Synthesis of alpha-fluoro- and alpha,alpha-difluoro-benzenemethanesulfonamides: new inhibitors of carbonic anhydrase

Direct fluorination of arenemethanesulfonamide anions under mild conditions and in high yield has been accomplished using N-fluorobisbenzenesulfonimide, NFSi, on carbanions of N-tert-butyl- and N-bis-(4-methoxyphenylmethyl)- benzenemethanesulfonamides giving novel alpha-fluoro- and alpha,alpha-difluoro-benzenemethanesulfonamides respectively: IC50 and pK(a) data show that alpha-halogenation enhances sulfonamide acidity incrementally and correlates well with increased carbonic anhydrase inhibition, while lipophilicity is also enhanced.