Parallel synthesis of amino bis-benzimidazoles by
multistep microwave irradiation
Chen-Hao Wu and Chung-Ming Sun
*Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan
Received 19 January 2006; revised 6 February 2006; accepted 6 February 2006 Available online 21 February 2006
Abstract—A multistep liquid phase synthesis of specifically functionalized bis-benzimidazoles is presented by the application of single-mode microwave irradiation technique. The sustained solubilizing power and stability of the PEG-ester derived from the commercially available 4-fluoro-3-nitrobenzoic acid has been successfully carried through 10 steps involving ipso-SNAr reaction,
neutral reduction and acid cyclization. All the steps in this synthetic sequence were assisted by microwave (MW) irradiation. The polymer support was cleaved to release the final head to tail bisbenzimidazoles in an efficient process.
Ó 2006 Elsevier Ltd. All rights reserved.
There has been an unlimited expansion of molecular diversity in synthetic organic compounds by the applica-tion of combinatorial methodology.1 Combinatorial
organic synthesis on polymer support integrated with microwave technology has emerged as a powerful tech-nique to generate a large number of aromatic and hetero-cyclic compounds with a variety of structural features having a high potential to act as lead molecules in drug discovery.2 Introduction of a soluble polymer support
in this field has resulted in functionalized polymer– organic conjugates, possessing a wide range of solubiliz-ing power, which leave the reactivity of the molecules unaltered, thereby facilitating the usual functional group interconversions (FGI) in a multistep organic synthesis and remaining stable to the surrounding molecular events.3 This has given rise to novel protocols for the
generation of molecular libraries of pharmacologically
active structural motifs viz. peptides, sulfonamides, azetidinones, tetrahydropyrimidines, triazoles and tetra-hydro b-carbolines.4–9 This technique still retains the
classical organic analytical methods such as TLC, IR and NMR to monitor reaction progress without cleavage of support.
The chemotherapeutic potential of head to tail bis-benz-imidazoles 4 (Fig. 1) was realized in early 1980’s when enviroxime 1 and enviradene 2 underwent clinical trials for their anti-rhinovirus activity.10 Renewed
interest of structure–activity relationship (SAR) studies in their acetylinic analogues11 and
1-benzyl-5,6-di-chloro-1H-benzo[d]imidazol-2-amine 312 has been
recognized as a potent inhibitor of viral RNA syn-thesis. Mechanistic studies on transcriptional induction of cytochrome P450 1A1 in rat cells has shown that
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.tetlet.2006.02.015
* Corresponding author. Tel.: +886 3 5131511; fax: +886 3 5736007; e-mail:[email protected]
N N NH2 Cl Cl N N NH2 N OH S O CH3 O N N NH2 S O O H3C
Enviroxime 1 Enviradene 2 viral RNA synthesisinhibitor 3
N N R2 N N NH2 R1 R3 Bis-benzimidazoles 4 Figure 1. Biologically active amino benzimidazoles.
2-amino-benzimidazole favoured the induction, thereby revealing the importance of a nucleophilic amino group at C-2 in benzimidazole.13 The generation of 2-amino
group in the bio-transformation of the broad spectrum anthelmintic drug mebendazole14 has further
strength-ened the need for the synthesis of benzimidazole mole-cular libraries with amino group at C-2 position.15
Bis-benzimidazoles are an established class of small mole-cules having an unusual property of selectively recogniz-ing the minor groove of DNA,16–19 which makes
them potential candidates for the synthetic regulation of gene expression. This site directed specificity has been linked to their promising DNA-topoisomerase I inhibit-ing20–24 and anti-tumour properties.25,26 Recently new
insights have been found in sequential binding of bis-benzimidazoles by incorporating an amidine moiety.27
Therefore rapid synthesis of structurally diverse bis-benzimidazoles28is of vital importance to have a better
understanding of structure–activity relationship. This is the first report on bis-benzimidazoles with a nucleophilic amino group at C-2 which can function as a masked
amidine, thereby retaining the configurational flexibility for the selective recognition of DNA.27
Synthesis of the target molecules (Scheme 1) was achieved by the initial formation of the PEG ester con-jugate with 4-fluoro-3-nitrobenzoic acid and SNAr
reac-tion of primary amines followed by reducreac-tion leading to the PEG bound anilines 5.6 To construct the second
benzimidazole ring, coupling of the polymer immobi-lized o-phenylenediamine 5 with 4-fluoro-3-nitrobenzoic acid again was achieved by using DCC/DMAP activa-tion in 20 min under microwave irradiaactiva-tion with higher yields of benzamides 6. Regioselectivity in this step lies in the sterically less congested primary amino group compared to the secondary amino group, the nucleophi-licity of which is reduced by the electron withdrawing ester group in the para position.
The transformation of benzamides 6 to the mono-benz-imidazole conjugates 9, with the introduction of the second point of diversity was achieved by two pathways. In the first path various aliphatic and benzyl amines
NH2 N H O O R1 NH N H O O R1 O F NO2 5 NH N H O O R1 O H N NO2 6 O O N N NO2 NH R1 8 O O N N NH2 N R1 O O N N R1 N N NH2 R2 10 PEG PEG PEG (a) PEG PEG (e) PEG (f) O O N N R1 N N NH2 R2 H3C 9 O O N N NO2 F R1 PEG 7 (b) 11 12 R2 (b) (c) (c) (d) H R2 R2
Scheme 1. Reagents and conditions: (a) 4-fluoro-3-nitrobenzoic acid, DCC/cat. DMAP, CH2Cl2, MW (300 W), 20 min; (b) TFA, CHCl3, MW
(300 W), 15 min; (c) R2NH2, CH2Cl2, MW (300 W), 10 min; (d) Zn/NH4Cl, CH3OH, MW (300 W), 30 min; (e) CNBr, CH2Cl2, MW (300 W),
20 min; (f) CH3ONa/CH3OH, MW (300 W), 10 min.
were reacted to obtain the polymer bound intermediates 8. The construction of the first benzimidazole ring was visualized in terms of an intramolecular N–C bond formation followed by dehydration. This ring closure was brought about by using trifluoroacetic acid (TFA) and chloroform under MW heating for 15 min, leading to the 2-aryl benzimidazole conjugates 9, which required 48 h in classical refluxing conditions. This was also arrived by the reverse sequence of reactions, that is, by the initial cyclization to obtain the 2-o-fluoronitro benzimidazoles 7 and then the SNAr reaction with
primary amines.
Reduction of the nitro group in mono-benzimidazole 9 was accomplished under MW conditions to obtain diamines 10. The amino group at C-2 was generated by the [4+1] approach with cyanogen bromide under microwave irradiation for 20 min to obtain the target compounds 11 on the support. The microwave induced cleavage of the polymer support achieved in methanolic sodium methoxide to obtain the final 2-amino bis-benz-imidazoles 12 in good yields (Table 1).
All the steps in this synthetic sequence have been accom-plished under focused microwave irradiation resulting in reduced reaction times and enhanced yields.29 It should
be noted that polymer-supported intermediates and polymer itself are stable during the MW irradiation. In conclusion, it is a rare sequence of reactions in which each step is powered by microwave irradiation in addi-tion to the chemical methods leading to the synthesis of flexible bis-benzimidazoles functionalized for poten-tial DNA minor groove recognition study.
Acknowledgements
The generous financial support from the National Science Council of Taiwan is gratefully acknowledged.
References and notes
1. (a) Dolle, R. E. Mol. Divers. 1996, 2, 223–236; (b) Dolle, R. E.; Nelson, K. H. J. Comb. Chem. 1999, 1, 235–282; (c)
Table 1. Novel head to tail bis-benzimidazoles 12 synthesized by multistep microwave irradiation on the support Compound R1–NH2 R2–NH2 Mass (FAB
+ ) Isolated yield (%) 12a NH2 NH2 454 84 12b NH2 NH2 406 81 12c NH2 NH2 440 78 12d NH2 NH2 432 82 12e NH2 NH2 446 82 12f NH2 NH2 480 82 12g NH2 NH2 O H3C 510 78 12h NH2 NH2 494 77 12i NH2 NH2 454 81 12j NH2 NH2 460 86 12k NH2 NH2 466 80 12l O NH 2 NH 2 384 85
Dolle, R. E. J. Comb. Chem. 2000, 2, 383–433; (d) Dolle, R. E. J. Comb. Chem. 2001, 3, 477–517; (e) Dolle, R. E. J. Comb. Chem. 2003, 5, 693–753; (f) Dolle, R. E. J. Comb. Chem. 2004, 5, 623–679.
2. Microwave-assisted combinatorial synthesis: (a) Lew, A.; Krutzik, P. O.; Hart, M. E.; Chamberlin, A. R. J. Comb. Chem. 2002, 4, 95–105; (b) Al-Obeidi, F.; Austin, R. E.; Okonya, J. F.; Bond, D. R. S. Mini Rev. Med. Chem. 2003, 3, 459–470; (c) Blackwell, H. E. Org. Biomol. Chem. 2003, 1, 1251–1255; (d) Swamy, K. M. K.; Yeh, W. B.; Lin, M. J.; Sun, C. M. Current Medicinal Chemistry 2003, 10, 2403–2423; (e) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250–6284.
3. Gravert, D. J.; Janda, K. D. Chem. Rev. 1997, 97, 489– 509.
4. (a) Sun, C. M. Soluble Polymer-Supported Synthesis of Heterocyclic Libraries. In Combinatorial Chemistry Meth-ods and Protocols, MethMeth-ods in Molecular Biology Series; Bellavance, L., Ed.; The Humana Press: New Jersey, 2002; Chapter 10, pp 345–371; (b) Lee, M. J.; Sun, C. M. Chin. Pharm. J. 2003, 55, 405–452.
5. Shey, J. Y.; Sun, C. M. Bioorg. Med. Chem. Lett. 1999, 9, 519–522.
6. Yeh, C. M.; Tung, C. L.; Sun, C. M. J. Comb. Chem. 2000, 2, 341–348.
7. Yeh, W. B.; Lin, M. J.; Lee, M. J.; Sun, C. M. Mol. Divers. 2003, 7, 185–198.
8. Yeh, W. B.; Lin, M. J.; Sun, C. M. Tetrahedron Lett. 2003, 44, 4923–4926.
9. Chung, W. J.; Yeh, W. B.; Sun, C. M. Synlett 2003, 11, 1688–1692.
10. Wikel, J. H.; Paget, C. J.; Delong, D. C.; Nelson, J. D.; Wu, C. Y. E.; Paschal, J. W.; Dinner, A.; Templeton, R. J.; Chaney, M. O.; Jones, M. D. J. Med. Chem. 1980, 23, 368–379.
11. Victor, F.; Brown, T. J.; Campanale, K.; Heinz, B. A.; Stripley, L. A.; Su, K. S.; Tang, J.; Vance, L. M.; Spitzer, W. A. J. Med. Chem. 1997, 40, 1511–1518.
12. Porcari, A. R.; Devivar, R. V.; Kucera, L. S.; Drach, J. C.; Townsend, L. B. J. Med. Chem. 1998, 41, 1252–1262. 13. Backlund, M.; Weidolf, L.; Sundberg, M. I. Eur. J.
Biochem. 1999, 261, 66–71.
14. Lee, J.; Doucette, A.; Wilson, N. S.; Lord, J. Tetrahedron Lett. 2001, 42, 2635–2638.
15. Iosifidou, E. G.; Haagasma, N.; Olling, M.; Boon, J. H.; Tanck, M. W. T. Drug. Metab. Disp. 1997, 25, 317– 320.
16. Alexandra, J.; Sun, X. W.; Eric, J.; Christian, B.; John, M.; Stephen, N. Biochemistry 2003, 42, 5984–5992. 17. Woynarowski, J. M.; McHugh, M.; Sigmund, R. D.;
Beerman, T. A. Mol. Pharmacol. 1988, 35, 177–182. 18. Minehan, T. G.; Gottwald, K.; Dervan, P. B. Helv. Chim.
Acta 2000, 83, 2197–2213.
19. Ji, Y. H.; Bur, D.; Hasler, W.; Schimitt, V. R.; Dorn, A.; Bailly, C.; Waring, M. J.; Hochstrasser, R.; Leupin, W. L. Bioorg. Med. Chem. 2001, 9, 2905–2919.
20. Goldman, G. H.; Yu, C.; Sanders, M. M.; LaVoie, E. J. Biochemistry 1997, 36, 6488–6494.
21. Kim, J. S.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J. J. Med. Chem. 1996, 39, 992–998.
22. Alper, S.; Arpaci, O. T.; Aki-Sener, E. S.; Yalcin, Y. Farmaco 2003, 58, 497–507.
23. Sun, Q.; Gatto, B.; Yu, C.; Liu, A.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. Lett. 1994, 4, 2871–2876.
24. Jin, S.; Kim, J. S.; Sim, S. P.; Liu, A.; Pilch, D. S.; Liu, L. F.; LaVoie, E. J. Bioorg. Med. Chem. Lett. 2000, 10, 719– 723.
25. Mann, J.; Baron, A.; Opoku-Boahen, Y.; Johansson, E.; Parkinson, G.; Kelland, L. R.; Neidle, S. J. Med. Chem. 2001, 44, 138–144.
26. Rastogi, K.; Chang, J. Y.; Pan, W. Y.; Chou, C. H.; Chen, T. C.; Su, T. L. J. Med. Chem. 2002, 45, 4485–4493. 27. Tanious, D.; Hamelberg, D.; Bailly, A.; Czamy, D.;
Boykin, W. D.; Wilson, W. D. J. Am. Chem. Soc. 2004, 126, 143–153.
28. Yeh, W. B.; Lin, M. J.; Sun, C. M. Comb. Chem. High T Scr. 2004, 7, 251–255.
29. All the microwave assisted polymer-supported reactions described here were performed in a 50 mL round bottom flask (attached to the reflux condenser) with CEM Discover Microwave System at a frequency of 2450 MHz (0–300 W). A detailed reaction procedure for the synthesis polymer bound intermediate 5 by domestic microwave oven can be found: Bendale, P. M.; Sun, C. M. J. Comb. Chem. 2002, 4, 359–361.
The spectral data for 12a: 1H NMR (300 MHz, CDCl3)
8.51 (s, 1H), 8.03 (d, J = 9.0 Hz, 1H), 7.73 (s, 1H), 7.2–7.5 (m, 8H), 5.22 (s, 2H), 4.23 (t, J = 7.6 Hz, 2H), 3.95 (s, 3H), 1.18–1.5 (m, 4H), 1.02 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) 168, 157, 155, 143, 142, 139, 136, 135,
129, 128, 126, 124, 123, 122, 121, 120, 117, 109, 108, 71, 52, 46, 43, 42, 32, 20, 13; mass spectrum (FAB) m/z 454 (MH+). Exact mass calcd for C
27H27N5O2: m/z 453.2159,
found 453.2153.
