Reductive Catalytic Difluorocarbene Transfer via Palladium Catalysis

Abstract

A palladium‐catalyzed reductive difluorocarbene transfer reaction that tames difluorocarbene to couple with two electrophiles has been developed, representing a new mode of difluorocarbene transfer reaction. The approach uses low‐cost and bulk industrial chemical chlorodifluoromethane (ClCF2H) as the difluorocarbene precursor. It produces a variety of difluoromethylated (hetero)arenes from widely available aryl halides/triflates and proton sources, featuring high functional group tolerance and synthetic convenience without preparing organometallic reagents. Experimental mechanistic studies reveal that an unexpected Pd0/II catalytic cycle is involved in this reductive reaction, wherein the oxidative addition of palladium(0) difluorocarbene ([Pd0(Ln)]=CF2) with aryl electrophile to generate the key intermediate aryldifluoromethylpalladium [ArCF2Pd(Ln)X], followed by reaction with hydroquinone, is responsible for the reductive difluorocarbene transfer.

Palladium-Catalyzed Difluorocarbene Transfer Enabled Divergent Synthesis of γ-Butenolides and Ynones from Iodobenzene and Terminal Alkynes

“…On the basis of the known research and our previous work, − we proposed a plausible mechanism (Scheme e). First, the oxidative addition of aryl halides 1 leads to the formation of aryl palladium species A .…”

“…Difluorocarbene as a building block has been widely employed in organic synthesis, drug development, and medicinal chemistry, by leading to difluoromethyl ethers, gem -difluorocyclopropanes, and gem -difluoroalkenes from corresponding substrates. Owing to the inherent electrophilicity, difluorocarbene is apt to be captured by a nucleophile to render an anion intermediate in situ, which promptly reacts with an electrophile to enable the production of the difluoroalkylated compounds, however, the palladium-catalyzed coupling reaction of difluorocarbene has only been explored in recent years. − In 2016, Zhang’s group reported the first example of a metal difluorocarbene-involved catalytic coupling reaction . Later on, the same group developed the research of palladium-catalyzed difluorocarbene transfer reaction, which could effectively couple difluorocarbene with proton sources and nucleophilic reagents, including aryl borons and terminal alkynes, and they synthesized, isolated, and characterized the first example of [Pd 0 ]CF 2, which shows strong nucleophilicity and can react with water to produce Pd II –CF 2 H. While [Pd II ]CF 2 exhibits electrophilicity and can be hydrolyzed by water to generate CO (Scheme a right).…”

“…Very recently, the same group disclosed a palladium-catalyzed reductive difluorocarbene transfer reaction utilizing chlorodifluoromethane as the difluorocarbene precursor. The reaction surmounts the characteristic electrophilic properties of difluorocarbene, and difluorocarbene can be harnessed to effectually react with two electrophiles, with hydroquinone as the reductant and proton source (Scheme a left). Our group also reported an interesting Pd-catalyzed difluorocarbene transfer reaction by combining C–H activation to assemble fluoren-9-ones using the ClCF 2 COONa as the carbonyl source …”

Difluorocarbene as a C–F source for the construction of fluorinated benzothiazoles

“…3 e ,8 The coordination model offers new opportunities for difluorocarbene chemistry, 9 and has found applications in the synthesis of unique R-CF 2 -R′ molecules (Scheme 1a, left side). 8 b ,10 In all of the above reactions, difluorocarbene functions as a CF 2 source without the loss of any fluorine atom. Recent studies have shown that difluorocarbene can also act as a nonfluorinated C 1 precursor of various functional groups, such as carbonyl, 8 b ,11 cyanide 12 and isocyanide 13 groups (Scheme 1b).…”

TBAF-Mediated [3+1] Cycloaddition of Difluorocarbene to Access gem-Difluorinated 1,2-Diazetidine Analogues as Potent Anticancer Agents

“…Not surprisingly, it could be successfully captured when various heteroatomic nucleophiles and activated C–H nucleophiles were used, providing CF 2 -containing products . Moreover, a number of transformations with metal difluorocarbene ([M]=CF 2 ) have been published since the pioneering work of Zhang and co-workers in 2015, namely, the metal difluorocarbene involved catalytic coupling (MeDIC) reaction . Despite significant progress, cyclization with difluorocarbene remains a significant challenge due to the limited reaction types .…”