A Four-Component Synthesis of Highly Substituted Imidazole Derivatives

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.

methoxyallene - imine - nitrile - imidazole - alkyne

References and Notes

Reviews:

1a Zimmer R. Reissig H.-U. Modern Allene Chemistry   Vol. 2:  Krause N. Hashmi ASK. Wiley-VCH; Weinheim: 2004.  p.847-876  

1b Reissig H.-U. Hormuth S. Schade W. Okala Amombo MG. Watanabe T. Pulz R. Hausherr A. Zimmer R. J. Heterocycl. Chem.  2000,  37:  597 

Original publications:

1c Okala Amombo MG. Hausherr A. Reissig H.-U. Synlett  1999,  1871 

1d Flögel O. Reissig H.-U. Synlett  2004,  895 

2a Synthesis of the γ-amino acid (-)-detoxinine: Flögel O. Okala Amombo MG. Reissig H.-U. Zahn G. Brüdgam I. Hartl H. Chem. Eur. J.  2003,  9:  1405 

2b Synthesis of (-)-preussin: Hausherr A. Dissertation   Freie Universität Berlin; Berlin: 2002. 

2c Synthesis of both enantiomers of anisomycin: Kaden S. Brockmann M. Reissig H.-U. Helv. Chem. Acta  2005,  88:  1826 

2d

Synthesis of codonopsinine: Chowdhury, M. A.; Reissig, H.-U. manuscript in preparation for Synlett.

3 For a review of the Ritter reaction, see: Krimen LI. Cota DJ. Org. React.  1969,  17:  213 

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.

7a Zhu J. Bienaymé H. Multicomponent Reactions   Wiley-VCH; Weinheim: 2005. 

7b Dömling A. Chem. Rev.  2006,  106:  17 

7c Zhu J. Eur. J. Org. Chem.  2003,  1133 

7d Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 ; Angew. Chem. 2000, 112, 3300

8 For an interesting alternative approach to highly substituted imidazoles, which employs a dilithiated allene derivative and nitriles, see: Langer P. Döring M. Seyferth D. Görls H. Eur. J. Org. Chem.  2003,  1948 

9a Reviews: Grimmett MR. Comprehensive Heterocyclic Chemistry   Vol. 5:  Katritzky AR. Rees CW. Pergamon Press; London: 1984.  p.374-498  

9b Grimmet MR. Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Pergamon Press; Oxford: 1996.  p.77-220  

Selected original publications:

9c Applications in medicinal chemistry: Lambardino JG. Wiesman EH. J. Med. Chem.  1974,  17:  1182 

9d Tsujii S. Rinehart KL. J. Org. Chem.  1988,  53:  5446 

9e Sakemi S. Sun HH. J. Org. Chem.  1991,  56:  4304 

9f Lee JC. Laydon JT. McDonnel PC. Gallagher TF. Kumar S. Green D. McNulty D. Blumenthal MJ. Heys JR. Landvatter SW. Strickler JE. Mclaughlin MM. Siemens IR. Fisher SM. Livi GP. White JR. Adams JL. Young PR. Nature (London)  1994,  372:  739 

9g Boehm JC. Smietana JM. Sorenson ME. Garigipati RS. Gallagher TF. Sheldrake PL. Bradbeer J. Badger AM. Laydon JT. Lee JC. Hillegass LM. Griswold DE. Breton JJ. Chabot-Fletcher MC. Adams JL. J. Med. Chem.  1996,  39:  3929 

9h McLay IM. Halley F. Souness JE. McKenna J. Benning V. Birrell M. Burton B. Belvisi M. Collis A. Constan A. Foster M. Hele D. Jayyosi Z. Kelley M. Maslen C. Miller G. Ouldelhkim M.-L. Page K. Phipps S. Pollock K. Porter B. Ratcliffe AJ. Redford EJ. Webber S. Slater B. Thybaud V. Wilsher N. Bioorg. Med. Chem.  2001,  9:  537 

Applications in material science:

9i Synthesis of fluorescent highly substituted imidazole derivatives: Thür W. Dissertation   LMU München: 2001. 

9j Langhals H. Jaschke H. Ring U. Unold P. Angew. Chem. Int. Ed.  1999,  38:  201 ; Angew. Chem. 1999, 111, 143

Selected new synthetic methods:

9k Sisko J. J. Org. Chem.  1998,  63:  4529 

9l Fresneda PM. Molina P. Sanz MA. Synlett  2001,  218 

9m Zhong YL. Lee J. Reamer RA. Askin D. Org. Lett.  2004,  6:  929 

9n Langhammer I. Erker T. Heterocycles  2005,  65:  1975 

9o Bellina F. Cauteruccio S. Mannina L. Rossi R. Viel S. Eur. J. Org. Chem.  2006,  693 

10 We have earlier named lithiated alkoxyallenes as ‘synthetic chameleons’ due to the many options they offer for the synthesis of heterocycles and other useful compounds: Flögel O. Dash J. Brüdgam I. Hartl H. Reissig H.-U. Chem. Eur. J.  2004,  10:  4283 ; see also ref. 1a