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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In this relatively new synthetic pathway the sulfur, which is electro active, is incorporated in a carbon electrode and used as a sacrificial cathode to yield S3. Arkivoc13, The reaction reported by authors represents the one-pot synthesis in which the reaction sequence follows the Gewald reaction process. The scope of presented work does not include gewapd of the publications on the chemistry of substituted 2-aminothiophenes, but the most interesting studies in the subject areas are considered.
In the base-promoted addition the elemental sulfur gewad with amines to yield polysulfide anions, that can behave as nucleophiles. The versatility of title compounds as a synthetic entry to fused heterocycles such as thieno[3,4-c]thiolactones, thieno[2,3-b]pyrroles, thieno[2,3-d]pyrimidines and thieno[2,3-b]pyridines is highlighted in following chapters.
The ultimate position of substituted 2-aminothiophenes in this field comes from their advantageous properties – the thiophene ring as is bioisosteric replacement for phenyl group geeald present in an active drugs, the thiophene core exists in many natural and synthetic pharmaceuticals and moreover, they represent an active precursors in broad range of reaftion pathways towards compounds used in therapy.
Jump to Figure 1. The availability of reagents and the mild reaction conditions all contribute to the versatility of this gewalv. The authors, have discovered a facile synthesis of substituted azometines by a condensation of diethyl 2,5-diaminothiophene-3,4dicarboxylate 76 with thiophenecarbaldehyde 77 or 5- thiophenyl thiophene-2carbaldehyde 78 the appropriate azomethines were achieved Scheme The advantage of this process is in possibility of the prediction of hydrophilic or hydrophobic character of final bewald with right choice of starting substrates bearing functional groups.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: Since when first report on the Gewald reaction was reported it became a universal method for synthesis of substituted 2-aminothiophenes and has gained prominence in recent times.
Thiazole formation through a modified Gewald reaction Carl J. Tetrahedron58, In subsequent treatment of 32 with sulfur the 2-aminothiophene core 33 is formed under basic conditions. Reaction towards substituted 2-aminothiophenes with an electron-withdrawing substituent in position C-5 R2 occurs within three base-promoted steps: Utilization of substituted 2-aminothiophenes and Gewald reaction in the synthesis of condensed heterocycles The substituted 2-aminothiophenes found enormous utility in dye chemistry, modern drug designbiodiagnostics, electronic and optoelectronic devices, conductivity-based sensors, and self-assembled superstructures.
Oxford, UK, ; Vol. In Purinergic Approaches in Experimental Therapeutics, ed. Please contact mpub-help umich. Metals, 3. 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 . This is presumably due to a subtle balance between the basicity and nucleophilicity of the intermediate anion, which could in the case of the more stable electron withdrawing group anion enable a retro-aldol reaction following.
►Gewald reaction –
To allow direct comparison and evaluation of the influence of substrate modifications on the reaction outcome we reactkon the standard reaction conditions generated above. The chemistry of aminothiophenes has been broadly summarized in in the monograph of R. Exploiting the reaction conditions with starting substrates tolerating a broad range of functional groups and alkyl, aryl and heteroaryl substituents about 15 new modifications of the Gewald reaction can be found in literature.
Consequently, details about the proposed mechanism of Gewald-like reactions and the wide scope of substituted 2-aminothiophenes for real life applications. While gwwald some cases the ylidene dimerization is significant and the by-product is isolated in higher yield than the desired 2-aminothiophene derivative58, on other hand under suitable reaction conditions not only is the straightforward reaction favored, but also the recyclization of dimerized ylidene 14 to appropriate aminothiophene 7 occurs.
Selected examples of biologically active thiazole containing molecules . ArkivocXII, Cinnamyl derivatives of thieno[2,3-d]oxazinones 72 Figure 5 inhibits herpes protease processing in HSV-2 infected cells.
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. By the use of improved methods and modified experimental procedures the scope of easily obtainable 2aminothiophenes ultimately spread.
The strategy presented by authors, is based on the replacement of the benzene ring in benzoxazinones by thiophene one. She has co-authored the publications concerning her research interests in the field of heterocyclic chemistry aminothiophenes and coordination chemistry copper complexes.
Scoping experiments using ethyl phenylcyanoacetate 16 with different solvents and bases. Several protocols have already been described for the synthesis of substituted thiazoles and benzothiazoles .
Thiazole formation through a modified Gewald reaction
The free C-5 position of derivative 33 is substituted with bromine in two following steps — first the free amino group is being Boc protected and then C-5 position brominated with Nbromosuccinimide Scheme However, 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.
Tetrahedron57, For more information, read Michigan Publishing’s access and usage policy. Thiophene and its derivatives. She finished her habilitation in and D. The fact that compounds 46 and 47 did not react implies mechanism A is the predominant pathway. The synthesis and pharmacology of this series of derivatives was presented by authors, from ethyl 2-aminomethylthiophenecarboxylate. Using the microwave irradiation reaction was carried out in very short times, but alternatively the reaction proceed well also under conventional heating Table 7.
The most crucial step in all cases of the basic Gewald reaction and its improvements is the final ring-closure process, which is performed as an intramolecular nucleophilic attack of the sulfur anion to reaxtion bond of the cyano group Scheme 7. KF-alumina, microwave irradiation, 3. Polymer,48, In this case the base, mainly secondary amine diethylamine, morpholineis used in 0.