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Synlett 2006(11): 1683-1686  
DOI: 10.1055/s-2006-947318
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Four-Component Synthesis of Highly Substituted Imidazole Derivatives

Maciej Gwiazda, Hans-Ulrich Reissig*
Institut für Chemie und Biochemie, Freie Universität Berlin, Takustrasse 3, 14195 Berlin, Germany
Fax: +49(30)83855367; e-Mail: hans.reissig@chemie.fu-berlin.de;
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Publication History

Received 12 April 2006
Publication Date:
04 July 2006 (online)

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Abstract

Addition of lithiated methoxyallene 1 to imines 2 provided allenyl amines 3, which upon reaction with iodine and nitriles furnished dihydroimidazole derivatives 5. Treatment of these intermediates with strong acids such as trifluoromethane sulfonic acid afforded tetrasubstituted imidazole derivatives 6 in good overall yields. Subsequent base-promoted conversion of 1-iodovinyl-substituted compounds 6 into alkynyl-substituted imidazole derivatives 7 proceeded smoothly. Products 6 and 7 are versatile intermediates for further transformations such as palladium-catalyzed coupling reactions.

Key words

methoxyallene - imine - nitrile - imidazole - alkyne

    References and Notes

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4

Typical Procedure for the Preparation of Imidazole 6a.
A solution of methoxyallene (2.80 g, 39.9 mmol) in dry THF (50 mL) under Ar was treated at -40 °C with n-BuLi (2.5 M in hexane, 14.4 mL, 35.9 mmol, deprotonation time 5-10 min). Imine 2a (5.10 g, 28.1 mmol) dissolved in dry THF (10 mL) was added within 5 min. The mixture was stirred for 2 h at -20 °C and quenched with H2O (100 mL). Warm up to r. t. was followed by extraction with Et2O (3 ¥ 100 mL), drying (Na2SO4), and concentration in vacuo, which led to crude product 3a, yield 7.00 g (99 %).
Iodine (2.54 g, 10.0 mmol) was dissolved in freshly distilled MeCN (50 mL) at 45 °C and stirred for 10 min. A solution of crude allenyl amine 3a (1.00 g, 3.98 mmol) dissolved in MeCN (10 mL) was added within 5 min and the mixture was stirred for 15 h at r. t. 10 % Na2S2O3 solution (30 mL) was added and the mixture was extracted with CH2Cl2 (3 ¥ 50 mL), dried over Na2SO4 and concentrated in vacuo furnishing crude 5a (1.95 g).
Crude 5a was dissolved in dry CH2Cl2 (4 mL) under Ar, and CF3SO3H (0.5 mL, 5.59 mmol) was added dropwise. The mixture was stirred for 1 h at r. t., treated with dilute NaHCO3 solution (30 mL), then with 10 % Na2S2O3 solution (10 mL) and extracted with CH2Cl2 (3 ¥ 50 mL). The combined organic phases were washed with H2O (1 ¥ 30 mL) and dried over Na2SO4. The crude product was purified by column chromatography (silica gel, hexane-EtOAc = 4:1) to yield 1.22 g (80 % overall yield) of 6a as yellow crystals.
Analytical Data for 4-(1-Iodoethenyl)-2-methyl-1,5-diphenylimidazole (6a).
Mp 104-105 °C. 1H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H, Me), 5.96, 6.14 (2 d, J = 1.4 Hz, each 1 H, =CH2), 7.07-7.36 (m, 10 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.1 (q, Me), 98.9 (s, =C-I), 127.8, 127.9, 128.3, 128.7, 129.4, 130.5 (6 d, Ph), 128.9 (t, =CH2), 129.1 (s, Ph), 129.8 (s, C-5), 136.5 (s, Ph), 138.0 (s, C-4), 144.4 (s, C-2) ppm. IR (KBr): 3185-2870 ( = CH, CH), 1600 (C = C) cm-1. MS (EI, 80 eV, 40 °C): m/z (%) = 386 (17) [M]+, 259 (100) [M - I]+, 218 (50), 184 (18), 77 (26) [C6H5]+, 43 (21), 28 (13). HRMS (EI, 80 eV, 40 °C): m/z calcd for C18H15IN2: 386.0280. Found: 386.0267.

5

Typical Procedure for the Preparation of Alkyne 7a.
To a solution of imidazole 6a (152 mg, 0.39 mmol) in dry THF (2 mL) was added at 0 °C dropwise a solution of potassium tert-butoxide (88 mg, 0.78 mmol) in THF (1 mL). The flask was flushed with Ar, sealed and allowed to stir at 0 °C for 1 h. The mixture was quenched with sat. aq NH4Cl solution (3 mL) and extracted with CH2Cl2 (3 ¥ 30 mL). The combined organic phases were dried over Na2SO4 and the crude product was purified by column chromatography (silica gel, hexane-EtOAc = 4:1), which provided 50 mg (50 %) of 7a as yellow crystals.
Analytical Data for 4-Ethynyl-2-methyl-1,5-diphenylimidazole (7a).
Mp 163-164 °C. 1H NMR (500 MHz, CDCl3): δ = 2.28 (s, 3 H, Me), 3.07 (s, 1 H, ºCH), 7.09-7.41 (m, 10 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.2 (q, Me), 78.3 (s, ºC), 78.4 (d, H-Cº), 127.7, 127.8, 128.2, 128.9, 129.0, 129.7 (6 d, Ph), 128.8, 137.2 (2 s, Ph), 120.3 (s, C-4), 136.6 (s, C-5), 146.0 (s, C-2) ppm. IR (KBr): 3290-2850 (C-H), 2105 (CºC), 1595 (C = C) cm-1. MS (EI, 80 eV, 40 °C): m/z (%) = 258 (71) [M]+, 216 (30), 181 (5) [M - C6H5]+, 114 (23), 91 (25), 77 (55) [C6H5]+, 51 (28), 28 (100). HRMS (EI, 80 eV, 40 °C): m/z calcd for C18H14N2: 258.1157. Found: 258.1163.

6

Typical Procedure for Sonogashira Reaction 7a → 8a.
To a solution of Et3N (0.8 mL) and DMF (0.4 mL) under Ar were added iodobenzene (0.08 mL, 0.69 mmol), alkyne 7a (150 mg, 0.58 mmol), PdCl2(PPh3)2 (18 mg, 0.025 mmol), and CuI (2 mg, 0.012 mmol). The mixture was stirred at r. t. for 16 h, then quenched with sat. aq NH4Cl solution (3 mL) and extracted with CH2Cl2 (3 ¥ 30 mL). The combined organic phases were dried over Na2SO4 and the resulting crude product was purified by column chromatography (silica gel, toluene-EtOAc = 4:1) to give 150 mg (77 %) of 8a as pale yellow crystals.
Analytical Data for 4-Phenylethynyl-2-methyl-1,5-diphenylimidazole (8a).
Mp 189-190 °C. 1H NMR (500 MHz, CDCl3): δ = 2.30 (s, 3 H, Me), 7.11-7.46 (m, 15 H, Ph) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.2 (q, Me), 84.3 (s, ºC), 90.4 (s, Ph-Cº), 127.7, 127.8, 127.9, 128.2, 128.3, 128.8, 128.9, 129.6, 131.4 (9 d, Ph), 121.4 (s, C-4), 123.7, 129.1, 136.8 (3 s, Ph), 136.4 (s, C-5), 146.3 (s, C-2) ppm. IR (KBr): 3055-2855 ( = CH, CH), 2570 (CºC), 1600 (C = C) cm-1. MS (EI, 80 eV, 40 °C): m/z (%) = 335 (31), 334 (100) [M]+, 333 (32), 292 (29), 291 (32), 189 (27), 167 (17), 145 (23), 139 (12), 126 (11), 125 (16), 123 (22), 105 (19), 91 (13), 57 (13). HRMS (EI, 80 eV, 40 °C): m/z calcd for C24H18N2: 334.1470. Found: 334.1464.