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].

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 

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.

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).