Zn(ANA)2Cl2 complex as efficient catalyst for the synthesis of dihydropyrano[2,3-c]pyrazoles in aqueous medium via one-pot multicomponent reaction: a green approach

Article abstract of DOI:10.1080/00397911.2018.1506034

The first example of recyclable Zn(ANA)₂Cl₂ catalyzed tandem one-pot three-component protocol reaction between aromatic aldehydes, malononitrile, and phenylmethylpyrazolone to furnish 4-substituted-1,4-dihydropyrano[2,3-c]pyrazole-5-

Full text of DOI:10.1080/00397911.2018.1506034

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Zn(ANA)2Cl2 complex as efficient catalyst for the
synthesis of dihydropyrano[2,3-c]pyrazoles in
aqueous medium via one-pot multicomponent
reaction: a green approach
Ramaiah Konakanchi, Venkata Bharat Nishtala, Shravankumar Kankala &
Laxma Reddy Kotha
To cite this article: Ramaiah Konakanchi, Venkata Bharat Nishtala, Shravankumar Kankala
& Laxma Reddy Kotha (2018) Zn(ANA)2Cl2 complex as efficient catalyst for the synthesis of
dihydropyrano[2,3-c]pyrazoles in aqueous medium via one-pot multicomponent reaction: a green
approach, Synthetic Communications, 48:20, 2642-2651, DOI: 10.1080/00397911.2018.1506034
To link to this article: https://doi.org/10.1080/00397911.2018.1506034
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SYNTHETIC COMMUNICATIONSV
2018, VOL. 48, NO. 20, 2642–2651
https://doi.org/10.1080/00397911.2018.1506034
Zn(ANA)2Cl2 complex as efficient catalyst for the synthesis
of dihydropyrano[2,3-c]pyrazoles in aqueous medium via
one-pot multicomponent reaction: a green approach
Ramaiah Konakanchia, Venkata Bharat Nishtalaa, Shravankumar Kankalab, and
Laxma Reddy Kothaa
b
aDepartment of Chemistry, National Institute of Technology, Warangal, Telangana, India; Department
of Chemistry, Kakatiya University, Warangal, Telangana, India
ABSTRACT
ARTICLE HISTORY
Received 17 June 2018
The first example of recyclable Zn(ANA)2Cl2 catalyzed tandem one-
pot three-component protocol reaction between aromatic aldehydes,
malononitrile, and phenylmethylpyrazolone to furnish 4-substituted-
1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (4a–l) in a short reac-
tion time (ꢀ10 min) in aqueous media at room temperature is
described.
KEYWORDS
dihydropyrano[2,3-c] pyra-
zole; green chemistry;
multi-component reaction;
Zn (ANA)2Cl2 catalyst
GRAPHICAL ABSTRACT
CHO
N
Zn
NH
2
CH
N
3
Cl
Cl
H2N
N
N
Ar
O
O
CH
N
3
OHC
Ph
NC
Water, RT, 5-10 min.
O
N
H N
2
CN
Ph
N
Ar
H
Yield upto 95%
12 examples
Introduction
Pyranopyrazole is a fused heterocycle comprised of pyrazole and pyran rings, which are
known as the substructural units of several biologically active compounds. These hetero-
cycles play an important role in medicinal chemistry[1,2] because of the many biological
evaluations like anti-inflammatory,[3] antidepressant, anti-pyretic, anti-fungal, analgesic,
anti-HIV,[4] antimicrobial,[5] anticancer[6] inhibition of human Chk1 kinase activities,[7]
photoactive materials,[8] and also find applications as pharmaceutical ingredients and
CONTACT Laxma Reddy Kotha
Technology, Warangal, Telangana 506004, India; Shravankumar Kankala
of Chemistry, Kakatiya University, Warangal, Telangana 506009, India.
laxmareddychem12@gmail.com
Department of Chemistry, National Institute of
shravankankala@yahoo.com Department
Supplemental data for this article can be accessed on the publisher’s website.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc
ß 2018 Taylor & Francis Group, LLC

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SYNTHETIC COMMUNICATIONSV
2643
biodegradable agrochemicals.[9] One of the main challenges in medicinal chemistry is
the design and synthesis of these poly functionalized heterocycles.
Owing to their broad spectrum of biological evolutions, the synthesis of title com-
pounds are still of interest. A number of methodologies were improved for the synthesis
of these compounds via three- or four- component reactions by using different catalysts
like amberlyst,[10] nano MgO,[11] L-proline,[12] sodium benzoate,[13] triethylamine,
b-cyclodextrin,[14] morpholine, piperidine, cetyltrietyl ammonium chloride, glycine,[7b]
ZnAl2O4NPs,[15] lemon juice,[16] cerium ammonium nitrate,[17] silica coated magnetic
NiFe2O4 nanoparticles supported H3PW12O40 (NFSPWA),[18] uncapped SnO2 quantum
dots.[19] Nevertheless, some of these methodologies have suffered from high-reaction
times, low yields, usage of toxic and expensive catalyst, strong basic conditions and dif-
ficult isolation procedure of the product. According to the literature, the synthesis of
dihydropyrano[2,3-c]pyrazoles by using reusable Zn-complex as catalyst are less
investigated.
Multicomponent reaction (MCR) is one type of modern perspective emerged in
organic synthesis, wherein three or more than three components react in one-pot
through sequential reactions and provides selectively the desired product by reducing
the waste. Various environmentally benign conditions are developed for the synthesis of
these heterocyclic organic compounds. Water is growing as a competitive reaction
media along with the other organic media like ionic liquid, ethanol, PEGs, in green
organic synthesis because of its benefits like high reaction rate, isolation by simple filtra-
tion and by considering its green credentials.[20] MCRs are indeed cost-effective, time-
saving, and environmentally benign as compared to step-by-step reactions of traditional
organic synthesis one-pot without isolating the intermediate from three or more sub-
strates[21] in achieving the desired final/target product.[14]
Hence, MCRs become a very useful tool in the drug discovery[10] along with the
environmentally benign solvents and a reusable catalyst creates a great scope for the
chemists to prevent the environmental contamination. Majority of MCRs require a
multifunctional catalyst to control the selectivity in the sequential reactions. At present,
catalyzed MCRs are in common practice to synthesize a variety of heterocycles and het-
eroatomic organic compounds. In line of these precedents, the use of zinc-based cata-
lysts (homogeneous/heterogeneous) and reagents would be a good choice to meet the
requirements of green chemistry.[22] We are interested in developing a facile MCR
protocol to synthesize pyranopyrazoles in view of their intriguing applications in medi-
cinal and materials chemistry. The use of a variety of catalysts has been reported previ-
ously to synthesize various 4-substituted-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
via traditional organic synthesis or MCR synthesis. This manuscript describes a facile
route for the synthesis of dihydropyrano[2,3-c]pyrazole (4a–l) efficiently via one-pot,
three-component reaction by using Zn(ANA)2Cl2 complex as a reusable efficient catalyst
with good to excellent yields in water at room temperature.
Results and discussion
In development of our research work in the fields of (i) MCRs[23] and (ii) NHCs[24]
herein, we report for the first time the use of Zn(ANA)2Cl2 as a catalyst that was

2644
R. KONAKANCHI ET AL.
Cl
H
Cl
H
H
H
N
Zn
N
N
N
O
Figure 1. Zn(ANA)2Cl2 used in the present work.
Table 1. Optimization of reaction conditions for the synthesis 4aa.
Entry
Catalyst (mol%)
Temperature (˚C)
Timeb
Yield (%)c
1
2
3
4
5
6
7
8
No catalyst
Zn(BF4)2
Zn(OTf)2
ZnBr2
Zn(NO3)2
Cu(OAc)2
CuBr2
Zn(ANA)2Cl2 (5 mol%)
Zn(ANA)2Cl2 (10 mol%)
Zn(ANA)2Cl2 (15 mol%)
Zn(ANA)2Cl2 (20 mol%)
Zn(ANA)2Cl2 (10 mol%)
Zn(ANA)2Cl2 (10 mol%)
Zn(ANA)2Cl2 (10 mol%)
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
60
80
60 min.
45 min.
45 min.
30 min.
30 min.
30 min.
30 min.
12 min.
5 min.
8 min.
7 min.
10 min
5 min.
5 min.
Trace
40
35
25
35
Trace
Trace
79
88
85
85
88
83
80
9
10
11
12
13
14
aAll the reactions were carried out by using benzaldehyde 1a (1 mmol), malononitrile 2 (1 mmol) and 3-Methyl-1-phe-
nyl-2-pyrazoline-5-one 3 (1 mmol) in water at room temperature to synthesize the compound 4a. bProgress of the
c
reaction was monitored by TLC. Isolated yields.
prepared by using the literature procedure.[25] The Zn(ANA)2Cl2 catalyst is shown in
Figure 1.
In preliminary experiments, the three-component sequential one-pot reaction (MCR)
between benzaldehyde (1a), malononitrile (2), and 3-methyl-1-phenyl-2-pyrazoline-5-
one (3), in water as a solvent at room temperature, and the scope of a variety of poten-
tial catalyst materials. The details of the reaction and the results are given in Table 1.
There was no MCR sequence observed without any catalyst (Table 1, entry 1). Later, we
have investigated the above MCR in the presence of different zinc and copper salts
including Zn(BF4)2, Zn(OTf)2, ZnBr2, Zn(NO3)2, (Table 1, entries 2–5) and copper salts
Cu(OAc)2 and CuBr2 as catalysts (Table 1, entries 6, 7) at RT conditions. However,
when 5 mol% of Zn(ANA)2Cl2 was employed as a catalyst, then the product 4a (Scheme
1) formed with the yield 79% in 12 min. (Table 1, entry 8). After that, the same reaction
was carried out by using 10, 15, and 20 mol % of Zn(ANA)2Cl2 catalyst, the results
were impressive producing the substituted dihydropyrano[2,3-c]pyrazoles (4a) selectively
and at room temperature in good yields at different times (Table 1, entries 8–11). The
catalyst with 10 mol% was the best catalyst in water resulting in high yields with less
reaction time (Table 1, entry 9). Continuing the work, we have also investigated the
above MCR to get the optimized reaction condition, the reaction further proceeded
with 10 mol% of Zn(ANA)2Cl2 catalyst for 30 min (Table 1, entry 12) without any
increased yields. There was also no progress in the above MCR when carried out at dif-
ferent temperatures (Table 1 entries 13, 14). The catalyzed MCRs of the present study

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SYNTHETIC COMMUNICATIONSV
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Ar
CN
NH
CN
CN
O
Zn(ANA) Cl
2
Water/ rt
2
+
N
O
N
+
N
Ph
Ar
N
O
2
Ph
1a
2
3
4a
Scheme 1. The synthetic pathway of compounds 4a.
Table 2. Recyclability studies of the catalyst (Zn(ANA)2Cl2 complex).
S. No.
Cycle No.
Reaction time (min.)a
Yield (%)b
1
2
3
4
5
1
2
3
4
5
5
5
8
8
10
86
86
85
85
80
aReaction progress was monitored by TLC. bIsolated yield.
in water are found to be slightly exothermic in the beginning as observed in other
works. It is also important to note that the above-catalyzed reaction was observed to be
sluggish and non-selective in non-protic solvents, THF, CH3CN, and CH2Cl2, and
finally ended up with a mixture of products. This information outlines that the choice
of solvent is also one of the key factors in this catalyzed MCR.
In order to recycle the Zn(ANA)2Cl2, the reaction mixture was filtered and the resi-
due was quenched two times with ethyl acetate to separate the crude product after the
first catalytic run. The water layers are dried and reused for the next catalytic runs. It
has been noticed that up to four successive catalytic runs yields dihydropyrano[2,3-
c]pyrazoles that are almost in the close range (entries 1–4 of Table 2) and there was no
considerable agglomeration of Zn(ANA)2Cl2. However, the yields were slowly reduced
from the fifth cycle (entry 5 of Table 2) due to increasing the operation time. This is
attributed to the decrease of multi-component activity of the catalyst due to the percent-
age of catalyst and metal deposition, which inhibits the activity of active sites of the
catalyst. The recyclability studies of the catalyst were shown in Table 2.
Employing the same reaction conditions for the synthesis of 4a (RT, Zn(ANA)2Cl2
(10 mol%, 5 min, water), we investigated the scope of the reaction with a variety of struc-
turally different aldehydes (1b–l) in combination with malononitrile (2) and 3-methyl-1-
phenyl-2-pyrazoline-5-one (3) for the three component condensation reaction. The
results are depicted in Table 3. The substrates of MCR bearing electron donating or elec-
tron-withdrawing groups on the aromatic ring proceeded smoothly and formed the cor-
responding substituted dihydropyrano[2,3-c]pyrazoles in good yields (85–95%) under the
chosen conditions. This reaction was considered as a green reaction because of its mild
reaction condition, usage of environmental benign solvent, and reusable catalyst.
Based on previous reports and current results in the MCR synthesis of
Pyranopyrazole (4), a plausible mechanism is proposed and depicted in Scheme 2,
which involves a domino Michael addition-tautomerism-O-cyclization sequence of reac-
tions. The reaction may proceed via forming chelation between phenylmethylpyrazolone
and Zn(ANA2Cl2 complex (A), and which then reacts with alkylidenemalononitrile (B)
(Knoevenagel condensed product of an aldehyde with malononitrile) to give

2646
R. KONAKANCHI ET AL.
Table 3. Time and yields for the formation of dihyhdropyrano[2,3-c]pyrazoles 4a-l.
Ar
CN
NH
CN
CN
2
H
Catalyst
Water/ rt
N
+
O
+
N
N
N
Ph
O
Ar
O
2
Ph
3
1a-1
4a-l
(time, yield)a,b,c
NO
CH
2
3
CH
3
NO
CN
2
2
H C
3
H C
3
H C
3
CN
NH
CN
NH
H C
3
N
N
N
N
CN
NH
N
NH
O
O
2
N
N
O
2
N
O
2
4c
4b
4d
4a
(8 min., 91)
(7 min., 93)
(10 min., 85)
Cl
(5 min., 86)
CN
OH
Cl
Cl
CN
H C
3
H C
H C
H C
3
3
3
CN
NH
CN
NH
CN
NH
N
N
N
N
N
N
N
N
NH
O
2
O
2
O
2
O
2
4e
4g
4f
4g
(11 min., 89)
(10 min., 89)
OH
(11 min., 86)
OCH
(7 min., 87)
Br
NO
3
2
O
H C
3
H C
3
H C
3
H C
H C
3
3
CN
NH
CN
NH
CN
NH
CN
NH
N
N
N
N
N
N
N
N
2
O
O
2
O
2
2
O
4l
(6 min., 95)
4k
(10 min., 85)
4j
4i
(10 min., 87)
(9 min., 88)
aAll the reactions were carried out by using aromatic aldehydes 1a-l, malononitrile 2 and 3-methyl-1-phenyl-2-pyrazo-
line-5-one 3 as starting material in water with the Zn(ANA)2Cl2 complex as catalyst. bProgress of the reaction was
c
monitored by TLC. Isolated yields (%)
intermediate (C) (Michael adduct). The Michael adduct then undergoes O-cyclization to
give Pyranopyrazoles (4).
Structures of the substituted dihydropyrano[2,3-c]pyrazoles (4a–l, Table 3) were
established and in good agreement on the basis of elemental analysis and spectral data
(1H NMR and 13C NMR). The details of the product characterization are presented in
the section Experimental and ESI.
Experimental
Instruments employed
All the melting points were recorded on Stuart SMP30. Elemental analyses were per-
formed on a Carlo–Erba model EA 1108 analytical unit (Triad, NJ, USA), and the

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SYNTHETIC COMMUNICATIONSV
2647
H
Cl
O
H
N
Zn
N
Cl
Ar
Ar
CN
CN
N
N
H
O
O
N
H
O
NC
O
N
Ph
Ph
N
N
N
(B)
N
N
(A)
H
C
Ar
CN
Ph
O
O
HN
N
H
N
Cl
N
H
Ar
O
Zn
N
H
CN
O
Cl
H
N
N
(C)
NH2
Ph
Scheme 2. Possible mechanism for the formation of pyranopyrazole via catalyzed by Zn(ANA2Cl2).
1
values are within 0.4% of theoretical values. H and 13C NMR spectra were recorded
on a Bruker Avance III 400 MHz spectrometer, using DMSO-D6 with TMS as the
internal reference and the chemical shift values were reported in ppm. Progress reaction
progress and purity were monitored by thin-layer chromatography (E. Merck, Mumbai,
India). Unless otherwise stated, all chemicals and solvents used were of high grade and
purchased from Sigma Aldrich and Spectrochem.
General procedure for the synthesis of the dihydropyrano[2,3-c]pyrazoles 4a-l
A mixture of aromatic aldehydes (1 mmol), malononitrile (1 mmol) and 3-methyl-1-phe-
nyl-2-pyrazoline-5-one (1 mmol) was stirred with water at room temperature in the
presence of 10 mol% of Zn(ANA)2Cl2 complex for an appropriate time to produce dihy-
dropyrano[2,3-c]pyrazoles. Reaction progress was monitored by TLC. After completion
of the reaction, the product was filtered. The residue was washed with ethyl acetate.
The ethyl acetate was evaporated under vacuum and the obtained solid was purified by
recrystallization process in ethyl acetate.
Spectral data of the compound 4a
6-amino-3-methyl-1,4-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile
(4a).
Colour: White solid; M. P.: 168–170 ꢁC; Anal. Calcd. For C20H16N4O: C, 73.15; H, 4.91;
1
N, 17.06; found: C, 73.37; H, 4.98; N, 17.29. H NMR (DMSO-d6, 400 MHz) d: 1.79 (s,
3H), 4.89 (s, 1H), 7.22–7.36 (m, 8H), 7.5 (d, 2 H, J ¼ 7.6 Hz), 7.8 (d, 2 H, J ¼ 7.6 Hz).
13 C NMR (100 MHz, DMSO) d: 159.90, 145.75, 144.36, 144.08, 138.02, 129.80, 129.00,
128.25, 127.52, 126.63, 120.43, 99.11, 58.68, 37.23, 13.03.
Conclusions
In conclusion, we have demonstrated the usefulness of a cheaper, low toxic, reusable,
and environmentally benign zinc metal complex, Zn(ANA)2Cl2 as a catalyst in the

2648
R. KONAKANCHI ET AL.
MCR. A room temperature, simple, clean, efficient and atom-economical one-pot multi-
component protocol between aromatic aldehyde, malononitrile, and phenylmethylpyra-
zolone to produce a variety of 4-substituted-1,4-dihydropyrano[2,3-c]pyrazole-5-
carbonitrile in excellent yields. The use of water has not only favored the fast accom-
plishment of MCR at RT conditions, but also promoted the non-toxic solvents for green
chemical synthesis. This transformation presumably occurs via Knoevenagel condensa-
tion-Michael addition-tautomerism-intramolecular O-cyclization-elimination sequence
of reactions.
Further studies are warranted to address the nature of the active catalysts under these
conditions. Our results indicate that it is not necessary to introduce Zn(II) and other
bases/acidic catalyst precursors separately into MCR. The significant advantages of this
protocol include readily available substrates, short reaction time, easy workup, and no
column chromatographic purification (without any tedious workup or purification).
These advantages make this methodology facile and appropriate to create diverse libra-
ries. The presence of reactive ꢂ CN and ꢂ NH2 groups makes further transformations
toward more complex heterocycles.
Acknowledgments
RK thanks the MHRD, New Delhi for a senior research fellowship.
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