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The Gewald reaction is an organic reaction involving the condensation of a ketone (or 
The reaction is named after the German chemist Karl Gewald (born 1930).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, .
Microwave irradiation has been shown beneficial to reaction yields and times.
Online article
aldehyde
In organic chemistry, an aldehyde () is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred to as an aldehyde but can also be classified as a formyl grou ...
when R2 = H) with a α-cyanoester in the presence of elemental sulfur and base to give a poly-substituted 2-amino-thiophene
Thiophene is a heterocyclic compound with the formula C4H4S. Consisting of a planar five-membered ring, it is aromatic as indicated by its extensive substitution reactions. It is a colorless liquid with a benzene-like odor. In most of its react ...
.
The reaction is named after the German chemist Karl Gewald (born 1930).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. The first step is aKnoevenagel condensation
In organic chemistry, the Knoevenagel condensation () reaction is a type of chemical reaction named after German chemist Emil Knoevenagel. It is a modification of the aldol condensation.
A Knoevenagel condensation is a nucleophilic addition o ...
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
Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert.
The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hyd ...
will produce the desired product (6).
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 adithiane
A dithiane is a heterocyclic compound composed of a cyclohexane core structure wherein two methylene bridges (-- units) are replaced by sulfur centres. The three isomeric parent heterocycles are 1,2-dithiane, 1,3-dithiane and 1,4-dithiane.
1,3 ...
(an adduct of sulfur and acetone
Acetone (2-propanone or dimethyl ketone), is an organic compound with the formula . It is the simplest and smallest ketone (). It is a colorless, highly volatile and flammable liquid with a characteristic pungent odour.
Acetone is miscib ...
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, 371-37Online article
References
{{reflist Sulfur heterocycle forming reactions Heterocycle forming reactions Multiple component reactions Name reactions