Synthesis of Heteroarylsulfonium Salts and Their Applications in Organic Synthesis

Abstract

This thesis describes the development of a scalable synthetic protocol for the preparation of heteroarylsulfonium salts, and the application of these salts in sulfur-mediated ligand-coupling reactions to synthesise bis-heteroaryls. The reactivity of novel heteroarylsulfonium salts in transition metal-catalysed cross-couplings is also discussed. Herein, a highly S-selective arylation methodology for the preparation of heteroarylsulfonium salts is reported. Heteroarylsulfides are reacted with iodonium salts under Cu-catalysed conditions, producing the desired heteroarylsulfonium salts on gram-scale in good yields (20 examples, 34-99%). The methodology for the synthesis of heteroarylsulfonium salts is functional group tolerant and the salts synthesised have demonstrated bench stability for >24 months. The heteroarylsulfonium salts reported are predominantly 2-pyridylsulfonium salts, however, pyrimidinylsulfonium and quinolinylsulfonium salts have also been prepared successfully. The synthetic utility of heteroarylsulfonium salts was then explored in sulfur-mediated ligand-couplings, the first time these reagents have been applied in such reactions. The reaction of heteroarylsulfonium salts with organolithium and Grignard reagents was shown to generate bis-heteroaryl products in good-to-excellent yields (up to 98%). Nucleophilic attack of the organometallic reagent on sulfur is proposed to lead to the formation of a hypervalent sulfurane intermediate, which collapses to give ligand-coupling products. Wide functional group tolerance has been demonstrated in the synthesis of >60 bis-heteroaryl products and 2,2’-, 2,3’- and 2,4’-linked bipyridines, as well as other bis-heteroaryl linkages, were accessible. Finally, this new synthetic methodology for the synthesis of bis-heteroaryls was applied to the synthesis of the natural products caerulomycin A (32%, 5 steps), caerulomycin E (35%, 4 steps) and the shortest synthesis of collismycin A (12%, 6 steps). The sulfur-mediated ligand-coupling methodology was also applied in the preparation of 3 functionalised, unsymmetrical 2,2’-bipyridines. These bipyridine ligands will be complexed to Ru and the photophysical properties of the resulting complexes will be investigated. Preliminary investigations into the use of heteroarylsulfonium salts as pseudohalides in transition metal-catalysed cross-coupling reactions are also reported.