The widespread presence of hydrocarbons makes C-H functionalization an attractive alternative to traditional cross-coupling methods. As indole is an important heteroarene in a plethora of natural products and pharmaceuticals, C-H functionalization of indole moieties has emerged as one of the most important topics in this field. Due to the presence of multiple C-H bonds in indoles, site selectivity is a long-standing challenge. Much effort has been devoted to the C-H functionalization of indoles at the C3 or C2 position, while accessing the benzene core (from C4 to C7) is considerably more challenging.This Account summarizes our recent efforts toward site-selective C-H functionalization of indoles at the benzene core based on innovative strategies. A common method to solve the issue involves the development of directing groups (DGs). Our early studies establish that the installation of the N-P(O)^tBu₂ group at the N position can produce C7 and C6 arylation products using palladium and copper catalysts, respectively. The developed system can also be extended to direct arylation of indoles at the C5 and C4 positions by installing a pivaloyl group at the C3 position. Further investigation of indoles bearing N-P^tBu₂ groups shows a more diverse reactivity for C-H functionalizations at the C7 position, including arylation, olefination, acylation, alkylation, silylation, and carbonylation with different coupling partners. Compared to the P(V) DG, the P(III) group can be easily attached to the indole substrates and detached from the products. However, these attractive reactions rely mostly on precious metal catalysts with ligands; this requirement can be a significant limitation, particularly for large-scale syntheses and the necessity of removal of toxic trace metals in pharmaceutical products. We have also uncovered a general strategy for chelation-assisted aromatic C-H borylation just using simple BBr₃ under mild conditions, in which the installation of pivaloyl groups at the N1 or C3 position of indoles can selectively deliver the boron species to the unfavorable C7 or C4 positions and allow subsequent C-H borylation without any metal. This transition-metal-free strategy can be extended to synthesize C7 and C4 hydroxylated indoles by boron-mediated directed C-H hydroxylation under mild reaction conditions and with broad functional group compatibility.In this Account, we describe our contributions to this topic since 2015. These studies provide efficient and attractive methods for the divergent synthesis of valuable substituted indoles and insights into the exploration of new strategies for the site-selective C-H functionalization and directives for other important heteroarenes.

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