An expedient four-component domino protocol for the regioselective synthesis of highly functionalized pyranopyrazoles and chromenopyrazoles via nitroketene-N,S-acetal chemistry under solvent-free condition

Article abstract of DOI:10.1016/j.tetlet.2014.02.019

Combinatorial library of pyranopyrazoles and chromenopyrazoles was regioselectively synthesized in excellent yield from ethylacetoacetate, hydrazinehydrate, substituted aldehyde/salicylaldehyde with nitroketene-N,S- acetal in the presence of piperidine under solvent-free condition (SFC) in an eco-benign manner. This novel strategy excludes tedious extraction, chromatographic separation and recrystallization processes. The final product could be obtained by simple filtration by the addition of ethanol to the reaction mixture. This domino protocol generates biologically significant heterocycles with the formation of CC, CC, CN, CN, CO bonds and one stereo-centre in a single operation via condensation/Knoevenagel/Michael/ annulation sequences.

Full text of DOI:10.1016/j.tetlet.2014.02.019

Tetrahedron Letters 55 (2014) 2010–2014
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expedient four-component domino protocol for
the regioselective synthesis of highly functionalized
pyranopyrazoles and chromenopyrazoles via
nitroketene-N,S-acetal chemistry under
solvent-free condition
⇑
Kamalraja Jayabal, Thirumalai Perumal Paramasivan
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, Tamilnadu, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Combinatorial library of pyranopyrazoles and chromenopyrazoles was regioselectively synthesized in
excellent yield from ethylacetoacetate, hydrazinehydrate, substituted aldehyde/salicylaldehyde with
nitroketene-N,S-acetal in the presence of piperidine under solvent-free condition (SFC) in an eco-benign
manner. This novel strategy excludes tedious extraction, chromatographic separation and recrystalliza-
tion processes. The final product could be obtained by simple filtration by the addition of ethanol to
the reaction mixture. This domino protocol generates biologically significant heterocycles with the for-
mation of CAC, C@C, CAN, C@N, CAO bonds and one stereo-centre in a single operation via condensa-
tion/Knoevenagel/Michael/annulation sequences.
Received 6 December 2013
Revised 5 February 2014
Accepted 9 February 2014
Available online 15 February 2014
Keywords:
Domino reaction
Greener approach
Regioselective synthesis
Nitroketene-N,S-acetal chemistry
Pyranopyrazoles and chromenopyrazoles
Ó 2014 Elsevier Ltd. All rights reserved.
In the modern drug development concern, synthesis of simple
and complex bioactive heterocycles in a vast diversity with a single
or minimum number of chemical routes is highly desirable. Multi-
component reactions (MCR)1–3 have gained a noteworthy emi-
nence as a synthetic tool for producing simple and structurally
complex molecular entities with captivating biological features
through the establishment and cleavage of numerous carbon–
carbon and carbon-heteroatom bonds with the single operation
under mild reaction condition, lesser reaction times, cost and
man power and minimal waste by one pot reaction technique in
both academics and industries. Due to ecological anxieties, the
modern synthetic organic chemists pay much attention on
synthetic pathways towards greener approaches to reduce drastic
prerequisites for the reactions. Owing to the harmful effects of or-
ganic solvents on the environment and humans, solvent-free reac-
tions have become a powerful tool in organic synthesis for
delivering a huge number of biologically important heterocycles
in greener approaches. Furthermore, solvent-free reactions offer
several advantages such as faster reaction rate, reduced reaction
time, less energy consumption, easy separation, and products with
high yields and purity.4 Diversity Oriented Synthesis (DOS)
employed to generate library of novel compounds provides skele-
tally diverse simple and complex scaffolds generating multiple
bonds and stereo-centres in single operation by integrating the
Single Reactant Replacement (SRR)5 strategy with MCR in greener
approach.
Pyrazole is an indispensable heterocycle analogue which plays a
vital role in many pharmaceutical and agrochemical industries.
Especially these analogues find application in a broad variety of
therapeutic areas, which include antimicrobials, analgesics, anti-
inflammatory agents, CNS and oncology drugs.6 Particularly some
of the leading commercial drugs based on the pyrazole scaffold in-
clude celecoxib,7 lonazolac8 and rimonabant.9 In recent days, pyr-
azole based analogues are constantly utilized as building blocks in
drug discovery and development programs,10 and are also found as
key constituents of ligands for transition metals,11 receptors in
supramolecular chemistry,12 liquid crystals13 and polymers.14 For
these reasons, the innovation of novel approaches for the synthesis
of polysubstituted pyrazole analogues is an important dynamic re-
search area of high impact in fine chemistry.15 Usually, the mani-
festation of two or more different heterocyclic moieties in a
single molecule often enhances the biological profile remarkably.
This encouraged us to focus on Target Oriented Syntheses (TOS)
⇑
Corresponding author. Tel.: +91 44 24437130; fax: +91 44 24911589.
E-mail address: ptperumal@gmail.com (T.P. Paramasivan).
http://dx.doi.org/10.1016/j.tetlet.2014.02.019
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

K. Jayabal, T. P. Paramasivan / Tetrahedron Letters 55 (2014) 2010–2014
2011
As part of our effort to develop biological potential small mole-
cules by a new synthetic method,35,36 a detailed literature survey
by us revealed that there is no report on the use of piperidine as
a catalyst in the synthesis of pyranopyrazoles and pyranochrom-
enes derivatives utilizing NMSM under solvent-free conditions.
Herein, we disclose a hitherto unreported facile chemo and regio-
selective four-component reaction for the combinatorial synthesis
of novel highly functionalized pyranopyrazoles and chromenopy-
razoles frameworks from ethylacetoacetate, hydrazinehydrate,
substituted aldehydes/salicylaldehydes with the NMSN under sol-
vent-free conditions at 120 °C in the presence of piperidine
(Scheme 1). The reactions were completed within 0.5–3 h and
the pure products were isolated in high yields simply by the addi-
tion of ethanol to the reaction mixture followed by filtration. The
synthetic route is facile, convergent and allows easy placement of
a variety of substituents around the periphery of the heterocyclic
ring system.
Michael donor site
Good leaving
group
Electron
NO2
withdrawing group
S
NH
Electron donors
site
Michael acceptor site
Figure 1. The special reactive profile of NMSM.
to design new heterocyclic compounds and develop novel a meth-
odology for the regioselective synthesis of pyrazole fused pyrans
and pyrazole substituted chromenes.
Pyranopyrazoles are fused heterocyclic compounds that deliver
a huge number of pharmacological activities such as, bacterici-
dal,16 fungicidal,17 insecticidal,18 molluscicidal,19,20 analgesic,21
anti-inflammatory activities22 and some of their analogues act as
vasodilators, hypotensive,23 hypoglycaemic and anticancer
agents.24,25 Similarly, chromene moiety broadly appears as an
important structural motif in biologically active and natural prod-
ucts. It is broadly present in natural alkaloids, flavonoids, tocophe-
rols and anthocyanins.26 In addition, modern year’s chromenes
occupy more space in synthetic organic chemistry due to their vast
utilities in medicinal chemistry.27 Especially 2-amino-4H-chrom-
enes are used as privileged medicinal scaffolds for the generation
of small-molecule ligands with highly pronounced spasmolytic,
diuretic, anticoagulant and antianaphylactic activities.28
The synthesis of 3-methyl-4-aryl-5-nitro-6- methylaminopy-
ranopyrazoles
5 was first undertaken. A four- component
reaction between ethylacetoacetate(1.0 mmol), hydrazinehydrate
(1.0 mmol), 4-methylbenzaldehyde (1.0 mmol) and NMSM
(1.0 mmol) was selected to optimize the reaction conditions. Ini-
tially, the above four-component coupling reaction was performed
with an equimolar mixture in EtOH at room temperature without
any catalyst. No product formation was observed even after 24 h
of stirring.
Next we performed the reaction at thermal condition with var-
ious solvents like EtOH, MeOH, CH3CN and different catalysts viz.
Et3N, piperidine, -proline and the results are summarized in
L
Table 1. All the catalysts promoted the reaction, albeit in low
efficiency.
The very first reported pyranopyrazole was synthesized from
the reaction between 3-methyl-1-phenylpyrazolin-5-one and tet-
racyanoethylene.29 Several methods for the synthesis of pyranopy-
razoles and chromene pyrazole derivatives have been reported in
the past decades.30 Recently, synthesis of pyranopyrazoles and
chromenopyrazoles derivatives has been reported via a multicom-
ponent approach using hydrazine with limited substrate scope.31
Therefore, explorations of more general, efficient, rapid and viable
routes are highly desirable.
This novel strategy to introduce an ambiphilic synthon which
holds both nucleophilic and electrophilic sites has great potential
for the development of pyranopyrazole and chromenopyrazoles
in an effective manner. (E)-N-Methyl-1-(methylthio)-2-nitroethen-
amine (NMSM) is one such versatile synthon,32 which contains
four active sites with three functional groups on an ethene motif
(Fig. 1) which was widely employed in the synthesis of several
pharmacological important heterocycles such as ranitidine33 and
nizatidine34 used for antiulcer drugs. Based on these key features,
herein we demonstrate the use of the special reactivity of NMSM,
for convenient combinatorial synthesis of pyranopyrazoles and
chromenopyrazoles.
Next we performed the reaction under solvent-free condition
and to our delight, the reaction was completed quickly providing
good yields of the desired product. The main notable observation
is that the product was obtained in 76% yield when piperidine
was used as catalyst. With better results in hand, next we opti-
mized the catalytic loading and found that by increasing the cata-
lytic amount from 0.1 to 0.25 equiv we obtained better yield.
Further by increasing the amount of catalyst, there was no
improvement of yield. The efficiency of reaction was also evaluated
with varying temperatures. Better results were obtained at 120 °C,
while increasing the temperature to 150 °C, resulted in reduced
yield due to decomposition of the product. Thus, the best yield
was achieved employing 0.25 equiv of piperidine under solvent-
free condition at 120 °C (Table 1, entries 19).
With the optimized conditions at hand, the scope and generality
of this protocol were next examined by employing N-phenyl
hydrazine and various aromatic aldehydes. A remarkably wide ar-
ray of aromatic aldehydes were well tolerated. No obvious elec-
tronic effects of the aldehyde were observed, and the products
were obtained in high yields (Table 2).37 The formation of phen-
ylpyrazolones needs a higher temperature for maximum yield in
R2
R2
R1
H
CHO
OH
N
2
N
N
R1
NO2
NH
H2N
R3
CHO
4
OH
O
O
6
NO2
NH
NO2
R3
O
Piperidine,
Piperidine,
Solvent free, 1200C
N
1
S
Solvent free, 1200C
O
N
NH
O
3
R1
5
7
Scheme 1. Synthesis of pyranopyrazoles 5 and chromenopyrazoles 7.

2012
K. Jayabal, T. P. Paramasivan / Tetrahedron Letters 55 (2014) 2010–2014
Table 1
Table 2
Optimization of the reaction condition for the synthesis of pyranopyrazolea 5a
Synthesis of pyranopyrazolesa
R2
R2
CH3
CH3
2
H
2
4
Piperidine, 120°C
N
H2N R1
CHO
NO2
NH2
O
Reaction conditions
CHO
4
H2N
Solvent-free condition
N
NO2
NO2
NO2
N
O
O
O
5
N
H
N
R1
O
O
N
S
NH
O
5
N
H
O
S
NH
H
1
3
1
3
Time (h) Yieldb (%)
Entry
Compd
R1
R2
Time (h)
Yield (%)b
Entry Reaction condition
c
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
5s
H
H
H
H
H
H
H
H
H
4-Me
4-NO2
4-OMe
2-F
0.5
0.5
1.0
0.5
0.75
1.0
0.75
0.5
0.5
2.5
0.5
2.25
2.5
3.0
2.5
2.25
2.75
3.0
86
81
82
85
82
79
76
83
86
83
78
81
80
78
82
78
77
76
79
1
2
3
4
5
6
7
8
No catalyst, EtOH, rt
No catalyst, EtOH, reflux
Piperidine (0.1 equiv), EtOH, rt
Piperidine (0.1 equiv), EtOH, reflux
Piperidine (0.25 equiv), EtOH, reflux
Piperidine (0.5 equiv), EtOH, reflux
Piperidine (0.5 equiv), MeOH, reflux
Piperidine (0.5 equiv), CH3CN, reflux
Piperidine (0.5 equiv), toluene, reflux
TEA (0.25 equiv), EtOH, reflux
24
8
24
5
4.5
6
8
6
8
12
8
12
—
—
—
c
c
65
68
68
61
58
10
55
58
65
4-Cl
C4H4
2,4-Cl
4-F
4-Br
4-Br
2-NO2
2-NO2
3-NO2
4-OMe
4-F
9
9
10
11
12
13
14
15
16
17
18
19
C6H5
H
10
11
12
TEA (1.0 equiv), EtOH, reflux
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
L
-Proline (0.25 equiv), EtOH, reflux
13
8
65
L
-Proline (1.0 equiv), EtOH, reflux
14
15
16
17
18
19
20
21
22
23
24
DABCO (0.25 equiv), EtOH, reflux
DABCO (1.0 equiv), EtOH, reflux
No catalyst, solvent free
Piperidine (0.1 equiv), solvent free, 80 °C
Piperidine (0.25 equiv), solvent free, 100 °C
Piperidine (0. 25 equiv), solvent free, 120 °C 0.5
Piperidine (0. 25 equiv), solvent free, 150 °C 0.5
Piperidine (1.0 equiv), solvent free, 120 °C
TEA (1.0 equiv), solvent free, 120 °C
DABCO (1.0 equiv), solvent free, 120 °C
6
8
12
2
1.5
57
61
2-F
c
—
2-Me
C4H4
2-Me
76
81
86
81
86
76
73
77
1.5
a
Reaction performed at 120 °C under SFC.
Isolated yield.
b
0.5
2.5
2
4
L
-Proline (1.0 equiv), solvent free, 120 °C
A plausible mechanistic pathway for chromenopyrazoles is
25
26
Pyrrolidine (1.0 equiv) solvent free, 120 °C
Morpholine (1.0 equiv) solvent free, 120 °C
5
6
75
72
depicted in Scheme 3. The first step is condensation of
ethylacetoacetate 1 with hydrazinehydrate 2 to give pyrazolone
A. The intermediate A undergoes Knoevenagel reaction with sali-
cylaldehyde 6 to give Michael acceptor B. The adduct B immedi-
ately undergoes Michael-type addition with nitoketene-N,Sacetal
(NMSM) 3 to generate the open chain intermediate C. The interme-
diate C undergoes intramolecular phenolic O-cyclization via path I
to give compound 7 with elimination of MeSH. The intermediate C
may exist in its two rotameric forms C0 and C00, which could prob-
ably undergo enolic O- or N-cyclizations via path II or III to give
a
The reaction of ethylacetoacetate (1.0 mmol), hydrazine (1.0 mmol), 4-meth-
ylbenzaldehyde (1.0 mmol), NMSM (1.0 mmol).
b
Isolated yield.
No product obtained.
c
solvent-free condition. The key point makes this methodology
suitable for vast structural diversity.
Taking into consideration the entire outcome, a plausible mech-
anistic pathway for the domino reaction is depicted in Scheme 2.
The first step is condensation of ethylacetoacetate 1 with hydra-
zinehydrate 2 to give pyrazolone A. The intermediate A undergoes
Knoevenagel reaction with aldehyde 4 to give Michael acceptor B.
The adduct B immediately undergoes Michael-type addition with
nitoketene-N,S-acetal (NMSM) 3 to generate the open chain inter-
mediate C. The intermediate C undergoes intramolecular O-cycliza-
tion via path I to give compound 5 with the elimination of MeSH.
The intermediate C may exist in another rotameric form C0, which
could probably undergo N-cyclizations via path II to give com-
pounds 50. During our investigation, we did not perceive even
traces of 50, and only 5 was obtained exclusively, suggesting
O-cyclization through the route I, making the protocol highly che-
mo- and regioselective.
After successful coupling of NMSM with ethylacetoacetate,
hydrazines and various aromatic aldehydes under solvent-free con-
ditions, salicylaldehyde was utilized in place of aromatic aldehydes
in order to gain further understanding about this transformation,
and to show the versatility of this protocol. Consequently, reaction
of 1, 2and 6 with nitroketene-N,S-acetal provided easy access to
chromenopyrazoles 7 in good yields (Table 3). The capacity of the
reaction was fruitfully proved for a wide range of salicylaldehydes
and phenyl hydrazines.
R2
R2
NO2
:B
N
R1
B:
H
N
O
B:
H
S
H
S
3 N
O
H
NO2
N
B
N
R1
N
R2
4
N
O
N
O
R1
C
A
path II
Concerted
path
O-attack
rotational
isomer
R2
O
O
path I
-MeSH
O
R2
H1
:B
H
N
H
1
NO2
N
R
H2N
N
R1
2
S
N
NO2
C'O
N
R1
R2
N
O
N
H
N-attack
5
NO2
S
-H2O
N
N
N
R1
5
'
Scheme 2. Plausible reaction scenario for the formation of 5.

K. Jayabal, T. P. Paramasivan / Tetrahedron Letters 55 (2014) 2010–2014
2013
Table 3
Synthesis of chromenopyrazolesa
R1
H
N N
O
O
N
H2N R1
OH
NO2
Piperidine, 120°C
2
O
1
R2
Solvent-free Condition
NO2
CHO
R2
O
7
N
H
S
NH
OH
6
3
Entry
Compd
R1
R2
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
H
H
5-Br
5-Cl
H
3,5-Br
5-NO2
4-OMe
3-OEt
3,5-Br
1.0
79
81
80
82
84
81
77
74
83
0.75
0.75
3.0
2.25
2.20
2.5
C6H5
C6H5
C6H5
C6H5
H
1.5
1.0
H
a
Reaction performed at 120 °C under SFC.
Isolated yield.
b
compounds 70 and 700, respectively. During our investigation, we
did not observe even traces of 70 or 700, and 7 was obtained exclu-
sively, suggesting phenolic O-cyclization through the route I was
more facile in simple greener approach.
Figure 2. ORTEP diagram of 5a.
chromenopyrazoles frameworks by the reaction of ethylacetoace-
tate, hydrazines, aromatic aldehydes/salicylaldehydes and nitroke-
tene-N,S-acetal in the presence of piperidine under solvent-free
conditions. Simple, novel and regioselective synthesis with the for-
mation of CAC, C@C, CAN, C@N and CAO bonds with one stereo-
center in a single operation with efficient utilization of all the
reactants has been accomplished in our approach. The salient fea-
ture of this methodology is short reaction time, excellent yield,
low-cost, operational simplicity, vast structural diversity and more
importantly the purification of compounds by a non-chromatogra-
phy method to make this process very significant for academic re-
search and practical applications in greener approach. Moreover,
the secondary amine and nitro substituents in the 2- and 3-posi-
tions of the compounds 5 and 7 are reactive entities, making these
compounds good candidates as precursors for further synthetic
transformations for various useful purposes. Further studies on
the extension of the scope of the use NMSM in synthetic applica-
tions are currently under way in our laboratory.
The main advantage of this domino protocol is the simple work-
up, and the product is obtained in high purity simply by trituration
with ethanol, which makes this methodology facile, practical and
rapid to perform. The purity of the product was enough for spectro-
scopic analysis without any further purification. The structures of
all the newly synthesized compounds 5 and 7 were well character-
ized from their satisfactory spectral (IR, 1H, 13C NMR, and Mass)
data. The mass spectra of the synthesized compounds displayed
molecular ion peaks at the appropriate m/z values. Further the
structure was explicitly established by the single crystal X-ray
diffraction analysis of compound 5a (Fig. 2).38
In summary, we have developed a convenient, efficient, chemo-
selective and regioselective synthesis of pyranopyrazoles and
R1
R1
R1
N N
N N
N N
Michael
addition
OH
NO2
O
B:
Acknowledgments
OH
NO2
H
path I
NO2
R2
R2
phenolic
O-attack
-MeSH
R2
:B
N
One of the authors, J.K. thanks the Council of Scientific and
Industrial Research (CSIR), New Delhi, India for the research
fellowship.
H
O
H
OH
C
S
3 N
S
O
N
H
B
rotational
isomerR2
7
R2
Knoevenagal
condensation
Supplementary data
OH
B:
H
S
path II
R2
NO2
OH
NO2
CHO
OH
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.02.
019.
O
N
N
N
enolic
N
5
N
O-attack
-MeSH
N
O
AR1
R1
C'
6
N
O
N
H
H
R1
7'
rotational
isomer
References and notes
R2
R2
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H2N
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-H2O
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Scheme 3. Plausible reaction scenario for the formation of 7.

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Spectral data of pyranopyrazole 5a
White solid; mp 234–236 °C. 1H NMR (400 MHz, DMSO-d6) d 1.93 (s, 3H, Me),
2.23 (s, 3H, Me), 3.15 (d, J = 4.2 Hz, 3H, NMe), 5.13 (s, 1H, CH), 7.05 (d,
J = 8.1 Hz, 2H, ArH), 7.09 (d, J = 8.2 Hz, 2H, ArH), 10.64 (s, 1H, NH), 12.29 (s, 1H,
NH).13C NMR (100 MHz, DMSO-d6) d 10.2, 21.1, 28.7, 37.3, 99.7, 109.5, 127.6,
129.1, 135.7, 136.5, 141.5, 153.6, 160.3. IR (KBr, cmꢀ1): 3218, 1638, 1604, 1535,
1467, 1361, 1213, 1161, 1058, 804, 553, 467. ESI-Mass m/z: 299 (M+ꢀ1).
Spectral data of chromenopyrazole 7a
Pale yellow solid; mp 258–260 °C. 1H NMR (400 MHz, DMSO-d6) d 2.24 (s, 3H,
Me), 3.14 (d, J = 5.0 Hz, 3H, NMe), 5.12 (s, 1H, CH), 7.08–7.31 (m, 4H, ArH), 9.33
(s, 1H, NH), 10.39 (q, J = 4.6 Hz, 1H, NH), 11.08 (s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6) d 10.3, 28.4, 30.6, 104.2, 106.9, 116.2, 125.2, 125.6, 128.1, 129.8,
136.9, 148.0, 159.6. IR (KBr, cmꢀ1): 8298, 1609, 1644, 1609, 1580, 1480, 1373,
1215, 1174, 762, 667, 473. ESI-Mass m/z: 303 (M++1).
38. Crystallographic data for the compound 5a in this manuscript have been
deposited with the Cambridge Crystallographic Data Centre as supplementary
publication number CCDC 957327. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK [fax:
+44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk].
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