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

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.

benzimidazoles - reductive cyclization - sodium dithionite - imidazopyridines - imidazoquinolines

References

1

Current address: Donglai Yang, SSCI, Inc., 3065 Kent Avenue, West Lafayette, IN 47906, USA. E-mail: [e-mail].

2a Spasov AA. Yozhitsa IN. Bugaeva LI. Anisimova VA. Pharm. Chem. J.  1999,  33:  232 

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.

For comprehensive reviews on the chemistry of benzimidazoles, see:

3a Wright JB. Chem. Rev.  1951,  48:  397 

3b Preston PN. Chem. Rev.  1974,  74:  279 

4 Gray DN. J. Heterocycl. Chem.  1970,  7:  947 

5 Hudkins RL. Heterocycles  1995,  41:  1045 

6a Balasubramaniyan V. Balasubramaniyan P. Patil SV. Indian J. Chem.: Sect. B: Org. Chem. Incl. Med. Chem.  1990,  29:  124 

6b Salakhov MS. Umaeva VS. Salakhova YS. Idrisova SS. Russ. J. Org. Chem.  1999,  35:  397 

7 von Niementowski S. Ber.  1897,  30:  3064 

8 Hölljes EL. Wagner EC. J. Org. Chem.  1944,  9:  31 

9 King FE. Acheson RM. J. Chem. Soc.  1949,  1396 

For palladium catalyzed intramolecular aryl amination leading to N-substituted benzimidazoles, see:

10a Brain CT. Brunton SA. Tetrahedron Lett.  2002,  43:  1893 

10b Brain CT. Steer JT. J. Org. Chem.  2003,  68:  6814 

11 Elderfield RC. Kreysa FJ. J. Am. Chem. Soc.  1948,  70:  44 

12 Weidenhagen R. Ber.  1936,  69B:  2263 

13

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

14 Beaulieu PL. Haché B. von Moos E. Synthesis  2003,  1683 

15 Cadogan JIG. Marshall R. Smith DM. Todd MJ. J. Chem. Soc. C  1970,  2441 

16 Tolari S. Cenini S. Crotti C. Gianella E. J. Mol. Catal.  1994,  87:  203 

17 Dohle W. Staubitz A. Knochel P. Chem.-Eur. J.  2003,  9:  5323 

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 

18b Sundberg RJ. Yamazaki T. J. Org. Chem.  1967,  32:  290 

18c

Ref. 17

19a Wang H. Partch RE. Li Y. J. Org. Chem.  1997,  62:  5222 

19b Kim BH. Han R. Han TH. Jun YM. Baik W. Lee BM. Heterocycles  2002,  57:  5 

19c Watanabe Y. Suzuki N. Tsuji Y. Bull. Chem. Soc. Jpn.  1982,  55:  2445 

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 

For reduction of nitro groups to hydroxylamines, see:

21a Rondestvedt CS. Johnson TA. Synthesis  1977,  850 

21b Yanada K. Yamaguchi H. Meguri H. Uchida S. J. Chem. Soc., Chem. Commun.  1986,  1655 

21c Feuer H. Bartlett RS. Vincent BF. Anderson RS. J. Org. Chem.  1965,  30:  2880 

22 Park KK. Oh CH. Joung WK. Tetrahedron Lett.  1993,  34:  7445 

23

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

24

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.

For other approaches to N-aryl benzimidazoles, see:

25a Lopez-Alvarado P. Avendano C. Menendez JC. J. Org. Chem.  1995,  60:  5678 

25b Kobayashi M. Uneyama K. J. Org. Chem.  1996,  61:  3902 

25c Katritzky AR. Yang B. Abonia R. Insuasty B. J. Chem. Res., Synop.  1996,  540 

25d Alberti A. Carloni P. Greci L. Stipa P. Andruzzi R. Marrosu G. Trazza A. J. Chem. Soc., Perkin Trans. 2  1991,  1019 

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

27a Ogretir C. Kaniskan N. Turk. J. Chem.  1992,  16:  189 

27b Alaimo RJ. Spencer CF. Sheffer JB. Storrin RJ. Hatton CJ. Kohls RE. J. Med. Chem.  1978,  21:  298 

28a Reddy APR. Veeranagaiah V. Indian J. Chem.: Sect. B: Org. Chem. Incl. Med. Chem.  1984,  23:  673 

28b Reddy APR. Veeranagaiah V. Indian J. Chem.: Sect. B  1985,  24:  372 

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 

29b

Disubstituted benzimidazoles were also formed as by-products.

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 

31

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.

32a Ridley HF. Spickett RGW. Timmis GM. J. Heterocycl. Chem.  1965,  2:  453 

32b Jonas R. Klockow M. Leus I. Prücher H. Schliep HJ. Wurziger H. Eur. J. Med. Chem.  1993,  28:  129 

33

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.

34 Ramsden CA. Rose HL. J. Chem. Soc., Perkin Trans. 1  1997,  2319 

35 Abdelhamid AO. Párkányi C. Rashid SMK. Lloyd WD. J. Heterocycl. Chem.  1988,  25:  403 

36 Jung MH. Park JM. Lee I.-YC. Ahn M. J. Heterocycl. Chem.  2003,  40:  37 

37 Servi S. S. Afr. J. Chem.  2002,  55:  119 

38 Sun Q. Gatto B. Yu C. Liu A. Liu LF. LaVoie EJ. J. Med. Chem.  1995,  38:  3638 

39 Kim JS. Sun Q. Gatto B. Yu C. Liu A. Liu LF. LaVoie EJ. Bioorg. Med. Chem.  1996,  4:  621 

40 Singh MP. Sasmal S. Lu W. Chatterjee MN. Synthesis  2000,  1380