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Courtney Williamson Phd Thesis Asymmetric Catalysis of Cyanide Addition Reactions Using Metal(Salen) Complexes A thesis submitted for the Degree of Doctor of Philosophy by Courtney M. Williamson Newcastle University September 2010 Contents. Declaration 1 Acknowledgements 2 Abbreviations 3 Abstract 4 1.1 Introduction: 1.1.1 Salen Ligands in Asymmetric Catalysis 5 1.1.2 Introduction to Cyanohydrin Synthesis 5 1.1.3 Asymmetric Cyanohydrin Synthesis 7 1.2 Titanium Based Salen Complexes as Catalysts for Asymmetric Cyanohydrin Synthesis: 1.2.1 Asymmetric Cyanation of Aldehydes Using Titanium(salen) Complexes 10 1.2.2 Mechanistic Studies on Titanium(salen) Complexes 24 1.2.3 Other C2-symmetric Salen Based Titanium Complexes in 28 Cyanohydrin Synthesis 1.2.4 Immobilised C2-symmetric Salen Derived Ligands 32 1.2.5 Asymmetric Cyanation of Ketones Using Titanium(salen) Complexes 36 1.3 Vanadium(salen) Based Catalytic Systems for Cyanohydrin Synthesis: 37 1.3.1 Asymmetric Cyanohydrin of Aldehydes Using Heterobimetallic 45 Catalyst Systems of Vanadium and Titanium 1.4 Aluminium Based Catalytic Systems for Cyanation of Aldehydes: 48 1.4.1 Aluminium(salen) Based Catalytic Systems for the 50 Cyanation of Ketones 1.5 Asymmetric Strecker Reaction Using Chiral Catalysts: 1.5.1 Introduction to the Strecker Reaction 51 1.5.2 Asymmetric Strecker Reaction Catalysed by Non-Metal Catalysts 52 1.5.3 Metal Catalysts Used in the Asymmetric Strecker Reaction: 1.5.3.1 Enantioselective Strecker Reactions Using Metal 63 BINOL Complexes 1.5.3.2 Enantioselective Strecker Reaction Using Lanthanide 67 Metal Complexes 1.5.3.3 Enantioselective Strecker Reaction Catalysed by 71 Metal(salen) Complexes ii 1.5.3.4 Enantioselective Strekcer Reactions Using Other 74 Metal Ligand Complexes 1.6 Aims 77 2.1 Results and Discussion: 2.1.1 Ligand and Catalyst Synthesis 79 2.1.2 Synthesis of New Catalysts 81 2.1.3 Testing New Catalysts in the Strecker Reaction and 87 Cyanohydrin Synthesis 2.1.4 Testing of Complexes 231a and 231b in Cyanohydrin 91 Synthesis and the Strecker Reaction 3.1 Research into the Strecker Reaction Using Metal(salen) 93 Complexes 3.1.1 Kinetic Study of the Strecker Reaction Using 101 Complex 118 4.1 Aluminium(salen) Complexes in Cyanohydrin Synthesis: 4.1.1 Cyanation of Aldehydes Using Aluminium(salen) Dimer 104 4.1.2 Cyanation of Ketones Using Aluminium(salen) Dimer 239 111 4.1.3 Using Complex 239 in the Strecker Reaction 113 5.1 Kinetic Studies of the Dimeric Aluminium(salen) System 114 6.1 Hammett Study of Complex 239 122 7.1 Arhenius Study of Cyanohydrin Synthesis Using 129 Complex 239 8.1 Summary of Results, Conclusion and Future Work: 8.1.1 Testing of New Catalysts in the Strecker Reaction and 136 Cyanohydrin Synthesis 8.1.2 The Strecker Reaction 137 8.1.3 Cyanohydrin Synthesis Using Complex 239 138 8.1.4 Future Work 139 9 Experimental 141 10 References 178 iii Declaration The work presented in this thesis was carried out at the University of Newcastle Upon Tyne chemistry department between September 2006 and September 2009. The work contains no material which has been accepted for the award of any other degree or diploma in any other university or other institution, and, to the best of my knowledge and belief, contains no material previously published or written by any other person, except where due reference has been made in the text. I give my consent to this copy of my thesis, when deposited in the University library, being available for loan or photocopying only after a period of three years. 1 Acknowledgements Firstly I would like to thank my supervisor Professor Michael North for his guidance throughout the past three years and, also to the EPSRC and the University of Newcastle Upon Tyne for the financial support throughout my studies. Without this, this work would not have been possible. I would also like to thank all the technical and clerical staff in the department, past and present, for their help with various issues throughout my time at Newcastle University. I have so many people I want to thank, first my family for all their support especially towards the end of my PhD. Next I would like to warmly thank all the great friends I made over the past three years. Unfortunately some of these people have now left Newcastle and moved onto other things. I would like to thank; Carl, Marta, Pedro, Eisuke, Jamie, Riccardo, Jaisiel, Ruth, Sophie, Victoria, Jenny, Kris and Luke. I hope I have not missed anyone! I would like to especially thank Paul, the ‘fastest dancer’ in the North East. Thank you for the many laughs, the boozy nights and just being there. Also, thank you to Rachel for listening to me when I needed to be listened to. You know how hard the past three years have been. Thank you for the nice meals you cooked for me and the many chats we’ve had over coffee. Last but not least, thank you to Francesca. That year we had in the flat was the best year I’ve had in Newcastle. I’ve never worn my dancing shoes as much as throughout that year!!! Thank you to you all. I am grateful for the support you have all given me. 2 Abbreviations [α]D optical rotation at the sodium-D-line ee enantiomeric excess GC gas chromatography IR infrared Lit. literature MS mass spectrometry NMR nuclear magnetic resonance UV ultraviolet 3 Abstract. Chiral cyanohydrins and α-aminonitriles are versatile intermediates and are of great importance to the pharmaceutical industry due to the ability to convert them into useful chemicals via simple chemical transformations. Chiral cyanohydrins and α-aminonitriles can be obtained from asymmetric cyanohydrin synthesis and asymmetric Strecker reactions respectively. In this project, bimetallic aluminium(salen) complex 1 was studied extensively and was shown to be very active in cyanohydrin synthesis using trimethylsilylcyanide (TMSCN), giving the cyanohydrin trimethylsilyl ether derived from benzaldehyde with 89% (S) enantioselectivity and 80% conversion after 18 hours at -40 oC. A variety of substituted benzaldehydes were screened giving moderate to excellent enantioselectivities. Ketones were also shown to be substrates when used in this catalytic system. Extensive kinetic studies of complex 1 gave the rate equation; rate = k[TMSCN][Ph 3PO][ 1] which is zero order with respect to benzaldehyde. A Hammett study using complex 1 showed that this catalytic system was dominated by Lewis basic catalysis, resulting from the activation of trimethylsilylcyanide by triphenylphosphine oxide. The catalyst was then responsible for the chirality of the product rather than the activation of the aldehyde. t Bu t Bu t Bu t Bu N O O O N Al Al N O O N t Bu t Bu t Bu t Bu 1 A variety of other titanium and vanadium(salen) complexes, containing various substituents on the aromatic ring of the salen ligand were synthesised and screened in the Strecker reaction and cyanohydrin synthesis under different reaction conditions. Enantiomeric excesses of 10-95% ( R and S) were achieved with conversions of 10-100% for both reactions. 4 1.1 Introduction 1.1.1 Salen Ligands in Asymmetric Catalysis. Salen ligands are commonly used throughout asymmetric synthesis as chiral ligands. The ligand can act as a tetradentate dianionic species, with the ability to co-ordinate to almost any element in the Periodic Table. This opens up the possibility to synthesise a large number of metal salen complexes, displaying catalytic activities in a wide range of useful organic transformations. These transformations include; alkene epoxidation, 1 Darzen’s 2 3 4,5 condensations, CO 2 fixation to form cyclic carbonates and many others. The structure of the salen ligand can vary depending on the aromatic substituents and the nature of the diamine used in the synthesis. The basic salen structure is shown in Figure 1. The structure of these ligands can vary enormously as the possible number of substituents for both the aromatic rings and diamine moieties are vast and can be prepared using simple chemical techniques. 6,7 Having the ability to modify the ligand structure allows any salen metal complex to be finely tuned, both sterically and electronically, to meet the requirements of the reaction for which it will be used. Since many of these complexes have been shown to display high levels of stereocontrol, this is a huge advantage in a forever expanding, vital area of synthetic and asymmetric catalytic chemistry. R3 R4 N N R1 OH HO R1 R2 R2 Figure 1: basic structure of the salen ligand Due to the diverse applications of salen ligands in asymmetric reactions, metal(salen) complexes were chosen as the focus of this research concentrating on two fundamental reactions in asymmetric catalysis; the Strecker reaction and cyanohydrin synthesis. 1.1.2 Introduction to Cyanohydrin Synthesis. Cyanohydrin synthesis (Scheme 1) is the nucleophilic addition of cyanide to a carbonyl bond, forming the cyanohydrin functional group. Cyanohydrin synthesis is one of the most fundamental reactions in organic synthesis as a new carbon-carbon bond is formed. The first reported cyanohydrin synthesis was in 1832 8 and this involved the use of hydrogen cyanide. Due to the toxicity of this reagent, a lot of work has followed, exploring the use of alternative cyanide sources. A variety of reagents have been found to be effective at 5 delivering cyanide to the carbonyl bond, including; cyanoformates, 9 cyanophosponates 10 and acyl cyanides. 11 O CN O CN H HO CN R R' R R' R R' Scheme 1: cyanohydrin synthesis. Trimethylsilylcyanide is the most common cyanide source used in cyanohydrin chemistry. The advantage of using trimethylsilylcyanide is that it is a liquid, so handling is easier and also the product obtained is the silyl protected cyanohydrin.
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