Weidenhagen synthesis

What is Weidenhagen synthesis?

The reaction known as the Weidenhagen modification or Weidenhagen imidazole synthesis was first reported by Weidenhagen and Herrmann in 1935. It is a variation of the Radziszewski reaction and involves treating a mixture of α-hydroxy ketones, aldehydes, and ammonia NH3 with cupric acetate Cu(OAc)2, followed by hydrogen sulfide H2S or sodium sulfide Na2S. Cupric acetate serves as an oxidant, converting α-hydroxy ketones into transient α-dicarbonyl compounds that react with aldehyde and ammonia to form imidazole derivatives.

Weidenhagen synthesis - general reaction scheme
Weidenhagen synthesis

This reaction has been referred to by various names, including the Weidenhagen reaction, Weidenhagen synthesis, and Weidenhagen imidazole synthesis. Some variations have been observed, such as the formation of imidazole from α-acyloxyketone and the failure of some imidazoles to complex with cupric ion.

While the Weidenhagen imidazole synthesis can produce imidazole derivatives, the yield is often low, and the procedure is laborious. As a result, it has not been widely used until recently. Dihydroxyacetone, for example, does not yield the corresponding imidazole derivative efficiently, while 1,4-dihydroxybutan-2-one from 1,4-butynediol can readily undergo the reaction.

References

Weidenhagen, R. and Herrmann, R. (1935), Eine neue Synthese von Imidazol-Derivaten.[A new synthesis of imidazole derivatives.Ber. Dtsch. Chem. Ges. A/B, 68: 1953-1961. https://doi.org/10.1002/cber.19350681012

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