Deprotonation and Alkylation of Weakly Acidic C(sp 3 )─H Bonds Through In Situ Generation of a Strong Hydride Base From 1,1,3,3‐Tetramethyldisiloxane and Potassium tert ‐Butoxide

Abstract

ABSTRACT The direct deprotonation of weakly acidic C(sp 3 )─H bonds remains a fundamental strategy for generating carbon nucleophiles, but typically requires strong bases, cryogenic conditions, and stepwise protocols. A general method enabling single‐step deprotonation and alkylation of these substrates remains elusive. Herein, we report that a combination of 1,1,3,3‐tetramethyldisiloxane (TMDSO) and potassium tert‐butoxide (KO t Bu) enables the direct alkylation of weakly acidic substrates, particularly 2‐alkyl and 4‐alkyl pyridines, in a single operational step using simple alkyl halide electrophiles. A broad range of C─H alkylation products is obtained via in situ activation and alkylation, without the need for preformation of organometallic intermediates. Mechanistic experiments and DFT calculations support a pathway in which TMDSO and KO t Bu cooperatively generate a transient, substrate‐associated hydridic base with KH‐like reactivity. Key substrate—potassium interactions, including N‐coordination and cation– π binding, preorganize the system and enable rate‐determining deprotonation with concurrent H 2 evolution, followed by S N 2 alkylation. These findings reveal a distinct mode of base activation that combines high basicity with unusual tolerance of alkyl halides, providing a practical approach to the alkylation of weakly acidic C─H bonds.