Microwave assisted, sequential two-step, one-pot synthesis of novel imidazo[1,2-a] pyrimidine containing tri/tetrasubstituted imidazole derivatives

Turkish Journal of Chemistry http://journals.tubitak.gov.tr/chem/ Research Article Turk J Chem (2021) 45: 219-230 © TÜBİTAK doi:10.3906/kim-2009-40 Microwave assisted, sequential two-step, one-pot synthesis of novel imidazo[1,2-a] pyrimidine containing tri/tetrasubstituted imidazole derivatives Tuğba GÜNGÖR* Department of Chemistry, Faculty of Sciences and Arts, Natural Products and Drug Research Laboratory, Çanakkale Onsekiz Mart University, Çanakkale, Turkey Received: 14.09.2020 Accepted/Published Online: 26.11.2020 Final Version: 17.02.2021 Abstract: A series of novel imidazo[1,2-a]pyrimidine containing tri/tetrasubstituted imidazole derivatives (1-10) has been synthesized via sequential two-step, one-pot, multicomponent reaction using imidazo[1,2-a]pyrimidine-2-carbaldehyde, benzil, primary amines, and ammonium acetate catalyzed by p-toluenesulfonic acid under microwave-assisted conditions. The results showed that target compounds can be obtained from a wide range of primary amines bearing different functional groups with moderate to good yields (46%-80%) under optimum reaction conditions. This method provides a green protocol for imidazo[1,2-a]pyrimidine containing tri/ tetrasubstituted imidazole derivatives due to ethyl alcohol as a green solvent, microwave irradiation as a greener heating method and one-pot multicomponent reaction as a green technique. The synthesized compounds have been elucidated using various spectroscopic tools such as FT-IR, 1H NMR, 13C NMR, and MS. Key words: Imidazo[1,2-a]pyrimidine, tri/tetrasubstituted imidazole, microwave synthesis, sequential, one-pot reaction, p-toluenesulfonic acid 1. Introduction Nitrogen containing heterocyclic compounds have a great interest within the field of pharmaceutical chemistry and drug industry due to their strong and selective hydrogen bonds with protein/enzyme moieties, which are responsible for important biological activities [1-3]. Imidazole moieties are privileged structures in today’s medicinal chemistry. Also, multisubstituted imidazoles exhibit good pharmaceutical properties such as antibacterial [4], antioxidant [5], anticancer [3], antifungal [5], p38α MAP kinase inhibitor [6], B-Raf kinase inhibitor [7] etc. [8-11]. In addition, imidazole derivatives are used as ionic liquids which are nonvolatile and clean solvents in green chemistry, and materials for energy-based areas [12]. Some APIs such as losartan, eprosartan, and olmesartan are well-known substituted imidazoles, which are used, in the treatment of especially high blood pressure (hypertension), indirectly diabetic kidney disease and heart failure and also trifenagrel drug uses, as arachidonate cyclooxygenase inhibitor [1,13-15] (Fig. 1). On the other hand, imidazo[1,2-a]pyrimidines are an important fused heterocyclic class, which shows significant biological properties such as antiinflammatory [16], cardiovascular [17], anticancer [18,19], antimicrobial [19], p38 MAP kinase inhibitors [20], HIV-1 inhibitor [21], and so on [22,23]. Some of the most successful imidazo[1,2-a]pyrimidinecontaining APIs are fasiplon, taniplon, and divaplon, which show anxiolytic and anticonvulsant effects [24-26] (Fig. 1). Also, our group has previously reported the synthesis and characterization of some imine and pyran derivatives of imidazo[1,2-a]pyrimidine and biological studies on these structures are ongoing [27,28]. Hence, to incorporate these two nitrogen containing heterocycles, imidazole and imidazo[1,2-a]pyrimidine, can contribute to obtaining a new class of compounds that may have good biological and medicinal properties. Some of the reported biologically potent imidazole and imidazo[1,2-a]pyrimidine derivatives were given in Figure 1 [18,19]. Various synthetic methodologies were developed to obtain 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazole derivatives by numerous scientists. One of the most studied methodology is one-pot multicomponent reactions of 1,2-diketone/α-hydroxyketone, primary amines, benzil, and ammonium acetate in the presence of catalysts of different properties such as acidic/basic/neutral, homogeneous/heterogenous, ionic liquids, or nanoparticles using conventional heating, microwave, or ultrasound energies [8,11,29-31]. FeCl3.6H2O [32], NaH2PO4 [33], ZnO [10], trityl chloride * Correspondence: This work is licensed under a Creative Commons Attribution 4.0 International License. 219 GÜNGÖR / Turk J Chem Figure 1. Structures of some biologically active imidazoles and imidazo[1,2-a]pyrimidines. [13], MCM-41silica or p-TsOH [34], benzotriazole [35], HBF4–SiO2 or LiBF4 [11], TBABr [36], γ-Fe2O3@TiO2-EGCu(II) [37] can be given as efficient catalysts in this area. Also, these targets can be synthesized from various starting materials at different reaction conditions such as one-pot condensation of nitriles, amines and benzoin, N-alkylation of trisubstituted imidazoles, cyclocondensation of N-alkyl-α-acetamidoketone/alcohol with ammonium acetate/ammonium trifluoroacetate, two-step reactions from alkenes through ketoiodonation/cyclisation, [3+2] or [2+2+1] annulation reactions from 2,3-disubstitutedazirines and imines, reaction of aldehydes with α-amido sulfones and so on [8,11,32,38]. Microwave energy is used extensively to heat or to carry out chemical reactions in a wide range of applications such as organic synthesis, polymer/material sciences, nanotechnological, and biochemical procedures since the first report on microwave assisted organic synthesis by Gedye and Giguere/Majetich in 1986 [39-42]. This environmentally friendly technique is applied to a wide variety of reaction types due to its superior properties such as short reaction time, high product yield, fewer by-products, high purity compared with conventional heating [39,40,43]. Also, there are some examples on microwave-promoted synthesis of imine functional group containing heterocyclic compounds and tri/ tetrasubstituted imidazole derivatives with one-pot multicomponent reaction in the literature [27,30,44-47]. In addition, one-pot multicomponent approach is a very useful tool to construct the complex compounds in recent years due to the advantages of short reaction time, high atom economy, minimum energy consumption, safety, cheapness, easy applicability, and environmentalist [48]. In this study, one-pot, sequential two step synthesis of imidazo[1,2-a]pyrimidine containing tri and tetrasubstituted novel imidazoles (1-10) from imidazo[1,2-a]pyrimidine-2-carbaldehyde, aliphatic/aromatic amines, benzil, and ammonium acetate in the presence of p-TsOH catalyst applying microwave energy was reported for the first time (Scheme 1). Spectroscopic characterizations of products were carried out with FT-IR, 1H NMR, 13C NMR, and MS analyses. The synthesized compounds are expected to exhibit good biological properties due to having two nitrogen-containing heterocycles, imidazole, and imidazo[1,2-a]pyrimidine as potential pharmacophores. 2. Materials and m (...truncated)