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.Gewald, K.; Schinke, E.; Böttcher, H. Ber. 1966, 99, 94-100.Sabnis, R. W. Sulfur Rep. 1994, 16, 1-17. (Review)
The reaction is named after the German chemist .John A. Joule, Keith Mills: Heterocyclic Chemistry, John Wiley & Sons, 5. Auflage (2010), p. 340, .Bradford P. Mundy, Michael G. Ellerd, Frank G. Favaloro, Jr.: Name Reactions and Reagents in Organic Synthesis, John Wiley & Sons, 2. Auflage (2005) p. 306, .Christopher Hume: Applications of Multicomponent Reactions in Drug Discovery – Lead Generation to Process Development, p. 311−341, see p. 332−334, In Jieping Zhu, Huges Bienaymé: Multicomponent Reactions, Wiles-VCH Verlag, 2005, .
Reaction mechanism The reaction mechanism of the Gewald reaction was elucidated 30 years after the reaction was discovered.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).
Microwave irradiation has been shown beneficial to reaction yields and times.Sridhar, M.; Raoa, R. M.; Babaa, N. H. K.; Kumbhare, R. M. Tetrahedron Lett. 2007, 48, 3171-3172. ()
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 if R = CH3 or acetaldehyde if R = H) and the sodium salt of cyanoacetone which in itself is very unstable:Gernot A. Eller, Wolfgang Holzer Molecules 2006, 11, 371-376 Online article.
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