Site‐Selective C–H Alkylation of Arylamines and Unprotected Indoles Enabled by HFIP ‐Mediated Covalently Masked Electrophiles

Comprehensive Summary Triarylmethane scaffolds bearing arylamine or indole moieties are ubiquitous core structures in natural products, pharmaceuticals, and organic functional materials. Site‐selective C–H alkylation offers a straightforward and atom‐economical route to these skeletons, but existing methods generally suffer from poor regiocontrol, reliance on transition metals and preinstalled directing groups, or limited compatibility with free N–H substrates. The HFIP‐based covalently masked electrophile strategy has emerged as a promising metal‐free alternative; however, current systems lack effective regiocontrol and cannot unify arylamine and indole substrates in a single reaction. Herein, we report a general metal‐free site‐selective C(sp 2 )–H alkylation of arylamines and unprotected indoles via HFIP‐mediated covalently masked electrophiles. Using readily available ene‐yne‐ketones as alkylating reagents, stable furan‐based electrophiles are generated in situ by intramolecular cycloisomerization, and the transformation can even be conducted in a one‐pot three‐step manner directly from terminal alkynes. Catalytic B 2 (NMe 2 ) 4 serves as a regioselectivity regulator: through boron‐amine coordination it perturbs the electron density of primary arylamines and boosts para ‐selectivity, typically to ratios exceeding 20 : 1. For indoles, the alkylation site is predictably modulated by the substitution pattern of the substrate, enabling C3‐, C2‐, or C6‐selective functionalization within the same reaction system. The protocol accommodates primary, secondary, and tertiary arylamines as well as unprotected indoles, and features a broad substrate scope with good functional group tolerance. Its synthetic utility is demonstrated by gram‐scale synthesis with recyclable HFIP and by late‐stage functionalization of bioactive molecules such as ibuprofen, flurbiprofen, indomethacin, melatonin, tryptophan, and a dipeptide, as well as diverse further transformations of the products. Mechanistic studies, including trapping of the hexafluoroisopropyl ether intermediate, Hammett analysis, and 1 H NMR experiments, support an intramolecular electrophilic cyclization pathway in which the diboron reagent modulates regioselectivity without participating in the rate‐determining step.