Alkyl Nitrites: Novel Reagents for One-Pot Synthesis of 3,5-Disubstituted Isoxazoles from Aldoximes and Alkynes

Abstract

An efficient, one-pot approach has been described for the synthesis of 3,5-disubstituted isoxazoles from substituted aldoximes (mixture of E and Z) and alkynes, using alkyl nitrites under conventional heating conditions. The key nitrile oxide intermediates that are required for the synthesis of isoxazoles are formed by treatment of substituted aldoxime with either tert-butyl nitrite or isoamyl nitrite. The generated nitrile oxides underwent in situ [3+2] dipolar cycloaddition to the substituted alkynes to give 3,5-disubstituted isoxazoles regioselectively in high to excellent yields. The developed synthetic methodology was applied for the synthesis of a previously reported potent hDGAT1 inhibitor.

Electrochemical Synthesis of Isoxazoles and Isoxazolines via Anodic Oxidation of Oximes

“…Conversion to the desired isoxazol(in)es requires initial oxidation to their respective nitrile oxides and subsequent 1,3‐dipolar cycloaddition with alkenes or alkynes. Therefore, hazardous and strong oxidizers such as m ‐CPBA in combination with iodobenzene, [11] hypervalent iodine reagents [12] or organo nitrites [13] need to be employed. Another route involves formation of N ‐hydroximidoyl halides which undergo base‐promoted formation of nitrile oxides.…”

Green multicomponent synthesis, antimicrobial and antioxidant evaluation of novel 5-amino-isoxazole-4-carbonitriles

“…Cycloisomerization of α,β-acetylenic oximes [12], cycloaddition of aldoxime and alkynes [13], reaction of alkyl nitriles and α -chlorooximes [14], 1,3-dipolar cycloaddition of in situ generated nitrile oxides and terminal acetylenes [15, 16], addition of hydroxylamine to α -cyano ketones [17] and palladium-catalyzed four-component coupling of a terminal alkyne, hydroxylamine and carbon monoxide [18] are some recently developed methods for isoxazole synthesis. Furthermore, multicomponent reaction of active methylene compounds, aldehydes and hydroxylamine derivatives were well studied under different conditions [19–23].…”