Highly Efficient Chemoselective Synthesis of Pyrrolo[2,3- c ]pyrazole Bearing Oxindole via Sequential Condensation-Michael Addition-Intramolecular Cyclization Reactions

Article abstract of DOI:10.1055/s-0039-1690887

An efficient and highly chemoselective approach for the synthesis of novel scaffolds based on pyrrolo[2,3- c ]pyrazole bearing oxindole is accomplished by the acid-promoted sequential reactions between benzoylacetonitriles, phenylhydrazine, and 3-phenacyl

Full text of DOI:10.1055/s-0039-1690887

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
©
Georg Thieme Verlag Stuttgart · New York
2020, 31, A–G
letter
A
en
Synlett
M. T. Nazeri et al.
Letter
Highly Efficient Chemoselective Synthesis of Pyrrolo[2,3-c]pyra-
zole Bearing Oxindole via Sequential Condensation–Michael
Addition–Intramolecular Cyclization Reactions
Mohammad Taghi Nazeri
Hassan Farhid
Siamak Javanbakht
Ahmad Shaabani*
Behrouz Notash
Faculty of Chemistry, Shahid Beheshti University,
G.C., P.O. Box 19396-4716, Tehran, Iran
a-shaabani@sbu.ac.ir
Received: 01.02.2020
Accepted after revision: 20.03.2020
Published online: 07.04.2020
Oxindoles are privileged heterocyclic scaffolds for the
discovery of new drugs and the creation of useful biologi-
cally active molecules. These biologically attractive scaf-
folds exhibited antibacterial and anticancer activity and are
inhibitors of Aurora B or bromodomain. In particular, sub-
stituted indolin-2-ones act as ligands for dopamine D4 re-
ceptor or -synuclein fibrils (Figure 1).3
DOI: 10.1055/s-0039-1690887; Art ID: st-2020-b0067-l
Abstract An efficient and highly chemoselective approach for the syn-
thesis of novel scaffolds based on pyrrolo[2,3-c]pyrazole bearing oxin-
dole is accomplished by the acid-promoted sequential reactions be-
tween
benzoylacetonitriles,
phenylhydrazine,
and
3-
phenacylideneoxindoles as readily available starting materials. This val-
ue structure is dexterously embraced with oxindole, pyrrole, and pyra-
zole heterocycles, which are famous for their enriched biological prop-
erties. Besides, this is an eco-friendly and atom-economy approach,
and water is the only side product of the reaction. In this protocol, the
requirement of column chromatography is completely avoided, and the
products were isolated by recrystallization in crude reactions. These
compounds due to their excellent fluorescence features and bioactive
scaffolds may be attracted great interest in biomedical applications and
clinical diagnostics in the future.
3-Phenacylideneoxindoles are versatile synthons with
multiple reactive sites for the synthesis of heterocycles con-
nected to oxindoles including pyrrole-oxindoles, imidazole-
oxindoles, spiro-oxindoles, and furan-oxindoles. These
compounds can be obtained from the reactions of isatins
and arylethanones. 4 Recently, N-heterocyclic rings were
employed as fluorescence scaffolds for applications with
5
high-quality demands. In semiconductors, for the prepara-
6
tion of low-bandgap-conjugated polymers or copolymers,
Key words oxindole, pyrazole, pyrrole, multicomponent reactions,
chemoselective
pyrrolo-pyrroles are applied in optoelectronics and biopho-
tonics platforms.7 Particularly Schutting et al. employed
pyrrolo-pyrrole dyes as the colorimetric and fluorescent pH
Pyrazoles and pyrroles have been known as the import-
ant classes of five-membered heterocycles, which are pres-
ent as the basic cores in many pharmaceutical and biologi-
Ph
O
1
cally active compounds and natural products. In addition,
H
Ph
N
N
pyrrole rings fused to pyrazole rings are an important
source of bioactive molecules, which are extensively stud-
ied for many applications including antimicrobial agents,
antitumor agents, antiviral agents, anti-inflammatory
agents, androgen receptor modulators, agents acting on
CNS disorders, inhibitors of K 3.1 and K 3.4 potassium
N
O
Ph
CN
neat, 120 °C
Ph
O
Ph
Ph
N
4
a
1a
Ph
H
N
O
+
H2N
N
PTSA·H O (20 mol%)
2
N
NH2
H
N
Ph
EtOH, reflux
H
3a
5a
2a
ir
ir
channels subunits subtypes, and skeletal muscle contractili-
ty modulators.
Scheme 1 The model reaction for the synthesis of pyrrolo[2,3-c]pyra-
zole bearing oxindole
2
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
M. T. Nazeri et al.
Letter
MeO
O
O
Me
N
N
O
NEt2
H
N
N
N
O
S
Me
N
NH
N
H2N
F
NH
H
O
O
O2N
NH2
Br
O
N
H
N
O
H
N
GI50 (μM)
HOP-92 <0.01 μM
Sunitinib
hCA XIIK = 3.7 nM
H
I
HO
HO
N
N
HN
HN
NH2
N
O
N
N
Ph
N
N
Ph
N
H
H
Antimicrobial activity
Antitumor activity
Figure 1 Representative natural products and bioactive compounds
8
indicators for optical detecting of CO . These compounds
vents, ethanol was found to be the optimal medium in
terms of the yield and reaction efficiency (entry 13). We
2
can be also used for fluorescence imaging in biomedical re-
9
search and clinical diagnostics.
proceeded further to optimize the amount of PTSA·H O.
2
In continuation of our interest in the synthesis of com-
Subsequently, by increasing the amount of PTSA·H O from
2
10
binatorial heterocyclic compounds, herein, we report an
efficient approach for the synthesis of unusual 5,5-fused
ring system bearing oxindole 5a from the reactions of ben-
zoylacetonitrile (1a), phenylhydrazine (2a), and 3-phena-
cylideneoxindole (4a, Scheme 1).
10% to 20%, the product 5a was obtained in an improved
yield of 80% after 6 h (entry 15). To test the role of tempera-
ture in this strategy, the reaction was performed at differ-
ent temperatures. By lowering the temperature from reflux
to 60 °C or room temperature, the reaction yield decreases
to 35% or 0% in 6 h, respectively (entries 20 and 21). It is
worth mentioning that the product 5a was isolated through
crystallization based on the crude reaction solvent and no
column chromatography technique was used for purifica-
tion. It should be highlighted that the product 5a was ob-
tained with complete chemoselectivity.
Upon optimization of the reaction conditions, the reac-
tion of a wide range of 3-phenacylideneoxindoles 4 was in-
vestigated. The results are summarized in Scheme 2. As
shown, various 3-phenacylideneoxindoles 4 with different
kinds of substituents in the oxindole and phenacyl moieties
were found suitable for this reaction. Different substituent
groups (Cl, Br, and Me) on the oxindole moieties had a good
compatibility, and the desired products were obtained in a
range of 86–90% yields in a highly chemoselective manner
(Scheme 2, 5d, 5n, and 5o). The effect of N-protecting
groups of 3-phenacylideneoxindoles 4 was also examined.
Interestingly, utilizing of N-protecting groups (Me and Bn)
had no effect on the chemoselectivity. 3-Phenacylideneoxi-
ndoles 4 containing N-methyl protecting groups could par-
ticipate in this reaction very well to provide the corre-
sponding products in a range of 89–93% yields. It is note-
worthy that the reaction can also be successfully extended
to benzoyl-substituted 3-phenacylideneoxindoles 4. For ex-
ample, the benzoyl-substituted component had good com-
This synthetic protocol is carried out in two steps. The
first step is the reaction of benzoylacetonitrile (1a) with
phenylhydrazine (2a) under neat conditions at 120 °C. The
second step is the reaction of 3-phenacylideneoxindole (4a)
with 5-aminopyrazole (3a), which is formed in the first
step. According to our previous report,1 the optimized con-
ditions for the synthesis of 5-aminopyrazole (3a) was used.
In a pilot experiment, phenylhydrazine (2a) is reacted with
benzoylacetonitrile (1a) to produce 5-aminopyrazole (3a)
under neat conditions at 120 °C. Afterwards, 3-phena-
cylideneoxindole (4a) is added to the reaction mixture and
investigated under various conditions. The reaction in the
second step did not occur in the presence of basic catalysts
1
even under reflux conditions in CH CN after 6 h (Table 1,
3
entries 1 and 2). Inorganic acids, such as H SO and HCl, had
2
4
a poor effect on the reaction progress (entries 3 and 4). In
continuation, various Lewis acid catalysts such as InCl , Sn-
3
Cl , ZnCl and an organic acid such as acetic acid were ex-
2
2
amined and the results showed medium catalytic activity
entries 5–8). Fortified by the results obtained, we exam-
(
ined the reaction in the presence of PTSA·H O as a catalyst,
2
and the product 5a was obtained in an acceptable yield (en-
try 9). The reaction was carried out in various solvents like
CH CN, THF, toluene, EtOH, and water. Among all the sol-
3
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

C
Synlett
M. T. Nazeri et al.
Letter
Table 1 Optimization of the Second-Step Reaction Conditionsa
that the chloro substituent in position 4 on the aromatic
ring was well tolerated under the reaction conditions and
afforded the desired products in satisfactory yields.
First step
Second step
Ph
O
The reaction of 3-phenacylideneoxindole (4a) with 5-
aminopyrazole (3a) as an intermediate may undergoes sev-
eral routes on the basis of multiple reactive sites available
H
Ph
N
N
O
N
Ph
CN
O
Ph
Ph
1
a
N
H
4a
12
neat, 120 °C
Ph
on compound 4a (Scheme 3). The reaction, in principle,
N
O
+
H2N
N
may generate products 5a, 6, or 7 or a mixture of these. No-
tably, our protocol is completely chemoselective and pro-
vides product 5a exclusively in high yield.
catalyst
solvent
reflux
N
Ph
NH2
Ph
H
N
H
3a
5a
2a
The structure of compound 5g was confirmed by their
Entry
Catalyst (mol%)
Solvent
Time (h) Yield (%)b
analytical and spectral data. In its 1H NMR spectrum at
room temperature (Figure 2, a), the singlet appears at  =
1
2
3
4
5
6
7
8
9
piperidine (10)
Et N (10)
SO (10)
HCl (10)
InCl
SnCl
ZnCl
AcOH (10)
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
6
6
0
2
.98 (3 H) ppm due to the NCH groups. Two singlets at  =
3
3
0
4.91 (0.88 H) and 5.01 (0.12 H) ppm are the tertiary protons
H
2
4
6
trace
trace
35
25
30
17
50
53
36
20
64
72
80
82
68
trace
46
35
0
of C-3 on the oxindole moiety, which confirmed the exis-
tence of the mixture of tautomers with a ratio of 88:12. The
two broad singlets at  = 11.84 and 11.93 ppm are for NH
groups. It is noteworthy that at higher temperature (70 °C)
no mixture of tautomers was observed and only a single
6
3
6
2
6
2
(10)
6
1
structure was detected in the H NMR spectrum (Figure 2,
6
c). Furthermore, the HMQC spectrum confirms the tautom-
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
PTSA·H
none
2
2
2
2
2
2
2
2
2
O (10)
O (10)
O (10)
O (10)
O (10)
O (10)
O (20)
O (20)
O (15)
6
13
er structures of 5g (see Supporting Information). In its
C
1
1
1
1
1
1
1
1
1
1
2
0
H
2
O
6
NMR, the carbonyl carbons resonated at  = 176.5 ppm (ox-
indole carbonyl), two signals in  = 44.3 ppm corresponds to
the carbon located at the third position of the oxindole moi-
1
THF
6
2
toluene
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
–
6
ety and  = 26.5 ppm for NCH . The mass spectra of 5g dis-
3
3
6
+
played the molecular ion peak at 514 for M consistent with
4
10
6
the molecular structure. Finally, the structure of 5g was un-
ambiguously verified by single-crystal X-ray analysis,
which is shown in Figure 3 (detailed information can be
seen in the Supporting Information).
5
6
10
6
7
The proposed mechanism for the formation of 5a is
shown in Scheme 4. The first reaction is the condensation
of benzoylacetonitrile (1a) with phenylhydrazine (2a). Af-
terwards, a chemoselective Michael addition of 5-aminopy-
razole (3a) to compound 4a followed by a chemoselective
intramolecular cyclization afforded 5a through the forma-
tion B, C, D, and E intermediates after final dehydration. The
chemoselective Michael addition can be explained by steric
hindrance, and the chemoselective intramolecular cycliza-
tion is due to the competition between the amide carbonyl
and ketone carbonyl of the intermediate C.
8
6
9c
0d
1e
PTSA·H
PTSA·H
PTSA·H
O (20)
O (20)
O (20)
6
2
2
2
EtOH
EtOH
6
2
a
6
Conditions: The one-pot and two-step reaction. First step: 1 (0.25 mmol),
(0.25 mmol) under neat conditions in 120 °C at 2 h. Second step: 4 (0.25
2
mmol), 2.5 mL solvent, reflux.
Isolated yields.
1
6
b
c
20 °C.
0 °C.
d
e
Room temperature.
UV/Vis and photoluminescence (PL) spectroscopy deliv-
ers useful information about the structure and the optical
properties of the synthesized compounds. As can be seen in
Figure 4 (a), the UV/Vis spectra of the pyrrolo[2,3-c]pyra-
zole bearing oxindole derivatives 5 contain maximum ab-
sorption at  = 220 ± 5 and at 335 ± 2 nm. At the C13 and
C21 positions of the pyrrolo[2,3-c]pyrazole bearing oxin-
dole 5 that bears a chlorine or bromine substituent in the
aromatic ring results in a decrement and shift of the ab-
sorption maxima to longer wavelengths.
patibility and the desired products 5s and 5t were obtained
in high yields. In addition, the substituents (such as bromo,
chloro, methyl, and methoxy groups) on phenacyl moieties
were well tolerated under the reaction conditions and af-
forded the desired products in satisfactory yields and excel-
lent chemoselectivity. To further explore the versatility of
this protocol, the feasibility of changing of benzoylacetoni-
trile 1 was investigated (Scheme 2). The results revealed
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

D
Synlett
M. T. Nazeri et al.
Letter
R3
O
R4
H
Ph
N
N
R3
N
O
R1
O
CN
N
4
neat, 120 °C
R2
N
R1
R4
+
H2N
O
N
1
HN NH2
Ph
PTSA·H2O (20 mol%)
EtOH, reflux
N
R2
Ph
R4
2
3
5, 65–93%
H
N
Ph
N
N
H
Ph
N
N
H
Ph
N
N
Ph
N
N
H
Ph
N
N
H
N
N
N
N
Me
Br
Ph
Cl
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
N
N
N
N
N
H
H
H
H
H
Me
Cl
Ph
N
N
5
a, 80%
5b, 68%
5c, 85%
5d, 90%
5e, 82%
H
N
Ph
N
N
H
Ph
N
N
H
N
Ph
N
N
H
N
Ph
N
N
H
N
N
Me
Cl
Cl
MeO
Ph
Ph
O
O
O
O
O
N
H
N
Me
N
N
H
N
H
H
Cl
Ph
N
N
Cl
Cl
Cl
Ph
5
f, 68%
5g, 92%
5h, 86%
5i, 82%
5j, 65%
H
N
H
N
Ph
N
N
Ph
N
N
H
Ph
N
N
H
H
N
N
Br
Cl
N
Cl
Br
N
Cl
Cl
Br
N
Ph
Ph
O
O
O
O
O
N
H
N
Me
N
N
Me
N
H
H
Cl
Cl
Cl
5k, 88%
5l, 93%
5m, 89%
5n, 87%
5o, 86%
Ph
N
N
Ph
N
N
H
Ph
N
N
H
Ph
N
N
H
N
Ph
N
N
H
N
H
N
N
N
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
N
N
N
N
N
Me
Me
Ph
Ph
Me
Cl
Cl
5
p, 89%
5q, 90%
5r, 92%
5s, 85%
5t, 86%
Scheme 2 Substrate scope. Reactions were performed with 1 (0.25 mmol) and 2 (0.25 mmol) under neat conditions in 120 °C at 2 h, afterwards 4
0.25 mmol), PTSA·H O (20 mol %), and ethanol (2.5 mL) were added to the reaction mixture for 6 h.
(
2
The PL spectra demonstrated in Figure 4 (b) revealed
neoxindole.13,14 Oxindole, pyrazole, and pyrrole scaffolds in
that the electron-donating group on the aromatic ring at
the C13 and C21 positions of the pyrrolo[2,3-c]pyrazole
bearing oxindole reduce the PL intensity. Also, these com-
pounds show a Stokes shift in the range of 50–65 nm. Digi-
tal photographs of synthesized compounds with a concen-
tration of 50 ppm in acetone under UV lamp are depicted in
Figure 4 (c, c′, d, and d′). The compound 5p, which bears a
methyl substituent in the aromatic groups, exhibits a high
PL intensity at  = 398 nm.
In summary, we have established a highly efficient ap-
proach for the synthesis of novel pyrrolo[2,3-c]pyrazoles
bearing oxindole from the sequential reactions between
phenylhydrazine, benzoylacetonitrile, and 3-phenacylide-
one structure were prepared by chemoselective Michael
addition of 5-aminopyrazole, which was in situ generated
from
phenylhydrazine,
benzoylacetonitrile
to
3-
phenacylideneoxindole followed by chemoselective intra-
molecular cyclization to create diverse products in high
yields. This protocol follows an eco-friendly approach and
avoids the use of column chromatography for the purifica-
tion of products. The sequential reactions involve the con-
comitant removal of the water molecule. In the future, we
believe that these fluorescence compounds, due to their
bioactive frameworks, may be attracted great attention in
the biomedical applications and clinical diagnostics.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

E
Synlett
M. T. Nazeri et al.
Letter
1
Figure 2 The H NMR spectra of 5g at 25 °C, 50 °C, and 70 °C
H
Ph
N
N
Ph
N
Ph
O
N
H
5a
Ph
O
Ph
N
O +
H2N
N
N
Ph
H
Ph
3a
O
4a
H
N
Ph
N
Ph
Ph
N
N
N
Ph
N
N
OPh
H
N
H
7
6
Scheme 3 The model reaction of 3-{1,3,5-triphenyl-1,6-dihydropyrro-
lo[2,3-c]pyrazol-4-yl}
Figure 3 X-ray crystal structure of compound 5g (CCDC 1974832)
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

F
Synlett
M. T. Nazeri et al.
Letter
H
Ph
N
N
– H2O
Ph
NH
N
Ph
Ph
H2N
2a
N
N
aromatization
Ph
Ph
CN
HN
– H2O
O
Ph
N
Ph
HO
1a
O
H
5a
Ph
Ph
intramolecular
cyclization
O
NH
O
N
H
N
N
E
Ph
O
Ph NH2
N
N
Ph
A
NH
4a
OH
p-TSA
Ph
O
D
N
H
O
Ph
Ph
p-TSA
+
N
N
3a Ph
Ph
N
N
Ph
N
H
OH H2N
Ph
O
Ph
Ph
N
N
H2N
H
O
Ph
O
Michael
addition
C
HN
HN
O
H
HN
B
Scheme 4 Plausible mechanism for the formation of compound 5
Figure 4 UV/Vis (a) and PL (b) spectra of 50 ppm of synthesized pyrrolo[2,3-c]pyrazole bearing oxindole in acetone, and digital photograph under
sunlight (c, c′) and UV light 265 nm (d, d′)
Funding Information
Supporting Information
We gratefully acknowledge financial support from the Research
Council of Shahid Beheshti University and the Iran National Science
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690887.
S
u
p
p
orti
n
g Inform ati
o
n
S
u
p
p
orti
n
g Inform ati
o
n
Foundation (INSF).
I
ra
n
N
ati
o
n
a
lS
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
()
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G

G
Synlett
M. T. Nazeri et al.
Letter
References and Notes
(6) (a) Rabindranath, A.; Zhu, Y.; Heim, I.; Tieke, B. Macromolecules
2006, 39, 8250. (b) Zhu, Y.; Heim, I.; Tieke, B. Macromol. Chem.
(1) (a) Karrouchi, K.; Radi, S.; Ramli, Y.; Taoufik, J.; Mabkhot, Y. N.;
Phys. 2006, 207, 2206. (c) Cao, D.; Liu, Q.; Zeng, W.; Han, S.;
Peng, J.; Liu, S. J. Polym. Sci., Part A: Polym. Chem. 2006, 44, 2395.
7) (a) Zhang, X.; Richter, L. J.; DeLongchamp, D. M.; Kline, R. J.;
Hammond, M. R.; McCulloch, I.; Heeney, M.; Ashraf, R. S.; Smith,
J. N.; Anthopoulos, T. D. J. Am. Chem. Soc. 2011, 133, 15073.
Al-aizari, F. A. Molecules 2018, 23, 134. (b) Raffa, D.; Migliara, O.;
Maggio, B.; Plescia, F.; Cascioferro, S.; Cusimano, M. G.; Tringali,
G.; Cannizzaro, C.; Plescia, F. Arch. Pharm. 2010, 343, 631. (c) El-
Sabbagh, O. I.; Baraka, M. M.; Ibrahim, S. M.; Pannecouque, C.;
Andrei, G.; Snoeck, R.; Balzarini, J.; Rashad, A. A. Eur. J. Med.
Chem. 2009, 44, 3746. (d) Ong, E. B. B.; Watanabe, N.; Saito, A.;
Futamura, Y.; El Galil, K. H. A.; Koito, A.; Najimudin, N.; Osada,
H. J. Biol. Chem. 2011, 286, 14049. (e) Arikawa, Y.; Nishida, H.;
Kurasawa, O.; Hasuoka, A.; Hirase, K.; Inatomi, N.; Hori, Y.;
Matsukawa, J.; Imanishi, A.; Kondo, M. J. Med. Chem. 2012, 55,
(
(b) Wang, B.; He, N.; Li, B.; Jiang, S.; Qu, Y.; Qu, S.; Hua, J. Austr.
J. Chem. 2012, 65, 387.
(8) Schutting, S.; Borisov, S. M.; Klimant, I. Anal. Chem. 2013, 85,
3271.
(9) (a) Burchak, O. N.; Mugherli, L.; Ostuni, M.; Lacapere, J. J.;
Balakirev, M. Y. J. Am. Chem. Soc. 2011, 133, 10058.
4446.
(
b) Javanbakht, S.; Shaabani, A. ACS Appl. Bio Mater. 2020, 3, 156.
10) (a) Shaabani, A.; Nazeri, M. T.; Afshari, R. Mol. Diversity 2019,
3, 751. (b) Shaabani, A.; Seyyedhamzeh, M.; Maleki, A.;
Behnam, M.; Rezazadeh, F. Tetrahedron Lett. 2009, 50, 2911.
c) Shaabani, A.; Maleki, A.; Mofakham, H.; Moghimi-Rad, J.
(2) (a) Raffa, D.; Maggio, B.; Raimondi, M. V.; Cascioferro, S.; Plescia,
(
F.; Cancemi, G.; Daidone, G. Eur. J. Med. Chem. 2015, 97, 732.
2
(b) Abdel-Mohsen, S. A. Bull. Korean Chem. Soc. 2005, 26, 719.
(c) Ochiana, S. O.; Pandarinath, V.; Wang, Z.; Kapoor, R.;
(
Ondrechen, M. J.; Ruben, L.; Pollastri, M. P. Eur. J. Med. Chem.
013, 62, 777.
3) (a) Nevagi, R. J.; Dighe, S. N.; Dighe, S. N. Eur. J. Med. Chem. 2015,
7, 561. (b) Stevens, F. C.; Bloomquist, W. E.; Borel, A. G.; Cohen,
J. Org. Chem. 2008, 73, 3925. (d) Ghandi, M.; Nazeri, M. T.;
Kubicki, M. Tetrahedron 2013, 69, 4979.
11) Nazeri, M. T.; Javanbakht, S.; Shaabani, A.; Khavasi, H. R. Chemis-
trySelect 2019, 4, 14271.
12) (a) Alizadeh, A.; Mokhtari, J. Tetrahedron 2011, 67, 3519. (b) Li,
M.-Y.; Xu, H.-W.; Fan, W.; Ye, Q.; Wang, X.; Jiang, B.; Wang, S.-L.;
Tu, S.-J. Tetrahedron 2014, 70, 1004.
2
(
(
9
M. L.; Droste, C. A.; Heiman, M. L.; Kriauciunas, A.; Sall, D. J.;
Tinsley, F. C.; Jesudason, C. D. Bioorg. Med. Chem. Lett. 2007, 17,
(
6270. (c) Estévez, V.; Villacampa, M.; Menéndez, J. C. Chem. Soc.
Rev. 2014, 43, 4633. (d) Gulevich, A. V.; Dudnik, A. S.; Chernyak,
N.; Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (e) Millemaggi, A.;
Taylor, R. J. Eur. J. Org. Chem. 2010, 4527. (f) Gangarapu, K.;
Thumma, G.; Manda, S.; Jallapally, A.; Jarapula, R.; Rekulapally,
S. Med. Chem. Res. 2017, 26, 819.
(
13) 3-{1,3,5-Triphenyl-1,6-dihydropyrrolo[2,3-c]pyrazol-4-
yl}indolin-2-one (5a); Typical Procedure
Benzoylacetonitrile (1a, 0.25 mmol) and phenylhydrazine (2a,
0.25 mmol) were mixed in neat conditions and heated at 120 °C
for 2.0 h. After completion of the reaction, the reaction mixture
was cooled to room temperature. Then, 3-(2-aryl-2-oxoe-
(
4) (a) Edeson, S. J.; Jiang, J.; Swanson, S.; Procopiou, P. A.; Adams,
H.; Meijer, A. J.; Harrity, J. P. Org. Biomol. Chem. 2014, 12, 3201.
thylidene)indolin-2-one (4a, 0.25 mmol) PTSA·H O (0.05 mmol)
2
(b) Jiang, S.; Guo, H.-M.; Yao, S.; Shi, D.-Q.; Xiao, W.-J. J. Org.
and EtOH (2.5 mL) were added to the reaction mixture. After-
wards, the mixture was stirred for 6 h under reflux conditions.
Upon the completion of the reaction (monitored by TLC), the
reaction mixture was cooled to room temperature. The precipi-
tate was collected by filtration and washed with cold ethanol to
give the pure product 5a (93 mg, yield 80%).
Chem. 2017, 82, 10433. (c) Gupta, A. K.; Ahamad, S.; Gupta, E.;
Kant, R.; Mohanan, K. Org. Biomol. Chem. 2015, 13, 9783. (d) Hu,
J.-D.; Cao, C.-P.; Lin, W.; Hu, M.-H.; Huang, Z.-B.; Shi, D.-Q.
J. Org. Chem. 2014, 79, 7935. (e) Sharma, N.; Peddinti, R. K. J. Org.
Chem. 2017, 82, 918. (f) Sun, J.; Xie, Y.-J.; Yan, C.-G. J. Org. Chem.
2013, 78, 8354. (g) Vivekanand, T.; Vinoth, P.; Agieshkumar, B.;
(14) 3-{1,3,5-Triphenyl-1,6-dihydropyrrolo[2,3-c]pyrazol-4-
Sampath, N.; Sudalai, A.; Menéndez, J. C.; Sridharan, V. Green
Chem. 2015, 17, 3415. (h) Shanthi, G.; Perumal, P. T. Tetrahedron
Lett. 2009, 50, 3959. (i) Sharma, N.; Peddinti, R. K. J. Org. Chem.
yl}indolin-2-one (5a)
White powder (92 mg, 80%); mp 214–216 °C. Anal. Calcd (%) for
C31H22N O: C, 79.81; H, 4.75. Found: C, 79.73; H, 4.70. IR (ATR):
4
2017, 82, 9360. (j) Vivekanand, T.; Vachan, B.; Karuppasamy, M.;
–1 1
max = 3146 (NH), 1708 (CO), 1467 (C=C) cm
. H NMR (300
Muthukrishnan, I.; Maheswari, C. U.; Nagarajan, S.; Bhuvanesh,
N.; Sridharan, V. J. Org. Chem. 2019, 84, 4009. (k) Jiang, Y.-H.;
Yan, C.-G. Synthesis 2016, 48, 3057. (l) Dai, L.; Shu, P.; Wang, Z.;
Li, Q.; Yu, Q.; Shi, Y.; Rong, L. Synthesis 2017, 49, 637.
MHz, CDCl ):  (mixture of tautomers) = 4.91 (s, 0.85 H, H ),
3
3
5
7
5
.16 (s, 0.15 H, H ), 6.71 (s, 1 H, H ), 6.88–6.96 (m, 2 H, H ),
3 Ar Ar
.08–7.28 (m, 10 H, H ), 7.39–7.52 (m, 5 H, H ), 7.69–7.76 (m,
Ar
Ar
13
H, H ), 8.10–8.23 (br s, 1 H, NH), 8.49 (br s, 1 H, NH). C NMR
Ar
(
5) Zollinger, H. Color Chemistry: Syntheses, Properties, and Applica-
(
125 MHz, CDCl ):  (mixture of tautomers) = 179.8 (CO), 146.1,
3
tions of Organic Dyes and Pigments; Wiley-VCH: Weinheim,
1
1
1
41.6, 141.6, 141.2, 139.3, 133.4, 132.2, 130.2, 129.7, 129.2,
28.7, 128.4, 128.3, 128.2, 127.8, 127.6, 125.5, 124.5, 122.6,
18.6, 115.4, 110.0 (C ), 44.9 (C ). MS (EI, 70 eV): m/z = 466
2003.
Ar
3
+
(100) [M ], 437 (25), 334 (47), 231 (23), 104 (29), 77 (91).
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–G