Gewald reaction

The Gewald reaction (or the Gewald aminothiophene synthesis) is an organic reaction involving the condensation of a ketone (or aldehyde when R2 = H) with a α-cyanoester in the presence of elemental sulfur and base to give a poly-substituted 2-amino-thiophene.

[1][2] The reaction is named after the German chemist Karl Gewald [de].

[6] The first step is a Knoevenagel condensation between the ketone (1) and the α-cyanoester (2) to produce the stable intermediate 3.

Microwave irradiation has been shown beneficial to reaction yields and times.

[7] In one variation of the Gewald reaction a 3-acetyl-2-aminothiophene is synthesized starting from a dithiane (an adduct of sulfur and acetone if R = CH3 or acetaldehyde if R = H) and the sodium salt of cyanoacetone which in itself is very unstable:[8] Media related to Gewald reaction at Wikimedia Commons