Thiophenes Gewald synthesis

Synthesis of 2-Amino-3-Carbonyl-Thiophenes - Gewald Synthesis. 17... 

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... 

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. 

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>. 

Pyrimidine-fused Systems.—The Gewald synthesis of thiophen analogues of anthranilic acid has opened the synthetic route to pyrimidine-fused thiophens. The interest in this field is mainly due to the potential pharmacological properties of these systems. Condensation of (603) with forma-mide at 200 °C yields (604). Similarly, (605) was prepared from 3-amino-2-methoxycarbonylthiophen or from its formamide derivative. Derivatives of (604) were also obtained by cyclization of the 2-amino-3-carboxamide... 

Hoener et al. [90] investigated a one-pot reaction for Gewald synthesis on solid support (Scheme 11.37). The products 2-amino-3 acyl thiophenes are used commercially as dyes. 

Gabriel-Isay synthesis (pteridine) Gabriel synthesis (thiazole) 207 Gassmann synthesis (indole) 135 Gattermann synthesis, HCN-free 509 Gewald synthesis (thiophene) 97 Graebe-Ullmann reaction 266 Guareschi synthesis (2-pyridone) 384... 

Scheme 41 The synthesis of a 2-amino-3-(benzothiazol-2-yl)thiophene using Gewald synthesis [62]...

Tetrasubstituted thiophenes obtained by the Gewald reaction serve as templates for structural diversification and semi-automated library synthesis. Thiophene 31, prepared from 3-ketoester 29 and t-butylcyanoacetate 30, could be selectively derivatized at three of the four substituents to maximize library diversity. This procedure represents an improvement over previously published methods for utilizing 1,3-dicarbonyl compounds in the Gewald reaction. 

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%. 

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