LETTER
Synthesis of 2,5,6-Trisubstituted Benzimidazoles
1781
(9) (a) Kawasaki, I.; Yamashita, M.; Ohta, S. Chem. Pharm.
Bull. 1996, 44, 1831. (b) Kawasaki, I.;Yamashita, M.; Ohta,
S. J. Chem. Soc., Chem. Commun. 1994, 2085. (c) Revesz,
L.; Bonne, F.; Makavou, P. Tetrahedron Lett. 1998, 39,
5171. (d) Revesz, L.; Di Padova, F. E.; Buhl, T.; Feifel, R.;
Gram, H.; Hiestand, P.; Manning, U.; Wolf, R.; Zimmerlin,
A. G. Bioorg. Med. Chem. Lett. 2002, 12, 2109.
Acknowledgment
Financial support by the DAAD (scholarship for S.-M. T. T.) is gra-
tefully acknowledged.
References and Notes
(e) Kawasaki, I.; Katsuma, H.; Nakayama, Y.; Yamashita,
M.; Ohta, S. Heterocycles 1998, 48, 1887. (f) Wang, D.;
Haseltine, J. J. Heterocycl. Chem. 1994, 31, 1637.
(10) For previous syntheses of benzimidazoles containing ester
groups located at carbon atoms C-5 and C-6, see:
(a) Cummings, C. G.; Ross, N. T.; Katt, W. P.; Hamilton,
A. D. Org. Lett. 2009, 11, 25. (b) Kalindjian, S. B.;
Dunstone, D. J.; Low, C. M. R.; Pether, M. J.; Roberts, S. P.;
Tozer, M. J.; Watt, G. F.; Shankley, N. P. J. Med. Chem.
2001, 44, 1125. (c) Neochoritis, C.; Livadiotou, D.;
Stephanidou-Stephanatou, J.; Tsoleridis, C. A. Tetrahedron
Lett. 2007, 48, 2275.
(11) For reviews of domino reactions, see: (a) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131;
Angew. Chem. 1993, 105, 137. (b) Tietze, L. F. Chem. Rev.
1996, 96, 115.
(12) De Meijere and coworkers reported twofold Heck reactions
of 1,2-dibromocycloalk-1-enes and related substrates and
subsequent 6p-electrocyclization: Voigt, K.; von
(1) (a) Römpp Lexikon Naturstoffe; Steglich, W.; Fugmann, B.;
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
(b) Alamgir, M.; Black, D. S. C.; Kumar, N. Top.
Heterocycl. Chem.; Springer: Berlin, 2007, 87–118.
(c) Imidazole and Benzimidazole Synthesis; Grimmett, M.
R., Ed.; Academic Press: Boston, 1997. (d) Spasov, A. A.;
Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A. Pharm.
Chem. J. 1999, 33, 6. (e) Benzimidazoles and Cogeneric
Tricyclic Compounds, In The Chemistry of Heterocyclic
Compounds, Part 1, Vol. 40; Preston, P. N., Ed.; Wiley-
VCH: Weinheim, 1981. (f) Grimmett, M. R. Imidazoles, In
Comprehensive Heterocyclic Chemistry II, Vol. 3;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Elsevier: Amsterdam, 1996, 77–220. (g) Grimmett, M. R.
Imidazole and Benzimidazole Synthesis; Academic Press:
Boston, 1997. (h) Brown, E. G. Ring Nitrogen and Key
Biomolecules; Kluwer Academic Press: Boston, 1998.
(i) Gilchrist, T. L. Heterocyclic Chemistry; The Bath Press:
Bath, 1985.
Zezschwitz, P.; Rosauer, K.; Lansky, A.; Adams, A.; Reiser,
O.; de Meijere, A. Eur. J. Org. Chem. 1998, 1521; and
references cited therein. For examples from our group, see
ref. 8c–e.
(2) (a) Kucukbay, H.; Durmaz, R.; Guven, M.; Gunal, S.
Arzneim.-Forsch. 2001, 51, 420. (b) Kawato, H. C.;
Nakayama, K.; Inagaki, H.; Ohta, T. Org. Lett. 2001, 3,
3451.
(13) General Procedure for the Synthesis of 4a-h and 8a-d
In a pressure tube (glass bomb) a suspension of Pd(OAc)2
(12 mg, 0.05 mmol, 5 mol%) and TCHP (28.04 mg, 0.10
mmol, 10 mol%) in DMF (5 mL) was purged with Ar and
stirred at 20 °C to give a yellowish or brownish clear
solution. To the stirred solution were added 2 or 7 (1.0
mmol), Et3N (1.1 mL, 8.0 mmol) and the alkene (2.5 equiv
per bromine atom of the substrate). The reaction mixture was
stirred at 100 °C for 24 h. The solution was cooled to 20 °C,
poured into a mixture of H2O and CH2Cl2 (25 mL each), and
the organic and the aqueous layer were separated. The latter
was extracted with CH2Cl2 (3 × 25 mL). The combined
organic layers were washed with H2O (3 × 20 mL), dried
(Na2SO4), and concentrated in vacuo. The residue was
purified by chromatography (flash silica gel, heptanes–
EtOAc).
(3) (a) Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.;
Fraga-Spano, S.; Macielag, M. J.; Werblood, H. M.; Foleno,
B. D.; Webb, G. C.; Barrett, J. F.; Hlasta, D. J. Bioorg. Med.
Chem. Lett. 2001, 11, 1545. (b) Kennedy, G.; Viziano, M.;
Winders, J. A.; Cavallini, P.; Gevi, M.; Micheli, F.;
Rodegher, P.; Seneci, P.; Zumerle, A. Bioorg. Med. Chem.
Lett. 2000, 10, 1751.
(4) Navarrete-Vazquez, G.; Cedillo, R.; Hernandez-Campos,
A.; Yepez, L.; Hernandez-Luis, F.; Valdez, J.; Morales, R.;
Cortes, R.; Hernandez, M.; Castillo, R. Bioorg. Med. Chem.
Lett. 2001, 11, 187.
(5) (a) Lopez-Rodriguez, M. L.; Benhamu, B.; Viso, A.; Murcia,
M.; Pardo, L. Tetrahedron 2001, 57, 6745. (b) Lopez-
Rodriguez, M. L.; Benhamu, B.; Ayala, D.; Rominguera,
J. L.; Murcia, M.; Ramos, J. A.; Viso, A. Tetrahedron 2000,
56, 3245.
(6) Chackalamannil, S.; Doller, D.; Eagen, K.; Czamiecki, M.;
Ahn, H. S.; Foster, C. J.; Boykow, G. Bioorg. Med. Chem.
Lett. 2001, 11, 2851.
(7) For reviews of cross-coupling reactions of polyhalogenated
heterocycles, see: (a) Schröter, S.; Stock, C.; Bach, T.
Tetrahedron 2005, 61, 2245. (b) Schnürch, M.; Flasik, R.;
Khan, A. F.; Spina, M.; Mihovilovic, M. D.; Stanetty, P. Eur.
J. Org. Chem. 2006, 3283.
(8) (a) Dang, T. T.; Dang, T. T.; Ahmad, R.; Reinke, H.; Langer,
P. Tetrahedron Lett. 2008, 49, 1698. (b) Dang, T. T.;
Villinger, A.; Langer, P. Adv. Synth. Catal. 2008, 350, 2109.
(c) Hussain, M.; Nguyen, T. H.; Langer, P. Tetrahedron Lett.
2009, 50, 3929. (d) Tengho Toguem, S.-M.; Hussain, M.;
Malik, I.; Villinger, A.; Langer, P. Tetrahedron Lett. 2009,
50, 4962. (e) Hussain, M.; Malik, I.; Langer, P. Synlett 2009,
2691. (f) Hussain, M.; Zinad, D. S.; Salman, G. A.; Sharif,
M.; Villinger, A.; Langer, P. Synlett 2010, 276. (g) Dang,
T. T.; Dang, T. T.; Rasool, N.; Villinger, A.; Langer, P. Adv.
Synth. Catal. 2009, 351, 1595.
(14) (2E,2¢E,2¢¢E)-Trimethyl 3,3¢,3¢¢-(1-Methyl-1H-imidazole-
2,4,5-triyl)triacrylate (4f)
Starting with 2 (318 mg, 1.0 mmol), 4f was isolated as a
yellow highly viscous oil (254 mg, 76%). 1H NMR (250
MHz, CDCl3): d = 3.70 (s, 3 H, NCH3), 3.72, 3.75, 3.76 (s, 3
H, OCH3), 6.20 (d, 1 H, J = 16.2 Hz, CH), 6.74 (d, 1 H,
J = 15.4 Hz, CH), 6.91 (d, 1 H, J = 15.3 Hz, CH), 7.41 (d, 1
H, J = 15.3 Hz, CH), 7.53 (d, 1 H, J = 16.2 Hz, CH), 7.57 (d,
1 H, J = 15.4 Hz, CH). 13C NMR (75 MHz, CDCl3): d = 31.7
(NCH3), 51.7 (OCH3), 52.0 (2 OCH3), 120.0, 121.0, 124.1,
127.4, 128.4 (CH), 130.7 (C), 133.1 (CH), 140.3, 146.1 (C),
166.5, 166.6, 167.4 (CO). IR (KBr): 3041, 2991, 2948, 2847
(w), 1708, 1695, 1622 (s), 1519 (w), 1431, 1411, 1306 (m),
1279, 1261, 1193, 1165 (s), 1065, 1034, 1014, 984 (m), 959
(s), 931, 879, 869, 811, 748, 713, 700, 665, 611 (m) cm–1.
GC-MS (EI, 70 eV): m/z (%) = 334(74) [M]+, 303(41),
276(13), 275(82), 244(16), 243(100), 231(27), 216(12),
215(18), 199(17), 185(28), 184(10), 171(25), 157(44),
156(21). HRMS (EI, 70 eV): m/z calcd for C16H18O6N2 [M]+:
334.11594; found: 334.11621.
Synlett 2010, No. 12, 1779–1782 © Thieme Stuttgart · New York