Synlett, Table of Contents Synlett 2019; 30(02): 225-229DOI: 10.1055/s-0037-1610679 letter © Georg Thieme Verlag Stuttgart · New YorkUrea–Zinc Chloride Eutectic Mixture-Mediated One-Pot Synthesis of Imidazoles: Efficient and Ecofriendly Access to Trifenagrel Authors Natalia López Higuera Diana Peña-Solórzano Cristian Ochoa-Puentes* Recommend Article Abstract Buy Article(opens in new window) All articles of this category(opens in new window) Abstract The low-melting mixture urea–ZnCl2 was evaluated as a novel reaction medium for the synthesis of imidazoles. The reaction between a dicarbonyl compound, ammonium acetate, and an aromatic aldehyde is efficiently catalyzed by the eutectic solvent, yielding a wide variety of triaryl-1H-imidazoles or 2-aryl-1H-phenanthro[9,10-d]imidazoles in good to excellent yields. In addition, the eutectic solvent was reused in five cycles without loss of its catalytic activity. This protocol was further explored for the synthesis of the drug trifenagrel, giving an excellent yield. Key words Key wordsimidazoles - deep eutectic solvent - multicomponent reaction - trifenagrel - phenanthroimidazoles Full Text References References and Notes 1 Black JW, Durant GJ, Emmett JC, Ganellin CR. Nature 1974; 248: 65 2 Silva VG, Silva RO, Damasceno SR. B, Carvalho NS, Prudêncio RS, Aragão KS, Guimarães MA, Campos SA, Véras LM. C, Godejohann M, Leite JR. S. A, Barbosa AL. R, Medeiros J.-VR. J. Nat. Prod. 2013; 76: 1071 3 Ali I, Lone MN, Aboul-Enein HY. MedChemComm 2017; 8: 1742 4 Rani N, Sharma A, Singh R. Mini-Rev. Med. Chem. 2013; 13: 1812 5 Sharma D, Narasimhan B, Kumar P, Judge V, Narang R, De Clercq E, Balzarini J. Eur. J. Med. Chem. 2009; 44: 2347 6 Uçucu Ü, Karaburun NG, Işikdağ İ. Farmaco 2001; 56: 285 7 Johnson JC, Martinez O, Honko AN, Hensley LE, Olinger GG, Basler CF. 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To this melt was added a mixture of the appropriate dicarbonyl compound (1 mmol), aryl aldehyde (1 mmol), and NH4OAc (2 mmol), and the mixture was stirred at 110 °C for 30 min. When the reaction was complete (TLC), the reaction was quenched by adding H2O to the hot mixture, which was then cooled to r.t. The crude solid was collected by filtration then washed with H2O and EtOH (3 × 2 mL) to afford the pure product.2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (3c)Yellow solid; yield: 327 mg (96%); mp 235–237 °C (Lit.42 237–239 °C). IR (KBr): 3250, 1681, 856 cm–1. 1H NMR (400 MHz, CDCl3): δ = 8.29 (d, J = 8.9 Hz, 2 H, ArH), 8.10 (d, J = 8.7 Hz, 2 H, ArH), 7.58–7.52 (m, 4 H, ArH), 7.40–7.32 (m, 6 H, ArH). 13C NMR (100 MHz, CDCl3): δ = 147.4, 143.4, 135.5, 134.9, 129.9, 129.0, 128.7, 127.8, 125.5, 124.3. MS: m/z = 341 [M+]. N,N-Dimethyl-4-(1H-phenanthro[9,10-d]imidazol-2-yl)aniline (3w)Green solid; yield: 313 mg (93%); mp 258–260 °C (Lit.43 257 °C). IR (KBr): 3381, 1689, 821 cm–1. 1H NMR (400 MHz, DMSO): δ = 8.91 (d, J = 8.1 Hz, 3 H, ArH), 8.66 (d, J = 8.1 Hz, 2 H, ArH), 8.21 (d, J = 9.0 Hz, 2 H, ArH), 7.82–7.79 (m, 3 H, ArH), 6.95 (d, J = 9.2 Hz, 2 H), 3.06 (s, 6 H, NMe2). 13C NMR (100 MHz, DMSO): δ = 154.8, 149.6, 149.0, 146.4, 142.1, 139.5, 133.5, 130.9, 129.6, 128.9, 128.3, 128.0, 127.2, 126.6, 124.8, 124.5, 123.6, 123.0, 122.5, 112.2, 109.2, 108.7, 40.5. MS: m/z = 337 [M+].{2-[2-(4,5-Diphenyl-4,5-dihydro-1H-imidazol-2-yl)phenoxy]ethyl}dimethylamine (Trifenagrel)Light-yellow solid; yield: 352 mg (92%); mp 133–135 °C. FTIR (KBr): 3429, 2922, 1734, 1219, 1039 cm–1. 1H NMR (400 MHz, DMSO): δ = 8.20 (dd, J = 7.8, 1.7 Hz, 1 H, ArH), 7.74 (s, 1 H, ArH), 7.49 (d, J = 7.3 Hz, 4 H, ArH), 7.37 (t, J = 8.9 Hz, 3 H, ArH), 7.24 (d, J = 8.2 Hz, 1 H, ArH), 7.12 (t, J = 7.5 Hz, 1 H, ArH), 7.06 (dd, J = 9.0, 3.4 Hz, 3 H, ArH), 4.28 (t, J = 5.2 Hz, 2 H, –OCH2), 2.64 (t, J = 4.8 Hz, 2 H, –CH2–N–), 1.90 (s, 6 H, NMe2). 13C NMR (100 MHz, DMSO): δ = 161.2, 155.4, 143.4, 138.6, 130.0, 128.9, 128.4, 127.8, 127.4, 122.2, 120.0, 115.0, 65.9, 57.8, 44.4. MS: m/z = 383 [M+]. 39a Maleki A, Movahed H, Paydar R. RSC Adv. 2016; 6: 13657 39b Zarnegar Z, Safari J. New J. Chem. 2014; 38: 4555 40 Abrahams SL, Hazen RJ, Baston AG, Philips AP. J. Pharmacol. Exp. Ther. 1989; 249: 359 41a Mukhopadhyay C, Tapaswi PK, Drew MG. B. Tetrahedron Lett. 2010; 51: 3944 41b Bharate JB, Abbat S, Sharma R, Bharate PV, Vishwakarma RA, Bharate SB. Org. Biomol. Chem. 2015; 13: 5235 41c Mirjafari A. Environ. Chem. 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