Gewald reaction

When Gewald reaction is a reaction name in organic chemistry, which was named after its discoverer Karl Gewald (* 1930). Here, a ketone (or aldehyde if R 2 = H) is reacted with an α - cyanoester in the presence of elemental sulfur and a base to give a substituted 2-amino -thiophene.

Overview reaction

A ketone, and an α - cyanoester react with morpholine in the base of a Knoevenagel condensation to an α -alkylidene- nitrile, which reacts with elemental sulfur to 2 -amino -thiophene.

Mechanism

The reaction mechanism could only be partially understood several years after the discovery of the reaction. In the first reaction step, the α - cyanoester is deprotonated by the base morpholine.

The resulting anion and the ketone add up to an alkoxide, which is protonated in another step by the protonated base to an alcohol. This is deprotonated to the stable intermediate α -alkylidene -nitrile.

The mechanism of the addition of elemental sulfur is unknown. It is believed that thereby the intermediate to be added is important. Cyclization and tautomerization then deliver the 2-amino -thiophene.

Energy supply with microwaves sometimes shortened response times, at the same time increased yield.

Variants

In a variation of Gewald reaction 3- acetyl-2- aminothiophene is obtained when reacting dithiane [ an adduct of sulfur and acetone ( R = CH3) ] with freshly prepared Cyanoaceton: