Benzimidazoles and related heterocycles: 11. A novel acid-catalyzed rearrangement in the system 3-benzoylquinoxalin-2(1H)-one-aldehyde-ammonium acetate as a simple and efficient route to 2-(imidazol-4-yl)benzimidazoles

Article abstract of DOI:10.1007/s11172-011-0146-3

A three-component condensation of 3-benzoylquinoxalin-2(1H)-one with 4-nitrobenzaldehyde and ammonium acetate in AcOH gives 2-[2-(4-nitrophenyl)-5- phenylimidazol-4-yl]benzimidazole via a rearrangement involving the fragment C(2)-C(3)-C(O)Ph of the quinox

Full text of DOI:10.1007/s11172-011-0146-3

Russian Chemical Bulletin, International Edition, Vol. 60, No. 5, pp. 933—936, May, 2011
933
Benzimidazoles and related heterocycles
11.* A novel acidꢀcatalyzed rearrangement in the system
3ꢀbenzoylquinoxalinꢀ2(1H)ꢀone—aldehyde—ammonium acetate
as a simple and efficient route to 2ꢀ(imidazolꢀ4ꢀyl)benzimidazoles**
V. A. Mamedov, N. A. Zhukova, T. N. Beschastnova, and A. T. Gubaidullin
A. E. Arbuzov Institute of Organic and Physical Chemistry, Kazan Research Center of the Russian Academy of Sciences,
8 ul. Akad. Arbuzova, 420088 Kazan, Russian Federation.
Fax: +7 (843) 273 2253. Eꢀmail: mamedov@iopc.ru
A threeꢀcomponent condensation of 3ꢀbenzoylquinoxalinꢀ2(1H)ꢀone with 4ꢀnitrobenzalꢀ
dehyde and ammonium acetate in AcOH gives 2ꢀ[2ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylimidazolꢀ4ꢀ
yl]benzimidazole via a rearrangement involving the fragment C(2)—C(3)—C(O)Ph of the quiꢀ
noxaline system and the other two reagents, which supply the fragment —N=C(Ar)—NH— for
constructing the imidazole ring. Possible pathways of this reaction are discussed.
Key words: 3ꢀbenzoylquinoxalinꢀ2(1H)ꢀone, aromatic aldehyde, ammonium acetate, acidꢀ
catalyzed rearrangement, 2ꢀ(imidazolꢀ4ꢀyl)benzimidazole, Xꢀray diffraction analysis.
Multicomponent reactions occupy a special place in
modern organic synthesis and medicinal chemistry beꢀ
cause they are highly economical and allow designing
structurally complex and pharmacologically attractive
compounds in a "one pot" manner simultaneously using
three or more reagents.2,3 At present, multicomponent
reactions contribute greatly to the synthesis of complex
and important organic molecules from simple and accesꢀ
sible starting materials and have become a powerful tool
for the preparation of drugs.4,5 Imidazoles and benzimidꢀ
azoles are essential heterocycles found in many natural
compounds and biological systems. Compounds containꢀ
ing an imidazole or benzimidazole fragment exhibit a vaꢀ
riety of pharmacological properties and are crucial for bioꢀ
chemical processes.6 The wide use of imidazole or benzꢀ
imidazole derivatives in pharmacology is due to their
hydrogenꢀbonding ability. They can act as both donors
and acceptors and show high affinity for metals (Zn, Fe,
and Mg) present on many active protein sites.7 Various
substituted imidazoles function as p38MAP8 and BꢀRafꢀ
kinase inhibitors,9 glucagon receptors,10 plant growth regꢀ
ulators,11 therapeutic antibacterial12 and antitumor13
agents, and pesticides.14 At the same time, benzimidazole
derivatives are part of various biologically active comꢀ
pounds with antiviral, hypotensive, and antitumor activiꢀ
ties.15 Benzimidazoleꢀcontaining compounds exhibit proꢀ
nounced activity against such viruses as HIV,16 herpes
(VSVꢀ1),16,17 human cytomegalovirus (HCMV),17 and flu
virus.18 Bisbenzimidazoles are DNAꢀcrosslinking agents
with antitumor activity.19
2,4,5ꢀTrisubstituted imidazoles are mainly obtained by
threeꢀcomponent cyclocondensation of 1,2ꢀdiketone,
hydroxy ketone, or monooxime of an αꢀdicarbonyl comꢀ
pound with aldehydes and ammonium acetate. The synꢀ
thesis may involve ionic liquids,20 boiling acetic acid,21
H2SO4ꢀimpregnated silica,22 InCl3•3H2O,23 ammonium
cerium nitrate (CAN),24 NiCl2•6H2O/Al2O3,25 and microꢀ
wave radiation.26
Earlier,27—31 we have demonstrated that 3ꢀaroylꢀ and
3ꢀalkanoylquinoxalinꢀ2(1H)ꢀones serve as suppliers of
a twoꢀcarbon fragment in reactions with 1,2ꢀdiaminoꢀ
benzenes. Due to the presence of the acyl group at the
endocyclic imino fragment, these compounds behave
like heteroanalogs of αꢀdiketones yielding 3ꢀsubstituted
2ꢀ(benzimidazolꢀ2ꢀyl)quinoxalines via contraction of the
pyrazine ring.31—33
In the present work, we propose a simple and efficient
route to 2ꢀ(imidazolꢀ4ꢀyl)benzimidazoles that involves
a novel rearrangement in the system 3ꢀbenzoylquinoxaꢀ
linꢀ2(1H)ꢀone (1)—4ꢀnitrobenzaldehyde (2)—ammonium
acetate (Scheme 1).
The reaction proceeds in boiling acetic acid for 19 h to
give 2ꢀ[2ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylimidazolꢀ4ꢀyl]benzꢀ
imidazole (3). Its composition was determined from eleꢀ
mental analysis data. The structure was proved by IR and
1H NMR spectroscopy and Xꢀray diffraction.
* For Part 10, see Ref. 1.
The reaction was also successful with urea instead of
ammonium acetate (as a nitrogen supplier for constructꢀ
** Dedicated to Academician V. N. Charushin on the occasion
of his 60th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 911—914, May, 2011.
1066ꢀ5285/11/6005ꢀ933 © 2011 Springer Science+Business Media, Inc.

934
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Mamedov et al.
Scheme 1
O(40)
O(50)
O(51)
O(60)
O(41)
O(282)
O(281)
O(61)
N(22)
N(20)
N(1)
N(3)
ing the imidazole system) in boiling methanol in the presꢀ
ence of catalytic amounts of Lꢀproline (0.3 mol.%) instead
of acetic acid.
2ꢀ(Imidazolꢀ4ꢀyl)benzimidazole 3 forms monoclinic
crystals (space group P21/n) and crystallizes in the protoꢀ
nated form (Fig. 1). The crystallographically independent
part of the unit cell contains three molecules of acetic
acid, one of which being present as the acetate anion. The
crystal of compound 3 has a very peculiar system of interꢀ
molecular interactions; the distinctive features of its crysꢀ
tal packing will be discussed elsewhere.
The formation of the rearrangement product in the
reaction of 3ꢀbenzoylquinoxalinꢀ2(1H)ꢀone (1) with
4ꢀnitrobenzaldehyde (2) and ammonium acetate in AcOH
can be represented by Scheme 2. Apparently, the initial
step is the formation of spiro compound B from 3ꢀbenzoylꢀ
quinoxalinone 1 and intermediate diamine A, which is
Fig. 1. Geometry of 2ꢀ[2ꢀ(4ꢀnitrophenyl)ꢀ5ꢀphenylimidazolꢀ4ꢀ
yl]benzimidazole (3) in the crystal with partial atomic numberꢀ
ing and thermal displacement ellipsoids for the nonꢀhydrogen
atoms (p = 50%). The hydrogen atoms are represented by spheres
of arbitrary radii.
followed by an acidꢀcatalyzed in situ rearrangement inꢀ
volving (1) the opening of the pyrazine ring of the quinꢀ
oxaline system with cleavage of the N(1)—C(2) bond in
intermediate spiro compound C and (2) cyclization of imidꢀ
azole derivative D into a benzimidazole system through
a newly formed amino group and the carbamoyl C=O
group (see Scheme 2).
Scheme 2
Ar = 4ꢀO2NC6H4

Benzimidazoles and related heterocycles
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
935
Center based on the Diffraction Investigations Laboratory of the
A. E. Arbuzov Institute of Organic and Physical Chemistry (Kaꢀ
zan Research Center, Russian Academy of Sciences). The crysꢀ
It should be noted that this reaction was successfully
extended to other 3ꢀaroylquinoxalinꢀ2(1H)ꢀones and aroꢀ
matic aldehydes in the presence of ammonium acetate,
giving the corresponding 2ꢀ(imidazolꢀ4ꢀyl)benzimidazoles
in good yields. These data provide evidence for the general
character of the reaction under discussion and will be pubꢀ
lished elsewhere.
tals of compound 3, (C22H16N5O2)+•CH3CO2 •2CH3CO2H, are
–
monoclinic; at 23 °C, the unit cell parameters are a = 8.075(2) Å,
3
b = 21.991(5) Å, c = 15.788(3) Å, β = 101.076(2)°, V = 2752(1) Å ,
Z = 4, dcalc = 1.356 g cm–3, space group P21/n. The unit cell
parameters and the intensities of 30 008 reflections (Rint = 0.0353)
were collected on a Bruker Smart Apex II CCD diffractometer
(MoꢀKα radiation, graphite monochromator, λ = 0.71073 Å,
ω scan mode; –10 ≤ h ≤ 10, –28 ≤ k ≤ 28, –20 ≤ l ≤ 20,
2.63° ≤ θ ≤ 28.18°). The number of independent reflections was
6465; the number of reflections with I ≥ 2σ(I) was 3642. An
absorption correction was applied semiempirically with the
SADABS program34 (μ(Mo) = 1.01 cm–1). The structure was
solved by the direct method and refined by the leastꢀsquares
method isotropically and then anisotropically for all nonꢀhydroꢀ
gen atoms. The hydrogen atoms at the N(1), N(3), N(20), O(41),
and O(61) atoms were located from difference electronꢀdensity
maps and refined isotropically. The coordinates of the other
H atoms were calculated from stereochemical considerations
and refined using appropriate riding models. Final discrepancy
factors are R1 = 0.0421 and wR2 = 0.0934 for 3642 independent
reflections with I > 2σ(I) and R1 = 0.0907 and wR2 = 0.1131 for
all reflections; GOOF = 0.978, the number of parameters reꢀ
fined was 393. The maximum and minimum peaks in the differꢀ
ence electronꢀdensity maps are 0.130 and –0.109 e Å–3, respecꢀ
tively. Experimental data were collected and edited, and the unit
cell parameters were refined, with the APEX2 program.35 All
calculations used to solve and refine the structure were perꢀ
formed with the SHELXTL36 and WinGX programs.37 Intermoꢀ
lecular interactions were analyzed, and the molecular structures
were drawn, with the PLATON program.38 The atomic coordiꢀ
nates and thermal parameters for structure 3 have been depositꢀ
ed with the Cambridge Crystallographic Data Center (http://
www.ccdc.cam.ac.uk; CCDC No. 779 105).
Experimental
1
H NMR spectra were recorded on a BrukerꢀAVANCEꢀ400
spectrometer (400.13 MHz). Chemical shifts δ are referenced to
the residual signals of DMSOꢀd6. IR spectra were recorded on
a Vectorꢀ22 FTIR spectrometer (Bruker) in KBr pellets. Melting
points were determined on a Boetius hot stage.
2ꢀ[2ꢀ(4ꢀNitrophenyl)ꢀ5ꢀphenylimidazolꢀ4ꢀyl]benzimidazole
(3). A. A solution of benzoylquinoxalinone 1 (0.2 g, 0.8 mmol),
4ꢀnitrobenzaldehyde (2) (0.12 g, 0.8 mmol), and NH4OAc
(0.62 g, 8 mmol) in AcOH (10 mL) was refluxed for 19 h, cooled
to room temperature, and concentrated in a water aspirator vacꢀ
uum. The residue was treated with 5% aqueous NaHCO3. The
precipitate that formed was filtered off, dried in air, refluxed in
PriOH, and filtered off hot. The yield of compound 3 was 0.22 g
(73%), orange powder, m.p. 338—340 °C. Found (%): C, 69.37;
H, 4.00; N, 18.29. C22H15N5O2. Calculated (%): C, 69.28;
H, 3.96; N, 18.36. IR, ν/cm–1: 3052, 2964, 2924, 2851, 1600,
1562, 1516, 1487, 1452, 1339, 853, 688, 586. 1H NMR, δ:
7.14—7.22 (m, 2 H, H(5), H(6) of benzimidazole); 7.44 (dd, 1 H,
pꢀHPh, J ≈ 7.2 Hz, J ≈ 7.2 Hz); 7.52 (dd, 2 H, 2 mꢀHPh, J ≈ 7.2 Hz,
J ≈ 7.2 Hz); 7.53—7.61 (m, 2 H, H(4), H(7) of benzimidazole);
8.08—8.16 (m, 2 H, 2 oꢀHPh); 8.41 (d, 2 H, HAr, J = 9.2 Hz);
8.44 (d, 2 H, HAr, J = 9.2 Hz). Recrystallization of compound 3
from aqueous acetic acid gave needleꢀlike orange crystals of the
formula (C22H16N5O2)+•CH3CO2 •2CH3CO2H, m.p. >350 °C.
–
Found (%): C, 59.75; H, 4.76; N, 12.54. C22H15N5O2•3AcOH.
Calculated (%): C, 59.89; H, 4.81; N, 12.48. IR, ν/cm–1: 3193,
3154, 3110, 2929, 2853, 1700, 1630, 1602, 1572, 1517, 1343,
1273, 1106, 756, 713, 452. 1H NMR, δ: 1.91 (s, 9 H, 3 Me);
7.15—7.19 (m, 2 H, H(5), H(6) of benzimidazole); 7.42 (dd, 1 H,
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 10ꢀ03ꢀ00413ꢀa).
References
pꢀHPh, J = 7.2 Hz, J = 7.2 Hz); 7.49 (dd, 2 H, 2 mꢀHPh
,
J = 7.4 Hz, J = 7.6 Hz); 7.54—7.58 (m, 2 H, H(4), H(7) of
benzimidazole); 8.10 (br.d, 2 H, 2 oꢀHPh, J ≈ 7.4 Hz); 8.39
(d, 2 H, HAr, J = 9.0 Hz); 8.43 (d, 2 H, HAr, J = 9.0 Hz).
B. A solution of benzoylquinoxalinone 1 (0.2 g, 0.8 mmol),
4ꢀnitrobenzaldehyde (2) (0.12 g, 0.8 mmol), and urea (0.19 g,
3.2 mmol) in AcOH (10 mL) was refluxed for 19 h. Workup of
the reaction mixture was carried out as described above. The
yield of compound 3 was 0.16 g (55%). Its melting point and
spectroscopic characteristics are identical with those of the comꢀ
pound obtained according to procedure A.
C. A solution of benzoylquinoxalinone 1 (0.2 g, 0.8 mmol),
4ꢀnitrobenzaldehyde (2) (0.12 g, 0.8 mmol), NH4OAc (0.62 g,
8 mmol), and Lꢀproline (11 mol.%) in anhydrous MeOH (15 mL)
was stirred at 65 °C for 19 h. Workup of the reaction mixture was
carried out as described above. The yield of compound 3 was
0.18 g (59%). Its melting point and spectroscopic characteristics
are identical with those of the compound obtained according to
procedure A.
1. V. A. Mamedov, E. A. Khafizova, A. T. Gubaidullin, A. M.
Murtazina, D. I. Adgamova, A. I. Samigullina, I. A. Litviꢀ
nov, Izv. Akad. Nauk, Ser. Khim., 2011, 359 [Russ. Chem.
Bull., Int. Ed., 2011, 60, 368].
2. Multicomponent Reactions, Eds J. Zhu, N. Bienayme,
Wiley—VCH, Weinheim, 2005.
3. A. Dömling, Chem. Rev., 2006, 106, 17.
4. L. Weber, Drug Discov. Today, 2002, 7, 143.
5. P. A. Tempest, Curr. Opin. Drug Discov. Dev., 2005, 8, 776.
6. J. G. Lombardino, E. H. Wiseman, J. Med. Chem., 1974,
17, 1182.
7. Eur. Pat. 58 890, 1982; Chem. Abstr., 1983, 98, 53894z.
8. J. C. Lee, J. T. Laydon, P. C. McDonnell, T. F. Gallagher,
S. Kumar, D. Green, D. McNulty, M. J. Blumenthal, J. R.
Keys, S. W. L. Vatter, J. E. Strickler, M. M. McLaughlin,
I. R. Siemens, S. M. Fisher, G. P. Livi, J. R. White, J. L.
Adams, P. R. Young, Nature, 1994, 372, 739.
Singleꢀcrystal Xꢀray diffraction study of compound 3 was
performed at the Crystallographic Division of the Collective Use
9. A. K. Takle, M. J. B. Brown, S. Davies, D. K. Dean,
G. Francis, A. Gaiba, A. W. Hird, F. D. King, P. J. Lovell,

936
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 5, May, 2011
Mamedov et al.
A. Naylor, A. D. Reith, J. G. Steadman, D. M. Wilson,
Bioorg. Med. Chem. Lett., 2006, 16, 378.
26. A. Y. Usyatinsky, Y. L. Khmelnitsky, Tetrahedron Lett., 2000,
41, 5031.
10. S. E. de Laszlo, C. Hacker, B. Li, D. Kim, M. MacCoss,
N. Mantlo, J. V. Pivnichny, L. Colwell, G. E. Koch, M. A.
Cascieri, W. K. Hagmann, Bioorg. Med. Chem. Lett., 1999,
9, 641.
11. DE Pat. 361 464; Chem. Abstr., 1988, 108, 37838.
12. J. Heeres, L. J. J. Backx, J. H. Mostmans, J. Van Cutsem,
J. Med. Chem., 1979, 22, 1003.
27. A. A. Kalinin, V. A. Mamedov, Ya. A. Levin, Khim. Geteroꢀ
tsikl. Soedin., 2000, 995 [Chem. Heterocycl. Compd.
(Engl. Transl.), 2000, 36, 882].
28. V. A. Mamedov, A. A. Kalinin, A. T. Gubaidullin, A. V.
Chernova, I. A. Litvinov, Ya. A. Levin, R. R. Shagidullin,
Izv. Akad. Nauk, Ser. Khim., 2004, 159 [Russ. Chem. Bull.,
Int. Ed., 2004, 53, 164].
13. L. Wang, K. W. Woods, Q. Li, K. J. Barr, R. W. McCroskey,
S. M. Hannick, L. Gherke, R. B. Credo, Y.ꢀH. Hui, K. Marsh,
R. Warner, J. Y. Lee, N. ZielinskyꢀMozng, D. Frost, S. H.
Rosenberg, H. L. Sham, J. Med. Chem., 2002, 45, 1697.
14. US Pat. 4 820 335; Chem. Abstr., 1989, 111, 19494w.
15. D. A. Horton, G. T. Bourne, M. L. Smythe, Chem. Rev.,
2003, 103, 893.
16. A. R. Porcari, R. V. Devivar, L. S. Kucera, J. C. Drach,
L. B. Towsend, J. Med. Chem., 1998, 41, 1252.
17. M. T. Migawa, J.ꢀL. Girardet, J. A. Walker, II, G. W. Kosꢀ
zalska, S. D. Chamberlain, J. C. Drach, L. B. Townsend,
J. Med. Chem., 1998, 41, 1242.
29. V. A. Mamedov, A. A. Kalinin, A. T. Gubaidullin, E. A.
Gorbunova, I. A. Litvinov, Zh. Org. Khim., 2006, 42, 1543
[Russ. J. Org. Chem. (Engl. Transl.), 2006, 42, 1532].
30. A. A. Kalinin, O. G. Isaikina, V. A. Mamedov, Khim.
Geterotsikl. Soedin., 2007, 1532 [Chem. Heterocycl. Compd.
(Engl. Transl.), 2007, 43, 1307].
31. V. A. Mamedov, D. F. Saifina, I. Kh. Rizvanov, A. T.
Gubaidullin, Tetrahedron Lett., 2008, 49, 4644.
32. V. A. Mamedov, D. F. Saifina, A. T. Gubaidullin, A. F.
Saifina, I. Kh. Rizvanov, Tetrahedron Lett., 2008, 49, 6231.
33. V. A. Mamedov, D. F. Saifina, A. T. Gubaidullin, A. F.
Saifina, I. Kh. Rizvanov, V. R. Ganieva, Izv. Akad. Nauk,
Ser. Khim., 2009, 1924 [Russ. Chem. Bull., Int. Ed., 2009,
58, 1986].
34. G. M. Sheldrick, SADABS. Program for Empirical Xꢀray
Absorption Correction, Bruker—Nonius, 1990—2004.
35. APEX2 (Version 2.1), SAINTPlus. Data Reduction and Correcꢀ
tion Program (Version 7.31A), Bruker Advanced Xꢀray Soluꢀ
tions/Bruker AXS, Madison, Wisconsin, USA, 2006.
36. G. M. Sheldrick, SHELXTL, Version 6.12, Structure Deterꢀ
mination Software Suite, Bruker AXS, Madison, Wisconsin,
USA, 2000.
18. I. Tamm, Science, 1957, 126, 1235.
19. J. Mann, A. Baron, Y. OpokuꢀBoahen, E. Johansson, G. Parꢀ
kinson, L. R. Kelland, S. Neidle, J. Med. Chem., 2001,
44, 138.
20. S. A. Siddiqui, U. C. Narkhede, S. S. Palimkar, T. Daniel,
R. J. Lahoti, K. V. Srinivasan, Tetrahedron, 2005, 61, 3539.
21. J. Wang, R. Mason, D. VanDerveer, K. Feng, X. R. Bu,
J. Org. Chem., 2003, 68, 5415.
22. A. Shaabani, A. Rahmati, J. Mol. Catal. A: Chem., 2006,
249, 246.
23. S. D. Sharma, P. Hazarika, D. Konwar, Tetrahedron Lett.,
2008, 49, 2216.
37. L. J. Farrugia, J. Appl. Crystallogr., 1999, 32, 837.
38. A. L. Spek, Acta Crystallogr., Sect. A, 1990, 46, 34.
24. J. N. Sangshetti, N. D. Kokare, S. A. Kotharkara, D. B.
Shinde, J. Chem. Sci., 2008, 120, 463.
25. M. M. Heravi, K. Bakhtiari, H. A. Oskooie, S. Taheri, J. Mol.
Catal. A: Chem., 2007, 263, 279.
Received June 30, 2010;
in revised form February 4, 2011