Synthesis of 3-Aminobenzisoxazoles Using an Electrophilic Aminating Reagent

Aminobenzisoxazoles are important scaffolds in medicinal chemistry. Traditionally, these heterocycles have been synthesized from 2-fluorobenzonitriles and N-protected hydroxylamines via the SNAr reaction and subsequent cyclization. We have developed a novel, orthogonal method that utilizes 2-hydroxybenzonitriles with O-(diphenylphosphoryl)hydroxyl amine as an electrophilic nitrogen source. This approach inverts the traditional polarity (making the arene the nucleophile) and allows for mild reaction conditions, a broad substrate scope, and extension to a few other heterocycles.