HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 5, 2013, pp. 1121-1126
Received, 20th March, 2013, Accepted, 2nd April, 2013, Published online, 10th April, 2013.
DOI: 10.3987/COM-13-12712

■ Facile Synthesis of Pyrido[1,2-a]benzimidazole Derivatives via Novel Tandem Reaction Involing Horner-Emmons Reaction

Wen-Jing Zhao, Ya-Fei Xie, Yan-Qing Ge,* Wei-Ren Xu, Gui-Long Zhao, and Jian-Wu Wang*

School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Nanlu, Jinan,Shandong, 250100, China

Abstract

Pyrido[1,2-a]benzimidazole derivatives were conveniently synthesized by a novel tandem reaction under mild conditions. The reaction mechanism was also proposed.

Imidazo[1,2-a]pyridines and related structures such as imidazo[1,2-a]pyrimidines, imidazo[1,2-a]quinoxaline or imidazo[1,2-a]isoquinoline have been extensively reported because of their pronounced biological activities.1-3 In contrast, the related pyrido[1,2-a]benzimidazole derivatives have not been noticed until two decades ago when several reports in the literature described their pharmaceutical applications.4-7 Furthermore, some of them also exhibit interesting photophysical and fluorescent properties.8-11 However, as a class of compounds their pharmaceutical and spectroscopic properties have remained largely unexplored perhaps as a consequence of the lack of general synthetic methods to this class of heterocycles from easily accessible precursors.
Sundberg and Ellis reported those compounds could be obtained by condensation of 1,2-benzenediamines and 2-halopyridine.12 Recently, a number of synthetic procedures for the synthesis of the compounds were reported. For example, one-step synthesis of the compounds by a multicomponent reaction was developed.13 They can also been prepared from 2-acylmethyl-1H-benzimidazoles.14 Previously, a novel tandem reaction15 found by our group has been successfully applied to the synthesize indolizines, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridines, pyrido[1,2-a]benzimidazole and [1,2,4]triazolo[1,5-a]pyridine.16-22 We recently reported several nitrogen bridgehead heterocycles with phosphonates via the tandem reaction.23 In continuation of our work on pyrido[1,2-a]benzimidazole heterocycles with phosphonates, we wish to expand this strategy as an convenient synthetic method for the synthesis of 4-substituted pyrido[1,2-a]benzimidazole phosphonates. However, when the material changed to benzimidazole ketone, we got the Horner-Emmons products not phosphonates. Herein, we reported the novel reaction and the proposed mechanism.
Benzimidazole ketones 1a-d and diethyl (3-bromoprop-1-enyl)phosphonate 2 were prepared according to a literature method (Scheme 1).20,23 The unexpected pyrido[1,2-a]benzimidazole 3a-d were obtained by the reactions of ketones 1a-d and diethyl (3-bromoprop-1-enyl)phosphonate 2 in the presence of K2CO3 in dry DMF at room temperature for 6-10 h. The experimental results are collected in Table 1.

On the basis of the structures of the products, we proposed the reaction mechanism as follows: Firstly, there would be an intermolecular SN2 reaction between 1 and phosphonate 2, through which intermediate A was formed. Afterwards, in the presence of K2CO3, intermediate A was deprotonated to form a γ-carbanion of the phosphonate. In order to be more stable, it would transform to α-carbanion of the phosphonate B. Then the final product 3 would be gained from C by intramolecular Horner-Emmons type reaction, but product 4 was not gained by the elimination of one water molecule; which may be due to the steric hindrance effect of Me or Ph group. The entire process is shown in Scheme 2.

In summary, we described a novel tandem reaction to synthesize pyrido[1,2-a]benzimidazole derivatives under mild conditions in good yields. The reaction mechanism was also proposed. The compounds are particularly interesting molecules due to their fluorescent activity, which will be presented in due course.

EXPERIMENTAL
All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd and used without further purification unless otherwise noted. Starting materials were prepared according to literatures. Thin-layer chromatography (TLC) was conducted on silica gel 60 F254 plates (Merck KGaA). 1H and 13C NMR spectra were recorded on a Bruker Avance 300 (300 MHz) spectrometer, using CDCl3 or DMSO-d6 as solvents and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an XD-4 digital micro-melting point apparatus and are uncorrected. IR spectra were recorded with an IR spectrophotometer Avtar 370 FT-IR (Termo Nicolet). The High Resolution Mass Spectrometry (HRMS) spectra were recorded on a Q-TOF6510 spectrograph (Agilent).
General procedure for the synthesis and analytical data of 3a-3d
Benzimidazole ketone 1 (6 mmol), diethyl (3-bromoprop-1-enyl)phosphonate 2 (12 mmol), potassium carbonate (1.8 g, 13.2 mmol) and DMF (40 mL) were added to a 100 mL round-bottomed flask. The reaction system was stirred for 6-10 h. Then the mixture was poured into water (200 mL) and extracted with CH2Cl2 (3 x 50 mL). Organic layers were combined and dried over anhydrous Na2SO4, then filtered. By rotary evaporation, the mixture was concentrated. After that, these crude products were depurated by using column chromatography.
4-Methylpyrido[1,2-a]benzimidazole(3a) white solid; mp 158-159 oC. 1H NMR (CDCl3, 300 MHz): δ 2.71 (s, 3H), 7.79 (t, J = 6.8 Hz, 1H), 7.22-7.26 (m, 1H), 7.36 (t, J = 7.7 Hz, 1H), 7.53 (t, J = 7.7 Hz, 1H), 7.86 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.33 (d, J = 6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 17.6, 110.4, 110.5, 120.0, 121.0, 122.8, 125.5, 127.6, 127.8, 129.2, 144.2, 149.1; IR (KBr) ν = 3055, 3019, 2957, 2918, 2852, 1633, 1605, 1492, 1465, 1356, 1338, 1266, 1220, 1164, 768, 750, 733 cm-1; HRMS (ESI): 183.0922 ([M+H]+); Calcd for C12H11N2: 183.0922.
4-Phenylpyrido[1,2-a]benzimidazole(3b) yellow solid; mp 138-140 oC. 1H NMR (CDCl3, 300 MHz): δ 6.97 (t, J = 6.9 Hz, 1H), 7.37-7.47 (m, 2H), 7.52-7.57 (m, 4H), 7.93 (d, J = 8.1 Hz, 1H), 8.01-8.07 (m, 3H), 8.47 (dd, J = 6.7 Hz, J = 1.0 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 110.9, 111.0, 120.9, 121.6, 124.5, 126.1, 128.0, 128.9, 129.1, 129.4, 131.3, 137.0, 145.1, 148.1; IR (KBr) ν = 3055, 2924, 2851, 1627, 1482, 1424, 1355, 1332, 1268, 1222, 1183, 893, 740, 694 cm-1; HRMS (ESI): 245.1092 ([M+H]+); Calcd for C17H13N2: 245.1079.
4,7,8-Trimethylpyrido[1,2-a]benzimidazole(3c) yellowish brown solid; mp 182-184 oC. 1H NMR (CDCl3, 300 MHz): δ 2.46 (s, 3H), 2.27 (s, 3H), 6.68 (s, 3H), 6.72 (t, J = 6.8 Hz, 1H), 7.16 (m, 1H), 7.61 (s, 1H), 7.74 (s, 1H), 8.24 (d, J = 6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 17.6, 20.62, 20.74, 110.1, 110.5, 119.8, 122.7, 126.9, 127.6, 127.7, 130.5, 134.9, 142.7, 148.6; IR (KBr) ν = 3041, 2979, 2916, 1617, 1493, 1378, 1355, 1318, 1220, 1157, 1131, 999, 858, 769, 748 cm-1; HRMS (ESI): 211.1238 ([M+H]+); Calcd for C14H15N2: 211.1235.
7,8-Dimethyl-4-phenylpyrido[1,2-a]benzimidazole(3d) pale yellow-green solid; mp 178-180 oC. 1H NMR (CDCl3, 300 MHz): δ 2.46 (s, 3H), 2.49 (s, 3H), 6.91 (t, J = 6.8 Hz, 1H), 7.40-7.46 (m, 1H), 7.48 (dd, J = 6.9 Hz, J = 0.9 Hz, 1H), 7.50-7.55 (m, 2H), 7.67 (s, 1H), 7.79 (s, 1H), 8.01-8.05 (m, 2H), 8.39 (dd, J = 1.0 Hz, J = 6.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 20.7, 20.8, 110.2, 110.4, 120.2, 123.9, 126.9, 127.4, 128.3, 128.6, 128.9, 130.6, 130.7, 135.0, 136.7; IR (KBr) ν = 3021, 2916, 1613, 1487, 1425, 1352, 1220, 1192, 1166, 837, 759, 697 cm-1; HRMS (ESI): 273.1379 ([M+H]+); Calcd for C19H17N2: 273.1392.

ACKNOWLEDGEMENTS
The authors gratefully acknowledge the Science and Technology Special Major Project for Significant New Drugs Formulation (2011ZX09401-009) and the Natural Science Foundation of Shandong Province (No. ZR2012BL04) for financial support of this work. We also thank Prof. Dao-Feng Sun for crystal data.

References

1. M. Leopoldo, E. Lacivita, E. Passafiume, M. Contino, N. A. Colabufo, F. Berardi, and R. Perrone, J. Med. Chem., 2007, 50, 5043. CrossRef
2. C. Enguehard-Gueiffier and A. Gueiffier, Mini-Rev. Med. Chem., 2007, 7, 888. CrossRef
3. O. Barun, H. Ila, and H. Junjappa, J. Org. Chem., 2000, 65, 1583. CrossRef
4. N. Fletcher, D. Abeln, and A. Zelewsky, J. Org. Chem., 1997, 62, 8577. CrossRef
5. K. Panda, J. R. Suresh, H. Ila, and H. Junjappa, J. Org. Chem., 2003, 68, 3498. CrossRef
6. A. B. Reitz, D. A. Gauthier, W. Ho, and B. E. Maryanoff, Tetrahedron, 2000, 56, 8809. CrossRef
7. E. Badawey and T. Kappe, Eur. J. Med. Chem., 1995, 30, 327. CrossRef
8. R. B. Bangar and T. S. Varadarajan, Spectrosc. Lett., 1993, 26, 1953. CrossRef
9. S. V. Dhamnaskar and D. W. Rangnekar, Dyes Pigments, 1988, 9, 467. CrossRef
10. R. W. Sabnis and D. W. Rangnekar, J. Heterocycl. Chem., 1990, 27, 417. CrossRef
11. D. A. Lener, P. M. Horowitz, and E. W. Evieth, J. Phys. Chem., 1977, 81, 12. CrossRef
12. R. J. Sundberg and J. E. Ellis, J. Heterocycl. Chem., 1982, 19, 585. CrossRef
13. C. G. Yan, Q. F. Wang, X. K. Song, and J. Sun, J. Org. Chem., 2009, 74, 710. CrossRef
14. I. B. Dzvinchuk, A. V. Turov, and M. O. Lozinskii, Chem. Heterocycl. Compd., 2006, 42, 929. CrossRef
15. J. W. Wang, J. Jia, D. J. Hou, H. M. Li, and J. Yin, Chin. J. Org. Chem., 2003, 23, 173.
16. Y. Q. Ge, J. Jia, Y. Li, L. Yin, and J. W. Wang, Heterocycles, 2009, 78, 197. CrossRef
17. Y. Q. Ge, J. Jia, H. Yang, G. L. Zhao, F. X. Zhan, and J. W. Wang, Heterocycles, 2009, 78, 725. CrossRef
18. J. Jia, Y. Q. Ge, X. T. Tao, and J. W. Wang, Heterocycles, 2010, 81, 185. CrossRef
19. W. M. Zhao, Y. Q. Ge, W. R. Xu, G. L. Zhao, J. Jia, and J. W. Wang, Heterocycles, 2013, 87, 869. CrossRef
20. Y. Q. Ge, J. Jia, H. Yang, X. T. Tao, and J. W. Wang, Dyes Pigments, 2011, 88, 344. CrossRef
21. Y. Q. Ge, B. Q. Hao, G. Y. Duan, and J. W. Wang, J. Lumin., 2011, 131, 1070. CrossRef
22. Y. Q. Ge, T. Wang, G. Y. Duan, L. H. Dong, X. Q. Cao, and J. W. Wang, J. Fluoresc., 2012, 22, 1531. CrossRef
23. Y. F. Xie, Y. Q. Ge, L. Feng, H. Q. Xu, S. Meng, G. L. Zhao, W. R. Xu, J. Jia, and J. W. Wang, Heterocycles, 2013, 87, 815. CrossRef