Additions of Organomagnesium Halides to α-Alkoxy Ketones: Revision of the Chelation-Control Model

Abstract

The chelation-control model explains the high diastereoselectivity obtained in additions of organometallic nucleophiles to α-alkoxy ketones but fails for reactions of allylmagnesium halides. Low diastereoselectivity in ethereal solvents results from no chelation-induced rate acceleration. Additions of allylmagnesium bromide to carbonyl compounds are diastereoselective using CHCl as the solvent even though rate acceleration is still absent. Stereoselectivity likely arises from the predominance of the chelated form in solution. Therefore, a revised chelation-control model is proposed.

Reactions of Allylmagnesium Halides with Carbonyl Compounds: Reactivity, Structure, and Mechanism

“…58 The difference between these two similar reagents was noted by Felkin in his studies of stereoselective additions to cycloalkanones, 59 and more recent studies document these differences in detail. 51,52 Examples such as those shown in Schemes 2 and 4 reinforce the fact that allylmagnesium reagents do not generally behave like other organomagnesium species.…”

“…77,78 This conclusion is supported by the fact that chelating ketones react with organomagnesium reagents ≥100 times faster than non-chelating ketones (Figure 1). 52,78,79 By contrast, allylmagnesium chloride does not differentiate between chelating and non-chelating ketones (Figure 1). 52 Without the kinetic advantage conferred by chelation, reactions of allylmagnesium reagents with chiral, α-alkoxy ketones are unselective (e.g., Scheme 2b) because non-chelated intermediates, which predominate in solution, can react without stereoselectivity.…”

“…48 Recent studies provide evidence that the high reactivity of allylmagnesium reagents can have adverse consequences in stereoselective synthesis. 52 For example, an important method for controlling the diastereoselectivity of nucleophilic addition reactions relies on chelation by an α-alkoxy group to differentiate the diastereofaces of a chiral carbonyl compound. 75,76 Obtaining the chelation-controlled product, however, requires that the chelated intermediate be more reactive than other species in solution.…”

“…52 Without the kinetic advantage conferred by chelation, reactions of allylmagnesium reagents with chiral, α-alkoxy ketones are unselective (e.g., Scheme 2b) because non-chelated intermediates, which predominate in solution, can react without stereoselectivity. 52…”

“…50 Few studies have examined the mechanisms of these reactions as it affects the stereoselectivity of reactions with chiral substrates. 51,52 This review will summarize the current understanding of the reactions of allylmagnesium halides with carbonyl compounds, focusing on aspects most relevant to synthetic chemists: reactivity, structure, and mechanism. The present review builds upon a detailed review of the chemistry of allyl-and crotylmagnesium reagents that appeared in this journal in 1971.…”