Studies with enamines: Functionally substituted enamines as aldehyde equivalents in Gewald reaction

Abstract

Several aryl and functionally substituted enamines reacted with ethyl cyanoacetate and elemental sulfur to form 2-aminothiophene-3-carboxylic acid derivatives that proved to be excellent precursors for a variety of thiophenes.

Design, synthesis, and biological evaluation of new thieno[2,3-d] pyrimidine derivatives as targeted therapy for PI3K with molecular modelling study

“…The designed thienopyrimidine based inhibitors ( IIIa–k, VIa–m, VIII , and IX ) were synthesised through the synthetic routes outlined in ( Schemes 1–3 ). Beginning with “Gewald Aminothiophene Synthesis” 29 to prepare the key 2-aminothiophene intermediates ( I and IV ) through a one-pot reaction involving ethyl acetoacetate or cyclohexanone, activated cyanoacetamide and elemental sulphur in presence morpholine as base in DMF as polar solvent 30–35 . Then thieno[2,3- d ]pyrimidin-4-one derivatives IIa–k and Va–e and Vg–m were synthesised by reaction of I or IV with different aldehydes in presence of a catalytic amount of concentrated HCl and in dry DMF 36–38 .…”

“…The targeted compounds I 34 and IV 35 were prepared through the “Gewald Aminothiophene Synthesis” 29 which is a one-pot reaction that involves a multi-component condensation between an α-methylene carbonyl compounds and activated nitriles with elemental sulphur in presence of a base to produce 2-aminothiophene derivatives. In the present study, the titled 2-aminothiophene ( I , IV ) were obtained by reacting cyanoacetamide (38.5 mmol, 1 equivalent) with ethyl acetoacetate or cyclohexanone (38.5 mmol, 1 equivalent) and elemental sulphur (38.5 mmol, 1 equivalent) in polar solvent DMF containing morpholine as base 30–35 . The product was assessed for its formation using TLC.…”

Synthesis of 2-Aminofurans and 2-Aminothiophenes through Elemental Sulfur-Promoted Switchable Redox Condensation Reaction of Enaminones with Methylene Nitriles

“…Procedure for Preparing 6-Benzoylthieno[2,3-d]pyrimidin-4(3H)-one (7a). 20 Under air atmosphere, 5a (0.5 mmol, 114 mg) and formic acid (10 mL) were added to a 50 mL reaction tube. The mixture was stirred at 110 °C reflux in an oil bath for 24 h. After cooling to room temperature, the reaction was quenched with saturated NaCl solution and extracted with 60 mL of EtOAc three times.…”

“…Catalytic processes have been developed to obtain structurally diverse 2-aminofurans or 2-aminothiophenes, for example, transition metal-catalyzed reaction of 2-halofurans, allenylamides, ynamides, multi-component mixture isocyanide/aldehyde/electron-poor alkyne, and α-haloketones with tertiary amines/enamines, but all the reported protocols generally require metal catalysts in high loading, properly functionalized, and not commonly available substrates. Additionally, cyclization of nitriles is also an important method for traditional synthesis of 2-aminofurans and 2-aminothiophenes, for example, the reaction of α-bromoacetophenones with malononitrile and the synthesis of Gewald 2-aminothiophenes . However, the cyclization of nitriles as well as all of its variations has an intrinsic limitation: the obtained 2-amino-furans/thiophenes should have an electron-withdrawing group (EWG) in the position C3 of the furan/thiophene ring, such as cyano, ketone, and so forth.…”

Surmounting the resistance against EGFR inhibitors through the development of thieno[2,3-d]pyrimidine-based dual EGFR/HER2 inhibitors

“…The synthetic route for the preparation of the target compounds (13)(14)(15)(16)(17)(18)(19)(20) for the first screening cycle is shown in scheme 1. Firstly, the core scaffold, 4-chloro-6-(4nitrophenyl)thieno [2,3-d]pyrimidine (12), was synthesized starting with a Batcho-Leimgruber-like condensation between 4-nitrotoluene and N,N-dimethylformamide dimethyl acetal in dimethylformamide affording the enamine (9) [37], followed by Gewald's 2-aminothiophene synthesis through a one-pot reaction between the enamine (9), ethyl cyanoacetate, elemental sulfur and morpholine in ethanol giving the 2aminothiophene (10) [38] which was then cyclized by heating with formamide into the thieno [2,3-d]pyrimidinone (11), eventually, (11) was activated for nucleophilic substitution by chlorination with phosphorus oxychloride producing the activated 4-chloro-6-(4-nitrophenyl)thieno [2,3-d]pyrimidine (12). Subsequently, the target compounds (13)(14)(15)(16)(17)(18) were obtained by nucleophilic substitution of the 4-chloro derivative (12) with varied aniline derivatives (R 1 ) in i-propanol or n-butanol.…”