Unconventional Transformations of Difluorocarbene with Amines and Ethers

ConspectusFluorine-containing compounds are extensively involved in various fields originating from intriguing and unique characteristics of fluorine atom; notably, in pharmaceuticals, the involvement of a fluorine atom or a fluorine-containing group is a chief technique for improving the pesticide effect and developing new drugs. Difluorocarbene, one of the most important and powerful fluorine-containing reagents, is widely employed and studied in many areas mainly to assemble gem-difluoromethyl molecules, including but not limited to the abundant reactions between difluorocarbene with nucleophilic substrates, Wittig reaction with ketones or aldehydes, cascade reaction with both a nucleophile and an electrophile, or [2+1] cycloaddition with alkenes or alkynes. However, its unconventional and intriguing protocols beyond as a difluoromethyl synthon have rarely been studied, and thus, it is highly desired given its abundance, inexpensiveness and peculiar properties. In this Account, we mainly discuss our discovery with unconventional transformations of difluorocarbene, instead of as a sole difluoromethyl source (different from other dihalocarbene), actually can serve as an electron acceptor to activate C-X bonds (X = N and O) and thus promote a myriad of fascinating transformations for the assembly of versatile valuable products with various aza-compounds (primary/secondary/tertiary amines as well as NH₃ and NaNH₂ and so on) and aliphatic ethers in the absence of transition metals and expensive ligands. Inspired by the electron-deficient characteristics of difluorocarbene, we first found that the isocyanides could be readily formed in situ when the unoccupied orbital of difluorocarbene meets the lone-pair of primary amines; in basic condition, a cascade defluorination and cyclizations could afford plethora of valuable N-containing heterocycles. Meanwhile, we disclosed that cyano anion could be accessible in situ as well when difluorocarbene and NaNH₂ or NH₃ were mixed up in suitable basic conditions, and thus a series of aryl nitrile compounds were obtained in the presence of Pd catalysis and ArI. Interestingly, when difluorocarbene encountered secondary amines, formamides were rendered under mild reactions. Of note, concomitant functionalizations of C and N moieties via cleavage of the unstrained C(sp³)-N bond in the absence of metal and oxidant are sparce, which indeed significantly add versatility and diversity to products. Gratifyingly, by uitilizing difluorocarbene and cyclic tertiary amines, we achieved difluorocarbene-mediated deconstructive functionalizations for the first time, showing successive C(sp³)-N bond scission of amines and simultaneous functionalization of C and N atoms which would be introduced into the products in the absence of transition metals and oxidants. This method provides a brand-new while very universal synthetic pathway to selectively cleave inert unactivated Csp³-N bonds, in which halodifluoromethyl reagents act as both C1 synthon and halo (Cl, Br, I) sources. Fascinatingly, nitrogen ylides are generated in situ from difluorocarbene and tertiary amines, and an intriguing and universal approach for deaminative arylation or alkenylation of tertiary amines was disclosed for the first time in appropriate basic conditions, which represents an intriguing reaction mode to lead to a formal transition-metal free Suzuki cross coupling. Besides, we also disclosed that difluorocarbene could proceed novel atom recombination to render meaningful 2-fluoroindoles or 3-(2,2-difluoroethyl)-2-fluoroindoles from ortho-vinylanilines, 3-fluorined oxindoles from 2-aminoarylketones, in which difluorocarbene acts as a C1 synthon and F1 source simultaneously. Last but not the least, we recently found that the lone-pair-electron of oxygen could trap difluorocarbene as well to form oxonium ylide, which eventually leads to C-O bond cleavage with the formation of difluoromethyl ethers.