Harnessing the TEMPO-Catalyzed Aerobic Oxidation for Machetti-De Sarlo Reaction toward Sustainable Synthesis of Isoxazole Libraries

Abstract

A practical synthesis of isoxazole/isoxazoline derivatives via Machetti-De Sarlo reaction under sustainable conditions has been accomplished. This protocol involves the use of readily available 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) to catalyze the cyclocondensation of primary nitroalkanes with alkynes/alkenes to afford a library of isoxazole/isoxazoline products. From an eco-benign perspective, notable advantages of this method are as follows: (i) water as the solvent, (ii) air as the oxidant, (iii) transition metal-free, (iv) no base required, (v) no toxic byproduct, (vi) no need of solvent extraction, (vii) diverse substrate scope, (viii) high chemical yields, (ix) excellent chemo- and regioselectivity, (x) short reaction time, (xi) gram-scale synthesis, (xii) extension to heterogeneous version, and (xiii) catalyst recyclability. For these reasons, the developed method is appropriate for safe laboratory use and can be expected to inspire the progress of TEMPO-based organocatalysis for the preparation of isoxazole/isoxazoline moieties in an environmentally benign fashion.