Araştırma Makalesi BAUN Fen Bil. Enst. Dergisi, 22(2), 428-438, (2020) DOI:10.25092/baunfbed.707673 J. BAUN Inst. Sci. Technol., 22(2), 428-438, (2020) Preparation of novel imidazo[1,2-a]pyrimidine derived schiff bases at conventional and microwave heating conditions Tuğba GÜNGÖR* Çanakkale Onsekiz Mart University, Faculty of Sciences and Arts, Department of Chemistry, Natural Products and Drug Research Laboratory, Terzioğlu Campus, Çanakkale. Geliş Tarihi (Received Date): 11.10.2019 Kabul Tarihi (Accepted Date): 30.01.2020 Abstract In this study, novel imidazo[1,2-a]pyrimidine derived schiff bases were synthesized via imine formation reaction and characterized with various spectral analysis such as FT- IR, 1H NMR, 13C NMR and MS. In addition to conventional heating reactions, microwave-assisted synthesis was applied to the C=N bond formation step. The reactions were carried out at reflux temperature in toluene and magnesium sulfate as drying agent. While final products were obtained at 10-36 h reaction times with moderate to good yields at conventional heating conditions, synthesized at 45-120 min reaction times with good yields at microwave heating conditions. Results showed that microwave-assisted synthesis which is a well-known green process for the synthesizing organic molecules provides to obtain shorter reaction times and higher yields in our study. Keywords: Schiff base, imidazo[1,2-a]pyrimidine, microwave synthesis, conventional heating. Geleneksel ve mikrodalga ısıtma koşullarında yeni imidazo[1,2-a]pirimidin türevi schiff bazlarının hazırlanması Öz Bu çalışmada yeni imidazo[1,2-a]pirimidin türevli schiff bazları, imin oluşum reaksiyonu ile sentezlenmiş ve FT-IR, 1H NMR, 13C NMR, MS gibi çeşitli spektral analizler ile yapıları aydınlatılmıştır. Geleneksel ısıtma ile gerçekleştirilen reaksiyonlara ek olarak C=N oluşum basamağına mikrodalga-destekli sentez de uygulanmıştır. Reaksiyonlar, magnezyum sülfatın kurutucu olarak kullanıldığı, toluen * Tuğba GÜNGÖR, [email protected], https://orcid.org/0000-0001-5261-1856 428 GÜNGÖR T. içerisinde kaynama sıcaklığı koşullarında yürütülmüştür. Son ürünler, geleneksel ısıtma koşullarında 10-36 sa reaksiyon sürelerinde orta-iyi verimlerle elde edilirken, mikrodalga ısıtma koşullarında 45-120 dk reaksiyon sürelerinde iyi verimlerle sentezlenmiştir. Sonuçlar göstermiştir ki, organik moleküllerin sentezinde, iyi bir yeşil proses olarak bilinen mikrodalga-destekli sentez, bizim çalışmamızda daha kısa reaksiyon süreleri ve yüksek verimler elde edilebilmesini sağlamıştır. Anahtar kelimeler: Schiff bazı, imidazo[1,2-a]pirimidin, mikrodalga sentez, geleneksel ısıtma. 1. Introduction Nitrogen containing heterocycles are significant inputs of the drug industry since commonly found in synthetic and natural drugs. Among them, the fused heterocyclic cores with pyrimidine ring have a central place due to their exclusive medicinal applications [1]. The synthesis, biological and pharmacological studies on imidazo[1,2- a]pyrimidines which forms the fusion of imidazole and pyrimidine moieties have speeded up in recent days because of their superior medical properties such as anticancer, cardiovascular, antibacterial, antimicrobial, antifungal, antiviral, anti- inflammatory, HIV inhibitor, local anesthetic, kinase inhibitors and their photophysical applications such as biomarkers and photochemical sensors due to their fluorophore properties [2-5]. Fasiplon, taniplon and divaplon are known as anxiolytic and anticonvulsant drugs in the market from the imidazo[1,2-a]pyrimidine drug family [3]. Schiff bases are obtained as a result of the condensation reaction with aldehyde/ketone and aromatic amines. Schiff bases are known as imine compounds containing C=N bond and synthesized the first time in 1869 by German chemist, Hugo Schiff. These compounds are an interesting class because of be stable, easily synthesized and their broad range applications such as biological including anticancer, antioxidant, antimicrobial, antitubercular, antifungal, analgesic, antiinflammatory and material science such as optical computer, photodetector, photostabilizer, solar filter, opto- electronic, electrode, organic battery, electrochromic device and corrosion areas [6-10]. Microwave energy has been using to synthesize various molecules by different type of reactions as an efficient eco-friendly technique since 1980s [11-14]. Microwave-assisted organic synthesis (MAOS) has many advantages over the conventional heating methods such as reduction in the reaction times, improvement in the yields, decreasement the decomposition of reactants and products, enhancement the product purities and selectivity in an environmentally friendly reaction medium [12-14]. However, there are not many examples on the microwave-assisted synthesis of imines in the literature [11, 15-17]. We report herein the conventional and green microwave-asssisted synthesis of a variety of imidazo[1,2-a]pyrimidine derived schiff bases. These compounds may be used for potential biological application in future drug research. 429 BAUN Fen Bil. Enst. Dergisi, 22(2), 428-438, (2020) 2. Material and method 2.1. General Information All chemicals were supplied from commercial sources and used directly in reactions. Microwave synthesis experiments were conducted by using CEM SP Discover Microwave Synthesis Reactor with dynamic mode option. The melting points were determined with X-4 Melting-point Apparatus. Analytical thin-layer chromatography was performed on precoated Kieselgel 60GF254 plates. The spots were visualized by UV light (254 nm) and KMnO4 stain. Silica gel 60 (230-400 mesh, Merck) was used for column chromatography. Perkin Elmer Spectrum 100 FTIR spectrophotometer was used for Infrared spectra by applying ATR techniques. 1H and 13C NMR spectras were obtained by Jeol 400 MHz NMR spectrometer using TMS as internal standard and DMSO-d6 as solvent. The molecular weights of products were determined at Shimadzu LC-MS/MS 8040 Liquid Chromatograph Mass Spectrometer using an ESI source. 2.2. Synthesis and Characterization of S1-S5 General Procedure for Conventional Heating Reactions The mixture of imidazo[1,2-a]pyrimidine-2-carbaldehyde (1.0 equiv.) and aromatic amines (aniline, 4-chloroaniline, 4-aminophenol, 1-naphthylamine and 3,5- difluoroaniline) (1.0 equiv.) were dissolved in appropriate volume of toluene. Magnesium sulfate (1.0 equiv.) was added to the reaction medium and the resulting mixture was refluxed for various reaction times (10-36 h). After completion of the reaction detected by TLC (EtOAc), toluene was evaporated to dryness. DCM was added to the residue, MgSO4 was filtered and washed with DCM. The solvent was concentrated in vacuo. The crude product was purified by using crystallization or column chromatography techniques. General Procedure for Microwave Irradiation Reactions Aldehyde (1.0 equiv.) and aromatic amines (1.0 equiv.) were dissolved in toluene at a 10 mL microwave reaction vessel. MgSO4 (1.0 equiv.) was added and stirred at room temperature for 3 min. The mixture was heated at 120 °C under dynamic mode of microwave irradiation for 45-120 min. After completion of the reaction, the mixture was warmed to room temperature. Same work-up and purification procedures mentioned above were applied. N-(Phenyl)-1-(imidazo[1,2-a]pyrimidin-2-yl)methanimine (S1). The reaction was performed under general procedure conditions as described above, using aldehyde derivative and aniline with 10 h and 60 min reaction times for conventional and microwave heating conditions, respectively. The crude product was purified by column chromatography on silica gel (hexane/ethyl acetate, 1:12) to give compound S1. Yellow solid; 82 and 80% yield (conventional and microwave reactions, respectively); m.p. 172-174°C; IR (ATR) ϑ 3112, 3089, 3060, 3003, 2990, 2949, 2923, 2907, 2869, 2851, 1620, 1607, 1520, 1471, 1404, 1342, 1283, 1277, 1224, 1162, 1140, 1080, 969, 886, -1 1 860, 801, 781, 761, 704 cm ; H NMR (400 MHz, DMSO-d6) δ 10.05 (dd, J=6.82 and 2.09 Hz, 1H), 8.89 (s, 1H), 8.76 (dd, J=4.18 and 2.07 Hz, 1H), 8.39 (s, 1H), 7.44-7.39 (m, 2H), 7.38-7.32 (m, 3H), 7.23 (tt, J=7.28 and 1.19 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 153.21, 151.65, 150.97, 149.96, 144.03, 137.24, 129.84, 126.53, 121.64, + 121.29, 111.50; LC/MS (ESI) m/z: (C13H10N4) 223.0 [M+H] . 430 GÜNGÖR T. N-(4-Chlorophenyl)-1-(imidazo[1,2-a]pyrimidin-2-yl)methanimine (S2). The reaction was performed under general procedure conditions as described above, using aldehyde derivative and 4-chloroaniline with 24 h and 60 min reaction times for conventional and microwave heating conditions, respectively. The crude product was purified by column chromatography on silica gel (ethyl acetate) to give compound S2. Light yellow solid; 46 and 79% yield (conventional and microwave reactions, respectively); m.p. 211-214°C; IR (ATR) ϑ 3100, 3091, 3061, 2948, 2923, 2852, 1619, 1607, 1489, 1479, 1414, 1337, 1284, 1229, 1157, 1085, 1009, 959, 869, 832, 793, 775, -1 1 761, 712, 682 cm ; H NMR (400 MHz, DMSO-d6) δ 10.02 (dd, J= 6.85 and 2.06 Hz, 1H), 8.89 (s, 1H), 8.76 (dd, J= 2.06 Hz, 1H), 8.39 (s, 1H), 7.46 (m, 2H), 7.36 (m, 3H); 13 C NMR (100 MHz, DMSO-d6) δ 153.35, 151.10, 150.53, 150.43, 144.41, 137.34, + 130.68, 129.76, 123.46, 121.21, 111.58; LC/MS (ESI) m/z: (C13H9ClN4) 257.0 [M+H] . N-(4-Hydroxyphenyl)-1-(imidazo[1,2-a]pyrimidin-2-yl)methanimine (S3). The reaction was performed under general procedure conditions as described above, using aldehyde derivative and 4-aminophenol with 18 h and 45 min reaction times for