Access to Difluoromethylated Arenes by Pd-Catalyzed Reaction of Arylboronic Acids with Bromodifluoroacetate

Abstract

An unprecedented example of Pd-catalyzed difluoromethylation of aryl boronic acids with bromodifluoroacetate is described. The reaction proceeds under mild reaction conditions with hydroquinone and Fe(acac)3 as additives. Preliminary mechanistic studies reveal that a difluorocarbene pathway is involved in the reaction, which is unusual compared to the most traditional approaches. This reaction has advantages of high efficiency and excellent functional group compatibility, even toward bromide and hydroxy group, thus providing a useful protocol for drug discovery and development.

Difluoroacetic Acid as a New Reagent for Direct C−H Difluoromethylation of Heteroaromatic Compounds

“…Based on our observation and the recent mechanistic studies, we propose the mechanism depicted in Scheme for mono‐difluoromethylation of quinoline. Specifically, we proposed that the formation of difluoromethyl radical is evoked by silver(I)‐catalyzed oxidative decarboxylation of difluoroacetic acid by persulfate and subsequent addition to the heteroaromatic ring.…”

“…Currently, synthetic chemists pay great attention to the development of novel metal‐catalyzed difluoromethylation reactions . Nevertheless, these reactions rely on substitution of a halogen atom,– a boronic acid, a triflyloxy group or diazonium salt with the difluoromethylated sources, respectively. The preparation of difluoromethylated compounds via silver‐catalyzed decarboxylation of α‐fluoroarylacetic acids, α,α‐difluoroarylacetic acids were also reported .…”

Pd‐Catalyzed Selective Carbonylation of gem‐Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters

“…[4] Moreover, the difluoromethyl group is recognized as being isosteric and isopolar with alcohols [5] or thiols. [7] Although significant advancements have been made in the direct introduction of CF 2 Hg roup into organic compounds, [8] including electrophilic, [9] nucleophilic, [10] free-radical, [11] and difluorocarbene-involving [12] reactions,t he preparation of functionalized difluoromethyl and a,a-difluoroalkyl carbonyl compounds is still highly desired. [7] Although significant advancements have been made in the direct introduction of CF 2 Hg roup into organic compounds, [8] including electrophilic, [9] nucleophilic, [10] free-radical, [11] and difluorocarbene-involving [12] reactions,t he preparation of functionalized difluoromethyl and a,a-difluoroalkyl carbonyl compounds is still highly desired.…”

Pd‐Catalyzed Selective Carbonylation of gem‐Difluoroalkenes: A Practical Synthesis of Difluoromethylated Esters

“…[6] Thus,atpresent there is astrong interest to replace hydroxyl, amino,o rt hio substituents by CF 2 H groups within lead structures of pharmaceuticals. [7] Although significant advancements have been made in the direct introduction of CF 2 Hg roup into organic compounds, [8] including electrophilic, [9] nucleophilic, [10] free-radical, [11] and difluorocarbene-involving [12] reactions,t he preparation of functionalized difluoromethyl and a,a-difluoroalkyl carbonyl compounds is still highly desired.…”