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Hydroamination and C-H activation reactivity of tetrakis(amido), bis(amidate) and bis(2-pyridonate) complexes… Bexrud, Jason 2008

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HYDROAMINATION AND C-H ACTIVATION REACTIVITY OF TETRAKIS(AMIDO), BIS(AMIDATE), AND BIS(2-PYRIDONATE) COMPLEXES OF TITANIUM AND ZIRCONIUM  by  Jason Adam Bexrud B.Sc., Simon Fraser University, 2003  A THESIS SUBMITI’ED 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 2008 © Jason Adam Bexrud, 2008  Abstract The work reported herein focuses on expanding the reaction scope of known group four bis(amidate) and tetrakis(amido) complexes in hydroamination catalysis.  The  development of new titanium and zirconium complexes exhibiting improved reactivity in hydroamination catalysis and unexpected C-C bond formation are disclosed. The exceptional hydroamination activity of a bis(amidate) titanium bis(amido) precatalyst towards alkynes in the presence of aryl amine co-substrates is elucidated, and the scope of this reactivity was found to include examples of room temperature intermolecular hydroamination. The application of commercially available tetrakis(dialkylamido) titanium(IV) as a precatalyst for the cyclohydroamination of aminoalkenes to form N heterocyclic products is a particularly attractive contribution due to the ready availability and ease of use associated with this catalyst system. The second section involves efforts to develop more reactive and selective bis(amidate) bis(amido) hydroamination precatalysts by the rational design and implementation of new amidate ligands modified for enhanced reactivity and selectivity including attempts at enantioselective catalysis. The synthesis and characterization of a bis(amidate)  titanium  bis(amido)  complex  incorporating  electron  withdrawing  perfluorophenyl groups for enhanced reactivity, along with the assessment of this system in terms of hydroamination is presented. The synthesis, characterization and evaluation of chiral amidate ligands for the asymmetric cyclohydroamination of aminoalkenes is also described. In order to generate more reactive group four hydroamination precatalysts, 2pyridone and its derivatives were investigated as a new class of amidate N,O chelating  11  proligand. The synthesis and characterization of the first group four bis(2-pyridonate) bis(amido) complexes is presented along with their reactivity towards aminoalkenes. These novel complexes were found to be reactive for both cyclohydroamination and catalytic intramolecular a-functionalization. The initial findings along with a substrate scope analysis, and preliminary mechanistic investigations for this unique and exciting 100% atom economic, catalytic C-C bond forming reaction is included. The work described in this dissertation contributes to understanding of group four metal catalyzed reactions by illuminating some previously unknown reactivity associated with titanium and zirconium as well as by providing further insight into how ligand structure influences complex reactivity.  111  Table of Contents  Abstract  ii  .  Table of Contents  iv  List of Tables  viii  List of Figures  x  List of Schemes  xiii  List of Abbreviations  xvii  Forward  xx  Acknowledgements  xxi  Co-Authorship Statement  xxii  GENERAL INTRODUCTION TO HYDROAMINATION AND THE DEVELOPMENT OF GROUP FOUR BASED HYDROAMINATION PRECATALYSTS 1 1.1  General introduction  1  1.2  Intramolecular alkene hydroamination  7  1.3  Modifying the ligand for enhanced reactivity  16  1.4  Scope of thesis  20  1.5  References  23  CHAPTER TWO: FURTHER DELiNEATING THE SYNTHETIC UTILITY OF EXISTING TETRAKIS(AMIDO) AND BIS(AMIDATE) TITANIUM BIS(AMIDO) HYDROAMINATION PRECATALYSTS  28  2.1  Introduction  28  2.2  Results and discussion  31  2.2.1  2.2.2  Hydroamination of terminal alkynes with aniline and p-anisidine at ambient temperature  31  Hydroamination of internal alkynes with p-anisidine  34  iv  2.2.3  Hydroamination of TBDMS protected propargyl alcohols with p-anisidine  2.2.4  2.2.5  36  Side reactivity observed during the hydroamination of. phenyl-acetylene with aniline  39  Intramolecular alkene hydroamination activity  42  2.2.5.1  The gem-disubstituent effect  42  2.2.5.2  Diastereoselectivity  45  2.2.5.3  Substrate scope  48  2.2.5.4  Mechanistic rationale  49  2.2.5.5  Tetrakis(amido) vs bis(amidate) titanium bis(amido) precatalysts  2.2.6  Hydroamination using in situ prepared precatalyst  51 53  2.3  Summary and conclusions  55  2.4  Experimental  57  2.5  References  79  CHAPTER THREE: CATALYST DEVELOPMENT OF GROUP FOUR BASED SYSTEMS INCORPERATING AMIDATES AS N,O CHELAT1NG ANCILLIARY LIGANDS  83  3.1  Introduction  83  3.2  Results and discussion  84  3.2.1  Modifying the electronics of the amidate ligand  84  3.2.1.1  Complex synthesis and characterization  85  3.2.1.2  Reactivity towards alkynes  88  3.2.1.3  Reactivity towards aminoalkenes  92  3.2.1.4  Reactivity of the N-2,6-diisopropylphenylperflourophenylamidate ligand  3.2.1.5  94  Summary of modifying the electronic properties of the amidate ligand  95  v  3.2.2  Modifying the structure of the amidate ligand for asymmetric cyclohydroamination  3.2.2.1  96  Synthesis and characterization of the proligand  101  3.2.2.2  Complex synthesis and characterization  104  3.2.2.3  Enantioselectivity determinations  107  3.2.2.4  Summary of incorporating (-)-menthone as a source of chirality for the asymmetric hydroamination of aminoalkenes  108  3.3  Overall summary and conclusions  110  3.4  Experimental  111  3.5  References  125  CHAPTER FOUR: GROUP FOUR BASED HYDROAMINATION CATALYSTS INCORPERATING 2-PYRIDONATES AS N,O CHELATING ANCILLIARY LIGANDS  127  4.1  Introduction  127  4.2  Results and discussion  134  4.2.1  Synthesis and characterization of titanium and zirconium complexes incorporating 2-pyridone and 6-tert-butyl-3 -phenyl 2-pyridone as proligands  4.2.2  134  Intramolecular alkene hydroamination activity and substrate scope investigation  141  4.3  Summary and conclusions  144  4.4  Experimental  145  4.5  References  154  vi  CHAPTER FIVE: cc-FU1’JCTIONALIZATION OF PRIMARY AMINES VIA sp 3 HYBRIDIZED C-H BOND ACTIVATION  157  5.1  Introduction  157  5.2  Results and discussion  159  5.2.1  Preliminary findings and catalyst screening  159  5.2.2  Substrate scope investigation  164  5.2.3  Mechanistic considerations  166  5.3  Summary and conclusions  171  5.4  Experimental  173  5.5  References  186  CHAPTER SIX: CONCLUSIONS AND FUTURE WORK  189  6.1  Summary, conclusions and suggested future work  189  6.2  References  196  APPENDIX I  197  vii  List of Tables Table 2.1. The impact of the gem-disubstituent effect on cyclohydroamination using 4 ) 2 Ti(NMe  44  Table 2.2. Investigating diastereoselectivity when Ti(NMe 4 is employed as a ) 2 precatalyst  45  Table 2.3. Substrate scope investigation using Ti(NMe 4 ) 2  48  Table 2.4. Comparison of cyclohydroamination activity of complex 1.1 to Ti(NMe 4 ) 2 52 Table 3.1. Selected Bond Distances  (A) and Angles (deg) for bis(N-2,6-  diisopropylphenyl-perfluorophenylamidate)titanium-bis(diethylamide) complex 3.1  87  Table 3.2. Hydroamination reactions with terminal alkynes and primary amines using complexes 1.1 and 3.1  90  Table 3.3. Comparing intramolecular aminoalkene hydroamination using precatalysts 1.1, 1.7, and 3.1  92  Table 3.4. Enantioselective hydroamination studies using bis(amidate) titanium bis(amido) precatalysts derived from (-)-menthone Table 4.1. Selected Bond lengths and angles for complexes 4.1, 4.2, and 4.3  107  139  Table 4.2. Substrate scope using complex 4.3 and the bis(N-2’,6’-diisopropylphenyl(phenyl)-amidate) zirconium bis(dimethylamido) complex  143  viii  Table 5.1. Catalyst screening for the c-activationJfunctiona1ization reaction  161  Table 5.2. Synthesis of cyclohexylamine derivatives via catalytic cL-functionalization 165  ix  List of Figures Figure 1.1. Titanium and zirconium hydroamination precatalysts  4  Figure 1.2. Possible coordination geometries of bis(amidate) bis(amido) complexes  5  Figure 1.3. ORTEP diagram of complex 1.1 with ellipsoids set at the 50 % probability level. Hydrogen atoms have been omitted for clarity 6 Figure 1.4. Pyrrolidine and piperidine natural products  8  Figure 1.5. Bis(amidate) zirconium bis(amido) complex 1.2 incorporating a chiral phosphinic amide proligand prepared by Bergman and coworkers for the asymmetric cyclohydroamination reaction  12  Figure 1.6. Bis(amidate) zirconium bis(amido) complex 1.3 incorporating an axially chiral ligand framework developed for enantioselective cyclohydroamination  13  Figure 1.7. Chiral-at-metal diamide zirconium complexes 1.4 and 1.5 reported by Scott and coworkers 15 Figure 1.8 Progression in the design of the bis(amidate) ligand framework  18  Figure 2.1. Side-products isolated from the hydroamination of phenylacetylene with aniline  40  Figure 3.1. Amidate proligands designed for improved reactivity (3.1) stereoselectivity (3.2) 83  x  Figure 3.2. Diagram of bis(amidate) titanium bis(amido) complex 3.1 with thermal  ellipsoids set at the 50% probability level  86  Figure 3.3. Bis(amidate) zirconium bis(amido) complex 1.3 incorporating an axially  chiral ligand framework developed for enantioselective cyclohydroamination  97  Figure 3.4. ORTEP diagrams of the N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-  benzamide proligand 3.7. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity  104  Figure 3.5. ORTEP diagram of the N-(( 1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-  benzamide proligand 3.2. Elipsoids are drawn at the 50% probability level. 104  Figure 4.1. Coordination geometries of the [(ri H 7 M ) 2 ] 3 ) 5 O,N-O Zr( C NC e ri complex  and the  -TiMe(r’ ) CsMe -O-0C ] complex ) 2 N 7 H 8 [( 5  132  Figure 4.2. Diagram of the bis(2-pyridonate) titanium bis(dimethylamido) complex 4.1 with thermal ellipsoids set at the 50% probability level. Hydrogen atoms have been omitted for clarity  137  Figure 4.3. ORTEP depiction of an dimer obtained by the reaction of Zr(NMe 4 ) 2  with 2-pyridone. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity  137  Figure 4.4. Diagram of the bis(6-tert-butyl-3 -phenyl-2-pyridonate) titanium  bis(dimethylainido) complex 4.2 with thermal ellipsoids set at the 50% probability level. Hydrogen atoms have been omitted for clarity  138  xi  Figure 4.5. Diagram of the bis(6-tert-butyl-3-phenyl-2-pyridonate) zirconium  bis(dimethylamido) complex 4.3 with thermal ellipsoids set at the 50% probability level. Hydrogen atoms have been omitted for clarity 138  xli  List of Schemes Scheme 1.1. Hydroamination of terminal or monosubstituted alkenes and alkynes  3  Scheme 1.2. Mechanism for the lanthanide and group three intramolecular alkene hydroamination  10  Scheme 1.3. Steric and electronic modification of the bis(phenoxide) ligand set and its impact on the hydroamination of 1-hexyne with benzylamine  17  Scheme 1.4. Simplified proposed catalytic cycle for the group 4 catalyzed hydroamination of alkynes  19  Scheme 2.1. Hydroamination of alkynes leading to PMP-protected primary amines. ..29 .  Scheme 2.2. Hydroamination of TBDMS protected propargyl alcohols leading to the formation of synthetically useful protected n-amino alcohols and ci-amino acids  30  Scheme 2.3. Intermolecular alkene hydroamination reactions with complex 1.1 as the precatalyst 33 Scheme 2.4. Intermolecular hydroamination of internal alkynes with aniline and p anisidine using complex 1.1  36  Scheme 2.5. Hydroamination of TBDMS protected -phenyl-2-propyne-1-ol and 4phenyl-3-butyne-2-ol with p-anisidine using complex 1 as the precatalyst. 38  xlii  Scheme 2.6. Proof of principle: p-methoxyphenyl protected amines prerpared via  hydroamination are subjected to known oxidative cleavage procedures 39 Scheme 2.7. Mechanistic rational for the proton mediated formation of the tetrahydroisoquinoline  41  Scheme 2.8. The components of the “gem-dialkyl” effect, Thorpe-Ingold theory and reactive rotamer theory  43  Scheme 2.9. Rationale for the diastereoselectivity observed in the cyclohydroamination of substrates differentially substituted in either the 1-position or 2-position. 47 Scheme 2.9. Proposed catalytic cycle for the intramolecular hydroamination of aminoalkenes catalyzed by Ti(NMe 4 ) 2  50  Scheme 2.10. Intermolecular alkyne hydroamination using in situ generated precatalyst. 54 Scheme 3.1. Evolution of the bis(amidate) system  85  Scheme 3.2. Hydroamination of l-phenyl-1-propyne with 2,6-dimethylaniline  88  Scheme 3.3. Reaction of N-2,6-diisopropylphenylperflourophenylamide with 2,2diphenylpentylamine and benzylamine  95  xiv  Scheme 3.4. Using commercially available (-)-menthone as a source of asymmetry for  the synthesis of chiral zirconium precatalysts (hypothetical geometry shown)  98  Scheme 3.5. Hypothesized preferred coordination geometries for the bis((N menthyl)benzamidate) zirconium bis(amido) complex  99  Scheme 3.6. Proposed eometry of the catalytically active zirconium imido species  101  Scheme 3.7. Overall synthetic route to the (-)-menthone derived bis((N-menthyl)phenyl amidate) zirconium bis(amido) complexes  102  Scheme 3.8. (-)-Menthone derived proligand synthesis  103  Scheme 4.1. Proposed synthetic route to the bis(2-pyridonate) complexes  127  Scheme 4.2. Improved accessibility to the metal center using 3,6-substituted 2-pyridones as proligands  129  Scheme 4.3. The tautomeric equilibrium between 2-pyridone and 2-hydroxypyridine.  130 Scheme 4.4. Possible binding modes adopted by the 2-pyridonate ligand  131  Scheme 4.5. Modular synthetic route to the 3,6-disubstituted 2-pyridones  133  Scheme 4.6. Synthesis of the bis(2-pyridonate) titanium and zirconium bis(amido)  complexes 4.1 —4.3  Scheme 4.7. NOE contacts observed for complexes 4.1, 4.2, and 4.3  136  140  xv  Scheme 4.8. Intramolecular hydroamination of 2,2-diphenyl-4-pentenylamine  142  Scheme 5.1. Mechanism proposed by Hartwig and coworkers for the tantalum catalyzed hydroaminoalkylation reaction  166  Scheme 5.2. Reactivity of zirconium 11 —imine complexes towards alkenes and 2 alkynes  167  Scheme 5.3. Postulated mechanism for the zirconium catalyzed a C-H activation/C-C bond forming reaction  169  Scheme 5.4. Experiment involving 1,1 -dideuterium labeled 2,2-diphenyl-6heptenylamine  170  Scheme 5.5. Rationalization of the diastereoselectivities observed in the intramolecular ct-functionalization reaction  171  xvi  List of Abbreviations 2-D  2-Dimensional  AcOH  Acetic acid  APCI  Atmospheric pressure chemical ionization mass spectrometry  APT  Attached proton test  Ar  Aryl  Bn  Benzyl  Bz  Benzoyl  br  Broad, in NMR spectroscopy  cat.  Catalytic  conc.  Concentrated  COSY  Correlation spectroscopy  Cp  Cyclopentadienyl  Cp*  Pentamethylcyclopentadienyl  d  Doublet, in NMR spectroscopy  d  Deuterium  dd  Doublet of doublets, in NMR spectroscopy  DCM  Dichloromethane  de  Diastereomeric excess  DMSO  Dimethyl sulfoxide  EA  Elemental analysis  ee  Enantiomeric excess  El-MS  Electron-impact mass spectrometry  eq.  Equation  ESI-MS  Electrospray ionization mass spectrometry  Et  Ethyl  Equiv.  Equivalent  Ii  time in hours  GCMS  Gas chromatography-mass spectrometry  HRMS  High resolution-mass spectrometry  Hz  Hertz  iPr  iso-propyl  xvii  J  Coupling constant, in NMR spectroscopy  LAH  Lithium aluminum hydride  Ln  Lanthanide atom  LR-MS  Low-resolution mass spectrometry  M  i) metal atom ii) central atom or parent peak in MS iii) concentration, in molarity  MS  Mass spectrometry  m  Multiplet, in NMR spectroscopy  Me  Methyl  MHz  Megahertz  mmol  Millimole  mol  Mole  N  Normality  nBu  n-But)’!  NMR  Nuclear magnetic resonance  OAc  Acetate  ORTEP  Oak Ridge Thermal Ellipsoid Plot  Ph  Phenyl  PMP  para-methoxyphenyl  ppm  Parts per million, in NMR spectroscopy  R  Alkyl group  RT  Room temperature  s  Singlet, in NMR spectroseopy  SAR  Structure-activity relationship  sat.  Saturated  sept  Septet, in NMR spectroscopy  t  Triplet, in NMR spectroscopy  T  Temperature,  t  tert  TBDMS  t-Butyl-dimethylsilyl  tBu  t-Butyl  oc  xviii  THF  Tetrahydrofuran  TLC  Thin layer chromatography  tol  Toluene  Ts  p-toluene sulfonyl  TM  Trademark  ©  Copyright  A  Change in Chemical shift in NMR spectroscopy, in ppm Wavelength, in cm-i Frequency in Hz or s-i  It  Pi, as in it-bond Sigma, as in cr-bond  xix  Foreword  The work that is reported in this thesis focuses on expanding the reaction scope of known group four bis(amidate) and tetrakis(amido) complexes in hydroamination catalysis as well as the development of new titanium and zirconium complexes for improved hydroamination activity. As this is a manuscript based thesis, each chapter is meant to be a stand-alone document. Therefore, one will find that there is some repetition in the introductory information between the chapters. However, compound labeling has been maintained throughout this thesis and therefore any compound referred to in multiple chapters will have the same identifier. Each chapter is organized with an introduction, results and discussion, summary and conclusions section, and references. An appendix containing tables of crystallographic parameters, ORTEP diagrams, and representative ‘H and ‘ C NMR spectra for the different classes of compounds 3 synthesized in chapters two, three, four and five is also included at the end of this thesis. Assignment of ‘H NMR spectra was based on chemical shift, peak shape and integration. Where confident assignment of 1D spectra was not possible, COSY, HMQC and HMBC NIvIR experiments were carried out to unambiguously interpret the data. Yields reported within this thesis are estimated to be accurate within +1- 5%. Instances where yields or product distributions were found to vary substantially have been highlighted.  xx  Acknowledgements  Firstly, I would like to thank my supervisor, Dr. Laurel Schafer, for her guidance and support in all aspects of this undertaking. I would also like to thank both past and present members of the Schafer group for their help in the lab. I would like to thank the various shops and services in the chemistry department at UBC, including the mech shop, the glassblower, the NMR staff, and the analytical services staff. In particular, I would like to thank Brian Patrick, Neal Yonson and Rob Thomson for assistance with X-ray crystallography. I would like to thank UBC, the UBC chemistry department, Boehringer Ingeihiem, and NSERC for funding. Finally, I would like to thank my parents for their support over the years.  xxi  Co-Authorship Statement  All of the work reported in this thesis was performed by Jason A. Bexrud. Any conclusions or experimental results referred to in the text of this thesis that were obtain ed  by other parties have been clearly identified and cited. Laurel L. Schafer is the princip le investigator for this work and assisted in design of the research program, data analysis, and manuscript preparation.  xxii  CHAPTER ONE: INTRODUCTION TO HYDROAMINATION AND THE DEVELOPMENT OF GROUP FOUR BASED HYDROAMINATION PRECATALYSTS  1.1 General introduction  Nitrogen containing compounds are ubiquitous in chemistry and are employed in a wide range of important agrochemical, pharmaceutical, and industrial roles. Therefore, the development of new methodologies that have the potential to reduce cost and simplif’ their production is of great importance. To this end, hydroamination (Equation 1.1) has drawn a great deal of attention in past years,’ primarily due to the potential for this strategy to be a much more efficient means of synthesizing these compounds than 2 traditional methods. 2 H—NR  H  2 NR  (.)  As depicted in Equation 1.1, the term hydroamination describes a chemical transformation in which a new C-N bond is formed via the net addition of N-H across a carbon-carbon multiple bond (double or triple). The absence of any byproducts renders this reaction a completely atom economic process, and therefore an extremely efficient means of generating nitrogen containing molecules from readily available starting materials.  From a thermodynamics standpoint, the hydroamination of alkenes is  considered to be nearly thermonuetral or even slightly exothermic, 3  while the  hydroamination of alkynes has been estimated to be even more exothermic than the hydroamination of alkenes. 4 Also, there is a high activation barrier associated with this transformation which results from electrostatic repulsion between the lone pair of the  1  nitrogen and the electron rich rr system of the unsaturated carbon-carbon bond. 3  In  addition, a direct [2+2] cycloaddition reaction between the N-H bond and the carboncarbon multiple bond is a symmetry forbidden process. 3 In order to circumvent the high activation barrier associated with this transformation, alkali metals, lanthanides and transition metal based complexes have been used to create alternative reaction pathways.  This has been done using two general approaches;  activation of the carbon-carbon multiple bond to nucleophilic attack, or activation of the N-H bond. Activation of an alkene or alkyne can be accomplished by their coordination to a Lewis acidic metal center, such as silver(I), 5  6 gold(I),  7 and palladium(II)  8 N-H bond activation on the other hand, is achieved in four distinct ways. platinum(II). These include deprotonation to generate a more nucleophilic amide species (alkali metal catalyzed reactions); 9 formation of a reactive M-N bond via protonolysis, with which a coordinated carbon-carbon multiple bond can then react through a-bond insertion (rare earth metals, lanthanides);’° formation of a reactive M=N bond via protonolysis, with which a coordinated carbon-carbon multiple bond can then react in a [2+2] cycloaddition reaction (group four and five metals);” and finally by oxidative addition to a low valent late transition metal such as iridium,’ 2 ruthenium’ 4 to form an H-M-N 3 or rhodium’ species which can then subsequently react with an alkene or alkyne by a coordinationlinsertiorilreductive elimination pathway. As is depicted in Scheme 1.1, the hydroamination of alkynes initially produces enamines, which rapidly undergo tautomerization to the corresponding imines and aldimines (not shown). These initial products are useful synthetic intermediates that can be converted to amines, carbonyl compounds or be used for more elaborate tandem  2  reactions, such as the Strecker reaction’ 5 and the Pictet-Spengler cyclization. 16 The hydroamination of alkenes directly affords more highly functionalized amines, and unlike alkyne hydroamination, has the potential to generate optically active products.  0 HNR  H +  hydrolysis  R  Markovnikov” “anti-Markovnikov”  2 R—NH  reduction  HN R’  -  R +  H R,NR  Scheme 1.1. Hydroamination of terminal or monosubstituted alkenes and alkynes.  While the development of systems for the hydroamination of alkynes has arguably reached a level of maturity, and the methodology is beginning to be applied as a synthetic tool; a robust, reactive, selective, and functional group tolerant catalyst system capable of reacting with a broad range of unactivated alkene substrates is still an illusive goal.’ Currently, state of the art catalyst systems developed for alkene hydroamination are only capable of the intramolecular reaction (this will be discussed in more detail in section 1.2) or are limited to activated alkenes. Group four based organometallic complexes have played a prominent role in the field of hydroamination catalysis, primarily due to their relative low cost, low toxicity, and high 6 reactivity.” 1 ’ 7  Recent reports highlighting the increasingly efficient and  diverse capability of these catalytic systems have shown that alkynes, ’ 4  16, 18  9 allenes,’  3  and alkenes ° can be converted to imines, amines and N-heterocycles with a high degree 2 of regio- and stereo-selectivity. Some of the more well recognized titanium and zirconium hydroamination catalyst systems are shown in Figure 1.1.  bis(phenoxide) Ti(IV) complex Zr(NHAr) Cp 2 Bergman  17s 1992  (  Ti(N Me (dmpm) ) 2  R/  Doye  17q 2000  Belier  R”\  2 NMe  Pr’—N Ti=NAr Pr’—NI /  I  —N  17k 2003  bis(su Ifonamido) Ti/Zr complexes  4 ) 2 Ti(NEt Odom  2 ‘NMe  2 ,\NMe  rç  2  TiMe Cp 2  /Pr  \  Ti  —  bis(guanidinate)  Odom  17j 2002  bis(thiophosphinic amidate) Zr(IV) complex  Richeson 200217m bis(amidate) complexes  17p 2001  Schafer  20h 2005  /Ar 2 NEt N,,, 2 Et Ar—  Zr(N Et 4 ) 2 Livinghouse  20g 2005  Ph’  Bergman 2003171  Livinghouse  20g 2005  Schafer  16a 2003  Figure 1.1. Titanium and zirconium hydroamination precatalysts.  The efforts of the Schafer group to further this endeavor have focused on the use of titanium and zirconium bis(amidate) bis(amido) complexes as hydroamination ’ 6 precatalysts.’  19a, 20a, 21  Amidates are a group of monoanionic, N,O chelating ligands  derived from amides that can be easily prepared from commercially available acid -  chlorides and primary amines (Equation 1.2).  4  R1CI  +  HNR  (1.2)  R1NR  The modular nature of this synthetic route allows one to systematically vary the substituents in the R 1 and R 2 position.  This in turn permits the study of how electronic  and steric properties of the ligand affect the catalytic activity in the resulting precatalyst. The bis(amidate) complexes are generated from commercially available Ti(NR 4 or ) 2 4 and two equivalents of the amide proligand via protonolysis according to ) 2 Zr(NR Equation 1.3.  0 2 Et RT, 24h  o R1 N 1 H  +  4 ) 2 M(NR 2 -2eq.HNR RMe, Et  / (R1_<M(NR ) 2  \  (1.3)  ‘2/ R,/  Solid state structural information for a number the bis(amidate) titaniumlzirconium bis(amido) complexes indicates that a pseudo octahedral coordination geometry about the metal center is prevalent in these compounds. 22 Of the five possible diastereomeric coordinational isomers shown in Figure 1.2, only the C , N-trans-C 1 , and the O-trans 2 2 geometry, have been observed, all of which position the two amido ligands in a cis C arrangement, which is desirable from a catalyst development standpoint as these represent the active sites during catalysis. 22 2 NR  2 NR 0,,,  N,,,  0TN NflN 2 NR 2 NR 1 C  0-trans C 2  N-trans C 2  C2h  , 2 C  Figure 1.2. Possible coordination geometries of bis(amidate) bis(amido) complexes. 5  To date, we have found that the titanium bis(N-2,6-diisopropylphenyl(phenyl)amidate) bis(diethylamido) complex 1.1 (R 1  =  Ph, R 2  =  2,6-diisopropylphenyl) is the  most effective bis(amidate) titanium bis(amido) precatalyst for the hydroamination of terminal alkynes with primary amines. 16 With this precatalyst, secondary, tertiary, and quatemary alkyl substituted primary amines can be coupled with a range of terminal alkynes to give exclusively the anti-Markovnikov aldimine products. In addition complex 1.1 was found to be tolerant of various functional groups including amides, esters, silyl protected propargylic alcohols, and imine protected propargylic amines. This particular bis(amidate) titanium bis(amido) complex adopts the N-trans-C 2 geometry (Figures 1.2 and 1.3) which is favored for steric reasons due to the presence of the bulky 2,6-diisopropylphenyl substituents.  Figure 1.3. ORTEP diagram of complex 1.1 with ellipsoids set at the 50 % probability level. Hydrogen atoms have been omitted for clarity.  6  1.2 Intramolecular alkene hydroamination  Intramolecular alkene hydroamination, or cyclohydroamination of aminoalkenes, is simply the addition of N-H across a C=C bond in an intramolecular fashion as depicted in Equation 1.4. The products of this transformation are referred to as N-heterocycles. catalyst conditions  (1.4)  N-heterocyclic compounds are employed in a wide range of important agrochemical, pharmaceutical, and industrial applications. There are a multitude of alkaloid natural products containing the N-heterocyclic framework which exhibit potent biological activities and therefore serve as lead compounds for the discovery of new and more effective drug treatments of diseases plaguing modem society. Some recent examples of pyrrolidine and piperidine alkaloids having useful pharmacological properties are shown in Figure 1.4. The pseudodistomin family of natural products are examples of piperidine alkaloids, which have been isolated from marine organisms and are known for their potent cytotoxicity and antitumor activity. 23 Synthetic derivatives of the natural product (-)-O acetyl-spectaline, a piperidine alkaloid isolated from a south American plant species Cassia spectabilis, have been examined as cholinesterase inhibitors for the treatment of Alzheimers disease. 24 (-)-x-Kainic acid belongs to the kainoid family of marine natural products and is an example of a pyrrolidine alkaloid. 25  Due to the neuroexcitatory  properties of this particular family of compound they have been used extensively in the  7  study of neurological diseases such as Alzheimers, epilepsy, and Huntingtons. 26 3,5Disubstituted indizolidines, such as (-)-monomorine, are pyrrolidine alkaloids which are also known for their pharmacological activity. 27 In particular due to their efficacy as nicotinic receptor ligands, this class of compound has drawn the attention of researchers working towards the development of treatments for Alzhiemers, Parkinsons, acute and chronic pain, as well as smoking cessation. 28  pseudodistomins A D -  2 NH R”’  R\’C  R\’’  C” 2 HO  H  1 A:RR  2 E:R=R  2 B:RR  3 C:R=R  D: R  =  2 R  (-)-cc-kainic acid  C: RR 3 = 1 R = 2 R  (-)-monomorine  = 3 R AcO,,  H C 3 ’N” H  (-)-O-acetyl-spectaline  Figure 1.4: Pyrrolidine and piperidine natural products.  Often, the actual quantities of these materials available from natural sources are severely limited, which makes their total synthesis the only available means of procuring  8  sufficient amounts for the study of the structure and activity of these compounds. In addition, synthetic analogues of the natural compounds designed to have different or more desirable biological properties would obviously benefit from a modular synthetic strategy.  Therefore, the development of new methodologies, such as hydroamination,  which have the potential to reduce cost and simplif’ the production of N-heterocyclic compounds is of great importance.  Although the intramolecular hydroamination of  aminoalkenes is a synthetically important transformation in itself, it also represents a starting point towards the ultimate goal of developing efficient methodologies for the more challenging intermolecular reaction. Among the earliest reported alkene hydroamination catalysts are lanthanide or group three based systems which exhibited limited functional group tolerance and high moisture sensitivity, making their preparation and implementation in synthesis problematic. ’ 3  29  The postulated mechanism for lanthanide and group three catalyzed cyclohydroamination is outlined in Scheme 1.2. The key intermediate in this cycle is the catalytically active amido species A, which undergoes a-bond insertion with the coordinated olefin to generate the new C-N bond. ° 3 Prior to this work a number of late metal based systems capable of affecting the hydroamination of alkenes had been reported. ’ 3  The operative mechanism for these  systems is thought to involve either alkene activation, or N-H activation via oxidative addition as described in section 1.1. These systems were found to be limited to activated olefinic substrates. ’ 3  9  LnN(SIMe L 2 ) 3 H N 2 HN(SiMe L  N  )—L’  H  N 2 H  (  A 1:  L\j7 [;Ln1  B L monoanionic liganci, e.g. Cp*  Scheme 1.2. Mechanism for the lanthanide and group three intramolecular alkene hydroamination.  As was also mentioned in section 1.1, group four systems; which are attractive for their low toxicity, low cost, and high reactivity; have been widely examined as alkyne and allene hydroamination catalysts, but prior to the work described in this thesis, the only known examples of alkene hydroamination using these metals involved cationic species which are isoelectronic to group three metals and are plagued with extreme moisture 20 sensitivity. k In addition, these cationic catalysts were ineffective in carrying ’ out the hydroamination of alkenes with primary amines. Although, the application of commercially available Ti(NMe 4 for both the intra and intermolecular hydroamination ) 2 of alkynes and allenes had been reported, ’ 2  17  no information was available in the  literature regarding its application; or the application of any other neutral group four  10  metal based complex; to alkene hydroamination. This challenge is a focus of catalyst development efforts reported in this thesis. Another important feature of the cyclohydroamination reaction is that a stereogenic carbon center is generated c to the nitrogen upon formation of the new C-N bond. Therefore, the ability to affect the cyclohydroamination reaction in an enantioselective fashion is extremely valuable, considering that all of the compounds depicted in Figure 1.4, along with a multitude of other biologically relevant compounds, possess the x-chiral amine structural motif. The earliest reported enantioselective hydroaminations involved the use of chiral ansa-lanthanocenes as catalysts for the cyclohydroamination of primary aminoalkenes, which attained a moderate level of success with enantiomeric excesses as high as  74%32  These systems have been superseded by a number of different non  cyclopentadienyl rare earth based complexes with enantiomeric excesses of greater than 90% being reported in some instances. 33 As was mentioned previously, there are some major drawbacks associated with the chemistry involving rare earth elements. Namely, the resultant complexes developed for catalysis are difficult to prepare and handle due to an extreme intolerance of moisture. The  first  group  four  complex  reported  to  affect  the  enantioselective  cyclohydroamination of amino alkenes was the cationic zirconium aminophenolate complex prepared by Scott and coworkers. 20 The system that they developed catalyzed the cyclization of a limited range of secondary aminoalkenes with enantioselectivities as high as  82%.  Although their work represented an important innovation in that it  demonstrated the capacity for group four based complexes to be used in this role, the fact that the title complex was cationic somewhat detracts from its usefulness, as the reactivity  11  of cationic zirconium complexes are known to more closely resemble that of rare earth based complexes and as a result they are also extremely moisture sensitive and challenging to prepare. Based upon the results presented in this thesis, the first published effort to exploit the aminoalkene hydroamination activity observed with neutral group four elements and extend the methodology to enantioselective catalysis was made by Bergman and coworkers. ° 2 ’ Their work involved the screening of various in situ prepared zirconium catalysts that utilized readily available chiral ancillary ligands. These proligands included sulfonamides, phosphinic amides, secondary amines, as well as alcohols, which were either bi-, tn-, or tetradentate. Being chiral ancillary ligands, most incorporated axially chiral biphenyl type frameworks or the chiral trans-i ,2-substituted cyclohexane backbone. The most effective in situ prepared precatalyst, which is depicted in Figure 1.5, was the bis(phosphinic amidate) zirconium bis(amido) complex 1.2 that utilized a chiral tetradentate phosphinic amide derivative of (R,R)- 1 ,2-diaminocyclohexane as an ancillary ligand. This compound proved to be competent in the role of enantioselective cyclohydroamination catalysis with enantiomeric excesses as high as 80% being attained.  ) 2 Zr(NMe “N  Figure 1.5. Bis(amidate) zirconium bis(amido) complex 1.2 incorporating a chiral phosphinic amide proligand prepared by Bergman and coworkers for the asymmetric cyclohydroamination reaction.  12  The zirconium complex 1.3 depicted in Figure 1.6 was developed simultaneously in our  oa 2 group  for the enantioselective cyclohydroamination reaction.  Like their most  effective precatalyst, it too incorporated a chiral, tethered, tetradentate bis(amidate) ancillary ligand in which the two groups binding the metal were linked via a chiral bridge. This design feature is common to most catalysts, and it is thought to improve enantioselectivity by reducing the number of possible geometric isomers and enforcing a rigid chiral steric environment about the metal center. The Schafer precatalyst employs an axially chiral 6,6-dimethylphenyl backbone, to which N-mesitoyl amide groups were appended in the 2 and 2’ positions. The use of an axially chiral biphenyl motif as a source of chirality for asymmetric catalysis is very well precedented 35 and was an obvious choice for these initial investigations.  Figure 1.6. Bis(amidate) zirconium bis(amido) complex 1.3 incorporating an axially chiral ligand framework developed for enantioselective cyclohydroamination.  Complex 1.3 was found to be as effective and in some instances more effective than complex 1.2 for the enantioselective conversion of primary aminoalkene substrates to the corresponding N-heterocyclic products with enantiomeric excesses ranging from 62  —  93  13  %.  The conversion of 2,2-dimethyl-4-pentenylamine to 2,4,4-trimethylpyrrolidine  proceeds with the highest yet reported enantiomeric excess for this widely used test substrate (Equation 1.5). Although pyrrolidine formation proceeds for the most part with good stereoselectivity, much lower enantiomeric excesses were obtained when piperidine compounds were produced, albeit in good yield, from the requisite aminoalkene substrates.  This diminished enantioselectivity in the formation of 6-membered ring  products was also observed by Bergman and coworkers using complex 1.2. It is argued that this results from a larger, less organized 8-membered ring transition state through which the reaction must proceed to form the piperidine products.  lOmoI%  (1.5) >98% yield 93% ee  H  More recently the Scott group has reported that the chiral-at-metal diamide oxazoline zirconium complexes 1.4 and 1.5 depicted in Figure 1.7 are capable of affecting the enantioselective cyclization of a limited number of aminoalkenes with moderate enantiomeric excesses. 36 A fundamental design aspect of this system that sets it apart from the previous two is that the chiral ancillary ligand is bidentate rather than tetradentate. One would expect this to be detrimental in terms of stereoselective catalysis as these complexes lack the configurational stability present in complexes 1.2 and 1.3, therefore more than one diastereomeric coordination isomer could then exist in solution. Interestingly, only the diastereomer depicted in Figure 1.7 was observed in solution and moderate selectivity was indeed obtained. This particular coordination geometry is likely  14  dictated by the bulky substituents (phenyl and t-butyl) appended to the oxazoline ring, which insure that the R group is oriented away from the pentamethylcyclopentadienyl ligand. Although the enantiomeric excesses that they observed using this system were moderate  ( 70%) relative to the previously described chiral complexes, reaction times  were notably faster.  H complex 1.4 complexl.5  R = Ph R=tBu  Figure 1.7. Chiral-at-metal diamide zirconium complexes 1.4 and 1.5 reported by Scott and coworkers.  Despite being able to obtain some impressive enantioselectivities with the systems developed thus far, these precatalysts can only be applied to a limited range of substrates which severely detract from their usefulness as tools for synthetic applications.  The  notable drop in enantioselectivity when they are applied to substrates that form larger piperidine compounds demonstrates a significant limitation. Clearly, a great deal of modification may be required in order to increase the reactivity of group four based complexes to a point where the intermolecular alkene hydroamination reaction becomes a possibility. To do this while maintaining stereoselectivity will be a considerable challenge.  15  1.3 Modifying the ligand for enhanced reactivity  Ancillary ligands play a crucial and varied role in transition metal chemistry. As we have seen in section 1.2, one of their primary functions in catalysis is to modulate the steric environment about the reactive site in order to impart a particular selectivity (regeo- or stereoselectivity) on a chemical transfonnation through non-bonding interactions. In the interest of achieving optimal reactivity, ancillary ligands are also often used to modif’ the Lewis acidity of the metal center through inductive effects. Compounds incorporating organic fragments are most commonly employed as ancillary ligands because they offer the greatest amount of flexibility in terms of structural variation, which is essential for fine tuning reactivity. Both steric and electronic properties of the ancillary ligand can have a dramatic impact on both the activity and selectivity of group four based hydroamination precatalysts. Beller and coworkers have demonstrated that steric modification alone, can have a substantial effect on both the reactivity and selectivity of the titanium bis(aryloxide) system (Scheme  1  3)171  181,  37  In terms of the intermolecular  hydroamination of alkynes they observed that the use of less bulky aryloxide ligands resulted in catalysts that exhibited diminished reactivity and produced regioselectivities that were opposite to what was obtained when they used bulkier aryloxide ligands.  16  1 R ) 2 (<_OTi(NR 2  2 R  tBu H  Bu  +  2 BnNH  -  N &Bu  H (anti-M) X X X X X  = = =  C, N, C, C, C,  1 R R 1 1 R 1 R 1 R  tBu, tBu, = tBu, = tBu, = iPr,  =  R= 2 = 2 R 2= R 2 R 2= R  tBu, tBu, Me, H, ,Pr,  99%, 80%, 44%, 52%, 72%,  tB UN +  Bu (M)  20:80 (anti-M:M) 2:3 (anti-M:M) 70:30 (anti-M:M) 84:16 (anti-M:M) 86:14 (anti-M:M)  Scheme 1.3. Steric and electronic modification of the bis(phenoxide) ligand set and its impact on the hydroamination of 1 -hexyne with benzylamine.  In conjunction with the work carried out by Belier and coworkers, members of our group have looked at the analogous bisQyrimidoxide) titanium bis(amido) complexes (X =  N, Scheme 1.3) as hydroamination precatalysts. 38 Based on the greater relative acidity  of pyrimidinols (approximate pKa value of  7),39  it was expected that the pyrimidoxide  ancillary ligand would increase the electrophilicity at the metal center, and thus increase catalyst activity. Indeed the bis(pyrimidoxide) catalysts were found to be more reactive, yet less regioselective than the corresponding, sterically equivalent phenoxide ligands. With respect to amidate ligands, previous work done by our group indicated that varying the electronic properties of this class of ligand while maintaining consistent steric properties could dramatically modify reactivity. ’ More specifically, it has been found 2 that by replacing the phenyl group in the R’ position of complex 1.6 (Figure 1.8) with a perfluorophenyl group (complex 1.7, Figure 1.8) the relative rate of intramolecular alkyne hydroamination could be increased by approximately 14 times (Equation 1.6). It  17  is thought that the electron withdrawing perfluorophenyl group in this position creates a more electrophilic metal center, resulting in a complex exhibiting enhanced reactivity.  / o\ (R1—_Ti(N R ) 2  ) 2 (c6H5Ti(NR  ) NTR2)2 2 (c6F5Ti(NR  Figure 1.8: Progression in the design of the bis(amidate) ligand framework.  (1.6) (3.5h)” complex 1.7 97% (O.25h)  In addition to varying the electronic nature of the amidate ligand, former members of our group have also probed the effect of the steric environment about the reactive metal center by changing the substituent in the R 2 position from a t-butyl group to a more bulky 2,6-diisopropylphenyl group (complex 1.1) while leaving the phenyl group in the R 1 d It was found that increasing the steric bulk of the ligand improves 3 position unchanged. the anti-Markovnikov regioselectivity for the reaction of 1 -hexyne with tert-butylamine (Equation 1.7).  18  tBu  tB UN  N Bu  H  +  2 tBuNH  (1.7) +  (anti-M)  Bu (M)  complex 1.6: 71% ( 5:1 anti-M : M) (24h) complex 1.1 : 82% (>99:1 anti-M : M) (6h)  As well as the enhanced regioselectivity, they also observed an increase in the relative rate of reaction when complex 1.1 was employed as the precatalyst (compared to complex 1.6). To explain the latter observation a mechanism based upon the catalytic Doye ’ 1 for cyclopentadienyl titanium imido cycles investigated by Bergman 8 and 2 ” 2 catalyzed intermolecular hydroamination of alkynes (Scheme 1.4) was proposed, and therefore, the increased rate of catalysis in the presence of complex 1.1 was attributed to the added steric bulk of the N-2,6-diisopropylphenyl substituents inhibiting the formation of the inactive dimeric species B. Ti(NMe L ) 2 TiL Ti 2 2 L N R B  I  NR R  HNR R  I II2INI 2 H2HNMe R  TiNR 2 L  —  R’  NHR Tj=NR L2  Ti—NR 2 L  R’  R R T1-NR 2 L NR 2 H  j  R’R’  Scheme 1.4. Simplified proposed catalytic cycle for the group 4 catalyzed hydroamination of alkynes. 19  Thus both electronic and steric effects have been noted to enhance reactivity in amidate complexes of group four metals. By taking advantage of the modular ligand framework accessible here, amidate ligands allow for facile optimization of catalytic reactivity and selectivity.  1.4 Scope of thesis  Two basic strategies were employed in this thesis to further the field of group four metal catalyzed reactions involving amines. Firstly, the capabilities of existing systems were expanded upon by modifying reaction conditions or by taking advantage of unique reactivity (chapters two and five); and secondly, attempts were made to generate more reactive and selective group four catalysts by the rational design and implementation of new ancillary ligands (chapters three and four). As was mentioned in section 1.1, the titanium bis(N-2,6-diisopropylphenylphenyl)amidate) bis(dimethylamido) complex 1.1 was found to be a very effective precatalyst for the hydroamination of terminal alkynes with primary aliphatic amines. Prior to this work little information with respect to the reactivity of complex 1.1 towards aryl amine substrates was available. However, there were some preliminary findings that suggested complex 1.1 might be particularly reactive in the presence of this type of amine co substrate. In chapter two the elucidation and synthetic exploitation of the exceptional reactivity of complex 1.1 towards aryl amines is described. In addition, the reactivity of 4 towards aminoalkenes, along with the initial efforts made to expand the ) 2 Ti(NMe  •  20  capabilities of the bis(amidate) bis(amido) system to include the intramolecular hydroamination of aminoalkenes is discussed. In chapter three, ligand design efforts to produce bis(amidate) complexes incorporating amidates modified for enhanced reactivity as well as enantioselective catalysis are described.  Based on previous findings discussed in section 1.3,  an  improved catalyst design was devised, having a perfluorophenyl group in the R’ position and a 2,6-diisopropylphenyl group in the R 2 position. Sections in chapter three present the synthesis and characterization of this new complex, as well as the results of alkyne and alkene hydroamination experiments carried out to assess it as a hydroamination precatalyst. As was mentioned in section 1.2, there are significant limitations in the capabilities of current group four asymmetric cyclohydroamination catalysts which utilize tethered ligand frameworks. One of the weaknesses of the tethered ligand design is that synthesis and resolution of non-racemic derivatives, in which the actual biphenyl portion has been modified can be difficult and time consuming.  These approaches impede structure  activity relationship studies. Another disadvantage of this type of scaffold is that the steric environment that it creates is somewhat removed from the reactive metal center, which in turn may limit the influence that it has on selectivity. In the interest of addressing these issues we considered using non-tethered chiral amides derived from simple, readily available chiral primary amines as an alternative class of proligand. Thus, ligand design addressed in chapter three also describe the attempts made to modify the bis(amidate) ligand design for enantioselective catalysis using commercially available (-)-menthone as a source of chirality.  21  As an alternative means of generating a more electrophilic, and hence reactive, metal center, we also considered 2-pyridone and its derivatives as a new class of N,O chelating ligands. Based loosely on relative pKa values, it was expected that the 2-pyridonate ligand framework would be more electron withdrawing than the amidate scaffold. Additionally, it was also expected that with the substituents adorning these ligands being somewhat removed from the metal center, it would be possible to create a more accessible reactive site while maintaining a sufficient level of steric bulk to mitigate the formation of catalytically inactive dimer species. Chapter four describes the synthesis and characterization of three different bis(2-pyridonate) complexes, as well as their assessment as catalysts for the cyclohydroamination of aminoalkenes. An unexpected outcome to the application of zirconium pyridonate complexes as cyclohydroamination precatalysts is described in chapter five, where the conversion of 6heptenylamines to aminocyclohexane derivatives via intramolecular c-functionalization is achieved. 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(32) Gagne, M.R.; Brard, L.; Conticello, V. P.; Giardello, M.A.; Stem, C. L.; Marks, T. J. Organometallics 1992, 11, 2003. (33) Birkov, D. V.; Hultzsch, K. C.; Hampel, F. J. Am. Chem. Soc. 2006, 128, 3748. (34) (a) Aillaud, I.; Collin, J.; Hannedouche, I.; Schulz, E. Dalton Trans. 2007, 5105. (b) Hultzsch, K.C. Org. Biomol. Chem. 2005, 3, 1819. (35) McCarthy, M.; Guiry, P. J.  Tetrahedron 2001, 57, 3809.  (36) Gott, A.L.; Clarke, A.J.; Clarkson, G.J.; Scott, P. Chem. Commun. 2008, 1422. (37) Tillack, A.; Khedkar, V.; Jiao, H.; Belier, M. Eur. J. Org. Chem. 2005, 5001. (38) Lee, A.V.; Schafer, L.L. Organometallics 2006, 25, 5249. (39) Mason, S. F. I Chem. Soc. 1958, 674.  27  CHAPTER TWO: FURTHER DELINEATING THE SYNTHETIC UTILITY OF EXISTING TETRAKIS(AMIDO) AND BIS(AMIDATE) TITANIUM BIS(AMIDO) HYDROAMINATION PRECATALYSTS  2.1 Introduction  Nitrogen containing compounds are ubiquitous in chemistry and are employed in a wide range of important agrochemical, pharmaceutical, and industrial roles. Therefore, the development of efficient methodologies, such as hydroamination, that have the potential to simplify their production is of great importance. The work carried out in the Schafer group focuses on the use of bis(amidate) bis(amido) complexes of titanium and zirconium as hydroamination precatalysts. To date, we have found that the bis(N-2,6diisopropylphenyl(phenyl)-amidate) titanium bis(dimethylamido) complex 1.1  is the  most effective bis(amidate) titanium bis(amido) precatalyst for the hydroamination of terminal alkynes with aliphatic primary amines. During the course of initial substrate scope investigations carried out by previous members of our group, it was revealed that sterically unencumbered aryl amines, such as aniline, might be particularly reactive as hydroamination co-substrates in the presence of complex 1.1.  In alkyne hydroamination reactions that were monitored by ‘H NMR  spectroscopy small amounts of product appeared to be forming prior to the application of heat.  Additionally, it was apparent that some sort of side reactivity leading to the  formation of unidentified byproducts was also taking place in these reactions. Sections 2.2.1 through 2.2.4 of this chapter deal with the elucidation and synthetic exploitation of the exceptional reactivity observed with aryl amines in the presence of complex 1.1. © A version of this chapter has been reproduced with pennission from Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959. Copyright 2007 American Chemical Society.  28  To fully take advantage of the possibility that this system may affect the hydroamination of alkynes under exceptionally mild conditions and in the interest of further demonstrating the synthetic utility of this methodology we also set out to investigate the possibility of using p-anisidine as the primary amine for the hydroamination of alkynes. This strategy would provide a means of preparing PMP protected primary amines from alkynes under relatively mild conditions.  The PMP  group is a well known protecting group for amines that can be cleaved under oxidative conditions typically using oxidizing agents such as eerie ammonium nitrate’ and more recently periodic acid. 2 The net transformation is the efficient conversion of an alkyne to a primary amine (Scheme 2.1).  NH  +  L 1  R  0 hydroamination then reduction  oxidation RNH2  +  0 2 OMe then H  OMe  0  ) 2 (PMPNH  Scheme 2.1. Hydroamination of alkynes leading to PMP-protected primary amines. To further expand the substrate scope, we also looked at the feasibility of using TBDMS protected propargyl alcohols as alkyne substrates. The majority of catalytic systems developed for the intermolecular hydroamination of alkynes reported to date have typically employed simple non-functionalized aliphatic or aromatic alkynes as test substrates.  To our knowledge only one system has been shown to affect the  hydroamination of alkynes bearing protccted hydroxyl functionalities directly adjacent to the carbon-carbon triple bond. Beller and coworkers 3 have recently reported the  29  hydroamination (or more accurately the hydrohydrazination) of silyl protected propargyl alcohol derivatives with N-methyl-N-phenylhydrazines using an in situ generated bis(2,6-di-tert-butyl-4-methylphenolate)titanium bis(amido) precatalyst. These reactions required elevated reaction temperatures (100 °C) and were low yielding. In addition this system appears to be limited to applications that involve N-methyl-N-phenylhydrazine derivatives as yields of less than 5% were obtained when either aniline or isobutylamine were used as the amine substrate.  The successful application of our system to the  hydroamination of these types of substrates would not only demonstrate that the bis(amidate) titanium bis(amido) precatalyst is tolerant of substrates bearing proximally located protected hydroxyl functionalities but would also further demonstrate the utility of this methodology by providing entry into useful synthetic precursors to 3-amino alcohols and a-amino acids (Scheme 2.2). 2 NH OTBDMS —  —  +  2 PMPNH  .  .  1)hydroamination  R  ..—  NHPMP—  HO  2) imine reducon TBDMSO  2 NH H 2 CO  Scheme 2.2. Hydroamination of TBDMS protected propargyl alcohols leading to the fonnation of synthetically useful protected n-amino alcohols and a-amino acids.  Section 2.2.5 describes the results of initial investigations into the neutral group four metal catalyzed intramolecular aminoalkene hydroamination reaction (Equation 1.2). As was mentioned in chapter one, prior to this work no information was available in the literature regarding the application of ) 2 Ti(NM 4 e to alkene hydroamination.  It was  30  therefore important for us to examine this complex for intramolecular aminoalkene hydroamination activity in addition to our bis(amidate) complexes, as this would provide a benchmark for comparison purposes. While the majority of the work in section 2.2.5 involves the reactivity of 2 Ti(NMe towards aminoalkenes, the results of experiments 4 ) using complex 1.1 as the precatalyst are also included, and the reactivity of this complex relative to ) 2 Ti(NM 4 e is discussed. Finally, the last section in this chapter describes experiments that were carried out to demonstrate the viability of using in situ generated bis(amidate) titanium bis(amido) complex 1.1 as a precatalyst for the hydroamination reaction. This is an important aspect of designing a practical catalyst system that can be conveniently utilized by synthetic chemists who do not have access to the equipment required for preparing air and moisture sensitive materials on gram scale.  2.2 Results and Discussion  2.2.1 Hydroamination of terminal alkynes with aniline andp-anisidine at ambient temperature  In order to elucidate the nature of the reactivity observed in the initial stages of the reaction involving complex 1.1 as the precatalyst for the hydroamination of phenylacetylene with aniline as the amine co-substrate, the original reaction conditions can be reproduced, but instead of heating the reaction, the NMR tube is simply left on a benchtop for a period of 24 hours. Isolation of the reduced amine product reveals that the  31  hydroamination of phenylacetylene with aniline catalyzed by complex 1.1 proceeds with good yield and almost exclusive regioselectivity for the anti-Markovnikov product (Equation 2.1).  This represents one of the few examples of intermolecular  hydroamination of terminal alkynes with arylamines at ambient temperature, 4 consequently substrate scope was evaluated.  a  NH 2  1)5mol% complex 1.1  2)NaCNBH3 83% (>49:1 AM:M)  H  (2.1)  The hydroamination of various terminal alkynes with p-anisidine was then carried (Scheme 2.3). p-Anisidine was examined extensively rather than aniline because hydroamination with this co-substrate is more synthetically useful in that it leads to the formation of PMP protected primary amines, as described in the introduction to this section. These results show that the reactivity of the p-methoxy substituted analogue of aniline is comparable in the hydroamination of phenylacetylene when complex 1.1 is used as the precatalyst.  32  R  Zr  +  1)5 or 10 mol% complex 11, C , Ar. H 6 NH RT24h Ar—NH 2 2) NaCNBH , ZnCl 3 R MeOH M  QD Q  H +  RAr AM  0OMe °0QMe  83%  76%  (>49:IAM:M)  (>49:1 AM:M)  80%  (>49:1 AM:M)  uoo OMeH  47% (>491AMM)  N  OMe  H N OMe  o  (2.3:1 AM:M)  77%  0 O Me  (>2:1 AM:M)  Scheme 2.3. Intermolecular alkene hydroamination reactions with complex 1.1 as the  precatalyst.  The above reactions are carried out on a small preparative scale, typically on the order of 1.0 mmol of the alkyne substrate. They are set up in a nitrogen filled glove box, and involve adding the precatalyst to 1 —2 mL of benzene followed by the amine and the alkyne. The solution is then transferred to a small Schlenk tube containing a magnetic stir bar, sealed, removed from the glove box, and left to stir at ambient temperature for 24 hours. The reduction protocol follows literature precedent for the reduction of imines 5 The reported yields are based on isolated amine products following . 3 with NaCNBH column chromatography.  33  With isolated yields greater than 70%, the efficiency of this method for preparing PMP protected amines from alkynes under such mild conditions is unparalleled.  It  should be noted that although the yield for the hydroamination of 3,3-dimethyl-l-propy ne is quite moderate relative to the other reactions in this section, a higher conversion of -70% is observed after 48 hours (vs. 50% after 24 hours).  The increased steric  encumbrance coupled with the volatility of this particular substrate likely inhibits the hydroamination reaction significantly. The regioselectivities observed for most of these reactions, as determined by 1 H NMR spectroscopy, are very high and favor the formation of the anti-Markovnikov product almost exclusively. The regioselectivity does drop off substantially when less sterically encumbered terminal alkyl substituted alkyne are s employed.  2.2.3  Ilydroamination of internal alkynes with p-anisidine  Internal alkynes had previously presented a particular challenge for our system. All previous attempts to effect the hydroamination of symmetrically substituted interna l alkynes with alkyl amine co-substrates using complex 1.1 as the precatalyst had failed. It was hoped that the increased hydroamination activity of this system in the presen ce of aryl amines would permit the reaction to proceed even if more forcing reaction conditi ons were required. Using aniline as the amine co-substrate the hydroamination of 1 -phenyl- 1 -propyne can be carried out efficiently, although an elevated temperature of 110 °C is require d (Equation 2.2). This hydroamination reaction and all other reactions described in this  34  section are set up and carried out in the same manner as the terminal alkyne experiments described in the last section. The one difference being that these reactions are heated for 24 hours in an oil bath rather than being left to stir for 24 hours at ambient temperature.  2 I1H  I  +  Lj  1) precatalyst (5 mcI  %)  ,C D 6 11O°C,24h  HN (2.2)  NaCNBH 2 , 2) 3 ZnCI MeOH  (anti-M)  >98%  The amine product shown in Equation 2.2 can be isolated in nearly quantitative yield as one regioisomer. By following the reaction by ‘H NMR spectroscopy it is apparent that the reaction goes to completion within 1 hour at this temperature, suggesting that more moderate temperatures could be employed, in combination with longer reaction times. As shown in Scheme 2.4 p-anisidine is as reactive as aniline, with essentially a quantitative yield of the amine product being isolated. A number of other internal alkyne substrates including diphenylacetylene, 3-hexyne, and 4,4-dimethyl-2-butyne were also utilized as the alkyne substrates. In most cases the desired amine products can be isolated in nearly quantitative yield and where regioselectivity is an issue, only the regioisomer shown can be detected by analysis of the crude ‘H NMR spectra. The lower relative yield (76%) obtained for (4-methoxy-phenyl)-(l ,3,3-trimethyl-butyl)-amine is due to incomplete hydroamination of 4-methyl-2-pentyne after 24 hours.  35  1)5 or 10 mol% complex 1.1, C , H 6  1 R  ZE  R  +  2 Ar—N H  HN  110°C, 24h 2) , 3 NaCN BH ZnCI 2  f  Ar  I  MeOH  OMe  >98% >98% conversion after 1 hour  >98%  OMe HN  >98%  OMe HN  >98/s  HN  76%  Scheme 2.4. Intermolecular hydroamination of internal alkynes with aniline and p anisidine using complex 1.1. 2.2.4 Hydroamination of TBDMS protected propargyl alcohols with p-anisidine  Prior to this work, previous attempts to carry out the hydroamination of silyl protected propargyl alcohols with complex 1.1 had failed. At the time it was suspec ted that adverse side reactivity between the complex and the silyl protected hydrox yl group proximal to the alkyne was leading to catalyst decomposition under the reaction conditions employed. These initial attempts were made using alkyl primar amines y and were carried out at a temperature of 65 °C. It was hoped that the more moder ate reaction temperature employed in the hydroamination of alkynes with aryl primary amines would  36  minimize catalyst decomposition and allow the hydroamination reaction to proceed. The tert-butyl-dimethylsilyl protecting group was selected mainly for the stability of this protecting group under the conditions utilized in the reduction protocol. These reactions are set up and carried out in the same manner as the reactions described in section 2.2.1. As shown in Equation 2.3 the hydroamination of TBDMS protected propargyl alcohol with p-anisidine proceeds with high efficiency at ambient temperature and generates the regioisomer shown almost exclusively as detennined by ‘H NMR spectroscopy. Again, the level of efficiency and selectivity for the anti-Markovnikov product under such mild conditions is without parallel.  1)10 mol% complex 1.1  +  rNH2  OTBDMS MeO  2)  2 Nd  PMPHN-OTBDMS  (2.3)  MeOH 75%  In addition to propargyl alcohol, the TBDMS protected alcohols 3-phenyl-2propyne-1-ol and 4-phenyl-3-butyne-2-ol were both also examined as substrates (Scheme 2.5) given that extension of this methodology to the generation of synthetically useful intermediates would require that it be applicable to the hydroamination of more challenging disubstituted alkynes.  Hydroamination of TBDMS protected 3-phenyl-2-  propyne-1-ol for example would generate a protected f3-amino alcohol which could potentially be used as a precursor in the synthesis of the amino acid phenylalanine.  37  %OTBDMS  2 1)10 mol% complex 1.1 NH  PhCH3jiO0C,2,1h  MeOX  2)  NHPMP JIJOTBDMS  MeOH 66%  OTBDMSQNH2  :  PhC1  ,t  30% 1.6 syn : 1.0 anti  Scheme 2.5. Hydroamination of TBDMS protected -phenyl-2-propyne-1 -ol and 4phenyl-3-butyne-2-ol with p-anisidine using complex 1 as the precatalyst.  As one can see by the moderate yields in Scheme 2.5 these substrates clearly present more of a challenge.  Catalyst decompositionlinactivation due to some adverse side  reactions between the complex and substrate at the elevated reactio n temperature may explain the lower conversions. Extending the reaction time at elevate d temperature does not improve conversion. In order to preserve the catalytically active species , a lower reaction temperature can be employed, and as a result the hydroaminati on of TBDMS protected 3-phenyl-2-propyne-1-ol does indeed proceed very slowly, with approximately a 56% yield being obtained after 144 hours of heating to only 40 °C. It is noted that further optimization of the reaction conditions may result in a better yield. When the PMP protected amines prepared via the hydroamination of 1-phenyl-1propyne and TBDMS protected 3-phenyl-2-propyne-l-ol are subjec ted to the oxidative cleavage procedures recently reported by Verkade and cowork 2 ers, the corresponding primary amines are obtained in moderate yield (Scheme 2.6). This result serves as a  38  proof of principle that hydroamination can be used to generate primary amines from alkynes. It should be noted that these yields are not optimized. OMe  6 1 5 H 0 (1 equiv) 4 S 2 H 0 (1 equiv) 0, MeCN 2 H  HN  63% (HCI salt) DL-amphetamine  OMe  QX2  (fre:;ine) OTBDMS  OH  Scheme 2.6. Proof of principle: p-methoxyphenyl protected amines prepared via hydroamination are subjected to known oxidative cleavage procedures.  2.2.4 Side reactivity observed during the hydroamination of phenylacetylene with aniline  When following the hydroamination of phenylacetylene with aniline by ‘H NMR. spectroscopy, it is apparent that compounds other than the desired hydroamination products are being formed.  These side products, although being generated in  comparatively minor quantities, are of interest as a better understanding of side-reactions may shed light on new reactivity profiles.  In the ‘H NMR spectrum of the reaction  mixture, the E and Z enamine products as well as the aldimine tautamer are discemable. Additionally, there are signals at 2.39  —  2.52, 3.18  —  3.24, 3.98  —  4.01, and 4.55  —  4.58  that result from the unidentified side product(s).  39  When the crude hydroamination reaction mixture is directly subjected to column chromatography in order to isolate and characterize the byproduct(s), only the known 6 tetrahydoisoq uinoline (A, Figure 2.1) can be isolated in addition to aniline, with a yield of about 20%. The hydroamination products can not be isolated due to their propensity to decompose upon exposure to silica gel.  Surprisingly the 1 H NMR spectrum of the  tetrahydroisoquinoline A is not consistent with any of the signals observed in the crude H NMR spectrum, which suggested that the formation of this species somehow occurs 1 upon work up/isolation.  NH  H  H  A  B  Figure 2.1. Side-products isolated from the hydroamination of phenylacetylene with aniline.  However, when the crude hyciroamination reaction mixture is subjected to reducing conditions, prior to attempting to isolate the components of the mixture, the amine corresponding to the reduced anti-Markovnikov hydroamination product is obtained in 77% yield along with an alternative side product (B, Figure 2.1) which is obtained in 18% yield. Based on the isolation of these two compounds (A and B, Figure 2.1), it is suggested that the aldimine-amine depicted in Equation 2.4 is formed initially by an intermolecular reaction between the two tautomers of the hydroamination product. The conversion of  40  the aldimine-amine to the 1 ,2,3,4-tetrahydroisoquinoline is then thought to proceed via proton catalyzed intramolecular electrophilic aromatic substitution (Scheme 2.7) upon exposure of the aldimine-amine to silica gel.  UN]  -  A  similar  mechanism  has  also  been  proposed  for  the  formation  of  tetrahydroisoquinolines via the rhodium catalyzed oxidative amination of styrene with 7, the condensation of phenylacetaldehyde with aniline hydrochloride in the aniline presence of , 3 NaCN 8 BH  and the benzotriazole promoted condensation of phenyl  acetaldehyde with aniline 6. Possibly, complex 1.1 may potentiate this transformation, perhaps by acting as a Lewis acid. I  ii  H  cat. H  I I  Scheme 2.7. Mechanistic rationale for the proton mediated formation of the tetrahydroisoquinoline. In light of the fact that these side products are generated in <20% yield and that neither increased catalyst loading nor extended reaction times nor increased reactio n temperature had any significant impact on the amount of the aldimine-amine being  41  formed (in fact yield drops off slowly over extended periods of heating), it was decided that further investigation was not warranted.  2.2.5 Intramolecular alkene hydroamination activity 2.2.5.1 Initial investigations and the gem-disubstituent effect We began our investigation into neutral group four metal catalyzed intramolecular amino-alkene hydroamination by looking at the precursor to our bis(amidate) titanium bis(amido) complexes, ) 2 Ti(NM . 4 e This compound is known to effect the intermolecular hydroamination of alkynes,  but previous to our work no examples of alkene  hydroamination using 2 Ti(NMe had been reported. 4 ) 2,2-Diphenyl-4-pentenylamine  was  our  initial  test  substrate  for  the  cyclohydroamination reaction with ) 2 Ti(NM . 4 e Heating this compound in the presence of 5 mol% ) 2 Ti(NM 4 e affords the requisite N-hetero cyclic product 1 -methyl-4,4diphenylpyrrolidine with an isolated yield of 92 % (Equation 2.5).  00  /  2 NH  5 mol% Ti(NM 2 e  (2.5)  PhMe, 110°C 24h 92 %  H  Alternatively this reaction can be monitored by ‘H NMR spectroscopy.  The  disappearance of the two olefin signals centered at 6 5.44 and 4.95 ppm and the appearance of two new signals at 6 2.38 and 1.80 ppm are used to measure the progress of the reaction. In this case the reaction goes to completion within 1 hour. In addition lower reaction temperatures can be used such that within 2.5 hours at 45 °C and 70 °C 2-  42  methyl-4,4-diphenylpyrrolidine forms in 38% and 70% respectively. Unfortunately, no appreciable reactivity is observed at room temperature. By testing this system with other substrates, the importance of the gem-disubstituent or the gem-dialkyl effect for the cyclohydroamination reaction has become increasingly apparent.  This effect has also been found to impact this reaction with other catalytic  9 system s. It is known that intramolecular cyclization reactions can be facilitated by substrates possessing geminal substitution in a position between the two ends of the substra te bearing the functional groups undergoing reactivity. In our case the aminoalkenes are substituted in the 2-position by groups such as phenyl and methyl, and when the steric bulk of the substituents in this position is decreased (phenyl to methyl to hydrogen), or when only one substituent is present, the reaction time increases dramatically.  This  phenomenon, known as the gem-disubstituent effect’° results from a combination of the Thorpe  —  Ingold effect” and the reactive rotamer effect (Scheme 2.8).12 Thorpe  -  Ingold  2 NH  Reactive Rotamer  HPhNH  anti  H42 gauche  Scheme 2.8. The components of the “gem-dialkyl” effect, Thorpe-Ingold theory and reactive rotamer theory. The extent to which this phenomenon dictates the relative reactivity of these substrates is obvious with this catalytic system. Table 2.1 lists a series of results for the  43  cyclohydroamination of various substrates bearing progressively less sterically demanding substituents in the 2-position, i.e. diphenyl to dimethyl to monomethyl to unsubstituted. The change from phenyl to methyl results in a drop in reaction progress after 24 hours of almost two thirds. Reduction in the number of substituents in the 2position further reduces the degree to which these reactions proceed within a given time frame. Going from 2,2-dimethyl- to 2-methyl-pentenylamine reduces reaction progress by about a quarter after 96 hours. The unsubstituted 4-pentenylamine substrate is completely unreactive with this system regardless of reaction time or temperature (up to 145 °C). Table 2.1. The impact of the gem-disubstituent effect on cyclohydroamination using Ti(NMe . 4 ) 2 )NH2  aminoalkene  Ph  5mol%  H  d8tol,11O0C,24h  R2  product  Ph  yield  92a(24h)  NH2 Ph  2 NH 6 2 5 h b(9 ) 43C(1 20h) NH  N/R a Isolated yield. b Yield determined by NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. cisolated yield following derivitization with benzoyl chloride.  44  2.2.5.2 Diastereoselectivity Generally, selectivity, be it regio-, diastereo- or enantioselectivity, is an important aspect of catalytic systems and chemical transformations. The cyclohydroamination of substrates possessing differential substitution in any one position can lead to the formation of at least two diastereomeric products. In the interest of investigating the diastereoselectivity associated with this system,  a number of substrates differentially  substituted in either the 1-position or 2-position were studied.  Table 2.2 lists these  substrates along with their resulting diasteriomeric pyrrolidine products and reaction outcomes. Table 2.2. Investigating diastereoselectivity when Ti(NMe 4 is employed as a ) 2 precatalyst. 5mol% R R 3 2 2 NH  H  -d 8 tol,11O°C,24h  2  1 R entry  H R a 1 .... N  Ti(NMe2)4  aminoalkene  PhPh  NH2  2  yield% (reaction time)  products H  N  3(+I—)  [cis:trans] H  ÷  gOa(24h)  +  2  3  NH2 Ph + Ph  2 JNH Ph alsolated yield. bNMR yield based on 1 ,3,5-trimethoxy- benzene as an internal standard. Clsolated yield following derivitization with benzoyl chloride.  45  For the most part, the diastereoselectivities are poor, and in line with what has been found with other hydroamination catalytic system 3 s.’ Entry 1 in Table 2.2 does stand apart from the other entries dramatically however, with a very high selectivity for the anti-product. It should be noted that this substrate is completely novel and therefo re no results from literature were available for comparison. These diastereoselectivities can be rationalized by invoking a chair like transition state argument for the mechanism of this transformation, which has been propos ed for other system 4 s.’ This rationalization is illustrated in Scheme 2.9. Substituents adorning the substrate can be oriented either axially or equatorially, and it is well known that cyclohexyl derivatives favor the conformation that positions bulky substit uents equatorially to avoid or minimize 1 ,3-diaxial steric interac 5 tions.’ With respect to the 2,5-substituted pyrrolidine products, the trans-diastereomer predominates due to the fact that the methyl group in the 1-position of the substrate is preferentially located in an equatorial position to minimize 1 ,3-diaxial interactions. The fact that the cis-pro duct is slightly favored when substrates bearing differential substitution in the 2 positio n are employed is also consistent with this hypothesis.  46  2,5-substituted pyrrolidine products  H C 3 —7 3 CH  3 CH  [Ti]j 3 CH  H C 3 _HN 3 CH  HN/  OR  trans-product  -  favored  2,4-substituted pyrrolidine products  H C 3 ._ HN ‘h  HNcPh  t  HNJ/  “Ph  cis-product favored  Scheme 2.9. Rationale for the diastereoselectivity observed in the cyclohydroamination of substrates differentially substituted in either the 1-position or 2-position. A qualitative explanation for the high diastereoselectivity observed with 1-methyl2,2-diphenyl-4-pentenylamine (entry 1, Table 2.2) relative to what was observed with 2methyl-4-pentenylamine (entry 2, Table 2.2) is that the bulky phenyl groups in the 2position of the substrate more rigidly enforce a chair like geometry in the transition state of this reaction and render other possible transition state geometries which could lead to the cis product being more energetically disfavored.  47  2.2.5.3 Substrate scope  In the interest of determining the limitations of ) 2 Ti(NM 4 e as an intramolecular alkene hydroamination precatalyst, substrates of varying chain length as well as substrates bearing substituted alkenes were investigated. All of these substrates incorporate two phenyl groups in the 2-position to take full advantage of the gem disubstituent effect. Table 2.3 presents the results of these experiments.  Table 2.3. Substrate scope investigation using 2 Ti(NMe . 4 ) 5 mol%  H  d8toI,iiO0C  Ph”  RXNH2 R = Ph, Me n = 2,3 entry  aminoalkene  product  yield%a  H Ph Ph 2 )4N H  80(24h) PhI Ph H  2  Ph Ph )4NH 2  Q>/ a  Isolated yield.  b  (  Nz \  N/Rb  Ph H N  Ph 2 NH  Ph Ph 2 N H  4  Ph  67(96h)  Ph Ph H N  Ph-’ Ph Determined by NMR after extended reaction times.  N/Rb  48  Both six and seven membered ring precursors (entries 1 and 2, Table 2.3) were tested, but only the six membered ring precursor undergoes cyclization. The seven membered ring precursor shows no signs of reaction even after 240 hours at 110 °C with 5 mol% catalyst loading. Heating this substrate to 145 °C in the presence of 20 mol% Ti(NMe 4 ) 2 however results in some unexpected side reactivity, which will be discussed in chapter five. The internal olefin bearing substrates 2,2,5-triphenyl-pent-4-enylamine and 2,2diphenyl-hex-4-enylamine (entries 3 and 4, table 2.3) were both tested and only the substrate bearing the activated alkene undergoes cyclization. No reaction is observed with 2,2-diphenyl-hex-4-enylamine even at 145 °C.  2.2.5.4 Mechanistic rationale  The trends observed with these reactions resulting from variation in substrate structure, namely the effect that geminal substitution had on reaction progress and the diastereoselectivies observed in the cyclization of racemic chiral substrates,  are  consistent with a chair like transition state which has been proposed for intramolecular hydroamination reactions. What is not apparent from these experiments is the nature of the reactive Ti-N bond in the catalytically active species (A, Scheme 2.9). Work carried out by Bergman, Doye, Mountford, as well as other members of our group has shown that for the catalytic hydroamination of alkynes, A is a titanium imido species) 6  49  2 Ti(NM 4 ) e  H N  N 2 L- H Ph Ph  H-  2 HNMe  Ph Ph H N 2 PV”Ph  (  A  B  Scheme 2.9. Proposed catalytic cycle for the intramolecular hydroamination of aminoalkenes catalyzed by 2 Ti(NMe . 4 ) An alternative reaction pathway involving the direct insertion of the olefin into a TiN a-bond is also plausible. This hypothesis, which proposes a titanium amido species as the active catalyst, has been established in the case of group three, lanthanide, and cationic group four catalyzed intramolecular alkene 4 ” hydroa 1 minati on’  17  and cannot be  refuted in the case of neutral group four systems based on the above mentioned observations. In situ generation of a titanium imido type complex requires the presence of a primary amine, otherwise formation of the reactive Ti=N bond is not possible. With this requirement in mind, a secondary aminoalkene can be used as the test substrate; if cyclization does not occur then the involvement of an amido species in catalysis is unlikely and the argument for a catalytically active imido intermediate as the active catalyst is supported. On the other hand, if cyclization of this secondary aminoalkene  50  substrate does indeed occur, then the cyclohydroamination of primary aminoalkenes may involve either an imido or amido complex as the active catalyst. When other members of our group attempted the cyclization of N-methyl -2 ,2diphenyl-4-pentenylamine using ) 2 Ti(NM 4 e as the precatalyst they saw no reaction whatsoever (Equation 2.6). Even elevated reaction temperatures and extended reaction times affords no N-methyl-pyrrolidine product. This result supports the argument that the reactivity with ) 2 Ti(NM 4 e and primary amino alkenes is proceeding via an in situ generated titanium imido species, consistent with what has been established for the better understood group 4 catalyzed hydroarnination of alkynes.  Ph  (2.6)  2.2.5.5 Tetrakis(amido) vs bis(amidate) titanium bis(amido) precatalysts Having investigated ) 2 Ti(NM 4 e and determined some of the limitations associated with this system, we turned our attention back to our amidate complexes. A substrate scope investigation was carried out using complex 1.1 as the precatalyst for cyclohydroamination under the same reaction conditions employed in the ) 2 Ti(NM 4 e catalyzed reactions (Table 2.4). It is apparent from these results that our most active catalyst for the hydroarnination of alkynes is substantially less effective than ) 2 Ti(NM 4 e for the cyclohydroamination of aminoalkenes. Although reactivity is comparable for the cyclization of 2,2-diphenyl-4.pentenylamine (entry 1,  Table 2.4), the dramatic effect of the gem-disubstituent  51  phenomenon is even more pronounced with complex 1.1.  Replacing the diphenyl  substituents with dimethyl groups in the 2-position of the substrate results in a substantially slower reaction with complex 1.1. In addition, whereas ) 2 Ti(NM 4 e affects the cyclization of 2-amino-5-hexene to some degree, no reaction whatsoever was observed using complex 1.1 as the precatalyst even after extended periods at 110 °C. The cyclohydroamination of the six membered ring precursor (entry 3, Table 2.4) again demonstrates the stark difference in reactivity between the two precatalysts. Table 2.4. Comparison of cyclohydroamination activity of complex 1.1 to ) 2 Ti(NM . 4 e 3 R 5 mol% Ti(NMe 4 ) 2 R R 3 2 12( 2 _-R )<NH or complex 4 R 2 R [ 4 ) 1 N 110°CPhMe R1 H entry  aminoalkene  1  Ph Ph 2 <N H  2  product Ph J-Ph  2 )N H  a 2 • fl(NMe a 4 ) complex 1  %b 90  92 (24h) %b (24h)  25% (120h) 52% (96h)  Ph Ph  Ph  1fPh  17% (48h) 80% (24h)  3 H Ph Ph Ph Ph r-Ph>4NH PhJ 2  67 NR (96h) %b (96h)  NR(144h) 33%(96h)  a Yield determined by NMR spectroscopy using 1 ,3,5-thmethoxybenzene as an  internal standard, unless otherwise stated. blsolated yield.  52  The current rationalization for the decrease in reactivity seen with complex 1.1 is that the large steric bulk of the amidate ligand, though adventitious for minimizing the in situ formation of catalytically inactive imido dimers 8 ,’ may at the same time be impeding these intramolecular aminoalkene reactions by reducing the accessibility to the reactive metal center. The fact that no reaction was observed with 2,2,5-triphenyl-4-pentenylamine or 2-amino-5-hexene (entries 4 and 5 respectively), which possess bulky substituents in close proximity to the nuclei directly involved in the bond formation processes, loosely supports this argument. In addition, while ) 2 Ti(NM 4 e catalyzes the cyclization of 1methyl-2,2-diphenyl-4-pentenylamine with a yield of 90% (entry 1, Table 2.2), complex 1.1 generates the corresponding cis and trans pyrrolidine with a slightly lower yield of 80%. Interestingly, a lower diastereoselectivity (1.7:1 trans:cis) was observed using complex 1.1 as the precatalyst with this substrate.  2.2.6 Flydroamination using in situ prepared precatalyst  There are a number of desirable characteristics necessary for any new catalyst system to be adopted by the organic synthetic community and chemists in general. Among these characteristics are: ease of use, availability from commercial sources and cost effectiveness. In an effort to demonstrate these aspects of our system, in particular ease of use, we carried out a series of hydroamination experiments in which we utilized an in situ generated precatalyst.  This protocol would require only ) 2 Ti(NM ; 4 e which is  inexpensive, can be purchased directly from any major chemical supplier, and is easily handled using standard syringe techniques; as well as the N-(2,6-diisopropyl-phenyl)-  53  benzamide proligand, which can be prepared in a straightforward manner using literatu re procedures from benzoyl chloride and 2,6-dii 9 sopropylaniline.’ Scheme 2.10 presents the results of a series of intermolecular alkyne hydroaminati on reactions carried out using in situ generated precatalyst. These reactions are set up on a 0.5 mmol scale in a nitrogen filled glove box. The procedure involves first weighi ng out  the appropriate amount of amide proligand into a small vial and then dispensing an accurately measured aliquot of a standardized solution of 2 Ti(NMe dissolved in benzene 4 ) to the same vessel. The amine, followed by the alkyne substrate is added, and the reactio n mixture is then transferred to a J. Young NMR tube, or a small Schienk tube, remov ed from the glovebox and stirred at the specified temperature for the specified amount of time. The reduction protocol employed in the previous hydroamination experiments is also utilized in these experiments. Overall, the yields and selectivities obtained for these examples are comparable to with the results obtained in which the precatalyst had been prepared in advance, isolated and characterized. 1) 5 mol% ) 2 Ti(NM 4 e 10 mol% pro-ligand 1 R  EEE  2 R  +  2 RNH  , RT or 110 C, 24h D 6 C 2) 3 NaCNBH or R 1 4 LiAIH  NHR 2 R  HN H >98% (93% isolated yield)  TBDMS  85%  85% cony.  (79% isolated yield)  (58% isolated yield)  Scheme 2.10. Intermolecular alkyne hydroamination using in situ generated precata lyst. 54  The intramolecular cyclohydroamination of 2,2-diphenyl-4-pentenylamine can be also carried out using in situ generated precatalyst (Equation 2.6) with no difference in yield being observed in comparison to using the bis(amidate)titanium bis(amido) complex prepared in advance as the precatalyst. This reaction is initiated and carried out in the same manner as the intermolecular alkyne hydroamination experiments.  Q /  NH  5 mol% ) 2 Ti(NM 4 e 10 mol% pro-ligand PhMe,110°C,24h >98%  \  /  (2.6)  N H  2.3 Summary and conclusions  The work in this chapter has demonstrated some unique capabilities, as well as further delineated the limitations of complex 1.1 as a hydroamination precatalyst. It was found that in conjunction with p-anisidine, complex 1.1 could be used to effect the hydroamination of various terminal alkynes at ambient temperature. In addition, it was found that complex 1.1 could effect the coupling of p-anisidine to symmetrically substituted internal alkynes, which were substrates that complex 1.1 had previously been unreactive towards when alkyl amines were used as the amine co-substrate.  These  coupling reactions of alkynes to p-anisidine provide a means of preparing PMP protected primary amines which can be liberated under oxidative conditions.  The net  transformation is the efficient conversion of an alkyne to a primary amine which was demonstrated by the preparation of DL-amphetamine. The successful application of our system to the hydroarnination of TBDMS protected propargyl alcohols demonstrates that  55  complex 1.1 is tolerant of substrates bearing proximally located silyl-protected hydroxyl functionalities. This is important in that this methodology can then provide entry into useful synthetic precursors to compounds such as ce-amino acids and their derivatives. In addition to the work with alkynes, it was established that commercially available 2 Ti(NM 4 ) e can be used for the catalytic preparation of pyrrolidine and piperidine heterocyclic products from aminoalkene substrates in good yields. This reaction is particularly efficient for geminally substituted substrates and proceeds with modest, diastereoselectivity that can be rationalized by invoking a chair-like transition state for the intramolecular hydroamination reaction. The inability of this system to affect the cyclization of secondary amine bearing aminoalkene substrates suggests that the mechanism of this transformation does not involve a-bond metathesis, and rather requires the formation of an in situ generated catalytically active titanium imido species in order to proceed through a mechanism analogous to the titanium catalyzed hydroamination of alkynes. This precatalyst was found to be effective for the intramolecular hydroamination of not only terminal alkenes, but also activated internal alkenes. These preliminary results with ) 2 Ti(NM 4 e have laid the groundwork for all subsequent and future development of neutral titanium catalysts for the hydroamination of alkenes. The assessment of complex 1.1, in terms of intramolecular aminoalkene hydroamination catalysis, revealed that this system is much less active than the precursor complex, ) 2 Ti(NM , 4 e in affecting this transformation, and illuminates a severe limitation to its synthetic utility. Clearly, substantial modification to the metal complexes will have to be made in order to increase the reactivity of this system to a level such that the  56  efficient intramolecular hydroamination of a broad range of aminoalkene substrates becomes feasible.  2.4 Experimental  General. 1 H and ‘ C NMR spectra were recorded on either a Bruker 300 MHz or 400 3 MHz Avance spectrometer at ambient temperature and chemical shifts are given relative to residual solvent. The assignment of N-benzoyl-pyrrolidine stereochemistry was based on NOE difference experiments. Cis/trans ratios were determined by GCMS analysis. GCMS spectra were recorded on an Agilent series 6890 GC system with a 5973 Mass Selective Detector.  MS (ESI), HRMS and elemental analyses determinations were  performed at the Department of Chemistry, University of British Columbia. All reactions were carried out using standard Schlenk line and glovebox techniques under an atmosphere of nitrogen. Unless otherwise stated. Ti(NR 4 (R=Me, Et) was purchased ) 2 from Strem and used as received. 6 -d benzene, dio-xylenes and 8 -d toluene were degassed and dried over molecular sieves. Amino alkenes ° 2 2,2-diphenyl -4-pentenylamine, 2,22 diphenyl-5-h ’ exenylamine,  ’ 2,2,5-triphen 2 yl-4-penteny 1 2 lamine,  2,2-diphenyl-4-  2 hexenylamin ’ e, 2,2-dimethyl 2 -4-pentenyla 2 mine, 2-methyl-4-p 2entenylamine 2, 2-phenyl2 4-pentenylam ’ ine, ’ 2 2-methyl-2-p henyl-4-pentenylamine, 4-pentenylam 22 ine, and 2,22eptenylamine diphenyl-6-h 3 were prepared as described in the literature with some modification from commercially available starting materials purchased from Aldrich. Characterization data for 2,2-diphenyl-6-heptenylamine is provided below. l-Methyl-2,2diphenyl-4-pentenylamme was prepared  from  3,3-diphenyl-hex-5-en-2-one  using  modified literature procedures 24 with full characterization data reported below. 1 -Chioro  57  3-prop-I 25 -ynyl-benzene,  tert-Butyl-dimethyl-(3 2 -phenyl-prop-2-ynyloxy)6 silane  tert-butyl-dimethyl-( I -methyl-3 -phenyl-prop-2-ynyloxy)-silane were  prepared  and using  modified literature 27 procedures with full characterization data for tert-butyl-dimethyl-( 1methyl-3-phenyl-prop-2-ynyloxy)-silane reported below. Prior to use, all substrates were purified either by distillation or recrystallization.  In addition liquid substrates were  degassed and dried over molecular sieves prior to use. Heterocyclic products 2-methyl2 4,4-diphenyl ° pyrrolidine,  2-methyl-5,5-diphenylpiperidine, 14b  2-methyl-4,4-  22 dimethylpyrr olidine, 2-methyl-4-m 2 ethylpyrrolid 8 ine, 2-methyl-4-p 2 henylpyrrolid 9 ine are  known  compounds.  (4-Methoxy-phenyl)-( 1 3 -methyl-2-phenyl-ethyl)-amine, °  31 phenethyl-ph enyl-aniine, hexyl-(4-met 3 hoxy-phenyl 2 )-amine, N-benzyl-hex 9 ylamine,’ 3 (1-Methyl-2phenyl-ethyl 3 )-phenyl-amine, and the hydrochloride salt of 1-methyl-234 phenyl-ethyl amine,  are  also  known  compounds.  The  diisopropylphenyl(phenyl)-amidate) titanium bis(dimethylamido) prepared as described in the literature.’ 9  bis(N-2’,6’-  complex  1  was  Full characterization data for all new  compounds are given below.  General  procedure  for  NMR-tube  scale  intramolecular  amino  alkene  hydroamination. All NMR-tube scale reactions were prepared in an N -filled glove box. 2 An NMR-tube equipped with a Teflon screw cap was charged with the internal standard (1,3,5-trimethoxybenzene) (0.5 mmol), the catalyst (0.025 mmol), and the amino alkene (0.5 mmol) dissolved in either 6 -d benzene (—‘1 mL), dio-xylenes (l mL) or 8 -c toluene (1 mL). The tube was then sealed, heated to, and maintained at, the appropriate temperature for the stated duration of time. The conversion and yield were determined by  -  58  comparing the integration of the internal standard with a well resolved signal for the cyclic product.  H2  2 2,2-Dipheny l-6-heptenyla 3 mine.  ‘H NMR (CDC1 , 300 MHz): 60.86 (2H, s, CH 3 2  NH ) 2 , 1.05-1.17 (2H, m, ) CH 2 CH , 1.97-2.05 (2H, m, ) =CH-CH 2 CH , 2.07-2.14 (2H, m, ) -CPh CH 2 CH , 3.31 (2H, s, ) C Ph 2 NH -CH , 4.89-4.98 (2H, m, 2 CH = CH), 5.65-5.75 (1H, m, 2 CH = CH), 7.15-7.31 (1OH, m, Ar-I]); ‘ C NMR (CDC1 3 , 75 MHz): 3 6 23.36, 34.18, 35.87, 49.06, 51.73, 114.63, 125.89, 127.96, 128.21, 138.57, 146.53; MS (ESI): m/z 266 (M+H); Anal. Calcd for C, N: 2 H 9 3 C, 85.99; H, 8.74; N, 5.28. Found: C, 85.64; H, 9.08; N, 5.24.  2 3,3-Dipheny l-hex-5-en-24 one. ‘H NMR (CDC1 , 300 MHz): 62.06 (3H, s, 2 3 Ph C -COCH ) 3 , 3.10 (2H, d, J  =  7.0 Hz, =CH-CH 2 CH ), 4.83  5.60 (1H, m, ) =CH-CH 2 CH , 7.24  —  —  4.90 (2H, m, 2 CH = CH-), 5.30  —  7.37 (1OH, m, Ar-I]); ‘ C NMR (CDC1 3 , 75 MHz): 3  627.42,42.06,66.28, 118.15, 126.99, 128.17, 130.18, 134.17, 140.97; HRMS Calcd for 0 C 1 H 84 9 [M+H ] : 251.1429; Found:251.1436.  59  2 NH  2 1-Methyl-2,2 -diphenyl-4-p 4 entenylamine. ‘H NMR (CDC1 , 300 MHz): 60.94 (2H, d, 3 J  =  6.5 Hz, 3 CH-CH ) , 1.06 (2H, br s, 2 -NH ) , 2.87 (2H, dd, 3  CH2=CHCH ) 2 , 3.81 (1H, q, J —  =  6.5, ) 2 3 CH CH-NH , 4.89  5.50 (1H, m, ) =CH-CH 2 CH , 7.20  —  —  =  6.8, 13.9 Hz,  5.00 (2H, m, 2 CH = CH-), 5.30  7.33 (1OH, m, Ar-H); ‘ C NMR (CDC1 3 , 75 MHz): 3  6 19.11, 43.62, 49.17, 56.24, 117.39, 126.07, 126.11, 127.30, 127.60, 129.68, 129.87, 134.67, 143.32, 144.37; MS (El): m/z 252 (M+H), 210 (M- ) =CH-CH 2 CH ; Anal. Caled for N: 21 C, 86.01; H, 8.42; N, 5.57. Found: C, 85.98; H, 8.25; N, 5.80. H 8 C,  2 1-Chloro-3-p rop-1-ynyl-b 5 enzene. Yield 90%. NMR (CDCI , 400 MHz): 6 2.06 (3H, 3 s, 3 Ar-CC-CH ) , 7.17  7.49 (4H, m, ArH); ‘ C NMR (CDC1 3 , 101 MHz): 6 5.2, 79.5, 3  88.3, 126.8, 128.8, 130.4, 130.6, 132.4, 135.0; MS (El): m/z 150 (M’).  2 tert-Butyl-di methyl-(3-phenyl-prop-26 ynyloxy)-silane. NMR 3 (CDC1 400 MHz): 6 , 0.20 (6H, s, 3 -Si(CH ) 2 ) , 0.97 (9H, s, 3 -Si-C(CH ) ) , 4.56 (2H, s, 2 -C-CH O-), 7.30  —  7.50(5H, m, Ar-H); , CNMR(CDCI 101 MHz): 6 -4.9, 18.5, 26.0, 52.4, 85.0, 3 ‘ 88.1, 123.1, 128.4, 131.74; MS(El): m/z(M) 246.  60  2 tert-Bu tyl-dimethyl-(1-methyl-3-ph 7 enyl-prop-2-ynyloxy)-silane. NMR (CDCI , 400 3 MHz): 6 0.17 (3H, s, ) -Si( ) 3 -CH ), CH 0.19 (3H, s, ) -Si( ) 3 -CH ), CH 0.95 (9H, s, Si( 2 ) 3 ) C(C CH , H 1.51 (3H, d, 3 CH-CH ) 3 , 7.25  —  =  6.5 Hz, ) 3 -CH-C , H 4.76 (1H, q, J  6.5 Hz,  -  -  7.45 (5H, m, Ar-H); ‘ C NMR (CDC1 3 , 101 MHz): 6 -4.7, -4.3, 3  18.4, 25.5, 26.0, 59.6, 83.4, 92.0, 123.3, 128.2, 131.7;  MS (El):  m/z (M-CH ) 3  245; Anal. Calcd. for. H OS 1 C 2 6 4 i: C, 73.79; H, 9.48; N. Found: C, 73.52; H, 9.48.  General procedure for amino alkene hydroamination experiments in which the product was isolated. All reactions were prepared in an N -fihled glovebox. A small 2 Schienk tube equipped with a magnetic stirbar would be charged with the catalyst (0.025 mmol) and the amino alkene (0.5 mmol) dissolved in 8 -D toluene  (—‘  1 mL). The Schienk  tube would then be sealed, heated to the appropriate temperature, and stirred for the stated duration of time. Following this the solution would be concentrated under reduce d pressure and the crude product would be either be converted to the N-benzoyl derivat ive according  to  literature  2 proced ° ures,  or  directly  subjected  to  flash  column  chromatography (hexanes/ether or ether or , 3 ether/N Et 2 Si0 to afford the purified ) pyrrolidine or piperidine product.  61  H  H  (+1-)  2,5-Dimethyl-3,3-diphenyl-pyrrolidine. A combined yield of 90% was obtained for the mixture of diastereomers. It was possible to separate a sufficient quantity of the major diastereomer by chromatography (hexane/ether, Si0 ) to provide ‘H NMR and ‘ 2 C NMR 3 data for this compound. This in turn facilitated the identification of the 1 H and ‘ C NMR 3 data for the minor diastereomer. ‘H NMR (major diastereomer) (CDC1 , 300 MHz): 3 6 0.95 (3H, d, J  =  6.4 Hz, ) 3 P C 2 -CHh , -CH 1.21 (3H, d, J  1.87 (1H, dd, J  =  6.8, 13.7 Hz, C 2 P -CIIHh CH), 2.45 (1H, br s, NH), 3.06 (1H, dd, 3  8.26, 13.7, C 2 P -CHHh CH), 3.67 2 P C -CH-N h H-), 6.98  —  —  6.5 Hz, ) 3 P C 2 CH -C -CH h , H  3.72 (1H, m, 2 -CH CH-NH-), 3.96 (1H, q, J  6.4 Hz,  7.31 (1OH, m, Ar-H); ‘H NMR (minor diastereomer) 3 (CDC1 300 ,  MHz): 6 0.89 (3H, d, J  =  6.7 Hz, ) 3 P C 2 -CHh , -CH 1.39 (3H, d, J  =  6.4 Hz, 2 -CH CH-  CH ) 3 , 2.36—2.54 (2H, m, P C 2 CH -CH h ), 3.11 (1H, br s, NH), 3.20—3.30 (1H, m, CH 2 CH-NH-), 4.19 (1H, q, J  6.7 Hz, C 2 P -CH-N h H), 7.04— 7.31 (1OH, m, Ar-H); 13 C NMR  (major diastereomer) (CDC1 , 100 MMz): 6 16.89, 24.78, 51.08, 51.55, 57.91, 60.32, 3 125.95, 126.08, 127.62, 127.81, 128.54, 129.08, 144.56, 148.60;  C NMR (minor 3 ‘  diastereomer) (CDCI , 75 MHz): 6 21.15, 21.61, 46.75, 51.74, 59.69, 60.21, 125.86, 3 125.91,  127.53,  127.81,  128.15,  128.28,  146.60,  149.10; HRMS (mixture of  cliastereomers) Calcd for 8 C, , 2 H N [Mj: 251.16740; Found: 251.16772.  62  2-Benzyl-4,4-diphenyl-pyrrolidme. Yield 67%; 1 H NMR (CDC1 , 300 MHz): 52.06 3 (1H, br s, NI]), 2.17 (1H, dd, J  =  9.0, 12.7 Hz, CHH-CH-Bn), 2.69-2.78 (2H, m, CRH  CH-Bn, Ph-CHH-CH), 2.88 (1H, dd, J  =  7.0, 13.3 Hz, Ph-CHH-CH), 3.50-3.61 (2H, m,  Bn-CH-NH, C 2 P -CHHh NH), 3.73 (1H, d, J  11.3 Hz, C 2 P -CIIH.h -NH), 7.17-7.29 (15H,  m, Ar-Il); ‘ C NMR (CDCI 3 , 75 MHz): 5 43.53, 44.85, 56.56, 57.64, 59.12, 125.99, 3 126.08, 126.40, 126.90, 127.04, 128.28, 128.34, 129.04, 129.34, 139.83, 146.77, 147.67 ; MS (ESI): m/z 314 4 (M+H ) , 336 (M+Na); Anal. Caled for H N: C 2 3 C, 88.13; H, 7.40; N, 4.47. Found: C, 87.80; H, 7.80; N, 4.75.  oQ  N-Benzoyl-2-methyl-4,4-dimethylpyrrolidine. Yield 43%; 1 H NMR 3 (CDC1 300 , MHz): 3 0.86 (311, s, ) C 2 ) 3 C(C C H , H H 1.00 (3H, s, ) C 2 ) 3 C(C C H , H H 1.33-1.42 (4H, m, 3 (CH ) CH, ) (C C 2 ) 3 -CH) JI-C H H(C , H 1.90 (IH, dd, 3 3 CHH-C ) ), H(CH 3.05 (1H, d, J  =  =  6.0, 12.0Hz, 3 (CH C 2 ) -  10.0 Hz, ) 3 (C C 2 -CHH-N H Bz), 3.25 (1H, d, J  =  10.0 Hz,  3 (C C 2 ) -CHH-N H Bz), 4.27-4.35 (1H, m, ) 3 C 2 CH), H (CH 7.30-7.49 (5H, m, Ar-I]); ‘ C 3 NMR 3 (CDC1 75 MHz): 3 20.15, 25.39, 25.64, 38.18, 47.49, 52.83, 62.53, 127.42 , , 128.08, 129.83, 137.22, 170.00; HRMS Calcd for H N0 C 1 4 [M]: 217.14666; Found: 9 217.14674.  63  —  (+1-)  N-Benzoyl-2-methyl-4-phenylpyrrolidine. A combined yield of 26% was obtained for the mixture of diastereomers. It was possible to separate a sufficient quantity of the major diastereomer by chromatography (hexane/ether, Si0 ) to provide ‘H NMR, ‘ 2 C NMR, 3 and GCMS (El) data for this compound. This in turn facilitated the identification of the ‘H, ‘ C NMR and GCMS (El) data for the minor diastereomer.’H NMR (major 3 diastereomer) (CDC1 , 400 MHz): 6 1.50 (3H, d, J 3  =  6.0 Hz, 3 -CH CH-NBz), 1.76  (1H, m, ) 3 PhCH-CHH), CH(CH 2.53 —2.61 (1H, m, ) 3 PhCH-CHH), CH(CH 3.15 (1H, m, ) -PhCH2 CH , CH 3.50 PhCH-CHH-NBz), 4.36  —  -  3.56 (1H, m, PhCH-CHH-NBz), 3.75  4.42 (1H, m, ) 3 C 2 H-N C(C H Bz), H 7.15  —  —  2.04 (1H, m, ) 3 PhCH-CHH), CH(CH 2.22  —  —  1.87 3.22  3.79 (1H, m,  7.58 (1OH, m, Ar  I]); ‘H NMR (minor diastereomer) 3 (CDCI 400 MHz): 6 1.44 (3H, d, J , CH-NBz), 1.98  —  —  =  6.3 Hz, CH 3  2.28 (1H, m, PhCH-CHH  CH(CH ) 3 ), 3.33 3.40 (1H, m, PhCH-CHH-NBz), 3.83 3.87 (1H, m, PhCH-CHH-NBz), -  4.05  —  4.20 (1H, m, ) -PhCH2 CH , CH 4.50  -  —  4.65 (1H, m, ) 3 C 2 H-N C(C H Bz), H 7.12  —  7.47 (1OH, m, Ar-Il’); ‘ C NMR (major diastereomer) (CDC1 3 , 75 MHz): 6 20.3, 40.8, 3 44.1, 54.0, 57.0, 127.0, 127.1, 127.7, 128.1, 128.6, 130.2, 136.9, 139.7, 169.8; ‘ C NMR 3 (minor diastereomer) 3 (CDC1 75 MHz): 6 20.0, 39.4, 42.5, 53.1, 56.0, 126.7, 126.8, , 128.3, 128.6, 129.5, 137.5, 141.3, 169.6; MS (El) (major diastereomer): m/z 265 (M), (MtCH ) ; MS (El) (minor diastereomer): m/z 265 (Md), 250 3 250 3 (M-CH ) ;  Anal.  64  Calcd for N 9 H 8 C, 0 , (mixture of diastereomers): C, 81.47; H, 7.22; N, 5.28. Found: C, 81.24; H, 7.29; N, 5.35.  oooo (+1-)  —  N-Benzoyl-2,4-dimethyl-4-phenylpyrrolidine. A combined yield of 52% was obtained for the mixture of diastereomers. It was possible to separate a sufficient quantity of the major diastereomer by chromatography (hexane/ether, Si0 ) to provide ‘H NMR, ‘ 2 C 3 NMR, and GCMS (El) data for this compound. This in turn facilitated the identification of the ‘H, ‘ C NMR and GCMS (El) data for the minor diastereomer. ‘H NMR (major 3 diastereomer) (CDC1 , 300 MHz): 3  0.86 (3H, s, ) 2 PhC ) 3 -CH (CH , 1.44 (3H, d, J  Hz, 3 )(CH CH-NBz), 1.93 (1H, dd, J  =  (1H, dd, J  =  7.2, 12.4 Hz,  10.0, 12.1 Hz, ) )(C 3 CH-CH ) H-CPh H , (CH 2.41  )(C 3 ) CH-CH ) H-CPh H , (CH 3.60 (1H, d, J  3 Ph ) C-CHJ (CH I-NBz), 3.72 (1H, d, J  6.0  =  10.4 Hz,  10.4, ) 3 Ph C-CBH (CH -NBz), 4.48—4.52 (in, m,  )(CH 3 CH-NBz), 7.10-7.59 (1OH, m, Ar-H); 1 H NMR (minor diastereomer) (CDC1 , 300 3 MHz):  1.35 (3H, s, ) 2 PhC ) 3 -CH (CH , 1.42 (3H, d, J  NBz), 1.74 (1H, dd, J  =  =  5.8 Hz, 3 (CH ) CH-  9.7, 12.8 Hz, ) )(C 3 CH-CH ) H-CPh H , (CH 2.65 (1H, dd, J  13.1 Hz, ) )(C 3 CH-CH ) H-CPh H , (CH 3.47 (1H, d, J 3.87 (IH, d, J  =  =  =  6.3,  7.1 Hz, ) 3 Ph C-CHH (CH -NBz),  7.1, ) 3 Ph C-CIIH (CH -NBz), 4.0-4.1 (IH, m, 3 )(CH CH-NBz), 7.10-7.59  (1OH, m, Ar-Il); 13 C NMR (major diastereomer) 3 (CDC1 75 MHz): ,  20.12, 27.27,  45.34, 45.64, 52.51, 60.88, 125.55, 126.42, 127.56, 128.26, 128.49, 130.12, 136.97, 146.54, 170.29; ‘ C NMR (minor diastereomer) (CDC1 3 , 75 MHz): 6 20.1, 27.3, 45.9, 3  65  47.4, 60.9, 125.3, 126.4, 127.2, 128.3, 128.5, 129.9, 137.2, 146.5, 169.8; MS (El) (major diastereomer): m/z 279 (M), 264 ) 3 (M-C ; H MS (El) (minor diastereomer): m/z 279 (M ) 4 , 264 ) 3 (M-C ; H  Anal. Calcd for H N0 1 C 2 9 (mixture of diastereomers): C, 81.68; 1  H, 7.58; N, 5.01. Found: C, 81.32; H, 7.28; N, 5.31.  General procedure for the NMR-tube scale intermolecular alkyne hydroaminati on reactions. All NMR-tube scale reactions were prepared in an 2 -N fihled glove box. A J. Young NMR tube was charged with the internal standard (1,3,5-trimethoxyben zene) (0.17 mmol, 0.33 equiv), the precatalyst (0.025 mmol, 0.05 equiv), the alkyne (0.5 mmol, 1.0 equiv) and the primary amine (0.6 mmol, 1.2 equiv) and dissolved in either 6 d benzene (‘—4 mL) or 8 -d toluene (‘--4 mL).  The tube was sealed, heated to, and/or  maintained at ambient temperature, 65 °C or 110 °C for the stated duration of time. The conversion and yield were determined by comparing the integration of the internal  standard with a well resolved signal for the imine product.  General procedure for intermolecular alkyne hydroamination where isolated yields are given. All hydroamination reactions were prepared in an 2 -N filled glovebox. A small Schienk tube equipped with a magnetic stir bar would be charged with a solutio n of the precatalyst (0.05 mmol, 0.05 equiv), the alkyne (1.0 mmol, 1.0 equiv), and the primary amine (1.2 mmol, 1.2 equiv) dissolved in benzene (‘-—2 mL) or toluene (‘-—2 mL). The Schienk tube would then be sealed and maintained at the stated temperature for 24 h. After allowing the reaction mixture to cool to room temperature the resulta nt hydroamination products were directly subjected to NaCN 3 BH as described in the  66  literature to afford the crude amine 5 products. Column chromatography then afforded the purified amine products either as single compounds or as a mixture of regioisomers.  C0OMe  (4-Methoxy-phenyl)-phenethyl-amine. Yield 76%. ‘H NMR 3 (CDC1 400 MHz): , 2.96 (2H, t, J  7.0 Hz, Ph 2 NHP C -CH MP) H , 3.41 (2H, t, J  =  7.0 Hz, Ph-C 2 CH H  NHPMP), 3.47 (1H, br s, NH), 3.80 (3H, s, 3 CH O-Ph), 6.62 (2H, d, J 6.85 (2H, d, J  =  8.9 Hz, Ar-H), 7.26  —  6  =  8.9 Hz, Ar-H),  7.40 (5H, m, Ar-H); C 13 NMR (CDC1 , 101 3  MHz): 6 35.8, 46.2, 56.0, 114.5, 115.1, 126.6, 128.8, 129.0, 139.6, 142.5, 152.4; MS (El):  m/z 227 (M); Anal. Calcd. for. H, 10: C N 7 5 C, 79.26;  H, 7.54;  N, 6.16.  Found: C, 79.06; H, 7.42; N, 6.37. OMe  3 (4-Met ° hoxy-phenyl)-(1-methyl-2-phenyl-ethyl)-amine. Yield , 400 MHz): 6 1.18 (3H, d, 3 3 (CDCI  =  >98%. ‘H NMR  6.0 Hz, 3 PMPNH-CH) , CH 2.71 (1H, dd, J  13.2 Hz, Ph-CHH-NHPMP), 2.97 (1H, dd, 3  =  4.8 13.2 Hz, Ph-CHH-NHPMP), 3.70  3.76 (1H, m, ) 2 -C 3 CH(NHPMP)H , CH 3.80 (3H, s, 3 CH OPh), 6.65 (2H, d, 3 Ar-H’), 6.85 (2H, d, 3  =  10.4 Hz, Ar-H), 7.20  —  7.6 —  10.4 Hz,  7.37 (5H, m, Ar-H’); ‘ C NMR (CDC1 3 , 3  101 MHz): 6 21.3, 43.4, 51.4, 56.8, 116.1, 127.3, 129.3, 130.5, 139.8, 142.5, 153.1; MS (El): m/z 241 4 (M ) .  67  OCOMe  (2-Cyclohex-1-enyl-ethyl)-(4-methoxy-phenyl)-amine. Yield 80%. NMR (CDC1 , 400 3 MHz):  1.5  -  1.7 (4H, m, CH2 CH CH CH ), 1.9  -C=) 2 CH CH , 2.27 (2H, t, J  =  -  2.1 (4H, m, =CH 2 CH -CH  6.8 Hz, C-C 2 NHA CH H r), 3.14 (2H, t, J  6.8 Hz, C  2 CH NHA CH r), 3.4 (1H, hr s, ArNH), 3.76 (3H, s, ) 3 Ar-OC , H 5.5 (1H, m, -CH2CH=C, 6.6 (2H, d, J  =  9 Hz, Ar-H), 6.8 (2H, d, J  =  9 Hz, Ar-H); ‘ C NMR (CDC1 3 , 101 3  MHz): ö 23.4, 23.9, 26.3, 28.9, 38.8, 43.5, 56.8, 115.3, 115.9, 124.5, 136.0, 143.8, 153.0;  MS (El):  m/z 231 (M) ; Anal. Calcd. for. H N0: 1 C 2 5 C, 77.88; 1  H,  9.15; N, 6.05. Found: C, 78.12; H, 9.11; N, 5.81.  3 Phenethyl-ph ’ enyl-amine. Yield 83%. NMR (CDCI , 400 MHz): 3 7.0, Ph2 NHA CH CH r), 3.51 (2H, t, J  =  3.01 (2H, t, J  =  7.0, Ph2 NHA CH CH r), 3.76 (1H, br s,  ArNH-); ‘ C NMR (CDC1 3 , 101 MHz): 3 35.8, 45.3, 113.3, 117.7, 126.7, 128.9, 3 129.1, 129.6, 139.6, 148.3; MS (El): m/z 197 (M).  oo (3,3-Dimethyl-butyl)-(4-methoxy-phenyl)-amine. Yield 80%. NMR (CDC1 , 400 3 MHz): 3 1.00 (9H, s, ) -C(C 2 -CH ) 3 , H 1.54 (2H, m, ) -C(C 2 -CH ) 3 , H 3.10 (2H, m, 2 ArNH), CH 3.25 (1H, hr s, ArNH-), 3.77 (3H, s, 3 -NHAr-OCH ) , 6.60 (2H, d, J 9 Hz, -NH-ArH-OMe), 6.81 (2H, d, J  =  =  9 Hz, -NH-ArH-OMe); ‘ C NMR (CDC1 3 , 3  68  101 MHz):  30.6, 31.0, 42.3, 44.7, 57.0, 115.1, 115.9, 143.9, 153.0;  MS (El):  m/z 207 (M); Anal. Calcd. for. C, N0: 2 H 3 1 C, 75.32; H, 10.21; N, 6.76. Found: C, 75.38; H, 10.33; N, 6.76. H  (4-Methoxy-phenyl)-(1-methyl-pentyl)-amine and hexyl-(4-methoxy-phenyl)-amine . A combined yield of 77% was obtained for the mixture of regioisomers (2.3 : 1, AM M), which were inseparable by chromatograghy. The ‘H and 13 C NMR spectra as well as the elemental analysis for the mixture have been provided.  Hexyl-(4-methoxy-  phenyl)-amine is a known compo 32 und. The ‘H, ‘ C NMR and HRMS data for (43 methoxy-phenyl)-( 1 -methyl-pentyl)-amine obtained by the reductive amination of 2hexanone 3 withp-anisidi 5 ne is reported herein. ‘H NMR ((4-methoxy-phenyl)-(1-methylpentyl)-amine) (CDC1 , 400 MHz): 3 J  =  0.91 (3H, t, J = 7.2 Hz, ) 3 2 -CH CH , 1.17 (3H, d,  6.4 Hz, ) 3 -CH(N HAr)-C , H 1.30— 1.70 (6H, m, ) C 3 ) 2 CH( (C N}{ H , Ar)H CH 3.15  (1H, br s, ArNH-), 3.30 6.57 (2H, d, J  —  3.50 (IH, m, -CH(NHAr)-), 3.76 (3H, s, ) 3 -NH-A , r-OCH  9 Hz, -NH-ArH-OMe), 6.79 (2H, d, J  =  9 Hz, -NH-ArH-OMe); ‘ C 3  NMR ((4-methoxy-phenyl)-(1-methyl-pentyl)-amine) (CDCI , 101 MHz): ö 14.2, 21.0, 3 28.5, 37.1, 49.6, 56.0, 114.8, 115.1, 142.1, 151.9; phenyl)-( 1 -methyl-pentyl)-amine) 3 C, , 2 H NO [Mj:  HRMSCalcdfor((4-methoxy-  207.1623;  Found:  207.16242;  Anal. Calcd. for. (mixture of regioisomers) C, N0: 2 H 3 1 C, 75.32; H, 1021; N, 6.76. Found: C, 75.44; H, 10.09; N, 6.61.  69  9 N-BenzyL-h exylamine.’ Yield 79%. NMR 3 (CDC1 400 MHz): 6 3.21 (3H, t, J ,  Hz, ) 3 2 -CH CH , 1.22  -  6.8  1.39 (7H, m, ) 3 Bn 2 C NH, H -CH 1.50  1.57 (2H, m, BnN 2 C ), H-C H H 2.65 (2H, t, J 3.81 (2H, s, 2 Ph-C NH-H ), 7.24  —  =  —  7.2 Hz, BnNH 2 CH ), -CH  7.37 (5H, m, ArH); ‘ C NMR (CDCI 3 , 101 MHz): 3  6 15.1, 21.4, 23.7, 24.2, 28.1, 31.2, 32.8, 50.6, 55.2, 127.8, 129.1, 129.4, 141.7; MS (El): m/z 191 (M).  oo 2,2-Dimethyl-propionic acid 5-(4-methoxy-phenylamino)-pentyl ester and 2,2dimethyl-propionic acid 4-(4-methoxy-phenylamino)-pentyl ester. A combined yield  of 77% was obtained for the mixture of regioisomers (>2: 1 , AM : M). It was possible to separate a sufficient quantity of the major diastereomer by chromatography (hexane/ether, Si0 ) to provide 1 2 H NMR and ‘ C NMR data for this compound. Due to 3 weak intensity and extensive overlap of peaks, it was not possible to definitively assign the ‘H NMR or 13 C NMR signals for the minor diastereomer. Yield 77% (mixture of regeoisomers). 1 H NMR (major regioisomer) (CDCI , 400 MHz): 6 1.21 (9H, s, O=C 3 C-(CH ) ) 3 , 1.45— 1.50 (2H, m, 2 ArN C ) H-C H , H 1.61 C 2 C C tB O H u), 3.09 (2H, t, J H  =  —  1.71 (4H, m, ArNH  7.1 Hz, ArNH2 CH ), CH 3.76  (1H, br s, 2 Ar-NH ), -CH 3.76 (3H, s, ) 3 -NH-A , 4.08 (2H, t, J r-OCH  =  6.5 Hz, -CH 2 CH  70  0 C 2 -tBu), 6.58 (2H, d, J  =  9 Hz, Ar-li), 6.77 (2H, d, J  =  9 Hz, Ar-H); 13 C NMR (major  regioisomer) (CDC1 , 101 MHz): 6 23.7, 27.3, 28.6, 29.4, 38.9, 45.0, 56.0, 64.3, 3 114.1, 115.1, 142.8, 152.2, 178.7;  MS (El) (mixture of regiosiomers):  293; Anal. Calcd. for. 3 N0 1 C 2 H 7 (mixture of regioisomers): C, 69.59;  m/z (M)  H, 9.28;  N,  4.77. Found: C, 69.71; H, 9.01; N, 5.15.  OIYD 3 (1-Met hyl-2-phenyl-ethyl)4 phenyl-amine. Yield >98%. NIvIR (CDC1 , 400 MHz): 6 3 1.23 (3H, d, J  6.4 Hz, ) 3 Ph 2 CH(NHA -C , H 2.77 (1H, dd, 3 r)-CH  3 Ph-CH ) H-CH(NHAr) , -CH 3.02 (1H, dd, J 3.6 (1H, br s, ArNJ]), 3.83  —  =  =  7.2, 13.2 Hz,  4.8, 13.2 Hz, ) 3 Ph-CII H-CH(NHAr) , -CH  3.88 (1H, m, ) 3 Ph 2 CH(NHA -C , H 6.71 (2H, d, J r)-CH  8 Hz, -NHArIf), 6.79 (1H, t, J  =  7.6 Hz, -NHArH), 7.25  —  7.40 (7H, m, AiR); ‘ C 3  NMR (CDC1 , 101 MHz): 6 21.3, 43.4, 50.4, 114.4, 118.3, 127.4, 129.4, 130.4, 3 130.6, 139.6, 148.3; MS (El): m/z 211 (M). J O 1 Me  (1,2-Diphenyl-ethyl)-(4-methoxy-phenyl)-amine. Yield >98%. NMR (CDC1 , 400 3 MHz): 6 3.06 (1H, dd, J  =  8.2, 13.9 Hz, Ph-CHH-CH(NHAr)-Ph), 3.18 (1H, dd, J  5.6, 13.8 Hz, Ph-CHH-CH(NHAr)-Ph), 3.72 (3H, s, ) 3 -NH-A r-OCH , 3.90 (1H, br s, ArNH-), 4.56  —  4.60 (1H, m, Ph-CHH-CH(NHAr)-Ph), 6.50 (2H, d, J =9 Hz, MeO-Ar  II), 6.71 (2H, d, J  =  9 Hz, MeO-Ar-H), 7.17— 7.39 (1OH, m, Ar-H) ; ‘ C NMR (CDC1 3 , 3  101 MHz): 6 45.4, 55.9, 60.3, 114.9, 115.1, 126.7, 126.9, 127.2, 128.7, 128.7, 71  129.4,  138.0,  141.7,  143.9,  152.3;  MS (El):  m/z 303 (M); Anal. Caled. for.  N0: C 2 H 1 C, 83.13; H, 6.98; N, 4.62. Found: C, 83.12; H, 6.93; N, 4.72. KOMe HN  (1-Ethyl-butyl)-(4-methoxy-phenyl)-amine. Yield >98%. NMR (CDC1 , 400 MHz): 6 3 0.94 (6H, t, J  =  7.2 Hz, ) C 3 H 2 CH( C -C NHA , r)-CH H H 1.40— 1.62 (6H, m, 3 H C -  3 C 2 ) CH( C NHA H , H r)-CH 3.15 (1H,br s, ArNR), 3.19  —  2 CH(NH ), Ar)-CH 3.76 (3H, s, ) 3 -NH-A , 6.56 (2H, d, J r-OCH d, J  =  3.24 (1H, m, -CH 2  9 Hz, Ar-H), 6.77 (2H,  9Hz, Ar-If); ‘ C NMR (CDC1 3 , 101 MHz): 6 11.0, 15.3, 20.2, 28.2, 37.7, 3  55.9, 56.9, 115.3, 116.0, 143.6, 152.6;  MS (El):  m/z 207 (M); Anal. Calcd. for.  N0: 1 C 2 H 3 C, 75.32; H, 10.21; N, 6.76. Found: C, 75.26; H, 10.10; N, 7.16. 1  (4-Methoxy-phenyl)-(1,3,3-trimethyl-butyl)-amine. Yield 76%. NMR (CDC1 , 400 3 MHz): 6 0.93 (3H, d, J CH-CH 2 ),  1.15 (3H,  =  d, J  6.6 Hz, 2 C 3 (H )-CH-C ), H 0.96 (3H, d, J 6.2 Hz, ) 3 -C 2 CH(NHH Ar)-CH ,  2 C 3 (H C H-CHH-CH-N ) HAr), 1.44  -  —  6.6 Hz, 3 (H C )1.31 (1H, m,  1.54 (1H, m, C 2 ( C 3 H-CHH H -CH-N ) HAr)), 1.71  1.85 (1H, m, C 3 (H C 2 H-C ), ) H 3.03 (1H, br s, ArNII), 3.41 3 ArNH) , 3.76 (3H, s, ) CH-CH 3 Ar-OC , H 6.57 (2H, d, J =  1.20  =  =  —  -  3.52 (IH, m, -CR 2  9 Hz, Ar-H), 6.79 (2H, d, J  9 Hz, Ar-H); ‘ C NMR (CDC1 3 , 101 MHz): 6 21.2, 22.7, 23.2, 25.2, 47.1, 47.7, 3  56.0,  114.7, 115.1,  142.1, 1551.9;  MS (El):  m/z 207 (M); Anal. Calcd. for.  N0: 1 C 2 H 3 C, 75.32; H, 10.12; N, 6.76. Found: C, 75.38; H, 10.18; N, 6.51. 1  72  H  II  -°Si  j3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-(4-methoxy-phenyl)-amine. Yield 75%. NMR (CDC1 , 400 MHz): 6 0.10 (6H, s, ) 3 -C 2 ) 3 Si( C(CH CH , H 0.95 (9H, s, -CH 2 Si( 2 ) 3 ) C(C CH , H 1.80 t, J  —  1.88 (2H, m, Ar 2 OT C NH I3DH -CH MS), 3.21 (2H,  6.5 Hz, ArN 2 CH ), H-CH 3.77 (3H, s, ) 3 -NHAr , OCH 3.78 (2H, t, J  C 2 OTB C H DMS H ), 6.59 (2H, d, J 13  =  9 Hz, Ar-Il), 6.80 (2H, d, J  =  5.7,  -  9 Hz, Ar-H);  NMR (CDCI , 101 MHz): 6 -5.2, 26.1, 32.3, 43.0, 56.0, 57.9, 62.1, 114.1, 3  115.1, 143.1, 152.1; MS (El): m/z 295 (M); Anal. Caled. for. H N0: 1 C 2 6 C, 65.03; 9 H, 9.89; N, 4.74. Found: C, 65.24; H, 9.77; N, 5.06.  0 S i—  [1-Benzyl-2-(tert-butyl-dimethyl-silanyloxy)-ethyll-(4-methoxy-phenyl)-am  ine.  Yield 80%. NMR (CDC1 , 400 MHz): 6 0.08 (3H, s, ) 3 3 -Si(CH 3)QBu , )-CH 0.10 (3H, s, , 3 -Si(CH 3)(tBu)-CH  1.00 (9H,  2 CH( OTB NHA DMS r)-CH ), 3.56 3.60 (1H, s, ArNIl), 3.71 Cl-I ) 3 , 6.65 (2H, d, J  =  —  s, -  -Si-C(C ) 3 ) , H 2.90  —  2.95 (2H, m, Ar-CH 2  3.62 (2H, m, -C 2 CH( OTNHA BDH MS r)-CH ),  3.73 (1H, m, -C 2 CH(NH ) Ar)-CH H , 3.79 (3H, s, Ar-O  9Hz, -NH-ArH-OMe), 6.82 (2H, d, J  =  9Hz, -NH-ArH  OMe), 7.22 —7.36 (5H, m, Ar-Il); 13 C NMR (CDC1 , 101 MHz): 6 -5.2, 18.5, 26.1, 3 37.0, 55.9, 56.9, 62.6, 115.1, 115.5, 126.3, 128.5, 129.6, 139.2, 141.5, 152.4; MS  73  (El):  m/z 371 (Mt); Anal. Calcd. for. 2 NO 2 C 3 H S i: C, 71.11; 2 3  H, 8.95;  N, 3.77.  Found: C, 71.26; H, 8.84; N, 3.63.  0 S i—  ’0 Si—  (+1-)  (+1-)  [(+/-)-1-(R)-Benzyl-2-(S)-((tert-butyl-dimethyl-silanyloxy)-propyll-(4-methoxyphenyl)-amine  and  [(+/-)-1-(S)-Benzyl-2-(R)-((tert-bntyl-dimethyl-silanyloxy)-  propyl]-(4-methoxy-phenyl)-amine. A combined yield of 30% was obtained for the mixture of diastereomers, which were subsequently separated for characterization purposes. Relative stereochemistry was assigned by comparing the ‘H NMR spectra of the deprotected compounds to the known (+/-)-(2R,3S)-3-.amino-4-phenyl-2-butanol and 3 (+/-)-(2S,3R) -3-amino-4-p 6 henyl-2-butanol. ‘H NMR (syn product) 3 (CDC1 400 MHz): , 6 0.12 (3H, s, ) -Si(C ) 3 (tBu)-C , H H 0.15 (3H, s, ) -Si(C ) 3 (tBu)-C , H H 1.00 (9H, s, Si(C ( 2 ) 3 ) C(C ), H H 1.16 (3H, d, J 2 Ar-C CH(NHAr)-), m, H 3.36  —  =  6.2 Hz, ) 3 -CH(OTBDM , S)-CH 2.78  —  -  2.85 (2H,  3.41 (1H, m, --C 2 CH(NHAr)-C H2-), 3.75 (3H, s, H  -  NH-Ar-OCH ) 3 , 3.98 -4.01 (1H, m, ) 3 -CH(NHAr)CH(OTBDM , S)-CH 6.56 (2H, d, J =  9 Hz, -NH-ArH-OMe), 6.77 (2H, d, J  =  9 Hz, -NH-ArH-OMe), 7.19  —  7.33 (5H,  m, 2 -CH ArIl); 13 C NMR (syn product) (CDC1 , 101 MHz): 6 -4.5, 18.3, 21.1, 26.1, 3 37.6, 56.0, 61.4, 68.2, 115.4, 115.2, 126.2, 128.5, 129.3, 140.0, 142.4, 151.8; MS (syn product) (El): m/z 385 (M); ‘H NMR (anti product) (CDC1 , 400 MHz): 6 0.01 3 (3H, s, ) -Si(C ) 3 (tBu)-C , H H 0.03 (3H, Si(C ( 2 ) 3 ) C(C ), H H 1.22 (3H, d, J  =  s, ) -Si(E ) 3 (tBu)-C , H H 0.93 (9H, s,  6.4 Hz, ) 3 -CH(OTBDM , S)-CH 2.74 (1H, dd, J  -  =  74  8.4,  14.4 Hz, Ar-CHR-CH(NHAr)-), 2.98 (1H, dd, J  CH(NHAr)-), 3.42  —  4.4,  14.4 Hz, Ar-CHH  3.48 (1H, m, -C 2 CH(NH ), Ar)-CH H 3.50 (1H, br s, ArNH-),  3.73 (3H, s, ) 3 -NH-A , 3.96 r-OCH  -  4.04 (1H, m, ) 3 -CH(NHAr)CH(OTBDM S)-CH ,  6.47 (2H, d, 3= 9 Hz, -NH-ArH-OMe), 6.72 (2H, d, J —  =  9 Hz, -NH-ArH-OMe), 7.14  7.30 (5H, m, 2 -CH ArH); ‘ C NMR (anti product) (CDCI 3 , 101 MHz): 6 -4.6, -4.1, 3  18.2, 20.7, 26.0, 35.8, 38.9, 55.9, 61.6, 69.5, 114.4, 115.1, 126.1, 128.4, 129.3, 140.0,  142.1,  152.0;  MS (anti product) (El):  m/z  385 (M); Anal. Calcd. for.  NO 2 C 3 H S 2 3 5 i (mixture of synfanti products): C, 71.64; H, 9.15; N, 3.63. Found: C, 72.00; H, 9.24; N, 3.89. jj3CI  Hydrochloride salt of l-meth 3 yl-2-phenyl-et 4 hylamine. Yield 63%. Although the ‘H NMR spectrum of the HCI salt displayed extensive peak broadening, the chemical shift and integration of each peak were consistent with the know compound. In addition, the ‘ C 3 -APT spectrum is consistent with the literature spectrum.  NMR (CDC1 , 400 MHz): 3  6 1.27 (3H, br), 2.80 (1H, br), 3.27 (1H, br), 3.62 (1H, br), 7.2 (5H, br), 7.8 (2H, br); ‘ C 3 -APT NMR (CDCI , 101 MHz): 6 18.9 3 3 (CH ) , 41.9 (CH2), 51.1 (CH), 128.2 (CH), 129.9 (CH), 130.3 (CH), 136.8 (C); HRMS Calcd for N 4 H 9 C , {MJ: 136.1131; Found: 136.1126.  75  2-Amino-3-phenyl-propan-1-ol. Yield 57%. NMR (CDC1 , 400 MHz): 6 2.54 (1H, dd, 3 J  8.6, 13.5 Hz, Ph-CHH-CH-), 2.80 (1H, dd, J  3.3 (1H, m, -C 2 CH ), -CH H 3.40 (1H, dd, J dd, J  =  3.8, 10.7 Hz,  HO-CHH-CH-), 7.17  101 MHz): 6 40.8, 54.3, 66.2,  126.6,  5.3, 13.5 Hz, Ph-CHJI-CH-),  3.1  —  7.2, 10.7 Hz, HO-CHH-CH-), 3.65 (1H, —  7.33 (5H, m, Ar-fl); 13 C NMR (CDC1 , 3  128.7,  129.3, 183.7;  HRMS Caled for  N0 1 H 9 C 3 [M+Na]: 174.0895; Found: 174.0891.  3 [2-(3-C hloro-phenyl)-1-met 4 hyl-ethyl]-phenyl-amine. Yield 93%. NMR (CDCI , 400 3 MHz): 6 1.17 (3H, d, J  =  6.4 Hz, ) 3 .Ph 2 -CH(NH -C Ar), H CH 2.70 (1H, dd, 7.2, 13  Hz, ) 3 Ph-CH JI-CH(NHAr) , -CH 2.93 (1H, dd, J CH ) 3 , 3.52 (1H, br s, ArNH-), 3.74 (2H, d, J  =  —  =  4.8, 13 Hz, Ph-CHH-CH(NHAr)  3.84 (1H, m, ) 3 Ph-CH H-CH(NHAr) , -CH 6.64  8 Hz, -NHArH), 6.76 (1H, t, J  7.2 Hz, -NHArH), 7.08  —  7.27 (6H, m,  ArIf); ‘ C NMR (CDCI 3 , 101 MHz): 6 20.33, 42.0, 49.3, 113.5, 117.5, 3  126.6,  127.8, 129.6, 129.7, 134.2, 140.8, 147.1; MS (El): m/z 245 (M); Anal. Caled. for. C1N C 1 H 5 6 : C, 73.31; H, 6.56; N, 5.70. Found: C, 73.62; H, 6.79; N, 5.79.  76  -  6 (2-Benzyl-3phenyl-1,2,3,4-tetrahydro-quinolin-4-yI)-phenyl-amine. Yield 20%. ‘H NMR (CDC1 , 400 MHz): ö 2.48 (1H, dd, J 3 (1H, dd, J 3.87  —  =  =  10.7, 13.6 Hz, Ph-CHH-CH-NH), 2.78  2.4, 13.6, Ph-CHII-CH-NH), 3.14 (1H, t, 3  9.7 Hz, NH-CH-CHPh-CH),  3.93 (IH, m, P 2 NHh)-C CH( HPh CH ), 3.93 (2H, br s, NH, Nil), 4.80 (1H, d, 3  9.8 Hz, PhNH-CH-CH(Ph)), 6.35  —  6.45 (3H, m, Ar-H), 6.60-6.70 (2H, m, Ar-H), 7.05  7.15 (3H, Ar-if), 7.2—7.5 (11H, m, Ar-H); ‘ C NMR (CDC1 3 , 75 MHz): 3  —  41.2, 51.0,  57.5, 57.7, 113.7, 114.2, 114.6, 117.4, 117.9, 124.2, 126.9, 127.3, 128.2, 128.5, 129.0, 129.0, 129.2, 129.3, 129.6, 138.4, 141.2, 143.8, 148.0; MS (El):  m/z 390  (M).  NH  cx H  2,4-N1,N3-Tetraphenyl-butane-1,3-dianiine. Yield 17 %. MHz):  2.48 (1H, dd, J  H NMR (CDC1 1 , 400 3  7.2 14.0 Hz, Ph-CI1H-CH-NH), 2.47 (1H, dd, J  =  Hz, Ph-CHH-CH-NH), 3.08  —  —  4.4 14.0  3.14 (1H, 2 m,N CHPH-C h-CH H ), 3.39 (1H, dd, J  12.0 Hz, PhNH-CHH-CHPh), 3.6 (2H, hr s, NH, NH), 3.74 (IH, dd, J PhNH-CHF1-CHPh), 4.10  =  =  8.8  4.8 12.4 Hz,  4.16 (ill, m, 2 (Ph CH-NH )CH Ph), 6.50 (2H, d, 3  =  8.4 Hz, 77  Ar-I]), 6.61 (2H, d, J  =  8.0 Hz, Ar-I]), 6.65  Ar-H); , CNMR(CDCI 101 MHz): 3 ‘  —  6.73 (2H, m, Ar-H), 7.00  —  7.50 (14H, m,  38.6, 47.9, 50.1, 57.7, 114.2, 114.6, 118.5,  118.6, 127.3, 128.3, 129.2, 129.9 129.9, 130.2, 130.5, 130.5, 139.0, 141.3, 148.5, 149.0; HRMS Caled for 2 N C 2 H N 8 a [M+NaJ: 415.2150; Found: 415.2146.  •  78  2.5 References  (1)  Ramirez de Areliano, C.; Fuentes, A. S. Org. Lett. 2003, 5, 2523.  (2)  Verkade, J.M.M.; van Hemert, L.J.C.; Quaedflieg, P.J.L.M.; Alsters,P.L.; van Deift F.L.; Rutjesa, F.P.J.T. Tet. Lett. 2006, 8109.  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Tetrahedron: Asymmetiy 1994, 5, 1727.  82  CHAPTER THREE: CATALYST DEVELOPMENT OF GROUP FOUR BASED SYSTEMS INCORPERATING AMIDATES AS N,O CHELATING ANCILLIARY LIGANDS  3.1 Introduction  Amidate ligands offer a great deal of versatility in terms of structural modifications that can be made to alter the electronic and steric properties of the resultant complexes. The relative proximity of R’, which largely impacts electronic properties, and R , which 2 effects steric properties, makes it easier to control the two effects independently. The work described in this chapter takes advantage of the modular nature of the amidate scaffold with the intent of generating more reactive and selective hydroamination catalysts (Figure 3.1).  (R1_(NR 2 )  F  3.1  3.2  Figure 3.1. Amidate proligands designed for improved reactivity (3.1) and stereoselectivity (3.2).  © A version of this chapter has been reproduced in part with permission from Bexrud, J.A.; Li, C.; Schafer, L.L. Organometallics 2007,26, 6366. Copyright 2007 American Chemical Society.  83  In section 3.2.1 the efforts to improve the reactivity of complex 1.1 by varyin g the substituent in the R’ position is presented. In particular, the phenyl group emplo yed in complex 1.1 is replaced by an electron withdrawing pentafluorophenyl group (ligand 3.1, Figure 3.1) with the intent of generating a more electrophilic, and hence reactiv e metal center. The synthesis, structural elucidation, and assessment of this new system as a hydroamination precatalyst is discussed In section 3.2.2 an optically active menthyl group is incorporated in the R 2 position (ligand 3.2, Figure 3.1) in order to impose a chiral steric environment about the metal active site for asymmetric catalysis. For the reasons described in section 1.4, this was done to ascertain whether or not a bis(amidate) complex utilizing a chiral non-te thered amidate ligand could affect the enantioselective cyclohydroamination of aminoalkene s. Ligand synthesis and characterization along with the results of enantioselecti vity determinations are presented.  3.2 Results and discussion  3.2.1 Altering the electronics of the amidate ligand for improved reactivity  As was discussed in section 1.3, both electron withdrawing substituents (e.g. comple x 1.7)’ and enhanced steric bulk (e.g. complex 1.1)2 have been shown to contrib ute to increased catalytic activity. Thus an improved catalyst design was devised, comple x 3.1 (Scheme 3.1), having a perfluorophenyl group in the R’ position and a 2,6diisopropylphenyl group in the R 2 position. It was expected that this complex which  84  takes advantage of both reactivity enhancing steric and electronic effects, would be an even more active precatalyst, capable of affecting the hydroamination of a wide range of alkyne and alkene substrates with optimized reactivity and selectivity.  This section  presents the synthesis and structural characterization of complex 3.1, as well as the results of experiments assessing its performance as a hydroamination precatalyst. In addition, the unexpected susceptibility to decomposition of this complex, under hydroamination reaction conditions, is also discussed.  5 F 6 C 7  --k\  0 ( Ti2 5 H 6 2 NR NJ  ,NR Ti  2 NR  )2 LNR  1.7  1.0  2 3.1  2 1.1  Scheme 3.1. Evolution of the bis(amidate) system. 3.2.1.1 Complex synthesis and characterization Synthesis of proligand 3.1 is carried out according to literature procedures by reacting pentafluorobenzoyl chloride with 2,6-diisopropylaniline. This compound can be easily isolated in analytically pure form following aqueous workup, washing with hexanes (or pentanes), and then recrystallizing the crude material from . CI Prior to use, the 2 CH  85  proligand is dried via sublimation. Characterization data for this compound is consistent with the assigned structure, however the signals in the ‘ C NMR spectrum for the carbons 3 of the aromatic ring bearing the fluorine atoms were obscured due to extensive coupling to fluorine. Complex 3.1  is  prepared by the reaction  of two equivalents of N-2,6-  diisopropylphenylperfluorophenylamide with one equivalent of Ti(NEt 4 in anhydrous ) 2 ether, followed by filtration through Celite and removal of all volatiles to give a red microcrystalline solid. Crystals suitable for X-ray crystallographic analysis are obtained by recrystallization from benzene, and the solid-state molecular structure is shown in Figure 3.2. (Selected bond lengths and angles are given in Table 3.1.) It should be noted that either the crude microcrystalline or the recrystallized product can be used for subsequent hydroamination experiments without any notable difference in activity.  Figure 3.2. Diagram of bis(amidate) titanium bis(amido) complex 3.1 with thermal ellipsoids set at the 50% probability level.  86  Table 3.1. Selected Bond Distances (A) and Angles (deg) for bis(N-2,6diisopropylphenyl-perfluorophenylamidate)titanium-bis(diethylamide) complex 3.1. Bond  Length A Angle (°)  Ti—N(2) Ti—O(1) Ti—N(1) C(1) 0(1) C(1)—N(1) O(1)—C(1)--N(1) C(21) N(2) C(23) 0(1) Ti O(1_2) N(1)— Ti —N(12) N(1) Ti N(2) N(1) Ti N(2_2) 0(1) Ti N(12) 0(1) Ti —N(2_2) 0(1) Ti N(1)  1.903(1) 2.170(1) 2.201(1) 1.281(2) 1.315(2) 117.4(1) 113.5(2) 80.53(5) 139.06(6) 104.82(4) 100.16(4) 87.22(4) 159.23(4) 60.98(4)  —  —  —  —  —  —  —  —  —  —  —  —  —  —  As previously reported for the structurally similar and non-fluorinated complex 1.1,2,3 the bis(amido) titanium complex 3.1 is rigorously 2 -C symmetric, with N atoms of the amidate ligand being trans to each other, while the amido ligands are in a cis orientation. This N-trans geometry is favored for steric reasons due to the bulky 2,6diisopropylphenyl substituents. Another notable feature of 3.1 is that like complex 1.1 the binding of the oxygen and nitrogen donors of the amidate ligand to the metal center is nearly symmetric, with the Ti-0 bond being the shorter (Ti  —  N(1)  =  2.201(1)  A and Ti  —  O(1)=2.170(1)Aforcomplex3.1 andTi—N(1)=2.156(1)AandTi—0(1)=2.146(1)  A for complex 1.1).2 In addition, one will notice that the Ti-N and Ti-0 bond lengths found in complex 3.1 are both longer than the analogous bonds found in complex 1.1. This is suggestive of an enhanced ionic ligand-metal interaction in complex 3.1 versus  87  complex 1.1. The nearly symmetric Ti-N and Ti-O bonding found in complexes 1.1 and 3.1 is in contrast to complex 1.7 which was reported to have substantially different Ti-O and Ti-N bond lengths (Ti  —  N  2.356(7)  A vs Ti  characterized as an alkoxide, neutral imine donor.  —  0  =  2.044(6)  A)’ and is best  Also, as with all of our previously  reported bis(amidate) titanium-bis(amido) complexes, the sum of the bond angles about the amido N atoms in complex 3.1 indicates sp 2 hybridization and formal donation of four electrons to the metal center, resulting in a sixteen electron complex.  3.2.1.2 Reactivity towards alkynes To probe the scope, activity, and regioselectivity of complex 3.1 in terms of the intermolecular hydroamination of alkynes, a selection of alkynes and primary amines with differing steric bulk and electronic properties were screened. The most notable results clearly demonstrate the much higher reactivity of complex 3.1 over complex 1.1 in terms of alkyne hydroamination. These results can be obtained with the internal alkyne phenyl-l-propyne and 2,6-dimethylaniline as substrates, as depicted in Scheme 3.2.  1) precatalyst (5 mol%) , 110°C, 24h D 6 C NH2  complex 1.1:  <  1 8%conv.  complex 3.1:  >  98%conv.  complex 1.1: 16% yield, >99:1, anti-M:M complex 3.1: 97% yield, >99:1, anti-M:M  , 2 4 2) LiAIH Et 0 , 0°C-RT, 24h (anti-M)  Scheme 3.2. Hydroamination of 1-phenyl-l-propyne with 2,6-dimethylaniline.  88  In this case, an elevated reaction temperature of 110 °C is required for the reaction to proceed to completion within 24 h. The imine product is subsequently reduced to the corresponding amine. Using complex 3.1 this reaction is nearly quantitative, and exhibi ts extremely high regioselectivity with the anti-Markovnikov product being formed exclusively.  Complex 1.1 also affords the anti-Markovnikov compound with high  selectivity, but with a substantially lower isolated yield. The symmetrically substit uted internal alkynes 3-hexyne and diphenylacetylene can also be screened on an NMR tube scale under the same hydroamination reaction conditions and are found to be modes tly reactive in the presence of complex 3.1 and completely unreactive in the presence of complex 1.1. With complex 3.1 conversions of up to 12% and 16% are observed for these two substrates respectively following 24 h at 110 °C, while no reaction is observ ed at all in the presence of complex 1.1 under the same conditions.  Interestingly, this  limited catalytic activity towards symmetrically substituted internal alkynes is in contras t to a number of other group 4 based systems, including 2 Ti(NR which have been found , 4 ) to be effective precatalysts for these 4 transformations. As substrates, we also screened a number of terminal alkynes such as phenylacetylene, 4-methoxy-phenylacetylene, and 1 -hexyne with the primary amines 2,6dimethylaniline,  t-butylamine, and benzylamine.  In an earlier report 2 it was  demonstrated that for some of these substrates, under the same reaction conditi ons employed here, these transformations proceed with excellent yield and selectivity with complex 1.1. Results for both complex 1.1 and complex 3.1 are listed in Table 3.2, thereby permitting a direct comparison of activity and regioselectivity.  89  Table 3.2. Hydroamination reactions with terminal alkynes and primary amines using complexes 1.1 and 3.1 1) precatalyst (5 mol%) H  1 R  +  N—R 2 H  2 NHR R1JH  2 NHR +  R1c  RT, 24h anti-Markovnikov Markovnikov (anti-M) (M) Entry 1 2 3 5  1 R  R2  2,6-dimethylphenyl Ph p-MeOPh 2,6-dimethylphenyl 2,6-dimethyiphenyl nBu nBu t-butyl benzyl nBu  complex 1.1 complex 3.1 YieIda(antiM:M)b Yielda(anti.M:M)b 62%(>49:1) 57%(>49:1) 72%(<1:49) 82%(>49:1)2 88%(>49:1)2  69%(3:1) 65%(1.2:1) 84%(<1:49) O%(> 9 > :l)C 49 45%(2:1)  alsolated yields unless otherwise stated. b Ratio determined by NMR. C Yield and ratio of the imine hydroamination product determined by NMR spectroscopy using 1 ,3,5-trimethoxybenzene as an internal standard.  These reactions are carried out on small scale with benzene as a solvent.  The  resulting imine mixture is diluted with ether and reduced with LiA1H 4 to give the corresponding amine products. It should be emphasized that the times and temperatures that are employed do not reflect optimized reaction conditions and are chosen for consistency. While monitoring by ‘HNMR spectroscopy it is found that in the case of entries 3 and 4, when using complex 3.1, the reactions both go to completion within 4 h at 65 °C, again consistent with the enhanced activity of this precatalyst. In general, with respect to entries 1 through 4 the yields that are obtained using complex 3.1 are comparable to, if not marginally better than those obtained using complex 1.1 as the precatalyst. However, the regioselectivity observed when using precatalyst 3.1 is found in some cases to be lower than when 1.1 is used as the  90  precatalyst. It should be noted that the comparable regioselectivities observed for entry 4 can be attributed to the significant steric bulk of the reactive t-butyl substituted titanium imido intermediate (A, of Scheme 1.5) which has been previously reported to favor the formation of the anti-Markovnikov produc 5 t. The enhanced steric accessibility to the reactive metal centre in complex 3.1, due to the increased ionic character of the metal ligand bonding interaction, may promote the observed enhanced rates of reaction and the reduced regioselectivity with less bulky substrate combinations. Although entries 1 through 4 suggest that the reactivity of complex 3.1 towards alkynes is similar to the analogous non-fluorinated complex 1.1, an important difference can be observed when 3.1 is used for the hydroamination of 1-hexyne with benzylamine (entry 5). Not only is the regioselectivity found to be diminished using 3.1 (only the anti Markovnikov product is detected when 1.1 is used as the precatalyst), but the yield obtained using this precatalyst (45%) is substantially lower than when 1.1 is used (88%).2 Interestingly, it has been previously shown that commercially available Ti(NR 4 shows ) 2 the reverse regioselectivity, with the Markvonikov product formation being favored over the anti-Markovnikov produc 6 t. Thus in the cases where bulkier amines are used as substrates, the yields obtained using complex 3.1 are slightly better than those obtained using complex 1.1 as the precatalyst. However, the dramatic change in reactivity when benzylamine is used as the substrate can be attributed to undesirable side reactions between benzylamine  and the pentafluorophenyl  bearing ligand  (vide  infra).  Furthermore, the significant differences in observed reactivity and regioselectivity between the bis(amidate) bis(amido) titanium complexes 1.1, 1.7 and 3.1 and Ti(NR 4 ) 2 (which could be formed in situ if conproportionation is occuring) suggest that the  91  modified reactivity reported here can be attributed to the unique reaction environment afforded by the N,O chelating ligands.  3.2.1.3 Reactivity towards aminoalkenes  As a further challenge to the competency of precatalysts 1.1, 1.7 and 3.1, they were also  tested  for  intramolecular  alkene  hydroamination  diphenylpentenylamine as a substrate (Table 3.3).  activity  using  2,2-  Alkene hydroamination reactivity  remains a significant challenge and provides a useful example for contrasting catalytic activity. This particular substrate, geminally disubstituted in the 2 position, is chosen to take advantage of the gem-disubstituent effect, which has been observed to have a significant effect on the rate of reaction using these and similar 7 precatalysts. 8 ’ Table 3.3. Comparing intramolecular amino alkene hydroamination using precatalysts 1.1, 1.7, and 3.1.  precatalyst 5 mol%,  Ph  110°C, 8 -D Tol, 24h  flPh Ph  Precatalyst  Yielda  1.1  90%  1.7 3.1  30%  alwlated yields.b Yield determined by NMR spectroscopy using I ,3,5-trimethoxy benzene as an internal standard.  92  A temperature of 110 °C is required for this transformation to occur in the presence of complex 1.1, and for consistency the reactions where complexes 1.7 and 3.1 are used as precatalysts are also carried out at 110 °C. Where isolated yields are given, the reactio n mixtures are quenched by the addition of 2 CI and all volatiles are removed in vacuo CH , to give an oily brown solid that could then be purified by column chromatography to yield the pyrrolidine product. Unfortunately, the results listed in Table 3.3 show that precatalysts 1.7 and 3.1 are substantially less effective than complex 1.1 in effecting this transformation. In fact only complex 1.1 exhibited reactivity similar to that of the precursor to these complexes, reported to catalyze this reaction with an isolate e 2t which has been previously 7 Ti(NE , 4 ) d yield of 92% using the same reaction conditions. This indicates that the perfluorophen yl group has a significant detrimental effect on the application of these complexes for intramolecular alkene hydroamination. In the reactions in which complexes 1.7 and 3.1 were used as precatalysts, extended reaction times at 110 °C did not significantly improve conversion. However, when the same reaction using complex 3.1 as the precatalyst was carried out with a higher catalys t loading (20 mol%) and at a lower reaction temperature (65 °C) over a longer period of time (168 h) a higher conversion (56%) was observed. It should be noted that comple x 1.1 does not promote intramolecular alkene hydroamination at this temperature. The improved low temperature reactivity of 3.1 suggests that at elevated temperatures this complex decomposes or converts to some catalytically inactive species. Again the substantial difference in catalytic activity between the fluorinated and non-fluorinate d  93  precatalysts can be attributed to undesirable side reactions of the pentafluorophenyl bearing ligand.  3.2.1.4 Side reactivity of the N-2,6-diisopropylphenylperflourophenylamidate ligand  To investigate catalyst decomposition/inactivation as a possible explanation for the differences in reactivity between the fluorinated and non-fluorinated precatalysts, the reaction conditions employed in the hydroamination experiments with complex 3.1 can be used for reaction with 2,2-diphenylpentylamine. This modified substrate does not contain an alkene, thereby eliminating hydroamination as a possible reaction pathway. The mixture of products obtained from this initial experiment result from nucleophilic displacement of fluorine on the perfluorinated aromatic ring of the ligand by 2,2diphenylpentylamine and also by the diethylamido ligancl of the 9 precatalyst. Simply heating complex 3.1 to 110 °C in toluene for several days results in significant complex decomposition caused by the addition of the amido ligand to the amidate ligand. In addition to these fmdings, while studying the hydroamination of 1 -hexyne with benzylamine using complex 3.1 as the precatalyst, it is possible to isolate a byproduct that is consistent with the addition of benzylamine to the amidate ligand via nucleophilic aromatic substitution. The characterization of these decomposition products 3.4 and 3.5 can be confirmed by their independent syntheses in the absence of metal, as shown in Scheme 3.3.  94  F 2 R—NH  RNH  0  llOocc;rPhMe  +  3.1 R=  Ph  0 F.i)L  3 NEt  FfF F  65°C,PhH  Ph  Ph  N H  \ /  Ph 3.4 68% yield  3.5  94% yield  Scheme 3.3. Reaction of N-2,6-diisopropylphenylperflourophenylamide with 2,2diphenylpentylamine and benzylamine. All these observations are consistent with the fact that perfluorrnated aromatic compounds can undergo nucleophilic aromatic substitution reactions due to their highly electron deficient ring systems and availability of leaving groups (F). ’ 9  10  In the  aforementioned decomposition reactions, the concomitant formation of HF would cause immediate catalyst decomposition via the formation of unidentified Ti-F species. This unexpected catalyst decomposition is consistent with the poor yields observed when less bulky amine substrates are used for hydroamination.  3.2.2.6 Summary and conclusions for modifying the electronic properties of the amidate ligand  A bis(N-2,6-diisopropyl(phenyl)perfluorophenylamidate)titanium-bis(dliethylamido) complex incorporating electron withdrawing perfluorophenyl groups in the ligand backbone was prepared, characterized and examined as a hydroamination precatalyst. The solid sate structure of this compound indicated that it is rigorously 2 -C symmetric, with N  95  atoms of the amidate ligand being trans to each other, while the amido ligands are in a cis orientation. The inclusion of the electron withdrawing perfluorophenyl group was expected to improve catalyst activity relative to previous non-perfluorophenyl bearing variants. However, hydroamination screening experiments revealed that this complex is susceptible to decomposition under the conditions employed for catalysis.  Catalyst  decomposition was attributed to the addition of amine substrate to the perfluorinated aromatic ring of the amidate ligand via nucleophilic aromatic substitution. The work described in this section highlights the need for the judicious selection of reactivity modifying substituents when designing catalyst systems, and indicates that pefluoro aromatic substituents may not be suitable as electron withdrawing groups for complexes employed as hydroamination catalysts.  3.2.2. Modifying the structure of the aniidate ligand for asymmetric cyclohydroamination  Modifications can, and have been made to the axially chiral biphenyl ligand of complex 1.3 (Figure 3.3) resulting in some significant changes to 7 reactivity. However, a as was mentioned previously, one of the weaknesses of this ligand design is that synthesis and resolution of non-racemic derivatives can be difficult and time consuming, which impedes structure activity relationship studies for asymmetric catalysis. In addition, the  steric environment imposed by this tethered amidate ligand is somewhat removed from the reactive metal center, which in turn limits the influence that it has on selectivity.  96  -  T  N,,,,  2 NMe  V Figure 3.3. Bis(amidate) zirconium bis(amido) complex 1.3 incorporating an axially chiral ligand framework developed for enantioselective cyclohydroamination. In the interest of addressing these issues we considered using non-tethered chiral amides derived from simple, readily available chiral primary amines as an alternative class of proligand. The use of non-tethered arnides would allow for a greater degree of structural variation and potentially accelerate structure activity relationship studies by virtue of the modular and simple synthetic route to these proligands. The use of non racemic, commercially available primary amines or amine precursors circumvents the need for chiral resolution of enantiomers.  It may also be easier to address the issue of  limited steric influence because, as will be discussed, these complexes are expected to adopt an N-trans C 2 geometry, and this geometry allows for a greater amount of steric bulk to be positioned closer the reactive site of the catalyst. As mentioned in the introduction to this thesis (-)-menthone was selected for these initial investigations as an inexpensive commercially available source of asymm etry (Scheme 3.3). The non-racemic ketone could easily be converted to the corresponding amine via reductive amination and then derivitized with benzoyl chloride to yield the  97  requisite amide. This synthetic protocol was expected to afford a mixture of diastereomers which could then be separated, before preparing the new chiral bis((N menthyl)phenylamidate) zirconium bis(amido) complexes (Scheme 3.4).  R>  corn mercially available (-)-menthone chiral bis((N-menthyl)phenylamidate) zirconium bis(amido) complex R  =  Ph  Scheme 3.4. Using commercially available (-)-menthone as a source of asymmetry for the synthesis of chiral zirconium precatalysts (hypothetical geometry shown).  Without a rigid, and configurationally defining tetradentate ligand framework, there are a number of possible coordination isomers that these bis((N-menthyl)phenylamidate) zirconium complexes could potentially adopt.  It is however possible, to propose a  preferred geometry based on structural information gathered from a range of known group four bis(amidate) bis(amido) comple 3 xes.  The solid state structures of these  compounds have indicated that the strongly donating amido ligands occupy adjacent coordination sites cis to one another. Furthermore, when the amidate ligands bear bulky N-substituents, such as 2,6-cliisopropylphenyl, it has been found that of the five possible diastereomeric coordination isomers, they preferentially adopt an N-trans C 2 geometry (Figure 1.2) in order to minimize the steric strain imposed by these bulky groups. Although structural assignment is based primarily on solid state X-ray crystallographic  98  data, the solution phase ‘H NMR spectra collected for a number of zirconium and titanium complexes bearing the bulky N-2,6-diisopropylphenyl substituent indicate the presence of only one highly organized, C 2 symmetric geometry that is consistent with the solid state structures. Considering these findings it is proposed that the ((N menthyl)phenylamidate) zirconium complexes would also adopt the N-trans C 2 geometry due to the steric bulk provided by the N-menthyl substituent (Scheme 3.5).  *  relative steochemistry has been omitted for clarity  Scheme 3.5. Hypothesized preferred coordination geometries for the bis((N menthyl)benzamidate) zirconium bis(amido) complex. In the N-trans C 2 coordination geometry, either of the two diastereomers shown in Scheme 3.5 are possible.  Assigning a preferred diastereomer at this point is only  99  speculative, but in light of the observations made by Scott and coworkers that complexes 1.6 and 1.7 exist as a single diastereomer 2 s,’ it is not unreasonable to suggest that differential steric interactions could potentially cause one diastereomer to be favored over the other. The primary objective of these investigations is to achieve enantioselective catalysis. Therefore, the geometries of some of the key intennediates and transition states implicated in the catalytic cycle deserve consideration, as these species will dictate the stereochemical outcome of the transformation.  For the group four catalyzed  cyclohydroamination of aminoalkenes, the chair-like transition state represents the point along the reaction pathway in which the stereochemistry of the newly created stereogenic carbon atom is set (for the proposed mechanism of the cyclohydroamination reaction see thesis). The intermediate immediately preceding a Scheme 2.9 in section 2.2.5.4 of this 7 this transition state is the actual catalyst for the transformation; an in situ generated zirconium-imido complex. It is the chiral steric environment created by the ancillary amidate ligands about the reactive zirconium imido bond that will ultimately determine the most energetically favorable geometric configuration for the chair-like transition state. The only well characterized bis(amidate) supported zirconium imido complex is the TPPO stabilized complex depicted in Scheme 3.6.” The structure of this compound was found to be a distorted-pentagonal-pyrimidal geometry in which the amidate ligands occupy the four coordination sites at the base of the pyramid, and are oriented in such a way that the bulky 2,6-diisopropylphenyl groups are again as far removed from one another as possible. This complex is chiral at metal and therefore is also comprised of  100  enantiomers. Exchanging the achiral 2,6-diisopropylphenyl group for a chiral R-group such as menthyl, would render these enantiomers optically active diastereomers. Again, as was suggested for the bis(amidate) bis(amido) diastereomers depicted in Scheme 3.4, possibly differential steric interactions will cause one isomer to be favored over the other, and therefore, enantioselective catalysis may be achieved using this conformationally flexible system.  TPPO  N R *  Ph  Ph  R. (OZr<N) *  R”  2,6-dilsopropylphenyl TPPO stabilized bis(amidate) supported Zr imido complex  Scheme 3.6. Proposed geometry of the catalytically active zirconium imido species.  3.2.2.1 Synthesis and characterization of the proligand  The proposed synthetic route to the (-)-menthone derived bis((N-menthyl)phenyl amidate) zirconium bis(amido) complexes is outlined in Scheme 3.7. It was expectated that the protocol employed to generate the benzamide proligand(s) would produce a mixture of two diastereomers differing only in the stereochemistry associated with the  101  carbon atom located cc to the nitrogen. The plan was to then separate these diastereomers via column chromatography and/or recrystallization,  and react each of the purified  amides with ) 2 Zr(NM 4 e using known 3 methods. The resulting bis(amidate) zirconium bis(dimethylamido) complexes were to be characterized and then screened using a standard test substrate for enantioselective cyclohyciroamination.  1) 2 NH Q H.HCI,  seerate  °NH 2 diastereomers -  NHBZ  Q”1NHBZ  (1 R,2R,5R)-3.2 (IS,2R,5R)3.6  (-)-menthone  O.5eq Zr(NMe 4 ) 2 NHBz 2  Scheme 3.7. Overall synthetic route to the (-)-menthone derived bis((N-menthyl)phenyl amidate) zirconium bis(amido) complexes. Instead of the expected (IR,2R,5R)-3.2 and (1 S,2R,5R)-3.6 N-benzoyl derivatives of menthylamine, the reagents and conditions outlined in Scheme 3.8 unexpectedly afford a mixture of (1R,2S,5R)-3.7 and (1R,2R,5R)-3.2 (Scheme 3.8). It is apparent that these compounds share the same stereochemistry at the 1-position of the cyclohexyl ring, cc to the nitrogen atom, but the stereochemistry at the carbon in the 2-position bearing the iso propyl group has undergone epimerization. It is suspected that the oxime initially formed  102  in the first step may be in equilibrium with the equivalent of an enamine tautomer, which upon protonation to reform the oxime can undergo epimerization at the 2-position.  1) NH OHHCI, 2 C  o  o  EtCH, A 40h 2) LIAIH , THF 4 A 40h 3) BzCI, NEt , CH 3 CI 2 RT 24h  (1 R,2S,5R)-3.7  (1 R,2R,5R)-3.2  <40%  Scheme 3.8. (-)-Menthone derived proligand synthesis.  Compounds 3.7 and 3.2 are obtained as a mixture following column chromatography in low yield (<40%) in a ratio of about three to one in favor of the 1R,2R,5R-isomer. Recrystallization of this mixture from diethyl ether affords analytically pure 3.7, while repeated recrystallization of the residue recovered from the mother liquor from C1 (‘-4:1) eventually gives 3.2 as a pure compound. It should be noted that 2 hexanes/CH these reactions were only carried out to generate chiral amide compounds in quantities sufficient for study as proligands, and therefore, the reaction conditions and purification protocols employed have not been optimized. The relative stereochemistries of 3.7 and 3.2 are assigned based on their solid state molecular structures determined by X-ray crystallography. Figures 3.4 and 3.5 depict the ORTEP diagrams for each diastereomer. Interestingly, the unit cell for 3.7 contains both of the possible chair conformations that this compound can adopt, while the ‘H NMR data is consistent with there being only one conformer present in solution.  103  Figure 3.4. ORTEP diagrams of the N-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)benzamide proligand 3.7. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity.  Figure 3.5. ORTEP diagram of the N-((1R,2R,5R)-2-isopropyl-5-methylcyclohexyl)benzamide proligand 3.2. Elipsoids are drawn at the 50% probability level.  3.2.2.2 Complex synthesis and characterization  It has been found by other members of our group that with a number of chiral bis(amidate) complexes, there is little variation in enantioselectivity between using recrystallized, crude, or in situ generated precatalysts.  For the purposes of this  investigation, complete structural elucidation of the complexes used for catalysis was not  104  thought to be crucial, as the primary concern was whether it was even possible to affect enantioselective catalysis using the non-tethered ligand framework.  Therefore, the  following described crude complexes were used in the subsequent enantioselective catalysis investigations without further purification or analysis. In addition, due to our inability to obtain an adequate amount of proligand 3.2 for complex synthesis we opted to test this proligand for enantioselective cyclohydroamination using in situ generated catalyst screening experiments. With  sufficient  quantities  of N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-  benzamide 3.7 in hand however, it was decided to proceed with complex synthesis using this proligand (Equation 3.1).  Complex 3.2 can be prepared simply by adding one  equivalent of Zr(NMe , which is dissolved in a small amount of benzene, to a vial 4 ) 2 containing a stir bar and two equivalents of proligand suspended in a small amount of benzene. The resulting solution is capped and then stirred for approximately 24h at ambient temperature.  Removal of the solvents under reduced pressure affords an  amorphous material having elemental analysis data consistent with the target complex.  O.5eq M(NMe 4 ) 2 PhH, RT 24h  4  22 (MN R 1)  2 MZr, complex 3.2 MTI, complex 3.3  The ‘H and ‘ C NMR spectra for this compound are quite convoluted, possibly due to 3 the presence of multiple rotational atropisomers in solution, and are not useful for  105  definitive structural characterization purposes. It is important to point out, however, that the H NMR spectrum is devoid of any significant peaks within the range of 5  —  7 ppm,  which is where one would expect to find the NH resonance corresponding to free proligand, if there was in fact free proligand remaining in solution. This is a strong indicator that the protonolysis reaction has gone to completion and the amide is now coordinated to the metal. Mass spectral data (electron impact) provided no additional useful information. Attempts to recrystallize the crude material for solid state structural determinations may have been complicated by the presence of multiple isomers, and were not successful. The  analogous  bis(N-(( 1 R,2S,SR)-2-isopropyl-5-methylcyclo-hexyl)benzamidate)  titanium bis(diethylamido) complex 3.3 can also prepared using the synthetic protocol described for the synthesis of complex 3.2 using Ti(NEt 4 in place of Zr(NMe ) 2 . The 4 ) 2 resulting crude titanium compound is a red oil. The 1 H and ‘ C NMR spectra for this 3 compound are also quite convoluted and not useful for characterization purposes. The ‘H NMR spectrum is again devoid of any significant peaks within the range of 5—7 ppm, suggesting that there is no free ligand remaining in the crude mixture. Although no molecular ion was discemable in the MS (El) of the crude material, the fragments corresponding to (M  -  ) and (M 2 2NEt  —  amidate ligand) were observed and are  consistent with other characterized bis(amidate) titanium bis(amido) type complexes. Attempts to recrystallize the crude material for solid state structural determinations may have been complicated by the presence of multiple isomers, and were not successful.  106  3.2.2.3 Enantioselectivity determinations  Both the zirconium and titanium bis(N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)benzamidate)  complexes  3.2  and  3.3  were  tested  for  enantioselective  cyclohydroamination using the standard test substrate 2,2-diphenyl-4-pentenylamine. In addition, the in situ generated zirconium catalyst using proligand 3.2 was also screened. The results of these experiments are listed in Table 3.4.  Table 3.4. Enantioselective hydroamination studies using bis(amidate) titanium bis(amido) precatalysts derived from (-)-menthone. Ph  precatalyst,  Ph  co::n  loading temp metal TIa Zrb  ligand (mole %) (°C)  Yield  ee  (h)  (%)  (%)  3.7  5  110  24  85  <5  3.7  10  110  5  >98c  26  d 91  23  b  Zre  time  3.2  a Complex 3.3.  b  10  65  48  10  65  48  94  <5  C  Complex 3.2. Conversion, 54% conversion after 1 hour. d 62% conversion after 24h at 65 oce Prepared in situ. 67% conversion after 24h at 65°C.  These cyclohydroamination reactions are prepared and carried on an NMR tube scale and are monitored by 1 H NMR spectroscopy. Enantiomeric excesses are based on 1 H NMR spectroscopy of the product following derivatization with (+)-(S)-c-methoxy-o* trifluoromethyiphenylacetyl chloride as previously described in the 7 literature. a  107  The most efficient and selective precatalyst of this group was the zirconium complex 3.2, with the cyclohydroamination reaction going to completion within 5 hours at 110 °C and an enantiomeric excess of 26%. Lowering the reaction temperature to 65 °C did not significantly impact the observed enantioselectivity with this precatalyst, but as one might expect the reaction time increased dramatically. The analogous titanium complex, complex 3.3, exhibited reasonably good reactivity with the cyclization going to completion (>98% conversion) within 24 hours, but no stereoselectivity was observed. The in situ prepared zirconium precatalyst that utilized proligand 3.2 was found to be about as reactive as complex 3.2, with comparable conversions after 24 hours at 65 °C, however, no appreciable enantioselectivity was observed using this system.  As a  benchmark example from the literature for comparison purposes, complex 1.3 catalyzes the complete conversion of 2,2-diphenyl-4-pentenylamine to the corresponding N heterocycle within 1.25 hours at 110 °C, and it does so with an enantiomeric excess of 74%7a  3.2.2.4 Summary of incorporating (-)-menthone as a source of chirality for the asymmetric hydroamination of aminoalkenes  In this section, the synthesis and characterization of two chiral amides derived from  (-  )-menthone has been described. The synthetic protocol that was employed unexpectedly afforded  N-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide  as  the  major  product along with a small amount of the (1R,2R,5R)-isomer. An attempt was made to prepare chiral titanium and zirconium bis(amidate) bis(amido) complexes using the (1R,2S,5R)-amide as a proligand.  It was not possible to purif’ or definitively  108  characterize the resulting products. The data that was obtained; in the form of NMR, elemental analysis, and mass spectral (El) data; was consistent with complexation of the metal by the amide proligand.  No attempt was made to prepare the corresponding  complexes using the (1R,2R,5R)-isomer due to the insufficient quantities of this compound. This proligand was instead used in the enantioselectivity investigations by generating the precatalyst in situ. The  zirconium  complex  methylcyclohexyl)-benzamide  as  incorporating proligand  proved  N-(( 1 R,2S,5R)-2-isopropyl-5to  be the  most  effective  enantioselective catalyst of those examined in this section, with an enantiomeric excess of 26% being observed for the cyclization of 2,2-diphenyl-4-pentenylamine. Although this selectivity is quite moderate in relation to what has been reported for other chiral neutral group four systems, the fact that any enantioselectivity at all was observed using the non-tethered ligand framework is impressive considering the less rigidly defined coordination environment and greater potential for the existence of multiple isomeric species in solution. To summarize, these investigations using bis((N-menthyl)phenylamidate) zirconium bis(amido) complexes were devised as a proof of principle, that chiral non-tethered amidate ligands can be used to generate bis(amidate) zirconium bis(amido) precatalysts capable of affecting the enantioselective cyclohydroamination of aminoalkenes. The chiral non-tethered amidate ligand framework is advantageous due to the modular and simple way in which the amide proligands can be produced. In most cases these amides can be made chiral by drawing from a wealth of commercially available, naturally occuring non-racemic chiral starting materials, which obviates the need for chiral  109  resolution and speeds up structure activity relationship studies. In order to obtain good enantioselectivities using metal based catalysts a readily accessible coordination geometry that imposes a sufficient degree of chiral steric influence on the reactive site is required. Although it is recognized that a major drawback to using the non-tethered ligand framework is the greater number of potential geometric isomers; it has been argued, based on previous work, that one could predominate over the others, and this may make enantioselective catalysis using these systems possible. Although the bis(N ((1 R,2S,5R)-2-isopropyl-5-methylcyclo-hexyl)benzamidate) system is itself not worth pursuing any further, this work does demonstrate that the non-tethered chiral amidate ligand motif can be used to generate chiral zirconium complexes capable of effecting enantioselective catalysis and may provide an alternative to the tethered bis(amide) ligand framework.  3.3 Overall summary and conclusions  The incorporation of an electron withdrawing substituent in the R’ position of the amidate ligand framework resulted in increased reactivity.  However, the particular  sub stituent used (perfluorophenyl) was found to suffer from adverse side reactivity with the amine substrate which results in catalyst inactivation. Therefore alternative electron withdrawing groups should be used in the design of hydroamination precatalysts. An optically active amidate ligand incorporating a menthyl derivative in the R 2 position was easily prepared from commercially available (-)-menthone. When the resultant bis(amidate)  complex  was used  as  a catalyst for the asymmetric  110  cyclohydroamination of 2,2-diphenyl-4-pentenylamine an enantiomeric excess of 26% was achieved. This enantioselectivity is quite modest relative to other contemporary group four based asymmetric cyclohydroamination precatalysts which incorporate configurationally rigid tethered ligand frameworks, and highlights the importance of this aspect to ligand design. These investigations have demonstrated the versatility that amidate ligands provide in terms of structural modifications that can be made to alter the electronic and steric properties of the resultant complexes. In particular, the work described in this chapter has further contributed to our understanding of how the modular nature of the amidate scaffold can be used to generate more reactive and selective hydroamination catalysts.  3.4 Experimental  General. ‘H and ‘ C NMR spectra were recorded on either a Bruker 300 MHz or 400 3 MHz Avance spectrometer at ambient temperature and chemical shifts are given relative to residual solvent. GCMS spectra were recorded on an Agilent series 6890 GC system with a 5973 Mass Selective Detector. Single crystal X-ray structure determinations, MS (ESI) and elemental analyses determinations were performed at the Department of Chemistry, University of British Columbia. All reactions were carried out using standard Schlenk line and glovebox techniques under an atmosphere of nitrogen, unless described otherwise. Ti(NR 4 and Zr(NR ) 2 4 (R = Et, Me) were purchased from Strem and used as ) 2 received. 6 -d benzene and 8 -d toluene were degassed and dried over molecular sieves. Acid chlorides were purchased from Aldrich and used as received. Amines were distilled  111  from CaH 2 under nitrogen.  Alkynes were purchased from Aldrich and purified by  distillation prior to use. 2,2-Diphenyl-4-pentenylamine, was prepared as described in the 3 with some modification from commercially available starting materials literature’ purchased from Aldrich.  2,2-Diphenylpentylamine was prepared using modified  literature procedures,’ 3 with full characterization data presented here.  The amide  proligands were prepared from the appropriate amines and acid chlorides according to literature procedures.” 4 Complexes 1.1 and 1.7 were prepared as previously reported in ” 2 the literature.” 2  FF F  H  N-2,6-dilsopropyl(phenyl)perflourophenylamide proligand 3.1. “  modified literature procedures. ’ 2  Prepared using  One should note that the signals in the ‘ C NMR 3  spectrum for the carbons of the aromatic ring bearing the fluorine atoms were obscured due to extensive coupling to fluorine. Yield: 51%. ‘H NMR (CDC1 , 300 MHz): ö 1.22 3 (12H, ci, J= 6.9 Hz, CH-(CH , 3.12 2 ) 3  -  3.21 (2H, septet, J= 6.9 Hz, 3 CH-(CH ) 2 ) , 7.06  7.40 (3H, m, Ar-B); ‘ C NMR (CDC1 3 , 75 MHz): 3  —  23.5, 28.8, 123.6, 129.2, 129.3,  146.2, 157.0; ‘ F NMR (CDC1 9 , 282 MHz): ö -63.6 (2F), -73.9 (iF), -83.0 (2F); MS (El): 3 m/z  ), 328 3 3 371 (M), 356 (MtCH (M-CH(CH ) 2 ) , 195 ) (M-N ( 3 H 6 ) 2 CH( ; CH HC  Anal. Calcd for F 8 H 9 C, N 5 O: , C, 61.45; H, 4.89; N, 3.77. Found: C, 61.71; H, 4.50; N, 3.78.  112  2 O 5 F 6 /C ,NEt  /2 Bis(N-2,6-dilsopropyl(phenyl)perflourophenylamidate)titanium-bis(diethylamido)  procedures. Yield: 65%. The NMR d complex 3.1.2 Prepared using modified literature 3 specta of this compound are very complicated and not helpful for characterization due to the presence of multiple isomers in solution. Suitable crystals for X-ray crystallography were grown from benzene at ambient temperature; MS (El): m/z 860 ) 2 (M-NE ,t 788 (M 2 X 2); Anal. Calcd. for 4 NEt N 4 C 5 H 1 F T 2 O 6 0 i: C, 59.10; H, 6.04; N, 5.99.  Found: C,  59.15; H, 5.99; N, 6.20.  General procedure for intermolecular alkyne hydroanunation. All hydroamination  reactions were prepared in an 2 -N fihled glovebox. A small Schienk tube equipped with a magnetic stir bar was charged with a solution of the precatalyst (0.05 mmol, 0.05 equiv), the alkyne (1.0 mmol, 1.0 equiv), and the primary amine (1.2 mmol, 1.2 equiv) dissolved in benzene (2 mL) or toluene (2 mL). The Schienk tube was then sealed and heated to either 65 °C or 110 °C for 24 h. The reaction mixture was then allowed to cool to room temperature and transferred to a small round bottom flask containing a stirring slurry of 4 (1.5 mmol, 1.5 equiv) in diethylether (5 LiA1H  -  10 mL). This mixture was stirred at  room temperature overnight under 2 N ( g). The reaction would then be quenched by the slow addition of water (0.06 mL), then I M NaOH (0.06 mL), and a further aliquot of water (0.18 mL). Following suction filtration and removal of the solvents under reduced  •  113  pressure, column chromatography (hexane: ether, Si0 ) afforded the purified amine 2 products either as single compounds or as a mixture of regioisomers.  N-(2,6-  5 Dimethylphe nyl)-2-phenylethylamine,’ N-(2,6-dimethylphenyl)phenylethyl amine, 16 N (2,6-dimethylphenyl)- 1 6 -(4-methoxyphenyl)ethylamine,’  N-(2,6-dimethylphenyl)- 1,2-  5 methylpheny lethylamine,’ N-benzylhex 2 ylamine, and N-benzyl- 1 7 -methylpentylamine’ are known compounds. methoxyphenyl)ethylamine  Full characterization data for N-(2,6-dimethylphenyl)-2-(4and  N-(2,6-dimethylphenyl)- 1 -methylpentylamine  is  provided below.  N-(2,6-Dimethylphenyl)-2-(4-methoxyphenyl)ethylamine.  ‘H NMR (CDC1 , 400 3  MHz): ö 2.25 (6H, s, 3 Ar-Cl-I ) , 2.92 (2H, t, J= 6.9 Hz, 2 pMeOPh-CH ) , 3.16 (1H, br s, -CH 2 NH-Ar), 3.33 (2H, J = 6.9 Hz, 2 ArNH-CH ) , 3.88 (3H, s, 3 Ar-O-CH ) , 6.88  —  7.26  (7H, m, Ar-H); ‘ C NMR (CDC1 3 , 75 MHz): 618.7, 36.3, 49.8, 55.5, 56.4, 114.2, 3 121.9, 129.0, 129.3, 130.0, 131.7, 132.8, 146.2, 158.5; HRMS Calcd for H N0 1 C 2 7 1 {M+J: 255.16231; Found: 255.16226.  N-(2,6-Dimethylphenyl)-1-methylpentylamine.  H 1  NMR  , 3 (CDC1  300  MHz):  60.91 (3H, t, J= 6.9 Hz, ) 3 CH 2 CH , 1.05 (3H, d, J= 6.3 Hz, ) 3 ArNH-CH-C , H 1.29 —  1.57 (6H, m, ) ArNH-CH-(C 3 ) 2 CH , H 2.26 (6H, s, 3 Ar-CH ) ; 13 C NMR (CDC1 , 75 3  MHz): 6 15.5, 20.5, 22.8, 24.3, 30.1, 39.6, 53.9, 122.5, 130.2, 130.3, 146.7; HRMS Calcd for N 23 [M+j: 205.18305; Found: 205.18315. H 4 C,  114  General procedure for the NMR-tube scale intermolecular akyne hydroamination  reactions. All NMR-tube scale reactions were prepared in an N -fihled glove box. A 3. 2 Young NMR tube was charged with the internal standard (1 ,3,5-trimethoxybenzene) (0.17 mmol, 0.33 equiv), the precatalyst (0.025 mmol, 0.05 equiv), the alkyne (0.5 mmol, 1.0 equiv) and the primary amine (0.6 mmol, 1.2 equiv) and dissolved in either d 6 benzene (-.1 mL) or d -toluene (1 mL). The tube was sealed, heated to, and maintained 8 at 65 °C or 110 °C for the stated duration of time. The conversion and yield were determined by comparing the integration of the internal standard with a well resolved signal for the imine product.  Procedure for the NMR-tube scale intramolecular hydroamination of 2,2-diphenyl-  4-pentenylamine. All NMR-tube scale reactions were prepared in an 2 -N filled glove box. A J. Young NMR tube was charged with the precatalyst (0.025 mmol), and 2,2diphenyl-4-pentenylamine (0.5 mmol) dissolved in 8 -d toluene (—4 mE). Where yields were determined 1 ,3,5-trimethoxybenzene (0.5 mmol) was also added as an internal standard.  The tube was then sealed, heated to, and maintained at, the appropriate  temperature for the stated duration of time. Yields were determined by comparing the integration of the internal standard with a well resolved signal for the heterocyclic product.  Conversions were determined by comparing well resolved signals for the  e 7 substrate and product. Procedure for the intramolecular hydroamination of 2,2-diphenyl-4-pentenylamine and isolation of 2-methyl-4,4--diphenylpyrrolidine. All reactions were prepared in an  -N 2 filled glovebox. A small Schlenk tube equipped with a magnetic stir bar was charged  115  with the catalyst (0.025 mmol) and 2,2-diphenyl-4-pentenylamine (0.5 mmol) dissolved in toluene  (  1 mL).  The Schienk tube was then sealed, heated to the appropriate  temperature, and stirred for the stated duration of time.  After cooling to room  temperature, “wet” CH C1 (-1 mE) would be added and the solution was stirred for -40 2 mm. Then, following concentration under reduced pressure, the crude product was directly subjected to flash column chromatography (ether, Si0 ) to afford 2-methyl-4,42 7 diphenylpyrr e olidine as a colorless oil.  2,2-Diphenylpentylamine compound  3•3•13  Prepared using modified literature  3 with full characterization data presented here. ‘H NMR (CDC1 procedures,’ , 300 MHz): 3 0.85  —  0.90 (5H, m, , 3 2 CH CH ) -NH 2 CH , 1.02  —  1.04 (2H, m, ) 3 CH 2 CH , 2.05  2.10 (2H, m, ) C Ph 2 CH -CH , 3.32 (2H, s, ) C Ph 2 NH -CH , 7.15 C NMR (CDC1 3 ‘ , 75 MHz): 3  —  —  7.30 (1OH, m, Ar-B);  14.75, 17.39, 38.94, 49.11, 51.89, 125.85, 127.94, 128.24,  146.71; MS (El): m/z 209 ) NH 2 (M-CH ; Anal. Calcd. for C, N: 2 H 7 1 C, 85.30; H, 8.84; N, 5.85. Found: C, 85.08; H, 8.93; N, 6.05.  / NH  0  FXXZ? N-(2,6-Diisopropylphenyl)-2-(N-2,2-diphenylpentylamino)-3,4,5,6-tetrafluorobenzamide compound 3.4. To a round bottom flask equipped with a magnetic stir bar 116  was added toluene (—10 mL), 2,2-diphenylpentylamine (0.125 g, 0.52 mmol, 1.0 equiv.), N-2,6-diisopropyl(phenyl)perflourophenylamide (0.187 g, 0.50 mmol, 1.0 equiv.), and triethylamine (0.22 mL, 1.6 mmol, 3.0 equiv.). The reaction mixture was heated to reflux for 16 h and then allowed to cool to room temperature. The crude reaction mixture was diluted with ether (250 mL), washed with 1 M NaOH, water, and brine.  Following  drying of the organic phase over 4 SO and removal of solvents under reduced pressure, 2 Na the crude material was subjected to column chromatography (36:1 hexanes: ether, Si0 ) 2 to provide 3.4 as a colorless foam. One should note that the signals in the ‘ C NMR 3 spectrum for the carbons of the aromatic ring bearing the fluorine atoms were obscured due to extensive coupling to fluorine. Yield: 68%. 1 H NMR (CDC1 , 400 MHz): 3 (3H, t, J  =  7.2 Hz, ) 2 3 CH CH , 1.01  Hz, 3 CH-(CH ) 2 ) , 2.18 4.23 (2H, d, J  =  —  —  0.87  1.09 (2H, m, ) 3 CH 2 CH , 1.24 (12H, d, J= 6.8  2.23 (2H, m, ) C Ph 2 CH -CH , 3.08  2.8 Hz, C 2 Ph NH), -CH 7.13  —  —  3.15 (2H, m, 3 CH-(CH ) 2 ) ,  7.60 (13H, m, Ar-I]), 7.75 (1H, br s,  NH); 13 C NMR (CDC1 , 75 MHz): 6 14.57, 17.33, 23.62, 28.79, 38.77, 50.51, 50.53, 3 52.33, 52.46, 101.49, 123.48, 126.06, 127.90, 127.95, 128.65, 130.43, 137.67, 146.09, 146.197, 163.60; 19 F NMR (CDC1 , 400 MHz): 6 -140.8 (iF), -152.3 (iF), -155.3 (iF), 3  -  175.0 (IF); MS (ESI): m/z 589 (M-H); Anal. Calcd. for. 4 F C 3 H 0 2 N 6 8 : C, 73.20; H, 6.48; N, 4.74. Found: C, 73.40; H, 6.38; N, 4.70.  117  /\  N-(2,6-Dilsopropylphenyl)-2-(N-benzylamino)-3,4,5,6-tetrafluorobenzamide compound 3.5.  To a round bottomed flask equipped with a magnetic stir bar was  added toluene (--‘10 mL), benzylamine (0.070 mL, 0.64 mmol, 1.2 diisopropyl(phenyl)perflourophenylamide  (0.200g,  0.5Ommol,  1.0  equiv.), N-2,6equiv.),  and  triethylamine (0.30 mL, 2.2 mmol, 4.0 equiv.). The reaction mixture was heated to reflux for 24 h and then allowed to cool to room temperature.  The crude reaction  mixture was diluted with CH CI (150 mL), washed with 1 M NaOH, water, and brine. 2 Following drying of the organic phase over Na 4 S 2 O and removal of solvents under reduced pressure, the crude material was subjected to column chromatography (16:1 hexanes: ether, Si0 ) to provide 3.5 as a white amorphous solid. One should note that 2 the signals in the ‘ C NMR spectrum for the carbons of the aromatic ring bearing the 3 fluorine atoms were obscured due to extensive coupling to fluorine. Yield: 94%. ‘H NMR (CDC1 , 300 MHz): 61.25 (12H, d, J 3  =  6.9 Hz, ) 3 CH-(C ) 2 , H 3.10  septet, J 6.9 Hz ) 3 CH-(C ) 2 , H 4.58 (2H, d, J= 3.6 Hz, 2 Ph-C NH) H , 7.25 m, Ar-fl), 7.6 (2H, br s, ArNHC=O, A 2 ArNHC r); H  —  —  3.17 (2H, 7.37 (8H,  C NMR (CDC1 3 ‘ , 75 3  MHz): 623.75, 29.09, 49.97, 50.13, 123.89, 127.58, 127.67, 128.79, 129.20, 130.24, 139.30, 146.35, 164.12; ‘ F NMR (CDC1 9 , 282 MHz): 6 -140.8 (iF), -151.8 (IF), 3  -  155.7 (iF), -173.1 (iF); MS (El): m/z 458 (M-H); Anal. Calcd. for. 4 F C 2 H O 2 N 6 : C, 68.11; H, 5.72; N, 6.11. Found: C, 67.95; H, 5.92; N, 6.21. 118  +  NH  N-((1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl)-benzamide proligand 3.7 and N ((1R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-benzantide proligand 3.2. To a small  round bottomed flask containing a magnetic stir bar was added: EtOH (3OmL), NH O 2 HHC1 (2.llg, 30.4 mmol), pyridine (2.5OmL, 30.9 mmol), and (-)-menthone (3.5OmL, 20.3 mmol). A reflux condenser was affixed and the mixture was heated to reflux for —‘40h, then allowed to cool to ambient temperature. Following removal of the EtOH under reduced pressure, the crude reaction mixture was dissolved in 2 Et (300mL), 0 washed with water (3X50 mL) followed by sat. aqueous NaCI (1X50 mL), dried over 4 S 2 Na , O gravity filtered, and then subjected to rotary evaporation to remove the 2 Et 0 . The crude oxime mixture was then dissolved in THF (100 mL), transferred to a round bottomed flask containing a stir bar and cooled to -‘0°C using an ice-water bath. LiA1H 4 (1.3 g, 34.3 mmol) was carefully added to the solution portion wise as it was stirred and maintained at -0°C. A reflux condenser was affixed, and the slurry was heated to reflux for 40h and then cooled to -0°C using an icewater bath. The reaction was then quenched by the slow, carefull addition of water (1.5 mE), aqueous 1M NaOH (1.5 mL), Et 0 (100 2 mE), and then another aliquot of water (4.5 mL). After allowing the resulting suspension to stir for a further 0.5h at ambient temperature, it was subjected to vacuum filtration and the filtrate was dried over MgSO . (Although not carried out here, it is recommended for 4 future reference that this reaction be worked up by extracting the HC1 salts of the amine products with water followed by neutralization and back extraction with ether) Following  119  removal of the solvents under reduced pressure, the crude reaction mixture was transferred to an oven dried, septum sealed, round bottomed flask containing a stir bar which was maintained under N 2 (g). Dry CH C1 (60 mL) was then added and the flask 2 was cooled to —0 °C using an icewater bath. After the addition of NEt 3 (8.0 mL, 57 mmol), and BzC1 (2.60 mL, 22.6 mmol) the reaction was stirred at ambient temperature for 2O h and then worked up by diluting with CH CI (240 mL), washing with 1 M HC1 2 (3X50 mL), 1M NaOH (3X50 mL), water (1X50 mL), and finally sat. aqueous NaC1 (1X50 mL). removed  The organic phase was then dried over MgSO , and the solvents were 4 under  reduced  pressure.  Colunm  chromatography  (18:1:1  hexane C 2 : MeO 1 s:CH H, Si0 ) afforded 2 g of a mixture of N-((1R,2S,5R)-2-isopropyl2 5-methylcyclohexyl)-benzamide and N-((1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)benzamide (along with a small amount of unidentified impurities) in a ratio of approximately 3:1 in favor of the (IR,2S,5R)-isomer. Repeated recrystallization from 0 afforded N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide as a pure 2 Et compound. Crystalls of the 1R,2S,5R-isomer suitable for x-ray chrystallography were obtained from 2 Et 0 . Repeated recrystallization from hexanes/CH C1 (4: 1) afforded N2 ((1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide as a pure compound. Crystalls of the 1R,2R,5R-isomer suitable for x-ray chrystallography were obtained from C1 (—4:1). 2 hexanes/CH  ‘H NMR (N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-  benzamide) (CDCI , 400 MHz): 6 0.8 3 m), 1.7 7.35  —  —  —  1.1 (9H, m), 1.2  —  1.4 (1H, m), 1.4  1.9 (1H, m), 4.3 —4.4 (1H, m, -CH(NHBz)-), 6.1  7.50 (3H, m, Ar-fl), 7.70  —  —  —  1.7 (7H,  6.2 (1H, br d, -NHBz),  7.80 (2H, m, Ar-If); 13 C NMR (N-((1R,2S,5R)-2-  isopropyl-5-methylcyclohexyl)-benzamide) (CDC1 , 101 MHz): 621.65, 21.75, 22.28, 3  120  24.02, 27.60, 29.28, 30.44, 36.60, 44.35, 49.73, 126.67, 128.63, 131.22, 135.25, 166.34; MS (N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide) (El): m/z 259 (M ); Anal. Calcd for N0 15 C 2 H 9 (N-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyl)benzamide): C, 78.72; H, 9.71; N, 5.40. Found: C, 79.10; H, 9.76; N, 5.42. ‘H NMR (N-((1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide) (CDC1 , 400 MHz): 6 0.8 3 —  0.9 (9H, m), 1.1  m), 2.0  —  —  1.2 (2H, m), 1.4— 1.6 (1H, m), 1.6  2.1 (1H, m), 3.9  NHBz), 7.35  —  —  —  1.8 (2H, m), 1.9 —2.0 (1H,  4.1 (1H, m, -CH(NHBz)-), 5.75  7.50 (3H, m, Ar-I]),  7.70  —  7.80 (2H, m  ,  —  5.85 (1H, hr d,  -  Ar-H); 13 C NMR (N  ((1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide) (CDC1 , 101 MHz): 6 16.30, 3 21.22, 22.16, 23.95, 27.06, 31.93, 34.58, 43.20, 48.43, 50.42, 126.83, 128.53, 131.23,  135.17,  166.69; MS (N-((1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-  benzamide) (El): m/z 259 (M ); Anal. Calcd for N0 15 C 2 H 9 (N-((1R,2R,5R)-2-isopropyl5-methylcyclohexyl)-benzamide): C, 78.72; H, 9.71; N, 5.40. Found: C, 78.64; H, 10.00; N, 5.62.  ) 2 Zr(NMe  Hcc Bis(N-((1R,2S,5R)-2-isopropyl-5-methylcyclo-hexyl)benzamidate)  zirconium  bis(dimethylamido) complex 3.2. All metal complex synthesis reactions were carried out in nitrogen filled glovebox. To a small screw capped vial containing a magnetic stir bar was added N-((1 R,2S,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide (0.471 g, 1.8 mmol), benzene (2 mL), and tetrakis(dimethylamido)zirconium (0.243 g, 0.9 mmol  121  dissolved in 1 mL of benzene). The mixture was then stirred at room temperature for —P24 h. The solvents were then removed under reduced pressure to afford 0.610 g (97%) of  the  analytically  pure  bis(N-(( 1 R,2S,5R)-2-isopropyl-5-methylcyclo-  hexyl)benzamidate) zirconium bis(dimethylamido) complex as a pale yellow foam. The NMR specta of this compound have been provided, but are very complicex and have not been assigned due to the possible presence of multiple isomers in solution. Attempts to recrystallize this compound were not successful. It was not possible to obtain usefull information from MS (El) spectal data. Elemental analysis was consistent with the desired compound. Anal. Calcd for 4 N 3 C 6 H Z 2 O 8 0 r: C, 65.56; H, 8.69; N, 8.05. Found: C, 65.90; H, 8.77; N, 7.73.  ) 2 Ti(NEt  Bis(N-((1R,2S,5R)-2-isopropyl-5-methylcyclo-hexyl)benzamidate)  titanium  bis(dimethylamido) complex 3.3. All metal complex synthesis reactions were carried  out in nitrogen filled glovebox. To a small screw capped vial containing a magnetic stir bar was added N-((1 R,2R,5R)-2-isopropyl-5-methylcyclohexyl)-benzamide (0.204g, 0.8 mmol), benzene (3 mL), and tetrakis(diethylamido)titanium (0.132 g, 0.4 mmol). The mixture was then stirred at room temperature for 24 h. The solvents were then removed under reduced pressure to afford 0.280 g (>98%) of the crude bis(N-((lR,2S,5R)-2isopropyl-5-methylcyclo-hexyl)benzamidate) titanium bis(diethylamido) complex as a red oil. The ‘H and 3 ‘ C -APT NMR specta of this compound have been provided. Two  122  of the aromatic C-H peaks could not be assigned in the 3 ‘ C -NMR spectrum as they were obscured by the C D solvent signal. Attempts to recrystallize this compound were not 6 successful. ‘H NMR (CDC1 , 400 MHz): 60.8 3 3 (-N) 2 ) CH (CH , 4.6  —  —  2.4 (26H, m), 3.5  4.7 (lH, m, -CH(NHBz)-), 7.2  —  —  4.0 (8H, m, 3 L Z r-  7.4 (4H, m, Ar-fl), 8.3  —  8.5 (2H, m, Ar-fl); ‘ C NMR (CDC1 3 , 101 MHz): 6 16.30, 21.22, 22.16, 23.95, 3 27.06, 31.93, 34.58, 43.20, 48.43, 50.42, 126.83, 128.53, 131.23, 135.17, 166.69; MS (El): m/z 2 635(M-HNEt ), 564 (M-2 X NEt ), 450 (M-1 X amide ligand). 2  Procedure for the NMR-tube scale enantioselective intramolecular hydroamination of 2,2-diphenyl-4-pentenylamine and enantiomeric excess determinations. All NMR tube scale reactions were prepared in an 2 -N filled glove box. A small vial would be charged with the precatalyst (0.05 mmol), and 2,2-diphenyl-4-pentenylamine (0.5 mmol) dissolved in 8 -d toluene (-4 mL). The reaction mixture would then be transferred to a J. Young NMR tube which would be sealed, heated to, and maintained at, the appropriate temperature for the stated duration of time. Where isolated yields have been given, the crude reaction mixture would be concentrated under reduced pressure, and then directly subjected to column chromatography (10:1 : C 2 CH MeOH 1, Si0 ) to afford the known 22 methyl-4,4-diphenylpyrrolidine as a colorless oil.  Conversions were determined by  comparing well resolved signals for the substrate and product. Enantiomeric excesses are based on ‘H NMR spectroscopy of the product following derivatization with (+)-(S)-x  123  methoxy-a-trifluoromethylphenylacetyl  chloride  as  previously described  in the  a 7 literature.  124  3.5 References  (1)  Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. 0.; Schafer, L. L. Chem. Commun. 2003, 2462.  (2)  Thang, Z.; Schafer, L. L. Org. Lett. 2003, 4733.  (3)  Thomson, R.K.; Zahariev, F.E.; Zhang, Z.; Patrick, B.O.; Wang, Y.A.; Schafer, L.L. Inorg. Chem. 2005, 44, 8680.  (4)  Odom, A. L. Dalton Trans. 2005, 225 and the references therein.  (5)  Tillack, A.; Castro, I. G.; Hartung, C. G.; Belier, M. Angew. Chem.  mt. Ed. 2002,  41, 2541. (6)  Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organometallics, 2001, 20, 3967.  (7)  (a) Wood, M. C.; Leitch, D. C; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem.,  mt. Ed.  2007, 46, 354. (b) Muller, C.; Loos, C.; Schulenburg, N.; Doye S.  Eur. I Org. Chem. 2006, 2499. (c) Watson, D. A.; Chiu, M.; Bergman, R. G. Organometallics 2006, 25, 4731. (d) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006, 25, 4069-4071. (e) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959. (f) Kim, H.; Lee, P. H.; Livinghouse, T. Chem. Commun. 2005, 41, 5205. (8)  Kim, Y. K.; Livinghouse, T.; Bercaw, J. E. Tetrahedron Lett. 2001, 42, 2933.  (9)  Li, C. Y. Masters Thesis, UBC, 2003. 186.  (10) (a) Chambers, R. D. Fluorine in Organic Chemistry; John Wiley & Sons, Inc.: New York, 1973. (b) Baron, A.; Sandford, G.; Slater, R.; Yufit, D. S.; Howard, J. A. K.; Vong, A. J. Org. Chem. 2005, 70, 9377 and the references therein.  125  (11) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006, 25, 40694071. (12) Gott, A.L.; Clarke, A.J.; Clarkson, G.J.; Scott, P. Chem. Commun. 2008, 1422. (13) Kondo, T.; Okada, T.; Mitsudo, T. J. Am. Chem. Soc. 2002, 124, 186. (14) Huang, B. H.; Yu, T. L.; Huang, Y. L.; Ko, B. T.; Lin, C. C. Inorg. Chem. 2002, 41, 2987. (15) Esteruelas, M. A.; Lopez, A. M.; Concepcion, M. A.; Onate, E. Organometallics 2005, 24, 5084. (16) Xiao, D.; Zhang, X. Angew. Chem.,  mt. Ed. 2001, 40, 3425.  (17) Willoughby, C. A.; Buchwalcl, S. L. I Am. Chem. Soc. 1992, 114, 7562.  126  CHAPTER FOUR: GROUP FOUR BASED HYDROAMINATION CATALYSTS INCORPERATING 2-PYRJDONATES AS N,O CHELATING ANCILLIARY LIGANDS  4.1 Introduction  To date, the work carried out in the Schafer group has focused on the use of bis(amidate) bis(amido) complexes of titanium and zirconium as hydroamination precatalysts. In the interest of expanding our N-O chelating ancillary ligand set beyond amidates, 2-pyridone and its derivatives were considered as a basis for further discovery. As proligands, these compounds offer some of the same desirable characteristics that make amides attractive as proligands, such as a modular structure and the availability of numerous derivatives which can be obtained commercially, or synthesized through various routes.’  In addition to this, there are unique electronic and steric properties  associated with 2-pyridones that set them apart from amides and may result in the formation of complexes exhibiting a level of reactivity not seen with the bis(amidate) based systems.  It was anticipated that the synthesis of these complexes could be  achieved efficiently following the same protocol to the one used for the preparation of the bis (amidate) complexes (Scheme 4.1).  6 R  0.5 eq M(NR , 4 ) 2 PhH RT 24h  M=Ti, Zr bis(2-pyridonate) bis(amido) complex  Scheme 4.1. Proposed synthetic route to the bis(2-pyridonate) complexes. A version of this chapter will be submitted for publication. Bexrud, J.A.; Schafer, L.L. Group Four Based Hydroamination Catalysts Incorporating 2-Pyridonates as N,O Chelating Ancillary Ligands.  127  As was mentioned in chapter one, 2-pyridonates were selected as a new class of N,O chelating ligand, primarily as an alternative means of increasing the Lewis acidity of the metal center for enhanced hydroamination catalysis. It was anticipated that these ligands would be more electron withdrawing than their amidate counterparts based on the respective pKa values for the neutral proligands (-lactam pKa  =  26.6 (in DMSO), N  phenylbenzamide pKa = 18.8, 2-pyridone pKa = 17.0 (in DMSO)). 2 Investigations into the intramolecular hydroamination of aminoalkenes have shown that the bis(amidate) systems developed to affect this transformation so far, exhibit only moderate reactivity, resulting in inordinately long reaction times and requiring somewhat 3. In addition, these catalysts have been found to temperatures extreme reaction a suffer from a severely limited substrate scope. One possible explanation for this is that the large steric bulk associated with the amidate ligands, though advantageous for minimizing the in situ formation of catalytically inactive imido 3 dimers, may be a impeding these intramolecular aminoalkene reactions by reducing accessibility to the reactive metal center. It was hoped that the 2-pyridonate ligand framework would address this issue by making it possible to increase accessibility to the reactive site while maintaining a sufficient level of steric bulk to mitigate the formation of catalytically inactive dimer species. This supposition is based on the fact that substituents located in the R 6 position of 2-pyridonates are more removed from the metal center than the N-substituents of amidates (Scheme 4.2). Therefore, the desirable steric properties of 2-pyridonates provide additional imputes for the study of titanium and zirconium hydroamination catalysts which incorporate them as ancillary ligands.  128  Scheme 4.2. Improved accessibility to the metal center using 3,6-substituted 2-pyridones as proligands.  There are also some fundamental coordination chemistry questions that this ligand set addresses. Firstly, although there are numerous examples of late transition metal complexes employing this type of ligand,” 5 only a few 2-pyridone complexes based on metals from groups three, four, or five have been reported. 6 Among those reported are the dinuclear vanadium complex , 3 C 0 2 [V ( 4 Hmhp 1 ) where Hmhp  =  6-methyl-2-  pyridone), the monopentamethylcyclopentadienyl zirconium (IV) complex [(95 6 M C ) 5 2 1 3 ) 8 H 7 ” O,N Zr -ON (n , e C and the monopentamethylcyclopentadienyl titanium (IV) complex  Therefore, group four complexes  incorporating 2-pyridone derivatives as ligands are rare and it was not known whether stable, isolable bis(2-pyridonate) titanium/zirconium bis(amido) complexes could actually be prepared and characterized as outlined above. Additionally, although there are many examples in the literature where 2-pyridones have been used to bridge two metals, comparatively few complexes have been reported where this type of ligand has been used as a chelate for one metal center. lb,6b,7 Therefore, the question of whether a group four metal based bis(2-pyridonate) bis(amido) complex would exist as discrete monomeric or polymeric species was of primary interest to us as this may impact resultant reactivity trends. Another feature of the 2-pyridone based ligand set derives from the fact 2-pyridone itself can exist in two tautomeric forms (Scheme 4.3), either the lactam (2-pyridone) or 129  the lactim (2-hydroxypyridine). This phenomenon has been well studied over the past decades.’ b,8 In solution it has been found that the relative abundance of each tautomer depends on conditions such as concentration, temperature, and the polarity of the solvent. Polar solvents strongly favor the 2-pyridone form, while in solutions employing non polar solvents both the 2-pyridone and 2-hydroxypyridine tautomers can exist in an equilibrium favoring the 2-hydroxypyridine 9 form. ” ° Additionally, intermolecular hydrogen bonding between the monomeric species can lead to the formation of dimers. 8 In the solid state and the gas phase, 2-pyridone is thought to be the prevailing 12 It is also known that substituents can also affect this equilibrium, with tautomer.” compounds having electron withdrawing substituents in the 6-position (adjacent to the nitrogen), favoring the pyridinol form.” This tautomerization leads to the basic question of how varied 2-pyridonate ligands will bind the metal center in the bis(2-pyridonate) bis(amido) Ti/Zr complexes.  0  OH  qNH  Scheme 4.3. The tautomeric equilibrium between 2-pyridone and 2-hydroxypyridine. Scheme 4.4 depicts the three distinct binding modes that the 2-pyridonate ligand could adopt in a monometallic complex. th At one extreme, ligation could occur exclusively through the oxygen as a phenoxide like ligand, and at the other extreme the 2-pyridone could bond to the metal solely through the nitrogen in an N bound mode. A number of complexes have been structurally characterized and reported in the literature  130  to date incorporating the anionic form of these ligands that adopt the N binding Ligation of 2-pyridonates through the oxygen in as a phenoxide appears to be quite rare, with the only example being the previously mentioned [(ri 5 M ) TiMe( C e ii’ ] ) 2 N 7 H 8 O-0C  -  complex. The other possibility lies intermediate between these two  extremes, where like the group 4 bis(amidate) complexes we have characterized so far,’ 4 a bidentate  ic2  N,O 2-pyridonate binding mode could predominate. Again, this type of  ligand interaction in monometallic species is relatively rare, with the reported examples that we could find being the ) mer-(P 0 3 s(H Me )( 7 ” the Ru(p 5 -O,N-ONC complex, 2 i ) 8 H cymene)( H 7 2 i ) 8 O,N-O Cl NC  5 complex,’  the  7 [ 1 M ) 5 2 j 3 ) 8 H O,N Zr C ( -ON (q r e C  ” H 6 complex, 7 [C M 2 O,N g) o(r -ON p ] C6 [PF ,16 and the Ir(COD)( 7 ] -O,N-O 2 1 ) 8 H C NC l ” 7 complex.  or 0  or  N—m]  ic N 2 ,O  N  Scheme 4.4. Possible binding modes adopted by the 2-pyridonate ligand. Information with respect to the charge localization on the deprotonated anionic form of 2-pyridone may provide additional information helpful in predicting the binding mode that the bis(2-pyridone) titaniumlzirconium bis(amido) complexes might adopt. It has been suggested by Spinner and White,’ 7 based on the analysis of the sodium salt of 2pyridone using infrared, ultraviolet and Raman spectroscopies, that the anion of 2pyridone exists as a pyridoxide type structure with the negative charge located mainly on the oxygen atom. This result seems to support either the 0 bound or  1(2  N,0 binding  131  modes, with the latter being comprised of largely an aryloxide covalent 0 bonding in combination with a dative N  —  —  M type  M type interaction.  Structural information for the two known group 4 complexes bearing these types of ligands suggests that either  2 K  N,O or 0 coordination could be expected in the bis(2-  pyridonato) bis(amido) complexes. The monocyclopentadienyl zirconium (IV) complex 7 [ M ) 5 2 j 3 ) 8 H O,N Zr C ( -ON (r r e C (Figure 4.1) was assigned the  ic2  N,O binding motif  with dynamic processes occurring in solution. This assignment was based on NMR spectroscopic data and the crystal structure for a related compound 2 ([(‘ M ) 5 Zr( C e q r 61 O,N } 3 ) 8 H 7 C 2 ’ ). -ON  —  I,,,  I  NC5CN  Figure 4.1. Coordination geometries of the 7 [( M ) 5 2 1 3 ) 8 H 0,N Zr C -ON ri (q e C complex and the 8 { M ) 5 1 ) 2 N 7 H TiM(i C e(ri’ -0-O e 1 C complex.. An 0 coordination mode was proposed for the monocyclopentadienyl titanium (IV) complex H 8 [( M ) 5 ] ) 2 N 7 TiMe(ri’ C ri -O-0 e C (Figure 4.1) which was based on NMR data. Notably, these complexes incorporate a bulky cyclopentadienyl a spectroscopic 6 type ligand which imposes a substantially different coordination environment than a dialkylamido ligand both sterically and electronically, therefore the nature of the ligand metal interaction occurring in the bis(2-pyridonato) bis(amido) complexes may differ. The basic question of coordination geometry is also of primary concern because from a catalyst development perspective, the amido ligands are ideally situated in adjacent  132  coordination sites, as these represent the active sites during catalys 18 is. Assuming that the bis(2-pyridonate) bis(amido) complexes are indeed monomeric, and that the 2pyridonate ligands bind in a bidentate  ic2  N,O fashion, then there are 5 possible  diasteromeric coordination geometries that these complexes could adopt (Figure 1.2, chapter 1).  It has been found that group four bis(amidate) bis(amido) complexes  preferentially adopt the N-trans C 2 geometry, which positions the two amido ligands in the desired cis arrangement. 4’ In order to be useful as precatalysts the bis(2-pyridonate) bis(amido) complexes, in addition to being monomeric, would also have to adopt this or a similar type of geometry in which the amido ligands are cis to one another. Knowing that substituents can influence the tautomeric equilibrium exhibited by 2pyridone derivatives, one would also expect the coordination chemistry of these ligands as well as any reactivity that the resulting complexes might have to be influenced by substituents on the 2-pyridone ring. To the best of our knowledge, there have been no investigations into this matter. We are therefore very interested in how the effect of substituents in the 3- and 6-position of the 2-pyridone will impact the structure and reactivity of these complexes in hydroamination catalysis.  133  4.2 Results and discussion  4.2.1 Synthesis and characterization of titanium and zirconium complexes incorporating 2-pyridone and 6-tert-butyl-3-phenyl-2-pyridone as proligands  2-Pyridone itself was employed as a proligand in order to provide a benchmark for  comparison with substituted proligands. The 3- and 6-positions of 2-pyridone were then chosen for derivitization because any sterie or electronic influences imposed by substituents in these positions would likely have the greatest impact on complex structure and activity due to their proximal location with respect to the atoms involved in chelation. 6-tert-Butyl-3-phenyl-2-pyridone was selected for these initial investigations primarily because this compound is analogous to N-tert-butyl-benzamide which was used as a proligand in the earliest bis(amidate) bis(amido) complexes, 8 and therefore it 4 ” 3 represents a useful starting point for comparative purposes. While the 2-pyridone proligand is commercially available, the 6-tert-butyl-3-phenylderivative must be prepared. The preparation of 3,6-disubstituted 2-pyridones can be achieved utilizing a modular procedure for the thermal rearrangement of pyrrolidine psuedoureas developed by Overman et al. (Scheme  )1G 45  The pyrrolidine pseudoureas  (which are subsequently converted to the 3,6-disubstituted-2-pyridones) are generated from a propargylic alcohol and 1-cyanopyrrolidine. The propargylic alcohol can easily be made from a terminal alkyne and derivatives of acetaldehyde. The substituents located at the 3 and 6 positions of the 2-pyridone ring are then determined by which acetaldehyde derivative and terminal acetylene (respectively) are used in the initial formation of the  134  propargylic alcohol.  This method affords 6-tert-butyl-3-phenyl-2-pyridone as an  amorphous solid with yields as high as 63%. The proligand is recrystallized and then dried by heating to 80°C under vacuum for at least 3-days prior to use.  1)BuLi 2) 0 6 R  OH  L  H 3)MeOH 1)  6 R  CN  3 R 6 R  2) xes  +  0  Scheme 4.5. Modular synthetic route to the 3,6-disubstituted 2-pyridones. The bis(2-pyridonate) titanium bis(dimethylamido) complex 4.1, as well as the bis(6tert-butyl-3-phenyl-2-pyridonate) titanium bis(dimethylamido) complex 4.2, and the bis(6-tert-butyl-3-phenyl-2-pyridonate) zirconium bis(dimethylamido) complex 4.3 can be prepared in a very simple and high yielding one step procedure according to Scheme 4.6. These reactions are carried out on a small (< ig) scale in a nitrogen filled glove box, and involve simply weighing out the proligand into a small vial equipped with a stir bar,  and then adding benzene. A concentrated solution of the tetrakis(dimethylamido) titanium or zirconium complex in benzene is then added and the mixture is stirred at ambient temperature for 24 hours. Solvent removal en vacuo affords the analytically pure products as either red (titanium) or pale yellow (zirconium) amorphous solids in nearly quantitative yields. Crystals suitable for X-ray crystallography can obtained from saturated solutions of each complex in benzene layered with either pentane or hexane. 135  ° R35H  (°M(NMe2)2  4.1: M=Ti, R =H, R 3 H 6 4.2: M=Ti, 3 R = Ph, R =tBu 6 4.3: M=Zr, R Ph, 6 3 R = tBu  Scheme 4.6. Synthesis of the bis(2-pyridonate) titanium and zirconium bis(amido) complexes 4.1 4.3. —  The zirconium analogue of complex 4.1 cannot be prepared using this protocol. Instead, when 2-pyridone is allowed to react with 2 Zr(NMe in this fashion, an 4 ) amorphous yellow solid consisting of a mixture of oligomers is obtained, as was determined by NMR spectroscopy and X-ray crystallography (Figure 4.3) In the solid state, complexes 4.1, 4.2 and 4.3 exhibit similar structural characteristics (Figures 4.2, 4.4, and 4.5). X-ray analysis of these compounds indicate that they are monomeric, and possess a distorted octahedral geometry about the metal center with the 2-pyridonate ligands adopting a bidentate binding motif. Importantly, these complexes assume an 0-trans C 2 coordination geometry with the dimethylamido ligands positioned cis to one another. Table 4.1 lists some pertinent bond lengths and angles for these three  compounds. The sum of the metallacyclic bond angles in complexes 4.1, 4.2, and 4.3 is 359.9°, 360.00, and 360.0  0  respectively, confirming that the ligand, bound in an  ic2  fashion, is planar. The binding of the 2-pyriclonate oxygen and nitrogen donors to the metal center is asymmetric however, as can be seen by the substantially different Ti O,Ti-N bond lengths. This result verifies that the 2-pyridonate binding motif is best described as  1(2  N,O and is comprised of an aryloxide 0  —  M bonding in combination  136  with a dative N  —  M interaction. The most pronounced asymmetry is present in the  bis(6-tert-butyl-3-phenyl-2-pyridonate) complexes, which is presumably due to steric repulsion between the bulky tert-butyl group of the 2-pyridonato ligand and the remainder of the metal complex.  01  Figure 4.2. Diagram of the bis(2-pyridonate) titanium bis(dimethylamido) complex 4.1 with thermal ellipsoids set at the 50% probability level. Hydrogen atoms have been omitted for clarity.  Figure 4.3. ORTEP depiction of an dimer obtained by the reaction of Zr(NMe 4 ) 2 with 2-pyridone. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity.  137  Figure 4.4. Diagram of the bis(6-tert-butyl-3-phenyl-2-pyridonate) titanium bis(dimethylamido) complex 4.2 with thermal ellipsoids set at the 50% probability level. Hydrogen atoms have been omitted for clarity.  Figure 4.5. Diagram of the bis(6-tert-butyl-3-phenyl-2-pyridonate) zirconium bis(dimethylamido) complex 4.3 with thermal ellipsoids set at the 50% probability level. Hydrogen atoms have been omitted for clarity.  138  Table 4.1. Selected Bond lengths and angles for complexes 4.1, 4.2, and 4.3.  Complex Bond Length (Angstroms)  4.1  4.2  4.3  M-N (amido)  1.880(2)  1.902 (3) 2.019(2)  M-N (2-pyridonato)  2.222 (2)  2.383 (3) 2.432 (2)  M-O  2.010(2)  1.961 (2) 2.091 (1)  Bond Angle (degrees) N(amido)-M-N(2-pyridonato) 155.69(7) 155.4(1) 148.06(6) O-M-O 145.90(6) 146.94(1)157.34(5) O-M-N(2-pyridonato) 61.97 (5) 60.8 (1) 58.35 (5)  The ‘H and 3 ‘ C -NMR spectra for compounds 4.1, 4.2, and 4.3 are consistent with their respective solid state structures. Results of NOE spectroscopic investigations, along with variable temperature NMR experiments suggest that these complexes have a discrete geometry, with the 2-pyridonato ligands being bound in an i2 fashion and no observable fluctional behavior. Complex 4.1 exhibits a strong NOE contact between the methyl groups of the dimethylamido ligand and the proton in the 6-position of the pyridonato ligand (Scheme 4.7), while little to no enhancement is observed with the protons in the other three positions of the 2-pyridonate ligand. This supports either the ic2  bonding motif or the N-bound species, as a phenoxide type complex would not  display an NOE signal corresponding to the H adjacent to N. Similar experiments carried out with complexes 4.2 and 4.3 show that the methyl groups of the amido ligand and the tert-butyl group of the 6-tert-butyl-3-phenyl-2-pyridonato ligand are located in close proximity to one another, as they would be in an  c2  bound or N-bound arrangement  (Scheme 4.7). In addition, an NOE contact was also found between the tert-butyl  group  139  and the phenyl group of the two adjacent 6-tert-butyl-3-phenyl-2-pyridonato ligands (Scheme 4.7), which are positioned approximately side by side, but in opposing orientations to one another (see Figures 4.4 and 4.5). Again, the close proximity of these groups on adjacent ligands supports the assignment of a highly organized  J(2  N,O,  geometry. Also, the addition of strong neutral donors, such as trimethyiphosphine oxide and triethylamine, to a solution of complex 4.1 do not appear to influence the binding modes of the 2-pyridone ligand as observed by NMR spectroscopy.  H  NMe 2  2 \NMe  /TI  H  complex 4.1 M M  = =  Ti: complex 4.2 Zr: complex 4.3  Scheme 4.7. NOE contacts observed for complexes 4.1, 4.2, and 4.3.  140  4.2.2 Intramolecular alkene hydroamination activity: substrate scope investigation  Complexes 4.1, 4.2, and 4.3 were tested for aminoalkene hydroamination activity using the standard test substrate 2,2-diphenyl-4-pentenylamine (Scheme 4.8). This aminoalkene, geminally disubstituted in the 2 position, is typically chosen as a primary screening substrate to take advantage of the gem-disubstituent effect,’ 9 which has been observed to have a significant effect on the rate of reaction using these and similar precatalysts. 20 The titanium complexes 4.1 and 4.2 are completely unreactive towards ’ 4 this substrate under these conditions. The zirconium complex 4.3 however, is capable of efficiently catalyzing this transformation, with the aminoalkene undergoing complete conversion to the N-heterocyclic product 2-methyl-4,4-diphenylpyrrolidine within five hours. The amorphous solid consisting of a mixture of oligomers that was obtained from the reaction of ) 2 Z(NM 4 e with two equivalents of 2-pyridone also affects this transformation with a yield of about 15 % after 24 hours at 110 °C. The disparity in catalytic activity between titanium complex 4.2 and zirconium complex 4.3 is consistent with what has been observed previously with bis(amidate) ’ and ’ 41 2 bis(pyrimidin oxide) systems when comparing aminoalkene hydroamination activity of analogous titanium and zirconium complexes.  141  5mol%  Ph  compl:x 110°C, 24h  H  complex 4.1: no rxn complex 4.2: no rxn complex 4.3: >98%  Scheme 4.8. Intramolecular hydroamination of 2,2-diphenyl-4-pentenylamine. Results of a cyclohydroamination substrate scope investigation using complex 4.3 as the precatalyst are listed in Table 4.2.  Yields obtained using the bis(N-2,6-  diisopropylphenyl-Q,henyl)-amidate) zirconium bis(dimethylamido) complex, which is one of the most effective bis(amidate) cyclohydroamination precatalysts reported to ” have also been included for comparison. 4 date, Overall, complex 43 exhibits an acceptable level of reactivity that is comparable to the zirconium bis(amidate) complex. Entry 6 however, illuminates an important difference. While no cyclization of 2,2-diphenyl-4-hexenylamine is observed using the bis(amidate) complex; this substrate, bearing an unactivated internal C=C bond, does indeed undergo cyclohydroamination in the presence of complex 4.3. This is an important result because the difference in reactivity between these two complexes towards this substrate may be a direct consequence of the more accessible metal center afforded by the 2-pyridone ligand being more accommodating to alkenes bearing non-activating alkyl substituents.  142  Table 4.2. Substrate scope using complex 4.3 and the bis(N-2,6-diisopropylphenyl(phenyl)-amidate) zirconium bis(dimethylamido) complex. H N  lOmoI% COeX  R.)4NH2  RPh,Me n = 2,3  entry  1  aminoalkene  Ph  Ph 2 NH  2  2 . 4 NH  3  Ph Ph -.)4,NH 2  4  Ph Ph 2 Ph-)<N H  6 a Yield determined by NMR  Ph  time (h)  temp (°C)  complex 43a  bis(amidate) zirconium complexa  5  110  >98%  >98%  96  110  87%  87%  5  110  >98%  >98%  96  110  43%  96  110  35%  72%  168  145  59%  NR  spectroscopy using 1 ,3,5-trimethoxybenzene as an internal  standard. b After 192 hours at 110°C.  Entry 5 shows that substrates with substitution ct to the nitrogen (in this case a methyl group) are amenable to cyclization.  The product of this reaction can generate two  possible diastereomers of 2,5-dimethylpyrrolidine, where one isomer has the two methyl groups oriented cis relative to each other, and the other isomer has the two methyl groups in an trans arrangement. A diastereoselectivity of greater than 10:1 in favor of the trans product is obtained using complex 4.3. This selectivity for the trans product is consistent with a preference for the ct-methyl group to be in an equatorial position in the proposed chair like transition state through which this reaction is thought to proceed.  4),20C  143  Taking advantage of the reactivity of complex 4.3 towards unactivated internal alkene bearing aminoalkene substrates, the cyclization of 2-cyclohex-2-enyl-2,2-diphenylethylamine can be carried with moderate yield and very high selectivity for the cis-fused octahydroindole (Equation 4.4).  This reaction demonstrates the potential of this  methodology for the generation of more complex, biologically relevant polycyclic structural motifs.  Ph  1) 20 mol % complex 3  Ph NH  Ph  -d 8 tol, 145°C, 168h 2) TsCI, NEt ,2 3 CI CH 52% isolated yield  Ph (4.1)  (+1-)  4.3 Summary and conclusions  The work in this chapter involved the synthesis and characterization of the first titanium and zirconium bis(2-pyridonate) bis(amido) complexes. Attempts were made to prepare complexes using either 2-pyridone or 6-tert-butyl-3-phenyl-2-pyridone as proligands. It was found that the bis(2-pyridonate) titanium bis(dimethylamido) complex 4.1, along with the bis(6-.tert-butyl-3 -phenyl-2-pyridonate) titanium bis(dimethylamido)  complex  4.2  and  the  bis(6-tert-butyl-3-phenyl-2-pyridonate)  zirconium  bis(dimethylamido) complex 4.3 can all be prepared in very high yield using the simple protocol described in section 4.2.1. The X-ray structures of complexes 4.1, 4.2, and 4.3 reveal that they are all monomeric, and possess a distorted octahedral geometry about the metal center with the 2-pyridonate ligands adopting a bidentate binding motif.  144•  Importantly, these complexes assume an 0-trans C 2 like coordination geometry with the dimethylamido ligands positioned cis to one another. NMR spectroscopic data for these compounds is consistent with their solid state structures. The bis(2-pyridonate) zirconium bis(dimethylamido) complex could not be prepared as a discrete monomeric compound using this method, and clearly demonstrates that there is a minimum level of steric bulk that these ligands must possess in order to form monomeric complexes. The activity of these complexes towards aminoalkenes was investigated and both titanium complexes 4.1 and 4.2 were found to be completely unreactive, while the zirconium complex 4.3 was found to be an efficient catalyst for the cyclohydroamination reaction.  Further substrate screening experiments demonstrated that complex 4.3 can  effect the cyclization of more challenging aminoalkenes bearing unactivated internal C=C bonds;  substrates  which had previously been inert towards  intramolecular  hydroamination using the most active bis(amidate) zirconium bis(amido) complex. This result is consistent with the greater accessibility to the metal center afforded by the 6-tertbutyl-3-phenyl-2-pyridonate ligand being more accommodating to substituents on the olefin.  4.4 Experimental  General. ‘H and ‘ C NMR spectra were recorded on either a Bruker 300 M}Iz or 400 3 MHz Avance spectrometer at ambient temperature and chemical shifts are given relativ e to residual solvent. GCMS spectra were recorded on an Agilent series 6890 GC system with a 5973 Mass Selective Detector. Single crystal X-ray structure determinations, MS,  145  and elemental analyses determinations were performed at the Department of Chemistry, University of British Columbia. All reactions were carried out using standard Schienk line and glovebox techniques under an atmosphere of nitrogen, unless described otherwise. ) 2 Ti(NM 4 e and ) 2 Zr(NM 4 e were purchased from Strem and used as received. -d 8 Toluene was degassed and dried over molecular sieves. Amino alkenes 2,2-diphenyl2 4-pent enylam 2 2 ine, 2,2-diphenyl -5-hexenylam 3 ine, 2 ’ 2,2,5-t riphenyl-4-pe 3 4 ntenylamine, 2 2,2-diphenyl -4-hexenylam 3 ine,  2,2-dimethyl-4-pentenyl amine, 24  and  1 -methyl-4.-  25 penten ylamine were prepared as described in the literature with some modification from commercially available starting materials purchased from Aldrich. Amino alkene substrates were dried over CaH or Heterocyclic  products  2 diphen ylpipe 6 ridine, 20 pyrroli c dine,  4A  molecular sieves and degassed prior to use.  2 2-methyl-4,4 -diphenylpyr 2 rolidine,  2 2-methyl-4,4 -dimethylpyr 4 rolidine,  2,5-dimethyl7 2 pyrrolidine  and  (+I-)-(S,S)-3,  2-methyl-5,5-  2-benzyl-4,4-diphenyl3-diphenyl-l -(  p  2 toluenesulfon yl)-octahydro 8 -mdole are known compounds. The 6-tert-butyl-3-phenyl-2pyridone proligand was prepared as described in the literature’° and was heated to 80 °C under vacuum for at least three days prior to use. 2-Pyridone was purchased from Aldrich and sublimed prior to use. 2-Cyclohex-2-enyl-2,2-diphenyl-ethylamine was prepared using modified literature proced 29 ures from commercially available starting materials with full characterization data provided below. l,3,5-Trimethoxybenzene purchased from Aldrich, was used as an internal standard and was sublimed under vacuum prior to use. The (N-2’,6’-diisopropylphenyl(phenyl)-amidate) zirconium bis(dimethylamido) complex was prepared as described in the 4 literature. 8 ”  146  6-tert-Butyl-3-phenyl-2-pyridone.” ‘H NMR (CDC1 , 300 MHz): 6 1.38 (9H, s, 3  (CH ) ) 3 , 6.19 (1H, d, J =  7.4 Hz, C4-H), 7.78  —  -  7.4 Hz, C5-H), 7.24— 7.41 (3H, m, Ar-H), 7.55 (1H, d, J 7.81 (2H, m, Ar-H), 12.00 (1H, br s, NH); ‘ C NMR (CDC1 3 , 3  101 MHz): 6 28.9, 34.8, 101.8, 127.2, 127.7, 127.9, 128.3, 136.6, 139.1, 156.2, 163.5; MS (El): m/z 227(M).  ($NT1Me22  Bis(2-pyridonate) titanium bis(diniethylamido) complex 4.1. All metal complex  synthesis reactions were carried out in a glovebox unless otherwise stated. To a small screw capped vial containing a magnetic stir bar was added 2-hydroxypyridine (0.8203 g, 8.44 mmol), benzene (3 mL), and tetrakis(dimethylamido)titanium (0.946 g, 4.22 mmol in 3 mL of benzene). The mixture was then stirred at room temperature for 20 hours. The solvents were then removed under reduced pressure to afford the analytically pure bis(2pyridonato)titanium-bis(dimethylamido) complex 4.1 as a deep red microcrystalline solid. Yield:  >  98%. Crystals suitable for X-ray crystallography were obtained from a  saturated solution of the complex in benzene.  ‘H NMR (CDC1 , 400 MHz): 6 3.60 3  (12H, s, ) 3 Ti-(N( ) 2 , CH 6.08 (2H, m, Ar-H), 6.51 (2H, m, Ar-H), 7.03 (2H, m, Ar H), 7.60 (2H, m, Ar-H); ‘ C NMR (CDCI 3 , 100 MHz): 646.2, 109.7, 112.2, 140.3, 3 143.0, 172.2; MS (El): m/z 324 (M), 280 2 (M-NMe ) ; 236 2 (M-2NMe ) ; Anal. Calcd  147  for 4 N C 2 H T 2 O 0 i: , C, 51.87; H, 6.22;  N, 17.28. Found: C, 51.87;  H, 6.25; N,  17.66.  /  I  o\  /  Zr(NMe 2 ) 2  Bis(2-pyridonate) zirconium bis(dimethylamido) complex. All metal complex  synthesis reactions were carried out in a glovebox unless otherwise stated. To a small screw capped vial containing a magnetic stir bar was added 2-hydroxypyridine (0.8576 g, 9.0 mmol), benzene (3 mL), and tetrakis(dimethylamido)zirconium (0.946 g, 4.5 mmol in 3mL of benzene). Vigorous evolution of gas was observed upon addition of the tetrakis(dimethylamido)zirconium  solution to  the  undissolved  2-hydroxypyridine  proigand. The mixture was then stirred at room temperature for 20 hours. The solvents were then removed under reduced pressure to afford the analytically pure bis(2pyridonato)zirconium-bis(dimethylamido) complex 2 as a bright yellow microcrystalline solid. Yield:  >  98%. Crystals suitable for X-ray crystallography were obtained from a  saturated solution of the complex in benzene. The ‘H and 13 C NMR spectra along with solid state X-ray crystallographic information for the material obtained from this reaction indicate that the product consists of a mixture of oligomers.  Anal. Calcd for  N 1 C 2 H Z 2 O 4 4 0 r: C, 45.75; H, 5.48; N, 15.24. Found: C, 45.55; H, 5.43; N, 14.90.  148  OT(NMe 4 ( 2 )  Bis(6-tert-butyl-3-phenyl-2-pyridonate) titanium bis(dimethylamido) complex 4.2. All metal complex synthesis reactions were carried out in a glovebox unless otherwise stated.  To  a  Schienk tube  containing  a magnetic  stir bar was  added  tetrakis(dimethylamido)titanium (0.740 g, 3.3 mmol), benzene (30 mL), and  6-tert-  butyl-3-phenyl-2-pyridone (1.50 g, 6.6 mmol). The mixture was then stirred at room temperature for 5 hours. The solvents were then removed under reduced pressure to afford  the  analytically  pure  bis(6-tert-butyl-3-phenyl-2-pyridonato)titanium-  bis(dimethylamiclo) complex 4.2 as a red microcrystalline solid. Yield:  >  98%. Crystals  suitable for X-ray crystallography were obtained from a saturated solution of the complex in benzene.  ‘H NMR (CDC1 , 400 MHz): 8 1.24 (18H, s, 3 3 -C(CH ) ) , 3.44  (12H, s, ) 3 Ti-(N( ) 2 , CH 6.59 (2H, d, J=8.0 Hz,  Ar-H), 7.24 (2H, m, Ar-H), 7.43  (4H, m, Ar-H), 7.55 (2H, d, J=8.0 Hz, Ar-H), 8.12 (4H, m, Ar-H); 3 ‘ NMR (CDC1 C , 3 100 MHz): 829.7, 36.5, 47.1, 110.4, 119.4, 127.1, 128.4, 128.9, 137.5, 139.7, 165.6, 168.8; MS (El): m/z 588 t (M ) , 544 2 (M-NMe ) , 500 2 (M-2NMe ) ; Anal. Calcd for HN 34 C T 2 O 4 i: C, 69.38; H, 7.53; N, 9.52. Found: C, 69.00; H, 7.59; N, 9.55. (Zr(NMe 2 )  Bis(6-tert-butyl-3-phenyl-2-pyridonate) zirconium bis(dimethylamido) complex 4.3. All metal complex synthesis reactions were carried out in a glovebox unless otherwise stated. To a small screw capped vial containing a magnetic stir bar was added 6-tert-  149  butyl-3-phenyl-2-pyridone  (0.850  g,  3.7  mmol),  benzene  (3  mL),  and  tetrakis(dimethylamido)zirconium (0.500 g, 1.9 mmol in 2mL of benzene). The mixtur e was then stirred at room temperature for 20 h. The solvents were then removed under reduced  pressure  to  afford  the  analytically pure  bis(6-tert-butyl-3-phenyl-2-  pyridonato)zirconium-bis(dimethylamido) complex 4.3 as a pale yellow microcrystall ine solid. Yield:  >  98%. Crystals suitable for X-ray crystallography were obtained from a  saturated solution of the complex in benzene/pentanes. ‘H NMR (CDC1 , 400 MHz): 3 6 1.26 (18H, s, ) -C(C ) 3 , H 3.26 (12H, s, ) 3 Zr-(N ) 2 , (CH 6.57 (2H, d, J=7.9 Hz, ArH), 7.25 (2H, m, Ar-H), 7.44 (4H, m, Ar-H), 7.55 (2H, d, J=7.8 Hz, Ar-H), 8.07 (4H, m, Ar-H); ‘ C NMR (CDCI 3 , 100 MHz): 629.7, 36.3, 42.6, 110.1, 121.1, 128.4, 3 128.9, 137.2, 140.4, 165.3;  MS (El):  m/z 631 (Mt), 587 ) 2 (M-NM , e 543 (M  2NMe ) 2 ; Anal. Calcd for O 4 3 C H Z 2 r: C, 64.62; H, 7.02; 4 N  N, 8.87. Found: C,  64.71; H, 7.18; N, 9.07.  NH  00 2 2-Cycl ohex-2-enyl-2,2-diph 9 enyl-ethylamine. ‘H NMR (CDC1 , 400 MHz): 6 0.77 3 (2H, br s, 2 -NH ) , 0.9  —  1.1 (IH, m, --C 2 CHH-CH-CH= H CH-), 1.5  —  1.6 (2H, m,  -  C 2 CH ), H 1.6- 1.8 (1H, m, 2 -CW= CH-CH )FI-CH , 1.8 -2.0 (2H, m, -CH=CH 2 CHH-C , H  2 --C CHH-CH-CW H =CH-),  2 CHH-N ) , H 3.45 (1H, d, J CH=CH-), 5.8  —  =  3.2  -  3.4 (2H, m, -CH=CH-CH-, 2 -Ph C -  13.2 Hz, ) -P C 2 -CHH-N , h H 5.5  —  5.7 (1H, m,  -  5.9 (1H, m, -CH=CH-), 7.1 —7.4(1011, m, ArH); ‘ C NMR (CDC1 3 , 3  101 MHz): 6 22.59, 24.97, 25.18, 39.77, 49.65, 56.74, 126.15, 126.20, 127.50 ,  150  127.92, 129.07, 129.38, 129.76, 129.90, 142.80, 144.80;  MS (El):  m/z 276 (M  H). Anal. Calcd for H N: C 2 0 C, 86.59; H, 8.36; N, 5.05. Found: C, 86.39; 3  H,  8.39; N, 5.04.  General  procedure  for  NMR-tube  scale  intramolecular  amino  alkene  hydroamination. All NMR-tube scale reactions were prepared in an N -fihled glove box. 2 A J. Young NMR-tube equipped with a Teflon screw cap would be charged with the internal standard (1 ,3,5-trimethoxybeiizene) (0.5 mmol), the catalyst (0.025 mmol), and the amino alkene (0.5 mrnol) dissolved in either 6 -d benzene (1 mL), dio-xylenes (-1 mL) or dg-toluene (—1 mL). The tube would then be sealed, heated to, and maintained at, the appropriate temperature for the stated duration of time. The conversion and yield were determined by comparing the integration of the internal standard with a well resolved signal for the cyclic product.  2-Ethyl-4,4-diphenyl-pyrrolidine. ‘H NMR (CDC1 , 400 MHz): 6 0.97 (3H, t, J 3 7.4 Hz, ) 3 2 -CH CH , 1.49  —  1.70 (2H, m, ) 3 2 -CH-CH CH , 2.10 (1H, dd, J  Hz, 2 Ph C -CHH-CH(Et)-NH-), 2.77 (1H, dd, 3 NH-), 3.15 =  —  =  =  9.6, 12.7  9.6, 12.6 Hz, 2 Ph C -CHR-CH(Et)-  3.24 (1H, m, 2 --CH CH(Et)-NH-), 3.34 (1H, br s, -NH-), 3.47 (1H, d, J  11.5 Hz, 2 Ph C -CHH-NH-), 3.80 (1H, d, J  =  11.5 Hz, 2 Ph C -CHH-NH-), 7.15  —  7.40  (1OH, m, ArH); ‘ C NMR 3 3 (CDC1 75 MHz): 6 12.6, 30.5, 45.7, 57.4, 58.0, 60.7, ,  151  127.2, 127.9, 128.0, 129.4, 129.5, 147.4, 148.2; HRMS Calcd for C, N 2 H 8 1 [Mj: 251.16740; Found: 251.16720.  (+1-)  2 (+/-)-(S,S)-3 ,3-Diphenyl-1-(p-toluenes 8 ulfonyl)-octahydro-indole. amination reaction was prepared in an N -fihled glovebox. 2  The  hydro  A J. Young NMR-tube  equipped with a Teflon screw cap was charged with a solution of the precatalyst (0.032 g, 0.05 nimol) and 2-cyclohex-2-enyl-2,2-.diphenyl-ethylamine (0.069 g, 0.25 n-imol) dissolved in 8 -d toluene  (--  1 mL). The NMR-tube was then sealed and heated to 145 °C  for 168 hours. Following this the solution was concentrated under reduced pressure and the crude hydroamination mixture was transferred to a small round bottomed flask containing TsC1 (1.3 eq) and NEt 3 (3.3 eq), dissolved in CH CI (2-3 mL). This mixture 2 was then stirred over night at room temperature. Following aqueous workup, purification by column chromatography (36:1 hexanes/EtOAc, Si0 ) afforded 0.056 g (52%) of the 2 analytically pure (+I-)-(S,S)-3, 3-diphenyl- 1 -( p-toluenesulfonyl)-octahydro-indole as a colorless foam. ‘H NMR (CDCI , 400 MHz): 6 1.10— 1.30 (2H, m), 1.40— 1.65 (5H, 3 m), 2.32 (3H, s), 2.40—2.60 (1H, m), 2.90 (1H, d, J  =  11 Hz), 4.48 (1H, d, J  =  —  3.0 (1H, m), 3.70— 3.80 (1H, m), 4.25  11 Hz), 6.90—7.44 (1OH, m, ArH); ‘ C NMR 3  , 101 MHz): 6 21.1, 22.4, 25.4, 26.4, 29.7, 45.2, 56.4, 59.1, 60.0, 126.6, 3 (CDC1 127.0, 127.6, 128.0, 128.5, 129.3, 129.5, 130.2, 135.3, 143.7, 144.8, 146.1; MS  152  (ESI):  m/z 454 (M + Naj. Anal. Calcd for N0 C 2 H S 2 7 9 : C, 75.14; H, 6.77;  N,  3.25. Found: C, 75.04; H, 6.84; N, 3.20.  153  4.5 References  (1)  (a) Torres, M.; Gil, S.; Parra, M. Current Organic Chemistry 2005, 9, 1757. (b) Rawson, J.M.; Winpenny, R.E.P. Coordination Chemistry Reviews 1995, 139, 313. (c) Overmann, L.E.; Tsuboi, S.; Roos, J.P.; Taylor, G.F. J. Am. Chem. Soc. 1980, 102, 747.  (2)  Values obtained from the Bordwell pKa table.  (3)  (a) Bexrud, J.A.; Li, C.; Schafer, L.L. Organometallics 2007, 26, 6366. (b) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. 0.; Schafer, L. L. Chem. Commun. 2003, 2462.  (4)  (a) Wood, M. C.; Leitch, D. C; Yeung, C. S.; Kozak, J. A.; Schafer, L. L. Angew. Chem.,  mt. Ed.  2007, 46, 354. (b) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L.  Organometallics 2006, 25,4069-4071. (5)  (a) Souza, E.J.; Defon, V.M.; Fernandes, A.G.A.; Lemos, S.S.; Hagenbach, A.; Abram, U. Inorg. Chim. Acta 2006, 359, 1513. (b) Schaffler, L.; Muller, B.; Maas, G. Inorg. Chim. Acta 2006, 359, 970. (c) Chattopadhyay, S.; Fanwick, P.E.; Walton, R.A. Inorg. Chim. Acta 2004, 357, 764. (d) Thwaite, S.E.; Schier, A.; Schmidbaur, H. Inorg. Chim. Acta 2004, 357, 1549. (e) Thwaite, S.E.; Schier, A.; Schmidbaur, H. Inorg. Chim. Acta 2004, 357, 970. (f) Kuang, S.M.; Fanwick, P.E.; Walton, R.A. I Chem. Soc., Dalton Trans. 2002, 2501. (g) Kelson, E.P.; Phengsy, P.P. I Chem. Soc., Dalton Trans. 2000, 4023. (h) Flood, T.C.; Lim, J.K.; Deming, M.A. Organometallics 2000, 19, 2310. (i) Parsons, S.; Winpenny, R.E.P. Acc. Chem. Res. 1997, 30, 89.  154  (6)  (a) Fandos, R.; Hemandez, C.; Otero, A.; Rodr’guez, A.M.; Ruiz, M.J.; Terreros, P. Eur. J. Inorg. Chem. 2003, 493. (b) Antinolo, A.; Carrillo-Hermosilla, F.; Corrochano, A.E.; Fandos, R.; Fernandez-Baeza, J.; Rodr’guez, A.M.; Ruiz, M.J.; Otero, A. Organometallics 1999, 18, 5219. (c) Cotton F.A.; Lewis, G.E.; Mott, G.N. Inorg. Chem. 1983, 22, 378.  (7)  (a) Fandos, R.; Hemandez, C.; Otero, A.; Rodr)guez, A.M.; Ruiz, M.J.; Terreros, P. Eur. J. Inorg. Chem. 2003,493. (b) Antinolo, A.; Carrillo-Hermosilla, F.; Corrochano, A.E.; Fandos, R.; Fernandez-Baeza, J.; Rodrguez, A.M.; Ruiz, M.J.; Otero, A. Organometallics 1999, 18, 5219. (c) Cotton F.A.; Lewis, G.E.; Mott, G.N. Inorg. Chem. 1983, 22, 378.  (8)  Tsuchida, N.; Yamabe, S. J. Phys. Chem. A 2005, 109, 1974.  (9)  Suradi, S.; E.I. Saiad, N.; Pilcher, G.; Skinner, H.A. J Chem. Thermodyn. 1982, 14, 45.  (10) Beak, P.; Covington, J.B. I Am. Chem. Soc. 1978, 100, 3961. (11) Slanina, Z.; Le, A.; Adamowicz, L. I Mo!. Struct. 1992, 257, 491. (12) Beak, P.Acc. Chem. Res. 1977, 10, 186. (13) (a) Schreiber, A.; Krizanivic, 0.; Fusch, E.C.; Lippert, B; Lianza, F.; Albinati, A.; Hill, S.; Goodgame, D.M.L.; Stratemeier, H.; Hitchmann, M.A. Inorg. Chem. 1994, 33, 6101. (b) Angus, P.M.; Jackson, W.G. Inorg. Chem. 1994, 33, 477. (14) Thomson, R.K.; Zahariev, F.E.; Zhang, Z.; Patrick, B.O.; Wang, Y.A.; Schafer, Li. Jnorg. Chem. 2005, 44, 8680.  155  (15) Lauhuerta, P.; Latorre, J.; Sanau, M.; Cotton, F.A.; Schwotzer W. Polyhedron 1988, 7, 1311. (16) Calhorda, M.L.; Carrondo, M.A.A.F. De C.T.; Da Costa R.G.; Dias, A.R.; Duarte, M.T.L.S.; Hursthouse, M.B. J. Organomet. Chem. 1987, 320, 53. (17) Spinner, E.; White, J.C.B. 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Chem. 2006, 71, 2514  •  156  CHAPTER FIVE: o-FUNCTIONALIZATION OF PRIMARY AMINES VIA sp 3 HYBRIDIZED C-H BOND ACTIVATION  5.1 Introduction  The direct, selective, catalytic activation of C-H bonds by transition metals and subsequent C-C bond formation represents an important avenue of research for synthetic chemists owing to the fact that C-H bonds are among the most abundant that can be found in organic molecules.’ Over the past couple of decades much of the work in this field has been devoted to the activation of sp and sp 2 hybridized C-H bonds, while the activation of sp 3 hybridized C-H bonds has received comparatively little attention due to the relatively inert nature of this bond.’ One particular area of research concerning sp 3 C-H bond activation that has drawn notable interest is the selective activation I flinctionalization of sp 3 C-H bonds located x to a heteroatom such as nitrogen. 2 Methodologies developed for the direct catalytic c functionalization of amines have enormous potential as tools for the synthesis of a broad range of amine containing natural products, pharmaceuticals, and other fine chemicals. Although numerous transition metal based systems have already been applied to the catalytic u C-H activation/functionalization of tertiary  only recently have  secondary amines been successfully implemented as substrates. Hartwig and coworkers reported that secondary aryl-alkyl amines undergo coupling with olefins via a tantalum catalyzed C-H activation and subsequent C-C bond forming reaction (Equation 5.l).  Aversion of this chapter has been submitted for publication. Bexrud, J.A.; Eisenberger, P.; Payne, P.R.; Schafer, L.L. Zirconium 2-Pyridonates for Catalytic, Intramolecular ci-Functionalization of Primary Ainines. September 2008.  157  4 mol% RNCH3 H  RR  3 Ta[NC 5 j 2 ) H +  toluene, 160  -  H  165°C  (5.1) 3 CH  To date, there have not yet been any systems designed specifically to effect the catalytic a-functionalization of primary amines reported in the literature. However, in a recent paper by Doye and coworkers, which described a series of group four metal based catalysts for the cyclohydroamination of aminoalkenes, it was noted that these types of substrates can also undergo undesirable side reactivity involving a-C-H bond activation and ensuing C-C bond formation to afford amino-cyclopentane derivatives in low yield (Equation 5.2).  5moI%  Ph  11(NMe  Ph  76%  (5.2)  +  10%  Additionally, titanium and zirconium imido complexes (the catalytically active species for the cyclohydroamination reaction) are known to be capable of activating sp, 2 and sp sp 3 hybridized C-H bonds. 6 In particular, Doye has observed the racemization of a-chiral primary amines in the presence of catalytic quantities of various titanium c To date, no attempt has been 6 complexes during alkyne hydroamination experiments. made to take advantage of this reactivity for the a-functionalization of primary amines. Prior to the work by Doye and coworkers, we had also encountered this side reaction when studying the aminoalkene hydroamination activity of the 2-pyridone derived zirconium complexes.  Recognizing the potential usefulness of this  158  transformation, we decided to undertake further investigations. This chapter describes our initial findings along with our attempts to delineate the scope of this unique reactivity, and deduce a plausible mechanistic rationale.  5.2 Results and discussion  5.2.1 Preliminary fmdings and catalyst screening  During our substrate scope investigations to determine the limits of the bis(6-tertbutyl-3-phenyl-2-pyridonate) zirconium system (complex 4.3) in terms of catalyzing the cyclohydroamination reaction, we had observed side reactivity attributable to ci. C-H activation.  Heating a J. Young NMR tube containing a solution of 2,2-diphenyl-6-  heptenylamine, 20 mol% complex 4.3, and 1,3,5-triinethoxybenzene to 145 °C for 96 hours,  produces a mixture of the cis and trans diastereomers of 2,2-diphenyl-6-  methylcyclohexylamine; the product formed presumably via c C-H activation/alkene insertion;  along with the intended 2-methyl-6,6-diphenylazepane hydroamination  product in yields of 56% and 28% respectively as is determined by ‘H NMR spectroscopy (Equation 5.3). The products of this reaction are all fully characterized, and relative stereochemistry is assigned based on the solid state structural data for the N-Ts derivative of the trans-product. Although this reaction has been previously viewed as undesirable side reactivity, 5 we adopt the alternative mindset that this reactivity illuminates a starting point for the development of a new efficient, atom economical methodology for the synthesis of c-chira1 amines.  159  Ph  2 NH  Ph  I  20 mol% complex 4.3 145 °C, 96h, 8 d tol  iPh  T  Ph 2 NH 56% 1.5: 1  +  Ph Q<Ph  (5.3)  H 28%  anti : syn  Screening of two other zirconium complexes; ) 2 Z(NM 4 e as well as the bis(N-2,6diisopropylphenyl-Q,henyl)-amidate) zirconium bis(dimethylamido) complex (entries 1, 2, and 5, Table 5.1); reveals that only the bis(6-tert-butyl-3-phenyl-2-pyridonate) zirconium bis(dimethylamido) complex 4.3 catalyzes the formation of the a. C-H activation product preferentially.  The bis(N-2,6-dimethylphenyl-(tert-butyl)-amidate)  zirconium bis(dimethylamido) complex has also recently been screened for this reactivity by other members of our group and only the hydroamination product is observed in nearly quantitative yield. 7 Interestingly, of the analogous titanium complexes, only 2 Ti(NM 4 ) e is capable of potentiating any reaction whatsoever, with the a. C-H activation product forming preferentially with a yield of 70%. It should be noted that ) 2 Ti(NM 4 e does not effect the cyclization of this substrate at 110 °C with 5 mol% catalyst loading, which is in agreement with what has been observed by Doye and ’ 5 cowork 8 ers.  160  Table 5.1. Catalyst screening for the cL-activationlfunctionalization reaction.  Ph  2 NH  J  precatalyst  Phj  145°C, 8 d tol A  B NMR A yield rans.cis) Ba  entry  precatalyst  loading  time  NMR yield Aa  I  4 ) 2 Zr(NMe  20 mol%  24h  23%  57%  (>1.5:1)  2  4 ) 2 Zr(NMe  40 mol%  24h  19%  62%  (>1.5:1)  3  4.3  20 mol%  96h  56%c  28%c (1.5 : 1)  4  4.3  40 mol%  48h  62%  21%  (1.7: 1)  5  Zr(NMe L d 2 )  20 mol%  96h  0%  28%  N/A  6  4 ) 2 Ti(NMe  20 mol%  24h  70%  8%  (1 : 1.5)  7  4.2  40 mol%  24h  N/R  N/R  N/A  1.1 8 N/A 20 mol% N/R 48h N/R 1 ,3,5-Trimeth a oxybenzene as an internal standard. bDeteined by C NMR. Average of five runs. dL = N-2,6-diisopropyl-phenyl(phenyl)-amidate  These reactions are carried out with either a 20 mol% catalyst loading or a 40 mol% catalyst loading since preliminary findings suggest (vide infra) that catalyst loading can impact product distribution. 9 It should also be noted that this particular substrate appears to give somewhat inconsistent product ratios, which may be due to the presence of undetectable trace impurities in the substrate or the precatalyst. Therefore, the reported yield using complex 4.3 at 20 mol% is based on the average of five runs. To give an indication of variability, combined overall yields using complex 4.3 range from 77% to 88%, and the product ratios vary between 0.9: 1 and 3 : 1 (A : B).  161  Entries 6 and 1 of Table 4.3 show that ) 2 Ti(NM 4 e dramatically favors formation of the smaller six membered ring a C-H functionalization product, while ) 2 Zr(NM 4 e favors the formation of the larger seven membered ring hydroamination product, which might suggest that the product distribution is influenced by the relative sizes of the metal involved in catalysis.  The complete inactivity of complex 4.2 and the bis(amidate)  titanium complex (entries 7 and 8) towards this substrate, may be due to the decreased size of titanium in combination with the added steric bulk imposed by the chelating ligands, rendering the metal center too sterically inaccessible for either a C-H activation/functionalization or hydroamination catalysis to proceed. The differences in activity among the zirconium complexes towards this substrate are intriguing, and somewhat more difficult to rationalize. The hydroamination activity of each complex, in combination with their propensity to form dimers in situ may play a role in determining product distribution. It is thought that the relatively open coordination environment afforded by the 6-tert-butyl-3-phenyl-2-pyridonate ligand; as compared to the very bulky N-2,6-diisopropylphenyl-(phenyl)-amidate ligand may increase the susceptibility of complex 4.3 to form a dimer in situ and therefore shift the product distribution in favor of compound A. This may then explain the different product distributions observed with complex 4.3 and the bis(amidate) zirconium complex, but it does not obviously account for why complex 4.3 favors a C-H activation/functionalization while ) 2 Zr(NM 4 e favors hydroamination. In order to rationalize the latter dissimilarity, one must also consider that the product distributions in Table 4.3 result from a competition between a C-H activation/functionalization and cyclohydroamination.  Considering the product  distributions listed for entries I and 6, in addition to the fact that ) 2 Zr(NM 4 e is an efficient  162  catalyst for the cyclohydroamination of aminoalkenes,’° it is clear that the rate of formation of product B exceeds the rate of formation of product A.  Therefore, the  presence of either the 6-tert-butyl-3-phenyl-2-pyridonate or the N-2,6-diisopropylphenyl(phenyl)-amidate ligands actually inhibits the hydroamination reaction, which is slightly favored with zirconium, but the relatively open coordination environment afforded by the 6-tert-butyl-3-phenyl-2-pyridonate ligand also permits the formation of dimeric species which may be responsible for the cx C-H activation reactivity. Therefore, ) 2 Zr(NM 4 e rapidly yields predominantly the hyciroamination product; the bis(amidate) zirconium complex slowly gives only the hydroamination product; and complex 4.3 slowly produces a mixture containing mainly the a C-H functionalization product. It is obvious that the most effective catalyst for the a C-H functionalization reaction in Table 4.3 is 2 Ti(NM . 4 ) e However, future efforts to realize enantiocontrol in this reaction are dependant upon the design of the coordination environment of the catalytically active metal complex. Thus, complex 4.3 is used for the following substrate scope investigations as chiral, modular pyridonate ligands could be targeted in future work.  163  5.2.2 Substrate scope investigation  The a C-H activation/intramolecular C-C bond forming reaction observed in the cyclization of 2,2-diphenyl-6-heptenylamine is not an isolated case. A number of other aminoalkene substrates also undergo cyclization via a C-H activationlfunctionalization in the presence of catalytic quantities of complex 4.3. Table 4.4 lists a series of substrates and the resulting cyclohexylamine derivatives which are generated as products of this transformation. All of these reactions give predominantly the a C-H functionalization products with only small amounts (< 15 %) of what could be the hydroamination product being detected upon analysis of the crude reaction mixture using ‘H NMR spectroscopy.  2-(3-  Butene)berizylamine  C-H  (entry  1)  should  be  particularly  susceptible to  a  functionalization because the C-H bonds undergoing activation are situated in a benzylic position; and in fact this reaction goes to completion within 24 hours. The N-tosyl derivative of the initially formed 1-amino-2-methyl-tetralin can then be isolated, following derivatization, in excellent yield and with modest diastereoselectivity. Entries 2 and 3 demonstrate that the intramolecular a C-H activation/functionalization reaction can be potentiated by the gem-disubstituent effect in analogy to the cyclohydroamination reaction. Importantly, entry 4 reveals that substituents are, however, not required for this reaction to proceed.  It should be noted that the low yields for entries 2 and 4 result in  part from product volatility as well as difficulties that are encountered during purification.  164  Table 5.2. Synthesis of cyclohexylamine derivatives via catalytic ct-functionalization.  Entry  Product  Aminoalkene  Time  Yield  trans:cis  1  24ha  1 )C : 3 %b( 90  2  24ha  50 : 3 %b( j)c  22ha  gl%b( : 2 l)c  72hL  43 ) 1 : 2 %b( c  l2Ohd  )c 1 : 1 %e( 51 9  f 3  2 NH  4  NH 2 NH  5  -y  2 NH /D  2 NH (+1-)  a 20 mol% catalyst at l4S0C.b Isolated yield of derivatized C-H activation 40 products.C Ratio from 1 H-NMR spectroscopy. d mol% catalyst at e 155°C. NMR yield using 1 ,3,5-trimethoxybenzene as internal standard. This experiment was carried out by another member of our group. Characterization data for the substrate and product can be found in reference 9.  The most notable of all these experiments is the cyclization of l-phenyl-6heptenylamine (entry 5) which demonstrates that sterically congested pseudo-quaternary, stereogenic carbon centers located a to a nitrogen atom can be generated by taking advantage of this unique reactivity.  The product of this cyclization, (+/-)-(1 S,2R)-2165  methyl-1-phenylcyclohexylamine, is a known precursor to biologically active PCP ’ 1 derivatives.  It is interesting, and worth highlighting that the relatively high  diasteroselectivity observed in this reaction is in stark contrast to what was found for entries 1—4.  5.2.3 Mechanistic considerations  When Doye and coworkers 5 described a possible mechanism for the formation of the aminocyclopentane side products as a C-H activation and subsequent alkene insertion into a Ti-C bond, they had drawn analogy to the hydroaminoalkylation process that had recently been reported by Hartwig and coworkers. 4 The mechanism proposed by Hartwig for the tantalum catalyzed hydroaminoalkylation of unactivated alkenes with N-alkyl aryl amines is shown in Scheme 5.1. It involves amine elimination to form a group five  2  imine complex followed by alkene insertion into the resulting M-C bond.  R 3 CH  2 NMe  NCH ‘ N)M 2 (Me N 2 (Me )fl<I -HNMe NMe 2 2 2 product  (Me N 2 )nMJJ R 2 HNMe  Scheme 5.1. Mechanism proposed by Hartwig and coworkers for the tantalum catalyzed hydroaminoalkylation reaction. A mechanism such as this is plausible considering that zirconium 11 —imine 2 complexes, or zirconaaziridines, are known to undergo stoichiometric reactions with alkenes and alkynes to form a functionalized products (Scheme  5.2).12  However, none of  166  these catalytic or stoichiometric systems involve primary amines as substrates. Therefore the N-methyl  and N-phenyl  secondary  amine  derivatives  of 2,2-diphenyl-6-  heptenylamine were prepared and tested as substrates using the same conditions employed in the original experiment. The N-phenyl derivative was included because it has been shown that zirconocene 2 11 — imine complexes are formed faster starting from N alkyl arylamido complexes than from their dialkylamido analogues.’ 3  =\ 7 Z 2 Cp 1 r  cp z 2 r/ Ph R  Cp Z 2 r<  R  =  R—------  R  CP ( 5 Z 2 Ph  TMS, Ph  Scheme 5.2. Reactivity of zirconium T1 —imine complexes towards alkenes and 2 alkynes.  Surprisingly, complex 4.3 does not catalyze the cyclization of either the N-methyl or the N-phenyl derivative of 2,2-diphenyl-6-heptenylamine (Equation 5.4). The N-phenyl substrate remains completely unreacted after 144 hours at 145 °C. This lack of reactivity with secondary amines suggests that the mechanism for group four catalyzed c C-H functionalization is fundamentally different from the one proposed by Hartwig for the tantalum catalyzed hydroaminoalkylation reaction. Namely, it is conceivable that the catalytically active species may be some form of group four metal imido complex, as both titanium and zirconium imido complexes are known to be capable of activating C-H 6 bonds.  167  Ix 4.3  c1.Ph  (54)  RMe,Ph  In addition to these findings, catalyst loading experiments carried out by other members of our group 9 demonstrate that higher catalyst concentrations shift the product distribution towards the cc C-H functionalized product. This suggests that a dimeric or higher order multi-metallic species is involved in catalyzing this transformation. Group four imido complexes are known to form dimers, and 2-pyridones have been used in the preparation of numerous bimetallic complexes. Based on all of the above information, the mechanism outlined in Scheme 5.3 is proposed for the group four catalyzed intramolecular cc C-H functionalization of aminoalkenes.  Initially the substrate reacts with the precatalyst to form an imido  complex, which can then undergo dimerization to form a bridging imido species.  13-  hydrogen abstraction/amine elimination leads to the bridging zirconium ii2 imine intermediate. Alkene insertion then ensues, followed by protonolysis of the resulting Zr C bond. Displacement of the product by another equivalent of substrate via protonolysis liberates the cc functionalized amine and regenerates the bridging imido dimer.  168  _ _  Ph 2 RNH Zr(NMe L 2 )  I  H  R[Z] [Zr]=NR  n-hydrogen  HN_[Zr]()[Zr] R  N R  N 2 H  R Ph  Ph  _c  1  product  -  2 RNH  Ph N  /\ HN—[Zr] [Zr] \ / R /  R  protonolysis  <N \/\ [Zr] [Zr]  / 2 H  \ / R  Scheme 5.3. Postulated mechanism for the zirconium catalyzed a C-H activationlC-C bond forming reaction.  This mechanism is only meant to serve as a working hypothesis that is consistent with the information gathered so far. Efforts to characterize intermediates of this catalytic cycle have not been successful. The stoichiometric reaction of complex 4.3 with 2,2diphenyl-6-heptenylamine yields an oil which consist of a complex mixture of compounds that has resisted characterization by solid state analysis or ‘H NMR spectroscopy. Experiments involving 1,1 -dideuterium labeled 2,2-diphenyl-6-heptenylamine show approximately 10% incorporation of deuterium onto the methyl group, and approximately 30% loss of deuterium a.-to the nitrogen in the o-C-H functionalized product (Scheme 5.4). These observations are consistent with the proposed mechanism outlined in scheme  169  5.3, and suggest that the 3-hydrogen abstraction/amine elimination step is reversible.  Deuterium labeling experiments utilizing 1,1 -dideutero-2,2-diphenyl-butylamine as a substrate also support the latter presumption, as exchange of deuterium for hydrogen is observed when this compound is heated to 145 °C in the presence of 20 mol% complex 4.3. —30% loss  Ph  20 mol%  Ph 2 NH  complex 4.3  -tol, 145°C 8 d  D D  —10% incorporation of deuterium  Scheme 5.4. Experiment involving 1,1 -dideutero labeled 2,2-diphenyl-6heptenylamine.  With the mechanism of this transformation being postulated to involve a zirconium —imine complex, rationalization of the observed diastereoselectivities can be 2 q accomplished by recognizing that the appended olefin can approach and insert into the Zr-C bond in a conformation that resembles a chairlike geometry (Scheme 5.5). Therefore, two chairlike conformations are possible; one having the nitrogen in a pseudoequatorial position and the R group (R = H entries 1-4 Table 5.2; or R = Ph entry 5 Table 5.2) in a pseudoaxial position; and in the other conformation these relative orientations are reversed. When R  =  H it is argued that the conformation that positions  the nitrogen in a pseudoequatorial orientation is favored over the conformation in which it is axial to minimize 1,3-diaxial interactions; and this results in the observed product distribution slightly favoring the 3 /trans 2 NH CH diastereomer. When R  =  Ph on the other  hand (entry 5, Table 5.2), the product distribution shifts dramatically in favor of the 170  3 / 2 NH CH cis diastereomer. This is consistent with the comparatively bulky phenyl group adopting the pseudoequatorial orientation to minimize 1 ,3-diaxial interactions, thus forcing the nitrogen into a psuedoaxial position resulting in the 3 / 2 NH CH cis diastereomer now being the favored product. H 3 ! 2 NH t rans CH  .  7 R  3 I 2 NH c CH 1s  Scheme 5.5. Rationalization of the diastereoselectivities observed in the intramolecular ct-functionalization reaction.  5.3 Summary and conclusions  While attempting to expand the substrate scope of this system by employing higher reaction temperatures and higher catalyst loadings, side reactivity attributable to cx. C-H activation and subsequent intramolecular C-C bond formation was observed. Heating 2,2-diphenyl-6-heptenylamine in the presence of 20 mol% complex 4.3 to 145 °C for 96 hours,  produced a mixture of the cis and trans diastereomers of 2,2-diphenyl-6-  methylcyclohexylamine, the product formed presumably via cx. C-H activationlalkene insertion,  along with the intended 2-methyl-6,6-diphenylazepane hydroamination  product in yields of 56% and 28% respectively. Similar side reactions have also been observed by Doye and coworkers.  171  Recognizing the potential value of this a functionalization reactivity to the synthetic community, further investigations were carried out. Catalyst screening experiments in which 2,2-diphenyl-6-heptenylamine was employed as the substrate revealed that of the catalysts tested, complex 4.3 is the most effective zirconium catalyst and Ti(NMe 4 is ) 2 the most effective overall, for the a C-H functionalization reaction. Substrate screening experiments using complex 4.3 as the catalyst demonstrated that this reactivity is not an isolated case.  In fact the a C-H activation products tend to be favored over the  hydroamination products to a greater extent when aminoalkenes other than 2,2-diphenyl6-heptenylamine were employed as substrates. Importantly, the N-methyl and N-phenyl derivatives of 2,2-diphenyl-6-heptenylamine were found to be completely unreactive as substrates for the a C-H functionalization reaction and the cyclohydroamination reaction in the presence of complex 4.3. Based on known stoichiometric and catalytic early transition metal chemistry involving the a functionalization of amines, along with our own observations that secondary aminoalkenes do not undergo a functionalization, and that increased catalyst loading favors the a functionalized products the mechanism of this reaction is thought to involve a bridging imido dimer and a group four bridging 11 —imine complex as key 2 intermediates. The mechanism proposed in section 5.2.3 is a working hypothesis that is consistent with previous work and our own observations. The exact nature of the intermediates, and the specific processes involved require further elucidation and is the focus of investigations for another doctoral student.  172  5.4 Experimental  General. ‘H and ‘ C NMR spectra were recorded on either a Bruker 300 MHz or 400 3 MHz Avance spectrometer at ambient temperature and chemical shifts are given relative to residual solvent. GCMS spectra were recorded on an Agilent series 6890 GC system with a 5973 Mass Selective Detector. Single crystal X-ray structure determinations, MS, and elemental analyses determinations were performed at the Department of Chemistry, University of British Columbia. All reactions were carried out using standard Schienk line and glovebox techniques under an atmosphere of nitrogen, unless described otherwise. Ti(NMe 4 and Zr(NMe ) 2 4 were purchased from Strem and used as received. ) 2 -d 8 Toluene was degassed and dried over molecular sieves.  2,2-Diphenyl-6-  4 was prepared as described in the literature with some modification from heptenylamine’ commercially available starting materials purchased from Aldrich.. Amino alkene substrates were dried over CaH or  4A molecular sieves and degassed prior to use. The 6-  tert-butyl-3-phenyl-2-pyridone proligand was prepared as described in the literature’ 5 and was heated to 80 °C under vacuum for at least three days prior to use. 1,1 -Dideutero-2,2diphenyl-butylamine was prepared using modified literature procedures’ 4 from commercially available starting materials with full characterization for this compound provided  below.  2-(3-Butene)benzylamine  was  prepared  from  2-(3-  6 via oxime formation’ butenyl)benzaldehyde’ 7 followed directly by reduction’ 8 with full characterization data provided below. 2,2-Dimethyl-6-heptenylamine was prepared from commercially available starting materials using modified literature  with full  characterization data provided below. 6-Heptenylamine was prepared using literature  173  9 from 6-heptenenitrile with full characterization data provided below. 1procedures’ Phenyl-hept-6-enylamine was prepared from ° 2 1-phenyl-hep t-6-en-1-one by reductive amination using NH OAc I NaCNBH 4 ’ 2,2-Diphenyl-hept-6-enal was prepared using 2 . 3 modified literature procedures. 22  with full characterization data provided below. 2,2-  Diphenyl-hept-6-enyl-phenyl-amine was prepared from 2,2-diphenyl-hept-6-enal and aniline using modified literature procedures with full characterization data provided 22 below.  (2,2-Diphenyl-hept-6-enyl)-methyl-amine was prepared from 2,2-diphenyl-6-  heptenylamine using modified literature procedures with full characterization data provided below. 23 l,3,5-Trimethoxybenzene purchased from Aldrich, was used as an internal standard and was sublimed under vacuum prior to use. The bis(N-2,6diisopropylphenylQhenyl)-amidate)  titanium  bis(dimethylamido)  and  (N-2,6-  diisopropylphenyl(phenyl)-amidate) zirconium bis(dimethylamido) complexes were prepared as described in the literature. 24  4 1,1-Dideuter o-2,2-diphenyl-butylamine.’ ‘H NMR 3 (CDC1 400 MHz): ,  J  =  7.2 Hz, 3 -CH ) , 2.19 (2H, q, J  NMR (CDC1 , 101 MHz): 3  8.8,  =  7.2 Hz, 2 -CH ), 7.10  28.9, 47.7, 52.1,  —  0.71 (3H, t,  7.40 (1OH, m, An]); ‘ C 3  126.0,  128.2,  128.5,  146.7;  HRMS Calcd for D C 1 H N 2 6 [M+H]: 228.1721; Found: 228.1721. 8  174  5NH2  6 2-(3-bu 8 7 ” tene)benzylamine.’ ‘H NMR (CDCJ , 400 MHz): 6 1.39 (2H, br s, 3 NH ) 2 , 2.34  —  2.41 (2H, m, ) Ar 2 CH= CH -CH CH 2.75 ,  —  -  2.80 (2H, m, Ar-C 2 CH H  2 CH=C ) , H 3.91 (2H, s, ) Ar-C 2 NH , H 5.00—5.11 (2H, m, ) 2 -CH=C , H 5.80—6.00 (1H, m, ) 2 -CH=C , H 7.19  —  7.36 (4H, m, An]);  C NMR (CDC1 3 ‘ , 101 MHz): 3  6 31.8, 35.4, 43.7, 115.2, 126.5, 127.0, 127.8, 129.4, 138.2, 139.4, 140.9; (El):  m/z 160 (M-H). Anal. Calcd for C, N: 1 H 1 5 C, 81.94; H, 9.38;  MS  N, 8.69.  Found: C, 81.92; H, 9.62; N, 8.94. 2 NH  4 2,2-Dimethy l-hept-6-enylamine.’ ‘H NMR (CDC1 , 400 MHz): 60.83 (6H, s, -CH 3 2 (C C ) 3 2 ) NH -CH , H 0.98  —  1.06 (2H, m, ) -C C ) 3 2 (C N C -C H , H H H 1,17  (2H, m, ) 3 -C C 2 (C C -) H H , 2.00 (2H, s,  -C C ) 3 2 ) (C N -C , H H H H 4.93  —  —  2.05 (2H, m,  —  1.21  C = 2 CHCH ), H CH 2.43  5.02 (2H, m, =CH-CH 2 CH ), 5.76  —  5.86  (1H, m, =CH-CH 2 CH ); ‘ C NMR (CDC1 3 , 101 MHz): 6 24.3, 25.7, 35.4, 35.6, 39.9, 3 53.9, 115.4, 140.0;HRMS Caled for N 19 [Md]: 141.15175; Found: 141.15164. H 9 C  9 6-Ileptenylai nine.’ ‘H NMR (CDCI , 300 MHz): 6 1.01 (2H, br s, 2 3 -NH ) , 1.23 (6H, m), 1.95  —  2.02 (2H, m), 2.62 (2H, t, J  (2H, m, C=CH-C 2 H ), H 5.67  -  5.79 (1H, m,  -  =  6.6 Hz, ) -CH 2 NH CH , 4.85 C=CH-C 2 H ); H  —  —  1.40 4.96  C NMR (CDC1 13 , 3  175  101 MHz): 626.5, 28.9, 33.8, 33.8, 42.2, 114.4, 139.0; HRMS Caled for C N 1 H 7 6 {M]: 114.1283; Found: 114.1282. 2 NH  1-Phenyl-hept-6-eny 2 ’ 2 0 lamine.  ‘H NMR (CDC1 , 400 MHz): 6 1.23 3  —  1.26 (1H, m),  1.30— 1.45 (3H, m), 1.50 (2H, br s, 2 -NH ) , 1.65— 1.71 (2H, m), 1.98—2.06 (2H, m), 3.88 (1H, t, J  =  6.8, Ph-C ) 2 -C ), H(N H H 4.91  (1H, m, ) -C 2 CH=, H CH 7.22  —  —  5.06 (2H, m, ) 2 -CH=C , H 5.73  —  5.84  7.28 (5H, m, Ar-B); 13 C NMR 3 (CDCI 101 MHz): ,  626.2, 29.0, 33.8, 39.7, 56.4, 114.5, 126.7, 127.0, 128.9, 139.0, 147.0; MS (El): m/z (M+H) 190; Anal. Calcd for 9 H, 1 C N 3 : C, 82.48; H, 10.12; N, 7.40. Found: C, 82.24; H, 10.05; N, 7.30.  2 2,2-Di phenyl2 -hept-6-enal. ‘H NMR 3 (CDC1 400 MHz): 6 1.16 , CH 2 CH ), 2.04 C 2 CP CH ), H h 4.93  ),  7.19  —  —  —  2.10 (2H, m, C=CH H 2 C ), -CH 2.28 H  —  —  1.22 (2H, m, 2.33 (2H, m,  -  -  H C =rCH), 5.69—5.80(111, m, 5.01 (2H, m, 2 C=CH-CH 2 H  7.40 (1OH, m, An]), 9.82 (1H, s, C 2 -P -CH=O h ); ‘ C NMR (CDCI 3 , 101 3  MHz): 6 25.0, 34.5, 35.1, 64.7, 115.8, 128.3, 129.7, 130.1, 139.3, 141.2, 199.6; HRIvIS Calcd for H, 18 [M-HCOj: 235.14868; Found: 235.14846. C 9  176  2 2 2,2-Dipheny l-hept-6-enyl 2 -phenyl-amine.  ‘H NMR 3 (CDC1 400 MHz): 6 1.18 ,  —  1.26 (2H, m, -CH 2 CH ), 1.97—2.03 (2H, m, C=CH-C H 2 CH ), H 2.21 —2.26 (2H, m, -CPh -CH 2 CH ), 3.25 (1H, br t, J  =  5.6 Hz, -NH-), 3.77 (2H, d, J  Hz, C 2 -Ph NH-), -CH 4.89 —4.97 (2H, m, 2 H C =CH-), 5.64 CH 2 ),  6.57  —  6.59 (2H, m, -NHArI]), 6.68  —  —  =  5.6  5.74 (1H, m, 2 H C =CH-  6.72 (1H, m, -NHArH), 7.14  —  7.22  (12H, m, ArH); , CNMR(CDC1 101 MHz): 6 24.6, 35.1, 38.1, 51.2, 51.4, 114.0, 3 ‘ 115.6, 118.4, 127.3, 129.0, 129.2, 130.2, 139.5, 147.2, 149.5; MS (ESI): m/z 342 (M+I-f’). Anal. Caled for H N: C 2 5 C, 87.93; H, 7.97; N, 4.10. Found: C, 87.92; 7 H, 7.96; N, 4.13. /  2 (2,2-Dipheny l-hept-.6-eny 3 l)-methyl-amine. ‘H NMR (CDC1 , 300 MHz): 6 0.4 (1H, 3 br s, ) 3 2 -CH NH-CH , 1.10 C=CH-C H 2 CH ), H 2.21  —  —  1.18 (2H, m, -CH 2 CH ), 2.00  —  2.08 (2H, m,  2.26 (2H, m, C Ph 2 CH -CH ), 2.39 (3H, s, 3 -NH-CH ) ,  3.21 (2H, s, C 2 -Ph NH-), -CH 4.90 C=CH-CH 2 H ), 7.18  —  —  5.00 (2H, m, 2 H C =CH-), 5.6- 5.8 (1H, m,  7.32 (1OH, m, ArE); ‘ C NMR (CDCI 3 , 101 MHz): 6 23.71, 3  34.40, 37.07, 37.55, 50.50, 59.36, 114.55, 126.04, 128.12, 128.21, 138.98, 147.35;  177  MS (El): m/z (Md). Anal. Calcd for H N: C 2 0 C, 85.97; H, 9.02; N, 5.01. Found: 5 C, 85.74; H, 9.07; N, 5.01.  General procedure for catalytic ct-funtionalization reactions. All ct-functionalization  reactions were carried out in a J. Young NMR-tube equipped with a Teflon screw cap and were prepared in an N -fihled glove box. A small vial would be charged with the internal 2 standard (1,3,5-trimethoxybenzene) (0.08 mmol), the precatalyst (0.05 or 0.1 mmol), d 8 toluene (1.0 g) followed by the aminoalkene (0.25 mmol). The solution would then be transferred to a J. Young NMR tube which would be sealed, heated to, and maintained at, the appropriate temperature for the stated duration of time. Unless otherwise stated, the crude amines would then be directly converted to either the N-benzoyl, N-tosyl, or N napthoyl derivative by transferring the crude hydroamination reaction mixture to a small round bottomed flask containing a solution of the acid chloride (0.38 mmol) and NEt 3 (1.25 mmol) dissolved in CH CI (2-3 mL). This mixture would then be stirred over 2 night. Following aqueous work up, the crude mixture would be subjected to column chromatography (Si0 ) to afford the analytically pure products as mixtures of 2 diastereomers which could then be separated by further column chromatography (Si0 ) 2 or recrystallization.  178  2-Methyl-6,6-diphenyl-azepane,  (+/-)-(1S,6R)-2,2-diphenyl-6-methylcyclohexyl-  amine, and (+/-)-(1S,6S)-2,2-diphenyl-6-methylcyclohexylamine. A yield of 83% was obtained for the mixture of compounds (1.1:1 [1.3:1], hydroamination:CH activation product [anti:syn]) isolated via column chromatography (4:1 0 2 Hexan es:Et with 2 % , 2 3 NEt Si0 ) , which were subsequently separated via chromatography (4:1 0 2 Hexan es:Et with 2 % NEt , Si0 3 ) for characterization purposes. Relative stereochemistry was 2 assigned based on the crystal structure of the NTs derivative of (+/-)-(1 S,6R)-2,2diphenyl-6-methylcyclohexylamine. ‘H NMR (2-methyl-6,6-diphenyl-azepane) (CDC1 , 400 MHz): 8 1.10 (3H, d, J 3  =  6.4  Hz, ) 3 -CH-C , H 1.26— 1.38 (IH, m, ) 3 -C 2 CHH -N-CH HH (CH ), 1.60 (1H, br s, -NH  ), 1.65  —  1.77 (1 H, m, ) 3 -C 2 CH CH -N HH (C H CH -), H 1.78  —  1.92 (2H, m, -CH 2  3 CH 2 ) CH -N H-C H(CH H , ) 3 -C 2 CHH -N -CH HH (CH ), 2.13 (1H, dd, J Hz, -P C 2 -CHH), CH 2.59 (1H, dd, J h 2.86 (1H, m, --C 2 CH(CH3)-NH H -), 7.14  =  —  6,6-diphenyl-azepane) (CDC1 , 101 MHz): 3  =  10, 14.8  8.4, 14.8 Hz, -P C 2 -CHH), CH 2.80 h  —  7.26 (1OH, m, ArE]); 13 C NMR (2-methyl6 23.97,  24.43,  41.06, 41.12,  53.31,  57.66, 58.46, 126.59, 126.77, 128.39, 128.54, 129.15, 129.19, 149.26, 151.16; HRMS (2-methyl-6,6-diphenyl-azepane) Calcd for H N 1 C 2 9 [M]: 265.18305; Found: 3 265.18365. ‘H NMR ((+/-)-( 1 S,6R)-2,2-diphenyl-6-methylcyclohexylamine) (CDC1 , 400 MHz): 6 3 1.02 (3H, d, J  =  6.4 Hz, ) -C 2 ) 3 -CH CH -) (NH (CH H , 1.19— 1.30 (111, m, 2 -CH CHH-  179  CH 2 ), 1.33  —  1.45 (3H, m, ) 3 -CH2-, CI-IHCH(CH -CH ) 2 -CH ), (NH 1.52— 1.57 (1H,  m, ) 3 -CH2-) CHH-CH(CH , 1.71  1.77 (1H, m, -C 2 CHH-C ), H H 2.10  —  m, ) 3 -CH(C -, P C 2 H -CHH), h CH 2.42 d, 3  =  ArH);  10.4 Hz, ) 2 -CH(N -), H 7.10  —  —  —  2.19 (2H,  2.47 (1H, m, P C 2 -CHH), h CH 3.04 (1H,  7.36 (8H, m, An]), 7.83 (2H, d, J  7.2 Hz,  C NMR ((+/-)-(1 S,6R)-2,2-diphenyl-6-methylcyclohexylamine) (CDC1 13 , 101 3  MHz): 8 20.93, 23.46, 35.08, 36.64, 40.85, 54.04, 67.30, 126.73, 126.95, 128.69, 129.01,  129.05,  132.04,  145.08,  150.21;  HRMS ((+/-)-(1S,6R)-2,2-diphenyl-6-  methylcyclohexylamine) Calcd for N 23 [Mj: 265.18305; Found: 265.18372. H 9 C, ‘H NMR ((+/-)-(1 S,6S)-2,2-diphenyl-6-methylcyclohexylamine) 3 (CDC1 400 MHz): 6 , 1.03 (3H, d, J  =  6.8 Hz, ) 3 -CH(C -), H 1.11 (2H, br s, 2 -NH ) , 1.27— 1.42 (3H, m,  3 C 2 ) CH( CH -, H CH ) 3 -C 2 CH CH -) H-C (CH H , H 1.65 3 2 CH ) CH( -) CH , 2.19  —  -  -  1.70 (1H, m, 2 -CH CHH-  2.26 (1H, m, ) C 2 ) 3 -CH CH -) (CH H (NH , 2.34— 2.41 (1H, m,  2 -Ph2C ), -CHH-CH 2.49  —  2.57 (1H, m, -P C 2 -CHH), CH 3.94 h  CH ) 3 ) 2 -CH -C ) (CH (NH Ph ,  7.06  —  —  3.95 (1H, m,  -  7.41 (1OH, m, An]); 13 C NMR ((+/-)-(1S,6S)-  2,2-diphenyl-6-methylcyclohexylamine) (CDC1 , 101 MHz): 6 20.62, 23.12, 28.46, 3 28.52, 32.36, 52.03, 149.32;  HRMS  57.64,  126.43,  126.57,  127.60,  128.32,  129.43,  146.88,  ((+/-)-( 1 S,6S)-2,2-diphenyl-6-methylcyclohexylamine) Calcd for  N 1 C 2 H 9 [M]: 265.18305; Found: 265.18367. 3 Anal. Calcd for C, N 2 H 9 3 (mixture of all three compounds): C, 85.99; H, 8.74;  N,  5.28. Found: C, 85.72; H, 8.73; N, 5.22.  180  /  TsHN  (+1-)  (+f-)-(1S,6S)-N-Tosyl-2,2-diphenyl-6-methylcyclohexylamine. ‘H NMR (CDCI , 400 3 MHz): 6 1.03 (3H, d, J 1.50 (1H, m), 1.60  —  =  6.8 Hz), 1.05  —  1.72 (1H, m), 1.90  1.15 (1H, m), 1.20— 1.40 (1H, m), 1.41  —  2.05 (1H, m), 2.25  (3H, s), 2.60 —2.70 (1H, m), 4.30 (111, d, J  =  —  —  2.35 (1H, m), 2.34  9 Hz), 4.82 (1H, d, J  =  9 Hz), 6.80  —  7.35 (14H, m); 13 C NMR (CDC1 , 101 MHz): 6 20.51, 22.35, 22.42, 32.93, 51.85, 3 62.60, 126.54, 126.79, 127.39, 127.78, 128.01, 129.04, 129.61, 130.07, 140.04, 142.89, 145.93, 147.78; HRMS Caled for 2 N0 C 2 H S 6 [M]: 9  419.19190;  Found:  419. 19243.  TsHN  /  (+1-)  (+/-)-(1S,6R)-N-Tosyl-2,2-diphenyl-6-methylcyclohexylamine. See Figure A4.2 for an ORTEP diagram of this compound. 1 H NMR (CDC1 , 400 MHz): 6 1.02 (3H, d, 3 3 Hz), 1.20  —  1.50 (2H, m), 1.55  —  1.65 (1H, m), 1.8  —  m), 2.23 —2.45 (2H, m), 2.4 (3H, s), 3.95 (1H, dd, J =  8.5 Hz), 6.97  —  1.9 (111, rn), 2.10  —  =  6.7  2.20 (1H,  8.6, 10.4 Hz), 4.90 (1H, d, J  7.32 (14H, m); ‘ C NMR (CDC1 3 , 101 MHz): 6 20.8, 21.5, 22.1, 3  35.4, 35.9, 40.6, 54.3, 67.6, 126.2, 126.4, 126.6, 127.9, 128.3, 128.4, 129.3, 130.1, 139.1, 142.3, 143.5, 147.9;  MS (El):  m/z 419 (M). Anal. Calcd for N0 C 2 H S 2 6 9 :  C, 74 .43; H, 6.97; N, 3.34. Found: C, 74.39; H, 7.13; N, 3.53.  181  +  NHTs  NHTs  (+1-)  (+1..)  (+/-)-N-tosyl-1,2,3,4-tetrahydro-(2R,1S)-methylnaphthalenamine and (+/-)-N-tosyl 1,2,3,4-tetrahydro-(2R,1R)-methylnaphthalenamine.  Relative stereochemistry was  assigned based on the crystal structure of (+/-)-N.-tosyl-1 ,2,3,4-tetrahydro-(2R,1 S) methylnaphthalenamine. H NMR ((+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 S)-methylnaphthalenamine) (CDC1 1 , 400 3 MHz): 6 0.87 (3H, d, J CH(CH ) 3 -), 1.92  -  =  6.8 Hz, 3 -CH-CH ) , 1.52  —  1.61 (1H, m, 2 Ar-CH CHH-  2.04 (2H, m, ) 3 Ar-C 2 CHH-CH(CH -, H ) 3 Ar-C 2 CHH-CH(CH -), H  2.47 (3H, s, 3 Ar-CH ) , 2.74 (2H, m, ) 3 Ar-C 2 CH(CH CH -), H 4.10 3 ArCH(NHTs ) -), )-CH(CH 4.58 (1H, d, J  =  —  4.14 (1H, m,  7.6 Hz, -NH-Ts), 6.89 (1H, d, ArH), 7.04  (2H, d, ArM), 7.14 (IH, t, ArH), 7.34 (2H, d, ArH), 7.81 (2H, d, ArH); ‘ C NMR 3 ((+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 S)-methylnaphthalenamine) (CDCI , 101 MHz): 3 6 17.54, 21.70, 26.02, 26.20, 34.58, 45.30, 58.48, 126.48, 127.27, 127.64, 129.12, 129.56, 129.84, 135.27, 137.13, 138.52, 143.46. ‘H NMR ((+/-)-N-tosyl- 1 ,2,3,4-tetrahydro-(2R, 1 R)-methylnaphthalenamine) (CDC1 , 3 400 MHz): 6 0.94 (3H, d, J CH(CH ) 3 -), 1.72  —  =  6.8 Hz, 3 -CH-CH ) , 1.53  1.76 (1H, m, ) 3 2 -CH CHH-CH(CH -),  2 ) 3 CH(CH -CH ), 2.46 (3H, s, 3 Ar-CH ) , 2.69 (2H, m, TsNH-CH-, TsNH-), 6.80 ArE);  —  —  —  1.60 (1H, m, 2 -CH CHJI1.94  —  2.00 (1H, m, -CH  2.85 (2H, m, -CH 2 Ar-CH ), 4.47-4.49  7.36 (6H, m, ArH), 7.80 (2H, d, J  =  8.2 Hz,  C NMR ((+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 R)-methylnaphthalenamine) 3 ‘  182  , 101 MHz): 3 (CDC1  16.42, 21.67, 26.43, 27.47, 32.93, 56.32, 58.47,  126.25,  127.30, 127.66, 129.01, 129.19, 129.78136.20, 136.50, 138.9, 143.39. MS (mixture of diastereomers) (ESI): m/z (M-W) 314.2. Anal. Calcd for 2 N0 1 C 2 H S 8 (mixture of diastereomers): C, 68.54; H, 6.71; N, 4.44. 1 Found: C, 68.44; H, 6.75; N, 4.44.  H÷  (+1—)  HN  (+1—)  (+/-)-N-Napthoyl-(1S,6R)-2,2,6-trimethylcyclohexylamine  and  (+/-)-N-Napthoyl  (1S,6S)-2,2,6-trimethylcyclohexylamine. Relative stereochemistry was assigned based on the crystal structure of (+/-)-N-Napthoyl-( 1 S,6R)-2,2,6-trimethylcyclohexylamine. H NMR ((+/-)-N-Napthoyl-( 1 S,6R)-2,2,6-trimethylcyclohexylamine) (CDC1 1 , 400 3 MHz):  0.91 (3H, s, ) -(CH 3 CH C-), 1.07 (3H, d, J  =  6.4 Hz, ) 3 -CH-C , H 1.03  —  1.24  (1H, m), 1.13 (3H, s, ) -(CH 3 CH C-), 1.43—1.57 (5H, m), 1.77—1.86 (1H, m), 3.75 —3.82 (1H, m, ) -( C 2 ) 3 -CH(N C HTs)-C ) H(CH H , 5.67 (IH, d, J 7.61 (4H, m, Ar-Il), 7.85  —  7.93 (2H, m, Ar-H), 8.30  —  10Hz, -NH-), 7.44—  8.33 (1H, m, Ar-H); ‘ C 3  NMR ((+/-)-N-Napthoyl-(1 S,6R)-2,2,6-trimethylcyclohexylamine) (CDC1 , 101 MHz): 3 19.7, 19.8, 21.6, 30.1, 33.9, 35.1, 35.6, 40.4, 61.5, 124.2, 124.8, 125.7, 126.6, 127.2, 128.3, 130.3, 130.4, 133.8, 135.8, 169.7. ;  MS ((+/-)-N-Napthoyl-(IS,6R)-  2,2,6-trimethylcyclohexylamine) (El): m/z 295 4 (M ) ;  183  ‘H NMR MHz):  ((+/-)-N-Napthoyl-( 1 S,6S)-2,2,6-trimethylcyclohexylamine)  1.05 (3H, d, J  =  , 3 (CDC1  400  6.4 Hz, ) 3 -CH-C , H 1.10 (3H, s, ) -(CH 3 CH C-), 1.11 —1.21  (1H, m), 1.15 (3H, s, ) -(CH 3 CH C-), 1.28— 1.38 (1H, m), 1.50— 1.61 (4H, m), 2.18— 2.21 (111, m, ) 3 -C 2 CH( -CH CH H -), 4.10 C(CH ) 3 -), 5.80  —  (2H, m, Ar-H),  —  4.16 (1H, m, --C 2 CH(NH-Napth H oyl)-  6.00 (1H, m, -NH-Napthoyl), 7.45 8.26  —  —  7.63 (4H, m, Ar-li), 7.85  —  7.95  8.33 (1H, m, Ar-H); ‘ C NMR ((+/-)-N-Napthoyl-(1S,6S)3  2,2,6-trimethylcyclohexylamine) (CDC1 , 101 MHz): 3  19.3, 21.6, 25.5, 29.0, 29.1,  30.6, 34.1, 34.9, 57.6, 124.2, 124.9, 125.8, 126.6, 127.3, 128.3, 130.4, 130.4, 133.9, 136.0, 169.7;  MS ((+/-)-N-Napthoyl-( 1 S,6S)-2,2,6-trimethylcyclohexylamine)  (El): m/z 295 (M); Anal. Calcd for H N0 C 2 0 (mixture of diastereomers): C, 81.31; H, 8.53; N, 4.74. 5 Found: C, 80.93; H, 8.51; N, 4.74.  +  (+/—)  (+1—)  (+/-)-N-benzoyl-(1R,2R)-methylcyclohexylamine and (+/-)-N-benzoyl-(1R,2S)-methyl cyclohexylamine. Both (+/-)-N-benzoyl-(1 2 R,2R)-methylcyclohexyla 5 mine and (+/-)-N benzoyl-(1R,2S)-methyl cyclohexylam 26 ine are known compounds. The ratio of 2:1 anti to cis was determined from the ‘H NMR of the reaction mixture following removal of the internal standard via colunm chromatography. The trans and cis products were isolated with a ratio of 8:1 respectively due to our inability to cleanly isolate the cis isomer along with the trans isomer. In light of this, it should be noted that the C-H activation reaction  184  proceeds to 75% conversion, and the lower isolated yield for the derivized products is likely also due to our inability to cleanly isolate the cis isomer. Only the peaks for the major diastereomer and the key diagnostic peaks for the minor diastereomer have been assigned in the ‘H NMR spectrum. ‘H NMR (CDC1 , 400 MHz): 6 0.95 (d, J 3 3 minor diast.), 1.00 (3H, d, J -CH 1.65  —  =  6.4 Hz, -CH 3 major diast.), 1.10— 1.44 (4H, m),  1.84 (4H, m), 2.02 —2.12 (1H, m), 3.66  —  3.76 (1H, m, -CH(NHBz)-), 4.24  4.32 (m, -(CH(NHBz)- minor diast.), 5.90 (1H, br d, -NHBz), 7.40 ArH), 7.74  —  6.8 Hz,  —  —  7.53 (3H, m,  7.79 (2H, m, ArH); ‘ C NMR (CDC1 3 , 101 MHz): 6 19.3, 25.6, 25.9, 3  33.9, 34.5, 38.9, 54.6, 126.9 128.7, 131.4, 135.3, 167.1. N 9 HRMS H 4 Calcdf 0 , orC, (mixture of diastereomers) [M]:  217.14666;  Found:  217.14661. Anal. Calcd for  9 H 4 C, N O: , C, 77.38; H, 8.81; N, 6.45. Found: C, 77.19; H, 8.82; N, 6.17.  (+/-)-(1S,2R)-2-Methyl-1-phenylcyclohexylamine.”  The reported yield of 52 % for  this compound is an NMR yield based on comparison of a well resolved doublet resulting from the methyl group of (+/-)-(1S,2R)-2-methyl-1-phenylcyclohexylamine to a well resolved signal generated by the internal standard 1 ,3,5-trimethoxybenzene. ‘H NMR , 400 MHz): 60.57 (3H, d, J = 6.8 Hz, 3 3 (CDCI -CH ) , 1.35  —  1.52 (4H, m), 1.55  —  1.68  (411, m), 1.72— 1.82 (2H, m), 1.95—2.06 (111, m), 7.17—7.23 (1H, m, ArIf), 7.30— 7.36 (2H, m, An]), 7.50— 7.54 (2H, m, ArH); ‘ C NMR (CDC1 3 , 101 MHz): 6 16.0, 3 22.4, 26.5, 30.6, 40.0, 42.4, 57.4, 126.1, 126.7,  128.9, 150.0; MS (ESI): m/z  (M+H); HRMS Calcd for 9 H, [M1: 189.15175; Found: 189.15192. 3 C, N  185  5.5 References  (1)  a) Labinger, J. A.; Bercaw, J. E. Nature, 2002, 417, 507—514. b) Shilov, A. E.; Shul’pin, G. B. Chem. Rev. 1997, 97, 2879  —  2932. c) Amdsen, B. A.;  Bergman, R. G.; Mobley, T. A.; Peterson, T. H. Acc. Chem. 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Soc. 1994, 116, 7447.  188  CHAPTER SIX: CONCLUSIONS AND FUTURE WORK  6.1 Summary, conclusions and suggested future work  Two basic strategies were employed in this dissertation to further the field of group  four metal catalyzed reactions involving amines. Firstly, the capabilities of existing catalyst systems were expanded upon by modif’ing reaction conditions or by taking advantage of their unique reactivity (chapters two and five); and secondly, attempts were made to generate more reactive and selective group four catalysts by the rational design and implementation of new N,O-chelating ancillary ligands (chapters three and four). The exceptional reactivity of the titanium bis(N-2,6-diisopropylphenyl(phenyl)amidate) bis(dimethylamido) complex 1.1 towards alkynes in the presence of arylamines was elucidated and then expanded upon in the work described in chapter two. It was found that in conjunction with aniline and p-anisidine, this complex could be used to effect the hydroamination of various terminal alkynes, including TBDMS protected propargyl alcohol, at ambient temperature. Internal alkynes, and most importantly symmetrically substituted internal alkynes, could also be used as substrates. However, heating was required for these reactions to proceed within a reasonable amount of time. Hydroamination reactions involving the coupling of alkynes with p-anisidine provide a means of preparing PMP protected primary amines using relatively mild conditions, and the hydroamination of protected propargyl alcohols is particularly advantageous, as this methodology can then provide entry into useful synthetic precursors to compounds such as 3-amino alcohols.  189  Preliminary investigations into the intramolecular hydroamination of aminoalkenes using commercially available ) 2 Ti(NM 4 e as the precatalyst showed that this system is capable of cyclizing primary aminoalkene substrates to form pyrollidine and piperidine heterocyclic products with moderate to good yield.’ Based on the observation that 2 Ti(NM 4 ) e does not effect the cyclization of secondary amine bearing aminoalkene substrates, it is argued that this system requires the formation of an in situ genera ted catalytically active titanium imido species in order to proceed through a mechanism analogous to the titanium catalyzed hydroamination of alkynes. Although the substra te scope using ) 2 Ti(NM 4 e was found to be quite limited, this first reported example of neutral group four metal catalyzed alkene hydroamination laid the groundwork for all subsequent developments involving neutral group four catalysts for this transformatio n. Indeed the area has received a substantial amount of attention from a number of research groups since this breakthrough was reported in 2005.2 The assessment of complex  1.1, in terms of intramolecular aminoalkene  hydroamination catalysis revealed that this system is much less active than the precursor complex, ) 2 Ti(NM 3 . 4 e Based on these results it became apparent that substantial modification to the bis(amidate) precatalysts would have to be made in order to increas e their reactivity to a level such that the efficient intramolecular hydroamination of a broad range of aminoalkene substrates could become feasible. In chapter three a titanium compound, which was analogous to complex 1.1 but incorporated amidate ligands bearing electron withdrawing perfluorophenyl groups was synthesized and evaluated as a hydroamination precata 4 lyst. The inclusion of electron withdrawing perfluorophenyl groups was expected to improve catalyst activity relative to  190  complex 1.1 by generating a more Lewis acidic metal center. Hydroamination screening experiments revealed that the perfluorophenyl variant of complex 1.1 is indeed more reactive; however, it was also found to be susceptible to decomposition under the conditions employed for catalysis. This was attributed to the addition of amine substrate to the perfluorinated aromatic ring of the amidate ligand via nucleophilic aromatic substitution. Based on these findings, it is evident that pefluoro-aromatic substituents are not suitable as electron withdrawing groups for complexes employed as hydroamination catalysts. The use of alternative electron withdrawing groups, such as trifluoromethyl, may achieve the desired effect while avoiding the aforementioned side reactivity. The investigations using amide proligands derived from (-)-menthone were intended explore whether chiral non-tethered amidate ligands could be used to generate group four bis(amidate)  bis(amido)  precatalysts  capable  of affecting  cyclohydroamination of aminoalkenes. The chiral  the  enantioselective  non-tethered amidate  ligand  framework attracted our attention due to the modular and simple way in which they can be produced, though a major drawback to this approach is the potential for more than one coordination isomer.  For reasons described in chapter three, it was argued that one  coordination isomer could predominate over the others, and this may make enantioselective catalysis using these systems possible. Indeed, enantioselectivity was achieved for the cyclohydroamination reaction, albeit with low enantiomeric excess. While the particular ligands described in chapter three are not worth pursuing, this work demonstrates that the non-tethered chiral amidate ligand motif can be used to generate chiral zirconium complexes capable of effecting enantioselective catalysis and may provide an alternative to the axially chiral tethered bis(amidate) ligand framework.  191  Future work to improve the performance of this system could include an investigation of how the steric and electronic properties of the substituent in the R’ position influence reactivity and stereoselectivity (Figure 6.1).  1 R  =  R 1 \NMe 2  2 9YINM e 1 R  F3cXI  Figure 6.1. Potential modifications to the bis(N-((1R,2S,5R)-2-isopropyl-5-Methylcyclohexyl)benzamiclate) zirconium bis(dimethylamido) precatalyst. This thesis also included the synthesis and characterization of the first titanium and zirconium bis(2-pyridonate) bis(amiclo) complexes which utilized either 2-pyridone or 6tert-butyl-3-phenyl-2-pyridone as proligands. For the reasons discussed in chapter four, this ligand set was devised as an alternative to the amidate ligand set in order to generate more reactive hydroamination catalysts. X-ray analysis indicated that the bis(2pyridonate) titanium bis(dimethylamido) complex 4.1, the bis(6-tert-butyl-3-phenyl-2pyridonate) titanium bis(dimethylamido) complex 4.2, and the bis(6-tert-butyl-3-phenyl2-pyridonate) zirconium bis(dimethylamido) complex 4.3 are all monometallic and adopt a pseudooctahedral 0-trans C 2 coordination geometry. The bis(2-pyridonate) zirconium bis(dimethylamido) complex could not be prepared as a discrete monomeric compound, and clearly demonstrates that there is a minimum level of steric bulk that these ligands must possess in order to form monomeric zirconium complexes.  192  Of the four compounds studied, zirconium complex 4.3 was the only one found to be an efficient catalyst for the cyclohydroamination reaction, and this complex exhibited reactivity comparable to the most active zirconium bis(amidate) bis(amido) complexes. Further substrate screening experiments demonstrated that complex 4.3 can affect the cyclization of more challenging aminoalkenes bearing unactivated internal C=C bonds; substrates which had previously been inert towards intramolecular hydroamination using the bis(amidate) system. This result is consistent with the greater accessibility to the metal center afforded by the 6-tert-butyl-3-phenyl-2-pyridonate ligand being more accommodating to substituents on the olefin. Future work involving the 2-pyridone derived ligand set may include further investigation into how the steric and electronic properties of the substituents in the R 3 and 6 positions of the pyridone ring influence catalysis (Figure 6.2). Based on reactivity R trends recently observed with the amidate ligand set, 5 a zirconium 2-pyridonate complex incorporating proligand 6.1 could be included in future structure/activity studies of these complexes. In addition, the incorporation of an electron withdrawing substituent in either the R 4 or the R 5 position may be of interest.  2  6.1  Figure 6.2. Bis(2-pyridonate) titanium and zirconium bis(amido) complexes.  193  The discovery that titanium(IV) and zirconium(IV) complexes catalyze the a C-H bond activation/intramolecular aminoalkylation of 6-heptenylamines has shed light on a unique transformation that has the potential to be developed into an efficient, atom economical new methodology which could ultimately be applied to the synthesis of a chiral amines. 6 Among the complexes tested for a functionalization reactivity, Ti(NMe 4 ) 2 proved to be the most effective catalyst over all; while the zirconium 2-pyridonate complex 4.3 was found to be the next most effective, and most effective of the zirconium complexes.  It should be noted that an important advantage associated with the 2-  pyridonate system is that the ancillary ligands provide a handle for modifying reactivity and selectivity. None of the bis(amidate) complexes tested were found to catalyze the a functionalization reaction. Through a brief substrate scope analysis it was shown that this reactivity is not exclusive to the substrate initially tested, and in fact other substrates undergo cyclization to form the respective cyclohexylamine derivatives more readily. More detailed mechanistic investigation, including kinetic studies as well as the characterization of reaction intermediates is required for a better understanding of this transformation.  Additional catalyst structure / activity studies coupled with a more  comprehensive substrate scope analysis should provide valuable insight into this intriguing reaction. The most significant work described in this dissertation contributes to the understanding of group four metal catalyzed reactions by illuminating some previously unknown reactivity associated with titanium and zirconium. Namely, it was established that neutral titanium(IV) complexes can be used as catalysts for the intramolecular hydroamination of 1 aminoalkenes; and also that both titanium and zirconium complexes  194  can potentiate the conversion of 6-heptenylamines to aminocyclohexane derivatives through an ci. C-H bond activationlalkene insertion type process. 2 If catalyst systems capable of efficiently and selectively promoting these transformations with a wide range of substrates in an intermolecular fashion could be developed, they would serve as powerful methodologies which could ultimately be applied to the synthesis of a multitude of highly sought after nitrogen containing fine chemicals. The work in this thesis  involving catalyst development has further demonstrated the dramatic influence that ligand structure can have on reactivity as well as provided some alternative avenues for future research.  •  195  6.2 References  (1) Bexrud, J. A.; Beard, J. D.; Leitch, D. C.; Schafer, L. L. Org. Lett. 2005, 7, 1959. (2) Muller, T.E.; Hultzsch, K.C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795 and the references therein. (3) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006, 25, 4069-4071. (4) (a) Bexrud, J.A.; Li, C.; Schafer, L.L. Organometallics 2007, 26, 6366. (b) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. 0.; Schafer, L. L. Chem. Commun. 2003, 2462 (c) Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 4733. (5) Thomson, R. K. Doctoral Thesis, UBC, 2007.  (6) Bexrud, J.A.; Eisenberger, P.; Payne, P.R.; Schafer, L.L. I Am. Chem. Soc. submitted September 24 2008.  196  APPENDIX  Tables of crystallographic parameters, ORTEP diagrams, selected ‘H and ‘ C NMR 3 spectra:  Representative ‘H and ‘ C NMR spectra for the different classes of compounds 3 synthesized in chapters two, three, four and five can be found in the following pages.  197  Table Al: Crystallographic parameters for complex 3.1, 4.1, 4.2, and 4.3.  Formula formulawt cryst dimens, mm temp. K wavelength (A) cryst syst space group a, A b,A c, A a., deg , deg ‘y, deg  3 v,A Z  3 D,Mg/ m abs coeff, mm F(000) Orange, deg indexranges  No. of rflns No.ofindeprflns No. of data /restraints /params goodnessoffiton 2 F final R indices (1> 2o(])) R indices (all data)  3.1  4.1  4.2  4.3  56 C 6 H 1 F 80 4 N 2i T  N 1 C 2 H T 2 O 4 4 0 i  N 3 C 4 H T 2 O 4 4 i  N 3 C 4 H Z 2 O 4 4 r  1245.26 0.40 x 0.40 x 0.20 293(2) 0.71073 Monoclinic C 2/c 29.207(3) 10.8442(9) 22.707(2) 90 115.209(4) 90 6507.0(10) 4  324.24 0.20 x 0.20 x 0.20 293(2) 0.71073 Monoclinic P 21/c 8.7587(14) 12.689(2) 14.739(2) 90 105.059(8) 90 1581.8(4) 4  588.63 0.20 x 0.20 x 0.20 293(2) 0.71073 Monoclinic P 21/n 12.4171(3) 18.1184(4) 15.0137(3) 90 100.768(1) 90 3318.28(13) 4  631.95 0.50 x 0.50 x 0.50 293(2) 0.71073 Monoclinic P21/n 13.206(2) 17.563(3) 13.563(3) 90 92.226(11) 90 3143.4(9) 4  1.271 0.207 2616 1.54 —28.02 -38h38 -13k14 -29l29 72029 7703 7703/0/393  1.362 0.550 680 2.15 —28.12 -11h11 -16k16 -19l19 16939 3831 3831/0/190  1.178 0.292 1256 1.78—22.04 -13h13 -18k19 -15l15 39391 4076 39391/0/370  1.335 0.3 86 1328 1.90— 34.98 -20h19 -27k28 -21l19 53325 13181 13181/0/370  1.027  1.041  1.122  0.981  0.0390,  0.0378,  0.0498,  0.0419,  0.0980 0.05 86, 0.1069  0.0905 0.0596, 0.0994  0.1328 0.0693, 0.1572  0.1020 0.0820, 0.1235  198  Figure Al. ORTEP depiction of (+/-)-(1S,6R)-N-Tosyl-2,2-diphenyl-6methylcyclohexylamine. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity.  Figure A2. ORTEP depiction of (+I-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 S) methylnaphthalenamine. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity.  199  Figure A3. ORTEP depiction of N-Napthoyl-( iS ,6R)-2,2,6-trimethyl-cyclohexylamine. Elipsoids are drawn at the 50% probability level. Hydrogen atoms have been omitted for clarity.  200  QQOMe  8.0  ppm (fi)  7.0  6.0  5.0  4.0  3.0  2.0  1.0  0.0  Figure A4. ‘H NMR spectrum of(4-methoxy-phenyl)-phenethyl-amine.  ppm (fI)  150  100  50  Figure AS. 13 C APT NMR spectrum of(4-methoxy-phenyl)-phenethyl-amine.  201  Y  00  H-s-H  I  7.0  6.0  ppm (11)  5.0  H—i  H-  I  4.0  3.0  2.0  1.0  0.0  Figure A6. ‘NMR spectrum of (3 ,3-dimethyl-butyl)-(4-methoxy-phenyl)-amine.  I  II  150 ppm(fl)  100  50  Figure A7. ‘ C APT NMR spectrum of(3,3.-dimethyl-butyl)-(4-methoxy-phenyl)3 amine.  202  -OMe HN  80  50  pp,,, (fi)  —  2O  l0  00  Figure A8. ‘H NMR spectrum of (1 ,2-diphenyl-ethyl)-(4-methoxy-phenyl)-amine.  JOMe  wag—  ppm (II)  150  100  50  Figure A9. ‘ C APT NMR spectrum of (1 ,2-diphenyl-ethyl)-(4-methoxy-phenyl)3 amine.  203  JL__  H S  II,rrr  8.0  --—1—  7.0  6.0  ppm (fi)  T1r]  I  rr1  5.0  --  S  5  1 r r11  4.0  I 3.0  2.0  10  0.0  Figure AlO. ‘H NMR spectrum of (4-methoxy-phenyl)-( 1 ,3,3-trimethyl-butyl)-amine.  .  ppm (fi)  ISO  ISO  m  50  Figure All. ‘ C APT NMR spectrum of (4-methoxy-phenyl)-( 1,3,3 -trimethyl-butyl) 3 amine.  204  I  I  I I  ppn (II)  810  P I  I  70  O!O  I I  I  I  1111  510 I  I I  Figure A12. ‘H NMR spectrum of [3-(tert-butyl-dimethyl-silanyloxy)-propylj-(4methoxy-phenyl)-amine.  iwqnqrnw$w$i  nRnuflrn*pewFi  ISO  ppm (II)  50  0  Figure A13. ‘ C APT NMR spectrum of [3-Qert-butyl-dimethyl-silanyloxy)-propylj-(43 • methoxy-phenyl)-amine.  205  Y  H-  Y-r’  IIIIIIIIjIItI,IIIIIIuIIIrIIIIIIII  I  80 ppn (fi)  7.0  60  5.0  4.0  30  2.0  I 1.0  0.0  Figure A14. ‘H NMR spectrum of [1 -benzyl-2-(tert-butyl-dimethyl-silanyloxy)-ethyl](4-methoxy-phenyl)-amine.  ppn, (0)  150  100  50  Figure A15. ‘ C APT NMR spectrum of[1-benzyl-2-(tert-butyl-dimethyl-silanyloxy)3 ethylj-(4-methoxy-phenyl)-amine.  206  t’J C  j.  CD  H  —  I.  J2  NHCI  ppm (11)  Figure A18. ‘H NMR spectrum of the hydrochloride salt of 1 -methyl-2-phenylethylamine.  C 3 J 3 I  — rr’wrm’ V•,  ,,.fl,p._97!rn!_,  .-  SflWfl’  -  150  ppm (Pt)  100  50  Figure A19. ‘ C APT NMR spectrum of the hydrochloride salt of 1-methyl-2-phenyl3 ethylamine.  208  Ho  ll’J H S  S  00  7.0  6.0  ppm (II)  5.0  4.0  3.0  2.0  1.0  0.0  Figure A20. ‘H NMR spectrum of 2,4-Ni ,N3-tetraphenyl-butane- 1,3 -diamine.  NH  H  1mi!  150  ppm (11)  h wiw  100  50  Figure A21. ‘ C APT NMR spectrum of 2,4-Ni ,1V3-tetraphenyl-butane- 1,3 -diamine. 3  209  •  I  4.  (a.)  ‘i’J  CD  k)  ppm  [I  JOB N  01 01  01 CU In 01 01  V  CU  In 0  In —  8  C)0  CII In  •CII  CU In  I  I  g  H  NH  V  CU CU 01 01 Ifl 01  L._.!__J  1’..  H 5pectrljrn ref. to CDCI3 at 7.27 corn  I  (0  I  C>  CU  4  “[‘  S  I  -....  1-.  I  C I.  0  /  g 1  CII C.  H  0  I 0  CII (0  2  rrrr  V In 01 In  I  In In  .r..i  0  -  —  us  Hz Hz me  0.10 Hz  Proceso2ng parameters 32768 400.1300052 NH EM  111 9.00 us 000 dO 400.1324008 IfH  CHANNELII  300 0 K 1.00000000 me  CDCI3 26 2 4990,020 0304567 1.6417269 905 100200  10 NMR plot paramet:r: CX 20.00 cmi CV 4.00cm FtP 10,000pp Ft 4001.30Hz F2P -0.200 pp P2 —80.03 Hz PPMCM 0.5i000 p HZCM 204.85630 Hz  P2 SI SF WOW  NLJCI Pt PL1 SF02  TE 01  SWH FIDPES 60 PG  OS  SOLVENT MS  P2 Acquisition Parameter Date 20060323 8. as PO8HD SmmBBIjl+-88 PULPROG zg3O  o PROCNO  i Current Data Parameters  C  1*  I I  Vt,  .  09  010)00  f__F  *  1.40  420  -  ,,.  j  100  ‘401  (0 50 0) 0 fl  c_A  N000005000505000200N[0’4NN ‘4 ‘4 ‘4 70 ([3 0) ([3 0) CI) (54 (53 (5) 0) CV)  N Dig) o N 60 05 In 03 0) ‘4 N 02 01 [0 0 07 01 (Ii [0 CU 0) 02 01 0 CI) 421 N 0 0)-’00)In—(900CV[Q205  80  0..F-[D N N N  ‘4 05 [0 (9 01 1% ID—N  )  Si  tO to  NN  Nlfl  0 05 — CV)  to  [0 05 0,  ‘s  00 ‘4  .  soc sec soec  soc  Sec  00  VCC  09420  SoC  lIz  VIz  00423  ..  cc co poe Hz ppm 047 p061c00 Hz/cm.  PeoCe9s1TgpaTaoVe0505 30769 70.4977395 090.’ 904 0 2.00 09 0 1.40  coo 03 0.09 03 300.1316000 0910  0100NNEL 00 6 ca1141 V 00.00  130 10.00 425CC 29.00 03CC 0.0020 75.0755100 607  CI1090EL 4  0 N60 pOOL 04C4605C’3 CX 2000 03 4.03 PIP 160.202 Fl 00274.64 FOP 00 300 75 1509,30 P?0H 7.00000 14506 026.07407  000 0.0 06 PC  WOW  P2 01 07  SF20002 947C2 PCO2 202 00.12 SF02  sO °LI 0001  03  100000  P15000 AS 20 36 09 19 CNST2 016011 01 002 2020 209 70  294  93939 00013.  000120113  4 100032.393 0.207360 I 7403300 16304 26.950 30.93 300.0 246,0000000 0.0000000 1.05000000 0.00002000 0.00699095 0.00000000 10.00  Fm  05  5  I LicT PArametNrs 20000323 9.53  95  SOLVENT  TO  09020524 060893  0406..  -  £0790 000090  )  Do 20r161e3 J00371  /  8.0 (fl)  7.0  6.0  5.0  4.0  3.0  2.0  1.0  00  Figure A24. ‘H NMR spectrum of 2-methyl-4,4-diphenylpyrrolidine.  7 aLII 1 rfl J9flW b$ 0fl_ 6  ppm (H)  160  1 .W* 1 M UflM ’f Stfl l  500  .  50  Figure A25. 13 C APT NMR spectrum of 2-methyl-4,4-diphenylpyrrolidine.  212  [  —rrrijr 8.0 ppo(fl)  -  I  rrjrrrI rr 7.0  60  -Irf rII —I TII  5.0  4.0  3.0  I  Illiji  2.0  1.0  III  0.0  Figure A26. ‘H NMR spectrum of 2-methyl-4,4-diphenylpiperidine.  ppm (el)  tOO  50  Figure A27. ‘ C NMR spectrum of 2-methyl-4,4-diphenylpiperidine. 3  213  pn(fI)  Figure A28. 1 H NMR spectrum ofN-benzoyl-2-methyl-4,4-dimethylpyrrolidine.  *rwmw  150 pç,n(fl)  100  50  Figure A29. ‘ C APT NMR spectrum of N-benzoyl-2-methyl-4,4-dimethylpyrrolidine. 3  214  8O’ ppm (P1)  Figure A30. ‘H NMR spectrum of 2-benzyl-4,4-diphenyl-pyrrolidine..  ppm(fI)  Figure A31. 13 C APT NMR spectrum of 2-benzyl-4,4-diphenyl-pyrrolidine..  215  C.’  CD  z  -  C)  0  pOrn  I’  cI  t’J  C  CD  —  IH  9  ()  N. N.  C..  IS. N.  f.. f..  N.  C.  N.  f  OCCff.-* C..  FT  8  7  .rnrnrpr  rn  6  LJJ  f.  N. N.  ,.‘OO)f%LflIflVflJON. f.  N. (I)  C, C)  •5  C) C)  a  ii’i:  ant:syn  80%  ‘1.7:1  (7)  —.O1flJOOtiO fl  LLLLLLL  fl  C3  ij-.t c.øcI. spectruni ref. to COCI3 t 7.27 ppm  r.rrrtT..r.rrr.  JO NO:  N.  3  N.  CJC NJ  (  OC,LflW)flV 0  flJr. C)  0 0  O”S 0  1 .r.rr..7. n._n.rrpir..Trn,.tr. 2 1  tOC  -  —  32768  Hz  SOC  usec user f  Hz sc  HZ/Cm  ppm/cm  lIz  Hz  cm ppe  Processzng parameters 32768 400.1300051 M EM 0 0.10 Hz 0 0.50  IN 1.25 usec 0.00 dS 400.132000? MHz  CHANNEL f 1  CDC13 26 2 4990 020 0.152283 3.2834036 22.6 100.200 6.00 300.0 1 .00000000  ID NHP olot oarameters Cx 20.30 Pip 10.000 fl 4001 30 P29 o:ooc P2 0.30 P PH CM 0.50000 HZCM 200.06530  NOW 558 LB GB PC  SF  P2 51  NIJC1 91 PL1 SF01  00 9.6 OW DE TE 01  FIURES  OS SWH  SOLVENT  SQ  Acquisitsmn Parameters 20351005 Time 7.58 INSTRUM av480 PROB 5 mm 081 IH—08 PULPRGG zg3O  P2  urrent Data Parameters NAME JA873 EXPND I ROCN0 1  8T  Imxuu)  uipqoL  (suoaisinp JO wn.ipds JJAIN IdV 3 EV ‘!J  /  9  -u I  ZI +  145.093  /  -  -  —  \ \\\“—  128.540 126.275 128.154 127.818 127.808 127.618 127.530 127.144 126.075 125.952 125. 909 87  77.615 77.266 75.918 60. 323 60.210 59.690 53.321 57.911 51 .736 51. 547 46.747  0 ._—  —  ———  24.782 21.611 21.148 16.888  .  I  C iii /  —  O  o  •  pm  to  m  ...‘  .  .8.  r- r-. r’ tI  1’. r-  —,  r.  in iii  Ph  to  cm r. to I In in  H  Ph  cml 001  a,t  ,  to to  to  I  2  ‘  to  ‘  to  i ml  V  to to  to cm to ru to to to OCUOtO  to  S  to to in to to to to to in to  L/  to  )..“  ..———.  I’. I- i I— t- 10  tocotototo—r-.cutocq’mto to to to to to in to — to to to o, to to  II—H3—J8 (2) Cl CDCI3  -  —  FPP F2 PPMCM KZCI.I  RIP  usei uset K sec  Hz Hz sec  10.000 3001.30 0.5O0 -150.07 0.52500 157.55825  ppm HZ ppm Hz ppm, HZ/i  Processing parameters 32768 300.1300041 MHZ EM 0 0.10 Hz  IN 10.80 uset 0.00 88 300.1318008 MHz  CHANNEL fi  3742,515 0.228425 2,1889524 128 133,600 0,00 300.0 1,00000000  C13  ig3O  D NMR plot parameters  F2 51 SF WOW SOB LB  NUC1 P1 PLI SF01  OW 00 TO 01  OWN ECORES 40  SOLVENT  PULPROG  Acquisition Parameters Date_ 20050811 Time 7.49 INSTRUM v300  —  Current Data Parameters NAME J8304 EXPNO PROCNO I  C  I  I  CD  C,)  PPOT  E  ,.  5O.’.’..  “‘“—“r’””—  II-ll3J6 (2) Cl CDCI3  14  .1’  dID CCDCDCDr’.r-’.  IDF’.  r. CD CD CD F’. Cu CD F’‘CDDU3 IDIDIDID  ‘COCiDJ  Cu Di C CO  OTCDLDCD  V \./V  CDCDO) C-F-h’.  CIDID  FT C ID  CO  ID  CO  CD —  CE  F’,  uoec 118 48 MIle  CHANNEL 12 0510515 10 80.90 0,00 17.39 300,1316000  cm ppm Hz ppm HZ eec/Ce Hz/ce  CA  ProceoSsnO ParaaUtCfO 32708 75,4576433 MHz CC 0 2.00 lIZ 0 1,40  050C 00Cc 48 MHz  13C 5.75 11,00 2.00 75.4795190  CHANNEL II  113 999 0100 paI’arneters CX 20.00 CV 4,00 FOP 000.000 Ft 15003.13 FOP 0.000 F2 0.40 P00CM 10,00000 .42CM 754.0745  F2 50 SF ADA SOS LB 09 PC  CPOPNB2 HOC? PCPD2 PL2 PLC? SF02  811CC Pt p2 PLC SF01  —  F? AC3400itiOn i’araIeL9r9 DaLe’.. 20050811 Tine 7.57 1900904 av300 P90860 5 se ONP 16/13 PULPROS jean TO 65535 SOLVENT COCID NO 110 4 OS 594 15532.393 Hz FIONES 0.287390 Hz AG 1.7480308 sec 80 16394 08 26.550 USAC 37.83 usec 05 TE 300.0 IC CNST2 145.0000000 CNSTII 1,0000000 01 3,00000000 sec 413 0.00000300 sec 420 0.00908655 Sec 0.00000732 sec DELTA  Current 0406 Parametoes NAME 29305 EXPNO I PROCNO I  —.  \  ppm  .5  -  E  .Y  .(.C  ..  c2.  P. C 01 C  P.  P.  P. C-  e in  P.  ...  P.  P. P. P. P.  P.  0) CD  -  CD —  m  N1  in  — CCC  01 CU CD DC P. Cfl P. 01 0  C- P.  S  q (CC CC) CCC (CC CCC C) () (CC (Cl  .  H  0 0  .—  ‘NCT)(’ CC  CD 0 (U  2  .  .  0  01 ‘  I  ..  (Cl Cl) (U (U Cl) Cl) Cl) CIC CU CCC — —  L/>  ‘  0  CC  00roo P. P.  LLj-J  C-  in  Cl C P. C P.  0db ref. to CDCI3 at 7.27 ppm  .o iDCD010intfl  (s’)  P=j3.50us at  f/—jj  1H observe  N /  0  I  —  0Hz  Processing parameters  13.50 use  IN  CHANELfI-——  Fl F2P P2 PPMCM KZCM  PIP  -0.500 ppm -150.07Hz 0.52500 ppm, 157 56825 HZ/C  l0000pm 3001.30 Hz  10 NMR plot paremeterS  14.101 P1  It 01  OW GE  3742.515 Hz 0.228425 Hz 2.1589624 sec 143.7 133,600 use 6.00 useC 300.00 .oooooooo sec  OWN FIORES AG  zg3O COCI3  mm  SOLVENT  PULPROG  v300  7.56  20050929  Acuistion ParameterS  INSTJM  T1m5  P2  EXPNO PROENO  tui’rent Ota Parameters NAME JB313  —fq  8.0  7.0  6.0  5.0  4.0  3.0  2.0  1.0  0.0  Figure A39. ‘H NMR spectrum of N-(2,6-dimethylphenyl)- I ,2-methyl-phenyleth ylamine  ppm(ft)  ISO  100  50  Figure A40. ‘ C NMR spectrum of N-(2,6-dimethylphenyl)- 1 ,2-methyl-phenyl 3 ethylamine.  222  H  S 8.0  7.0  6.0  ppm (II)  5.0  4.0  3.0  2.0  l.0  00  Figure A4 1. 1 H NMR spectrum ofN-(2,6-dimethylphenyl)- 1 -methylpentylamine.  pjg  .  150 ppm(fl)  100  .  M  .  k  50  Figure A42. ‘ C NMR spectrum of N-(2,6-dimethylphenyl)-1-methylpentylamine. 3  223  —  c  CD  I  CD  CD  St  • •  o  —  N  /,  U UI UI N N C  tOLD  S..—S—..  H  -1  to CDCI3 at 7 27 ppm  N  N N  N  -f’S N N r, N. N  .Sfl-.O]0(OOSNCtJfltD ID C UI UI 0 5’S 03 CU fi N 0 0  JOB NO: IIl—31—J8 (C+D) IH spectrum ref  COrn  N CSC}  ‘000  If) 0O QCiLIO  CUNJCUCU.’-.o...-e  COO  ID ‘0  ‘003 CC  0  oooo  LDn,NCUm—fl-.t0or-mNmr-r1Co’,tflcLDCUflc OflCCUIUIIOCULO’S’*WItOUILDCCflN ‘.tflCUtfl CU N N NJ 01 0 (‘1 — NJ CD 0 01 fi fl 00 (Ii CO — N 0 CD ) fi . t% fi CCC CD CO In N LOIn — PC 0:0 fi cn CU — 0 en ., cm UI ON. N. N. 10 CD CD CD CO 10 CD In Ni In 10 CO 01 01 01  {0510: N  NJ  .)  Processrig 5aremeters 32760 400.1300051. MM EM 0 010Hz 0 0.50  F2 SI SF WOW 058 LB 68 PC  10 NI4R plot premeters CX 20,00 cm CV 8.00 cm F IP 10,000 P0 Fl 4001,30 Hz F2P —0.200 pp F -80.03 Hz PPMCM 0.5100000 HZCM 204.06630 Hz  —  iN 5.38 us 4.00 48 400.1324008 MN  CHANNEL fi  Mud P1 PU SF01  —  P2 Acusjtjsn Parameter Oste_ 20060613 Tine 9,39 INSTRUM avAOO PROBHO 5 ,mt 681 IH-B0 PULPROS zg3O TO 16384 SOLVENT COCI3 MS 28 OS 2 SWH 4990020 Hz FIORES 0.304567 Hz 1.6417269 se P0 22.6 OW 100.200 us 06 6.00 us TO 300.0 K 60 1.00000000 so  poco  Current Ota Parometers NAME JA8122  /  N  CD •  —.  —+  CD  N  SD  CD  CD  a.’  0  CD  g  N  +  H  H  V  (0 (LI C) N  I  to  CD.C13 8t 7723 jp,n  i-,-----.—-.--  I  C) (V 0 0  N C) C) NI C)  III-3—J.B (C443J 3C 58 EXPr ref.  II  BII  0 (0-0  0 0 0 0 C) (0 0 tO  PD  r—’—----r--—-i--—,  \/ V  ‘J 0 0 0 tO 0 —. 0 N N C) CLI N N N (A (0 0 0 N (V (0 (0  -  Aa  65036 C0013  au300 11(/  1903? 3:3 0.0873601* 1.7000308 uxe 16394 25.050 U5c 37.93 COo 300.0 K  ON  00 dO 00 PHZ  050  32768 75.4677395 HO ow 0 2.00 1* 0 1.00  19 60.00 0.60 05.97 19.00 300.1016000  -wuit-C059-  CHANNEL 12  11.00 uoec 0.0008 75.0705090 WHo  e—  0-03000000 00.0 0.00602(10(1 soc  INN  CHANNEL II  S  SL(0H Puuotor 000130013  PHCN CH  FOP  N (10100 ppeVcie (4 ii 03/ a  0000 opm  (0 NHO plot parumeors ox 20.00 tin Cl 16.00 tin  02 SI SF wow 008 tO 09 PC  PLO PLI2 PL(3 0002  PEPO  CPOPR00 N002  9001  P1_I  P1  011 0(2  I1 F00000 HO RN OW 00 is  ULP0 TO )0(VENT  INST900  02  Curront ONLH PNr5m5teu N000 16402 EXPNO I P00C60 I  7  9Z  j punodwoo pTumzuq-oJon J-9’ç’j7’ ‘N)-Z-(I1cUtJdIAd01d0S!P-9’l)-NJO mnods mi H, ctv ‘S  I  Il 7.214  I[r7.245  •:;;>-  I J/184 -:  ../  I.-Ii  \  —  I  9.8  m  q  _..::  /  \  m  d  ..,  —o  !‘LS t  6L  •_________ 9 Ct 999L€!  —  t609Pt L6t9’t  — (.0  (-) (-)  .0  0  0  I Figure A46. ‘ C NMR spectrum ofN-(2,6-diisopropylphenyl)-2-(N-2,23 diphenylpentylamino)-3 ,4,5,6-tetrafluoro-benzamide compound 3.4.  227  00  (  •  ..  —  I  (6  ‘  0  ON  ,  I  CI tJ  O  o  (6  I 0.1  8  O  I  Ui  ‘•r. ‘•t  ‘7’  o  _..  —  ,pm  1.  I  C  1H decoupled  V  0 Cl V  —140  c 0 V V  0  0-05.—IflaUC CS aU 0) 0) 05  e.. V  -145  .  -150  -155  (•JflJ5J IN Cli CS III U] II] Li I.) LI] U] In In Li] IL]  It)  p,w,—cvaUOr-.CS flu 01 0] 01 V Cli Cu 01  ref. to CFCJ3 at 0 ppm  -(2-3o C’)C’!  19F  /  -160  .  -165  -170  CS  •_—_•_—_  1.  IL] IL] LI]  CS  flJV’O’.. 05 Ifi 0 0 ‘1  r  MHZ  usz 00 00 78  Proressirg poramztcrs 163.84 282.4044813 lIMO 6. 0 3.00Hz 3 ION  CHANNEL /2 ealtOIb IA 80.00 0,00 16.46 19.00 000.1310000  8.03 usec 3.0078 287.3702054 480  000SNEL 11  ‘41.4  P614CM  620  -6363? 60 At 2.25000 op’s/cm 664101340cc  -180.000 ElM  00 )8 Blat parmmeters CX 20.00 cm FtP —1:15.003 ppl Fl —38124.61 H:  F2 61 SF WOW SOB LB 66 PC  sroo  PLI3  0800602 MiLD CP02 762 PL1?  MiLl 6! 001 SF01  —  F? &cnuUitwn Parameters DatO. 70050018 TIme II 17 1851808 UsD60 380)8110 6 mm 680 14/1? 001.6803 zpg30 TO 06536 SOLVENT MeSH 416 18 06 55497 176 HZ 548 StORES 0 867076 8/ 6.5800436 SeC 00 19300.4 OW 9.850 aseC 01. 10.57 uSeC TV 300.00 01 2.00000002 sec 011 0.03000000 sec 016 0.60002000 ses  EXPNO POliCeD  Current Data Parameters NAME 03321  /  0  d 1  1.00  }oio  ]-.  i-lo4  1314 }2.02  C  —  0  z  0  —  -o 0  —  C  C  0  F  /  /Ti(NMe ) 2 QN7  9.0  8.0  LH  H H  7.0  80  5.0  pp (fi)  4.0  3.0  2.0  1.0  Figure A50. ‘H NMR spectrum of bis(2-pyridonate) titanium bis(dimethylamido) complex 4.1.  /  ) 2 Ti(NMe  —  ISO ppn, (fi)  100  50  Figure A51. ‘ C APT NMR spectrum of bis(2-pyridonate) titanium bis(dimethylamido) 3 complex 4.1.  230  I  iF h  m  L  —  £ C99  LOt’’L  0  G)  / Figure A52. ‘H NMR spectrum of bis(6-tert-butyl-3-phenyl-2-pyridonate) titanium bis(dimethylamido) complex 4.2.  231  L’J  cm  ..  S.  CD  -‘  0  1•  CEO  8H  I-S.  I-.  tea.  — r1c24fMm.  0  ..  3C JMOD EXPT  SOLD  eae,  o P. 0)50  160  ref. to  2 NMe NMe 2  —.  — — 050) 0, 0) V V r- V 1DV-0,rnc,jo,coornr, aop.p.p.o,o  CDCI3 at 7723 ppm  100...  —  V  p.  0, SI) L0; 0) Cl  0, 5) 05 p. 51110  20  .  •  parameters 32768  10 NOV plot parameters CX 00.00 Cs CY 5.00 cs PIP 200.000 2110 VI 15003.55 17 FOP 0.000 p7m P2 0.00 Hz PPHCH 10.00000 060/ce MCCII 754.67743 HZ/cm  EM  0 2.00 112 0 1.40  75.4677303 MHz  9 PrOCNSSIC  usec 99 06 MHZ  usec usec 08 8811  WOW  —  10 80.00 0.00 06.85 300.1316000  CHAN0€L f2 wH11z16  625 12.50 2,00 75.4755190  CHAIHEL II  008 LB 09 PC  SE  Sf  F?  CPSPH02 NUC? PCPO2 PLO PU? SF02  52 PU SF01  6001  -  VS AcluaSlUos Paraeetero Data. 20051103 Time 7,57 16506124 av.300 P60850 5 ma, 081’ IH/13 PILPPOG lead TO 65536 SOLVENT 0606 85 760 115 4 S)*4 16832.303 Hz FISHES 0.287350 HZ 50 1.7400308 sec 60 13004 DC 26.550 usec SE 37.93 usoc TE 300.0 K 08002 145.0000000 CNSTII 1.0000000 01 2.00000000 sec 113 0.00000300 seC 820 0.00669655 sec IELTA 0.00000766 Sec  Cu re I Sate Perameta 090€ .326 EXPNO I  \  (Ph\Zr(NMe 2 )  A  11i1 , 1 rr  8.0  ——1r—  7.0  6.0  I  —rI IIjIC  5.0  4.0  (fl)  111 —t  rI  3.0  2.0  III  1.0  I—  0.0  Figure A54. ‘H NMR spectrum of bis(6-tert-butyl-3-phenyl-2-pyridonate) zirconium bis(dimethylamido) complex 4.3.  (PhO Zr(N Me ) 2  tBU 2  ‘r  150 p,m  (fi)  100  50  Figure A55. ‘ C APT NMR spectrum of the bis(6-tert-butyl-3-phenyl-2-pyridonate) 3 zirconium bis(dimethylamido) complex 4.3.  233  2 NH  810  60’  70  ppm (81)  5O  30  20’l0  010  Figure A56. 1 H NMR spectrum of 2-cyclohex-2-enyl-2,2-diphenyl-ethylamine in d 6 benzene.  NH  00  ipo  lao  ppm(tI)  Figure A57. 3 ‘ NMR spectrum of 2-cyclohex-2-enyl-2,2-diphenyl-ethylamine in d C 6 benzene.  234  (÷1-)  ppm (fi)  Figure A58. NMR spectrum of (+I-)-(S,S)-3 , 3 -‘diphenyl- 1 -( p-toluenesulfonyl) octahydro-indole.  (+1-)  r 150  ppm (fi)  100  50  Figure A59. ‘ C APT NMR spectrum of(+/-)-(S,S)-3, 3-diphenyl-1-(p-toluenesulfonyl)3 octahydro-indole.  235  ppm (P1)  Figure A60. ‘H NMR spectrum of 2-ethyl-4,4-diphenyl-pyrrolidine.  ibHrL I  ppm (Pt)  150  VUIlIJfl  100  risT— 50  Figure A61. ‘ C APT NMR spectrum of 2-ethyl-4,4-diphenyl-pyrrolidine. 3  236  L’J  a’;  I  C)  nc  In  L’J  CD  Cl)  00  I  I  I  “I,  NHTs  (+1-)  610  510  0210Ib0  00  pm (fi)  Figure A66. ‘H NMR spectrum of (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, is) methylnaphthalenamine.  NHTs  (+1-)  ç;;*  Sc’” (11)  ISO  100  .  50  Figure A67. ‘ C APT NMR spectrum of(+/-)-N-tosyl-1,2,3,4-tetrahydro-(2R,1 5)3 methylnaphthalenamine.  239  NHTs  (+1-)  Y  YYYY  iii  8.0  7.0  II  6.0  ppm (51)  IIII  rfT1 -  5.0  4.0  trJ  3.0  I  2.0  -—  1.0  0.0  Figure A68. ‘H NMR spectrum of(+/-)-N-Tosyl-1,2,3,4-tetrahydro-(2R,1R)methylnaphthalenamine.  (+1-)  I  PTW’  ?  ppm (II)  150  iCC)  I  50  Figure A69. ‘ C APT NMR spectrum of(+/-)-N-Tosyl-1,2,3,4-tetrahydro-(2R,1R)3 methylnaphthalenamine.  240  ppm (fI)  Figure A70. ‘H NMR spectrum of 1 -phenyl-hept-6-enylamine.  ppm (fi)  Figure A71. ‘ C APT NMR spectrum of 1-phenyl-hept-6-enylamine. 3  241  o”  °  —  I  I  r  -  CD  S  I  C,)  +  +  o  CD  cDZ  o  a  D  I  0 tr CD  C)  CD  I  I  -  I  C,)  I  0  I  CD  -n  Nt  70 C  I  CD 0  Cl)  z  .1  C  0  0  0  0  +  <ZZ N.  ‘-‘—-—  —  z  fi/  I//I  !/llr  1.037 1.021  1.401 1.385 1.378 1.369  2.160 2.152 2.126  7.116 7.153  7.182 7.179 7169 7.184 7.159  7.249 7.239 7.235 7.225  7.315  i— 7.940 7,837 7.819 If 7.353  CD  o  0-  —  I  ON  —  I  I-”  Cd  p  I  Ii  EL 0  0  E  ON  CD  C-  5-,  Ce’)  I L’J  is)  CI’)  C/)  CiD ON  I  o  +  0  I  CD 0  —  N3  -  0  2 —F  p  [  CD  C:2  p  N  CD  —.  NHTs  LI___ H  IllIllIllIllIrl  9.o ppm  8.0  7.0  rjTI  6.0  (fi)  Y  . I I i i 1 , p ii II i, it I ii I I i  5.0  4.0  3.0  2.0  1.0  Figure A80. ‘H NMR spectrum of(+/-)-(1S,6S)-N-tosyl-2,2-diphenyl-6methylcyclohexylamine.  J‘  I  ai11i .  •11  Ill--I  (11)  L&_LhAL4.h.  I  _I___ 150  ppm  i  100  ,._  1.  -  IIII 50  Figure A81. ‘ C APT NMR spectrum of(+7-)-(1S,6S)-N-tosyl-2,2-diphenyl-63 methylcyclohexylamine.  246  ppn (f-I)  Figure A82. ‘H NMR spectrum of (+/-)-(1 S,6R)-N-tosyl-2,2-diphenyl-6methylcyclohexylamine.  150  ppm (fl)  100  50  Figure A83. ‘ C APT NMR spectrum of (+I-)-(1 S,6R)-N-tosyl-2,2-diphenyl-63 methylcyclohexylamine.  247  Go  I  C)  {  6O -C  9O -C  oo-[  (+1—)  (+1—)  LJ  5- H  Y  7.0  8.o  60  ppn(fl)  Y H-Y-r Y  ,-  5.0  40  3.0  20  1.0  0.0  Figure A86. ‘H NMR spectrum of(+/-)-N-tosyl-1,2,3,4-tetrahydro-(2R,1S)methylnaphthalenamine and (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 R) methylnaphthalenamine.  HN  1fEo  (+1-)  (+1-)  *r1Er  150 pr’n’(fl)  100  &T%  I  50  Figure A87. ‘ C NMR spectrum of (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 S) 3 methylnaphthalenamine and (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 R) methylnaphthalenamine.  249  8.0  7.0  6.0  ppn (II)  5.0  4.0  3.0  2.0  to  0.0  Figure A88. ‘H NMR spectrum of (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 S)  ISO ppn(fl)  50  Figure A89. ‘ C APT NMR spectrum of (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 S) 3 methylnaphthalenamine.  250  H  (+1-)  8.0  7.0  6.0  ppm (fi)  5.0  4.0  3.0  2.0  1.0  0.0  Figure A90. ‘H NMR spectrum of (+/-)-N-tosyl- 1,2,3 ,4-tetrahydro-(2R, 1 R) methylnaphthalenamine.  H  (+1-)  ..  ... .  150  ppm(ft)  100  50  Figure A91. 13 C NMR spectrum of (+/-)-N-tosyl-1,2,3,4-tetrahydro-(2R,1R)methylnaphthalenamine.  251  cJ  I  60  pp (fi)  510  Figure A94. ‘H NMR spectrum of complex 1.1.  I.  ji  —  rj  ,.  ppm(tt)  ISO  ISO  50  Figure A95. ‘ C NMR spectrum of complex 1.1. 3  253  

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