A methodology for the photocatalyzed radical trifluoromethylation of indoles: A combined experimental and computational study

Abstract

A methodology for the direct introduction of the trifluoromethyl group on to indole scaffolds is presented. The procedure involves the use of sodium trifluoromethylsulfinate (Langlois reagent) as the source of the trifluoromethyl radical, and is performed photochemically with 2-tert-butylanthraquinone as a photocatalyst. The reaction has also been probed computationally. Reaction kinetics and molecular orbital analyses from our quantum chemical computations successfully predict and rationalize the formation of the experimentally observed product and, in the case of 1-methylbenzimidazole, even reproduce the same qualitative trends in regioisomer preference. Lefebvre later reported a hydrotrifluoromethylation method which

Electrophotocatalytic Undirected C−H Trifluoromethylations of (Het)Arenes

“…We attribute this event to the formation of SO 2 . [20] In the presenceo f the photocatalyst (PC) this behavior remained unaltered. However,u pon blue light irradiation, ac onsumption of sodium trifluoromethanesulfinate 2 was observed.…”

“…Very recently, elegant examples of electrophotochemical transformations were achieved by Xu, [17d] Stahl, [17f] Hu, [17c] and Lambert. [17a,b] within our program on sustainable CÀHa ctivation [18] induced by photocatalysis, [19] we have now developed the first electrophotochemical CÀHt rifluoromethylation through single electron transfer (SET) with the inexpensive, solid, and stable Langlois reagent (CF 3 SO 2 Na) [20] (Figure 1). Hence, our strategy set the stage for the merger of sustainable electrochemical and photochemical transformationst owards trifluoromethylation.…”

Recent Developments in Photo‐Catalyzed/Promoted Synthesis of Indoles and Their Functionalization: Reactions and Mechanisms

“…Leadbeater and co‐workers discovered a photocatalyzed radical trifluoromethylation of indoles using trifluoromethylsulfinate (Langlois reagent) as the source of trifluoromethyl radical, 2‐tert‐butylanthraquinone (AQN) as a photocatalyst (Scheme 105). [162] A series of trifluoromethyl‐substituted indoles is obtained in good yield. Furthermore, when using 3‐substituted indoles as substrates, the 2‐CF 3 substituted indoles were obtained.…”

An Efficient Approach to 2-CF3-Indoles Based on ortho-Nitrobenzaldehydes

“…Most synthetic approaches to such indoles can be divided to the methods of direct trifluoromethylation of indole core and cyclizations of various precursors having CF 3 group in appropriate position [ 38 ]. Both radical and electrophilic trifluoromethylations was performed using bis(perfluoroalkanoyl) peroxides [ 48 ], difluorodiiodomethane [ 49 ], hypervalent iodine reagents [ 50 , 51 , 52 , 53 ], CF 3 I [ 54 , 55 , 56 , 57 , 58 ], Umemoto’s reagents [ 59 , 60 ], [(phen)CuCF 3 ] [ 61 ], and CF 3 SO 2 Na [ 62 , 63 , 64 , 65 ]. Cyclization approaches are based on formation of C2-C3 bond as a key step and deal with transformations of compounds having ortho -toluidine fragment [ 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 ].…”