[\3 9 :- This is to certify that the dissertation entitled STUDIES OF THE STILLE REACTION USING 119 TIN NMR AND RELATED REACTIONS presented by NICOLE M. TORRES has been accepted towards fulfillment of the requirements for the Doctoral degree in Chemistry WEW Major Professor’ 5 Signature 3 — I < — Zoo? Date MSU is an Affirmative Action/Equal Opportunity Employer LIBRARY Michigan State University PLACE IN RETURN BOX to remove this checkout from your record. To AVOID FINES return on or before date due. MAY BE RECALLED with earlier due date if requested. DATE DUE DATE DUE - DATE DUE 5/08 K:IProj/Acc&Pres/CIRCIDateDue.indd STUDIES l STUDIES OF THE STILLE REACTION USING 119 TIN NMR AND RELATED REACTIONS By Nicole M. Torres A DISSERTATION Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Chemistry 2010 The Stills . . "="‘""“' . “nu min. primtzi mini and retain 5,; I ' .r Nile reactmn ensure that is D‘p’fi-‘r‘ +‘ .' Emmeriblc I I .ha-JOL.‘ W1. Amman-ex tirercnccs mi. ..;.It..tn.\i\c stud 3:1'1‘0'1] I n 0 I 5' “ c p ‘ y L Mime relatixe L" Willis. Ilicxc .~' i‘ ,i_ Tic ‘ ll_\ Ul lilc iL‘-~ 1'33} ' * m the tin ABSTRACT STUDIES OF THE STILLE REACTION USING 119 TIN NMR AND RELATED REACTIONS By Nicole M. Torres The Stille reaction is a widely utilized method for carbon-carbon bond formation, primarily due to its high functional group tolerance and ability to control and retain regio- and stereochemistries. Our groups initial interest in the Stille reaction began with the development of a hydrostannation Stille sequence that is catalytic in tin. Unfortunately, limitations of the nontransferable ligands on tin required the use of more toxic trimethylstannanes vs. tributylstannanes. Conventional wisdom suggests that rate differences exist between trimethyl and tributyl stannanes, however no comprehensive studies to prove this have been reported. To address this shortcoming, we performed a series of rate studies using 119Sn NMR to detennine relative cross coupling rates across a variety of organohalides and conditions. These studies revealed much about the course of this reaction, with many of the results proving unexpected. These findings are discussed in detail in the following dissertation with particular attention paid to the mechanistic aspects of the Stille coupling and the corresponding synthetic implications. Copyright by NICOLE M. TORRES 2010 To my parents and grandparents for their everlasting love and support .1... ACKNOWLEDGEMENTS I would like to express my deepest gratitude to my advisor, Professor Robert E. Maleczka, Jr'. for his guidance, support, and enthusiasm for chemistry. Thank you for the opportunity to work in your lab and for fostering my development as a chemist. Perhaps more importantly, thank you for always believing in me. Thank you to my guidance committee members, Professors Gregory Baker, Jetze Tepe, and James McCusker, for intriguing discussions and suggestions about kinetics! Thank you also to Professor Mitch Smith, for all of the time and support you have given me over these past five years. I would like to thank all of the Professors at MSU for being open to students coming and asking questions, your dedication, and your friendships. Given the nature of my work, I am extremely grateful to Dr. Daniel Holmes for teaching me the ins and outs of the NMR. Many thanks to the past and current Maleczka group members, especially Jill Muchnij and Ron Rahaim who were instrumental in the early stages of my graduate career. Thank you also to Jerome Lavis for his work on germanium couplings. Thank you to other friends in the department, especially Erin Vogel and Amanda Palumbo. vi it I would like to thank all my family for always being there for me, especially my mom (Jinann), dad (Carlos) stepdad (Rod), and stepmom (Helen). Without your love and support, I would not have made it this far. To my sister Julia and brother Victor, thank you for lighting up my life. Finally, I would like to thank Troy Knight. You have been there for me through every step of the way, you have had so much patience with me, and you have taught me so much. I am proud of you for everything you have accomplished and happy that I could be a part of it. I am grateful for your love and friendship, and I am excited to start our lives together! vii TABLE OF CONTENTS LIST OF TABLES ...................................................................................... xi LIST OF FIGURES ................................................................................... xiii LIST OF SCHEMES .................................................................................. xx LIST OF ABBREVIATIONS AND SYMBOLS ..................................... xxiii Chapter 1. An Introduction to the Stille Reaction ......................................... 1 1.1. Synthetic Importance of the Stille Coupling ....................................... 1 1.2. The Catalytic Cycle ............................................................................ 3 1.2.1. Ligand Substitution: Associative vs. Dissociative ........................ 4 1.2.2. Ligand Substitution: Direct vs. Solvent Assisted .......................... 6 1.3. Oxidative Addition: Pd Insertion into C-X bond ................................ 7 1.4. Transmetallation: Transfer of Tin Ligand to Palladium ...................... 9 1.4.1. Mechanism of Transmetallation ................................................... 9 1.4.2. Improvements on the Transmetallation Step ............................... 12 1.5. Reductive Elimination: Carbon-Carbon Bond Formation and Pd Regeneration ........................................................................................... 14 1.6. Towards a Better Understanding of the Stille Reaction .................... 15 Chapter 2. An Introduction to Kinetics, 119Sn NMR, and Data Analysis 16 2.1. Homogeneous Catalysis Kinetics ..................................................... 16 2.2. Development of a Data Acquisition Method ..................................... 17 2.3. Properties of 119Sn NMR .................................................................. 20 2.4. Data Analysis Methods .................................................................... 25 Chapter 3. Quantifying Rate Differences for Trialkyl Stannanes ................ 28 3.1. Initial Objective of the Study ............................................................ 28 3.2. Coupling Partner Choices ................................................................. 28 3.3. Discussion on Stannane Coupling Partners ....................................... 29 3.4. Discussion on Aryl Halide Coupling Partners .................................. 30 3.5. Preparation of Vinyl Stannanes ........................................................ 31 3.6. Development of the Standard Kinetics Procedure ............................. 35 3.7. Monitoring the Course of the Stille Reaction with 119Sn NMR ........ 37 viii 3.8. Control Experiments ........................................................................ 38 3.9. Preliminary Study on Electrophile Scope Leading to Phenyl Exchange ................................................................................................................ 44 3.10. Aryl Iodide Couplings .................................................................... 48 3.11. Aryl Bromide Couplings ................................................................ 54 3.12. Mechanistic Considerations of Aryl Bromide Couplings ................ 56 Chapter 4. Quantifying Rate Differences for Trialkyl Stannanes: Expanding Scope .......................................................................................................... 67 4.1. Conditions to be Screened ................................................................ 67 4.2. Solvent Effects ................................................................................. 67 4.2.1. N-Methyl-Z-pyrrolidinone (NMP) .............................................. 67 4.2.2. Benzene ..................................................................................... 70 4.3. Ligand Effects .................................................................................. 79 4.3.1. Tri-2-furylphosphine (TFP) ........................................................ 81 4.3.2. Tri-tert-butylphosphine P(t-Bu)3 ................................................ 95 4.3.3. Triphenylphosphine ................................................................... 97 4.4. Conclusions ...................................................................................... 98 Chapter 5. Side Reactions of the Stille Reaction ......................................... 99 5.1. Why Use an Internal Standard? ........................................................ 99 5.2. Me4Sn As the Internal “Standard” .................................................... 99 5.3. Formation of Transient Tin Species ................................................ 102 5.4. Implications of Aryl Tin Formation ................................................ 112 5.5. Relation of Aryl Tin Formation to Homocoupling .......................... 114 5.6. Insight into the Basis of R for X vs. R for R Transmetallation ........ 118 Chapter 6. Effect of Additives on the Rate of the Stille Reaction .............. 123 6.1. Reassessing the Goals of Our Study ............................................... 123 6.2. The 2nd Generation Hydrostannation/Stille Sequence Catalytic in . 33,56,57 Tm .............................................................................................. 123 6.3. Correlating Stille Kinetic Data to the Hydrostannation/Stille Sequence .............................................................................................................. 126 6.4. The Fluoride Effect ........................................................................ 127 6.4.1. Couplings of Aryl Iodides in the Presence of Aqueous KF/TBAF .......................................................................................................... 129 6.5. The Water Effect on Aryl Iodide Couplings ................................... 133 6.6. Fluoride and Water Effect on Aryl Bromides ................................. 137 6.7. Insight into the Mechanism of Fluoride and Water Activation ........ 139 ix 6.8. The Copper Effect .......................................................................... 144 6.8.1. Aryl Iodide Couplings in the Presence of CuI .......................... 146 6.8.2. Aryl Bromide Couplings in the Presence of CuI ....................... 153 6.9. Determining the Impact of the Order of Addition for Reactions with CuI ........................................................................................................ 155 Chapter 7. Heck-Like Cross Couplings of Vinyl Germanes ...................... 163 7.1. Why Germanium? .......................................................................... 163 7.2. Development of Organogermane Reactions .................................... 164 7.3. Synthesis of Vinyl Germanes ......................................................... 168 7.4. Finding the Right Coupling Conditions .......................................... 170 7.5. Mechanistic Insight ........................................................................ 176 7.6. Conclusions .................................................................................... 182 Chapter 8. Future Work ............................................................................ 183 Chapter 9. Experimental Details ............................................................... 188 REFERENCES ............................................................................................ 296 LIST OF TABLES Table 2.1. Determination of the Relaxation Time in THF and NMP ........... 25 Table 3.1. Synthesis of Vinyl Stannanes ..................................................... 33 Table 3.2. Methyl Protection of Hydroxyl Stannanes ................................. 33 Table 3.3. Vinyl Stannane Synthesis ........................................................... 34 Table 3.4. Standard Kinetics Sample Preparation ....................................... 36 Table 3.5. Pd Concentration Dependence Data ........................................... 44 Table 3.6. Determination of Cross-Coupled and Phenyl Transfer Product Distribution .......................................................................................... 48 Table 3.7. Aryl Iodide Couplings in THF ................................................... 49 Table 3.8. Temperature Dependent Rate Constants .................................... 53 Table 3.9. Aryl Bromide Couplings in THF ................................................ 55 Table 4.1. Aryl Iodide Couplings in NMP .................................................. 68 Table 4.2. Aryl Bromide Couplings in NMP .............................................. 70 Table 4.3. Aryl Halide Couplings in Benzene ............................................. 72 Table 4.4. Ligand Effectszs ........................................................................ 81 Table 5.1. Testing Conditions for Formation of the Unknown Tin Species .......................................................................................................... 105 Table 5.2. Testing Conditions for Formation of Phenyl Tin from Tin Halide .......................................................................................................... 111 Table 5.3. Product Yields for Stille Reactions in THF .............................. 1 16 Table 5.4. Product Yields for Stille Reactions in NMP and Benzene ........ 117 xi Table 6.1. Comparison of Results Using Me vs. Bu Trialkylstannanes ..... 127 Table 6.2. Fluoride Effect on Me/Bu Rate Differences ............................. 133 Table 6.3. The Copper Effect: Farina & Liebskind’s Results22 ................. 146 Table 6.4. Effect of CuI on Reaction Rate ................................................ 148 Table 6.5. CuI Effect with Higher Catalyst Loading and Temperature: Farina’s Results ................................................................................. 151 Table 6.6. Timing of Cul Addition and Impact on Reaction Outcome in THF .......................................................................................................... 155 Table 6.7. Qualitative Experiments to Determine the Effect of the Order of Addition for Reactions with CuI and the Effect of Air ....................... 157 Table 6.8. Order of Addition for Reactions with CuI ................................ 159 Table 6.9. Cu] Effect on Me/Bu Ratio Under F arina's Conditions ............ 161 Table 7.1. Hydrogermylations .................................................................. 169 Table 7.2. Screening Heck Conditions ...................................................... 172 Table 7.3. Comparing Stille vs. Heck Conditions ..................................... 173 Table 7.4. Scope of Coupling with Various Aryl Halides at 0.05 M ......... 175 Table 7.5. Scope of Coupling with Various Aryl Halides at 0.2 M ........... 176 Table 7.6. Concentration Impact on Z/E Ratios ........................................ 177 Table 7.7. Cross-coupling of Unhindered Vinyltributylgermanes ............. 179 Table 7.8. Effect of Germane Geometry on Coupling ............................... 182 Table 9.1. Reagent Amounts for Pd Dependence Study ............................ 206 Table 9.2. Reagent Amounts for Aryl Bromide Dependence Study .......... 233 xii LIST OF FIGURES Figure 1.1. Selected Natural Products Prepared with a Stille Coupling as a Key Synthetic Step ................................................................................ 2 Figure 1.2. Open Transition State14 ............................................................ 10 Figure 2.1. 1H NMR of Vinyl Protons in Starting Material and Product ..... 19 Figure 2.2. 119Sn NMR Spectrum of Distinct Vinyl Stannanes in THF ...... 20 Figure 2.3. Spin States During an NMR Experiment .................................. 21 Figure 2.4. Pulse Sequence of a Typical 119Sn NMR Kinetics Experiment. A11 kinetics experiments utilized inverse gated decoupling where 1H decoupling is only performed during the acquisition (green box) and not during the rest period (blue line). For the reaction with 40, the recycle delay (d1) is set to 28 sec as shown ...................................................... 24 Figure 2.5. First Order Exponential Curve Fitting with OriginPro 7.5. 186 MHz 119Sn NMR spectra were obtained every 5 min over the course of the reaction of 40 with PM under a szdba3/AsPh3 catalyst system. Each spectrum was integrated relative to the first to obtain the relative ~ integration data shown in the black trace. The solid red line represents the fit to a first order exponential decay model to reveal 1: = 58.7 :I: 0.71 min, which is related to kobS by 1/1: where kobs = 0.017 min.1 ............... 27 Figure 3.1. Substituted Vinyl Stannanes of Interest .................................... 30 Figure 3.2. Electrophiles of Interest ............................................................ 31 Figure 3.3. Course of the Stille Reaction Monitored by 119Sn NMR ........... 38 Figure 3.4. Verification of Zero-Order Electrophile Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of 40 upon coupling with either 1.2 equiv (black trace) or 2.2 equiv (red trace) of PM under a szdba3/ASPh3 catalyst system. Both sets of data were fit to xiii a first order exponential decay model (not shown) to reveal kobs = 0.006 . -1 mm . ................................................................................................... 40 Figure 3.5. Verification of Pseudo-First-Order Stannane Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of either 1.0 equiv (black trace) or 0.5 equiv (red trace) of 40 upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system. Both sets of data were fit to a first order exponential decay model (not shown) to reveal kobs = 0.006 min-l. Instantaneous rates are approximated for illustrative purposes only, as the slope of a tangent line is equal to the instantaneous rate. The true value is determined by the following relationship: rate = kobS[Sn]. For 1.0 equiv, [Sn] :1 0.19 M and for 0.50 equiv, [Sn] is 2 0.095 M. ..................................................................... 41 Figure 3.6. Pd Concentration Dependence. The 186 MHz 119Sn NMR relative integration data for the consumption of 39 or 40 upon coupling with-PhI under different szdba3/AsPh3 catalyst loadings were obtained and the data were fit to a first order exponential decay model (not shown) to obtain kobs for each catalyst loading and stannane combination (red trace: 39 R = Me, blue trace: 40 R = Bu). The ln(kobs) vs. ln([Pd]) were then plotted to reveal a linear relationship between kobs and” [Pd]. The black solid lines represent a fit to a linear regression model and gave a slope of 1.0 and 1.2 for 39 and 40, respectively, indicating a first order dependence on Pd concentration. ..................... 43 Figure 3.7. Plot of Temperature Dependence for Trimethyl and Tributyl Stannane Reactions. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (top) or 40 (bottom) upon coupling with PM under a szdba3/AsPh3 catalyst system at 40 °C (black trace), 50 °C (red trace), and 55 °C (blue trace). All sets of data were fit to a first order exponential decay model (not shown) to reveal the rate constants outlined below in Table 3.8 .................................................................. 52 Figure 3.8. Arrhenius Plot to Determine the Activation Energy, Ea. An Arrhenius Plot was prepared by plotting ln(kobs) vs. 1/T, where the kobs values at various temperatures were determined in Table 3.8. The black lines represent a fit to a linear regression model, with the slope = -Ea/R. xiv For 39, Ea = 12.4 kcal/mol (fit A: red solid line) or 8.4 kcal/mol when only 45 and 50 °C are fit (fit B: red dashed line) and for 40, Ea = 6.8 kcal/mol. .............................................................................................. 54 Figure 3.9. Determination of Electrophile Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of 41 or 42 upon coupling with 1.2 equiv (black), 3.5 equiv (red), 5.3 equiv (green), or 7.1 equiv (blue) of 4-bromobenzotrifluoride. The data were fit to a first order exponential decay model (not shown) to obtain kobs. The solid colored lines are to guide the eye. The ln(kobs) vs. ln([ArBr]) were then plotted (inset) to reveal a linear relationship between kobS and [ArBr]. The red solid lines represent a fit to a linear regression model and gave a slope of 0.9, indicating first order aryl bromide concentration dependence. ......................................................................................... 58 Figure 3.10. Stille coupling of 42 with 4-iodobenzotrifluoride monitored by 19F NMR. ............................................................................................ 61 Figure 3.11. Stille coupling of 42 with 4-bromobenzotrifluoride monitored by 19F NMR ......................................................................................... 61 Figure 3.12. ‘91: NMR Spectra of the Oxidative Addition of 4- Iodobenzotrifluoride (Scheme 3.8) Compared with the Unknown Signals Observed During the Stille Coupling of 42 with 4- Iodobenzotrifluoride (Scheme 3.7) ....................................................... 64 Figure 4.1. Coupling of 39 or 40 with PM in Benzene. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (black) or 40 (green) upon coupling with PM under a szdba3/AsPh3 catalyst system in benzene. Data for 39 from t = 0-20 min was fit to a linear regression plot (inset, red solid line). First order exponential fit (red solid line) did not provide an accurate fit. Data for 40 was fit to a first order exponential decay model (blue solid line). .............................................................. 73 Figure 4.2. Stannantrane: Activation of Sn—C Bond ................................... 74 Figure 4.3. Coordination of Stannanes to Palladium ................................... 75 XV Figure 4.4. Individual Experiments. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (black trace) or 40 (red trace) upon coupling with 1.2 equiv of Pb] under a szdba3/AsPh3 catalyst system in benzene. Both sets of data were fit to a first order exponential decay model (not shown) to reveal for 39, kobs = 0.0044 mm1 and for 40, k0,, = 0.022 min“. ......................................................................... 78 Figure 4.5. Competition Experiment. 186 MHz 119Sn NMR normalized relative integration data for the consumption of 39 (black trace) and 40 (red trace) upon coupling with 1.2 equiv of PM under a szdba3/ASPh3 catalyst system in benzene. Both sets of data were fit to a first order exponential decay model (not shown) to reveal for 39, kobS = 0.005 min- 1 and for 40, km = 0.01 min" .............................................................. 79 Figure 4.6. Studies of Couplings with Pd/TFP. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (black trace) or 40 (red trace) upon coupling with 1.2 equiv of PM under a szdba3/TFP catalyst system. Both sets of data were fit to a first order exponential decay model (not shown) after the induction period (~100 min) to reveal for 39, kob, = 0.033 min" and for 40, kobs = 0.024 min". .................... 82 Figure 4.7. Autocatalytic Reaction Process ................................................. 83 Figure 4.8. Determining if a Protected Hydroxyl Affects Autocatalysis. 186 MHz 119Sn NMR relative integration data for the consumption of 42 (black trace) upon coupling with 1.2 equiv of PM under a szdba3/TF P catalyst system. The data was fit to a first order exponential decay model (not shown) after the induction period (~500 min) to reveal a kobs = 0.024 min“. ...................................................................................... 85 Figure 4.9. Relative Decay of Pd(Pt-Bu3)2 (74) and Pd(Pt—Bu3)2(H)(Br) (77) During the Oxidative Addition of PhBr in 2-Butanone at 70 °C.47 Reproduced with permission from Barrios-Landeros, F .; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 5842-5843. Copyright 2008 American Chemical Society ................................................................. 86 xvi Figure 4.10. Oxidative Addition of szdba3/TFP to PM in THF. Selected 202 MHz 31P NMR spectra during an arrayed experiment monitoring the oxidative addition of szdba3/TFP to Pb] in THF. The first spectra (from front to back) was taken before the addition of PM, the second was taken immediately following the addition of PhI, and the third was taken after the reaction proceeded for 2 h by which time a new signal appeared at -1.5 ppm ............................................................................ 90 Figure 4.11. Coupling of 39 and PhBr by Pd/P(t-Bu)3 Monitored by GC. Consumption of 39 upon coupling with 1.2 equiv of PhBr under a szdba3/PPh3 catalyst system as monitored by GC with mesitylene as an internal standard. The concentration was determined by comparison to the appropriate calibration curve. The black trace represents the data collected by GC. The two red dots represent an extrapolation if the reaction proceeded by first order kinetics while the red solid line represents a fit of the data that would be first order to a first order exponential decay model ...................................................................... 97 Figure 5.1. Course of the Stille Reaction Monitored by 119Sn NMR ......... 102 Figure 5.2. Spiked 119Sn NMR Experiment. The lower 186 MHz 119Sn NMR spectrum shows the crude reaction mixture for the coupling of 39 with 4-bromoanisole in a szdba3/AsPh3 catalyst system where by a small amount of a tin compound was formed at -31 ppm. The upper spectrum shows the crude mixture spiked with an authentic sample of 4- trimethylstannylanisole, showing a signal at -31 ppm. ....................... 109 Figure 5.3. Possible Structures for the 119Sn NMR Signal at +50 ppm ..... 111 Figure 5.4. Interplanar Angles Between Aryl Plane and Metal Coordination Plane .................................................................................................. 121 Figure 6.]. Reaction Profile of Fluoride Additive Effect. 186 MHz 119Sn NMR relative integration data for the consumption of 39 or 40 without fluoride (black trace) and with fluoride (red trace) upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system. All sets of data were fit to a first order exponential decay model (not shown) to reveal for 39 without fluoride, kob, = 0.016 min" and with fluoride, kob, = 0.21 xvii figure 6.2. R: NMR relal 1503017!) U catalyst 5}"; [‘ISS CIICC 0 All 56 ets 01 sp'lt‘twn)~ T} Fimm6t 40 with 11.; 1356...; D81: .\'.\IR reldti “L” “ll'lt: \\ m the PT CV61 .- e 6 4 RC 1‘ 1 . ' 1‘ 6‘13“ 01‘ 01 fluoride ll “PA. [lshcnk‘c Uf‘ min'1 and for 40, kobs = 0.0068 min'1 and with fluoride, kobs = 0.048 min". ................................................................................................. 131 Figure 6.2. Reaction Profile with Water as an Additive. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (top) or 40 (bottom) upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system in the absence of fluoride and water (black trace), in the presence of fluoride (red trace), or in the presence of water (blue trace). All sets of data were fit to a first order exponential decay model (not shown). The rate constants with and without fluoride were described in Figure 6.1. For the reaction of 39 with water, kobs = 0.27 min'1 and for 40 with water, kobs = 0.036 min". ...................................................... 134 Figure 6.3. Determination of Water Activation Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of 39 or 40 upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system in the presence of the indicated amount of water ................................ 136 Figure 6.4. Reaction Profile of Water as an Additive. 186 MHz 119Sn NMR relative integration data for the consumption of 40 upon coupling with 1.2 equiv of PhBr under a szdba3/AsPh3 catalyst system in the absence of fluoride (black trace), in the presence of fluoride (red trace), or in the presence of water (blue trace). ........................................................... 138 Figure 6.5 . Activation of Stannane by Hydrogen Bonded Chelation ......... 141 Figure 6.6. Mechanism of Transmetallation .............................................. 143 Figure 6.7. Energy Diagram of a Retro-Transmetallation Mechanism20 144 Figure 6.8. Overcoming the Inhibitory Effects of CuI with H20. 186 MHz ll9$n NMR relative integration data for the consumption of 58 (0.1 mmol) upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system in the absence of any additives (black trace), in the presence of 5 pL of water (red trace), in the presence of 8 mol% CuI and 5 [IL of water (green trace), or in the presence of 8 mol% CuI and 15 pL of water (blue trace). The solid colored lines are to guide the eye. ..... 153 xviii Figure 6.9. Effect of Cu] Using Farina’s Order. 186 MHz 119Sn NMR relative integration data for the consumption of trimethylvinyltin (57, black traces) or tributylvinyltin (58, red traces) upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system in the absence of any additives (solid traces) or in the presence of 8 mol% CuI (dashed traces). ............................................................................................... 162 Figure 7.1. Activation of Ge—Carbon Bond by Oxygen Chelation ............. 182 Figure 8.1. Stannanes with No Coordinative Oxygen ............................... 185 Figure 8.2. Pattenden’s Sequential Stille Coupling Partners ..................... 186 Figure 8.3. Proposed One-Pot Stille Coupling Partners ............................ 186 Figure 8.4. Head to Tail Controled Couplings .......................................... 187 xix LIST OF SCHEMES Scheme 1.1. The Stille Reaction ................................................................... 2 Scheme 1.2. Mechanism of the Stille Reaction ............................................. 4 Scheme 1.3. Ligand Substitution Process ..................................................... 5 Scheme 1.4. DFT Calculations: Associative vs. Dissociative Pathway8 ........ 6 Scheme 1.5. Direct Nucleophilic Attack or Solvent Assisted Attack as Possible Pathways for Associative Ligand Substitution ......................... 7 Scheme 1.6. Nucleophilic Aromatic Substitution .......................................... 8 Scheme 1.7. Three-Center Mechanism ......................................................... 8 Scheme 1.8. Stille’s Inversion of 01-Stereochemistry14 ................................ 10 Scheme 1.9. F alck's Retention of tit-Stereochemistry17 ............................... 11 Scheme 1.10. Dual Catalytic Cycle ............................................................ 12 Scheme 1.11. Facile Reductive Elimination ................................................ 15 Scheme 3.1. Palladium Catalyzed Hydrostannation .................................... 32 Scheme 3.2. In Situ Tin Hydride Generation .............................................. 32 Scheme 3.3. Initial Stille Reaction of Interest for Kinetics Study ............... 36 Scheme 3.4. Stille Coupling with 4-Bromoanisole ..................................... 45 Scheme 3.5. Aryl-Phenyl Exchange Process Leading to Cross-Coupled and Phenyl Transfer Products ..................................................................... 46 Scheme 3.6. Mechanism of Transmetallation8 ............................................ 50 Scheme 3.7. Stille Coupling Monitored by 19F NMR ................................. 60 XX Scheme 3.8. Oxidative Addition of 4-Iodobenzotrifluoride ........................ 63 Scheme 4.1. Formation and Inhibition of the Active Catalyst ..................... 75 Scheme 4.2. Competition Experiment to Test for Trimethyl Stannane Coordination ........................................................................................ 77 Scheme 4.3. Effect of Products On Autocatalysis ....................................... 84 Scheme 4.4. Oxidative Addition Studies by Hartwig47 ............................... 86 Scheme 4.5 . Catalytic Cycle for the Regeneration of Hydrido Palladium Halide .................................................................................................. 87 Scheme 4.6. Proposed Preparation of TFPZPd(H)(I) 79 .............................. 91 Scheme 4.7. Impact of P(t-Bu)3 on Bromobenzene Coupling ..................... 97 Scheme 5.1. Stille Reaction Utilizing Me4Sn as an Internal Standard ....... 100 Scheme 5.2. Kocheshkov Disproportionation for the Synthesis of Alkyl Tin Halides ............................................................................................... 100 Scheme 5.3. Synthesis of 2-Tributylstannylfuran ...................................... 107 Scheme 5.4. Benzyl Stannane Formation Observed by Stille52 ................. 112 Scheme 5.5 . Pathway to the Formation of Aryl Tins and Resulting Compounds ........................................................................................ 113 Scheme 5.6. R for X vs. R for R Illustration ............................................. 119 Scheme 5.7. Possible Mechanism of R for R Transmetallation ................. 121 Scheme 6.1. Hydrostannation/Stille Sequence Catalytic in Tin ................. 124 Scheme 6.2. Me3SnCl as the Tin Source .................................................. 125 Scheme 6.3. Buganl as the Tin Source ................................................... 126 xxi Scheme 6.4. Scheme 6.5. Scheme 6.6. Scheme 7.]. Scheme 7.2. Scheme 7.3. Scheme 7.4. Scheme 7.5. Scheme 7.6. Scheme 7.7. Fluoride Activation of Stannates58 ....................................... 128 Promoting the Stille Reaction with CsF ................................ 129 Stille Coupling to Determine Fluoride Effect ....................... 130 Allylations with Allyl Germane“ ......................................... 165 Cross-Couplings of Germatranes65 ....................................... 166 Vinyl Tris(trimethylsilyl)germane Couplings by Wnuk7l'73. 167 Tricholorgerrnane Couplings by Kosugi78 ............................ 167 Germane Cross-Coupling with Inversion of Olefin Geometry31 .............................................................................................. 170 Proposed Mechanism of Germanium Cross—Coupling .......... 171 Synthesis of Z Germanes ...................................................... 180 xxii LIST (. it it) \\. Fl.» \. 1;» ’l—II a . 41W .33.- Lil Ac ACN AgNO3 aq Bu cat CH2C12 C uTC d1 dba El Et equiv LIST OF ABBREVIATIONS AND SYMBOLS gyromagnetic ratio change acetyl acetonitrile silver nitrate aqueous magnetic field butyl catalytic dichloromethane copper(I)-thiophene-2-carboxylate cyclohexyl recycle delay dibenzylideneacetone entgegen (German for opposite) electron ionization ethyl equivalents xxiii FID GC GC/MS HRMS Int min mmol mol m.p. NBS NMP NMR NOE Ph PMHS free induction decay gas chromatography gas chromatography/mass spectrometry hour high resolution mass spectrometry internal rate constant molarity methyl milliliter minute millimole mole melting point N—bromosuccinimide N—methyl-2-pyrrolidinone nuclear magnetic resonance nuclear Overhauser effect phenyl polymethylhydrosiloxane xxiv Bil I TBABI sat. SM TBABr TBAF TBS Tf TFP THF TMS rate determining step room temperature saturated starting material tetrabutylammonium bromide tetrabutylammonium fluoride t-butyldimethylsilyl triflate tri-2-furylphosphine tetrahydrofuran trimethylsilyl zusammen (German for together) XXV fhipter 1. An Intrt l.l.S}nthetic lmpU Carbon-carbor :iizipulitinns in syn itsniplc organic >1 :r-duts. Cross-c011 ninetl under pulldt Exit formation. Ex; irgazotinl. Suzuki3 'T‘Tgsnnzinc I reactittt it llSh l‘unctiunttl 3 “It” condition, 1 £6 natural W: , mulllpUlilllUI‘. \Itrlltgfi, ‘ . “"-(0n,1umt ‘lcitl c ‘: X‘mlllcs \\h L 3...}, “Mil 7 - e lllgllltghmt Chapter 1. An Introduction to the Stille Reaction 1.]. Synthetic Importance of the Stille Coupling Carbon-carbon bond forming reactions are among the most useful manipulations in synthetic organic chemistry; they allow for the elaboration of simple organic substrates into larger, more complex, and more valuable products. Cross-couplings of organometallics and organic halides (or triflates) under palladium catalysis are a common method for carbon-carbon bond formation. Examples of such include the Stillel’2 (organometallic = organotin), Suzuki3 (organoboron), Hiyama (organosilane), and Negishi4 (organozinc) reactions. The Stille reaction (Scheme 1.1) is often used due to the high functional group tolerance of the organotin reagents and the mild reaction conditions necessary to effect coupling. Therefore, it has been useful in convergent approaches to highly functionalized compounds (i.e. late stage natural product synthesis) without the need for tedious protecting group manipulations that may severely diminish the overall yield of a ' synthesis. Conjugated 7t systems are particularly accessible by this method. A few examples where the Stille reaction has been utilized as a key synthetic step are highlighted in Figure 1.1. Additionally, the increased access to organotin reagents5 and the stability to both air and moisture has allowed for the implementation of this method. Scheme 1.1. The Stille Reaction X cat. Pd, / /\Sn13u3+ 0 /\© + Bu3SnX Ligand X = halide or triflate Figure 1.1. Selected Natural Products Prepared with a Stille Coupling as a Key Synthetic Step HO“. Stille o - NH Smith, A. 3., 111 et al. Maleczka, R. E., Jr. et al. ro osed Iituarine C proposed amphidinolide A Mo p p St'll °- -- 1e \HO Nicolaou, K. C. et al. palmerolide A 1.2. The Catalytic Cycle Cross-coupling reactions are most often mediated by catalytic amounts of palladium through a three step catalytic cycle. The main steps of the catalytic cycle are common to all cross coupling reactions and include oxidative addition, transmetallation, and reductive elimination as shown in Scheme 1.2 specifically for the Stille reaction. Oxidative addition occurs when a Pd(0) species (1) inserts into a carbon-halide or -triflate bond to form an activated Pd(II) species (3). Transmetallation involves the transfer of an organo group from the organometallic to Pd while also producing the tin halide by-product (5). Lastly, reductive elimination of the Pd(II) species (6) affords the cross—coupled organic product (7) and regenerates the Pd(0) catalyst (1).6 Mechanistically however, these steps are quite complex. Ligand isomerizations, dissociations, and substitutions are necessary for the reaction to progress and should not be overlooked in order to fully understand the “mechanism” of the Stille reaction, or any other cross- coupling reaction. l\\ Scheme 1.2. Mechanism of the Stille Reaction R'-R” PdoLn R'-x 7 1 2 Reductive Oxidative Elimination Addition 1 \R” l & Fide-L RLv-Pd- 6 3 R3SnX n3snrx2” 5 4 Transmetallation 1.2.1. Ligand Substitution: Associative vs. Dissociative The catalytic cycle is a series of ligand substitutions and isomerizations about palladium. To achieve ligand substitution, two pathways are plausible: associative or dissociative. In an associative mechanism, a nucleophile attacks the 16 e' square planar Pd center (8) resulting in an 18 e' trigonalbipyramidal complex (9) (Scheme 1.3).7 The site of substitution to afford 11 is dependent on the trans effect of the ligands. In the dissociative mechanism, the ligand with the highest trans influence determines which ligand will dissociate to afford a 14 e' T—Shape complex (10) in which the nucleophile may then occupy the vacant site to afford 11.7 Although there are two possible pathways, dissociative l\\. tr 31 In“ mechanisms are rare in ligand substitution processes. Typically a very electron rich metal center such as Pt is necessary to invoke a dissociative mechanism and it is realized that in most cases ligand substitutions in the . . . . . 2,7 Stllle reaction occur by an assocrative mechantsm. Scheme 1.3. Ligand Substitution Process associative: 18 e' trigonalbipyramidal complexes I 1 .L R3SnR' L. .R L. 11 LgPd-L —> L -Pd-L + L -Pd' LT T 'L T 'L 8 9a 9b in R33 I an A I LLjpd-L —* LL—‘Pd‘L + LL:Pd—R T 10 T 11a T 11b dissociative: 14 e' T-shape complex Recently, Espinet conducted DFT calculations that provide fiirther evidence for a dominant associative process.8 He showed that the transmetallation step has a 21 kcal/mol barrier to overcome in a dissociative process but only a 5.7 kcal/mol barrier through an associative process when L = AsH3 in the gas phase (Scheme 1.4). The same trend is observed with PPh3 as the ligand in the gas phase as well as in THF for both ligands. This clearly indicates that ligand substitutions favor an associative process. Scheme 1.4. DFT Calculations: Associative vs. Dissociative Pathway8 ‘ i F ?r + SI'IM63 21 kcal/mol L'Pd—‘j K dissociative 13-Br - 7 i Br 5.7 kcal/mol Lt. Br SnMe3 L-Pd-L + SnMe3 L,Pd-\ associative / 12-Br 14-Br 0 kcal/mol _ _ 1.2.2. Ligand Substitution: Direct vs. Solvent Assisted Although ligand substitutions are typically envisioned as a direct replacement of one ligand with an incoming nucleophile (Nu), it can also proceed through a solvent assisted pathway (Scheme 1.5). Solvent molecules are in high concentration relative to other ligands or nucleophiles. Thus, when a strongly coordinating solvent such as N-methyl—Z-pyrrolidinone (NMP) is utilized, it is able to replace ligands through an associative mechanism, providing a more activated Pd species. This solvento complex may then undergo substitution with the nucleophile. The overall ligand substitution is achieved either directly or by solvent assisted pathways, but the solvent assisted pathways greatly facilitate ligand substitutions.2 Solvent molecules can aid in ligand substitutions, as well as help to stabilize Pd complexes throughout the catalytic cycle to avoid decomposition to unreactive Pd black. Scheme 1.5. Direct Nucleophilic Attack or Solvent Assisted Attack as Possible Pathways for Associative Ligand Substitution L. .X L. _X .Pd. N” .Pd. X L X Nu 15 17 (8) Nu L. .X .Pd X ‘(S) 16 1.3. Oxidative Addition: Pd Insertion into C-X bond Oidative addition involves insertion of a low-valent, coordinatively unsaturated nucleophilic Pd(0) species into a carbon-halide or -triflate bond. This species is accessed through solvent assisted ligand dissociation of the precatalyst, PdL4, to afford the solvent stabilized “active” catalytic species, (S)PdL2. Formation of these types of stabilized compounds have been observed and intensely studied by Jutand and Amatore.9 Initially however, two mechanisms for the oxidative addition to aryl halides were proposed by Stille.10 One proposal is similar to nucleophilic aromatic substitution” (Scheme 1.6) where electron withdrawing substituents on the ring have been shown to facilitate the oxidative addition -J M —* guess. The seem: itchinism via a 111 complex (23'). It NIIR. only the inn:- paint has an R g in? influence of l at} isnmerize 10 I?‘ iodine in a tit t. rite-detenninin g i, . ‘ w nethinhm ' St‘llt‘ft Pdo + S Di. Ni .3 I”? + B process. The second proposed mechanism proceeds through a concerted mechanism via a three-center transition state12 (Scheme 1.7) resulting in a cis complex (23). However, upon monitoring the oxidative addition by 31P NMR, only the trans oxidative addition product (24) was observed. The cis product has an R group and phosphine ligand in a trans relationship. The trans influence of these ligands results in destabilization and the product may isomerize to the thermodynamically stable trans isomer (with R and phosphine in a cis relationship).13 This isomerization occurs fast relative to the rate-determining transmetallation step and is typically not considered in - 2 the mechanism. Scheme 1.6. Nucleophilic Aromatic Substitution x +Pd X W 18 19 20 Scheme 1.7. Three-Center Mechanism PPh3 R Ph3P\ ’13 i Ph3P\ ,R Pth ,9 Pd + )I( ——> ‘ Pd; ———> Pd ’Pq I \- / \ PPh3 Ph3P' X Phsp .X X Pph3 CIS trans 21 22 23 24 h\ . \ -' 1.1,Transmetallati While OXltlclll. cu: coupling react tip 15 unique to tinned step 01 rittt‘ernla ligand . “.11.," ' ' I [tenant lnitidl >2 ." 3i . ' .1} PNIIRret'cul. ii. upon addition ind to be zero-(t: T2] . not results 511;- ri.” L entitlitle electn r-olitdllon. and fill" “Jill” 9 '11 . .tittlttllmn I\ tut..’lll_ Otgunutrt l W‘ . . . te addition \i ll .l.1ltchanism U l . ‘ nthtongin ::~\-l’€ll It) [Like 1.4. T ransmetallation: Transfer of Tin Ligand to Palladium While oxidative addition and reductive elimination are common to all cross coupling reactions and have been studied in depth, the transmetallation step is unique to each cross coupling reaction and is thus the least understood step of the Stille reaction. Overall, transmetallation involves transfer of a ligand coordinated to tin in exchange for a ligand coordinated to palladium. Initial studies where Stille monitored the course of the reaction by 31P NMR revealed the observation of only the oxidative addition product, . . 1,14 . even upon addition of excess stannane. Furthermore, the reaction. was found to be zero-order in electrophile (iodobenzene) by Stille and others. These results suggest that transmetallation is the slow step when organohalide electrophiles are utilized, while oxidative addition, reductive elimination, and any necessary isomerizations occur much faster. Therefore, tr'ansmetallation is considered the rate-determining step for the Stille reaction. Organotriflate electrophiles proved more complex15 such that Oxidative addition was suggested as the rate-determining step in THF.16 1 -4.1. Mechanism of Transmetallation In the original mechanistic proposal by Stille, transmetallation was Sllggested to take place by an 852 mechanism (in which Pd is the l\\,. iatophfle) iii a morn experime: aton to tin occur innnhflphospht couriers obsen‘et M” iii catalyst 5} st unnunntuuk Scheme H? p‘SHBU3 + % 26 electrophile) via an open transition state (Figure 1.2).14 This proposal supports experimental evidence that inversion of configuration at the 01- carbon to tin occurs when subjected to Stille cross-coupling conditions in hexamethylphosphoramide (HMPA).14 About a decade later, Falck and coworkers observed retention of configuration in toluene when utilizing a Pd/Cu catalyst system.17 Reevaluation of the transmetallation mechanism was necessary to account for retention and inversion of stereochemistry. Figure 1.2. Open Transition State14 CI II? R‘P:d ..... C ..... San3 L 25 Scheme 1.8. Stille’s Inversion of a-Stereochemistryl4 D o [Pd(CH Ph)Cl(PPh ) 1(4 mo|°/) o D H‘1 2 3 2 ° V‘H IC-SnBu3 + )L > >—C‘ Ph 0' Ph HMPA, 65 °c Ph Ph 26 27 28 10 acii UL ‘C-SI‘BS3 + I MetC-Hgls 29 A dual catal y t tithe opposing st rinsition state is iscciatit'e process: 5:13:13 resulting lion a: PI complex (35.1 :I‘tpled product. lit trenchemistry at lli Tia’1‘7”l‘Used by Stil an be lomietl. \\ it "flit“ ' filiuukl. T1115 pdlll in. The dumi attainment. (jenc' 1:1: it -~ I . thhdnlsm 1.x ' 1L". :1 til. the cyclic m" E. ' op] ne ,. '" .1 his rentic Scheme 1.9. Falck's Retention of tit-Stereochemistry17 H o [PdCl2(PPh3)2] CuCN (2 mol%) H , B BZOTb‘SDBUs + > 20:2:4 Me(CH2)6 CI Ph toluene, 75°C Me(CH2)6 Ph 29 27 30 A dual catalytic cycle (Scheme 1.10) proposed by Espinet can account for the opposing stereochemical outcome where either a cyclic or open transition state is possible and where both pathways operate by an associative processz’18 The cyclic transition state pathway forms a Sn—X—Pd bridge resulting from substitution for L (not X) and subsequently affords the cis Pd complex (35) and immediate reductive elimination to give the cross- Coupled product. Evaluation of the transition state suggests retention of Stereochemistry at the ct-carbon. Following an open transition state similar to that proposed by Stille, both cis (6) and trans (33) transmetallation products may be formed, with the cis isomer directly leading to the cross-coupled product. This pathway results in inversion of stereochemistry at the 01- Carbon. The dominant pathway is dependent on the substrates and environment. Generally, although there are many determining factors, the Open mechanism is favored for triflates and very polar solvents (i.e. HMPA), While the cyclic mechanism is favored for halides since bridging can occur. I38pinet has verified the possibility for both an openl6’19 and cyclicg’20 11 . J ‘l unionism bl W - ' at! it .\'.\lR. E>P‘“‘ remediates ini'oli RLR“ [PI ’V 35 RII-Pld-L T‘ 11.2. Improvement It has h ccn sli- _~‘. , .htiism of the , . \ i) r'i-rlllCI) and additi .irtctctl to a reyicw mechanism by kinetically deducing the pathway and observing intermediates by NMR. Espinet,8 along with Alvarez and deLeraZI, have revised the intermediates involved in the dual catalytic cycle based on DF T calculations. Scheme 1.10. Dual Catalytic Cycle R'-x 2 I II A F3| R-R [PdLn] I Bl X-P|d-L 31 7 1 /C ..... Id:'l-_ L R35" """ X Y=(S)orX :L I cyclic TS . (S) or so vent Fl" BI ‘x 6' 35 RH-Pd-L ._.____ ,Iqii_F.|d_L . L_P|d_L 3 R' . +( ) l/L 1.? -(S) /P|d ..... C ..... SnRa Ly 1 H R' + open TS “ RI'SnR L-P'd-L _ R Fl" 3 I X L-Pd-L + R”-P|d-L A (s) Rll L 32 33 6 l .4.2. Improvements on the Transmetallation Step It has been shown that solventM’17 can greatly affect the outcome and rnechanism of the reaction. Other studies have indicated that coupling 15,19,22,23 partners” and additives, can affect changes as well. The reader is directed to a review on the Stille reaction, published by Farina in 1997, for a 12 l\1 note in depth on: . :4 and additnes. A major at at: enhancernet‘ ‘- grids.”3 Prior iiPPh; 14- Hum ic- store it in the nice the ligand: lifli't stable Pdgd nature to the S tlhlytic hehay ll mined under item ”318 [liar 13:11»: . ct 121m 911111] ”d rdllo of l .4 ler Incrca_ I .l*_i~ more in depth analysis of the scope and limitations of the coupling partners and additives.24 A major advancement for the Stille reaction was Farina’s report on rate enhancements using tri-2-fi1rylphosphine (TFP) and AsPh3 as Pd ligands.25 Prior to this report, the most common Pd catalyst used was Pd(PPh3)4. However, this catalyst is somewhat unstable; care must be taken to store it in the freezer and use it in a glove box, or at least a glove bag since the ligands are susceptible to oxidation. Farina showed that starting with stable szdba3, premixing it with PPh3, then subjecting this catalyst mixture to the Stille coupling partners resulted in a reaction with identical Catalytic behavior to that with Pd(PPh3)4. These reactions could also be performed under mild reaction temperatures of only 50 °C. He went on to demonstrate that substituting either TFP or AsPh3 as the ligand resulted in lElrge rate enhancements, two to three orders of magnitude over PPh3, r eSpectively. Furthermore, controlling the stoichiometry with a palladium to ligand ratio of 1:2 would favor formation of the active (S)PdL2 species and further increase the rate of reaction. Excess ligand slowed the reactions dOWn, confirming that ligand dissociation is a key step in the catalytic cycle. 13 lictnd inhibition 12211011 condition'i ”at 1,5.Reductiye El Regeneration 01erall. ICC inning step and C are coupled tugetl' rensmetallation m at can immediate it in a (it relatiot imitation >Ul)\llli Reductiye e Feeding Cl\ prod tlbuth fi-hy dride mt: ~‘ ‘CJUL1116 @1111 930d 11”] [5 Ul‘lk‘ 115? ~ , ‘I layllL‘ Wilt] int tilL‘ H)” \ ~Uggeu Ligand inhibition factors were calculated based on these results.25 These reaction conditions are now commonly used in Stille couplings. 1.5.Reductive Elimination: Carbon-Carbon Bond Formation and Pd Regeneration Overall, reductive elimination is the actual carbon-carbon bond- forrning step and occurs when two organogroups in a cis relationship on Pd are coupled together and eliminate a reduced Pd(0) species. In the cyclic transmetallation mechanism, transmetallation directly forms the cis product and can immediately undergo reductive elimination. If the organogroups are not in a cis relationship, they must first isomerize via solvent assisted ligand dissocation/substitutions described in Sections 1.2.1 and 1.2.2. Reductive eliminations are thought to be fast reactions once the preceding cis product is formed. In fact, Stille found that a species capable of both B-hydride elimination and reductive elimination (36) only produces 1ihe reductive elimination product (37) (Scheme 1.11).1 Since B-hydride elimination is often a problem in organometallic chemistry because it is a Very facile reaction, the preference for reductive elimination over [ii-hydride elimination suggests that reductive elimination is faster. l4 Pa/\V/\ 37 m'l'ou'ards Nuaiert‘ 19“ ‘~— iiiitiyes. mechanism. C ions on the ffginls on tin stannane is in The non-tram marines red A...‘ - ~centrallo “"3 Objectiye "53315011 tin Scheme 1.11. Facile Reductive Elimination o i? 'r i? 1- Dev ‘— +> + W L 37 36 33 1.6. Towards a Better Understanding of the Stille Reaction Numerous studies have shown that solvent,l4’17 ligands on Pd,25’26 additives,19’22 and electrophiles27 can change the kinetics and/or operative mechanism. Our approach to further understanding the Stille reaction was to focus on the stannane. Specifically, we asked how the non-transferable ligands on tin (denoted R in Scheme 1.2) would affect the reaction since the stannane is involved in the rate determining transmetallation step. Typically the non-transferable ligands are either methyl or butyl, where the trimethyl Stannanes react faster, but are more toxic and more expensive. It would be beneficial to further understand the differences between them and it became Our objective to provide relative rates of reaction per the non-transferable ligands on tin. (hapter 2. A" 2.1. Homogenet As discu: thee-step proc Ttd’h‘llw elirtti second order re: :11 4 :1: '2 i: more specific Chapter 2. An Introduction to Kinetics, 119Sn NMR, and Data Analysis 2.1. Homogeneous Catalysis Kinetics As discussed in Chapter 1, the Stille reaction proceeds through a three-step process including oxidative addition, transmetallation, and reductive elimination (Figure 1.1). The reaction scheme is a catalyzed second order reaction of the form A] + A2 —) P (1) or more specifically RIX + R3SnR" -) RI-RH (2) Since the transmetallation is said to be rate determining, the overall rate of the reaction will be defined by this step. The rate equation should then be dependent on both the concentration of the oxidative addition product ([RlPdXD and starting stannane ([Sn]) rate = ktranS[Sn][RIPdX] (3) Since Pd is catalytic and there is excess electrophile (RIX), the concentration of RIPdX is constant relative to Sn and can be combined with the rate COnstant ktrans to obtain a new observable rate constant, kobs- The rate ecltlation then becomes independent of RIX and can be reevaluated as the 16 pseudo first or rate = I15" tiilt should b1 t:- o‘ei‘iate fron‘ negation of. I" 1 _ nil-.3. . - L. ct» EXPLIHL‘IT _r __ tsnlt ‘ [h ‘iliere the cor i‘lilgumplllln (l i "1 Dt‘I'e 10p [1' “if nL’Xl he ability to t‘ lllt'tillltlllll" rcpt NHL}; With Oltc U‘ch ltir 5T1: , . Dorm 3111c pseudo first order rate law rate = kobS[Sn] (4) It should be realized that this analysis is only valid when [RIX] > [Sn]. If [RIX] < [Sn], towards the end of the reaction, when [RIX] approaches zero, [RIPdX] will decrease and no longer be constant. This will cause the kinetics to deviate from first order behavior. Integration of Eq. 4 reveals the linear equation ln[Sn]t = ln[Sn]0 — kobst (5) or the exponential firnction -kt [Snlt = [Snloe (6) where the consumption of stannane is exponential in time and therefore consumption of stannane may be monitored to study the kinetics. 2.2. Development of a Data Acquisition Method We next decided upon a method to monitor the reaction. We required the ability to monitor consumption of the stannane and also have the option of monitoring product formation to ensure that consumption and formation track with one another. Gas chromatography meets these requirements and is often used for kinetic studies. Unfortunately, aliquots must be taken for each time point and are typically worked up or filtered. This is not only tedious l7 and allows for 13! pints collected. 7 3331173 the data: teatntenl pub“ 11"" that error as t treblem. only the simple kinetics ey {satires toward 111-. Monitoring striated iiith G attenuation of II do. running the mists to be culled Chi disadt antuge if “I'Ultl bt‘ pert}: tactiuny be done ,‘ttld be Utilized tullCd 80h Unis ‘ 1X Costs as]; $ and allows for larger amounts of error, but also limits the number of data points collected. Therefore, one must rely on linear regression analysis to analyze the data: ln[Sn] vs. time is plotted where the slope = -k. This treatment puts great emphasis on the later parts of the reaction that has the highest error as the signal to noise ratio approaches zero. To avoid this problem, only the first few half-lives of the reaction are typically analyzed in simple kinetics experiments but could allow one to miss key mechanistic features toward the end of the reaction. Monitoring reaction progress by NMR can alleviate shortcomings associated with GC. With 1H NMR, the consumption of starting material and formation of the product can be monitored simultaneously (Figure 2.1a). Also, running the reaction in the spectrometer allows for numerous data points to be collected as well as minimization of human error/interference. One disadvantage is that the use of deuterated solvents is necessary. Since we would be performing a series of studies, it was important that all of the reactions be done at precisely the same concentration. Therefore, solutions would be utilized for the preparation of each sample, making the use of deuterated solvents unreasonable from a cost standpoint: A 0.7 mL vial of THF-d8 costs ~$15 and over $100 for NMP-d9. Furthermore and perhaps more importantly, we did not want to be confined by the availability of 18 M deuterated solvent: bi suppressing 11 However, in our c: not ideal for quant: hotter]. ‘tt‘. ~LSMWLJ M k. atthXt We then C0 Jt‘lH NMR. 11111 a n atoms in the competition CHM} it p" .. . it} Inct gliy , . ‘ endl In h'.\‘ \lR Schll‘u at . ‘6“mddhu \ 'él‘; . n "is [_]n . Ell “Rm-“Cd deuterated solvents as the study progressed. Protonated solvents may be used by suppressing the intensity of the solvent signal with presaturation. However, in our case this resulted in peak broadening and overlap, which is not ideal for quantitative analysis (Figure 2.1b). Figure 2.1. 1H NMR of Vinvl Protons in Starting Material and Product it 30 30 0 0 time (min) time (min) a) 1H NMR: THF-d8 b) 1H NMR: solvent suppression We then considered 1198n NMR. This method retains the advantages of 1H NMR, but allows for the use of protonated solvents since there are no tin atoms in the solvent. 119Sn NMR would also allow for us to run competition experiments between trialkyl stannanes. Each stannane has a distinct signal in the 119Sn NMR (Figure 2.2) whereas the vinyl protons in a 1H NMR Spectrum would be difficult to distinguish. It is also advantageous that we would be able to monitor the fate of the tin species as tin by-products are often ignored in the context of kinetic studies. 19 Figure 3.3. l 3.1 Propertic The pro: trier to Ullll/I 1‘5th 10 Ct Titties (if | 5326': W p 1l h phi! 1 .il - “”1111” it ill Figure 2.2. 1198n NMR Spectrum of Distinct Vinyl Stannanes in THF l R3SI’I \ OH M63811}: BU3SD3< i-PI'3SD)‘: Y T V r T O -10 -20 -30 -4O -50 -60 ppm 2.3. Properties of 119Sn NMR The process of how NMR data is obtained often goes unconsidered. In order to utilize 119Sn NMR as a true representation of the reaction course, we had to consider the underlying principles of NMR as well as the properties of the Sn nucleus. When an NMR experiment is performed, the sample is placed in a magnetic field, BO, where a slight majority of the spins will align with the magnetic field in the ground state of spin +‘/2 while the rest will occupy -1/2. The preference for +1/2 over -‘/2 occupance is increased as the energy difference between these two states is increased. When a short radio frequency (RF) pulse with a frequency spread due to the Heisenberg uncertainty principle is applied, excitation of all the nuclei in the local enviroment is achieved in the form of absorption (from +l/2 to -1/2) and emission (—'/2 to +1/2) (Figure 2.3). Since the ground state of +16. has slightly 20 I higher occupancy, there will be net absorption. The absorption of energy back to the ground state is displayed in the NMR spectra as a signal after Fourier transform of the F ID. It is important to understand the correlation between all of these factors: Increasing Bo, increases the energy difference between the spin states, which in turn increases the occupancy of the lower spin states allowing for greater net absorption upon irradiation and a larger observed signal. Figure 2.3. Spin States During an NMR Experiment 30 30 1t rLLLl—l—I /=-1/2 1 Mil 1:-1/2 ; i .5 ‘3” AEE _”_.. AE: 8‘ S . I g 6 I I (U 3 LUJJILILT i-_-+1/2 iiLLLlL l=+1/2 The energy difference between the two spin states is dependent on the constant 71, the magnetic field, and the gyromagnetic ratio (y) by AB = YhBo (7) Here it is necessary to discuss the importance of the gyromagnetic ratio in 15 the context of tin NMR. There are three spin 1/2 tin nuclei: 1 Sn, 117'Sn, and 119Sn. We will be utilizing “gSn because it has the highest natural abundance of 8.59%. The Sn nuclei all exhibit negative gyromagnetic ratios 21 there that of 1 193“ tilt respect to AF. it does have implies The nuclear ( fiat is doubly irradi. n= (1- Int 1... there n is the el‘l‘cc it is the intensity u fedescribed as llzrax : It” 2" I if . tthe N0 nuclei aha ‘ ‘ t ntement of Illt I‘ 'I " tr. ; ts necatiye f ... study is to (this w Mil - to artificially il't XOE buildup where that of 119Sn is -10.0317. The fact that it is negative is not important with respect to AE, as this just means that -‘/2 is the ground state. However, it does have implications regarding the data acquisition. The nuclear Overhauser effect is a phenomenon in which one nucleus that is doubly irradiated can enhance the signal of another and is defined by II = (1 - I01/10 (8) where n is the effect (or enhancement), 1 is the intensity with irradiation, and 10 is the intensity without double irradiation. The maximum effect, nmax, can be described as Tlmax = Yin/ZYobs (9) If the two nuclei are the same (i.e. both are protons), there is net enhancement of the signal. However, in regards to proton decoupling of the tin, y is negative for tin and would thus decrease the signal. Since the key to our study is to observe the consumption of our starting stannane, we do not want to artificially deplete the stannane signal. Care must be taken to avoid an NOE build-up, which is actually depletion in this case. In the pulse sequence of the NMR experiment (Figure 2.4) we use inverse gated proton decoupling such that decoupling (the green box) is only performed during the acquisition time. The time preceding the acquisition is the rest time 22 there N035 ”‘3 doing the rest tin recycle delay (d1 ) take is detennint he applied RF. ' recovered. If sub depletion ofthe si r . teen nucleus ha hierefctre, the d1 1:. ics lound that where NOE’s may build up if set to decouple. By avoiding decoupling during the rest time, we avoid depleting the signal. It is important to set the recycle delay (d1) to an appropriate value in the pulse sequence as well. This value is determined by the time constant (T1) in which the spins relax afier the applied RF. When d1 = 5 x T], 99.33% of magnetization has been recovered. If substantial time is not given, this too will result in artificial depletion of the signal because relaxation relates to occupation of spin states. Each nucleus has a different relaxation time in different environments. Therefore, the dl’s for the stannanes of interest were obtained (Table 2.1). It was found that relaxation time was independent of solvent. 23 I\\ ‘1 .2305 we 08 mm 8 Em E 23 Eve 2982 05 .3 EB 22882 2: com Ave: 2%: coca $2 2: merge Ho: can 983 :8de :oEmeom 05 maize oncottom Eco mm mew—350% EL 22:» mamasgon Beam 3.52: cogs: $525098 850:3 =< .EoEtomxm 8:er MEZ cm 329C. a mo oozes—com 33m {N BLAME a: 24 Table 3-1- DC“ With the w performed such tl‘ t'tcaghout the cot concentration deter :zegrated relatiy e t 2.4. Data Anal} sis Once data \\t he macro TRAIL-13.7 hintegrated oxer new ' Table 2.1. Determination of the Relaxation Time in THF and NMP eaten/94m R T1 (sec) (11 (sec) Me (39) 1.65 10 Bu (40) 5.80 28 With the 119Sn parameters defined, arrayed experiments could be performed such that spectra are acquired at designated time intervals throughout the course of the reaction. The use of internal standards for concentration determination is unnecessary because the signals could be integrated relative to each other. 2.4. Data Analysis Methods Once data were collected, the spectra were identically integrated using the macro iritall3.T This allows for spectra in a given arrayed experiment to be integrated over precisely the same regions as well as normalizing the integration values relative to each other. For instance, the first spectrum in the series was set to 100 and the subsequent spectra are integrated relative to 4. that. The integration values” (stannane consumption) were then plotted vs. T intall3 is a macro written by Dr. Daniel Holmes of the Max T. Rogers NMR Facility to integrate all spectra within an arrayed experiment over the same region and relative to the first spectra. Typically kinetics plots show concentration vs. time. However, ~2 min passes from the time the stannane is injected into the sample and the data collection begins. At this point, 25 inc. The pro: 151 to a first 1 he reaction in time. The program OriginPro 7.528 was used to plot and fit the data (Figure 2.5) to a first order exponential function (Eq. 6) to obtain a rate constant for the reaction in the form of the lifetime, 1:, where k = 1/13. a portion of the starting material has already been consumed and we cannot be sure of the exact concentration. Therefore, the signal intensity, which is a proportional value to concentration, is used instead. 26 a) C11 1 CI: Intensity (Normalized) a) Graphical representation of exponential fit 100: Reaction Progress Followed jg . by 119$n NMR ‘75“ 80‘ - Sn Intensity g ‘ Exponential Fit 0 604 E . e .0. C 3 i E 20- l 04 .- 67100'260'360'460'500r6607760' T1me,m'n b) Numerical parameters from fit Equation: y = Ae'X/t1 + y R2 = 0.99502 y0 = 0.16169 a 0.13013 A = 93.06808 :l: 0.68886 1: = 58.71986 2t 0.71412 0 Figure 2.5. First Order Exponential Curve Fitting with OriginPro 7.5. 186 MHz 119Sn NMR spectra were obtained every 5 min over the course of the reaction of 40 with PM under a szdba3/AsPh3 catalyst system. Each spectrum was integrated relative to the first to obtain the relative integration data shown in the black trace. The solid red line represents the fit to a first order exponential decay model to reveal 1: = 58.7 :t 0.71 min, which is related to kobs by 1/1: where kobS = 0.017 min-l. 27 Chapter 3. Qua" 3.1. Initial Obicc Most of Ill transmetallation organohalides. C11; tithe reaction. I client and Pd lig ion-transferable i;i-:t=.i'ledge that t; ctii‘interparts. no j :derstand the exrc .etnmethyl statina Chapter 3. Quantifying Rate Differences for Trialkyl Stannanes 3.1. Initial Objective of the Study Most of the kinetic studies on the Stille reaction have regarded transmetallation as the rate-determining step for reactions with organohalides. Changes to this step should lead to changes in the overall rate of the reaction. Therefore, many studies have focused on the effects of solvent and Pd ligands. In addition, the ligands employed on the stannane (non-transferable ligands) have an impact. Although it is common knowledge that trimethyl stannanes couple faster than their tributyl counterparts, no in depth systematic studies have been performed to understand the extent and generality of these differences. Given the fact that the trimethyl stannanes are far more toxic and more expensive than tributyl stannanes, it would be useful to further understand the benefits of using one over the other. Thus, our first objective was to provide the synthetic organic community with a systematic analysis of the coupling rates between these trialkyl stannanes across a range of electrophiles. 3.2. Coupling Partner Choices The Stille reaction is useful in the formation of new carbon-carbon 0 bonds between variations of sp3, sp2, and sp-hybridized carbon atoms. 28 However. spl- zoiards coupl side-reaction i and are prei'alt Since ct tic—Lght it 11.3) mph Vinyl 5 vinyl stannane 3.1. Discussio We util access to st i3crustannatic However, spz-sp2 couplings are most common as they are highly activated towards coupling, are known to retain olefin geometry], and have limited side-reaction issues. The resulting conjugated 11: systems are easily accessed and are prevalent in natural products (highlighted briefly in Chapter 1). Since conjugated 1: systems are often the target of Stille couplings, we thought it was important to utilize them in our studies. We therefore chose to couple vinyl stannanes with aryl halides due to the ease of access to the vinyl stannane partners and the commercial availability of aryl halides. 3.3. Discussion on Stannane Coupling Partners We utilized the stannanes outlined in Figure 3.1 for our studies. Access to stannanes 39-40 and 43-44 can be realized through the hydrostannation of the corresponding alkynes. The fully substituted propargylic position allows for selective formation of the E isomer as opposed to the internal isomer; this regioselectivity has been well precedented.29 Stannanes 41 and 42 can be accessed through methyl protection of 39 and 40, respectively. 29 Alth- i’iaetics m3 is miihll ‘ ire proton C tydrogen bi an my (the a-stiiate met. stannanes ac iris eliniina tiretics acro 'i’oild also bl lit respect 1 z I ..I. Discussit. T0 pit; 5p. . .. .lltlpltlllt‘ a “it" {'Fr . “hid. d‘kl nf :- C Figure 3.1. Substituted Vinyl Stannanes of Interest n33n/\)<0H R3Sn/\><0Me R3Sn/\> TBAF R38nF] R3SnH The hydrostannation method developed by Maleczka et al.33 was utilized to synthesize the vinyl stannanes and is outlined in Table 3.1. For the synthesis of stannane 44 (entry 6), a slight excess of the alkyne was 32 necessary 10 CC problems of the reduced pressurl stannane 43. sine be removed in ll 41 and 42 were respectiyely. The necessary to consume all of the Bu3SnH as to avoid Si02 separation problems of the non—polar stannane. Any residual alkyne was removed under reduced pressure. Excess alkyne was not necessary for the synthesis of stannane 43, since Me3SnH is slightly soluble in H20 and any excess could be removed in the extraction/wash work-up procedure. Methoxy stannanes 41 and 42 were accessed by etherification of pure stannanes 39 and 40, respectively. These syntheses are outlined in Table 3.2. Table 3.1. Synthesis of Vinyl Stannanes R38nX, KF (aq, 3 equiv), (PPh3)2PdCl2 (1 mol%), Ax // R| : R33” \ RI TBAF (cat), PMHS (1.5 equiv), THF entry R Rl X time temp product: yield 1 Me OH Cl 1 h rt 39: 37% 2 Bu OH CI 2.5 h rt 40: 80% 3 Cy OH Cl 7.5 h 50 °C 55: 53% 4a i-Pr OH F 1.5 h rt 56: 94% 5 Me CH3 CI 1.5 h rt 43: 20% 6 Bu CH3 Cl 1.5 l] rt 44: 66% a KF was not necessary for in situ SnF generation 33 Table FISn (A) 61111” [J In order 11 prepared the uni These substrates such of the trim solution in Tlll method demon: tiny] stannane ~ Stille 1“ I11 - e re: Table 3.2. Methyl Protection of Hydroxyl Stannanes ' AX NaH, Mel, Ax R38” \ OH R38” \ OMe THF, 80 °c, 4 hr entry R product: yield 1 Me (39) 41: 84% 2 Bu (40) 42: 83% In order to compare our results to previous studies by Farina, we prepared the unsubstituted vinyl trimethyl and tributyl stannanes as well. These substrates are quite volatile and even with purification by distillation, much of the trimethyl vinyl stannane was lost and could only be isolated as a solution in THF. Tributyl vinyl stannane was prepared by the Grignard method demonstrated by Seyferth,34 where the more sensitive trimethyl vinyl stannane was prepared by the adapted procedure of Scott, Crisp, and Stille.35 The reaction conditions and yields are described in Table 3.3. Table 3.3. Vinyl Stannane Synthesis WM gBr R3SnC| > ferric, THF, 66-67 °c 5.5 h entry R time temp product: yield 1 Me 5.5 h 70 °C 57: 4% 2 Bu 20 h 70 °C 58: 87% 34 16.09““ \l'it} 531 Slflic ruinous aetilO’PCd tied IO 0t NMR 5’33 '\ statentrat ;urtentrat rurtentra: W!“ kw .. urgutli' 3‘? A“. anunenl\ is ' . MUSIH. Ii] 9L, «C tolurn :eteaeh :gand TCi _\,,‘.‘_“ ‘ ~ ‘itlialnln: 5., .,_‘"}..P4 fwzg a 3.. K I 5"?“ \If ‘I 3.6. Development of the Standard Kinetics Procedure With the synthesis of the vinyl stannanes completed, we chose the first Stille coupling reaction of interest as shown in Scheme 3.3. The conditions were based on the widely utilized Pd/ligand combination developed by Farina25 and were discussed in Section 1.4.2. Benene-d6 was used to obtain‘field lock since these reactions would be carried out in a NMR spectrometer. Since reaction kinetics are dependent on substrate concentration, it was essential that our reactions were carried out at the same concentration and that we knew the precise volume of each reaction. A final concentration of ~0.2 M in stannane was desired since this is a common concentration used in organic synthesis (e.g. 1 mmol reactions are commonly run in 5 mL of solvent). Each stannane of interest has a different density, thus a different volume to incorporate in the reaction. To normalize the volume incorporated across stannanes, 1 M solutions were prepared so that each reaction would utilize the same volume of solution. The Pd and ligand required time to “premix” to obtain the active catalyst before combining all reagents.25 Therefore, a solution of the Pd and ligand was prepared and stirred for about 10 min until color change from purple to green signified formation of the active catalyst. A set volume of the Pd/ligand solution could then be utilized for each reaction, ensuring 35 umshtent riknred 01857 51 consistent catalyst loadings. The electrophile would then be added neat followed by an additional amount of THF to bring the concentration to 0.1857 M in the organostannane. The standard protocol is described in Table 3.4. Scheme 3.3. Initial Stille Reaction of Interest for Kinetics Study Pdgdba3 (2 mol%), M AsPh3 (8 mol%), /\>< R3Sn OH > Ph \ OH Phl (1.2 equiv), 39 0' 4° 0606 (4.6 vol%), 59 TH F, 50 °c Table 3.4. Standard Kinetics Sample Preparation reagent/solution volume added to sample C6D6 50 PL 39 or 40 200 ”La szdbag, b 600 pL ASPh3 Pb] 27 uL additional THF 200 uL Total Stannane Concentration: 0.185 7 M aTHF solution that is 1 M in 39 or 40 bTHF solution that is 0.0067 M in Pd and 0.0267 M in ASPh3 To prepare the samples, all of the reagents except the electrophile (aryl halide) were added to an NMR tube. The order of addition was irrelevant. The sample was inserted into a 500 MHz spectrometer, heated to 36 rag reinser further dill its descril 3.7..\ltmit L'sin .310 see I product. {it mt fror' przriucts t: 1 .K ‘ t,'i'"\~‘""- ‘ 3‘ ~—‘\l t L T'il'lg'i 3 Uknel ‘ie - blgn; 50 °C,T tuned to the 119Sn nucleus, and properly shimmed. The sample was then ejected so that the electrophile could be added, after which the sample was reinserted, reshimmed, and an arrayed kinetics experiment was initiated. Further details are available in the experimental section. Work up of the data was described in Section 2.4. 3.7. Monitoring the Course of the Stille Reaction with 119Sn NMR Using 119Sn NMR to monitor the course of the Stille reaction allows us to see the consumption of the stannane, formation of the tin halide by— product, and any other tin containing species formed during the reaction. We know from experiments using 1H NMR and by analyzing the reaction products that stannane consumption tracks with Stille coupling. We do not observed stannane decomposition. Figure 3.3 shows that monitoring the course of a Stille coupling (for the reaction in Scheme 3.3 where R = Me) by 119Sn NMR is a viable method. The starting material and by—product peaks are visible and distinct. The tin halide signal is somewhat suppressed and broadened due to a longer relaxation time and oligomerization, which causes the signal to drift downfield upon increased concentration.36 Two other T The NMR temperature was calibrated using ethylene glycol every few months. Actual temperatures ranged from 50.3-50.6 °C. 37 unexpected tin containing species are also observed that would likely be overlooked by other monitoring methods. These species will be discussed in detail in Chapter 5. Figure 3.3. Course of the Stille Reaction Monitored by 119Sn NMR \ Phl (1.2 equiv), A Jr \ M933” OH szdbas (2 m0l°/o), AsPh3 (8 m0|°/o), P“ OH 39 0606 (4.6 vol%), THF, 50 °C 59 flaunt WWWOH I! “i- “can HW‘WI‘OM “9'1““... Norm wd- i, “Mummwmfiw .., '1 Wu «lmflnmwéraguuwmww rm. ”W- ‘W . .‘. ‘ 10 0 -1O —20 -30 -40 -50 ppm 3.8. Control Experiments With the standard protocol for the kinetics study developed, it was essential to verify our assumptions of zero—order electrophile dependence, pseudo-first—order stannane dependence, and that Pd concentration is consistent and can be incorporated in an observable rate constant, kobs. The 38 control experimcn‘ ranirlg the stoichi [’an doubl ceilined in Schem gratile as seen in i electrophile \i hen nertry reducing th 11. if the concei rallylrinylstannai I'l'drds the end of it’ll l: lilmlillltln \l ’1'?” i ' ,..nded the same ‘ control experiments were performed on the reaction outlined in Scheme 3.3, varying the stoichiometries accordingly. Upon doubling the amount of iodobenzene added to the reaction outlined in Scheme 3.3 where R = Bu, there was no effect on the reaction profile as seen in Figure 3.4. This verifies that the reaction is zero-order in electrophile when run under pseudo-first order stannane conditions. We did not try reducing the amount of iodobenzene. As discussed earlier in Section 2.1, if the concentration of RX is less than the concentration of the trialkylvinylstannane, we would observe deviations from first order kinetics towards the end of the reaction. We also ran a reaction in the dark to be sure that 12 formation was not initiated by light. Reaction in the dark and light provided the same rate profiles. 39 / 33.1350 16 Pd2dba3 (2 mol%), AsPh3( (8 mol%), Bu3Sn THF, 0605 (4. 6 vol%), 59 50 °C 1 equiv 1.2 or 2.2 equiv Phl Concentration Dependence 1004 -_ 7?: . j - 1.2 equiv g 80- i. 2.2 equiv g . ’t '5 60- ‘q: E , "'1' G) " “h" a. ‘ 3'5' 204 %w .- ‘ l “Keri: Oi 0'100'260'360'460'560'660'700 Time,m'n Figure 3.4. Verification of Zero-Order Electrophile Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of 40 upon coupling with either 1.2 equiv (black trace) or 2.2 equiv (red trace) of PM under a szdba3/AsPh3 catalyst system. Both sets of data were fit to a first order exponential decay model (not shown) to reveal kobS = 0.006 min-l. Since the reaction conditions set forth are pseudo-first-order in stannane, we would expect that by reducing the concentration of the stannane, the rate of the reaction would change but the rate constant would remain the same because rate = kObS[Sn]. When only half of the tin concentration (0.5 equiv) was used for the reaction outlined in Scheme 3.3 where R = Bu, the instantaneous rate was less than when 1 equiv was used, 40 is expected. This at lg (signifying I i316 CODSIflDlS “'1 reaction first orde /\>< 3038n 40 1,0 orOSO equi Intensity (Normalized) as expected. This is visualized by comparing the slopes of the tangent lines at to (signifying the instantaneous rate) as seen in Figure 3.5. However, the rate constants were the same for both reactions, which is indicative of a reaction first order in stannane. Pd2dba3 (2 mol%), AsPh3( (8 mol%), BU3SH THF, 0606 (4. 6 VOlo/o), 59 50 °C 1.0 or 0.50 equiv 1.2 equiv Sn Concentration Dependence 100.l , 5,; l - 1.0 equnv .(gu Bol .. — instantaneous rate g 60 ‘t '13, - 0.5 equiv g A it, '_ _ - instantaneous rate . \ m ’5‘ 40- '3. ':-.-, 0c) ‘ ‘1'.» ~* I E 20~ i “he. fig"... WM _ MN“ I"? O 4 i ‘fiqtfibyc‘i'e-zzgm - ,. W . A’:- ‘7...“wa 'u“ 6T160T200r360’460T500'660'7700 Time,min Figure 3. 5. Verification of Pseudo-First-Order Stannane Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of either 1.0 equiv (black trace) or 0.5 equiv (red trace) of 40 upon coupling with 1.2 equiv of Phl under a szdba3/AsPh3 catalyst system. Both sets of data were fit to a first order exponential decay model (not shown) to reveal kobS = 0.006 min-l. Instantaneous rates are approximated for illustrative purposes only, as the slope of a tangent line is equal to the instantaneous rate. The true value is determined by the following relationship: rate = kobs[Sn]. For 1.0 equiv, [Sn] 2 0.19 M and for 0.50 equiv, [Sn] is ’2 0.095 M. 41 T0 establ' Figure 3.6 for b lire data indica media Varies lir. he reaction to t iiégure 3.6. Tat . I In hbeI To establish continuity of the catalyst, we ran the reaction outlined in Figure 3.6 for both R = Me and Bu over a range of catalyst concentrations. The data indicate that the amount of active catalyst present in the reaction media varies linearly with the amount of catalyst added at the beginning of the reaction to the same extent for both the trimethyl and tributyl stannanes (Figure 3.6, Table 3.5). The Pd concentration may therefore be incorporated in kobs. 42 /\>< R35” 0! 40 1.0 equiv |()Q( kobs ) szdba3 (x mol%), /\>< l AsPh3 (4x mol%), \ + > OH R3Sn \ OH G 40 THF, 0606 (4.6 VOIO/o), 59 50 °C 1.0 equiv ' 1.2 equiv _1_4_ Pd Concentration Dependence -15- y=1.03853x+0.65829 - Bu(40) A R2 = 0.99313 U) 5 -1.8« ‘53 2 -20- y = 1.19924x + 0.75314 .2.2_ R7- = 0.99709 .2'.6 ' .214 ' —2'.2 ' 5.0 '09 ( [Pd] ) Figure 3.6. Pd Concentration Dependence. The 186 MHz ll9Sn NMR relative integration data for the consumption of 39 or 40 upon coupling with PM under different szdba3/AsPh3 catalyst loadings were obtained and the data were fit to a first order exponential decay model (not shown) to obtain kobs for each catalyst loading and stannane combination (red trace: 39 R = Me, blue trace: 40 R = Bu). The ln(kobs) vs. ln([Pd]) were then plotted to reveal a linear relationship between kobs and [Pd]. The black solid lines represent a fit to a linear regression model and gave a slope of 1.0 and 1.2 for 39 and 40, respectively, indicating a first order dependence on Pd concentration. 43 l ‘70 Q :3 II 3.9. Preli [Hitting Th the ’5'Cetr Effie, “t In a hen. Eloisa rm, 7. [hi-1r!“ d :5 [int Tu‘hkl\ 1 . , r " 1 (‘11- Cine Table 3.5. Pd Concentration Dependence Data [Pd], M 10g [Pd] kobs 108 (kobs) R = Me (39) R = Bu (40) 0.0031 .2.51 0.01074 .1.97 0.0037 —2.43 0.0145 —1.84 0.0037 —2.43 0.0068 —2.17 0.050 -231 0.01 —2.0 0.0062 -2.21 0.013 -1.89 0.0074 .2.13 0.02764 -1.56 0.0074 .2.13 0.01543 -1.8 3.9. Preliminary Study on Electrophile Scope Leading to Phenyl Exchange Thus far, all experiments have been performed using iodobenzene as the electrophilic aryl halide. To gain an understanding of how substituted arenes would affect the rate, 4-bromoanisole was utilized as the electrophile in a bench-top reaction (Scheme 3.4). Monitoring the reaction by TLC revealed that the stannane was mostly consumed after 10.5 h. Afier reaction work-up and purification, two products were identified: the desired cross- coupled product (60) and a phenyl coupled product (59). The phenyl product was not a result of impure 4—bromoanisole. In fact, phenyl exchange 37-4l products are quite common when PPh3 is utilized as the Pd ligand. After oxidative addition, transfer of a phenyl from the Pd ligand, PPh3, in 44 addition mat; exchange for the aryl Pd ligand (from the electrophile) can occur. This process is presumed to proceed through a reductive elimination of PPh3 and Ar to afford the phosphonium salt (Ph3ArP+X') (62) and Pd(0). Oxidative addition of a P-Ph bond of the phosphonium salt would then lead to a PhXPsz species (63) capable of transmetallation and reductive elimination (Scheme 3.5). Less is known regarding triphenylarsine ligands although transfer has been observed and used as a method to construct various aryl . . . 42 arsme derivatlves. Scheme 3.4. Stille Coupling with 4-Bromoanisole szdba3 (2 mol%), AsPh (8 mol%), \ /\>< /\>< 3 : OH + Ph \ OH Bu3Sn OH 4-bromoanisole 40 (1.2 equiv), M90 60 59 THF, 50 °C, 10.5 h cross-coupled phenyl transfer product product 45 Scheme 3'5 'PdiPPhslz" \Ve becan complicate our l stannane. but v a“ Diiterent electr :eiction. I'loxs'e reaction. A's lt' Sim one TBdCl ’iilifdinu the r Scheme 3.5. Aryl-Phenyl Exchange Process Leading to Cross- Coupled and Phenyl Transfer Products 6) G Pd(O) + Ph3PAr X reductive oxidative elimination 62 addition Ph-Ar Ar-X Ph P. ,x exchange ArthP. ,x "Pd(PPhal2" ——> 3 Pd Pd. Ar’ PPh3 Ph’ PPh3 61 63 R3SHRI l Ar-R' + Ph-R' cross-coupled phenyl transfer product product We became concerned that the phenyl transfer processes would complicate our kinetic analysis. The exchange itself is independent of the stannane, but would alter the catalytic species during the experiments. Different electronically substituted ligands are known to affect rates of reaction. However, we were particularly interested in relative rates of reaction. As long as the catalytic systems for the trimethyl and tributyl stannane reactions are similar, we should obtain useful information regarding the relative rates of reaction. For this to be true, the distribution of products should be the same at any given point of the reaction regardless of the stannane employed. We therefore ran separate bench-top Stille couplings 46 0mg trimethi'1 the reaction was Table 3.1 doiin for each :1 [or the trimethj product produce and tribunl 51.111 that there is hit slituld not impai- ten-transferable i'iclhllldlt‘tl tiur e of the trimethyl and tributyl stannanes with 4-bromoanisole. After 3 hours the reaction was stopped to determine the distribution of the two products. Table 3.1 shows the total yield for both products as well as a break down for each and the percentage of phenyl transfer product out of the total. For the trimethyl and tributyl reactions, the percentage of phenyl transfer product produced was 42% and 46%, respectively. Assuming the trimethyl and tributyl stannanes react through the same mechanism, these data indicate that there is little problem arising from the phenyl transfer process and should not impact our kinetic studies on the relative rates of reaction per the non—transferable ligands on tin. With the necessary control experiments run, we initiated our systematic study of cross-couplings with aryl iodides. 47 Table 36- De" AX Fifi-Sn O 39 or 40 entry R 1 Me (391 ‘ Bu (401 3.10Aryl Iodide L'tilizing t We monitored thc Table 3.6. Determination of Cross-Coupled and Phenyl Transfer Product Distribution szdba3 (2 mol%), AsPh (8 mol%), \ /\>< /\>< 3 OH Ph \ OH R38" 0H + .- ' 4-bromoanisole 39 Ol' 40 (1.2 equiv), MeO 60 59 THF, 50 °C, 3 h cross-coupled phenyl transfer product product total cross- phenyl phenyl entry R product % coupled transfer (59) transfer/ yield (60) % yield % yield total product Me 1 (39) 30 17.5 12.5 0.42 Bu 2 (40) 26 14 12 0.46 3.10.Aryl Iodide Couplings Utilizing the conditions and reagents outlined earlier in this chapter, we monitored the rate of the reaction for vinyl stannanes coupled with aryl iodides. The observable rate constants, kobs, were determined as shown in Table 3.7. Trimethyl stannanes showed reactivity 1.4-2.4 times that of the corresponding tributyl stannanes. These rate differences are presented as a Me/Bu ratio relative to Bu for each RI/electrophile combination. The presence of the free hydroxyl does not appear to alter the mechanistic course of the reaction since methyl protection does not affect the rate to a large degree (e.g. comparison of entries 3 & 4 vs. 9 & 10). 48 E35” Ella-3”. Y 1 H 3 H 3 (R 4 (F3 5- Il‘Bu 6 "‘8” 7 H 3 H 9 C F: 10 CF: 11 "‘3“ 1: "B” \ lleBU “mm electrophile RI Determined t“ \MR grade Tl (appeal '11ch for a mo 5 addition is th Table 3.7. Aryl Iodide Couplings in THF ' szdba3 (2 mol%), /\>< AsPh3 (8 mol%), \ . _ R R33" \ RI + O Y THF, CSDG (4.6 V0l°/o), Y 50°C entry Y R R1 Sn kobS relative rates yieldb (min-1) of Me/Bua 1 H Me OH 39 0.015 59: 34% 2.38/1 2 H Bu OH 40 0.006 59: 51% 3 CF, Me OH 39 0.039 61: 87% 2.29/1 4 CF, Bu OH 40 0.017 61: 79% 5 n-Bu Me OH 39 0.013 1 41/1 62: 30% 6 n-Bu Bu OH 40 0.009 ° 62: 36% 7 H Me OMe 41 0.018 1 50/1 63: 60% s H Bu OMe 42 0.012 ' 63: 65% 9 CF3 Me OMe 41 0.032 64: 87% 2.13/1 10 CF3 Bu OMe 42 0.015 64: 82% 11 n-Bu Me OMe 41 0.019 1 90/1 65: 45% 12 n-Bu Bu OMe 42 0.010 ' 65: 70% aMe/Bu ratios are the relative rates of methyl to butyl for each electrophile/Rl combination. bDetermined by 1H NMR analysis of the crude reaction mixture using NMR grade TMS-O-TMS as the internal standard. It appears that more electron withdrawing substituents, such as CF3, allow for a more facile reaction. This may lead one to believe that oxidative addition is the rate-determining step. However, it must be realized that the oxidative addition product species must still act as an electrophile to achieve 49 (mil Stannane [1'3 SmelflllalIOI substituents aCC the reactions L-Pd-L 12 sedative add/tn product Determinat 19.: carried out at bi Others at <0 i ital? ~ ..nte between t fill?!" 16‘ = .\S by NMR itif’li‘ -~ ' hill, 35 lildlt'ulc vinyl stannane coordination and subsequent transmetallation (Scheme 3.6).8 Therefore, we would see a substituent effect on the rate even when transmetallation is the rate-determining step whereby electron poor substituents accelerate the reaction and electron rich substituents slow down the reactions Scheme 3.6. Mechanism of Transmetallation8 i )I( L )I( KShMG3 I'- _ _ /\ 1.. _ _ L Pd L / SnMe3 L(Pd l| L Pd—\\ —> ——> 12 14 67 oxidative addition product Determination of the relative rates of trimethyl and tributyl stannanes was carried out at 50 °C to correlate our data with previous kinetic studies by others at 50 °C. Furthermore, this temperature achieves a good rate balance between the fast and slow reactions in order to monitor reaction progress by NMR. However, temperature can greatly affect the rate of reaction, as indicated by the Arrhenius equation, which is defined as k = A6” RT (7) and can be linearized by ln(k) = 1n(A)+ (-Ea/R)(1/T) (8) 50 ShnCC‘“i3 tributyl stannan' 1:: trimethyl 3” energy bamers' 11,50. and 5: temperature CM“ 3‘] (Figure 3.8 5,151. For the r63 wfi=68kad rehtdh B).the emgyof40.\Vn ;-'e not significant rehtland but}l than different actl\ hmdhylandtrdiut it"? rdutirely the tanons are (uteri Elli-Will . be al‘lllicable Since we are interested in the rate differences between trimethyl and tributyl stannanes, it is important that the rate differences are a reflection of the trimethyl and tributyl ligands, and not a reflection of different activation energy barriers. To this end, we repeated entries 1 and 2 from Table 3.7 at 40, 50, and 55 °C under our standard conditions (Figure 3.7). The temperature dependence data was then plotted as an Arrhenius plot, ln(k) vs. l/T (Figure 3.8), where the slope of the linear regression fit is equal to - Ea/R. For the reaction with 39, Ea = 12.4 kcal/mol and for the reaction with 40, Ea = 6.8 kcal/mol. However, if only the data for 39 at for 45 and 50 0C are fit (fit B), the Ea = 8.4 kcal/mol and is more in line with the activation energy of 40. Within the range of temperatures studied, the E21 differences are not significant for these lines to cross, such that rate differences between methyl and butyl appear to be a reflection of the steric differences rather than different activation energy barriers. This trend further supports that the trimethyl and tributylstannanes react through the same mechanism since they have relatively the same activation barrier. In addition, Stille coupling reactions are often performed from rt to 100 OC, therefore our rate data should be applicable to those situations as well. 51 Pd2dba3 (2 [HOP/o) , /\>< I ASPh3 (8 mol%), \ + = OH R3Sn \ OH O THF, C D (4.6 vol%), 4 6 6 39 or 0 40, 50, or 55 °C 59 1.0 equiv 1.2 equiv - Me (39) Temperature Dependence 1004 a 8 . - - 40°C 3 80- l: . 50°C g . g. . 55°C 0 60‘ " ~23 1 2* '6 40. C a, . E 20- l 0‘ are... 67160'260300‘400500'600'7007600 Time,min Figure 3.7. Plot of Temperature Dependence for Trimethyl and Tributyl Stannane Reactions. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (top) or 40 (bottom) upon coupling with Phl under a szdba3/AsPh3 catalyst system at 40 °C (black trace), 50 °C (red trace), and 55 °C (blue trace). All sets of data were fit to a first order exponential decay model (not shown) to reveal the rate constants outlined below in Table 3.8. 52 . . 1-:ltlll.d~ . n‘u“c. - able 100— 1 .1: 6042':- Figure 3.7 (cont’d) l Bu (40) Terrperature Dependence - 40°C - 50°C . 55°C ‘5 (D .u E o 4 - .2. 6°. 3- 19,; e 4o— “1 e. c , 121+, 'h‘b 2 Wm; ' - E 20‘ “Axfihfhfim ‘ ‘Mw ‘ way/Erie» 0i “5%9 011007200'300'400'500’6700'760'660 Time, min Table 3.8. Temperature Dependent Rate Constants kobsmin" R 40 °c 50°C 55 °C Me (39) 0.0099 0.0150 0.0260 Bu (40) 0.0040 0.0059 0.0065 Me/Bu 2.49 2.46 4.02 53 ln(k“h°\ Figure 3.8. Arrl Arrhenius Plot 1 tallies at t'ariou lines represent a lor39. E3 = ll: 45 and 50 3C are 3.11. Aryl Bromi With 21 met is extended the : bromides. These 1 ituld see the sari [fifth 1“ (rings. The in Arrhenius Plot 0.06305 . 0.06310 . 0.06315 ' 0.00320 1/T Figure 3.8. Arrhenius Plot to Determine the Activation Energy, Ea. An Arrhenius Plot was prepared by plotting ln(kobs) vs. l/T, where the kobs values at various temperatures were determined in Table 3.8. The black lines represent a fit to a linear regression model, with the slope = -Ea/R. For 39, E3 = 12.4 kcal/mol (fit A: red solid line) or 8.4 kcal/mol when only 45 and 50 °C are fit (fit B: red dashed line) and for 40, E2, = 6.8 kcal/mol. 3.11. Aryl Bromide Couplings With a method for studying the kinetics of the Stille reaction in hand, we extended the studies to include couplings with the corresponding aryl bromides. These results are reported in Table 3.9. We expected that we would see the same types of Me/Bu rate differences seen with aryl iodide couplings. The overall rates of the reaction were much slower than the corresponding aryl iodide couplings. Much to our surprise, the coupling rates for trimethyl and tributyl stannanes with aryl bromides were similar. 54 ' .OCSIS ll Thissuga mmmHMnot entry 1 \n 1 3 H 3 cr3 4 cr3 5 IrBu 6 IrBu 7 11 i H 9 tr. :0 0,3 11 "‘Bu ll "—86 iueBurano, This suggests that transmetallation is no longer the rate-determining step and reevaluation of the mechanistic course of the reaction is necessary. Table 3.9. Aryl Bromide Couplings in THF Br Pd2db33 (2 mol%), /\>< AsPh3 (6 mol%), \ R. R3811 R' + : O Y THF, C606 (4.6 VOI%), Y 50 °C entry Y R R] Sn kobs relative rates yieldb (min'l) of Me/Bua 1 H Me OH 39 0.0073 mm 59: 35% 2 H Bu OH 40 0.0062 59: 33% 3 CF3 Me OH 39 0.0210 61: 49% 4 (:1:3 Bu OH 40 0.0230 1.11/1 61: 83% 5 n-Bu Me OH 39 0.0065 0.92/1 62: 23% 6 n-Bu Bu OH 40 0.0058 62: 23% 7 H Me OMe 41 0.0051 1.09/1 63: 45% 8 H Bu OMe 42 0.0047 63: 51% 9 CF3 Me OMe 41 0.0200 64: 44% 10 CF3 Bu OMe 42 0.0190 1'3“] 64: 58% 11 n-Bu Me OMe 41 0.0046 65: 33% 12 n-Bu Bu OMe 42 0.0035 1.05/1 65: 37%c a Me/Bu ratios are the relative rates of methyl to butyl for each electrophile/RI combination. bDetermined by 1H NMR analysis of the crude reaction mixture using NMR grade TMS-O-TMS as the internal standard. 0 Yield of 65 and the phenyl transfer product 63 combined. 55 3.12. Mechanist We obsert iodides 0r bromi 1.2. it is unlike]; nie-determinin g explanation is the it: performed co. ‘iere performed transmetallation i elitterimemS “ere in the Stille reac' lesson in itself; c ermine (l 5C0pe_ In addition 1 3.12. Mechanistic Considerations of Aryl Bromide Couplings We observe different rate determining steps when using either aryl iodides or bromides. Looking back to the mechanism described in Scheme 1.2, it is unlikely that isomerization or reductive elimination would be the rate-determining step since they are independent of halide. One logical explanation is that oxidative addition is the rate-determining step. Although we performed control experiments to exclude this possibility, these studies were performed on aryl iodides. Given the common consensus that transmetallation is the rate-determining step, we thought that our control experiments were sufficient. This assumption is common in kinetic studies on the Stille reaction and other cross-coupling reactions and has proven a lesson in itself; do not extend the generality of any studies beyond the examined scope. In addition to the Me/Bu data, other observations were consistent with oxidative addition as the rate-determining step. Reactions of electron neutral and electron rich electrophiles (Table 3.9, entries 1-2, 5-8 and 11-12) did not reach completion and black precipitate was observed. We suspect that the catalyst decomposed as a result of a slow oxidative addition and is in accordance with Stille’s‘43 findings. Also, self-catalyzed Pd decomposition has been reported.44 In contrast, couplings with an electron deficient aryl 56 halide (entrics 5'6 ‘1 more facile oxidath catalyst was Compr0 To further tes aryl bromide cont etidatit'e addition 1 iterate should be . (ft-trimethyl (41') till with 4-bromol constant dependcr 13911.1.) is plotted l indicating that th were obtained by C L: "i “M Place. Fitr l Grim Ll halide (entries 5-6 and 11-12) went to completion. We submit that here a more facile oxidative addition allowed the reactions to proceed before the catalyst was compromised. To further test whether the oxidative addition is rate determining, an aryl bromide concentration dependence study was performed. If the oxidative addition is the rate-determining step for aryl bromide couplings, the rate should be a firnction of electrophile concentration. The reaction of (E)—trimethyl (41) and (E)—tributyl(3-methoxy-3-methylbut-1-enyl)stannane (42) with 4-bromobenzotrifluoride at different concentrations reveals a rate constant dependence on electrophile concentration (Figure 3.9). When log(kobs) is plotted vs. log[E+], a linear correlation is realized with a slope of 1 indicating that the reaction is first order in aryl bromide. Although our data were obtained by monitoring stannane consumption and were based on the assumption that the transmetallation is the rate-determining step, our data still reflects the overall reaction progress since the stannane can only be consumed after the rate-determining oxidative addition (for aryl bromides) takes place. Furthermore, studies monitoring the consumption of 4- bromobenzotrifluoride by 19F NMR provided the same rate profile as when 57 the stannane u'a excess electrophi R 81A>
    < Br szdba3 (2 mol%), + AsPh3 (8 mol%), \ R3Sn \ OMe O ____. OMe 41 0'42 F3C C D (4.6 vol%) 1 equiv "x" equiv 61—31:, 50 cc F3C 64 R = Me (41) _ Effect of CF3PhBr Concentration on Reaction Rate A 100— —— 1.2 equiv '0 . ——--—- 3.5 equiv ' _ ' ' ' / a 8,. 5.3m .00. pigggggyt-i-Owezr- Tés _ —7.1 equiv ' ' _// .5 60— 531.25 // .2. , 8 / > -1.50 ’5 40~ / C I 52 ‘ -1.75— ’ E 20- -0.'75 0'50 0'25 000 7 log ([CF3PhBr]) 0- ('1 -55- 5'0 ' 7'5 '160'125'150'175fi260 Time, min Figure 3.9. Determination of Electrophile Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of 41 or 42 upon coupling with 1.2 equiv (black), 3.5 equiv (red), 5.3 equiv (green), or 7.1 equiv (blue) of 4-bromobenzotrifluoride. The data were fit to a first order exponential decay model (not shown) to obtain kobs- The solid colored lines are to guide the eye. The ln(kobs) vs. ln([ArBr]) were then plotted (inset) to reveal a linear relationship between kobS and [ArBr]. The red solid lines represent a fit to a linear regression model and gave a slope of 0.9, indicating first order aryl bromide concentration dependence. 58 i885 .3 intensity (Normalized) Figure 3.9 (Cont’d) R = Bu (40) “Effect of CF3PhBr Concentration on Reaction Rate A 100- — 1.2 equiv . 1 . . ‘8 - —— 3.5 eqUiv _1 00_ y = 0.92692x + (-1 .09594) g 80- 3113 equiv ' R2 =0.98219 l to — . equrv A . - E ' . «425- // o 60— O, // .2. 2 > ‘ 4.50- / :5; 40“ ,./ 9:3 1 -1.75 // t E 20— 0.75 T 0.50 F0325 ' 0.00 ' - log ([CF3PhBr]) o_ ('1'2'5'5'0'7'5'160'125'150i1i5r200 Time, min While reactions of all stannane/bromo-electrophile combinations in various stoichiometries all pointed to oxidative addition as rate determining, we deemed it important to probe the influence of the oxygen substituents in stannanes 39-44. Therefore we reacted tert-butyl substituted vinyl stannanes 43 and 44 with 4-bromo- and 4-iodobenzotrifluoride. Similar reaction profiles were observed when the bromide was coupled with spectroscopically clean stannanes 39, 41, and 43 as well as when the iodide was coupled with spectroscopically clean stannanes 40, 42, and 44. Furthermore, in reactions of 4-bromobenzotrifluoride and 44, doubling the amount of electrophile accelerated the reaction. These data indicate that 59 there is no pecul oxidative addition across a range of st liNMRe icdobenzotritluorit signals for the rea observed with tltl tierent resting st resting state \1 he all]: ' notion product 3 ntedetemiininu is tvbsert‘ations are deter ' ' Winning step ("1 Schen \ BU3Sn/\/ 42 there is no peculiar effect of the oxygen in stannanes 39-42 and that oxidative addition remains rate determining for the reaction of aryl bromides across a range of stannanes. l9F NMR studies were performed on reactions with 4-bromo and 4- iodobenzotrifluoride (Scheme 3.7). We observed several unknown minor signals for the reaction with the iodide (Figure 3.10), but no signals were observed with the bromide (Figure 3.11). In principle, we should see different resting species depending on the rate-determining step. That is, the resting state when transmetallation is rate determining is the oxidative addition product 31 or 3, while the resting state when oxidative addition is rate determining is free Pd 1 and electrophile 2 (see Scheme 1.10). Thus our observations are consistent with the oxidative addition being the rate- determining step of the Stille reaction with aryl bromides. Scheme 3.7. Stille Coupling Monitored by 19F NMR OX F C /\>< 3 % \ OMe Bu3Sn OMe Pd2db33 (2 mol%), 42 AsPh3 (8 mol%), F3C 54 60 figure 3.10. Stille 1 V ‘f.\'_\lR. ‘A ‘ h _ ‘ N-\ _ \o‘ L: - .- > . H .. “i‘ \ _‘ F30 Figure 3.10. Stille coupling of 42 with 4-iodobenzotrifluoride monitored by 19FNMR F3C ~~~~~ _ -64.2 -64.6 -65.0 -65.4 —65.8 ppm Figure 3.11. Stille coupling of 42 with 4-bromobenzotrifluoride monitored bymFNMR. ‘ 61 In an em aryl iodide COUP it compared thi‘ oxidative additio piOilUt‘l does 110 hon that tiny inhibit the actitt Stannane-coordin. 1e hare no firm 1 doing the experii hoe reactions is consisting of the iflillli. When the little solution to drastic color chat olution, Hmm e: h r - ..o.ililsli~pum]c t‘ inordinatintt 10 l l‘ijr‘iri I tidinatcd t0 Pd -c In an effort to determine whether the unknown signals present in the aryl iodide coupling (Figure 3.10) are oxidative addition products 31 or 3, we compared the spectra from our kinetic Stille study with an independent oxidative addition study (Scheme 3.8) (Figure 3.12). The oxidative addition product does not correspond with the unknown signals. However, it is known that vinyl tin species are able to coordinate to Pd and as a result inhibit the active catalyst.9 We hypothesize that the unknown products are a stannane-coordinated variation on the oxidative addition product. Although we have no firm proof that this type of species is present, a few observations during the experimentation led us to this hypothesis. The catalyst system for these reactions is szdba3 and AsPh3. The szdbag, is a dark purple powder consisting of the dibenzylideneacetone ligands coordinating to Pd via the olefin. When these reagents are mixed together in THF for ~10 min, the purple solution turns green as the olefin ligands are displaced by AsPh3. No drastic color change occurs when the electrophile is added to this green solution. However, when the vinyl tin is then added, the color changes to a brownish-purple color. If color change to purple were indicative of an olefin coordinating to Pd, then it would follow that the vinyl stannane is coordinated to Pd in Stille reaction conditions. As a result, we would not see 62 the oxidative addit species. If these 51 than in the 119Sn 1 llllliial abundance. they were not ob: iinetics experiment Scheme 3. the oxidative addition product in the Stille reaction, but instead other minor species. If these species do in fact contain tin, we would expect to observe them in the 119Sn NMR spectra. However, due to the low concentration, low natural abundance, and the low signal to noise in the 119Sn NMR spectrum, they were not observed. It should be noted that occasionally during a kinetics experiment, a minor signal around +10 ppm is observed. Scheme 3.8. Oxidative Addition of 4-lodobenzotrifluoride F3C < > ' AsPh3 ASPh3 I szdba3 ——-> [Pd(ASPh3)2] : F3C‘QPd—I I ASPh3 63 Oxidative Addition PmdUCt 44.2 -64. 5 Figure 3.12. 1‘F lntobenzntritluo it Observed Durin. iScheme3.7) In conelu ~i nnmmnhnonzi hrnda generalizz :i L' ' nnetre course. \\ : addition is the rate t in the best of t) i. adlitiun of Still C( at , mush a compu .. fig , ' - ~n0ndnne add: tithillatcg and Dr Oxidative Addition Product | 1 Unknown ‘ '\ \I f L w i: i ‘- “AMI km“ item WW.” .j‘s i. L. W, W, , , . / W0:2:ir‘ia’tive Addition .‘ . . a “W. ~ wt." 7‘ ~'" 3:1, “n~".ovf‘v_fi ;WI7\.'-.¢A ‘v‘k‘fl" J w W‘FJ i ‘ Awwf‘m 4" lIm—Wflww M w ' " W M wWWWWWMITW;WTWWW Stille Coupling -64.2 -64.6 -65.0 -65.4 -65.8 ppm Figure 3.12. 19F NMR Spectra of the Oxidative Addition of 4- Iodobenzotrifluoride (Scheme 3.8) Compared with the Unknown Signals Observed During the Stille Coupling of 42 with 4-Iodobenzotrifluoride (Scheme 3.7) In conclusion, our studies suggest that considering the transmetallation as the rate-determining step for Stille reactions may be too broad a generalization and the halide choice is quite important regarding the kinetic course. We have provided evidence suggesting that the oxidative addition is the rate-determining step in the Stille reaction with aryl bromides. To the best of our knowledge, no reports have identified the oxidative addition of Stille couplings with aryl bromides as the rate-determining step, although a computational study by Alvarez and de Lera has indicated that the oxidative addition step might become rate determining for certain substrates and/or reaction conditions?‘ Also, Amatore and Jutand have 64 irritated that the probably the rate-dc ention that studie as ride.“ Our discm'e understanding of I] hgical choices can ' 931135 in the Opti hhlth an an] hm]. reaction is not rent“ nnethyl stannane would lead to no sii rate-limiting step supposed rate-dete are npieally expt .tattinn. Honete hm ' ‘ est optimizatini it '~ is apparent than and it would be, t indicated that the oxidative addition of low reactive aryl bromides is probably the rate-determining step in cross-coupling reactions, but go on to mention that studies have only focused on isolated steps of the catalytic 45 cycle. Our discovery is significant in that it enhances our kinetic understanding of the Stille reaction. With this data, more informed and logical choices can be made regarding electrophile and stannnane partners as well as in the optimization of reaction conditions. Imagine a scenario in which an aryl bromide is to be coupled with a tributyl stannane and the reaction is not reaching expectations. Changing to the faster but more toxic trimethyl stannane, activated stannatranes, or less elaborated stannanes would lead to no significant improvement. Since the oxidative addition is the rate-limiting step, standard optimization techniques would focus on the supposed rate-determining transmetallation step, as only changes to that step are typically expected to increase the rate and overall efficiency of the reaction. However, with oxidative addition as the rate-determining step, these optimization efforts would have no beneficial impact. From our results it is apparent that optimization should focus on the oxidative addition step and it would be of no benefit to employ trimethyl stannanes. Therefore, the 65 'es: toxic and less ant bromide coupli less toxic and less expensive tributyl stannanes would be sufficient for the aryl bromide coupling. 66 Chapter 4. Q l‘ Expanding SC 4.1. Condition Having e Stille condition: Croices of soli documented to . continued studic 4.2. Solvent Eff: SolVent ca molecules assist catalstic cycle (s accelerate these {a . te. For instant. Chapter 4. Quantifying Rate Differences for Trialkyl Stannanes: Expanding Scope 4.1. Conditions to be Screened Having established a foundation for our kinetic studies under common Stille conditions, we sought to determine the generality of the Stille reaction. Choices of solvent,”’17 Pd ligands,25’26 and additiveslg’22 have all been documented to affect reaction outcomes and thus became the focus of our continued studies. 4.2. Solvent Effects Solvent can have a significant effect on the rate of reaction. Solvent molecules assist in ligand dissociations that are necessary throughout the catalytic cycle (see Sections 1.2.1—1.2.2). Highly coordinative solvents can accelerate these ligand dissociations resulting in a faster overall reaction rate. For instance, N—methyl-Z-pyrrolidinone (NMP) is a common Stille solvent that leads to faster reaction rates relative to THF due to its higher coordinative ability and was thus our first solvent of interest. 4.2.1. N-Methyl-Z-pyrrolidinone (NMP) As expected, we observed faster rates (IO-30 fold) upon coupling vinyl stannanes with aryl iodides in NMP (Table 4.1), than those performed 67 all“: (Table .L. ~ i an the corre. ranged from I titansrnetall. 6 \ a . hEiectrn; ibi‘iem‘ NR 5 In t dttermm in «it - . ‘mmillng' } in THF (Table 3.7). We also observed that trimethyl stannanes reacted faster than the corresponding tributyl stannanes 2.3-4.3 fold. Rate differences only ranged from l.4-2.4 in THF. These results agree with previous assessments of transmetallation as the rate-determining step for aryl iodide couplings. Table 4.1. Aryl Iodide Couplings in NMP I szdba3 (2 mol%), AsPh3 (8 mol%), \ O _ H R3Sn/\>< OH Me3Sn 0H szdba3 (2 mol%), 39 48 mol% /‘-\>< 52 mol% AsPh3 (8 mol%), M933" 5 0H 39 = + _ ' _ s, L P'd L benzene, 50 °C L Ax 71 4 mol% AX BU3Sn OH BU3S“ 0“ 40 48 mol% 48 mOIO/o L J 40 Y M OH ¢ 1 "Active" Pd F3C 61 ' ,0... F3 When run individually, as described inTable 4.3, entries 5-6, tributyl stannane 40 reacted faster than trimethyl stannane 39. The reaction profile is shown in Figure 4.4. When the competition experiment described in Scheme 4.2 was performed, the rate profile for the trimethyl stannane 39 was not affected but the tributyl stannane 40 rate was suppressed (Figure 4.5). Furthermore, both 1:2 and 2:] ratios of trimethyl to tributyl stannanes afforded the same trend. The data suggests a diminished concentration of active catalyst brought on by the presence and coordination of trimethylvinyl stannanes, e. g. 71. 77 tx\ Individual Experiments f~_’ 80_ " BU (40) E g 4 O _ E 60 a .. '6 40. C 3 '1 s 20— O- 0'260'460'600‘300'1600' T1me,rnin Figure 4.4. Individual Experiments. 186 MHz 119Sn NMR relative integration data for the consumption of 39 (black trace) or 40 (red trace) upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system in benzene. Both sets of data were fit to a first order exponential decay model (not shown) to reveal for 39, kobs = 0.0044 min'1 and for 40, kobs = 0.022 mm“. 78 h \ m; X01 0p CHEEEQ been ; 4.3. tr imthu Competition Experiment A 100- '0 . a: .5 80— To g . o _ E 60 > a 40— C 2 _ E 20— o- Figure 4.5. Competition Experiment. 186 MHz 119Sn NMR normalized relative integration data for the consumption of 39 (black trace) and 40 (red trace) upon coupling with 1.2 equiv of Phl under a szdbag/AsPh3 catalyst system in benzene. Both sets of data were fit to a first order exponential decay model (not shown) to reveal for 39, kobs = 0.005 min'1 and for 40, kobs = 0.01 min']. We have seen that solvent can have a major impact on the reaction. Not only can solvent increase the rate of reaction as with NMP, but can also change the mechanistic details as seen with benzene. This scenario has not been previously reported and could be quite important when considering reaction optimization. 4.3. Ligand Effects The electronic and steric nature of the Pd ligands can also affect the kinetics of the Stille reaction. Since ligand dissociations are necessary 79 k\ throughout the catalytic cycle, a strongly coordinating ligand (strong 0 donor) would be unfavorable. On the other hand, the solvent and/or ligand needs to be coordinative enough to stabilize Pd in the active (S)PdL2 form to avoid thermal decomposition to Pd black. Moreover, the oxidative addition requires an electron rich Pd species (Pd = nucleophile, aryl halide = electrophile), while the transmetallation requires an electron poor Pd species (stannane = nucleophile, Pd = electrophile). The ligands need to achieve a good balance between these requirements has been explored and discussed by Farina.25 After screening ligands for the coupling of vinyltributyl stannane and iodobenzene, he reported that AsPh3 and tri-Z-firrylphosphine (TFP) were efficient ligands from a rate and yield perspective because they most likely achieve the desired ligand bonding characteristics (Table 4.4). It is unclear exactly how this balance is achieved, but may be correlated to metal-ligand bond enthalpy. Later, Fu proposed that strong 0 donors may actually be good ligands, provided they are sterically bulky enough to easily dissociate such as with P(t-Bu)346 and have given access to aryl chloride couplings that were previously resistant to oxidative addition. We sought to explore these ligand effects on the rate differences between trimethyl and tributyl stannane couplings. 80 i\\ ‘. rt'10.: Table 4.4. Ligand Effects25 Phl Pd2db83, Ligand, \ THF, 50 °C entry ligand relative rate % yield 1 ppm 1 15.2 2 TFP 105 > 95 3 AsPh3 1100 > 95 4.3.1. Tri—2-furylphosphine (TF P) Upon changing the palladium ligands from AsPh3 to TFP, we expected that similar rate differences between the trimethyl and tributyl stannanes would ensue, albeit with overall slower rates as compared with AsPh3. Much to our surprise, reacting the tributyl stannane with iodobenzene resulted in an apparent induction period as seen in Figure 4.6. This curve is indicative of an autocatalyzed reaction where starting material reacts through one pathway to produce a product (either the main product, by-product, or any side products) that is able to catalyze a faster pathway to the desired product, as outlined in Figure 4.7. 81 i\\ In Pd2dba3 (2 mol%), \ Ax + ' TFP (8 mol%), OH R33” OH = + THF, CSDB (4.6 VOlo/o), 50 0C R3Snl Coupling With Pd/TFP =5 . is? - R = Me (39) (D H _ % 80 _ a“: - R — Bu (40) E 50 ""- ’~ g, . a . .2 40 s ' cu ‘ ‘- - E 20 4 ‘\ 1 “TVMQ’u-i'v'flwp,‘ 0 _ ‘ b'ibo'zboiséo'ribo'sboiebofibo' T1me,rrin Figure 4.6. Studies of Couplings with Pd/TFP. 186 MHz “9Sn NMR relative integration data for the consumption of 39 (black trace) or 40 (red trace) upon coupling with 1.2 equiv of Phl under a szdba3/T F P catalyst system. Both sets of data were fit to a first order exponential decay model (not shown) after the induction period (~100 min) to reveal for 39, kob, = 0.033 min" and for 40, kob, = 0.024 min“. 82 l\\ itliiil under .. 1. Wild luttt‘ Figure 4.7. Autocatalytic Reaction Process "0 _ r A kCP >>k0 p \ . ch One important aspect of our kinetic studies is that for first order reactions, the initial concentration does not need to be known as was discussed in Section 2.1. For reactions exhibiting an induction period, this feature is no longer valid. Therefore, our first objective was to qualitatively understand the basis of the autocatalysis, such as finding what species or conditions cause the autocatalysis. We would then be able to implement the autocatalytic species to achieve first order behavior and quantify the relative rates of reaction. The two main products in Stille reactions are the cross-coupled product and the tin halide by-product. Since the onset of autocatalysis occurs at ~20% conversion, we expect to have ~80% of the organostannane starting material and ~20% each of the cross-coupled and tin halide by-product in solution. To test whether either product autocatalyzes the reaction, experiments were set up to mimic the conditions at the point of autocatalysis, ~100 min (Scheme 4.3). Analysis of the reaction profile 83 l\\ revealed that the induction period was still present and to approximately the same extent when either or both of the products were incorporated. Scheme 4.3. Effect of Products On Autocatalysis l Ax O \ °” + "Product" A Bu3Sn \ OH 7 59 Pd2db33 (2 mol%), 4° 59 0' 73 TFP (8 mol%), + 0.8 equiv 0.2 equiv THF, C6D6 (4.6 vol%), Bu 3m 50 °c 3 Expt. 1: Product = BU3SnI Expt. 2: Product = cross-coupled product Expt. 3: Product: cross-coupled product + Bu3Snl 73 We next asked if the free hydroxyl is involved in initiating the autocatalysis. Reactions with methoxy vinylstannane 42 also exhibit an induction period, although over a much longer period of time (Figure 4.8). The extent of free hydroxyl involvement is not yet understood but it seems to allow for faster formation of the autocatalytic species and likely involves oxygen chelation. 84 szdba3 (2 mol%), \ l M + TFP (8 mol%), _ 0M9 BU3SH OMe 7 63 42 45 THF, 0505 (4.6 vol%), 50 °C + Bu3Snl 73 100‘ Couplingof423ndPh|WitthlTFP a i "u is? 80- "E. g i "'3. '5 604 \x E ‘h._ > W 3: 40_ N... 8 i "2 33 204 ‘s. o- 0 '100'200'300'400'500'600'700'800 Time, rn'n Figure 4.8. Determining if a Protected Hydroxyl Affects Autocatalysis. 186 119 MHz trace) upon coupling with 1.2 equiv of Phl under a szdba3/TFP catalyst system. The data was fit to a first order exponential decay model (not shown) after the induction period (~500 min) to reveal a kobs = 0.024 min-1. Sn NMR relative integration data for the consumption of 42 (black 4.3.1.1. Insight into the Source and Mechanism of Autocatalysis To the best of our knowledge, autocatalysis in the context of Pd- catalyzed reactions was not reported in the literature until recently. In 2008, the Hartwig group described the autocatalytic oxidative addition kinetics of aryl bromides with a Pd/t—Bu3P system.47 Upon oxidative addition of (Pt-Bu3)2Pd to PhBr, the oxidative addition product 75 was formed. This species can undergo thermal 85 //_ uLl [ F [I inhi decomposition to afford the bridged halo palladium species 76 and upon further heating, decomposes to the hydridopalladium bromide 77 (Scheme 4.4). Scheme 4.4. Oxidative Addition Studies by Hartwig47 (Pt-Bu3)2Pd(Ph)(Br) 75 [(Pt—Bu3)Pd(p.-Br)]2 76 (Pt-Bu3)2Pd(H)(Br) 77 70 °C PhBr (Pt-Bu3)2Pd + 74 toluene The oxidative addition was then performed with compounds 75-77 and revealed that 77 sufficiently catalyzed the reaction such that the oxidative addition to PhBr followed first order kinetics (Figure 4.9). Once 77 is formed and undergoes reaction with PhBr, a new catalytic cycle is formed for the regeneration of 77 as seen in Scheme 4.5 . 0.07 1 . - . Pd(P‘Bu3)2 ‘ i‘ 0.06 page“ ‘ (P'Bu3)2Pd(H)(Br) - 0.05“; a 3%- g, - .7 i. QR} l -J 0.04 5% 4 - .74. 9% O ’ 1... ‘09 ‘ E 0.03 - « 0.02 - “if Xe, ~ .1: Q a 0'01 L "3.32.... M 0.00 - : L - 1 ' 0 1x10“ 2x10’ 3x103 4x10” time (s) FigUre 4.9. Relative Decay of Pd(Pt-Bu3)2 (74) and Pd(Pt-BU3)2(H)(Br) (77) During the Oxidative Addition of PhBr in 2-Butanone at 70 °C.47 Reproduced with permission from Barrios-Landeros, F .; Carrow, B. P.; Hartwig, J. F. J. Am. Chem. Soc. 2008, 130, 5842—5843. Copyright 2008 American Chemical Society 86 i\\ § "r-i Scheme 4.5. Catalytic Cycle for the Regeneration of Hydrido Palladium Halide (t—Bu3P)2Pd t-Bu3PeHBr (t—BusP)Pd(Ph)(Br) 74 X 78 X 75b t-Bu3P (t-Bu3P)2Pd(H)(Br) PhBr 77 Our efforts to identify the species responsible for autocatalysis had focused on the reaction products but we had not considered any transient Pd species. To this end, we wanted to see if a similar hydrido palladium halide species was responsible for our autocatalysis. There are several considerations however. In the previous chapter we discussed how oxidative addition is the rate-determining step for aryl bromide couplings while transmetallation is the rate-determining step for aryl iodide couplings. We also observed autocatalysis in aryl iodide couplings with TFP as the Pd ligand. If transmetallation is rate determining for Pd/TFP systems, then we Should not see this type of behavior since the species undergoing the transmetallation (the oxidative addition product analogous to 75) would be the same regardless of the initial Pd source. This indicates that with TFP as the palladium ligand, oxidative addition may be rate determining until a Sufficient concentration of a more active Pd species is formed to allow for facile reaction. We hypothesize that the initial Pd species is not reaction enOugh to promote a fast oxidative addition, but after slow formation of a 87 new Pd species, the reaction proceeds. Subsequently, transmetallation becomes rate determining such that the reaction is first order in stannane. This is observed qualitiatively by comparing reaction profiles of the trimethyl vs. tributyl stannane in Figure 4.6, where the rates of the induction period between the trimethyl and tributyl stannanes are equivalent, after which there is clearly a difference in the reaction profile. To determine whether an autocatalytic species is at play, we chose to change the order of addition in our kinetic studies. Since Hartiwg reported that the oxidative addition alone afforded three different products, including the autocatalytic species 77, we imagined that allowing the oxidative addition to proceed first, the hydrido palladium species might be formed in situ. Upon addition of the stannane, we would be able to see if there was an effect on the induction period due to the presence of the preformed alltocatalytic species. Initially, we took a 31P NMR of the szdba3/TFP mixture as seen in Figure 4.10. We expected to see a signal around -35 ppm for different Pd/dba/TFP complexes and/or a signal around -80 ppm for free TFP, both as seen by Farina and others.25 However, we saw only 3 Significant peak at -11 ppm likely corresponding to TF P oxide. We allowed the catalyst mixture and iodobenze to react for 2 hours in the NMR at 50 °C While monitoring the 31F nucleus. A reaction time of 2 hours was chosen 88 i\\ because the induction period lasts about 100 min with (E)-2-methyl-4- (trimethylstannyl)but—3-en-2-ol (39) as well as with the tributyl variant (40). By this time, a new small signal appeared in the 31P NMR around -1.5 ppm. To determine whether this was the species responsible for autocatalysis, we injected (E)—tributyl(3-methoxy-3-methylbut-l-enyl)stannane (42), which had previously exhibited an induction period of ~500 min under our standard procedure (Figure 4.8), into the reaction mixture. We expected to see immediate consumption of the stannane while monitoring by 119Sn NMR if we had in fact formed the autocatalytic species. Instead we saw kinetics identical to Figure 4.8 while monitoring for the first 1.5 h. In order to establish if a hydrido palladium species is responsible for the signal at -1.5 ppm and/or the autocatalysis, it should be independently synthesized, fully characterized, and tested for autocatalysis. 89 new signal 1 W’T’WWW‘V .-.,—.,—T..'-«,.~Y._r_..r~,._ 7*r 7 v “Trrmrww “TT’Y’"V*‘r-T"T“W"Y"T*T‘T 'r--r- r -r~~ r- ‘7'"7'”"""‘_1 10 O -10 -20 -30 -4O -50 -60 -70 -80 ppm Figure 4.10. Oxidative Addition of szdba3/TFP to Phl in THF. Selected 202 MHz 31P NMR spectra during an arrayed experiment monitoring the oxidative addition of szdba3/TFP to PM in THF. The first spectra (from front to back) was taken before the addition of Phl, the second was taken immediately following the addition of Pb], and the third was taken after the reaction proceeded for 2 h by which time a new signal appeared at -l.5 4.3.1.2. Attempts to Synthesize the Autocatalytic Species We sought to independently synthesized the hydrido palladium halide (TFP)2Pd(H)(I) (79) to test its influence on the induction period. Preparation of this exact species has not been reported in the literature, although similar species have been described.“48 For example, PdHC1(P-t-Bu3)2 is stable stable once isolated but may decompose if left in solution.48 Our attempt to 90 l\\ make and isolate 79 started with the preparation of bis ligated palladium Pd(TFP)2 (80) via treatment of Pd(OAc)2 with TFP in THF (Scheme 4.6). This medium'brown comound was insoluble in common NMR solvents and thus not characterized. Oxidative addition to H1 was then performed on compound 80, and again the product (79) was insoluble and not characterized by NMR. An IR spectra (KBr) of 79 was taken to determine whether a Pd-H bond was formed but the spectra was inconclusive. Although we could not confirm the structure of 79, we perfomed a kinetic experiment with the presumed compound as the Pd catalyst. Unfortunately, we did not observe any reaction and could therefore not confirm, or deny the involvement of 79 as the autocatalytic species in Stille reactions with szdba3/TFP catalyst systems. The known HPdBrLz should be tested in our kinetics reaction to see if autocatalysis is affected. Scheme 4.6. Proposed Preparation of TFPde(H)(I) 79 TFP (2 equiv), HI, Pd(OAc)2 -------------- > (TFP)2Pd --------- > (TFP)2Pd(H)(I) THF, 25 min, rt hexanes, 80 rt, 15 min 79 4.3.1.3. Pd/TFP System for Couplings of Unsubstituted Vinyl Stannanes One of the most surprising aspects of the autocatalysis was that it had not been observed before with this catalyst system. In fact, Farina had 91 i\\ \ reported first order kinetics with TFP as the Pd ligand. However, his studies were performed on tributylvinylstannane coupled with iodobenzene. In order to extend our studies of relative rates to complement Farina’s studies on ligand effects, we chose to study the couplings of both the unsubstituted trimethyl and tributylvinylstannanes. Neither stannane afforded autocatalytic behavior when coupled with iodobenzene; first order behavior as reported by Farina was observed. This suggests that either 1) the autocatalytic species may be more easily formed and does not require oxygen Chelation or 2) that the hydroxyl actually inhibits the reaction and/or formation of the autocatalytic species. It became clear that the reaction kinetics of Pd/TFP systems are also affected by stannane substitution and further experimentation could provide insight into the mechanism. 4.3.1.4. Insight into the Induction Period for a Pd/TFP System We see a difference in the induction period between the free hydroxyl substituted stannanes (39 and 40) and the methoxy substituted stannane (42). Given the similar rates during the induction period between 39 and 40 (Figure 4.6), the oxidative addition may be the rate-determining step at the beginning of the reaction. We therefore chose to couple both 39 and 40 with the more activated 4-iodobenzotrifluoride. Both reactions followed first 92 l\\ (14 order kinetics, where the trimethyl stannane (39) reacted faster than the tributyl (40). We , next coupled unsubstituted trimethyl and tributylvinylstannanes (57 and 58, respectively) with iodobenzene. These reactions proceeded without an induction period as well. This provides evidence that the oxidative addition of PM in the presence of oxygen substituted stannanes may be problematic since changing to a more activated electrophile eliminated the induction period and unsubstituted vinylstannanes coupled with PM also did not exhibit an induction period. If the oxidative addition of Phl were simply the rate-determining step, then the reaction with 39 and 40 coupled with Phl would exhibit 1St order behavior. It appears that the oxygen plays a role in inhibiting the reaction, and to different extents for 011’s and OMe’s. If we are seeing an induction period with oxygen bearing vinyl stannanes, the oxygen may somehow inhibit the oxidative addition thus making it the rate-determining step in the beginning of the reaction. Differences between the hydroxyl and methoxy vinylstannanes may stem from the ability of the hydroxyl to hydrogen bond to the TFP acting as a ligand scavenger or assisting in ligand dissociation whereas the methoxy does not have that hydrogen bonding capability and therefore has a longer induction period. 93 4.3.1.5. Comparison of TFP and AsPh3 Systems Further analysis of the reaction profile of trimethyl and tributylvinylstannanes coupled with iodobenzene in a Pd/TF P system indicated that they reacted at essentially the same rate, suggesting that the oxidative addition is the rate-determining step. However, this seems unlikely due to the fact that we have shown that the oxidative addition of iodobenzene is quite facile since the reaction course is completed before an arrayed kinetics experiment can be initiated. We believe that the coinciding rates were in fact a coincidence of competitive vinyl stannane coordination as was seen for couplings in benzene (Section 4.2.2). An analogous competition experiment was performed and the trimethylvinylstannane did react faster than the tributylvinylstannane indicating that the transmetallation is actually the rate-determining step but competitive vinyl stannane coordination to Pd can inhibit the reaction. In conclusion, it is of no benefit to employ trimethylvinylstannane over tributylvinylstannane from a kinetic standpoint. Also, trimethylvinylstannane is very volatile and tedious to prepare. What struck our interest as well was the comparison of reaction rates between AsPh3 and TFP as the Pd ligands. Farina reported that AsPh3 reactions provided rates 10 times that of TFP, while we found the opposite 94 trend for most instances. For reactions of trimethyl and tributylvinylstannane coupled with iodobenzene run individually or in competition, the Pd/T F P system provided faster rates than the Pd/AsPh3 system. When comparing the reaction profile afier autocatalysis for both trimethyl and tributyl stannanes coupled with iodobenzene, again the Pd/TFP system was faster than the Pd/AsPh3 system. Only for the coupling of the activated electrophiles 4- iodobenzotrifluoride with the hydroxyl stannanes was the reaction faster with Pd/AsPh3 vs. Pd/TFP. (Note: methoxy and t-Bu stannanes were not studied under the TFP system) This provides firrther evidence that the oxidative addition is problematic for Pd/TFP systems. 4.3.2. Tri-tert-butylphosphine P(t-Bu)3 We then became curious whether the autocatalysis and apparent limitations on the oxidative addition with Pd/TFP arise with only this particular ligand, or if another phosphine ligand would produce similar results. Bulky phosphine ligands have proved effective for oxidative addition of otherwise “inert” aryl chlorides.26 The bulk of the phosphine alkyl groups coupled with the strong coordination of a phosphine allows for a balance in the overall coordinative ability of P(t-Bu)3. This species is rather prone to oxidation and is therefore more complicated to use and has 95 i\\ '(l not been the focus of our kinetic studies. However, we thought it prudent to see what impact it has on aryl bromide couplings since we proposed the oxidative addition as the rate-determining step. The reaction of (E)-2-methyl-4-(trimethylstannyl)but-3-en-2-ol (39) with bromobenzene catalyzed by Pd(P(t-Bu)3)2 was set up in a bench-top reaction and monitored by GC throughout the day (Scheme 4.7). However, after ~7 hours only 25% of the starting stannane had been consumed (Figure 4.11). The reaction was left overnight and by the time 21 hours had elapsed, 100% of the stannane had been consumed. First order extrapolation of the data (shown as a solid line in Figure 4.11) suggests that the reaction would not reach completion for several days if ever. It appears that an autocatalyzed system must be operating with P(t-Bu)3 as the Pd ligand as well in order to have full conversion after 21 hours. Although we have not analyzed a wide variety of phosphine ligands, there may be an induction period trend for phosphines involved as seen with TFP. 96 Scheme 4.7. Impact of P(t-Bu)3 on Bromobenzene Coupling Pd2dba3 (2 MOP/o), /:>< 2 3( q ) 3t 9 i: \ OH M633“ \ OH THF, 0606 (4.6 vol%), 50 °C 39 59 Scheme 5.2. Kocheshkov Disproportionation for the Synthesis of Alkyl Tin Halides R4Sn + SnCl4 —> R3SnCI + RSnCl3 R=Alkyl or Aryl If this process proceeds from the trialkylvinylstannane, then upon disproportionation we would expect to see divinyl tins upon Me4Sn 100 i\\ formation. We do not observe divinyl tin speciesT in the 119Sn NMR of our kinetic experiments and therefore believe the disproportionation process proceeds from the tin halide by-product. If Me4Sn is formed from the tin halide, then it is formed after the transmetallation step and should not interfere with the Stille coupling process. Furthermore, since Me ligands transfer slower than vinyl ligands, Me4Sn should not enter back into the Stille cycle. It is important to note, that adding Me4Sn intentionally does not change the rate of reaction. Therefore, we are reasonably sure that Me4Sn is not detrimental to the reaction, although we cannot run a control experiment in absence of Me4Sn since it is formed in situ. With respect to tin recycling in our catalytic tin case (to be discussed in Ch. 6), formation of Me4Sn is a termination step in the tin catalytic cycle because of slow alkyl transfer. To advance the use of trimethylstannanes in the catalytic Stille, we first need to understand why Me4Sn is forming, and then find a way to suppress it. As we are interested in using the less toxic tributylstannanes instead of the trimethylstannanes for this sequence, the fact that we do not see Bu4Sn formation is in our favor. T We do observe other tin species as will be discussed in the next section, but we do not observe tin species related to MerSn formation. 101 5.3. Formation of Transient Tin Species We have also observed the formation of a transient tin species in the 119Sn NMR denoted “7” in Figure 5.1. These species are typically ~5 ppm downfield 0f the starting vinyl stannane signal, and are present for all substituted stannane, electrophile, and Pd/L combinations. The formation occurs faster than consumption, and both rates appear to be increased when more activated (electronwithdrawing substituted) aryl halides are used. Figure 5.1. Course of the Stille Reaction Monitored by 119Sn NMR Me3Sn/\>< \ OH \ OH F135n 0H Pd2dba3 (2 mol%), 92 AsPh3 (8 mol%), Y 10° 10‘ cross-coupled phenyl transfer 4. x 0606 (4.6 vol%), solvent, 50 °C H0 \ \ OH Y 99 102 homocoupled diene solvent = NMP entry stannane Y product % yield % yield R = Me R = Bu X: I Br I Br 1a 92 H 100 81 74 84 76 b 102 11 35 13 12 2a 92 (31:3 100 82 79 a 88 b 101 <1 3 76 c 102 4 18 4 6 3a 92 n-Bu 100 69 50 57 61 b 101 <1 10 1 l 12 c 102 ll 33 24 21 aYield of 100 and 101 as the signals overlapped in the 1H NMR spectrum. ll7 ta 9‘ 53 9A 5.6. Insight into It is uncle X transmetalllati difference in [11" bromides. The proceed though . R for R (see 1 structural confo: hale consideret 'TPPhsldeRX .\ explanation, Table 5.4 (cont’d) solvent = benzene 4a 92 H 100 b 102 5a 92 CF3 100 b 101 c 102 6a 92 n-Bu 100 b 101 c 102 27 37 83 <1 16 18 <1 44 n.d. n.d. 18 7 40 n.d. n.d. n.d. 53 28 91 45 2 23 n.d. n.d. 30 29 n.d. n.d. n.d. 5.6. Insight into the Basis of R for X vs. R for R Transmetallation It is unclear why a stannane undergoes R for R vs. the common R for X transmetalllation (Scheme 5.6) based on our data alone. We have seen a difference in the yield of homocoupled products between aryl iodides and bromides. The mechanism of R for X transmetallation has been shown to proceed though a Sn-X-Pd halo-bridge.8’20 Therefore _it seems probable that R for R (see Scheme 5.7) transmetallation is a reflection of different structural conformation and coordination interactions during this step. We have considered the x-ray diffraction data by Antipin and Grushin on (PPh3)2PdRX square planar systems54 and developed a preliminary explanation. 118 4‘,- . PdL2 n-X —’ In their 19 tPPhjigPdRX S} oxidative additit and Pd-Br influ transmetallation. transmetallation. for R transmetal arene and Sn is p the phenyl ring dependent on [h are] ring has an Br and i. the a pimendlCUlar d the ””8 System [hug leading to Scheme 5.6. R for X vs. R for R Illustration L I — — l L '_ | RforX > RPIdR + X-SnR3 PdL2 I H-SnR3 L R-X ——> R-P'd-X L L > | RforR R-PId-X + R-SnR'3 L In their 1998 paper,54 Antipin and Grushin measured bond lengths for (PPh3)2PdRX systems (where X = F, Cl, Br, and I), which are akin to the oxidative addition products we are studying. The bond lengths of the Pd—I and Pd-Br influence Sn-X-Pd bridge formation leading to the R for X transmetallation. A better-matched bond length may favor R for X transmetallation, while a less matched one may turn favor to R for R. An R for R transmetallation may be favored if a coordination bridge between the arene and Sn is possible. Antipin and Grushin54 report that the orientation of the phenyl ring with respect to the metal coordination plane is highly dependent on the nature of the halide (Figure 5.4). When X = F and C1, the aryl ring has an interplanar angle of 71.5 and 754°, respectively. When X = Br and I, the aryl ring plane and metal coordination plane become more perpendicular at 86.0 and 848°, respectively. Changing the orientation of the ring system may expose the electron rich arene to coordinate with Sn thus leading to an associative R for R transmetallation as shown in Scheme ll9 5.7. Furthermore where 1 makes Consequently tru Since the This could 3111 electrophilicity t for the less trad bromides may 11 thus leading tr stannanes pfOVlt halides, aryl st However, we c hindered trime' point. We be Conformation transmetallatit 5.7. Furthermore, the electrophilicity of Pd changes depending on the halide, where I makes Pd more positive (electrophilic) than the Pd in L2PdRBr. Consequently transmetallation will be slower for bromides vs. iodides. Since the aryl ring is more perpendicular for bromides vs. iodides.54 This could allow for more arene coordination with Sn. The lower electrophilicity of the PdBr lends to a slower reaction and allows more time for the less traditional coordination to ensue. It is then reasonable that the bromides may have a higher propensity to undergo R for R transmetallation thus leading to higher amounts of homocoupled product. Trimethyl stannanes provide larger amounts of homocoupled products across solvents, . halides, aryl substitution of the electrophiles, and stannane substitution. However, we cannot make a clear correlation between the less sterically hindered trimethyl stannanes and higher amounts of homocoupling at this point. We believe that a balance between coordination and structural conformation may give rise to preference between R for X and R for R transmetallation. 120 I. . Figure 5.4. Inter Qt 71.5 Scheme 1 L‘ QPd-x ~ \ 103 Figure 5.4. Interplanar Angles Between Aryl Plane and Metal Coordination Plane L L L L I I I l Grid-F Did-CI Q—T-l grid-Br 71 .5° 75.4° 84.8° 86.0° Scheme 5.7. Possible Mechanism of R for R Transmetallation R3SHL R38”? Q:pd— x _. 0:36 x ——> .—Pd—X —. .132? x + _. Q5093 Pd x <— OI? "Pd- x R3Snk 109 108 107 There is another explanation for the higher amounts of homocoupling with respect to the aryl bromide couplings. As has been noted in several cases, dark reaction media indicates the presence of molecular halides. We note a color change to an opaque dark/black color for aryl bromide couplings while the iodide reactions turn transparent reddish brown. Therefore, it is reasonable that if Brz is formed, it can undergo halogen-tin exchange to afford the vinyl bromide species. Then, since vinyl bromides . 55 react faster than aryl bromrdes, the vinyl bromides could undergo oxidative addition and transmetallate with the vinyl stannane to produce the 121 homocoupled P homocoupling 0. exchange more e We have stannanes are l1 product must arr are a transient throughout the r homocoupled st; rs reached in a g products can be i L'nforturrul on the basis off that the highest « iodides in XMP any] bromides a obtain lesser an an ~ drheaper stu homocoupled product. We can correlate this phenomenon to higher homocoupling of trimethyl stannanes because they should undergo halide-tin exchange more easily based on sterics. We have proposed two pathways for homocoupling. Since the aryl stannanes are formed, we do know that some amount of homocoupled product must arise from the R for R pathway. However, since the aryl tins are a transient species, we do not know the total amount of formation throughout the reaction and thus cannot quantitatively correlate it with the homocoupled stannane. We do know that a threshold of ~10% aryl stannane is reached in a given experiment; therefore at least 10% of the homocoupled products can be attributed to the R for R pathway via aryl stannanes. Unfortunately, at this juncture we are unable to draw any conclusions on the basis of R for R vs. R for X transmetallation. Our data does suggest that the highest desired product yielding reactions are those that employ aryl iodides in NMP with either trimethyl or tributyl stannanes. However, when aryl bromides are called for, one should implement the tributyl stannanes to obtain lesser amounts of side products with the benefit of using a less toxic and cheaper stannane. 122 Chapter 6. EfoC 6.1. Reassessing The goal i how the non-Iran would provide rt. chemists in their relate this inforn project in our gro Thus. the remair generation hydro 63. The 2"d Ge .1 - - Trn‘3‘°6‘°7 The toxici their use. To add h3drosrannation into the fact that Produced in S Iil Chapter 6. Effect of Additives on the Rate of the Stille Reaction 6.1. Reassessing the Goals of Our Study The goal in the beginning of this project was to further understand how the non-transferable ligands on tin affect the rate of reaction. The study would provide relative rates of reaction that would aid synthetic organic chemists in their substrate and conditions choices. We would then be able to relate this information to further understand the limitations of an ongoing project in our group: a hydrostannation/Stille sequence that is catalytic in tin. Thus, the remaining kinetic studies highlight our progress toward a 3rd generation hydrostannation/Stille sequence. 6.2. The 2nd Generation Hydrostannation/Stille Sequence Catalytic'in . 3,56,57 Tm3 The toxicity inherent to organotin substrates is a major drawback of their use. To address this problem, the Maleczka group developed a one-pot 33,56,57 hydrostannation/Stille sequence catalytic in tin. This method plays into the fact that both a hydrostannation and Stille coupling are Pd catalyzed events and that a stoichiometric amount of trialkyltin halide by—product is produced in Stille couplings. Central to the development of this catalytic 123 ‘ sequence, was ti hydride. Scheme 6 Staning from a fluoride, which trialkyltin hydric afi‘urd a vinyl ( coupling with ar trialkyltin hydriq Eduction of the 1 Scheme 6 \__ _Hydrostan Nu; HQ \ sequence, was the ability to convert the trialkyltin halide to a trialkyltin hydride. Scheme 6.1 outlines the tin catalyzed hydrostannation/Stille cycle. Starting from a trialkyltin halide, treatment with KP affords a trialkyltin fluoride, which is then reduced to a trialkyltin hydride with PMHS. The trialkyltin hydride then participates in a Pd-catalyzed hydrostannation to afford a vinyl organostannane that subsequently undergoes Stille cross- coupling with an organohalide. Recycling of the trialkyltin halide back to trialkyltin hydride completes the catalytic cycle. Also noteworthy, no reduction of the halides were observed under these conditions. Scheme 6.1. Hydrostannation/Stille Sequence Catalytic in Tin {Hydrostannation ! I LStiIIe-Coupling -X R M — M €3Sf'l \/\ R H'—_—R PdO x”! 0 \ I \~-----—-;:,/ Pd R \/\ R // I / Me3SnH Me3SnX * / \K / rm» - "PM FS" KF x. ‘i i” ‘4 \ Me3Sn F "3. PMHS _____ KX Tin-Recycling .u... musflaazi-Mfimv.ficxel This protocol minimizes the handling of the organostannanes, since the reaction setup and purification are carried out once instead of three times 124 for the synthes reaction. Further Often times, tin tin from the be gi The Male \‘anety of SUbSiI‘ 9016 yield over toxic Bu3SnCl a longer reaction I Optimization was OH 110 \\ for the synthesis of the trialkyltin hydride, hydrostannation, and Stille reaction. Furthermore, it allows one to use substoichiometric amounts of tin. Often times, tin residues are problematic to remove. Using lesser amounts of tin from the beginning allows for fewer tin residues in the end. The Maleczka group has showcased the utility of this protocol for a variety of substrates. For example, using only 6 mol% of Me3SnCl affords 90% yield over 15 tin-turnovers (Scheme 6.2). However, use of the less toxic Bu3SnCl at 6 mol% met with diminished yields, lower tin—tumovers, longer reaction times, and more forcing conditions (Scheme 6.3). Further optimization was unsuccessful. Scheme 6.2. Me3SnCl as the Tin Source M63SHCL (B-B-bromostyrene, . PMHS, aq. KF, cat. TBAF, . ‘ \ é Ph \ OH OH 1 mol% Pd2dba3, 1 mol% PdCl2(PPh3)2, 110 1 mol% trifurylphosphine. 1" EtzO, 37 °C. 11 h mol% Me3SnCI: 1 2 4 6 % yield: 19 39 63 90 Sn turnovers: 19 19 16 15 125 7). Results i respectable res‘ alkyne hydrosta in less than 30 cycle is the Stil decided to furtli Stannanes in 1]~I hydrostannation 63' COrrelating Sequence LOUklnt (I- aopears there is r \ expect to rcacti 1. l . “our kmEIiC . cl Scheme 6.3. Bu3SnCl as the Tin Source Phl, 6 mol% Bu3SnCI, % PMHS, aq. KF, _ /\)< é OH Ph OH .°".‘/"1°-'7°"i"ed"ae 59 mo °o rI uryp osp me, o THF, reflux, 48 h 21 /0 (<4 turnovers) Results indicate that trimethylstannanes are required to obtain respectable results and that tributylstannanes prove problematic. Since alkyne hydrostannantion with in situ generated tributyltinhydride can occur in less than 30 minutes, it seems logical that the rate-limiting step of this cycle is the Stille coupling. It was at this impasse that the Maleczka group decided to further understand the differences between trimethyl and tributyl stannanes in the Stille reaction before further attempts to optimize the hydrostannation/Stille sequence. 6.3. Correlating Stille Kinetic Data to the Hydrostannation/Stille Sequence Looking at the data from the hydrostannation/Stille sequence, it appears there is a 4-fold benefit to using trimethyl vs. tributyl stannanes with respect to reaction time, turnover numbers, and yields as shown in Table 6.1. In our kinetic analysis of the Stille reaction, we observed a 2.4 fold rate enhancement at best for Me/Bu in THF (see Table 3.7). This indicates that 126 the Stille r63“ complex due to Table 6.1. C 6.4. The F luori Fluoride shoun that at‘te resulting mono: hiperx'alent st Hypervalent tir tins. It is unli'. the Stille reaction in the hydrostannation/Stille sequence may be more complex due to the additional reagents utilized such as fluoride or PMHS for tin recycling. Table 6.1. Comparison of Results Using Me vs. Bu Trialkylstannanes R reaction time turnover numbers yields Me 1 1 h 15 90% Bu 48 h <4 21% Me/Bu 4.4/1 3.8/1 4.3/1 6.4. The Fluoride Effect Fluoride is a well-known additive in Stille couplings. Fouquet has shown that after oxidative addition of a stannylene and alkyl halide, the resulting monoalkyl tin can be treated with TBAF to afford the activated hypervalent stannate that undergoes an efficient Stille coupling.58 Hypervalent tin species are typically formed from heteroatom substituted tins. It is unlikely that our system is proceeding through a hypervalent pathway since we employ trialkyltins. 127 Scheme 6.4. Fluoride Activation of Stannates58 Sn(N(TMS)2)2 ArBr (0.67 equiv), CH3 (113) H30. ..N(TMS)2 TBAF (3 equiv), CHS'l > S,"‘N(TMS)2 7— 0C 115 THF, rt ' 114 Pd(PPh3)4 (1 mol%), immediate dioxane, 101 °C 91% quantitative ArBr TBAF if N (TMS) - (0.67 equiv), H3C-Sn': 2 Pd(PPh3)4 f': N(TMS)2 (1 mol%) 115 However, Fu reported the cross-coupling of aryl chlorides with tributylvinyl stannane with the use of t—Bu3P and CsF.26 They claim that the CsF activates the stannane, although they show no evidence. Given our recent understanding of aryl bromide couplings, it seems likely that the oxidative addition of aryl chlorides would be the rate-determining step. If this is true, then activation of the stannane would not affect the rate of reaction. It could however enhance the catalytic Pd species, which would in turn affect the reaction rate. Nonetheless, we thought it would be beneficial to study the effect of aq. KF/TBAF on the rate of the Stille reaction. We envisioned that if stannane activation was possible, perhaps the more prominent rate differences between trimethyl and tributyl stannanes is a reflection of the steric ease of activation. That is, trimethyl stannanes are less sterically hindered about tin, and thus easier to activate. 128 Scheme 6.5. Promoting the Stille Reaction with CsF Cl szdba3 (1.5 mol%), \ P(t—Bu)3 (6.0 mol%) + Ban“ = 118 CsF (2.2 equiv), O "7 58 dioxane, 80 °C,12h O 87% 6.4.1. Couplings of Aryl Iodides in the Presence of Aqueous KF/TBAF Our first objective was to see whether we were effecting hypercoordination of tin. We therefore treated a trimethylvinyl stannane with 3 equiv of KF (aq., 3 M) and cat. TBAF (1 drop of a 1 M THF solution) in THF (0.1857 M in tin). Hypercoordinate tin species typically appear further downfield in 119Sn NMR spectra. Incrementally scanning from 400 to -200 ppm revealed only a signal at -36 ppm belonging to the starting stannane. Although we did not see evidence for a hypercoordinate tin species, we could not rule it out. We then tested the effect of fluoride on the kinetics of the Stille coupling between trialkylvinylstannanes and iodobenzene (Scheme 6.6). The fluoride additive consisted of 3 equiv of KF (aq., 3 M) and cat. TBAF (1 drop of a 1 M THF solution). Although the reaction is biphasic, the organic phase was run at the same concentration as previous kinetic studies (see Ch. 3) and thus can be correlated to the reactions without additive. As seen in 129 Figure 6.1, the reaction rate was dramatically increased when both trimethyl and tributyl stannanes were utilized. Scheme 6.6. Stille Coupling to Determine Fluoride Effect Additive, Pd2dba3 (2 mol%), l AsPh3 (8 mol%), \ /\X + 7* OH R33” OH C506 (4.6 vol%), 39 or 40 THF, 50 °C 59 130 i\\ ‘. Fluoride Effect 1004 . = ”a i : R Me (39) No Additive S 80“ k=o.01552 T; i‘ ' KFaq.rrBAF E i k=0.21386 o m‘ o- 3, . ,t e? 40. .‘t .9 . . ._ C " I _ 20 . a“; 04 .3 m5 '. --. ,4 6 i 260 T 450 660 8.30 Tlme, min ‘ Fluoride Effect A 100- .- R=Bu(4o) 8 i 1' - NOAdditive 2' 80“ i: k=0.00676 g i '1 - KFaq.rrBAF 5 60— ‘3 k=0,0476 g, . .__ 3‘ i x .5 4o_ . .5. E9 - x; E 20_ N. . vs m 0 - . ‘ -: 2:}: (.12? :1, (3 260 Figure 6.1. Reaction Profile of Fluoride Additive Effect. 186 MHz 119Sn NMR relative integration data for the consumption of 39 or 40 without fluoride (black trace) and with fluoride (red trace) upon coupling with 1.2 equiv of Phl under a szdba3/AsPh3 catalyst system. All sets of data were fit to a first order exponential decay model (not shown) to reveal for 39 without fluoride, kobs = 0.016 min'1 and with fluoride, kobs = 0.21 min'1 and for 40, kobs = 0.0068 min" and with fluoride, kob, = 0.048 min“. 131 k\ Interestingly, reactions of trimethyl and tributyl stannanes were activated to different extents. Table 6.2 outlines the effect fluoride plays on the rates of reaction. The kobs (additive)/ kobs (none) shows that with fluoride, the trimethyl stannane reaction was activated ~14 times that without fluoride and the tributylstannane reaction was only activated 7 fold. These different amounts of activation affect the rate differences between trimethyl and tributyl stannanes, such that the Me/Bu ratio without fluoride is only 2.3, and with fluoride, 4.5! The rate difference with fluoride is more in line with what we were observing in the hydrostannation/Stille case. Therefore, we initially concluded that the fluoride is an important factor in the hydrostannation/Stille sequence and to further understand this situation, a systematic Stille study should be conducted in the presence of fluoride. We also initially believed that we were invoking some type of stannane activation, since we observed that trimethyl stannanes were activated to a greater extent than tributyl stannanes, and this could be correlated to steric influence about tin. 132 h\ Table 6.2. Fluoride Effect on Me/Bu Rate Differences R kobs (min-1) kobs (min'l) relative ratio no additive KF aq./TBAF additive/none Me 0.0155 0.2139 13.8/1 Bu 0.0068 0.0476 7.0/1 Me/Bu 2.28/1 4.49/1 Before we carried out a systematic Stille study with fluoride, we thought it prudent to take a step back and run the obvious control experiment. Since we were utilizing aqueous KF, and there are often minute amounts of water in TBAF, we wanted to determine the effect of water on the Stille reaction. Many people go to great pains to avoid the incorporation of water in the Stille reaction. For instance, they may dry solvents, flame dry glassware, and run reactions under an inert atmosphere. However, Farina has indicated in his vast overview of the Stille reaction, that moisture has been reported to be helpful sometimes, although no references were provided.24 Therefore, we wanted to determine if and how water affects the reaction so that we could more clearly understand the effect of fluoride. 6.5. The Water Effect on Aryl Iodide Couplings To determine the effect of water on the rate of the Stille reaction, the same additive experiment was performed as outlined in Table 6.2 with water as the additive. The same volume of water was added as with the aq. KF 133 h) experiment to keep the concentration of the biphasic systems consistent. Therefore, 200 uL (55.4 equiv) of deionized water was added to a 0.2 mmol reaction. The result was quite surprising; Water activated the coupling of both the trimethyl and tributyl stannanes to essentially the same level as KF/TBAF! Utilizing both HPLC grade and Milli-Q water provided the same results suggesting water is in fact activating the reaction, not trace ions. 100 Additive Effect :5 ‘ R = Me (39) ,g 80_ —NOAdditive a ——-———KFaq./TBAF g 60 ' —— Water .2, - a . .5 40. C 9 -t 5 20. i 0 a o's'o‘ido'iéo'zdo’zéo'sdo Time,m'n Figure 6.2. Reaction Profile with Water as an Additive. 18.6 MHz 119Sn NMR relative integration data for the consumption of 39 (top) or 40 (bottom) upon coupling with 1.2 equiv of PM under a szdba3/AsPh3 catalyst system in the absence of fluoride and water (black trace), in the presence of fluoride (red trace), or in the presence of water (blue trace). All sets of data were fit to a first order exponential decay model (not shown). The rate constants with and without fluoride were described in Figure 6.1. For the reaction of 39 with water, kobs = 0.27 min'1 and for 40 with water, kobs = 0.036 min]. 134 h\ Figure 6.2 (cont’d) 100i Additive Effect ’6 R=Bu (40) g 30— —NOAdditive a —KFanTBAF g 60- —Water .2. i e; 4o- C 9 . 5 20— o- 0'100'200'300'400'500'600' Time,min Since we had used a large excess of water (55.4 equiv), we were curious as to how much water was necessary for activation. To this end, we ran a water dependence study for both the trimethyl and tributyl stannane reactions (Figure 6.3) and found that as little as 1.4 equiv of water activated the reaction. It is likely that lower and higher amounts of water will activate the reaction as well, but our studies were limited by the fact we were running the reactions on small scale in an NMR tube. It should be noted that the water dependence test for the tributyl stannane was performed at ~47 °C due to problems associated with the NMR temperature controller. The overall reactions were slower than when run at 50 °C, but still had a similar correlation of rate enhancement to equivalents of water. 135 l\\ Water Dependence Study A 100— R = Me (39) E . temp = 50 C Equiy oLWater fi 80- — 0 equiv g - increasing water "— 2'8 equiv o 60— ~ - 5.5 equrv g 4 11.1 equiv g. 40. 16.6 equiv 0:) ——-—-—— 55.4 equiv a) '1 E 20. 0 ”V‘s/V“ 6'2'0'4'0'5'0'8'0'100f1i0 Time. min . Water Dependence Study A 100- R = Bu (40) 8 . temp = 47 °C Equiy etiolater "TE 80- — 0 equiv E _ — 1.4 equiv .5 60- — 2.8 equiv Z, _ .\ 4.2 equiv ”0:; 40_ ‘1. mm 55.4 equrv ac) . it E 2.. t... ilr't‘a 0— ..,.....».».V~ d'so'ido'iéo'zdo'zéo'ado Time,min Figure 6.3. Determination of Water Activation Dependence. 186 MHz 119Sn NMR relative integration data for the consumption of 39 or 40 upon coupling with 1.2 equiv of Phl under a szdba3/AsPh3 catalyst system in the presence of the indicated amount of water. From these data it is clear that water activates the reaction and should be considered as a cheap and green additive to Stille reactions. 136 i\\ \ Unfortunately at this point, we could not pinpoint the mechanism of activation, although it seems reasonable that the activation is involved in the rate-determining transmetallation step. Further studies were needed to fully understand the details of this activation. 6.6. Fluoride and Water Effect on Aryl Bromides We have suggested the oxidative addition is the rate-determining step for aryl bromide couplings. If water activates the transmetallation, then we would not expect water to have an influence on the reaction rate for aryl bromide couplings where the oxidative addition is rate determining. Therefore, we asked whether fluoride and/or water would activate the coupling of aryl bromides (Figure 6.4). When a trimethylvinylstannane was coupled with bromobenzene in the presence of water, after ~ 100 min the reaction was slightly faster than without water. Upon the addition of aq. KF/TBAF however, the rate was slightly increased for around the first 100 min, after which the reaction rate was dramatically increased. We have seen this type of autocatalytic behavior before when TFP was used as a Pd ligand and in Hatwig’s oxidative addition studies of aryl bromides. This leads us to believe that we are forming a new Pd species in situ. When a tributylvinylstannane was coupled with bromobenzene, the addition of water had no effect on the rate of reaction at the begininning of the reaction, and 137 h\ \ data was not collected after the first 165 min. Upon coupling in the presence of fluoride, modest rate acceleration was observed. Additive, szdba3 (2 mol%), Br AsPh3 (8 mol%), \ \ + > OH R38” OH THF, c506 (4.6 vol%), 39 or 40 50 °c 59 i Additive Effect ’6 100* R = Me (39) .93 80: -— NoAdditive E —— KF anTBAF CE) 60‘ —Water .2. T e; 40- C 9 . s 20. O 1 0 '2oofi4oo'eooraooi1doo Time,m'n Figure 6.4. Reaction Profile of Water as an Additive. 186 MHz 119Sn NMR relative integration data for the consumption of 40 upon coupling with 1.2 equiv of PhBr under a szdba3/AsPh3 catalyst system in the absence of fluoride (black trace), in the presence of fluoride (red trace), or in the presence of water (blue trace). 138 Figure 6.4 (cont’d) ‘ AdditiveEffect a 100- R=Bu(40) g 80; —NoAdditive g 60 —Water .2, i e; 4o— C 3 . s 20— l 0- 0’260'460'660'860'1000 Time, m'n 6.7. Insight into the Mechanism of Fluoride and Water Activation From this preliminary data we were able to develop a hypothesis on the mechanism of activation. Since aryl iodides were activated by water and aryl bromides were not, water appears to activate the transmetallation step, which is rate determining for aryl iodides. Water can activate the transmetallation for the aryl bromide coupling, but since the oxidative addition is rate determining, there will be no observable effect. It is likely that water activates the stannane, since any activation of the catalytic Pd species should show an effect for aryl bromide couplings as well. Furthermore, the greater acceleration for trimethyl stannanes vs. tributyl stannanes correlates well with steric influences. With respect to aq. fluoride, 139 h‘t the aryl iodide was accelerated, but it could be due to the water. A closer look at the data reveals that at least for the tributyl coupling (Figure 6.2, bottom), that the aq. fluoride accelerates the reaction slightly more than with just water. The aryl bromide coupling with fluoride does show an effect, indicating that the activation is involved in the oxidative addition. Furthermore, the effect is autocatalytic with trimethyl stannane 39 and leads us to believe that a new catalytic Pd species is formed. We believe this new Pd species may be related to the L2PdHX species as described in Sections 4.3.1.1 and 4.3.1.2. We do not fully understand why trimethyl stannanes appear to induce autocatalytic behavior with fluoride while the tributyl stannane exhibits first order behavior. If the water in fact activates the stannane, an explanation for the mechanism remains elusive. It is unlikely that water simply activates the tetraorganostannane via hypercoordination for two reasons: 1. A heteroatom-substituted stannane is needed to achieve hypercoordination 2. The 119Sn NMR spectra did not indicate the presence of hypercoordinated tin However, we thought that with the assistance of the free hydroxyl, we might be able to effect a type of pseudo-intemal Chelation via hydrogen-bonded 140 h\ \ water as shown in Figure 6.5. If this were true, we would expect that either shutting down the ability of the free hydroxyl to chelate, such as with a silyl protecting group, or by taking it away altogether, that water would not be able to activate the reaction. Figure 6.5. Activation of Stannane by Hydrogen Bonded Chelation To determine whether the free hydroxyl was crucial for activation, we tested if a reaction with unsubstituted tributylvinylstannane 58 was accelerated upon the addition of water. The addition of 55.4 equiv of water accelerated the reaction suggesting that the OH is not involved in water activation. Another thought on the mechanism of activation relates to the fact that heteroatom substituted stannanes can be hypercoordinated. The mechanism of transmetallation involves the transfer of a ligand from tin to Pd. Recently it has been shown both experimentally and computationally that 124 is an intermediate in the transmetallation where X-SnR3 serves as a Pd ligand through the halogen (Figure 6.6).8’20 Completion of the transmetallation step relies on this ligand to dissociate. Although we have not come across any discussions pertaining to the rate-determining step of the transmetallation, 141 tx\ we consider that if the ligand dissociation is the rate-determining step, then perhaps the water can facilitate dissociation and the overall rate of reaction. Water may coordinate to tin because it is heteroatom substituted, thus affording a hypercoordinate tin ligand, which may more easily dissociate, likely via an associative pathway. One could also imagine direct attack on the Pd to kick off the 4-coordinate XSnR3 ligand in an SN2-fashion. However, if water attacked Pd, it should also affect the kinetics of aryl bromide couplings in the oxidative addition. We have no hard evidence that ligand dissociation is the rate-determining step, although Espinet has indicated that the highest energy barrier obtained experimentally was for this step (Figure 6.7).20 142 tx\ Figure 6.6. Mechanism of Transmetallation Er L-P.d-L I 121 A, “330.3: R3Sn ----- er R3Sn-R ———’ R-P'd-L ——’ Rl-pd_|_ I 120 Ar Ar 122 123 H20:\ '.- L R38? RLPId-L <—— Eir 126 Ar R'-F‘.d-L 124 Ar — —t L R~9H2 H20 R'SIH'R Br I ') L R-P'd-L 125 143 Figure 6.7. Energy Diagram of a Retro-Transmetallation Mechanism20 30‘ —G(experimental,THF) T32 26.5 25‘ TS1 _ q. - 20.7 II- -sneual 20‘ L-Pld-F'it >~ ‘ Rt c» _ .. 15 15- C l LIJ 10- 5.. d 0.0 |/SnBu3 0' I IT L'P'd'Flf L-P|d-th + BUSSnI Rf Rf 6.8. The Copper Effect CuI has emerged as an efficient promoter of the Stille reaction, although the mechanism is not fully understood. From the work of Farina and Liebeskind,22 it appears that two different mechanisms are possible; CuI can act as a ligand scavenger or a transmetallating agent. The reaction conditions, namely ligand and solvent coordination strength, heavily dictate which mechanism dominates. Utilizing various Pd/L/Cu loadings, they were able to reveal how the Cu was playing into the mechanism. When a mild coordinating solvent (dioxane or THF) was used in conjunction with a 144 [\\ ‘ strongly coordinating PPh3 ligand, the addition of catalytic CuI acts as a ligand scavenger. When a strongly coordinating solvent (NMP or DMF) was utilized with a dissociating soft AsPh3 ligand, instead a tin to copper transmetallation takes place. Depending on which conditions are utilized, different degrees of activation may be accomplished with the addition of catalytic copper and their results are presented in Table 6.3. We therefore became interested how the “Copper Effect” affects the relative rates of reaction for trimethyl and tributyl vinyl stannanes. 145 Table 6.3. The Copper Effect: Farina & Liebskind’s Results22 Electrophile (1 equiv), Pd2dba3 (5 mol%), Bu3Sn/\ Ligand, Cul, = Ar/\ Solvent, 50 °C entry electrophile ligand solvent Pd:L:Cu kobs % molar ratio (min'l) yielda 1 iodobenzene pph3 dioxane 1:4:0 2.66 x 10'5 85 2 iodobenzene pph3 dioxane 1:4:4 523 x 10‘5 45 3 iodobenzene pph3 dioxane 122:0 170 x 10'5 91 4 iodobenzene pph3 dioxane 1:2:2 547 x 10‘5 56 5 4-iodoanisole AsPh3 NMP 12420 5.9 x 10‘3 51 6 4-iodoanisole AsPh3 NMP 1:4:4 16.6 x 10‘3 61 I 7 4-iodoanisole AsPh3 NMP 1:4:8 21.0 x 10‘3 52 8 4-iodoanisole AsPh3 NMP 1:4:16 25.2 x 10'3 51 9b iodobenzene AsPh3 DMF 1:2:0 3 5% c 56d 10" iodobenzene AsPh3 DMF 1:2:1 47% C 76d a % Yield determined by HPLC bReaction run at 50 °C c % Conversion after 5 min determined by GLC vs. internal standard d% Yield determined by GLC 6.8.1. Aryl Iodide Couplings in the Presence of Cu] A series of reactions were performed to determine the rate differences of trimethyl and tributyl stannanes in the presence of CuI. For both ligand/solvent systems, the presence of Cul did not largely accelerate the reaction as was expected. In fact, the addition of Cu] suppressed the rate of 146 l\\ i reaction and was more pronounced for AsPh3/NMP systems. This outcome is clearly in contrast to what was expected, and several aspects of the reaction were tailored to find the source of the discrepancy. For instance, the CuI utilized in Table 6.4 was freshly purified by the method of Kauffman59 then ground to a fine powder and dried under vacuum with light heating, ~30 oC. Although we were confident that the CuI was pure and dry, we also purchased 99.999% pure CuI stored under argon from Strem. Utilizing this batch of CuI produced the same negative effect. Finally, we thought that the problem was a result of the stannane we were using. 147 l\\ ‘ Table 6.4. Effect of CuI on Reaction Rate Cut, szdba3 (2 mol%), l Ligand (8 mol%), \ AX + > OH R33" OH Y Solvent, 0606 (4.6 vol%), 50 °c Y entry R Y CuI ligand solvent kobs effect of (mol%) (min-1)a ‘ CHI addition b 1 Me CF3 0 ppm THF 0.029 slightly 2b Me (31:3 8 ppm THF 0.027 slower 3b Bu (31:3 0 1313113 THF n.d. d n. . 4b Bu (31:3 8 Pph3 THF 0.022 5 Me H 0 AsPh3 NMP 0.49 slower 6 Me H 8 AsPh3 NMP 0.29 7 Bu H 0 AsPh3 NMP 0.15 slower 8 Bu H 8 AsPh3 NMP 0.058 a . . . . Rate constants were determmed by llnear regressron analysrs. bReaction profiles without CuI do not show exponential behavior. The copper effect is regarded as relatively general; therefore we did not strictly repeat those experiments performed by Farina and Liebeskind with regards to the stannane coupling partners. Since we have noticed differences in the trends between substituted and unsubstituted vinyl stannanes, we thought it was necessary to study tributylvinylstannane 58, which was utilized in Farina and Liebeskind’s study, along with trimethylvinylstannane 57 for the context of our study. Unfortunately, the 148 h\ § same inhibitory trend upon the addition of CuI was observed for both stannanes in a szdba/AsPh3 system in NMP. Lastly, we thought there might be a problem with running these reactions in the NMR. When CuI is added to the NMR tube containing all reagents except the electrophile, the CuI sinks to the bottom of the tube. We were afraid that since the CuI was insoluble in the reaction. media, we were having a mass transfer problem as the GUI sits on the bottom of the reaction vessel. We were also worried that 119 monitoring the reaction with Sn NMR was somehow giving us false data, such as any paramagnetic Cu(II) species broadening our signals. We therefore set up two reactions in parallel with and without CuI. They were run on the bench-top with magnetic stirring to alleviate any mass transfer problems. We cold quenched the reactions after 1 h 5 min at 0 °C and took a 1H NMR of the crude reaction mixtures. The ratio of starting material to product for the reaction without CuI was ~1:1. For the reaction with Cul, there was more starting material than product, indicating that CuI inhibited the reaction. These results are in line with our observations for reactions run in the NMR. All of our results suggest that Cul does not accelerate the reaction. A brief review of the literature showed several instances in which 149 k\ copper was utilized in Stille couplings. However, we did not come across any additional comparisons with and without Cu. At this point we have seen the same inhibitory trend using different batches and sources of CuI as well as with different stannanes and electrophiles. We then considered that the CuI used by Farina and Liebskind may not have been pure. They report purifying the CuI by the method of Kauffman59 as did we. This involves dissolving CuI in a saturated aq. salt solution, then precipitating the CuI out by the addition of water. Seeing as we have seen a dramatic acceleration by the addition of water, we were curious whether adventitious water in the CuI from the purification was responsible for their acceleration. We therefore developed a series of reactions with CuI to determine the amount of water necessary to 1) overcome the inhibitory effect of Cu] and 2) determine the amount of water necessary to reach the activation levels reported. For this experiment, it was essential that we replicated the literature conditions as closely as possible. We chose Farina’s conditions outlined in Table 6.5 where double the typical catalyst loading is used (8% vs. 4% Pd) and higher temperature (60 °C). However, for us to monitor the reaction by 119Sn NMR, we brought the temperature down to 25 °C, which was still too fast, and finally down to 15 °C, which was fast but observable. We feared 150 l\\ that lower temperatures might cause solubility problems since the reactions are run at a much higher concentration of Pd/As. Table 6.5. CuI Effect with Higher Catalyst Loading and Temperature: Farina’s Results Buasn/\ + ‘1 Pd2d0a3 (0.04 equiiti','7tsph3 (0.16 equiv) > 58 NMP, 60 °C entry amount of Cu] % conversion after 5 min final % Yield 1 None 35 56 2 8 % 47 76 Farina and Liebskind’s results revealed that the addition of CuI increased the rate such that at 5 min, 47% of the stannane was consumed vs. only 35% with no CuI (Table 6.5 entries 1 vs. 2). Although we observe rate suppression upon CuI addition, we could mimic a similar acceleration by instead using 5 (1L (2.8 equiv) of water as seen in Figure 6.8, Expts. 1 vs. 2. We then wanted to see if and how much water can compensate for the rate inhibition of CuI. We found that on a 0.1 mmol scale reaction with Cu] present, adding 5 uL (0.2775 mmol) of water produced a rate profile similar to that without CuI, thereby overcoming the inhibition (expts. 1 vs. 3). It was necessary to add 15 (1L (0.8236 mmol) of water in the presence of Cul to obtain similar levels of activation we saw with only 5 uL of water or Farina saw with CuI (expts. 2 vs. 4). It is unlikely that 15 uL of water is 151 l\\ adventitious considering we are only using 0.0015 g of CuI, which results in a water to CuI molar ratio of 104:1. There could be lesser amounts of water present in the CuI if it was not dried properly after the purification, although not as much as is necessary to achieve acceleration. We also weighed out 0.0015 g of CuI and added 15 (LL of water to see if Cul would absorb the water. The CuI dispersed on the surface of the water, which was expected since CuI is not soluble in water. At this point we cannot conclude whether the acceleration seen by Farina is real, or an artifact of residual water in the Cul. 152 l\\ H20, CHI, 1 Pdgdba3 (0.04 equiv) AsPh3 (0.16 equiv) 9 \ BU33"/\ + : 58 NMP, CGDG (4.6 VOl°/o), 15 °C 0.10mmol . AmountofWatertoCompensate 100.. for Cul Retardation '0 l g 80- -—-—NoWaterorCul E ———--—5uLWater E ‘ . , ~ ~Cul+5uLWater 2 60‘ . f, —--—Cut+15uLWater b 1 x .5 40- C 2 . E 20- 0- I I r ' fi I r I T 0 4 8121620221'2'8' T1me,rrin Figure 6.8. Overcoming the Inhibitory Effects of CuI with H20. 186 MHz 119Sn NMR relative integration data for the consumption of 58 (0.1 mmol) upon coupling with 1.2 equiv of PM under a 'szdba3/AsPh3 catalyst system in the absence of any additives (black trace), in the presence of 5 uL of water (red trace), in the presence of 8 mol% CuI and 5 (AL of water (green trace), or in the presence of 8 mol% CuI and 15 uL of water (blue trace). The solid colored lines are to guide the eye. 6.8.2. Aryl Bromide Couplings in the Presence of Cu] We next chose to determine the effect of Cul on aryl bromide couplings. Since the oxidative addition is rate determining, we expected that the rate would be unchanged for the AsPh3/NMP system since CuI activation is proposed to affect the transmetallation step (vide supra). 153 [\‘1 However, we should see an effect for the PPh3/T HF system since CuI acts as a ligand scavenger and would thus increase the rate of oxidative addition. What we found however was that CuI shut down the reaction for both systems. We then asked how the addition of CuI would impact a reaction that was already proceeding. Two sets of experiments were performed on the bench-top (Table 6.6). For set A, reaction 1 was the control in which vinyl tin and aryl bromide were allowed to react as normal for l h. For reaction 2, the same reaction was performed except CuI was added after 10 min and allowed to react for an additional 50 min (1 h total). After 1 h, both reactions were cold quenched, concentrated, and NMR samples were prepared. The NMR samples were also kept cold to prevent the reaction from proceeding. A 1H NMR of each crude reaction mixture was taken and the starting material/product ratios determined (Table 6.6). From the ratios, it appears that the addition of CuI has a negative effect on the reaction even when the reaction is already proceeding. We then ran set B, which is identical to set A except the CuI was added after 25 min instead of 10 min, allowing the reaction to proceed fiarther. The 1H NMR of the crude reactions showed that Cul did not inhibit the reaction and may have even accelerated it to a small 154 I\\ degree, although this may be within experimental error. It appears that CuI does not shut down a reaction that is already proceeding after a long enough wait period. These results indicate that the order of addition is important when Cu] is used. This is an important fact that was not indicated in the original report. Table 6.6. Timing of Cu] Addition and Impact on Reaction Outcome in THF Additive, Pd2dba3 (0.02 equiv), 3’ AsPh (008e ' 3 . qurv), \ arisen“ + > THF, c606, 50 °c F3C F3C set A set B reaction 1 reaction 2 reaction 1 reaction 2 Initiation Period 1 h 10 min 55 min 25 min . . CuI CuI Addme (0.08 equiv) . ' (0.08 equiv) Additional - 50 min - 30 min Time Tee“ ReaCt‘on 1 h 1 h 55 min 55 min Tlme NMR Ratios (SM /Pro (1) 81/19 87/13 80/20 79/21 6.9. Determining the Impact of the Order of Addition for Reactions with Cu] Our data suggests that the order of addition is an important factor for the rate of reaction. Farina’s order of addition depends on the exact reaction 155 I\\ ‘V conditions, and are either: solvent, electrophile, ligand, Pd, CuI, and then after 10 min at rt, equilibrated to temperature and then the stannane is added; or electrophile, CuI, solvent, Pd/L stock solution, equilibrated to temperature, and then stannane addition. Both of their systems are run under nitrogen. The differences between the two systems are when and how the Pd is introduced, either before or after the Cu], and either as separate Pd and ligand additions or as a Pd/L premixed solution. We run our reactions in air and first premix the Pd, ligand, and solvent, then to an NMR tube we add solvent, stannane, Pd/L solution, CuI, equilibrate to temperature, then add the electrophile. In both Farina and our own conditions, the CuI is present before both coupling partners are present, thus before the coupling takes place. However, they add the stannane last and run the reactions under nitrogen, while we add the electrophile last and run the reactions in air. Several experiments were performed to test whether we could effect rate acceleration by implementing the order of addition reported by Farina compared with our order, and whether nitrogen is crucial for the acceleration. These experiments are outlined in Table 6.7. Entry 1 without Cul shows that after 5 min, the amount of starting material and product are approximately the same as determined by 1H NMR. When Cul was used however, lower amounts of product were formed after 5 min, indicating that 156 [\\ the addition of CuI suppresses the reaction under our order of addition (Entry 2). For Farina’s order, the presence of CuI increased the amount of product indicating that CuI accelerates the reaction (Entries 3 vs. 4). A nitrogen atmosphere was not necessary, as the reaction in air provided acceleration as well (Entry 5). Table 6.7. Qualitative Experiments to Determine the Effect of the Order of Addition for Reactions with CuI and the Effect of Air Cut (0 mol% or 8 mol%) ' Pd db ° ° 2 a3 (2 mol /o), ASPh3 (8 mol /o) \ BU33"/\ + = NMP, rt, 5 min entry order of atmosphere CuI SM vs. effect of additiona (mol%) Prodb CuI 1 Conditions A Air 0 SM :1 Prod _ , , Suppresses 2 Conditions A An 8 SM > Prod 3 Conditions B N; O ' SM > Prod 4 Conditions B N; 8 SM < Prod Accelerates 5 Conditions B Air 8 SM < Prod a Conditions A (Ours): Solvent, stannane, Pd/L solution, CuI, and electrophile. Conditions B (Farina’s): electrophile, CuI, solvent, Pd/L solution, and stannane. bAmount of starting material vs. product as determined by 1H NMR after 5 min. From the results presented in Table 6.7, it is clear that the order of addition is important. During sample preparation for entries 3-5 under Farina’s conditions, the reaction media turned yellow with a small amount of powder remaining at the bottom of the reaction vessel after the addition of 157 k\ . . electrophile, then CuI, and then solvent. For our conditions, the CuI sank to the bottom of the reaction vessel and did not appear to dissolve. As a control experiment, we combined CuI with NMP and saw the same color change from clear to yellow. This suggests that we need to allow the CuI to solubilize before adding the remaining reagents. Therefore, we changed when the CuI was added, while still retaining the order of other reagents. The reason being, that it is easier to add the stannane to the reaction before the electrophile, so that the NMR can be tuned to 119Sn, and then the electrophile added to initiate the reaction. Therefore, we ran parallel reactions to determine if allowing the CuI to disperse is enough to invoke rate acceleration. We ran one control of Farina’s order (Conditions B) and one of our new order (Conditions C), which are indicated below. After steps 3b and 2c, the reaction turned yellow as expected. However, for Conditions C, after the stannane was added (step 3c.), the reaction turned a darker green color after sitting for the amount of time it took to add the Pd/L solution to the Conditions B experiment, around 3 min. After both experiments were set up and run for 5 min, an analysis identical to that in Table 6.7 was performed. For Farina’s order, there was more product formed than remaining starting material where as for our conditions, there was more unreacted starting material left than product. This indicates that despite 158 h\ allowing the CuI to dissolve, the reaction was still suppressed. At first glance, one would think that if for the AsPh3/NMP conditions Cu and Sn undergo a transmetallation, then having the stannane present with CuI before the coupling starts would allow more time for the initial Cu—Sn transmetallation and certainly not suppress the reaction. However, given the color change to darker green after the stannane sat in the CuI solution, perhaps a transmetallation occurred and the new possibly unstable Cu species had nothing to react with (e.g. electrophile) and therefore decomposed to a Cu(II) species as indicated by the color change. Therefore, the crucial events for Cu] to accelerate the Stille reaction are that CuI is allowed to dissolve and that the stannane is added last. These criteria are met with Farina’s order and thus any continuing experiments should utilize these conditions. Table 6.8. Order of Addition for Reactions with CuI Farina’s Order (Conditions B) Our New Order (Conditions C) la. Electrophile 1c. CuI 2b. CuI 20. Solvent 3b. Solvent 3c. Stannane 4b. Pd/L from stock solution 4c. Pd/L from stock solution 5b. Stannane 5c. Electrophile 159 Having determined that we should use Farina’s order of addition (Conditions B), we carried out the coupling of a substituted trimethyl and tributyl vinyl stannane with iodobenzene to determine the effect of CuI on the Me/Bu ratio. The reaction and results are shown in Table 6.9. In entries 1 vs. 2 without CuI present, the Me/Bu ratio is 4.36/1. However, the addition of CuI reduces the rate difference of Me/Bu to only 2.5/1 (entries 3 vs. 4). This is due to the fact that although CuI accelerated the reaction of the tributyl stannane to 1.45 times faster with CuI than without, while it suppresses the reaction with trimethyl stannane (see column CuI/No CuI). Since Farina did not utilize trimethyl stannanes in his study nor provide the specific details regarding the timing for the order of addition, it is difficult to understand these results at this juncture. We therefore went on to determine the effect of Cul on the Me/Bu rate differences for the coupling of unsubstituted vinylstannanes 57 and 58 with iodobenzene under Farina’s conditions (Figure 6.9). While the reaction with tributylvinylstannane 58 was slightly accelerated by the addition of CuI, the reaction with trimethylvinylstannane 57 was not accelerated, nor was the rate suppressed. Perhaps in this instance the oxidative addition is the rate-determining step since the transmetallation with the sterically unhindered vinylstannane is very facile. It is clear that the stannane substitution is again a large factor in 160 the rate and mechanism of the Stille reaction. However, more experiments are necessary to truly understand the effect of CuI. Table 6.9. CuI Effect on Me/Bu Ratio Under Farina's Conditions Col (0 or 8 mol%), I szdba3 (2 mol%), R s AXOH + ASPh3(8 [ml/O), T O \ OH n 3 NMP, 0605 (4.6 vol%), 50 °C entry R CuI (mol%) kobS (min'l)a Me/Bu CuI/ No CuI 12' Me 0 0.48 . 4.36/1 Me. 0.83/1 2a Bu 0 0.11 (entry l/entry 3) 3 Me 8 0.40 - 2.5/1 Bu. 1.45/1 4 Bu 8 0.16 (entry 2/entry 4) a Results from Table 4.1 161 f\\ H20, CuI, Pdgdba3 (0.04 equiv), ' AsPh o 16 ' 3( . equrv) \ em + (j =©¢ 58 NMP, C606 (4.6 vol%), 15 °c 0.10mmol EffectofCul 100— —Me(NoCul) A . —Bu(NoCu|) 8 80_ ----- Me(Cul8mol%) a; ‘ ' ----- Bu(Cu18mol°/o) E 8 60- E. . e .0- C 9 . C _ 20_ 02 0'5'1b'1'5'2b'2'5'3'0'35'4o Time,m'n Figure 6.9. Effect of Cu] Using Farina’s Order. 186 MHZ 119Sn NMR relative integration data for the consumption of trimethylvinyltin (57, blacktraces) or tributylvinyltin (58, red traces) upon coupling with 1.2 equiv of Phl under a szdba3/AsPh3 catalyst system in the absence of any additives (solid traces) or in the presence of 8 mol% CuI (dashed traces). 162 i\\ \ Chapter 7. Heck-Like Cross Couplings of Vinyl Germanes 7.1. Why Germanium? Thus far our work has been focused on understanding the reactivity differences between trimethyl and tributyl Vinyl stannanes. Our reasons for embarking on this study were two fold. First of all, we would provide the synthetic organic community with relative rate data in order to logically choose substrates and conditions (trialkyl stannanes, electrophiles, solvents, additives, etc). Secondly, we could use this information to better understand the problems associated with our hydrostannantion/Stille cascade in order to provide a next generation approach. Both of these purposes tie into the fact that it would be beneficial to use less toxic tributyl stannanes as opposed to the trimethyl variants. Another approach would be to eliminate the use of tin altogether while still retaining the versatility that is inherent to the Stille reaction. Hiyama60 (organosilane) cross—couplings are also widely utilized alternatives to Stille couplings since they are less toxic, have a decent substrate scope, and are easy to handle. The electronic structure of the silicon is similar to that of tin because they are in the same group in the periodic table. Mechanistically however, the silicon is less reactive and must be activated with fluoride for the reaction to proceed. Working our way up 163 l\\ the group 14 metals from tin, we come across germanium before silicon. We can infer that organogermanes may have enhanced reactivity compared with silicon and may not require activation. Furthermore, organogermanes are far less toxic than the corresponding organostannanes. For example: Bu3GeCl: LD50 = 1970 mg/kg (intraperitoneal injection in rat) Bu3SnC1: LD50 = 117 mg/kg (oral in mouse) 7.2. Development of Organogermane Reactions Several reports have appeared in the literature exploring organogermane reactions. A report by Sano in 1986 highlights the similarity in reactivity of organogermanes with organostannanes and organosilanes.61 Allylic and allenyl germanes were prepared by desulfurizative germylation analogous to their stannylation protocol62 and were subsequently exploited in allylation reactions of aldehydes (Scheme 1.1). This allylation reaction indicates that Ge instills negative character on the (it carbon, similar to Si and Sn organometallic nucleophiles. 164 Scheme 7.1. Allylations with Allyl Germane61 Ph/\/IL H OH WGePh3 Te th BF3‘OE12 127 CH2Cl2, -78 °c + rt 128 55% Organogermanes can also act as electrophiles. Oshima illustrated the iodo- and bromodegermylation of Z—vinyl germanes in 1984.63 In 1990, Ikenaga and Kikukawa extended the types of organogermane transformations to include a Pd—catalyzed aryldegermylation with an arylpalladium tetrafluoroborate.64 The reaction proceeded through an addition-elimination pathway much like aryldesilylation. Kosugi considered a more traditional cross-coupling approach in 1996 where organogermatranes were coupled with aryl bromides under Pd catalysis.65 Most couplings of the corresponding tributylgermanes did not provide cross-coupled products where 59-95% yields were achieved with organogermatranes.T This indicates that activation via the nitrogen lone pair provides a more nucleophilic species and may react along the lines of stannatranes in Stille couplings.30 T Vinyltributyl germane coupled in 60% yield with bromotoluene. The transferable group on germatrane was vinyl, allyl, or ethynyl. When it is alkyl, the yield is <10%. 165 Scheme 7.2. Cross-Couplings of Germatranes65 .J‘ N \ Br szdba3-CHCI3 (1 mol%), \ <: 9 + P(0—to|)3 (4 mol%), Ge T H c H3C 129 K 3 \ THF, 120 °C, 24 h, 82% 130 Further advances were reported in 2002 by Oshima, where aryltri(2- fury1)germanes were shown to react with aryl halides under palladium 66,67 catalysis to provide access to unsymmetrical biaryls. Unfortunately, large amounts of TBAF (5 equiv) are necessary to achieve coupling. A mechanistic study revealed that refluxing aryltri(2-furyl)germane with TBAF for 5 h resulted in the loss of the 2-furyl ligands, most likely because fluoride has been shown to cleave Si-heteroaryl bonds68 and can cleave Ge- heteroaryl bonds as well. This would produce a hypervalent organogermanium compound, such as [ArGe(OH)3F]', which could be responsible for the transmetallation. Tetraphenyl germanes did not couple under the same conditions, further suggesting that the Ge-heteroaryl bond is essential for these transformations. Also in 2002, Faller began reporting on the expanded scope and utility of germatrane couplings.69’7O Vinyl tris(trimethylsilyl)germanes have also found their place as efficient coupling partners upon basic-oxidative treatment described by 166 Wnuk (Scheme 7.3).71'73 Kosugi has continued to develop germanium coupling chemistry demonstrating that aryl tricholorgermanes, or the hydrolyzed sesquioxide variant,74 can partake in biaryl couplings in aqueous media (Scheme 7.4). More recently Spivey has shown progress towards polymer or fluorous tagged germane couplings which are activated by photooxidation thus allowing for implementation in library syntheses.75 Continuing efforts to expand germane synthesis76’77 and utility clearly indicate the viability of germanium cross-coupling chemistry. Scheme 7.3. Vinyl Tris(trimethylsilyl)germane Couplings by Wnuk“-73 t-BuOOH, KH (TMS)3Ge/\/Ph = [ah/V Ph Phl, Pd(PPh3)4, ‘31 THF, 45 °C, 10 h 132 Scheme 7.4. Tricholorgermane Couplings by Kosugi78 Pd(OAc)2 (5 mol%), F 0 OF 0 + > MeO Br dioxane, H20, 0 133 0.5 h, 860/0 M90 134 Prompted by these recent reports, our group decided to explore germanium cross-couplings of tributylvinylgermanes. We imagined that information gained from our Stille kinetic studies may correlate to these 167 germanium cross-couplings and would give us a unique perspective on how to approach any problems. The work presented in this chapter is a continuation of a former group member’s project, Jérdme M. Lavis. The results obtained by him have been indicated and referenced to his Ph.D. Dissertation.31 7.3. Synthesis of Vinyl Germanes The synthesis of vinyl germanes can be achieved though hydrogerrnylation of an alkyne (Table 7.1). When terminal alkynes are used, only the E and internal Vinyl germanes are produced. The level of selectivity depends on the substitution at the propargylic position; greater substitution leads to larger E selectivity. Entries 4 through 8 proved difficult to separate. Careful column chromatography allowed for the separation of isomers in entry 7: 98% pure internal isomer and >99% pure E. 168 Table 7.1. Hydrogermylations Pd(PPh3)4 (3 mol °/o), R R BU3G9 R // > Bu3Ge/\/ + \il/ Bu4GeH (1.2 equiv), THF, rt, 8 h (E) int entr alkyne product % yielda E/intb 1 2%., 135a 96 100% E 2 135b 89 100% E // OH 3c ///k 135c 73 100% E 4c ///\/\/OH 1350 64 4.0/1 5° WOH 135e 75 3.8/1 6“ é/V 135f 78 3.6/1 7 // OH 135g 81 1.7/1d SC ///\/\/OTHP 13511 62 1.3/1 9 24mm 135i 91 100% E a Isolated material bDetermined by 1H NMR analysis of the isolated product. 0 Results from J éréme Lavis’ dissertation31 dDetermined by 1H NMR analysis of the crude reaction mixture; reaction time: 14.5 h 169 7.4. Finding the Right Coupling Conditions Since it was believed that germanium cross-couplings could proceed through a Stille-like mechanism, we first tested Stille conditions for the cross-coupling of 135a with bromobenzene. The reaction proceeded in modest yield (only 28%), but with a surprising transformation of the olefin geometry; the E germane afforded the Z product. Scheme 7.5. Germane Cross-Coupling with Inversion of Olefin Geometry31 Pth szdbag, (20 mol%), A>< AsPh3 (80 mol%), Ph BuaGe OH > \ OH NMP, 70 c, 48 h 28% This sort of change in geometry is not typical for traditional cross- coupling mechanisms. As such, we considered a Heck-type mechanism (Scheme 7.6). A syn B-germyl elimination would account for formation of the Z olefin. Such eliminations are not without mention in the literature. Palladium-germyl eliminations were used to explain the mechanism of Ikenaga and Kikukawa’s aryldegermylation64 and more recently in Faller’s work69 although they proceed through an E2 elimination pathway. 170 Scheme 7.6. Proposed Mechanism of Germanium Cross-Coupling Bu3GeBr PhBr Pd(O) Reductive Oxidative Elimination Insertion Bu3€tePd(")Br Ph-Pd(")Br R E ‘— Ph R BuaGe Pd(I')Br BU3Ge Elimination Ph“"' ""‘Ft Addition H H Further screening of Stille reaction conditions did not improve the initial results.31 Heck conditions were next considered based on those developed by leffrey.79 Screening different quaternary ammonium salt additives, bases, and solvents (Table 7.2) identified Bu4NBr and K2CO3 in a mixture of MeCN/HZO (9:1) as the most effective conditions (entry 1). The palladium catalyst loading was screened (entries 1 and 7-9) whereby 20 mol% struck the best balance between stoichiometry and yield (entry 8). Temperatures ranging from 60-70 C’C proved best; lower temperatures did not effect coupling and higher temperatures afforded lower yields presumably due to catalyst decomposition.31 l7l Table 7.2. Screening Heck Conditions Pd(OAc)2, PPh3 (Pd/L 1:2) 1 equiv Additive, Ph Bu3 Ge /\>< OH 2.5 equrv Base, Solvent, 7 \ OH 2 equiv Phl, 60 or 70 °C, 16 h entry mol% additive base solvent % % Yielda Pd SMa (Z/E/int) 1 10 BU4NBI' K2CO3 act 53 47 MeCNC (17/4/ 1) 2b 10 Bu4NHSO4 cho3 219- 21 34 MeCNC 3 10 — K2CO3 aq. 66 34 MeCNC (21/1/5) 4 10 Bu4NBr NaHCO3 39- 57 43 5b 10 Bu4NBr NaHCO3 DMF 80 6 6b 10 Bu4NBr Ag2C03 a9- 65 30 MeCNC 7 5 Bu4NBr K2C03 aq- 54 46 MeCNC (17/5/ 1) 8 20 BU4NBI’ K2CO3 aq- 45 55 9b 50 Bu4NBr cho3 219- 63 37 MeCNC (4/1/0) a Yields of product and unreacted starting material as well as Z/E/intemal ratios were determined by 1H NMR analysis of crude reactions with MeOH, mesitylene, or TMS-O-TMS as an internal standard. b , ,. . , . . 31 Results from Jerome Lav1s dissertation ° MeCN/HZO (9: 1) 172 We then ran a few coupling reactions under Stille and Heck conditions to determine if there is a general benefit to using Heck over Stille conditions (Table 7.3) across electrophiles. Although the Stille conditions were effective at times, Heck conditions proved superior. Table 7.3. Comparing Stille vs. Heck Conditions entry Ar-X % yield % yield % yield A)a 13)b 1d Phl 30 25 47 2 PhBr 289 289 30 3 4-bromoacetophenone 1 5 3 1d 61d 4 1 -bromo-4-nitrobenzene l O 0 48 a Stille A: 20 mol % szdba3, 80 mol % Ast3, 135a, 2 equiv ArX, NMP, 70 °C, 48 h. bStille B: Stille A conditions using Pd(OAc)2 instead of szdba3. c Heck: 20 mol % Pd(OAc)2, 40 mol % PPh3, 135a, 2 equiv ArX, 1 equiv KZCO3, 1 equiv Bu4NBr, MeCN/I-IzO (9:1), 70 °C, 16 h. d r A ' g - - 31 Results from Jerome LaVis dissertation Convinced that Heck conditions provided the best results, we proceeded to outline the scope of the reaction over a variety of electrophiles. These results are presented in Table 7.4 and were performed by Jéréme . 31 Laws. The reactions proceeded with moderate yields and favored formation of the Z product. Electron deficient aryl halides tended to afford higher yields and competitive formation of the E product, suggesting the 173 involvement of multiple mechanistic pathways. In all of these cases, the starting material was not fully consumed at the end of the reaction. Allowing the reaction to proceed for up to 24 hours did not appear to impact the yields to a large extent, presumably because the catalyst had decomposed; therefore all reactions were run for 16 h. 174 Table 7.4. Scope of Coupling with Various Aryl Halides at 0.05 MT AVJOH 2 equiv Ar-X, A 20 mol % Pd(OAc)2, 40 mol % PPh3, Bu3Ge \ OH 1 equiv Bu4NBr, 2.5 equiv K2003, MeCN/HZO (9:1), ~0.05 M, 70 °C, 16 h ¥ 7 entry germane halide yield Z/Ea Bu3Ge/\>20/1 2 Bromobenzene 136: 26% >20/1 3 4-Iodotoluene 137: 47% >20/1 4 4-Bromoanisole 138: 27% >20/1 5 4-Bromoacetophenone 139: 61% 4.7/1 6 Methy14' 140: 68% 5/1 bromobenzoate 7 liBmmO'4' 141: 56% 4.6/1 nitrobenzene 9 4-Bromoacetophenone 142: 61% >20/1 BU3G€ \ OH _. . 0 _ 10 Bu3Ge/\J\ 4 Bromoacetophenone 143. 0A) 3' Yields and Z/E ratios based on isolated material. The results were not reproducible following an experimental indicating the reaction was run at a concentration of 0.2 M. These results are outlined in Table 7.5. Although the yields appeared to be in the same range and selectivity still favored formation of the Z product, the level of selectivity was much lower. It was finally assessed that the reactions . . , . . 31 Experiments performed by from Jerome Lavrs. 175 performed by Lavis were actually run ~0.05M. It appears that the concentration is very important regarding isomeric outcome, and may provide insight into the mechanistic course. Thus the effect of concentration was explored next. Table 7.5. Scope of Coupling with Various Aryl Halides at 0.2 M 2 equiv Ar-X, /\>< 20 mol % Pd(OAc)2, 40 mol % PPha. Maj—OH BuaGe \ 0H 5 — 1 equiv Bu4NBr, 2.5 equiv K2CO3, MeCN/HZO (9:1), ~0.2 M, 70 °C, 16 h entry germane halide yield Z/E/inta 1 Bu3Ge/\>< 20 mol % Pd(OAc)2, 40 mol °/o PPh3, PthH Bu3Ge \ OH 5 — 1 equiv Bu4NBr, 2.5 equiv K2003, MeCN/HZO (9:1)}?1 70 °c, 16 h Entry Molarity %Yield Z%Yield E%Yield Z/E 131 ~0.05 26 25 1 >20/1 2 0.1 29 27 2 135/1 3 0.168 26 21 5 4.2/1 4 0.2 23 17 6 2.8/1 a Amount of solvent adjusted to obtain the indicated molarity. It was unclear whether the concentration was affecting the isomeric distribution of products, or if it was a reflection on the amount of water 177 present since the solvent system employed was a 9:1 mixture of MeCN/11120. Jeffrey had discussed the impact of water on the reaction depending on the quaternary ammonium salt and base, along with whether a phosphine ligand was used.79 We therefore ran a reaction in the absence of water to see if the isomeric ratio was affected. The standard conditions were used, although with anhydrous MeCN as solvent at 0.19 M. The K2CO3 was not solubilized, and perhaps this is why the reaction only afforded 28% yield. However, the Z/E ratio of products (3.9:1) was consistent with an analogous reaction run in MeCN/HZO (9:1) that afforded 55% of Z/E (3.7:1). Next, we reacted vinyltributylgerrnanes that were not fully substituted at the allylic position. Within the context of our putative Heck mechanism, two carbons possessing [i-hydrogens flank the Pd-intermediate formed upon addition across the olefin of such substrates. In theory this would allow us to probe any competition between Pd—Ge and Pd—H eliminations. The results are shown in Table 7.7. 178 Table 7.7. Cross-coupling of Unhindered Vinyltributylgermanes 2 equiv Halide, 20 mol % Pd(OAc)2, Bu3Ge/\/R 40 mol % PPh3, : Ar\=/R + Ar/\/R + Ar/[LR ‘35 3.5923352233; ‘2’ ‘5 ‘"‘ MeCN/1120 (9:1), ~0.05 M, 70 °C, 16 h entry germane halide % yield Z/E/int 1 135g 4-Bromoacetophenone 1 5 100% int 23 135eb 4-Bromoacetophenone 49 4/1/20 3a 135db Iodobenzene 3 5 5/1/ 19 4a 135db 4-Bromoacetophenone 49 3/1/20 5 135hc 4-Bromoacetophenone 39d 1 .2/ 1/ 7. 1 6a 1351,6 4-Bromoacetophenone 37d 1 . 1/1/4.2 a Results Jér6me Lavis’ dissertation.31 b Starting E/int ratio of 4/1 6 Starting E/int ratio of 10/1 dDetermined by 1H NMR analysis of the crude reaction using anisole as an internal standard. 6 Starting E/int ratio 4.3/1 Interestingly, (E)-135g gave exclusively the cine (internal) product, albeit in only 15% yield. Regioisomeric mixtures of 135e, 125d, and 135h each afforded mixtures of E, Z, and cine products, where the cine products were formed in yields exceeding the amounts of starting internal germane. Notably, submitting the starting material to the reaction conditions without the aryl bromide did not change the E/intemal ratio. All these experiments 179 / A suggest that (E)—vinyltributylgermanes unhindered at the allylic position give rise in significant part to the cine products. This conclusion, in combination with the low yield of the Z products and no indication of Pd-H elimination, indicates the involvement of non-Heck pathways. Lastly, we sought to examine the stereospecificty of the reaction. Since E germanes favor formation of the Z product, we asked whether a Z germane would afford the E product? The Z germane was prepared germylation of the terminal alkyne, hydroboration of the germylalkyne, and finally deborylation with acetic acid (Scheme 7.7). Scheme 7.7. Synthesis of Z Germanes % 2 equiv n-BuLi, THF, 0 °C, 10 min; then 1 equiv Bu3GeX, 0 °C *rt, 7 h Bu3Ge 145a R = H (X = Br for 17a, CI for 17]) 146a R = H 69% 145' R = TBS 1461 Ft = TBS 40% 2 equiv Cy2BH, THF, -10 °C then alkyne,» rt, 1 h; Bu3Ge\__>|—OR . = (Z)-135a R = H 33% then 35 equrv AcOH, rt, 3 h (2)4 351 R = TBS 28% (Z)-Germane 135a, was then cross-coupled with Phl under our standard conditions at 0.2 M. TLC analysis indicated that the reaction did not proceed after 6 h although starting material was still present. The reaction was stopped and purified to afford 45% yield favoring the E isomer ((Table 7.8, entry 1). The reaction of (E)-135a afforded only 35% at 6 h in 180 favor of the Z product (entry 2). The increased reactivity of the Z germane can be may be explained by the observation made by Faller that 0-che1ated germatranes are more reactive than C—chelated ones.69 We suggest that our system is undergoing a similar activation in which electron donation of the oxygen increases the reactivity of the germanium (Figure 7.1).31 To this end, we synthesized the TBS ether (Z)-1j (Scheme 7.7) in order to shut down any Chelation by the oxygen. When this substrate was subjected to our Heck conditions, only trace amounts of Z product were present by 1H NMR analysis of the crude mixture after 6 and 24 h, supporting our hypothesis that oxygen activates the Stille pathway via germanium chelation. Furthermore, the level of stereoselectivity for entries 1 and 2 were much different. The Z germane favored the E product by 1.4/1 (E/Z) whereas the E germane favored the Z product 8.8/1 (Z/E). We believe the level of stereoselectivity is a reflection of the oxygen chelation. Since oxygen can activate the Ge- carbon bond, the Z germane is more activated towards Stille coupling thus affords a larger amount of the Z product. 181 Table 7.8. Effect of Germane Geometry on Coupling Bu Ge OR 2 equiv Phl Ph 3 J 20 mol o/o Pd(OAC)2, 40 mol o/o PPh3, _ OR 1358 R = H 1 equiv Bu4NBr, 2.5 equiv K2003, 59 R = H 135' R = TBS MeCN/H20 (9:1), 0.2 M, 70 °C, 6 h ‘44 R = TBS entry germane % total yield Z % yield E % yield Z/E 1 (Z)—135a 45 (59) 19 26 0.73/1 23 (E)-135a 35 (59) 31 4 8.8/1 3 (Z)-135i traces (144) traces not detected Z only a (E)-l35a required 16 h to reach 47% yield Figure 7.1. Activation of Ge-Carbon Bond by Oxygen Chelation H o’lO Bu3Ge'\")< 147 7.6. Conclusions We have described a method by which tributylvinylgermanes are cross-coupled with aryl halides under Pd catalysis. A mixture of mechanistic pathways are possible whereby E germanes afford the E, Z, or cine substituted products. Concentration and oxygen Chelation are among the factors that can influence preference for one pathway over the other. 182 Chapter 8. Future Work Throughout the course of study, a number of interesting observations warrant further investigation. We found that using TFP as the Pd ligand effects autocatalytic behavior. Although we attempted preparation of a hydrido palladium iodide species, similar to what Hartwig showed47 to exhibit autocatalysis in oxidative additions, we were unable 'to characterize the compound. Furthermore, it did not influence a change in the rate- determining step when employed instead of the szdba3/TFP precatalyst system. Allowing the oxidative addition to proceed for several hours prior to addition of the stannane in an effort to prepare the autocatlytic species in situ led to no acceleration either. We have observed autocatalytic behavior as well with other phosphine ligands, including PPh3 and P(t-Bu)3. It is known that coordinative phosphine ligands can inhibit reaction rates since progress is dependent on ligand dissociations (See Section 1.2 and 4.3). This suggests that perhaps the induction period simply involves ligand dissociation to afford the solvent stabilized bisligated system TFPde(S). However, when iodobenzene is coupled with Vinyltributyl tin, there is no indution period and the reaction follows first order behavior. The behavior of phosphine ligands appears to be substrate depended and should be further studied to understand 183 the influnce of the vinylstannane substitutents (e. g. oxygen). Coupling of either a carbon substituted stannane or silyl-protected stannane (Figure 8.1) would allow one to probe the oxygen influence. Identification of the autocatalytic species is also important, and should focus on preparation of the known LdeHBr species. The role of additives also needs to be examined further. Preliminary results indicate that fluoride activates Stille reactions and to different levels for trimethyl and tributyl stannanes coupled with iodobenzene. When aryl bromides were tested, the trimethyl stannane was accelerated with autocatalytic behavior, while the tributyl stannane was accelerated but not with autocatalytic behavior. A systematic study should be performed to truly understand the role of fluoride in activation. Once these studies are performed, one may apply the information towards the development of an efficient next generation Stille reaction catalytic in tributyltin. With respect to copper additives, now that we have identified that the order of addition of CuI is important, it would be prudent to extend the systematic studies to include reactions with CuI and other Cu salts (e. g. CuTc, CuClz). 184 Figure 8.1. Stannanes with No Coordinative Oxygen R33n/\)< R3Sn/\> /' Q SnMe3 C B Our rate studies provide further insight into the mechanistic details of the Stille reaction. They may be directly utilized in advancing Stille coupling procedures or may even be applied to other cross-coupling reactions where the carbon-metal bond has similar polarity. 187 Chapter 9. Experimental Details 9.1. Materials and Methods Tetrahydrofuran was freshly distilled from sodium/benzophenone under nitrogen. Benzene was freshly distilled from calcium hydride under nitrogen. Benzene-d6 was purchased from the Cambridge Isotope Labs and used without further purification. Anhydrous N-methyl-2-pyrrolidinone was purchased from Aldrich in a Sure/SealTM bottle and used without further purification. Deionized water was used unless otherwise noted. Triphenylarsine was recrystalized in EtOH and 4-iodobenzotrifluoride was distilled and run through activated neutral alumina (Brockmann 1). Tri-2- fury] phosphine (TFP) was either purchased from Aldrich or prepared by the method of Zapata and Rondon.82 All other commercial reagents were used without purification unless otherwise noted. Flash chromatography was performed with silica gel 60 A (230—400 mesh) purchased from Silicycle. Yields of cross-coupled products via organostannanes and organogermanes were determined by 1H NMR of crude material versus mesitylene or hexamethyldisiloxane (NMR grade) as an internal standard. All other yields refer to chromatographically and spectroscopically pure compounds. Melting points were determined on a Thomas-Hoover Apparatus, 188 uncorrected. Infiared spectra were recorded on a Nicolet IR/42 119 spectrometer. 1H, 13C, 19F, 31F, and Sn NMR spectra were recorded on a 500 MHz spectrometer (500 MHz for 1H, 125 MHz for 13C, 470 MHz for 19F, 202 MHz for 31P, and 186 MHz for 119Sn) with chemical shifts reported relative to the residue peaks of solvent chloroform (5 7.24 for 1H and 8 77.0 for 13C). High-resolution mass spectra (HRMS) were obtained on a Waters QTOF Ultima mass spectrometer at the Michigan State University Mass Spectrometry Facility by Luis Sanchez. 9.1.1. Standard Reaction Methods All reactions were carried out in oven—dried glassware, with magnetic stirring, and monitored by thin—layer chromatography with 0.25-mm precoated silica gel plates, unless otherwise noted. Visualization of reaction progress was achieved by UV lamp or phosphomolybdic acid stain. 9.1.2. Kinetic Methods All reactions were carried out in 507-HP-7 Norell NMR tubes in a Varian Unity Plus—500 MHz NMR spectrometer tuned to the 119Sn (186 MHz) or 19F (470 MHz) nucleus. All glassware (NMR tubes and volumetric flasks) were carefiilly cleaned by soaking in aqua regia (HCleNO3, 3:1), 189 k\ \ then rinsing with base bath (KOH in i—PrOH/HZO), and then rinsing with water and acetone. They were then dried on top of an oven to avoid compromising the integrity of the glass. Vials used to weigh out reagents for solution preparation were flame dried and cooled under nitrogen. All reactions were set up in air unless otherwise noted. T1 measurements, temperature calibration, and arrayed kinetics experiments on the NMR were set up using the protocol described on the Max T. Rogers’ NMR Facility 83 119 19 webpage. Heteronuclear ( Sn and F) parameters were set up by Dr. Daniel Holmes of the Max T. Rogers NMR Facility. 9.2. Preparation of Stannanes Ax Representative Hydrostannation Procedure: Me3Sn \ OH 39 Preparation of (E)-2-methyl-4- (trimethylstannyl)but—3-en-2-ol (39) (Table 3.1, entry 1). PMHS (0.09 mL, 1.5 mmol) was added to a solution of 2-methyl-3-butyn-2-ol (0.1 mL, 1.0 mmol), Me3SnCl (1.2 mL, 1 mmol; 1 M solution in THF), aqueous KF (176 mg, 3 mmol; 3 mL H20), (PPh3)2PdC12 (7 mg, 0.01 mmol), and TBAF (1 drop of a 1 M solution in THF; ca. 8 (1L) in THF (5 mL). The biphasic reaction mixture was stirred at room temperature for 2 hours and a 0.5 M 190 solution of NaOH (1 mL) was subsequently added and stirred for an additional 2 hours. The two phases were then separated and the aqueous layer was extracted with diethyl ether (x3). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography [silica; 90:10 hexanes/EtOAc, 1% TEA] to afford (E)-3-methyl-1-trimethylstannyl-1- buten-2-ol (39) as a colorless oil in 47% yield. 1H NMR (500 MHz, CDC13) 8 0.09 (s, 9 H), 1.26 (s, 6 H), 1.67 (s, 1 H), 6.00-6.20 (AB, JAB = 19.0 Hz, 2 H); 13C NMR (125 MHz, CDCl3) 8 -97, 29.3, 72.2, 123.4, 155.0; 119Sn NMR (186 MHz, CDC13) 5 -35.8. Spectroscopic data (1H and 13C NMR) . . . . 57 were consrstent wrth prior literature reports. A Preparation of (E)-2-methyl-4-(tributylstannyl)but- BU3Sn OH 40 3-en-2-ol (40) (Table 3.1, entry 2). Applying the above conditions to 2-methyl-3-butyn-2-ol (0.1 mL, 1.0 mmol), with 'Bu3SnCl (0.2 mL, 1 mmol) stirring at room temperature for 1 hour and after column chromatography [silica; 90:10 hexanes/EtOAc, 1% TEA] afforded (E)-3-methyl-l-tributylstanny1—1-buten-2-ol (40) as a colorless oil in 80% yield. IR (neat) 3357 (br, m) cm“, 1H NMR (500 MHz, 191 CDC13) 8 0.69-1.01 (m, 15 H), 1.21-1.34 (m, 12 H), 1.37-1.52 (m, 6 H), 1.52-1.55 (s, l H), 6.02—6.19 (AB, JAB = 19.5 Hz, 2 H); 13C NMR (125 119 MHz, CDC13) 5 155.6, 122.4, 72.4, 29.4, 29.0, 27.2, 13.7, 9.4; Sn NMR (186 MHz, CDCl3) 5 -46.6. Spectroscopic data (1H and 13C NMR) were consistent with prior literature reports.29 This procedure was scaled up to 100 mmol to afford enough material for kinetic studies. The internal isomer was isolated when run on larger scale (Ezint of 100:1) as indicated by the 1H NMR of the crude material. Internal isomer: 1H NMR (500 MHz, CDCl3) 8 0.82-0.94 (m, 15 H), 1.21-1.36 (m, 12 H), 1.39-1.55 (m, 6 H), 5.12 (d, J= 1.5 Hz, 1 H), 5.7 (d, J: 1.5 Hz, 1 H); 13C NMR (125 MHz, CDC13) 8 8.8, 10.7, 13.7, 27.3, 29.1, 30.7, 120.9, 165.0; “9Sn NMR (186 MHz, CDC13) 8 - 51.2. /\>< Preparation of (E)-(3-methoxy-3-methylbut-1- Me3Sn OMe enyl)trimethylstannane (41) (Table 3.2, entry 1). To a flame dried 200 mL round bottom flask fitted with a condenser, stir bar, rubber septa, and nitrogen inlet/outlet was added THF (40 mL) and (E)-2- methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (2.5161 g, 10.1073 mmol). NaH suspension in mineral oil (60% by weight; 0.5012 g, 12.5525 mmol) 192 was washed with hexanes (x3) and then transferred to the reaction vessel with the assistance of THF. Hydrogen evolution was evidenced via the bubbler. Mel (0.95 mL, 15.26 mmol) was then added slowly via a syringe and the solution was submerged into a preheated oil bath at 75 °C and stirred for 2 hrs. The reaction was cooled to room temperature and quenched with H20 (3 mL) slowly. The organics were separated and the aqueous layer was extracted with EtzO (x3). The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated. The crude mixture was purified by column chromatography [silica; 90:10 hexanes/EtOAc] to afford 41 as a colorless oil in 89% yield. IR (neat) 1076 (C-O-C, vs) cm'l; 1H NMR (500 MHz, CDC13) 6 0.08 (s, 9 H), 1.19 (s, 6 H), 3.08 (s, 3 H), 5.74- 6.20 (AB, JAB = 19.5 Hz, 2 H); 13C NMR (125 MHz, CDC13) 8 -97, 25.2, 50.3, 76.3, 127.4, 152.6; “9Sn NMR (186 MHz, CDC13) 8 35.5. ’ Preparation of (E)-(3-methoxy-3-methylbut-l- Bu3Sn/§><0Mel enyl)tributylstannane (42) (Table 3.2, entry 2). NaH (0.1213 g, 5.05 mmol) was washed with hexanes (x3) and then transferred with hexanes to a round bottom flask charged with (E)-2-methyl- 4-(tributylstannyl)but-3-en-2-ol (40) (1.5 g, 4.0 mmol) and THF (~20 mL). 193 Mel (0.4 mL, 6.42 mmol) was then added slowly via a syringe. Hydrogen evolution was evidenced through the bubbler. The reaction was stirred over nitrogen at reflux until no hydrogen evolution persisted and full consumption of starting material checked by TLC. The reaction mixture was then quenched with very slow addition of water. The two phases were then separated and the aqueous layer was extracted with diethyl ether (x2). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography [silica; 90:10 hexanes/EtOAc, 1% TEA] to afford 42 as a colorless oil in 97% yield. IR (neat) 1078 (c—o—c, s) cm"; 1H NMR (500 MHz, CDC13) 8 0.76-0.94 (m, 15 H), 1.22 (s, 3 H), 1.23-1.33 (m, 6 H), 1.38-1.55 (m, 6 H), 3.12 (s, 3 H), 5.76-6.13 (AB, JAB = 19.5 Hz, 2 H); 13c: NMR (125 MHz, CDC13) 8 9.4, 13.7, 25.4, 27.2, 29.1, 50.4, 76.6, 126.7, 153.0; ”9Sn NMR (186 MHz, CDC13) 8 -47; HRMS (ESI) m/z 359.1764 [(M+-OMe) calcd. for C17H353n 359.1761]. Spectroscopic data (IH and 13C NMR) were consistent with prior literature reports.84 194 Preparation of (E)-(3,3-dimethylbut-1- Me3$n/\)< CH 43 3 enyl)trimethylstannane (43) (Table 3.1, entry 5). PMHS (0.9 mL, 15 mmol) was added to a solution of 3,3-dimethyl-1-butyne (1.2 mL, 9.7 mmol), Me3SnC1 (10 mL, 10 mmol; 1 M solution in THF), aqueous KF (1.73 g, 29.8 mmol; 30 mL H20), (PPh3)2PdC12 (71.4 mg, 0.102 mmol), and TBAF (1 drop of a 1 M solution in THF) in THF (50 mL). The biphasic reaction mixture was stirred at room temperature for 1 h and 20 min and a l M solution of NaOH (10 mL) was subsequently added and stirred for an additional 2 h. The two phases were then separated and the aqueous layer was extracted with diethyl ether (x2). The combined organics were washed with water then brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography [silica; hexanes, 1% TEA] to afford (E)-(3,3- dimethylbut-l-enyl)trimethylstannane (43) as a colorless oil in 19% yield. 1H NMR (500 MHz, CDC13) 5 0.08 (s, 9 H), 0.98 (s, 9 H), 5.78-6.0 (AB, JAB = 19.0 Hz, 2 H); 119Sn NMR (186 MHz, CDC13) 5 -36.4. Spectroscopic data (1H) was consistent with prior literature reports.85’86 195 Preparation of (E)-tributyl(3,3-dimethylbut-1- enyl)stannane (44) (Table 3.1, entry 6). PMHS (0.9 mL, 15 mmol) was added to a solution of 3,3-dimethyl-1-butyne (1.23 mL, 9.99 mmol), Bu3SnCl (2.7 mL, 10 mmol), aqueous KF (1.75 g, 30.1 mmol; 30 mL H20), (PPh3)2PdC12 (69.9 mg, 0.010 mmol), and TBAF (1 drop of a 1 M solution in THF) in THF (50 mL). The biphasic reaction mixture was stirred at room temperature for 2 h and 40 min and a 0.5 M solution of NaOH (10 mL) was subsequently added and stirred for an additional 1.5 h. The two phases were then separated and the aqueous layer was extracted with diethyl ether (x2). The combined organics were washed with water then brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography [silica; hexanes, 1% TEA] to afford (E)—tributyl(3,3-dimethylbut-1- enyl)stannane (44) as a colorless oil in 28% yield. 1H NMR (500 MHz, CDC13) 6 0.80—0.88 (m, 6 H), 0.87 (t, J = 7.3 Hz, 9 H) 0.98 (s, 9 H), 1.23- 1.34 (m, 6 H), 1.43-1.52 (m, 6 H), 5.63-6.05 (AB, JAB = 19.3 Hz, 2 H); 13C NMR (125 MHz, CDC13) 6 9.4, 13.7, 27.2, 29.1, 29.2, 35.9, 119.7, 160.0; ”9Sn NMR (186 MHz, CDC13) 8 —47.7; HRMS (ESI) m/Z 317.1293 [(M+- 196 Bu) calcd. for C14H29Sn 317.1291]. Spectroscopic data (1H and 13C NMR) . . . . 87,88 were conSistent With prior literature reports. 1 Preparation of (E)-2-methyl-4-(tri-iso- i—Pr38n/\> 600, which are likely more easily ionizable Pd impurities. Spectroscopic data . . . . 90 93 were conSIStent With prior literature reports. ’ 213 9.4.1.3. Preparation of (E)-4-(4-butylphenyl)- O \ OH 2-methylbut-3-en-2-ol (62). 62 n-Bu The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 39 with 4-n-butyliodobenzene (Table 3.7, entry 5). (E)-2-Methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol) as the stannane, 4-n-buty1iodobenzene (43 (LL, 0.0624 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 (AL of C6D6, and 184 11L of additional THF. The reaction was monitored for 650 min, 100% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-4-(4-butylphenyl)-2-methylbut-3-en-2-ol (62) (30%), (E)-2- methyl-4-phenylbut-3-en-2-ol (59) (4%, phenyl transfer product from AsPh3), (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (29% of stannane used to afford the homocoupled product), and an unidentified E- coupled product (9%). No unreacted stannane was observed. 214 Coupling of 40 with 4-n-butyliodobenzene (Table 3.7, entry 6). (E)-2-Methy1-4-(tributy1stannyl)but-3 -en-2-ol (40) (200 11L of a 1 M solution in THF; 0.0750 g, 0.2 mmol) as the stannane, 4-n-butyliodobenzene (43 11L, 0.0624 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 184 uL of additional THF. The reaction was monitored for 710 min, ~85% starting material consumption. Bench-top reaction time: 13 h 40 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-4-(4-butylphenyl)-2-methylbut-3-en-2-ol (62) (36%), (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (2%, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (23% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Characterization: 1H NMR (500 MHz, CDC13) 8 0.90 (t, 3 H), 1.30-1.36 (m, 2 H), 1.40 (s, 6 H), 1.52-1.60 (m, 2 H), 2.57 (t, J = 7.7 Hz, 2 H), 6.27- 6.23 (AB, JAB = 16.1 Hz, 1 H), 6.51-6.57 (AB, JAB = 16.1 Hz, 1 H), 7.09- 7.13 (AB, JAB = 7.8 Hz, 2 H), 7.26-7.30 (AB, JAB = 8.8 Hz, 2 H); 13C NMR 215 (125 MHz, CDC13) 8 13.9, 22.3, 29.9, 33.6, 35.3, 71.0, 126.2, 126.3, 128.6, 134.3, 136.5, 142.3. Spectroscopic data were consistent with prior literature reports.56’94 9.4.1.4. Preparation of (E)-(3-methoxy-3- \ OMe O 53 methylbut—l-enyl)benzene (63). The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 41 with iodobenzene (Table 3.7, entry 7). (E)-(3-Methoxy-3-methylbut—1-enyl)trimethylstannane (41) (200 11L of a 1 M solution in THF; 0.0526 g, 0.2 mmol) as the stannane, iodobenzene (27 (LL, 0.0490 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 ML of C6D6, and 200 11L of additional THF. The reaction was monitored for 620 min, 100% starting material consumption. Bench-top reaction time: 16 h 25 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-(3-methoxy-3-methylbut-l-enyl)benzene (63) (60%) and (3E,5E)-2,7-dimethoxy-2,7-dimethylocta-3,5—diene (102b) (34% of 216 stannane used to afford the homocoupled product). No unreacted stannane was observed. Coupling of 42 with iodobenzene (Table 3.7, entry 8). (E)-(3-Methoxy-3-methylbut-1-enyl)tributy1stannane (42) (200 11L of a 1 M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, iodobenzene (27 (LL, 0.0490 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdbag, and 0.016 mmol AsPh3), 50 11L of C6D6, and 200 11L of additional THF. The reaction was monitored for 680 min, 100% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)—(3-methoxy-3-methylbut-1-eny1)benzene (63) (65%) and (3E,5E)-2,7-dimethoxy-2,7-dimethylocta-3,5-diene (102b) (29% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Characterization: IR (neat) 1075 (vs) cm“; 1H NMR (500 MHz, CDC13) 8 1.36 (s, 6 H), 3.20 (s, 3 H), 6.15-6.51 (AB, JAB = 16.1 Hz, 2 H), 7.20-7.24 (tt, J: 1.2, 7.3 Hz, 1 H), 7.28-7.33 (ddd, J: 7.6, 6.8, 2.0 Hz, 2 H), 7357.40 217 (ddd, J = 7.6, 1.2, 0.5 Hz, 2 H); 13C NMR (125 MHz, CDC13) 8 25.9, 50.5, 75.1, 126.4, 127.5, 128.6, 129.1, 135.2, 136.9; HRMS (ESI) m/z 177.1283 [(M++H) calcd. for C12H160H 177.1279]. 9.4.1.5. Preparation of (E)-1-(3-methoxy-3- \ OMe O 64 methylbut—l-enyl)-4-(trifluoromethyl)benzene F3C (64). The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 41 with 4-iodobenzotrifluoride (Table 3.7, entry 9). (E)-(3-Methoxy-3-methylbut-1-enyl)trimethylstannane (41) (200 11L of a 1 M solution in THF; 0.0526 g, 0.2 mmol) as the stannane, 4- iodobenzotrifluoride (35 11L, 0.0653 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 ML containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 192 11L of additional THF. The reaction was monitored for 270 min, 100% starting material consumption. Bench-top reaction time: 16 h 25 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-1 -(3 -methoxy-3 -methylbut- l -enyl)-4- 218 (trifluoromethyl)benzene (64) (87%), (E')-(3-methoxy-3—methylbut-1- enyl)benzene (63) (1%), (3E,5E)—2,7-dimethoxy-2,7—dimethylocta-3,5-diene (102b) (12% of stannane used to afford the homocoupled product). No unreacted stannane was observed. Coupling of 42 with 4-iodobenzotrifluoride (Table 3.7, entry 10). (E)-(3—Methoxy-3-methylbut-1-enyl)tributylstannane (42) (200 11L of a 1 M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, 4- iodobenzotrifluoride (35 11L, 0.0653 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 192 ML of additional THF. The reaction was monitored for 480 min, 100% starting material consumption. Bench-top reaction time: 11 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-l- (3-methoxy-3-methy1but-l-enyl)-4-(trifluoromethy1)benzene (64) (82%), (E)-(3-methoxy-3-methylbut-1-enyl)benzene (63) (3-4%), and (3E,5E)-2,7- dimethoxy-2,7-dimethylocta-3,5-diene (102b) (12% of stannane used to afford the homocoupled product). No unreacted stannane was observed. Characterization: IR (neat) 1325 (CF3, s) cm"; 1H NMR (500 MHz, CDC13) 8 1.37 (s, 6 H), 3.20 (s, 3 H), 6.19-6.49 (AB, JAB = 16.4 Hz, 2 H), 219 7.43-7.48 (AB, JAB = 8.3 Hz, 2 H), 752757 (AB, JAB = 8.3 Hz, 2 H); 13C NMR (125 MHz, CDC13) 8 25.8, 50.6, 75.0, 124.2 (CF3, q, JG. = 271.6 Hz), 125.5 (CF3, q, JCF = 3.7 Hz), 126.5, 127.7, 129.3 (q, JCF = 32.2 Hz), 138.1, 140.4. 9.4.1.6. Preparation of (E)-1-butyl-4-(3- \ OMe O 65 methoxy-3-methylbut-1-enyl)benzene (65). The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 41 with 4-n-butyliodobenzene (Table 3.7, entry 11). (E')-(3-Methoxy-3-methy1but—1-enyl)trimethylstannane (4]) (200 11L of a l M solution in THF; 0.0526 g, 0.2 mmol) as the stannane, 4-n- butyliodobenzene (43 11L, 0.0624 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 uL containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 uL of C6D6, and 184 11L of additional THF. The reaction was monitored for 600 min, 100% starting material consumption. Bench-top reaction time: 16 h 25 min. Yields determined by lH NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-1-butyl-4-(3-methoxy-3-methylbut-1-enyl)benzene 220 (65) (45%), (E)-(3 -methoxy-3-methylbut—1-enyl)benzene (63) (2%), (3E,5E)-2,7-dimethoxy-2,7-dimethylocta-3,5-diene (102b) (42% of stannane used to afford the homocoupled product). No unreacted stannane was observed. Coupling of 42 with 4-n—butyliodobenzene (Table 3.7, entry 12). (E)-(3-Methoxy-3-methylbut-1-eny1)tributylstannane (42) (200 11L of a 1 M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, 4-n-buty1iodobenzene (43 uL, 0.0624 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 184 11L of additional THF. The reaction was monitored for 715 min, 100% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-l -butyl-4-(3 -methoxy-3 -methy1but-1 -eny1)benzene (65) (70%), (E)-(3-methoxy-3-methy1but-1-enyl)benzene (63) (8%), and (3E,5E)- 2,7-dimethoxy-2,7-dimethylocta-3,5-diene (102b) (22% of stannane used to afford the homocoupled product). No unreacted starting material was observed. 221 Characterization: IR (as mixture of 65 and 63) 1205 (C-O-C, s), 741 (para substitution, vs) cm"; 1H NMR (500 MHz, CDC13) 8 0.90 (t, J = 7.3 Hz, 3 H), 1.29-1.34 (m, 2 H), 1.35 (s, 6 H), 1.52-1.61 (m, 2 H), 2.58 (t, J = 7.8 Hz, 2 H), 3.18 (s, 3 H), 6.10-6.16 (AB, JAB = 16.1 Hz, 1 H), 6.42-6.47 (AB, JAB = 16.1 Hz, 1 H), 7.10-7.14 (AB, JAB = 7.8 Hz, 2 H), 7.27-7.31 (AB, JAB = 8.3 Hz, 2 H); 13C NMR (125 MHz, CDC13) 8 13.9, 22.3, 26.0, 33.6, 35.3, 50.5, 75.1, 126.3, 128.6, 129.0, 134.2, 134.3, 142.4; HRMS (ESI) m/Z 201.1644 [(M+—OMe) calcd. for C15H21O 201.1643]. 9.4.2. Control Experiment — Temperature Dependence Determination of Temperature Dependence Figure 3.7 & Table 3.8. The coupling of trimethyl and tributyl stannanes 39 and 40 coupled with iodobenzene as described above for Table 3.7 entries 1 and 2 were performed at 40, 50, and 55 °C. 9.4.3. Aryl Bromide Couplings in THF — Table 3.9 9.4.3.1.Preparation of (E)-2-methyl-4-phenylbut- \ OH 59 3-en-2-ol (59). The standard kinetics study procedure was applied to the following reagent and solvent combinations: 222 Coupling of 39 with bromobenzene (Table 3.9, entry 1). (E)-2-Methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol) as the stannane, bromobenzene (25 11L, 0.0337 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 uL of C6D6, and 202 11L of additional THF. The reaction was monitored for 700 min, ~55% starting material consumption. Bench-top reaction time: 13 h 15 min. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (35%), (3E,5E)-2,7- dimethylocta-3,5-diene-2,7-diol (102a) (42% of stannane used to afford the homocoupled product), and unreacted stannane (10%). Coupling of 40 with bromobenzene (Table 3.9, entry 2). (E)-2-Methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 11L of a l M solution in THF; 0.0750 g, 0.2 mmol) as the stannane, bromobenzene (25 uL, 0.0337 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 223 11L of C6D6, and 202 uL of additional THF. The reaction was monitored for 870 min, ~57% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methy1-4-phenylbut-3-en-2-ol (59) (33%), (3E,5E)-2,7- dimethylocta-3,5-diene-2,7-diol (102a) (23% of stannane used to afford the homocoupled product), and unreacted stannane (3 5%). 9.4.3.2. Preparation of (E)-2-methyl-4-(4- \ OH 0 61 (trifluoromethyl)-phenyl)but—3-en-2-ol (61). F3C The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 39 with 4—bromobenzotrifluoride (Table 3.9, entry 3). (E)-2-Methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol) as the stannane, 4- bromobenzotrifluoride (33 uL, 0.0540 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 (1L of C6D6, and 194 (1L of additional THF. The reaction was monitored for 650 min, 100% starting material consumption. 224 Bench-top reaction time: 13 h 15 min. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2-methyl-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (61) (49%), (E)-2-methyl-4-phenylbut-3—en-2-ol (59) (11%, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5—diene-2,7-diol (102a) (36% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with 4-bromobenzotrifluoride (Table 3.9, entry 4). (E)-2-Methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 11L of a 1 M solution in THF; 0.0750 g, 0.2 mmol) as the stannane, 4- bromobenzotrifluoride (33 11L, 0.0540 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 (LL containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 194 11L of additional THF. The reaction was monitored for 600 min, 100% starting material consumption. Bench-top reaction time: 10 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2- methyl-4-(4—(trifluoromethyl)phenyl)but-3-en-2-ol (61) (82%), (E)-2- methyl-4-phenylbut-3-en—2-ol (59) (9%, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta—3,5-diene-2,7-diol (102a) (9% of 225 stannane used to afford the homocoupled product). No unreacted starting material was observed. 9.4.3.3. Preparation of (E)—4-(4—butylphenyl)- \ OH O 62 2-methylbut—3-en-2-ol (62). n-Bu The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 39 with 4-n-butylbromobenzene (Table 3.9, entry 5). (E)-2-Methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 (AL of a 1 M solution in THF; 0.0498 g, 0.2 mmol) as the stannane, 4-n- butylbromobenzene (42 .uL, 0.0511 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 ML of C6D6, and 185 11L of additional THF. The reaction was monitored for 600 min, ~45% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-4- (4-butylphenyl)-2-methylbut-3-en—2-ol (62) (23%), (E)-2-methyl-4- phenylbut-3-en-2-ol (59) (11%, phenyl transfer product from AsPh3), (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (39% of stannane used to afford the homocoupled product), and unreacted stannane (10%). 226 Coupling of 40 with 4-n-butylbromobenzene (Table 3.9, entry 6). (E)-2-Methyl-4-(tributylstannyl)but—3-en-2-ol (40) (200 (AL of a 1 M solution in THF; 0.0750 g, 0.2 mmol) as the stannane, 4-n- butylbromobenzene (42 (LL, 0.0511 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 185 11L of additional THF. The reaction was monitored for 690 min, ~55% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-4- (4-butylphenyl)-2-methylbut-3-en-2-ol (62) (23%), (E)-2-methyl-4- phenylbut-3-en-2-ol (59) (10%, phenyl transfer product from AsPh3), (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (24% of stannane used to afford the homocoupled product), and unreacted stannane (38%). 9.4.3.4. Preparation of (E)-(3-methoxy-3- \ OMe O 63 methylbut—l-enyl)benzene (63). The standard kinetics study procedure was applied to the following reagent and solvent combinations: 227 Coupling of 41 with bromobenzene (Table 3.9, entry 7). (E)-(3-Methoxy-3-methylbut-1-enyl)trimethylstannane (41) (200 ML of a 1 M solution in THF; 0.0526 g, 0.2 mmol) as the stannane, bromobenzene (25 11L, 0.0337 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 uL containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 11L of C6D6, and 202 11L of additional THF. The reaction was monitored for 760 min, ~70% starting material consumption. Bench-top reaction time: 16 h 25 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-(3-methoxy—3-methylbut—1—enyl)benzene (63) (45%) and (3E,5E)-2,7-dimethoxy-2,7-dimethylocta-3,5-diene (102b) (55% of stannane used to afford the homocoupled product). No unreacted stannane was observed. Coupling of 42 with bromobenzene (Table 3.9, entry 8). (E)-(3-Methoxy-3-methylbut-1-enyl)tributylstannane (42) (200 11L of a l M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, bromobenzene (25 11L, 0.0337 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 or. containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 228 11L of C6D6, and 202 11L of additional THF. The reaction was monitored for 670 min, ~73% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-(3- methoxy-3-methylbut—1-eny1)benzene (63) (23%), (3E,5E)—2,7-dimethoxy- 2,7-dimethylocta—3,5-diene (102b) (39% of stannane used to afford the homocoupled product), and unreacted stannane (10%). 9.4.3.5. Preparation of (E)-1-(3-methoxy-3- \ OM O 54 e methylbut-l-enyl)—4-(trifluoromethyl)benzene F3C . l (64). The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 41 with 4-bromobenzotrifluoride (Table 3.9, entry 9). (E)-(3-Methoxy-3-methylbut-1-enyl)trimethylstannane (41) (200 11L of a 1 M solution in THF; 0.0526 g, 0.2 mmol) as the stannane, 4- bromobenzotrifluoride (33 11L, 0.0540 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 (LL of C6D6, and 194 11L of additional THF. The reaction was monitored for 660 min, 100% starting material consumption. 229 Bench-top reaction time: 16 h 25 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-1-(3 -methoxy-3-methylbut—1-enyl)-4- (trifluoromethyl)benzene (64) (44%), (E)-(3-methoxy-3-methylbut—1- enyl)benzene (63) (10%), (3E,5E)-2,7-dimethoxy-2,7-dimethylocta-3,5- diene (102b) (40% of stannane used to afford the homocoupled product). No unreacted stannane was observed. Coupling of 42 with 4-bromobenzotrifluoride (Table 3.9, entry 10). (E)—(3-Methoxy-3-methylbut—1-enyl)tributylstannane (42) (200 11L of a 1 M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, 4- bromobenzotrifluoride (33 (1L, 0.0540 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 (1L of C6D6, and 194 (1L of additional THF. The reaction was monitored for 600 min, 100% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-l- (3-methoxy-3-methy1but-1-enyl)-4-(trifluoromethyl)benzene (64) (58%), (E)-(3-methoxy-3-methylbut-1-enyl)benzene (63) (1%), and (3E,5E)-2,7- 230 dimethoxy-Z,7-dimethylocta-3,5-diene (102b) (29% of stannane used to afford the homocoupled product). No unreacted stannane was observed. 9.4.3.6. Preparation of (E)-1-butyl-4-(3- \ OMe 55 methoxy-3-methylbut-l-enyl)benzene (65). n-Bu The standard kinetics study procedure was applied to the following reagent and solvent combinations: Coupling of 41 with 4-n-butylbromobenzene (Table 3.9, entry 11). (E)-(3-Methoxy-3-methylbut-1—enyl)trimethylstannane (41) (200 11L of a l M solution in THF; 0.0526 g, 0.2 mmol) as the stannane, 4-n- butylbromobenzene (42 11L, 0.0511 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 1.1L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 uL of C6D6, and 185 ML of additional THF. The reaction was monitored for 660 min, ~65% starting material consumption. Bench-top reaction time: 16 h 25 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-1-butyl-4-(3-methoxy-3 -methylbut-1-enyl)benzene (65) (33%), (E)-(3—methoxy-3-methylbut-1-enyl)benzene (63) (10%), (3E,5E)-2,7-dimethoxy-2,7-dimethylocta-3,5-diene (102b) (56% of stannane 231 used to afford the homocoupled product). No unreacted stannane was observed. Coupling of 42 with 4-n-butylbromobenzene (Table 3.9, entry 12). (E)-(3-Methoxy-3-methylbut-1-enyl)tributylstannane (42) (200 ”L of a 1 M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, 4-n- butylbromobenzene (42 11L, 0.0511 g, 0.24 mmol) as the electrophile, szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 (1L of C6D6, and 185 uL of additional THF. The reaction was monitored for 700 min, ~60% starting material consumption. Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-l- butyl-4-(3-methoxy-3-methylbut-1-eny1)benzene (65) and (E)-(3-methoxy- 3-methylbut-l-enyl)benzene (63) (37%), (3E,5E)-2,7-dimethoxy-2,7- dimethylocta-3,5-diene (102b) (45% of stannane used to afford the homocoupled product), and unreacted stannane (18%). 232 9.4.4. Control Experiment — Electrophile Dependence Determination of Electrophile Dependence for Aryl Bromide Couplings (Figure 3.8). A series of kinetics reactions at different electrophile concentrations were carried out for couplings of both 39 and 40 with 4-bromobenzotrifluoride under the standard kinetic reaction conditions. The amounts of the reagents are described in the following table: Table 9.2. Reagent Amounts for Aryl Bromide Dependence Study Volume of Reagents added at different Electrophile Concentrations 1.2 equiv 3.6 equiv 5.4 equiv 7.1 equiv Stannane 39 or 40 200 11L 200 HL 200 HL 200 11L (1 M solution) Pd/As solution 600 1.1L 600 11L 600 (AL 600 11L 4-bromobenzotrifluoride 34 11L 100 11L 150 11L 200 (1L Additional Solvent 400 (AL 127 uL 77 (AL 27 11L Total Volume 1027 (AL 1027 11L 1027 (LL 1027 11L 9.5. Kinetics Experiments for Chapter 4 9.5.1. Aryl Iodide Couplings in NMP (Table 4.1). The kinetics procedures are identical to those described for Table 3.7 entries 1-6 using NMP instead of THF for solution preparation and additional solvent. The following are the results from the bench-top reactions. 233 9.5.1.1. Preparation of (E)-2-methyl-4-phenylbut- O \ OH 3-en-2-ol (59) in NMP. 59 Coupling of 39 with iodobenzene (Table 4.1, entry 1). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (81%) and (3E,5E)-2,7- dimethylocta-3,5-diene—2,7-diol (102a) (11% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with iodobenzene (Table 4.1, entry 2). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal ‘ standard: (E)—2-methyl—4-phenylbut-3-en-2-ol (59) (87%), and (3E,5E)-2,7- dimethylocta-3,5-diene-2,7—diol (102a) (13% of stannane used to afford the homocoupled product). No unreacted stannane was observed. 9.5.1.2. Preparation of (E)-2-methyl-4-(4- \ OH O 61 (trifluoromethyl)-phenyl)but-3-en-2-ol (61) in F30 NMP. 234 Coupling of 39 with 4-iodobenzotrifluoride (Table 4.1, entry 3). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methyl-4-(4—(trifluoromethyl)phenyl)but-3-en-2-ol (61) (82%), (E)-2-methyl-4-pheny1but-3—en-2-ol (59) (trace amounts, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta—3,5-diene-2,7- diol (102a) (4% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with 4-iodobenzotrifluoride (Table 4.1, entry 4). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E')-2-methyl-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (61) (90%), (E)-2—methyl-4-phenylbut-3-en-2-ol (59) (trace amounts, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7- diol (102a) (8% of stannane used to afford the homocoupled product). No unreacted starting material was observed. 235 9.5.1.3. Preparation of (E)—4-(4-butylphenyl)-2- \ 62 0” methylbut-3-en-2-ol (62) in NMP. n-Bu Coupling of 39 with 4-n-butyliodobenzene (Table 4.1, entry 5). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-4-(4-butylphenyl)-2-methylbut-3-en-2-ol (62) (69%), (E)-2- methyl-4-phenylbut-3-en-2-ol (59) (trace amounts, phenyl transfer product from AsPh3), and (3E,5E)-2,7—dimethylocta-3,5-diene-2,7-diol (102a) (11% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with 4-n-butyliodobenzene (Table 4.1, entry 6). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-4-(4-butylphenyl)-2-methylbut-3-en-2-ol (62) (86%), (E)-2- methyl-4-phenylbut-3-en-2—ol (59) (4%, phenyl transfer product from AsPh3), and (3E,5E)—2,7-dimethylocta-3,5-diene-2,7-diol (102a) (17% of stannane used to afford the homocoupled product). No unreacted stannane was observed. 236 9.5.2. Aryl Bromide Couplings in NMP (Table 4.2). The kinetics procedures are identical to those described for Table 3.9 entries 1-6 using NMP instead of THF for solution preparation and additional solvent. The following are the results from the bench-top reactions. 9.5.2.1. Preparation of (E)-2-methyl-4-phenylbut- \ OH O 59 3-en-2-ol (59) in NMP. Coupling of 39 with bromobenzene (Table 4.2, entry 1). Bench-top reaction time: 16 h at 55 °C. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (60%) and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (40% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with bromobenzene (Table 4.2, entry 2). Bench-top reaction time: 16 h 55 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (76%), (3E,5E)- 237 2,7vdimethylocta-3,5-diene-2,7-diol (102a) (23% of stannane used to afford the homocoupled product), and unreacted stannane (1%). 9.5.2.2. Preparation of (E)-2-methyl-4-(4- \ OH O 51 (trifiuoromethyl)-phenyl)but-3-en-2-ol (61) in F3C NMP. Coupling of 39 with 4-bromobenzotrifluoride (Table 4.2, entry 3). Bench-top reaction time: 16 h at 55 °C. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methy1-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (61) (69%), (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (7%, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (24% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with 4-bromobenzotrifluoride (Table 4.2, entry 4). Bench-top reaction time: 16 h 55 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methy1-4-(4-(trifluoromethyl)phenyl)but—3-en-2-ol (61) (88%), (E)-2-methyl~4-phenylbut-3-en-2-ol (59) (6%, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol 238 (102a) (6% of stannane used to afford the homocoupled product). No unreacted starting material was observed. 9.5.2.3. Preparation of (E)-4-(4-butylphenyl)— \ OH O 52 2-methylbut—3-en-2-ol (62) in NMP. n-Bu Coupling of 39 with 4-n-butylbromobenzene (Table 4.2, entry 5). Bench-top reaction time: 16 h at 55 °C. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-4-(4-butylpheny1)-2-methylbut-3-en-2-ol (62) (44%), (E)—2-methyl-4-phenylbut-3 -en-2-ol (59) (12%, phenyl transfer product from AsPh3), and (3E,5E)-2,7—dimethylocta—3,5—diene-2,7-diol (102a) (44% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with 4-n—butylbromobenzene (Table 4.2, entry 6). Bench—top reaction time: 16 h 55 min. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-4-(4-buty1phenyl)-2-methylbut-3-en-2-ol (62) (61%), (E)-2-methyl-4-pheny1but-3-en-2-ol (59) (12%, phenyl transfer product from AsPh3), (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (21% of 239 stannane used to afford the homocoupled product), and unreacted stannane (1%). 9.5.3. Aryl Halide Couplings in Benzene (Table 4.3). The kinetics procedures are identical to those described for Table 3.7 and Table 3.9 entries 1-6 using benzene instead of THF for solution preparation and additional solvent. The following are the results from the bench-top reactions. 9.5.3.1. Preparation of (E)-2-methyl-4-phenylbut— \ OH O 59 3-en-2-ol (59) in benzene. Coupling of 39 with iodobenzene (Table 4.3, entry 1). Bench-top reaction time: 15 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2-methy1-4-phenylbut-3- en-2-ol (59) (27%) and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (37% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with iodobenzene (Table 4.3, entry 2). Bench-top reaction time: 15 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2- 240 methyl-4-phenylbut-3-en-2-ol (59) (53%) and (3E,5E)-2,7-dimethylocta—3,5- diene-2,7-diol (102a) (28% of stannane used to afford the homocoupled product). No unreacted starting material was observed. 9.5.3.2. Preparation of (E)-2-methyl-4-(4- \ OH O 51 (trifluoromethyl)-phenyl)but-3-en-2-ol (61) in F3C benzene. Coupling of 39 with 4-iodobenzotrifluoride (Table 4.3, entry 3). Bench-top reaction time: 15 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2- methyl-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (61) (83%), (E)-2- methyl-4-phenylbut-3-en-2-ol (59) (trace amounts, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (16% of stannane used to afford the homocoupled product). No unreacted starting material was observed. Coupling of 40 with 4-iodobenzotrifluoride (Table 4.3, entry 4). Bench-top reaction time: 15 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-2- methyl-4-(4-(trifluoromethyl)phenyl)but—3-en-2-ol (61) (91%), (E)-2- methyl—4-phenylbut-3-en-2-ol (59) (2%, phenyl transfer product from 241 AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (7% of stannane used to afford the homocoupled product). No unreacted starting material was observed. 9.5.3.3. Preparation of (E)-4-(4-butylphenyl)- \ OH O 52 2-methylbut—3-en-2-ol (62) in benzene. n-Bu Coupling of 39 with 4-n-butyliodobenzene (Table 4.3, entry 5). Bench-top reaction time: 15 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-4- (4-butylphenyl)-2-methy1but-3-en-2-ol (62) (18%), (E)-2-methyl-4- phenylbut-3-en-2-ol (59) (trace amounts, phenyl transfer product from AsPh3), (3E,5E)-2,7-dimethylocta-3,5-diene-i2,7-diol (102a) (44% of stannane used to afford the homocoupled product), and unreacted stannane (20%). Coupling of 40 with 4-n-butyliodobenzene (Table 4.3, entry 6). Bench- top reaction time: 15 h. Yields determined by 1H NMR analysis of the crude reaction mixture using mesitylene as an internal standard: (E)-4-(4- butylphenyl)—2-methylbut-3—en-2-ol (62) (45%), (E)-2-methyl-4-phenylbut- 3-en-2-ol (59) (2%, phenyl transfer product from AsPh3), and (3E,5E)-2,7- 242 dimethylocta-3,5-diene—2,7-diol (102a) (23% of stannane used to afford the homocoupled product). No unreacted starting material was observed. 9.5.3.4.Preparation of (E)-2-methyl-4-(4- \ OH O 51 (trifluoromethyl)—phenyl)but-3-en-2-ol (61) in F3C benzene. Coupling of 39 with 4—bromobenzotrifluoride (Table 4.3, entry 7). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2-methyl-4-(4-(trifluoromethyl)phenyl)but-3-en-2-ol (61) (17%), (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (6%, phenyl transfer product from AsPh3), and (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) (40% of stannane used to afford the homoscoupled product). No unreacted starting material was observed. Coupling of 40 with 4-bromobenzotrifluoride (Table 4.3, entry 8). Bench-top reaction time: 16 h. Yields determined by 1H NMR analysis of the crude reaction mixture using hexamethyldisiloxane as an internal standard: (E)-2—methyl-4-(4-(trifluoromethyl)phenyl)but—3-en-2-ol (61) (30%), (E)-2-methy1-4-phenylbut-3-en-2-ol (59) (6%, phenyl transfer product from AsPh3). (3E,5E)-2,7-dimethylocta-3,5-diene-2,7-diol (102a) 243 (30%, of stannane used to afford the homocoupled product), and unreacted stannane (19%). 9.5.4. Experiments Discussed Throughout the Text 9.5.4.1. Determination of Stannane Coordination in Benzene: Me vs. Bu Competition Experiment (Scheme 4.2 & Figure 4.5). A standard kinetics experiment was setup using a 1:1 mixture of trimethyl and tributyl stannanes l and 2 to invoke a competition. Specifically, the following reagents were used: (E)-2-methyl-4-(trimethylstannyl)but-3-en-2- 01 (39) (100 11L of a 1 M solution in benzene; 0.0249 g, 0.1 mmol) and (E)- 2-methyl-4-(tributylstannyl)but-3-en-2-ol (40) (100 11L of a 1 M solution in benzene; 0.0375 g, 0.1 mmol) as the stannanes, iodoobenzene (27 11L, 0.0490 g, 0.24 mmol) as the electrophile, szdba3/A8Ph3 solution in benzene (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), 50 (1L of C6D6, and 200 uL of additional benzene. 9.5.4.2. Initial Stille Couplings Using a Pd/TFP Catalyst System (Figure 4.6). A series of kinetics experiments were performed using TFP as the Pd ligand instead of AsPh3. To prepare the Pd/TFP solution, szdba3 (0.0305 g, 244 0.0333 mmol) and TFP (0.0309 g, 0.1333 mmol) were weighed into a 20 mL vial. The mixture was then transferred to a 5 mL volumetric flask with the assistance of THF. The solution was then diluted to volume with THF. A stir bar was carefully added and the solution was tightly capped and stirred to homogeneity for 10 min. The remainder of the procedure is as described in the standard kinetics procedure and was applied to couplings of stannanes 39, 40, and 56 (200 11L of a 1 M solution in THF; 0.2 mmol) with iodobenzene (27 11L, 0.0490 g, 0.24 mmol) by szdba3/TFP solution in THF (600 uL containing 0.004 mmol szdba3 and 0.016 mmol TFP), 50 (AL of C6D6, and 200 uL of additional THF. 9.5.4.3. Determining the Effect of Stille Products on the Autocatalytic Behavior of a Pd/TFP Catalyst System (Scheme 4.3). The indicated Stille products were added to standard Stille reactions to determine the effect on the induction period. The amount of additional solvent was tailored to maintain the standard Sn concentration of 0.1857 M. Effect of Bu3SnI: The standard kinetics procedure was applied to the following reagents: (E)- 2-methyl-4-(tributylstanny1)but-3-en-2-ol (40) (160 11L of a 1 M solution in 245 THF; 0.0600 g, 0.16 mmol) as the stannane, iodoobenzene (27 uL, 0.0490 g, 0.24 mmol) as the electrophile, Bu3SnI (12 11L, 0.0167 g, 0.040 mmol) as the Stille product additive, szdba3/TFP solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol TFP), 50 11L of C6D6, and 228 11L of additional THF . Effect of (E)-2-methyl-4-phenylbut-3-en-2-ol (59): The standard kinetics procedure was applied to the following reagents: (E)- 2—methyl-4-(tributylstanny1)but-3-en-2-ol (40) (80 uL of a 1 M solution in THF; 0.0300 g, 0.08 mmol) as the stannane, iodoobenzene (13.5 11L, 0.0245 g, 0.12 mmol) as the electrophile, (E)-2-methy1-4-phenylbut-3-en-2-ol (59) (40 11L of a 0.5 M solution in THF; 0.0032 g, 0.02 mmol) as the Stille product additive, szdba3/TFP solution in THF (300 uL containing 0.002 mmol szdbag and 0.008 mmol TFP), 25 (AL of C6D6, and 80 11L of additional TlHF . Effect of Bu3SnI and (E)-2-methy1-4-phenylbut-3-en-2-ol (59): The above procedure was applied with both BU3SnI (6 itL, 0.0083 g, 0.02 mmol) and (E)-2-methyl-4-phenylbut-3-en-2-ol (59) (40 11L of a 0.5 M solution in THF; 0.0032 g, 0.02 mmol) as the Stille product additives. 246 9.5.4.4. Determination of the Effect of the Free Hydroxyl on Autocatalysis: Coupling of Methoxy Protected Stannane (42) under Pd/T F P (Figure 4.8). The standard kinetics procedure was applied to the following reagents: (E)- (3-methoxy-3—methylbut-1-enyl)tributylstannane (42) (200 uL of a 1 M solution in THF; 0.0778 g, 0.2 mmol) as the stannane, iodoobenzene (27 (LL, 0.0490 g, 0.24 mmol) as the electrophile, szdba3/TF P solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol TFP), 50 11L of C6D6, and 200 11L of additional THF. 9.5.4.5. Oxidative Addition of szdba3/TFP to PM in THF: In Search of the Autocatalytic Species (Figure 4.10). The substrate solution preparation was prepared as described in the standard kinetics procedure. An NMR tube was charged with Pd/TFP solution in THF (600 11L containing 0.004 mmol szdbag, and 0.016 mmol TFP), iodobenzene (27 11L, 0.0490 g, 0.24 mmol), 50 11L of C6D6, and 200 uL of additional THF. The reaction mixture was inserted in a preheated. NMR at 50 °C and tuned to the 31P nucleus. The reaction was allowed to proceed for 2 h, during which a small signal appeared at -1.5 ppm. To probe whether this 247 peak is a catalytic species responsible for autocatalysis, (E)—2-methy1-4- (tributylstannyl)but-3-en-2-o1 (40) (2000 11L of a 1 M solution in THF; 0.0750 g, 0.2 mmol) was added to the sample. The NMR was then tuned to the 119Sn nucleus and monitored for another 1.5 h. The new species did not affect the induction period, as the rate profile was the same as seen in Figure 4.6. 9.5.4.6.Coupling of Unsubstituted Stannanes Under a Pd/TFP Catalyst System (Section 4.3.1.4). Coupling of 57 with iodobenzene: The standard kinetics procedure was applied to the following reagents: trimethylvinylstannane (57) (200 11L of a l M solution in THF; 0.0382 g, 0.2 mmol) as the stannane, iodoobenzene (27 ML, 0.0490 g, 0.24 mmol) as the electrophile, szdba3/TF P solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol TFP), 50 ML of C6D6, and 200 11L of additional THF . Coupling of 58 with iodobenzene: The above conditions were applied to tributylvinylstannane (58) (200 uL of a 1 M solution in THF; 0.0634 g, 0.2 mmol). 248 9.5.4.7. Coupling Under a Pd/P(t-Bu)3 Catalyst System (Section 4.3.2). To a 3.7 mL vial fitted with a septa cap was added szdba3 (0.0038 g, 0.0041 mmol), P(t-Bu)3 (80 11L of a 2 M solution in pentane, 0.016 mmol), and THF (520 11L). The reaction was stirred at rt for 10 min. Mesitylene (200 uL of a 1 M solution in THF, 0.2 mmol), (E)-2-methyl—4- (trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol), and bromobenzene (25 11L, 0.24 mmol) were then added. The reaction was capped, inserted into a preheated oil bath at 50 °C, and allowed to stir over 7 h, during which aliquots were taken for GC analysis. The reaction was allowed to stir overnight and samples taken after 21 and 26 h. A GC calibration curve of the stannane vs. mesitylene was obtained and the consumption of stannane was calculated accordingly. The kinetic data indicates that an autocatalytic reaction proceeded. 9.5.4.8. Coupling Under a Pd/PPh3 Catalyst System (Section 4.3.3). To a 3.7 mL vial was added szdba3 (0.0091 g, 0.0099 mmol), PPh3 (0.0105 g, 0.04 mmol), and THF (500 uL). The reaction was stirred at rt for 15 min. (E)—(3—methoxy-3-methylbut-1-enyl)tributylstannane (42) (0.1950 g, 0.5010 mmol) was then transferred to the reaction vial with the assistance of 2 mL of THF after which 4-iodobenzotrifluoride (88 11L, 0.6 mmol) was added. 249 The reaction was capped, inserted into a preheated oil bath at 50 °C, and allowed to stir for 6 h. A sample was taken for GC/MS analysis that did not show any product formation. The reaction was allowed to react further overnight for a total of 13 h 20 min where trace amounts of product were formed. After 4 days, there was full consumption of the starting material and a large amount of product was formed. No internal standards were utilized to quantify the kinetics. 9.6. Experiments Related to Side Reactions of the Stille Reaction from Chapter 5 1 9.6.1. Preparation of (3E,3'E)-4,4'- BUZSnMOH) 2 40b (dibutylstannanediyl)bis-(2-methylbut—3-en-2-ol) (40b) (Section 5.3). PMHS (0.45 mL, 15 mmol) was added to a solution of 2-methyl-3-butyn-2- 01 (0.97 mL, 9.9 mmol), BuZSnClz (1.5166 g, 4.99 mmol), aqueous KF (1.76 g, 30.3 mmol; 10 mL H20), (PPh3)2PdC12 (0.0357 g, 0.05 mmol), and TBAF (1 drop of a 1 M solution in THF) in THF (30 mL). The biphasic reaction mixture was stirred at room temperature for 17.5 hours and a 1 M solution of NaOH (10 mL) was subsequently added and stirred for an additional 2 hours. The two phases were then separated and the aqueous 250 layer was extracted with diethyl ether (x3). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated. The crude material was purified by column chromatography [silica; 90:10 hexanes/EtOAc, 1% TEA] to afford (3E,3'E)-4,4'— (dibutylstannanediyl)bis(2-methylbut-3-en-2-ol) as a yellow oil in 3% yield along with a slight unidentified impurity and small amount of PMHS. 1H NMR (500 MHz, CDC13) 8 0.87 (t, 4 H), 1.23 (t, 4 H), 1.33 (m, 6 H), 1.34 (s, 12 H), 1.6 (m, 4 H), 3.13 (s, 1 H), 5.95-6.22 (2 H), 6.28-6.80 (2 H); 13C NMR (125 MHz, CDC13) 5 13.9, 21.5, 26.9, 28.3, 30.4, 75.9, 129.3, 150.7; 119Sn NMR (186 MHz, CDC13) 8 -50. 9.6.2. Preparation of (E/Z) 2-methyl-4- Bu3Snij—OH ”5'40 (tributylstannyl)but-3-en-2-ol (40) (Section 5.3). To a flame dried 25 mL round bottom flask fitted with a condenser, stir bar, rubber septa, and nitrogen balloon was added THF (10 mL), 2-methyl-3- butyn-2-ol (0.20 mL, 2.05 mmol), BU3SnCl (0.65 mL, 2.41 mmol), KF (0.35 g, 6.02 mmol; in 6 mL H20), AIBN (0.0500 g, 0.3045 mmol), and PMHS (0.18 mL, 3.00 mmol). The reaction was submerged in a preheated 80 °C oil bath and stirred for 17 hrs. The reaction was then cooled to room 251 temperature and quenched with 6 mL of a 1 M solution of NaOH. The organics were then separated and the aqueous layer was extracted with EtzO (x2). The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated. The crude mixture was purified by column chromatography [silica; 95:5 hexames/EtOAc] to afford the title compound Note 119 as an E/Z mixture with an undetermined yield. Sn NMR (186 MHz, CDC13) 5 Z isomer: -61.6, E isomer: -45.8. Now This compound was synthesized to compare 119Sn NMR spectra therefore yield determination and isolation of pure material were not performed. 9.6.3. Testing for Conditions to Produce the Unknown Tin Species (Table 5.1). Stannane treated with Pd/AsPh3 (entry 1). Stannane and catalyst solutions were prepared as described in the standard kinetic procedure. An NMR tube was charged with (E)-2-methyl-4- (trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol), szdba3/AsPh3 solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), and C6D6 (50 uL) for NMR 252 lock. The NMR tube was capped and placed in a preheated oil bath at 50 °C and periodically shaken over the course of 1 h 15 min. A 119Sn NMR spectra was then taken where only the starting material was observed. The sample was heated again in an oil bath for an additional 2 h 45 min and another 119Sn NMR taken. Still only starting stannane was present. Stannane treated with Me3SnI (entry 2). Stannane and catalyst solutions were prepared as described in the standard kinetic procedure. An NMR tube was charged with (E)-2-methyl-4- (trimethylstannyl)but-3-en-2-ol (39) (200 uL of a 1 M solution in THF; 0.0498 g, 0.2 mmol), Me3SnI (0.0603 g, 0.208 mmol) and THF (300 11L) ), and C6D6 (50 11L) for NMR lock. The NMR tube was capped and placed in a preheated oil bath at 50 °C and periodically shaken over the course of 1.5 h. A 119Sn NMR was taken to reveal only the two starting tins. The reaction was allowed to heat overnight and another 119Sn NMR taken. Still only the two tins were present. Stannane treated with Pd/T F P then Bu3SnI (entry 3). Stannane and catalyst solutions were prepared as described in the standard kinetic procedure with TFP instead of AsPh3. An NMR tube was charged 253 with (E)-2-methyl-4-(trimethylstannyl)but-3-en-2—ol (39) (200 uL of a 1 M solution in THF; 0.0498 g, 0.2 mmol), Pd/TFP solution in THF (600 11L containing 0.004 mmol szdba3 and 0.016 mmol TFP), and (and C6D6 (50 11L) for NMR lock. The sample was capped and placed in a preheated oil bath at 50 °C and periodically shaken over the course of 6 h. A 119Sn NMR was taken to reveal only the starting stannane. An unspecified amount of Bu3SnI was then added and allowed to stir overnight. A 119Sn NMR was then taken to reveal only starting stannane. Stannane treated with 12 (entry 4). Stannane and catalyst solutions were prepared as described in the standard kinetic procedure. All NMR tube was charged with (E)-2-methyl-4- (trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol) and C6D6 (50 (LL) for NMR lock. 12 (0.0319 g, 0.1257 mmol) was weighed into a vial and transferred to the NMR tube with the assistance of 500 uL of THF. The sample was then placed in a preheated oil bath at 50 °C for 1 h. A 119Sn NMR was taken to reveal that the starting material converted to Me3SnI. The reaction was allowed to heat overnight and another 119Sn NMR taken that indicated no further reaction. 254 Stannane treated with Pd(OAc)2 (entry 5). Stannane and catalyst solutions were prepared as described in the standard kinetic procedure. An NMR tube was charged with (E)-2-methyl-4- (trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol), Pd(OAc)2 (0.0049 g, 0.0073 mmol), THF (600 11L), and C6D6 (50 11L) for NMR lock. The sample was then placed in a preheated oil bath at 50 °C for l h 45 min. A 119Sn NMR was taken to reveal that the starting material converted to Me4Sn. 9.6.4. Identification of the Unknown Tin Unknown SnBu3 Tin Species: 21 Species as tributylphenylstannane (Section 5.3). To a flame dried 25 mL round bottom flask was added szdba3 (0.0488 g, 0.0533 mmol), AsPh3 (0.0653 g, 0.2132 mmol), and THF (10 mL). The reaction was stirred at rt for 10 min until a green color persisted. (E)-2- Methyl-4-(tributylstannyl)but-3-en-2-ol (40) (1.0003 g, 2.6660 mmol) was then weighed and transferred to the reaction flask with the assistance of THF (4 mL) and stirred for 15 min to allow for a similar situation as when kinetic experiments are performed. Iodobenzene (360 11L, 3.2169 mmol) was then 255 added and the reaction vessel capped with a plastic plug to prevent evaporation of the solvent. The reaction was submerged into a preheated oil bath at 49-51 °C and allowed to stir for 3 h 20 min after which it was removed from the heat and the reaction vessel was submerged into an ice bath to cold quench the reaction. A 1 mL aliquot was removed, concentrated, and a 119Sn NMR in C6D6 was taken to see if the unknown tin signal was present. Once confirmed, the remainder of the reaction mixture was concentrated and column chromatography performed [silica; 90:10 hexanes/EtOAc, 1% TBA]. Of the 125 fractions collected, the unknown species was found in fractions 10-12 (Rf = 0.93). The sample was spiked with authentic Bu38nPh and the 119Sn NMR revealed still only one signal. Spectroscopic data matches commercially available material. CTSHBW 9.6.5. Determination of the Source for Aryl Exchange. \ / 83 95,96 Preparation of 2-furyl-tributylstannane (83) (Scheme 5.3) To a 250 mL round bottom flask was added THF (100 mL) and furan (8.5 mL, 118.78 mmol). An addition funnel was attached and capped with a rubber septa and N2 inlet/outlet. The reaction was submerged into a cooling bath at -32 °C (acetone bath with chiller). n-BuLi (42 mL of a 1.6 M 256 solution in hexane, 67 mmol) was added dropwise via the addition fiinnel and the mixture became a milky yellow color and was stirred for 1 h 20 min. Bu3SnCl was then added dropwise through the addition funnel at a rate .of 2 drop/sec and the reaction became a clear yellow color and was stirred for 30 min at -32 °C. The reaction was quenched with sat. aq. NH4C1 (50 mL) and stirred for 15 min. H20 (100 mL) was then added to dissolve the salts. The layers were separated; the aqueous layer was extracted with EtzO (50 mL x 3); the combined organics washed with brine (75 mL), dried with NaZSOa, filtered, and concentrated. The crude material was purified by vacuum distillation (0.4 Torr ; oil bath temp = 130 °C; vapor temp = 111°C) to afford the title compound in 94% yield. 1H NMR (500 MHz, CDC13) 8 0.89 (t, J = 7.3 Hz, 9 H), 1.08 (m, 6 H), 1.33 (m, J = 7.2, 7.3, 7.4 Hz, 6 H), 1.46-1.68 (m, 6 H), 6.41 (dd with 2nd order effects, J = 1.7, 3.1 Hz, 1 H), 6.55 (d with 2nd order effects, J: 3.1 Hz, 1 H), 7.72 (d with 2nd order effects, J: 1.7 Hz, 1 H); 13CNMR (125 MHz, CDC13) 8 10.0 (5195.. = 180.7, J1175n_c = 172.4 Hz), 13.641, 27.2 (Jgn-c = 29.5 Hz), 28.9 (J5n-c = 10.8, 10.4 Hz), 109.0, 121.1, 146.9, 160.6; “98n NMR NMR (186 MHz, CDC13) 8 -63.8. 257 Spectroscopic data (1H and 13C NMR) were consistent with prior literature 96 reports.95’ A IT' ' SnMe . . Hg“ 15333555113115: 0 3 9.6.6. Determination of the Source for MeO 84 Aryl Exchange. Coupling with 4-bromoanisole to afford 4-tributylstannylanisole (Figure 5.2). To a flame dried 10 mL round bottom flask was added szdba3 (0.0174 g, 0.0190 mmol), AsPh3 (0.0232 g, 0.0756 mmol), and THF (2.5 mL). The reaction was stirred at rt for 15 min until a green color persisted. (E)-2- Methyl-4-(trimethylstannyl)but-3-en-2-o1 (39) (0.2354 g, 0.9456 mmol) was then weighed and transferred to the reaction flask with the assistance of THF (2.5 mL) followed by the addition of 4-bromoanisole (140 11L, 1.1183 mmol). The reaction was submerged in a preheated oil bath at 50 °C for 1 h 50 min. An aliquot was removed, concentrated, and a 119Sn NMR in C6D6 was taken to see if the new tin signal was present. Once confirmed, the remainder of the reaction mixture quenched with sat. aq. NH4C1. The layers were separated; the aqueous layer was extracted with E120 (5 mL x 2); the 258 combined organics were washed with H20 (10 mL), dried with MgSO4, filtered, and concentrated. A 119Sn NMR was taken to observe the new signal, then the NMR sample was spiked with an authentic sample of 4- tributylstannylanisole to provide still one signal. The NMR sample was then spiked with an authentic sample of tributylphenylstannane to reveal two signals in close proximity. 9.6.7. Testing for Conditions to Produce the Unknown Tin Species from Bu3SnI in the Presence of an Electrophile (Table 5.2). Tributyltin iodide treated with iodobenzene (entry 1). Bu3SnI (30 uL, 0.1050 mmol), iodobenene (12 uL, 0.1072 mmol), THF (500 ML), and C6D6 (50 uL) were mixed in an NMR tube and allowed to sit in an oil bath at 50 °C for 1.5 h. A 119Sn NMR was then taken to reveal only the starting stannane. Tributyltin iodide treated with iodobenzene and Pd/AsPh3 (entry 2). szdba3 (0.0018 g, 0.0020 mmol) and AsPh3 (0.0029 g, 0.0095 mmol) were weighed into a 3.7 mL vial to which was added THF (500 uL). The vial was capped and stirred for 15 min at rt until a greenish color persisted. The 259 solution was then transferred to an NMR tube charged with Bu3SnI (30 11L, 0.1050 mmol) and PM ( 12 11L, 0.1072 mmol). The sample was allowed to sit in a 50 °C oil bath for 45 min. A 119Sn NMR was taken that revealed the B'u3SnI signal at +77 ppm, and an unidentified signal at +50 ppm, but no tributylphenyltin signal. 9.6.8. Yields for Tables 5.3 and 5.4 can be found above for the corresponding kinetics experiments (See Section 9.4). Characterization of homocoupled dienes: * Characterization of (3E,5E)-2,7-dimethylocta- 102a 3,5-diene-2,7-diol (102a). Whlte solld [mp = 91- 92 °; lit. mp = 107-108 °C].97 IR (neat) 3264 (br, s), 3027 (s, w), 1154 (s, m), 988 (s, m)cm'1; ‘H NMR (500 MHz, CDCl3) 5 1.32 (m, 12 H), 1.39 (s, 2 H), 5.76-6.23 (AA’BB’, JAB = 14.8 Hz, 14.7 Hz); 13c NMR (125 MHz, CDC13) 5 29.7, 70.7, 126.2, 141.2; HRMS (ESI) m/z 153.1278 [(M+-OH) calcd. for C10H17O 153.1279]. 9 Characterization of (3E,5E)-2,7—dimethoxy- 102b 2,7-dimethylocta-3,5-diene (102b). IR (neat) 1240 cm"; ‘H NMR (500 MHz, CDCl3) 5 1.27 (s, 12 H), 3.14 (s, 6 H), 5.58- 260 6.20 (AA’BB’, JAB = 15.1 Hz, 4 H); 130 NMR (125 MHz, CDC13) 5 25.8, 50.5, 74.9, 129.1, 138.8; HRMS (ESl) m/Z 199.1698 [(M++H) calcd. for C12H2202H 199.1698] 9.7. Experiments Related to Additives for the Stille Reaction from Chapter 6 9.7.]. Determination of aq. KF/TBAF Effect on Stannane (Section 6.4.1). To an NMR tube was added (E)-2-methyl-4—(trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498 g, 0.2 mmol), KF (200 11L of a 3 M aqueous solution, 0.6 mmol) and TBAF (1 drop of a 1 M solution in THF; ca. 8 uL), and THF (200 ML) to bring the volume of the sample to an appropriate level for the NMR. A 119Sn NMR was taken and showed only the starting material. No other tin signals were observed upon scanning from +400 to -200 ppm. 9.7.2. Representative Procedure for Kinetic Studies with Additives: Additive = Aqueous KF/TBAF or Water. The standard kinetic procedure is followed with the use of additives: 261 Aqueous KF/TBAF Effect on the Coupling of 39 with Iodobenzene (Scheme 6.6 and Figure 6.1a). szdba3 (0.0305 g, 0.0333 mmol) and AsPh3 (0.0408 g, 0.1333 mmol) were weighed into a 20 mL via]. The mixture was then transferred to a 5 mL volumetric flask with the assistance of THF. The solution was then diluted to volume with THF. A stir bar was carefully added and the solution was tightly capped and stirred to homogeneity for 10 min. As the solution was stirring, (E)-2-methyl-4-(trimethylstannyl)but—3-en-2-ol (39) (0.2489 g, 1.0 mmol) was weighed directly into a 1 mL volumetric flask and diluted to volume with THF. Again, a stir bar was carefully added, the flask was capped, and the 1 M solution was stirred for 10 min. A solution of aqueous KF (3 M) was prepared by weighing KF (0.1743 g, 3 mmol) into a 1 mL volumetric flask and diluted to volume with deionized water. A stir bar was carefully added and the solution was capped and stirred to homogeneity for 10 min. An NMR tube was charged with C6D6 (50 uL), the Pd/As solution (600 11L, containing 0.0037 g, 0.004 mmol szdba3 and 0.0245g, 0.016 mmol AsPh3), (E)-2-methyl—4—(trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in THF; 0.0498g, 0.2 mmol), and an additional amount of THF such that the final reaction concentration is 0.1857 M in stannane. The 262 additives, aq. KF solution (200 11L, 0.6 mmol) and 1 drop of TBAF (1 M solution in THF), were then added to the NMR tube. The NMR tube was then capped and inserted into a 500 MHz NMR spectrometer. The NMR probe was set to 50 0C and once equilibrated, tuned to the 119Sn nucleus (186 MHZ). The sample was then locked and shimmed. The sample was ejected and iodobenzene (27 uL, 0.0490 g, 0.24 mmol) was added to the sample. Immediately thereafter the sample was injected, reshimmed, and an arrayed kinetics experiment was initiated to monitor the consumption of stannane. 9.7.2.1. Coupling of 40 with iodobenzene and aq. KF/TBAF (Scheme 6.6 and Figure 6.1b). The representative kinetics procedure with additives was applied to (E)-2- methyl-4-(tributylstannyl)but—3-en-2-ol (40) (200 11L of a 1 M solution in THF; 0.0750 g, 0.2 mmol), iodobenzene (27 11L, 0.0490 g, 0.24 mmol), and aq. KF solution (200 11L, 0.6 mmol) and 1 drop of TBAF (l M solution in THF) 263 9.7.2.2. Water Effect on the Coupling of 39 with Iodobenzene (Section 6.5). The representative kinetics procedure with additives was applied to (E)-2- methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 uL of a 1 M solution in THF; 0.0498 g, 0.2 mmol), iodobenzene (27 11L, 0.0490 g, 0.24 mmol), and water (200 11L, 11.1 mmol). Using dionized water from the faucet, HPLC grade water, or Milli-Q water provided the same kinetics. 9.7.2.3. Water Effect on the Coupling of 40 with Iodobenzene (Section 6.5). The representative kinetics procedure with additives was applied to (E)-2- methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 11L of a l M solution in THF; 0.0750 g, 0.2 mmol), iodobenzene (27 11L, 0.0490 g, 0.24 mmol), and water (200 11L, 11.1 mmol). 9.7.2.4. Water Dependence Study (Figure 6.3). The conditions described above for water-activated reactions (Scheme 6.5) were performed over a range of equiv of water. For couplings of l with iodobenzene, 2.8, 5.5, 16.6, and 55.4 equiv of water was implemented. For couplings of 2 with iodobenzene, 1.4, 2.8, 4.2, and 55.4 equiv of water was implemented. 264 9.7.2.5. Additive Effect on Aryl Bromide Couplings (Section 6.6). Additive = Fluoride: The representative kinetics procedure with additives was applied to (E)-2- methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 11L of a 1 M solution in THF; 0.0750 g, 0.2 mmol), bromobenzene (25 11L, 0.0377 g, 0.24 mmol), and aq. KF solution (200 uL, 0.6 mmol) and 1 drop of TBAF (1 M solution in THF). Additive = Water: The representative kinetics procedure with additives was applied to (E)-2- methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 uL of a 1 M solution in THF; 0.0750 g, 0.2 mmol), bromobenzene (25 11L, 0.0337 g, 0.24 mmol), 202 11L of additional THF, and water (200 uL, 11.1 mmol). 9.7.2.6. Effect of Water on an Unsubstituted Vinyl Stannane Coupled with Iodobenzene (Section 6.7). The representative kinetics procedure with additives was applied to tributylvinylstannane (30 uL, 0.0326 g, 0.1026 mmol), iodobenzene (27 11L, 0.0490 g, 0.12 mmol), 170 uL of additional THF, and water (100 11L, 5.5508 mmol, 54.1 equiv). 265 9.7.3. Purification of Cu] by the Method of Kauffman.59 Kl (65.00 g, 391.6 mmol) was added to 50 mL of H20 in a 250 mL Erlenmeyer flask. The solution was swirled and water was added until all of the K1 was dissolved. CuI (6.55 g, 34.39 mmol) was added to the solution and allowed to magnetically stir until all the CuI was dissolved, ~20 min. The brownish solution was decolorized with 1 g of decolorizing charcoal and shaken vigorously for 1 min then filtered to afford a clear solution. The solution was diluted with water to precipitate out the CuI. The muddy precipitate was filtered in a Biichner filnnel, then covered with a kimwipe and stored in a vacuum dessicator overnight. The crispy wafer of CuI was transferred to an amber bottle and ground to a fine powder. The CuI was dried again under vacuum with light heating (30 °C) for 3 h. Light gray CuI (4.6032, 24.1701) in 70.3% yield was recovered. 9.7.4. Representative Procedure for Kinetic Studies with Cu]. Coupling of 39 with iodobenzene in the presence of Cu] under Pd/PPh3 in THF (Table 6.4, entry 2). szdba3 (0.0305 g, 0.0333 mmol) and PPh3 (0.0350 g, 0.1333 mmol) were weighed into a 20 mL vial. The mixture was then transferred to a 5 mL volumetric flask with the assistance of THF. The solution was then diluted to 266 volume with THF. A stir bar was carefully added and the solution was tightly capped and stirred to homogeneity for 10 min. As the solution was stirring, (E)-2-methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (0.2489 g, 1.0 mmol) was weighed directly into a 1 mL volumetric flask and diluted to volume with THF. Again, a stir bar was carefully added, the flask was capped, and the l M solution was stirred for 10 min. An NMR tube was charged with C6D6 (50 11L), the Pd/PPh3 solution (600 11L, containing 0.0037 g, 0.004 mmol szdba3 and 0.0245g, 0.016 mmol PPh3), (E)-2- methyl-4-(trimethylstannyl)but-3—en-2-ol (39) (200 uL of a 1 M solution in THF; 0.0498g, 0.2 mmol), and 200 11L of THF to achieve a final reaction concentration of 0.1857 M in stannane. The additive, CuI (0.0031 g, 0.0163 mmol, Cu:L 1:1), was then weighed into weigh paper and carefully transferred to the NMR tube. The NMR tube was then capped and inserted into a 500 MHz NMR spectrometer. The NMR probe was set to 50 °C and once equilibrated, tuned to the 119Sn nucleus (186 MHz). The sample was then locked and shimmed. The sample was ejected and iodobenzene (27 uL, 0.0490 g, 0.24 mmol) was added to the sample. Immediately thereafter the sample was injected, reshimmed, and an arrayed kinetics experiment was initiated to monitor the consumption of stannane. 267 9.7.4.1. Coupling of 40 with iodobenzene in the presence of Cu] under Pd/PPh3 in THF (Table 6.4, entry 4). The representative kinetics procedure in the presence of CuI was applied to (E)-2-methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 uL of a l M solution in THF; 0.0750g, 0.2 mmol), iodobenzene (27 uL, 0.0490 g, 0.12 mmol), Pd/PPh3 solution (600 uL, containing 0.0037 g, 0.004 mmol szdba3 and 0.0245g, 0.016 mmol PPh3), C6D6 (50 11L), 200 11L of additional THF, and CuI (0.0031 g, 0.0163 mmol, Cu:L 1:1). 9.7.4.2. Coupling of 39 with iodobenzene in the presence of Cu] under Pd/AsPh3 in NMP (Table 6.4, entry 6). The representative kinetics procedure in the presence of CuI was applied to (E)-2-methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 11L of a 1 M solution in NMP; 0.0498 g, 0.2 mmol), iodobenzene (27 11L, 0.0490 g, 0.12 mmol), Pd/AsPh3 solution (600 uL, containing 0.0037 g, 0.004 mmol szdba3 and 0.0245g, 0.016 mmol AsPh3), C6D6 (50 11L), 200 11L of additional NMP, and CuI (0.0031 g, 0.0163 mmol, Cu:L 1:1). 268 9.7.4.3. Coupling of 40 with iodobenzene in the presence of Cu] under Pd/AsPh3 in NMP (Table 6.4, entry 8). The representative kinetics procedure in the presence of CuI was applied to (E)-2-methyl-4-(tributylstannyl)but-3-en-2-ol (40) (200 uL of a 1 M solution in NMP; 0.0750 g, 0.2 mmol), iodobenzene (27 ML, 0.0490 g, 0.12 mmol), Pd/AsPh3 solution (600 11L, containing 0.0037 g, 0.004 mmol szdba3 and 0.0245g, 0.016 mmol AsPh3), C6D6 (50 uL), 200 uL of additional NMP, and CuI (0.0031 g, 0.0163 mmol, Cu:L 1:1). 9.7.4.4. Coupling of tributylvinylstannane and iodobenzene in the presence and absence of Cu] under Pd/AsPh3 in NMP on the bench-top (Table 6.5). szdba3 (0.0018 g, 0.002 mmol), AsPh3 (0.0025 g, 0.008 mmol), and NMP (470 11L) were added to a 3.7 mL vial with Teflon lined cap and stirred for 1 h 15 min at rt. CuI (0.0015 g, 0.008 mmol) and tributylvinylstannane (30 11L, 0.0326 g, 0.1026 mmol) were then added and 4 min later, iodobenzene (13.5 ' 11L, 0.121 1 mmol) was added. The reaction was allowed to stir for exactly 5 min at rt and immediately cold quenched in an ice bath. A control reaction under the same conditions except without Cul was run in parallel. A 1H 269 NMR of the crude Cul reaction showed more starting material than product, while the control reaction showed ~equal amounts. This indicates that the reaction without CuI was faster, as it had higher conversion, thus CuI slows down the reaction. 9.7.5. Overcoming the Inhibitory Effects of Cu] with Water (Figure 6.8) 9.7.5.]. Determining the Amount of Water Necessary to Effect the Same Acceleration as Farina Observed with Cu] (Figure 6.8, 2.8 equiv H20). The representative procedure for kinetic studies with additives was applied to tributylvinylstannane (30 11L, 0.0326 g, 0.1026 mmol), iodobenzene (13.5 11L, 0.121] mmol), szdba3/AsPh3 solution in NMP (300 uL containing 0.002 mmol szdba3 and 0.008 mmol AsPh3), 25 uL of C6D6, 170 11L of additional NMP, and H20 (5 ML, 0.2775 mmol, 2.7754 equiv). 9.7.5.2. Determining the Amount of Water Necessary to Compensate for the Inhibitory Effect of Cu] (Figure 6.8, 0.08 equiv Cu] + 2.8 equiv H20). The representative procedure for kinetic studies with additives was applied to tributylvinylstannane (30 uL, 0.0326 g, 0.1026 mmol), iodobenzene (13.5 11L, 0.1211 mmol), szdba3/AsPh3 solution in NMP (300 1.1L containing 270 0.002 mmol szdba3 and 0.008 mmol AsPh3), 25 11L of C6D6, 170 uL of additional NMP, Cul (0.0015 g, 0.008 mmol), and H20 (5 uL, 0.2775 mmol, 2.7754 equiv). 9.7.5.3. Determining the Amount of Water Necessary to Compensate for the Inhibitory Effect of Cu] (Figure 6.8, 0.08 equiv Cu] + 8.3 equiv H20). The representative procedure for kinetic studies with additives was applied to tributylvinylstannane (30 11L, 0.0326 g, 0.1026 mmol), iodobenzene (13.5 uL, 0.1211 mmol), szdba3/AsPh3 solution in NMP (300 11L containing 0.002 mmol szdba3 and 0.008 mmol AsPh3), 25 11L of C6D6, 170 11L of additional NMP, CuI (0.0015 g, 0.008 mmol), and H20 (15 ML, 0.2775 mmol, 8.3262 equiv). 9.7.6. Aryl Bromide Couplings In the Presence of Cu]. 9.7.6.1. Coupling of 39 with Bromobenzene in a Pd/PPh3 Catalyst System in THF (Section 6.8.2). The representative procedure for kinetic studies with CuI was applied to (E)- 2-methyl-4-(trimethylstannyl)but-3-en-2-ol (39) (200 uL of a l M solution in THF; 0.0750 g, 0.2 mmol), 4-bromobenzotrifluoride (34 uL, 0.0540 g, 271 0.24 mmol), Pd/PPh3 solution (600 11L, containing 0.004 mmol szdba3 and 0.016 mmol PPh3), 50 uL of C6D6, 193 11L of additional THF, and CuI (0.0031 g, 0.0163 mmol, Cu:L 1:1). 9.7.6.2. Coupling of 40 with Bromobenzene in a Pd/AsPh3 Catalyst System in NMP (Section 6.8.2). The representative procedure for kinetic studies with CuI was applied to (E)- 2-methyl-4-(tributylstannyl)but-3-en-2-ol (40) (100 uL of a 1 M solution in NMP; 0.0375 g, 0.1 mmol), 4-bromobenzotrifluoride (17 11L, 0.0270 g, 0.12 mmol), Pd/AsPh3 solution (300 ML, containing 0.002 mmol szdba3 and 0.008 mmol AsPh3), 25 uL of C6D6, 96.5 uL of additional NMP, and CuI (0.0016 g, 0.0084 mmol, Cu:L 1.05:1). 9.7.6.3. Effect of Cu] on an Aryl Bromide Coupling that is Already Proceeding (Table 6.6). Set A: szdba3 (0.0305 g, 0.0333 mmol) and PPh3 (0.0350 g, 0.1333 mmol) were weighed into a 20 mL vial. The mixture was then transferred to a 5 mL volumetric flask with the assistance of THF. The solution was then diluted to volume with THF. A stir bar was carefully added and the solution was 272 tightly capped and stirred to homogeneity. for 10 min. THF (380 uL), Pd/AsPh3 solution (600 11L, containing 0.004 mmol szdba3 and 0.016 mmol AsPh3), and tirbutylvinylstannane (60 11L, 0.0651 g, 0.2053 mmol) were added to a 3.7 mL vial with septa lined cap. 4-bromotrifluorobenzene (34 11L, 0.0540 g, 0.24 mmol) was then added and stirred at 50 °C for 10 min exactly. CuI (0.0031 g, 0.0163 mmol, Cu:L 1:1) was then added and stirred at 50 °C for another 50 min (1 h total). The reaction was then removed from the oil bath and concentrated. A control reaction under the same conditions except without CuI was run in parallel. A 1H NMR of the crude Cul reaction showed a starting material to product ratio of 100215 while the reaction without CuI showed a starting material to product ratio of 100223. This indicates that adding CuI to the reaction after it begins shuts down and/or slows down the reaction to some extent. Set B: The reactions above were repeated except the CuI was added after 25 min and stirred for an additional 30 min (55 min total). A 1H NMR of the crude Cul reaction showed a starting material to product ratio of 100126 while the reaction without CuI showed a starting material to product ratio of 100225. This indicates that when CuI is added after the reaction has proceeded for a 273 longer time, there is little impact on the reaction. Comparing the results from Set A and Set B indicate that the order of addition may be important. 9.7.7. Determining the Effect of the Order of Addition with Cu] (Table 6.7). Conditions A: See the coupling of tributylvinylstannane and iodobenzene in the presence and absence of CuI under Pd/AsPh3 in NMP on the Bench-top (Section 9.7.4.4). Conditions B: The following reagents were added to a 3.7 mL vial in the following order: iodobenzene (13.5 uL, 0.1211 mmol), CuI (0.0016 g, 0.0084 mmol, Cu:L 1.05:1), and 170 uL of additional NMP, Pd/AsPh3 solution (300 ML, containing 0.002 mmol Pdgdba3 and 0.008 mmol AsPh3), and tributylvinylstannane (30 11L, 0.0326 g, 0.1026 mmol). The reaction was stirred under N2 at rt for exactly 5 min and immediately cold quenched in an ice bath. A control reaction under the same conditions except in air as well as one without CuI under N2 were run in parallel. A 1H NMR of the crude CuI reaction in both N2 and air showed more product than starting material, 274 while the control reaction without Cu] in N2 showed more starting material than product. This indicates that the the order of addition is important but N2 is not. Conditions C: The following reagents were added to a 3.7 mL vial in the following order: CuI (0.0016 g, 0.0084 mmol, Cu:L 1.05:1), and 170 uL of additional NMP, tributylvinylstannane (30 11L, 0.0326 g, 0.1026 mmol), Pd/AsPh3 solution (300 11L, containing 0.002 mmol szdba3 and 0.008 mmol AsPh3), and iodobenzene (13.5 11L, 0.1211 mmol). The reaction was stirred in air at rt for exactly 5 min and immediately cold quenched in an ice bath. A control reaction under Conditions B was run in parallel. A 1H NMR of the crude CuI reaction under Conditions C showed there was more starting material than product while for Conditions B there was more product than starting material. 9.7.7.1. CuI Effect on Me/Bu Ratio Under Conditions B (Table 6.9). Coupling of 39 with iodobenzene (Entry 3). The representative procedure for kinetic studies with CuI following the order in Conditions B was applied to the following reagents. iodobenzene ( 13.5 275 uL, 0.1211 mmol), CuI (0.0016 g, 0.0084 mmol, Cu:L 1.05:1), and 100 11L of additional NMP, Pd/AsPh3 solution (300 11L, containing 0.002 mmol szdba3 and 0.008 mmol AsPh3), and (E)-2-methyl-4-(trimethylstanny1)but- 3-en-2-ol (39) (100 11L of a 1 M solution in THF; 0.0375 g, 0.1 mmol). Coupling of 40 with iodobenzene (Entry 4). The representative procedure for kinetic studies with CuI following the order in Conditions B was applied to the following reagents. iodobenzene (13.5 uL, 0.1211 mmol), CuI (0.0016 g, 0.0084 mmol, Cu:L 1.05:1), and 100 11L of additional NMP, Pd/AsPh3 solution (300 uL, containing 0.002 mmol szdba3 and 0.008 mmol AsPh3), and (E)-2—methyl-4-(tributylstannyl)but-3- en-2-ol (40) (100 11L of a l M solution in THF; 0.0248 g, 0.1 mmol). 9.8. Experimentals for Tributylgermane Couplings From Chapter 7 9.8.1. Preparation of Vinyl Germanes Representative Procedure for the Hydrogermylation of Alkynes. Preparation of (E)- 2-methyl-4-(tributylgermyl)but-3-en-2-ol (135a) (Table 7.1, entry 1). To a flame dn'ed 25 mL round bottom flask fitted with a stir bar was flushed with nitrogen, fitted with a septa, and placed in a nitrogen glove-bag. Inside 276 the glove bag, Pd(PPh3)4 (0.0725 g, 0.0627 mmol) was added. Outside of the glovebag the reaction was fitted with a N2 balloon, then THF (10 mL), 2- methyl-3-butyn-2-ol (0.19 mL, 1.9447 mmol), and Bu3GeH (0.6 mL, 2.3242 mmol) were added via syringe. The yellow reaction mixture was allowed to stir at room temperature for 20.5 hrs. The reaction can be stopped once the solution turns from yellow to dark brown or orange. The dark brown reaction was then quenched with 4 mL of l M NaOH and stirred in open air for 30 min. The organics were then separated and the aqueous layer was extracted with EtzO (5 mL x 2). The combined organics were washed with water then brine, dried with MgSO4, filtered, and concentrated. The crude mixture was purified by column chromatography [silica; 90:10 hexanes/EtOAc] to afford the title compound in 96% yield. 1H NMR (500 MHz, CDC13) 8 0.67-0.82 (m, 6 H), 0.82-0.96 (m, 9 H), 1.20-1.40 (m, 18 H), 1.28 (s, 6 H), 1.44 (s, l H), 5.73-6.17 (AB, JAB = 18.8 Hz, 2 H); 13C NMR (125 MHz, CDCl3) 8 12.8, 13.8, 26.4, 27.3, 29.5, 72.1, 122.9, 152.4; HRMS (ESI) m/z 313.1954 [(M+-OH) calcd. for C17H3sGe 313.1951]. Spectroscopic data (1H and 13C NMR) were consistent with prior reports.31 , . . , . . 31 For IR data, see Jerome Lav1s d1ssertat10n. 277 Preparation of (E)-l-(2- 135h l (tributylgermyl)vinyl)cyclohexanol (135h) (Table \ Bu3Ge OH 7.1, entry 2). Applying the representative hydrogermylation conditions with l-ethynyl-l- cyclohexanol (0.1242 g, 1.0 mmol) after 8 h and column chromatography [silica; 90:10 hexanes/EtOAc] afforded the title compound in 89% yield. 1H NMR (500 MHz, CDC13) 5 0.75 (t, J = 8.4, 6 H), 0.86 (t, J = 7.08, 9 H), 1.22-1.38 (m, 12 H), 1.43-1.56 (m, 6 H), 1.58-1.68 (m, 2 H), 5.8-6.1 (AB, JAB = 18.8 Hz, 2 H); 13’c NMR (125 MHz, CDC13) 5 12.8, 13.8, 22.2, 25.6, 26.4, 27.4, 37.7, 72.6, 123.7, 152.4. Spectroscopic data (‘H and 13C NMR) were consistent with prior reports,31 and rectify the incorrect coupling constant and proton count. For IR and HRMS data, see Jéréme Lavis’ . . 31 d1ssertat1on. Preparation of (E)-3- Bu3Ge/VOH "' Bu GeJk/OH 1359 3 int-1359 (tributylgermyl)prop-2-en-1-ol (135g) (Table 7.1, entry 7). Applying the representative hydrogermylation conditions with propargyl alcohol (0.12 mL, 2.0614 mmol) after 21.5 h afforded an mixture of isomers 278 (crude E :int = 1.7:] determined by 1H NMR). After column chromatography [silica; 95:5 hexanes/EtOAc] several fractions of various isomeric ratios were obtained as well as fractions with 100% pure E and up to 98% pure internal (64:1 intzE) for a total combined yield of 91%. E isomer: 1H NMR (500 MHz, CDC13) 5 0.72-0.81 (m, 6 H), 0.82-0.93 (m, 9 H), 1.24-1.36 (m, 12 H), 4.16 (s, 2 H), 5.95-6.13 (AB, JAB = 18.6 Hz, 2 H); 13C NMR (125 MHz, CDC13) 6 12.8, 13.8, 26.5, 27.3, 65.8, 128.5, 143.8. internal isomer: 1H NMR (500 MHz, CDC13) 5 0.81 (t with 2nd order effects, J = 8.3 Hz, 6 H), 0.87 (t with 2 "d order effects, J = 7.08 Hz, 9 H), 1.25-1.37 (m, 12 H), 4.22 (s, 2 H), 5.21-5.26 (m, 1 H), 5.76-5.81 (m, 1 H); Spectroscopic data (1H and 13C NMR) were consistent with prior reports,31 and rectify the incorrect coupling constant and proton count. For 13C data of the internal isomer, and IR and HRMS data of both E and internal isomer, see Jéréme Lavis’ . . . 31 dlssertat1on. 279 Preparation of (Eytert-butyldimethyl(2-methyl- 4-(tributylgermyl)but—3-en-2-yloxy)silane (135i) (Table 7.1, entry 9). Applying the representative hydrogermylation conditions with tert- butyldimethyl(2-methylbut-3-yn-2-yloxy)silane (0.3962 g, 1.9972 mmol) overnight and column chromatography [silica; 90:10 hexanes/EtOAc] afforded the title compound in 91% yield. 9.8.2. Screening Heck Conditions (Table 7.2) Preparation of an E/Z/int Mixture of 59. All reactions were run in a 3.7 mL vial with a Teflon lined cap to avoid solvent evaporation. Small-scale reactions run in a round bottom flask with a condenser proved problematic. 9.8.2.1. Representative Procedure for Catalyst Loading Screen: 10 mol% (Entry 1). A TBABr/ K2CO3/germane/Phl solution was prepared as follows: To a 2 mL volumetric flask was added Bu4NBr (0.1291 g, 0.4005 mmol), K2CO3 (0.1387, 1.0035 mmol), and 1.5 mL of MeCN/H20 (9:1). A magnet was carefully added to the flask then capped and stirred for 30 min. (E)-2- Methyl-4-(tributylgermyl)but-3-en-2-ol (135a) (0.1314 g, 0.3993) was then 280 weighed into a pipette and transferred to the volumetric flask with a small amount of solvent. The magnet was removed and rinsed into the flask with a small amount of solvent up to the 2 mL mark. The magnet was then replaced and the solution was stirred to homogeneity. The reaction was set up as follows: The solution (500 11L; containing 0.1 mmol Bu4NBr, 0.25 mmol K2CO3, 0.1 mmol germane, and 0.2 mmol Phl), and PPh3 (0.0053 g, 0.0202 mmol) were added to a 3.7 mL vial then capped and stirred, at rt for 15 min. Pd(OAc)2 (0.0023 g, 0.0103 mmol) was then the reaction was stirred at 70 °C for 16 h. The reaction was cooled to rt then quenched with sat. aq. NHaCl (1 mL). The layers were separated and the aqueous layer was extracted with EtzO (x2). The combined organics were washed with brine, dried with MgSO4, filtered, and concentrated. Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (53%) and a mixture of cross-coupled isomers (Z/E/int = 17/4/1) were formed in 47% yield. Pd loading of 5 mol% (Entry 7). The representative conditions were applied to a 5 mol% catalyst system of PPh3 (0.0025 g, 0.0095 mmol) and Pd(OAc)2 (0.0012 g, 0.0053 mmol). 281 Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (54%) and a mixture of cross-coupled isomers (Z/E/int = 17/5/1) were formed in 46% yield. Pd loading of 20 mol% (Entry 8). The representative conditions were applied to a 20 mol% catalyst system of PPh3 (0.0105 g, 0.0400 mmol) and Pd(OAc)2 (0.0046 g, 0.0205 mmol). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (45%) and a mixture of cross-coupled isomers (Z/E/int = 10/3/1) were formed in 55% yield. 9.8.2.2. Reaction with No Bu4NBr (Entry 3). KzCO3 (0.0346 g, 0.2503 mmol) and 0.5 mL of MeCN/1120 (9:1) were added to a 3.7 mL vial and stirred for 15 min at rt. (E)-2-Methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0330 g, 0.1003 mmol) was weighed into a pipette and transferred to the reaction vial with the assistance of 1.5 mL of solvent. PPh3 (0.0053 g, 0.0202 mmol) and PM (22.5 uL, 0.201] mmol) were then added and stirred for 15 min at rt. Pd(OAc)2 (0.0023 g, 0.0103 mmol) was then added and the reaction was capped and stirred at 60- 65 °C for 16 h. The reaction was quenched as described above. Yield as 282 determined by 1H NMR with hexamethyldisiloxane as an internal standard: unreacted starting germane (66%) and a mixture of cross-coupled isomers (Z/E/int = 21/1/5) were formed in 34% yield. 9.8.2.3. Reaction with NaHCO3 Instead of KzCO3 (Entry 4). Bu4NBr (0.0321 g, 0.0996 mmol) was added to a reaction vial. The remainder of the procedure follows the above conditions substituting NaHCO3 (0.0212 g, 0.2524 mmol) for K2C03. Yield as determined by 1H NMR with hexamethyldisiloxane as an internal standard: unreacted starting germane (57%) and a mixture of cross-coupled isomers (Z/E/int #- 17/1/2) were formed in 43% yield. 9.8.3. Comparison of Stille vs. Heck Conditions (Table 7.3) ‘J\; I Representative Stille A conditions for coupling OH O N 2 215-141 with 4-bromonitrobenzene (Table 7.3, entry 4): szdba3 (0.0183 g, 0.0200 mmol), AsPh3 (0.0245 g, 0.0800 mmol), and NMP (2 mL) were added to a vial with a Teflon lined cap. The reaction was stirred at rt for 15 min then (E)-2-methyl-4-(tributylgermyl)but-3-en-2-ol (1353) (0.0320 g, 0.0972 mmol) (weighed into a pipette and transferred with 3 mL NMP) and 4-bromonitrobenzene (0.0405 g, 0.2005 mmol) were added. 283 The reaction was capped and stirred at 70 °C for 24 h. Reaction concentration is ~0.02 M, e.g. 0.1 mmol Ge in 5 mL NMP. The reaction was then cooled to rt and quenched with sat. aq. NHaCl (10 mL). The layers were separated and the aqueous layer was extracted with EtzO (5 mL x2). The combined organics were then washed with H20 then brine, dried with MgSO4, filtered, and concentrated. Yield. as determined by 1H NMR with hexamethyldisiloxane as an internal standard: unreacted starting germane (51%) and a mixture of cross-coupled isomers (Z/E = 10/1) were formed in 10% yield. Representative Stille B conditions for coupling with 4- bromonitrobenzene (Table 7.3, entry 4). Stille A conditions except Pd(OAc)2 used instead of szdbag, were applied to Pd(OAc)2 (0.0045 g, 0.0199 mmol), AsPh3 (0.0245 g, 0.0800 mmol, (E)-2- methyl-4-(tributylgermyl)but-3-en-2-ol (135a) (0.0320 g, 0.0972 mmol), and 4-bromonitrobenzene (0.0404 g, 0.2000 mmol). Reaction concentration is ~0.02 M, e.g. 0.1 mmol Ge in 5 mL NMP. GC/MS and 1H NMR of the crude reaction indicated no reaction took place. Otherwise, reaction quenching follows the Stille A procedure. 284 Representative Heck conditions for for coupling with 4- bromonitrobenzene (Table 7.3, entry 4). Bu4NBr (0.0197 g, 0.0611 mmol), KzCO3 (0.0207 g, 0.1497 mmol) and 0.8 mL of MeCN/H20 (9:1) were added to a vial and stirred for 15 min at rt. (E)-2-Methyl-4-(tributylgermyl)but-3—en-2-ol (135a) (0.0187 g, 0.0568 mmol) was weighed into a pipette and transferred to the reaction vial with the assistance of 0.4 mL of solvent. PPh3 (0.0066 g, 0.0252 mmol) and 4- bromonitrobenzene (0.0241 g, 0.1195 mmol) were then added and stirred for 15 min at rt. Pd(OAc)2 (0.0030 g, 0.0134 mmol) was then added and the reaction was capped and stirred at 70 °C for 16 h 20 min. Reaction concentration is ~0.05 M; 0.06 mmol Ge in 1.2 mL NMP. The reaction was then cooled to rt and quenched with sat. aq. NHaCl (0.5 mL). The layers were separated and the aqueous layer was extracted with EtzO (4 mL x2). The combined organics were then washed with H20 then brine, dried with MgSO4, filtered, and concentrated. The crude material was purified by column chromatography [silica; 90:10 hexanes/EtOAc] to afford a mixture of cross-coupled isomers (Z/E = 2.4/1) in 48% yield. 285 9.8.3.1. Coupling with bromobenzene under Heck Conditions (Table 7.3, entry 2 — Heck). The representative Heck conditions were applied to (E)- 2-methyl-4-(tributylgermyl)but-3-en-2-ol (135a) (0.0329 g, 0.1 mmol) and bromobenzene (21 11L, 0.1944 mmol). Yield as determined by 1H NMR with hexamethyldisiloxane as an internal standard: unreacted starting germane (48%) and a mixture of cross-coupled isomers (Z/E = 26/1) were formed in 30% yield. 0 \ OH 139 O 9.8.3.2. Coupling with 4-bromoacetophenone under Stille A Conditions (Table 7.3, entry 3 — Stille A). The representative Stille A conditions were applied to (E)-2-methyl-4- (tributylgermyl)but—3-en-2—ol (135a) (0.0329 g, 0.1 mmol) and 4- bromoacetophenone (0.0399 g, 0.2005 mmol). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (69%) and a mixture of cross-coupled isomers (Z/E = 1.88/1) were formed in 24% yield. The crude material was purified by column chromatography [silica; 80:20 hexanes/EtOAc] to afford only the Z isomer in 15% yield and recovered starting material (135a) in 48% yield. 286 9.8.4. Aryl Halide Scepe for Couplings Under Heck Conditions at 0.2 M* (Table 7.5) * unless otherwise noted X 9.8.4.1. Preparation of 2-methyl-4-phenylbut—3-en- \ ‘ OH 2411: Coupling of 135a with iodobenzene (Table 7.5, Z/E/int-59 entry 1). Experimental details described in Section 9.8.2 for Table 7.2, entry 8. I \ 9.8.4.2. Preparation of 2-methyl-4-phenylbut—3-en-2- ' ; ‘OH 01: Coupling of 135a with bromobenzene (Table 7.5, entry 2). The representative Heck conditions were applied to (E)-2-methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0330 g, 0.1003 mmol) and bromobenzene (25 uL, 0.1994 mmol) in 0.5 mL of MeCN/HZO (9:1). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (41%) and a mixture of cross-coupled isomers (Z/E = 1.4/1) were formed in 19% yield. 287 9.8.4.3. Preparation of 2-methyl—4-p-tolylbut—3- en-2-ol: Coupling of 135a with 4-iodotoluene (Table 7.5, entry 3). The representative Heck conditions were applied to (E)-2-methyl-4- (tributylgermyl)but-3~en-2-ol (135a) (0.0324 g, 0.0984 mmol) and 4- iodotoluene (0.0436 g, 0.2 mmol) in 0.5 mL of MeCN/Ile (9:1). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (37%) and a mixture of cross-coupled isomers (Z/E = 2.1/1) were formed in 63% yield. 9.8.4.4. Preparation of 4-(4-methoxyphenyl)-2- methylbut—3-en-2-ol: Coupling of 135a with 4- bromoanisole (Table 7.5, entry 4). The representative Heck conditions were applied to (E)-2-methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0332 g, 0.1009 mmol) and 4- bromoanisole (25 uL, 0.1997 mmol) in 0.5 mL of MeCN/HZO (9:1). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (54%) and a mixture of cross-coupled isomers (Z/E = 2.95/1) were formed in 19% yield. 288 9.8.4.5. Preparation of (E)-2-methy1-4—(4- nitrophenyl)but-3-en-2-ol: Coupling of 135a with 4-brom0nitrobenzene (Table 7.5, entry 5). Experimental details described in Section 9.8.2 for Table 7.2, entry 8. The reaction was run at 0.05 M. \‘XOTBS Z/int-144 The representative Heck conditions were applied to (E)-tert- 9.8.4.6. Preparation of ten-butyldimethyl(2- methyl-4-phenylbut—3-en-2-yloxy)silane: Coupling of 135i with iodobenzene (Table 7.5, entry 6). butyldimethyl(2-methyl-4-(tributylgermyl)but-3-en-2-yloxy)silane (0.03 16 g, 0.0712 mmol) and iodobenzene (17 11L, 0.1519 mmol) in 1.3 mL of MeCN/H20 (9:1). The reaction was run at 0.05 M. Yield as determined by 1H NMR with 1,3,5-trimethoxybenzene as an internal standard: unreacted starting germane and a mixture of cross-coupled isomers (Z/int = 1/1 .1) were formed in 10% yield. 289 9.8.4.7. Impact of Concentration on the Z/E Ratios OH (Table 7.6). Z/E-59 Preparation of Z/E-59 at 0.1 M (Entry 2). The representative Heck conditions were applied to (E)-2-methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0330 g, 0.1003 mmol) and bromobenzene (21 11L, 0.1994 mmol) in 1.0 mL of MeCN/HZO (9:1). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (66%) and a mixture of cross-coupled isomers (Z/E = 11.6/1) were formed in 29% yield. Preparation of Z/E-59 at 0.168 M (Entry 3). The representative Heck conditions were applied to (E)-2-methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0331 g, 0.1006 mmol) and bromobenzene (21 uL, 0.1994 mmol) in 0.6 mL of MeCN/HZO (9:1). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (62%) and a mixture of cross-coupled isomers (Z/E = 4.2/1) were formed in 26% yield. 290 Preparation of Z/E-59 at 0.2 M (Entry 4). The representative Heck conditions were applied to (E)-2-methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0327 g, 0.09936 mmol) and bromobenzene (21 11L, 0.1994 mmol) in 0.5 mL of MeCN/HZO (9:1). Yield as determined by 1H NMR with mesitylene as an internal standard: unreacted starting germane (61%) and a mixture of cross-coupled isomers (Z/E = 2.8/l) were formed in 23% yield. I \ 9.8.4.8. Preparation of Z/E-59: Coupling of 135a with ' ; ‘OH iodobenzene under anhydrous conditions (Section Z/E-59 7.5). The representative Heck conditions were applied to (E)—2-methyl-4- (tributylgermyl)but-3-en-2-ol (135a) (0.0168 g, 0.0511 mmol) and iodobenzene (12 ML, 0.1072 mmol) in 270 11L of anhydrous MeCN instead of a MeCN/HZO mixture. Yield as determined by 1H NMR with mseitylene as an internal standard: unreacted starting germane (49%) and a mixture of cross-coupled isomers (Z/E = 3.9/1) were formed in 28% yield. 291 9.8.4.9. Preparation of tert- butyldimethyl(2methyl-4-(tributylgermyl)but- 3-yn-2-yloxy)silane (146i) (Scheme 7.7). To a flame dried 100 mL 3-neck round bottom flask fitted with a 10 mL addition filnnel, stir bar, rubber septa, and nitrogen balloon was added 10 mL of THF, and tert-butyldimethyl(2-methylbut-3-yn-2-yloxy)silane (0.9934 g, 5.0076 mmol). The reaction was cooled to to 0 °C and a solution n-butyllithium (1.6 M in hexanes, 6.5 mL, 10.4 mmol) was added dropwise over 10 min via the addition funnel and allowed to stir for an additional 10 min at 0 8C. Bu3GeCl (1.3982 g, 5.0047 mmol) was then added and the solution was allowed to warm to room temperature and stirred for 31 hrs. The reaction was quenched with saturated NH4C1 (5 mL) and stirred for 30 min. The organics were separated; the aqueous layer was extracted with E120 (x2). The combined organics were washed with water (30 mL), and then brine (30 mL), dried with MgSO4, filtered, and concentrated. The crude reaction mixture was purified by column chromatography [silica; hexanes] to afford the title compound as a clear oil in 40% yield. 1H NMR (500 MHz, CDC13) 5 0.16 (s, 6 H), 0.78 (m, 24 H), 1.28-1.46 (m, 18 H); 13’C NMR (125 292 MHz, CDCl3) 5 -3.0, 13.8, 14.0, 25.8, 26.1, 27.4, 33.3, 66.6, 70.6, 84.5, I 11.8. * 9.8.4.10. Preparation of (Z)-tert-butyldimethyl(2- Bu3oe\j—0TBS 2" 35' methyl-4-(tributylgermyl)but-3-en-2-yloxy)silane (Z-135i) (Scheme 7.7) To a flame dried 25 mL round bottom flask fitted with a stir bar, rubber seprta, and a nitrogen inlet/outlet was added THF (3 mL) and a solution of BH3-DMS (2 M solution in THF, 2 mL, 4 mmol). The solution was cooled to 0 °C and cyclohexene was added (0.61 mL, 6.0 mmol). The solution was stirred for 1 hr maintaining the temperature between 0-5 °C, during which a white precipitate forms. The solution was then cooled to -8 °C using a saturated NH4Cl ice bath and tert—butyldimethyl(2-methyl-4- (tributylgermyl)but-3-yn-2-yloxy)silane (0.8702 g, 1.9717 mmol) was added dropwise. After the addition, the reaction was warmed to 10 °C and stirred for 1.25 hrs maintaining a temperature between 8-12 °C. The solution was then allowed to warm to room temperature after which acetic acid (3 mL) was added very slowly and allowed to stir for 21 hrs. EtzO (3 mL) and H20 (2 mL) were added to the reaction as the solvent evaporated overnight. The organics were then separated, the aqueous layer extracted with EtzO (20 mL 293 x2), the combined organics washed with water (20 mL) and then brine (20 mL), dried with MgSO4, filtered, and concentrated. The crude mixture was purified by column chromatography [silica; 2 cm diameter, 13 cm height; hexanes] to afford the title compound as a clear oil in 52% yield. 1H NMR (500 MHz, CDCl3) 8 0.05 (s, 6 H), 0.74-0.98 (m, 24 H), 1.18-1.44 (m, 18 H), 5.26-6.70 (AB, JAB = 14.9 Hz, 15.0 Hz, 2 H); 13C NMR (125 MHz, CDC13) 5 -2.1, 13.7, 15.1, 18.0, 25.8, 26.5, 27.5, 30.4, 75.0, 123.6, 156.7. 9.8.5. Impact of Germane Geometry on Product Geometry (Table 7.8). 9.8.5.1. Preparation of E/Z—59 (Entry 1) from Z- 135a. The representative Heck conditions were applied to (Z)-2-methyl—4- (tributylgermyl)but-3-en-2-ol (135a) (0.0193 g, 0.0586 mmol) and iodobenzene (13 11L, 0.1162 mmol) at ~O.6 M in Ge for 6 h. Yield as determined by 1H NMR with mseitylene as an internal standard: unreacted starting germane (8%) and a mixture of cross-coupled isomers (E/Z = 1.4/ 1) were formed in 45% yield. 294 9.8.5.2. Preparation of BIZ-59 (Entry 2) from E-135a. \ ‘10}4 The representative Heck conditions were applied to (E)- Z/E-59 2-methyl-4-(tributylgermyl)but-3 -en-2-ol (135a) (0.0326 g, 0.0991 mmol) and iodobenzene (22.5 11L, 0.2011 mol) at ~0.6 M in Ge for 6 h. Yield as determined by 1H NMR with mseitylene as an internal standard: unreacted starting germane (52%) and a mixture of cross- coupled isomers (Z/E = 8.8/ l) were formed in 35% yield. 9.8.5.3. Preparation of Ell-144 (Entry 3) from Z- 135i. The representative Heck conditions were applied to (Z)-tert butyldimethyl(2-methyl-4-(tributylgermyl)but-3-en-2-yloxy)—silane (0.0334 g, 0.0753 mmol) and iodobenzene (17 11L, 0.1519 mmol) for 6 h. Only trace amounts of Z—product were observed by 1H NMR of the crude material. A parallel reaction was also run for 24 h providing only trace amounts of product as indicated by 1H NMR of the crude material. 295 (1) (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) REFERENCES Stille, J. K. Angew. 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