Bunte Salt-Mediated Functionalization of Kojic Acid at the C-2 Position

This work describes the sulfur-functionalization of kojic acid at the C-2 position, mediated by Bunte salt intermediates. The process involves the reaction of kojyl chloride with sodium thiosulfate to form the corresponding Bunte salt, which is subsequently treated with sodium borohydride. An optimization study was conducted to determine the best reaction conditions for promoting the in situ cleavage of the S–S bond, thereby generating nucleophilic thiol/thiolate species for nucleophilic substitution; this optimization utilized iodomethane to form the methyl sulfide derivative (59% overall yield). Additionally, the C-5 hydroxyl group was selectively protected with a benzyl group, followed by the conversion of the primary hydroxyl group into a chloride. Similarly, this intermediate was successfully transformed into the methyl sulfide derivative by incorporating a deprotection step (55% overall yield). Work is currently underway to expand the reaction scope by varying the halide, with future plans to evaluate the biological potential.