Gewald aminothiophene synthesis

Base-promoted aminothiophene formation from ketone, a-active methylene nitrile and elemental sulfur. 

Tinsley, J. M. Gewald Aminothiophene Synthesis In Name Reactions in Heterocyclic Chemistry, Li, J. J. Corey, E. J., Eds. Wiley Sons Hoboken, NJ, 2005, 193—198. (Review). 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 110, Springer-Verlag Berlin Heidelberg 2009 

JVame Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10.1007/978-3-319-03979-4 118, Springer International Publishing Switzerland 2014 

Example 6, A -Methylpiperazine-Functionalized Polyacrylonitrile Fiber Catalyst  

The Gewald aminothiophene synthesis involves the condensation of aldehydes, ketones, or 1,3-dicarbonyl compounds 1 with activated nitriles such as malononitrile or cyanoacetic esters 2 and elemental sulfur in the presence of an amine to afford the corresponding 2-aminothiophene 3.  

The first step in the Gewald reaction is a Knoevenagel condensation of an activated nitrile with a ketone or aldehyde to produce an acrylonitrile 8, which is then thiolated at the methylene position with elemental sulfur. The sulfurated compound 9 initially decays 

Enamines can be used in place of an aldehyde or ketone in the Gewald reaction. Compound 19 reacted with ethylcyanoacetate and sulfur in the presence of morpholine to give aminothiophene 20 in good yield.  

4-Diaminothiophenes 24 were prepared in good yield from 3-amino-4,4-dicyano-3-butenoate 23, sulfur, and diethylamine at room temperature.  

When an aldehyde is used as the starting material in the Gewald reaction, a 5-alkyl-2-aminothiophene is the product isolated. For example, when 3-methylbutanal 25 was combined with ethylcyanoacetate 15 and sulfur in the presence of triethylamine, aminothiophene 26 is the only product observed in this reaction. However, when an a-tosyloxy-ketone 27 and sodium sulfide were employed in the reaction, the corresponding 4-alkyl-2-aminothiophene 28 was the sole reaction product.  

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The Gewald aminothiophene synthesis was employed in the production of thienotriazine-4-ones as potential antimicrobial agents. The most potent derivative, illustrated below, exhibited inhibition for both Grampositive and Gram-negative bacteria in the micro-molar range. ... 

The Gewald aminothiophene synthesis was also performed under ultrasonic aqueous conditions to give high yields of the corresponding substituted aminothiophenes in several minutes. ... 

The Gewald aminothiophene synthesis was employed in the generation of 2-amino-3-(3,4,5-trimethoxybenzoyl)-5-aryl thiophenes as derivatives of the anti-tubulin agent combretastatin A." Condensation of 2,5-dihydroxy-1,4-dithiane with 3-oxo-3-(3,4,5-trimethoxyphenyl)-propionitrile and elemental sulfur in the presence of triethylamine afforded the thiophene product in 74% yield. Further synthetic steps yielded an antitubulin agent that not only inhibited tubulin polymerization but also showed anti-proliferation activity against both L1210 and K562 cancer cell lines. 

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