Synthesis of Pyrazolo[3,4-d]-4,5-dihydropyrimidines through [5+1] Cyclocondensation

Abstract

Twenty-five diverse pyrazolo[3,4-d]-4,5-dihydropyrimidines were synthesized in 73–91% yield through TMS-promoted [5+1] heterocyclization of aldehydes with pyrazolylamidines.

Key words

heterocycles - cyclization - fused-ring systems - aldehydes - ring closure

• References

• 1 Pacher P, Nivorozhkin A, Szabó C. Pharm. Rev. 2006; 58: 87
• 2a Kumar R, Darpan Sharma S, Singh R. Exp. Opin. Therap. Pat. 2011; 21: 1071
• 2b Davidson GS. Int. J. Pharm. Comp. 2006; 10: 405
• 2c Shukla N, Jones R, Persad R, Angelini GD, Jeremy JY. Eur. J. Pharm. 2005; 517: 224
• 3a Radi M, Dreassi E, Brullo C, Crespan E, Tintori C, Bernardo V, Valoti M, Zamperini C, Daigl H, Musumeci F, Carraro F, Naldini A, Filippi I, Maga G, Schenone S, Botta M. J. Med. Chem. 2011; 54: 2610
• 3b Carraro F, Naldini A, Pucci P, Locatelli GA, Maga G, Schenone S, Bruno O, Ranise A, Bondavalli F, Brullo C, Fossa P, Menozzi G, Mosti L, Modugno M, Tintori C, Manetti F, Botta M. J. Med. Chem. 2006; 49: 1549
• 4a Rashad AE, Mahmoud AE, Ali MM. Eur. J. Med. Chem. 2011; 1019
• 4b Ibrahim DA. Eur. J. Med. Chem. 2009; 44: 2776
• 5a Kota RK, Kompelly KK, Surampudi R, Kulakarni R. J. Chem. Pharm. Res. 2011; 3: 848
• 5b Youssef AM, Neeland EG, Villanueva EB, White MS, El-Ashmawy IM, Patrick B, Klegeris A, Abd-El-Aziz AS. Bioorg. Med. Chem. 2010; 18: 5685
• 5c Raffa D, Maggio B, Plescia F, Cascioferro S, Raimondi MV, Plescia S, Cusimano MG. Arch. Pharm. 2009; 342: 321
• 6a Higashino T, Sato S, Miyashita A, Katori T. Chem. Pharm. Bull. 1987; 35: 4803
• 6b Miyashita A, Sato S, Taido N, Tanji K, Oishi E, Higashino T. Chem. Pharm. Bull. 1990; 38: 230
• 7a Volochnyuk DM, Kovaleva SA, Chernega AN, Chubaruk NG, Kostyuk AN, Pinchuk AM, Tolmachev AA, Schmutzler R. Synthesis 2006; 1613
• 7b Ryabukhin SV, Granat DS. Plaskon A. S, Shivanyuk AN, Tolmachev AA, Volovenko YM. ACS Comb. Sci. 2012; 14: 465
• 8a Volochnyuk DM, Ryabukhin SV, Plaskon AS, Grygorenko OO. Synthesis 2009; 3719
• 8b Ryabukhin SV, Plaskon AS, Ostapchuk EN, Volochnyuk DM, Tolmachev AA. Synthesis 2007; 417
• 8c Ryabukhin SV, Plaskon AS, Ostapchuk EN, Volochnyuk DM, Shishkin OV, Shivanyuk AN, Tolmachev AA. Org. Lett. 2007; 9: 4215
• 8d Ryabukhin SV, Plaskon AS, Bondarenko SS. Ostapchuk E. N, Grygorenko OO, Shishkin OV, Tolmachev AA. Tetrahedron Lett. 2010; 51: 4229
• 8e Ryabukhin SV, Plaskon AS, Boron SY, Volochnyuk DM, Tolmachev AA. Mol. Diversity 2011; 15: 189

See also:
• 9a Ryabukhin SV, Plaskon AS, Volochnyuk DM, Pipko SE, Shivanyuk AN, Tolmachev AA. J. Comb. Chem. 2007; 9: 1073
• 9b Ryabukhin SV, Naumchik VS, Plaskon AS, Grygorenko OO, Tolmachev AA. J. Org. Chem. 2011; 76: 5774
• 10 General Procedure for the Synthesis of Amidines 3 To a stirred solution of aminopyrazole 1 (0.01 mol) and Et₃N (1.53 mL, 0.011 mol) in CH₂Cl₂ (30 mL) at 0 °C a solution of imidoyl chloride 2 (0.01 mol) in CH₂Cl₂ (30 mL) was added. The reaction mixture was left to stand for 1 h at r.t. and then heated at 40 °C for 4 h. The solvent was evaporated in vacuo, and the residue was triturated with H₂O and crystallized from dioxane–DMF (ca. 3:1). Selected Spectroscopic Data of Compounds 3
  N-Methyl-N′-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-benzamidine (3a) Yield 67%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 2.08 (s, 3 H), 3.03 (d, 3 H, ³ J _H,H = 4.2 Hz), 4.82 (br s, 1 H), 7.15 (t, 1 H, ³J_H,H = 6.4 Hz), 7.19 (t, 1 H, ³J_H,H = 7.8 Hz), 7.26–7.38 (m, 6 H), 7.54 (br s, 1 H), 7.71 (d, 2 H, ³ J _H,H = 7.8 Hz) ppm. APSI MS: M⁺+1 = 291. N-Cyclopropyl-N′-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-benzamidine (3b) Yield 64%. ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.59 (br s, 2 H), 0.69 (br s, 2 H), 1.95 (s, 3 H), 2.88 (br s, 1 H), 4.65 (br s, 1 H), 7.16 (m, 3 H), 7.32–7.36 (m, 5 H), 7.59 (br s, 1 H), 7.86 (d, 2 H, ³ J _H,H = 7.6 Hz) ppm. MS (APCI) [M⁺ +1]: m/z = 317. N-Cyclopropyl-4-fluoro-N′-(5-methyl-2-phenyl-2H-pyrazol-3-yl)-benzamidine (3f) Yield 62%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.58 (br s, 2 H), 0.70 (br s, 2 H), 1.96 (s, 3 H), 2.86 (br s, 1 H), 4.71 (br s, 1 H), 7.11 (t, 2 H, ³ J _H,H,F = 7.6 Hz), 7.14 (br s, 1 H), 7.16 (t, 2 H, ³ J _H,H,F = 7.6 Hz), 7.36 (t, 2 H, ³ J _H,H = 7.8 Hz), 7.62 (br s, 1 H), 7.83 (d, 2 H, ³ J _H,H = 7.8 Hz) ppm. MS (APCI) [M⁺ +1]: m/z = 335. N-(2-Isopropyl-2H-pyrazol-3-yl)-N′-methyl-benzamidine (3g) Yield 52%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.32 (d, 6 H, ³ J _H,H = 7.2 Hz), 2.96 (d, 3 H, ³ J _H,H = 4.8 Hz), 4.45 (s, 1 H), 4.74 (sept, 1 H, ³ J _H,H = 7.2 Hz), 6.88 (s, 1 H), 7.15 (m, 2 H), 7.33–7.41 (m, 4 H) ppm. MS (APCI) [M⁺ +1]: m/z = 243. N-Cyclopropyl-N′-(2-isopropyl-2H-pyrazol-3-yl)-benzamidine (3h) Yield: 55%. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.59 (br s, 2 H), 0.71 (br s, 2 H), 1.34 (d, 6 H, ³ J _H,H = 6.5 Hz), 2.96 (br s, 1 H), 4.46 (s, 1 H), 4.77 (sept, 1 H, ³ J _H,H = 6.5 Hz), 6.83 (s, 1 H), 7.17 (m, 2 H), 7.35–7.43 (m, 4 H) ppm. MS (APCI) [M⁺ +1]: m/z = 269.
• 11 General Procedure for the Synthesis of Pyrazolodihydropyrimidines 5 DMF (1 mL), amidine 3 (1 mmol), TMSCl (3 mmol), and carbonyl compound (1.1 mmol) were placed in a sealed tube (10 mL). The tube was heated at 100 °C for 4–8 h. Than the reaction mixture was diluted by H₂O (8 mL) and sonicated at r.t. for 1–2 h (BRANSON 2510E-MT). The precipitate formed was filtered and washed with of 5% aq NaHCO₃ (8 mL), then i-PrOH (1 mL) and MeCN (1 mL). Selected Spectroscopic Data of Compounds 5 3,5-Dimethyl-1,4,6-triphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (5aa) Yield 88%; mp 162 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.89 (s, 3 H), 2.75 (s, 3 H), 5.88 (s, 1 H), 7.17 (t, 1 H, ³ J _H,H = 7.4 Hz), 7.41 (m, 3 H), 7.47 (m, 9 H), 8.01 (d, 2 H, ³ J _H,H = 7.6 Hz) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 12.6, 63.0, 102.1, 120.8, 121.3, 125.4, 127.2, 128.3, 128.7, 129.0, 129.2, 129.5, 130.0, 130.2, 137.0, 140.2, 143.5, 144.4, 158.7 ppm. MS (APCI) [M⁺ +1]: m/z = 379. Anal. Calcd for C₂₅H₂₂N₄: C, 79.34; H, 5.86; N, 14.80. Found: C, 79.21; H, 5.98; N, 14.68. 5-Cyclopropyl-4-(4-methoxy-phenyl)-3-methyl-1,6-diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (5bb) Yield 82%; mp 154 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.32 (m, 2 H), 0.81 (m, 2 H), 1.96 (s, 3 H), 2.55 (m, 1 H), 3.77 (s, 3 H), 5.80 (s, 1 H), 7.00 (d, 2 H, ³ J _H,H = 8.3 Hz), 7.20 (t, 1 H, ³J_{H ,H} = 7.2 Hz), 7.36 (d, 2 H, ³ J _H,H = 8.3 Hz), 7.41–7.45 (m, 7 H), 8.04 (d, 2 H, ³ J _H,H = 8.0 Hz) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 8.9, 12.5, 13.3, 34.2, 55.6, 60.8, 103.3, 114.8, 120.8, 125.4, 128.3, 128.4, 128.5, 129.2, 129.7, 135.6, 137.9, 140.2, 143.4, 144.1, 158.5, 159.6 ppm. MS (APCI) [M⁺ +1]: m/z = 435. Anal. Calcd for C₂₈H₂₆N₄O: C, 77.39; H, 6.03; N, 12.89. Found: C, 77.55; H, 6.19; N, 13.08. 5-Cyclopropyl-6-(4-fluoro-phenyl)-3-methyl-1-phenyl-4-thiophen-2-yl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (5fd) Yield 85%; mp 176 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.31 (m, 1 H), 0.40 (m, 1 H), 0.81 (m, 2 H), 2.08 (s, 3 H), 2.75 (m, 1 H), 6.23 (s, 1 H), 7.08 (br s, 1 H), 7.22 (m, 2 H), 7.29 (m, 2 H), 7.42 (m, 2 H), 7.57 (m, 3 H), 8.04 (d, 2 H, ³ J _H,H = 8.0 Hz) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 9.2, 12.4, 13.3, 34.4, 56.6, 103.1, 115.6 (d, ² J _C,F = 22.0 Hz), 120.8, 124.9, 125.6, 127.0, 127.5, 129.3, 130.4 (d, ³ J _C,F = 9.0 Hz), 134.0, 140.0, 143.4, 143.8, 157.1, 163.0 (d, ¹ J _C,F = 248.0 Hz) ppm. MS (APCI) [M⁺ +1]: m/z = 429. Anal. Calcd for C₂₅H₂₁FN₄S: C, 70.07; H, 4.94; N, 13.07. Found: C, 70.12; H, 4.80; N, 12.89. 1-Isopropyl-5-methyl-4,6-diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (5ga) Yield 75%; mp 118 °C. ¹H NMR (500 MHz, DMSO-d ₆): δ = 1.35 (m, 6 H), 2.73 (s, 3 H), 4.69 (sept, 1 H, ³ J _H,H = 7.0 Hz), 5.84 (s, 1 H), 6.99 (br s, 1 H), 7.32 (t, 1 H, ³ J _H,H = 7.8 Hz), 7.38–7.45 (m, 4 H), 7.47 (br s, 5 H) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 22.5, 22.9, 47.7, 63.3, 101.8, 117.2, 126.6, 128.2, 128.3, 128.9, 129.4, 129.8, 132.8, 137.2, 142.2, 144.3, 158.0 ppm. MS (APCI) [M⁺ +1]: m/z = 331. Anal. Calcd for C₂₁H₂₂N₄: C, 76.33; H, 6.71; N, 16.96. Found: C, 76.46; H, 6.57; N, 16.83. 5-Cyclopropyl-1-isopropyl-4-(4-methoxy-phenyl)-6-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine (5hb) Yield 77%; mp 134 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 0.24 (m, 2 H), 0.71 (m, 2 H), 1.36 (d, 6 H, ³ J _H,H = 6.7 Hz), 2.55 (m, 1 H), 3.71 (s, 3 H), 4.73 (sept, 1 H, ³ J _H,H = 6.7 Hz), 8.78 (s, 1 H), 6.96 (d, 2 H, ³ J _H,H = 8.6 Hz), 7.02 (s, 1 H), 7.25 (d, 2 H, ³ J _H,H = 8.6 Hz), 7.43 (m, 5 H) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 8.9, 13.4, 22.7, 22.8, 34.1, 47.9, 55.6, 61.1, 102.8, 114.7, 127.9, 128.3, 128.4, 129.5, 132.5, 136.5, 138.1, 142.1, 157.7, 159.4 ppm. MS (APCI) [M⁺ +1]: m/z = 387. Anal. Calcd for C₂₄H₂₆N₄O: C, 74.58; H, 6.78; N, 14.50. Found: C, 74.74; H, 6.51; N, 14.34. Spiro[3,5-dimethyl-1,6-diphenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidine-4,3′-(7′,8′-dihydro-1′H,6′H-5′,9′-dioxa-1′-aza-cyclohepta[f]indene]-2′-one (8a) Yield 73%; mp 294 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.58 (s, 3 H), 2.10 (m, 2 H), 3.30 (s, 3 H), 4.08 (m, 2 H), 4.17 (m, 2 H), 6.57 (s, 1 H), 7.11 (s, 1 H), 7.22 (t, 1 H, ³ J _H,H = 8.9 Hz), 7.41 (t, 2 H, ³ J _H,H = 7.8 Hz), 7.51 (m, 5 H), 7.95 (d, 2 H, ³ J _H,H = 7.8 Hz), 10.71 (s, 1 H) ppm. MS (APCI) [M⁺ +1]: m/z = 492. Anal. Calcd for C₂₉H₂₅N₅O₃: C, 70.86; H, 5.13; N, 14.25. Found: C, 71.03; H, 5.02; N, 14.34. N-(4-Cyclohex-1-enyl-5-methyl-2-phenyl-2H-pyrazol-3-yl)-N′-methyl-benzamidine (9a) Yield 76%; mp 131 °C. ¹H NMR (400 MHz, DMSO-d ₆): δ = 1.50 (s, 4 H), 1.73 (br s, 2 H), 1.97 (m, 5 H), 2.89 (s, 3 H), 5.08 (s, 1 H), 6.98 (d, 2 H, ³ J _H,H = 6.3 Hz), 7.19 (t, 1 H, ³ J _H,H = 6.3 Hz), 7.24 (t, 2 H, ³ J _H,H = 7.5 Hz), 7.31 (m, 1 H), 7.40 (t, 2 H, ³ J _H,H = 7.8 Hz), 7.51 (br s, 1 H), 7.74 (d, 2 H, ³ J _H,H = 7.8 Hz) ppm. ¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.2, 22.2, 23.0, 25.6, 27.8, 29.0, 111.1, 121.8, 124.6, 125.1, 127.8, 128.2, 129.0, 129.9, 130.3, 135.2, 140.8, 143.2, 145.8, 160.5 ppm. MS (APCI) [M⁺ +1]: m/z = 371. Anal. Calcd for C₂₄H₂₆N₄: C, 77.80; H, 7.07; N, 15.12. Found: C, 78.02; H, 6.97; N, 14.98.