Improved Reformatsky reaction robustness:Using a small-scale reaction to 'seed'a large-scale one

02 July 2004

The Reformatsky reaction is renowned for its relative lack of robustness on scale (even in the lab), and while it is generally accepted that the primary factors are the nature and activation of the zinc, very few, if any, of the various reported literature procedures can be claimed to be universally effective. While exploring the transformation below, chemists at Bayer* observed that whenever a small amount of the Reformatsky end product was detected by tlc, the batch always proceeded rapidly to completion, even if the induction period varied.

This observation led them to a “seeding” process, whereby a small scale (1-10g indanone input) Reformatsky reaction is performed to completion, and this reaction mixture is used without workup as ”seed” for a larger batch reaction (40-80g indanone input). By transferring 90% of this bulk reaction mixture to another vessel for workup, fresh starting materials could charged to the reaction vessel and a further Reformatsky reaction performed, the 10% reaction mixture residue acting as the “seed”. This could be repeated iteratively.

Interestingly, a tightly closed sample of “seed” was effective even after 5 months storage on the bench.

*M. Zhang et al.,Tetrahedron Asymmetry, 2003, 14, 3447.