MECHANISTIC INVESTIGATIONS OF RHODIUM- CATALYZED ALKYNE HYDROTHIOLATION by Matthew James Wathier B.Sc.H., Queen’s University, 2009 A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF DOCTOR OF PHILOSOPHY in THE FACULTY OF GRADUATE AND POSTDOCTORAL STUDIES (Chemistry) THE UNIVERSITY OF BRITISH COLUMBIA (Vancouver) September, 2016 © Matthew James Wathier, 2016 Abstract Herein, thorough mechanistic investigations into alkyne hydrothiolation catalyzed by I [Tp*Rh (PPh3)2] (Tp* = tris(3,5-dimethylpyrazolyl)borate) are reported. The mechanism is shown to proceed through an intermediate [Tp*RhIIIH(SR)] complex (R = alkyl, aryl). Alkyne migratory insertion is shown to occur chemoselectively into the Rh-SR bond, despite the availability of a Rh-H bond, to produce a rhodathiacyclobutene intermediate. The regioselectivity of product formation is revealed to be the result of a competition between 1,2 and 2,1 migratory insertion of the alkyne to produce regioisomeric rhodathiacyclobutene intermediates. Product formation occurs upon reductive elimination, which is associatively induced by coordination of thiol. Putative off-cycle intermediates [Tp*RhH(SR)(PMe3)] (R = alkyl, aryl) have been successfully synthesized from [Tp*RhH(CH3)(PMe3)]. The mechanism of formation of the [Tp*RhH(SR)(PMe3)] complexes is proposed to involve the reductive elimination of methane, associatively induced by coordination of thiol. This mechanism is analogous to the mechanism proposed for alkyne hydrothiolation catalyzed by [Tp*Rh(PPh3)2]. Alkyne hydrothiolation reactions in the presence of [Tp*RhH(SR)(PMe3)] are shown to produce the same product regioisomer as reactions catalyzed by [Tp*Rh(PPh3)2]. The synthesis of the vinyl sulfone-containing drug K777, currently in clinical trials for the treatment of Chagas disease, via alkyne hydrothiolation methodology catalyzed by [RhCl(PPh3)3], is reviewed. The methodology proves to be versatile in the synthesis of K777 and related analogues. The analogues are assessed in terms of their reactivity towards Michael addition as a method of predicting pharmacodynamics properties. ii The methanolic pKAs of a series of para-substituted aryl thiols are reported and correlated to their predicted aqueous pKA values. The Hammett dual parameter correlation to the experimental data reveals that the acidity constants are more dependent on the inductive effects of the para-substituent compared to the resonance effect. The dual parameter correlation also allows for the prediction of the methanolic and aqueous acidity constant of any para-substituted aryl thiol, as long as the substituent’s resonance and induction Hammett constants are known. iii Preface A version of the review of hydroelementation of carbon-carbon unsaturated bonds catalyzed by metal-scorpionate complexes presented in Chapter 2 has been published in the European Journal of Inorganic Chemistry. I was responsible for writing the manuscript, while Dr. Jennifer A. Love was responsible for editing the manuscript. Doi: 10.1002/ejic.201501272 A version of Chapter 4 has been published in Organic Letters. The synthesis of K777 described in 4.2.1 was performed by Erica R. Kiemele. I was responsible for the kinetic assays of Michael addition relating to expected potency in Cruzain inhibition, writing of the manuscript and supporting information. E. R. Kiemele, M. Wathier, P. Bichler, J. A. Love. Org. Lett. 2016, 18, 492−495. In conjunction with Moonhee Lee and Dr. Patrick McGeer, from the Kinsmen Laboratory of Neurological Research, Department of Psychiatry at UBC, and Aurin Biotech, I was responsible for the synthesis of compounds with potential application in the treatment of, among others, Alzheimer’s and Parkinson’s disease. M. Lee, M. Wathier, J. A. Love, E. McGeer, P. L. McGeer, Neurobiology of Aging, 2015, 36, 2748-2756. iv Table of Contents Abstract ........................................................................................................................................... ii Preface............................................................................................................................................ iv Table of Contents ............................................................................................................................ v List of Tables .................................................................................................................................. x List of Figures ................................................................................................................................ xi List of Schemes ........................................................................................................................... xvii List of Abbreviations .................................................................................................................... xx Acknowledgements .................................................................................................................... xxvi Dedication ................................................................................................................................. xxvii Chapter 1 Introduction ............................................................................................................... 1 1.1 Sulfur-Containing Compounds ................................................................................. 1 1.2 Synthetic Methods Towards Vinyl-Sulfides ............................................................. 3 1.2.1 Alkyne Hydrothiolation ............................................................................................ 4 1.2.2 Transition Metal Catalyzed Alkyne Hydrothiolation ............................................... 6 1.3 Mechanisms of Metal-Catalyzed Hydrothiolation .................................................. 10 1.3.1 Class I Mechanisms ................................................................................................ 10 1.3.2 Class II Mechanisms ............................................................................................... 11 1.3.2.1 Regioselectivity in Class II Mechanisms ............................................................ 15 1.4 Insertions into Rhodium-Heteroatom Bonds .......................................................... 18 1.4.1 Systems with Direct Evidence for Rhodium-Heteroatom Insertion ....................... 18 1.4.2 Systems with Indirect Evidence for Rhodium-Heteroatom Insertion ..................... 22 1.5 Thesis Outline ......................................................................................................... 28 Chapter 2 Review of Hydroelementation of Carbon-Carbon Unsaturated Bonds Catalyzed by Metal-Scorpionate Complexes ...................................................................................................... 29 2.1 Hydrothiolation of Alkynes .................................................................................... 32 2.1.1 Alkyne Hydrothiolation Catalyzed by Tris(pyrazolyl)borate Complexes of Rhodium ................................................................................................................................ 34 2.2 Hydroamination ...................................................................................................... 40 2.2.1 Hydroamination with Homoscorpionate Ligands ................................................... 41 2.2.2 Hydroamination with Heteroscorpionate Ligands .................................................. 49 2.3 Hydroalkoxylation of Alkynes ................................................................................ 56 2.3.1 Cyclization of Alkynoic Acids................................................................................ 57 v 2.4 Hydrophosphinylation of Alkynes .......................................................................... 61 2.5 Conclusion .............................................................................................................. 63 Chapter 3 Substrate-Activity Relationships in Mechanistic Elucidation ................................ 65 3.1 Introduction ............................................................................................................. 65 3.1.1 Linear Free Energy Relationships ........................................................................... 66 3.1.2 Interpretation of ρ ................................................................................................... 68 3.1.3 Hammett σ- and σ+ constants ................................................................................. 68 3.1.4 Dual substituent parameter LFER ........................................................................... 69 3.2 Measurement of Aryl Thiol pKA in Methanolic Solution ....................................... 71 3.2.1 Single and Dual Parameter Hammett Treatment of Aryl Thiol pKA Values .......... 75 3.3 Conclusion .............................................................................................................. 81 3.4 Experimental ........................................................................................................... 82 3.4.1 Measurements of Acidity Constants of Substituted Aryl Thiols in Methanol ........ 82 Chapter 4 Application of Alkyne Hydrothiolation in the Synthesis of K777 ......................... 83 4.1 Chagas Disease ....................................................................................................... 83 4.1.1 Existing Treatments for Chagas Disease ...............................................................