Aza-oxyallyl cation-mediated synthesis of α-sulfonyl hydroxamic acid derivatives from α-halo hydroxamates and sodium sulfinates

Abstract

α-Sulfonyl hydroxamic acid derivatives are important pharmacophores with wide-ranging applications in medicinal chemistry, particularly as enzyme inhibitors targeting metalloproteins such as MMPs, HDACs, and TACE. Here, we report a straightforward and efficient method for the synthesis of α-sulfonyl hydroxamic acid derivatives directly from α-halo hydroxamates via an aza-oxyallyl cation pathway. The transformation proceeds through nucleophilic substitution of α-halo hydroxamates with sodium sulfinates in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) under mild, base-mediated conditions, delivering the desired α-sulfonyl hydroxamic acids in good to excellent yields at room temperature. The developed method is compatible with a wide range of substituents on both the halo hydroxamate and the sulfinate partner, including aryl, heteroaryl, and alkyl groups, thereby providing a broad substrate scope.