Gewald synthesis

Diels-AIder reactions, I, 618 reactions, 1, 617-620 synthesis, 1, 614-616 2-Germoxetanes heterosubstituted germacyclobutanes and, 1, 596 Gewald synthesis thiophenes, 4, 888-889 ( )-Gingerol synthesis, 1, 453 (+)-(S)-Gingerol synthesis, I, 435 Ginkgolide A... 

Preparation of Thiophenes by Microwave-Promoted Gewald Synthesis. .. 101... 

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. 

Ring closure of unsaturated nitriles with sulfur (Gewald synthesis) 888... 

The Gewald synthesis provides a convenient synthetic pathway to substituted 2-aminothiophenes (Section 3.15.3.1.5), and has been widely applied. Condensation of a carbonyl compound with a methylene activated acetonitrile, followed by heating with sulfur in the presence of base, gives the 2-aminothiophene in yields ranging up to 90% (equation 47). Arylpropynthioanilides react with acidic bromomethylene compounds, BrCH2X, where... 

Hoener, A.P.F., Henkel, B. and Gauvin, J.C., Novel one-pot microwave-assisted Gewald synthesis of 2-acyl amino thiophenes on solid support, Synlett, 2003, 63-66. 

Another interesting multi-component reaction is the Gewald synthesis leading to 2-amino-3-acyl thiophenes (Scheme 7.25), which are of current interest since they are commercially used as dyes, conducting polymers and have shown extensive potential for pharmaceutical purposes. 

Figure 7.12 Structural representation of 2-acylaminothiophene products generated by microwave-assisted Gewald synthesis.

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. 

The Gewald synthesis can be performed on a solid support. Treatment of resin-bound nitrile 559 with carbonyl compounds and sulfur gives resin-bound aminothiophenes 560. Acylation and removal of the resin provide thiophenes 561 (Scheme 88) <2001TL7181>. The same resin-bound nitrile 559 reacts under MW irradiation to give 560 <2004S3055>. MW-assisted synthesis of 2-A -acylthiophenes 563 from 562 on a solid support has also been reported <2003SL63>. 

Microwave assisted Gewald synthesis of 2-acyl aminothiophenes 13 on solid support has been carried out by Gauvin and co-workers <03SL63>, wherein the solid support was a cyanoacetic acid Wang resin 12 (Scheme 3),... 

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