Fruit juice of Citrus limon as a biodegradable and reusable catalyst for facile, eco-friendly and green synthesis of 3,4-disubstituted isoxazol-5(4H)-ones and dihydropyrano[2,3-c]-pyrazole derivatives

Article abstract of DOI:10.1007/s11164-016-2553-4

Abstract: Fruit juice of Citrus limon (lemon juice) has been utilized as a natural and renewable catalyst for the green and environmentally friendly preparation of 3,4-disubstituted isoxazol-5(4H)-one derivatives and 6-amino-1,4-dihydropyrano[2,3-c]-pyraz

Full text of DOI:10.1007/s11164-016-2553-4

Res Chem Intermed
DOI 10.1007/s11164-016-2553-4
Fruit juice of Citrus limon as a biodegradable
and reusable catalyst for facile, eco-friendly and green
synthesis of 3,4-disubstituted isoxazol-5(4H)-ones
and dihydropyrano[2,3-c]-pyrazole derivatives
Rajesh H. Vekariya1 Kinjal D. Patel1
•
•
Hitesh D. Patel1
Received: 25 February 2016 / Accepted: 18 April 2016
Ó Springer Science+Business Media Dordrecht 2016
Abstract Fruit juice of Citrus limon (lemon juice) has been utilized as a natural and
renewable catalyst for the green and environmentally friendly preparation of 3,4-dis-
ubstituted isoxazol-5(4H)-one derivatives and 6-amino-1,4-dihydropyrano[2,3-c]-pyra-
zole-5-carbonitrile derivatives in hydroalcoholic media at 90 °C. A one-pot three-
component reaction of b-oxoesters with hydroxylamine hydrochloride and various
aromatic aldehydes afforded 3,4-disubstituted isoxazole-5(4H)-one derivatives in
excellent yields. The rate constant (K = 6.12 9 10-2 min-1 at 25 °C) for the formation
of isoxazole derivative (1g) was also calculated. Similarly, a four-component reaction of
ethyl acetoacetate, hydrazine hydrate, aryl aldehydes, and malononitrile gives pyr-
ano[2,3-c]-pyrazole derivatives in very good yields. After completion of the reaction, the
products were isolated by simple filtration. A simple work-up process, high product
yields, short reaction times, and the use of an inexpensive and biodegradable catalyst are
the advanced rewards of the present protocol.
Electronic supplementary material The online version of this article (doi:10.1007/s11164-016-2553-4)
contains supplementary material, which is available to authorized users.
&
Hitesh D. Patel
drhiteshpatel1@gmail.com
1
Department of Chemistry, School of Sciences, Gujarat University, Ahmedabad, Gujarat, India
123

R. H. Vekariya et al.
Graphical Abstract
Keywords Isoxazole-5(4H)-ones Á Pyrano[2,3-c]-pyrazole Á Lemon juice Á
One-pot Á Multi-component reaction Á Homogeneous catalysis Á Green synthesis
Introduction
Recently, multi-component reactions (MCRs) have received much attention in the
field of synthetic organic chemistry as well as medicinal chemistry, because the
strategies of MCR offer significant advantages over conventional synthetic
methodologies [1]. Therefore, planning reactions that achieve multi-bond formation
in one operation is becoming one of the leading challenges in the field of green
organic synthesis [2]. The approach of MCRs delivers numbers of advantages over
conventional transformations, such as shorter reaction times, higher product yields,
lower costs, an easy work-up process, and environmental being [3].
Isoxazole scaffolds are important class of heterocyclic compounds, and they are
predominant in nature and display a wide range of biological and pharmaceutical
activities such as b-adrenergic receptor antagonists [4], immunosuppressive [5],
anti-inflammatory [6], antibacterial [7], HDAC inhibitors [8], antifungal (I) [9],
antitumor [10], antioxidant [11], antiprotozoal [12], antiviral [13], anti-tubercular
[14], anti-inflammatory [15], anti-HIV [16], analgesic [17], antibiotics [18, 19], and
anti-androgens (II) [20, 21]. Furthermore, compound (III) (drazoxolon) [22] and
compound (IV) [23], which possess an isoxazolone ring, have been investigated as a
fungicide and an inhibitor of tumor necrosis factor-alpha (TNF-a), respectively. In
addition, the isoxazole-5(4H)-one scaffold can also be found as the essential moiety
of compound (V) (merocyanine dyes) (Fig. 1), which are used in optical recording
and nonlinear optical research [24].
4H-Pyrans analogue heterocyclic scaffolds signify a privileged structural motif
that is well-distributed in naturally occurring compounds [25]. This important class
of heterocyclic compounds displays a broad spectrum of biological activities
(Fig. 2) such as anticancer [26], anti-HIV [27], anti-inflammatory [28], antimalarial
123

Fruit juice of Citrus limon as a biodegradable and…
Fig. 1 Some biologically important isoxazolone compounds
Fig. 2 Biologically active dihydropyrano derivatives
[29], antimicrobial [30], antiviral [31], molluscicidal [32], anticancer, fungicidal,
analgesic, vasodilator, hypotensive, hypoglycemic [33], kinase inhibitor properties
[34], and anti-proliferative [35]. Several pyrano[2,3-c]pyrazoles are reported to have
beneficial biological activities such as anti-inflammatory and analgesic properties
[36]. In addition, the biological activity of fused azoles has led to exhaustive
research on their synthesis [37].
Due to the highly potent biological activities, isoxazoles and pyrano[2,3-c]-
pyrazole scaffolds are attractive synthetic targets for investigation of efficient and
green synthetic protocols for their synthesis. In the literature, a,b-unsaturated
isoxazol-5(4H)-one derivatives have been prepared via a three-component
123

R. H. Vekariya et al.
condensation of b-oxoesters, hydroxylamine hydrochloride and aromatic aldehydes
by use of catalytic amounts of sodium benzoate [38], sodium sulfide [39], sodium
silicate [40], catalyst-free/grinding or heating [41], nano Fe2O3, clinoptilolite, and
H3PW12O40 [42], N-bromosuccinimide (NBS) [43], potassium hydrogen phthalate
(KHP) [44], Ag/SiO2 [45], 2-Hydroxy-5-sulfobenzoic acid (2-HSBA) [46],
phthalimide-N-oxyl salts [47], tartaric acid [48], tetrabutylammonium perchlorate
(TBAP) [49], potassium phthalimide (PPI) [50], sodium saccharin [51], pyridine
[52–54], DABCO [55], CH3COONa [56], sodium ascorbate [57], sodium tetrab-
orate [58], and boric acid [59]. Many of these methods have some limitations and
drawbacks, such as the use of toxic reagents, strong acidic or basic conditions,
expensive reagents and catalysts, a tedious work-up process, low product yields, and
long reaction times. Similarly, several protocols have also been developed for the
synthesis of pyrano[2,3-c]-pyrazoles through a one-pot synthetic approach that is of
great attention. In this context, some catalysts have been used to promote these
condensations, such as maltose [60], saccharose [61], urea [62], lipase [63],
meglumine [64], diaminocyclohexane-thiourea [65], isonicotinic acid [66], acetic
acid [67], DBU [68], DABCO [69], piperidine and pyridine [70], pyrrolidine [71],
citric acid [72], disulfonic acid imidazolium chloroaluminate [73], sodium benzoate
[74], nano-titania sulfuric acid [75], nano-ZnO [76], CuO-CeO2nanocomposite
[77], nano-titania-supported preyssler-type heteropolyacid [78], nano TiO2 [79],
nano-CuFe2O4 [80], nickel nanoparticles [81], nano-CuI [82], Fe3O4 nanoparticles
[83], SnO2 quantum dots [84], amberlyst A21 [85], cetyltrimethylammonium
chloride (CTACl) [86], NaOH [87], tetraethylammonium bromide (TEABr) [88],
CeCl3 [89], CSF [90], poly(4-vinylpyridine) [91], borax [92], silica-supported
tetramethylguanidine [93], I2 [94], cerium ammonium nitrate (CAN) [95], and
tungstate sulfuric acid (TSA) [96].
In accordance with the demand for more sustainable chemistry, the search for
more environmentally benign forms of catalysis has received irresistible attention,
and one of the leading contestants for environmentally acceptable alternatives is the
category of biodegradable and renewable materials [97–99]. Already, several
biodegradable materials, such as chitosan [100, 101], gluconic acid [102, 103],
cellulose sulfuric acid [104, 105], xanthan sulfuric acid [106, 107], starch sulfuric
acid [108], sulfuric acid-modified PEG (PEG-OSO3H) [109, 110], melamine
trisulfonic acid (MTSA) [111, 112], and eggshell [113] have been proposed as
catalysts in many organic transformations. In addition, a number of organic
reactions using natural catalysts such as clay [114–117], natural phosphate [118,
119], animal bone [120] and also various fruit juices [121] are reported in the
literature. Due to their acidic nature, aqueous fruit juices like those from lemon
[122–128], pineapple [129, 130], coconut [131], Acacia concinna [132], Sapindus-
trifolistus [133] and Tamarindusindica [134, 135] have been found to be a
suitable replacement for various homogeneous acid catalysts.
Citrus limonium, Citrus aurantium, and Citrus indica are some of the important
species of the citrus family, commonly known as the lemon. The lemon is
indigenous to the northwestern regions of India and is also cultivated in Asia and
Europe. It is now widely grown in all tropical and subtropical countries. In India, it
is also cultivated in home gardens. The main ingredients of the extract of Citrus
123

Fruit juice of Citrus limon as a biodegradable and…
Scheme 1 Synthesis of 3,4-disubstituted isoxazol-5(4H)-ones and 6-amino-1,4-dihydropyrano[2,3-c]-
pyrazole-5-carbonitriles catalyzed by lemon juice as a green catalyst. (Color figure online)
limonium species of lemon are moisture (85 %), carbohydrates (11.2 %), citric acid
(5–7 %), protein (1 %), ascorbic acid or vitamin-C (0.5 %),fat (0.9 %), minerals
(0.3 %), fibers (1.6 %), and some other organic acids [122]. The juice is soluble in
water. Due to the presence of citric and ascorbic acids, lemon juice is acidic
(pH = 2–3) in nature, and thus it works as an acid catalyst in organic reactions.
Considering the above facts, we performed research on the development of green
and sustainable protocols for the preparation of important organic compounds [136–
138], and herein we report lemon juice as a new biodegradable and renewable
natural catalyst for the synthesis of 3,4-disubstituted isoxazol-5(4H)-ones from the
one-pot cyclocondensation of aromatic aldehydes, ethyl acetoacetate, and hydrox-
ylamine hydrochloride in aqueous ethanol at 90 °C (Scheme 1). Similarly, we have
demonstrated the synthesis of a series of 6-amino-1,4-dihydropyrano[2,3-c]-
pyrazole-5-carbonitriles via the one-pot, four-component reaction of ethyl acetoac-
etate (10 mmol), hydrazine hydrate (15 mmol, 80 %), aromatic aldehydes
(10 mmol), and malononitrile (10 mmol) in water–ethanol media at 90 °C using
lemon juice as a catalyst (Scheme 1).
Results and discussion
In the beginning, the optimal conditions for the synthesis of 3,4-disubstituted
isoxazol-5(4H)-ones (1a–1t) were investigated. Conducting a reaction between
ethyl acetoacetate, hydroxylamine hydrochloride, and 4-hydroxybenzaldehyde in
the presence of 1 mL of lemon juice as a catalyst for 60 min at refluxing
temperature in different solvents such as methanol, ethanol, toluene, acetonitrile,
dichloromethane, ethyl acetate, chloroform, water, and a mixture of water:ethanol
(9:1) as well as water:acetone (9:1) resulted in the corresponding product 1b in 65,
70, 27, 45, 36, 34, 31, 86, 94, and 67 % of yields, respectively (Table 1, entries
4–13). Among all of these solvents, water:ethanol (9:1) was found to be the best
123

R. H. Vekariya et al.
Table 1 Optimization of the reaction conditions for the synthesis of 3,4-disubstituted isoxazol-5(4H)-
ones
Entry Solvent (10 ML)
Catalyst loading (mL) Temperature (°C) Time (min) Yield (%)a
1
–
–
r.t.
60
60
60
60
60
60
60
60
60
60
60
55
60
60
60
60
60
60
60
60
60
60
60
Trace
24
62
65
70
27
45
36
34
31
86
94
67
84
45
58
68
77
89
52
70
82
94
2
–
–
90 °C
90 °C
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
90 °C
90 °C
Reflux
90 °C
40 °C
50 °C
60 °C
70 °C
80 °C
90 °C
90 °C
90 °C
90 °C
3
–
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
4
MeOH
EtOH
5
6
Toluene
MeCN
CH2Cl2
EtOAc
CHCl3
H2O
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
H2O:EtOH (9:1)
H2O:Acetone (9:1) 1.00
H2O:EtOH (5:5)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
1.00
1.00
1.00
1.00
1.00
1.00
0.25
0.50
0.75
1.25
Bold letters in the table demonstrated the optimize reaction conditions
a
Isolated product yield
reaction media in terms of the yield of the product and time of completion in
comparison with other solvents. The amount of lemon juice required for this
transformation was also evaluated. On conducting the same reaction in the absence
of solvent at room temperature (r.t.), only trace amounts of yield of (1b) was
achieved even after a prolonged reaction (Table 1, entry 1). Increasing the reaction
temperature from r.t. to 90 °C had considerable influence on the yield of the product
(Table 1, entry 2). In addition, we also carried out the model reaction using 1 mL
lemon juice as a catalyst under solvent-free conditions (Table 1, entry 3). However,
only moderate yield (62 %) of the product (1b) was observed, which allowed us to
conclude that solvent is also necessary to accomplish the reaction in the forward
direction. Variations of the amount of lemon juice such as 0.25, 0.50, 0.75, and
1.25 mL led to product (1b) in 52, 70, 82, and 94 % of yields, respectively (Table 1,
entries 20–23). These results indicated that 1 mL of lemon juice gives high yield of
the product over the duration of the reaction. Having optimized the solvent for this
reaction, we proceeded to investigate the use of different temperatures: 40, 50, 60,
123

Fruit juice of Citrus limon as a biodegradable and…
70, and 80 °C (Table 1, entries 15–19). Increasing the temperature of the reaction
from 40 to 80 °C led to a reduction in the reaction time with an increase in product
yield. Hence, using 1 mL of lemon juice in water:ethanol (9:1) at 90 °C is the
optimal condition for this reaction.
After optimizing the conditions, the broad view of this process was studied by the
reaction of various substituted aryl aldehydes and heterocyclic aldehydes with
hydroxylamine hydrochloride and ethyl acetoacetate in the presence of 1 mL lemon
juice in water:ethanol (9:1) at 90 °C. The results of this study are presented in
Table 2. The reaction was clean, and no chromatographic separation was required
because no impurities were observed. After completion of the reaction, the solid
product was collected by simple filtration and, if required, was then recrystallized in
ethanol to afford pure products. The structure of the title compounds were
confirmed by IR, ESI–MS, 1H-NMR, and 13C-NMR as well as by comparison of
their melting points with those of the reported compounds. For example, the 1H-
NMR spectrum of 1b exhibited a sharp singlet signal at d = 2.25 ppm due to the
methyl group in the isoxazol unit. Two doublets were observed at d = 6.95
(J = 8.76 Hz) and d = 8.45 (J = 8.8 Hz), which assigned four protons of aromatic
Table 2 The synthesis of 3,4-disubstituted isoxazol-5(4H)-ones (1a–1t) catalyzed by lemon juice
Entry
Product
code
Ar
Time
(min)
Yield
(%)a
(Mp °C)
found
(Mp °C)
literature
1
1a
1b
1c
1d
1e
1f
C6H5
50
55
60
56
60
57
60
52
120
60
60
58
54
120
120
50
52
56
55
52
96
142–143
211–212
198–200
173–175
135–137
200–201
225–226
215–217
–
141–142 [46]
211–213 [46]
198–199 [46]
174–175 [46]
135–136 [46]
200–201 [46]
225–227 [46]
216–217 [46]
–
2
4-OHC6H4
94
3
2-OHC6H4
93
4
4-OMeC6H4
4-CH3C6H4
98
5
97
6
3-OHC6H4
94
7
1g
1h
1i
4-N(CH3)2C6H4
3-OCH3-4-OHC6H3
2-Pyridyl
95
8
96
NRb
9
10
11
12
13
14
15
16
17
18
19
20
a
1j
2-Thienyl
90
144–145
143–145
238–240
265–267
–
144–146 [46]
145–146 [46]
239–241 [50]
266–267 [50]
–
1k
1l
3-Thienyl
92
2-Furyl
90
1m
1n
1o
1p
1q
1r
1s
4-OH-3-NO2-C6H3
4-Cl-C6H4
96
NRb
NRb
94
4-NO2-C6H4
2,3-diOMe-C6H3
2,5-diOMe-C6H3
3,4-diOH-C6H3
3,5-diOMe-4-OHC6H2
3-OH-4-OCH3C6H3
–
–
210–212
178–180
212–214
194–197c
185–187c
210–211 [45]
178–179 [45]
212–213 [45]
–
96
98
97
1t
95
–
Isolated product yields
b
c
No product was formed
Novel compounds
123

R. H. Vekariya et al.
rings. Also, the 1H-NMR showed one singlet signal at d = 7.78 ppm for the =CH
proton between the isoxazol and aromatic rings. In addition, a proton of 4-OH
exhibited a singlet at d = 11.06 ppm. The 13C-NMR spectrum of 1b displayed the
isoxazol ring carbons C=O and C=N at d = 168.80 and 163.82 ppm, respectively,
which confirms the isoxazol unit. The signal at d = 11.25 ppm corresponds to the
CH3 group. The other carbon signals were observed at the expected chemical shifts.
Furthermore, the ESI–MS spectrum of compound 1b shows a peak at 204.2
(M ? H)?, which confirms the structure of compound 1b.
We found that aromatic substrates having electron-donating functional groups
afforded good to high yields of products. In addition, the reaction with electron-
reaching heterocyclic aldehydes also preceded smoothly with high yields in shorter
reaction times. It is important to note that the aldehydes with electron-withdrawing
(–NO2) as well as ring-deactivating (–Cl) groups and deficient heterocyclic aldehyde-
like pyridine-2-carbaldehyde are not favored under these conditions (Table 2, entries
9, 14, and 15). Interestingly, when the 4-hydroxy-3-nitrobezaldehyde containing both
electron-withdrawing (–NO2) and electron-donating (–OH) groups was used, the
corresponding product (1 m) was obtained in a shorter reaction time and with higher
yield (Table 2, entry 13). Similarly, 2-hydroxy-5-bromobezaldehyde gave a corre-
sponding product in excellent yield within a shorter period of time (Table 2, entry 19).
Accordingly, we concluded that the electronic nature of the functional groups and their
position on aryl aldehydes have various effects on this reaction.
Although the exact mechanism of this transformation is not completely clear, a
possible reaction mechanism is proposed based on these results and the provided
mechanism in the literature (Scheme 2). According to the proposed reaction
Scheme 2 The proposed mechanism for the lemon juice-mediated synthesis of 3,4-disubstituted
isoxazol-5(4H)-ones (1a–1t)
123

Fruit juice of Citrus limon as a biodegradable and…
mechanism, at first, the nucleophilic attack of the amino group and hydroxyl group
of hydroxylamine hydrochloride on the two carbonyl carbon of the ethyl
acetoacetate in the presence of lemon juice resulted in a cyclized adduct (A). The
aldehyde was attacked on the cyclized adduct (A) and a subsequent Knoevenagel
adduct is formed via removal of the water molecule.
In all reactions, the catalytic system is recoverable. After completion of the
reaction, the product was filtered off. The filtrated solution could be applied up to
three times in the same model reaction under the optimized conditions (1st use:
94 % isolated yield, 2nd use: 90 % isolated yield, and 3rd use: 87 % isolated yield).
Decreases in the yield are probably related to a minor reduction in the efficiency of
the catalyst or decrease in the amount of catalyst recycled, which is accredited to the
handling.
The kinetics of this cyclocondensation reaction were studied in a standard quartz
cuvette with a 1-cm path length and 4.5-mL volume. Initially, 2 mL of ethanol and
8 mL water were mixed with 10 mmol of ethyl acetoacetate and 10 mmol of
hydroxylamine hydrochloride. Then, the reaction mixture was stirred for 10 min at
room temperature. After that 10 mmol of Para-dimethylaminobenzaldehyde was
added into the reaction mixture. After mixing these solutions, 1 mL lemon juice was
added in the reaction flask. Now, the reaction mixture was heated at 90 °C. After
10 min we took 0.5 mL of the reaction mixture and performed an extraction with
2.5 mL ethyl acetate, which is 4.0 9 10-4 M solution of Para-dimethylaminoben-
zaldehyde. This solution was diluted with ethyl acetate to make it 16 nM. UV–
visible spectra were recorded at every 10 min interval in the range of 250–550 nm
for at least 60 min at 25 °C of the above diluted solution (Fig. 3).
The rate constant was determined by measuring the change in absorbance of a
peak at 300 nm, the initially observed peak for the Para-dimethylaminobenzalde-
hyde, as a function of time. The peak shows a gradual decrease in intensity with
time and a new peak appeared at 455 nm, indicating the formation of 3-Methyl-4-
(4-dimethylaminophenyl)methylene-isoxazole-5(4H)-one.
The reaction shows pseudo first-order kinetics with respect to Para-dimethy-
laminobenzaldehyde, and the rate constants were calculated to be 6.12 9
10-2 min-1 at 25 °C (Figs. 4, 5).
After the successful synthesis of a series of 3,4-disubstituted isoxazol-5(4H)-ones,
we turned our attention toward the synthesis of 6-amino-1,4-dihydropyrano[2,3-c]-
Fig. 3 UV–visible spectra for the formation of product 1g measured at 10-min intervals at 25 °C
123

R. H. Vekariya et al.
0.3
0.25
0.2
Fig. 4 Plot of absorbance
versus time for the formation of
product 1g
0.15
0.1
0.05
0
0
10
20
30
40
50
60
70
Time (min)
2.5
2
Fig. 5 Plot of ln(At/A0) versus
time for the formation of
product 1g
1.5
1
y = -0.0608x + 2.1625
R² = 0.8989
0.5
0
0
10
20
30
40
50
60
70
-0.5
-1
-1.5
-2
-2.5
Time
pyrazole-5-carbonitriles in the presence of lemon juice as a catalyst in a non-toxic
solvent, e.g., the mixture of water and ethanol. In the beginning, the reaction of
equimolar quantities of ethyl acetoacetate (10 mmol), hydrazine hydrate (15 mmol,
80 %), benzaldehyde (10 mmol), and malononitrile (10 mmol) was selected as a
model reaction to identify suitable reaction conditions using lemon juice (1 mL) as a
catalyst.
Different reaction conditions were examined including solvents, amounts of
catalyst, and temperatures, to identify the optimal reaction conditions. The results
are summarized in Table 3. From the results table, we concluded that the product
yield obtained was very poor in the absence of a solvent at room temperature as well
as at 90 °C under catalyst-free conditions (Table 3, entries 1, 2). We also carried out
the model reaction using 1 mL lemon juice as a catalyst under solvent-free
conditions, however, only a moderate yield (68 %) of the product (2a) was observed
in this case (Table 3, entry 3). The model reaction was then performed in water,
methanol, ethanol, toluene, acetonitrile, dichloromethane, ethyl acetate, and
chloroform using lemon juice (1 mL) as a catalyst (Table 3, entries 4–11). The
reactions furnished poor yields when aprotic solvents like toluene, acetonitrile,
dichloromethane, ethyl acetate, and chloroform were used (Table 3, entries 6–10).
Therefore, these solvents were determined to be unsuitable for this model reaction.
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Fruit juice of Citrus limon as a biodegradable and…
Table 3 Optimization of the reaction conditions for the synthesis of 6-amino-1,4-dihydropyrano[2,3-c]-
pyrazole-5-carbonitriles (2a–2t)
Entry
Solvent
Catalyst
loading (mL)
Temperature
(°C)
Time
(min)
Yield
(%)a
1
–
–
r.t.
60
60
60
60
60
60
60
60
60
60
60
45
60
60
60
60
60
60
60
60
60
50
45
Trace
17
68
72
76
32
55
43
38
36
84
96
88
54
60
66
75
83
90
62
76
89
95
2
–
–
90 °C
90 °C
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
90 °C
90 °C
90 °C
r.t.
3
–
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
1.00
0.25
0.50
0.75
1.50
4
MeOH
5
EtOH
6
Toluene
7
MeCN
8
CH2Cl2
9
EtOAc
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CHCl3
H2O
H2O:EtOH (9:1)
H2O:EtOH (5:5)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
H2O:EtOH (9:1)
40 °C
50 °C
60 °C
70 °C
80 °C
90 °C
90 °C
90 °C
90 °C
Bold letters in the table demonstrated the optimize reaction conditions
a
Isolated product yields
The product (2a) was obtained in a moderate yield and with a long reaction time in
protic solvents like methanol, ethanol, and water (Table 3, entries 4, 5, 11), and the
reaction in the mixture of water:ethanol (9:1) was performed in the shortest reaction
time with the best yield. Therefore, it can be concluded that water:ethanol (9:1) is a
superior solvent as compared to the others (Table 3, entry 12). We also
demonstrated the water:ethanol (5:5) solvent system for this transformation.
However, it did not yield any better results compared to the water:ethanol (9:1)
solvent system (Table 3, entry 13).
The amount of the catalyst plays a crucial role in the success of the reactions in
terms of the rate and the yields, and these experiments are summarized in Table 3.
Having optimized the solvent for this reaction, we proceeded to investigate the use
of different temperatures including room temperature, 40, 50, 60, 70, and 80 °C
(Table 3, entries 14–19). Increasing the temperature of the reaction from room
temperature to 90 °C led to a reduction in the reaction time with increments of
product yield. The greatest yield in the shortest reaction time was obtained in
123

R. H. Vekariya et al.
water:ethanol (9:1) at 90 °C (Table 3, entry 12). In the next step, the reaction was
carried out with various amounts of catalyst in water:ethanol (9:1) at 90 °C.
(Table 3, entries 20–23). Increasing the catalyst to 0.25, 0.50, 0.75, and 1.50 mL
resulted in increasing the reaction yields to 62, 76, 89, and 96 %, respectively. In
addition, a higher amount of catalyst, i.e., 1.5 mL of lemon juice, does not improve
product yield or the reaction time (Table 3, entry 23). Hence, the best result was
obtained by performing the reaction in the presence of 1 mL of lemon juice at 90 °C
in water:ethanol (9:1) system.
With the above optimized reaction conditions, a series of the 6-amino-1,4-
dihydropyrano[2,3-c]-pyrazole-5-carbonitriles (2a–2t) were synthesized using var-
ious aldehydes (Table 4, entries 1–20). A wide range of aromatic aldehydes bearing
either electron-releasing or electron-withdrawing substituents reacted successfully
to give the corresponding products in high to excellent yields over short reaction
times. In all cases, the reaction was found to be selective and afforded the desired
products in high purity without any evidence of the formation of any side products.
In addition, heterocyclic aldehydes such as 2-furfuraldehyde also reacted efficiently
with this protocol and afforded excellent product yields (Table 4, entry 20).
We also proposed a possible mechanism for the building of final products (2a–2t)
(Scheme 3). The nitrile anion (E) is formed by the removal of acidic hydrogen from
Table 4 The synthesis of 6-amino-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitriles (2a–2t) catalyzed
by lemon juice
Entry
Product
code
Ar
Time
(min)
Yield
(%)a
(Mp °C)
found
(Mp °C)
literature [136]
1
2a
2b
2c
2d
2e
2f
C6H5
45
40
42
55
60
45
40
45
60
45
48
55
60
52
45
48
45
55
52
48
96
95
97
93
94
95
98
95
96
94
92
97
94
94
93
96
97
92
94
92
245–246
209–211
226–227
193–195
251–252
224–226
147–148
211–212
196–197
233–235
207–209
179–180
242–244
168–170
199–201
190–191
209–210
254–255
227–228
218–219
244–246
208–210
224–226
193–195
251–253
225–228
145–147
210–212
196–198
234–236
206–208
178–180
240–242
167–169
199–201
192–194
209–211
254–255
227–228
217–219
2
2-OH-C6H4
3
4-OH-C6H4
4
3-NO2-C6H4
4-NO2-C6H4
3-OH-C6H4
5
6
7
2g
2h
2i
2-Cl-C6H4
8
4-OMe-C6H4
4-CN-C6H4
9
10
11
12
13
14
15
16
17
18
19
20
a
2j
4-Cl-C6H4
2k
2l
4-Me-C6H4
4-Br-C6H4
2m
2n
2o
2p
2q
2r
2s
4-F-C6H4
4-N(Me)2-C6H4
3,5-diOMe-4-OH-C6H2
3,4-diOMe-C6H3
3,4,5-triOMe-C6H2
2-OH-5-NO2-C6H3
2-OH-5-Br-C6H3
2-furayl
2t
Isolated product yields
123

Fruit juice of Citrus limon as a biodegradable and…
Scheme 3 The proposed mechanism for the lemon juice-mediated synthesis of 6-amino-1,4-
dihydropyrano[2,3-c]-pyrazole-5-carbonitriles
malononitrile (D) catalyzed by lemon juice. Finally, the arylidene nitrile intermediates
(Knoevenagel adducts, F) are formed through the Knoevenagel condensation reaction
of the intermediate nitrile anion (E) with aldehydes (C). On other hand, the reaction of
ethyl acetoacetate and hydrazine hydrate afforded compound (G), which was enolized
in the presence of lemon juice to form compound (H). Subsequently, the enolizable
compound (H) condensed with the Knoevenagel adducts (F) via the Michael addition,
which results in the in-situ formation of intermediate (I) (Michael adducts). Finally, it
subsequently undergoes intramolecular nucleophilic cyclization (Thorpe–Ziegler
type reaction) and tautomerization to afford the desired compounds (2a–2t).
123

R. H. Vekariya et al.
Table 5 Comparison of various catalysts in this reaction
Entry Catalyst
Conditions
Time Yield References
(min) (%)a
1
2
3
Sodium benzoate (15 mol%)
Water, r.t.
60
10
85
75
89
[74]
[61]
[86]
Saccharose (20 mol %)
Solvent-free, 100 °C
Water, 90 °C
Cetyltrimethylammonium
chloride (CTACl) (30 mol %)
240
4
Nano-ZnO (5 mol %)
Nano-CuI (1.2 mol %)
TBABr (10 mol %)
Water, 70 °C
Water, reflux
60
40
94
90
90
80
92
86
92
85
90
96
[76]
5
[82]
6
Water, reflux
15
[88]
7
c-Alumina (30 mol %)
b-Cyclodextrin (10 mol %)
Urea (10 mol %)
Water, reflux
50
[139]
[140]
[141]
[142]
[143]
[144]
This work
8
Water–ethanol (9:1), 80 °C
Water–ethanol (1:1), r.t.
Water, reflux
15
480
15
9
10
11
12
13
DABCO (5 mol %)
DCDBTSD (10 mol%)
[bmim]OH (20 mol%)
Lemon juice (1 mL)
Water, 80 °C
Solvent-free, 50–60 °C
Water–ethanol (9:1), 90 °C
60
45
45
Bold letters in the table demonstrated the optimize reaction conditions
Table 5 indicates the comparison of the activity of the different catalysts by
considering the yield for the reaction. We observed that the lemon juice catalyst gives
the best catalytic activity in terms of product yield and reaction time compared to the
other catalysts in the literature such as c-Alumina, nano-ZnO, TBABr, Sodium
benzoate, b-Cyclodextrin, Cetyltrimethylammonium chloride (CTACl), Urea,
DABCO, nano-CuI, Saccharose, DCDBTSD, and [bmim]OH. Lemon juice is easily
available as a natural and inexpensive catalyst, which makes this protocol green and
clean. In addition, lemon juice is a renewable catalyst, thus it follows one of the green
chemistry principles regarding the maximum use of renewable sources. Therefore, the
present protocol is considered as a sustainable and environmentally friendly protocol.
In general, at the end of the reaction, the system became a suspension and finally
the product was precipitated. The products were obtained through simple filtration
and washed with water and recrystallized in ethanol (if required) to afford pure
products. The filtered solution could be reused three times without major loss of
efficiency (1st use: 96 % isolated yield, 2nd use: 92 % isolated yield, and 3rd use:
87 % isolated yield). The structure of the products (2a–2t) were characterized by
IR, ESI–MS, 1H-NMR, and 13C-NMR spectral data and by comparison of their
melting points with those of authentic samples.
Experimental
Apparatus and analysis
All chemicals, unless otherwise specified, were purchased from commercial sources
and were of used analytical grade. The products were characterized by a comparison
123

Fruit juice of Citrus limon as a biodegradable and…
of their physical data and melting points with those of known samples or by their
spectral data. Melting points were measured on an Optimelt MPA 100 melting point
apparatus and are uncorrected. Fourier transform infrared spectroscopy (FT-IR)
spectra were recorded on a Perkin Elmer FT-IR 377 spectrometer using KBr. Proton
NMR spectra were recorded on Bruker AV 400 MHz spectrometer using DMSO as
solvent and TMS as the internal reference. Mass spectra were recorded at Advion
expression CMS, USA. Acetone was used as the mobile phase, and electron spray
ionization (ESI) was used as the ion source. The progress of the reaction was
monitored by thin layer chromatography (TLC) analysis on Merck pre-coated silica
gel 60 F254 aluminum sheets, visualized by UV light.
General procedure for extraction of lemon juice (preparation of catalyst)
Fresh lemon was cut using a knife and pieces were pressed in a fruit juicer to obtain
the juice extract. Then the juice was filtered through cotton/muslin cloth and finally
through filter paper to remove solid material and to get the clear juice that was used
as a catalyst. The pH of the lemon juice was between 3.0 and 3.4.
General method for the preparation of 3,4-disubstituted isoxazol-5(4H)-
ones (1a–1t)
A mixture of hydroxylamine hydrochloride (10 mmol), ethyl acetoacetate
(10 mmol), and lemon juice (1 mL) in 10 mL water:ethanol (9:1) was stirred at
room temperature for 15 min, then aromatic aldehyde (10 mmol) was added to the
mixture. The reaction mixture was stirred at RT until the reaction was completed.
The reaction was monitored by TLC analysis. After completion of the reaction, the
precipitate was separated by simple filtration, and washed with cold distilled water
and dried in the air. Crude products were recrystallized from ethanol (95 %) to
afford the title pure compounds. After filtration, the filtered solution could reused
for the three subsequent reactions. The identity of the known products was
confirmed by comparison of their spectroscopic data and physical properties with
those available in recent articles. The novel products were identified by spectral data
(i.e., IR, 1H-NMR, and 13C-NMR and Mass). The spectral data of the novel
compounds as well as some representative compounds are described below.
4-(3-hydroxybenzylidene)-3-methylisoxazol-5(4H)-one (1b) Yellow solid IR mmax
(KBr) cm-1: 3232, 2363, 1734, 1559, 1358, 1297, 1179, 669. 1H-NMR (400 MHz,
DMSO-d6): dH (ppm) 2.25 (s, 3H, CH3), 6.95 (d, J = 8.76 Hz, 2H, ArH), 7.78 (s,
1H, = CH), 8.45 (d, J = 8.80 Hz, 2H, ArH), 11.06 (s, 1H, OH). 13C-NMR
(100 MHz, DMSO-d6): dC (ppm) 11.25, 113.81, 116.12, 124.54, 135.42, 137.51,
151.15, 151.48, 162.23, 163.82, 168.80. MS (ESI) m/z for (203.19): 203.1 (M)?,
204.2 (M ? 1)?.
4-(3-(dimethylamino)benzylidene)-3-methylisoxazol-5(4H)-one (1g) Red solid IR
mmax (KBr) cm-1: 1734, 1589, 1530, 1429, 1180, 1096, 870. 1H-NMR (400 MHz,
DMSO-d6): dH (ppm) 2.22 (s, 3H, CH3), 3.14 (s, 6H, N(CH3)2), 6.86 (d,
123

R. H. Vekariya et al.
J = 9.16 Hz, 2H, ArH), 7.63 (s, 1H, = CH), 8.47 (d, J = 8.20 Hz, 2H, ArH). 13C-
NMR (100 MHz, DMSO-d6): dC (ppm) 11.31, 108.95, 111.61, 120.96, 137.54,
150.47, 154.31, 162.11, 169.81. MS (ESI) m/z for (230.26): 230.2 (M)?, 253.2
(M ? Na)?.
4-(3-hydroxy-2,4-dimethoxybenzylidene)-3-methylisoxazol-5(4H)-one (1s) Yel-
lowish orange solid IR mmax (KBr) cm-1: 3532, 2358, 1711, 1587, 1377, 1201,
1165, 670. 1H-NMR (400 MHz, DMSO-d6): dH (ppm) 2.19 (s, 3H, CH3), 3.83 (s,
6H, 2 OCH3), 7.66 (s, 1H, =CH), 7.99 (s, 2H, ArH), 10.20 (s, 1H, OH). 13C-NMR
(100 MHz, DMSO-d6): dC (ppm) 11.15, 55.83, 112.46, 113.75, 123.94, 143.13,
147.40, 151.88, 162.08, 168.93. MS (ESI) m/z for (263.25): 263.1 (M)?, 264.2
(M ? 1)?.
4-(3-hydroxy-4-methoxybenzylidene)-3-methylisoxazol-5(4H)-one (1t) Orange
solid IR mmax (KBr) cm-1: 3502, 2367, 1699, 1529, 1264, 1126, 674. 1H-NMR
(400 MHz, DMSO-d6): dH (ppm) 2.25 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 7.13 (d,
J = 8.60 Hz, 1H, ArH), 7.73 (s, 1H, = CH), 7.90 (d, J = 10.56 Hz, 1H, ArH), 8.19
(s, 1H, ArH), 9.61 (s, 1H, OH). 13C-NMR (100 MHz, DMSO-d6): dC (ppm) 11.25,
15.77, 55.84, 111.68, 114.70, 119.52, 126.72, 129.61, 146.51, 151.75, 153.68,
158.11, 162.23, 168.54, 170.92. MS (ESI) m/z for (233.22): 233.3 (M)?, 256.1
(M ? Na)?.
General method for the preparation of 6-amino-1,4-dihydropyrano[2,3-c]-
pyrazole-5-carbonitriles (2a–2t)
In a typical experiment, ethyl acetoacetate (10 mmol), hydrazine hydrate (15 mmol,
80 %), aromatic aldehydes (10 mmol), malononitrile (10 mmol), and lemon juice
(1 mL) in water: ethanol (9:1, 10 mL) were placed in a 25-ml round-bottom flask.
During the reflux (90 °C), the progress of the reaction mixture was monitored by
TLC analysis. After completion of the reaction, the solid precipitate was filtered off
and washed with water and purified by recrystallization from hot ethanol, if
necessary. The reaction products were identified by comparing their physical and
spectral data (i.e., IR, 1H NMR and 13C NMR and Mass) with those reported in the
literature. The spectral data of the representative compounds are described below.
6-amino-4-(4-nitrophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (2e) Yellow solid IR mmax (KBr) cm-1: 3414, 3389, 3323, 3073, 3025, 2936,
2209, 1485, 1354, 1563, 818. 1H NMR (400 MHz, DMSO-d6): dH (ppm) 1.82 (s,
3H, CH3), 4.84 (s, 1H, 4H), 7.08 (s, 2H, NH2), 7.46-7.48 (d, 2H, J = 8.48 Hz, Ar–
H), 8.20-8.22 (d, 2H, J = 8.48 Hz, Ar–H), 12.22 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): dC (ppm) 9.71, 35.84, 55.84, 96.52, 120.47, 123.87, 128.81,
135.84, 146.34, 152.08, 154.63, 161.11. MS (ESI) m/z for (297.1): 397.2 (M)?,
398.3 (M ? 1)?.
6-amino-4-(4-chlorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carboni-
trile (2j) Off-white solid, IR mmax (KBr) cm-1: 3400, 3391, 3317, 3066, 3017,
2931, 2211, 1488, 1058, 815. 1H NMR (400 MHz, DMSO-d6): dH (ppm) 1.79 (s,
123

Fruit juice of Citrus limon as a biodegradable and…
3H, CH3), 4.64 (s, 1H, 4H), 6.96 (s, 2H, NH2), 7.19–7.21 (d, 2H, J = 8.40 Hz, Ar–
H), 7.37-7.39 (d, 2H, J = 8.40 Hz, Ar–H), 12.17 (s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): dC (ppm) 9.71, 35.51, 56.68, 97.15, 120.65, 128.43, 129.07,
129.34, 129.70, 130.00, 131.20, 135.67, 143.44, 154.65, 160.87. MS (ESI) m/z for
(286.06): 286.1 (M)?, 288.1 (M ? 2)?.
6-amino-4-(4-hydroxy-3,5-dimethoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyra-
zole-5-carbonitrile (2o) Off-white solid IR mmax (KBr) cm-1: 3452, 3393, 3384, 3310,
3059, 3010, 2925, 2590, 2205, 1481, 742, 772, 805. 1H NMR (400 MHz, DMSO-d6):
dH (ppm) 1.86 (s, 3H, CH3), 3.71 (s, 6H, 2 9 OCH3), 4.53 (s, 1H, 4H), 6.43 (s, 2H,
NH2), 6.85 (s, 2H, Ar–H), 8.28 (s, 1H, –OH), 12.08 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6):dC (ppm) 9.88, 36.24, 55.93, 57.32, 97.63, 104.82, 120.89, 134.25, 134.45,
135.66, 147.80, 154.66, 160.73. MS (ESI) m/z for (328.1): 329.1 (M ? 1)?, 351.1
(M ? Na)?.
6-amino-4-(3,4,5-trimethoxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (2q) Off-white solid IR mmax (KBr) cm-1: 3432, 3391, 3382, 3316,
3069, 3017, 2922, 2593, 2207, 1487, 742, 772, 805. 1H NMR (400 MHz, DMSO-
d6): dH (ppm) 1.89 (s, 3H, CH3), 3.55 (s, 9H, 3 9 OCH3), 4.61 (s, 1H, 4H), 6.49 (s,
2H, NH2), 6.92 (s, 2H, Ar–H), 12.13 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
dC (ppm) 9.91, 36.46, 55.74, 56.84, 59.91, 97.28, 104.49, 105.50, 120.87, 135.73,
136.07, 140.07, 152.76, 153.13, 154.67, 160.95. MS (ESI) m/z for (342.13): 343.1
(M ? 1)?, 366.2 (M ? Na)?.
Conclusion
In summary, we have established effective and practical one-pot protocols for the
synthesis of a library of 3,4-disubstituted isoxazol-5(4H)-ones (1a–1t) as well as
6-amino-1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitriles (2a–2t) in the presence
of biodegradable, renewable, easily assessable, inexpensive, and highly efficient
lemon juice as the catalyst in a hydroalcoholic system. Moreover, all products were
obtained through simple filtration with no need for column chromatography, which
reduces the waste as well as environmental pollution. These protocols, which
enabled 3,4-disubstituted isoxazol-5(4H)-ones and 6-amino-1,4-dihydropyrano[2,3-
c]-pyrazole-5-carbonitriles to be prepared in excellent yields and with the shortest
reaction times, represent some rather attractive synthetic methods for use in the near
future. The rate constant (K = 6.12 9 10-2 min-1 at 25 °C) for the formation of
Isoxazole derivative (1g) was also calculated, which indicated that the reaction
shows pseudo-first-order kinetics. The use of lemon juice in these MCRs has
benefits such as clean reaction profiles, lack of side reactions, green properties,
minimization of waste, a simple experimental procedure, recyclability of the
catalyst, simplicity of operation, and easy work-up.
Acknowledgments The authors are thankful to the Department of Chemistry, Gujarat University,
Ahmedabad, for providing the necessary facilities. UGC-Info net and INFLIBNET Gujarat University are
acknowledged for providing the e-resource facilities, the NFDD Centre for proton NMR and carbon
123

R. H. Vekariya et al.
NMR, and the Synzeal Research Laboratory for mass spectroscopy. R.H.V. is thankful to UGC-BSR (F.7-
74/2007 (BSR)) for financial assistance.
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