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Synlett 2010(12): 1779-1782  
DOI: 10.1055/s-0030-1258092
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of 2,5,6-Trisubstituted Benzimidazoles by Heck and Subsequent 6π-Electrocyclization-Dehydrogenation Reactions of 2,4,5-Tribromo-N-methylimidazole and 2-Aryl-4,5-dibromo-N-methylimidazoles

Serge-Mithérand Tengho Toguema, Peter Langer*a,b
a Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Fax: +49(381)4986412; e-Mail: peter.langer@uni-rostock.de;
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Publication History

Received 4 February 2010
Publication Date:
14 June 2010 (online)

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Abstract

2,5,6-Trisubstituted benzimidazoles were prepared by Heck reactions of 2,4,5-tribromo-N-methylimidazole and 2-aryl-4,5-dibromo-N-methyl-imidazoles and subsequent 6π-electro­cyclization-dehydrogenation reactions.

Key words

catalysis - palladium - Heck reaction - electrocyclization - benzimidazole

    References and Notes

  • 1a Römpp Lexikon Naturstoffe   Steglich W. Fugmann B. Lang-Fugmann S. Thieme; Stuttgart: 1997. 
    Google Scholar
  • 1b Alamgir M. Black DSC. Kumar N. Top. Heterocycl. Chem.   Springer; Berlin: 2007.  p.87-118  
    Google Scholar
  • 1c Imidazole and Benzimidazole Synthesis   Grimmett MR. Academic Press; Boston: 1997. 
    Google Scholar
  • 1d Spasov AA. Yozhitsa IN. Bugaeva LI. Anisimova VA. Pharm. Chem. J.  1999,  33:  6 
    Google Scholar
  • 1e Benzimidazoles and Cogeneric Tricyclic Compounds, In The Chemistry of Heterocyclic Compounds   Part 1, Vol. 40:  Preston PN. Wiley-VCH; Weinheim: 1981. 
    Google Scholar
  • 1f Grimmett MR. Imidazoles, In Comprehensive Heterocyclic Chemistry II   Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; Amsterdam: 1996.  p.77-220  
    Google Scholar
  • 1g Grimmett MR. Imidazole and Benzimidazole Synthesis   Academic Press; Boston: 1997. 
    Google Scholar
  • 1h Brown EG. Ring Nitrogen and Key Biomolecules   Kluwer Academic Press; Boston: 1998. 
    Google Scholar
  • 1i Gilchrist TL. Heterocyclic Chemistry   The Bath Press; Bath: 1985. 
    Google Scholar
  • 2a Kucukbay H. Durmaz R. Guven M. Gunal S. Arzneim.-Forsch.  2001,  51:  420 
    Google Scholar
  • 2b Kawato HC. Nakayama K. Inagaki H. Ohta T. Org. Lett.  2001,  3:  3451 
    Google Scholar
  • 3a Weidner-Wells MA. Ohemeng KA. Nguyen VN. Fraga-Spano S. Macielag MJ. Werblood HM. Foleno BD. Webb GC. Barrett JF. Hlasta DJ. Bioorg. Med. Chem. Lett.  2001,  11:  1545 
    Google Scholar
  • 3b Kennedy G. Viziano M. Winders JA. Cavallini P. Gevi M. Micheli F. Rodegher P. Seneci P. Zumerle A. Bioorg. Med. Chem. Lett.  2000,  10:  1751 
    Google Scholar
  • 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 
    CrossrefGoogle Scholar
  • 5a Lopez-Rodriguez ML. Benhamu B. Viso A. Murcia M. Pardo L. Tetrahedron  2001,  57:  6745 
    Google Scholar
  • 5b Lopez-Rodriguez ML. Benhamu B. Ayala D. Rominguera JL. Murcia M. Ramos JA. Viso A. Tetrahedron  2000,  56:  3245 
    Google Scholar
  • 6 Chackalamannil S. Doller D. Eagen K. Czamiecki M. Ahn HS. Foster CJ. Boykow G. Bioorg. Med. Chem. Lett.  2001,  11:  2851 
    CrossrefGoogle Scholar
  • For reviews of cross-coupling reactions of polyhalogenated heterocycles, see:
  • 7a Schröter S. Stock C. Bach T. Tetrahedron  2005,  61:  2245 
    Google Scholar
  • 7b Schnürch M. Flasik R. Khan AF. Spina M. Mihovilovic MD. Stanetty P. Eur. J. Org. Chem.  2006,  3283 
    Google Scholar
  • 8a Dang TT. Dang TT. Ahmad R. Reinke H. Langer P. Tetrahedron Lett.  2008,  49:  1698 
    Google Scholar
  • 8b Dang TT. Villinger A. Langer P. Adv. Synth. Catal.  2008,  350:  2109 
    Google Scholar
  • 8c Hussain M. Nguyen TH. Langer P. Tetrahedron Lett.  2009,  50:  3929 
    Google Scholar
  • 8d Tengho Toguem S.-M. Hussain M. Malik I. Villinger A. Langer P. Tetrahedron Lett.  2009,  50:  4962 
    Google Scholar
  • 8e Hussain M. Malik I. Langer P. Synlett  2009,  2691 
    Google Scholar
  • 8f Hussain M. Zinad DS. Salman GA. Sharif M. Villinger A. Langer P. Synlett  2010,  276 
    Google Scholar
  • 8g Dang TT. Dang TT. Rasool N. Villinger A. Langer P. Adv. Synth. Catal.  2009,  351:  1595 
    Google Scholar
  • 9a Kawasaki I. Yamashita M. Ohta S. Chem. Pharm. Bull.  1996,  44:  1831 
    Google Scholar
  • 9b Kawasaki I. Yamashita M. Ohta S. J. Chem. Soc., Chem. Commun.  1994,  2085 
    Google Scholar
  • 9c Revesz L. Bonne F. Makavou P. Tetrahedron Lett.  1998,  39:  5171 
    Google Scholar
  • 9d Revesz L. Di Padova FE. Buhl T. Feifel R. Gram H. Hiestand P. Manning U. Wolf R. Zimmerlin AG. Bioorg. Med. Chem. Lett.  2002,  12:  2109 
    Google Scholar
  • 9e Kawasaki I. Katsuma H. Nakayama Y. Yamashita M. Ohta S. Heterocycles  1998,  48:  1887 
    Google Scholar
  • 9f Wang D. Haseltine J. J. Heterocycl. Chem.  1994,  31:  1637 
    Google Scholar
  • For previous syntheses of benzimidazoles containing ester groups located at carbon atoms C-5 and C-6, see:
  • 10a Cummings CG. Ross NT. Katt WP. Hamilton AD. Org. Lett.  2009,  11:  25 
    Google Scholar
  • 10b Kalindjian SB. Dunstone DJ. Low CMR. Pether MJ. Roberts SP. Tozer MJ. Watt GF. Shankley NP. J. Med. Chem.  2001,  44:  1125 
    Google Scholar
  • 10c Neochoritis C. Livadiotou D. Stephanidou-Stephanatou J. Tsoleridis CA. Tetrahedron Lett.  2007,  48:  2275 
    Google Scholar
  • For reviews of domino reactions, see:
  • 11a Tietze LF. Beifuss U. Angew. Chem., Int. Ed. Engl.  1993,  32:  131 ; Angew. Chem. 1993, 105, 137
    Google Scholar
  • 11b Tietze LF. Chem. Rev.  1996,  96:  115 
    Google Scholar
  • 12 De Meijere and coworkers reported twofold Heck reactions of 1,2-dibromocycloalk-1-enes and related substrates and subsequent 6π-electrocyclization: Voigt K. von 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
    CrossrefGoogle Scholar
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).

14

(2 E ,2′ E ,2′′ E )-Trimethyl 3,3′,3′′-(1-Methyl-1 H -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): δ = 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): δ = 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.

15

(2 E ,2′ E )-Dibutyl 3,3′-[2-(4-Methoxyphenyl)-1-methyl-1 H -imidazole-4,5-diyl]diacrylate (8a) Starting with 7 (346 mg, 1.0 mmol), 8a was isolated as a yellow highly viscous oil (400 mg, 91%). ¹H NMR (300 MHz, CDCl3): δ = 0.87 (t, 3 H, J = 7.4 Hz, CH3), 0.90 (t, 3 H, J = 7.3 Hz, CH3), 1.31-1.41 (m, 4 H, 2 CH2), 1.55-1.65 (m, 4 H, 2 CH2), 3.64 (s, 3 H, NCH3), 3.78 (s, 3 H, OCH3), 4.12 (t, 2 H, J = 6.6 Hz, CH2O), 4.16 (t, 2 H, J = 6.7 Hz, CH2O), 6.20 (d, 1 H, J = 16.1 Hz, CH), 6.77 (d, 1 H, J = 15.3 Hz, CH), 6.92 (dd, 2 H, J = 2.0, 6.8 Hz, ArH), 7.48 (dd, 2 H, J = 2.1, 6.8 Hz, ArH), 7.62 (d, 1 H, J = 16.1 Hz, CH), 7.69 (d, 1 H, J = 15.3 Hz, CH). ¹³C NMR (75 MHz, CDCl3): δ = 13.7 (2 CH3), 19.2 (2 CH2), 30.7, 30.8 (CH2), 33.9 (NCH3), 55.4 (OCH3), 64.2, 64.8 (CH2O), 114.2 (2 CH), 119.1, 119.4 (CH), 121.6 (C), 129.1 (CH), 130.0 (C), 130.7 (2 CH), 133.5 (CH), 139.7, 152.1, 160.8 (C), 166.7, 167.5 (CO). IR (KBr): 2957, 2933, 2871 (w), 1694 (s), 1622, 1612 (m), 1578, 1531 (w), 1456, 1443 (m), 1387, 1338 (w), 1278 (m), 1249, 1158 (s), 1114, 1065, 1024, 965, 835 (m), 815, 793 (w), 741 (m), 695, 638, 620, 536 (w) cm-¹. GC-MS (EI, 70 eV): m/z (%) = 440(30) [M]+, 339(25), 338(20), 284(22), 283(100), 281(12), 266(14), 265(71), 240(18), 239(96), 237(17), 41(11). HRMS (EI, 70 eV): m/z calcd for C25H32O5N2 [M]+: 440.23057; found: 440.22968.

16

General Procedure for the Synthesis of Benzimidazoles 5a,b,d-g, 6d-f, and 9a-d
A diphenylether solution (3 mL) of 8a-d or 4a,b,d-g was stirred at 200 ˚C for 24 h in a pressure tube. The solution was allowed to cool to 20 ˚C and Pd/C (30 mg, 10 mol%) was added. The solution was stirred at 200 ˚C for 48 h under argon atmosphere. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography (flash silica gel, heptanes-EtOAc).

17

Dibutyl 2-(4-Methoxyphenyl)-1-methyl-1 H -benzo[ d ]imidazole-5,6-dicarboxylate (9a)
Starting with 7 (346 mg, 1.0 mmol), 9a was prepared over two steps as a yellowish highly viscous oil (354 mg, 81%). ¹H NMR (300 MHz, CDCl3): δ = 0.89 (t, 6 H, J = 7.3 Hz, 2 CH3), 1.31-1.43 (m, 4 H, 2 CH2), 1.61-1.70 (m, 4 H, 2 CH2), 3.79 (s, 3 H, OCH3), 3.80 (s, 3 H, NCH3), 4.25 (t, 4 H, J = 6.7 Hz, 2 CH2O), 6.96 (dd, 2 H, J = 2.0, 6.9 Hz, ArH), 7.64 (dd, 2 H, J = 2.0, 6.5 Hz, ArH), 7.65 (s, 1 H, ArH), 8.05 (s, 1 H, ArH). ¹³C NMR (62 MHz, CDCl3): δ = 12.7 (2 CH3), 18.1, 18.2 (CH2), 29.5, 29.6 (CH2), 31.1 (NCH3), 54.4 (OCH3), 64.3, 64.6 (CH2O), 111.0 (CH), 113.3 (2 CH), 119.9 (CH), 120.5, 125.9, 126.1 (C), 129.9 (2 CH), 136.5, 143.0, 156.0, 160.3 (C), 167.1, 167.3 (CO). IR (KBr): 2957, 2932, 2872 (w), 1713 (s), 1609 (m), 1577, 1532 (w), 1478, 1463, 1438 (m), 1381, 1358 (w), 1327, 1306, 1271 (m), 1245, 1174 (s), 1099, 1059, 1024, 962, 943, 836, 782, 740 (m), 661, 638, 588, 549 (w) cm-¹. GC-MS (EI, 70 eV): m/z (%) = 438(45) [M]+, 310(19), 309(100), 308(12). HRMS (EI, 70 eV): m/z calcd for C25H30O5N2 [M]+: 438.21492; found: 438.21393.