Reaction of acyl chlorides with organometallic reagents: A banquet table of metals for ketone synthesis

The principal synthetic routes to ketones from carbonyl compounds involve reaction of carboxylic acids and their derivatives with organometallic reagents via nucleophilic acyl substitution, Friedel-Crafts acylation of alkenes and arenes, and 1,2-nucleophilic addition to aldehydes followed by oxidation. Nitriles can serve as a carboxylic acid equivalent since 1,2-nucleophilic addition of organometallic reagents followed by hydrolysis affords ketones (Scheme VII). Nucleophilic addition to amides (e.g., the Weinreb procedure), lactones, carboxylic acids, aldehydes, and nitriles is generally limited to potent nucleophilic reagents that are also strongly basic, although the enhanced reactivity of aldehydes permits utilization of less basic allylic metal derivatives. Friedel-Crafts acylation requires the use of Bronsted or Lewis acids. In contrast, the acylation of organometallic reagents permits the widest range of reaction conditions and opportunities to moderate reagent reactivity and basicity. The utilization of transmetallation relays allows for synthetic pathways that avoid the use of strongly basic reagents and extends the range of functional groups that can be converted into the organometallic reagent. In short, the reaction of acid chlorides with organometallic reagents remains the most versatile ketone synthesis.