1 Synthesis of 5-cinnamoyl-3,4-dihydropyrimidine-2(1H)-ones Supplementary Information Maksim A. Kolosov*, lesia G. Kulyk, Elena G. Shvets, Valeriy D. rlov Department of organic chemistry, V.N.Karazin Kharkiv National University, Svobody sq., 4, Kharkiv 61022, Ukraine Phone: +38 (057) 707 56 13 Fax: +38 (057) 705-12-36 E-mails: Maksim A. Kolosov, kolosov@univer.kharkov.ua (corresponding author) EXPERIMENTAL Aldehydes, urea, 1,3-pentanedione, alkylhalides, solvents and inorganic reagents were commercially available. NaH was used as 60% suspension in mineral oil. Cinnamoylacetone was synthesized according to ref. [10] DMF and 1,4-dioxane were distilled and stored under molecular sieves (4 Å). Reactions with air- and/or moisturesensitive compounds were performed under argon. Melting points were determined using a Kofler hot-stage apparatus. Column chromatography was performed using Al 2 3 (60 100 μm) and silica with CH 2 Cl 2, EtAc and EtAc/CH 2 Cl 2 mixtures as eluents. The purity of the compounds, monitoring of the reaction course and fraction selection in preparative column chromatography were performed by TLC on MERCK ALUGRAM Xtra SIL G/UV 254 and KAVALIER Silufol UV-254 plates, using EtAc CH 2 Cl 2 mixtures as eluents). 1 H NMR spectra were recorded at 200 MHz using a Varian Mercury VX-200 spectrometer with Si(CH 3 ) 4 as internal standard, chemical shifts are performed in ppm, coupling constants are given in Hz. 13 C NMR-spectra were
2 recorded in DMS-d 6 at 100 MHz using Bruker Avance 400 spectrometer with Si(CH 3 ) 4 as internal standard. Mass spectra (EI, 70 ev) were obtained using a Varian 1200L instrument using a direct probe exposure (DEP) method. IR spectra were recorded on KBr pellets using a Specord IR-75 spectrometer. Elemental analyses (C, H, N) were obtained using EuroEA-3000 instrument. FULL EXPERIMENTAL DETAILS 5-Acetyl-6-methyl-1-methoxymethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)- one (2) The solution of 1 (8 g, 0.035 mol) in 1,4-dioxane (60 ml) was added to the flask with NaH (60% suspension in mineral oil, 1.53 g, 0.038 mol) with the use of syringe. The reaction mixture was stirred for 1 h at 60 C. After cooling to the room temperature, МОМ-Сl (3.08 g, 0.038 mol) was added dropwise. Then the mixture was stirred for 1 h at room temperature and 30 min at 60 C. After filtration through the thin (3-5 mm) layer of Al 2 3, the obtained solution was evaporated to dryness. The residual solid was purified by flash column chromatography (Al 2 3, 250 ml of EtAc) and then crystallized from the mixture of benzene/hexane (1:1) to give compound 2. White solid; yield: 3.17 g (33%); mp 114 116 C. IR (KBr): 1682, 1659, 1598, 1457, 3216 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 8.17 (d, J = 3.4 Hz, 1Н, NH), 7.2 7.4 (m, 5Н, Ph), 5.23 (d, J = 3.4 Hz, 1Н, H-4), 5.12 (d, J = 11.0 Hz, 1Н, CH 2 ), 5.02 (d, J = 11.0 Hz, 1Н, CH 2 ), 3.13 (s, 3Н, CH 3 ), 2.43 (s, 3Н, CH 3 ), 2.11 (s, 3Н, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 16.23, 31.12, 53.66, 56.03, 73.47, 114.39, 127.21, 128.35, 129.36, 143.72, 147.75, 153.18, 197.23. MS (EI, 70 ev): m/z (%) = 274 (M +, 15), 259 (55), 229 (70), 167 (75), 45 (100). Anal. Calcd. for C 15 H 18 N 2 3 (274.32): C, 65.68; H, 6.61; N, 10.21. Found: C, 65.63; H, 6.56; N, 10.20.
3 5-Acetyl-6-methyl-1-methoxymethyl-4-phenyl-3,4-dihydropyrimidin-2(1H)- one (2) and 5-acetyl-1,3-dimethoxymethyl-6-methyl-4-phenyl-3,4- dihydropyrimidin-2(1h)-one (3) A solution of 1 (5 g, 0.022 mol) in DMF (30 ml) was added to the flask with NaH (60% suspension in mineral oil, 1.15 g, 0.029 mol) with the use of syringe. The obtained mixture was stirred for 1 h at 0-5ºС. Then МОМ-Сl (1.93 g, 0.024 mol) was added dropwise to the reaction mixture. After additional stirring for 1.5 h at room temperature, the solution was poured into 350 ml of water and the product was extracted 3 times with 50 ml of EtAc, The combined organic layers were dried over Na 2 S 4, filtered and concentrated under vacuum. The residual solid was purified by column chromatography (EtAc/CH 2 Cl 2 (1:1, 100 ml), EtAc (150 ml)) to give compound 2 (0.65 g, 11%) as a white solid and 3. 5-Acetyl-1,3-bis(methoxymethyl)-6-methyl-4-phenyl-3,4-dihydropyrimidin- 2(1H)-one (3). Yellow viscous oil; yield: 0.9 g (13%). IR (KBr): 1682, 1662, 1614, 1456 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 7.2 7.4 (m, 5Н, Ph), 5.46 (s, 1Н, H- 4), 5.19 (d, J = 11.0 Hz, 1Н, CH 2 ), 5.06 (d, J = 11.0 Hz, 1Н, CH 2 ), 5.05 (d, J = 11.0 Hz, 1Н, CH 2 ), 4.47 (d, J = 11.0 Hz, 1Н, N(3)CH 2 ), 3.18 (s, 3Н, CH 3 ), 3.12 (s, 3Н, CH 3 ), 2.42 (s, 3Н, CH 3 ), 2.21 (s, 3Н, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 16.43, 31.43, 55.88, 56.39, 57.28, 74.68, 78.09, 116.25, 127.43, 128.65, 129.39, 141.37, 146.91, 153.47, 196.80. MS (EI, 70 ev): m/z (%) = 318 (M+, 22), 303 (20), 285 (82), 241 (100), 198 (11), 45 (75). Anal. Calcd for C 17 H 22 N 2 4 : C, 64.13; H, 6.97; N, 8.80. Found: C, 64.10; H, 6.90; N, 8.80. 5-[1-(Methoxymethoxy)vinyl]-1,3-bis(methoxymethyl)-6-methyl-4-phenyl- 3,4-dihydropyrimidin-2(1H)-one (4)
4 Under argon atmosphere, the solution of 1 (5 g, 0.022 mol) in DMF (30 ml) was added to the flask with NaH (60% suspension in mineral oil, 3.13 g, 0.078 mol). After stirring for 1 h at 60 C, the reaction mixture was cooled to 0 5ºС and then МОМ- Сl (5.25 g, 0.065 mol) was added dropwise. After additional stirring for 1.5 h at room temperature, the solution was poured into 350 ml of water and the product was extracted 3 times with 50 ml of EtAc. The combined organic layers were dried over Na 2 S 4, filtered and concentrated under vacuum. The residual solid was purified by column chromatography (EtAc/CH 2 Cl 2 (1:1, 100 ml), EtAc (100 ml)) to give 4. Yellow viscous oil; yield: 4.33 g (55%). IR (KBr): 1668, 1456 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 7.15 7.4 (m, 5Н, Ph), 5.14 (d, J = 11.0 Hz, 1Н, N(1)CH 2 ), 5.08 (d, J = 11.0 Hz, 1Н, N(3)CH 2 ), 5.05 (s, 1Н, H-4), 4.96 (d, J = 11.0 Hz, 1Н, N(1)CH 2 ), 4.87 (s, 2Н, CH 2 ), 4.43 (d, J = 1.8 Hz, 1H, С=CH 2 ), 4.23 (d, J = 11.0 Hz, 1Н, N(3)CH 2 ), 3.93 (d, J = 1.8 Hz, 1Н, С=CH 2 ), 3.26 (s, 3Н, CH 3 ), 3.23 (s, 3Н, CH 3 ), 3.15 (s, 3Н, CH 3 ), 2.09 (s, 3Н, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 15.86, 55.78, 56.14, 56.34, 59.24, 74.62, 77.30, 92.83, 94.12, 111.79, 127.38, 127.43, 128.47, 129.22, 129.38, 134.32, 141.23, 153.99, 155.34. MS (EI, 70 ev): m/z (%) = 344 (М+, 5), 329 (10), 317 (65), 285 (20), 45 (100). Anal. Calcd for C 19 H 26 N 2 5 : C, 62.97; H, 7.23; N, 7.73. Found: C, 62.95; H, 7.16; N, 7.69. 5-[3-(4-Bromophenyl)-2-propenoyl]-1-methoxymethyl-6-methyl-4-phenyl- 3,4-dihydropyrimidin-2(1H)-one (5) A mixture of 2 (1.1 g, 4.01 mmol), 4-bromobenzaldehyde (0.81 g, 4.41 mmol) and KH (saturated solution in MeH, 1.1 ml) in MeH (7 ml) was stirred at ambient temperature for 3.5 h. The product precipitated over night. After filtration and washing 3 times with MeH (3 ml) the product was crystallized from EtH to give compound 5. Bright orange solid; yield: 0.80 g (45%); mp 159 161 C. IR (KBr) 1688,
5 1657, 1613, 1485 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 8.15 (d, J = 3.1 Hz, 1H, NH), 7.53 7.67 (m, 4H, Ar), 7.16 7.36 (7H, m, CH=CH, Ph), 5.4 (d, J = 3.1 Hz, 1H, H- 4), 5.15 (d, J = 10.8 Hz, 1H, CH 2 ), 5.04 (d, J = 10.8 Hz, 1H, CH 2 ) 3.17 (s, 3Н, CH 3 ), 2.35 (s, 3Н, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 16.95, 53.92, 56.04, 73.46, 115.26, 124.29, 127.06, 127.79, 128.23, 129.24, 131.08, 132.51, 134.60, 141.08, 144.15, 145.73, 153.26, 190.53. MS (EI, 70 ev): m/z (%) = 440 (М +, 90), 409 (16), 379 (33), 129 (98), 102 (80). Anal. Calcd for C 22 H 21 BrN 2 3 : C, 59.87; H, 4.80; Br, 18.11; N, 6.35. Found: C, 59.81; H, 4.70; Br, 18.11; N, 6.33. 6-Methyl-4-phenyl-5-(3-phenyl-2-propenoyl)-3,4-dihydropyrimidin-2(1H)- one (6b) A solution of urea (0.18 g, 3.3 mmol), benzaldehyde (0.37 ml, 3.62 mmol), cinnamoylacetone (0.62 g, 3.3 mmol) and a catalytic amount of HCl in 3 ml of EtH was refluxed for 20 min. While heating the mixture from yellow became dark brown colored. After cooling the formed precipitate was filtered off and washed 3 times with 1 ml of EtH. The obtained crude compound was crystallized from EtH to give 6b. Yellow solid; yield: 0.41 g (43%); mp 193 195 C. IR (KBr) 1702, 1665, 1618, 1475, 3222 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 9.25 (s, 1H, NH), 7.88 (s, 1H, NH), 7.58-7.66 (m, 2H, CH=CH), 7.21-7.39 (m, 10H, Ph), 5.46 (d, J = 3.4 Hz, 1H, H-4), 2.27 (s, 3H, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 19.58, 54.71, 110.73, 126.85, 127.08, 128.01, 128.91, 129.18, 129.53, 130.60, 135.59, 140.96, 145.25, 148.25, 152.79, 188.10. MS (EI, 70 ev): m/z (%) = 318 (М +, 50), 303 (21), 241 (10), 227 (19), 187 (15), 131 (16), 103 (39), 77 (54), 49 (100). Anal. Calcd for C 20 H 18 N 2 2 : C, 75.45; H, 5.70; N, 8.80. Found: C, 75.43; H, 5.65; N, 8.79. 4-[4-(N,N-Dimethylamino)phenyl]-6-methyl-5-(3-phenyl-2-propenoyl)-3,4- dihydropyrimidin-2(1h)-one (6c).
6 A solution of urea (0.14 g, 2.4 mmol), n-dimethylaminobenzaldehyde (0.36 g, 2.4 mmol) and cinnamoylacetone (0.45 g, 2.4 mmol) in 2.5 ml of HCl was stirred for 1 h at the ambient temperature. After that saturated aqueous solution of KH was added to the mixture. The formed precipitate was filtered off and washed with water. The obtained crude compound was crystallized from EtH to give compound 6c. Yellow solid; yield: 0.31 g (37%); mp 212 214 C. IR (KBr) 1709, 1655, 1620, 1515, 3230 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 9.14 (s, 1H, NH), 7.71 (s, 1H, NH), 7.53-7.67 (m, 2H, CH=CH), 7.17-7.46 (m, 5H, Ph), 7.08 (d, J = 8.7 Hz, 2H, Ar), 6.62 (d, J = 8.7 Hz, 2H, Ar), 5.31-5.42 (m, 1H, H-4), 2.80 (s, 6H, N(CH 3 ) 2 ), 2.26 (s, 3H, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 19.27, 54.11, 110.63, 112.81, 126.49, 127.66, 128.66, 129.34, 130.35, 132.76, 135.46, 140.61, 147.53, 150.28, 152.56, 187.87. Anal. Calcd for C 22 H 23 N 3 2 : C, 73.11; H, 6.41; N, 11.63. Found: C, 73.13; H, 6.39; N, 11.60. 6-Methyl-4(4-nitrophenyl)-5-(3-phenyl-2-propenoyl)-3,4-dihydropyrimidin- 2(1H)-one (6d) A solution of urea (0.13 g, 2.2 mmol), n-nitrobenzaldehyde (0.32 g, 2.2 mmol), cinnamoylacetone (0.40 g, 2.2 mmol) in 2.5 ml of HAc was refluxed during 3 h. While heating the mixture from yellow became dark brown colored. After cooling the solvent was evaporated under reduced pressure and the obtained crude was crystallized from EtH to give compound 6d. Yellow solid; yield: 0.24 g (31%); mp 198 200 C. IR (KBr) 1702, 1659, 1575, 1515, 3256 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 9.39 (s, 1H, NH), 8.18 (d, J = 8.6 Hz, 2Н, Ar), 8.03 (s, 1H, NH), 7.60-7.77 (m, 2H, CH=CH), 7.53 (d, J = 8.6 Hz, 2Н, Ar), 7.26-7.47 (m, 5H, Ph), 5.52-5.63 (m, 1H, H-4), 2.29 (s, 3H, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 19.61, 54.07, 110.08, 124.32, 126.76, 128.19, 128.78, 129.34, 130.49, 135.35, 141.03, 147.20, 148.91, 152.21, 152.40,
7 187.86. Anal. Calcd. for C 22 H 17 N 3 4 (363.38): C, 66.11; H, 4.72; N, 11.56. Found: C, 66.08; H, 4.70; N, 11.55. 5-[3-(4-Bromophenyl)-2-propenoyl]-4-ethyl-1,6-dimethyl-3,4- dihydropyrimidin-2(1h)-one (9) A mixture of 8 (0.9 g, 4.6 mmol), 4-bromobenzaldehyde (0.85 g, 4.6 mmol), KH (saturated solution in MeH, 1.1 ml) in MeH (7 ml) was stirred at ambient temperature for 3.5 h. The product precipitated over night. After filtration and washing 3 times with 3 ml of MeH the product was crystallized from EtH to give compound 9. Yellow solid; yield: 0.92 g (55%); mp 137 140 C. IR (KBr) 1687, 1654, 1620, 1485, 3232 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 7.53-7.77 (m, 5H, Ar, NH), 7.32 (q, J = 15.7 2H, CH vinyl =C), 4.06-4.22 (m, 1H, H-4), 3.06 (s, 3H, CH 3 ), 2.27 (s, 3H, CH 3 ), 1.25-1.46 (m, 2H, CH 2 ), 0.77 (t, J = 7.1 Hz, 3H, CH 3 ). 13 C NMR (100 MHz, DMSd 6 ): δ = 9.48, 18.25, 30.34, 51.43, 114.21, 123.98, 128.08, 130.95, 132.49, 134.87, 140.22, 148.63, 154.15, 189.83. MS (EI, 70 ev): m/z (%) = 364 (М +, 4), 334 (8), 211 (15), 180 (12), 152 (15), 102 (100). Anal. Calcd for C 17 H 19 BrN 2 2 : C, 56.21; H, 5.27; Br, 22.00; N, 7.71. Found: C, 56.16; H, 5.27; Br, 22.03; N, 7.70. 5-[3-(4-Bromophenyl)-2-propenoyl]-1-ethyl-6-methyl-4-phenyl-3,4- dihydropyrimidin-2(1h)-one (10) A mixture of compound 6a (0.45 g, 1.2 mmol), EtBr (0.51 ml, 6.8 mmol,) and KH (saturated water solution, 1.1 ml) in acetonitrile (7 ml) was heated under reflux during 1 h. The mixture was poured into brine (50 ml), water phase was extracted with EtAc (4 portions by 30 ml), extract was dried over Na 2 S 4, filtered and solvent was removed under reduced pressure. The residual solid was purified by column chromatography (silica, 150 ml of CH 2 Cl 2, 100 ml EtAc/CH 2 Cl 2, 100 ml EtAc) to give a compound 10. Pale yellow solid; yield: 0.15 g (32%); mp 137 140 C (EtAc
8 CH 2 Cl 2 ) (lit. mp 158 160 С (EtH)). IR (KBr) 1689, 1634, 1585, 1515 cm 1. 1 H NMR (200 MHz, DMS-d 6 ): δ H = 7.91 (bd, J = 3.4 Hz, 1H, NH), 7.54 7.66 (m, 4H, Ar), 7.15 7.4 (m, 7H, CH=CH, Ph), 5.34 (d, J = 3.4 Hz, 1H, H-4), 3.5 4.0 (m, 2H, CH 2 ), 2.37 (s, 3H, CH 3 ), 1.07 (t, J = 7.0 Hz, 3H, CH 3 ). 13 C NMR (100 MHz, DMS-d 6 ): δ = 15.53, 17.72, 37.66, 53.61, 114.31, 124.07, 126.89, 128.06, 128.11, 129.18, 130.96, 132.50, 134.77, 140.30, 144.64, 147.78, 153.16, 189.74. Anal. Calcd. for C 22 H 21 BrN 2 2 (425.33): C, 62.13; H, 4.98; Br, 18.79; N, 6.59. Found: C, 62.10; H, 4.90; Br, 18.81; N, 6.50. REFERENCES 1. Kolosov, M. A.; rlov, V. D.; Vashchenko, V. V.; Shishkina, S. V.; Shishkin,. V. Collect. Czech. Chem. Commun. 2007, 72, 1219.
1 H NMR spectra of synthesized compounds 9
10 Ph N N
11 N Ph CH 2 N
12 Ph HN N Br
13
14 HN Ph N H
15 N HN Ph N H
16 N 2 HN Ph N H
17 HN N Br
18
13 С NMR spectra of synthesized compounds 19 PPM 16.23 PPM 197.23 153.18 147.75 143.72 129.36 128.35 127.21 114.39 73.47 56.03 53.66 40.63 40.58 40.42 40.37 40.16 39.95 39.74 31.12 Ph HN N (2) 200 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 File name: ok-11-88-p4 wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
20 PPM PPM 196.80 153.47 146.91 141.37 129.39 128.65 127.43 116.25 78.09 74.68 57.28 56.39 55.88 31.43 16.43 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 File name: ok-10-09p2-13c wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
21 PPM PPM 155.34 153.99 141.23 134.32 129.38 129.22 128.47 127.43 127.38 111.79 94.12 92.83 77.30 74.62 59.24 56.34 56.14 55.78 31.41 16.42 15.86 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 File name: ok-10-05l2-13c wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
22 PPM PPM 190.53 153.26 145.73 144.15 141.08 134.60 132.51 131.08 129.24 128.23 127.79 127.06 124.29 115.26 73.46 56.04 53.92 40.80 40.64 40.59 40.43 40.38 40.17 39.96 39.75 16.95 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 File name: ok-12-08p2 wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
23 PPM PPM 187.90 152.74 148.55 145.26 139.59 134.92 132.46 130.84 129.17 128.00 127.63 127.07 123.85 110.69 54.61 40.84 40.80 40.63 40.58 40.37 40.16 39.95 39.75 39.54 19.62 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 File name: ok-12-09p1 wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
24 PPM PPM 130.60 129.53 129.18 128.91 128.01 127.08 126.85 PPM 188.10 152.79 148.25 145.25 140.96 135.59 130.60 129.53 129.18 128.91 128.01 127.08 126.85 110.73 54.71 19.58 132.0 131.0 130.0 129.0 128.0 127.0 126.0 125.0 PPM 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 File name: ok-12-40f2-13c wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
25
26
27 PPM PPM 189.83 154.15 148.63 140.22 134.87 132.49 130.95 128.08 123.98 114.21 51.43 30.34 18.25 9.48 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 10 File name: ok-12-16p2-13c wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
28 PPM PPM 189.74 153.16 147.78 144.64 140.30 134.77 132.50 130.96 129.18 128.11 128.06 126.89 124.07 114.31 53.61 37.66 17.72 15.53 190 180 170 160 150 140 130 120 110 100 90 80 70 60 50 40 30 20 File name: mb-05-36-13c wner: SF: 100.7017 MHz NS: SI: 262144, TD: 100000 Date: Solvent: "DMS-d6 SW: 25000 TE: 294
IR spectra of synthesized compounds 29 Ph HN N (2)
30
31
32
33
34
35
36
37
38
39
40
MS spectra of synthesized compounds 41
42
43
44 Ph HN N (5) Br
45
46
47