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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Data of the utilization of 2aminothiophenes in the synthesis of novel type of fused heterocycles and their application are included. Proposed mechanisms for the formation of thiazoles. Microwave enhanced Gewald reaction in combination with synhhesis accelerated method was presented as an easy access to polysubstituted 2-aminothiophenes.
Based on these author observations reported a synthesis of the number of analogs of 74 via the Gewald reaction and evaluated for cytotoxic activity against Rifampicin-resistant S. However, the alternative mechanism for the thiazole formation as described herein has not previously been reported and initially presented some queries.
WoldChristopher L. Circulation83, Screening for the bifurcation conditions Initially, the reaction of several nitriles was screened with aldehyde precursor 10 to determine the selectivity between thiophene and thiazole products. Cell, — We have collected together detailed descriptions of selected important new reactions and works used Gewald reaction.
It was proved, that the parent thuophene occurs exclusively in the amino form.
Gewald reaction – Wikipedia
Oxford, UK, ; Vol. To date, she has synthesized with her research group more than new thiopheje substances, mainly with heterocyclic structure, and participated on the quantitative studies of aromaticity of p-electronrich newly synthesized furo[b]pyrroles. Synthesis44, — The most suitable base for the activation with sulfur and the subsequent sulfur addition morpholine has been proved. 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 synthesis of 3-deazathiamine 61 was effected in ten chemical steps, though it was necessary to prepare and isolate substituted 2-aminothiophene. Tetrahedron54, Polymer,48, The free amino group allowed the 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 synthesis and pharmacology of this series of derivatives was presented by authors, from ethyl 2-aminomethylthiophenecarboxylate.
Other researchers50 deal that thoophene use acid-base catalyst ammonium salts: Tetrahedron63, From the data thiophdne was concluded that elevated temperatures resulted in lower isolated yields most probably due to decomposition of compound 10 or the resulting aldehyde. Scoping experiments using ethyl phenylcyanoacetate 16 with different solvents and bases. 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 Exploiting the reaction conditions with starting substrates tolerating thiophrne broad range of functional groups and alkyl, aryl and heteroaryl substituents about 15 new modifications of the Gewald reaction can be found in literature.
Initially, the reaction of several nitriles was screened with aldehyde precursor 10 to determine the selectivity between thiophene and thiazole products. Applications of 2-aminothiophenes in drug design, optoelectronics and dyes Substituted 2-aminothiophenes represents a category of an important precursors broadly employed in the synthesis of pharmaceuticals, dyes and potential building blocks in materials chemistry.
The reaction was successful it the R-substituted 2-bromo-1phenylethanones 27 were reacted with 3-oxophenylpropanenitrile 28 and sulfur in the presence of diethylamine as a base in ethanol Scheme However, it is sure, that S8 has to be activated to react with Knoevenagel-Cope product 9.
The advantage of this process is in possibility of the prediction of hydrophilic or hydrophobic character of final structures with right choice thiophne starting substrates bearing functional groups. How to cite this article: Scheme 12 Table 6.
Reaction towards substituted 2-aminothiophenes with an electron-withdrawing substituent in position C-5 R2 occurs within three base-promoted steps: 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. Using thoophene microwave irradiation reaction was carried out in very short times, but alternatively the reaction proceed well also under conventional heating Table 7.
Introduction Results and Discussion Screening for the bifurcation conditions Optimisation and thiophenee of thiazole formation Conclusion Experimental Supporting Information Acknowledgements References. S8, DBU, toluene, microwave irradiation, 20 min. The substituted 2-aminothiophenes act as the most suitable synthetic precursors to various thieno[2,3d] pyrimidines. Cinnamyl derivatives of thieno[2,3-d]oxazinones 72 Figure 5 inhibits herpes protease processing in HSV-2 infected cells.
Starting from substituted 2-aminothiophenes 36a-c, the target fused heterocyclic derivatives 39a-c was prepared in a four step reaction sequence.
The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for synthexis number of different substrates.
Jump to Scheme 1. Tetrahedron58, Utilization of substituted 2-aminothiophenes and Gewald reaction in the synthesis of condensed heterocycles 3. Finally, in Scammells and co-workers have presented the synthetic pathway to 5-bromo substituted 2-aminothiophenes Heterogeneous organic reactions using reagents immobilized on porous solid supports have been often proved advantageous over conventional solution phase reactions because of good dispersion of active reagent sites, better selectivity and easier work-up.
In a reaction of 3trifluoromethylacetophenone 30 with either benzoylacetonitrile or ethyl cyanoacetate 31 in the presence titanium IV chloride afforded Knoevenagel-Cope product 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 triple bond of the cyano group Scheme 7.
In syntheiss, lower concentration was beneficial but at a consequence of longer reaction times in order to obtain a good yield. Deprotection of tertbutoxycarbonyl group resulted directly to ring closure of the intermediates isothiocyanatothiophenecarboxylic acids leading directly to 64a,b. Originally, reactions were performed using conventional heating, however, to allow for a wider temperature range, microwave heating was introduced.
Only a small impact upon conversion was observed with geald the ratio of compound 10 and so it was decided to also maintain this at equimolar concentration i.