The new green procedure for pyrazolopyrimidinone based dihydropyrimidinones and their antibacterial screening

Article abstract of DOI:10.1134/S1070363217110299

A series of novel hybrid aza heterocycles containing pyrazolopyrimidinone and dihydropyrimidinone scaffolds was developed using Cu(II) catalyzed Biginelli condensation as an efficient, new green synthetic method under mild and solvent free conditions. Pyr

Full text of DOI:10.1134/S1070363217110299

ISSN 1070-3632, Russian Journal of General Chemistry, 2017, Vol. 87, No. 11, pp. 2712–2718. © Pleiades Publishing, Ltd., 2017.
The New Green Procedure for Pyrazolopyrimidinone Based
Dihydropyrimidinones and Their Antibacterial Screening1
Muralidhar Allam, A. K. D. Bhavani*, and Sumathi Vodnala
Department of Chemistry, University College of Science, Osmania University, Hyderabad, Telangana, 500007 India
*e-mail: durgabhavani237@gmail.com
Received October 7, 2017
Abstract—A series of novel hybrid aza heterocycles containing pyrazolopyrimidinone and dihydro-
pyrimidinone scaffolds was developed using Cu(II) catalyzed Biginelli condensation as an efficient, new green
synthetic method under mild and solvent free conditions. Pyrazolopyrimidinone based aldehydes, alkyl
acetoacetates and urea/thiourea were used as the components in the reaction to afford hybrid aza heterocycles
in high to excellent yields. The products were screened for in vitro antibacterial activity and all of those
demonstrated high to excellent activity.
Keywords: pyrazolo[3,4-d]pyrimidin-4(5H)-one, 3,4-dihydropyrimidin-2(1H)-one, Biginelli reaction, CuCl2·2H2O,
antibacterial activity
DOI: 10.1134/S1070363217110299
Pyrazolo[3,4-d]pyrimidin-4(5H)-one ring system,
structurally analogous to nucleotide base, is an
important structural template in medicinal research and
in drug discovery. The derivatives of pyrazolopyri-
midinones have potential biological properties by
exhibiting anti-viral, antitumor activity [1] in addition
to analgesic, antifungal, antimicrobial, anti-prolifera-
tive, anticoagulant and anti-inflammatory activities [2].
dihydropyrimidinones from pyrazolopyrimidinone based
aldehydes utilizing CuCl2·2H2O catalyzed Biginelli
method as an environmentally benign synthesis under
mild and solvent free conditions at 100°C.
RESULTS AND DISCUSSION
6-(Chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyri-
midin-4(5H)-one (3) was chosen as the starting
compound for preparation of target pyrazolo[3,4-d]pyri-
midin-4(5H)-one based dihydropyrimidinones. The
former was synthesized in two steps from 5-amino-1-
phenyl-1H-pyrazole-4-carbonitrile (1) via the amide
compound 2 (Scheme 1) [16].
On the other hand, 3,4-dihydropyrimidin-2(1H)-one
(DHPM), either from natural or synthetic origin are
having wide range of biological applications. The
marine alkaloids Crambescidins and Crambescins con-
taining a DHPM core were significantly known to
possess antiviral and cytotoxic properties [3]. Batzella-
dines A and B with DHPM core were recognized as
anti HIV agents [4]. The synthesized DHPM deri-
vatives are also well known for potent vasodilative,
antiviral, anti-tubercular and anticancer activities
[5, 6]. Generally, the dihydropyrimidinones are syn-
thesized by Biginelli condensation method as an oldest
well known multicomponent acid or Lewis acid
catalyzed reaction [7–12]. Low price, readily available
cupric chloride dihydrate was also used as a green
catalyst in the preparation of DHPM either in the
presence of aqueous surfactant [13] or concentrated
HCl [14] or under microwave conditions [15]. Here we
are reporting an efficient green synthesis of novel
The amide nitrogen in compound 3 was methylated
using dimethyl sulfide in dry acetone to afford me-
thylated derivative 4. The structure of compound 4 was
confirmed by spectral data. The presence of N-CH3
and CH2Cl groups in 4 were evidenced by the
appearance of singlet signals at 3.76 and 4.66 ppm
1
respec-tively in its H NMR spectrum and at 30.4 and
44.4 ppm in 13C NMR spectrum.
The key precursors of the target compounds, pyra-
zolopyrimidinone based aldehydes, were obtained by
using the chloromethyl compound 4 and various
p-hydroxy araldehydes. Dehydrohalogenation reaction
of compound 4 with p-hydroxy araldehydes 5a–5d in
the presence of potassium carbonate in DMF at room
temperature lasted for 2–4 h and gave the corres-
1 The text was submitted by the authors in English.
2712

THE NEW GREEN PROCEDURE FOR PYRAZOLOPYRIMIDINONE
2713
Scheme 1. Synthesis of 6-(chloromethyl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (3).
O
O
NH2
NH2
CN
NH2
NH
Cl
N
N
N
H2SO4
N
Chloroacetyl chloride
N
N
N
0−5° C, 2 h
Δ, 4 h
1
2
3
Scheme 2. Synthesis of 4-{(5-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methoxy}araldehydes
(6a–6d).
CHO
O
O
O
R1
R2
R1
NH
N
N
OH
Cl
Cl
O
Dimethyl sulfide,
acetone
N
N
5a−5d
N
N
N
N
N
CHO
N
N
K2CO3, DMF
K2CO3, 0−5°C,
1−2 h
R2
room temperature, 2−4 h
6a−6d
3
4
6: R1 = R2 = H (a); R1 = H, R2 = OMe (b); R1 = H, R2 = OEt (c); R1 = R2 = OMe (d).
ponding 4-{(5-methyl-4-oxo-1-phenyl-4,5-dihydro-1H-
pyrazolo[3,4-d]pyrimidin-6-yl)methoxy}araldehydes
(6a–6d) in high yields (Scheme 2). In the aldehyde
derivatives 6a–6d presence of the singlet signal in the
range of 9.86–9.92 ppm and at 190.7 ppm in the corres-
out individually with ethyl acetoacetate 7a or methyl
acetoacetate 7b and urea 8a or thiourea 8b under the
optimized conditions (Table 1).
Structures of dihydropyrimidinone derivatives 9a–
9j were confirmed based on their spectral data. For
example, the compound 9a exhibited signals for
dihydropyrimidinone ring protons at 5.29 ppm as a
singlet (CH). The ethoxy and methyl groups of DHPM
were indicated by signals at 1.11 as a triplet (CH2CH3),
3.99 as quartet (CH2CH3) and at 2.54 ppm as a singlet
1
ponding H NMR and 13C NMR spectra, respectively,
indicated the aldehyde group in the products. Presence
of the OCH2 group was confirmed by appearance of a
1
singlet in the region of H NMR 5.22–5.33 ppm and a
singlet signal at 69.2–73.6 ppm of 13C NMR spectra.
1
Initially, the Biginelli condensation of pyrazolopyri-
midinone based aldehyde 6a with ethyl acetoacetate
7a, and urea 8a was carried out in approximately
equimolar ratio using 20 mol % of copper chloride as a
catalyst at 100°C under solvent free conditions giving
the product 9a (Scheme 3). The reaction did not
proceed without a catalyst or gave traces of the product.
(DHPM–CH3) in the H NMR spectrum. Structure for
the compound 9a was confirmed by HRMS that
demonstrated the [M + H]+ peak m/z at 515.2013,
correlated with the molecular formula C27H27N6O5.
Biological evaluation. Antibacterial activity. The
newly synthesized compounds 9a–9j were screened for
their antibacterial activity against Escherichia coli,
Klebsyella pneumonia, Staphylococcus aureus, and
Bacillus subtilis strains by the disk diffusion method
[17]. Ampicillin was used as a control and its solution
as well as the test compounds solutions were made
The method was further extended to the synthesis
of various pyrazolopyrimidinone based dihydropyri-
midinones. The Biginelli condensation reaction of pyra-
zolopyrimidinone based aldehydes 6a–6d was carried
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 11 2017

2714
MURALIDHAR ALLAM et al.
Scheme 3. Synthesis of pyrazolopyrimidinone based dihydropyrimidinones 9a–9j.
O
O
O
R1
O
R1
R3
N
O
N
O
H
X
O
N
R3 = Et, Me
N
N
CHO
N
N
.
N
CuCl2 2H2O (20 mol %)
N
NH
7a, 7b
R2
R2
+
O
100°C, 2−4 h
X
O
R3
H2N
NH2
9a−9j
6a−6d
8a, 8b
X = O, S.
with concentrations of 10, 20, and 30 µg/mL in DMSO.
Antibacterial activity was measured as zone of
inhibition in mm (Table 2). According to the
accumulated data all compounds demonstrated high to
excellent activity. Though the compounds 9e and 9f
did not show any activity against E. coli, and 9d was
inactive against K. pneumonia.
mass spectrometer. Purity of the compounds was
tested by TLC on silica gel plates.
Synthesis of 6-(chloromethyl)-5-methyl-1-phenyl-
1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (4). To a
solution of compound 3 (5 g, 19.23 mmol) in dry
acetone 3 equiv. of K2CO3 (7.96 g, 57.69 mmol) were
added. The mixture was stirred at 0–5°C for 10 min,
then 1.2 equiv. of dimethyl sulfide (1.41 g, 22.8 mmol)
was added drop wise and stirred for 2 h. After
completion of the reaction, the solvent was distilled off
and the remaining mixture poured into ice cold water.
The separated crude product was filtered off and
purified by silica gel column chromatography using
petroleum ether–ethyl acetate mixture (8 : 2) as an
eluent to afford the compound 4. Yield 90%, mp 168–
170°С. 1Н NMR spectrum, δ, ppm: 3.76 s (3H, NCH3),
4.66 s (2H, CH2Cl), 7.34–7.40 m (1H, Ar-H), 7.48–
7.56 m (2H, Ar-H), 8.03–8.09 m (2H, Ar-H), 8.26 s
(1H, pyrazole-H). 13С NMR spectrum, δС, ppm: 30.4,
44.4, 106.3, 122.0, 127.2, 129.1, 136.2, 138.3, 149.7,
154.6, 158.0.
EXPERIMENTAL
Melting points were measured in open capillary
1
tubes. H and 13C NMR spectra were measured on a
Bruker-Avance (400 MHz) Spectrometer using TMS
as an internal standard and CDCl3 as a solvent. High
Resolution Mass Spectra were measured on a Q-TOF
Table 1. Physical data of the compounds 9a–9ja,b
Comp.
Substituents
Yield, %
no.
9a
9b
9c
9d
9e
9f
R1 = H, R2 = H, R3 = Et, X = O
R1 = H, R2 = H, R3 = Me, X = O
R1 = H, R2 = OMe, R3 = Et, X = O
R1 = H, R2 = OMe, R3 = Me, X = O
R1 = H, R2 = OEt, R3 = Me, X = O
R1 = R2 = OMe, R3 = Me, X = O
R1 = H, R2 = OEt, R3 = Et, X = S
R1 = H, R2 = OEt, R3 = Me, X = S
R1 = R2 = OMe, R3 = Et, X = S
80
81
89
78
76
96
80
80
81
88
Synthesis of 4-{(5-methyl-4-oxo-1-phenyl-4,5-di-
hydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methoxy}-
araldehydes (6a–6d). To a solution of compound 4 (1
g, 3.63 mmol) in DMF, 3 equiv. of K2CO3 (1.5 g,
10.9 mmol) were added and stirred for 10 min. Then
4.3 mmol of p-hydroxy aromatic aldehyde
5
(4.3 mmol) were added and the reaction mixture was
stirred for 2–4 h. After completion of the process, the
resultant mixture was poured into the ice cold water,
the solid residue was filtered off and dried. The crude
product was purified by column chromatography using
petroleum ether–ethyl acetate mixture (8 : 2) as an
eluent to afford the corresponding compounds 6a–6d.
9g
9h
9i
9j
R1 = R2 = OMe, R3 = Me, X = S
a
b
Isolated yields. All reactions were carried out using 0.2 mmol
of 6, 8 with 0.22 mmol of 7 in the presence of 20 mol %
of CuCl2·2H2O at 100°C for 2–4 h.
4-{(5-Methyl-4-oxo-1-phenyl-4,5-dihydro-1H-py-
razolo[3,4-d]pyrimidin-6-yl)methoxy}benzaldehyde
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 11 2017

THE NEW GREEN PROCEDURE FOR PYRAZOLOPYRIMIDINONE
2715
Table 2. Anti-bacterial activity of synthesized compounds 9a–9j
Bacterial growth inhibition zone, mm
B. Subtilis
E. Coli
K. Pneumonia
concentration, µg/mL
S. Aureus
Comp. no.
10
14
15
14
15
12
13
14
16
14
17
16
20
16
16
17
15
16
16
16
19
16
20
18
30
20
19
19
17
17
19
18
22
18
22
21
10
15
–
20
16
–
30
20
–
10
12
12
13
–
20
14
15
16
–
30
17
17
18
–
10
13
14
12
11
14
15
14
19
16
19
18
20
15
16
16
13
17
17
17
21
17
21
20
30
9a
18
19
18
17
19
19
21
24
19
23
22
9b
9c
16
14
–
18
18
–
20
20
–
9d
9e
12
14
15
16
14
16
15
18
16
17
18
15
18
17
18
20
19
21
17
21
20
9f
–
–
–
9g
14
19
15
18
17
16
21
17
19
18
18
23
19
23
22
9h
9i
9j
Ampicillin
1
(6a). Yield 93%, mp 164–166°С. Н NMR spectrum,
δ, ppm: 3.74 s (3H, NCH3), 5.30 s (2H, OCH2), 7.13–
7.19 m (2H, Ar-H), 7.32–7.39 m (1H, ArH), 7.43–7.50
m (2H, Ar-H), 7.85–7.92 m (2H, Ar-H), 7.96–8.01 m
(2H, Ar-H), 8.26 s (1H, pyrazole-H), 9.92 s (1H,
CHO). 13С NMR spectrum, δС, ppm: 30.3, 69.3, 106.3,
115.1, 121.8, 127.3, 129.1, 131.1, 132.0, 136.2, 138.3,
149.7, 153.8, 158.0, 162.1, 190.5.
9.86 s (1H, CHO). 13С NMR spectrum, δС, ppm: 14.6,
30.2, 64.5, 70.4, 106.4, 111.0, 113.9, 121.8, 125.7,
127.1, 129.0, 131.6, 136.1, 138.4, 149.7, 149.8, 152.0,
154.0, 158.1, 190.7.
3,5-Dimethoxy-4-{(5-methyl-4-oxo-1-phenyl-4,5-
dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
oxy}benzaldehyde (6d). Yield 90%, mp 174–176°С.
1Н NMR spectrum, δ, ppm: 3.84 s (6H, OCH3), 3.93 s
(3H, NCH3), 5.22 s (2H, OCH2), 7.10 s (2H, Ar-H),
7.28–7.35 m (1H, Ar-H), 7.7–7.48 m (2H, Ar-H), 7.81–
7.92 m (2H, Ar-H), 8.25 s (1H, pyrazole-H), 9.86 s
(1H, CHO). 13С NMR spectrum, δС, ppm: 30.5, 56.1,
73.6, 106.2, 121.1, 126.9, 128.9, 132.7, 136.0, 138.3,
140.3, 149.8, 153.7, 154.9, 158.3, 190.8.
3-Methoxy-4-{(5-methyl-4-oxo-1-phenyl-4,5-di-
hydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)methoxy}-
benzaldehyde (6b). Yield 93%, mp 189–191°С. Н
1
NMR spectrum, δ, ppm: 3.76 s (3H, NCH3), 3.92 s
(3H, OCH3), 5.33 s (2H, OCH2), 7.16 d (1H, J =
8.1 Hz, Ar-H), 7.30–7.39 m (1H, Ar-H), 7.49–7.43 m
(4H, Ar-H), 7.94–8.00 m (2H, Ar-H), 8.25 s (1H,
pyrazole-H), 9.87 s (1H, CHO). 13С NMR spectrum,
δС, ppm: 30.2, 56.06, 69.2, 106.3, 115.1, 121.8, 127.3,
129.1, 131.1, 132.0, 136.2, 138.3, 149.7, 153.8, 158.0,
162.1, 190.5.
Synthesis of pyrazolopyrimidinone based dihyd-
ropyrimidinone derivatives (9a–9j). CuCl2·2H2O
(20 mol %) was added to a mixture of an aldehyde 6
(0.2 mmol) with 1.1 equiv. of alkyl acetoacetate 7
(0.22 mmol) and 1 equivalent of urea/thiourea 8
(0.2 mmol). The reaction mixture was heated at 100°C
for 2–4 h. Upon completion of the process (according
to TLC), the reaction mixture was poured into an ice-
cold water and stirred for 5–10 min. The precipitated
crude product was filtered off and purified by column
chromatography using petroleum ether–ethyl acetate
mixture (6 : 4) as an eluent to afford the compounds
9a–9j.
3-Ethoxy-4-{(5-methyl-4-oxo-1-phenyl-4,5-dihydro-
1H-pyrazolo[3,4-d]pyrimidin-6-yl)methoxy}benzal-
dehyde (6c). Yield 95%, mp 128–130°С. Н NMR
spectrum, δ, ppm: 1.45 t (3H, J = 7.0 Hz, CH2–CH3,),
3.79 s (3H, NCH3), 4.15 q (2H, J = 7.0 Hz, CH2–CH3),
5.32 s (2H, OCH2), 7.18 d (1H, J = 8.0 Hz, Ar-H), 7.35
t (1H, J = 7.4 Hz, Ar-H), 7.39–7.51 m (4H, Ar-H),
7.99 d (2H, J = 7.7 Hz, Ar-H), 8.26 s (H, pyrazole-H),
1
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 11 2017

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MURALIDHAR ALLAM et al.
Ethyl 6-methyl-4-(4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
Methyl 4-(3-methoxy-4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
oxy}phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (9d). Yield 78%, mp 238–240°С.
1Н NMR spectrum, δ, ppm: 2.34 s (3H, DHPM-CH3),
3.62 s (3H, NCH3), 3.77 s (3H, OCH3), 3.84 s (3H,
OCH3), 5.21 s (2H, OCH2), 5.31 br.s (1H, NH), 5.36 s
(1H, CH), 6.63 br.s (1H, NH), 6.84 d.d, (1H, J = 8.2,
2.1 Hz, Ar-H), 6.89 d (1H, J = 2.0 Hz, Ar-H), 6.98 d
(1H, J = 8.3 Hz, Ar-H), 7.35 t (1H, J = 7.4 Hz, Ar-H),
7.48 t (2H, J = 7.9 Hz, Ar-H), 8.02–8.03 m (2H,
Ar-H), 8.25 s (1H, pyrazole-H). 13С NMR spectrum,
δС, ppm: 18.4. 30.3, 51.1, 54.4, 56.0, 70.5, 100.2,
106.2, 110.7, 114.8, 118.3, 121.6, 127.0, 128.9, 135.8,
138.3, 139.1, 146.0, 147.6, 149.6, 149.9, 158.0, 166.2.
HRMS [ESI], m/z: 531.1969 (531.1992) [M + H]+.
C27H27N6O6.
oxy}phenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
1
carboxylate (9a). Yield 80%, mp 260–262°С. Н
NMR spectrum, δ, ppm: 1.11 t (3H, J = 7.0 Hz, CH2-
CH3), 2.54 s (3H, DHPM-CH3), 3.67 s (3H, NCH3),
3.99 q (2H, J = 7.2 Hz, CH2–CH3), 5.14 s (2H, OCH2),
5.29 s (1H, CH), 5.75 br.s (1H, NH), 6.91 d (2H, J =
8.4 Hz, Ar-H), 7.22–7.25 m (2H, Ar-H), 7.29 d (1H,
J = 7.6 Hz, Ar-H), 7.43 s (2H, Ar-H), 7.71 br.s (1H,
NH), 7.97 d (2H, J = 7.3 Hz, Ar-H), 8.19 s (1H,
pyrazole-H). 13С NMR spectrum, δС, ppm: 14.4, 18.2,
53.6, 59.5, 66.7, 70.2, 100.0, 105.7, 115.1, 121.3,
127.2, 127.6, 129.5, 136.5, 138.1, 138.4, 148.6, 150.3,
152.6, 157.0, 157.3, 157.7, 165.8. HRMS [ESI], m/z:
515.2013 (515.2043) [M + H]+. C27H27N6O5.
Methyl 6-methyl-4-(4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
oxy}phenyl)-2-oxo-1,2,3,4-tetrahydropyrimidine-5-
Methyl 4-(3-ethoxy-4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
oxy}phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (9e). Yield 76%, mp 240–242°С.
1Н NMR spectrum, δ, ppm: 1.39 s (3H, OCH2–CH3),
2.33 s (3H, DHPM-CH3), 3.63 s (3H, NCH3), 3.81 s
(3H, OCH3), 4.04 d (2H, J = 6.3 Hz, OCH2–CH3), 4.95
br.s (1H, NH), 5.21 s (2H, OCH2), 5.62 br.s (1H, NH),
6.74 s (1H, CH), 6.89–6.95 m (2H, Ar-H), 7.29–7.36
m (2H, Ar-H), 7.45–7.54 m (2H, Ar-H), 8.03 d (2H,
J = 7.0 Hz, Ar-H), 8.25 s (1H, pyrazole-H). 13С NMR
spectrum, δС, ppm: 14.7, 18.8, 30.4, 55.4, 60.1, 64.4,
71.4, 101.7, 106.4, 111.8, 116.2, 118.6, 121.8, 127.0,
129.0, 136.1, 138.4, 138.91, 145.7, 146.5, 149.6,
149.9154.8, 158.3, 165.6. HRMS [ESI], m/z: 545.2137
(545.2149) [M + H]+. C27H27N6O5.
1
carboxylate (9b). Yield 81%, mp 256–258°С. Н
NMR spectrum, δ, ppm: 2.30 s (3H, DHPM-CH3),
3.56 s (3H, NCH3), 3.68 s (3H, OCH3), 5.15 s (2H,
OCH2), 5.30 s (1H, CH), 5.72 br.s (1H, NH), 6.59 br.s
(1H, NH), 6.92 d (2H, J = 8.7 Hz, Ar-H), 7.23 s (1H,
Ar-H), 7.26 – 7.34 m (1H, Ar-H), 7.44 t (2H, J =
7.9 Hz, Ar-H), 7.73 s (1H, Ar-H), 7.99 d (2H, J =
7.6 Hz, Ar-H), 8.20 s (1H, pyrazole-H). 13С NMR
spectrum, δС, ppm: 17.4, 28.3, 49.7, 68.1, 76.2, 113.4,
120.5, 124.0, 125.8, 126.7, 127.8, 134.7, 136.9, 142.4,
146.5, 147.4, 148.5, 151.4, 155.6, 157.8, 161.4, 165.9.
HRMS [ESI], m/z: 501.1880 (501.1808) [M + H]+.
C26H25N6O5.
Ethyl 4-(3-methoxy-4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
oxy}phenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyri-
midine-5-carboxylate (9c). Yield 89%, mp 212–214°С.
1Н NMR spectrum, δ, ppm: 1.16 t (3H, J = 7.1 Hz,
CH2–CH3), 2.35 s (3H, DHPM-CH3), 3.77 s (3H,
NCH3), 3.83 s (3H, OCH3), 4.07 q (2H, J = 7.1 Hz,
CH2-CH3), 5.21 s (2H, OCH2), 5.38 s (1H, CH), 5.49
br.s (1H, NH), 6.85 d (1H, J = 8.1 Hz, Ar-H), 6.89 d
(1H, J = 1.8 Hz, Ar-H) 6.97 d, (1H, J = 8.2 Hz, Ar-H),
7.22 br.s (1H, NH), 7.34 t (1H, J = 7.4 Hz, Ar-H), 7.48
t (2H, J = 7.9 Hz, Ar-H), 8.02 d (2H, J = 7.7 Hz,
Ar-H), 8.25 s (1H, pyrazole-H). 13С NMR spectrum,
δС, ppm: 14.2. 18.9, 30.3, 55.4, 55.9, 60.1, 70.9, 101.4,
110.4, 113.5, 114.8, 116.7, 117.7, 118.6, 121.9, 127.0,
129.1, 136.0, 138.5, 145.9, 146.4, 150.0, 152.8, 154.8,
165.5. HRMS [ESI], m/z: 545.2137 (545.2149) [M +
H]+. C28H29N6O6.
Methyl 4-(3,5-dimethoxy-4-{(5-methyl-4-oxo-1-
phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-
yl)methoxy}phenyl)-6-methyl-2-oxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (9f). Yield 96%, mp
1
249–251°С. Н NMR spectrum, δ, ppm: 1.19 s (3H,
DHPM-CH3), 3.52 s (3H, OCH3), 3.69 s (6H, 2OCH3),
3.87 s (3H, NCH3), 5.03 s (2H, OCH2), 5.25 s (1H,
CH), 6.00 br.s (1H, NH), 6.47 s (1H, Ar-H), 7.27 s
(2H, Ar-H), 7.40 s (2H, Ar-H), 7.90 d (2H, J = 7.0 Hz,
Ar-H), 7.98 br.s (1H, NH), 8.18 s (1H, pyrazole-H).
13С NMR spectrum, δС, ppm: 18.6, 30.6, 51.0, 55.4,
55.9, 73.8, 100.5, 103.2, 106.2, 121.7, 126.9, 128.9,
134.7, 135.9, 138.5, 140.8, 147.0, 150.1, 153.1, 153.3,
155.5, 158.5, 166.1.
Ethyl 4-(3-ethoxy-4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 11 2017

THE NEW GREEN PROCEDURE FOR PYRAZOLOPYRIMIDINONE
2717
oxy}phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
yl)methoxy}phenyl)-6-methyl-2-thioxo-1,2,3,4-tetra-
pyrimidine-5-carboxylate (9g). Yield 80%, mp 225–
227°С. Н NMR spectrum, δ, ppm: 1.15 t (3H, J =
hydropyrimidine-5-carboxylate (9j). Yield 88%, mp
261–263°С. Н NMR spectrum, δ, ppm: 2.09 s (3H,
1
1
7.1 Hz, CH2–CH3), 1.41 t (3H, J = 7.0 Hz, CH2–CH3),
2.34 s (3H, DHPM-CH3), 3.81 s (3H, NCH3), 4.05 d.q
(4H, J = 10.2, 7.0 Hz, 2CH2–CH3), 5.21 s (2H, OCH2),
5.36 s (1H, CH), 5.44 br.s (1H, NH), 6.84 d.d (1H, J =
8.2 Hz, ArH), 6.87 s ( 1H, Ar-H), 6.97 d (1H, J =
8.3 Hz, Ar-H), 6.99 br.s (1H, NH), 7.35 t (1H, J =
7.4 Hz, Ar-H), 7.48 t (2H, J = 7.9 Hz, Ar-H), 8.02 d
(2H, J = 7.6 Hz, Ar-H), 8.25 s (1H, pyrazole-H). 13С
NMR spectrum, δС, ppm: 13.8, 14.5, 18.6, 30.2, 55.2,
59.9, 64.2, 71.2, 101.5, 106.2, 111.6, 116.0, 118.4,
121.6, 126.8, 128.8, 135.9, 138.2, 138.7, 145.5, 146.3,
149.4, 149.7, 154.6, 158.1, 165.3, 174.1.
DHPM-CH3), 3.48 s (3H, NCH3), 3.65 s (6H, 2OCH3),
3.84 s (3H, OCH3), 5.01 s (2H, OCH2), 5.23 s (1H,
CH), 6.06 br.s (1H, NH), 6.45 d (2H, J = 7.7 Hz,
Ar-H), 7.24 d (1H, J = 2.2 Hz, Ar-H), 7.37 d (2H, J =
7.6 Hz, Ar-H), 7.87 s (2H, Ar-H), 8.06 br.s (1H, NH),
13
8.14 s (1H, pyrazole-H). С NMR spectrum, δС, ppm:
18.6, 30.6, 51.0, 55.3, 55.9, 73.7, 100.5, 103.2, 106.2,
121.7, 126.9, 129.0, 134.7, 135.9, 138.5, 140.8, 147.2,
150.1, 153.2, 155.6, 158.5, 166.1, 173.1.
Antibacterial activity. The final compounds 9a–9j
were screened for anti-bacterial activity by the disk
diffusion method in nutrient agar. The medium was
prepared by adding agar powder to the nutrient broth
(NB), pH was adjusted to 7.2–7.4 and sterilized in
autoclave at 121°C for 15 min. The sterile nutrient
agar was placed in Petri dishes and cooled to 50–45°C.
Actively growing agar slant culture suspension of
bacteria was inoculated separately on the agar plates.
Sterile filter paper discs (6 mm diameter) prepared
from standard Whatman filter paper were dipped in the
test compound solutions as well as ampicillin solution
of different concentrations and after drying, they were
introduced on test organism seeded plates. The plates
with test compound discs were incubated for 24 h at
37°C. After 24 h, and the diameters of the inhibition
zones were measured in mm.
Methyl 4-(3-ethoxy-4-{(5-methyl-4-oxo-1-phenyl-
4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-yl)meth-
oxy}phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-
pyrimidine-5-carboxylate (9h). Yield 80%, mp 238–
1
240°С. Н NMR spectrum, δ, ppm: 1.41 t (3H, J =
7.0 Hz, OCH2–CH3), 2.34 s (3H, DHPM-CH3), 3.62 s
(3H, NCH3), 3.81 s (3H, OCH3), 4.04 q (2H, J =
6.9 Hz, OCH2–CH3), 5.21 s (2H, OCH2), 5.35 s (1H,
CH), 5.44 br.s (1H, NH), 6.88–6.84 m (2H, Ar-H),
6.99 d (1H, J = 8.2 Hz, Ar-H),7.09 br.s (1H, NH), 7.35
t (1H, J = 7.4 Hz, Ar-H), 7.48 t (2H, J = 7.9 Hz, Ar-H),
8.03 d (2H, J = 7.8 Hz, Ar-H), 8.25 s (1H, pyrazole-
H). 13С NMR spectrum, δС, ppm: 14.6, 18.5, 30.3, 50.8,
54.7, 64.2, 71.3, 100.3, 106.2, 111.8, 115.9, 118.5,
121.7, 126.9, 129.0, 135.8, 138.3, 139.5, 146.2, 147.5,
149.3, 150.0, 154.4, 155.0, 158.1, 166.2, 176.3.
CONCLUSIONS
A number of new hybrid aza heterocycles
containing pyrazolopyrimidinone and dihydropyri-
midinone scaffolds was synthesized by an efficient,
simple, green method using inexpensive copper
chloride catalyzed Biginelli reaction under mild and
solvent free conditions. All final compounds 9a–9j
demonstrated high to excellent antibacterial activity.
Activity of 9h and 9j is comparable with that of
ampicillin drug.
Ethyl 4-(3,5-dimethoxy-4-{(5-methyl-4-oxo-1-
phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-
yl)methoxy}phenyl)-6-methyl-2-thioxo-1,2,3,4-tetra-
hydropyrimidine-5-carboxylate (9i). Yield 81%, mp
1
265–267°С. Н NMR spectrum, δ, ppm: 1.12 t (3H,
J = 7.1 Hz, OCH2–CH3), 2.33 s (3H, DHPM-CH3),
3.74 s (6H, 2OCH3), 3.93 s (3H, NCH3), 4.03 q (2H,
J = 7.1 Hz, OCH2–CH3), 5.09 s (2H, OCH2), 5.34 s
(1H, J = 2.7 Hz, CH), 5.40 br.s (1H, NH), 6.51 br.s
(1H, NH), 7.01 d (1H, J = 7.8 Hz, Ar-H), 7.32 t (2H,
J = 7.4 Hz, Ar-H), 7.43–7.47 m (2H, Ar-H), 7.91–7.99
m (2H, Ar-H), δ 8.24 s (1H, pyrazole-H). 13С NMR
spectrum, δС, ppm: 14.1, 18.9, 30.7, 56.0, 60.1, 70.5,
73.9, 101.3, 103.2, 106.3, 121.7, 126.9, 128.9, 134.8,
136.0, 138.5, 140.6, 145.9, 146.2, 150.1, 152.6,153.3,
155.5, 158.4, 165.5, 176.1.
ACKNOWLEDGMENTS
Authors are grateful to the Director, Central
Facilities for Research and Development (CFRD),
Osmania University, Hyderabad for providing
laboratory facilities. This work was also financially
supported by the project under UGC-UPE FAR
program. One of the authors, Muralidhar Allam, is
grateful to UGC, New Delhi for award of SRF.
Methyl 4-(3,5-dimethoxy-4-{(5-methyl-4-oxo-1-
phenyl-4,5-dihydro-1H-pyrazolo[3,4-d]pyrimidin-6-
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 87 No. 11 2017

2718
MURALIDHAR ALLAM et al.
8. De, S.K. and Gibbs, R.A., Synthesis, 2005, p. 1748. doi
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