Efficient and inexpensive synthesis of benzimidazoles and quinoxalines

Article abstract of DOI:10.1080/00397910802372525

o-Phenylenediamines were reacted with carbonyl compounds, β-ketoesters, and 1,2-diketones in presence of ammonium salts to give benzimidazoles and quinoxalines in very good yields. Ammonium salts are commercial and environmentally benign catalysts. Copyright Taylor & Francis Group, LLC.

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Efficient and Inexpensive
Synthesis of Benzimidazoles
and Quinoxalines
B. China Raju a , N. Dharma Theja a & J. Ashok
Kumar a
a Natural Products Laboratory, Organic Chemistry
Division 1, Indian Institute of Chemical Technology,
Hyderabad, India
Version of record first published: 15 Feb 2011
To cite this article: B. China Raju, N. Dharma Theja & J. Ashok Kumar (2008):
Efficient and Inexpensive Synthesis of Benzimidazoles and Quinoxalines, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:1, 175-188
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Synthetic Communications1, 39: 175–188, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802372525
Efficient and Inexpensive Synthesis
of Benzimidazoles and Quinoxalines
B. China Raju, N. Dharma Theja, and J. Ashok Kumar
Natural Products Laboratory, Organic Chemistry Division 1, Indian
Institute of Chemical Technology, Hyderabad, India
Abstract: o-Phenylenediamines were reacted with carbonyl compounds,
b-ketoesters, and 1,2-diketones in presence of ammonium salts to give benzimida-
zoles and quinoxalines in very good yields. Ammonium salts are commercial and
environmentally benign catalysts.
Keywords: Ammonium salts, benzimidazoles, 1,2-diketones, b-ketoesters, OPDA,
quinoxalines
Benzimidazoles and its derivatives are well documented in the literature to
exhibit a wide range of biological activities. They are potent inhibitors of
TIE-2 and VEGFR-2 tyrosine kinase receptors,[1] antitumor agents,[2]
gamma-aminobutyric acid (GABA) agonists,[3] and 5-HT3 antagonists.[4]
Similarly, quinoxaline- containing antibiotics such as actinomycin, levo-
mycin, and echinomycin are known to inhibit the growth of gram-positive
bacteria and are active against various transplantable tumors.[5] The
general synthesis of benzimidazoles is by the condensation reaction of
1,2-phenylenediamine with carboxaldehydes, carboxylic acids,[6] or their
derivatives[7] such as chlorides, nitriles, and orthoesters under strong acidic
conditions with high temperatures. The most common method for quinox-
alines is aryl 1,2-diamines with 1,2-dicarbonyl compounds in refluxing
ethanol in the presence of acetic acid.[8] Other methods developed include
Received April 10, 2008.
Address correspondence to B. China Raju, Natural Products Laboratory,
Organic Chemistry Division 1, Indian Institute of Chemical Technology,
Hyderabad 500 607, India. E-mail: chinarajuiict@yahoo.co.in
175

176
B. C. Raju, N. D. Theja, and A. Kumar
metal precursors, acids, zeolites,[9] microwave,[10] and solid-phase synthe-
sis.[11] Recently I2[12] and NH2SO3H[13] were also reported in the literature.
Ammonium halides[14] are inexpensive, commercially available
reagents for few organic transformation reactions such as
halogenation of aromatic compounds and synthesis of 3,4-dihydropyrimi-
dine-2(1H)-ones. However, there are no reports of the use of ammonium
salts as catalyst for the synthesis of benzimidazoles and quinoxalines. In
continuation of our efforts on synthesis of heterocycles[15] and on develop-
ment of synthetic methodologies,[16] herein we report a facile method for
the synthesis of benzimidazoles and quinoxalines by the condensation of
1,2-phenylenediamine with carbonyl compounds, b-ketoesters, and 1,2-
diketones in the presence of ammonium salts in very good yields. It is
known that the reaction of O-phenylenediamine (OPDA) with carbonyl
compounds under strong acidic conditions gives benzimidazoles, whereas
OPDA in the presence of b-ketoesters under neutral reflux conditions gives
benzodiazepin-2-ones, with the elimination of water and alcohol. Under
acidic conditions, initially it forms ethyl b-2-amino aniline crotonate at
room temperature; upon heating it gives 2-methyl-1H-benzo[d]imidazole
instead of benzodiazepin-2-ones with the elimination of ethyl acetate. So
we made an attempt to react OPDA with carbonyl compounds and
b-ketoesters with different ammonium salts to see the feasibility of the for-
mation of compounds. To select favorable reaction conditions, we first
examined the model reaction of 1,2-phenylenediamine (1 mol) with benzal-
dehyde (1mol) in the presence of NH4Cl (1 mol) under solvent-free condi-
tions at room temperature. The reaction was monitored by thin-layer
chromatography (TLC) and 2-phenyl-1H-benzo[d]imidazole obtained in
10% yield. Similarly the reaction was conducted in different solvents such
as CH3CN, MeOH, CHCl3, ether, and DMF; methanol is found to be the
most suitable solvent to give benzimidazole in 30% yield. Next we carried
out the same reaction with different ammonium salts such as NH4F,
NH4Br, NH4NO3, (NH4)2CO3, and (NH4)2SO4 in the presence of metha-
nol at room temperature; among these NH4Br (4 mol) gave 2-phenyl-1H-
benzo[d]imidazole in 94% yield 4 h (Scheme 1, Table 1, entry 2). The
results, tabulated in Table 2, indicate the formation of benzimidazoles.
Scheme 1. Ammonium halide catalyzed synthesis of 2-arylbenzimidazoles.

Benzimidazoles and Quinoxalines
177
Table 1. Optimization of reaction conditions for the synthesis of 2-phenyl
benzimidazole by the condensation of OPDA with benzaldehyde using various
ammonium salts at room temperature in MeOH
Entry
NH4Xa
Time (h)
Yield (%)b
1
2
3
4
5
6
NH4Cl
NH4Br
NH4F
NH4NO3
(NH4)2SO4
(NH4)2CO3
4
4
5
6
10
12
90
94
78
80
84
52
aReaction carried out with 4 mol of NH4X.
bIsolated and unoptimized yields.
Next we studied the reaction of OPDA (1 mol) with ethyl acetoacetate
4a (1 mol) in the presence of NH4Cl (1 mol) at room temperature: the reac-
tion is futile. Similarly the reaction was carried out at 85 ꢀC under solvent-
free conditions (20 min, TLC) to afford 2-methyl-1H-benzo[d]imidazole 5a
in 96% yield (Scheme 2). The obtained product was confirmed based on
spectral data (1H NMR and MS). Then we carried out the reaction with
different ammonium salts such as NH4F, NH4Br, NH4NO3, (NH4)2CO3,
(NH4)2SO4, NH4OAc, and (NH4)2S2O8; among these NH4Br gives the
better yield (Table 3, entry 2, 98%). The results, tabulated in Table 4, indi-
cate the formation of 2-methylbenzimidazoles in very good yields. The
results encouraged us to carry out the reactions with substituted OPDA
and b-ketoesters; the obtained results, tabulated in Table 3, indicate the for-
mation of substituted benzimidazoles (Table 4, entry 5a–i). All the products
were well characterized based on spectral data (1H NMR, IR, and MS).
Similarly, next we carried out the reaction of OPDA 1a (1 mol), ben-
zil 6a (1 mol), and NH4Br (1 mol) in the presence of CH3CN at room tem-
perature (5 min, TLC), which gave 2,3-diphenylquinoxaline 7a in 98%
yield (Scheme 3). The product was well characterized by its spectral data
(1H NMR, IR, and MS). The results encouraged us to carry out the reac-
tion with different substituted OPDA with 1,2-diketones in the presence
of NH4Br at room temperature, but the reactions were sluggish at room
temperature, whereas under reflux conditions quinoxalines 7a–f were
obtained in very good yields with NH4Br (4 mol). The results were tabu-
lated in Table 5, and all the products were well characterized based on
spectral data (1H NMR, IR, and MS). Under similar conditions, the
attempted reaction of OPDA with 1,3-diketones such as dibenzoyl
methane gave 2-phenylbenzimidazole instead of benzodiazepine. The
reactions of OPDA with 1,3-diketones are presently under investigation.

178

179

180
B. C. Raju, N. D. Theja, and A. Kumar
Scheme 2. Synthesis of substituted benzimidazoles.
In conclusion we devised an efficient, inexpensive protocol for the
synthesis of benzimidazoles and quinoxalines using readily available
and inexpensive reagents under mild conditions with very good yields.
EXPERIMENTAL
1H NMR spectra were recorded on a Varian Gemini 200- and 300-MHz
instrument in CDCl3, DMSO-d6 using TMS as an internal standard. The
mass spectra were measured on a LCMS Agilent mass spectrometer. The
IR spectra were recorded on a Nicolet 740 FT IR spectrometer. Melting
points were measured in a Buchi-510 apparatus and are uncorrected.
General Procedure
Typical Experimental Procedure for the Synthesis of Benzimidazoles
Benzaldehyde (2a, 1 mmol) was added to a stirred solution of 1,2-pheny-
lenediamine (1, 1 mmol) and NH4Br (4 mmol) in methanol (5 ml) for 5 min
at room temperature. Stirring was continued for 4 h. After completion of
the reaction (TLC), the solvent was removed under reduced pressure and
Table 3. Optimization of reaction conditions for the synthesis of 2-methyl
benzimidazole by the condensation of OPDA with EAA using various
ꢀ
ammonium salts at 85 C
Entry
NH4X
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
NH4Cl
NH4Br
NH4F
NH4NO3
(NH4)2SO4
(NH4)2CO3
NH4OAc
(NH4)2S2O8
25
20
25
35
40
40
40
60
96
98
88
82
92
56
65
62
aIsolated and unoptimized yields.

181

182
B. C. Raju, N. D. Theja, and A. Kumar
Scheme 3. Synthesis of quinoxalines.
extracted with ethyl acetate (2 ꢁ 20 ml); the organic layer was washed with
water (2 ꢁ 10 ml). Layers were separated, and the organic layer was dried
over sodium sulfate. Solvent was removed under reduced pressure, and
crude product was subjected to column chromatography using petroleum
ether=EtOAc (9:1), which gave 2-phenyl-1H-benzo[d]imidazole (3a) as a
solid in 94% yield.
Typical Experimental Procedure for the Synthesis of Benzimidazoles
1,2-Phenylenediamine (1, 1 mmol) and ethyl acetoacetate (4a, 1 mmol) in
presence of NH4Br (1 mmol) were heated at 85 ꢀC for 20 min. The reac-
tion mixture was cooled, extracted with ethyl acetate (2 ꢁ 20 ml), and
washed with water (2 ꢁ 10 ml). The layers were separated, the organic
layer was dried over sodium sulfate, solvent was removed under reduced
pressure, and crude product was subjected to column chromatography
using petroleumether=EtOAc (9:1) to give 2-methyl-1H-benzo[d]imida-
zole (5a) as a solid in 96% yield.
Typical Experimental Procedure for the Synthesis of Quinoxalines
4-Nitro-1,2-phenylenediamine (1, 1 mmol), benzil (6b, 1 mmol), and
NH4Br (4 mmol) were refluxed in acetonitrile for 45 min. The reaction
mixture was cooled; solvent was removed under reduced pressure,
extracted with ethyl acetate (2 ꢁ 20 ml), and washed with water
(2 ꢁ 10 ml). The layers were separated, the organic layer was dried over
sodium sulfate, and solvent was removed under reduced pressure to give
6-nitro-2,3-diphenylquinoxaline (7b) as a solid in 88% yield.
Spectral Data
4-(5,6-Dimethyl-1H-benzo[d]imidazol-2-yl) phenol (3g)
Solid; 1H NMR: d 2.30 (s, 6H, 2CH3), 6.86 (d, 2H, aromatic), 7.28 (s, 2H,
aromatic), 7.92 (d, 2H, aromatic; IR (KBr): 3426, 2923, 2855, 1742, 1631,

183

184

Benzimidazoles and Quinoxalines
185
1461, 1378, 1258, 1217, 1027, 760 cmꢂ1; mass (LCMS): m=z 239
(Mþ þ H). Anal. calcd. for C15H14N2O: C, 75.63; H, 5.88; N, 11.76.
Found: C, 75.59; H, 5.84; N, 11.79.
2-(4-Methylphenyl)-6-nitro-1H-benzo[d]imidazole (3h)
Solid; 1H NMR: d 2.44 (s, 3H, CH3), 7.28 (d, 2H, aromatic), 7.60 (d, 1H,
aromatic), 7.96 (d, 2H, aromatic), 8.16 (d, 1H, aromatic), 8.44 (s, 1H,
aromatic); IR (neat): 2962, 2869, 1462, 1384, 1217, 760 cmꢂ1; mass
(LCMS): m=z 254 (Mþ þ H). Anal. calcd. for C14H11N3O2: C, 66.40;
H, 4.34; N, 16.60. Found: C, 66.32; H, 4.37; N, 16.64.
2-Methyl-1H-benzo[d]imidazole (5a)
Solid; 1H NMR: d 2.64 (s, 3H, CH3), 6.08 (bs, 1H, NH), 7.16–7.24
(m, 2H, aromatic), 7.50–7.58 (m, 2H, aromatic); IR (KBr): 3093, 3068,
2996, 1622, 1488, 1360, 896 cmꢂ1; mass (LCMS): m=z 133 (Mþ þ H).
2-Methyl-6-nitro-1H-benzo[d]imidazole (5e)
Solid, 1H NMR: d 2.64 (s, 3H, CH3), 7.54 (d, 1H, aromatic), 8.12 (d, 1H,
aromatic), 8.44 (s, 1H, aromatic); mass (LCMS): m=z 178 (Mþ þ H).
2,6-Dimethyl-1H-benzo[d]imidazole (5h)
Solid; 1H NMR: d 2.46 (s, 3H, CH3), 2.64 (s, 3H, CH3), 7.02 (d, 1H, aro-
matic), 7.32 (s, 1H, aromatic), 7.46 (s, 1H, aromatic), 9.48 (brs, 1H, NH);
mass (LCMS): m=z 147 (Mþ þ H).
2,3-Diphenylquinoxaline (7a)
Solid; 1H NMR: d 7.24–7.38 (m, 6H, aromatic), 7.44–7.52 (m, 4H,
aromatic), 7.72–7.80 (m, 2H, aromatic), 8.12–8.20 (m, 2H, aromatic);
mass (LCMS): m=z 283 (Mþ þ H).
6-Nitro-2,3-diphenylquinoxaline (7b)
Solid, 1H NMR: d 7.30–7.44 (m, 6H, aromatic), 7.50–7.56 (m, 4H,
aromatic), 8.26 (d, 1H, aromatic), 8.52 (d, 1H, aromatic), 9.06 (s, 1H,
aromatic); mass (LCMS): m=z 328 (Mþ þ H).

186
B. C. Raju, N. D. Theja, and A. Kumar
2-Methyl-3-phenylquinoxaline (7f)
Solid, 1H NMR: d 2. 78 (s, 3H, CH3), 7.40–7.56 (m, 3H, aromatic), 7.58–
7.76 (m, 4H, aromatic), 7.98–8.16 (m, 2H, aromatic); mass (LCMS): m=z
221 (Mþ þ H).
ACKNOWLEDGMENTS
The authors are thankful to the head, Organic Chemistry Division 1, and
the director, Indian Institute of Chemical Technology, for constant
encouragement.
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