R² = 0.9655-1.9-1.8-1.7-1.6-1.5-1.4-1.3-1.2-1.1-1-0.90.003 0.0032 0.0034 0.0036 0.0038 0.004ln((κ2-2d)/(κ1-2d))T-1 (K-1)44  2.2.2 Reactivity of Zirconocene Amidate Hydride Complexes 2.2.2.1 Reaction of Styrene with Zirconocene Amidate Hydride Complexes The reaction of the zirconocene amidate hydride complexes with styrene affords the insertion product (Scheme 2-12). Mechanistic data suggests this reaction establishes an equilibrium (vide infra), but in certain cases the reaction conditions can be tuned to favor the formation of the insertion product. In all cases, the crude 1H NMR spectra of these reactions showed selective formation of the unexpected branched insertion product. The diagnostic signals are the methine proton of the product showing at approximately 2.7 ppm as a quartet and the methyl protons at approximately 1.9 ppm as a doublet (Figure 2-14). No linear product could be observed.    Scheme 2-12: Insertion reaction with styrene to form the branched insertion product. 45   Figure 2-14: Crude 1H NMR spectrum of styrene insertion with complex 2d (400 MHz, C6D6).   Equilibria between the starting material and inserted product can be observed. Initially, Dr. Haehnel found that at room temperature, complex 2a forms an equilibrium between the branched insertion product and the starting terminal hydride complex. Insertion of styrene with complex 2b was complete after 4 hours at 70 °C. Complex 2c was reacted with an equimolar amount of styrene at room temperature (3 days, 50% conversion by 1H NMR spectroscopy) but required elevated temperature to reach full conversion (3 hr at 70 °C, >95% conversion). This behavior was similar to complex 2b, where these two complexes only differed by the carbonyl substituent of the amidate ligand. Increasing the steric strain between the carbonyl and nitrogen substituents, such as in complex 2d, further accelerated the reactivity and the insertion reaction took place at room temperature in 17 hr to lead to 74% conversion of the starting material. Reaction 46  of 2d with an excess of styrene (10 equiv.) reduced the required reaction time for complete conversion (>95%) to less than 2 hr. However, when complex 2e, which contains only κ1 bound amidate, was reacted with an equimolar amount of styrene, very sluggish reactivity was observed (3 days at room temperature, 21% conversion by 1H NMR spectroscopy).  The insertion products of complexes 2b-d were successfully isolated and fully characterized (3b-d). Their solid state molecular structures are shown in Figure 2-15 – Figure 2-17 together with selected bond lengths and angles. The X-ray diffraction studies show the formation of the branched product in all cases and all amidate ligands are now bound in a κ1 O-bound fashion with these sterically demanding alkyl substituents. Complexes 3b-d display similar metrical parameters to complex 2e. In contrast to complex 2e, the C1-O1-Zr1 bond angles deviate from linearity (3b 155.0842(12)°; 3c 163.7(2)°; 3d 157.304(12)°), possibly due to steric constraints imposed by the inserted styrene substrate. The solution phase 13C NMR specta of 3b-d further support that the κ1-bound motif is maintained in solution by the carbonyl signals, which appear at 156.1, 166.0 and 163.5 ppm in the 13C NMR spectra for complexes 3b, 3c and 3d, respectively. 47   Figure 2-15: Molecular structure of 3b in the solid state. Hydrogen atoms except for H30 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.336(2), C1-N1 1.276(2), Zr1-O1 2.0173(12), Zr1-C30 2.3613(19); O1-C1-N1 124.95(16), C1-O1-Zr1 155.0842(12), Zr1-C30-C31 118.10(13), Cp-Zr1-Cp 127.555(3) sum of angles of C1 360.0(3). 48   Figure 2-16: Molecular structure of 3c in the solid state. Hydrogen atoms except for H28 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.338(5), C1-N1 1.272(5), Zr1-O1 2.004(3), Zr1-C28 2.333(5); O1-C1-N1 124.6(4), O1-Zr1-C28 91.63(13), C1-O1-Zr1 163.7(2) Zr1- C28-C29 112.4(3), Cp-Zr1-Cp 128.35(10), sum of angles around C1 359.8(6).  49   Figure 2-17: Molecular structure of 3d in the solid state. Hydrogen atoms except for H16 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.36290(9), C1-N1 1.26829(8), Zr1-O1 2.01074(10), Zr1-C16 2.36129(14); O1-C1-N1 128.3161(12), O1-Zr1-C16 95.443(5), C1-O1-Zr1 157.304(12), Zr1-C16-C17 114.67(8), Cp-Zr1-Cp 126.54(2), sum of angles of C1 359.957(7).  Electrophilic quenching is known to cleave the organometallic insertion product.35 In an NMR-scale experiment, cleavage of the inserted product was achieved by the addition of I2 (Scheme 2-13) to afford 1-iodo-1-phenylethane (>95% conversion by 1H NMR spectroscopy). This was identified by 1H NMR spectroscopy with diagnostic signals at 4.92 (q, PhCH(I)(CH3)) and 1.81 ppm (d, PhCH(I)(CH3)).210 Furthermore, the organometallic byproduct was identified as a amidate iodo zirconocene complex. The formation of a related iodo zirconium complex from the 50  reaction with iodine has been observed previously.211 Further confirmation was obtained by the independent synthesis from the reaction of complex 2d with iodobenzene (vide infra).   Scheme 2-13: Electrophilic quenching of the insertion product 3d with iodine.  Other styrene derivatives was also found to inserted into complex 2d, such as para-trifluoromethylstyrene and para-methylstyrene. The reaction (with a large excess of the substituted styrene reagent) was accelerated by the presence of electron-withdrawing groups (p-CF3 reaches >95% conversion within 10 min.) and sluggish reactivity was observed with electron-donating substituents on the styrene (p-Me reaches >95% conversion in 4 hr). These results indicate that the electronic nature of the styrene substrate significantly influences the reaction rate. The mechanistic rationale for this qualitative observation is discussed in Section 2.2.3.  2.2.2.2 Attempted Asymmetric Hydrozirconation Due to the facile nature of the proligand synthesis from amines and acid chlorides, the inclusion of a stereocenter can be easily achieved by using a commercial available chiral amine to prepare the proligand. This could lead to the stereoselective insertion of styrene, which can be highly desirable as a new stereocenter would be generated from the achiral styrene starting material. As shown for complex 2e, the amidate adopts the κ1-binding mode if the amidate ligand 51  possesses too much steric bulk. For κ1-structures, the stereocenter would be quite far removed from the hydride. Proligand 4 can address this concern, as the ethyl substituent was replaced by a hydrogen atom and the racemic and enantiopure versions of proligand 4 could be easily synthesized from the reaction of commercially available adamantanecarbonyl chloride and (rac)-α-methylbenzylamine or (R)-α-methylbenzylamine. Complexes 5a and b was then synthesized in the usual manner with proligands 4a and b. Complexes 5a and b were characterized by 1H and 13C NMR spectroscopy, mass spectrometry and elemental analysis. A crystal of sufficient quality for X-ray analysis of complex 5b was obtained from recrystallization from hot hexanes at room temperature. The solid state molecular structure is shown in Figure 2-18 together with selected bond lengths and angles. Complex 5b crystallized in the chiral space group P212121. To confirm that the ligand did not undergo racemization, 5b was quenched with water and the optical rotation of the ligand was obtained ([α]D23 = +51.6° (c = 0.02, DCM); free ligand: [α]D23 = +52.3° (c = 0.02, DCM)).    Scheme 2-14: Synthesis of complexes 5a and 5b and their reactivity with styrene. 52   Figure 2-18: Molecular structure of (R)-5b in the solid state. H1 was located in electron density maps and refined. The adamantyl group and the minor component of the disordered cyclopentadienyl ring are omitted for clarity. Hydrogen atoms except for H1 and H12 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.3021(18), C1-N1 1.313(2), Zr1-O1 2.246(1), Zr1-N1 2.2757(13); O1-C1-N1 112.63(13), O1-Zr1-N1 57.53(4), Cp-Zr-Cp 132.117(2), O1-C1-N1-Zr1 0.33(12). Flack parameter = -0.008(8).200   The solid state molecular structure reveals that the amidate indeed adopts the κ2 binding mode with an asymmetric coordination of the amidate exhibiting a shorter Zr─O than Zr─N bond. The asymmetric unit contains one entire molecular unit.  Again, the hydride ligand was assigned from residual electron density and then freely refined. The amidate ligand is bound in a nearly planar geometry (O1-C1-N1-Zr1 0.33(12)°) in contrast to complex 2d. The solution phase structures of complexes 5a and b correspond to the solid state molecular structure of complex 5b with a signal for the terminal hydride appearing at 4.89 ppm in the 1H NMR spectrum and a 53  carbonyl signal in the 13C{1H} NMR spectrum appearing at 185.4 ppm, indicative of the amidate ligand being bound in a κ2 mode. The solution phase NMR spectra do not display hemilability of the amidate at temperatures between 25 – 75 °C (in C6D6). Upon exposure of complexes 5a or 5b to an excess of styrene at 65 °C for 2 hours, the reaction reaches 73% conversion. Due to the stereocenter in the ligand, following insertion of styrene, diastereomers are formed. As expected, starting from the racemic complex, a 1 : 1 ratio of the two diastereomers was obtained as determined by 1H NMR spectroscopy using the methine proton of the ligand as a handle. The methine proton of the inserted styrene product has signals from the two diastereomers overlapped. However, when starting with the enantiopure complex, the resultant insertion product is also a 1 : 1 mixture of diastereomers showing that there is no stereoselective insertion taking place (Figure 2-19). The lack of stereoselective insertion suggests that the stereocenter has no influence in the insertion reaction of styrene.  54   Figure 2-19: Partial 1H NMR spectra of the reaction between 5a and 5b with styrene.  2.2.2.3 Reactivity of Zirconium Amidate Hydride Complexes with Other Alkenes  Zirconium hydride complexes are well known to affect the insertion of other terminal alkenes and the isomerization of internal alkenes. In particular, Schwartz’s reagent can be used to convert internal alkenes to selectively afford the terminal insertion product in good yields using moderate reaction conditions.34-35 This reaction is proposed to proceed via a series of insertion and β-hydride elimination steps (chain walking mechanism) to ultimately yield the terminal alkene.34-35 For example, it is well known that the reaction of 1-octene, cis-4-octene or trans-3-octene with Schwartz’s reagent all result in the formation of the terminal insertion products.34 Similarly, exposure of (E)-1-phenyl-1-propene with Schwartz’ reagent at room temperature for 4 hours, followed by an oxidative quench results in the formation of the oxidized product corresponding to 55  branched versus linear insertion in a 88:5 ratio (Scheme 2-15).162 In the same study, it was noted that the reaction of 3-phenyl-1-propene and Schwartz’s reagent at room temperature for 4 hours, followed by an oxidative quenching resulted in the formation of the oxidized product corresponding to branched versus linear insertion in a 9 : 90 ratio.162    Scheme 2-15: Hydrozirconation of 1-phenylpropene by Schwartz reagent followed by an oxidative quench.162      In contrast, for the zirconocene amidate hydride complexes, isomerization of terminal olefin substrates to yield the internal alkenes was observed. Using complex 2d, the reaction with 1-octene at 65 °C for 17 hours resulted in the formation of a mixture of 2-octene, 3-octene and 4-octene as determined by 13C NMR spectroscopy. The reaction of complex 2d with 3-phenylprop-1-ene resulted in the formation of (Z)-1-phenyl-1-propene at 70 °C for 16 hours with >95% conversion when monitored by 1H NMR spectroscopy. Alternatively, (Z)-1-phenyl-1-propene is afforded from the isomerization of (E)-1-phenyl-1-propene with complex 2d at 70 °C for 3 hours. When (Z)-1-phenyl-1-propene was heated under identical conditions without any metal complex, no isomerization was observed. In each example, the product of the insertion of the olefin substrate into the Zr─H bond was not observed. The insertion of other terminal olefin substrates, such as acrylonitrile or vinylcyclohexane, was investigated with limited success. To probe the effect of varying the electronic properties of 56  the C=C double bond, acrylonitrile and trimethylsilyl ethylene were investigated as substrates. Unfortunately, the reaction of complex 2d with acrylonitrile resulted in a gel-like mixture of products that could not be characterized, presumably oligomeric or polymeric products were formed. No reactivity was observed for complex 2b with trimethylsilyl ethylene between 22 and 60 °C. Other alkyl hydrocarbon substituents were investigated for their steric effects. No reactivity was observed for t-butyl ethylene or vinylcyclohexane, possibly due to the steric bulk of this substrate. To probe if insertion of the olefin occurs but β-hydride elimination is so rapid that the inserted product cannot be observed, a deuterated variant of complex 2d was reacted with vinylcyclohexane. No reaction was observed at room temperature or at elevated temperatures (65 °C). This indicates that the insertion, which leads to olefin isomerization, is highly dependent on the steric congestion around the C=C double bond.   2.2.2.4 Insertion of Phenylacetylene  Schwartz’s reagent also undergoes regioselective alkyne insertion. For example, phenylacetylene is readily inserted in the Zr─H bond of Schwartz’s reagent at room temperature after 30 min. After a subsequent CO insertion and cross coupling reaction the ketone derivative was obtained in 75% yield.212   Complex 2d displayed reactivity with phenylacetylene at 65 °C. After 19 hours, full consumption of complex 2d is observed although a mixture of products was obtained. Following careful recrystallization from the reaction mixture, a single crystal suitable for X-ray diffraction experiments was selected from the sample using an optical microscope. The solid state molecular structure of the branched insertion product (6) is shown in Figure 2-21 including relevant bond 57  lengths and angles. In analogy to the styrene insertion product, the amidate ligand adopts a κ1 O-binding motif to accommodate the extra steric congestion imposed by the substrate.    Figure 2-20: Insertion reaction with phenylacetylene with complex 2d.  Figure 2-21: Molecular structure of 6 in the solid state. Hydrogen atoms except for H1 are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [deg]: C1-O1 1.358(2), C1-N1 1.266(3), Zr1-O1 2.0010(15), Zr1-C16 2.3306(19); O1-C1-N1 127.62(17), O1-Zr1-C16 98.65(7), C1-O1-Zr1 155.72(14), Zr1-C16-C17 116.12(15), sum of angles of C1 359.9(3), sum of angles of C16 359.9(3). 58  Analysis of the crude reaction mixture by 1H NMR spectroscopy, shows a complex mixture of products including the branched insertion product and another unknown zirconium amidate complex. Signals corresponding to the branched insertion product were observed (δ 6.10 and 5.60 ppm, 2JH,H = 1.7 Hz). There is no evidence for the formation of the linear insertion product (lack of dianogistic trans or cis alkene signals). Unfortunately, further purification was not possible, although another zirconocene amidate complex is present speculated based upon a new t-Bu signal at 1.26 ppm and Cp signal at 5.86 ppm from the 1H NMR spectrum. The reduced reactivity of 2d vs. Schwartz’s reagent is attributed to the increased steric hindrance of the amidate ligand.    2.2.2.5 Reactivity of Amidate Hydride Complexes with Other Reagents To probe the hydridic character of the Zr─H, small molecules were reacted with complex 2d. PMe3, pyridine and DMAP displayed no observable reactivity with 2d. Reaction with lutidinium hydrochloride resulted in the formation of a complex mixture of products, including H2(g) and CpZr(amidate)Cl as detected by 1H NMR spectroscopy and MS respectively. Our initial hypothesis for the mechanistic rationale for the observed regioselectivity of styrene insertion with the zirconocene amidate complexes was due to the formation of a transient Zr(II) species via the reductive elimination of the amide. To probe this hypothesis, complex 2d was reacted with various reagents to obtain a trapped Zr(II) species. Reduced zirconium species can react with reagents such as halobenzenes or disulfide reagents which can oxidatively add to the reduced zirconium species to obtain an isolable Zr(IV) complex.   During the course of our investigations for reduced zirconium intermediates, complex 2d was reacted with phenyl iodide. At room temperature or slightly elevated temperature (up to 80 °C), no reactivity was observed. However, prolonged heating at 110 °C for 3 days resulted in the 59  complete conversion to a new complex as monitored by 1H NMR spectroscopy. Formation of benzene was observed concurrently to complex formation when the reaction was monitored by 1H NMR spectroscopy in d8-toluene.    Scheme 2-16: Reaction of 2d with halobenzene to form 7a and 7b.  Following recrystallization, complex 7a was isolated in 46% yield. Full characterization of the novel complex was achieved, which included X-ray diffraction studies as shown in Figure 2-22. Complex 7a is best described as a bent metallocene with a distorted tetrahedral geometry. The zirconium metal center is flanked by two η5-cyclopentadienyl ligands, an iodo ligand and the amidate ligand bound κ1 through the oxygen atom. This amidate binding geometry is supported by the short C1-N1 bond (1.267(4) Å) and longer C1-O1 bond length (1.358(3) Å), indicating a more alkoxide like nature. Compared to complex 3d, the amidate ligand is bound in a more linear fashion (C1-O1-Zr1: 7a 168.6(2)° vs. 3d 157.304(12)°). This κ1-binding motif is also observed in solution, as evidenced by the carbonyl signal in the 13C NMR spectrum (163.7 ppm). 60   Figure 2-22: Molecular structure of 7a in the solid state. Hydrogen atoms are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.358(3), C1-N1 1.267(4), Zr1-O1 1.986(2), Zr1-I1 2.8674(9); O1-C1-N1 128.2(3), O1-Zr1-I1 101.99(6), C1-O1-Zr1 168.6(2), sum of angles around C1 360.1(5).  Bromo- and chlorobenzene also reacted with complex 2d under similarly harsh reaction conditions. However, the reaction proceeded much more sluggishly. In the case of chlorobenzene, it was not possible to isolate the product and the formation of the chloro complex was only detected by 1H NMR spectroscopy and MS. Reaction of 2d with bromobenzene afforded complex 7b in 44% yield after 3 days at 110 °C. Extending the reaction time or increasing the reaction temperature to 130 °C did not result in any further conversion as monitored by 1H NMR spectroscopy. Both solid state molecular structure213 and solution phase 1H and 13C NMR spectroscopic analysis reveal the amidate ligand again adopting a κ1 O-bound geometry (13C NMR: 61  163.7 ppm (C=O)). The solid state molecular structure of 7b is nearly identical to that of 7a, with a shorter Zr─X bond and smaller O1-Zr1-X1 angle due to the smaller bromine atom as compared to iodine. The amidate is again bound through the oxygen atom in a nearly linear fashion, similar to 7a (C1-O1-Zr1 7b: 168.7(3)° 7a: 168.6(2)°).     Other Zr─H complexes also exhibited reactivity with halobenzene resulting in the displacement of the hydride ligand by the halide. In a control experiment, Schwartz’s reagent also displayed reactivity with PhI (Scheme 2-17). In an NMR scale experiment, Schwartz’s reagent and PhI were heated to 110 °C for 24 hr. The resulting mixture of Cp2ZrClI, Cp2ZrCl2 and Cp2ZrI2 was identified (13C NMR (d8-toluene, Cp signals): 115.7, 115.2, 114.6 ppm) by comparison to reported values for the complexes (13C NMR (d8-toluene): 115.7, 115.3, 114.6 ppm),214 where the homodihalide complexes are presumably formed from halogen exchange.   Scheme 2-17: Reaction of Schwartz’s reagent and iodobenzene.  Interestingly, the reaction of the styrene insertion product complex 3d with iodobenzene was also found to afford the zirconium iodide product. Full conversion was observed under much milder reaction conditions (60 °C for 2 hr). In a competition experiment, 2d was subjected to equimolar amounts (1 equiv.) of styrene and PhI in the same flask (Scheme 2-18). After 16 hours at room temperature, full consumption of 2d was observed with a mixture of the styrene insertion product 3d and the iodide substituted complex 7a in a ratio of 1 : 1.3 as determined by 1H NMR 62  spectroscopy. The fate of the styrene substrate remains unclear; although one possibility is the formation of oligomeric styrene. In contrast, the exposure of Schwartz’s reagent to both styrene and iodobenzene in the same flask resulted in the formation of a mixture of insertion product with the iodobenzene unreacted in the mixture, as determined by 1H NMR spectroscopy.     Scheme 2-18: Competition experiment with styrene and iodobenzene. (a, top) with complex 2d. (b, bottom) with Schwartz’s reagent.    One proposal that was considered saw the reaction occurring through a Zr(II) species. First reductive elimination of the amide would generate a transient Zr(II) species, which is followed by oxidative addition of the halobenzene substrate. Protonolysis of the arene ligand by the free amide proligand would then result in the formation of complex 7 and benzene. However, these results do not preclude a radical pathway. Trace amounts of a Zr(III) species could be formed from thermally induced homolytic cleavage of the Zr─H bond (ca. 246 kJ mol-1).215 It has been previously shown that a Zr(III) radical generated from Schwartz’s reagent can undergo single electron processes for 63  halide abstraction to yield Cp2ZrCl(X).216,217 A thermally induced Zr(III) radical could abstract the halide to directly generate the observed zirconium product while recombination of the phenyl and hydrogen radicals would generate the observed benzene.  To probe whether zirconocene amidate complexes can support a Zr(III) radical, a preliminary cyclic voltammetry study of complex 2d under inert conditions was conducted (Figure 2-23). At room temperature (in 0.2 M NBu4PF6/THF measured versus ferrocene), the voltammogram shows the behavior of a pseudoreversible process with Ep (red) =  -2.7 V (or as calculated Ep (red) = -2.1 V vs. SHE) and Δ [Ep(red) – Ep(ox)] = 350 mV. Looking at the literature, an electrochemical study of [(tBuC6H5)2ZrH2]2 showed a Ep (red) =  -1.9 V vs. SHE.202 Due to limitations in the experimental setup, the voltammogram obtained was rather elongated compared to the ferrocene internal standard with Δ [Ep(red) – Ep(ox)] = 274 mV. The signal observed can be related to a single electron redox process; a Zr(IV) to Zr(III) transition. The observed enhanced reactivity of the styrene inserted complexes over their hydride counterparts may be due to a weaker Zr─C(benzyl) bond undergoing facile homolytic cleavage.   64   Figure 2-23: Cyclic voltammogram of complex 2d (5 × 10-3 M) in THF at 25 °C (scan speed 100 mV/s).    Furthermore, Zr(III) species are unstable and have been proposed to disproportionate to form Zr(II) and Zr(IV) species.218-219 Similar reactivity could be consistent with our observations. The initially formed Zr(III) could form a transient Zr(II) complex which might cause the observed reactions. While the observed reactivity with halobenzenes suggests the formation of reduced zirconium species, the exact nature of the reduced zirconium species is unknown.  Trapping of the transient Zr(II) species was also attempted by reacting with a disulfide.220 Interestingly, treatment of complex 2d with 1.1 equivalents of dibenzyl disulfide in d8-toluene resulted in an immediate color change from colorless to pink. The progress of the reaction was monitored via 1H NMR spectroscopy. It was observed that 50% of 2d was consumed after 3 hours at room temperature, and fully consumed after 16 hours. A mixture of three products formed, where Cp2Zr(SBn)2 (8) was the predominant species in solution (Scheme 2-19). The diagnostic signals at 4.21 and 5.78 ppm corresponded to benzylic and Cp protons of 8 respectively, and agreed -1.25E-05-7.50E-06-2.50E-062.50E-067.50E-061.25E-051.75E-052.25E-052.75E-053.25E-05-4-3.5-3-2.5-2Current (A)Potential  (V vs. Fc/Fc+)65  with literature values.221 The formation of 8 was accompanied by the generation of the free proligand, which is consistent with the initial hypothesis.  Scheme 2-19: Reaction of dibenzyldisulfide with complex 2d.  Surprisingly, a third species, complex 9 was observed in the product mixture. 2D NMR spectroscopic experiments suggest that this species is a mixed complex (9) with a κ1 bound amidate ligand at a zirconocene (carbonyl signal in 13C NMR spectrum: 163.9 ppm) and an additional benzylsulfide ligand (benzylic signal in 1H NMR spectrum: 4.3 ppm). Integration of the benzylic protons revealed a ratio of 2.1 : 1 for 8 : 9. No other byproduct was observed by 1H NMR spectroscopy. A mass spectrum of the crude mixture supported the formation of the two zirconium species (8: m/z 466 (M+); 9: m/z 486 (M+)). Isolation of the products via recrystallization resulted in small yellow crystals, which were identified as the known complex, Cp2Zr(SBn)2.222 Attempts to isolate 9 remained unsuccessful, hence this product could not be fully characterized.  The formation of the observed products is then proposed to be the result of a stepwise process. Initially, the disulfide is reduced by the zirconium complex to form HSBn and 9. Although HSBn was not directly observed during the course of the reaction, a subsequent and rapid protonolysis reaction of HSBn with 9 could result in the formation of Cp2Zr(SBn)2. In addition, 66  the reaction of complex 2d with HSBn may result in the formation of 9. To probe this hypothesis, complex 2d was treated with 0.5 or 2.0 equiv. of dibenzyl disulfide for 3 hours at room temperature. The reaction was complete after 3 hours as confirmed by 1H NMR spectroscopy, where the full consumption of the limiting reagent was observed. As shown in Scheme 2-19, the product ratios of 8 : 9 varied with the amount of disulfide reagent used (0.5 equiv. 1.3 : 1; 2.0 equiv. 2.8 : 1). Reaction of dibenzyl disulfide with Schwartz’s reagent also afforded Cp2Zr(SBn)2, however, the reaction proceeded more slower possibly due to the low solubility of Schwartz’s reagent in toluene. These results are consistent with a stepwise mechanism; however, further investigation including monitoring the progress of the reaction using 1H NMR spectroscopy is needed to fully elucidate the mechanism of this reaction.  2.2.3   Mechanistic Rationale for the Observed Regioselectivity The most intriguing observation regarding the reactivity of our newly prepared zirconocene amidate hydride complexes is the exclusive formation of the branched insertion product upon reaction with styrene. Hence, the mechanistic rationale for the observed regioselectivity is of interest. As noted in Section 2.1, Schwartz’s reagent, commonly utilized as a hydrozirconation reagent, typically forms the terminal linear insertion products selectively upon reaction with either terminal or internal olefins. Only in the case of styrene is a mixture of products observed (85 : 15), with the linear regioisomer being favored.162-163 Two strategies to control the regioselectivity have been attempted (Section 2.1): 1) modifying the electronic nature of the metal complex by varying the Cl ligand166 or 2) varying the steric parameters of the complex (substitution of Cp with Cp* ligands).169 Hence, the amidate ligands on complex 2 perturb both the electronic or steric parameters of the zirconocene and result in reactivity that favours the branched product. 67  While substitution of the chloro ligand with a triflate ligand resulted in the formation of both regioisomers upon styrene insertion in nearly equal ratios,166 a following study using zirconocene alkoxy hydrides was met with limited success (95 : 5, linear : branched).167 On the other hand, Bercaw and Chirik have shown that the insertion of aryl olefins can be controlled by the steric effects imposed by the use of bulky Cp derivatives.169 While the use of the bulky Cp*2ZrH2 resulted in linear insertion, reduction of some of this steric bulk by using [(t-BuC5H4)2ZrH2]2 led to the exclusive formation of the branched reaction product. The mechanism of insertion of these systems were proposed to proceed via olefin coordination to the exterior position of the complex, followed by rate-limiting insertion of the olefin into the Zr─H bond. This is in contrast to Schwartz’s reagent, where olefin coordination is thought to occur in the interior position.158-159 The change in regioselectivity of the insertion of aryl olefins to the dihydride systems was rationalized by dominating substrate electronic effects that favour the formation the branched insertion product.  These electronic factors originate from the interaction of the Zr─H σ bond orbital and the alkene π* anti-bonding orbital during the insertion step. Computational results have shown a greater LUMO orbital co-efficient contribution from the methylene carbon of styrene vs. the aryl substituted carbon.223 This is rationalized by the electron-withdrawing nature of the phenyl substituent, shifting the electron density towards the substituted carbon in the HOMO, which leaves the methylene carbon more electrophilic.223  Alternatively, hydrozirconation of styrene could proceed through alternative mechanistic pathways which would then allow for selective access to the branched product. As reduced zirconium species (Zr(III) or Zr(II)) are well-known and utilized in organic synthesis (vide supra),36-39 it is possible that a reduced zirconium complex can be generated in situ. A radical 68  pathway or alternatively a transient Zr(II) species formed through a formal reductive elimination of the amide could then be responsible for the observed selectivity. Our investigations focused on the factors that affect the regioselectivity of the insertion of styrene in order to gain more insight into the reaction mechanism.  To probe the possibility of a radical pathway, styrene insertion with complex 2d was performed in the dark and showed no difference to the reaction carried out in the light. Unfortunately, subjecting complex 2d to radical probe 10 resulted in no observable reaction (Scheme 2-20). If a radical species was formed during the insertion of styrene or from a side reaction of the zirconium complex with styrene, then the radical clock (10) would trap these species. In a competition experiment of 2d with 10 and excess styrene, only the previously observed branched insertion product was formed exclusively. These experiments suggest radical (Zr(III)) species are not responsible for the observed reactivity.   Scheme 2-20: Reaction of 2d with radical probe 10 and competition experiment with 10 and styrene.    Alternatively, Zr(II) species could be transiently produced from the formal reductive elimination of the amide proligand; the microscopic reverse of the oxidative addition of the N─H bond to form hydride complexes.190 Notably, complex 2d does not form via this direct oxidative addition pathway. In an attempt to explore the possibility of a transient Zr(II) species, several 69  trapping experiments were performed. These experiments led to mixed results: 1) no reaction was observed between complex 2d and PMe3 or biphenylene suggesting no reduced species could be formed, 2) reaction occurred between 2d and halobenzenes under harsh reaction conditions (vide supra) suggesting reduced species could be formed. To further investigate the possibility of this pathway, the exchange of the amidate ligand was probed. If reductive elimination occurred to form a transient Zr(II) species and protio ligand, the presence of another amide could result in exchange between the amidate and amide ligands upon reformation of the Zr(IV) amidate complex.  Due to the fact that proligand 1d does not react with 2d to form the bis(amidate) complex, this ligand is well-suited for the exchange experiment using complex 2d and the N─H and N─D derivatives of amide 1d. If a Zr(II) is indeed accessed then a mixture of Zr─H and Zr─D products should be formed.  However, the reaction of 2d and N-d-1d did not result in observable reactivity even at 60 °C, as monitored by 2H NMR spectroscopy. However, addition of styrene to this reaction mixture resulted in the formation of the predicted protio insertion product exclusively.   Other mechanistic pathways considered involved either ligand dissociation or ring-slippage to generate a coordinatively unsaturated reactive species. One possible pathway involves the dissociation of the amidate ligand to result in a coordinatively unsaturated zirconium complex, where olefin coordination can then occur followed by insertion. However, spontaneous dissociation of the amidate ligand is not likely due to the strong oxophilic nature of the zirconium center. Another route to produce an open coordination site is for the Cp ligand to undergo ring-slippage. Ring-slippage of Cp ligands is observed for transition-metal based metallocenes.224 Although examples of ring-slippage have been proposed for titanocene and zirconocene derivatives, these examples are typically limited to larger Cp derivatives such as indenyl or fluorenyl ligands,225-226 require under photochemical conditions,227 or extremely sterically 70  hindered complexes such as Cp4Zr.228 To the best of our knowledge, examples of ring-slippage with neutral bis(cyclopentadienyl) zirconium complexes with a hydride ligand remain unknown. In an attempt to probe the role of the amidate ligand, the reactivity of complexes 2a and 2c-e (2b was viewed as redundant as its reactivity is similar to 2c) were directly compared. Here 0.05 mmol of the hydride complexes were reacted with 1.1 equiv. of styrene with 1,3,5-trimethoxybenzene used as an internal standard. The reaction was monitored by 1H NMR spectroscopy at selected intervals (3 hours at room temperature, followed by 2 hours at 50 °C then an additional 17 hours at 50 °C) and the methine proton of the product was used for monitoring the reaction progress. Complex 2a showed no reactivity after 3 hours at room temperature and reached equilibrium after 2 hours at 50 °C. Although no reactivity was observed at room temperature, complex 2c did afford the insertion product at 50 °C but <50% yield was reached after 17 hr at 50 °C. Only complex 2d, which displays a hemi-labile amidate ligand where an equilibrium of the κ1 and κ2 isomers was observed in solution, showed reactivity at room temperature and reached 75% yield after heating the reaction to 50 °C for 19 hours. Complex 2e, which adopts a κ1-binding mode in both the solution phase and solid state, displayed very sluggish reactivity and only trace amounts of product were found at the end of the reaction. These qualitative results demonstrate the enhanced reactivity of the hemi-labile complex and the slow reactivity of κ1-species. To probe the dependence on the concentration of the styrene substrate, complex 2d was reacted with 5 equiv. of styrene. After 3 hours at room temperature, a higher conversion (73%) was observed. As further enhanced reactivity was observed under these conditions, this reaction was left at room temperature over the selected times. The reaction reached 93% conversion after a total of 5 hours at room temperature.  71  Table 2-3: Qualitative comparison of reactivity of hydride complexes 2 with styrene.  Complex 3 hours at room temperature (% yield) 2 hours at 50 °C (% yield) 17 hours at 50 °C (% yield) 2a 0% 10% 11% 2c 0% 17% 45% 2d 11% 52% 75% 2e 0% 0% <5% * Yield determined by 1H NMR spectroscopy with 1,3,5-trimethoxybenzene as an internal standard.   In similar zirconium systems, insertion products can undergo β-hydride elimination at elevated temperature (Scheme 2-21).169 As such, complex 3d was heated to 85 °C and β-hydride elimination did occur to result in the reformation of styrene and 2d as observed by 1H NMR spectroscopy.229 The methine proton was used to monitor the consumption of 3d and the alkene proton was used to monitor the released styrene. Equilibrium was reached after ~20 min at this temperature. Complex 3d was then monitored by 1H NMR spectroscopy over a temperature range of 25 to 100 °C.230 Between 50 - 60 °C, both styrene and complex 2d were observed. Upon reaching 100 °C, complex 3d was depleted as indicated by the disappearance of the methine proton in the NMR spectrum. Subsequent cooling of the reaction mixture to room temperature leads to the reformation of the insertion product (60% conversion to 3d after 16 hours at room temperature).   72   Scheme 2-21: β-hydride elimination is observed upon heating for complex 3d.  To gain more insight into the mechanistic details of the observed reactivity, an isotopic labeling experiment was undertaken. Zirconocene amidate deuteride complex d-2d was synthesized using the known salt metathesis procedure starting from deuterated Schwartz’s reagent (Scheme 2-22), which was prepared by the reduction of Cp2ZrCl2 with lithium aluminum deuteride following a literature procedure.231 Following recrystallization, complex d-2d was obtained in 50% yield and characterized by 1H/13C{1H}/2H NMR spectroscopy, EI-MS, and elemental analysis. The 2H NMR spectrum of d-2d displayed two distinct signals in the hydride region corresponding to the κ1 O-bound and κ2 isomers, as observed for the hydride complex 2d. The reaction of complex d-2d with an excess of styrene at room temperature resulted in the formation of the predicted branched insertion product, although longer reaction times were required. The 2H NMR spectrum of the insertion product (d-3d) showed only one signal at 1.76 ppm, which was attributed to the deuteration of the β-carbon of styrene. This was confirmed by the 1H NMR spectrum, which is a 1:2:1 triplet due to the small 3JDH coupling constant instead of the quartet at 2.62 ppm. GC-MS analysis of the reaction mixture resulting from quenching the reaction with 1M HCl(aq) and extraction with ethyl acetate revealed a signal consistent with mono-deuterated ethylbenzene (m/z 107). These observations show that the Zr-deuteride was cleanly added to the organic substrate. In 73  contrast, Bercaw and coworkers have shown that styrene insertion with deuterated Schwartz’s reagent results in isotopic scrambling.163    Scheme 2-22: Synthesis of the deuterated amidate complex d-2d and their insertion reaction with styrene d-3d.  To further probe the mechanism of the insertion, the kinetic isotope effect was determined using styrene insertion with complex 2d and d-2d. The progress of each reaction was monitored by 1H NMR spectroscopy by tracking product formation. The product methine proton (δ 1.68 ppm) was used as a handle to accurately measure the amount of products present. Again, these experiments were carried out under pseudo first-order conditions with an excess of styrene (10 equiv.) at 25 °C with 1,3,5-trimethoxybenzene as an internal standard. A primary kinetic deuterium isotope effect of 2.01(2) was measured (Figure 2-24). This is consistent with a rate-determining insertion event, as found previously in studies of related hydride complexes.169   74   Figure 2-24: Kinetic plot showing the rates of reaction between 1 equiv. of complex 2d (2 runs) and d-2d (2 runs) and 10 equiv. of styrene at 25 °C.  The zirconium amidate hydride complexes is purposed to undergo insertion of styrene via 2 possible pathways: 1) first the hemilabile N,O-chelate adopting a κ1-binding geometry where the complex can then access a coordinatively unsaturated complex. This unsaturated species allows for olefin coordination to occur, which is then followed by a rate-determining insertion event (Scheme 2-23, top pathway) or 2) a concerted insertion occurs through a 4-membered transition state (Scheme 2-23, bottom pathway). With both pathways, olefin coordination is thought to occur in the exterior position due to the presence of the bulky amidate ligand.  kobs(ZrH) = 5.62 ± 0.06 x 10-4 s-1R² = 0.9828kobs(ZrD) = 2.79 ± 0.06 x 10-4 s-1R² = 0.9874-7-6.5-6-5.5-5-4.5-4-3.5-3-2.5-20 1000 2000 3000 4000 5000 6000 7000ln[Pt-P]Time (sec)ZrH ZrD75   Scheme 2-23: Possible mechanistic pathway for styrene insertion of zirconocene amidate hydride complexes.   With either mechanistic proposal, the regioselectivity for the branch product is hypothesized to be dictated by electronic factors of the substrate, similar to the dihydride systems described by Bercaw and Chirik.169 The hydride preferentially adds to the more electron-deficient methylene carbon of styrene. The observed increased rates of reaction of the styrene derivatives with electron-withdrawing substituent also supports this hypothesis. Either proposed mechanistic pathways is consistent with the lack of enantioselectivity in reactions with enantiopure complex 5b, due to the distill position the styrene upon coordination. These observation do not conclusively discern between the two possible mechanisms. However, the fast rates of reaction with complex 2d (κ1 and κ2 isomers) and slow rates of reaction with complex 2e (κ1-isomer only) suggests the concerted pathway is more likely.    76  2.3 Conclusions  A series of zirconocene amidate hydride complexes was synthesized in a straightforward process via salt metathesis. These complexes were characterized in the solid state and solution phase and in all cases these complexes were monometallic bearing a terminal hydride. In most examples, the amidate ligand in these complexes exhibited a κ2 coordination geometry. However, with very bulky nitrogen and carbonyl substituents, complex 2e exhibited an amidate ligand in a κ1 O-bound motif. By tuning this steric parameter, a rare example of a complex with an equilibrium between the κ2 and κ1 coordination geometry of the amidate ligand could be characterized. In the solid state, complex 2d included a κ2 bound amidate ligand; however, in the solution phase an equilibrium between two isomers was observed. These zirconium hydride complexes displayed reactivity with a variety of reagents. Most importantly, in all cases, these complexes reacted with styrene to exclusively afford the branched insertion product. With complexes 2b-d the insertion products could be isolated and characterized. The insertion product can undergo electrophilic quenching to form halogenated products. The insertion products can also undergo β-hydride elimination to release styrene and regenerate the starting zirconium hydride complex. An asymmetric variant was synthesized using an enantiomerically pure ligand. However, no enantioselective insertion was observed. Phenylacetylene was found to react with complex 2d to form a mixture of products including the branched insertion product. 1-Octene, a non-sterically hindered terminal alkene, was found to be isomerized to the internal alkenes by our zirconium hydride complexes, while sterically hindered terminal alkenes did not undergo insertion. (Z)-1-phenylprop-1-ene was obtained from an isomerization process facilitated by the zirconium hydride complexes from 3-phenylprop-1-ene and (E)-1-phenylprop-1-ene. Halobenzenes reacted with complex 2d under harsh reaction 77  conditions to afford the zirconocene amidate halide complexes with benzene as the only by-product. This behavior is thought to arise from the formation of a transient reduced zirconium species produced by the harsh reaction conditions. Styrene insertion is proposed to proceed through a coordination-insertion mechanism. Kinetic isotope effects experiments support a rate-determining insertion step. This insertion is proposed to be preceded by the coordination of the olefin at the exterior position of the zirconocene. This mechanism also rationalizes the observed regioselectivity for the insertion of styrene. The relative rates of insertion of styrene derivatives suggest a strong electronic influence, which is also consistent with the proposed mechanism.     2.4 Experimental 2.4.1 Materials and Methods All reactions were performed under an inert atmosphere of nitrogen using either standard Schlenk line or glovebox techniques and were conducted in oven-dried glassware unless otherwise stated.  Benzene, hexanes and toluene were purified and dried by passage through a column of activated alumina and sparged with nitrogen. d6-Benzene and d8-toluene were dried over activated 4 Å molecular sieves and degassed via three cycles of freeze-pump-thaw and stored over activated 4 Å molecular sieves in the glovebox. Tetrahydrofuran was dried by refluxing over sodium with benzophenone indicator, then distilled and sparged with nitrogen. All alkene substrates were dried over CaH2, distilled and degassed by three freeze-pump-thaw cycles prior to use. Cp2ZrHCl was purchased from Alfa Aesar and used as received. Other zirconium starting materials (Cp2Zr(BTMSA)142 and Cp2ZrDCl231) were prepared as described in the literature. Proligands 1a- c were prepared as described.85, 114 2-Phenylbutan-2-amine was synthesized according to the 78  literature procedure.232  All other reagents were purchased from commercial sources and used as received. Synthesis and characterization (excluding X-ray diffraction studies) of complexes 2a and b (excluding the synthesis of complex 2a via salt metathesis), 3b and bis(amidate) zirconocene complex were described in previous publications and performed by Dr. Martin Haehnel.182, 233 Compound 10 was synthesized by Dr. Jean Michel Lauzon. DFT calculations were performed by Mr. Jason Brandt.  1H and 13C{1H} NMR spectra were recorded on Bruker 300 MHz, 400 MHz or 600 MHz Avance spectrometers as solutions in the solvents stated in non-spinning mode at 298 K unless otherwise noted. Chemical shifts δ for 1H and 13C{1H} NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an external standard and calibrated against the solvent residual peak. Chemical shifts for 19F NMR spectra are relative to CFCl3 in CDCl3 (external reference). Chemical shifts for 2H NMR spectra are relative to d8-toluene (external reference). NMR spectra were assigned by using distortionless enhancement by polarization transfer (DEPT) and 2D techniques (COSY, NOESY, HMQC and/or HMBC).  Coupling constants J are given in Hertz (Hz). Infrared (IR) spectra were collected on a PerkinElmer Frontier FT-IR with attenuated total reflectance (ATR) setup. GC-MS measurements were performed on an Agilent Technologies GC 6890N/ MS 5973N equipped with an Agilent Technologies HP-5HS column (length: 30 m, 0.25 mm inner diameter, 0.25 μm coating thickness) coupled to a quadrupole mass filter. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 eV) source with a TOF detector. Fragment signals are given in mass per charge number (m/z). Elemental analyses were recorded on a Carlo Erba elemental analyzer EZ 1108. The content of the specified element is expressed in percent (%).  79  2.4.2 Synthesis and Characterization of Proligands and Complexes General Procedure Amine (1 equiv.) was dissolved in DCM and Et3N (1.3 equiv.). The mixture was stirred while being cooled to 0 °C in an ice bath. Acid chloride (1.1 equiv.) was added dropwise. The reaction was then allowed to warm to room temperature and stirred for 10 hours. The solution was diluted with water and transferred to a separatory funnel. The organic layer was separated and the aqueous layer was further extracted with 2 × 50 mL DCM. The combined organic layers were washed sequentially with 1M HCl(aq), 1M NaOH, water and saturated NaCl(aq). The combined organic layers were dried over MgSO4, filtered and the solvent removed in vacuo. The crude product was recrystallized from hot ethyl acetate to afford a white solid.  2,2-Dimethyl-N-tricyclo[3.3.1.13,7]dec-1-yl-propanamide (1d). 1-Adamantylamine (15.12 g, 0.10 mol) was dissolved in DCM (200 mL) and Et3N (18.0 mL, 0.13 mol) to give a colourless solution. The mixture was stirred while being cooled to 0 °C in an ice bath. Trimethylacetyl chloride (13.5 mL, 0.11 mol) was added dropwise. The reaction was then allowed to warm to room temperature and stirred for 10 hours. The solution was transferred to a separatory funnel with an equal part of water. The organic layer was separated and the aqueous layer was further extracted with 2 × 50 mL DCM. The combined organic layers were washed sequentially with 3 × 75 mL of 1M HCl(aq), 3 × 75 mL of 1M NaOH, water, and saturated NaCl(aq). The combined organic layers were dried over MgSO4, filtered and the solvent was removed in vacuo. The crude product was recrystallized from a minimal amount of hot ethyl acetate to afford a white solid. Yield: 16.73 g (0.07 mol, 71%). 1H NMR (CDCl3, 300 MHz) δ (ppm) 5.26 (br s, 1H, NH), 2.08 (br m, 3H, Ad), 2.00 (br d, 6H, Ad), 80  1.68 (br t, 6H, Ad), 1.16 (s, 9H, C(CH3)3); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 177.7 (C=O), 51.3, 41.6, 39.0, 36.4, 29.5, 27.7; MS (EI-TOF): m/z 235 (M+); Anal. Calcd. (%) for C15H25NO: C, 76.55; H, 10.71; N, 5.95; Found: C, 76.82; H, 11.04; N, 5.98.  N-(1-Methyl-1-phenylpropyl)- tricyclo[3.3.1.13,7]decane-1-carboxamide (1e).  The title compound was synthesized following the general procedure for amide synthesis with 2-phenylbutan-2-amine (1.43 g, 9.7 mmol), adamantylcarbonyl chloride (2.18 g, 10.9 mmol) and NEt3 (1.8 mL, 13.0 mmol). White solid. Yield: 2.08 g (6.7 mmol, 62%).  1H NMR (CDCl3, 400 MHz) δ (ppm) 7.34 – 7.29 (m, 4H, Ph), 7.24 – 7.19 (m, 1H, Ph), 5.81 (br s, 1H, NH), 2.11 (dq, 3JH,H = 7.5 Hz, 2JH,H = 13.8 Hz, 1H, CCH2CH3), 2.06 (m, 3H, Ad), 1.96 (dq, 3JH,H = 7.5 Hz, 2JH,H = 13.8 Hz, 1H, CCH2CH3), 1.89 (br d, 6H, Ad), 1.78 – 1.69 (m, 6H, Ad), 1.68 (s, 3H, Me), 0.78 (t, 3J = 7.5 Hz, 3H, CCH2CH3); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 176.7 (C=O), 146.1, 128.2, 126.4, 124.9, 58.2, 41.0, 39.5, 36.5, 33.9, 28.2, 25.7, 8.4; MS (EI-TOF): m/z 311 (M+), 282 (M+ – Et ); Anal. Calcd. (%) for C21H29NO: C, 80.98; H, 9.39; N, 4.50; Found: C, 81.13; H, 9.61; N, 4.59.  (±)-N-(1-Phenylethyl)- tricyclo[3.3.1.13,7]decane-1-carboxamide (4a).  The title compound was synthesized following the general procedure for amide synthesis with (±)-α-methylbenzylamine (1.3 mL, 10.0 mmol),  adamantylcarbonyl chloride (2.18 g, 11.0 mmol) and NEt3 (1.8 mL, 13.0 mmol). White solid. Yield: 2.35 g (8.3 mmol, 83%). 1H NMR (CDCl3, 400 MHz) δ  (ppm) 7.36 – 7.24 (m, 5H, Ph), 5.79 (br d, 1H, NH), 5.13 (q, 3JH,H = 6.8 Hz, 1H, NCHPhMe), 2.05 (br s, 3H, Ad), 1.87 (br d, 6H, Ad), 1.77 – 1.68 (m, 6H, Ad), 1.48 (d, 3JH,H = 6.8 Hz, 3H, Me); 13C{1H} NMR (CDCl3, 100 MHz) 81  δ (ppm) 177.0 (C=O), 143.6, 128.8, 127.2, 126.3, 48.1, 40.5, 39.3, 36.5, 28.1, 21.8;  MS (EI-TOF): m/z 283 (M+); Anal. Calcd. (%) for C19H25NO: C, 80.52; H, 8.89; N, 4.94; Found: C, 80.48; H, 9.10; N, 4.97.  Synthesis of (R)-N-(1-Phenylethyl)- tricyclo[3.3.1.13,7]decane-1-carboxamide (4b). The title compound was synthesized following the general procedure for amide synthesis with (R)-(+)-α-methylbenzylamine (1.3 mL, 10.0 mmol), adamantylcarbonyl chloride (2.18 g, 11.0 mmol) and NEt3 (1.8 mL, 13.0 mmol). White solid. Yield: 1.82 g (6.4 mmol, 64%). 1H NMR (CDCl3, 400 MHz) δ  (ppm) 7.36 – 7.24 (m, 5H, Ph), 5.79 (br d, 1H, NH), 5.13 (q, 3JH,H = 6.8 Hz, 1H, NCHPhMe), 2.05 (br s, 3H, Ad), 1.87 (br d, 6H, Ad), 1.77 – 1.68 (m, 6H, Ad), 1.48 (d, 3JH,H = 6.8 Hz, 3H, Me); 13C{1H} NMR (CDCl3, 100 MHz) δ (ppm) 177.0 (C=O), 143.6, 128.8, 127.2, 126.3, 48.1, 40.5, 39.3, 36.5, 28.1, 21.8; MS (EI-TOF): m/z 283 (M+); Anal. Calcd. (%) for C19H25NO: C, 80.52; H, 8.89; N, 4.94; Found: C, 80.74; H, 9.15; N, 4.98.; [α]D23 = +52.3° (c = 0.017, CH2Cl2).  2.4.3 Synthesis and Characterization of Zirconocene Amidate Hydride Complexes General Procedure. Amide proligand (1 equivalent) and NaHMDS (1.1 equivalent) were suspended in dry toluene (15 mL) and the mixture was stirred for 24 hr to give an off-white suspension. Cp2ZrHCl (1 equivalent) was added to the suspension and the mixture was allowed to stir for 24 hr to give an off-white suspension. The suspension was filtered through Celite and all volatiles were removed in vacuo. The product was recrystallized from the minimal amount of hot hexanes. The mother 82  liquor was removed, the solid product was washed with cold hexanes (ca. 5 mL) and dried in vacuo.   [Cp2Zr(H){κ2-N,O-(Ad)NC(tBu)O}] and [Cp2Zr(H){κ1-N,O-(Ad)NC(t-Bu)O}]  (2d). Proligand 1d (305 mg, 1.3 mmol) and NaHMDS (251 mg, 1.37 mmol) were suspended in dry toluene (15 mL) and the mixture was stirred for 24 hours to give an off-white suspension. Cp2ZrHCl (338 mg, 1.30 mmol) was added to the suspension and the mixture was allowed to stir for 24 hours to give an off-white suspension. The suspension was filtered through Celite and all volatiles were removed in vacuo. The product was recrystallized from the minimal amount of hot hexanes. The mother liquor was removed, the solid product was washed with cold hexanes (ca. 5 mL) and dried in vacuo. Yield: 490 mg (1.07 mmol, 82%). 1H NMR (C6D6, 400 MHz) δ (ppm)  5.84 – 5.26 (11H, C5H5 and ZrH), 2.16 – 1.63 (15H, Ad), 1.20 – 1.19 (9H, t-Bu); Assignments: 5.84 (s, C5H5, κ1), 5.82 (s, C5H5, κ2), 5.26 (s, Zr-H, κ2), 2.16 (br s, Ad, κ1), 2.11 – 2.06 (br m, Ad, overlapped signals), 1.91 – 1.89 (br m, Ad, κ1), 1.76 – 1.73 (br m, Ad, κ1), 1.63 (ap t, Ad, κ2), 1.20 (s, t-Bu, κ1), 1.19 (s, t-Bu, κ2), (1H from Zr-H of the κ1 isomer is obscured); 13C{1H} NMR (C6D6, 100 MHz) δ (ppm)  182.8 (C=O, κ2), 165.8 (C=O, κ1), 108.7 (C5H5, κ1), 106.5 (C5H5, κ2), 53.4 (Ad, κ2), 53.3 (Ad, κ1),  45.2 (Ad, κ1), 44.3 (Ad, κ2), 41.1 (C(CH3)3, κ2), 38.4 (C(CH3)3, κ1), 37.9 (Ad, κ2), 37.8 (Ad, κ1), 31.1 (C(CH3)3, κ1), 30.1 (C(CH3)3, κ2), 29.5 (Ad, κ1), 29.4 (Ad, κ2). MS (EI-TOF): m/z 455 (M+), 320 (M-Ad+), 220 (Cp2Zr+); Anal. Calcd. (%) for C25H35NOZr: C, 65.74; H, 7.72; N, 3.07; Found: C, 66.04; H, 7.57; N, 2.93. IR (ATR, cm-1) 2893 (m), 2845 (w), 1585 (w), 1494 (m), 1462 (m), 1397 (w), 1335 (m), 1302 (m), 1197 (w), 1023 (m), 1015 (w), 1007 (w), 994 (w), 962 (w), 804 (s), 789 (s), 685 (w). Single crystal 83  X-ray quality samples were obtained by recrystallization from slow diffusion of hexanes to a saturated solution in toluene.  Large scale synthesis: Proligand 1d (8.60 g, 37.1 mmol) and NaHMDS (7.04 g, 38.4 mmol) were suspended in dry THF (250 mL) and the mixture was stirred for 24 hours to give an off-white suspension. Cp2ZrHCl (10.09 g, 39.1 mmol) was added to the suspension and the mixture again stirred for 24 hours to give an off-white suspension. The suspension was filtered through Celite and all volatiles were removed in vacuo. The remaining solid was dissolved in about 350 mL of toluene. The suspension was filtered once more and the product was recrystallized from reduced amounts of toluene. The remaining toluene was removed by decanting and the product was washed with cold hexanes twice (25 mL) to afford an off-white solid. Yield: 9.87 g (21.6 mmol, 56%).  [Cp2Zr(H){κ2-N,O-(i-Pr)NC(t-Bu)O}] (2a). The title complex was synthesized following the general procedure for complex synthesis with proligand 1a (222 mg, 1.57 mmol), NaHMDS (341 mg, 1.89 mmol) and Cp2ZrHCl (386 mg, 1.50 mol). Spectral data matched literature references.198 White solid. Yield: 274 mg (0.91 mmol, 58%). 1H NMR (C6D6, 300 MHz) δ (ppm) 5.81 (s, 10H, Cp), 5.01 (s, 1H, Zr-H), 3.70 (sept, 3JH,H = 6.2 Hz, 1H, CH), 1.08 (d, 3JH,H = 6.2 Hz, 6H, Me), 1.01 (s, 9H, t-Bu).   [Cp2Zr(H){κ2-N,O-(Dipp)NC(t-Bu)O}] (2c). The title complex was synthesized following the general procedure for complex synthesis with proligand 1c (217 mg, 0.83 mmol), NaHMDS (161 mg, 0.87 mmol) and Cp2ZrHCl (217 mg, 0.84 mol). Off-white solid. Yield: 170 mg (0.36 mmol, 84  56%).1H NMR (C6D6, 300 MHz) δ (ppm) 7.38 – 7.13 (m, 3H, Ar), 6.08 (s, 10H, Cp), 5.71 (s, 1H ZrH), 3.51 (sept., 3JH,H = 6.8 Hz, 2H, CH(CH3)2), 1.54 (d, 3JH,H = 6.8 Hz, 6H, CH(CH3)2), 1.40 (d, 3JH,H = 6.8 Hz, 6H, CH(CH3)2), 1.10 (s, 9H, t-Bu); 13C{1H} NMR (C6D6, 100 MHz) δ (ppm) 186.1 (C=O), 143.7, 142.4, 125.5, 124.0 (Ph), 107.5 (Cp), 42.0 (C(CH3)3), 29.6 (CH(CH3)2), 28.6 (CH(CH3)2), 28.5 (C(CH3)3), 27.9 (CH(CH3)2), 26.7 (CH(CH3)2). MS (EI-TOF): m/z 481 (M+), 415 (M+ – CpH), 220 (Cp2Zr); Anal. Calcd. (%) for C27H37NOZr: C, 67.17; H, 7.72; N, 2.90; Found: C, 67.56; H, 7.86; N, 2.93. Single crystal X-ray quality samples were obtained by recrystallization from hot hexanes. IR (ATR, cm-1) 3315 (m), 2961 (m), 1646 (s), 1507 (s), 1472 (m), 1361 (m), 1211 (w), 1169 (w), 935 (m), 789 (s), 736 (s).   [Cp2Zr(H){κ1-N,O-(CMeEtPh)NC(Ad)O}] (2e). The title complex was synthesized following the general procedure for complex synthesis with proligand 1e (405 mg, 1.30 mmol), NaHMDS (250 mg, 1.37 mmol) and Cp2ZrHCl (335 mg, 1.30 mmol). White solid. Yield: 410 mg (0.77 mmol, 59%). 1H NMR (C6D6, 300 MHz) δ (ppm) 7.51 – 7.48 (m, 2H, Ph), 7.31 – 7.28 (m, 2H, Ph), 7.15 – 7.10 (m, 1H, Ph), 5.67 (s, 5H, Cp), 5.60 (s, 1H, ZrH), 5.15 (s, 5H, Cp), 2.09 (br m, 3H, Ad), 1.96 – 1.95 (br m, 6H, Ad, partially overlapped), 1.91 (q, 3JH,H = 7.3 Hz, 2H, CCH2CH3, partially overlapped), 1.83 – 1.72 (br m, 6H, Ad), 1.65 (s, 3H, Me), 1.07 (t, 3JH,H = 7.3 Hz, 3H, CH2CH3); 13C{1H} NMR (C6D6, 75 MHz) δ (ppm) 166.63 (C=O), 151.7, 127.7, 126.1, 125.4 (Ph), 107.9 (C5H5), 58.9 (Ad), 41.0 (CH2CH3), 40.2 (Ad), 39.9 (CCH3), 37.0 (Ad), 29.9 (Ad), 27.0 (CCH3), 9.0 (CH2CH3). MS (EI-TOF): m/z 531 (M+), 502 (M-Et+), 398 (M-CEtMePh+), 220 (Cp2Zr+); Anal. Calcd. (%) for C31H39NOZr: C, 69.87; H, 7.38; N, 2.63; Found: C, 70.18; H, 7.69; N, 2.65. Single crystal X-ray quality samples were obtained by recrystallization 85  from hot hexanes. IR (ATR, cm-1) 2900 (m), 2847 (w), 1626 (s), 1491 (w), 1445 (m), 1318 (w), 1229 (s), 1184 (w), 1104 (m), 1083 (m), 939 (m), 799 (s), 758 (s), 700 (s).  [Cp2Zr(H){κ2-N,O-(CHMePh)NC(Ad)O}] (5a). The title complex was synthesized following the general procedure for complex synthesis with proligand 4a (420 mg, 1.50 mol), NaHMDS (342 mg, 1.89 mmol) and Cp2ZrHCl (390 mg, 1.50 mol). White solid. Yield: 509 mg (1.01 mmol, 67%). 1H NMR (C6D6, 400 MHz) δ (ppm) 7.51 (d, 3JH,H = 7.5 Hz, 2H, Ph), 7.26 (t, 3JH,H = 7.5 Hz, 2H, Ph), 7.15 (m, 1H, Ph), 5.78 (s, 5H, Cp), 5.48 (s, 5H, Cp), 5.15 (q, 3JH,H = 6.6 Hz, 1H, CHMePh), 4.89 (s, 1H, ZrH), 2.03 – 1.85 (m, 9H, Ad), 1.58 (br s, 6H, Ad), 1.49 (d, 3JH,H = 6.6 Hz, 3H, Me); 13C{1H} NMR (d8-toluene, 100 MHz) δ (ppm) 185.4 (C=O), 144.9, 128.3, 127.8, 126.9 (Ph), 106.3, 105.8 (Cp), 52.6 (CHMePh), 43.0, 39.2, 36.9, 28.8 (Ad), 22.2 (Me); MS (EI-TOF): m/z 503 (M+), 398 (M-CMeHPh+), 220 (Cp2Zr+); Anal. Calcd. (%) for C29H31NOZr: C, 69.00; H, 6.99; N, 2.77; Found: C, 68.80; H, 7.00; N, 2.62; IR (ATR, cm-1) 2902 (m), 2848 (w), 1601 (w), 1512 (m), 1449 (m), 1394 (m), 1363 (w), 1297 (w), 1244 (m), 1154 (w), 1106 (w), 1012 (m), 954 (w), 793 (s), 759 (m), 707 (m).   [Cp2Zr(H){κ2-N,O-((R)-CHMePh)NC(Ad)O}] (5b).  The titled complex was synthesized following the general procedure for complex synthesis with proligand 4b (370 mg, 1.30 mmol), NaHMDS (251 mg, 1.37 mmol) and Cp2ZrHCl (330 mg, 1.30 mmol). White solid. Yield: 347 mg (0.69 mmol, 53%). 1H NMR (C6D6, 400 MHz) δ (ppm) 7.51 (d, 3JH,H = 7.5 Hz, 2H, Ph), 7.26 (t, 3JH,H = 7.5 Hz, 2H, Ph), 7.15 (m, 1H, Ph), 5.78 (s, 5H, Cp), 5.48 (s, 5H, Cp), 5.15 (q, 3JH,H = 6.6 86  Hz, 1H, CHMePh), 4.89 (s, 1H, ZrH), 2.03 – 1.85 (m, 9H, Ad), 1.58 (br s, 6H, Ad), 1.49 (d, 3JH,H = 6.6 Hz, 3H, Me); 13C{1H} NMR (d8-toluene, 100 MHz) δ (ppm) 185.4 (C=O), 144.9, 128.3, 127.8, 126.9 (Ph), 106.3, 105.8 (Cp), 52.6 (CHMePh), 43.0, 39.2, 36.9, 28.8 (Ad), 22.2 (Me). MS (EI-TOF): m/z 503 (M+), 398 (M-CMeHPh+), 220 (Cp2Zr+); Anal. Calcd. (%) for C29H31NOZr: C, 69.00; H, 6.99; N, 2.77; Found: C, 68.83; H, 6.95; N, 2.63; Single crystal X-ray quality samples were obtained by recrystallization from hot hexanes; IR (ATR, cm-1) 2896 (m), 2848 (w), 1591 (w), 1519 (m), 1453 (m), 1387 (m), 1364 (w), 1299 (w), 1243 (m), 1154 (w), 1106 (w), 1012 (m), 953 (w), 798 (s), 764 (m), 707 (m).  [Cp2Zr(D){κ2-N,O-(Ad)NC(tBu)O}] and [Cp2Zr(D){κ1-N,O-(Ad)NC(tBu)O}] (d-2d). The title mixture of complexes was synthesized following the general procedure for complex synthesis with proligand 1d (118 mg, 0.50 mmol), NaHMDS (97 mg, 0.52 mmol) and Cp2ZrDCl (128 mg, 0.50 mmol). Orange solid. Yield: 115 mg (0.25 mmol, 50%). 1H NMR (d8-toluene, 400 MHz) δ  (ppm)  5.92 – 5.76 (10H, C5H5), 2.11 – 1.58 (15H, Ad), 1.17 – 1.14 (9H, t-Bu), Assignments: 5.92 (s, C5H5, κ1), 5.76 (s, C5H5, κ2), 2.11 (br s, Ad), 1.98 (br s, Ad), 1.87 – 1.84 (br m, Ad), 1.73 – 1.70 (br m, Ad), 1.67 – 1.58 (br m, Ad), 1.17 (t-Bu, κ2), 1.14 (s, t-Bu, κ1); 13C{1H} NMR (C6D6, 75 MHz) δ (ppm) κ1-O: 165.8 (C=O), 108.7 (C5H5), 53.3 (Ad),  45.2 (Ad), 38.4 (C(CH3)3), 37.8 (Ad), 31.1 (C(CH3)3), 29.5 (Ad); κ2-N,O: 106.5 (C5H5), 53.4 (Ad), 44.3 (Ad), 41.1 (C(CH3)3), 37.9 (Ad), 30.1 (C(CH3)3), 29.5 (Ad) (C=O signal for κ2 was not observed). 2H(1H) NMR (toluene, 400 MHz) δ  (ppm) 5.79, 5.22; MS (EI-TOF): m/z 456 (M+), 389 (M+–CpH), 220 (Cp2Zr); Anal. Calcd. (%) for C25H34DNOZr: C, 65.59; H, 7.93; N, 3.06; Found: C, 65.46; H, 7.76; N, 3.05. IR (ATR, cm-1) 2896 (m), 2847 (w), 1494 (m), 1465 87  (m), 1397 (w), 1335 (m), 1302 (m), 1133 (m), 1197 (w), 1113 (m), 1015 (w), 1007 (w), 994 (w), 962 (w), 804 (s), 790 (s), 685 (w).  2.4.4 Synthesis and Characterization of Styrene Insertion Products General procedure for insertion of styrene.  The zirconium hydride complex (1 equiv.) was dissolved in dry C6D6 or d8-toluene and transferred to a J. Young NMR tube. Then styrene (1 – 10 equiv.) was added. The reaction was monitored by 1H NMR spectroscopy. For complexes 3c-d, upon completion of reaction, the contents were transferred to a vial and the volatile component removed in vacuo. Recrystallization from hexanes afforded the insertion product     [Cp2Zr(CHMePh){κ1-N,O-(Dipp)NC(tBu)O}] (3c). The title complex was synthesized following the general procedure for styrene insertion with complex 2c (23.7 mg, 0.050 mmol) and styrene (10 μL, 0.086 mmol) reacted at 70 °C for 3 hr. Yellow solid. Yield: 18.2 mg (0.032 mmol, 63%). 1H NMR (C6D6, 400 MHz) δ (ppm) 7.21 (m, 2H, Ar), 7.12 (br t, 3H, Ar), 7.03 (br d, 2H, Ar), 6.92 (m, 1H, Ar), 5.49 (s, 5H, Cp), 5.44 (s, 5H, Cp), 3.03 – 2.89 (m, 2H, CH(CH3)2), 2.46 (q, 3JH,H = 7.0 Hz, 1H, ZrCH(Me)Ph), 1.68 (d, 3JH,H = 7.0 Hz, 3H, ZrCH(CH3)Ph), 1.38 – 1.27 (m, 21H, CH(CH3)2 + t-Bu, signals overlapped); 13C{1H} NMR (C6D6, 100 MHz) δ (ppm) 166.0 (C=O), 155.9, 137.6, 137.6, 128.8, 126.8, 123.3, 122.8, 122.7 (Ar), 113.6 (Cp), 112.8 (Cp), 60.5 (ZrC(Me)Ph), 40.2 (CH(CH3)2), 39.8 (C(CH3)3), 29.6 (C(CH3)), 25.5 (ZrCH(CH3)Ph), 23.3 (CH(CH3)2), 23.2 (CH(CH3)2), 21.6 (CH(CH3)2). MS (EI-TOF): m/z 480 (M+ - PhCHCH3); Anal. 88  Calcd. (%) for C15H20NOZr: C, 71.62; H, 7.73; N, 2.39; Found: C, 71.16; H, 7.86; N, 2.73. Single crystal X-ray quality samples were obtained by recrystallization from hot hexanes.   [Cp2Zr(CHMePh){κ1-N,O-(Ad)NC(tBu)O}] (3d).   The title complex was synthesized following the general procedure for styrene insertion with complex 2d (200 mg, 0.44 mmol) and styrene (76 μL, 1.32 mmol) reacted at room temperature for 24 hr. Yellow solid. Yield: 0.221 g (0.395 mmol, 90%). 1H NMR (C6D6, 400 MHz) δ (ppm) 7.29 (t, 3JH,H = 7.3 Hz, 2H, Ph), 7.19 (m, 2H, Ph, partially overlapped), 7.01 – 6.97 (m, 1H, Ph), 5.93 (s, 5H, Cp), 5.59 (s, 5H, Cp), 2.62 (q, 3JH,H = 6.8 Hz, 1H, ZrCH(Me)Ph), 2.13 – 2.04 (m, 9H, Ad), 1.84 (d, 3JH,H = 6.8 Hz, 3H, ZrCH(CH3)Ph, partially overlapped), 1.81 (m, 3H, Ad, partially overlapped), 1.71 – 1.68 (m, 3H, Ad), 1.23 (s, 9H, t-Bu); 13C{1H} NMR (C6D6, 100 MHz) δ (ppm) 163.5 (C=O), 156.4, 129.0, 126.8, 122.9 (Ph), 113.7 (Cp), 112.2 (Cp), 61.1 (ZrCH(Me)Ph), 52.6 (Ad), 44.4 (Ad), 40.1 (CMe3), 37.5 (Ad), 30.7 (Ad), 30.0 (C(CH)3), 26.4 (ZrCH(CH3)Ph);  MS (EI-TOF): m/z 455 (M+ - PhCHCH3); Anal. Calcd. (%) for C33H43NOZr: C, 70.66; H, 7.73; N, 2.50; Found: C, 70.87; H, 7.88; N, 2.49. Single crystal X-ray quality samples were obtained by slow evaporation from hot pentanes.   [Cp2Zr(CH(Ph)(CH2D){κ1-N,O-(Ad)NC(tBu)O}] (d-3d).  The title complex was synthesized following the general procedure for styrene insertion with complex d-2d (8 mg, 0.018 mmol) and styrene (6 μL, 0.033 mmol). Orange solid. Yield: 7 mg (0.012 mmol, 66%). 1H NMR (C6D6, 300 MHz) δ (ppm) 7.26 (t, 3JH,H = 7.5 Hz, 2H, Ph), 7.13 (br s, 2H, Ph), 6.96 (ap t, 1H, Ph), 5.90 89  (s, 5H, C5H5), 4.27 (s, 5H, C5H5), 2.58 (t, 3JH,H = 6.7 Hz, 1H, ZrCH(Me)Ph), 2.08 – 2.01 (br m, 9H, Ad), 1.81 – 1.64 (br m, 8H, Ad + ZrCH(CH2D)Ph), 1.20 (s, 9H, t-Bu); 13C{1H} NMR (C6D6, 75 MHz) δ (ppm) 163.5 (C=O), 156.4, 129.0, 126.8, 122.9 (Ph), 113.7 (Cp), 112.8 (Cp), 61.0 (ZrCH(Me)Ph), 52.4 (Ad), 44.4 (Ad), 40.1 (CMe3), 37.5 (Ad), 30.7 (Ad), 30.0 (C(CH)3), 26.1 (t, 1JC,D = 19.0 Hz, ZrCH(CH2D)Ph).  2H(1H) NMR (toluene, 300 MHz) δ (ppm) 1.76.  2.4.5 Insertion Reaction with Styrene Derivatives A J. young NMR tube was charged with a solution of complex 2d (200 μL, 0.25 M, 0.05 mmol) in dry C6D6 and a solution of 1,3,5-trimethoxybenzene (0.055 mmol, 50 μL of 0.11 M solution in C6D6). The mixture was diluted with 300 μL of C6D6. Either para-trifluoromethylstyrene (73.9 μL, 0.5 mmol) or para-methylstyrene (65.9 μL, 0.5 mmol) was added. The reaction was monitored by 1H NMR spectroscopy until >95% conversion was achieved and the products were characterized in situ without further purification.   [Cp2Zr(C(p-CF3C6H4)HMe){κ1-N,O-(Ad)NC(tBu)O}]  1H NMR (C6D6, 300 MHz) δ (ppm) 7.48 (d, 3JH,H = 8.1 Hz, 2H, Ar), 7.03 (d, 3JH,H = 8.1 Hz, 2H, Ar), 5.86 (s, 5H, Cp), 5.52 (s, 5H, Cp), 2.62 (q, 3JH,H = 6.8 Hz, 1H, ZrCH(Me)Ar), 2.12 – 1.97 (m, 9H, Ad), 1.68 – 1.60 (m, 9H, Ad + ZrCH(CH3)Ar), 1.20 (s, 9H, t-Bu); 13C{1H} NMR (C6D6, 75 MHz)  δ (ppm)  163.5 (C=O), 125.5 (Ar), 123.5 (Ar), 113.7 (Cp), 112.6 (Cp), 59.2 (ZrCH(CH3)Ar), 52.7 (Ad), 44.4 (Ad), 40.1 (CMe3) 37.5 (Ad), 30.8 (Ad), 29.9 (C(CH)3), 25.3 (ZrCH(CH3)Ph), (2 aryl carbon and CF3 carbon signals were not detected); 19F NMR (C6D6, 282 MHz) δ (ppm) 61.56. 90  [Cp2Zr(C(p-MeC6H4)HMe){κ1-N,O-(Ad)NC(tBu)O}]  1H NMR (C6D6, 300 MHz) δ (ppm) 6.00 (s, 5H, Cp), 5.66 (s, 5H, Cp), 2.65 (quint, 3JH,H = 6.8 Hz, 1H, ZrCH(Me)Ar), 2.32 (s, 3H, p-(CH3)C6H5), 1.90 – 1.71 (m, 9H, Ad + ZrCH(CH3)Ar), 1.27 (s, 9H, t-Bu), (Some aryl and adamantly protons were obsured); 13C{1H} NMR (C6D6, 75 MHz)  δ (ppm)  163.5 (C=O), 131.7 (Ar), 129.7 (Ar), 126.8 (Ar), 113.6 (Cp), 112.2 (Cp), 55.2 (ZrCH(CH3)Ar), 52.6 (Ad), 44.4 (Ad), 40.1 (CMe3) 37.5 (Ad), 30.8 (Ad), 30.0 (C(CH)3), 26.6 (ZrCH(CH3)Ph), 21.3 (C6H4CH3), (1 aryl carbon was not detected).  2.4.6 Procedures for the Reactivity of Complex 2d with Other Reagents Reaction of Complex 2d with 1-Octene  In a 2 mL vial, complex 2d (12 mg, 0.03 mmol) was dissolved in dry d8-toluene and transfered into a J. young NMR tube. 1-octene (25 μL, 0.16 mmol) was then added. The tube was sealed and heated to 65 °C for 17 hours. The reaction was monitored by 1H and DEPT-135 13C NMR spectroscopy. In the 1H NMR spectra, product formation was monitored by the appearance of the diagnostic internal olefin signal (5.41 – 5.37 ppm, m). In the DEP-135 13C NMR spectra, diagnostic signals of the internal olefins were used, which displayed at δ  (300 MHz, d8-toluene) 132.5, 132.3, 131.5, 131.0, 130.0, 125.1, 124.1 ppm. Lit. values (500 MHz, d6-acetone): (E)-2-octene (132.4, 125.3 ppm), (Z)-2-octene (131.2, 124.3 ppm), (E)-3-octene (130.1, 132.7 ppm), (E)-4-octene (131.2 ppm).234    91   Synthesis of [Cp2Zr(I){κ1-N,O-(Ad)NC(tBu)O}] (7a). In a 20 mL vial, complex 2d (50 mg, 0.11 mmol) was dissolved in ca. 5 mL of dry toluene and then transferred to a 10 mL Schlenk bomb equipped with a stir bar. PhI (13.5 μL, 0.12 mmol) was then added. The bomb was sealed and heated to 110 °C for three days. After cooling, the reaction mixture was transferred to a 20 mL vial in a glovebox and the volatiles were removed in vacuo. Recrystallization from hot hexanes afforded the product as a yellow solid.  Yield: 29.1 mg (0.04 mmol, 46%). 1H NMR (C6D6, 300 MHz) δ (ppm) 6.02 (s, 10H, Cp), 2.09 (br m, 3H, Ad), 1.97 (br s, 6H, Ad), 1.74 (br q, 6H, Ad), 1.36 (s, 9H, t-Bu); 13C{1H} NMR (C6D6, 100 MHz) δ (ppm) 163.7 (C=O), 114.6 (Cp), 53.4 (Ad), 45.4 (Ad), 41.2 (C(CH3)3), 37.6 (Ad), 30.7 (Ad), 29.6 (C(CH3)3); MS (EI-TOF): m/z 581 [M]+, 525 [M – tBu]+, 454 [M – I]+, 220 [Cp2Zr]+; Anal. Calcd. (%) for C25H34INOZr: C, 51.53; H, 5.88; N, 2.40; Found: C, 52.41; H, 6.51; N, 2.49. Single crystal X-ray quality samples were obtained by recrystallization from a saturated solution in toluene stored at -35 °C for 24 hours.   Synthesis of [Cp2Zr(Br){κ1-N,O-(Ad)NC(tBu)O}] (7b).  In a 20 mL vial, complex 2d (100 mg, 0.22 mol) was dissolved in ca. 5 mL of dry toluene and transferred to a 10 mL Schlenk bomb equipped with a stir bar. PhBr (25.4 μL, 0.24 mmol) was then added. The bomb was sealed and heated to 110 °C for three days. After cooling, the reaction mixture was transferred to a 20 mL vial in a glovebox and the volatiles were removed in vacuo. Recrystallization from hot hexanes afforded the product as a yellow solid.  Yield: 51.9 mg (0.10 mmol, 44%). 1H NMR (C6D6, 300 MHz) δ (ppm) 6.00 (s, 10H, Cp), 2.11 (br m, 3H, Ad), 2.01 (br s, 6H, Ad), 1.82 – 1.70 (br q, 6H, Ad), 1.35 (s, 9H, t-Bu); 13C{1H} NMR (C6D6, 100 MHz) δ (ppm) 163.7 (C=O) (detected by 92  HMBC), 114.6 (Cp), 53.4 (Ad), 45.4 (Ad), 41.2 (C(CH3)3), 37.6 (Ad), 30.7 (Ad), 29.6 (C(CH3)3); MS (EI-TOF): m/z 535 [M]+; Anal. Calcd. (%) for C25H34BrNOZr: C, 56.05; H, 6.40; N, 2.61; Found: C, 55.33; H, 6.93; N, 2.74. Single crystal X-ray quality samples were obtained by recrystallization from a saturated solution in toluene stored at -35 °C for 24 hours.  Reaction of complex 2d with iodobenzene and styrene In a 2 mL vial, complex 2d (22.8 mg, 0.05 mmol), styrene (5.5 μL, 0.05 mmol) and iodobenzene (5.6 μL, 0.05 mmol) were suspended in dry d8-toluene. The solution was then transferred to a J. Young NMR tube and sealed. The reaction left at room temperature was monitored by 1H NMR spectroscopy. Formation of 3d was monitored by the methine signal at 2.62 ppm and Cp signals at 5.49 and 5.44 ppm. Formation of 7a was monitored by the Cp signal at 6.02 ppm and t-Bu signal at 1.36 ppm. The ratio of formation of 3d : 7a was measured from Cp signals.   Reaction with dibenzyl disulfide. In a 2 mL vial, complex 2d (10 mg, 0.020 mmol) and dibenzyl disulfide (8 mg, 0.023 mmol) were dissolved in dry d8-toluene. The solution was then transferred to a J. Young NMR tube, sealed, and periodically monitored by 1H NMR spectroscopy. Under inert conditions, the reaction mixture was transferred into a 2 mL vial and the volatiles were removed in vacuo. Recrystallization from toluene with a slow diffusion of pentanes at -35 °C resulted in a yellow solid identified as Cp2Zr(SBn)2. Spectral data matched literature references.222 1H NMR (C6D6, 400 MHz) δ (ppm) 7.45 (m, 4H), 7.20 (m, 4H), 7.08 (m, 2H), 5.78 (s, 10H, Cp), 4.21 (s, 4H, SCH2PH); 13C NMR (C6D6, 100 MHz) δ (ppm) 144.2, 129.2, 128.3, 127.0, 110.9, 43.4; MS (EI): 466 (M+).  93  2.4.7 Comparison of Relative Reactivity of Insertion Reaction with Styrene The hydride complex (0.05 mmol) was weighed into a 2 mL vial. A standard solution of 1,3,5-trimethoxybenzene (50 μL, 0.11 M, 0.055 mmol) was added. The solution was transferred to a J. Young NMR tube with 900 μL C6D6, followed by the addition of a standard solution of styrene in C6D6 (50 μL, 1.1 M, 0.055 mmol). The solution was mixed well and the reaction was monitored by 1H NMR spectroscopy after 3 hours at room temperature. The reaction was then heated to 50 °C for 19 hours.  2.4.8 Variable temperature van’t Hoff study for the Equilibrium of κ1- and κ2-2d Complex 2d (96 mg, 0.21 mmol) was dissolved in 3 mL of d8-toluene and 1 mL of this solution was transferred to a sealed J. Young NMR tube. The tube was inserted into a temperature controlled NMR probe and inverse-gated 13C NMR spectra were collected at a 10 K interval from 255 K to 329 K, allowing for 30 minutes for equilibration at each temperature (Data point at 298 K was not included due to instability of temperature). This measurement were repeated two more times. The relative amounts of κ2-2d / κ1-2d were determined using the integrations of the Cp C-H resonances of the respective complexes. The equilibrium constant of the reaction was calculated according to the expression:  KObs =[𝜅2  ̶𝟐𝐝][𝜅1  ̶𝟐𝐝] The plot of ln(Kobs) as a function of T-1 was fit by a line according to the expression:  ln(Kobs) =  − ∆𝐻𝑅𝑇+∆𝑆𝑅 The enthalpy and entropy of the reaction were extracted from the slope and intercept, respectively.   94  2.4.9 Kinetics Experiments These reactions were carried out on an NMR tube scale and monitored at 25 °C on a Bruker AV300 spectrometer. One equivalent of complex 2d (0.050 mmol, 200 μL of 0.25 M solution in C6D6) and 1.1 equivalent of 1,3,5-trimethoxybenzene (0.055 mmol, 50 μL of 0.11 M solution in C6D6) was added to a J. Young NMR tube with 300 μL of C6D6 and then 10 equivalents of styrene were (0.5 mmol) added.  Data points were collected every 5 minutes. Each run was repeated at least once to estimate the error of kobs. The runs were averaged, and the percent error was estimated from (kobs(max) – kobs(min)) / kobs(average).  This percent error was used to calculate absolute error.  In all cases, the percent error of rate constants was below 20%.  The ratios of kobs or  were taken using the average values.  The error on the ratios was estimated using the following formula: a = A(b/B + c/C) where A = B/C, and a, b, c are the errors on A, B, C respectively. The methine peak (δ 1.68 ppm, q, 1H) was integrated and referenced to the internal standard to determine the number of moles of product complex. As this reaction produced no detectable byproduct, it was assumed that all starting complex was converted to the inserted product. Under this assumption, the number of moles of zirconium hydride complex was calculated by taking the total number of moles of product minus the number of moles of product at a particular time. The concentration was determined using the moles of Zr─H and the total volume of the reaction. A plot of [ZrH] vs. time in seconds gave a logarithmic correlation, while a plot of ln[ZrH] vs. time in seconds produced a linear correlation which was used to estimate the rate of the reaction. Slopes and R2 values were determined using the trendline routine in Microsoft Excel.      95  Zirconium hydride complex (2d). kobs (run 1) = 5.85 × 10-4 s-1, kobs (run 2) = 5.39 × 10-4 s-1 kobs (average) = 5.62 ± 0.06 × 10-4 s-1 R2 = 0.9861 (both runs plotted in same series).  Zirconium deuteride complex (d-2d). kobs (run 1) = 2.82 × 10-4 s-1, kobs (run 2) = 2.75 × 10-4 s-1 kobs (average) = 2.79 ± 0.06 × 10-4 s-1 R2 = 0.9874 (both runs plotted in same series).  kobs (H)/ kobs (D) = 2.01(2)  2.4.10 General Procedure for Electrochemical Analysis All electrodes were fitted with a b14 septum with a 5/16” opening cut by a cork borer. Before being brought into an argon filled glove box, the working (platinum button, 2 mm diameter) and counter (glassy carbon, 3 mm diameter) electrodes were polished with 0.3, 0.1 and 0.05 μm powder polish (alumina slurry) sequentially, sonicated for 10 minutes in deionized water, and rinsed with acetone. The reference electrode (99.9% silver wire, 0.25 mm diameter) was exposed to the flame of a butane torch and wiped with a fine polish pad in order to remove the residual organic matter before being brought into the glove box with the other electrodes. The electrolyte, TBAPF6 (387 mg, 1 mmol) was dissolved in 10 mL of dry THF (0.1 mol L-1) three necked round bottom flask with b14 female joints. The electrodes were connected to the appropriate leads from the potentiostat and inserted into the necks of the flask with the counter electrode installed in the central position. Once the solution had settled, a cyclic voltammogram (100 mV s-1, -2.8 to 1.2 V, negative scan starting at 0 V) was collected to act as the baseline for the experiment. Upon successful completion of the baseline, complex 2d (22.7 mg, 0.05 mmol) was dissolved in the electrolyte/THF solution and added to the flask and further CV experiments were conducted. 96  Between each run, the flask was agitated to aid with diffusion and if a decrease in signal intensity was observed, the electrodes were wiped with a KimWipe. After completion of the set of experiments, a single crystal of ferrocene (Fc) was added to the solution and a cyclic voltammogram (100 mV s-1, -2.8 to 1.2 V, negative scan starting at 0 V) was collected for reference.  2.4.11 Crystallographic Structure Determination  All X-ray diffraction measurements were performed on a Bruker X8 APEXII CCD diffractometer at 100 K or on a Bruker DUO APEXII CCD diffractometer at 90 K with Mo Kα graphite-monochromated radiation (λ = 0.71073 Å). Data were collected and integrated using the Bruker SAINT235 software packages. Unless otherwise noted, crystallographic structure determination was as follows. Absorption correction was applied using the program SADABS.236 The structures were solved by direct methods using the programs SHELXS237 or XT237 and structure refinement was conducted based on the program SHELX.237 The structures were drawn by ORTEP-3 software.238 The suite OLEX-2 was used as integrated system for all crystallographic programs and software.239 All non-hydrogen atoms were refined with anisotropic displacement parameters. Unless otherwise noted, all H atoms were inserted in calculated positions and refined with a riding model. Hydride ligands on zirconium hydride complexes were located from residual electron density and refined with isotropic displacement parameters. Crystal data collection and refinement parameters are tabulated in Table 2-4 for zirconium hydride complexes and Table 2-5 for other zirconium complexes. The crystals of 7b form non-merihedral twins consisting of two components. Data were integrated for both twin components, including both overlapped and non-97  overlapped reflections. Data were corrected for absorption effects using the multi-scan techniques (TWINSABS240).   Table 2-4: Crystal data collection and refinement parameters for zirconium hydride complexes. Compounds 2a 2b 2c 2d 2e 4b Empirical Formula C29H33NOZr C18H26NOZr C27H37NOZr C27H37NOZr C31H39NOZr C29H35NOZr Mw 503.78 363.62 482.79 456.76 532.85 504.80 Space Group P21/c P21/n P21/n P21/c Pna21 P212121 a [Å] 11.3883(3) 13.9518(7) 11.2753(8) 13.779(4) 10.5710(9) 11.0327(14) b [Å] 11.9863(3) 8.2467(5) 16.173 (1) 14.686(4) 13.6435(11) 11.5601(15) c [Å] 18.2089(5) 15.4305(8) 13.782(1) 10.424(3) 17.7929(14) 18.672(2) α [°]       β [°] 93.4990(10) 104.166(2) 105.136(2) 90.013(6)   γ [°]       V [Å3] 2480.9(2) 1721.39(16) 2426.5(5) 2109.5(10) 2566.2(4) 2381.4(5) Z 4 4 4 4 4 4 Dcalc (g cm-3) 1.346 1.403 1.322 1.438 1.379 1.408 μ [mm-1] 0.464 0.638 0.471 0.537 0.452 0.483 Crystal Size (mm) 0.19 × 0.15 × 0.15 0.27× 0.24 × 0.20 0.32 × 0.23 × 0.19 0.31 × 0.23 × 0.04 0.23 × 0.17 × 0.14 0.32 × 0.29 × 0.15 θ range (°) 2.2 – 30.0 2.8 – 30.1 2.5 – 29.6 2.4 – 30.1 3.3 – 30.0 3.4 – 30.1 No. of reflections measured 23362 14546 54061 42682 28510 53026 No. of independent reflections 7211 5054 6841 6203 7080 7011 R1 [F2 > 2σ(F2)], wR2(F2) 0.036, 0.075 0.018, 0.050 0.012, 0.049 0.026, 0.062 0.026, 0.057 0.017, 0.042 S 1.02 1.16 1.03 1.06 1.04 1.04 Flack Parameter     -0.026(12) -0.008(8)   98  Table 2-5: Crystal data collection and refinement parameters for other zirconium complexes Compounds 3b 3c 3d 6 7a 7b Empirical Formula C37H41NOZr C35H45NOZr C33H43NOZr C33H41NOZr C25H34INOZr C25H34BrNOZr Mw 606.93 586.94 560.90 558.89 582.65 535.66 space group Pbca Pca21 P21/n P21/n P21/c P21/c a [Å] 11.7545(9) 17.450(5) 13.6258(11) 13.835(4) 11.436(4) 11.649(3) b [Å] 17.1857(14) 10.454(5) 14.3078(11) 13.798(4) 20.661(7) 20.037(5) c [Å] 29.603(2) 16.805(5) 14.5708(11) 14.512(4) 10.159(4) 10.161(3) α [°]       β [°]   107.105(2) 107.189(7) 100.111(8) 10.161(3) γ [°]       V [Å3] 5980.1(14) 3065.6(19) 2715.0(4) 2646.6(12) 2362.9(15) 2339.2(11) Z 8 4 4 4 4 4 Dcalc (g cm-3) 1.348 1.403 1.372 1.403 1.379 1.521 μ [mm-1] 0.398 0.385 0.431 0.442 1.788 2.194 Crystal Size (mm) 0.29 × 0.13 × 0.11 0.20 × 0.15 × 0.11 0.28 × 0.20 × 0.19 0.19 × 0.16 × 0.11 0.33 × 0.30 × 0.10 0.32 × 0.29 × 0.15 θ range (°) 2.5 – 30.4 2.3 – 27.0 2.8 – 30.1 2.4 – 30.1 2.6 – 29.4 2.7 – 25.7 No. of reflections measured 301348 56820 59450 45810 37402 50180 No. of independent reflections 9105 7082 7990 5417 6114 7657 R1 [F2 > 2σ(F2)], wR2(F2) 0.039, 0.085 0.035, 0.073 0.023, 0.057 0.030, 0.075 0.036, 0.078 0.044, 0.103 S 1.12 1.04 1.05 1.00 1.04 1.14 Flack Parameter  -0.02(2)     99  Chapter 3: Bis(Amidate)Bis(Amido) Titanium Complex as a Versatile Hydroamination Catalyst  3.1 Introduction  Nitrogen-containing organic molecules are ubiquitous in pharmaceuticals and agrochemicals, making the efficient construction of C−N bonds of considerable interest. In this regard, the catalytic addition of an N−H bond across an unsaturated C−C bond, known as hydroamination, is an often targeted 100% atom economic C−N bond forming reaction.67-73 For intermolecular versions of this reaction, the starting materials employed (amines, alkenes, and alkynes) are inexpensive, commercially available, and do not require the installation of activating or protecting groups. Due to the electron-rich nature of both the amine and alkene/alkyne, this reaction is particularly kinetically challenging and demands catalytic conditions to realize this desirable transformation.67, 72-73  Numerous catalysts based on elements from across the periodic table have been reported to induce hydroamination.84, 196, 233, 241-285 Notably, early transition metal systems, especially those based on group 4 metals, have been extensively reported.67, 69, 71, 79-80, 84-85, 108, 115, 233, 279-283, 286-302  The main advantages of using such group 4 metal complexes are improved cost effectiveness and low toxicity in comparison to late-transition metals. Group 4 metal complexes also show improved robustness and functional-group tolerance when compared to lanthanide- and alkaline-earth metal-based systems.67-68, 72, 196, 247-274, 303 The hydroamination reaction of amines with alkynes is well established.68, 72-73, 80, 290, 300, 304  The products of this reaction are reactive imine and enamine species, which are useful synthetic intermediates that can be used for subsequent transformations in "one-pot" procedures.69-70, 84-85, 100  136-138, 242, 244, 258, 305-316 Although the hydroamination of alkenes affords secondary and tertiary amines directly, the development of catalytic systems able to affect such transformations is more challenging.68, 108, 196, 249, 251-252, 256, 271, 276, 289, 301 Historically, aminoalkynes are typical substrates used for the hydroamination reaction, as intramolecular cyclizations are easier to achieve than the intermolecular variant.317-321 Such aminoalkynes typically yield only one regioisomer that is defined by the cyclic transition state for the reaction.  While the hydroamination of aminoalkynes has been demonstrated to be an excellent tool for annulation chemistry,70, 277, 322-324 complementary intermolecular alkyne hydroamination allows for access to desirable acyclic imines and enamines. Besides the unfavourable entropic nature of intermolecular hydroamination (Scheme 3-1), regioselectivity is also a significant challenge. Both the Markovnikov and anti-Markovnikov products are possible when terminal alkyne substrates are used. Additionally, intermolecular hydroamination with unsymmetric internal alkyne substrates could result in two regioisomeric products.  Control of regioselectivity increases the yield of the desired products and simplifies the product purification process.  This control can be achieved through catalyst development.  Late-transition metal catalyzed intermolecular-alkyne hydroamination, with the exception of one rhodium catalyst, typically affords the Markovnikov product.317, 319, 323, 325-330  While early-transition metal based catalysts generally favour the formation of the anti-Markovnikov isomer.  This change can be attributed to the differences in mechanism for product formation using these different classes of catalysts, where early-transition metal complexes typically activate the amine substrate (vide infra) and late-transition metal complexes typically activate the alkyne substrate. For example, π-acidic gold(I) and cationic gold(III) hydroamination catalysts excel at the 101  activation of alkynes, which allows for the addition of the amines331-334 and due to electronic factors, Markovnikov addition is preferred.335   Scheme 3-1: General intermolecular hydroamination of terminal alkynes.  Early-transition metal complexes typically catalyze hydroamination by the activation of an amine to form an imido-metal moiety.  This method of activation is generally invoked for titanium-based catalysts.80, 300 Although the catalytic cycle (Scheme 3-2) was originally proposed for the zirconium catalyzed hydroamination of alkynes with bulky primary amines,80, 300 the catalytic cycle has been shown to be operational for titanium catalysts as well.71, 289, 336 A number of studies have proposed that following the generation of the catalytically active titanium-imido species, a reversible [2+2] cycloaddition of the alkyne forms an azatitanacyclobutene intermediate.71, 289, 336  Two subsequent protonolysis events with a primary amine on the azatitanacyclobutene intermediate regenerate the active imido catalyst and release the organic product.  As the titanium-imido complex is the active catalyst, secondary amines are not able to form such intermediates, and thus cannot undergo hydroamination using catalysts which rely on this mechanism. This proposed mechanism has also been supported by both kinetic71 and computational studies.289 Furthermore, discrete titanium-imido complexes have been reported and are known to be efficient 102  hydroamination catalysts.84, 233, 288-289, 337-341 However, the reactive nature of such imido species render their handling more difficult and the use of precatalysts that generate imido species in situ is typically preferred.    Scheme 3-2: General mechanism of titanium catalyzed hydroamination.  Although many examples of both zirconium and titanium complexes as hydroamination catalysts have been reported,67, 69, 71-73, 78-80, 84-85, 108, 115, 233, 279-283, 286, 288-300, 302, 317, 323, 342-344 these group 4 metal complexes can undergo dimerization via imido intermediates in the presence of primary amines, which result in catalyst deactivation. Consequently, there are fewer examples using the metal of larger ionic radius, zirconium, as efficient catalysts for intermolecular hydroamination of alkynes with primary amines.78, 80, 300, 345 Titanium-based systems are more prevalent for the intermolecular hydroamination of alkynes with primary amines.  Titanium is also 103  very abundant and the typically decomposition product, TiO2, is benign to nature, where TiO2 is generally considered to be biologically and chemically inert. A brief summary of the development of titanium catalyzed hydroamination is presented herein. As there are many examples of titanium hydroamination catalysts in the literature, only those relevant to the development of an anti-Markovnikov selective, generally applicable catalyst (wide substrate scope) will be discussed.  Although the imine or enamine products are valuable synthetic intermediates, their isolation and purification can be difficult due to their susceptibility to hydrolysis. Determination of isolated yields can be achieved by a subsequent quantitative hydrolysis or reduction with hydride sources, such as lithium aluminum hydride, sodium borohydride, or sodium cyanoborohydride.  Alternatively, yields can be obtained from integration of the 1H NMR spectrum of the imine product itself.   In 1999, Doye et al. reported the first example of intermolecular hydroamination using a titanium catalyst.290 In this report, the readily available and inexpensive dimethyltitanocene (11a) was used for intermolecular hydroamination of internal alkynes. Reaction of internal alkynes and arylamines and bulky alkylamines in the presence of 11a afford high yields of the corresponding amine or carbonyl products. These amines are generally well tolerated by titanium hydroamination catalysts.79, 84, 290, 295, 317, 323, 346 However, non-bulky amines, such as hexylamine or benzylamine, afforded very low yields of the corresponding amine or carbonyl products. These non-bulky amines are a challenging class of substrate for titanium catalyzed hydroamination and typically affords low yields and poor regioselectivity.79, 84, 290, 295, 317, 323, 346 Both symmetric and electronically biased unsymmetric internal alkynes, such as 1-phenyl-1-propyne, were shown to be effective substrates and only one regioisomer, the anti-Markovnikov product, was observed.  Terminal alkynes were also reacted with arylamines using 11a, but considerably lower yields were 104  obtained. A full summary of modifications and scope of application of 11a for intermolecular hydroamination is presented by Doye in their review.67  It is important to note that increasing the steric bulk around the cyclopentadienyl ligands by using Cp*2TiMe2 (11b) allows for hydroamination with non-sterically bulky alkylamines (Scheme 3-3);347 however, regioselectivity is lost (Scheme 3-4).347   Scheme 3-3: Hydroamination of butylamine and diphenylacetylene in the presence of 11.290,347   Scheme 3-4: Hydroamination of hexylamine and 1-phenyl-1-propyne in the presence of 11b.347  By replacing the cyclopentadienyl ligands of 11a with indenyl ligands (12), a broader scope of reactivity was achieved.295 Using 12 the hydroamination of internal and terminal alkynes with aryl and bulky alkylamines was effective and afforded good yields of the corresponding secondary amines upon reduction. Again, the use of electronically biased alkynes or bulky alkylamines resulted in the formation of the anti-Markovnikov isomer with moderate to excellent selectivity, while arylamines gave the Markovnikov isomer preferentially. Furthermore, the hydroamination 105  of less sterically bulky alkylamines was found to be effective only when the amine was slowly added to the reaction mixture (Scheme 3-5).  It has also been noted by Esteruelas et al. that half-sandwich titanocene with an additional donor pendent on cyclopentadienyl or indenyl ligands improves the reactivity of the hydroamination of particular substrates. A comparative summary of these half-sandwich titanium complexes is given in their article published in 2007.346   Scheme 3-5: Regioselective hydroamination of benzylamine in the presence of 12.295  By employing Rosenthal's titanocene complex (13a), Beller et al. were able to catalyze the hydroamination of internal and terminal alkynes with both aryl and alkylamines.79  This catalyst was reported to have a larger scope of substrates than 11, even tolerating hydrazines for the analogous hydrohydrazination reaction.  As well, excellent anti-Markovnikov selectivity was observed for the hydroamination of terminal alkylalkynes with bulky alkylamines.  For less bulky alkylamines, the anti-Markovnikov product was still preferred, but with reduced selectivity and yield.  Using 13a and arylamines, the regioselectivity is reversed and the Markovnikov product is preferred.  This reversal of regioselectivity can also be achieved with alkylamines when the more sterically bulky Cp* version of Rosenthal's titanocene (13b) is employed (Scheme 3-6).336  106   Scheme 3-6: Control of regioselectivity of hydroamination using Cp ligands.336  Moving away from titanocene based systems, amido-titanium complexes have also been found to be active intermolecular hydroamination catalysts. The homoleptic titanium-amido complex, tetrakis(dimethylamido)titanium (14) is an active hydroamination catalyst.77  Under mild reaction conditions (10 mol%, 75 °C), 14 can catalyze the hydroamination of 1-hexyne with a broad range of arylamines with varying degrees of regioselectivity favouring the Markovnikov product.  However, when non-sterically bulky alkylamines are used, very limited reactivity is observed.  Odom et al. developed a titanium-amido complex bearing a di(pyrrolyl-α-methyl)-methylamine (dpma) ligand, 15 (Figure 3-1), which was able to facilitate hydroamination with both bulky and non-bulky alkylamines without the need of slow addition.291  The use of complex 15 typically gave good regioselectivity for the Markovnikov isomer. However, the use of electronically-biased alkynes, such as 1-phenyl-1-propyne, result in the formation of the anti-Markovnikov products. Odom et al. later reported the use of a titanium dipyrrolylmethane complex (16) as a very fast hydroamination catalyst.81  Under a comparative study, it was found that 16 was an order of magnitude faster than 13a and 15 (Figure 3-1).  By changing the binding motif of one of the linked pyrrole ligands and significantly lowering the electron density at the metal center, 107  17a and b are to date, the fastest hydroamination catalysts reported for this reaction.299, 348  However, the reported substrate scope of these catalysts is limited to only simple aryl and alkyl substituted amines and alkynes and requires a large excess of amine.    Figure 3-1: Rate constants of hydroamination for several titanium catalysts.294, 299  Beller et al. have demonstrated control of regioselectivity by varying the steric environment around the metal center with the use of aryloxide ligands.293, 349  By employing these in situ generated catalyst systems (18, 19), regioselective hydroamination of alkylalkynes with alkylamines is achieved (Scheme 3-7).  These precatalysts also exhibited broad functional group tolerance, as alkynes with silyl ethers, silyl-protected alkynes, and tertiary amines are tolerated. 108  However, regardless of which catalyst is used, the hydroamination with arylamines affords the Markovnikov product preferentially.   Scheme 3-7: Control of regioselectivity of hydroamination using aryloxo ligands.349  In 2003, the Schafer group reported a bis(amidate)bis(amido) titanium complex (20) for intermolecular terminal alkyne hydroamination (Scheme 3-8 and Figure 3-2).85  Complex 20 is easily synthesized from inexpensive and commercially available starting materials in two synthetic steps on a multigram scale.  First, the amide proligand 21 is synthesized from benzoyl chloride and 2,6-diisopropylaniline in the presence of trimethylamine. Complex 20 is afforded from the protonolysis reaction of tetrakis(dimethylamido) titanium with 2 equiv. of amide 21. Precatalyst 20 displays outstanding selectivity for the anti-Markovnikov product and more impressively, it can be used with all primary amine substrates, even benzylamine and allylamine, without any modification in synthetic protocol. Furthermore, good functional group tolerance has been established. For example, protected alcohols, ethers, and esters can all be incorporated into 109  substrates that are suitable for hydroamination with precatalyst 20. As such, this commercially available271 bis(amidate)bis(amido) titanium complex 20 is a broadly useful precatalyst for regioselective alkyne hydroamination.       Scheme 3-8: Synthesis of bis(amidate)bis(amido)titanium precatalyst 20.  Figure 3-2: ORTEP diagram of the structure of complex 20 at 50% probability.  110  The broad applicability is important as it allows for subsequent reactivity to access desired products, either in terms of sequential reactivity for formation of key moieties or its use in natural product synthesis. Hydroamination has recently received significant attention in terms of its synthetic use, particularly in the field of annulation chemistry.70, 277 For example, intramolecular alkyne hydroamination has been utilized in the key step for the total synthesis of (−)-crambidine,350 (±)-monomorine I,351 (+)-pseudodistomin D,352 nupharamine,353-355 porantheridine,353-355 nitidine,356 (+)-saxitoxin,357 and (+)-terreusinone.324  In each of these cases, late-transition metal complexes were employed to catalyze hydroamination, in part due to the readily accessible nature of these complexes and to their ease of handling. Additionally, late-transition metal hydroamination catalysts have been utilized in the synthesis of pyrroles, 315, 358-361 indoles,362-371 and other N-heterocycles. 29, 70, 242, 328, 362, 372-382 On the other hand, the synthetic application of hydroamination with early transition metal complexes has been largely overlooked.  Doye and co-workers reported the enantioselective synthesis of (+)-(S)-Laudanosine and (-)-(S)-Xylopinine. These naturally occurring tetrahydroisoquinolines (THIQ) were synthesized by an asymmetric reduction of the resulting imine from an intramolecular hydroamination.383 Odom and coworkers have synthesized the natural alkaloid withasomnine in 6 steps using a key Ti catalyzed multicomponent coupling reaction that includes a hydroamination reaction (Scheme 3-9).384   111   Scheme 3-9: Synthesis of withasomnine using a Ti catalyzed hydroamination as a key step.   Using a similar tactic of multicomponent reactions with hydroamination, Odom and coworkers have developed effective routes to generate hydropyridines,385 pyrroles,305 quinolines,375 pyrimidines,386 and pyrazoles.384  Indole synthesis with group 4 catalyzed hydroamination has also been widely studied, and coupled with Fischer indole synthesis.387 The Schafer group has previously shown that complex 20 is also able to facilitate the synthesis of N-heterocycles using sequential reactivity.  Another benefit of a broadly applicable hydroamination catalyst is its availability to be used to synthesize novel materials, in particular amine-containing polymers. Amine-containing polymers are important for a broad range of industrial applications including compatibilizers for polymeric blends,388-389 coatings for adhesion of polymers to other surfaces,389,390 fillers in composite materials,391 CO2 uptake materials,392-393 catalytic materials,394-396 water purification,397 supports for ion-exchange chromatography,398 biomedical materials,399-400 and as antimicrobial materials.401 One of the most well-known amine containing polymers is polyaniline,402 which has been extensively investigated for its electronic properties.403-404  Other types of amine containing polymers are synthesized by ring-opening polymerization of N-protected aziridines,405 ROMP of amine functionalized monomers,390, 406-412 or the nitrogen 112  is installed during post-polymerization processing.413 These methods have inherent drawbacks that limit the efficiency of the synthesis or structural possibilities of the polymer. Specifically, N-protected aziridines are often difficult to synthesize and purify and they also limit the structure of the backbone to having two methylene units per nitrogen. On the other hand, reported ROMP monomers that result in an amine containing polymer required multi-step syntheses (3 or more steps).171, 184-190  Furthermore, typical ROMP catalysts and reaction conditions are not suitable with free N-H bonds.  Thus both methods typically required post-polymerization deprotection to N-H bonds. However, the control on the degree of funcationlization of the polymer is limited during post-polymerization processes.  As such, hydroamination can offer an alternative synthetic route to polymers with nitrogen in the backbone. Specifically, the hydroamination of an alkynylaniline would result in a polymer consisting of enamines that are resonance stabilized. Such poly(alkynylanilines), although unknown, are structurally related to poly(p-phenylene vinylene) and polyaniline, both of which are known to be conductive polymers with desirable physical properties.12  To the best of our knowledge, hydroamination has only been reported once for the attempted synthesis of such polymers, and this example used the commercially available titanium tetrakis(dialkylamido) catalyst with limited success.19  Complex 20 with its a broader scope of reactivity and excellent regioselectivity should be better suited for this desirable application.   3.1.1 Scope of this Chapter This chapter describes the extended substrate scope of complex 20 and the synthetic application of complex 20 in tandem reactions and oligomerization.  First, a comprehensive comparison of complex 20 to other benchmark titanium catalysts will be presented. The extended substrate scope, including protected propargyl alcohol and internal alkynes, with complex 20 will 113  be discussed.  To facilitate versatile benchtop use, complex 20 can be prepared in situ using simple syringe techniques with limited reduction in catalytic efficiency. In addition, complex 20 can be prepared, stored, and used as a standard solution in toluene.  These observed reactivity trends will be discussed in terms of the mechanism of this reaction with complex 20, where such trends are consistent with a [2+2] cycloaddition mechanistic proposal with a turnover limiting associative protonolysis step.71  Synthetic applications of complex 20 for tandem reactions will be presented; including a hydroamination/hydrosilylation reaction sequence, a hydroamination/isomerization reaction sequence and a hydroamination/alkynylation reaction sequence. Finally, the use of complex 20 to afford N-containing oligomers will be shown.   3.2 Results and Discussion  3.2.1 Bis(amidate)bis(amido) Titanium Complex for Hydroamination   Bis(amidate)bis(amido) titanium complex 20 has been previously reported by the Schafer group to be a broadly applicable and regioselective titanium precatalyst for alkyne hydroamination.84-85  Not only can this complex catalyze hydroamination with benchmark substrates, it is able to tolerate more difficult substrates such as benzylamine and even some oxygenated substrates (vide infra).  Furthermore, the synthesis of complex 20 is easily achieved (vide supra).  Complex 20 is an orange powder that is indefinitely stable under inert conditions. Like most other early transition metal complexes, complex 20 is moisture sensitive and will decompose upon exposure to water, affording white precipitates.  However, complex 20 is fairly robust as it is able to tolerate ethereal solvents and oxygenated substrates, which can be difficult for Ti complexes due to their oxophilic nature.  Consistent with other Ti hydroamination catalysts, complex 20 is typically employed in 5 mol% loading at 65 °C for 24 hours, particularly for the 114  benchmark terminal alkynes and primary alkylamines.  Following hydroamination, the aldimine product or an aldimine-enamine mixture is produced. The resulting mixture is then quantitatively reduced with a stoichiometric hydride reductant (such as LiAlH4 or NaBH4) to the secondary amine product to facilitate isolation and purification.  In all cases, spectroscopic monitoring of these reactions shows only the formation of the anti-Markovnikov hydroamination product and no Markovnikov intermediates could be detected.    In a direct comparison with the other notable hydroamination catalysts mentioned in the introduction, 20 demonstrates excellent reactivity and anti-Markovnikov selectivity with both simple and more challenging substrates (Table 3-1 – 3-4). Upon comparison of the different catalysts with 1-phenyl-1-propyne and aniline (or p-toluidine) as hydroamination substrates, 20 affords similar yields (under comparable reaction conditions) to most other catalysts (Table 3-1).  Only 15 and 16 are more amenable for this substrate combination, where similar yields were obtained under much milder reaction conditions.   Moving to terminal alkynes, where regioselectivity can be more of a challenge, 20 offers excellent reactivity and regioselectivity.  For the hydroamination of phenylacetylene and aniline (Table 3-2), using 20, a high yield of the corresponding amine is obtained with mild reaction conditions.  Using this substrate combination, 20 is the most selective towards the anti-Markovnikov isomer.  Here, other catalysts including 15 give Markovnikov selectivity and only 12 shows selectivity for the anti-Markovnikov product, but with considerably less selectivity than 20. Removing the strong electronic influence of the phenyl substituent of the alkyne, anti-Markovnikov selective hydroamination with 1-hexyne (or 1-octyne) is more challenging (Table 3-3). Indeed the hydroamination of 1-hexyne (or 1-octyne) and aniline affords the Markovnikov product in all other reported examples.  Benzylamine (Table 3-4) is another benchmark substrate 115  for hydroamination, as this sterically unhindered amine typically affords poor yields and low regioselectivities.  When compared to other catalysts, 20 is able to catalyze the reaction of 1-hexyne (or 1-octyne) with benzylamine with high yields at modest temperatures with low catalyst loading, and only the anti-Markovnikov product is isolated.  Table 3-1: Hydroamination of 1-phenyl-1-propyne and aniline (or p-toluidine) catalyzed by selected titanium complexes.  Entry (ref.) R Cat. (mol %) Temp (°C) Time (hr) Yield (%)a (M:AM) 1290 Ph 11a (3) 100 40 99 (1:>49) 2347 p-tol 11b (6) 114 24 95b (1:31) 3295 p-tol 12 (5) 105 24 99b (1:49) 479 Ph 13a (3) 140 24 98 (1:>49) 5291 Ph 15 (10) 75 144 99 (1:24) 681 Ph 16 (5) 50 6 83 (1:50) 7293 Ph 18 (10) 130 48 97 (1:>49) 884 Ph 20 (10) 110 24 >98b (1:>49) a Yield determined by GC of corresponding ketone or aldehyde following hydrolysis. b Isolated yield of the corresponding amine following reduction.   116  Table 3-2: Hydroamination of phenylacetylene and aniline (or p-toluidine) catalyzed by selected titanium complexes.  Entry (ref.) R Cat. (mol %) Temp (°C) Time (hr) Yield (%)a (M:AM) 1295 p-tol 12 (5) 75 6 77b (1:4.5) 277 Ph 14 (10) 75 2 49 (2:1) 3291 Ph 15 (10) 75 8 38 (2:1) 481 Ph 16 (5) 25 0.08 41b (3.6:1) 5293 Ph 18 (10) 115 24 72 (>49:1) 6349 Ph 19 (10) 100 24 86 (1.9:1) 784 Ph 20 (10) 25 24 83b (1:>49) a Yield determined by GC of corresponding ketone or aldehyde following hydrolysis. b Isolated yield of the corresponding amine following reduction.    117  Table 3-3: Hydroamination of 1-hexyne (or 1-octyne) and aniline catalyzed by selected titanium complexes.  Entry (ref.) R Cat. (mol %) Temp (°C) Time (hr) Yield (%)a (M:AM) 179 n-Bu 13a (5) 100 24 80 (3:1) 277 n-Bu 14 (10) 75 2 90 (3:1) 3291 n-Bu 15 (10) 75 6 90 (>50:1) 481 n-Bu 16 (5) 25 0.08 57b (40:1) 5293 n-Hex 18 (10) 100 24 99 (3.5:1) 6349 n-Hex 19 (10) 100 24 86 (1.9:1) 784 n-Bu 20 (10) 25 24 62c (1:1.6) a Yield determined by GC of corresponding ketone or aldehyde following hydrolysis.  b Isolated yield of imine by distillation. c Isolated yield of the corresponding amine following reduction.    118  Table 3-4: Hydroamination of 1-hexyne (or 1-octyne) and benzylamine catalyzed by selected titanium complexes.  Entry (ref.) R Cat. (mol %) Temp (°C) Time (hr) Yield (%)a (M:AM) 1336 n-Hex 13a (10) 120 24 46 (1:4.6) 2336 n-Hex 13b (10) 120 24 51 (4.3:1) 377 n-Bu 14 (10) 75 8 17 (5:1) 4291 n-Bu 15 (10) 75 48 71 (>50:1) 5293 n-Hex 18 (10) 100 24 99 (1:4) 6349 n-Hex 19 (10) 100 24 72 (1:6.1) 784 n-Bu 20 (5) 65 24 88b (1:>49) a Yield determined by GC of corresponding ketone or aldehyde following hydrolysis. b Isolated yield of the corresponding amine following reduction.    To draw a direct comparison of the rate of catalysis of 20 to available literature data, the observed rate constant of the hydroamination of 1-phenylpropyne with excess aniline was determined.  Using the same conditions as Odom et al.,299, 348 the kobs of this reaction employing 20 was found to be 44 × 10-6 s-1.  Although 20 is an order of magnitude slower than the fastest hydroamination catalysts 15 and 16 (198 – 696 × 10-6 s-1), the observed rate for 20 is comparable to most other systems that were measured by Odom and coworkers (13a, 14 and 17; 20 – 76 × 10-6 s-1).77, 291    119  3.2.1.1 Expansion of Substrate Scope  Besides having comparable reactivity and better regioselectivity than other Ti hydroamination catalysts, complex 20 has a broad substrate scope. Complex 20 can not only tolerate hydrocarbon substrates but also a wide range of functional groups.  As shown in Table 3-5, good yields of the secondary amine products (22a-e) can be obtained in all cases.  Here, the reaction conditions for hydroamination with complex 20 were chosen for consistency and could be further optimized for select substrate combinations.  For example, the reaction of benzylamine and 1-hexyne (Table 3-5, entry 3) in the presence of complex 20 required only 12 hr to go to completion, as noted by monitoring the reaction by 1H NMR spectroscopy. Thus, product decomposition with extended reaction times was not observed.   Tert-butylamine is a commonly used substrate for regioselective alkyne hydroamination as the favourable steric bulk of the amine often translates to higher yields and better anti-Markovnikov selectivity.295, 336, 349  In previous publications, we noted that complex 20 is able to afford the anti-Markovnikov product not only for tert-butylamine, but also for other amines including benzylamine with no need to modify reaction conditions.84-85 We have found that precatalyst 20 is also able to tolerate other amine substrates such as allylamine. To the best of our knowledge, precatalyst 20 is the only complex reported to promote hydroamination with allylamine.136, 138, 316  This provides a useful handle for further synthetic elaboration of the amine product.  Catechol derivatives, such as 3,4-dimethoxyphenethylamine are known to coordinate to Lewis acidic metal centers;414-415 however, this deactivation pathway was not observed with complex 20 and illustrates the functional-group tolerance of this system. The tolerance of complex 20 to secondary amines was investigated. Reaction of 1-hexyne with N-benzyl-1,2-ethylenediamine in the presence of 5 mol% of complex 20 (Scheme 3-10) resulted in the formation 120  of a mixture of products as observed by 1H NMR spectroscopy. Initial hydroamination was observed by 1H NMR spectroscopy via the diagnostic imine proton signal. However, reduction of the reaction mixture with NaBH4 did not result in the formation of the predicted diamine product.  Following column chromatography only N-heterocycle 23 was obtained as a mixture with the proligand. GC-MS of the crude mixture displayed signals with masses that are related to the reduced diamine product and N-heterocycle 23. Unfortunately, isolation of the diamine was not possible. N-heterocycle 23 is proposed to be from the intramolecular nucleophilic cyclization of aminoimines, which has been observed previously.416     Table 3-5: Hydroamination of 1-hexyne and alkylamines by complex 20.a  121   Scheme 3-10: Hydroamination of 1-hexyne and N-benzyl-1,2-ethylenediamine in the presence of complex 20.  Next, the alkyne substrate scope was explored and a challenging substrate, benzylamine, was selected for this investigation.  As shown in Table 3-6, an extensive array of alkynes react regioselectively with benzylamine to give the anti-Markovnikov products (24a-l).  Entries 1-3 and 5-8 in Table 3-6 have been previously published by the Schafer group.84-85 Phenylacetylene is known to form the anti-Markovnikov product in Group 4 hydroamination catalysis.77, 81, 291, 293  Indeed this was also the case for complex 20 as the desired regioisomer was obtained in excellent yield (Table 3-6, entry 1), using a similar protocol that was described above. Due to the choice of using a challenging amine substrate, benzylamine (1.2 equiv.) was added with a slight excess. It was found that increasing the steric demands of the substituent of the terminal alkyne does not affect regioselectivity (Table 3-6, entries 2 & 3). These results show that precatalyst 20 can accommodate steric bulk on both the amine and alkyne partners, although sluggish reactivity was observed with t-butyl substituted alkyne (Table 3-6, entry 3).  Most importantly, a broad range of functionalized terminal alkynes undergo hydroamination to give only the anti-Markovnikov amine products 24 c−k in good to excellent yields (72 − 93%, Table 3-6, entries 4 − 12) after reduction of the imine/enamine intermediates. Notably, challenging protected propargyl alcohols and protected propargyl amines can be used as substrates with benzylamine. When standard reaction conditions were employed, catalyst decomposition was observed. As such, reduced reaction temperatures (room temperature) was used in an attempt to suppress catalyst decomposition. To 122  ensure completion of the reaction, higher catalyst loadings (10 mol%) were used.417 Both benzhydryl and silyl protected propargyl alcohols are well tolerated (Table 3-6, entries 9 − 11). It has been previously shown that complex 20 is able to facilitate the reaction of propargyl amine protected as a diphenylmethinimine, with tert-butylamine or iso-propylamine as monitored by 1H NMR spectroscopy.85 Here, protected propargyl amine is reacted with benzylamine in the presence of complex 20, where following global reduction, the diamine was afforded in 79% yield (Table 3-6, entry 12). One limitation of this alternative protocol is that phenyl O-substituted proparyl alcohol was not tolerated as formation of the desired product was not observed. Preliminary results suggest that this substrate results in catalyst decomposition.   123  Table 3-6: Hydroamination of benzylamine and terminal alkynes catalyzed by complex 20.a  The hydroamination of terminal alkyl alkynes with aromatic amines is also of interest and, as described earlier, these substrates typically afford the Markovnikov product preferentially.67, 293, 295, 297, 336, 349 Using the general protocol described above (5 mol% 20, 65 °C) with aniline as a 124  substrate results in complex product mixture as observed by 1H NMR spectroscopy.  Specifically, when phenylacetylene and aniline were reacted at 65 °C for 24 hr, multiple products were observed. Aniline is known to be a highly reactive substrate in hydroamination and can be used at ambient temperature with some catalyst systems.81 In order to reduce the unwanted side reactivity, a variety of arylamines and terminal alkynes were reacted at room temperature (Table 3-7).  Subsequent reduction generally afforded the corresponding secondary amine product in moderate to high yields (25a-f, 62 − 83%). Good regioselectivity for the anti-Markovnikov product was observed when aniline was reacted with phenylacetylene or TBDMS protected propargyl alcohol (Table 3-7, entries 1 and 2). However, when a linear alkylalkyne such as 1-hexyne was used, selectivity was diminished, although the anti-Markovnikov product remains the major regioisomer (Table 3-7, entry 3).  To the best of our knowledge, complex 20 is the only system reported for accessing the anti-Markovnikov product as the major product with such linear alkyl substituted substrates with aryl amines. Bulky 2,6-dimethylaniline can be used for hydroamination, although higher reaction temperatures were required, presumably due to the increased steric demand of this starting material.  Notably, exclusive anti-Markovnikov selectivity was achieved with this bulky substrate with electronically biased phenylacetylene (Table 3-7, entry 4).  However, only the Markovnikov product was observed when 1-hexyne and protected propargyl alcohol were used with this bulky substrate (Table 3-7, entries 5 and 6).  This complete change in regioselectivity is proposed to result from a turnover limiting associative protonolysis step during the catalytic cycle (vide infra).  125  Table 3-7: Hydroamination of terminal alkynes and arylamines catalyzed by complex 20.a    Internal alkynes have also been examined as substrates for hydroamination with complex 20 (Table 3-8).  Such substrates are more challenging for this sterically bulky catalyst.  Thus, arylamines were investigated first, due to their increased reactivity. These more challenging hydroamination reactions require 10 mol% catalyst loading and elevated temperatures of 110 °C.  126  While these temperatures are higher than those presented previously in this work, this temperature is consistent with other state-of-the-art literature protocols.67, 73, 295   The hydroamination/reduction sequence of symmetric and unsymmetric internal alkynes with aniline affords 26a−c in high yields (Table 3-8, entries 1 − 3).  Symmetric alkynes are consistently observed to be more challenging substrates due to a lack of bond polarization,291, 301, 343, 418 but are still tolerated by 20.  The imine-enamine mixture from the reaction of aniline and diphenylacetylene required the use of H2 and Pd/C to quantitatively reduce the mixture.  Similar to other related catalysts, the use of an unsymmetric alkyne, 1-phenyl-1-propyne, only gave the anti-Markovnikov isomer.79, 295 However, excellent regioselectivity is not limited to alkynes with electronic biases. The reaction of a dialkyl substituted alkyne with a bulkier isopropyl group incorporated on one side and methyl on the other with para-methoxyaniline (Table 3-8, entry 4) resulted in only one isolable product in good yield (26d, 76%). This result suggests that steric factors effectively control the regioselectivity achieved with complex 20.  Complex 20 is also able to catalyze hydroamination with pentafluoroaniline, which has been noted to be a difficult substrate for this reaction due to the large electron-withdrawing effects of the aryl substituent (Table 3-8, entry 5).290 Furthermore, regioselective reactivity is not limited to arylamines as even benzylamine can be used for the regioselective hydroamination of internal alkynes. Here, with these less reactive amines, elevated temperatures and longer reaction time were required when non-polar diphenylacetylene was used (Table 3-8, entries 6 − 8). These investigations were undertaken in collaboration with a former graduate student, Dr. Jason Bexrud, who prepared compounds 25c, d, f and 26a, d. 127  Table 3-8: Hydroamination of internal alkynes by complex 20.a   The reaction of a sterically symmetric but electronically unsymmetric diarylacetylene, (4-methoxyphenyl)phenylacetylene, with aniline under these reaction conditions was successful but loss of regioselectivity was observed (Scheme 3-11). Upon reduction using H2 and Pd/C, an inseparable mixture of regioisomers 27 was isolated in a 1 : 2 ratio as determined by quantitative 13C NMR spectroscopy. By comparing the chemical shifts to known literature examples,419 the major regioisomer was identified as the product where the aniline addition occurred α- to the more electron-rich arene. Additionally, the reaction of (4-(trifluoromethyl)phenyl)phenylacetylene with 128  para-methoxyaniline was successfully facilitated by complex 20 (Scheme 3-12), yielding a mixture of regioisomers 28 in a 2.1 : 1 ratio as determined by quantitative 19F NMR spectroscopy. To assign which regioisomer is formed preferentially, partial separation was achieved by column chromatography. X-ray diffraction studies were then utilized to determine the regiochemistry of compound 28i. Single crystals of compound 28i suitable for X-ray diffraction studies were grown from a solution in CDCl3 as the DCl salt, presumably from adventitious DCl from the solvent. With this substrate combination, the major isomer was also the product where the aniline derivative addition occurred closer to the more electron-rich arene. These results suggest the observed regioselectivity is influenced by some electronic factors; however, they only play a role in the absence of overriding steric factors.     Scheme 3-11: Hydroamination of (4-methoxyphenyl)phenylacetylene with aniline catalyzed by complex 20. 129   Scheme 3-12: Hydroamination of (4-(trifluoromethyl)phenyl)phenylacetylene with para-methoxyaniline catalyzed by complex 20.  Figure 3-3: ORTEP diagram of compound 28i as the DCl salt at 50% probability. All hydrogens except for H1n and H2n have been omitted for clarity. The minor components of the disordered CF3 moiety are omitted for clarity.  130  3.2.1.2 Discussion of Mechanism  Detailed mechanistic studies with Group 4 metal complexes for alkyne hydroamination have been reported by several groups.71, 288 In the case of titanium, the most widely accepted mechanism involves a catalytically active imido-titanium complex 29 (Scheme 3-13).  Computational calculations by Bergman and Straub suggested that [2+2] cycloaddition of 30 (step A) could be the turnover-limiting step; however, the authors also discuss the possibility of a turnover-limiting protonolysis step that would proceed by an associative mechanism.289  Kinetic studies by Doye and coworkers suggested that the protonation of the azacyclobutene 30 (step B) is slow compared to the retro-cycloaddition of 30.71    Scheme 3-13: General mechanism of bisamido group 4 catalyzed hydroamination.  131  In our previous investigations, we demonstrated that an imidotitanium variant of 20 showed catalytic activity comparable to that of complex 20.84  Furthermore, complex 20 cannot catalyze hydroamination with secondary amine substrates.84  These results suggest that our system follows the same mechanistic pathway as these other Group 4 catalysts.  Efforts to probe this catalytic system using computational methods have been complicated by multiple equilibria that must be considered due to the known hemilability of the amidate ligands.420  However, in a previous kinetic isotope effect experiment, the hydroamination reaction with deuterium-enriched t-butylamine (>95% d incorporation by integration of the 1H NMR spectrum) has shown a primary kinetic isotope effect of 3.40 ± 0.15.184 This observation suggests that hydroamination with complex 20 cannot invoke a turnover-limiting [2+2] cycloaddition and instead, the protonolysis of the metallacyclic intermediate would be turnover limiting.  Analogous to this proposal, detailed kinetic investigations of alkene hydroamination with a zirconium analogue of 20 are also consistent with a protonolysis event being turnover limiting.108  With a rapid and reversible [2+2] cycloaddition and a turnover-limiting protonolysis step, as previously presented by Doye, the Curtin-Hammett principle applies for determining regioselectivity in the reaction of alkyne hydroamination.71 Presuming protonolysis proceeds via an associative mechanism, we attribute the excellent substrate scope and anti-Markovnikov selectivity, even when more challenging arylamines are used, to the flexible steric environment provided by the amidate ligand, which can accommodate the more sterically demanding anti-Markovnikov metallacyclic intermediate.  However, when excessively sterically hindered amines, such as 2,6-dimethylaniline, are used, Markovnikov selectivity is observed.  This change in regioselectivity would put the bulky substituent of the alkyne away from the sterically demanding coordinated 2,6-dimethylaniline in the proposed transition state for the turnover-limiting associative protonolysis step (30 to 31).  132  3.2.1.3 Improved Protocol While complex 20 displays a promising scope of reactivity and functional group tolerance, the air and moisture sensitivity of this crystalline material limits the use of this commercially available precatalyst271 and it is preferably stored and handled using a glovebox.  However, the facile synthesis of complex 20 from the addition of 2 equivalents of the easily prepared amide proligand 21 to a solution of commercially available Ti(NMe2)4 in toluene85 illustrates that this catalyst system could be easily assembled in situ using simple syringe techniques. Table 3-9 shows the comparison of the in situ prepared complex 20 in a variety of reactions on NMR tube scale.  We were delighted to observe that the use of in situ generated complex was comparable to the use of isolated complex 20 in all cases (Table 3-9, Entries 1 – 3).  The modestly reduced yields reported here are due to the small scale of the reaction and not a loss in catalytic activity.  Most importantly, the scope of reactivity, as well as the excellent regioselectivity for the anti-Markovnikov product was preserved when the in situ precatalyst was used (Table 3-9, Entries 4 & 5).  Using this method of precatalyst generation, the use of a glovebox can be completely avoided. 133  Table 3-9: Comparison of crystalline precatalyst 20 and in situ generated complex 20.a   When developing catalysts for application in synthesis, one must develop systems that are amenable to scale-up.  Scheme 3-14 shows that these simple syringe techniques under an inert atmosphere can be used in a representative hydroamination reaction of phenylacetylene with benzylamine on multigram scale.  On this scale column chromatography can be avoided.  Thus, after reduction with NaBH4 and isolation of the free amine using a back extraction protocol, product 24a was obtained in 77% yield (3.01 g).  This example demonstrates the practicality and versatility of this easy to use and broadly applicable catalytic system for the synthesis of secondary amines from alkynes and primary amines.   134   Scheme 3-14: Precatalyst 20 prepared in situ for multigram synthesis and column-free isolation of 24a.   To further facilitate bench-top use, a standard solution of complex 20 can be utilized. A standard solution is made from simply mixing 2 equivalents of proligand and 1 equivalent of Ti(NMe2)4 in toluene overnight in a sealable Schlenk flask. This standard solution is then delivered to the reaction mixture using simple syringe techniques under air-sensitive conditions and provides only a slight reduction in yield (72%) when compared to isolated or in situ generated precatalyst (Scheme 3-15).    Scheme 3-15: Multigram synthesis of 24a with a premade solution of complex 20.  Furthermore, this solution appears to be relatively stable and can be stored in a Schlenk flask for long periods of time. For example, a sample that was store for 6 months was used to catalyze the same substrate combination with only a modest reduction in yield (54%). The solution of precatalyst is still moisture sensitive as when reagents were used as received, (i.e. not dried over CaH2 before use) decomposition of the precatalyst was observed, as indicated by the loss of colour 135  of the solution and formation of a white precipitate. Surprisingly, complex 20 is tolerant to less rigorous air-sensitive conditions. By simply equipping a round bottom flask with a N2 filled balloon, 24a was afforded in 62% yield following reduction and isolation with a back-extraction protocol. To further extend this concept, the N2 balloon was replaced with a drying tube filled with DrieriteTM, initial productive reactivity was observed by GC-MS after 2 hours at 65 °C with phenylacetylene and benzylamine using 5 mol% of 20. However, when the reaction was left for 24 hours, 24a was not observed by GC-MS, but the corresponding aldehyde was observed. To avoid this side reactivity, the reaction temperature was increased to 110 °C. Again initial formation of the desired product was observed after 1 hour but prolonged reaction times (24 hours) resulted in the formation of a new imine byproduct. Following reduction and isolation by column chromatography, this byproduct was identified as dibenzylamine via 1H/13C NMR spectroscopy and GC-MS.  To avoid this byproduct formation, reaction time was reduced to 30 min., which resulted in the formation of the intended product. Following reduction with NaBH4 in the usual manner, 24a was afforded in 43% yield.   3.2.2 Tandem Sequential Reactions with Hydroamination  The imine functional groups can not only be reduced to access corresponding amines, they can also be utilized as a reactive moiety for further reactivity.421-423  Although typically formed through classical Schiff base chemistry,424 titanium catalyzed hydroamination can be utilized as an alternative method to generate the reactive imines. A distinct advantage of using titanium catalyzed hydroamination is the anhydrous nature of the reaction. Although the titanium catalyst requires anhydrous conditions, subsequent reactivity, such as further reaction with organometallic reagents, may also require such conditions. With traditional Schiff base chemistry, water is a 136  byproduct of the reaction and would require the thorough removal of this water before the next reaction step.  Condensation is also less useful for the synthesis of less stable aldimines, which can easily undergo hydrolysis.  Our group has previously shown that precatalyst 20 can be utilized in a one-pot synthesis of tetrahydroisoquinolines using first hydroamination and a subsequent modified Pictet-Spengler cyclization.84  Furthermore, α-cyanoamines, diamines, imidazolidinones, α-amino acids and their derivatives can be synthesized in a one-pot procedure featuring hydroamination with precatalyst 20 in a modified Strecker reaction.136-137  Coupling hydroamination with Fischer indole synthesis can also be achieved with complex 20.184  Starting from aminoalkynes, enantioselective synthesis of morpholines were achieved by intramolecular hydroamination with complex 20 and enantioselective transfer hydrogenation.138  Piperazines have been prepared using two sequential hydroamination reactions, with one step featuring the use of complex 20.138  Most previous examples of tandem synthesis with complex 20 targeted N-heterocycle synthesis. Here, this investigation focused on the synthesis of acyclic amines that uses the imine moiety as a reactive intermediate.  3.2.2.1 Hydroamination/hydrosilylation Reaction Sequence Although standard reducing agents, such as NaBH4 or LiAlH4, smoothly afford the secondary amine following hydroamination, an alternative, catalytic approach is desirable. Doye and coworkers have previously described a one-pot hydroamination-hydrosilylation reaction sequence to access secondary amines.425 Notably, the titanium catalyst they used for hydroamination (Cp2TiMe2) is also utilized as a catalyst for hydrosilylation.425 Upon completion of hydroamination at 105 °C, phenylsilane, methanol and piperidine were added and reacted at 105 137  °C. Following hydrolysis of the completed reaction mixture, the secondary amine was afforded in up to 99% yield. The Ti(IV) precursor for hydroamination is thought to be reduced in situ to generate Ti(III) species, which then catalyze the hydrosilylation of imines.  This raises the question, can complex 20 is also able to be reduced in situ to facilitate hydrosilylation of imines.  As complex 20 is more selective and tolerates a broader scope of substrates, it could be used to access a broader range of secondary amine products.     Scheme 3-16: General scheme of titanium catalyzed tandem sequential hydroamination reaction followed by a titanium catalyzed reduction.  Following a similar protocol as described by Doye,425 primary amines are afforded following a hydroamination/hydrosilylation reaction sequence. In this protocol, our bis(amidate)bis(amido) titanium complex is utilized first as a hydroamination precatalyst then as a precatalyst for hydrosilylation. Unfortunately, although productive reactivity was observed for a range of substrates, low yields of the product were obtained (17 – 47%, Table 3-10).  As a direct comparison, using 11a (Cp2TiMe2) with this reaction sequence using 1-phenyl-1-propyne and p-methoxyaniline afforded the corresponding secondary amine in 86% yield, however, using 20 only 17% was successfully isolated (Entry 1). Despite the relatively poor reactivity, complex 20 is known to tolerate a broader substrate scope then 11a.  As such, substrate combinations that are not possible with 11a or ones which generate a mixture of regioisomers, could be accessed with 20. 138  Indeed, these substrate combinations led to selective formation of the anti-Markovnikov isomer albeit in low to moderate yields.  For example, the reaction of 1-phenyl-1-propyne and 1-phenylethylamine (a more sterically bulky derivative of benzylamine) in the presence of 11a resulted in 11% isolated yield following hydrolysis.425  As shown in entry 2, complex 20 was able to afford the corresponding secondary amine in 33% yield using the more challenging benzylamine. With complex 20, terminal alkyl alkynes could also be used in this reaction sequence to afford selectively one isomer as shown in entry 3.  Unfortunately, when compared to reduction using standard hydride reagents, a significant decrease in yield was observed.  This is most exemplified by entry 4, where following this reaction pathway, 18% isolated yield was obtained, yet NaBH4 reduction gave this product in 87% yield.  As phenylacetone (presumably from imine hydrolysis) was detected by GC-MS from the crude product mixture, this observation suggests that complex 20 is a sluggish hydrosilylation catalyst. Although productive reactivity was found, complex 20 afforded low yields of the secondary amine products, although this method using complex 20 could accommodate substrates that were not possible with complex 11a.   139  Table 3-10: Hydroamination/hydrosilylation reaction sequence in the presence of complex 20.   3.2.2.2 Hydroamination/Isomerization/Deprotection Sequence  As primary amines are a simple and common functional group, many methods have been developed to access this moiety.426-430  One method described by de Kimpe and coworkers431 is particularly interesting, as it utilizes benzylamine as the nitrogen source to synthesize primary amines. In their report, first an aldimine was formed from a functionalized aldehyde and benzylamine. This was followed by a base-catalyzed imine isomerization and acid-catalyzed deprotection, which afforded the primary amine. The key imine isomerization was based on seminal reports from the Cram group.432-433  In this work, by further coupling hydroamination to this reaction sequence, benzylamine can be used as a nitrogen source to convert terminal alkynes into primary amines (Scheme 3-17). 140  This method allows for the addition of nitrogen directly to the alkyne and avoids the formation of oxygenated or halogenated intermediates.  Hydroamination using 20 with 1-hexyne and benzylamine affords imine 32. Using a one-pot method, isomerization is achieved using KOt-Bu via a base-catalyzed methylene-azomethine rearrangement431-434 to give the benzylidene protected amine.  Acid-promoted deprotection yields the corresponding primary amine, whereupon derivatization to facilitate isolation, the tosylamide (33) is isolated in 42% overall yield.   Scheme 3-17: Synthesis of primary amine (33) using 20 by a sequential hydroamination/isomerization/deprotection sequence.   Unfortunately, attempts to extend this methodology with other alkyne substrates were unsuccessful.  When phenylacetylene was used, a mixture of benzylamine and phenethylamine was produced following work-up, which indicates incomplete isomerization.  When benzhydryl protected propargyl alcohol was used, the base-catalyzed isomerization step lead to product decomposition, resulting in an intractable mixture.  These limitations restricted the use of this reaction sequence for a broad range of substrates, thus further investigation was not conducted.  141  3.2.2.3 Synthesis of Substituted Allylamine via Hydroamination/Alkynylation Reaction Sequence The reactive imine generated by hydroamination can also be subjected to a Re catalyzed alkynylation, as shown by Fukumoto et al.,435 to access 2,3-disubstituted allylamines in three synthetic steps (Scheme 3-18). These 2,3-disubstituted allylamines are challenging to synthesize, with reports of their syntheses requiring multiple steps.436  Notably, such substituted allylamines are desirable synthetic building blocks.436-438 For example, benzhydrylamine can be used as a nitrogen source and alkynes furnish the α-carbon fragment.   Hydroamination of 1-hexyne with benzhydrylamine affords imine 34. In a one-pot procedure a Re catalyzed alkynylation with another equivalent of 1-hexyne gives protected allylamine 35 in 61% yield. Subsequent acid induced deprotection gives the substituted allylamine 36 as the hydrochloride salt in an overall yield of 45%.  Scheme 3-18: Synthesis of substituted primary allylamine (36) using 20 by a sequential hydroamination/alkynylation/deprotection sequence.  142  Attempts in scaling up the reaction to afford synthetically useful quantities (>1 g) of the substituted allylic amine product were unsuccessful. Only trace amounts of desired products were detected in these attempts, further investigations were not conducted.   3.2.3 Synthesis of Nitrogen Containing Oligomers via Hydroamination By using an aminoalkyne substrate that cannot undergo intramolecular reactivity, it is proposed that hydroamination would result in the formation of oligomers with imine or enamine functional groups. In particular, if an alkynylaniline was utilized then the corresponding material formed would resemble poly(para-phenylene vinylene) or polyaniline, which are known conductive polymers.402-404, 439   As hydroamination of ortho-alkynylaniline has been used in the synthesis of indoles via intramolecular hydroamination with late-transition metal complexes,364, 370-371, 440 either meta- or para-substituted alkynylanilines are more preferable monomers.  To the best of our knowledge, only one example of using hydroamination to form oligomers has been reported in the literature by the Stephan group.441  In this report, para-(2-phenylethyn-1-yl)aniline was oligomerized in the presence of 10 mol% of tetrakis(dialkylamido) titanium at 70 °C for 80 – 90 hours. The resulting material was obtained in 36% yield. End group analysis revealed a free primary amine and a NR2 end group. Analysis by MALDI-TOF showed up to 15 repeat units were formed and analysis by NMR spectroscopy supported the formation of an imine-enamine mixture. Surprisingly, the UV-Vis spectrum of the oligomer was the same as the monomer, suggesting no extended conjugation.  Complex 20 demonstrates a broader scope of reactivity and improved regioselectivity than the homoleptic amido titanium complex used in the only previously disclosed example. It is proposed that complex 20 would result in longer oligomers with a more extended conjugation 143  network.  If these polymers were successfully synthesized, they could be used as a complementary conjugated polymer to the more, well known polyaniline. One major drawback of polyaniline is its low solubility in organic solvents, which leads to processability challenges.  If desirable physical and electronic properties are found with the novel polymers, they could be used in photoelectrochemical cells or electronic devices.402  3.2.3.1 Synthesis of Oligomers from Meta-ethynylaniline  Initial investigations focused on the oligomerization of commercially available meta-ethynylaniline (37) and were carried out by an undergraduate student, Ms. Ellen Pope. Once dried over CaH2 and purified by distillation, monomer 37 was reacted with complex 20 (1 – 10 mol%) in toluene. Over 16 hours, the reaction mixture turned cloudy with the formation of a red precipitate. Isolation by filtration afforded 38 as a red powder in high yields (95 - 99%) (Scheme 3-19). Unfortunately, the resultant product was not soluble in any common organic solvents and was found to decompose with the addition of HCl(aq).  As such, the product was characterized in the solid state using IR spectroscopy, MALDI-MS, thermogravimetric analysis (TGA), and solid state NMR spectroscopy. The IR spectrum of the resulting red powder lacked the signal corresponding to the alkyne (2103 cm-1) and primary amine (3370 cm-1), which supports the consumption of the starting monomer. New signals at 1652 cm-1 and 1590 cm-1 are observed, which is attributed to the C=N stretching frequency of an imine moiety and the C=C stretching frequency of the enamine moiety, respectively. MALDI-MS revealed signals that repeat with m/z 117, corresponding to the molecular mass of the monomer with n = 1 - 12 units.  TGA of the monomer showed thermal decomposition starting at 120 °C consistent with simple organic compounds. TGA of the red powder showed thermal decomposition at 360 °C, which was 144  significantly higher than the monomer (120 °C) and supports the formation of higher molecular weight oligomers. Analysis of the 13C{1H} MAS-NMR spectroscopy suggested the formation of an enamine isomer with minor amounts of the imine isomer, as evidenced by the enamine Csp2 signal δ = 141.3 and 137.2 ppm and the imine Csp2 signal at 164.5 ppm.442,443 Another key observation was the absence of a methyl signal, if such a signal was observed then the branched hydroamination product would be present. The lack of such a signal suggests the formation of only the linear hydroamination product, consistent with the observed reactivity trends of complex 20. These observations support the formation of oligomers.    Scheme 3-19: Oligomerization of meta-ethynylaniline in the presence of complex 20.   If this reaction was proceed as a living polymerization, it was predicted that by changing the monomer to catalyst ratio from 10 mol% to either 5 or 1 mol% catalyst loading would have a profound effect on the length of the oligomer formed. High reactivity was observed for all catalyst loadings; however, the characteristics (MALDI-TOF and TGA) of all three samples were very similar.  Slight changes were observed (TGA: 10 mol%, 360 °C, 1 mol%, 383 °C. MALDI: 10 mol%, n = 1-10; 1 mol%, n = 1-14), which suggests a slightly longer chain for lower catalyst loading. However, such changes are relatively small for a 10 fold decrease in catalyst loading.  Para-ethynylaniline was also tested as a monomer for this reaction.  This substrate was synthesized from a Sonogashira cross-coupling reaction with trimethylsilylacetylene and para-145  iodoaniline, followed by a base facilitated silyl deprotection. Oligomerization of this substrate was also successful, affording a red powder that is equally insoluble in common organic solvents. MALDI-TOF (n = 1-10) and IR analysis (disappearance of the primary amine and alkyne signals) show oligomer formation.  The characteristics were quite similar to the oligomers formed from meta-ethynylaniline, where the oligomer was not soluble in common organic solvents. Although the formation of the oligomers was observed, thus providing proof-of-principle with complex 20, the material obtained from the reaction with meta-ethynylaniline was very difficult to analyze due to its insolubility.  More soluble versions are desirable for more complete analysis of the material, in particular by UV-Vis spectroscopy to probe the molecular electronics of the material.   3.2.3.2 Synthesis of Oligomers from Para-1-hexynylaniline   One strategy to address the problem of insolubility of oligomers is to install a long alkyl chains to the monomer.  To this extent, para-1-hexynylaniline (39) was synthesized from para-iodoaniline and 1-hexyne under palladium catalyzed Sonogashira cross-coupling reaction conditions. Purification of the monomer was accomplished via column chromatography and then dried in vacuo. Oligomerization of 39 was attempted with 10 mol% of complex 20 at 110 °C for 24 hours and a red solution was obtained (Scheme 3-20).   146   Scheme 3-20: Oligomerization of para-1-hexynylaniline in the presence of complex 20.  The reaction conditions were chosen due to internal alkynes being more challenging than terminal alkynes for hydroamination with complex 20.  Oligomerization was not observed at room temperature. Initial attempts to isolate oligomers under atmospheric conditions were unsuccessful and instead only yielded the hydrolyzed substrate. Furthermore, upon exposure of a small sample of 40 dissolved in CDCl3 to atmospheric conditions for 24 hours resulted in loss of color and degradation of the oligomer.  This was further supported by MALDI-TOF spectrometry, where no signals corresponding to any oligomer masses were detected. These observations suggest productive hydroamination reactivity occurred, but the product is not air stable. To avoid exposure to air, a second reaction mixture was subjected to high vacuum in a glovebox to remove volatile components, resulting in a deep red brittle solid.  The 1H NMR spectrum of this solid dissolved in C6D6 displayed broad signals that were characteristic for the formation of oligomers. MALDI-TOF mass spectrometry was then performed on this solid.  Two sets of masses were observed where each has a difference of m/z 173, which corresponds to the mass of the monomer, indicating the formation of oligomers. This observation suggests that different end groups are present. One set of signals is consistent with having a terminal amine and a ketone, formed from hydrolysis, with n = 1 – 13 units. The other set of signals is consistent with a terminal alkyne and possibly a titanium species with n = 1 – 14 units.  147  In a comparison study of the monomer and product by infrared spectroscopy (Scheme 3-21), it is evident that the broad signal from the N─H bond stretching (3361 cm-1) is lost.  Interestingly a new signal at 1644 cm-1 appears, which is assigned to C=N stretching mode.  This observation alludes to the formation of an imine oligomer rather than the expected enamine structure; moreover, this is consistent with the observed atmospheric instability of the resulting product.  Presumably facile hydrolysis of the material results in ketones and oligomer cleavage.  4000 3500 3000 2500 2000 1500 100092949698100 Oligomer 40Transmittance (%)Wavenumber (cm-1)78849096 Monomer 391644 (C=N) Scheme 3-21: Infrared spectra of the monomer 39 (top) and of the oligomer 40 (bottom).   Due to its atmospheric instability, UV-Vis spectral measurements on the monomer and product were performed under an inert atmosphere (Scheme 3-22). These measurements were performed on samples that were dissolved in anhydrous DCM and then transferred to a cuvette equipped with a Teflon seal.  The spectrum of the monomer shows two peaks at 275 and 305 nm. 148  The spectrum of the product oligomer again showed two peaks, however; the signals are blue shifted to 241 and 290 nm. This is consistent with the formation of an imine type oligomer as conjugation is broken by the methylene unit, resulting in the blue shifted signal.  300 400 500 600 700 8000.00.51.0 Monomer 39 Oligomer 40Wavelength (nm)Normalized Abs241275305290 Scheme 3-22: UV-Vis spectrum of monomer 39 and oligomer 40 in DCM.    As shown in Section 3.2.1.1 the reaction of aniline with 1-phenyl-1-propyne is readily facilitated by complex 20.  When this hydroamination reaction was monitored by 1H NMR spectroscopy, the selective formation of the imine product was observed. It was hypothesized that the extended conjugation of the oligomers would favour the formation of the enamine tautomeric form when para-1-hexynylaniline was used. However, all observations contradicts this hypothesis.  Although a soluble N-containing oligomer was synthesized it did not contain the desired electronic properties.  As such, the design of the monomer was reconsidered to favour the enamine tautomer. 149  3.2.3.3 Synthesis of Oligomers from Para-(2-phenylethyn-1-yl)aniline  One method to favour the formation of the enamine over the imine tautomer is to replace the alkyl substituent with an aryl substituent of the alkyne, for example para-(2-phenylethyn-1-yl)aniline (41), to extend the possible conjugation into the appended aryl ring, where the extended resonance would help stabilize the enamine structure.  As shown in the introduction, the Stephan group have shown that oligomerization occurs with homoleptic amido titanium complex, however, low yields and limited conjugation was observed.441   The synthesis of the monomer was achieved using Sonogashira cross-coupling, as described previously. The oligomerization of para-(2-phenylethyn-1-yl)aniline was conducted with 10 mol% of complex 20 at 110 °C for 24 hours (Scheme 3-23). Initially, the volatile components of the red solution were removed under an inert atmosphere, to give a red solid. UV-Vis spectroscopy showed a new red shifted signal when compared to the monomer.  The resulting material showed some air stability, as the red shifted signal remained in the UV-Vis spectrum when the analysis was performed again after 16 hours at atmospheric conditions. Subsequently, a revised protocol was used, whereby the resulting solution was precipitated from a vortex of hexanes with a few drops of water resulting in a yellow solid powder.  This powder was soluble in chlorinated solvents such as DCM and chloroform.    Scheme 3-23: Oligomerization of para-(2-phenylethyn-1-yl)aniline in the presence of complex 20.  150   When comparing the IR spectra of the monomer versus the oligomer (Scheme 3-24), consumption of the starting material was clearly observed by the disappearance of the alkyne stretching vibration at 2212 cm-1 and the primary amine N─H stretch at 3476 and 3382 cm-1.  The relatively strong signal at 1590 cm-1 can be attributed to the stretching frequency of a highly conjugated alkene, which suggests the formation of the desired enamine.  4000 3500 3000 2500 2000 1500 1000 Oligomer 42Transmittance (%)Wavenumber (cm-1)  Monomer 41129015132212159116151210151313031590 Scheme 3-24: Infrared spectrum of monomer 41 and oligomer 42.    MALDI-TOF analysis revealed a repeating mass of m/z 193, which is consistent with the molecular mass of the monomer.  Masses consistent with up to 10 repeat units were observed. Terminal amine and ketone end groups are consistent with the respective masses that were observed.  151  Thermogravimetric analysis of the product, under air, showed an initial decomposition of 42 starting at 190 °C (Figure 3-4).  As monomer also showed initial decomposition at 190 °C, this suggests that 42 is contaminated with the presence of some unreacted monomer.  However, the monomer was shown to be mostly degraded by ~314 °C. The plot of thermogravimetric analysis of 42 show only a loss of 14 weight% at ~314 °C, which indicates the presence of a second, more thermally robust, species.  The plot then showed a slow weight loss until 511 °C, at which point a sharp and steady weight loss was observed with respect to increasing temperature.  At the end of the run 5 weight% remained, with a white solid residue appearing in the analysis pan. Presumably some titanium species remain in the sample and the white solid is TiO2 from the oxidation of the titanium complex. When TGA was performed under N2, significant changes in the profile of the plot were observed and a sharp decrease of weight% was observed at 400 °C. However, the largest difference is that at the end of the scan, where 45% of the original weight remained was a black solid residue.  152  0 200 400 600 800050100Weight %Temp. (°C)~511° C Figure 3-4: TGA curve of oligomer 42. The sample was heated from 30 to 900 °C at a heating rate of 10 °C min-1.   UV-Vis spectroscopic analysis of the monomer shows a single signal at 315 nm. The UV-Vis spectrum of the oligomer revealed two signals (311 and 360 nm) (Scheme 3-25).  One signal was red shifted, which suggests the formation of an extended conjugated network. Solution phase 1H and 13C NMR spectroscopy was possible for this product, and broad signals were observed that could not be rigorously assigned.  In an attempt to determine the regioselectivity of hydroamination-polymerization, a sample of 42 was hydrolyzed with 1M HCl(aq).  Following work-up, a mixture of regioisomers of the ketone was observed by 1H and 13C NMR spectroscopy. This is consistent with previous results, where hydroamination with sterically symmetric but electronically unsymmetrical internal alkynes results in a mixture of regioisomers.  Because of different regioisomers, this rationalized the difficulty in assigning the spectra of 42.   153  300 400 500 600 700 8000.00.51.0 Monomer 41 Oligomer 42Wavelength (nm)Normalized Abs311315360 Scheme 3-25: UV-Vis spectra of monomer 41 and oligomer 42 in THF.    The effects of the reaction conditions were then investigated.  When the reaction time was extended to 4 days or the catalyst loading changed to either 5 or 20 mol%, no significant changes were observed to the product that was afforded (the same IR spectra was obtained and all UV-Vis spectra display a shoulder signal at 360 nm). In a control experiment, the monomer was heated without the presence of the catalyst.  Following removal of the volatile components, the 1H NMR spectra of the residue showed no evidence of oligomerization.   When tetrakis(dimethylamido) titanium was used as a catalyst at 110 °C, it was found to also afford a product that also showed the shoulder signal at 360 nm when analyzed by UV-Vis spectroscopy.  This is in contrast to previously published results from Greenberg and Stephan, where the same catalyst and substrate combination did not result in a new signal in the UV-Vis spectrum. Under the harsher reaction conditions (110 °C vs. 70 °C), the material obtained showed 154  a similar TGA plot to when complex 20 was used and a similar MALDI-TOF spectrum. The red shifted signal at 360 nm was also observed in the UV-Vis spectrum, although weaker in intensity. Although full analysis of the new materials was hindered by its properties, these preliminary investigations show that complex 20 can be used to synthesize oligomers from alkynylanilines.  Terminal alkynes gave materials that were not soluble in common organic solvents, while an alkyl substituent resulted in a material that was not air stable.  Using the same substrate as the previously reported study resulted in the synthesis of 42, which showed evidence for extended conjugation. These promising initial results suggest it possible to utilize hydroamination to obtain oligomers that show some extended conjugation character. Future work to improve polymer chain length and further extend conjugation could result in new usable materials.   3.3 Conclusions  In comparison to other benchmark titanium hydroamination catalysts, complex 20 displays comparable reactivity, tolerates a broader substrate scope and is the most regioselective catalyst reported to date.  Due to mechanistic restrictions, amine substrate scope is restricted to primary amines.  However, alkyl, aryl and functionalized amines are well tolerated. Complex 20 is able to catalyze hydroamination with both terminal and internal alkynes. Using modified reaction conditions, protected propargyl alcohols and amines are reacted in the presence of complex 20.  The reaction of benzylamine and internal alkynes was also successfully accomplished in the presence of complex 20. In most cases excellent regioselectivity was observed, which is hypothesized to be primarily dictated by steric interactions. Interestingly, when sterically symmetric but electronically unsymmetric internal alkynes were used, a mixture of regioisomers 155  were observed, which favours the addition of the amine to the carbon α- to the more electron rich arene.  Several improved protocols were developed to facilitate benchtop use of complex 20.  The precatalyst can be made and immediately used in situ by using simple Schlenk line techniques. Alternatively, a standard solution of the precatalyst can be made in toluene and stored in a sealed vessel. These improved protocols facilitate scaling-up the reaction using complex 20 to more than 3 g.  Complex 20 has been investigated for its use in several tandem reaction sequences; hydroamination/hydrosilylation to afford secondary amines, hydroamination/isomerization to afford a primary amine, and hydroamination/alkynylation to afford a disubstituted allylamine. Preliminary results show complex 20 can be used for the oligomerization of an alkynylaniline to afford several novel nitrogen containing oligomers.  Despite some drawbacks to its physical properties, oligomer 42 displays some extended conjugation. This acts as a starting point, where future work could be done to refine this process to yield applicable materials.   3.4 Experimental  3.4.1 Materials and Methods Synthesis of the metal complexes and subsequent reactions involving these precatalysts were performed under an inert atmosphere of nitrogen using standard Schlenk line or glovebox techniques. Diethylether was distilled from sodium/benzophenone under inert atmosphere.  Benzene was purified and dried by passage through a column of activated alumina and sparged with nitrogen.  d6-Benzene was degassed via three cycles of freeze-pump-thaw and stored over activated 4 Å molecular sieves in the glovebox.  All substrates were distilled from either 4 Å 156  molecular sieves or CaH2 and stored over molecular sieves before use.  The amide proligand and titanium precatalyst were prepared according to literature procedures.84-85  Unless otherwise stated, all reagents were purchased from commercial sources. The syntheses of the following compounds were previously published: 22a-c, and 24a-c, e-h.84-85 The following compounds were synthesized using isolated precatalyst 20 by Dr. Jason Bexrud: 25c-d,f, and 26a,d.184 All syntheses and characterization of meta-ethynylaniline were performed by Ms. Ellen Pope.442 1H and 13C{1H} NMR spectra were recorded on Bruker 300 MHz, 400 MHz or 600 MHz Avance spectrometers with chemical shifts given relative to the residual solvent at 298 K unless otherwise noted. Chemical shifts δ for 1H and 13C{1H} NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an external standard and calibrated against the solvent residual peak. Chemical shifts for 19F NMR spectra are relative to CFCl3 in CDCl3 (external reference). NMR spectra were assigned by using distortionless enhancement by polarization transfer (DEPT) and 2D techniques (COSY, NOESY, HMQC and/or HMBC). Coupling constants J are given in Hertz (Hz).  FT-IR spectra were recorded on a PerkinElmer FT-IR equipped with an ATR step up. Thermogravimetric analyses were performed on a PerkinElmer simultaneous thermal analyzer (STA) 6000. UV-Vis spectra were recorded on a Cary 500. GC-MS measurements were performed on an Agilent Technologies GC 6890N/ MS 5973N equipped with an Agilent Technologies HP-5HS column (length: 30 m, 0.25 mm inner diameter, 0.25 μm coating thickness) coupled to a quadrupole mass filter. Helium was used as the carrier gas with a constant flow of 1.2 mL/min. All mass spectrometry and microanalysis was performed at the Department of Chemistry, University of British Columbia by the service staff. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 eV) source with a TOF detector. Elemental analyses were recorded on a Carlo Erba elemental analyzer EZ 1108.  157   3.4.2 Synthesis and Characterization of Titanium Complex   [Ti(NMe2)2{κ2-N,O-(Dipp)NC(Ph)O}2] (20). A Schlenk flask equipped with a stir bar was charged with dry N-(2,6-diisopropylphenyl)benzamide 21 (5.21 g, 18.5 mmol) and then suspended in ~ 30 mL dry hexanes. In another Schlenk flask, Ti(NMe2)4 (2.2 mL. 9.3 mmol) was dissolved in ~ 20 mL hexanes.  The solution of Ti(NMe2)4 was slowly added to the proligand suspension. The reaction was stirred at room temperature for 18 hours, resulting in a deep red solution. Following removal of the volatiles in vacuo, complex 20 was obtained in 93% yield (6.01 g) as an orange solid. Complex 20 was used without further purification. Analytically pure sample was obtained after recrystallization from hexanes. 1H NMR (d8-toluene, 400 MHz) δ  (ppm) 7.66 (d, 4H, 3JH,H = 7.0 Hz, Ar), 7.15 (s, 6H, Ar), 6.98 – 6.84 (m, 6H, Ar), 3.61 (sept, 4H, 3JH,H = 6.7 Hz, CH(CH3)2), 3.31 (s, 12H, N(CH3)2), 1.32 (d, 12H, 3JH,H = 6.7 Hz, CH(CH3)2), 0.93 (d, 12H, 3JH,H = 6.7 Hz, CH(CH3)2); 13C{1H} NMR (d8-toluene, 100 MHz) δ  (ppm) 177.2 (C=O), 142.6, 142.4, 133.1, 131.4, 130.2, 125.9, 124.1 (Ar), 47.7, 28.1, 24.6, 24.3 (1 aryl carbon is obscured). MS(EI): m/z 652 [M – NMe2]+, 608 [M – (NMe2)2]+; Anal. Calcd. (%) for C42H56N4O2Ti: C, 72.40; H, 8.10; N, 8.04; Found: C, 72.27; H, 8.14; N, 8.02. Single crystal X-ray quality samples were obtained by recrystallization from hexanes at room temperature for 24 hours.    158  3.4.3 Synthesis and Characterization of Hydroamination Substrates  The following substrates were prepared by using literature procedures: prop-2-ynyloxydiphenylmethane,444 N-benzyl-1,2-ethyldiamine,445 (tert-butyldimethylsilyloxy)-1-propyne,446 and N-(diphenylmethylene)-2-propyne-1-amine.85  4-fluoro-4’-methoxybenzophenone.   A 100 mL round bottom flask equipped with a stir bar was charged with K2CO3 (19.1 g, 0.138 mol) dissolved in ~ 40 mL of acetone and 4-fluoro-4’-hydroxybenzophenone (10.0 g, 0.046 mol). Methyl iodide (16.4 g, 0.115 mol) was then added in dropwise fashion to furnish a yellow solution. The reaction mixture was stirred at room temperature for three hours. The reaction mixture was then filtered, washed with brine (2 × 50 mL), dried with MgSO4, filtered, the volatiles removal in vacuo and purified by recrystallization from hot hexanes. Yield: 9.99 g (94%). Spectral data matched literature references.447 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.81 – 7.77 (m, 4H, Ar), 7.15 (t, 3JH,H = 8.6 Hz, 2H, Ar), 6.99 – 6.95 (m, 2H, Ar), 3.89 (s, 3H, OMe).  (4-fluorophenyl(4-methoxyphenyl))methanol.  159  In a 250 mL round bottom flask equipped with a stir bar, 4-fluoro-4’-methoxybenzophenone (5.0 g, 23.1 mmol) was suspended in ~ 100 mL of MeOH and cooled to 0 °C. NaBH4 (1.13 g, 30.0 mml) was then added portion-wise. The reaction mixture vigorously effervesced. The reaction mixture was warmed to room temperature and stirred for 16 hours. The reaction was then quenched with ~ 30 mL of 1 M NaOH(aq) and extracted with dichloromethane (3 × ~ 30 mL). The combined organic fraction was washed with saturated brine (1 × ~ 30 mL), dried with MgSO4, filtered, and volatiles were removal in vacuo. The product was further dried under high vacuum before using without further purification. Yield: 4.60 g (91%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.36 – 7.26 (m, 4H, Ar), 7.02 (t, 3JH,H = 8.7 Hz, 2H, Ar), 6.88 (d, 3JH,H = 8.7 Hz, 2H, Ar), 5.80 (m, 1H CH), 3.80 (s, 3H, OMe), 2.15 (br s, 1H, OH); 13C{1H} NMR (CDCl3, 300 MHz): δ (ppm) 136.0, 133.0, 128.1 (3JC,F = 8.0 Hz), 127.8, 115.2 (2JC,F = 21.3 Hz), 113.9, 75.2, 55.3 (two aryl carbon signals were not observed); 19F NMR (CDCl3, 282 MHz) δ (ppm) -115.0; MS (EI): m/z 232 (M+). HRMS (EI-EB) m/z: Calcd for C14H13FO2 (M+), 232.0900; Found: 232.0903.  1-fluoro-4-((4-methoxyphenyl)(prop-2-yn-1-yloxy)methyl)benzene.  In an oven-dried, vacuum cooled 100 mL Schlenk flask equipped with a stir bar under N2, NaH (60 wt %, 0.93 g, 23.2 mmol) was suspended in 50 mL of dry THF and cooled to 0 °C. In a separate round bottom flask, (4-fluorophenyl(4-methoxyphenyl))methanol (4.20 g, 19.3 mmol) was dissolved in 10 mL of dry THF and subsequently slowly transferred to the NaH suspension with a cannula. The reaction mixture was warmed to room temperature and stirred for 2 hours. The 160  reaction mixture was then cooled to 0 °C and propargyl bromide (2.6 mL, 25.8 mmol) was added drop-wise. The mixture was allow to warm to room temperature and stirred for 16 hours. The mixture was then poured into ca. 50 mL of distilled water and the mixture was extracted with 3 × 25 mL of EtOAc. The combined organic layers were dried with MgSO4, filtered and concentrated with rotary evaporation. Following column chromatography (10 : 1 Hex : EtOAc, Rf = 0.28), the title compound was afforded as a yellow oil. Yield: 4.33 g (83%).  1H NMR (CDCl3, 300 MHz): δ (ppm) 7.44 – 7.34 (m, 4H, Ar), 7.12 – 7.06 (m, 2H, Ar), 6.96 (d, 3JH,H = 7.7 Hz, 2H, Ar), 5.72 (m, 1H, CH), 4.22 – 4.20 (m, 2H, OCH2), 3.83 (s, 3H, OMe), 2.58 – 2.57 (m, 1H, CCH); 13C{1H} NMR (CDCl3, 300 MHz): δ (ppm) 162.0 (1JC,F = 245.7), 159.1, 137.3 (4JC,F = 3.0 Hz), 132.7, 128.6 (3JC,F = 8.3 Hz), 128.4, 115.0 (2JC,F = 21.3 Hz), 113.7, 80.3, 79.6, 74.6, 55.3, 54.9. 19F NMR (CDCl3, 282 MHz) δ (ppm) -114.9; MS (EI): m/z 270 (M+). HRMS (EI-EB) m/z: Calcd for C17H15FO2 (M+), 270.1056; Found: 270.1059.  1-methoxy-4-(phenylethynyl)benzene.  A 250 mL round bottom Schlenk flask equipped with a stir bar was charged with PdCl2(PPh3)2 (70 mg, 0.1 mmol), CuI (44 mg, 0.4 mmol), and para-iodoanisole (2.34 g, 10 mmol). The solids were dissolved in NEt3 (10 mL) and THF (10 mL). To this mixture, phenylacetylene (1.1 mL, 10 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Distilled water (~ 25 mL) and Et2O (~ 15 mL) was then added to the solution. The aqueous layer was separated and extracted with Et2O (3 × 25 mL). The combined organic layer was dried with MgSO4, filtered, and the volatiles were removed by rotary evaporation. Following column chromatography (15 : 1 PE : EtOAc, Rf = 0.5 in 10 : 1 PE : EtOAc), the compound was obtained as a pale yellow solid in 90% yield (1.87 g, 9.0 mmol). 161  Spectral data matched literature references.448 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.60 – 7.51 (m, 4H, Ar), 7.39 – 7.36 (m, 3H, Ar), 6.94 (d, 3JH,H = 8.8 Hz, 2H, Ar), 3.84 (s, 3H, OMe).  para-1-hexynylaniline (39). This compound was prepared from a modified literature procedure.449 An  oven-dried, vacuum cooled 100 mL Schlenk flask equipped with a stir bar was charged with para-iodoaniline (2.19 g, 10.0 mmol), Pd(PPh3)2Cl2 (0.230 g, 0.33 mmol), and copper iodide (0.040 g, 0.20 mmol). It was then placed under a vacuum and nitrogen cycled three times and back filled with nitrogen. Triethylamine (20 mL) and anhydrous THF (~50 mL) was added and the reaction mixture was stirred for 10 minutes at room temperature. 1-hexyne (1.07 g, 13 mmol) was added, resulting in a red reaction mixture, which was further stirred at room temperature for 16 hours. After removal of the volatiles in vacuo, the crude product was purified by column chromatography (6 : 1, hexanes : ethyl acetate) to give 1.31 g (75%) of para-1-hexynylaniline as a solid. Spectral data matched literature references.450 1H NMR (CDCl3, 400 MHz): δ  (ppm) 7.51 (d, 2H, 3JH,H = 8.5 Hz, Ar), 6.24 (d, 2H, 3JH,H = 8.5 Hz, Ar), 2.82 (br s, 2H, NH2), 2.40 (t, 3JH,H = 7.0 Hz, 2H, CCH2), 1.62 – 1.44 (m, 4H, CH2), 0.92 (t, 3JH,H = 7.1 Hz, 3H, CH3). FT-IR (thin film, cm-1) ν(N-H) 3361 (broad weak), ν(C-H) 2956 (medium), ν(C-H) 2922 (medium), ν(C-H) 2850 (medium), δ(N-H) 1619 (strong), ν(C=Caryl) 1513 (strong), ν(C-N) 1174 (medium); UV-Vis (DCM, ca. 10-5 M): λmax = 275, 305 nm.  4-(2-phenylethynyl)aniline (41). A 250 mL round bottom Schlenk flask equipped with a stir bar was charged with PdCl2(PPh3)2 (70 mg, 0.1 mmol), CuI (19 mg, 0.1 mmol) 162  and para-iodoaniline (2.19 g, 10 mmol). It was then placed under high vacuum for 30 min. NEt3 (10 mL) and THF (10 mL) were added to the mixture, followed by the dropwise addition of freshly distilled phenylacetylene (13 mL, 15 mmol). The reaction mixture was stirred at room temperature for 16 hours. Distilled water (~ 25 mL) and Et2O (~ 15 mL) were added to the solution. The aqueous layer was separated and extracted with Et2O (3 × 25 mL). The combined organic layers were dried with MgSO4, filtered and the volatiles were removed by rotary evaporation. Following column chromatography (4 : 1 → 1 : 1 PE : Et2O), the compound was obtained as a pale yellow solid in 70% yield (1.26 g). Spectral data matched literature references.441 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.49 (br s, 2H, Ar), 7.34 (m, 5H, Ar), 6.65 (d, 3JH,H = 7.4 Hz, 2H, Ar), 3.84 (br s, 2H, NH2); MS (EI): 193 [M+]; FT-IR (ATR, cm-1) ν(N-H) 3476 (weak), ν(N-H) 3382 (weak), ν(C-H) 2956 (medium), ν(C≡C) 2212 (medium), δ(N-H) 1615 (medium), ν(C=Caryl) 1591 (medium), ν(C=Caryl) 1513 (medium), ν(C-N) 1290 (medium); UV-Vis (THF, ca. 10-5 M): λmax = 315 nm.  3.4.4 General Methods for Hydroamination with Complex 20.  Method A.  A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with a solution of 20 (0.05 equiv) dissolved in anhydrous benzene (~2 mL), the alkyne (1 equiv), and the amine (1 equiv).  The Schlenk tube was then sealed and stirred at 65 oC for 24 hr.  After cooling the reaction mixture to room temperature, the resulting hydroamination products were directly subjected to a reduction method listed below.  Removal of solvent by rotary evaporation and purification by column chromatography afforded the purified amine products.  163  Method B.  A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with a solution of 20 (0.1 equiv) dissolved in anhydrous toluene (~2 mL), the alkyne (1 equiv), and the amine (1.2 equiv).  The Schlenk tube was sealed and stirred at 110 oC for 24 hr.  After allowing the reaction mixture to cool to room temperature the resultant hydroamination products were directly subjected to a reduction method listed below.  Removal of solvent by rotary evaporation and purification by column chromatography afforded the purified amine products.  Method C.  A J. Young NMR tube was charged with a solution of 20 (0.05 equiv) dissolved in anhydrous d6-benzene (~1 mL), the alkyne (1 equiv), and the amine (1.2 equiv).  The J. Young NMR tube was sealed and kept at ambient temperature for 24 hr.  The progress of the reaction was monitored by 1H NMR spectroscopy.  The resultant hydroamination products were transferred to a 10 mL vial equipped with a magnetic stir bar and subjected to a reduction method listed below.  Removal of solvent by rotary evaporation and purification by column chromatography afforded the purified amine products.  Method D.  A standard solution of Ti(NMe2)4 (0.035 M, 0.05 equiv) in d6-benzene was added to N-(2,6-diisopropylphenyl)benzamide (0.10 equiv) suspended in d6-benzene (0.100 mL) in a 1 dram vial.  The vial was gently shaken until all the solid completely dissolved (< 5 min), after which the alkyne (1 equiv) and the amine (1.2 equiv) were added.  The mixture was quantitatively transferred into a J. Young NMR tube by rinsing the vial twice with C6D6 (0.05 mL).  The NMR tube was sealed and maintained at the specified reaction temperature for 24 hr.  The progress of the reaction was monitored by 1H NMR spectroscopy.  The resulting hydroamination products were transferred to a 10 mL vial equipped with a magnetic stir bar and subjected to a reduction 164  method listed below.  Removal of solvent by rotary evaporation and purification by column chromatography afforded the purified amine products.  3.4.5 General Methods for Reduction.  Method I: Lithium Aluminum Hydride.  The resultant mixture from the hydroamination reaction was diluted with anhydrous diethylether (~10 mL).  LAH (1.4 equiv) was added and the reaction mixture was stirred for 24 hr at room temperature.  Saturated NH4Cl (0.1 mL) was added to quench the reaction and the mixture was subjected to suction filtration to remove solids.  The solid residue was washed with 3 portions of diethylether (~5 mL).  The organic filtrates were combined.  Method II: Sodium Borohydride.  The resultant mixture from the hydroamination reaction was diluted with MeOH (~10 mL).  NaBH4 (1.2 equiv) was added and the reaction mixture was stirred for 24 hr at room temperature.  After removal of the solvent by rotary evaporation, saturated Na2CO3 (10 mL) and DCM (10 mL) were added to the residue.  The aqueous layer was extracted with DCM (3 × 25 mL) and the combined organic layers were dried over Na2SO4 and filtered.    Method III: Sodium Cyanoborohydride.  A modified literature procedure was used.293 The resultant mixture from the hydroamination reaction was diluted with MeOH (~10 mL).  NaCNBH3 (2 equiv) and ZnCl2 (1 equiv) were added and the reaction mixture was stirred for 24 hr at room temperature.  The mixture was filtered and the solid residue was washed with DCM (~15 mL).  165  Saturated Na2CO3 (7 mL) was added to the filtrate.  After extraction with DCM (6 × 30 mL), the organic layer was dried over MgSO4 or Na2SO4 and filtered.  3.4.6 Synthesis and Characterization of Hydroamination Products. N-(3,4-dimethoxyphenethyl)hexan-1-amine (22d).  This compound was prepared from 3,4-dimethoxyphenethylamine (0.045 mL, 0.6 mmol) and 1-hexyne (0.022 g, 0.5 mmol) following hydroamination Method A and reduced using Method I. The desired compound was isolated as a colorless oil (0.059 g, 78%). Rf = 0.11, DCM with 2% NEt3.  Spectral data matched literature references.451 1H NMR (CDCl3, 300 MHz): δ (ppm) 6.81 − 6.73 (m, 3H, Ph), 3.86 (s, 3H, OMe), 3.85 (s, 3H, OMe), 2.87 − 2.82 (m, 2H, NCH2CH2Ar), 2.77 − 2.73 (m, 2H, NCH2CH2Ar), 2.60 (t, 3JH,H = 7.2 Hz, 2H, NCH2CH2CH2), 1.47 − 1.43 (m, 2H, NCH2CH2CH2), 1.30 − 1.23 (m, 7H, CH2 and NH), 0.87 (br t, 3H, Me),   N-allylhexan-1-amine (22e). This compound was prepared from allylamine (0.055 g, 1 mmol) and 1-hexyne (0.086 g, 1 mmol) following hydroamination Method A and reduced using Method II.  This compound was isolated through a back-extraction protocol, as follows: Following removal of solvent from the crude mixture of Method II, EtOAc (2 mL) and 1M HCl(aq) (2 mL) were added to the residue.  The organic layer was extracted with 1 M HCl(aq) (3 × 2 mL).  The combined aqueous layer was washed with EtOAc (10 mL), basified with 3M NaOH(aq), and extracted with  EtOAc (4 × 10 mL).  The combined organic layers were dried over Na2SO4, filtered, and solvent was removed by rotary evaporation. The product was afforded as a 166  colorless oil (0.095 g, 70%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 5.95  − 5.86 (m, 1H, olefin), 5.19 − 5.06 (m, 2H, olefin), 3.24 (d, 3JH,H = 6.1 Hz, 2H, NCH2), 2.60 (t, 3JH,H = 7.1 Hz, 2H, NCH2), 1.52  − 1.45  (m, 2H, CH2), 1.31 − 1.23 (m, 7H, CH2 and NH), 0.87 (t, 3JH,H = 6.8 Hz, 3H, CH3); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 136.7, 115.9, 52.4, 49.3, 31.7, 30.0, 27.0, 22.6, 14.0; MS (ESI): m/z 142 ([M+H]+); HRMS (ESI-TOF) m/z: Calcd for C9H20N ([M+H]+), 142.1596; Found: 142.1596.  1-benzyl-2-pentylimidazolidine (23). This compound was prepared from N-benzyl-1,2-ethyldiamine (150 mg, 1 mmol) and hexyne (82 mg, 1 mmol) using Method C followed by reduction using Method II. Following column chromatography, 0.117 g of an oil was obtained. 1H NMR and GC-MS analysis revealed a mixture of compound 23 and N-benzyl-N’-hexylethane-1,2-diamine.  1H NMR (CDCl3, 300 MHz): δ (ppm) 7.34 – 7.23 (m, 5H, Ph), 4.99 (s, 1H, PhCH2N), 4.86 (s, 1H, PhCH2N), 3.83 (m, 2H, NCH2), 3.46 – 3.42 (m, 1H, NCHNH), 2.80 – 2.54 (m, 2H, NCH2), 2.07 – 1.92 (m, 2H, CHCH2), 1.47 – 1.26 (m, 6H, CH2), 0.90 (t, 3JH,H = 7.2 Hz, 3H, CH3); GC-MS (ESI) : m/z 323 ([M+H]+).  N-[2-(Cyclohexen-1-yl)ethyl]-phenylmethanamine (24d).  This compound was prepared from benzylamine (0.055 mL, 0.6 mmol) and 1-ethynyl-1-cyclohexene (0.060 g, 0.5 mmol) following Method C and reduced using Method II.  Isolated as a yellow oil (0.075 g, 70%). Rf = 0.57, 25 : 1 Et2O : NEt3.  An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.28 – 7.20  (m, 167  5H,  Ph), 5.43 (s, 1H, C=CHCH2), 3.76 (s, 2H, PhCH2NH), 2.71 – 2.69 (m, 2H, CH2N), 2.14 − 2.11  (m, 2H, CCH2CH2), 1.95 (br s, 2H, Cy and NH), 1.84 (br s, 2H, Cy), 1.60 − 1.49 (m, 5H, Cy); 13C{1H} NMR (CDCl3, 101 MHz): δ (ppm) 140.7, 135.6, 128.5, 128.2, 127.0, 122.9, 54.0, 47.1, 38.4, 28.3, 25.4, 23.1, 22.6; MS (ESI): m/z 216 ([M+H]+); Anal. Calcd for C15H21N: C, 83.67; H, 9.83; N, 6.50. Found: C, 83.44; H, 9.78; N, 6.19.  3-(diphenylmethoxy)-N-(benzyl)propan-1-amine (24i).   This compound was prepared from benzylamine (0.055 mL, 0.6 mmol) and prop-2-ynyloxydiphenylmethane (0.109 g, 0.5 mmol) following Method C and reduced using Method II.  Isolated as a yellow oil (0.147 g, 89%). This compound was also prepared from benzylamine (0.066 mL, 0.6 mmol) and prop-2-ynyloxydiphenylmethane (0.107 g, 0.5 mmol) following Method D (reacted at room temperature) and reduced using Method II.  Isolated as a yellow oil (0.119 g, 72%). Rf = 0.13, DCM with 10% MeOH and 1% NEt3. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.29 – 7.16 (m, 15H, Ph), 5.25 (s, 1H, Ph(Ph)CHO), 3.75 (s, 2H, PhCH2NH)), 3.48 (t, 3JH,H = 6.4 Hz, 2H, OCH2CH2), 3.33 (br s, 1H, NH), 2.67 (t, 3JH,H = 6.4 Hz, 2H, NCH2CH2), 1.86 (quint, 3JH,H = 6.4 Hz, 2H, NCH2CH2); 13C{1H} NMR (CDCl3, 101 MHz): δ (ppm) 142.2, 138.9, 128.4, 128.3, 127.3, 127.1, 126.8, 126.5, 83.6, 67.3, 53.5, 46.5, 29.4; MS (ESI): m/z 332 ([M+H]+).  HRMS (ESI-TOF) m/z: Calcd for C23H26NO ([M+H]+), 332.2007; Found: 332.2014.  N-Benzyl-3-((tert-butyldimethylsilyl)oxy)propan-1-amine (24j).  This compound was prepared from benzylamine (65.5 μL, 0.6 mmol) and tert-butyldimethyl(prop-2-yn-1-yloxy)silane (87 mg,  0.5 mmol) 168  following Method C except at 110 °C in d8-toluene and reduced using Method II.  Isolated as a colorless oil (110 mg, 79%). Rf = 0.4, 50 : 1 Et2O : NEt3. Spectral data matched literature references.452 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.33 – 7.32 (m, 4H, Ph), 7.26 – 7.24 (m, 1H, Ph), 3.79 (s, 2H, PhCH2NH), 3.71 (t, 3JH,H = 6.1 Hz, 2H, OCH2CH2), 2.74 (t, 3JH,H = 6.9 Hz, 2H, NCH2CH2), 1.74 (quint, 3JH,H = 6.4 Hz, 2H, NCH2CH2), 1.57 (br s, 1H, NH), 0.89 (s, 9H, tBu), 0.05 (s, 6H, SiMe2); MS (EI): m/z 280 ([M+H]+).  N-benzyl-3-((4-fluorophenyl)(4-methoxyphenyl)methoxy)propan-1-amine (24k). This compound was prepared from benzylamine (64 mg, 0.6 mmol) and 1-fluoro-4-((4-methoxyphenyl)(prop-2-yn-1-yloxy)methyl)benzene (135 mg, 0.5 mmol) following Method C and reduced using Method II.  Isolated as a yellow oil (135 mg, 71%). Rf = 0.53, 1 : 1 Hex : EtOAc with 10% NEt3.  1H NMR (CDCl3, 300 MHz): δ (ppm) 7.25 – 7.17 (m, 9H, Ar), 6.98 – 6.93 (m, 2H, Ar), 6.84 – 6.81 (m, 2H, Ar), 5.24 (s, 1H, ArCHO), 3.75 (s, 2H, NHCH2Ph, overlapped signal), 3.75 (s, 3H, OMe, overlapped signal), 3.48 (t, 3JH,H = 6.2 Hz, 2H, OCH2CH2), 2.76 (t, 3JH,H = 6.7 Hz, 2H, NCH2CH2), 1.88 – 1.79 (m, 2H, NCH2CH2), 1.69 (br s, 1H, NH); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 161.9 (1JC,F = 245.2 Hz), 158.9, 140.3, 138.4 (4JC,F = 3.3 Hz), 134.2, 128.3, 128.2 (3JC,F = 8.0 Hz), 128.1, 128.0, 126.8, 115.0 (2JC,F = 21.0 Hz), 113.7, 83.4, 67.4, 55.1, 54.0, 46.8, 30.0; 19F NMR (CDCl3, 282 MHz) δ (ppm) -114.9; MS (ESI): m/z 380 ([M+H]+).  HRMS (ESI-TOF) m/z: Calcd for C24H27FNO2 ([M+H]+), 380.2026; Found: 380.2022.   169  N-(diphenylmethyl)-N'-(phenylmethyl)-propyl-1,3-diamine (24l).   This compound was prepared from benzylamine (0.052 mL, 0.5 mmol) and N-(diphenylmethyl)-2-propyne-1-amine (0.087 g, 0.4 mmol) following Method C and reduced using Method II except 3 equiv of NaBH4 was used.  Isolated as a colourless oil (0.100 g, 79%). Rf = 0.32, 25 : 1 Et2O : NEt3. An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography.  1H NMR (CDCl3, 400 MHz): δ (ppm) 7.36 – 7.15 (m, 15H, Ph), 4.77 (s, 1H, Ph2CHN), 3.75 (s, 2H, PhCH2N), 2.70 (t, 3JH,H = 6.3 Hz, 2H, NCH2), 2.63 (t, 3JH,H = 6.3 Hz, 2H, NCH2), 1.71 (m, 4H, CH2 and NH); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 144.2, 140.4, 128.4, 128.3, 128.1, 127.2, 126.8, 126.7, 67.7, 54.1, 48.1, 46.8, 30.2; MS (ESI): m/z 331 ([M+H]+); Anal. Calcd for C23H26N2: C, 83.59; H, 7.93; N, 8.48. Found: C, 83.67; H, 8.01; N, 8.54.  Phenethyl(phenyl)amine (25a).  This compound was prepared from aniline (0.109 mL, 1.2 mmol) and phenylacetylene (0.109 mL, 1.0 mmol) following Method D (reacted at room temperature) and reduced using Method III. Isolated as a yellow oil (0.170 g, 86%). Rf = 0.88, 4 : 1 Hex : Et2O. Spectral data matched literature references.453  1H NMR (CDCl3, 400 MHz): δ (ppm) 7.44 ─ 7.26 (m, 7H, Ph), 6.83 (t, 3JH,H = 7.3 Hz, 1H, Ph), 6.72 (d, 3JH,H = 8.9 Hz, 2H, Ph), 4.13 (br s, 1H, NH), 3.49 (t, 3JH,H = 7.0 Hz, 2H, NCH2CH2Ph), 3.01 (t, 3JH,H = 7.0 Hz, 2H, NCH2CH2Ph).    170  [3-(tert-Butyl-dimethyl-siloxy)-propyl]-phenylamine (25b).   This compound was prepared from aniline (0.056 g, 0.6 mmol) and (tert-butyldimethylsilyloxy)-1-propyne (0.093 g, 1.5 mmol) following Method C except with 10 mol% of 1 and reduced using Method III.  Isolated as a yellow oil (0.106 g, 80%). Rf = 0.67, 5 : 1 Hex : EtOAc. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.22 − 7.18 (m, 2H, Ph), 6.73 − 6.62 (m, 3H, Ph), 3.95 (br s, 1H, NH), 3.80 (t, 3JH,H = 5.8 Hz, 2H, OCH2CH2), 3.26 (t, 3JH,H = 6.5 Hz, 2H, NCH2CH2), 1.90 − 1.84 (m, 2H, NCH2CH2), 0.96 (s, 9H, tBu), 0.11 (s, 6H, SiMe2); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 148.6, 129.2, 116.9, 112.6, 61.9, 41.9, 32.0, 25.9, 18.3, -5.4; MS (EI): m/z 226 (M+).  HRMS (EI-EB) m/z: Calcd for C15H28NOSi (M+), 266.1940; Found: 266.1926.   [2-(tert-Butyl-dimethyl-siloxy)-1-methylethyl]-(2,6-dimethyl-phenyl)-amine (25e).   This compound was prepared from 2,6-dimethylaniline (0.074 mL, 0.6 mmol) and (tert-butyldimethylsilyloxy)-1-propyne (0.084 g, 0.5 mmol) following Method C and reduced using Method II.  Isolated as a yellow oil (0.042 g, 23%).  Rf  = 0.54, DCM with 1% NEt3. An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography.  1H NMR (CDCl3, 400 MHz): δ (ppm) 6.98 (d, 3JH,H = 7.2 Hz, 2H, Ar), 6.80 (t, 3JH,H = 7.2 Hz, 1H, Ar), 3.65 (m, 1H, MeCHCH2O), 3.56 (br m, 2H, MeCHCH2O + NH), 3.33 (br m, 1H, CH(NAr)), 2.29 (s, 6H, PhMe), 1.14 (d, 3JH,H = 6.4 Hz, 3H, CH3), 0.95 (s, 9H, tBu), 0.08 (s, 6H, SiMe2); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 129.6, 129.0, 121.5, 66.7, 53.8, 26.2, 19.1, 18.4, -5.1, -5.2; MS (ESI):  m/z 294 ([M+H]+); Anal. Calcd for C17H31NOSi: C, 69.56;  H, 10.65;  N, 4.77.  Found: C, 69.41; H, 10.55; N, 4.90.   171  N-(hexan-3-yl)aniline (26b).   This compound was prepared from aniline (0.055 mL, 0.6 mmol) and 3-hexyne (0.057 mL, 0.5 mmol) following Method C except at 110 °C in d8-toluene and reduced using Method II.  Isolated as a colourless oil (0.086 g, >98%).  Rf = 0.76, 4 : 1 Hex : Et2O. An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.27 − 7.18 (m, 2H, Ph), 6.72 – 6.62 (m, 3H, Ph), 3.45 (br s, 1H, NH), 3.36 (quint, 3JH,H = 5.8 Hz, 1H, CH2CHCH2CH3), 1.68 − 1.40 (m, 6H, CH2), 0.99 (t, 3JH,H = 7.5 Hz, 6H, Me); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 148.2, 129.2, 116.4, 112.8, 53.8, 36.7, 27.3, 19.1, 14.2, 10.0;  MS (EI):  m/z 178 ([M+H)+); Anal. Calcd for C12H19N: C, 81.30;  H, 10.80;  N, 7.90.  Found: C, 81.36; H, 10.80; N, 7.90.  N-(1,2-diphenylethyl)aniline (26c).  This compound was prepared from aniline (0.112 g, 1.2 mmol) and diphenylacetylene (0.107 g, 1.0 mmol) following Method B and reduced using a literature procedure.287 To a round bottom flask, Pd/C (53 mg, 10 mol% of Pd, 0.05 mmol of Pd, 5 mol%) and dry THF was added and stirred under an H2 atmosphere for 30 min.  The volatile components of the crude hydroamination reaction mixture were removed in vacuo, dissolved in dry THF and added to the Pd/C suspension.  The resulting mixture was stirred under 1 atm of H2 for 72 h.  Filtration over Celite, removal of solvent in vacuo and purification by column chromatography afforded the pure product.  Isolated as a colourless oil (0.269 g, 98%). Rf = 0.56, 4 : 1 Hex : Et2O. Spectral data matched literature references.60, 239 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.35 − 7.23 (m, 8H, Ph), 7.13 (d, 3JH,H = 6.7 Hz, 2H, Ph), 7.08 − 7.04 (m, 2H, Ph), 6.65 − 6.62 (m, 1H, Ph), 6.47 (d, 3JH,H = 7.8 Hz, 2H, Ph), 4.62 − 4.58 (m, 172  1H, NCH(Ph)CH2), 4.13 (br s, 1H, NH), 3.15 (dd, 2JH,H = 14.0 Hz, 3JH,H = 5.8 Hz, 1H, PhCH2CHPh), 3.02 (dd, 2JH,H = 14.0 Hz, 3JH,H = 8.4 Hz, 1H, PhCH2CHPh).  2,3,4,5,6-pentafluoro-N-(1-phenylpropan-2-yl)aniline (26e).   This compound was prepared from pentafluoroaniline (0.110 g, 0.6 mmol) and 1-phenyl-1-propyne (0.058 g, 0.5 mmol) following Method B and reduced using Method I. Rf = 0.59, 4 : 1 Hex : Et2O. Isolated as a colourless oil (0.137 g, 91%).  1H NMR (CDCl3, 400 MHz): δ 7.32 − 7.16 (m, 5H, Ph), 4.03 − 3.95 (br m, 1H, NH), 3.37 − 3.34 (m, 1H, NHCH(CH2Ph)Me), 2.89 (1H, dd, 2JH,H = 13.7 Hz, 3JH,H = 5.7 Hz, 1H NHCH(CH2Ph)Me), 2.70 (dd, 2JH,H = 13.7 Hz, 3JH,H = 7.0 Hz, 1H, NHCH(CH2Ph)Me), 1.18 (d, 3H, 3JH,H = 6.7 Hz, CH3); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 129.0, 128.4, 126.6, 52.3, 44.1, 21.2 (13C NMR signals for the fluorinated arene and 1 signal from an aryl carbon were not observed); 19F NMR (CDCl3, 282 MHz): δ (ppm) −159.1, −164.8, −171.9; MS (ESI):  m/z 300 ([M−H]-); HRMS (ESI-TOF) m/z: Calcd for C15H11NF5 ([M−H]-), 300.0806; Found: 300.0812.  N-(1-methyl-2-phenylethyl)-N-benzylamine (26f).   This compound was prepared from benzylamine (0.066 mL, 0.6 mmol) and 1-phenyl-1-propyne (0.063 mL, 0.5 mmol) following Method C except at 110 °C in d8-toluene and reduced using Method III.  Isolated as a colorless oil (0.151 g, 78%). Rf = 0.05, CH2Cl2 and 1% NEt3. Spectral data matched literature references.299  1H NMR (CDCl3, 400 MHz): δ (ppm) 3.34 − 7.17 (m, 10H, Ph), 3.87 (d, 2JH,H = 13.3 Hz, 1H, PhCH2N), 3.75 (d, 2JH,H = 13.3 Hz, 1H, PhCH2N), 2.96 (ap sextet, 3JH,H = 6.6 Hz, 173  1H, NCH), 2.79 (dd, 2JH,H = 13.3 Hz, 3JH,H = 6.6 Hz, 1H, PhCH2CH), 2.66 (dd, 2JH,H = 13.3 Hz, 3JH,H = 6.6 Hz, 1H, PhCH2CH), 1.45 (br s, 1H, NH), 1.11 (d, 3JH,H = 6.4 Hz, 3H, CH3).  N-Benzyl-3-hexylamine (26g).  This compound was prepared from benzylamine (66 μL, 0.6 mmol) and 3-hexyne (41 mg, 0.5 mmol) following Method B and reduced using Method III. Isolated as a colorless oil (0.070 g, 74%). Rf = 0.25, DCM : 10% MeOH : 1% NEt3.  Spectral data matched literature references.264  1H NMR (CDCl3, 400 MHz): δ (ppm) 7.29 − 7.14 (m, 5H, Ph), 3.72 − 3.67 (m, 2H, PhCH2N), 2.44 (quint, 3JH,H = 5.8 Hz, 1H, NCH), 1.46 − 1.25 (m, 7H, CH2 and NH), 0.87 − 0.81 (m, 6H, CH3).  N-(1,2-Diphenyl-ethyl)-N-benzylamine (26h).  This compound was prepared from benzylamine (66 μL, 0.6 mmol) and (phenylethynyl)benzene (92 mg, 0.5 mmol) following Method B except in anhyd toluene at 130 °C for 48 h and reduced using Method III.  Isolated as a yellow oil (94 mg, 65%). Rf = 0.13, 30 : 1 Et2O : NEt3. Spectral data matched literature references.454 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.38 − 7.11 (m, 15H, Ph), 3.90 (dd, 3JH,H = 8.5, 5.5 Hz, 1H, PhCH2CH(NHBn)Ph), 3.67 (d, 2JH,H = 13.7 Hz, 1H, NHCH2Ph), 3.47 (d, 2JH,H = 13.7 Hz, 1H, NHCH2Ph), 3.00 − 2.88 (m, 2H, PhCH2CH(NHBn)Ph).    174  N-(2-(4-methoxyphenyl)-1-phenylethylphenylamine (27i) and N-(1-(4-methoxyphenyl)-2-phenylethylphenylamine (27ii).   These compounds were prepared from aniline (0.056 g, 0.6 mmol) and (4-methoxyphenyl)phenylacetylene (0.104 g, 1.0 mmol) following Method B and reduced using a literature procedure.287 To a round bottom flask, Pd/C (27 mg, 10 mol% of Pd, 0.025 mmol of Pd, 5 mol%) and dry THF were added and stirred under an H2 atmosphere for 30 min.  The volatile components of the crude hydroamination reaction mixture were removed in vacuo, dissolved in dry THF and added ti the Pd/C suspension.  The resulting mixture was stirred under 1 atm of H2 for 72 hr.  Filtration over Celite, removal of solvent in vacuo and purification by column chromatography (5 : 1, PE : Et2O, Rf = 0.26) afforded the pure product. A combined yield of 71% (0.105 g) was obtained for the mixture of regioisomers (1 : 2, i : ii) as a pale yellow oil,  which were inseparable by chromatography.  The 1H and 13C NMR spectra for the mixture have been provided. Spectral data of 27ii matched literature references.419  1H NMR (CDCl3, 300 MHz): δ (ppm) 7.40 – 7.28 (m, 5H,  i and ii), 7.20 – 7.09 (m, 4H, i and ii), 6.94 – 6.87 (m, 2H,  i and ii), 6.74 – 6.69 (m, 1H, i and ii), 6.55 (2H,  d,  J = 8.1 Hz, i and ii), 4.65 – 4.61 (m, 1H, i and ii), 4.18 (br s, 1H,  i and ii), 3.85 (s, 3H, i and ii), 3.21 –  3.00 (m, 2H,  i and ii);  13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 158.5, 158.3, 147.3, 143.4, 137.7, 135.3, 130.1, 129.5, 129.2, 128.9, 128.4, 128.4, 127.4, 126.9, 126.6, 126.4, 117.3, 117.3, 113.9, 113.6, 59.2, 58.5 (ii), 55.1 (i and ii), 45.1 (ii), 44.2;   MS (ESI):   m/z  304 ([M+H]+); HRMS (ESI-TOF) Calcd for C21H22NO [M+H]+:   304.1701;  Found:  304.1699.  175  4-methoxy-N-(2-phenyl-1-(4-(trifluoromethyl)phenyl)ethyl)aniline (28i) and 4-methoxy-N-(1-phenyl-2-(4-(trifluoromethyl)phenyl)ethyl)aniline (28ii) These compounds were prepared from para-methoxyaniline (69 mg, 0.6 mmol) and (4-trifluoromethylphenyl)phenylacetylene (90 mg, 0.6 mmol) following Method B and reduced using a literature procedure.287 To a round bottom flask, Pd/C (27 mg, 10 mol% of Pd, 0.025 mmol of Pd, 5 mol%) and dry THF were added and stirred under an H2 atmosphere for 30 min.  The volatile components of the crude hydroamination reaction mixture were removed in vacuo, dissolved in dry THF and added the to Pd/C suspension.  The resulting mixture was stirred under 1 atm of H2 for 72 hr.  The reaction mixture was then filtration over Celite and the volatile components were removed in vacuo. 19F NMR spectroscopy of the crude product mixture was obtained to ratio of regioisomers. Two subsequent column chromatography (3 : 2 : 1 PE : benzene : Et2O then 5 : 1 : 1 PE : benzene : Et2O, Rf = 0.57, 3 : 2 : 1 PE : benzene : Et2O) resulted in partial separation, which afforded 28i in 37% (61 mg) and 28ii in 10% (14 mg) with a combined yield of 70% (93 mg). 28i: 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.40 (br d, 2H, Ar), 7.19 – 7.08 (m, 7H, Ar), 6.57 (br d, 2H, Ar), 6.37 (br d, 2H Ar), 4.45 (t, 3JH,H = 6.7 Hz, 1H, PhCH2CHAr), 3.58 (s, 3H, OMe), 3.06 (d, 3JH,H = 6.7 Hz, 2H, PhCH2CHAr), 1.45 (br s, 1H , NH). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 152.2, 142.9, 142.0 (q, 3JF,C = 1.7 Hz), 141.0, 129.5, 128.6, 127.3, 126.5, 125.3 (q, 4JF,C = 3.9 Hz), 114.9, 114.7, 59.8, 55.6, 44.7 (CF3 and 1 aryl carbon are not observed); 19F NMR (CDCl3, 282 MHz) δ (ppm) - 62.8;  MS (ESI):   m/z  372 ([M+H]+); HRMS Calcd for C22H21 F3NO [M+H]+:   372.1575;   Found:   372.1577.  An X-ray quality crystal was obtained from first dissolving the product in 176  DCM, followed by rotary evaporation and then recrystallization from hexanes at room temperature. 28ii: 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.47 (d, 3JH,H = 8.1 Hz, 2H, Ar), 7.34 (d, 3JH,H = 8.1 Hz, 2H, Ar), 7.22 – 7.14, (m, 3H, Ar), 7.02 (d, 3JH,H = 6.7 Hz, 2H, Ar), 6.55 (d, 3JH,H = 8.7 Hz, 2H, Ar), 6.27 (d, 3JH,H = 8.7 Hz, 2H, Ar), 4.46 (ap t, 1H, PhCHCH2Ar), 3.04 - 2.86 (m, 2H, PhCHCH2Ar), 2.57 (s, 3H, OMe), 1.46 (br s, 1H, NH). 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 152.2, 147.9 (br s), 141.0, 137.1, 129.1, 128.7, 127.0, 126.8, 125.6, 125.5 (q, 4JF,C = 4.0 Hz), 115.0, 114.7, 59.7, 55.7, 45.1 (CF3 and 1 aryl carbon are not observed); 19F NMR (CDCl3, 282 MHz) δ (ppm) - 62.7; MS (ESI):  m/z  372 ([M+H]+); HRMS (ESI-TOF) Calcd for C22H21F3NO [M+H]+: 372.1575; Found:  372.1574.    3.4.7 Synthesis of Standard Solution of Complex 20 and Hydroamination Reaction with the Solution of Precatalyst A 100 mL Schlenk bomb equipped with a stir bar was charged with N-(2,6-diisopropylphenyl)benzamide (0.563 g, 2.0 mmol). The vessel was placed under high vacuum for 24 hours at 40 °C. At room temperature, 30 mL of toluene was added. A separate Schlenk flask was charged with Ti(NMe2)4 (0.237 g, 1.0 mmol) and diluted with 20 mL of toluene. The solution of the titanium complex was slowly added to the proligand suspension. The total amount of toluene was kept at 50 mL. The mixture was then stirred at room temperature for 24 hours resulting in a deep red solution at a concentration of 0.050 M. The precatalyst was stored in the Schlenk bomb at room temperature and did not exhibit any observable signs of decomposition. The reactions with this solution of precatalyst were carried out as follows. The reaction is carried out in either a Schlenk flask or round bottom flask (equipped with a septa and a N2 balloon) equipped with a stir bar charged with 5 mL of the precatalyst solution. Prior to use both substrates were dried over 177  CaH2 (4-5 hours at room temp.) and freshly distilled by bulb-to-bulb distillation. Phenylacetylene (0.55 mL, 5.0 mmol) and benzylamine (0.55 mL, 5.0 mmol) was then added to the solution of catalyst. The reaction was then carried out in the usual manner (65 °C, 24 hr), and following reduction, the secondary amine product was isolated using back extraction. The same procedure was also carried out using a round bottom flask equipped with a condenser and a dry tube. The reaction was carried out at 110 °C for 30 min. The same setup was used at 110 °C for 24 hours, GC-MS revealed a signal at m/z 195. The mixture was diluted with methanol and NaBH4 (0.58 g, 15.3 mmol) was added. The reaction was stirred at room temp. for 24 hours. The reaction was then diluted with 10 mL of EtOAc and quenched with 10 mL of 1M HCl(aq). Following separation, the organic layer was extracted with 3 × 10 mL 1M HCl(aq). The combined aqueous layer was basified with 6M NaOH and extracted with 3 × 40 mL EtOAc. The combined organic layer was dried with K2CO3, filtered and the volatiles were removed by rotary evaporation. Following column chromatography (1 : 1 hex : Et2O → Et2O with 1% NEt3), dibenzylamine was obtained in 32% (0.157 g) as yellow oil.  1H NMR (CDCl3, 300 MHz): δ (ppm) 7.26 – 7.16 (m, 10H, Ph), 3.73 (s, 4H, PhCH2N), 1.58 (br s, 1H, NH); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 140.3, 128.3, 128.1, 126.9, 53.1; GC-MS (CI) m/z 198 ([M+H]+).    3.4.8 General Procedure for Hydroamination/Hydrosilylation Reaction Sequence The following procedure was modified from literature.425 In a 2 mL vial, complex 20 (5 – 10 mol%) and alkyne (1 equiv.) were dissolved in toluene and transferred to a Schlenk bomb equipped with a stir bar. Amine (1.2 equiv.) was dissolved in toluene and added to the reaction mixture. The bomb was sealed and stirred at specified temperature. Following cooling to room temperature, PhSiH3 (3 equiv.), piperidine (0.4 equiv.) and MeOH (0.4 equiv.) were added to the 178  reaction mixture. The bomb was sealed and heated to 110 °C. The reaction was diluted with 15 mL of Et2O and then poured into 15 mL of 1M NaOH. The mixture was vigorously stirred at room temperature for 16 hours. The aqueous layer was separated and extracted with 4 × 30 mL of Et2O. The combined organic layer was washed with 10 mL of saturated NaCl(aq), dried with Na2SO4, filtered and the volatiles were removed using rotary evaporation. The secondary amine products were isolated using column chromatography.   4-methoxy-N-(1-phenylpropan-2-yl)aniline.  This compound was prepared by following the general procedure for the hydroamination/hydrosilylation reaction sequence with 1-phenyl-1-propyne (116 mg, 1.0 mmol), para-methoxyaniline (147 mg, 1.2 mmol), complex 20 (69 mg, 0.1 mmol), PhSiH3 (0.37 mL, 3.0 mmol), piperidine (0.04 mL, 0.4 mmol) and MeOH (0.02 mL, 0.4 mmol). Column chromatography (16 : 1 hex:  Et2O) afforded the title compound in 17% yield as an oil. Spectral data matched literature references.455 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.36 − 7.21 (m, 5H, Ar), 6.87 − 6.82 (m, 2H, Ar), 6.67 − 6.63 (m, 2H, Ar), 3.79 (s, 3H, OCH3), 3.75 − 3.71 (m, 1H, CH), 3.30 (br s, 1H, NH), 2.97 (dd, 1H, 2JH,H = 13.2 Hz, 3JH,H = 4.8 Hz, PhCH2C), 2.71 (dd, 1H, 2JH,H = 13.2 Hz, 3JH,H = 7.2 Hz, PhCH2C), 1.17 (d, 3H, 3JH,H = 6.0 Hz, CH3).  N-(1-methyl-2-phenylethyl)-N-benzylamine.  This compound was prepared by following the general procedure for the hydroamination/hydrosilylation reaction sequence with 1-phenyl-1-propyne (116 mg, 1.0 mmol), benzylamine (128 mg, 1.2 mmol), complex 20 (69 mg, 0.1 mmol), PhSiH3 (0.37 mL, 3.0 mmol), piperidine (0.04 mL, 0.4 mmol) and MeOH (0.02 mL, 0.4 mmol). Column 179  chromatography (DCM: 1.5% MeOH, 1% NEt3) afforded the title compound in 33% yield (74 mg) as an oil. Spectral data matched literature references.299 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.34−7.17 (m, 10H, Ph), 3.87 (d, 1H, 2JH,H = 13.3 Hz, PhCH2N), 3.75 (d, 1H, 2JH,H = 13.3 Hz, PhCH2N), 2.96 (sext, 1H, 3JH,H = 6.4 Hz, CH), 2.79 (dd, 1H, 2JH,H = 13.3, 3JH,H = 6.4 Hz, PhCH2C), 2.66 (dd, 1H, 2JH,H = 13.3, 3JH,H = 6.4 Hz, PhCH2C), 1.45 (br s, 1H, NH), 1.11 (d, 3H, 3JH,H = 6.4 Hz, CH3).  N-hexylbenzylamine.  This compound was prepared by following the general procedure for the hydroamination/hydrosilylation reaction sequence with 1-hexyne (82 mg, 1.0 mmol), benzylamine (128 mg, 1.2 mmol), complex 20 (69 mg, 0.1 mmol), PhSiH3 (0.37 mL, 3.0 mmol), piperidine (0.04 mL, 0.4 mmol) and MeOH (0.02 mL, 0.4 mmol). Following column chromatography (Et2O with 2% NEt3) afforded the title compound in 47% yield (89 mg) as an oil. Spectral data matched literature references.85 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.34 – 7.25 (m, 5H, Ph), 3.80 (s, 2H, NHCH2Ph), 2.63 (t, 3JH,H = 7.3 Hz, 2H, CH3(CH2)4CH2NH), 1.54 – 1.30 (m, 9H, CH2 and NH), 0.89 (t, 3JH,H = 6.5 Hz, 3H, CH3).  N-(phenylmethyl)-2-phenylethylamine This compound was prepared by following the general procedure for the hydroamination/hydrosilylation reaction sequence with phenylacetylene (102 mg, 1.0 mmol), benzylamine  (102 mg, 1.2 mmol), complex 20 (69 mg, 0.1 mmol), PhSiH3 (0.37 mL, 3.0 mmol), piperidine (0.04 mL, 0.4 mmol) and MeOH (0.02 mL, 0.4 mmol). Column chromatography afforded the titled compound in 18% (41 mg) yield as an oil.  1H NMR (CDCl3, 180  400 MHz): δ (ppm) 7.40 − 7.24 (m, 10H, Ph), 3.86 (s, 2H, NCH2), 2.99 − 2.89 (m, 4H, CH2), 2.36 (br s, 1H, NH).  3.4.9 Hydroamination/Isomerization Reaction Sequence: N-hexyl-4-methylbenzenesulfonamide (33).    In 2 mL vial, complex 20 (139 mg, 0.2 mmol) and 1-hexyne (0.329 mg, 4.0 mmol) were dissolved with C6H6 (~5 mL) and transferred to a Schlenk flask equipped with a stirbar. Benzylamine (514 mg, 4.7 mmol) was then added and the flask was sealed and heated to 65 °C for 12 hours. In a separate Schlenk flask, t-BuOK (673 mg, 6.0 mmol) was dissolved in Et2O (~20 mL). The solution of t-BuOK was then added to the reaction mixture via a cannula transfer resulting in a red solution. The resulting mixture was heated to reflux for 2 hours resulting in an orange-yellow solution. The solution was then poured into 25 mL of distilled water. The organic layer was separated and washed with 2 × 15 mL distilled water, 15 mL brine, dried with K2CO3 and filtered. Following the removal of the volatile components via rotary evaporation, the title compound was obtained in 1.023 g as a mixture with the amide proligand and was used without further purification. The mixture was dissolved in distilled water (ca 10 mL) and the mixture was cooled to 0 °C, where concentrated HCl(aq) (0.48 mL, 4.7 mmol) was added dropwise. The solution 181  was then washed with 3 × 10 mL of DCM and volatiles were removed by rotary evaporation to afford an oil. Ethanol was then added and the volatiles were removed by rotary evaporation to afford a white solid. The solid was dissolved in DCM. To the solution, NEt3 (1.16 mL, 8.2 mmol) and TsCl (1.14 g, 10.3 mmol) were added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was reduced in vacuo and purified by column chromatography (5:1 hexanes : EtOAc, Rf = 0.545). The title compound was obtained in 42% yield (427 mg, 1.7 mmol) as a white solid. Spectral data matched literature references.456 1H NMR (CDCl3, 300 MHz): δ  (ppm) 7.77 (d, 3JH,H = 8.3 Hz, 2H, Ar), 7.30 (d, 3JH,H = 8.3 Hz, 2H, Ar), 5.01 (t, 3JH,H = 6.7 Hz, 1H, NH), 2.91 (q, 3JH,H = 6.7 Hz, 2H, CH2NH), 2.42 (s, 3H, ArCH3), 1.46 – 1.39 (m, 2H, CH2CH2NH), 1.26 – 1.15 (m, 6H, CH2), 0.83 (t, 3JH,H = 7.1 Hz, 3H, CH3).  3.4.10 Hydroamination/Alkyne Addition: Synthesis of Substituted Allylamine 36.  In a 2 mL vial, complex 20 (34 mg, 0.05 mmol) and 1-hexyne (82 mg, 1.0 mmol) were dissolved in d8-toluene (600 μL) and transfered to a J. young NMR tube. Benzhydrylamine (183 mg, 1.0 mmol) was dissolved in d8-toluene (400 μL) and added to the reaction mixture. The tube 182  was sealed and heated to 65 °C for 24 hours. After cooling to room temperature, ReBr(CO)5 (41 mg, 0.1 mmol) and 1-hexyne (82 mg, 1.0 mmol) were added to the reaction mixture. The tube was resealed and heated to 110 °C for 24 hours and monitored by 1H NMR spectroscopy.  The reaction was diluted with Et2O (~ 20 mL) and quenched with distilled water (~ 10 mL). Following separation, the aqueous layer was extracted with 2 × 10 mL of Et2O. The combined organic layer was dried with Na2SO4, filtered, and the volatiles were removed by rotary evaporation. Using an automated column chromatography machine, the compound 35 was obtained as an orange oil in 61% yield (213 mg). 1H NMR (CDCl3 , 400 MHz): δ  (ppm) 7.74 - 7.71 (m, 2H, Ar), 7.49 – 7.35 (m, 6H, Ar), 7.21 – 7.19 (m, 2H, Ar), 4.88 (s, 1H, NCHRCRCH2), 4.82 (s, 1H, NCHRCRCH2), 3.84 (m, 1H, NCHRCRCH2), 2.27 – 2.08 (m, 2H), 1.77 – 1.72 (m, 2H), 1.45 – 1.17 (m, 10H), 0.97 – 0.89 (m, 6H, CH3); 13C NMR (CDCl3, 100 MHz): δ  (ppm)  165.9 (Ph(Ph)CN), 152.3, 141.2, 137.3, 129.6 (NCHRCRCH2), 128.4, 128.1, 128.0, 127.9, 127.8, 109.5 (NCHRCRCH2), 67.5 (NCHRCRCH2), 35.6, 32.3, 31.8, 30.3, 26.3, 22.6, 22.6; MS (ESI):  m/z  348 ([M+H]+); HRMS (ESI-TOF) Calcd for C25H34N [M+H]+:   348.2691;   Found:   348.2692.  Alternatively, after the reaction was completed, the mixture was transferred to a round bottom flask equipped with a stir bar. To this solution, 10 mL of MeOH and 10 mL of 1 M HCl(aq) was added and the mixture was stirred as room temperature for 16 hours. The mixture was concentrated by rotary evaporation. Concentrated NaOH(aq) was added dropwise until the solution was basic. The resulting solution was then extracted with 3 × 10 mL of DCM. The combined organic layer was dried using Na2SO4, filtered and concentrated by rotary evaporation. Following column chromatography, compound 36 was obtained in 45% (81 mg) overall yield over 3 steps as a yellow oil. (Rf = 0.34, DCM with 5% MeOH and 1% NEt3). Spectral data matched literature references.438 1H NMR (C6D6, 300 MHz): δ (ppm) 5.01 (s, 1H, C=CH2), 4.83 (s, 1H, C=CH2), 3.21 – 3.17 (m, 183  1H, NH2CH), 2.11 – 1.94 (m, 2H, NH2CHCH2), 1.47 – 1.26 (m, 14H, CH2 and NH2), 0.92 – 0.87 (m, 6H, CH3).  3.4.11 Procedure for Oligomerization with Hydroamination Oligomerization of para-1-hexynylaniline (39). A Schlenk flask equipped with a stir bar was charged with complex 20 (35 mg, 0.05 mmol) dissolved in 1.5 mL of anhydr. toluene. para-1-Hexynylaniline (87 mg, 0.5 mmol) was then added resulting in a deep red solution. The flask was then sealed and heated to 110 °C for 24 hours. Under an inert atmosphere, the reaction mixture was transfered to a vial and the volatile components were removed in vacuo resulting in a red solid that is a mixture of the oligomers and the titanium precatalyst (133 mg). FT-IR (ATR, cm-1) ν(N─H) 3296 (weak), ν(C─H) 2968 (medium), ν(C─H) 2956 (medium), ν(C─H) 2928 (medium), no signals from 2500 – 2000, ν(N=C) 1644 (strong), ν(C=Caryl) 1500 (strong); UV-Vis (DCM, ca. 10-5 M): λmax = 241, 290 nm; MALDI-TOF MS: highest molecular weight species 2266 = 13 × (173) + 17 m/z and 2334 = 14 × (173) + 88.  Oligomerization of 2-phenylethynylaniline (41). A Schlenk flask equipped with a stir bar was charged with complex 20 (35 mg, 0.05 mmol) dissolved in 1.5 mL of anhydr. toluene. 2-Phenylethynylaniline (96 mg, 0.5 mmol) was then added resulting in a deep red solution. The flask was then sealed and heated to 110 °C for 24 hours. After cooling the solution was poured into a vortex of hexanes mixed with a few drops of H2O. The yellow precipitate was collected (89.9 mg). FT-IR (ATR, cm-1) ν(C─H) 3062 (weak), no signals from 2500 – 2000, ν(C=Caryl) 1590 (medium), ν(C=Caryl) 1513 (medium), ν(C─N) 1303 (medium), 184  ν(C─N) 1210 (medium); UV-Vis (THF, ca. 10-5 M): λmax = 311, 360 nm; MALDI-TOF MS: highest molecular weight species 1951 = 10 × (193) + 21 m/z.   3.4.12 Crystallographic Structure Determination  All X-ray diffraction measurements were performed on a Bruker X8 APEXII CCD diffractometer at 100 K or on a Bruker DUO APEXII CCD diffractometer at 90 K with Mo Kα graphite-monochromated radiation (λ = 0.71073 Å). Data were collected and integrated using the Bruker SAINT235 software packages. Both crystals formed non-merihedral twins consisting of two components. Data were integrated for both twin components, including both overlapped and non-overlapped reflections. Data were corrected for absorption effects using the multi-scan techniques (TWINSABS240). The structures were solved by direct methods using the programs SHELXS237 or XT237 and structure refinement was conducted based on the program SHELX.237 The structures were drawn by ORTEP-3 software.238 The suite OLEX-2 was used as integrated system for all crystallographic programs and software.239 All non-hydrogen atoms were refined with anisotropic displacement parameters. Unless otherwise noted, all H atoms were inserted in calculated positions and refined with a riding model. Crystal data collection and refinement parameters are tabulated in Table 3-11.       185  Table 3-11: Crystal data collection and refinement parameters for complex 20 and compound 28i. Compounds 20 28i Empirical Formula C42H56N4O2Ti C22H21ClF3NO Mw 696.80 407.85 Space Group P-1 Pbca a [Å] 10.377(11) 6.6923(9) b [Å] 13.548(14) 20.874(3) c [Å] 16.291(18) 28.511(4) α [°] 101.183(19)  β [°] 99.22(2)  γ [°] 108.176(19)  V [Å3] 2074(4) 3983.0(9) Z 2 8 Dcalc (g cm-3) 1.116 1.360 μ [mm-1] 0.243 0.231 Crystal Size (mm) 0.48 × 0.42 × 0.11 0.14 × 0.07 × 0.05 θ range (°) 2.6 – 27.8 2.4 – 25.0 No. of reflections measured 10890 3491 No. of independent reflections 10890 2708 R1 [F2 > 2σ(F2)], wR2(F2) 0.0485, 0.1215 0.068, 0.259 S 1.06 1.24 186  Chapter 4: Library Synthesis of Aminoethers via Hydroamination as Target for Calcium Ion Channel Blockers  4.1 Introduction   Prostate cancer is the most common cancer among Canadian men and is a devastating disease. In 2010 alone, Statistics Canada reported 21,930 new cases457 and 3,833 deaths458 related to prostate cancer. The progression of prostate cancer is divided into four distinct phases: localized, recurrent, metastatic, and hormone refractory. The two early phases (localized and recurrent) are readily treatable with current medical technology.459 When the cancer cells start to migrate and invade other organs (metastatic phase), the treatment options are limited to only hormone therapies and some chemotherapy.460  The most advanced stage of prostate cancer, where cancer cells still proliferate even with hormone suppression therapy (hormone refractory phase), currently has no curative treatments.460  A recent study has shown that human prostate cancer cells express higher levels of T-type calcium channels.461 This presents a new method to selectively target cancerous cells during therapy. T-type calcium channels are ion channels that allow calcium ions to enter the cell when a low voltage electrical stimulus is applied. Since cancer is the uncontrolled growth of cells and intracellular calcium concentration regulates cell cycle processes (cellular differentiation, cell cycle progression, locomotion, apoptosis, and proliferation),462 alteration of the calcium homeostasis is a potential method to directly control the growth of cancer cells. These particular voltage-dependent calcium channels possess unique biophysical properties that allow the selective inhibition of T-type calcium channels without the disruption of other down-stream calcium 187  dependent processes.462 Consequently, T-type calcium channel blockers have been developed as new tools for cancer elimination.463  A classic example of a T-type calcium channel blocker is Mibefradil (Figure 4-1, 43), formerly commercially available as Posicor®. Although it was not used to treat prostate cancer, it was effective at treating hypertension and angina. Mibefradil is an effective T-type calcium channel blocker but due to its lack of selectivity and other off-target drug-drug interactions it was removed from the market. A variant of this drug, Mibefradil dihydrochloride, in combination with temozolomide, has recently entered phase 1 clinic trails towards treating patients with Glioma (a type of tumor in the brain or spine) (NCT01480050).     Figure 4-1: Structural formula of Mibefradil (43).  One challenge in choosing T-type calcium channels as the drug target is the difficulty of selectively targeting one ion channel. Due to the fact that sodium or potassium ion channels, as well as other calcium channels, such as the high voltage-dependent L- (found in heart cells) and N-type (found in neural cells),464 are required for other essential biological processes, successful T-type calcium channel blockers should ideally only inhibit the desired T-type calcium channels.  188  Voltage-dependent calcium channels, in the simple “ball and chain” model (Figure 4-2), can exist in three states: closed, open, and inactivated. The closed state is the resting state of the channels, where ions are not able to enter the cell. When an electrical stimulus is applied, the channels exist in the open configuration in which ions can enter into the cell. Once the peak potential is reached, the channels quickly enter into the inactive state, where ions once again cannot enter the cell. From a clinical perspective, a successful compound should selectively interact with the channels in the inactivated state.465     Figure 4-2: The “ball and stick” model of a voltage-gated ion channel. Image was reprinted from Biochemistry, Sixth Edition, © 2007 W.H. Freeman and Company.466  To identify a potential compound of interest, the assembly of libraries of compounds is  common practice for medicinal chemists.467 These chemical libraries can undergo high-throughput screening of a drug target against the compounds in the library which allow for the rapid assessment of the biological activity of a large set of compounds.467 With this information, common structural features of active compounds can be identified. These structural features can provide a map of pharmacophores, which could be used to refine the design of future target compounds.467 Despite these voltage-gated calcium ion channels being extensively studied where the general structure has been determined,464, 468-470 many questions about the details of its structure 189  remain unknown. Only recently, the structural basis for the ion selectivity for these ion channels has been established based on X-ray crystallography studies.469 However, the exact nature of how an antagonist interacts with the channel remains unknown. A virtual screening study by Pae and coworkers has identified potential pharmacophores with a 6-feature model,471 which others have used to aid in their design of T-type calcium ion channel blockers.472 However, using the same method in a different study with a different set of substrates, a revised 5-feature pharmacophore model has been proposed.473 While these models can offer guidelines on how to design bioactive molecules, the conflicting nature of these models suggest variability of the active structural motifs. As a gross generalization, currently known active T-type calcium channel blockers typically have a structural motif containing a rigid core scaffold that is flanked by two functionalized end-groups (Figure 4-3).    Figure 4-3: Simplified model of a typical T-type calcium channel blocker.  In an effort to develop a potent and more selective drug than Mibefradil, McCalmont et al. synthesized two novel T-type calcium channel blockers (Figure 4-4, 44 and 45). Compound 44 and 45 exhibited similar potency to and increased selectivity over Mibefradil, but they are still insufficiently active to be commercialized as T-type calcium channel blockers.474-475 Despite the structural differences of lead compounds 44 and 45, they share one very important similarity: both molecules contain an amine functionality linked to a heteroatom that has aromatic substituents, 190  which is key to the biological activity of the compound.8-10 In McCalmont’s synthetic strategy of 44 and 45, traditional synthetic routes for the preparation of amines are used, which generally suffer from drawbacks such as over N-alkylation and generation of stoichiometric by-products as waste.10 Catalytic amine syntheses, on the other hand, can be 100% atom economical reactions and product purification can be simplified due to minimal by-product formation.  Such catalytic synthetic strategies can be used to rapidly assemble two libraries of compounds (Figure 4-6, class I and class II) with variable aryl group (R1, R2, R3), the heteroatoms (X) and the carbon tether lengths (a-c). These libraries could then be used to study the structure-activity relationship towards T-type calcium channel antagony, which can be used to advantage to better understand desirable small molecule interactions with T-type Ca2+ ion channels.  Such insight may help in developing T-type calcium channel blockers with further enhanced selectivity and potency.  Figure 4-4: (top) Reported T-type calcium channel blockers with similar potency with improved selectivity than Mibefradil. (bottom) Our class of target compounds. R1-4  = varying substituents, a-c = 0-6, X = O or N.  191   In particular, class I compounds can be rapidly prepared via intermolecular hydroamination. As shown in the previous chapter, aminoethers can be assembled from benzylamine derivatives and protected alkynylalcohols with the aid of complex 20. By varying the coupling partners, a number of aminoethers can be rapidly synthesized. In addition, the synthesized secondary aminoethers can be further functionalized to access other molecular scaffolds. The Schafer group has not only developed efficient catalysts for intermolecular hydroamination but also catalysts for the intramolecular variant.103, 106, 109-110    Scheme 4-1: Retrosynthetic scheme for the synthesis of aminoether-type compounds.  The assembly of the library of class II N-heterocyclic compounds was undertaken in collaboration with Dr. Robbie Zhai. Dr. Zhai used conventional stoichiometric based transformations to synthesize various compounds with either a pyrrolidine or piperidine core (Figure 4-5). These N-heterocyclic cores could also be accessed by intramolecular cyclohydroamination reaction, which is a catalytic method to assemble these compounds. Additionally, the benzhydryl moiety is a relatively common feature in calcium ion channel blockers, which are typically located at the peripheries of the compound.316, 472, 474-477 By using hydroamination, pyrrolidine or piperidine cores with a benzhydryl moiety on the backbone could be assembled (Scheme 4-2). These complementary compounds with a unique core could then be tested for activity as T-type calcium ion channel blockers. 192   Figure 4-5: Pyrrolidine and piperidine derivatives synthesized by Dr. Robbie Zhai.   Scheme 4-2: Retrosynthetic scheme for the synthesis of N-heterocyclic compounds with hydroamination.  4.1.1 Scope of this Chapter  This chapter describes the preparation of a library of aminoethers via intermolecular hydroamination catalyzed by complex 20. The novel products were characterized by 1H and 13C{1H} NMR spectroscopy and mass spectrometry.  The synthesis of these products further confirm the wide scope of reactivity of complex 20. Furthermore, cyclic amines were synthesized using intramolecular hydroamination with complex 50 to assess the activity of the resulting scaffolds. These compounds were tested by our collaborators, Prof. Terrance Snutch and his academic research group and Zalicus Pharmaceuticals Ltd, using a FLIPR assay (vide infra) to probe rapidly their bioactivity towards blocking calcium ion channels.  193  4.2 Results and Discussion  4.2.1 Synthesis of Aminoether Library  As shown in the previous chapter, complex 20 can catalyze the hydroamination reaction of various amine and benzhydryl protected propargyl alcohols to assemble the aminoether core. Additionally, complex 20 is able to tolerate a wide range of functional groups. This allows various alcohol protecting groups and substituted amines to be used, which would provide variations to the end groups of the scaffold. In total 20 aminoether compounds were prepared as a small library (Figure 4-6). Each aminoether was prepared on a 100-200 mg scale and was characterized with 1H/13C{1H} NMR spectroscopy and mass spectrometry.   Figure 4-6: Complete library of aminoether (Class I) compounds synthesized for biological screening.  194  These aminoether compounds were synthesized using hydroamination of a protected propargyl alcohol with an amine. As shown in Chapter 3, complex 20 has a large amine substrate scope which then allows for the synthesis of various aminoethers. As shown in Scheme 4-3, not only can derivatives of benzylamine (24i, 46a and b) but arylamines (46c), alkylamines (46d-f) and phenethylamines (46g and h) can also be used to afford the corresponding secondary amines following reduction.  Compounds 46d and e were prepared by Mr. David Le, a part-time summer undergraduate student who worked under my supervision.     Scheme 4-3: Hydroamination of an amine and benzhydryl protected propargyl alcohol in the presence of complex 20 to afford aminoether (Class I) compounds.     Synthesis of the alkyne substrates is accomplished by starting with the reduction of commercially available benzophenone using NaBH4. A subsequent Williamson ether synthesis with the resulting alcohol and propargyl bromide affords the protected propargyl alcohol substrates. Other derivatives of benzophenone could be used to alter the end group of the resulting aminoether (Scheme 4-4, 47a-d). Compound 47d was prepared by Mr. David Le. As shown in 195  Chapter 3, complex 20 is also able to tolerate silyl protected propargyl alcohols, these substrates were also used to obtain the corresponding aminoethers (24j, 25b), which would probe the effect of a silyl ether on the bioactivity of these compounds.  Scheme 4-4: Hydroamination of an amine and protected propargyl alcohol in the presence of complex 20 to afford aminoether (Class I) compounds.  Complex 20 was also used to generate new core structures with variable carbon tethers to be tested for their bioactivity. Extension of the linker length between the N and O atoms of the aminoether core, homopropargyl bromide was used to afford the corresponding compounds (Scheme 4-5, 48a-c).  These investigations were completed in collaboration with a previous visiting scholar, Dr. Christine Rogers, who synthesized compounds 47a, 48a and b. The nitrogen atom aminoethers, such as compound 24i, can be further functionalized with the addition of a N-benzyl (49a) or N-tosyl (49b) substituent, which can then be used to probe the effect of N-substituents (Scheme 4-6). Finally, the heteroatom X can be varied in diamine 24l, which was 196  shown in Chapter 3 made by the hydroamination of benzhydryl protected propargyl amine with benzylamine followed by global reduction.    Scheme 4-5: Hydroamination of an amine and protected homopropargyl alcohol in the presence of complex 20 to afford aminoether (Class I) compounds.   Scheme 4-6: Functionalization of compound 24i.  197   The Schafer group has reported other competent hydroamination catalysts. For example, tethered bis(ureate) zirconium complex 50 has been shown to be an efficient intramolecular and intermolecular hydroamination catalyst with a unique substrate scope for group 4 metal complexes.109-110 It is well established that cyclohydroamination of an aminoalkene, such as 51, offers access to cyclic amines. Using complex 50, the cyclohydroamination of aminoalkene 51 afforded the N-heterocycles 52 (Scheme 4-7). Further functionalization of these amines offers a small set of cyclic tertiary amines (53a and b) to test their bioactivity (Scheme 4-8).    Scheme 4-7: Synthesis of benzhydryl substituted cyclic amines (Class II) with complex 50.   Scheme 4-8: Functionalization of compound 52a.  Notably, complex 50 is also able to facilitate intermolecular hydroamination.110 Thus, instead of two sequential synthetic steps, hydroamination can be used to synthesize a substituted 198  pyrrolidine product in a one-pot fashion to afford the N-substituted pyrrolidine (Scheme 4-9). First, cyclic hydroamination of aminoalkene 51a catalyzed by complex 50 (10 mol% at 110 °C in d8-toluene) affords pyrrolidine 52a, where upon the addition of phenylacetylene, a subsequent intermolecular hydroamination gives the enamine product 54. A slightly higher reaction temperature (145 °C) is needed to promote reactivity with the ortho-substituted variant of the pyrrolidine, to give >95% conversion to enamine 54 as observed by 1H NMR spectroscopy. Subsequent reduction of 50 with sodium triacetoxyborohydride, followed by isolation and purification using flash column chromatography, affords the 1,2,4,4-substituted pyrrolidine 55, with an isolated yield of 54%. This reaction sequence is the first example of a sequential intramolecular/intermolecular hydroamination reaction. In general, syntheses of substituted pyrrolidines can be challenging and often require multiple protection-deprotection steps, late-transition metal catalyst or harsh conditions;17 therefore, this new one-pot reaction from open-chain aminoalkenes to give substituted pyrrolidines is an interesting and potentially powerful synthetic transformation.  199   Scheme 4-9: Tandem-sequential intramolecular-intermolecular hydroamination using complex 50.   Using catalyzed inter- and intramolecular hydroamination with group 4 metal complexes bearing [N,O]-chelating ligands, a library of aminoethers and N-heterocycles was synthesized. These compounds were generated in a 100-200 mg scale and characterized by 1H and 13C{1H} NMR spectroscopy and mass spectrometry. Incorporation of various functional groups and manipulation of the core structure allows for investigation of structure-activity relationships in biological activity investigations.  4.2.2 Biological Studies Biological screening was performed by our collaborators, Prof. Terrance Snutch, his academic research group and the former local company Zalicus Pharmaceuticals Ltd. Assays were completed using a Fluorescent Imaging Plate Reader (FLIPR)-based technique, as a high-200  throughput screening method.478 This technique relies on a calcium sensitive fluorescent indicator. A cell line with the desired calcium channel expressed is loaded with this fluorophore, and by measuring the fluorescence signal the amount of calcium present is detected. The ability to express selectively certain calcium channels allows for the selective measurement of one type of calcium channel over another.478 As each of these channels has its own biological role and characteristics, five-fold selective blocking is desirable for the controlled pharmaceutical response.  Furthermore, state-selective blocking is also advantageous for drug development. Each channel can exist in three states: closed, open, and inactive. A two-fold selectivity for the inactive state over the closed state is preferred. The state of the channels is controlled in this assay through the use of external ions to generate a potential, which dictates the channel's state. Using concentration-dependent response curves, the concentration that inhibits 50% fluorescence signal can be obtained, which is also the half maximal inhibitory concentration (IC50). This IC50 value is an indication of the potency of the compound, where a lower value is a more effective blocker.  The compounds were tested on four calcium ion channels, two T-type (CaV3.1 and CaV3.2), one N-type (CaV2.2) and one L-type (CaV1.1). A successful compound would selectively affect only one of the T-type calcium ion channels. It is imperative that the compound displays limited activity against the L-type calcium ion channels, as these are the main calcium currents recorded in muscles and endocrine cells, and are essential for initiating contractions and secretions.464 N-type calcium channels are currently targeted for chronic pain treatment,479 antagonistic activity against this calcium channel could lead to advancement towards novel pain treatment, which may be attractive. However, this investigation focuses on T-type calcium ion channels. A successful compound in this investigation would block CaV3.1 and/or CaV3.2 over CaV2.2 or CaV1.1 with potency that is equal to or greater than Mibefradil. Using the FLIPR assay with Mibefradil (Figure 201  4-7), the following benchmark IC50 (nM) values were obtained: CaV3.1, 130; CaV3.2 (Closed), 840; CaV3.2 (Inactivated), 540; CaV2.2 (Closed), 4230; CaV2.2 (Inactivated), 2260; CaV1.1 (Closed), 1670; CaV1.1 (Inactivated), 1690. Note that state selective measurement for CaV3.1 is not available with this assay.  Figure 4-7: Biological data for Mibefradil.  Using the FLIPR-assay to screen the library of compounds, the importance of specific core structures and end group motifs towards the selectivity and efficacy of the inhibition of T-type Ca2+ channels was revealed. All biological data are shown in Appendix C. The extensive screening of different functionalities on the aminoether core showed the limitations of this core towards the desired biological effects. Unfortunately, any changes to the periphery of the aminoether core either negligibly or negatively impacted the activity against CaV3.2, such as the removal of the methoxy or chloro substituents (Figure 4-8; IC50 of 1740-2430 (Closed) and 1030-2610 (Inactive) nM). Intriguingly, the simple aminoether core (24i) with no additional substituents provided similar potency as compound 46b, which have similar substituents to compound 44 by McCalmont.475 Compounds 24i, 46a,b, and 48a-b, all show similar state or channel selectivity. Compound 48c showed significantly less potency (higher IC50 value) towards CaV3.2 and CaV1.1 than the other compounds in this series. This results in compound 48c offering better channel 202  selectivity towards CaV3.1 than the other compounds in this series. However, the potency towards this CaV3.1 is rather low (IC50 of 3000 nM) when compared to Mibefradil (IC50 of 130 nM).  203   Figure 4-8: Biological data for various aminoethers. 204  When focusing on the CaV3.1 channel (Figure 4-9), it was again found that the removal of the chloro (IC50 of 3800 (47c) vs. 3000 (46a) nM) and methoxy (IC50 of 3800 (47b) vs. 3860 (47c) nM and 970 (46g) vs. 980 (46f) nM) substituents resulted in minimal effect on potency of the compound towards this ion channel. However, by extending the phenyl moiety from the nitrogen atom of the amine by one methylene unit (46a vs. 46g), a significant increase in inhibition of the CaV3.1 channel was found. This change did not affect the potency towards the other calcium ion channels. 205   Figure 4-9: Schematic changes to the aminoether core to obtain the most potent compound towards blocking CaV3.1.  Replacement of the oxygen atom with a nitrogen atom (24i vs. 24l) resulted in decreased biological activity across both T- and N-type calcium channels (Figure 4-10). This would indicate 206  that having an area of positive ionization in that position is not as favourable as a hydrogen bond acceptor, which is consistent with previous pharmacophore models.471, 473 Similarly, replacement of the benzhydryl protecting group with a silyl ether protecting group (24i vs. 24j) also displayed decreased inhibition. This is in contrast to other results obtained with different amine heterocycles synthesized and tested towards the same targets.316 Functionalization of the nitrogen atom of the aminoethers with either a benzyl or a tosyl substituent resulted in loss of activity (Figure 4-11).   Figure 4-10: The effect on the biological activity of switching the benzhydryl protected oxygen atom to a nitrogen atom or a silyl protecting group.   Figure 4-11: The effect on the biological activity of additional substituents to the nitrogen atom to the aminoether core.   The biological activity of the cyclic amines was also tested using the FLIPR-assay (Figure 4-12). It was found that while the compounds with a pyrrolidine core display some inhibition of 207  the calcium ion channels, none of the compounds with the piperidine core display any inhibition of the calcium ion channels. In the small series of benzhydryl substituted pyrrolidine compounds, it was found that the free N─H pyrrolidine (52a) was inactive towards the blocking of the calcium ion channels. Substitution of the nitrogen atom with a benzyl moiety (53a) resulted in some activity where it is most effective towards CaV3.1. Extension of the tether chain length, where the nitrogen atom is substituted with a phenethyl moiety (55), also showed comparable reactivity towards the studied calcium ion channels. These results show that benzhydryl substituted pyrrolidine core could be a novel core structural motif for T-type calcium channel blockers.    Figure 4-12: Biological data for a series of N-substituted heterocycles.    These biological studies showed that generally small changes with peripheral functionalities of the aminoether core did not result in drastic changes in the potency towards calcium ion channels and the major changes to the core structure results in loss of bioactivity. However, during the course of this study it was found that by using phenethyl substituted secondary amines, the resulting aminoethers were found to be more potent towards CaV3.1. These 208  biological studies also show that the benzhydryl substituted pyrrolidine core could be a potential scaffold of interest towards T-type calcium ion channel blocking.   4.3 Conclusions   Complex 20 was previously found to be an efficient catalyst for hydroamination, as such it has been utilized for the synthesis of a library of aminoethers, utilizing both intramolecular and intermolecular hydroamination. These compounds were tested for the ability to inhibit T-type calcium ion channels, which are biological targets for the treatment of prostate cancer. It was found that the changes to the peripheries of the blocker compounds did not result in a drastic increase in potency to CaV3.2 channel. One change was realized through the use of a phenethyl substituent instead of a benzyl substituent on the nitrogen atom, resulting in improved potency towards the inhibition of the CaV3.1 channel. However, most changes made to the core structure were found to decrease or shut down any inhibitory action towards T-type calcium ion channels. For example, replacement of the oxygen atom in the core structure with a nitrogen atom, functionalization of the amine with either a benzyl or tosyl substituent, or replacement of the benzhydryl protecting group with a silyl ether protecting group, all decreased the inhibitory action of the compound. Cyclic amines bearing the benzhydryl substituent in the backbone were also probed for their activity towards calcium ion channels. It was found that the piperidine derivative with this motif was ineffective, while the pyrrolidine core showed some inhibitory action when the nitrogen was substituted. Further investigation with this core scaffold is necessary to investigate its effect on the potency and selectivity towards the calcium ion channels.    209  4.4 Experimental  4.4.1 Methods and Materials Synthesis of the metal complexes and subsequent reactions involving these precatalysts were performed under an inert atmosphere of nitrogen using standard Schlenk line or glovebox techniques. Diethylether was distilled from sodium/benzophenone under an inert atmosphere.  Benzene was purified and dried by passage through a column of activated alumina and sparged with nitrogen. d6-Benzene was degassed via three cycles of freeze-pump-thaw and stored over activated 4 Å molecular sieves in the glovebox. All substrates were distilled from either 4 Å molecular sieves or CaH2 and stored over molecular sieves before use.  The amide proligand and titanium precatalyst were prepared according to literature procedures.84-85  Unless otherwise stated, all reagents were purchased from commercial sources. The following compounds were prepared by Mr. David Le: 46d,e and 47d. The following compounds were prepared by Dr. Christine Rogers: 47a, 48a and 48b. Compounds 52a and 52b are synthesized following published procedures.110 1H and 13C{1H} NMR spectra were recorded on Bruker 300 MHz or 400 MHz Avance spectrometers with chemical shifts given relative to the residual solvent at 298 K unless otherwise noted. Chemical shifts δ for 1H and 13C{1H} NMR spectra are reported in parts per million (ppm) relative to tetramethylsilane (TMS) as an external standard and calibrated against the solvent residual peak. Chemical shifts for 19F NMR spectra are relative to CFCl3 in CDCl3 (external reference). Coupling constants J are given in Hertz (Hz). All mass spectrometry and microanalysis was performed at the Department of Chemistry, University of British Columbia by the service staff. Mass spectra were recorded on a Kratos MS-50 spectrometer using an electron impact (70 210  eV) source with a TOF detector. Elemental analyses were recorded on a Carlo Erba elemental analyzer EZ 1108.   4.4.2 Synthesis and Characterization of Compounds. General Procedure for Aminoether Synthesis by Hydroamination. A J. Young NMR tube was charged with a solution of 20 (0.05 equiv) dissolved in anhydrous d6-benzene (~1 mL), the alkyne (1 equiv), and the amine (1.2 equiv).  The J. Young NMR tube was sealed and kept at ambient temperature for 24 hr.  The progress of the reaction was monitored by 1H NMR spectroscopy.  The resultant hydroamination products were transferred to a 10 mL vial equipped with a magnetic stir bar and diluted with MeOH (~10 mL).  NaBH4 (1.2 equiv) was added and the reaction mixture was stirred for 24 hr at room temperature.  After removal of the solvent by rotary evaporation, saturated Na2CO3 (10 mL) and DCM (10 mL) were added to the residue.  The aqueous layer was extracted with DCM (3 × 25 mL) and the combined organic layers were dried over Na2SO4 and filtered. Removal of solvent by rotary evaporation and purification by column chromatography afforded the purified amine products.   3-(diphenylmethoxy)-N-(2-methoxybenzyl)propan-1-amine (46a). The title compound was synthesized following the general method with prop-2-ynyloxydiphenylmethane (116 mg, 0.50 mmol), o-methoxybenzylamine (78 μL, 0.60 mmol), complex 20 (34 mg, 0.05 mmol) and reduced with NaBH4 (23 mg, 0.6 mmol). Following column chromatography with 1 : 1 Hex : EtOAc with 1% isopropylamine (Rf = 0.40),  the title compound was obtained as a yellow oil (114 mg, 63%). 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.34 – 7.27 (m, 12H, Ar), 6.90 211  (m, 1H, Ar), 6.33 (m, 1H, Ar), 5.33 (s, 1H, Ph2CHO), 3.80 (s, 2H, ArCH2N), 3.74 (s, 3H, OCH3), 3.52 (t, 3JH,H = 6.4 Hz, 2H, OCH2CH2), 2.76 (t, 3JH,H = 6.7 Hz, 2H, NCH2CH2), 1.87 (tt, 3JH,H = 6.4, 6.7 Hz, 2H, NCH2CH2), 1.74 (br s, 1H, NH); 13C{1H} NMR (CDCl3, 101 MHz): δ (ppm) 157.4, 142.4, 129.6, 128.4, 128.2, 127.9, 127.2, 126.8, 120.2, 110.0, 83.5, 67.5, 55.0, 49.2, 46.7, 30.2;  MS (EI):  m/z 361 ([M+]); HRMS (EI-EB) m/z: Calcd for C24H27NO2 (M+), 361.20418; Found: 361.20440.  3-(diphenylmethoxy)-N-(2-fluorobenzyl)propan-1-amine (46b). The title compound was synthesized following the general method with prop-2-ynyloxydiphenylmethane (111 mg, 0.50 mmol), p-fluorobenzylamine (69 μL, 0.60 mmol), complex 20 (34 mg, 0.05 mmol) and reduced with NaBH4 (23 mg, 0.6 mmol). Following column chromatography with 1.5 : 1 hex : EtOAc with 5% isopropylamine, (Rf = 0.41, 1 : 1 hex : EtOAc with 10% diisopropylamine),  the title compound was obtained as a clear colourless oil (173 mg, 86%). An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.30 – 7.15 (m, 12H, Ar), 6.92 (t, 3JH,H = 8.7 Hz, 2H, Ar), 5.28 (s, 1H, Ph2CHO), 3.67 (s, 2H, ArCH2N), 3.48 (t, 3JH,H = 6.3 Hz, 2H, OCH2CH2), 2.72 (t, 3JH,H = 6.3 Hz, 2H, NCH2CH2), 2.01 (br s, 1H, NH), 1.81 (quint, 3JH,H = 6.3 Hz, 2H, NCH2CH2); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 161.8 (1JC,F = 244.4 Hz), 142.3, 136.0 (4JC,F = 3.0 Hz), 129.6 (3JC,F = 8.0 Hz), 128.3, 127.3, 126.8, 115.0 (2JC,F = 21.0 Hz), 83.6, 67.6, 53.2, 46.8, 30.0; 19F NMR (CFCl3, 282 MHz): δ (ppm) −128;  MS (ESI):  m/z 372 ([M+Na+]), 350 ([M+H+]); HRMS (ESI-TOF) m/z: Calcd for C23H25FNO 350.1920 ([M+H+]), ; Found: 350.1924. Anal. Calcd for C23H25FNO: C, 79.05; H, 6.92; N, 4.01. Found: C, 78.90; H, 7.22; N, 4.52. 212   N-(3-(diphenylmethoxy)propyl)aniline (46c) The title compound was synthesized following the general method with prop-2-ynyloxydiphenylmethane (111 mg, 0.50 mmol), aniline (55 mg, 0.60 mmol), complex 20 (34 mg, 0.05 mmol) and reduced with NaBH4 (23 mg, 0.60 mmol). Following column chromatography with 10 : 1 → 5 : 1, hex : EtOAc (Rf = 0.46, 5 : 1 hex : EtOAc),  the title compound was obtained as a yellow oil (72 mg, 45%). 1H NMR (300 MHz, CDCl3): δ (ppm) 7.44 – 7.19 (m, 12H, Ar), 6.74 (t, 3JH,H = 7.3 Hz, 1H, Ar), 6.60 (d, 3JH,H = 8.2 Hz, 2H, Ar), 5.41 (s, 1H, Ar2CHO), 4.04 (br s, 1H, NH), 3.65 (t, 3JH,H = 6.1 Hz, 2H, CH2O), 3.34 (t, 3JH,H = 6.4 Hz, 2H, NHCH2CH2), 2.00 (quint, 3JH,H = 6.1 Hz, 2H, CH2CH2CH2); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 148.4, 142.2, 129.1, 128.4, 127.5, 126.8, 117.0, 112.6, 83.8, 67.5, 41.8, 29.2; ESI MS (m/z): 318 ([M+H]+). HRMS (EI) m/z: Calcd for C22H24NO ([M+H]+), 318.1858; Found: 318.1858.  3-(diphenylmethoxy)-N-phenethylpropan-1-amine (46f). The title compound was synthesized following the general method with prop-2-ynyloxydiphenylmethane (111 mg, 0.50 mmol), phenylethylamine (84 μL, 0.60 mmol), complex 20 (34 mg, 0.05 mmol) and reduced with NaBH4 (23 mg, 0.60 mmol). Following column chromatography with 1 : 1 Hex : EtOAc with 2% isopropylamine → EtOAc with 2% isopropylamine (Rf = 0.31 with EtOAc with 2% isopropylamine),  the title compound was obtained as a colourless oil (63 mg, 37%). An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography. 1H NMR (400 MHz, CDCl3): δ (ppm) 7.39 – 7.24 (m, 15H, Ar), 5.36 (s, 1H, Ar2CHO), 3.55 (t, 213  3JH,H = 6.4 Hz, 2H, CH2O), 2.94 – 2.91 (m, 2H, NHCH2CH2), 2.80 – 2.84 (m, 4H, NHCH2, Ar-CH2CH2), 1.88 (tt, 2H, 3JH,H = 6.7, 6.4 Hz, CH2CH2CH2), 1.60 (br s, 1H, NH ); 13C{1H} NMR (CDCl3 100 MHz): δ (ppm) 142.4, 140.1, 128.6, 128.4, 128.3, 127.3, 126.9, 126.1, 83.6, 67.5, 51.3, 47.3, 36.4, 30.1; ESI MS (m/z): 346 ([M+H]+); Anal. Calcd for C24H27NO: C, 83.44; H, 7.88; N, 4.05. Found: C, 83.34; H, 7.92; N, 4.09.  3-(diphenylmethoxy)-N-(3,4-dimethoxyphenethyl)propan-1-amine (46g). The title compound was synthesized following the general method with prop-2-ynyloxydiphenylmethane (111 mg, 0.5 mmol), 2-(3,4-dimethoxyphenyl)ethan-1-amine (101 μL, 0.6 mmol), complex 20 (34 mg, 0.05 mmol) and reduced with NaBH4 (23 mg, 0.6 mmol). Following column chromatography with 1 : 1 : 2% Hex : EtOAc : isopropylamine → EtOAc with 2% isopropylamine, (Rf = 0.36 with EtOAc with 2% isopropylamine),  the title compound was obtained as a yellow oil (145 mg, 72%). 1H NMR (400 MHz, CDCl3): δ (ppm) 7.37 – 7.33 (m, 8H, Ar), 7.30 – 7.26 (m, 2H, Ar), 6.81 – 6.76 (m, 3H, Ar), 5.35 (s, 1H, Ph2CHO), 3.90 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),  3.55 (t, 3JH,H = 6.4 Hz, 2H, CH2O), 2.92 – 2.89 (m, 2H, NHCH2CH2Ar), 2.85 – 2.77 (m, 4H, NHCH2, ArCH2CH2), 2.43 (br, s, 1H, NH), 1.89 (tt, 3JH,H = 6.7, 6.4 Hz, 2H CH2CH2CH2); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm)  147.3, 142.3, 132.4, 128.3, 127.3, 126.8, 120.4, 111.8, 111.2, 83.6, 67.4, 55.8, 55.7, 51.2, 47.1, 35.6, 29.6 (1 aryl carbon signal was obscured); EI MS (m/z): 405 (M+). HRMS (EI) m/z: Calcd for C26H31NO3 (M+), 405.2304; Found: 405.2304.    214  3-((4-chlorophenyl)(phenyl)methoxy)-N-(4-methoxybenzyl)propan-1-amine (47b)  The title compound was synthesized following the general method with 1-chloro-4-(phenyl(prop-2-ynyloxy)methyl)benzene (253 mg, 1.0 mmol), p-methoxybenzylamine (156 μL, 1.2 mmol), complex 20 (68 mg, 0.1 mmol) and reduced with NaBH4 (46 mg, 1.2 mmol). Following column chromatography with 1 : 1 Hex : EtOAc with 1% isopropylamine (Rf = 0.31),  the title compound was obtained as a clear colourless oil (142 mg, 36%). Spectra data mached literature refernces.475 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.32 – 7.12 (m, 11H, Ar), 6.74 (d, 3JH,H = 8.5 Hz, 2H, Ar), 5.29 (s, 1H, Ar2CHO), 3.77 (s, 2H, ArCH2N), 3.72 (s, 3H, OCH3), 3.45 (t, 3JH,H = 6.3 Hz, 2H, OCH2), 2.71 (t, 3JH,H = 6.7 Hz, 2H, NHCH2CH2), 1.83 (tt, 2H, 3JH,H = 6.7, 6.3 Hz, CH2CH2CH2), 1.71 (br s, 1H, NH).  3-((4-chlorophenyl)(phenyl)methoxy)-N-(2-methoxybenzyl)propan-1-amine (47c) The title compound was synthesized following the general method with 1-chloro-4-(phenyl(prop-2-ynyloxy)methyl)benzene (253 mg, 1.0 mmol), o-methoxybenzylamine (156 μL, 1.2 mmol), complex 20 (78 mg, 0.1 mmol) and reduced with NaBH4 (46 mg, 1.2 mmol). Following column chromatography with 1 : 1 Hex : EtOAc with 1% isopropylamine (Rf = 0.33),  the title compound was obtained as a yellow oil (249 mg, 63%). An analytically pure sample was obtained by a bulb-to-bulb distillation after column chromatography. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.29 – 7.18 (m, 11H, Ar), 6.88 (t, 3JH,H = 7.3 Hz, 1H, Ar), 6.83 (d, 3JH,H = 8.2 Hz, 1H, Ar), 5.27 (s, 1H, Ar2CHO), 3.76 (s, 215  2H, NCH2Ar), 3.74 (s, 3H, OCH3), 3.48 (t, 3JH,H = 6.3 Hz, 2H, OCH2), 2.72 (t, 3JH,H = 6.8 Hz, 2H, NHCH2CH2), 1.83 (tt, 2H, 3JH,H = 6.8, 6.3 Hz, CH2CH2CH2), 1.72 (br s, 1H, NH). 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 157.5, 141.9, 141.1, 133.0, 129.8, 128.5, 128.4, 128.2, 128.12, 128.14, 127.6, 126.8, 120.3, 110.2, 82.9, 67.7, 55.1, 49.3, 46.7, 30.2; EI MS (m/z): 395 (M+). Anal. Calcd for C24H26ClNO2: C, 72.81; H, 6.62; N, 3.54. Found: C, 72.60; H, 6.91; N, 3.53.  4-(diphenylmethoxy)-N-(2-methoxybenzyl)butan-1-amine (48c). The title compound was synthesized following the general method with ((but-3-yn-1-yloxy)methylene)dibenzene (111 mg, 0.50 mmol), o-methoxybenzylamine (78 μL, 0.60 mmol), complex 20 (18 mg, 0.025 mmol) at 65 °C for 24 hours and reduced with NaBH4 (23 mg, 0.60 mmol). Following column chromatography with EtOAc with 2% isopropylamine and 1% diisopropylamine, (Rf = 0.51, EtOAc with 2% isopropylamine), the title compound was obtained as a colourless oil (113 mg, 62%). 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.42 – 7.27 (m, 12H, Ar), 6.99 – 6.90 (m, 2H, Ar), 5.39 (s, 1H, Ph2CHO), 3.88 (s, 3H, OCH3), 3.84 (s, 2H, ArCH2NH), 3.52 (m, 2H, OCH2), 2.68 (m, 2H, NHCH2CH2), 1.88 (br s, 1H, NH ), 1.74 – 1.69 (m, 4H, NHCH2(CH2)2); 13C{1H} NMR (CDCl3, 75 MHz): δ (ppm) 142.9, 130.2, 128.8, 128.7, 128.5, 127.7, 127.3, 120.7, 110.6, 103.4, 84.0, 69.4, 55.6, 49.7, 49.5, 28.1, 27.3; ESI MS (m/z): 376 ([M+H]+); HRMS (ESI) m/z: Calcd for C25H29NO2 ([M+H]+), 376.2269; Found: 376.2277.     216  3-(diphenylmethoxy)-N,N-dibenzylpropan-1-amine (49a). Hydroamination was carried out as described for compound 24i but was not purified by column chromatography and used without any further purification. The product mixture was dissolved in DCM (ca. 10 mL), where benzoyl chloride (0.06 mL, 0.6 mmol) and NEt3 (0.10 mL) were then added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with 5 mL of distilled water and 5 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with 3M NaOH(aq) (2 × 10 mL) and saturated brine solution (2 × 10 mL). The solution was dried with Na2SO4, filtered and the volatiles were removed by rotary evaporation. The mixture was passed through a short silica plug with DCM to afford N-(3-(diphenylmethoxy)propyl)-N-benzylbenzamide as a clear colourless oil in 71% yield. This compound was used without further purification. A round bottom flask equipped with a stir bar and a nitrogen balloon was charged with lithium aluminum hydride (0.019 g, 0.54 mmol). Anhydrous THF (10 mL) was then added and the flask was cooled to 0 °C. In a separate flask compound N-(3-(diphenylmethoxy)propyl)-N-benzylbenzamide (0.209 g, 0.50 mmol) was diluted with anhydrous THF (2 mL) and then dropwise added to the LAH suspension. The reaction was then warmed to room temperature and stirred for 16 hours. The reaction was then cooled to 0 °C, where distilled water (19 μL), 3M NaOH(aq) (19 μL), and distilled water (57 μL) was sequentially added. The mixture was vigorously stirred for 2 hours and then filtered through a pad of Celite with diethyl ether.  Following column chromatography (5 : 1, hex : EtOAc, Rf = 0.83), the product was obtained as a clear colourless oil in 81% yield (0.164 g, 0.4 mmol). 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.34 – 7.26 (m, 20H, Ph), 5.24 (s, 1H, Ph2CHO), 3.55 (s, 4H, (PhCH2)2N), 3.44 (t, 3JH,H = 6.5 Hz, 2H, OCH2), 2.56 (t, 3JH,H =  6.9, 2H, NHCH2CH2), 1.86 (tt, 3JH,H = 6.9, 6.5 Hz, 2H, 217  CH2); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 142.2, 128.4, 128.29, 128.32, 127.3, 127.1, 126.8, 126.5, 83.6, 67.3, 53.5, 46.5, 29.4; EI MS (m/z): 421 (M+); Anal. Calcd for C30H31NO ([M+H]+): C, 85.47; H, 7.41; N, 3.32; Found: C, 85.13; H, 7.51; N, 3.39.  N-(3-(diphenylmethoxy)propyl)-N-benzyl-4-methylbenzenesulfonamide (49b). The title compound was synthesized from the hydroamination of benzyl amine and 24i followed by derivatization with tosyl chloride. Hydroamination was carried out as described for compound 24i but was not purified by column chromatography and used without any further purification. The product mixture was dissolved in DCM (ca. 10 mL), where tosyl chloride (0.112 g, 0.6 mmol) and 1M NaOH(aq) (3 mL) were then added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with 5 mL of distilled water and 5 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic layers was washed with 3M NaOH(aq) (2 × 10 mL) and saturated brine solution (2 × 10 mL). The solution was dried with Na2SO4, filtered and the volatiles were removed by rotary evaporation. Following column chromatography (5 : 1 hex : EtOAc, Rf = 0.3), the title compound was afforded in 71% yield (0.173 g, 0.4 mmol) as a clear colourless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.78 (d, 3JH,H = 8.2 Hz, 2H, Ar), 7.45 – 7.29 (m, 17H, Ar), 5.23 (s, 1H, Ph2CHO), 4.38 (s, 2H, PhCH2N), 3.34 – 3.29 (m, 4H, OCH2, NHCH2CH2), 2.49 (s, 3H, CH3), 1.75 – 1.71 (m, 2H, CH2); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 143.1, 142.2, 136.8, 136.4, 129.7, 128.5, 128.3, 127.7, 127.3, 127.2, 126.6, 126.5, 85.9, 83.3, 52.2, 45.5, 28.6, 21.5; EI MS (m/z): 485 (M+); Anal. Calcd for C30H31NO3S: C, 85.47; H, 7.41; N, 3.32; Found: C, 85.13; H, 7.51; N, 3.39.  218  Synthesis of 1-benzyl-2-methyl-4,4-diphenylpyrrolidine (53a). The compound 51a (0.125 g, 0.50 mmol) was dissolved in DCM (ca. 10 mL) and NEt3 (0.10 mL). The reaction mixture was cooled to -78 °C and benzoyl chloride (0.06 mL, 0.60 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 16 hours. The reaction was diluted with 5 mL of distilled water and 5 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic layers were washed with saturated brine solution (2 × 10 mL). The solution was dried with Na2SO4, filtered and the volatiles were removed by rotary evaporation. The mixture was passed through a short silica plug with DCM to afford (2-methyl-4,4-diphenylpyrrolidin-1-yl)(phenyl)methanone as a clear colourless oil in 45% yield. This compound was used without further purification. A 20 mL vial equipped with stir bar was charged with lithium aluminum hydride (0.028 g, 0.80 mmol). Anhydrous THF (6 mL) was then added and the flask was cooled to 0 °C. In another vial, (2-methyl-4,4-diphenylpyrrolidin-1-yl)(phenyl)methanone (50 mg, 0.15 mmol) was dissolved with anhydrous THF (2 mL) and then dropwise added to the LAH suspension. The reaction was then warmed to room temperature and stirred for 16 hours. The reaction was then cooled to 0 °C, where distilled water (28 μL), 3M NaOH(aq) (28 μL), and distilled water (84 μL) were sequentially added. The mixture was vigorously stirred for 2 hours and then filtered through a pad of Celite with diethyl ether. The solution was concentrated by rotary evaporation, the solution was cooled to 0 °C and 2M HCl in Et2O was added dropwise until a white precipitate was obtained, which was collected by vacuum filtration. Recrystallization using Et2O afforded the HCl salt of the title compound as a white solid in 98% yield (55 mg, 0.15 mmol). Prior to biological testing, the HCl salt was free based using 1M NaOH(aq). Spectral data matched literature references.480 1H NMR (400 MHz, CDCl3): δ (ppm) 219  7.37 ─ 7.07 (m, 15H, Ph), 4.05 (d, 2JH,H = 13.4 Hz, 1H, Ph2CCH2N), 3.63 (d, 2JH,H = 10.0 Hz, 1H, PhCH2N), 3.24 (d, 2JH,H = 13.4 Hz, 1H, Ph2CCH2N), 2.91 (m, 1H, Ph2CCH2CHMe), 2.85 ─ 2.76 (m, 2H, PhCCH2N, CH), 2.22 – 2.19 (m, 1H, Ph2CCH2CHMe), 1.16 (d, 3JH,H = 5.7 Hz, 3H, Me).  Synthesis of 1-tosyl-2-methyl-4,4-diphenylpyrrolidine (53b). The compound 51a (0.125 g, 0.50 mmol) was dissolved in DCM (ca. 10 mL), where tosyl chloride (0.112 g, 0.60 mmol) and 1M NaOH(aq) (3 mL) was then added. The reaction was stirred at room temperature for 16 hours. The reaction was diluted with 5 mL of distilled water and 5 mL of EtOAc. The aqueous layer was separated and extracted with EtOAc (2 × 10 mL). The combined organic layers was washed with 3M NaOH(aq) (2 × 10 mL) and saturated brine solution (2 × 10 mL). The solution was dried with Na2SO4, filtered and the volatiles were removed by rotary evaporation. Following column chromatography (6 : 1 hex : EtOAc, Rf = 0.32), the title compound was afforded in 90% yield (0.173 g, 0.45 mmol) as a white solid. Spectral data matched literature references.481 1H NMR (400 MHz, CDCl3): δ (ppm) 7.54 (d, 3JH,H = 8.4 Hz, 2H, Ph), 7.20 – 7.01 (m, 12H, Ph), 4.11 (d, 2JH,H = 10.6 Hz, 1H, Ph2CCH2N), 3.89 (d, 2JH,H = 10.6 Hz, 1H, Ph2CCH2N), 3.75 – 3.67 (m, 1H, Ph2CCH2CHMe), 2.76 – 2.69 (m, 1H, CH), 2.33 (s, 3H, PhCH3), 2.18 – 2.14 (m, 1H, Ph2CCH2CHMe), 1.17 (d, 3JH,H = 4.8 Hz, 3H, Me).  220  Synthesis of 2-methyl-1-phenethyl-4,4-diphenylpyrrolidine (55).  In a glove box, complex 50 (21 mg, 0.035 mmol) and 1-amino-2,2-diphenylpent-4-ene (95 mg, 0.399 mmol) were dissolved in toluene (500 μL) by gentle heating. Once dissolution was achieved, the solution was transferred to a Schlenk tube equipped with a stir bar. The reaction vessel was sealed and heated to 110 °C for 4 h. Spectroscopic data was in agreement with previously reported data.19 Phenylacetylene (175 μL, 1.59 mmol) was added to the reaction mixture and the tube was heated to 145 °C for 16 h. The reaction mixture was diluted with dichloromethane (~5 mL). Sodium triacetoxyborohydride (187 mg, 0.884 mmol) and glacial acetic acid (22.9 μL, 0.4 mmol) were added to the reaction mixture and the solution was stirred overnight. Quenching by a saturated solution of sodium bicarbonate, extraction with diethyl ether (3 × 20 mL), drying over MgSO4 and removal of solvent by rotary evaporation gave the crude N-substituted pyrrolidine as a deep red oil. Purification by flash chromatography of hexane/ethyl acetate (9:1) with 1% triethyl amine as an eluent, yielded the pure product as a red oil in 54% yield (74 mg); 1H NMR (400 MHz, CDCl3): δ (ppm) 7.33 – 7.12 (m, 15H, Ar), 4.00 (d, 2JH,H = 9.8 Hz, 1H, 4’), 3.14 – 3.07 (m, 1H, 5’), 2.92 – 2.85 (m, 4H, 2’, 4, 6), 2.76 – 2.71 (m, 1H, 1), 2.50 – 2.43 (m, 1H, 5), 2.18 – 2.13 (m, 1H, 2), 1.11 (d, 3JH,H = 5.8 Hz, 3H, 7); 13C{1H} NMR (CDCl3, 100 MHz): δ (ppm) 150.6, 148.7, 140.7, 128.7, 128.2, 128.1, 127.9, 127.4, 127.2, 125.9, 125.8, 125.4, 66.8, 60.1, 55.6, 52.6, 47.8, 35.5, 19.4; ESI MS (m/z): 342 ([M+H]+); Anal. Calcd for C25H27N: C, 87.93; H, 7.97; N, 4.10. Found: C, 88.20; H, 7.59; N, 3.82.   221  Chapter 5: Summary, Future Work and Conclusions  5.1 Summary  This thesis focused on the development and utilization of titanium or zirconium amidate complexes for organic transformations. The aim of this thesis was to further explore titanium and zirconium amidate complexes to be used as either reagents or catalysts for targeted applications. Chapter 1 presented an overview of how titanium and zirconium complexes can be used as organic synthetic tools. This chapter further elaborated on the role of N,O-chelating ligands as easily modified auxiliary ligands to tune the reactivity at group 4 metal centers. Chapter 2 focused on the synthesis, characterization and reactivity of zirconocene amidate hydride complexes, and their application in the hydrozirconation reaction. Chapters 3 and 4 looked at applications of a known bis(amidate) bis(amido) titanium hydroamination precatalyst (20). This titanium complex was used in intermolecular alkyne hydroamination reactions to synthesize secondary amines, a primary amine, a substituted allylamine, and nitrogen containing oligomers. Additionally, a library of aminoethers were prepared in a modular fashion and were tested for their bioactivity towards T-type calcium ion channels. In this work, a series of mononuclear zirconium amidate complexes bearing terminal hydrides was synthesized using salt metathesis. These zirconocene amidate hydride complexes can be made in a facile and scalable manner and display reactivity complementary to Schwartz’s reagents. These complexes were characterized by X-ray crystallography, NMR spectroscopy and mass spectrometry. It was found that the amidate ligands adopted different binding modes (either κ1-O bound or κ2-chelating) depending on the steric parameters of the auxiliary amidate ligands. Similar to the majority of other group 4 amidate complexes, the amidate ligand typically binds in 222  a κ2-chelating fashion. However, when sterically bulky substituents were incorporated into the carbonyl moiety and/or the nitrogen substituent of the amidate, the amidate ligand adopts a κ1 O-bound geometry. Interestingly, an equilibrium between the κ1 O-bound or κ2 isomers of complex 2d was observed in solution by 1H and 13C{1H} NMR spectroscopy. The κ1 O-bound isomer was found to be the entropically favoured product through VT-NMR spectroscopic and computational studies.  The reactivity of these zirconocene amidate hydride complexes was explored as potential alternatives to Schwartz’s reagent. Schwartz’s reagent is known to heavily favour the formation of the linear hydrozirconation product with alkenes, including styrene. When the zirconium amidate complexes were reacted with styrene or styrene derivatives, exclusive formation of the branched hydrozirconation products was observed. These insertion products were found to be in equilibrium with the starting hydride complex. Alteration of the reaction conditions can favour the formation of the insertion products and complexes 3b-d were isolated and fully characterized. By heating an insertion product, the equilibrium was found to favour the formation of the starting hydride complex. The use of the electrophilic quenching agent, iodine, resulted in the selective formation of 1-iodo-1-phenylethane. By installing a stereocenter on the amidate ligand prior to complex formation, asymmetric hydrozirconation of styrene was attempted but no enantiomeric excess were observed.  Hydrozirconation with other substrates was also attempted. The reaction between complex 2d and phenylacetylene resulted in a mixture of products. By recrystallization, the branched product could be obtained from this reaction mixture. The linear insertion product could not be observed by 1H NMR spectroscopy. Complex 2d was also found to isomerize 1-octene to a mixture of internal octenes, and 3-phenylprop-1-ene or (E)-1-phenylprop-1-ene to (Z)-1-phenylprop-1-ene. 223  Complex 2d reacts with halobenzenes under harsh reaction conditions (110 °C) to form benzene and the zirconocene amidate halide complexes. This behavior is hypothesized to proceed through a transient reduced zirconium species, although the exact nature of such reduced species is unknown.  The mechanism of styrene insertion with the zirconocene amidate hydride complexes was proposed to proceed through a coordination-insertion type mechanism, where coordination of the styrene occurs at the exterior position of the zirconocene. As under the mild reaction conditions for styrene insertion complex 2d did not react with halobenzenes, a mechanism involving transient reduced zirconium species was ruled out. Kinetic studies revealed a primary deuterium kinetic isotope effect for the hydride, which indicated that Zr─H cleavage is involved in the rate-determining step. The rate of insertion was found to be dependent on the electron donating or withdrawing substituent on the phenyl ring of styrene. It is proposed that the coordination of the styrene occurs in the exterior position of the zirconocene complex. With coordination at this position, electronic factors would favour the formation of the branched insertion product over the linear insertion product. Coordination of styrene in this location is consistent with the lack of enantioselectivity when a stereocenter is present in the amidate ligands as it is too remote to affect the insertion step.  In Chapter 3, a previously known bis(amidate) bis(amido) titanium complex (20)84-85 for the intermolecular hydroamination catalyst for primary alkylamines and terminal alkynes was further explored. When this complex was compared to other notable titanium-based hydroamination catalysts, complex 20 was able to invoke comparable reactivity with benchmark substrates (including benzylamine), tolerate a broader scope of substrates and was the most regioselective towards the anti-Markovnikov product. To expand the synthetic utility of complex 224  20, further substrate scope investigations were undertaken in Chapter 3. This complex was able to tolerate alkenes, catechol derivatives and secondary amine functional groups. By lowering the reaction temperature, complex 20 was able to tolerate protected propargyl alcohols and amines. With these substrates, complex 20 typically afforded good yields with excellent regioselectivity for the anti-Markovnikov product. Complex 20 also catalyzed the hydroamination of alkynes with arylamines; however, with certain substrate combinations strict control of regioselectivity was lost. Hydroamination with internal alkynes was also catalyzed by complex 20, albeit higher reaction temperatures were required. It was found that while hydroamination with sterically unsymmetric internal alkyne gave excellent regioselectivity, sterically symmetric but electronically unsymmetric internal alkynes resulted in a mixture of regioisomers in ca. 2 : 1 ratio favoring the addition of the amine to the carbon α- to the more electronically rich arene. These examples show the breadth of substrate scope of complex 20.  The mechanistic proposal for hydroamination catalyzed by complex 20 is consistent with the established mechanistic proposals for titanium catalyzed hydroamination, which proceed through a reversible [2+2] cycloaddition from a catalytically active titanium imido species, followed by a rate-limiting associative protonolysis.71, 288-289 It is proposed that under these conditions, the Curtin-Hammett principle applies for determining the regioselectivity of alkyne hydroamination.71 The amidate is proposed to provide a flexible steric environment for the metal center due to the ligand’s hemilabile nature. This results in the observed excellent regioselectivity across a range of substrates. However, sterically bulky arylamines would hinder the coordination of the amine to form the proposed transition state for the turnover-limiting associative protonolysis step. Indeed, such amine substrates are the only examples that afford Markovnikov products with precatalyst 20. Computational studies can be useful to corroborate this mechanistic proposal.  225  To extend the synthetic applicability of complex 20, facile benchtop protocols were developed.  These improved protocols include either in situ generation of the complex or preparation of a storable standard solution.  These approaches allow for the use of complex 20 without the need of a glovebox.  To demonstrate the synthetic utility of complex 20, it was used in tandem-sequential reactions to afford secondary amines from a hydroamination/hydrosilylation reaction sequence,425 a primary amine from a hydroamination/isomerization/deprotection reaction sequence431 and a substituted primary allylamine from a hydroamination/alkynylation reaction sequence.435  Nitrogen-containing oligomers were synthesized using hydroamination catalyzed by complex 20. It was hypothesized that an enamine structure could be resonance stabilized, which would also result in a conjugated polymer. Initial studies show that oligomerization of alkynylaniline 37 to form 38 is possible.  This formed a solid that was insoluble in common organic solvents and could only be characterized in the solid state, where MADLI-TOF MS, TGA, IR spectroscopy and solid state NMR spectroscopy supported the formation of the targeted oligomer. These observations provided the proof of concept for oligomerization via hydroamination. However, to aid in the study of these oligomers, a soluble version was preferable. A hexynyl moiety was added to the alkyne to improve solubility in organic solvents. However, the resulting oligomer was found to be moisture sensitive as the imine isomer predominates. Para-(2-phenylethyn-1-yl)aniline was used to form oligomer 42, where the phenyl substituent was thought to promote the extended conjugated network. Oligomer 42 was characterized by IR spectroscopy, MALDI-TOF MS and TGA. UV-Vis spectroscopy revealed a red shifted band compared to the monomer, which suggests a more delocalized structure. These preliminary results suggest that it 226  is possible to form conjugated polymer using hydroamination and, as such future investigations could lead to longer oligomer chains and more extended conjugation.  In Chapter 4, complex 20 was used to synthesize a library of aminoethers, which were then screened for biological activity as T-type calcium ion channel blockers. It was found that most changes made to the peripheries lead to the same or decreased bioactivity across all ion channels that were tested. The addition of a phenethyl substituent on the nitrogen atom resulted in improved inhibition of CaV3.1; however, no increase in channel selectivity was observed. All changes made to the core structure in this study resulted in decreased inhibitory action. Interestingly, N-substituted pyrrolidines bearing a benzhydryl moiety in their backbones showed some inhibitory action towards T-type calcium ion channels and could be potential targets for future core scaffold designs.   5.2 Future Work 5.2.1 Use of Zirconium Amidate Hydride Complexes for Hydrosilylation: Preliminary Results and New Directions  Although the zirconium amidate hydride complexes presented in Chapter 2 showed some interesting reactivity as stoichiometric reagents, it is desirable to utilize these complexes as catalysts. It is proposed that these complexes can catalyze a transformation with alkenes, where a reagent would cleave the Zr─C bond of the inserted product, such as complex 3d, to generate an organic product. This reagent should also be a hydride source, which could regenerate the zirconium hydride thus completing a catalytic cycle. One way to cleave a M─C bond is through the use of silanes, where a new C─Si bond is formed and the M─H is regenerated. This formal addition of a Si─H bond across an C─C bond unsaturation (such as alkene or alkyne) is generally 227  known as hydrosilylation.482 In regards to the zirconium amidate complexes presented in Chapter 2 could be applied to this reaction. Whereby following insertion of the alkene, σ-bond metathesis with a silane could regenerate the hydride complex and generate a new organosilicon product. Indeed this is the accepted mechanism for yttrium catalyzed alkene hydrosilylation and has been proposed for some zirconium catalysts (Figure 5-1).483-486 This is in contrast the standard olefin hydrosilylation catalysts, such as Speier’s catalyst (H2PtCl6·6H2O/i-PrOH),487-488 which rely on the formation of a metal hydrido-silyl complex.482 Some zirconium systems, such as Cp2ZrCl2/BuLi, catalyze hydrosilylation by oxidative addition of the Si─H bond to a low-valent zirconium species, thus generating a zirconium hydrido-silyl complex.489-490 As discussed in Chapter 2, evidence suggested that zirconium amidate hydride complexes do not generate low-valent zirconium species under mild reaction conditions, and it is speculated that these zirconium amidate hydride complexes would follow the insertion-σ-bond metathesis mechanism for hydrosilylation, similar to a published tripodal amido zirconium alkyl system.486   Figure 5-1: Insertion-σ-bond metathesis mechanism for hydrosilylation. Redrawn with permission from Journal of Chemical Society, Dalton Transactions.486  In a preliminary investigation, a 1:1 mixture of styrene and phenylsilane was reacted in the presence of 10 mol% of complex 2d (Scheme 5-1). The reaction was monitored by 1H NMR 228  spectroscopy and following 18 hours at room temperature, 50% conversion was observed based on consumption of styrene. This consumption of styrene was concurrent with the formation of a silylated ethylbenzene product. The formation of the inserted product 3d was also observed during the course of this reaction as evidenced by the appearance of a quartet at 2.62 ppm and a doublet at 1.84 ppm. By heating the reaction to 40 °C for another 12 hours, full consumption of styrene was observed. Interestingly, the regioselectivity observed for this organosilicon product was selectively linear as confirmed by 2D COSY NMR spectroscopic studies. Based on the proposed mechanism (Figure 5-1), the formation of the branched product from styrene insertion should precede via σ-bond metathesis. As such, it was predicted that the branched product would have been afforded selectively. However, the opposite regioisomer was observed. Interesting, the control experiment where complex 2d was reacted with phenylsilane alone did not show any observable reactivity under the same reaction conditions. It is, thus, of interest to explore the mechanism of both the alkene insertion (presumably rapid and reversible) and hydrosilylation. Future investigations in the mechanistic rationale can provide valuable insight not only to hydrosilylation but can also provide insight for the hydrozirconation reaction.    Scheme 5-1: Hydrosilylation of styrene and phenylsilane catalyzed by complex 2d.  229  5.2.2 Use of Zirconium Amidate Hydride Complexes for Cross-Dehydrocoupling Reactions: Preliminary Results and New Directions In the hydrosilylation section shown above, the hydride of the zirconium amidate complexes inserts into an electrophile and σ-bond metathesis regenerates a Zr─H bond while forming a Si─C bond. The hydridic character of these zirconium hydrides could be further exploited with other electrophiles, such as the protic hydrogen from amines or alcohols via a hypothesized metathesis, where the E─H bond would be cleaved to produce H2(g) and a Zr─E bond. One could then use an appropriate hydride source, such as silanes, to regenerate the Zr─H bond and form a Si─E bond, through an overall formal cross-dehydrocoupling reaction (Scheme 5-2).491-492  Scheme 5-2: General reaction scheme for cross-dehydrocoupling of a silane and amine.  There are only a limited number of reported cross-dehydrocoupling catalysts.493-500 Silylated amines are commodity chemicals, often used as silylating agents501-504 and monomeric precursors for ceramic materials.505-506 A state-of-the-art example is provided by Sadow and co-workers, who have shown that by using a magnesium catalyst, they are able to facilitate this reaction to afford the silazane product.494 Their system also showed selectivity, where the reaction of primary amines and primary silanes only afforded RHNSiH2R as the product (up to 99% yield under optimized conditions) and further reactivity was avoided.494  230  In the primary study, initial results showed that the exposure of 2d (5 mol%) to isopropylamine and phenylsilane (2 equiv.) at room temperature for 21 hours resulted in the formation of the mono-aminated silane with 99% conversion with only trace amounts of the diaminated product as monitored by 1H NMR spectroscopy (Scheme 5-3). Further optimization of this system and exploration of the substrate scope of this method could result in a facile route to these desirable silazane products. Furthermore, this methodology could be extended for E─H bonds such as alcohols and amides, to generate the corresponding silylated products.    Scheme 5-3: Cross-dehydrocoupling of phenylsilane and isopropylamine catalyzed by complex 2d.  5.2.3 Hydroamination to form N-containing Oligomers with Other Alkynylanilines: Preliminary Results and New Directions  Although Chapter 3 shows the proof of concept that hydroamination could be used to form nitrogen-containing oligomers, a new goal could be to synthesize polymers that could be used in various applications. One such target is towards electronic applications, where extended conjugation is crucial. To achieve this ordered, extended network of delocalized π-electrons in the oligomers, regiocontrol during oligomerization is important and the enamine tautomer is required over the imine tautomer. Redesigning the monomer to access soluble products with the enamine tautomeric structure could be targeted. 231  Para-substituted oligomer 42 was not formed with high levels of regiocontrol, which may have limited the length of the conjugated network. As complex 20 has been shown to provide higher regioselectivity when a substrate is sterically unsymmetrical, for example in the hydroamination of 4-methylpent-2-yne and para-methoxyaniline, a methyl substituent installed on the arene may promote more regioselective oligomer formation (Scheme 5-4).  To test this hypothesis, 2,5-dimethyl-4-(phenylethynyl)aniline (56) was synthesized (Scheme 5-5).  This monomer was accessed from commercially available 2,5-dimethylaniline. First, iodination of 2,5-dimethylaniline afforded the corresponding disubstituted iodoaniline, which was then used in a Sonogashira cross-coupling reaction with phenylacetylene to generate 2,5-dimethyl-4-(phenylethynyl)aniline (56) in good overall yield. It was thought that the 5-methyl substituent would provide enough steric hindrance to control regioselectivity of hydroamination. Monomer 56 was subjected to the standard hydroamination conditions when using complex 20 with an internal alkyne (10 mol% complex 20, 1.5 mL toluene, 110 °C for 24 hr). Unfortunately, no polymerization was observed, even when the temperature was increased to 120 °C. Starting material was recovered following removal of the volatile components. This lack of reactivity could be caused by excess steric hindrance. Exploration of other possible hydroamination catalysts that may polymerize this monomer with high regiocontrol should be attempted.    Scheme 5-4: Proposed oligomerization of a monomer with methyl substituent to afford an oligomer with higher regioselectivity. 232    Scheme 5-5: Synthesis of monomer 56.  An alternative method to control the enamine-imine tautermization with oligomer 20 is to further substitute the nitrogen of the substrate.  It is well known that enamines would typically rearrange to the preferred imine tautomer. Under special circumstances, such as with aromatic amines as in the case with oligomer 42, enamine-imine mixtures can occur. Another method to favour the enamine formation is through the use of an N,N-disubstituted amine. As such, it is predicted that the oligomers from an N-substituted alkynylaniline would result in only enamine character in the oligomer backbone (Scheme 5-6). However, due to the reliance of a catalytically active metal imido species, typical neutral group 4 metal based hydroamination catalysts are not able to facilitate the reaction with secondary amines. Fortunately, complex 50 is a rare example of such complex that is able to catalyze the hydroamination with secondary amines, as shown in Chapter 4.  In a preliminary study, N-methyl-4-(phenylethynyl)aniline (57) was synthesized and tested as a monomer to form N-containing oligomers through hydroamination catalyzed by complex 50. 233  Monomer 57 was synthesized using the same method as 56, where starting from commercially available N-methylaniline, iodination afforded the iodoaniline product, which is then used in a Sonogashira cross-coupling reaction with phenylacetylene to afford 57 (Scheme 5-7). As internal alkynes are challenging substrates for this catalyst, oligomerization was attempted at 145 °C for 24 hours. In this initial attempt, no oligomeric product was observed. Monomer 57 was recovered as evidenced by 1H NMR spectroscopy of the crude reaction mixture. Although, the initial attempt to form oligomers from 57 was unsuccessfully, other effective hydroamination catalysts for secondary amines are known. For example, gold based complexes have been known to be able to catalyze the hydroamination of alkynes with secondary amines in high yields.259    Scheme 5-6: Proposed oligomerization of an N-substituted alkynylaniline.  Scheme 5-7: Synthesis of monomer 57.   Once more oligomers or polymers with extended conjugated networks are synthesized, even more complex monomers could be used to further alter the electronic properties of the polymer. For example, electron-withdrawing or electron-donating substituents could be added to 234  the phenyl ring, which can then modulate the electronic properties of the oligomers. These studies could lead to a reliable synthetic route to a novel class of N-containing conjugated polymers.   5.2.4 Conductivity Measurements of N-containing oligomers: New Direction In the preliminary results in Chapter 3, the N-containing oligomers synthesized from hydroamination were found to contain some degree of extended conjugation, which suggest these polymers could have conductive properties. Conductivity studies could be initiated to measure this electronic property. These measurements are typically made by a four-probe method on polymer pellets or thin film.507-508 Oligomer 42 could be pressed into a pellet, or a thin film of 42 could be made from a spin-coating procedure, where its conductive properties can then be measured.  The measured values could be compared to the electric conductivity of polyaniline; at its most conductive form, it has an electrical conductivity of 10-2 S cm-1.509 In this conductive form, polyaniline is partially oxidized and doped with an acid.509 To improve electric conductivity, the novel oligomers presented in Chapter 3 could be chemically or electrochemically oxidized and subsequently doped with an acid.510-511 If the new polymers are found to be semi-conductors, it could be used as a complementary conductive polymer to polyaniline. These novel polymers could be used in photoelectrochemical cells or electronic devices.402   5.3 Conclusions This thesis further demonstrates that titanium and zirconium amidate complexes are useful reagents or catalysts for synthetic transformations. For example, a novel class of zirconocene amidate hydride complexes demonstrated reactivity that they could be potential alternatives to Schwartz’s reagent. Additionally, the reactivity of a bis(amidate) bis(amido) titanium 235  hydroamination precatalyst was used to synthesize secondary amines, a substituted allylamine, and nitrogen containing oligomers. These products have applications from medicinal to materials chemistry.  5.4 Experimental for Preliminary Results Hydrosilylation catalyzed by complex 2d  In a small vial, complex 2d (11 mg, 0.01 mmol) was dissolved in C6D6 (300 μL). The solution was transferred to a J. Young NMR tube. A small vial was charged with styrene (26 mg, 0.25 mmol) and PhSiH3 (27 mg, 0.25 mmol), which was then diluted with C6D6 (300 μL). The contents of the vial were then transferred to the J. Young tube. C6D6 was then added until the reaction mixture reached ca. 1 mL in volume. The NMR tube was sealed and left at room temperature for 18 hours and then an additional 16 hours at 40 °C. The reaction was periodically monitored by 1H NMR spectroscopy. Formation of the linear product was observed, regioselectivity was assigned by COSY NMR spectroscopy (Figure 5-2). 1H NMR (C6D6, 300 MHz): δ (ppm) 7.50 – 7.47 (m, 2H, Ar), 7.20 – 7.03 (m, 8H, Ar), 4.48 (t, J = 3.6 Hz, 2H, SiH2), 2.68 – 2.63 (m, 2H, PhCH2), 1.17 – 1.11 (m, 2H, SiCH2). 236   Figure 5-2: Partial COSY NMR spectrum of the crude product mixture following hydrosilylation.   Cross dehydrocoupling catalyzed by complex 2d  This reaction was carried out using a modified published procedure.494 In a small vial, complex 2d (6 mg, 0.013 mmol) was dissolved in C6D6 (600 μL) and transferred to a J. Young NMR tube. Phenylsilane (15 mg, 0.25 mmol) diluted with C6D6 (300 μL) was then added to the reaction mixture, followed by iso-propylamine (54 mg, 0.5 mmol). The NMR tube was sealed and 237  reacted at room temperature where it was periodically monitored by 1H NMR spectroscopy. Following 21 hours at room temperature, full consumption of the amine was observed as indicated by the septet at 2.89 ppm. Formation of N-isopropyl-1-phenylsilanamine was identified by the diagnostic doublet at 5.13 ppm (2H, SiH2) and the multiplet at 3.01 ppm (1H, NHCHMe2).494  Synthesis of 4-iodo-2,5-dimethylaniline  The compound was synthesized using a modified published procedure.512 A 250 mL round bottom flask equipped with a stirbar was charged with 2,5-dimethylaniline (5.1 mL, 40 mmol) dissolved in 40 mL methanol. The solution was cooled to 0 °C. A solution of NaHCO3 (5.4 g, 64 mmol) in 24 mL of water was then added. To the reaction mixture, I2 (10.2 g, 40 mmol) was added in portion wise. The reaction was warmed to room temperature and stirred for 2.5 hours. The mixture was then poured into ca. 50 mL of H2O. The quenched mixture was extracted with ethyl acetate (2 × ca. 40 mL), and the combined organic fractions were washed with saturated Na2SO4(aq) (2 × ca. 40 mL), saturated brine solution (2 × ca. 40 mL), dried over MgSO4 and filtered by gravity filtration. The filtrate was concentrated by rotary evaporation and subsequently passed through a short silica column with 1 : 1 Et2O : PE. Following removal of the volatile components by rotary evaporation, the title compound was afforded in 91% yield (8.95 g) as an off-white solid. This compound was used without further purification. Spectral data matched literature reference.513      238  Synthesis of 2,5-dimethyl-4-(phenylethynyl)aniline A 250 mL round bottom Schlenk flask equipped with a stir bar was charged with PdCl2(PPh3)2 (70 mg, 0.1 mmol), CuI (44 mg, 0.4 mmol), and 4-iodo-2,5-dimethylaniline (2.47 g, 10 mmol). The solids were dissolved in NEt3 (50 mL). To this mixture, phenylacetylene (1.17 g, 12 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Distilled water (~ 25 mL) and Et2O (~ 15 mL) were then added to the solution. The aqueous layer was separated and extracted with Et2O (3 × 25 mL). The combined organic layer was dried with MgSO4, filtered, and the volatiles were removed by rotary evaporation. Following column chromatography (4 :1 → 2 : 1 PE : Et2O, Rf = 0.68 in 1 : 1 PE : Et2O), the compound was obtained as a pale yellow solid in 62% yield (1.37 g, 6.2 mmol). 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.53 – 7.49 (m, 2H, Ar), 7.37 – 7.29 (m, 3H, Ar), 7.22 (s, 1H, Ar), 6.54 (s, 1H, Ar), 3.71 (br s, 2H, NH2), 2.42 (s, 3H, Me), 2.14 (s, 3H, Me);  13C{1H} NMR (CDCl3, 101 MHz): δ (ppm) 144.9, 139.3, 133.9, 131.2, 128.2, 127.4, 124.3, 119.4, 115.7, 112.5, 90.9, 89.2, 20.3, 16.7; MS (ESI): m/z 222 ([M+H]+); HRMS (ESI-TOF) m/z: Calcd for C16H16N ([M+H]+), 222.1283; Found: 222.1280.  Synthesis of 4-iodo-N-methylaniline  The compound was synthesized using a modified published procedure.512 A 250 mL round bottom flask equipped with a stirbar was charged with N-methylaniline (4.5 mL, 40 mmol) dissolved in 40 mL methanol. The solution was cooled to 0 °C. A solution of NaHCO3 (5.4 g, 64 mmol) in 24 mL of water was then added. To the reaction mixture, I2 (10.2 g, 40 mmol) was added in portion wise. The reaction was warmed to room temperature and stirred for 2.5 hours. The mixture was then poured into ca. 50 mL of H2O. The quenched mixture was 239  extracted with ethyl acetate (2 × ca. 40 mL), and the combined organic fractions were washed with saturated Na2SO4(aq) (2 × ca. 40 mL), saturated brine solution (2 × ca. 40 mL), dried over MgSO4 and filtered by gravity filtration. The filtrate was concentrated by rotary evaporation and subsequently passed through a short silica column with 4 : 1 Et2O : PE. Following removal of the volatile components by rotary evaporation, the titled compound was afforded in 18% yield (1.69 g) as an off-white solid. This compound as used without further purification. Spectral data matched literature reference.513   Synthesis of N-methyl-4-(phenylethynyl)aniline  A 100 mL round bottom Schlenk flask equipped with a stir bar was charged with PdCl2(PPh3)2 (35 mg, 0.5 mmol), CuI (10 mg, 0.1 mmol), and 4-iodo-N-methylaniline (1.17 g, 5.0 mmol). The solids were dissolved in NEt3 (25 mL). To this mixture, phenylacetylene (0.7 mL, 5.0 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. Distilled water (~ 15 mL) and Et2O (~ 6 mL) were then added to the solution. The aqueous layer was separated and extracted with Et2O (3 × 15 mL). The combined organic layer was dried with MgSO4, filtered, and the volatiles were removed by rotary evaporation. 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Lett. 2001, 3, 991-992.  273  Appendices  Appendix A  Supplementary Figures for Chapter 2   Figure A- 1: Partial TOCSY NMR spectra of complex 2d.   274   Figure A- 2: Variable temperature 1H NMR spectra of complex 2d (400 MHz, C6D6).   275   Figure A- 3: Stacked 1H NMR spectra of inserted product 3d (bottom), crude reaction mixture of inserted product with I2 (middle) and complex 2d (top) (300 MHz, C6D6). Highlighted quartet signal refers to ZrCH(Me)Ph (bottom) and CHI(Me)Ph (middle). 276   Figure A- 4: Molecular structure of 7b in the solid state. Hydrogen atoms are omitted for clarity. The thermal ellipsoids correspond to 50% probability. Selected bond lengths [Å] and angles [°]: C1-O1 1.363(6), C1-N1 1.259(6), Zr1-O1 1.978(3), Zr1-Br1 2.6318(9); O1-C1-N1 127.9(4), O1-Zr1-Br1 101.27(10), C1-O1-Zr1 168.7(3), sum of angles around C1: 360.0(7). 277   Figure A- 5: Plot of integrations of 3d and styrene over time when complex 3d is held at 85 °C as monitored by 1H NMR spectroscopy.00.10.20.30.40.50.60.70.80.910 10 20 30 40 50Normalized IntegrationTime (min)3d styrene278  Figure A- 6: Variable temperature 1H NMR spectra of complex 3d (400 MHz, d8-toluene).     279  Appendix B  NMR Spectra for Select Compounds   280    281    282    283   284              285  286    287    288     289    290    291   292    293    294    

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