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 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.
Lepore
S D
SD
Eli Lilly and Company, Indianapolis, Indiana, USA.
Wiley
M R
MR
D000577:Amides / Q000737:chemistry; D002851:Chromatography, High Pressure Liquid; D006863:Hydrogen-Ion Concentration; D007202:Indicators and Reagents; D007555:Isoxazoles / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D010091:Oximes / Q000138:chemical synthesis; D012997:Solvents; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
D000577:Amides; D007202:Indicators and Reagents; D007555:Isoxazoles; D010091:Oximes; D012997:Solvents