Isotope Effects and the Mechanism of Chlorotrimethylsilane-Mediated Addition of Cuprates to Enones

Kinetic isotope effects were determined for the chlorotrimethylsilane-mediated reactions of cyclohexenone with lithium dibutylcuprate in tetrahydrofuran and with lithium butyl(tert-butylethynyl)cuprate in ether. For the reaction in tetrahydrofuran, the observation of a significant carbonyl oxygen isotope effect (¹⁶k/¹⁷k = 1.018−1.019) and small olefinic carbon isotope effects (¹²k/¹³k = 1.003−1.008) is consistent with rate-limiting silylation of an intermediate π-complex. Theoretically predicted isotope effects for model reactions support this conclusion. Rate-limiting silylation is also supported by relative reactivity studies of chlorotrimethylsilane versus chlorodimethylphenylsilane. The absence of a significant butyl-group carbon isotope effect on product formation indicates that the cuprate butyl groups are nonequivalent in the intermediate leading to the product-determining step. In diethyl ether the isotope effects revert to values similar to those found previously in reactions of cyclohexenone with lithium dibutylcuprate in the absence of chlorotrimethylsilane, consistent with no change in the overall mechanism in this solvent. A mechanistic hypothesis for the differing effects of TMSCl with changes in solvent and substrate is presented.