Journal of Organic Chemistry 2000-05-19

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

S D Lepore, M R Wiley

Index: J. Org. Chem. 65(10) , 2924-32, (2000)

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Abstract

Further exploration of the scope of our solid-phase method for the synthesis of 3-aminobenzisoxazoles (using the Kaiser oxime resin 1) is described. The effects of base, leaving group, and solvent on the nucleophilic aromatic substitution based resin-loading reaction are discussed. Representative aryloxime intermediates were subjected to a variety of acidic conditions commonly used in protecting group removal to establish the acid stability profile of this linker. Regioselectivity was evaluated with various di- and trifluorobenzonitriles, 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 plays a critical role in the oxime hydrolysis mechanism. Finally, to establish the compatibility of the aryloxime linker with a variety of useful on-resin synthetic transformations, functionalized substrates were loaded onto resin 1, and carbon-nitrogen, carbon-oxygen, and carbon-carbon bond-forming reactions were successfully executed.