Tandem Schiff-Base Formation/Heterocyclization: An Approach to the Synthesis of Fused Pyrazolo–Pyrimidine/Isoxazolo-Pyrimidine Hybrids

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.

Key words

pyrazolo[4,3-d]pyrimidine - isoxazolo[4,5-d]pyrimidine - Stille coupling - Schiff base

• 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.