Deprotonation and Alkylation of Weakly Acidic C(sp3)–H Bonds through In Situ Generation of a Strong Hydride Base from 1,1,3,3-Tetramethyldisiloxane and Potassium tert-Butoxide

The direct deprotonation of weakly acidic C(sp3)–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 (KOtBu) enables the direct alkylation of weakly acidic substrates in a single operational step using simple alkyl halide electrophiles. With a focus on alkylpyridines, a broad range of C–H alkylation products are 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 KOtBu 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 H2 evolution, followed by SN2 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.