Diaryliodonium Salts Development of Synthetic Methodologies and α-Arylation of Enolates Marcin Bielawski © Marcin Bielawski, Stockholm 2011 Cover picture: Diphenyliodonium lacking an anion! ISBN: 978-91-7447-233-2 Printed in Sweden by US-AB, Stockholm 2011 Distributor: Department of Organic Chemistry, Stockholm University ii The most exciting phrase to hear in science, the one that heralds the most di s- coveries, is not "Eureka!" (I found it!) but "That's funny..." Isaac Asimov (1920–1992) iii iv Abstract This thesis describes novel reaction protocols for the synthesis of diaryl- iodonium salts and also provides an insight to the mechanism of α-arylation of carbonyl compounds with diaryliodonium salts. The first chapter gives a general introduction to the field of hypervalent iodine chemistry, mainly focusing on recent developments and applications of diaryliodonium salts. Chapter two describes the synthesis of electron-rich to electron-poor di- aryliodonium triflates, in moderate to excellent yields from a range of arenes and iodoarenes. In chapter three, it is described that molecular iodine can be used together with arenes in a direct one-pot, three-step synthesis of symmetric diaryl- iodonium triflates. A large scale synthesis of bis(4-tert -butylphenyl)- iodonium triflate is also described, controlled and verified by an external research group, further demonstrating the reliability of this methodology. The fourth chapter describes the development of a sequential one-pot syn- thesis of diaryliodonium salts from aryl iodides and boronic acids, furnishing symmetric and unsymmetric, electron-rich to electron-poor diaryliodonium tetrafluoroborates in moderate to excellent yields. This method was devel- oped to overcome the regiochemical limitations imposed by the reaction mechanism in the protocols described in the preceding chapters. Chapter five describes a one-pot synthesis of heteroaromatic iodonium salts under similar conditions described in chapter two. The final chapter describes the reaction of enolates with chiral diaryliodo- nium salts or together with a phase transfer catalyst yielding racemic prod- ucts. DFT calculations were performed, which revealed a low lying energy transition state (TS) between intermediates, which is believed to be respon- sible for the lack of selectivity observed in the experimental work. It is also proposed that a [2,3] rearrangement is preferred over a [1,2] rearrangement in the α-arylation of carbonyl compounds. The synthetic methodology described in this thesis is the most generally applicable, efficient and high-yielding to date for the synthesis of diaryl- iodonium salts, making these reagents readily available for various applica- tions in synthesis. v vi List of Publications This thesis is based on the following publications, in the text referred to by their Roman numerals I-V and Appendix B. My contribution to these papers is summarized in Appendix A. I. High-Yielding One-Pot Synthesis of Diaryliodonium Triflates from Arenes and Iodine or Aryl Iodides Marcin Bielawski and Berit Olofsson Chem. Commun. 2007 , 2521-2523. Reproduced by permission of The Royal Society of Chemistry (RSC). II. Efficient and General One-Pot Synthesis of Diaryliodonium Triflates: Optimization, Scope and Limitations Marcin Bielawski, Mingzhao Zhu and Berit Olofsson Adv. Synth. Catal. 2007 , 349 , 2610-2618. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. III. Efficient One-pot Synthesis of Bis(4-tert -Butylphenyl)Iodonium Triflate Marcin Bielawski and Berit Olofsson Org. Synth. 2009 , 86 , 308-314. IV. Reproduced with permission from Regiospecific One-Pot Synthesis of Diaryliodonium Tetrafluoroborates from Arylboronic Acids and Aryl Iodides Marcin Bielawski, David Aili and Berit Olofsson J. Org. Chem. 2008 , 73 , 4602-4607. Copyright 2011 American Chemical Society. vii V. α-Arylation by Rearrangement: On the Reaction of Enolates with Diaryliodonium Salts Per-Ola Norrby, Tue B. Petersen, Marcin Bielawski and Berit Olofsson Chem. Eur. J. 2010 , 16 , 8251-8254. Copyright Wiley-VCH Verlag GmbH & Co. KGaA. Reproduced with permission. One-Pot Synthesis of Heteroaromatic Iodonium Salts Marcin Bielawski, Leticia M. Pardo, Ylva Wikmark and Berit Olofsson Appendix B. Paper not included in the thesis: Metal-Free Synthesis of Indanes by Iodine(III)-Mediated Ring Contraction of 1,2-Dihydronaphthalenes Fernanda A. Siqueira, Eloisa E. Ishikawa, André Fogaça, Andréa T. Faccio, Vânia M. T. Carneiro, Rafael R. S. Soares, Marcin Bielawski, Berit Olofsson and Luiz F. Silva, Jr. Submitted to Tetrahedron. viii Contents Abstract ......................................................................................................... v List of Publications .................................................................................... vii Contents ....................................................................................................... ix Abbreviations ............................................................................................... xi Chapter 1 Introduction to Hypervalent Iodine Compounds .............. 1 1.1 Nomenclature, Oxidation State and Bonding ................................................ 3 1.2 Some λ3- and λ5-Iodanes and their Applications .......................................... 4 1.3 Diaryliodonium Salts .......................................................................................... 5 1.3.1 Synthesis ..................................................................................................... 6 1.3.2 Mechanistic Limitations ............................................................................ 9 1.3.3 Application Areas ..................................................................................... 10 1.4 Objectives of This Thesis ................................................................................ 13 Chapter 2 One-Pot Synthesis of Diaryliodonium Triflates from Aryl Iodides and Arenes (Paper I & II) ................................................. 15 2.1 Initial Experiments ........................................................................................... 15 2.2 Optimization Studies ........................................................................................ 17 2.3 Arene Scope ...................................................................................................... 19 2.4 Aryl Iodide Scope ............................................................................................. 22 2.5 Limitations to the Developed Protocol .......................................................... 25 2.5.1 Electron-Rich Aryl Iodides ...................................................................... 25 2.5.2 Electron-Poor Arenes .............................................................................. 26 2.6 Conclusions ........................................................................................................ 27 Chapter 3 One-Pot Synthesis of Diaryliodonium Triflates from Iodine and Arenes (Paper I, II & III) .................................................... 29 3.1 Optimization ...................................................................................................... 29 3.2 Substrate Scope ............................................................................................... 31 3.3 Large Scale Synthesis ...................................................................................... 33 3.3.1 Selection of a Suitable Substrate ......................................................... 33 3.3.2 Scale-up, Isolation and Results ............................................................ 34 3.4 Conclusions ........................................................................................................ 37 ix Chapter 4 Regiospecific Synthesis of Diaryliodonium Tetrafluoroborates (Paper IV) ................................................................. 39 4.1 Initial Experiments ........................................................................................... 40 4.2 Optimization ...................................................................................................... 40 4.3 Arylboronic Acid Scope .................................................................................... 42 4.4 Aryl Iodide Scope ............................................................................................. 44 4.5 Conclusions ........................................................................................................ 46 Chapter 5 Synthesis of Heteroaromatic Iodonium Salts (Appendix B) ............................................................................................... 47 5.1 Initial Experiments and Optimization ........................................................... 48 5.2 Substrate Scope and the Identity of the Products ..................................... 48 5.3 Future Work and Conclusions ......................................................................... 53 Chapter 6 α-Arylation of Enolates by Rearrangement (Paper V) ..................................................................................................... 55 6.1 α-Arylation of Carbonyl Compounds ............................................................. 55 6.1.1 Aim of the Project .................................................................................... 58 6.2 Approaching α-Arylation– the Asymmetric Way ......................................... 58 6.2.1 α-Arylation with Diaryliodonium Salts having a Chiral Counterion