A novel and efficient five-component synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones in water: A triply green synthesis

Article abstract of DOI:10.3390/molecules21040441

A novel one pot synthesis of pyrazolo[4' ,3' :5,6]pyrido[2,3-d]pyrimidine-diones, via a five-component reaction, involving, hydrazine hydrate, ethyl acetoacetate, and 1,3-dimethyl barbituric acid, an appropriate aryl aldehydes and ammonium acetate catalyz

Full text of DOI:10.3390/molecules21040441

molecules
Article
A Novel and Efficient Five-Component Synthesis of
Pyrazole Based Pyrido[2,3-d]pyrimidine-diones in
Water: A Triply Green Synthesis
Majid M. Heravi * and Mansoureh Daraie
Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran 1993893973, Iran;
daraie_m@yahoo.com
* Correspondence: mmh1331@yahoo.com; Tel.: +98-21-8804-4040
Academic Editor: Romano V. A. Orru
Received: 25 February 2016; Accepted: 24 March 2016; Published: 1 April 2016
Abstract: A novel one pot synthesis of pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-diones, via
a five-component reaction, involving, hydrazine hydrate, ethyl acetoacetate, and 1,3-dimethyl
barbituric acid, an appropriate aryl aldehydes and ammonium acetate catalyzed via both of
heterogeneous and homogeneous catalysis in water, is reported.
Keywords: pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-diones; green synthesis; multi-component
reaction; in water reaction
1. Introduction
Among the known infectious diseases, tuberculosis (TB) [1] and malaria [2] are the most
distressing and devastating, both from impermanence and sickness points of view. Malaria and TB are
primeval and prolonged infectious diseases initiated chiefly by the parasite Plasmodium falciparum and
the pathogen Mycobacterium tuberculosis (MTB), respectively [3,4].
Electron-rich nitrogen heterocycles, such as some pyrimidine derivatives, are well established as
antimalarial agents [
range of pyrimidine derivatives show other widespread biological activities and are being used as
pharmaceuticals for industrial and prescribed drugs [ ]. They show potencies such as Tie-2 kinase
inhibitors [ ], HIV-1 inhibitors [ ], adenosine A1 receptor antagonism [ ], anticancer agents [10],
analgesics [11], cardiovascular agents and anti-allergic agents [12].
5]. They also play key roles in diverse biological activities. For instance, a wide
6
7
8
9
Facile and green synthetic approaches are an important issue in organic synthesis. The generation
of divergent and complicated molecules from either commercially available or readily accessible
starting materials is an inspiring theme in contemporary organic synthesis [13]. The compatible
combination of multi-component reactions (MCRs) and unconventional reaction conditions has
recently attracted much attention and stirred up the interest of synthetic organic chemists, resulting
in concurrent advance and growth of both MCRs and green chemistry toward ideal synthetic
chemistry [14,15]. Multi-component reactions (MCRs), in which multiple reactions are joined in
a single synthetic operation performed in one pot, have been extensively and broadly employed in
the total synthesis of natural products and their building blocks [16]. Using such strategies for the
synthesis of a desired target avoids purification of different precursors as well as tedious protection and
deprotection of functional groups frequently, required in multistep synthesis. Due to the shortening of
the reaction steps and atom economy involved, a higher degree of component-multiplicity leads to
greener conditions.
Nowadays, green chemistry has become a main motivation and inspiration for organic chemists
to develop eco-friendly and benign pathways for the synthesis of organic compounds, particularly
Molecules 2016, 21, 441; doi:10.3390/molecules21040441
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those exhibiting biological activity [17
,
18]. Manipulation of multi-component reactions, performed
in water as a green and abundant solvent, is another attractive concern of organic synthetic chemists,
complying with green chemistry principles. A wide variety of divergent chemical transformations
can occur in water. Breslow [19], Li [20], Kobayashi [21], Sharpless [22] and many other renowned
organic chemists have momentously extended the number of reactions that can be conducted in water.
Reaction in water offers unique reactivity and selectivity. Moreover, water can be readily separated
and isolated from organic materials by simple procedures.
Another latent opportunity for in water synthesis is the development of a high atom economy
that can facilitate catalyst recovery, recycling and simple product isolation. Idyllically, the reactant and
the product should have no or very little water-solubility. Thus, the product can be isolated by simple
phase separations and the catalyst can be easily recycled. As a matter of fact, in such circumstances,
it is possible to recycle the catalyst-bearing aqueous solution for a prolonged period of time without
the requirement either discharging it or recreating it, providing the low atom-efficiency process that
resulted in the accretion of undesired materials in the solution.
Heterogeneous catalysis is of paramount importance in green chemistry, due to simplicity of
separation, recovery and recyclability of most heterogeneous catalysts [23,24].
Pyrazolo based pyrido[2,3-d]pyrimidine-diones and their derivatives are a very important class
of heterocycles with a wide range of pharmacological and biological activities.
The synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones was reported in 2012 and
2014 via a three component reaction using barbituric acids, 1H-pyrazol-5-amines and differently
substituted aromatic aldehydes using PTSA (p-Toluenesulfonic acid) under solvent-free conditions,
IL-cells (cellulose supported ionic liquid) and ethanol have been reported respectively [25,26].
We are interested in heterocyclic chemistry and chemical and molecular diversity in this
field [27
using different heterogeneous nanocatalysts in organic reactions and, in particular, different
heterocyclic systems [35 44], and expansion of our work on multi-component reactions and green
chemistry [45 54], herein, we report an efficient triply green protocol for the synthesis of pyrazole
–34]. In continuation of our investigation on the synthesis of heterocyclic compounds
–
–
based pyrido[2,3-d]pyrimidine-diones.
2. Results
Initially, we designed a one pot four-component reaction, employing different starting materials
leading to pyrazole based pyrido[2,3-d]pyrimidine-diones in the absence of any catalyst in water
(Scheme 1).
Scheme 1. Model reaction for pyrazole based pyrido[2,3-d]pyrimidine-dione synthesis.
In this strategy, as a model reaction, we used 3-methyl-pyrazolone 1, 1,3-dimethyl barbituric
acid 2, ammonium acetate 3 and benzaldehyde 4 in refluxing water. This reaction was monitored by
TLC (Thin layer chromatography), showing no progress.
Thus, we examined the reaction in the presence of various catalysts in different solvents under
mild reaction conditions (Table 1).

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Table 1. Optimization of the reaction conditions for the synthesis of pyrazole based pyrido[2,3-d]
pyrimidine-diones under thermal conditions.
Entry
Catalyst
H6P2W18O62
Solvent
Time (h)
Yield (%)
1
2
3
4
4
5
¨
18H2O
Water
Water
Water
Water
Water
EtOH
2
2.5
3.5
5
0.66
1
60
65
85
80
94
80
Sulfamic acid
DABCO
ZnO
Nano-ZnO
Nano-ZnO
Considering this point that has now been turned into a fact, nowadays, a plethora of nanometal
oxides are used as efficient catalysts in several of the organic transformations. Among other
catalysts examined, we initially used ZnO and then selected nano-ZnO from analyzing our results
obtained from sets of reactions, as a green catalyst. We have also found that the amount of our
model reaction, and, in general, 0.04 g of nano-ZnO is the optimum amount of catalyst. Under
optimized reaction conditions, using optimal amounts of nano-ZnO as heterogeneous catalyst in
boiling water1as solvent, we designed this four component reaction, providing the corresponding
1
pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-diones in high yield.
As far as green chemistry is concerned, our methodology was superior than that of the preparation
of pyrazole based pyrido[2,3-d]pyrimidine-diones, using PTSA, previously [25].
When PTSA is heated with acid and water, a hydrolysis reaction takes place and toluene is formed
along sulphuric acid.
Our strategy also looks more promising when compared with the recently reported synthesis of
pyrazole based pyrido[2,3-d]pyrimidine-diones, using pre-prepared IL-Cells [26] as catalyst, due to the
commercial availability of nano-ZnO.
The reaction pathway for both strategies are the same and depicted in Figure 1.
Figure 1. Synthesis of pyrazole based pyrido[2,3-d]pyrimidine-diones [25,26].
Under optimized conditions, using nano-ZnO as heterogeneous catalyst in boiling water
as solvent, this four component reaction gave the corresponding pyrazolo-[41,31:5,6]pyrido[2,3-d]
pyrimidine-diones in excellent yield (Table 2).
Table 2. One pot, four-component synthesis of pyrazolo-[41,31:5,6]pyrido[2,3-d]pyrimidine-diones in
refluxing water using a catalytic amount of nano-ZnO.
Entry
Ar
R
Time (h)
Yield (%) a
M.p. (˝C)
M.p. rep. (˝C) [26]
1
2
3
4
5
6
7
C6H5
4-FC6H4
H
H
H
H
H
H
H
3
94
90
94
92
92
94
91
194–196
281–283
285–286
286–288
285–287
172–173
221–223
195–196
——
2.5
2.5
2.8
3.2
3
4-ClC6H4
4-BrC6H4
2,4-ClC6H3
4-NO2C6H4
3-NO2C6H4
284–285
286–287
286–287
173–174
220–221
3.2

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Table 2. Cont.
Entry
Ar
R
Time (h)
Yield (%) a
M.p. (˝C)
M.p. rep. (˝C) [26]
8
9
4-OHC6H4
4-N(Me)2C6H4
C6H5
H
H
4
3.8
3.5
3
3
3
87
89
92
89
94
92
88
90
220–222
222–224
208–210
207–208
200–202
160–161
155–157
205–506
219–220
221–223
210–211
208–210
——
158–159
156–157
207–209
10
11
12
13
14
15
Ph
Ph
Ph
Ph
Ph
Ph
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-CH3C6H4
3.7
4
a
isolated yield.
Although the literature survey discloses a plethora of multi-component reactions, five-component
reactions are scarcely found [55–61].
During our practical work, we observed that the reaction of ethyl acetoacetate and hydrazine
hydrate proceeded smoothly and was completed rapidly [62,63] to afford 3-methyl-5-hydrazolone,
virtually in quantitative yield. Thus, we decided to investigate the synthesis of pyrazolo-[41,31:5,6]
pyrido[2,3-d]pyrimidine-diones via a one pot five component reaction (Scheme 2).
O
O
+
H2N NHR
O
N
O
N
R
1
2
A
O
N
O
O
N
N
H
Cat.
N
N
+
+ NH4OAc
+
O
N
N
R
H2O, ref.
O
O
N
N
H
O
H
A
4
3
5
6
Scheme 2. Five-component reaction for pyrazole based pyrido[2,3-d]pyrimidine-dione synthesis.
The proposed mechanism for a five-component reaction is summarized in Scheme 3.
Scheme 3. Proposed mechanism for nano ZnO catalyst.

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For experimental purposes, initially, hydrazine hydrate (1.1 mmol) was added drop wise to ethyl
acetoacetate (1 mmol) and then an already prepared mixture of nano ZnO, benzaldehyde, 1,3-dimethyl
barbituric acid and ammonium acetate was added. This mixture was refluxed in water. The progress
of our mod1el 1reaction was monitored by TLC. Upon completion of the reaction, the corresponding
pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-dione was obtained in high yield. (Table 3).
Table 3. One pot, five-component synthesis of pyrazolo-[41,31:5,6]pyrido[2,3-d]pyrimidine-diones in
refluxing water using a catalytic amount of nano-ZnO.
Entry
Ar
R
Time (h)
Yield (%) a
M.p. (˝C)
M.p. rep. (˝C) [26]
1
2
3
4
5
6
7
8
9
C6H5
4-FC6H4
4-ClC6H4
H
H
H
H
H
H
H
H
H
4
91
90
91
90
90
91
89
85
85
194–196
281–283
285–286
286–288
285–287
172–173
221–223
220–222
222–224
195–196
——
3.5
3.5
3.8
4
284–285
286–287
286–287
173–174
220–221
219–220
221–223
4-BrC6H4
2,4-ClC6H3
4-NO2C6H4
3-NO2C6H4
4-OH-C6H4
4-N(Me)2C6H4
4
4.2
4.5
4.5
a
isolated yield.
The product was deposited in the water to form a separate filtrate, thus consuming much energy
to evaporate the solvent being non-required. Upon filtering of the cold reaction mixture, the Zno
nano-catalyst remains on the top of funnel along with product. Upon recrystallization of the product
from CH2Cl2, it can be recovered, recycled and reused with a simple washing up, at least in three
consecutive runs without appreciable loss of activity.
As is clear from the structure, there is a chiral center in the final product. Since our suggested
mechanism involves sequential Knoevenagel–Michael addition reactions that can be catalyzed in
both acidic 1and basic conditions, we thought it was worthwhile to examine asymmetric synthesis of
1
pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-diones via asymmetric organocatalysis.
L-proline is a readily obtainable naturally occurring amino acid. It has also been reported as an
eco-friendly catalyst for the synthesis of several heterocycles [64–66]. We thought it was worthwhile to
examine it as an asymmetric basic organocatalyst to attain optical activity in our products.
Since several asymmetric synthesis using L-proline has been done at room temperature [67],
initially, the model reaction was performed at 25 ˝C to afford compound 6a. Unfortunately, the yield
of the product was very low, so the reaction mixture was heated at reflux temperature for the indicated
times. Although the reaction proceeded smoothly leading to the desired product, we did not observe
any optical activity in the isolated product, perhaps due to reflux conditions. To establish the generality
of proline-catalyzed reaction, various aromatic aldehydes were used to give the desired products it
worked as an ordinary base (Scheme 4). However, the results obtained from the nano-ZnO-catalyzed
reaction had overshadowed this approach.
The corresponding product was produced in high yield, but unfortunately does not show any
optical activity. The results are summarized in Table 4.

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Scheme 4. Proposed mechanism for the synthesis of compound 6 using L-proline.
Table 4. One pot, four-component synthesis of pyrazolo-[41,31:5,6]pyrido[2,3-d]pyrimidine-diones in
refluxing water using a catalytic amount of nano-ZnO.
Comp.
Ar
R
Time (h)
Yield (%) a
M.p. (˝C)
M.p. rep. (˝C) [26]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
C6H5
4-FC6H4
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Ph
Ph
4
91
90
91
90
89
90
88
84
86
89
87
90
90
84
85
195–197
280–281
283–285
284–286
286–288
171–173
220–223
218–221
223–224
209–212
207–209
201–204
157–159
154–157
206–508
195–196
——
3.5
3.5
4
4.5
4.2
4.5
5
4.2
6
5.5
5.5
6
4-ClC6H4
4-BrC6H4
2,4-ClC6H3
4-NO2C6H4
3-NO2C6H4
4-OHC6H4
4-N(Me)2C6H4
C6H5
284–285
286–287
286–287
173–174
220–221
219–220
221–223
210–211
208–210
——
4-FC6H4
4-ClC6H4
4-BrC6H4
4-NO2C6H4
4-CH3C6H4
158–159
156–157
207–209
5.2
5.5
a
isolated yield.
3. Experimental
Melting points were measured by using the capillary tube method with an electro thermal
1
9200 apparatus. H-NMR and 13C-NMR spectra were recorded on a Bruker spectrometer (Ettlingen,
Germany) at 400 MHz, respectively, using TMS (Tetramethylsilane) as an internal standard (DMSO
solution). IR spectra were recorded from KBr disk on the FT-IR spectrometer (Ettlingen, Germany)
Bruker Tensor 27. The reactions were monitored by TLC. All solvents and reagents were purchased

Molecules 2016, 21, 441
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from Aldrich (Taufkirchen, Germany) and Merck (Darmstat, Germany) with high-grade quality, and
used without any purification. All products are new and were fully characterized by their spectral and
physical data (Please find Supplementary Materials for more details).
3.1. General Procedure
1
1
3.1.1. Synthesis of Pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-diones: Using 4-Component Reaction
To a mixture of 3-methyl-pyrazol-5-one or 3-methyl-1-phenyl-pyrazole-5-one (1 mmol),
1,3-dimethyl barbitueic acid (1 mmol), ammonium acetat (1.2 mmol) and benzaldehyde (1 mmol),
a catalytic amount of nano-ZnO (0.04 g) was added and the resulting mixture was heated at reflux
in H2O (5 mL). The progress of the reaction was monitored by TLC. On completion, the mixture was
cooled and filtered. The precipitate was recrystallized from CH2Cl2 to give pure target compounds.
All the products were identified by comparison of their physical and spectroscopic data with those
reported for authentic samples. The physical and spectral data are given.
1
1
3.1.2. Synthesis of Pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-diones Using 5-Component Reaction
Initially, hydrazine hydrate (1.1 mmol) was added drop wise to ethyl acetoacetate (1 mmol) and
then other components containing 1,3-dimethyl barbitueic acid (1 mmol), ammonium acetat (1.2 mmol),
benzaldehyde (1 mmol), ZnO nanoparticles (0.04 g) were added at once, and the mixture was heated
at reflux temperature for the time indicated in Table 3. After completion of the reaction (as monitored
by TLC), the mixture was cooled and filtered. The precipitate was recrystallized from CH2Cl2 to give
pure target compounds.
1
1
3.1.3. Synthesis of Pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-diones: Using 4-Component Reaction
A solution of 3-methyl-pyrazol-5-one or 3-methyl-1-phenyl-pyrazole-5-one (1 mmol), 1,3-dimethyl
barbitueic acid (1 mmol), ammonium acetat (1.2 mmol), benzaldehyde (1 mmol) and L-proline (0.04 g)
in H2O (5 mL) was stirred under heating conditions for appropriate time. After completion of the
reaction which was monitored by TLC, the mixture was cooled to room temperature. The solid product
was collected by filtration, washed with water and aqueous ethanol and purified by recrystallization
from CH2Cl2.
3.2. Spectral Data
1
1
3,6,8-Trimethyl-4-phenyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione (Entry 1,
˝
1
Table 2). m.p.: 194–196 C; IR (KBr,
2.22 (s, 3H, CH3), 2.81 (s, 3H, CH3), 3.07 (s, 3H, CH3), 5.63 (s, 1H, CH), 7.006–7.084 (m, 3H, Ar-H),
7.158–7.196 (t, 2H, J = 7.2, Ar-H), 10.46 (brs, 2H, 2-NH).
ν
max, cm´1): 3332, 2971, 1654, 1248. H-NMR (400 MHz, DMSO-d6):
δ
1
1
4-(4-Fluorophenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
1
(Entry 2, Table 2). m.p.: 281–283 ˝C; IR (KBr,
ν
max, cm´1): 3312, 2956, 1663, 1280. H-NMR (400 MHz,
DMSO-d6):
J = 7.6 Hz, 2H, Ar-H), 7.36–7.38 (d, J = 7.6 Hz, 2H, Ar-H), 9.81 (s, 1H, NH), 11.99 (s, 1H, NH); 13C-NMR
(100 MHz, DMSO-d6) : 10.02, 27.15, 30.28, 33.84, 88.63, 106.23, 125.06, 130.41, 134.57, 135.63, 137.31,
δ 1.96 (s, 3H, CH3), 3.06 (s, 3H, CH3), 3.46 (s, 3H, CH3), 4.99 (s, 1H, CH), 7.14–7.16 (d,
δ
142.28, 149.62, 150.19, 158.24; calcd for C17H16FN5O2: C, 57.07; H, 4.51; N, 19.57; found: C, 57.12;
H, 4.50; N, 20.02
1
1
4-(4-Chlorophenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
˝
(Entry 3, Table 2). m.p.: 285–285 C; IR (KBr, νmax, cm´1): 3321, 2948, 1647, 1263.
1
1
4-(4-Bromophenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
˝
(Entry 4, Table 2). m.p.: 286–288 C; IR (KBr, νmax, cm´1): 3329, 2948, 1644, 1261.

Molecules 2016, 21, 441
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1
1
4-(2,4-Dichlorophenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-
˝
dione (Entry 5, Table 2). m.p.: 285–287 C; IR (KBr, νmax, cm´1): 3341, 2937, 1640, 1258.
1
1
4-(4-nitrophenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
˝
(Entry 6, Table 2). m.p.: 172–173 C; IR (KBr, νmax, cm´1): 3320, 2949, 1671, 1269.
1
1
3,6,8-Trimethyl-4-(3-nitrophenyl)-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
˝
(Entry 7, Table 2). m.p.: 221–223 C; IR (KBr, νmax, cm´1): 3325, 2951, 1643, 1271.
1
1
4-(4-Hydroxyphenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-
˝
dione (Entry 8, Table 2). m.p.: 220–222 C; IR (KBr, νmax, cm´1): 3318, 2963, 1617, 1280.
4-(4-(Dimethylamino)phenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-5,7
˝
(4H,6H)-dione (Entry 9, Table 2). m.p.: 222–224 C; IR (KBr, νmax, cm´1): 3331, 2949, 1631, 1271.
3,6,8-Trimethyl-1,4-diphenyl-8,9-d˝ihydro-1H-pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
1
(Entry 10, Table 2). m.p.: 208–210 C; IR (KBr,
ν
max, cm´1): 3315, 2936, 1650, 1241. H-NMR (400 MHz,
DMSO-d6):
δ 1.55 (s, 3H, CH3), 2.70 (s, 3H, CH3), 2.82 (s, 3H, CH3), 5.09 (s, 1H, CH), 7.42–7.46
(t, J = 8.0 Hz, 6H, Ar-H), 7.87–7.89 (d, J = 8.0 Hz, 4H, Ar-H), 11.77 (s, 1H, NH).
3,6,8-Trimethyl-4-(4-fluorophenyl)-1-phenyl-8,9-d˝ihydro-1H-pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-5,7
(4H,6H)-dione (Entry 11, Table 2). m.p.: 207–208 C; IR (KBr, νmax, cm´1): 3324, 2949, 1647, 1270.
1
1
4-(4-Chlorophenyl)-3,6,8-trimethyl-8,9-dihydro-1H-pyrazolo[4 ,3 :5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-dione
˝
1
(Entry 12, Table 2). m.p.: 200–202 C; IR (KBr,
DMSO-d6): 1.96 (s, 3H, CH3), 2.88 (s, 3H, CH3), 3.46 (s, 3H, CH3), 4.86 (s, 1H, CH), 7.14–7.19 (m, 5H,
Ar-H), 7.54–7.56 (d, 2H, J = 7.6 Hz, Ar-H), 7.96–7.98 (d, 2H, J = 7.6 Hz, Ar-H), 11.97 (s, 1H, NH);
13C-NMR (100 MHz, DMSO-d6)
: 10.91, 26.55, 29.13, 32.69, 87.17, 101.45, 117.40, 122.81, 124.54, 126.33,
ν
max, cm´1): 3321, 2946, 1641, 1273. H-NMR (400 MHz,
δ
δ
127.91, 128.17, 129.21, 134.52, 135.71, 145.43, 147.38, 149.09, 161.98; calcd for C23H20ClN5O2: C, 66.18;
H, 4.83; N, 16.78; found: C, 66.34; H, 4.76; N, 16.18.
4-(4-Bromophenyl)-3,6,8-trimethyl-1-phenyl-8,9-d˝ihydro-1H-pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-5,7
(4H,6H)-dione (Entry 13, Table 2). m.p.: 160–161 C; IR (KBr, νmax, cm´1): 3317, 2944, 1641, 1279.
3,6,8-Trimethyl-4-(4-nitrophenyl)-1-phenyl-8,9-dihydro-1H-pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-5,7
˝
(4H,6H)-dione (Entry 14, Table 2). m.p.: 155–157 C; IR (KBr, νmax, cm´1): 3330, 2954, 1648, 1266.
3,6,8-Trimethyl-1-phenyl-4-(p-tolyl)-8,9-dihydro-1H-pyrazolo[41,31:5,6]pyrido[2,3-d]pyrimidine-5,7(4H,6H)-
˝
dione (Entry 15, Table 2). m.p.: 205–206 C; IR (KBr, νmax, cm´1): 3315, 2938, 1640, 1259.
4. Conclusions
1
1
In summary, herein, we report a high yielding one-pot synthesis of pyrazolo-[4 ,3 :5,6]pyrido[2,3-d]
pyrimidine-dione derivatives from the condensation of ethyl acetoacetate, hydrazine hydrate or phenyl
hydrazine, 1,3-dimethyl barbituric acid, aryl aldehydes and ammonium acetate catalyzed by nano ZnO
and L-proline under triply green conditions, including using green catalysis in water via MCR reaction.
The conditions are mild and a wide range of functional groups can be tolerated. Using nano-ZnO as
catalyst offers advantages including simplicity of operation, easy work-up and high yields of products.
This work will not only lead to establishing a practical synthetic method but will also expand the
versatility of clean organic reactions in water.
Supplementary Materials: Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/
21/4/441/s1.
Acknowledgments: Majid M. Heravi gratefully recognizes partial financial support from Iran National Science
Foundation (INSF) and Alzahra University.
Author Contributions: M.M.H. and M.D. conceived and designed the experiments, M.D. performed the
experiments, MMH and MD analyzed the data, MMH contributed reagents/materials/analysis tools, M.M.H.
wrote the paper.

Molecules 2016, 21, 441
9 of 12
Conflicts of Interest: The authors declare no conflict of interest.
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