An efficient four-component reaction was developed to take advantage of the reactivity of the 2-aminothiophenecarbonitrile functionality. The Gewald reaction is a very useful and versatile method for condensation of aliphatic aldehyde or ketone or β-dicarbonyl compound with active nitrile and. 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.

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Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes

Scheme 5 Alkyl aryl ketones and some cycloalkyl ketones which are not reactive under the one-pot modifications version 1 or version 2 give acceptable yields of thiophenes in the two-step procedure Table 3. Illustration of substrates that form thiophenes under Gewald-type conditions. Registration is open for this Beilstein Symposium, 9 – 11 April, The lack of reactivity of substrate 47 can be attributed to the high degree of steric hindrance inhibiting its enolisation.

Initially, the reaction of several nitriles was screened with aldehyde precursor 10 to determine the selectivity between thiophene and thiazole products. Proposed mechanisms for the formation of thiazoles. In the base-promoted addition the elemental sulfur reacts with amines to yield polysulfide anions, that can behave as nucleophiles.

Received on ; Accepted on ; Published on After the treatment of 1 with potassium hydrosulfide the reactive sufanyl-substituted intermediate 2 was created, which in the subsequent intramolecular addition of sulfanyl group to cyano group proceeded ethyl 2-amino-4hydroxythiophene- 3-carboxylate 4 in equilibrium with its cyclic tautomer — the appropriate imine geqald Scheme 1.

The substituted 2-aminothiophenes act as the most suitable synthetic precursors to various thieno[2,3d] pyrimidines. After the dispersion of reagent 17 in ethanol Gewald reaction was performed in QuestTM synthesizer by mixing with the starting compound – a-methylene carbonyl compounds 18 and substrates – sulfur and morpholine.


Thiazole formation through a modified Gewald reaction

Please enable Javascript and Cookies to allow this site to work correctly! It was proved, that the parent aminothiophene occurs exclusively in the amino form. Synthesis of substituted 2-aminothiophenes via Gewald reaction 2. Tetrahedron57, Jump to Figure 2.

The latter conditions were then chosen to progress due to the increased productivity based upon the higher concentration and slightly shorter reaction time. It was shown that the presence of an alkyl or aryl substituent adjacent to the cyano group leads selectively to the thiazole by blocking the Gewald type mechanism responsible for the formation of the 2-aminothiophene. Microwave heating is an area of increasing interest in both academic and industrial laboratories because it can raise the rate of reaction and rezction many cases improve product yields.

Polymer,48, Scheme 13 Table 7. Conclusions In this review we have extended the problems of synthesis of variety of substituted 2aminothiophenes and their scope and utilization.

In addition, a sulfonic acid bound resin QP-SA was also trialled as an additive but showed no conversion allowing full recovery of the starting nitrile see later discussion on mechanism.

►Gewald reaction –

The review starts with an extensive introduction that discusses the most multidisciplinary areas of 2-aminothiophene research with inputs from medicine, pharmacology, chemistry, biology, biochemistry, materials science and physics. Reactivity of bromoselenophenes in palladium-catalyzed direct arylations.

Aminothiophenes 62 were converted to isothiocyanato-thiophenes 63 by the thiophosgene method. This further shows the need for the rapid and facile formation of 2-substituted thiazole compounds as core building blocks. Tetrahedron64, The study demonstrates the versatility of 2-aminothiophenes as a synthetic entry to serine protease-inhibiting, fused 1,3-oxazinones. Scheme 18 The same authors have published an improved two step method for the synthesis of Nphenylaminothiophenes 44, which is based on preparation and isolation ketene phenylamino methylthioacetals The most suitable base for the activation with sulfur and the subsequent sulfur addition morpholine has been proved.


Gewald Reaction

Some authors report that the activation of sulfur and the following addition of sulfur on a methylene group is base-promoted, others detail the electrochemical activation of the S8. Ionic liquids used as solvents in combination with ethylenediammonium diacetate were shown to be very efficient in the case of the Gewald synthesis with aliphatic and alicyclic reaftion with possibility of regeneration of used liquids.

She completed her Ph. Gewal, if the activation with sulfur does not occur properly, the ylidene-sulfur adduct of presumed structure 10 or 12 is not formed and the side-reaction takes place.

Suecica5, The availability of reagents and the mild reaction conditions all contribute to the versatility of this reaction. Recent progress in the racemic and enantioselective synthesis of monofluoroalkene-based dipeptide isosteres. Phenyl isothiocyanate has been almost exclusively used for related studies and reacfion choice could be explained by the availability of this compound, but above all it appeared to be the best candidate for this reaction.

Mallia 1Lukas Englert 1Gary C.