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

Md Imran Hossain; Md Imdadul H Khan; Seong Jong Kim; Hoang V Le

doi:10.3762/bjoc.18.47

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

Beilstein J Org Chem. 2022 Apr 22:18:446-458. doi: 10.3762/bjoc.18.47. eCollection 2022.

Authors

Md Imran Hossain¹, Md Imdadul H Khan¹, Seong Jong Kim², Hoang V Le¹

Affiliations

¹ Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Mississippi 38677, USA.
² Natural Products Utilization Research Unit, United States Department of Agriculture, Agricultural Research Service, University of Mississippi, Mississippi 38677, USA.

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.

Keywords: 1,2,5-oxadiazole 2-oxides; 3,4,5-trisubstituted isoxazoles; environmentally friendly; furoxans; trifluoromethyl-substituted isoxazoles.

Grants and funding

This work was supported by the American Association of Colleges of Pharmacy (2018 New Investigator Award to H. V. L.), the National Institute of General Medical Sciences (P30GM122733 pilot project award to H. V. L.), and funds from the Department of BioMolecular Sciences at the University of Mississippi, School of Pharmacy. The content is solely the responsibility of the authors and does not necessarily represent the official views of these funders.