An efficient and convenient synthesis of imidazolines and benzimidazoles via oxidation of carbon-nitrogen bond in water media

Article abstract of DOI:10.1002/cjoc.201100210

The metal coordination complex K₄[Fe(CN)₆] is an efficient and environmentally benign catalyst for the synthesis of imidazolines and benzimidazoles from various aldehydes and 1,2-diamines in aqueous medium at room temperature. This protocol gives excellent yield of product with desired purity. Copyright

Full text of DOI:10.1002/cjoc.201100210

FULL PAPER
DOI: 10.1002/cjoc.201100210
An Efficient and Convenient Synthesis of Imidazolines and
Benzimidazoles via Oxidation of Carbon-Nitrogen Bond in
Water Media
Shaikh, Kabeer A.*
Patil, Vishal A.
Shaikh, Parveen A.
Organic Synthesis Laboratory, Department of Chemistry, Sir Sayyed College, Aurangabad-431 001,
Maharashtra, India
The metal coordination complex K4[Fe(CN)6] is an efficient and environmentally benign catalyst for the syn-
thesis of imidazolines and benzimidazoles from various aldehydes and 1,2-diamines in aqueous medium at room
temperature. This protocol gives excellent yield of product with desired purity.
Keywords aldehyde, 1,2-diamines, K4[Fe(CN)6], imidazolines, benzimidazoles, water
NH2
Introduction
N
N
O
S
N
H
An efficient and convenient chemical process or
method for the synthesis of biologically active com-
pounds from the simple reagent is always a challenging
task for chemists working in the field of organic synthe-
sis. The imidazolines and benzimidazoles are the im-
portant heterocycles found in many biologically active
compounds.[1] They are biologically active pharma-
cophores and synthetic intermediates in medicinal
chemistry[2] (Figure 1). They are also used as chiral
catalysts,[3] chiral auxiliaries,[4] and ligands for asym-
metric catalysis.[5] It is a continuation of our interest in
the synthesis of these heterocycles due to their broad
spectrum of biological activities including antihyper-
glycemic,[6] antiinflammatory,[7] antihypertensive,[8]
anticancer,[9] and antihypercholesterolemic[10] agents. In
addition, they have also shown excellent biological ac-
tivities like antiulcer, antiviral, antifungal, antibacterial,
antitubercular, antiasthmatic, anti-diabetic and antipro-
tozoal.[11-19]
In recent years, potassium ferro-cyanide has gained
special attention as a catalyst in organic synthesis like
synthesis of anti-Alzheimer drug (－)-Galanthamine[28]
due to its high stability, oxidizing power selectivity and
a nontoxic byproduct Fe(III). It is useful to promote
oxidative cyclization of 5-S-Cysteinyldopa.[29] Xiao et
al.[30] studied the liberation of cyanide into the envi-
ronment which has terristerial importance for ecosystem
and Gaffar et al.[31] studied the kinetics of the potassium
ferro cyanide. Because of many advantages such as ex-
cellent solubility in water, uncomplicated handling, in-
expensiveness and eco-friendly nature, readily avail-
N
N
O
N
F3C
O
O
O
N
P
O S
O
O
O
O
O
O
N
O
N
N
HN
H2N
OH
OH
Figure 1 Structures of biologically active compounds contain-
ing imidazole pharmacophore
able and highly reactive potassium ferrocyanide is used
as a green, efficient and environmentally friendly cata-
lyst for the development of various synthetic methods.
Nowadays, several methods have been developed,
for the synthesis of benzimidazoles in presence of vari-
ous catalyst such as sulfur/ultrasonic,[20] homogeneous
Lewis acids,[21] I2/KI/K2CO3/H2O,[22] pyridinium-p-
toluenesulfonate,[23] ionic liquids,[24] polyaniline-
sulfate,[25] (bromodimethyl)sulfonium bromide[26] and
Zeolites.[27]
However, all of the synthetic protocols reported so
far suffer from disadvantages such as, use of organic
solvents,[21,23,25] harsh reaction conditions,[22,26] elevated
temperature,[22] prolonged reaction times,[23,25] use of
expensive reagents.[21,24] To overcome all these disad-
vantages herein we report a practical, inexpensive and
*
E-mail: shaikh_kabeerahmed@rediffmail.com
Received August 8, 2011; accepted October 25, 2011; published online March 7, 2012.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201100210 or from the author.
924
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 924—928

An Efficient and Convenient Synthesis of Imidazolines and Benzimidazoles
green method for the synthesis of imidazolines and ben-
zimidazoles by using potassium ferro-cyanide as a cata-
lyst in water.
found 195.14.
2-(4-Methylphenyl)-1H-benzimidazole (5)
NMR (CDCl3/DMSO-d6, 200 MHz) δ: 7.60—7.54 (m,
2H), 7.24 (dd, J＝8.0, 1.2 Hz, 2H), 7.19—7.13 (m, 2H),
6.98 (dd, J＝8.0, 1.2 Hz, 2H), 3.98 (br s, 1H), 2.36 (s,
1H
Experimental
－
1
3H); IR (KBr) ν: 3146 (NH), 2949 (CH), 1665 cm ;
MS (ES) calcd for C14H12N2 (M ＋ ) 208.25, found
208.20.
All chemicals were purchased from Merck, Aldrich
and Rankem Chemical Companies and used without
further purification. Purity of the compounds were
checked by thin layer chromatography (TLC) on Merck
silica gel 60 F254 pre-coated sheets. Melting points of
the synthesized compounds were determined in open-
glass capillaries on a stuart-SMP10 melting point appa-
ratus. IR absorption spectra were recorded on a Perkin
2-(4-Methoxyphenyl)-1H-benzimidazole (6) 1H
NMR (DMSO-d6, 200 MHz) δ: 7.64—7.58 (m, 2H),
7.18 (dd, J＝7.8, 1.0 Hz, 2H), 7.10—7.06 (m, 2H), 6.74
(dd, J＝7.8, 1.0 Hz, 2H), 4.14 (br s, 1H), 3.56 (s, 3H);
－
1
IR (KBr) ν: 3153 (NH), 2951 (CH), 1623 cm ; MS (ES)
calcd for C14H12N2O (M＋) 224.25, found 224.22.
Elmer 1650 FTIR using KBr pellets in the range of
1
1
2-Phenyl-1H-benzimidazole (7) 1H NMR (CDCl3,
200 MHz) δ: 7.67—7.62 (m, 2H), 7.38—7.14 (m, 7H),
4.20 (br s, 1H); IR (KBr) ν: 3171 (NH), 2938 (CH),
－
4000—450 cm . H NMR spectra were recorded on a
1
Bruker spectrometer operating at 200 MHz. The H
NMR chemical shifts are reported downfield from TMS
(tetramethylsilane) used as an internal standard. Mass
spectra were recorded on LCQ ion trap mass spectro-
meter. All compounds were known, and obtained
physical and spectroscopic data were compared with
literatures data.
－
＋
1
1638 cm ; MS (ES) calcd for C13H10N2 (M ) 294.23,
found 194.17.
2-(4-Nitrophenyl)imidazoline (8)
1H NMR
(DMSO-d6, 200 MHz) δ: 8.01 (d, J＝8.2 Hz, 2H), 7.85
(d, J＝8.2 Hz, 2H), 4.38 (br s, 1H), 3.56 (s, 4H); IR
－
1
(KBr) ν: 3185 (NH), 2941 (CH), 1680 cm ; MS (ES)
calcd for C9H9N3O2 (M＋) 191.18, found 191.16.
General procedure for the synthesis of imidazo-
lines/benzimidazoles
2-(4-Methylphenyl) imidazoline (9) 1H NMR
(DMSO-d6, 200 MHz) δ: 7.37—6.95 (m, 4H), 4.28 (br s,
1H), 3.45 (s, 4H), 2.37 (s, 3H); IR (KBr) ν: 3142 (NH),
A mixture of 1,2-diamine (1.1 mmol), aldehyde (1
mmol) and water (10 mL) was taken in a round bottom
flask. To this mixture, potassium ferro-cyanide
(K4[Fe(CN6)], 10 mol%) was added and stirred at room
temperature for given time period. After completion of
the reaction (TLC) the solid obtained was filtered,
washed with water, dried and recrystallized from etha-
nol to obtain the desired product with excellent yield.
－
1
2934 (CH), 1621 cm ; MS (ES) calcd for C10H12N2
(M＋) 160.21, found 160.15.
2-(2,4-Dichlorophenyl)imidazoline (10) 1H NMR
(CDCl3, 200 MHz) δ: 7.75—7.24 (m, 3H), 4.32 (br s,
1H), 3.78 (s, 4H); IR (KBr) ν: 3134 (NH), 2928 (CH),
－
＋
1
1607 cm ; MS (ES) calcd for C9H8N2Cl2 (M ) 215.08,
＋
found 215.10, 217.06 (MH2 ).
Spectral data of the synthesized compounds
2-(4-N,N-Dimethylaminophenyl)imidazoline (11)
1H NMR (DMSO-d6, 200 MHz) δ: 7.80 (d, J＝8.1 Hz,
2H), 6.90 (d, J＝8.1 Hz, 2H), 4.77 (s, 4H), 4.39 (br s,
1H), 3.01 (s, 6H); IR (KBr) ν: 3176 (NH), 2961 and
5-Methyl-2-phenyl-1H-benzimidazole (1)
1H
NMR (200 MHz, CDCl3) δ: 7.47—7.38 (m, 4H),
7.22—7.15 (m, 3H), 6.94—6.87 (m, 1H), 3.54 (br s,
1H), 2.19 (s, 3H); IR (KBr) ν: 3178 (NH), 2937 (CH),
－
1
2919 (CH), 1617 cm ; MS (ES) calcd for C11H15N3
－
＋
1
1611 cm ; MS (ES) calcd for C14H12N2 (M ) 208.25,
(M＋) 189.26, found 189.19.
found 208.17.
2-(4-Bromophenyl)imidazoline (12)
1H NMR
5-Methyl-2-(4-nitrophenyl)-1H-benzimidazole (2)
1H NMR (CDCl3/DMSO-d6, 200 MHz) δ: 8.16 (dd, J＝
8.1, 2.1 Hz, 2H), 7,78 (dd, J＝8.1, 2.1 Hz, 2H),
6.98—7.48 (m, 3H), 3.98 (br s, 1H), 2.23 (s, 3H); IR
(DMSO-d6, 200 MHz) δ: 7.82—7.71 (m, 4H), 4.30 (br s,
1H), 3.87 (s, 4H); IR (KBr) ν: 3185 (NH), 2960, 2940
－
＋
1
(CH), 1608 cm ; MS (ES) calcd for C9H9N2Br (M )
－
1
225.08, found 225.05.
(KBr) ν: 3242 (NH), 2951 (CH), 1648 cm ; MS (ES)
calcd for C14H11N3O2 (M＋) 253.25, found 253.14.
2-[3-Fluoro-4-(trifluoromethyl)phenyl]-5-methyl-
1H-benzimidazole (3) 1H NMR (CDCl3, 200 MHz) δ:
7.48—7.42 (m, 3H), 7.10—6.92 (m, 3H), 3.65 (br s,
1H), 2.29(s, 3H); IR (KBr) ν: 3239 (NH), 2965 (CH),
Phenyl(2-phenyl-1H-benzimidazol-5-yl)meth-
anone (13) 1H NMR (200 MHz, CDCl3/DMSOD6) δ:
7.95—6.74 (m, 13H), 4.52 (br s, 1H); IR (KBr) ν: 3178
－
1
(NH), 2968 and 2914 (CH), 1707, 1640 cm ; MS (ES)
calcd for C20H14N2O (M＋) 298.33, found 298.21.
－
＋
1
[2-(4-Nitrophenyl)-1H-benzimidazol-5-yl](phe-
nyl)methanone (14) 1H NMR (200 MHz, CDCl3/
DMSOD6) δ: 8.25—8.14 (m, 3H), 7.80—7.70 (m, 6H),
7.45—7.36 (m, 3H), 4.72 (br s, 1H); IR (KBr) ν: 3190
1639 cm ; MS (ES) calcd for C15H10F4N2 (M ) 294.24,
found 294.19.
2-(Pyridin-2-yl)-1H-benzimidazole (4) 1H NMR
(DMSO-d6, 200 MHz) δ: 8.24—7.94 (m, 2H),
7.64—7.51 (m, 3H), 7.24—7.17 (m, 3H), 4.07 (br s,
1H); IR (KBr) ν: 3187 (NH), 2948 and 2925 (CH), 1675,
－
1
(NH), 2972 and 2910 (CH), 1712, 1645 cm ; MS (ES)
calcd for C20H13N3O3 (M＋) 343.33, found 343.12.
{2-[3-Fluoro-4-(trifluoromethyl)phenyl]-1H-
－
＋
1
1613 cm ; MS (ES) calcd for C12H9N3 (M ) 195.21,
Chin. J. Chem. 2012, 30, 924—928
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
925

Shaikh, Patil & Shaikh
FULL PAPER
benzimidazol-5-yl}(phenyl)methanone (15)
NMR (200 MHz, CDCl3/DMSOD6) δ: 8.07 (s, 1H),
7.78—7.65 (m, 4H), 7.51—7.16 (m, 6H), 4.91 (br s,
1H); IR (KBr) ν: 3182 (NH), 2968 and 2907 (CH), 1709,
1641 cm－1; MS (ES) calcd for C21H12F4N2O (M＋)
384.32, found 384.24.
1H
Table 1 solvent effect for the synthesis of 5-methyl-2-phenyl-
1H-benzimidazole
Solvent
Time/min
Yielda/%
Acetic acid
Hexane
20
18
17
21
12
24
20
28
18
89
Methanol
Acetonitrile
Water
Results and Discussion
In the beginning the mixture of 4-methyl-o-phenyl-
enediamine (1.1 mmol), benzaldehyde (1 mmol) and
water (10 mL) was taken in the round bottom flask.
Catalytic amount of potassium ferro-cyanide
(K4[Fe(CN6)], 10 mol%) was added to the reaction
mixture and stirred at room temperature for the given
time period (Scheme 1). After completion of the reac-
tion (TLC), the solid obtained was filtered and washed
with water. This protocol gives excellent yield of the
product (89%).
a Isolated yield of the products.
vents (18%—28%) whereas water gives excellent yield
of product (89%). Thus, water is found to be the more
efficient and environmentally friendly solvent for the
synthesis of benzimidazoles and imidazolines.
The generality of this reaction was authenticated by
the use of various aromatic aldehydes containing elec-
tron-donating and electron-withdrawing groups and
various 1,2-diamines (Table 2). Aldehydes containing
electron withdrawing groups enhanced the rate of reac-
tion because of increase in the electrophilic character at
aldehydic carbon. In case of 1,2-diamines, 4-methyl-o-
phenylenediamine reacted faster because of electron
donating nature of methyl group on aromatic ring,
which increases the nucleophilic character of 1,2-di-
amine.
Scheme 1 Synthesis of 5-methyl-2-phenyl-1H-benzimidazole
CHO
NH2
NH2
N
K4[Fe(CN)6]
H2O
+
N
H
1
2
3
To study the effect of solvent on the rate and yield of
product, the same reaction was carried out in some other
polar as well as non-polar solvents under the same reac-
tion conditions (Table 1). The results in Table 1 reveal
that very poor yields were obtained in the organic sol-
The possible mechanism of this reaction is shown in
Scheme 2. The K4[Fe(CN)6] increase the electrophilic
character at aldehydic carbon, which will facilitate the
nucleophilic addition of 1,2-diamines to gave an inter-
Table 2 Synthesis of benzimidazoles and imidazolines
Yielda/%
89
m.p. (lit. m.p.)/℃
234—236
Entry 1,2-Diamine
Aldehyde
Product
Time/min
CHO
CHO
NH2
N
1
12
(235—236[34]
)
N
H
NH2
NH2
NH2
N
240—242
(240—241[34]
NO2
2
10
90
N
H
)
NO2
CHO
F3
NH2
NH2
N
174—176
3
4
11
13
13
87
88
89
CF3
(174[32]
)
F3
N
H
CF3
NH2
N
218—219
(216—219[22]
N
H
N
)
)
NH2
N
CHO
CHO
NH2
NH2
N
274—276
(275—276[35]
5
N
H
926
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© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2012, 30, 924—928

An Efficient and Convenient Synthesis of Imidazolines and Benzimidazoles
Continued
m.p./℃ (lit. m.p.)
Entry 1,2-Diamine
Aldehyde
Product
Time/min
14
Yielda/%
86
CHO
NH2
N
225—227
OCH3
6
(223—226[22]
)
N
H
NH2
OCH3
CHO
NH2
N
290—292
7
13
12
90
88
(295[22]
)
N
H
NH2
CHO
N
229—231
(230—232[33]
NO2
8
NH2
NH2
NH2
NH2
NH2
H2N
H2N
H2N
H2N
H2N
N
H
)
)
)
)
)
)
)
)
NO2
CHO
H
N
180—182
(177—179[33]
9
14
13
12
14
13
12
15
86
84
89
88
87
90
85
N
CHO
Cl
Cl
H
N
106—108
(105—108[22]
10
11
12
13
14
15
Cl
N
N
Cl
CHO
H
N
258—260
(258—260[22]
N
N
CHO
H
N
242—245
(242—246[22]
Br
N
Br
O
O
O
CHO
NH2
NH2
N
220—222
(221—222[34]
N
H
CHO
O
O
NH2
NH2
N
240—242
(240—241[34]
NO2
N
H
NO2
CHO
O
F3
NH2
NH2
N
226—227
(226—227[34]
CF3
F3
N
H
CF3
a Isolated yield of the products.
Chin. J. Chem. 2012, 30, 924—928
© 2012 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
927

Shaikh, Patil & Shaikh
FULL PAPER
Scheme 2 Proposed mechanism for the synthesis of benzimidazoles and imidazolines
NH2
H
N
H
N
Ph
N
..
Ph
H
Oxidation
-H2
O
+
Ph
NH2
N
N
H
NH2
..
Ph
H
K4[Fe(CN)6]
O
Ph
H
K4[Fe(CN)6]
N
Ph
NH2
NH2
H
N
H
N
..
Oxidation
Ph
H
Ph
N
NH2
..
-H2
R
R
N
H
R
R
tens. Res. 2010, 33, 348.
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In conclusion, simple, efficient, environmentally be-
nign and high yielding protocol has been developed via
oxidation of carbon-nitrogen bond for the synthesis of
biologically active imidazoline and benzimidazole de-
rivatives using cheap, eco-friendly and water soluble
catalyst potassium ferro-cyanide. The great achievement
of present protocol is the organic solvent-free reaction
conditions and it avoids the use of hazardous catalysts.
These advantages make the present method very effec-
tive for the synthesis of biological active imidazoline
and benzimidazole derivatives.
Acknowledgements
We thank DST, New Delhi for Financial Support
1
and Shivaji University, Kolhapur for providing IR, H
NMR and MASS facilities.
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