Aluminium triflate-mediated organic synthesis by Adam Cullen Thesis submitted in fulfilment of the requirements for the degree Philosophiae Doctor in Chemistry in the Faculty of Science of the University of Johannesburg Promoter: Prof. D. B. G. Williams December 2011 Litany against fear I must not fear. Fear is the mindkiller. Fear is the little-death that brings total obliteration. I will face my fear. I will permit it to pass over me and through me. And when it has gone past I will turn the inner eye to see its path. Where the fear has gone there will be nothing. Only I will remain. Bene Gesserit Litany Against Fear From Frank Herbert's Dune Acknowledgements I would like to thank all involved in the preparation of this manuscript. They include but are not limited to the following. Professor Williams for his guidance throughout this study in both chemistry and life. Professor Holzapfel for sharing with me his enthusiasm and passion for chemistry. Dr Megan Shaw for her help with NMR and MS spectra. The organic chemistry students at UJ for providing a colourful background in which to work, especially Tanya and Tyler. The University of Johannesburg, SASOL, NRF and THRIP for financial support. Anzani and Eduan, you were there from the start, always. My Mom, Sister and Ouma for having the patience and trust to let me do as I please. Carlé for exposing me to a world full of ideas, experiences and love. My Oupa for instilling in me the basic concepts of logic, hard work and perseverance. The Creator for providing the raw materials. Contents Synopsis i Abbreviations iii List of tables figures and schemes vi Contributions xviii Chapter 1 Metal triflates as Lewis acids-A literature overview Section Heading Page 1.1 Introduction to Lewis acids 1 1.1.1 Acid/base definitions 1 1.1.2 Metal triflates in organic synthesis 3 1.1.2.1 Introduction to metal triflates 3 1.1.2.2 Rare earth metal triflates 3 1.1.2.3 Group III metal triflates 22 1.2 Ring-opening reactions 31 1.2.1 Aminolysis of epoxides 31 1.2.2 Alcoholysis of epoxides 38 1.3 Nucleophilic substitution of “activated” alcohols 43 1.3.1 Introduction 43 1.3.2 Reactions of “activated” alcohols promoted 44 by stoichiometric amounts of acid 1.3.3 Reactions of “activated” alcohols promoted 45 by catalytic amounts of acid 1.3.3.1 Brønsted acid catalysed reactions 45 1.3.3.2 Lewis acid catalysed reactions 48 1.4 Conclusions 65 1.5 Aims of the present study 66 1.6 References 67 Chapter 2 Aluminium triflate : A Lewis acid catalyst for the alcoholysis of epoxides Section Heading Page 2.1 Introduction 75 2.2 Ring-opening of cyclohexene oxide 78 2.2.1 Reduction in equivalents of alcohol required 78 for the ring-opening of cyclohexene oxide 2.2.2 Stereochemistry of the ring-opened products 83 of cyclohexene oxide 2.2.3 Ring-opening of cyclohexene oxide with chiral 85 alcohols 2.3 Ring-opening of allyl glycidyl ether 92 2.3.1 Reduction in equivalents of alcohol required 92 for the ring-opening of allyl glycidyl ether 2.4 Conclusions 94 2.5 References 95 Chapter 3 Synthesis of piperazine derived β-amino alcohols via the aluminium triflate mediated ringopening of epoxides Section Heading Page 3.1 Introduction 97 3.2 Synthesis of epoxide substrates 100 3.2.1 Synthesis of S-glycidyl ethers 100 3.2.2 Synthesis of O-glycidyl ethers 100 3.2.3 Synthesis of -glycidyl ethers 104 3.3 Synthesis of diphenylmethylpiperazine based 112 amines 3.4 Al(OTf)3-mediated ringopening of epoxides 116 to give piperazine-derived β-amino alcohols 3.4.1 Initial optimisation reactions 116 3.4.2 Method evaluation for the formation of the 120 β-amino alcohol 3.4.3 Synthesis of piperazine derived β-amino alcohols 125 bearing a sulfur heteroatom 3.4.4 Synthesis of piperazine-derived β-amino alcohols 127 bearing an oxygen heteroatom 3.4.5 Synthesis of piperazine derived β-amino alcohols 129 bearing a nitrogen heteroatom 3.4.6 Scale up and recycling reactions 131 3.5 Conclusions 134 3.6 References 134 Chapter 4 The nucleophilic substitution of “activated” alcohols using aluminium triflate as a Lewis acid catalyst Section Heading Page 4.1 Introduction 137 4.2 The reaction of (S)-1phenylethanol 139 4.3 Optimisation reactions 140 4.3.1 Temperature study 140 4.3.2 Solvent study 141 4.4 Reaction scope 143 4.4.1 Reactions with benzhydrol as the “activated” 143 alcohol 4.4.2 Reactions with trans-1,3diphenylprop-2en-1ol 158 as the “activated” alcohol 4.4.3 Nitrogen nucleophiles 161 4.5 Al(OTf)3 catalysed intramolecular cyclisation 165 of “activated” alcohols 4.5.1 Introduction 165 4.5.2 Intramolecular cyclisation utilising an oxygen 169 nucleophile 4.5.3 Intramolecular cyclisation utilising a nitrogen 180 nucleophile 4.5.4 Intramolecular cyclisation utilising a sulfur 189 nucleophile 4.5.5 Comparison of the yields for the cyclised 196 products starting from the starting aldehydes 4.5.6 Intramolecular cyclisation utilising an oxygen 197 nucleophile revisited 4.6 Conclusions 199 4.7 Final conclusions 200 4.8 References 201 Chapter 5 Experimental data Section Heading Page 5.1 Standard experimental techniques 206 5.1.1 Chromatography 206 5.1.2 Anhydrous solvents and reagents 206 5.2 Spectroscopic methods 206 5.2.1 Nuclear Magnetic Resonance Spectroscopy (NMR) 206 5.2.2 Mass spectroscopy (m/z) 207 5.2.3 Infrared Spectroscopy (IR) 207 5.3 Melting points 207 5.4 Chemical methods 208 5.4.1 Aluminium triflate : A Lewis acid catalyst for the 208 alcoholysis of epoxides 5.4.2 Synthesis of piperazine-derived β-amino alcohols 214 via the aluminium triflate mediated ring-opening of epoxides 5.4.2.1 Typical procedure for the preparation of S-glycidyl 214 ethers 5.4.2.2 Typical procedure for the preparation of O-glycidyl 216 ethers 5.4.2.3 Typical procedure for the preparation of -glycidyl 219 ethers 5.4.2.4 Synthesis of the diphenylmethanols 228 5.4.2.5 Preparation of the diphenylmethylchlorides 230 5.4.2.6 Preparation of the diphenylmethylpiperazines 231 5.4.2.7 Typical procedure for the aminolysis of epoxides 233 5.4.3 The nucleophilic substitution of “activated” 249 alcohols using aluminium triflate as a Lewis acid catalyst 5.4.3.1 General procedure for the Al(OTf)3 catalysed 249 nucleophilic substitution of benzhydrol 5.4.3.2 Benzylation of phenols 261 5.4.3.3 Al(OTf)3 catalysed rearrangement of phenol 263 derived benzylic ethers 5.4.3.4 General procedure for the Al(OTf)3 catalysed 265 nucleophilic substitution of trans-1,3diphenylprop2-en1ol 5.4.3.5 Synthesis of 2H-chromenes 273 5.4.3.6 Synthesis of 1,2dihydroquinolines 290 5.4.3.7 Synthesis of 2H-thiochromenes 299 5.5 References 300 Synopsis The work described in this thesis was directed at advancing the applications of Al(OTf)3, a metal triflate, in organic synthesis. Lewis acids play an important role in catalysis and catalyse reactions with high selectivities, unique reactivities under mild conditions. Metal triflates have become the Lewis acids of choice for acid catalysed organic transformations. A detailed literature study of metal triflates provided numerous examples of their use in organic transformations. Al(OTf)3 has been widely neglected as a Lewis acid which is contrasting to the attention the other metal triflates have received. Previous work in our laboratories had established Al(OTf)3 as an effective Lewis acid catalyst for the ring-opening of epoxides with simple alcohols and amines. The alcoholysis of epoxides provides a ready access to β-alkoxy alcohols. Whilst this reaction has been shown to occur with Al(OTf)3 as a catalyst, the established protocol calls for the use of the nucleophilic alcohol in an excess amount. Whilst this proves no problem when simple alcohols are employed as nucleophiles in the ring-opening reaction, it is a problem when more complex and expensive alcoholic nucleophiles are utilised. A modified procedure utilising Al(OTf)3 as a catalyst was developed which tolerates the use of only 1 equivalent of the nucleophilic alcohol for the ring opening reaction. The desymmetrisation of a meso-epoxide with chiral alcoholic nucleophiles was also investigated and the outcome of the diastereoselectivity of the reaction reported. The aminolysis of epoxides has been established utilising Al(OTf)3 as the Lewis acid catalyst. However, this has only been demonstrated for the ring opening of simple epoxides with simple amines. Piperazine derived β-amino alcohols with known biological activity were chosen as substrates with which to test the Al(OTf)3 catalysed aminolysis of epoxides in the synthesis of more complex β-amino alcohols. The various starting epoxides and amine nucleophiles were synthesised. During which a new approach towards the synthesis of - glycidyl amines was developed utilising a two step approach with the first step being i catalysed by Al(OTf)3. It was also found that the optimal method for forming the β-amino alcohol bond was one in which the glycidyl motif was placed on the less basic heteroatom and ring opened by the more nucleophilic piperazine amine. It was also demonstrated that these reactions could be scaled up and the Al(OTf)3 recovered and reused without significant loss in catalytic activity. During the ring-opening of meso-epoxides by chiral alcohols it was found that Al(OTf)3 could promote the nucleophilic substitution of proelectrophilic/“activated” alcohols.