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Bis(amidate) titanium, zirconium, and tantalum complexes : applications in catalytic synthesis of N-containing… Ayinla, Rashidat Omolabake 2011

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BIS(AMIDATE) TITANIUM, ZIRCONIUM, AND TANTALUM COMPLEXES: APPLICATIONS IN CATALYTIC SYNTHESIS OF N-CONTAINING COMPOUNDS  by RASHIDAT OMOLABAKE AYINLA  B.Sc. (Honours), Ahmadu Bello University, 2000 M.Sc., The University of British Columbia, 2005  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry)  THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver)  December, 2011  © Rashidat Omolabake Ayinla, 2011  ABSTRACT A two-part study involving the synthesis and catalytic investigations of amidate complexes of early transition metals is described. In the first part, the substrate scope of an achiral bis(amidate) titanium hydroamination precatalyst has been broaden to include challenging substrates. This complex efficiently catalyzes the hydroamination of heteroatomcontaining allenes with arylamines. Control experiments rule out allene-alkyne isomerization as a reaction pathway during this catalysis. The hydrohydrazination of a variety of alkynes with 1,1disubstituted hydrazines also proceed efficiently in the presence of this precatalyst giving the anti-Markovnikov hydrazone products predominantly. These hydrazones have been transformed into substituted indoles by a one-pot tandem sequential hydroamination/ZnCl2-mediated cyclization. Importantly, the bis(amidate) titanium precatalyst can be generated in situ for these reactions with no impact on the reactivity or selectivity of the complex. The second part of this thesis focuses on the synthesis, characterization, stability and catalytic investigations of chiral zirconium and tantalum complexes ligated with amidate ancillary ligands. Seven new axially chiral proligands have been synthesized and used for in situ generation of zirconium hydroamination precatalysts.  These chiral complexes efficiently  produce N-heterocycles in up to 94% isolated yield with ee reaching 74%. Preparative scale synthesis and characterization of the zirconium complexes revealed coordination geometry that is greatly influenced by the steric properties of the ligand. Bulky proligands produce monomeric complexes, wherein the biphenyl ligand displays a κ2-O,O-bonding motif which accounts for the modest enantioselectivities realized with this system. The less sterically-congested proligands initially  form  similar  monomeric  complexes;  however,  these  complexes  dimerize  diastereoselectively to κ4-N,O,O-N-bonding amidate complexes within a few hours in solution.  ii  The binding motif of the amidate ligand of the chiral biphenyl tantalum complexes is also dictated by the size of the N-substituent of the ligand. While a bulky proligand results in a discrete tantalum κ2-O,O-bonding amidate complex, less sterically-encumbered proligands produce a mixture of κ2-O,O-bonding and κ3-N,O,O-bonding amidate complexes. Using these tantalum complexes as precatalysts, alkenes undergo hydroaminoalkylation reactions with secondary amines to give branched alkylated secondary amines in isolated yields of up to 92% and enantiomeric excesses reaching 66%, for the first examples of an enantioselective hydroaminoalkylation reaction.  iii  PREFACE The original experimental ideas in this thesis are consistent with the research interests of the Schafer group and were conceived in discussion with Dr. Laurel L. Schafer.  The  experimental design and research work presented herein were carried out by me with supervision and mentoring by Dr. Laurel L. Schafer and assistance from certain members of the group as detailed below. I synthesized all the proligands and complexes presented in Chapters 3 and 4, however, Travis Gibson, a 449-student who worked under my supervision helped in the preparation of proligand 68f. Travis also helped with the catalytic investigations featured in Table 3.2, as the results presented in entries 1 and 6 as well as the NMR yield in entry 2 emerged from his effort. All other investigations in this chapter were executed by me. I performed all the catalytic investigations presented in Chapters 2 and 4. The aminoalkene substrates utilized in Chapter 3 were synthesized by various members (past and present) of the Schafer group namely: Jason Bexrud, David Leitch, Jacky Yim, Philippa Payne, Eugene Chong, Rachel Platel, Neal Yonson, and me. The complexes presented in Chapter 4 emerged solely from my investigation. The data collected for the solid-state molecular structures featured in this thesis were completed by Neal Yonson or Jacky Yim while I performed the final refinements, sometimes with assistance from Dr. Brian Patrick. A portion of Chapter 3 has been published in the Journal of Organometallic Chemistry published by Elsevier B. V. as: Ayinla R. O.; Gibson, T.; Schafer, L. L. “Amidate ligand design effects in zirconium-catalyzed enantioselective hydroamination of aminoalkenes” J. Organomet. Chem. 2011, 696, 50–60. A part of Chapter 4 has also appeared in Angewandte Chemie International Edition published by Wiley-VCH: Eisenberger, P.; Ayinla, R. O.; Lauzon, J. M. P.; Schafer, L. L. “Tantalum-Amidate Complexes for the Hydroaminoalkylation of Secondary  iv  Amines: Enhanced Substrate Scope and Enantioselective Chiral Amine Synthesis” Angew. Chem., Int. Ed. 2009, 48, 8361–8365. Finally, I wrote this thesis with constructive criticism from Dr. Laurel L. Schafer.  v  TABLE OF CONTENTS ABSTRACT .................................................................................................................................... ii PREFACE ...................................................................................................................................... iv TABLE OF CONTENTS ............................................................................................................... vi LIST OF TABLES ........................................................................................................................ xii LIST OF FIGURES ..................................................................................................................... xiv LIST OF SCHEMES................................................................................................................... xvii LIST OF SYMBOLS AND ABBREVIATIONS ........................................................................ xxi ACKNOWLEDGEMENTS ....................................................................................................... xxiv DEDICATION ........................................................................................................................... xxvi  CHAPTER 1. AXIALLY CHIRAL COMPLEXES IN THE ATOM-ECONOMIC ENANTIOSELECTIVE SYNTHESIS OF AMINES .................................................................... 1 1.1 Catalytic Synthesis of Amines .............................................................................................. 1 1.2 Enantioselective Catalytic Synthesis of Amines................................................................... 3 1.3 Enantioselective Synthesis of Amines by Metal-Catalyzed Hydroamination Reactions ..... 4 1.3.1. Enantioselective Lanthanide-Based Hydroamination Precatalysts ............................... 5 1.3.2 Enantioselective Group 1 and 2 Metal-Based Hydroamination Precatalysts .............. 11 1.3.3 Enantioselective Late Transition Metal-Based Hydroamination Precatalysts ............. 15 1.3.4 Enantioselective Early Transition Metal-Based Hydroamination Precatalysts ........... 20 1.4 Synthesis of Secondary Amines by Metal-Catalyzed Hydroaminoalkylation Reactions ... 25 vi  1.5 Scope of this Thesis ............................................................................................................ 30 CHAPTER 2. APPLICATION OF A BIS(AMIDATE) BIS(AMIDO) TITANIUM(IV) PRECATALYST IN THE SYNTHESIS OF N-CONTAINING COMPOUNDS BY INTERMOLECULAR HYDROAMINATION............................................................................ 33 2.1 Introduction ......................................................................................................................... 33 2.2 Results and Discussion ....................................................................................................... 36 2.2.1 Hydroamination of Heteroatom-Substituted C–C Unsaturated Systems ..................... 36 2.2.2 Hydrohydrazination of Alkynes with 1,1-Disubstituted Hydrazines ........................... 44 2.2.3 One-Pot Synthesis of N-substituted Indoles by Tandem Hydrohydrazination, Fischer Indole Reaction ............................................................................................................ 52 2.2.4 Hydroamination Reactions with In Situ Generated Precatalyst 49 .............................. 55 2.3 Conclusions ......................................................................................................................... 57 2.4 Experimental ....................................................................................................................... 58 2.4.1 Materials and Methods ................................................................................................. 58 2.4.2 Catalytic Procedures .................................................................................................... 59 2.4.3 Representative Procedure for the Hydrohydrazination Reactions ............................... 63 2.4.3.1 Procedure 1 for the Hydrohydrazination Reactions .............................................. 63 2.4.3.2 Procedure 2 for the Hydrohydrazination Reactions .............................................. 65 2.4.4 Representative Procedure for the Formation of Indoles .............................................. 66 2.4.5 Representative Procedure for Hydroamination Reactions with In Situ Generated Precatalyst .................................................................................................................... 66  vii  CHAPTER 3. SYNTHESIS AND CHARACTERIZATION OF AXIALLY CHIRAL ZIRCONIUM BIPHENYL AMIDATE COMPLEXES: APPLICATION IN THE ENANTIOSELECTIVE HYDROAMINATION OF AMINOALKENES .................................. 68 3.1 Introduction ......................................................................................................................... 68 3.2 Results and Discussion ....................................................................................................... 73 3.2.1 Proligand Synthesis and Characterization ................................................................... 73 3.2.2 Hydroamination Catalysis ............................................................................................ 79 3.2.2.1 Hydroamination of Primary Aminoalkenes .......................................................... 79 3.2.2.2 Secondary Aminoalkenes as Substrates ................................................................ 85 3.2.3 Synthesis and Characterization of Zirconium Bis(amidate) Complexes ..................... 89 3.2.3.1 Sterically-Congested Zirconium Bis(amidate) Complexes .................................. 89 3.2.3.2 Dimerization of Sterically-Accessible Zirconium Complexes ............................. 95 3.2.3.3 Sterically-Congested Zirconium Complexes with Pyridine as Neutral Donor ... 104 3.2.3.4 Stability of Sterically-Congested Zirconium Precatalysts .................................. 107 3.2.4 Investigation of Non-Linear Effects .......................................................................... 109 3.3 Conclusions.......................................................................................................................110 3.4 Experimental Procedures .................................................................................................. 111 3.4.1 Methods and Materials ............................................................................................... 111 3.4.2 Synthetic Procedures .................................................................................................. 112 3.4.3 Representative Procedures ......................................................................................... 114 3.4.3.1 Procedure 1: Representative Procedure for the Synthesis of Bis(amide) Proligands .............................................................................................................................. 114 viii  3.4.3.2 Procedure 2: Representative Procedure for the Enantioselective Hydroamination of Aminoalkenes ................................................................................................ 120 3.4.3.3 Procedure 3: Representative Procedure for the Enantioselective Hydroamination of Aminoalkenes in Table 3.3. ............................................................................ 121 3.4.3.4 Procedure 4: Representative Procedures for the Determination of Enantiomeric Excesses of Mosher Amides by 1H and 19F NMR Spectroscopies ..................... 122 3.4.3.5 Procedure 5: Representative Procedures for the Synthesis of Zirconium Complexes........................................................................................................... 123 3.5.3.6 Procedure 6: Representative Procedure for the Synthesis of Zirconium Complexes with Pyridine as Neutral Donor .......................................................................... 126  CHAPTER 4. SYNTHESIS AND CHARACTERIZATION OF CHIRAL TANTALUM AMIDATE COMPLEXES: APPLICATION IN THE ENANTIOSELECTIVE HYDROAMINOALKYLATION REACTION.......................................................................... 129 4.1 Introduction ....................................................................................................................... 129 4.2 Results and Discussion ..................................................................................................... 134 4.2.1 Synthesis and Characterization of Axially Chiral Tantalum Amidate Complexes.... 134 4.2.1.1 Sterically-Congested Axially Chiral N-Aryl Tantalum Amidate Complex ........ 134 4.2.1.2 Sterically-Accessible Axially Chiral N-Aryl Tantalum Amidate Complexes .... 137 4.2.1.3 Axially Chiral N-Alkyl Tantalum Amidate Complexes ..................................... 152 4.2.2 Enantioselective Hydroaminoalkylation Reactions ................................................... 157 4.2.2.1 Catalytic Screening of Tantalum Amidate Complexes for the Hydroaminoalkylation Reaction ......................................................................... 157 ix  4.2.2.2 Substrate Scope Investigation of Complex 82a in Enantioselective Hydroaminoalkylation Reactions........................................................................ 160 4.2.2.3 Determination of the Absolute Configuration of the Hydroaminoalkylation Products............................................................................................................... 166 4.2.2.4 Thermal Stability of Precatalyst 82a................................................................... 168 4.2.3 Synthesis and Characterization of Cyclohexyl-Tethered Tantalum Amidate Complexes .................................................................................................................................... 170 4.2.3.1 Synthesis of Cyclohexyl-Tethered Bis(amide) Proligands ................................. 170 4.2.3.2. Synthesis of Cyclohexyl-Tethered Tantalum Amidate Complexes ................... 171 4.2.3.3. Hydroaminoalkylation Reaction Using Cyclohexyl-Tethered Tantalum Amidate Complexes as Precatalysts ................................................................................. 174 4.2.4 Synthesis of an Amino Alcohol by Hydroaminoalkylation and Oxidative PMPCleavage ...................................................................................................................... 175 4.3 Conclusions ....................................................................................................................... 177 4.4 Experimental Procedures .................................................................................................. 179 4.4.1 Materials and Methods ............................................................................................... 179 4.4.2 Representative Procedures ......................................................................................... 179 4.4.2.1 Procedure 1: Representative Procedure for the Synthesis of Tantalum Complexes ............................................................................................................................. 179 4.4.2.2 Procedure 2: Representative Procedure for Hydroaminoalkylation of Alkenes..183 4.4.2.3 Procedure 3: Representative Procedure for the Synthesis of Benzamides ......... 187 4.4.2.4 Procedure 4. Representative Procedure for the Synthesis of Sulfonamides ....... 194  x  CHAPTER 5. SUMMARY AND FUTURE DIRECTIONS ..................................................... 203 5.1 Summary ........................................................................................................................... 203 5.2 Future Directions .............................................................................................................. 207 5.2.1 Tandem Reaction Sequence Involving Hydroamination Reactions Catalyzed by 49 ................................................................................................................................... 207 5.2.1.1 Proposed Synthesis of 1,2-Diamines by Hydroamination and Aza-Henry Reactions ............................................................................................................. 207 5.2.1.2 Proposed Synthesis of Secondary Aminoalkenes by Hydroamination and AzaCope Reactions ................................................................................................... 208 5.2.2 Axially Chiral Proligands and Complexes ................................................................. 210 5.2.2.1 Biphenyl-Tethered Amide-Acid Proligands ....................................................... 210 5.2.2.2 Proposed Sterically-Encumbered 3,3′-Disubstituted Biphenyl Proligands ........ 212 5.2.3 Optimization of Reaction Conditions.........................................................................214 5.3 Experimental Procedures .................................................................................................. 218 5.3.1 Materials and Methods ............................................................................................... 218 5.3.2 Synthetic Procedures..................................................................................................218 REFERENCES ........................................................................................................................... 222 APPENDIX A. X-RAY CRYSTALLOGRAPHIC DATA ....................................................... 244 APPENDIX B. 1H AND 13C NMR SPECTRA OF SELECTED COMPOUNDS ..................... 251  xi  LIST OF TABLES Table 2.1. Selected bond lengths and angle of 53b·H2C2O2 ....................................................... 41 Table 2.2. Intermolecular hydrohydrazination of alkynes with 1,1-disubstituted hydrazines ..... 49 Table 2.3. One-pot synthesis of N-substituted indoles ................................................................ 54 Table 2.4. Hydroamination reactions conducted with in situ prepared precatalyst 49 ................ 56 Table 3.1. Selected bond lengths and angles of 68g .................................................................... 78 Table 3.2. Ligand screening in enantioselective hydroamination of aminoalkenes .................... 81 Table 3.3. Substrate scope investigation in enantioselective hydroamination of primary aminoalkenes catalyzed by in situ generated precatalyst using proligand 68f ........... 83 Table 3.4. Selected bond lengths and angles of (±)-76a·HNMe2................................................ 91 Table 3.5. Selected bond lengths and angles of (±)-76f·HNMe2 ................................................ 93 Table 3.6. Selected bond lengths and angles of [76b]2 ................................................................ 98 Table 3.7. Selected bond lengths and angles of complex [76c]2 ............................................... 101 Table 3.8. Selected bond lengths and angles of complex 77 ..................................................... 104 Table 3.9. Selected bond lengths and angles of (±)-76a·(py)2 .................................................. 106 Table 3.10. Cyclohydroamination of 71d using varying enantiopurity of precatalyst 76f·HNMe2 ................................................................................................................................. 109 Table 4.1. Selected bond lengths and angles of (±)-82a ............................................................ 137 Table 4.2. Selected bond lengths and angles of (±)-82b·HNMe2 ............................................. 140 Table 4.3. Selected bond lengths and angles of (±)-83c ............................................................ 145 Table 4.4. Selected bond lengths and angles of (±)-83d............................................................ 147 Table 4.5. Selected bond lengths and angles of 84 .................................................................... 148 Table 4.6. Selected bond lengths and angles of (±)-94 .............................................................. 153  xii  Table 4.7. Selected bond lengths and angles of 81f ................................................................... 155 Table 4.8. Selected bond lengths and angles of (±)-82f ............................................................ 156 Table 4.9. Precatalyst screening in the enantioselective hydroaminoalkylation reaction .......... 159 Table 4.10. Selected bond lengths and angles of 97e ................................................................ 164 Table 4.11. Selected bond lengths and angles of (±)-101 .......................................................... 170 Table 4.12. Selected bond lengths and angles of (±)-106 .......................................................... 174 Table A.1. X-ray crystallographic parameters for 53b·H2C2O4, 69, and 68g ........................... 244 Table A.2. X-ray crystallographic parameters for (±)-76a·HNMe2, (±)-76f·HNMe2, and [76b]2 .................................................................................................................................... 245 Table A.3. X-ray crystallographic parameters for [76c]2, 77, and (±)-76a·(py)2 ...................... 246 Table A.4. X-ray crystallographic parameters for (±)-82a, (±)-82b·HNMe2, and (±)-83c....... 247 Table A.5. X-ray crystallographic parameters for (±)-83d, 84, and (±)-94 ............................... 248 Table A.6. X-ray crystallographic parameters for 81f, (±)-82f, and 97e ................................... 249 Table A.7. X-ray crystallographic parameters for (±)-101 and (±)-106 .................................... 250  xiii  LIST OF FIGURES Figure 1.1. Biologically active α-chiral amines synthesized by hydroamination reactions. ......... 1 Figure 1.2. Selected examples of axially chiral lanthanide-based hydroamination precatalysts. .. 9 Figure 1.3. (Pro)ligands and complexes utilized in main group metal-catalyzed hydroamination reactions. .................................................................................................................... 12 Figure 1.4. Selected examples of late-transition metal complexes and ligands for enantioselective hydroamination reactions. ............................................................... 16 Figure 1.5. Selected examples of early transition metal-based hydroamination precatalysts. .... 22 Figure 1.6. Highly reactive and stereoselective hydroamination precatalyst. ............................. 30 Figure 2.1. Efficient lanthanide-based precatalysts for the hydroamination reaction. ................ 34 Figure 2.2. ORTEP representation of the solid-state molecular structure of 53b·H2C2O4. ........ 41 Figure 2.3. Examples of early transition metal hydrazido complexes. ........................................ 45 Figure 2.4. Early transition metal catalysts for hydrohydrazination reaction. ............................. 46 Figure 3.1. Possible coordination isomers accessible to monoanionic amidate ligands..............69 Figure 3.2. Early examples of enantioselective aminoalkene hydroamination precatalysts. ....... 70 Figure 3.3. Highly enantioselective precatalysts and proligand for the hydroamination of aminoalkenes.............................................................................................................. 71 Figure 3.4. Chiral bis(amide) proligands and zirconium precatalyst for the asymmetric hydroamination of aminoalkenes. .............................................................................. 72 Figure 3.5. ORTEP representation of the solid-state molecular structure of 69.. ........................ 76 Figure 3.6. ORTEP representation of the solid-state molecular structure of 68g ........................ 78 Figure 3.7. ORTEP representation of the solid-state molecular structure of (±)-76a·HNMe2. .. 91 Figure 3.8. ORTEP representation of the solid-state molecular structure of (±)-76f·HNMe2 .... 93 Figure 3.9. ORTEP representation of the solid-state molecular structure of [76b]2.................... 97 xiv  Figure 3.10. ORTEP representation of the solid-state molecular structure of [76c]2 ................ 101 Figure 3.11. ORTEP representation of the solid-state molecular structure of 77 ...................... 103 Figure 3.12. ORTEP representation of the solid-state molecular structure of (±)-76a·(py)2 .... 106 Figure 3.13. Enantiomeric excess of pyrrolidine 72d as a function of enantiomeric excess of precatalyst 76f·HNMe2 .......................................................................................... 110 Figure 4.1. Bis(amide) proligands for tantalum amidate complex formation............................ 132 Figure 4.2. ORTEP representation of the solid-state molecular structure of (±)-82a ................ 136 Figure 4.3. ORTEP representation of the solid-state molecular structure of (±)-82b·HNMe2....... ..................................................................................................................................................... 139 Figure 4.4. Ball and stick representation of the molecular connectivity of a low quality crystal of (±)-83b.. ................................................................................................................... 140 Figure 4.5. A stacked plot of selected spectra of the high temperature variable temperature 1H NMR spectroscopy of a solution containing a mixture of 82b and 83b. ................. 142 Figure 4.6. ORTEP representation of the solid-state molecular structure of (±)-83c ................ 144 Figure 4.7. ORTEP representation of the solid-state molecular structure of (±)-83d . ............. 146 Figure 4.8. ORTEP representation of the solid-state molecular structure of 84. ....................... 148 Figure 4.9. ORTEP representation of the solid-state molecular structure of (±)-94 .................. 153 Figure 4.10. ORTEP representation of the solid-state molecular structure of 81f. ................... 155 Figure 4.11. ORTEP representation of the solid-state molecular structure of (±)-82f. ............. 156 Figure 4.12. ORTEP representation of the solid-state molecular structure of 97e .................... 163 Figure 4.13. ORTEP representation of the solid-state molecular structure of (±)-101.............. 169 Figure 4.14. ORTEP representation of the solid-state molecular structure of (±)-106............. 173 Figure 5.1. Proligands and precatalysts utilized for the atom economic synthesis of amines ... 204  xv  Figure 5.2. Percentage conversion of amine substrate as a function of time.............................217  xvi  LIST OF SCHEMES Scheme 1.1. Selected examples of metal-catalyzed amine synthesis. ........................................... 3 Scheme 1.2. Intermolecular and intramolecular hydroamination reactions. ................................. 5 Scheme 1.3. Pioneering enantioselective intramolecular hydroamination reactions.....................6 Scheme 1.4. Synthesis of (+)-coniine by lanthanide-catalyzed hydroamination. .......................... 6 Scheme 1.5. Proposed mechanism for lanthanide-catalyzed hydroamination. .............................. 7 Scheme 1.6. Yttrium-catalyzed enantioselective intermolecular hydroamination reactions. ...... 10 Scheme 1.7. Lithium-mediated intramolecular hydroamination of activated aminoalkenes. ...... 13 Scheme 1.8. Postulated mechanism for magnesium-catalyzed intramolecular hydroamination. ..................................................................................................................................................... ..14 Scheme 1.9. Palladium-catalyzed enantioselective intermolecular hydroamination of activated olefins with arylamines. .......................................................................................... 17 Scheme 1.10. Proposed mechanism for palladium-catalyzed intermolecular hydroamination of vinylarenes with arylamines. ................................................................................ 18 Scheme 1.11. Proposed mechanistic pathway for intermolecular hydroamination via oxidative addition of amine. ................................................................................................. 19 Scheme 1.12. Synthesis of a cationic zirconium hydroamination precatalyst. ............................ 21 Scheme 1.13. Proposed mechanism for early transition metal-catalyzed intramolecular hydroamination of aminoalkenes. .......................................................................... 24 Scheme 1.14. Intermolecular and intramolecular hydroaminoalkylation reactions. ................... 25 Scheme 1.15. Deuterium scrambling in dimethylamine: Metallaaziridine as a key intermediate in the catalytic hydroaminoalkylation reaction. ........................................................ 26 Scheme 1.16. Highly efficient tantalum-catalyzed hydroaminoalkylation reactions. ................. 27  xvii  Scheme 1.17. Proposed mechanism for group 5 metal-catalyzed intermolecular hydroaminoalkylation reaction. .............................................................................. 28 Scheme 2.1. Synthesis of a highly reactive and regioselective hydroamination precatalyst. ...... 35 Scheme 2.2. Multiple regioisomeric products accessible from the intermolecular hydroamination of allenes. ................................................................................................................ 37 Scheme 2.3. Intermolecular hydroamination of N-substituted allene with arylamines. .............. 39 Scheme 2.4. Proposed mechanism for the intermolecular hydroamination of heteroatomsubstituted allenes with aryl- and alkylamines. ....................................................... 42 Scheme 2.5. Intermolecular hydroamination of 1-(prop-2-ynyl)-1H-indole with arylamines. ... 44 Scheme 2.6. Regioisomeric products accessible from the hydrohydrazination reaction between an alkyne and a hydrazine. ...................................................................................... 47 Scheme 2.7. Tandem sequential hydrohydrazination/cyclization reactions for indole synthesis...................................................................................................................53 Scheme 3.1. Intramolecular and intermolecular hydroamination of alkenes............................... 69 Scheme 3.2. Epimerization of chiral lanthanide complexes via reversible protolytic cleavage of metal–chiral ligand bond.......................................................................................... 70 Scheme 3.3. Synthesis of (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid............................... 73 Scheme 3.4. Synthesis of biphenyl-tethered proligands. ............................................................. 75 Scheme 3.5. Proposed route for the formation of cyclic imide side product. .............................. 75 Scheme 3.6. Synthesis of (S)-proligand 68g ................................................................................ 77 Scheme 3.7. Rationalization of diastereoselectivity in the hydroamination of aminoalkenes catalyzed by in situ generated precatalyst using proligand 68f ............................... 85 Scheme 3.8. Cycloaddition mechanism for group 4 metal-catalyzed hydroamination reaction  xviii  .............................................................................................................................. 86 Scheme 3.9. Hydroamination reaction with secondary aminoalkenes. ....................................... 87 Scheme 3.10. Simplified σ-bond insertion mechanism for the hydroamination of secondary aminoalkenes.......................................................................................................... 88 Scheme 3.11. Rationalization of enantioselectivity in zirconium-catalyzed hydroamination of aminoalkenes.......................................................................................................... 94 Scheme 3.12. Dimerization of sterically-accessible zirconium complex...................................102 Scheme 4.1. Catalytic intramolecular and intermolecular hydroaminoalkylation reactions. .... 130 Scheme 4.2. Tantalum amidate-catalyzed hydroaminoalkylation reactions. ............................. 131 Scheme 4.3. Enantioselective intermolecular hydroaminoalkylation reactions catalyzed by group 5 metal complexes................................................................................................. 133 Scheme 4.4. Synthesis of bis(amidate) tantalum complex 82a. ................................................ 135 Scheme 4.5. Synthesis of sterically-accessible tantalum complexes with proligand 68b. ........ 138 Scheme 4.6. Synthesis of tantalum complexes with proligand 68c. .......................................... 143 Scheme 4.7. Unexpected formation of N,N-chelating (dimethylaminomethylene)methylamide tantalum complexes. ............................................................................................. 149 Scheme 4.8. Proposed mechanism for the formation of N,N-chelating dimethylaminomethylene)methylamide tantalum complexes. .................................................. 150 Scheme 4.9. Proposed mechanism for the formation of complex 84. ....................................... 151 Scheme 4.10. Amine products from substrate scope investigation of enantioselective hydroaminoalkylation reaction using precatalyst 82a. ........................................ 163 Scheme 4.11. Hydroaminoalkylation of norbornene with N-methylaniline using precatalyst (R)82a....................................................................................................................... 164  xix  Scheme 4.12. Enantioselective hydroaminoalkylation of norbornene with N-methylbenzylamine using precatalyst 82a........................................................................................... 165 Scheme 4.13. Synthesis of amide diastereomers for stereochemical configuration analysis. ... 166 Scheme 4.14. Synthesis of cyclohexyl-tethered amide proligands. ........................................... 171 Scheme 4.15. Hydroaminoalkylation reactions catalyzed by tantalum cyclohexyl-tethered amidate complexes. .............................................................................................. 175 Scheme 4.16. Synthesis of Fmoc-protected amino alcohol. ...................................................... 177 Scheme 5.1. Proposed tandem sequential formation of 1,2-diamine by hydroamination/azaHenry/reduction reaction sequence. ....................................................................... 208 Scheme 5.2. Proposed synthesis of aminoalkenes by hydroamination/aza-Cope rearrangement ............................................................................................................................... 210 Scheme 5.3. Synthesis of amide-acid proligand 110. ................................................................ 211 Scheme 5.4. Synthesis of mixed amide-acid proligand 111. ..................................................... 211 Scheme 5.5. Proposed synthesis of new bis(amide) proligands. ............................................... 214  xx  LIST OF SYMBOLS AND ABBREVIATIONS Å  Angstrom  Ac  Acetyl  Anal.  Analysis  Ar  Aryl  BINAP  2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl  br  Broad  Calcd  Calculated  Cbz  Carboxybenzyl  cod  1,5-Cyclooctadiene  coe  Cyclooctene  Cy  Cyclohexyl  d  Doublet  DCC  N,N′-Dicyclohexylcarbodiimide  dd  Doublet of doublet  DFT  Density functional theory  dt  Doublet of triplet  DTBM  3,5-Di-tert-butyl-4-methoxyphenyl  Et  Ethyl  eq  Equation  Fmoc-OSu  N-(9-fluorenylmethoxycarbonyloxy) succinimide  ΔG‡  Activation energy  GC  Gas chromatography  HPLC  High performance liquid chromatography xxi  Hz  Hertz  i  Pr  Isopropyl  J  Coupling constant  KHMDS  Potassium hexamethyldisilazane  m  Multiplet  M  Molar  Me  Methyl  mol  Mole  mmol  Millimole  MS  Mass spectrometry  m/z  Mass to charge ratio  N  Normal  n-Bu  n-Butyl (linear)  NMR  Nuclear Magnetic Resonance  ORTEP  Oakridge Thermal Ellipsoid Program  OTf  Trifluoromethanesulfonate (Triflate)  Ph  Phenyl  py  Pyridine  quin  Quintet  rt  Room temperature  s  Singlet  SFC  Supercritical fluid chromatography  t  Triplet  xxii  t  Bu  tert-Butyl  Tc  Coalescence temperature  tR  Retention time  TBDMS  tert-Butyldimethylsilyl  TMS  Trimethylsilyl  Ts  Toluenesulfonyl (tosyl)  VT  Variable temperature  δ  delta, Chemical shift  κ  kappa, Denticity  η  eta, Hapticity  xxiii  ACKNOWLEDGEMENTS It is befitting to begin this appreciation note with Dr. Laurel Schafer, my supervisor, who tirelessly oversees all aspects of my post-graduate studies. I am immensely grateful to Laurel for all her support, encouragement, and constructive criticism during my studies at UBC. I am grateful to all past and present members of the Schafer group: Rob, for his tremendous help during the beginning of my studies; Patrick, for the helpful suggestion and discussion toward the end of my studies; Jacky and Neal, for assistance with X-ray diffraction, Rachel, for tips on Microsoft word; Johnson, for running some NMR spectra on my behalf, Louisa, for the lab talk; and Robby, for his help on getting started with the SFC. Special thanks are due to JM and Dave, for proof-reading this thesis with eagle eyes and to Pippa for her huge help with the submission of this thesis. I acknowledge other members of the department: Ken Love of the mechanical workshop and Brian Greene of the electronic workshop for their help with the GC-MS, Dr. Brian Patrick of the X-ray crystallography laboratory for assistance with X-ray crystallography, Brian Ditchburn of the glassblowing shop for the various glassware. To members of the Dake‟s group especially Julian, I say thank you for access to HPLC analytical instruments. I thank the Andersen group for access to the polarimeter. I am also grateful to Dr. Glenn Sammis for the opportunity to use the SFC analytical instrument. My husband, Nurudeen, has been a rock of support every step of the way and I am truly blessed to have him in my life. Thanks to my beautiful daughter, Fawziyah, for the interest in what I do and for the unfailing „I love you Mom, see you later‟ when I drop her off at the daycare and the fierce hug I get when I pick her up, you are indeed very special. Dad and mum have always being there for me; I truly appreciate their prayers and support. I would like to thank my  xxiv  sisters and brothers: Latifat, Bilkisu, Silifat, Suliat, Ahmed, and Ibrahim; as well as my in-laws for their prayers and support.  xxv  DEDICATION This thesis is dedicated to my loving husband, Nurudeen Oluwagbemiga Olagunju and My beautiful daughter, Fawziyah Olamide Olagunju; with you as family my heart desires are achievable.  xxvi  CHAPTER 1. AXIALLY CHIRAL COMPLEXES IN THE ATOM-ECONOMIC ENANTIOSELECTIVE SYNTHESIS OF AMINES  1.1 Catalytic Synthesis of Amines Interest in the development of efficient synthetic protocols for amines has increased tremendously in the last two decades.1-3 These molecules are critical synthetic intermediates in industrial and chemical processes and many are biologically relevant (Figure 1.1).1-3  In  particular, α-chiral amines are prevalent in bioactive compounds and research efforts are geared toward efficient syntheses of these molecules.2  Figure 1.1. Biologically active α-chiral amines synthesized by hydroamination reactions.  A variety of methods are available for preparing amines including reductive amination, N-alkylation of amines, and nucleophilic addition to imines.2,  3  However, these traditional  methodologies are often plagued by a number of limitations, namely low chemoselectivity, production of by-products, and harsh reaction conditions.2,  3  Furthermore, the difficulties  associated with developing enantioselective variants, which are more highly desired for chiral amine synthesis, are major drawbacks of these traditional methods.4 For example, the coupling of aldehydes and ketones with amines via reductive amination is one of the most widely used transformations for synthesizing amines with a plethora of reported achiral examples5-7 but few enantioselective variants.4, 8 Many of the documented enantioselective reductive aminations are achieved indirectly with late transition metal-based catalysts bearing chiral ancillary ligands.4, 9-12 1  This approach requires prior isolation of the imine intermediates (that are prone to hydrolysis) as the starting carbonyl compounds are susceptible to hydrogenation using these catalytic systems. 4, 13  Alternatively, the synthesis of primary or secondary amines via the N-alkylation of ammonia  or primary amines is susceptible to over-alkylation and often leads to a complex mixture of products.2 This limitation is usually circumvented with the use of excess amine; however, asymmetric synthesis may require chiral primary amines as substrates, rendering alkylation a rather inefficient and expensive method.2 The challenges associated with the traditional approaches to synthesizing amines have led to the development of metal-catalyzed reactions for the preparation of these molecules. Notable examples among these metal-catalyzed reactions include: Buchwald-Hartwig amination (Scheme 1.1 (a)),14-22 direct reductive amination (Scheme 1.1 (b)),4, 23-32 condensation reactions (Scheme 1.1 (c)),2,  3  hydroaminomethylation,33-39 hydroamination,1,  40-42  and hydroaminoalkylation.43  Using these methods, primary, secondary, and tertiary amines have been prepared in good yields as shown with the selected examples in Scheme 1.1.24, 44, 45 Importantly, some of these metalcatalyzed reactions are amenable to asymmetric catalysis via the use of chiral ancillary ligands on the metal catalysts.  2  Scheme 1.1. Selected examples of metal-catalyzed amine synthesis.24, 44, 45  1.2 Enantioselective Catalytic Synthesis of Amines Chiral N-containing molecules are ubiquitous in naturally occurring and biologically relevant compounds and efficient syntheses of these molecules are highly desired.  These  compounds are accessible via the asymmetric catalytic synthesis of amines through the use of metal catalysts bearing chiral ancillary ligands.1,  3, 4  In particular, asymmetric direct reductive  amination,4 hydroamination,1 and hydroaminoalkylation have been developed using this approach. Due to the fact that hydroamination and hydroaminoalkylation are the focus of this thesis, an in-depth discussion of the Buchwald-Hartwig amination,14-18,  21  direct reductive 3  amination,  4, 23-32  and condensation reactions2,  3  will not be presented. Interested readers are  referred to the referenced articles, which includes excellent reviews.2-4, 14-18, 21, 23-32 This chapter includes a review of the hydroamination and hydroaminoalkylation reactions,1,  43  with a  particular emphasis on metal-catalyzed enantioselective hydroamination using metal catalysts bearing axially chiral ligands.31  1.3 Enantioselective Synthesis of Amines by Metal-Catalyzed Hydroamination Reactions The hydroamination reaction can be regarded as the alkylation of amines with C–C unsaturated systems (Scheme 1.2). It is a 100% atom-efficient reaction thus offering both economic and environmental benefits.  This reaction can proceed in an intermolecular or  intramolecular fashion and can afford two regioisomeric products: Markovnikov (M) and the anti-Markovnikov (AM) products (Scheme 1.2 (a) and (b)) in the case of terminal alkynes and alkenes.1  The hydroamination reaction has been widely investigated with complexes  incorporating metals from across the periodic table.1 Many of these complexes bear modular ancillary ligands that are amenable to steric and electronic tuning for improved reactivity and selectivity in the synthesis of amines.1 Importantly, this approach allows access to chiral amines through the use of chiral ancillary ligands in enantioselective variants.1, 41, 46, 47 The vast majority of reported enantioselective hydroamination catalysts are based on axially chiral biaryl ligands. These ligand sets display high stability of configuration and impressive chirality transfer in many metal-catalyzed transformations,48 including the hydroamination reaction.1  4  Scheme 1.2. Intermolecular and intramolecular hydroamination reactions.  1.3.1. Enantioselective Lanthanide-Based Hydroamination Precatalysts Marks and co-workers pioneered enantioselective hydroamination reactions in the early 1990s with the development of lanthanide complexes for the asymmetric hydroamination of aminoalkenes.49-51  Cyclopentadienyl bearing chiral moieties such as (–)-menthyl, (–)-  phenylmenthyl, or (+)-neomenthyl were employed as ligands for the synthesis of C1-symmetric ansa-lanthanocene complexes (1 and 2, Scheme 1.3) by a series of salt metathesis reactions.49-51 These complexes effectively catalyze the intramolecular hydroamination of aminoalkenes to generate N-containing heterocycles with enantiomeric excesses of up to 74% obtained for the pyrrolidine products (Scheme 1.3).50, 51 However, the enantiomeric excess of the lone example of a six-membered piperidine product is only 17%,51 prompting the development of the “extended wingspan” precatalysts such as 3 (Scheme 1.4).52 Although these latter complexes are generally less active than the initial complexes, they afforded six-membered piperidines in much higher enantioselectivities (up to 67%), paving the way for the synthesis of the naturally occurring alkaloid (+)-coniine (isolated as the HCl salt, Scheme 1.4).53 The synthetic procedure for (+)-coniine outlined in Scheme 1.4 is one of a number of natural product syntheses utilizing  5  the hydroamination reaction as a key reaction step (see other examples in Figure 1.1) and thus demonstrating the potential of this transformation.42, 54, 55  Scheme 1.3. Pioneering enantioselective intramolecular hydroamination reactions.  Scheme 1.4. Synthesis of (+)-coniine by lanthanide-catalyzed hydroamination.  The mechanism proposed for the lanthanide-catalyzed hydroamination reaction is outlined in Scheme 1.5.49 The precatalyst undergoes a protonolysis reaction with the amine 6  substrate to form the catalytically active complex 4.  The immediate observation of free  protonated amine eliminated from the precatalyst as observed by 1H NMR spectroscopy, indicates a very rapid initial step to form the active catalyst. Migratory insertion of the olefin into the lanthanide–nitrogen bond of 4 via the four-membered chair-like transition state 5 affords complex 6. Detailed kinetic analyses by these researchers have identified this insertion step as the rate determining step.49 Subsequent protonolysis of complex 6 by the substrate would afford the amine product and regenerate the catalytically active complex 4.  Scheme 1.5. Proposed mechanism for lanthanide-catalyzed hydroamination.49  7  Despite being highly active precatalysts, the ansa-lanthanocene complexes are configurationally unstable due to reversible protolytic cleavage of the metal–cyclopentadienyl bond under the catalytic conditions.49,  50  Consequently, the absolute configurations of the  products do not vary predictably with the absolute configurations of the precatalysts.49,  50  Further, the elaborate synthetic protocols required to modify the cyclopentadienyl ligands render investigation into the effects of steric and electronic properties on the catalytic activities of these complexes time consuming.52 Importantly, these complexes cannot be generated in situ (the combination of proligand and starting metal complex to form the precatalyst just before the addition of the substrate in a one-pot process) for rapid screening of catalytic activities.49, 50, 52 Generation of the precatalyst in situ refers to the combination of the proligand and the starting metal complex immediately prior to the addition of the substrate without the isolation or purification of the precatalyst. The limitations associated with the lanthanocene complexes prompted the development of chiral non-metallocene lanthanide complexes for the hydroamination reaction, with the most successful being ligated with axially chiral biaryls.1,  41, 46, 47  Lanthanide complexes featuring  biphenyl or binaphthyl linkages with various donor functionalities including O,O-chelating,56-61 N,N-chelating,62-70 O,N-chelating,71, 72 O,S-chelating,61 and N,S-chelating73, 74 ligands are among the various atropisomers described as enantioselective hydroamination precatalysts (Figure 1.2). Importantly, these complexes can be prepared in situ for rapid screening of catalytic activity as was first demonstrated by Scott et al. with biaryl diamido complex 7 (Figure 1.2).62  By  combining racemic lanthanide amides and chiral biphenyl diamine proligands prior to substrate addition, chiral lanthanide biphenyl diamido complexes such as 7 were generated in situ for the cyclization of 2,2-dimethyl-4-pentenylamine.62 Although these complexes are less efficient,  8  requiring reaction times of days rather than minutes, and less selective with 50% being the highest ee achieved, in comparison to the pioneering lanthanocenes, they represent the first examples of enantioselective non-metallocene hydroamination precatalysts.62  Figure 1.2. Selected examples of axially chiral lanthanide-based hydroamination precatalysts.  A major improvement in ee values over those obtained using the lanthanocene precatalysts was achieved by Livinghouse and co-workers with in situ generated bis(thiolate) complex 8 (Figure 1.2).73 Complex 8 effectively catalyzes the cyclization of aminopentenes to pyrrolidines in enantiomeric excesses of up to 89%.73 Also noteworthy among the lanthanidebased chiral hydroamination precatalysts reported to date is the binaphtholate complex 9 (Figure 9  1.2) which performs the intramolecular hydroamination of aminoalkenes with enantiomeric excesses as high as 95%.56  Using just 2 mol% of complex 9, Hultzsch and co-workers  synthesized five- and six-membered azacycles in high yielding reactions with very good enantioselectivities.56 Recently, yttrium (complex 10, Scheme 1.6) and lutetium analogs of 9 have been reported as precatalysts for enantioselective intermolecular hydroamination of unactivated alkenes with simple amines (Scheme 1.6).75 This development represents a significant advance in the hydroamination reaction as very few complexes are competent precatalysts for intermolecular reactivity.76-82 Previously reported systems that display such reactivity are mostly based on late transition metals and require the use of activated substrates.77-82 By employing 10 as a precatalyst, terminal alkenes are reacted with simple primary amines to furnish chiral secondary amines with Markovnikov selectivity and enantiomeric excesses reaching 61%.75 However, these reactions require a significant excess of alkene (fifteen equivalents) for product formation at 150 °C.75  Scheme 1.6. Yttrium-catalyzed enantioselective intermolecular hydroamination reactions.  Although chiral lanthanide complexes are the most investigated enantioselective (pre)catalysts for the hydroamination reaction due to their high catalytic activities, their extreme 10  sensitivity to air/moisture and polar functional group incompatibility have motivated efforts to develop easily-handled systems with increased functional group tolerance.1,  41, 46, 47  As such,  other metal-based systems including group 1 and 2, late transition, and early transition metal complexes have been reported as precatalysts for enantioselective catalytic hydroamination reactions.  1.3.2 Enantioselective Group 1 and 2 Metal-Based Hydroamination Precatalysts In contrast to the lanthanide complexes, there are very few examples of enantioselective hydroamination precatalysts based on group 1 and 2 metals.83-87 The first of these reports describes the investigation of chiral lithium salts synthesized from a combination of n-butyl lithium and chiral diamine proligands as hydroamination precatalysts.85  These complexes  effectively cyclize aminopentenes to the corresponding pyrrolidines, albeit requiring longer reaction times in comparison to the lanthanides. The largest enantiomeric excess (74%) is achieved with the diamidobinaphthyl proligand 11 (Figure 1.3).85 However, the dilithium salt presumably generated upon treatment of 11 with n-butyl lithium is unstable. This is evidenced by structural data that revealed a dimeric complex with four uniquely located lithium atoms which contrasts with the highly symmetric NMR spectroscopic data.85 Switching the metal center from lithium to magnesium allows for the synthesis of a well-defined bimetallic complex 12 (Figure 1.3). Unfortunately, the enantioselectivities realized with complex 12 are limited to 14%.83  11  Figure 1.3. (Pro)ligands and complexes utilized in main group metal-catalyzed hydroamination reactions.  Ogata et al. reported the asymmetric hydroamination of activated secondary aminoalkenes with in situ generated lithium salts.84 By employing 40 mol% of chiral oxazoline (Box) ligand 13 (Figure 1.3), and 20 mol% each of n-butyl lithium and diisopropylamine in toluene at low temperatures, activated secondary aminoalkenes 14 and 15 are exo-cyclized to 16 and 17 with enantiomeric excesses of 60% and 91% respectively (Scheme 1.7). While this transformation is quite interesting, as internal alkenes are particularly difficult to cyclize, the substrate scope is limited to these two examples.  12  Scheme 1.7. Lithium-mediated intramolecular hydroamination of activated aminoalkenes.  More recently, chiral group 2 metal complexes supported by oxazolinylphenylborate and 1,2-diamine ancillary ligands (complexes 18 and 19, Figure 1.3) have been shown to catalyze the intramolecular hydroamination of aminopentenes.86,  87  These complexes display poor  enantioselectivities presumably due to ligand redistribution processes that cause the catalyst to revert to racemic starting metal complexes (which are also hydroamination precatalysts) during the catalysis.86 Complexes of group 1 and 2 metals are generally believed to catalyze the hydroamination reaction according to the mechanism postulated for lanthanide complexes (Scheme 1.5).1,  88  However, Sadow et al. recently suggested a slightly different mechanism based on stoichiometric and kinetic investigations (Scheme 1.8).89 In this alternative mechanism, magnesium complex 20 reacts with the substrate to form complex 21 which further adds a second equivalent of substrate to generate complex 22. This proposal is supported by kinetic analyses as well as the lack of insertion of the olefin into the Mg–N bond in 21 upon exposure of this compound to the  13  catalytic temperatures that previously afforded the cyclized product.89  Complex 22 then  undergoes concerted C–N and C–H bond formations via a six-centered transition state 23 (as evidenced by a significant primary isotope effect) to produce 24.  Subsequent ligand  displacement of the product from 24 by the substrate will regenerate the active species 22 (Scheme 1.8).  Scheme 1.8. Postulated mechanism for magnesium-catalyzed intramolecular hydroamination.89  14  As previously mentioned, the propensity to aggregate in solution and undergo ligand redistribution processes are the major drawbacks of complexes of group 1 and 2 metals.85-87 These limitations not only inhibit wide application of these complexes in enantioselective hydroamination catalysis but also complicate mechanistic investigations with the proven competent precatalysts.88, 90  1.3.3 Enantioselective Late Transition Metal-Based Hydroamination Precatalysts Generally, late transition metal complexes have lower sensitivity to air and moisture and higher functional group tolerance than their early transition metal counterparts and therefore have found wide application as hydroamination catalysts.1,  41  Early investigations of late  transition metals in enantioselective hydroamination catalysis focused on the intermolecular reactions involving activated alkenes and arylamines.41 The first of these reports made by Togni and co-workers describes the use of iridium(I) complexes bearing chiral phosphine ancillary ligands as enantioselective hydroamination precatalysts.76 Well-defined dimeric iridium complexes including 25 and 26 (Figure 1.4) were accessed by ligand displacement reactions between commercially available [Ir(coe)2Cl]2 (where coe is cyclooctene) and the phosphine ligand of choice.76  These complexes catalyze the  hydroamination of norbornene with aniline to afford the secondary amine product predominantly with exo-selectivity in low to modest yields and enantioselectivities (eq 1.1). The addition of Schwesinger‟s fluoride agent ([N(P(NMe2)3)2]F) to the reaction mixture was found to be beneficial as yield and enantioselectivities increased in the presence of this compound (eq 1.1) but the positive effect of ([N(P(NMe2)3)2]F)was not investigated in detail. The binaphthyl complex 26 furnishes the product with the best ee of 95% but the yield is only 22%. On the  15  other hand, complex 25 affords the product in the best yield of 81% and modest enantioselectivity of 50% (eq 1.1).  Figure 1.4. Selected examples of late-transition metal complexes and ligands for enantioselective hydroamination reactions.  Building  upon  these  results,  late  transition  metal-catalyzed  enantioselective  intermolecular hydroamination reactions were extended to other activated alkenes by Hartwig et al. in a series of publications.77-79,  81, 82, 91  Using a BINAP-ligated palladium complex as a  precatalyst, the addition of aniline to trifluoromethylstyrene and vinylnaphthalene is achieved under mild conditions to furnish the corresponding secondary amine products with high 16  Markovnikov selectivity in good yields with moderate to good enantioselectivities (Scheme 1.9 (a)).77 Also, a combination of [Pd(π-allyl)Cl]2 and ligand 27 (Figure 1.4) as catalyst precursors promotes the hydroamination of cyclohexadiene with arylamines in high yielding reactions with very good enantioselectivities (Scheme 1.9 (b)).78  Scheme 1.9. Palladium-catalyzed enantioselective intermolecular hydroamination of activated olefins with arylamines.  Based on kinetic measurements and stoichiometric reactions, these authors propose a mechanistic pathway that invokes the Pd(0) complex 28 (Scheme 1.10) as the active species.82 Complex 28 could form following a reaction of both substrates with the bisphosphine-ligated catalyst precursor to generate triflic acid and imine 29. The observation of compound 29 by GC analysis of the reaction mixture and the successful trapping of Pd(0) with triphenylphosphine gave credence to this proposal. Reaction of 28 with the alkene and liberated acid would lead to η3-coordinated intermediate 30 that was characterized in the solution phase for a number of alkene substrates.82 Two pathways were deemed feasible for the formation of 30: insertion of the olefin into a palladium hydride species or nucleophilic attack of the acid on a coordinated olefin (Scheme 1.10). Formation of the C–N bond then occurs by external nucleophilic attack of the amine substrate on the η3-coordinated complex 30 (Scheme 1.10). 17  Scheme 1.10. Proposed mechanism for palladium-catalyzed intermolecular hydroamination of vinylarenes with arylamines.82  Furthermore, by hypothesizing that the fluoride agent employed by Togni (eq 1.1) acts as a base to generate an arylamide, Hartwig and co-workers developed iridium-catalyzed asymmetric intermolecular hydroamination reactions with a base as co-catalyst (eq 1.2).91 Bisphosphine-ligated iridium catalyst generated in situ from [Ir(coe)2Cl]2 and chiral DTBMSegphos ligand 31 (where DTBM is 3,5-di-tert-butyl-4-methoxyphenyl, see Figure 1.4) catalyzes the addition of arylamines to bicylic alkenes and dienes in high yields and excellent enantioselectivities (eq 1.2).91 18  This metal/base catalyst system was postulated to promote the hydroamination reaction via oxidative addition of the amine to the catalyst (Scheme 1.11) leading to the formation of the metal hydride 32 (Scheme 1.11).91 Migratory insertion of the olefin into the Ir–N bond in complex 32 would generate complex 33 (Scheme 1.11). This proposal has been supported by the isolation and characterization of an achiral iridium complex of the type 33 as well as the successful product formation from the isolated complex upon exposure to the catalytic reaction conditions.92  Scheme 1.11. Proposed mechanistic pathway for intermolecular hydroamination via oxidative addition of amine.91  19  A few other late-transition metal complexes have also been reported for enantioselective intermolecular hydroamination reactions.93, 94 The more successful of these systems bear axially chiral ancillary ligands as the stereo-determining moieties. Similar to the preceding catalysts, these latter complexes only effect the addition of arylamines to activated alkenes with Markovnikov selectivity.93, 94 More recently, Buchwald et al. extended late-transition metal-catalyzed enantioselective hydroamination to unactivated substrates.95 Using a combination of [Rh(cod)2]BF4 (where cod is 1,5-cyclooctadiene) and binaphthyl amino-phosphine ligands (such as 34, Figure 1.4) as catalyst precursors, intramolecular hydroaminations of secondary aminopentenes can be achieved with enantiomeric excesses as high as 91% (eq 1.3). Primary aminopentenes are poorly cyclized and only a single example of these substrates has been presented. In addition, no example of sixmembered ring formation appeared in this communication. However, as is customary with late transition metals, the catalyst system is compatible with polar functional groups lending itself to the preparation of amines suitable for further manipulation.95  1.3.4 Enantioselective Early Transition Metal-Based Hydroamination Precatalysts Many recent advances in atom economic synthesis of secondary amines are based on early transition metal-catalyzed reactions as these complexes are more easily handled than lanthanides and are inexpensive in comparison to the late transition metal systems.1, 41 Scott et 20  al. pioneered early transition metal-catalyzed enantioselective hydroamination with the report of a cationic zirconium complex used as a precatalyst for this transformation.96 A protonolysis reaction between Zr(CH2Ph)4 and proligand 35 afforded complex 36, featuring a metallated Nmethyl group and one benzyl ligand (Scheme 1.12). Complex 36 presumably results from the expected zirconium complex ZrL(CH2Ph)2 (where L is the ligand produced from proligand 35) undergoing a proton transfer from an N-methyl group on the biphenyl linkage to the benzyl ligand to eliminate another equivalent of toluene. Subsequent protonation of the metallacycle in 36 led to the formation of precatalyst 37 (Scheme 1.12). Complex 37 is efficient for the cyclization of secondary aminoalkenes generating five- and six-membered heterocycles in enantiomeric excesses ranging from 20–82% (eq 1.4). The corresponding primary aminoalkenes are not viable substrates under these catalytic conditions.  Scheme 1.12. Synthesis of a cationic zirconium hydroamination precatalyst.  21  Following this advancement, neutral chiral group 4 metal complexes were investigated as hydroamination precatalysts. In 2006, Bergman and co-workers cyclized aminopentenes with zirconium complexes generated in situ from commercially available Zr(NMe2)4 and diphosphinic amide proligands.97 The most active member of this class of complexes (complex 38, Figure 1.5) gives the azacyclic products in yields ranging from 33–95% and enantioselectivities between 33–80%. Notably, substrates lacking geminal substituents also undergo cyclization in the presence of this catalyst precursor. However, a large amount (20 mol%) of precatalyst 38 is needed for all the cyclizations to occur at temperatures between 85 and 135 °C. This is probably due to the formation of the catalytically inactive homoleptic complex ZrL2 (where L is the ancillary ligand on 38) in addition to 38 upon combination of Zr(NMe2)4 and the proligand. Furthermore, complete conversion of complex 38 into this inactive species occurred within 24 hours at 150 °C, suggesting catalyst deactivation at higher temperatures.  Figure 1.5. Selected examples of early transition metal-based hydroamination precatalysts.  At the same time as the aforementioned neutral complexes were reported, the Schafer group communicated neutral amidate-ligated zirconium complexes for the hydroamination of aminoalkenes.98  These complexes were synthesized by a protonolysis reaction between  Zr(NMe2)4 and easily modified bis(amide) proligands. Preliminary catalytic screening identified 22  complex 39 (Figure 1.5) as the most efficient of this class of complexes. Precatalyst 39 is efficient for the cyclization of aminoalkenes to α–chiral amines with enantiomeric excesses of up to 93%. In addition, 39 is more reactive than the in situ generated 38, requiring lower catalyst loading (10 mol%) and much shorter reaction times to completely cyclize the aminoalkenes. However, the high reactivity of 39 is limited to primary aminoalkene substrates containing geminal substituents (see eq 1.3 for aminoalkenes geminally substituted with R1 groups). Generally, early transition metal-catalyzed hydroamination reactions are postulated to occur via a [2+2] cycloaddition mechanism (Scheme 1.13).1, 99-101 In the case of an aminoalkene substrate, this [2+2] cycloaddition is an intramolecular process involving the catalytically active imido 40 and leads to metallacycle 41. Protonolysis of 41 by the substrate would generate amido complex 42 which can undergo further protonolysis to afford the azacyclic product. Evidence for this mechanistic pathway includes isolation and characterization of achiral imido and metallacyclic complexes of early transition metals and successful utilization of these intermediates in hydroamination reactions.99, 100, 102-109 In addition, kinetic measurements by a number of research groups are in accordance with this mechanistic pathway.100, 101, 103 Further, the inability of these complexes to react with secondary aminoalkenes also supports this mechanism.98,  103, 110-113  While this mechanism applies to most early metal hydroamination  precatalysts, a few complexes, including cationic complex 37, that are competent precatalysts for the cyclization of secondary aminoalkenes have been postulated to proceed via the insertion mechanism proposed for lanthanides (Scheme 1.5).96, 114-117 Other examples of axially chiral early transition metal complexes, including complex 43 (Figure 1.5), that catalyze the hydroamination of aminoalkenes have also been reported.118-121 Generally, these latter complexes are less active and selective in comparison to the earlier ones.  23  Scheme 1.13. Proposed mechanism for early transition metal-catalyzed intramolecular hydroamination of aminoalkenes.1  As discussed, the enantioselective hydroamination reaction has been investigated with a wide variety of complexes including lanthanide, alkali and alkaline earth, late transition, and early transition metal complexes. This extensive investigation is partly due to in situ reactivity that allows for rapid screening of the metal complex catalytic activity and has resulted in significant advances in terms of enantioselectivity for this catalytic reaction. However, all the catalytic systems suffer from limited substrate scope. In addition, in situ generation of metal complexes offer limited insight of the coordination environment about the metal center which could offer important reactivity details and provide rationale for selectivity. Importantly, a wellunderstood catalytic system would allow for the rational design of broadly applicable hydroamination catalysts.  24  1.4 Synthesis of Secondary Amines by Metal-Catalyzed Hydroaminoalkylation Reactions The hydroaminoalkylation reaction, also known as the α–alkylation of amines, is a C–C bond forming reaction between an amine and a C–C unsaturated system (Scheme 1.14).43 This transformation proceeds via C–H activation of a sp3 center α to the amine nitrogen and results in the addition of this bond across the C–C multiple bond. Unlike the hydroamination reaction, the hydroaminoalkylation reaction was only recently developed into a synthetically relevant transformation by Herzon and Hartwig122, 123 with less than fifteen articles published to date.43, 122-133  Similar to the hydroamination reaction, the hydroaminoalkylation reaction is a 100% atom  efficient process that can occur in an intermolecular or intramolecular fashion with the potential to afford two regioisomeric products (Scheme 1.14). Importantly, this reaction results in the formation of α- or β-chiral amines that are prevalent in natural products.1 Maspero and co-workers reported the first catalytic hydroaminoalkylation reaction in 1980.  These authors performed the α-alkylation of secondary dialkylamines with terminal  alkenes using homoleptic group 4 and 5 metal complexes as precatalysts.133 The reaction exclusively affords the branched regioisomer 44 (Scheme 1.14 (a)), however in this initial report, the products were generated in very poor yields (10–38%) despite the high reaction temperatures (160–200 °C) and prolonged reaction times (up to 150 hours).133  Scheme 1.14. Intermolecular and intramolecular hydroaminoalkylation reactions.  25  Shortly thereafter, mechanistic investigations by Nugent et al. showed deuterium scrambling into the C–H bonds when N-deuterated dimethylamine was heated (without alkene co-substrate) in the presence of early transition metal dimethylamido complexes to the high temperatures employed by Maspero for the hydroaminoalkylation reaction.132 This observation suggests a reversible cyclometallation of the dimethylamido ligand on the metal complex and the authors proposed a metallaaziridine (45) as a key intermediate in the catalytic hydroaminoalkylation reaction (Scheme 1.15).132  Scheme 1.15. Deuterium scrambling in dimethylamine: Metallaaziridine as a key intermediate in the catalytic hydroaminoalkylation reaction.  More than two decades following these initial reports, Herzon and Hartwig impressively improved the yield (up to 96%) and significantly broadened the substrate scope of the reaction (Scheme 1.16).123 They discovered that a simple change in amine structure, namely using N-aryl alkylamines instead of dialkylamines, results in the highly efficient Ta(NMe2)5-catalyzed hydroaminoalkylation of alkenes.123  Further, the introduction of chloro ligands into the  precatalyst to access more electrophilic metal complexes allows for the α-alkylation of dialkylamines in synthetically useful yields (up to 96%, Scheme 1.16).122  26  Scheme 1.16. Highly efficient tantalum-catalyzed hydroaminoalkylation reactions.  The  mechanism  proposed  for  group  5  metal-catalyzed  intermolecular  hydroaminoalkylation by Nugent and further support by mechanistic investigations by Hartwig is outlined in Scheme 1.17.122, 123, 132 The initial step involves transamination of the dimethylamido ligand by the amine substrate followed by intramolecular C–H bond activation and elimination of dimethylamine to afford the catalytically active tantallaaziridine 46. Insertion of the olefin into the Ta–C bond of 46 would produce the five membered metallacycle 47. Subsequent protonolysis of 47 with the amine substrate would afford the mixed amido complex 48 which can undergo another C–H bond activation reaction to give the product and regenerate the catalytically active aziridine 46.  27  Scheme 1.17. Proposed mechanism hydroaminoalkylation reaction.122, 123, 132  for  group  5  metal-catalyzed  intermolecular  Inspired by the work of Hartwig, the Schafer group developed achiral amidate-ligated tantalum complexes for intermolecular hydroaminoalkylation reactions.130 Enhanced reactivity is observed with amidate complexes as reaction temperatures are as low as 110 °C and excellent diastereoselectivity is consistently obtained (eq 1.5). Previous to this report, only titanium129 and tantalum complexes122, 123 featuring ligands such as dialkylamido, chloro, and cyclopentadienyl which cannot be easily modified for asymmetric catalysis have been reported as precatalysts for the intermolecular hydroaminoalkylation reaction.  The successful utilization of amidate  complexes in the hydroaminoalkylation reaction paved the way for the development of the first enantioselective hydroaminoalkylation reactions using axially chiral tantalum amidate complexes.130 The first reported examples of enantioselective hydroaminoalkylation will be 28  presented in Chapter 4.  Since our communication of the first enantioselective  hydroaminoalkylation in late 2009, two other research groups have followed up this new approach for the catalytic synthesis of amines including a contribution that focused on closely related amidate complexes of tantalum.124, 125, 127  The use of group 4 metal complexes as precatalysts for the hydroaminoalkylation reaction has also been investigated by our group131 and Doye et al.128, 129, 134 Group 4 complexes are more effective for the intramolecular hydroaminoalkylation of aminoalkenes and are less chemoselective, as hydroamination is a competitive reaction pathway.129, 131 Significant advances in the hydroaminoalkylation reaction have only recently been achieved with the report of high yielding reactions122-125, 127-130 including asymmetric versions.124, 125, 127, 130  However, very few complexes of group 4 and 5 metals can effect this transformation  and catalytic activity is restricted to select substrates. Furthermore, functional group tolerance is yet to be extensively explored in these systems and the compatibility of this reaction with other synthetic pathways has not been reported.  29  1.5 Scope of this Thesis The synthesis and fundamental understanding of well-defined early transition metal complexes featuring amidate ancillary ligands is a major research focus in the Schafer group.135140  Amidates are desirable ancillary ligands for early transition metal complexes as the hard  N,O-donor atoms are well-suited to bind to early transition metals. In addition, this ligand motif is easily modified for steric and electronic effects upon reactivity of the resulting complexes. Over the past decade, the group has firmly established protonolysis as a facile approach to these amidate complexes.98,  103, 112, 130, 131, 135-144  Discrete amidate-ligated complexes have been  synthesized by protonolysis reactions between easily prepared amide proligands and commercially available metal precursors.98, 103, 112, 130, 131, 135-144 In addition to understanding the fundamental chemistry of amidate complexes, the ability to promote metal-catalyzed transformations with these complexes is another important goal that is being pursued within the group with great success being recorded in the catalytic synthesis of N-containing molecules.98, 103, 112, 113, 130, 131, 136, 137, 141, 143-147  In line with this focus, this thesis focuses on the synthesis,  characterization, stability, and catalytic investigations of amidate complexes of select early transition metals.  Figure 1.6. Highly reactive and stereoselective hydroamination precatalyst.  30  Among the amidate complexes developed by the Schafer group, achiral bis(amidate) complex 49 (Figure 1.6) stands out as a highly reactive precatalyst for the intramolecular and intermolecular hydroamination of alkynes113, 143 and allenes.147 While a plethora of complexes catalyzes the hydroamination reaction,1 only very few display the broad substrate scope capabilities of 49.42 To further distinguish this precatalyst from other hydroamination catalysts, exploitations of 49 as a precatalyst for the hydroamination of particularly difficult substrates have been performed and will be presented in Chapter 2. Precatalyst 49 has been employed in the hydroamination of N-substituted C–C unsaturated systems as described in this chapter. In addition, intermolecular hydroamination reactions involving hydrazines, which are known challenging hydroamination substrates,148 have also been studied. Being an atom-economic process that does not generate any by-products, the hydroamination reaction lends itself nicely to further synthetic manipulations.  In this regard, tandem reaction sequences involving the  hydroamination reaction have been developed to realize the synthesis of N-substituted indoles and this investigation will also be discussed. Further, the ability to generate metal complexes in situ for catalytic reactions is particularly appealing for broader application of these complexes in organic synthesis. As such, in situ generation of 49 for the hydroamination of C–C multiple bonds with various N–H sources will be presented. Previous hydroamination studies with bis(amidate) complex 49 as a precatalyst have revealed a limited substrate scope with respect to alkene substrates.103  Importantly, the  hydroamination of alkenes generates chiral amines but catalysis with 49 would lead to racemic products. Therefore, investigation of new in situ generated axially chiral biphenyl amidate complexes for the hydroamination of alkenes will be presented in Chapter 3. The isolation, characterization, and stability of these zirconium complexes will also be discussed. This chapter  31  also includes rationalizations of the observed diastereoselectivities and the absolute configurations observed for the major isomer of the catalysis products. Chapter 4 describes the synthesis, characterization, and stability investigations including variable temperature (VT) NMR studies of chiral biphenyl tantalum complexes. In an efficient approach to preparing chiral secondary amines, the tantalum complexes have been employed as precatalysts for the hydroaminoalkylation of alkenes with amines. In addition, the synthesis, characterization, and catalytic activities of chiral cyclohexyl-based tantalum complexes have also been carried out and will be discussed in the context of the effect of steric properties on catalytic hydroaminoalkylation. Further, the atom-economic nature of the hydroaminoalkylation reaction allows for further synthetic transformations as was demonstrated in the synthesis of a chiral γamino alcohol described in this chapter. Finally, Chapter 5 includes a summary of, and conclusions drawn, from the research work presented in Chapters 2–4. Also presented in this chapter are suggestions for future research including other tandem reaction sequences involving the hydroamination reaction catalyzed by complex 49. In addition, new proligands are proposed for use as ancillary ligands for zirconium and tantalum complexes with the goal of increasing reactivity and selectivities in catalytic hydroamination and hydroaminoalkylation.  32  CHAPTER 2. APPLICATION OF A BIS(AMIDATE) BIS(AMIDO) TITANIUM(IV) PRECATALYST IN THE SYNTHESIS OF N-CONTAINING COMPOUNDS BY INTERMOLECULAR HYDROAMINATION  2.1 Introduction The transition metal-catalyzed hydroamination reaction has been intensely investigated in the last two decades.1, 40-42, 46, 47, 149, 150 This transformation, which involves the formal addition of an N–H bond across a C–C multiple bond, furnishes N-containing compounds in an atom efficient manner. Complexes incorporating a wide variety of metals including early transition metals,99, 100, 106, 111, 114, 116, 151-176 late transition metals,82, 177-213 main group metals,84, 85, 88, 90, 214-222 as well as lanthanides54, reaction.  55, 223-248  have been described as catalysts for the hydroamination  Notwithstanding these sustained efforts, a broadly applicable catalyst for this  seemingly simple transformation remains elusive as reported catalyst systems are only efficient for select substrates. To date, only a few lanthanide catalyst systems (Figure 2.1) developed by Marks and co-workers have shown broad applicability for intramolecular and intermolecular hydroamination of alkynes and alkenes and the intramolecular hydroamination of allenes. 42 However, the incompatibility of lanthanide catalysts with polar functional groups limits their application in organic synthesis.  Examples of early or late transition metal catalysts with  efficiency that mirrors those of the above-mentioned lanthanides are unknown. Early transition metal catalysts offer potential improvements over lanthanide catalysts due to their reduced sensitivity to air/moisture and enhanced functional group tolerance. relatively  inexpensive  in  comparison  to  the  late  Furthermore, they are transition  metals.1  33  Figure 2.1. Efficient lanthanide-based precatalysts for the hydroamination reaction.  Efforts focused on broadening the scope of application of our previously reported alkyne hydroamination precatalyst 49143 have led to the utilization of complex 49 (Scheme 2.1) in the hydroamination of diverse C–C unsaturated compounds. Precatalyst 49 is easily prepared by a protonolysis reaction using commercially available Ti(NMe2)4 and proligand N-(2,6diisopropylphenyl)benzamide (Scheme 2.1). The amide proligand is in turn easily synthesized by treating 2,6-diisopropylaniline with benzoyl chloride in the presence of excess triethylamine (Scheme 2.1). During the investigation of 49, it was discovered that this complex displays broader substrate scope than most early transition metal hydroamination catalysts.113, 143, 145-147 Precatalyst 49 was found to be efficient for the intra- and intermolecular hydroamination of alkynes113, 143 and allenes147, 249 as well as the intramolecular hydroamination of alkenes.103 More importantly, with alkynes and allenes, complex 49 shows remarkable functional group tolerance.113, 143 The impressive hydroamination substrate scope of complex 49 prompted further exploration of 49 as a precatalyst for the hydroamination of more challenging substrates. Furthermore, the high functional group tolerance of precatalyst 49 suggests the possibility of preparing functionalized products ready for further synthetic manipulations. Thus, in a single reaction vessel using a one-pot tandem sequential approach, functionalized N-containing target compounds can be prepared using hydroamination as a key step in the synthetic sequence.  34  Scheme 2.1. Synthesis of a highly reactive and regioselective hydroamination precatalyst.  This chapter describes the continuation of the substrate scope investigation of precatalyst 49 in the hydroamination reaction and focuses on heteroatom containing substrates as a further probe of the functional group tolerance of this system. In Section 2.2.1, the hydroamination of N-substituted allenes will be presented; further, control experiments with the corresponding Ncontaining alkyne are used to rule out allene-alkyne isomerization during hydroamination catalysis. Generally, amines are employed as N–H substrates to be reacted with C–C unsaturated systems in the intermolecular hydroamination reaction. The use of hydrazines as the N–H containing reactant could afford products amenable to further synthetic manipulations. To this end, the competency of 49 for the hydroamination reaction between a variety of 1,1-disubstituted hydrazines and various alkynes has been explored and will be discussed in Section 2.2.2. Following literature precedent,148 the N-aryl hydrazones generated from the reaction of alkynes with hydrazines can be transformed into substituted indoles by a ZnCl2-mediated Fischer indole synthesis. This results in a two-step, one-pot synthesis of selectively substituted indoles as presented in Section 2.2.3. Furthermore, the feasibility of preparing precatalyst 49 in situ is explored in Section 2.2.4 to render this catalyst system more amenable to use in organic  35  synthesis. Efficient catalysis with in situ generated complex implies fewer reaction steps and shorter reaction times as isolation and purification of the precatalyst is unnecessary.  2.2 Results and Discussion 2.2.1 Hydroamination of Heteroatom-Substituted C–C Unsaturated Systems The bulk of reported allene hydroaminations are catalyzed by late transition metals,178, 189, 202, 250-266  notably gold178,  189, 202, 251, 253, 254, 258-260, 262-267  and palladium.250,  255-257  The use of  lanthanide complexes as precatalysts for allene hydroamination has mainly been studied by Marks and co-workers.54,  226, 240, 242, 268  Importantly, these authors have employed allenes as  substrates in a hydroamination step for the synthesis of naturally occurring alkaloids.54 A few examples of early transition metal-catalyzed intramolecular108, 269-271 and intermolecular99, 100, 168 allene hydroamination have also been developed. All of the above reports involve alkyl- or arylsubstituted allenes; however, the intermolecular hydroamination of heteroatom-substituted allenes in which the heteroatom is directly attached to the highly reactive allene moiety has only recently been reported.249 Furthermore, Bergman and co-workers have disclosed an unsuccessful attempt to perform the latter transformation with an early transition metal catalyst.99  The  previously reported unsuccessful attempt at realizing the hydroamination of heteroatomsubstituted allenes prompted the investigation of this challenging transformation with our robust and functional group tolerant precatalyst 49. The achievement of heteroatom-substituted allene hydroamination with 49 would further serve to distinguish this precatalyst from other group 4 metal-based hydroamination precatalysts. In principle, the intermolecular hydroamination of allenes (50) with amines can generate three products as outlined in Scheme 2.2.  Generally, the early transition metal-catalyzed  36  intermolecular hydroamination of allenes produces ketimine 5199, 100, 168 (which are reduced to secondary amine 52 for ease of handling) while catalysis with late transition metals affords allylamine 53178, 189, 251, 256-258, 261, 262, 266, 272 and/or 54.272  Scheme 2.2. Multiple regioisomeric products accessible from the intermolecular hydroamination of allenes.  We have investigated the application of precatalyst 49 in the hydroamination of monosubstituted allenes 50 including aryl-,147 alkyl-,147 and oxygen-substituted allenes249,  273  with  primary aryl- and alkylamines. The reaction of aryl- and alkyl-substituted allenes with aryl- and alkylamines exclusively affords the ketimine product 51, consistent with the aforementioned preference observed in other early transition metal-catalyzed intermolecular hydroamination of allenes. The hydroamination of the oxygen-substituted allenes proceeds much faster than those of their aryl- or alkyl-substituted analogs, requiring lower reaction temperatures and even displaying reactivity at room temperature. Interestingly, with the oxygen-substituted allenes, judicious selection of the amine substrate allows exclusive access to either ketimine 51 or allylamine 53 (Scheme 2.2).273  The formation of allylamines by the intermolecular  hydroamination of allenes has been previously reported for late transition metal catalysts but has not been observed in early transition metal systems. Allylamines are particularly important  37  because of the presence of C–C unsaturation in these compounds, leaving room for further reactivity such as oxidation, reduction, or olefin metathesis.3 In the present studies, the substrate scope investigation of precatalyst 49 for the hydroamination of nitrogen-substituted allene 50a with primary amines has been undertaken. The progress of the NMR tube scale reaction of 1 equivalent of 50a with 1 equivalent of 2,6dimethylaniline in the presence of 10 mol% of 49 in d6-benzene at 90 °C was monitored by 1H NMR spectroscopy and the diagnostic allene signal at δ 5.14 is noted to have completely disappeared after five hours. New signals, all singlets at δ 1.11, 1.74, 2.01, 2.14, and 4.53, suggestive of ketimine product 51a as well as signals corresponding to the starting 2,6dimethylaniline are observed in the 1H NMR spectrum. The presence of unreacted amine starting material after the complete consumption of the allene suggests allene decomposition and/or polymerization are alternate reaction pathways occurring at this catalytic temperature. It has been previously noted that nitrogen-substituted allenes are thermally unstable.274 Unfortunately, the catalysis does not proceed at ambient temperature, therefore, excess of 50a (2 equivalents) in combination with a dilute reaction mixture are used to minimize the side reactions (Scheme 2.3 (a)). The ketimine product 51a is reduced to the corresponding secondary amine 52a using sodium cyanoborohydride/zinc chloride for ease of isolation and characterization.  38  Scheme 2.3. Intermolecular hydroamination of N-substituted allene with arylamines.  In contrast, using aniline and 10 mol% of 49, substrate 50a is consumed within 24 hours at 65 °C (Scheme 2.3 (b)); and a mixture of both ketimine 51b and secondary allylamine 53a is detected in a 1:2 ratio by 1H NMR spectroscopy.  The diagnostic signals for 53a include a  doublet of doublets at δ 3.49 for the methylene protons and a doublet of triplets at δ 4.95 representing the olefinic proton adjacent to the aforementioned methylene protons. Hydrolysis (by the addition of a few drops of water and stirring over silica overnight) of the reaction mixture followed by column chromatography allows for isolation of 53a and the corresponding ketonederivative of 51b, 1-(1H-indol-1-yl) propan-2-one. The outcome of this reaction is in contrast to those of the oxygen-substituted allenes, in which aniline affords exclusively allylamine products. However, similar excellent diastereoselectivity for the Z-isomer (vide infra) of 53a is observed by 1H NMR spectroscopy as the coupling constant of 8.8 Hz for the olefinic protons falls within the range (6–15 Hz) expected for Z-alkenes. 39  Unambiguous evidence for the allylamine Z-geometry for this reaction profile is provided by the solid-state molecular structure of 53b·H2C2O2 (Figure 2.2). The hydroamination of 2,6dimethylphenoxyallene (50b), an alternative heteroatom-substituted allene, with aniline in the presence of 49 affords allylamine 53b which upon treatment with oxalic acid produces 53b·H2C2O2 (eq 2.1). Previously, 2,6-dimethylphenoxyallene has been shown to display aminedependent product regioselectivity similar to that observed for 50a in hydroamination reactions catalyzed by 49.273 Notably, the diagnostic methylene and olefinic proton signals for 53b appear at δ 4.20 and 4.81 respectively. Furthermore, the coupling constant of 6.2 Hz for the olefinic protons in 53b is consistent with the Z-geometry of the double bond (vide supra). All the bond lengths and angles of 53b·H2C2O2 fall within the expected range and selected examples are presented in Table 2.1. Unfortunately, the hydroamination reaction of 50a with an alkylamine, benzylamine, in the presence of 49 did not proceed, instead resulting in the decomposition of 50a.  40  Figure 2.2. ORTEP representation of the solid-state molecular structure of 53b·H2C2O4 (ellipsoids plotted at 50% probability ellipsoids). All H-atoms except those attached to N1 and O5 are omitted for clarity; the H atoms shown were not experimentally located.  Table 2.1. Selected bond lengths and angles of 53b·H2C2O2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  C9–C10  1.328(2)  O1–C9–C10  122.22(12)  O1–C9  1.347(2)  C9–C10–C11  123.73(13)  C10–C11  1.479(2)  C10–C11–N1  111.02(11)  N1–C11  1.517(2)  O2–C18–O3  127.35(11)  C18–C19  1.532(2)  O4–C19–O5  125.98(11)  O2–C18  1.232(1)  O2–C18–C19  119.07(10)  O3–C18  1.277(1)  O3–C18–C19  113.57(10)  O4–C19  1.208(2)  O4–C19–C18  122.72(11)  O5–C19  1.314(1)  O5–C19–C18  111.27(10)  The preferential formation of one regioisomer over the other could be rationalized by considering the extensively investigated [2+2] cycloaddition mechanism for early transition metal-catalyzed alkyne hydroamination (which is postulated to be operative in this system).99, 100 Support for the [2+2] cycloaddition mechanism in this system comes from the lack of reaction of the oxygen-substituted allenes: methoxyallene (50c) or 2,6-dimethylphenoxyallene (50b) with  41  secondary amines such as morpholine. With a secondary amine, the catalytically active imido complex would be inaccessible and the reaction would not proceed (see catalytic cycle, Scheme 2.4). Furthermore, in previous work, both of these allenes can be reacted with primary amines using 49 as a precatalyst.273 In the postulated mechanism, the regioselective outcome of the reaction is established during the cycloaddition step of the catalytic cycle (Scheme 2.4) and by the formation and subsequent protonolysis of metallacycles 55a and 55b (Scheme 2.4).  Scheme 2.4. Proposed mechanism for the intermolecular hydroamination of heteroatomsubstituted allenes with aryl- and alkylamines.  The observed regioselectivity is proposed to be determined by steric accessibility of metallacycle 55a and 55b for protonation in the step with the amine in an associative mechanism, thus, employing bulky 2,6-dimethylaniline, complex 55a is preferentially protonated resulting in the formation of ketimine product 51 via path A (Scheme 2.4). Protonation by 2,6-  42  dimethylaniline would be more hindered with 55b due to steric interactions between the incoming amine and the α-substituted metallacycle. In contrast, aniline, the less bulky amine, can protonate metallacycle 55b to afford the allylamine product 53 (Scheme 2.4, path B). The isomerization of alkynes is one of the general methods of synthesizing allenes. 275 To exclude allene-alkyne isomerization during the hydroamination catalysis, control experiments with the alkyne analogue of 50a, 1-(prop-2-ynyl)-1H-indole, have been performed.  1-(Prop-2-  ynyl)-1H-indole reacts with 2,6-dimethylaniline within 21 hours at ambient temperature to give a 1:5.9 mixture of both the Markovnikov ketimine 51a and the anti-Markovnikov aldimine 51c products (Scheme 2.5 (a)), with the anti-Markovnikov aldimine predominating.  1-(Prop-2-  ynyl)-1H-indole also reacts with aniline at room temperature in less than 15 minutes to give the Markovnikov ketimine 51b and anti-Markovnikov enamine and aldimine 51d in a 1:18:4.5 ratio (Scheme 2.5 (b)). The outcomes of these comparative reaction studies do not suggest major isomerization of allene 50a to alkyne prior to undergoing hydroamination with the amine. In addition, previous work has shown that the alkyne analog of methoxyallene 50c does not undergo hydroamination reaction with 2,6-dimethylaniline even with similar reaction conditions as that employed for the successful reaction of 50c with 2,6-dimethylaniline.249  43  Scheme 2.5. Intermolecular hydroamination of 1-(prop-2-ynyl)-1H-indole with arylamines.  In summary, precatalyst 49 is an efficient precatalyst for the hydroamination of allene 50a with primary amines to give imine and/or allylamine products.  Sterically bulky 2,6-  dimethylaniline affords only the ketimine product while aniline gives a mixture of both ketimine and allylamine products. The regioselectivity of these reactions is proposed to be determined by the steric accessibility of the metallacyclic intermediates for protonation by the amine substrate. Allene-alkyne isomerization during this catalysis is unlikely as the reactions of the alkyne analogue of 50a, 1-(prop-2-ynyl)-1H-indole, with primary amines result in different product combinations and ratios.  2.2.2 Hydrohydrazination of Alkynes with 1,1-Disubstituted Hydrazines Although complex 49 has been intensely investigated as a precatalyst in the intermolecular hydroamination reaction, these reactions have been carried out exclusively with primary amines, albeit with various unsaturated substrates. To further extend the competency of  44  precatalyst 49 beyond primary amines to more challenging N–H compounds, the use of 49 as a precatalyst for intermolecular hydroamination reactions involving hydrazines, a class of heteroatom-substituted amines, has been targeted. The hydroamination reaction with hydrazines, otherwise known as the hydrohydrazination reaction, is more challenging because of the potential formation of dimeric hydrazido complexes that features stable, catalytically inactive chelates.167 A number of such chelating hydrazido complexes have been identified and fully characterized by various analytical methods, including X-ray crystallography, and examples are displayed in Figure 2.3.167, 276, 277 In contrast to these dimeric complexes, complex 49 contains bulky amidate ancillary ligands that inhibit the formation of dimers. Therefore, complex 49 could potentially catalyze the hydroamination reaction involving hydrazines.  Figure 2.3. Examples of early transition metal hydrazido complexes.  Hydroamination reactions involving N–H containing substrates allow access to Ncontaining compounds that are potentially valuable for tandem reaction sequences.  While  functional group bearing N–H compounds are common substrates in late transition metalcatalyzed hydroamination reactions,192,  194, 198, 202, 206, 259, 278-284  reported examples of early  transition metal-catalyzed hydroamination reactions involving N–H containing substrates other than amines are few.148,  166, 167, 285-287  Hydrazines are particularly interesting hydroamination  substrates because the hydrazone products of the reaction (hydroamination of an alkyne with a  45  hydrazine) are useful synthetic intermediates, for example in the Fischer indole synthesis. 148, 285289  The hydrohydrazination of alkynes with hydrazines was pioneered in 2002 by Odom and co-workers with the description of titanium amido complexes 56 and 57 (Figure 2.4) as precatalysts that promote this transformation.148 It is noteworthy that the alkyne hydroamination precatalysts previously communicated by the Odom group were ineffective for the hydrohydrazination reaction, hence the development of complexes 56 and 57.148 Interestingly, the N-aryl hydrazone products of the hydrohydrazination were elegantly transformed into substituted indoles by a Lewis acid-mediated Fischer indole synthesis giving rise to tandem C–N, C–C bond forming reactions in one-pot.148 Since this initial report, only a few other examples of hydrohydrazination reactions have emerged166, 192, 198, 285-291 and even fewer descriptions of the hydrohydrazination/cyclization tandem reactions.285-289 Of note among the developed catalysts is the recently reported highly active complex 58 (Figure 2.4) which performs the hydrohydrazination reaction of terminal alkynes at room temperature.291  Figure 2.4. Early transition metal catalysts for hydrohydrazination reaction.  In principle, there are four observable products from the hydroamination reaction between a 1,1-disubstituted-hydrazine (59) and an alkyne (60) (Scheme 2.6). These products are  46  the ene-hydrazines 61 (anti-Markovnikov when R3 = H) and 62 (Markovnikov when R3 = H) and their respective tautomers 63 and 64 (Scheme 2.6).  Scheme 2.6. Regioisomeric products accessible from the hydrohydrazination reaction between an alkyne and a hydrazine.  Initial experiments were carried out with 1,1-diphenylhydrazine 59a.  This diaryl-  substituted hydrazine should be more reactive than any alkyl-containing hydrazine as the electron-withdrawing aryl substituents on the α–N could potentially reduce the donor ability of this atom to the metal center thereby mitigating the formation of catalytically inactive hydrazido complexes. Furthermore, the investigation was performed with a slight excess of hydrazine as this has been found to be optimal for reactivity, as reported by Odom and co-workers. The reaction conducted with 1 equivalent of phenylacetylene 60a, a slight excess (1.2 equivalents) of 1,1-diphenylhydrazine 59a, and 5 mol% of 49 in a J. Young NMR tube (Table 2.2, entry 1) goes to completion within one hour at 65 °C and results in the sole production of hydrazone 63a as detected by 1H NMR spectroscopy. The diagnostic signals for 63a include a triplet at δ 6.68 indicative of the proton of the carbon of the C=N moiety and a doublet centered at δ 3.57 representing the methylene protons of this product. Purification of the reaction mixture by flash column chromatography allows the isolation of 63a in 71% yield.  47  Using the alkyl-substituted acetylene, tert-butylacetylene 60b with 59a, the catalysis with complex 49 is much slower requiring an elevated temperature of 110 °C for the reaction to proceed (Table 2.2, entry 2). Unfortunately, the high temperature required for catalysis to proceed in this case also results in significant cleavage of the N–N bond in 59a, leading to the formation of N-phenylaniline.  The cleavage of the N–N bond in hydrazines is a well-  documented occurrence292-301 and the observation of this bond-breaking process with hydrazine 59a thwarts any further catalytic hydrohydrazination reaction with 59a at these elevated temperatures. The mixed aryl-alkyl hydrazine, 1-methyl-1-phenylhydrazine 59b, is also a viable substrate for hydrohydrazination using complex 49. The reaction conducted with 1 equivalent of phenylacetylene 60a, 1.2 equivalents of 1-methyl-1-phenylhydrazine 59b, and 5 mol% of 49 in a J. Young NMR tube (Table 2.2, entry 3) shows immediate formation of all four products as detected by 1H NMR spectroscopy. Fortunately, by heating the mixture at 65 ºC for four hours, the ene-hydrazine products 61c and 62c could be converted into the respective tautomers 63c and 64c in a 6:1 ratio with anti-Markovnikov product 63c predominating. Furthermore, compounds 63c and 64c are easily separated by flash column chromatography in isolated yields of 75% and 6% respectively.  48  Table 2.2. Intermolecular hydrohydrazination of alkynes with 1,1-disubstituted hydrazines  Entry  Hydrazine  Alkyne  Temp (°C)  Yield (%)c-g  Time (h)  Product ratioh 71c  1a  65 1 42c  2b  110 96 75c  3a  65 4 63c:64c 6:1h  4b  110  83d  96 63d:64d 1:1h 5a  110  81e  3 61e:62e:63e:64e 1:1:2:9h Table 2.2 continued on page 50  49  Table 2.2. Intermolecular hydrohydrazination of alkynes with 1,1-disubstituted hydrazines (continued from page 49) Entry 6a  Hydrazine  Alkyne  Temp (°C)  Yield (%)c-g  Time (h)  Product ratioh  65  66f  18  7a  90  80c  6 63g:64g 6:1h 8a  110  23g  24 a  Alkyne, 1.96 mmol; hydrazine, 2.35 mmol. b Alkyne, 0.061 mmol; hydrazine, 0.050 mmol. Isolated yield of 63. d % Conversion determined by 1H NMR spectroscopy. e Combined isolated yield following reduction/deprotection by LiAlH4. f Isolated yield of the corresponding hydrazine following LiAlH4 reduction. g Yield determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. h Determined by 1H NMR spectroscopy. c  With the alkyl-substituted acetylene tert-butylacetylene 60b and hydrazine 59b, the catalysis with complex 49 required 96 hours at 110 ºC to attain 83% conversion as estimated by 1  H NMR spectroscopy (Table 2.2, entry 4). Here, there was no selectivity for either of the  hydrazones as 63d and 64d are formed in a 1:1 ratio. The reaction of TBDMS-protected propargyl alcohol 60c with 59b is much faster than either of the aforementioned reactions involving 59b; complete consumption of 60c occurs within one hour at room temperature and results in the formation of all four possible products: 61e, 62e, 63e, and 64e in 1:1:2:9 ratio (Table 2.2, entry 5). Similar room temperature reactivity has being previously observed in the  50  hydroamination of oxygen-substituted allenes with primary amines catalyzed by 49.273 It should be noted that the selectivity of the reaction between hydrazine 59b and the oxygen-bearing alkyne 60c favours the Markovnikov product. This is presumably due to alleviation of the steric congestion between the bulky TBDMS group and the ancillary ligand on the metal center that could occur in the intermediate metallacycle required for the formation of the anti-Markovnikov product (see Scheme 2.4). Unfortunately, the corresponding ene-hydrazines 61e and 62e (about 9% by 1H NMR spectroscopy) do not fully tautomerize to hydrazones 63e and 64e even with increased reaction time and elevated temperature (110 °C). The four products are not separated from each other, thus, the combined yield after reduction/deprotection and separation from decomposed precatalyst 49 by column chromatography is 81%. Complex 49 is also an efficient precatalyst for the hydrohydrazination of internal alkyne 60d with hydrazine 59b. Hydrazone 63f (Table 2.2, entry 6) is the sole product after 18 hours at 65 °C and subsequent reduction with LiAlH4 allows the isolation of the corresponding hydrazine in 66% yield following purification by column chromatography. The competency of complex 49 is not limited to aryl-containing hydrazines; a 1,1dialkylhydrazine, 1,1-dimethylhydrazine 59c, also reacts with terminal alkyne 60a and internal alkyne 60d (Table 2.2, entries 7 and 8). Notably, internal alkynes are less reactive, as only 23% conversion is observed after 24 hours at 110 °C (Table 2.2, entry 8). In comparison to group 4 metal-based hydrohydrazination precatalysts from the literature, complex 49 is more reactive than 56 but less reactive than complexes 57 and 58. It is worth mentioning that complex 58 is the stoichiometrically prepared catalytically active species containing the highly reactive but difficult to handle imido moiety. Comparison with late transition metal catalyst systems for alkyne hydrohydrazination is not as straightforward, as these  51  complexes are more effective for monosubstituted hydrazines.192,  290  This is in contrast to  precatalyst 49 and most early transition metal systems that favoured disubstituted hydrazines as substrates.  Additionally, hydrohydrazination catalysis with late transition metals is  regioselective for the Markovnikov product.192, 290 The hydrohydrazination reaction of allenes has not yet been reported. Here, it was unsuccessful as allenes 50a, 50b, and 50c did not react with 1,1-diphenylhydrazine 59a even after prolonged reaction times at 65 °C. Decomposition of the allenes is observed upon elevation of the reaction temperature to 110 °C. As earlier mentioned, the N-aryl hydrazone products of the reactions between alkynes and aryl-containing hydrazines are useful synthetic intermediates, such as for the Fischer indole synthesis. Odom and co-workers pioneered the employment of hydrazones generated in situ by the hydrohydrazination reaction in zinc chloride mediated indole synthesis. In the next section, the exploration of complex 49 in the hydrohydrazination reaction to give hydrazones for the preparation of indoles by zinc chloride promoted cyclization is reported.  2.2.3 One-Pot Synthesis of N-substituted Indoles by Tandem Hydrohydrazination, Fischer Indole Reaction The indole skeleton is a common scaffold in naturally occurring and biologically active compounds including many drug candidates and marketed pharmaceuticals,302,  303  therefore,  methods for efficiently generating these compounds are attractive. In the classic Fischer indole synthesis, a commonly used method for preparing indoles, N-aryl hydrazones generated from the Schiff base reaction between aldehydes or ketones and N-aryl hydrazines undergo acid-catalyzed or thermal 3,3-sigmatropic rearrangement and subsequent elimination of ammonia to afford the  52  indoles.303 The hydrohydrazination reaction of alkynes with N-aryl hydrazines, a 100% atom economic process, is an efficient alternative route to N-aryl hydrazones, the intermediates in the Fischer indole synthesis. This complementary pathway to indole synthesis, originally disclosed by Odom and co-workers,148 involves tandem sequential C–N, C–C bond forming processes by hydrohydrazination and Fischer indole synthesis leading to a one-pot synthetic procedure without the need for prior isolation of the hydrazones (Scheme 2.7).  Scheme 2.7. Tandem sequential hydrohydrazination/cyclization reactions for indole synthesis.  Following literature precedent, the N-aryl hydrazones produced from the reaction of arylcontaining hydrazines 1,1-diphenylhydrazines (59a) and 1-methyl-1-phenylhydrazine (59b) are converted to N-substituted indoles by a ZnCl2-mediated Fischer indole process (Table 2.3). In a typical reaction, 3 equivalents of ZnCl2 are added to the reaction mixture after the completion of the hydrohydrazination step and the mixture is heated to 100 °C for 16 hours resulting in a onepot tandem sequential reaction for the preparation of indoles (Table 2.3). The regioselectivity of the major indole product in entry 2 is in agreement with the major hydrohydrazination product. All the indoles are obtained in respectable isolated yields ranging from 62–75% (Table 2.3,  53  entries 1–3) with the exception of 65c which is formed in 33% yield. The lower yield of this compound is due to significant cleavage of the N–N bond of the hydrazone intermediate that accompanied indole formation at elevated temperatures (Table 2.3, entry 4).  Table 2.3. One-pot synthesis of N-substituted indoles  Entry  Hydrazine  Alkyne  Yield (%) Product/ratio 75a  1  65a:66a 24:1c  2  62b  3  66b  Table 2.3 continued on page 55  54  Table 2.3. One-pot synthesis of N-substituted indoles (continued from page 54) Entry  Hydrazine  Alkyne  Product/ratio 33b  4  a  Combined isolated yield.  Yield (%)  b  Isolated yield.  c  Ratio of isolated product.  2.2.4 Hydroamination Reactions with In Situ Generated Precatalyst 49 Although precatalyst 49 is easily synthesized by a protonolysis reaction between commercially available Ti(NMe2)4 and the amide proligand,304 the ability to generate 49 in situ with no loss in catalytic activity or selectivity is desirable. A catalytically active in situ prepared complex implies that prior isolation and purification of the precatalyst is not required for efficient catalysis and lends itself to bench top application using commonly employed syringe techniques. Therefore, selected hydroamination substrates have been subjected to catalysis using in situ generated complex 49. The selected substrates have all been previously shown to undergo successful hydroamination using isolated 49 as a precatalyst.147,  273  However, it is worth  mentioning that the substrates presented here were selected to illustrate the diverse substrate scope. In a typical reaction, 1 equivalent of Ti(NMe2)4 (0.350 M standard solution in d6benzene) is added to 2 equivalents of the amide proligand in a 1 dram vial. Upon dissolution of the entire solid (< 5 minutes), the appropriate amount of substrates are added and the reaction mixture can be quantitatively transferred into a J. Young NMR tube. The mixture is then subjected to reaction conditions identical to that applied when the catalysis is carried out using  55  isolated precatalyst 49. The results of this investigation are compiled in Table 2.4. Gratifyingly, the yields and selectivities observed compare favourably with those obtained using pre-made 49. The only exception to this general trend is the reaction of benzylallene (50d) with 2,6dimethylaniline, where the in situ reaction required prolonged reaction time of 66 hours (Table 2.4, entry 4) in comparison to the reaction time of 24 hours noted for the pre-made complex.  Table 2.4. Hydroamination reactions conducted with in situ prepared precatalyst 49 Entry  Allene/Alkyne  Amine/ Hydrazine  1  2  Product(s)  Temp (°C)  Yielda,  Time (h)  (previousb)  65  85  12  (81)  65  80  5  (81) 63c:64c 6:1  3  4  90  92c  24  (83d)  90  63c  66  (93d)  a  Isolated yield of product(s) obtained using in situ generated precatalyst 49. b Isolated yield of product(s) obtained using pre-made 49. c Yield of corresponding secondary amine following reduction with LiAlH4 or NaCNBH3/ZnCl2. d Yield of corresponding secondary amine following reduction with LiAlH4 or NaCNBH3/ZnCl2, using pre-made 49.  56  2.3 Conclusions The intermolecular hydroamination of N-containing allene 50a with arylamines can be successfully catalyzed by precatalyst 49. Bulky 2,6-dimethylaniline exclusively affords the ketimine regioisomer while the sterically-accessible aniline has a slight preference for the allylamine regioisomer. This is in contrast to the oxygen-substituted allenes, which exclusively afford allylamine products with aniline. The regioselective formation of ketimine observed with the bulky 2,6-dimethylaniline is believed to be due to steric effects which favours the protonation of one metallacyclic intermediate over the other. Control experiments with the alkyne analogue of 50a results in different regioselective outcomes and product ratios and suggests that allenealkyne isomerization prior to catalytic hydroamination is improbable. Interestingly, complex 49 efficiently catalyzes the intermolecular hydroamination of alkynes with 1,1-disubstituted hydrazines. Three different hydrazines with different electronic properties have been reacted with terminal and internal alkynes in this substrate scope investigation of complex 49. The reaction generally proceeds with a preference for the antiMarkovnikov product, consistent with the regioselectivity observed in the hydroamination of alkynes and alkylamines, as previously reported for this complex. These results illustrate the wide substrate scope applicability of precatalyst 49 in the hydroamination reaction such that the activity of 49 compares favourably with the highly reactive yet less functional group tolerant lanthanide-containing precatalysts. Importantly, these results give credence to our designation of 49 as a broadly applicable, regioselective alkyne hydroamination precatalyst. Furthermore, the hydrohydrazination reaction can be combined with the Fischer indole reaction conditions to produce N-substituted indoles in a one-pot tandem sequential reaction; an illustration of the application of 49 in the synthesis indoles.  57  Importantly, in situ generated precatalyst 49 is similarly efficient for hydroamination catalysis suggesting that prior isolation of this complex is unnecessary for effective reactivity. This eliminates additional isolation/purification steps for precatalyst 49, accentuating the simplicity and ease of application of this methodology.  2.4 Experimental 2.4.1 Materials and Methods All reactions were carried out under an atmosphere of dry nitrogen using standard Schlenk line techniques or an MBraun Unilab glove-box unless otherwise stated.  1  H and  13  C  NMR spectra were recorded on 300 MHz or 400 MHz Bruker Avance spectrometers and chemical shifts are reported in parts per million (ppm) relative to the residual proton in the solvents indicated. The deuterated solvents used and the assigned chemical shift values are as follows: CDCl3 – 1H NMR 7.27 ppm, 13C NMR 77.2 ppm; d6-benzene – 1H NMR 7.16 ppm, 13C NMR 128.4 ppm; DMSO – 1H NMR 2.50 ppm, 13C NMR 39.5 ppm. Thin layer chromatography was performed on silica gel (Macheney-Nagel Silica Gel 60) aluminium plates (layer 0.20 mm). Column chromatography was performed using SiliaFlash F60 silica gel 70–230 or 230–400 mesh unless otherwise stated.  Mass spectrometry and elemental analysis were performed at the  Department of Chemistry, University of British Columbia. High resolution mass spectrometry is provided in certain situations where repeated elemental analysis does not provide satisfactory result.  Diethyl ether, THF, hexanes, and toluene were purified over columns of alumina.  Hydrazines were dried over CaH2 and distilled under vacuum or nitrogen. Ti(NMe2)4 was purchased from Strem and used as received. d8-Toluene and d6-benzene were degassed by freeze-pump-thaw cycles and stored over molecular sieves in the glovebox.  Bis(amidate)  58  bis(amido) precatalyst 49, was prepared as described in the literature. 143 The spectral data for the  following  compounds  are  consistent  with  literature  values:  1,1-diphenyl-2-(2-  phenylethylidene)hydrazine (63a), 1,1-dimethyl-2-(2-phenylethylidene)hydrazine (63g),148 1,1dimethyl-2-(1-phenylethylidene)hydrazine (64g),148 1,3-diphenyl-1H-indole (65a),305 1-methyl3-phenyl-1H-indole (65b),148 1,2-dimethyl-3-phenyl-1H-indole (65c),148 1-methyl-2-phenyl-1Hindole (66a),306 and 1-methyl-3-(tert-butyldimethylsilyloxy)-2-methyl-1H-indole.307  2.4.2 Catalytic Procedures All catalytic reactions were set up inside the glovebox and then transferred into a J. Young NMR tube equipped with a Teflon cap for further manipulation outside of the glovebox. The NMR tubes were heated in an oil bath set at the temperature indicated in the main text for the specific substrate combination.  N-(1-(1H-indol-1-yl)propan-2-yl)-2,6-dimethylaniline (52a) A mixture of 0.167 g (1.07 mmol) of indoleallene, 0.065 g (0.54 mmol) of 2,6-dimethyaniline, 0.037 g (0.054 mmol) of precatalyst 49, and 1 mL of d6-benzene were heated at 90 °C in a J. Young NMR tube. After 5 h at 90 °C, it was cooled to room temperature and then added to a mixture of 0.067 g (1.1 mmol) of sodium cyanoborohydride and 0.073 g (0.54 mmol) of zinc chloride in 20 mL of methanol, followed by stirring at room temperature for 16 h. The mixture was quenched by the addition of 10 mL of saturated aqueous sodium carbonate solution. The layers were separated and the organic solvents were removed by rotary evaporation. The solid was dissolved in 20 mL of diethyl ether and extracted with 0.5 M aqueous HCl solution (5 × 20 mL). The aqueous layer was treated with 2 M aqueous NaOH until the solution became strongly  59  basic as tested by litmus paper. The basic solution was extracted with diethyl ether (3 × 20 mL) and the organic extract was dried over anhydrous magnesium sulphate, the solid was filtered off and the solvent was removed by rotary evaporation. Subsequent column chromatography using a 20:1 mixture of hexanes/ethyl acetate afforded the product as pale yellow oil in 40% yield (0.060 g, 0.22 mmol). 1H NMR (CDCl3, 400 MHz, ): 1.09 (3H, d, J = 6.3 Hz, –CHCH3), 2.20 (6H, s, 2 × Ar–CH3), 2.90 (1H, br s, –CHNH–), 3.69 (1H, m, –CHCH3), 4.06 (1H, dd, J = 14.3, 7.6 Hz, –CH2CH–), 4.28 (1H, dd, J = 14.1, 4.7 Hz, –CH2CH–), 6.51 (1H, m, Ar–H), 6.85 (1H, t, J = 7.4 Hz, Ar–H), 7.01 (2H, d, J = 7.0 Hz, 2 × Ar–H), 7.11 (2H, m, 2 × Ar–H), 7.19 (1H, t, J = 7.4 Hz, Ar–H), 7.28 (1H, m, Ar–H), 7.63 (1H, d, J = 7.8 Hz, Ar–H);  13  C{1H} NMR (CDCl3,  100 MHz, ): 19.0, 20.1, 52.6, 53.5, 101.5, 109.5, 119.5, 121.1, 121.7, 122.2, 128.7, 128.8, 129.2, 129.7, 136.5, 144.3; GC–MS (EI) m/z: 278 (M+); HRMS–EI (m/z): [M+] calcd for C19H22N2, 278.17830; found: 278.17827.  N-(3-(1H-Indol-1-yl)propyl)-2,6-dimethylaniline (52c) A mixture of 1-(prop-2-ynyl)-1H-indole (0.064 g, 0.41 mmol), 2,6-dimethylaniline (0.050 g, 0.41 mmol) and 0.029 g of 49 (0.041 mmol) in 0.4 mL of d6-benzene in a J. Young NMR tube was left at room temperature for 21 h. It was then added to a mixture of 0.052 g (0.082 mmol) of sodium cyanoborohydride and 0.056 g (0.41 mmol) of zinc chloride in 20 mL of THF, followed by stirring at room temperature for 16 h. The reaction was quenched by the addition of 10 mL of saturated aqueous sodium carbonate solution. The precipitate was filtered and washed with dichloromethane (25 mL). The organic layer was separated and the aqueous layer was extracted  60  with dichloromethane (3 × 30 mL).  The combined extracts were dried over anhydrous  magnesium sulphate, the solid was filtered off and the solvents removed by rotary evaporation. Purification by column chromatography using a 20:1 mixture of hexanes/ethyl acetate afforded 52a (pale yellow oil, 10% yield, 0.012 g, 0.043 mmol) and 52c (pale yellow oil, 47% yield, 0.054 g, 0.19 mmol) respectively. Characterization data for 52c: 1H NMR (CDCl3, 400 MHz, ): 2.11 (2H, quin, J = 7.0 Hz, –CH2CH2CH2NH–), 2.22 (6H, s, 2 × Ar–CH3), 2.85 (1H, br s, – CH2NH–), 3.00 (2H, t, J = 6.8 Hz, –CH2NH–), 4.24 (2H, t, J = 7.0 Hz, –CH2CH2CH2NH–), 6.50 (1H, m, Ar–H), 6.82 (1H, m, Ar–H), 6.98 (2H, d, J = 7.0 Hz, 2 × Ar–H), 7.10 (2H, m, 2 × Ar– H), 7.20 (1H, m, Ar–H), 7.33 (1H, br d, J = 8.2 Hz, Ar–H), 7.64 (1H, d, J = 7.8 Hz, Ar–H); C{1H} NMR (d6-benzene, 100 MHz, ): 18.7, 31.9, 44.3, 46.0, 101.5, 109.4, 119.5, 121.2,  13  121.7, 122.2, 127.8, 128.8, 129.1, 129.6, 136.1, 146.0; MS(EI) m/z: 278 (M+); Anal. Calcd for C19H22N2: C, 81.97; H, 7.97; N, 10.06. Found: C, 82.06; H, 7.78; N, 10.04.  N-(3-(1H-Indol-1-yl)propyl)aniline (52d) Compound 52d was obtained using the same procedure outlined above for 52c. The quantities of reagents utilized for the catalysis are: 0.083 g (0.54 mmol) of 1-(prop-2-ynyl)-1H-indole, 0.050 g (0.54 mmol) of aniline, and 0.037 g (0.054 mmol) of precatalyst 49.  Compound 52d was  obtained as pale yellow oil after purification by column chromatography using a 20:1 mixture of hexanes/ethyl acetate in 50% yield (0.067 g, 0.27mmol).  1  H NMR (d6-benzene, 300 MHz, ):  1.41 (2H, quin, J = 6.7 Hz, –CH2CH2CH2NH–), 2.50 (2H, t, J = 6.8 Hz, –CH2CH2CH2NH–), 2.74 (1H, br s, –CH2CH2CH2NH–), 3.51 (2H, t, J = 6.8 Hz, –CH2CH2CH2NH–), 6.35 (2H, d, J =  61  7.7 Hz, 2 × Ar–H), 6.52 (1H, br d, J = 2.9 Hz, Ar–H), 6.65 (1H, br d, J = 2.9 Hz, Ar–H), 6.75 (1H, t, J = 7.3 Hz, Ar–H), 7.11–7.26 (5H, m, 5 × Ar–H), 7.73 (1H, br d, J = 8.3 Hz, Ar–H); C{1H} NMR (CDCl3, 100 MHz, ): 30.0, 41.4, 44.0, 101.6, 109.5, 113.1, 117.8, 119.6, 121.3,  13  121.8, 128.0, 128.8, 129.5, 136.1, 148.2; GC–MS (EI) m/z: 250 (M+); Anal. Calcd for C17H18N2: C, 81.56; H, 7.25; N, 11.19. Found: C, 81.93; H, 7.26; N, 11.01.  (Z)-N-(3-(1H-indol-1-yl)allyl)aniline (53a) A mixture of 0.167 g (1.07 mmol) of indoleallene, 0.050 g (0.54 mmol) of aniline, 0.037 g (0.054 mmol) of precatalyst 49, and 1 mL of d6-benzene were heated at 65 °C in a J. Young NMR tube. After 24 h, the mixture was poured into a suspension of silica gel (0.3 g) in 5 mL dichloromethane and stirred for 16 h at room temperature. It was then filtered and the residue washed with 20 mL of dichloromethane. The solvents were removed by rotary evaporation and the products purified by column chromatography using a 40:1 mixture of hexanes/ethyl acetate to afford compound 53a as pale yellow oil in 29% yield (0.039 g, 0.16 mmol) and corresponding ketone-derivative for 51b in 24% yield (0.022 g, 0.13 mmol). Characterization data for 53a: 1  H NMR (d6-benzene, 300 MHz, ): 3.02 (1H, br s, –CH2NH–), 3.49 (2H, br dd, J = 6.7, 1.5 Hz,  –CHCH2–), 4.95 (1H, br dt, J = 8.8, 6.7 Hz, –CHCH2–), 6.35 (2H, m, 2 × Ar–H), 6.46 (1H, br dt, –CHCHCH2–), 6.49 (1H, d, J = 3.3 Hz, Ar–H), 6.74 (1H, m, Ar–H), 6.98 (1H, d, J = 3.3 Hz, Ar–H), 7.10–7.25 (5H, m, 5 × Ar–H), 7.63 (1H, m, Ar–H); 13C{1H} NMR (CDCl3, 75 MHz, ), 41.3, 104.2, 110.1, 113.3, 118.1, 118.2, 120.9, 121.2, 122.7, 125.8, 127.7, 128.6, 129.5, 136.5,  62  147.7; GC–MS (EI) m/z: 248 (M+), 156 (M+ – NHPh); HRMS–EI (m/z): (M+) calcd for C17H16N2, 248.13135; found, 248.13156.  2.4.3 Representative Procedure for the Hydrohydrazination Reactions 2.4.3.1 Procedure 1 for the Hydrohydrazination Reactions Example: Intermolecular hydroamination of phenylacetylene with 1-methyl-1-phenylhydrazine A mixture of 0.200 g (1.96 mmol) of phenyacetylene (60a), 0.287 g (2.35 mmol) of 1-methyl-1phenylhydrazine (59b), 0.068 g (0.098 mmol) of complex 49, and 0.3 mL of d6-benzene were transferred into a J. Young NMR tube and heated at 65 °C for 4 h. The reaction mixture was cooled to room temperature and diluted with 10 mL of hexanes. The precipitate was filtered off and the solvents were removed using rotary evaporation. The crude product was purified by flash chromatography (hexanes/ethyl acetate 20:1) to give 75% (0.329 g, 1.47 mmol) of 63c and 6% of (0.0263 g, 0.117 mmol) 64c.  1-methyl-1-phenyl-2-(2-phenylethylidene)hydrazine (63c)308 Detailed characterization data for this previously reported compound are as follows: 1H NMR (d6-benzene, 400 MHz, ): 2.56 (3H, s, –NCH3), 3.57 (2H, d, J = 5.7 Hz, –CH2CH–), 6.45 (1H, t, J = 5.4 Hz, –CH2CH–), 6.86 (1H, t, J = 7.2 Hz, Ar–H), 7.07 (1H, m, Ar–H), 7.15 (4H, m, 4 × Ar–H), 7.24 (2H, m, 2 × Ar–H), 7.32 (2H, dd, J = 8.7, 1.3 Hz, 2 × Ar–H); 13C NMR (d6-benzene, 100 MHz, ): 32.6, 40.4, 115.4, 120.5, 127.0, 129.2, 129.6, 129.6, 133.7, 139.6, 149.0; MS(EI) m/z: 224 (M+); HRMS–ESI (m/z): [M + Na]+ calcd for C15H16N2Na, 247.1213; found, 247.1211.  63  1-methyl-1-phenyl-2-(1-phenylethylidene)hydrazine (64c)309 Detailed characterization data for this previously reported compound are as follows: 1H NMR (d6-benzene, 400 MHz, ): 1.95 (3H, s, –CCH3), 2.89 (3H, s, –NCH3), 6.89 (1H, t, J = 7.2 Hz, Ar–H), 7.04 (2H, m, 2 × Ar–H), 7.17 (3H, m, 3 × Ar–H), 7.22 (2H, m, 2 × Ar–H), 7.88 (2H, m, 2 × Ar–H);  13  C NMR (d6-benzene, 100 MHz, ): 16.3, 43.6, 116.7, 120.9, 127.4, 128.8, 129.5,  130.2, 139.1, 152.6, 164.6; MS(EI) m/z: 224 (M+); Anal. Calcd for C15H16N2: C, 80.32; H, 7.19; N, 12.49. Found: C, 80.17; H, 7.23; N, 12.20.  2-(3,3-dimethylbutylidene)-1,1-diphenylhydrazine (63b) The compound was synthesized according to procedure 1 using the following quantities of reagents: 1,1-diphenylhydrazine, 0.093 g, 0.50 mmol; tert-butylacetylene, 0.050 g, 0.61 mmol; complex 49, 0.018 g, 0.025 mmol. The product was obtained as pale yellow oil in 42% yield (0.057 g, 0.21 mmol) following purification by column chromatography with Alumina (neutral) using hexanes as eluent. 1H NMR (d6-benzene, 300 MHz, ): 0.81 (9H, s, C(CH3)3), 2.16 (2H, d, J = 6.1 Hz, –CH2CHNN–), 6.61 (1H, t, J = 6.1 Hz, –CH2CHNN–), 6.91 (2H, m, 2 × Ar–H), 7.14 (8H, m, 8 × Ar–H);  13  C NMR (d6-benzene, 75 MHz, ): 29.9, 31.7, 46.9, 123.2, 124.5, 130.3,  138.0, 145.4; GC–MS (EI) m/z: 266 (M+), 168 [M+ – NCHCH2C(CH3)3]; Anal. Calcd for C18H22N2: C, 81.16; H, 8.32; N, 10.52. Found: C, 81.20; H, 8.48; N, 10.82.  64  2.4.3.2 Procedure 2 for the Hydrohydrazination Reactions Example: Intermolecular hydroamination of phenylpropyne with 1-methyl-1-phenylhydrazine A mixture of 0.227 g (1.96 mmol) of phenylpropyne 60d, 0.287 g (2.35 mmol) of 1-methyl-1phenylhydrazine 59b, 0.068 g (0.098 mmol) of complex 49, and 0.3 mL of d8-toluene were heated in a J. Young NMR tube. After 18 h at 65 °C, the reaction mixture was cooled to room temperature, and then added to 0.149 g (3.92 mmol) of lithium aluminum hydride in 15 mL of diethyl ether at 0 ºC. This was then warmed up to room temperature and stirred overnight. The reaction was quenched by dropwise addition of saturated NH4Cl solution, filtered through Celite, and the residue washed with dichloromethane (25 mL). The solvents were removed by rotary evaporation and the crude product purified by column chromatography (eluting solvents hexanes/ethyl acetate 80:1) to afford the product in 66% (0.310 g, 1.29 mmol).  1  H NMR (CDCl3, 400 MHz, ): 1.14 (3H, d, J = 6.1 Hz, –CHCH3), 2.68–2.75 (1H, m, –CH2CH–  ), 2.81–2.89 (1H, m, –CH2CH–), 3.03 (3H, s, –NCH3), 3.35–3.43 (2H, m, –CH2CH–, –NH–), 6.80 (1H, t, J = 7.2 Hz, Ar–H), 6.96 (2H, d, J = 7.9 Hz, 2 × Ar–H), 7.26–7.39 (7H, m, 7 × Ar– H);  13  C NMR (CDCl3, 75 MHz, ): 19.3, 40.0, 42.1, 54.5, 113.2, 118.0, 126.5, 128.6, 129.0,  129.5, 139.5, 152.4; MS(ESI): 241 [M+H]+, HRMS-EI (m/z): [M+H]+ calcd for C16H21N2, 241.1705; found, 241.1705.  65  2.4.4 Representative Procedure for the Formation of Indoles Example: Synthesis of 1-methyl-3-phenylindole (65a)148 and 1-methyl-2-phenylindole (66a)306 A mixture of 0.200 g (1.96 mmol) of phenylacetylene (60a), 0.287 g (2.35 mmol) of 1-methyl-1phenylhydrazine (59b), 0.068 g (0.098 mmol) of complex 49, and 0.3 mL of benzene was transferred into a Schlenk tube and placed in an oil bath set at 65 °C. After 4 h at 65 °C, 0.801 g (5.88 mmol) of ZnCl2 in 15 mL of toluene was added. The reaction mixture was then heated at 100 °C for 16 h. The reaction was quenched with 30 mL of diethyl ether and the mixture was filtered through a plug of silica gel. The solvents were removed by rotary evaporation and the crude product was purified by column chromatography to afford 72% (0.292 g, 1.41 mmol) of 65a and 3% (0.0122 g, 0.0587 mmol) of 66a. 1H NMR for 65a (CDCl3, 300 MHz, ): 3.87 (3H, s, –NCH3), 7.24–7.32 (5H, m, 5 × Ar–H), 7.49 (2H, t, J = 7.6 Hz, 2 × Ar–H), 7.71 (2H, m, 2 × Ar–H), 8.01 (1H, d, J = 7.9 Hz, Ar–H). 1H NMR for 66a (CDCl3, 300 MHz, ): 3.76 (3H, s, – NCH3), 6.57 (1H, s, Ar–H), 7.14–7.26 (1H, m, Ar–H), 7.39 (1H, m, Ar–H), 7.44–7.53 (6H, m, 6 × Ar–H), 7.63 (1H, d, J = 7.8 Hz, Ar–H).  2.4.5 Representative Procedure for Hydroamination Reactions with In Situ Generated Precatalyst Example: Synthesis of (Z)-N-Isopropyl-3-(2,6-dimethylphenoxy)prop-2-en-1-amine (Table 2.4, entry 1) Using a micro-syringe, 0.178 mL (0.062 mmol) of a 0.350 M standard solution of Ti(NMe2)4 in d6-benzene was added to 0.035 g (0.12 mmol) of N-(2,6-diisopropylpheny)benzamide suspension in 0.100 mL of d6-benzene in a 1 dram vial. The vial was gently shaken until all the solid completely  dissolved  (<5  minutes),  after  which  0.200 g  (1.25 mmol)  of  2,6-  66  dimethylphenoxyallene and 0.221 g (3.75 mmol) of isopropylamine were added. The mixture was quantitatively transferred into a J. Young NMR tube by rinsing the vial twice with 0.05 mL of d6-benzene. The NMR tube was then placed in an oil bath set at 65 °C. Upon reaction completion (12 h), the mixture was poured into a 100 mL beaker containing 5 mL of H2O and 20 mL of diethyl ether. The precipitate was filtered and the filtrate was extracted with 1 M aqueous HCl (3 × 20 mL). The aqueous layer was treated with 2 M aqueous NaOH until the solution became strongly basic as tested by litmus paper (pH 10). The basic solution was extracted with diethyl ether (3 × 20 mL) and the organic extract was dried over anhydrous magnesium sulphate, the drying agent was filtered off and the solvent was removed by rotary evaporation to afford the product as colourless oil in 85% yield (0.233 g, 1.06 mmol).  67  CHAPTER 3. SYNTHESIS AND CHARACTERIZATION OF AXIALLY CHIRAL ZIRCONIUM BIPHENYL AMIDATE COMPLEXES: APPLICATION IN THE ENANTIOSELECTIVE HYDROAMINATION OF AMINOALKENES  3.1 Introduction In the preceding chapter, the use of bis(amidate) bis(amido) titanium complex 49 as a precatalyst for intermolecular hydroamination using a variety of substrates was described. These studies, coupled with various others from the group, substantiate our designation of complex 49 as a broadly applicable alkyne hydroamination precatalyst.113,  136, 143, 145-147  Unfortunately,  preliminary efforts aimed at extending the efficiency of 49 to alkenes have been disappointing as the competency of 49 for the hydroamination of alkenes is quite limited.103 During these efforts, it has been established that zirconium amidate complexes are more effective catalysts for alkene hydroamination than their titanium counterparts.103 Importantly, the hydroamination of alkenes can afford α-chiral nitrogen containing molecules (Scheme 3.1),1,  40-42, 46, 47, 149, 150  ubiquitous in naturally occurring and biologically relevant compounds.  which are  Enantioselective  catalysis can be addressed by using chiral substituents on either the N or carbonyl functionality of the amidate ligand in bis(amidate) complexes. However, this approach results in very poor enantioselectivity,310, 311 presumably due to the various coordination isomers that can be adopted by bis(amidate) complexes featuring monoanionic amidate ligands (Figure 3.1).138  Reproduced in part with permission from Ayinla, R. O.; Gibson, T.; Schafer, L. L. J. Organomet. Chem. 2011, 696, 50–60. Copyright © 2010 Elsevier B.V.  68  Scheme 3.1. Intramolecular and intermolecular hydroamination of alkenes.  Figure 3.1. Possible coordination isomers accessible to monoanionic amidate ligands.  Therefore,  to  access  enantioenriched  nitrogen  containing molecules  via  the  hydroamination of alkenes, the proligand precursor for complex 49 needs to be redesigned to include a stereo-determining moiety and a rigid framework to limit the accessible coordination modes about the metal center.  In view of the limitations of precatalyst 49 for alkene  hydroamination, this chapter focuses on the preparation of new chiral proligands for the synthesis of zirconium complexes that catalyze the hydroamination of alkenes in an enantioselective fashion. Since the development of the first metal-catalyzed asymmetric hydroamination reaction in the early 1990s,49-51 much effort has been focused on enantioselective variant of this reaction.1, 41, 46, 47  In the early work of Marks and co-workers, C1-symmetric ansa-lanthanocenes featuring  stereo-determining chiral moieties such as (–)-menthyl, (–)-phenylmenthyl, or (+)-neomenthyl were employed as precatalysts for the cyclization of aminoalkenes (Figure 3.2).49-51 These  69  complexes effectively furnish α-substituted pyrrolidines with up to 74% enantiomeric excess (ee) but suffer from racemization under the catalytic reaction conditions via reversible protolytic cleavage of the metal–chiral cyclopentadienyl bond (Scheme 3.2).49,  50  Consequently,  enantiomeric excesses and absolute configurations of the α-substituted pyrrolidine products are independent of the enantiopurity of the precatalysts.49, 50  Figure 3.2. Early examples of enantioselective aminoalkene hydroamination precatalysts.  Scheme 3.2. Epimerization of chiral lanthanide complexes via reversible protolytic cleavage of metal–chiral ligand bond.  In light of this, many recent advances employ rigid chiral scaffolds such as biaryl linkages in an effort to control geometric isomerization by enforcing configurational stability in the resulting metal complexes and avoid the drawbacks of the pioneering chiral ansalanthanocenes. Using this approach, enantiomeric excesses of >90% have been achieved with select examples of axially chiral biaryl-containing complexes (Figure 3.3);56,  84, 95, 98, 121, 312  however, such high enantioselectivities are limited to a specific substrate/product per catalyst. Our exploration of amidate ligated group 3 and 4 metal complexes98, 103, 112, 113, 117, 130, 131, 137, 138,  70  141-147, 313-315  in metal-catalyzed transformations has led to the development of an axially chiral  C2-symmetric bis(amide) proligand 67 as a precursor to a highly active and enantioselective zirconium precatalyst 39.98  This catalyst is capable of achieving up to 93% ee for the  hydroamination of aminoalkenes (Figure 3.4).98 Following this report, other examples of chiral amidate supported group 4 metal complexes for efficient hydroamination catalysis have emerged.121,  312, 316, 317  Detailed catalytic investigations of the zirconium precatalyst 39 have  revealed that the high reactivity and selectivity are restricted to geminal-substituted substrates for five-membered ring formation,98 in accord with general observations in group 4 metal-catalyzed hydroamination.1  Figure 3.3. Highly enantioselective precatalysts and proligand for the hydroamination of aminoalkenes. In an attempt to broaden the substrate scope of zirconium amidate complexes in hydroamination catalysis and improve stereoselectivities in the asymmetric hydroamination of aminoalkenes, the biphenyl dicarboxamide proligand 68 (Figure 3.4) was envisioned as a more sterically-encumbered alternative to the previously reported bis(amide) 67.98 The solid-state molecular structure of the zirconium biphenyl amidate complex 39 shows a lack of steric shielding about the O-donor atoms as the groups attached to the carbonyl carbon are far from the  71  metal center upon complex formation.98 However, in proligand 68 the modified substituent pattern should effectively shield the metal center upon complexation, assuming a similar κ4N,O,O,N-bonding motif is adopted. Thus, proligands 67 and 68 are closely related, with the major difference being the position of the carbonyl and N-functionality relative to the biphenyl framework (Figure 3.4).  Figure 3.4. Chiral bis(amide) proligands and zirconium precatalyst for the asymmetric hydroamination of aminoalkenes.  This chapter focuses on an investigation of a series of proligands of type 68 with sterically and electronically diverse substituents on the N-functionality. In Section 3.2.1, the synthesis and characterization of the novel proligands are presented. In Section 3.2.2, the in situ preparation of zirconium complexes from proligands (68a–g) and commercially available Zr(NMe2)4 is discussed.  The complexes display good catalytic activities and moderate  enantioselectivities, consistent with a related system reported by Hultzsch and co-workers during the course of this work.316 In an effort to understand the modest stereoselectivities reported here and previously,312, 316, 317 the synthesis and full characterization of these complexes, including solid-state molecular structures and thermal stability investigations have been carried out; the results are presented in Section 3.2.3.  Importantly, the modified architecture of type 68  proligands is noted to promote alternative coordination geometries, ligand redistribution, and 72  unexpected complex aggregation at catalytically relevant temperatures. The findings of these studies provide valuable guidance in the design of future ligand systems.  3.2 Results and Discussion 3.2.1 Proligand Synthesis and Characterization Proligands 68a–f can be synthesized in a two step procedure from (S)-6,6′dimethylbiphenyl-2,2′-dicarboxylic acid, which in turn is synthesized from commercially available 3-methyl-2-nitrobenzoic acid using a modification of the method reported by Denmark and co-workers (Scheme 3.3).318  These synthetic protocols include palladium-catalyzed  hydrogenation of 3-methyl-2-nitrobenzoic acid to 2-amino-3-methylbenzoic acid followed by copper-mediated homo-coupling of in situ generated diazonium ion to form racemic 6,6′dimethylbiphenyl-2,2′-dicarboxylic acid. The racemic diacid is resolved by diastereomeric salt formation with quinine and subsequent acid cleavage to give (S)-6,6′-dimethylbiphenyl-2,2′dicarboxylic acid.  Scheme 3.3. Synthesis of (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid.  73  The preparation of proligands 68a–f from (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid involves the in situ generation of (S)-6,6′-dimethylbiphenyl-2,2′-dicarbonyl dichloride by treating (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid with excess thionyl chloride under reflux conditions (Scheme 3.4).319  The dichloride is then immediately reacted with the  appropriate primary amine in the presence of an excess of triethylamine (Scheme 3.4) to afford the desired proligand. These proligands are obtained as white solids after purification, by either recrystallization or washing with organic solvents, in modest to good isolated yields of 50–72% (Scheme 3.4), with the exception of 68c, which is isolated in only 25% yield. The chiral bis(amide) proligands are dried by heating at 70 °C under high vacuum for a minimum of 16 h prior to being used for the in situ formation of zirconium complexes. The poor isolated yield of 68c is due to the significant formation (50% yield) of cyclic imide side product 69 (Scheme 3.5). This side product is most likely formed from the mixed amide-chloride 70 by intramolecular nucleophilic attack of the amide nitrogen on the carbonyl (Scheme 3.5). This side product is not observed during the synthesis of proligands (68e and 68f) with the more nucleophilic alkyl groups on the nitrogen suggesting bis-addition of the amine is faster than intramolecular cyclization in these cases. Furthermore, the cyclic imide side product has not been observed in any appreciable quantities during the synthesis of the other N-aryl proligands.  74  Scheme 3.4. Synthesis of biphenyl-tethered proligands.  Scheme 3.5. Proposed route for the formation of cyclic imide side product.  The structure of 69 was confirmed by X-ray crystallographic analysis of a single crystal obtained by recrystallization from a mixture of hexanes and ethyl acetate. The solid-state structure is C2-symmetric (Figure 3.5) in agreement with 1H and  13  C NMR spectroscopic data.  All the bond lengths and angles are as expected and unremarkable.  75  Figure 3.5. Solid-state molecular structure of 69 with ellipsoids plotted at 50% probability. All H-atoms and one ethyl acetate solvent molecule are omitted for clarity.  The modular nature of the bis(amide) proligands allows for the synthesis of proligands with sterically and electronically diverse properties by appropriate choice of amine precursors as demonstrated by the preparation of 68a–f. Proligand 68a incorporates sterically demanding substituents. Furthermore, the substituents on the N and C atoms of the amide moieties in 68a are similar to those on the same atoms of the amidate ligands of the highly efficient hydroamination precatalyst 49 that was discussed in the preceding chapter.130 The substituents on the amide N and C atoms of proligands 68b and 68c were chosen to mimic the highly enantioselective zirconium complex 39. Proligands 68d and 68e are less bulky than 68a, 68b, and 68c and provide a useful comparison for investigating the effect of steric properties on reactivity and selectivity.  Finally, proligand 68f features a sterically demanding N-alkyl  substituent to probe electronic effects on reactivity and selectivity. Axially chiral compounds have been known to undergo thermal racemization at temperatures high enough to effect rotation about the bond between the aryl rings.320 Racemization of the 6,6′-dimethylbiphenyl chiral backbone under these preparative conditions has been ruled out by synthesizing bis(amide) 68g from (S)-biphenyl and (R)-1-  76  methylbenzylamine (Scheme 3.6). If racemization is occurring under the reaction conditions, bis(amide) 68g would be obtained as a mixture of diastereomers. However, the 1H NMR spectrum of crude 68g is consistent with the formation of only one diastereomer, suggesting that thermal racemization of the axially chiral backbone during dichloride synthesis does not occur.319 All the proligands have been fully characterized by spectroscopic methods, elemental analyses, and optical rotation measurements. In addition, the absolute configuration of the biphenyl backbone was confirmed to be (S) by X-ray diffraction studies of 68g (Figure 3.6). The additional stereogenic centers in this compound serve as internal reference for the absolute configuration assignment. This proligand crystallizes in the chiral space group P65 with three independent molecules in the asymmetric unit. The structure refinement includes the use of SQUEEZE program in PLATON321 to exclude electron density associated with a disordered hexanes molecule within the crystal lattice. All bond angles and bond lengths are within the expected range and selected examples are presented in Table 3.1. The extended solid-state structure of 68g reveals the presence of intra- and intermolecular hydrogen-bonding between the carbonyl O and the proton on the N of the amide unit, leading to a helical supramolecular structure (Figure 3.6). The network of helices takes on a tubular shape, with the center being occupied by ethyl acetate solvent molecules.  Scheme 3.6. Synthesis of (S)-proligand 68g.  77  Figure 3.6. ORTEP representation of the solid-state molecular structure of 68g (Top left, ellipsoids plotted at 50% probability). All H-atoms except those attached to N1and N2 and one ethyl acetate solvent molecule have been omitted for clarity. The H atoms shown were not experimentally located. Top right and bottom: extended solid-state structure of 68g along the crystallographic c axis; hydrogen-bonds are in green.  Table 3.1. Selected bond lengths and angles of 68g Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  C1–O1  1.235(3)  O1–C1–N1  122.3(2)  C1–N1  1.339(3)  C1–N1–C18  121.5(2)  C9–O2  1.235(3)  O2–C9–N2  123.7(2)  C9–O2  1.338(3)  C9–N2–C26  123.7(2)  N1–H100  0.87(3)  O2–C9–C10  122.4(2)  78  3.2.2 Hydroamination Catalysis 3.2.2.1 Hydroamination of Primary Aminoalkenes The in situ generation of metal complexes for catalytic hydroamination reactions has already been established as a rapid approach for investigating the catalytic activities of these complexes.62, 63, 67, 70, 73, 97, 141, 322 Therefore, in situ examinations of zirconium complexes formed from the combination of commercially available Zr(NMe2)4 and bis(amide) proligand of the type 68 (eq 3.1) for enantioselective hydroamination reactions have been undertaken. The NMR tube scale reactions with the test substrate 71a (Table 3.2, entries 1–6) are accomplished by combining equimolar quantities of Zr(NMe2)4 and the proligand of choice in d6-benzene in a 1 dram vial before the addition of substrate 71a. The reaction mixture is then transferred to a J. Young NMR tube and heated in an oil bath set at 110 °C. Reaction progress is monitored by 1H NMR spectroscopy and reaction products are isolated upon completion. The results of this catalyst screen are compiled in Table 3.2.  A reaction of aminoalkene 71a with 10 mol% each of proligand 68a and Zr(NMe2)4 gives pyrrolidine 72a within three hours with an enantiomeric excess of only 17% (Table 3.2, entry 1).  79  Proligands 68b–68e (Table 3.2, entries 2–5) do not fare better in this cyclization, with 72a being produced with low enantioselectivities (6–26%) in all cases. The sterically bulky proligand 68f gives 72a with a modest ee of 52%, making 68f the most enantioselective proligand for this substrate (Table 3.2, entry 6). These findings are in contrast to the recently reported analogous systems, where the least sterically demanding proligand bearing the 2,4,6-trimethylphenyl substituent on the N-functionality is the most stereoselective.316 The effect of steric properties on the catalytic efficiency of the in situ generated complexes is pronounced, as a direct comparison of times required for >96% substrate consumption shows that longer reaction times are required when the less sterically demanding proligands 68d and 68e are used (Table 3.2, entries 4 and 5). This observation would be consistent with the formation of a mixture of complexes in situ, including coordination isomers and/or aggregate species that may reduce precatalyst efficiency. Such unwanted mixtures are more likely to form when there is inadequate steric protection about the metal center (vide infra). The absolute configuration of product 72a was determined to be (S) in all cases by comparison of the NMR spectroscopic data for the corresponding Mosher amide with literature data.56  80  Table 3.2. Ligand screening in enantioselective hydroamination of aminoalkenes  Proligand  Time (h)c  Yieldd  % eee  1a  68a  3  92  17  2a  68b  2  91  26  3a  68c  3  94  18  4a  68d  19  89  7  5a  68e  30  91  6  6a  68f  3  92  52  7  b  68a  1.25  92  19  8b  68b  1  90  16  9b  68c  1.25  94  19  10b  68d  24  92  22  11b  68e  24  90  13  b  68f  1  92  28  13  b  68g  1  93  7  14b  68ff  1  92g  27  Entry  12  Substrate  Product  a  Aminoalkene = 0.33 mmol. b Aminoalkene = 0.42 mmol. c Time required to reach >96% conversion. d % Yield of isolated product. e Determined by 1H NMR or 19F NMR spectroscopy after derivatization with (S)-Mosher acid chloride. f 5 mol% loading. g % Conversion estimated by 1H NMR spectroscopy.  An additional comparative investigation of catalyst efficiency (as measured by the times required for >96% substrate consumption) with substrate 71b was undertaken. The results of these screenings using the highly reactive substrate 71b also highlight proligand 68f as the most enantioselective proligand of the series (Table 3.2, entries 7–12), giving 72b with an ee of 28%. Notably, the additional stereogenic center in proligand 68g (which has comparable steric bulk to 68e) has no positive influence on the enantioselectivity of this precatalyst, giving 72b with an ee  81  of only 7% (Table 3.2, entry 13). These preliminary results with both substrates (71a and 71b) show that the in situ prepared catalyst system with proligand 68f, in addition to being the most selective of this class of complexes, also results in short reaction times for complete consumption of starting material. This is further illustrated by using a 5 mol% loading of 68f and Zr(NMe2)4 for the cyclization of 71b with no consequence to the ee and little impact on reaction time (92% conversion within one hour, Table 3.2, entry 14). As a result of these catalytic screens, proligand 68f (5 mol%) was chosen for subsequent investigations of enantioselective hydroamination catalysis.  Similar to most group 4 metal catalyzed aminoalkene hydroamination, the presence of geminal substituents on the aminoalkenes is crucial for the high reactivity of this system, due to Thorpe-Ingold and reactive rotamer effects.1 Aminoalkenes 71c and 71d with gem-dialkyl substituents undergo quantitative cyclization within a few hours to afford 72c (with 67% ee) and 72d (with 57% ee) respectively (Table 3.3, entries 1 & 2). Although the previously reported zirconium precatalyst 39 can only cyclize gem-disubstituted aminoalkenes,98 here the catalyst precursors Zr(NMe2)4 and 68f can be used with substrate 71e bearing only one substituent to give two diastereomers (Table 3.3, entry 3).  Even in the absence of substituents (71f),  cyclohydroamination reaction proceeds, albeit sluggishly (Table 3.3, entry 4).  The  diastereomeric ratio for asymmetrically gem-substituted products (entries 3, 5, and 6) has a modest selectivity for the diastereomer with the bulkier substituent in the equatorial position of the proposed chair-like transition state, as has been previously reported and as illustrated in Scheme 3.7 (also see catalytic cycle, Scheme 3.8).314  Substrate 71h, with Ph and Me as  substituents, gives diastereomeric products in a 1.7:1 ratio with the minor diastereomer 72h′ being formed in 74% ee, the highest value obtained with this catalytic system. The formation of  82  a six-membered ring proceeds more slowly than the corresponding five-membered ring and with lower stereoselectivity (entry 7). This reduced stereoselectivity is also consistent with previous observations and is proposed to be due to a less organized seven-membered transition state (see metallacycle in proposed catalytic cycle, Scheme 3.8)  Table 3.3. Substrate scope investigation in enantioselective hydroamination of primary aminoalkenes catalyzed by in situ generated precatalyst using proligand 68f  Entry  Substratea  Product  Yield  % eej  7b  94c  67  5b  87d  57  Time (h)  1  2  (98c)  3  96f,l  24e  37/5k  72e:72e′ 1.2:1g Table 3.3 continued on page 84  83  Table 3.3. Substrate scope investigation in enantioselective hydroamination of primary aminoalkenes catalyzed by in situ generated precatalyst using proligand 68f (continued from page 83) Entry  Substratea  Product  Time  Yield  % eej  (h)  4  120f  27h  n.d.  5  3b  68i  73/66  72g:72g′ 1.5:1g  6  3b  92i  45/74  72h:72h′ 1.7:1g 7  48b  98c  23  a  Aminoalkene = 0.42 mmol. b Time required to reach >96% conversion. c NMR Yield using 1,3,5-trimethoxybenzene as internal standard. d % Isolated yield. e % Combined isolated yield after derivatization with benzoyl chloride. f Reaction temperature is 145 °C. g Determined by 1H NMR in comparison with literature assignments.98 h % Conversion estimated by 1H NMR spectroscopy. i Combined isolated yield. j Determined by 1H NMR or 19F NMR spectroscopy after derivatization with (S)-Mosher acid chloride. k Determined by HPLC analyses of the benzamides. l % conversion is 75% as estimated by 1H NMR spectroscopy. n.d. = not determined.  84  Scheme 3.7. Rationalization of diastereoselectivity in the hydroamination of aminoalkenes catalyzed by in situ generated precatalyst using proligand 68f.  3.2.2.2 Secondary Aminoalkenes as Substrates The vast majority of reported group 4 hydroamination catalysts operate exclusively with primary aminoalkene substrates.1 In contrast, only a few examples of group 4 metal-catalyzed hydroamination of secondary aminoalkenes have been described.96,  114-116, 155  The lack of  reactivity with secondary aminoalkenes generally observed with group 4 metal-based systems is consistent with the widely proposed [2+2] cycloaddition mechanism (Scheme 3.8) for the hydroamination reaction involving this class of catalysts. Specifically, the proposed catalytically active imido species 73 (Scheme 3.8) would be inaccessible with secondary aminoalkenes. As such, subjection of secondary aminoalkenes to the optimized catalytic conditions has been used as a mechanistic probe.  85  Scheme 3.8. Cycloaddition mechanism for group 4 metal-catalyzed hydroamination reaction.  Secondary aminoalkenes 74 and 75 have been subjected to the catalytic hydroamination reaction in the presence of the catalyst precursors Zr(NMe2)4 and 68f (Scheme 3.9). Aminoalkene 74 bearing the sterically-congested cyclohexyl substituent on the N-atom did not undergo cyclization with 10 mol% each of Zr(NMe2)4 and 68f despite prolonged reaction times and elevated reaction temperature.  However, secondary aminoalkene 75 with a methyl  substituent on the N-atom is effectively cyclized at 145 °C (90 h). Our group recently disclosed an achiral zirconium ureate precatalyst that effectively cyclizes a wide range of primary and secondary aminoalkenes with equal efficiency.117  Detailed mechanistic studies and  stoichiometric reactions with this ureate-based precatalyst suggest a proton-assisted σ-bond insertion mechanism similar to that commonly invoked for the lanthanides and recently proposed for magnesium and zirconium catalysts (Scheme 3.10).89, 323, 324 However, based on the different  86  reaction conditions (temperature and time) and catalyst efficiency noted between cyclization of substrate 75 and the corresponding primary aminoalkene 71b, a substrate dependent mechanism might be operative here. The cyclohydroamination of primary aminoalkenes presented in Tables 1 and 2 may proceed via the cycloaddition mechanism (Scheme 3.8) while cyclization of the less sterically-congested secondary aminoalkene 75 may occur via an insertion-based mechanism (Scheme 3.10). Furthermore, the poor enantioselectivity observed in the hydroamination of 75 suggests this reaction may be catalyzed by Zr(NMe2)4 which could form via ligand redistribution processes at the elevated temperature require for this cyclization (vide infra).  Scheme 3.9. Hydroamination reaction with secondary aminoalkenes.  87  Scheme 3.10. Simplified σ-bond insertion mechanism for the hydroamination of secondary aminoalkenes.89  While the reactivity of these in situ prepared zirconium compounds are comparable to other reported chiral tethered bis(amidate) complexes,98, 312 the enantiomeric excesses generated with these complexes are significantly less than the high values obtained with our previously reported precatalyst 39.98 To better understand how steric bulk about the metal center affects reactivity and stereoselectivity, the isolation, solid-state and solution-phase structures, and thermal stabilities of the complexes derived from proligands 68a–g have been investigated. Most importantly, the full characterization of the most enantioselective precatalyst of this system, including the solid-state molecular structure, provides information about the coordination environment and potential substrate binding sites at the metal center that result in modest enantioselectivities. This detailed understanding of metal-ligand complexation provides valuable insight for the design of advanced catalytic systems.  88  3.2.3 Synthesis and Characterization of Zirconium Bis(amidate) Complexes 3.2.3.1 Sterically-Congested Zirconium Bis(amidate) Complexes The Schafer group have established protonolysis as a facile route to amidate complexes of early transition metals.98, 103, 117, 130, 135, 137-140, 143, 144, 325 Here, protonolysis reactions have also been utilized in the synthesis of zirconium complexes from equimolar quantities of commercially available Zr(NMe2)4 and proligands of the type 68 in benzene. A preparative scale reaction between Zr(NMe2)4 and racemic 68a produces the dimethylamine adduct (±)-76a·HNMe2 in 96% crude isolated yield after removal of volatiles in vacuo (eq 3.2). The 1H and  13  C NMR  spectra display only the signals associated with the complex; therefore, further purification was not performed. The resonance of the methyl protons of the neutral amine donor appear at δ 1.35, which is shifted 0.53 ppm upfield from the signal for the free dimethylamine. The protons of the isopropyl methyl groups are inequivalent and appear as four doublets at δ 0.89, 1.15, 1.29, and 1.41. The corresponding methine protons for these fragments are noted as two multiplets centered at δ 2.55 and 3.43. The resonances for the methyl protons of the biphenyl linkage and those of the amido ligands are singlets at δ 2.21 and 2.27, which integrate for 6 and 12 protons respectively. These spectral data suggest a C2-symmetric complex with hindered rotation about the N–Caryl bond. Furthermore, the presence of a signal at δ 161.1 in the  13  C NMR spectrum,  consistent with localized C=N bond character,130, 312 suggests an alkoxy-imine bonding mode for this complex in the solution phase (eq 3.2).  89  Single crystals of the racemic complex were obtained from a benzene/hexanes solution at –35 °C. The solid-state molecular structure shows the presence of a neutral dimethylamine donor ligand, consistent with the aforementioned spectroscopic evidence (Figure 3.7). The geometry about the zirconium center is best described as distorted trigonal bipyramidal with one of the O-donor atoms and the neutral amine occupying axial positions. While this binding motif has been previously proposed for bis(amidate) complexes of group 4 metals,312, 316 this is the first solid-state structural evidence of a bis(amidate) group 4 metal with a κ2-O,O-bonding motif. Selected bond lengths and angles of (±)-76a·HNMe2 are given in Table 3.4. The average Zr–O bond length in complex (±)-76a·HNMe2 (2.029 Å, Table 3.4) is much shorter than the typical Zr–O bond distance in N,O-chelating amidate complexes (2.112–2.252 Å).121, 138, 330 While the solid-state molecular structure is C1-symmetric, however, if one considers the neutral amine donor to be labile on the NMR time-scale, this binding motif is consistent with the C2-symmetric structure observed in the solution phase. The κ2-O,O-bonding mode is probably a consequence of the release of the ring strain, that may occur in a putative κ4-N,O,O,N-chelate. Unfortunately,  90  the observed κ2-O,O-bonding arrangement places the chiral biphenyl framework at a significant distance from the reactive metal center and the alkoxy-imine bonding motif of the amidate group ensures that the bulky N-substituent is also far removed from the metal center.  Figure 3.7. ORTEP representation of the solid-state molecular structure of (±)-76a·HNMe2 (ellipsoids plotted at 50% probability). All H-atoms except that attached to N5 are omitted for clarity; the H atom shown was calculated from the coordinates of N5.  Table 3.4. Selected bond lengths and angles of (±)-76a·HNMe2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Zr–O1  2.026(4)  N5–Zr–O1  171.1(2)  Zr–O2  2.033(4)  N4–Zr–O1  98.0(2)  Zr–N3  2.034(5)  O1–Zr–O2  92.2(2)  Zr–N5  2.404(5)  N3–Zr–O2  122.8(2)  C1–N1  1.265(7)  N4–Zr–N3  113.0(2)  N5–H100  0.963(19)  C6–C8–C11–C10  84.6(7)  As mentioned previously, racemization of axially chiral ligands upon metal complex formation has been reported in the literature.326 In contrast, there is no racemization of this chiral  91  ligand upon metal complex formation, as deliberate decomposition of the precatalyst followed by re-isolation and characterization of proligand results in identical values for specific rotations. This complex has a sterically-accessible five-coordinate zirconium metal center, in contrast to the highly enantioselective system 39, which is isolated as a seven-coordinate zirconium complex.98 This suggests that increased accessibility to the reactive metal center results in improved substrate scope, but that this steric accessibility also limits the enantioselectivity that can be obtained.130, 316 Reacting a 1:1 molar ratio of Zr(NMe2)4 and racemic proligand 68f in benzene similarly produces the dimethylamine adduct (±)-76f·HNMe2 which can be recrystallized from a mixture of hexanes and toluene in 42% yield. The diagnostic 13C NMR spectroscopic signal for C=N in this complex is observed at δ 158.6. The solid-state molecular structure of (±)-76f·HNMe2 is isostructural with (±)-76a·HNMe2 and is depicted in Figure 3.8; selected bond lengths and angles are given in Table 3.5. While the most sterically-encumbered complexes (76a·HNMe2 and 76f·HNMe2) could be fully characterized in both the solution phase and solid-state, the reliable formation of a single species in solution, as observed by NMR spectroscopy, is limited to sterically demanding proligands (68a and 68f). More complex spectra, due to the formation of multiple species and/or ligand fluxionality, are observed for the more sterically-accessible systems (68b–e).  92  Figure 3.8. ORTEP representation of the solid-state molecular structure of (±)-76f·HNMe2 (ellipsoids plotted at 50% probability). All H-atoms except that attached to N5 and one toluene solvent molecule are omitted for clarity; the H atom shown was calculated from the coordinates of N5.  Table 3.5. Selected bond lengths and angles of (±)-76f·HNMe2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Zr–O1  2.044(1)  N5–Zr–O2  174.51(6)  Zr–O2  2.004(1)  N3–Zr–O1  123.77(6)  Zr–N3  2.039(2)  O1–Zr–N4  116.19(6)  Zr–N5  2.428(2)  O2–Zr–N3  98.72(6)  C1–N1  1.262(2)  N3–Zr–N5  85.42(6)  N5–H100  0.87(2)  C6–C8–C9–C10  84.9(2)  Based on the κ2-O,O-bonding motif of amidate ligand in complex (±)-76f·HNMe2 and according to the [2+2] cycloaddition mechanism (see Scheme 3.8), the transition states depicted in Scheme 3.11 are postulated to rationalize the absolute configurations of the hydroamination products.  Furthermore, the neutral donor ligand, dimethylamine, of the precatalyst is also  postulated to be liberated prior to this step (presumably during the first step) in the catalytic cycle  93  as spectroscopic data suggest lability of this donor molecule in solution. In these illustrations of Scheme 3.11, the fragment stemming from the nitrogen atom of the imido unit can orient itself in two possible chair-like transition states. The unfavourable orientation features some steric interaction between the geminal substituents on the substrate and the adamantyl group on the amidate-N and leads to the formation of the R-enantiomer (Scheme 3.11). The other orientation would lead to the preferred S-enantiomer. The minimal steric interaction that differentiates the two proposed intermediates is consistent with the modest stereoselectivity realized with this system.  Scheme 3.11. Rationalization of enantioselectivity in zirconium-catalyzed hydroamination of aminoalkenes.  94  3.2.3.2 Dimerization of Sterically-Accessible Zirconium Complexes The use of ligands with reduced steric congestion results in different solution-phase behaviour than that observed for the complexes prepared using proligand 68a or 68f. For example, an NMR tube scale reaction of the less sterically demanding proligand (±)-68b and Zr(NMe2)4 was carried out to give complex (±)-76b: initially, the 1H NMR spectrum displays signals associated with (±)-76b and free dimethylamine, and the 13C NMR spectrum contains a diagnostic signal for C=N at δ 161.9. A signal associated with bound dimethylamine was not observed; however, this could be due to exchange on the NMR time scale with the free dimethylamine liberated during the protonolysis reaction.  Based upon this solution-phase  characterization data, the initial experimental evidence suggests the major product is a complex analogous to that observed for (±)-76a·HNMe2 and (±)-76f·HNMe2. However, after as little as three hours in solutions at room temperature, new signals are observable in the 1H and 13C NMR spectra, including singlets at δ 1.90, 2.08, and 2.56 in the 1H NMR spectrum and a new signal at δ 179.2 in the 13C NMR spectrum, all of which are consistent with the formation of dimer [76b]2 (vide infra).  Indeed, recrystallization from a mixture of benzene and hexanes at ambient  temperature afforded only the D2-symmetric homochiral dimer [76b]2 in 44% isolated yield (eq 3.3). Furthermore, the quantitative formation of [76b]2 can be achieved by exposing the crude product obtained from the combination of Zr(NMe2)4 and (±)-68b to high vacuum for 24 hours. The solid-state molecular structure of [76b]2 reveals that the biphenyl tether bridges between two metal centers using one amidate to form an N,O-chelate with one metal center and the other amidate to form another N,O-chelate with the second metal (Figure 3.9). This results in a distorted octahedral geometry about each zirconium metal. Selected bond lengths and angles of [76b]2 are presented in Table 3.6. This complex is one of only a few examples of group 4  95  amidate dimers reported in the literature.312, 327 In addition to being an interesting example of the spontaneous and diastereoselective formation of a chiral, metallacyclic coordination complex, most importantly, this is a well characterized example of a rarely discussed aggregate complex that can form when using amidates as ligands. The 1H NMR spectrum of [76b]2 is also highly symmetric, consistent with the solid-state molecular structure. The spectrum shows the formation of only one diastereomer of [76b]2 and no meso-compound is observed. This has been verified by using enantiopure proligand for the synthesis of [76b]2, which leads to identical product as confirmed by NMR spectroscopy. Furthermore, this dimer is persistent in solution, as there is no signal for an imine carbon in the 13  C NMR spectrum of [76b]2; instead, a single carbonyl resonance is observed at δ 179.2. This  chemical shift is in good agreement with previous complexes that exhibit delocalized electron density throughout the amidate backbone while adopting an N,O-chelating bonding mode.98 While a variety of other axially chiral tethered bis(amidate) complexes have been reported for asymmetric hydroamination with modest to good enantioselectivities, there have been widely ranging ee‟s that do not vary predictably with substrate and/or catalyst structure.316  This  characterized dimeric complex illustrates a significant challenge when using amidate ligands in catalysis; optimized ligand design needs to promote the formation of robust complexes that do not readily undergo isomerization and or aggregation.  96  Figure 3.9. ORTEP representation of the solid-state molecular structure of [76b]2 (ellipsoids plotted at 50% probability). All hydrogen atoms, substituents on amidate nitrogens, and six benzene solvent molecules are omitted for clarity.  97  Table 3.6. Selected bond lengths and angles of [76b]2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Zr1–O1  2.221(2)  N6–Zr1–O2  150.94(7)  Zr1–O2  2.218(2)  N6–Zr1–N2  92.76(8)  Zr2–O3  2.227(2)  O1–Zr1–O2  88.67(6)  Zr2–O4  2.234(2)  N8–Zr2–N4  93.17(8)  Zr1–N1  2.263(2)  O3–Zr2–O4  86.42(6)  Zr1–N6  2.048(2)  N7–Zr2–O3  154.86(7)  Zr2–N3  2.263(2)  C14–C16–C8–C6  92.0(3)  Zr2–N8  2.051(2)  C30–C32–C24–C22  88.6(3)  Complex [76b]2 itself has been tested as a precatalyst for the cyclization of aminoalkene 71b to pyrrolidine 72b and its efficiency compared to a freshly prepared sample of 76b·HNMe2 (eq 3.4). In side-by-side reactions under identical experimental conditions, precatalyst [76b]2 requires twice the amount of time as freshly prepared 76b·HNMe2 (two hours vs. one hour) to reach 98% conversion. Notably, the enantiomeric excess of 25% obtained using [76b]2 is identical (within experimental error) to the value obtained with the in situ generated 76b·HNMe2 (Table 3.2, entry 2). Based on these results, it is possible that [76b]2 is a slower but still active catalyst, or perhaps more likely, based upon the observation of identical ee‟s with both precatalysts, a smaller amount of the catalytically active species is generated when using [76b]2 as a precatalyst.  98  To examine the stability of [76b]2 at catalytically relevant temperature, a solution of [76b]2 in d6-benzene was heated to 110 °C and after one hour at this temperature, 11% of the monomer is formed as estimated by the 1H NMR spectroscopy. The monomer to dimer ratio is not altered with extended time (up to 24 hours) at 110 °C. However, complete reconversion of the monomer to the dimer is observed upon cooling to ambient temperature in solution. To further examine the stability of complex [76b]2, a solution of [76b]2 and excess pyridine in benzene was stirred at ambient temperature for sixteen hours and complete conversion of the dimer to monomer 76b·(py)2 is observed (eq 3.5). The 1H NMR spectrum of 76b·(py)2 shows only the signals associated with this compound, hence further purification was not performed. The signals in the aromatic region of the 1H NMR spectrum integrate for the equivalent of two molecules of pyridine being coordinated to the metal center. The pyridine signals in the 1H NMR spectrum of 76b·(py)2 includes two broad singlets at δ 7.42 and 8.04 suggesting that two inequivalent neutral donor molecules are undergoing rapid exchange in solution. This spectrum indicates a C2-symmetric structure with rapidly exchanging pyridine molecules. The diagnostic signal for the alkoxy-imine C=N bond in the  13  C NMR spectrum is  present at δ 162.5. The formation of the monomer at the elevated temperature and in the presence of strong donor ligand further supports the notion of a catalytically active monomeric species. Even with the strongly coordinating pyridine donor ligands, complex 76b·(py)2 does not persist in solution as formation of the parent dimer with concomitant elimination of pyridine was observed after 48 hours in solution by 1H NMR spectroscopy. However, 76b·(py)2 is slightly more stable in solution than 76b·HNMe2 which starts to dimerize only after three hours in solution.  99  Reaction of a 1:1 molar ratio of racemic proligand 68c and Zr(NMe2)4 also immediately produces (±)-76c·HNMe2.  Exposure of this reaction mixture to high vacuum led to the  formation of dimer [76c]2, however, there is no evidence for the quantitative formation of [76c]2 even after extended time (24 hours) under high vacuum.  Instead, the 1H NMR spectrum  indicates solution phase equilibria occur. Single crystals of [76c]2 were obtained from a mixture of both (±)-76c·HNMe2 and [76c]2 in toluene/hexanes at –35 °C. The solid-state molecular structure of complex [76c]2 is isostructural with [76b]2 with the biphenyl tethers bridging the two metal centers (Figure 3.10). Furthermore, the bond lengths and angles of [76c]2 are similar to those of [76b]2 and selected examples for [76c]2 are presented in Table 3.7.  100  Figure 3.10. ORTEP representation of the solid-state molecular structure of [76c]2 (ellipsoids plotted at 50% probability). All hydrogen atoms, substituents on amidate nitrogens, two toluene and one hexanes solvent molecules are omitted for clarity.  Table 3.7. Selected bond lengths and angles of complex [76c]2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Zr1–O1  2.225(1)  N8–Zr1–O2  151.26(8)  Zr1–O2  2.249(2)  N7–Zr1–N2  104.37(9)  Zr2–O3  2.242(1)  O1–Zr1–O2  86.17(6)  Zr2–O4  2.245(1)  N6–Zr2–O3  153.79(8)  Zr1–N1  2.275(2)  N6–Zr2–N4  106.24(8)  Zr2–N3  2.261(2)  O3–Zr2–O4  86.42(6)  Zr2–N6  2.058(2)  C26–C25–C24–C18  85.6(3)  Zr1–N8  2.064(2)  C2–C8–C9–C10  90.0(3)  Reacting the more sterically-accessible proligand (±)-68e with Zr(NMe2)4 results in the formation of complex aggregate species. The initial 1H NMR spectrum (taken within twenty minutes of the reaction start time) of the reaction mixture containing equimolar quantities of  101  Zr(NMe2)4 and (±)-68e indicates the formation of C1-symmetric complex (±)-76e·(HNMe2)2 (Scheme 3.12). The methyl protons of the isopropyl fragments appear as overlapping doublets at δ 1.07 and 1.46. The corresponding methine protons for these fragments are noted as two multiplets centered at δ 4.30 and 4.42.  The methyl protons for the biphenyl moiety are  inequivalent and resonate at δ 2.25 and 2.39. The  13  C NMR spectrum shows two signals at δ  158.3 and 160.3 and no other signals downfield of this region confirming the inequivalence of each half of the biphenyl ligand and indicating the amidates are O-bound to the metal center. The lack of symmetry about the metal center in this complex is postulated to be due to the coordination of two molecules of neutral dimethylamine that are cis-oriented and do not exchange in solution. A closer inspection of the 1H NMR spectrum of (±)-76e·(HNMe2)2 reveals a series of low intensity doublets, indicating the presence of aggregate species. The intensities of these signals increase with time while those representing the C1-symmetric complex decrease. After four days at ambient temperature in solution, the 1H NMR spectrum becomes complicated; thus, the signals cannot be reliably assigned. Exposure of the reaction mixture to high vacuum in an attempt to remove the solvent also hastens the converison of (±)76e·(HNMe2)2 to the aggregate species.  Scheme 3.12. Dimerization of sterically-accessible zirconium complex.  102  Single crystals suitable for X-ray analysis were obtained from this mixture at –35 °C. The solid-state structure reveals a dimeric complex with one dimethylamido and two biphenyl ligands bridging two zirconium metal centers (Figure 3.11 and Scheme 3.12). One of the zirconium metal centers is seven-coordinate with one amidate ligand from both biphenyl units N,O-chelating to this metal center. The other zirconium is six-coordinate with both amidates from each biphenyl units O-bound to this metal center. The average Zr–O bond length (2.113 Å) in the six-coordinate metal center is significantly shorter than the average (2.354 Å) in the sevencoordinate zirconium center (Table 3.8). Based on the 1H NMR spectrum, it is most likely that dimer 77 is only one of many dimeric/aggregate species that are present in solution. This is consistent with the long reaction times that were observed in the hydroamination reactions catalyzed by the zirconium complex generated in situ from proligand 68e and Zr(NMe2)4 (see Table 3.2).  Figure 3.11. ORTEP representation of the solid-state molecular structure of 77 (ellipsoids plotted at 50% probability). All hydrogen atoms and substituents on amidate nitrogens are omitted for clarity.  103  Table 3.8. Selected bond lengths and angles of complex 77 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Zr1–O1  2.258(1)  N6–Zr1–O3  110.75(6)  Zr1–O2  1.998(1)  N5–Zr1–N6  91.61(6)  Zr1–O3  2.186(1)  O2–Zr1–O3  154.24(5)  Zr1–O4  2.010(1)  N5–Zr1–O4  153.76(5)  Zr1–N5  2.314(2)  N6–Zr1–O1  164.89(6)  Zr1–N6  2.045(1)  N6–Zr1–O4  95.22(6)  Zr2–O3  2.342(1)  N3–Zr2–N1  174.91(5)  Zr2–O1  2.395(1)  N3–Zr2–N7  88.17(6)  Zr2–N1  2.360(1)  N7–Zr2–N8  106.60(7)  Zr2–N3  2.441(1)  O3–Zr2–N7  91.33(6)  Zr2–N5  2.363(2)  O3–Zr2–N1  120.76(5)  Zr2–N7  2.041(2)  N5–Zr2–N8  99.71(6)  3.2.3.3 Sterically-Congested Zirconium Complexes with Pyridine as Neutral Donor To further corroborate the lability of the neutral dimethylamine ligand in 76a·HNMe2 and 76f·HNMe2 in solution, the preparation of the zirconium complexes was carried out in the presence of excess pyridine. The greater donor ability of pyridine could result in stronger bonding and multiple pyridines coordinating to the zirconium center, thereby creating a more congested environment about the metal center.  This could lead to highly enantioselective  precatalysts if the coordinating pyridines are not labile in solution or in the presence of the aminoalkene substrate. The reaction of Zr(NMe2)4 and racemic 68a in the presence of twenty equivalents of pyridine produces (±)-76a·(py)2 in 95% isolated yield following the removal of the volatiles in vacuo (eq 3.6). The solution phase NMR spectroscopic data is consistent with a C2-symmetric (±)-76a·(py)2 in which the amidate ligand is coordinated to the metal with the O-donor atoms in  104  an alkoxy-imine type structure. The diagnostic signal in the  13  C NMR spectrum for the C=N  bond of this coordination mode appears at δ 161.7. The pyridine signals in the 1H NMR spectrum includes broad singlets at δ 7.42 and 7.89 which integrate for the equivalent of two molecules of pyridine.  Unfortunately, the broad nature of these signals suggests a rapid  exchange between these two pyridine ligands in solution In the solid state, (±)-76a·(py)2 is C1-symmetric and features a pseudo-octahedral geometry about the metal center (Figure 3.12). The pyridine ligands are in a cis orientation about the metal center, with one of the pyridines being trans to an amidate O-donor atom while the other is trans to an amido ligand. This arrangement results in Zr–N6 bond length (2.513 Å) being significantly longer than the Zr–N5 bond length (2.388 Å, Table 3.9) which reflects the strong trans influence of the amido ligand.  105  Figure 3.12. ORTEP representation of the solid-state molecular structure of (±)-76a·(py)2 (ellipsoids plotted at 50% probability). All hydrogen atoms and two benzene solvent molecules are omitted for clarity.  Table 3.9. Selected bond lengths and angles of (±)-76a·(py)2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Zr–O1  2.048(2)  O2–Zr–N3  164.17(9)  Zr–O2  2.085(2)  O1–Zr–N5  163.29(8)  Zr–N4  2.048(2)  N4–Zr–N6  172.20(8)  Zr–N5  2.388(2)  O2–Zr–N4  92.47(8)  Zr–N6  2.513(2)  C6–C7–C15–C10  80.6(3)  Reaction of a 1:1 molar ratio of Zr(NMe2)4 and racemic proligand 68f in the presence of excess pyridine similarly produces the pyridine adduct (±)-76f·(py)2 in 94% isolated yield following the removal of the volatiles in vacuo (eq 3.6). Although the 1H NMR spectrum contains only the signals associated with 76f·(py)2, recrystallization from benzene/hexanes results in microcrystalline material that is not suitable for X-ray analysis. However, the NMR  106  spectroscopic data suggest the solution phase coordination geometry for this complex is analogous to that observed for 76a·(py)2 in solution. Complexes 76a·(py)2 and 76f·(py)2 have been employed as precatalysts in the hydroamination of aminoalkene 71b in separate reactions. Both complexes are highly active precatalysts and effectively furnish pyrrolidine 72b within one hour at 110 °C (eq 3.7) with just 5 mol% loading. Using 76a·(py)2 as a precatalyst, the product was generated with an ee of 33%, a slight increase over the value (17%) obtained with the in situ prepared parent compound (see Table 3.2). On the other hand, complex 76f·(py)2 produces the product with an ee of 22% which is slightly lower than the value of 27% obtained with the in situ generated complex presented in Table 3.2. These data suggest that the pyridine ligands do not offer any significant advantage over the in situ generated complexes, consistent with the observation that the pyridine molecules are labile in solution.  3.2.3.4 Stability of Sterically-Congested Zirconium Precatalysts The facile formation and characterization of dimer [76b]2 prompted the investigation of similar dimerizations in the more sterically demanding complexes 76a·HNMe2 and 76f·HNMe2. Prolonged exposure of 76a·HNMe2 to high vacuum (24 hours) in an attempt to remove the neutral dimethylamine and hasten dimerization produces a small amount of the corresponding dimer (approximately 5% conversion, as estimated by 1H NMR spectroscopy). Further efforts to  107  effect dimerization by subjecting a solution of 76a·HNMe2 (NMR tube scale reaction) in d6benzene to an elevated temperature of 110 °C for five hours did not result in any observable dimer formation. On the other hand, after three days at ambient temperature a solution of 76f·HNMe2 shows the presence of new signals consistent with dimer formation.  Most  importantly, these signals are observed within one hour at 110 °C. Unfortunately, isolation and complete characterization of this particular dimer was not possible as solution phase equilibria persist. However, to probe the effect of potential thermal catalyst deactivation, two concurrent catalytic reactions have been carried out using consistent concentrations of aminoalkene 71a ([0.84 M]) and precatalyst 76f·HNMe2 ([0.042 M]) (eq 3.8).  In one of the reactions, the  precatalyst solution was heated to 110 °C for one hour prior to the addition of 71a, while the other had substrate added immediately upon precatalyst preparation.  While preheating the  solution to 110 °C before substrate addition does not affect the enantioselectivity, a decrease in catalytic activity is observed; the preheated reaction mixture is at 68% conversion after three hours at 110 °C versus quantitative conversion for the mixture without preheating. This behaviour mirrors that of complexes 76b·HNMe2 and [76b]2 (see eq 3.4); strongly suggesting that dimerization is a thermal decomposition pathway of concern, even in the cases with the more sterically-encumbered ligand sets.  108  3.2.4 Investigation of Non-Linear Effects The observation of dimer formation at elevated temperature prompted the investigation of the statistical relationship between the enantiopurity of precatalyst 76f·HNMe2 and the enantiomeric excess of product 72d (Table 3.10).  The enantiomeric excess of precatalyst  76f·HNMe2 was varied from 0–100% using freshly prepared solutions containing different ratios of enantiopure and racemic 76f·HNMe2. The resulting mixtures were then employed in the cyclohydroamination of substrate 71d in concurrent reactions. The result indicates there is no significant nonlinear effect in this system (Figure 3.13).  Table 3.10. Cyclohydroamination of 71d using varying enantiopurity of precatalyst 76f·HNMe2  Entry  Mol% (S)precatalyst  Mol% racprecatalyst  Ratio % ee S:rac 76f·HNMe2 precatalyst 1:0 100  % ee of product  % ee expecteda  1  5  0  57  57  2  2.5  2.5  1:1  50  24  28  3  1.67  3.33  1:2  33  11  19  4  1.25  3.75  1:3  25  11  14  5  0  5  0:1  0  0  0  a  Calculated using the formula: % eeexpected = eemax × eeprecatalyst × 100, where eemax is the maximum ee of product obtained with enantiopure precatalyst.328, 329  109  % ee of product vs % ee of precatalyst 60  % ee product  50  40 observed  30  calculated 20  10  0 0  20  40  60  80  100  120  % ee precatalyst  Figure 3.13. Enantiomeric excess of pyrrolidine 72d as a function of enantiomeric excess of precatalyst 76f·HNMe2.  3.3 Conclusions To summarize, seven new amidate-based zirconium complexes have been investigated for the enantioselective hydroamination of alkenes.  While these catalyst systems display  enhanced aminoalkene substrate scope over our earlier reported enantioselective group 4 catalysts,98 the activity and stereoselectivity of this system is observed to be very substrate dependent. These observations can be attributed to the multiple coordination modes accessible in solution, including the observed and characterized monomeric O-bound amidate bonding mode.  Unfortunately, the O-bonding mode of the amidate ligand seems to facilitate the  formation of dimers. While ligand redistribution in amidate complexes has been previously observed,121,  330  clear examples of aggregation in these systems are rare.312,  327  The  110  characterization data presented herein serves to provide diagnostic signals indicative of dimerization, a potential catalyst deactivation pathway. The multiple accessible ligand bonding modes and/or ligand redistribution/aggregation pathways are surely contributing factors in recently reported examples in which the absolute stereoselectivity of the catalyst system varies even with relatively small changes in catalyst structure and/or substrate.121, 316 Thus, idealized catalytic systems should be resistant to such isomerization/dimerization pathways. Interestingly, dimerization proceeds diastereoselectively to give homochiral dimers in the solution-phase, and the formation of these D2-symmetric metallacycles has been verified by Xray crystallography.  As expected, as the steric bulk of the proligand is enhanced, dimer  formation is inhibited. This is critical for improved efficiency of the catalyst system, as the elevated temperatures used to promote catalysis also promote deactivation of the catalytic system via dimer formation. This results in a hypothesis for improved ligand design in amidate catalyst systems: increased steric bulk results in improved reactivity. This work also demonstrates the importance of designing ligands which favour a tetradentate bonding mode to inhibit unwanted catalyst deactivation routes and improve reactivity and selectivity.  3.4 Experimental Procedures 3.4.1 Methods and Materials General manipulations and techniques are as outlined in Chapter 2, Section 2.4.1 and also include the following additions. HPLC analyses were run on an Agilent series 1100 with a UV/VIS detector (λ = 215 nm) using a CHIRALPAK AS-H column (250 x 4.6 mm). Optical rotations were measured on a Jasco P-1010 digital polarimeter at 589 nm. Single crystal X-ray diffraction measurements were performed on a Bruker X8 APEX diffractometer using a Mo Kα  111  radiation source (λ = 0.71073 Å) at 173 K at the Department of Chemistry, University of British Columbia.  Chloroform was distilled over K2CO3; benzene was purified over columns of  alumina.  Zr(NMe2)4 was purchased from Strem and used as received.  allylcyclohexyl)methylamine 71a,331 2,2-diphenyl-4-pentenylamine 71b,332  C-(1-  2,2-dimethyl-4-  pentenylamine 71c,331, 333 C-(1-allylcyclopentyl)methylamine 71d,67 2-phenyl-4-pentenylamine 71e,334 4-pentenylamine 71f,247 2-allyl-2-methyl-4-pentenylamine 71g,335 2-methyl-2-phenyl-4pentenylamine 71h,334 and 2,2-dimethyl-5-hexenylamine 71i,247 were prepared as described in the literature.  The spectral data for heterocyclic hydroamination products: 3-methyl-2-  azaspiro[4.5]decane 72a,335 2-methyl-4,4-diphenylpyrrolidine 72b,332 2,4,4-trimethylpyrrolidine 72c,247 3-methyl-2-azaspiro[4.4]nonane 72d,67 N-benzoyl-2-methyl-4-phenylpyrrolidine,314 4allyl-2,4-dimethylpyrrolidine 72g and 72g′,335 and 2,5,5-trimethylpiperidine 72i,222 are consistent with literature data.  All other commercially available reagents and solvents were used as  received.  3.4.2 Synthetic Procedures Synthesis of 2-amino-3-methylbenzoic acid A 2 L Schlenk flask equipped with a stir bar was charged with 15.0 g (82.8 mmol) of 3-methyl2-nitrobenzoic acid, 0.878 g of 10% wt Pd/C (0.828 mmol of Pd), and 500 mL of ethanol. The mixture was vigorously stirred and a continuous flow of H2 gas was passed in for 15 minutes after which the system was closed. The H2 gas in the reaction mixture was replenished every hour with a continuous flow for 5 minutes until the reaction was complete (48 h) as indicated by TLC analysis. The mixture was filtered through Celite and the residue was washed with 200 mL of ethanol. The filtrate was  112  concentrated by rotary evaporation and recrystallization of the solid from ethyl acetate affords 2amino-3-methylbenzoic acid in 91% yield.  Synthesis of (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid 318 A 500 mL round bottom flask containing 6.00 g (39.7 mmol) of 2amino-3-methylbenzoic acid in 20.6 mL (51.6 mmol) of 10% NaOH was cooled to 0 °C.  The mixture was stirred at 0 °C for 10 minutes,  following which 5.48 g (79.4 mmol) of NaNO2 and 15 mL of H2O were added. After additional stirring for 20 minutes, 83 mL of ice cold 4 M HCl was slowly added. The resulting mixture was further stirred at 0 °C for 30 min. In a separate 1-L 3-necked round bottom flask, a solution 16.8 g of CuSO4·5H2O in 53 mL of H2O was cooled to 0 °C. After 10 minutes at 0 °C, 34 mL of 30% NH4OH was added and the resulting deep blue solution was stirred for additional 30 minutes. A solution of NH2OH, freshly prepared by adding 27 mL of 3 M NaOH to 6.19 g (37.7 mmol) of (NH2OH)2·H2SO4 was added (note: evolution of H2 gas) and the resulting pale blue mixture (the solution may be protected from the atmosphere with a nitrogen balloon at this stage) was further stirred for 30 min at 0 °C. The diazonium salt solution prepared above was transferred into an addition funnel (in two portions to maintain the temperature of the mixture below 8 °C) and added to the copper solution at the rate of about 10 mL per minute. The mixture was refluxed at 130 °C for 30 minutes and then cooled to room temperature. Concentrated HCl (27 mL) was slowly added and the reaction mixture was stirred for 16 h at room temperature. The precipitate was filtered and washed twice with 25 mL of H2O. The solid was dried by azeotropic removal of water with toluene (3 × 30 mL) by rotary evaporation. The crude solid was taken up in 150 mL of chloroform and the  113  precipitate collected by suction filtration. The last step was repeated twice, following which the filtrate (about 450 mL) was concentrated to give a yellow solid. The yellow solid was further washed with 15 mL of chloroform and suction filtered to afford a pale yellow precipitate of (rac)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid in 67% yield (3.58 g, 13.2 mmol, 90% pure). A mixture of 2.90 g (10.7 mmol) of (rac)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid and 3.87 g (10.7 mmol) of quinine (90% pure) in a 100 mL round bottom flask was dissolved in the minimum amount of boiling 90% ethanol (~ 12 mL). The mixture was allowed to cool to room temperature and the precipitate was collected by suction filtration. The precipitate was washed twice with 1 mL of ice cold ethanol and then crystallized from 90% ethanol to afford a white solid. To the white solid in a 250 mL beaker, 27 mL of ethyl acetate and 31 mL of 3 M HCl were added. The layers were separated and the aqueous layer was extracted twice with 20 mL of ethyl acetate. The combined organic layer was washed twice with 10 mL of H2O, dried over magnesium sulphate, filtered, and concentrated by rotary evaporation to give (S)-6,6′dimethylbiphenyl-2,2′-dicarboxylic acid as a white solid in 50% yield (0.72 g, 2.66 mmol). [α  23 D  + 21.5 (c 1.00, MeOH).  3.4.3 Representative Procedures 3.4.3.1 Procedure 1: Representative Procedure for the Synthesis of Bis(amide) Proligands Example: (S)-N,N′-bis(2,6-diisopropylphenyl)-6,6′-dimethylbiphenyl-2,2′-dicarboxamide 68a130 Thionyl chloride (2.15 mL, 29.6 mmol) was added to a suspension of 6,6′-dimethyl-biphenyl-2,2′-dicarboxylic acid (0.800 g, 2.96 mmol) in 10 mL of toluene in a 50 mL Schlenk flask. The mixture was heated at 120 °C for 3 h after which the excess thionyl chloride and  114  toluene were removed in vacuo. The dichloride formed was dissolved in 20 mL of chloroform, cooled to –78 °C and then added to a mixture of 2,6-diisopropylaniline (1.10 g, 1.17 mL, 6.22 mmol) and triethylamine (0.898 g, 1.25 mL, 8.88 mmol) in 20 mL of chloroform at –78 °C. The reaction mixture was allowed to warm up to room temperature and then heated at 70 °C for 16 h. The mixture was diluted with 50 mL of chloroform and extracted with 3 M HCl (3 × 30 mL), H2O (1 × 30 mL), and brine (1 × 30 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. The solvent was removed by rotary evaporation and 50 mL of ethyl acetate was added to the crude product. The precipitate was collected by suction filtration and washed several times with ethyl acetate to give the product as a white solid in 60% yield (1.05 g, 1.78 mmol).  [α  21 D  + 76.0 (c 1.00, MeOH).  1  H NMR  (CDCl3, 300 MHz, ): 1.01 (24H, m, 4 × Ar–CH(CH3)2), 2.04 (6H, s, 2 × Ar–CH3), 2.38–2.86 (4H, m, 4 × –CH(CH3)2), 7.06 (4H, d, J = 7.9 Hz, 4 × Ar–H), 7.20 (2H, t, J = 7.9 Hz, 2 × Ar–H), 7.39 (4H, m, 4 × Ar–H), 7.48 (2H, m, 2 × Ar–H), 8.43 (2H, br s, 2 × –CONH– );  13  C{1H} NMR (CDCl3, 100 MHz, ): 20.5, 24.0, 28.6, 123.6,  124.9, 128.3, 128.4, 131.0, 132.1, 136.3, 137.1, 138.1, 146.4, 170.3; MS(EI) m/z: 588 (M+), 412 {M+ – NH[((CH3)2CH)2C6H3]}; Anal. Calcd for C40H48N2O2: C, 81.59; H, 8.22; N, 4.76. Found: C, 81.50; H, 8.07; N, 4.78.  (S)-N,N′-dimesityl-6,6′-dimethylbiphenyl-2,2′-dicarboxamide 68b The synthetic approach to 68b is outlined in procedure 1. The quantities of reactants utilized are: (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid, 1.63 g (6.03 mmol); thionyl chloride, 4.39 mL (60.3 mmol); 2,4,6-trimethylaniline, 1.71 g (12.7 mmol); triethylamine, 2.54 mL (18.1 mmol).  115  Purification was effected by washing the crude solid with 50 mL of hexanes, collecting the solid by suction filtration and further washing with 2 mL of ice-cold ethyl acetate to deliver a white solid in 50% yield (1.52 g, 3.01 mmol); [α  23 D  + 138.9 (c 1.00, MeOH).  1  H NMR (CDCl3,  400 MHz, ): 1.90 (12H, s, 4 × Ar–CH3), 2.01 (6H, s, 2 × Ar–CH3), 2.19 (6H, s, 2 × Ar–CH3), 6.76 (4H, br s, 4 × Ar–H), 7.29–7.36 ( 4H, m, 4 × Ar–H), 7.48 (2H, m, 2 × Ar–H), 8.52 (2H, br s, 2 × –CONH–);  13  C{1H} NMR (CDCl3, 100 MHz, ): 18.3, 20.6, 21.0, 125.4, 128.1, 128.9,  131.4, 132.2, 135.3, 136.7, 136.8, 136.8, 137.7, 169.3; MS(EI) m/z: 504 (M+), 370 [M+ – NH(CH3)3C6H2]; HRMS-EI (m/z): (M+) calcd for C34H36N2O2, 504.27768; found, 504.27737; Anal. Calcd for C34H36N2O2 C, 80.92; H, 5.55; N, 7.19. Found: C, 80.70; H, 5.44; N, 7.51.  (S)-N,N- bis(2,6-dimethylphenyl)-6,6′-dimethylbiphenyl-2,2′-dicarboxamide 68c Thionyl chloride (1.35 mL, 18.5 mmol) was added to a solution of (S)-6,6-dimethyl-biphenyl-2,2′-dicarboxylic acid (0.500 g, 1.85 mmol) in 5 mL of toluene. The mixture was heated at 120 °C for 3 h after which the volatiles were removed in vacuo. The dichloride formed was dissolved in 20 mL chloroform, cool to –78 °C and then added to a mixture of 0.471 g of 2,6-dimethylaniline (0.48 mL, 3.89 mmol) and 0.56 g of triethylamine (0.80 mL, 5.55 mmol) in 20 mL of chloroform at –78 °C. The reaction mixture was warmed to room temperature and then heated at 70 °C for 16 h. It was then diluted with 20 mL of chloroform and extracted with 3 M HCl (3 × 20 mL), H2O (20 mL), brine (20 mL). The organic layer was dried over anhydrous magnesium sulphate, the solid was filtered off and the solvent removed by rotary evaporation. Recrystallization of the crude product from ethanol gave the cyclic imide 69 in 50% yield (0.33 g, 0.93 mmol). The mother  116  liquor was further purified by column chromatography using a 2:1 mixture of hexanes and ethyl acetate to afford the bis(amide) as a white solid in 25% yield (0.22 g, 0.46 mmol).  [α  21 D  +117.5  (c 0.50, MeOH). 1H NMR (CDCl3, 400 MHz, ): 1.95 (12H, s, 4 × Ar–CH3), 2.02 (6H, s, 2 × Ar–CH3), 6.94–7.02 (6H, m, 6 × Ar–H), 7.31–7.38 (4H, m, 4 × Ar–H), 7.49 (2H, d, J = 7.3 Hz, 2 × Ar–H), 8.63 (2H, br s, 2 × –CONH–); 13C NMR (CDCl3, 100 MHz):  18.4, 20.6, 125.4, 127.3, 128.3, 132.3, 134.0, 135.6, 136.7, 136.9, 137.6, 169.2; MS(EI) m/z: 476 (M+), 356 [M+ – NH(CH3)2C6H3]; Anal. Calcd for C32H32N2O2: C, 80.64; H, 6.77; N, 5.88. Found: C, 80.79; H, 6.69; N, 5.97.  Cyclic imide 69 1  H NMR (CDCl3, 400 MHz, ): 2.03 (6H, s, 2 × Ar–CH3), 2.20 (6H,  s, 2 × Ar–CH3), 7.11 (2H, m, 2 × Ar–H), 7.18 (1H, m, Ar–H), 7.38– 7.46 (4H, m, 4 × Ar–H), 7.60 (2H, m, 2 × Ar–H); 13C NMR (CDCl3, 100 MHz):  18.5, 19.9, 127.2, 128.5, 128.6, 128.9, 133.1, 133.3, 136.3, 137.3, 138.0, 138.5, 171.5; MS(EI) m/z: 355 (M+), 327 (M+ – CO); Anal. Calcd for C24H21NO2: C, 81.10; H, 5.96; N, 3.94. Found: C, 80.93; H, 5.93; N, 4.06.  (S)-6,6′-dimethyl-N,N′-diphenylbiphenyl-2,2′-dicarboxamide 68d Procedure 1 was followed in the preparation of this compound. The quantities of reactants employed are: (S)-6,6′-dimethylbiphenyl-2,2′dicarboxylic acid, 0.600 g (2.22 mmol); thionyl chloride, 1.61 mL (22.2 mmol); aniline, 0.43 mL (4.7 mmol); triethylamine, 0.94 mL (6.7 mmol).  Purification was effected by column chromatography using a 4:1 mixture of  117  hexanes and ethyl acetate to give the product as a white solid in 58% yield (0.54 g, 1.3 mmol). [α  21 D  + 82.1 (c 0.50, MeOH).  1  H NMR (CDCl3, 400 MHz, ): 1.95 (6H, s, 2 × Ar–CH3), 7.05  (2H, t, J = 7.2 Hz, 2 × Ar–H), 7.19–7.26 (4H, m, 4 × Ar–H), 7.28–7.33 (4H, m, 4 × Ar–H), 7.45 (4H, d, J = 7.2 Hz, 4 × Ar–H), 7.49 (2H, dd, J = 6.8, 2 Hz, 2 × Ar–H), 8.99 (2H, br s, 2 × – CONH–);  13  C{1H} NMR (CDCl3, 75 MHz, ): 20.4, 120.3, 124.6, 125.0, 128.3, 129.0, 132.7,  136.6, 136.8, 137.1, 138.2, 169.2; MS(EI) m/z: 420 (M+), 328 (M+ – NHPh); Anal. Calcd for C28H24N2O2: C, 79.98; H, 5.75; N, 6.66. Found: C, 79.74; H, 5.82; N, 6.70.  (S)-N,N′- diisopropyl-6,6′-dimethylbiphenyl-2,2′-dicarboxamide 68e The title compound was prepared according to procedure 1 (heat is not required for the second step). The quantities of reactants employed are as follows: (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid, 0.406 g (1.50 mmol); thionyl chloride, 1.09 mL (15.0 mmol); isopropylamine, 0.61 mL (7.5 mmol); triethylamine, 0.63 mL (4.6 mmol). The product was obtained as a white solid in 72% yield (0.38 g, 1.1 mmol) after purification by flash column chromatography using 1:1 mixture of hexanes and ethyl acetate. The product can also be obtained pure by recrystallization of the crude compound from ethyl acetate but in a lower yield (50%). [α  21 D  + 4.9 (c 1.00, MeOH). 1H NMR (CDCl3, 300 MHz, ): 0.76 (6H, d, J = 6.6 Hz,–  CH(CH3)2), 0.96 (6H, d, J = 6.6 Hz, –CH(CH3)2), 1.89 (6H, s, 2 × Ar–CH3), 3.87–3.94 (2H, m, 2 × –CH(CH3)2), 6.99 (2H, br d, J = 7.7 Hz, 2 × –CONH–), 7.21–7.30 (6H, m, 6 × Ar–H); C{1H} NMR (CDCl3, 75 MHz, ): 20.2, 22.2, 22.5, 41.4, 124.5, 127.9, 131.6, 136.4, 136.5,  13  137.7, 169.8; MS(ESI) m/z: 352 (M+), 294 [M+ – NHCH(CH3)2]; Anal. Calcd for C22H28N2O2: C, 74.97; H, 8.01; N, 7.95. Found: C, 75.12; H, 7.77; N, 7.96.  118  (S)-N,N′-bis(adamantyl)-6,6′-dimethylbiphenyl-2,2′-dicarboxamide 68f The synthetic protocol for 68f is outlined in procedure 1 (heat is not required for the second step). The quantities of reactants utilized are: (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid, 0.30 g (1.1 mmol); thionyl chloride, 0.81 mL (11 mmol); 1-adamantanamine, 0.35 g (2.3 mmol); triethylamine, 0.47 mL (3.3 mmol). The product was obtained as a white solid in 72% yield (0.43 g, 0.80 mmol) after purification by column chromatography using 1:1 mixture of hexanes and ethyl acetate. [α  21 – D  20.4 (c 1.00, CHCl3).  1  H NMR (CDCl3, 300 MHz, ): 1.59  (12H, br s, adamantyl H), 1.70–1.82 (12H, m, adamantyl H), 1.97 (12H, br s, 2 × Ar–CH3, adamantyl H), 6.71 (2H, br s, 2 × –CONH–), 7.30 (4H, m, 4 × Ar–H), 7.37 (2H, m, 2 × Ar–H); C{1H} NMR (CDCl3, 75 MHz, ): 20.2, 29.5, 36.7, 41.4, 52.3, 124.7, 127.8, 131.4, 136.5,  13  136.9, 138.8, 169.6; MS(EI) m/z: 536 (M+); Anal. Calcd for C36H44N2O2: C, 80.56; H, 8.26; N, 5.22. Found: C, 80.22; H, 8.30; N, 5.15.  (S)-6,6′-dimethyl-N,N′-bis((R)-1-phenylethyl)biphenyl-2,2′-dicarboxamide 68g The synthetic approach to 68g is outlined in procedure 1. The quantities of reactants used are: (S)-6,6′-dimethylbiphenyl-2,2′-dicarboxylic  acid,  0.65 g  (2.4 mmol); thionyl chloride, 1.74 mL (24.0 mmol); (R)-1methylbenzylamine, 0.61 g (5.0 mmol); triethylamine, 1.0 mL (7.2 mmol).  The 1H NMR spectrum of the crude product is  consistent with the formation of one diastereomer. Purification by recrystallization from ethyl acetate affords a white solid in 87% yield (1.00 g, 2.10 mmol).  119  [α  24 D  + 84.6 (c 1.00, MeOH).  1  H NMR (CDCl3, 300 MHz, ): 1.14 (6H, d, J = 7.0 Hz, 2 × –  CHCH3), 1.82 (6H, s, 2 × Ar–CH3), 5.01 (2H, m, 2 × –CHCH3), 7.16–7.29 (14H, m, 2 × – CONH–, 12 × Ar–H), 7.34 (2H, m, 2 × Ar–H), 7.42 (2H, br d, J = 8.2 Hz, 2 × Ar–H); C{1H} NMR (CDCl3, 75 MHz, ): 20.2, 21.3, 48.7, 124.7, 126.4, 127.3, 127.9, 128.6, 131.9,  13  136.6, 136.6, 137.3, 143.0, 169.7; MS(EI) m/z: 476 (M+); HRMS-EI (m/z): (M+) calcd for C32H32N2O2, 476.24638; found, 476.24598.  3.4.3.2 Procedure 2: Representative Procedure for the Enantioselective Hydroamination of Aminoalkenes Example 1: Synthesis of 3-methyl-2-azaspiro[4.5]decane (72a) –Table 3.2, entry 1 C-(1-allylcyclohexyl)methylamine (71a), 0.050 g (0.33 mmol), was added to a 0.3 mL d6benzene solution containing 0.019 g (0.033 mmol) of proligand 68a and 0.009 g (0.03 mmol) of Zr(NMe2)4 in a 1 dram vial. The mixture was transferred into a J. Young NMR tube after which the vial was rinsed twice with d6-benzene and the rinse added to the J. Young NMR tube for a total volume of 0.5 mL in the NMR tube. The sealed J. Young tube was placed in an oil bath set at 110 °C. After 3 h at 110 °C, the reaction mixture was loaded onto a 3 × 2.5 cm sintered glass filter filled to about ¾ with silica gel. The proligand was eluted with 100 mL of a 1:1 mixture of hexanes and ethyl acetate while the product was eluted with 100 mL of an 89:10:1 mixture of dichloromethane, methanol and triethylamine respectively. The solvent was removed under reduced pressure to deliver the pure product in 92% yield (0.046 g, 0.30 mmol).  120  Example 2: Synthesis of 2-methyl-4,4-diphenylpyrrolidine (72b) – Table 3.2, entry 7 2,2-diphenyl-4-pentenylamine (71b), 0.100 g (0.421 mmol) was added into a 1 dram vial containing 0.3 mL d6-benzene solution of proligand 68a (0.025 g, 0.042 mmol) and 0.011 g (0.042 mmol) of Zr(NMe2)4. The mixture was quantitatively transferred into a J. Young NMR tube by rinsing the vial twice with d6-benzene for a total volume of 0.5 mL in the NMR tube. The mixture was heated at 110 °C in an oil bath for 75 minutes after which loaded onto a 3 × 2.5 cm sintered glass filter filled to about ¾ with silica gel. The proligand was eluted with 100 mL of a 1:1 mixture of hexanes and ethyl acetate while the product was eluted with 100 mL of an 89:10:1 mixture of dichloromethane, methanol and triethylamine respectively. The solvent was removed under reduced pressure to deliver the pure product in 92% yield (0.092 g, 0.39 mmol).  3.4.3.3 Procedure 3: Representative Procedure for the Enantioselective Hydroamination of Aminoalkenes in Table 3.3. Example: Synthesis of 3-methyl-2-azaspiro[4.4]nonane (72d) – Table 3.3, entry 2 An in situ precatalyst standard solution was freshly prepared using Zr(NMe2)4, 0.0199 g (0.0744 mmol) and 0.040 g (0.074 mmol) of proligand 68f in 1 mL volumetric flask. Using a micro pipette, 0.28 mL (0.021 mmol) of the standard solution was added to 0.058 g (0.42 mmol) of C-(1-allylcyclopentyl)methylamine (71d) in a 1 dram vial (note: in case involving internal standard, 0.42 mmol of 1,3,5-trimethoxybenzene was also added).  The mixture was  quantitatively transferred into a J. Young NMR tube by rinsing the vial with d6-benzene for a total volume of 0.5 mL in the NMR tube. The reaction mixture was heated at 110 °C (oil bath) for 5 h after which it was loaded onto a 3 × 2.5 cm sintered glass filter filled to about ¾ with silica gel. The proligand was eluted with 100 mL of a 1:1 mixture of hexanes and ethyl acetate  121  while the product was eluted with 100 mL of an 89:10:1 mixture of dichloromethane, methanol and triethylamine respectively. The solvent was removed under reduced pressure to deliver the pure product in 87% yield (0.043 g, 0.31 mmol).  2,4-dimethyl-4-phenylpyrrolidine - mixture of diastereomers (72h and 72h′) 1  H NMR (CDCl3, 600 MHz,  a  denotes major diastereomer,  b  denotes minor diastereomer,  occurring in a 1.7:1 ratio as determined by integration of signals at δ 1.13 and 1.17 respectively, ): 1.13a (3H, d, J = 6.1 Hz, CH3CH–), 1.17b (3H, d, J = 6.1 Hz, CH3CH–), 1.29a (3H, s, – CPhCH3,), 1.32b (3H, s, –CPhCH3), 1.39b (1H, br dd, J = 12.8, 8.2 Hz, –CHCH2–), 1.63a (1H, br dd, J = 12.0, 9.5 Hz, –CHCH2–), 1.90a,b (1H, br s, –CH2NH–), 2.06a (1H, br dd, J = 12.3, 6.1 Hz, –CHCH2–), 2.33b (1H, br dd, J = 13.1, 7.9 Hz, –CHCH2–), 2.99–3.01a,b (1H, 2 overlapping doublets, –CCH2–), 3.13b (1H, d, J = 10.7 Hz, –CCH2–), 3.21a (1H, d, J = 10.7 Hz, –CCH2–), 3.25b (1H, m, CH3CH–), 3.44a (1H, m, CH3CH–), 7.12a,b (1H, m, Ar–H), 7.20a,b (2H, m, 2 × Ar– H), 7.24a,b (2H, m, 2 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, ): 22.2, 22.5, 29.5, 30.4, 48.4, 48.5, 48.7, 53.6, 54.8, 59.6, 60.7, 125.9, 126.1, 126.2, 128.4, 128.5, 149.4, 149.8; MS(EI) m/z: 175 (M+), 160 (M+ – CH3); HRMS-EI (m/z): (M+) calcd for C12H17N, 175.1361; found, 175.1360.  3.4.3.4 Procedure 4: Representative Procedures for the Determination of Enantiomeric Excesses of Mosher Amides by 1H and 19F NMR Spectroscopies (S)-Mosher acid chloride 0.009 g, (0.04 mmol) in 1 mL of dichloromethane was added to 0.005 g (0.03 mmol) of 72a and 0.016 g (0.16 mmol) of triethylamine in 1 mL of dichloromethane. The mixture was filtered through a 2 mL pipette filled half way with silica gel  122  using 5 mL of dichloromethane. The volatiles were removed by rotary evaporation and the product was dissolved in CDCl3 for analysis by 1H NMR spectroscopy at 25 °C and  19  F NMR  spectroscopy at 60 °C.  N-benzoyl-2-methyl-4-phenylpyrrolidine 314 HPLC analysis (CHIRALPAK AS-H, 1% 2-propanol in hexanes, 1.00 mL/min) of the above benzamides: tR enantiomers of major diastereomer: 35.8 min and 106.20 min, tR enantiomers of minor diastereomer: 46.6 min and 86.2 min indicated an enantiomeric excesses of 37% and 5% respectively.  3.4.3.5 Procedure 5: Representative Procedures for the Synthesis of Zirconium Complexes Example: Complex (±)-76a·HNMe2 A solution of 0.088 g (0.33 mmol) of Zr(NMe2)4 in 5 mL of benzene was added to a suspension of 0.194 g (0.329 mmol) of (±)68a in 5 mL of benzene in a 20 mL scintillation vial equipped with a magnetic stir bar. After the dissolution of the entire solid, the volatiles were removed in vacuo to produce the complex as a white solid in 96% yield (0.257 g, 0.317 mmol). Low quality crystals suitable for X-ray were obtained from a mixture of benzene and hexanes at –35 °C. Note: Prolonged exposure to high vacuum results in the formation of a small quantity of the corresponding dimer; a process that is hastened by the removal of the neutrally coordinated HNMe2.  1  H NMR (d6-benzene, 300 MHz, ): 0.89  (6H, d, J = 6.9 Hz, –CH(CH3)2), 0.99–1.05 (1H, m, HN(CH3)2), 1.15 (6H, d, J = 6.4 Hz, –  123  CH(CH3)2), 1.29 (6H, d, J = 6.9 Hz, –CH(CH3)2), 1.35 (6H, d, J = 5.9 Hz, HN(CH3)2), 1.41 (6H, d, J = 6.9 Hz, –CH(CH3)2), 2.21 (6H, s, 2 × Ar–CH3), 2.27 (12H, s, N(CH3)2), 2.50–2.59 (2H, m, 2 × –CH(CH3)2), 3.41–3.50 (2H, m, 2 × –CH(CH3)2), 6.96–7.01 (2H, m, 2 × Ar–H), 7.04–7.09 (4H, m, 4 × Ar–H), 7.13–7.18 (4H, m, 4 × Ar–H), 7.68 (2H, br dd, J = 6.9, 1.4 Hz, 2 × Ar–H) C{1H} NMR (d6-benzene, 75 MHz, ): 21.4, 23.2, 23.3, 23.9, 25.4, 28.3, 29.5, 38.9, 40.7,  13  122.4, 122.9, 123.4, 126.3, 130.6, 137.7, 138.3, 138.7, 139.7, 141.1, 146.7, 161.1; (M+) for complex 76f·HNMe2 was not observed in the MS(EI), however, a signal corresponding to the (M+) for the proligand was noted. Anal. Calcd for C46H65N5O2Zr: C, 68.10; H, 8.08; N, 8.63. Found: C, 68.01; H, 7.84; N, 8.69.  Complex (±)-76b·HNMe2 (NMR tube scale synthesis) 1  H NMR (d6-benzene, 300 MHz):  1.13 (2H, br s, 2 × HN(CH3)2)  rapid exchange between free and bound HN(CH3)2), 1.74 (6H, s, 2 × Ar–CH3), 1.84 (12H, br s, 2 × HN(CH3)2 rapid exchange between free and bound HN(CH3)2), 2.22 (6H, s, 2 × Ar–CH3), 2.31 (6H, s, 2 × Ar–CH3), 2.41 (6H, s, 2 × Ar–CH3), 2.53 (12H, s, 2 × –N(CH3)2), 6.74 (2H, br s, 2 × Ar–H), 6.84 (2H, br s, 2 × Ar–H), 7.15 (4H, m, 4 × Ar–H), 7.60 (2H, m, 2 × Ar–H); 13C NMR (d6-benzene, 75 MHz):  19.2, 19.6, 21.3, 21.6, 39.6, 44.1, 126.1, 127.6, 128.8, 129.2, 130.4, 137.8, 139.0, 141.9, 147.0, 161.9.  Complex (±)-76c·HNMe2 (NMR tube scale synthesis) 1  H NMR (d6-benzene, 300 MHz):  1.18 ( 2H, br s, 2 × HN(CH3)2)  rapid exchange between free and bound HN(CH3)2), 1.73 (6H, s, 2 ×  124  Ar–CH3), 1.79 (12H, br d, J = 6.1 Hz, 2 × HN(CH3)2, rapid exchange between free and bound HN(CH3)2), 2.31 (6H, s, 2 × Ar–CH3), 2.42 (6H, s, 2 × Ar–CH3), 2.49 (12H, s, 2 × –N(CH3)2), 6.88 (4H, m, 4 × Ar–H), 7.04 (2H, d, J = 7.0 Hz, 2 × Ar–H), 7.19 (4H, m, 4 × Ar–H), 7.59 (2H, br dd, J = 6.4, 2.0 Hz, 2 × Ar–H);  13  C NMR (d6-benzene, 75 MHz):  19.1, 19.7, 21.6, 39.6,  40.0, 122.0, 126.0, 127.6, 128.2, 128.9, 129.5, 130.5, 137.7, 139.0, 141.7, 149.6, 161.8.  Complex (±)-76f·HNMe2 1  H NMR (d6-benzene, 300 MHz, ): 1.69 (12H, br s, 2 ×  HN(CH3)2, rapid exchange between free and bound HN(CH3)2), 1.96–2.13 (30H, m, adamantyl H), 2.28 (6H, s, 2 × Ar–CH3), 2.53 (12H, s, 2 × –N(CH3)2), 7.11 (4H, m, 4 × Ar–H), 7.42 (2H, m, 2 × Ar–H);  C{1H} NMR (d6-benzene, 75 MHz, ): 21.4,  13  31.0, 37.9, 39.1, 41.5, 43.5, 54.0, 125.4, 127.4, 129.4, 138.3, 138.5, 142.2, 158.6; Anal. Calcd for C40H54N4O2Zr: C, 67.28; H, 7.62; N, 7.85. Found: C, 67.36; H, 8.02; N, 8.00 (note: prolonged exposure to high vacuum eliminates the neutrally coordinated HNMe2.  Complex (±)-76e·(HNMe2)2 1  H NMR (d6-benzene, 300 MHz, ): 1.07 (6H, m, –NCH(CH3)2), 1.46  (6H, m, –NCH(CH3)2), 1.88 (2H, br d, J = 5.5 Hz, 2 × HN(CH3)2), 2.06 (12H, br s, 2 × HN(CH3)2), 2.25 (3H, s, Ar–CH3), 2.39 (3H, s, Ar–CH3), 2.98 (12H, s, 2 × –N(CH3)2), 4.30 (1H, m, –NCH(CH3)2), 4.42 (1H, m, –NCH(CH3)2), 7.03–7.31(6H, m, 6 × Ar–H);  13  C{1H} NMR (d6-  125  benzene, 100 MHz, ): 21.1, 21.5, 24.5, 24.6, 25.5, 25.6, 39.5, 45.5, 45.8, 46.3, 124.8, 124.5, 127.3, 127.5, 129.5, 130.3, 137.8, 137.9, 139.2, 139.4, 141.0, 142.4, 158.3, 160.3.  3.5.3.6 Procedure 6: Representative Procedure for the Synthesis of Zirconium Complexes with Pyridine as Neutral Donor Example: Synthesis of complex (±)-76a·(py)2 A solution of 0.048 g (0.18 mmol) of Zr(NMe2)4 in 5 mL of benzene was added into a 20 mL scintillation vial containing 0.105 g (0.178 mmol) of (±)-68a and 0.29 mL (0.282 g, 3.56 mmol) of pyridine in 5 mL of benzene. The reaction mixture was stirred for 16 h at ambient temperature after which the volatiles were removed in vacuo to produce the complex as a pale yellow solid in 95% yield (0.157 g, 0.170 mmol). Crystals suitable for X-ray diffraction were obtained from a mixture of benzene and hexanes at – 35 °C.  1  H NMR (d6-benzene, 400 MHz, ): 1.12 (6H, br s, Ar–CH(CH3)2), 1.19 (6H, d, J = 6.7  Hz, Ar–CH(CH3)2), 1.30 (6H, d, J = 6.7 Hz, Ar–CH(CH3)2), 1.45 (6H, d, J = 6.7 Hz, Ar– CH(CH3)2), 2.28 (6H, br s, 2 × Ar–CH3), 2.40 (12H, s, 2 × –N(CH3)2), 2.94 (2H, m, 2 × Ar– CH(CH3)2), 3.49 (2H, m, 2 × Ar–CH(CH3)2), 6.60 (4H, m, 4 × Ar–H), 6.90 (2H, m, 2 × Ar–H), 7.01–7.17 (8H, m, 8 × Ar–H), 7.24 (2H, m, 2 × Ar–H), 7.42 (2H, br s, 2 × Ar–H), 7.89 (4H, br s, 4 × Ar–H);  13  C{1H} NMR (d6-benzene, 100 MHz, ): 21.6, 23.1, 23.1, 23.9, 26.0, 28.5, 29.3,  42.4, 122.8, 122.9, 123.2, 124.7, 126.4, 128.0, 128.9, 130.3, 137.9, 138.2, 139.4, 139.7, 141.5, 147.0, 150.0, 161.4. Anal. Calcd for C49H63N5O2Zr: C, 69.62; H, 7.51; N, 8.29. Found: C, 69.82; H, 7.28; N, 8.31 (note: prolonged exposure to high vacuum eliminates one of the neutrally coordinated pyridines).  126  Complex (±)-76f·(py)2 1  H NMR (d6-benzene, 300 MHz, ): 1.68 (12H, br s, adamantyl H),  1.85–2.06 (18H, m, adamantyl H), 2.36 (6H, s, 2 × Ar–CH3), 2.74 (12H, s, 2 × –N(CH3)2), 6.72 (2H, m, 2 × Ar–H), 6.94–7.08 (2H, m, 2 × Ar–H), 7.16–7.23 (6H, m, 6 × Ar–H), 1.31 (2H, m, 2 × Ar–H), 8.25 (4H, m, 4 × Ar–H);  13  C{1H} NMR (d6-benzene, 75 MHz, ): 21.4,  31.0, 37.9, 42.0, 43.2, 54.0, 125.1, 125.7, 127.6, 128.9, 129.6, 138.2, 138.4, 142.1, 150.1, 159.5.  Complex [76b]2 A 20 mL scintillation vial equipped with a magnetic stir bar was charged with 0.101 g (0.200 mmol) of (±)68b and 5 mL of benzene, 0.053 g (0.20 mmol) of Zr(NMe2)4 in 5 mL of benzene was then added to the suspension. After the dissolution of the entire solid, the volatiles were removed in vacuo and the solid was recrystallized from a hot mixture of benzene and hexanes to deliver 0.060 g (0.044 mmol) of [76b]2 in 44% yield.  1  H NMR (d6-  benzene, 400 MHz, ): 1.90 (12H, s, 4 × Ar–CH3), 2.09 (12H, s, 4 × Ar–CH3), 2.21 (12H, s, 4 × Ar–CH3), 2.23 (12H, s, 4 × Ar–CH3), 2.59 (24H, s, 4 × –N(CH3)2), 6.76 (4H, t, J = 7.7 Hz, 4 × Ar–H), 6.83 (4H, s, 4 × Ar–H), 6.97 (4H, d, J = 7.7 Hz, 4 × Ar–H), 7.05 (4H, s, 4 × Ar–H), 7.66 (4H, d, J = 7.7 Hz, 4 × Ar–H); 13C{1H} NMR (d6-benzene, 150 MHz, ): 19.5, 21.0, 21.3, 21.4, 43.2, 126.6, 128.7, 129.6, 130.5, 131.1, 132.5, 133.3, 134.0, 135.1, 142.9, 145.2, 179.2; Anal. Calcd for C76H92N8O4Zr2: C, 66.92; H, 6.80; N, 8.21. Found: C, 67.11; H, 7.12; N, 7.98.  127  Complex (±)-76b·(py)2 1  H NMR (d6-benzene, 300 MHz, ): 2.00 (6H, s, 2 × Ar–CH3), 2.28  (6H, s, 2 × Ar–CH3), 2.34 (6H, s, 2 × Ar–CH3), 2.42 (6H, s, 2 × Ar– CH3), 2.51 (12H, s, 2 × –N(CH3)2), 6.55 (4H, br t, J = 6.6 Hz, 4 × Ar– H), 6.86 (6H, m, 6 × Ar–H), 7.00 (2H, m, 2 × Ar–H), 7.13 (2H, m, 2 × Ar–H), 7.42 (2H, br s, 2 × Ar–H), 8.04 (4H, br s, 4 × Ar–H); C{1H} NMR (d6-benzene, 100 MHz, ): 19.5, 19.7, 21.4, 21.8, 44.5, 124.4, 126.7, 127.4,  13  129.0, 129.1, 129.3, 129.6, 130.0, 130.2, 137.4, 137.7, 138.1, 141.8, 147.4, 150.4, 162.5.  128  CHAPTER 4. SYNTHESIS AND CHARACTERIZATION OF CHIRAL TANTALUM AMIDATE COMPLEXES: APPLICATION IN THE ENANTIOSELECTIVE HYDROAMINOALKYLATION REACTION  4.1 Introduction The utilization of amines as synthetic intermediates in chemical and industrial processes has continued to fuel intense research into the development of efficient synthesis of these molecules.1, 3, 43 Many recent efforts in this field employ metal catalysts with electronically and sterically tunable ancillary ligands to optimize catalyst efficiency and selectivity in the synthesis of amines.1 Importantly, this strategy is amenable to asymmetric synthesis through the design of chiral ancillary ligands. In this regard, the hydroamination reaction discussed in Chapter 3 has been extensively explored.1 An emerging, alternative, 100% atom-economic catalytic approach for the synthesis of amines is the hydroaminoalkylation reaction.43 The hydroaminoalkylation reaction is the α-alkylation of simple amines with alkenes via C–H bond activation of a sp3 hybridized C–H bond α to the amine N resulting in the formation of a new C–C bond.43 This reaction can proceed in an intramolecular or intermolecular fashion with the potential to afford two regioisomeric products (Scheme 4.1).43 Although achiral catalytic hydroaminoalkylation reactions were initially reported about three decades ago, significant improvement in reactivity was only recently achieved by Herzon and Hartwig.122,  123  Following these publications, our  group130, 131 and others124-129 have reported early transition metal-catalyzed hydroaminoalkylation reactions. Reproduced in part with permission from Eisenberger, P.; Ayinla, R. O.; Lauzon, J. M. P.; Schafer, L. L. Angew. Chem., Int. Ed. 2009, 48, 8361–8365. Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.  129  Scheme 4.1. Catalytic intramolecular and intermolecular hydroaminoalkylation reactions.  Studies on the intermolecular hydroaminoalkylation reaction in the Schafer group began with the observation of the spontaneous formation of an amidate-ligated tantallaaziridine, the proposed key intermediate in the hydroaminoalkylation reaction (see Scheme 1.17), during the synthesis of a tantalum amidate complex by graduate student Jean Michel Lauzon.130 The isolation of this intermediate coupled with the electrophilic nature of amidate complexes hinted at tantalum amidate complexes being efficient catalysts for the hydroaminoalkylation reaction. This hypothesis was explored by postdoctoral researcher, Dr. Patrick Eisenberger, with the development of achiral tantalum amidate complex 78. Complex 78 is highly efficient and regioselective for the hydroaminoalkylation of a variety of terminal and internal alkenes with Naryl alkylamines as well as dialkylamines.130 Enhanced reactivity is observed with 78 as reaction temperatures can be as low as 110 °C and excellent diastereoselectivity is consistently obtained (Scheme 4.2).130  Interestingly, Patrick discovered that mono(amidate) complexes are more  efficient precatalysts than their bis(amidate) counterparts, suggesting that a coordinatively saturated metal center has a negative impact on catalytic activity.130  130  Scheme 4.2. Tantalum amidate-catalyzed hydroaminoalkylation reactions.  The successful utilization of amidate-ligated tantalum complexes as precatalysts for the hydroaminoalkylation reaction opens up the possibility of achieving this transformation in an enantioselective fashion. Therefore, the bis(amide) (Figure 4.1) proligands discussed in Chapter 3  were  employed  in  chiral  tantalum  amidate  complex  formation  for  catalytic  hydroaminoalkylation. This investigation represents the first example of enantioselective αalkylation of amines.  131  Figure 4.1. Bis(amide) proligands for tantalum amidate complex formation.  Following our publication of these results, three other reports of this asymmetric catalysis have emerged.124, 125, 127 These reports include the use of related amidate complexes of group 5 as precatalysts for this transformation.124, 127 The most efficient of these complexes, complex 79, promotes the hydroaminoalkylation reactions between N-aryl alkylamines and alkenes to generate chiral secondary amines in up to 93% ee (Scheme 4.3 (a)). However, reaction times of 120 hours are required for good conversions (71–89%) at 130 °C. Hultzsch and co-workers recently reported tantalum and niobium complexes containing binaphtholate ancillary ligands as precatalysts for the α-alkylation of amines. The niobium complex 80 (Scheme 4.3 (b)) was found to promote this transformation in up to 80% ee. Similar  132  to the aforementioned amidate complexes, these complexes require high temperatures for catalysis to proceed.  Scheme 4.3. Enantioselective intermolecular hydroaminoalkylation reactions catalyzed by group 5 metal complexes.  This chapter focuses on catalytic hydroaminoalkylation using axially chiral tantalum amidate complexes as precatalysts. The synthesis and characterization of the axially chiral tantalum biphenyl amidate complexes will be presented in Section 4.2.1. Akin to the observation for the related zirconium complexes that were presented in Chapter 3, steric properties of the ligand were found to greatly influence the coordination geometry of the complexes as some of the complexes exhibit two coordination isomers (κ2-O,O and κ3-N,O,O) at ambient temperature. The variable temperature (VT) NMR studies of these complexes along with the associated thermodynamic parameters will also be presented. The investigation of these axially chiral tantalum amidate complexes as precatalysts for the intermolecular hydroaminoalkylation of  133  terminal and internal alkenes with secondary amines in the first examples of enantioselective hydroaminoalkylation reactions will be discussed in Section 4.2.2. The hydroaminoalkylation reactions catalyzed by these complexes exclusively afford the branched regioisomer with modest enantioselectivities of up to 66% and excellent diastereoselectivities.  The effect of the  precatalyst steric properties on the reactivity and selectivity of the hydroaminoalkylation reaction has been investigated with cyclohexyl-tethered tantalum amidate complexes, the results of this investigation will be presented in Section 4.2.3. Finally, the catalytic synthesis of an amino alcohol via hydroaminoalkylation will be presented in Section 4.2.4.  4.2 Results and Discussion 4.2.1 Synthesis and Characterization of Axially Chiral Tantalum Amidate Complexes 4.2.1.1 Sterically-Congested Axially Chiral N-Aryl Tantalum Amidate Complex Over the past decade, the Schafer group has discovered that protonolysis is a facile route toward amidate-ligated complexes98,  103, 112, 130, 131, 136-138, 141-144  as was demonstrated with the  zirconium complexes presented in Chapter 3. Similarly, tantalum amidate complexes can be synthesized by a protonolysis reaction between commercially available Ta(NMe2)5 and the proligand of choice.  However, in contrast to the immediate complexation observed with  Zr(NMe2)4, protonolysis with Ta(NMe2)5 is notably slower, requiring longer times to attain complete conversion.  For example, the progress of an NMR tube scale reaction between  equimolar amounts of Ta(NMe2)5 and proligand 68a in d6-benzene can be monitored by 1H NMR spectroscopy. The spectrum obtained after 30 minutes at room temperature shows two sets of signals; one set of signals includes a broad singlet at δ 11.60 that is postulated to be indicative of the N–H proton in intermediate 81a, in which one amide moiety of the proligand remains  134  protonated142 while the other has undergone protonolysis and is N,O-chelating to the metal center (Scheme 4.4). This N–H signal is shifted 3.2 ppm downfield of the resonance frequency of the N–H signal in the free proligand. A similar downfield shift of the N–H proton signal has been previously observed in a neutrally O-bound amidate complex that was also structurally characterized by X-ray crystallography.142 The second set of signals in the 1H NMR spectrum can be assigned to the final product 82a. As the reaction progresses, the signals associated with 81a disappear and complete conversion to 82a is observed within 7 h at ambient temperature.  Scheme 4.4. Synthesis of bis(amidate) tantalum complex 82a.  Compound 82a is isolated as a pale yellow solid in 98% yield after the removal of all volatiles in vacuo. The 1H NMR spectrum of 82a shows four doublets centered at δ 1.08, 1.25, 1.41, and 1.47, representing the methyl protons of the isopropyl groups on the aryl rings. The methine protons for these fragments appear as two multiplets centered at 2.37 and 3.55, each integrating for two protons. The methyl protons on the biphenyl backbone and those on the amido ligands can be assigned based on integration and are singlets at δ 2.33 (six protons) and 2.89 (18 protons) respectively. The above spectroscopic evidence suggests a C2-symmetric structure with inequivalent isopropyl methyl protons. The presence of a signal at δ 159.9 in the  135  13  C NMR spectrum indicative of a C=N double bond suggests that the ligand in 82a adopts a κ2-  O,O-bonding mode in solution. The absence of any signal downfield of 170 ppm where the C of N,O-chelating amidate complexes are observed98,  103, 130, 140, 141  further supports the proposed  solution phase structure for 82a. Single crystals of (±)-82a amenable to X-ray diffraction can be obtained from a mixture of pentane and benzene. The solid-state molecular structure reveals that the amidates are bound to the tantalum in a κ2-O,O-bonding mode consistent with the aforementioned spectroscopic evidence.  This binding motif results in pseudo-trigonal bipyramidal geometry about the  tantalum metal center (Figure 4.2). The Ta–O bond lengths of 2.015(2) Å and 1.973(2) Å (Table 4.1) are significantly shorter than the Ta–O bond lengths (2.099–2.215 Å, vide infra) in N,Ochelating amidate complexes,130 suggesting a higher degree of multiple bond character in the former.  Figure 4.2. ORTEP representation of the solid-state molecular structure of (±)-82a (ellipsoids plotted at 50% probability). All H-atoms and a benzene solvent molecule of crystallization have been omitted for clarity.  136  Table 4.1. Selected bond lengths and angles of (±)-82a Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Ta–O1  2.015(2)  Ta–O2  1.973(2)  O2–Ta–N3  131.65(12)  Ta–N3  1.926(3)  O2–Ta–N4  90.11(11)  Ta–N4  1.988(3)  N3–Ta–N4  89.86(11)  C1–N1  1.277(4)  C6–C7–C9–C10  87.9(4)  O1–Ta–N4  173.79(10)  4.2.1.2 Sterically-Accessible Axially Chiral N-Aryl Tantalum Amidate Complexes The use of ligands with reduced steric congestion results in different solution-phase behaviour than that observed for the complex prepared using proligand 68a. The 1H NMR spectrum of an NMR tube scale reaction between a 1:1 molar ratio of Ta(NMe2)5 and proligand 68b in benzene, obtained after 10 hours of reaction time, indicates the formation of complex 82b. The methyl protons on the N-aryl rings resonate at three different frequencies, δ 1.76, 2.22, and 2.24, each integrating for six protons, while the methyl protons on the biphenyl backbone occur as a singlet at δ 2.37, consistent with a C2-symmetric structure in solution. The methyl protons of the dimethylamido ligands occur as a singlet at δ 2.93 presumably due to rapid exchange of pseudo axial and equatorial ligands on the NMR time scale. The 1H NMR spectrum also contains a broad doublet centered at δ 2.10 which integrates for 12 protons representing two molecules of neutral dimethylamine.  Whether or not these potential neutral donors are  coordinated to the metal center is not obvious from this spectrum. The  13  C NMR spectrum of  this complex contains a diagnostic signal for C=N moiety at δ 160.8, once again indicative of a κ2-O,O-bonding motif for the biphenyl amidate ligand in solution. However, exposure of the reaction mixture to high vacuum for three hours in an attempt to remove all volatiles results in the formation of a new complex 83b in addition to the initial complex. In the 1H NMR spectrum  137  of the mixture, the initial complex has been identified as the dimethylamine adduct 82b·HNMe2 (Scheme 4.5). These complexes exist in a 1:2 ratio favouring 82b·HNMe2 as determined by 1H NMR spectroscopy. This 1H NMR spectrum also indicates that complex 82b·HNMe2 is C2symmetric which would be consistent with the neutral donor being labile in solution. The  13  C  NMR spectrum of this mixture contains a signal at δ 159.9 indicative of a C=N moiety and another at δ 180.1 representing the C of a N,O-chelating amidate ligand. These spectroscopic data are consistent with 83b being a C1-symmetric complex with a κ3-N,O,O-bonding motif wherein one of the amidates on the biphenyl ligand is N,O-chelating and the other is O-bound (Scheme 4.5).  Scheme 4.5. Synthesis of sterically-accessible tantalum complexes with proligand 68b.  138  Attempts to purify complex 82b·HNMe2 by recrystallization from a mixture of benzene and hexanes results in the formation of both 82b·HNMe2 and 83b, as crystals of both complexes can be obtained in a combined 70% yield. These crystals consist of two discernable crystal shapes: pale yellow micro-crystals and larger yellowish-brown block-shaped crystals. X-ray analysis of a single blocked-shaped crystal confirms the coordination of the neutral dimethylamine in 82b·HNMe2 with a pseudo-octahedral geometry about the metal center (Figure 4.3). The average Ta–O bond length (2.049(1) Å) in 82b·HNMe2 (Table 4.2) is slightly longer than the average Ta–O bond length (1.994(3) Å) in 82a (Table 4.1). This is presumably due to the presence of the neutral donor in 82b·HNMe2 which results in a less electrophilic and more sterically-congested metal center. The Ta–N5 bond length (2.410(2) Å) of the neutral dimethylamine ligand is significantly longer than the average Ta–N bond length (1.988(3) Å) of the monoanionic dimethylamido ligands. Furthermore, the dimethylamido ligands are planar and are considered to be four electrons donors to this electrophilic metal center.  Figure 4.3. ORTEP representation of the solid-state molecular structure of (±)-82b·HNMe2 (ellipsoids plotted at 50% probability). All H-atoms except that attached to N5 are omitted for clarity. The H atom shown was calculated from the coordinates of N5.  139  Table 4.2. Selected bond lengths and angles of (±)-82b·HNMe2 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Ta–O1  2.026(1)  O1–Ta–N3  176.80(6)  Ta–O2  2.072(1)  N4–Ta–N5  164.84(6)  Ta–N3  1.997(2)  O2–Ta–N3  87.50(6)  Ta–N5  2.401(2)  N5–Ta–N6  89.68(6)  C7–N1  1.276(3)  O1–Ta–O2  89.84(6)  N5–H100  0.81(3)  C2–C1–C11–C12  90.0(2)  A single crystal of 83b was also subjected to X-ray diffraction; however, the low quality nature of this crystal precludes any inference of detail beyond connectivity. In the structure obtained, the amidate ligand adopts a κ3-N,O,O-bonding motif (Figure 4.4), which is in agreement with the aforementioned spectroscopic evidence.  Figure 4.4. Ball and stick representation of the molecular connectivity of a low quality crystal of (±)-83b. Depiction is only meant to show atom connectivity.  140  Variable temperature (VT) NMR spectroscopy has been carried out to probe the solution phase equilibrium between 82b·HNMe2 and 83b. The high temperature 1H NMR spectra of a mixture of these complexes in d8-toluene have been recorded from 298–358 K in increments of 5 K. A stacked plot of selected spectra of the alkyl region of these spectra is displayed in Figure 4.5. It is believed that the neutral dimethylamine ligand in 82b·HNMe2 is liberated (is in the gas phase) at high temperatures; thus, the observable dynamic equilibrium under consideration is between 82b and 83b (eq 4.1). As the temperature increases, the signals are noted to broaden with coalescence occurring at 347.9 K.  This is particularly obvious with the signals  corresponding to the dimethylamido protons in both complexes which appear at δ 2.93 (signal a) and δ 3.30 (signal b) for 82b and 83b respectively. A comparison of the integral values ratio of signals a:b at 298 K (2.2:1) to the ratio at 318 K (2.6:1) just before extensive broadening of these signals occurs, indicates that the equilibrium favours 82b at high temperature as might be predicted. The original spectrum containing both complexes was restored upon cooling the solution back to 298 K. Using eq 4.2,336 the ΔG‡ for the interconversion between these isomers at the coalescence temperature of 347.9 K and Δv = 148.7 Hz was estimated to be 16.4 ± 0.5 kcal mol-1 (error in ΔGc‡ was estimated by assuming an error of ± 10 K in Tc).  141  Figure 4.5. A stacked plot of selected spectra of the high temperature variable temperature 1H NMR spectroscopy of a solution containing a mixture of 82b and 83b. ΔGc‡(Tc) = 0.00457Tc[9.972 + log10 (Tc/Δv)]  (4.2)336  A protonolysis reaction between Ta(NMe2)5 and proligand 68c in a 1:1 molar ratio in benzene produces 82c·HNMe2 as the exclusive product in 97% yield after exposure of the reaction mixture (upon reaction completion) to high vacuum for four hours. This is in contrast to the reaction involving proligand 68b where the initially formed complex 82b·HNMe2 cannot be exclusively isolated. Spectroscopic evidence indicates the ligand in 82c·HNMe2 adopts a κ2O,O-bonding motif (Scheme 4.6). However, complex 82c·HNMe2 also interconverts to 83c in which the amidate adopts a κ3-N,O,O-bonding mode after extended time (sixteen hours) under high vacuum (Scheme 4.6). In addition, attempts to recrystallize complex 82c·HNMe2 also promotes the formation of 83c to afford a mixture of 82c·HNMe2 and 83c in a 1:1.5 ratio with  142  83c predominating as determined by integration of the signals corresponding to the methyl protons of the dimethylamido ligands in the 1H NMR spectrum.  Scheme 4.6. Synthesis of tantalum complexes with proligand 68c.  The solid-state molecular structure of (±)-83c reveals a distorted octahedral geometry about the metal center with the biphenyl amidate ligand exhibiting a κ3-N,O,O-bonding motif (Figure 4.6). The Ta–O bond length (2.166(2) Å) of the N,O-chelating amidate is longer than the Ta–O bond length (2.050(2) Å) of the O-bound amidate.  The C15–O1 bond length of  1.291(3) Å is similar to the C15–N1 bond length of 1.304(3) Å (Table 4.3), which is in agreement with electron delocalization over the chelating N1–C15–O1 framework (Figure 4.6). The torsion angle between the aryl rings of the biphenyl linkage is 66(3)°, a significant deviation  143  from the values (81–91°) observed in all the previous complexes discussed thus far. In addition, this torsion angle is ~ 19° less than the value (84.9°)337 observed for the parent 6,6′dimethylbiphenyl-2,2′-dicarboxylic acid from which the amide proligands are prepared. The significant distortion of the arrangement of the biphenyl rings in 83c implies that coordination of the N-donor atoms is sterically unfavourable and would explain the absence of κ4-N,O,O,Nbonding motif in monomeric complexes of both the zirconium complexes discussed in Chapter 3 and the tantalum complexes in the current Chapter.  Figure 4.6. ORTEP representation of the solid-state molecular structure of (±)-83c (ellipsoids plotted at 50% probability). All H-atoms are omitted for clarity.  144  Table 4.3. Selected bond lengths and angles of (±)-83c Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Bond angles (°) Ta–O1  2.166(2)  O2–Ta–N3  167.09(8)  Ta–O2  2.050(2)  C15–Ta–N5  116.57(8)  Ta–N1  2.295(2)  C15–Ta–N4  139.54(9)  Ta–N3  1.978(2)  N1–Ta–N3  85.12(8)  O1–C15  1.291(3)  O2–Ta–N4  86.46(6)  C15–N1  1.304(3)  C15–Ta–O2  74.49(7)  O1–Ta–N4  163.91(8)  N5–Ta–N4  100.80(9)  N1–Ta–N5  145.23(8)  C5–C6–C8–C9  66.0(3)  High temperature VT 1H NMR spectroscopy of a d8-toluene solution of a mixture of the complexes shows the conversion of 83c to 82c at elevated temperatures. Here, the ΔG‡ for the interconversion between these complexes at the coalescence temperature (358.0 K) and Δv = 185.9 Hz was estimated to be a similar 16.8 ± 0.5 kcal mol-1 using eq 4.2.336 Proligand 68d reacts with Ta(NMe2)5 within sixteen hours at ambient temperature to produce pale yellow micro-crystalline solid in 61% yield after recrystallization from a mixture toluene and pentane. The 1H NMR spectrum of the crystals indicates the formation of two complexes. The major product, complex 83d, is C1-symmetric (eq 4.3) as implied by the inequivalence of the methyl protons on the biphenyl backbone which resonate as two singlets at δ 1.44 and 2.09. The methyl protons of the dimethylamido ligands on 83d appear as a singlet at δ 3.37 presumably due to fast exchange between these ligands on the NMR time scale. A singlet at δ 3.64 in the region associated with the methyl protons of dimethylamido ligands suggests the presence of a minor product. While the identity of complex 83d can be easily deduced from the spectroscopic data, the structure of complex 84 was established by fortuitous single crystal X-ray  145  crystallography (vide infra) as this product was isolated in a small quantity in an overall yield of only ~ 4% as estimated by 1H NMR spectroscopy.  X-ray crystallographic analysis of a single crystal corroborates the spectroscopic assignment and ligand binding motif proposed for 83d. Metrical parameters about the tantalum center are consistent with a distorted octahedral complex (Figure 4.7). All the bond lengths and angles of 83d (Table 4.4) are analogous to those of the previously discussed complex 83c that features a similar κ3-N,O,O-ligand bonding motif.  Figure 4.7. ORTEP representation of the solid-state molecular structure of (±)-83d (twinned structure, ellipsoids plotted at 50% probability). All H-atoms are omitted for clarity.  146  Table 4.4. Selected bond lengths and angles of (±)-83d Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Bond angles (°) Ta–O1  2.195(4)  O2–Ta–N4  167.2(2)  Ta–O2  2.053(5)  C1–Ta–N5  118.8(2)  Ta–N1  2.250(5)  C1–Ta–N3  134.6(2)  Ta–N3  1.987(5)  N1–Ta–N4  85.4(2)  O1–C1  1.293(7)  O2–Ta–N5  98.5(2)  C1–N1  1.329(8)  C1–Ta–O2  74.8(2)  O1–Ta–N3  162.4(2)  N3–Ta–N4  105.1(2)  O2–Ta–N5  148.1(2)  C2–C8–C15–C10  57.7(8)  The identity of 84 was ascertained by X-ray crystallographic analysis of another single crystal obtained by recrystallization of crude materials from concentrated benzene solution. In the solid-state, 84 is a C1-symmetric distorted octahedral complex with the amidate ligand bound to the metal center via the O-donor atoms only (Figure 4.8). Interestingly, the structure reveals the presence of a new N,N-chelating (dimethylaminomethylene)methylamide ligand. This new ligand is formed between the nitrogen atom of a dimethylamido ligand and the carbon atom of another dimethylamido ligand via an intramolecular C–H bond activation reaction (eq 4.3). This results in a four-membered metallacycle (Ta–N4–C35–N6) as depicted by the ORTEP representation in Figure 4.8. One of the chelating N-atoms, N6, is datively coordinated to the metal center and has a much longer Ta–N bond length (2.368(3) Å) than the other chelating Natom whose Ta–N bond length of 1.970(2) Å is similar to those of the non-chelating dimethylamido ligands (Table 4.5).  147  Figure 4.8. ORTEP representation of the solid-state molecular structure of 84 (ellipsoids plotted at 50% probability). All H-atoms are omitted for clarity.  Table 4.5. Selected bond lengths and angles of 84 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Ta–O1  2.031(2)  O2–Ta–N5  168.17(9)  Ta–O2  2.014(2)  O1–Ta–N4  146.25(9)  Ta–N3  1.977(2)  N3–Ta–N6  159.42(9)  Ta–N4  1.970(2)  N3–Ta–N5  93.18(10)  Ta–N6  2.368(3)  C10–C11–C8–C2  84.2(3)  There are only three documented examples of this intramolecular C–H bond activation reaction between amido ligands on group 5 metal complexes.338-340 Xue and co-workers have isolated similar four-membered N,N-chelating metallacycles of tantalum during the reaction of Ta(NMe2)5 with molecular oxygen (Scheme 4.7).338, 340 Exposure of Ta(NMe2)5 to O2 results in various  oxo  complexes  including  complexes  85  and  86  having  N,N-chelating  148  (dimethylaminomethylene)methylamide ligands (Scheme 4.7).340 Using DFT calculations, the authors proposed a reaction mechanism that involves the peroxide intermediate 87 undergoing hydride abstraction to yield an oxo-imine complex 88 (Scheme 4.8).340 Subsequent insertion of the imine into a Ta–NMe2 bond would then afford 89 featuring the N,N-chelating ligand (Scheme 4.8).340 Shortly after this initial report, the same group observed the formation of the C–H bond activation products, 90 and 91, during the synthesis of Ta(NMe2)5 and Nb(NMe2)5 (eq 4.4) by salt metathesis from lithium amide and homoleptic chloro complexes (eq 4.4).339 Here, the reaction mechanism was not clearly understood as various experimental investigations were either negative or inconclusive. In particular, it was discovered that the imine H2C=NMe, which was originally proposed as a neutral ligand in the mechanism outlined in Scheme 4.8, does not react with Ta(NMe2)5.339  Scheme 4.7. Unexpected formation of N,N-chelating (dimethylaminomethylene)methylamide tantalum complexes.  149  Scheme 4.8. Proposed mechanism for the formation (dimethylaminomethylene)methylamide tantalum complexes.  of  N,N-chelating  Based on the isolation of a tantallaaziridine with ancillary amidate ligands in our research group, complex 84 is proposed to form via metallaaziridine 92 (Scheme 4.9). Nucleophilic attack by the datively bound amine on the aziridine C-atom would lead to the tantalum hydride 93 which could react with the liberated dimethylamine to produce 84 and eliminate H2 (Scheme 4.9). Tantalum hydride-amido complexes such as 93 have been reported.341 Cummins and coworkers have spectroscopically and structurally characterized a number of tantalum and niobium hydride-amido complexes during studies aimed at small molecule activation and catalytic reduction of CO2.341-343 In addition, these researchers have observed H2 loss upon treating a  150  niobaaziridine-amido-hydride complex with benzaldehyde.343  The reductive elimination of  dimethylamine from 93 is presumably unfavourable as this will lead to a highly reactive and sterically-accessible Ta(III) species.  Scheme 4.9. Proposed mechanism for the formation of complex 84.  The possibility of 84 being formed by a protonolysis reaction between tantalum precursor 90 (eq 4.4) and proligand 68d cannot be eliminated as the Ta(NMe2)5 used as a starting material could be contaminated with 90. Although, the 1H NMR spectrum of Ta(NMe2)5 does not reveal the presence of any contaminant, 90 could be present in levels below the NMR detection limit. The formation of 84 as a side product during tantalum complex formation with proligand 68d is not well understood, but could be due to a sterically-accessible metal center.  151  4.2.1.3 Axially Chiral N-Alkyl Tantalum Amidate Complexes The importance of steric protection for reliable formation of well-defined complexes is more pronounced in the protonolysis reaction with proligand 68e.  Reaction of this alkyl-  containing, sterically unencumbered proligand with Ta(NMe2)5 results in complex product mixtures. The initial 1H NMR spectrum of the reaction mixture reveals complex 81e as the predominant product (eq 4.5). Neither the ratio of the products nor the number of products could be determined, as the overlapping signals corresponding to the minor products could not be reliably integrated. However, based on the number of doublets corresponding to the methyl protons of the isopropyl fragments, multiple minor products are formed. A singlet at δ 3.65 in the 1H NMR spectrum strongly suggests the formation of a complex similar to 84, containing a N,N-chelating (dimethylaminomethylene)methylamide ligand.  Performing the reaction at a  temperature of 65 °C increases the amounts of the minor products as suggested by 1H NMR spectroscopy. Attempts to separate the products by recrystallization were unsuccessful and results in co-precipitation of the products.  X-ray crystallographic analysis on a single isolated crystal revealed the identity of one of the minor products as C2-symmetric dimer 94 (eq 4.5 and Figure 4.9) in which the biphenyl linkage is bridging two tantalum centers with one amidate as an N,O-chelate for one metal center  152  and the second amidate also chelating to the other. The geometry about each metal center is distorted octahedral (Figure 4.9). Selected bond lengths and angles of 94 are given in Table 4.6.  Figure 4.9. ORTEP representation of the solid-state molecular structure of (±)-94 (ellipsoids plotted at 50% probability). All H-atoms and substituents on the amidate N are omitted for clarity.  Table 4.6. Selected bond lengths and angles of (±)-94 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Ta1–O1  2.154(3)  N3–Ta1–N5  173.73(18)  Ta1–N1  2.387(4)  O1–Ta1–N6  97.62(16)  Ta1–N3  2.035(4)  N4–Ta1–O1  158.63(16)  Ta2–O2  2.199(3)  N8–Ta2–N10  170.73(18)  Ta2–N2  2.289(4)  C6–C7–C10–C11  92.7(6)  Equimolar quantities of proligand 68f and Ta(NMe2)5 also react to afford a mixture of products. The mixture of products formed include C1-symmetric 81f featuring an N,O-chelating amidate and a neutral amide (the predominant product, eq 4.6) and C2-symmetric κ2-O,Obonding 82f. Using 1H NMR spectroscopy, the ratio of κ2-N,O-chelating C1-symmetric 81f to κ2-O,O-bonding C2-symmetric 82f was estimated as 7.5:1. Subjecting the reaction mixture to 153  higher temperatures does not facilitate exclusive formation of 82f. However, the ratio of 81f:82f changes from 7.5:1 to 1:1.2 after 3 days at 65 °C. A further increase in the reaction temperature to 110 °C increases the amount of the unidentifiable products as suggested by 1H NMR spectroscopy.  Recrystallization from a mixture of toluene and pentane afforded 81f  (contaminated with an unidentifiable minor product) in 20% yield as estimated by 1H NMR spectroscopy. The 1H NMR spectrum of this mixture contains a diagnostic broad singlet at δ 8.45 for the proton attached to nitrogen of the neutral amide moiety. This signal is shifted about 1.7 ppm downfield of the region where the signal associated with the free proligand N–H protons is observed, presumably due to a dative interaction between this amide moiety and the metal center.142 The 13C NMR spectrum contains two signals at δ 168.7 and 174.0 representing the neutral amide carbon and the N,O-chelating amidate carbon respectively.  In the solid-state, 81f is C1-symmetric with a distorted octahedral geometry about the metal center (Figure 4.10). The proton attached to the neutral amide cannot be located in the solved structure. However, the orientation of the amide moiety, which is away from the metal center, suggests that the N-atom remains protonated as the potential donor atoms (N and O) cannot interact with the metal center in this orientation. In addition, the Ta1–N2 and Ta1–O2 distances of 4.986 Å and 6.902 Å respectively, obviate any interaction of these donor atoms with  154  the metal center in the solid-state. The O2–C9 and C9–N2 bond distances of 1.203(15) and 1.329(16) respectively (Table 4.7) is also in agreement with a protonated amide moiety.  Figure 4.10. ORTEP representation of the solid-state molecular structure of 81f showing one molecule of a twinned structure (ellipsoids plotted at 50% probability). All H-atoms have been omitted for clarity.  Table 4.7. Selected bond lengths and angles of 81f Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Bond angles (°) Ta1–O1  2.215(8)  N6–Ta1–N7  174.8(4)  Ta1–N1  2.314(9)  O1–Ta1–N8  162.9(3)  C1–N1  1.312(12)  N1–Ta1–N5  148.7(4)  C1–O1  1.301(12)  N6–Ta1–N5  91.0(5)  O2–C9  1.203(15)  C1–Ta1–N6  84.9(4)  C9–N2  1.329(16)  C1–Ta1–N8  134.0(3)  N7–Ta1–N8  92.2(4)  C1–Ta1–N5  119.4(4)  O1–Ta1–N1  58.1(3)  C6–C8–C15–C14  88.3(12)  155  Recrystallization of another batch of reaction mixture from benzene over an extended period at ambient temperature affords 82f in 10% yield. The solid-state structure of 82f is isostructural with 82a as a similar distorted trigonal bipyramidal geometry can be seen about the metal center with one of the coordinating O-atoms and a dimethylamido occupying the axial positions. This solid-state structure (Figure 4.11) is also consistent with the spectroscopic data which indicates a C2-symmetric complex. The bond lengths and angles of 82f are also analogous to those of 82a and selected examples for 82f are given in Table 4.8.  Figure 4.11. ORTEP representation of the solid-state molecular structure of (±)-82f (ellipsoids plotted at 50% probability). All H-atoms and a benzene solvent molecule of crystallization have been omitted for clarity.  Table 4.8. Selected bond lengths and angles of (±)-82f Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Ta–O1  1.957(1)  O2–Ta–N5  174.66(6)  Ta–O2  2.023(1)  O1–Ta–N5  89.21(6)  Ta–N3  1.957(2)  O2–Ta–N3  94.18(6)  Ta–N4  1.955(2)  N3–Ta–N4  116.23(6)  C1–N1  1.258(2)  C14–C16–C3–C4  90.7(2) 156  The outcomes of the aforementioned protonolysis reactions with various amide proligands clearly highlight the importance of steric and electronic effects of the N-substituent for the reliable formation of well-defined monomeric complexes with this ligand motif. While exclusive formation of a κ2-O,O-coordinating ligand can be achieved with the bulky proligand 68a, less sterically demanding proligands 68b and 68c adopt two observable coordination geometries, κ3-N,O,O and κ2-O,O, upon complexation with tantalum. With proligand 68d and Ta(NMe2)5, an intramolecular C–H activation between the dimethylamido ligands results in a new N,N-chelating (dimethylaminomethylene)methylamide ligand being coordinated to tantalum in the resulting complex. The reason for the formation of this four-membered N,N-chelating metallacycle when this particular ancillary ligand is coordinated to tantalum is not well understood. However, it could be a consequence of sterics about the metal center as similar fourmembered N,N-chelating metallacycles have been observed during the synthesis of the stericallyaccessible homoleptic precursor to these complexes. Further, N-alkyl proligands 68e and 68f formed more complex products upon reaction with Ta(NMe2)5.  4.2.2 Enantioselective Hydroaminoalkylation Reactions 4.2.2.1 Catalytic Screening of Tantalum Amidate Complexes for the Hydroaminoalkylation Reaction Following the report of tantalum dialkylamido and chloro complexes as precatalysts for the hydroaminoalkylation reaction by Herzon and Hartwig,122, 123 the Schafer group developed achiral amidate-ligated tantalum complexes as precatalyst for this α-alkylation of amines. The successful utilization of amidate complexes as hydroaminoalkylation precatalysts suggests the feasibility of conducting enantioselective versions of this transformation reaction using the  157  above-discussed axially chiral tantalum amidate complexes as precatalysts. As such, these chiral tantalum complexes have been investigated as precatalysts for the enantioselective hydroaminoalkylation of alkenes. Preliminary screening of these complexes has been performed to determine the most effective precatalyst with the general test substrates 1-octene and Nmethylaniline (eq 4.7). Each reaction was set up inside the glove-box by adding 2 equivalents of 1-octene into a 1 dram vial containing 1 equivalent of N-methylaniline and 10 mol% of the precatalyst of choice (Table 4.9). The mixture was then quantitatively transferred into a J. Young NMR tube and the tube was placed in an oil bath set at 130 °C outside the box. The progress of the reaction was periodically monitored by 1H NMR spectroscopy. Using bulky complex 82a as a precatalyst, the 1H NMR spectrum indicates the exclusive formation of the branched regioisomer 95a (eq 4.7) from 1-octene and N-methylaniline. This spectrum also indicates the formation of another compound, 96a (eq 4.7), which is the product of the double hydroaminoalkylation reaction between one dimethylamido ligand on the precatalyst and 2 equivalents of the alkene substrate (eq 4.7). Purification by column chromatography allows for the isolation of 95a in 86% yield. The formation of compound of the type 96 accompanies all hydroaminoalkylation reactions catalyzed by this class of axially chiral tantalum complexes.  158  Table 4.9. Precatalyst screening in the enantioselective hydroaminoalkylation reaction  Entry  Precatalyst(s)  Time/h  82a  % eec  (benzamide)b  (S)1  Yielda  48  86  44  (89) 2  82b·HNMe2/83b  48  79  5  (82) 3  82c·HNMe2/83c  72  80  21  (82) 4  83d  38d  28  1  (81) a  Isolated yield of amine product. b Isolated yield of benzamide. of the benzamide. d Reaction stalled after 38 h.  c  Determined by HPLC analysis  The desired hydroaminoalkylation product 95a was derivatized to the corresponding benzamide 97a using 2 equivalents of benzoyl chloride in the presence of an excess of triethylamine.  Analysis of 97a by HPLC equipped with a chiral column allows for the  determination of the enantiomeric excess of this product as 44% (Table 4.9, entry 1). This result is quite gratifying as it represents the first example of enantioselective hydroaminoalkylation. The less bulky complexes in entries 2 and 3 of Table 4.9 afford the product in a lower ee of 5% and 21% respectively. The reactions presented in these entries are performed with a mixture of complexes as these complexes could not be separated from each other. Using the stericallyaccessible complex 83d as the precatalyst, the reaction is very slow and does not proceed beyond 38% conversion after 38 hours at 130 °C (Table 4.9, entry 4). In addition, the product of this 159  particular reaction is a racemate. This catalyst screen suggests complex 82a is the most reactive and enantioselective precatalyst of this series of complexes and as such, complex 82a is utilized for further substrate scope investigation.  4.2.2.2  Substrate  Scope  Investigation  of  Complex  82a  in  Enantioselective  Hydroaminoalkylation Reactions The initial reports of the tantalum catalyzed hydroaminoalkylation reaction show that the precatalyst activities are limited to select substrates. While Ta(NMe2)5 is effective for the reactions involving N-aryl alkylamines,123 the corresponding reactions with dialkylamines occur in very poor yield.133 Likewise, the publications detailing the use of chiral tantalum complex 79 as a precatalyst describe only aryl containing secondary amines as the N–H containing substrates.124,  127  Similarly, the report on the hydroaminoalkylation reaction performed with  precatalyst 80 is limited to terminal alkenes.  Precatalyst Ta(NEt2)2Cl3 is efficient for the  hydroaminoalkylation reaction of 1-octene with dialkylamines but the efficiency of this complex for reactions involving N-aryl alkylamines and other alkenes is yet to be reported. Achiral amidate-ligated tantalum complex 78 of the Schafer group has a broader substrate scope than all the aforementioned catalytic systems. Complex 78 is efficient for the hydroaminoalkylation of dialkylamines and N-aryl alkylamines with various alkenes including terminal, internal, and polar functional groups bearing alkenes. Similar to 78, chiral complex 82a is competent for the hydroaminoalkylation reactions involving diverse substrates (Scheme 4.10) as revealed by the substrate scope investigation described below. Precatalyst 82a is tolerant of bulky substituents on the alkene as demonstrated with the reaction of vinylcyclohexane with N-methylaniline to generate product 95b in 92% isolated yield  160  after 48 hours at 130 °C (Scheme 4.10). Chiral SFC analysis of the corresponding benzamide 97b indicates an ee of 51% (Scheme 4.10). Alternatively, the crude reaction mixture can be treated with p-toluenesulfonyl chloride under basic conditions to afford the tosyl-derivative 98b in 40% yield (eq 4.8). The modest isolated yield realized with this particular method is due to poor separation during purification by column chromatography. Although this approach results in moderate isolated yield of the tosylated product, it allows for the isolation of the tosylderivative (99b, eq 4.8) of the double hydroaminoalkylation product thereby confirming the formation of compound 96b. Allylbenzene also reacts with N-methylaniline in the presence of 10 mol% of 82a to generate 95c in 70% isolated yield and analysis of 97c by chiral SFC indicates an enantiomeric excess of 30% (Scheme 4.10). Oxygen functionality on the alkene is also compatible with this catalyst system; TBDMS-protected 5-hexenol reacts with Nmethylaniline to produce 95d in 81% yield with 37% ee (Scheme 4.10). The competency of 82a was extended to internal alkenes using norbornene as a co-substrate with N-methylaniline to afford 95e in 80% isolated yield with 61% ee (Scheme 4.10).  Importantly, amine 95e is  produced with excellent diastereoselectivity as only one diastereomer is observed in the 1H NMR spectrum. Further, using the R-enantiomer of complex 82a as a precatalyst, product 95e is obtained in 85% yield with 64% ee of the opposite stereoisomer as indicated by chiral HPLC analysis of the corresponding benzamide 97e (Scheme 4.11). The exo-selectivity has been established by single crystal X-ray crystallographic analysis of 97e. This compound crystallizes in the triclinic chiral space group P1 with two independent molecules in the asymmetric cell. The solid-state structure is depicted in Figure 4.12 and selected bond lengths and angles are given in Table 4.10. The diastereoselectivity observed for product 95e can be rationalized by the  161  steric accessibility of the exo-face of the π-bond for selective insertion into the Ta–C of the metallaaziridine. While the exo-selectivity of the amine substituent in 97e is clearly observable from the solid-state structure, the absolute configuration of this product cannot be determined from this structure as the single crystal isolated was obtained from enantioenriched materials. Furthermore, this molecule does not contain an internal stereogenic center of known configuration that could serve as an internal reference for absolute configuration determination.  162  Scheme 4.10. Amine products from substrate scope investigation of enantioselective hydroaminoalkylation reaction using precatalyst 82a.  Figure 4.12. ORTEP representation of the solid-state molecular structure of 97e showing one of two independent molecules in the asymmetric unit (ellipsoids plotted at 50% probability). All Hatoms are omitted for clarity.  163  Table 4.10. Selected bond lengths and angles of 97e Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  C1–O2  1.235(3)  O1–C2–N1  121.4(2)  C2–N1  1.373(3)  C2–N1–C1  119.3(2)  C1–N1  1.472(3)  N1–C1–C5  113.6(2)  C1–C5  1.510(4)  C12–N1–C1  117.3(2)  Scheme 4.11. Hydroaminoalkylation of norbornene with N-methylaniline using precatalyst (R)82a. Various amines also undergo hydroaminoalkylation reactions with alkenes in the presence of precatalyst 82a.  Product 95f is isolated in 90% yield with excellent  diastereoselectivity following the reaction of N-methyl-4-methoxyaniline with norbornene for 24 hours under catalytic conditions (Scheme 4.10).  Examination of the corresponding  benzamide 97f by chiral HPLC reveals an ee of 52%. Similarly, N-methyl-4-methoxyaniline reacts with vinylcyclohexane and TBDMS-protected allyl alcohol to afford 95g (73% yield with 43% ee) and 95h (74% yield with 29% ee) respectively. Importantly, the p-methoxyphenyl (PMP) substituent on the N-functionality in products 95f, 95g, and 95h can be easily deprotected thereby allowing access to primary amines which can undergo further synthetic manipulations (vide infra). Product 95i is also obtained with excellent diastereoselectivity and a modest enantiomeric excess of 57% from norbornene and 1,2,3,4-tetrahydroquinoline, although this reaction proceeds sluggishly.  164  The competency of 82a for the hydroaminoalkylation reaction is not limited to arylcontaining amines. The dialkylamine, N-methylbenzylamine, reacts with norbornene to afford two regioisomeric products 95j and 95k in a 1:1 ratio as determined by 1H NMR spectroscopy (Scheme 4.12). Compounds 95j and 95k were tosylated to 98j (66% ee) and 98k (55% ee) for ease of characterization and enantiomeric excess determination (Scheme 4.12).  Scheme 4.12. Enantioselective hydroaminoalkylation of norbornene with N-methylbenzylamine using precatalyst 82a.  The substrate scope investigation shows that complex 82a is a competent precatalyst for the hydroaminoalkylation reaction between secondary dialkyl- and N-aryl alkylamines with various alkenes including terminal, internal, and functionalized alkenes. These reactions proceed at 130 °C to give only the branched regioisomer for these combinations of reactants in isolated yield of up to 92% and enantiomeric excess reaching 66%.  Importantly, the reactions  consistently display excellent diastereoselectivity as suggested by 1H NMR spectroscopy.  165  4.2.2.3 Determination of the Absolute Configuration of the Hydroaminoalkylation Products Initial attempts to determine the absolute configuration of the hydroaminoalkylation reaction products focused on the formation of amide diastereomers via the reaction of the secondary amine products with chiral carbonyl derivatives. Separation of these diastereomers by column chromatography and subsequent X-ray crystallography would allow for absolute configuration determination as the additional stereogenic center in the diastereomers would serve as an internal reference.  Unfortunately, the diastereomers made using various carbonyl  derivatives could not be separated by column chromatography (Scheme 4.13), therefore, this approach was abandoned.  Further attempts to assign the absolute configuration of the  hydroaminoalkylation products were directed toward obtaining enantiomerically pure sample of 97e for X-ray analysis. However, repeated recrystallization attempts with 97e did not afford enantiomerically pure crystalline materials.  Scheme 4.13. Synthesis of amide diastereomers for stereochemical configuration analysis.  Finally, the absolute configuration of the hydroaminoalkylation products was established by comparison of the optical rotation of amino alcohol 100 (eq 4.9) with literature values.344  166  Compound 100 is obtained from 95h by treating the crude hydroaminoalkylation reaction mixture with 3 M aqueous HCl solution (eq 4.9). It is worth mentioning that R-enantiomer of complex 82a was employed as precatalyst in the synthesis of 95h outlined in eq 4.9. The deprotected amino alcohol 100 is isolated in 62% yield following an acid-base extraction process and flash column chromatography. Tan and co-workers have previously prepared a number of amino alcohols including 100 via catalytic enantioselective hydroformylation and subsequent reduction.344  Using two different approaches, these authors ascertained the absolute  configuration of the hydroformylation products by synthesizing two different compounds of known configurations from the amino alcohols.344 The absolute configurations of the other products, including 100, were then assigned by analogy to these compounds. The reported specific rotation value for (S)-100 is [α measured in this study is [α  22 D  20 D  + 2.2 (c 0.110, CHCl3, l = 0.5)344 while the value  + 2.9 (c 0.38, CHCl3, l = 1.0), indicating the same sense of  absolute configuration.  The mechanism of the hydroaminoalkylation reaction catalyzed by this class of precatalysts was not investigated; as such little is known about the mechanistic pathway. The understanding of the mechanistic pathway is currently being investigated by another member of the group.  167  4.2.2.4 Thermal Stability of Precatalyst 82a In addition to the amine products isolated during the catalytic hydroaminoalkylation reactions with complex 82a, a small quantity of a ligand rearrangement product is also isolated. The 1H NMR spectrum of this compound indicates a C1-symmetic molecule as evidenced by the inequivalence of the isopropyl group‟s methyl protons, which resonate as eight doublets between δ 0.46 and 1.26. In addition, the methyl protons on the biphenyl backbone appear as two singlets at δ 2.18 and 2.23. Furthermore, the 13C NMR spectrum shows two signals at δ 153.4 and 170.1 representing an imine and carbonyl C respectively. Based on this NMR spectroscopic data and the mass spectrometry data, which reveals a molecular ion peak of 570, this compound was identified as the tricycle 101 (eq 4.10). Compound 101 is probably formed from 82a by nucleophilic attack of the N atom of one amidate moiety of the biphenyl ligand on the imine C of the other amidate on the same ligand with the resultant intramolecular cyclization of the biphenyl ligand (eq 4.10). The above observation prompted an investigation into the thermal stability of precatalyst 82a. A solution of complex 82a in d8-toluene is subjected to heating at 130 °C and after 46 hours, about 8% of 101 is observed by 1H NMR spectroscopy (estimated by comparison of the integral values of the isopropyl group‟s methyl protons of the original ligand with the same protons on 101). Heating the d8-toluene solution of 82a at a higher temperature of 145 °C for 24 hours increases the conversion to 101 to 16%. Deliberate hydrolysis and subsequent column chromatography allows the isolation of 101 (eq 4.10) in 10% yield. The increase in ligand rearrangement that corresponds to an increase in temperature suggests elevated reaction temperatures are detrimental to the catalytic activity of complex 82a.  168  Single crystals of 101 suitable for X-ray analysis were obtained by recrystallization from a mixture of hexanes and ethyl acetate. The solid-state structure confirms the proposed tricyclic solution phase structure and shows the formation of a new seven-membered ring involving the donor atoms of the ligand (Figure 4.13). Selected bond lengths and angles of 101 are given in Table 4.11.  Figure 4.13. ORTEP representation of the solid-state molecular structure of (±)-101 (ellipsoids plotted at 50% probability). All H-atoms are omitted for clarity.  169  Table 4.11. Selected bond lengths and angles of (±)-101 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  C15–O  1.220(1)  N2–C15–O  120.58(11)  C16–N1  1.267(1)  C15–N2–C16  125.33(10)  C15–N2  1.384(1)  N2–C16–N1  116.68(10)  C16–N2  1.432(1)  C16–N1–C17  121.96(10)  Based on all the above investigations, the optimal catalytic conditions for hydroaminoalkylation reactions with precatalyst 82a have been determined to be as follows: 1 equivalent of amine, an excess of alkene (at least 2 equivalents), d6-benzene as the solvent with the total final concentration being 1.0 M in amine and a reaction temperature of 130 °C. Using these optimized conditions, reaction time for the test substrates: 1-octene and N-methyl aniline has been improved from 48 hours to 24 hours.  4.2.3 Synthesis and Characterization of Cyclohexyl-Tethered Tantalum Amidate Complexes 4.2.3.1 Synthesis of Cyclohexyl-Tethered Bis(amide) Proligands While tantalum complex 82a is quite efficient as a precatalyst for the intermolecular hydroaminoalkylation reaction, the enantioselectivities obtained with this catalyst system are only moderate. The modest enantioselectivities are attributed to the distal location of both the chiral biphenyl backbone and the distance of the substituent on the amidate N from the metal center due to the κ2-O,O-bonding mode of the ligand. To investigate the effect of increased steric bulk about the metal center in tantalum-catalyzed hydroaminoalkylation reactions, the cyclohexyl-tethered amides 102 and 103 (Scheme 4.14) have been employed as proligands for tantalum complex formation. This class of proligand is capable of providing a more sterically-  170  congested environment about the metal center as the donor atoms are well-positioned to adopt a tetradentate binding motif upon complex formation. Furthermore, the tethered backbone would limit coordination isomers accessible if two monoanionic amidate ligands are used.138 The syntheses of 102 and 103 have been achieved via the procedure outlined in Scheme 4.14. Refluxing 2,4,6-trisubstituted benzoic acid with thionyl chloride in the presence of catalytic amount of 4-dimethylaminopyridine (DMAP) generates the corresponding benzoyl chloride in situ. The in situ generated benzoyl chloride is then reacted with 1R,2R-(–)-diaminocyclohexane under reflux conditions to afford the amide proligand.  Following purification by column  chromatography, the proligands are obtained as white solids in isolated yield of 32% and 46% for 102 and 103 respectively. These proligands are dried at 80 °C for at least sixteen hours before being employed in metal complex formation.  Scheme 4.14. Synthesis of cyclohexyl-tethered amide proligands.  4.2.3.2. Synthesis of Cyclohexyl-Tethered Tantalum Amidate Complexes A protonolysis reaction between equimolar amounts of 102 and Ta(NMe2)5 in benzene affords complex 104 as a yellow solid in 98% yield (eq 4.11). The 1H NMR spectrum shows a series of overlapping doublets between δ 1.20 and 1.44, which represents the methyl protons of  171  the isopropyl fragments. The methyl protons for the dimethylamido ligands appear as two singlets at δ 3.80 and 3.90, integrating for 12 and 6 protons respectively. The  13  C NMR  spectrum contains a single signal for the amidate C at δ 182.0 indicating that both the amidates are N,O-chelating to the metal center and likely adopting a tetradentate binding motif (eq 4.11). Attempts to structurally characterize this complex by X-ray crystallography were unsuccessful as recrystallization results in microcrystalline materials. However, the proposed formulation (eq 4.11) is supported by 1H and 13C NMR spectroscopy, mass spectrometry, and elemental analysis.  Proligand 103 reacts with an equivalent amount of Ta(NMe2)5 to afford a mixture of two products: complex 105 in which the ligand adopts a κ4-O,N,N,O-bonding motif, and complex 106 in which the ligand is coordinated to the metal center in a κ3-O,N,N-bonding mode (eq 4.12). These complexes exist in a ratio of 1:5 as estimated by 1H NMR spectroscopy with 106 being the prevalent species. In the solid-state, complex 106 is C1-symmetric and features a distorted octahedral geometry about the metal center (Figure 4.14). The Ta–O bond length (2.240(3) Å) of the N,O-chelating amidate is significantly longer than the Ta–O bond length (2.018(3) Å) of the O-bound amidate, suggesting a higher degree of multiple bond character in the latter (Table  172  4.12). The C1–N1 bond length of 1.305(5) Å is similar to the C1–O1 of 1.299(5) Å in agreement with electron delocalization over the N1–C1–O1 framework.  Figure 4.14. ORTEP representation of the solid-state molecular structure of (±)-106 (twinned structure, ellipsoids plotted at 50% probability). All H-atoms are omitted for clari  173  Table 4.12. Selected bond lengths and angles of (±)-106 Atoms  Bond lengths (Å)  Atoms  Bond angles (°)  Ta–O1  2.240(3)  O1–Ta–N5  171.93(12)  Ta–O2  2.018(3)  O2–Ta–N4  166.50(13)  Ta–N1  2.213(3)  N1–Ta–N3  143.07(14)  Ta–N3  1.979(3)  O1–Ta–N4  89.33(13)  C1–N1  1.305(5)  O2–Ta–O1  90.49(11)  C1–O1  1.299(5)  N1–Ta–O1  58.64(3)  4.2.3.3. Hydroaminoalkylation Reaction Using Cyclohexyl-Tethered Tantalum Amidate Complexes as Precatalysts Catalytic investigations performed using the aforementioned optimized conditions shows that the cyclohexyl-tethered amidate complexes are much less active and less selective precatalysts for the hydroaminoalkylation reaction in comparison to the biphenyl-tethered amidate complexes. The test reaction with complex 104 only achieved 42% conversion after 144 hours at 130 °C in d6-benzene, while the mixture of 105 and 106 attained 62% conversion after 72 hours (75% conversion after 144 h) under the same condition (Scheme 4.15). In addition, these complexes generate the product as a racemic mixture. This observation suggests that increased steric bulk about the metal center has a negative effect on the catalytic activity of the complex.  The slow reactivity of seven-coordinate complex 104 is probably due to the  coordinatively saturated metal center in this complex and the slightly increased activity observed with 105/106 mixture is attributed to a faster reaction via the coordinatively less saturated sixcoordinate complex 106. These results are consistent with earlier findings in our group by Dr. Patrick Eisenberger that six-coordinate mono(amidate) complexes are more efficient hydroaminoalkylation precatalysts than their seven-coordinate bis(amidate) counterparts. This  174  would suggest that an open coordination site is required, presumably for pre-coordination of the amine substrate during the catalysis (according to the catalytic cycle in Scheme 1.17).  Scheme 4.15. Hydroaminoalkylation reactions catalyzed by tantalum cyclohexyl-tethered amidate complexes.  4.2.4 Synthesis of an Amino Alcohol by Hydroaminoalkylation and Oxidative PMPCleavage Amino alcohols are important molecules that have wide applications in synthetic and medicinal chemistry.345, 346 These compounds have been utilized as chiral auxiliaries and ligands for asymmetric catalysis.347 In addition, the amino alcohol moiety is a key structural unit in many natural products,348-350 potent drugs351-353 and bioactive molecules.351-353  Therefore,  efficient methods of synthesizing these molecules are highly attractive. A variety of methods are available for preparing amino alcohols including epoxide ring opening by amines,354-357 aminohydroxylation,358,  359  aldehydes.366,  The  367  reduction of amino ketones,360-365 and nucleophilic addition to hydroaminoalkylation  reaction  between  TBDMS-protected  hydroxyalkenes and amines is an alternative route to amino alcohols as the TBDMS protecting group can be easily removed to reveal the unprotected amino alcohols as demonstrated with the synthesis 100 from 95h. Furthermore, the p-methoxyphenyl (PMP) substituent on the N-atom in  175  these compounds (100 and 95h) can be cleaved to reveal a primary amino group that could undergo further manipulations. Therefore, as a proof of principle, both the alcohol and the amino group in 95h have been unmasked as outlined in Scheme 4.16. This procedure involves removing the solvent from crude hydroaminoalkylation reaction and taking up the product in ice cold hexanes to induce precipitation of the ligand/Ta species.  Oxidative cleavage of the PMP-group with cerium  ammonium nitrate leads to in situ formation of amino alcohol 107. Compound 107 is then converted to 108 by treatment with N-(9-fluorenylmethoxycarbonyloxy) succinimide (FmocOSu) under basic conditions for ease of isolation and characterization as 107 is extremely water soluble. Unlike the PMP-protecting group, the Fmoc-protecting group can be easily removed under milder conditions and as a result has found wide application in peptide synthesis.368 The successful deprotection of the hydroxyl and amino groups in 95h suggests possible further synthetic transformation of these functional groups. For example, the primary alcohol could be oxidized to carboxylic acid thereby allowing access to β-amino acids in a tandem reaction sequence.  176  Scheme 4.16. Synthesis of Fmoc-protected amino alcohol.  4.3 Conclusions A series of tantalum biphenyl-tethered amidate complexes with varied steric and electronic substituents on the N-functionality of the amidate ligand have been synthesized and characterized by various analytical methods including NMR spectroscopy and single crystal Xray analysis. The formation of discrete, well-defined tantalum complexes with this ligand motif is found to be greatly influenced by the steric bulk of the substituent on the amidate-nitrogen. Sterically-congested proligand 68a exclusively affords a κ2-O,O-bound amidate complex and the less bulky proligands 68b and 68c afford a mixture of both κ2-O,O, and κ3-N,O,O-bound coordination isomers. VT NMR spectroscopy shows that the κ2-O,O-bound amidate complexes predominate in solution at high temperatures. In contrast, more sterically-accessible proligands result in dimeric/aggregate species. Interestingly, tantalum complex formation with stericallyaccessible proligand 68d promotes C–H bond activation between the amido ligands resulting in the formation of a new N,N-chelating (dimethylaminomethylene)methylamide ligand.  177  Preliminary catalyst screening identifies complex 82a as the most reactive and enantioselective precatalyst for hydroaminoalkylation with this ligand motif. A wide range of alkenes, including terminal and internal alkenes and diverse amines such as dialkylamine, arylalkylamines, and cyclic-amines are viable substrates in these first examples of enantioselective hydroaminoalkylation catalysis. The reactions exclusively afford the branched regioisomer with enantioselectivity of up to 66% with excellent diastereoselectivity. Sterically-congested metal environments have been found to have a negative effect on both reactivity and selectivity of the hydroaminoalkylation reaction. Longer reaction times and lack of selectivity is observed upon employing sterically-congested cyclohexyl-tethered tantalum complexes as precatalysts. This observation corroborates earlier findings in the group that seven-coordinate bis(amidate) tantalum complexes are less active in comparison to their sixcoordinate mono(amidate) tantalum counterparts. The work presented herein demonstrates the importance of the steric properties of the N-amidate substituent for the reliable formation of welldefined tantalum amidate complexes and would serve as a guide toward designing more effective hydroaminoalkylation precatalysts. Finally, the hydroaminoalkylation reaction has been combined with an oxidative deprotection to access a γ-amino alcohol thereby demonstrating the potential utility of this transformation. Importantly, this reaction sequence can be performed without prior purification of the hydroaminoalkylation product by column chromatography.  178  4.4 Experimental Procedures 4.4.1 Materials and Methods General manipulations and techniques are as outlined in Chapter 2 Section 2.4.1 and Chapter 3 Section 3.4.1 and also include the following additions. Enantiomeric excesses were determined by HPLC (Agilent series 1100 with a UV/VIS detector, λ = 215 nm) or SFC (TharSFC with a UV/VIS detector, λ = 200–215 nm) analysis of the amines or corresponding benzamides using the chiral stationary column indicated and comparing to the appropriate racemic mixtures. Ta(NMe2)5 was purchased from Strem and used as received; 1R,2R-(–)diaminocyclohexane was purchased from TCI and used without further purification. analytical  data  for  N-(2-methyl-3-phenylpropyl)aniline,123  The  N-(bicyclo[2.2.1]heptan-2-  ylmethyl)aniline123 are consistent with literature data.  4.4.2 Representative Procedures 4.4.2.1 Procedure 1: Representative Procedure for the Synthesis of Tantalum Complexes Example: Tantalum biphenyl amidate complex 82a A solution of 0.162 g (0.404 mmol) of Ta(NMe2)5 in benzene was added to a suspension of 0.238 g  (0.404  mmol)  of  N,N′-bis(2,6-diisopropylphenyl)-6,6′-dimethylbiphenyl-2,2′-  dicarboxamide in benzene and the mixture was stirred for 7 h at room temperature. The volatiles were removed in vacuo to give the product as a pale yellow solid in 98% yield (0.357 g, 0.397 mmol). The crude product was used for catalysis without further purification.  Crystals suitable for X-ray crystallography were  obtained from a mixture of benzene and pentane.  179  1  H NMR (d6-benzene, 400 MHz, ): 1.08 (6H, d, J = 6.7 Hz, 2 × Ar–CHCH3), 1.25 (6H, d, J =  6.7 Hz, 2 × Ar–CHCH3), 1.41 (6H, d, J = 7.3 Hz, 2 × Ar–CHCH3), 1.47 (6H, d, J = 7.3 Hz, 2 × Ar–CHCH3), 2.33 (6H, s, 2 × Ar–CH3), 2.40 (2H, m, 2 × CH(CH3)2), 2.89 (18H, s, 3 × – N(CH3)2), 3.55 (2H, m, CH(CH3)2), 7.10–7.27 (10H, m, 10 × Ar–H), 7.68 (2H, br d, J = 6.7 Hz, 2 × Ar–H);  C{1H} NMR (d6-benzene, 100 MHz, ): 21.3, 22.4, 22.9, 24.1, 26.0, 28.4, 29.3,  13  45.6, 122.7, 122.8, 123.0, 125.4, 128.0, 130.3, 137.5, 138.7, 139.2, 140.9, 146.0, 159.9; MS(EI) m/z: 899 (M+), 855 (M+ – NMe2), 811 [M+ – (NMe2)2]; Anal. Calcd for C46H64N5O2Ta: C, 61.39; H, 7.17; N, 7.78. Found: C, 61.54; H, 7.23; N, 7.39.  Tantalum biphenyl amidate complex 82f Complex 82f was synthesized according to procedure 1 with the following starting compounds: Ta(NMe2)5, 0.075 g (0.186 mmol); proligand 68f, 0.100 g (0.186 mmol). The reaction mixture was stirred at room temperature for 16 h. Recrystallization from benzene solution afforded 82f in 10% yield (0.016 g, 0.019 mmol). 1  H NMR (d6-benzene, 300 MHz, ): 1.71 (12H, br s, adamantly–  H), 2.10–2.04 (18H, m, adamantyl–H), 2.25 (6H, s, 2 × Ar–CH3), 3.12 (18H, s, 3 × N(CH3)2), 7.12 (4H, m, 4 × Ar–H), 7.45 12 (2H, m, 2 × Ar–H); 13C{1H} NMR (d6-benzene, 100 MHz, ): 21.0, 30.9, 37.8, 43.6, 45.4, 54.5, 125.4, 127.5, 129.6, 138.0, 141.3, 157.5; Anal. Calcd for C42H60N5O2Ta: C, 59.49; H, 7.13; N, 8.26. Found: C, 60.48; H, 7.28; N, 8.06.  180  Tantalum biphenyl amidate complexes 82b·HNMe2 and 83b (mixture) The above complexes were synthesized according to procedure 1 by reacting 0.240 g (0.600 mmol) of Ta(NMe2)5 with 0.303 g (0.600 mmol) of proligand 68b in benzene for 16 h at ambient temperature. Recrystallization from a mixture of benzene and hexanes afforded the complexes in 70% yield (0.360 g). 1  H NMR (d6-benzene, 600 MHz, a denotes 82b·HNMe2, b denotes 83b, occurring in a 2:1 ratio  as determined by integration of signals at δ 2.93 and 3.30 respectively, ): 1.16b (3H, s, Ar–CH3), 1.42b (3H, s, Ar–CH3), 1.71b (3H, s, Ar–CH3), 1.76a (6H, br s, 2 × Ar–CH3), 1.87b (3H, s, Ar–CH3), 1.93a (6H, br s, HN(CH3)2), 2.09b (3H, s, Ar–CH3), 2.19b (3H, s, Ar–CH3), 2.22a (6H, s, 2 × Ar–CH3), 2.24a (6H, s, 2 × Ar–CH3), 2.26b (3H, s, Ar–CH3), 2.37a (6H, s, 2 × Ar–CH3), 2.56b (3H, s, Ar–CH3), 2.93a (18H, s, 3 × (NCH3)2), 3.30b (18H, s, 3 × (NCH3)2), 6.47b (1H, s, Ar–H), 6.51b (1H, s, Ar–H), 6.76a ( 2H, s, 2 × Ar–H), 6.81a,b (3H, m, 3 × Ar–H), 6.86b (1H, s, Ar–H), 6.90b (1H, d, J = 7.1 Hz, Ar–H), 7.04– 7.17a,b (7H, m, 7 × Ar–H), 7.49b (1H, d, J = 7.2 Hz, Ar–H), 7.52a (2H, d, J = 7.2 Hz, 2 × Ar–H), 7.58b (1H, d, J = 7.7 Hz, Ar–H);  13  C{1H} NMR (d6-benzene, 150 MHz, ):  18.2, 18.9, 19.2,  19.5, 19.7, 19.8, 20.9, 21.4, 21.4, 21.4, 21.5, 40.2, 47.3, 47.4, 126.0, 126.3, 127.3, 127.9, 128.5, 128.7, 128.8, 128.9, 129.0, 129.1, 130.0, 130.2, 130.3, 130.6, 130.9, 131.9, 132.3, 133.7, 134.2, 135.1, 137.5, 138.4, 138.6, 138.7, 138.7, 139.1, 139.3, 141.1, 141.5, 145.1, 146.1, 159.9, 160.8, 180.1; MS(EI) m/z: 815 (M+), 771 (M+ – NMe2).  181  Tantalum biphenyl amidate complex 82c·HNMe2 Complex 82c·HNMe2 was synthesized by reacting 0.095 g (0.24 mmol) of Ta(NMe2)5 with 0.11 g (0.24 mmol) proligand 68c in benzene for 16 h at ambient temperature according to procedure 1. The complex was isolated as a pale yellow solid in 97% yield (0.19 g, 0.23 mmol) after removal of the volatiles in vacuo (4 h). 1  H NMR (d6-benzene, 400 MHz, ): 1.79 (6H, br s, 2 × Ar–CH3), 1.91 (6H, br d, J = 5.5 Hz,  HN(CH3)2), 2.23 (6H, s, 2 × Ar–CH3), 2.38 (6H, s, 2 × Ar–CH3), 2.92 (18H, s, 3 × –N(CH3)2), 6.87 (2H, br t, J = 7.4 Hz, 2 × Ar–H), 6.94 (2H, d, J = 7.0 Hz, 2 × Ar–H), 7.00 (2H, d, J = 7.0 Hz, 2 × Ar–H), 7.13 (4H, m, 4 × Ar– H), 7.50 (2H, d, J = 7.0 Hz, 2 × Ar–H);  13  C{1H} NMR (d6-  benzene, 100 MHz, ): 19.4, 19.8, 21.5, 40.1, 47.6, 122.2, 126.0, 127.9, 128.3, 128.9, 129.2, 130.4, 137.4, 138.8, 141.0, 148.7, 160.9.  MS(EI) m/z: 787 (M+ – HNMe2), 743 [M+ – HNMe2,  NMe2]; Anal. Calcd for C38H48N5O2Ta (note: neutral dimethylamine is not included in this molecular formula): C, 57.94; H, 6.14; N, 8.89. Found: C, 57.34; H, 5.91; N, 8.43.  Tantalum biphenyl amidate complex 83d 1  H NMR (d6-benzene, 400 MHz, ): 1.44 (3H, s, Ar–CH3), 2.09  (3H, s, Ar–CH3), 3.37 (18H, s, 3 × N(CH3)2), 6.37 (2H, br d, J = 7.8 Hz, 2 × Ar–H), 6.62 (1H, d, J = 7.4 Hz, Ar–H), 6.70 (1H, m, Ar–H), 6.77 (2H, m, 2 × Ar–H), 6.89 (1H, t, J = 8.0 Hz, Ar–H), 6.99–7.05 (3H, m, 3 × Ar–H), 7.12–7.18 (4H, m, 4 × Ar–H), 7.61 (1H, d, J = 7.8 Hz, Ar–H), 7.68 (1H, br t, Ar–H); 13C{1H} NMR (d6-benzene, 100 MHz, ): 20.6, 21.1, 47.3,  182  121.7, 122.2, 123.0, 123.7, 124.3, 125.8, 127.1, 127.3, 127.7, 129.3, 129.8, 132.4, 137.2, 137.4, 139.0, 139.1, 141.8, 144.1, 150.9, 161.6, 177.8.  4.4.2.2 Procedure 2: Representative Procedure for Hydroaminoalkylation of Alkenes Example: N-(bicyclo[2.2.1]heptan-2-ylmethyl)aniline 95e A mixture of 0.054 g (0.50 mmol) of N-methylaniline, 0.094 g (1.0 mmol) of norbornene, and 0.045 g (0.05 mmol) of complex 82a in 0.5 mL of d8-toluene was heated at 130 °C (in an oil bath) for 46 h in a J. Young NMR tube. A few drops of hexanes was added to the mixture and then stirred for 30 minutes at room temperature. The precipitate was filtered off and the solvent was removed by rotary evaporation. The crude product was purified by flash column chromatography using a 40:1 mixture of hexanes/ethyl acetate to afford a viscous colourless oil (dr > 20:1) in 80% yield (0.080 g, 0.40 mmol).  N-(2-cyclohexylpropyl)aniline 95b The quantities of reagents employed in the synthesis of N-(2cyclohexylpropyl)aniline are as follows: N-methylaniline, 0.058 g (0.54 mmol); vinylcyclohexane, 0.12 g (1.1 mmol); precatalyst 82a, 0.049 g, (0.054 mmol). The product was obtained as colourless oil after column chromatography with a 20:1 mixture of hexanes/ethyl acetate in 92% yield (0.11 g, 0.49 mmol). 1  H NMR (CDCl3, 400 MHz, ): 0.98 (3H, d, J = 6.8 Hz, –CHCH3), 1.04–1.44 (6H, m, 5 × Cy–H,  –CHCH3), 1.64–1.72 (4H, m, 4 × Cy–H), 1.80 (2H, m, 2 × Cy–H), 2.93 (1H, dd, J = 12.3, 7.8 Hz, –CH2NHPh), 3.20 (1H, dd, J = 12.3, 5.5 Hz, –CH2NHPh), 3.66 (1H, br s, –CH2NHPh), 6.64 (2H, d, J = 8.2 Hz, 2 × Ar–H), 6.72 (1H, t, J = 7.3 Hz, Ar–H), 7.21 (2H, t, J = 7.7 Hz, 2 ×  183  Ar–H);  13  C{1H} NMR (CDCl3, 100 MHz, ): 15.0, 26.9, 26.9, 27.0, 28.9, 31.1, 38.2, 41.0, 48.1,  112.8, 117.1, 129.4, 148.9; GC–MS(EI) m/z: 217 (M+), 106 (M+ – CyCHCH3); HRMS-EI (m/z): (M+) calcd for C15H23N, 217.18305; found, 217.18311.  N-(6-(tert-butyldimethylsilyloxy)-2-methylhexyl)aniline 95d This compound was synthesized according to procedure 2, quantities of substrates  employed  are  as  follows:  N-methylaniline,  0.054 g  (0.50 mmol); TBDMS-protected 5-hexen-1-ol, 0.214 g (1.00 mmol); precatalyst 82a, 0.045 g (0.054 mmol). The compound was isolated as colourless oil in 81% yield (0.13 g, 0.40 mmol) following column chromatography with a 20:1 mixture of hexanes/ethyl acetate. 1  H NMR (CDCl3, 400 MHz, ): 0.08 (6H, s, –OSi(CH3)2C(CH3)3), 0.93 (9H, s, –  OSi(CH3)2C(CH3)3),  1.00  (3H,  d,  J  =  6.5  Hz,  –CHCH3),  1.19–1.59  (6H,  m,  CH3CHCH2CH2CH2–), 1.73–1.81 (1H, m, –CHCH3), 2.91 (1H, dd, J = 12.3, 7.2 Hz, – CH2NHPh), 3.08 (1H, dd, J = 12.3, 5.8 Hz, –CH2NHPh), 3.64 (2H, t, J = 6.5 Hz, –CH2OSi–), 3.72 (1H, br s, –CH2NHPh), 6.62 (2H, d, J = 8.2 Hz, 2 × Ar–H), 6.70 (1H, t, J = 7.3 Hz, Ar–H), 7.19 (2H, t, J = 7.8 Hz, 2 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, ): –5.0, 18.2, 18.6, 23.4, 26.2, 33.2, 33.3, 34.8, 50.5, 63.3, 112.8, 117.1, 129.4, 148.8; GC–MS(EI) m/z: 321 (M+), 264 [M+ – C(CH3)3]; HRMS-EI (m/z): (M+) calcd for C19H35NOSi, 321.24879; found, 321.24870.  N-(bicyclo[2.2.1]heptan-2-ylmethyl)-4-methoxyaniline 95f Procedure 2 was followed in the preparation of this compound. The amounts of substrates used are as follows: N-methyl-4-  184  methoxyaniline, 0.050 g (0.36 mmol); norbornene, 0.069 g (0.73 mmol); precatalyst 82a, 0.033 g (0.036 mmol). The product was obtained as a viscous colourless oil (dr > 20:1) in 90% yield (0.076 g, 0.33 mmol) following column chromatography with a 20:1 mixture of hexanes/ethyl acetate. 1  H NMR (CDCl3, 400 MHz, ): 1.05–1.33 (5H, m, norbornyl–H), 1.42–1.56 (3H, m, norbornyl–  H), 1.65–1.72 (1H, m, –CHCH2–), 2.12 (1H, br s, norbornyl–H), 2.22 (1H, br s, norbornyl–H), 2.75 (1H, br dd, J = 11.9, 7 Hz, –CHCH2–), 2.88 (1H, br dd, J = 11.6, 8.5 Hz, –CHCH2–), 3.36 (1H, br s, –CH2NH–), 3.73 (3H, s, –OCH3), 6.55 (2H, d, J = 9.1 Hz, 2 × Ar–H), 6.76 (2H, d, J = 9.1 Hz, 2 × Ar–H); 13C{1H} NMR (CDCl3, 75 MHz, ): 29.1, 30.1, 35.6, 36.2, 36.5, 39.6, 42.4, 50.7, 56.1, 114.1, 115.1, 143.2, 152.1; MS(EI) m/z: 231 (M+), 136 (M+ – C7H11); HRMS-EI (m/z): (M+) calcd for C15H21NO, 231.16231; found, 231.16315.  N-(2-cyclohexylpropyl)-4-methoxyaniline 95g The quantities of substrates employed for the synthesis of N-(2cyclohexylpropyl)-4-methoxyaniline  are  vinylcyclohexane,  mmol);  0.120 g  (1.09  as  follows: N-methyl-4-  methoxyaniline, 0.075 g (0.55 mmol); precatalyst 82a 0.049 g (0.055 mmol). The product was obtained as colourless oil in 73% yield (0.10 g, 0.40 mmol) after column chromatography with a 20:1 mixture of hexanes/ethyl acetate. 1  H NMR (CDCl3, 400 MHz, ): 0.95 (3H, d, J = 6.7 Hz, –CHCH3), 1.04–1.38 (6H, m, 5 × Cy–H,  –CHCH3), 1.61–1.78 (6H, m, 6 × Cy–H), 2.86 (1H, m, –CH2NH–), 3.13 (1H, m, –CH2NH–), 3.38 (1H, br s, –CH2NH–), 3.76 (3H, s, –OCH3), 6.59 (2H, m, 2 × Ar–H), 6.79 (2H, m, 2 × Ar– H);  13  C{1H} NMR (CDCl3, 100 MHz, ): 15.0, 26.9, 27.0, 27.1, 28.9, 31.1, 38.3, 41.0, 49.1,  185  56.1, 114.1, 115.1, 143.2, 152.0; GC–MS(EI) m/z: 247 (M+), 136 (M+ – CyCHH3); Anal. Calcd for C16H25NO: C, 77.68; H, 10.19; N, 5.66. Found: C, 77.74; H, 9.97; N, 5.84.  N-(3-(tert-butyldimethylsilyloxy)-2-methypropyl)-4-methoxyaniline 95h The title compound was synthesized according to procedure 2 with the following substrates: allyloxy(tert-butyl)dimethylsilane, 0.173 g (1.00 mmol); N-methyl-4-methoxyaniline, 0.069 g (0.50 mmol); precatalyst 82a, 0.091 g (0.10 mmol). After reaction completion, the solvent was removed and 0.5 mL of hexanes was added. The mixture was cooled in the freezer overnight and the precipitate was filtered off and washed with 0.5 mL of cold hexanes. The filtrate was purified by column chromatography using a mixture of 20:1 hexanes/ethyl acetate to give the product as colourless oil (0.114 g, 0.368 mmol, 73% yield). SFC analysis (OJ-H, 1% 2-propanol, 1.00 mL/min, minor isomer tR 35.9 min, major isomer tR 41.6 min) indicated an ee of 29%. 1  H NMR (CDCl3, 300 MHz, ): 0.07 (6H, 2 overlapping singlets, –OSi(CH3)2C(CH3)3), 0.93  (9H, s, –OSi(CH3)2C(CH3)3), 0.96 (3H, d, J = 6.7 Hz, –CHCH3), 1.93–2.01 (1H, m, –CHCH3), 3.00 (1H, dd, J = 12.0, 5.5 Hz, –CH2–), 3.11 (1H, dd, J = 12.0, 7.0 Hz, –CH2–), 3.53 (1H, dd, J = 9.9, 7.0 Hz, –CH2–), 3.64 (1H, dd, J = 9.9, 4.7 Hz, –CH2–), 3.76 (3H, s, CH3OAr), 3.95 (1H, br s, HNAr), 6.59 (2H, m, 2 × Ar–H), 6.79 (2H, m, 2 × Ar–H); 13C{1H} NMR (CDCl3, 75 MHz, ): –5.3, 15.4, 18.5, 26.1, 35.5, 49.7, 56.0, 67.7, 114.0, 115.1, 143.3, 151.9; GC–MS(EI) m/z: 309 (M+); HRMS-EI (m/z): (M+) calcd for C17H31NO2Si, 309.21241; found, 309.21253.  186  2-(Bicyclo[2.2.1]heptan-2-yl)-1,2,3,4-tetrahydroquinoline 95i Procedure 2 was employed in the synthesis of the above-named compound. The quantities of substrates used are as follows: 1,2,3,4tetrahydroquinoline, 0.051 g (0.38 mmol); norbornene, 0.072 g (0.77 mmol); precatalyst 82a, 0.034 g (0.038 mmol). The product was obtained as a viscous colourless oil (dr > 20:1) in 50% yield (0.044 g, 0.19 mmol) following column chromatography using a 20:1 mixture of hexanes/ethyl acetate. 1  H NMR (CDCl3, 300 MHz, ): 1.11–1.22 (3H, m, CHalkyl), 1.25–1.36 (2H, m, CHalkyl), 1.41–  1.67 (5H, m, CHalkyl), 2.04–2.12 (1H, m, CHalkyl), 2.20 (1H, br s, CHalkyl), 2.28 (1H, br s, CHalkyl), 2.72–2.78 (2H, m, CHalkyl), 2.83–2.92 (1H, m, CHalkyl), 3.78 (1H, br s, –CHNH–), 6.44 (1H, m, Ar–H), 6.77 (1H, m, Ar–H), 6.93 (2H, m, 2 × Ar–H); 13C{1H} NMR (CDCl3, 75 MHz, ): 26.7, 27.4, 28.7, 30.8, 35.2, 36.5, 36.9, 38.4, 48.0, 56.0, 114.2, 117.0, 121.7, 126.9, 129.4, 145.1; MS(EI) m/z: 227 (M+), 132 (M+ – C7H11); Anal. Calcd for C16H21N: C, 84.53; H, 9.31; N, 6.16. Found: C, 84.68; H, 9.53; N, 6.27.  4.4.2.3 Procedure 3: Representative Procedure for the Synthesis of Benzamides Example: N-(2-methyloctyl)-N-phenylbenzamide 97a (an atmosphere of nitrogen is not required) A solution of 0.038 g (0.27 mmol) of benzoyl chloride in dichloromethane was added to a mixture of 0.030 g (0.14 mmol) of 95a and 0.042 g (0.41 mmol) of triethylamine in 5 mL of dichloromethane at –78 °C. The reaction mixture was warm up to room temperature and then stirred until complete disappearance of the amine as indicated by TLC analysis. Dichloromethane 20 mL and 5 mL of 2 M NaOH solution were added and additional stirring for  187  30 minutes at ambient temperature was allowed to occur. The layers were separated and the organic layer was washed with 2 M NaOH (2 × 10 mL), 3 M HCl (3 × 10 mL), water (1 × 10 mL), and brine (1 × 10 mL) after which it was dried over anhydrous magnesium sulphate. The drying agent was filtered and the solvent was removed by rotary evaporation. Purification was effected by column chromatography using a mixture of 20:1 hexanes/ethyl acetate to afford the amide product as a colourless gel in 89% yield (0.039 g, 0.12 mmol). HPLC analysis (AS-H, 1% 2-propanol in hexanes, 0.50 mL/min, minor isomer tR 36.9 min, major isomer tR 40.7 min) indicated an ee of 44%. 1  H NMR (CDCl3, 400 MHz, ): 0.79 (3H, t, J = 7.0 Hz, –CH2CH3), 0.88 (3H, d, J = 6.7 Hz, –  CHCH3), 1.11–1.36 (10H, br m, –CH2(CH2)4CH3), 1.69 (1H, m, – CHCH3), 3.72–3.82 (2H, m, –NCH2–), 6.95 (2H, d, J = 7.3 Hz, 2 × Ar–H), 7.05–7.19 (8H, m, 8 × Ar–H);  13  C{1H} NMR (CDCl3,  100 MHz, ): 14.3, 17.3, 22.8, 27.0, 29.7, 31.9, 32.0, 34.6, 55.9, 126.6, 127.9, 127.9, 128.7, 129.2, 129.4, 136.9, 143.9, 170.9; MS(EI) m/z: 323 (M+), 210 (M+ – C8H17); HRMS-EI (m/z): (M+) calcd for C22H29NO, 323.22491; found, 323.22501; Anal. Calcd for C22H29NO: C, 81.69; H, 9.04; N, 4.33. Found: C, 81.83; H, 8.95; N, 4.47.  N-(2-cyclohexylpropyl)-N-phenylbenzamide 97b The above-named compound was synthesized according to procedure 3. The quantities of substrates used are as follows: 95b, 0.032 g (0.15 mmol); benzoyl chloride, 0.041g (0.29 mmol); triethylamine, 0.045 g (0.44 mmol). The amide product was obtained as a white solid following column chromatography using a mixture of 20:1 hexanes/ethyl acetate in 93% yield (0.044 g,  188  0.14 mmol). SFC analysis (OJ-H, 1% 2-propanol as modifier, 1.00 mL/min, minor isomer tR 44.9 min, major isomer tR 48.4 min) indicated an ee of 51%. 1  H NMR (CDCl3, 300 MHz, ): 0.88 (3H, d, J = 6.8 Hz, –CHCH3), 0.94–1.35 (6H, br m,  CHalkyl), 1.50–1.71 (6H, br m, CHalkyl), 3.82 (1H, br dd, J = 13.2, 5.9 Hz, –CH2CH–), 3.96 (1H, br dd, J = 13.2, 9.1 Hz, –CH2CH–), 6.99 (2H, d, J = 7.8 Hz, 2 × Ar–H), 7.07–7.24 (8H, m, 8 × Ar–H); 13C{1H} NMR (CDCl3, 75 MHz, ): 14.1, 26.9, 26.9, 27.1, 28.4, 31.1, 36.7, 40.9, 53.7, 126.6, 127.8, 127.9, 128.6, 129.1, 129.4, 137.0, 143.8, 170.9; MS(EI) m/z: 321 (M+), 210 (M+ – CyCHCH3); Anal. Calcd for C22H27NO: C, 82.20; H, 8.47; N, 4.36. Found: C, 81.90; H, 8.46; N, 4.45.  N-(2-methyl-3-phenylpropyl)-N-phenylbenzamide 97c Procedure 3 was followed in the preparation of the above compound. The quantities of substrates used are as follows: 95c, 0.029 g (0.13 mmol); benzoyl chloride, 0.036 g (0.26 mmol); triethylamine, 0.039 g (0.39 mmol). The product was obtained as viscous colourless gel in 85% yield (0.036 g 0.11 mmol) after column chromatography using a 20:1 mixture of hexanes/ethyl acetate. SFC analysis (AS-H, 5% 2-propanol as modifier, 3.00 mL/min, major isomer tR 19.3 min, minor isomer tR 28.6 min) indicated an ee of 30%. 1  H NMR (CDCl3, 300 MHz, ): 0.90 (3H, d, J = 6.8 Hz, –CHCH3), 2.07 (1H, m, –CHCH3), 2.41  (1H, br dd, J = 13.5, 8.9 Hz, –NCH2–), 2.81 (1H, br dd, J = 13.7, 5.5 Hz, –NCH2–), 3.85–3.99 (2H, m, –CH2CH–), 6.98 (2H, m, 2 × Ar–H), 7.06 (2H, m, 2 × Ar–H), 7.11–7.24 (11H, m, 11 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, ): 17.6, 33.9, 41.1, 55.5, 126.1, 126.7, 127.9, 127.9,  189  128.4, 128.8, 129.2, 129.3, 129.5, 136.8, 140.7, 143.6, 171.0; MS(EI) m/z: 329 (M+), 210 [M+ – CH(CH3)CH2Ph]; HRMS-EI (m/z): (M+) calcd for C23H23NO, 329.17796; found, 329.17696.  N-(6-(tert-butyldimethylsilyloxy)-2-methylhexyl)-N-phenylbenzamide 97d The title compound was synthesized according to procedure 3. The quantities of reagents employed are as follows: 95d, 0.040 g (0.12 mmol); benzoyl  chloride,  0.035 g  (0.25 mmol);  triethylamine,  0.038 g  (0.37 mmol). The product was obtained as colourless viscous gel in 66% yield (0.035g, 0.082 mmol) following column chromatography with a 20:1 hexanes/ethyl acetate mixture. HPLC analysis (AS-H, 1% 2-propanol in hexanes, 1.10 mL/min, major isomer tR 7.1 min, minor isomer tR 8.8 min) indicated an ee of 37%. 1  H NMR (CDCl3, 400 MHz, δ): 0.04 (6H, s, –OSi(CH3)2C(CH3)3), 0.89 (9H, s, –  OSi(CH3)2C(CH3)3), 0.96 (3H, d, J = 6.7 Hz, CH3CHCH2CH2CH2CH2–), 1.17–1.31 (2H, m, CH3CHCH2CH2CH2CH2–), 1.38–1.50 (4H, m, CH3CHCH2CH2CH2CH2–), 1.76–1.81 (1H, m, CH3CHCH2CH2CH2CH2–), 3.58 (2H, t, J = 6.1 Hz, CH3CHCH2CH2CH2CH2O–), 3,80–3.90 (2H, m, –CH2NPh), 7.02 (2H, br d, J = 7.9 Hz, 2 × Ar–H), 7.10–7.16 (3H, m, 3 × Ar–H), 7.18–7.22 (3H, m, 3 × Ar–H), 7.26 (2H, br d, J = 7.9 Hz, 2 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, ): –5.1, 17.6, 18.5, 23.3, 26.2, 31.9, 33.2, 34.3, 55.8, 63.3, 126.6, 127.8, 127.9, 128.7, 129.2, 129.4, 136.9, 143.8, 170.9; MS(EI) m/z: 425 (M+), 368 [M+ – C(CH3)3]; Anal. Calcd for C26H39NO2Si: C, 73.36; H, 9.23; N, 3.29. Found: C, 73.66; H, 8.99; N, 3.42.  190  N-(bicyclo[2.2.1]heptan-2-ylmethyl)-N-phenylbenzamide 97e The above-named compound was synthesized according to procedure 3. The quantities of substrates used are as follows: 95e, 0.047 g (0.22 mmol); benzoyl chloride, 0.063 g (0.45 mmol); triethylamine, 0.068 g (0.67 mmol). The amide product was obtained as a white solid following purification by column chromatography using a mixture of 20:1 hexanes/ethyl acetate in 89% yield (0.060 g, 0.20 mmol). HPLC analysis (AS-H, 1% 2-propanol in hexanes, 0.85 mL/min, minor isomer tR 33.0 min, major isomer tR 41.9 min) indicated an ee of 61%. 1  H NMR (CDCl3, 300 MHz, ): 1.04 (2H, m, norbornyl–H), 1.12 (2H, m, norbornyl–H), 1.24–  1.31 (1H, m, norbornyl–H), 1.46 (3H, m, norbornyl–H), 1.61–1.71 (1H, m, norbornyl–H), 2.08 (1H, br s, norbornyl–H), 2.21 (1H, br s, norbornyl–H), 3.65 (1H, dd, J = 13.5, 7.1 Hz, –CHCH2– ), 3.91 (1H, dd, J = 13.5, 8.9 Hz, –CHCH2–), 7.00 (2H, d, J = 7.8 Hz, 2 × Ar–H), 7.08–7.25 (8H, m, 8 × Ar–H);  13  C{1H} NMR (CDCl3, 100 MHz, ): 29.1, 29.8, 35.5, 35.8, 36.7, 39.3, 40.7,  54.1, 126.7, 127.8, 128.2, 128.7, 129.2, 129.4, 136.9, 143.6, 170.9; MS(EI) m/z: 305 (M+); HRMS-EI (m/z): (M+) calcd for C21H23NO, 305.17796; found, 305.17840; Anal. Calcd for C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C, 82.05; H, 7.58; N, 4.69.  N-(bicyclo[2.2.1]heptan-2-ylmethyl)-N-(4-methoxyphenyl)benzamide 97f Procedure 3 was followed in the preparation of the title compound. The quantities of substrates used are as follows: 95f, 0.029 g (0.13 mmol); benzoyl chloride, 0.035 g (0.25 mmol); triethylamine, 0.038 g (0.38 mmol). The product was obtained as a white solid in 57% yield (0.024 g, 0.072 mmol) after column chromatography with a 20:1 mixture of  191  hexanes/ethyl acetate. HPLC analysis (AS-H, 5% 2-propanol in hexanes, 1.00 mL/min, minor isomer tR 23.5 min, major isomer tR 30.6 min) of a 2 mg/mL solution indicated an ee of 52%. 1  H NMR (CDCl3, 400 MHz, ): 1.05 (2H, m, norbornyl–H), 1.13 (2H, m, norbornyl–H), 1.24–  1.29 (1H, m, norbornyl–H), 1.41–1.50 (3H, m, norbornyl–H), 1.61–1.67 (1H, m, norbornyl–H), 2.08 (1H, br s, norbornyl–H), 2.21 (1H, br s, norbornyl–H), 3.56–3.62 (1H, br unresolved dd, – NCH2–), 3.72 (3H, s, –OCH3), 3.84–3.90 (1H, br unresolved dd, –NCH2–), 6.70 (2H, br d, J = 7.9 Hz, 2 × Ar–H), 6.91 (2H, m, 2 × Ar–H), 7.12–7.24 (5H, m, 5 × Ar–H);  13  C{1H} NMR  (CDCl3, 100 MHz, ): 29.1, 29.8, 35.5, 35.8, 36.7, 39.3, 40.6, 54.1, 55.5 (br s), 114.4, 127.8, 128.6, 129.2, 129.3, 136.3 (br s), 137.1, 158.1, 171.0; MS(EI) m/z: 335 (M+); HRMS-EI (m/z): (M+) calcd for C22H25NO2, 335.18853; found, 335.18848.  N-(2-cyclohexylpropyl)-N-(4-methoxyphenyl)benzamide 97g The above amide was synthesized according to procedure 3 with the following reagents: 95g, 0.050 g (0.20 mmol); benzoyl chloride 0.057 g (0.40 mmol); triethylamine, 0.061 g (0.61 mmol). The product was obtained as a viscous colourless gel in 86% yield (0.061 g, 0.17 mmol) after column chromatography with a 20:1 mixture of hexanes/ethyl acetate. HPLC analysis (AS-H, 1% 2-propanol in hexanes, 1.10 mL/min, major isomer tR 29.1 min, minor isomer tR 33.7 min) indicated an ee of 43%. 1  H NMR (CDCl3, 300 MHz, ): 0.92 (3H, d, J = 6.4Hz, –CHCH3), 0.99–1.32 (6H, m, 5 × Cy–H,  –CHCH3), 1.55–1.76 (6H, m, 6 × Cy–H), 3.76–3.82 (4H, singlet overlapping with multiplet, – OCH3, –CH2NH–), 3.96 (1H, m, –CH2NPh–), 6.74 (2H, m, 2 × Ar–H), 6.95 (2H, m, 2 × Ar–H), 7.17–7.20 (5H, m, 5 × Ar–H); 13C{1H} NMR (CDCl3, 75 MHz, ): 14.1, 26.9, 26.9, 27.1, 28.4,  192  31.1, 36.6, 40.8, 55.5, 114.3, 127.8, 128.6, 129.0, 129.2, 137.2, 158.0, 170.7; GC–MS(EI) m/z: 351 (M+), 268 (M+ – Cy); HRMS-EI (m/z): (M+) calcd for C23H29NO2, 351.21983; found, 351.22009.  N-(2-cyclohexylpropyl)-N-(4-methoxyphenyl)benzamide 97i (2-(bicyclo[2.2.1]heptan-2-yl)-3,4-dihydroquinolin-1-(2H)-yl)(phenyl)methanone Procedure 3 was followed in the preparation of the above compound. The quantities of substrates used are as follows: 95i, 0.036 g (0.16 mmol); benzoyl chloride, 0.044 g (0.32 mmol); triethylamine 0.048 g (0.47 mmol). The product was obtained as a white solid in 78% yield (0.041 g, 0.12 mmol) after column chromatography with a 20:1 mixture of hexanes/ethyl acetate. HPLC analysis (AS-H, 5% 2-propanol in hexanes, 1.00 mL/min, minor isomer tR 8.0 min, major isomer tR 12.6 min) indicated an ee of 57%. 1  H NMR (CDCl3, 300 MHz, ): 0.99–1.10 (3H, m, norbornyl–H), 1.15–1.19 (1H, m, norbornyl–  H), 1.28–1.36 (1H, m, norbornyl–H), 1.40–1.65 (4H, m, norbornyl–H), 1.97–2.07 (1H, m, – CH2CH2CH–), 2.11 (1H, br s, norbornyl–H), 2.30 (1H, br s, norbornyl–H), 2.34–2.46 (1H, m, – CH2CH2CH–), 2.88 (2H, t, J = 7.3 Hz, –CH2CH2CH–), 4.74 (1H, br s, –NCH–), 6.47 (1H, br s, Ar–H), 6.82 (1H, br t, J = 7.5 Hz, Ar–H), 6.99–7.04 (1H, m, Ar–H), 7.16–7.34 (6H, m, 6 × Ar– H);  13  C{1H} NMR (CDCl3, 100 MHz, ): 24.6, 28.3, 28.9, 30.4, 34.2, 36.2, 37.0, 39.1, 44.5,  55.2, 125.1, 125.8, 127.0, 128.0, 128.5, 128.7, 129.8, 132.0, 137.0, 138.8, 170.1; MS(EI) m/z: 331 (M+), 236 (M+ – C7H11); HRMS-EI (m/z): (M+) calcd for C23H25NO, 331.19361; found, 331.19331.  193  4.4.2.4 Procedure 4. Representative Procedure for the Synthesis of Sulfonamides Example: Reaction of N-methylbenzylamine with norbornene A mixture of 0.083 g (0.68 mmol) of N-methylbenzylamine, 0.129 g (1.37 mmol) of norbornene, and 0.062 g (0.068 mmol) of 82a in 0.3 mL of d8-toluene was placed in a J. Young NMR tube and heated at 130 °C for 24 h. The reaction mixture was poured into a 20 mL scintillation vial equipped with a magnetic stir bar and containing a mixture of 1 mL of 2 M NaOH solution, 0.209 g (1.10 mmol) of p-toluenesulfonyl chloride, and 2 mL of dichloromethane. After stirring for 48 h at ambient temperature, the mixture was poured into 20 mL of water and extracted thrice with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saturated brine and dried over sodium sulphate. The solvents were removed by rotary evaporation and the crude solid purify by flash column chromatography using a 40:1 hexanes/ethyl acetate mixture to give 98j (44% yield, 0.11 g, 0.30 mmol) and 98k (13% yield, 0.034 g, 0.092 mmol).  N-(bicylo[2.2.1]heptan-2-yl(phenyl)methyl)-N,4-dimethylbenzenesulfonamide 98j SFC analysis (AD-H, 8% 2-propanol as modifier, 1.00 mL/min, major isomer tR 30.8 min, minor isomer tR 37.8 min) indicated an ee of 66%. 1  H NMR (CDCl3, 300 MHz, δ): 1.03–1.20 (3H, m, norbornyl–  H), 1.29–1.58 (5H, m, norbornyl–H), 1.65 (1H, br s, norbornyl– H), 2.01–2.10 (1H, m, norbornyl–H), 2.30–2.32 (4H, 2 overlapping singlets, Ar–CH3, norbornyl–H), 2.64 (3H, s, –NCH3), 4.63 (1H, d, J = 11.7 Hz, – CHCHPh), 7.09 (2H, m, 2 × Ar–H), 7.16–7.22 (5H, m, 5 × Ar–H), 7.44 (2H, m, 2 × Ar–H); C{1H} NMR (CDCl3, 100 MHz, ): 21.6, 28.9, 29.5, 30.3, 35.3, 35.9, 37.2, 39.5, 43.4, 65.0,  13  194  127.4, 127.8, 128.4, 128.6, 129.4, 137.4, 139.2, 142.8; MS(EI) m/z: 369 (M+), 274 (M+ – C7H11); Anal. Calcd for C22H27NO2S: C, 71.51; H, 7.36; N, 3.79. Found: C, 71.12; H, 7.15; N, 3.81.  N-benzyl-N-(bicyclo[2.2.1]heptan-2-ylmethyl)-4-methylbenzenesulfonamide 98k SFC analysis (AS-H, 5% 2-propanol as modifier, 2.00 mL/min, major isomer tR 26.7 min, minor isomer tR 31.2 min) indicated an ee of 55%.  1  H NMR (CDCl3, 400 MHz, δ): 0.68–0.72 (1H, m,  norbornyl–H), 0.80–0.87 (1H, m, norbornyl–H), 0.90–0.95 (2H, m, norbornyl–H), 1.01–1.12 (2H, m, norbornyl–H), 1.21–1.42 (3H, m, norbornyl–H), 1.89 (1H, br s, norbornyl–H), 2.06 (1H, br s, norbornyl–H), 2.39 (3H, s, Ar–CH3), 2.69 (1H, dd, J = 13.5, 6.8 Hz, –NCH2CH–), 2.97 (1H, dd, J = 13.7, 9.4 Hz, –NCH2CH–), 4.16 (1H, d, J = 15.3 Hz, – NCH2Ph), 4.34 (1H, d, J = 15.3 Hz, –NCH2Ph), 7.22–7.28 (7H, m, 7 × Ar–H), 7.67 (2H, d, J = 8.2 Hz, 2 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, δ): 21.7, 28.9, 29.5, 35.1, 35.5, 36.6, 38.9, 40.5, 52.9, 53.9, 127.4, 127.7, 128.4, 128.6, 129.8, 137.1, 137.2, 143.3; MS(EI) m/z: 369 (M+), 274 (M+ – C7H11); Anal. Calcd for C22H27NO2S: C, 71.51; H, 7.36; N, 3.79. Found: C, 71.49; H, 7.36; N, 3.92.  N,N-bis(2-cyclohexylpropyl)-4-methylbenzenesulfonamide 96b 1  H NMR (CDCl3, 400 MHz, mixture of diastereomers, δ): 0.79–  0.83 (6H, m, 2 × –CHCH3), 0.91–1.29 (12H, m, CHalkyl), 1.50– 1.73 (12H, m, CHalkyl), 2.42 (3H, s, Ar–CH3), 2.88–3.02 (4H, m,  195  2 × –NCH2CH–), 7.30 (2H, m, 2 × Ar–H), 7.68 (2H, m, 2 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, mixture of diastereomers, ): 14.0, 14.1, 21.7, 26.7, 26.8, 26.9, 26.9, 27.0, 27.1, 27.9, 28.3, 31.1, 31.4, 36.8, 37.1, 39.9, 40.5, 53.4, 54.0, 127.6, 129.6, 129.7, 136.9, 137.0, 143.0, 143.0.  Compound 101 1  H NMR (CDCl3, 400 MHz, δ): 0.47 (3H, d, J = 6.7 Hz, Ar–  CHCH3), 0.54 (3H, d, J = 6.7 Hz, Ar–CHCH3), 0.88 (3H, d, J = 6.7 Hz, Ar–CHCH3), 0.99 (3H, d, J = 6.7 Hz, Ar–CHCH3), 1.10 (3H, d, J = 6.7 Hz, Ar–CHCH3), 1.14–1.19 (6H, 2 overlapping doublets, Ar–CH(CH3)2), 1.26 (3H, d, J = 6.7 Hz, Ar–CHCH3), 2.01 (1H, m, Ar–CHCH3), 2.16–2.21 (4H, singlet overlapping with multiplet, Ar–CH3, Ar– CHCH3), 2.24 (3H, s, Ar–CH3), 2.52 (1H, m, Ar–CHCH3), 3.20 (1H, m, Ar–CHCH3), 6.67 (1H, m, Ar–H), 6.85 (1H, m, Ar–H), 6.92 (1H, m, Ar–H), 6.99 (1H, m, Ar–H), 7.08 (1H, m, Ar–H), 7.20 (1H, m, Ar–H), 7.23 (1H, m, Ar–H), 7.27 (1H, m, Ar–H), 7.35 (1H, m, Ar–H), 7.49 (2H, m, 2 × Ar–H), 7.75 (1H, m, Ar–H);  13  C{1H} NMR (CDCl3, 150 MHz, ): 20.2, 20.3, 21.2, 21.6,  22.0, 23.3, 23.3, 24.0, 24.8, 25.8, 27.9, 28.9, 29.1, 30.1, 122.4, 122.6, 123.7, 123.8, 124.1, 124.4, 127.3, 127.4, 128.5, 129.0, 131.4, 132.5, 133.4, 133.8, 134.0, 136.6, 137.1, 137.6, 138.1, 138.4, 138.5, 142.8, 145.9, 148.2, 153.4, 170.1; GC–MS(EI) m/z: 570 (M+), 527(M+ – CH(CH3)2); HRMS-EI (m/z): (M+) calcd for C40H46N2O, 570.36101; found, 570.36078.  Synthesis of 3-(4-methoxyphenylamino)-2-methylpropan-1-ol (S)-100344 A mixture of 0.069 g (0.50 mmol) of N-methyl-4-methoxyaniline, 0.17 g (1.0 mmol) of allyloxy(tert-butyl)dimethylsilane, and 0.090 g (0.10 mmol) of complex (R)-82a and 0.25 mL of  196  d6-benzene was heated at 130 °C (in an oil bath) for 24 h in a J. Young NMR tube. The reaction mixture was diluted with 30 mL of diethyl ether and extracted thrice with 20 mL of 3 M aqueous HCl solution. The aqueous layer was basified to a pH of 10 with 5 M aqueous NaOH solution and then extracted with diethyl ether (3 × 30 mL).  The organic layer was dried over anhydrous  magnesium sulphate, filtered, and the solvent removed by rotary evaporation. Purification by flash chromatography using a 2:1 mixture of hexanes/ethyl acetate afforded the product in 62% yield (0.061 g, 0.31 mmol). [α 1  22 D  + 2.9 (c 0.38, CHCl3).  H NMR (CDCl3, 400 MHz, δ): 0.97 (3H, d, J = 7.0 Hz, –CHCH3), 1.98–2.05 (1H, m, –CHCH3),  3.04–3.13 (4H, multiplet overlapping with broad signal, –CHCH2–, –CH2NH–, –CH2OH), 3.59 (1H, dd, J = 10.8, 7.2 Hz, –CH2CH–), 3.66 (1H, dd, J = 11.0, 4.7 Hz, –CH2CH–), 3.75 (3H, s, – OCH3), 6.64 (2H, m, 2 × Ar–H), 6.80 (2H, m, 2 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, ): 15.2, 35.4, 50.6, 56.0, 68.1, 115.0, 115.1, 142.6, 152.6.  Synthesis of N,N′-((1R,2R)-cyclohexane-1,2-diyl)bis(2,4,6-triisopropylbenzamide) 102 Thionyl chloride (5.36 mL, 73.6 mmol) was added to a suspension of 2,4,6-triisopropylbenzoic acid (1.83 g, 7.36 mmol) and DMAP (0.045 g, 0.368 mmol) in 10 mL of toluene in a 50 mL Schlenk flask. The mixture was heated at reflux (120 °C) for 16 h after which the excess thionyl chloride and toluene were removed in vacuo. The dichloride formed was dissolved in 20 mL of 1,2-dichlororethane, cooled to –78 °C and then added to a mixture of 1R,2R-(–)diaminoyclohexane (0.200 g, 1.75 mmol) and triethylamine (1.06 g, 1.48 mL, 10.5 mmol) in 20 mL of 1,2-dichloroethane at –78 °C. The reaction mixture was allowed to warm up to room temperature and then heated at 90 °C for 48 h.  The mixture was diluted with 50 mL of  197  chloroform and extracted with 3 M HCl (3 × 30 mL), 2 M NaOH (3 × 30 mL), H2O (1 × 30 mL), and brine (1 × 30 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. The solvent was removed by rotary evaporation and the crude product was purified by column chromatography using 200 mL of a 5:1 hexanes/ethyl acetate mixture followed by a 1:1 hexanes/ethyl acetate mixture to give the product as a white solid in 32% yield (0.319 g, 0.555 mmol). [α 1  20 D  – 66.3 (c 1.00, CHCl3).  H NMR (CDCl3, 300 MHz, δ): 1.16–1.25 (36H, m, 6 × Ar–CH(CH3)2), 1.36–1.51 (4H, m, 4 ×  Cy–H), 1.75 (2H, m, 2 × Cy–H), 2.47 (2H, m, 2 × Cy–H), 2.81–3.00 (6H, m, 6 × Ar– CH(CH3)2), 3.91 (2H, br s, 2 × Cy–H), 6.11 (2H, br s, 2 × – CONH–), 6.97 (4H, s, 4 × Ar–H);  13  C{1H} NMR (CDCl3, 75  MHz, ): 24.1, 24.5, 25.0, 31.0, 31.4, 34.5, 54.0, 121.1, 133.0, 145.1, 149.9, 171.3; MS(EI) m/z: 574 (M+), 327 [M+ – (CH(CH3)2)3C6H3CONH2]; Anal. Calcd for C38H58N2O2: C, 79.39; H, 10.17; N, 4.87. Found: C, 79.09; H, 9.92; N, 4.93.  Synthesis of N,N′-((1R,2R)-cyclohexane-1,2-diyl)bis(2,4,6-trimethylbenzamide) 103 Thionyl chloride (4.43mL, 60.9 mmol) was added to a suspension of 2,4,6-trimethylbenzoic acid (1.000 g, 6.09 mmol) and DMAP (0.0074 g, 0.0609 mmol) in 10 mL of toluene in a 50 mL Schlenk flask. The mixture was heated at reflux (120 °C) for 16 h after which the excess thionyl chloride and toluene were removed in vacuo. The dichloride formed was dissolved in 20 mL of chloroform, cooled to –78 °C and then added to a mixture of 1R,2R-(– )-diaminocyclohexane (0.278 g, 2.43 mmol) and triethylamine (1.23 g, 1.71 mL, 12.1 mmol) in  198  20 mL of chloroform at –78 °C.  The reaction mixture was allowed to warm up to room  temperature and then heated at 70 °C for 24 h.  The mixture was diluted with 50 mL of  chloroform and extracted with 3 M HCl (3 × 30 mL), 2 M NaOH (3 × 30 mL), H2O (1 × 30 mL), and brine (1 × 30 mL). The organic layer was dried over anhydrous magnesium sulphate and filtered. The solvent was removed by rotary evaporation and the crude product was purified by column chromatography using 200 mL of a 4:1 hexanes/ethyl acetate mixture followed by a 1:1 chloroform/ethyl acetate mixture to give the product as a white solid in 46% yield (0.457 g, 1.13 mmol). [α 1  20 D  – 102.5 (c 1.00, CHCl3).  H NMR (CDCl3, 400 MHz, δ): 1.30–1.44 (4H, m, 4 × Cy–H), 1.80 (2H, m, 2 × Cy–H), 2.21  (12H, s, 4 × Ar–CH3), 2.25 (6H, s, 2 × Ar–CH3), 2.37 (2H, m, 2 × Cy–H), 3.91 (2H, br s, 2 × Cy–H), 6.33 (2H, br s, 2 × –CONH–), 6.78 (4H, s, 4 × Ar–H); 13C{1H} NMR (CDCl3, 100 MHz, ): 19.7, 21.2, 24.8, 32.5, 54.2, 128.5, 134.2, 134.4, 138.6, 171.3; MS(EI) m/z: 406 (M+), 243 [M+ – (CH3)3C6H3CONH2]; Anal. Calcd for C26H34N2O2: C, 76.81; H, 8.43; N, 6.89. Found: C, 76.49; H, 8.46; N, 6.73.  Synthesis of cyclohexyl-tethered complex 104 A solution of 0.044 g (0.11 mmol) of Ta(NMe2)5 in benzene was added to a suspension of 0.063 g (0.11 mmol) of N,N′-((1R,2R)cyclohexane-1,2-diyl)bis(2,4,6-triisopropylbenzamide) in benzene and the mixture was stirred for 16 h at ambient temperature. The volatiles were removed in vacuo to give the product as a pale yellow solid in 98% yield (0.095 g, 0.11 mmol). 1  H NMR (d6-benzene, 300 MHz, δ): 0.73 (2H, m, 2 × Cy–H), 1.07  199  (3H, m, 3 × Cy–H), 1.16–1.22 (13H, m, Cy–H, 2 × Ar–CH(CH3)2), 1.28–1.32 (12H, 2 overlapping doublets, 2 × Ar–CH(CH3)2), 1.37–1.44 (12H, 2 overlapping doublets, 2 × Ar– CH(CH3)2), 1.56 (2H, m, 2 × Cy–H), 2.78 (2H, m, 2 × Ar–CH(CH3)2), 2.97 (2H, m, 2 × Ar– CH(CH3)2), 3.56–3.80 (16H, singlet overlapping with multiplet, 2 × –N(CH3)2, 2 × Cy–H, 2 × Ar–CH(CH3)2), 3.92 (6H, s, –N(CH3)2), 7.10 (2H, s, 2 × Ar–H), 7.17 (2H, s, 2 × Ar–H); 13C{1H} NMR (d6-benzene, 75 MHz, ): 24.3, 24.5, 24.6, 25.0, 25.2, 25.6, 26.8, 31.5, 31.8, 32.1, 35.1, 42.1, 49.6, 66.4, 121.3, 121.8, 134.3, 145.7, 146.8, 150.9, 182.0; MS(EI) m/z: 885 (M+), 841 [M+ – N(CH3)2]; Anal. Calcd for C44H74N5O2Ta: C, 59.64; H, 8.42; N, 7.90. Found: C, 59.82; H, 8.52; N, 7.79.  Synthesis of cyclohexyl-tethered complexes 105 and 106 A solution of 0.043 g (0.11 mmol) of Ta(NMe2)5 in benzene was added to a suspension of 0.044 g (0.11 mmol) of N,N′-((1R,2R)-cyclohexane-1,2-diyl)bis(2,4,6-trimethylbenzamide) in benzene and the mixture was stirred for 16 h at ambient temperature. The volatiles were removed in vacuo to give a mixture of the product as pale yellow solid in 99% yield (0.077 g, 0.11 mmol, 105:106 1:5). 1  H NMR (d6-benzene, 400 MHz,  denotes major isomer,  b  a  denotes minor  isomer, δ): 0.75–0.90a,b (3H, m, 3 × Cy–H), 1.09–1.29a,b (3H, m, 3 × Cy–H), 1.44a,b (3H, m, 3 × Cy–H), 1.58–1.66a,b (3H, m, 3 × Cy–H),1.74–1.83a,b (4H, m, 4 × Cy–H), 1.99a (3H, s, Ar–CH3),  200  2.07b (6H, s, 2 × Ar–CH3), 2.15a (3H, s, Ar–CH3), 2.28–2.33a,b (10H, 2 singlets overlapping with a multiplet, 3 × Ar–CH3, Cy–H), 2.44a (3H, s, Ar–CH3), 2.52b (6H, s, 2 × Ar–CH3), 2.78a (6H, s, 2 × Ar–CH3), 3.46–3.70a,b (21H, broad singlet overlapping with multiplet, 3 × N(CH3)2), 3 × Cy– H), 3.76b (12H, s, 2 × N(CH3)2), 3.91b (6H, s, N(CH3)2), 6.53a (1H, br s, Ar–H), 6.66b (2H, br s, 2 × Ar–H), 6.68b (2H, br s, 2 × Ar–H), 6.71a (1H, br s, Ar–H), 6.86b (2H, br s, 2 × Ar–H); C{1H} NMR (d6-benzene, 100 MHz, ): 19.8, 20.5, 20.7, 21.4, 21.4, 21.5, 22.2, 23.9, 25.3,  13  25.4, 25.7, 31.2, 34.8, 36.0, 42.3, 45.3, 48.3, 49.6, 51.1, 61.7, 62.4, 66.6, 128.5, 128.7, 128.9, 129.3, 130.2, 134.0, 134.0, 134.5, 135.3, 135.6, 135.7, 136.7, 137.1, 138.7, 138.8, 139.1, 160.7, 179.1, 181.2; MS(EI) m/z: 771 (M+), 673 [M+ – N(CH3)2].  Synthesis of (9H-fluoren-9-yl)methyl 3-hydroxy-2-methylpropylcarbamate (108) A mixture of 0.069 g (0.50 mmol) of N-methyl-4-methoxyaniline, 0.17 g (1.0 mmol) of  allyloxy(tert-butyl)dimethylsilane,  and  0.090 g (0.10 mmol) of complex 82a and 0.25 mL of d6-benzene was heated at 130 °C (in an oil bath) for 24 h in a J. Young NMR tube. The solvent was removed and the crude was diluted with 0.5 mL of hexane. The mixture was cooled at –35 °C for 16 h, after which the precipitate was filtered and the solvent removed to give 95h. In a separate 50 mL round bottom flask, 0.69 g of cerium ammonium nitrate in 8 mL of water was cooled to 0 °C.  A solution of 95h in 6 mL of acetonitrile was added drop-wise  over a period of 10 minutes. The mixture was stirred at 0 °C for 3 h and then warm up to ambient temperature and further stirred for 2 h. The mixture was basified to a pH of 10 with saturated Na2CO3 and a solution of Fmoc-OSU (0.25 g, 0.75 mmol) in 3 mL of THF was added. The mixture was stirred at ambient temperature for 36 h and then extracted with ethyl acetate (3  201  × 50 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered, and the solvent removed by rotary evaporation.  The crude product was purified by flash column  chromatography using a mixture of hexanes/ethyl acetate to afford 108 as a white solid in 15% yield (0.024 g, 0.077 mmol) over three steps. 1  H NMR (CDCl3, 300 MHz, δ): 0.90 (3H, d, J = 7.0 Hz, –CHCH3), 1.79–1.89 (1H, m, –CHCH3),  2.78 (1H, br s, –OH), 3.08–3.17 (1H, m, –CH2–), 3.31–3.38 (2H, m, –CH2–), 3.53–3.58 (1H, m, –CH2–), 4.23 (1H, m, –CHCH2O–), 4.46 (2H, d, J = 6.7 Hz, –CHCH2O–), 5.03 (1H, br s, – NHCH2–), 7.33 (2H, m, 2 × Ar–H), 7.41 (2H, m, 2 × Ar–H), 7.60 (2H, d, J = 7.6 Hz, 2 × Ar–H), 7.78 (2H, d, J = 7.6 Hz, 2 × Ar–H); 13C{1H} NMR (CDCl3, 150 MHz, ): 29.9, 36.4, 43.4, 47.5, 64.7, 66.9, 120.2, 125.2, 127.3, 127.9, 141.6, 144.0, 157.9; MS(ESI) m/z: 334 (M+ + Na); HRMS-EI (m/z): (M+) calcd for C19H21NO3, 311.15214; found, 311.15235.  202  CHAPTER 5. SUMMARY AND FUTURE DIRECTIONS  5.1 Summary This thesis is a two-part study involving the synthesis and catalytic investigation of amidate complexes of early transition metals. The first part (Chapter 2) deals with broadening the hydroamination substrate scope of a previously disclosed highly reactive and regioselective achiral titanium amidate complex 49 (Figure 5.1). The second part (Chapters 3 and 4) focuses on the synthesis, characterization, stability, and catalytic investigations of chiral zirconium and tantalum complexes ligated with amidate ancillary ligands.  Specifically, the catalytic  investigations in these latter chapters concentrate on enantioselective atom economic synthesis of amines by hydroamination and hydroaminoalkylation. In Chapter 2, the efficiency of complex 49 as a precatalyst for the hydroamination of challenging substrates was presented. Precatalyst 49 is competent for the hydroamination of heteroatom-containing substrates including N- and O-substituted allenes. Importantly with the allenes, judicious selection of the amine substrate allows for the sole formation of ketimine (which can be reduced to secondary amines) or allylamine product.  Control experiments  effectively eliminate the possibility of allene-alkyne isomerization during catalysis, as the alkyne analogue of allene 50a reacts with amines to give a combination of regioisomeric products that is different from that obtained with the allene. Precatalyst 49 also catalyzes the hydrohydrazination reactions between alkynes and hydrazines.  Terminal, internal, and heteroatom-substituted  alkynes as well as 1,1-diaryl, 1,1-dialkyl-, and 1-alkyl-1-arylhydrazines are all viable substrates in the exploration of 49 as a precatalyst for the hydroamination of these particularly difficult substrate combinations, substantiating our designation of 49 as a broadly applicable alkyne  203  hydroamination precatalyst. These reactions afford the anti-Markonikov products predominantly and purifications are easily effected by column chromatography either before or after reduction processes. Further, being a 100% atom efficient process that does not generate any by-products, the hydroamination reaction allows for the synthesis of substituted indoles in a one-pot process. N-substituted indoles have been prepared in respectable isolated yields by a tandem sequential hydrohydrazination and ZnCl2-mediated cyclization thus highlighting the compatibility of this precatalyst with subsequently catalyzed synthetic pathways.  Importantly, in situ generated  complex 49 affords products in yields and with selectivities comparable to that realized with the isolated precatalyst, convincingly demonstrating that prior isolation and purification of 49 are not required for efficient catalysis.  Figure 5.1. Proligands and precatalysts utilized for the atom economic synthesis of amines.  204  As complex 49 is achiral, reactivity with this catalyst is not suitable for chiral amine synthesis.310 Thus, new axially chiral amide proligands have been synthesized for chiral precatalyst preparations. Seven novel axially chiral biphenyl-tethered bis(amide) proligands have been prepared using modified literature protocols318 and well-known acid-chloride/amine coupling reactions. The combination of a variety of bis(amide) proligands and commercially available Zr(NMe2)4 prior to substrate addition lead to the in situ formation of zirconium amidate complexes that efficiently catalyze the enantioselective cyclization of aminoalkenes (Chapter 3). The most reactive and enantioselective zirconium complex 76f·HNMe2 (Figure 5.1) effectively cyclizes aminoalkenes, including those lacking geminal substituents, generating α-chiral amines in up to 74% ee. The diastereoselectivities in relevant examples are modest and consistent with a substrate controlled ring closure wherein the larger of the gem-dialkyl substituents is in the equatorial position in a chair-like transition state. While complex 76f·HNMe2 is more efficient for the cyclohydroamination of aminoalkenes than our highly enantioselective group 4 metal precatalyst 39 (Figure 5.1), the enantioselectivities achieved with 76f·HNMe2 are less than the values communicated for 39. The lower ee values obtained with 76f·HNMe2 are a consequence of its κ2-O,O-bonding motif which places the biphenyl linkage and the bulky N-substituents on the ligand further away from the metal center. Interestingly, the sterically-accessible proligands 68b and 68c (Figure 5.1) form zirconium complexes that dimerize in solution to give N,O-chelating homochiral dimers with bridging biphenyl linkages; an example of diastereoselective dimerizations. Unfortunately, dimerization has been shown to be a catalyst resting state as proligands that are more susceptible to dimerization require much longer reaction times to effect complete cyclization of aminoalkenes. In addition, the slower catalytic activity observed for isolated dimer [76b]2 in  205  comparison with the in situ generated monomeric complex further supports formation of a catalyst dormant state via dimerization. The biphenyl-tethered bis(amide) proligands have also been employed in the formation of tantalum complexes.  Again, the amidate binding motif and consequently the coordination  geometry about the metal center is greatly influenced by the steric bulk of the N-substituent on the ligand.  The sterically-encumbered N-aryl proligand 68a (Figure 5.1) forms a discrete  bidentate amidate complex while less bulky proligands 68b and 68c afford a mixture of two coordination isomers (bidentate and tridentate) in solution. Interestingly, a C–H bond activation reaction between the dimethylamido ligands on the tantalum complex bearing N-phenyl amidate ligand leads to the formation of a new four-membered metallacyclic complex. Unfortunately, the failure of the attempts made to exclusively isolate this complex precludes complete characterization of this metallacycle. Similar to the analogous zirconium complexes, stericallyaccessible proligands lead to complex mixture of products. The featured biphenyl-tethered tantalum complexes are competent precatalysts for the enantioselective synthesis of chiral secondary amines. A variety of alkenes including terminal and internal alkenes as well as dialkyl- and N-aryl alkylamines are viable substrates in these first examples of enantioselective hydroaminoalkylation reactions.  The reaction regioselectively  affords only the branched isomer with enantioselectivities of up to 66%. Hydroaminoalkylation catalysis with the cyclohexyl-tethered amidate complexes featuring coordinatively saturated metal centers show that these complexes are less reactive and selective than the biphenyltethered amidate complexes. These comparative studies also corroborate earlier findings that sterically saturated metal environments negatively affect reactivity and selectivity of the amidate complexes in catalytic hydroaminoalkylation reactions.  206  These tantalum complexes are not stable at elevated temperatures, as prolonged exposure to a temperature of 145 °C results in ligand rearrangement to generate a tricyclic product. This rearrangement also occurs at the catalytic temperature of 130 °C but at a much slower rate. This stability investigation coupled with other reaction condition optimization studies led to the following optimum conditions for reactivity: an excess of alkene (2 equivalents), reaction temperature of 130 °C, and total concentration of 1.00 M in amine. The excess of alkene required for this catalysis may render this catalytic system unsuitable for certain tandem reaction sequences as the excess alkene could interfere with further synthetic manipulation. The work presented in this dissertation expands the breadth of the substrate scope of precatalyst 49 in catalytic hydroamination.  Importantly, the investigations involving chiral  amidate complexes highlight the effects of the coordination geometry of amidate ligands on the catalytic activities and selectivities of amidate-ligated early transition metal complexes. Thus, this study provides valuable guidance in the design of future amidate-ligated catalytic systems for enantioselective hydroamination and hydroaminoalkylation reactions.  5.2 Future Directions 5.2.1 Tandem Reaction Sequence Involving Hydroamination Reactions Catalyzed by 49 5.2.1.1 Proposed Synthesis of 1,2-Diamines by Hydroamination and Aza-Henry Reactions The achievements and limitations of precatalyst 49 discussed in Chapter 2 clearly leave room for further investigations.  Although complex 49 has been utilized in various  hydroamination reactions103, 113, 136, 143, 147, 249 very few tandem reaction sequences involving this precatalyst have been performed.145,  146  Further, the imine and allylamine products of these  hydroamination reactions are known substrates for organic synthesis3, 369-371 and could therefore  207  be prepared in situ in one-pot approaches for multi-step syntheses. A particularly interesting transformation utilizing imines as substrates is the aza-Henry reaction.372,  373  The aza-Henry  reaction, also known as the nitro-Mannich reaction, is the nucleophilic addition of nitroalkanes to imines to form β-nitroamines.372,  373  This C–C bond forming reaction has been catalyzed by  various metal-based and metal-free catalysts including Lewis acids,372, 373 and titanium complex 49 could potentially mediate this transformation. In the proposed tandem reaction sequence outlined in Scheme 5.1, the aldimine substrate for the aza-Henry reaction would be generated in situ by the hydroamination of alkynes with primary amines which has been previously shown to give these products. In addition to amines, hydrazines could be used as N–H substrates with alkynes to form hydrazones that also possess the C=N moiety required for this transformation. Importantly, the β-nitroamine products obtained after the nucleophilic addition reaction could be reduced to 1,2-diamines, which are ubiquitous moieties in many natural products with biological activities.372  Scheme 5.1. Proposed tandem sequential formation of 1,2-diamine by hydroamination/azaHenry/reduction reaction sequence.  5.2.1.2 Proposed Synthesis of Secondary Aminoalkenes by Hydroamination and Aza-Cope Reactions Similar to the imines, allylamine products of the hydroamination reactions catalyzed by 49 could be subjected to further transformations in more extended explorations of the compatibility of this precatalyst with other synthetic pathways. In particular, the allylamines  208  could react with aldehydes in Schiff base reactions to afford enamines that are poised to undergo the aza-Cope reaction (Scheme 5.2 (a)).374-376 This 3,3-sigmatropic rearrangement could be effected under thermal or catalytic conditions and results in the formation of new C–C and C–N bonds.374-376 Overall, this proposal would lead to the generation of a C–C and two C–N bonds in a single reaction vessel without the isolation of an intermediate. Preliminary investigation of this tandem hydroamination/aza-Cope synthetic pathway has been performed.  Methoxyallene (1.2 equivalents) reacts with aniline (1 equivalent) in the  presence of 49 to give compound 109 (Scheme 5.2 (b)). The reaction mixture was then treated with 3 equivalents of isobutyraldehyde and 10 mol% of p-toluenesulfonic acid monohydrate under reflux conditions (Scheme 5.2 (b)).  Monitoring the reaction by TLC shows the  consumption of 109 and the formation of a yet to be identified compound. Purification by flash column chromatography was not successful presumably due to the hydrolysis of the targeted imine product assuming the reaction occurred as anticipated. However, reduction with lithium aluminum hydride prior to flash chromatography may allow for the isolation of the corresponding amine product. This sequential hydroamination/aza-Cope/reduction process is currently being pursued by another member of the group. Importantly, the amine product shown in Scheme 5.2 (b), if accessed, could undergo further cyclohydroamination reaction in the presence of an appropriate catalyst to afford 2,3,4,4-tetrasubstituted pyrrolidine.  209  Scheme 5.2. Proposed synthesis of aminoalkenes by hydroamination/aza-Cope rearrangement.  5.2.2 Axially Chiral Proligands and Complexes 5.2.2.1 Biphenyl-Tethered Amide-Acid Proligands The enantioselectivities realized in the tantalum-catalyzed hydroaminoalkylation reactions are at best modest and therefore require further improvement. In addition, the long reaction times in certain examples merit further attention. The use of biphenyl ligands that bear donor atoms from another functional group in addition to N,O-donor atoms of an amide moiety could result in electronically different amidate complexes that could exhibit high catalytic activities and enantioselectivities. In this regard, proligands 110 (Scheme 5.3) and 111 (Scheme 5.4) featuring potential donor atoms from an amide and an acid are promising. The synthesis of proligand 110 has been achieved via N,N′-dicyclohexylcarbodiimide (DCC) mediated coupling of 2,6-diisopropylaniline with 6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid as outlined in Scheme 5.3.377 Attempts to purify 110 by column chromatography or recrystallization were unsuccessful as the product was contaminated with unreacted diacid after these purification attempts. Treatment of the impure product with thionyl chloride and methanol results in the  210  formation of amide-ester that was easily purified by column chromatography. The amide-ester was subsequently reconverted to the amide-acid by basic hydrolysis with potassium hydroxide under reflux conditions (Scheme 5.3).377  . Scheme 5.3. Synthesis of amide-acid proligand 110.  Scheme 5.4. Synthesis of mixed amide-acid proligand 111.  211  Compound 111 was obtained as a white solid by treating 69 with potassium hydroxide in refluxing ethanol for 48 hours (Scheme 5.4). The requisite compound 69 is in turn synthesized in two steps from 6,6′-dimethylbiphenyl-2,2′-dicarboxylic acid as discussed in Section 3.2.1 of Chapter 3 (Scheme 3.5). Reaction of 110 or 111 with an equimolar quantity of Ta(NMe2)5 results in ill-defined complexes as suggested by the complex NMR spectroscopic data. The formation of these complex mixtures of products is presumably due to the faster protonolysis reaction between Ta(NMe2)5 and the acid moiety of the proligands in comparison to the same reaction with the amide moiety of the proligands. This is attributed to the larger difference in pKa values and improved steric accessibility between the two reacting functional groups. The large difference in reactivity between the two functional groups bearing the potential donor atoms on the proligand could result in a different number of biphenyl-ligands being coordinated to each metal center and therefore lead to a mixture of complexes. The inaccessibility of well-defined complexes using proligands 110 and 111 thwarts further investigation of these proligands as ancillary ligands in the tantalum-catalyzed hydroaminoalkylation reaction. However, by using the corresponding amide-ester or amide-ether as proligands instead of the amide-acid, well-defined tantalum complexes may be accessed for enantioselective hydroaminoalkylation reactions.  5.2.2.2 Proposed Sterically-Encumbered 3,3′-Disubstituted Biphenyl Proligands The investigations of different tantalum amidate complexes in hydroaminoalkylation reactions have shown that a coordinatively saturated metal environment is detrimental to the activities and selectivities of these complexes.  As such, improved reactivity and  enantioselectivity in tantalum-catalyzed hydroaminoalkylation reactions could be achieved by  212  increasing the bulkiness of the biphenyl ligand (at positions that could influence substrate orientation on approaching the catalyst) without altering the denticity of this ligand.  The  introduction of substituents at the 3 and 3′ positions of the biphenyl ligand could result in tantalum amidate complexes that meet these criteria (Scheme 5.5). The proposed synthesis of these new ligands is shown in Scheme 5.5. Diester 112 obtained using standard protocol could undergo ortho-metallation with magnesium bis(2,2,6,6-tetramethylpiperamidyl), Mg(TMP)2 and subsequent reaction with bromine to afford the dibromo compound 113. Using the SuzukiMiyaura coupling reaction, different substituents could then be installed at the 3,3′-positions of the biphenyl ring to produce compound 114. This proposed synthetic pathway was originally developed by Maruoka and co-workers for introducing substituents at the 3,3′-positions of related 1,1′-binaphthyl-2,2′-dicarboxylic acid378 and have been successfully used to prepare a number of 3,3′-disubstituted binaphthyl compounds.379-382 The targeted bis(amide) proligands 115 could then be obtained according to the standard procedure shown in Scheme 5.5. These new proligands could be employed in tantalum complex formation for use in the enantioselective hydroaminoalkylation reaction with the goal of increasing stereoselectivity in this reaction.  213  Scheme 5.5. Proposed synthesis of new bis(amide) proligands.  In addition to forming tantalum complexes, proligands of the type 115 could also be utilized in the formation of zirconium complexes for enantioselective hydroamination reactions as the bulky 3,3′-substituents could dictate the orientation of the substrate in the transition state (Scheme 3.11) that determined product selectivity. These substituents could bias substrate orientation in a more pronounced way that could result in highly enantioselective reactions. The introduction of bulky substituents at the 3 and 3′ positions of binaphthyl ligands have been shown to positively influence stereoselectivities in various asymmetric catalysis.383-387  5.2.3 Optimization of Hydroaminoalkylation Reaction Conditions While precatalyst 82a is efficient for the hydroaminoalkylation of a variety of substrates including terminal and internal alkenes, dialkyl- and aryl-alkylamines, further optimization of the reaction conditions is necessary to reduce the sometimes lengthy reaction times. Initial attempts  214  at optimizing the reaction conditions have been performed by determining the effect of alkene concentration on the relative rate of reaction. Two concurrent reactions were set up with Nmethylaniline, vinylcyclohexane, 10 mol% of 82a, and 1,3,5-trimethoxybenzene (internal standard) with the total concentration in amine being ~ 1.0 M in both cases. One of the reactions contained 1.2 equivalents of vinylcyclohexane while the other contained 2.4 equivalents; all other reagents and conditions were identical. After 21 hours at 130 °C, a 12% conversion to product is observed in the reaction mixture containing 1.2 equivalents of alkene while the reaction containing 2.4 equivalents is at 39% conversion (eq 5.1). This three-fold increase in the relative rate of product formation suggests alkene insertion is involved in turnover limiting step, based on the mechanistic proposal of Nugent and Hartwig outlined in Scheme 1.17.  To further probe the potential of an alkene insertion turnover limiting step, preliminary investigation of the effect of pressure on the relative rate of product formation have been performed. An increase in pressure implies lower entropy which could increase the rate of product formation. The reaction pressure can be easily increased by using a solvent with a lower boiling point than toluene used thus far. Indeed, the use of d6-benzene (boiling point of 80 °C) as the reaction solvent for the hydroaminoalkylation reaction between 1-octene and Nmethylaniline in the presence of 10 mol% of 82a results in much faster reactivity as the reaction  215  proceeds to 95% conversion within 24 hours with heating in a sealed tube at 130 °C. On the other hand, the same reaction in d8-toluene requires 48 hours under the same condition to attain 95% conversion. Further optimization of the reaction conditions was performed by determining the optimal concentration for reactivity. Four different molar concentrations of amines: 1.33 M, 1.00 M, 0.50 M, and 0.25 M reaction mixtures each containing 2 equivalents of 1-octene, 1 equivalent of N-methylaniline, and 10 mol% of precatalyst 82a in d6-benzene were prepared and heated to 130 °C.  The progress of this reaction was periodically monitored by 1H NMR  spectroscopy and the results are presented in Figure 5.2. The results show that the total reaction concentration does not significantly influence the reactivity. However, 1.00 M concentration of amine appears to be optimal for reactivity as this particular reaction mixture attained 95% conversion within 23 hours at 130 °C while 1.33 M, 0.50 M, and 0.25 M are at 79%, 91%, and 86% conversion respectively.  216  % Conversion vs Time 120  % Conversion  100 80 1.33 M  60  1.00 M 0.50 M  40  0.25 M 20 0 0  10  20  30  40  50  60  Time (h)  Figure 5.2. Percentage conversion of amine substrate as a function of time.  The preliminary optimization studies show that an excess of alkene substrate results in a higher rate of product formation. The use of d6-benzene as reaction solvent also leads to a higher catalytic activity in comparison to the higher boiling d8-toluene. This is presumably due to an increase in the pressure of the system which increases upon conducting the reaction in d6benzene thereby decreasing the system entropy. However, more conclusive investigation of the effect of pressure on the catalytic activity of precatalyst 82a needs to be performed by conducting the reaction in specialized glassware that would allow accurate monitoring and determination of the system pressure. In short, while substantial progress has been achieved during the course of this work, many avenues for further investigation have been identified. Most importantly, spectroscopic signatures for various amidate chelation modes have been identified and many well characterized  217  examples of previously suspected decomposition products have been reported here. The insight provided by these investigations is presently guiding the on-going work of two postdoctoral researchers and one graduate student.  5.3 Experimental Procedures 5.3.1 Materials and Methods General manipulations and techniques are as outlined in Chapter 2 Section 2.4.1, Chapter 3 Section 3.4.1, and Chapter 4 Section 4.4.1.  5.3.2 Synthetic Procedures Synthesis of 2′-(2,6-diisopropylphenylcarbamoyl)-6,6′-dimethylbiphenyl-2-carboxylic acid (110) This compound was prepared using a modification of literature procedure as described below.377 A solution of 0.316 g (1.53 mmol) of N,N′-dicyclohexylcarbodiimide in 3 mL of THF was added to a solution of 0.414 g (1.53 mmol) of 6,6′-dimethyl-2,2′-dicarboxylic acid in 5 mL of THF over a period of 30 minutes at ambient temperature. The mixture was stirred for 2 h at ambient temperature after which it was refluxed for 4 h. After cooling to ambient temperature, 0.31 g (0.43 mL, 3.1 mmol) of triethylamine and 0.392 g (0.42 mL, 1.99 mmol) of 90% 2,6diisopropylaniline were added and the mixture was further refluxed for 3 h. Upon cooling to ambient temperature, the urea precipitate was filtered off and rinsed with 2 mL of THF. The filtrate was concentrated by rotary evaporation and the crude solid was dissolved in 20 mL of chloroform and washed with concentrated HCl (2 × 10 mL) and water (4 × 10 mL). The organic layer was dried over anhydrous magnesium sulphate, filtered, and concentrated by rotary evaporation. The urea impurity was removed by flash column chromatography with a 7:1  218  mixture of hexanes/ethyl acetate and the product contaminated with unreacted diacid was eluted with a 50:1 mixture of dichloromethane/methanol. The impure product was purified via methyl ester formation as follows: a solution of the impure product in 5 mL of methanol was cooled to 0 °C and 0.546 g (0.33 mL, 4.60 mmol) of thionyl chloride was added over a period of 10 minutes. The mixture was warmed to ambient temperature and then heated at reflux for 2 h. The volatiles were removed in vacuo and the crude solid was taken up in a mixture of 50 mL of ethyl acetate and 25 mL of water. The layers were separated and the organic layer was washed with 10 mL of saturated sodium bicarbonate solution.  The organic layer was dried over  anhydrous sodium sulphate, filtered, and concentrated by rotary evaporation. The pure amideester was isolated as a white solid in 31% yield (0.210 g, 0.475 mmol) following flash chromatography with a 10:1 mixture of hexanes/ethyl acetate. The amide-ester was converted back to the amide-acid as follows: a solution of 0.27 g of KOH in 0.8 mL of water was added to a solution of the 0.210 g of the amide-ester in 3 mL of ethanol and the mixture was refluxed for 16 h. After cooling to ambient temperature, the solvents/volatiles were removed by rotary evaporation. The solid was dissolved in 30 mL of water and washed with diethyl ether (2 × 15 mL). Concentrated HCl (3 mL) was added to the aqueous layer and the precipitate was extracted with ethyl acetate (3 × 30 mL). The organic layer was washed with 10 mL of water, dried over magnesium sulphate, filtered, and concentrated by rotary evaporation. Flash column chromatography with a 20:1 mixture of dichloromethane/methanol allows isolation of the pure product as a white solid in 50% yield (0.10 g, 0.22 mmol, 15% over the three steps).  219  1  H NMR (CDCl3, 300 MHz, δ): 0.73–1.10 (12H, br m, 2 × –CH(CH3)2), 1.76 (3H, s, Ar–CH3),  1.82 (3H, s, Ar–CH3), 2.48 (1H, br s, Ar–CHCH3), 2.76 (1H, br s, Ar–CHCH3), 7.00 (2H, m, 2 × Ar–H), 7.13–7.30 (6H, m, 6 × Ar–H), 7.41 (1H, m, Ar–H), 7.96 (1H, d, J = 4.4 Hz,–CONH–); C{1H} NMR (CDCl3, 100 MHz, ): 20.0, 20.2, 28.9, 123.8, 124.5, 126.1, 128.4, 128.6, 129.1,  13  129.9, 132.6, 133.4, 135.1, 136.1, 137.0, 138.1, 171.8, 172.3; MS(ESI) m/z: 430 (M+ + H); Anal. Calcd for C28H31NO3: C, 78.29; H, 7.27; N, 3.26. Found: C, 77.99; H, 7.34; N, 3.23.  Synthesis of 2′-(2,6-dimethylphenylcarbamoyl)-6,6′-dimethylbiphenyl-2-carboxylic acid (111) To a solution of 0.225 g (0.633 mmol) of cyclic imide 69 (obtained during the synthesis of proligand 68c) in 4 mL of ethanol was added a solution of 0.195 g (3.48 mmol) of KOH in 0.6 mL of water.  The mixture was heated at reflux for 48 h.  After cooling to ambient  temperature, the solvent/volatiles were removed by rotary evaporation. The solid was dissolved in 20 mL of water and acidified with 2 mL of concentrated HCl after which it was extracted with ethyl acetate (3 × 20 mL). The organic layer was washed with water (20 mL), dried over anhydrous magnesium sulphate, filtered, and concentrated by rotary evaporation. The product was isolated as a white solid in 64% yield (0.151 g, 0.404 mmol) after flash chromatography with a 20:1 mixture of dichloromethane/methanol. 1  H NMR (CDCl3, 300 MHz, δ): 1.93 (3H, s, Ar–CH3), 1.97 (3H, s,  Ar–CH3), 2.05 (6H, s, 2 × Ar–CH3), 7.03 (2H, m, 2 × Ar–H), 7.11 (1H, m, Ar–H), 7.34 (2H, m, 2 × Ar–H), 7.42 (2H, m, 2 × Ar–H), 7.48 (1H, m, Ar–H), 7.56 (1H, m, Ar–H), 7.74 (1H, m, Ar–H); C{1H} NMR (DMSO, 100 MHz, ): 18.2, 20.2, 20.5, 125.4, 126.9, 127.3, 128.0, 128.1, 128.3,  13  132.0, 133.3, 133.7, 135.0, 135.8, 136.4, 136.6, 137.2, 137.7, 138.2, 168.8, 170.1; MS(ESI) m/z:  220  374 (M+ + H); Anal. Calcd for C24H23NO3: C, 77.19; H, 6.21; N, 3.75. Found: C, 76.84; H, 6.18; N, 3.68.  221  REFERENCES 1.  Mueller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795.  2.  Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron 2001, 57, 7785.  3.  Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98, 1689.  4.  Tararov, V. I.; Borner, A. 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J. Am. Chem. Soc. 2006, 128, 1086.  384.  Ishihara, K.; Kobayashi, J.; Nakano, K.; Ishibashi, H.; Yamamoto, H. Chirality 2003, 15, 135.  385.  Tsang, W. C. P.; Schrock, R. R.; Hoveyda, A. H. Organometallics 2001, 20, 5658.  386.  Kobayashi, S.; Kusakase, K-i.; Komiyama, S.; Ishitani, H. J. Org. Chem. 1999, 64, 4220.  387.  Maruoka, K.; Itoh, T.; Shirasaka, T.; Hisashi, Y. J. Am. Chem. Soc. 1998, 110, 310.  243  APPENDIX A. X-RAY CRYSTALLOGRAPHIC DATA  Table A.1. X-Ray crystallographic parameters for 53b·H2C2O4, 69, and 68g 53b·H2C2O4 formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  68g  C19H21NO5 343.37 0.4×0.3×0.3 colourless, prism P21/c:b1 monoclinic 11.6270(5) 9.5769(4) 16.3785(6) 90 91.7318(18) 90 1822.92(13) 4 1.251 Mo Kα (λ = 0.71073 Å) 103(2) 728 0.091 1.75–30.07 19769 5329  69 + CH3CO2C2H5 C28H29NO4 443.52 0.45×0.45×0.46 colourless, prism P21/c monoclinic 10.7899(7) 15.7591(10) 13.4954 90(1) 94.1129(19) 90(1) 2288.8(15) 4 1.287 Mo Kα (λ = 0.71073 Å) 103(2) 944 0.086 1.89–29.00 22697 6075  SIR92 248 0.0579 0.1399 0.0479 0.1300 1.027  SIR92 304 0.0582 0.1321 0.0444 0.1214 1.044  SIR92 1065 0.0975 0.1894 0.0650 0.1766 1.059  C97.50H98.8O6.67 1461.33 0.4×0.3×0.3 colourless, prism P65 hexagonal 38.961 38.961 10.272 90 90 120 13503.5 6 1.078 Mo Kα (λ = 0.71073 Å) 103(2) 4675 0.067 1.05–27.89 302284 21145  244  Table A.2. X-ray crystallographic parameters for (±)-76a·HNMe2, (±)-76f·HNMe2, and [76b]2 formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  76a·HNMe2 C46H65N5O2Zr 811.25 0.5×0.5×0.5 colourless, prism P21/c:b1 monoclinic 19.5464(23) 10.6634(13) 21.4716(22) 90 95.419(4) 90 4455.3(9) 4 1.209 Mo Kα (λ = 0.71073 Å) 173(2) 1728 0.288 1.91–22.57 19371 5547  76f·HNMe2 C49H69N5O2Zr 851.31 0.4×0.3×0.3 colourless, prism P-1 triclinic 12.0091(4) 13.2817(5) 15.8533(5) 102.4246(18) 109.8836(17) 103.0128(17) 2196.21(3) 2 1.287 Mo Kα (λ = 0.71073 Å) 173(2) 908 0.295 1.44–22.57 37104 10044  [76b]2 C112H128N8O4Zr2 1832.66 0.4×0.4×0.3 colourless, prism P21/c monoclinic 15.7199(4) 45.9711(13) 13.6236(4) 90 92.8300(10) 90 9833.2(5) 4 1.238 Mo Kα (λ = 0.71073 Å) 103(2) 3872 0.268 1.57–27.90 80588 23405  SIR 92 507 0.0947 0.1732 0.0673 0.1597 1.113  SIR 92 527 0.0448 0.0979 0.0353 0.0922 1.089  SIR 92 1159 0.0732 0.1023 0.0524 0.0964 1.138  245  Table A.3. X-ray crystallographic parameters for [76c]2, 77, and (±)-76a·(py)2  formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  [76c]2 + 2 C7H8 + 77 C6H6 C89H103N8O4Zr2 C52H76N8O4Zr2 1531.23 1059.65 0.6×0.5×0.4 0.4×0.4×0.3 colourless, prism colourless, prism P-1 P21:b triclinic monoclinic 13.7950(16) 11.7389(2) 15.3529(16) 18.1439(4) 20.5222(15) 12.6437(3) 85.525(5) 90 78.148(5) 104.3891(8) 75.554(5) 90 4117.7 2608.50(10) 2 2 1.235 1.349 Mo Kα Mo Kα (λ = 0.71073 Å) (λ = 0.71073 Å) 173(2) 173(2) 1610 1112 0.0307 0.405 1.68–24.97 1.66–30.06 50233 30551 14374 14902  (±)-76a·(py)2 + C6H6 C66H80N6O2Zr 1080.58 0.5×0.3×0.2 yellow P21/n monoclinic 17.9388(8) 15.6843(8) 23.5663(12) 90 110.9577(21) 90 6191.9(5) 4 1.159 Mo Kα (λ = 0.71073 Å) 103(2) 2296 0.224 1.77–30.08 67721 18007  SIR 92 1051 0.0528 0.0949 0.0371 0.0866 1.057  SIR 92 690 0.0684 0.2191 0.0559 0.2043 1.118  SIR 92 615 0.0345 0.0578 0.0287 0.0558 1.022  2  246  Table A.4. X-ray crystallographic parameters for (±)-82a, (±)-82b·HNMe2, and (±)-83c formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  (±)-82a C49H67N5O2Ta 939.03 0.5×0.5×0.5 pale yellow, prism C2/c:b1 monoclinic 36.0117(16) 12.4454(5) 20.8985(9) 90 94.602(2) 90 9336.1(7) 8 1.336 Mo Kα (λ = 0.71073 Å) 173(2) 3880 2.397 1.73–30.07 42095 11466  (±)-82b·HNMe2 C42H59N6O2Ta 860.90 0.5×0.4×0.4 pale yellow, prism P21/c:b1 monoclinic 12.6833(5) 16.1029(6) 19.7762(8) 90 97.981 90 3999.9(3) 4 1.430 Mo Kα (λ = 0.71073 Å) 103(2) 1768 2.790 2.06–30.11 80998 11737  (±)-83c C38H48N5O2Ta 787.77 0.5×0.5×0.5 pale yellow P21/n monoclinic 13.3131(15) 16.3255(19) 16.2353(17) 90 99.151(5) 90 3483.7(9) 4 1.506 Mo Kα (λ = 0.71073 Å) 173(2) 1608 3.196 1.78–30.23 57513 9972  SIR 92 531 0.0422 0.0770 0.0306 0.0.0711 1.101  SIR 92 480 0.0269 0.0533 0.0206 0.0492 1.145  SIR 92 427 0.0390 0.0712 0.0261 0.0630 1.052  247  Table A.5. X-ray crystallographic parameters for (±)-83d, 84, and (±)-94  formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  (±)-83d  84  C34H40N5O2Ta 731.66 0.3×0.1×0.1 yellow, prism P-1 triclinic 10.2854(15) 15.0536(22) 21.4357(32) 106.4841(37) 97.5882(39) 97.5070(40) 3104.9(8) 4 1.565 Mo Kα (λ = 0.71073 Å) 173(2) 1472 3.579 1.01–28.30 23506 23506  C36H45N6O2Ta 774.73 0.6×0.4×0.2 yellow, prism P32 trigonal 16.2144(4) 16.2144(4) 11.2918(4) 90 90 120 2570.96(13) 3 1.501 Mo Kα (λ = 0.71073 Å) 173(2) 1176 3.247 2.31–27.58 67903 7796  (±)-94 (twin structure) C38H74N10O2Ta2 1064.97 1.0×0.2×0.2 yellow, needles P-1 triclinic 10.2755(8) 14.4464(10) 16.8177(14) 77.5820(31) 81.5513(35) 71.7713(31) 2307.2(3) 2 1.533 Mo Kα (λ = 0.71073 Å) 173(2) 1068 4.780 1.77–25.02 29356 8035  SIR 92 758 0.0511 0.1179 0.0463 0.1164 1.325  SIR 92 415 0.0187 0.0437 0.0178 0.0434 1.040  SIR 92 491 0.414 0.0757 0.0290 0.0690 1.034  248  Table A.6. X-ray crystallographic parameters for 81f, (±)-82f, and 97e formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  81f (twin structure) C96H142N12O4Ta2 1890.12 0.6×0.4×0.4 yellow, needles P21:b monoclinic 11.009 15.149 24.707 90 94.31 90 4108.9 2 1.528 Mo Kα (λ = 0.71073 Å) 103(2) 1960 2.724 1.58–27.60 9857 9857  (±)-82f C48H66N5O2Ta 926.01 0.65×0.42×0.36 yellow, prism P-1 triclinic 11.9598(10) 13.3472(11) 15.5692(12) 106.2718(38) 108.5153(38) 98.9601(40) 2178.9(14) 2 1.411 Mo Kα (λ = 0.71073 Å) 103(2) 956 2.566 1.65–27.56 36553 10004  97e C42H46N2O2 610.81 0.6×0.5×0.3 colourless, prism P1 triclinic 9.3774(6) 9.4666(6) 9.5073(7) 88.441(3) 81.253(2) 89.251(3) 833.83(16) 1 1.216 Mo Kα (λ = 0.71069 Å) 173(2) 328 0.074 2.15–25.07 10316 4852  SIR 92 956 0.0638 0.1441 0.0492 0.1230 1.091  SIR 92 956 0.0197 0.0417 0.0172 0.0408 1.035  SIR 92 487 0.0488 0.1036 0.0407 0.0975 1.043  249  Table A.7. X-ray crystallographic parameters for (±)-101 and (±)-106 formula Fw crystal size (mm) colour, habit space group cell setting a (Å) b (Å) c (Å) α (°) β (°) γ (°) V (Å3) Z ρcalcd (g cm-1) radiation temp (K) F(000) μ (Mo Kα) (mm-1) θ range (°) total no. of reflns no. of unique reflns I = 2σ(I) structure soln no. of variables R1 (all data) wR2 (all data) R1 (I ˃ 2σ(I)) wR2 (I ˃ 2σ(I)) goodness of fit  (±)-101 C40H46N2O 570.79 0.6×0.5×0.5 colourless, prism P21/c:b1 monoclinic 16.0977(7) 12.1120(5) 16.9585(8) 90.0101(15) 98.4230(15) 89.9812(15) 3270.8(2) 4 1.159 Mo Kα (λ = 0.71073 Å) 173(2) 1232 0.069 1.28–30.06 61533 9175  (±)-106 C32H50N5OTa 717.72 0.4×0.1×0.1 yellow, needles C2/c:b1 monoclinic 35.1051(19) 9.2798(5) 19.8790(11) 90 94.098(3) 90 6459.4(6) 8 1.496 Mo Kα (λ = 0.71073 Å) 103(2) 2928 3.438 1.16–27.92 7695 7695  SIR 92 398 0.0859 0.1239 0.0495 0.1102 1.022  SIR 92 361 0.0407 0.0755 0.0339 0.0738 1.191  250  APPENDIX B. 1H AND 13C NMR SPECTRA OF SELECTED COMPOUNDS  251  252  253  254  255  256  257  258  259  260  261  262  263  264  265  

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