N-Heterocyclic Carbene-Catalysed Transformations: the Crossed Benzoin Condensation and Oxidative Aldehyde Esterifications A thesis submitted to Trinity College Dublin, the University of Dublin for the degree of Doctor of Philosophy by Eoghan Delany Under the supervision of Prof. Stephen Connon 2015 Declaration I declare that this thesis has not been submitted as an exercise for a degree at this or any other university and it is entirely my own work. Due acknowledgements and references are given to the work of others. I agree to deposit this thesis in the University’s open access institutional repository or allow the library to do so on my behalf, subject to Irish Copyright Legislation and Trinity College Library conditions of use and acknowledgement. ____________________________ Eoghan Delany 1. E. G. Delany, C.-L. Fagan, S. Gundala, A. Mari, T. Broja, K. Zeitler and S. J. Connon, Chem. Commun., 2013, 49, 6510. 2. E. G. Delany, C.-L. Fagan, S. Gundala, K. Zeitler and S. J. Connon, Chem. Commun., 2013, 49, 6513. 3. S. Gundala, C.-L. Fagan, E. G. Delany, S. J. Connon, Synlett, 2013, 24, 122. Acknowledgements i Abstract ii Abbreviations iii Chapter 1 Introduction 1.0 Organocatalysis: a brief introduction 1 1.1 Carbenes 4 1.1.1 General overview 4 1.1.2 Singlet vs. triplet carbenes 4 1.1.3 Typical reactivity of singlet and triplet carbenes 7 1.1.4 ‘Wanzlick’ carbenes 11 1.1.5 N-heterocyclic carbenes 13 1.1.5.1 Historical overview 13 1.1.5.2 Common N-heterocyclic carbene structures 15 1.2 NHCs and the benzoin condensation 17 1.2.1 Wöhler and von Liebig: discovery of the benzoin condensation 17 1.2.2 The N-heterocyclic carbene-catalysed benzoin condensation 18 1.2.2.1 Mechanism of the thiamine-mediated benzoin condensation 19 1.2.2.2 Lemal and Castells: postulated thiazolylidene dimer-based mechanism and alternative proposals 21 1.3 Crossed acyloin condensations employing NHC organocatalysts 22 1.3.1 Intermolecular NHC-catalysed crossed acyloin condensation 23 1.3.1.1 Chemoselective considerations of the crossed acyloin condensation 24 1.3.1.2 Seminal studies: cyanide- and thiazolylidene-catalysed crossed acyloin condensations 24 1.3.1.3 Triazolylidene-mediated intermolecular crossed acyloin condensations 29 1.3.1.4 Alternative cross-condensation coupling partners 35 1.4 The intermolecular crossed benzoin condensation 37 1.4.1 Scope and limitations 37 1.4.2 Intermolecular cross-coupling of aromatic aldehydes using benzaldehyde lyase 38 1.4.3 Cross-coupling of two non-identical aromatic aldehydes using a thiazolium ion-based precatalyst 40 1.5 The asymmetric benzoin condensation 43 1.5.1 Chiral thiazolium ion precatalysts 43 1.5.1.1 Sheehan’s seminal studies 43 1.5.1.2 Second generation thiazolium salt-based precatalysts 44 1.5.2 The advent of triazolium salts for the asymmetric benzoin condensation 47 1.5.2.1 Enders’ pioneering studies 47 1.5.2.2 Rigid chirality: the fused ring system 48 1.5.2.3 Chiral triazolium precatalysts derived from pyroglutamic acid 52 1.5.3 The asymmetric intermolecular crossed benzoin condensation 55 1.5.3.1 The NHC-catalysed asymmetric intermolecular crossed benzoin condensation 55 1.5.3.2 Alternative approaches for enantioselective synthesis of cross-benzoin derivatives 56 1.6 Alternative fates of the Breslow intermediate: variants on the benzoin condensation 58 1.6.1 The Stetter reaction: overview 58 1.6.1.1 The intermolecular Stetter reaction 59 1.6.1.2 Chiral NHC catalysts for the intermolecular asymmetric Stetter reaction 60 1.6.2 Internal redox chemistry 1.6.3 ‘Homoenolate’ chemistry 62 1.7 NHC-catalysed oxidative aldehyde transformations 65 1.7.1 Aerobic oxidation of aldehydes in NHC-catalysed esterifications 65 1.7.1.1 Aldehyde esterifications in the presence of an external oxidant 65 1.7.1.2 Aldehyde esterifications in the absence of an external oxidant 67 1.7.2 Proposed oxidative/oxygenative pathways for the aerobic oxidationof aldehydes through NHC catalysis 70 1.7.3 Aerobic oxidation of aldehydes in NHC-catalysed amidations 71 1.7.4 Scope and limitations associated with current methodologies 72 Chapter 2 Development of a Chemoselective NHC-Catalysed Intermolecular Crossed Benzoin Condensation 2.1 Intermolecular crossed benzoin condensations: initial considerations 74 2.2 Synthesis of achiral heteroazolium salts 75 2.3 Preliminary studies on the intermolecular crossed benzoin condensation using achiral heteroazolium salts 78 2.4 Rational design of novel achiral triazolium precatalysts based upon preliminary findings 80 2.4.1 Synthesis of novel achiral triazolium salts 81 2.4.2 Evaluation of novel achiral triazolium salts in the intermolecular crossed benzoin condensation 83 2.5 Crossed benzoin condensation: substrate scope of the non-ortho- substituted aromatic aldehyde 84 2.6 Crossed benzoin condensation: substrate scope of the ortho-substituted aromatic aldehyde 87 2.7 Quantifying the chemoselective importance of the ortho-substituent 80 2.7.1 Exploitation of the ortho-bromine as removable functional handle 92 2.7.2 Reductive hydrodebromination of cross-benzoin adducts in the presence of Pd/C 95 2.8 Rationalising the observed chemoselectivity using precatalyst 308 97 2.8.1 Initial considerations 97 2.8.2 Crude NMR analysis: kinetic vs thermodynamic product formation 98 2.8.3 Examining the electrophilicity of 2-bromobenzaldehyde and benzaldehyde 101 2.8.4 Proposed mechanistic rationale for observed chemoselectivity using precatalyst 308 105 2.8.5 Mechanistic studies upon the rate and equibria constants of triazolylidene-mediated processes: alternative considerations 105 2.8.6 Alternative mechanistic considerations 111 2.9 Conclusions 112 Chapter 3 Studies on the Asymmetric Intermolecular Crossed Benzoin Condensation as Catalysed by a Suite of Chiral Bifunctional N- Heterocyclic Carbenes 3.1 Expanding beyond the achiral intermolecular crossed benzoin condensation 115 3.2 Pyroglutamic acid-derived chiral bifunctional triazolium salts precatalysts: design rationale 115 3.3 Synthesis of chiral bifunctional triazolium salts 116 3.3.1 Synthesis of chiral lactam precursors 116 3.3.2 Preparation of substituted arylhydrazine precursors 117 3.3.3 Generation of a suite of chiral triazolium precatalysts possessing a hydroxy functionality 119 3.4 The NHC-mediated asymmetric crossed benzoin condensation between two non-identical aromatic aldehydes 120 3.4.1 Preliminary experiments: base optimisation 120 3.4.2 Preliminary experiments: homogeneous base screening 123 3.4.3 Screening of chiral bifunctional triazolium salts in the asymmetric crossed benzoin condensation 125 3.4.3.1 Assigning the absolute configuration: reductive hydrodebromination of the obtained cross-benzoin adduct 305d 127 3.4.3.2 Effect of the ortho group upon face selectivity 129 3.4.4 Rationalising the observed influence of selected precatalysts upon the enantioselectivity of the reaction 132 3.4.4.1 Quantifying the racemisation of enantioenriched 305d through base-mediated enolisation: deuterium studies 132 3.4.4.2 Quantifying catalyst-mediated racemisation of 305d: plausibility of an E2-type elimination pathway 134 3.4.5 Further optimisation of reaction conditions 138 3.5 Asymmetric crossed benzoin condensation: substrate scope of non-ortho- substituted aromatic aldehyde 142 3.6 Re-evaluation of the ortho-substituted aldehyde: development of an enantioselective system through α-proton chelation 144 3.7 Rationalising for the observed enantioselectivity employing precatalyst 412a in the asymmetric crossed benzoin condensation 147 3.8 Conclusions 154 Chapter 4 NHC-Catalysed Aerobic Aldehyde Esterifications in the Absence of External Oxidants or Co-Catalysts 4.1 NHC-catalysed aerobic esterifications: preamble 156 4.2 Preliminary experiments 156 4.3 Optimisation of reaction conditions 158 4.4 NHC-mediated aldehyde esterification: reaction scope 160 4.4.1 Substrate scope: aldehyde component 160 4.4.2 Substrate scope: alcohol component 162 4.5 Oxidative or oxygenative? Elucidating the reaction pathway 164 4.5.1 Mechanistic studies 165 4.5.2 Proposed pathway 169 4.6 Expanding the scope of the reaction to effect NHC-catalysed aerobic aldehyde amidations 169 4.7 Expansion of the protocol: NHC-catalysed oxidative cleavage of 1,2-diketones 171 4.8 Intramolecular lactone formation through NHC-catalysed oxidative esterifications 172 4.9 Conclusions 175 Experimental 177 References 252 Acknowledgements I would like to begin by thanking my supervisor, Prof. Stephen Connon, for initially taking me on and giving me the chance to complete a PhD. He has a great love for organic chemistry and this is evident in his willingness to always offer advice, ideas and inspiration whenever a problem presented itself. I have learned more under his supervision than I could have hoped from any book. I owe a huge thanks to all those who I have shared a lab with over the past four years – Claudio, Francesco, Emiliano, Neasa, Franciane, Seán, Simon, Lauren, Carole, Esther, Zaida, Cormac, Nagaraju, Michelle, Umar, Vikas, Astrid, Maria-Luisa, Mili, Romain, Chiara, Sarah, Aaron, Bruce. Everyone has contributed in their own little way to the great experience I’ve had. Particular thanks must go to Sivaji for all his help in my first few months; to Claire-Louise for her endless optimism and willingness to help and to Ryan for being the all-round nice guy. For all the proof-reading, I have further thanks for Ryan, Bruce, Claire-Louise and Sarah. To Ian/Godwini, most tales of misadventure from the past four years usually feature you. Looking forward to many more to come! The chemistry department in Trinity has been a fantastic place to conduct research. I would like to thank the technical staff who ensured everything ran as smoothly as possible as I went about my work – Dr. John O’Brien and Dr. Manuel Reuther (NMR), Dr. Martin Feeney (mass spectrometry) and Mr. Patsy Greene. To my parents – you have been a fantastic support, not just over the course of my PhD but throughout every venture I have undertaken in life.