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

Tetrahedron29, Her scientific achievements are focused on the synthesis of new heterocyclic compounds. 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.

Substrates which did not react under the optimised conditions. In Purinergic Approaches in Experimental Therapeutics, ed. The availability of reagents and the mild reaction conditions all contribute to the versatility of this reaction. Selected examples of biologically active thiazole containing molecules []. Skip to main content Skip to quick search Skip to global navigation.

Gewald Reaction

Oxford, UK, ; Vol. The readily available and inexpensive starting vewald and reagents, and the lack of protection and de-protection steps make this synthesis very fashionable Scheme Suecica5, 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 3 Scheme 1.

The latter conditions were then chosen to progress due to the increased productivity based upon the higher concentration reactiin slightly shorter reaction time. Five-Membered Heterocycles, Chapter 5, Section 5. The scope of presented work does not include all of the publications on the chemistry of substituted 2-aminothiophenes, but the most interesting studies in the subject areas are considered. After the dispersion of reaaction 17 in ethanol Gewald reaction was performed in QuestTM gewale by mixing with the starting compound – a-methylene carbonyl compounds 18 and substrates – sulfur and morpholine.


The first report on the development and the use of substituted 2-aminothiophenes and the Gewald reaction was published by authors. Metals, Please contact mpub-help umich. Jump to Scheme 2. In summary, although our reacyion indicates mechanism A is the most likely pathway it should be noted that several benzonitrile derivatives have been shown to successfully result in thiazole formation when reacted with coupling partners such as 2-mercaptopropionic acid, therefore mechanism B could operate under certain conditions [32].

TDP is co-enzyme present in a number reactioj enzymes, including pyruvate decarboxylase, transketolase, pyruvate oxidase. Particular attention is given to studies published in the previous years. In subsequent treatment of 32 with sulfur the 2-aminothiophene core 33 is formed under basic conditions.

The synthetic protocol for thieno[2,3-b]pyrroles, which is based on the reaction of 1,3-dicarbonyl compounds, can be applied also for preparation of thieno[2,3-b]thiophenes.

His main research interests are focused on gewal design and synthesis of novel pconjugated organic materials in particular poly- and oligothiophenes and pyrroles and its fluorine substituted analogs. Walter 2 and Ian R.

Deprotection reatcion tertbutoxycarbonyl group resulted directly to ring closure of the intermediates isothiocyanatothiophenecarboxylic acids leading directly to 64a,b. Norris25 and ten years of the last Gewald reaction review26 we felt the time was ripe for a fresh look at this field of heterocyclic chemistry. Home About Search Browse.

This review summarizes the synthetic strategies for substituted 2-aminothiophenes. In the base-promoted addition the elemental sulfur reacts with amines to yield polysulfide anions, that can behave as nucleophiles.

Consequently, expanding rezction scope of thiazole synthesis by developing new methodologies remains an active area of research. Applications of substituted 2-aminothiophenes in drug design, optoelectronics and dyes 4.

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 recation S8. Tetrahedron63, Scoping experiments using ethyl phenylcyanoacetate 16 with different solvents and bases. It displayed good antibacterial activity against S. Illustration of substrates that form thiophenes under Gewald-type conditions.


In this particular version the more stable dimeric forms of an a-sulfanylcarbonyl compound — substituted 1,4-dithiane-2,5-diols 5c undergo condensation and subsequent cyclization with aactivated acetonitrile 6 requiring reation amine in stochiometric amount Scheme 6. Please enable Javascript and Cookies to geaction this site to work correctly! 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 eraction of the 2-aminothiophene.

The free amino group is acylated first and then the methyl group in C-4 position undergoes the radical bromination to create the crucial intermediates 37a-c.

Kemi16, For more information please contact mpub-help umich. Even though 2-substituted thiazoles are important structures in their own right, further substitution can be easily achieved through published protocols to form 2,4-substituted thiazoles, 2,5-substituted thiazoles and also 2,4,5-substituted thiazoles geeald.

The synthesis and antitumor activity of thieno[2,3-b]azepinone based antineoplastic agents was reported. Polymer,48, SSR5, The synthetic route to novel thieno[2,3d][ 1,3]oxazinones 65 using alkyl 2-aminothiophene carboxylates 62 as a substrates exhibits a facile three step synthesis, as is presented on Scheme Such derivatives represent a p-heteropentalene system with tetracovalent sulfur nucleus and are investigated from synthetic and theoretical point of view.

Finally, in Scammells and co-workers have presented the synthetic pathway to 5-bromo substituted 2-aminothiophenes The air-stable, readily available 1,4-dithian-2,5-diol 10 has been previously reported as a coupling partner with feaction nitriles to give 2-aminothiophenes through a Gewald mechanism [21,22]. 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 reactiln.