New four-component reactions in water: A convergent approach to the metal-free synthesis of spiro[indoline/acenaphthylene-3,4′-pyrazolo[3,4-b] pyridine derivatives

Article abstract of DOI:10.1016/j.tet.2011.03.020

New four-component domino reactions are described that allow the one-pot synthesis of spiro[indoline/acenaphthylene-3,4′-pyrazolo[3,4-b]pyridine derivatives from the reaction of phenylhydrazine, 3-aminocrotononitrile, isatin/acenaphthylene-1,2-dione, and

Full text of DOI:10.1016/j.tet.2011.03.020

Tetrahedron 67 (2011) 3201e3208
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Tetrahedron
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New four-component reactions in water: a convergent approach to the metal-free
synthesis of spiro[indoline/acenaphthylene-3,40-pyrazolo[3,4-b]pyridine
derivatives
,
b,
Kamaraj Balamurugan a, Subbu Perumal a , J. Carlos Menendez
*
*
ꢀ
a Department of Organic Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 625021, India
Departamento de Química Organica y Farmaceutica, Facultad de Farmacia, Universidad Complutense, 28040 Madrid, Spain
b
ꢀ
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
New four-component domino reactions are described that allow the one-pot synthesis of spiro[indoline/
acenaphthylene-3,40-pyrazolo[3,4-b]pyridine derivatives from the reaction of phenylhydrazine, 3-ami-
nocrotononitrile, isatin/acenaphthylene-1,2-dione, and cyclic 1,3-dicarbonyl compounds, including cy-
clohexane-1,3-diones, barbituric acid, and 2-thioxodihydropyrimidine-4,6(1H,5H)-dione, in the presence
of (ꢀ)-camphor-10-sulfonic acid (CSA). These processes take place in water and involve the generation of
two rings and five new bonds (two CeC, two CeN and one C]N) in a single synthetic operation, with
expedient work-up and diminished waste generation due to the absence of extraction and purification
steps.
Received 31 January 2011
Received in revised form 3 March 2011
Accepted 7 March 2011
Available online 12 March 2011
Keywords:
Multi-component reactions
Domino reactions
Water as reaction medium
Spirooxindoles
Ó 2011 Elsevier Ltd. All rights reserved.
Fused pyrazoles
1. Introduction
organic reactions, that take place ‘on water’, i.e., with the reactants
initially emulsionated in water, exhibit important rate enhance-
Multicomponent domino reactions (MDRs), particularly those
performed in aqueous media, have become an increasingly useful
tool for the synthesis of chemically and biologically important
compounds because of their convergence, atom economy, and
other suitable characteristics from the point of view of green
chemistry.1e3 These reactions, which involve at least three different
simple substrates, are powerful for the expedient building up of
molecular complexity and diversity4 through the facile formation of
several new covalent bonds in a one-pot transformation, quite
closely approaching the concept of an ideal synthesis, and are
particularly well adapted for combinatorial synthesis.5 The search
for alternative reaction media to replace volatile, flammable, and
often toxic solvents commonly employed in organic synthesis is
also a priority area for the development of green chemical pro-
cesses. From both environmental and economic points of view,
water has emerged as the medium of choice to perform organic
reactions, as it is the most environmentally acceptable, safest, and
most abundant solvent.6 In addition, water generally enables facile
work-up protocols, as most organic compounds, being lipophilic,
are readily segregated from aqueous media. In addition, many
ments.7 Finally, water as a reaction medium enables novel solvation
and assembly processes conferring unique selectivity and reac-
tivity.6e For these reasons, the development of synthetically useful
reactions that take place in water is of considerable topical interest.
Pyrazoles constitute an interesting family of heterocycles due to
their application as pharmaceuticals8 and in the agrochemical in-
dustry as herbicides and insecticides.9 Pyrazoles also provide
privileged scaffolds in lead identification/drug discovery pro-
grammes10 and have provided therapeutically useful compounds in
fields, such as cyclooxygenase 2 inhibitors (e.g., SC-558, tepoxalin,
and celecoxib)11,12 and cannabinoid-1 inverse agonists, which are
very promising for reducing obesity (e.g., rimonabant).13 Fused
pyrazoles, and pyrazolopyridines in particular, also display a variety
of interesting pharmacological properties,14 besides finding appli-
cations as fluorescence standards and luminophores in organic
light emitting diodes,15 and therefore their synthesis has been an
attractive research topic in recent years16,17 Moreover, pyrazolo
[3,4-b]quinoline derivatives also display relevant bioactivities.18
Other important structural fragments present in our final prod-
ucts include the pyridopyrimidine motif, a well known pharma-
cophore in drug design which is associated with a wide range of
biological activities,19 and spiro-oxindole substructures, present in
many alkaloids (e.g., spirotryprostatin B, alantrypinone, and cit-
rinadin A), which have received much attention from the synthetic
* Corresponding authors. Tel./fax: þ91 452 2459845; e-mail addresses: subbu.
ꢀ
perum@gmail.com (S. Perumal), josecm@farm.ucm.es (J.C. Menendez).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.03.020

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K. Balamurugan et al. / Tetrahedron 67 (2011) 3201e3208
community,20 prompted by their interesting structures and bi-
ological properties (Fig. 1).21
transformations in aqueous medium.24 As the selection of an ap-
propriate reaction medium is of crucial importance for the success
of reactions under conventional heating conditions, the four-com-
ponent reaction was examined in polar, non-protic solvents like
N,N-dimethylformamide and acetonitrile (entries 3 and 4), and
other protic solvents including ethanol (entry 5) and ethylene
glycol (entry 6). From the data listed in Table 1, water emerge as the
solvent of choice, furnishing the highest yield of the product. Fur-
thermore, when the reaction was performed in water in the pres-
ence of CSA, the product could be obtained in high purity by simple
filtration. Other catalysts were also assayed, with the previously
mentioned CAN and sulfamic acid giving relatively sluggish re-
actions (entries 7 and 8). In the presence of other catalysts, the
model four-component reaction failed to give 10a and thus, in the
presence of citric acid, SnCl4.6H2O, YbCl3, Yb(OTf)3, BiCl3, and InCl3
the reaction instead afforded exclusively 3-(5-amino-3-methyl-1-
phenyl-1H-4-pyrazolyl)-3-hydroxy-2-indolinone 13a, presumably
an intermediate of the four-component process, in 75e95% yields
(entries 9e14). From the above experiments, it follows that: (i) The
CSA/water pair is the ideal catalyst-solvent combination for the
expedient four-component synthesis of 10a in high yield and (ii)
the product selectivity of the reaction can be tuned by employing
appropriate catalysts.
Fig. 1. Structures of representative pyrazole drug and spiro-oxindole alkaloid.
In this context, we describe in this paper the one-pot, four-
component, domino reactions of phenylhydrazine 1, 3-amino-
crotononitrile 2, cyclic 1,3-diketones 3e6, and substituted isatins 7
or acenaphthylene-1,2-diones 8 in water for the construction of
spiro-heterocycles 9e12 (Scheme 1), comprising spiro-oxindole,
pyrazole, pyrazolopyridine, pyridopyrimidine, pyrazolopyrido-py-
rimidine, and pyrazoloquinoline substructures. This work bears
some relationship with a recently reported CAN-catalyzed three-
component reaction between 5-aminopyrazoles, isatins, and cyclic
1,3-diketones,16a but some crucial differences exist, namely the
higher yields and broader scope of our method, its four-component
nature, which makes it more efficient, and the absence of any
metal-containing catalyst, which renders our method more envi-
ronmentally benign. The study reported here constitutes a part of
our ongoing research program, aimed at evolving new methodol-
ogies by systematic use of tandem/domino multi-component re-
actions for the construction of novel heterocycles22 and/or
unearthing new lead molecules with antimycobacterial activities.23
Scheme 2. Model reaction for optimization studies.
Table 1
Solvent and acids screen for the synthesis of 10a
Entry
Solvent
Acid (mol%)
Time (h)
Yield
Yield
of 10a (%)
of 13a (%)
1
2
3
4
5
6
7
8
Water
Water
DMF
CH3CN
EtOH
Ethylene/glycol
Water
Water
p-TSA (100)
CSA (50)
CSA (50)
CSA (50)
CSA (50)
CSA (50)
CAN (10)
Sulfamic
acid (100)
Citric acid
SnCl4.6H2O
YbCl3
10
2
8
10
8
8
80
92
35
40
55
65
75
68
0
0
0
0
0
0
0
0
7
7
Scheme 1. Disconnections explored in the present work.
9
Water
Water
Water
Water
Water
Water
0.5
1
0.25
0.10
0.25
0.10
0
0
0
0
0
0
82
76
90
75
80
95
10
11
12
13
14
2. Results and discussion
Yb(OTf)3
BiCl3
InCl3
We started our investigation by examining the four-component
reaction of phenylhydrazine, 3-aminocrotononitrile, isatin, and
barbituric acid in the presence of 1 equiv of p-toluenesulfonic acid
(p-TSA) under reflux for 10 h, which afforded compound 10a in 80%
After determining the optimal conditions, the scope of the
reaction was examined in more detail. As shown in Scheme 3, the
four-component reactions of phenylhydrazine 1, 3-amino-
crotononitrile 2, substituted isatins 7 (R¼H, Cl, and NO2) or
acenaphthylene-1,2-dione 8 and cyclic 1,3-diketones, viz. cyclo-
hexane-1,3-dione 3, dimedone 4, barbituric acid 5, and thio-
barbituric acid 6 were carried out in water in the presence of CSA
yield (Scheme
2 and Table 1, entry 1). Interestingly, when
(ꢀ)-camphor-10-sulfonic acid (CSA) was used instead, 0.5 equiv of
acid were sufficient for the reaction to achieve completion in 2 h,
affording an enhanced yield of 92% (Table 1, entry 2). It is pertinent
to note that CSA, a mild, inexpensive, readily available Brønsted
acid, has recently emerged as a powerful catalyst for organic

K. Balamurugan et al. / Tetrahedron 67 (2011) 3201e3208
3203
under heating at 100 ꢁC for 2e3 h, and these conditions afforded
excellent yields of spiro-heterocycles 9e12 (Fig. 2).
Fig. 3. Selected HMBCs and chemical shifts of 9d.
appeared as doublets at 1.98 and 2.10 ppm (J¼15.9 Hz), which
showed HMBCs with C-80 at 41.1 and C-50 at 195.7 ppm. The 80-CH2
hydrogens appearing as broad singlet at 2.56 ppm, with negligible
coupling, showed HMBCs with C-70 at 32.3 ppm, C-60 at 48.9 ppm,
C-90a at 153.4 ppm and C-50a at 108.1 ppm. The fact that these two
hydrogens have coupling connection is established by a clear H,H-
COSY correlation. The two singlets at 9.70 and 10.34 ppm are due to
the NH groups in pyrazolopyridine and oxindol, respectively. The
NMR spectroscopic data of the known compounds, 9a, 9d, 9e, and
9g reported in the present work agree well with those reported
earlier.16a
Scheme 3. Camphorsulfonic acid-promoted, four-component synthesis of spirocyclic
compounds 9e12 in aqueous solution.
A plausible mechanism for the formation of the spiro-hetero-
cycles is proposed in Scheme 4. The domino sequence of reactions
is, presumably triggered by the formation of 5-amino-3-methyl-1-
phenylpyrazole 15 from the acid-catalyzed reaction of phenyl-
hydrazine with 3-aminocrotononitrile. Intermediate 15, upon
reaction with isatin 7, affords intermediate 13, which has been
isolated as the sole reaction product in some of the reactions car-
ried out during the optimization studies. This compound, upon
Fig. 2. Scope and yields of the synthesis of spirocycles 9e12.
The structure of the spiro-heterocycles 9e12 is in full agreement
with elemental analyses, HRMS and 1H, 13C, and 2D NMR spectro-
scopic data, as illustrated below for a representative example
(compound 9d). In the 1H NMR spectrum of 9d, hydrogens of the
two methyl groups the cyclohexenone part appeared as singlets at
0.98 and 1.01 ppm, which showed HMBCs with C-80 at 41.1 ppm, C-
70 at 32.3 ppm and C-60 at 48.9 ppm (Fig. 3). The 60-CH2 hydrogens
Scheme 4. Mechanism proposed to explain the formation of compounds 9 and 10.

3204
K. Balamurugan et al. / Tetrahedron 67 (2011) 3201e3208
reaction with the starting cyclic 1,3-diketones under acidic condi-
tions presumably furnishes intermediate 16, which subsequently
undergoes annulation leading to the final spiro-heterocycles via
intermediate 17. The involvement of aminopyrazole 15 in this re-
action is supported by the fact that when phenylhydrazine
(1 mmol), 3-aminocrotononitrile (1 mmol), CSA (0.5 mmol), and
water (10 ml) are refluxed for 10 min at 100 ꢁC, 15 is formed in 98%
yield.25 Furthermore, the reaction of 15 with barbituric acid and
isatin 7 (R¼H) in the presence of CSA under reflux conditions for 2 h
afforded the corresponding spiro-product 10a in near quantitative
(96%) yield. The intermediacy of 13 in the domino reactions is also
evident from (i) the isolation of 3-(5-amino-3-methyl-1-phenyl-
1H-4-pyrazolyl)-3-hydroxy-2-indolinone 13a16a in 90% yield in the
reaction of phenylhydrazine (1 mmol), 3-aminocrotononitrile
(1 mmol), isatin, and barbituric acid (1 mmol) in the presence of
CSA in water for 1 h at room temperature and (ii) the fact that the
subsequent reaction of 13a with dimedone in the presence of CSA at
reflux conditions for 3h afforded the corresponding spirocyclic
product 9d in 90% yield. The greater efficacy of CSA (pKa ꢂ1.2)
compared with p-toluenesulfonic acid (pKa 0.7) is explicable on the
basis of higher acidity of the former.26
Finally, due to the importance of both pyrazole and oxindole
systems, we decided to take the opportunity of the isolation of
compound 13a as the sole reaction product in some of the reactions
carried out during optimization work to establish a new, three-
component method for the synthesis of 3-(4-pyrazolyl)oxindoles and
chose for this purpose InCl3 (0.10 equiv) as the catalyst. The results
obtained in the reaction between arylhydrazines, 3-amino-
crotonitrile and isatins in water at 100 ꢁC for 10 min are summarized
in Scheme 5 and Table 2, where it can be appreciated that these
conditions ledtoanexcellentyieldof5-aminopyrazolederivatives13.
operation, and broad scope of applicability. Furthermore, it can be
considered as environmentally friendly, since it does not require the
use of metal-containing catalysts, uses water as the reaction medium
andpurification is done bysimple filtration,avoidingtheuseoforganic
solvents at any point of the experimental procedure. Our study also
demonstrates that the product selectivity of the reactions can be
controlled by judicious choice of the catalyst, leading to the de-
velopment of a three-component synthesis of 3-(5-amino-4-pyr-
azolyl)oxindoles. Further synthetic applications of this methodology
andscreeningof thenovelheterocyclicring systems thus generatedfor
biological activities are in progress in our laboratory.
4. Experimental section
4.1. General
Melting points were measured in open capillary tubes and are
uncorrected. The 1H NMR, 13C NMR, H,H-COSY, C,H-COSY, and
HMBC spectra were recorded on a Bruker (Avance) 300 MHz NMR
instrument using TMS as internal standard and DMSO-d6 as sol-
vent. Standard Bruker software was used throughout. Chemical
shifts are given in parts per million (d scale) and the coupling
constants are given in Hertz. Silica gel-G plates (Merck) were used
for TLC analysis with a mixture of petroleum ether (60e80 ꢁC) and
ethyl acetate as eluent. Elemental analyses were performed on
a Perkin Elmer 2400 Series II Elemental CHNS analyzer. HRMS
measurements were performed by the CAI de Espectrometria de
Mass, Universidad Complutense, using an FTMS Bruker APEX QIV
instrument.
4.2. General procedure for synthesis of spiro[indoline/
acenaphthylene-3,40-pyrazolo[3,4-b]pyridines (9e12)
A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile
(1 mmol), and CSA (0.5 mmol) in water (10 ml) was added to isatin
(1 mmol) and a suitable cyclic 1,3-dicarbonyl compound (1 mmol)
and the reaction mixture was heated under reflux at 100 ꢁC for
2e3 h. After completion of the reaction (TLC), the reaction mixture
was cooled to room temperature, the precipitate filtered off, and
washed with methanol to obtain the pure spiro-heterocycles 9e12
as yellow solids. Spectroscopic data for all these compounds are
given below.
Scheme 5. Three-component reaction for the synthesis of 3-hydroxy-3-(3-pyrazolyl)
oxindoles 13.
Table 2
Yields of 3-(5-amino-3-methyl-1-aryl-1H-4-pyrazolyl)-3-hydroxyoxindoles 13
4.2.1. (ꢀ)-30-Methyl-10-phenyl-60,70,80,90-tetrahydrospiro-[indoline-
3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione (9a). Isolated as a
yellow solid, yield: 88%, mp >300 ꢁC (recrystallization from
EtOH/DMF mixture); 1H NMR (300 MHz, DMSO-d6) dH 1.56 (s, 3H,
CH3), 1.86 (s, 2H, CH2), 2.15 (s, 2H, CH2), 2.69 (s, 2H, CH2), 6.80e6.87
(m, 3H, AreH), 7.41e7.52 (m, 6H, AreH), 9.77 (s,1H, NH),10.37 (s,1H,
NH); 13C NMR (75 MHz, DMSO-d6) dC 11.4, 21.1, 27.7, 37.1, 48.9, 101.7,
108.6, 109.3, 121.6, 123.4, 123.6, 127.4, 129.6, 136.6, 137.1, 137.9, 141.8,
145.1, 155.1, 179.8, 193.8. Anal. Calcd for C24H20N4O2: C, 72.71; H,
5.08; N, 14.13%. Found: C, 72.65; H, 5.17; N, 14.18%.
Compd
Ar
R1
R2
Yield (%)
13a
13b
13c
13d
13e
13f
13g
13h
13i
C6H5
C6H5
C6H5
C6H5
H
Cl
Br
NO2
CH3
CH3
Cl
Br
CH3
H
H
H
H
CH3
H
H
H
CH3
96a
94
90
95
86
88
90
91
82
C6H5
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
a
This compound was described in Ref. 29.
4.2.2. (ꢀ)-5-Chloro-30-methyl-10-phenyl-60,70,80,90-tetra-hydrospiro
[indoline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
(9b). Isolated as a yellow solid, yield: 91%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (300 MHz, DMSO-
d6) dH 1.56 (s, 3H, CH3), 1.86 (s, 2H, CH2), 2.15 (s, 2H, CH2), 2.69 (s, 2H,
CH2), 6.80e6.87 (m, 3H, AreH), 7.41e7.52 (m, 6H, AreH), 9.77 (s, 1H,
NH), 10.37 (s,1H, NH); 13C NMR (75 MHz, DMSO-d6) dC 11.4, 21.1, 27.7,
37.1, 48.9,101.7,108.6,109.3,121.6,123.4,123.6,127.4,129.6,136.6,137.1,
137.9, 141.8, 145.1, 155.1, 179.8, 193.8. Anal. Calcd for C24H19ClN4O2: C,
66.90; H, 4.44; N, 13.00%. Found: C, 66.98; H, 4.38; N, 12.92%.
3. Conclusions
In conclusion, we describe new four-component domino reactions
for the synthesis of spiro[indoline-3,40-pyrazolo[3,4-b]pyridines con-
taining up to five rings in good to excellent yields from the reactions of
phenylhydrazine, 3-aminocrotononitrile, isatin/acenaphthylene-1,2-
dione, and cyclic 1,3-dicarbonyl compounds in the presence of CSA in
aqueous medium. This protocol is endowed with prominent advan-
tages such as convergence, short reaction time, excellent yields, easy

K. Balamurugan et al. / Tetrahedron 67 (2011) 3201e3208
3205
4.2.3. (ꢀ)-5-Bromo-30-methyl-10-phenyl-60,70,80,90-tetra-hydrospiro
[indoline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
(9c). Isolated as a yellow solid, yield: 84%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (300 MHz,
DMSO-d6) dH 1.59 (s, 3H, CH3), 1.87 (s, 2H, CH2), 2.18e2.28 (m, 2H,
CH2), 2.69 (s, 2H, CH2), 6.80e7.12 (m, 2H, AreH), 7.30e7.52 (m, 6H,
AreH), 9.86 (s, 1H, NH), 10.52 (s, 1H, NH); 13C NMR (75 MHz, DMSO-
d6) dC 11.5, 21.1, 27.7, 37.0, 49.2,100.9,108.7,110.6,113.2,123.8,125.6,
126.1, 127.5, 129.5, 130.1, 136.7, 137.8, 139.4, 141.2, 144.9, 155.6, 179.4,
193.9. Anal. Calcd for C24H19BrN4O2: C, 60.64; H, 4.03; N, 11.79%.
Found: C, 60.71; H, 4.08; N, 11.71%.
(recrystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
300 MHz)
d
1.00 (s, 6H, 2CH3), 1.59 (s, CH3), 2.08 (br s, 2H, 60CH2),
2.61 (br s, 2H, 80CH2), 7.04 (dd, 1H, J¼9.0, 3.0 Hz, AreH), 7.43e7.55
(m, 5H, AreH), 7.22 (d, 1H, J¼2.1 Hz, AreH), 8.14 (dd, 1H, J¼8.7,
2.4 Hz, AreH), 9.93 (s, 1H, NH), 11.14 (s, 1H, NH); 13C NMR (DMSO-
d6, 75 MHz)
d 11.5, 27.4, 27.7, 32.3, 40.9, 48.9, 50.2, 100.2, 107.0,
108.9,118.5,123.9,125.2,127.6,129.5,137.0,137.7,137.8,142.3,144.8,
148.5, 154.1, 180.2, 193.8. Anal. Calcd for C26H23N5O4: C, 66.51; H,
4.94; N, 14.92%. Found: C, 66.44; H, 4.87; N, 14.99%.
4.2.9. (ꢀ)-30-Methyl-10-phenylspiro[indoline-3,40-pyrazolo [40,30:5,6]
pyrido[2,3-d]pyrimidine]-2,50,70(60H,80H,90H)-trione (10a). Isolated
as a yellow solid, yield: 92%, mp >300 ꢁC (recrystallization from
4.2.4. (ꢀ)-30,70,70-Trimethyl-10-phenyl-60,70,80,90-tetrahydro-spiro[in-
doline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione (9d). Isolated
as a yellow solid, yield: 90%, mp >300 ꢁC (recrystallization from
EtOH/DMF mixture); 1H NMR (300 MHz, DMSO-d6) dH 0.98 (s, 3H,
CH3),1.01 (s, 3H, CH3),1.56 (s, CH3),1.98 (d,1H, J¼15.9 Hz, H-60a), 2.10
(d, 1H, J¼15.9 Hz, H-60b), 2.56 (br s, 2H, 80CH2), 6.80e6.85 (m, 4H,
AreH), 7.40e7.53 (m, 5H, AreH), 9.70 (s, 1H, NH), 10.34 (s, 1H, NH);
13C NMR (75 MHz, DMSO-d6) dC 11.5, 27.1, 28.3, 32.3, 38.7, 41.1, 48.9,
101.8, 108.1, 108.8, 121.7, 123.3, 123.6, 127.5, 129.7, 136.9, 137.1, 141.8,
145.2, 153.4, 179.9, 193.7. HRMS (ESI) m/z calcd for C26H24N4O2
[Mꢂ1]þ: 423.1899 found: 423.1847. Anal. Calcd for C26H24N4O2: C,
73.56; H, 5.70; N, 13.20%. Found: C, 73.66; H, 5.64; N, 13.15%.
EtOH/DMF mixture); 1H NMR (DMSO-d6, 300 MHz)
d 1.57 (s, 3H,
CH3), 6.85 (d, 1H, J¼7.8 Hz, AreH), 6.90 (d, 1H, J¼7.5 Hz, AreH), 6.97
(d, 1H, J¼7.2 Hz, AreH), 7.15 (t, 1H, J¼7.5 Hz, AreH), 7.41e7.62 (m,
5H, AreH), 9.32 (s, 1H, NH),10.21 (s,1H, NH),10.50 (s, 1H, NH),10.77
(s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 11.4, 47.8, 87.3, 100.4,
108.9, 121.8, 122.7, 123.8, 127.5, 127.9, 129.9, 135.8, 136.0, 137.7,
142.0, 145.2, 146.7, 149.7, 162.2, 178.9. Anal. Calcd for C22H16N6O3: C,
64.07; H, 3.91; N, 20.38%. Found: C, 63.99; H, 3.86; N, 20.44%.
4.2.10. (ꢀ)-30,5-Dimethyl-10-phenylspiro[indoline-3,40-pyrazolo
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(60H,80H,90H)-trione
(10b). Isolated as a yellow solid, yield: 85%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.2.5. (ꢀ)-30,5,70,70-Tetramethyl-10-phenyl-60,70,80,90-tetrahydro-
spiro[indoline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
(9e). Isolated as a yellow solid, yield: 87%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (300 MHz,
DMSO-d6) dH 1.01 (s, 6H, 2CH3), 1.58 (s, 3H, CH3), 2.02 (d, 1H,
J¼15.9 Hz, H-60a), 2.07e2.29 (m, 2H, H-60b, H-80a), 2.58 (s, 1H, H-
80b), 6.68e6.90 (m, 3H, AreH), 7.41e7.52 (m, 5H, AreH), 9.69 (s, 1H,
NH), 10.25 (s, 1H, NH); 13C NMR (75 MHz, DMSO-d6) dC 11.50, 20.8,
27.3, 28.1, 32.3, 48.9, 50.6, 101.8, 108.5, 123.5, 123.8, 127.3, 127.7,
129.6, 130.2, 136.7, 137.2, 137.9, 139.4, 145.2, 153.2, 179.7, 193.5. Anal.
Calcd for C27H26N4O2: C, 73.95; H, 5.98; N, 12.78%. Found: C, 73.88;
H, 5.92; N, 12.83%.
300 MHz) d 1.59 (s, 3H, CH3), 2.00 (s, 3H, CH3), 6.44 (s, 1H, NH), 7.02
(d, 1H, J¼8.1 Hz, AreH), 7.13 (d, 1H, J¼8.1 Hz, AreH), 7.34e7.45 (m,
3H, AreH), 7.60 (d,1H, J¼9.0 Hz, AreH), 7.97 (t, 1H, J¼8.4 Hz, AreH),
9.58 (s, 1H, NH), 10.75 (s, 1H, NH), 10.83 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz)
d 11.5, 20.1, 49.9, 82.6, 111.6, 117.1, 119.9, 121.1,
124.5, 126.9, 127.8, 129.7, 130.0, 130.2, 131.0, 132.4, 146.1, 149.3,
149.9, 162.0, 178.4. Anal. Calcd for C23H18N6O3: C, 64.78; H, 4.25; N,
19.71%. Found: C, 64.72; H, 4.32; N, 19.65%.
4.2.11. (ꢀ)-5-Chloro-30-methyl-10-phenylspiro[indoline-3,40-pyrazolo
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(60H,80H,90H)-trione
(10c). Isolated as a yellow solid, yield: 87%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.2.6. (ꢀ)-5-Chloro-30,70,70-trimethyl-10-phenyl-60,70,80,90-tetrahy-
drospiro[indoline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
(9f). Isolated as a yellow solid, yield: 95%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (300 MHz, DMSO-
d6)dH 0.99 (s, 3H, CH3),1.01 (s, 3H, CH3),1.59 (s, 3H, CH3), 2.01e2.13(m,
2H, H-60a, H-60b), 2.49 (m,1H, H-80a), 2.58(s,1H, H-80b), 6.82e7.17 (m,
3H, AreH), 7.42e7.52(m, 5H, AreH), 9.80 (s,1H, NH),10.51 (s,1H, NH);
13C NMR (75 MHz, DMSO-d6) dC 11.5, 27.3, 27.9, 32.2, 49.1, 50.4, 100.9,
107.4, 110.1, 123.3, 123.7, 125.5, 127.3, 127.4, 129.5, 136.8, 137.8, 139.0,
140.8,144.9,153.6,179.4,193.6. Anal. Calcd forC26H23ClN4O2: C,68.04;
H, 5.05; N, 12.21%. Found: C, 67.97; H, 5.12; N, 12.15%.
300 MHz)
d
1.59 (s, 3H, CH3), 6.86 (dd, 1H, J¼6.0, 2.1 Hz, AreH), 7.08
(d, 1H, J¼6.0 Hz, AreH), 7.18e7.22 (m, 1H, AreH), 7.44e7.59 (m, 5H,
AreH), 9.33 (s, 1H, NH), 10.18 (s, 1H, NH), 10.63 (s, 1H, NH), 10.80 (s,
1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 11.4, 48.0, 86.7, 99.7, 110.3,
122.8, 124.0,125.7,127.6,127.8,129.9, 136.1,137.6,137.8,140.9, 145.0,
146.8, 149.6, 162.6, 178.7. HRMS (ESI) m/z calcd for C22H15ClN6O3
[Mꢂ1]þ: 445.0894; found: 445.0810. Anal. Calcd for C22H15ClN6O3:
C, 59.13; H, 3.38; N, 18.81%. Found: C, 59.19; H, 3.31; N, 18.73%.
4.2.12. (ꢀ)-5-Bromo-30-methyl-10-phenylspiro[indoline-3,40-pyr-
azolo[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(60H,80H, 90H)-trione
(10d). Isolated as a yellow solid, yield: 86%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.2.7. (ꢀ)-5-Bromo-30,70,70-trimethyl-10-phenyl-60,70,80,90-tetrahy-
drospiro[indoline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
(9g). Isolated as a yellow solid, yield: 93%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
300 MHz)
d
1.60 (s, 3H, CH3), 6.82 (d, 1H, J¼8.1 Hz, AreH), 7.19 (s, 1H,
AreH), 7.34 (dd, 1H, J¼8.4, 1.5 Hz, AreH), 7.42e7.47 (m, 1H, AreH),
7.57e7.59(m, 4H,AreH), 9.34(s,1H,NH),10.18(s,1H, NH),10.65(s,1H,
300 MHz) d
1.00 (s, 6H, 2CH3), 1.59 (s, CH3), 2.01 (s, 2H, 60CH2), 2.58
(s, 2H, 80CH2), 6.79 (d, 1H, J¼8.1 Hz, AreH), 6.99 (s, 1H, AreH), 7.29
(d, 1H, J¼7.8 Hz, AreH), 7.43e7.52 (m, 5H, AreH), 9.80 (s, 1H, NH),
NH), 10.82 (s,1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 11.4, 48.0, 86.7,
99.7, 110.9, 113.5, 122.8, 126.7, 127.6, 129.9, 130.6, 136.1, 137.6, 138.2,
141.3,145.0,146.8,149.6,162.2,178.6. Anal. Calcd for C22H15BrN6O3: C,
53.78; H, 3.08; N, 17.11%. Found: C, 53.71; H, 3.13; N, 17.19%.
10.52 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 11.5, 27.4, 27.9,
32.2, 40.9, 49.0, 50.4, 100.9, 107.4, 110.6, 113.2, 123.7, 125.9, 127.4,
129.5, 130.1, 136.8, 137.8, 139.4, 141.2, 144.9, 153.6, 179.3, 193.6. Anal.
Calcd for C26H23BrN4O2: C, 62.03; H, 4.61; N,11.13%. Found: C, 61.96;
H, 4.54; N, 11.19%.
4.2.13. (ꢀ)-30-Methyl-5-nitro-10-phenylspiro[indoline-3,40-pyrazolo
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(60H,80H,90H)-trione
(10e). Isolated as a yellow solid, yield: 81%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.2.8. (ꢀ)-30,70,70-Trimethyl-5-nitro-10-phenyl-60,70,80,90-tetrahy-
drospiro[indoline-3,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
300 MHz)
d
1.59 (s, 3H, CH3), 6.20 (d, 1H, J¼8.4 Hz, AreH), 6.66 (d,
(9h). Isolated as
a
yellow solid, yield: 94%, mp >300 ꢁC
1H, J¼8.7 Hz, AreH), 6.94 (t, 2H, J¼8.1 Hz, AreH), 7.02e7.10 (m, 3H,

3206
K. Balamurugan et al. / Tetrahedron 67 (2011) 3201e3208
AreH), 7.19 (dd, 1H, J¼6.3, 2.4 Hz, AreH), 9.47 (s, 1H, NH), 10.05 (s,
1H, NH), 10.11 (s, 1H, NH), 10.82 (s, 1H, NH); 13C NMR (DMSO-d6,
(m, 1H, AreH), 7.57e7.66 (m, 4H, AreH), 7.85 (d, 1H, J¼6.9 Hz,
AreH), 7.92 (d, 1H, J¼8.4 Hz, AreH), 7.99 (d, 1H, J¼6.9 Hz, AreH),
8.27 (d,1H, J¼8.1 Hz, AreH), 9.42 (s, 1H, NH),10.29 (s, 1H, NH),10.73
75 MHz)
d 11.5, 49.2, 82.8, 109.0, 110.9, 111.4, 120.1, 124.2, 125.5,
126.9, 129.0, 130.5, 130.9, 134.5, 142.1, 146.7, 148.5, 148.7, 161.4,
178.5. Anal. Calcd for C22H15N7O5: C, 57.77; H, 3.31; N, 21.44%.
Found: C, 57.85; H, 3.37; N, 21.38%.
(s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 12.3, 52.8, 88.7, 101.8,
120.7, 121.6, 123.0, 124.5, 127.8, 128.9, 129.4, 129.8, 130.2, 131.8,
133.3, 136.3, 137.9, 140.8, 144.8, 145.3, 147.1, 150.0, 162.9, 204.9.
HRMS (ESI) m/z calcd for C26H17N5O3 [Mꢂ1]þ: 446.1331; found:
446.1272. Anal. Calcd for C26H17N5O3: C, 69.79; H, 3.83; N, 15.65%.
Found: C, 69.71; H, 3.88; N, 15.59%.
4.2.14. (ꢀ)-30-Methyl-10-phenyl-70-thioxo-spiro[indoline-3,40-pyr-
azolo[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50(60H,80H,90H)-dione
(10f). Isolated as a yellow solid, yield: 84%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.2.19. (ꢀ)-30-Methyl-10-phenyl-70-thioxo-spiro[acenaph-thylene-
3,40-pyrazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50(60H,80H,90H)-di-
one (12b). Isolated as a yellow solid, yield: 84%, mp >300 ꢁC
(recrystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
300 MHz)
d
1.53 (s, 3H, CH3), 6.82 (d, 1H, J¼7.8 Hz, AreH), 6.87 (d,
1H, J¼7.5 Hz, AreH), 6.98 (d, 1H, J¼7.2 Hz, AreH), 7.13 (t, 1H,
J¼7.5 Hz, AreH), 7.40e7.54 (m, 5H, AreH), 9.29 (s, 1H, NH), 10.52 (s,
1H, NH), 11.90 (s, 1H, NH), 12.05 (s, 1H, NH); 13C NMR (DMSO-d6,
300 MHz)
d 0.99 (s, 3H, CH3), 7.39e7.47 (m, 2H, AreH), 7.58e7.67
75 MHz)
d
11.3, 48.7, 91.4, 100.1, 109.0, 121.9, 122.5, 124.0, 127.5,
(m, 5H, AreH), 7.85 (t, 1H, J¼7.2 Hz, AreH), 7.94 (d, 1H, J¼8.4 Hz,
AreH), 8.01 (d, 1H, J¼6.9 Hz, AreH), 8.29 (d, 1H, J¼8.1 Hz, AreH),
9.42 (s, 1H, NH), 11.82 (s, 1H, NH), 12.19 (s, 1H, NH); 13C NMR
128.1, 129.9, 135.3, 135.4, 137.5, 141.9, 145.2, 146.0, 159.6, 173.6,
178.4. Anal. Calcd for C22H16N6O2S: C, 61.67; H, 3.76; N, 19.61%.
Found: C, 61.60; H, 3.85; N, 19.55%.
(DMSO-d6, 75 MHz) d 11.5, 52.0, 92.0, 100.7, 120.3, 121.1, 122.1, 123.9,
127.2, 128.2, 128.7, 129.0, 129.5, 131.2, 132.3, 135.0, 137.0, 140.1,
143.5, 144.6, 145.8, 159.5, 173.2, 203.7. Anal. Calcd for C26H17N5O2S:
C, 67.37; H, 3.70; N, 15.11%. Found: C, 67.43; H, 3.62; N, 15.19%.
4.2.15. (ꢀ)-5-Chloro-30-methyl-10-phenyl-70-thioxo-spiro-[indoline-
3,40-pyrazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50(60H,80H,90H)-
dion (10g). Isolated as a yellow solid, yield: 80%, mp >300 ꢁC
(recrystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.3. General procedure for synthesis of 3-(5-amino-3-methyl-
300 MHz)
d
1.59 (s, 3H, CH3), 6.86 (d, 1H, J¼8.1 Hz, AreH), 6.87 (d,
1-phenyl-1H-4-pyrazolyl)-3-hydroxy-2-indolinone (13)
1H, J¼2.1 Hz, AreH), 7.22 (dd, 1H, J¼6.0, 2.1 Hz, AreH), 7.42e7.47
(m, 1H, AreH), 7.57e7.59 (m, 4H, AreH), 9.35 (s, 1H, NH), 10.71 (s,
1H, NH), 11.91 (s, 1H, NH), 12.07 (s, 1H, NH); 13C NMR (DMSO-d6,
A mixture of phenylhydrazine (1 mmol), 3-aminocrotononitrile
(1 mmol), and InCl3 (0.1 mmol) in water (10 ml) was added to isatin
(1 mmol) and the reaction mixture heated under reflux at 100 ꢁC for
10 min. After completion of the reaction (TLC), the reaction mixture
was cooled to room temperature; the precipitate was filtered off
and washed with methanol to obtain pure 13 as a colorless solid.
Spectroscopic data for all the compounds are given below.
75 MHz)
d 11.4, 48.1, 90.8, 99.4, 110.5, 122.6, 124.2, 125.9, 127.7,
128.0,129.9,135.5,137.3,137.5,140.9,145.1,146.2,159.7,173.6,178.2.
HRMS (ESI) m/z calcd for C22H15ClN6O2S [Mꢂ1]þ: 461.0666; found:
461.0571. Anal. Calcd for C22H15ClN6O2S: C, 57.08; H, 3.27; N, 18.15%.
Found: C, 57.15; H, 3,22; N, 18.23%.
4.2.16. (ꢀ)-5-Bromo-30-methyl-10-phenyl-70-thioxo-spiro-[indoline-
3,40-pyrazolo[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50(60H,80H,90H)-di-
one (10h). Isolated as a yellow solid, yield: 80%, mp >300 ꢁC
(recrystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.3.1. 3-(5-Amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-2-
indolinone (13a)16a. Isolated as a colorless solid, yield: 96%, mp
236 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR (DMSO-d6,
300 MHz) d 1.43 (s, 3H, CH3), 5.28 (s, 2H, NH2), 6.63 (s, 1H, OH), 6.84
300 MHz)
d
1.67 (s, 3H, CH3), 6.83 (d,1H, J¼8.4 Hz, AreH), 7.26 (s, 1H,
(d, J¼7.8 Hz, 1H, AreH), 6.97 (t, J¼7.5 Hz, 1H, AreH), 7.20e7.28 (m,
AreH), 7.36 (dd, 1H, J¼8.4, 1.5 Hz, AreH), 7.43e7.45 (m, 1H, AreH),
3H, AreH), 7.44 (t, J¼7.5 Hz, 2H, AreH), 7.54 (d, J¼7.5 Hz, 2H, AreH),
7.58e7.65(m, 4H, AreH), 9.35(s,1H, NH),10.72(s,1H,NH),11.90(s,1H,
10.35 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 12.8, 74.6, 99.7,
NH), 12.05 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d
11.4, 48.0, 90.8,
109.9, 122.1, 122.8, 125.1, 126.2, 129.2, 129.6, 132.9, 139.0, 141.7,
144.8, 146.3, 178.3. HRMS (ESI) m/z calcd for C18H16N4O2 [Mꢂ1]þ:
319.1273; found: 319.1200. Anal. Calcd for C18H16N4O2: C, 67.49; H,
5.03; N, 17.49%. Found: C, 67.42; H, 4.97; N, 17.45%.
99.5, 111.0, 113.7, 122.7, 126.9, 127.7, 129.9, 130.9, 135.6, 137.4, 137.7,
141.3,145.1,146.2,159.7,173.6,178.1. Anal. Calcd for C22H15ClN6O2S: C,
52.08; H, 2.98; N, 16.56%. Found: C, 52.01; H, 3.04; N, 16.50%.
4.2.17. (ꢀ)-30,70,70-Trimethyl-10-phenyl-60,70,80,90-tetra-hydro-2H-
spiro[acenaphthylene-1,40-pyrazolo[3,4-b]quinoline]-2,50(10H)-dione
(11). Isolated as a yellow solid, yield: 82%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
4.3.2. 3-(5-Amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-5-chloro-3-
hydroxy-2-indolinone (13b). Isolated as a colorless solid, yield: 94%,
mp 243 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR (DMSO-d6,
300 MHz) d 1.45 (s, 3H, CH3), 5.31 (s, 2H, NH2), 6.80 (s, 1H, OH), 6.87
300 MHz)
d
0.94 (s, 3H, CH3), 1.00 (s, 3H, CH3), 1.02 (s, 3H, CH3), 1.94
(t, 2H, J¼7.2 Hz, AreH), 7.28e7.32 (m, 2H, AreH), 7.44e7.48 (m, 2H,
(d, 1H, J¼16.2 Hz, H-6a), 2.05 (d, 1H, J¼16.2 Hz, H-6b), 2.63 (br s, 2H,
8eCH2), 7.24 (d, 1H, J¼6.6 Hz, AreH), 7.41e7.43 (m, 1H, AreH),
7.52e7.62 (m, 5H, AreH), 7.82 (d, 1H, J¼7.2 Hz, AreH), 7.87 (d, 1H,
J¼8.7 Hz, AreH), 8.08 (d, 1H, J¼6.9 Hz, AreH), 8.23 (d, 1H, J¼8.1 Hz,
AreH), 7.52e7.57 (m, 2H, AreH), 10.53 (s, 1H, NH); 13C NMR
(DMSO-d6, 75 MHz) d 12.7, 74.5, 99.0, 111.3,122.8, 124.8, 125.9, 126.1,
129.1, 129.2, 134.9, 138.9, 140.4, 144.3, 146.2, 177.7. Anal. Calcd for
C18H15ClN4O2: C, 60.94; H, 4.26; N, 15.79%. Found: C, 60.87; H, 4.20;
N, 15.72%.
AreH), 9.87 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
d 12.2, 27.2,
28.3, 32.4, 41.0, 50.1, 53.7, 103.1, 109.6, 120.0, 120.9, 121.5, 123.9,
127.6, 128.6, 129.2, 129.5, 129.7, 131.0, 134.0, 136.9, 137.9, 139.9,
145.1, 145.9, 153.8, 193.9, 205.0. Anal. Calcd for C30H25N3O2: C,
78.41; H, 5.48; N, 9.14%. Found: C, 78.47; H, 5.55; N, 9.08%.
4.3.3. 3-(5-Amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-5-bromo-3-
hydroxy-2-indolinone (13c). Isolated as a colorless solid, yield: 90%,
mp 254 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR (DMSO-d6,
300 MHz) d 1.48 (s, 3H, CH3), 5.30 (s, 2H, NH2), 6.79 (s, 1H, OH), 6.83
4.2.18. (ꢀ)-30-Methyl-10-phenyl-spiro[acenaphthylene-3,40-pyrazolo
[40,30:5,6]pyrido[2,3-d]pyrimidine]-2,50,70(60H,80H,90H)-trione
(12a). Isolated as a yellow solid, yield: 82%, mp >300 ꢁC (re-
crystallization from EtOH/DMF mixture); 1H NMR (DMSO-d6,
(t, 2H, J¼8.1 Hz), 7.29 (t, 2H, J¼8.1 Hz, AreH), 7.38e7.48 (m, 3H,
AreH), 7.55 (d, 1H, J¼7.8 Hz), 10.53 (s, 1H, NH); 13C NMR (DMSO-d6
75 MHz) d 12.7, 74.5, 99.0,111.9,113.5,122.8,126.1,127.5,129.0,132.0,
135.2, 138.8, 140.8, 144.3, 146.2, 177.6. Anal. Calcd for C18H15BrN4O2:
C, 54.15; H, 3.79; N, 14.03%. Found: C, 54.09; H, 3.71; N, 13.96%.
300 MHz)
d
0.93 (s, 3H, CH3), 7.35 (d,1H, J¼6.9 Hz, AreH), 7.43e7.45

K. Balamurugan et al. / Tetrahedron 67 (2011) 3201e3208
3207
4.3.4. 3-(5-Amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-
5-nitro-2-indolinone (13d). Isolated as a colorless solid, yield: 95%,
mp 268 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR (DMSO-d6,
C20H19FN4O2: C, 65.56; H, 5.23; N, 15.29%. Found: C, 65.50; H, 5.16;
N, 15.22%.
300 MHz) d 1.47 (s, 3H, CH3), 5.37 (s, 2H, NH2), 7.00 (s, 1H, OH), 7.08
Acknowledgements
(t, 2H, J¼8.7 Hz), 7.30 (t, 2H, J¼8.7 Hz, AreH), 7.46e7.56 (m, 2H,
AreH), 8.06 (s, 1H, AreH), 8.23 (d, 1H, J¼7.5 Hz), 10.35 (s, 1H, NH);
S.P. and J.C.M. thank MICINN, Spain and the Department of
Science and Technology, New Delhi, for funding for Indo-Spanish
collaborative major research project (grants ACI2009-0956 and
DST/INT/SPAIN/09). SP and JCM also gratefully acknowledge DST for
funds under IRHPA program for the purchase of a high resolution
NMR spectrometer and MICINN for grant CTQ2009-12320-BQU,
respectively. K.B. thanks the Council of Scientific and Industrial
Research, New Delhi for the award of a Senior Research Fellowship.
13C NMR (DMSO-d6, 75 MHz)
d 12.8, 74.0, 98.2, 110.2, 120.1, 122.9,
126.2, 126.7, 129.1, 133.8, 138.7, 142.4, 144.1, 146.4, 147.9, 178.3. Anal.
Calcd for C18H15N5O4: C, 54.15; H, 3.79; N, 14.03%. Found: C, 59.18;
H, 4.14; N, 19.17%.
4.3.5. 3-(5-Amino-3-methyl-1-phenyl-1H-4-pyrazolyl)-3-hydroxy-
5,7-dimethyl-2-indolinone (13e). Isolated as a colorless solid, yield:
86%, mp 216 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR (DMSO-
d6, 300 MHz)
d 1.45 (s, 3H, CH3), 2.17 (s, 3H, CH3), 2.19 (s, 3H, CH3),
Supplementary data
5.25 (s, 2H, NH2), 6.52 (s, 1H, OH), 6.87e6.90 (m, 1H, AreH), 7.27 (t,
2H, J¼7.5 Hz, AreH), 7.45 (t, 2H, J¼7.5 Hz, AreH), 7.53 (s, 1H, AreH),
7.57 (s, 1H, AreH), 10.30 (s, 1H, NH); 13C NMR (DMSO-d6, 75 MHz)
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2011.03.020. These data in-
clude MOL files and InChiKeys of the most important compounds
described in this article.
d
12.6, 16.1, 20.4, 74.8, 99.9, 118.6, 122.6, 122.7, 125.8, 128.9, 130.6,
130.8, 132.5, 137.6, 139.0, 144.7, 145.8, 178.4. Anal. Calcd for
C20H20N4O2: C, 68.95; H, 5.79; N,16.08%. Found: C, 68.86; H, 5.72; N,
16.02%.
References and notes
4.3.6. 3-[5-Amino-1-(4-fluorophenyl)-3-methyl-1H-4-pyrazolyl]-3-
hydroxy-5-methyl-2-indolinone (13f). Isolated as a colorless solid,
yield: 88%, mp 222 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR
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(DMSO-d6, 300 MHz)
d 1.44 (s, 3H, CH3), 2.23 (s, 3H, CH3), 5.26 (s,
2H, NH2), 6.58 (s, 1H, OH), 6.74 (d, 2H, J¼7.5 Hz, AreH), 7.03e7.08
(m, 1H, AreH), 7.26e7.35 (m, 3H, AreH), 7.55e7.59 (m, 1H, AreH),
10.30 (s, 1H, NH); 13C NMR (DMSO-d6 75 MHz)
d 12.6, 20.6, 74.6,
99.8, 109.5, 115.6, 115.9, 124.9, 125.0, 125.5, 129.6, 130.8, 132.8, 139.1,
144.7, 146.1, 178.1. Anal. Calcd for C19H17FN4O2: C, 64.76; H, 4.86; N,
15.90%. Found: C, 64.71; H, 4.79; N, 15.84%.
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4.3.7. 3-[5-Amino-1-(4-fluorophenyl)-3-methyl-1H-4-pyrazolyl]-5-
chloro-3-hydroxy-2-indolinone (13g). Isolated as a colorless solid,
yield: 90%, mp 235 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR
(DMSO-d6, 300 MHz)
d 1.48 (s, 3H, CH3), 5.30 (s, 2H, NH2), 6.80 (s,
1H, OH), 6.87 (d, 1H, J¼8.1 Hz, AreH), 7.26e7.32 (m, 4H, AreH),
7.54e7.59 (m, 2H, AreH), 10.54 (s, 1H, NH); 13C NMR (DMSO-d6,
75 MHz)
d 12.6, 74.4, 99.1, 111.3, 115.5, 115.8, 124.7, 125.0, 125.1,
125.9, 129.1, 134.8, 140.4, 144.3, 146.2, 177.6. Anal. Calcd for
C18H14ClFN4O2: C, 57.99; H, 3.79; N, 15.03%. Found: C, 57.91; H, 3.73;
N, 14.98%.
4.3.8. 3-[5-Amino-1-(4-fluorophenyl)-3-methyl-1H-4-pyrazolyl]-5-
bromo-3-hydroxy-2-indolinone (13h). Isolated as a colorless solid,
yield: 91%, mp 249 ꢁC (recrystallized from EtOH/AcOEt); 1H NMR
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d 1.40 (s, 3H, CH3), 5.30 (s, 2H, NH2), 6.79 (s,
1H, OH), 6.82 (d, 2H, J¼8.1 Hz, AreH), 7.26 (d, 2H, J¼8.1 Hz, AreH),
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75 MHz)
d 12.6, 74.4, 99.1, 111.9, 113.5, 115.6, 115.9, 125.0, 125.1,
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d
12.7, 16.2, 20.5, 74.8, 99.9, 118.7, 122.6, 122.8, 125.9, 129.0, 130.6,
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