Synthesis and characterization of new benzimidazole derivatives using 2-substituted 1,3-bis(dimethylamino)-trimethinium salts

Article abstract of DOI:10.1016/j.tetlet.2014.05.038

Novel benzimidazole derivatives are synthesized by the reaction of 2-substituted 1,3-bis(dimethylamino)-trimethinium salts with 2-aminobenzimidazole in the presence of acetic acid or triethylamine in acetonitrile as the solvent. The ultraviolet spectral b

Full text of DOI:10.1016/j.tetlet.2014.05.038

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis and characterization of new benzimidazole derivatives
using 2-substituted 1,3-bis(dimethylamino)-trimethinium salts
⇑
A. M. Mehranpour , M. Zahiri
Department of Chemistry, Faculty of Sciences, Persian Gulf University, Bushehr 75169, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel benzimidazole derivatives are synthesized by the reaction of 2-substituted 1,3-bis(dimethyl-
amino)-trimethinium salts with 2-aminobenzimidazole in the presence of acetic acid or triethylamine
in acetonitrile as the solvent. The ultraviolet spectral behavior of these compounds is examined in DMSO.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 7 March 2014
Revised 18 April 2014
Accepted 7 May 2014
Available online xxxx
Keywords:
Trimethinium salts
Benzimidazole derivatives
2-Aminobenzimidazole
Benzimidazole derivatives have attracted significant attention
as an important class of heterocyclic compounds in the field of
chemotherapy and other types of cancer treatment.1–8 Some of
these compounds have also shown antimicrobial activity.9–13
Because of their broad spectrum of biological activity,13,14 the
benzimidazoles have received significant attention in connection
with their synthesis.
Although numerous imidazole derivatives have been synthe-
sized,15–23 to the best of our knowledge, there are no reports on
the synthesis of these derivatives using 2-substituted vinamidini-
um salts as starting compounds. In this Letter, we describe the
synthesis of seven new benzimidazole derivatives using the
reaction of 2-substituted 1,3-bis(dimethylamino)-trimethinium
salts with 2-aminobenzimidazole, and evaluate their molecular
structures on the basis of their ultraviolet (UV) absorption, infrared
(IR), 1H, and 13C NMR, as well as mass spectra.
The novel benzimidazole derivatives 2–8 were synthesized
using a two-step procedure as shown in Scheme 1: (i) synthesis
of the 2-substituted vinamidinium salts 1a–g by Vilsmeier–Arnold
formylation as described in our previous work;24–27 and (ii) syn-
thesis of benzimidazole derivatives 2–8 using the reaction of the
2-substituted vinamidinium salts 1a–g with 2-aminobenzimidaz-
ole in the presence of acetic acid or triethylamine in acetonitrile as
the solvent. In acetonitrile, the reaction rate and yield of products
were higher in comparison to other solvents. Application of this
methodology gave derivatives 2–8 in high yields. The products
are well-defined, stable solids and have a long shelf-life when
stored in an anhydrous environment.
The molecular structures of all seven new derivatives 2–8 were
confirmed by elemental analysis, IR, 1H, and 13C NMR as well as
mass spectra. The UV/vis spectra of 2–8 were measured in DMSO.
In conclusion, we have established a simple protocol for the effi-
cient synthesis of benzimidazole derivatives 2–8 using 2-substi-
tuted vinamidinium salts as starting compounds. Clearly, the
advantage of this synthetic method is ready preparation of the
2-substituted vinamidinium salts from the corresponding substi-
tuted acetic acid under Vilsmeier–Haack conditions.
Typical procedure for the synthesis of benzimidazole
derivatives 2–8
Vinamidinium salt 1a–g (1.0 mmol) was dissolved in CH3CN
(5.0 mL) and treated with AcOH (1.0 mL for the synthesis of 2–4)
or Et3N (1.0 mL for the synthesis of 5–8). The resulting solution
was heated at 80 °C and 2-aminobenzimidazole (1.0 mmol) in
CH3CN (5.0 mL) was then added dropwise to the stirred mixture.
TLC was used to monitor the progress of the reactions. After
cooling in a refrigerator, the resulting precipitate was filtered,
recrystallized from EtOAc, and dried in vacuo at 80 °C.
3-Bromobenzo[4,5]imidazo[1,2-a]pyrimidine (2)
Colorless powder; yield 72%; mp > 250 °C; IR (KBr): 3046, 1689
cmꢀ1 1H NMR (DMSO-d6): d/ppm = 7.56 (t, J = 6.8 Hz, 1H), 7.66 (t,
;
J = 5.6 Hz, 1H), 7.94 (d, J = 8 Hz, 1H), 8.44 (d, J = 8 Hz,1H), 9.18 (d,
⇑
Corresponding author. Tel./fax: +98 771 4541494.
E-mail address: ammehranpour@hotmail.com (A.M. Mehranpour).
http://dx.doi.org/10.1016/j.tetlet.2014.05.038
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Mehranpour, A. M.; Zahiri, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.038

2
A. M. Mehranpour, M. Zahiri / Tetrahedron Letters xxx (2014) xxx–xxx
R
Me2N
NH2
NMe
2 ClO4
1a-g
H
N
+
-2 × Me2NH
N
Et N
in
in AcOH / CH3CN
CH CN
⁄
3
3
Br
N
N
N
N
ClO4
N
N
2
N
N
N
7
N
N
ClO4
5
N
N
N
N
3
ClO4
N
N
N
N
N
N
8
N
ClO4
6
N
N
N
4
1a
1b
1e
1f
1g
1c
1d
Br
R
N
N
N
1
1
1
N
1
1
1
Scheme 1.
J = 2 Hz, 1H), 10.26 (d, J = 2 Hz, 1H); 13C NMR (DMSO-d6):
d/ppm = 113.7, 117.5, 117.6, 120.2, 123.3, 127.7, 128.1, 143.2,
143.3, 144.8; UV: kmax (DMSO)/nm = 266; EI-MS (70 eV): m/z =
246 [M+]; Anal. calcd for C10H6BrN3: C, 48.41; H, 2.44; N, 16.94.
Found: C, 47.77; H, 2.21; N, 16.22.
5-(4-t-Butylpyridinium-1-yl)-1-(benzo[4,5]imidazo[1,
2-a]pyrimidine)perchlorate (4)
Yellow powder; yield 85%; mp 182–185 °C; IR (KBr): 3036, 1639,
1087 cmꢀ1; 1H NMR (DMSO-d6): d/ppm = 1.48 (s, 9H, CH3), 7.60 (t,
J = 7.6 Hz, 1H), 7.70 (t, J = 7.6 Hz, 1H), 8.00 (d, J = 8.4 Hz, 1H), 8.28
(d, J = 8 Hz, 1H), 8.51 (d, J = 6.8 Hz, 2H), 9.27(d, J = 2.8 Hz, 1H),
9.36 (d, J = 6.8 Hz, 2H), 10.33 (d, J = 2.8 Hz, 1H); 13C NMR (DMSO-
d6): d/ppm = 29.5, 36.8, 112.8, 120.0, 123.0, 125.0, 125.2, 127.2,
127.3, 134.6, 142.8, 144.5, 145.0, 152.2, 152.3. UV: kmax (DMSO)/
nm = 312; MS: m/z = 303 [M+ꢀClO4ꢀ]. Anal. calcd for (C19H19N4)
(ClO4): C, 75.22; H, 6.31; N, 18.47. Found: C, 74.92; H, 6.20; N, 18.11.
5-(Pyridinium-1-yl)-1-(benzo[4,5]imidazo[1,2-a]pyrimidine)
perchlorate (3)
Yellow powder; yield 69%; m.p.180 °C; IR (KBr): 3073, 1682,
;
1090 cmꢀ1 1H NMR (DMSO-d6): d/ppm = 7.23 (dd, J1 = 6 Hz,
J2 = 3.2 Hz, 1H), 7.36 (dd, J1 = 6 Hz, J2 = 3.2 Hz, 1H), 7.61 (m, 1H),
7.71 (m, 1H), 8.47 (dd, J1 = 8 Hz, J2 = 6.8 Hz, 2H), 8.91 (m, 1H),
9.30 (d, J = 3.2 Hz,1H), 9.46 (dd, J1 = 6.4 Hz, J2 = 1.2 Hz, 2H), 10.36
(d, J = 3.2 Hz, 1H); 13C NMR (DMSO-d6): d/ppm = 111.3, 112.9,
120.0, 123.0, 123.1, 127.3, 127.5, 128.2, 134.7, 145.6, 145.7, 147.5,
152.1. UV: kmax (DMSO)/nm = 312; MS: m/z = 247 [M+ꢀClO4ꢀ].
Anal. calcd for (C15H11N4)(ClO4): C, 51.96; H, 3.20; N, 16.16. Found:
C, 50.78; H, 2.91; N, 16.22.
5-(Isoquinolinium-2-yl)-2-(benzo[4,5]imidazo[1,
2-a]pyrimidine)perchlorate (5)
Brown powder; yield 63%; mp 200 °C; IR (KBr): 3072, 1640,
1085 cmꢀ1 1H NMR (DMSO-d6): d/ppm = 7.62 (t, J = 7.2 Hz, 1H),
;
7.72 (t, J = 7.2 Hz, 1H), 8.03 (d, J = 8.0 Hz, 1H), 8.23 (t, J = 7.2 Hz,
Please cite this article in press as: Mehranpour, A. M.; Zahiri, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.038

A. M. Mehranpour, M. Zahiri / Tetrahedron Letters xxx (2014) xxx–xxx
3
1H), 8.35 (d, J = 8.0 Hz, 1H), 8.44 (t, J = 7.2 Hz, 1H), 8.51(d, J = 8.0 Hz,
1H), 8.65 (d, J = 8.4 Hz, 1H), 8.90 (d, J = 6.8 Hz, 1H), 9.17 (d, J = 6.4
Hz, 1H), 9.40 (d, J = 2.8 Hz, 1H), 10.43 (d, J = 2.8 Hz, 1H), 10.53
(s, 1H); 13C NMR (DMSO-d6): d/ppm = 111.3, 112.9, 120.0, 123.0,
123.1, 125.5, 125.8, 127.1, 127.2, 127.3, 127.5, 131.2, 131.9, 135.4,
137.3, 138.3, 144.6, 151.4, 152.1. UV: kmax (DMSO)/nm = 287; MS:
m/z = 297[M+ꢀClO4ꢀ]. Anal. calcd for (C19H13N4)(ClO4): C, 57.51;
H, 3.30; N, 14.12. Found: C, 56.87; H, 3.20; N, 14.33.
J = 2.4 Hz, 1H); 13C NMR (DMSO-d6): d/ppm = 113.1, 119.1, 119.3,
119.6,121.5, 126.2, 127.1, 127.3, 127.4, 127.7, 129.0, 132.4, 132.7,
139.3, 139.7, 143.9, 155.6; UV: kmax (DMSO)/nm = 296; MS:
m/z = 321 [M+]. Anal. calcd for C22H15N3: C, 82.22; H, 4.70; N,
13.08. Found: C, 81.29; H, 4.80; N, 13.01.
Acknowledgement
Financial support of this work by the Research Council of the
Persian Gulf University is gratefully acknowledged.
5-(3,5-Dimethylpyridinum-1-yl)-1-(benzo[4,5]imidazo[1,
2-a]pyrimidine)perchlorate (6)
References and notes
Brown powder; yield 78%; mp 220–224 °C; IR (KBr): 3062, 1639,
1067 cmꢀ1; 1H NMR (DMSO-d6): d/ppm = 3.23 (s, 6H, CH3), 7.61 (t,
J = 7.2 Hz, 1H), 7.71 (t, J = 7.6 Hz, 1H), 8.01 (d, J = 8.4 Hz, 1H), 8.33 (d,
J = 8.4 Hz, 1H), 8.62 (s, 1H), 9.24 (s, 2H), 9.28 (d, J = 2.8 Hz, 1H),
10.35 (d, J = 2.8 Hz, 1H); 13C NMR (DMSO-d6): d/ppm = 18.3,
113.3, 120.5, 123.5, 125.8, 127.8, 127.9, 134.8, 138.7, 142.8, 145.0,
148.6, 149.0, 152.4. UV: kmax (DMSO)/nm = 314; MS: m/z = 275
[M+ꢀClO4ꢀ]. Anal. calcd for (C17H15N4)(ClO4): C, 54.48; H, 4.03; N,
14.95. Found: C, 54.21; H, 4.30; N, 14.80.
1. Boruah, C. R.; Skibo, E. B. J. Med. Chem. 1994, 37, 1625.
2. Srivastava, R. P.; Sharma, S. Pharmazie 1990, 45, 34.
3. Boiani, M.; González, M. Mini-Rev. Med. Chem. 2005, 5, 409.
4. El Rashedy, A. A.; Aboul-Enein, H. Y. Curr. Drug Ther. 2013, 8, 1.
5. Kubo, K.; Inoda, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh, K.; Furukawa, Y.;
Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36, 1772.
6. Kubo, K.; Kohara, Y.; Imamiya, E.; Sugiura, Y.; Inada, Y.; Furukawa, Y.;
Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36, 2182.
7. Kubo, K.; Kohara, Y.; Yoshmora, Y.; Inada, Y.; Shibouta, Y.; Furukawa, Y.; Kato,
T.; Nishikawa, K.; Naka, T. J. Med. Chem. 1993, 36, 2343.
8. Ito, K.; Kagawa, H.; Fududa, T.; Yoshino, K.; Nose, T. Arzneim.-Forsch. 1982, 31,
49.
9. Rizk, M. Egypt J. Pharm. Sci. 1993, 34, 243.
5-(Naphthalene-1-yl)-benzo[4,5]imidazo[1,2-a]pyrimidine (7)
Yellow powder; yield 57%; mp 190–194 °C; IR (KBr): 3091,
10. Ozkay, Y.; Tunali, Y.; Karaca, H.; Isikdag, I. Eur. J. Med. Chem. 2010, 45, 3293.
11. Metwally, K. A.; Abdel-Aziz, L. M.; Lashine, el-S. M.; Husseiny, M. I.; Badawy, R.
H. Bioorg. Med. Chem. 2006, 14, 8675.
12. Arjmand, F.; Mohani, B.; Ahmad, S. Eur. J. Med. Chem. 2005, 40, 1103.
13. Ansari, K. F.; Lal, C. Eur. J. Med. Chem. 2009, 44, 4028.
14. Bansal, Y.; Silakari, O. Bioorg. Med. Chem. 2012, 20, 6208.
15. El-Masry, A. H.; Fahmy, H. H.; Ali Abdelwahed, S. H. Molecules 2000, 5, 1429.
16. Bhatnagar, A.; Sharma, P. K.; Kumar, N. Int. J. Pharm. Technol. Res. 2011, 3, 268.
17. Ermolat’ev, D. S.; Svidritsky, E. P.; Babaev, E. V.; Eycken, E. V. Tetrahedron Lett.
2009, 50, 5218.
1687 cmꢀ1 1H NMR (DMSO-d6): d/ppm = 7.45 (t, J = 6.8 Hz, 1H),
;
7.60 (t, J = 6.4 Hz, 1H), 7.93 (d, J = 7.6 Hz, 1H), 7.97–8.19 (m, 7H),
8.41 (d, J = 7.6 Hz, 1H), 8.97 (d, J = 4.4 Hz, 1H), 9.78 (d, J = 4.4 Hz,
1H); 13C NMR (DMSO-d6): d/ppm = 111.3, 113.0, 119.2, 121.5,
122.5, 125.1, 125.6, 126.2, 126.4, 127.0, 127.2, 128.4, 128.5,
128.9, 131.4, 132.0, 133.4, 135.0, 143.9, 157.5. UV: kmax (DMSO)/
nm = 288; MS: m/z = 295 [M+]. Anal. calcd for C20H13N3: C, 81.34;
H, 4.44; N, 14.23. Found: C, 81.29; H, 4.70; N, 14.11.
18. Marek, A.; Kulhanek, J.; Bures, M.; Ludwig, F.; Sirivennela, B.; Smarani, S.;
Kumar, H. P.; Suthakaran, R. Molecules 2007, 12, 1183.
19. Safari, J.; Khalili, S. D.; Banitaba, S. H. J. Chem. Sci. 2010, 122, 437.
20. Kamila, S.; Ankati, H.; Biehl, E. R. Molecules 2011, 16, 5527.
21. Pal, S. K.; Kumar, S. Tetrahedron Lett. 2006, 47, 8993.
22. Ermolat’ev, D. S.; Babaev, E. V.; Eycken, E. V. Org. Lett. 2006, 8, 5781.
23. Pandey, J.; Tiwari, V. K.; Verma, S. S.; Chaturvedi, V.; Bhatnagar, S.; Sinha, A. N.;
Gaikwadb, A. N.; Tripathi, R. P. Eur. J. Med. Chem. 2009, 44, 3350.
24. Mehranpour, A. M.; Hashemnia, S.; Ameri Rad, J. J. Heterocycl. Chem. 2013, 50,
821.
5-[(1,10-Biphenyl)-4-yl]-benzo[4,5]imidazo[1,2-a]pyrimidine (8)
Yellow powder; yield 76%; mp >250 °C; IR (KBr): 3032, 1628,
;
1486 cmꢀ1 1H NMR (DMSO-d6): d/ppm = 6.91 (dd, J1 = 5.6 Hz,
25. Mehranpour, A. M.; Hashemnia, S.; Bashiri, E. Synth. Commun. 2013, 43,
1931.
26. Mehranpour, A. M.; Hashemnia, S.; Maghamifar, R. Synth. Commun. 2010, 40,
3594.
J2 = 3.2 Hz, 1H), 7.12 (dd, J1 = 5.6 Hz, J2 = 3.2 Hz, 1H), 7.42 (d, J =
7.6 Hz, 1H), 7.51 (dd, J1 = 16, J2 = 7.6 Hz, 2H), 7.59 (t, J = 7.2 Hz,
1H), 7.78 (d, J = 7.2 Hz, 2H), 7.88 (d, J = 8 Hz, 2H), 8.03 (d, J = 8 Hz,
2H), 8.47 (d, J = 8.4 Hz, 1H), 9.31 (d, J = 2.4 Hz, 1H), 9.95 (d,
27. Mehranpour, A. M.; Hashemnia, S.; Azamifar, F. Tetrahedron Lett. 2013, 54, 321.
Please cite this article in press as: Mehranpour, A. M.; Zahiri, M. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.05.038