A Journey of the Development of Privileged Difluorocarbene Reagents TMSCF2X (X = Br, F, Cl) for Organic Synthesis

Conspectus As fluorine has played an increasingly important role in modulating the physical, chemical, and biological properties of organic molecules, the selective introduction of fluorine atom(s) or fluorinated moieties into target molecules has become a powerful tool in the development of new pharmaceuticals, agrochemicals, and functional materials. In this context, the difluoromethylene (CF 2 ) and difluoromethyl (CF 2 H) groups are of special interest because of their ability to serve as bioisosteres of ethereal oxygen atoms and hydroxyl (OH) and thiol (SH) groups, respectively. Difluorocarbene is one of the most versatile reactive intermediates to incorporate CF 2 and CF 2 H groups; however, before 2006, most of the previously known difluorocarbene reagents suffered from several drawbacks such as using ozone-depleting substances (ODSs), difficult-to-handle reagents, or harsh reaction conditions or having narrow substrate scope and/or low yields. Moreover, the reactivity of difluorocarbene generated from different precursors (reagents) was often unpredictable, since the difluorocarbene generation conditions (activation modes) of various difluorocarbene precursors are different, and these conditions may mismatch those required for subsequent difluorocarbene-involved transformations. Therefore, the development of new environmentally friendly and versatile difluorocarbene reagents, as well as the investigation of the mechanistic insights into difluorocarbene-involved reactions, has been highly desirable. In this Account, we summarize our contributions to the development of new difluorocarbene reagents and their applications in organic synthesis since 2006. We have developed seven new difluorocarbene reagents, including 2-chloro-2,2-difluoroacetophenone ( 1 ), chlorodifluoromethyl phenyl sulfone ( 2 ), S -difluoromethyl- S -phenyl- N -tosylsulfoximine ( 3 ), difluoromethyltri( n -butyl)ammonium chloride ( 4 ), (chlorodifluoromethyl)trimethylsilane (TMSCF 2 Cl, 5 ), (bromodifluoromethyl)trimethylsilane (TMSCF 2 Br, 6 ), and (trifluoromethyl)trimethylsilane (TMSCF 3, 7 ). In this journey, we realized the key factor for an ideal difluorocarbene reagent that can be used for a broad range of reactions, that is, the reagent should allow various activation modes for the generation of difluorocarbene species, such as under basic/acidic/neutral conditions, at wide range of temperatures, and in different solvents, which are compatible with a wide range of difluorocarbene-involved transformations. Among all known difluorocarbene reagents, silanes TMSCF 2 X (X = Br, F, Cl) have stood out as privileged ones, which paves a new avenue for further developing difluorocarbene chemistry. In particular, TMSCF 2 Br was recognized as an “all-rounder”: TMSCF 2 Br can be applied in almost all common difluorocarbene-involved reactions, and more importantly, TMSCF 2 Br also enables many other novel transformations that other difluorocarbene reagents cannot achieve, thanks to its unique structure and rich activation modes of releasing difluorocarbene under different reaction conditions. It can be expected that with the commercial availability of TMSCF 2 X reagents (X = Br, F, Cl) now, the development of difluorocarbene chemistry will be accelerated in the years to come.