Iridium-Catalyzed C–H Activation and Deuteration of Primary Sulfonamides: An Experimental and Computational Study

Abstract

Iridium-catalyzed C–H activation and ortho-hydrogen isotope exchange is an important technology for allowing access to labeled organic substrates and aromatic drug molecules and for the development of further C–H activation processes in organic synthesis. The use of [(COD)Ir(NHC)Cl] complexes (NHC = N-heterocyclic carbene) in the ortho-deuteration of primary sulfonamides under ambient conditions is reported. This methodology has been applied to the deuteration of a series of substrates, including the COX-2 inhibitors Celecoxib and Mavacoxib, demonstrating selective complexation of the primary sulfonamide over a competing pyrazole moiety. The observed chemoselectivity can be reversed by employing more encumbered catalyst derivatives of the type [(COD)Ir(NHC)(PPh3)]PF6. Computational studies have revealed that, although C–H activation is rate-determining, substrate complexation or subsequent C–H activation can be product-determining depending on the catalyst employed.