Design and application of α-ketothioesters as 1,2-dicarbonyl-forming reagents

The 1,2-dicarbonyl motif is vital to biomolecules, especially natural products and pharmaceuticals. Conventionally, 1,2-dicarbonyl compounds are prepared via an alpha-keto acyl chloride. Based on the methods used in nature, a transition-metal-free approach for the synthesis of an alpha-ketothioester reagent via the combination of an alpha-hydroxyl ketone, elemental sulfur and a benzyl halide is reported. Mechanistic studies demonstrate that the trisulfur radical anion and the alpha-carbon radical of the alpha-hydroxy ketone are involved in this transformation. The dicarbonylation of a broad range of amines and amino acids, and importantly, cross couplings with aryl borates to construct dicarbonyl-carbon bonds are realized under mild conditions by employing this stable and convenient alpha-ketothioester as a 1,2-dicarbonyl reagent. The dicarbonyl-containing drug indibulin and the natural product polyandrocarpamide C, which possess multiple heteroatoms and active hydrogen functional groups, can be efficiently prepared using the designed 1,2-dicarbonyl reagent.