0QVDOHQFDWDO\]HGDV\PPHWULFHSR[LGDWLRQ VHDUFKIRUQHZR[LGDWLRQV\VWHPV Pekka Pietikäinen University of Helsinki Faculty of Science Department of Chemistry Laboratory of Organic Chemistry P. O. Box 55, FIN-00014 University of Helsinki, Finland $&$'(0,&',66(57$7,21 7REHSUHVHQWHGZLWKWKHSHUPLVVLRQRIWKH)DFXOW\RI6FLHQFHRIWKH8QLYHUVLW\RI +HOVLQNLIRUSXEOLFFULWLFLVPLQ$XGLWRULXP$RIWKH'HSDUWPHQWRI&KHPLVWU\ $,9LUWDVHQDXNLRRQ-XQHVWDWSP Helsinki 2001 ISBN 952-91-3434-7 (nid.) ISBN 951-45-9974-8 (PDF) Helsinki 2001 Yliopistopaino &217(176 ABSTRACT 3 PREFACE 4 LIST OF ORIGINAL PUBLICATIONS 5 ABBREVIATIONS 6 1. ,1752'8&7,21 7 2. 0Q6$/(1&$7$/<=('$6<00(75,&(32;,'$7,21 9 2.1. Background: oxo-based transition metal catalysis 9 2.2. Chiral Mn(III)-salen complexes: steric and electronic effects on 12 enantioselectivity 2.3. Synthesis of chiral Mn(III)-salen complexes 18 2.4. Epoxidation method: effects of the reaction conditions 19 2.4.1. Choice of oxidant 19 2.4.2. Axial ligand effects 25 2.5. Substrate effects 27 2.6. Mechanistic considerations 30 3. $,062)7+(35(6(17678'< 33 4. 5(68/76$1'',6&866,21 34 4.1. Synthesis of Mn(III)-Schiff base complexes 34 4.1.1. Synthesis of symmetrical Mn(III)-salen complexes 34 4.1.2. Synthesis of unsymmetrical Mn(III)-Schiff base 35 complexes 4.2. Asymmetric epoxidation with hydrogen peroxide 38 4.2.1. Axial ligand effects 38 4.2.2. Asymmetric epoxidation of various alkenes with H2O2 42 4.2.3. Catalyst structure effects in asymmetric epoxidations 43 with H2O2 4.3. Asymmetric epoxidation with periodates 45 4.4. Asymmetric epoxidation with peroxymonosulfates 47 4.4.1. Effects of reaction conditions 47 4.4.2. Asymmetric epoxidation of various alkenes with 48 peroxymonosulfates 4.4.3. Catalyst structure effects in asymmetric epoxidation 49 with peroxymonosulfates 4.5. Asymmetric epoxidation with LQVLWX generated peroxyacids 51 4.5.1. Generation of the peroxyacids and the epoxidation 51 procedure 4.5.2. Comparison with other oxidation systems utilizing H2O2 54 4.5.3. Possible catalytic routes for asymmetric epoxidation 55 with peroxyacids 4.6. Asymmetric epoxidation catalyzed with unsymmetrical 56 Mn(III)-Schiff base complexes &21&/86,216$1')8785(3(563(&7,9(6 58 (;3(5,0(17$/ 60 5()(5(1&(6$1'127(6 62 ORIGINAL PUBLICATIONS I-VII $%675$&7 During the last decade Mn(III)-salen complexes [salen= 1,1¶-bis(salicylidene)- ethylenediaminato] have emerged as efficient and practical catalysts for the asymmetric epoxidation of various unfunctionalized FLV-disubstituted, tri- and tetrasubstituted alkenes. The literature review of this thesis outlines the development of Mn-salen-based asymmetric epoxidation methodology. The essentials of Mn(III)-salen catalysis, such as design and synthesis of the salen ligand, the steric and electronic effects of catalyst structure on stereoselectivity, and the mechanism of asymmetric induction are surveyed. Also, other important aspects affecting the outcome of asymmetric epoxidation are covered including the effects of the oxidant and additives (axial ligands). The present study describes the development of new oxidation systems based on chiral Mn-salen complexes. This development work included a systematic search for suitable stoichiometric oxidants and additives for asymmetric epoxidation, and the synthesis of Mn(III)-salen type catalysts. Several oxidants were investigated and found to be applicable to Mn-salen-based epoxidation: hydrogen peroxide, periodates, quaternary ammonium and phosphonium monopersulfates, and LQ VLWX generated peroxyacids. Moderate-to-high enantioselectivities in alkene epoxidation (ee up to 96 %), especially for electron-rich FLV-disubstituted and trisubstituted olefins, were obtained with all oxidants. The presence of additives such as imidazoles, pyridines and amine-1-oxides was beneficial with all the oxidants. The effect of catalyst structure on the stereochemical outcome of the epoxidation was also studied. Particular attention was paid to hydrogen peroxide due to its advantages over many other oxidants: high oxygen content, low price, ready availability, and environmental acceptability. A simple and practical epoxidation system involving oxidation-resistant carboxylate salts as additives was developed. A mechanistic basis for the role of these additives is proposed. Hydrogen peroxide was further utilized in the generation of peroxyacids LQVLWX from carboxylic acid anhydrides, which increased reactivity and selectivity. In addition to symmetrical Mn(III)-salen complexes, two novel non-C2- symmetric Mn(III)-Schiff-base complexes containing salicylaldehyde and 1-(2- hydroxyphenyl)ketone units were synthesized using a stepwise procedure. One of the two complexes was catalytically active in asymmetric epoxidation of various alkenes and showed moderate-to-good enantioselectivity, although it was lower than that obtained for analogous C2-symmetric salen-based catalysts. Possible reasons for the differences in reactivity and selectivity between these two types of catalysts are briefly discussed. 3 )6HGIXJLWLQWHUHDIXJLWLQUHSDUDELOHWHPSXV) (Time meanwhile flies, never to return) Virgil (70-19 B. C.) 35()$&( The experimental part of this study was carried out at the Laboratory of Organic Chemistry of the University of Helsinki during the years 1992-1998. I am indebted to Professor Gösta Brunow for introducing me into the field of biomimetic oxidation chemistry and for his support and encouragement during the years of this work. I am also grateful to Professor Tapio Hase, Head of the Organic Chemistry Laboratory, for placing the excellent research facilities of the Laboratory at my disposal. I wish to thank Dr. Jorma Matikainen for running the mass spectra, Mr. Anssi Haikarainen (M.Sc.) for fruitful cooperation and Ms. Mia-Riitta Malmström for technical assistance. Thanks are extended to professors Tapio Hase and Markku Leskelä for reviewing the manuscript of the thesis and to Mr. Harri Salonen (BA) for revising the language. I would like to express my warmest thanks to all my colleagues at the Laboratory of Organic Chemistry for valuable comments and for their friendship. Also refreshing moments spent with the members of the late (?) “Thursday Club” are gratefully appreciated. This work was supported by the Technology Development Centre of Finland (TEKES) during the years 1992-1997, University of Helsinki, Research Foundation of Orion Corporation, and Orion Corporation Fermion, which I acknowledge with gratitude. Finally, my sincerest appreciation goes to my parents, to my wife Tiina and to Enni, and Jeannette for their encouragement, patience, and love during all these years. Espoo, March 2001 Pekka Pietikäinen 4 /,672)25,*,1$/38%/,&$7,216 This thesis is based on the following original publications, referred to in the text by their Roman numerals (I-VII). Data published and discussed here for the first time are referred to as VIII. I. Pietikäinen, P. "Catalytic and Asymmetric Epoxidation of Unfunctionalized Alkenes with Hydrogen Peroxide and (Salen)Mn(III) Complexes"; 7HWUDKHGURQ /HWW. , , 941-944. II. Pietikäinen, P. "Asymmetric Epoxidation of Unfunctionalized Alkenes with Periodates Catalyzed by Chiral (Salen)Mn(III) Complexes"; 7HWUDKHGURQ /HWW. , , 319-322. III. Pietikäinen, P. "Convenient Asymmetric (Salen)Mn(III)-catalyzed Epoxidation of Unfunctionalized Alkenes with Hydrogen Peroxide Using Carboxylate Salt Cocatalysts"; 7HWUDKHGURQ, , 4319-4326. IV. Pietikäinen, P. "Asymmetric Mn(III)-Salen Catalyzed Epoxidation of Unfunctionalized Alkenes with Tetrabutylammonium Monopersulfate"; 7HWUDKHGURQ/HWW., , 1001-1004. V. Pietikäinen, P. "Asymmetric Epoxidation of Unfunctionalized Alkenes with Ammonium and Phosphonium Monopersulfates Catalyzed by Chiral Mn(III)- Salen Complexes"; 7HWUDKHGURQ , , 417-424. VI. Pietikäinen, P. "Asymmetric Mn(III)-Salen Catalyzed Epoxidation of Unfunctionalized Alkenes with LQ VLWX Generated Peroxycarboxylic Acids";- 0RO&DWDO$&KHP. , , 73-79. VII. Pietikäinen, P.; Haikarainen, A. "Synthesis and Catalytic Activity of New Chiral Mn(III)-Schiff-base Complexes Containing Salicylaldehyde and 1-(2- Hydroxyphenyl)ketone Units"; -0RO&DWDO$&KHP., submitted. 5 $%%5(9,$7,216 Ac acetyl Ar aryl Bu butyl W-Bu WHUW-butyl DMAP 4-dimethylaminopyridine DMF 1,1-dimethylformamide ee enantiomeric excess EI electron impact Et ethyl Eu(hfc)3 tris[3-(heptafluoropropylhydroxymethylene)-(+)-camphorato]- europium(III) FAB fast atom bombardment ImH imidazole IR infrared MCPBA P-chloroperoxybenzoic acid Me methyl MMPP magnesium monoperoxyphthalate MS mass spectrometry 1-MeIm 1-methylimidazole NMO 1-methymorpholine 1-oxide NMR nuclear magnetic resonance Oxone potassium monopersulfate, 2KHSO5·KHSO4·K2SO4 triple salt Ph phenyl POHP triphenylphosphine oxide-hydrogen peroxide adduct, Ph3PO·½H2O2 PPNO 4-phenylpyridine 1-oxide L-Pr LVR-propyl Py pyridine PyNO pyridine 1-oxide salen 1,1¶-bis(salicylidene)ethylenediamine dianion ligand SPC sodium percarbonate, Na2CO3·1½H2O2 UHP urea-hydrogen peroxide adduct, urea·H2O2 6 ,1752'8&7,21 Epoxides are versatile intermediates in organic chemistry. The inherent polarity and strain of their three-membered ring makes them readily undergo stereospecific ring-opening reactions with nucleophiles to form 1,2-difunctional compounds.1 Optically pure epoxides with two contiguous stereogenic centers are particularly useful intermediates for the preparation of biologically and pharmaceutically active compounds.2 The first attemps to prepare optically active epoxides were reported in 1965 and since then considerable attention has been paid to asymmetric