Photoredox Catalyzed Single C−F Bond Activation of Trifluoromethyl Ketones: A Solvent Controlled Divergent Access ofgem‐Difluoromethylene Containing Scaffolds

Abstract

Selective defluorinative functionalization of trifluoromethyl ketones is a long-standing challenge owing to the exhaustive mode of the process. To meet the demands for the installation of the gem-difluoromethylene unit for the construction of the molecular architectures of well-known pharmaceuticals and agrochemicals, a distinct pathway is thereby highly desirable. Here, a protocol is introduced that allows the divergent synthesis of gem-difluoromethylene group containing tetrahydrofuran derivatives and linear ketones via single CÀ F bond activation of trifluoromethyl ketones using visible-light photoredox catalysis in the presence of suitable olefins as trapping partner. The choice of appropriate solvent and catalyst plays a significant role in controlling the divergent behavior of this protocol. Highly reducing photo-excited catalysts are found to be responsible for the generation of α,α-difluoromethyl ketone (DFMK) radicals as the key intermediate via a SET process. This protocol also results in a high diastereoselectivity towards the formation of partially fluorinated cyclic ketal derivatives with simultaneous construction of one CÀ C and two CÀ O bonds. State-of-the-art DFT calculations are performed to address the origin of diastereoselectivity as well as the divergence of this protocol.

Photocatalytic redox-neutral selective single C(sp3)–F bond activation of perfluoroalkyl iminosulfides with alkenes and water

“…Based on our mechanistic investigations and precedent literature, 55,56 we proposed a plausible reaction mechanism outlined in Fig. 5.…”

Hexafluoroisopropanol (HFIP) as a Multifunctional Agent in Gold-Catalyzed Cycloisomerizations and Sequential Transformations

“…Despite the low nucleophilicity of HFIP and its ability to stabilize cationic species, there are several cases in which the hexafluoroisopropoxy moiety is incorporated, not always intentionally, into the structure of organic molecules acting as substrates or products. ,, This non-innocent behavior of HFIP is anything but a disadvantage when occurring in a controllable manner, as we showcase here, given that the moiety in question may serve as an additional functionalization handle. This has been shown in an early example examining the spontaneous acetalization of enol ethers in HFIP, as well as more recently in the generation of the corresponding HFIP-derived N , O -acetals. , Based on these precedents, as well as the recently reported Rh-catalyzed C–H activation/base-assisted solvolysis of enol esters with TFE, we next explored a sequential transformation.…”

Selective Defluoroalkylation and Hydrodefluorination of Trifluoromethyl Groups Photocatalyzed by Dihydroacridine Derivatives

“…The primary and secondary alcohol-derived trifluoroacetates also reacted smoothly in this protocol, giving compounds (42) and (44). Both naturally occurring bioactive molecules were tolerant (43,45)�in moderate to good yields.…”

“…The existing methods for the selective C–F activation of CF 3 groups can be classified into four categories: (1) Lewis-acid-promoted formation of a difluorocarbocation intermediate; − (2) metal or electrochemical-induced formation of a difluorocarbonanion intermediate; − (3) single electron transfer (SET) or spin-center shift pathways leading to a difluorocarboradical intermediate; − and (4) a carbene strategy catalyzed by rhodium or silver (Scheme a). − Using these strategies, besides defluoroalkylation and hydrodefluorination of trifluoromethylarenes, Zhang’s group reported selective defluoroarylation and Zhang’s group later developed a method for the selective defluorination bifunctionalization of trifluoromethyl aromatics with active alkenes . Although these strategies are now well-established, the selective C–F activation and defluorination functionalization of the CF 3 motif continue to pose challenges due to the high energy of C­(sp 3 )–F bonds and the need to prevent excessive defluorination.…”