Triple Mode of Alkylation with Ethyl Bromodifluoroacetate: N, or O‐Difluoromethylation, N‐Ethylation and S‐(ethoxycarbonyl)difluoromethylation

Abstract

AbstractIn this report, we have explored a triple mode of chemical reactivity of ethyl bromodifluoroacetate. Typically, bromodifluoroacetic acid has been used as a difluorocarbene precursor for difluoromethylation of soft nucleophiles. Here we have disclosed nucleophilicity and base dependent divergent chemical reactivity of ethyl bromodifluoroacetate. It furnishes lithium hydroxide and cesium carbonate promoted difluoromethylation of tosyl‐protected aniline and electron‐deficient phenols respectively. Interestingly, switching the base from lithium hydroxide to 4‐N,N‐dimethylamino pyridine (DMAP) tosyl‐protected anilines afforded the corresponding N‐ethylation product. Whereas, highly nucleophilic thiophenols furnished the corresponding S‐carboethoxydifluoromethylation product via a rapid SN2 attack to the bromine atom prior to the ester hydrolysis. This mechanistic divergence was established through several control experiments. It was revealed that difluoromethylation reaction proceeds through a tandem in situ ester hydrolysis/decarboxylative‐debrominative difluorocarbene formation and subsequent trapping by the soft nucleophile‐NHTs or electron‐deficient phenolic −OH groups. In the presence of DMAP the hydrolysis of the ester is perturbed instead a nucleophilic attack at the ethyl moiety provides the N‐ethylation product. Hence, besides the development of a practical base‐promoted N‐difluoromethylation of amines and electron‐deficient phenols, divergent reactivity pattern of inexpensive and user‐friendly ethyl bromodifluoroacetate has been explored.magnified image