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One-Pot Synthesis of Imidazoles CHEMICAL SOCIETY

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One-Pot Synthesis of Imidazoles CHEMICAL SOCIETY View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by ePrints@Bangalore University JOURNAL OF THE CHINESE Article CHEMICAL SOCIETY One-Pot Synthesis of 2,4,5-Triphenyl Imidazoles from 1,2-Diols as Key Reagents Narasashetty Jagadishbabu and Kalegowda Shivashankar* P. G. Department of Chemistry, Central College Campus, Bangalore University, Bangalore 560 001, India (Received: September 16, 2016; Accepted: February 2, 2017; DOI: 10.1002/jccs.201600746) A simple one-pot procedure for the preparation of 2,4,5-triphenyl imidazole derivatives is pre- sented. The procedure involves the lead tetraacetate oxidation of 1,2-diols to give aldehydes in situ, which then undergo a three-component reaction with benzil and ammonium acetate to yield the imidazole derivatives. Keywords: Imidazoles; Lead tetraacetate; Multicomponent reaction; 1,2-Diols; Benzil; Ammonium acetate. INTRODUCTION aldehydes with benzoin or benzil and ammonium Multicomponent reactions (MCRs) have emerged acetate,23 (2) one-pot cyclocondensation of aldehydes as a powerful tool for industrial and academic research with benzil, aromatic amine, and ammonium acetate,24 groups because of their shorter reaction times as well as and (3) one-pot cyclocondensation of aromatic the avoidance of the isolation of intermediates, their nitriles.25 This has led to the development of new, purification, and characterization.1–3 Imidazoles have a improved methodologies involving the use of a number 26 27 privileged structure as they occur as fragments in drugs of catalysts such as Yb(OPf )3, Cu(NO3)2/zeolite, 28 29 displaying a wide spectrum of pharmacological potassium dihydrogen phosphate, ZrOCl2.8H2O, 4–9 30 31 activities. A large number of compounds bearing Zr(acac)4, NiCl2.6H2O, p-toluenesulfonic acid 32 33 34 35 substituted imidazole derivatives have entered preclini- (PTSA), TiCl4-SiO2, MCM-41, ZrCl4, sodium cal and clinical trials over the last few years. These deri- bisulfite,36 polymer-supported zinc chloride,37 alum,38 vatives represent an important structural motif in zinc oxide,39 trichloroisocyanuric acid,40 tetrabutyl commercial drugs10 such as the anti-gastroesophageal ammonium bromide,41 ceric ammonium nitrate,42 nano reflux drug Omeprazole, platelet aggregation inhibitor copper/cobalt ferrites,43 microwave,44 amberlyst,45 Trifenagrel, angiotensin II receptor blocker Olmesartan, novel polymers,46 antimony trichloride/stannous chlo- 47 48 49 and the anti-high-blood-pressure drugs Eprosartan and ride dihydrate, SbCl3/SiO2, sulfamic acid/Fe3O4, Losartan (Figure 1). and nano aluminum nitride.50 Although several meth- Imidazole derivatives have received significant odologies have been documented, most of them have importance because of their diverse biological properties their own drawbacks such as poor yields, the use of such as anti-inflammatory,11 antimicrobial,12 anticancer,13 toxic catalysts, and tedious work-up. Aldehydes are antitubercular,14 antifungal,15 antibacterial,16 antiviral,17 ubiquitous substrates in many powerful MCRs. How- antioxidant,18 and amebicidal activities.19 The great ever, they are in general unstable, especially because of potential of substituted imidazole derivatives in the phar- aerial oxidation to acids, and are prone to polymeriza- maceuticals field has therefore triggered growing interest tion or hydrolysis. Thus, in many cases aldehydes must in their synthetic study. be purified just before their use because the presence of These applications have stimulated widespread other products not only affects the concentration of the interest in the synthesis of imidazole derivatives. The active aldehyde but also interferes with the chemical typical syntheses of imidazole derivatives have been reactions.51 Hence, there is a need to develop a rapid well documented in the literature.20–22 The most impor- and efficient synthetic protocol for the one-pot synthesis tant of these are (1) one-pot cyclocondensation of of substituted imidazole scaffolds. *Corresponding author. Email: [email protected] J. Chin. Chem. Soc. 2017 © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1 Article Jagadishbabu and Shivashankar OH Table 1. Optimization of solvents for the synthesis (4a) N N O N N N NH S N RO N N O N N Entry Solvents Time (h) Yield (%) H H O O NMe2 O 1 DCM 5.5 48 Omeprazole Trifenagrel Olmesartan 2 Dioxane 4.5 71 Cl N N N N NH 3 Acetonitrile 3 90 S HO N N N 4 Ethanol 3 96 HOOC COOH 5 Acetone 4.5 74 Eprosartan Losartan 6 THF 4 76 Fig. 1. Typical imidazole drugs. 7 Methanol 3.5 84 8 DMF 5.5 45 9 DMSO 5.5 52 In continuation of our work on the synthesis of heterocycles and development of useful synthetic same reaction. Among the solvents, ethanol was found to methodologies,2,52–57 in this study we report the use of be the best one for this reaction in terms of yield and lead tetraacetate as an oxidizing agent for the synthesis reaction time. of 2,4,5-triphenyl imidazole derivatives under mild con- The scope and limitations of this three-component ditions. Lead tetraacetate is an inexpensive, commer- reaction under optimized reaction conditions were stud- cially available, and easy-to-handle reagent. ied using a variety of 1,2-diols, benzil, and ammonium acetate. The reaction worked well in case of 1,2-diols RESULTS AND DISCUSSION tethered with OH, Cl, Br, F, and OCH3 groups. Mod- In our preliminary studies, 1 equiv of 1,2-diphe- erate yield was obtained for the reaction involving 1,2- nyl-1,2-ethanediol 1a, 2 equiv of benzil 2, 4 equiv of diol tethered with NO2 group. In all cases, the reaction ammonium acetate 3, and 1 equiv of lead tetraacetate proceeded smoothly to afford the desired products with in dioxane were chosen for the model reaction good to excellent yields (Table 2). 60,61 (Scheme 1). Initially, when the model reaction was Mechanistically, lead tetraacetate oxidizes 1,2- carried without lead tetraacetate from room tempera- diol to benzaldehyde giving acetic acid, which facilitates ture to 101C, no desirable product was observed even the formation of the imine between benzaldehyde and after prolonged reaction time. This indicated that an oxi- ammonium acetate. The imine then reacts with the dizing agent was absolutely necessary for the reaction. intermediate that is formed by the reaction of benzil Interestingly, in the presence of lead tetraacetate, when with ammonium acetate to give the corresponding imid- the same set of substrates were tested under reflux condi- azole via cyclization and dehydration (Figure 2). tion in dioxane, they provided 4a in 71% yield in 4.5 h. The compound 4a was confirmed by IR and 1HNMR. EXPERIMENTAL From this encouraging result, we were prompted to check General information whether the yield could be further improved by changing Melting points were determined on an electric the solvent. Other solvents such as DCM, acetonitrile, melting point apparatus and were uncorrected. Fourier ethanol, acetone, THF, methanol, DMF, and DMSO transform infrared (FT-IR) spectra were recorded on were screened (Table 1) under reflux condition for the an Agilent Cary 630 instrument. 1H NMR (400 MHz) O Pb(OAc) / Dry EtOH/ Reflux N OH 4 + 4NH4OAc 2 + 2 N O H OH 3 Pb(OAc)2 + 6H O + 6AcOH 2 4a 1a 2 Scheme 1 Synthesis of 2,4,5-triphenyl imidazole derivatives using lead tetraacetate as a reagent. 2 www.jccs.wiley-vch.de © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim J. Chin. Chem. Soc. 2017 JOURNAL OF THE CHINESE One-Pot Synthesis of Imidazoles CHEMICAL SOCIETY Table 2. Synthesis of 2,4,5-triphenyl imidazole derivatives (4a–o) Entry 1,2-Diols Products Time (h) Yield (%) Obs. Mp (C) Lit. Mp (C)ref 43 1 OH 3 96 276–278 275–277 N OH N H 1a 4a 2 Cl 2.5 89 233–235 234–23639 OH N Cl OH N Cl H 1b 4b 3 2.5 90 244–246 245–24738 OH Cl Cl N Cl OH N H 1c 4c 4 OEt 3 91 218–220 218–22058 OH N OEt OH N EtO H 1d 4d 5 O 3.5 92 231–233 OH Br Br N Br O OH N O H 4e 1e 6 NO 4.5 82 242–244 240–24223 OH 2 N NO2 OH N O2N H 1f 4f 7 Br 4 89 255–257 Br Cl OH N Cl N H OH Cl 4g Br 1g 39 8 OH 3 92 232–234 233–235 N OH N H 1h 4h 9 Br 3.5 91 246–248 248–25039 OH N Br OH N Br H 1i 4i J. Chin. Chem. Soc. 2017 © 2017 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.jccs.wiley-vch.de 3 Article Jagadishbabu and Shivashankar Table 2. Continued Entry 1,2-Diols Products Time (h) Yield (%) Obs. Mp (C) Lit. Mp (C)ref 10 F 3 90 238–240 239–24123 OH N F OH N F H 1j 4j 11 Br 4 89 257–259 OH Cl Cl N Cl Br OH N Br H 4k 1k 12 OH 2.5 95 255–257 256–25854 OH N OH OH N HO H 1l 4l 13 Cl 4 88 263–265 265–26759 Cl OH Cl N OH Cl N Cl H Cl 1m 4m 14 2 96 219–221 218–22036 O O O OH N O N H OH O 4n O 1n 15 F 4 89 263–265 Cl OH F N OH Cl N F H Cl 1o 4o and 13C NMR (100 MHz) spectra were recorded in room temperature for 5 min. Then, benzil (0.42 g, 2 mmol) CDCl3 and DMSO-d6 with TMS as internal standard and ammonium acetate (0.32 g, 4.2 mmol) were added to a using a Bruker spectrometer.
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