Gewald reaction


The Gewald reaction is an organic reaction involving the condensation of a ketone with a α-cyanoester in the presence of elemental sulfur and base to give a poly-substituted 2-amino-thiophene.
The reaction is named after the German chemist Karl Gewald.

Reaction mechanism

The reaction mechanism of the Gewald reaction was elucidated 30 years after the reaction was discovered. The first step is a Knoevenagel condensation between the ketone and the α-cyanoester to produce the stable intermediate 3. The mechanism of the addition of the elemental sulfur is unknown. It is postulated to proceed through intermediate 4. Cyclization and tautomerization will produce the desired product.
Microwave irradiation has been shown beneficial to reaction yields and times.

Variations

In one variation of the Gewald reaction a 3-acetyl-2-aminothiophene is synthesized starting from a dithiane and the sodium salt of cyanoacetone which in itself is very unstable: