Download PDF
Synlett 2007(2): 0336-0338  
DOI: 10.1055/s-2007-968001
LETTER
© Georg Thieme Verlag Stuttgart · New York

Convenient Syntheses of Tröger’s Base Derivatives in Ionic Liquids

Hui Wu*a,b, Pu Zhanga, Yang Shena, Fu-ren Zhanga, Yu Wana,b, Da-qing Shia,b
a Department of Chemistry, Xuzhou Normal University, Jiangsu 221116, P. R. of China
Fax: +86(516)83403164; e-Mail: wuhui72@xznu.edu.cn;
b Key Laboratory of Biotechnology on Medical Plant of Jiangsu Province, Jiangsu 221116, P. R. of China
Further Information

Publication History

Received 25 September 2006
Publication Date:
24 January 2007 (online)

    Permissions and Reprints All articles of this category

Abstract

Derivatives based on Tröger’s base’s skeleton bearing fused pyrazole or isoxazole rings were prepared in good yields by reacting amino-substituted pyrazole or isoxazole with formaldehyde or acetaldehyde in ionic liquid [bpy][BF4].

Key words

Tröger’s base - ionic liquid - aromatic amines - aldehydes

    References and Notes

  • 1 Tröger J. J. Prakt. Chem.  1887,  36:  225 
    CrossrefGoogle Scholar
  • 2a Goldberg Y. Alper H. Tetrahedron Lett.  1995,  36:  369 
    Google Scholar
  • 2b Harmata M. Kahraman M. Tetrahedron: Asymmetry  2000,  11:  2875 
    Google Scholar
  • 2c Blaser HU. Jalett HP. Lottenbach W. Studer M. J. Am. Chem. Soc.  2000,  122:  12675 
    Google Scholar
  • 2d Sigman MS. Jensen DR. Acc. Chem. Res.  2006,  39:  221 
    Google Scholar
  • 3a Wilcox CS. Cowart MD. Tetrahedron Lett.  1986,  27:  5563 
    CrossrefPubMedGoogle Scholar
  • 3b Cowart MD. Sucholeiki I. Bukowruk RR. Wilcox CS. J. Am. Chem. Soc.  1988,  110:  6204 
    CrossrefPubMedGoogle Scholar
  • 3c Adrian JC. Wilcox CS. J. Am. Chem. Soc.  1991,  113:  678 
    CrossrefPubMedGoogle Scholar
  • 3d Wilcox CS. Adrian JC. Webb TH. Zawacki FJ. J. Am. Chem. Soc.  1992,  114:  10189 
    CrossrefPubMedGoogle Scholar
  • 3e Goswami S. Ghosh K. Dasgupta S. J. Org. Chem.  2000,  65:  1907 
    CrossrefPubMedGoogle Scholar
  • 4a Baldeyrou B. Tardy C. Bailly C. Colson P. Houssier C. Charmantray F. Demeunynck M. Eur. J. Med. Chem.  2002,  37:  315 
    Google Scholar
  • 4b Johnson RA. Gorman RR. Wnuk RJ. Crittenden NJ. Aiken JW. J. Med. Chem.  1993,  36:  3202 
    Google Scholar
  • 4c Bailly C. Laine W. Demeunynck M. Lhomme J. Biochem. Biophys. Res. Commun.  2000,  273:  681 
    Google Scholar
  • 5a Johnson RA. Gorman RR. Wnuk RJ. Crittenden NJ. Aiken JW. J. Med. Chem.  1993,  36:  3202 
    CrossrefGoogle Scholar
  • 5b Tatibouët A. Demeunynck M. Andraud C. Collet A. Lhomme J. Chem. Commun.  1999,  161 
    CrossrefGoogle Scholar
  • 6a Pardo C. Sesmilo E. Gutiérrez-Puebla E. Monge A. Elguero J. Fruchier A. J. Org. Chem.  2001,  66:  1607 
    CrossrefGoogle Scholar
  • 6b Manjula A. Nagarajan M. Tetrahedron  1997,  53:  11859 
    CrossrefGoogle Scholar
  • 6c Crossley MJ. Hambley TW. Machay LG. Try AC. Walton R. J. Chem. Soc., Chem. Commun.  1995,  1077 
    CrossrefGoogle Scholar
  • 7a Cudero J. Pardo C. Ramos M. Gutierrez-Puebla E. Monge A. Elguero J. Tetrahedron  1997,  53:  2233 
    CrossrefGoogle Scholar
  • 7b Abonia R. Albornoz A. Larrahondo H. Quiroga J. Insuasty B. Insuasty H. Hormaza A. Sánchez A. Nogueras M. J. Chem. Soc., Perkin Trans. 1  2002,  1588 
    CrossrefGoogle Scholar
  • 7c Li Z. Xu XY. Peng YQ. Jiang ZX. Ding CY. Qian XH. Synthesis  2005,  1228 
    CrossrefGoogle Scholar
  • 7d Čekavičus B. Liepinsh E. Vigante B. Sobolevs A. Ozols J. Duburs G. Tetrahedron Lett.  2001,  42:  4239 
    CrossrefGoogle Scholar
  • 8a Welton T. Chem. Rev.  1999,  99:  2071 
    CrossrefGoogle Scholar
  • 8b Wasserscheid P. Keim W. Angew. Chem. Int. Ed.  2000,  39:  3772 
    CrossrefGoogle Scholar
  • 8c Dupont J. de Souza RF. Suarez PAZ. Chem. Rev.  2002,  102:  3667 
    CrossrefGoogle Scholar
  • 8d Jain N. Kumar A. Chauhan S. Chausan SMS. Tetrahedron  2005,  61:  1015 
    CrossrefGoogle Scholar
  • 9a Olivier-Bourbigou H. Magna L. J. Mol. Catal. A: Chem.  2002,  182:  419 
    CrossrefGoogle Scholar
  • 9b Baudequin C. Baudoux J. Levillain J. Cahard D. Gaumont AC. Plaquevent JC. Tetrahedron: Asymmetry  2003,  14:  3081 
    CrossrefGoogle Scholar
  • 14a Yashima E. Huang S. Okamoto Y. J. Chem. Soc., Chem. Commun.  1994,  1811 
    CrossrefGoogle Scholar
  • 14b Tálas E. Margitfalvi J. Machytka D. Czugler M. Tetrahedron: Asymmetry  1998,  9:  4151 
    CrossrefGoogle Scholar
  • 14c

    White crystal; mp 212-214 °C. Anal. Calcd for C23H18N2: C, 85.68; H, 5.63; N, 8.69. Found: C, 85.65; H, 5.60; N, 8.67. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 4.57 (s, 2 H), 4.79 (d, J gem = 16.8 Hz, 2 H, 8-Hendo, 16-Hendo), 5.07 (d, J gem = 16.8 Hz, 2 H, 8-Hexo, 16-Hexo), 7.38-7.75 (m, 12 H, ArH). Reported data: [14b] mp 213-215 °C. 1H NMR: δ = 4.52 (t, J = 1.1 Hz, 2 H), 4.75 (dt, J = 1.1, 16.7 Hz, 2 H), 5.02 (d, J = 16.7 Hz, 2 H), 7.34 (ddd, J = 1.3, 6.9, 8.1 Hz, 2 H), 7.35 (d, J = 8.8 Hz, 2 H), 7.43 (ddd, J = 1.4, 6.9, 8.3 Hz, 2 H), 7.64 (d, J = 8.8 Hz, 2 H), 7.65 (dd, J = 1.3, 8.3 Hz, 2 H), 7.69 (dd, J = 1.4, 8.1 Hz, 2 H).
    Crossref
10

Preparation of 2; General Procedure: Compound 1 (1 mmol) was introduced into a flask containing formaldehyde (aq 37-40%, 1 mL) and ionic liquid (1 mL). The mixture was stirred at r.t. for 5-7 h. When the reaction was finished (monitored by TLC), distilled H2O was added, the pre-cipitate was filtered and recrystallized with absolute EtOH.
2a: white crystal; mp 263-264 °C. Anal. Calcd for C23H22N6: C, 72.1; H, 5.9; N, 22.1. Found: C, 72.2; H, 5.8; N, 22.0. 1H NMR (400 MHz, DMSO-d 6, Me4Si): δ = 1.96 (s, 6 H, 5-Me, 12-Me), 3.56 (d, J gem = 15.6 Hz, 2 H, 7 Hendo, 14-Hendo), 4.26 (d, J gem = 15.6 Hz, 2 H, 7-Hexo, 14-Hexo), 4.32 (s, 2 H, 15-H), 7.28-7.97 (m, 10 H, ArH).
2b; colorless crystal; mp 280-281 °C. Anal. Calcd for C35H30N6O2: C, 74.19; H, 5.34; N, 14.83; O, 5.65. Found: C, 74.15; H, 5.35; N, 14.80; O, 5.64. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 3.81 (s, 6 H, OCH3), 3.96 (d, J gem = 15.6 Hz, 2 H, 7-Hendo, 14-Hendo), 4.45 (s, 2 H, 15-H), 4.56 (d, J gem = 15.6 Hz, 2 H, 7-Hexo, 14-Hexo), 6.89 (d, J = 8.8 Hz, 4 H, ArH), 7.29-7.52 (m, 10 H, ArH), 8.09 (d, J = 7.6 Hz, 4 H).
2c: white solid; mp 186-188 °C. Anal. Calcd for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12; O, 13.78. Found: C, 56.88; H, 5.21; N, 24.11; O, 13.75. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 2.21 (s, 3 H, 5-Me, 12-Me), 2.27 (s, 3 H, 5-Me, 12-Me), 3.45 (d, J gem = 15.6 Hz, 2 H, 7-Hendo, 14-Hendo), 3.76 (d, J gem = 15.6 Hz, 2 H, 7-Hexo, 14-Hexo), 4.77 (s, 2 H).

11

Preparation of 3; General Procedure: Compound 1 (1 mmol) was introduced into a flask containing acetaldehyde (aq 40%, 1 mL), HCl (3.3 M, 1 mL) and ionic liquid (1 mL), and the mixture was stirred at r.t. for 6-7 h. When the reaction was finished (monitored by TLC), distilled H2O was added, the precipitate was filtered and recrystallized with absolute EtOH.
3a: colorless crystal; mp 265-266 °C. Anal. Calcd for C26H28N6: C, 73.56; H, 6.65; N, 19.80. Found: C, 73.57; H, 6.65; N, 19.79. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 1.44 (d, J = 6.8 Hz, 3 H), 1.52 (d, J = 7.6 Hz, 3 H), 1.62 (d, J = 6.8 Hz, 3 H), 2.09 (s, 3 H, 5-Me, 12-Me), 2.14 (s, 3 H, 5-Me, 12-Me), 3.78 (q, J = 6.8 Hz, 1 H, 7-H or 14-H), 3.78 (q, J = 6.8 Hz, 1 H, 7-H or 14-H), 4.59 (q, J = 6.8 Hz, 1 H, 15-H), 7.28-8.04 (m, 10 H, ArH).
3b: white solid; mp >295 °C. Anal. Calcd for C38H36N6O2: C, 74.98; H, 5.96; N, 13.81; O, 5.26. Found: C, 74.95; H, 5.95; N, 13.80; O, 5.25. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 1.27 (d, J = 6.8 Hz, 3 H), 1.65 (d, J = 7.2 Hz, 6 H), 3.73 (q, J = 6.8 Hz, 1 H, 7-H or 14-H), 3.73 (q, J = 6.8 Hz, 1 H, 7-H or 14-H), 3.82 (s, 6 H, OCH3), 4.35 (q, J = 6.8 Hz, 1 H), 6.83 (d, J = 8.8 Hz, 4 H, ArH), 7.37-7.52 (m, 10 H, ArH), 7.61 (d, J = 7.6 Hz, 4 H, ArH).


3c: white solid; mp 189-191 °C. Anal. Calcd for C14H18N4O2: C, 61.30; H, 6.61; N, 20.42; O, 11.66. Found: C, 61.30; H, 6.60; N, 20.41; O, 11.64. 1H NMR (400 MHz, CDCl3, Me4Si): δ = 1.18 (d, J = 6.8 Hz, 3 H), 1.24 (d, J = 6.8 Hz, 3 H), 2.00 (s, 3 H), 2.20 (s, 3 H, 5-Me, 12-Me), 2.27 (s, 3 H, 5-Me, 12-Me), 3.36 (q, J = 7.2 Hz, 1 H), 3.86 (q, J = 6.4 Hz, 1 H), 4.78 (s, 1 H).

12

The single crystal growth was carried out in EtOH at r.t. Crystal data for 2b: Empirical formula: C35H30N6O2, colorless, crystal dimension: 0.23 × 0.16 × 0.06 mm, triclinic, space group: P1, a = 9.79(2) Å, b = 12.21(3) Å, c = 13.47(3) Å, α = 86.71(4)°, β = 84.35(4)°, γ = 67.39(4)°, V = 1480(6) Å3, M r = 566.65, Z = 2, D c = 1.271 Mg/m3, λ = 0.71073 Å, µ (Mo-Kα) = 0.082 mm-1, F(000) = 596, S = 0.996, R 1 = 0.0601, wR 2 = 0.0753. Crystallographic data for the structure of 2b reported in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-626763.

13

The single crystal growth was carried out in EtOH at r.t. Crystal data for 3a: Empirical formula: C26H28N6, colorless, crystal dimension: 0.32 × 0.19 × 0.17 mm, monoclinic, space group: P21/n, a = 10.372(3) Å, b = 13.986(3) Å, c = 15.905(4) Å, α = 90°, β = 104.893(4)°, γ = 90°, V = 2229.7(9) Å3, M r = 424.54, Z = 4, D c = 1.265 Mg/m3, λ = 0.71073 Å, µ (Mo-Kα) = 0.078 mm-1, F(000) = 904, S = 1.029, R 1 = 0.0508, wR 2 = 0.1145. Crystallographic data for the structure of 3a reported in this letter have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication no. CCDC-620792.