Palladium-Catalyzed Remote C-H Phosphonylation of Indoles at the C4 and C6 Positions by a Radical Approach.

Palladium-catalyzed direct C-H activation of indole benzenoid moiety has been achieved in the past decade. However, palladium-catalyzed remote C-H activation of indoles is rare. Herein, we report a challenging palladium-catalyzed remote C4-H phosphonylation of indoles by a radical approach. The method provides access to a series of C4-phosphonylated indoles, including tryptophan and tryptophan-containing dipeptides, which are typically inaccessible by direct C4-H activation due to its heavy reliance on C3 directing groups. Notably, unexpected C6-phosphonylated indoles were obtained through blocking of the C4 position. The preliminary mechanistic studies indicated that the reactions may proceed via a C7-palladacycle/remote-activation process. Based on the strategy, examples of remote C4-H difluoromethylation with BrCF2 COOEt are also presented, suggesting that the strategy may offer a general blueprint for other cross-couplings.