Synthesis of 3,4,5-trisubstituted isoxazoles in water via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides

Abstract

Herein we report a method for the synthesis of 3,4,5-trisubstituted isoxazoles in water under mild basic conditions at room temperature via a [3 + 2]-cycloaddition of nitrile oxides and 1,3-diketones, β-ketoesters, or β-ketoamides. We optimized the reaction conditions to control the selectivity of the production of isoxazoles and circumvent other competing reactions, such as O-imidoylation or hetero [3 + 2]-cycloaddition. The reaction happens fast in water and completes within 1–2 hours, which provides an environmentally friendly access to 3,4,5-trisubstituted isoxazoles, an important class of structures found in numerous bioactive natural products and pharmaceuticals. Additionally, we optimized the reaction conditions to produce trifluoromethyl-substituted isoxazoles, a prevalent scaffold in biomedical research and drug discovery programs. We also proposed a plausible mechanism for the selectivity of the [3 + 2]-cycloaddition reaction to produce 3,4,5-trisubstituted isoxazoles. Not to be overlooked are our optimized reaction conditions for the dimerization of hydroximoyl chlorides to form furoxans also known as 1,2,5-oxadiazole 2-oxides, a class of structures with important biological activities due to their unique electronic nature and coordination ability.

Trifluoromethyl‐β‐dicarbonyls as Versatile Synthons in Synthesis of Heterocycles

“…N-Hydroximidoyl halides are used as stable nitrile oxide precursors, for [3 + 2]-cycloaddition with dipolarophiles in constructing isoxazoles. [171] Yang et al disclosed regioselective synthesis of 2,6-dimethyl-3,5-bis[(3-aryl-5-trifluoromethyl)-isoxazol-4-carbonyl]-pyridines 266 by 1,3-dipolar cycloaddition of 2,6-dimethyl-3,5-bis(4,4,4-trifluoro-1,3-oxo-butyl)-pyridine 264 with aryl imidoyl chlorides 265 in the presence of potassium bicarbonate using DMF as solvent at room temperature (Scheme 88). [172] Zhang et al reported Et 3 N induced 1,3-dipolar cycloaddition of N-hydroxybenzimidoyl chlorides 265 with ethyl 4,4,4trifluoro-3-oxobutanoate 1 to synthesize fluorinated isoxazoles 267 (Scheme 89).…”

“…Hossain et al developed a fast and environmentally friendly approach to access 3,4,5-trisubstituted isoxazoles 271 by [3 + 2]-cycloaddition of imidoyl chlorides 265 and trifluoromethyl-βdiketones 1 in aqueous medium using N,N-diisopropylethyl-amine (DIPEA) as a base at room temperature (Scheme 90). [171] Nitrile oxides 265 A are generated in situ which undergo cycloaddition with carbanion of 1,3-diketones.…”

“…N ‐Hydroximidoyl halides are used as stable nitrile oxide precursors, for [3+2]‐cycloaddition with dipolarophiles in constructing isoxazoles [171] . Yang et al.…”