Solvent-less Dehydrogenative C–H Etherification with Alcohols Using Mechanochemistry

Abstract

The aromatic C–H bond etherification with alcohols is one of the most atom-efficient ways to construct aryl ethers. However, it often requires a large excess of alcohols as etherification reagents, which limits the substrate scope (especially for the valuable alcohols). Herein, an alternative mechanochemical C–H bond etherification of oximes with diverse primary and secondary alcohols was developed for the first time. Given the solvent-less condition of ball milling technique, the amount of alcohols used in this chemistry has been significantly reduced (1.5–3.0 equiv to the substrates), thus enabling the incorporation of a wide range of alcohols in the C–H bond etherification for the first time. The present mechanochemical protocol enhances the application prospect of the cross dehydrogenative C–H etherification strategy in the late-stage synthesis of complex aromatic ethers.

A guide to direct mechanocatalysis

“…the highest average length of the polymer chains was obtained after 4 h. Longer milling times resulted in shorter average chain length, an observation that we attributed to the mechanical stress-induced destruction of the polymer. 22 Furthermore, the milling process also causes abrasion of the milling equipment and prolonged milling thus leads to unnecessary contamination of the reaction mixture, as well as the slow wearing down of the milling equipment. As such in mechanochemistry, one often has to fine-tune the reaction time to minimize adverse effects while maximizing the yield of a reaction.…”

“…the highest average length of the polymer chains was obtained after 4 h. Longer milling times resulted in shorter average chain length, an observation that we attributed to the mechanical stress-induced destruction of the polymer. 22 …”

“…17 Indeed, a plethora of catalytic reactions have already been performed in ball mills. Well-known catalytic reactions such as, C-N and C-C cross coupling, 18,19 cycloaddition, 20 polymer reactions, 21 C-H activation 22 were successfully conducted in the ball-mill, although the question whether they process via comparable reaction mechanism or entirely different remains widely unanswered. Interestingly, some of these reactions that were conducted mechanochemically showed remarkable advantages over the corresponding conventional methods.…”

Mechanochemical C−X/C−H Functionalization: An Alternative Strategic Access to Pharmaceuticals

“…Recently, Luo, Xu and coworkers disclosed an efficient Pd‐catalyzed mechanochemical C−H etherification of arenes ( 58 ) with various primary and secondary alcohols ( 59 ) using oxime as the directing group (Scheme 18). [103j] This protocol featured with broad substrate scope and very low alcohols loading (commonly used as solvent or cosolvent in previous methods), which has great potential in the late‐stage synthesis of complex ethers ( 60 a – c ).…”