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Synlett 2019; 30(05): 586-592
DOI: 10.1055/s-0037-1612081
DOI: 10.1055/s-0037-1612081
letter
Tandem Schiff-Base Formation/Heterocyclization: An Approach to the Synthesis of Fused Pyrazolo–Pyrimidine/Isoxazolo-Pyrimidine Hybrids
Further Information
Publication History
Received: 06 December 2018
Accepted after revision: 02 January 2019
Publication Date:
05 February 2019 (online)
Abstract
A new synthesis of pyrazolo[4,3-d]pyrimidines and isoxazolo[4,5-d]pyrimidines is described. Key steps in the synthesis involve Stille coupling of 4,6-dichloro-2-phenyl-pyrimidine with tributyl(1-ethoxyvinyl)stannane and tandem Schiff-base formation/heterocyclization of 2,6-di-aryl-5-fluoro-4-acetylpyrimidine with hydrazines or hydroxylamine to give pyrazolo[4,3-d]pyrimidines and isoxazolo[4,5-d]pyrimidines, respectively. The position of the fluoro group in the pyrimidine ring is important for the success of heterocylization reaction.
Supporting Information
- Supporting information for this article is available online at https://doi.org/10.1055/s-0037-1612081.
- Supporting Information
-
References and Notes
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- 37 Typical Experimental Procedures 3-Methyl-5,7-diphenyl-1H-pyrazolo [4,3-d]pyrimidine (14a) To a stirred solution of compound 12a (0.25 g, 0.85 mmol) in ethanol (10 mL) was added hydrazine hydrochloride (0.055 g, 1.71 mmol), and the resulting reaction mixture was heated to 110 °C for 6 h. The progress of the reaction was monitored by TLC (20% ethyl acetate in petroleum ether). The ethanol was evaporated, and the crude the 13a was dissolved in DMF (10 mL), K2CO3 (0.177 g, 1.28 mmol) was added and the reaction mixture stirred at 100 °C for 2 h. After completion of reaction; water was added, and the reaction mixture was extracted with ethyl acetate (X × Y mL). The combined organic extracts were washed with water (X × Y mL), brine (X × Y mL), dried over Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by silica gel column chromatography, eluting with 10% ethyl acetate in petroleum ether to afford pure 14a (180 mg, 73%) as a pale yellow solid; mp 268–272 °C. 1H NMR (400 MHz, CDCl3): δ = 10.24 (br s, 1 H), 8.67 (dd, J = 8 Hz, 2 H), 8.23 (d, J = 8 Hz, 2 H), 7.63 (m, 6 H), 2.78 (s, 3 H). IR (KBr): 3247, 2920, 1954, 1554, 1465, 1375, 1292, 1203, 990, 930, 755, 685, 542 cm–1. 13C NMR (100 MHz, DMSO-d 6) = 156.2, 148.9, 145.3, 142.3, 137.9, 135.3, 131.2, 129.7, 129.7, 129.6, 129.0, 128.7, 128.5, 128.5, 128.5, 127.5, 127.5, 10.7. MS (EI): m/z = 286 (100) [M + 1]. HRMS (ESI): m/z calcd for C18H14N4 [M + H]: 287.1218; found: 287.1298. 1-Isopropyl-3-methyl-5,7-diphenyl-1H-pyrazolo[4,3-d]pyrimidine (14c) Pale yellow solid (0.2 g, 90%); mp 109–113 °C. 1H NMR (400 MHz, CDCl3): δ = 8.59 (d, J = 8 Hz, 2 H), 7.78 (d, J = 4 Hz, 2 H), 7.75 (m, 3 H), 7.43 (m, 3 H), 4.53 (m 1 H), 2.75 (s, 3 H), 1.37 (d, J = 4 Hz, 6 H). IR (KBr): 3423, 2974, 1996, 1550, 1414, 1369, 1230, 1123, 1070, 926, 767, 603, 544 cm–1. 13C NMR (100 MHz, CDCl3) = 157.1, 151.5, 145.9, 143.1, 138.3, 137.3, 130.0, 130.0, 129.5, 129.5, 129.5, 129.5, 128.8, 128.8, 128.5, 128.5, 128.4, 128.0, 51.4, 22.2, 10.9. MS (EI): m/z = 328 (100) [M + 1]. HRMS (ESI): m/z calcd for C21H20N4 [M + H]: 329.1688; found: 329.1770. 7-[3-(Trifluoromethyl)phenyl]-3-methyl-5-phenyl-1H-pyrazolo [4,3-d]pyrimidine (14f) Yellow solid (0.18 g 74%); mp 217–221 °C. 1H NMR (400 MHz, CDCl3): δ = 10.40 (br s, 1 H), 8.66 (m, 2 H), 8.53 (m, 1 H), 8.45 (d, J = 8 Hz, 1 H), 7.88 (m, 1 H), 7.81 (t, J = 8, 8 Hz, 1 H), 7.54 (m, 3 H), 2.80 (s, 3 H). IR (KBr): 3243, 3069, 1556, 1469, 1425, 1328, 1250, 1166, 1119, 1070, 993, 772, 544 cm–1. 13C NMR (100 MHz, CDCl3): δ =158.4, 148.3, 138.0, 137.1, 132.1, 131.8, 131.5, 130.0, 129.9, 129.9, 129.8, 128.5, 128.5, 128.1, 127.6, 127.6, 125.2, 124.8, 10.8. MS (EI): m/z = 354 (100) [M + 1]. HRMS (ESI): m/z calcd for C19H13N4 [M + H]: 355.1092; found: 355.1173. 1-(3,5-Dichlorophenyl)-7-[4-(trifluoromethyl)phenyl]-3-methyl-5-phenyl-1H-pyrazolo[4,3-d]pyrimidine (14g) Off-white solid (0.28 g, 67%); mp 216–220 °C. 1H NMR (400 MHz, CDCl3): δ = 8.65 (m, 2 H), 7.61 (m, 4 H), 7.51 (m, 3 H), 7.21 (m, 1 H), 7.00 (d, J = 1.6 Hz, 2 H), 2.80 (s, 3 H). IR (KBr): 3086, 2323, 1585, 1455, 1326, 1167, 1124, 1069, 1018, 848, 704, 628, 600 cm–1. 13C NMR (100 MHz, CDCl3): δ = 158.7, 149.8, 148.7, 146.8, 140.3, 139.1, 137.4, 134.9, 132.4, 132.1, 130.4, 129.7, 129.7, 128.6, 128.6, 128.2, 127.1, 127.0, 127.0, 125.0, 125.0, 124.7, 123.1, 122.5, 10.9. MS (EI): m/z = 498 (100) [M + 1]. HRMS (ESI): m/z calcd for C25H15Cl2N4 [M + H]: 499.0626; found: 499.0708. 1-(3,5-Dichlorophenyl)-7-(2,4-dimethoxyphenyl)-5-(furan-3-yl)-3-methyl-1H-pyrazolo[4,3-d]pyrimidine (14m) Off-white solid (0.19 g, 90%); mp 208–217 °C. 1H NMR (400 MHz, CDCl3): δ = 8.33 (m, 1 H), 7.73 (d, J = 8 Hz, 1 H), 7.52 (m, 1 H), 7.22 (m, 1 H), 7.16 (m, 1 H), 7.04 (m, 2 H), 6.72 (d, J = 8 Hz, 1 H), 6.08 (s, 1 H), 4.85 (s, 3 H), 3.19 (s, 3 H), 2.81 (s, 3 H). IR (KBr): 3438, 2926, 1736, 1610, 1584, 1504, 1461, 1277, 1111, 1027, 934, 795, 596 cm–1. 13C NMR (100 MHz, CDCl3): δ =163.4, 157.9, 157.9, 155.0, 149.4, 146.7, 146.6, 145.3, 144.2, 143.5, 141.0, 134.2, 131.6, 127.8, 127.2, 126.1, 122.2, 118.6, 109.8, 105.7, 97.3, 55.6, 54.5, 10.8. MS (EI): m/z = 480 (100) [M + 1]. HRMS (ESI): m/z calcd for C24H18Cl2N4O3 [M + H]: 480.0756; found: 481.0845. 3-Methyl-1,7-diphenyl-5-(pyridin-3-yl)-1H-pyrazolo [4,3-d]pyrimidine (14n) Light brown solid (0.13 g, 52%); mp 181–185 °C. 1H NMR (400 MHz, CDCl3): δ = 9.86 (s, 1 H), 8.93 (d, J = 4 Hz, 1 H), 8.72 (d, J = 4 Hz, 1 H), 7.48 (m, 3 H), 7.39 (m, 1 H), 7.23 (m, 5 H), 7.12 (m, 2 H), 2.85 (s, 3 H). IR (KBr): 3481, 3036, 2922, 1558, 1498, 1417, 1376, 1227, 1118, 1015, 759, 696, 686 cm–1. 13C NMR (100 MHz, CDCl3): δ =156.1, 152.1, 152.1, 150.7, 150.1, 147.8, 147.8, 145.5, 139.6, 135.6, 133.8, 130.1, 129.6, 129.6, 128.7, 128.7, 127.9, 127.9, 127.7, 127.5, 125.1, 123.4, 11.0. MS (EI): m/z = 363 [M + 1]. HRMS (ESI): m/z calcd for C23H17N5 [M + H]: 363.1484; found: 364.1571.
- 38 Preparation of 3-Methyl-5,7-diphenylisoxazolo[4,5-d]pyrimidine (16j) To a stirred solution of compound 12a (0.2 g, 0.68 mmol) in MeOH (8 mL) were added hydroxylamine hydrochloride (0.052 g, 0.75 mmol) and powdered NaOH (0.033 g, 0.82 mmol) at RT, then the reaction mixture was stirred under N2 atmosphere for 16 h. Progress of the reaction was monitored by TLC (5% ethyl acetate in petroleum ether). After completion of the reaction, the methanol was evaporated to give crude 15a as a solid. This was dissolved in DMF under N2 and cooled to 0 °C. To this, NaOH (0.033 g, 0.82 mmol) powder was added and the mixture stirred at RT for 6 h. The progress of the reaction was monitored by TLC (5% ethyl acetate in petroleum ether). After completion of reaction, water was added, and the mixture was extracted with ethyl acetate (X × Y mL). The combined extracts were washed with water (X mL), brine (Y mL), dried over Na2SO4, filtered, and evaporated to afford the crude product, which was purified by silica column chromatography, eluting with 3% ethyl acetate in petroleum ether to give the pure 16j (80 mg, 40%) as a pale yellow solid; mp 153–157 °C. 1H NMR (400 MHz, CDCl3): δ = 8.73 (m, 2 H), 8.71 (m, 2 H), 7.65 (m, 3 H), 7.56 (m, 3 H), 2.77 (s, 3 H). IR (KBr): 3414, 2921, 1589, 1457, 1376, 1274, 1164, 1067, 920, 853, 797, 750, 688 cm–1. 13C NMR (100 MHz, CDCl3): δ = 161.2, 156.5, 150.3, 149.0, 147.7, 137.3, 133.5, 132.1, 130.6, 130.5, 129.7, 129.4, 129.0, 128.6, 128.5, 128.3, 127.5, 9.2. MS (EI): m/z = 287 (100) [M + 1]. HRMS (ESI): m/z calcd for C18H13N3O [M + H]: 288.3153; found: 288.1143. 3-Methyl-5-phenyl-7-[3-(trifluoromethyl)phenyl]isoxazolo[4,5-d]pyrimidine (16b) Pale yellow solid (0.12 g, 41%); mp 161–165 °C. 1H NMR (400 MHz, CDCl3): δ = 8.96 (m, 1 H), 8.91 (d, J = 8 Hz, 1 H), 8.64 (m, 2 H), 7.88 (m, 1 H), 7.79 (t, J = 8, 4 Hz, 1 H), 7.53 (m, 3 H), 2.79 (s, 3 H). IR (KBr): 3073, 2329, 1655, 1594, 1412, 1326, 1231, 1161, 1069, 920, 769, 690, 594 cm–1. 13C NMR (100 MHz, CDCl3): δ = 161.4, 161.4, 156.6, 150.0, 149.6, 145.9, 136.9, 134.9, 134.3, 132.8, 132.6, 131.8, 131.5, 130.7, 130.2, 129.6, 128.7, 128.6, 9.2. MS (EI): m/z = 355 (100) [M + 1]. HRMS (ESI): m/z calcd for C19H12F3N3O [M + H]: 356.0932; found: 356.1014. 7-(4-Chloro-3-nitrophenyl)-3-methyl-5phenylisoxazolo[4,5-d]pyrimidine (16d) Pale yellow solid (0.07 g, 48%); mp 187–191 °C. 1H NMR (400 MHz, CDCl3): δ = 9.20 (d, J = 4 Hz, 1 H), 8.86 (d, J = 8 Hz, 1 H), 8.62 (m, 2 H), 7.84 (d, J = 8 Hz, 1 H), 7.58 (m, 3 H), 2.79 (s, 3 H). IR (KBr): 3092, 2921, 2850, 2324, 1742, 1600, 1542, 1355, 1272, 1038, 844, 758, 696 cm–1. 13C NMR (100 MHz, CDCl3): δ = 162.4, 162.4, 156.7, 154.8, 150.2, 149.6, 143.9, 138.1, 136.6, 133.5, 133.2, 132.6, 131.0, 130.3, 128.8, 128.3, 125.7, 9.26. MS (EI): m/z = 366 (100) [M + 1]. HRMS (ESI): m/z calcd for C18H11ClN4O [M + H]: 367.0520; found: 366.9997. 7-(2,4-Dimethylphenyl)-3-methyl-5-phenylisoxazolo[4,5-d]pyrimidine (16g) Pale yellow solid (0.07 g, 20%); mp 99–103 °C. 1H NMR (400 MHz, CDCl3): δ = 8.59 (m, 2 H), 7.86 (d, J = 4 Hz, 1 H), 7.54 (m, 3 H), 7.24 (m, 2 H), 2.81 (s, 3 H), 2.61 (s, 3 H), 2.40 (s, 3 H). IR (KBr): 3418, 2919, 2626, 2525, 1591, 1533, 1392, 1354, 1276, 1219, 841, 769, 695 cm–1. 13C NMR (100 MHz, CDCl3): δ =161.0, 161.0, 156.6, 150.9, 150.8, 148.0, 141.0, 138.0, 137.4, 132.6, 131.1, 130.4, 129.9, 129.9, 128.6, 128.3, 126.9, 21.4, 21.0, 9.3. MS (EI): m/z = 315 (100) [M + 1]. HRMS (ESI): m/z calcd for C20H17N3O [M + H]: 316.1372; found: 316.1458. (E)-7-(4-Chlorostyryl)-3-methyl-5-phenylisoxazolo[4,5-d]pyrimidine (16h) Pale yellow solid (0.07g, 35%); mp 89–93 °C. 1H NMR (400 MHz, CDCl3): δ = 8.57 (m, 2 H), 8.30 (d, J = 20 Hz, 1 H), 7.68 (d, J = 8 Hz, 1 H), 7.53 (m, 4 H), 7.45 (m, 3 H), 2.75 (s, 3 H). IR (KBr): 3443, 3044, 2920, 2299, 1978, 1586, 1502, 1409, 1176, 1083, 964, 809, 705 cm–1. 13C NMR (100 MHz, CDCl3): δ = 161.5, 161.5, 156.5, 150.1, 148.1, 147.1, 137.3, 136.0, 134.1, 130.4, 129.2, 129.1, 129.1, 129.1, 128.6, 128.3, 128.3, 128.3, 123.1, 9.26. MS (EI): m/z = 347 (100) [M + 1]. HRMS (ESI): m/z calcd for C20H14ClN3O [M + H]: 347.0825; found: 348.0908. 7-(2,4-Dimethoxyphenyl)-3-methyl-5-phenylisoxazolo[4,5-d]pyrimidine (16i) Pale brown solid (0.05 g, 34%); mp 170–174 °C. 1H NMR (400 MHz, CDCl3): δ = 8.60 (m, 2 H), 7.92 (d, J = 8 Hz, 1 H), 7.51 (m, 3 H), 6.73 (m, 1 H), 6.65 (d, J = 4 Hz, 1 H), 3.95 (s, 3 H), 3.92 (s, 3 H), 2.75 (s, 3 H). IR (KBr): 3445, 2923, 2841, 1600, 1503, 1374, 1283, 1147, 1025, 922, 821, 770, 696 cm–1. 13C NMR (100 MHz, CDCl3): δ =163.8, 161.0, 161.0, 159.8, 156.2, 151.1, 147.8, 147.5, 137.6, 133.0, 130.2, 130.2, 128.5, 128.3, 128.3, 105.9, 98.7, 55.8, 55.6, 9.3. MS (EI): m/z 347 (100) [M + 1]. HRMS (ESI): m/z calcd for C20H17N3O3 [M + H]: 347.1270; found: 348.1352.
- 39 See Supporting Information for biological activity graphs, intermediates preparation, and spectroscopic data.