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Pt-catalyzed cross-coupling of arylfluorides : reaction development and mechanistic analysis Wang, Tongen 2009

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PT-CATALYZED CROSS-COUPLING OF ARYLFLUORIDES: REACTION DEVELOPMENT AND MECHANISTIC ANALYSIS by TONGEN WANG B.Sc., Tsinghua University, 1997 M.Sc., Tsinghua University, 2000 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) October 2009 © Tongen Wang, 2009 ii Abstract Fluoroaromatics have been widely utilized in practical applications such as plastics, refrigerants, pharmaceuticals and pesticides. In fact, it has been reported that 30% of new agrochemicals and 20% of new drugs contain fluorine. However, as no aryl fluorides have been isolated from natural products, fluoroaromatic building blocks are only available through synthesis. Partial functionalization of polyfluoroaromatics is a promising methodology to generate functionalized fluoroarenes. The work reported in this thesis firstly focuses on the development of Pt(II)-catalyzed cross-coupling of polyfluoroaryl imines. This methodology has been applied to a wide range of polyfluoroaryl imines with a variety of functional groups, producing methylated fluoroaryl imines in high yields and with high selectivity for the imine-directed ortho position, even in the presence of much weaker Br-aryl and CN-aryl bonds. These methylated fluoroaryl imine products are potential synthetic building blocks for the construction of pharmaceutically active molecules and agrochemicals. Next, insight into the mechanism of this Pt(II)-catalyzed cross-coupling of polyfluoroaryl imines is provided. We propose that the catalytic reaction involves the following steps: C-F activation, transmetalation and reductive elimination. Specifically, the Me2Pt(IV)-F complex formed in the C-F activation step with Me2Pt(II) undergoes transmetalation with Me2Zn to generate a Me3Pt(IV) species. Reductive elimination from Me3Pt(IV) leads to the formation of the methylated imine product and re-generates Me2Pt(II), which can then promote C-F activation of remaining substrates, thus completing the catalytic cycle. Both transmetalation and reductive elimination occur from 5-coordinate species. iii Finally, examples of unusual preference for Csp2-Csp3 coupling over Csp2-Csp2 or Csp3-Csp3 coupling are illustrated. We anticipated that a biphenyl product would be formed in the reductive elimination of a tetrafluorinated aryl-Me2Pt(IV)Ph complex, based on the premise that Csp2-Csp2 coupling is much faster than Csp2-Csp3 or Csp3-Csp3 coupling. However, the dominant organic products in the reductive elimination from a tetrafluorinated aryl-Me2Pt(IV)Ph complex are methylated imine and toluene, both of which result from  Csp2-Csp3 coupling. In contrast, the biphenyl product is only formed in trace amounts. These unexpected results can be explained by Hartwig’s “push-pull” theory that the largest difference of electronic properties between two ligands leads to the fastest rate of reductive elimination. iv Table of Contents Abstract ............................................................................................................................. ii Table of Contents............................................................................................................. iv List of Tables.................................................................................................................. viii List of Figures ....................................................................................................................x List of Schemes ............................................................................................................... xii List of Abbreviations..................................................................................................... xvi Forward.......................................................................................................................... xix Acknowledgements ..........................................................................................................xx Co-Authorship Statement ............................................................................................. xxi CHAPTER ONE: INTRODUCTION..............................................................................1 1.1      General introduction.................................................................................................1 1.2      Metal-involved C-F activation of arylfluorides........................................................5            1.2.1      Rh complexes .............................................................................................6            1.2.2      Ni complexes ..............................................................................................8            1.2.3      Pd complexes............................................................................................11            1.2.4      Comparison of Pd and Pt complexes in C-F activation............................12            1.2.5      Pt(0) complexes in C-F activation............................................................13            1.2.6      Pt(II) complexes in C-F activation ...........................................................14 1.3      The reactivity of M-F complexes ...........................................................................16 1.4      Catalytic C-F activation processes .........................................................................23            1.4.1      Hydrodefluorination of polyfluoroarenes.................................................24            1.4.2      Cross-coupling of monofluoroarenes .......................................................27            1.4.3      Cross-coupling of polyfluoroarenes .........................................................31            1.4.4      Summary of literature...............................................................................40 1.5      Our proposal ...........................................................................................................41 1.6      Metal-catalyzed cross-coupling..............................................................................44 1.7      Contents of this thesis.............................................................................................48 1.8      References ..............................................................................................................49 vCHAPTER TWO: APPROACH TO PT(II) CATALYZED CROSS-COUPLING OF POLYFLUOROARYL IMINES ................................................................................... 60 2.1      Introduction ............................................................................................................60 2.2      Our proposal and initial goals.................................................................................62 2.3      Stoichiometric transmetalation using phenylmetal reagents ..................................64            2.3.1      Reactions with silicon-based reagent .......................................................64            2.3.2      Reactions with PhSnMe3 and PhLi...........................................................67            2.3.3      Stoichiometric isotopic study ...................................................................68 2.4      Initial catalytic studies............................................................................................70            2.4.1      Exploration of transmetalation reagents...................................................70            2.4.2      Optimization of catalytic reaction conditions for Me4Sn .........................71            2.4.3      Optimization of catalytic reaction conditions for Me2Zn.........................73 2.5      Exploration of cross-coupling of polyfluoroaryl imines ........................................77 2.6      Exploration of different directing groups ...............................................................82 2.7      Conclusions ............................................................................................................83 2.8      Experimental...........................................................................................................84 2.9      References ............................................................................................................107 CHAPTER THREE: INSIGHT INTO THE MECHANISM OF PT(II) CATALYZED CROSS-COUPLING OF POLYFLUOROARYL IMINES ........... 113 3.1      Introduction ..........................................................................................................113 3.2      The involvement of C-F activation step in catalytic reaction...............................114            3.2.1      Comparison of substrate reactivities in catalytic and stoichiometric                         reactions..................................................................................................114            3.2.2      Stoichiometric C-F activation in acetonitrile .........................................116            3.2.3      Mechanism of C-F activation step..........................................................118 3.3      Conversion of Pt(IV)-F complex 2.2 to 2a...........................................................119            3.3.1      Stoichiometric transmetalation of 2.2 with Me2Zn to generate                         Me3Pt(IV) complex 3.7 ..........................................................................119            3.3.2      Observation of 3.7 (or a related species) during catalysis......................121            3.3.3      Reductive elimination from Me3Pt(IV) (3.7) .........................................125 vi 3.4      Regeneration of Me2Pt(II) species in reductive elimination            from Me3Pt(IV) (3.7)............................................................................................126 3.5      Exploration on the reversibility of the formation of 2.2.......................................128 3.6      Complex 2.2 as a pre-catalyst...............................................................................130 3.7      Effects of excess SMe2 .........................................................................................131            3.7.1      Effects of excess SMe2 on catalytic reaction ......................................... 131            3.7.2      Effects of excess SMe2 on the transmetalation reaction                         of Pt(IV)-F and Me2Zn ...........................................................................133            3.7.3      Effects of excess SMe2 on reductive elimination from                         complex 3.7 ............................................................................................137 3.8      Proposed mechanism of cross-coupling ...............................................................138 3.9      Studies of Me3Pt(IV) species................................................................................140            3.9.1      Isolation of Me3Pt(IV) species............................................................... 141            3.9.2      Comprehensive analysis of 3.16 ............................................................ 142 3.10    Unexpected further C-H activation complex........................................................147 3.11    Conclusions ..........................................................................................................150 3.12    Unexpected further C-H activation complex........................................................151 3.13    References ............................................................................................................165 CHAPTER FOUR: REDUCTIVE ELIMINATION FROM PT(IV): AN UNUSUAL PREFERENCE FOR Csp2-sp3 OVER Csp2-sp2 BOND FORMATION .............................................................................................................. 166 4.1      Introduction ..........................................................................................................166            4.1.1      The effect of ligand electronic properties on reductive                         elimination..............................................................................................168            4.1.2      Csp2-Csp2 v.s. Csp2-Csp3 v.s. Csp3-Csp3 reductive elimination.............169            4.1.3      The Pt(II) catalyzed Csp2-Csp3 coupling reaction and the mechanism                         of this reaction ........................................................................................174 4.2      Results and discussion..........................................................................................176            4.2.1      Stoichiometic isotopic transmetalation of 4.14·SMe2............................ 177            4.2.2      Transmetalation of 4.14·SMe2 with Ph2Zn.............................................178 vii            4.2.3      Expected product from reductive elimination from mixture                         of isomers I·SMe2, II·SMe2 and III·SMe2..............................................180            4.2.4      Observed products in reductive elimination from 4.16·SMe2................ 183            4.2.5      Proposed explanation for unusual preference for Csp2-Csp3 over                         Csp2-Csp2 in reductive elimination from 4.16·SMe2..............................186            4.2.6      Observation of unusual preference for unusual preference for Csp2-Csp3                         over  Csp2-Csp2 in reductive elimination from 4.21·SMe2.....................187            4.2.7     Observation of unusual preference for unusual preference for Csp2-Csp3                         over  Csp2-Csp2 in reductive elimination from 4.23·SMe2.....................188 4.3      Conclusions ..........................................................................................................190 4.4      Experimental.........................................................................................................191 4.5      References ............................................................................................................203 CHAPTER FIVE: CONCLUSIONS AND FUTURE WORK ..................................211 5.1      Conclusions ..........................................................................................................211 5.2      Near future work (5 years) ...................................................................................212 5.3      Future work (10 years) .........................................................................................214 5.4      References ............................................................................................................215 APPENDICES................................................................................................................216 Appendix I .......................................................................................................................216 Appendix II......................................................................................................................236 Appendix III ....................................................................................................................270 Appendix IV ....................................................................................................................296 viii List of Tables Table 1.1    Cross-coupling of bifluorobenzene with 4-MeC6H4MgBr............................36 Table 1.2    Cross-coupling of bifluorobenzene with arylMgBr catalyzed                    by PdCl2(PCy3)2.............................................................................................37 Table 2.1    Optimization of reaction conditions for Pt-catalyzed cross-coupling of                    1a with MeM .................................................................................................71 Table 2.2   Optimization of reaction conditions for Pt-catalyzed cross-coupling of                    1a with Me4Sn ...............................................................................................72 Table 2.3    Optimization of reaction conditions for Pt-catalyzed cross-coupling of                    1a with Me2Zn...............................................................................................73 Table 2.4    The comparison of dielectric constants of solvents and conversions of                    1a to 2a in solvents........................................................................................75 Table 2.5    Optimization of reaction conditions for Pt-catalyzed cross-coupling of                    1a with methylzinc reagents..........................................................................76 Table 2.6    Scope of Pt-catalyzed methylation of fluoroimines.......................................78 Table 2.7    Scope of Pt-catalyzed methylation of fluoroimines.......................................80 Table 3.1    1H NMR spectroscopic data for 3.7 in stoichiometric reaciton ...................121 Table 3.2    1H NMR spectroscopic data for Me3Pt(IV) species in catalytic reaction ... 124 ix Table 3.3    Comparison of 1H and 19F spectroscopic data between Me3Pt(IV) species                    observed in catalysis and 3.7 synthesized in the stoichiometric reaction                     between 2.2 and Me2Zn ..............................................................................125 Table 3.4    Data of angles on the plane of C2, C3, C22, N1 and Pt(1) for 3.16 ........... 144 Table 3.5    Three C-Pt bond lengths for 3.16 ................................................................ 144 Table 3.6    1H NMR spectroscopic data for 3.16 .......................................................... 145 Table 3.7    NMR spectroscopic data for three methyl groups of complex 3.16 ........... 146 Table 4.1    Rate constants for thermal decomposition of platinum complexes ............ 169 Table 4.2    Decomposition of the iridium complex (C5Me5)Ir(CO)(R)(R’) ................. 170 Table 4.3    Reductive elimination data on Ir complexes............................................... 171 xList of Figures Figure 1.1    Structures of lipitor and risperdal .................................................................. 1 Figure 2.1    Structures of lipitor and risperdal.................................................................60 Figure 2.2    Possible structure of complex 2.4 ................................................................66 Figure 3.1    Plot of [1a] (mM) vs time (min) (■) and [2.2] (mM) vs time (min) (▲)                     at 60 ˚C .......................................................................................................118 Figure 3.2    Plot of [1a] (mM) vs time (min) (■) and [2a] (mM) vs time (min) (▲)                     at 60 ˚C .......................................................................................................122 Figure 3.3    Plot of [3.7] (mM) vs time (min) (■) and [2a] (mM) vs time (min) (▲)                     at 60 ˚C .......................................................................................................126 Figure 3.4    Conversion vs time (h) for the reaction in the absence (■) and                     presence (▲) of excess SMe2 at 60 ˚C .......................................................132 Figure 3.5    ORTEP diagram of complex 3.16 ..............................................................143 Figure 3.6    The structure of complex 3.16 ...................................................................146 Figure 3.7    ORTEP diagram of complex 3.16 ..............................................................148 Figure 3.8    The twisted chair conformation for six-membered ring ............................148 Figure 4.1    Structures of complex 4.2, 4.3 and 4.4.......................................................171 xi Figure 4.2    Structures of (PNP)RhPh2 (4.5) and (PNP)RhPhMe (4.6) complexes.......171 Figure 4.3    Structures of complexes 4.7 and 4.8 ..........................................................172 Figure 4.4    Structures of complexes I·SMe2, II·SMe2 and III·SMe2 ...........................181 xii List of Schemes Scheme 1.1    Methodologies for the synthesis of arylfluorides .........................................2 Scheme 1.2    Proposed mechanism of cross-coupling of ArX...........................................4 Scheme 1.3    C-F activation of hexafluorobenzene with (η5-C5Me5)Rh(PMe3)(C2H4) and                        (η5-C5Me5)Rh(PMe3)(H)(C6H5) ...................................................................6 Scheme 1.4    C-F activation with (η5-C5Me5)Rh(PMe3)(H)2.............................................7 Scheme 1.5    C-F activation of pentafluoropyridine with RhH(PEt3)3 ..............................8 Scheme 1.6    Reactions between Rh(SiPh3)(PMe3)3 and fluoropyridines .........................8 Scheme 1.7    Reactions between Ni(COD)2 and pentafluoropyridine or                       2,4,6- trifluoropyrimidine.............................................................................9 Scheme 1.8    C-F activation of 1,2,4,5-tetrafluorobenzene .............................................10 Scheme 1.9    Reactions of pyridine-Ni-F complexe 1.70 ................................................20 Scheme 1.10    Reactions of pyridine-Ni-F complexe 1.73 ..............................................20 Scheme 1.11 Reaction of pyrimidine-Ni-F complex and tolboronic acid .......................21 Scheme 1.12 Reaction of pyridine-Pd-F complex ...........................................................22 Scheme 1.13 Catalytic reaction catalyzed by trans-PdF(4-C5NF4)(P iPr3)2 complex.......22 xiii Scheme 1.14 Hydrodefluorination of C6F6 catalyzed by Rh(I) complex.........................24 Scheme 1.15 Hydrodefluorination of perfluorocyclohexane and                       octafluoronaphthalene ................................................................................25 Scheme 1.16 Hydrodefluorination catalyzed by Fe-F complex (1.83) ............................25 Scheme 1.17 Hydrodefluorination catalyzed by a silylium-carborane catalyst...............26 Scheme 1.18 Hydrodefluorination catalyzed by ruthenium N-heterocyclic                       carbene catalysts.........................................................................................27 Scheme 1.19 Cross-coupling between monofluorobenzene and iPrMgCl.......................28 Scheme 1.20 Cross-coupling between monofluorobenzene and ArMgBr.......................28 Scheme 1.21 Cross-coupling between monofluorobenzene and ArMgX catalyzed by                       Ni(acac)2 and an air-stable ligand...............................................................29 Scheme 1.22 Cross-coupling between monofluorobenzene and phenylboronic acids                       catalyzed by Pd2(dba)3...............................................................................30 Scheme 1.23 Amination, Stille coupling and Suzuki coupling catalyzed                       by Pd(PPh3)4 (1.92) ....................................................................................30 Scheme 1.24 The formation of perfluoropolyphenylene from hexafluorobenzene .........31 Scheme 1.25 The cross-coupling of pentafluoropyridine and Bu3SnCH=CH2 ...............32 Scheme 1.26 The cross-coupling of polyfluoroarenes and Grignard reagents ................33 xiv Scheme 1.27 The cross-coupling of 5-chloro-2,4,6-trifluoropyrimidine and                       arylboronic acids ........................................................................................34 Scheme 1.28 Carbene-Ni complex catalyzed cross-coupling of polyfluoroarenes                       and arylboronic acids..................................................................................35 Scheme 1.29 Co(acac)2 catalyzed cross-coupling of polyfluoroarene with                       aryl-Cu(CN)MgCl ......................................................................................38 Scheme 1.30 TaCl2 catalyzed cross-coupling of polyfluoroarenes with                       PhCH2CH2MgCl.........................................................................................39 Scheme 1.31 Rh-catalyzed cross-coupling of hexafluorobenzene with disulfides..........40 Scheme 1.32 Proposed catalytic cycle for Pt(II) catalyzed cross-coupling of                       a general  organometallic reagent RM with a polyfluoroarylimine ...........43 Scheme 2.1    Proposed catalytic cycle for Pt(II) catalyzed cross-coupling of                       a general  organometallic reagent RM with a polyfluoroarylimine ...........63 Scheme 2.2    Stoichiometric isotopic study on the resource of methyl group of 2a........70 Scheme 3.1    Mechanism of C-X activation ..................................................................119 Scheme 3.2    Possible formation and trapping of complex 3.8......................................127 Scheme 3.3    Comparison of transmetalation reaction of 3.11 and that of 3.12 ............135 Scheme 3.4    Proposed mechanism of cross-coupling of polyfluoroaryl imines...........140 Scheme 3.5    Preparation process of 3.16 ......................................................................142 xv Scheme 3.6    A plausible mechanism for formation of 3.17..........................................149 Scheme 4.1    Reductive elimination from Pt(II) complexes ..........................................169 Scheme 4.2    Reductive elimination from complex 4.9 .................................................173 Scheme 4.3    Proposed mechanism of Pt(II)-catalyzed cross-coupling of                        polyfluoroarenes .......................................................................................175 Scheme 4.4    Reaction between complex 2.2 and PhSi(OMe)3 .....................................176 Scheme 4.5    The equilibrium between complex 2.3 and complex 4.16 .......................176 Scheme 4.6    The transmetalation of complex 4.14·SMe2 with Ph2Zn..........................178 Scheme 4.7    Possible paths for reductive elimination from I, II and III......................182 Scheme 4.8    Reductive elimination from 4.16·SMe2....................................................184 Scheme 4.9    Reductive elimination from 4.21·SMe2....................................................188 Scheme 4.10  Reductive elimination from 4.23·SMe2....................................................189 xvi List of Abbreviations 1-D Acac Anal. Calcd Bn bpy br COD Cp Cy Calcd d d dba DCE dd ddd dddd ddt dm DMF DMSO DPPBz dppp dppf dt dtbpm dtt EI-MS eq equiv 1-Dimensional Acetylacetone Analysis Calculated Benzyl 2,2’-Bypyridine Broad, in NMR spectroscopy Cyclooctadiene Cyclopentadienyl Cyclohexanyl Calculated Doublet, in NMR spectroscopy Deuterium Dibenzylideneacetone Dichloroethane Doublet of doublets, in NMR spectroscopy Doublet of doublet of doublet of doublets, in NMR spectroscopy Doublet of doublet of doublet of doublet of doublets, in NMR spectroscopy Doublet of doublet of triplets, in NMR spectroscopy Doublet of multiplets, in NMR spectroscopy Dimethylformamide Dimethyl sulfoxide 1,2-Bis(diphenylphosphino)benzene 1,3-Bis(diphenylphosphino)propane 1,1’-Bis(diphenylphosphino)ferrocene Doublet of triplets, in NMR spectroscopy Bis(di-tert-butyl-phosphosphino)methane Doublet of triplet of triplets, in NMR spectroscopy Electron-ionization mass spectrometry Equation Equivalent xvii ESI-MS ESI – Et EWGs GCMS h HRMS Hz iPr iPr2Im J L L-type ligand M  m Me MeOTf min mM MHz mmol mol MS m/z NMR NOE OAc OTf ORTEP Electrospray ionization mass spectrometry Negative electrospray ionization Ethyl Electron-withdrawing-groups Gas chromatography-mass spectrometry Time in hours High resolution-mass spectrometry Hertz iso-propyl 1,3-Di(isopropyl)imidazol- 2-ylidene Coupling constant, in NMR spectroscopy i) Ligand ii) Liter Ligand which coordinates to metal through a lone pair located on one of their atoms i) Metal atom ii) Concentration, in molarity Multiplet, in NMR spectroscopy Methyl Methyl triflate Time in minutes Concentration, milli molarity Megahertz Millimole Mole Mass spectrometry Mass-to-charge ratio, in mass spectrometry Nuclear magnetic resonance Nuclear Overhauser Effects Acetate Triflate Oak Ridge Thermal Ellipsoid Plot xviii PCy3 Ph P(iPr)3 PPh3 ppm PTFE P(tBu)3 PNP ligand q R RT s SMe2 SEt2 t td t tBu THF tm tol X-type ligand μ  © Δ δ υ hv σ η1, η2,or η5 Tricyclohexanylphosphine Phenyl Tri-iso-propylphosphine Triphenylphosphine Parts per million, in NMR spectroscopy Polytetrafluoroethene Tri-tert-butylphosphine Ligand with three coordinate atoms, two phosphines and one nitrogen Quartet, in NMR spectroscopy Alkyl group Room temperature Singlet, in NMR spectroscopy Dimethylsulfide Diethylsulfide Triplet, in NMR spectroscopy Triplet of doublets, in NMR spectroscopy tert t-Butyl Tetrahydrofuran Triplet of multiplets, in NMR spectroscopy Toluene Ion ligand which coordinates to metal i) micro (e.g. μL = microliter) ii) bridge in complex (e.g. Pt2Me4(μ-SMe2)2) Copyright Heating, in reaction equation Chemical shift in NMR spectroscopy, in ppm Frequency in Hz or s-1 Energy of light Sigma, as in σ-bond The coordinate number xix Foreword The work in this thesis focuses on developing the Pt(II)-catalyzed cross-coupling of polyfluoroarylimines, exploring the mechanism of this catalytic reaction, and discovering the unusual preference for Csp2-Csp3 coupling over Csp2-Csp2 coupling in the reductive elimination of Pt(IV) complexes.   Because this is a manuscript based thesis, each chapter is meant to be a stand-alone document. Therefore, there is some repetition in the introductory information between the chapters. Each chapter has its own compound labeling for organic compounds and metal complexes. Each chapter contains an introduction, results and discussion section, conclusions section, experimental, and references. An appendix containing tables of crystallographic parameters, ORTEP diagrams, and representative 1H, 19F, and 13C NMR spectra for the different classes of compounds synthesized in chapters two,  three, four is also included at the end of this thesis.  Assignment of 1H NMR spectra was based on chemical shift, peak shape and integration. Yields reported within this thesis were based on the integration of resonances of products with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectra. Yields are estimated to be accurate within +/- 5%. xx Acknowledgements Firstly, I would like to express my sincere thanks to my supervisor, Dr. Jennifer A. Love, for her guidance and support in all aspects of this work. I am much obliged to Professor Laurel L. Schafer and Professor Pierre Kennepohl for spending their precious time to read through the manuscript of this thesis. The valuable opinions they provided have been most beneficial to the preparation of this dissertation. I would also like to thank both past and present members of the Love group for their help in the lab and their suggestions in revising this thesis. 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 for assistance with X-ray crystallography. I would like to thank UBC, the UBC chemistry department, NSERC (Discovery Grant, Research Tools, and Instrumentation Grants), Merck Frosst, the Canada Knowledge Development Fund and AstraZeneca Canada for funding. I would express my special thanks to my family members, especially to my mother, wife, daughter, brothers and sisters for their strong support throughout years. I would also thank my father-in-law and mother-in-law for their strong support for years. xxi Co-Authorship Statement All of the work reported in this thesis was performed by Tongen Wang, including identification and design of research program, performing research, data analyses and manuscript preparation. Any conclusions or experimental results referred to in the text of this thesis that were obtained by other parties have been clearly identified and cited. Brian J. Alfonso performed the experiment on one substrate in Table 2.6. Jennifer A. Love is the principle investigator for this work and assisted in design of the research program, data analysis, and manuscript preparation. 1CHAPTER ONE: INTRODUCTION 1.1 General introduction Fluorocarbons have become important chemicals in our lives because they have been widely utilized as refrigerants, pharmaceuticals, pesticides and plastics.1 The wide application of fluorinated compounds was attributed to their exceptional and unique physical and chemical properties, including metabolic stability, solubility, lipophilicity and the ability to form hydrogen bonds.1 Recently, it has been estimated that around 30% of new agrochemicals and 20% of new drugs contain fluorine.1b,2 Several top selling drugs, including Pfizer’s Lipitor and Johnson & Johnson’s Risperdal, contain arylfluorides (Figure 1.1). F N HO HO CO2Ca Ph PhHN O iPr Lipitor (cholesterol-lowering) F O N N N O Risperdal (treating schizophrenia) N Figure 1.1 Structures of lipitor and risperdal Organic fluorinated compounds are of great interest in organic chemistry because of the wide application described above. However, arylfluorides rarely occur in nature because terrestrial fluorine are of low bioavailability.1b To date, arylfluorides have not 2been isolated from natural products.3 Therefore, arylfluorides, a class of important molecules, must be synthesized. There are three common methodologies to synthesize arylfluorides (Scheme 1.1): a) the pyrolysis of diazonium tetrafluoroborates;4 b) nucleophilic aromatic substitution reactions;5 c) use of highly reactive elemental fluorine gas.6 Each of these routes has significant limitations, such as harsh reaction conditions, limited substrate scope, the involvement of explosive reagents, low yields and long reaction times.7,8,9 Method a: ArN2 + BF4 - - N2, - BF3 ArF Method b: ArCl F- source ArF Method c: ArH F2, HCOOH ArF Method d: ArH or Ar-M F+ source ArF M = Sn, B Ag or Pd Method e: Ln-Pd-F Reductive elimination ArF Ar Pd(II) or Pd(IV) complexes Scheme 1.1 Methodologies for the synthesis of arylfluorides More recently, another two routes have been discovered. Method d (Scheme 1.1), the synthesis of arylfluorides involving electrophilic fluorinating agents, has been developed by Ritter and Sanford.7a-7c Ritter synthesized aryl fluorine bonds in the silver mediated fluorination of functionalized aryl stannanes.7a Arylboronic acids could also be converted 3into arylfluorides in the palladium-mediated fluorination.7b Sanford and co-workers reported the palladium-catalyzed electronic fluorination of specific C-H bonds of phenylpyridine derivatives.7c Route e (Scheme 1.1) provides a promising method to synthesize arylfluorides in the reductive elimination from Pd(II)8a-8c or Pd(IV)9a,9b fluoride complexes. In spite of extensive efforts in the synthesis of functionalized arylfluorides, the substrate scope in each of the cases discussed above is still limited. Selectively forming aryl fluoride bonds still remains as a great challenge. Given these limitations, it is reasonable to consider whether selective C-F bond cleavage in cross-coupling reaction might afford an alternative approach to the selective functionalization of aryl compounds. The mechanism of cross-coupling of ArX is illustrated in Scheme 1.2, involving oxidative addition, transmetalation and reductive elimination.10 Cross-coupling of more easily obtained symmetrical polyfluorinated arenes could be used to generate more valuable unsymmetric fluorinated species. For example, the symmetrical 2,4,6-trifluorobenzaldehyde is commercially available; but 2-bromo-4,6-difluoro- benzaldehyde, a mixed halo compound, is not on sale in the market. 4LnM RM' M'X ArMX(Ln) Ar-X ArMR(Ln) Ar-R Oxidative addition Transmetalation Reductive elimiantion LnM = Transition metal complex as the catalyst in cross-coupling reaction RM = Organometallic reagent X = I, Br, Cl, F Scheme 1.2 Proposed mechanism of cross-coupling of ArX Catalytic cross-coupling of arylfluorides has been a challenge in organometallic and organic chemistry for decades, in part because fluorocarbons are resistant to chemical processes (C-F bond strength: 110-154 kcal/mol).11 The great strength of the C-F bond and the high electronegativity of fluorine lead to the tardiness of fluorocarbons to react with metal centers.12 To activate strong C-F bonds, chemists have explored a variety of metal complexes with extensive efforts. Examples of stoichiometric C-F activation of arylfluorides involving metal complexes are described in section 1.2. The reactivity of M-F (M = Rh, Ni, Pd and Pt) complexes is presented in section 1.3. Section 1.4 briefly reviews the catalytic C-F activation processes. Hydrodefluorination of polyfluoroarenes is introduced in section 1.4.1 Sections 1.4.2-1.4.3 illustrate cross-coupling of monofluoroarenes and 5cross-coupling of polyfluoroarenes, respectively. The limitations of known methodologies on cross-coupling of polyfluoroarenes are pointed out in section 1.4.4. Our proposal on Pt(II) catalyzed cross-coupling of polyfluoroarenes to synthesize functionalized arylfluorides is introduced in section 1.5. Section 1.6 compares Csp2-Csp2 coupling and Csp2-Csp3 coupling. Finally, the contents of chapters 2-5 of this thesis are introduced in section 1.7. 1.2 Metal-involved C-F activation of arylfluorides Carbon fluorine bond activation by metal complexes has been explored extensively, resulting in several elegant works. The chemistry of C-F activation has been reviewed by Kiplinger et al. (1994),12a Burdeniue et al. (1997),10b Torrens (2005)13a and Perutz and Braun (2007).13b Numerous transition metals have been applied in the field of stoichiometric C-F activation.14-25 Examples include: Lanthanides/Actinides: Yb,14a,14d,14f U,14b Ce,14c,14d La,14d Nd,14d Sm,14d Ho,14d Er14d and Th14e; group 3 metals Sc;15 group 4 metals: Ti,16a-16g Zr16h,16i and Hf16j; group 5 metals: Nb, 17a-17b Ta17c; group 6 metals: W18a,18b and Mo18c; group 7 metals: Mn19a and Re19b,19c; group 8 metals: Fe,20a-20d Ru20e-20g and Os20g-20j; group 9 metals: Co,21a-21d Rh21e-21i and Ir21j-21m; group 10 metals: Ni,22 Pd23 and Pt24,25. Herein, the C-F activation examples involved Rh, Ni, Pd and Pt complexes are presented in detail. 61.2.1 Rh complexes One of the first examples of C-F activation by rhodium complexes was reported by Jones, Perutz and co-workers.21e,21f They reported that the photolysis of (η5-C5Me5)Rh(PMe3)(C2H4) (1.1) in C6F6 generated (η5-C5Me5)Rh(PMe3)(η5-C6F6). (1.2) (Scheme 1.3). The photolysis of 1.2 in C6F6 afforded (η5-C5Me5)Rh(PMe3)(C6F5)(F) (1.3) (Scheme 1.3). The C-F activation process with complex 1.1 was photochemically promoted. A few years later, Jones et al.21g reported a similar C-F cleavage of C6F6, C6F5H, C12F10 and C10F8 utilizing (η5-C5Me5)Rh(PMe3)(H)2 (1.4) to afford (η5-C5Me5)Rh(PMe3)(H)(Aryl group) (aryl group = C6F5, C6F4H, C12F9, or C10F7) (complexes 1.5 – 1.8) (Scheme 1.4). F F F Rh Me3P C6F6 hv Rh Me3P F FF 1.1 1.3 Rh Me3P 1.2 F F F FF F C6F6 hv Scheme 1.3 C-F activation of hexafluorobenzene with (η5-C5Me5)Rh(PMe3)(C2H4) and (η5-C5Me5)Rh(PMe3)(H)(C6H5) 7Rh Me3P H H H FF F F F Rh Me3P H F F HF F FF F F F FF F FF Rh Me3P H F F F F F F FF FF FF F F F Rh Me3P H F F FF F F F F F F F F F Rh Me3P H F F F F F FF 1.4 1.5 1.6 1.7 1.8 Scheme 1.4 C-F activation with (η5-C5Me5)Rh(PMe3)(H)2 More recently, Braun and co-workers reported the C-F activation reaction between RhH(PEt3)3 (1.9) and pentafluoropyridine, providing Rh(4-C5NF4)(PEt3)3 (1.10) (Scheme 1.5).21h The C-F activation occurred at 4-position of pentafluoropyridine. In 2007, Perutz and co-workers realized the C-F activation of pentafluoropyridine by Rh(SiPh3)(PMe3)3 (1.11) to afford Rh(2-C5NF4)(PMe3)3 (1.12) and Rh(4-C5NF4)(PMe3)3 (1.13) in a 3 : 1 ratio (Scheme 1.6).21i The reaction between 1.11 and 2,3,5,6-tetrafluoro-4-methylpyridine produced Rh(2-C5NF3Me)(PMe3)3 (1.14) exclusively because the 4-position was substituted by a methyl group (Scheme 1.6). 8RhH(PEt3)3 NEt3 N F F F F F NF F Rh F F PEt3 PEt3 Et3P 1.9 1.10 Scheme 1.5 C-F activation of pentafluoropyridine with RhH(PEt3)3 SiPh3 Rh PMe3 PMe3 Me3P N F F F F F Rh PMe3 PMe3 Me3P N F F F F Rh PMe3 PMe3 Me3P NF F F F - FSiPh3 N F F Me F F - FSiPh3 Rh PMe3 PMe3 Me3P N Me F F F 1.11 1.12 1.13 1.14 + 3 : 1 Scheme 1.6 Reactions between Rh(SiPh3)(PMe3)3 and fluoropyridines 1.2.2 Ni complexes Ni(0) complexes have also been utilized in stoichiometric C-F activation of arylfluorides. For example, Fahey and Mahan reported C-F activation of C6F6 by a low-valent nickel complex Ni(PEt3)2(COD) (1.15) to afford C6F5Ni(F)(PEt3)2 (1.16). 22a Richmond and co-workers reported the chelate-assisted C-F activation with bis(cyclooctadiene)-nickel(0) complex (1.17) to obtain an air-stable Ni-F complex 1.18 (eq 1.1).22b 9N NMe2 F FF F F Ni(COD)2 - 2 COD N NMe2 Ni FF F F F 1.18 (1.1) Perutz and co-workers noted that the oxidative addition of pentafluoropyridine on Ni(COD)2 (1.17) selectively occurred at the 2-position and afforded trans-NiF(2-C5NF4)(PEt3)2 (1.19) exclusively (Scheme 1.7). 22c-22g However, the C-F activation reaction between 2,4,6-trifluoropyrimidine and Ni(COD)2 occurred at the 4-position to generate trans-NiF(4-C4N2F2H)(PEt3)2 (1.20) (Scheme 1.7). Ni(COD)2 N F FF F F PEt3 N F Ni F F F PEt3 F Et3P PEt3 N N Ni F F PEt3 F Et3P N N FF F 1.201.19 1.17 Scheme 1.7 Reactions between Ni(COD)2 and pentafluoropyridine or 2,4,6-trifluoropyrimidine Radius and co-workers reported that fast C-F activation of hexafluorobenzene within 1 h at room temperature to afford NiF(C6F5)( iPr2C3N2H2)2 (1.22) (eq 1.2), using carbene complex Ni2( iPr2C3N2H2)4(COD) (1.21). 22h,22i Another C-F activation of hexafluorobenzene with Ni complex was reported by Yamamoto et al.22j The reductive elimination of butane from NiEt2(bpy) (bpy = 2,2’-bypyridine) (1.23) produced Ni(0) complex (1.24). The reaction between C6F6 and 1.24 generated NiF(C6F5)(bpy) (1.25) (eq 10 1.3). N N iPr iPr N N iPr iPr Ni Ni N N iPr iPr N N iPr iPr C6F6 -COD (1.2) N N Ni Et Et C6F6 N N Ni C6F5 F (1.3) 1.21 1.22 1.23 1.25 - Butane N N Ni 1.24 Ni C6F5 F N NN N iPr iPr iPr iPr Recently, Johnson and co-workers observed the C-F bond activation product 1.27 in the reaction between 1,2,4,5-tetrafluorobenzene and complex 1.26 (Scheme 1.8).22k Unexpected hydrodefluorination products and C-H bond rearrangement product were also formed in the course of C-F activation. Ni PEt3Et3P + FF FF Ni Et3P PEt3F F FF initial product at low conversion + FF FF Ni F PEt3 PEt3 + FF F F FF Ni F PEt3 PEt3 + hydrodef luorination products C-H bond rearrangement product toluene 2 weeks 1.26 1.27 1.28 1.29 Scheme 1.8 C-F activation of 1,2,4,5-tetrafluorobenzene 11 1.2.3 Pd complexes To date there are only a few examples of C-F activation involving palladium complexes. For example, Usón and co-workers reported base-promoted nucleophilic C-F activation with HPPh2, KOH, and the chlorobridged dimer cis-{Pd2(μ-Cl)2- [μ-C(C6F5)=N(CH3)]2}n (1.30), generating the imidoyl-bridged dimer complex 1.31 (eq 1.4).23a Pd N=CCl C=N CH3 Pd C6F5 CH3 Cl HPPh2 KOH, Acetone, - 2 HF Pd N=CCl C=N CH3 Pd CH3 Cl PPh2 C6F5 Ph2P F FF F F FF F (1.4) 1.30 1.31 Braun and co-workers reported C-F activation on 4-position of pentafluoropyridine with PdMe2(Cy2PCH2PCy2) (1.32) in toluene in the presence of excess water (eq 1.5). 23b The reaction between 1.32 and 2,4,6-trifluoropyrimidine in benzene generated the palladium derivative PdMe{4-C4N2F2H(=O)}(Cy2PCH2PCy2) (1.34) (eq 1.6) in the presence of excess water.23c 12 Pd P P CyCy Cy Cy Me Me Pd P P CyCy Cy Cy Me O (1.5) N F FF F F Excess H2O N F F F F Pd P P CyCy Cy Cy Me Me Pd P P CyCy Cy Cy Me (1.6) N N FF F Excess H2O NN F O F 1.32 1.33 1.341.32 1.2.4 Comparison of Pd and Pt complexes in C-F activation Perutz and co-workers reported an interesting C-F activation reaction between pentafluoropyridine and Pd(PR3)2 (1.35) and Pt(PR3)2 (1.37) (R= Cy or iPr), and compared the reactivity of Pd relative to Pt.23d The palladium complexes reacted with pentafluoropyridine at 100 ˚C to afford trans-PdF(4-C5NF4)(PR3)2 (1.36) (R= Cy or iPr) (eq. 1.7), whereas the platinum(0) complex reacted with pentafluoropyridine in THF at room temperature to yield Pt(Cy)(4-C5NF4)(PR3)(PFR2) (1.38) (R= Cy or iPr) (eq. 1.8). F/R exchange occurred in the C-F activation using complex 1.37. 13 PR3, R = Cy, iPr N F FF F F N F Pd F F PR3R3P F F [Pt(PR3)2] R = Cy, iPr N F FF F F N F Pt F F PR3P F R R R FTHF, rt [Pd(PR3)2] (1.7) (1.8) 1.35 1.36 1.37 1.38 100 °C 1.2.5 Pt(0) complexes in C-F activation To date, there are another three examples of Pt(0) complexes used in the C-F activation of arylfluorides, in addition to the example of a Pt(0) complex in the previous section. The oxidative state of platinum metal increased two units in the process of C-F activation. Hofmann and Unfried reported C-F activation of hexafluorobenzene with cis-hydridoneopentyl[η2-bis(di-tert-butylphosphosphino)methane]platinum(II) (1.39). The reductive elimination from this platinum complex afforded neopentane and a very reactive 14-electron Pt(0) intermediate (dtbpm)Pt (1.40). Complex 1.40 reacted with C6F6 to give (dtbpm)Pt(F)(C6F5) (1.41) (eq 1.9). 24a In 2004, Crespo and co-workers reported C-F bond activation on C6F5CH=NCH2CH2NMe2 by Pt(dba)2 (1.42) (dba = dibenzylideneacetone) in the presence of LiBr to afford a cyclometallated platinum (II) complex PtBr-(Me2NCH2CH2NCHC6F4) (1.43) (eq 1.10). 24b It is noteworthy that in the absence of LiBr, no C-F activation was observed.24b Recently, Milstein et al. synthesized 14 a pincer-type anionic platinum(0) complex (1.44), which was capable of activating the strong C-F bond of hexafluorobenzene, generating complex 1.45, even at -35 ˚C (eq 1.11).24c Pt P P tButBu tBu tBu H C6F6 Pt P P tButBu tBu tBu F C6F5 (1.9) PtBu2 PtBu2 Pt Na C6F6 THF, -35 °C, - NaF PtBu2 PtBu2 Pt C6F5 (1.11) F F F F CH=N F NMe2 Pt(dba)2 1.42 LiBr, -LiF F F F Pt CH F N N Me2 Br (1.10) 1.39 1.41 1.43 1.44 1.45 Pt P P tButBu tBu tBu 1.40 1.2.6 Pt(II) complexes in C-F activation There are two types of Pt(II) complexes that have been used for stoichiometric C-F activation of arylfluorides. In the first type, the oxidative state of platinum does not change in the C-F activation. Roundhill and co-workers reported C-F activation between a platinum(II) complex, trans-[Pt(CH3)(THF)(PPh2-C6F5)2]ClO4 (1.46), and aqueous KOH at room temperature, affording trans-Pt(CH3)(2-OC6F4PPh2)(PPh2C6F5) (1.47) (eq 1.12).25a,25b Another example was illustrated by Perutz and Jasim.25c They reported the 15 application of platinum dihydride complex, trans-Pt(H)2(PCy3)2 (1.48), in C-F activation of hexafluorobenzene. This reaction afforded the bifluoride complex trans-PtH(FHF)(PCy3)2 (1.49) and trans-PtH(C6F5)(PCy3)2 (1.50) in a ratio of 1:13 (eq 1.13) (note: FHF- is bifluoride ion). Torrens and co-workers discovered the C-F bond activation during the treatment of trans-PtCl2(PPh2-n(C6F5)n+1)2 (n = 0 or 1) (1.51) with Pb(SC6HF4-4)2 (1.52), providing a mixture of Pt(SRf)2(1,2-C6F4(SRf)-R2) (R2 = Ph2 or Ph(C6F5) (eq 1.14). 25d tr ans-Pt(PCy3)2H2 C6F6, NMe4F THF/50 °C tr ans-Pt(PCy3)2H(C6F5) + tr ans-Pt(PCy3)2H(FHF) (1.13) Pt PPh2C6F5 PPh2C6F5 THFMe OH -THF, -HF ClO4 (1.12) Pb(SC6HF4-4)2 -PbCl2 Pt C6HF4S C6HF4S S P R2 C6HF4 F4 R1 = Ph2(C6F5) or Ph(C6F5)2, R2 = Ph2 or Ph(C6F5) (1.14) 1.46 1.47 1.48 1.49 1.50 1.51 1.53 Pt Ph2P Me O PPh2C6F5 F F F F Pt R1P Cl PR1 Cl Other Pt(II) complexes react via oxidative addition to generate Pt(IV) complexes. For example, Puddephatt and co-workers25e,25f reported C-F activation of the Schiff base ligand by a platinum(II) center, [(CH3)2Pt(μ-SMe2)]2 (1.54), in acetone to afford six-coordinate platinum (IV) fluoride complexes 1.55 and 1.56 (eq 1.15). Crespo et al. 16 discovered that C-F bond activation took place on the ortho position to the imine group in the presence of weaker C-X bonds (X = H, Cl, and Br) and produced complex 1.57 (eq 1.16).25g,25h The coordinated nitrogen of the imine group directed the activation to the ortho C-F bond. The C-F activation required at least three electron withdrawing groups (EWGs) on the arene (in addition to the imine group). F F F F F N NMe2 -2 SMe2, Acetone, rt, 2h Acetone X = H, Cl, Br FF F F F CH=NCH2 X (1.16) 1.55 1.56 1.57 [(CH3)2Pt(-SMe2)]2 [(CH3)2Pt(-SMe2)]2 F F F F N NMe2 Pt H3C CH3 F H N Pt CH3 SMe2H3C F F F F F X CH2 (1.15) O CH3 N Me2 N PtMe Me F FF F F 1.3 The reactivity of M-F complexes Late transition M-F complexes synthesized in the transition-metal-mediated stoichiometric C-F activation have been increasingly valuable compounds because the characteristics of fluorine impart an exceptional reactivity to the M-F bonds. For example, 17 the metathesis of M-F complexes with salts (LiX, X = Br and I) produced M-X complexes; transmetalation reaction of M-F species with organometallic reagents generated M-R species; and M-F species were proposed to be the key intermediates in catalytic reactions.26-28 These properties indicate that late-transition M-F complexes could be potentially useful in preparative organometallic chemistry or in catalysis.26-28 Herein, literature describing the reactivity of M-F (M = Rh, Ni, Pd and Pt) is briefly reviewed. In particular, the transmetalation with organometallic reagents, which could be used in cross-coupling reactions, are focused on in detail. These discussions on the reactivity of metal-F complexes will provide fundamental background for the catalytic C-F activation process, which is the focus of the remainder of this thesis. M-F complexes are so reactive that they cannot always obtained in the stoichiometric C-F activation reactions.21j, 23d In certain cases, phosphine ligands react to form F-PEt2 (eq 1.17)21j (eq 1.8).23d F/Ph exchange between M-F and phenyl on phosphine was also observed on the complex Rh(PPh3)3F. 27 C6F6 60 °C + C2H4 + CH4 (1.17)Et3P Ir Me PEt3 PEt3 FEt2P Ir C6F5 PEt3 PEt3 1.58 1.59 M-F complexes have been utilized to generate other M-X (X = Cl, Br, I) complexes.21e,28a,28b,22g,24b For example, the Rh-F complex 1.60 reacted with chloroform 18 to generated Rh-Cl species 1.61 (eq 1.18);21e the reaction between Me3SiCl and Ni-F complex 1.62 formed Ni-Cl complex 1.63 (eq 1.19);28a the Ni-I complex 1.65 was synthesized in the reaction between Ni-F 1.64 and KI (eq 1.20); 22g the Pd-F complex 1.66 reacted with Et3SiCl, generating Pd-Cl complex 1.67 (eq 1.21); 28b and reactions of Pt-F species 1.68 and LiX (X = Br or Cl) formed Pt-X complexes 1.69 (eq 1.22).24b F F F Rh Me3P F FF CHCl3 F F F Rh Me3P F FCl (1.18) Ph3P Ni PPh3 F N N F F Cl Me3SiCl Ph3P Ni PPh3 Cl N N F F Cl (1.19) Et3P Ni PEt3 F N F F F F KI Et3P Ni PEt3 I N F F F F (1.20) Pr3P Pd P iPr3 F NF F F F i Et3SiCl Pr3P Pd P iPr3 Cl NF F F F i (1.21) 1.60 1.61 1.62 1.63 1.64 1.65 1.66 1.67 19 LiX, -LiF F F F Pt CH F N N Me2 X (1.22) F F F Pt CH F N N Me2 F X = Br, Cl 1.68 1.69 On the other hand, M-F complexes can be obtained from M-I complexes through the method of I/F exchange promoted by ultrasound.29 In this method, synthetic M-F complexes, which are impossible to obtain through C-F activation, could be synthesized30 and studied by a number of research groups.8a-8c,9a,9b,30,31,32 The exploration of the reactivity of such synthetic M-F complexes are not discussed here because we focus on the reactivity of M-F complexes synthesized in the C-F activation. Especially, the transmetalation of such M-F complexes are discussed because the reactivity of such M-F complexes might be utilized in catalytic cross-coupling of arylfluorides. It should be pointed out that transmetalation of M-F complexes (M = Rh, Ni, Pd and Pt) synthesized from C-F activation have been rarely studied. To date, only a few examples have been reported. In 2005, Perutz and co-workers illustrated pyridine-Ni-F complexes, which were synthesized in the C-F activation, reacted with a variety of reagents (Scheme 1.9).22g Trans-NiF(2-C5NF3H)(PEt3)2 (1.70) reacted with Me3SiN3 and Me3SiNCO, generating trans-Ni(N3)(2-C5NF3H)(PEt3)2 (1.71) and trans-Ni(NCO)(2-C5NF3H)(PEt3)2 (1.72), respectively (Scheme 1.9). The reactions of trans-NiF(2-C5NF4)(PEt3)2 (1.73) with Me3SiN3, phenylacetylene, KCN and NaOAc 20 provided trans-Ni(X)(2-C5NF4)(PEt3)2 (1.74) (X = N3, η1-CCPh, CN and OAc, respectively) (Scheme 1.10). Me3SiN3 Me3SiNCO N F F H NiEt3P PEt3 F F N F F H NiEt3P PEt3 F NCO N F F H NiEt3P PEt3 N3 F 1.701.71 1.72 Scheme 1.9 Reactions of pyridine-Ni-F complex 1.70 N F F F NiEt3P PEt3 F F N F F F NiEt3P PEt3 F X 1.73 1.74 (X = N3, -CCPh, CN, OAc) Me3SiN3 KCN NaOAc HC CPh Scheme 1.10 Reactions of pyridine-Ni-F complex 1.73 Braun and co-workers reported some elegant work on transmetalation of pyrimidine-Ni-F complex with 4-methylphenylboronic acid.28a The stoichiometric reaction between pyrimidine-Ni-F complex 1.75 and 4-methylphenylboronic acid afforded another pyrimidine-Ni-F complex 1.76 (pyrimidine with new aryl-toluene bond) (Scheme 1.11). In this stoichiometric process, the reductive elimination of aryl-toluene and C-F activation of the new pyrimidine occurred. Based on the formation of aryl-toluene bond in this stoichiometric reaction, Braun and co-workers successfully 21 developed a cross-coupling reaction between pyrimide and RB(OH)2 (R = phenyl, toluene) catalyzed by pyrimide-Ni-F complex. N N FF NiPh3P PPh3 F TolB(OH)2 Cl N N TolF NiPh3P PPh3 F Cl 1.75 1.76 Scheme 1.11 Reaction of pyrimidine-Ni-F complex and tolboronic acid More recently, Braun and co-workers studied the reactivity of pyridine-Pd-F complex with a number of reagents, e.g. Me3SiN3, Ph3SiH, FMe2SiSiMe2F, and Bu3SnC2H3 (Scheme 1.12).28b The reaction between trans-PdF(4-C5NF4)(P iPr3)2 (complex 1.77) with Me3SiN3 afforded organometallic compound trans-Pd(N3)(4-C5NF4)(P iPr3)2 (1.78). In contrast, reactions of trans-PdF(4-C5NF4)(P iPr3)2 complex with Ph3SiH, FMe2SiSiMe2F, or Bu3SnCH=CH2 generated reductive elimination products, 2,3,5,6-tetrafluoropyridine, 4-(fluorodimethylsilyl)tetrafluoropyridine and 4-vinyltetrafluoropyridine, respectively. The basis of such observation led to the development of hydrodefluorination of pentafluoropyridine catalyzed by pyridine-Pd-F complex (1.77) (Scheme 1.13).28b 22 Pr3P Pd P iPr3 F NF F F F i Me3SiN3 Pr3P Pd P iPr3 N3 NF F F F i Ph3SiH - [Pd(PiPr3)2] NF F F F H FMe2SiSiMe2F - [Pd(PiPr3)2] NF F F F SiMe2F Bu3SnCH=CH2 - [Pd(PiPr3)2] NF F F F 1.78 1.77 Scheme 1.12 Reaction of pyridine-Pd-F complex 1.77 N FF FF F 10 mol% THF Ph3SiH N FF FF HPr3P Pd P iPr3 F NF F F F i Scheme 1.13 Catalytic reaction catalyzed by trans-PdF(4-C5NF4)(P iPr3)2 complex (1.77) 23 1.4 Catalytic C-F activation processes As discussed above, stoichiometric C-F activation has been realized with many transition metal complexes. However, even though extensive efforts have been focused on catalytic C-F activation, limited examples of catalytic processes have been reported.33-35 Catalytic C-F activation includes two types of reactions: hydrodefluorination and cross-coupling of fluoroarenes. Hydrodefluorination does not generate new C-C bond, although new fluoroarenes are formed in the partial hydrodefluorination of polyfluoroarenes.34 In contrast, cross-coupling of fluoroarenes forms new C-C bond. However, most strategies focus mainly on cross-coupling of monofluoroarenes.33 Synthesis of functionalized fluoroarenes is one of the goals of this thesis. The cross-coupling of monofluoroarenes are not applicable to the synthesis of functionalized fluoroarenes, as this process involves cleavage of the only C-F bond. Indeed, cross-coupling of polyfluoroarenes provides a promising route to generate functionalized fluoroarenes. However, methodologies for cross-coupling of polyfluoroarenes are still rare.35 Development on catalytic C-F activation has been partially reviewed by Perutz and Braun13b in 2007 and Amii and Uneyama36 in 2009. In the next sections 1.4.1-1.4.3, hydrodefluorination of polyfluoroarenes, cross-coupling of monofluoroarenes and cross-coupling of polyfluoroarenes are reviewed. 24 1.4.1 Hydrodefluorination of polyfluoroarenes Hydrodefluorination of polyfluoroarenes is a potential method to synthesize new arylfluoride compounds. The first example of catalytic hydrodefluorination of fluoroarenes was provided by Aizenberg and Milstein.34a, 34b The Rh(I)(PMe3)3L (L = SiMe2Ph or Ph3; 34a L = H34b) (1.79) catalysis system converted hexafluorobenzene into 1,2,3,4,5-pentafluorobenzene, utilizing R3SiH (R = Ph, OEt) 34a or utilizing a base and H2 to complete the catalytic cycle34b (Scheme 1.14). Jones and co-workers used (C5Me5)Rh(III)(PMe3)(C6F5)H (1.80) in a similar catalytic hydrodefluorination of hexafluorobenzene in the presence of base and H2, generating 1,2,3,4,5-pentafluorobenzene.34c F F F F F F Rh(I), R3SiH F F F F F F F F F F F Rh(I) base, H2 F F F F F Scheme 1.14 Hydrodefluorination of C6F6 catalyzed by Rh(I) complex In 1996, Kiplinger and Richmond reported hydrodefluorination of octafluoronaphthalene by zirconocene (IV) complex (1.81) (Scheme 1.15).34d Furthermore, perfluorocyclohexane could be hydrodefluorinated into 1,2,4,5-tetrafluorobenzene by Cp2ZrCl2 (1.81) or Cp2TiCl2 (1.82) (Scheme 1.15). 34e 25 F F F F Cp2ZrCl2 Mg, HgCl2 F F F F F F F Cp2MCl2, M = Zr, Ti F FF F F F F F F2C F2C C F2 CF2 CF2 F2 C Mg, HgCl2 Scheme 1.15 Hydrodefluorination of octafluoronaphthalene and perfluorocyclohexane In 2005, Holland and co-workers reported Fe-F complex (1.83) catalyzed hydrodefluorination of hexafluorobenzene, pentafluoropyridine and octafluorotoluene with a silane R3SiH, affording mainly the singly hydrodefluorinated products (Scheme 1.16).34h It is noteworthy that the hydrodefluorination of octafluorotoluene occurs on the C-F bond para to the electron-withdrawing group, CF3. N F F F F F Fe-F complex N F FF F R3SiH R3SiF CF3 F F F F F Fe-F complex F FF F CF3 R3SiH R3SiF F F F F F F Fe-F complex F FF F F R3SiH R3SiF N N RR Fe iPr iPriPr iPr F R = Me, tBu Fe-F complex 1.83 Scheme 1.16 Hydrodefluorination catalyzed by Fe-F complex 1.83 26 More recently, Ozerov and Douvris have developed an interesting catalytic system consisting of R3SiH and [Ph3C] +[CHB11H5Cl6] -, which act as precursors to [Et3Si] +[CHB11H5Cl6] -.34l [Et3Si] +[CHB11H5Cl6] - (1.84) is an efficient catalyst in the hydrodefluorination of octafluorotoluene at room temperature. A highlight of this system is that Csp3-F reacts preferentially over Csp2-F (Scheme 1.17). CF3 F F F F F CH3 F F F F F 3.2 equiv R3SiH R = ethyl or hexyl 0.08 mol% Ph3C[HCB11H5Cl6] BB B B B B B B B B C B Cl Cl Cl Cl ClCl H H HH H H [HCB11H5Cl6] Scheme 1.17 Hydrodefluorination catalyzed by a silylium-carborane catalyst In early 2009, Whittlesey and co-workers34n reported catalytic hydrodefluorination of aromatic fluorocarbons by ruthenium N-heterocyclic carbene complexes (1.85 or 1.86) (Scheme 1.18). For all of the ruthenium catalysts, the hydrodefluorination of C6F6 affords C6F5H as a major product. It is noteworthy to point out that the hydrodefluorination of C6F5H gave the 1,2-isomer (1,2,3,4-tetrafluorobenzene) as the predominant isomer, as opposed to the 1,4-isomer (1,2,4,5-tetrafluorobenzene). 27 F F F F F F F F F F[Ru] F F F F F [Ru] R'3SiH R'3SiF [Ru] = Ru OC Ph3P H H PPh3 NN RR R = 2,6-diisopropylphenyl (IPr), or 2,4,6-trimethylphenyl (IMes) Ru OC Ph3P H H PPh3 NN RR or R' = Et, EtO, Ph, iPr 1.85 1.86 Scheme 1.18 Hydrodefluorination catalyzed by ruthenium N-heterocyclic carbene catalysts 1.4.2 Cross-coupling of monofluoroarenes The cross-coupling of monofluoroarenes catalyzed by Ni, Pd, Mn and Ti complexes provides a novel and important method to obtain compounds with new aryl-aryl, aryl-alkene or aryl-alkyl bonds.33 Herein, a few key reactions in this field are presented. The first example of cross-coupling of fluoroarenes was discovered by Kumada and co-workers in 1973.33a This reaction between monofluorobenzene and iPrMgCl was catalyzed by Ni(Me2PCH2CH2PMe2)Cl2 (1.87), generating coupling product in 62% yield (Scheme 1.19). The n-propyl derivative was the major product and iso-propyl derivative was the minor product. 28 F + MgCl NiCl2 Me2 P P Me2 + 62% 1 : 7 ether, refluxing, 40h Scheme 1.19 Cross-coupling between monofluorobenzene and iPrMgCl In 2001, the Herrmann group speculated that a highly electron-rich metal center was required for the activation of C-F bonds.33b Because N-heterocyclic carbenes are strong electron-donating ligands, the Hermann group elected to use the complex 1.88, bis[1,3-di(2’,6’-diisopropylphenyl)imindazolin-2-ylidene] nickel(0), as the catalyst (Scheme 1.20). They proposed the catalytically active species was complex 1.89 (Scheme 1.20) with only one carbene ligand. F + BrMg-Ar Ar 5 mol % [Ni] THF, rt, 18 h -MgBrF N N 2 Ni N N Ni 1.88 1.89 R R Scheme 1.20 Cross-coupling between monofluorobenzene and ArMgBr A few years later, Ackermann and co-workers reported another example catalyzed Ni complex (Scheme 1.21).33d They used Ni(acac)2 (1.90) and air stable phosphine oxide 29 proligands in the cross-coupling of arylfluorides. This catalysis system was highly efficient in the coupling of monofluorobenzene with different Grignard reagents at ambient temperature. F + 3 mol % [Ni(acac)2] 3 mol% L THF, 20 °C, 5-24h -MgFX R1 R 1 MgX R2 R 2 X = Br, Cl N P N O H L = 55-89% Scheme 1.21 Cross-coupling between monofluorobenzene and ArMgX catalyzed by [Ni(acac)2] and an air-stable ligand The first example of cross-coupling of monofluorobenzene catalyzed by a Pd complex was reported by the Widdowson group in 1999 (Scheme 1.22).33i Pd2(dba)3 (tris(dibenzylidenacetone)dipalladium) (1.91) catalyzed the cross-coupling of C-F bond with electron-rich arylboronic acids, generating biaryl compounds in good yields. Tricarbonylchromium(0) acted as the electron-withdrawing-group on aryl fluoride ring to assist the C-F activation. However, the greater reactivity of the C-Br bond over the C-F bond led to the polymerization of 4-bromophenylboronic acid under the reaction conditions. This limitation is not surprising, given that C-Br bonds are considerably weaker than C-F bonds. 30 CrOC OC CO F B(OH)2 R1 5 mol% Pd2(dba)3 Cs2CO3, PMe3 Dimethyl ether, refluxing, 16h R1 CrOC OC CO R1 = H, 4-MeO, 2-MeO, 4-Me, 2-Me 61%-87% R1 = 4-Br 0% Odba = Scheme 1.22 Cross-coupling between monofluorobenzene and phenylboronic acids catalyzed by Pd2(dba)3 In 2003, the Yu group discovered an efficient catalyst Pd(PPh3)4 (1.92) which was used in the cross-coupling of electronic-deficient 2-fluoronitrobenzene with amines, tin reagents or phenylboronic acids (Scheme 1.23).33m,33n For Stille coupling (reactions with tin reagents) and Suzuki coupling (reactions with boronic acids), a second electron-withdrawing-group (in addition to the nitro group) is required on the fluorobenzene ring. Cs2CO3/DMF 65 °C, 24h NH2 (H3C)3C F NO2 + 10 mol% Pd(PPh3)4 H N (H3C)3C NO2 65% DMF, 65 °C,18h F NO2 + 10 mol% Pd(PPh3)4 R1 NO2 28%-65% R2R 1SnR3 R = butyl R1 = phenyl or vinyl R2 = CN or CHO R2 Cs2CO3/DMF, 65 °C,18h F NO2 + 10 mol% Pd(PPh3)4 R3 NO2 33%-86% R4 R3 = H or OMe R4 = CN or CHO R4 B(OH)2 R3 Amination Stille coupling Suzuki coupling Scheme 1.23 Amination, Stille coupling and Suzuki coupling catalyzed by Pd(PPh3)4 (1.92) 31 1.4.3 Cross-coupling of polyfluoroarenes Cross-coupling of monofluoroarenes is not applicable to synthesize functionalized arylfluorides, as this process involves cleavage of the C-F bond. However, partial and selective cross-coupling of polyfluoroaromatics provides a potential methodology for the formation of functionalized arylfluorides. Up to now, only a few examples for cross-coupling of polyfluoroaromatics have been reported. In this section, these examples are discussed. The first cross-coupling example of polyfluoroarenes was reported by Jones and co-workers in 1999 (Scheme 1.24).35a Perfluoropolyphenylene oligomers were generated when Cp2Zr(C6F5)2 (1.93) was heated in the presence of C6F6. This reaction was proposed to follow a rapid radical chain mechanism. Zr C6F5 C6F5 THF 85 °C, C6F6 FF F FF F n (n = 2- 13) 1.93 Scheme 1.24 The formation of perfluoropolyphenylene from hexafluorobenzene In 2001, the first Ni-catalyzed example of cross-coupling of polyfluoroarenes was presented by Braun and Perutz.35b They used the trans-NiF(4-C4N2F2H)(PEt3)2 (1.94) (Scheme 1.25) in the reaction between pentafluoropyridine and Bu3SnCH=CH2 in the presence of base. The reaction produced 2-vinyl-3,4,5,6-tetrafluoropyridine in 38% yield 32 and 2,3,5,6-tetrafluoropyridine in 20% yield (Scheme 1.25). However, the coupling reaction between pentafluoropyridine and Bu3SnCH=CH2 catalyzed by trans-PdF(4-C5NF4)(P iPr3)2 (1.77) provided a different coupling product, 4-vinyl-2,3,5,6-tetrafluoropyridine in 60% yield (Scheme 1.25).35g The different reaction results between reactions catalyzed by Ni complex (1.94) and Pd complex (1.77) were attributed to the difference in the C-F activation step. The C-F activation of pentafluoropyridine using 1.94 and 1.77 occurs on the 2-position and the 4-position, respectively. 10 mol % N F F F F F + H2C=CHSnBu3 PEt3, 50 °C,THF,Cs2CO3 N CH=CH2 F F F F + N F FF F 38% 20% Et3P Ni PEt3 F N F F F F Pr3P Pd P iPr3 F NF F F F i N F F F F F + H2C=CHSnBu3 10 mol % 50 °C,THF,Cs2CO3 N F F CH=CH2 F F 60% 1.94 1.77 Scheme 1.25 The cross-coupling of pentafluoropyridine and Bu3SnCH=CH2 33 Nakamura and co-workers reported the cross-coupling reaction of polyfluoroarenes with Grignard reagents catalyzed by Ni(acac)2(O,P-ligand) complex (1.95) (Scheme 1.26), with all aryl-F bonds being converted into aryl-phenyl bonds.35c Because all the aryl-F bonds reacted, this method is not applicable to the synthesis of functionalized arylfluorides. OH Me PPh2 F F + 2.1 -2.5 PhMgBr Ph Ph 0.5-5% Ni(acac)2/Ligand 85-92% F FF + 3.5 PhMgBr 2.5% Ni(acac)2/Ligand 88% Ph PhPh L = Scheme 1.26 The cross-coupling of polyfluoroarenes and Grignard reagents Braun and co-workers developed pyrimidine-Ni-F complex (1.96) for the cross-coupling of 5-chloro-2,4,6-trifluoro-pyrimidine with arylboronic acids (Scheme 1.27).35d 5-Chloro-2,4,6-trifluoropyrimidine coupled with TolB(OH)2, PhB(OH)2 and p-F3CC6H4B(OH)2, generating the corresponding 5-chloro-2-fluoro-4,6-diaryl- pyrimidines in 73%, 88% and 37% yield, respectively. This is the first catalytic C-C coupling reaction involving the activation of a stronger C-F bond in the presence of a weaker C-Cl bond. 34 N N F FF + ArB(OH)2 10 mol% THF, Cs2CO3 PPh3, 36 h, 50 °C N N F ArAr Cl Cl Ar = Tol, Ph, p-F3CC6H4 37%-88% N N FF NiPh3P PPh3 F Cl 1.96 Scheme 1.27 The cross-coupling of 5-chloro-2,4,6-trifluoropyrimidine and arylboronic acids As discussed in section 1.2.2, Radius and co-workers reported the stoichiometric C-F activation of hexafluorobenzene with Ni2( iPr2Im)4(COD) (1.21) ( iPr2Im = 1,3-di(isopropyl)imidazol-2-ylidene) (eq. 1.2). In the following year, the Radius group used this carbene-Ni complex (1.21) as a catalyst in the cross-coupling of polyfluoroarenes with phenylboronic acids (Scheme 1.28).35e The coupling between octafluorotoluene and phenylboronic acid, 4-methoxyphenylboronic acid, 4-methylphenylboronic acid and p-biphenylboronic acid afforded coupling products in 83%, 66%, 50% and 44% respectively. It is noteworthy that the coupling selectively occurred on the position trans to the CF3 group. 35 ArylB(OH)2 2 mol% Ni2( iPr2Im)4(COD) THF, 3 NEt3, 60 °C N N iPr iPr N N iPr iPr Ni Ni N N iPr iPr N N iPr iPr F F FF F F3C Ni2( iPr2Im)4(COD) = F aryl FF F F3C aryl = phenyl 36 h 4-methoxyphenyl 12 h 4-methylphenyl 12 h 4-phenylphenyl 12 h 83% 66% 50% 44% F FF F F3C 2 mol% Ni2( iPr2Im)4(COD) THF, 3 K2CO3, 18 h, 60 °C 66% F FF FF F FF F F3C Ph FF FF 1.21 + PhenylB(OH)2+ Scheme 1.28 Carbene-Ni complex catalyzed cross-coupling of polyfluoroarenes and arylboronic acids. The Tamao group compared the activities of NiCl2(dppp) (1.97) (dppp = 1,3-bis(diphenylphosphino)propane) and PdCl2(dppf) (1.98) (dppf = 1,1’-bis(diphenyl- phosphino)ferrocene) in the cross-coupling of bifluorobenzene or trifluorobenzene with Grignard reagents (Table 1.1).35f Use of the Ni complex provided a mixture of the corresponding mono-coupled and di-coupled products. In contrast, the Pd complex afforded mono-coupled products exclusively. 36 Table 1.1 Cross-coupling of bifluorobenzene with 4-MeC6H4MgBr 1 mol% catalyst THF, reflux, 48 h F MgBrMe + F Me Me Me + F F F NiCl2(dppp) PdCl2(dppf) NiCl2(dppp) PdCl2(dppf) NiCl2(dppp) PdCl2(dppf) Entry Substrate Catalyst Yield (%) (a) (b) (a) (b) F F F 38 40 91 0 37 36 15 0 23 45 6 0 1 2 3 4 5 6 F More recently, Manabe and co-workers envisaged electron-donating groups, such as OH- group, would function as ortho-directing groups for cross-coupling of fluorobenzenes.35h They reported the first examples of ortho-selective cross-coupling of difluorobenzene derivatives bearing electron-donating groups, however, the mechanism of this reaction is not clear. The results of PdCl2(PCy3)2 (1.99) catalyzed ortho-selective cross-coupling of difluoroarenes with a variety of Grignard reagents are listed in Table 1.2. It is noteworthy that hydroxymethyl works well as a directing group to provide ortho-selective product (entry 3). 37 Table 1.2 Cross-coupling of bifluorobenzene with arylMgBr catalyzed by PdCl2(PCy3)2 2 mol% PdCl2(PCy3)2 THF, 50 °C, 24 h F Entry Substrate Yield (%) 851 ArF + 3.0 equiv RMgBr Ar-R RMgBr Ar-R OH BrMg OH F 792 OH BrMg OH F F F 813 BrMg F F OMe OMe F F OH OH To date, only one example of Co-catalyzed cross-coupling of polyfluoroarenes has been reported. The Knochel group developed catalytic cross-coupling of polyfluoroarenes bearing a carbonyl function with organocopper compounds, using Co(acac)2 (1.100) as the catalyst (Scheme 1.29).35i,35j The coupling reactions proceeded smoothly at room temperature, with both C-F bonds ortho to the ketone directing group coupled under this reaction condition. The coupling reactions with 3,4-chlorophenylmagnesium chloride and 3-cyanophenylmagnesium chloride afford the diarylated products in 50% yield and 39% yield, respectively. 38 Ph OF F F F F 6 equiv Aryl-Cu(CN)MgCl Co(acac)2 (15 mol%) rt, 0.5 h Ph Oaryl aryl F F F Aryl = Cl Cl CN 50% 39% Scheme 1.29 Co(acac)2 catalyzed cross-coupling of polyfluoroarene with aryl-Cu(CN)MgCl As presented above, a number of late transition metals, e.g. Ni, Pd and Co have been utilized in the cross-coupling of polyfluoroarenes. However, only two examples of early transition metals, Zr and Ta, have been utilized in a similar fashion. The Zr-catalyzed cross-coupling of polyfluoroarenes has been discussed previously (Scheme 1.24). Ta-catalyzed cross-coupling of hexafluorobenzene was reported by Takahashi group (Scheme 1.30).35k The TaCl5 (1.101) catalyzed coupling between hexafluorobenzene and Grignard reagent exclusively provided mono-coupled product in 75% yield when 1.5 equiv of Grignard reagent was used. It was of interest that the coupling process involved complete isomerization of the phenethyl group. When 3.0 equiv of Grignard reagent was used, the yield of mono-coupled product and di-coupled product was 14% and 57%, respectively. It is noteworthy that the only di-coupled product formed was the para regioisomer; this can be explained by a combination of electronic and steric factors, which would exclude the meta and ortho products, respectively. The para regioisomer was also observed in the cross-coupling of 2,3,4,5,6-pentafluorotoluene with 39 phenethylmagnesium chloride and the yield of 4-(1-phenethyl)-2,3,5,6-tetrafluorotoluene was 73%. F F F F F 5 mol% TaCl5 THF-DME 50 °C, 24 h F F F F 75% 14% F FF F Me Ph Me Ph FF MePh+ PhCH2CH2MgCl PhCH2CH2MgCl (1.5 equiv) (3.0 equiv) 0% 57% F F Me F F 5 mol% TaCl5 F Me F F 73% F Me Ph F + PhCH2CH2MgCl (1.5 equiv) THF-DME 50 °C, 24 h Scheme 1.30 TaCl2 catalyzed cross-coupling of polyfluoroarenes with PhCH2CH2MgCl The Yamaguchi group reported the first cross-coupling of polyfluoroarenes with disulfides (Scheme 1.31).35l The polyarylthiolation reaction proceeded with hexafluorobenzene was catalyzed by Rh complex 1.102, generating para-difluorides with high selectivity (Scheme 1.31). When hexafluorobenzene (2 equiv) was reacted with (ArS)2 at 80 ºC for 4 h, the main product was 1,4-bis(p-tolylthio)-2,3,5,6-tetrafluoro- benzene in 95% yield (note: this yield was based on the equiv of disulfides). The minor product was 1,2,4,5-tetra(p-tolylthio)-3,6-difluorobenzene (5%). The reaction using 0.5 equiv of hexafluorobenzene required longer time (12 h) to complete, forming 40 1,2,4,5-tetra(p-tolylthio)-3,6-difluorobenzene in 95% yield and hexakis(p-tolythio)- benzene in 5% yield. When 0.33 equiv of hexafluorobenzene was used, the reaction required much longer time (48 h) to complete, generating hexakis(p-tolythio)-benzene (main product) (92%), 1,4-bis(p-tolylthio)-2,3,5,6-tetrafluorobenzene (3%) and 1,2,4,5- tetra(p-tolylthio)-3,6-difluorobenzene (3% ). F F F F F PPh3 (n equiv) Chlorobenzene,80 C, F SAr F FF F + (ArS)2 Ar = p-MeC6H4 RhH(PPh3)4 (1.102) (2x mol%) dppBz (4x mol%) SAr + SAr SAr F ArS F SAr + SAr SAr ArS ArS SAr SAr 1.02.0 n = 0.5, x = 1 95% 5% not detected 1.00.5 n = 2, x = 2 not detected 95% 5% 1.00.33 n = 3, x = 5 3% 3% 92% 4 h 12 h 48 h The yields are calculated on the basis of the equivalent of disulfides. Scheme 1.31 Rh-catalyzed cross-coupling of hexafluorobenzene with disulfides 1.4.4 Summary of literature Functionalized arylfluorides are becoming important compounds for their wide application. Arylfluorides have not been discovered in nature and they are required to synthesize. Current synthesis methodologies of arylfluorides have disadvantages, such as low selectivity. Selective C-F cleavage of polyfluoroarenes is a possible route to obtain high-valuable unsymmetrical arylfluorides from symmetrical polyfluoroarenes. Cross-coupling of polyfluroarenes has been realized by transition metals, such as Ni, Pd, Co, Rh, Zr and Ta. These studies indicated that such methodologies are feasible. But the substrate and organometallic reagent scope in each catalytic reaction is limited. This 41 indicates that considerable challenges remain for selective cross-coupling of polyfluoroarenes and the exploration of cross-coupling of polyfluoroarenes is still at an early stage. Moreover, other metals, except the extensively studied Ni and Pd complexes, need to be explored in this field. Application of Pt complex in the cross-coupling of polyfluoroarenes is the focus of this thesis. 1.5 Our proposal In the fall of 2003, we proposed to develop the first Pt-catalyzed cross-coupling of polyfluoroarenes. It is noteworthy to mention that, prior to our research, no examples of Pt-catalyzed C-F activation have been published. Our proposal was inspired by Crespo and Martinez’s work25g on stoichiometric chelation-assisted C-F activation of polyfluoroarylimines by [Me2Pt(μ-SMe2)]2 (1.54) to provide Pt(IV)-F species (1.57) (eq 1.16). Prior to our research, however, there was no examples of the transmetalation of such Pt(IV)-F complexes; thus, the feasibility of transmetalation was an important first consideration. On the basis of the high reactivity of M-F complexes with a number of organometallic reagents (section 1.3), we proposed that these Pt(IV)-F complexes (1.57) would serve as a starting point for transmetalation with M-R (M = Si, B, Li, Sn and Zn, etc; R = aryl or alkyl), generating aryl-Pt(IV)-R complexes; the formation of strong F-M bonds would act as the driving force, e.g. F-Si bond (130-140 kcal/mol),10a,10b given that 42 the strong F-Si bond formation serves as the driving force in the catalytic hydrodefluorination of hexafluorobenzene.34a,34b Prior to our research, both Csp3-Csp3 and Csp2-Csp2 reductive elimination from Pt(IV) complexes were known.37,38 It was reasonable to propose that aryl-R (R = aryl or alkyl) would reductively eliminate from aryl-Pt(IV)-R complexes (1.104) (Scheme 1.32); Pt(II) would be regenerated and could further activate C-F bonds on the remaining substrates. Therefore, Pt(II)/Pt(IV) catalytic cycle would be realized, as illustrated in Scheme 1.32. 43 [(CH3)2Pt(SMe2)(imine)] Pt Pt S Me2 Me2 S Me Me Me Me C-F activation NCH2Ph Pt CH3 FH3C F 0.5 [(CH3)2Pt(imine)] imine SMe2 RM F R NCH2Ph Transmetalation Reductive elimination MF Fn F F NCH2Ph Fn Fn or isomers M = Si, B, Sn, Zn, etc 1.54 1.103 NCH2Ph Pt CH3 FH3C SMe2 F Fn or isomers 1.57 + SMe2- SMe2 NCH2Ph Pt CH3 RH3C F Fn or isomers 1.104 NCH2Ph Pt CH3 RH3C SMe2 F Fn or isomers 1.105 + SMe2- SMe2 Scheme 1.32 Proposed catalytic cycle for Pt(II) catalyzed cross-coupling of a general organometallic reagent RM with a polyfluoroarylimine. In the catalytic cycle illustrated in Scheme 1.32, the initial C-F activation process (indicated with solid arrows) had already been established by Crespo and Martinez.25g The processes with dashed arrows (transmetalation and reductive elimination) were proposed by our group. Note that we propose 5-coordinate intermediates to be involved in each step, in accord with expectations from other Pt(IV) studies.37 44 Our first goal was to establish the feasibility of transmetalation of Pt(IV)-F with a suitable organometallic reagent to form [Pt]-R complex (1.104) (Scheme 1.32) Subsequent Ar-R reductive elimination from complex 1.104 would produce the cross-coupling product with new aryl-R (R = aryl or alkyl) bond formation. In the reductive elimination step, [Pt] will be released as Me2Pt(II)(SMe2), which will be in equilibrium with the starting Pt complex used to activate the C-F bond. Alternatively, Me2Pt(II)(SMe2) could coordinate another equivalent of imine substrate, thereby completing the catalytic cycle. 1.6 Metal-catalyzed cross-coupling reactions As presented in section 1.5, our research proposal is to realize Pt(II) catalyzed cross-coupling of polyfluoroarenes and to synthesize funactionalized arylfluorides with aryl or alkyl groups. It is of importance to compare metal catalyzed Csp2-Csp2 and Csp2-Csp3 cross-coupling in order to figure out which one would be more feasible. Metal catalyzed Csp2-Csp2 cross-coupling is the most common cross-coupling reaction and has been well-established after extensive studies in last three decades.39 Coupling reactions between aryl halides (Ar-X, X = I, Br and Cl) and vinyl-M or phenyl-M reagents have been catalyzed mainly by Pd or Ni complexes. Among various catalysis systems, the Pd/Pt(t-Bu)3 catalyst discovered by the Fu group is unusually reactive and has been used in a variety of cross-coupling processes, including Suzuki, Heck, Negishi and Stille couplings.40 45 Considerable recent efforts have been directed toward incorporating substituents with sp3 hybridization because aryl-Csp3 bond forming is important in organic synthesis.41 One of the first examples of catalytic aryl-alkyl (Csp2-Csp3) cross-couplings was reported by the Fu group.40a The cross-coupling reactions between arylchlorides and alkyl or aryl zinc chlorides catalyzed by Pd(Pt-Bu3)2 (1.106) were illustrated in eq 1.23. Under the same reaction conditions, the yield of the aryl-alkyl (Csp2-Csp3) coupling product (70%) was much lower than that of the aryl-aryl (Csp2-Csp2) coupling product (96%). In 2002, the Fu group reported a similar trend in the cross-coupling of arylchlorides with phenyltributyltin or tetrabutyltin.40b 2 mol% Pd(P(t -Bu)3)2 THF/DMF 100 °C Cl Me R Me ClZnR R = sec-Bu 2-methyl-phenyl 70% 96% (1.23) 24 h 20 h A recent example illustrated in eq 1.24 also indicated that the yield of the aryl-alkyl (Csp2-Csp3) coupling product (70%) was much lower than that of the aryl-aryl (Csp2-Csp2) coupling product (95%). Furthermore, complex 1.107 catalyzed coupling of an arylchloride with alkylzinc chloride required higher temperature and longer time than that of arylcholoride with vinylzinc chloride (eq 1.24).40c Csp2-Csp3 coupling was performed at 70 ˚C for 20 h. In contrast, Csp2-Csp2 coupling was completed in 1 hour at 50 ˚C. 46 + RZnCl 5 mol % 1.107 NMP R R Vinyl CH2CH2Ph Temp Yield 50 °C 70 °C 95% 70% (1.24) CN Cl CN Time 1 h 20 h Pd Pd Cl Cl P P P P O OO O CyCy CyCy H CyCy Cy Cy H 1.107 It was reported that the complex 1.108 catalyzed coupling of arylbromide with n-butylboronic acid also required stronger reaction conditions than the coupling of arylbromide with phenylboronic acid (eq 1.25).42a In this reaction system, Csp2-Csp2 coupling only needed 0.1 mol% catalyst and was performed at 100 ˚C for 3 h (eq 1.25). In contrast, Csp2-Csp3 coupling required 2 mol% catalyst and was performed at 130 ˚C for 20 h (eq 1.25). In this reaction, Csp2-Csp3 coupling provided a much lower yield than Csp2-Csp2 coupling. 47 OMe Br OMe R R = phenyl n-Bu 92% 61% 100 °C 3 h 130 °C 20 h 0.1 mol% 2 mol% RB(OH)2 (1.25) N H Pd PPh2 N N Cl 1.108 Herein was provided another example in which the differences of Csp2-Csp3 and Csp2-Csp2 coupling were demonstrated by studying Na2PdCl4 (1.109) catalyzed cross-coupling between para-substituted arylbromides and RB(OH)2 (R = Ph, Me) (eq 1.26).42b The Csp2-Csp3 coupling reactions (reaction time: 25 min and a yield of 70%) required longer times to reach completion and resulted in lower yields than the Csp2-Csp2 coupling (reaction time: 5 min and a yield of 95%). NC Br + RB(OH)2 Na2PdCl4, SDS K3PO4, H2O 100 °C NC R R Phenyl CH3 Time Yield 5 min 25 min 95% 70% (1.26) SDS = Sodium dodecyl sulfate In light of the literature examples described previously, it is reasonable to conclude that catalytic Csp2-Csp3 cross-coupling are generally considered to be more challenging, preceding with lower yields and requiring harsh conditions and longer reaction times, 48 compared to the well-established Csp2-Csp2 cross-coupling. This trend applies to the cross-coupling between arylchlorides or arylbromides with RM (R = aryl or alkyl, M = B, Sn, Zn) catalyzed by a variety of metal complexes. Considering our project to realize Pt(II)-catalyzed cross-coupling of polyfluoroarenes, we planned to develop Csp2-Csp2 cross-coupling initially for it seemed more feasible than Csp2-Csp3 cross-coupling. 1.7 Contents of this thesis Chapter 2 discusses the development of Pt(II)-catalyzed cross-coupling of polyfluoroaryl imines with MeM reagents (M = Si, B, Sn and Zn). 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Tetrahedron Lett. 2009, 50, 1003-1006. 60 CHAPTER TWO: APPROACH TO PT(II) CATALYZED CROSS-COUPLING OF POLYFLUOROARYL IMINES a  2.1 Introduction Fluorocarbons have exceptional and unique physical and chemical properties, including high metabolic stability, solubility, lipophilicity, and the ability to form hydrogen bonds.1 Fluorocarbons have therefore been widely used in practical applications such as plastics, refrigerants, pharmaceuticals, and pesticides,1d with up to 30% of new agrochemicals containing fluorine and 20% of new drugs.1c,2 For example, two top-selling drugs (Pfizer’s Lipitor and Johnson & Johnson’s Risperdal) contain an aryl fluoride moiety. F N HO HO CO2Ca Ph PhHN O iPr Lipitor (cholesterol-lowering) F O N N N O Risperdal (treating schizophrenia) N Figure 2.1 Structures of lipitor and risperdal To date, no aryl fluorides have been isolated from natural products,3 which necessitates the synthesis of aryl fluoride building blocks for the construction of fluorinated drugs and materials. Selective cross-coupling of polyfluoroaromatics provides  a A version of this chapter has been published. Wang, T.; Alfonso, B. J.; Love, J. A. (2007) Platinum(II)-Catalyzed Cross-Coupling of Polyfluoroaryl Imines. Org. Lett. 9:5629-5631. 61 a potential methodology to prepare functionalized aryl fluorides. However, catalytic cross-coupling of aryl fluorides has been a challenge in organometallic and organic chemistry for decades in part because fluorocarbons are resistant to chemical processes (C-F bond strength: 110-150 kcal/mol).4 Although a number of methods for stoichiometric C-F activation have been developed,5 only limited examples of catalytic C-F activation have been reported.6-8 Most of these catalytic processes are successful for only the cross-coupling of monofluoroarenes6 and thus are not applicable to the synthesis of functionalized fluoroarenes. In contrast to catalytic hydrodefluorination of polyfluoroarenes,7 methodologies for cross-coupling of polyfluoroarenes to form C-C bond are still rare.8 Despite the limitations of substrate scope, these studies indicated that cross-coupling of polyfluoroarenes is in fact feasible. Herein, the contents of this chapter are introduced briefly. Our proposal for Pt(II)-catalyzed cross-coupling of polyfluoroarenes and our initial goals are introduced in section 2.2. Section 2.3 illustrates the stoichiometric reactions between Pt(IV)-F and phenyl transmetalation reagents and the observation of an unexpected product from substitution of methyl for fluoride, suggesting the feasibility of catalytic methylation. In section 2.4, the catalytic cross-coupling of polyfluoroaryl imines with diverse functional groups is described. Finally, the exploration of non-imine directing groups is mentioned in section 2.5. 62 2.2 Our proposal and initial goals Our approach was to develop Pt(II) catalyzed cross-coupling of polyfluoroaryl- imines. It is noteworthy to mention that, prior to our research, no examples of Pt-catalyzed C-F activation had been published. Our proposal was inspired by work from Crespo and Martinez9 on stoichiometric chelation-assisted C-F activation of polyfluoroaryl imines by [Me2Pt(μ-SMe2)]2 (2.1) to provide Pt(IV)-F species (e.g., conversion of 2.1 to 2.2, eq 2.1). The imine was proposed to act as a directing group for C-F activation. Crespo and Martinez also pointed out that at least three electron-withdrawing-groups on the arene (in addition to the imine) were required for C-F activation to occur. We proposed that formation of 2.2 could be coupled with with subsequent transformations, allowing for catalytic cross-coupling of fluoroaryl imines. F F N Ph NCH2Ph Pt Me FMe SMe2 F 2.2 acetone rt, 24 h R R R = Electron withdrawing groups 0.5 [(CH3)2Pt(-SMe2)]2+ (2.1) Generally, cross-coupling reactions involve oxidative addition, transmetalation, and reductive elimination. On this basis, we hypothesized that a reasonable catalytic cycle would include these fundamental steps, as illustrated in Scheme 2.1. Transmetalation between Pt(IV)-F 2.2, formed as indicated in eq 2.1, and a suitable transmetalation reagent (RM) would generate [Pt]-R 2.3 (geometry unknown), presumably with 63 formation of a strong M-F bond as the driving force. Subsequent Ar-R reductive elimination from 2.3 would produce the cross-coupling product with release of a Pt(II) species. Coordination of imine starting material would complete the catalytic cycle. This process would therefore constitute catalytic C-F activation. We first focused our attention on stoichiometric transmetalation to determine the feasibility of such a process. [(CH3)2Pt(SMe2)(imine)] Pt Pt S Me2 Me2 S Me Me Me Me C-F activation 0.5 2.2 [(CH3)2Pt(imine)] imine SMe2 RM F R NCH2Ph Transmetallation Reductive elimination MF F F NCH2Ph Fn Fn (or isomers) 2.1 2.3 NCH2Ph Pt CH3 FH3C SMe2 F FnNCH2Ph Pt CH3 RH3C SMe2 F Fn Scheme 2.1 Proposed catalytic cycle for Pt(II) catalyzed cross-coupling of a general organometallic reagent RM with a polyfluoroarylimine. 64 2.3 Stoichiometric transmetalation using phenylmetal reagents 2.3.1 Reactions with silicon-based reagent Our first goal was to explore the stoichiometric reaction between Pt(IV)-F species 2.2 and different phenyl transmetalation reagents. We initially considered RSi(OMe)3 (R = phenyl) for several reasons. The transmetalation should be aided by the strength of the Si-F bond (130-140 kcal/mol),10 which should serve as a driving force for the reaction. For example, Milstein and co-workers illustrated that the reaction of HSiPh3 with [Rh]-F is thermodynamically driven by the irreversible formation of the very strong Si-F bond.7a Moreover, siloxanes have the obvious advantage over stannanes in that they are significantly less toxic. Unfortunately, however, they reportedly have lower reactivity than stannanes. Nevertheless, HSiPh3 7a has been successfully reacted with Rh(I)-F in catalytic reduction of aryl C-F bonds. Intramolecular transmetalation between silanes and Pd(II) and Pt(II) iodide complexes is also known.12 Likewise, PhSi(OMe)3 11a and PhSi(OEt)3 11b also work well as transmetalation reagents in Pd(II)-catalyzed reactions. It is also noteworthy that the comparison of Pt(II)-F and Pd(II)-F bonds in C-F activation of fluoropyridines revealed that the Pt(II)-F bond is weaker than the Pd(II)-F bond, which could indicate that transmetalation of Pt(II)-F would be easier than transmetalation of Pd(II)-F.13 65 F F N Ph NCH2Ph Pt Me FMe SMe2 F 2.2 F F 1a acetone-d6 rt, 24 h, 70% 0.5 [(CH3)2Pt(-SMe2)]2+ (2.2) Complex 2.2 was prepared according to the literature process (eq 2.2).9 The stoichiometric transmetalation of complex 2.2 with 1.2 equiv of PhSi(OMe)3 14a in acetone-d6 was monitored by 1H and 19F NMR spectroscopy. The resonance at -261 ppm in the 19F NMR spectrum, attributed to the Pt(IV)-F of 2.2, disappeared gradually and a new resonance at -136 ppm (with silicon satellites, JSi-F = 146 Hz) appeared at the same time. This data indicates the breaking of the Pt-F bond and the formation of a F-Si bond. (Note: the F-Si resonance of neat liquid FSi(OMe)3 is at -158 ppm (JSi-F = 196 Hz) 14b). After 21 h at room temperature methylated imine 2a was formed in 32% yield (eq 2.3). The identity of this product was confirmed by GCMS and 1H and 19F NMR spectroscopy. It should be pointed out that this methylated imine was not the expected cross-coupling product; we had instead anticipated transfer of the phenyl group from PhSi(OMe)3. 1.2 PhSi(OMe)3 F NCH2Ph F CH3 (2.3) 2a acetone-d6, rt, 21 h, 32% NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F 66 The unexpected formation of 2a inspired us to study transmetalation and reductive elimination in more detail. The questions that we wished to address were: (i) is a phenyl group transferred from PhSi(OMe)3 to Pt(IV) or does PhSi(OMe)3 serve only to remove fluoride from 2.2 (presumably by formation of the silicon “-ate” complex), with reductive elimination occurring from complex 2.4 (Figure 2.2)? and (ii) if the phenyl group is in fact transferred, why does reductive elimination of methyl occur preferentially? (or isomers) 2.4 NCH2Ph Pt CH3 H3C SMe2 F F Figure 2.2 Possible structure of complex 2.4 It was difficult to investigate the possible transfer of phenyl from PhSi(OMe)3 to 2.2 only based on 1H NMR spectroscopy because the resonance for the phenyl group overlapped with the resonance for aryl groups of the coordinated imine. Low resolution ESI-MS analysis of the reaction between 2.2 and PhSi(OMe)3 showed a peak with m/z of 594 (see MS data on page 235), which is consistent with 2.3 (stereochemistry unknown) resulting from phenyl transfer (eq 2.4). This result suggests that 2a is formed from 2.3 (or a complex derived from 2.3), in which case the question of why methyl reductive 67 elimination is preferred over phenyl persists. We attempt to answer this question in Chapter 4 section 4.2. PhSi(OMe)3, (2.4) FSi(OMe)3 (or isomers) Expected MS: 594 Observed MS: 594 2.3 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F NCH2Ph Pt CH3 PhH3C SMe2 F F 2.3.2 Reactions with PhSnMe3 and PhLi After demonstrating successful phenyl transmetalation, we next attempted the stoichiometric reaction of Pt(IV)-F complex 2.2 with more active phenyl reagents, namely PhSnMe3 and PhLi. Both the reaction between 2.2 and PhSnMe3 and the reaction between 2.2 and PhLi generated methylated product 2a with yields of 44% (eq. 2.5) and 32% (eq. 2.6), respectively.14c As mentioned above, the resonance of the Pt-Ph was not observed by 1H NMR spectroscopy because it was overlapped with the resonance of aryl group on imine in both reactions in equations 2.5 and 2.6. The reaction with PhLi, which was done in 50 min, was considerably faster than the reactions with either PhSnMe3 (5 h) or PhSi(OMe)3 (21 h), consistent with the expected trend in reactivity of the phenyl-containing reagents.14d 68 F NCH2Ph F CH3 (2.5) 2a F NCH2Ph F CH3 (2.6) 2a 1.2 PhSnMe3, acetone-d6 rt, 5 h, 44% 1.2 PhLi, toluene-d8 rt, 50 min, 32% NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F NCH2Ph Pt CH2 FH3C SMe2 F 2.2 F We hypothesized that transmetalation of phenyl does occur with both PhSnMe3 and PhLi to form Me2Pt-Ph species 2.3 (eq 2.4), with subsequent reductive elimination forming methyl imine 2a. It is noteworthy that this hypothesis requires preferential reductive elimination of methyl over phenyl, which is counter to what would be expected, based on literature reports of reductive elimination from Pt group metals.15 (see Chapter 4, section 4.2) 2.3.3 Stoichiometric isotopic study For all PhM reagents studied (M = Si, Sn and Li), the unexpected methylated product (2a) was formed in the stoichiometric reaction with Pt(IV)-F complex 2.2. When the reaction with PhLi was considered, it was logical to propose that the methyl group was provided by (imine)Me2Pt(IV)-F complex 2.2 although we could not exclude the possibility of SMe2 being the source. For the reactions with PhSnMe3 and PhSi(OMe)3, 69 the methyl group could come from 2.2, the transmetalation reagent, SMe2 or even multiple sources in a particular reaction. In order to unambiguously determine the source of the methyl group, isotopically-labeled [(CD3)2Pt(μ-SMe2)]2 (2.5) was synthesized from PtCl2(SMe2)2 with CD3Li, following a literature procedure. 16 Complex 2.6 (Scheme 2.2) was prepared using the same procedure as 2.2. Complex 2.6 was treated with PhSi(OMe)3 at room temperature over 24 h to provide labeled methylated imine exclusively (Scheme 2.2), based on 1H and 19F NMR spectroscopy and GC-MS data. All resonances for methylated imine 2a appeared in the 1H and 19F NMR spectroscopy except the resonance for aryl-methyl group at 2.60 ppm in the 1H NMR spectrum. The mass of the imine product increased 3 units (m/z = 248) relative to imine 2a (m/z = 245), which is consistent with formation methyl-labeled imine 3a. This data indicates that the source of the methyl group on methylated imine 2a was one of the methyl groups from the original platinum species (2.1). F NCH2Ph F CD3 Expected MS: 248 Observed MS: 248 2.6 3a 1.2 PhSi(OMe)3 Acetone,rt, 24 h, 18%F F N Ph Acetone, rt, 24 h, 65% 1a 0.5 equiv. (CD3)4Pt2(SMe2)2 complex 2.5 NCH2Ph Pt CD3 FD3C SMe2 F F Scheme 2.2 Stoichiometric isotopic study on the source of methyl group of 2a 70 At this point, we had accomplished stoichiometric cross-coupling of imine 1a. To realize a full catalytic cycle, the catalyst must be regenerated. However, complex 2.1 was consumed and could not be regenerated using PhM (M = Si, Sn, and Li). In contrast, the use of a MeM (M = Si, Sn, B, Zn, etc) reagent for transmetalation would potentially regenerate the original catalytic species. As a result, we next explored the suitability of different MeM reagents in catalysis. 2.4 Initial catalytic studies 2.4.1 Exploration of transmetalation reagents We proposed that the use of MeM would lead to catalytic cross-coupling of polyfluoro arylimine catalyzed by 2.1. We therefore treated imine 1a with 5 mol% 2.1 in acetone-d6 at 35 ˚C for 24 h in the presence of various MeM reagents, as shown in Table 2.1. The reaction of MeSi(OMe)3 (entry 1) generated 2a in 10% yield. Likewise, a low yield of 2a was obtained using MeB(OH)2 (entry 2). These reactions are both consistent with stoichiometric reactivity. We were pleased to discover that use of Me4Sn and Me2Zn provided 2a in 30% yield and 52% yield, respectively (entries 3 and 5). Importantly, control experiments revealed the necessity for the platinum complex (entry 4). Although the best result obtained involved only five turnovers of Pt, we were nevertheless delighted with this data because it strongly supported our proposal that the use of MeM 71 (M = Si, B, Sn, Zn) could lead to a catalytic cross-coupling reaction. We next embarked on optimizing the reaction conditions in order to achieve higher yields. Table 2.1 Optimization of reaction conditions for Pt-catalyzed cross-coupling of 1a with MeM FF F N Ph CH3F F N Ph5 mol% 2.1 1.2 equiv. RM, acetone-d6 35 °C, 24 h Entry YieldaRM 1 2 3 4 5 MeSi(OMe)3 MeB(OH)2 Me4Sn Me4Sn Me2Zn 10% 6% 30% 0% 52% 1a 2a mol% Pt 5 5 5 0 5 a Yields based on 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. 2.4.2 Optimization of catalytic reaction conditions for Me4Sn As illustrated above, we observed catalytic methylation using Me4Sn in acetone-d6 to form imine 2a in a yield of 30% (Table 2.1, entry 3). To obtain a higher yield of product 2a, the solvent and reaction temperature were varied. The results of these studies are listed in Table 2.2; the best yields are indicated in bold. Increasing the reaction temperature to 50 ˚C in acetone-d6 decreased the yield from 30% to 14% (Table 2.2, entry 2). The reaction in DMF-d7 at 35 ˚C produced 2a with the yield of 90% (entry 3). It is worthwhile to point out that in the absence of catalyst, the yield of 2a was 0% (entry 4). This indicates that catalyst is needed to perform the catalytic cross-coupling of 1a and Me4Sn. A 69% yield of 2a was obtained when the reaction was carried out in acetonitrile-d3 (entry 5). The catalytic reaction in toluene-d8 at 72 50 ˚C (entry 7) provided 21% of product, much higher than the reaction in toluene-d8 at 35 ˚C (entry 6), which proceeded in only 4% yield. Likewise, the reaction in benzene-d6 at 35 ˚C also generated 4% of 2a (entry 8). No detectable conversion to 2a was observed in THF, DCE, or DMSO-d6 (entries 9-11). Table 2.2 Optimization of reaction conditions for Pt-catalyzed cross-coupling of 1a with Me4Sn Entry YieldaSolvent 1 2 3 4 5 6 7 8 9 10 11 acetone-d6 acetone-d6 DMF-d7 DMF-d7 acetonitrile-d3 Toluene-d8 Toluene-d8 Benzene-d6 THF DCE DMSO-d6 30%b 14% 90% 0% 69% 4% 21% 4% 0% 0% 0% FF F N Ph CH3F F N Ph5 mol% 2.1 1.2 Me4Sn, 24 h 1a 2a Temp.(°C) 35 50 35 35 35 35 50 35 50 35 35 5 5 5 0 5 5 5 5 5 5 5 mol% Pt a Yields based on 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. b Same result as Table 2.1, entry 3. At this point, we had established that Me4Sn provided the methylated product in modest to excellent yields. The optimal solvent was found to be DMF. Despite these impressive results, we sought an alternative reagent with comparable reactivity and lower toxicity. Therefore, we were poised to optimize reaction conditions for Me2Zn, which has lower toxicity than Me4Sn. 73 2.4.3 Optimization of catalytic reaction conditions for Me2Zn As illustrated in Table 2.1, the attempted catalytic reaction of 1a and Me2Zn catalyzed by complex 2.1 provided 2a in 52% yield (Table 2.1, entry 5). We anticipated that we could obtain higher yield of product by changing the solvent. The data for these studies are listed in Table 2.3; the best yields are indicated in bold. Table 2.3 Optimization of reaction conditions for Pt-catalyzed cross-coupling of 1a with Me2Zn Entry ConversionaSolvent 1 2 3 4 5 6 7 8 9 acetone-d6 Toluene-d8 THF dichloromethane-d2 DMSO-d6 acetonitrile-d3 acetonitrile-d3 DMF acetonitrile-d3 52%b 4% 44%c 4% 0% 88% 0% 20%c >95% FF F N Ph CH3F F N Ph5 mol% 2.1 1.2 Me2Zn, 24 h 1a 2a Temp.(°C) 35 35 35 35 35 35 35 35 60 5 5 5 5 5 5 0 5 5 mol% Pt a Conversions based on integration of resonance of CH=N on 1H NMR spectroscopy. b Same as Table 2.1, entry 5. c Conversions based on integration of resonance on 19F NMR spectroscopy. In section 2.4.2, we illustrated the Pt(II)-catalyzed cross-coupling of 1a with Me4Sn in toluene at 35 ˚C generated the product in < 5% yield. Likewise, the catalytic reaction between 1a and Me2Zn in toluene-d8 at 35 ˚C (Table 2.3, entry 2) provided the product in <5% yield. These results indicated that this Pt(II)-catalyzed cross-coupling of 1a with Me4Sn or Me2Zn is inefficient in non-polar solvents. Therefore, we sought to more polar 74 solvents. The conversion of 1a to 2a was 44% when the reaction was performed in THF (entry 3), but the reaction in dichloromethane-d2 only provided 2a with the yield lower than 5% (entry 4). The reaction in DMSO-d6 did not form the cross-coupling product 2a (entry 5). The conversion of 1a to 2a was 88% in acetonitrile-d3 (entry 6). However, the reaction in DMF only provided the conversion of 20% (entry 8). It is worthwhile to point out that in the absence of catalyst in control experiment, the yield of 2a was 0% (entry 7). The result of this control experiment indicates that catalyst is necessary for formation of the methylated product. The conversion was >95% when the reaction in acetonitrile-d3 was heated at 60 ˚C for 24 h (entry 9). Obviously, Me2Zn is an excellent transmetalation reagent in the cross coupling reaction with 1a. To further understand the solvent effect on Pt(II)-catalyzed cross-coupling of 1a with Me2Zn, the dielectric constants of solvents were compared with conversions, listed in Table 2.4. Non-polar solvent toluene with a low dielectric constant provided the lowest conversion (Table 2.4, entry 1). The reaction in THF with higher dielectric constant than toluene converted 44% of 1a into 2a, indicating that THF is a moderate solvent for the reaction (entry 2). However, the reaction in dichloromethane which has higher dielectric constant than THF only provided the product in low conversion (entry 3). The reactions in acetone and acetonitrile provided much higher conversion than the reaction in THF (entries 4 and 5). The dielectric constants of acetone and acetonitrile are 21 and 37, respectively. However, DMF with almost the same dielectric constant as acetonitrile, provided a much lower yield (entry 6). The very polar solvent, DMSO, did not work for 75 the reaction. Thus, this Pt(II)-catalyzed cross-coupling reaction performed best in somewhat donating solvents, e.g. THF, acetone and acetonitrile, but really non-polar or very polar solvents do not work well. It is apparent that the donating ability of solvent is essential to the catalytic reaction. Because the catalyst 2.1 is dissolved well in donating solvents, the solvent effect could be the solubility issue that these solvent could stabilize Pt species. The donating solvents could possibly accelerate rate-determining step. This will be studied by someone else. We were delighted by the excellent yield and regioselectivity of monomethylated product (2a) in the catalytic reaction between 1a and Me2Zn. There was no further methylation of 2a even when Me2Zn was in excess, indicating that C-F activation of 2a was slow under catalytic conditions at 60 ˚C. Furthermore, there was no C-F activation in the stoichiometric reaction between 2a and [(CH3)2Pt(μ-SMe2)]2 (0.5 equiv) in acetonitrile-d3 at 60 ˚C for 24 h. Table 2.4 The comparison of dielectric constants of solvents and conversions of 1a to 2a in solvents Entry ConversionaSolvent 1 2 3 4 5 6 7 Toluene THF dichloromethane acetone acetonitrile DMF DMSO 4% 44% 4% 52% 88% 20% 0% Dielectric constants16b 2.4 7.5 9.1 21 37 38 47 a Same as Table 2.3. 76 We continued to explore other zinc transmetalation reagents, such as MeZnCl, because MeZnCl is considerably less flammable than Me2Zn, although Me2Zn does have the advantage of being commercially available. Nevertheless, MeZnCl is readily prepared by dropwise addition of MeLi ether solution into ZnCl2 THF solution under N2. When 1.2 equiv of MeZnCl was used in the reaction (Table 2.5, entry 2), the conversion of 1a to 2a was again > 95%. Table 2.5 Optimization of reaction conditions for Pt-catalyzed cross-coupling of 1a with methylzinc reagents Entry Conversiona 1 2 3 Me2Zn MeZnCl Me2Zn >95% >95% >95% FF F N Ph CH3F F N Ph5 mol% 2.1 CD3CN, 24 h 1a 2a 60 60 60 1.2 equiv. 1.2 equiv. 0.6 equiv. amountRZn Temp.(°C) a Conversions based on integration of resonance of CH=N on 1H NMR spectroscopy Presumably, the side product in the cross-coupling of 1a and 1.2 equiv Me2Zn is MeZnF. Given that MeZnCl provides high conversion of 1a to 2a, we anticipated similar reactivity from MeZnF, meaning that both methyl groups of Me2Zn should be transferable. In this case, less than a stoichiometric amount of Me2Zn should be able to provide high conversion of 1a to 2a. Indeed, the cross-coupling reaction between 1a and 77 0.6 equiv Me2Zn converted more than 95% of 1a to 2a (Table 2.5, entry 3), indicating that both methyl groups could be transferred from zinc. In these preliminary catalytic studies, we discovered that several methyl-metal reagents can be used to efficiently convert 1a to 2a. Less toxic methyl-metal reagent Me2Zn could cross-couple with 1a to form 2a in excellent yield and high regioselectivity. The cross-coupling reaction occurs exclusively at the ortho-position relative to the imine group. These data are consistent with our hypothesis that application of methyl transmetalation reagents could realize catalytic cross-coupling reaction to functionalize polyfluoroaryl imines. Thus, our next task was to explore the scope of polyfluoroaryl imines that could participate in the catalytic reaction. 2.5 Exploration of cross-coupling of polyfluoroaryl imines As discussed above, we have developed the cross-coupling reaction of N-(2,4,6- trifluorobenzylidene)benzylamine 1a with Me2Zn to form methylated arylimine 2a. In order to expand our new methodology, we next explored the cross-coupling of a series of polyfluoroaryl imines with Me2Zn to provide selectively methylated products (Table 2.6). 78 Table 2.6 Scope of Pt-catalyzed methylation of fluoroimines Entry Time, YieldaImine 5 8 h, 91% + 5 mol % 2.1 CH3CN, 60 °C 8 h, 95%1 7 8 h, 86%c Product F F N R 0.6 Me2Zn F CH3 N R F F N F Ph F CH3 N F Ph F F N F Ph F CH3 N F Ph F F N F Br F CH3 N F Br 2 8 h, 85% 3 4 h, 94%b F F N Br Ph F CH3 N Br Ph F F N NC Ph F CH3 N NC Ph 1a-g 2a-g 1a 2a 1b 2b 1c 2c 1e 2e 1g 2g R R 4 24 h, <10%b 1d 2d F F N Ph F CH3 N Ph 6 24 h, 0% F F N F Me F CH3 N F Me 1f 2f a Isolated yield, unless otherwise indicated. b Conversion based on integration of resonance of CH=N on 1H NMR spectroscopy. The isolated yield of 2c is 70%. c This substrate was initially studied by Brian J. Alfonso, undergraduate student in the Love group. Consistent with the reactivity of 1a, the cross-coupling of 1b with Me2Zn occurs exclusively at ortho-position (Table 2.6, entry 2), despite the presence of a much weaker 79 C-Br bond. Likewise, in the presence of an aryl-CN group, the methylation of 1c is also directed to 2-position (entry 3), without any detectable competing reactions of the cyano group. The high selectivity of the stronger C-F bonds over the weaker and potentially reactive bonds presumably is due to the coordination of the imine group (C=N) to the platinum metal centre, which directs preferential ortho-activation. Reaction of difluoro imine (1d) is sluggish, which is consistent with the low activity observed in the stoichiometric C-F activation reactions by Crespo and Martinez.9 These authors explained that at least three electron withdrawing groups (EWGs), in addition to the imine, were required to achieve C-F activation. Methylation occurs uneventfully when the imine substituent is modified from the benzyl group (1a) to a phenyl group (1e) (Table 2.6, entry 5). However, no cross-coupling reaction occurs with imine 1f, which contains a methyl substituent on the imine nitrogen (entry 6). These data indicate that some variation of the imine substituent is tolerated. Like 1b, in the presence of much weaker C-Br bond, the cross-coupling of 1g occurs exclusively at the 2-position (entry 7). Table 2.7 details the results of cross-coupling of polyfluoroaryl imines with modification of the position of fluoro substituents or the number of EWGs. It is worthwhile to point out that imine 1h reacts exclusively at the more hindered site ortho to the imine (Table 2.7, entry 1), which is consistent with the stoichiometric C-F activation results.9 Martinez and Crespo explained the selectivity on the basis of the electron-withdrawing effect of the adjacent fluorine atom, which enhances the reactivity 80 of C-F bond. Imine 1i (entry 2) reacts with Me2Zn to provide the same product as 1h, as cross-coupling occurs on the electronically favoured and weaker C-Cl bond. Furthermore, tetrafluoro imine (1j, entry 3) and pentafluoro imine (1k, entry 4) each react with Me2Zn to provide the corresponding monomethylated products in good yields. Table 2.7 Scope of Pt-catalyzed methylation of fluoroimines Entry Condition, Time, Yielda,bImine B, 12 h, 74%c,e 3 B, 24 h, 70% d 4 + 5 mol % 2.1 CH3CN Product F F N R 0.6 Me2Zn F CH3 N R F F N Ph F F F CH3 N Ph F F F F N Ph F F F F CH3 N Ph F F F A, 8 h, 92%1 F F N Ph F F CH3 N Ph F 2 A, 4 h, 99%c F Cl N Ph F F CH3 N Ph F 1h-k 2h-k 1h 2h 1i 2h 1j 2j 1k 2k R R a A: 60 ˚C; B: 80 ˚C. b Isolated yield, unless otherwise indicated. c Yield based on 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as an internal standard. e 1.2 equiv Me2Zn used. f Less than 5% N-(3,4,5-trifluoro-2,6-dimethylbenzylidene)benzylamine (3k) appeared. Overall, the reaction is highly selective for monomethylation. However, less than 5% of dimethylated product (3k) could be generated in the cross-coupling of imine 1k and 81 Me2Zn (Table 2.7, entry 4), presumably by methylation of the initially formed product 2k. In support of this assumption, imine 2k can be subsequently methylated with excess Me2Zn (eq 2.8) to form imine 3k. It is explained that four electron withdrawing groups on 2k makes the further C-F activation on ortho-position possible. However, there is no further cross-coupling reaction between 2j and Me2Zn although there are three EWGs on the phenyl ring (entry 3). CH3F F N 5 mol% 2.1 CD3CN, 80 °C, 15 h 72% 2k F F (2.8) Ph CH3F CH3 N F F Ph 3k + 0.6 Me2Zn The cross-coupling of easily obtained symmetrical imines in this catalysis system could provide more valuable unsymmetrical arylfluorides. For example, the symmetrical 2,4,6-trifluorobenzaldehyde is commercially available; but 2-bromo-4,6-difluoro- benzaldehyde, a mixed halo compound, is not on sale in the market. Moreover, the imine cross-coupled products formed in this process are potential substrates for further functionalization and thus have potential use in the synthesis of complex molecules. For example, 2b and 2c, with aryl-Br and aryl-CN bonds, respectively, can potentially undergo further functionalization (e.g., cross-coupling of the aryl-Br bond, reduction of the nitrile, etc). The methyl group can potentially be functionalized by directed metalation with subsequent trapping with alkyl halides17 and CO2 18. Furthermore, imines 82 can be readily hydrolyzed to aldehydes, which could be further transformed into many functional groups including acids, alcohols, esters, etc. Therefore, the methylated imine products are potential building blocks for pharmaceuticals, polymers and supramolecular structures. 2.6 Exploration of different directing groups As demonstrated above, the imine group directs the cross-coupling reaction to the ortho-position. In order to expand our substrate scope, we tried a series of other different directing groups, e.g. amide and aldehyde, as they are common directing groups. However, neither the dimethyl amide nor aldehyde has successfully provided the methylated product (eqs 2.9 and 2.10). As stoichiometric C-F activation is a good indicator of success in the catalytic reaction, amide 1n, which should be more susceptible to C-F activation than 1l, was explored to complex 2.1 under standard conditions. Despite being left to react at room temperature for 21 h, no detectable C-F activation had occurred (eq 2.11). Heating the sample to 50 ˚C led to the decomposition of Pt complex to a black powder. The unsuccessful C-F activation on 1n might be explained by the weak coordination of amide group to Pt center. Despite these initial set-backs, exploration of other directing groups is currently underway by other members of the group. 83 FF F N 5 mol% 2.1 CD3CN, 0.6 equiv Me2Zn 60 °C, 24 h1l FF F 1m CH3F F 2m 0% O H O H O FF F N 0.5 equiv 2.1 CD3CN, rt, 21h 1n O F F no C-F activation (2.11) CH3F F N 2l O 0% (2.9) (2.10) 5 mol% 2.1 CD3CN, 0.6 equiv Me2Zn 60 °C, 24 h 2.7 Conclusions In this chapter, the first examples of Pt-catalyzed C-F cross-coupling have been demonstrated. Polyfluoroaryl imines with diverse functional groups are able to react with Me2Zn to provide methylated fluoroarenes. This methodology has high selectivity for ortho C-F activation, even in the presence of much weaker bonds. Moreover, extraordinary selectivity of monomethylation has been obtained because the methylated products are not as reactive as the substrates in the methylation process. Lastly, and most importantly, we have developed a new methodology to catalytically form sp2-sp3 C-C bonds via C-F cross-coupling. This methodology is currently limited in substrate scope to imines with benzyl or phenyl substituents, but shows great promise due to the high yields and selectivity. 84 2.8 Experimental General Procedures. Manipulation of organometallic compounds was performed using standard Schlenk techniques under an atmosphere of dry nitrogen or in a nitrogen-filled MBraun drybox (O2 < 2 ppm). NMR spectra were recorded on Bruker Avance 300 or Bruker Avance 400 spectrometers. 1H and 13C chemical shifts are reported in parts per million and referenced to residual solvent. 19F NMR spectra are reported in parts per million and referenced to C6F6 in acetone-d6 (-162.9 ppm). Coupling constant values were extracted assuming first-order coupling. The multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, td = triplet of doublets. All spectra were obtained at 25 ˚C. Elemental analyses were performed using a Carlo Erba Elemental Analyzer EA 1108. GC spectra were recorded on a Varian CP-3800 gas chromatograph. Mass spectra were recorded on a Kratos MS-50 mass spectrometer. Characterization of chemicals is listed in Appendix I on pages 216-235. Materials and Methods. Acetonitrile was dried by refluxing over calcium hydride. THF was dried by passage through solvent purification column.19 1,2-dichloroethane (DCE) was distilled from molecular sieves and degassed prior to use. Acetone-d6, toluene-d8, benzene-d6, DMSO-d6, DMF-d7 and acetonitrile-d3 and all organic reagents were obtained from commercial sources and used as received. K2PtCl4 was purchased from Strem Chemicals and was used without further purification. All imines were prepared 85 according to a published procedure9 and further purified before use (described below). cis/trans-PtCl2(SMe2)2 was prepared according to a published procedure. 16a [Me2Pt(μ-SMe2)]2 and [(CD3)2Pt(μ-SMe2)]2 were prepared according to a modification of the published procedure (described below).16a 4-Bromo-2,6-difluorobenzaldehyde was prepared according to the published procedure.20 2,4,6-Trifluorobenzaldehyde, 4-Nitrile-2,6-difluorobenzaldehyde, 2,3,6-Trifluorobenzaldehyde, 2-Chloro-3,6-difluoro- benzaldehyde, 2,3,5,6-Tetrafluorobenzaldehyde, Pentafluorobenzaldehyde, PhSi(OMe)3, PhSnMe3, PhLi, MeSi(OMe)3, MeB(OH)2, Me4Sn were purchased and used without further purification. Methyl lithium (1.6 M solution in ether), phenyl lithium (1.9 M solution in n-butyl ether) and dimethyl zinc (2.0 M solution in toluene) were purchased from Aldrich and used without further purification. Methyl zinc chloride was synthesized according to the published procedure.21 Methyl lithium,22 and phenyl lithium,22 Me2Zn 23 and MeZnCl23 were titrated following the published procedure. N,N-Dimethyl-2,4,6-trifluoro-benzamide (1l) and N,N-Dimethyl-pentafluorobenzamide (1n) were prepared according to a published procedure.24 Synthesis of [Me2Pt(μ-SMe2)]2 (2.1) (modification of literature procedure16) A 250 mL Schlenk tube was fitted with a Teflon coated magnetic stir bar and was flame-dried under vacuum. After the flask cooled to room temperature, powdered cis/trans PtCl2(SMe2)2 (0.716 g, 1.84 mmol) was added to the flask. The schlenk tube was opened to vacuum and then refilled with N2 three times. Anhydrous Et2O (30 mL) 86 was transferred into this tube, which was then cooled to 0 ˚C. The solution was kept in a 0 ˚C bath for 45 min. MeLi (2.5 mL, 1.69 M in Et2O) was added dropwise via syringe over 10 min. The mixture was stirred for an additional 45 min at 0 ˚C. Cold saturated, aqueous NH4Cl (2 mL) and 0 ˚C distilled water (20 mL) were then added sequentially. The mixture was extracted with ice-cold Et2O (3 x 20 mL). The combined organic extracts were cooled to 0 ˚C and dried over anhydrous MgSO4. Decolorizing charcoal was then added to this mixture. After 10 minutes, filtration of the black suspension provided a light yellow solution. Concentration of the solution by rotary evaporation yielded [Me2Pt(μ-SMe2)]2 (0.420 g, 80%) as a white solid. If necessary, the product is purified by recrystallization from acetone at -35 ˚C overnight. 1H NMR spectral data were consistent with literature values.16 1H NMR (CD2Cl2, 300 MHz) : δ 2.72 (m, JPt-H = 20.7 Hz, S(CH3)2); 0.50 (s, JPt-H = 87.0 Hz, Pt-CH3). Synthesis of [(CD3)2Pt(μ-SMe2)]2 (2.5): The titration of the concentration of CD3Li is the same procedure as the titration of MeLi solution. The preparation procedure of isotopic [(CD3)2Pt(μ-SMe2)]2 is the same as preparation of [Me2Pt(μ-SMe2)]2, except using CD3Li. The solid after rotary evaporation was light yellow. The light yellow solid was recrystallized in acetone (0.5 mL) at -35 ˚C overnight to get colorless crystal. After recrystallization, the yield of [(CD3)2Pt(μ-SMe2)]2 was 20 %. 1H NMR (CD2Cl2, 300 MHz) : δ 2.72 (m, JPt-H = 20.7 Hz, S(CH3)2). 87 General experimental procedure for preparation of imine substrates: F F H O R + H2N-R F F R R R = CH2Ph, Ph, Me In a 100 mL three-necked round bottom flask equipped with a Teflon coated magnetic stir bar, the appropriate fluorobenzaldehyde (3 mmol) was dissolved in absolute ethanol (30 mL). Amine (3.15 mmol) was then added by syringe. The resulting solution was evacuated and refilled with N2 three times. The solution was then heated to reflux (90 ˚C) for 2-3 h (Note: pentafluorobenzaldehyde was heated at 100 ˚C for 2 h). The solution was cooled to room temperature and the solvent was removed under vacuum over 3-5 h. The residue was extracted with n-pentane (3 x 20 mL). The combined organic extracts were filtered through Celite. The filtrate was concentrated by rotary evaporation to provide the imine. Liquid imines were further purified by Kugelrohr distillation. Imines 1a, 1d and 1h were reported in reference 9, but no characterization data was given. 1a) N-(2,4,6-trifluorobenzylidene)benzylamine (light yellow oil, 87%) F F N F Ph (see spectra on page 217) 1H NMR (acetonitrile-d3, 300 MHz): δ 8.54 (s, CH=N, 1H), 7.37-6.84 (m, Ar-H, 7H), 4.80 (s, CH2, 2H). 19F NMR (acetonitrile-d3, 282 MHz): δ -104.0 (m, 1F), -109.0 (t, J = 88 9.0 Hz, 2F).  13C{1H} NMR (acetonitrile-d3, 100 MHz): δ 164.4 (dt, J = 250.6 Hz, J = 15.1 Hz), 163.2 (ddd, J = 256.6 Hz, J = 15.1 Hz, J = 10.1 Hz), 152.6 (s), 140.4 (s), 129.5 (s), 129.0 (s), 128.0 (s), 111.8 (td, J = 13.1 Hz, J = 4.0 Hz), 102.1 (td, J = 26.2 Hz, J = 3.0 Hz), 67.0 (s). HRMS (EI) m/z calcd for C14H10F3N: 249.0765; found: 249.0765. Anal. Calcd for C14H10F3N: C, 67.47; H, 4.04; N, 5.62; found: C, 67.51; H, 4.04; N, 5.71. 1b) N-(4-bromo-2,6-difluorobenzylidene)benzylamine (light yellow solid, 97%) F F N Br Ph (see spectra on page 218) 1H NMR (acetone-d6, 400 MHz): δ 8.61 (s, CH=N, 1H), 7.41-7.25 (m, Ar-H, 7H), 4.86 (s, CH2, 2H). 19F NMR (acetone-d6, 282 MHz): δ -110.9 (broden singlet). 13C{1H} NMR (acetone-d6, 100 MHz): δ 162.5 (dd, J = 259.6 Hz, J = 8.1 Hz), 152.3 (s), 140.3 (s), 129.3 (s), 128.8 (s), 127.8 (s), 124.5 (t, J = 13.1 Hz), 117.0 (dd, J = 27.2 Hz, J = 2.0 Hz), 114.4 (t, J = 13.6 Hz), 67.0 (s). HRMS (EI) m/z calcd for C14H10F2N 79Br: 308.9965; found: 308.9963.  Anal. Calcd. for C14H10F2N 79Br: C, 54.22; H, 3.25; N, 4.52; found: C, 54.62; H, 3.39; N, 4.55. 1c) N-(4-nitrile-2,6-difluorobenzylidene)benzylamine (yellow solid, 89%) F F N NC Ph (see spectra on page 219) 89 1H NMR (acetone-d6, 300 MHz): δ 8.68 (s, CH=N, 1H), 7.64-7.20 (m, Ar-H, 7H), 4.92 (s, CH2, 2H). 19F NMR (acetone-d6, 282 MHz): δ -109.7 (d, J = 8.5 Hz).  13C{1H} NMR (acetone-d6,  75 MHz): δ 162.3 (dd, J = 258.1 Hz, J = 7.5 Hz), 152.2 (s), 140.0 (s), 129.4 (s), 128.9 (s), 127.9 (s), 119.6 (t, J = 13.6 Hz), 117.4 (dd, J = 20.0 Hz, J = 1.9 Hz), 117.1 (t, J = 3.3 Hz), 115.6 (t, J = 12.8 Hz), 67.0 (s). HRMS (EI) m/z calcd for C15H10F2N2: 256.0812; found: 256.0805. Anal. Calcd for C15H10F2N2: C, 70.31; H, 3.93; N, 10.93; found: C, 70.57; H, 4.19; N, 11.00. 1d) N-(2,6-trifluorobenzylidene)benzylamine (yellow oil, 80%) F F N Ph (see spectra on page 220) 1H NMR (acetonitrile-d3, 400 MHz): δ 8.63 (s, CH=N, 1H), 7.47-6.99 (m, Ar-H, 8H), 4.82 (s, CH2, 2H). 19F NMR (acetonitrile-d3, 282 MHz): δ -113.2 (s).  13C{1H} NMR (acetonitrile-d3, 100 MHz): δ 162.7 (dd, J = 254.6 Hz, J = 7.0 Hz), 153.5 (s), 140.5 (s), 133.2 (t, J = 11.1 Hz), 129.5 (s), 129.1 (s), 128.0 (s), 114.7 (t, J = 13.1 Hz), 113.1 (dd, J = 20.1 Hz, J = 6.0 Hz), 67.1 (s). HRMS (EI) m/z calcd for C14H11F2N: 231.0860; found: 231.0858. Anal. Calcd for C14H11F2N: C, 72.72; H, 4.79; N, 6.06; found: C, 72.86; H, 4.67; N, 6.06. 90 1e) N-(2,4,6-trifluorobenzylidene)phenylamine (yellow oil, 92%) F F N F Ph (see spectra on page 221) 1H NMR (acetone-d6, 400 MHz): δ 8.62 (s, CH=N, 1H), 7.44-7.04 (m, Ar-H, 7H).  19F NMR (acetone-d6, 282 MHz): δ -102.6 (quintet, J = 9.0 Hz, 1F), -108.1 (t, J = 9.0 Hz, 2F).  13C{1H} NMR (acetone-d6, 100 MHz): δ 164.9 (dt, J = 252.6 Hz, J = 16.0 Hz), 163.5 (ddd, J = 258.5 Hz, J = 15.4 Hz, J = 9.1 Hz), 153.2 (s), 150.7 (s), 130.5 (s), 127.4 (s), 121.6 (s), 112.0 (td, J = 12.9 Hz, J = 4.5 Hz), 102.1 (td, J = 26.4 Hz, J = 3.5 Hz). HRMS (EI) m/z calcd for C13H8F3N: 235.0609; found: 235.0602. Anal. Calcd for C13H8F3N: C, 66.38; H, 3.43; N, 5.96; found: C, 66.20; H, 3.39; N, 6.35. 1f) N-(2,4,6-trifluorobenzylidene)methylamine (colorless oil, 40%) 1H NMR (acetonitrile-d3, 300 MHz): δ 8.64 (s, CH=N, 1H), 6.24-6.09 (m, Ar-H, 2H), 3.43 (s, CH=N-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ-105.2 (m), -117.6 (m). 1g) N-(2,4,6-trifluorobenzylidene)-4-bromobenzylamine (white solid, 85%) F F N F Br (see spectra on page 222) 1H NMR (acetone-d6, 300 MHz): δ 8.62 (s, CH=N, 1H), 7.54-7.00 (m, Ar-H, 6H), 4.84 (s, CH2, 2H). 19F NMR (acetone-d6, 282 MHz): δ -104.0 (quintet, J = 9.0 Hz, 1F), 91 -109.2 (t, J = 9.0 Hz, 2F).  13C{1H} NMR (CDCl3, 75 MHz): δ 163.5 (dt, J = 253.9 Hz, J = 15.8 Hz), 162.3 (ddd, J = 258.3 Hz, J = 14.9 Hz, J = 9.3 Hz), 152.1 (s), 137.9 (s), 131.6 (s), 129.5 (s), 121.0 (s), 110.5 (td, J = 13.2 Hz, J = 4.6 Hz), 101.0 (td, J = 26.2 Hz, J = 3.3 Hz), 65.7 (s). HRMS (EI) m/z calcd for C14H9F3N 79Br: 326.9871; found: 326.9872. Anal. Calcd for C14H9F3NBr: C, 51.25; H, 2.76; N, 4.27; found: C, 51.05; H, 2.72; N, 4.40. 1h) N-(2,3,6-trifluorobenzylidene)benzylamine (yellow solid, 97%) F F N Ph F (see spectra on page 223) 1H NMR (acetone-d6, 300 MHz): δ 8.62 (s, CH=N, 1H), 7.41-7.00 (m, Ar-H, 7H), 4.88 (s, CH2, 2H). 19F NMR (acetone-d6, 282 MHz): δ -118.2 (m, 1F), -136.6 (m, 1F), -142.0 (m, 1F).  13C{1H} NMR (acetone-d6, 75 MHz): δ 158.0 (ddd, J = 251.2 Hz, J = 4.0 Hz, J = 2.9 Hz), 152.4 (s), 149.9 (ddd, J = 258.5 Hz, J = 14.9 Hz, J = 7.2 Hz), 148.2 (ddd, J = 243.1 Hz, J = 12.5 Hz, J = 3.5 Hz), 140.2 (s), 129.3 (s), 128.8 (s), 127.8 (s), 119.5 (dd, J = 19.8 Hz, J = 10.5 Hz), 116.3 (dd, J = 15.5 Hz, J = 9.9 Hz), 112.6 (ddd, J = 24.2 Hz, J = 6.3 Hz, J = 4.8 Hz), 66.9 (s). HRMS (EI) m/z calcd for C14H10F3N: 249.0765; found: 249.0763. Anal. Calcd for C14H10F3N: C, 67.47; H, 4.04; N, 5.62; found: C, 67.53; H, 4.39; N, 5.64. 92 1i) N-(2-chloro-3,6-difluorobenzylidene)benzylamine (light yellow oil, 87%) F Cl N Ph F (see spectra on page 224) 1H NMR (acetonitrile-d3, 300 MHz): δ 8.64 (s, CH=N, 1H), 7.37-7.10 (m, Ar-H, 7H), 4.87 (s, CH2, 2H). 19F NMR (acetonitrile-d3, 282 MHz): δ -117.5 (m, 1F), -119.0 (m, 1F).  13C{1H} NMR (acetonitrile-d3, 100 MHz): δ 158.1 (dd, J = 251.6 Hz, J = 2.5 Hz), 155.8 (dd, J = 242.5 Hz, J = 3.0 Hz), 155.7 (t, J = 2.0 Hz), 140.2 (s), 129.6 (s), 129.0 (s), 128.1 (s), 125.2 (d, J = 15.1 Hz), 122.5 (dd, J = 20.1 Hz, J = 5.0 Hz), 118.9 (dd, J = 24.2 Hz, J = 10.0 Hz), 116.9 (dd, J = 25.2 Hz, J = 8.0 Hz), 66.7 (s). HRMS (EI) m/z calcd for C14H10F2N 35Cl: 265.0470; found: 265.0462. Anal. Calcd for C14H10F2N 35Cl: C, 63.29; H, 3.79; N, 5.27; found: C, 63.22; H, 3.81; N, 5.33. 1j) N-(2,3,5,6-tetrafluorobenzylidene)benzylamine (white solid, 87%) F F N Ph F F (see spectra on page 225) 1H NMR (acetone-d6, 300 MHz): δ 8.65 (s, CH=N, 1H), 7.60-7.26 (m, Ar-H, 6H), 4.91 (s, CH2, 2H). 19F NMR (acetone-d6, 282 MHz): δ -139.3 (m, 2F), -143.2 (m, 2F). 13C{1H} NMR (acetone-d6, 75 MHz): δ 151.9 (s), 147.0 (dddd, J = 246.5 Hz, J = 13.2 Hz, J = 10.9 Hz, J = 4.6 Hz), 146.2 (ddt, J = 254.1 Hz, J = 14.5 Hz, J = 4.0 Hz), 140.0 (s), 129.3 (s), 128.8 (s), 127.9 (s), 117.5 (t, J = 11.7 Hz), 108.5 (t, J = 23.2 Hz), 66.9 (s). 93 HRMS (EI) m/z calcd for C14H9F4N: 267.0671; found: 267.0676. Anal. Calcd for C14H9F4N: C, 62.93; H, 3.39; N, 5.24; found: C, 62.85; H, 3.09; N, 5.64. 1k) N-(pentafluorobenzylidene)benzylamine (white solid, 89%) F F N Ph F F F (see spectra on page 226) Data are consistent with literature values.25 1l) N,N-dimethyl-2,4,6-trifluorobenzamide (colorless solid, 90%) FF F N O 1H NMR (CDCl3, 300 MHz): δ 6.73-6.64(m, Ar-H, 2H), 3.10 (s, N-CH3, 3H), 2.91(s, N-CH3, 3H). 19F NMR (CDCl3, 300 MHz): δ -103.8 (t, J = 6.8 Hz), -108.2 (d, J = 6.8 Hz). 1n) N,N-dimethyl-pentafluorobenzamide (colorless oil, 40%) FF F N O F F Characterization data are consistent with literature values.13 94 Procedure for stoichiometric C-F activation of 1a to form complex 2.2.9 In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine 1a (8.5 mg, 0.034 mmol), [Me2Pt(μ-SMe2)]2 (9.8 mg, 0.017 mmol) and 1,3,5-trimethoxy- benzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in acetone-d6 (1.0 mL). The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was left at room temperature for 24 h to obtain Pt-F complex 2.2 (70%), as evidenced by 1H and 19F NMR spectroscopy. The yield of 2.2 was based on integration of the CH2 resonance of 2.2 with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. The characterization data is consistent with literature values.9 Characterization for 2.2: 1H NMR (acetone-d6, 300 MHz): δ 9.01 (s, JPt-H = 47.4 Hz, CH=N, 1H), 7.72-6.35 (m, overlapping peaks), 5.17 (m, CH2, 2H), 1.98 (s, JPt-H =12.0 Hz, S(CH3)2, 6H), 1.16 (d, JPt-H = 65.7 Hz, JF-H = 7.5 Hz, Pt-CH3, 3H), 0.77 (d, JPt-H = 68.1 Hz, JF-H = 7.8 Hz, Pt-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -101.3 (m, aryl-F), -110.3 (m, aryl-F), -261.6 (broad singlet, Pt-F). General procedure for stoichiometric reaction between 2.2 and PhM reagents (PhSi(OMe)3, PhSnMe3) In the glovebox, complex 2.2 was prepared in an NMR tube as previously described. The solution of complex 2.2 was added with PhM (0.041 mmol) by syringe. The tube was then removed from the glovebox. The reaction was monitored by 1H and 19F NMR 95 spectroscopy. The Pt-F resonance of 2.2 at -261 ppm in the 19F NMR spectrum disappeared gradually. 1H NMR spectroscopic analysis revealed the formation of methylated imine 2a. The yield of 2a was based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Characterization data for 2a: 1H NMR (acetone-d6, 300 MHz): δ 8.77 (s, CH=N, 1H), 7.40-6.90 (m, Ar-H, 7H), 4.85 (s, CH2, 2H), 2.60 (s, aryl-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -107.8 (quartet, J = 8.5 Hz, 1F), -114.0 (t, J = 8.5 Hz, 1F). HRMS (EI) m/z calcd for C15H13F2N: 245.1016; found: 245.1015. Reaction between complex 2.2 and PhSi(OMe)3 (21 h, 2a in 32% yield) Reaction between complex 2.2 and PhSnMe3 (5 h, 2a in 44% yield) Stoichiometric reaction between complex 2.2 and PhLi. Complex 2.2 was prepared in an NMR tube as previously described. The solution was evaporated to dryness under vacuum in the glovebox. Toluene-d8 (1.0 mL) was added into the NMR tube by syringe and the tube was capped with screw cap fitted with a septum. Subsequently the NMR tube was cooled to 0 ˚C for 10 min and PhLi solution (0.041 mmol) was added to the tube by syringe. The reaction was monitored by 1H and 19F NMR spectroscopy. The sample was left at room temperature to react for 50 min. 1H NMR spectroscopic analysis revealed the formation of methylated imine 2a, in 32% yield, based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. 96 Stoichiometic isotopic study a) Preparation of (CD3)2Pt(IV)-F complex (2.6): Complex 2.6 was prepared by replacing [Me2Pt(μ-SMe2)]2 (9.8 mg, 0.017 mmol) with [(CD3)2Pt(μ-SMe2)]2 (2.5) (10.0 mg, 0.017 mmol) using the same procedure to form 2.2. Characterization of 2.6: 1H NMR (acetone-d6, 300 MHz): δ 9.00 (s, JPt-H = 47.7 Hz, CH=N, 1H), 7.70-6.61 (m, aryl-H, overlapping peaks), 5.18 (m, CH2, 2H), 1.98 (s, JPt-H =11.1 Hz, S(CH3)2, 6H). 19F NMR (acetone-d6, 282 MHz): δ -101.3 (m, aryl-F), -110.3 (m, aryl-F), -261.6 (broad singlet, Pt-F). b) Stoichiometric reaction between 2.6 and PhSi(OMe)3 generated 3a in 18% yield. Characterization of labeled methylated product 3a: F NCH2Ph F CD3 1H NMR (acetone-d6, 300 MHz): δ 8.78 (s, CH=N, 1H), 7.80-6.60 (m, overlapping peaks), 4.86 (s, CH2, 2H). 19F NMR (acetone-d6, 282 MHz): δ -107.8 (quartet, J = 9.0 Hz, 1F), -114.1 (t, J = 9.0 Hz, 1F). HRMS (EI) m/z calcd for C15H13F2N: 248.1204; found: 248.1202. 97 General procedure of optimization of reaction conditions for Pt-catalyzed cross-coupling of 1a and MeM (MeSi(OMe)3, MeB(OH)2, Me4Sn, and Me2Zn, MeZnCl). In a 20 mL vial in the glovebox, 1a (8.4 or 8.5 mg, 0.034 mmol), complex 2.1 (1.0 mg, 0.0017 mmol), and 1,3,5-trimethoxybenzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in one appropriate solvent (1.0 mL) (solvents: acetone-d6, toluene-d8, benzene-d6, THF, DCE, DMSO-d6, DMF-d7 and acetonitrile-d3). The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. MeM (0.041 mmol) was added by syringe (Note: MeB(OH)2 was weighted in the glovebox; and Me4Sn was added by syringe after the NMR tube was removed from glovebox) The tube was then removed from the glovebox. The solution was heated at 35 ˚C or 50 ˚C or 60 ˚C for 24 h. The reaction was monitored by 1H and 19F NMR spectroscopy. The yield of 2a was based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. General experimental procedure for scope of Pt-catalyzed methylation of fluoroimines NMR reactions: In a 20 mL vial in the glovebox, imine (0.034 mmol) was dissolved in CD3CN (1 mL). 100 μL of complex 2.1 solution (0.017 mmol in 1.0 mL CD3CN) and 100 μL of trimethoxybenzene solution (0.34 mmol in 1.0 mL CD3CN) was then added by syringe. The resulting solution was transferred to an NMR tube. The tube was fitted with a screw cap containing a septum. Me2Zn (0.022 mmol, solution in toluene) was then 98 added to the NMR tube by syringe. The tube was then removed from the glovebox. The solution was heated at 60 ˚C or 80 ˚C. Reactions were monitored by 1H and 19F NMR spectroscopy. The yield of 2a was based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Note: There are no background reactions in the absence of the catalyst. Preparative scale reactions: In a 20 mL vial in the glovebox, imine (0.40 mmol) and [Me2Pt(μ-SMe2)]2 (2.1) (11.5 mg, 0.020 mmol) were dissolved in CH3CN (3 mL). The resulting solution was transferred into a test tube fitted with a screw cap containing a septum. Me2Zn (0.240 mmol, 120 µL of 2M solution in toluene) was then added into the tube by syringe. The tube was then removed from the glovebox and was heated at 60 ˚C or 80 ˚C for 8-12 h. The solution was cooled to room temperature. The solution was transferred to small one-necked flask and the solvent was removed by rotary evaporation. The residue was washed with n-pentane (3 x 20 mL). The combined organic solution was filtered through Celite. The filtrate was concentrated by rotary evaporation to provide the crude imine product. Further column separation provides clean imine products (SiO2, 70-230 mesh, n-pentane: Et3N = 100: 6 as eluant). 99 2a) N-(4,6-difluoro-2-methylbenzylidene)benzylamine (yellow oil, 95%) F CH3 N F Ph (see spectra on page 227) 1H NMR (acetone-d6, 300 MHz): δ 8.77 (s, CH=N, 1H), 7.40-6.90 (m, Ar-H, 7H), 4.85 (s, CH2, 2H), 2.60 (s, aryl-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -107.8 (quartet, J = 8.5 Hz, 1F), -114.0 (t, J = 8.5 Hz, 1F).  13C{1H} NMR (acetone-d6, 75 MHz): δ 164.1 (dd, J = 251.9 Hz, J = 13.2 Hz), 163.7 (dd, J = 249.7 Hz, J = 14.3 Hz), 156.5 (d, J = 5.5 Hz), 144.0 (dd, J = 9.9 Hz, J = 3.5 Hz), 140.8 (s), 129.3 (s), 128.7 (s), 127.7 (s), 120.2 (dd, J = 8.8 Hz, J = 3.5 Hz), 115.0 (dd, J = 21.1 Hz, J = 3.2 Hz), 102.2 (t, J = 26.2 Hz), 67.0 (s), 22.2 (s). HRMS (EI) m/z calcd for C15H13F2N: 245.1016; found: 245.1015. Anal. Calcd for C15H13F2N: C, 73.45; H, 5.34; N, 5.71; found: C, 73.11; H, 5.57; N, 5.99. 2b) N-(4-bromo-6-difluoro-2-methybenzylidene)benzylamine (light yellow oil, 85%) F CH3 N Br Ph (see spectra on page 228) 1H NMR (acetonitrile-d3, 300 MHz): δ 8.70 (s, CH=N, 1H), 7.36-7.22 (m, Ar-H, 7H), 4.80 (s, CH2, 2H), 2.51 (s, aryl-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -115.5 (d, J = 8.5 Hz). 13C{1H} NMR (acetonitrile-d3, 75 MHz): δ 163.1 (d, J = 254.0 Hz), 157.1 (d, J = 4.7 Hz), 143.4 (d, J = 2.6 Hz), 140.0 (s), 131.0 (d, J = 3.2 Hz), 129.5 (s), 128.9 (s), 128.0 (s), 123.9 (d, J = 11.5 Hz), 123.0 (d, J = 9.2 Hz), 117.7 (d, J = 26.0 Hz), 67.0 (s), 20.5 (d, J = 2.1 Hz). HRMS (EI) m/z calcd for C15H13FN 79Br: 305.0215; found: 100 305.0212.  Anal. Calcd for C15H13FN 79Br: C, 58.84; H, 4.28; N, 4.57; found: C, 59.21; H, 4.38; N, 4.64. 2c)N-(4-nitrile-6-difluoro-2-methybenzylidene)benzylamine (yellow solid, 94% conversion based on integration of the CH=N resonance of 2c and 1c in 1H NMR spectrum) F CH3 N NC Ph (see spectra on page 229) 1H NMR (acetonitrile-d3, 400 MHz): δ 8.75 (s, CH=N, 1H), 7.45-7.13 (m, Ar-H, 7H), 4.86 (s, CH2, 2H), 2.54 (s, aryl-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -115.8 (d, J = 8.5 Hz). 13C{1H} NMR (acetone-d6, 100 MHz): δ 162.9 (d, J = 252.1 Hz), 156.5 (d, J = 5.3 Hz), 143.3 (d, J = 2.8 Hz), 140.4 (s), 131.6 (d, J = 3.5 Hz), 129.4 (s), 128.8 (s), 128.3 (d, J = 9.2 Hz), 127.9 (s), 118.1 (d, J = 3.0 Hz), 117.8 (d, J = 26.3 Hz), 114.6 (d, J = 11.7 Hz), 67.0 (s), 21.5 (d, J = 2.2 Hz). HRMS (EI) m/z calcd for C16H13FN2: 252.1063; found: 252.1060. Anal. Calcd for C16H13FN2: C, 76.17; H, 5.19; N, 11.10; found: C, 76.08; H, 5.18; N, 11.07. 101 2e) N-(4,6-difluoro-2-methylbenzylidene)phenylamine (yellow oil, 91%) F CH3 N F Ph (see spectra on page 230) 1H NMR (acetonitrile-d3, 300 MHz): δ 8.74 (s, CH=N, 1H), 7.43-6.86 (m, Ar-H, 7H), 2.67 (s, aryl-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -106.6 (quartet, J = 8.5 Hz, 1F), -112.6 (t, J = 8.5 Hz, 1F). 13C{1H} NMR (acetonitrile-d3, 100 MHz): δ 164.6 (dd, J = 253.6 Hz, J = 13.1 Hz), 164.3 (dd, J = 250.6 Hz, J = 14.1 Hz), 155.8 (d, J = 5.0 Hz), 153.5 (s), 144.6 (dd, J = 10.0 Hz, J = 3.0 Hz), 130.3 (s), 127.2 (s), 121.7 (s), 120.2 (dd, J = 9.1 Hz, J = 4.0 Hz), 115.3 (dd, J = 21.1 Hz, J = 4.0 Hz), 102.7 (t, J = 26.2 Hz), 22.2 (broad singlet). HRMS (EI) m/z calcd for C14H11F2N: 231.0860; found: 231.0853. Anal. Calcd for C14H11F2N: C, 72.71; H, 4.80; N, 6.06; found: C, 72.94; H, 4.81; N, 6.35. 2g) N-(4, 6-difluoro-2-methylbenzylidene)-p-bromobenzylamine (white solid, 86%) F CH3 N F Br (see spectra on page 231) 1H NMR (acetone-d6, 400 MHz): δ 8.78 (s, CH=N, 1H), 7.53-6.91 (m, Ar-H, 6H), 4.83 (s, CH2, 2H), 2.60 (s, aryl-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -107.5 (quartet, J = 9.0 Hz, 1F), -113.9 (t, J = 9.0 Hz, 1F). 13C{1H} NMR (acetone-d6, 100 MHz): δ 164.1 (dd, J = 252.6 Hz, J = 13.0 Hz), 163.8 (dd, J = 250.1 Hz, J = 14.5 Hz), 157.0 (d, J = 5.0 Hz), 144.0 (dd, J = 10.1 Hz, J = 3.0 Hz), 140.4 (s), 132.3 (s), 130.8 (s), 121.1 (s), 120.1 (dd, J = 9.1 Hz, J = 4.0 Hz), 115.0 (dd, J = 21.1 Hz, J = 3.0 Hz), 102.3 (t, J = 26.2 Hz), 102 66.0 (s), 22.2 (t, J = 1.8 Hz). HRMS (EI) m/z calcd for C15H12F2N 79Br: 323.0121; found: 323.0119. Anal. Calcd for C15H12F2N 79Br: C, 55.58; H, 3.73; N, 4.32; found: C, 55.82; H, 3.79; N, 4.29. 2h) N-(3,6-difluoro-2-methylbenzylidene)benzylamine (light yellow oil, 92%) F CH3 N Ph F (see spectra on page 232) 1H NMR (acetone-d6, 300 MHz): δ 8.79 (s, CH=N, 1H), 7.41-7.10 (m, Ar-H, 7H), 4.88 (s, CH2, 2H), 2.48 (d, J = 2.5 Hz, aryl-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -120.8 (broad singlet, 1F), -123.2 (broad d, J = 14.1 Hz, 1F).  13C{1H} NMR (acetone-d6, 75 MHz): δ 159.6 (dd, J = 245.4 Hz, J = 2.1 Hz), 158.3 (dd, J = 238.0 Hz, J = 2.2 Hz), 157.1 (dd, J = 5.4 Hz, J = 1.8 Hz), 140.6 (s), 129.3 (s), 128.8 (s), 127.8 (s), 127.5 (dd, J = 19.5 Hz, J = 1.7 Hz), 125.0 (dd, J = 11.0 Hz, J = 4.0 Hz), 118.2 (dd, J = 27.0 Hz, J = 9.9 Hz), 114.7 (dd, J = 25.1 Hz, J = 9.2 Hz), 66.9 (s), 12.5 (d, J = 5.1 Hz). HRMS (EI) m/z calcd for C15H13F2N: 245.1016; found: 245.1014. Anal. Calcd for C15H13F2N: C, 73.45; H, 5.34; N, 5.71; found: C, 73.48; H, 5.49; N, 6.11. 2h) N-(3,6-difluoro-2-methylbenzylidene)benzylamine synthesized from 1i (99% yield, based on integration of the methyl resonance of 2h with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum). 103 F CH3 N Ph F The product is the same as 2h synthesized from 1h. HRMS (EI) m/z calcd for C15H13F2N: 245.1016; found: 245.1019. 2j) N-(3, 5, 6-tetrafluoro-2-methylbenzylidene)benzylamine (yellow oil, 70% yield) F CH3 N Ph F F (see spectra on page 233) 1H NMR (acetonitrile-d3, 400 MHz): δ 8.70 (s, CH=N, 1H), 7.46-7.11 (m, Ar-H, 6H), 4.85 (s, CH2, 2H), 2.36 (dd, J = 2.4 Hz, J = 1.2 Hz, aryl-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -117.4 (m, 1F), -138.5 (m, 1F), -148.0 (m, 1F). 13C NMR (acetonitrile-d3, 100 MHz): δ 157.0 (ddd, J = 240.5 Hz, J = 10.1 Hz, J = 4.0 Hz), 156.4 (q, J = 3.0 Hz), 149.0 (dt, J = 245.6 Hz, J = 14.1 Hz), 147.6 (ddd, J = 246.6 Hz, J = 13.1 Hz, J = 4.0 Hz), 140.32 (s), 129.5 (s), 128.9 (s), 128.2 (s), 126.4 (dd, J = 8.1 Hz, J = 6.0 Hz), 122.5 (dd, J = 19.1 Hz, J = 4.0 Hz), 106.9 (dd, J = 31.2 Hz, J = 21.1 Hz), 66.8 (s), 11.7 (d, J = 5.3 Hz). HRMS (EI) m/z calcd for C15H12F3N: 263.0922; found: 263.0919. Anal. Calcd for C15H12F3N: C, 68.44; H, 4.59; N, 5.32; found: C, 68.48; H, 4.59; N, 5.25. 104 2k) N-(3, 4, 5, 6-tetrafluoro-2-methylbenzylidene)benzylamine (78% yield, based on integration of the methyl resonance of 2k with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum) F CH3 N Ph F F F (see spectra on page 234) 1H NMR (acetonitrile-d3, 400 MHz): δ 8.66 (s, CH=N, 1H), 7.39-7.21 (m, Ar-H, 5H), 4.84 (s, CH2, 2H), 2.42 (dd, J = 2.8 Hz, J = 1.2 Hz, aryl-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -142.3 (dd, J = 20 Hz, J = 9.0 Hz, 1F), -144.8 (dd, J = 20 Hz, J = 9.0 Hz, 1F), -155.1 (t, J = 20 Hz, 1F), -160.9 (t, J = 20 Hz, 1F). 13C NMR (acetonitrile-d3, 100 MHz): δ 155.8 (t, J = 2.0 Hz), 148.2 (ddt, J = 243.0 Hz, J = 10.0 Hz, J = 3.8 Hz), 146.9 (dddd, J = 240.7 Hz, J = 10.0 Hz, J = 3.8 Hz, J = 2.3 Hz), 142.0 (dddd, J = 252.3 Hz, J = 16.6 Hz, J = 12.3 Hz, J = 3.8 Hz), 140.4 (s), 139.5 (dddd, J = 246.2 Hz, J = 16.9 Hz, J = 13.1 Hz, J = 4.6 Hz), 129.6 (s), 129.0 (s), 128.1 (s), 123.2(ddd, J = 15.4 Hz, J = 3.8 Hz, J = 1.6 Hz), 120.7 (m), 66.8 (s), 11.8 (d, J = 5.3 Hz). HRMS (EI) m/z calcd for C15H11F4N: 281.0828; found: 281.0824. Preparation procedure of imine 3k N-(3,4,5,6-tetrafluoro-2-methylbenzylidene)benzylamine 2k was prepared in NMR tube at 80 ˚C for 12 h, following the general procedure for the scope of Pt-catalyzed methylation of fluoroimines. The NMR tube was taken into glovebox and additional 105 Me2Zn (0.022 mmol, solution in toluene) was added by syringe. The NMR tube was then removed from the glovebox. The solution was heated at 80 ˚C for an additional 15 h. The reaction was monitored by 1H and 19F NMR spectroscopy. The yield of 3k was 72%, based on integration of the methyl resonance of 3k with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Characterization for 3k: CH3 CH3 N Ph F F F 1H NMR (acetonitrile-d3, 300 MHz): δ 8.65 (s, CH=N, 1H), 7.40-7.25 (m, aryl-H, overlapping peaks), 4.84 (s, CH2, 2H), 2.29 (t, J = 2.0 Hz, aryl-CH3, 6H). 19F NMR (acetonitrile-d3, 282 MHz): δ -141.2 (d, J = 19.8 Hz, 2F), -160.3 (t, J = 19.8 Hz, 1F). HRMS (EI) m/z calcd for C16H14F3N: 277.1078; found: 277.1080. General procedure for attempted methylation of imine with various directing groups In a 20 mL vial in the glovebox, aldehyde or amide (0.034 mmol) was dissolved in CD3CN (1.1 mL). Complex 2.1 (100 μL of a solution of 0.017 mmol in 1.0 mL CD3CN) and trimethoxybenzene (100 μL of a solution of solution of 0.34 mmol in 1.0 mL CD3CN) were then added by syringe. The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. Me2Zn (0.022 mmol, 106 solution in toluene) was then added to the NMR tube by syringe. The tube was then removed from the glovebox. 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Ni: (b) Braun, T.; Perutz, R. N.; Sladek, M. I. Chem. Comm. 2001, 2254–2255. (c) Saeki, T.; Takashima, Y.; Tamao, K. Synlett 2005, 7, 1771-1774. (d) Yoshikai, N.; Mashima, H.; Nakamura, E. J. Am. 110 Chem. Soc. 2005, 127, 17978-17979. (e) Steffen, A.; Sladek, M. I.; Braun, T.; Neumann, B.; Stammler, H.-G. Organometallics 2005, 24, 4057-4064. (f) Schaub, T.; Backes, M.; Radius, U. J. Am. Chem. Soc. 2006, 128, 15964-15965. Pd: (g) Braun, T.; Izundu, J.; Steffen, A.; Neumann, B.; Stammler, H.-G. Dalton Trans., 2006, 5118–5123. (h) Manabe, K.; Ishikawa, S. Synthesis, 2008, 2645-2649. Co: (i) Korn, T. J.; Schade, M. A.; Wirth, S.; Knochel, P. Org. Lett. 2006, 8, 725-728. 9) Crespo, M.; Martinez, M.; Sales, J. Organometallics 1993, 12, 4297-4304. 10) (a)Cotton, F. A.; Wilkinson, G. In Advanced Inorganic Chemistry; Wiley-Interscience: 1980, pp. 375. (b) Burdeniuc, J.; Jedlicka, B.; Crabtree, R. H. Chem. Ber.1997, 30, 145-154. 11) (a) Ishii, Y.; Chatani, N.; Yorimitsu, S.; Murai, S. Chem. Lett. 1998, 157-158. (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Organometallics 2004, 23, 4317-4324. (c) Denmark, S. E.; Amishiro, N. J. Org. Chem. 2003, 68, 6997-7003. 12) (a)Mateo, C.; Fernandez-Rivas, C.; Cardenas, D. J.; Echavarren, A. M. Organometallics 1998, 17, 3661-3669. (b) Mateo, C.; Fernandez-Rivas, C.; Echavarren, A. M.; Cardenas, D. J. Organometallics 1997, 16, 1997-1999. 13) Jasim, N. A.; Perutz, R. N.; Whitwood, A. C.; Braun, T.; Izundu, J.; Neumann, B.; Rothfeld, S.; Stammler, H.-G. Organometallics 2004, 23, 6140-6149. 14) (a) Before testing the transmetalation reaction between complex 2.2 with PhSi(OMe)3, we checked if there was a background reaction between complex 2.1 and PhSi(OMe)3. No reaction was observed by 1H NMR spectroscopy. (b) Muller, A. 111 J. J. Org. Chem. 1988, 53, 3364-3365. (c) The reaction between 2.2 and PhLi was performed in toluene to avoid the side reaction between acetone and PhLi. (Complex 2.2 was prepared in acetone-d6 at room temperature for 24 h. Acetone was removed by vacuum, followed by addition of toluene-d8 was added to the sample). d) “The Hiyama couplings in which silanes act organometalic reagents require fluoride as activating agent.” referring to: Lee, J-Y.; Fu, G. C. J. Am. Chem. Soc. 2003, 125, 5616–5617. 15) (a) Ananikov, V. P.; Musaev, D. G.; Morokuma, K. Organometallics 2005, 24, 715-723. (b) Gatard, S.; Çelenligil-Çetin, R.; Guo, C.; Foxman, B. M.; Ozerov, O. V. J. Am. Chem. Soc. 2006, 128, 2808–2809. 16) (a) Hill, G. S.; Irwin, M. J.; Levy, C. J.; Rendina, L. M.; Puddephatt, R. J.; Andersen, R. A. and McLean, L. Inorg. Synth. 1998, 32, 149-151. (b) www.orioninstruments.com/html/tools/dielectric.aspx 17) (a) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49, 1078-1083. (b) Forth, M. A.; Mitchell, M. B.; Smith, S. A. C.; Gombatz, K. Snyder, L. J. Org. Chem. 1994, 59, 2616-2619. 18) Flippin, L. A.; Muchowski, J. M.; Carter, D. S. J. Org. Chem. 1993, 58, 2463-2467. 19) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J. Organometallics 1996, 15, 1518-1520. 20) Paik, Y.; Yang, C.; Metaferia, B.; Tang, S.; Bane, S.; Ravindra, R.; Shanker, N.; Alcaraz, A. A.; Johnson, S. A.; Schaefer, J.; O’Connor, R. O.; Cegelski, L.; Snyder, J. 112 P. and Kingston, D. G. I. J. Am. Chem. Soc. 2007, 129, 361-370. 21) Shintani, R.; Yamagami, T.; Hayashi, T. Org. Lett. 2006, 8, 4799-4801. 22) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879-1880. 23) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890-891. 24) Hall, L. R.; Iwamoto, R. T.; Hanzlik, R. P. J. Org. Chem. 1989, 54, 2446-2451. 25) Ono, T.; Kukhar, V. P.; Soloshonok, V. A. J. Org. Chem. 1996, 61, 6563-6569. 113 CHAPTER THREE: INSIGHT INTO THE MECHANISM OF PT(II) CATALYZED CROSS-COUPLING OF POLYFLUOROARYL IMINES b  3.1 Introduction In chapter two, we demonstrated that [(CH3)2Pt(μ-SMe2)]2 (2.1) catalyzed the cross-coupling of polyfluoroaryl imines with (CH3)2Zn to generate ortho-methylated imines in high yields (eq 3.1).1 The development of this Pt(II) catalyzed cross-coupling of polyfluoroarenes was based on the known stoichiometric Pt(II) mediated C-F activation reaction reported by Crespo and Martinez (eq 3.2).2 Now we are poised to study the mechanism of this catalytic reaction to fully understand what fundamental steps are involved. We anticipated that an understanding of the reaction mechanism would be helpful in expanding the substrate scope and exploring new catalytic systems. F F N Ph NCH2Ph Pt CH3 FH3C SMe2 F (3.2) 0.5 [(CH3)2Pt(-SMe2)]2 F F 2.2 FF F N Ph CH3F F N Ph 5 mol % [(CH3)2Pt(-SMe2)]2 0.6 equiv (CH3)2Zn, CH3CN 60 °C, 8 h 95% 1a 2a (3.1) 1a Acetone, rt, 24 h  b A version of this chapter has been published. Wang, T.; Love, J. A. (2008) Insight into the Mechanism of Pt-Catalyzed Cross-Coupling of Polyfluoroaryl Imines. Organometallics 27:3290-3296. 114 Herein, the contents of this chapter are introduced briefly. The basic steps of the mechanism – C-F activation, transmetalation and reductive elimination – are discussed in sections 3.2-3.4. The irreversibility of C-F activation is presented in section 3.5. Section 3.6 introduces the catalytic reaction using a Pt(IV)-F complex as a pre-catalyst. The studies on the effect of excess of SMe2 (section 3.7) on the catalytic reaction, transmetalation and reductive elimination indicate that both transmetalation and reductive elimination involve the dissociation of SMe2 and occur from five-coordinate species. The proposed mechanism for the catalytic reaction is illustrated in section 3.8. Section 3.9 presents the isolation and characterization of a Pt(IV) complex that is relevant to the catalytic cycle. Finally, further C-H activation to form a six-membered chelated ring is discussed in section 3.10. 3.2 The involvement of C-F activation step in catalytic reaction 3.2.1 Comparison of substrate reactivities in catalytic and stoichiometric reactions Generally, a cross-coupling reaction involves oxidative addition, transmetalation and reductive elimination steps; we therefore expected that these steps would be involved in the Pt-catalyzed cross-coupling of aryl fluorides. We focused first on the question: is the C-F activation step (oxidative addition step) involved in the Pt(II) catalyzed cross-coupling reaction? We proposed that a comparison of substrate reactivities in catalytic cross-coupling and stoichiometric C-F activation could provide some important clues about this question. Specifically, if the reactivities of substrates in the catalytic 115 reaction are similar with those in stoichiometric C-F activation, it would be reasonable to propose that a C-F activation step is involved in the catalytic reaction. While exploring the reaction scope, as described in Chapter two, we noticed that imine substrates with three electron-withdrawing-groups (in addition to the imine) have excellent reactivities in the catalytic reaction (Chapter 2, Table 2.5). In contrast, difluoro imine 1b reacts only sluggishly (eq 3.3). Thus, three electron-withdrawing-groups (not including the imine) appear to be required for the catalytic reaction to occur. Importantly, these observations are consistent with the reported results in stoichiometric C-F activation of the same imine substrates (e.g., eq 3.4).2 Increasing the number of electron-withdrawing-groups on the aryl ring facilitates the stoichiometric C-F activation. For example, the experimentally determined enthalpies of C-F activation of trifluoroaryl imine and pentafluoroaryl imine are 54  1 and 30  4 kJ/mol, respectively.2 Furthermore, the high regioselectivity of the methylation reaction of 2,3,6-trifluoro imine 1c for the more hindered site ortho to the imine (eq 3.5) is also consistent with the stoichiometric C-F activation results (eq 3.6). Martinez and Crespo explained this result on the basis of the electron-withdrawing effect of the adjacent fluorine atom.2 These similarities between the catalytic C-F activation and the stoichiometric C-F activation led us to propose that C-F activation is likely part of the catalytic cycle. 116 F F N Ph CH3 F N Ph 5 mol % [(CH3)2Pt(-SMe2)]2 0.6 equiv (CH3)2Zn, CD3CN 60 °C, 11 h 97% 1c 2c (3.5) F F F F N Ph CH3 F N Ph 5 mol % [(CH3)2Pt(-SMe2)]2 0.6 equiv (CH3)2Zn, CD3CN 60 °C, 24 h <10%1b 2b (3.3) F F N Ph NCH2Ph Pt CH3 FH3C SMe2 F (3.4) [(CH3)2Pt(-SMe2)]2 Not observed X 1b F F N Ph NCH2Ph Pt CH3 FH3C SMe2 F (3.6) [(CH3)2Pt(-SMe2)]2 1c F F 3.2 3.1 Crespo & Martinez2 Crespo & Martinez2 3.2.2 Stoichiometric C-F activation in acetonitrile The stoichiometric C-F activation of fluoroaryl imines in acetone was studied in detail by Martinez and Crespo.2 In contrast, our catalytic reactions were performed in acetonitrile, which had been found to be the optimal solvent for cross-coupling (see Chapter 2). We therefore deemed it crucial to study stoichiometric C-F activation in acetonitrile to ensure that similar reactivity occurred in this solvent. The 2,4,6-trifluoro imine 1a was selected for study as this substrate reacts cleanly and efficiently in catalytic cross-coupling.1 Complex 2.1 (9.8 mg, 0.017 mmol), 1a (8.5 mg, 117 0.034 mmol) and 1,3,5-trimethoxybenzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in 1.1 mL of acetonitrile. The resulting solution was transferred to an NMR tube and was heated at 60 ˚C. The reaction was monitored by 1H and 19F NMR spectroscopy. After 6 h, no further reaction was observed. Complex 2.2 had been formed in 70% yield, along with other unidentified species formed in low yields. (Note: The yield of 2.2 was based on integration of the CH2 resonance of 2.2 with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum.) The plot in Figure 3.1 shows the concentration changes of 1a and complex 2.2 over time. The discrepancy between the consumption of starting material 1a and the formation of 2.2 was attributed to the unidentified species. However, Martinez and Crespo did not report the yield of 2.2 due to its low stability. This information demonstrates that C-F activation occurs readily in acetonitrile, consistent with the results of Crespo and Martinez in acetone. Moreover, this result indicates that C-F activation might be the rate-determining step in the catalytic cycle because this step occurred on the same time scale as the catalytic reaction.1 118 0 5 10 15 20 25 0 50 100 150 200 250 300 350 Time(min) C o n ce n tr at io n (m M ) Figure 3.1 Plot of [1a] (mM) vs time (min) (■) and [2.2] (mM) vs time (min) (▲) at 60 ˚C. 3.2.3 Mechanism of C-F activation2,3 We expected C-F activation in acetonitrile to follow the same general mechanism as in acetone. Martinez and co-workers have studied the detailed mechanism of C-F activation in acetone using 2.1, illustrated in Scheme 3.1.2,3 Coordination of imine to 2.1 leads to 3.3. Dissociation of SMe2 from 3.3 generates 3.4. Oxidative addition of the C-X bond (X = Br, Cl, F) to Pt forms 3.5 (geometry unknown); isomerization and coordination of dimethylsulfide provides 3.6. Notably, SMe2 can dissociate from 3.6, evidenced by the ability to substitute SMe2 with PPh3. 3-5 119 NCH2Ph Pt CH3H3C X 0.5 [(CH3)2Pt(-SMe2)]2 NCH2Ph Pt X CH3H3C + SMe2 + SMe2 NCH2Ph Pt CH3 XH3C SMe2 X N Ph Me2S NCH2Ph Pt CH3H3C 3.3 3.5 (+ isomers)3.6 X - SMe2 - SMe2 3.4 2.1 Acetone, rt Scheme 3.1 Mechanism of C-X activation (see references 2 and 3) 3.3 Conversion of Pt(IV)-F 2.2 to 2a The next task was to determine if the Pt(IV)-F species formed by C-F activation could undergo transmetalation with (CH3)2Zn. The hypothesis was that the resulting Me3Pt(IV) species would then undergo reductive elimination to form 2a. In order to test our proposal, we sought to explore stoichiometric transmetalation of Pt(IV)-F complex 2.2 with (CH3)2Zn. 3.3.1 Stoichiometric transmetalation of 2.2 with (CH3)2Zn to generate Me3Pt(IV) complex (3.7) The stoichiometric transmetalation reaction between 2.2 and (CH3)2Zn in CD3CN was completed within a few minutes (eq 3.7), much faster than the stoichiometric C-F activation process (60 ˚C, 6 h). Unfortunately, however, formation of 2a was too rapid at 120 room temperature to permit isolation of the initially formed product. Nevertheless, based on 1H NMR spectroscopic data, the initial product of transmetalation was identified as a trimethyl Pt(IV) complex (3.7). The 1H NMR resonances are listed in Table 3.1. The resonance at δ 8.86 (JPt-H = 39 Hz) (Table 3.1, entry 1) was assigned to the CH=N of an imine coordinated to Pt. The resonance at δ 4.99 (entry 2) was assigned to the methylene group of the imine. The peak at δ 1.78 (JPt-H = 13 Hz) (entry 3) was attributed to SMe2 bound to Pt. The three remaining resonances at δ 0.75 (JPt-H = 69 Hz), δ 0.36 (JPt-H = 73 Hz) and δ 0.16 (JPt-H = 46 Hz) were assigned to three methyl groups coordinated to Pt. The coupling constants of the resonances at δ 0.75 (JPt-H = 69 Hz) and δ 0.36 (JPt-H = 73 Hz) are typical coupling constants between Pt and the protons on a methyl group trans to L-type ligands (herein, the L-type ligands are the imine nitrogen and sulfide).6 The coupling constant of 46 Hz is a typical coupling constant between Pt and the protons on a methyl group trans to an X-type ligand, including carbon; thus, the resonance at δ 0.16 was assigned to the methyl group trans to the fluoroaryl ring. These resonances are proposed to come from the same Pt species, Me3Pt(IV) 3.7 (eq 3.7) on the basis of their relative integrations. The two resonances at δ -104.3 (m) and -111.6 (m) in the 19F NMR spectrum were consistent with this assignment. It is also noteworthy that the absence of (CH3)2Zn, heating 2.2 at 60 ˚C for 8 h did not lead to imine 2a product, suggesting that the presence of (CH3)2Zn is necessary for the conversion of 2.2 to 2a. 121 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F (CH3)2Zn CD3CN, rt, 5 min NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F (3.7) Yield > 95%, based on amount of 2.2 formed from the reaction of 1a and 2.1 Table 3.1 1H NMR spectroscopic data for 3.7 in stoichiometric reaction Entry δ Multiplicity Relative intensity Assignment 1 8.86 s (JPt-H = 40 Hz) 1 CH=N 2 4.99 m 2 CH2Ph 3 1.78 s (JPt-H = 13 Hz) 6 S(CH3)2 4 0.75 s (JPt-H = 69 Hz) 3 CH3-Pt 5 0.36 s (JPt-H = 73 Hz) 3 CH3-Pt 6 0.16 s (JPt-H = 46 Hz) 3 CH3-Pt 3.3.2 Observation of 3.7 (or a related species) during catalysis At this point, the relevance of complex 3.7 in the catalytic reaction mechanism was not clear. It is possible that 3.7 could be an intermediate in the catalytic cycle or, more likely, could be a resting state for the catalytic cycle. We thus considered the possibility that 3.7 could be observed during a catalytic reaction. The Pt(II) catalyzed cross-coupling of imine 1a (0.034 mmol) and (CH3)2Zn (eq 3.8) was monitored at 60 ˚C by 1H and 19F NMR spectroscopy. The plot in Figure 3.2 illustrates the concentration changes of the substrate 1a and the product 2a over time. The concentration was measured by integration of the imine CH=N resonances based on integration of the aryl resonance of internal standard using 1H NMR spectroscopy. 122 During the catalytic process, in addition to imine 1a and 2a, which dominated the spectrum, a number of much smaller resonances were observed in the region where the Pt-methyl resonances of 3.7 appeared. Herein, unfortunately, we could not identify with certainty what species were present. These resonances disappeared when the reaction was complete. It is noteworthy to mention that diagnostic resonances for complex 2.2 were not observed in the catalytic reaction. FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CD3CN 60 °C 1a 2a (3.8) 0 5 10 15 20 25 30 0 100 200 300 400 500 600 Time(min) C o n ce n tr at io n (m M ) Figure 3.2 Plot of [1a] (mM) vs time (min) (■) and [2a] (mM) vs time (min) (▲) at 60 ˚C. 123 In order to gain greater insight into the possibility that 3.7 was generated during catalysis, the catalytic reaction was performed at a higher concentration (eq 3.9, 10x the concentration of the reaction in eq 3.8). At least one identifiable new species with multiple Pt-methyl peaks was observed during the catalytic process. The chemical shifts, integration of the resonances for the methyl-Pt species and assignments for these resonances were listed in Table 3.2. The resonance at δ 8.87 (JPt-H = 39 Hz) (Table 3.2, entry 1) was assigned to the CH=N of an imine coordinated to Pt. The resonance at δ 4.98 (entry 2) was assigned to the methylene group of the imine bound to Pt. The peak at δ 1.77 (JPt-H = 12 Hz) (entry 3) was attributed to SMe2 coordinated to Pt. The three remaining resonances at δ 0.78 (JPt-H = 69 Hz), δ 0.41 (JPt-H = 73 Hz) and δ 0.20 (JPt-H = 46 Hz) were assigned to three methyl groups coordinated to Pt. These resonances were attributed to the same Pt species based on their relative integrations. Furthermore, two resonances at δ -104.4 and -111.7 in the 19F NMR spectrum, which were much smaller than the resonances for 1a and 2a, were also assigned to this Me3Pt(IV) species. FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CD3CN 60 °C 1a 2a (3.9) The concentration of this reaction is 10x the concentration of the reaction in eq 3.8 124 Table 3.2 1H NMR spectroscopic data for Me3Pt(IV) species in catalytic reaction Entry δ Multiplicity Relative intensity Assignment 1 8.87 s (JPtH = 39 Hz) 1 CH=N 2 4.98 m 2 CH2Ph 3 1.77 s (JPtH = 12 Hz) 6 S(CH3)2 4 0.78 s (JPtH = 69 Hz) 3 CH3-Pt 5 0.41 s (JPtH = 73 Hz) 3 CH3-Pt 6 0.20 s (JPtH = 46 Hz) 3 CH3-Pt To discover the identity of the Me3Pt(IV) species observed in catalysis, it is of importance to compare the 1H and 19F NMR spectroscopic data between this Me3Pt(IV) species and Me3Pt(IV) 3.7 synthesized in the stoichiometric reaction between 2.2 and (CH3)2Zn. The data for these two Me3Pt(IV) species (Table 3.3) are almost identical except the chemical shifts for three methyl groups, which are indicated in bold (entries 4-6). The chemical shifts for three methyl groups on Me3Pt(IV) observed in catalysis were about 0.03-0.05 ppm downfield from those in 3.7. Likewise, there were minor differences in the 19F spectra. Thus, we cannot unequivocally assign the Me3Pt(IV) species observed in catalysis as 3.7 although the slight differences could be due to the higher concentration and/or the presence of excess imine in the catalytic reaction. Furthermore, the addition of 3.7 in the catalytic reaction, in which the Me3Pt(IV) species was observed, increased the concentration of Me3Pt(IV) species in catalysis (see spectra on page 242), indicating that 3.7 and Me3Pt(IV) species in true catalysis system are identical. Therefore, we can conclude that this Me3Pt(IV) species is the species as 3.7. As such, we propose that the catalytic reaction involves transmetalation of Pt(IV)-F 2.2 with 125 (CH3)2Zn and that 3.7 is the resting state of the catalytic cycle. Now we were poised to explore if reductive elimination from 3.7 could produce the methylated imine 2a. Table 3.3 Comparison of 1H and 19F NMR spectroscopic data between Me3Pt(IV) species observed in catalysis and 3.7 synthesized in the stoichiometric reaction between 2.2 and (CH3)2Zn Me3Pt(IV) species observed in catalytic reaction 3.7 synthesized in the stoichiometric reaction between 2.2 and (CH3)2Zn Entry δ Multiplicity δ Multiplicity 1 8.87 s (JPtH = 39 Hz) 8.86 s (JPtH = 40 Hz) 2 4.98 m 4.99 m 3 1.77 s (JPtH = 12 Hz) 1.78 s (JPtH = 13 Hz) 4 0.78 s (JPtH = 69 Hz) 0.75 s (JPtH = 69 Hz) 5 0.41 s (JPtH = 73 Hz) 0.36 s (JPtH = 73 Hz) 6 0.20 s (JPtH = 46 Hz) 0.16 s (JPtH = 46 Hz) 7 -104.4 m -104.3 m 8 -111.7 m -111.6 m 3.3.3 Reductive elimination from Me3Pt(IV) (3.7) It is highly interesting to explore if 3.7 is able to undergo reductive elimination to generate 2a. Complex 3.7 was synthesized in the transmetalation of 2.2 with (CH3)2Zn (eq 3.7). The sample with 3.7 was heated at 60 ˚C and the reaction progress was monitored by 1H NMR spectroscopy. The concentration changes of 3.7 and 2a over time are shown in Figure 3.3. Overall, reductive elimination from 3.7 was finished in 30 min (eq 3.10). The conversion of 3.7 to 2a was over 98% and the conversion is based on the integration of resonance of CH=N on 1H NMR spectroscopy; however, the yield of 2a (based on 1a) was only 69% because 3.7 was formed in only 70% yield from 1a. The low 126 yield of 3.7 was attributed to the formation of unidentified side products in the C-F activation step, consistent with what was observed in the formation of 2.2. 0 5 10 15 20 25 0 5 10 15 20 25 30 35 Time(min) C o n ce n tr at io n (m M ) Figure 3.3 Plot of [3.7] (mM) vs time (min) (■) and [2a] (mM) vs time (min) (▲) at 60 ˚C. NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F CD3CN, 60 °C, 30 min Conversion >98% Yield of 2a: 69% CH3F F N Ph 2a (3.10) 3.4 Regeneration of Me2Pt(II) species in reductive elimination from Me3Pt(IV) (3.7) Having established that reductive elimination from Me3Pt(IV) (3.7) generated imine 2a, the last piece of the puzzle of the basic mechanism was to establish the identity of the resulting platinum species. It is believed that this species should be CH3Pt(Ln) (L = imine and/or CD3CN and/or SMe2) (3.8). Presumably, 3.8 can re-enter the catalytic cycle 127 upon coordination of imine and activate C-F bond on the imine. The formation of 3.8 in the reductive elimination from 3.7 was difficult to confirm by comparing the 1H NMR spectra after reductive elimination with the 1H NMR spectra of [(CH3)2Pt(μ-SMe2)]2 (2.1) in acetonitrile because the coordination of imine and/or acetonitrile led to complicated spectra. In order to confirm the formation of 3.8, we sought to explore the reductive elimination from 3.7 in the presence of another equivalent of imine (Scheme 3.2). If 3.8 was regenerated, it would be trapped by the most reactive imine, thereby forming a new Pt-F species and providing indirect evidence for regeneration of a Pt(II) complex. NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F F F N Ph F F F 1d NCH2Ph Pt CH3 FH3C SMe2 F F F F CH3F F N Ph 3.9 + CH3PtLn (L = CD3CN or SMe2) 2a 3.8 + Scheme 3.2 Possible formation and trapping of complex 3.8 To test this hypothesis, the reductive elimination from Me3Pt(IV) 3.7, generated in-situ from the treatment of 2.2 with (CH3)2Zn, was performed in the presence of a different imine substrate, namely pentafluoro imine 1d. Assuming that 3.8 was generated 128 upon reductive elimination of 2a from 3.7, imine 1d would then undergo C-F activation to form Pt(IV)-F species 3.9 (Scheme 3.2). In the presence of imine 1d, the reductive elimination from in-situ Me3Pt(IV) 3.7 generated imine 2a in 70% yield and the new Pt-F species 3.9 in 68% yield as expected (eq 3.11). These results were consistent with our hypothesis that 3.8 could be regenerated in the reductive elimination from 3.7. NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F (3.11) NCH2Ph Pt CH3 FH3C SMe2 F F + F F2a 1d, 0.5 equiv (CH3)2Zn CD3CN, 60 °C, 30 min 3.9 70% 68% 3.5 Exploration of the reversibility of the formation of 2.2 We next sought to test if there are other ways for 2.2 to release Pt(II) species 3.8, apart from reacting with (CH3)2Zn to form Me3Pt(IV) 3.7 (eq 3.7). Complex 2.2 might undergo the reductive elimination reaction, as shown in eq 3.12. This reductive elimination reaction is the microscopic reverse of the C-F activation of 1a (eq 3.2). If the formation of 2.2 is reversible, reductive elimination would regenerate imine 1a and CH3PtLn (L = imine and/or SMe2 and/or CD3CN) (3.8) (eq 3.12). In the presence of a different imine, the regenerated Pt(II) species 3.8 could react with either 1a or the new imine. Importantly, 3.8 should react preferentially with the more reactive imine. 129 Pentafluoro imine 1d was chosen for this study because the activation barrier for C-F activation of pentafluoro imine 1d is much lower than that of 1a.2 Thus, the regenerated 3.8 should react with 1d more favourably to form Pt(IV)-F 3.9 than with 1a to reform 2.2. To explore this possibility, we heated 2.2 and 10 equiv of 1d at 60 ˚C for 8 h (eq 3.13). No new Pt(IV)-F 3.9 was generated, indicating that the formation of 2.2 is irreversible under these conditions. These data also suggested that the only way for 2.2 to release a Pt(II) species was by reacting with (CH3)2Zn to generate Me3Pt(IV) species 3.7, which could undergo reductive elimination to provide Pt(II) species 3.8 and the imine product 2a (e.g., section 3.4). NCH2Ph Pt CH3 FH3C SMe2 F F F F N Ph F F F 1d + 60 °C, 8 h (3.13)no reaction F F N Ph NCH2Ph Pt Me FMe SMe2 F (3.12) CH3PtLn, L = imine, SMe2 or solvent F F 2.2 + 3.8 ? 2.2 CD3CN As discussed in section 3.3.3, Pt(IV)-F complex 2.2 is either directly involved in the catalytic reaction or 2.2 can enter the catalytic reaction. In addition, as illustrated in section 3.4, CH3PtLn species 3.8, regenerated in the reductive elimination from Me3Pt(IV) 130 complex 3.7, can effect C-F bond activation, indicating that the regenerated species 3.8 can enter the catalytic cycle. These results all suggested that complex 2.2 could act as a pre-catalyst in the cross-coupling reaction in the following way: complex 2.2 would react with (CH3)2Zn to produce Me3Pt(IV) complex 3.7; subsequent reductive elimination from 3.7 would produce methylated imine 2a and regenerate CH3PtLn species 3.8, which would continue the catalytic cycle. 3.6 Complex 2.2 as a pre-catalyst The results in the last section ruled out other ways for complex 2.2 to release CH3PtLn species 3.8. The only way for complex 2.2 to release 3.8 is by reacting with (CH3)2Zn to generate Me3Pt(IV) species 3.7, which could undergo reductive elimination to provide Pt(II) species 3.8 and the imine product 2a. Herein, we were poised to test our hypothesis that complex 2.2 could act as a pre-catalyst. We utilized 2.2 (10 mol%) in the cross-coupling reaction of imine 1c (eq 3.14) instead of [(CH3)2Pt(-SMe2)]2 2.1 (5 mol%) (eq 3.5). It was expected that 2.2 would react with (CH3)2Zn to generate 2a and regenerate Pt(II) species 3.8. Complex 3.8 would then catalyze the cross-coupling of imine 1c and (CH3)2Zn. The catalytic reaction utilizing 2.2 as the pre-catalyst provided 8% of 2a and 92% of 2c, consistent with the reaction using 5% 2.1 as catalyst in eq 3.5. 131 F F N Ph CH3 F N Ph 10 mol % 2.2 0.6 equiv (CH3)2Zn CD3CN, 60 °C, 11 h 1c 2c (3.14) F F CH3 F N Ph 2a F 8%92% + These data are consistent with the hypothesis that 2.2 could act as a pre-catalyst and it also indicated that 2.2 is either part of catalytic cycle or able to enter the catalytic cycle. It is of interest to study whether 2.2 is part of catalytic cycle or not, which will be described after discussing the effects of excess SMe2 on the catalytic reaction, as well as C-F activation, transmetalation and reductive elimination. 3.7 Effects of excess SMe2 In this section, the effects of excess SMe2 on the catalytic reaction, as well as the individual steps of the catalytic cycle, will be investigated in detail. If excess of SMe2 retards any of these processes, dissociation of SMe2 is involved in the mechanism. 3.7.1 Effects of excess SMe2 on the catalytic reaction To explore further the effect of excess SMe2, catalytic reactions both in the presence and in the absence of excess SMe2 were performed. Trifluoro imine (1a, 8.4 mg, 0.034 mmol), (CH3)2Zn (11.0 μL of a 2.0 M solution in toluene), [(CH3)2Pt(μ-SMe2)]2 (2.1) (0.0017 mmol, 100 μL from 0.017 M acetonitrile-d3 solution) and 1,3,5-trimethoxybenzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in 1.1 mL of acetonitrile-d3 in an NMR tube. Another sample was prepared by the same 132 procedure and combined with excess SMe2 (2.6 μL, 0.034 mmol, 10 equiv relative to Pt). The two samples were monitored by 1H NMR spectroscopy. Plots showing the conversion of 1a to 2a over time for both reactions are illustrated in Figure 3.4. The conversion is based on the integration of resonance of CH=N on 1H NMR spectroscopy. The conversion of 1a to 2a in the presence of excess SMe2 (10 equiv relative to Pt) was 16% at 60 ˚C after 2 h (Figure 3.4, triangle dots). In comparison, the conversion of 1a to 2a in the absence of excess SMe2 was 75% at 60 ˚C after 2 h (Figure 3.4, square dots). In the absence of excess SMe2, the reaction was completed in 8 h. During the same time period, for the reaction in the presence of excess SMe2, the conversion was only 56%. The conversion was only 81% after 25 h at 60 ˚C. The effect of excess of dimethylsulfide on catalytic reaction 0 20 40 60 80 100 120 0 5 10 15 20 25 30 Time(h) C o n ve rs io n (% ) Figure 3.4 Conversion vs time (h) for the reaction in the absence (■) and presence (▲) of excess SMe2 at 60 ˚C. 133 These data indicated that excess SMe2 plays an important role in the rate of the catalytic reaction. Excess SMe2 could potentially affect any (or all) of the fundamental steps in the cross-coupling reaction. To fully understand the effect of excess SMe2 on the catalytic process, it is important to study each fundamental step - oxidative addition, transmetalation and reductive elimination - in presence of excess SMe2. As the effect of excess SMe2 on C-F activation (oxidative addition) had already been studied, 2 we focused our efforts on the effects of excess SMe2 on transmetalation and reductive elimination. 3.7.2 Effects of excess SMe2 on the transmetalation reaction of Pt(IV)-F and (CH3)2Zn As discussed in section 3.6, our data indicated that complex 2.2 is either part of the catalytic cycle or can enter the catalytic cycle. We were now poised to explore these possibilities. Martinez and co-workers have shown that 3.6 equilibrates with five-coordinate Pt(IV) 3.5 via the dissociation and re-association of SMe2 (Scheme 3.1). 2 They also utilized PPh3 to substitute SMe2 successfully, indicating that there is an equilibrium between 2.2 and a five-coordinate species.3 This brings up a question: which species is part of the catalytic cycle, complex 2.2 or five-coordinate species 3.10 (eq 3.15)? Exploring the effect of excess SMe2 on transmetalation of 2.2 with (CH3)2Zn would provide an answer to this question. If excess SMe2 retards the reaction, the 134 transmetalation would be dissociative in SMe2 and thus 3.10 would be part of the catalytic cycle. NCH2Ph Pt CH3 FH3C SMe2 F F NCH2Ph Pt CH3 FH3C F F + SMe2 (or isomer) (3.15) - SMe2 2.2 3.10 The transmetalation of 2.2 with (CH3)2Zn was monitored by 1H NMR spectroscopy using an internal standard. The conversion is based on the integration of resonance of CH=N on 1H NMR spectroscopy. In the absence of excess SMe2 the reaction was completed in 5 min (eq 3.16); however, in the presence of excess SMe2 the reaction was slowed, but was still completed in less than 10 min (eq 3.17). 1.2 Me2Zn, CD3CN, rt, 5 min (3.16) In the absence of excess SMe2 NCH2Ph Pt CH3 FH3C SMe2 F F 2.2 NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F Conversion > 95% (3.17)NCH2Ph Pt CH3 FH3C SMe2 F F 2.2 NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F Conversion > 95% In the presence of excess SMe2 1.2 Me2Zn, CD3CN, rt, < 10 min 135 In an effort to gain more insight into the extent that excess ligand slowed transmetalation, we elected to use a less labile ligand than SMe2. Crespo and Martinez had found that PPh3Pt-F complexes were more stable than SMe2Pt-F complexes and that substitution of SMe2 with PPh3 involved dissociation of SMe2. 2,3 If the dissociation of the ligand were involved in the transmetalation reaction, the coordination of acetonitrile to five-coordinate platinum complex might be possible and the coordination of solvent is expected to play the same role in the two reactions. Thus, if the dissociation of the ligand were involved, the solvent effect does not change the expected trend that PPh3Pt-F complex (3.11) with (CH3)2Zn would be slower than the reaction of SMe2Pt-F complex (2.2) with (CH3)2Zn (Scheme 3.3). NCH2Ph Pt CH3 FH3C PPh3 F F 1.2 Me2Zn NCH2Ph Pt CH3 CH3H3C PPh3 F F 3.11 3.12 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F 1.2 Me2Zn NCH2Ph Pt CH3 CH3H3C SMe2 F F 3.7 Slower Faster Scheme 3.3 Comparison of transmetalation reaction of 3.11 and that of 2.2 Complex 3.11 was prepared by a published procedure.2 The solution with 2.2 was combined with PPh3 at room temperature for 24 h, generating 3.11 in 70% yield. The transmetalation of 3.11 with (CH3)2Zn required 20 min to complete, based on the 19F 136 NMR spectroscopic data. The transmetalation of 3.11 with (CH3)2Zn (eq 3.18) is much slower than the transmetalation of 2.2 with (CH3)2Zn (eq 3.16). The conversion is based on the integration of resonance of CH=N on 1H NMR spectroscopy. NCH2Ph Pt CH3 FH3C PPh3 F F 1.2 Me2Zn NCH2Ph Pt CH3 CH3H3C PPh3 F F 3.11 3.12 CD3CN, rt, 20 min (3.18) Conversion > 95% These data clearly indicated that transmetalation involves ligand dissociation (ligand = PPh3 or SMe2). Presumably, the five-coordinate species 3.10 (eq 3.19), which is in equilibrium with 3.11, is the complex that then reacts with (CH3)2Zn. It is noteworthy to point out that the geometry of 3.10 is unknown and this species could exist as a mixture of isomers. NCH2Ph Pt CH3 FH3C PPh3 F F NCH2Ph Pt CH3 FH3C F F (3.19) 3.11 3.10 + PPh3 - PPh3 (or isomer) Thus, we propose that 2.2 is not directly involved in catalysis, but that the five-coordinate species proposed by Martinez2 to lead to 2.2 (via association of SMe2) is 137 the complex that undergoes transmetalation. This also suggests that complex 2.2 would be able to enter the catalytic cycle upon dissociation of SMe2. 3.7.3 Effects of excess SMe2 on reductive elimination from complex 3.7 Having studied the effect of excess SMe2 on the transmetalation reaction, we were now ready to study how excess SMe2 affects on the reductive elimination from Me3Pt(IV) 3.7. Complex 3.7 was prepared from 2.2 and (CH3)2Zn (e.g., eq 3.7); reductive elimination from this complex was performed at 60 ˚C and monitored by 1H NMR spectroscopy using an internal standard. In the absence of excess SMe2, the reductive elimination from 3.7 was completed in 30 min and provided imine 2a in 70% yield (eq 3.10). However, in the presence of 10 equiv SMe2, 2a was formed in < 20% yield after 30 min, with the majority of 3.7 unreacted (eq 3.20). Clearly, the conversion of 3.7 to 2a was considerably retarded by excess SMe2. This result is consistent with the need for dissociation of SMe2 to form five-coordinate species 3.13 prior to reductive elimination (eq 3.21). 138 NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F 10 equiv SMe2 60 °C, 30 min Yield of 2a: < 20% CH3F F N Ph 2a (3.20) NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F NCH2Ph Pt CH3 CH3H3C F F + SMe2 (or isomer) (3.21) - SMe2 3.13 In the light of the experimental data above, it was concluded that both transmetalation and reductive elimination were slowed by excess SMe2 and that both the transmetalation and reductive elimination steps in the catalytic reaction involve five-coordinate species. Of the two steps, reductive elimination was affected by excess ligand to a much greater extent than transmetalation because the effect of SMe2 on the transmetalation of 2.2 with (CH3)2Zn could not be definitively observed (eq 3.17), whereas the reductive elimination from 3.7 was significantly retarded (eq 3.20). This could indicate that ligand dissociation from the Me3Pt complex is slower than that from the Pt-F complex and/or that reductive elimination is considerably slower than transmetalation. 3.8 Proposed mechanism of cross-coupling Based on the above experimental data, we proposed the following mechanism for the Pt-catalyzed cross-coupling of polyfluoroaryl imines (Scheme 3.4). Complex 2.1 reacts 139 with imine 1a to form the five-coordinate species 3.10, which is in equilibrium with 2.2 via association of SMe2. 2 Complex 3.10 reacts with (CH3)2Zn to form five-coordinate species 3.13 (or isomer). Complex 3.13 can undergo reductive elimination to form imine 2a and regenerate a Pt(II) species, which will associate with another imine to complete the catalytic cycle; at the same time, complex 3.13 is able to equilibrate with Me3Pt species 3.7, which we propose is the resting state in the catalytic cycle. Considering the slow stoichiometric C-F activation process (60 ˚C, 6 h) and much faster transmetalation (rt, < 10 min) and reductive elimination (60 ˚C, 30 min), it is reasonable to propose that C-F activation is the rate-determining step in the catalytic cycle. The role of solvents in the catalytic reaction is not clear at this moment. The effect of solvent on the reaction will be investigated by other group members in the future. 140 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F 0.5 [(CH3)2Pt(-SMe2)]2 NCH2Ph Pt CH3 FH3C F 3.10 F NCH2Ph Pt CH3 CH3H3C F 3.13 F - 2a + 1a + SMe2 (or isomer)(or isomer) 3.7 + SMe2 NCH2Ph Pt CH3 CH3H3C SMe2 F F [(CH3)2Pt(SMe2)(imine)] + 1a [(CH3)2Pt(imine)] + (CH3)2Zn -CH3ZnF - SMe2 - SMe2- SMe2 Scheme 3.4 Proposed mechanism of cross-coupling of polyfluoroaryl imines 3.9 Studies of Me3Pt(IV) species Having established a reasonable mechanism for the cross-coupling of polyfluoroaryl imines catalyzed by 2.1, we sought to explore the reductive elimination step in further detail, as we expected that such a study would reveal insights into the scope limitations. We first aimed to isolate and fully characterize 3.7 and related complexes. 141 3.9.1 Isolation of Me3Pt(IV) species Isolation of Me3Pt species (3.7) from the catalytic reaction would be very difficult because only a small amount of catalyst was used in the cross-coupling reaction. Therefore, we chose to prepare 3.7 from complex 2.2 and (CH3)2Zn. Unfortunately, reductive elimination from 3.7 was too rapid at room temperature to permit isolation of 3.7. Thus, we sought a Me3Pt(IV) species that would be less susceptible to reductive elimination. For this reason, pentafluoro imine 1d was utilized, as the additional electron-withdrawing groups on the aryl ligand (compared to 1a) leads to an increase in the strength of the CAryl-Pt bond strength, which should slow down reductive elimination.7 When pentafluoro imine 1d was used to prepare the corresponding Me3Pt(IV)(PPh3) species, however, crystallization and purification proved to be difficult. For example, crystals suitable for X-ray analysis required three months to form. We sought to use imine 1e, expecting that the bromide substituent would facilitate crystallization. Pentafluoro imine 1e reacted with 2.1 to form Pt(IV)-F 3.14, which was further reacted with (CH3)2Zn to provide trimethyl-Pt(IV) species 3.15 (Scheme 3.5). Complex 3.15 was trapped with PPh3 to form 3.16. Crystals of 3.16 suitable for X-ray analysis were obtained by layering pentane on saturated dichloromethane solution. 142 F F N R 0.5 equiv 2.1 CH3CN, rt, 24 h Yield > 90% F F F PPh3 1e BrCH2R = NR Pt CH3 FH3C SMe2 F F F F NR Pt CH3 CH3H3C SMe2 F F F F NR Pt CH3 CH3H3C PPh3 F F F F 3.153.16 3.14 Me2Zn, Yield > 90%rt, 20 min rt, 24 h Yield 40% Scheme 3.5 Preparation process of 3.16 3.9.2 Comprehensive analysis of 3.16 Complex 3.16 was characterized by X-ray diffraction, NMR spectroscopy (1H, 19F, 13C, 31P), NOE, HRMS and elemental analysis. The full characterization data is listed in the experimental section included at the end of this chapter. Herein, representative X-ray and NMR data are discussed and presented in Tables 3.4 - 3.6. 143 Figure 3.5 ORTEP diagram of complex 3.16. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms are excluded for clarity. Selected angles (deg) are given in Table 3.4 and bond lengths (Å) are given in Table 3.5. The molecular structure (Figure 3.5) clearly illustrates that 3.16 has three methyl substituents on the platinum center and has an octahedral geometry, with atoms N1, C2, C3, C22 in the square plane and P1 and C1 in the apical positions. Consistent with this analysis, the sum of the angles around the platinum center in the plane of N1, C2, C3, C22 is 359.06º (Table 3.4, entries 1-4). Table 3.5 lists the three C-Pt bond lengths determined from X-ray analysis. The C2-Pt bond trans to the fluoroaryl ring is longest; the C3-Pt bond trans to the nitrogen of CH=N group is shortest. 144 Table 3.4 Data of angles on the plane of C2, C3, C22, N1 and Pt(1) for 3.16 Entry Angles [deg] 1 C(3)-Pt(1)-C(2) 89.43(10) 2 C(3)-Pt(1)-C(22) 97.49(9) 3 C(2)-Pt(1)-N(1) 93.33(8) 4 C(22)-Pt(1)-N(1) 78.81(8) Table 3.5 Three C-Pt bond lengths for 3.16 C1 C2 C3 Length of C-Pt/[Å] 2.076(2) 2.095(2) 2.057(2) 1H NMR spectroscopic data in CD3CN for 3.16 are listed in Table 3.6. The resonance at δ 8.59 (JPt-H = 41 Hz) (Table 3.6, entry 1) was assigned to the CH=N of the imine coordinated to Pt. The resonances at δ 4.55 and 4.53 (entry 2) were assigned to the methylene group of the imine bound to Pt. The coupling constant (JPt-H = 71 Hz) of the resonances at δ 1.37 (entry 3) is a typical coupling constant for methyl groups trans to L-type ligands (herein, the L-type ligands are the imine nitrogen and the triphenylphosphine ligand). Furthermore, this resonance has coupling with the fluoroaryl group (JF-H = 2.7 Hz), indicating that the methyl group and fluoroaryl groups are in the same plane.2 Thus, this resonance was assigned to the methyl group trans to the imine nitrogen. The resonance at δ 0.42 (JPt-H = 62 Hz, JP-H = 7.5 Hz) (entry 5) was attributed to the methyl groups trans to another L-type ligand, PPh3, based on Pt-H coupling constant. The remaining resonance at δ 0.62 (JPt-H = 50 Hz, JP-H = 7.3 Hz) was assigned to the methyl group trans to the fluoroaryl group. 145 Table 3.6 1H NMR spectroscopic data in CD3CN for 3.16 Entry δ Multiplicity Relative intensity Assignment 1 8.59 s (JPt-H = 41 Hz) 1 CH=N 2 4.55 & 4.53 d (JH-H = 15 Hz), AB pattern 2 CH2Ph 3 1.37 dd (JPt-H = 71 Hz, JF-H = 2.7 Hz, JP-H = 7.7 Hz) 3 CH3-Pt 4 0.62 d (JPt-H = 50 Hz, JP-H = 7.3 Hz) 3 CH3-Pt 5 0.42 d (JPt-H = 62 Hz, JP-H = 7.5 Hz) 3 CH3-Pt To further explore the geometry of three methyl groups for 3.16, NOE enhancement was performed for three methyl groups. When NOE enhancement was measured for the methyl resonance at δ 1.37 (see spectrum on page 257), the resonances at δ 7.41-7.43 (for phenyl group on PPh3), 0.62 (for one methyl group on Pt), and 0.42 (for one methyl group on Pt) increased, indicating the resonance at δ 1.37 is the C3 methyl-Pt on the molecular structure, trans to the imine nitrogen. When NOE enhancement was also performed for the resonance at δ 0.62 (see spectrum on page 257), the resonances at δ 7.43 (for phenyl group on PPh3), 4.54-4.58 (for the CH2 group on imine), and 1.37 (for the C3 methyl on Pt) and 0.42 (for another methyl on Pt) increased, indicating the resonance at δ 0.62 is the C2 methyl-Pt on the molecular structure, trans to the fluoroaryl group. As NOE enhancement was measured for the resonance at δ 0.42 (see spectrum on page 258), the resonances at δ 1.37 (for the C3 methyl on Pt) and 0.62 (for the C2 methyl on Pt) increased, indicating the resonance at δ 0.42 is the C1 methyl-Pt on the molecular structure, trans to the triphenylphosphine ligand. NOE studies on the three methyl-Pt(IV) 146 groups are consistent with above assignments of methyl groups on 3.16 based on coupling constants of the satellite peaks. NR Pt C1 C2C3 PPh3 F F F F1 22 BrCH2R = Figure 3.6 The structure of 3.16 Table 3.7 lists 1H and 13C NMR spectroscopic data for three methyl groups connected to Pt. Both the coupling constants with Pt metal (JPt-CH3) in the 1H NMR spectrum and JPt-CH3 in the 13C NMR spectrum are consistent with the lengths of C-Pt bonds (Table 3.5) because the shorter the C-Pt bonds have the larger coupling constants (JPt-CH3 and JPt-CH3). There is coupling between F1 and C3 methyl (Figure 3.6), which is consistent with the data of the Pt-F complex published by Martinez and Crespo.2 Table 3.7 NMR spectroscopic data for three methyl groups of complex 3.16 entry C1 C2 C3 1 Chemical shift(1H) δ 0.42 0.62 1.37 2 JPt-CH3 62.0 Hz 49.8 Hz 70.8 Hz 3 JF1-CH3 0 0 2.7 Hz 4 JP-CH3 7.5 Hz 7.3 Hz 7.7 Hz 5 Chemical shift(13C) δ 7.29 2.17 -12.9 6 JPt-CH3 543.4 Hz 478.0 Hz 613.9 Hz 7 JF1-CH3 0 0 4.0 Hz 8 JP-CH3 114.7 Hz N/A 11.1 Hz 147 The coupling constants of the methyl protons with the phosphorous atom only show slight differences in the 1H NMR spectrum (Table 3.7, entry 4). The longer the C-Pt bond, the smaller the coupling constant between the methyl protons and the phosphine ligand. However, the coupling constants between carbon atom on CH3 and phosphine show large differences in the 13C NMR spectrum (entry 8). For example, the coupling constant of C1 with triphenylphosphine is 114.7 Hz, much larger than JP-C3 (11.1 Hz). This is attributed to the trans relationship between the phosphine ligand and C1. Coupling between C2 and phosphine does not show up in 13C NMR spectrum. The chemical shift of C1 in the 13C NMR spectrum is at the lowest field among those of three methyl groups connected to Pt, indicating that the electron density on C1 is lowest among the three methyl groups. 3.10 Unexpected C-H activation While exploring the isolation of complex 3.16, we observed an interesting and unexpected Pt(II) complex through C-H activation. As mentioned above, Me3Pt (3.16) was obtained from CH2Cl2/hexanes (1:4 vol:vol) solution. When the crystals were left in the CH2Cl2/hexanes solution for more than two days, the crystals re-dissolved and some precipitate appeared. The mixture was filtered through a plug of glass wool to provide a clear solution, which was concentrated to dryness under vacuum. Although NMR analysis in CD3CN was inconclusive, some brown colored crystals appeared unexpectedly in the NMR tube after two weeks at room temperature. The crystals were 148 thus analyzed by X-ray crystallography. The C-H activation occurred in the solvent mixture of CH2Cl2 and hexanes. Figure 3.7 ORTEP diagram of complex 3.17. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms are excluded for clarity. The molecular structure of complex 3.17 (Figure 3.7) revealed a Pt(II) complex with a six membered chelate ring. The six-membered ring is in a twist chair conformation (Figure 3.8), with the CH2 group pointing out of the twisted chair. C H2 N Pt Figure 3.8 The twisted chair conformation for six-membered ring 149 A plausible mechanism for the formation of this unexpected Pt(II) complex is given in Scheme 3.6. Reductive elimination from 3.16 produces 2e and Me2PtPPh3 species 3.18, which subsequently activates a methyl C-H bond of 2e, generating complex 3.19. Reductive elimination from 3.19 generates the unexpected Pt(II) complex 3.17. This is similar to the mechanism proposed by Crespo and Martinez for the aryl C-H activation to form a five membered chelated ring.2 Pt PPh3H3C NR F F F F - CH4 NR FF F CH3 Me2Pt(PPh3) Pt PPh3 H3C NR F F F F H CH3 - CH4 C-H activation CH2R = Br F 3.16 3.17 2e 3.18 3.19 NR Pt CH3 CH3H3C PPh3 F F F F Scheme 3.6 A plausible mechanism for formation of 3.17 C-H activation to form a six membered chelated ring is unusual; to date only a few examples have been published in the literature. Co,9 Ir10 and Au11 complexes have been 150 reported by Mukherjee, Dahlenburg and Nonoyama, respectively. The observation of this unexpected C-H activation and the slow rate of C-H activation relative to cross-coupling imply that the tandem cross-coupling/C-H functionalization of the resulting methyl group is possible. Although the formation of 3.17 produces CH4 gas, indicating that Me2Pt(II) species might not be regenerated, this does not preclude catalytic C-H functionalization, assuming that the Pt species resulting from functionalization can also catalyze the reaction. However, thus far, reproduction of this result has been problematic. Nevertheless, this project will be carried forward by another graduate student. 3.11 Conclusions In summary, a general mechanism for the Pt-catalyzed methylation of polyfluorinated aryl imines has been established. The mechanism involves rate-limiting C-F activation followed by transmetalation and reductive elimination. Both transmetalation and reductive elimination occur at five-coordinate Pt(IV) species. Furthermore, a six-coordinate Me3Pt(IV) species, the resting state of catalytic cycle, was observed transiently during the catalytic reaction. This species was independently synthesized and characterized by X-ray analysis and NMR studies. Finally, a new Pt(II) complex resulting from unexpected reactivity of the Me3Pt(IV) species was identified. This complex has an unusual six-membered chelated ring and presumably resulted from a reductive elimination, C-H activation pathway. This observation leads to exciting possibilities for tandem catalysis. 151 3.12 Experimental General Procedures. Manipulation of organometallic compounds was performed using standard Schlenk techniques under an atmosphere of dry nitrogen or in a nitrogen-filled MBraun drybox (O2 < 2 ppm). NMR spectra were recorded on Bruker Avance 300 or Bruker Avance 400 spectrometers. 1H and 13C chemical shifts are reported in parts per million and referenced to residual solvent. 19F NMR spectra are reported in parts per million and referenced to C6F6 in acetone-d6 (-162.9 ppm). Coupling constant values were extracted assuming first-order coupling. The multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, m = multiplet. All spectra were obtained at 25 ˚C. Elemental analyses were performed using a Carlo Erba Elemental Analyzer EA 1108. Mass spectra were recorded on a Kratos MS-50 mass spectrometer. In Appendix II, NMR spectra of reactions, the characterization NMR data for chemicals and X-ray data are listed (see pages 236-269). Materials and Methods. Acetonitrile was dried by heating to reflux over calcium hydride. Acetonitrile-d3 and all organic reagents were obtained from commercial sources and used as received. K2PtCl4 was purchased from Strem Chemicals and was used without further purification. Complexes cis/trans-PtCl2(SMe2)2 and [Me2Pt(μ-SMe2)]2 were prepared by previously reported procedures.1,11 All imines were prepared by previously reported procedures.1,2 (CH3)2Zn (2.0 M solution in toluene) was purchased from Aldrich and titrated following a published procedure prior to use.12 152 General process for preparative scale reactions (eq 3.1 and eq 3.5) In a 20 mL vial in the glovebox, imine (100.0 mg, 0.4 mmol) and [Me2Pt(μ-SMe2)]2 (11.5 mg, 0.02 mmol) were dissolved in CH3CN (3 mL). The resulting solution was transferred to a test tube, which was then fitted with a screw cap containing a septum. (CH3)2Zn (0.240 mmol, 120 µL of 2.0 M solution in toluene) was added by syringe. The tube was then removed from the glovebox. The solution was heated at 60 ˚C for 8 h or 11 h and was then cooled to room temperature. The solution was transferred to a small one-necked flask and the solvent was removed by rotary evaporation. The residue was washed with n-pentane (3 x 20 mL). The combined organic solution was filtered through Celite. The filtrate was concentrated by rotary evaporation to provide the crude imine product. Further column separation provides clean imine products (SiO2, 70-230 mesh, n-pentane: Et3N = 100: 6 as eluant). NMR spectroscopic data were consistent with those previously reported.1 N-(4,6-Difluoro-2-methylbenzylidene)benzylamine 2a (eq 3.1). F CH3 N F Ph (8 h, 95%) N-(3,6-Difluoro-2-methylbenzylidene)benzylamine 2c (eq 3.5). F CH3 N Ph F (11 h, 97%) 153 Preparation of N-(6-Fluoro-2-methylbenzylidene)benzylamine 2b (eq 3.3). F CH3 N Ph In a 20 mL vial in the glovebox, N-(2,6-difluorobenzylidene)benzylamine (1b) (7.9 mg, 0.034 mmol,) was dissolved in CD3CN (1.1 mL). [Me2Pt(μ-SMe2)]2 (0.0017 mmol, 100 µL of 0.017 M solution in CD3CN) and 1,3,5-trimethoxybenzene (0.034 mmol, 100 µL of 0.34 M solution in CD3CN, internal standard) were then added by syringe. The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. (CH3)2Zn (0.022 mmol, 11 µL of 2.0 M solution in toluene) was added by syringe. The NMR tube was then removed from the glovebox. The solution was heated at 60 ˚C for 24 h. The reaction progress was monitored by 1H NMR and 19F NMR spectroscopy. The yield of 2b was < 10%, based on integration of the methyl resonance of 2b with the aryl resonances of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Preparation of Pt(IV)-F complex 2.2 (Figure 3.1). In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine (1a) (8.5 mg, 0.034 mmol), [Me2Pt(μ-SMe2)]2 (9.8 mg, 0.017 mmol) and 1,3,5-trimethoxybenzene (0.034 mmol, 100 µL of 0.34 M solution in CD3CN) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was removed from the glovebox. The 154 solution was then placed in the NMR spectrometer at 60 ˚C. The solution was left to equilibrate for a few minutes at 60 ˚C. The reaction was monitored by 1H NMR spectroscopy every 10 minutes for 8 h. No evidence of formation of 2a was observed. Characterization of 2.2: 1H NMR (acetonitrile-d3, 400 MHz): δ 8.78 (s, JPt-H = 47.5 Hz, CH=N, 1H), 7.7-6.6 (m, overlapping peaks, ary-H), 5.05 (m, CH2, 2H), 1.90 (s, JPt-H = 12.1 Hz, S(CH3)2, 6H,), 1.11 (d, JPt-H = 65.6 Hz, JF-H = 7.1 Hz, Pt-CH3, 3H), 0.72 (d, JPt-H = 68.3 Hz, JF-H = 7.1 Hz, Pt-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -101.8 (m, aryl-F), -110.5 (m, aryl-F), -260.9 (broad singlet, Pt-F). Preparation of complex 3.7 from 2.2 and (CH3)2Zn. Complex 2.2 was prepared in an NMR tube, as previously described. The NMR tube was taken into the glovebox. (CH3)2Zn (0.040 mmol, 20 µL of 2.0 M solution in toluene) was subsequently added by syringe. The NMR tube was then removed from the glovebox. The resulting solution in NMR tube was monitored by 1H NMR and 19F NMR spectroscopy. The reaction was completed in less than 10 min. Characterization of 3.7: 1H NMR (acetonitrile-d3, 300 MHz): δ 8.86 (s, JPt-H = 40 Hz, 1H, CH=N), 7.37-7.13 (m, overlapping peaks, aryl-H), 4.99 (m, CH2, 2H), 1.78 (s, JPt-H = 13 Hz, S(CH3)2, 6H), 0.75 (s, JPt-H = 69 Hz, Pt-CH3, 3H), 0.36 (s, JPt-H = 73 Hz, Pt-CH3, 3H), 0.16 (s, JPt-H = 46 Hz, Pt-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -104.3 (m), -111.6 (m). (Note: see spectra on pages 237-238) 155 Pt(II)-catalyzed cross-coupling of 1a and (CH3)2Zn monitored by 1H NMR spectroscopy (eq 3.8, Figure 3.2). In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine (1a) (8.5 mg, 0.034 mmol) was dissolved in CD3CN (1.1 mL). [Me2Pt(μ-SMe2)]2 (0.0017 mmol, 100 µL of 0.017 M solution in CD3CN) and 1,3,5-trimethoxybenzene (0.034 mmol, 100 µL of 0.34 M solution in CD3CN, internal standard) were added by syringe. The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. (CH3)2Zn (0.022 mmol, 11 µL of 2.0 M solution in toluene) was then added by syringe. The NMR tube was then removed from the glovebox. The solution was heated in the NMR machine at 60 ˚C. The reaction was monitored by 1H NMR spectroscopy every 10 minutes for 9 h. The concentration of 2a did not change after 8 h. Observation of Me3Pt(IV) species in the Pt(II)-catalyzed cross-coupling of 1a and (CH3)2Zn monitored by 1H NMR spectroscopy (eq 3.9). In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine (1a) (85 mg, 0.34 mmol), [Me2Pt(μ-SMe2)]2 (9.8 mg, 0.017 mmol) and 1,3,5-tri- methoxybenzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. (CH3)2Zn (0.22 mmol, 110 µL of 2.0 M solution in toluene) was then added by syringe. The NMR tube was then removed from the glovebox. The solution was then heated at 60 ˚C. The reaction was monitored by 1H and 19F NMR spectroscopy. Me3Pt(IV) species was observed. (see pages 239-244) 156 Reductive elimination from 3.7 to generate 2a (eq 3.10, Figure 3.3). Complex 3.7 was prepared in an NMR tube as previously described. The sample with 3.7 was heated at 60 ˚C in the NMR machine and the reaction was monitored by 1H NMR spectroscopy every 2 minutes for 1 hour. The formation of 2a was completed in 30 min. The yield of 2a was 69%, based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. (Note: see spectra on pages 246-247) Test of reductive elimination from Pt(IV)-F complex 2.2 (eq 3.11). Complex 2.2 was prepared in an NMR tube as previously described. The sample was heated at 60 ˚C for 8 h. The reaction was monitored by 1H and 19F NMR spectroscopy. No evidences for the formation of 2a were observed. Reaction between Pt-F complex 2.2, (CH3)2Zn, and 1d (eq 3.12). Complex 2.2 was prepared in an NMR tube as previously described. The NMR tube was taken into the glovebox. The solution of 2.2 was transferred to the 20 mL vial with N-(2,3,4,5,6-pentafluorobenzylidene)benzylamine 1d (19.4 mg, 0.068 mmol). The resulting solution was transferred back to the NMR tube, which was then fitted with a screw cap containing a septum. (CH3)2Zn (0.017 mmol, 8.5 µL of 2M solution in toluene) was subsequently added by syringe. The NMR tube was removed from the glovebox. The solution was heated at 60 ˚C for 30 minutes. The reaction was monitored by 1H NMR and 19F NMR spectroscopy. The yield of complex 3.9 was 68%, based on 157 integration of the CH2 resonance of 3.9 with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. The yield of 2a was 70%, based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. (Note: see spectra on pages 248-250) Reaction between Pt-F complex 2.2 and 1d (eq 3.14). Complex 2.2 was prepared in an NMR tube as previously described. The NMR tube was taken into the glovebox. The solution of 2.2 was transferred to the 20 mL vial with N-(2,3,4,5,6-pentafluorobenzylidene)benzylamine 1d (97.0 mg, 0.34 mmol). The resulting solution was transferred back to the NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was then removed from the glovebox. The solution was heated at 60 ˚C for 8 h. The reaction was monitored by 1H NMR and 19F NMR spectroscopy. No evidence was observed indicating the formation of complex 3.9 and the resonance of Pt-F of complex 2.2 decreased with time. Cross-coupling reaction between 1c and (CH3)2Zn catalyzed by Pt-F complex 2.2 (eq 3.15). Step 1: Preparation of Pt-F complex 2.2: In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine (1a) (0.0034 mmol, 100 µL of 0.034 M solution in CD3CN) and [Me2Pt(μ-SMe2)]2 (0.0017 mmol, 100 µL of 0.017 M solution in CD3CN) were dissolved in CD3CN (1.1 mL). The 158 resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was removed from the glovebox. The solution was then heated at 60 ˚C for 8 h to obtain Pt-F complex 2.2 in-situ, as evidenced by 1H and 19F NMR spectroscopy. Step 2: Cross-coupling of 1c and (CH3)2Zn catalyzed by Pt-F complex 2.2 The NMR tube with 2.2 was taken into the glovebox. The solution of 2.2 was transferred to the 20 mL vial with N-(2,3,6-trifluorobenzylidene)benzylamine (1c) (8.5 mg, 0.034 mmol). 1,3,5-trimethoxybenzene (0.034 mmol, 100 µL of 0.34 M solution in CD3CN, internal standard) was then added to the vial by syringe. The resulting solution was transferred back to the NMR tube, which was then fitted with a screw cap containing a septum. (CH3)2Zn (0.022 mmol, 11.0 µL of 2.0 M solution in toluene) was subsequently added by syringe. The NMR tube was then removed from the glovebox. The solution was heated at 60 ˚C. The reaction was monitored by 1H NMR and 19F NMR spectroscopy over 11 h. The yield of 2c was 92%, based on integration of the methyl resonance of 2c with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. The yield of 2a was 8%, based on integration of the methyl resonance of 2a with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. (Note: see spectra on pages 251-252) 159 Effects of excess SMe2 on catalytic reaction (Figure 3.4). a) Catalytic reaction in the absence of excess SMe2 In a 20 mL vial in the glovebox, 1a (8.4 mg, 0.034 mmol), (CH3)2Zn (0.022 mmol, 11 µL of a 2.0 M solution in toluene), [(CH3)2Pt(µ-SMe2)]2 (0.0017 mmol, 100 µL of 0.017 M acetonitrile-d3 solution) and 1,3,5-trimethoxybenzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred to an NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was then removed from the glovebox. The solution was heated at 60 ˚C. The reaction was monitored by 1H and 19F NMR spectroscopy. b) Catalytic reaction in the presence of excess SMe2 Another NMR sample was prepared in the glovebox by the above procedure. The NMR tube was removed from the glovebox and was added with excess SMe2 (2.6 μL, 0.034 mmol, 10 equiv. to Pt metal). The NMR tube was heated at 60 ˚C. The reaction was monitored by 1H and 19F NMR spectroscopy. Effects of excess SMe2 on the transmetalation reaction of Pt(IV)-F 2.2 and (CH3)2Zn (eq 3.17) Complex 2.2 was prepared in an NMR tube, as previously described. The NMR tube was taken into the glovebox. (CH3)2Zn (0.040 mmol, 20 µL of 2.0 M solution in toluene) was subsequently added by syringe. The NMR tube was then removed from the glovebox and was added with SMe2 (26 μL, 0.34 mmol, 10 equiv. to Pt metal). The reaction was 160 monitored by 1H NMR and 19F NMR spectroscopy. The transmetalation reaction of 2.2 with (CH3)2Zn was completed in less than 10 min. Preparation of Pt(IV)-F(PPh3) (3.11) Complex 2.2 was prepared in an NMR tube as previously described. The NMR tube was taken into the glovebox and was added with triphenylphosphine (9.0 mg, 0.034 mmol). The sample was left at room temperature for two days and was then removed from the glovebox. The reaction was monitored by 1H and 19F NMR spectroscopy. The characterization data of 2.2 was consistent with literature values.2 The yield of 3.11 was 70%, based on integration of the methyl resonance of 3.11 with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. The transmetalation of 2.2 with (CH3)2Zn (eq 3.18) Complex 3.11 was prepared in an NMR tube as previously described. (CH3)2Zn (0.040 mmol, 20 µL of 2.0 M solution in toluene) was subsequently added by syringe. The reaction was monitored by 1H and 19F NMR spectroscopy. At room temperature, the transmetalation reaction of 3.11 with (CH3)2Zn required 20 min to complete. The yield of 3.12 was 60%, based on integration of the methyl resonance of 3.12 with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Characterization data of 3.12: 1H NMR (acetonitrile-d3, 300 MHz): δ 8.25 (s, JPt-H = 44 Hz, CH=N, 1H), 7.55-6.85 (m, overlapping peaks, Ar-H), (4.57 (d), 4.15 (d), JH-H = 16 161 Hz, CH2, 2H, AB pattern), 0.98 (d, JPt-H = 69 Hz, JP-H = 7.8 Hz, Pt-CH3, 3H), 0.47 (d, JPt-H = 46 Hz, JP-H = 6.9 Hz, Pt-CH3, 3H), 0.27 (d, JPt-H = 61 Hz, JP-H = 7.8 Hz, Pt-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -104.7 (m, 1F), -112.2 (m, 1F). 31P{1H}NMR (acetonitrile-d3, 121 MHz): δ -7.08 (s, JPt-P = 1041.0 Hz). Effects of excess SMe2 on conversion of complex 3.7 to 2a. (eq 3.20) Complex 2.2 was prepared in an NMR tube, as previously described. The NMR tube was taken into glovebox and was added with 1.2 equiv. (CH3)2Zn (0.04 mmol, 20 μL of a 2.0 M solution in toluene) by syringe. The NMR tube was then removed from the glovebox and was added with 10 equiv. SMe2 (26 μL, 0.34 mmol). The sample was heated at 60 ˚C. The reaction was monitored by 1H and 19F NMR spectroscopy. The conversion of 3.7 to 2a was less than 10% at 60 ˚C for 30 min. (Note: see spectra on page 253) N-(2,3,4,5,6-pentafluorobenzylidene)para-bromo-benzylamine (1e) (white solid, 84%) 1H NMR (acetonitrile-d3, 300 MHz): δ 8.53 (s, CH=N, 1H), 7.51-7.25 (m, Ar-H, 4H), 4.79 (s, CH2, 2H). 19F NMR (acetonitrile-d3, 282 MHz): δ -143.0 (m, 2F), -152.2 (m, 1F), -162.7 (m, 2F).  13C{1H} NMR (acetonitrile-d3, 100 MHz): δ 152.1 (q, J = 2.0 Hz), 147.1 (dddd, J = 254.6 Hz, J = 13.6 Hz, J = 7.0 Hz, J = 4.0 Hz), 143.2 (dtt, J = 253.6 Hz, F F N F Br F F 162 J = 13.1 Hz, J = 5.0 Hz), 139.4 (s), 138.9 (dm, J = 253.6 Hz), 132.5 (s), 131.0 (s), 126.0 (t, J = 13.1 Hz), 121.5 (s), 66.0 (s). HRMS (EI) m/z calcd for C14H7F5N 79Br: 362.9682; found: 362.9684. Anal. Calcd for C14H7F5NBr: C, 46.18; H, 1.94; N, 3.85; found: C, 46.42; H, 1.70; N, 3.81. Preparation of [PtMe2F(SMe2)(C6F4CH=NCH2C6H4Br)], complex 3.13. N Pt CH3 FH3C SMe2 F F F F CH2 Br In a 20 mL vial in the glovebox, 1e (12.6 mg, 0.034 mmol), [(CH3)2Pt(µ-SMe2)]2 (10.0 mg, 0.017 mmol) and 1,3,5-trimethoxybenzene (5.7 mg, 0.034 mmol, internal standard) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred into an NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was then removed from the glovebox and was left at room temperature for 24 h. The reaction was monitored by 1H and 19F NMR spectroscopy. Characterization data of 3.13: 1H NMR (acetonitrile-d3, 300 MHz): δ 8.98 (s, JPt-H = 48.0 Hz, CH=N, 1H), 7.67-7.45 (m, aryl-H, 4H), 5.02 (m, 2H), 1.96 (s, JPt-H = 12.0 Hz, S(CH3)2, 6H), 1.50 (dd, JPt-H = 63.0 Hz, JF-H = 9.0 Hz, JF-H = 6.0 Hz, Pt-CH3, 3H), 0.80 (d, JPt-H = 66.0 Hz, JF-H = 6.0 Hz, Pt-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δδ -128.2 (m, 1F), -139.4 (m, 1F), -148.0 (m, 1F), -162.8 (m, 1F), -253.5 (tm, JPt-F = 175.1 Hz, 1F). 163 Isolation of Me3Pt(IV) complex 3.16. In a 20 mL vial in the glovebox, 1e (63 mg, 0.174 mmol) and [(CH3)2Pt(µ-SMe2)]2 (50 mg, 0.087 mmol) were dissolved in CD3CN (1.1 mL). The resulting solution was left at room temperature for 24 h and was added with 1.2 equiv. (CH3)2Zn (0.204 mmol, 102 μL of a 2.0 M solution in toluene) by syringe. The resulting solution was left at room temperature for another 20 min and then was added with triphenylphosphine (45 mg, 0.174 mmol). The 20 ml vial was swirled by hand for few minutes until triphenylphosphine was totally dissolved. The solution was left at room temperature for 24 h, orange color solid precipitated. The solid was separated by filtration through a glasswool plug and was washed with 2 mL of hexanes or pentanes. The solid was collected in a clean 20 mL vial and was dissolved in 2 mL of CH2Cl2. The clear solution was layered carefully with 8 mL of n-pentanes. When the solution was left at room temperature for 24 h, red colored crystals formed at the bottom of the glass vial. The crystals (3.16) were separated from solution in 40% yield. X-ray analysis was performed on such single crystals. 1H NMR (acetone-d6, 300 MHz): δ 8.59 (s, JPt-H = 40.5 Hz, CH=N, 1H), 7.54 – 7.04 (m, overlapping peaks, Aryl-H), (4.55 (d), 4.23 (d), JH-H = 15.3 Hz, CH2, 2H, AB pattern), 1.37 (dd, JPt-H = 70.8 Hz, JF-H = 2.7 Hz, JP-H = 7.7 Hz, Pt-CH3, 3H), 0.62 (d, JPt-H = 49.8 Hz, JP-H = 7.3 Hz, Pt-CH3, 3H), 0.42 (d, JPt-H = 62.0 Hz, JP-H = 7.5 Hz, Pt-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -124.4 (m, 1F), -140.2 (t, J = 19.7 Hz, 1F), -149.8 (m, 1F), -165.2 (t, J = 19.7 Hz, 1F). 31P {1H} NMR (acetone-d6, 121 MHz): δ -6.94 (s, JPt-P = 1039.2 Hz). 13C (CD2Cl2, 100 MHz): δ 169.2 (broad singlet), 164 154.7(dm, JBr-C = 43.3 Hz), 151.8 (dm, JF-C = 230.5 Hz), 148.8 (dm, JF-C = 261.6 Hz), 143.5 (dm, JF-C = 265.7 Hz), 137.2 (m, the other half overlaps with the resonances for PPh3), 134.5 (t, JPt-C = 7.6 Hz, overlapping with resonances for PPh3), 134.3 (d, JP-C = 9.9 Hz), 132.6 (s), 132.1 (s), 131.8 (d, JPt-C = 10.8 Hz, JP-C = 37.5 Hz), 130.7 (d, JP-C = 2.3 Hz), 128.6 (d, JP-C = 8.4 Hz), 122.9 (s), 59.2 (s, JPt-C = 14.5 Hz), 7.29 (d, JPt-C = 543.4 Hz, JP-C = 114.7 Hz), 2.17 (broad singlet, JPt-C = 478.0 Hz), -12.9 (dd, JPt-C = 613.9 Hz, JP-C = 11.1 Hz, JF-C = 4.0 Hz). HRMS (ESI-) m/z calcd for C35H30NF4P 79Br194Pt (M-H): 844.0862; found: 844.0850. Anal. Calcd for C35H31NF4PBrPt: C, 49.60; H, 3.69; N, 1.65; found: C, 49.80; H, 3.72; N, 1.75. Geometry of this complex was confirmed by NOE study and X-ray analysis. (Note: see NMR spectra and X-ray data on pages 254-264) Formation of complex 3.17. The crystals of 3.16 were left in the recrystalization solution at room temperature for more than two days. Crystals of 3.16 would be dissolved in the solution and some precipitate appeared. The solution was filtered by glasswool plug to obtain a clear solution. Solvents were evaporated to dryness under vacuum in the glovebox. The remainder was dissolved in CD3CN for NMR analysis. The NMR data was too complicated to be identified. Some brown color crystals appeared in the NMR tube after another two weeks at room temperature. The corresponding molecular structure was shown in Figure 3.6. (Note: see X-ray data on pages 265-269) 165 3.13 References 1) Wang, T.; Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629–5631. 2) Crespo, M.; Martinez, M.; Sales, J. Organometallics 1993, 12, 4297-4304. 3) Bernhardt, P. V.; Gallego, C.; Martinez, M. Organometallics 2000, 19, 4862–4869. 4) Bernhardt, P. V.; Gallego, C.; Martinez, M.; Parella, T. Inorg. Chem. 2002, 41, 1747–1754. 5) Gallego, C.; Gonzalez, G.; Martinez, M.; Merbach, A. E. Organometallics 2004, 23, 2434–2438. 6) (a) van Asselt, R.; Rjinberg, E.; Elsevier, C. J. Organometallics 1994, 13, 706–720. (b) Clegg, D. E.; Hall, J. R.; Swile, G. A. J. Organomet. Chem. 1972, 38, 403–420. (c) Ruddick, J. R.; Shaw, B. L. J. Chem. Soc. A 1969, 2969–2970. 7) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936-1947. 8) Singh, A. K.; Mukherjee, R. Dalton Trans. 2008, 260-270. 9) Dahlenburg, L; Menzel, R.; Puchta, R.; Heinemann, F. W. Inorg. Chim. Acta 2008, 361, 2623-2630. 10) Nonoyama, M.; Nakajima, K.; Nonoyama, K. Polyhedron, 1997, 16, 4039-4044. 11) Hill, G. S.; Irwin, M. J.; Levy, C. J.; Rendina, L. M.; Puddephatt, R. J.; Andersen, R. A. and McLean, L. Inorg. Synth. 1998, 32, 149-151. 12) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890-891. 166 CHAPTER FOUR: REDUCTIVE ELIMINATION FROM PT(IV): AN UNUSUAL PREFERENCE FOR Csp2-sp 3 OVER Csp2-sp 2 BOND FORMATION c  4.1 Introduction Formation of C-C bonds by transition-metal-catalyzed cross-coupling reactions is an important tool in synthetic chemistry, as cross-coupling reactions have been widely utilized to synthesize natural products, biologically active compounds, drug precursors, ligands, supramolecular structures, organic materials and polymers.1-3 Metal catalyzed Csp2-Csp2 cross-coupling has become well-established after extensive studies over the last three decades and is thus the most common type of cross-coupling reaction.2 Considerable recent efforts have been directed towards sp2-sp3 bond formation, as aryl-Csp3 bonds are common motifs.1b As introduced in Chapter one, the catalytic Csp2-Csp3 cross-coupling reaction is generally considered to be more challenging than the well-established Csp2-Csp2 cross-coupling reactions, proceeding with lower yields and often requiring harsh conditions and longer reaction times compared to catalytic Csp2-Csp2 cross-coupling reactions. Csp3-Csp3 cross-coupling is even less successful than Csp2-Csp2 and Csp2-Csp3 coupling reactions.1c-1e Therefore, it is of interest to explore what leads to the difficulty of coupling Csp3 hybridized reactants. Critical insights into this issue are  c A version of this chapter will be submitted for publication. Wang, T.; Love, J. A. Reductive Elimination from Pt(IV): An Unusual Preference for Csp2-Csp3 over Csp2-Csp2 Bond Formation. 167 expected from the investigation of the cross-coupling reaction mechanism and the factors controlling the rate-determining step in cross-coupling reactions. Cross-coupling reactions typically involve three fundamental steps: oxidative addition, transmetalation and reductive elimination.2a The slow Csp2-Csp3 cross-coupling of alkylboronic acids has been attributed to the low reactivity of alkylboronic acids in the transmetalation step relative to arylboronic acids.4 It is noteworthy, however, that other chemists have pointed out that failures in the cross-coupling of alkyl organometallic reagents should not be attributed only to the transmetalation step.5a-5c Instead, Espinet, Maseras, Álvarez and Lei have proposed that the sluggish coupling reactions involving Csp3 nucleophiles are caused by slow Csp2-Csp3 reductive elimination.5a-5c However, studies directly comparing Csp2-Csp2, Csp2-Csp3 and Csp3-Csp3 reductive elimination are still rare. Despite the fact that the reductive elimination step is of great importance in organic and organometallic chemistry, the mechanism of the C-C bond formation still remains unsolved.1a,2c,3 Fully understanding the factors that control reductive elimination could provide the needed insight into the poor performance of Csp3 nucleophiles in cross-coupling. This chapter discusses factors that control reductive elimination. The effects of ligand electronic properties on reductive elimination are treated in section 4.1.1. In sections 4.1.2, Csp2-Csp3, Csp2-Csp2 and Csp3-Csp3 reductive elimination are compared. The Pt(II) catalyzed Csp2-Csp3 cross-coupling of polyfluoroaryl imines and mechanistic studies are 168 summarized in section 4.1.3. The stoichiometric isotopic transmetalation reaction of Pt(IV)-F with Me2Zn, which illustrates that isomerization is faster than reductive elimination, is described in section 4.2.1. Sections 4.2.2-4.2.7 discuss the unusual preference for Csp2-Csp3 over Csp2-Csp2 in reductive elimination from a few Pt(IV) complexes. 4.1.1 The effect of ligand electronic properties on reductive elimination Hartwig and co-workers studied the effect of ligand electronic properties on rates of Csp2-Csp2 reductive elimination from Pt(II) complexes (Scheme 4.1).6a Table 4.1 lists the rate constants of Csp2-Csp2 reductive elimination from Pt(II) complexes with electron-rich and electron-poor groups. Hammett analysis showed a small positive slope, however, it was not linear. The complex with one electron-rich group and one electron-poor aryl group eliminates fastest (Table 4.1, entry 6). This is contrary to the traditional view that compounds with electron-withdrawing groups would reductively eliminate more slowly than those with electron-donating groups.6c,6d Hartwig explained that the traditional wisdom only considered the stronger metal-ligand bonds in the reactants in ground state. In contrast, Hartwig found that Pt complexes with one electron-rich and one electron-poor groups had lower barriers to reductive elimination.6a The lower barrier was explained with the rationale that the electron-rich group destabilizes the ground state by making the metal-ligand bond weaker and that the transition state is stabilized by the larger difference in electronic properties between the electron-poor and electron-rich groups. 169 Fe P Ph2 Ph2 P Pt NMe2 X 95 °C Toluene-d8 10 PPh3 X NMe2 4.1 Scheme 4.1 Reductive elimination from platinum (II) complexes Table 4.1 Rate constants for thermal decomposition of platinum complexes6a Entries X kobs (s -1) x 10-5 1 NMe2 32.3 2 CH3 33.2 3 OMe 32.3 4 H 30.8 5 Cl 52.3 6 CF3 159 4.1.2 Csp2-Csp2 v.s. Csp2-Csp3 v.s. Csp3-Csp3 reductive elimination Generally, reductive elimination of Csp2 hybridized ligands is thought to proceed faster than reductive elimination of Csp3 hybridized ligands. This has been explained by the higher energy required to re-orient the more directional sp3 hybrid orbital before reductive elimination.7a,2c In addition, Calhorda and co-workers illustrated that Csp2 coupling could also occur via a 1,2-shift, but Csp3-Csp3 bond formation would not have this option.7b Herein some examples are presented. In 1996, Maitlis and co-workers studied the decomposition of the iridium complex (C5Me5)Ir(CO)(R)(R’). 7c Results listed in Table 4.2 indicated that vinyl-vinyl coupling was fastest (Table 4.2, entry 1); vinyl-methyl and phenyl-methyl coupling were next(entries 2 and 3) and little methyl-methyl coupling occurred (entry 4). These results clearly demonstrated that the 170 rate order of reductive elimination: Csp2-Csp2 > Csp2-Csp3 > Csp3-Csp3. In 2005, Ananikov, Musaev and Morokuma studied the C-C reductive elimination from palladium and platinum complexes, RR’M(PH3)2 (M = Pd or Pt) using theoretical calculations. 2c Consistent with Maitlis’s study, the following reaction order has been established for both palladium and platinum complexes: vinyl-vinyl > phenyl-phenyl > methyl-methyl. Table 4.2 Decomposition of the iridium complex (C5Me5)Ir(CO)(R)(R’) 7a Entries R R’ Decomposition conditions Product Yield (%) 1 CH2=CH CH=CH2 60 ˚C (2 h) CH2=CHCH=CH2 95 2 CH2=CH Me 200 ˚C (2 h) CH2=CHMe 56 3 Ph Me 360 ˚C (4 h) PhMe 15 4 Me Me 400 ˚C (6 h) MeMe 3 More recently, an example that contrasts with the above results was provided by Krogh-Jespersen and Goldman.1a They studied reductive elimination from complexes 4.2, 4.3 and 4.4 (Figure 4.1). The reductive elimination rate order was the following: Csp3-Csp3 (4.2) > Csp2-Csp3 (4.3) > Csp2-Csp2 (4.4) (Table 4.3). The calculated activation free energies for reductive elimination from complexes 4.2-4.4 were consistent with the experimental data on reductive elimination. The higher energies for phenyl reductive elimination were attributed to a steric effect between the bulky ligand group and phenyl. The reductive elimination of a phenyl group required 90º rotation, which was severely hindered by the bulky PtBu2 groups. Therefore, steric hindrance plays an 171 important role in C-C reductive elimination from complexes 4.2 - 4.4.1a However, this result might be particular to this system and not necessarily broadly applicable. PtBu2 PtBu2 Ir CH3 CH3 4.2 PtBu2 PtBu2 Ir Ph CH3 4.3 PtBu2 PtBu2 Ir Ph Ph 4.4 Figure 4.1 Structures of complex 4.2, 4.3 and 4.4 Table 4.3 Reductive elimination data on Ir complexes1a Calculated activation free energy for reductive elimination 18.2 kcal/mol 27.1 kcal/mol Complexes Temp/°C 4.2 15 4.3 45 32.4 kcal/mol4.4 80 Rate/10-4 9.94 < 9.94 < 1.27 In 2007, Ozerov and co-workers found that the rate of reductive elimination of Ph-Ph from 4.5 (Figure 4.2) (t1/2 = 7 min at 40 ˚C) was greater than the rate of the reductive elimination of Ph-Me from 4.6 (Figure 4.2) (t1/2 = 17 min at 40 ˚C).8 This result is consistent with the trend that Csp2-Csp2 reductive elimination is faster than Csp2-Csp3 reductive elimination, although it was surprising that both occur on similar timescales. PiPr2 N Rh PiPr2 Me Ph 4.6 PiPr2 N Rh PiPr2 Ph Ph 4.5 Figure 4.2 Structures of (PNP)RhPh2 (4.5) and (PNP)RhPhMe (4.6) complexes 172 A few experimental examples comparing Csp2-Csp3 and Csp3-Csp3 reductive elimination have been reported. The Csp2-Csp3 reductive elimination from complex 4.7 (Figure 4.3) occurred at room temperature to form toluene, but the Csp3-Csp3 reductive elimination from complex 4.8 (Figure 4.3) required elevated temperature (45 ˚C).9a-9d Pd H3C Ph2P PPh2 CH3 CH3 CH3 Pd H3C PhP PPh Ph Et2 Et2 4.84.7 Figure 4.3 Structures of complexes 4.7 and 4.8 Houk, Wender, and co-workers also illustrated the preference for Csp2-Csp3 reductive elimination over Csp3-Csp3 reductive elimination in [5+2] reactions of vinyl cyclopropanes with alkynes, allenes and alkenes, catalyzed by [Rh(CO)2Cl]2. 10 The catalyst worked well with alkynes and allenes, but not with alkenes. It was explained that the reaction with alkenes involves Csp3-Csp3 reductive elimination, which was more difficult than Csp2-Csp3 reductive elimination in the reaction with alkynes or allenes. In contrast, in 2007, Williams and co-workers reported an unusual competitive Csp3-Csp3 and Csp2-Csp3 C-C reductive elimination from a platinum(IV) complex 4.9 (Scheme 4.2).11a Complex 4.9 could undergo Csp3-Csp3 reductive elimination to generate ethane and 4.10 or undergo Csp2-Csp3 reductive elimination to form 4.11. The product ratio between Csp3-Csp3 and Csp2-Csp3 is 1:7 at -40 ˚C, indicating that Csp3-Csp3 173 reductive elimination was slower than Csp2-Csp3 reductive elimination, but that reductive elimination rates could be competitive. Hwang and co-workers explained these observations by theoretical calculations in which they found only a small activation barrier difference between Csp3-Csp3 reductive elimination and Csp2-Csp3 reductive elimination.11b Another possible explanation is that formation of complex 4.11 presumably involves the entropically disfavored reductive elimination of a cyclometalated ligand. Pt NEt2 NEt2 CH3 4.9 MeOTf CD2Cl2 Pt NEt2 NEt2 OTf 4.10 -C2H6 NMe2 NMe2 Pt CH3 CH3 OTf 4.11 Scheme 4.2 Reductive elimination from complex 4.9 Although the prevailing wisdom is that the relative rates of reductive elimination follow the trend: Csp2-Csp2 > Csp2-Csp3 > Csp3-Csp3, some examples do not follow this trend. In this chapter, we will present another exception: the reductive elimination from Pt(IV) complexes, in which Csp2-Csp3 reductive elimination is preferred over Csp2-Csp2 reductive elimination. 174 4.1.3 The Pt(II) catalyzed Csp2-Csp3 coupling reaction and the mechanism of this reaction The preference for Csp2-Csp3 over Csp2-Csp2 coupling from various Pt(IV) complexes will be illustrated in this chapter. The studies described in chapter two and three led to the discovery of this unexpected result. Therefore, it is of importance to briefly introduce contents in chapters two and three. In chapter two, Pt(II)-catalyzed cross-coupling of polyfluoroarenes (eq 4.1) was illustrated. This was the first example using platinum in cross-coupling of fluoroarenes.12 Methylated fluoroarenes were formed in high yield and high selectivity at ortho position directed by the imine group. The functionalized polyfluoroarene products are potentially building blocks for pharmaceuticals, polymers and supramolecular frameworks. F F NBn 5 mol % [(CH3)2Pt(-SMe2)]2 0.6 equiv (CH3)2Zn CH3CN, 60 °C 8 h, 85% (4.1) CH3 F NBn 1a 2a Br Br Insight gained into the mechanism of this reaction was illustrated in chapter three. The reaction involves intramolecular C-F activation of 4.13 to generate 4.14,13 followed by transmetalation of 4.14 with Me2Zn to form 4.15. Subsequent reductive elimination from 4.15 provides the methylated product and regenerates the Pt(II) species 4.13 (Scheme 4.3), completing the catalytic cycle.14 175 0.5 [(CH3)2Pt(-SMe2)]2 NR Pt CH3 FH3C F F NR Pt CH3 CH3H3C F F + SMe2 (or isomer)(or isomer) + SMe2 + 1b [(CH3)2Pt(imine 1b)] - SMe2 - SMe2- SMe2 4.13 4.15 Me2ZnMeZnF 2b 1b F F F F CH3 F NR F F F 4.144.15 4.12 SMe2 4.14 SMe2 F F NR F F F Scheme 4.3 Proposed mechanism of Pt(II)-catalyzed cross-coupling of polyfluoroarenes It is of importance to point out that no ethane formation is observed in either Pt(II)-catalyzed cross-coupling reaction or reductive elimination from Me3Pt(IV) complex 4.15. These results are consistent with the prevalent idea that Csp2-Csp3 reductive elimination is much faster than Csp3-Csp3 reductive elimination. As illustrated in chapter three, excess SMe2 retarded both transmetalation and reductive elimination. Furthermore, reductive elimination was slowed by excess ligand to a much greater extent than transmetalation. These results indicate that both the 176 transmetalation and reductive elimination steps involve the dissociation of SMe2 and occur from five-coordinate species. 4.2 Results and Discussion The reactions between Pt-F complex 2.2 with PhM reagents, including PhSi(OMe)3, PhLi and PhSnMe3, were presented in chapter two, only formed methylated product and did not produce phenylated product, although the transmetalation of phenyl group to platinum occurred (Scheme 4.4). Considering that the reductive elimination occurs from five-coordinate Pt(IV) species, Me2Pt(IV)Ph complex 4.16 might be involved in the reductive elimination of methylated product. PhSi(OMe)3 FSi(OMe)3 (or isomers) 2.3 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F NCH2Ph Pt CH3 PhH3C SMe2 F F F NCH2Ph F CH3 Acetone-d6 32% rt, 21 h Scheme 4.4 Reaction between complex 2.2 and PhSi(OMe)3 (or isomers) 2.3 NCH2Ph Pt CH3 PhH3C SMe2 F F (or isomers) NCH2Ph Pt CH3 PhH3C F F - SMe2 + SMe2 4.16 Scheme 4.5 The equilibrium between complex 2.3 and complex 4.16 177 It is of importance to study whether or not complex 4.16 can undergo isomerization. If it could, a series of isomeric complexes should be in equilibrium. One of these could have the phenyl group in the apical position. C-C reductive elimination is believed to occur from the apical position because many literatures point out that reductive elimination of apical-equatorial ligands is symmetry-allowed.15 As Csp2-Csp2 coupling is expected to be faster than Csp2-Csp3 coupling, the phenylated product should be formed faster than the methylated product.15 The remainder of this chapter focuses on whether isomerization does occur and why the phenylated product is not observed. 4.2.1 Stoichiometic isotopic transmetalation of 4.14·SMe2 The first question was whether or not 4.16 could exist as a mixture of isomers. A hint came from the study of stoichiometric transmetalation of d6-4.14·SMe2 with Me2Zn. We discovered that scrambling of the methyl groups was completed at room temperature in 10 min to generate d6-4.15·SMe2 (mixture of isomers) (eq 4.2). 16 It is noteworthy that during this period, no reductive elimination products appeared. This result suggests that isomerization of d6-4.15·SMe2 is faster than reductive elimination. Me2Zn ( 0.5 equiv) (4.2) CD3CN, rt, 10 min 69% NBn Pt CD3 FD3C SMe2 F F NBn Pt CD3 CH3D3C SMe2 F F NBn Pt CD3 CD3H3C SMe2 F F NBn Pt CH3 CD3D3C SMe2 F F + + 1 : 1 : 1 d6-4.14 SMe2 d6-4.14 SMe2 (mixture of isomers) 178 4.2.2 Transmetalation of 4.14·SMe2 with Ph2Zn To explore (CH3)2Pt(IV)Ph complex 4.16, we chose to use Ph2Zn as the phenyl transmetalation reagent. The stoichiometric reaction between pentafluoroimine 1b with 0.5 equiv of [(CH3)2Pt(-SMe2)]2 generated Pt(IV)-F complex (4.14·SMe2) in 95% yield. The transmetalation of 4.14·SMe2 with 0.5 equiv of Ph2Zn generated a mixture of multiple isomers (4.16·SMe2) (Scheme 4.6), 17 indicating that isomerization is rapid. The isomerization process of 4.16·SMe2 could be slowed by excess ligand (10 equiv SMe2); under these conditions, two complexes, I·SMe2 and II·SMe2, were formed in a 1.1:1 ratio. The same result was obtained in the reaction between 4.14·SMe2 with Ph2Zn in the presence of 10 equiv SMe2. NR Pt CH3 FH3C SMe2 F F NR Pt CH3 PhH3C SMe2 F F F F F F NR Pt Ph CH3H3C SMe2 F F F F (mixture of isomers) SMe2 (10 equiv) Ph2Zn (0.5 equiv) SMe2 (10 equiv) R = CH2(p-BrC6H4) ( 1.1 : 1) [Me2Pt(-SMe2)]2 CH3CN, rt 24 h, 95% 1b NR PtMe2Ph(SMe2) F F F F Ph2Zn (0.5 equiv) CD3CN, rt 10 min, 90% 4.14 SMe2 4.16 SMe2 I SMe2 II SMe2 43% 39% Scheme 4.6 The transmetalation of complex 4.14·SMe2 with Ph2Zn 179 On the basis of 1H NMR spectroscopy, the stuctures of complexes I·SMe2 and II·SMe2 were assigned. For complex I·SMe2, the singlet at  0.70 (JPt-H = 71.9 Hz) was attributed to the apical methyl on the basis of Nuclear Overhauser Effect (NOE) data. The NOE enhancement for the resonance at δ 0.70 enhanced the resonances at δ 7.39-7.41 (for the phenyl group on the Pt center) and 1.28 (for the other methyl group on the Pt center) (note: see NOE spectrum on page 286). For the resonance at  0.70, the coupling constant (JPt-H = 71.9 Hz) is a typical coupling constant for a methyl group trans to L-type ligand (herein, SMe2, C=N) on the Pt center, 18 consistent with the assignment that the apical methyl on complex I·SMe2 is trans to SMe2. Likewise, for the doublet at  1.28, JPt-H is 71.3 Hz, suggesting that the methyl group is trans to the other L-type ligand, e.g. C=N. This proposal is also consistent with the observed F-H coupling (JF-H = 3.0 Hz), indicating that the methyl group is in the same plane as the fluoroaryl ligand. This is also consistent with Crespo and Martinez’s assignments for a related complex.13 Further support comes from the NOE data; the resonances at δ 7.39-7.41 (for the phenyl group on the Pt center), 1.90 (for the SMe2 coordinated to the Pt center), and 0.70 (for the apical methyl group on the Pt center) increased (note: see NOE spectrum on page 286). The multiplet at δ 7.39-7.41 was attributed to the phenyl group on the basis of NOE data. The NOE enhancement for the resonances at δ 7.39-7.41 increased the resonances at δ 1.90 (for the SMe2 coordinated to the Pt center), and 0.70 (for the apical methyl group) (note: see NOE spectrum on page 287). 180 For complex II·SMe2, the singlet at δ 0.57 (JPt-H = 49.8 Hz) was assigned as the methyl trans to the fluoroaryl group on the basis of NOE data. The coupling constant of the resonance at δ 0.57 (JPt-H = 49.8 Hz) is typical of a methyl group trans to a carbon atom on the Pt center.18 The NOE enhancement for the resonance at δ 0.57 enhanced the resonances at δ 6.98-7.00 (for the phenyl group on the Pt center) and 1.37 (for the other methyl group on the Pt center) (note: see NOE spectrum on page 288). The doublet at δ 1.37 (JPt-H = 71.6 Hz, JF-H = 1.8 Hz) was assigned as the methyl cis to the fluoroaryl group, consistent with the observed F-H coupling. This is also consistent with Crespo and Martinez’s assignments for a related complex.13 The assignment is also consistent with the NOE data, as the resonances at δ 6.98-7.00 (for the phenyl group on the Pt center), 1.90 (for the SMe2 coordinated to the Pt center) and 0.57 (for the other methyl group on the Pt center) increased (note: see NOE spectrum on page 287). The multiplet at δ 6.98-7.00 was attributed to the phenyl group on the basis of the NOE enhancement of the resonances at δ 1.37 and 0.57, indicating the phenyl group is trans to the SMe2 ligand (note: see NOE spectrum on page 288). 4.2.3 Expected product from reductive elimination from mixture of isomers I·SMe2, II·SMe2 and III·SMe2 The transmetalation of 4.14·SMe2 with Ph2Zn in the absence of excess SMe2 produces a mixture of isomers (4.16·SMe2) (Scheme 4.6). Presumably, the mixture is composed of complexes I·SMe2, II·SMe2, and III·SMe2, as shown in Figure 4.4. The structural assignments for I·SMe2 and II·SMe2 have been discussed in section 4.2.2. 181 Unfortunately, the geometry of III·SMe2 – assuming it is present in solution - is difficult to study because of the low concentration. Nevertheless, we hypothesized that dissociation of SMe2 4.16·SMe2 would generate intermediates I, II and III; trapping with SMe2 would thus generate I·SMe2, II·SMe2 and III·SMe2 (Figure 4.4). NR Pt CH3 PhH3C SMe2 F F F F NR Pt Ph CH3H3C SMe2 F F F F NR Pt CH3 CH3Ph SMe2 F F F F I SMe2 II SMe2 III SMe2 Figure 4.4 Structures of complexes I·SMe2, II·SMe2 and III·SMe2 Under appropriate reaction conditions, intermediates I, II and III could undergo reductive elimination. Three paths (a, b and c) are available from each intermediate,15 with the ligand in the apical position undergoing reductive elimination with an equatorial ligand. Therefore, the selectivity of the reductive elimination from the mixture isomers of (I·SMe2, II·SMe2 and III·SMe2) would be controlled by the relative rates of the pathways shown in Scheme 4.7. 182 II NR Pt Ph CH3H3C F FF F III NR Pt CH3 CH3Ph F FF F Path a Path c Path b 2b Pt H3C SMe2 Ph or isomer PhCH3 NR Pt SMe2H3C F or isomer CH3CH3 NR Pt PhMe2S F or isomer a c b a c b + + + F F F F F F 3b Pt H3C SMe2 H3C or isomer PhCH3 NR Pt SMe2H3C F or isomer PhCH3 NR Pt CH3Me2S F or isomer + + + F F F F F F 2b Pt H3C SMe2 Ph or isomer CH3CH3 NR Pt SMe2Ph F or isomer PhCH3 NR Pt CH3Me2S F or isomer + + + F F F F F F NR Pt CH3 PhH3C F FF F a c b I NR FF F F CH3 NR FF F F Ph NR FF F F CH3 4.17 2.1 4.17 4.18 4.194.18 4.19 4.18 4.18 Scheme 4.7 Possible paths for reductive elimination from I, II and III Intermediate I could generate the methylated arylimine 2b and complex 4.17 through path a, form toluene and complex 4.18 through path b, and produce ethane and complex 4.19 by path c (Scheme 4.7). The same organic and organometallic products would be 183 formed from intermediate III, albeit by different paths; path a would produce 2b and complex 4.17, path c would lead to toluene and complex 4.18 and path b would generate ethane and complex 4.19. For both intermediates I and III, ethane would not be expected, as ethane formation has not been observed when using methyl nucleophiles.12,14 In contrast to intermediates I and III, intermediate II could generate the desired biaryl product 3b and complex 2.1 in path a, as well as toluene and complex 4.18 in paths b and c. It is noteworthy that formation of both methylated arylimine 2b and toluene involves sp2-sp3 coupling, whereas formation of biphenyl arylimine 3b would involve sp2-sp2 coupling. Considering the expected faster rate of sp2-sp2 coupling than sp2-sp3 coupling discussed in the section 4.1, we expected that formation of 3b should predominate. 4.2.4 Observed products in reductive elimination from 4.16·SMe2 On the basis of the analysis in the previous section, we sought to explore reductive elimination from Pt(IV). The reductive elimination from 1.1:1 mixture of I·SMe2 and II·SMe2 (in presence of excess SMe2) was sluggish, caused by the excess ligand. Instead, we studied the reductive elimination from 4.16·SMe2, the isomeric mixture. Surprisingly, the reductive elimination from 4.16·SMe2 generated the methylated product 2b in 50% yield and 12% of toluene after 19 h at 60 ˚C (Scheme 4.8), with 3b being formed in only trace amounts, as detected by EI-MS.19,20 It is noteworthy to point out that formation of both major products, 2b and toluene, involves sp2-sp3 coupling, whereas product from 184 sp2-sp2 coupling (3b) was generated in only trace amount. The major Pt complex that was identified was consistent with observed major organic product (Scheme 4.8). Pt complex 4.17 was expected to accompany the formation of 2b (Scheme 4.7).21 Indeed, 4.17 was formed in 31% yield, based on comparison of the 1H NMR spectral data to that of the known complex [CH3PhPt(SMe2)2] (Scheme 4.8). 22,23 In comparison, Pt complexes with a fluoroimine ligand (e.g. 4.18 and 4.19), which would accompany the formation of 3b and toluene, respectively, were detected in trace amounts. It is noteworthy that the trace amount of 4.18 is consistent with the observed amount of 3b. However, the amount of 4.19 would be expected to be more than that of 4.18 as toluene was observed more than 3b. CH3 NR 2b Ph NR 3b PhCH3 50% trace Pt CH3 Ph SMe2 or isomer 4.17 31% NR Pt SMe2H3C 4.18 NR Pt SMe2Ph 4.19 or isomer or isomer trace 12% trace mixture of isomers CD3CN, 60 °C 19 h F F F F F F F F FF F F FF F F 4.16 SMe2 Scheme 4.8 Reductive elimination from 4.16·SMe2 Given that the major products are 2b and 4.17, these results indicate reductive elimination is faster via path a from intermediates I and/or III (Scheme 4.7). Toluene 185 could be formed from all of the three intermediates: path b from intermediates I and II and path c from intermediate III (Scheme 4.7). Reductive elimination from Pt(II) complexes, e.g. 4.17 and 4.18, would contribute the formation of 2b and toluene. However, the amounts of 2b and toluene did not increase when the sample with 4.16·SMe2 was monitored at 60 ˚C over time for 48 h, indicating that the possibility of reductive elimination from Pt(II) complexes might be of trace amount under this reaction condition. Importantly, the observation of II·SMe2 in the transmetalation of Pt-F with Ph2Zn (Scheme 4.6) indicated that the phenyl ligand was able to occupy the apical position. The phenylated product 3b was formed with a trace amount. This phenomenon could be explained by the following two reasons: (i) reductive elimination of 3b from II is slower than both isomerization from II to I or III and reductive elimination of 2b from I or III; or (ii) reductive elimination from II to form toluene through paths b and c is faster than reductive elimination of 3b from II through path a. Considering the ratio of I·SMe2 to II·SMe2 is 1.1:1, if reductive elimination of toluene (paths b and c) from II were faster than reductive elimination of 3b and isomerization from II, the ratio of 2b to toluene should be around 1.1:1 (for simplicity, this assumes that toluene is formed only from II, which is not necessarily correct). However, the ratio of 2b to toluene was observed to be 4:1. Therefore, the latter explanation is not consistent with experimental data. The first scenario that reductive elimination of 3b from II is slower than both isomerization from II to I or III and reductive elimination of 2b from I or III seems to be more likely than 186 the latter one. Thus, the lack of observation of 3b was caused by the slower reductive elimination of 3b than both isomerization from II and reductive elimination of 2b or toluene. This study led to two surprising discoveries. (i) sp2-sp2 reductive elimination (phenyl-aryl coupling from intermediate II) is slower than sp2-sp3 reductive elimination (methyl-aryl coupling from intermediates I and/or III); this unusual observation is contrast to the prevailing view that sp2-sp2 coupling is faster than sp2-sp3 coupling and (ii) the entropically disfavored reductive elimination of a cyclometalated ligand (forming 2b) is faster than the reductive elimination of PhCH3. In the next section, we present a possible explanation for these intriguing observations. 4.2.5 Proposed explanation for unusual preference for Csp2-Csp3 over Csp2-Csp2 in reductive elimination from 4.16·SMe2 These results from the reductive elimination from 4.16·SMe2 could be explained based on Hartwig’s study of reductive elimination from Pt(II) biaryls.12b In that study, Hartwig discovered that the Pt(II) complexes, which underwent reductive elimination with the fastest rate, involved ligands with the largest electronic difference (i.e., one electron rich and one electron poor), which was in contrast with the expectation that electron rich ligands undergo reductive elimination the fastest.6c,6d Such a “push-pull” explanation is consistent with our observations. For intermediates I, II and III, the fluoroaryl group is the most electron-deficient and the methyl group is the most electron-donating of the ligands on the Pt(IV) metal center.24 Accordingly, the 187 methyl and fluoroaryl groups have the greatest electronic difference of any other two ligands, which, extrapolating from Hartwig’s results with Pt(II), suggests that methyl-fluoroaryl reductive elimination will be faster than any other reductive elimination path from intermediates I, II and III. The “push-pull” scenario also explains the preference for reductive elimination of the cyclometalated fluoroaryl ring over the phenyl group because the electronic difference between methyl and fluoroaryl is larger than the electronic difference between methyl and phenyl. 4.2.6 Observation of unusual preference for Csp2-Csp3 over Csp2-Csp2 in reductive elimination from 4.21·SMe2 Hartwig’s studies on electronic effects of ligands on reductive elimination inspired us to explore the electronic effects of the fluoroaryl ligand on the reductive elimination from (CH3)2Pt(IV)Ph derived from different fluoroaryl imines. Changes to the electronic nature of the fluoroaryl ligand were expected to influence the product ratio. To date, we have explored reductive elimination from (CH3)2Pt(IV)Ph prepared from imine 1c (Scheme 4.9). Imine 1c was combined with [(CH3)2Pt(μ-SMe2)]2 at room temperature for 24 h, providing complex 4.20·SMe2. Complex 4.20·SMe2 was subsequently reacted with Ph2Zn to obtain complex 4.21·SMe2, which was composed of a mixture of many isomers, as expected. It is noteworthy to mention that the isomeric ratios did not change in the presence of excess SMe2 This result indicated that the dissociation of SMe2 from 4.21·SMe2 and association of SMe2 to 4.21 are fast at room temperature. The reductive elimination from 4.21·SMe2 was complete in 30 min at 60 ˚C, providing methylated 188 imine 2c in 64% yield and phenylated imine 3c in 12% yield. This data also indicates that sp2-sp2 coupling is slower than sp2-sp3 coupling. It is interesting that no ethane or toluene were observed by 1H NMR spectroscopy. The differences in product formation from complexes 4.16·SMe2 and 4.21·SMe2 attributed to the electronic effects of the fluoroaryl ligands. It is hypothesized that having fewer electron withdrawing groups on the fluoroaryl ring might render the non-fluorinated phenyl group competitive with the fluoroaryl group for reductive elimination. NR Pt CH3 FH3C SMe2 F F (mixture of isomers) R = CH2C6H5 [(CH3)2Pt(-SMe2)]2 CH3CN, rt 24 h, 90% 1c NR PtMe2Ph(SMe2) F FPh2Zn (0.5 equiv) CD3CN, rt 10 min CH3 NR 2c Ph NR 3c 64% 12% F F F F F NR F F 60 °C, 30 min 4.20 SMe2 4.21 SMe2 Scheme 4.9 Reductive elimination from 4.21·SMe2 4.2.7 Observation of unusual preference for Csp2-Csp3 over Csp2-Csp2 in reductive elimination from MePt(IV)Ph2 complex 4.23·SMe2 As illustrated in Schemes 4.7 and 4.9, reductive elimination from (CH3)2Pt(IV)Ph (4.16·SMe2 and 4.16·SMe2) results in preferential sp 2-sp3 coupling over sp2-sp2 coupling. We decided that it is also of importance to study reductive elimination from an analogous complex CH3Pt(IV)Ph2 (4.23·SMe2). We expected that increasing the number of phenyl 189 ligands would increase the chance for sp2-sp2 coupling product because the phenyl ligand should have more opportunity to occupy the apical position. The preparation of 4.23·SMe2 is illustrated in Scheme 4.10. Imine 1b was combined with [CH3PhPt(μ-SMe2)]2 in acetonitrile at room temperature for 3 days to obtain complex 4.22·SMe2. Complex 4.23·SMe2 was prepared from the transmetalation of 4.22·SMe2 with Ph2Zn. The reductive elimination from complex 4.23·SMe2 required 87 h to complete, which is much slower than the other reductive elimination reactions studied to date. Methylated imine 2b was formed in 46% yield, along with a 19% yield of toluene (Scheme 4.10). No phenylated products were observed, indicating that in the reductive elimination from 4.23·SMe2, sp 2-sp3 coupling is also unusually favored over sp2-sp2 coupling. 60 °C, 87 h NR Pt CH3 FPh SMe2 F F F F (mixture of isomers)R = CH2(p-BrC6H4) [CH3PhPt(-SMe2)]2 CH3CN, rt 3 d, >95% 1b NR PtMePh2(SMe2) F F F F Ph2Zn (0.5 equiv) CD3CN, rt 10 min mixture of isomers CH3 NR 2b Ph NR 3b PhCH3 46% trace19% F F F F F F F F 4.22 SMe2 4.23 SMe2 Scheme 4.10 Reductive elimination from 4.23·SMe2 190 4.3 Conclusions In summary, we have demonstrated an unusual preference for Csp2-sp3 coupling over Csp2-sp2 coupling from Pt(IV), which is explained by the apparent slower rate of Csp2-sp2 coupling than that of Csp2-sp3 coupling. This unusual data might provide new insight towards fundamental chemistry by changing the prevailing idea that Csp2-sp2 coupling is much faster than Csp2-sp3 coupling. This might provide new directions for organic chemistry and organometallic chemistry by improving our ability to predict cross-coupling products and to design new catalytic systems. Further kinetic studies on the reductive elimination from Pt(IV) are underway in the group. 191 4.4 Experimental General Procedures. Manipulation of organometallic compounds was performed using standard Schlenk techniques under an atmosphere of dry nitrogen or in a nitrogen-filled MBraun dry box (O2 < 2 ppm). NMR spectra were recorded on Bruker Avance 300 or Bruker Avance 400 spectrometers. 1H and 13C chemical shifts are reported in parts per million and referenced to residual solvent. 19F NMR spectra are reported in parts per million and referenced to C6F6 in acetone-d6 (-162.9 ppm). Coupling constant values were extracted assuming first-order coupling. The multiplicities are abbreviated as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet. All spectra were obtained at 25 ˚C. Mass spectra were recorded on a Kratos MS-50 mass spectrometer. In appendix III, the NMR spectra for chemicals and key reactions are listed (pages 270-295). Materials and Methods. Acetonitrile was dried by heating to reflux over calcium hydride. Acetonitrile-d3 and all organic reagents were obtained from commercial sources and used as received. K2PtCl4 was purchased from Strem Chemicals and was used without further purification. cis/trans-PtCl2(SMe2)2 was prepared by a previously reported procedure.25 [Me2Pt(μ-SMe2)]2 and [(CD3)2Pt(μ-SMe2)]2 were prepared by a previously reported procedure.12,25 [MePtPh(SMe2)]2 was prepared by a previously reported procedure.23a,23b All imines were prepared by previously reported procedures.12,13 Dimethyl zinc (2.0 M solution in toluene) was purchased from Aldrich 192 and titrated following a published procedure prior to use.26 Diphenyl zinc was purchased from Alfa Aesar. Transmetalation between [Pt(CD3)2F(SMe2)(C6F2H2CH=NCH2C6H5)] (complex d6-4.14·SMe2) and Me2Zn. 1) Preparation of complex d6-4.14·SMe2 In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine (8.0 mg, 0.032 mmol), [(CD3)2Pt(μ-SMe2)]2 (9.4 mg, 0.016 mmol) and 1,3,5-trimethoxybenzene (5.4 mg, 0.032 mmol) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred into an NMR tube, which was then fitted with a screw cap containing a septum. The NMR tube was left at 60 ˚C for 19 h. The sample was cooled to room temperature and then was analyzed by 1H NMR and 19F NMR spectroscopy. The yield of d6-4.14·SMe2 was based on integration of the CH2 resonance of d6-4.14·SMe2 with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Characterization of d6-4.14·SMe2 (see spectra on pages 271 and 272): 1H NMR (acetonitrile-d3, 300 MHz): δ 8.78 (s, JPt-H = 47.1 Hz, CH=N, 1H), 7.8-6.6 (m, overlapping peaks, aryl-H), 5.05 (m, CH2, 2H), 1.89 (s, JPt-H = 12.0 Hz, S(CH3)2, 6H), (There were no resonances for CD3-Pt). 19F NMR (acetonitrile-d3, 282 MHz): δ -102.0 (m, 1F), -110.7 (m, 1F), -261.8 (broad singlet, 1F). 2) Transmetalation of complex d6-4.14·SMe2 with 1.2 Me2Zn to generate complex d6-4.15·SMe2 193 The solution of (d6-4.14·SMe2) was added with Me2Zn (0.042 mmol, 21 µL of 2.0 M solution in toluene) by syringe. After 15 min at room temperature, the sample was monitored by 1H NMR and 19F NMR spectroscopy. Three resonances for the three methyl groups on d6-4.15·SMe2 appeared with a ratio of 1: 1: 1. Characterization of d6-4.15·SMe2 (see spectra on pages 273-275): 1H NMR (acetonitrile-d3, 400 MHz): δ 8.86 (s, JPt-H = 39.2 Hz, CH=N, 1H), 7.7-6.6 (m, overlapping peaks, aryl-H), 4.98 (m, CH2, 2H), 1.78 (s, JPt-H = 13.2 Hz, S(CH3)2, 6H), 0.74 (s, JPt-H = 69.6 Hz, Pt-CH3, 2H) (overlapped three singlets), 0.36 (s, JPt-H = 72.8 Hz, Pt-CH3, 2H) (overlapped three singlets), 0.15 (s, JPt-H = 44.8 Hz, Pt-CH3, 2H) (overlapped three singlets). Preparation of N-(2,3,4,5,6-pentafluorobenzylidene)para-bromo-benzylamine, 1b. In a 100 mL three-necked round bottom flask equipped with a Teflon coated magnetic stir bar, 2,3,4,5,6-pentafluorobenzaldehyde (0.54 g, 2.75 mmol) and para-bromobenzyl amine (0.51 g, 2.74 mmol) were dissolved in absolute ethanol (30 mL). The resulting solution was evacuated and refilled with N2 three times. The solution was then heated to reflux (100 ˚C) for 3 h. The solution was cooled to room temperature and the solvent was removed under vacuum over 3 h. n-Pentane: Et3N (100: 6) (20 mL) was then added, and the resulting mixture was shaken. The n-Pentane: Et3N (100: 6) solution was collected F F N F Br F F 194 and underwent column purification. Column chromatography (SiO2, 70-230 mesh, n-pentane: Et3N = 100: 6 as eluant) provided imine product as a white solid in 84% yield. 1H NMR (acetonitrile-d3, 300 MHz): δ 8.53 (s, CH=N, 1H), 7.51-7.25 (m, aryl-H, 4H), 4.79 (s, CH2, 2H). 19F NMR (acetonitrile-d3, 282 MHz): δ -143.0 (m, 2F), -152.2 (m, 1F), -162.7 (m, 2F).  13C{1H} NMR (acetonitrile-d3, 100 MHz): δ 152.1 (q, J = 2.0 Hz), 147.1 (dddd, J = 254.6 Hz, J = 13.6 Hz, J = 7.0 Hz, J = 4.0 Hz), 143.2 (dtt, J = 253.6 Hz, J = 13.1 Hz, J = 5.0 Hz), 139.4 (s), 138.9 (dm, J = 253.6 Hz), 132.5 (s), 131.0 (s), 126.0 (t, J = 13.1 Hz), 121.5 (s), 66.0 (s) (Note: see NMR spectra on page 276). HRMS (EI) m/z calcd for C14H7F5N 79Br: 362.9682; found: 362.9684. Anal. Calcd for C14H7F5NBr: C, 46.18; H, 1.94; N, 3.85; found: C, 46.42; H, 1.70; N, 3.81. Preparation of [PtMe2F(SMe2)(C6F4CH=NCH2C6H4Br)], 4.14·SMe2. N Pt CH3 FH3C SMe2 F F F F CH2 Br In a 20 mL vial in the glovebox, N-(2,3,4,5,6-pentafluorobenzylidene)para- bromobenzylamine (12.6 mg, 0.034 mmol) and [Me2Pt(μ-SMe2)]2 (10.0 mg, 0.017 mmol) were dissolved in CD3CN (1.1 mL). The resulting solution was left at room temperature for at least 12 h and was then transferred into an NMR tube, which was fitted with a screw cap containing a septum. The solution was monitored by 1H and 19F NMR spectroscopy. Characterization of 4.14·SMe2: 1H NMR (acetonitrile-d3, 300 MHz): 195 δ 8.98 (s, JPt-H = 48.0 Hz, CH=N, 1H), 7.67-7.45 (m, resonances of aryl protons, 4H), 5.02 (m, CH2, 2H), 1.96 (s, JPt-H = 12.0 Hz, Pt-CH3, 6H), 1.50 (dd, JPt-H = 63.0 Hz, JF-H = 9.0 Hz, JF-H = 6.0 Hz, Pt-CH3, 3H), 0.80 (d, JPt-H = 66.0 Hz, JF-H = 6.0 Hz, Pt-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -128.2 (m, 1F), -139.4 (m, 1F), -148.0 (m, 1F), -162.8 (m, 1F), -253.5 (tm, JPt-F = 175.1 Hz, 1F). The geometry of this complex was confirmed by NOE study. (Note: see NMR spectra on pages 278-280) Transmetalation between [Pt(CD3)2F(SMe2)(C6F4CH=NCH2C6H4Br)] and Me2Zn. 1) Preparation of complex d6-4.14·SMe2 In a 20 mL vial, N-(2,3,4,5,6-pentafluorobenzylidene)para-bromobenzylamine (12.6 mg, 0.034 mmol), [(CD3)2Pt(μ-SMe2)]2 (10.2 mg, 0.017 mmol) and 1,3,5-tri- methoxybenzene (5.9 mg, 0.034 mmol) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred into an NMR tube, which was then fitted with a screw cap containing a septum and left at room temperature for 12 h. The solution was monitored by 1H and 19F NMR spectroscopy. Characterization of d6-4.14·SMe2: 1H NMR (acetonitrile-d3, 300 MHz): δ 8.98 (s, JPt-H = 47.4 Hz, CH=N, 1H), 7.64-7.52 (m, resonances of aryl protons, 4H), 5.01 (m, CH2, 2H), 1.96 (s, JPt-H = 12.6 Hz, S(CH3)2, partially overlapping with the resonance for acetonitrile-d3), no resonances for methyl-Pt groups. 19F NMR (acetonitrile-d3, 282 MHz): δ -128.3 (m, 1F), -139.5 (m, 1F), -148.2 (m, 1F), -163.0 (m, 1F), -254.5 (tm, JPt-F = 170.5 Hz, 1F). 196 2) Transmetalation of (complex d6-4.14·SMe2) with 1.2 Me2Zn to generate complex d6-4.15·SMe2 The solution with d6-4.14·SMe2 was added with Me2Zn (0.034 mmol, 17 µL of 2.0 M solution in toluene) by syringe. After a few minutes, the sample was monitored by 1H NMR and 19F NMR spectroscopy. Three resonances for methyl-Pt appeared in a 1: 1: 1 ratio and were ca. 2/3 the integration of the imine resonance (note: The integration for methyl-Pt should be 1/3 the integration of the imine resonance. It is not clear why the integration of resonances for methyl-Pt is 2/3 the integration of the imine resonance.). 1H NMR (acetonitrile-d3, 300 MHz): δ 9.03 (s, JPt-H = 38.7 Hz, CH=N, 1H), 4.94 (m, CH2, 2H), 1.91 (s, JPt-H = 13.2 Hz, S(CH3)2, 6H), 1.08 (s, JPt-H = 70.8 Hz, Pt-CH3, 2H), 0.49 (s, JPt-H = 70.2 Hz, Pt-CH3, 2H), 0.30 (s, JPt-H = 47.4 Hz, Pt-CH3, 2H). Preparation of 4.16·SMe2, mixture of isomers. In the glovebox, complex 4.14·SMe2 was prepared in an NMR tube as previously described. The solution was then transferred to a 20 mL vial with Ph2Zn (4.0 mg, 0.017 mmol). After 20 minutes, the resulting solution was then transferred back to the NMR tube. The solution was monitored by 1H and 19F NMR spectroscopy (see spectra on pages 281-282). This sample has many isomers, including I·SMe2 (27%) and II·SMe2 (34%). The characterization of complex 4.16·SMe2: HRMS (ESI negative ion mode) m/z calcd for C23H21NF4S 79BrPt (M-CH3): 694.0164; found: 694.0151. 197 Preparation of I·SMe2 and II·SMe2 from 4.14·SMe2, Ph2Zn, and 10 equiv. SMe2. In the glovebox, complex 4.14·SMe2 was prepared in an NMR tube as previously described. The NMR tube was then removed from the glovebox. SMe2 (24 μL, 0.34 mmol) was added into the NMR tube by syringe. The tube was then taken into the glovebox. In the glovebox, the solution in NMR tube was transferred to a 20 mL vial with Ph2Zn (4.0 mg, 0.017 mmol). After 20 minutes, the resulting solution was then transferred back to the NMR tube. The solution was monitored by 1H and 19F NMR spectroscopy. Complex I·SMe2 and II·SMe2 were main isomers. The yields of I·SMe2 and II·SMe2 were 43% and 39%, respectively. The geometries of complex I·SMe2 and II·SMe2 were assigned based on 1H NMR spectroscopy. For complex I·SMe2, the singlet at 0.70 ppm (JPt-H = 71.9 Hz) was assigned as the apical methyl on the basis of NOE data. The doublet at 1.28 ppm (JPt-H = 71.3 Hz, JF-H = 3.0 Hz) was assigned as the methyl in the same plane as the fluoroaryl group, consistent with the observed F-H coupling and NOE data.5 The multiplet at 7.39-7.41 ppm observed in NOE data was attributed to the phenyl group. For complex II·SMe2, the singlet at 0.57 ppm (JPt-H = 49.8 Hz) was assigned as the methyl trans to the fluoroaryl group. The doublet at 1.37 ppm (JPt-H = 71.6 Hz, JF-H = 1.8 Hz) was assigned as the methyl cis to the fluoroaryl group. The multiplet at 6.98-7.00 observed in NOE data was assigned as the phenyl group. (Note: see spectra on pages 283-288) 198 Preparation of I·SMe2 and II·SMe2 from 4.16·SMe2 and 10 equiv SMe2. Complex 4.16·SMe2 was prepared in an NMR tube as previously described. The NMR tube was removed from the glovebox. The sample was then added with SMe2 (24 μL, 0.34 mmol) by syringe. After a few minutes, the sample was monitored by 1H NMR and 19F NMR spectroscopy. Complexes I·SMe2 and II·SMe2 were main isomers, based on the 1H NMR spectrum. Preparation of N-(3,4,5,6-Pentafluoro-2-methylbenzylidene)para-Bromobenzyl- amine, 2b. In a 20 mL vial in the glovebox, N-(2,3,4,5,6-pentafluorobenzylidene)para- bromobenzylamine (64.0 mg, 0.174 mmol) and [Me2Pt(μ-SMe2)]2 (5.0 mg, 0.0087 mmol) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred into an NMR tube fitted with a screw cap containing a septum. Me2Zn (0.088 mmol, 44 µL of 2.0 M solution in toluene) was then added by syringe. The NMR tube was removed from the glovebox. The resulting solution was heated at 80 ºC. The sample was monitored by 1H NMR and 19F NMR spectroscopy. After heating for 18 h, the reaction was completed. The solution in NMR tube was cooled to room temperature and was transferred to a 20 F CH3 N F Br F F 199 mL vial. The solution was evaporated to dryness under vacuum. The remainder in the vial was washed by n-pentane: Et3N (100: 6) (20 mL) for three times. The solution was collected and filtered through glasswool. The filtrate was concentrated by rotary evaporation to provide crude imine product. Column chromatography (SiO2, 70-230 mesh, n-pentane:Et3N = 100:6 as eluent) provided imine product as a light yellow solid in 69% yield. 1H NMR (acetonitrile-d3, 300 MHz): δ 8.66 (s, CH=N, 1H), 7.53-7.28 (m, Ar-H, 4H), 4.80 (s, CH2, 2H), 2.42 (dd, JF-H = 3.0 Hz, JF-H = 1.2 Hz, aryl-CH3, 3H). 19F NMR (acetonitrile-d3, 282 MHz): δ -142.2 (dd, J = 19.8 Hz, J = 11.3 Hz, 1F), -144.7 (m, 1F), -154.8 (td, J = 19.8 Hz, J = 4.7 Hz), -160.8 (t, J = 19.8 Hz). 13C{1H} NMR (acetonitrile-d3, 150 MHz): δ 156.2 (d, J = 7.5 Hz), 148.2 (dm, J = 249.0 Hz), 146.9 (dm, J = 246.0 Hz), 142.0 (dddd, J = 253.5 Hz, J = 18.1 Hz, J = 12.1 Hz, J = 4.5 Hz), 139.8 (s), 139.5 (dddd, J = 247.5 Hz, J = 18.1 Hz, J = 12.1 Hz, J = 4.5 Hz), 132.5 (s), 131.0 (s), 123.2 (dd, J = 15.1 Hz, J = 6.0Hz), 121.4 (s), 120.5 (m), 65.9 (s), 11.8 (s). (Note: see NMR spectra on page 277). HRMS (EI) m/z calcd for C15H10F4N 79Br: 358.9933; found: 358.9932. Anal. Calcd for C15H10F4N 79Br: C, 50.02; H, 2.80; N, 3.89; found: C, 49.70; H, 2.71; N, 4.00. Reductive elimination from 4.16·SMe2, mixture of isomers. In the glovebox, complex 4.16·SMe2 was prepared in an NMR tube as previously described. The NMR tube was then removed from the glovebox. The solution was heated at 60 ˚C. This reaction was monitored by 1H NMR and 19F NMR spectroscopy. After 200 heating at 60 ˚C for 19 h, reductive elimination was completed (see spectra on 286-287). Based on 1H NMR spectrum, the main organic products were 2b and toluene. The yield of 2b and toluene was 50% and 12%, respectively. The yield of 2b was based on integration of the resonance for the methyl group of 2b with integration of the resonance for aryl protons of internal standard (1,3,5-trimethoxybenzene). The yield of toluene was based on integration of the methyl resonance of toluene with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. The main Pt species was complex 4.17. The yield of complex 4.17 was determined by the following procedure. After heating at 60 ˚C for 19 h, the sample in NMR tube was cooled to room temperature and was taken into the glovebox. The solution was evaporated to dryness under vacuum in the glovebox. The residue was dissolved in dichloromethane-d2. The tube was then removed from the glovebox. The resulting solution was added with excess SMe2 (5 μL, 0.069 mmol) by syringe. The yield of [MePhPt(SMe2)2] was based on integration of the methyl resonance of S(CH3)2 coordinated to Pt with the aryl resonance of the internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Reductive elimination from complexes I·SMe2 and II·SMe2. In the glovebox, complexes I·SMe2 and II·SMe2 were prepared in NMR tube as previously described. The tube was then removed from the glovebox and was heated at 60 ˚C. The reaction was monitored by 1H NMR and 19F NMR spectroscopy. After heating at 60 ˚C for 83 h, the yield of 2b and toluene was 19% and 14%, respectively 201 (see spectra on pages 291-292). The yield of 2b was based on integration of the resonance for the methyl group of 2b with integration of the resonance for aryl protons of internal standard (1,3,5-trimethoxybenzene). The yield of toluene was based on integration of the methyl resonance of toluene with the aryl resonance of internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. Evidence of formation of complex MePtPh(SMe2) in the reductive elimination from complex 4.16·SMe2, mixture of isomers. Many species showed up in the 1H NMR spectrum of the synthetic [MePtPh(SMe2)]2 in CD2Cl2. The major species was cis-MePtPh(SMe2)2. 24b When the sample was added with excess SMe2, two main species cis-MePtPh(SMe2)2 and trans-MePtPh(SMe2)2 were in the spectrum. Cis-MePtPh(SMe2)2: 1H NMR (dicholoromethane-d2, 400 MHz): δ 2.39 (s, JPt-H = 22.8 Hz, S(CH3)2), the resonance for the other S(CH3)2 overlapped with free S(CH3)2, 0.57 (s, JPt-H = 85.2 Hz, Pt-CH3). Trans-MePtPh(SMe2)2: 1H NMR (dicholoromethane-d2, 400 MHz): δ 2.35 (s, JPt-H = 23.2 Hz, S(CH3)2), the resonance for the other S(CH3)2 overlapped with free S(CH3)2, 0.51 (s, JPt-H = 83.2 Hz, Pt-CH3). (Note: see spectra on page 293) Comparison between the 1H NMR spectrum of reductive elimination from complex 4.16·SMe2 and the synthetic [MePtPh(SMe2)]2 in CD3CN indicated that MePtPh(SMe2)L was formed. The formation of [MePtPh(SMe2)]2 in the reductive elimination from 4.16·SMe2 was also confirmed by the enhancement of the resonances for 202 MePtPh(SMe2)(L) when the reductive elimination sample was added with [MePtPh(SMe2)]2. (Note: see spectra on page 295) In addition, the solution with reductive elimination products was evaporated to dryness under vacuum in the glovebox. The remainder in NMR tube was dissolved in CD2Cl2. The tube was then removed from the glovebox. The solution was added with excess SMe2 ((5 μL, 0.069 mmol) by syringe. The sample was monitored by monitored by 1H NMR spectroscopy (see spectrum on page 294). The resonances for MePtPh(SMe2)2 were same as literature values.24b Reductive elimination from complex 4.21·SMe2 (a) Preparation of 4.20·SMe2 In a 20 mL vial in the glovebox, N-(2,4,6-trifluorobenzylidene)benzylamine (8.5 mg, 0.034 mmol), [Me2Pt(μ-SMe2)]2 (10.0 mg, 0.017 mmol) and 1,3,5-trimethoxybenzene (5.7 mg, 0.034 mmol) were dissolved in CD3CN (1.1 mL). The resulting solution was left at room temperature and was then transferred into an NMR tube fitted with a screw cap containing a septum. The tube was then removed from the glovebox. The solution was monitored by 1H and 19F NMR spectroscopy. At room temperature for 24 h, the reaction was completed. Characterization data of complex 4.20·SMe2 were consistent with literature values.15 203 (b) Preparation of 4.21·SMe2 In the glovebox, the NMR tube with 4.21·SMe2 was transferred to a 20 mL vial with Ph2Zn (4.0 mg, 0.017 mmol). After a few minutes, the resulting solution was then transferred back to the NMR tube. The tube was then removed from the glovebox. The sample was monitored by 1H NMR and 19F NMR spectroscopy. Complex 4.21·SMe2 was a mixture of many isomers. NOE data on geometry of complex 4.21·SMe2 isomers is not conclusive. (c) Reductive elimination from 4.21·SMe2 The solution with complex 4.21·SMe2 isomers was heated at 60 ˚C. The solution was monitored by 1H NMR and 19F NMR spectroscopy. The reaction was completed at 60 ˚C for 30 min. The main products were methylated imine 2c and phenylated imine 3c. The yield of 2c and 3c was 58% and 12%, respectively. The yield of 2c was based on integration of the resonance for the methyl group of 2c with integration of the resonance for aryl protons of internal standard (1,3,5-trimethoxybenzene). The yield of 3c was based on integration of the CH2 resonance of 3c with the aryl resonance of internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. The characterization data of imine 2c were consistent with literature values.13 Characterization of N-(4,6-difluoro-2-phenylbenzylidene)benzylamine 3c: 1H NMR (acetintrile-d3, 400 MHz): δ 8.19 (s, 1H), 4.63 (s, 2H), the resonances for aryl-H overlap 204 with those for imine 2c. HRMS (EI) m/z calcd for C20H14F2N (M-H): 306.1094; found: 306.1064. Reductive elimination from complex 4.23·SMe2 (a) Preparation of 4.22·SMe2 In a 20 mL vial in the glovebox, N-(2,3,4,5,6-pentafluorobenzylidene)para- bromobenzylamine (12.7 mg, 0.034 mmol), [MePtPh(μ-SMe2)]2 (16.8 mg, 0.024 mmol) and 1,3,5-trimethoxybenzene (5.9 mg, 0.034 mmol,) were dissolved in CD3CN (1.1 mL). The resulting solution was transferred into an NMR tube fitted with a screw cap containing a septum. The tube was then removed from the glovebox. The solution was monitored by 1H and 19F NMR spectroscopy. The reaction was completed at room temperature for 3 days. Complex 4.22·SMe2 was found to be a mixture of some isomers. Two types of Pt(IV)-F species appeared on 19F NMR spectroscopy. Complex 4.22·SMe2 (A): δ -128.0 (m, 1F), -138.4 (m, 1F), -146.6 (m, 1F), -161.8 (m, 1F), -238.6 (tm, JPt-F = 229.0 Hz, 1F); Complex 4.22·SMe2 (B): δ -128.3 (m, 1F), -139.4 (m, 1F), -148.1 (m, 1F), -162.9 (m, 1F), -253.5 (broden triplet, 1F). (b) Preparation of 4.23·SMe2 The NMR tube with complex 4.22·SMe2 was taken into the glovebox. The solution of complex 4.22·SMe2 was transferred to a 20 mL vial with Ph2Zn (4.0 mg 0.018 mmol). After 20 min, the resulting solution was transferred back to the NMR tube. The solution 205 was monitored by 1H and 19F NMR spectroscopy. The characterization of complex 4.23·SMe2 was not conclusive. (c) Reductive elimination from 4.23·SMe2 The NMR tube was heated at 60 ˚C and was monitored by 1H and 19F NMR spectroscopy. The reaction was completed at 60 ˚C for 87 h. The predominant products are 2b in 46 % yield and toluene in 19% yield. The yield of 2b was based on integration of the resonance for the methyl group of 2b with integration of the resonance for aryl protons of internal standard (1,3,5-trimethoxybenzene). The yield of toluene was based on integration of the methyl resonance of toluene with the aryl resonance of internal standard (1,3,5-trimethoxybenzene) in the 1H NMR spectrum. 206 4.5 References 1) (a) Ghosh, R.; Emge, T. J.; Krogh-Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc. 2008, 130, 11317–11327. (b) Liu, Q.; Duan, H.; Luo, X.; Tang, Y.; Li, G.; Huang, R.; Lei, A. Adv. Synth. Catal. 2008, 350, 349-354. (c) Cárdenas, D. J. Angew. Chem. Int. Ed. 1999, 38, 3018-3020. (d) Cárdenas, D. J. Angew. Chem. Int. Ed. 2003, 42, 384-387. (e) Terao, J.; Kambe, N. Acc. Chem. Res. 2008, 41, 1545–1554. 2) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F.; Stang, P. J., Eds.; Wiley-VCH: Weinheim, Germany, 1998. (b) Metal-Catalyzed Cross-Coupling Reactions, 2nd ed.; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH: New York, 2004. (c) Ananikov, V. P.; Musaev, D. G.; Morokuma, K. Organometallics 2005, 24, 715-723. 3) (a) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259-281. (b) Suzuki, A. Chem. Commun. 2005, 4759-4763. (c) Littke, A. F.; Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176-4211. (d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457-2483. (e) Hartwig, J. F. Pure Appl. Chem. 1999, 71, 1417-1423. (f) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-209. (g) Negishi, E.-I.; Anastasia, L. Chem. Rev. 2003, 103, 1979-2017. 4) For a review on cross-coupling of alkylboronic acid, see: Doucet, H. Eur. J. Org. Chem. 2008, 2013-2030. 5) a) Pérez-Rodríguez, M.; Braga, A. A. C.; Garcia-Melchor, M.; Pérez-Temprano, M. H.; Casares, J. A.; Ujaque, G.; de Lera, A. R.; Álvarez, R.; Maseras, F.; Espinet, P. J. 207 Am. Chem. Soc. 2009, 131, 3650-3657. (b) Luo, X.; Zhang, H.; Duan, H.; Liu, Q.; Zhu, L.; Zhang, T.; Lei, A. Org. Lett. 2007, 9, 4571-4574. (c) Liu, Q.; Duan, H.; Luo, X.; Tang, Y.; Li, G.; Huang, R.; Lei, A. Adv. Synth. Catal. 2008, 350, 349-354. 6) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 13016-13027; (b) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936-1947. (c) Low, J. J.; Goddard, W. A., III. J. Am. Chem. Soc. 1986, 108, 6115-6128. (d) Tatsumi, K.; Hoffmann, R.; Yamaoto, A.; Stille, J. K. Bull. Chem. Soc. Jpn. 1981, 54, 1857-1867. 7) (a) Gandelman, M.; Shimon, L. J.; Milstein, D. Chem –Eur.J. 2003, 9, 4295-4300; (b) Calhorda, M. J.; Brown, J. M.; Cooley, N. A. Organometallics 1991, 10, 1431-1438. (c) Maitlis, P. M.; Long, H. C.; Quyoum, R.; Turner, M. L.; Wang, Z-Q. Chem. Comm. 1996, 1-8. 8) Gatard, S.; Çelenligil-Çetin, R.; Guo, C.; Foxman, B. M.; Ozerov, O. V. J. Am. Chem. Soc. 2006, 128, 2808–2809. 9) (a) Ozawa, F.; Ito, T.; Nakamura, Y.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1981, 54, 1868-1880. (b) Ozawa, F.; Kurihara, K.; Yamamoto, T.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1985, 58, 399-340. (c) Loar, M. K.; Stille, J. K. J. Am. Chem. Soc. 1981, 103, 4174–4181. (d) Ozawa, F.; Kurihara, K.; Fujimoro, M.; Hikada, T.; Toyoshima, T.; Yamamoto, A. Organometallics 1989, 8, 180-188. 10) (a) Yu, Z.-X.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2004, 126, 9154-9155. (b) Yu, Z.-X.; Cheong, P. H.-Y.; Liu, P.; Legault, C. Y.; Wender, P. A.; Houk, K. N. J. Am. Chem. Soc. 2008, 130, 2378–2379. 208 11) (a) Madison, B. L.; Thyme, S. B.; Keene, S.; Williams, B. S. J. Am. Chem. Soc. 2007, 129, 9538–9539. (b) Hwang, S.; Woo, H. Y.; Cho, H.; Jang, J. Bull. Korean Chem. Soc. 2008, 29, 537-538. 12) Wang, T.; Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629–5631. 13) Crespo, M.; Martinez, M.; Sales, J. Organometallics 1993, 12, 4297-4304. 14) Wang, T.; Love, J. A. Organometallics 2008, 27, 3290-3296. 15) It is believed that reductive elimination of group in the apical position. See reference 11a and (a)Tatsumi, K.; Nakamura, A.; Komiya, S.; Yammoto, A.; Yamamoto, T. J. Am. Chem. Soc. 1984, 106, 8181–8188. (b)Morken, J. P.; Didiuk, M. T.; Hoveyda, A. H. Tetrahedron Lett. 1996, 21, 3613-3616. (c)Komlya, S.; Abe, Y.; Yamamoto, A.; Yamamoto, T. Organometallics, 1983, 2, 1466-1488. 16) (a)Isotopic study of transmetalation reaction between (CD3)2PtF(SMe2) and Me2Zn indicated that the reaction completed in few minutes and there are three equivalent methyl-Pt resonances appearing, the integration of resonances is 2/3 the integration of the imine resonance. For isomerization literatures, see: (b) Williams, B. S.; Goldberg, K. J. Am. Chem. Soc. 2001, 123, 2576-2587. (c) Font-Bardia, M.; Gallego, C.; Gonzalez, G.; Martinez, M.; Merbach, A. E.; Solans, X. Dalton Trans. 2003, 1106-1113. (d)Yahav-Levi, A.; Goldberg, I.; Vigalok, A.; Vedernikov, A. N. J. Am. Chem. Soc. 2008, 130, 724-731. 17) The transmetallation reaction between Pt-F and Ph2Zn was confirmed by the disappearance of Pt-F species, appearance of new aryl fluorine resonances. ESI (-) 209 MS (m/Z = 694, M - 15) indicated that complex 4.14·SMe2 was formed. Another unidentified Me3Pt complex was formed along many isomers of 4.14·SMe2. 18) (a) van Asselt, R.; Rjinberg, E.; Elsevier, C. J. Organometallics 1994, 13, 706–720. (b) Clegg, D. E.; Hall, J. R.; Swile, G. A. J. Organomet. Chem. 1972, 38, 403–420. (c) Ruddick, J. D.; Shaw, B. L. J. Chem. Soc. A 1969, 2969–2970. 19) The ratio between methylated imine 2b and toluene is underestimated because some 2b underwent further C-F activation. The ratio between 2b and toluene resulting from reductive elimination from Me2Pt(IV)Ph(SMe2) in presence of 1 equiv of 2,4,6-trifluorobenzyl imine is 4.6:1, in which 2,4,6-trifluorobenzyl imine trapped MePtPh(L) to form Pt-F species. (The yield of 2b and toluene is 55% and 12% respectively) 20) Yields are given as an average of several runs. 21) The yield of [MePhPt(SMe2)2] was determined as following: After heating at 60 ˚C for 19 h, the acteonitrile-d3 was removed. The resulting residue was dissolved in dichloromethane-d2, into which excess SMe2 (5 μL, 0.069 mmol) was injected by syringe. The yield of [MePhPt(SMe2)2] was based on the integration of the resonance for SMe2 that coordinates to platinum. 22) See the comparison information in experimental data. 23) Synthesis of [MePtPh(SMe2)]2 was referenced to the following literature: (a) Scott, J. D.; Puddephatt, R. J. Organometallics 1983, 2, 1643-1648. (b) Johansson, L.; Tilset, M.; Labinger, J. A.; Bercaw, J. E. J. Am. Chem. Soc. 2000, 122, 10846-10855. 210 24) A methyl substituent has a greater trans influence than phenyl; this phenomenon is typically ascribed to the greater electron-donating ability of the methyl group. 25) Hill, G. S.; Irwin, M. J.; Levy, C. J.; Rendina, L. M.; Puddephatt, R. J.; Andersen, R. A.; McLean, L. Inorg. Syn. 1998, 32, 149-151. 26) Krasovskiy, A.; Knochel, P. Synthesis 2006, 890-891. 211 CHAPTER FIVE: CONCLUSIONS AND FUTURE WORK 5.1 Conclusions We have successfully developed the first Pt(II)-catalyzed cross-coupling of polyfluoroaryl imines with Me2Zn to provide mono-methylated fluoroimines. 1 Diverse functional groups are well-tolerated. This methodology has high selectivity for activation of the C-F bond ortho to the imine nitrogen even in the presence of much weaker aryl C-Br and C-CN bonds. It is noteworthy to point out that we provided a new methodology to catalytically form sp2-sp3 C-C bonds in C-F cross-coupling. Moreover, a general mechanism for the Pt-catalyzed methylation of polyfluoroaryl imines has been established.2 The mechanism involves C-F activation as a fundamental step, followed by transmetalation and reductive elimination. C-F activation is much slower than either the transmetalation or reductive elimination steps. Both transmetalation and reductive elimination occur from five-coordinate Pt(IV) species. Furthermore, a six-coordinate Me3Pt(IV) species, assuming to be the resting state of catalytic cycle, was observed and isolated. The structure of the Me3Pt(IV) species was confirmed by X-ray analysis and NOE (1H) studies. In addition, an unusual six-membered ring Pt(II) complex through C-H activation of a methylation products was obtained. This species may open the door for tandem cross-coupling and C-H functionalization. We also have demonstrated an unexpected preference of Csp2-Csp3 coupling over Csp2-Csp2 coupling from Pt(IV) complexes, which is explained by the apparent slower 212 rate of Csp2-Csp2 reductive elimination compared to Csp2-Csp3 reductive elimination.3 This result, in conjunction with recent literature reports, challenges the prevailing view that Csp2-Csp2 coupling should always be much faster than Csp2-Csp3 coupling. These studies will hopefully provide new directions for organic and organometallic chemistry. 5.2 Near Future work (next 5 years) We have developed Pt(II)-catalyzed C-F cross-coupling, investigated the mechanism and provided examples with unusual preference for Csp2-Csp3 coupling over Csp2-Csp2 coupling. However, the chemistry of catalytic C-F cross-coupling involved platinum complex is still in the early stages of development. This section details future work to be pursued by other members of the Love group in the near future. The exploration of directing groups other than imines will expand the substrate scope. Currently, Lauren Keyes in our group is studying other directing groups, including pyridine, imidazole and oxazole. To expand the scope from methylation, other organometallic reagents, e.g. Zn-Et, Zn-Ph and Zn-CN, are also being studied. To date, the initial results indicate that some of these reagents are successful in the cross-coupling of polyfluoro arenes catalyzed by Pt(II). In addition, we have achieved the synthesis of aryl ethers using siloxanes reagents.4 To expand the substrate scope, another approach is to use other metal complexes that are capable of catalytic cross-coupling of aryl fluorides. Alex Sun in the Love group has discovered that certain Pt(0) complexes can catalyze the 213 cross-coupling of aryl fluorides. A variety of LnPt(0) complexes will be examined for their ability to catalyze cross-coupling and hydrodefluorination reactions. The second area of investigation involves detailed kinetic studies of Pt(II)-catalyzed C-F cross-coupling reactions, as well as the fundamental reaction steps. Such studies will establish reaction orders in each component and lead to the full understanding of the cross-coupling reaction. The third area of exploration is the study of electronic effects in the reductive elimination from Me2Pt(IV)Ph and MePt(IV)Ph2 complexes. Herein, we expect ratios of the reductive eliminants (e.g. Csp2-Csp3 coupling and Csp2-Csp2 coupling products) would be different for different imines. Such studies might involve kinetic studies on reductive elimination from the Me2Pt(IV)Ph complexes. In these studies, we will learn how electronic effects affect reductive elimination products of Pt(IV) complexes. In addition, these studies will hopefully be helpful to design new catalytic system. The fourth area is the application of the Pt(II)-catalyzed C-F cross-coupling of polyfluoroarenes in the synthesis of functionalized fluoroarene building blocks for bioactive molecules or potential drugs. The final area is to explore tandem aryl fluoride cross-coupling and C-H functionalization in one pot. This proposal is based on the observation that the methyl product of cross-coupling underwent stoichiometric C-H activation, as described in Chapter 3. 214 5.3 Future work (next 10 years) Reductive elimination is of importance in organic and organometallic chemistry, however, studies on reductive elimination are still in the early stage. Although electronic and steric effects on the reductive elimination have been studied in recent years, the explanations are limited to a few examples.3,5,6 To get a more complete picture of the factors controlling the reductive elimination from late transition metal complexes, it is required to systematically explore the rates of reductive elimination of a series of late metal complexes with variable steric and electronic properties. These studies will hopefully be helpful in the design of new catalytic reaction systems and will hopefully provide a model for predicting reactivity. Known methods for the cross-coupling of polyfluoroarenes only work on limited substrates. To expand the substrates, new catalysis systems are desired. The following ways to explore new catalysts in the field: (a) the synthesis of new ligands with strong electron donating ability because increasing electron density on the metal is essential in the C-F activation; (b) application of other late transition metal complexes (e.g. Rh, Ir, Ru and Os) beyond the traditional boundaries of Ni, Pd and Pt. (c) the application of early transition metal complexes, Lanthanoids and Actinoids metal complexes. 215 5.4 References 1) Wang, T.; Alfonso, B. J.; Love, J. A. Org. Lett. 2007, 9, 5629–5631. 2) Wang, T.; Love, J. A. Organometallics 2008, 27, 3290-3296. 3) Wang, T.; Love, J. A. (manuscripts) 2009. 4) Buckley, H. L.; Wang, T.; Tran, O.; Love, J. A. Organometallics 2009, 28, 2356-2359. 5) (a) Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 13016-13027; (b) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936-1947. 6) Ghosh, R.; Emge, T. J.; Krogh-Jespersen, K.; Goldman, A. S. J. Am. Chem. Soc. 2008, 130, 11317–11327. 216 APPENDICES Appendix I: characterization data for chapter two In this appendix I, the characterization NMR data for chemicals in chapter two are listed. 217 w71026-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1 .9 4 0 w71026-1F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w71026-1C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.390 1a, 1H NMR (acetonitrile-d3, 300 MHz) 1a, 19F NMR (acetonitrile-d3, 282 MHz) 1a, 13C{1H} NMR (acetonitrile-d3, 100 MHz) F FF N 218 w70803-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 -1.0 Chemical Shift (ppm) 2 .0 5 0 w70803-1F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70803-1C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 2 9 .9 2 0 1b, 1H NMR (acetone-d6, 300 MHz) 1b, 19F NMR (acetone-d6, 282 MHz) 1b, 13 {1H} NMR (acetone-d6, 100 MHz) F FBr N 219 w70809-4H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 -1.0 Chemical Shift (ppm) 2 .0 5 0 w70809-4F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70809-4C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Chemical Shift (ppm) 2 9 .9 2 0 1c, 1H NMR (acetone-d6, 300 MHz) 1c, 19F NMR (acetone-d6, 282 MHz) 1c, 13C{1H} NMR (acetone-d6, 75 MHz) F FNC N 220 w70726-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70726-1F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70726-1C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.390 1d, 1H NMR (acetonitrile-d3, 400 MHz) Chapter two: 1d, 19F NMR (acetonitrile-d3, 282 MHz) Chapter two: 1d, 13C{1H} NMR (acetonitrile-d3, 100 MHz) F F N 221 w70508-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 2. 05 0 w70508-2F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70508-2C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 2 9 .9 2 0 1e, 1H NMR (acetone-d6, 400 MHz) 1e, 19F NMR (acetone-d6, 282 MHz) 1e, 13C{1H} NMR (acetone-d6, 100 MHz) F FF N 222 w70514-4H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 2. 05 0 w70514-4F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) 1f(13C).esp 230 220 210 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 0 -10 -20 Chemical Shift (ppm) 16 5. 41 5 16 5. 21 0 16 3. 87 7 16 1. 84 4 16 0. 77 8 16 0. 58 0 16 0. 45 8 15 2. 08 2 13 7. 88 1 13 1. 59 9 12 9. 52 7 12 0. 96 1 11 0. 68 1 11 0. 56 7 11 0. 50 6 11 0. 33 1 10 1. 36 1 10 0. 96 5 10 0. 62 2 77 .6 56 77 .2 30 76 .8 04 65 .6 94 1g, 1H NMR (acetone-d6, 300 MHz) 1g, 19F NMR (acetone-d6, 282 MHz) 1g, 13C{1H} NMR (CDCl3, 75 MHz) F FF N Br 223 w70406-4H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 2. 05 0 w70406-4F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70406-4C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 29.920 1h, 1H NMR (acetone-d6, 300 MHz) 1h, 19F NMR (acetone-d6, 282 MHz) 1h, 13C{1H} NMR (acetone-d6, 75 MHz) F F N F 224 w70724-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70724-2F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70724-2C2_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.39 0 1i, 1H NMR (acetonitrile-d3, 300 MHz) 1i, 19F NMR (acetonitrile-d3, 282 MHz) Chapter two: 1i, 13C{1H} NMR (acetonitrile-d3, 100 MHz) F Cl N F 225 w70406-3H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 2. 05 0 w70406-3F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70406-3C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Chemical Shift (ppm) 2 9 .9 2 0 F F N F F 1j, 1H NMR (acetone-d6, 300 MHz) 1j, 19F NMR (acetone-d6, 282 MHz) 1j, 13C{1H} NMR (acetone-d6, 75 MHz) 226 w71110-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w71110-2F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w71110-2C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.390 1k, 1H NMR (acetonitrile-d3, 300 MHz) 1k, 19F NMR (acetonitrile-d3, 282 MHz) 13C{1H} NMR (acetonitrile-d3, 100 MHz) F F N F F F 227 w70810-4H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 -1.0 Chemical Shift (ppm) 2. 05 0 w70810-4F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70810-4C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 2a, 1H NMR (acetone-d6, 300 MHz) F CH3F N 228 w70809-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70809-1F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70809-1C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.390 2b, 1H NMR (acetonitrile-d3, 300 MHz) 2b, 19F NMR (acetonitrile-d3, 282 MHz) 2b, 13C{1H} NMR (acetonitrile-d3, 75 MHz) F CH3Br N 229 w70818-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70818-2F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70820-1C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 29.920 2c, 1H NMR (acetonitrile-d3, 300 MHz) F CH3NC N 2c, 19F NMR (acetonitrile-d3, 282 MHz) 2c, 13C{1H} NMR (acetone-d6, 100 MHz) 230 w70811-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70811-1F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70510-4C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.390 2e, 1H NMR (acetonitrile-d3, 300 MHz) 2e, 9F NMR (acetonitrile-d3, 282 MHz) 2e, 13C{1H} NMR (acetonitrile-d3, 100 MHz) F CH3F N 231 w70513-3H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 2. 05 0 w70513-3F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70513-3C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 29.920 2g, 1H NMR (acetone-d6, 400 MHz) 2g, 19F NMR (acetone-d6, 282 MHz) 2g, 13C{1H} NMR (acetone-d6, 100 MHz) F CH3F N Br 232 w70811-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 -1.0 Chemical Shift (ppm) 2. 05 0 w70811-2F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70811-2C_001000fid 216 208 200 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 29.920 2h, 1H NMR (acetone-d6, 300 MHz) F CH3 N F 2h, 19F NMR (acetone-d6, 282 MHz) 2h, 13C{1H} NMR (acetone-d6, 100 MHz) 233 w70905-1pdtH_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70905-1pdtF_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70905-1pdtC_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1. 39 0 2j, 1H NMR (acetonitrile-d3, 400 MHz) 2j, 19F NMR (acetonitrile-d3, 282 MHz) 2j, 13C{1H} NMR (acetonitrile-d3, 100 MHz) F CH3 N F F 234 w70510-6H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 w70510-6F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) w70510-6C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 Chemical Shift (ppm) 1.390 2k, 13C{1H} NMR (acetonitrile-d3, 100 MHz) 2k, 19F NMR (acetonitrile-d3, 282 MHz) 2k, 1H NMR (acetonitrile-d3, 400 MHz) F CH3 N F F F 235 The ESI-MS data of complex 2.3, expected MS: 594, observed MS: 594. 236 Appendix II: characterization data for chapter three In this appendix part II, NMR spectra of reactions, the characterization NMR data for chemicals and X-ray data of 3.16 and 3.17 are listed. 1,3,5-Trimethoxybenzene was utilized as the internal standard in 1H NMR spectrum. 237 1H NMR spectrum of complex 3.7 prepared from 2.2 and Me2Zn w70621-1H_001000fid.esp 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) -0 .8 63 0. 08 2 0. 15 9 0. 23 6 0. 36 5 0. 48 6 0. 63 1 0. 74 6 0. 86 2 1. 75 6 1. 77 8 1. 94 0 2. 33 4 4. 81 1 4. 98 5 8. 56 3 8. 79 3 8. 86 0 8. 92 6 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F (CH3)2Zn rt, 5 min NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F Yield > 95%, based on amount of 2.2 formed from the reaction of 1a and 2.1 δ 8.60 (s, CH=N for 3.7), 8.56 (s, CH=N for 1a)   4.99 (s, CH2 for 3.7), 4.81 (s, CH2 for 1a)   1.78 (s, S(CH3)2 bound to Pt for 3.7)   0.75 (Pt satellite peaks: 0.86 and 0.63, CH3-Pt for 3.7)   0.36 (Pt satellite peaks: 0.49 and 0.24, CH3-Pt for 3.7)   0.16 (Pt satellite peaks: 0.24 and 0.08, CH3-Pt for 3.7)   -0.86 (s, CH3ZnF) (300 MHz, rt, CD3CN) Toluene (from Me2Zn solution) Internal standard FF F N Ph 1a Aryl protons, overlapping peaks Internal standard Solvent CD3CN: δ 1.94 Free S(CH3)2: δ 2.08 238 19F NMR spectrum of complex 3.7 prepared from 2.2 and Me2Zn w70621-1F_001000fid -92 -94 -96 -98 -100 -102 -104 -106 -108 -110 -112 -114 -116 -118 Chemical Shift (ppm) -1 15 .2 35- 11 5. 19 5 -1 15 .1 47 -1 12 .2 70 -1 12 .2 47 -1 11 .5 95 -1 11 .5 63 -1 11 .5 23 -1 10 .9 59 -1 10 .9 27 -1 10 .8 88 -1 10 .8 40 -1 09 .6 48 -1 09 .6 24 -1 09 .5 92 -1 07 .6 69 -1 07 .5 97-1 04 .5 14- 10 4. 46 6 -1 04 .3 39 -1 04 .3 07 -1 04 .2 84 -1 04 .2 52 -1 02 .4 95 -1 02 .4 64 -1 02 .4 32 -9 8. 91 9 -9 8. 88 0-9 8. 84 8 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F (CH3)2Zn rt, 5 min NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F Yield > 95%, based on amount of 2.2 formed from the reaction of 1a and 2.1 δ  -104.3 (m, aryl-F for 3.7)    -111.6 (m, aryl-F for 3.7)    -104.4 (m, aryl-F for 1a)    -109.6 (m, aryl-F for 1a) Unknown compounds: δ  -98.8 (m), -102.5 (m)    -107.7 (m), -110.97 (m)    -112.3 (m), -115.2 (m) (282 MHz, rt, CD3CN) FF F N Ph 1a 239 Observation of Me3Pt(IV) during catalytic conversion of 1a to 2a w70925-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) -0 .7 97 0. 12 0 0. 19 6 0. 28 50 .4 06 0. 52 9 0. 77 8 0. 89 4 1. 74 9 1. 77 1 1. 94 0 2. 54 6 4. 82 2 4. 98 4 8. 55 4 8. 71 0 8. 86 5 8. 93 1 FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CH3CN 60 °C 1a 2a Me3Pt(IV) species: δ 8.87 (s, JPt-H = 39 Hz, CH=N), 4.98 (m, CH2Ph), 1.77 (s, JPt-H = 12 Hz, S(CH3)2), 0.78 (s, JPt-H = 69 Hz, CH3-Pt), 0.41 (s, JPt-H = 73 Hz, CH3-Pt), 0.20 (s, JPt-H = 46 Hz, CH3-Pt) δ 8.56 (s, CH=N for 1a)   8.72 (s, CH=N for 2a)   2.55 (s, CH3 for 2a)   2.09 (s, free S(CH3)2)   1.94 (m, CD3CN)   -0.80 (s, (CH3)2Zn) Toluene (from Me2Zn solution) 1H NMR spectrum (300 MHz, rt, CD3CN) Aryl protons, overlapping peaks CH2 for 1a and 2a 240 Observation of Me3Pt(IV) during catalytic conversion of 1a to 2a (0 – 1 ppm) w70925-1H_001000fid 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 Chemical Shift (ppm) 0. 12 0 0. 19 6 0. 27 1 0. 28 5 0. 40 6 0. 52 9 0. 66 2 0. 77 8 0. 89 4 FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CH3CN 60 °C 1a 2a 1H NMR spectrum (300 MHz, rt, CD3CN) Me3Pt(IV): δ 0.78 (s, JPt-H = 69 Hz, CH3-Pt) 0.41 (s, JPt-H = 73 Hz, CH3-Pt) 0.20 (s, JPt-H = 46 Hz, CH3-Pt) 241 Observation of Me3Pt(IV) during catalytic conversion of 1a to 2a (8.0 – 10 ppm) w70925-1H_001000fid.esp 9.9 9.8 9.7 9.6 9.5 9.4 9.3 9.2 9.1 9.0 8.9 8.8 8.7 8.6 8.5 8.4 8.3 8.2 8.1 8.0 Chemical Shift (ppm) 8. 55 4 8. 71 0 8. 80 0 8. 86 5 8. 93 1 FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CH3CN 60 °C 1a 2a CH=N for Me3Pt(IV) in catalysis: δ 8.87 (Pt satellite peaks: 8.93 and 8.80) CH=N for 2a: δ 8.71 CH=N for 1a: δ 8.56 1H NMR spectrum (300 MHz, rt, CD3CN) 242 Observation of Me3Pt(IV) during catalytic conversion of 1a to 2a w70925-1F_001000fid -92 -94 -96 -98 -100 -102 -104 -106 -108 -110 -112 -114 -116 -118 Chemical Shift (ppm) -1 13 .7 01 -1 13 .6 70 -1 13 .6 38 -1 11 .7 15 -1 11 .6 75 -1 09 .7 36 -1 09 .7 12 -1 09 .6 80 -1 08 .1 70 -1 08 .1 30 -1 04 .4 67 -1 04 .4 35 FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CH3CN 60 °C 1a 2a Aryl fluorides for Me3Pt(IV) in catalysis: δ -104.3 (m) and -111.7 (m) Aryl fluorides for 2a: δ -108.1 (quartet, JF-F = 8.5 Hz, JF-H = 8.5 Hz, 1F) -113.7 (t, JF-F = 8.5 Hz, JF-H = 8.5 Hz, 1F) Aryl fluorides for 1a: δ -104.4 (m, 1F) and -109.6 (t, JF-F = 9.0 Hz, JF-H = 9.0 Hz, 2F) 19F NMR spectrum (282 MHz, rt, CD3CN) 243 Observation of Me3Pt(IV) during catalytic conversion of 1a to 2a (-105 ppm – -103 ppm) w70925-1F_001000fid -103.1 -103.2 -103.3 -103.4 -103.5 -103.6 -103.7 -103.8 -103.9 -104.0 -104.1 -104.2 -104.3 -104.4 -104.5 -104.6 -104.7 -104.8 -104.9 Chemical Shift (ppm) -1 04 .4 67 -1 04 .4 35 -1 04 .3 87 -1 04 .3 71 -1 04 .3 56 FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CH3CN 60 °C 1a 2a 19F NMR spectrum (282 MHz, rt, CD3CN) Aryl fluoride for Me3Pt(IV) in catalysis: δ -104.37 (m) Aryl fluoride for 1a: δ -104.44 (m) 244 Observation of Me3Pt(IV) during catalytic conversion of 1a to 2a (-114 ppm – -110 ppm) w70925-1F_001000fid -110.5 -111.0 -111.5 -112.0 -112.5 -113.0 -113.5 -114.0 Chemical Shift (ppm) -1 13 .7 01 -1 13 .6 70 -1 13 .6 38 -1 11 .7 15 -1 11 .6 75 FF F N Ph CH3F F N Ph 5 mol % 2.1 0.6 equiv (CH3)2Zn, CH3CN 60 °C 1a 2a 19F NMR spectrum (282 MHz, rt, CD3CN) Aryl fluorides for Me3Pt(IV) in catalysis: δ -111.7 (m) Aryl fluorides for 2a: δ -113.7 (t, JF-F = 8.5 Hz, JF-H = 8.5 Hz) 245 1H NMR spectrum of Me3Pt(IV) in catalysis (0 – 1.30 ppm) w90524-2H_001000fid 1.25 1.20 1.15 1.10 1.05 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 Chemical Shift (ppm) 0.90373.39940.83302.95530.74523.2681 1H NMR spectrum of Me3Pt(IV) in catalysis added with complex 3.7 (0 – 1.30 ppm) w90524-2Hb_001000fid 1.25 1.20 1.15 1.10 1.05 1.00 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 0 Chemical Shift (ppm) 1.68185.84321.54625.52891.41735.9179 The addition of 3.7 increased the concentration of Me3Pt(IV) in catalysis because the integration of the resonances for methyl-Pt (Me3Pt(IV) in catalysis was enhanced. (300 MHz, rt, CD3CN) (300 MHz, rt, CD3CN) Me3Pt(IV): δ 0.78 (s, JPt-H = 69 Hz, CH3-Pt) 0.41 (s, JPt-H = 73 Hz, CH3-Pt) 0.20 (s, JPt-H = 46 Hz, CH3-Pt) Me3Pt(IV): δ 0.78 (s, JPt-H = 69 Hz, CH3-Pt) 0.41 (s, JPt-H = 73 Hz, CH3-Pt) 0.20 (s, JPt-H = 46 Hz, CH3-Pt) 246 1H NMR spectrum of the reductive elimination from complex 3.7 at 60 ˚C for 30 min w70708-1Hc_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 2. 55 1 4. 81 5 8. 72 0 NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F 60 °C, 30 min Conversion >98% Yield of 2a: 69% CH3F F N Ph 2a δ 8.72 (s, CH=N for 2a)   4.82 (s, CH2 for 2a)   2.55 (s, aryl-CH3 for 2a) Solvent CD3CN: δ 1.94 Toluene (from Me2Zn solution) (CH3)2Zn Internal standard Internal standard Aryl protons, overlapping peaks (3 0 MHz, rt, CD3CN) 247 19F NMR spectrum of the reductive elimination from complex 3.7 at 60 ˚C for 30 min w70708-1Fc_001000fid -92 -94 -96 -98 -100 -102 -104 -106 -108 -110 -112 -114 -116 -118 Chemical Shift (ppm) -1 15 .2 35 -1 15 .1 95 -1 15 .1 55 -1 13 .6 93 -1 13 .6 61 -1 13 .6 30 -1 12 .0 00 -1 10 .9 59 -1 10 .9 28 -1 10 .8 88 -1 08 .1 86 -1 08 .1 54 -1 08 .1 22 -1 08 .0 90 -1 04 .5 46- 10 4. 50 6 -1 04 .4 67 -1 03 .5 92 -1 03 .5 61 -1 02 .4 88 -1 02 .4 56 -1 02 .4 24 -1 02 .3 92 NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F 60 °C, 30 min Conversion >98% Yield of 2a: 69% CH3F F N Ph 2a (2 2 MHz, rt, CD3CN) δ -108.1 and -113.7 for aryl-F for 2a   other resonances for unknown compounds 248 1H NMR spectrum of the reductive elimination from complex 3.7 at 60 ˚C for 30 min in the presence of 1d w80111-1H2_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 76 5 0. 78 8 0. 87 7 0. 90 3 1. 01 7 1. 51 3 1. 53 9 1. 56 6 1. 61 8 1. 64 5 1. 94 0 1. 98 3 2. 00 3 2. 55 9 4. 82 5 4. 87 1 5. 06 4 5. 10 0 5. 14 68. 55 98. 72 3 8. 91 4 8. 99 1 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F NCH2Ph Pt CH3 FH3C SMe2 F F + F F 0.5 equiv (CH3)2Zn 60 °C, 30 min 3.9 F F N Ph F F F 1d + CH3 F N Ph 2a F δ 8.91 (s, JPt-H = 46.2 Hz, CH=N for 3.9)   5.10 (m, CH2 for 3.9) 1.98 (s, JPt-H = 12.0 Hz, S(CH3)2 bound to Pt for 3.9)   1.54 (t, JPt-H = 63.9 Hz, JF-H = 8.1 Hz, CH3 for 3.9)   0.89 (d, JPt-H = 68.7 Hz, JF-H = 7.8 Hz, CH3 for 3.9) δ 8.72 (s, CH=N for 2a)   8.56 (s, CH=N for 1d)   4.87 (s, CH2 for 1d)   4.83 (s, CH2 for 2a)   2.56 (s, aryl-CH3 for 2a) (300 MHz, rt, CD3CN) Internal standard Internal standard Toluene (from Me2Zn solution) Aryl protons, overlapping peaks Solvent CD3CN: δ 1.94 249 19F NMR spectrum of the reductive elimination from complex 3.7 at 60 ˚C for 30 min in the presence of 1d w80111-1F2_031000fid -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260 -280 Chemical Shift (ppm) 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a liz e d  I n te n si ty - 1 0 8 .1 2 2 -1 0 8 .1 5 4 -1 1 3 .4 6 3 -1 2 7 .8 1 5 -1 3 9 .6 0 1 -1 4 2 .7 9 6 -1 4 8 .3 0 3 - 1 5 2 .4 2 8 -1 6 2 .7 2 7 -1 6 2 .9 0 2 -2 5 4 .2 5 4 NCH2Ph Pt CH3 FH3C SMe2 F 2.2 F NCH2Ph Pt CH3 FH3C SMe2 F F + F F 0.5 equiv (CH3)2Zn 60 °C, 30 min 3.9 F F N Ph F F F 1d + CH3 F N Ph 2a F δ -128.2 (m, aryl-F for 3.9); -139.6 (m, aryl-F for 3.9)   -148.3 (m, aryl-F for 3.9); -162.9 (m, aryl-F for 3.9)   -254.3 (m, Pt-F for 3.9) δ -108.1 (aryl-F for 2a) -113.5 (m, aryl-F for 2a)   -142.8 (m, aryl-F for 1d)   -152.4 (m, aryl-F for 1d)   -162.7 (m, aryl-F for 1d) Other resonances are for unknown compounds. (282 MHz, rt, CD3CN) 250 19F NMR spectra of 2a, 1d and complex 3.9 NONAME02 -40 -60 -80 -100 -120 -140 -160 -180 -200 -220 -240 -260 -280 Chemical Shift (ppm) -0.3 -0.2 -0.1 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 N o rm a liz e d  I n te n si ty When the 19F NMR spectra of 2a, 1d and complex 3.9 were stacked together, a new spectrum was formed and was almost identical to the spectrum shown in the previous page. This indicated that the mixture in the reductive elimination from complex 3.7 at 60 ˚C for 30 min in the presence of 1d contained 2a, 1d and complex 3.9. 1d 3.9 2a (282 MHz, rt, CD3CN) 251 1H NMR spectrum of cross-coupling of 1c and Me2Zn in which 2.2 as pre-catalyst at 60 ˚C for 11 h w80212-1Hb_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 2. 43 3 2. 44 2 2. 54 7 8. 73 4 F F N Ph CH3 F N Ph 10 mol % 2.2 0.6 equiv (CH3)2Zn CH3CN, 60 °C, 11 h 1c 2c F F CH3 F N Ph 2a F 8%92% + δ 8.73 (s, CH=N, 2c)   2.55 (s, aryl-CH3 for 2a) 2.44 (d, J = 2.5 Hz, aryl-CH3 for 2c) CD3CN: δ 1.94 (300 MHz, rt, CD3CN) CH2 for 2a and 2c Internal standard Internal standard Toluene (from Me2Zn sample) Aryl protons, overlapping peaks (CH3)2Zn 252 19F NMR spectrum of cross-coupling of 1c and Me2Zn in which 2.2 as pre-catalyst at 60 ˚C for 11 h w80212-1Fb_001000fid.esp -95 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 -180 Chemical Shift (ppm) -1 42 .3 26 -1 42 .2 55 -1 37 .3 83 -1 22 .9 19 -1 22 .8 56 -1 20 .9 25 -1 20 .8 77 -1 18 .8 11 -1 18 .7 55 -1 13 .7 09 -1 13 .6 77 -1 13 .6 37 -1 08 .1 78 -1 08 .1 46 F F N Ph CH3 F N Ph 10 mol % 2.2 0.6 equiv (CH3)2Zn CH3CN, 60 °C, 11 h 1c 2c F F CH3 F N Ph 2a F 8%92% + (282 MHz, rt, CD3CN) δ -120.9 and -122.9 (aryl-F for 2c)   -108.1 and -113.7 (aryl-F for 2a) Other resonances are unknown compounds 253 1H NMR spectrum of the reductive elimination from 3.7 in the presence of excess SMe2 at 60 ˚C for 30 min w70927-1Hc_001000fid.esp 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 18.3084100.0073 0. 07 7 0. 15 4 0. 22 9 0. 35 8 0. 48 0 0. 62 5 0. 74 1 1. 75 6 1. 77 8 1. 94 0 2. 54 9 4. 81 6 4. 98 5 8. 72 0 8. 79 0 8. 85 6 8. 92 3 NCH2Ph Pt CH3 CH3H3C SMe2 F 3.7 F 10 equiv SMe2 60 °C, 30 min Yield of 2a: < 20% CH3F F N Ph 2a Resonances for 3.7: δ 8.86 (s, JPt-H = 40 Hz, CH=N), 4.99 (m, CH2), 1.78 (s, JPt-H = 13 Hz, S(CH3)2 bound to Pt), 0.75 (Pt satellite peaks: 0.86 and 0.63), 0.36 (Pt satellite peaks: 0.49 and 0.24), 0.16 (Pt satellite peaks: 0.24 and 0.08). δ 2.55 (s, CH3 for 2a)   4.82 (s, CH2 for 2a)   8.72 (s, CH=N for 2a) (300 MHz, rt, CD3CN) Internal standard Free S(CH3)2 Toluene Internal standard Aryl protons, overlapping peaks Solvent CD3CN: δ 1.94 (CH3)2Zn 254 1H NMR spectrum of 3.16 w81121-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1H{19F} NMR spectrum of 3.16 w81121-1H{19F}_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm) (300 MHz, rt, acetone-d6) (300 MHz, rt, acetone-d6) N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 Acetone-d6 Acetone-d6 H2O H2O 255 1H{31P} NMR spectrum of 3.16 w81121-1H{31P}_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm) 19F NMR spectrum of 3.16 w80423-1F_001000fid -85 -90 -95 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 -180 Chemical Shift (ppm) (300 MHz, rt, acetone-d6) ( 82 MHz, rt, acetone-d6) N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 δ -124.4 (m, 1F) -140.2 (t, J = 19.7 Hz, 1F) -149.8 (m, 1F) -165.2 (t, J = 19.7 Hz, 1F) CH=N CH2 H2O Acetone-d6 256 31P{1H} NMR spectrum of 3.16 w80423-1P_001000fid 35 30 25 20 15 10 5 0 -5 -10 -15 -20 -25 -30 -35 -40 Chemical Shift (ppm) 13C NMR spectrum of 3.16 w80630-1C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 -8 -16 Chemical Shift (ppm) (121 MHz, rt, acetone-d6) (10 MHz, rt, CD2Cl2) N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 δ -6.94 (s, JPt-P = 1039.2 Hz) 257 NOE NMR data on Me3Pt(IV) complex 3.16 (performed at rt): 1) NOE effects of the resonance at δ 1.37 w80426-1H_002000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 .4 1 9 0 .4 2 9 0 .4 3 7 0 .6 1 7 0 .6 3 1 1 .3 6 8 1 .3 8 7 7 .4 1 2 7 .4 3 2 2) NOE effects of the resonance at δ 0.62 w80426-1H_003000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 .4 1 8 0 .4 3 3 0 .6 1 6 1 .3 6 3 1 .3 8 7 4 .5 4 1 4 .5 8 0 7 .4 3 0 (400 MHz, acetone-d6) (400 MHz, acetone-d6) N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 258 3) NOE effects of the resonance at δ 0.42 w80426-1H_004000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 .4 2 2 0 .6 1 5 0 .6 3 4 1 .3 6 1 1 .3 8 8(400 MHz, acetone-d6) N Pt CH3 CH3H3C PPh3 F F F F BrCH2 3.16 259 X-ray data for complex 3.16 ORTEP diagram of complex 3.16. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms are excluded for clarity. 1H NMR (acetone-d6, 300 MHz): δ 8.59 (s, JPt-H = 40.5 Hz, CH=N, 1H), 7.54 – 7.04 (m, overlapping peaks, Aryl-H), (4.55 (d), 4.23 (d), JH-H = 15.3 Hz, CH2, 2H, AB pattern), 1.37 (dd, JPt-H = 70.8 Hz, JF-H = 2.7 Hz, JP-H = 7.7 Hz, Pt-CH3, 3H), 0.62 (d, JPt-H = 49.8 Hz, JP-H = 7.3 Hz, Pt-CH3, 3H), 0.42 (d, JPt-H = 62.0 Hz, JP-H = 7.5 Hz, Pt-CH3, 3H). 19F NMR (acetone-d6, 282 MHz): δ -124.4 (m, 1F), -140.2 (t, J = 19.7 Hz, 1F), -149.8 (m, 1F), -165.2 (t, J = 19.7 Hz, 1F). 31P {1H} NMR (acetone-d6, 121 MHz): δ -6.94 (s, JPt-P = 1039.2 Hz). 13C (CD2Cl2, 100 MHz): δ 169.2 (broad singlet), 154.7(dm, JBr-C = 43.3 Hz), 151.8 (dm, JF-C = 230.5 Hz), 148.8 (dm, JF-C = 261.6 Hz), 143.5 (dm, JF-C = 265.7 Hz), 260 137.2 (m, the other half overlaps with the resonances for PPh3), 134.5 (t, JPt-C = 7.6 Hz, overlapping with resonances for PPh3), 134.3 (d, JP-C = 9.9 Hz), 132.6 (s), 132.1 (s), 131.8 (d, JPt-C = 10.8 Hz, JP-C = 37.5 Hz), 130.7 (d, JP-C = 2.3 Hz), 128.6 (d, JP-C = 8.4 Hz), 122.9 (s), 59.2 (s, JPt-C = 14.5 Hz), 7.29 (d, JPt-C = 543.4 Hz, JP-C = 114.7 Hz), 2.17 (broad singlet, JPt-C = 478.0 Hz), -12.9 (dd, JPt-C = 613.9 Hz, JP-C = 11.1 Hz, JF-C = 4.0 Hz). HRMS (ESI-) m/z calcd for C35H30NF4P 79Br194Pt (M-H): 844.0862; found: 844.0850. Anal. Calcd for C35H31NF4PBrPt: C, 49.60; H, 3.69; N, 1.65; found: C, 49.80; H, 3.72; N, 1.75. 261 Complex 3.16 (jl044.cif in database of chemistry department of UBC) Experimental Data Collection A pink prism crystal of C35H31NF4PPtBr having approximate dimensions of 0.28 x 0.38 x 0.50 mm was mounted on a glass fiber. All measurements were made on a Bruker X8 APEX II diffractometer with graphite monochromated Mo-K radiation. The data were collected at a temperature of -100.0 + 0.1oC to a maximum 2 value of 56.2o. Data were collected in a series of and  scans in 0.50o oscillations with 5.0 second exposures. The crystal-to-detector distance was 36.00 mm. EXPERIMENTAL DETAILS A. Crystal Data Empirical Formula C35H31NF4PPtBr Formula Weight 847.58 Crystal Color, Habit pink, prism Crystal Dimensions 0.28 X 0.38 X 0.50 mm Crystal System triclinic Lattice Type primitive Lattice Parameters a = 10.5281(7) Å b = 10.5282(7) Å c = 15.3290(15) Å  = 86.304(3) o  = 76.090(3) o  =  69.947(3) o 262 V = 1548.98(18) Å3 Space Group P -1 (#2) Z value 2 Dcalc 1.817 g/cm3 F000 824.00 (MoK) 59.21 cm-1 B. Intensity Measurements Diffractometer Bruker X8 APEX II Radiation MoK ( = 0.71073 Å) graphite monochromated Data Images 2299 exposures @ 5.0 seconds Detector Position 36.00 mm 2max 56.2o No. of Reflections Measured Total: 33132 Unique: 7494 (Rint = 0.036) Corrections Absorption (Tmin = 0.119, Tmax= 0.191) Lorentz-polarization 263 C. Structure Solution and Refinement Structure Solution Direct Methods (SIR97) Refinement Full-matrix least-squares on F2 Function Minimized  w (Fo2 - Fc2)2 Least Squares Weights w=1/(2(Fo2)+(0.0124P) 2+ 0.8852P) Anomalous Dispersion All non-hydrogen atoms No. Observations (I>0.00(I)) 7494 No. Variables 391 Reflection/Parameter Ratio 19.17 Residuals (refined on F2, all data): R1; wR2 0.020; 0.041 Goodness of Fit Indicator 1.04 No. Observations (I>2.00(I)) 7027 Residuals (refined on F): R1; wR2 0.017; 0.040 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.74 e-/Å3 Minimum peak in Final Diff. Map -0.88 e-/Å3 264 Selected bond lengths [A] for 3.16 Bonds Lengths C(1)-Pt(1) 2.076 (2) C(2)-Pt(1) 2.095 (2) C(3)-Pt(1) 2.057 (2) C(22)-Pt(1) 2.099 (2) N(1)-Pt(1) 2.1435 (17) P(1)-Pt(1) 2.3743 (5) Selected angles [deg] for 3.16 Angles Degrees C(28)-N(1)-Pt(1) 114.42 (15) C(29)-N(1)-Pt(1) 122.87 (13) C(3)-Pt(1)-C(1) 87.37 (9) C(3)-Pt(1)-C(2) 89.43 (10) C(1)-Pt(1)-C(2) 86.52 (10) C(3)-Pt(1)-C(22) 97.49 (9) C(1)-Pt(1)-C(22) 85.96 (9) C(2)-Pt(1)-C(22) 169.52 (8) C(3)-Pt(1)-N(1) 172.14 (8) C(1)-Pt(1)-N(1) 85.46 (8) C(2)-Pt(1)-N(1) 93.33 (8) C(22)-Pt(1)-N(1) 78.81 (8) C(3)-Pt(1)-P(1) 90.67 (7) C(1)-Pt(1)-P(1) 177.87 (7) C(2)-Pt(1)-P(1) 92.64 (7) C(22)-Pt(1)-P(1) 95.12 (5) N(1)-Pt(1)-P(1) 96.55 (5) 265 X-ray data for complex 3.17 ORTEP diagram of complex 3.17. Thermal ellipsoids are drawn at the 50% probability level. Hydrogen atoms are excluded for clarity. 266  Complex 3.17 (jl052.cif in database of chemistry department of UBC) EXPERIMENTAL DETAILS Data Collection A brown prism crystal of C34H27NF4PPtBr having approximate dimensions of 0.38 x 0.44 x 0.54 mm was mounted on a glass fiber. All measurements were made on a Bruker X8 APEX II diffractometer with graphite monochromated Mo-K radiation. The data were collected at a temperature of -100.0 + 0.1oC to a maximum 2 value of 55.8o. Data were collected in a series of and  scans in 0.50o oscillations with 5.0 second exposures. The crystal-to-detector distance was 36.00 mm. EXPERIMENTAL DETAILS A. Crystal Data Empirical Formula C34H27NF4PPtBr Formula Weight 831.54 Crystal Color, Habit brown, prism Crystal Dimensions 0.38 X 0.44 X 0.54 mm Crystal System monoclinic Lattice Type primitive Lattice Parameters a = 8.4349(4) Å b = 21.6442(10) Å c = 16.9321(7) Å  = 90.0 o  = 101.601(1) o  = 90.0 o 267 V = 3028.1(2) Å3 Space Group P 21/c (#14) Z value 4 Dcalc 1.824 g/cm3 F000 1608.00 (MoK) 60.56 cm-1 B. Intensity Measurements Diffractometer Bruker X8 APEX II Radiation MoK ( = 0.71073 Å) graphite monochromated Data Images 1041 exposures @ 5.0 seconds Detector Position 36.00 mm 2max 55.8o No. of Reflections Measured Total: 32500 Unique: 7213 (Rint = 0.033) Corrections Absorption (Tmin = 0.070, Tmax= 0.100) Lorentz-polarization 268 C. Structure Solution and Refinement Structure Solution Direct Methods (SIR97) Refinement Full-matrix least-squares on F2 Function Minimized  w (Fo2 - Fc2)2 Least Squares Weights w=1/(2(Fo2)+(0.0152P) 2+ 4.001P) Anomalous Dispersion All non-hydrogen atoms No. Observations (I>0.00(I)) 7213 No. Variables 380 Reflection/Parameter Ratio 18.98 Residuals (refined on F2, all data): R1; wR2 0.033; 0.053 Goodness of Fit Indicator 1.09 No. Observations (I>2.00(I)) 6305 Residuals (refined on F): R1; wR2 0.026; 0.051 Max Shift/Error in Final Cycle 0.00 Maximum peak in Final Diff. Map 0.88 e-/Å3 Minimum peak in Final Diff. Map -1.38 e-/Å3 269 Selected bond lengths [A] for 3.17 Bonds Lengths C(1)-Pt(1) 2.052 (3) N(1)-Pt(1) 2.135 (3) C(36)-Pt(1) 2.077 (3) P(1)-Pt(1) 2.2719 (8) C(28)-N(1) 1.279 (4) C(28)-C(27) 1.456 (5) C(27)-C(22) 1.413 (5) C(22)-C(36) 1.479 (4) Selected angles [deg] for 3.17 Angles Degrees C(28)-N(1)-C(29) 116.1 (3) C(28)-N(1)-Pt(1) 121.8 (2) C(29)-N(1)-Pt(1) 121.96 (19) C(22)-C(36)-Pt(1) 106.2 (2) C(1)-Pt(1)-C(36) 86.92 (13) C(1)-Pt(1)-N(1) 169.30 (12) C(36)-Pt(1)-N(1) 83.23 (12) C(1)-Pt(1)-P(1) 89.66 (10) C(36)-Pt(1)-P(1) 172.34 (10) N(1)-Pt(1)-P(1) 100.60 (7) C(22)-Pt(1)-P(1) 95.12 (5) N(1)-Pt(1)-P(1) 96.55 (5) 270 Appendix III: characterization data for chapter four In this appendix part, the characterization NMR data for chemicals in chapter four are listed. 1,3,5-Trimethoxybenzene was utilized as the internal standard in 1H NMR spectra. 271 1H NMR spectrum of complex [Pt(CD3)2F(C6F2H2CH=NCH2C6H5)], d6-4.14·SMe2 w71023-1Hb_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1 .8 9 2 1 .9 4 0 2 .0 7 3 3 .7 4 0 4 .8 0 6 4 .9 8 4 5 .0 2 8 5 .0 6 5 5 .1 1 0 6 .0 9 4 8 .5 6 5 8 .6 9 8 8 .7 7 6 8 .8 5 5 F F N Ph NCH2Ph Pt CD3 FD3C SMe2 F CD3CN, rt, 24 hF F 1a 0.5 equiv [(CD3)2Pt(-SMe2)]2 d6-4.14 SMe2 δ 8.78 (JPt-H = 47.1 Hz, CH=N for the complex d6-4.14·SMe2)   5.05 (CH2 for the complex d6-4.14·SMe2)   1.89 (JPt-H = 12.0 Hz, S(CH3)2 of complex d6-4.14·SMe2)   8.57 (s, CH=N for 1a)   4.81 (s, CH2 for 1a)   2.07 (s, free S(CH3)2) (300 MHz, rt, CD3CN) Aryl protons, overlapping peaks Internal standard Internal standard 272 19F NMR spectrum of complex [Pt(CD3)2F(C6F2H2CH=NCH2C6H5)], d6-4.14·SMe2 w71023-1Fb_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) -2 61 .8 27 -1 11 .0 63 -1 10 .6 97 -1 02 .6 15 -1 02 .0 11 F F N Ph NCH2Ph Pt CD3 FD3C SMe2 F CD3CN, rt, 24 hF F 1a 0.5 equiv [(CD3)2Pt(-SMe2)]2 d6-4.14 SMe2 Complex d6-4.14·SMe2: δ -102.0 (m, 1F), -110.7 (m, 1F), -261.8 (broad singlet, Pt-F, 1F) 1a: δ -104.4 (m, aryl-F), -109.6 (m, aryl-F) Other resonances are for unknown compounds. (300 MHz, rt, CD3CN) 273 1H NMR spectrum of complex [Pt(CD3)2CH3(C6F2H2CH=NCH2C6H5)], d6-4.15·SMe2 w71026-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0.32832.08786.11132.00720.1808 8. 90 9 8. 86 1 8. 81 1 6. 10 1 5. 00 3 4. 99 0 4. 97 8 4. 96 5 3. 74 4 1. 94 0 1. 79 2 1. 77 6 1. 75 9 0. 82 2 0. 74 1 0 .7 36 0. 64 9 0. 44 9 0. 35 7 0. 35 3 0. 26 7 0. 15 2 0. 09 6 -0 .8 51 Me2Zn ( 0.5 equiv) CD3CN, rt, 10 min NBn Pt CD3 FD3C SMe2 F F NBn Pt CD3 CH3D3C SMe2 F F NBn Pt CD3 CD3H3C SMe2 F F NBn Pt CH3 CD3D3C SMe2 F F + + 1 : 1 : 1 d6-4.14 SMe2 d6-4.14 SMe2 (mixture of isomers) The resonances for complex d6-4.15·SMe2: δ 8.86 (JPt-H = 39.2 Hz, CH=N)   4.98 (CH2)   1.78 (JPt-H = 13.2 Hz, S(CH3)2)   0.74 (JPt-H = 69.6 Hz, Pt-CH3)   0.36 (JPt-H = 72.8 Hz, Pt-CH3)   0.15 (JPt-H = 44.8 Hz, Pt-CH3) (400 MHz, rt, CD3CN) Aryl protons, overlapping peaks Internal standard Internal standard Toluene CH3ZnCl 274 1H NMR spectrum of complex [Pt(CD3)2CH3(C6F2H2CH=NCH2C6H5)], d6-4.15·SMe2 (0 – 1 ppm) w71026-2H_001000fid 0.95 0.90 0.85 0.80 0.75 0.70 0.65 0.60 0.55 0.50 0.45 0.40 0.35 0.30 0.25 0.20 0.15 0.10 0.05 Chemical Shift (ppm) 0.32831.33452.15182.0878 0. 82 7 0. 82 2 0. 74 1 0 .7 36 0. 65 3 0. 64 9 0. 44 9 0. 44 4 0. 35 7 0. 35 3 0. 26 7 0. 26 2 0. 15 2 0. 14 9 0. 09 6 0. 09 1 Me2Zn ( 0.5 equiv) CD3CN, rt, 10 min NBn Pt CD3 FD3C SMe2 F F NBn Pt CD3 CH3D3C SMe2 F F NBn Pt CD3 CD3H3C SMe2 F F NBn Pt CH3 CD3D3C SMe2 F F + + 1 : 1 : 1 d6-4.14 SMe2 d6-4.14 SMe2 (mixture of isomers) δ 0.74 (JPt-H = 69.6 Hz, Pt-CH3 for complex d6-4.15·SMe2)   0.36 (JPt-H = 72.8 Hz, Pt-CH3 for complex d6-4.15·SMe2)   0.15 (JPt-H = 44.8 Hz, Pt-CH3 for complex d6-4.15·SMe2) (400 MHz, rt, CD3CN) For unknown compounds 275 1H NMR spectrum of complex [Pt(CD3)2CH3(C6F2H2CH=NCH2C6H5)], d6-4.15·SMe2 (8.5 – 9.0 ppm) w71026-2H_001000fid 8.95 8.90 8.85 8.80 8.75 8.70 8.65 8.60 8.55 Chemical Shift (ppm) 0.18360.9053 Me2Zn ( 0.5 equiv) CD3CN, rt, 10 min NBn Pt CD3 FD3C SMe2 F F NBn Pt CD3 CH3D3C SMe2 F F NBn Pt CD3 CD3H3C SMe2 F F NBn Pt CH3 CD3D3C SMe2 F F + + 1 : 1 : 1 d6-4.14 SMe2 d6-4.14 SMe2 (mixture of isomers) δ 8.86 (JPt-H = 39.2 Hz, CH=N for d6-4.15·SMe2) (400 MHz, rt, CD3CN) F F N Ph F 1a CH=N for 1a 276 w80930-2H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm) 1. 93 1. 94 1. 95 4. 79 7. 24 7. 25 7. 27 7. 48 7. 49 7. 51 7. 51 8. 54 w80930-2F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) -1 6 2 .9 3 -1 6 2 .8 7 -1 6 2 .8 0 -1 5 2 .3 7 -1 5 2 .3 0 -1 5 2 .2 3 -1 4 3 .1 1 -1 4 3 .0 3 w80930-2C_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 Chemical Shift (ppm) 1b, 1H NMR (acetonitrile-d3, rt, 400 MHz) F F N F Br F F 1b, 19F NMR (acetonitrile-d3, rt, 28  MHz) 1b, 13C{1H} NMR (acetonitrile-d3, rt, 100 MHz) 277 w80805-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 Chemical Shift (ppm) w80805-1F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) wang11898_001000fid 192 184 176 168 160 152 144 136 128 120 112 104 96 88 80 72 64 56 48 40 32 24 16 8 0 Chemical Shift (ppm) 2b, 1H NMR (acetonitrile-d3, rt, 300 MHz) F CH3 N F Br F F 2b, 19F NMR (acetonitrile-d3, rt, 282 MHz) 2b, 13C{1H} NMR (acetonitrile-d3, rt, 150 MHz) 278 4.14·SMe2, 1H NMR (acetonitrile-d3, rt, 300 MHz) w80930-3H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 .6 8 0 .7 0 0 .7 9 0 .8 2 0 .9 1 0 .9 3 1 .3 9 1 .3 9 1 .4 7 1 .4 9 1 .5 0 1 .5 2 1 .6 0 1 .6 0 1 .9 4 1 .9 6 2 .0 7 3 .7 4 4 .9 55 .0 0 5 .0 3 5 .0 7 6 .0 9 7 .5 5 7 .5 6 8 .9 08 .9 8 9 .0 6 N Pt CH3 FH3C SMe2 F F F F CH2 Br 4.14·SMe2 Resonances for 4.14·SMe2: δ 8.98 (s, JPt-H = 48.0 Hz, CH=N, 1H), 7.67-7.45 (m, resonances of aryl protons, 4H) 5.02 (m, CH2, 2H), 1.96 (s, JPt-H = 12.0 Hz, Pt-CH3, 6H) 1.50 (dd, JPt-H = 63.0 Hz, JF-H = 9.0 Hz, JF-H = 6.0 Hz, Pt-CH3, 3H) 0.80 (d, JPt-H = 66.0 Hz, JF-H = 6.0 Hz, Pt-CH3, 3H) δ 2.07 (s, free S(CH3)2), 1.94 (CD3CN) Internal standard Internal standard Aryl-H for 4.14·SMe2 279 NOE measurement on the resonance at 1.50 ppm for 4.14·SMe2, 1H NMR (acetonitrile-d3, rt, 400 MHz) w80723-1HNOE_002000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 .8 0 11 .9 6 2 N Pt CH3 FH3C SMe2 F F F F CH2 Br 4.14·SMe2 The geometry of 4.14·SMe2 was consistent with NOE data. 280 4.14·SMe2, 19F NMR (acetonitrile-d3, rt, 282 MHz) w80930-3F_001000fid -88 -96 -104 -112 -120 -128 -136 -144 -152 -160 -168 -176 -184 -192 -200 -208 -216 -224 -232 -240 -248 -256 -264 -272 Chemical Shift (ppm) N Pt CH3 FH3C SMe2 F F F F CH2 Br 4.14·SMe2 Resonances for 4.14·SMe2: δ -128.2 (m, 1F), -139.4 (m, 1F), -148.0 (m, 1F), -162.8 (m, 1F), -253.5 (tm, JPt-F = 175.1 Hz, 1F). 281 1H NMR spectrum of complexes 4.16·SMe2, mixture of isomers w80829-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 56 2 0. 68 9 1. 15 4 1. 16 5 1. 24 1 1. 24 8 1. 27 3 1. 28 3 1. 36 1 1. 36 8 1. 48 0 1. 48 6 1. 93 1 1. 94 0 2. 07 2 8. 88 2 8. 94 7 9. 01 1 9. 10 3 9. 17 2 9. 23 8 NR Pt CH3 FH3C SMe2 F F F F (mixture of isomers)R = CH2(p-BrC6H4) NR PtMe2Ph(SMe2) F F F F Ph2Zn (0.5 equiv) CD3CN, rt 10 min, 90% 4.14 SMe2 4.16 SMe2 δ 2.07 (s, free S(CH3)2), 1.94 (CD3CN) 9.3 - 8.9 (CH=N for 4.16·SMe2), 5.2 - 4.7 (CH2 for 4.16·SMe2), 1.5 - 0.3 (CH3-Pt for 4.16·SMe2). (300 MHz, rt, CD3CN) Internal standard Internal standard Aryl protons, overlapping peaks 282 19F NMR spectrum of 4.16·SMe2, mixture of isomers w80829-1F_001000fid -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 Chemical Shift (ppm) -1 6 4 .2 2 1-1 6 4 .1 5 7 -1 6 3 .5 6 1 -1 6 3 .4 4 2 -1 6 3 .3 0 7 -1 4 9 .4 5 5 -1 4 9 .3 2 0 -1 4 8 .8 1 1 -1 4 8 .7 4 8 -1 4 8 .7 0 8 -1 4 8 .1 9 1 -1 4 8 .1 2 8 -1 4 8 .0 7 2 -1 4 8 .0 0 9 -1 4 0 .3 2 4 -1 3 9 .3 3 0 -1 3 9 .2 8 3 -1 3 9 .2 1 9 -1 3 9 .1 6 3 -1 2 7 .5 9 2-1 2 7 .4 8 1 -1 2 7 .4 1 8 -1 2 7 .0 6 8 -1 2 7 .0 0 4 -1 2 6 .9 4 9 NR Pt CH3 FH3C SMe2 F F F F (mixture of isomers)R = CH2(p-BrC6H4) NR PtMe2Ph(SMe2) F F F F Ph2Zn (0.5 equiv) CD3CN, rt 10 min, 90% 4.14 SMe2 4.16 SMe2 The resonances for mixture of isomers: δ -127.0 (m), -127.1 (dd, J = 20.0 Hz, J = 27.1 Hz), -127.5 (dd, J = 18.0 Hz, J = 31.3 Hz), -139.2 (m), -148.1 (m), -148.5 (m),-148.7 (m), -163.4 (t, J = 19.0 Hz), -163.6 (t, J = 20.0 Hz) Resonances for unknown compounds: δ -143.6 (dd, J = 20.3 Hz, J = 6.8 Hz), -156.0 (t, J = 20.3 Hz), -162.8 (m) ( 82 MHz, rt, CD3CN) 283 1H NMR spectrum of complexes I·SMe2 and II·SMe2 w80905-1H_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 48 3 0. 56 60. 69 6 0. 81 6 1. 15 9 1. 16 9 1. 24 6 1. 27 8 1. 28 8 1. 36 6 1. 37 2 1. 39 7 1. 49 1 1. 94 0 2. 07 4 8. 88 4 8. 94 6 9. 00 7 9. 17 0 9. 23 6 NR Pt CH3 FH3C SMe2 F F NR Pt CH3 PhH3C SMe2 F F F F F F NR Pt Ph CH3H3C SMe2 F F F F SMe2 (10 equiv) R = CH2(p-BrC6H4) ( 1.1 : 1) Ph2Zn (0.5 equiv) CD3CN, rt 10 min, 90% 4.14 SMe2 I SMe2 II SMe2 δ 9.17 (s, JPt-H = 39.6 Hz, CH=N for I·SMe2/ II·SMe2), 8.95 (s, JPt-H = 37.2 Hz, CH=N for II·SMe2/ I·SMe2) Resonances for I·SMe2 δ 7.39 – 7.41 (m, Ph-Pt), 1.90 (s, overlapping peaks for S(CH3)2), 1.28 (d, JPt-H = 71.3 Hz, JF-H = 3.0 Hz, Pt-CH3), 0.70 (d, JPt-H = 71.9 Hz, Pt-CH3) Resonances for II·SMe2 δ 6.98 – 7.00 (m, Ph-Pt), 1.91 (s, overlapping peaks for S(CH3)2), 1.37 (d, JPt-H = 71.6 Hz, JF-H = 1.8 Hz, Pt-CH3), 0.57 (d, JPt-H = 49.8 Hz, Pt-CH3) Note: The resonances of coordinated S(CH3)2 for II·SMe2 and I·SMe2 are overlapped. δ 2.07 (s, free S(CH3)2), 1.94 (CD3CN) (300 MHz, rt, CD3CN) Aryl protons, overlapping peaks Internal standard Internal standard CH2 for I·SMe2 and II·SMe2 284 1H NMR spectrum of complexes I·SMe2 and II·SMe2 w80905-1H_001000fid 1.7 1.6 1.5 1.4 1.3 1.2 1.1 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Chemical Shift (ppm) 0. 48 3 0. 56 6 0. 57 6 0. 64 9 0. 69 6 0. 81 6 1. 15 9 1. 16 9 1. 24 6 1. 25 3 1. 27 8 1. 28 8 1. 36 6 1. 37 2 1. 39 7 1. 40 6 1. 48 4 1. 49 1 NR Pt CH3 FH3C SMe2 F F NR Pt CH3 PhH3C SMe2 F F F F F F NR Pt Ph CH3H3C SMe2 F F F F SMe2 (10 equiv) R = CH2(p-BrC6H4) ( 1.1 : 1) Ph2Zn (0.5 equiv) CD3CN, rt 10 min, 90% 4.14 SMe2 I SMe2 II SMe2 I·SMe2: δ 0.70 (JPt-H = 71.9 Hz), 1.28 (JPt-H = 71.3 Hz, JF-H = 3.0 Hz) II·SMe2: δ 0.57(JPt-H = 49.8 Hz), 1.37 (JPt-H = 71.6 Hz, JF-H = 1.8 Hz) (300 MHz, rt, CD3CN) 285 19F NMR spectrum of complexes I·SMe2 and II·SMe2 w80905-1F_001000fid -85 -90 -95 -100 -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 Chemical Shift (ppm) -1 6 3 .6 1 7 -1 6 3 .5 5 3 -1 6 3 .3 7 0 -1 6 3 .3 0 7 -1 6 2 .8 3 0 -1 5 6 .0 4 3 -1 4 8 .7 3 2 -1 4 8 .6 9 2-1 4 8 .1 2 0 -1 4 8 .0 6 4 -1 4 3 .6 3 8 -1 3 9 .3 3 8 -1 3 9 .2 7 5 -1 3 9 .2 1 1 -1 3 9 .1 5 6 -1 2 7 .5 4 5 -1 2 7 .4 3 4 -1 2 7 .3 7 0 -1 2 7 .1 3 2 -1 2 7 .1 0 8 -1 2 7 .0 3 6 NR Pt CH3 FH3C SMe2 F F NR Pt CH3 PhH3C SMe2 F F F F F F NR Pt Ph CH3H3C SMe2 F F F F SMe2 (10 equiv) R = CH2(p-BrC6H4) ( 1.1 : 1) Ph2Zn (0.5 equiv) CD3CN, rt 10 min, 90% 4.14 SMe2 I SMe2 II SMe2 Resonances of aryl-Fs for I·SMe2 and II·SMe2: δ -127.1 (dd, J = 20.0 Hz, J = 27.1 Hz), -127.5 (dd, J = 18.0 Hz, J = 31.3 Hz), -139.2 (m), -148.1 (m), -148.7 (m), -149.4 (m), -163.4 (t, J = 19.0 Hz), -163.6 (t, J = 20.0 Hz) Resonances for unknown compounds: δ -143.6 (dd, J = 20.3 Hz, J = 6.8 Hz), -156.0 (t, J = 20.3 Hz), -162.8 (m) (282 MHz, rt, CD3CN) 286 NOE studies on the mixture of I·SMe2 and II·SMe2 1) NOE studies on the resonance at δ 1.28 w81114-1H(NOE)_004000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 69 71. 89 7 7. 39 2 7. 40 8 2) NOE studies on the resonance at δ 0.70 w81114-1H(NOE)_006000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 27 9 1. 28 7 2. 07 4 7. 38 37. 39 0 7. 40 8 7. 41 5 Internal standard Internal standard Free SMe2 Internal standard Free SMe2 ( 00 MHz, rt, CD3CN) (400 MHz, rt, CD3CN) δ 1.897 (s, S(CH3)2 coordinated to Pt 287 3) NOE studies on the resonance at δ 7.39-7.41 w81114-1H(NOE)_012000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 69 7 1. 28 0 1. 28 8 1. 89 7 2.068 4) NOE studies on the resonance at δ 1.37 w81114-1H(NOE)_003000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 56 8 1. 90 7 2. 06 6 6. 97 8 6. 98 4 6. 99 3 7. 00 3 Internal standard Free SMe2 Internal standard Free SMe2 (400 MHz, rt, CD3CN) (400 MHz, rt, CD3CN) δ 1.897 (s, S(CH3)2 coordinated to Pt δ 1.907 (s, S(CH3)2 coordinated to Pt 288 5) NOE studies on the resonance at δ 0.57 w81114-1H(NOE)_007000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 36 7 1. 37 1 1. 90 7 5. 05 3 5. 07 5 6. 97 8 6. 98 4 6. 99 3 7. 00 3 6) NOE studies on the resonance at δ 6.98-7.00 w81114-1H(NOE)_013000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 56 7 1. 37 1 Internal standard Free SMe2 Internal standard Free SMe2 Internal standard ( 00 MHz, rt, CD3CN) (400 MHz, rt, CD3CN) δ 1.907 (s, S(CH3)2 coordinated to Pt 289 1H NMR spectrum of reductive elimination products of 4.16·SMe2 w81001-2Hc_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 1. 94 0 2. 32 9 2. 41 6 2. 42 0 2. 42 5 4. 80 3 8. 65 7 CH3 NR 2b Ph NR 3b PhCH3 50% trace Pt CH3 Ph SMe2 or isomer 4.17 31% NR Pt SMe2H3C 4.18 NR Pt SMe2Ph 4.19 or isomer or isomer trace 12% trace mixture of isomers CD3CN, 60 °C 19 h F F F F F F F F FF F F FF F F 4.16 SMe2 Resonances for 2b: δ 8.66 (s, CH=N), 4.80 (s, CH2), 2.42 (dd, J = 3.0 Hz, J = 1.2 Hz, aryl-CH3). Resonances for Ph-CH3: δ 2.33 (s) Resonances for 4.17 or isomers: δ 2.22 (s, JPt-H = 23.4 Hz, S(CH3)2), 2.20 (s, JPt-H = 23.4 Hz, S(CH3)2), 0.49 (s, Pt-CH3, the coupling constant is not clear on this spectrum). (3 0 MHz, rt, CD3CN) Internal standard Internal standard Aryl protons, overlapping peaks 290 19F NMR spectrum of reductive elimination products of 4.16·SMe2 w81001-2Fc_001000fid -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 -180 Chemical Shift (ppm) -1 6 0 .8 7 2 -1 6 0 .8 0 0 -1 6 0 .7 2 8 -1 5 4 .8 8 7 -1 5 4 .8 7 1 -1 5 4 .8 1 6 -1 5 4 .8 0 0 -1 5 4 .7 4 4 -1 4 4 .7 3 1-1 4 4 .6 9 1 -1 4 4 .6 2 0 -1 4 4 .6 0 4 -1 4 2 .2 5 1 -1 4 2 .2 1 2 -1 4 2 .1 8 0 -1 4 2 .1 4 0 CH3 NR 2b Ph NR 3b PhCH3 50% trace Pt CH3 Ph SMe2 or isomer 4.17 31% NR Pt SMe2H3C 4.18 NR Pt SMe2Ph 4.19 or isomer or isomer trace 12% trace mixture of isomers CD3CN, 60 °C 19 h F F F F F F F F FF F F FF F F 4.16 SMe2 The resonances for 2b: δ -142.2 (dd, J = 19.8 Hz, J = 11.3 Hz, 1F), -144.7 (m, 1F), -154.8 (td, J = 19.8 Hz, J = 4.7 Hz), -160.8 (t, J = 19.8 Hz). Other resonances are for other unidentified compounds. (282 MHz, rt, CD3CN) 291 1H NMR spectrum of reductive elimination products of I·SMe2 and II·SMe2 w81114-1Hg_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0 .4 7 8 0 .4 9 8 0 .5 6 2 0 .6 8 9 0 .9 4 4 1 .0 6 2 1 .0 7 1 1 .2 7 3 1 .3 6 1 1 .3 6 8 2 .3 2 7 2 .3 6 7 2 .4 1 3 2 .4 1 7 2 .4 2 2 4 .8 0 2 4 .9 3 4 8 .6 5 8 9 .0 2 6 9 .1 7 4 R = CH2(p-BrC6H4) NR Pt CH3 PhH3C SMe2 F F F F NR Pt Ph CH3H3C SMe2 F F F F CD3CN, 60 C 83 h CH3 NR 2b PhCH3 19% 14% F F F F ( 1.1 : 1) I SMe2 II SMe2 Resonances for 2b: δ 8.66 (s, CH=N), 4.80 (s, CH2), 2.42 (dd, J = 3.0 Hz, J = 1.2 Hz, aryl-CH3). Resonances for Ph-CH3: δ 2.33 (s) δ 9.17 (s, JPt-H = 39.6 Hz, CH=N for I·SMe2/ II·SMe2), 8.95 (s, JPt-H = 37.2 Hz, CH=N for II·SMe2/ I·SMe2) Resonances for I·SMe2 δ 7.39 – 7.41 (m, Ph-Pt), 1.90 (s, overlapping peaks for S(CH3)2), 1.28 (d, JPt-H = 71.3 Hz, JF-H = 3.0 Hz, Pt-CH3), 0.70 (d, JPt-H = 71.9 Hz, Pt-CH3) Resonances for II·SMe2 δ 6.98 – 7.00 (m, Ph-Pt), 1.91 (s, overlapping peaks for S(CH3)2), 1.37 (d, JPt-H = 71.6 Hz, JF-H = 1.8 Hz, Pt-CH3), 0.57 (d, JPt-H = 49.8 Hz, Pt-CH3) Note: The resonances of coordinated S(CH3)2 for II·SMe2 and I·SMe2 are overlapped. (300 MHz, rt, CD3CN) Internal standard Internal standard Free S(CH3)2 292 19F NMR spectrum of reductive elimination products of I·SMe2 and II·SMe2 w81114-1Fg_001000fid -105 -110 -115 -120 -125 -130 -135 -140 -145 -150 -155 -160 -165 -170 -175 Chemical Shift (ppm) -1 6 4 .3 8 4 -1 6 4 .3 2 1 -1 6 4 .2 4 9 -1 6 3 .2 8 0 -1 6 3 .2 0 8 -1 6 0 .8 6 4 -1 6 0 .8 0 0 -1 6 0 .7 2 8 -1 5 5 .9 4 4 -1 5 4 .8 7 1 -1 5 4 .8 0 0 -1 5 4 .7 2 8 -1 5 4 .7 1 3 -1 4 9 .4 2 0 -1 4 9 .3 5 6 -1 4 9 .3 0 1 -1 4 9 .2 4 5 -1 4 7 .9 7 3 -1 4 7 .9 1 0 -1 4 4 .7 3 1 -1 4 4 .6 5 9 -1 4 4 .6 2 0 -1 4 2 .2 5 9 -1 4 2 .1 8 8 -1 4 2 .1 4 8 -1 3 9 .8 6 7 -1 3 9 .7 9 6 -1 3 9 .7 4 0 -1 3 9 .1 2 0 -1 3 9 .0 5 7 -1 2 7 .3 9 8 -1 2 7 .3 2 7- 1 2 6 .9 0 6 -1 2 6 .8 3 4 -1 2 6 .7 9 4 -1 2 6 .7 2 3 R = CH2(p-BrC6H4) NR Pt CH3 PhH3C SMe2 F F F F NR Pt Ph CH3H3C SMe2 F F F F CD3CN, 60 C 83 h CH3 NR 2b PhCH3 19% 14% F F F F ( 1.1 : 1) I SMe2 II SMe2 The resonances for 2b: δ -142.2 (dd, J = 19.8 Hz, J = 11.3 Hz, 1F), -144.7 (m, 1F), -154.8 (td, J = 19.8 Hz, J = 4.7 Hz), -160.8 (t, J = 19.8 Hz). Resonances of aryl-Fs for I·SMe2 and II·SMe2 and other isomers: δ -126.8 (dd, J = 20.0 Hz, J = 27.1 Hz), -127.4 (dd, J = 18.0 Hz, J = 31.3 Hz), -139.1 (m), -139.9 (t, 17.9 Hz), -148.1 (m), -148.7 (m), -149.4 (m), -163.3 (t, J = 19.0 Hz), -163.5 (t, J = 20.0 Hz), -164.3 (t, J = 19.0 Hz). Resonances for unknown compounds: δ -143.6 (dd, J = 20.3 Hz, J = 6.8 Hz), -155.9 (t, J = 20.3 Hz), -162.7 (m) (282 MHz, rt, CD3CN) 293 1H NMR spectrum of [PtMePh(SMe2)]2 with excess SMe2 w80930-1H_002000fid 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 Chemical Shift (ppm) 0 .4 0 8 0 .4 7 1 0 .5 1 2 0 .5 7 6 0 .6 8 3 2 .3 5 1 2 .3 9 9 Cis-MePtPh(SMe2)2: 1H NMR (dicholoromethane-d2, 400 MHz): δ 2.40 (s, JPt-H = 22.8 Hz, S(CH3)2), the resonance for the other S(CH3)2 overlapped with free S(CH3)2, 0.57 (s, JPt-H = 85.2 Hz, Pt-CH3). Trans-MePtPh(SMe2)2: 1H NMR (dicholoromethane-d2, 400 MHz): δ 2.35 (s, JPt-H = 23.2 Hz, S(CH3)2), the resonance for the other S(CH3)2 overlapped with free S(CH3)2, 0.51 (s, JPt-H = 83.2 Hz, Pt-CH3). (4 0 MHz, rt, CD2Cl2) Free S(CH3)2 The resonances for Ph-Pt CD2Cl2 294 1H NMR spectrum of reductive elimination products of 4.16·SMe2 (the resonances for Pt(II) complexes were clear with the addition of excess SMe2) w90203-1Hf_001000fid 10.5 10.0 9.5 9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 -0.5 Chemical Shift (ppm) 0. 42 60 .5 67 0. 70 9 2. 39 5 4. 79 9 5. 32 0 8. 64 7 CH3 NR 2b Ph NR 3b PhCH3 50% trace Pt CH3 Ph SMe2 or isomer 4.17 31% NR Pt SMe2H3C 4.18 NR Pt SMe2Ph 4.19 or isomer or isomer trace 12% trace mixture of isomers CD3CN, 60 °C 19 h F F F F F F F F FF F F FF F F 4.16 SMe2 Resonances for 2b: δ 8.66 (s, CH=N), 4.80 (s, CH2), 2.42 (dd, J = 3.0 Hz, J = 1.2 Hz, aryl-CH3). Resonances for Ph-CH3: δ 2.33 (s) Compared to the spectrum on the previous page, PtMePh(SMe2) was formed in the reductive elimination of 4.16·SMe2. Cis-PtMePh(SMe2)2 δ 2.40 (s, JPt-H = 22.8 Hz, SMe2), 0.57 (s, JPt-H = 85.2 Hz), the resonance of the other SMe2 overlapped with free SMe2. (300 MHz, CD2Cl2) Free S(CH3)2 Internal standard Internal standard Aryl protons, overlapping peaks 295 w81011-1Hb_001000fid 2.95 2.90 2.85 2.80 2.75 2.70 2.65 2.60 2.55 2.50 2.45 2.40 2.35 2.30 2.25 2.20 2.15 2.10 2.05 2.00 1.95 1.90 1.85 1.80 Chemical Shift (ppm) 110.2431.8845.7283.02 1. 94 w81001-2Hc_001000fid 2.95 2.90 2.85 2.80 2.75 2.70 2.65 2.60 2.55 2.50 2.45 2.40 2.35 2.30 2.25 2.20 2.15 2.10 2.05 2.00 1.95 1.90 1.85 1.80 Chemical Shift (ppm) 30.9114.4110.6161.82 1. 94 The resonances for Pt(II) species in the reductive elimination solution increased with the addition of MePtPh(SMe2). 1H NMR spectrum of reductive elimination from 4.16·SMe2 1H NMR spectrum of reductive elimination from 4.16·SMe2 with the addition of MePtPh(SMe2) (300 MHz, rt, CD3CN) (300 MHz, rt, CD3CN) Free S(CH3)2 CD3CN Aryl-CH3 for 2b Toluene CD3CN 296 Appendix IV: List of compounds Chapter 1 Complex 1.1    (η5-C5Me5)Rh(PMe3)(C2H4)...................................................................6 Complex 1.2   (η5-C5Me5)Rh(PMe3)(η5-C6F6)...............................................................6 Complex 1.3    (η5-C5Me5)Rh(PMe3)(C6F5)(F) ..............................................................6 Complex 1.4    (η5-C5Me5)Rh(PMe3)(H)2.......................................................................6 Complex 1.5    (η5-C5Me5)Rh(PMe3)(H)(C6F5)..............................................................6 Complex 1.6    (η5-C5Me5)Rh(PMe3)(H)(C6F4H)...........................................................6 Complex 1.7    (η5-C5Me5)Rh(PMe3)(H)(C12F9) ............................................................6 Complex 1.8    (η5-C5Me5)Rh(PMe3)(H)(C10F7) ............................................................6 Complex 1.9    RhH(PEt3)3 .............................................................................................7 Complex 1.10   Rh(4-C5NF4)(PEt3)3................................................................................7 Complex 1.11   Rh(SiPh3)(PMe3)3...................................................................................7 Complex 1.12   Rh(2-C5NF4)(PMe3)3..............................................................................7 Complex 1.13   Rh(4-C5NF4)(PMe3)3..............................................................................7 Complex 1.14   Rh(2-C5NF3Me)(PMe3)3 ........................................................................7 Complex 1.15   Ni(PEt3)2(COD)......................................................................................8 Complex 1.16   C6F5Ni(F)(PEt3)2 ....................................................................................8 Complex 1.17   bis(cyclooctadiene)-nickel(0) complex..................................................8 Complex 1.18   Air stable Ni-F complex.........................................................................9 Complex 1.19   trans-NiF(2-C5NF4)(PEt3)2 ....................................................................9 Complex 1.20   trans-NiF(4-C4N2F2H)(PEt3)2 ................................................................9 Complex 1.21   Carbene complex Ni2( iPr2C3N2H2)4(COD) ............................................9 Complex 1.22   NiF(C6F5)( iPr2C3N2H2)2 .........................................................................9 Complex 1.23   NiEt2(bpy) (bpy = 2,2’-bypyridine) .......................................................9 Complex 1.24   Ni(0)(bpy) (bpy = 2,2’-bypyridine)........................................................9 Complex 1.25   NiF(C6F5)(bpy).......................................................................................9 Complex 1.26   Ni(C14H8)(PEt3)2 .................................................................................10 Complex 1.27   trans-NiF(2,4,5-trifluorophenyl)(PEt3)2..............................................10 Complex 1.28   trans-NiF(2,3,5,6-tatrafluorophenyl)(PEt3)2 .......................................10 297 Complex 1.29   trans-NiF(2,3,5-trifluorophenyl)(PEt3)2..............................................10 Complex 1.30 cis-[{Pd2(μ-Cl)2- [μ-C(C6F5)=N(CH3)]2}n] ..........................................11 Complex 1.31 Imidoyl-bridged dimer complex .........................................................11 Complex 1.32 PdMe2(Cy2PCH2PCy2)..........................................................................11 Complex 1.33 PdMe(OC5NF4)(Cy2PCH2PCy2) ...........................................................11 Complex 1.34 PdMe{4-C4N2F2H(=O)}(Cy2PCH2PCy2) .............................................11 Complex 1.35 Pd(PR3)2(R= Cy or iPr) ......................................................................12 Complex 1.36 trans-PdF(4-C5NF4)(PR3)2 (R= Cy or iPr) ........................................12 Complex 1.37 Pt(PR3)2(R= Cy or iPr) .......................................................................12 Complex 1.38 trans-PtR(4-C5NF4)(PR3)(FPR2)(R= Cy or iPr).................................12 Complex 1.39 cis-hydridoneopentyl[η2-bis(di-tert-butylphosphosphino)methane]-                          platinum(II)....................................................................13 Complex 1.40 (dtbpm)Pt ..............................................................................................13 Complex 1.41 (dtbpm)Pt(F)(C6F5) ...............................................................................13 Complex 1.42 Pt(dba)2..................................................................................................13 Complex 1.43 PtBr-(Me2NCH2CH2NCHC6F4) ............................................................13 Complex 1.44 A pincer-type anionic platinum(0) complex .....................................14 Complex 1.45 A pincer-type platinum(II)-C6F5 complex .........................................14 Complex 1.46 trans-[Pt(CH3)(THF)(PPh2-C6F5)2]ClO4...............................................14 Complex 1.47 trans-Pt(CH3)(2-OC6F4PPh2)(PPh2C6F5) ..............................................14 Complex 1.48 trans-Pt(H)2(PCy3)2...............................................................................15 Complex 1.49 trans-PtH(FHF)(PCy3)2.........................................................................15 Complex 1.50 trans-PtH(C6F5)(PCy3)2.........................................................................15 Complex 1.51 trans-PtCl2(PPh2-n(C6F5)n+1)2 (n = 0 or 1) ........................................15 Complex 1.52 Pb(SC6HF4-4)2.......................................................................................15 Complex 1.53 Pt(SRf)2(1,2-C6F4(SRf)-R2) (R2 = Ph2 or Ph(C6F5) .........................15 Complex 1.54 [(CH3)2Pt(μ-SMe2)]2 .............................................................................15 Complex 1.55 A six-coordinate platinum (IV) fluoride complex ...........................15 Complex 1.56 The six-coordinate platinum (IV) fluoride complex produced in the                          reaction of 1.55 and acetone........................................15 Complex 1.57 (Imine)Platinum (IV) fluoride complexes ........................................16 298 Complex 1.58 MeIr(PEt3)3 ..........................................................................................17 Complex 1.59 C6F5Ir(PEt3)2(FPEt2) ...........................................................................17 Complex 1.60 (Cp*)RhF(PMe3)(C6F5) .......................................................................18 Complex 1.61 (C5Me5)RhCl(PMe3)(C6F5) .................................................................18 Complex 1.61 (C5Me5)RhCl(PMe3)(C6F5) .................................................................18 Complex 1.62 NiF(PPh3)2(2-C4N2F2Cl) .....................................................................18 Complex 1.63 NiCl(PPh3)2(2-C4N2F2Cl) ....................................................................18 Complex 1.64 NiF(PEt3)2(2-C5NF4) ...........................................................................18 Complex 1.65 NiI(PEt3)2(2-C5NF4) ............................................................................18 Complex 1.66 PdF(PiPr3)2(4-C5NF4) ..........................................................................18 Complex 1.67 PdCl(PiPr3)2(4-C5NF4) ........................................................................18 Complex 1.68 Pt(IV)-F complex ...............................................................................18 Complex 1.69 Pt(IV)-X complex ...............................................................................18 Complex 1.70 trans-NiF(2-C5NF3H)(PEt3)2 ..............................................................19 Complex 1.71 trans-NiN3(2-C5NF3H)(PEt3)2 .............................................................19 Complex 1.72 trans-NiNCO(2-C5NF3H)(PEt3)2 ........................................................19 Complex 1.73 trans-NiF(2-C5NF4)(PEt3)2 .................................................................19 Complex 1.74 trans-Ni(X)(2-C5NF4)(PEt3)2 ..............................................................20 Complex 1.75 Pyrimidine-Ni-F complex ....................................................................20 Complex 1.76 Pyrimidine-Ni-F complex (pyrimidine with new aryl-toluene bond) ....20 Complex 1.77 trans-PdF(4-C5NF4)(P iPr3)2 ..................................................................21 Complex 1.78 trans-Pd(N3)(4-C5NF4)(P iPr3)2..............................................................21 Complex 1.79 Rh(I)(PMe3)3L.......................................................................................24 Complex 1.80 (C5Me5)Rh(III)(PMe3)(C6F5)H .............................................................24 Complex 1.81 Cp2ZrCl2................................................................................................24 Complex 1.82 Cp2TiCl2 ................................................................................................24 Complex 1.83 Fe-F complex .......................................................................................25 Complex 1.84 [Et3Si] +[CHB11H5Cl6] -...........................................................................26 Complex 1.85 Ru(NHC)(PPh3)2(CO)H2 [NHC = IPr (1,3-bis(2,6-diisopropylphenyl)- imidazole-2-ylidene) or IMes (1,3-bis(2,4,6-trimethylphenyl)imidazole-2-ylidene)........26 Complex 1.86 Ru(NHC)(PPh3)2(CO)H2 [NHC = IPr (1,3-bis(2,6-diisopropylphenyl)- 299 imidazolin-2-ylidene) or IMes (1,3-bis(2,4,6-trimethylphenyl)imidazolin-2-ylidene) .....26 Complex 1.87 Ni(Me2PCH2CH2PMe2)Cl2 ...................................................................27 Complex 1.88 Ni(IPr)2 [IPr = (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene)28 Complex 1.89 Ni(IPr) [IPr = (1,3-bis(2,6-diisopropylphenyl)imidazole-2-ylidene).28 Complex 1.90 Ni(acac)2................................................................................................28 Complex 1.91 Pd2(dba)3 ...............................................................................................29 Complex 1.92 Pd(PPh3)4...............................................................................................30 Complex 1.93 Cp2Zr(C6F5)2 .........................................................................................31 Complex 1.94 trans-NiF(4-C4N2F2H)(PEt3)2 ...............................................................32 Complex 1.95 Ni(acac)2(O,P-ligand)............................................................................33 Complex 1.96 Pyrimidine-Ni-F complex ....................................................................33 Complex 1.97 NiCl2(dppp) ...........................................................................................35 Complex 1.98 NiCl2(dppf)............................................................................................35 Complex 1.99 PdCl2(PCy3)2 .........................................................................................36 Complex 1.100 Co(acac)2 .............................................................................................37 Complex 1.101 TaCl5 ...................................................................................................38 Complex 1.102 RhH(PPh3)4 .........................................................................................39 Complex 1.103 Five coordinate Pt(IV)-F species .....................................................43 Complex 1.104 Five coordinate Pt(IV)-R species .....................................................43 Complex 1.105 Six coordinate Pt(IV)-R species.......................................................43 Complex 1.106 Pd(Pt-Bu3)2..........................................................................................45 Complex 1.107 PdCl2(PCy2OHOPCy2)2 ......................................................................45 Complex 1.108 PCN-type palladium pincer complex ...................................................46 Complex 1.109 Na2PdCl4 .............................................................................................47 300 Chapter 2 Complex 2.1 [(CH3)2Pt(μ-SMe2)]2.................................................................................62 Complex 2.2 Pt(IV)-F complex ...................................................................................62 Complex 2.3 Pt(IV)-R complex...................................................................................62 Complex 2.4 [(Imine)Pt(IV)Me2(SMe2)] + ....................................................................63 Complex 2.5 [(CD3)2Pt(μ-SMe2)]2 ...............................................................................70 Complex 2.2 (Imine)(CD3)2Pt(IV)-F complex ............................................................70 1a N-(2,4,6-trifluorobenzylidene)benzylamine ..............................................................65 1b N-(4-bromo-2,6-difluorobenzylidene)benzylamine ..................................................78 1c N-(4-nitrile-2,6-difluorobenzylidene)benzylamine ...................................................78 1d N-(2,6-trifluorobenzylidene)benzylamine.................................................................78 1e N-(2,4,6-trifluorobenzylidene)phenylamine ..............................................................78 1f N-(2,4,6-trifluorobenzylidene)methylamine ..............................................................78 1g N-(2,4,6-trifluorobenzylidene)-4-bromobenzylamine...............................................78 1h N-(2,3,6-trifluorobenzylidene)benzylamine..............................................................80 1i N-(2-chloro-3,6-difluorobenzylidene)benzylamine ...................................................80 1j N-(2,3,5,6-tetrafluorobenzylidene)benzylamine ........................................................80 1k N-(pentafluorobenzylidene)benzylamine ..................................................................80 1l N,N-dimethyl-2,4,6-trifluorobenzamide ....................................................................83 1m 2,4,6-trifluorobenzylaldehyde ..................................................................................83 1n N,N-dimethyl-pentafluorobenzamide .......................................................................83 2a N-(4,6-difluoro-2-methylbenzylidene)benzylamine..................................................65 2b N-(4-bromo-6-difluoro-2-methybenzylidene)benzylamine ......................................78 2c N-(4-nitrile-6-difluoro-2-methybenzylidene)benzylamine........................................78 2e N-(4,6-difluoro-2-methylbenzylidene)phenylamine..................................................78 2g N-(4,6-difluoro-2-methylbenzylidene)-p-bromobenzylamine...................................78 2h N-(3,6-difluoro-2-methylbenzylidene)benzylamine .................................................80 2j N-(3, 5, 6-tetrafluoro-2-methylbenzylidene)benzylamine .......................................80 2k N-(3, 4, 5, 6-tetrafluoro-2-methylbenzylidene)benzylamine .................................80 3a N-(4,6-difluoro-2-methylbenzylidene)benzylamine (with labeled CD3) ...............69 3k N-(3,4,5-trifluoro-2,6-dimethylbenzylidene)benzylamine........................................81 301 Chapter 3 Complex 2.1 [(CH3)2Pt(μ-SMe2)]2...............................................................................113 Complex 2.2 Pt(IV)-F complex ...................................................................................113 Complex 3.1 (6-fluoroimine)Pt(IV)-F complex ........................................................116 Complex 3.2 (3,6-difluoroimine)Pt(IV)-F complex ..................................................116 Complexes 3.3-3.6 in the C-F activation mechanism...............................................119 Complex 3.7  Me3Pt(IV) species prepared from 2.2 with Me2Zn .........................120 Complex 3.7  Me3Pt(IV) species observed in catalysis ...........................................123 Complex 3.8  MePtLn (L = imine and/or CD3CN and/or SMe2) .........................126 Complex 3.9  (tetrafluoro imine)Pt(IV)-F complex...................................................127 Complex 3.10  Five coordinate Pt(IV)-F complex ...................................................134 Complex 3.11  Me2Pt(IV)-F(PPh3) complex ..............................................................135 Complex 3.12  Me3Pt(IV)(PPh3) complex..................................................................135 Complex 3.13  Five coordinate Me3Pt(IV)(PPh3) complex......................................137 Complex 3.14 Me2Pt(IV)F prepared from imine 1e ...............................................142 Complex 3.15 Me3Pt(IV)(SMe2) prepared from imine 1e ......................................142 Complex 3.16 Me3Pt(IV)(PPh3) prepared from imine 1e .......................................142 Complex 3.17 Six-membered Pt(II) complex ...........................................................148 Complex 3.18 Me2PtPPh3 .............................................................................................149 Complex 3.19 Pt(IV)-H complex.................................................................................149 1a N-(2,4,6-trifluorobenzylidene)benzylamine ............................................................112 1b N-(2,6-trifluorobenzylidene)benzylamine...............................................................116 1c N-(2,3,6-trifluorobenzylidene)benzylamine ............................................................116 1d N-(pentafluorobenzylidene)benzylamine ................................................................127 1e N-(pentafluorobenzylidene)para-bromobenzylamine .............................................141 2a N-(4,6-difluoro-2-methylbenzylidene)benzylamine................................................113 2b N-(6-fluoro-2-methylbenzylidene)benzylamine......................................................116 2c N-(3,6-difluoro-2-methylbenzylidene)benzylamine................................................116 2e N-(3,4,5,6-tetrafluoro-2-methylbenzylidene)para-bromobenzylamine...................148 302 Chapter 4 Complex 4.1 diphenyl-Pt(II)(dppf)..............................................................................169 Complex 4.2 PCP-Ir(CH3)2...........................................................................................171 Complex 4.3 PCP-Ir(CH3)Ph........................................................................................171 Complex 4.4 PCP-IrPh2 ................................................................................................171 Complex 4.5 PNP-RhPh2..............................................................................................171 Complex 4.6 PNP-Rh(CH3)Ph......................................................................................171 Complex 4.7 Pd(PEt2Ph)2(CH3)Ph ...............................................................................171 Complex 4.8 Pd[P(CH3)2Ph]2(CH3)2 ............................................................................171 Complex 4.9 NCN-Pt-CH3 ...........................................................................................173 Complexes 4.10-4.11 Reductive elimination products from 4.9 ..............................173

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