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Regiocontrol in the Heck-Reaction and Fast Fluorous Chemistry Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 244 _____________________________ _____________________________ Regiocontrol in the Heck-Reaction and Fast Fluorous Chemistry BY KRISTOFER OLOFSSON ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2001 Dissertation for the Degree of Doctor of Philosophy (Faculty of Pharmacy) in Organic Pharmaceutical Chemistry presented at Uppsala University in 2001. Abstract Olofsson, K. 2001. Regiocontrol in the Heck-Reaction and Fast Fluorous Chemistry. Acta Universitatis Upsaliensis. Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 244. 74 pp. Uppsala. ISBN 91–554–4883–6 The palladium-catalysed Heck-reaction has been utilised in organic synthesis, where the introduction of aryl groups at the internal, β-carbon of different allylic substrates has been performed with high regioselectivity. The β-stabilising effect of silicon enhances the regiocontrol in the internal arylation of allyltrimethylsilane, while a coordination between palladium and nitrogen induces very high regioselectivities in the arylation of N,N-dialkylallylamines and the Boc-protected allylamine, producing β-arylated arylethylamines, which are of interest for applications in medicinal chemistry. Phthalimido-protected allylamines are arylated with poor to moderate regioselectivity. Single-mode microwave heating can reduce the reaction times of Heck-, Stille- and radical mediated reactions drastically from approximately 20 hours to a few minutes with, in the majority of cases, retained, high regioselectivity. The use of heavily fluorinated tin reagents, which proved to be unreactive under thermal heating, is shown to be applicable with microwave-heating and the high fluorous content of the products is utilised with the aim of improving and simplifying the work- up procedure. Kristofer Olofsson, Organic Pharmaceutical Chemistry, Department of Pharmaceutical Chemistry, Uppsala University, Box 574, SE-75123, Uppsala, Sweden © Kristofer Olofsson 2000 ISSN 0282–7484 ISBN 91–554–4883–6 Printed in Sweden by Lindbergs Grafiska HB, Uppsala 2000 2 List of Papers The thesis is based on the following papers: I. Kristofer Olofsson, Mats Larhed and Anders Hallberg Highly Regioselective Palladium-Catalyzed Internal Arylation of Allyltrimethylsilane with Aryl Triflates. J. Org. Chem. 1998, 63, 5076-5079. II. Kristofer Olofsson, Sun-Young Kim, Mats Larhed, Dennis P. Curran and Anders Hallberg High-Speed, Highly Fluorous Organic Reactions. J. Org. Chem. 1999, 64, 4539-4541. III. Kristofer Olofsson, Mats Larhed and Anders Hallberg Highly Regioselective Palladium-Catalyzed β-Arylation of N,N- Dialkylallylamines. J. Org. Chem. 2000, 65, 7235-7239. IV. Kristofer Olofsson, Helena Sahlin, Mats Larhed and Anders Hallberg Regioselective Palladium-Catalysed Synthesis of β-Arylated Primary Allylamine Equivalents. J. Org. Chem. Accepted. Reproduced in part with permission from Journal of Organic Chemistry, American Chemical Society. Copyright 1998-2000. 3 4 CONTENTS LIST OF PAPERS......................................................................................................................................3 ABBREVIATIONS.....................................................................................................................................6 1 INTRODUCTION.............................................................................................................................7 1.1 PALLADIUM(0) CATALYSED ORGANIC REACTIONS ........................................................................7 1.1.1 The Heck-Reaction ...............................................................................................................8 1.1.2 The Stille-Reaction ...............................................................................................................9 2 THE CATALYTIC CYCLE AND REACTANTS OF THE HECK-REACTION....................10 2.1 THE CATALYTIC CYCLE................................................................................................................10 2.1.1 Catalyst Formation.............................................................................................................10 2.1.2 Oxidative Addition..............................................................................................................10 2.1.3 π-Complex Formation and σ-Complex Formation (Insertion) ..........................................12 2.1.4 Elimination and Palladium(0) Regeneration .....................................................................17 2.2 REACTION CONDITIONS ................................................................................................................18 2.2.1 Palladium ...........................................................................................................................18 2.2.2 The Ligand (dppf) ...............................................................................................................18 2.2.3 The Base .............................................................................................................................21 2.2.4 The Solvent .........................................................................................................................22 2.3 REGIOCONTROL IN THE HECK-REACTION .....................................................................................23 2.3.1 The β-Effect of Allylsilanes.................................................................................................23 2.3.2 The Chelation of Palladium to Allylamines and Allylamides. ............................................26 3 RECENT DEVELOPMENTS........................................................................................................30 3.1 MICROWAVE CHEMISTRY .............................................................................................................30 3.1.1 The Microwave Oven..........................................................................................................30 3.1.2 General Physics..................................................................................................................31 3.1.3 Rate Enhancements with Microwave Chemistry.................................................................33 3.2 FLUOROUS CHEMISTRY.................................................................................................................35 3.2.1 History ................................................................................................................................35 3.2.2 Applications in Modern Chemistry .....................................................................................35 4 AIMS OF THE PRESENT STUDY ..............................................................................................38 5 RESULTS AND DISCUSSION .....................................................................................................39 5.1 HIGHLY REGIOSELECTIVE INTERNAL ARYLATION OF ALLYLTRIMETHYLSILANE (PAPER I)..........39 5.2 HIGHLY REGIOSELECTIVE INTERNAL ARYLATION OF N,N-DIALKYLALLYLAMINES AND PRIMARY ALLYLAMINE EQUIVALENTS (PAPER III AND IV). ........................................................................45 5.3 INTERNAL ARYLATION OF FLUOROALLYLAMINES (APPENDIX) ....................................................58 5.4 MICROWAVE HEATED FLUOROUS STILLE-COUPLINGS AND RADICAL REACTIONS (PAPER II)......60 6 CONCLUDING REMARKS .........................................................................................................64 7 APPENDIX......................................................................................................................................65 8 SUPPLEMENTARY MATERIAL................................................................................................66 9 REFERENCES................................................................................................................................70 10 ACKNOWLEDGEMENTS............................................................................................................74 5 Abbreviations Ac acetyl AIBN azobisisobutyronitrile Ar aryl BINAP 2,2´-bis(diphenylphosphino)-1,1´-binaphthyl Boc tert-butoxycarbonyl BTF benzotrifluoride Bu butyl cbz carbobenzyloxy DABCO 1,4-diazabicyclo[2.2.2]octane disoppf (diisopropylphosphino)-ferrocene DMA dimethylacetamide DMF dimethylformamide dmpe bis(dimethyl-phosphino)ethane DMSO dimethylsulfoxide dppb 1,4-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1´-bis(diphenylphosphino)ferrocene dppm 1,1-bis(diphenylphosphino)methane dppp 1,3-bis(diphenylphosphino)propane EDG electron-donating group equiv equivalents Et ethyl EWG electron-withdrawing group FBS fluorous biphase system FC-84 a perfluorinated solvent FRP fluorous reverse phase GC gas chromatography L ligand MAO monoamine oxidase Me methyl MS mass spectroscopy NMR nuclear magnetic resonance NR no reaction Ph phenyl Pht (NPht) phthalimido PMP 1,2,2,6,6-pentamethylpiperidine ref reference SSAO semicarbazide-sensitive amine oxidase t tertiary TBAF tetrabutylammonium fluoride temp temperature Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography triflate trifluoromethanesulfonyl X halide or pseudohalide 6 1 Introduction Palladium was discovered by William Hyde Wollaston in 1803 and was named after the asteroid Pallas, the second largest in the asteroid belt, that had been discovered the year before. The name Pallas itself can be traced to the Grecian
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