Poly(vinylpyrrolidonium) perchlorate catalyzed one-pot synthesis of tricyclic dihydropyrimidine derivatives

Article abstract of DOI:10.1007/s11164-016-2456-4

A simple and efficient procedure for the synthesis of benzo[4,5]imidazo[1,2-α]pyrimidine and 2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-α]pyrimidine-3-carbonitrile derivatives using poly(vinylpyrrolidonium) perchlorate {[PVPH]ClO₄

Full text of DOI:10.1007/s11164-016-2456-4

Res Chem Intermed
DOI 10.1007/s11164-016-2456-4
Poly(vinylpyrrolidonium) perchlorate catalyzed
one-pot synthesis of tricyclic dihydropyrimidine
derivatives
Masoumeh Abedini1 Farhad Shirini1
•
•
Maryam Mousapour1 Omid Goli Jolodar1
•
Received: 21 November 2015 / Accepted: 19 January 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract A simple and efficient procedure for the synthesis of benzo[4,5]imi-
dazo[1,2-a]pyrimidine and 2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo
[1,2-a]pyrimidine-3-carbonitrile derivatives using poly(vinylpyrrolidonium) per-
chlorate {[PVPH]ClO4} as a newly reported, modified polymeric catalyst is
reported. Some of the advantages of this novel synthetic method are: easy prepa-
ration of the catalyst, simple and easy work-up procedure, short reaction times, high
to excellent yields of the products and reusability of the catalyst.
Keywords Benzo[4,5]imidazo[1,2-a]pyrimidines Á 2-Amino-4-substituted-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles Á
Poly(vinylpyrrolidonium) perchlorate {[PVPH]ClO4} Á Heterogeneous reaction
conditions Á Polymer-based catalyst
Introduction
Dihydropyrimidine derivatives are among the most important classes of tricyclic
compounds which show an interesting wide range of biological and pharmaceutical
properties such as antiviral, antibacterial, anti-inflammatory, anti-hypertensive, anti-
tubercular, anti-malarial and cytotoxic activities [1–5]. In addition, they can be used as
calcium channel blockers and antihypertensive agents [6]. These significant properties
have attracted the attention of many organic chemists to the synthesis of these types of
compounds, so that their investigations have led to various synthetic methods using
&
&
1
Masoumeh Abedini
mabedini@guilan.ac.ir
Farhad Shirini
shirini@guilan.ac.ir
Department of Chemistry, College of Science, University of Guilan, Post Box 1914,
Rasht 41335, Islamic Republic of Iran
123

M. Abedini et al.
different types of catalysts. Some of these catalysts are: H3BO3 [7], 1,1,3,3-N,N,N0,N0-
tetramethylguanidinium trifluoroacetate [8], tetrabutylammonium hydrogen sulfate
[9], thiamine hydrochloride [10], Zn(ClO4)2Á6H2O [11], [bmim]BF4 [12], H2NSO3H
[13], ionic liquid supported-nanoporous silica (SBA-IL) [14], N,N,N0,N0-tetrabro-
mobenzene-1,3-disulfonamide (TBBDA) [15] and p-toluenesulfonic acid [16]. The
reaction was also investigated under catalyst-free conditions [17].
Although a number of these methods have their own advantages, some of them
suffer from one or more disadvantages, such as use of large amounts of catalysts,
long reaction times, unsatisfactory products yields, high temperatures and the use of
toxic organic solvents; these disadvantages have limited the use of these methods.
Therefore, it is necessary to find more convenient methods for the synthesis of
dihydropyrimidines.
Experimental
Chemicals were purchased from Fluka, Merck, and Sigma-Aldrich chemical
companies. Cross-linked poly(vinylpyrrolidone) was purchased from BASF Corp.
(Germany). All products were characterized by comparison of their physical
constants, infrared (IR) spectra and nuclear magnetic resonance (NMR) spec-
troscopy with authentic samples and those reported in the literature.
Preparation of catalyst [PVPH]ClO4 [18]
HClO4 (5 mmol, %0.43 mL, as a 70 % aqueous solution) was added to a suspension
of 0.05 g of powdered poly(vinylpyrrolidone) [crosslinked poly(vinylpyrrolidone)
with MW [ 1,000,000] in 10 mL of dry CH2Cl2 over a period of 10 min in an ice bath.
After the addition was completed, the mixture was stirred for 2 h and then filtered. The
solid residue was washed with diethyl ether (10 mL) and dried at 80 °C to afford
[PVPH]ClO4 as a white powder (Scheme 1) [18].
General procedure for the synthesis of the benzo[4,5]imidazo[1,2-a]
pyrimidine (A) or 2-amino-4-substituted-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile (B) derivatives
A mixture of ethyl acetoacetate and/or acetylacetone (1 mmol) or malononitrile
(1.1 mmol), 2-aminobenzimidazole (1 mmol), aldehyde (1 mmol) and [PVPH]ClO4
n
n
n
ClO4
OH
N
N
N
HClO4
O
O
CH2Cl2, Ice bath, 2 h
Scheme 1 Preparation of [PVPH]ClO4
123

Poly(vinylpyrrolidonium) perchlorate catalyzed one-pot…
(30 mg, 6.84 mol %) was heated at 100 °C in an oil bath for the appropriate time.
After completion of the reaction [monitored by thin layer chromatography (TLC): n-
hexane: ethyl acetate (3:1)], the reaction mixture was cooled to room temperature
and EtOH (5 mL) was added to it and filtered to separate the catalyst. After
evaporation of the solvent from the filtrate, the crude solid product was
recrystallized from ethanol to obtain pure A or B products.
1
The spectral [IR, proton ( H) NMR and 13C NMR] data of new compounds are
presented below.
(Compound 4, Table 2): Ethyl 4-(4-methylthiophenyl)-2-methyl-1,4-
dihydrobenzo[4,5]imidazo[1,2-a]pyrimidine-3-carboxylate
Yellow solid, m.p. 271–273 °C; IR (KBr): m = 3232, 3103, 3031, 1695, 1611, 1568,
1
1449, 1251, 1014, 874, 829, 733 cm-1. H NMR [deuterated dimethyl sulfoxide
(DMSO-d6), 400 MHz] r: 1.17 (t, J = 7.2 Hz, 3H, CH3), 2.40 (s, 3H, CH3), 2.47
(s, 3H, CH3), 4.0–4.07 (m, 2H, CH2), 6.40 (s, 1H, CH), 6.96 (t, J = 7.2 Hz, 1H,
ArH), 7.05 (t, J = 7.6 Hz,1H, ArH), 7.14 (d, J = 8.4 Hz, 2H, ArH), 7.25–7.36 (m,
3H, ArH), 7.8 (d, J = 8 Hz, 1H, ArH), 10.8 (brs, 1H, NH) ppm. 13C NMR (DMSO-
d6, 100 MHz): 14.5, 14.8, 19.1, 55.9, 59.8, 98.3, 110.1, 117.26, 120.6, 122.2, 126.0,
128.1, 131.3, 138.2, 139.0, 142.7, 146.0, 146, 9, 165.6 ppm.
(Compound 10, Table 3): 2-Amino-4-(pyridin-3-yl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
m.p. 242–244 °C; IR (KBr): v = 3452, 3315, 3056, 2180, 1663, 1590, 1465, 1399,
712 cm-1. 1HNMR (DMSO-d6, 400 MHz) r: 5.37 (s, 1H), 6.97 (s, 2H, NH2), 7.03
(t, J = 7.6 Hz, 1H), 7.14 (t, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz,1H), 7.40–8.54
(m, 5H), 8.64 (s, 1H, NH) ppm. 13CNMR (DMSO-d6, 100 MHz): 51.6, 61.4, 113,
116.6, 120.5, 123.9, 124.4, 129.7, 134.4, 136, 138.5, 143, 148, 149.5, 150, 152.
Table 1 Effect of temperature, solvent and amount of the catalyst on the synthesis of benzo[4,5]imi-
dazo[1,2-a] pyrimidine derivative of 4-chlorobenzaldehyde
Entry
Catalyst (mg)
Condition
Time (min)
Yield (%)a
1
2
3
4
5
6
7
8
9
10 (2.28 mol%)
Solvent-free, 100 °C
Solvent-free, 100 °C
Solvent-free, 100 °C
Solvent-free, 100 °C
Solvent-free, 50 °C
Solvent-free, 120 °C
EtOH, Reflux
40
35
85
90
97
98
50
98
40
50
30
20
30
40
30
30
30
30
30
30
30
120
30
50
CH2Cl2, Reflux
50
H2O, Reflux
50
Reaction conditions: 2-aminobenzimidazole (1 mmol), ethylacetoacetate (1 mmol) and 4-chloroben-
zaldehyde (1 mmol)
a
GC yield
123

M. Abedini et al.
Very recently we reported the preparation of poly(vinylpyrrolidonium) perchlo-
rate {[PVPH]ClO4} [18] and its applicability in the promotion of the synthesis of
polyhydroquinoline derivatives via Hantzsch condensation. Herein and in contin-
uation of this study, we wish to report the applicability of this reagent in the
accelerated preparation of tricyclic dihydropyrimidine derivatives.
At the first step, optimization of the reaction conditions was done by studying the
reaction of 2-aminobenzimidazole with 4-chlorobenzaldehyde and ethylacetoacetate
in the presence of various amounts of [PVPH]ClO4 in the absence of solvent and
also in different solvents such as dichloromethane, ethanol and water under thermal
conditions (Table 1). We found that the reaction was rapid and gave excellent yields
of the products in the presence of 30 mg of the catalyst at 100 °C in the absence of
solvent (Scheme 2).
Results and discussion
Catalytic activity
After optimization of the reaction conditions and in order to show the general
applicability of the method, different types of aldehydes were subjected to the same
reaction under the determined conditions. The obtained results showed that in all
cases the corresponding products were obtained in good to excellent yields in
appropriate times (Table 2, entries 1–11). We have also found that the same results
were obtained when acetylacetone was used in place of ethylacetoacetate (Table 2,
R1
O
R
O
O
CH3
N
N
R
N
H
R=OEt /Me
CHO
A
R1
[PVPH]ClO4 ( 30 mg, 6.84 mol %)
Solvent-free, 100 oC
R1: H, Cl, Br, NO2,...
+
N
R1
NH2
CN
N
NH2
N
N
B
NC
CN
N
H
Scheme 2 Optimized conditions for the preparation of the tricyclic dihydropyrimidine derivatives
123

Poly(vinylpyrrolidonium) perchlorate catalyzed one-pot…
entries 12–14). The results showed that in all cases, regardless of the substituent, the
reaction gave the products in good to high yields within relatively short reaction
times.
After successful synthesis of a series of benzo[4,5]imidazo[1,2-a] pyrim-
idine derivatives, we decided to study the preparation of 2-amino-4-
substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles
by the reaction of malononitrile, 2-aminobenzimidazole and aldehydes in
the presence of [PVPH]ClO4 under the above-mentioned reaction conditions
(Scheme 2).
The results showed that various aldehydes were reacted with the other starting
materials using this method to produce the desired products in excellent yields
within very short reaction times (Table 3). It should be noted that only two
methods for the preparation of these compounds are reported in the literature
[16, 17].
In a plausible mechanism, at first, the aldehyde is activated by the proton of the
catalyst. Then, the carbonyl group is attacked by ethylacetoacetate or malonon-
itrile to form the Knoevenagel products (I). In continuation, 2-aminobenzimida-
zole is reacted with these intermediates via Michael addition reaction to produce
the related intermediate (II). Finally, this intermediate is converted to the
requested products via intermolecular cyclization and dehydration reactions
(Scheme 3).
Table 2 Synthesis of benzo[4,5]imidazo[1,2-a]pyrimidine derivatives catalyzed by [PVPH]ClO4
Entry
Aldehyde
R
Time (min)
Yield (%)
Melting point (°C)
Found.
Reported [references]
1
H
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
OEt
Me
45
30
60
15
35
40
30
40
40
20
55
30a
30a
20a
92
97
92
90
95
94
92
98
95
98
96
90
97
96
281–283
297–300
307–309
271–273
258–260
256–258
300–302
254–257
210–213
263–266
296–298
280–282
282–285
268–270
282–285 [14]
301–303 [15]
[275 [10]
2
p-Cl
3
p-CN
p-SCH3
p-CH3
p-CH3O
p-NO2
m-Br
4
–
5
262.2–262.4 [10]
250–253 [8]
302–303 [14]
266–268 [15]
211–214 [15]
269.6–269.8 [10]
294–296 [13]
[275 [10]
6
7
8
9
m-CH3O
m-Cl
10
11
12
13
14
m-NO2
H
p-Cl
Me
[285 [10]
p-CH3O
Me
278.6–279.5 [10]
The desired products were characterized by their physical data, comparison with melting points, IR and/or
1H NMR spectroscopy
Isolated yield
a
40 mg of catalyst
123

M. Abedini et al.
Table 3 Synthesis of 2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-car-
bonitriles derivatives catalyzed by [PVPH]ClO4
Entry
Aldehyde
Time (min)
Yield (%)
Melting point (°C)
Found.
Reported [references]
1
2
H
2
15
20
5
92
96
95
90
98
98
90
95
97
80
233–236
236–238
307–309
252–254
232–234
242–244
239–241
234–236
237–239
242–244
235–236 [16]
238 [17]
p-Cl
3
p-Br
317–319 [16]
266–268 [16]
230–232 [16]
240 [17]
4
p-F
5
p-(CH3)2CH
4
6
m-Br
4
7
m-NO2
8
236 [17]
8
o-Cl
5
236–238 [16]
236 [17]
9
o-CH3
3
10
3-Pyridyl carbaldehyde
10
–
The desired products were characterized by their physical data, comparison with melting points, IR and/or
1H NMR spectroscopy
Isolated yield
x
y
n
N
ClO4
O-H
N
x
y
H2N
x
y
N
H
Ar
O
N
HN
Ar
- H2O
Ar
H
HN
( II )
( I )
if x=Me; y= COOEt, Me
if x=CN; y=CN
n
ClO4
O-H
N
z
x
y
y
HN
HN
Ar
N
H2N
Ar
if y=COOEt, Me ; z=Me
if y=CN; z=NH2
N
- H2O
HN
Scheme 3 Plausible mechanism of the reactions
In continuation, we decided to examine the catalytic activity of the recycled
catalyst for the synthesis of the title derivatives. After separation of the product, the
catalyst was washed with EtOH, dried and reused for the same reaction. This
123

Poly(vinylpyrrolidonium) perchlorate catalyzed one-pot…
Fig. 1 Reusability of
[PVPH]ClO4 in the synthesis of
ethyl 4-(4-chlorophenyl)-2-
methyl-1,4-
dihydrobenzo[4,5]imidazo[1,2-
a]pyrimidine-3-carboxylate
Fig. 2 Reusability of [PVPH]ClO4 in the synthesis of 2-Amino-4-(4-chlorophenyl)-1,4-
dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitrile
process was carried out over three runs and all reactions led to the desired products
with high efficiency (Figs. 1, 2). It should be noted that the Fourier transform
infrared (FT-IR) and pH analysis of the recovered catalyst showed nearly the same
loading of H? as the freshly prepared catalyst. These results suggest that changing
of the catalyst and/or leaching of the acid species does not occur during the course
of the reaction.
Table 4 compares the efficiency of [PVPH]ClO4 with the other catalysts in the
synthesis of tricyclic dihydropyrimidine derivatives of benzaldehyde. The presented
results show that the same reactions are carried out in the presence of the larger
amounts of the catalysts (Table 4, entries 1, 4, 8, 10) or the reaction times are longer
compared with the present method (Table 4, entries 2, 3, 4, 8).
123

M. Abedini et al.
Table 4 Comparison of various catalysts in the synthesis of benzo[4,5]imidazo[1,2-a] pyrimidine and
2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-carbonitriles derivatives
Entry Product
Catalyst (mol%)
Conditions
Time Yield (%)
(min) [references]
1
H3BO3 (20)
H2O, r.t.
30
75 [7]
73 [8]
O
2
TMGT (80 mg)
Solvent-free,
100° C
H2O, Reflux
5 h
OEt
N
N
CH3
N
H
3
Thiamine hydrochloride
(VB1) (5)
3 h
90 [10]
4
5
Sulfamic acid (10)
SBA-IL (20 mg)
Solvent-free, 85 °C 8 h
88 [13]
87 [14]
Solvent-free,
150 °C
Solvent-free,
40
6
N,N,N0,N0-
80
88 [15]
tetrabromobenzene-
1,3-disulfonamide
[TBBDA] (5)
100° C
7
H3PO4–Al2O3 (120 mg)
Silica suforic acid (8)
[PVPH]ClO4 (6.84, 30 mg)
p-TSA (10)
Solvent-free,
100° C
Solvent-free,
85
6 h
45
30
90 [19]
94 [20]
8
110° C
Solvent-free,
9
92 [this work]
93 [16]
100 °C
Solvent-free,
Cl
10
11
80 °C
H2O, 90 °C
Solvent-free,
Catalyst-free
9 h
15
70 [17]
CN
N
12
[PVPH]ClO4 (6.84, 30 mg)
96 [this work]
N
NH2
N
H
100 °C
Conclusion
In this paper, we have developed an efficient and green procedure for the synthesis
of two types of tricyclic compounds including benzo[4,5]imidazo[1,2-a]pyrimidines
and 2-amino-4-substituted-1,4-dihydrobenzo[4,5]imidazolo[1,2-a]pyrimidine-3-car-
bonitriles using [PVPH]ClO4 as a new polymeric catalyst. These procedures have
several advantages, including heterogeneous reaction conditions, easy work-up,
simple procedure for the preparation of the catalyst, appropriate times and high to
excellent yields of the products. Also, the catalyst could be successfully recovered
and reused for at least three runs without significant loss in its activity.
Acknowledgments We are thankful to the University of Guilan Research Council for the partial
support of this work.
123

Poly(vinylpyrrolidonium) perchlorate catalyzed one-pot…
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