Gewald reaction

Entry R Ball Mill 24h Ball Milb 0.5h, Heat Gun Oven 120°C, 1h Oven 120°C, 1 h, Cat. Morpholine 

Reproduced from Shearouse WC, Shumba MZ, Mack J. A solvent-free, one-step, one-pot gewald reaction for alkyl-aryl ketones via mechanochemistry. AppI Sol 2014 4 171-9. With permission from MDPI. 

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The first step in the Gewald reaction is a Knoevenagel condensation of an activated nitrile with a ketone or aldehyde to produce an acrylonitrile 8, which is then thiolated at the methylene position with elemental sulfur. The sulfurated compound 9 initially decays... 

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. ... 

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. 

The Gewald reaction was utilized to prepare glycopyranosyl thiophene C-... 

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%. 

Figure 15.6. Mechanisms of thiophene formation by the Thorpe-Ziegler and Gewald reactions. X leaving group Z electron-withdrawing group.

Furthermore, the Gewald reaction [66] opened a simple and economic route from aliphatic reactants to amino thiophenes that were formerly only accessible from multistep reactions [67] (see, e.g., the dye 31). For example, 2-amino-3-car-bethoxy-5-nitrothiophene, a precursor for the dye 32, can be prepared by reaction of 1,4-dithiane with ethyl cyanoacetate and subsequent nitration. 

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. 

The solid-state synthesis of thienopyridines by the Gewald reaction was documented. For example, 214 was prepared in 92% yield by cyanoacetylation of a polymer support and the reaction of the resulting ester on the polymer support with sulfur and piperidin-4-one 212 followed by acylation and elimination of the polymer matrix (2001TL7181). 

Annulation reactions, in which thieno[2,3-c]pyridines and, in particular, tetra-hydrothienopyridines of general formula 229, serve as building blocks, are of considerable interest. This choice is associated primarily with the ease of preparation of these compounds by the Gewald reaction, as well as with the presence of two vicinal functional groups, favorable for the formation of additional rings. 

Multi-component condensation of ketones (or aldehydes), a-aclivc methylene nitriles and elementary sulfur (the Gewald reaction) is an efficient methodol-... 

Scheme 14 Microwave-assisted Gewald reaction on solid support...

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 . 

Sridhar and co-workers [192] have described a microwave-promoted synthesis of 2-aminothiophenes 146 by reaction of a ketone with a nitrile and elemental sulfur using KF-alumina as a base via multicomponent condensation reaction. This method offers an efficient and convenient modification to the Gewald reaction replacing organic base with KF-alumina (Scheme 111). 

Sridhar M, Rao RM, Baba NHK et al (2007) Microwave accelerated Gewald reaction synthesis of 2-aminothiophenes. Tetrahedron Lett 48 3171-3172... 

The Gewald reaction [54] is one of the most facile methods of preparing 2-aminothiophenes from activated nitriles, active methylene compounds and elemental sulfur (Fig. 14). 

Gewald reaction of compounds 99 with sulfur under reflux conditions or with microwave heating yielded the final products 100. 

Sabnis RW, Rangnekar DW, Sonawane ND (1999) 2-Aminothiophenes by the Gewald reaction. J Heterocycl Chem 36 333-345... 

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