A Versatile Method for the Synthesis of Benzimidazoles from o-Nitroanilines and Aldehydes in One Step via a Reductive Cyclization

 

 Buy Article Permissions and Reprints All articles of this category

Abstract

A highly efficient and versatile method for the synthesis of benzimidazoles was achieved in one step via the Na₂S₂O₄ reduction of o-nitroanilines in the presence of aldehydes. Heating a solution of o-nitroaniline (1c) and an aldehyde in EtOH or another appropriate solvent, in the presence of aqueous or solid Na₂S₂O₄, provided facile access to a series of 2-substituted N-H benzimidazoles 5a-m containing a wide range of functional groups not always compatible with the existing synthetic methods. This methodology has also been applied to the regioselective synthesis of N-alkyl and N-aryl benzimidazoles 6a-f via the cyclization of the corresponding N-substituted nitroanilines 13a-e, respectively. In addition, the method was applied successfully to the synthesis of other imidazole containing heterocyclic ring systems such as 1H-imidazo[4,5-b]pyridines 14a,b and 1H-imidazo[4,5-f]quinoline 15.

References

• 2a Spasov AA. Yozhitsa IN. Bugaeva LI. Anisimova VA. Pharm. Chem. J.  1999,  33:  232 
  CrossrefGoogle Scholar
• 2b Preston PN. In The Chemistry of Heterocyclic Compounds, Benzimidazoles and Congeneric Tricyclic Compounds   Vol. 40, Part 2:  John Wiley & Sons; New York: 1980.  Chap. 10.
  CrossrefGoogle Scholar
• For comprehensive reviews on the chemistry of benzimidazoles, see:
• 3a Wright JB. Chem. Rev.  1951,  48:  397 
  CrossrefGoogle Scholar
• 3b Preston PN. Chem. Rev.  1974,  74:  279 
  CrossrefGoogle Scholar
• 4 Gray DN. J. Heterocycl. Chem.  1970,  7:  947 
  CrossrefGoogle Scholar
• 5 Hudkins RL. Heterocycles  1995,  41:  1045 
  CrossrefGoogle Scholar
• 6a Balasubramaniyan V. Balasubramaniyan P. Patil SV. Indian J. Chem.: Sect. B: Org. Chem. Incl. Med. Chem.  1990,  29:  124 
  Google Scholar
• 6b Salakhov MS. Umaeva VS. Salakhova YS. Idrisova SS. Russ. J. Org. Chem.  1999,  35:  397 
  Google Scholar
• 7 von Niementowski S. Ber.  1897,  30:  3064 
  Google Scholar
• 8 Hölljes EL. Wagner EC. J. Org. Chem.  1944,  9:  31 
  CrossrefGoogle Scholar
• 9 King FE. Acheson RM. J. Chem. Soc.  1949,  1396 
  Google Scholar
• For palladium catalyzed intramolecular aryl amination leading to N-substituted benzimidazoles, see:
• 10a Brain CT. Brunton SA. Tetrahedron Lett.  2002,  43:  1893 
  CrossrefPubMedGoogle Scholar
• 10b Brain CT. Steer JT. J. Org. Chem.  2003,  68:  6814 
  CrossrefPubMedGoogle Scholar
• 11 Elderfield RC. Kreysa FJ. J. Am. Chem. Soc.  1948,  70:  44 
  CrossrefGoogle Scholar
• 12 Weidenhagen R. Ber.  1936,  69B:  2263 
  Google Scholar
• 14 Beaulieu PL. Haché B. von Moos E. Synthesis  2003,  1683 
  Article in Thieme ConnectGoogle Scholar
• 15 Cadogan JIG. Marshall R. Smith DM. Todd MJ. J. Chem. Soc. C  1970,  2441 
  CrossrefGoogle Scholar
• 16 Tolari S. Cenini S. Crotti C. Gianella E. J. Mol. Catal.  1994,  87:  203 
  CrossrefGoogle Scholar
• 17 Dohle W. Staubitz A. Knochel P. Chem.-Eur. J.  2003,  9:  5323 
  Google Scholar
• Cyclization might invoke a nitrene or N-O nitrenoid intermediate resulting from the deoxygenation of the nitro group. For more information, see:
• 18a Sundberg RJ. J. Org. Chem.  1965,  30:  3604 
  CrossrefGoogle Scholar
• 18b Sundberg RJ. Yamazaki T. J. Org. Chem.  1967,  32:  290 
  CrossrefGoogle Scholar
• 18c

  Ref. 17

  CrossrefGoogle Scholar
• 19a Wang H. Partch RE. Li Y. J. Org. Chem.  1997,  62:  5222 
  CrossrefGoogle Scholar
• 19b Kim BH. Han R. Han TH. Jun YM. Baik W. Lee BM. Heterocycles  2002,  57:  5 
  CrossrefGoogle Scholar
• 19c Watanabe Y. Suzuki N. Tsuji Y. Bull. Chem. Soc. Jpn.  1982,  55:  2445 
  CrossrefGoogle Scholar
• 20 Diimines of this type were observed as side products in a recent benzimidazole synthesis. For more information, see ref. 14. 2,3-Diarylquinoxalines were obtained as by-products by cyclization of these diimines at 350 °C: Ochoa C. Rodriguez J. J. Heterocycl. Chem.  1997,  34:  1053 
  CrossrefGoogle Scholar
• For reduction of nitro groups to hydroxylamines, see:
• 21a Rondestvedt CS. Johnson TA. Synthesis  1977,  850 
  CrossrefGoogle Scholar
• 21b Yanada K. Yamaguchi H. Meguri H. Uchida S. J. Chem. Soc., Chem. Commun.  1986,  1655 
  CrossrefGoogle Scholar
• 21c Feuer H. Bartlett RS. Vincent BF. Anderson RS. J. Org. Chem.  1965,  30:  2880 
  CrossrefGoogle Scholar
• 22 Park KK. Oh CH. Joung WK. Tetrahedron Lett.  1993,  34:  7445 
  CrossrefGoogle Scholar
• For other approaches to N-aryl benzimidazoles, see:
• 25a Lopez-Alvarado P. Avendano C. Menendez JC. J. Org. Chem.  1995,  60:  5678 
  CrossrefGoogle Scholar
• 25b Kobayashi M. Uneyama K. J. Org. Chem.  1996,  61:  3902 
  CrossrefGoogle Scholar
• 25c Katritzky AR. Yang B. Abonia R. Insuasty B. J. Chem. Res., Synop.  1996,  540 
  CrossrefGoogle Scholar
• 25d Alberti A. Carloni P. Greci L. Stipa P. Andruzzi R. Marrosu G. Trazza A. J. Chem. Soc., Perkin Trans. 2  1991,  1019 
  CrossrefGoogle Scholar
• 26 For a synthesis of imidazopyridines from the ureas of 2,3-diaminopyridines, see: Senanayake CH. Fredenburgh LE. Reamer RA. Liu J. Larsen RD. Verhoeven TR. Reider PJ. Tetrahedron Lett.  1994,  35:  5775 ; and references therein for other approaches
  CrossrefGoogle Scholar
• 27a Ogretir C. Kaniskan N. Turk. J. Chem.  1992,  16:  189 
  CrossrefGoogle Scholar
• 27b Alaimo RJ. Spencer CF. Sheffer JB. Storrin RJ. Hatton CJ. Kohls RE. J. Med. Chem.  1978,  21:  298 
  CrossrefGoogle Scholar
• 28a Reddy APR. Veeranagaiah V. Indian J. Chem.: Sect. B: Org. Chem. Incl. Med. Chem.  1984,  23:  673 
  Google Scholar
• 28b Reddy APR. Veeranagaiah V. Indian J. Chem.: Sect. B  1985,  24:  372 
  Google Scholar
• 29a For a similar one-pot conversion of nitroaniline and aldehydes to benzimidazoles, in solid phase, using SnCl₂ as the reducing agent, see: Wu Z. Rea P. Wickham G. Tetrahedron Lett.  2000,  41:  9871 
  CrossrefGoogle Scholar
• 29b

  Disubstituted benzimidazoles were also formed as by-products.

  Crossref
• 30 For a chemoselective reduction of aromatic nitro groups with samarium(0) and 1,1-dioctyl-4,4′-bipyridinium dibromide, see: Yu C. Liu B. Hu L. J. Org. Chem.  2001,  66:  919 
  Google Scholar
• 32a Ridley HF. Spickett RGW. Timmis GM. J. Heterocycl. Chem.  1965,  2:  453 
  CrossrefGoogle Scholar
• 32b Jonas R. Klockow M. Leus I. Prücher H. Schliep HJ. Wurziger H. Eur. J. Med. Chem.  1993,  28:  129 
  CrossrefGoogle Scholar
• 34 Ramsden CA. Rose HL. J. Chem. Soc., Perkin Trans. 1  1997,  2319 
  CrossrefGoogle Scholar
• 35 Abdelhamid AO. Párkányi C. Rashid SMK. Lloyd WD. J. Heterocycl. Chem.  1988,  25:  403 
  CrossrefGoogle Scholar
• 36 Jung MH. Park JM. Lee I.-YC. Ahn M. J. Heterocycl. Chem.  2003,  40:  37 
  CrossrefGoogle Scholar
• 37 Servi S. S. Afr. J. Chem.  2002,  55:  119 
  Google Scholar
• 38 Sun Q. Gatto B. Yu C. Liu A. Liu LF. LaVoie EJ. J. Med. Chem.  1995,  38:  3638 
  CrossrefGoogle Scholar
• 39 Kim JS. Sun Q. Gatto B. Yu C. Liu A. Liu LF. LaVoie EJ. Bioorg. Med. Chem.  1996,  4:  621 
  CrossrefGoogle Scholar
• 40 Singh MP. Sasmal S. Lu W. Chatterjee MN. Synthesis  2000,  1380 
  Article in Thieme ConnectGoogle Scholar

Current address: Donglai Yang, SSCI, Inc., 3065 Kent Avenue, West Lafayette, IN 47906, USA. E-mail: dyang@ssci-inc.com.

For oxidative methods, see ref. 14 and references cited therein.

Old solutions were ineffective. A fresh solution of sodium dithionite was used each time as it gradually decomposes in water.

Reaction with solid sodium dithionite was found to work as well as an aqueous solution of the reagent. However, better results were obtained in some cases utilizing solid sodium dithionite rather than an aqueous solution.

We observed that the presence of the aldehyde had a dramatic effect on the reduction of the starting o-nitroaniline as shown in Scheme [3] .
Imine formation could facilitate the aryl nitro group reduction because of electronic effects. Indeed, the fact that the corresponding benzimidazole (rather than the arylene diamine) is captured in high yield as the end product could indicate that the thermodynamically formed benzimidazole might be the one driving the nitro reduction.

This method has been routinely applied in our AMAP^TM (Automated Molecular Assembly Plant) for the high throughput solution phase synthesis of benzimidazole containing structures. More details will be communicated in due course.