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Synlett 2013; 24(20): 2675-2678
DOI: 10.1055/s-0033-1340158
letter
© Georg Thieme Verlag Stuttgart · New York

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

Sergey V. Ryabukhin*
a   The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov str., Building 5, 03187, Kyiv, Ukraine   Fax: +380506424763   Email: s.v.ryabukhin@gmail.com   Email: a.shivanyuk@univ.kiev.ua
b   Department of Chemistry, Kyiv National Taras Shevchenko University, 62 Volodymyrska str., 01033, Kyiv, Ukraine
,
Dmitry S. Granat
b   Department of Chemistry, Kyiv National Taras Shevchenko University, 62 Volodymyrska str., 01033, Kyiv, Ukraine
,
Andrey S. Plaskon
b   Department of Chemistry, Kyiv National Taras Shevchenko University, 62 Volodymyrska str., 01033, Kyiv, Ukraine
,
Dmitriy M. Volochnyuk
c   Institute of Organic Chemistry, National Academy of Sciences of Ukraine, 5 Murmanska str., 02094, Kyiv, Ukraine
,
Alexander N. Shivanyuk*
a   The Institute of High Technologies, Kyiv National Taras Shevchenko University, 4 Glushkov str., Building 5, 03187, Kyiv, Ukraine   Fax: +380506424763   Email: s.v.ryabukhin@gmail.com   Email: a.shivanyuk@univ.kiev.ua
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Publication History

Received: 06 August 2013

Accepted after revision: 25 September 2013

Publication Date:
07 November 2013 (online)

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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

Supporting Information

    for this article is available online at http://www.thieme-connect.com/ejournals/toc/synlett.
  • Supporting Information
 

  • References

  • 1 Pacher P, Nivorozhkin A, Szabó C. Pharm. Rev. 2006; 58: 87
    Crossref
    • 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
      Crossref
    • 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
      Crossref
    • 4a Rashad AE, Mahmoud AE, Ali MM. Eur. J. Med. Chem. 2011; 1019
    • 4b Ibrahim DA. Eur. J. Med. Chem. 2009; 44: 2776
      Crossref
    • 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
      Crossref
    • 5c Raffa D, Maggio B, Plescia F, Cascioferro S, Raimondi MV, Plescia S, Cusimano MG. Arch. Pharm. 2009; 342: 321
      Crossref
    • 6a Higashino T, Sato S, Miyashita A, Katori T. Chem. Pharm. Bull. 1987; 35: 4803
      Crossref
    • 6b Miyashita A, Sato S, Taido N, Tanji K, Oishi E, Higashino T. Chem. Pharm. Bull. 1990; 38: 230
      Crossref
    • 7a Volochnyuk DM, Kovaleva SA, Chernega AN, Chubaruk NG, Kostyuk AN, Pinchuk AM, Tolmachev AA, Schmutzler R. Synthesis 2006; 1613
      Article in Thieme Connect
    • 7b Ryabukhin SV, Granat DS. Plaskon A. S, Shivanyuk AN, Tolmachev AA, Volovenko YM. ACS Comb. Sci. 2012; 14: 465
      Crossref
    • 8a Volochnyuk DM, Ryabukhin SV, Plaskon AS, Grygorenko OO. Synthesis 2009; 3719
      Article in Thieme Connect
    • 8b Ryabukhin SV, Plaskon AS, Ostapchuk EN, Volochnyuk DM, Tolmachev AA. Synthesis 2007; 417
      Article in Thieme Connect
    • 8c Ryabukhin SV, Plaskon AS, Ostapchuk EN, Volochnyuk DM, Shishkin OV, Shivanyuk AN, Tolmachev AA. Org. Lett. 2007; 9: 4215
      Crossref
    • 8d Ryabukhin SV, Plaskon AS, Bondarenko SS. Ostapchuk E. N, Grygorenko OO, Shishkin OV, Tolmachev AA. Tetrahedron Lett. 2010; 51: 4229
      Crossref
    • 8e Ryabukhin SV, Plaskon AS, Boron SY, Volochnyuk DM, Tolmachev AA. Mol. Diversity 2011; 15: 189
      Crossref

      See also:
    • 9a Ryabukhin SV, Plaskon AS, Volochnyuk DM, Pipko SE, Shivanyuk AN, Tolmachev AA. J. Comb. Chem. 2007; 9: 1073
      Crossref
    • 9b Ryabukhin SV, Naumchik VS, Plaskon AS, Grygorenko OO, Tolmachev AA. J. Org. Chem. 2011; 76: 5774
      CrossrefPubMed
  • 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, 3JH,H = 6.4 Hz), 7.19 (t, 1 H, 3JH,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, 3JH ,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.