Verjuice as a green and bio-degradable solvent/catalyst for facile and eco-friendly synthesis of 5-arylmethylenepyrimidine-2,4,6-trione, pyrano[2,3-d]pyrimidinone and pyrimido[4,5-d]pyrimidinone derivatives

Article abstract of DOI:10.1007/s13738-018-1565-y

Verjuice (unripe grape juice), a natural mixture of organic acids, which is identified by pH-metric and TGA analysis, is efficiently used for the promotion of the synthesis of 5-arylmethylenepyrimidine-2,4,6-triones, via Knovenagel condensation reaction between barbituric or thiobarbituric acid and aldehydes. Verjuice is also employed for the effective synthesis of pyrano[2,3-d]pyrimidinone derivatives via a three-component reaction of barbituric acid or its thio analogue, aldehydes and malononitrile. In the same way, pyrimido[4,5-d]pyrimidinone derivatives are simply produced via the reaction of barbituric acid, aldehydes and urea or thiourea in the presence of verjuice. This green methodology rewards notable advantages including simple procedures, acceptable reaction times, easy work-up, high yields, circumventing the use of any expensive starting materials, volatile and hazardous organic solvents during the reaction and work-up process, and use of a natural, low-cost, reusable, and bio-degradable catalyst.

Full text of DOI:10.1007/s13738-018-1565-y

Journal of the Iranian Chemical Society
https://doi.org/10.1007/s13738-018-1565-y
ORIGINAL PAPER
Verjuice as a green and bio-degradable solvent/catalyst for facile
and eco-friendly synthesis of 5-arylmethylenepyrimidine-2,4,6-
trione, pyrano[2,3-d]pyrimidinone and pyrimido[4,5-d]pyrimidinone
derivatives
Niloufar Safari1 · Farhad Shirini1 · Hassan Tajik1
Received: 7 July 2018 / Accepted: 30 November 2018
© Iranian Chemical Society 2018
Abstract
Verjuice (unripe grape juice), a natural mixture of organic acids, which is identified by pH-metric and TGA analysis, is
efficiently used for the promotion of the synthesis of 5-arylmethylenepyrimidine-2,4,6-triones, via Knovenagel condensa-
tion reaction between barbituric or thiobarbituric acid and aldehydes. Verjuice is also employed for the effective synthesis
of pyrano[2,3-d]pyrimidinone derivatives via a three-component reaction of barbituric acid or its thio analogue, aldehydes
and malononitrile. In the same way, pyrimido[4,5-d]pyrimidinone derivatives are simply produced via the reaction of bar-
bituric acid, aldehydes and urea or thiourea in the presence of verjuice. This green methodology rewards notable advantages
including simple procedures, acceptable reaction times, easy work-up, high yields, circumventing the use of any expensive
starting materials, volatile and hazardous organic solvents during the reaction and work-up process, and use of a natural,
low-cost, reusable, and bio-degradable catalyst.
Keywords Verjuice as a bio-degradable catalyst · Multi-component reactions · 5-Arylmethylenepyrimidine-2,4,6-triones ·
Pyrano[2,3-d]pyrimidinones · Pyrimido[4,5-d]pyrimidinones
Introduction
in it biological reactions can be catalyzed more efficiently
compared to organic ones [5].
Some of the traditional methods for the synthesis of various
organic compounds with outstanding application in indus-
try produce large amounts of chemical waste involving car-
cinogen and pollutant solvents or corrosive and hazardous
catalysts. Bearing in mind these facts, in recent years both
academic and industrial researches have been focused on
the development of synthetic procedures which fulfill green
chemistry principles [1, 2]. According to these principles,
when solvent is required for an organic transformation, water
is the first and the best choice [3, 4], due to its availability,
low cost, environmentally benign character, high polarity
that leads to be immiscible with most organic compounds
and, therefore, easy work-up conditions. Moreover, water is
the natural solvent of all alive organisms and enzymes which
In recent years, application of catalysts based on natural
materials in organic synthesis has been received significant
attention. Several examples are reported in the literature;
these include application of: (1) Lemon juice for the syn-
thesis of isoxazolones and pyrano[2,3-c]-pyrazoles [6],
arylidene-malononitriles [7], dihydropyrimidinones [8],
4-triazole derivatives [9], Schiff bases [10], bis-, and tris
(indolyl) methanes [11], and quinoxaline and benzoxazine
derivatives [12], (2) Pineapple juice for the synthesis of
dihydropyrimidinones [13], (3) Fruit juice of tamarind for
the promotion of the synthesis of bis-, tris(indolyl)methanes
and tetraindolyl compounds [14], (4) Fruit juice of coco-
nut for the selective bio-reduction of aromatic and aliphatic
carbonyl compounds, dimerization of aromatic nitro com-
pounds and also for the hydrolysis of esters, amides and
anilides [15]. (5) CuFe2O4/chitosan magnetic bionanocom-
posite for the synthesis of 2-amino-4H-pyrans, 2-amino-
4H-chromens and polyhydroquinolines [16], chitosan/gra-
phene oxide synthesis of 3,4-dihydropyrimidin-2(1H)-one
* Farhad Shirini
shirini@guilan.ac.ir
1
Department of Chemistry, College of Sciences, University
of Guilan, Rasht 41335, Iran
Vol.:(0123456789)
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Journal of the Iranian Chemical Society
derivatives [17], Fe3O4@camphor-for the synthesis of
dihydropyrimidines [18], Cellulose/Fe2O3/Ag bionanostruc-
ture for the synthesis of dihydrotetrazolopyrimidines [19],
MgFe2O4/cellulose/SO3H nanocatalyst for the synthesis of
tetrahydropyridines and dihydropyrimidinones [20], and
magnetic guanidinylated chitosan nanobiocomposite for the
synthesis of 1,4-dihydropyridines [21].
antimalarial [38], and antitumour [39] properties. They
have been also known as efficient and low-cost synthetic
dyes in the industry [40].
Pyrimido[4,5-d] pyrimidinone derivatives have been
also considered as attractive target molecules due to their
outstanding anti-inflammatory [41], antioxidant [42],
antimicrobial [43], antitumor [44], and antiviral [45]
activities.
Unripe grape juice (verjuice) is sour in taste and, there-
fore, acidic juice [22], extracted from the mechanical press-
ing of unripe green grapes. In Iran, and the Mediterranean,
Southeastern regions of Turkey, it is used as a viable alterna-
tive to vinegar and lemon juice in the production of various
pleasant traditional and industrial drinks and food flavorings
[23]. The consumption of verjuice has been reported to pos-
sess cardioprotective properties in individuals with abnor-
mal blood lipids. In hyperlipidemic and hyperlipidemic plus
hypertensive patients, verjuice consumption has noticeable
increase in high-density lipoprotein (HDL) and decrease in
total cholesterol (TC), low-density lipoprotein (LDL), and
triglycerides (TG) concentrations [24, 25].
Regarding notable biological and pharmacological
activities of 5-arylmethylenepyrimidine-2,4,6-triones,
pyrano[2,3-d]-pyrimidinediones and pyrimido[4,5-d]
pyrimidinones, their synthesis have been investigated
in the presence of different types of catalysts including
PVP-Ni nanoparticles [46], sodium p-toluene sulfonate
(NaPTSA) [47], BF3/nano-γ-Al2O3 [48], Ce1MgxZr1−xO2
(CMZO) [49], ethylammoniumnitrate (EAN) [50], ami-
nosulfonic acid [51], [bmim]BF4 [52], NaOH/fly ash [53],
taurine [54], cetyltrimethyl ammonium bromide [55],
[DABCO](SO3H)2(HSO4)2 [56], [DABCO](SO3H)2Cl2
[57] (for the synthesis of 5-arylmethylenepyrimi-
dine-2,4,6-triones), Fe3O4@cellulose nanocomposite [58],
succinimidinium hydrogensulfate([H-Suc]HSO4) [59],
nano-sawdust-OSO3H [60], trichloroisocyanuric acid [61],
choline chloride-ZnCl2 [62], 1,4-diazabicyclo[2.2.2]octane
(DABCO) [63], [DABCO](SO3H)2(HSO4)2 [56], Zn[l-
proline]2 [64], l-proline [65], sulfonic acid nanoporous
silica (SBA-Pr-SO3H) [66], tetrabutylammonium bromide
(TBAB) [67], Alum [68], CaHPO4 [69], Al-HMS-20 [70]
and taurine [54] (for synthesis of pyrano[2,3-d]-pyrimidin-
ediones), and l-proline [71], DAHP [72], Al2O3 [73], CAN
[74], and (α-Fe2O3)-MCM41-DAIL [75], (for the prepara-
tion of pyrimido[4,5-d]pyrimidinones).
100 mL of verjuice has been found to contain titratable
acidity (TA) 3 g, total phenolic matter 0.75 g, and total solid
4.8 g. However, chemical composition of verjuice depends
on geographical conditions, cultivar, and ripeness stage of
the grapes [23]. On the basis of HPLC and HPLC–MS anal-
ysis, tartaric, malic, succinic, oxalic and citric acids are the
main organic acids found in sour grapes [26, 27] (Fig. 1).
Due to the presence of organic acids, verjuice is acidic (pH
2–3) in nature and, therefore, it can be used as an acid cata-
lyst in organic transformations.
Heterocycle compounds containing pyrimidine moiety
have been attracted widespread attention among organic
chemists due to their diverse biological activities [28–30].
5-Arylidine barbituric and thiobarbituric acids can be used
as active precursors for the synthesis of a large number of
relevant heterocyclic compounds including oxadiazafavines
[31], unsymmetrical disulphides [32], and benzyl barbituric
derivatives [33].
Considering the merit of all the above-mentioned
methods, some of them suffer from several undesirable
effects such as low yields, harsh conditions for the prepa-
ration of the catalyst, application of corrosive inorganic
acids and/or polluting organic solvents, expensive cata-
lysts and reagents, tedious work-up, necessity of excess
amounts of catalysts or reagents and non-reusability of
the catalyst. Therefore, taking in to account the principles
of green chemistry [1, 2], and environmental concerns,
we decided to introduce an eco-friendly, simple, efficient,
green and natural catalyst for the promotion of the pre-
sented reactions.
Pyrano[2,3-d]pyrimidinone derivatives with an annu-
lated uracil moiety have been attracted significant and
widespread interest in organic chemistry, due to their
broad spectrum of biological and pharmacological activi-
ties such as antihypertensive [34], cardiotonic [34],
bronchodilators [35], antiallergic [36], herbicidal [37],
O
O
OH
O
O
OH
O
O
HO
HO
HO
HO
OH
HO
OH
OH
OH
OH
O
O
OH
O
O
OH
O
OH
Oxalic acid
Citric acid
Succinic acid
Tartaric acid
Malic acid
Fig. 1 Main organic acids present in verjuice
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Journal of the Iranian Chemical Society
where MH+ = 0.0066 mol L−1, pH 2.18.
Results and discussion
As indicated in Fig. 3, thermal stability of the catalyst was
determined by thermogravimetric analysis. For this purpose,
water was removed under vacuum and the obtained solid
powder was used for TGA analyses. The DTGA–TGA data
confirm that the catalyst is stable to 171 °C. The TGA curves
of verjuice show two thermal decomposition peaks, one at
171.33–269.05 °C which shows a weight loss of 65.27% and
the other one at 404.97–431.39 °C which shows a weight
loss of 3.92%. The observed decomposition peaks can be
related to thermal dehydroxylation, decarboxylation, and
demethoxylation of organic acids and polysaccharide mol-
ecules which are presented in verjuice.
Recently, the use of natural catalysts such as montmorillonite,
rice husk and taurine in the promotion of organic transforma-
tions became a significant part of our research group program
[54, 76–82]. In continuation of these studies, and based on the
acidity power of verjuice, we were interested to investigate
the effect of this natural, green, cheap and recyclable catalyst
on the synthesis of 5-arylmethylene-pyrimidine-2,4,6-trione,
pyrano[2,3-d]pyrimidinone and pyrimido[4,5-d]pyrimidinone
derivatives.
To determine the pH factor, 5 mL of verjuice was diluted
with 20 mL distilled water and was titrated with NaOH,
0.018 M solution. According to Fig. 2, when 1.8 mL of
the basic solution was added, all the acidic protons were
neutralized.
To investigate the efficiency of verjuice as a catalyst and
solvent for organic reactions, synthesis of 5-arylmethylene-
pyrimidine-2,4,6-triones was selected as the first reaction
(Scheme 1). At the first step, the optimal conditions of the
reaction of 4-chlorobenzaldehyde and barbituric acid were
investigated, by altering the temperature and the amount of
verjuice. The optimized conditions were determined accord-
ing to the results represented in Table 1 (entry 3). After
these studies and in order to demonstrate the efficiency of
the catalyst, the reaction was performed using various aro-
matic aldehydes containing electron-donating and electron-
withdrawing groups (Table 2). The products were isolated
in high yields without using neither toxic organic solvent
nor expensive chromatographic methods. The reusability of
verjuice was also investigated in the reaction of 4-chloroben-
zaldehyde and barbituric acid under the optimized reaction
conditions. After isolation of the product, verjuice was
stirred with activated charcoal (0.02 g) and, after filtration,
was reused for the same reaction. This process was repeated
at least five times. Results clarified that verjuice is able to
catalyze the model reaction without any noticeable change
in the reaction times and yields (Fig. 4).
M
NaOH × VNaOH = MH+ × VH+,
0.018 × 1.8 = MH+ × 5,
12
10
8
6
4
2
0
0
0/5
1
1/5
2
2/5
3
3/5
Volume of NaOH (mL)
Fig. 2 Titration and its first derivative curves of verjuice by NaOH
(0.018 M)
120
0/02
0
Fig. 3 TGA curves and DTGA
curves for verjuice
100
-0/02
-0/04
-0/06
-0/08
-0/1
80
60
40
20
0
-0/12
-0/14
0
100
200
300
400
500
600
700
Temperature (°C)
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Journal of the Iranian Chemical Society
Scheme 1 Synthesis of 5-aryl-
methylene-pyrimidine-2,4,6-
trione derivatives in verjuice
H
O
N
X
O
O
O
Verjuice (10 mL), 60oC
Ar
NH
HN
NH
Ar
H
O
X
X= O, S
X= O, S
After the effective application of verjuice in the synthesis
of 5-arylmethylene-pyrimidine-2,4,6-triones, we decided to
investigate the efficiency of this novel catalyst in the promo-
tion of the synthesis of pyrano[2,3-d]pyrimidinone deriva-
tives (Scheme 2). In the optimization study, the reaction of
4-chlorobenzaldehyde, barbituric acid, and malononitrile
was considered as the model reaction. As shown in Table 3,
the best results were observed in 10 mL of verjuice under
reflux conditions (Table 3, entry 4). After optimization of
the reaction conditions, different types of aldehydes were
reacted with (thio)barbituric acid and malononitrile under
the selected conditions to provide the target molecules in
Table 1 The effect of temperature, and amount of verjuice, on the
synthesis of 5-arylmethylene-pyrimidine-2,4,6-trione derivative of
4-chlorobenzaldehyde and barbituric acid
Entry
Catalyst (mL)
Temp.
Time (min)
Conversion
1
2
3
4
5
6
7
10
10
10
10
10
5
r.t.
50
60
80
Reflux
60
60
40
20
7
6
6
12
8
100
100
100
100
100
100
100
15
Table 2 Preparation of
Entry Aldehyde
X
Time (min) Yield (%)a TON TOF/h Mp (°C)
5-arylidene barbituric and
thiobarbituric acid derivatives
using verjuice as the solvent/
catalyst
Found
Reported [Refs.]
1
2
C6H4CHO
4-ClC6H4CHO
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
9
7
8
8
7
8
9
7
9
11
13
6
11
11
5
13
5
7
17
16
14
21
17
10
13
89
96
91
88
92
95
86
88
86
87
86
93
89
87
92
89
90
87
88
94
89
87
85
89
88
13.48 89.87 253–255
14.54 124.63 295–298
13.79 103.42 276–278
13.33 99.98 265–266
13.94 104.55 290–291
14.26 106.95 >300
13.03 86.87 273–274
13.33 114.26 238–240
13.03 86.87 273–276
13.18 71.89 >300
13.03 60.14 251–253
14.09 140.9 295–298
13.48 73.53 283–284
13.18 71.89 279–282
13.94 167.28 269–271
255–256 [57]
298–300 [51]
274–278 [51]
268 [47]
288–290 [83]
309–310 [83]
268–270 [83]
242–243 [52]
274–276 [57]
>300 [52]
249–250 [57]
296–298 [83]
281–283 [49]
281–282 [49]
266–268 [84]
3
4
3-ClC6H4CHO
2-ClC6H4CHO
5
6
4-BrC6H4CHO
4-FC6H4CHO
7
8
9
4-NO2C6H4CHO
3-NO2C6H4CHO
2-NO2C6H4CHO
4-OHC6H4CHO
2-OHC6H4CHO
4-CH3OC6H4CHO
4-CH3-C6H4CHO
4-NMe2C6H4CHO
C6H5CH=CHCHO
2-Naphtaldehyde
4-CHOC6H4CHO
3-CHOC6H4CHO
C6H4CHO
4-Cl-C6H4CHO
4-CH3O-C6H4CHO
4-CH3-C6H4CHO
3-NO2C6H4CHO
4-CHOC6H4CHO
3-CHOC6H4CHO
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
13.48 62.22 263 (dec.) 266 (dec.) [46]
13.64 163.68 >300
13.18 112.97 >300
13.33 47.05 273–274
14.24 53.4 288–290
13.48 57.77 >300
13.18 37.66 >300
12.89 45.49 257–259
13.48 80.88 >300
13.13 60.6 >300
>300 [57]
>300 [57]
271–272 [50]
291–292 [50]
>300 [52]
>300 [46]
261–263 [52]
>300 [56]
>300 [56]
S
S
S
S
S
S
aIsolated yield
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Journal of the Iranian Chemical Society
96
95
94
93
93
93
92
91
90
90
90
88
88
87
84
100
80
60
40
20
0
42
40
37
37
35
22
20
20
18
18
12
10
10
8
7
2
4
1
3
5
5-arylmethylenepyrimidine-2,4,6-trione
pyrano[2,3-d]pyrimidinone
pyrimido[4,5-d]pyrimidinone
Fig. 4 Reusability of verjuice in the studied reactions
Scheme 2 Synthesis of
O
Ar
pyrano[2,3-d]pyrimidinone
CN
O
O
derivatives in verjuice
HN
O
CN
CN
Verjuice (10 mL), reflux
HN
NH
X
N
H
O
NH2
Ar
H
X
X= O, S
X= O, S
Table 3 The effect of temperature, and amount of verjuice on the
synthesis of pyrano[2,3-d]pyrimidinone derivative of 4-chlorobenza-
ldehyde, barbituric acid and malononitrile
of the aromatic ring, leading to the corresponding prod-
ucts in excellent yields, high reaction times and acceptable
turnover number (TON) and turnover frequency (TOF)
values (Table 6). The reusability of verjuice was also
determined in the model reaction. As illustrated in Fig. 4,
even after five consecutive runs, no appreciable changes
in yields and times were observed.
Entry
Catalyst (mL)
Temp.
Time (min)
Conversion
1
2
3
4
5
6
10
10
10
10
5
r.t.
60
80
Reflux
Reflux
Reflux
90
90
26
18
26
16
60
75
100
100
100
100
A reasonable mechanism for the synthesis of the
above-mentioned reactions in the presence of verjuice
is presented in Scheme 4. According to the proposed
mechanism, the carbonyl group of aldehyde is activated
by organic acids found in verjuice and then attacked by
the active methylene group in (thio)barbituric acid to
form the Knoevenagel product [5-arylidenepyrimidine-
2,4,6(1H,3H,5H)-trione]. The condensation of previously
formed product with malononitrile or urea leads to the
formation of acyclic intermediates which, respectively,
generate pyrano[2,3-d]pyrimidinone and pyrimido[4,5-d]
pyrimidinone derivatives via intramolecular cyclization.
To illustrate the efficiency of verjuice in the studied
reactions, the results of the presented methods were com-
pared with those reported in the literature as summarized
in Table 7. On the basis of these comparisons, the prepara-
tion of some of the indicated catalysts needs to expensive
starting materials, corrosive liquid acids, toxic organic
solvents and/or harsh conditions. Looking at the success
of this methodology, verjuice as a green, non-toxic and
15
high yields through simple filtration as tabulated in Table 4.
The reusability of the catalyst was studied according to
the method which has mentioned in the first reaction. The
obtained results show that verjuice is active enough to
catalyze the model reaction for at least five sequential runs
(Fig. 4).
Ultimately, the efficiency of verjuice in the preparation
of pyrimido[4,5-d] pyrimidinone derivatives was investi-
gated (Scheme 3). In the optimization study, one-pot three-
component reaction of 4-chlorobenzaldehyde, barbituric
acid and urea was selected as the model reaction and the
effect of temperature and the amounts of the catalyst on
the progress of the reaction was examined on it (Table 5,
entry 7). Furthermore, and after optimization of the reac-
tion conditions, the reaction was performed with various
aromatic aldehydes containing electron-withdrawing and
electron-donating groups in ortho, meta and para positions
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Journal of the Iranian Chemical Society
Table 4 Preparation of
pyrano[2,3-d]pyrimidinone
derivatives using verjuice as the
solvent/catalysts
Entry Aldehyde
X
Time (min) Yield (%)a TON TOF/h Mp (°C)
Found
13.33 39.99 220–223
Reported [Refs.]
1
2
3
4
5
8
C6H4CHO
O
O
O
O
O
O
O
O
O
O
O
O
S
20
18
21
20
20
20
26
28
28
38
30
20
30
26
28
40
42
42
88
95
94
92
95
91
87
86
89
89
93
93
89
93
91
87
88
86
221–224 [70]
242–243 [70]
240–241 [67]
212–214 [60]
230–231 [72]
268–270 [85]
238–240 [85]
267–269 [86]
253–256 [86]
>300 [70]
272–274 [60]
335–337 [85]
224–225 [70]
>300 [52]
4-ClC6H4CHO
3-ClC6H4CHO
2-ClC6H4CHO
4-BrC6H4CHO
4-FC6H4CHO
14.26 47.53 242–244
14.24 40.68 238–239
13.94 41.82 209–212
14.26 42.78 231–233
13.79 41.37 272–273
13.18 30.42 235–237
13.03 27.92 268–269
13.48 28.88 258–259
13.48 21.28 >300
14.09 28.18 270–273
14.09 42.27 >300
13.48 26.96 224–226
14.09 32.52 >300
9
4-NO2C6H4CHO
3-NO2C6H4CHO
2-NO2C6H4CHO
4-OHC6H4CHO
4-CH3OC6H4CHO
4-CHOC6H4CHO
C6H4CHO
4-Cl-C6H4CHO
4-Br-C6H4CHO
4-NO2C6H4CHO
3-NO2C6H4CHO
2-NO2C6H4CHO
10
11
12
13
14
15
16
17
18
19
20
S
S
S
S
13.79 29.55 239 (Dec.) 236 (Dec.) [72]
13.18 19.77 233–237
13.33 19.04 234–236
13.03 18.61 243–244
235–236 [72]
233–234 [72]
242–246 [56]
S
aIsolated yield
Scheme 3 Synthesis of
pyrimido[4,5-d]pyrimidinone
derivatives in verjuice
O
Ar
O
O
O
X
HN
NH
Verjuice (15 mL), reflux
HN
NH
Ar
H
H2N
NH2
O
N
H
N
H
X
O
X= O, S
X= O, S
Table 5 The effect of temperature, and amount of verjuice, on the
synthesis of pyrimido[4,5-d]pyrimidinone derivative of 4-chloroben-
zaldehyde, barbituric acid and urea
filtration with no need for chromatographic methods or
organic solvents.
Entry
Catalyst (mL)
Temp.
Time (min)
Conversion
Experimental
1
2
3
4
5
6
7
10
10
10
10
5
15
20
r.t.
60
80
Reflux
Reflux
Reflux
Reflux
90
90
60
45
57
35
32
40
60
100
100
100
100
100
General
All materials and solvents were purchased from Fluka,
Merck, and Aldrich chemical companies and used without
further purification. All the products were separated and
characterized by their physical properties, such as melting
point, color, and spectroscopic data, in comparison with
authentic samples. The purity determination of the sub-
strates and reaction monitoring were accompanied by TLC
using silica gel SIL G/UV 254 plates. All yields refer to the
isolated products. Melting points were determined using a
Buchi B-545 apparatus in open capillary tubes. The Fou-
rier transform (FT)-IR spectra were recorded on a Perkin
metal-free natural catalyst efficiently accelerates the stud-
ied reactions. The target molecules are formed in accept-
able times and high yields and also separated by simple
1
Elmer 781 Spectrophotometer (KBr disks). The H NMR
(400 MHz) and 13C NMR (100 MHz) were run on Bruker
1 3

Journal of the Iranian Chemical Society
Table 6 Preparation of
Entry Aldehyde
X
Time (min) Yield (%)a TON TOF/h Mp (°C)
Found
pyrimido[4,5-d]pyrimidinone
derivatives using verjuice as the
solvent/catalysts
Reported [Refs.]
1
2
3
4
5
6
7
8
C6H4CHO
O
O
O
O
O
O
O
O
O
S
S
S
S
S
40
35
37
50
55
55
60
40
50
50
40
43
45
65
63
88
93
92
90
88
87
88
91
90
89
94
91
88
89
86
8.89 13.34 246–247
9.40 16.11 297–300
9.29 15.06 208–211
9.10 10.92 205–207
244–246 [87]
296–298 [87]
210–212 [73]
202–204 [73]
196–198 [88]
>300 [74]
258–260 [74]
284–286 [73]
248–250 [73]
290–292 [87]
4-ClC6H4CHO
4-BrC6H4CHO
4-NO2C6H4CHO
3-NO2C6H4CHO
4-OHC6H4CHO
2-OHC6H4CHO
4-CH3OC6H4CHO
4-CH3-C6H4CHO
C6H4CHO
8.89
8.79
8.89
9.70 196–198
9.59 >300
8.89 256–259
9.19 13.78 286–287
9.10 10.92 248–250
8.99 10.79 294–295
9.49 14.24 281 (dec.) 278(dec.) [87]
9.19 12.82 >300
8.89 11.85 >300
9
10
11
12
13
14
15
4-Cl-C6H4CHO
4-CH3O-C6H4CHO
4-CH3-C6H4CHO
3-NO2C6H4CHO
4-OHC6H4CHO
>300 [73]
>300 [87]
175–177 [88]
262–263 [74]
8.99
8.69
8.30 179–182
8.28 263–265
S
aIsolated yield
AV-400 in DMSO-d6 using TMS as an internal standard.
Thermogravimetric analyses were obtained using Polymer-
Laboratories TGA1500+. Samples were heated 25–600 °C
with a heating rate of 10 °C/min.
the solid product was collected by filtration and washed with
water (3×10 mL) to obtain the pure target compounds.
General procedure for the preparation
of pyrimido[4,5‑d]pyrimidinones
General procedure for the extraction of verjuice
A mixture of aldehyde (1 mmoL), barbituric acid (1 mmoL),
urea or thiourea (1.2 mmoL), verjuice (15 mL) was refluxed
until the completion of the reaction as identified by TLC
[n-hexane: EtOAc (7:3)]; the crude was filtered off and
washed with water (3×10 mL) leading to pure products.
The identity of the known products was confirmed by
comparison of their melting points and spectroscopic data
with those reported in recent articles.
Fruit juice extract was obtained by pressing fresh sour
grapes in a fruit juicer. Then, the juice extract was filtered
through a cotton cloth and finally through a filter paper to
remove solid material resulting in a clear juice that was used
as the catalyst.
General procedure for the preparation
of 5‑arylmethylene‑pyrimidine2,4,6‑trione
derivatives
Spectroscopic data for selected derivatives:
5-(2-nitrobenzylidene)pyrimidine-2,4,6(1H,3H,5H)-trione:
M.p. 273–276 °C; IR (KBr) νmax (cm1)=3325, 3197, 3091,
1
1735, 1687, 1572, 1513, 1345, 733; HNMR (400 MHz,
A mixture of aldehyde (1 mmoL), (thio)barbituric acid
(1 mmoL) and verjuice (10 mL) was heated in an oil bath
(60 °C). After completion of the reaction, as monitored by
TLC, using n-hexane:EtOAc (7:3) as the eluent, the reaction
mixture was filtered and the precipitated product was washed
with water (3×10 mL) to afford the pure compound.
DMSO-d6) (δ, ppm)=7.58 (d, J=7.6, 1H), 7.68 (td, J1 =8,
J2 = 0.8, 1H), 7.79 (td, J1 = 7.6, J2 = 1.2, 1H), 8.24 (dd,
J1 = 8, J2 = 1.2, 1H), 8.61 (s, 1H, HC = C), 11.26 (NH, s,
1H), 11.51(NH, s, 1H); 13CNMR (400 MHz, DMSO-d6)
(δ, ppm)=120.9, 124.5, 130.6, 130.8, 132.1, 134.2, 146.7,
150.7, 152.9, 161.6, 162.8.
5,5′-(1,3-Phenylenebis(methanylylidene))bis(pyrimidine-
2,4,6(1H,3H,5H)-trione): M.p. > 300 °C; IR(KBr) νmax
(cm−1)=3457, 3201, 3074, 1757, 1682, 1571, 800; 1HNMR
(400 MHz, DMSO-d6) (δ, ppm)=7.55 (t, J=7.6, 1H), 8.20
(dd, J1 = 7.8, J2 = 1.6, 2H), 8.29 (s, 2H, HC = C), 8.49 (s,
1H), 11.29 (NH, s, 2H), 11.44. (NH, s, 2H); 13CNMR
(400 MHz, DMSO-d6) (d, ppm)=120.3, 128.0, 132.9, 135.9,
137.6, 150.6, 153.9, 161.9, 163.6.
General procedure for the preparation
of pyrano[2,3‑d]pyrimidinones
A mixture of aldehyde (1 mmoL), malononitrile (1 mmoL),
barbituric acid (1 mmoL) in verjuice (10 mL) was refluxed
in an oil bath for the appropriate time as mentioned by TLC
[n-hexane: EtOAc (7:3)]. After completion of the reaction,
1 3

Journal of the Iranian Chemical Society
verjuice
O
O
O
OH
NH
O
HN
NH
HN
Ar
H
X
X
O
OH
Ar
HN
X
N
O
H
-H2O
verjuice
O
HN
Ar
X
N
H
O
X
NC
O
CN
H2N
NH2
Ar
O
O
Ar
N
O
Ar
O
H
H
Ar
H
H
CN
NH
NH
X
HN
HN
NH
CN
N
HN
HN
O
N
X
X
N
H
X
NH2
N
H
O
H
O
N
H
O
O
Ar
O
Ar
O
CN
HN
NH
HN
O
N
H
N
H
X
N
H
NH2
O
Scheme 4 Proposed mechanism for the formation of the target molecules studied in the present work
5 , 5 ʹ - ( 1 , 4 - P h e nyl e n e b i s ( m et h a nylyl i d e n e ) )
bis(pyrimidine-2,4,6(1H,3H,5H)-trione): M.p.> 300 °C;
IR(KBr) νmax (cm−1): 3495, 3202, 3085, 1749, 1685, 1584,
4H), 8.29 (s, 2H, HC = C), 11.30 (NH, s, 2H), 11.45 (NH,
s, 2H); 13CNMR (400 MHz, DMSO-d6) (δ, ppm) = 120.9,
129.0, 132.3, 136.1, 150.6, 153.4, 161.9, 163.6.
1
808; HNMR (400 MHz, DMSO-d6) (δ, ppm) = 8.05 (s,
1 3

Journal of the Iranian Chemical Society
Table 7 Comparison of the
efficiency of verjuice with some
of the reported catalysts for
the promotion of the studied
reactions
Entry
Catalyst/conditions
Time (min)
Yield (%)a
References
1
2
3
4
5
6
7
8
9
PVP-Ni nanoparticles/ethylene glycol 50 °C
NaPTSA/r.t.
BF3/nano-γ-Al2O3/Ethanol, R.T
Ce1MgxZr1−xO2 (CMZO)/MW
EAN/r.t.
Aminosulfonic acid/grinding
[bmim]BF4/ Grinding-laying
NaOH/fly ash/water 70–80 °C
Taurine/water 90 °C
5
4
93
92
84
94
83
96
78
86
96
96
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
30
3
180
180
120
35
9
[54]
This work
10
Verjuice/60 °C
7
1
2
3
4
5
6
7
8
9
Nano-sawdust-OSO3H/EtOH, reflux
Trichloroisocyanuric acid/H2O, reflux
Choline chloride-ZnCl2/U.S., EtOH,75 °C
DABCO/(H2O, EtOH) r.t.
Zn[l-proline]2/EtOH, reflux
SBA-Pr-SO3H/solvent free, 140 °C
TBAB/H2O, reflux
CaHPO4/H2O:EtOH (4:1) 80 °C
Taurine/H2O, reflux
Verjuice/reflux
10
90
120
120
50
15
35
120
40
18
92
93
94
92
90
90
80
92
94
95
[60]
[61]
[62]
[63]
[64]
[66]
[67]
[69]
[54]
This work
10
1
2
3
4
5
7
8
9
–/H2O, reflux
–/H2O, MW
l-Proline/MW
DAHP/r.t., H2O:EtOH
Al2O3/MW
CAN/H2O, reflux
(α-Fe2O3)-MCM41-DAIL/Solvent free, 120 °C
Verjuice/reflux
240
3
13
120
0.58
20
480
35
72
86
76
72
96
98
97
93
[87]
[87]
[71]
[72]
[73]
[74]
[75]
This work
aIsolated yield
1 3

Journal of the Iranian Chemical Society
16. A. Maleki, M. Ghassemi, R. Firouzi-Haji, Pure Appl. Chem. 90,
387 (2018)
7-Amino-5-(2-nitrophenyl)-4-oxo-2-thioxo-1,3,4,5-
tetrahydro-2H-pyrano[2,3-d]pyrimidine-6-carbonitrile:
M.p.=243–244 °C; IR (KBr) νmax (cm−1): 3426, 3317, 3062,
2197, 1675, 1573, 1518, 1349; 1H NMR (400 MHz, DMSO-
d6): (δ, ppm) 5.06 (s, 1H), 7.34 (s, 2H), 7.48 (td, J1 =7.6 Hz,
J2 = 1.6 Hz, 1H), 7.54 (dd, J1 = 8 Hz, J2 = 1.2 Hz, 1H),
7.67 (td, J1 =7.6 Hz, J2 =1.2 Hz, 1H), 7.86 (dd, J1 =8 Hz,
J2 = 1.2 Hz, 1H), 12.43 (NH, s, 1H), 13.67 (NH, s, 1H);
13C NMR (100 MHz, DMSO-d6): (δ, ppm) 30.7, 56.9, 93.4,
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26. A. Sabir, E. Kafkas, S. Tangolar, Spanish J. Agric. Res. 8, 425
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In summary, we have introduced verjuice as an efficient
natural solvent/catalyst for the promotion of the synthesis
of 5-arylmethylenepyrimidine-2,4,6-trione, pyrano[2,3-d]
pyrimidinone and pyrimido[4,5-d]pyrimidinone derivatives.
All the target products were synthesized with acceptable
rates and excellent yields. The presented method avoids the
disadvantages associated with using expensive starting mate-
rials, harsh reaction conditions, chromatographic purifica-
tion, and employing of inorganic acids and organic solvents.
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