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An efficient synthesis of fluorine-containing polyfunctional 1,2,3,4-tetrahydropyrimidines
Journal of Fluorine Chemistry 125 (2004) 1491–1496
An efficient synthesis of fluorine-containing polyfunctional 1,2,3,4-tetrahydropyrimidines Fu-Lu Zhao, Jin-Tao Liu* Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China Received 30 March 2004; received in revised form 17 May 2004; accepted 18 May 2004 Available online 8 July 2004
Abstract A convenient one-pot synthesis of fluorine-containing 1,2,3,4-tetrahydropyrimidines was described. Fluoroalkylated enaminoketones reacted readily with primary amines and formalin (37% formaldehyde solution) under mild conditions to give the title compounds in high yields. a-Amino acids were introduced into tetrahydropyrimidine rings for the first time by this reaction. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluoroalkylated enaminoketone; Primary amine; Formalin; Fluorine-containing 1,2,3,4-tetrahydropyrimidines
1. Introduction
2. Results and discussion
It is well known that the introduction of fluorine atoms or fluoroalkyl groups into heterocyclic compounds may have significant influence on their biological and physical properties [1,2]. Therefore the development of synthetic methods for fluorine-containing heterocyclic compounds has been an important field in both organofluorine chemistry and organic synthesis. 1,2,3,4-Tetrahydropyrimidine is an important heterocyclic ring and many compounds containing it show interesting biological activities. For example, compound I was reported as antihistaminic and antibacterial [3], and compound II has been prepared as bioisosteric congeners of arecoline which is a muscarinic agonist for treatment of Alzheimer’s disease [4]. Due to their potent biological properties, much attention has been paid to the synthesis of tetrahydropyrimidines [5–10]. In 1981, Moehrle and Reinhardt reported the synthesis of acetylated 1,2,3,4-tetrahydropyrimidines from the reaction of enaminoketones with primary amines and formalin [11]. But to the best of our knowledge, there are no reports involving the synthesis of fluorine-containing 1,2,3,4-tetrahydropyrimidines. So it is our interest to develop a facile method for this kind of fluorine-containing heterocyclic compounds (Scheme 1).
Fluoroalkylated enaminoketones (1) are useful precursors and have been used to synthesize fluoroalkylated quinolines [12]. In our continuous study on their applications in the synthesis of fluorine-containing heterocyclic compounds, it was found that 1-chloro-1,1-difluoro-4phenylamino-but-3-en-2-one (1a) reacted readily with npropyl amine (2a) and formalin (37% formaldehyde solution) in DMSO under mild conditions and the corresponding 5-chlorodifluoroacetyl-1-phenyl-3-propyl-1,2,3,4tetrahydropyrimidines (3aa) was obtained along with an unexpected product, 5-chlorodifluoroacetyl-1,3-diphenyl1,2,3,4-tetrahydropyrimidines (3ae) (Scheme 2). Conditional experiments indicated that the distribution of two products was significantly influenced by the ratio of reactants, and 3aa was obtained predominantly (>89%) when the ratio of 1a:2a:formalin was 1:2:4. DMF, HMPA, MeCN and 1,4-dioxane could also be used as solvent, but the best results were obtained in DMSO. How was 3ae formed? Was it formed directly from 1a and formalin? To obtain mechanistic information on the reaction, 1a was allowed to react with formalin in the absence of amines under similar conditions for 10 h, but no reaction occurred. When a small amount of DABCO was added, the reaction took place and 3ae was formed with a low conversion of 1a. However, 1a was completely converted to 3ae when equivalent or excess DABCO was used. The same
*
Corresponding author. Tel.: þ86-21-64163300; fax: þ86-21-64166128. E-mail address: [email protected] (J.-T. Liu). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.05.016
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Scheme 3. Scheme 1.
result was obtained when NH4OH was used as a base instead of DABCO (Scheme 3). Based on the above results, it was surmised that on the attack of amine, an aniline was released from 1a and then reacted with 1a and formalin to give 3ae. This was further proved by the following experiment. The reaction of 1a with excess p-methoxyaniline (2j) and formalin afforded three products, 3ej, 3ee and 3aj. The latter two could not be separated by column chromatography and were obtained as a mixture. Obviously the formation of 3ej and 3ee involved a new enaminoketone, 1-chloro-1,1-difluoro-4-(40 -methoxyphenylamino)-but-3-en-2-one (1e), which was formed from the exchange reaction of 1a and p-methoxyaniline [13]. The reaction of 1e with p-methoxyaniline and formalin gave 3ej, while 3ee were formed by the reaction of 1e with aniline and formalin (Scheme 4). Using the optimized conditions, the reaction of fluorinecontaining enaminoketones with various primary amines and formalin was studied (Scheme 5). As shown in Table 1, both aliphatic and aromatic primary amines gave the desired product in good yields. The bulkiness of primary amines and the length of fluorine-containing group in enaminoketones have little influence on the reaction. But electrondeficient primary amines such as p-nitroaniline, acetamide and p-toluenesulphonamide could not give the corresponding products. It was worth noting that a-amino acids such as glycine, alanine and phenylalanine could also react with 1 and formalin to give the corresponding cyclization products in good yields. This is the first time to introduce a-amino acid into tetrahydropyrimidine rings, which might lead to positive effects on their biological activities. In conclusion, a convenient one-pot synthesis of fluorinecontaining tetrahydropyrimidine from the reaction of fluoroalkylated enaminoketones with primary amines and formalin was described. Considering the wide scope of primary amines and fluoroalkylated enaminoketones, this procedure provided a versatile method for the preparation of fluorinecontaining tetrahydropyrimidines.
Table 1 The reaction of 1 with primary amines and formalin Entry
Enaminoketone
Amine
Time (h)
Product
Yielda (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1c 1c 1c 1d 1c 1c
2a 2b 2c 2d 2e 2f 2a 2b 2c 2d 2d 2f 2g 2d 2h 2i
10 10 8 6 10 6 6 5 7 9 6 6 8 2 6 6
3aa 3ab 3ac 3ad 3ae 3af 3ba 3bb 3bc 3bd 3cd 3cf 3cg 3dd 3ch 3ci
80 53 53 85 92 78 73 75 86 86 85 70 43b 82b 73 89
a b
Isolated yields based on 1. The reaction was carried out in MeCN.
3. Experimental 3.1. General Melting points were uncorrected. IR spectra were taken on a Perkin-Elmer Jeol 983 spectrophotometer. 1 H NMR spectra were measured on a Bruker AM300 (300 MHz) spectrometer using TMS as internal standard. 19 F NMR spectra were taken on a Bruker AM300 (282 MHz) spectrometer using CFCl3 as external standard. 13 C NMR were recorded on a Bruker AM300 (75 MHz) spectrometer. Mass spectra were obtained on a Hewlett-Packard HP-5989A spectrometer. Column chromatography was performed using silica H, particle size 10–40 mm. Starting materials 1a, 1b and 1d were obtained in Z-configuration according to Ref. [14] as indicated by the coupling constant between two
Scheme 2. The reaction of 1a with n-propyl amine and formalin.
F.-L. Zhao, J.-T. Liu / Journal of Fluorine Chemistry 125 (2004) 1491–1496
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Scheme 4. The reaction of 1a with p-methoxyaniline.
olefinic protons (J ¼ 7.2–7.5 Hz), 1c was prepared according to Ref. [13] as a mixture of Z- and E-isomer (Jcis ¼ 7.5 Hz, Jtrans ¼ 13.2 Hz).
the solvent was removed by rotary evaporation, the residue was chromatographed on silica gel eluting with petroleum/ ethyl acetate to give 3.
3.2. General procedure for the preparation of fluorinecontaining 1,2,3,4-tetrahydropyrimidines (3)
3.2.1. 3-Propyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3aa) Light yellow oil. IR (film): u 2964, 2935, 2875, 1651, 1608, 1581, 1496, 1274, 1162, 1132, 756, 695 cm1. 1 H NMR (CDCl3): d 8.13 [s, 1H, C(6)-H], 7.42 (m, 2H, PhH), 7.25 (m, 1H, Ph-H), 7.10 (m, 2H, Ph-H), 4.59 [s, 2H, C(2)-H], 3.70 [s, 2H, C(4)-H], 2.54 (t, 3 JH;H ¼ 7.5 Hz, 2H, CH2), 1.53 (m, 2H, CH2), 0.91 (t, 3 JH;H ¼ 7.5 Hz, 3H, CH3). 13 C NMR (CDCl3): d 177.61, 146.18, 144.06, 129.97, 125.81, 121.29, 119.63, 101.20, 68.81, 54.46, 46.82, 21.13, 11.69. 19 F NMR (CDCl3): d 57.21 (s). MS (EI, 70 eV): m/z 314 (30) [Mþ], 279 (33), 243 (30),
A mixture of primary amine 2 (1 mmol), formalin (37% formaldehyde in water, 2 mmol) and DMSO (5 mL) was stirred at room temperature for 1 h, 1 (0.5 mmol) was added and the resulting mixture was stirred at 70 8C for 2–10 h (monitored by TLC or 19 F NMR). After completion of the reaction, the mixture was cooled to room temperature, diluted with water and then extracted with dichloromethane (3 15 mL). The organic layer was combined, washed with saturated NaCl solution and dried over sodium sulfate. After
Scheme 5.
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208 (56), 158 (61), 130 (100). Anal. Calcd. for C15H17ClF2N2O (314.76): C, 57.24; H, 5.44; N, 8.90. Found: C, 57.53; H, 5.43; N, 8.70. 3.2.2. 3-Ethyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ab) Light yellow oil. IR (film): u 3045, 2977, 2934, 1650, 1607, 1577, 1495, 1274, 1161, 1133, 755, 694 cm1. 1 H NMR (CDCl3): d 8.11 [s, 1H, C(6)-H], 7.42 (m, 2H, Ph-H), 7.22 (m, 1H, Ph-H), 7.10 (m, 2H, Ph-H), 4.58 [s, 2H, C(2)-H], 3.70 [s, 2H, C(4)-H], 2.64 (q, 3 JH;H ¼ 7.5 Hz, 2H, CH2), 1.13 (t, 3 JH;H ¼ 7.5 Hz, 3H, CH3). 13 C NMR (CDCl3): d 177.53, 146.16, 144.01, 129.98, 125.85, 121,26, 119.62, 101.18, 68.22, 46.63, 46.52, 13.15. 19 F NMR (CDCl3): d 57.27 (s). MS (EI, 70 eV): m/z 300 (27) [Mþ], 265 (24), 208 (47), 158 (55), 130 (99), 77 (100). Anal. Calcd. for C14H15ClF2N2O (300.73): C, 55.91; H, 5.03; N, 9.32. Found: C, 56.19; H, 5.09; N, 9.31. 3.2.3. 3-Methyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ac) Light yellow solid. m.p.: 73–74 8C. IR (KBr): u 3053, 2961, 2800, 1642, 1605, 1570, 1499, 1475, 1356, 1281, 1160, 1126, 750, 691 cm1. 1 H NMR (CDCl3): d 8.05 [s, 1H, C(6)-H], 7.35 (m, 2H, Ph-H), 7.17 (m, 1H, Ph-H), 7.02 (m, 2H, Ph-H), 4.44 [s, 2H, C(2)-H], 3.57 [s, 2H, C(4)-H], 2.44 (s, 3H, Me). 13 C NMR (CDCl3): d 177.69, 145.67, 144.05, 129.96, 125.88, 121.25, 119.63, 100.89, 70.05, 48.84, 40.89. 19 F NMR (CDCl3): d 57.30 (s). MS (EI, 70 eV): m/z 286 (31) [Mþ], 251 (27), 208 (45), 158 (59), 130 (100). Anal. Calcd. for C13H13ClF2N2O (286.70): C, 54.46; H, 4.57; N, 9.77. Found: C, 54.29; H, 4.66; N, 9.66. 3.2.4. 3-Tertbutyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ad) Light yellow solid. m.p.: 72–73 8C. IR (KBr): u 3046, 2965, 2873, 1648, 1606, 1569, 1494, 1463, 1272, 1148, 758, 695 cm1. 1 H NMR (CDCl3): d 8.07 [s, 1H, C(6)-H], 7.43 (m, 2H, Ph-H), 7.24 (m, 1H, Ph-H), 7.10 (m, 2H, Ph-H), 4.61 [s, 2H, C(2)-H], 3.73 [s, 2H, C(4)-H], 1.19 (s, 9H, CMe3). 13 C NMR (CDCl3): d 176.93, 146.76, 143.60, 129.98, 125.62, 125.30, 121.25, 119.34, 117.21, 105.23, 63.85, 54.55, 42.00, 27.43. 19 F NMR (CDCl3): d 57.03 (s). MS (EI, 70 eV): m/z 328 (23) [Mþ], 293 (24), 208 (50), 158 (64), 130 (100). Anal. Calcd. for C16H19ClF2N2O (328.78): C, 58.45; H, 5.82; N, 8.52. Found: C, 58.48; H, 5.90; N, 8.49. 3.2.5. 1,3-Diphenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ae) Light yellow solid. m.p.: 86–88 8C. IR (KBr): u 3090, 2923, 1650, 1577, 1496, 1276, 1150, 757, 694 cm1. 1 H NMR (CDCl3): d 8.11 [s, 1H, C(6)-H], 7.46 (m, 2H, PhH), 7.28 (m, 3H, Ph-H), 7.10 (m, 2H, Ph-H), 6.97 (m, 3H,
Ph-H), 5.19 [s, 2H, C(2)-H], 4.39 [s, 2H, C(4)-H]. 13 C NMR (CDCl3): d 177.30, 147.98, 146.87, 143.53, 130.11, 129.47, 126.12, 121.83, 121.22, 119.71, 118.08, 102.57, 66.47, 46.36. 19 F NMR (CDCl3): d 57.34 (s). MS (EI, 70 eV): m/z 348 (32) [Mþ], 313 (27), 263 (10), 243 (35), 235 (5), 105 (100). Anal. Calcd. for C18H15ClF2N2O (348.77): C, 61.99; H, 4.33; N, 8.03. Found: C, 61.77; H, 4.14; N, 7.90. 3.2.6. 2-(1-Phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)acetic acid (3af) Light yellow solid. m.p.: 114–115 8C. IR (KBr): u 3463 2534 (br), 1737, 1655, 1608, 1579, 1495, 1413, 1341, 1274, 1162, 1128, 959, 845, 756, 693 cm1. 1 H NMR (acetone-d6): d 8.17 [s, 1H, C(6)-H], 7.47 (m, 2H, Ph-H), 7.27 (m, 3H, Ph-H), 4.82 [s, 2H, C(2)-H], 4.39 (br, 1H, COOH), 3.76 [s, 2H, C(4)-H], 3.52 (s, 2H, CH2). 13 C NMR (acetone-d6): d 176.71, 171.07, 145.28, 144.02, 129.92, 125.87, 121.34, 119.88, 100.47, 68.19, 53.04, 47.19. 19 F NMR (acetone-d6): d 57.90 (s). MS (EI, 70 eV): m/z 330 (18) [Mþ], 295 (20), 243 (31), 208 (41), 158 (66), 130 (100). Anal. Calcd. for C14H13ClF2N2O3 (330.71): C, 50.84; H, 3.96; N, 8.47. Found: C, 50.35; H, 4.17; N, 8.19. 3.2.7. 3-Propyl-1-(4-nitrophenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3ba) Yellow solid. m.p.: 76–77 8C. IR (KBr): u 3088, 2965, 2936, 2876, 1662, 1605, 1576, 1502, 1340, 1272, 1160, 1112, 847, 751 cm1. 1 H NMR (CDCl3): d 8.25 (m, 2H, Ph-H), 8.15 [s, 1H, C(6)-H], 7.17 (m, 2H, Ph-H), 4.65 [s, 2H, C(2)-H], 3.67 [s, 2H, C(4)-H], 2.52 (t, 3 JH;H ¼ 7.2 Hz, 2H, CH2), 1.49 (m, 2H, CH2), 0.89 (t, 3 JH;H ¼ 6.9 Hz, 3H, Me). 13 C NMR (CDCl3): d 178.28, 148.65, 143.94, 143.64, 125.81, 120.79, 117.86, 104.78, 68.23, 54.48, 46.72, 21.03, 11.59. 19 F NMR (CDCl3): d 58.25 (s). MS (EI, 70 eV): m/z 359 (27) [Mþ], 324 (39), 253 (53), 42 (100). Anal. Calcd. for C15H16ClF2N3O3 (359.76): C, 50.08; H, 4.48; N, 11.68. Found: C, 50.10; H, 4.64; N, 11.53. 3.2.8. 3-Ethyl-1-(4-nitrophenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3bb) Yellow solid. m.p.: 94–97 8C. IR (KBr): u 3082, 2978, 2830, 1647, 1605, 1579, 1564, 1514, 1500, 1468, 1436, 1342, 1331, 1272, 1154, 1137, 1109, 952, 853, 751 cm1. 1 H NMR (acetone-d6): d 8.30 [m, 3H, Ph-H, C(6)-H], 7.51 (m, 2H, Ph-H), 4.86 [s, 2H, C(2)-H], 3.69 [s, 2H, C(4)-H], 2.69 (q, 3 JH;H ¼ 7.2 Hz, 2H, CH2), 1.10 (t, 3 JH;H ¼ 7.2 Hz, 3H, Me). 13 C NMR (acetone-d6): d 177.54, 148.90, 144.11, 144.01, 125.42, 121.08, 118.47, 104.08, 67.61, 67.56, 46.08, 12.58. 19 F NMR (acetone-d6): d 58.71 (s). MS (EI, 70 eV): m/z 345 (42) [Mþ], 310 (54), 253 (89), 149 (87), 42 (100). Anal. Calcd. for C14H14ClF2N3O3 (345.73): C, 48.64; H, 4.08; N, 12.15. Found: C, 48.69; H, 4.02; N, 12.21.
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3.2.9. 3-Methyl-1-(4-nitrophenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3bc) Yellow solid. m.p.: 100–102 8C. IR (KBr): u 3091, 2953, 2799, 1654, 1604, 1578, 1513, 1475, 1445, 1341, 1280, 1242, 1164, 1112, 934, 748 cm1. 1 H NMR (acetone-d6): d 8.10 [m, 3H, Ph-H, C(6)-H], 7.17 (m, 2H, Ph-H), 4.58 [s, 2H, C(2)-H], 3.64 [s, 2H, C(4)-H], 2.50 (s, 3H, Me). 13 C NMR (acetone-d6): d 177.64, 148.96, 144.03, 143.65, 125.40, 121.07, 118.53, 103.75, 69.28, 48.46, 39.92. 19 F NMR (acetone-d6): d 58.30 (s). MS (EI, 70 eV): m/z 331 (50) [Mþ], 296 (59), 253 (100). Anal. Calcd. for C13H12ClF2N3O3 (331.70): C, 47.07; H, 3.65; N, 12.67. Found: C, 47.51; H, 3.96; N, 12.62. 3.2.10. 3-Tertbutyl-1-(4-nitrophenyl)-5chlorodifluoroacetyl-1,2,3,4-tetrahydropyrimidine (3bd) Yellow solid. m.p.: 116–118 8C. IR (KBr): u 3074, 2978, 2808, 1655, 1612, 1575, 1512, 1497, 1436, 1339, 1274, 1168, 1150, 1107, 882, 849, 748, 707 cm1. 1 H NMR (acetone-d6): d 8.30 (d, 3 JH;H ¼ 9.6 Hz, 2H, Ph-H), 8.20 [s, 1H, C(6)-H], 7.51 (d, 3 JH;H ¼ 9.0 Hz, 2H, Ph-H), 4.86 [s 2H, C(2)-H], 3.72 [s, 2H, C(4)-H], 1.17 (s, 9H, CMe3). 13 C NMR (acetone-d6): d 177.04, 148.24, 144.80, 143.87, 125.54, 121.01, 118.27, 108.38, 63.46, 54.36, 41.90, 26.83. 19 F NMR (acetone-d6): d 58.55 (s). MS (EI, 70 eV): m/z 373 (13) [Mþ], 253 (25), 57 (100). Anal. Calcd. for C16H18ClF2N3O3 (373.78): C, 51.41; H, 4.85; N, 11.24. Found: C, 51.46; H, 4.86; N, 11.09. 3.2.11. 3-Tertbutyl-1-phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidine (3cd) Light yellow solid. m.p.: 78–80 8C. IR (KBr): u 2964, 2872, 1659, 1608, 1571, 1496, 1465, 1418, 1362, 1339, 1312, 1236, 1202, 1177, 1126, 879, 762 cm1. 1 H NMR (acetone-d6): d 7.98 [s, 1H, C(6)-H], 7.47 (m, 2H, Ph-H), 7.28 (m, 3H, Ph-H), 4.74 [s, 2H, C(2)-H], 3.68 [s, 2H, C(4)H], 1.16 (s, 9H, CMe3). 13 C NMR (acetone-d6): d 174.19, 146.86, 143.63, 129.91, 125.57, 119.80, 119.43, 106.90, 63.98, 54.16, 41.49, 26.80. 19 F NMR (acetone-d6): d 69.47 (s). MS (EI, 70 eV): m/z 312 (48) [Mþ], 297 (6), 255 (24), 227 (32), 158 (55), 130 (100). Anal. Calcd. for C16H19F3N2O (312.33): C, 61.53; H, 6.13; N, 8.97. Found: C, 61.50; H, 6.08; N, 8.80. 3.2.12. 2-(1-Phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)acetic acid (3cf) Light yellow solid. m.p.: 138–140 8C. IR (KBr): u 3300 2700 (br), 1742, 1716, 1646, 1608, 1575, 1497, 1345, 1299, 1255, 1195, 1183, 1120, 858, 753, 723, 693 cm1. 1 H NMR (acetone-d6): d 8.07 [s, 1H, C(6)-H], 7.47 (m, 2H, Ph-H), 7.28 (m, 3H, Ph-H), 4.83 [s, 2H, C(2)-H], 4.43 (br, 1H, COOH), 3.75 [s, 2H, C(4)-H], 3.52 (s, 2H, CH2). 13 C NMR (acetone-d6): d 174.91, 171.07, 146.41, 143.99, 129.89, 125.94, 120.01, 119.69, 102.33, 68.30, 53.00, 46.80. 19 F NMR (acetone-d6): d 69.54 (s). MS (EI, 70 eV): m/z 314 (37) [Mþ], 227 (100), 158 (46), 130 (74). Anal. Calcd. for
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C14H13F3N2O3 (314.26): C, 53.51; H, 4.17; N, 8.91. Found: C, 53.14; H, 4.17; N, 8.65. 3.2.13. 3-(2-Hydroxyethyl)-1-phenyl-5-trifluoroacetyl1,2,3,4-tetrahydropyrimidine (3cg) White solid. m.p.: 80–82 8C. IR (KBr): u 3312, 3072, 2938, 2849, 1649, 1610, 1575, 1500, 1470, 1345, 1303, 1240, 1197, 1130, 913, 883, 759, 718 cm1. 1 H NMR (CDCl3): d 8.03 [s, 1H, C(6)-H], 7.45 (m, 2H, Ph-H), 7.28 (m, 1H, Ph-H), 7.11 (m, 2H, Ph-H), 4.67 [s, 2H, C(2)-H], 3.74 [s, 2H, C(4)-H], 3.69 (t, 3 JH;H ¼ 5.1 Hz, 2H, CH2CH2OH), 2.78 (t, 3 JH;H ¼ 5.1 Hz, 2H, CH2CH2OH), 2.61 (s, 1H, OH). 13 C NMR (CDCl3): d 176.03, 146.47, 143.74, 130.06, 126.21, 119.79, 119.48, 115.62, 102.61, 69.28, 59.33, 54.41, 46.39. 19 F NMR (CDCl3): d 68.94 (s). MS (EI, 70 eV): m/z 300 (34) [Mþ], 269 (13), 227 (32), 158 (58), 130 (100), 77 (90). Anal. Calcd. for C14H15F3N2O2 (300.28): C, 56.00; H, 5.04; N, 9.33. Found: C, 55.60; H, 5.23; N, 9.10. 3.2.14. 3-Tertbutyl-1-phenyl-5-heptafluorobutanoyl1,2,3,4-tetrahydropyrimidine (3dd) Light yellow oil. IR (film): u 2976, 2879, 1643, 1608, 1583, 1497, 1465, 1355, 1338, 1280, 1231, 1208, 1155, 1117, 753, 695 cm1. 1 H NMR (CDCl3): d 8.03 [s, 1H, C(6)H], 7.45 (m, 2H, Ph-H), 7.28 (m, 1H, Ph-H), 7.11 (m, 2H, Ph-H), 4.64 [s, 2H, C(2)-H], 3.76 [s, 2H, C(4)-H], 1.20 (s, 9H, CMe3). 13 C NMR (CDCl3): d 176.06, 147.58, 143.59, 130.02, 125.87, 119.51, 115.40, 111.25, 109.50, 64.02, 54.57, 42.05, 27.32. 19 F NMR (CDCl3): d 80.45 (3F), 112.40 (2F), 126.34 (2F). MS (EI, 70 eV): m/z 412 (55) [Mþ], 355 (39), 327 (28), 158 (64), 130 (100), 77 (52). Anal. Calcd. for C18H19F7N2O (412.35): C, 52.43; H, 4.64; N, 6.79. Found: C, 52.80; H, 4.67; N, 6.74. 3.2.15. 2-(1-Phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)propionic acid (3ch) Yellow solid. m.p.: 137–140 8C. IR (KBr): u 3231, 2991, 2917, 1732, 1636, 1603, 1567, 1500, 1359, 1301, 1199, 1126, 759 cm1. 1 H NMR (acetone-d6): d 8.02 [s, 1H, C(6)H], 7.48 (m, 2H, Ph-H), 7.30 (m, 3H, Ph-H), 4.85 [s, 2H, C(2)-H], 3.73 [m, 3H, C(4)-H, CH], 1.35 (d, 3 JH;H ¼ 6.90 Hz, 3H, Me). 13 C NMR (acetone-d6): d 174.39, 173.31, 146.41, 143.79, 129.84, 125.73, 119.98, 119.76, 104.26, 65.82, 58.88, 44.23, 15.07. 19 F NMR (acetone-d6): d 69.63 (s). MS (EI, 70 eV): m/z 328 (31) [Mþ], 255 (26), 227 (42), 158 (55), 130 (100), Anal. Calcd. for C15H15F3N2O3 (328.29): C, 54.88; H, 4.61; N, 8.53. Found: C, 54.93; H, 4.78; N, 8.37. 3.2.16. 3-Phenyl-2-(1-phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)propionic acid (3ci) Yellow solid. m.p.: 51–53 8C. IR (KBr): u 3030 (br), 1732, 1716, 1651, 1609, 1579, 1496, 1301, 1189, 1129, 753, 695 cm1. 1 H NMR (acetone-d6): d 7.97 [s, 1H, C(6)-H], 7.35 (m, 10H, Ph-H), 4.88 [s, 2H, C(2)-H], 3.93 (m, 1H,
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CHCOOH), 3.84 [s, 2H, C(4)-H], 3.12 (m, 2H, CH2Ph). 13 C NMR (acetone-d6): d 174.27, 172.07, 146.35, 143.80, 137.88, 129.81, 129.22, 128.25, 126.42, 125.84, 119.83, 115.92, 104.74, 66.13, 66.06, 44.40, 36.10. 19 F NMR (acetone-d6): d 69.38 (s). MS (EI, 70 eV): m/z 404 (9) [Mþ], 228 (50), 158 (42), 130 (90), 91 (63), 77 (100). Anal. Calcd. for C21H19F3N2O3 (404.38): C, 62.37; H, 4.74; N, 6.93. Found: C, 62.30; H, 5.01; N, 6.95. 3.2.17. 1,3-Di(4-methoxyphenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3ej) Yellow solid. m.p.: 109–111 8C. IR (KBr): u 3003, 2982, 2840, 1631, 1576, 1512, 1253, 1143, 1030, 826 cm1. 1 H NMR (CDCl3): d 8.02 [s, 1H, C(6)-H], 7.026.79 (m, 8H, Ph-H), 5.02 [s, 2H, C(2)-H], 4.27 [s, 2H, C(4)-H], 3.80 (s, 3H, OMe), 3.73 (s, 3H, OMe). 13 C NMR (CDCl3): d 176.72, 158.15, 154.93, 147.70, 141.84, 136.97, 125.47, 121.96, 120.06, 115.11, 114.77, 101.34, 68.22, 55.60, 55.45, 46.69. 19 F NMR (CDCl3): d 56.83 (s). MS (EI, 70 eV): m/z 408 (7) [Mþ], 378 (10), 273 (29), 135 (100). Anal. Calcd. for C20H19ClF2N2O3 (408.83): C, 58.76; H, 4.68; N, 6.85. Found: C, 58.75; H, 4.71; N, 6.84. 3.2.18. Mixture of 3-phenyl-1-(4-methoxyphenyl)-5chlorodifluoroacetyl-1,2,3,4-tetrahydropyrimidine (3ee) and 1-phenyl-3-(4-methoxyphenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3aj) Yellow liquid. IR (film): u 3003, 2956, 2837, 1648, 1577, 1506, 1465, 1331, 1251, 1149, 1080, 1034, 862, 829, 757, 695 cm1. 1 H NMR (CDCl3): d 8.13 [s, 1H, C(6)-H], 8.00 [s, 1H, C(6)-H], 7.44 (m, 2H, Ph-H), 7.27 (m, 3H, Ph-H), 7.096.80 (m, 13H, Ph-H), 5.13 [s, 2H, C(2)-H], 5.10 [s, 2H, C(2)-H], 4.37 [s, 2H, C(4)-H], 4.30 [s, 2H, C(4)-H], 3.84 (s, 3H, OMe), 3.75 (s, 3H, OMe). 19 F NMR (CDCl3): d 57.27 (s). MS (EI, 70 eV): m/z 378 (15) [Mþ], 273 (21),
135 (100). Anal. Calcd. for C19H17ClF2N2O2 (378.80): C, 60.24; H, 4.52; N, 7.40. Found: C, 59.81; H, 4.41; N, 7.39.
Acknowledgements We thank the National Natural Science Foundation of China for financial support (No. 20172065).
References [1] R. Filler, Y. Kobayashi, L.M. Yagupolskii, Organofluorine Compounds in Medicinal Chemistry and Biomedical Applications, Elsevier, Amsterdam, 1993. [2] H. Yoshioka, C. Tukayama, N. Mastuo, J. Synth. Org. Chem. Jpn. 42 (1984) 809–812. [3] A. Takamizawa, K. Hirai, JP Patent 1 184 (1967). [4] M.H. Jung, J.G. Park, K.J. Yang, M.J. Lee, Arch. Pharm. 334 (2001) 79–85. [5] K. Goerlitzer, C. Heinrici, Pharmazie 53 (1998) 843–847. [6] C.N. O’Callaghan, T. Brian, H. McMurry, J. Chem. Soc., Perkin Trans I (1993) 755–757. [7] T. Wakita, S. Matsuo, K. Odaka, K. Oonuma, N. Yasui, Jpn. Kokai Tokkyo Koho JP Patent 08 259 563 (1996). [8] J. Kanellakopulos, D. Wollweber, C. Erdelen, WO Patent 9 732 878 (1997). [9] H. Uneme, I. Minamida, N. Higuchi, T. Okauchi, EP Patent 366 085 (1990). [10] T. Kishimoto, K. Ishimitsu, T. Yamada, N. Takakusa, R. Hatano, EP Patent 407 594 (1991). [11] H. Moehrle, H.W. Reinhardt, Arch. Pharm. 314 (1981) 767–778. [12] [a] R.J. Lindermann, K.S. Kirollos, Tetrahedron Lett. 31 (1990) 2689–2692; [b] H. Keller, M. Schlosser, Tetrahedron Lett. 52 (1996) 4637–4644. [13] M. Hojo, R. Masuda, E. Okada, S. Sakaguchi, H. Narumiya, K. Morimoto, Tetrahedron Lett. 30 (1989) 6173–6176. [14] X.J. Yang, J.T. Liu, F.L. Zhao, J. Fluorine Chem. 125 (2004) 415– 419.
An efficient synthesis of fluorine-containing polyfunctional 1,2,3,4-tetrahydropyrimidines Fu-Lu Zhao, Jin-Tao Liu* Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China Received 30 March 2004; received in revised form 17 May 2004; accepted 18 May 2004 Available online 8 July 2004
Abstract A convenient one-pot synthesis of fluorine-containing 1,2,3,4-tetrahydropyrimidines was described. Fluoroalkylated enaminoketones reacted readily with primary amines and formalin (37% formaldehyde solution) under mild conditions to give the title compounds in high yields. a-Amino acids were introduced into tetrahydropyrimidine rings for the first time by this reaction. # 2004 Elsevier B.V. All rights reserved. Keywords: Fluoroalkylated enaminoketone; Primary amine; Formalin; Fluorine-containing 1,2,3,4-tetrahydropyrimidines
1. Introduction
2. Results and discussion
It is well known that the introduction of fluorine atoms or fluoroalkyl groups into heterocyclic compounds may have significant influence on their biological and physical properties [1,2]. Therefore the development of synthetic methods for fluorine-containing heterocyclic compounds has been an important field in both organofluorine chemistry and organic synthesis. 1,2,3,4-Tetrahydropyrimidine is an important heterocyclic ring and many compounds containing it show interesting biological activities. For example, compound I was reported as antihistaminic and antibacterial [3], and compound II has been prepared as bioisosteric congeners of arecoline which is a muscarinic agonist for treatment of Alzheimer’s disease [4]. Due to their potent biological properties, much attention has been paid to the synthesis of tetrahydropyrimidines [5–10]. In 1981, Moehrle and Reinhardt reported the synthesis of acetylated 1,2,3,4-tetrahydropyrimidines from the reaction of enaminoketones with primary amines and formalin [11]. But to the best of our knowledge, there are no reports involving the synthesis of fluorine-containing 1,2,3,4-tetrahydropyrimidines. So it is our interest to develop a facile method for this kind of fluorine-containing heterocyclic compounds (Scheme 1).
Fluoroalkylated enaminoketones (1) are useful precursors and have been used to synthesize fluoroalkylated quinolines [12]. In our continuous study on their applications in the synthesis of fluorine-containing heterocyclic compounds, it was found that 1-chloro-1,1-difluoro-4phenylamino-but-3-en-2-one (1a) reacted readily with npropyl amine (2a) and formalin (37% formaldehyde solution) in DMSO under mild conditions and the corresponding 5-chlorodifluoroacetyl-1-phenyl-3-propyl-1,2,3,4tetrahydropyrimidines (3aa) was obtained along with an unexpected product, 5-chlorodifluoroacetyl-1,3-diphenyl1,2,3,4-tetrahydropyrimidines (3ae) (Scheme 2). Conditional experiments indicated that the distribution of two products was significantly influenced by the ratio of reactants, and 3aa was obtained predominantly (>89%) when the ratio of 1a:2a:formalin was 1:2:4. DMF, HMPA, MeCN and 1,4-dioxane could also be used as solvent, but the best results were obtained in DMSO. How was 3ae formed? Was it formed directly from 1a and formalin? To obtain mechanistic information on the reaction, 1a was allowed to react with formalin in the absence of amines under similar conditions for 10 h, but no reaction occurred. When a small amount of DABCO was added, the reaction took place and 3ae was formed with a low conversion of 1a. However, 1a was completely converted to 3ae when equivalent or excess DABCO was used. The same
*
Corresponding author. Tel.: þ86-21-64163300; fax: þ86-21-64166128. E-mail address: [email protected] (J.-T. Liu). 0022-1139/$ – see front matter # 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.jfluchem.2004.05.016
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Scheme 3. Scheme 1.
result was obtained when NH4OH was used as a base instead of DABCO (Scheme 3). Based on the above results, it was surmised that on the attack of amine, an aniline was released from 1a and then reacted with 1a and formalin to give 3ae. This was further proved by the following experiment. The reaction of 1a with excess p-methoxyaniline (2j) and formalin afforded three products, 3ej, 3ee and 3aj. The latter two could not be separated by column chromatography and were obtained as a mixture. Obviously the formation of 3ej and 3ee involved a new enaminoketone, 1-chloro-1,1-difluoro-4-(40 -methoxyphenylamino)-but-3-en-2-one (1e), which was formed from the exchange reaction of 1a and p-methoxyaniline [13]. The reaction of 1e with p-methoxyaniline and formalin gave 3ej, while 3ee were formed by the reaction of 1e with aniline and formalin (Scheme 4). Using the optimized conditions, the reaction of fluorinecontaining enaminoketones with various primary amines and formalin was studied (Scheme 5). As shown in Table 1, both aliphatic and aromatic primary amines gave the desired product in good yields. The bulkiness of primary amines and the length of fluorine-containing group in enaminoketones have little influence on the reaction. But electrondeficient primary amines such as p-nitroaniline, acetamide and p-toluenesulphonamide could not give the corresponding products. It was worth noting that a-amino acids such as glycine, alanine and phenylalanine could also react with 1 and formalin to give the corresponding cyclization products in good yields. This is the first time to introduce a-amino acid into tetrahydropyrimidine rings, which might lead to positive effects on their biological activities. In conclusion, a convenient one-pot synthesis of fluorinecontaining tetrahydropyrimidine from the reaction of fluoroalkylated enaminoketones with primary amines and formalin was described. Considering the wide scope of primary amines and fluoroalkylated enaminoketones, this procedure provided a versatile method for the preparation of fluorinecontaining tetrahydropyrimidines.
Table 1 The reaction of 1 with primary amines and formalin Entry
Enaminoketone
Amine
Time (h)
Product
Yielda (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
1a 1a 1a 1a 1a 1a 1b 1b 1b 1b 1c 1c 1c 1d 1c 1c
2a 2b 2c 2d 2e 2f 2a 2b 2c 2d 2d 2f 2g 2d 2h 2i
10 10 8 6 10 6 6 5 7 9 6 6 8 2 6 6
3aa 3ab 3ac 3ad 3ae 3af 3ba 3bb 3bc 3bd 3cd 3cf 3cg 3dd 3ch 3ci
80 53 53 85 92 78 73 75 86 86 85 70 43b 82b 73 89
a b
Isolated yields based on 1. The reaction was carried out in MeCN.
3. Experimental 3.1. General Melting points were uncorrected. IR spectra were taken on a Perkin-Elmer Jeol 983 spectrophotometer. 1 H NMR spectra were measured on a Bruker AM300 (300 MHz) spectrometer using TMS as internal standard. 19 F NMR spectra were taken on a Bruker AM300 (282 MHz) spectrometer using CFCl3 as external standard. 13 C NMR were recorded on a Bruker AM300 (75 MHz) spectrometer. Mass spectra were obtained on a Hewlett-Packard HP-5989A spectrometer. Column chromatography was performed using silica H, particle size 10–40 mm. Starting materials 1a, 1b and 1d were obtained in Z-configuration according to Ref. [14] as indicated by the coupling constant between two
Scheme 2. The reaction of 1a with n-propyl amine and formalin.
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Scheme 4. The reaction of 1a with p-methoxyaniline.
olefinic protons (J ¼ 7.2–7.5 Hz), 1c was prepared according to Ref. [13] as a mixture of Z- and E-isomer (Jcis ¼ 7.5 Hz, Jtrans ¼ 13.2 Hz).
the solvent was removed by rotary evaporation, the residue was chromatographed on silica gel eluting with petroleum/ ethyl acetate to give 3.
3.2. General procedure for the preparation of fluorinecontaining 1,2,3,4-tetrahydropyrimidines (3)
3.2.1. 3-Propyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3aa) Light yellow oil. IR (film): u 2964, 2935, 2875, 1651, 1608, 1581, 1496, 1274, 1162, 1132, 756, 695 cm1. 1 H NMR (CDCl3): d 8.13 [s, 1H, C(6)-H], 7.42 (m, 2H, PhH), 7.25 (m, 1H, Ph-H), 7.10 (m, 2H, Ph-H), 4.59 [s, 2H, C(2)-H], 3.70 [s, 2H, C(4)-H], 2.54 (t, 3 JH;H ¼ 7.5 Hz, 2H, CH2), 1.53 (m, 2H, CH2), 0.91 (t, 3 JH;H ¼ 7.5 Hz, 3H, CH3). 13 C NMR (CDCl3): d 177.61, 146.18, 144.06, 129.97, 125.81, 121.29, 119.63, 101.20, 68.81, 54.46, 46.82, 21.13, 11.69. 19 F NMR (CDCl3): d 57.21 (s). MS (EI, 70 eV): m/z 314 (30) [Mþ], 279 (33), 243 (30),
A mixture of primary amine 2 (1 mmol), formalin (37% formaldehyde in water, 2 mmol) and DMSO (5 mL) was stirred at room temperature for 1 h, 1 (0.5 mmol) was added and the resulting mixture was stirred at 70 8C for 2–10 h (monitored by TLC or 19 F NMR). After completion of the reaction, the mixture was cooled to room temperature, diluted with water and then extracted with dichloromethane (3 15 mL). The organic layer was combined, washed with saturated NaCl solution and dried over sodium sulfate. After
Scheme 5.
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208 (56), 158 (61), 130 (100). Anal. Calcd. for C15H17ClF2N2O (314.76): C, 57.24; H, 5.44; N, 8.90. Found: C, 57.53; H, 5.43; N, 8.70. 3.2.2. 3-Ethyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ab) Light yellow oil. IR (film): u 3045, 2977, 2934, 1650, 1607, 1577, 1495, 1274, 1161, 1133, 755, 694 cm1. 1 H NMR (CDCl3): d 8.11 [s, 1H, C(6)-H], 7.42 (m, 2H, Ph-H), 7.22 (m, 1H, Ph-H), 7.10 (m, 2H, Ph-H), 4.58 [s, 2H, C(2)-H], 3.70 [s, 2H, C(4)-H], 2.64 (q, 3 JH;H ¼ 7.5 Hz, 2H, CH2), 1.13 (t, 3 JH;H ¼ 7.5 Hz, 3H, CH3). 13 C NMR (CDCl3): d 177.53, 146.16, 144.01, 129.98, 125.85, 121,26, 119.62, 101.18, 68.22, 46.63, 46.52, 13.15. 19 F NMR (CDCl3): d 57.27 (s). MS (EI, 70 eV): m/z 300 (27) [Mþ], 265 (24), 208 (47), 158 (55), 130 (99), 77 (100). Anal. Calcd. for C14H15ClF2N2O (300.73): C, 55.91; H, 5.03; N, 9.32. Found: C, 56.19; H, 5.09; N, 9.31. 3.2.3. 3-Methyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ac) Light yellow solid. m.p.: 73–74 8C. IR (KBr): u 3053, 2961, 2800, 1642, 1605, 1570, 1499, 1475, 1356, 1281, 1160, 1126, 750, 691 cm1. 1 H NMR (CDCl3): d 8.05 [s, 1H, C(6)-H], 7.35 (m, 2H, Ph-H), 7.17 (m, 1H, Ph-H), 7.02 (m, 2H, Ph-H), 4.44 [s, 2H, C(2)-H], 3.57 [s, 2H, C(4)-H], 2.44 (s, 3H, Me). 13 C NMR (CDCl3): d 177.69, 145.67, 144.05, 129.96, 125.88, 121.25, 119.63, 100.89, 70.05, 48.84, 40.89. 19 F NMR (CDCl3): d 57.30 (s). MS (EI, 70 eV): m/z 286 (31) [Mþ], 251 (27), 208 (45), 158 (59), 130 (100). Anal. Calcd. for C13H13ClF2N2O (286.70): C, 54.46; H, 4.57; N, 9.77. Found: C, 54.29; H, 4.66; N, 9.66. 3.2.4. 3-Tertbutyl-1-phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ad) Light yellow solid. m.p.: 72–73 8C. IR (KBr): u 3046, 2965, 2873, 1648, 1606, 1569, 1494, 1463, 1272, 1148, 758, 695 cm1. 1 H NMR (CDCl3): d 8.07 [s, 1H, C(6)-H], 7.43 (m, 2H, Ph-H), 7.24 (m, 1H, Ph-H), 7.10 (m, 2H, Ph-H), 4.61 [s, 2H, C(2)-H], 3.73 [s, 2H, C(4)-H], 1.19 (s, 9H, CMe3). 13 C NMR (CDCl3): d 176.93, 146.76, 143.60, 129.98, 125.62, 125.30, 121.25, 119.34, 117.21, 105.23, 63.85, 54.55, 42.00, 27.43. 19 F NMR (CDCl3): d 57.03 (s). MS (EI, 70 eV): m/z 328 (23) [Mþ], 293 (24), 208 (50), 158 (64), 130 (100). Anal. Calcd. for C16H19ClF2N2O (328.78): C, 58.45; H, 5.82; N, 8.52. Found: C, 58.48; H, 5.90; N, 8.49. 3.2.5. 1,3-Diphenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidine (3ae) Light yellow solid. m.p.: 86–88 8C. IR (KBr): u 3090, 2923, 1650, 1577, 1496, 1276, 1150, 757, 694 cm1. 1 H NMR (CDCl3): d 8.11 [s, 1H, C(6)-H], 7.46 (m, 2H, PhH), 7.28 (m, 3H, Ph-H), 7.10 (m, 2H, Ph-H), 6.97 (m, 3H,
Ph-H), 5.19 [s, 2H, C(2)-H], 4.39 [s, 2H, C(4)-H]. 13 C NMR (CDCl3): d 177.30, 147.98, 146.87, 143.53, 130.11, 129.47, 126.12, 121.83, 121.22, 119.71, 118.08, 102.57, 66.47, 46.36. 19 F NMR (CDCl3): d 57.34 (s). MS (EI, 70 eV): m/z 348 (32) [Mþ], 313 (27), 263 (10), 243 (35), 235 (5), 105 (100). Anal. Calcd. for C18H15ClF2N2O (348.77): C, 61.99; H, 4.33; N, 8.03. Found: C, 61.77; H, 4.14; N, 7.90. 3.2.6. 2-(1-Phenyl-5-chlorodifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)acetic acid (3af) Light yellow solid. m.p.: 114–115 8C. IR (KBr): u 3463 2534 (br), 1737, 1655, 1608, 1579, 1495, 1413, 1341, 1274, 1162, 1128, 959, 845, 756, 693 cm1. 1 H NMR (acetone-d6): d 8.17 [s, 1H, C(6)-H], 7.47 (m, 2H, Ph-H), 7.27 (m, 3H, Ph-H), 4.82 [s, 2H, C(2)-H], 4.39 (br, 1H, COOH), 3.76 [s, 2H, C(4)-H], 3.52 (s, 2H, CH2). 13 C NMR (acetone-d6): d 176.71, 171.07, 145.28, 144.02, 129.92, 125.87, 121.34, 119.88, 100.47, 68.19, 53.04, 47.19. 19 F NMR (acetone-d6): d 57.90 (s). MS (EI, 70 eV): m/z 330 (18) [Mþ], 295 (20), 243 (31), 208 (41), 158 (66), 130 (100). Anal. Calcd. for C14H13ClF2N2O3 (330.71): C, 50.84; H, 3.96; N, 8.47. Found: C, 50.35; H, 4.17; N, 8.19. 3.2.7. 3-Propyl-1-(4-nitrophenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3ba) Yellow solid. m.p.: 76–77 8C. IR (KBr): u 3088, 2965, 2936, 2876, 1662, 1605, 1576, 1502, 1340, 1272, 1160, 1112, 847, 751 cm1. 1 H NMR (CDCl3): d 8.25 (m, 2H, Ph-H), 8.15 [s, 1H, C(6)-H], 7.17 (m, 2H, Ph-H), 4.65 [s, 2H, C(2)-H], 3.67 [s, 2H, C(4)-H], 2.52 (t, 3 JH;H ¼ 7.2 Hz, 2H, CH2), 1.49 (m, 2H, CH2), 0.89 (t, 3 JH;H ¼ 6.9 Hz, 3H, Me). 13 C NMR (CDCl3): d 178.28, 148.65, 143.94, 143.64, 125.81, 120.79, 117.86, 104.78, 68.23, 54.48, 46.72, 21.03, 11.59. 19 F NMR (CDCl3): d 58.25 (s). MS (EI, 70 eV): m/z 359 (27) [Mþ], 324 (39), 253 (53), 42 (100). Anal. Calcd. for C15H16ClF2N3O3 (359.76): C, 50.08; H, 4.48; N, 11.68. Found: C, 50.10; H, 4.64; N, 11.53. 3.2.8. 3-Ethyl-1-(4-nitrophenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3bb) Yellow solid. m.p.: 94–97 8C. IR (KBr): u 3082, 2978, 2830, 1647, 1605, 1579, 1564, 1514, 1500, 1468, 1436, 1342, 1331, 1272, 1154, 1137, 1109, 952, 853, 751 cm1. 1 H NMR (acetone-d6): d 8.30 [m, 3H, Ph-H, C(6)-H], 7.51 (m, 2H, Ph-H), 4.86 [s, 2H, C(2)-H], 3.69 [s, 2H, C(4)-H], 2.69 (q, 3 JH;H ¼ 7.2 Hz, 2H, CH2), 1.10 (t, 3 JH;H ¼ 7.2 Hz, 3H, Me). 13 C NMR (acetone-d6): d 177.54, 148.90, 144.11, 144.01, 125.42, 121.08, 118.47, 104.08, 67.61, 67.56, 46.08, 12.58. 19 F NMR (acetone-d6): d 58.71 (s). MS (EI, 70 eV): m/z 345 (42) [Mþ], 310 (54), 253 (89), 149 (87), 42 (100). Anal. Calcd. for C14H14ClF2N3O3 (345.73): C, 48.64; H, 4.08; N, 12.15. Found: C, 48.69; H, 4.02; N, 12.21.
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3.2.9. 3-Methyl-1-(4-nitrophenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3bc) Yellow solid. m.p.: 100–102 8C. IR (KBr): u 3091, 2953, 2799, 1654, 1604, 1578, 1513, 1475, 1445, 1341, 1280, 1242, 1164, 1112, 934, 748 cm1. 1 H NMR (acetone-d6): d 8.10 [m, 3H, Ph-H, C(6)-H], 7.17 (m, 2H, Ph-H), 4.58 [s, 2H, C(2)-H], 3.64 [s, 2H, C(4)-H], 2.50 (s, 3H, Me). 13 C NMR (acetone-d6): d 177.64, 148.96, 144.03, 143.65, 125.40, 121.07, 118.53, 103.75, 69.28, 48.46, 39.92. 19 F NMR (acetone-d6): d 58.30 (s). MS (EI, 70 eV): m/z 331 (50) [Mþ], 296 (59), 253 (100). Anal. Calcd. for C13H12ClF2N3O3 (331.70): C, 47.07; H, 3.65; N, 12.67. Found: C, 47.51; H, 3.96; N, 12.62. 3.2.10. 3-Tertbutyl-1-(4-nitrophenyl)-5chlorodifluoroacetyl-1,2,3,4-tetrahydropyrimidine (3bd) Yellow solid. m.p.: 116–118 8C. IR (KBr): u 3074, 2978, 2808, 1655, 1612, 1575, 1512, 1497, 1436, 1339, 1274, 1168, 1150, 1107, 882, 849, 748, 707 cm1. 1 H NMR (acetone-d6): d 8.30 (d, 3 JH;H ¼ 9.6 Hz, 2H, Ph-H), 8.20 [s, 1H, C(6)-H], 7.51 (d, 3 JH;H ¼ 9.0 Hz, 2H, Ph-H), 4.86 [s 2H, C(2)-H], 3.72 [s, 2H, C(4)-H], 1.17 (s, 9H, CMe3). 13 C NMR (acetone-d6): d 177.04, 148.24, 144.80, 143.87, 125.54, 121.01, 118.27, 108.38, 63.46, 54.36, 41.90, 26.83. 19 F NMR (acetone-d6): d 58.55 (s). MS (EI, 70 eV): m/z 373 (13) [Mþ], 253 (25), 57 (100). Anal. Calcd. for C16H18ClF2N3O3 (373.78): C, 51.41; H, 4.85; N, 11.24. Found: C, 51.46; H, 4.86; N, 11.09. 3.2.11. 3-Tertbutyl-1-phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidine (3cd) Light yellow solid. m.p.: 78–80 8C. IR (KBr): u 2964, 2872, 1659, 1608, 1571, 1496, 1465, 1418, 1362, 1339, 1312, 1236, 1202, 1177, 1126, 879, 762 cm1. 1 H NMR (acetone-d6): d 7.98 [s, 1H, C(6)-H], 7.47 (m, 2H, Ph-H), 7.28 (m, 3H, Ph-H), 4.74 [s, 2H, C(2)-H], 3.68 [s, 2H, C(4)H], 1.16 (s, 9H, CMe3). 13 C NMR (acetone-d6): d 174.19, 146.86, 143.63, 129.91, 125.57, 119.80, 119.43, 106.90, 63.98, 54.16, 41.49, 26.80. 19 F NMR (acetone-d6): d 69.47 (s). MS (EI, 70 eV): m/z 312 (48) [Mþ], 297 (6), 255 (24), 227 (32), 158 (55), 130 (100). Anal. Calcd. for C16H19F3N2O (312.33): C, 61.53; H, 6.13; N, 8.97. Found: C, 61.50; H, 6.08; N, 8.80. 3.2.12. 2-(1-Phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)acetic acid (3cf) Light yellow solid. m.p.: 138–140 8C. IR (KBr): u 3300 2700 (br), 1742, 1716, 1646, 1608, 1575, 1497, 1345, 1299, 1255, 1195, 1183, 1120, 858, 753, 723, 693 cm1. 1 H NMR (acetone-d6): d 8.07 [s, 1H, C(6)-H], 7.47 (m, 2H, Ph-H), 7.28 (m, 3H, Ph-H), 4.83 [s, 2H, C(2)-H], 4.43 (br, 1H, COOH), 3.75 [s, 2H, C(4)-H], 3.52 (s, 2H, CH2). 13 C NMR (acetone-d6): d 174.91, 171.07, 146.41, 143.99, 129.89, 125.94, 120.01, 119.69, 102.33, 68.30, 53.00, 46.80. 19 F NMR (acetone-d6): d 69.54 (s). MS (EI, 70 eV): m/z 314 (37) [Mþ], 227 (100), 158 (46), 130 (74). Anal. Calcd. for
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C14H13F3N2O3 (314.26): C, 53.51; H, 4.17; N, 8.91. Found: C, 53.14; H, 4.17; N, 8.65. 3.2.13. 3-(2-Hydroxyethyl)-1-phenyl-5-trifluoroacetyl1,2,3,4-tetrahydropyrimidine (3cg) White solid. m.p.: 80–82 8C. IR (KBr): u 3312, 3072, 2938, 2849, 1649, 1610, 1575, 1500, 1470, 1345, 1303, 1240, 1197, 1130, 913, 883, 759, 718 cm1. 1 H NMR (CDCl3): d 8.03 [s, 1H, C(6)-H], 7.45 (m, 2H, Ph-H), 7.28 (m, 1H, Ph-H), 7.11 (m, 2H, Ph-H), 4.67 [s, 2H, C(2)-H], 3.74 [s, 2H, C(4)-H], 3.69 (t, 3 JH;H ¼ 5.1 Hz, 2H, CH2CH2OH), 2.78 (t, 3 JH;H ¼ 5.1 Hz, 2H, CH2CH2OH), 2.61 (s, 1H, OH). 13 C NMR (CDCl3): d 176.03, 146.47, 143.74, 130.06, 126.21, 119.79, 119.48, 115.62, 102.61, 69.28, 59.33, 54.41, 46.39. 19 F NMR (CDCl3): d 68.94 (s). MS (EI, 70 eV): m/z 300 (34) [Mþ], 269 (13), 227 (32), 158 (58), 130 (100), 77 (90). Anal. Calcd. for C14H15F3N2O2 (300.28): C, 56.00; H, 5.04; N, 9.33. Found: C, 55.60; H, 5.23; N, 9.10. 3.2.14. 3-Tertbutyl-1-phenyl-5-heptafluorobutanoyl1,2,3,4-tetrahydropyrimidine (3dd) Light yellow oil. IR (film): u 2976, 2879, 1643, 1608, 1583, 1497, 1465, 1355, 1338, 1280, 1231, 1208, 1155, 1117, 753, 695 cm1. 1 H NMR (CDCl3): d 8.03 [s, 1H, C(6)H], 7.45 (m, 2H, Ph-H), 7.28 (m, 1H, Ph-H), 7.11 (m, 2H, Ph-H), 4.64 [s, 2H, C(2)-H], 3.76 [s, 2H, C(4)-H], 1.20 (s, 9H, CMe3). 13 C NMR (CDCl3): d 176.06, 147.58, 143.59, 130.02, 125.87, 119.51, 115.40, 111.25, 109.50, 64.02, 54.57, 42.05, 27.32. 19 F NMR (CDCl3): d 80.45 (3F), 112.40 (2F), 126.34 (2F). MS (EI, 70 eV): m/z 412 (55) [Mþ], 355 (39), 327 (28), 158 (64), 130 (100), 77 (52). Anal. Calcd. for C18H19F7N2O (412.35): C, 52.43; H, 4.64; N, 6.79. Found: C, 52.80; H, 4.67; N, 6.74. 3.2.15. 2-(1-Phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)propionic acid (3ch) Yellow solid. m.p.: 137–140 8C. IR (KBr): u 3231, 2991, 2917, 1732, 1636, 1603, 1567, 1500, 1359, 1301, 1199, 1126, 759 cm1. 1 H NMR (acetone-d6): d 8.02 [s, 1H, C(6)H], 7.48 (m, 2H, Ph-H), 7.30 (m, 3H, Ph-H), 4.85 [s, 2H, C(2)-H], 3.73 [m, 3H, C(4)-H, CH], 1.35 (d, 3 JH;H ¼ 6.90 Hz, 3H, Me). 13 C NMR (acetone-d6): d 174.39, 173.31, 146.41, 143.79, 129.84, 125.73, 119.98, 119.76, 104.26, 65.82, 58.88, 44.23, 15.07. 19 F NMR (acetone-d6): d 69.63 (s). MS (EI, 70 eV): m/z 328 (31) [Mþ], 255 (26), 227 (42), 158 (55), 130 (100), Anal. Calcd. for C15H15F3N2O3 (328.29): C, 54.88; H, 4.61; N, 8.53. Found: C, 54.93; H, 4.78; N, 8.37. 3.2.16. 3-Phenyl-2-(1-phenyl-5-trifluoroacetyl-1,2,3,4tetrahydropyrimidin-3-yl)propionic acid (3ci) Yellow solid. m.p.: 51–53 8C. IR (KBr): u 3030 (br), 1732, 1716, 1651, 1609, 1579, 1496, 1301, 1189, 1129, 753, 695 cm1. 1 H NMR (acetone-d6): d 7.97 [s, 1H, C(6)-H], 7.35 (m, 10H, Ph-H), 4.88 [s, 2H, C(2)-H], 3.93 (m, 1H,
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CHCOOH), 3.84 [s, 2H, C(4)-H], 3.12 (m, 2H, CH2Ph). 13 C NMR (acetone-d6): d 174.27, 172.07, 146.35, 143.80, 137.88, 129.81, 129.22, 128.25, 126.42, 125.84, 119.83, 115.92, 104.74, 66.13, 66.06, 44.40, 36.10. 19 F NMR (acetone-d6): d 69.38 (s). MS (EI, 70 eV): m/z 404 (9) [Mþ], 228 (50), 158 (42), 130 (90), 91 (63), 77 (100). Anal. Calcd. for C21H19F3N2O3 (404.38): C, 62.37; H, 4.74; N, 6.93. Found: C, 62.30; H, 5.01; N, 6.95. 3.2.17. 1,3-Di(4-methoxyphenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3ej) Yellow solid. m.p.: 109–111 8C. IR (KBr): u 3003, 2982, 2840, 1631, 1576, 1512, 1253, 1143, 1030, 826 cm1. 1 H NMR (CDCl3): d 8.02 [s, 1H, C(6)-H], 7.026.79 (m, 8H, Ph-H), 5.02 [s, 2H, C(2)-H], 4.27 [s, 2H, C(4)-H], 3.80 (s, 3H, OMe), 3.73 (s, 3H, OMe). 13 C NMR (CDCl3): d 176.72, 158.15, 154.93, 147.70, 141.84, 136.97, 125.47, 121.96, 120.06, 115.11, 114.77, 101.34, 68.22, 55.60, 55.45, 46.69. 19 F NMR (CDCl3): d 56.83 (s). MS (EI, 70 eV): m/z 408 (7) [Mþ], 378 (10), 273 (29), 135 (100). Anal. Calcd. for C20H19ClF2N2O3 (408.83): C, 58.76; H, 4.68; N, 6.85. Found: C, 58.75; H, 4.71; N, 6.84. 3.2.18. Mixture of 3-phenyl-1-(4-methoxyphenyl)-5chlorodifluoroacetyl-1,2,3,4-tetrahydropyrimidine (3ee) and 1-phenyl-3-(4-methoxyphenyl)-5-chlorodifluoroacetyl1,2,3,4-tetrahydropyrimidine (3aj) Yellow liquid. IR (film): u 3003, 2956, 2837, 1648, 1577, 1506, 1465, 1331, 1251, 1149, 1080, 1034, 862, 829, 757, 695 cm1. 1 H NMR (CDCl3): d 8.13 [s, 1H, C(6)-H], 8.00 [s, 1H, C(6)-H], 7.44 (m, 2H, Ph-H), 7.27 (m, 3H, Ph-H), 7.096.80 (m, 13H, Ph-H), 5.13 [s, 2H, C(2)-H], 5.10 [s, 2H, C(2)-H], 4.37 [s, 2H, C(4)-H], 4.30 [s, 2H, C(4)-H], 3.84 (s, 3H, OMe), 3.75 (s, 3H, OMe). 19 F NMR (CDCl3): d 57.27 (s). MS (EI, 70 eV): m/z 378 (15) [Mþ], 273 (21),
135 (100). Anal. Calcd. for C19H17ClF2N2O2 (378.80): C, 60.24; H, 4.52; N, 7.40. Found: C, 59.81; H, 4.41; N, 7.39.
Acknowledgements We thank the National Natural Science Foundation of China for financial support (No. 20172065).
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