P-Toluenesulfonic acid-catalyzed one-pot synthesis of 2-amino-4- substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles under neat conditions

Article abstract of DOI:10.1016/j.crci.2013.08.007

A simple, efficient, and green procedure for the preparation of 2-amino-4-substituted-1,4-dihydrobenzolo[4,5]imidazolo[1,2-a] pyrimidine-3-carbonitriles has been developed by multi-component condensation of 2-aminobenzimidazole with aldehydes and malononitrile in the presence of a catalytic amount of p-toluenesulfonic acid, affording excellent yields under neat conditions. The protocol avoids the use of expensive catalysts, toxic solvents, and chromatographic separation. We believe that this new environmentally metal-free procedure, combined to a solvent-free reaction, would be of importance in the search of green laboratory-scale synthesis.

Full text of DOI:10.1016/j.crci.2013.08.007

C. R. Chimie 17 (2014) 484–489
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Full paper/Memoire
p-Toluenesulfonic acid-catalyzed one-pot synthesis of
2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo
[1,2-a]pyrimidine-3-carbonitriles under neat conditions
*
Mudumala Veeranarayana Reddy, Jeongsu Oh, Yeon Tae Jeong
Department of Image Science and Engineering, Pukyong National University, Busan 608-737, Korea
A R T I C L E I N F O
A B S T R A C T
Article history:
A simple, efficient, and green procedure for the preparation of 2-amino-4-substituted-1,4-
dihydrobenzolo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles has been developed by
multi-component condensation of 2-aminobenzimidazole with aldehydes and malononi-
trile in the presence of a catalytic amount of p-toluenesulfonic acid, affording excellent
yields under neat conditions. The protocol avoids the use of expensive catalysts, toxic
solvents, and chromatographic separation. We believe that this new environmentally
metal-free procedure, combined to a solvent-free reaction, would be of importance in the
search of green laboratory-scale synthesis.
Received 23 May 2013
Accepted after revision 19 August 2013
Available online 26 September 2013
Keywords:
p-Toluenesulfonic acid
1,4-Dihydrobenzo[4,5]imidazolo[1,2-
a]pyrimidines
ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
Solvent-free reaction
2-Aminobenzimidazole
Malononitrile
1. Introduction
in biologically active pharmaceuticals, agrochemicals and
medicinal chemistry [11]. Pyrimidinobenzimidazoles pos-
Nowadays, multi-component reactions (MCRs) have
proven to be appreciated in organic, medicinal chemistry
and other industries [1–4]. Such protocols can be used for
drug design and diversity-oriented synthesis of hetero-
cycles because of their simplicity, efficiency, and high
selectivity [5]. This environmentally friendly process can
avoid waste of time as well as energy consumption, and
permits to reduce the number of steps. MCRs under
solvent-free conditions have attracted much interest from
chemists, particularly from the viewpoint of green
chemistry. The possibility of performing MCR reactions
sess antimicrobial activity, molluscidal activities, antidia-
betic, herbicidal activity, platelet anti-aggregant antiulcer
activity, DNA-gyrase inhibitors and anti-inflammatory
activities as well as anticancer efficacy; they can play
the role of antagonists of the paralyzing action of
antidiabetic activity and are important core motifs in a
broad range of biologically active compounds that are
frequently used in pharmaceutical and drug research,
agricultural science, and dye industry [12–14]. N-Fused
heterocycles of imidazole and pyrimidines frameworks,
imidazopyrimidine derivatives are important biological
molecules, and they exhibit more biological activity [15],
such as anti-inflammatory, antiviral, antimicrobial, antic-
onvulsant, anti-asthma, anti-diabetes, anti-hepatitis B,
anti-vascular hypertension, anti-arrhythmia, and antic-
ancer activities [15d]. Only a few methods have been
reported for the one-pot synthesis of imidazopyrimidine
derivatives [16]. However, these procedures suffer from
relatively long reaction times and low yields. Therefore,
the development of an easy and efficient method for the
under solvent-free conditions with
a catalyst could
enhance their efficiency from an economic as well as
ecological point of view [6–10].
Nitrogen-containing heterocycles are widely found in
nature and gain much importance due to their applications
*
Corresponding author.
E-mail address: ytjeong@pknu.ac.kr (Y.T. Jeong).
1631-0748/$ – see front matter ß 2013 Acade´mie des sciences. Published by Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.crci.2013.08.007

M.V. Reddy et al. / C. R. Chimie 17 (2014) 484–489
485
º
Scheme 1. Synthesis of 2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles catalyzed by p-TSA under neat
conditions.
preparation of 2-amino-4-substituted-1,4-dihydrobenzo-
lo[4,5]imidazo[1,2-a]pyrimidine-3-carbonitriles is still a
challenging task.
products when using p-TSA (Table 1, entry 19). Most
excitingly, when p-TSA was used, the reaction proceeded
very smoothly and gave the product 4a in 92% yield (Table
1, entry 19). Moreover, we found that the yields were
obviously affected by the amount of p-TSA loaded. When
2 mol%, 5 mol%, 10 mol%, and 20 mol% of p-TSA were used,
the yields were 65, 85, 92, and 93%, respectively (Table 1,
entries 19–22). Therefore, 10 mol% of p-TSA was sufficient
and excessive amounts of catalyst did not increase the
yields significantly.
To find the optimum reaction temperature, the reaction
was studied at different temperatures for the preparation
of 4a with 10 mol% p-TSA under neat conditions (Table 2).
It was observed that the reaction did not proceed at room
temperature. We were pleased to find that the reaction
proceeded smoothly and that almost complete conversion
of reactants was observed at 80 8C to afford the desired
product (4a) in 92% yield within 30 min (Table 2 entry 4).
Further increase of the temperature did not affect the
product yield.
p-Toluenesulfonic acid (p-TSA) has received consider-
able attention as a catalyst for various organic transforma-
tions due to its non-toxicity, ease of handling,
commercially availability, inexpensiveness, air and water
compatibility, and strong organic acidic nature [17].
Solvent-free reaction-endorsed p-TSA reactions are well
known as environmentally benign methods that also
usually provide improved selectively, enhanced reaction
rates, cleaner products, and manipulative simplicity [18].
In a continuation of our interest in developing more
efficient and environmental benign methodologies [19],
we described a method for the synthesis of 2-amino-
4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyr-
imidine-3-carbonitriles by a one-pot, multi-compound
condensation of 2-aminobenzimidazole, aldehydes, and
malononitrile catalyzed by p-TSA under neat conditions at
80 8C (Scheme 1).
2. Results and discussion
Table 1
In our initial study, the reaction of 2-aminobenzimi-
dazole 1, 4-bromobenzaldehyde 2a, and malononitrile 3
was chosen as a model reaction to optimize the reaction
conditions at 80 8C. The results are summarized in Table 1.
The reaction was first carried out in ethanol in the absence
and presence of several acid catalysts. The reaction did not
proceed even after prolonged reaction time and no desired
product was formed in the absence of catalyst. But under
vigorous reaction conditions, a small amount of product
was observed (Table 1, entry 1). Therefore, our efforts
focused on the search for a suitable catalyst. Some Lewis
acid (Table 1, entries 2–7) can catalyze this reaction with
moderate yields. With these merits, like reaction time,
product yield, the p-TSA is the desired protocol for MCR
reactions (Table 1, entry 8) and for the model reaction. In
addition, methanol, water, DMF, and CH3CN (Table 1,
entries 9–12) were also tested as the solvents. In these
cases, product 4a was formed in slightly lower yields.
With respect to the solvent system, the best results
were achieved using ethanol (Table 1, entry 8). In recent
years, the synthesis of compounds under solvent-free
conditions is an important task in heterocyclic synthesis.
Therefore, we decided to test a solvent-free version with
various catalysts (Table 1, entries 13–18). We found that
the reaction was rapid and gave excellent yields of the
Optimization of catalysts and solvents in the synthesis of 4aa.
Entry
Catalyst (%)
Solvent
Time
Yield
(%)b
1
None
Ethanol (10 mL)
Ethanol (10 mL)
Ethanol (10 mL)
Ethanol (10 mL)
Ethanol (10 mL)
Ethanol (10 mL)
Ethanol (10 mL)
Ethanol (10 mL)
Methanol (10 mL)
Water (10 mL)
DMF (10 mL)
Acetonitrile (10 mL)
Neat
6 h
20
65
56
45
65
45
70
80
70
45
65
55
75
65
54
70
55
75
92
60
85
93
2
InCl3 (10)
InF3 (10)
3 h
3
4 h
4
GaCl3 (10)
FeCl3 (10)
ZnCl2.H2O (10)
Li(OTf) (10)
p-TSA (10)
p-TSA (10)
p-TSA (10)
p-TSA (10)
p-TSA (10)
InCl3 (10)
InF3 (10)
3 h
5
4 h
6
5 h
7
2 h
8
1 h
9
1.5 h
4 h
10
11
12
13
14
15
16
17
18
19
20
21
22
2 h
3 h
2 h
Neat
3 h
GaCl3 (10)
FeCl3 (10)
ZnCl2.H2O (10)
Li(OTf) (10)
p-TSA (10)
p-TSA (2)
Neat
2 h
Neat
1 h
Neat
3 h
Neat
2 h
Neat
30 min
60 min
45 min
30 min
Neat
p-TSA (5)
Neat
p-TSA (20)
Neat
a
Reaction of 2-aminobenzimidazole 1 (1 mmol), 4-bromobenzalde-
hyde 2a (1 mmol) and malononitrile 3 (1 mmol) at 80 8C.
b
Isolated yield.

486
M.V. Reddy et al. / C. R. Chimie 17 (2014) 484–489
Table 2
A variety of substrates were submitted to the optimum
Effect of temperature for the preparation of 4aa.
reaction conditions and the desired products were
obtained in excellent yields (Table 3). Various functional
groups were found to be compatible under our reaction
conditions. It is noteworthy that there are no report of the
Entry
Temperature (8C)
Time (min)
Yield (%)b
1
2
3
4
5
Room temperature
120
75
45
30
20
78
85
92
93
50
synthesis
of
2-amino-4-substituted-1,4-dihydroben-
70
80
zo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles from
aliphatic aldehydes [16]. In general, the reactions were
clean and no side products were detected. In all cases, the
reactions proceeded efficiently at 80 8C in solvent-free
conditions and with 10 mol% of the catalyst. All the new
compounds were characterized by 1H NMR, 13C NMR, and
HRMS.
100
30
a
Reaction of 2-aminobenzimidazole 1 (1 mmol), 4-bromobenzalde-
hyde 2a (1 mmol) and malononitrile 3 (1 mmol) using p-TSA (10%) under
neat condition.
b
Isolated yield.
Under these appropriate reaction conditions (neat,
80 8C, 10 mol% p-TSA), a series of 2-amino-4-substituted-
1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-car-
bonitriles (4) were synthesized. The results are summar-
ized in Table 3.
A schematic presentation of the catalytic activity of p-
TSA in the synthesis of title compounds (4a–q) should be
postulated, as shown in Scheme 2. The reaction is thought
to proceed in a stepwise manner. Firstly, we assumed that
the reaction occurs via
a
Knoevenagel condensation
Table 3
p-TSA catalyzed multi-component synthesis of 4a–q.
Entry
Product
Aldehyde R
Yielda (%)
Found
Time (min)
Mp (8C)
Reported
Found
Reported
1
4a
4b
4c
4d
4e
4f
4-Br–C6H4
92
93
90
90
91
89
92
93
89
85
88
90
88
90
30
317–319
234–236
224–226
234–236
266–268
238–240
230–232
202–204
230–232
236–238
204–206
228–230
233–235
203–205
–
2
4-Cl–C6H4
70 [16c]
30
35
32
28
36
33
31
38
40
32
34
40
31
238[16c]
3
2-F–C6H4
–
4
3-F–C6H4
–
5
4-F–C6H4
85[16b]
83[16c]
270[16b]
6
3-Br–C6H4
240[16c]
7
4g
4h
4i
4-isopropyl–C6H4
4-OEt–C6H4
3,4-5-OMe–C6H2
2-Cl–C6H4
–
8
–
9
–
10
11
12
13
14
4j
69[16c]
72[16c]
237[16c]
4k
4l
2-F-4-OMe–C6H3
3-F-4-Me–C6H3
2-Me–C6H4
O
–
–
4m
4n
236[16c]
–
O
15
16
17
4o
4p
4q
C2H5
88
89
85
40
40
45
198–200
225–227
238–240
–
–
–
CH(CH3)2
C3H7
a
Isolated yield.
Scheme 2. Schematic mechanism for the catalytic activity of p-TSA in the synthesis of title compounds (4a–q).

M.V. Reddy et al. / C. R. Chimie 17 (2014) 484–489
487
between an enolic form like malononitrile, 3, and
aldehyde, 2, to form the intermediate 5 in the presence
of acidic p-TSA, which suffers immediate Michael addition
of 2-aminobenzimidazole (1) to be the conjugated C5C
bond of 5, forming intermediate 6. Finally, the title
compounds (4a–q) were formed by intramolecular con-
certed cyclisation by tautomerization of Michael adduct 6.
4.2.2. 2-Amino-4-(4-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4b)
Yield 93%; yellow powder; mp 234–236 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.60 (s, 1H), 7.61 (d, J = 8.0 Hz, 1H),
7.43–7.38 (m, 2H), 7.30 (d, J = 8.2 Hz, 2H), 7.21 (d, J = 7.5 Hz,
1H), 7.14 (d, J = 8.2 Hz, 2H), 6.85 (s, 2H), 5.25 (s, 1H). 13C
NMR (100 MHz, DMSO-d6):
d 151.5, 149.3, 143.1, 134.3,
132.4, 130.8, 129.1, 128.5, 123.0, 121.8, 119.9, 119.0, 116.0,
112.8, 61.2, 55.5.
3. Conclusion
In conclusion, we have developed an efficient and
environmentally benign methodology for the preparation
4.2.3. 2-Amino-4-(2-fluorophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4c)
of
2-amino-4-substituted-1,4-dihydrobenzolo[4,5]imi-
dazo[1,2-a]pyrimidine-3-carbonitriles in the presence of
an inexpensive p-TSA catalyst under neat conditions. The
advantages of this method over other existing ones are
reduced reaction times, high to excellent yields, simple
experimental procedure, low cost, easy handling, and
economic viability of the catalyst. The procedures provide
access to compounds that are useful in heterocyclic
synthesis.
Yield 90%; yellow powder; mp 224–226 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.58 (s, 1H), 7.66 (d, J = 7.8 Hz, 1H),
7.37–7.10 (m, 5H), 7.01 (t, J = 7.9 Hz, 1H), 7.11 (t, J = 7.5 Hz,
1H), 6.86 (s, 2H), 5.48 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): d 160.7, 151.7, 149.4, 143.5, 130.0, 129.8, 129.3, 127.9,
124.7, 123.3, 119.9, 118.7, 116.5, 112.4, 60.7, 48.5. HRMS
(ESI, m/z): calcd for C17H12FN5 (M + H+) 305.108; found:
305.103.
4. Experimental
4.2.4. 4.2.4. 2-Amino-4-(3-fluorophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4d)
4.1. General
Yield 90%; yellow powder; mp 234–236 8C. 1H NMR
Chemicals were purchased from Aldrich and Alfaaesar
Chemical Companies. NMR spectra were recorded in ppm
in DMSO-d6 on a Jeol JNM ECP 400 NMR instrument using
TMS as an internal standard. Mass spectra were recorded
on a Jeol JMS-700 mass spectrometer. All melting points
were determined using open capillaries on an Electro-
thermal-9100 (Japan) instrument. Infrared (IR) spectra
were obtained using a Shimadzu IR Prestige-21 FT IR
spectrophotometer.
(400 MHz, DMSO-d6): d 8.65 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.45–7.38 (m, 1H), 7.24 (d, J = 7.3 Hz, 1H), 7.14–7.08 (m,
4H), 7.02–6.98 (m, 1H), 6.89 (s, 2H), 5.28 (s, 1H). 13C NMR
(100 MHz, DMSO-d6):
d 161.0, 151.5, 149.3, 145.8, 143.8,
130.8, 129.2, 123.3, 121.9, 119.9, 119.0, 116.1, 112.9, 112.7,
112.4, 61.2, 52.5. HRMS (ESI, m/z): calcd for C17H12FN5
(M+H+) 305.108; found: 305.102.
4.2.5. 42-Amino-4-(4-fluorophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4e)
4.2. Synthesis of 2-amino-4-(4-bromophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4a)
Yield 91%; yellow powder; mp 266–268 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.23 (s, 1H), 7.58 (d, J = 8.2 Hz, 1H),
7.21–7.14 (m, 5H), 7.08 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.5 Hz,
A mixture of 2-aminobenzimidazole (1, 1 mmol), 4-
bromobenzaldehyde (2a, 1 mmol), malononitrile (3,
1 mmol) and p-TSA (10 mol%) was stirred at 80 8C under
solvent-free conditions for 30 min (Table 3, entry 1). The
progress of the reaction was monitored by TLC. After
completion of the reaction, the reaction mixture was
washed with water and ethanol, and the residue recrys-
tallized from ethanol to afford the pure product 4a (92%).
1H), 6.71 (s, 2H), 5.30 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): d 160.5, 151.9, 148.9, 143.8, 135.5, 130.8, 129.1, 123.3,
121.7, 119.8, 119.3, 116.7, 114.8, 112.9, 112.7, 60.2, 54.5.
4.2.6. 2-Amino-4-(3-bromophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4f)
Yield 89%; yellow powder; mp 238–240 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.60 (s, 1H), 7.60 (d, J = 7.8 Hz, 1H),
4.2.1. 2-Amino-4-(4-bromophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4a)
7.54 (d, J = 8.5 Hz, 2H), 7.26(t, J = 8.5 Hz, 3H), 7.10 (t,
J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.85 (s, 2H), 5.25 (s,
d 151.2, 149.1, 143.5,
141.2, 131.6, 130.5, 129.6, 128.5, 123.2, 121.5, 119.9, 119.0,
116.1, 112.2, 61.5, 52.8.
1H). 13C NMR (100 MHz, DMSO-d6):
Yield 92%; yellow powder; mp 317–319 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.62 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H),
7.56 (d, J = 8.5 Hz, 2H), 7.24 (t, J = 8.5 Hz, 3H), 7.11 (t,
J = 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.87 (s, 2H), 5.24 (s,
4.2.7. 2-amino-4-(4-isopropylphenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4g)
1H). 13C NMR (100 MHz, DMSO-d6):
d 151.2, 149.2, 143.5,
142.2, 131.6, 129.2, 128.2, 123.4, 121.0, 119.9, 119.0, 116.1,
112.4, 61.4, 52.6. HRMS (ESI, m/z): calcd for C17H12BrN5
(M + H+) 366.025; found: 366.0038.
Yield 92%; yellow powder; mp 230–232 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.55 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H),

488
M.V. Reddy et al. / C. R. Chimie 17 (2014) 484–489
7.22–7.16 (m, 5H), 7.10 (t, J = 7.3 Hz, 1H), 6.99 (t, J = 7.3 Hz,
DMSO-d6): d 161.7, 151.6, 149.2, 143.5, 142.9, 131.9, 129.2,
1H), 6.80 (s, 2H), 5.15 (s, 1H), 2.86–2.80 (m, 1H), 1.65 (d,
123.8, 123.6, 121.6, 119.9, 116.1, 115.0, 112.6, 61.4, 52.4,
13.8. HRMS (ESI, m/z): calcd for C18H14FN5 (M+H+)
319.1234; found: 319.1236.
J = 6.6 Hz, 6H). 13C NMR (100 MHz, DMSO-d6):
d 151.7,
149.0, 148.0, 143.6, 129.2, 126.5, 125.8, 123.2, 119.8, 119.2,
116.0, 112.3, 62.0, 53.0, 33.0, 23.7. HRMS (ESI, m/z): calcd
for C20H19N5 (M + H+) 329.164; found: 329.162.
4.2.13. 2-Amino-4-(o-tolyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4m)
4.2.8. 2-amino-4-(4-ethoxyphenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4h)
Yield 88%; yellow powder; mp 233–235 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.55 (s, 1H), 7.60 (d, J = 8.0 Hz, 1H),
Yield 93%; yellow powder; mp 202–204 8C. 1H NMR
7.35 (d, J = 8.2 Hz, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.14–7.15 (m,
3H), 7.05 (t, J = 7.5 Hz, 1H), 6.95 (t, J = 7.5 Hz, 1H), 6.68 (s,
2H), 5.30 (s, 1H), 2.25 (s, 3H). 13C NMR (100 MHz, DMSO-
d6): d 151.3, 149.2, 143.5, 137.5, 135.5, 131.2, 129.5, 128.5,
125.6, 122.9, 119.6, 116.8, 112.1, 59.4, 55.2, 17.4.
(400 MHz, DMSO-d6): d 8.49 (s, 1H), 7.96 (d, J = 8.8 Hz, 2H),
7.62 (t, J = 8.0 Hz, 1H), 7.20–7.15 (m, 1H), 7.10 (t, J = 7.3 Hz,
1H), 6.99 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.8 Hz, 2H), 6.77 (s,
2H), 5.13 (s, 1H), 4.01–3.94 (m, 2H), 1.28 (t, J = 6.6 Hz, 3H).
13C NMR (100 MHz, DMSO-d6):
d 160.4, 151.2, 149.2, 143.5,
133.5, 133.4, 129.2. 127.2, 123.9, 123.2, 119.7, 115.5, 114.8,
4.2.14. 2-Amino-4-(benzo[d][1,3]dioxol-5-yl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4n)
113.9, 64.0, 62.9, 52.7, 14.3. HRMS (ESI, m/z): calcd for
C
19H17N5O (M+H+) 331.143; found: 331.142.
Yield 90%; yellow powder; mp 203–205 8C. 1H NMR
4.2.9. 2-Amino-4-(3,4,5-trimethoxyphenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4i)
(400 MHz, DMSO-d6):
7.21–6.81 (m, 6H), 6.21 (s, 2H), 5.97 (s, 2H), 5.15 (s, 1H). 13
NMR (100 MHz, DMSO-d6): 160.3, 152.9, 148.3, 129.9,
125.5, 123.3, 119.8, 116.0, 113.7, 112.3, 109.2, 106.4, 102.4,
62.0, 52.9. HRMS (ESI, m/z): calcd for C18H13N5O2 (M+H+)
331.1070; found: 331.1065.
d 8.34 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H),
C
d
Yield 89%; yellow powder; mp 230–232 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.52 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H),
7.22 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 7.3 Hz, 1H), 7.00 (t,
J = 7.3 Hz, 1H), 6.83 (s, 2H), 6.62 (s, 2H), 5.18 (s, 1H), 3.69 (s,
6H), 3.62 (s, 3H). 13C NMR (100 MHz, DMSO-d6):
d
152.8,
4.2.15. 2-Amino-4-ethyl-1,4-
151.7, 149.2, 143.5, 138.1, 137.1, 129.2, 123.3, 119.9, 119.1,
116.0, 112.3, 103.6, 61.6, 59.9, 55.8, 53.3. HRMS (ESI, m/z):
calcd for C20H19N5O3 (M+H+) 377.1490; found: 377.1485.
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4o)
Yield 88%; yellow powder; mp 198–200 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.24 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H),
4.2.10. 2-Amino-4-(2-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4j)
7.20 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.95 (t,
J = 7.3 Hz, 1H), 6.68 (s, 2H), 4.01 (t, J = 5.4 Hz, 1H), 1.60–154
(m, 2H), 0.88 (t, J = 7.3 Hz, 3H). 13C NMR (100 MHz, DMSO-
Yield 85%; yellow powder; mp 236–238 8C. 1H NMR
d6):
112.2, 60.7, 51.2, 29.2, 7.6. HRMS (ESI, m/z): calcd for
C
13H13N5 (M + H+) 239.1175; found: 239.1170.
d 152.7, 150.2, 144.3, 129.8, 123.5, 120.6, 119.5, 116.3,
(400 MHz, DMSO-d6): d 8.55 (s, 1H), 7.65 (d, J = 8.2 Hz, 1H),
7.58 (d, J = 8.2 Hz, 1H), 7.35–7.20 (m, 5H), 7.08 (t, J = 7.5 Hz,
1H), 6.80 (s, 2H), 5.23 (s, 1H). 13C NMR (100 MHz, DMSO-
d6):
d
151.5, 149.5, 143.5, 138.3, 135.5, 132.5, 130.5, 129.1,
4.2.16. 2-Amino-4-isopropyl-1,4-
128.5, 127.5, 123.0, 121.8, 119.9, 116.0, 112.8, 59.5, 52.5.
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4p)
4.2.11. 2-Amino-4-(2-fluoro-4-methoxyphenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4k)
Yield 89%; yellow powder; mp 225–227 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.23 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H),
7.20 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.3 Hz, 1H), 6.95 (t,
J = 7.3 Hz, 1H), 6.69 (s, 2H), 3.83 (d, J = 5.1 Hz, 1H), 1.76–172
(m, 1H), 0.83 (t, J = 5.8 Hz, 6H). 13C NMR (100 MHz, DMSO-
Yield 88%; yellow powder; mp 204–206 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.44 (s, 1H), 7.64 (d, J = 7.6 Hz, 1H),
7.23–7.09 (m, 4H), 7.00 (t, J = 6.9 Hz, 1H), 6.81 (s, 2H), 6.75
(dd, J = 2.5, 11.0 Hz, 1H), 5.38 (s, 1H), 3.73 (s, 3H). 13C NMR
d6):
112.2, 59.0, 55.8, 35.4, 17.4. HRMS (ESI, m/z): calcd for
C
14H15N5 (M+H+) 253.1335; found: 253.1330.
d 152.3, 149.8, 143.7, 129.2, 123.1, 119.9, 119.5, 115.7,
(100 MHz, DMSO-d6):
d
160.3, 155.6, 151.7, 149.2, 143.3,
129.3, 128.6, 123.3, 121.2, 119.8, 118.7, 116.0, 112.3, 110.4,
102.0, 61.1, 56.0, 55.6. HRMS (ESI, m/z): calcd for
C
4.2.17. 2-Amino-4-propyl-1,4-
18H14FN5O (M+H+) 335.1184; found: 335.1184.
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4q)
4.2.12. 4.2.12. 2-Amino-4-(3-fluoro-4-methylphenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
(4l)
Yield 85%; yellow powder; mp 238–240 8C. 1H NMR
(400 MHz, DMSO-d6): d 8.24 (s, 1H), 7.59 (d, J = 8.2 Hz, 1H),
7.20 (d, J = 8.8 Hz, 1H), 7.08 (t, J = 7.5 Hz, 1H), 6.95 (t,
J = 7.5 Hz, 1H), 6.69 (s, 2H), 3.83 (d, J = 5.1 Hz, 1H), 1.77–
1.69 (m, 2H), 1.29–1.27 (m, 2H), 0.83 (t, J = 6.9 Hz, 3H). 13
C
Yield 90%; yellow powder; mp 228–230 8C. 1H NMR
(400 MHz, DMSO-d6):
d
8.60 (s, 1H), 7.63 (d, J = 7.8 Hz, 1H),
7.27–7.21 (q, 2H), 7.11 (t, J = 7.5 Hz, 1H), 7.04–7.00 (m, 3H),
6.86 (s, 2H), 5.22 (s, 1H), 2.17 (s, 3H). 13C NMR (100 MHz,
NMR (100 MHz, DMSO-d6):
123.2, 119.9, 115.8, 112.2, 59.0, 55.8, 35.4, 20.8, 17.4.
d 152.3, 149.8, 143.7, 129.2,

M.V. Reddy et al. / C. R. Chimie 17 (2014) 484–489
489
HRMS (ESI, m/z): calcd for C14H15N5 (M+H+) 253.1335;
found: 253.1330.
Fujisaki, H. Shibata, T. Wakabayashi, PCT Int. Appl. (1989) WO8910927;
(b) C. Hansch, P.G. Sammes, J.B. Taylor, Comprehensive medicinal
chemistry:the rational design mechanistic study & therapeutic appli-
cation of chemical compounds, 1st ed., Pergamon Press, Oxford, New
York, 1990.
Acknowledgements
[14] (a) S. Sarel, R. Mechoulam, I. Agranat, 11th Proc. Int. Symp. Med. Chem.,
Trends Med. Chem. 90 (1992) 315;
(b) A.O. Adbelhamid, Arch. Pharm. 320 (1987) 642;
(c) M. Ibrahim, A. Kamal, Ind. J. Chem. B 27B (1987) 478;
(d) K. Arya, 11th International Electronic Conference on Synthetic
Organic Chemistry, 1–30 November, 2007.
This research work was supported by the second stage
of BK21 Program.
References
[15] (a) T. Yasuda, T. Iwamoto, M. Ohara, S. Sato, Jpn. J. Pharmacol. 79
(1999) 65;
(b) G.F. Yang, R.F. Lu, X.N. Fei, H.Z. Yang, Chin. J. Chem. 18 (2000) 435;
(c) K.E. Tahir, H.A. Khamees, S.M. Bayomi, Bull. Chem. Farm. 134 (1995)
604;
(d) D.J. Brown, in: E.C. Taylor (Ed.), The Chemistry of Heterocyclic
Compounds, Fused Pyrimidines, Part III: Pteridines, Vol. 24/3, John
Wiley & Sons, New York, Chichester, Brisbane–Toronto, Singapore,
1988.
[1] J. Zhu, H. Bienayme, Multicomponent Reactions, Wiley-VCH, Wein-
heim, Germany, 2005.
[2] R.C. Nuno, M. Francesco, M.S.D.C. Pedro, M.P.G. Pedro, Chem. Rev. 110
(2010) 6169.
[3] S. Jimenez-Alonso, H. Chavez, A. Estevez-Braan, A. Ravelo, G. Feresin, A.
Tapia, Tetrahedron 64 (2008) 8938.
[4] (a) Z.N. Siddiqui, C. R. Chimie 16 (2013) 183;
(b) F. Shirini, S. Akbari-Dadamahaleh, A. Mohammad-Khah, A. Reza
Aliakbar, C. R. Chimie 16 (2013) 207;
[16] (a) C. Yong Tae, W. Jian Qiang, Y. Jichun, G. Xiang, C.H. Cheng, Chin. J.
Appl. Chem. 27 (2010) 53;
(b) Z.M. Nofal, H.H. Fahmy, H.S. Mohamed, Arch Pharm. Res. 25
(2002) 28;
(c) S. Ahmad, R. Abbas, R. Ali Hossein, D. Mariya, B. Zahra, S. Afshin,
QSAR Comb. Sci. 26 (2007) 973.
(c) C. Altug, E. Caner, C. R. Chimie 16 (2013) 217.
[5] (a) S. Morteza, Chem. Rev. 112 (2012) 3508;
(b) B.A. Amol, Y.T. Jeong, Tetrahedron Lett. 54 (2013) 1302.
[6] X. Li, B. Zhou, J. Zhang, M. She, S. An, H. Ge, C. Li, B. Yin, J. Li, Z. Shi, Eur. J.
Org. Chem. (2012) 1626.
[7] M. Li, B. Zhanga, Y. Gu, Green Chem. 14 (2012) 2421.
[8] M. Veeranarayana Reddy, Y.T. Jeong, Synlett 23 (2012) 2985.
[9] M. Veeranarayana Reddy, J. Kim, Y.T. Jeong, J. Fluorine Chem. 135
(2012) 155.
[17] (a) A. Herath, R. Dahl, N.D.P. Cosford, Org. Lett. 12 (2010) 412;
(b) D. Palakodety Radha Krishna, S. Palabindela, Tetrahedron Lett. 51
(2010) 2295;
(c) B. Zhu, G.W. Wang, Org. Lett. 11 (2009) 4334;
(d) C.L. Peng, Y. Wang, L.Y. Liu, H.J. Wang, J.J. Zhao, Q. Zhu, Eur. J. Org.
Chem. 2010 (2010) 818;
(e) L. Pei, M.P. Ying, X. Yan-Li, W. Heng-Shan, Org. Biomol. Chem. 10
(2012) 4696.
[10] (a) M. Veeranarayana Reddy, G. Chandra Sekhar Reddy, Y.T. Jeong,
Tetrahedron 68 (2012) 6820;
(b) S. Koichi, O. Takumi, T. Naoko, Tetrahedron Lett. 54 (2013) 661;
(c) P.S. Harikrishnan, S.M. Rajesh, P. Subbu, I.A. Abdulrahman, Tetra-
hedron Lett. 54 (2013) 1076;
[18] (a) Z. Yanan, L. Jian, L. Chunju, Y. Kun, Y. Dongyan, J. Xueshun, Green
Chem. 12 (2010) 1370;
(b) L. Kelvis, N.M. Dayse, R.B.M. Mara, M.F. Vagner, G.B.Z. Helio Nilo,
A.P.M. Marcos, Tetrahedron Lett. 51 (2010) 3193;
(c) M.K. Jitender, M. Devanshi, Tetrahedron Lett. 50 (2009) 4777;
(d) R. Dushyant Singh, K. Nand Singh, Tetrahedron Lett. 52 (2011)
5702.
(d) A.P.M. Marcos, P.F. Clarissa, N.M. Dayse, B. Lilian, M. Pablo, Chem.
Rev. 109 (2009) 4140;
(e) M.K. Patil, M. Keller, B.M. Reddy, P. Pale, J. Somme, Eur. J. Org. Chem.
(2008) 4440.
[11] (a) J.M. Weibel, A. Blanc, P. Pale, Chem. Rev. 108 (2008) 3149;
(b) Q. Xiao, W.H. Wang, G. Liu, F.K. Meng, J.H. Chen, Z. Yang, Z.J. Shi,
Chem. Eur. J. 15 (2009) 7292;
[19] (a) M. Veeranarayana Reddy, S.D. Dindulkar, Y.T. Jeong, Tetrahedron
Lett. 52 (2011) 4764;
(b) M. Veeranarayana Reddy, Y.T. Jeong, J. Fluorine Chem. 142
(2012) 45;
(c) D.D. Someshwar, G.P. Vedavati, Y.T. Jeong, Tetrahedron Lett. 53
(2012) 4376.
(c) N.T. Patil, Y. Yamamoto, Chem. Rev. 108 (2008) 3395.
[12] Z.M. Nofal, H.H. Fahym, H.S. Mahamed, Arch. Pharm. Res. 25 (2002) 28.
[13] (a) S. Souda, S. Miyazawa, N. Ueda, K. Tagami, S. Nomoto, M. Okita, N.
Shimomura, T. Kaneko, M. Fujimoto, M. Murakami, K. Oketani, H.