Green multicomponent synthesis of 1,2-dihydro-pyrimido[1,2-a]- benzimidazole-3-carbonitrile

Article abstract of DOI:10.1002/jhet.5570450429

(Chemical Equation Presented) 1,2-dihydro-pyrimido[1,2-a]benzimidazole-3- carbonitrile derivatives were synthesized via the three-component reaction of aldehyde, malonodinitrile and 2-aminobenzimidazole in water under microwave irradiation. The new protocol has the advantages of excellent yield, low cost, reduced environment impact, wide scope and convenient procedure.

Full text of DOI:10.1002/jhet.5570450429

Jul-Aug 2008
1127
Green Multicomponent Synthesis of 1,2-Dihydro-pyrimido[1,2-a]-
benzimidazole-3-carbonitrile
Guangmin Liu,a Qingqing Shao,b Shujiang Tuꢀꢁ* Longji Cao,b Chunmei Li,
bDianxiang Zhou,b Baoping Hana,b*
aChina University of Mining and Technology School of Environmental Science and Spatial Informatics
bSchool of Chemistry and Chemical Engineering, Xuzhou Normal University, Key Laboratory of Biotechnology
on Medical Plant, Xuzhou, Jiangsu 221116, PR China
laotu2001@263.net
Received November 4, 2007
R
CN
HN
N
CN
CN
H2O
MWI
N
NH2
+
NH2
RCHO
+
N
N
H
3
1
2
4
1,2-dihydro-pyrimido[1,2-a]benzimidazole-3-carbonitrile derivatives were synthesized via the three-
component reaction of aldehyde, malonodinitrile and 2-aminobenzimidazole in water under microwave
irradiation. The new protocol has the advantages of excellent yield, low cost, reduced environment impact,
wide scope and convenient procedure.
J. Heterocyclic Chem., 45, 1127 (2008).
INTRODUCTION
to design and implement MCRs in both academia and
industry [19].
As early as in the 1980s Breslow demonstrated that
hydrophobic effects could strongly enhance the rate of
some organic reactions and rediscovered the use of water
as solvent in organic chemistry [1,2]. Since then, the use
of water as a solvent has attracted considerable research
interest [3-5]. Water, compared with organic solvents, is
abundant, nontoxic and environment-friendly. Therefore,
it has become an attractive medium for many organic
reactions [6-8], not only for the advantages concerning the
avoidance of expensive drying reactants, catalysts and
solvents, but also for some unique reactivity and
selectivity [9-12]. Furthermore, organic reactions in water
without using harmful organic solvents is one of the
current focuses today especially in the environmentally
conscious society.
The rapid assembly of molecular diversity is an
important goal of synthetic organic chemistry and one of
the key paradigms of modern drug discovery [13,14]. One
approach to address this challenge involves the
development of multicomponent reactions (MCRs), in
which three or more reactants are combined together in a
single reaction flask to generate a product incorporating
most of the atoms contained in the starting materials
[15,16]. Diversity can be achieved by simply varying each
component or just changing the reaction conditions
[17,18]. In addition to the intrinsic atom economy and
selectivity underlying such reactions, simpler procedures
and equipment, time, and energy savings, as well as
environmental friendliness have all led to a sizable effort
Microwave (MW) assisted organic synthesis has been a
topic of continued studies as it could lead to higher yields
of pure products, easier operation and shorter reaction
time as compared to traditional heating methods [20-23].
Use of MW irradiation for the formation of carbon-
heteroatoms, especially carbon-nitrogen bonds, has been
reported [24-28]. This study is a continuation of our
earlier work [29,30], in which we have shown green
methods for the formation of heterocyclic compounds
containing the nitrogen atom.
Much attention has been devoted towards dihydro-
pyrimidine derivatives due to their significant therapeutic
and medicinal properties [31-33]. Several marine
alkaloids having the dihydropyrimidine core unit were
found to show interesting biological activities such as
antiviral, antibacterial and anti-inflammatory activities
[34,35]. Many functionalized derivatives are used as
calcium channel blockers, antihypertensive agents and
ꢀ-la antagonists [36,37]. Therefore, the preparation of this
heterocyclic core unit has gained much importance.
2-Aminobenzimidazole has been used as material in the
synthesis of many kinds of compounds [38]
Sergey A. Komykhov [39] and co-workers reported the
reaction of ꢀ,ꢁ-unsaturated nitrile with 2-aminobenz-
imidazole to get 1,2-dihydro-benzo[4,5]imidazo[1,2-a]-
pyrimidine-3-carbonitrile derivatives. Their protocol
performed the reactions in ethanol with Me2NH catalyst
and yields of around 30%-40% (Scheme 1).

1128
G. Liu, Q. Shao, S. Tuꢀ L. Cao, C. Li, D. Zhou, B. Han
Vol 45
Table 1.
Solvent Optimization for the Synthesis of 4a under MWI at 80 °C
Scheme 1
Ar
N
Entry
X/Y
10(X)
8/2
6/4
4/6
Power / W
200
200
200
200
Time / min
Yield / %
H
CN
N
1
2
3
4
5
6
4
5
5
5
4
4
91
91
90
91
90
91
Me2NH
CN
HN
NH2
+
Ar HC
MeOH, reflux
N
CN
NH2
N
2/8
10(Y)
200
200
X=EtOH, Y=H2O; Volume proportion
Braulio Insuasty [40] and co-workers have reported the
reaction of aromatic aldehyde, 2-aminobenzimidazole and
malonodinitrile in ethanol (Scheme 2). Their protocol has
the advantages of less toxic solvent and higher yields
(50%-60%). However, their reactions needed triethyl-
amine as catalyst.
Microwave irradiation power and temperature were
also optimized for the synthesis of 4a. The most suitable
irradiation power was 200 W and temperature was 80 °C.
Based on these optimized reaction conditions, a series
of 1,2-dihydro-pyrimido[1,2-a]benzimidazole-3-carbo-
nitrile derivatives were synthesized. The results are
summarized in Table 2.
Scheme 2
As shown in Table 2, this protocol could be applied not
only to the aromatic aldehydes with either electron-with-
drawing groups or electron-donating groups, but also to
aliphatic aldehydes, which highlighted the wide scope of
this three-component condensation. Furthermore, the
procedure is easy to operate and the workup procedure is
just simple filtration.
Ar
N
O
CN
HN
H
N
Ar
CN
CN
Et3N
NH2
+
NH2
N
N
EtOH, reflux
Moreover, we performed the synthesis of 4a with water
as solvent under both MWI and classical heating
conditions. The reaction was efficiently promoted by MWI
and the reaction time was strikingly shortened to 5 min
from 2.5 h required under traditional heating condition and
the yield was increased to 91% from 45%. Therefore,
microwave irradiation exhibited several advantages over
the conventional heating by significantly reducing the
reaction time and dramatically improving the reaction yield
owing to a specific nonthermal microwave effect [41].
In this study, all the products were characterized by
Therefore we wish to report a facile, rapid and green
protocol for the three component condensation reaction of
an aldehyde, malonodinitrile and 2-aminobenzimidazole
in water under microwave irradiation without catalyst
(Scheme 3).
Scheme 3
R
CN
HN
N
CN
CN
H2O
MWI
N
NH2
RCHO
NH2
+
+
N
N
H
1
melting point, IR and H NMR spectral data, as well as
elemental analyses.
2
1
3
In conclusion, we have developed a three-component
reaction of an aldehyde, malonodinitrile and 2-amino-
benzimidazole in water under microwave irradiation
conditions for the synthesis of 1,2-dihydro-pyrimido[1,2-
a]benzimidazole-3-carbonitrile derivatives. Particularly
valuable features of this method include excellent yields
of the products, shorter reaction time, reduced enviro-
nmental impact, and straightforward procedure.
4
RESULTS AND DISCUSSION
Choosing an appropriate solvent is of crucial
importance for successful MW promoted synthesis. In
order to search for the best condition for this reaction, the
MW assisted reaction of 4-chlorobenzaldehyde (1a),
malonodinitrile and 2-aminobenzimidazole was examined
in various volume proportions of EtOH and H2O, with the
total volume of 2 mL, at 80°C. All the reactions were
carried out with 200 W of power. The results are
summarized in Table 1.
As shown in Table 1, to our delighted, with all the
volume of water as solvent, satisfying result were obtained.
Water was used as the solvent for all further microwave-
assisted reactions as it is also environmentally friendly and
the use of expensive organic reagents can be avoided.
EXPERIMENTAL
Microwave irradiation was carried out in a monomodal EmrysTM
Creator from Personal Chemistry, Uppsala, Sweden. Melting points
were determined in open capillaries and are uncorrected. IR spectra
1
were recorded on a TENSOR 27 spectrometer in KBr. H NMR
spectra were measured on a DPX 400 spectrometer operating at 400
MHz, using DMSO-d6 as solvent and TMS as internal standard.
Elemental analyses were performed by using a Perkin-Elmer 240c
elemental analysis instrument.

Jul-Aug 2008 Green Multicomponent Synthesis of 1,2-Dihydro-pyrimido[1,2-a]-benzimidazole-3-carbonitrile
1129
Table 2
Synthesis of 4 in water under Microwave Irradiation Conditions at 80 °C
Entry
1
2
3
4
5
6
7
8
9
10
11
4
R
Time(min)
Yield(%)(lit)
Mp(°C)
4a
4b
4c
4d
4e
4f
4g
4h
4i
4-ClC6H4
C6H5
4-BrC6H4
2-ClC6H4
4-FC6H4
2,4-Cl2C6H3
4-CH3OC6H4
3,4-(CH3O)2C6H3
3,4,5-(CH3O)3C6H2
4-CH3C6H4
n-C4H9
5
5
4
5
4
4
5
5
6
5
6
91(37)38(60)39
241-242(232decomp)38(238)39
230-233(205-207)38(218)39
240-242(209)39
242-243
90(45)38(55)39
91(60)39
89
91
94
246-248
255-256
89(30)38(50)39
230-233(212-213)38(197)39
246-249
88
90(60)39
92
84
247-248(225)39
238-239
4j
4h
220-223
General Procedure for the synthesis of 1,2-dihydropyrim-
ido[1,2-a]benzimidazole-3-carbonitrile derivatives (4a-4j). In
a
C17H12ClN5: C, 63.46; H, 3.76; N, 21.77. Found: C, 63.38; H,
3.77; N, 21.69.
10 mL EmrysTM reaction vial, aldehyde (1 mmol),ꢀ
4-Amino-2-(4-fluorophenyl)-1,2-dihydropyrimido[1,2-a]-
benzimidazole-3-carbonitrile (4e). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3424, 3314, 3206, 3052, 2890, 2190, 1675, 1632,
malonodinitrile (1 mmol), 2-aminobenzimidazole (1 mmol) and
water (2 mL) were mixed and then capped. After irradiation
for 4-6 min, the reaction mixture was cooled to room
temperature. Then the solid was collected by filtration give
crude product, which was further purified by recrystallized from
95% EtOH.
4-Amino-2-(4-chlorophenyl)-1,2-dihydropyrimido[1,2-a]-
benzimidazole-3-carbonitrile (4a). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3420, 3326, 3214, 3058, 2884, 2188, 1677, 1598,
1468, 738 cm-1; 1H nmr: ꢀ 8.60 (s, 1H, NH), 7.63 (d, 1H, J = 8.0
Hz, ArH), 7.43 (d, 2H, J = 8.8 Hz, ArH), 7.31 (d, 2H, J = 8.4 Hz,
ArH), 7.24 (d, 1H, J = 7.6, ArH), 7.12 (t, 1H, J = 7.6 Hz, ArH),
7.01 (t, 1H, J = 7.6 Hz, ArH), 6.89 (s, 2H, NH2), 5.26 (s, 1H,
CH). Anal calcd. for C17H12ClN5: C, 63.46; H, 3.76; N, 21.77.
Found: C, 63.39; H, 3.75; N, 21.65.
4-Amino-2-phenyl-1,2-dihydropyrimido[1,2-a]benzim-
idazole-3-carbonitrile (4b). This compound was obtained
according to above general procedure; ir (potassium bromide):
3444, 3321, 3217, 3057, 2877, 2189, 1682, 1601, 1440, 1310,
1026, 816, 751 cm-1; 1H nmr: ꢀ 8.59 (s, 1H, NH), 7.61 (d, 1H, J
= 8.0 Hz, ArH), 7.37-7.23 (m, 6H, ArH), 7.12 (t, 1H, J = 7.2 Hz,
ArH), 7.01 (t, 1H, J = 8.0 Hz, ArH), 6.84 (s, 2H, NH2), 5.21 (s,
1H, CH). Anal calcd. for C17H13N5: C, 71.06; H, 4.56; N, 24.37.
Found: C, 71.73; H, 4.55; N, 24.43.
1
1598, 1252, 1066, 958, 810, 732 cm-1; H nmr: ꢀ 8.60 (s, 1H,
NH), 7.63 (d, 1H, J = 7.6 Hz, ArH), 7.35-7.31 (m, 2H, ArH),
7.24-7.18 (m, 3H, ArH), 7.12 (t, 1H, J = 7.6Hz, ArH), 7.01 (t,
1H, J = 7.6 Hz, ArH), 6.89 (s, 2H, NH2), 5.25 (s, 1H, CH). Anal
calcd. for C17H12FN5: C, 66.88; H, 3.96; N, 22.94. Found: C,
66.69; H, 3.95; N, 22.86.
4-Amino-2-(2,4-dichlorophenyl)-1,2-dihydropyrimido[1,2-a]-
benzimidazole-3-carbonitrile (4f). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3422, 3310, 3208, 2902, 2198, 1675, 1562, 1281,
1
1044, 864, 740 cm-1; H nmr: ꢀ 8.52 (s, 1H, NH), 7.68-7.66 (m,
2H, ArH), 7.48-7.46 (m, 1H, ArH), 7.40-7.38 (m, 1H, ArH),
7.25 (d, 1H, J = 8.0 Hz, ArH), 7.14 (t, 1H, J = 7.6 Hz, ArH),
7.03 (t, 1H, J = 7.6 Hz, ArH), 6.96 (s, 2H, NH2), 5.64 (s, 1H,
CH). Anal calcd. for C17H11Cl2N5: C, 57.32; H, 3.11; N, 19.66.
Found: C, 57.52; H, 3.10; N, 19.59.
4-Amino-2-(4-methoxyphenyl)-1,2-dihydropyrimido[1,2-a]-
benzimidazole-3-carbonitrile (4g). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3423, 3323, 3216, 3157, 3006, 2907, 2187, 1679,
1637, 1599, 1424, 1249, 1032, 835, 739 cm-1; 1H nmr: ꢀ 8.51 (s,
1H, NH), 7.63 (d, 1H, J = 8.0 Hz, ArH), 7.24-7.19 (m, 3H,
ArH), 7.15-7.09 (m, 1H, ArH), 7.12 (t, 1H, J = 7.2 Hz, ArH),
7.00 (t, 1H, J = 7.6 Hz, ArH), 6.91 (d, 2H, J = 8.8 Hz, ArH),
6.80 (s, 2H, NH2), 5.20 (s, 1H, CH), 3.72 (s, 3H, OCH3). Anal
calcd. for C18H15N5O: C, 68.13; H, 4.76; N, 22.07,. Found: C,
68.35; H, 4.75; N, 22.13
4-Amino-2-(4-bromophenyl)-1,2-dihydropyrimido[1,2-a]-
benzimidazole-3-carbonitrile (4c). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3423, 3325, 3213, 3057, 2905, 2187, 1676, 1597,
1
1467, 1245, 829, 737 cm-1; H nmr: ꢀ 8.61 (s, 1H, NH), 7.64-
7.56 (m, 3H, ArH), 7.26-7.23 (m, 3H, ArH), 7.12 (t, 1H, J = 7.2
Hz, ArH), 7.01 (t, 1H, J = 7.6 Hz, ArH), 6.89 (s, 2H, NH2), 5.23
(s, 1H, CH). Anal calcd. for C17H12BrN5: C, 55.75; H, 3.30; N,
19.15. Found: C, 55.86; H, 3.31; N, 19.22.
4-Amino-2-(3,4-dimethoxyphenyl)-1,2-dihydropyrimido-
[1,2-a]benzimidazole-3-carbonitrile (4h). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3431, 3323, 3217, 3064, 2932, 2837, 2189, 1682,
1600, 1469, 1400, 1263, 1026, 816, 740 cm-1; 1H nmr: ꢀ 8.51 (s,
1H, NH), 7.63 (d, 1H, J = 8.0 Hz, ArH), 7.12 (d, 1H, J = 7.6 Hz,
ArH), 7.11 (t, 1H, J = 7.6 Hz, ArH), 7.02-6.96 (m, 2H, ArH),
6.91 (d, 2H, J = 8.4 Hz, ArH), 6.84 (s, 2H, NH2), 6.77 (d, 1H, J
= 8.4 Hz, ArH), 5.19 (s, 1H, CH), 3.71 (s, 6H, 2OCH3). Anal
calcd. for C19H17N5O2: C, 65.69; H, 4.93; N, 20.16. Found: C,
65.50; H, 4.92; N, 20.23.
4-Amino-2-(2-chlorophenyl)-1,2-dihydropyrimido[1,2-a]-
benzimidazole-3-carbonitrile (4d). This compound was
obtained according to above general procedure; ir (potassium
bromide): 3426, 3313, 3208, 3058, 2896, 2198, 1678, 1630,
1
1599, 1443, 1242, 1061, 950, 817, 739 cm-1; H nmr: ꢀ 8.50
(s, 1H, NH), 7.67 (d, 1H, J = 8.0 Hz, ArH), 7.50-7.48 (m, 1H,
ArH), 7.35-7.34 (m, 3H, ArH), 7.25 (d, 1H, J = 8.0 Hz, ArH),
7.14 (t, 1H, J = 7.2 Hz, ArH), 7.03 (t, 1H, J = 7.6 Hz, ArH),
6.90 (s, 2H, NH2), 5.64 (s, 1H, CH). Anal calcd. for
4-Amino-2-(3,4,5-trimethoxyphenyl)-1,2-dihydropyrimido-
[1,2-a]benzimidazole-3-carbonitrile (4i). This compound was

1130
G. Liu, Q. Shao, S. Tuꢀ L. Cao, C. Li, D. Zhou, B. Han
Vol 45
[8] Delair, P.; Luche, J. L. J. Chem. Soc., Chem. Commun. 1989,
[9] R.; Maitra, U.; Rideact, D. C. Tetrahedron Lett. 1983, 24,
obtained according to above general procedure; ir (potassium
bromide): 3447, 3331, 3225, 3161, 3001, 2937, 2838, 2186,
1686, 1593, 1459, 1325, 1005, 843, 725 cm-1; 1H nmr: ꢀ 8.52 (s,
1H, NH), 7.63 (d, 1H, J = 8.0 Hz, ArH), 7.23 (d, 1H, J = 9.2 Hz,
ArH), 7.12 (t, 1H, J = 7.2 Hz, ArH), 7.01 (t, 1H, J = 8.0 Hz,
ArH), 6.87 (s, 2H, NH2), 6.63 (s, 2H, ArH), 5.19 (s, 1H, CH),
3.70 (s, 6H, 2OCH3), 3.63 (s, 3H, OCH3). Anal calcd. for
C20H19N5O3: C, 63.65; H, 5.07; N, 18.56. Found: C, 63.84; H,
5.06; N, 18.46.
398.
1901.
[10] Tan, X. H.; Hou, Y. Q.; Huang, C.; Liu, Li.; Guo, Q. X.
Tetrahedron, 2004, 60, 6129
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2001, 4, 1.
4-Amino-2-p-tolyl-1,2-dihydropyrimido[1,2-a]benzimidaz-
ole-3-carbonitrile (4j). This compound was obtained according
to above general procedure; ir (potassium bromide): 3484, 3421,
3325, 3214, 3052, 2918, 2187, 1687, 1597, 1400, 1247, 1100,
1
819, 738 cm-1; H nmr: ꢀ 8.53 (s, 1H, NH), 7.62 (d, 1H, J = 8.0
[16] Weber, L.; Illgen, K.; Almstetter, M. Synlett, 1999, 366.
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Hz, ArH), 7.23-7.09 (m, 6H, ArH), 7.00 (t, 1H, J = 7.2 Hz,
ArH), 6.80 (s, 2H, NH2), 5.15 (s, 1H, CH), 2.26 (s, 3H, CH3).
Anal calcd. for C18H15N5: C, 71.74; H, 5.02; N, 23.24. Found: C,
71.93; H, 5.03; N, 23.17.
4-Amino-2-butyl-1,2-dihydropyrimido[1,2-a]benzimidazole-
3-carbonitrile (4k). This compound was obtained according to
above general procedure; ir (potassium bromide): 3390, 3270,
3164, 2954, 2929, 2190, 1688, 1598, 1398, 1144, 822, 732 cm-1;
1H nmr: ꢀ 8.03 (s, 1H, NH), 7.59 (d, 1H, J = 7.6 Hz, ArH), 7.20
(d, 1H, J = 8.0 Hz, ArH), 7.09 (t, 1H, J = 7.2 Hz, ArH), 6.97 (t,
1H, J = 7.6 Hz, ArH), 6.67 (s, 2H, NH2), 4.04 (s, 1H, CH), 1.54
(s, 2H, CH2), 1.34-1.29 (m, 4H, 2CH2), 0.85 (s, 3H, CH3). Anal
calcd. for C15H17N5: C, 67.39; H, 6.41; N, 26.20. Found: C,
67.20; H, 6.42; N, 26.21.
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Acknowledgement. We thank for the National Natural
Science Foundation of China (No. 20672090), the Nature
Science Foundation of the Jiangsu Province (No. BK 2006033)
for financial support, Six Kinds of Professional Elite Foundation
of the Jiangsu Province (No. 06-A-039).
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