STUDIES ON THE OPTIMIZATION OF BUCHWALD-HARTWIG AMINATION OF ARYL HALIDES by Sogol Borjian Borojeni A thesis submitted to the Department of Chemistry In conformity with the requirements for the degree of Doctor of Philosophy Queen’s University Kingston, Ontario, Canada September 2014 Copyright © Sogol Borjian Borojeni, 2014 Abstract Developing new catalyst systems for cross-coupling reactions such as Buchwald-Hartwig aminations has been one of the remarkable topics in the palladium-catalyzed, cross-coupling reaction research area. In this thesis, the use of the easily synthesized and handled Pd(3-1-Ph- C H )(5-C H ) (I) as a catalyst precursor for Buchwald-Hartwig amination of aryl 3 4 5 5 halides was investigated utilizing various phosphines (PtBu Xphos and Mor- 3, Dalphos), different phosphine (L) to Pd ratios (L:Pd = 2:1 and 1:1) and different procedures; in situ generation of PdL prior to addition of other reactants (Method n A) and in situ generation of PdL in the presence of aryl halide but prior to the n addition of other reactants (Method B). The reaction profiles are monitored by gas chromatography (GC) and the effect of each of the mentioned parameters on the reaction rate is determined. The reaction profiles of I with various phosphines are also compared with those of other precursors, Pd (dba) , Pd(OAc) and 2 3 2 [Pd(η3-1-Ph-C H )Cl] (IV). 3 4 2 In spite of a large number of studies involving modification of Buchwald- Hartwig amination reactions by developing new precursors and phosphines, fewer studies have been carried out on catalytic mechanisms and there is still ambiguity about the catalytically active species in these palladium-catalyzed reactions. This study on a representative Buchwald-Hartwig amination finds that, in Buchwald-Hartwig aminations, various species might be participating as the catalytically active species via various mechanisms, utilizing different catalyst i systems. This finding is contrary to the observations for other cross-coupling reactions such as Suzuki-Miyaura and Mizoroki-Heck in which the efficient formation of putative PdL from Pd(3-1-Ph-C H )(5-C H ) (I) resulted in higher 2 3 4 5 5 initial rates and higher conversions under mild reaction conditions, than other common precatalysts (Pd(OAc) , Pd(PPh ) , Pd dba , etc.) containing a variety 2 3 4 2 3 of phosphine ligands. Therefore, to further our studies, the solution chemistry of I and IV with PtBu , XPhos and Mor-DalPhos has been studied by 1H NMR and 3 31P NMR spectroscopy. All intermediates observed were characterized by NMR spectroscopy. ii Acknowledgements In these acknowledgements, I would like to express my gratitude to many people for their help and encouragements throughout my doctoral studies. Firstly, to my supervisor, Dr. Michael Baird for giving me the opportunity to be part of his research group. I sincerely appreciate your guidance, friendship and patience. Working with your group has been a great inspiration to me. A special thank-you to Dr. Françoise Sauriol for all the assistanse and guidance with NMR experiments, Dr. Gabriele Schatte for X-ray crystallography, and other support staff of Chernoff Hall and Queen’s University. Also I would like to acknowledge the contributions of Dr. Andrew Fraser to the first steps of this project. I would like to thank all the past and present members in the Baird group, especially Andrew, Alex, Kevin, Dave, Nicole, Xin, Adeela and of course Shirley Baird, for all the good times and memories. Thanks to Emilia and Rolf for all the support from the first day of my stay in Canada. Great thank-you to Dr. Nahid Aghighi, I have truly appreciated your encouragements. I would also like to thank all of my friends at Queen’s University, Hanna, Mona, Klaus, Marina, Calista, Gillian, John, Lili, Raya and Marjan, thank-you for making my PhD experience as much as enjoyable as it could be. Lastly and most importantly, I would like to express my deepest gratitude to my parents and dear sister, Sarah, for the endless love and support. I wouldn’t be where I am without you. iii Co-Authorship All published papers resulting from this thesis have been co-authored with my supervisor, Dr. M. C. Baird, along with undergraduate students, D.M.E Tom and X. Zhang. In particular, the following publications are based on chapters of this thesis: 1. Borjian, S.; Tom, D. M. E.; Baird, M. C. “Pd(3-1-Ph-C H )(5-C H ) (I) 3 4 5 5 as a Catalyast Precursor for Buchwald Hartwig Amination Reactions”, Organometallics 2014, 33, 3928, is based on Chapter 2. 2. Borjian, S.; Tom, D. M. E.; Baird, M. C. “NMR Studies of the Species Present in Cross-coupling Catalysis Systems Involving Pd(3-1-Ph- C H )(5-C H ) (I) and [Pd(η3-1-Ph-C H )Cl] (IV) Activated by PtBu , 3 4 5 5 3 4 2 3 XPhos and Mor-Dalphos: Nonexistance of Pd(XPhos) and Pd(Mor- n Dalphos) (n= 1, 2) at Moderate Temperatures”, Organometallics 2014, n 33, 3936, is based on Chapter 3. 3. Zhang, X.; Borjian, S.; Baird, M. C. “An Investigation of the Formation and Entrapment of Palladium(0)-PPh Species to Give Products with 3 Low (<3:1) Ligand:Pd Ratios”, submitted, is based on Chapter 4. It was carried out under my supervision in parallel with and complementing a much more extensive, analogous study by me which involved other phosphines but was not included in my thesis because of time considerations. iv Statement of Originality The research discussed in this work was carried out or directed by the author in the Department of Chemistry at Queen’s University under the supervision of Dr. M. C. Baird. D.M.E Tom carried out duplicate runs of the amination reactions to complement work done by the author in order to check for reproducibility (some of the plots shown in chapter 2). X. Zhang carried out NMR experiments in Chapter 4 under my supervision and in parallel with analogous, as yet unreported, experiments carried out by me. Sogol Borjian Borojeni September, 2014 v Table of Contents Abstract ................................................................................................................. i Acknowledgements .............................................................................................. iii Co-Authorship .......................................................................................................iv Statement of Originality ........................................................................................ v List of Figures ....................................................................................................... x List of Schemes .................................................................................................. xiii List of Tables .......................................................................................................xv List of Abbreviations ........................................................................................... xvi Chapter 1 Introduction .......................................................................................... 1 1.1 Buchwald-Hartwig Amination of Aryl Halides .............................................. 1 1.2 Mechanism of Buchwald-Hartwig Amination ............................................... 3 1.2.1 Oxidative Addition ................................................................................. 6 1.2.2 Reductive Elimination ............................................................................ 9 1.2.3 β-Hydride Elimination .......................................................................... 10 1.3 Common Palladium Precursors ................................................................. 11 1.3.1 Pd (dba) ............................................................................................. 12 2 3 1.3.2 Pd(OAc) ............................................................................................. 12 2 1.3.3 [Pd(η3-1-Ph-C H )Cl] (IV) ................................................................... 15 3 4 2 1.3.4 Pd(η3-1-Ph-C H )(η5-C H ) (I) ............................................................. 16 3 4 5 5 1.4 Commonly Used Phosphines .................................................................... 18 1.4.1 PtBu ................................................................................................... 22 3 1.4.2 Xphos .................................................................................................. 24 vi 1.4.3 Mor-Dalphos ....................................................................................... 26 1.5 Reagents ................................................................................................... 28 1.5.1 Bases .................................................................................................. 28 1.5.2 Electrophiles ....................................................................................... 29 1.5.3 Amine Nucleophiles ............................................................................ 31 1.5.3.1 Secondary Amines ........................................................................ 31 1.5.3.2 Primary Amines ............................................................................ 32 1.5.3.3 Ammonia ....................................................................................... 33 1.6 Research Objectives ................................................................................. 34 1.6.1 Developing of Efficient New Catalyst Systems for Buchwald-Hartwig Amination ..................................................................................................... 35 1.6.2 Investigation of the Solution Chemistry of Various Catalyst Systems Based on I or IV with Various Phosphines ................................................... 35 1.7 References ................................................................................................ 36 Chapter 2 Pd(3-1-Ph-C H )(5-C H ) (I) as a Catalyast Precursor for Buchwald 3 4 5 5 Hartwig Amination Reactions.............................................................................. 46 2.1 Preface ...................................................................................................... 46 2.2 Introduction ............................................................................................... 46 2.3 Experimental ............................................................................................. 53 2.3.1 General Procedures ............................................................................ 53 2.3.2 General Experimental Methodologies for Determining Reaction Profiles ..................................................................................................................... 54 vii 2.3.2.1 Utilizing Pd(η3-1-Ph-C H )(η5-C H ) (I) (in Situ Generation of PdL 3 4 5 5 n Prior to Addition of Other Reactants: Method A) ....................................... 54 2.3.2.2 Utilizing Pd(η3-1-Ph-C H )(η5-C H ) (I) (in Situ Generation of PdL 3 4 5 5 n in Presence of Chloro- or Bromoanisole but Prior to Addition of Other Reactants; Method B) ............................................................................... 54 2.3.2.3 Utilizing Pd (dba) (II) .................................................................... 55 2 3 2.3.2.4 Utilizing Pd(OAc) (III) ................................................................... 55 2 2.3.2.5 Utilizing [Pd(η3-1-Ph-C H )Cl] (IV) ............................................... 56 3 4 2 2.4 Results and Discussion ............................................................................. 56 2.5 Summary and Conclusions ....................................................................... 69 2.6 References. ............................................................................................... 72 Chapter 3 NMR Studies of the Species Present in Cross-coupling Catalysis Systems Involving Pd(3-1-Ph-C H )(5-C H ) (I) and [Pd(η3-1-Ph-C H )Cl] (IV) 3 4 5 5 3 4 2 Activated by PtBu , XPhos and Mor-Dalphos ..................................................... 78 3 3.1 Preface ...................................................................................................... 78 3.2 Introduction ............................................................................................... 78 3.3 Experimental ............................................................................................. 79 3.3.1 General Procedures ............................................................................ 79 3.3.2 General Experimental Methodologies ................................................. 80 3.3.2.1 Utilizing Pd(η3-1-Ph-C H )(η5-C H ) (I) ......................................... 80 3 4 5 5 3.3.2.2 Utilizing [Pd(η3-1-Ph-C H )Cl] (IV) ............................................... 80 3 4 2 3.4 Results and Discussion ............................................................................. 81 3.5 Summary and Conclusions ....................................................................... 92 viii 3.6 References ................................................................................................ 94 Chapter 4 An Investigation of the Formation and Entrapment of Palladium(0)- PPh Species to Give Products with Low (<3:1) Ligand:Pd Ratios ..................... 98 3 4.1 Preface ...................................................................................................... 98 4.2 Introduction ............................................................................................... 98 4.3 Experimental ........................................................................................... 102 4.3.1 General Procedures .......................................................................... 102 4.3.2 General Experimental Methodology to Prepare Reaction Mixtures ... 102 4.3.3 General Experimental Methodology to Study Catalysis .................... 102 4.4 Results and Discussion ........................................................................... 103 4.4.1 Catalysis by the I/PPh /PhBr System ................................................ 110 3 4.5 Summary and Conclusions ..................................................................... 111 4.6 References. ............................................................................................. 112 Chapter 5 Conclusions and Future Work .......................................................... 117 5.1 Summary and Conclusions ..................................................................... 117 5.2 Future Work ............................................................................................ 120 Appendix A GC Calibration Curves .................................................................. 121 Appendix B NMR Spectra ................................................................................. 123 Appendix C X-ray Crystallographic Data for (1-Ph-C H )(PtBu )Br .................. 133 3 4 3 A. Crystal Data .............................................................................................. 133 B. Data Collection and Refinement Conditions ............................................. 134 ix