Versatile One‐Step One‐Pot Direct Aldol Condensation Promoted by MgI2.

Abstract

A true one-step one-pot aldol-reaction procedure has been developed for the synthesis of -hydroxy ketones and esters. The reaction can be run at room temperature by simply mixing four components in CH2Cl2, with medium-to-high yields of aldol products obtained after regular workup. Mechanistically, the process probably proceeds via Mg-enolate formation of the ketone or ester component, followed by addition to the electrophilic aldehyde. Introduction. ± The development of new multicomponent-coupling processes for the construction of complex target molecules from simple starting materials has attracted much attention in recent years. Aldol reactions, i.e., the condensation of a nucleophilic enolate with an electrophilic carbonyl compound, are considered to be among the most-powerful C,C-bond-forming reactions. The development of direct aldol reactions from unmodified ketones and aldehydes does not require the pre- conversion of a ketone or an ester to a more-reactive species (e.g., an enol silyl ether or a ketene silyl acetal) and has, thus, attracted considerable attention. Generally, direct aldol reactions fall into one out of two categories: 1) the carbonyl compound is first converted to its Li (or other metal) enolate by treatment with a strong base, typically lithium diisopropylamide (LDA) or a metal hexamethyldisilazide (MHMDS), followed by the addition of a carbonyl acceptor; or 2) the carbonyl compound is converted to its metal enolate under relatively mild conditions by treatment with a Lewis acid and a tertiary amine, followed by the reaction with the carbonyl acceptor. Both methods are two-step one-pot reactions, since the enolate needs to be formed before the addition of the carbonyl acceptor (1) (2). Recently, we found that MgI2 is an excellent Lewis acid for C,C-bond-forming reactions in the synthesis of -iodo BaylisHillman adducts (3). We think that, in this process, MgI2 serves both as a Lewis acid and an iodine source for a Michael-type addition in which an ,-ethynyl ketone (or ester) is converted to an active −-iodo- allenolate× intermediate, which, in turn, reacts with aldehydes to yield -iodo BaylisHillman adducts. Consequently, we were interested in testing whether MgI2, in the presence of a tertiary amine, would be a suitable reagent for the mild in situ formation of Mg enolates.