Cooperative Photoredox and N‐Heterocyclic Carbene Catalyzed Fluoroaroylation for the Synthesis of α‐Trifluoromethyl‐Substituted Ketones

Abstract

α‐Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Such compounds are generally accessed through trifluoromethylation of ketones. Here we report an alternative disconnection approach for the construction of α‐CF3 carbonyl compounds by using aroyl fluorides as bifunctional reagents for fluoroaroylation of gem‐difluoroalkenes through cooperative photoredox and N‐heterocyclic carbene (NHC) catalysis. This strategy bypasses the use of expensive or sensitive trifluoromethylation reagents and/or the requirement for ketone pre‐functionalization, thus enabling an efficient and general synthetic method to access α‐CF3‐substituted ketones. A wide variety of gem‐difluoroalkenes and aroyl fluorides bearing a diverse set of functional groups are eligible substrates. Notably, the developed methodology also provides rapid access to mono‐ or difluoroalkyl ketones. Mechanistic studies reveal that merging photoredox catalysis with NHC catalysis is essential for the reaction.

NHC-Mediated Photochemical/Electrochemical Synthesis of Carbonyl Compounds

“…Scheme 17 Synthesis of α-aminoketones from carboxylic acids α-Trifluoromethylated ketones have attracted significant attention as valuable building blocks in organic synthesis. Studer and colleagues [36] reported a new disconnection strategy for the rapid synthesis of α-CF3-substituted ketones from readily available starting materials without CF3-based reagents and selected gemdifluoroalkenes as the substrates (Scheme 19). Using aryl fluorine as a difunctional reagent, they provided an alternative disconnection method for the construction of α-CF3 carbonyl compounds catalyzed by NHC through cooperative photoredox.…”

C−F Bond Insertion: An Emerging Strategy for Constructing Fluorinated Molecules

“…b . Dual NHC/photoredox‐catalyzed 1,2‐fluoroaroylation of gem ‐difluorostyrenes 6 with acid fluorides 2 [13] …”

“…In a follow up paper in 2023, the same group presented a route for synthesis of α‐trifluoromethyl‐substituted ketones 7 using the same cooperative catalytic system (Scheme 2b) [13] . In this setup, however, a radical cation intermediate generated upon single electron oxidation of a gem ‐difluorostyrene 6 ( E 1/2 =1.45 V vs SCE in MeCN) by the excited Ir(III)* photocatalyst, is trapped by the released fluoride ion directly, resulting in the formation of a benzylic radical H .…”

Copper‐Catalyzed Oxidative Trifluoromethylation of Aromatic Alkenes for the Synthesis of α‐Trifluoromethylated Ketones

“…[3] Traditional methods for accessing α-trifluoromethylated ketones rely on the electrophilic or radical trifluoromethylation of enolates or silyl enol ethers, which were prepared in advance from corresponding carbonyl compounds. [4] Recently, several new and elegant mehods to make α-trifluoromethylated ketones has also been developed, [5][6][7][8][9][10][11] including nucleophilic trifluoromethylation of α-haloketones with CuCF 3 , [5] oxidative desulfur-fragmentation and reconstruction of enol triflates, [8] and fluoroaroylation of gem-difluoroalkenes with aroyl fluorides. [10] However, these methods necessitate the use of preformed substrates as the raw materials, which might reduce their efficiency.…”

“…[4] Recently, several new and elegant mehods to make α-trifluoromethylated ketones has also been developed, [5][6][7][8][9][10][11] including nucleophilic trifluoromethylation of α-haloketones with CuCF 3 , [5] oxidative desulfur-fragmentation and reconstruction of enol triflates, [8] and fluoroaroylation of gem-difluoroalkenes with aroyl fluorides. [10] However, these methods necessitate the use of preformed substrates as the raw materials, which might reduce their efficiency. On the contrary, alkenes are abundant, inexpensive and readily available feedstocks and are widely used in chemical industry.…”