Double Reformatsky Reaction: Divergent Synthesis of δ‑Hydroxy-β-ketoesters

The double Reformatsky reaction,
tandem addition of two molecules
of zinc alkanoate to a carbonyl compound, and its synthetic application
to a series of δ-hydroxy-β-ketoesters has been developed.
The key to accelerate the double Reformatsky reaction is considered
to be a complex-induced proximity effect of the in situ generated
zinc alkoxide coordinated with the pyridyl group of the substrate
or bidentate amines. A noteworthy feature of the reaction system is
its high tolerance of functional groups due to the moderate nucleophilicity
of organozinc reagents and the mild reaction conditions. Moreover,
spectroscopic and crystallographic analyses of the zinc complex of
the double Reformatsky product support the proposed mechanism of reaction
site discrimination for ketones, aldehydes, nitriles, carboxylic acid
anhydrides, and esters.