Caffeine as a Naturally Green and Biodegradable Catalyst for Preparation of Dihydropyrano[2,3-c]pyrazoles

Full text of DOI:10.1080/00304948.2020.1780883

Organic Preparations and Procedures International
The New Journal for Organic Synthesis
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Caffeine as a Naturally Green and
Biodegradable Catalyst for Preparation of
Dihydropyrano[2,3-c]pyrazoles
Farzaneh Mohamadpour
To cite this article: Farzaneh Mohamadpour (2020): Caffeine as a Naturally Green and
Biodegradable Catalyst for Preparation of Dihydropyrano[2,3-c]pyrazoles, Organic Preparations
and Procedures International, DOI: 10.1080/00304948.2020.1780883
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ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
https://doi.org/10.1080/00304948.2020.1780883
OPPI BRIEF
Caffeine as a Naturally Green and Biodegradable Catalyst
for Preparation of Dihydropyrano[2,3-c]pyrazoles
Farzaneh Mohamadpour
School of Engineering, Apadana Institute of Higher Education, Shiraz, Iran
ARTICLE HISTORY Received 27 May 2019; Accepted 22 March 2020
The dihydropyrano[2,3-c]pyrazole structure is a common motif in a variety of useful
natural and non-natural products. For example these heterocyclic compounds have been
used as therapeutic agents.1 They are potential inhibitors of human Chk1 kinase,2 and
they have anticancer,3 molluscicidal4 and antimicrobial5 properties. The known proce-
dures for the synthesis of dihydropyrano[2,3-c]pyrazoles include the reaction of hydra-
zine hydrate and phenylhydrazine with malononitrile, three-component reactions of
aldehydes, malononitrile, and pyrazolones, and the cyclocondensation reactions of ethyl
acetoacetate, hydrazine hydrate, aldehydes and malononitrile.6, 7
Typically, the syntheses of these important compounds are catalyzed by ZrO2 nano-
particles,8 choline chloride/urea deep eutectic mixtures,9 isonicotinic acid,10 molecular
sieves,11 meglumine,12 CAPB,13 L-proline/KF-alumina,14 CTACl,15 lipase,16 bovine
serum albumin,17 b-cyclodextrin,18 morpholine triflate,19 TPSPPTNM,20 [Dabco-
H][AcO]21 and DABCO.22 All of these methodologies are attractive and have merits;
but common problems encountered are low yields, the toxicity of both solvents and cat-
alysts, harsh reaction conditions and expensive materials. Based on these considerations
and our interest in efficient and environmentally benign methodologies,23–30 we now
report a green, simple and efficient procedure for the multi-component synthesis
of dihydropyrano[2,3-c]pyrazole derivatives via the domino Knoevenagel-Michael
cyclocondensation reaction of ethyl acetoacetate, hydrazine hydrate, aryl aldehydes and
malononitrile; we used caffeine as a catalyst in aqueous ethanol and found good yields
and short reaction times.
To begin our study, the optimal conditions for this reaction (Scheme 1) were investi-
gated. Conducting the reaction for compound 5c, we examined catalyst loading, solvents,
and reaction times. The best result was obtained with 15 mol % of the caffeine as catalyst at
60 ꢀC in H2O/EtOH (1:1) and gave 5c in 25 min in 83% yield (Table 1, entry 5).
After optimizing the conditions, the scope of this process was studied by varying the
aldehyde component. The results of this study are presented in Table 2. The reaction
does not appear to be particularly sensitive to substrate structure, with good yields
generally observed for the reactions involving aryl aldehydes. In our hands, the process
was not satisfactory for aliphatic aldehydes. After completion of the reaction (as
CONTACT Farzaneh Mohamadpour
mohamadpour.f.7@gmail.com
School of Engineering, Apadana Institute of
Higher Education, Shiraz, Iran.
ß 2020 Taylor & Francis Group, LLC

2
F. MOHAMADPOUR
Scheme 1. Synthesis of dihydropyrano[2,3-c]pyrazole derivatives.
determined by thin layer chromatography), the solid product was collected by simple
filtration and the analytical sample was recrystallized from ethanol.
We made a comparison of caffeine’s catalytic ability in this process to those of previously
reported catalysts for this purpose, and the comparison can be seen in Table 3. Yields for
all of these processes tend to be good, with comparatively short reaction times. The princi-
pal advantage to using caffeine as a catalyst for this process is its ready availability, bio-
degradability and eco-friendliness. Another important advantage of our procedure is its
simplicity. We hope that the convenience of our method will lead to an increase in the
preparation of these useful compounds and further exploration of their applications.
Experimental section
Melting points of all compounds were determined using an Electrothermal 9100 appar-
1
atus and are corrected. HNMR spectra were recorded on a Bruker DRX-400 Avance
instrument with DMSO-d6 as solvent. All reagents and solvents were purchased from
Merck, Fluka and Acros chemical companies and were used without further purifica-
tion. Completion of the reaction was determined by thin layer chromatography (silica
gel, n-hexane/ethyl acetate 9/3).
General procedure for preparation of dihydropyrano[2,3-c]pyrazole derivatives
(5a-s)
Caffeine (15 mol%) was added to a mixture of ethyl acetoacetate (1, 1 mmol), hydrazine
hydrate (2, 1 mmol), aryl aldehyde (3, 1 mmol) and malononitrile (4, 1 mmol) in H2O/
EtOH (3 mL, 1:1) at 60 ꢀC. After completion of the reaction (as determined by TLC) the
mixture was cooled to rt, the precipitated product was filtered and washed with aqueous
ethanol. The crude material was purified by recrystallization from ethanol to afford the
desired product (5a-s). All of the compounds were known and were identified by com-
paring their corrected melting points with those in the literature cited. For the sake of
completeness, spectral data of selected products are given below.
6-Amino-3-methyl-4-phenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5c)
1
Yield: 83%; mp 246-248 ꢀC; H NMR (400 MHz, DMSO-d6): 1.79 (3H, s, CH3), 4.61
(1H, s, CHAr), 6.89 (2H, s, NH2), 7.18 (2H, d, J ¼ 9.2 Hz, ArH), 7.21-7.26 (1H, m,
ArH), 7.31-7.36 (2H, m, ArH), 12.11 (1H, s, NH).

ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL
3
Table 1. Optimization of the reaction condition on the synthesis of 5c.
Entry
Caffeine (mol %)
Catalyst free
Catalyst free
Solvent/Conditions
Time (min)
Isolated Yields (%)
trace
1
2
3
4
5
6
7
8
H2O/EtOH, rt
180
180
60
40
25
60
40
35
55
40
30
25
65
55
80
75
85
55
85
25
H2O/EtOH, 60 ꢀC
H2O/EtOH, 60 ꢀC
H2O/EtOH, 60 ꢀC
H2O/EtOH, 60 ꢀC
Solvent free, 60 ꢀC
H2O , 60 ꢀC
trace
27
59
83
34
52
57
34
48
62
74
38
42
27
35
28
49
26
83
5
10
15
15
15
15
15
15
15
15
15
15
15
15
15
15
15
20
EtOH, 60 ꢀC
MeOH,60 ꢀC
H2O/EtOH, rt
H2O/EtOH, 40 ꢀC
H2O/EtOH, 50 ꢀC
H2O, rt
EtOH, rt
MeOH, rt
THF, rt
CHCl3, rt
9
10
11
12
13
14
15
16
17
18
19
20
CH3CN, rt
CH2Cl2, rt
H2O/EtOH, 60 ꢀC
Table 2. Caffeine catalyzed synthesis of dihydropyrano[2,3-c]pyrazole derivatives.
Entry
R
Product
Time (min)
Isolated Yields (%)
mp ꢀC
Lit mpꢀC
1
2
3
4
5
6
7
8
2-OHC6H4
3-FC6H4
C6H5
5aa
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
25
20
25
35
25
20
35
30
30
35
35
20
30
20
35
35
30
25
25
80
89
83
79
84
86
72
81
82
77
76
83
85
86
78
81
78
87
85
209-211
241-243
246-248
235-237
208-210
244-245
221-223
228-230
188-190
221-223
224-226
192-194
211-213
248-250
227-229
180-182
246-248
248-250
206-208
210-21222
242-24312
244-24613
234-23512
210-21212
243-24412
220-22311
230-23112
188-19111
223-22413
225-22813
190-19313
210-21222
249-25012
229-23012
180-1818
245-24612
248-24912
205-20813
4-ClC6H4
4-OMeC6H4
2-O2NC6H4
4-OHC6H4
3-ClC6H4
3,4-(OMe)2C6H3
3-BrC6H4
3-OHC6H4
3-O2NC6H4
3,4,5-(OMe)3C6H2
2-OMeC6H4
2,4-Cl2C6H3
4-BrC6H4
9
10
11
12
13
14
15
16
17
18
19
2-ClC6H4
4-O2NC6H4
4-MeC6H4
5s
aDisplayed the characteristic infrared nitrile function band near 2250 cmꢁ1
.
6-Amino-4-(3-chlorophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile (5h)
1
Yield: 81%; mp 228-230 ꢀC; H NMR (400 MHz, DMSO-d6): 1.77 (3H, s, CH3), 5.08
(1H, s, CHAr), 7.19–7.45 (6H, m, ArH and NH2), 12.15 (1H, s, NH).

4
F. MOHAMADPOUR
Table 3. Comparison of catalytic ability some of catalysts reported in the literature for synthesis of
dihydropyrano[2,3-c]pyrazole derivatives.a
Entry
Catalyst
Conditions
Time/Yield (%)
References
1
2
3
4
5
6
7
8
ZrO2 NPs
EtOH/H2O,rt
5 min/95
10 min/95
30 min/90
1 h/84
15 min/95
4 min/96
10 min/87
12 min/80
240 min/89
1h/90
[8]
[9]
Choline chloride
Isonicotinic acid
Molecular sieves
Meglumine
CAPB
L-proline
KF-alumina
CTACl
Lipase
Caffeine
Urea Deep, 80 ꢀC
Solvent-free, 85 ꢀC
EtOH, Reflux
EtOH/H2O, rt
H2O,50-60 ꢀC
H2O, Reflux
[10]
[11]
[12]
[13]
[14]
[14]
[15]
[16]
This work
EtOH, Reflux
9
10
11
H2O,90 ꢀC
EtOH, 30 ꢀC
H2O/EtOH, 60 ꢀC
25 min/83
aBased on the four-component reaction of benzaldehyde, hydrazine hydrate, malononitrile and ethyl acetoacetate.
Acknowledgments
We gratefully acknowledge financial support from the Research Council of the Apadana Institute
of Higher Education.
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