Difluoroalkylated compounds play a remarkably important role in life and materials sciences because of the unique characteristics of the difluoromethylene (CF) group. In particular, precise introduction of a CF group at the benzylic position can dramatically improve the biological properties of the corresponding molecules. As a consequence, difluoroalkylation of aromatic compounds has become a powerful strategy in modulating the bioactivities of organic molecules. However, efficient strategies to selectively synthesize difluoroalkylated arenes had been very limited before 2012. Traditional synthetic methods in this regard suffer from either harsh reaction conditions or narrow substrate scope, significantly restricting their widespread applications, particularly for late-stage difluoroalkylation of bioactive molecules. To overcome these limitations, a straightforward route to access these valuable difluoroalkylated skeletons is the direct introduction of the difluoroalkylated group (CFR) onto aromatic rings through transition-metal-catalyzed cross-coupling. However, because of the instability of some difluoroalkylated metal species, which are prone to protonation, dimerization, and/or generation of other unknown byproducts, it is difficult to selectively control the catalytic cycle to suppress these side reactions. In this context, we proposed the use of low-cost and widely available difluoroalkyl halides as fluoroalkyl sources for transition-metal-catalyzed difluoroalkylation reactions via cross-coupling. In this Account, we summarize our major efforts on copper-, palladium-, and nickel-catalyzed difluoroalkylations of aromatics with low-cost and widely available difluoroalkyl halides as fluoroalkyl sources. Four modes of catalytic difluoroalkylation reactions, including nucleophilic difluoroalkylation, electrophilic difluoroalkylation, radical difluoroalkylation, and metal-difluorocarbene coupling (MeDiC), have been demonstrated through careful modulation of the catalytic systems. Among these reactions, the MeDiC reaction represents a new mode of fluoroalkylation. These processes enable difluoroalkylation of a variety of aryl halides and arylboron reagents under mild reaction conditions. A wide range of difluoroalkyl halides, including activated difluoroalkyl halides (Cl/BrCFR, R = π system), unactivated difluoroalkyl halides (BrCFR, R = alkyl, H), and especially the inert and inexpensive industrial chemical chlorodifluoromethane (ClCFH), are applicable to these reactions, providing straightforward and facile routes to a diverse range of difluoroalkylated (hetero)arenes. These difluoroalkyl halide-based strategies can also be applied to prepare difluoroalkylated alkenes, alkynes, and alkanes and feature impressive advantages over conventional methods for the synthesis of difluoroalkylated compounds in terms of synthetic efficiency, functional group tolerance, and structural diversity. In particular, the late-stage difluoroalkylation of bioactive molecules through these processes offers good opportunities for the...

A straightforward and practical method for direct Pd(OAc)(2)-catalyzed oxidative cross-coupling of electron-deficient perfluoroarenes with aromatic heterocycles has been developed. Because of its low catalyst loading (2.5 mol %), high reaction efficiency, good chemo- and regioselectivity, and excellent functional-group compatibility, this protocol provides a useful and operationally simple access to perfluoroarene-thiophene structures of interest in functional materials for electronic devices.

The palladium-catalyzed difluoroalkylation of aryl boronic acids with bromodifluoromethylphosphonate, bromodifluoroacetate, and further derivatives has been developed. This method provides a facile and useful access to a series of functionalized difluoromethylated arenes (ArCF2 PO(OEt)2 , ArCF2 CO2 Et, and ArCF2 CONR(1) R(2) ) that have important applications in drug discovery and development. Preliminary mechanistic studies reveal that a single electron transfer (SET) pathway may be involved in the catalytic cycle.