Studies on the synthetic compatibility of aryloxime linkers in the solid-phase synthesis of 3-aminobenzisoxazoles

Further exploration of the scope of our solid-phase method for the synthesi s of 3 -aminobenzisoxazoles (using the Kaiser oxime resin 1) is described. The effects of base, leaving group, and solvent on the nucleophilic aromati c substitution based resin-loading reaction are discussed. Representative a ryloxime intermediates were subjected to a variety of acidic conditions com monly used in protecting group removal to establish the acid stability prof ile of this linker. Regioselectivity was evaluated with various di- and tri fluorobenzonitriles, which gave single benzisoxazole products after loading and cyclorelease reactions. Substituent effects observed in the course of the acid stability and regioselectivity studies suggest that the nitrile pl ays a critical role in the oxime hydrolysis mechanism. Finally, to establis h the compatibility of the aryloxime linker with a variety of useful on-res in synthetic transformations, functionalized substrates were loaded onto re sin 1, and carbon-nitrogen, carbon-oxygen, and carbon-carbon bond-forming r eactions were successfully executed.