FeF3 as a green catalyst for the synthesis of dihydropyrimidines via Biginelli reaction European Journal of Chemistry 11 (3) (2020) 206-212 European Journal of Chemistry ISSN 2153-2249 (Print) / ISSN 2153-2257 (Online) – Copyright © 2020 The Authors – Atlanta Publishing House LLC – Printed in the USA. This work is published and licensed by Atlanta Publishing House LLC – CC BY NC – Some Rights Reserved. http://dx.doi.org/10.5155/eurjchem.11.3.206-212.1992 European Journal of Chemistry View Journal Online View Article Online FeF3 as a green catalyst for the synthesis of dihydropyrimidines via Biginelli reaction Thalishetti Krishna 1,2, Eppakayala Laxminarayana 3,* and Dipak Kalita 1 1 Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Hyderabad 500049, India thalishettikrishna@gmail.com (T.K.), kalitadipak@yahoo.com (D.K.) 2 Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500085, Telangana, India 3 Sreenidhi Institute of Science and Technology (Autonomous), Ghatkesar, Hyderabad 501301, Telangana, India elxnkits@yahoo.co.in (E.P.) * Corresponding author at: Sreenidhi Institute of Science and Technology (Autonomous), Ghatkesar, Hyderabad 501301, Telangana, India. e-mail: elxnkits@yahoo.co.in (E. Laxminarayana). 10.5155/eurjchem.11.3.206-212.1992 Received: 02 May 2020 Received in revised form: 01 June 2020 Accepted: 06 June 2020 Published online: 30 September 2020 Printed: 30 September 2020 A facile and highly efficient FeF3-catalyzed method has been developed for the direct synthesis of functionalized dihydropyrimidines from readily available starting materials via Biginelli reaction. These reactions proceed at low-catalyst loadings with high functional group tolerance under mild conditions. This method provides efficient reusability of the catalyst and good to excellent yields of the products, making the protocol more attractive, economical, and environmentally benign. FeF3 is an attractive catalyst for the Biginelli reaction because of its high acidity, thermal stability and water tolerance. FeF3 Green chemistry Biginelli reaction One-pot synthesis Dihydropyrimidines Multicomponent reactions Cite this: Eur. J. Chem. 2020, 11(3), 206-212 Journal website: www.eurjchem.com 1. Introduction One of the major goals of organic chemistry is the development of environmentally benign and greener protocols for the synthesis of complex molecular frameworks. In this scenario, multicomponent reactions (MCRs) are one of the most straightforward and powerful tools for the production of diverse heterocyclic compounds in the various scientific disciplines [1,2]. Recently, much attention has been devoted to MCRs because they enable the combination of three or more reactants in a one-pot process to access complex product with most meaningful parts of the starting materials and the manipulation of several transformations in a single step [3-5]. Although a large number of MCR strategies have been inves- tigated to explore their applications in organic and medicinal chemistry, the development of MCRs in an eco-friendly manner is still of promising interest. Of these MCRs, the Biginelli reaction is one of the most powerful MCRs that allows the condensation of aldehyde, ketoester, and urea to synthesize dihydropyrimidine derivatives [6,7]. Moreover, this efficient reaction was first discovered by Bigineli in 1893; unfortunately, it was ignored for many years by organic chemists. Later on, various research groups have focused on novel approaches and mechanistic studies to improve this attractive Biginelli reaction [8-14]. On the other hand, dihydropyrimidines (DHPMs) are privileged and significant pharmacophores among nitrogen- containing heterocyclic frameworks and are widely found in a wide range of natural products, agrochemicals, biologically active systems, and drug candidates (Figure 1) [15-23]. In particular, functionalized DHPMs have attracted considerable attention because of their interesting biological activities, such as antibacterial, antiviral, antimalarial, antitumor, anti- inflammatory, antitubercular, antidiabetic, antileishmanial, antiepileptic, and antiproliferative activities [24]. Moreover, DHPMs have been used as potent calcium channel blockers [25], neuropeptide Y antagonists [26], antihypertensive agents [27], mitotic kinesin inhibitors [28], mPGES-1 inhibitors [29], adrenergic antagonists [30], and A2B receptor antagonists [31]. Indeed, they are versatile and crucial building blocks in organic synthesis and recognized as a new lead for drug discovery [15- 24]. ABSTRACT RESEARCH ARTICLE KEYWORDS http://dx.doi.org/10.5155/eurjchem.11.3.206-212.1992 http://www.eurjchem.com/ http://dx.doi.org/10.5155/eurjchem.11.3.206-212.1992 mailto:thalishettikrishna@gmail.com mailto:kalitadipak@yahoo.com mailto:elxnkits@yahoo.co.in mailto:elxnkits@yahoo.co.in http://www.eurjchem.com/ https://crossmark.crossref.org/dialog/?doi=10.5155/eurjchem.11.3.206-212.1992&domain=pdf&date_stamp=2020-09-30 Krishna et al. / European Journal of Chemistry 11 (3) (2020) 206-212 207 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.206-212.1992 Figure 1. Biologically active dihydropyrimidines. Despite their fascinating pharmaceutical applications, DHPMs have also been found in the development of functional materials, such as polymers, adhesives, optical materials, and dyes [32-34]. Recently, considering the synthetic and biological importance of Biginelli reaction, various efficient strategies have been explored for the expansion of Biginelli reaction to synthesize functionalized dihydropyrimidine derivatives that use a variety of Brönsted acids, metal-based Lewis acids, ionic liquids, polymer supported catalysts, microwave-assisted conditions, and base-mediated conditions [35-58]. Although the significant advances have been achieved in the synthesis of dihydropyrimidines, most of these are expensive, environment- tally unfriendly, and difficult to handle large-scale reactions. Therefore, there is a need for the investigation of recyclable and reusable catalytic conditions for this reaction, which can overcome limitations for large-scale reactions. Among the transition metal catalysts, iron catalysts play an important role in the organic synthesis, owing to their indispensable advantages, such as relatively safe, inexpensive, stable, recyclable, less hazardous, low-catalyst loading, and environmentally benign nature [59]. Moreover, iron-catalyzed tandem sequences have gained considerable attention [60]. Recently, Surasani et al. reported a FeF3-catalyzed method for the synthesis of polyhydroquinoline derivatives via unsymmet- rical Hantzsch reaction [61]. In this context, as a part of ongoing research efforts [62,63], we envisaged accessing pharmaceu- tically active dihydropyrimidines via Biginelli reaction using FeF3 as a catalyst. Therefore, we wish to report an efficient and eco-friendly MCR protocol for the one-pot facile synthesis of functionalized dihydropyrimidine scaffolds by the reaction of aldehydes, ketoesters, and urea or thiourea in ethanol at reflux temperature using FeF3 as an environmentally benign catalyst. The present study also explores good recyclability and reusability of the catalyst. 2. Experimental Unless stated otherwise, reactions were performed under nitrogen atmosphere using oven dried glassware. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60F254), visualizing with ultraviolet light or iodine spray. Flash chromatography was performed on silica gel (230- 400 mesh) using distilled hexane, ethyl acetate, and dichloro- methane. 1H NMR and 13C NMR spectra were determined in CDCl3 or DMSO-d6 solution by using 400 or 100 MHz spectro- meters, respectively. Proton chemical shifts (δ) are relative to tetramethylsilane (TMS, δ = 0.00) as internal standard and expressed in ppm. Spin multiplicities are given as s (singlet), d (doublet), t (triplet) and m (multiplet) as well as b (broad). Coupling constants (J) are given in hertz. Melting points were determined using melting point B-540 apparatus and are uncorrected. HRMS was determined using waters LCT premier XETOF ARE-047 apparatus. 2.1. General procedure for the synthesis of 3,4-dihydro pyrimidin-2(1H)-one or thione (DHPMs) derivatives (4) A mixture of aldehyde 1 (1.0 mmol), urea or thiourea 2 (1.0 mmol), alkyl acetoacetate 3 (1.0 mmol), and FeF3 (5 mol%) in ethanol (5 mL) was stirred at room temperature. Then the reaction mixture was slowly heated to 75-80 °C, and the reaction was completed within one hour. After completion of the reaction (TLC), the mixture was cooled and diluted with 15 mL of ethyl acetate and 10 mL of water. The organic layer was separated and washed with cold water (20 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to afford the crude product, which was finally recrystallized from ethanol to afford the pure product 4. The aqueous layer containing the catalyst (FeF3) was evaporated under reduced pressure to give a solid [62]. Then the recovered catalyst was dried in an oven at 120 °C for 3-5 h and reused in subsequent reactions without loss its catalytic activity. The products obtained were identified by comparison of their NMR, IR, and mass spectra. The spectroscopic data of all the desired products were identical with those were reported in the literature [64-70]. Ethyl-6-methyl-2-oxo-4-phenyl-1, 2, 3, 4-tetrahydropyrimidi ne-5-carboxylate (4a): Color: Colorless solid. Yield: 93%. M.p.: 202-204 °C. FT- IR (KBr, ν, cm-1): 3375, 3329, 3106, 1670, 1574, 1465, 1327, 1284, 1196, 1118, 1028, 760, 693. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.10 (t, J = 7.4 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 4.00-3.95 (q, J = 6.8 Hz, 2H, OCH2), 5.14 (d, J = 3.0 Hz, 1H, C-H), 7.33-7.22 (m, 5H, Ar-H), 7.72 (s, 1H, N-H), 9.17 (s, 1H, N- H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.3, 152.2, 148.3, 144.8, 128.3, 127.2, 126.2, 99.2, 59.2, 53.9, 17.7, 14.0. HRMS (ESI, m/z) calcd. for C14H16N2O3 [M+H]: 261.1239. Found 261.1229. Ethyl-6-methyl-2-oxo-4-(o-tolyl)-1, 2, 3, 4-tetrahydropyrimi dine-5-carboxylate (4b): Color: Colorless solid. Yield: 91%. M.p.: 208-210 °C. FT- IR (KBr, ν, cm-1): 3672, 3291, 2958, 2811, 1927, 1707, 1454, 1228, 1025. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.07 (t, J = 6.9 Hz, 3H, CH3), 2.29 (s, 3H, CH3), 2.49 (s, 3H, CH3), 3.91-3.87 (q, J = 2.8 Hz, 2H, OCH2), 5.40 (d, J = 2.5 Hz, 1H, CH), 7.16-7.11 (m, 4H, Ar-H), 7.61 (s, 1H, N-H), 9.13 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.2, 151.6, 148.4, 143.3, 134.6, 130.1, 127.2, 126.5, 99.2, 59.1, 50.5, 18.6, 17.9, 13.9. HRMS (ESI, m/z) calcd. for C15H18N2O3 [M+H]: 275.1396. Found 275.1389. Ethyl-4-(4-hydroxyphenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahyd ropyrimidine-5-carboxylate (4c): Color: Colorless solid. Yield: 88%. M.p.: 226-228 °C. FT- IR (KBr, ν, cm-1): 3683, 3514, 3106, 2695, 1688, 1655, 1514, 1460, 1318, 1229, 1172, 1098, 967, 752. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.10 (t, J = 7.3 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 4.02-3.95 (q, J = 6.9 Hz, 2H, OCH2), 5.07 (d, J = 2.9 Hz, 1H, C-H), 6.68 (d, J = 8.3 Hz, 2H, Ar-H), 7.03 (d, J = 8.3 Hz, 2H, Ar-H), 7.60 (s, 1H, N-H), 9.09 (s, 1H, N-H), 9.31 (s, 1H, O-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.5, 156.6, 152.3, 147.8, 135.5, 127.5, 115.0, 99.8, 59.2, 53.5, 17.8, 14.1. HRMS (ESI, m/z) calcd. for C14H16N2O4 [M+H]: 277.1188. Found 277.1180. 208 Krishna et al. / European Journal of Chemistry 11 (3) (2020) 206-212 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.206-212.1992 Scheme 1. FeF3-catalyzed synthesis of dihydropyrimidines. Ethyl-4-(3-(benzyloxy)phenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetra hydropyrimidine-5-carboxylate (4d): Color: Colorless solid. Yield: 92%. M.p.: 230-234 °C. FT- IR (KBr, ν, cm-1): 3291, 2958, 2697, 1927, 1707, 1641, 1454, 1228, 1141, 1098, 1025, 805. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.11 (t, J = 6.8 Hz, 3H, CH3), 2.23 (s, 3H, CH3), 4.01-3.95 (q, J = 6.8 Hz, 2H, OCH2), 5.06 (s, 2H, OCH2), 5.11 (d, J = 1.5 Hz, 1H, C-H), 6.91-6.81 (m, 3H, Ar-H), 7.44-7.21 (m, 6H, Ar-H), 7.71 (s, 1H, N-H), 9.17 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.3, 158.4, 152.2, 148.5, 146.4, 137.0, 129.5, 128.4, 127.9, 127.7, 118.6, 113.2, 99.1, 69.2, 59.2, 53.8, 17.8, 14.1. HRMS (ESI, m/z) calcd. for C21H22N2O4 [M+H]: 367.1658. Found 367.1649. Ethyl-4-(3-hydroxyphenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahyd ropyrimidine-5-carboxylate (4e): Color: Colorless solid. Yield: 85%. M.p.: 168-170 °C. FT- IR (KBr, ν, cm-1): 3655, 3230, 2932, 2795, 1702, 1645, 1228, 1079, 1027, 786, 745, 682. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.13 (t, J = 7.4 Hz, 3H, CH3), 2.23 (s, 3H, CH3), 4.02-3.96 (q, J = 7.3 Hz, 2H, OCH2), 5.05 (d, J = 1.9 Hz, 1H, C-H), 6.67-6.60 (m, 3H, Ar-H), 7.10 (t, J= 7.8 Hz, 1H, Ar- H), 7.66 (s, 1H, N-H), 9.13 (s, 1H, N-H), 9.34 (s, 1H, O-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.4, 157.4, 152.2, 148.1, 146.3, 129.3, 116.9, 114.2, 113.1, 99.4, 59.2, 53.8, 17.8, 14.1. HRMS (ESI, m/z) calcd. for C14H16N2O4 [M+H]: 277.1188. Found 277.1199. Ethyl-4-(3-bromophenyl)-6-methyl-2-oxo-1, 2,3,4-tetrahydro pyrimidine-5-carboxylate (4f): Color: Colorless solid. Yield: 88%. M.p.: 185-187 °C. FT- IR (KBr, ν, cm-1): 3291, 2958, 2697, 2065, 1927,1707,1641,1454, 1346, 1228, 1098, 965, 798, 752, 652. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.10 (t, J = 7.4 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 4.01-3.98 (q, J = 7.4 Hz, 2H, OCH2), 5.14 (d, J = 3 Hz, 1H, CH), 7.46-7.22 (m, 4H, Ar-H), 7.78 (s, 1H, N- H), 9.26 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.2, 151.9, 148.9, 147.5, 130.8, 130.1, 129.2, 129.1, 125.3, 121.6, 98.6, 59.3, 53.5, 17.8, 14.1. HRMS (ESI, m/z) calcd. for C14H15BrN2O3 [M+H]: 339.0344. Found 339.0366. Ethyl-6-methyl-4-(4-nitrophenyl)-2-oxo-1, 2, 3, 4-tetrahydro pyrimidine-5-carboxylate (4g): Color: Yellow solid. Yield: 85%. M.p.: 205-207 °C. FT- IR (KBr, ν, cm-1): 3434, 2920, 2065, 1639, 1346, 1226, 1049. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.10 (t, J = 6.9 Hz, 3H, CH3), 2.26 (s, 3H, CH3), 4.01-3.96 (q, J = 6.9 Hz, 2H, OCH2), 5.27 (d, J = 3 Hz, 1H, C-H), 7.51 (d, J = 8.4 Hz, 2H, Ar-H), 7.80 (s, 1H, N-H), 8.22 (d, J = 8.4 Hz, 2H, Ar-H), 9.34 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.0, 151.9, 151.7, 149.4, 146.7, 127.6, 123.8, 98.2, 59.4, 53.7, 17.8, 14.0. Ethyl-4-(4-chlorophenyl)-6-methyl-2-oxo-1, 2,3,4-tetrahydro pyrimidine-5-carboxylate (4h): Color: Colorless solid. Yield: 86%. M.p.: 212-214 °C. FT- IR (KBr, ν, cm-1): 3564, 3176, 3105, 2998, 2798, 2053, 1673, 1574, 1456, 1347, 1285,1 181, 941. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.08 (t, J = 6.9 Hz, 3H, CH3), 2.29 (s, 3H, CH3), 3.91-3.87 (q, J = 6.9 Hz, 2H, OCH2), 5.62 (d, J = 2.4 Hz, 1H, CH), 7.41-7.26 (m, 4H, Ar-H), 7.68 (s, 1H, N-H), 9.25 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 164.9, 151.3, 149.3, 141.7, 131.6, 129.3, 129.0, 128.8, 127.7, 97.9, 59.1, 51.4, 17.6, 13.9. Ethyl-4-(4-acetylphenyl)-6-methyl-2-oxo-1, 2, 3,4-tetrahydro pyrimidine-5-carboxylate (4i): Color: Colorless solid. Yield: 90%. M.p.: 201-203 °C. FT- IR (KBr, ν, cm-1): 3315, 3171, 2983, 1891, 1668, 1575, 1463, 1372, 1285, 1269, 1252, 1196, 1171, 1028, 766. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.13 (t, J =6.8 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 2.52 (s, 3H, CH3), 4.01-3.95 (q, J = 6.8 Hz, 2H, OCH2), 5.21 (d, J = 2.4 Hz, 1H, CH), 7.36 (d, J = 7.3 Hz, 2H, Ar-H), 7.93 (d, J = 8.3 Hz, 2H, Ar-H), 8.13 (s, 1H, N-H), 9.29 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 197.4, 165.2, 151.9, 149.7, 148.9, 135.9, 129.0, 128.5, 126.5, 98.6, 59.3, 53.8, 26.7, 17.8, 14.0. Ethyl-4-(2,4-difluorophenyl)-6-methyl-2-oxo-1, 2, 3, 4-tetra hydropyrimidine-5-carboxylate (4j): Color: Colorless solid. Yield: 88%. M.p.: 150-152 °C. FT- IR (KBr, ν, cm-1): 3171, 3108, 2937, 2836, 2501, 1891, 1668, 1463, 1269, 1171, 1028, 767. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.10 (t, J = 6.9 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 4.03-3.95 (q, J = 6.9 Hz, 2H, OCH2), 5.15 (d, J = 3.5 Hz, 1H, CH), 7.08-7.05 (m, 1H, Ar-H), 7.23-7.18 (m, 1H, Ar- H), 7.41-7.23 (m, 1H, Ar-H), 7.79 (s, 1H, N-H), 9.27 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.1, 158.9, 149.1, 142.5, 122.93, 117.5, 115.37, 98.5, 59.3, 53.2, 17.8, 14.06. HRMS (ESI, m/z) calcd. for C14H14F2N2O3 [M+H]: 297.1051. Found 297.1046. Ethyl-4-(3,4-dimethoxyphenyl)-6-methyl-2-oxo-1, 2,3,4-tetra hydropyrimidine-5-carboxylate (4k): Color: Colorless solid. Yield: 96%. M.p.: 176-178 °C. FT- IR (KBr, ν, cm-1): 3176, 2996, 2798, 2590, 1926, 1673, 1574, 1506, 1285, 1198, 1119, 838, 762. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.11 (t, J = 6.9 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.71 (s, 6H, OCH3), 4.02-3.97 (q, J = 6.9 Hz, 2H, OCH2), 5.09 (d, J = 3.0 Hz, 1H, C-H), 6.72 (d, J = 6.4 Hz, 1H, Ar-H), 6.73 (s, 1H, Ar-H), 6.89 (d, J = 8.4 Hz, 1H, Ar-H), 7.66 (s, 1H, N-H), 9.13 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.5, 152.3, 148.5, 148.1, 148.0, 137.3, 117.9, 111.7, 110.4, 99.4, 59.2, 55.5, 55.4, 53.5, 17.8, 14.2. HRMS (ESI, m/z) calcd. for C16H20N2O5 [M+H]: 321.1450. Found 321.1452 Ethyl-4-(benzo[d][1, 3]dioxol-4-yl)-6-methyl-2-oxo-1, 2, 3, 4- tetrahydropyrimidine-5-carboxylate (4l): Color: Colorless solid. Yield: 91%. M.p.: 180-182 °C. FT- IR (KBr, ν, cm-1): 3694, 3354, 3221, 3100, 2962, 1702, 1641, 1490, 1451, 1225, 1092, 1040, 928, 795, 675. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.12 (t, J = 6.9 Hz, 3H, CH3), 2.24 (s, 3H, CH3), 3.96-4.01 (q, J = 6.9 Hz, 2H, OCH2), 5.06 (d, J = 3.4 Hz, 1H, CH), 5.98 (s, 2H, -OCH2O-), 6.69 (d, J = 1.4 Hz, 1H, Ar-H), 6.74 (d, J = 1.4 Hz, 1H, Ar-H), 6.83 (t, J = 8.4 Hz, 1H, Ar-H), 7.67 (s, 1H, N-H), 9.16 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.4, 152.1, 148.3, 147.3, 146.9, 138.9, 119.3, 108.0, 106.7, 100.9, 99.3, 59.2, 53.7, 17.8, 14.1. HRMS (ESI, m/z) calcd. for C15H16N2O5 [M+H]: 305.1137. Found 305.1129. Ethyl-6-methyl-4-(naphthalen-1-yl)-2-oxo-1, 2, 3, 4-tetrahyd ropyrimidine-5-carboxylate (4m): Color: Colorless solid. Yield: 94%. M.p.: 246-248 °C. FT- IR (KBr, ν, cm-1): 3250, 3121, 2978, 2817, 1708, 1602, 1466, 1384, 1229, 1094, 770, 690. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.09 (t, J = 6.9 Hz, 3H, CH3), 2.28 (s, 3H, CH3), 3.99-3.94 (q, J = 6.9 Hz, 2H, OCH2), 5.32 (d, J = 2.9 Hz, 1H, CH), 7.50-7.43 (m, 3H, Ar-H), 7.67 (s, 1H, N-H), 7.86-7.90 (m, 4H, Ar-H), 9.24 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.4, 152.2, 148.6, 142.2, 132.7, 132.3, 128.3, 127.8, 127.5, 126.3, 125.9, 124.9, 124.5, 99.2, 59.2, 54.4, 17.9, 14.1. HRMS (ESI, m/z) calcd. for C18H18N2O3 [M+H]: 311.1396. Found 311.1409. Ethyl-4-(furan-2-yl)-6-methyl-2-oxo-1, 2, 3, 4-tetrahydropyri midine-5-carboxylate (4n): Color: Colorless solid. Yield: 92%. M.p.: 204-206 °C. Krishna et al. / European Journal of Chemistry 11 (3) (2020) 206-212 209 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.206-212.1992 Table 1. The reaction of benzaldehyde (1a), ethylacetoacetate (2a) and urea (3a): screening of fluoride sources a. Entry Catalyst (Fluoride source) Temp. (°C) Time (h) Yield (%) b 1 CsF 80 1 34 2 CaF2 80 1 30 3 KF 80 1 28 4 NH4F 80 1 20 5 TBAF 80 1 35 6 FeF3 80 1 93 7 None 80 1 None a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), catalyst (5 mol%), ethanol (5 mL), at 75-80 °C. b Isolated yields. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.15 (t, J = 6.4 Hz, 3H, CH3), 2.22 (s, 3H, CH3), 4.05-3.99 (q, J = 6.4 Hz, 2H, OCH2), 5.20 (d, J = 3.4, Hz, 1H, CH), 6.09 (d, J = 3.5 Hz, 1H, Ar-H), 6.35 (t, J = 2.0 Hz, 1H, Ar-H), 7.55 (d, J = 1.0 Hz, 1H, Ar-H), 7.74 (s, 1H, N- H), 9.23 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 165.0, 155.9, 152.4, 149.4, 142.2, 110.4, 105.3, 96.7, 59.2, 47.7, 17.7, 14.1. HRMS (ESI, m/z) calcd. for C12H14O4N2 [M+H]: 251.1032. Found 251.1038. Methyl-6-methyl-2-oxo-4-phenyl-1, 2, 3, 4-tetrahydropyrimi dine-5-carboxylate (4o): Color: Colorless solid. Yield: 91%. M.p.: 211-213 °C. FT- IR (KBr, ν, cm-1): 3514, 3106, 2608, 1655, 1460, 1318, 1229, 1093, 965, 652. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.23 (s, 3H, CH3), 3.51 (s, 3H, OCH3), 5.13 (d, J = 2.9 Hz, 1H, C-H), 7.32-7.20 (m, 5H, Ar-H), 7.73 (s, 1H, N-H), 9.20 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 166.1, 165.6, 152.5, 148.8, 144.8, 128.7, 127.6, 126.4, 99.3, 54.1, 51.09, 17.9. HRMS (ESI, m/z) calcd. for C13H14N2O3 [M+H]: 247.1083. Found 247.1094. Ethyl-6-methyl-4-phenyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimi dine-5-carboxylate (4p): Color: Colorless solid. Yield: 92%. M.p.: 208-210 °C. FT- IR (KBr, ν, cm-1): 3329, 3178, 2980, 2806, 1964, 1670, 1574, 1465, 1327, 1284, 1118, 693. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.12 (t, J = 6.9 Hz, 3H, CH3), 2.20 (s, 3H, CH3), 4.03-3.98 (q, J = 6.9 Hz, 2H, OCH2), 5.17 (d, J = 3.4 Hz, 1H, C-H), 7.36-7.21 (m, 5H, Ar-H), 9.64 (s, 1H, N-H), 10.32 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.3, 165.1, 145.0, 143.5, 128.5, 127.7, 126.4, 100.7, 59.6, 54.1, 17.2, 14.0. HRMS (ESI, m/z) calcd. for C14H16N2O2S [M+H]: 277.1011. Found 277.1008. Ethyl-4-(4-methoxyphenyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetra hydropyrimidine-5-carboxylate (4q): Color: Colorless solid. Yield: 93%. M.p.: 151-153 °C. FT-IR (KBr, ν, cm-1): 3315, 3171, 3108, 2983, 2836, 1891, 1668, 1575, 1509, 1463, 1285, 1196, 1122, 1028, 766. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.12 (t, J = 6.8 Hz, 3H, CH3), 2.28 (s, 3H, CH3), 3.72 (s, 3H, OCH3), 4.03- 3.97 (q, J = 6.8 Hz, 2H, OCH2), 5.11 (d, J = 3.4 Hz, 1H, C-H), 6.91 (d, J = 8.8 Hz, 2H, Ar-H), 7.13 (d, J = 8.8 Hz, 2H, Ar-H), 9.59 (s, 1H, N-H), 10.25 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.0, 165.2, 158.7, 144.7, 135.7, 127.6, 113.8, 100.9, 59.5, 55.1, 53.4, 17.14, 14.0. HRMS (ESI, m/z) calcd. for C15H18N2O3S [M+H]: 307.1116. Found 307.1104. Ethyl-4-(benzo[d][1, 3]dioxol-4-yl)-6-methyl-2-thioxo-1, 2, 3, 4-tetrahydropyrimidine-5-carboxylate (4r): Color: Colorless solid. Yield: 88%. M.p.: 172-174 °C. FT- IR (KBr, ν, cm-1): 3672, 3291, 2958, 2811, 1927, 1707, 1454, 1228, 1025. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.11 (t, J = 7.3 Hz, 3H, CH3), 2.28 (s, 3H, CH3), 4.04-3.99 (q, J = 7.3 Hz, 2H, OCH2), 5.09 (d, J = 3.9 Hz, 1H, CH), 5.99 (s, 2H, -OCH2O-), 6.66 (d, J = 6.4 Hz, 1H, Ar-H), 6.72 (m, 1H, Ar-H), 6.88 (t, J = 7.8 Hz, 1H, Ar-H), 9.59 (s, 1H, N-H), 10.31(s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.0, 165.1, 147.4, 146.7, 145.0, 137.5, 119.6, 108.1, 106.7, 101.0, 100.7, 59.6, 53.7, 17.1, 14.0. HRMS (ESI, m/z) calcd. for C15H16O4N2S [M+H]: 321.0909. Found 321.0906. Ethyl-4-(3, 5-bis(trifluoromethyl)phenyl)-6-methyl-2-thioxo- 1,2,3,4-tetrahydropyrimidine-5-carboxylate (4s): Color: Color- less solid. Yield: 90%. M.p.: 105-107 °C. FT- IR (KBr, ν, cm-1): 3315, 2937, 2836, 1668, 1463, 1285, 1198, 1095, 762. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 1.08 (t, J = 7.4 Hz, 3H, CH3), 2.25 (s, 3H, CH3), 4.05-3.95 (q, J = 7.3 Hz, 2H, OCH2), 5.38 (d, J = 2.9 Hz, 1H, C-H), 7.92-7.85 (m, 3H, Ar-H), 8.05 (s, 1H, N-H), 9.41 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 164.9, 157.7, 151.59, 149.9, 148.2, 130.5, 129.9, 129.7, 127.3, 124.6, 121.8, 97.8, 59.4, 53.5, 17.8, 13.8. Methyl-6-methyl-4-phenyl-2-thioxo-1, 2, 3, 4-tetrahydropyri midine-5-carboxylate (4t): Color: Colorless solid. Yield: 90%. M.p.: 222-225 °C. FT- IR (KBr, ν, cm-1): 3321, 3176, 2998, 2798, 2590, 1900, 1673, 1456, 1347, 1198, 1043, 941. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.27 (s, 3H, CH3), 3.54 (s, 3H, OCH3), 5.15 (d, J = 3.4 Hz, 1H, CH), 7.35-7.19 (m, 5H, Ar-H), 9.64 (s, 1H, N-H), 10.20 (s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.2, 165.6, 145.3, 143.3, 128.6, 127.7, 126.3, 100.5, 53.9, 51.09, 17.2. HRMS (ESI, m/z) calcd. for C13H14N2O2S [M+H]: 263.0854. Found 263.0842. Methyl-4-(4-fluorophenyl)-6-methyl-2-thioxo-1, 2, 3, 4-tetra hydropyrimidine-5-carboxylate (4u): Color: Colorless solid. Yield: 89%. M.p.: 184-186 °C. FT- IR (KBr, ν, cm-1): 3308, 3176, 2998, 2851, 2796, 1900, 1673, 1574, 1456, 1347, 1285, 1119, 941, 852. 1H NMR (400 MHz, DMSO-d6, δ, ppm): 2.29 (s, 3H, CH3), 3.55 (s, 3H, OCH3), 5.18 (d, J = 3.4 Hz, 1H, C-H), 7.26-7.15 (m, 4H, Ar-H), 9.67 (s, 1H, N-H), 10.3(s, 1H, N-H). 13C NMR (100 MHz, CDCl3, δ, ppm): 174.2, 165.5, 162.8, 160.4, 145.5, 139.6, 128.4, 115.5, 1153, 100.4, 53.3, 51.1, 17.2. HRMS (ESI, m/z) calcd. for C13H13FN2O2S [M+H]: 281.0760. Found 281.0755. 3. Results and discussion Initially, benzaldehyde (1a), ethyl acetoacetate (2a), and urea (3a) were selected as model substrates to optimize the reaction. The reaction was carried out using 5 mol% of FeF3 as a catalyst in ethanol at room temperature and reflux temperature (Scheme 1). It is worth mentioning that the reaction was slower at room temperature than at reflux temperature. Moreover, the desired product (4a) was obtained in 93% yield at the latter temperature within a short period (1 h). However, the increasing or decreasing the loading of the catalyst did not improve the product yield. In absence of the catalyst, no product could be detected within 1 h at 80 °C under the present experimental conditions (Table 1, entries 7). With optimized reaction conditions in hand, we then investigated the scope and generality of aromatic aldehydes (1a-n) with ethyl acetoacetate (2a) and urea (3a), and the results are compiled in Table 1. To our delight, various aromatic aldehydes bearing electron-donating and electron-with- drawing groups were smoothly employed under these reaction conditions, thereby affording the desired products (4a-i) in good to excellent yields. Surprisingly, the sterically demanding ortho-2-tolualdehydealso worked well and gave the resulting product (4b) in 91% yield. The results suggested that the steric and electronic effects of the aromatic ring had negligible influence in this transformation. Notably, the reaction of disubstituted aldehydes also proceeded smoothly, providing the corresponding products (4j-l) in 88-96% yields. Moreover, extended aromatic aldehyde 1-naphthaldehydeand hetero- cyclic aldehyde 2-thiophenecarboxaldehydewere also found to be suitable reaction partners to give the resulting products (4m-n) in high yields. 210 Krishna et al. / European Journal of Chemistry 11 (3) (2020) 206-212 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.206-212.1992 Table 2. Substrate scope for the synthesis of dihydropyrimidines a. a Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), 3 (1.0 mmol), catalyst (5 mol%), ethanol (5 mL), at 75-80 °C. b Isolated yields. As can be seen in Table 2, halogen substituents such as F, Cl, and Br were compatible in this reaction, which are the useful handle for further functionalization. Besides, a whole range of functional groups, such as ester, keto, ether, methyl, hydroxyl, and nitro could be efficiently tolerated with this catalytic system. Next, we also tested the reactivity of methyl acetoacetate (2b) with benzaldehyde (1a) and urea (3a) under optimized reaction conditions, and the reaction underwent efficiently to give the wanted product (4o) in 90% yield. Moreover, we also investigated the scope and generality of thiourea (3b) with various aldehydes and ethyl or methyl acetoacetate (2a-b) under optimized catalytic conditions, and the results are shown in Table 2. All the reactions proceeded smoothly and afforded the corresponding products (4p-u) in 88-93% yields. To further explore, the synthetic expediency and potential viability of this reaction, the scale-up reaction (10.0 mmol) was efficiently performed by using compound 1a, ethyl acetoacetate and urea under optimized catalytic conditions to deliver the desired product 4a in 88% yield. Moreover, we also studied the recyclability and reusability of the catalyst, which was checked with a model reaction. After completion of the reaction, the catalyst was recovered according to our previous procedure [62]. Then the recovered catalyst was dried in an oven at 120 °C for 3-5 h and reused in subsequent reactions up to five runs without significant loss its catalytic activity (Figure 2). We have further compared the catalytic process of FeF3 by screening other fluoride sources under the same reaction conditions (Table 1), it was found that FeF3 is the most reactive than other fluoride sources (Table 1, entry 6). The corres- ponding product was obtained in low yield in the presence of CsF, CaF2, KF, NH4F and TBAF (Table 1, entries 1-5), respect- tively. The use of other solvents like toluene, dichloro-methane, cyclohexane, etc. was also examined among which ethanol and acetonitrile were found to be effective. Krishna et al. / European Journal of Chemistry 11 (3) (2020) 206-212 211 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.206-212.1992 Figure 2. Reusability of catalyst in synthesis of compound 4a. Figure 3. Proposed mechanism for the formation of ethyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a). FeF3 is more soluble in water than that in organic solvents. The catalyst was recovered almost quantitatively from the aqueous layer, which was subsequently reused for several runs. The yield of compound 4a was found to be 93, 92, 92, 91 and 90 after the 1st, 2nd, 3rd, 4th and 3rd recovery and reuse of the catalyst. A comparison of the powder X-ray diffraction (XRD) spectrum obtained for fresh FeF3 and the reused catalyst indicated no change in its crystalline nature [61]. Mechanistically, the reaction seems to proceed via a sequence (Figure 3) involving the FeF3 promoted formation of the Schiff base 6 to form intermediate 7, followed by cyclization 8 and dehydration to yield product 4a. 4. Conclusion We have developed an efficient multicomponent protocol for the synthesis of biologically active functionalized dihydro pyrimidines via Biginelli reaction using easily accessible FeF3 as a catalyst. This method has several advantages, such as readily available starting materials, low-catalyst loading with high activity, good to excellent yields, high functional group tolerance, and environmentally benign conditions. The catalyst can be easily recycled and reused up to five runs with high performance. Furthermore, efficient strategies by using FeF3 as a catalyst are now underway in our laboratory. Acknowledgments We would like to thank Dr. Hindupur Ramamohan for his encouragement and Department of Chemistry, Jawaharlal Nehru Technological University, Hyderabad, India for support. Authors thank Analytical Department of Dr. Reddy’s Laboratories Limited, Hyderabad, India for spectra. Disclosure statement Conflict of interests: The authors declare that they have no conflict of interest. Author contributions: All authors contributed equally to this work. Ethical approval: All ethical guidelines have been adhered. Sample availability: Samples of the compounds are available from the author. 93 92 92 91 90 0 10 20 30 40 50 60 70 80 90 100 1 2 3 4 5 Yi el d (% ) Run 212 Krishna et al. / European Journal of Chemistry 11 (3) (2020) 206-212 2020 – European Journal of Chemistry – CC BY NC – DOI: 10.5155/eurjchem.11.3.206-212.1992 Funding Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Limited, Hyderabad 500049, India ORCID Thalishetti Krishna http://orcid.org/0000-0002-8548-7545 Eppakayala Laxminarayana http://orcid.org/0000-0003-4465-042X Dipak Kalita http://orcid.org/0000-0001-8421-9357 References [1]. Domling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083-3135. [2]. Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev. 2014, 114, 8323-8359. [3]. Zhu, J.; Bienayme, H. Multicomponent Reactions, Wiley-VCH, Weinheim, 2005. [4]. Brauch, S.; van Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948-4962. [5]. Cioc, R. C.; Ruijter, E.; Orru, R. 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The full terms of this license are available at http://www.eurjchem.com/index.php/eurjchem/pages/view/terms and incorporate the Creative Commons Attribution-Non Commercial (CC BY NC) (International, v4.0) License (http://creativecommons.org/licenses/by-nc/4.0). By accessing the work, you hereby accept the Terms. This is an open access article distributed under the terms and conditions of the CC BY NC License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited without any further permission from Atlanta Publishing House LLC (European Journal of Chemistry). No use, distribution or reproduction is permitted which does not comply with these terms. Permissions for commercial use of this work beyond the scope of the License (http://www.eurjchem.com/index.php/eurjchem/pages/view/terms) are administered by Atlanta Publishing House LLC (European Journal of Chemistry). http://orcid.org/0000-0002-8548-7545 http://orcid.org/0000-0003-4465-042X http://orcid.org/0000-0001-8421-9357 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms http://creativecommons.org/licenses/by-nc/4.0 http://www.eurjchem.com/index.php/eurjchem/pages/view/terms 1. Introduction 2. Experimental 2.1. General procedure for the synthesis of 3,4-dihydro pyrimidin-2(1H)-one or thione (DHPMs) derivatives (4) 3. Results and discussion 4. Conclusion Acknowledgments Disclosure statement Funding ORCID References PrintField10: PrintField11: PrintField12: PrintField13: PrintField14: PrintField15: PrintField16: PrintField20: PrintField21: PrintField22: PrintField23: PrintField24: PrintField25: PrintField26: