Gewald reaction

The Gewald reaction 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. [Gewald, K.; Schinke, E.; Böttcher, H. "Ber." 1966, "99", 94-100.] [Sabnis, R. W. "Sulfur Rep." 1994, "16", 1-17. (Review)]

Reaction mechanism

The reaction mechanism of the Gewald reaction has only recently been elucidated. [Sabnis, R. W.; Rangnekar, D. W.; Sonawane, N. D. "J. Heterocyclic Chem." 1999, "36", 333.] The first step is a Knoevenagel condensation between the ketone (1) and the α-cyanoester (2) 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 (6).

Variations

In one variation of the Gewald reaction a "3-Acetyl-2-aminothiophene" is synthesized starting from a dithiane (an adduct of sulfur and acetone) and the sodium salt of "cyanoacetone" which in itself is very unstable [Gernot A. Eller, Wolfgang Holzer Molecules 2006, 11, 371-376 [http://www.mdpi.org/molecules/papers/11050371.pdf Online article] ] :

References