Visible-Light-Induced para-Difluoroalkylation of Aniline Derivatives

Abstract

Visible-light-induced, iridium catalyzed, para-selective C–H difluoroalkylation of aniline derivatives under mild reaction conditions is reported. Various substrates and bioactive compounds, such as precursors of vorinostat and chlorpropham, were all well tolerated. This protocol features a wide substrate scope, high regioselectivity, low catalyst usage, and operational simplicity.

Direct Perfluoroalkylation of C−H Bonds in (Hetero)arenes

“…Subsequently, the Liu group extended these processes to the direct difluoroacetamidation and the difluoromethylenephosphonylation of (hetero)arenes by using a very similar photocatalytic system and a large excess of the starting (hetero)aromatic substrate (Scheme 46, Equation (3)) [114] . Additionally, the Bai, Chen, Wang and Zhang group also recently reported the perfluoroalkylation of nitroimidazoles in a similar manner [115] and the Li, Shi and Zhao group reported the para ‐selective difluoroalkylation of aniline derivatives [116] . The mechanism of theses reactions relies on the reduction of the difluoroalkyl bromide by the excited state of the iridium(III) photocatalyst to afford the key difluoroalkyl radical species that can then perform the alkylation of the (hetero)arene, as previously discussed.…”

“…[114] Additionally, the Bai, Chen, Wang and Zhang group also recently reported the perfluoroalkylation of nitroimidazoles in a similar manner [115] and the Li, Shi and Zhao group reported the para-selective difluoroalkylation of aniline derivatives. [116] The mechanism of theses reactions relies on the reduction of the difluoroalkyl bromide by the excited state of the iridium(III) photocatalyst to afford the key difluoroalkyl radical species that can then perform the alkylation of the (hetero)arene, as previously discussed.…”

Copper-catalyzed selective C5-H bromination and difluoromethylation of 8-aminoquinoline amides using ethyl bromodifluoroacetate as the bifunctional reagent

“…1a, Wang, Zhao, Wu, and Jin, performed the ethoxycarbonyldifluoromethylation of 8-aminoquinolines with the aid of Ni, Ru, Cu, and Ir catalysts through direct C5-H functionalization employing ethyl bromodifluoroacetate as the difluoromethylation reagent. 20 These intelligent strategies demonstrated that ethyl difluorobromoacetate is an excellent reagent for introducing the CF 2 CO 2 Et group on the C5-position of 8-aminoquinolines.…”

Synthesis of α-Fluorinated Areneacetates through Photoredox/Copper Dual Catalysis

“…Although significant progress has been made in recent years, the development of direct (di)­fluoroalkylation reactions of arenes is still underexploited . Among examples reported recently, many include the use of thermal reactions catalyzed by transition metals (palladium, nickel, copper, or even ruthenium) and visible-light-induced C–H activation of electron-rich arenes (Scheme ).…”

“…Dihalogenated aromatic boronic acids underwent selective difluoroalkylation, with better results being achieved with the meta regioisomers. Thus, ethyl difluoro acetates 3j–m and 3q–s were formed in moderate to good yields, leaving a halide handle intact for further diversification of their structures by well-established procedures, and showcasing the complementarity of this method with respect to other difluorination procedures. − Additionally, sterically hindered dibenzo­[ b , d ]­furan-4-ylboronic acid was successfully incorporated ( 3y ), as well as multifunctional boronic acids ( 3w and 3x ). To establish the synthetic utility of this photoredox/copper dual catalysis, ethyl difluoro acetate 3q was synthesized on a gram scale from (3-chlorophenyl)­boronic acid.…”