Saccharin: a green, economical and efficient catalyst for the one-pot, multi-component synthesis of 3,4-dihydropyrimidin-2-(1H)-one derivatives and 1H-pyrazolo [1,2-b] phthalazine-5,10-dione derivatives and substituted dihydro-2-oxypyrrole

Article abstract of DOI:10.1007/s13738-016-0871-5

Abstract: In this method, we have reported the catalytic ability of saccharin as a green, eco-friendly catalyst for the multi-component efficient synthesis of 3,4-dihydropyrimidin-2-(1H)-one derivatives and 1H-pyrazolo [1,2-b]phthalazine-5,10-dione derivatives and substituted dihydro-2-oxypyrrole with excellent yields and short reaction times. This present methodology has notable benefits such as green, inexpensive and non-toxic catalyst, one-pot, environmental benign nature, solvent-free conditions, simplicity of operation with no necessity of chromatographic purification steps and eco-friendly. Graphical Abstract: We have studied the catalytic ability of saccharin as a green, economical and environmentally benign nature for the multi-component efficient synthesis of 3,4-dihydropyrimidin-2-(1H)-ones derivatives, 1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives and substituted dihydro-2-oxypyrrole with excellent yields and short reaction times. Green catalyst, mild, non-toxic, inexpensive, simple operational procedures, one-pot, high catalytic activity, eco-friendly, easily separated from the reaction mixture with no column chromatographic for the one-pot multi-component synthesis of these compounds are the most important advantages of this procedure.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s13738-016-0871-5

J IRAN CHEM SOC
DOI 10.1007/s13738-016-0871-5
ORIGINAL PAPER
Saccharin: a green, economical and efficient
catalyst for the one‑pot, multi‑component synthesis
of 3,4‑dihydropyrimidin‑2‑(1H)‑one derivatives and 1H‑pyrazolo
[1,2‑b] phthalazine‑5,10‑dione derivatives and substituted
dihydro‑2‑oxypyrrole
Farzaneh Mohamadpour1 · Malek Taher Maghsoodlou1 · Reza Heydari1 ·
Mojtaba Lashkari2
Received: 30 November 2015 / Accepted: 25 April 2016
© Iranian Chemical Society 2016
Abstract In this method, we have reported the catalytic
ability of saccharin as a green, eco-friendly catalyst for
the multi-component efficient synthesis of 3,4-dihydropy-
rimidin-2-(1H)-one derivatives and 1H-pyrazolo [1,2-b]
phthalazine-5,10-dione derivatives and substituted dihy-
dro-2-oxypyrrole with excellent yields and short reaction
times. This present methodology has notable benefits such
as green, inexpensive and non-toxic catalyst, one-pot, envi-
ronmental benign nature, solvent-free conditions, simplic-
ity of operation with no necessity of chromatographic puri-
fication steps and eco-friendly.
Graphical Abstract We have studied the catalytic abil-
ity of saccharin as a green, economical and environmen-
tally benign nature for the multi-component efficient syn-
thesis of 3,4-dihydropyrimidin-2-(1H)-ones derivatives,
1H-pyrazolo[1,2-b]phthalazine-5,10-dione derivatives and
substituted dihydro-2-oxypyrrole with excellent yields
and short reaction times. Green catalyst, mild, non-toxic,
inexpensive, simple operational procedures, one-pot, high
catalytic activity, eco-friendly, easily separated from the
reaction mixture with no column chromatographic for the
one-pot multi-component synthesis of these compounds are
the most important advantages of this procedure.
* Malek Taher Maghsoodlou
mt_maghsoodlou@yahoo.com; mt_maghsoodlou@chem.usb.
ac.ir
1
Department of Chemistry, Faculty of Science, University
of Sistan and Baluchestan, P. O. Box 98135-674, Zahedan,
Iran
2
Faculty of Science, Velayat University, Iranshahr, Iran
1 3

J IRAN CHEM SOC
Ar1
Ar1 CHO
CO2R1
CH3
O
O
1
OR1
CH3
HN
Saccharin (15 mol %)
Solvent free, 80 °C
+
X
N
H
NH2
X
NH2
4 a-t
3
2
O
NH2NH2 .H2O
+
+
NH
O
O
Ar2
N
N
6
Saccharin (20 mol %)
Solvent free, 90 °C
5
CN
NH2
CN
Ar2 CHO
O
CN
7
8
9 a-r
CO2R3
R2
O
H
N
NH2
+
R2
N Ar3
H
10
Saccharin (15 mol %)
MeOH, r.t.
CO2R3
11
R3O2C
14 a-s
H
O
Ar3 NH2
H
+
H
12
13
Keywords Green synthesis · Saccharin · Eco-friendly ·
3,4-Dihydropyrimidinone · 1H-pyrazolo[1,2-b]phthalazine-
5,10-dione derivatives · Dihydro-2-oxypyrrole substituted ·
Multi-component reaction
and pharmaceutical properties [12, 13], for example anti-
microbiological [14, 15], anti-tumor [16], anti-inflammatory
[17]. Moreover, these compounds have been employed as
calcium channel blockers, α-1a-antagonists [18], antifungal
[19], anti-diabetics [20] activity. In addition, they have been
used as Pl-091 [21]; many of number alkaloids with biologi-
cal activities have pyrrole rings [22].
Introduction
In recent decades, a number of methodologies for prepa-
ration of these compounds have been reported that is includ-
ing Brønsted or Lewis acid catalysts such as Cu(OAc)2
[23], bakers’ yeast [24], TBAB [25], calcium fluoride [26],
copper(II) tetrafluoroborate [27], hexaaquaaluminium(III)
tetrafluoroborate [28], hydrotalcite [29], NiCl2·6H2O [30],
[Btto][p-TSA] [31], PTSA/[Bmim]Br [32], CuI nanopar-
ticles [33], InCl3 [34, 35], STA [36], ultrasound-assisted
[37], SBA-Pr-SO3H [38], I2 [39], [n-Bu4N][HSO4] [40],
Al(H2PO4)3 [41], oxalic acid dehydrate [42], AcOH [43]
and ZrCl4 [44]. Some of these methodologies have limita-
tions such as toxic and expensive catalysts, long time reac-
tions, low yields, use of strongly acidic conditions, difficult
work-up, high temperature. Because of their pharmaceu-
tical and biological properties, the development of green,
simple and environmentally safe methodology for the syn-
thesis of these heterocyclic compounds has become the
In recent years, green chemistry has become to one of the
best approaches for green and efficient synthesis of organic
compounds. The special benefits of green chemistry are
using non-toxic substrate and environmentally benign sol-
vent for the synthesis of organic compounds. Herein, our
recent studies focused on developing of green catalyst [1–
6] in multi-component reactions [7–10].
In the past decades, most of the researches have been
focused on a study for the synthesis of heterocyclic com-
pounds. Organic compounds containing nitrogen heterocy-
clic rings are important compounds in medicinal chemistry.
Recently, extensive studies have been accomplished on
Biginelli reaction for the synthesis of 3,4-dihydropyrimidin-
2-(1H)-ones, 1H-pyrazolo[1,2-b]phthalazine-5,10-dione and
substituted dihydro-2-oxypyrroles using multi-component
reactions [11]. These compounds have several biological
1 3

J IRAN CHEM SOC
Ar1
Scheme 1 Synthesis of
3,4-dihydropyrimidin-2-(1H)-
one derivatives
Ar1 CHO
CO2R1
CH3
O
O
1
OR1
CH3
HN
Saccharin (15mol%)
Solvent free, 80 °C
+
X
N
H
NH2
X
NH2
4 a-t
3
2
most important aim of our researches, and finally, we have
reported saccharin as a green, economical and efficient
acidic catalyst. The advantages of saccharin as a catalyst
in organic compounds synthesis is environmental-friendly,
green, mild, inexpensive, non-toxic. We carried out the
one-pot, multi-component condensations by saccharin cata-
lyst in excellent yields and short reaction times, and also,
saccharin can be successfully used in the formation of
carbon–carbon bonds as mild and green acidic catalyst in
organic synthesis.
Results and discussion
In this protocol, we reported saccharin as a green acidic
catalyst for an efficient and environmental-friendly meth-
odology to diverse synthesis of 3,4-dihydropyrimidin-
2-(1H)-ones derivatives via one-pot three-component
condensation Biginelli reaction of aldehyde derivatives 1
(1.0 mmol), urea/thiourea 2 (1.5 mmol) and ethyl/methyl
acetoacetate 3 (1.0 mmol) under thermal and solvent-free
conditions (Scheme 1).
Table 1 Optimization of the reaction condition for the synthesis of 4b
Ph
O
CO2Et
CH3
OEt
CH3
NH2
NH2
HN
+
Ph CHO
+
O
O
N
H
O
Entry
Saccharin (mol%)
Time (min)
Isolated yields (%)
1
2
3
4
5
Catalyst free
240
30
25
15
15
Not product
5
53
71
88
91
10
15
20
Reaction conditions: Benzaldehydes (1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.5 mmol) and saccharin were heated at 80 °C for the
appropriate time
Table 2 Effect of temperature on the synthesis of 4b
Ph
O
CO2Et
OEt
CH3
NH2
NH2
HN
+
PhCHO
+
O
O
N
H
CH3
O
Entry
Temperature (°C)
Time (min)
Isolated yields (%)
1
2
3
4
5
rt
240
35
25
15
15
Not product
40
60
80
100
58
77
88
90
Reaction conditions: Benzaldehydes (1.0 mmol), ethyl acetoacetate (1.0 mmol), urea (1.5 mmol) and saccharin (15 mol%) were heated under
various temperatures for the appropriate time
1 3

J IRAN CHEM SOC
In order to optimize the reaction conditions, the synthe-
sis of compound 4b (Table 3, entry 2) was used as a model
reaction. The influence of catalyst loading on the reac-
tion has been studied in this protocol. No product could
be detected in the absence of the catalyst even after 4 h
(Table 1, entry 1). Good yields were obtained in the pres-
ence of catalyst. The best catalyst loading was 15 mol%
(0.027 g) (Table 1, entry 4). The higher amount of catalyst
did not increase the yield of the product. (Table 1, entry 5).
And the highest yield of the product was obtained in the
presence of 0.027 g of catalyst, and the results are summa-
rized in Table 1.
Also, the effect of temperature on the reaction has been
studied. No product could be detected in room tempera-
ture condition (Table 2, entry 1). The reaction was investi-
gated by changing temperature from 40 to 100 °C and the
high yield of product was obtained in 80 °C temperature
(Table 1, entry 4) and yields of product at different tem-
perature are reported in Table 2.
In this regard, a series of 3,4-dihydropyrimidin-2-(1H)-
ones have been synthesized with type of electron-donating
and electron-withdrawing aldehydes derivatives such as Cl,
Br, NO2, OH, OMe, in the presence of catalytic amount of
saccharin (15 mol%) at 80 °C temperature and the results
are given in Table 3.
After the successful synthesis of 3, 4-dihydropyrimidin-
2-(1H)-one derivatives, we turned our attention toward
the synthesis of pyrazolo [1,2-b] phthalazine-5, 10-dione
derivatives. In order to the optimal conditions, we inves-
tigated the four-component of phthalimide (5, 1.0 mmol),
hydrazine monohydrate (6, 1.0 mmol), aromatic aldehydes
derivatives (7, 1.0 mmol) and malononitrile (8, 1.0 mmol)
in the presence of saccharin as a green and efficient cata-
lyst. (Scheme 2).
In order to optimize the reaction conditions, the synthe-
sis of compound 9c (Table 6, entry 3) was used as a model
reaction. The effect of different amount of catalyst on the
reaction has been studied in this protocol. No product could
Table 3 Saccharin
Entry Ar1
R1
X
Product Time (min) Isolated yields (%) M.p. (°C) M.p. (°C)
catalyzed synthesis of
3,4-dihydropyrimidin-2-(1H)-
one derivatives
1
2-Cl–C6H4
CH3
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
4a
4b
4c
4d
4e
4f
25
15
15
20
20
15
25
15
20
20
15
20
15
25
20
20
25
25
25
20
84
88
90
85
92
80
90
93
87
82
84
85
86
87
82
85
91
86
82
89
248–250 248–252 [27]
201–203 202–204 [31]
200–202 202–203 [29]
228–230 230–232 [27]
213–214 214–216 [27]
203–205 205–206 [24]
205–207 207–209 [27]
176–178 174–176 [25]
257–259 255–257 [29]
213–215 214–216 [23]
219–221 220–223 [27]
192–194 190–194 [27]
190–192 191–193 [27]
203–205 204–205 [24]
244–246 245–246 [24]
206–208 205–206 [31]
206–208 208–210 [25]
152–154 154–156 [23]
149–152 150–151 [24]
195–197 191–195 [26]
2
C6H5
C2H5
C2H5
C2H5
CH3
3
4-OMe–C6H4
4-OH–C6H4
4-O2N–C6H4
3-OMe–C6H4
4-O2N–C6H4
4-F–C6H4
4
5
6
C2H5
C2H5
C2H5
7
4g
4h
4i
8
9
4-(Me)2N–C6H4 C2H5
10
11
12
13
14
15
16
17
18
19
20
4-Cl–C6H4
2-Cl–C6H4
4-OMe–C6H4
3-Cl–C6H4
4-Me–C6H4
4-OH–C6H4
C6H5
C2H5
C2H5
CH3
4j
4k
4l
C2H5
C2H5
CH3
4m
4n
4o
4p
4q
4r
4s
4t
C2H5
CH3
4-F–C6H4
S
4-OMe–C6H4
3-OMe–C6H4
4-Cl–C6H4
C2H5
C2H5
C2H5
S
S
S
Scheme 2 Synthesis of
pyrazolo[1,2-b]phthalazine-
5,10-dione derivatives
O
NH2NH2 .H2O
+
+
NH
O
O
Ar2
N
N
6
Saccharin(20mol%)
Solvent free, 90 °C
O
5
CN
NH2
CN
Ar2 CHO
CN
7
8
9 a-r
1 3

J IRAN CHEM SOC
Table 4 Optimization of the reaction condition for the synthesis of pyrazolo[1,2-b]phthalazine-5,10-dione 9c
O
O
Ph
CN
CN
N
N
NH
+ NH2NH2 .H2O
CN
NH2
Ph CHO
+
+
O
O
Entry
Saccharin (mol%)
Time (h)
Isolated yields (%)
1
2
3
4
5
6
Catalyst free
10
6
Not product
5
42
65
79
89
91
10
15
20
25
4
3
3
3
Reaction conditions: Phthalimide, hydrazine monohydrate, benzaldehyde and malononitrile (1:1:1:1) in the presence of saccharin were heated at
90 °C for the appropriate time
Table 5 Effect of the reaction temperature on the synthesis of 9c
O
O
O
Ph
CN
CN
N
N
NH
+ NH2NH2 .H2O
CN
NH2
Ph CHO
+
+
O
Entry
Temperature (°C)
Time (h)
Isolated yields (%)
1
2
3
4
5
6
Rt
8
6
4
3
3
3
Not product
40
60
80
90
110
39
61
78
89
90
Reaction conditions: Phthalimide, hydrazine monohydrate, benzaldehyde and malononitrile (1:1:1:1) with saccharin (20 mol%) were heated
under various temperatures for the appropriate time
be detected in the absence of the catalyst even after 10 h
(Table 4, entry 1). Good yields were obtained in the pres-
ence of catalyst. The best amount of catalyst was 20 mol%
(0.036 g) (Table 4, entry 5). The higher amount of cata-
lyst did not increase the yields products. (Table 4, entry
6). However, the higher yield of product is obtained with
20 mol% of catalyst and the results are summarized in
Table 4.
Also, the effect of temperature on the reaction has been
investigated. No product could be detected in room temper-
ature condition (Table 5, entry 1). The reaction was inves-
tigated by changing temperature from 40 to 110 °C and
the high yield of product is obtained in 90 °C temperature
(Table 5, entry 5) and yields of product at different tem-
perature are reported in Table 5.
In order to study of this procedure, we have synthesized
a series of compounds with the type of electron-donating
and electron-withdrawing aldehydes derivatives such as
Cl-, Br-, NO2-, OH-, OMe-substituted benzaldehydes
which gave excellent yields and the generality of these
four condensation reaction was studied by using of sac-
charin (20 mol%) via phthalimide (1.0 mmol), hydrazine
monohydrate (1.0 mmol) and the type of aldehydes deriva-
tives (1.0 mmol) malononitrile (1.0 mmol) under thermal
and solvent-free conditions and the results are given in
Table 6.
Also, successfully, we reported a green, mild and
simple procedure for the synthesis of substituted dihy-
dro-2-oxypyrrole by using of a one-pot four-compo-
nent domino reaction via amines (aromatic or aliphatic)
1 3

J IRAN CHEM SOC
Table 6 Saccharin catalyzed
synthesis of pyrazolo[1,2-b]
phthalazine-5,10-dione
derivatives under solvent-free
conditions
Entry
Ar2
Product
Time (h)
Isolated yields (%)
M.p. (°C)
Lit. M.p. (°C)
1
C4H3S
9a
9b
9c
9d
9e
9f
2.5
3
85
92
89
93
83
86
83
91
92
87
82
89
88
91
89
84
84
86
242–244
262–264
270–272
270–272
264–266
259–261
268–270
250–252
263–265
252–254
241–242
228–230
253–255
264–266
254–256
272–274
272–274
265–267
244–246 [33]
264–266 [36]
270–272 [33]
269–271 [32]
265–267 [38]
257–259 [32]
270–272 [38]
248–251 [37]
265–266 [38]
250–252 [33]
242–244 [38]
228–229 [32]
253–255 [34]
263–265 [38]
253–255 [33]
270–272 [33]
270–272 [32]
266–267 [38]
2
3-F–C6H4
3
C6H5
3
4
3-O2N–C6H4
4-Br–C6H4
2-Cl–C6H4
3-Br–C6H4
3-OMe–C6H4
2-O2N–C6H4
3-Me–C6H4
2,4-(Cl)2–C6H3
4-O2N–C6H4
3,4,5-(OMe)3–C6H2
4-F–C6H4
3
5
4
6
4
7
9g
9h
9i
3
8
2.5
3
9
10
11
12
13
14
15
16
17
18
9j
3
9k
9l
3
3
9m
9n
9o
9p
9q
9r
3
3
4-Me–C6H4
4-OH–C6H4
4-Cl–C6H4
3-Cl–C6H4
3.5
4
4
3.5
CO2R3
Scheme 3 Synthesis of substi-
tuted dihydro-2-oxypyrrole
R2
O
H
N
NH2
+
R2
N Ar3
H
10
Saccharin (15 mol %)
MeOH, r.t.
CO2R3
R3O2C
14 a-s
11
H
O
Ar3 NH2
H
+
H
12
13
10, 12 (2.0 mmol), dialkyl acetylenedicarboxylate 11
(1.0 mmol) and formaldehyde 13 (1.5 mmol) in the pres-
ence of saccharin as a green catalyst at ambient tem-
perature with excellent yields and short reaction times
(Scheme 3).
increase the yields products (Table 8, entry 5), and the
results are summarized in Table 8.
In order to study of this procedure, we have synthesis
a series of dihydro-2-oxypyrrole derivatives with the type
of aromatic or aliphatic amines with electron-donating
or electron-withdrawing groups such as Cl, Br, F, Me,
OMe,… and diethyl/dimethyl acetylenedicarboxylate with
formaldehyde under ambient temperature in MeOH which
gave excellent yields and the results are given in Table 9.
The proposed mechanism for the synthesis of 3,4-dihy-
dropyrimidin-2-(1H)-one derivatives, 1H-pyrazolo[1,2-b]
phthalazine-5,10-dione derivatives is shown in Schemes 4
and 5 and that of dihydro-2-oxypyrroles is shown in
Scheme 6.
Comparison of catalytic ability some of catalysts
reported in the literature for synthesis of 3, 4-dihydropy-
rimidin-2-(1H)-one derivative, 1H-pyrazolo[1,2-b]phthala-
zine-5,10-dione derivatives is given in Tables 10 and 11
and that of substituted dihydro-2-oxypyrrole is given in
Table 12.
The generality of this four condensation reaction was
studied under optimized conditions. And the reaction
between aniline, dimethyl acetylenedicarboxylate (DMAD)
and formaldehyde was investigation as a model reaction
14e (Table 9, entry 5), and then, the effect of various sol-
vents was investigated for this method EtOH, H2O, CHCl3,
CH2Cl2, CH3CN, MeOH. And among these solvents,
MeOH (Table 7, entry 3) was found to be the best solvent
for this methodology and the results are given in Table 7.
The effect of different amount of catalyst was also stud-
ied in this protocol, and in the absence of catalyst, a trace
amount of this product was detected after 6 h (Table 8,
entry 1). Good yields were obtained in the presence of cata-
lyst. The best amount of catalyst was 15 mol% (0.027 g)
(Table 8, entry 4). The higher amount of catalyst did not
1 3

J IRAN CHEM SOC
Table 7 Optimization of the reaction condition in the presence of different solvents
O
CO2Me
O
N
H
NH2
+
+
N
H
+
NH2
H
H
MeO2C
CO2Me
Catalyst (mol%)
H
Entry
Solvent
Time (h)
Product
Isolated yields (%)
1
2
3
4
5
6
7
Saccharin (20 mol%)
Saccharin (20 mol%)
Saccharin (20 mol%)
Saccharin (20 mol%)
Saccharin (20 mol%)
Saccharin (20 mol%)
Saccharin (20 mol%)
Solvent-free
EtOH
6
4
3
6
5
6
5
14e
14e
14e
14e
14e
14e
14e
34
73
92
23
27
51
24
MeOH
H2O
CH2Cl2
CH3CN
CHCl3
Reaction conditions: Aniline (2.0 mmol), dimethyl acetylenedicarboxylate (1.0 mmol), and formaldehyde (1.5 mmol) and catalyst in various sol-
vents were heated under room temperature conditions for the appropriate time
Table 8 Optimization of the reaction condition in the presence of different amounts of saccharin
O
CO2Me
CO2Me
O
N
H
NH2
+
+
N
H
+
NH2
H
H
MeO2C
Time (h)
H
Entry
Saccharin (mol%)
Product
Isolated yields (%)
1
2
3
4
5
Catalyst free
6
14e
14e
14e
14e
14e
trace
56
5
6
10
15
20
4.5
3
79
92
3
93
Reaction conditions: Aniline (2.0 mmol), dimethyl acetylenedicarboxylate (1.0 mmol) and formaldehyde (1.5) and saccharin in MeOH were
heated under room temperature conditions for the appropriate time
General procedure for preparation
of 3,4‑dihydropyrimidin‑2‑(1H)‑one derivatives (4a–t)
Experimental
General
A mixture of aldehydes derivatives (1, 1.0 mmol) and
urea/thiourea (2, 1.5 mmol), ethyl/methyl acetoacetate (3,
1.0 mmol) under solvent-free conditions was heated for
appropriate time in the presence of saccharin (15 mol%)
at 80 °C (Table 3). After completion of the reaction (by
thin-layer chromatography TLC), the mixture was cooled
to r.t. and cold water was added and the precipitated was
separated with filtration and solid was recrystallized from
Melting points of all compounds were determined using
an Electro thermal 9100 apparatus. Also, nuclear magnetic
resonance, H NMR spectra were recorded on a Bruker
DRX-400 Avance instruments with CDCl3 or DMSO-d6 as
solvents. In this article, all reagents and solvents were pur-
chased from Merck, Fluka and Acros chemical companies
and were used without further purification.
1
1 3

J IRAN CHEM SOC
Table 9 Synthesis of dihydro-2-oxypyrrole derivatives
Entry
R2
R3
Ar3
Product
Time (h)
Isolated Yields (%)
M.p. (°C)
Lit. M.p. (°C)
1
4-Cl–C6H4
4-Cl–C6H4
4-F–C6H4
4-F–C6H4
Ph
Me
Et
4-Cl–C6H4
4-Cl–C6H4
4-F–C6H4
4-F–C6H4
Ph
14a
14b
14c
14d
14e
14f
3
90
88
93
92
92
94
89
91
87
85
92
91
87
87
85
93
90
85
87
170–172
167–169
163–165
170–172
154–156
138–140
176–178
130–132
175–176
152–154
176–178
170–172
176–178
95–97
170–172 [44]
168–170 [44]
163–165 [42]
171–173 [44]
155–156 [39]
138–140 [43]
177–178 [39]
131–132 [43]
172–175 [40]
152–154 [41]
175–177 [40]
169–171 [43]
175–177 [40]
94–96 [44]
2
3
3
Me
Et
4
4
3.5
3
5
Me
Et
6
Ph
Ph
3
7
4-Me–C6H4
4-Me–C6H4
4-OMe–C6H4
4-OMe–C6H4
4-Br–C6H4
4-Br–C6H4
n-C4H9
Me
Et
4-Me–C6H4
4-Me–C6H4
4-OMe–C6H4
4-OMe–C6H4
4-Br–C6H4
4-Br–C6H4
4-Br–C6H4
4-Br–C6H4
3,4-Cl2–C6H3
Ph
14g
14h
14i
3.5
4
8
9
Me
Et
3.5
3.5
2.5
3
10
11
12
13
14
15
16
17
18
19
14j
Me
Et
14k
14l
Me
Et
14m
14n
14o
14p
14q
14r
14s
3
n-C4H9
3.5
4
n-C4H9
Me
Me
Me
Me
Et
97–99
97–99 [41]
n-C4H9
4
58–60
60 [39]
PhCH2
4-F–C6H4
Ph
4
167–169
140–142
131–133
166–168 [41]
140–141 [43]
130–132 [43]
PhCH2
2.5
3
PhCH2
Ph
ethanol to afford the pure products (4a–t). The products
have been characterized by melting points and H NMR
5‑Ethoxycarbonyl‑6‑methyl‑4‑(4‑methylphenyl)‑3,4‑
dihydropyrimidin‑2(1H)‑one (4n)
1
spectroscopy. Spectra data of selected and known products
are represented below:
Yellow solid, mp: 203–205 °C; 1H NMR (400 MHz,
DMSO-d6): 1.11 (3H, t, J = 7.2 Hz, CH3CH2), 2.26 (6H,
d, J = 9.2 Hz, 2CH3), 3.99 (2H, q, J = 7.2 Hz, CH2O),
5.11 (1H, s, CHN), 7.13 (4H, s, ArH), 7.70 and 9.17(2H,
2s, 2NH).
5‑Methoxycarbonyl‑6‑methyl‑4‑(2‑chloro‑phenyl)‑3,4‑
dihydropyrimidin‑2(1H)‑one (4a)
Yellow solid, mp: 248–250 °C; 1H NMR (400 MHz,
DMSO-d6): 2.31(3H, s, CH3), 3.46 (3H, s, OCH3), 5.62
(1H, s, CHN), 7.28–7.34 (3H, m, ArH), 7.42 (1H, d,
J = 7.2 Hz, ArH), 7.72 and 9.36 (2H, 2s, 2NH).
5‑Ethoxycarbonyl‑6‑methyl‑4‑phenyl‑3,4‑dihydropyri‑
midin‑2(1H)‑thione (4p)
White solid, mp: 206–208 °C; 1H NMR (400 MHz,
DMSO-d6): 1.11 (3H, t, J = 7.2 Hz, CH3CH2), 2.31 (3H, s,
CH3), 4.02 (2H, q, J = 7.2 Hz, CH2O), 5.19 (1H, s, CHN),
7.23 (2H, d, J = 7.2 Hz, ArH), 7.28 (1H, t, J = 7.2 Hz,
ArH), 7.36 (2H, t, J = 7.2 Hz, ArH), 9.68 and 10.36 (2H,
2s, 2NH).
5‑Ethoxycarbonyl‑6‑methyl‑4‑phenyl‑3,4‑dihydropyri‑
midin‑2(1H)‑one (4b)
Yellow solid, mp: 201–203 °C; 1H NMR (400 MHz,
DMSO-d6): 1.10 (3H, t, J = 7.2 Hz, CH3CH2), 2.26 (3H, s,
CH3), 3.99 (2H, q, J = 7.2 Hz, CH2O), 5.15 (1H, s, CHN),
7.26 (3H, d, J = 7.2 Hz, ArH),7.33 (2H, t, J = 7.2 Hz,
ArH), 7.76 and 9.21(2H, 2s, 2NH).
General procedure for preparation of pyrazolo [1,2‑b]
phthalazine‑5,10‑dione derivatives (9a–r)
5‑Methoxycarbonyl‑6‑methyl‑4‑(4‑nitro‑phenyl)‑3,4‑
dihydropyrimidin‑2(1H)‑one (4e)
A mixture of phthalimide (5, 1.0 mmol), hydrazine mono-
hydrate (6, 1.0 mmol) and saccharin (20 mol%) was heated
for 2 h at 90 °C. Then aromatic aldehyde (7, 1.0 mmol)
and malononitrile (8, 1.0 mmol) were added and the mix-
ture was heated for the appropriate time (Table 6). After
completion of the reaction (by thin-layer chromatography
TLC), the mixture was cooled to rt the solid products were
Brown solid, mp: 213–214 °C; 1H NMR (400 MHz,
DMSO-d6): 2.28 (3H, s, CH3), 3.55 (3H, s, OCH3), 5.28
(1H, s, CHN), 7.52 (2H, d, J = 8.4 Hz, ArH), 8.22 (2H, d,
J = 8.8 Hz, ArH), 7.93 and 9.40 (2H, 2s, 2NH).
1 3

J IRAN CHEM SOC
X
Scheme 4 Proposed mecha-
nistic route for the synthesis of
3,4-dihydropyrimidin-2-(1H)-
ones
X
O
N
NH2
H
+
Ar1
H
O
Ar1
NH
H2N
O
NH2
-H2O
Ar1
Ar1
O
A
1
R1O
2
H
R1O
NH
-H2O
N
H
X
OH
X
O
O
O
H
H2N
OR1
OR1
4
C
B
3
Scheme 5 Proposed mecha-
nistic route for the synthesis of
1H-pyrazolo[1,2-b]phthalazine-
5,10-dione derivatives
O
O
O
O
NH2NH2 .H2O
NH
NH
6
NH-NH2
NH2
NH
-NH3
O
O
5
D
E
O
O
Ar2
CN
NC
8
NC
NC
E
+
CN
N
NH
C
H
Ar2
CN
Ar2 CHO
F
G
7
O
O
Ar2
O
Ar2
N
N
N
N
CN
NH2
CN
G
NH
O
H
9
R2
H
Scheme 6 Proposed mecha-
nistic route for the synthesis of
substituted dihydro-2-oxypyr-
role
CO2R3
O
N
:
Michael
addition
OR3
R2 NH2
10
R2
R3O
+
N
O
OR3
R3O
I
CO2R3
11
H
H
O
NH
Ar3
H
H
H
H+
Ar3 NH2
N
+
CH2O
Ar3
K
12
13
J
R2
R2
N
NH
R3O
H
H
R3O
K
O
O
-R3OH
H
H
Tautomerization
N
N
H
Ar3
Ar3
L
14
1 3

J IRAN CHEM SOC
Table 10 Comparison of catalytic ability some of catalysts reported
in the literature for synthesis of 3,4-dihydropyrimidin-2-(1H)-ones
derivatives
3‑Amino‑1‑(2‑thenaldehyde)‑5,10‑dihydro‑5,10‑dioxo‑
1H‑pyrazolo[1,2‑b]phthalazine‑2‑carbonitrile (9a)
Entry Catalyst
Conditions
Time/yield
(%)
References
Brown solid, mp: 242–244 °C; 246–248 °C; 1H NMR
(400 MHz, DMSO-d6): 6.09 (1H, s, CHAr), 6.88–7.30
(4H, m, ArH), 7.96–8.28 (6H, m, NH2 and ArH).
1
2
3
4
5
bakers, yeast
Room tem-
perature
24 h/84
[24]
Cu(BF4)2 × H2O Room tem-
30 min/90
20 h/81
[27]
3‑Amino‑1‑(3‑methoxyphenyl)‑5,10‑ihydro‑5,10‑dioxo‑
1H‑pyrazolo[1,2‑b]phthalazine‑2‑carbonitrile (9 h)
perature
[Al(H2O)6](BF4)3 MeCN,
Reflux
[28]
Brown solid, mp: 250–252 °C; 1H NMR (400 MHz,
DMSO-d6): 3.34 (3H, s, OCH3), 6.09 (1H, s, CHAr), 6.88–
7.30 (4H, m, ArH), 7.83–8.26 (6H, m, NH2 and ArH).
Hydrotalcite
Solvent-free, 35 min/84
80 °C
[29]
Saccharin
Solvent-free, 15 min/88
80 °C
This work
3‑Amino‑1‑(3,4,5‑trimethoxyphenyl)‑5,10‑dihydro‑5,
10‑dioxo‑1H‑pyrazolo[1,2‑b]phthalazine2‑carbonitrile
(9m)
Based on the three-component reaction of benzaldehyde, ethyl ace-
toacetate and urea
Yellow solid, mp: 253–255 °C; 1H NMR (400 MHz,
DMSO-d6): 3.66 (3H, s, OCH3), 3.76 (6H, s, 2 OCH3), 6.07
(1H, s, CHAr), 6.78 (2H, s, ArH), 7.89–8.29 (6H, m, NH2
and ArH).
Table 11 Comparison of catalytic ability some of catalysts reported
in the literature for synthesis of 1H-pyrazolo[1,2-b]phthalazine-
5,10-dione derivatives
Entry Catalyst
Conditions
Time/yield
(%)
References
3‑Amino‑1‑(4‑fluorophenyl)‑5,10‑dihydro‑5,10‑dioxo‑
1H‑pyrazolo[1,2‑b]phthalazine‑2carbonitrile (9n)
1
2
NiCl2·6H2O
EtOH, Reflux 3 h/87
[30]
[32]
PTSA
[Bmim]Br,
100 °C
3 h/94
Yellow solid, mp: 264–266 °C; 1H NMR (400 MHz, DMSO-
d6): 6.17 (1H, s, CHAr), 7.20 (2H, t, J = 8.8 Hz, ArH), 7.53–
7.57 (2H, m, ArH), 7.96–8.26 (6H, m, NH2 and ArH).
3
4
5
CuI nanopar-
ticles
MeCN, Reflux 27 min/91
[33]
STA
Solvent-free,
70 °C
20 min/94
3 h/89
[35]
saccharin
Solvent-free,
90 °C
This work
3‑Amino‑1‑(4‑methylphenyl)‑5,10‑dihydro‑5,10‑dioxo‑
1H‑pyrazolo[1,2‑b]phthalazine‑2‑carbonitrile (9o)
Based on the four-component reaction of benzaldehyde, phthalimide,
hydrazine monohydrate and malononitrile
Yellow solid, mp: 254–256 °C; 1H NMR (400 MHz,
DMSO-d6): 2.30 (3H, s, CH3), 6.10 (1H, s, CHAr), 7.18
(2H, d, J = 8.0 Hz, ArH), 7.34 (2H, d, J = 8.0 Hz, ArH),
7.97–8.28 (6H, m, NH2 and ArH).
Table 12 Comparison of catalytic ability some of catalysts reported
in the literature for synthesis of substituted dihydro-2-oxypyrrole
Entry Catalyst
Conditions Time/yield (%) References
General procedure for preparation of substituted
dihydro‑2‑oxypyrrole (14a–s)
1
2
3
4
5
InCl3
I2
MeOH, r.t. 3 h/85
MeOH, r.t. 1 h/82
[35]
[38]
A mixture of amine (10, 1.0 mmol) and dialkyl acetylen-
edicarboxylate (11, 1.0 mmol) was stirred in MeOH (3 mL)
for 15 min. Next, amine (12, 1.0 mmol) and formaldehyde
(13, 1.5 mmol) and saccharin (15 mol%) were added and
the reaction was stirred for appropriate time (Table 9).
After completion of the reaction (by thin-layer chromatog-
raphy TLC), the mixture was separated with filtration and
the solid washed with ethanol (3 × 2 mL) with no column
chromatographic separation to give pure compounds (14a–
s). The products have been characterized by melting points
[n-Bu4N][HSO4] MeOH, r.t. 4 h/88
[39]
ZrCl4
MeOH, r.t. 4 h/84
MeOH, r.t. 3 h/92
[43]
Saccharin
This work
Based on the four-component reaction of aniline, dimethyl acetylen-
edicarboxylate, formaldehyde
filtered and then were recrystallized from ethanol to give
pure compounds (9a–r). The products have been character-
ized by melting points and H NMR spectroscopy. Spectra
data of selected and known are represented below:
1
1
and H NMR spectroscopy. Spectra data of selected and
known products are represented below:
1 3

J IRAN CHEM SOC
Methyl 4‑(4‑fluoroyphenylamino)‑1‑(4‑fluorophenyl)‑2,5‑
dihydro‑5‑oxo‑1H‑pyrrole‑3‑carboxylate (14c)
starting materials. And we reported saccharin as a solid
acid catalyst which has developed a new procedure in the
field of green approach which has important benefits such
as non-toxic, eco-friendly, green, high efficiently, environ-
mentally benign nature, high catalytic activity, low cost.
White solid, mp: 163–165 °C; 1H NMR (400 MHz,
CDCl3): 3.79 (3H, s, OCH3), 4.52 (2H, CH2–N), 7.04 (2H,
t, J = 8.4 Hz, ArH), 7.08–7.16 (4H, m, ArH), 7.73–7.79
(2H, m, ArH), 8.05 (1H, s, NH).
Acknowledgments We gratefully acknowledge financial support
from the research council of the university of Sistan and Baluchestan.
Methyl 4‑(4‑methylphenylamino)‑1‑(4‑methylphenyl)‑2,5‑
dihydro‑5‑oxo‑1H‑pyrrole‑3‑carboxylate (14g)
References
White solid, mp: 176–178 °C; 1H NMR (400 MHz,
CDCl3): 2.36 (3H, s, 2CH3), 3.77 (3H, s, OCH3), 4.52
(2H, CH2–N), 7.06 (2H, d, J = 8.4 Hz, ArH), 7.14 (2H, d,
J = 8.4 Hz, ArH), 7.21 (2H, d, J = 8.4 Hz, ArH), 7.68 (2H,
d, J = 8.8 Hz, ArH), 8.03 (1H, s, NH).
1. M.R. Mousavi, M.T. Maghsoodlou, N. Hazeri, S.M. Habibi-
Khorassani, J. Iran. Chem. Soc. 11, 1419–1424 (2015)
2. M.R. Mousavi, M.T. Maghsoodlou, J. Iran. Chem. Soc. 12, 743–
749 (2015)
3. L. Xu, C. Gu, R. Li, Y. Yu, T. Wang, J. Iran. Chem. Soc. 13, 597–
604 (2016)
4. S. Karimian, H. Tajik, Lett. Org. Chem. 13, 163–170 (2016)
5. S. Mahdudi, D. Saberi, A. Heydari, J. Iran. Chem. Soc. 12, 903–
907 (2015)
Ethyl 4‑(4‑methylphenylamino)‑1‑(4‑methylphenyl)‑
2,5‑dihydro‑5‑oxo‑1H‑pyrrole‑3‑carboxylate (14h)
6. S. Salahi, M.T. Maghsoodlou, N. Hazeri, M. Lashkari, Chin. J.
Catal. 36, 1023–1028 (2015)
White solid, mp: 130–132 °C; 1H NMR (400 MHz, CDCl3):
1.25 (3H, t, J = 7.2 Hz, CH2CH3), 2.37 (6H, s, 2CH3), 4.23
(2H, q, J = 7.2 Hz, 2CH2CH3), 4.53 (2H, s, CH2–N), 7.06
(2H, d, J = 8.4 Hz, ArH), 7.1 (2H, d, J = 8.4 Hz, ArH),
7.21 (2H, d, J = 8.4 Hz, ArH), 8.00 (1H, s, NH).
7. A. Strecker, Leibigs Ann. Chem. 7, 27 (1850)
8. K. Niknam, A. Piran, Z. Karimi, J. Iran. Chem. Soc. 13, 859–871
(2016)
9. O. Goli-Jolodar, F. Shirini, M. Seddighi, J. Iran. Chem. Soc. 13,
457–463 (2016)
10. F. Boukezzoula, T. Boumoud, B. Boumoud, A. Debache, Lett.
Org. Chem. 13, 734–740 (2015)
11. P. Biginelli, Gazz. Chim. Ital. 23, 360 (1893)
12. M.J. Genin, C. Biles, B.J. Keiser, S.M. Poppe, S.M. Swaney,
W.G. Tarpley, Y. Yagi, D.L. Romero, J. Med. Chem. 43, 1034–
1040 (2000)
Methyl 4‑(4‑methoxyphenylamino)‑1‑(4‑methoxyphenyl)
‑2,5‑dihydro‑5‑oxo‑1H‑pyrrole‑3‑carboxylate (14i)
1
Pale yellow solid, mp: 175–176 °C; H NMR (400 MHz,
13. S. Wisen, J. Androsavich, C.G. Evans, L. Chang, J.E. Gestwicki,
Bioorg. Med. Chem. Lett. 18, 60–65 (2008)
14. S. Chitra, D. Devanathan, K. Pandiarajan. Eur. J. Med. Chem.
45, 367–371 (2010)
CDCl3): 3.77 (3H, s, CH3), 3.83 (6H, s, 2OCH3), 4.50
(2H, CH2–N), 6.89 (4H, d, J = 17.6 Hz, ArH), 7.13 (1H, s,
ArH), 7.68 (1H, s, ArH), 8.03 (1H, s, NH).
15. J.N. Liu, J. Li, L. Zhang, L.P. Song, M. Zhang, W.J. Cao, S.Z.
Zhu, H.G. Deng, M. Shao, Tetrahedron Lett. 53, 2469–2472
(2012)
16. F. Wei, B.X. Zhao, B. Huanget, L. Zhang, C. Sun, W. Dong, D.
Shin, J. Miao, Bioorg. Med. Chem. Lett. 16, 6342–6347 (2006)
17. T. Nakamura, M. Sato, H. Kakinuma, N. Miyata, K. Taniguchi,
K. Bando, A. Koda, K. Kameo, J. Med. Chem. 46, 5416–5427
(2003)
18. A.D. Patil, N.V. Kumar, W.C. Kokke, M.F. Bian, A.J. Freyer,
C.D. Brossi et al., J. Org. Chem. 60, 1182–1188 (1995)
19. O. Prakash, R. Kumar, V. Parkash, Eur. J. Med. Chem. 43, 435–
440 (2008)
20. G.R. Madhavan, R. Chakrabarti, S.K.B. Kumar, P. Misra,
R.N.V.S. Mamidi, V. Balraju, K. Kasiram, R.K. Babu, J. Suresh,
V.B. Lohray, J. Iqbal, R. Rajagopalan, Eur. J. Med. Chem. 36,
627–637 (2001)
Ethyl 4‑(4‑methoxyphenylamino)‑1‑(4‑methoxyphenyl)‑2,5‑
dihydro‑5‑oxo‑1H‑pyrrole‑3‑carboxylate (14j)
1
Pale yellow solid, mp: 152–154 °C; H NMR (400 MHz,
CDCl3): 1.26 (3H, t, J = 7.2 Hz, CH2CH3), 3.83 (6H, s,
2OCH3), 4.23 (2H, q, J = 7.2 Hz, CH2CH3), 4.50 (2H,
s, CH2–N), 6.87 (2H, d, J = 8.8 Hz, ArH), 6.93 (2H, d,
J = 8.8 Hz, ArH), 7.12 (2H, d, J = 8.8 Hz, ArH), 7.69 (2H,
d, J = 8.8 Hz, ArH), 8.02 (1H, s, NH).
21. R. Shiraki, A. Sumino, K. Tadano, S. Ogawa, Tetrahedron Lett.
Conclusion
36, 5551–5554 (1995)
22. Y. Chen, D.X. Zeng, N. Xie, Y.Z. Dang, J. Org. Chem. 70, 5001–
5005 (2005)
23. I.A. Khodja, R. Boulcina, A. Debache, J. Chem. Pharm. Res. 6,
1040–1045 (2014)
24. A. Kumar, R.A. Maurya, Tetrahedron Lett. 48, 4569–4571
(2007)
In summary, we have studied the use of saccharin as a
green, economical and efficient catalyst for the multi-
component synthesis of 3,4-dihydropyrimidin-2-(1H)-one
derivatives and pyrazolo [1, 2-b] phthalazine-5,10-dione
derivatives and dihydro-2-oxypyrrole derivatives from
1 3

J IRAN CHEM SOC
25. B. Ahmad, R.A. Khan, Habibullah, M. Keshai, Tetrahedron Lett.
50, 2889–2892 (2009)
26. S. Chitra, K. Pandiarajan, Tetrahedron Lett. 50, 2222–2224
(2009)
27. A. Kamal, T. Krishnaji, M.A. Azhar, Catal. Commun. 8, 1929–
1933 (2007)
28. M. Litvic, I. Vecani, Z.M. Ladisic, M. Lovric, V. Voncovic, M.
Filipan-Litvic, Tetrahedron 66, 3463–3471 (2010)
29. J. Lai, M. Sharma, S. Gupta, P. Parashar, P. Sahu, D.D. Agarwal,
J. Mol. Catal. A Chem. 352, 31–37 (2012)
36. M. Veeranarayana Reddy, P. Chenna Rohini Kumar, G. Chandra
Sekhar Reddy, C. Suresh Reddy, Comptes Rendus Chimie 17,
1250–1256 (2014)
37. M.R. Nabid, S.J.T. Rezaei, R. Ghahremanzadeh, A. Bazgir,
Ultrason. Sonochem. 17, 159–161 (2010)
38. G. Mohammadi-Ziarani, N. Hosseini-Mohtasham, A. Badiei,
N. Lashgari, J. Chin. Chem. Soc. (2014). doi:10.1002/
jccs.201300538
39. A.T. Khan, A. Ghosh, M. Musawwer Khan, Tetrahedron Lett. 53,
2622–2626 (2012)
30. S.H. Song, J. Zhong, Y.H. He, Z. Guan, Tetrahedron Lett. 53,
7075–7077 (2012)
40. S.S. Sajadikhah, N. Hazeri, Res. Chem. Intermed. 40, 737–748
(2014)
31. Y. Zhang, B. Wang, X. Zhang, J. Huang, C. Liu, Molecules 20,
3811–3820 (2015)
32. R. Ghahremanzadeh, G. Imani Shakibaei, A. Bazgir, Synlett 8,
1129–1132 (2008)
41. S.S. Sajadikhah, N. Hazeri, M.T. Maghsoodlou, S.M. Habibi-
Khorassani, J. Iran. Chem. Soc. 10, 863–871 (2013)
42. S.S. Sajadikhah, N. Hazeri, M.T. Maghsoodlou, J. Chem. Res.
37, 40–42 (2013)
33. J. Safaei-Ghomi, H. Shahbazi-Alavi, A. Ziarati, R. Teymuri,
M.R. Saberi, Chin. Chem. Lett. 25, 401–405 (2014)
34. M. Veeranarayana Reddy, Y. TaeJeeong, Tetrahedron Lett. 54,
3546–3549 (2013)
35. S.S. Sajadikhah, M.T. Maghsoodlou, N. Hazeri, Chin. Chem.
Lett. 25, 58–60 (2014)
43. Q. Zhu, H. Jiang, J. Li, S. Liu, C. Xia, M. Zhang, J. Comb.
Chem. 11, 685–696 (2009)
44. S.S. Sajadikhah, M.T. Maghsoodlou, N. Hazeri, S. Moham-
adian-Souri, Res. Chem. Intermed. (2015). doi:10.1007/
s11164-015-2178-z
1 3