The copper(ii)-catalyzed and oxidant-promoted regioselective C-2 difluoromethylation of indoles and pyrroles

Abstract

A novel and efficient approach for the highly selective C-2 difluoromethylation of indole derivatives was developed by using sodium difluoromethylsulfinate (HCF2SO2Na) as the source of difluoromethyl groups and a Cu(ii) complex as the catalyst.

Difluoromethylation of heterocyclesviaa radical process

“…In 2020, Guo and coworkers developed a practical approach by using HCF 2 SO 2 Na as a fluorinated source to functionalize pyrimidyl indoles at the C-5 position through a Cu-catalyzed radical process (Scheme 6). 42 Multi-substituted pyrimidyl indole derivatives 52–59 have been synthesized by this transformation in moderate to good yields. The direct difluoromethylation of indoles with HCF 2 SO 2 Na occurred regioselectively at the C-2 position of the aromatic ring, and this system has good compatibility with electron-donating groups 53 and 56–58 , and electron-withdrawing groups 54 and 55 regardless of the substituents on either the phenyl ring or N-heterocyclic ring.…”

Direct Difluoromethylation of Heterocycles through Photosensitized Electron Transfer

“…For instance, Baran's group developed that was utilized equivalents tert‐butyl hydroperoxide as oxidant to the direct C−H difluoromethylation of heteroarenes in 2012 (Scheme 1a) [6] . After that, recently, Qing [7] and Guo [8] disclosed strategies to directly difluoromethylation of heteroarenes using Cu(II)‐catalyzed and oxidant (Scheme 1c, Scheme 1d). Using metal‐free and visible light to synthesis of difluoromethylated heterocycle has several samples [9] .…”

Electrochemical-Oxidation-Promoted Direct N-ortho-Selective Difluoromethylation of Heterocyclic N-Oxides

“…First, the difluoromethyl group is weakly acidic and can serve as a lipophilic hydrogen-bond donor to improve the binding selectivity of biologically active compounds. Second, it can also serve as a bioisostere for thiol, alcohol, and amide group functionalities . Therefore, the exploitation of operationally convenient and efficient methods for introducing the difluoromethyl group into the aromatic heterocycle is very meaningful, especially in the pharmaceutical industry.…”