AmericanChemicalSociety.com

The direct preparation of cyclic hydroxamic acids remains a difficult synthetic transformation and these compounds show numerous biological activities.   We have examined and reported on the ring expansion of cyclic ketones with N-hydroxybenzenesulfonamide (Piloty's acid).  Treatment of cyclobutanone or cyclopentanone with N-hydroxybenzenesulfonamide under basic conditions yields the ring expanded cyclic hydroxamic acid in 18-69% yield.  Reactions of substituted cyclobutanones give ring expanded products where the –NOH group regio and stereoselectively inserts to the more substituted position.  This expansion likely proceeds through a mechanism that includes addition of the N-anion of N-hydroxybenzenesulfonamide to the ketone and a C-nitroso intermediate that rearranges to the final product.   These results indicate that any process that leads to a similar C-nitroso intermediate should rearrange to the corresponding cyclic hydroxamic acid.   These pathways are currently being explored for natural product and therapeutic synthesis.