One-pot synthesis of 2-(1-alkyl/aralkyl-1H-benzimidazole-2-yl)-quinoxaline derivatives using molecular iodine

Article abstract of DOI:10.1080/00397910701798135

The title compound (5) has been prepared in one pot by refluxing 1-(1-alkyl/aralkyl-1H-benzimidazole-2-yl)-ethanone (1) with substituted o-phenylenediamine (2) in ethanol in the presence of iodine. Alternatively, 5 could also be prepared by treating 2-bromo-1-(1- alkyl/aralkyl-1H-benzimidazole- 2-yl)-ethanone (3A) with 2 in refluxing ethanol. The formation of 5 from 1 and 2 probably occurs through the intermediacy of 3B (i.e., 3, X=I) and 4. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701798135

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One‐Pot Synthesis of 2‐(1‐Alkyl/
aralkyl‐1H‐benzimidazole‐2‐yl)‐quinoxaline
Derivatives using Molecular Iodine
P. K. Dubey a , P. V. V. Prasada Reddy a & K. Srinivas a
a Department of Chemistry , College of Engineering, JNT University ,
Kukatpally, Hyderabad, India
Published online: 27 Feb 2008.
To cite this article: P. K. Dubey , P. V. V. Prasada Reddy & K. Srinivas (2008) One‐Pot Synthesis of 2‐(1‐Alkyl/
aralkyl‐1H‐benzimidazole‐2‐yl)‐quinoxaline Derivatives using Molecular Iodine, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 38:4, 613-618, DOI:
10.1080/00397910701798135
To link to this article: http://dx.doi.org/10.1080/00397910701798135
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Synthetic Communicationsw, 38: 613–618, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701798135
One-Pot Synthesis of 2-(1-Alkyl/aralkyl-1H-
benzimidazole-2-yl)-quinoxaline Derivatives
using Molecular Iodine
P. K. Dubey, P. V. V. Prasada Reddy, and K. Srinivas
Department of Chemistry, College of Engineering, JNT University,
Kukatpally, Hyderabad, India
Abstract: The title compound (5) has been prepared in one pot by refluxing 1-(1-alkyl/
aralkyl-1H-benzimidazole-2-yl)-ethanone (1) with substituted o-phenylenediamine (2)
in ethanol in the presence of iodine. Alternatively, 5 could also be prepared by treating
2-bromo-1-(1- alkyl/aralkyl-1H-benzimidazole-2-yl)-ethanone (3A) with
2 in
refluxing ethanol. The formation of 5 from 1 and 2 probably occurs through the inter-
mediacy of 3B (i.e., 3, X ¼ I) and 4.
Keywords: 1-(1-alkyl/aralkyl-1H-benzimidazole-2-yl)-ethanone, bromine, ethanol,
iodine, substituted o-phenylenediamine
Among the various classes of nitrogen-containing heterocyclic compounds,
benzimidazoles and quinoxalines have been shown[1] to exhibit a wide
range of biological and pharmacological properties. The benzimidazole
derivatives have commercial application in veterinary medicine as anthelmin-
tic agents[2] and in such diverse human therapeutic areas[3–6] as anti-ulcerous,
antihypertensive, antiviral, antifungal, anticancerous, and antihistaminic
agents. They also find application as molecular probes,[7] to name just a few
of their uses. The quinoxaline ring is a part of a number of antibiotics such
as echinomycin, leromycin, and actinomycin that are known to inhibit the
growth of gram-positive bacteria and are also active against various
Received August 22, 2007
Address correspondence to P. K. Dubey, Department of Chemistry, College of
Engineering, JNT University, Kukatpally, Hyderabad 500 085, India. E-mail:
pvvpr@rediffmail.com
613

614
P. K. Dubey, P. V. V. P. Reddy, and K. Srinivas
transplantable tumors.[8] Incorporating two biologically active moieties—
benzimidazole and quinoxaline—in a single molecule may lead to interesting
pharmacological properties.
In recent years, molecular iodine has received considerable attention as an
inexpensive, nontoxic, readily available catalyst for various organic trans-
formations[9] under mild and convenient conditions to afford the correspond-
ing products in excellent yields with high selectivity. As part of our ongoing
interest in the use of cheap and ecofriendly materials as catalysts for various
organic transformations, we had the opportunity to look into the synthesis of
title compound using molecular iodine.
In continuation of our earlier studies[10–12] on the synthesis of benzimida-
zoles, we have treated 1-(1-alkyl/aralkyl-1H-benzimidazole-2-yl)-ethanone[13]
(1) with substituted o-phenylenediamine (2) in the presence of molecular
iodine, and the results of our studies in this direction are presented in this
communication.
1-(1-Methyl-1H-benzimidazole-2-yl)-ethanone[13] (1a, i.e., 1, R ¼ CH3)
on reaction with o-phenylenediamine (2a, i.e., 2, R1 ¼ H) in ethanol in the
presence of a molar equivalent of iodine under refluxing conditions resulted
in the formation of 2-(1-methyl-1H-benzimidazole-2-yl)-quinoxaline (5a,
i.e., 5, R ¼ CH3, R1 ¼ H) (Scheme 1). The structure of 5 was assigned
based on the spectral data.
Probably, formation of 5a occurs through the intermediacy of 3B (i.e., 3,
X ¼ I), which, being the a-iodo ketone derivative, could not be isolated, and
4, which, being the dihydroderivative, undergoes dehydrogenation (oxidation)
under heating conditions to yield the thermally stable, aromatized product 5a
(Scheme 2).
The reaction has been found to be a general one and has been extended to
1a and 2a. The products thus obtained were assigned structure 5a on the basis
of their spectral and analytical data.
The a-iodomethyl derivative 3B (i.e., 3, X ¼ I) is the intermediate in
Scheme 1, as shown by treating 1-(1-methyl-1H-benzimidazole-2-yl)-
ethanone (1a, i.e., 1, R ¼ CH3) with bromine in acetic acid, resulting in the
isolation of the known[14] 2-bromo-1-(1-methyl-1H-benzimidazole-2-yl)-
ethanone (3A). Subsequent reaction of 3A with o-phenylenediamine
(2a, i.e., 2, R1 ¼ H) in ethanol under refluxing conditions in the absence of
any acid or base catalyst results in 5a (i.e., 5, R ¼ CH3, R1 ¼ H) (Scheme 3).
Scheme 1.

2-(1-Alkyl/aralkyl-1H-benzimidazole-2-yl)-quinoxaline
615
Scheme 2. Mechanism.
The advantages of this protocol are one-pot synthesis of the title
compound without isolating intermediate, thus avoiding use of harmful
bromine to get title compounds in good yields.
The formation of 5 from 1 probably occurs by a mechanism shown in
Scheme 2.
EXPERIMENTAL
Melting points are uncorrected and were determined in open capillary tubes in a
sulphuric acid bath. Thin-layer chromatography (TLC) was performed on silica
gel-G, and spotting was done using iodine or UV light. IR spectra were recorded
Scheme 3.

616
P. K. Dubey, P. V. V. P. Reddy, and K. Srinivas
with Perkin-Elmer 1000 instrument in KBr phase. 1H NMR were recorded on
Varian 200-MHz instrument, and mass spectra were recorded on an Agilent-
LC-MS instrument giving only Mþ. values using Q þ 1 mode.
Typical Procedure for 5: One-Pot Synthesis
A mixture of 1a (10 mmol), substituted o-phenylenediamine (11 mmol),
iodine (12 mmol), and ethanol (20 mL) was refluxed on a steam bath for
2 h. At the end of this period, the reaction mixture was reduced to half of
its volume by distilling off ethanol, and the residue was cooled in ice water.
The separated solid (which is HI salt of 5) was filtered, washed with
ethanol, and filter-press dried. The latter was then suspended in water
(50 mL) and treated with aq. NaHCO3 (30 mL, 5%) with stirring at rt for
15 min until neutral. The separated solid was filtered, washed, and dried to
obtain 5. The crude product was recrystallized from ethyl acetate–ethanol
to obtain pure 5.
Typical Procedure for 5: Alternative Synthesis
A mixture of 3A (10 mmol), substituted o-phenylenediamine (10.5 mmol),
and ethanol (20 mL) was refluxed for 3 h. At the end of this period, a solid
was given that was filtered, washed with ethanol, and filter-press dried.
The latter was then suspended in water and treated with saturated aq.
NaHCO3 solution (30 mL, 5%) at rt until the solution was neutral. The
separated solid was filtered, washed with water, and dried to obtain 5.
The crude product was recrystallized from ethyl acetate–ethanol to obtain
pure 5.
The compounds 5 [IR (KBr)] showed no characteristic peak in the region
3400–3000 cm21, indicating absence of -NH- functional group, and also no
absorption in the region 1750–1650 cm21, indicating the absence of -CO-
grouping.
Data
Compound 5a: R ¼ CH3, R1 ¼ H; yield ¼ 89%,a 82%.b Mp 191–1928C.
1H NMR (DMSO-d6/TMS) showed signals at d 4.4 (s, 3H, -CH3), 7.3–8.3
(m, 8H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ þ 1: 261.
Compound 5b: R ¼ C2H5, R1 ¼ H; yield ¼ 88%,a 80%.b Mp 170–1728C. 1H
NMR (DMSO-d6/TMS) showed signals at d 1.5 (t, 3H, CH3), 4.9 (q, 2H,
-CH2), 7.3–8.2 (m, 8H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline).
Mþ þ 1: 276.

2-(1-Alkyl/aralkyl-1H-benzimidazole-2-yl)-quinoxaline
617
Compound 5c: R ¼ CH2-Ph, R1 ¼ H; yield ¼ 84%,a 76%.b Mp 164–1668C.
1H NMR (DMSO-d6/TMS) showed signals at d 6.3 (s, 2H, -CH2), 7.2–8.1
(m, 13H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ þ 1: 337.
1
Compound 5d: R ¼ CH3, R1 ¼ Br; yield ¼ 90%,a 82%b. Mp 70–728C. H
NMR (DMSO-d6/TMS) showed signals at d 4.4 (s, 3H, -CH3), 7.3–8.3
(m, 7H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ þ 1: 339.
1
Compound 5e: R ¼ CH3, R1 ¼ F; yield ¼ 81%,a 68%b. Mp 150–1528C. H
NMR (DMSO-d6/TMS) showed signals at d 4.4 (s, 3H, -CH3), 7.3–8.3
(m, 7H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ þ 1: 279.
1
Compound 5f: R ¼ C2H5, R1 ¼ Br; yield ¼ 87%,a 72%b. Mp 78–808C. H
NMR (DMSO-d6/TMS) showed signals at d 1.5 (t, 3H, -CH3), 4.9 (q, 2H,
-CH2), 7.3–8.3 (m, 7H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline).
Mþ þ 1: 354.
1
Compound 5g: R ¼ C2H5, R1 ¼ F; yield ¼ 80%,a 73%b. Mp 48–508C. H
NMR (DMSO-d6/TMS) showed signals at d 4.4 (s, 3H, -CH3), 7.3–8.3
(m, 8H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ þ 1: 293.
Compound 5h: R ¼ CH2-C6H5, R1 ¼ Br; yield ¼ 72%,a 69%b. Mp 118–
1
1208C. H NMR (DMSO-d6/TMS) showed signals at d 6.3 (s, 2H, -CH2),
7.2–8.1 (m, 13H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ
þ1: 415.
Compound 5i: R ¼ CH2-C6H5, R1 ¼ F; yield ¼ 81%,a 74%b. Mp 98–1008C.
1H NMR (DMSO-d6/TMS) showed signals at d 6.3 (s, 2H, -CH2), 7.2–8.1
(m, 13H, aryl protons), 9.8 (s, 1H, -CH55N in quinoxaline). Mþ þ 1: 355.
aThe products obtained by the Scheme 1.
bThe products obtained by the Scheme 2.
ACKNOWLEDGMENT
The authors are highly indebted to the University Grants Commission, Gov-
ernment of India, New Delhi, for financial support.
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