present-day thiophene research. Since when first report on the Gewald reaction was reported it became a universal method for synthesis of substituted. PDF | Chemistry of 2-aminothiophenes is arguably one of the most extensive and dynamic field of present-day thiophene research. Since when first report. Gewald thiophene synthesis – Method A. Siloxycyclopropanes 53 and 55 were reacted with Et3Nx3HF and Et3N in DMF in order to obtain γ- oxocarboxylates.
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The free amino group allowed synthexis chain elongation and the growth of p-conjugated system to achieve structure with three thiophene units 86 Figure 9 upon its modification via deamination reaction38,39,82, followed by the 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.
Emphasis is given to the recent studies published, in which the most general approaches to the synthesis of basic 2-aminothiophenes via the Gewald reaction and other target structures were considered. 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. Deprotection of tertbutoxycarbonyl group resulted directly to ring closure of the intermediates isothiocyanatothiophenecarboxylic acids leading directly to 64a,b.
Tetrahedron62, 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. Adenosine is an important endogenous tissue-protective compound released during ischemia, hypoxia or inflammation. One of the important preparations of 2-aminothieno[2,3-d]pyrimidines was investigated by authors ArkivocXII, The most crucial synthdsis 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 triple bond of the cyano group Scheme 7.
Gfwald TGase isoenzymes are involved in diverse pathological conditions like celiac disease, atherosclerosis and neurodegenerative disorders. Thiazole formation through a modified Gewald reaction Carl J.
Ac2O, Mg ClO4 2; b: Cinnamyl derivatives of gwwald 72 Figure 5 inhibits herpes protease processing in HSV-2 infected cells. From the symmetric ketone 47 the Gewald thiophene synthesis was conducted in a stepwise fashion through Knoevenagel-Cope condensation to give the intermediate 48 followed by base-promoted thiophene cyclization with sulfur.
VolumeIssue 1Reviews and Accountspp. 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.
Utilization of substituted 2-aminothiophenes and Gewald reaction in the synthesis of condensed heterocycles 3. 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 an amine in stochiometric amount Scheme 6. Introduction Highly substituted thiophene derivatives are important heterocycles found in numerous biologically active and natural compounds.
The lack of reactivity of substrate 47 can be attributed to the high degree of steric hindrance inhibiting its enolisation.
International Patent No WO The availability of reagents and the mild reaction conditions all contribute to the versatility of this reaction. Recently, the improvements of the Gewald synthesis were announced. Gewald reaction, substituted 2-aminothiophenes, drug design, optoelectronics, dyes Table of Contents 1. However, if the activation with sulfur does not occur properly, the ylidene-sulfur syntheiss of presumed structure 10 or 12 is not formed and the side-reaction takes place.
Using the microwave irradiation reaction was carried out in very short times, but alternatively the reaction proceed well also under conventional heating Table 7. Additionally, the sulfur atom plays a decisive role by acting thikphene an efficient electron sink as explained by valence band theory.
Thiazole formation through a modified Gewald reaction
The reaction continuation is based on the condensation of the intermediate salt ketene N,S-acetal 43 with the halide ethyl bromoacetate or chloroacetonitrile leading to the corresponding aminothio-acetal which smoothly undergo a Dieckmann type cyclization in basic medium at room temperature Scheme His main research interests are focused on the design and synthesis of novel pconjugated organic materials in particular poly- and oligothiophenes and pyrroles and its fluorine substituted analogs.
Scheme 5 Alkyl aryl ketones and some cycloalkyl ketones which are thiophee 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. Kemi16, SSR5, All reactions were assessed for conversion using 1 H NMR analysis of a crude sample followed by work-up and purification via column chromatography to determine the yields.
A high- throughput screening program based on this enzyme from Staphylococcus aureus had identified a 2-ureido-thiophenecarboxylate 74 Figure 7 as a low micromolar inhibitor. Even though 2-substituted gewa,d 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 .
These key intermediates were alkylated with appropriate alkyl halides to furnish the final derivatives 65 Scheme It was proved, that the parent aminothiophene occurs exclusively in the amino form.
Reaction starting from 1,4-dithiane-2,5-diol 21 and vewald acetonitrile 6 was completed after 2 min. Generally, there are four basic variations described by Gewald and co-workers and about up to fifteen modifications to accomplish the synthesis of highly functionalized 2-aminothiophenes.
The further investigations of such structures are challenging in development of therapeutics of the diabetes mellitus. Scheme 11 Table 5. However, it is sure, that S8 has to be activated to react with Knoevenagel-Cope product 9.
The synthetic protocol for thieno[2,3-b]pyrroles, which is based on the reaction syntheeis 1,3-dicarbonyl compounds, can aynthesis applied also for preparation of thieno[2,3-b]thiophenes. 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 Jump to Figure 1.
S8, DBU, toluene, microwave irradiation, 20 min. This further shows the need for the rapid and facile formation of 2-substituted thiazole compounds as core building blocks. Applications of substituted 2-aminothiophenes in drug design, optoelectronics and dyes 4.