Nickel‐Catalyzed Regioselective C(2)−H Difluoroalkylation of Indoles with Difluoroalkyl Bromides

Abstract

Regioselective C(2)-H difluoroalkylation of C-3 unsubstituted indoles with commonly available fluoroalkyl bromides is successfully achieved employing a simple nickel catalyst system, (DME)NiCl /Xantphos. This methodology shows excellent regioselectivity and exhibits a broad substrate scope. Various functional groups, such as -OMe, -F, and -Br, are tolerated on the indole backbone to give the difluoroalkylated products in moderate to good yields. Preliminary mechanistic findings demonstrate that the reaction is homogeneous in nature and involves a radical manifold. Synthetic utility of this nickel-catalyzed method is demonstrated by synthesizing melatonin receptor antagonist Luzindole derivative.

Nickel‐Catalyzed C−H Bond Functionalization of Azoles and Indoles

“…Recently, we have shown the regioselective C-2 difluoroalkylation of indoles with fluoroalkyl bromides (Scheme 16b). [51] In this report, an air-stable (DME)NiCl 2 /Xantphos catalyst system was employed without using a directing group. The reaction tolerated diverse substitution on the indole backbone.…”

“…Substantial substrate scope has been demonstrated using Ni(II)/dppb (1,4‐bis(diphenylphosphino)butane) catalyst system. Recently, we have shown the regioselective C‐2 difluoroalkylation of indoles with fluoroalkyl bromides (Scheme 16b) [51] . In this report, an air‐stable (DME)NiCl 2 /Xantphos catalyst system was employed without using a directing group.…”

C−H Functionalization of Indoles by 3d Transition‐Metal Catalysis

“…The authors demonstrated the removal of directing groups and synthesized the biologically active Luzindoles. In addition to simple benzylation protocol, the group came up with regioselective C(2)−H difluoroalkylation of indoles with readily available fluoroalkyl bromides (Scheme ) . In this report, operationally simple (DME)NiCl 2 /Xantphos catalyst system was employed without the use of a directing group.…”

“…In addition to simple benzylation protocol, the group came up with regioselective C(2)À H difluoroalkylation of indoles with readily available fluoroalkyl bromides (Scheme 30). [63] In this report, operationally simple (DME)NiCl 2 / Xantphos catalyst system was employed without the use of a directing group. Various functional groups, such as À OMe, À F, and À Br were tolerated on the indole backbone.…”

Ligand- and Additive-Free 2-Position-Selective Trifluoromethylation of Heteroarenes Under Ambient Conditions

“…Recently, directing group (DG) has emerged as a powerful tool to achieve regioselective C2-H functionalization of indoles (Nishino et al, 2012; Zhou et al, 2013; Yu et al, 2014). For example, Shi group and Punji group, respectively, achieved trifluoroethylation and difluoroalkylation of indoles at C2 position by introducing a directing group at the N -center of indoles (Scheme 2B; Yan et al, 2017; Soni et al, 2018). Also, Sodeoka group, Cho group, and Shi group accomplished trifluoromethylation of indoles at the C2 position with Togni's reagent, CF 3 I and CF 3 SO 2 Na respectively.…”