Eaction inside the presence of triethylamine wasnished, the dehydrogenation reaction having a lightly excess of DDQ was carried out at elevated temperature. Aer workup, the corresponding thiophene derivatives 3aj were ready in great yields. Resulting from formation of aromatized thiophene derivatives, 1H and 13C NMR spectra clearly showed a single set with the characterized absorptions, which also indicated that thereSchemeIllustration of two diastereoisomers for compounds 2an.22500 | RSC Adv., 2018, 8, 22498This journal could be the Royal Society of ChemistryPaperRSC Advancesis only one diastereoisomer in the solutions 3aj. The single crystal structures of the compounds 3a (Fig. three), 3d, 3g (Fig. s5 and s6) had been determined by X-ray diffraction process (Table three). For explaining the formation with the dihydrothiophene derivatives, a plausible reaction mechanism was proposed around the basis on the previously reported reactions.ten Firstly, thebase catalyzed condensation reaction of aromatic aldehyde with malononitrile afforded arylidene malononitrile (A). Secondly, Michael addition with the in situ generated carbanion of 1,3-thiazolidinedione resulted in the adduct (B). In the meantime, totally free a-amino acid ethyl ester was made by the neutralization of triethylamine with a-amino acid ethyl ester hydrochloride. Then the nucleophilic attack of amino groupFig.Crystal structure in the compound 3a.TableSynthesis of thiophene derivatives 3ajaEntry 1 two 3 four 5 6 7 eight 9Compd 3a 3b 3c 3d 3e 3f 3g 3h 3i 3jAr p-CH3OC6H4 m-CH3OC6H4 o-CH3OC6H4 p-CH3C6H4 p-ClC6H4 p-BrC6H4 p-CH3C6H4 p-CH3OC6H4 p-CH3OC6H4 p-CH3OC6HR Bn Bn Bn Bn Bn Bn H Me CH2CH2Ph CH2C6H4OH-pYield ( )b 62 60 60 55 63 55 60 68 58a Reaction circumstances: 1.DBCO-Biotin PROTAC ArCHO (2.0 mmol), CH2(CN)two (2.0 mmol), a-amino acid ethyl ester (two.0 mmol), 1,3-thiazolidinedione (two.0 mmol), Et3N (three.0 mmol), 400 C, 6 h; two. DDQ (2.two mmol), 60 C, 4 h. b Isolated yields.This journal is the Royal Society of ChemistryRSC Adv., 2018, 8, 224982505 |RSC AdvancesPaperSchemeProposed reaction mechanism for the four-component reaction.PBIT Formula towards the carbonyl group of intermediate (B) resulted in the ringopening sulde anion (C).PMID:24624203 The intramolecular nucleophilic addition of sulde anion to a single cyano group with sequential protonation gave the imino-substituted dihydrothiophene (D), which in turn converted for the dihydrothiophene derivatives 1 or two via imino namino tautomerization. The thermodynamically stable trans-isomer was predominately formed inside the cyclization process. At last, DDQ oxidation of dihydrophene resulted inside the thiophene product three (Scheme 2).multicomponent reaction in organic and medicinal chemistry could be signicant.4 Experimental section4.1. General process for the preparation of your dihydrothiophene derivatives 1ag and 2am A mixture of aromatic aldehyde (two.0 mmol) and malononitrile (two.0 mmol) and triethylamine (3.0 mmol) in ethanol (20.0 mL) was stirred at room temperature for a single hour. Then, 1,3-thiazolidinedione (2.0 mmol) and a-amino acid ethyl ester hydrochloride (two.0 mmol) was added. The resulting mixture was stirred at about 400 C for six hours. Aer removing the solvent by rotatory evaporation at decreased stress, the residue was subjected to column chromatography with light petroleum and ethyl acetate (v/v 2 : 1) as eluent to provide pure item for evaluation. 4.1.1 Ethyl ((5-amino-4-cyano-3-phenyl-2,3-dihydrothiophene2-carbonyl)carbamoyl)glycinate (1a). Yellow solid, 49 , mp 188190 C; 1H NMR (400 MHz, DMSO-d6) d: ten.53 (s, 1H, NH), eight.50 (s, 1H,.