Direct Synthesis of 1,2-Benzoisoxazol-3-amines from 2-Fluorobenzonitriles with Hydroxylamine Hydrochloride

Abstract 1,2-Benzoisoxazol-3-amines are obtained in 52–96% isolated yields directly from 2-fluorobenzonitriles using a combination of hydroxylamine salts and quaternary ammonium hydroxide bases in aqueous media, as opposed to the literature precedent that requires lengthy synthesis or the use of hazardous hydroxylamine derivatives. This streamlined approach improves operational safety and atom economy, simplifying access to medicinally relevant motifs. Mechanistic experiments and DFT calculations support an SNAr-first pathway with rate-limiting substitution followed by rapid cyclization.