Site-selective electrochemical C(sp3)–H late-stage functionalization of pyrazolones

Abstract

Selective activation of inert and ubiquitous C(sp³)–H bonds has long been a challenging task in organic synthesis, through which chemists can directly synthesize value-added compounds from inexpensive and readily available alkane feedstocks. Herein, we report a site-selective electrochemical C(sp³)–H late-stage functionalization of pyrazolones under metal-, oxidant-, and base-free conditions. Notably, this approach exhibits broad substrate scope (116 examples) and enables scalable synthesis (0.5 mol) of ethers through a continuous flow process. Mechanistic investigations suggest that ⁿBu₄NOAc operates not only as an electrolyte but also by making the solution slightly basic via its acetate ion to facilitate deprotonation. In vivo and in vitro bioactivity data demonstrate that compound 65 possesses significant cyclooxygenase-2 (COX-2) inhibitory potency and anti-inflammatory efficacy, positioning it as a promising candidate for the development of novel pharmaceutical entities.