Convenient Syntheses of Tröger’s Base Derivatives in Ionic Liquids

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 
• 2a Goldberg Y. Alper H. Tetrahedron Lett.  1995,  36:  369 
• 2b Harmata M. Kahraman M. Tetrahedron: Asymmetry  2000,  11:  2875 
• 2c Blaser HU. Jalett HP. Lottenbach W. Studer M. J. Am. Chem. Soc.  2000,  122:  12675 
• 2d Sigman MS. Jensen DR. Acc. Chem. Res.  2006,  39:  221 
• 3a Wilcox CS. Cowart MD. Tetrahedron Lett.  1986,  27:  5563 
• 3b Cowart MD. Sucholeiki I. Bukowruk RR. Wilcox CS. J. Am. Chem. Soc.  1988,  110:  6204 
• 3c Adrian JC. Wilcox CS. J. Am. Chem. Soc.  1991,  113:  678 
• 3d Wilcox CS. Adrian JC. Webb TH. Zawacki FJ. J. Am. Chem. Soc.  1992,  114:  10189 
• 3e Goswami S. Ghosh K. Dasgupta S. J. Org. Chem.  2000,  65:  1907 
• 4a Baldeyrou B. Tardy C. Bailly C. Colson P. Houssier C. Charmantray F. Demeunynck M. Eur. J. Med. Chem.  2002,  37:  315 
• 4b Johnson RA. Gorman RR. Wnuk RJ. Crittenden NJ. Aiken JW. J. Med. Chem.  1993,  36:  3202 
• 4c Bailly C. Laine W. Demeunynck M. Lhomme J. Biochem. Biophys. Res. Commun.  2000,  273:  681 
• 5a Johnson RA. Gorman RR. Wnuk RJ. Crittenden NJ. Aiken JW. J. Med. Chem.  1993,  36:  3202 
• 5b Tatibouët A. Demeunynck M. Andraud C. Collet A. Lhomme J. Chem. Commun.  1999,  161 
• 6a Pardo C. Sesmilo E. Gutiérrez-Puebla E. Monge A. Elguero J. Fruchier A. J. Org. Chem.  2001,  66:  1607 
• 6b Manjula A. Nagarajan M. Tetrahedron  1997,  53:  11859 
• 6c Crossley MJ. Hambley TW. Machay LG. Try AC. Walton R. J. Chem. Soc., Chem. Commun.  1995,  1077 
• 7a Cudero J. Pardo C. Ramos M. Gutierrez-Puebla E. Monge A. Elguero J. Tetrahedron  1997,  53:  2233 
• 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 
• 7c Li Z. Xu XY. Peng YQ. Jiang ZX. Ding CY. Qian XH. Synthesis  2005,  1228 
• 7d Čekavičus B. Liepinsh E. Vigante B. Sobolevs A. Ozols J. Duburs G. Tetrahedron Lett.  2001,  42:  4239 
• 8a Welton T. Chem. Rev.  1999,  99:  2071 
• 8b Wasserscheid P. Keim W. Angew. Chem. Int. Ed.  2000,  39:  3772 
• 8c Dupont J. de Souza RF. Suarez PAZ. Chem. Rev.  2002,  102:  3667 
• 8d Jain N. Kumar A. Chauhan S. Chausan SMS. Tetrahedron  2005,  61:  1015 
• 9a Olivier-Bourbigou H. Magna L. J. Mol. Catal. A: Chem.  2002,  182:  419 
• 9b Baudequin C. Baudoux J. Levillain J. Cahard D. Gaumont AC. Plaquevent JC. Tetrahedron: Asymmetry  2003,  14:  3081 
• 14a Yashima E. Huang S. Okamoto Y. J. Chem. Soc., Chem. Commun.  1994,  1811 
• 14b Tálas E. Margitfalvi J. Machytka D. Czugler M. Tetrahedron: Asymmetry  1998,  9:  4151 
• 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-H_endo, 16-H_endo), 5.07 (d, J _gem = 16.8 Hz, 2 H, 8-H_exo, 16-H_exo), 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).

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 H_endo, 14-H_endo), 4.26 (d, J _gem = 15.6 Hz, 2 H, 7-H_exo, 14-H_exo), 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-H_endo, 14-H_endo), 4.45 (s, 2 H, 15-H), 4.56 (d, J _gem = 15.6 Hz, 2 H, 7-H_exo, 14-H_exo), 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-H_endo, 14-H_endo), 3.76 (d, J _gem = 15.6 Hz, 2 H, 7-H_exo, 14-H_exo), 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) ų, M _r = 566.65, Z = 2, D _c = 1.271 Mg/m³, λ = 0.71073 Å, µ (Mo-K_α) = 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) ų, M _r = 424.54, Z = 4, D _c = 1.265 Mg/m³, λ = 0.71073 Å, µ (Mo-K_α) = 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.