through the well-known Gewald’s thiophene synthesis ..

In another paper, thiophene c was synthesized by Gewald and Hain, startingfrom disubstituted β-chloroacrylonitrile, ­sodiumsulfide and bromonitro­methane.

Gewald aminothiophene synthesis

Thiophene is a heterocyclic compound with the formula C 4 H 4 S
Photo provided by
Flickr

THE GEWALD SYNTHESIS: Sulfur reports: Vol 16, No 1

Highly substituted thiophene derivatives first synthesized by Gewald synthesis in 1965, are important heterocyclic compounds present in numerous biologically active compounds. The synthesis of title compounds was carried out by preparing derivatives of Gewald product. In the present study, a series of 2-aminothiophene derivatives were first prepared by Gewald reaction and further converted into 2-...

Abstract views Pdf views Html views.

Combinatorial chemistry is an important discipline in organic chemistry and highly useful to pharmaceutical industry since the majority of drug discovery projects currently relies on high throughput screening of large compound collection. Gewald reactions have been described to be purification intensive in the past. Improvements to overcome this issue and to increase synthesis speed have been solid phase bound synthesis. However these methods have attached issues, such as low compound generation and the use of often special linker systems which compromise the chemistry. Other generally used methods include mass triggered automatic preparative HPLC or the faster and more efficient SC-CO2-HPLC. The use of automatic HPLC purification systems however is expensive and needs special equipment. The best organic chemistry work-up procedures can avoid chromatography and can purify the products by extraction and/or crystallization. These procedures are of particular value in the context of parallel synthesis since herein all efforts are multiplied. Therefore we believe that our described often chromatography free Gewald-3CR procedure based on simple precipitation and filtration is advancement in Gewald chemistry. Equally important is the general use of cyanoacetic acid amides as highly variable class of compounds in the Gewald-3CR which renders this reaction a true MCR with two highly variable inputs instead of mostly one in the past. Thus a skilled lab worker using very simple equipment can synthesize hundreds of Gewald products in a short time frame on a multi mg scale with very high purity including the synthesis of the required cyanoacetamide building blocks. In summary the herein described modified Gewald-3CR procedure allows for the robust, fast, resource saving and efficient construction of large arrays of highly substituted 3-amido-2-aminothiophenes.

The Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene-3-carboxylates.
Photo provided by
Flickr

The synthesis of thiazoles and ..

We herein describe a convenient way to synthesize arrays of Gewald thiophene-3-amides. The convenience of this procedure is based on two points: first the reaction can be performed in many cases in a way that the Gewald products precipitate and this leads to high quality products without the need to run time and cost intensive purifications. Second the starting material class of cyanoacetamides was recently described by us to be accessible in a very convenient way by simply mixing methyl cyanoacetate with an appropriate primary or secondary amine, thus leading to potentially large arrays of starting materials for subsequent cyanoacetamide dependant MCRs. This extension of the Gewald-3CR is significant since in the past mostly simple and non variable malondinitrile, cyanoacetic acid and their esters or hydrazides where used. Thus Gewald reaction variability in the past was mostly confined to the variation of the α -methylene oxo component and the secondary reactions of their primary Gewald products. The herein described and generally shown reaction of sulfur, and cyanoacetamides, however renders the Gewald-3CR a truly variable MCR with two points of diversity.

New Azo Heterocyclic Disperse Dyes with Thiophene …

A simple and efficient procedure was developed for the synthesis of 11H(2H)-4-oxothiophene[3',4':6,5]pyrido[3,2-a]azulene-10-carboxylates (3) in moderate to good yields via the Gewald reaction of ethyl 1-cyanoacetyl-2-methoxyazulene-3-carboxylate (1) with carbonyl compounds (2) and elemental sulfur utilizing imidazole as catalyst. This reaction provides a new procedure for synthesis of pyridinone-fused azulenes.

Facile Synthesis and Crystal Structure of N-(3-Cyano …

Next, we moved towards studying the reactivity of compound 4 towards thiophene synthesis through the well-known Gewald’s thiophene synthesis.,)