Versatility of alternative reaction media: Water-mediated domino and green chemical synthesis of pyrimido[1,2-a]benzimidazole under nonconventional conditions

Article abstract of DOI:10.1080/00397910802164732

A convenient and clean water-mediated synthesis of a series of 4-amino-2-aryl-1,2-dihydro pyrimido[1,2-a]benzimidazoles (4) is reported using alternative nonconventional energy sources. The products are obtained in shorter times with excellent yields (78-89%) from the multicomponent reaction of 2-aminobenzimidazole (1), malononitrile/ethylcyanoacetate (2a/b), and carbonyl compounds (3). The reaction is found to be general with respect to the cyclic and acyclic carbonyl compounds. The procedure does not involve the use of any additional reagent/catalyst, produces no waste, and represents a green synthetic protocol with high atom economy. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802164732

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Versatility of Alternative
Reaction Media: Water-
Mediated Domino and Green
Chemical Synthesis of
Pyrimido[1,2-a]benzimidazole
Under Nonconventional
Conditions
Anshu Dandia a , Ruby Singh a , Anuj Kumar Jain a &
Dharmendra Singh a
a Department of Chemistry, University of Rajasthan,
Jaipur, India
Version of record first published: 29 Sep 2008
To cite this article: Anshu Dandia, Ruby Singh, Anuj Kumar Jain & Dharmendra
Singh (2008): Versatility of Alternative Reaction Media: Water-Mediated Domino and
Green Chemical Synthesis of Pyrimido[1,2-a]benzimidazole Under Nonconventional
Conditions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:20, 3543-3555
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Synthetic Communications1, 38: 3543–3555, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802164732
Versatility of Alternative Reaction Media:
Water-Mediated Domino and Green Chemical
Synthesis of Pyrimido[1,2-a]benzimidazole
Under Nonconventional Conditions
Anshu Dandia, Ruby Singh, Anuj Kumar Jain, and
Dharmendra Singh
Department of Chemistry, University of Rajasthan, Jaipur, India
Abstract: A convenient and clean water-mediated synthesis of a series of
4-amino-2-aryl-1,2-dihydro pyrimido[1,2-a]benzimidazoles (4) is reported using
alternative nonconventional energy sources. The products are obtained in shorter
times with excellent yields (78–89%) from the multicomponent reaction of 2-
aminobenzimidazole (1), malononitrile=ethylcyanoacetate (2a=b), and carbonyl
compounds (3). The reaction is found to be general with respect to the cyclic
and acyclic carbonyl compounds. The procedure does not involve the use of
any additional reagent=catalyst, produces no waste, and represents a green
synthetic protocol with high atom economy.
Keywords: Aqueous media, microwave irradiations, pyrimido[1, 2-a]benzimidazole
INTRODUCTION
Several benzimidazole(1,3-dideazapurine) derivatives are important as
pharmaceuticals because they have been found to possess various biolo-
gical activities.[1–5] The notable clinical examples[6] being the antihistami-
nic astemizole, antiulcerative omeprazole, and fungicide rabenzazole.
Received February 20, 2008.
Address correspondence to Anshu Dandia, Department of Chemistry,
University of Rajasthan, Jaipur 302004, India. E-mail: dranshudandia@yahoo.
co.in
3543

3544
A. Dandia et al.
Pyrimido[1,2-a]benzimidazoles represent a pharmaceutically important
class of compound because of their diverse range of biological activities.[7]
Synthetic chemists continue to explore new methods to carry out che-
mical transformations. One of these new methods is to run the reactions
in aqueous media. Organic reactions in water, without the use of any
harmful organic solvent, are of great interest, because water is nontoxic,
nonflammable, abundantly available, and inexpensive.[8] Thus, water as
the reaction medium is generally considered a cheap, safe, and environ-
mentally benign alternative to synthetic solvent. Furthermore, because
of the low solubility of common organic compounds in water, the use
of water as solvent often makes the purification of product very easy
by simple filtration or extraction.[9]
Microwave[10] and ultrasonic irradiation,[11] as nonconventional
energy sources for activation of reactions, has now become a very popu-
lar and useful technology in organic chemistry. Further, the utility of a
multicomponent reaction in preparing libraries to screen for functional
molecules is well appreciated.[12]
The combination of microwave irradiation, ultrasonic irradiation,
and aqueous-mediated conditions using multicomponent reactions lead
to enhanced reaction rates, higher yields of pure products, easier workup,
and sometimes selective conversions. Consequently, this protocol should
be welcome in these environmentally conscious days.
Conventional syntheses of pyrimido[1,2-a]benzimidazole derivatives
have been extensively studied by various workers,[13] and they suffer
many drawbacks, such as multistep synthesis, low yields, and strong acid-
s=bases as catalysts with volatile organic solvents that are difficult to
recover. Consequently, there is a need for milder conditions, increased
variation of the substituents in the components, and better yields.
As a continuation of our research devoted to performing reactions
under solvent-free conditions[14] and using water as reaction medium,[15]
herein we report a versatile, environmentally friendly, one-pot, multicom-
ponent synthesis of a potentially biologically important scaffold, pyri-
mido[1,2-a]benzimidazoles (4), using nonconventional energy sources
(i.e., microwaves and ultrasound) by reacting 2-aminobenzimidazole with
malononitrile=ethylcynoacetate and various carbonyl compounds by
different synthetic pathways.
RESULTS AND DISCUSSION
A multicomponent condensation reaction of 1, 2, and 3 afforded the
product 4. To find the best method, we studied the synthesis of 4b, 4e,
and 4h with different parameters as shown in Table 1.

Pyrimido[1,2-a]benzimidazole
3545
Scheme 1.
The facile reaction occurs in neat condition in absence of any solvent
and catalyst under microwave irradiation but the product required further
purification and recrystallization with suitable solvents, giving compara-
tively lower yield. Further, although a reaction in ethanol also occurs
smoothly, it requires due precautions and modifications in microwave
oven for operational safety. However, reaction in aqueous medium save
better results under both microwaves and ultrasonic waves, probably
because of the beneficial hydrophobic effect=solvophobicity and hydrogen
bonding in water described previously.[16] For microwave-irradiated reac-
tions, the crystalline product was separated after the reaction by cooling
yields were high. With no need of further purification and crystallization.
Further comparison reactions were also studied under conventional
conditions and in the absence of catalyst. No reaction occurred in ethanol,
whereas in an aqueous medium, long reaction times with lower yield were
observed.
To further improve the procedure, the reaction was also studied using
cetyl trimethyl ammonium bromide as phase-transfer catalyst (Table 1,
entries ix and x), but no change in yield was observed. Although reaction
time was reduced slightly, it may be concluded that the aqueous medium is
the perfect method for the synthesis of pyrimido[1,2-a]benzimidazoles (4).
To demonstrate its generality, the method was then extended for
aromatic aldehydes with electron-withdrawing or donating groups, as
well as a-tetralone.
EXPERIMENTAL
Melting points were determined on a Toshniwal apparatus. The purity of
compounds was checked on thin layers of silica gel in various nonaqueous
solvent systems [e.g., benzene–ethylacetate (9:1), benzene–dichloromethane

Table 1. Comparative study for synthesis of 4b, 4e, and 4h
Time=yield (%)
Entry
Reaction conditions
Ethanol (MCR)a
Method
4b
4e
4h
i
ii
iii
iv
V
Vi
D
D
MW
No reaction
8 h=68
6 min=84
5 h=85
9 h=75
No reaction
7 h=52
5 min=82
4 h=86
8 h=70
No reaction
5 h=62
4 min=82
4 h=84
7 h=68
Ethanol þ triethylamine (MCR)
Ethanol (MCR)
Ethanol (MCR)
Ultrasound
Water (MCR)
Water (MCR)
D
MW
8 min=88
10 min=82
6 min=89

Vii
Viii
ix
x
xi
xii
xiii
xiv
Water (MCR)
Neat (MCR)
Ultrasound
MW
MW
Ultrasound
MW
MW
6 h=88
3.5 min=81
6 min=87
6 h=78
3 min=81
8 min=80
3.5 h=80
8 þ 4 min=82
5 þ 3 min=80
6 þ 5 min=83
4 þ 4 min=82
5 h=84
2.5 min=70
6 min=83
2.5 h=82
3 þ 2 min=78
4 þ 3 min=76
2 þ 3 min=84
3 þ 3.5 min=82
Water=PTCb (MCR)
Water=PTCb (MCR)
4 h=86
Alkene nitrilec (2 þ 3) þ 1 (ethanol)
Alkene nitrile (2 þ 3) þ 1 (water)
Anild (1 þ 3) þ 2a=b (ethanol)
Anil (1 þ 3) þ 2a=b (water)
5 þ 4emin=80
4 þ 4 min=78
4 þ 5f min=82
5 þ 6 min=80
MW
MW
Note. Power ¼ 600 W for water and 360 W for alcohol.
aMulticomponent reactions carried out in one pot.
bCetyl trimethyl ammonium bromide is used as phase-transfer catalyst for entries ix and x.
cAlkene-nitrile synthesized in situ by malononitrile (2)þcarbonyl compound (3).
dAnil synthesized in situ by 2-aminobenzimidazole (1)þcarbonyl compound (3).
e5 þ 4 indicates that first irradiation for 5 min gave intermediate alkene-nitrile (detected by TLC), which was synthesized in situ, and
then further irradiation for 4 min after adding 2-aminobenzimidazole.
f4 þ 5 indicates that first irradiation for 4 min gave intermediate anil (detected by TLC), which was synthesized in situ, and then
further irradiation for 5 min after adding malononitrile.

3548
A. Dandia et al.
(8:2)]. IR spectra (KBr) were recorded on a Magna FT IR–550 spectro-
1
photometer, and H NMR and 13C NMR spectra were recorded on a
Bruker DRX-300 using CDCl3 at 300.15 and 75.47 respectively. TMS
was used as internal reference. Mass spectram of representative com-
pounds were recorded on a Kratos 50 mass spectrometer at 70 eV. The
microwave-assisted reactions were carried out in a multimode microwave
oven (Panasonic-NN-781JF) equipped with inverter technology (generat-
ing fixed frequency throughout the required time) for realistic control of
the microwave operating at 1000 W generating 2450 MHz frequency and
the ultrasonic bath (Bandelin Sonorex) operating at 230 V generating 33
KHz output frequency.
General Procedure for the Reaction of 2-Aminobenzimidazole (1), Active
Methylene Reagents (2), and Carbonyl Compounds (3)
Conventional Method
A solution of 2-aminobenzimidazole (1) (0.01 mol), active methylene
reagent (2) (0.01 mol), and carbonyl compound (3) (0.011 mol) in ethanol
(50 ml) was refluxed for 3 days. However, no reaction occurred after the
intermediate stage. Drops of trietylamine (4–5) were added to reaction
mixture, and there was an immediate colour change from light yellow
to reddish yellow. The reaction was continued for 5 h (thin-layer chroma-
tography, TLC, control). The reaction mixture was kept overnight at
room temperature, and the resulting precipitate was filtered, washed with
ethanol, dried, and recrystallized from ethanol.
Neat=MW
An equimolar (0.01mol) neat mixture of 1, 2, and 3 in an open vessel was
mixed thoroughly with a rod. Heat evolved, and the color changed from
white to pale yellow. The mixture was then irradiated in the MW oven at
a power output of 600 W for an appropriate time (monitored by TLC).
The mixture took on a dark yellow to reddish color. After completion of
the reaction, ethanol (10ml, sufficient to dissolve melted solid) was added
before filtration. The filtrate was kept overnight in the refrigerator, and white
shiny crystals formed, which were filtered and recrystallizsed from ethanol.
Ethanol=MW
An equimolar (0.01 mol) quantity of 1, 2, and 3 was placed in a beaker,
and the minimum quantity of ethanol, sufficient to make slurry, was

Pyrimido[1,2-a]benzimidazole
3549
added. The mixture was placed in the MW oven and irradiated at power
output of 360 W for 4–5 min (TLC). The product started to separate out
immediately after cooling the reaction mixture to room temperature (or
in some cases during the course of reaction). The crystalline solid that
separated out was filtered and found to be pure on TLC with no need
of further recrystallization.
Ultrasonic Bath
An equimolar (0.01 mol) quantity of 1, 2, and 3 was placed in a beaker, and
dissolved in ethanol with 3–4 drops of triethylamine. The mixture was
placed under ultrasonic waves using an ultrasonic bath (operating at
230 V generating 33 KHz output frequencies) for 30–40 min (TLC) at
room temperature. The product started to separate out during the course
of the reaction. The crystalline solid that separated out was filtered and
found to be pure on TLC with no need of further recrystallization.
Water=MW
An equimolar (0.01 mol) quantity of 1, 2, and 3 was placed in a beaker,
and the minimum quantity of water (10 ml) was added. The mixture was
placed in the microwave oven and irradiated at power output of 600 W
for 7–8 min (TLC). The product started to separate out immediately after
the reaction mixture cooled to room temperature. The crystalline solid
that separated out was filtered and found to be pure on TLC with no
need of further recrystallization. All compounds 4a-k were similarly
synthesized comparatively in high yields and reduced times using water
under microwaves.
Data
4-Amino-2-Phenyl-1,2-Dihydropyrimido[1,2-a]benzimidazole-3-
carbonitrile (4a)
Yield: 2.52 g (88%); white crystal; Mp ¼ 208–209 ꢀC. IR (KBr) Vmax
1
3420–3215 (br, NH & NH2), 2202 (CN), 1610 cmꢁ1 (C ¼ N). H NMR
(DMSO) (d, ppm) 5.20 (s, 1H, CH), 6.80 (s, 2H, NH2), 7.03 (t, 1H,
Ar-H), 7.12 (t, 1H, Ar-H), 7.23 (d, 1H, Ar-H), 7.63 (d, 1H, Ar-H),
7.28–7.38 (m, 5H, Ar-H), 8.61 (s, 1H, NH). C17H13N5 (287.32): calc. C,
71.06; H, 4.56; N, 24.37. Found:C, 71.30; H, 4.57; N, 24.45%.

3550
A. Dandia et al.
4-Amino-2-(4-Methoxyphenyl)-1,2-Dihydropyrimido[1,2-a]benzimidazole-
3-carbonitrile (4b)
Yield: 2.59 g (88%); white shiny crystal; Mp ¼ 197–199 ꢀC. IR (KBr) Vmax
1
3470–3240 (br, NH & NH2), 2180 (CN), 1620 cmꢁ1 (C ¼ N). H NMR
(DMSO) (d, ppm) 3.71 (s, 3H, CH3), 5.14 (s, 1H, CH), 6.79 (s, 2H,
NH2), 7.02 (t, 1H, Ar-H), 7.11 (t, 1H, Ar-H), 7.22 (d, 1H, Ar-H), 7.63
(d, 1H, Ar-H), 6.63–6.91 (m, 4H, Ar-H), 8.53 (s, 1H, NH). C18H15
N5O (317.34): calc. C, 68.13; H, 4.76; N, 22.07. Found: C, 68.34; H,
4.77; N, 22.14%.
4-Amino-2-(3-Nitrophenyl)-1,2-Dihydropyrimido[1,2-a]benzimidazole-
3-carbonitrile (4c)
Yield: 2.65 g (80%); pale yellow crystal; Mp ¼ 242–243 ꢀC. IR (KBr) Vmax
3460–3230 (br, NH & NH2), 2190 (CN), 1625 (C ¼ N), 1575 & 1380 cmꢁ1
1
(NO2). H NMR (DMSO) (d, ppm) 5.25 (s, 1H, CH), 6.86 (s, 2H, NH2),
7.01 (t, 1H, Ar-H), 7.11 (t, 1H, Ar-H), 7.23 (d, 1H, Ar-H), 7.23 (d, 1H,
Ar-H), 7.30–7.42 (m, 4H, Ar-H), 8.71 (s, 1H, NH). C17H12
N6O2 (332.32): calc. C, 61.44; H, 3.64; N, 25.29. Found: C, 61.24; H,
3.65; N, 25.36%.
4-Amino-2-Methyl-2-Phenyl-1,2-Dihydropyrimido[1,2-a]benzimidazole-
3-carbonitrile (4d)
Yield: 2.16 g (79%); white crystal; Mp ¼ 228–230 ꢀC. IR (KBr) Vmax
1
3470–3240 (br, NH & NH2), 2180 (CN), 1620 cmꢁ1 (C ¼ N) HNMR
(DMSO) (d, ppm) 1.60 (s, 1H, CH3), 6.79 (s, 2H, NH2), 7.01 (t, 1H,
Ar-H), 7.11 (t, 1H, Ar-H), 7.21 (d, 1H, Ar-H), 7.63 (d, 1H, Ar-H),
7.16–7.40 (m, 5H, Ar-H), 8.61 (s, 1H, NH). C18H15N5 (301.35): calc. C,
71.74; H, 5.02; N, 23.24. Found: C, 71.98; H, 5.03; N, 23.31%.
40-Amino-10H-spiro[cyclopentane-1,20-pyrimido[1,2-a]benzimidazole]-
30-carbonitrile (4e)
Yield: 2.12g (80%); white crystal; Mp¼ 170–172 ꢀC. IR (KBr) Vmax 3470–
3250 (br, NH & NH2), 2915–2885 (br, ali. CH), 2175 (CN), 1630 cmꢁ1
1
(C ¼ N). H NMR (DMSO) (d, ppm) 1.43–1.48 (m, 4H, CH2), 1.53–1.80
(m, 4H, CH2), 5.95 (s, 2H, NH2), 7.07 (t, 1H, Ar-H), 7.19 (t, 1H, Ar-H),
7.36 (d, 1H, Ar-H), 7.60 (d, 1H, Ar-H), 8.50 (s, 1H, NH). C15H15N5
(265.31): calc. C, 67.90; H, 5.70; N, 26.40. Found: C, 67.67; H, 5.72; N,
26.48%.

Pyrimido[1,2-a]benzimidazole
3551
40-Amino-3,4-dihydro-2H,10H-spiro[naphthalene-1,20-pyrimido[1,2-a]-
benzimidazole]-30-carbonitrile (4f)
Yield: 2.35 g (78%); brown powder; Mp ¼ 310–311ꢀC. IR (KBr) Vmax
3480–3245 (br, NH & NH2), 2925–2865 (br, ali. CH), 2175 (CN),
1
1605 cmꢁ1 (C ¼ N). HNMR (DMSO) (d, ppm) 2.19 (m, 2H,CH2), 2.64
(m, 2H, cH2), 3.02 (m, 2H, CH2), 6.46 (s, 2H, NH2) 7.12 (t, 1H,
Ar-H), 7.27 (t, 1H, Ar-H), 7.60 (m, 3H, Ar-H), 7.93 (m, 3H, Ar-H),
8.62 (s, 1H, NH). C20H17N5 (327.38): calc. C, 73.37; H, 5.23; N, 21.39.
Found: C, 73.62; H, 5.25; N, 21.46%.
Ethyl-4-amino-2-phenyl-1,2-dihydropyrimido[1,2-a]benzimidazole-3-
carboxylate (4 g)
Yield: 2.97 g (89%); white crystal; mp ¼ 220–221ꢀC. IR (KBr) Vmax 3465–
3240 (br, NH & NH2), 1740 (C ¼ O), 1620 (C ¼ N), 1080 cmꢁ1 (C-O).
1H NMR (DMSO) (d, ppm) 1.45 (t, 3H, CH3, J ¼ 6.1Hz), 4.39 (q, 2H,
CH2, J ¼ 6.1Hz), 5.25 (s, 1H, CH), 6.85 (s, 2H, NH2), 7.05 (t, 1H, Ar-
H), 7.15 (t, 1H, Ar-H), 7.25 (d, 1H, Ar-H), 7.65 (d, 1H, Ar-H), 7.25–7.32
(m, 5H, Ar-H), 8.65 (s, 1H, NH). C19H18N4O2 (334.37): calc. C, 68.25; H,
5.43; N, 16.76. Found: C, 68.50; H, 5.41; N, 16.80%.
Ethyl-4-amino-2-(3-nitrophenyl)-1,2-dihydropyrimido[1,2-a]
benzimidazole-3-carboxylate (4 h)
Yield: 3.37 g (89%); yellow needles; Mp ¼ 246–247ꢀC. IR (KBr) Vmax
3473–3242 (br, NH & NH2), 1745 (C ¼ O), 1622 (C ¼ N), 1575 & 1380
1
(NO2), 1085 cmꢁ1 (C-O). H NMR (DMSO) (d, ppm) 1.39 (t, 3H, CH3,
J ¼ 6.3Hz), 4.42 (q, 2H, CH2, J ¼ 6.3 Hz), 5.27 (s, 1H, CH), 6.88 (s, 2H,
NH2), 7.05 (t, 1H, Ar-H), 7.10 (t, 1H, Ar-H), 7.22 (d, 1H, Ar-H), 7.24
(d, 1H, Ar-H), 7.35–7.41 (m, 4H, Ar-H), 8.70 (s, 1H, NH).
C19H17N5O4 (379.37): calc. C, 60.15; H, 4.52; N, 18.46. Found: C,
60.35; H, 4.54; N, 18.51%
Ethyl-40-amino-10H-spiro[cyclohexane-1,20-pyrimido[1,2-a]
benzimidazole]-30-carboxylate (4i)
Yield: 2.60 g (80%); white crystal; mp ¼ 247–249 ꢀC. IR (KBr) Vmax 3480–
3240 (br, NH & NH2), 2930–2880 (br, ali. CH), 1730 (C ¼ O), 1630
(C ¼ N), 1120 cmꢁ1 (C–O). 1H NMR (DMSO) (d, ppm) 1.25–1.31
(m, 4H, CH2), 1.42 (t, 3H, CH3, J ¼ 6.2 Hz),1.63–1.93 (m, 6H, CH2),

3552
A. Dandia et al.
4.40 (q, 2H, CH2, J ¼ 6.2 Hz), 5.87 (s, 2H, NH2), 7.06 (t, 1H, Ar-H), 7.14
(t, 1H, Ar-H), 7.34 (d, 1H, Ar-H), 7.64 (d, 1H, Ar-H), 8.72 (s, 1H, NH).
C18H22N4O2 (326.39): calc. C, 66.24; H, 6.79; N, 17.17. Found: C, 66.46;
H, 6.77; N, 17.22%.
Ethyl-40-amino-10H-spiro[cyclopentane-1,20-pyrimido[1,2-a]-
benzimidazole]-30-carboxylate (4j)
Yield: 2.34 g (85%); white crystal; Mp ¼ 230–231ꢀC. IR (KBr) Vmax 3470–
3240 (br, NH & NH2), 2920–2880 (br, ali. CH), 1720 (C ¼ O), 1620
(C ¼ N), 1110 cmꢁ1 (C-O). 1H NMR (DMSO) (d, ppm) 1.34 (t, 3H,
CH3, J ¼ 6.4 Hz), 1.41–1.47 (m, 4H, CH2), 1.52–1.81 (m, 4H, CH2),
4.37 (q, 2H, CH2, J ¼ 6.4 Hz), 5.96 (s, 2H, NH2), 7.06 (t, 1H, Ar-H),
7.18 (t, 1H, Ar-H), 7.38 (d, 1H, Ar-H), 7.62 (d, 1H, Ar-H), 8.51 (s, 1H,
NH). C17H20N4O2 (312,37): calc. C, 65.37; H, 6.45; N, 17.94. Found:
C, 65.15, H, 6.47; N, 17.99%.
Ethyl-40-amino-3,4-dihydro-2H,10H-spiro[naphthalene-1,20-
pyrimido[1,2-a]benzimidazole]-30-carboxylate (4k)
Yield: 2.91 g (78%); brown powder; mp ¼ 208–210 ꢀC. IR (KBr) Vmax
3475–3245 (br, NH & NH2), 2925–2870 (br, ali. CH), 1735 (C ¼ O),
1625 (C ¼ N), 1130 cmꢁ1 (C–O). 1HNMR (DMSO) (d, ppm) 1.40 (t,
3H, CH3, J ¼ 6Hz), 2.17 (m, 2H, CH2), 2.66 (m, 2H, CH2), 3.04 (m,
2H, CH2), 4.41 (q, 2H, CH2, J ¼ 6 Hz), 6.48 (s, 2H, NH2), 7.14 (t, 1H,
Ar-H), 7.28 (t, 1H, Ar-H), 7.62 (m, 3H, Ar-H), 7.95 (m, 3H, Ar-H),
8.65 (s, 1H, NH). C22H22N4O2 (374.44): calc. C, 70.57; H, 5.92; N,
14.96. Found: C, 70. 80; H, 5.94; N, 14.91%.
Presence and position of NH and NH2 protons were confirmed by
deuterium exchange.
CONCLUSION
We have described herein an efficient, cleaner, green methodology
for watermediated synthesis of pyrimido[1,2-a]benzimidazoles. The
advantages, such as (i) no requirement of additional reagent=catalyst,
(ii) nonflammable and nontoxic reaction medium, (iii) high yields, (iv)
virtually no waste generation, and (vi) ease of product isolation=
purification, fulfill the philosophy of green chemistry and make the pre-
sent methodology environmentally benign.

Pyrimido[1,2-a]benzimidazole
ACKNOWLEDGMENTS
3553
Financial assistance from the Council for Scientific and Industrial
Research (01/2248/08/EMR-II) (9/149/398/2005/EMR-I), New Delhi
are gratefully acknowledged. We are also thankful to the Regional
Sophisticated Instrumentation Centre Chandigarh, and Central Drug
Research Institute, Lucknow, for the elemental and spectral analyses.
REFERENCES
1. Kubo, K.; Inada, Y.; Kohara, Y.; Sugiura, Y.; Ojima, M.; Itoh, K.;
Yoshiyasu, F.; Kohei, N.; Nakat, T. Nonpeptide angiotensin I1 receptor
antagonists: Synthesis and biological activity of benzimidazoles. J. Med.
Chem. 1993, 36, 1772–1784.
2. Bartlett, M. S.; Edlind, T. D.; Durkin, M. M.; Shaw, M. M.; Queener, S. F.;
Smith, J. W. Antimicrotubule benzimidazoles inhibit in vitro growth of
Pneumocystis carinii. Antimicrob. Agents. Chemother. 1992, 36, 779–782.
3. Paramashivappa, R.; Phani Kumar, P.; Subba Rao, P. V.; Rao, S. A. Design,
synthesis, and biological evaluation of benzimidazole=benzothiazole and
benzoxazole derivatives as cyclooxygenase inhibitors. Bioorg. Med. Chem.
2003, 13, 657–660.
4. Dhage, A. N.; Jashi, N. S.; Wadokar, S. G.; Kasture, A. V. Antimicrobial
and local anthesthetic activity of some benzimidazoles. Indian Drugs 1986,
23, 601; Chem. Abstr. 1987, 106, 168513.
5. Elnima, E. I.; Zubair, M. U.; Al-Badr, A. A. Antibacterial and antifungal
activities of benzimidazole and benzoxazole derivatives. Antimicrob Agents
Chemother. 1981, 19, 29–32.
6. Ramalingan, C.; Balasubramanian, S.; Kabilan, S. A convenient synthesis of
novel 1-[2-(benzimidazol-2-yl)ethoxy]-2,6-diarylpiperidin-4-ones. Synth. Commun.
2004, 34(6), 1105–1116.
7. (a) De Araujo, J. E.; Huston, J. P.; Brandao, M. Opposite effects of substance
P fragment C (anxiogenic) and N (anxiolutic) injected into doal pariaqueduc-
tal gray. Eur. J. Pharmaco. 2001, 432(1), 43–51. (b) Wonda, N.; Michal, Z.
Synthesis and immunotropic activity of some 2-aminobenzimdazoles. Archiv
der pharmazie 1999, 337, 249–253; (c) Trapani, G.; Farnco, M.; Latrofa, A.;
Genchi, G.; Iacobazzi, V. Synthesis and benzodiazepine receptor binding of
some imidazo-pyrimido[2,1-b] benzoxazoles and pyrimido[1,2-a]benzimida-
zoles. Eur. J. Med. Chem. 1997, 32(1), 83–90.
8. (a) Sheldon, R. A. Green solvents for sustainable organic synthesis: State of the
art. Green Chem. 2005, 7, 267–278. (b) Manabe, K.; Limura, S.; Sun, X.-M.;
Kobyashi, S. Dehydration reactions in water: Brønsted acid surfactant-
combined catalyst for ester, ether, thioether, and dithioacetal formation in
water. J. Am. Chem. Soc. 2002, 124, 11971–11978, and references cited therein.
9. (a) Li, C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; New York:
Wiley Interscience, 1997; (b) Lindstrom, U. M. Stereoselective organic

3554
A. Dandia et al.
reactions in water. Chem. Rev. 2002, 102, 2751–2772; (d) Li, C.-J. Organic
reactions in aqueous media with a focus on C-C bond formations. Chem.
Rev. 2005, 105, 3095–3165.
10. (a) Loupy, A. Microwaves in Organic Synthesis; Wiley-VCH: Weinheim,
2006; (b) Kappe, C. O.; Stadler, A. Microwaves in Organic and Medicinal
Chemistry; Wiley-VCH: Weinheim, 2005.
11. Pang, Y.; Song, G.; Dou, R. Surface cleaning under combined microwave
and ultrasound irradiation: Flash synthesis of 4H-pyrano[2,3-c]pyrazoles in
aqueous media. Green Chem. 2006, 8, 573–575.
12. Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.; Keating,
T. A. Multiple-component condensation strategies for combinatorial library
synthesis. Acc. Chem. Res. 1996, 29, 123–131; (b) Dax, S. L.; McNally, J. J.;
Yougman, M. A. Multi-component methodologies in solid-phase organic
synthesis. Curr. Med. Chem. 1999, 6, 255–270.
13. (a) Krasovsky, A. L.; Hartulyari, A. S.; Nenajdenko, V. G.; Balenkova, E. S.
Efficient syntheses of new CF3-containing diazolopyrimidines. Synthesis 2002,
1, 133–137; (b) Lipson, V. V.; Orlov, V. D.; Desenko, S. M.; Shishkina, S.
V.; Shishkin, O. V.; Shirobokova, M. G. 1,2,3,4-Tetrahydropyrimido[1,2-a]-
benzimidazole-2 and -4-ones, Chem. Het. Compd. 2000, 36(9), 1039–1042; (d)
Afeefy, H. Y. Synthesis of new pyrimido[1,2]benzimidazole and triazole[1,5-
a]pyrimidine. Boll. Chim. Farm. 1998, 137(11), 480–483; (e) Asobo, P. F.; Wahe,
H.; Mabafor, J. T.; Nkengfack, A. E. Fonum, Z. T.; Sopbue, E. F.; Dopp, D. J.
The formation of novel biologically active pyrimido[1,2-a]benzimidazoles
from allenicnitriles and aminobenzimidazoles. Chem. Soc. Perkin Trans. 2001,
457–461; (f) Wahe, H.; Asobo, P. F.; Cherkasov, R. A.; Fomum, Z. T.; Doepp,
D. Formation of pyrimido[1,2-a]benzimidazoles and oxazolo[3,2-a]benzimida-
zoles. Arkivoc 2004, (1), 130; (g) Dawood, K. M.; Farog, A. M.; Kandeel,
Z. E. J. Chem. Res,. Syno. 1999, 88; (h) Al-Afaleq Eljazi, I. Heterocyclic
synthesis via naminonitriles. Synth. Commun. 2000, 30(11), 1985–1999.
14. (a) Dandia, A.; Singh, R.; Khaturia. Efficient microwave enhanced solvent-
free synthesis of potent antifungal fluorinated benzothiazepine fused b-lactam
derivatives. J. Fluorine Chem. 2007, 128, 524–529; (b) Dandia, A.; Singh, R.;
Khaturia, S. Microwave enhanced solid support synthesis of fluorine containing
benzopyrano-triazolo-thiadiazepines as potent antifungal agents. Bioorg.
Med. Chem. 2006, 14, 1303–1308; (c) Dandia, A.; Arya, K.; Sati, M.;
Gautam, S. Microwave assisted green chemical synthesis of novel spiro
[indole-pyrido thiazines]: A system reluctant to be formed under thermal condi-
tions. Tetrahedron 2004, 60, 5253–5258; (d) Dandia, A.; Sati, M.; Arya, K.;
Loupy, A. Dry-media one-pot syntheses of fluorinated-2,3-dihydro-1,5-
benzothiazepines under microwave activation. Green Chem. 2002, 4, 599–602;
(e) Dandia, A.; Sachdeva, H.; Singh, R. J. Chem. Res,. Synop. 2000, 272–275.
15. (a) Dandia, A.; Arya, K.; Sarawgi, P. Facile one-pot green chemical synthesis
of 1,3,5-tri-(quinazolinyl=benzothiazolyl=benzimidazolyl)-s-triazines in aqu-
eous medium under microwaves. J. Indian Chem. Soc. 2003, 80, 1183–1186;
(b) Dandia, A.; Arya, K.; Sati, M.; Sarawgi, P. J. Fluorine Chem. 2004,
125, 1273–1277; (c) Dandia, A.; Arya, K.; Sati, M. Microwave assisted

Pyrimido[1,2-a]benzimidazole
3555
synthesis of fluorinated hexahydro-1,3,5-triazine derivatives in aqueous
medium and one-pot synthesis of 1,2,4-triazolo-(4,3-a)-1,3,5-triazines. Synth.
Commun. 2004, 34(6), 1141–1155.
16. (a) Breslow, R. Hydrophobic effects on simple organic reactions in water.
Acc. Chem. Res. 1991, 24, 159; (b) Otto, S.; Engberts J. B. F. N. Diels-Alder
reactions in water. Pure Appl. Chem. 2000, 72, 1365–1372; (c) Otto, S.;
Engberts, J. B. F. N. Hydrophobic interactions and chemical reactivity.
Org. Biomol. Chem. 2003, 1, 2809–2820.