Control of Regioselectivity: Oxidation and Deprotection
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CONTROL OF REGIOSELECTIVITY: OXIDATION AND DEPROTECTION Joseph A. Wright Department of Chemistry, University of Cambridge 2002 A dissertation submitted to the University of Cambridge in partial fulfilment for the degree of Doctor of Philosophy Nemo mortalium omnibus horis sapit Pliny, Natural History, VII, xl, 131 PREFACE This dissertation is a summary of research work carried out in the Department of Chemistry of the University of Cambridge between October 1999 and December 2002. Unless stated otherwise, the results are those of the author’s own work. It has not, either in whole or in part, been submitted for any qualification to any other University. Joseph A. Wright December 2002 i ACKNOWLEDGEMENTS Sincere thanks to my family, for all of their help and support both before and during my PhD. Without them, I would not have had the opportunity to carry out this work. Thanks to all of the many people that I have known in the Chemistry Department. Particular thanks to all of the past and current members of the Spencer group for some good times; special mentions for Matthew for starting off the Wacker work, Jin for intense discussions, Tobias for organisation and Sam for many long chats. The members of the other groups we have shared lab space / office space / tea-breaks with must be mentioned: the Williams, Leeper, Jackson, Balasubramanian and Wright groups. Thanks to all of the technical staff of the department, without whom no one could get anything done. Particular thanks to Tim, Keith and Kevin for floor services and Alan Dickerson for keeping the G.L.C. working. Thank you to the people who read this work – Zoe Jones, Tobias Wabnitz, Dr. Jinquan Yu, Lydia Wright and Dr. Oliver Choroba – finding my spelling and grammar mistakes, and plain nonsense. Particular thanks to Dr. Jinquan Yu for his useful discussions, and help during the NAP group project. Thanks to the B.B.R.S.C. (and ultimately the British Government) for providing funding for this work. Thanks to all of the libraries I have used to obtain my references: the departmental, University and Scientific Periodical libraries in Cambridge, and the Royal Society of Chemistry and British libraries in London. Particular thanks to the Science and Technology helpdesk at the British Library for tracking down some obscure journals. Finally, for allowing me the opportunity to do all of this, my sincere thanks to my supervisor, Dr. Jonathan B. Spencer ii ABSTRACT Palladium is a highly versatile metal, capable of catalysing oxidations, reductions and a myriad of organic transformations. The inorganic chemistry of palladium, and the relation of this to the catalytic activity of the metal, is briefly discussed. A short survey of the range of palladium- catalysed reactions is undertaken. The Wacker reaction, the palladium(II)-catalysed oxidation of alkenes to carbonyls, is considered in detail. In the absence of heteroatoms, the Wacker reaction of terminal alkenes is known to produce methyl ketones. However, it is shown that the Wacker reaction of styrenes is unusual; under reoxidant-free conditions, the reaction proceeds to give aldehydes as the major products. The scope of this transformation is probed with a series of ring-substituted styrenes: it is found to be general for all substituents studied. The mechanism responsible for this anti-Markovnikov regioselectivity is investigated. Palladium(0) is eliminated as a possible cause of unusual reactivity. NMR studies and reactions of suitable substrates are used to suggest a side-on complex of either an agostic or 4-type. Kinetic studies show no evidence of an agostic interaction, and thus an 4-complex is more likely. Attempts at achieving catalytic activity in the formation of aldehydes are unsuccessful with small-molecule reoxidants. However, the use of heteropolyacids is found to lead to a catalytic reaction. A second source of unexpected regioselectivity in the Wacker reaction is the agostic interaction of hydrogens on the allylic position with the palladium centre. Some new evidence is obtained for this effect in the reaction of 1-phenylbut-1-ene and 1-phenyl-3-methylbut-1-ene. Attempts are made to gain additional insight by seeking a kinetic isotope effect in the Wacker reaction of dec-1-ene and a partially-deuterated analogue. Some evidence of a kinetic isotope effect is found. The use of benzyl (Bn) groups is one of the most common methods used in synthesis to protect alcohols and amines. The method of choice for the removal of Bn groups is hydrogenolysis over a palladium catalyst. Oxidative deprotection methods are also available, particularly when the MPM (4-methoxybenzyl) group is used in place of Bn. The NAP (2-naphthylmethyl) protective group has recently been introduced and has been shown to be removed by hydrogenolysis more readily than Bn groups. The usefulness of the NAP group is extended: it is demonstrated that NAP is less sensitive to oxidative cleavage with CAN [hexa-amminecerium(IV) nitrate(V)] than MPM. A series of glucose-based substrates are prepared, and used to demonstrate this oxidative selectivity. iii CONTENTS 1 Abbreviations 1 2 Palladium – a versatile catalytic metal 5 2.1 The discovery and isolation of palladium 5 2.2 Inorganic and co-ordination chemistry 5 2.2.1 Introduction 5 2.2.2 Oxidation states 6 2.2.3 Hard and soft behaviour of palladium(II) 9 2.2.4 Co-ordination of organic compounds 9 2.2.5 Co-ordination of hydrogen 11 2.3 Palladium catalysis – concepts 11 2.3.1 Homogeneous and heterogeneous catalysis 11 2.3.2 The elementary reactions of palladium catalysis 12 2.3.3 Intrinsic and extrinsic catalysis 13 2.4 Palladium(II) catalysed oxidation 14 2.4.1 Introduction 14 2.4.2 The reaction of alkenes 14 2.4.3 The reaction of conjugated dienes 24 2.4.4 The reaction of aromatic compounds 25 2.4.5 The reaction of alkynes 26 2.4.6 Miscellaneous reactions 27 2.5 Palladium catalysed hydrogenation and hydrogenolysis 28 2.5.1 Reductions: an overview 28 2.5.2 Choice of metal 29 2.5.3 Reduction of alkenes 29 2.5.4 Reduction of alkynes 31 2.5.5 Dehalogenation of acyl chlorides 31 2.5.6 Hydrogenolysis of benzyl groups 32 2.6 Palladium(0) catalysed reactions 32 2.6.1 The Heck reaction 33 2.6.2 The Tsuji-Trost reaction 34 3 The Wacker reaction of styrenes 37 3.1 Introduction 37 iv 3.1.1 The Wacker Process 37 3.1.2 Reoxidation of palladium(0) to palladium(II) 38 3.1.3 Environmental considerations 39 3.1.4 The mechanism of the Wacker reaction 40 3.1.5 Regioselectivity of the Wacker reaction 43 3.2 The Wacker reaction of styrene 46 3.3 Mechanistic investigation of the anti-Markovnikov reaction 47 3.3.1 The effect of temperature 49 3.3.2 The effect of the counter-ion for palladium 49 3.3.3 Solution acidity 50 3.3.4 Electronic effects: substituted styrenes 51 3.3.5 Reaction stoichiometry 53 3.3.6 The influence of palladium(0) 53 3.3.7 Steric factors: Non-aromatic substrates 54 3.3.8 Complex formation 55 3.3.9 NMR studies 55 3.3.10 Deuterium labelling studies 58 3.3.11 2-Methyl effect 59 3.3.12 Mechanistic proposals 60 3.4 Catalysis 61 3.4.1 Small molecule reoxidants 61 3.4.2 Heteropolyanion reoxidation 62 3.5 Summary 62 4 the Wacker reaction of alkenes with allylic hydrogens 63 4.1 Regioselectivity in the Wacker reaction of internal alkenes 63 4.2 Investigations into the reaction of 1-phenylprop-1-enes 66 4.3 The reaction of terminal alkenes 67 4.3.1 Possible involvement of allylic hydrogens 67 4.3.2 Kinetic experiments 69 4.4 Conclusions 72 5 Extension of a protective group: removal of the NAP group by oxidation 73 5.1 Protective groups 73 5.1.1 The need for protective groups 73 5.1.2 The benzyl group 74 v 5.1.3 The MPM group: oxidative cleavage 75 5.1.4 The NAP group 76 5.2 Oxidative removal of the NAP group 77 5.2.1 Removal using DDQ 77 5.2.2 Selective removal using CAN oxidation 77 5.2.3 Synthesis of glucose-based substrates 78 5.2.4 Selective deprotection of challenging substrates 81 5.3 Conclusions 83 6 Experimental 84 6.1 General 84 6.2 The Wacker reaction of styrenes (styrenes) 85 6.2.1 Reference Wacker reaction 85 6.2.2 Preparation of non-commercial alkenes 85 6.2.3 Preparation of aldehyde standards 89 6.2.4 The anti-Markovnikov Wacker reaction of a series of substituted styrenes 90 6.2.5 Effect of temperature 95 6.2.6 Catalyst counter-ions 95 6.2.7 Mechanistic investigations 97 6.2.8 NMR studies 98 6.2.9 Effects of acids and bases on the Wacker reaction 99 6.2.10 Kinetic studies 100 6.2.11 Catalysis of the reaction 102 6.3 The agostic interaction in the Wacker reaction 104 6.3.1 Agostic interaction: synthesis and reactions of aromatic 104 6.3.2 Agostic interaction: synthesis and reactions of [3,3-D2]dec-1-ene 106 6.4 Selective oxidative removal of the NAP group 110 6.4.1 Synthesis and deprotection of linker 110 6.4.2 Synthesis of glucose-based deprotection substrates 113 6.4.3 Deprotection of glucose-based substrates 128 7 References 131 8 Appendix: Analysis of kinetic NMR data for dec-1-ene 143 vi 1 ABBREVIATIONS chemical shift (parts per million) heat Ac ethanoyl (“acetyl”) acac pentan-2,4-dionate (“acetylacetonate”) Ad adamantyl app apparent Ar aromatic / aryl BINAP 2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl Bn benzyl / phenylmethyl BQ 1,4-benzoquinone br broad Bu butyl calcd calculated CAN hexa-amminecerium(IV) nitrate(V) (“ceric ammonium nitrate”) cat.