Efficient Synthesis of 1,4-Dihydropyrano[2,3-c]pyrazoles Using Snail Shell as a Biodegradable and Reusable Catalyst

Full text of DOI:10.1080/00304948.2019.1677991

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
ISSN: 0030-4948 (Print) 1945-5453 (Online) Journal homepage: https://www.tandfonline.com/loi/uopp20
Efficient Synthesis of 1,4-Dihydropyrano[2,3-
c]pyrazoles Using Snail Shell as a Biodegradable
and Reusable Catalyst
Zakaria Benzekri, Sara Sibous, Houda Serrar, Said Boukhris, Amina
Hassikou, Rachida Ghailane & Abdelaziz Souizi
To cite this article: Zakaria Benzekri, Sara Sibous, Houda Serrar, Said Boukhris, Amina Hassikou,
Rachida Ghailane & Abdelaziz Souizi (2019): Efficient Synthesis of 1,4-Dihydropyrano[2,3-
c]pyrazoles Using Snail Shell as a Biodegradable and Reusable Catalyst, Organic Preparations and
Procedures International, DOI: 10.1080/00304948.2019.1677991
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Organic Preparations and Procedures International, 0:1–10, 2019
# 2019 Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2019.1677991
Efficient Synthesis of 1,4-Dihydropyrano[2,3-
c]pyrazoles Using Snail Shell as a Biodegradable
and Reusable Catalyst
Zakaria Benzekri, Sara Sibous, Houda Serrar, Said Boukhris,
Amina Hassikou, Rachida Ghailane, and Abdelaziz Souizi
Laboratory of Organic, Organometallic and Theoretical Chemistry, Faculty of
Sciences, Ibn Tofaïl University, BO 133, 14000 Kenitra, Morocco
The 4H-pyranopyrazoles are an important class of heterocyclic compounds due to their
pharmacological and biological properties.1 Compounds bearing the pyranopyrazole
system have been found to have various biological activities, for instance antimicro-
bial,2 anti-cancer3 and anti-inflammatory properties,4 analgesic activity,5 activity as
hypoglycemic,3 hypotensive,6 and vasodilatory agents,7 inhibitory activity toward
human Chk1 kinase,8 molluscicidal activity9 and antifungal properties.10 In addition,
such heterocycles bearing 4H-pyran units are important precursors in the synthesis of a
large family of medicinally useful compounds.11
One-pot, multicomponent reactions (MCRs) are synthetically powerful, owing to
their short reaction times, high efficiencies and unique selectivities.12 They can form
several chemical bonds simultaneously13–14 and have emerged as an efficient tool in
organic and medicinal chemistry.15–16 They are well suited for the synthesis of valuable
heterocyclic compounds.17
A number of synthetic approaches have been made for the synthesis of 1,4-dihydro-
pyranopyrazoles using CAPB,18 CTACl,19 MDOs,20 urea,21 amberlyst-A21,22 piperidine,
23
[Dsim]AlCl4,24 isonicotinic acid,25 EDDF,26 triethylamine,27 1-butyl-3-methylimida-
zolium tetrafluoroborate,28 Ba(OH)2,29 L-proline,30 c-alumina,31 per-6-amino-b-cyclo-
dextrin,32 molecular sieves,33 NaBr,34 b-CD,35 polystyrene supported p-toluenesulfonic
acid,36 ZrO2-NPs,37 NFS-PWA,38 DES,39 PPI40 and Fe-CaOx/glutamic acid.41
Despite considerable progress, the need for the greener synthesis of biologically
active molecules has emerged. The use of natural catalysts in organic synthesis offers
many advantages in sustainable chemistry because the catalysts are inexpensive, readily
available, non-toxic and show high selectivity.
In continuation of our interest in the development of synthetic methodologies for
organic transformations,42–55 We now report on the use of snail shell, abundant in
Morocco, as a natural catalyst. In the present work, we describe the synthesis of 1,4-
dihydropyrano[2,3-c]pyrazoles using snail shell as a biocatalyst (Scheme 1).
Received June 1, 2018; in final form July 19, 2019.
Address correspondence to Said Boukhris, Laboratory of Organic, Organometallic and
Theoretical Chemistry, Faculty of Sciences, Ibn Tofaïl University, BO 133, 14000 Kenitra,
Morocco. E-mail: nsboukhris@yahoo.com
1

2
Boukhris et al.
Scheme 1. Synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles 5a-k in the presence of snail shell.
Snail shells are widely available as waste products in Morocco. Snail shells were col-
lected, cleaned, and dried in an oven at 100 ꢀC for 24h. The shells, thus obtained without
resorting to expensive calcination, were crushed into a white soft powder. The latter
material has been fully characterized by X-ray diffraction, by scanning electron micros-
copy, by FT-IR and by measuring the specific surface area.52
To study the catalytic activity of the snail shell powder in the synthesis of dihydro-
pyranopyrazoles, we began the process of optimization of reaction conditions. For this,
we chose a four-component condensation reacting p-chloro benzaldehyde 1a, malononi-
trile 2, ethyl acetoacetate 3, and hydrazine 4 as a model reaction. We used different sol-
vents and various amounts of the catalyst at room temperature (Scheme 1). No product
formation was observed when the mixture was stirred in ethanol in the absence of snail
shell, even after 180 min (Table 1, entry 1).
We sought to find the effect of different solvents (MeOH, EtOH, CH3CN, butanol,
AcOEt, THF and DMF) for the four component coupling protocol (Table 1). The reac-
tion using MeOH or EtOH gave the corresponding product 5a (Ar ¼ 4-ClC6H4) in high
yields (Table 1, entries 10, 11). From the environmental point of view, EtOH was
chosen as the reaction medium for all further reactions. Different masses of snail shell
were then used at room temperature. From the results, it is clear that the best amount of
catalyst for this reaction at 1 mmole scale in the given conditions is 0.05 g (Table 1,
entry 11).
It is fundamental to examine the evolution turnover number (TON) and turnover fre-
quency (TOF) as a function of the catalyst mass used, for the pilot reaction. Table 1
presents these values.
The separation of the catalyst and isolation of the desired product from the reaction
mixture is one of the most crucial aspects of organic synthesis. In our protocol, after
completion of the reaction, the crude mixture was dissolved in EtOH (2 mL), and the
catalyst was recovered by simple filtration, washed with ethanol and dried. For this pur-
pose, the reusability of the catalyst was tested for the synthesis of 5a applying the
developed protocol. The catalyst was found to be reusable for at least ten cycles without
any severe loss of activity (Table 2).
We also investigated the structural stability of the snail shell catalyst by comparing
its FT-IR spectra before and after the synthesis of dihydropyrano[2,3-c]pyrazole 5a. We
could see that these spectra were nearly identical, indicating that the snail shell was
structurally stable under the applied reaction conditions; and the spectra remained simi-
lar through ten catalytic cycles.
We examined the scope of our procedure, and the results are presented in Table 3.
The condensation of aldehydes 1 with malononitrile 2, ethyl acetoacetate 3, and hydra-
zine provided the corresponding 1,4-dihydropyrano[2,3-c]pyrazoles 5a-k with remark-
able time savings (8-30 min), excellent yields (90-99%) and high purities.
Based on the obtained results and the literature survey, we suggest a mechanism
for these reactions using our catalyst (Scheme 2).

1,4-Dihydropyrano[2,3-c]pyrazoles
3
Table 1
Screening of the Reaction Conditions for the Synthesis of 5aa
Time
Entry
Catalyst (g)
Solvent (1 mL)
(min)b
TON
TOF
Yield (%)c
1
2
3
4
5
6
7
8
–
EtOH
EtOH
MeOH
Butanol
THF
180
10
10
10
10
7
15
10
15
15
15
15
15
15
20
Trace
96
97
73
76
83
69
85
37
98
97
97
96
95
90
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.02
0.05
0.05
0.1
64
64.67
48.67
50.67
55.33
46
56.67
185
196
194
97
96
47.5
36
376,47
380.41
286.29
298.05
472.90
184
333.35
740
784
776
388
384
190
AcOEt
DMF
CH3CN
MeOH
MeOH
EtOH
MeOH
EtOH
EtOH
EtOH
9
10
11
12
13
14
15
0.1
0.2
0.25
109.09
aReaction conditions: p-chlorobenzaldehyde (1a, 1 mmol), malononitrile (2, 1 mmol), ethyl
acetoacetate (3, 1 mmol) and hydrazine hydrate (4, 1 mmol), snail shell (50 mg), r.t.
bTime reported in min monitored by thin layer chromatography (TLC).
cIsolated yield.
Scheme 2. A plausible mechanism for the formation of 1,4-dihydropyrano[2,3-c]pyrazoles 5.
Given the well-documented ease of formation of pyrazolones,59 it seems likely that
pyrazolone A is easily formed by the condensation of hydrazine and ethyl acetoacetate.
As previously known, aragonite is plentiful in our catalyst.52 Thus the carbonate ion in
aragonite catalyzes the Knoevenagel condensation of malononitrile and an aldehyde
(potentially activated by Ca2þ of the catalyst) to form arylidenemalononitrile as the

4
Boukhris et al.
Table 2
Reusability of Snail Shell Biocatalyst for the
Synthesis of Compound 5a
Runa
Yield (%)b
1
2
3
4
5
6
7
8
9
10
98
96
94
91
90
87
85
84
84
83
aTypically, 48 mg of catalyst was recovered
from an individual run.
bIsolated yields.
Table 3
Synthesis of Compounds 5a-k
M.p (ꢀC)
Obs. Lit.
Entry Product
Ar
Time (min) Yield %
1
2
3
4
5
6
5a
5b
5c
5d
5e
5f
4-ClC6H4
2-ClC6H4
15
20
20
20
8
98
92
96
94
99
91
92
90
96
95
96
244-246 244-24636,56
144-146 144-14636,56
4-MeC6H4
4-MeOC6H4
4-NO2C6H4
2,4-Cl2C6H3
C6H5
175-177
211-213
175-17736
211-21336
250-252 250-25256,57
20
15
30
10
12
15
229-230
164-166
176-178
229-23057
164-16636
176-17836
7
8
9
5g
5h
5i
2-furyl
3-NO2C6H4
4-HOC6H4
4-N(Me)2C6H4
213-215 214-21656,57
10
11
5j
5k
222-224
167-169
223-22558
168-16958
aIsolated yields.
intermediate B. Next, the Michael addition of the enolized pyrazolone to the aryliden-
malononitrile is carried out to produce the intermediate C. Finally, the corresponding
product is formed by tautomerization of the intermediate C.60
It is useful to compare the catalytic activity of our catalyst with those reported in
the literature.39,40,58,61–65 We find that our catalytic system is noteworthy in terms of
short time and high efficiency (Table 4).
In summary, a catalyst derived from snail shells proved to be extremely effective
in the four-component synthesis of pyranopyrazole derivatives via the one-pot reaction
of aromatic aldehydes, ethyl acetoacetate, hydrazine, and malononitrile. The merits for
the presented methodology are its biodegradability, excellent product yields, short reac-
tion times and ease of product isolation.

1,4-Dihydropyrano[2,3-c]pyrazoles
5
Table 4
Comparison of Our Studies with Reported Works
Time
(min)
Yield
(%)
Catalyst
Conditions
10 mol %, 5 mL H2O, 80 ꢀC
SiO2NPs61
NH4H2PO4/Al26O33
Nano-CuFe2O4
NMPs64
30-40
15-20
120-180 88-97
15-90
8-15
40-150
20
5-40
8-30
87-94
74-91
62
0.03 g, 3 mL EtOH, reflux
8 mol %, 5 mL H2O, 60 ꢀC
0.007 g, solvent-free, r.t
2 mg, H2O, 60 ꢀC
85-98
90-98
73-91
71-91
52-96
90-99
NMIL65
58
Ca9.5 Mg0.5(PO4)5.5F1.5
DES39
2 mol %, 8 mL H2O-EtOH (1:1), 70 ꢀC
5 mL, 80 ꢀC
PPI40
20 mol%, 5 mL EtOH, reflux
0.05 g, 1 mL EtOH, r.t
Snail shell
Experimental Section
All the chemicals used were purchased from Sigma-Aldrich and were used as received.
All products are known, and were identified by comparison of spectral and physical
data with the literature. Melting points were taken on a KOFLER hot stage apparatus
and are uncorrected. Powder X-ray diffraction (XRD) measurements were performed
using a panalytical x'pert pro diffractometer. Scans were taken with a 2h with an incre-
ment of 0.03ꢀ ranging from 10ꢀ to 90ꢀ using Cu Ka radiation source generated at 45 kV
and 40 mA. Please see our previous work52 for the complete physical characterization
of the catalyst. Data are available from the corresponding author upon request.
Elemental analyses were performed on a Perkin Elmer 2400 Serie II CHNS/O micro-
1
analyzer. FTIR spectra were recorded on an Equinox 55 spectrometer. H NMR spectra
were recorded on a Bruker 300-MHz spectrometer in DMSO-d6.
Typical Procedure for the Preparation of Snail Shell Catalyst (Aragonite)
Snail shells, products from cuisine, were collected, cleaned, and dried at 100ꢀC for 24h.
The shells obtained, without calcinations, were crushed into white soft powder. It is import-
ant to note that good activity was obtained without the costly process of calcination.
General Procedure for the Synthesis of 1,4-dihydropyrano[2,3-c]pyrazoles 5a-k
To a solution of aldehyde 1 (1mmol), malononitrile 2 (1mmol), ethyl acetoacetate 3
(1mmol) and hydrazine hydrate 4 (1mmol) in EtOH (1mL), was added the snail shell cata-
lyst (0.05 g). The mixture was then stirred at room temperature. The progress of the reac-
tion was monitored by TLC (Solid phase: silica gel. Eluent: ethyl acetate:n-hexane, 2:8,
v:v). After completion of the reaction, the crude mixture was dissolved in EtOH (2mL),
and the catalyst was recovered by filtration. The filtrate was cooled in ice water. The result-
ing solid precipitate was recrystallized from ethanol to give pure 1,4-dihydropyrano[2,3-
c]pyrazoles 5a-k in high yields. All products prepared are known compounds and identified
by comparison of their 1H NMR spectra and melting points with authentic samples
reported in literature.36,56,57 In order to recover the catalyst, the filtrate was dried under

6
Boukhris et al.
reduced pressure, and the recovered catalyst was washed with ethanol (2mL) and reused
after drying. Typically, 48 mg of catalyst was recovered from an individual run.
6-Amino-4-(4-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5a)
1H NMR (300 MHz, DMSO-d6) d ppm 12.10 (s, 1H, NH), 7.20-7.22 (d, 2H,
J ¼ 8.40 Hz, Ar-H), 7.36-7.38 (d, 2H, J ¼ 8.40 Hz, Ar-H), 6.79 (s, 2H, NH2), 4.52 (s,
1H, CH), 1.76 (s, 3H, CH3).
Anal. Calcd for C14H11ClN4O: C, 58.62; H, 3.90; N, 19.53. Found: C, 58.62; H,
3.88; N, 19.56.
6-Amino-4-(2-chlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5b)
1H NMR (300 MHz, DMSO-d6): d ppm 11.98 (s, 1H, NH), 7.16-7.24 (m, 1H, Ar-H),
7.28-7.34 (m, 2H, Ar-H), 7.40 (dd, 1H, J ¼ 6.9, 0.9 Hz, Ar-H), 6.71 (s, 2H, NH2), 5.06
(s, 1H, CH), 1.75 (s, 3H, CH3).
Anal. Calcd for C14H11ClN4O: C, 58.65; H, 3.87; N, 19.54. Found: C, 58.46; H,
3.79; N, 19.73.
6-Amino-3-methyl-4-(p-tolyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5c)
1H NMR (300 MHz, DMSO-d6): d ppm 12.05 (s, 1H, NH), 6.98 (d, 2H, J ¼ 8.4 Hz,
Ar–H), 7.12 (d, 2H, J ¼ 7.6 Hz, Ar–H), 6.79 (s, 2H, NH2), 4.51 (s, 1H, CH), 2.24 (s,
3H, CH3), 1.76 (s, 3H, CH3).
Anal. Calcd for C15H14N4O: Calculated. C 67.65, H 5.32, N 21.05; found C 67.64,
H 5.30, N 21.03.
6-Amino-4-(4-methoxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5d)
1H NMR (300 MHz, DMSO-d6): d ppm 12.06 (s, 1H, NH), 7.30-7.32 (d, 2H,
J ¼ 7.96 Hz, Ar-H), 7.76-7.78 (d, 2H, J ¼ 8.67 Hz, Ar-H), 6.61 (s, 2H, NH2), 4.51 (s,
1H, CH), 3.80 (s, 3H, OCH3), 1.76 (s, 3H, CH3).
Anal. Calcd for C15H14N4O2: C, 63.82; H, 5.00; N, 19.85. Found: C, 63.77; H,
5.07; N, 19.65.
6-Amino-3-methyl-4-(4-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5e)
1H NMR (300 MHz, DMSO-d6): d ppm 11.69 (s, 1H, NH), 7.68-7.97 (d, 2H,
J ¼ 8.48 Hz, Ar-H), 8.21-8.23 (d, 2H, J ¼ 8.48 Hz, Ar-H), 7.81 (s, 2H, NH2), 4.74 (s,
1H, CH), 2.18 (s, 3H, CH3).
Anal. Calcd for C14H11N5O3: C, 56.57; H, 3.73; N, 23.56. Found: C, 56.53; H,
3.75; N, 23.43.

1,4-Dihydropyrano[2,3-c]pyrazoles
7
6-Amino-4-(2,4-dichlorophenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5f)
1H NMR (300 MHz, DMSO-d6): d ppm 12.15 (s, 1H, NH), 7.20-7.89 (m, 3H, ArH),
6.98 (s, 2H, NH2), 5.03 (s, 1H, CH), 1.76 (s, 3H, CH3).
Anal. Calcd for C14H10Cl2N4O: C, 52.36; H, 3.14; N, 17.45. Found: C, 52.02; H,
2.99; N, 17.38.
6-Amino-3-methyl-4-phenyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5g)
1H NMR (300 MHz, DMSO-d6): d ppm 11.95 (s, 1H, NH), 7.14-7.24 (m, 3H, Ph-H),
7.28-7.33 (m, 2H, Ph-H), 6.63 (s, 2H, NH2), 4.57 (s, 1H, CH), 1.77 (s, 3H, CH3).
Anal. Calcd for C14H12N4O: C, 66.65; H, 4.79; N, 22.21. Found: C, 66.67; H, 4.75;
N, 22.21.
6-Amino-4-(furan-2-yl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5h)
1H NMR (300 MHz, DMSO-d6): d ppm 12.14 (s, 1H, NH), 7.51 (s, 2H, NH2), 6.15 (d,
1H, J ¼ 3.0 Hz, furan-H), 6.37-6.39 (m, 1H, furan-H), 7.50 (t, 1H, J ¼ 0.9 Hz, furan-H),
4.75 (s, 1H, CH), 1.95 (s, 3H, CH3).
Anal. Calcd for C12H10N4O2: C, 59.50; H, 4.16; N, 23.13. Found: C, 59.70; H,
4.24; N, 23.32.
6-Amino-3-methyl-4-(3-nitrophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5i)
1H NMR (300 MHz, DMSO-d6): d ppm 12.14 (1H, s, NH), 7.56 (t, 1H, J ¼ 8.0 Hz, Ar-
H), 7.61 (d, 1H, J ¼ 7.6 Hz, Ar-H), 8.00-8.04 (m, 2H, Ar-H), 6.93 (s, 2H, NH2), 4.61
(s, 1H, CH), 1.17 (s, 3H, CH3).
Anal. Calcd for C14H11N5O3: C, 56.57; H, 3.73; N, 23.56. Found: C, 56.53; H,
3.75; N, 23.43.
6-Amino-4-(4-hydroxyphenyl)-3-methyl-2,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5j)
1H NMR (300 MHz, DMSO-d6): d ppm 12.10 (s, 1H, NH), 7.23-7.25 (d, 2H,
J ¼ 8.40 Hz, Ar–H), 7.34-7.39 (d, 2H, J ¼ 8.40 Hz, Ar-H), 6.90 (s, 1H, OH), 6.78 (s,
2H, NH2), 4.86 (s, 1H, CH), 1.83 (s, 3H, CH3).
Anal. Calcd for C14H12N4O2: C, 62.65; H, 4.50; N, 20.87. Found: C, 62.70; H,
4.52; N, 20.88.
6-Amino-3-methyl-4-(4-N,N-dimethylanimophenyl)-2,4-dihydropyrano[2,3-c]pyrazole-
5-carbonitrile (5k)
1H NMR (300 MHz, DMSO-d6): d ppm 11.87 (s, 1H, NH), 6.55 (d, 2H, J ¼ 8.4 Hz, Ar-
H), 6.93 (d, 2H, J ¼ 8.4 Hz, Ar-H), 6.68 (s, 2H, NH2), 4.55 (s, 1H, CH), 2.79 (s, 6H,
CH3), 1.81 (s, 3H, CH3).
Anal. Calcd for C16H17N5O: C, 65.10; H, 5.81; N, 23.70. Found: C, 65.11; H, 5.80;
N, 23.72.

8
Boukhris et al.
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