The Gewald multicomponent reaction

Abstract

The Gewald reaction of sulfur, cyanoacetic acid derivatives, and oxo-component (G-3CR) yielding highly substituted 2-aminothiophene derivatives has seen diverse applications in combinatorial and medicinal chemistry. Its products are of great use in pharmaceutical industry mainly as small molecular weight inhibitors. We herein review synthetic scope and variations, usage, and structural biology of Gewald products.

Aqueous DABCO, an efficient medium for rapid organocatalyzed Knoevenagel condensation and the Gewald reaction

“…Ethyl cyanoacetate showed a slightly slower reaction due to the lower activity it has (entry 2). Other aldehydes behaved in a similar manner and produced high yields of their respective products (entries [3][4][5][6][7][8][9][10][11][12][13][14]. In all reactions with 2b, only geometric E isomers were obtained in high yields within 1-2 min.…”

A Structurally Diverse Heterocyclic Library by Decoration of Oxcarbazepine Scaffold

“…Thus, access to the pentacyclic pyrazolo [1,5-a] Nevertheless, the participation of 1 in other cyclocondensation reactions proved to be a tricky undertaking. The application of Gewald conditions [32] to the reaction of 1 with ethyl cyanoacetate and sulphur in the presence of diethylamine (MeOH, 65 °C, 20 h) provided only extensive decomposition products and no isolable quantities of the expected 2-aminotiophene derivative 33. Furthermore, attempts at replacing sulphur by selenium under the same conditions to achieve a seleno-Gewald multicomponent reaction [33] also gave a complex mixture of products, none of which was the desired 2-aminoselenophene 34.…”

“…When the reaction was complete, the solvent was removed under vacuum, water was added to the residue and the aqueous phase was extracted with AcOEt (3 × 10 mL). The combined organic layers were dried (Na 2 [1',2':1,5]pyrazolo [3,4-d]azepine-9-carboxamide (32). Oxcarbazepine (1, 300 mg, 1.19 mmol), 1-aminopyridinium iodide (317 mg, 1.43 mmol) and potassium carbonate (493 mg, 3.57 mmol) were dissolved in a mixture of H 2 O (20 mL) and i-PrOH (20 mL).…”

A facile and environmentally benign polyethylene glycol 600-mediated method for the synthesis of densely functionalized 2-aminothiophene derivatives under ultrasonication

“…Lower reaction and purification steps, and high atom economy as well as highly convergent and requiring minimum time compared to multi-step alternative synthetic routs make MCRs good candidates for green organic processes (12)(13)(14)(15)(16)(17)(18)(19). The Gewald reaction is a popular catalytic and one-pot three-component reaction between elemental sulfur, a cyanomethylene containing an electron-withdrawing group and an enolizable carbonyl compound that affords highly substituted 2-aminothiophene derivatives (12,20). Indeed, 2-aminothiophene scaffold has found wide applications from modern drug design (21,22) to dye chemistry (23,24) (Figure 1).…”