Thiophene Gewald synthesis

The application of the Gewald thiophene synthesis to the preparation of selenophenes has so far met with only very limited success. The reaction of cyclohexanone with ethyl cyanoacetate and selenium to provide the selenophene (213) gave only an 8% yield (73KGS326). 

The few thiophene syntheses reported in which the formation of the heterocycle is realized on an insoluble support (Entries 1-3, Table 15.10) are based on the intramolecular addition of C,H-acidic compounds to nitriles (Thorpe-Ziegler reaction), or on the Gewald thiophene synthesis. The mechanism of these cyclizations is outlined in Figure 15.6. In thiophene preparations performed on solid phase, the required a-(cya-... 

A microwave-assisted Gewald thiophene synthesis has recently been described [362]. 

A variety of new thiophene ring syntheses, including useful new variants of some well-established methods have appeared during the year 2005. For example, a microwave-assisted variant of the Gewald thiophene synthesis allows preparation of a series of 2-aminothiophene-... 

Benzothiophenes may be accessed by a variety of methods including variations of the Fiesselmann and Gewald thiophenes synthesis. In addition, acid-catalyzed and electrophilic (iodo) cyclizations have been used to create valuable synthetic thiophene and benzothiophene intermediates with varied substitution patterns. 

In 1961, Gewald and co-workers published the synthesis of poly-substituted thiophenes involving condensation of cyanoacetate and elemental sulphur with ketones or aldehydes in a three-component reaction (Scheme 5.9). Beyond their industrial use in dyes and conducting polymers, 2,5-substituted thiophenes have shown extensive potential in the pharmaceutical industry. Most published Gewald thiophene synthetic procedures require reaction times between 8 and 48 h for the condensation step. Hoener and... 

Peseke and co-workers investigated the effect of incorporating a thienopyrimidine moiety into C-nucleoside analogues to increase cell membrane permeability and antimicrobial and anti-tumor activity. The C-nucleoside derivatives were constructed through the Gewald amino thiophene synthesis in 55% yield under standard conditions. The thiophene intermediate was further converted into a thienopyrimidine to produce the desired compound. 

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. 

Synthesis of 2-aminobenzothiophene derivatives were achieved via a modified Gewald aminobenzothiophene synthesis under the Willgerodt-Kindler conditions." This procedure produced the desired 2-aminobenzothiophenes, such as A-methyl-5-nitrobenzo[b]thiophen-2-amine shown below, in moderate to good yields. 

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... 

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%. 

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. 

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