Reductive Sulfonamidation of Amides via Zirconium Hydride Catalysis

Keywords

sulfonamides - amides - zirconium - reduction

Significance

Sulfonamides are the largest class of sulfur-containing functional groups in FDA approved drugs. As such, the synthesis of sulfonamides is an important area of research. Typically, secondary sulfonamides are synthesized through N-sulfonylation of amines using sulfonyl chlorides. While this strategy can be effective, there are some limitations including selectivity, stability, and commercial availability. Efforts to employ reductive amination protocols to access secondary sulfonamides have had limited success due to a sulfonamide’s poor nucleophilicity. Additionally, reductive amination is not without limitations; specifically, problems can arise around the stability and availability of the aldehyde partner. A direct reductive sulfonamidation between primary sulfonamides and amides would not only represent novel reactivity but could also overcome the limitations in sulfonamide syntheses outlined above. Here, the authors report a zirconium-catalyzed reductive sulfonamidation between primary sulfonamides and amides, which generates new secondary sulfonamide products.

Comment

Semireductive transformations of amides to imines using zirconium hydrides (Zr-H) have been demonstrated previously. However, complete reduction to amines using Zr-H is challenging. The authors hypothesized that they could overcome this limitation through transamination of the imine intermediate with electron-deficient amines to generate a new imine that is sufficiently electrophilic as to undergo reduction with Zr-H. Successful reductive sulfamidation was achieved between N,N-dimethylbenzamide and p-toluenesulfonamide using catalytic Zr and super-stoichiometric silane. Selective mono-functionalization is achieved generating a secondary sulfonamide. Water sensitivity is mitigated by the addition of molecular sieves. This reaction exhibited broad functional group tolerance, giving a range of products in high yields. Ortho-substituted aryl amides were unsuccessful in this report. Late-stage functionalization of drug molecules was demonstrated. Overall, this is a novel and direct approach to secondary sulfonamides.