Aminothiophene synthesis

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 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. 

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

Preparation and characterization of 3,4-diaryl-substituted 2-diary lamino thiophenes, (e) O. Zeika, H. Hartmann, Tetrahedron 2004, 60, 8213-8219. On the oxidative coupling of V,V-disubstituted 2-aminothiophenes—synthesis of N,N -persub stituted 5,5 -diamino -2,2 -bithiophenes. 

D. Subba Rao, S. Rasheed, S. K. Thashm Basha, C. Naga Raju, K. Naresh, Pharma Chem. 2013, 5, 61-74. SiOj/ZnCl catalyzed a-aminophosphonates and phosphonated N-(substituted phenyl) sulfonamides of 2-aminothiophene synthesis and biological evaluation. 

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