Alkylation to Ketones with Grignard Catalyzed by Zinc(II) Chloride

J. Am. Chem. Soc., 128 (31), 9998 -9999, 2006.

For carbon-carbon bond-forming reactions, the addition of organometal reagents to ketones is a versatile method for synthesizing tertiary alcohols.^1,2 However, Grignard and alkyllithium reagents for ketones give the desired adducts along with (1) competitive reduction products due to the -hydride transfer of alkyl groups and (2) aldol adducts due to enolization by their strong basicity (eq 1).³ Recently, the addition of stoichiometric or an excess amount of CeCl₃,³ LiCl,⁴ LiClO₄,⁵ FeCl₂,⁶ and LnCl₃·2LiCl⁷ with Grignard reagents has shown good results with smooth alkylations and minimum side products. These additive effects were based on either a stoichiometric Lewis acid activation of carbonyl compounds or enhancement of the nucleophilicity of stoichiometric alkylation reagents (e.g., RCeCl₂, RMgCl₂·Li, etc.), which were prepared in situ from oligomeric Grignard reagents by binary metal complexations or transmetalations. While somewhat expensive LnCl₃ (Ln = La, Ce) salts have been the best alternatives to date, these stoichiometric compounds must be synthesized prior to use.^3,7 In our previous research, trialkylmagnesium(II) ate complexes, as good alkylation reagents with weak basicity, namely, R₃MgLi, which can be easily prepared from Grignard reagents (RMgX) and alkyllithiums (RLi) in situ,⁸ have improved the efficiency of alkylation to ketones (eq 1).⁹

However, in that case, more than equimolar amounts of expensive RLi (1-2 equiv) were indispensable. To overcome these problems, we report here the highly efficient alkylation to ketones and aldimines with Grignard reagents in the presence of catalytic trialkylzinc(II) ate complexes (R₃ZnMgCl) derived from ZnCl₂ in situ. The catalytic use of simple and inexpensive ZnCl₂ without further purification, instead of above stoichiometric additives, would offer significant advantage over the existing technologies.