Synthesis of Bicyclic Isoxazoles and Isoxazolines via Intramolecular Nitrile Oxide Cycloaddition.

Wen-Chang Chen,Ching-Fa Yao,Yu-Hsuan Wang,Tang-Hao Yang,Yu-Hsuan Shih,Chun-Wei Kuo,Hao-Hsiang Chiu,Chia-Yu Huang,Veerababurao Kavala

doi:10.3390/molecules200610910

Wen-Chang Chen, Ching-Fa Yao + Show 7 more

Open Access

https://doi.org/10.3390/molecules200610910

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Abstract

An efficient and straight forward procedure for the syntheses of bicyclic isoxazole/isoxazoline derivatives from the corresponding dimethyl-2-(2-nitro-1-aryl/alkyl)-2-(prop-2-yn-1yl)malonates or dimethyl 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonate is described. High yields and simple operations are important features of this methodology.

Highlights

Isoxazole and isoxazoline derivatives are important scaffolds found in many naturally occurring and biologically active compounds [1,2,3,4,5]
We initiated our studies of the reaction by using dimethyl-2-(2-nitro-1-phenylethyl)-2-(prop-2-yn-1yl)malonate
1a was treated with potassium tert-butoxide (2.5 equiv.) and the Yamaguchi reagent (2,4,6-trichlorobenzoyl chloride) in dichloromethane at −78 °C

Summary

Introduction

Isoxazole and isoxazoline derivatives are important scaffolds found in many naturally occurring and biologically active compounds [1,2,3,4,5]. The dehydration of the nitroalkanes followed by intramolecular dipolar cycloaddition is the most popular method for the construction of carbocycle fused isoxazole/isoxazoline derivatives. The literature procedures for the generation of carbocycle fused isoxazole/isoxazoline from various nitroalkane derivatives [43,44,45,46,47] involve the use of phenyl isocyanate and triethylamine, treatment of the nitronate with di-tert-butyl dicarbonate in the presence of catalytic amounts of dimethylaminopyridine (DMAP), the use of chlorformates in the presence trimethylamine and trimethylsilyl chloride (TMSCl) in the presence of trimethylamine. We reported on a different procedure for the construction of bicyclicisoxazole/isoxazoline derivatives by using trichlorotriazine (TCT), chloroformate and phenyl isocyante as dehydrating agents. 2-allyl-2-(2-nitro-1-aryl/alkyl ethyl)malonates using the Yamaguchi reagent as a dehydrating agent

Results and Discussion

General Information

General Procedure for the Preparation of 1a–1o

General Procedure for the Synthesis of 3a–3f

General Procedure for the Preparation of 2a–2o and 4a–4f

Conclusions