Direct nucleophilic difluoromethylation of aromatic isoxazoles activated by electron-withdrawing groups using (difluoromethyl)trimethylsilane

Xin Wang,Etsuko Tokunaga,Norio Shibata

doi:10.14293/s2199-1006.1.sor-chem.ad1qvw.v2

Abstract

Abstract The activation of aromatic diaryl isoxazoles with strong electron-withdrawing groups, such as the nitro, triflyl, and the phenylsulfonyl groups, at the 4-position has enabled the first regio- and diastereoselective difluoromethylation at the 5-position of isoxazoles by nucleophilic addition using (difluoromethyl) trimethylsilane, Me3SiCF2H, to provide difluoromethylated isoxazolines in good yields. Conjugated styryl-4-nitroisoxazoles were also nicely converted into the corresponding CF2H adducts with high regio- and excellent diastereoselectivities. Since the trifluoromethylated analogs of the corresponding diaryl-isoxazolines are effective ectoparasiticides, represented by fluralaner, should a series of difluoromethylated isoxazolines be obtained, they would be of great importance as promising drug candidates in this field.

Highlights

BRAVECTOTM is a highly potent insect and acarid RDL and GluCl inhibitor that was just recently approved in chewable tablets for dogs against fleas and ticks [35]
Nucleophilic difluoromethylation of 1,6-conjugated styryl4-nitro isoxazoles was achieved with Me3SiCF2H under the same reaction conditions to provide CF2H-adducts 4, with high regio- and excellent diastereoselectivities
Wang et al.: Direct nucleophilic difluoromethylation of aromatic isoxazoles can be removed under radical reaction conditions to afford 2 (X = H)

Summary

Introduction

BRAVECTOTM (fluralaner) is a highly potent insect and acarid RDL and GluCl inhibitor that was just recently approved in chewable tablets for dogs against fleas and ticks [35]. Nucleophilic difluoromethylation of 1,6-conjugated styryl4-nitro isoxazoles was achieved with Me3SiCF2H under the same reaction conditions to provide CF2H-adducts 4, with high regio- and excellent diastereoselectivities. Wang et al.: Direct nucleophilic difluoromethylation of aromatic isoxazoles can be removed under radical reaction conditions to afford 2 (X = H).

Results

Conclusion