untitled European Journal of Chemistry 4 (1) (2013) 1‐6 European Journal of Chemistry ISSN 2153‐2249 (Print) / ISSN 2153‐2257 (Online)  2013 EURJCHEM DOI:10.5155/eurjchem.4.1.1‐6.718 European Journal of Chemistry Journal homepage: www.eurjchem.com Synthesis of 2‐substituted 6‐(5‐oxo‐1‐phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ ones Uroš Grošelj a,*, Georg Dahmann b, Branko Stanovnik a, and Jurij Svete a,* a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, SI‐1000, Slovenia b Medicinal Chemistry, Boehringer‐Ingelheim Pharma GmbH & Co. KG, Biberach, D‐88397, Germany *Corresponding author at: Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana, SI‐1000, Slovenia. Tel.: +386.1.2419254; fax: +386.1.2419220. E‐mail address: jurij.svete@fkkt.uni‐lj.si (J. Svete). ARTICLE INFORMATION ABSTRACT Received: 19 December 2012 Received in revised form: 07 January 2013 Accepted: 08 January 2013 Online: 31 March 2013 KEYWORDS 2‐Substituted 6‐(5‐oxo‐1‐phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ones were synthesized in three steps from itaconic acid derivatives via cyclization with primary amines followed by Masamune‐Claisen condensation, and cyclization of the newly formed β‐keto esters with amidines. Preparation and/or isolation of β‐keto esters with polar N‐substituents failed, but the corresponding final products were obtained in a different way. 6‐(1‐(3‐Hydroxypropyl)‐5‐ oxopyrrolidin‐3‐yl)‐2‐phenylpyrimidin‐4(3H)‐one was obtained by hydrogenolytic o‐ deprotection of its o‐benzyl derivative. Depending on reaction conditions, further mesylation of 6‐(1‐(3‐(benzyloxy)propyl)‐5‐oxopyrrolidin‐3‐yl)‐2‐phenylpyrimidin‐4(3H)‐one followed by treatment with pyrrolidine gave either the monoaminated‐ or the diaminated product. The structures of novel compounds were determined by NMR. Lactams Cyclization Heterocycles Medicinal chemistry Nitrogen heterocycles Nucleophilic substitution 1. Introduction Histamine, dopamine, tryptamine, serotonin, and melatonin are representative chemical messengers playing a crucial role in biological processes [1]. Various 2‐[(hetero)aryl]ethylamines are analogues of the above chemical messengers and, consequently, such 2‐ethylamino‐functionalized heterocyclic compounds represent attractive synthetic targets. In this context, the preparation of novel synthetic analogues of naturally occurring 2‐((hetero)aryl)ethylamines is of particular interest in medicinal, synthetic organic, and combinatorial chemistry [2‐9]. In the last decade, the synthesis of aminoethyl functionalized heterocycles has represented an important part of our research studies. Within this context, we have been so far focused on the synthesis of two types of 2‐(heteroaryl) ethylamines: a) the open‐chain analogues of histamine, 1, [10‐ 13] and bicyclic conformationally constrained analogues of histamine, 2‐4, [14‐16] and b) 2‐substituted 6‐(5‐oxo‐1‐ phenylpyrrolidin‐3‐yl)pyrimidine‐5‐carboxamides, 5, as 2‐ aminoethyl‐functionalized pyrimidines [17]. In continuation, we have focused our attention on 2‐substituted 6‐(5‐oxo‐1‐ phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ones, 6, as novel type of 2‐aminoethyl‐functionalized pyrimidines (Scheme 1). 2. Experimental [1,1'‐Biphenyl]‐4‐carboxamidine hydrochloride (11d), and 4‐((pyrrolidin‐1‐yl)methyl)benzamidine dihydrochloride (11e) were purchased from Ukrorgsyntez Ltd. 5‐Oxo‐1‐ phenylpyrrolidine‐3‐carboxylic acid (9a) [18], methyl 3‐oxo‐3‐ (5‐oxo‐1‐phenylpyrrolidin‐3‐yl)propanoate (10a) [16], and 3‐ (benzyloxy)propylamine (8b) [19] were prepared according to the literature procedures. All other compounds were purchased from Sigma‐Aldrich. N N R1 N N R1 R3R2 NOC N N R1 N R2 O N N R1 NH2 N O Ph 1 2 N N R1N O Ph 5 NH N R2N O R1 O 6 NR4R5 R2 R3 3 4 R3R2 NOC Scheme 1 2 Grošelj et al. / European Journal of Chemistry 3 (1) (2012) 1‐6 2.1. Instrumentation Melting points were determined on a Stanford Research Systems MPA100 OptiMelt automated melting point system. The NMR spectra were obtained on a Bruker Avance DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C nucleus. All NMR measurements were performed with TMS as the internal standard. Mass spectra were recorded on an Agilent 6224 Accurate Mass TOF LC/MS spectrometer. IR spectra were recorded on a Perkin‐Elmer Spectrum BX FT‐IR spectrophoto‐ meter. Microwave irradiations were performed on CEM Discover Laboratory Microwave Oven. Microanalyses were performed on a Perkin‐Elmer CHN Analyzer 2400 II on the Faculty of Chemistry and Chemical Technology, University of Ljubljana. Flash column chromatography (FC) and column chromatography (CC) were performed on silica gel (Fluka, Silica gel 60, particle size 0.035‐0.070 mm). Medium pressure liquid chromatography (MPLC) was performed on a Büchi Flash Chromatography System (Büchi Fraction Collector C‐660, Büchi Pump Module C‐605, Büchi Control Unit C‐620) on silica gel (LiChroprep® Si 60, 15‐25 µm), column dimensions: 26×460 mm, backpressure: 10 Bar, detection: UV (254 nm). 2.2. Synthesis 2.2.1. Synthesis of 1‐(3‐(substituted)propyl)‐5‐ oxopyrrolidine‐3‐carboxylic acids (9c,d) Compounds 9c and 9d were prepared following modified literature procedure [18]. A mixture of itaconic acid (7a) (1.30 g, 10 mmol), water (4 mL), and 3‐amino‐1‐propanol (8c) (751 mg, 10 mmol) or 3‐(dimethylamino)propanamine (8d) (1.021 g, 10 mmol) was heated in a sealed vessel under microwave irradiation (300 W, 120 °C, ~3 bar) for 1 h. The reaction mixture was evaporated in vacuum and the residual water was removed by repetitive co‐evaporation in vacuum with ethyl acetate (3×20 mL) and dichloromethane (3×20 mL) to give the crude oily compounds 9c and 9d, which were used in the following step without purification (Scheme 2). 1‐(3‐(Hydroxy)propyl)‐5‐oxopyrrolidine‐3‐carboxylic acid (9c): Yield: 100% of brownish oil. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.57 (p, 2H, J = 6.8 Hz, CH2CH2CH2), 2.38‐2.43 (m, 2H, 4‐CH2), 2.93‐3.04 (m, 1H, 3‐H), 3.19 (dt, 2H, J = 4.0, 7.1 Hz, CH2CH2CH2N), 3.37 (t, 2H, J = 6.3 Hz, CH2CH2CH2O), 3.44‐3.50 (m, 2H, 2‐CH2), OH and COOH exchanged. 1‐(3‐(Dimethylamino)propyl)‐5‐oxopyrrolidine‐3‐carboxylic acid (9d): Yield: 100% of brownish oil. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.60 (p, 2H, J = 7.2 Hz, CH2CH2CH2), 2.21 (s, 6H, NMe2), 2.26‐2.34 (m, 2H, CH2CH2CH2NMe2), 2.38‐2.44 (m, 2H, 4‐CH2), 2.95‐3.06 (m, 1H, 3‐H), 3.09‐3.24 (m, 2H, CH2CH2CH2N), 3.44‐3.50 (m, 2H, 2‐CH2), COOH exchanged. 2.2.2. Synthesis of methyl 1‐(3‐(benzyloxy)propyl)‐5‐ oxopyrrolidine‐3‐carboxylate (12) This compound was prepared following a slightly modified literature procedure [20]. A solution of 3‐(benzyloxy)propan‐1‐ amine (8b) (2.484 g, 15 mmol) in methanol (20 mL) was added drop wise to a stirred solution of dimethyl itaconate (7b) (2.378 g, 15 mmol) in methanol (70 mL) at room temperature (r.t.) and the mixture was stirred at r.t. for 24 h. The solvent was removed in vacuum to give the crude oily 12, which was used in the following step without further purification (Scheme 2). Yield: 100% of yellowish oil. FT‐IR (KBr, cm‐1): 3029 (CH) (br, alkyl), 2948 (CH) (br, alkyl), 2860 (CH) (br, alkyl), 1733 (C=O) (ester), 1683 (C=O) (br, amide), 1493, 1452, 1434, 1362, 1265, 1199, 1178, 1098, 1026, 937, 848, 737, 698, 609. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.84 (tt, 2H, J = 7.2, 6.1 Hz, CH2CH2CH2), 2.61 (dd, 1H, J = 17.1, 9.6 Hz, 4‐Ha), 2.68 (dd, 1H, J = 17.1, 7.6 Hz, 4‐Hb), 3.12‐3.24 (m, 1H, 3‐H), 3.40 (td, 2H, J = 2.7; 7.0 Hz, CH2CH2CH2N), 3.50 (t, 2H, J = 6.2 Hz, CH2CH2CH2O), 3.55‐3.65 (m, 2H, 2‐CH2), 3.73 (s, 3H, CO2Me), 4.49 (s, 2H, PhCH2O), 7.27‐7.38 (m, 5H, Ph). 13C NMR (CDCl3, 75.5 MHz, δ, ppm): 27.0, 33.5, 35.4, 39.4, 48.6, 51.7, 67.2, 72.4, 127.0, 127.1, 127.8, 137.9, 171.7, 172.7. HRMS (EI): m/z found for C16H21NO4: m/z = 292.1544 (MH+); calcd.: m/z = 292.1549 (MH+). 2.2.3. Synthesis of 1‐(3‐(Benzyloxy)propyl)‐5‐oxopyrrolidine‐ 3‐carboxylic acid (9b) LiOH·H2O (839 mg, 20 mmol) was added to a solution of the ester 12 from the above experiment (15 mmol) in a mixture of THF (7 mL), H2O (7 mL), and MeOH (7 mL). The resulting mixture was stirred at r.t. for 1 h. MeOH and THF were removed by evaporation in vacuum at 50 mbar/35 oC, the aqueous residue was diluted with H2O (20 mL), and washed with CH2Cl2 (3×100 mL). The aqueous phase was acidified with aq. HCl (1M, 22 mL) and the product was extracted with EtOAc (3×100 mL). The combined organic phase was dried over anh. Na2SO4, filtered, and the filtrate was evaporated in vacuum to give compound 9b (Scheme 2). Yield: 87% of yellowish oil. FT‐ IR (NaCl, cm‐1): 2926 (CH) (alkyl), 1731 (C=O) (ester), 1650 (C=O) (amide), 1496, 1454, 1366, 1199, 1105, 745, 700. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.84 (p, 2H, J = 6.9 Hz, CH2CH2CH2), 2.67 (dd, 1H, J = 17.3, 9.7 Hz, 4'‐Ha), 2.75 (dd, 1H, J = 17.2, 7.2 Hz, 4'‐Hb), 3.11‐3.27 (m, 1H, 3'‐H), 3.41 (td, 2H, J = 7.2, 2.5 Hz, CH2CH2CH2N), 3.50 (t, 2H, J = 6.1 Hz, CH2CH2CH2O), 3.58 (dd, 1H, J = 10.1, 8.5 Hz, 2'‐Ha), 3.66 (dd, 1H, J = 10.1, 6.1 Hz, 2'‐Hb), 4.48 (s, 2H, PhCH2O), 6.91 (br s, 1H, COOH), 7.23‐ 7.43 (m, 5H, Ph). 13C NMR (CDCl3, 75.5 MHz): δ 27.4, 34.2, 36.0, 40.4, 49.6, 67.7, 73.1, 127.8, 127.9, 128.5, 138.2, 173.9, 175.7. HRMS (EI): m/z found for C15H19NO4: 278.1379 (MH+); calcd.: m/z = 278.1392 (MH+). 2.2.4. Synthesis of methyl 3‐(1‐(3‐(benzyloxy)propyl)‐5‐ oxopyrrolidin‐3‐yl)‐3‐oxopropanoate (10b) This compound was prepared following the literature procedure for the synthesis of closely related compounds [2,3]. Under argon, 1,1'‐carbonyldiimidazole (CDI) (2.69 g, 16.59 mmol) was added to a stirred solution of carboxylic acid 9b (3.63 g, 13.1 mmol) in anh. THF (60 mL) at r.t. and the resulting mixture was stirred at r.t. for 1 h. During this time CO2 evolved, therefore the reaction flask was not completely sealed. A solid powdered mixture of MgCl2 (1.21 g, 12.71 mmol) and potassium monomethyl malonate (3.07 g, 19.65 mmol) was added under a blanket of argon in one portion via a powder funnel, which was then rinsed with anh. THF (20 mL), and the resulting suspension was stirred under argon at r.t. for 12 h. Volatile components were evaporated in vacuum, aq. NaHSO4 (1M, 100 mL) was added to the residue, and the product was extracted with EtOAc (3×100 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate were evaporated in vacuum and the crude oily reside was purified by CC (EtOAc). Fractions containing the product were combined and volatile components were evaporated in vacuum to give compound 10b (Scheme 2). Yield: 3.50 g (80%) of yellowish oil. FT‐IR (NaCl, cm‐1): 2952 (CH) (alkyl), 2866 (CH) (alkyl), 1747 (C=O) (ester), 1715 (C=O) (ketone), 1682 (C=O) (amide), 1495, 1454, 1362, 1317, 1268, 1100, 1027, 743, 700. 1H NMR (CDCl3, 300 MHz, δ, ppm): 1.85 (p, 2H, J = 7.0, 6.6 Hz, CH2CH2CH2), 2.50‐2.72 (m, 2H, 4'‐CH2), 3.36‐3.45 (m, 1H, 3'‐H), 3.40 (td, 2H, J = 7.0, 2.0 Hz, CH2CH2CH2N), 3.46‐3.54 (m, 5H, CH2CH2CH2O, CH2COOMe, and 2'‐Ha), 3.64 (dd, 1H, J = 9.5, 5.9 Hz, 2'‐Hb), 3.75 (s, 3H, COOMe), 4.48 (s, 2H, PhCH2O), 7.23‐7.40 (m, 5H, Ph). 13C NMR (CDCl3, 75.5 MHz, δ, ppm): 27.4, 33.3, 40.2, 42.9, 47.5, 47.9, 52.5, 67.8, 73.1, 127.6, 127.7, 128.4, 138.3, 167.0, 171.9, 200.9. HRMS (EI): m/z found for C18H23NO5: m/z = 334.1658 (MH+); calcd.: m/z = 334.1654 (MH+). Grošelj et al. / European Journal of Chemistry 4 (1) (2013) 1‐6 3 Scheme 2 2.2.5. General procedure for the synthesis of 2‐substituted 6‐ (5‐oxo‐1‐phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ones (6a‐f) A mixture of β‐keto ester 10a,b (1 mmol), MeOH (4 mL), amidine salt 11a‐e (1 mmol), and KOBu‐t (112 mg, 1 mmol) was stirred at r.t. for 48 h. Then, water (4 mL) was added, the mixture was stirred at r.t. for 1 h, and the precipitate was collected by filtration to give 6a‐f. In this manner, analytically pure compounds 6a‐d were obtained (Scheme 2). Compounds 6e and 6f were further purified by FC over silica gel (d = 3 cm, l = 5 cm). Fractions containing the product were combined and evaporated in vacuo to give compound 6e and 6f (Scheme 2). 6‐(5‐Oxo‐1‐phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐one (6a): Prepared from 10a (261 mg, 1 mmol), formamidine acetate (11a) (104 mg, 1 mmol), and KOBu‐t (112 mg, 1 mmol). White. Yield: 33%. M.p.: 223‐228 oC (with slow decomp. above 200 oC). FT‐IR (KBr, cm‐1): 2794 (OH) (br, alkyl), 1682 (C=O) (amide), 1662 (C=O) (amide), 1601, 1500, 1488, 1458, 1427, 1398, 1307, 1283, 1242, 1221, 1203, 1176, 1147, 1118, 1022, 979, 946, 916, 896, 877, 805, 773, 752, 721, 685, 661. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.70 (dd, 1H, J = 16.8, 7.7 Hz, 4'‐Ha), 2.85 (dd, 1H, J = 16.8, 9.0 Hz, 4'‐Hb), 3.60 (p, 1H, J = 8.1 Hz, 3'‐ H), 3.88 (dd, 1H, J = 9.8, 6.5 Hz, 2'‐Ha), 4.13 (t, 1H, J = 9.1 Hz, 2'‐ Hb), 6.32 (s, 1H, 5‐H), 7.13 (t, 1H, J = 7.3 Hz, p‐Ph), 7.37 (t, 2H, J = 7.8 Hz, m‐Ph), 7.66 (d, 2H, J = 8.0 Hz, o‐Ph), 8.19 (s, 1H, 2‐H), 12.44 (s, 1H, NH). 13C NMR (75.5 MHz, DMSO‐d6, δ, ppm): 36.7, 37.3, 52.0, 112.3, 119.4, 124.0, 128.7, 139.3, 150.4, 161.2, 167.0, 172.3. Anal. calcd. for C14H13N3O2∙1¼H2O: C, 55.89; H, 4.77; N, 13.97. Found: C, 55.82; H, 4.47; N, 13.68%. 2‐Methyl‐6‐(5‐oxo‐1‐phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ one (6b): Prepared from 10a (261 mg, 1 mmol), acetamidine hydrochloride (11b)(95 mg, 1 mmol), and KOBu‐t (112 mg, 1 mmol). White. Yield: 49%. M.p.: 234‐237 oC. FT‐IR (KBr, cm‐1): 2986 (CH) (br, alkyl), 1670 (C=O) (br, amide), 1591, 1497, 1474, 1450, 1410, 1386, 1355, 1305, 1280, 1230, 1212, 1176, 1128, 1048, 1017, 955, 888, 847, 752, 697, 684, 663. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.28 (s, 3H, 2‐Me), 2.72 (dd, 1H, J = 16.8, 8.4 Hz, 4'‐Ha), 2.81 (dd, 1H, J = 16.9, 9.0 Hz, 4'‐Hb), 3.55 (qd, 1H, J = 8.5, 6.9 Hz, 3'‐H), 3.88 (dd, 1H, J = 9.7, 7.0 Hz, 2'‐Ha), 4.10 (dd, 1H, J = 9.7, 8.4 Hz, 2'‐Hb), 6.16 (s, 1H, 5‐H), 7.03‐7.22 (m, 1H, p‐Ph), 7.28‐7.45 (m, 2H, m‐Ph), 7.60‐7.76 (m, 2H, o‐Ph), 12.38 (s, 1H, NH). 13C NMR (75.5 MHz, DMSO‐d6, δ, ppm): 21.3, 36.9, 37.2, 52.0, 109.2, 119.4, 124.0, 128.7, 139.3, 159.7, 162.4, 166.7, 172.3. Anal. calcd. for C15H15N3O2: C, 66.90; H, 5.61; N, 15.60. Found: C, 66.60; H, 5.54; N, 15.38%. 6‐(5‐Oxo‐1‐phenylpyrrolidin‐3‐yl)‐2‐phenylpyrimidin‐4(3H)‐ one (6c): Prepared from 10a (261 mg, 1 mmol), benzamidine hydrochloride (11c)(157 mg, 1 mmol), and KOBu‐t (112 mg, 1 mmol). Yield: 72% of white solid. M.p.: 235‐236 oC. FT‐IR (KBr, cm‐1): 3065 (CH) (br, alkyl), 1684 (C=O) (amide), 1685 (C=O) (amide), 1597, 1542, 1497, 1471, 1444, 1389, 1348, 1301, 1281, 1228, 1180, 1126, 1034, 982, 925, 857, 792, 757, 688, 669, 660, 641, 615. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.82 (dd, 1H, J = 16.3, 7.4 Hz, 4'‐Ha), 2.90 (dd, 1H, J = 16.2, 8.0 Hz, 4‐Hb), 3.69 (qd, 1H, J = 8.2, 6.5 Hz, 3'‐H), 3.98 (dd, 1H, J = 9.8, 6.5 Hz, 2'‐Ha), 4.20 (dd, 1H, J = 9.8, 8.2 Hz, 2'‐Hb), 6.36 (s, 1H, 5‐H), 7.05‐7.20 (m, 1H, p‐Ph), 7.38 (dd, 2H, J = 8.6, 7.3 Hz, m‐Ph), 7.47‐7.61 (m, 3H, p‐Ph and m‐Ph), 7.66‐7.72 (m, 2H, o‐ Ph), 8.11‐8.17 (m, 2H, o‐Ph), 12.65 (s, 1H, NH). 13C NMR (75.5 MHz, DMSO‐d6, δ, ppm): 37.1, 37.4, 52.3, 109.6, 119.5, 124.0, 127.9, 128.6, 128.7, 131.8, 132.5, 139.4, 157.8, 163.6, 167.2, 4 Grošelj et al. / European Journal of Chemistry 3 (1) (2012) 1‐6 172.4. Anal. calcd. for C20H17N3O2: C, 72.49; H, 5.17; N, 12.68. Found: C, 72.16; H, 5.01; N, 12.54%. 2‐([1,1'‐Biphenyl]‐4‐yl)‐6‐(5‐oxo‐1‐phenylpyrrolidin‐3‐yl) pyrimidin‐4(3H)‐one (6d): Prepared from 10a (261 mg, 1 mmol), [1,1'‐biphenyl]‐4‐carboxamidine hydrochloride (11d)(232 mg, 1 mmol), and KOBu‐t (112 mg, 1 mmol). Yield: 72% of white solid. M.p.: 303‐308 oC. FT‐IR (KBr, cm‐1): 2877 (CH) (br, alkyl), 1693 (C=O) (amide), 1649 (C=O) (amide), 1594, 1542, 1519, 1491, 1384, 1356, 1296, 1281, 1223, 1187, 1128, 1040, 1008, 980, m900, 847, 756, 732, 688, 674. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 2.85 (dd, 1H, J = 16.8, 7.9 Hz, 4'‐ Ha), 2.91 (dd, 1H, J = 16.7, 8.8 Hz, 4'‐Hb), 3.70 (p, 1H, J = 7.8 Hz, 3'‐H), 4.00 (dd, 1H, J = 9.6, 6.5 Hz, 2'‐Ha), 4.21 (dd, 1H, J = 9.7, 8.2 Hz, 2'‐Hb), 6.37 (s, 1H, 5‐H), 7.14 (t, 1H, J = 7.3 Hz, p‐Ph), 7.35‐7.45 (m, 3H, m,p‐Ph), 7.50 (t, 2H, J = 7.7 Hz, m‐Ph), 7.71 (dd, 2H, J = 8.3, 1.3 Hz, m‐C6H4), 7.75 (d, 2H, J = 7.3 Hz, o‐Ph), 7.82 (d, 2H, J = 8.5 Hz, o‐C6H4), 8.25 (d, 2H, J = 8.0 Hz, o‐Ph), 12.76 (s, 1H, NH). 13C NMR (75.5 MHz, DMSO‐d6, δ, ppm): 37.1, 37.3, 52.3, 119.4, 123.8, 126.6, 126.7, 127.9, 128.3, 128.5, 128.8, 139.0, 139.2, 172.1. Anal. calcd. for C26H21N3O2·⅓H2O: C, 75.53; H, 5.28; N, 10.16. Found: C, 75.82; H, 5.23; N, 10.16%. 6‐(5‐Oxo‐1‐phenylpyrrolidin‐3‐yl)‐2‐(4‐((pyrrolidin‐1‐yl) methyl)phenyl)pyrimidin‐4(3H)‐one (6e): Prepared from 10a (261 mg, 1 mmol), 4‐((pyrrolidin‐1‐yl)methyl)benzamidine dihydrochloride (11e)(232 mg, 1 mmol), and KOBu‐t (224 mg, 2 mmol); flash chromatography (FC) first EtOAc:EtOH = 10:1 to elute less polar impurities, then EtOAc:EtOH = 3:1 to elute the product 6e. Yield: 37% of yellowish solid. M.p.: 202‐214 oC (with slow decomp. above 200 oC). FT‐IR (KBr, cm‐1): 2954 (br, CH) (alkyl), 2772 (CH) (alkyl), 1690 (C=O) (amide), 1651 (C=O) (amide), 1594, 1541, 1514, 1495, 1476, 1421, 1386, 1358, 1299, 1280, 1219, 1186, 1127, 1042, 981, 861, 756, 690, 673, 661. 1H NMR (300 MHz, DMSO‐d6, δ, ppm):1.64‐1.76 (m, 4H, 2×CH2 of pyrrolidine), 2.40‐2.52 (m, 4H, 2×CH2 of pyrrolidine), 2.82 (dd, 1H, J = 16.7, 7.8 Hz, 4'‐Ha), 2.90 (dd, 1H, J = 16.7, 8.6 Hz, 4'‐Hb), 3.65 (s, 2H, ArCH2N), 3.66 (p, 1H, J = 8.1 Hz, 3'‐H), 3.97 (dd, 1H, J = 9.7, 6.5 Hz, 2'‐Ha), 4.19 (dd, 1H, J = 9.8, 8.2 Hz, 2'‐Hb), 6.33 (s, 1H, 5‐H), 7.13 (t, 1H, J = 7.4 Hz, p‐ Ph), 7.38 (dd, 2H, J = 8.7, 7.2 Hz, m‐Ph), 7.43 (d, 2H, J = 8.2 Hz, m‐C6H4), 7.70 (dd, 2H, J = 8.7, 7.2 Hz, o‐Ph), 8.09 (d, 2H, J = 8.3 Hz, o‐C6H4), 12.56 (s, 1H, NH). 13C NMR (DMSO‐d6, 75.5 MHz, δ, ppm): 23.1, 37.1, 37.4, 52.3, 53.5, 59.0, 109.2, 119.5, 124.0, 127.8, 128.6, 128.7, 131.3, 139.4, 143.1, 157.8, 163.9, 167.1, 172.4. Anal. calcd. for C25H26N4O2·H2O: C, 69.42; H, 6.53; N, 12.95. Found: C, 69.37; H, 6.31; N, 12.97%. 6‐(1‐(3‐(Benzyloxy)propyl)‐5‐oxopyrrolidin‐3‐yl)‐2‐phenyl pyrimidin‐4(3H)‐one (6f): Prepared from 10b (261 mg, 1 mmol), benzamidine hydrochloride (11c)(157 mg, 1 mmol), and KOBu‐t (112 mg, 1 mmol); FC first EtOAc to elute less polar impurities, then EtOAc:MeOH = 10:1 to elute the product 6f. Yield: 58% of yellowish oil. FT‐IR (NaCl, cm‐1): 3063 (CH) (NH) (alkyl, lactam), 2928 (CH) (NH) (alkyl, lactam), 2861 (CH) (NH) (alkyl, lactam), 1657(C=O) (amide), 1603, 1548, 1502, 1444, 1310, 1265, 1102, 982, 850, 697. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.89 (p, 2H, J = 6.5 Hz, CH2CH2CH2), 2.71 (dd, 1H, J = 16.7, 9.0 Hz, 4'‐Ha), 2.81 (dd, 1H, J = 16.8, 7.8 Hz, 4'‐Hb), 3.41‐3.50 (m, 1H, 3'‐H), 3.46 (t, 2H, J = 7.1 Hz, CH2CH2CH2N), 3.52 (t, 2H, J = 6.2 Hz, CH2CH2CH2O), 3.59 (dd, 1H, J = 9.6, 6.5 Hz, 2'‐Ha), 3.71 (dd, 1H, J = 9.6, 8.5 Hz, 2'‐Hb), 4.46 (s, 2H, PhCH2O), 6.29 (s, 1H, 5‐H), 7.20‐7.34 (m, 5H, Ph), 7.49‐7.61 (m, 3H, m,p‐Ph), 8.16‐8.22 (m, 2H, o‐Ph), 12.73 (s, 1H, NH). 13C NMR (75.5 MHz, DMSO‐d6, δ, ppm): 27.7, 36.4, 38.5, 40.1, 51.8, 67.8, 73.1, 110.1, 127.6, 127.7, 127.9, 128.4, 129.0, 131.8, 132.3, 138.3, 157.4, 165.3, 168.6, 173.4. HRMS (EI): m/z found for C24H25N3O3: m/z = 404.1967 (MH+); calcd.: m/z = 404.1974 (MH+). 2.2.6. Synthesis of 6‐(1‐(3‐hydroxypropyl)‐5‐oxopyrrolidin‐3‐ yl)‐2‐phenylpyrimidin‐4(3H)‐one (6g) A mixture of 6f (1 g, 2.48 mmol), MeOH (100 mL), and 10% Pd‐C (350 mg) was hydrogenated (P = 60 psi of H2) at 50 °C for 7 days. The reaction mixture was filtered through a plug of Celite® and thoroughly washed with CH2Cl2. Volatile components were evaporated in vacuum and the residue was purified by CC (EtOAc:MeOH; 10:1). Fractions containing the product were combined and volatile components were evaporated in vacuum to give compound 6g. Yield: 471 mg (60%) of white semi‐solid. FT‐IR (KBr, cm‐1): 3425 (OH) (alcohol), 2934 (CH) (NH) (alkyl, lactam), 1652 (C=O) (amide), 1550, 1496, 1444, 1401, 1308, 1269, 1179, 1058, 983, 853, 756, 694. 1H NMR (300 MHz, CDCl3, δ, ppm): 1.74 (p, 2H, J = 6.0 Hz, CH2CH2CH2), 2.80 (dd, 1H, J = 17.0, 8.9 Hz, 4'‐Ha), 2.88 (dd, 1H, J = 16.9, 7.3 Hz, 4'‐Hb), 3.32‐3.44 (m, 1H, 3'‐H), 3.44 (dt, 1H, J = 14.1, 5.9 Hz, 1H of CH2CH2CH2N), 3.52‐3.67 (m, 5H, 1H of CH2CH2CH2N, CH2CH2CH2OH, and 2'‐Ha), 3.74 (dd, 1H, J = 9.5, 8.5 Hz, 2'‐Hb), 6.32 (s, 1H, 5‐H), 7.51‐7.63 (m, 3H, m,p‐Ph), 8.11‐8.17 (m, 2H, o‐Ph), 12.15 (br s, 1H, NH). 13C NMR (75.5 MHz, DMSO‐d6, δ, ppm): 29.6, 36.2, 38.2, 39.1, 51.8, 58.5, 110.0, 127.7, 128.8, 131.6, 132.2, 157.4, 165.0, 168.2, 174.3. HRMS (EI): m/z found for C17H19N3O3: m/z = 314.1499 (MH+); calcd.: m/z = 314.1505 (MH+). 2.2.7. Synthesis of 3‐(4‐(6‐((methylsulfonyl)oxy)‐2‐phenyl‐ pyrimidin‐4‐yl)‐2‐oxopyrrolidin‐1‐yl)propyl methane sulfonate (13) To a cooled (‐5 °C) stirred solution of compound 6g (250 mg, 0.80 mmol) in anh. CH2Cl2 (5 mL) was added anh. Et3N (280 µL, 2 mmol) followed by addition of methanesulfonyl chloride (131 µL, 1.7 mmol) and the resulting mixture was stirred at ‐5 °C for 20 min. and at r.t. for 30 min. The reaction mixture was directly (without previous evaporation) purified by FC (EtOAc). Fractions containing the product were combined and volatile components were evaporated in vacuum to give compound 13 (Scheme 3). Yield: 326 mg (86%) of white semi‐solid. FT‐IR (KBr, cm‐1): 2936 (CH) (alkyl), 1682 (C=O) (amide), 1592, 1574, 1556, 1496, 1370, 1317, 1190, 1040, 929, 802, 776, 701. 1H NMR (300 MHz, CDCl3, δ, ppm): 2.02 (p, 2H, J = 6.4 Hz, CH2CH2CH2), 2.83 (d, 2H, J = 7.7 Hz, 4'‐CH2), 3.00 (s, 3H, NSO2Me), 3.48 (t, 2H, J = 6.8 Hz, CH2CH2CH2N), 3.65 (s, 3H, OSO2Me), 3.68‐3.87 (m, 3H, 3'‐H and 2'‐CH2), 4.24 (t, 2H, J = 6.1 Hz, CH2CH2CH2O), 6.86 (s, 1H, 5‐H), 7.44‐7.55 (m, 3H, m,p‐Ph), 8.34‐8.39 (m, 2H, o‐Ph). 13C NMR (75.5 MHz, CDCl3, δ, ppm): 26.9, 36.6, 37.1, 38.5, 39.0, 41.4, 51.7, 67.8, 106.9, 128.4, 128.7, 131.8, 135.8, 164.88, 164.91, 173.1, 174.2. 2.2.8. Synthesis of 4‐(2‐phenyl‐6‐(pyrrolidin‐1‐yl)pyrimidin‐ 4‐yl)‐1‐(3‐(pyrrolidin‐1‐yl)propyl)pyrrolidin‐2‐one (14) To a solution of compound 13 (300 mg, 0.638 mmol) in anh. CH2Cl2 (5 mL) under argon was added pyrrolidine (700 µL, 8.3 mmol) and the mixture was stirred under reflux for 19 h. Volatile components were evaporated in vacuum and the residue was purified by FC (EtOAc:MeOH:Et3N, 10:1:1). Fractions containing the product were combined and volatile components were evaporated in vacuum to give compound 14 (Scheme 3). Yield: 60 mg (22%) of colorless oil. 1H NMR (300 MHz, CDCl3, δ, ppm): 1.73‐1.90 (m, 6H, CH2CH2CH2 and 2×CH2 of pyrrolidine), 1.98‐2.12 (m, 4H, 2×CH2 of pyrrolidine), 2.49‐ 2.60 (m, 6H, 3×CH2N of pyrrolidine), 2.73 (dd, 1H, J = 16.7, 9.1 Hz, 4'‐Ha), 2.90 (dd, 1H, J = 16.7, 7.4 Hz, 4'‐Hb), 3.19‐3.61 (m, 7H, 3'‐H, CH2N of pyrrolidine, CH2CH2CH2N, and CH2CH2CH2O), 3.67 (dd, 1H, J = 9.7, 6.4 Hz, 2'‐Ha), 3.74 (dd, 1H, J = 9.7, 8.7 Hz, 2'‐Hb), 6.05 (s, 1H, 5‐H), 7.38‐7.46 (m, 3H, m,p‐Ph); 8.39‐8.47 (m, 2H, o‐Ph). 13C NMR (75.5 MHz, CDCl3, δ, ppm): 23.5, 25.4, 26.6, 37.1, 38.8, 40.8, 46.5, 52.5, 53.7, 54.2, 98.9, 128.3, 128.3, 130.2, 138.8, 160.8, 163.7, 167.6, 174.2. ESI: m/z found for C25H33N5O: m/z = 420.2745 (MH+); calcd.: m/z = 420.2763 (MH+). Grošelj et al. / European Journal of Chemistry 4 (1) (2013) 1‐6 5 Scheme 3 2.2.9. Synthesis of 1‐(3‐hydroxypropyl)‐4‐(2‐phenyl‐6‐ (pyrrolidin‐1‐yl)pyrimidin‐4‐yl)pyrrolidin‐2‐one (15) To a cooled (‐5 °C) solution of compound 6g (471 mg, 1.503 mmol) in anh. CH2Cl2 (5 mL) was added anh. Et3N (252 µL, 1.804 mmol) followed by addition of methanesulfonyl chloride (116 µL, 1.503 mmol) and the resulting mixture was stirred at ‐ 5 °C for 20 min. and then at r.t. for 1 h. The reaction mixture was directly (without previous evaporation) purified by FC (EtOAc). Fractions containing the intermediate mono‐mesylate were combined, evaporated in vacuum, and the residue was dried under high vacuum (r.t./0.1 Torr). The residue was dissolved in anhydrous CH2Cl2 (5 mL) under argon followed by addition of pyrrolidine (253 µL, 3 mmol), the mixture was stirred at r.t. for two days, and evaporated in vacuum. The residue was purified by FC (EtOAc:MeOH, 10:1). Fractions containing the product were combined, volatile components were evaporated in vacuo, and the residue was purified by MPLC (EtOAc:MeOH, 10:1). Fractions containing the product were combined and volatile components were evaporated in vacuum to give compound 15 (Scheme 3). Yield: 174 mg (31%) of white solid. M.p.: 101‐105 °C (white solid). FT‐IR (KBr, cm‐1): 3406 (CH) (alcohol), 2942 (CH) (alkyl), 2872 (CH) (alkyl), 1668 (C=O) (amide), 1596, 1536, 1505, 1455, 1381, 1347, 1168, 1062, 1028, 700. 1H NMR (300 MHz, DMSO‐d6, δ, ppm): 1.64 (p, 2H, J = 6.8 Hz, CH2CH2CH2), 1.97 (br s, 4H, 2×CH2 of pyrrolidine), 2.63 (d, 2H, J = 8.1 Hz, 4'‐CH2), 3.21‐3.36 (m, 2H, CH2CH2CH2N), 3.36‐3.46 (m, 5H, 2×CH2N of pyrrolidine and 3'‐ H), 3.50‐3.66 (m, 3H, CH2CH2CH2O and 2'‐Ha), 3.73 (t, 1H, J = 7.5 Hz, 2'‐Hb), 4.43 (br s, 1H, OH), 6.35 (s, 1H, 5‐H), 7.43‐7.48 (m, 3H, m,p‐Ph), 8.29‐8.42 (m, 2H, o‐Ph). 13C NMR (75.5 MHz, CDCl3, δ, ppm): 25.2, 29.6, 36.9, 38.7, 39.0, 46.3, 52.7, 58.5, 98.8, 128.1, 128.2, 130.1, 138.6, 160.7, 163.6, 167.3, 175.0. HRMS (EI): m/z found for C21H26N4O2: m/z = 367.2122 (MH+); calcd.: m/z = 367.2134 (MH+). 2.2.10. Synthesis of tert‐butyl 4‐(1‐(3‐(benzyloxy)propyl)‐5‐ oxopyrrolidin‐3‐yl)‐6‐oxo‐2‐phenylpyrimidine‐1(6H)‐ carboxylate (16) To a solution of compound 6f (360 mmol 0.89 mmol) in anh. THF (5 mL) was added Et3N (63 mL, 0.45 mmol) and DMAP (56 mg, 0.45 mmol) followed by addition of (Boc)2O (397 mg, 1.78 mmol) and the mixture was stirred at r.t. for 3 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with water (2×50 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and volatile components were evaporated in vacuum. The residue was purified by CC (EtOAc). Fractions containing the product were combined and volatile components were evaporated in vacuum to give compound 16 (Scheme 3). Yield: 365 mg (81%) of light yellowish oil. FT‐IR (NaCl, cm‐1): 2930 (CH) (alkyl), 1767 (C=O) (ester), 1693 (C=O) (amide), 1590, 1573, 1558, 1494, 1455, 1386, 1246, 1132, 1057, 852, 698. 1H NMR (300 MHz, CDCl3, δ, ppm): 1.60 (s, 9H, t‐Bu), 1.90 (dq, 2H, J = 7.5, 6.2 Hz, CH2CH2CH2), 2.73‐2.94 (m, 2H, 4'‐CH2), 3.48 (t, 2H, J = 7.1 Hz, CH2CH2CH2N), 3.53 (t, 2H, J = 6.1 Hz, CH2CH2CH2O), 3.61‐3.84 (m, 3H, 3'‐H and 2'‐CH2), 4.46 (s, 2H, PhCH2O), 6.93 (s, 1H, 5‐H), 7.21‐7.36 (m, 5H, Ph), 7.42‐7.54 (m, 3H, m,p‐Ph), 8.39‐8.46 (m, 2H, o‐Ph). 13C NMR (CDCl3, 75.5 MHz): δ 27.8, 27.9, 37.1, 39.1, 40.4, 52.4, 68.0, 73.3, 85.3, 107.6, 127.8, 128.0, 128.6, 128.7, 131.6, 136.6, 138.5, 149.6, 165.6, 165.8, 173.3. HRMS (EI): m/z found for C29H33N3O5: m/z = 504.2478 (MH+); calcd.: m/z = 504.2498 (MH+). 3. Results and discussion First, methyl 3‐oxo‐3‐(5‐oxo‐1‐phenylpyrrolidin‐3‐yl) propanoate (10a) was prepared in two steps form itaconic acid (7a) following the literature procedure [16]. Treatment of the β‐keto ester 10a with formamidine acetate (11a), acetamidine hydrochloride (11b), benzamidine hydrochloride (11c), [1,1'‐ biphenyl]‐4‐carboxamidine hydrochloride (11d), and 4‐ ((pyrrolidin‐1‐yl)methyl)benzamidine dihydrochloride (11e) in methanol in the presence of potassium tert‐butoxide at room temperature afforded the corresponding 2‐substituted 6‐(5‐ oxo‐1‐phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ones 6a‐e in 33‐ 72% yields (Scheme 2). Next, we tried to prepare the analogues of 6a‐e bearing polar substituents at the pyrrolidine nitrogen 6 Grošelj et al. / European Journal of Chemistry 4 (1) (2013) 1‐6 atom following the above synthetic route. Though treatment of itaconic acid (7a) with 3‐amino‐1‐propanol (8c) and 3‐ (dimethylamino)propanamine (8d) in water under reflux [18] did afford the corresponding 5‐oxopyrrolidin‐3‐carboxylic acids 9c and 9d, further carboxymethylation under Masamune‐ Claisen conditions did not give the desired β‐keto esters. This was not really surprising, since carboxylic acids bearing highly polar and/or basic substituents are usually difficult substrates for Masamune‐Claisen condensations [13]. On the other hand, condensation of dimethyl itaconate (7b) with 3‐(benzyloxy) propylamine (8b) [19] in methanol at room temperature proceeded smoothly to afford methyl 1‐(3‐(benzyloxy)propyl)‐ 5‐oxopyrrolidine‐3‐carboxylate (12) in quantitative yield. Hydrolysis of the ester 12 then gave the carboxylic acid 9b in 87% yield. Quite expectedly, Masamune‐Claisen homologation of the carboxylic acid 9b with protected OH functionality at the side chain led to the corresponding β‐keto ester 10b, which was cyclized with benzamidine (11c) to furnish 6‐(1‐(3‐ (benzyloxy)propyl)‐5‐oxopyrrolidin‐3‐yl)‐2‐phenylpyrimidin‐ 4(3H)‐one (6f) in 46% yield over two steps (Scheme 2). Finally, some transformations and derivatizations using functionalized pyrimidinone 6f as a starting material were carried out. Catalytic hydrogenation under 3 bar of hydrogen in the presence of 10% Pd‐C resulted in removal of the O‐benzyl group to afford the N'‐(3‐hydroxypropyl)‐substituted analogue 6g in 60% yield. Subsequent mesylation of 6g with two equivalents of mesyl chloride at ‐5 °C → 20 °C produced the bis‐ o‐mesylate 13 in 86% yield, while further treatment of 13 with excess pyrrolidine in refluxing dichloromethane for 19 h did not proceed to completion and furnished 4‐(2‐phenyl‐6‐ (pyrrolidin‐1‐yl)pyrimidin‐4‐yl)‐1‐(3‐(pyrrolidin‐1‐yl)propyl) pyrrolidin‐2‐one (14) along with several by‐products. Upon chromatographic workup, the bis‐substitution product 14 was isolated in 22% yield. To obtain the mono‐aminated compound as well, the pyridone 6g was treated first with one equivalent of mesyl chloride at ‐5 °C → 20 °C and the intermediate mono‐ mesylate was treated further with two equivalents of pyrrolidine in dichloromethane at room temperature for 48 h. Subsequent chromatographic workup afforded 1‐(3‐ hydroxypropyl)‐4‐(2‐phenyl‐6‐(pyrrolidin‐1‐yl)pyrimidin‐4‐yl) pyrrolidin‐2‐one (15) in 31% yield. It is noteworthy, that low yields of the amination products 14 and 15 were due to incomplete conversion and competitive formation of by‐ products upon treatment of the mesylates with excess pyrrolidine. Further, low yield of the mono‐aminated product 15 could also be explained by lack of chemoselectivity in the mesylation step, since formation of the bis‐mesylate 13 as the by‐product was detected by TLC. Acylation of pyrimidone 6f with Boc2O in the presence of 4‐dimethylaminopyridine (DMAP) proceeded smoothly to furnish the N‐acylated pyrimidone 16 in 81% yield (Scheme 3). The structures of newcompounds 9b, 10b, 6a‐g, and 12‐16 were determined by spectroscopic methods (1H NMR, 13C NMR, IR, HRMS) and by elemental analyses for C, H, and N. Compounds 9b, 10b, 6f,g, and 12‐16 were not obtained in analytically pure form. Their identities were confirmed by 13C NMR and HRMS. Spectral data for compounds novel compounds 9b, 10b, 6a‐g, and 12‐16 were in agreement with the data for closely related known compounds [16,17]. Structural assignment of 1‐(3‐hydroxypropyl)‐4‐(2‐phenyl‐6‐ (pyrrolidin‐1‐yl)pyrimidin‐4‐yl)pyrrolidin‐2‐one (15) was based on 1H NMR data. A broad singlet at 4.43 ppm was in agreement with the aliphatic OH group, whereas the regioisomeric 6‐(5‐oxo‐1‐(3‐(pyrrolidin‐1‐yl)propyl)pyrroli‐ din‐3‐yl)‐2‐phenylpyrimidin‐4(3H)‐one should exhibit a broad signal at ~12 ppm corresponding to the pyridone NH group. 4. Conclusion In conclusion, s simple three step synthesis of 6‐(5‐oxo‐1‐ phenylpyrrolidin‐3‐yl)pyrimidin‐4(3H)‐ones 6a‐f from comer‐ cially available itaconic acid (7a) was developed. The synthesis comprises cyclisation of 7a with a primary amine 8, Masamune‐Claisen homologation of 5‐pyrrolidone‐3‐carboxylic acid 9, and cyclisation of the so formed β‐keto ester with an amidine 11. Unfortunately, polar N‐substituents bearing basic or acidic functional groups are not compatible with the Masamune‐Claisen condensation; however, this problem can be circumvented by suitable protection of these functional groups or by transformation of the N‐substituents after the pyrimidine ring formation. Acknowledgements This work was supported by Boehringer‐Ingelheim Pharma GmbH & Co. KG (Biberach, Germany) and Slovenian Research Agency (Ljubljana, Slovenia) (Grant No: P1‐0179). References [1]. Patrick, G. L. An Introduction to Medicinal Chemistry; 3rd edition, Oxford University Press, 2005. [2]. Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.; Kimura, R.; Matsumoto, S. I.; Furuichi, K.; Matsuda, A.; Shuto, S. J. Med. Chem. 2003, 46, 1980‐ 1989. [3]. Paillet‐Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.; Butt‐Gueulle, S.; Dauphin, F.; Lesnard, A.; Delarue, C.; Vaudryb, H.; Rault, S. Bioorg. Med. Chem. Lett. 2007, 17, 3018‐3022. [4]. Pullagurla, M.; Dukat, M.; Roth, B. 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