ARTICLE Citrate trisulfonic acid: A heterogeneous organocatalyst for the synthesis of highly substituted Imidazoles Elham Kanaani | Masoud Nasr-Esfahani Department of Chemistry, Yasouj University, Yasouj, Iran Correspondence Masoud Nasr-Esfahani, Department of Chemistry, Yasouj University, Yasouj 75918-74831, Iran. Email: manas@yu.ac.ir; m_nasr_e@yahoo.com Citrate trisulfonic acid (CTSA), as a novel recyclable and eco-benign organocata- lyst, was employed for the efficient and one-pot synthesis of trisubstituted imidaz- oles and tetrasubstituted imidazoles using aldehydes, ammonium acetate or aniline, and benzoin, benzyl, or 9,10-phenanthrenequinone under solvent-free conditions providing high to excellent yields. CTSA is easily prepared via the reaction of tri- sodium citrate and chlorosulfonic acid in high purity. Compared to the conven- tional procedures, the present method offers several advantages, including high yields, easy work-up, short reaction time, reusability of the catalyst, and simple purification of the products. KEYWORDS citrate trisulfonic acid, organocatalyst, reusable catalyst, solvent-free, tetrasubstituted imidazoles, trisubstituted imidazoles 1 | INTRODUCTION Imidazole and its derivatives form an important class of heterocycles and show a wide variety of biological activities such as herbicidal, [1] antiallergic, [2] analgesic, [3] antidepressant, [4] antitubercular, [5] anticancer, [6] anti-inflam- matory, [7] antifungal, [8] and antiviral. [9] They are present in important building blocks including histidine [10] and the related hormone histamine. [11] A number of these ring sys- tems are used in electronic and optoelectronic devices. [12] Trisubstituted imidazoles are used in photography as photo- sensitive compounds. [13] They are also found to possess high anti-inflammatory activity. Tetrasubstituted imidazoles are active ingredients in many pharmaceuticals including olme- sartan, eprosartan, medoxomil, losartan, and trifenagrel. [14] Imidazole was synthesized for the first time by Heinrich Debus in 1858 from the reaction between glyoxal, formalde- hyde, and ammonia. [15] In 1882, poly-substituted imidazole was synthesized using an aldehyde, a 1,2-dicarbonyl com- pound, and ammonia. [16] In recent years, a number of proce- dures for the preparation of trisubstituted and tetrasubstituted imidazoles have been reported. 2,4,5-Trisubstituted imidaz- oles are generally synthesized via the three-component con- densation reaction of α-hydroxyketone or 1,2-diketone, ammonium acetate, and an aldehyde in the presence of a strong protic acid such as H 3 PO 4 , [17] H 2 SO 4 , [18] or other cata- lysts in HOAc [19] under reflux conditions, Wells–Dawson het- eropolyacid supported on silica (WD/SiO 2 ), [20] silica gel, or zeolite HY, [21] ionic liquid, [22] InCl 3 ċ3H 2 O, [23] Yb(OTf ) 3 , [24] and KH 2 PO 4 . [25] Tetrasubstituted imidazoles have been obtained by the four-component cyclocondensation of 1,2-diketone, aldehyde, a primary amine, and ammonium ace- tate using various Lewis or protic acidic reagents such as BF 3 -SiO 2 , [26] silica gel/NaHSO 4 , [27] InCl 3 ċ3H 2 O-MeOH, [23] HPA-EtOH, [28] , L-proline, [29] K 5 CoW 12- O 40 ċ3H 2 O, [30] heteropolyacid, [31] zeolite-HY–Cu(NO 3 ) 2 , [32] and silica- supported Wells–Dawson acid, [20] hetero-Cope rearrange- ment, [33] the reaction between 1,2-diketone, a nitrile, and a primary amine under microwave irradiation, [34] and the reac- tion of 1,3-oxazolium-5-olates with N-(arylmethylene) benzenesulfonamides. [35] Most of the reported literature on the preparation of 2,4,5-triaryl-1H-imidazole has examined benzile as a dike- tone. In this work, we used both benzil and 9,10- phenan- threnequinone as diketones or an α-hydroxyketone. However, most of the existing methods have one or more disadvantages such as expensive catalysts, long reaction time, high cost, and cumbersome work-up procedures. Received: 12 January 2018 Revised: 19 July 2018 Accepted: 21 July 2018 DOI: 10.1002/jccs.201800015 © 2018 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J Chin Chem Soc. 2018;1–7. http://www.jccs.wiley-vch.de 1