Gewald aminothiophene reaction

Rosowsky and co-workers sought to synthesize thiophene-containing derivatives of trimetrexate and piritrexim in their search for potential inhibitors of Pneumocystis carinii and Toxoplasma gondii dihydrofolate reductase. Their goal was to improve selectivity and limit the potential side effects found in trimetrexate and piritrexim. The thiophene moieties were installed by means of a Gewald aminothiophene reaction similar to those used in the creation of the C-nucleosides shown previously. Desired substitution patterns were accessed by the use of appropriate substrates as shown below. 

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). 

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. ... 

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. ... 

Microwave irradiation has been used to accelerate the Gewald reaction for the one-pot synthesis of N-acyl aminothiophenes on solid support [67]. A suspension of cyanoacetic acid Wang resin 35, elemental sulfur, DBU and an aldehyde or ketone 36 in toluene was irradiated for 20 min at 120 °C in a single-mode microwave synthesizer (Scheme 13). Acyl chloride 37 was added, followed by DIPEA, and the mixture was irradiated for 10 min at 100 °C. After cooling to room temperature, the washed resin was treated with a TEA solution to give M-acylated thiophenes 38 in 81-99% yield and purities ranging from 46-99%. 

Cyclization reactions effected by intramolecular attack of a heteroatom on a nitrile group provide a useful source of 2-amino heterocycles, e.g. (120) —> (121), and numerous syntheses employ this strategy (vide infra). Thus, the reaction of a,(3-unsaturated nitriles (122) with elemental sulfur in basic media, the Gewald synthesis, provides a most convenient route to 2-aminothiophenes (123), many of which are a useful as intermediates in the preparation of dyestuffs and pharmaceuticals. 

The Gewald Reaction is a synthesis of 2-aminothiophenes via a multi-component condensation between sulfur, an a-methylene carbonyl compound and an a-cyanoester. 

Three component condensation reactions (Gewald reaction) between an activated nitrile, ketone or aldehyde, and sulfur has been utilized to prepare a variety of a-aminothiophenes. Recent examples utilizing this condensation reaction include the synthesis of 4,5-dialkyl-2-... 

The Gewald reaction can be conveniently performed via a multicomponent condensation between sulfur, an -methylene carbonyl compound, and an -cyanoester. The use of ionic liquids as solvents <2004SC3801>, or performing this condensation under microwave irradiation without solvent (Scheme 84) <2005SC1351>, leads to generally better yields of 2-aminothiophenes . 

Reaction of a four-carbon unit with sulfur sources such as hydrogen sulfide, carbon disulfide, and elemental sulfur is one of the traditional thiophene syntheses that belong to this category (Equation 18). A wide variety of hydrocarbons, for example, alkanes, alkenes, dienes, alkynes, and diynes, serve as four-carbon units. Another practical method is the sulfuration of 1,4-dicarbonyl compounds (Paal synthesis). The method has become very popular with development of sulfuration reagents such as Lawesson s reagent. The reaction of a,/3-unsaturated nitriles with elemental sulfur in basic media, Gewald synthesis, is also useful for the preparation of 2-aminothiophenes which are important compounds in dyestuff and pharmaceutical industries. 

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