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

Abstract

In 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 Scarboethoxydifluoromethylation product via a rapid S N 2 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/decarboxylativedebrominative difluorocarbene formation and subsequent trapping by the soft nucleophile-NHTs or electrondeficient phenolic ÀOH 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.

Recent Progress on the Synthesis of CF2H-Containing Derivatives

“…Jana and co-workers, in their paper on triple-mode alkylation with BrCF 2 CO 2 Et, presented conditions for the difluoromethylation of N-tosyl-protected anilines and electron-deficient phenols. 93 Using LiOH in DMF at room temperature the reactions afforded the corresponding Ndifluoromethyl tosyl products in good yields for most of the N-tosyl-protected aniline derivatives (40-99%), but did not furnish any product with an o-nitrotosyl derivative. Cs 2 CO 3 was used as the base with electron-deficient phenols and the reactions proceeded smoothly (48-83% yield).…”

Late-stage difluoromethylation: concepts, developments and perspective

“…In 2018, Jana and co-workers disclosed alternative conditions for the difluoromethylation of N-tosyl protected anilines (Scheme 54C). 198 Using an aqueous solution of LiOH in DMF to generate difluorocarbene from BrCF 2 CO 2 Et at room temperature, a broad range of N-difluoromethylated products were accessible. Neither electronic or steric perturbation compromised reactivity.…”

Selective difluoromethylation of ketones promoted by sodium tert-butoxide

“…同年, 刘国凯课题组 [32] 和沈其龙 课题组 [33] 分别用硫鎓盐和硫叶立德为亲电二氟甲基化 试剂, 实现了对β-酮酸酯类化合物的二氟甲基化. 2019 年, 胡金波课题组 , 又能产生二氟卡宾 [19,35] , 前者自由基的产生往 往需要使用过渡金属或光敏剂, 尤其是昂贵的铱光敏 最近, 本课题组 [36,37] 对光催化的二氟烷基化反应 取得较好的研究进展. 我们发现在蓝光催化下, 无需氧 化剂, 能够实现炔烃、烯烃分别与二氟碘乙酸乙酯的 二氟烷基化反应 [36] ; 进一步研究实现了光催化芳基酮 的二氟烷基化反应(图1(b)) [37] .…”