A clean synthesis of 3,3-bis(5-amino-1H-pyrazol-4-yl)-indolin-2-one derivatives

Article abstract of DOI:10.3987/COM-08-11391

A clean and efficient method has been reported for the condensation of 1,3-diphenyl-1H-pyrazol-5-amine with isatines in aqueous media to afford the corresponding 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-one derivatives in good yields. The Japan Institute

Full text of DOI:10.3987/COM-08-11391

HETEROCYCLES, Vol. 75, No. 9, 2008
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HETEROCYCLES, Vol. 75, No. 9, 2008, pp. 2293 - 2299. © The Japan Institute of Heterocyclic Chemistry
Received, 13th March, 2008, Accepted, 21st April, 2008, Published online, 24th April, 2008. COM-08-11391
A CLEAN SYNTHESIS OF 3,3-BIS(5-AMINO-1H-PYRAZOL-4-YL)-
INDOLIN-2-ONE DERIVATIVES
Somayeh Ahadi, Ghazaleh Imani Shakibaei, Peiman Mirzaei, and
Ayoob Bazgir*
Department of Chemistry, Faculty of Science, Shahid Beheshti University, Tehran
1983963113, Iran, E-mail: a_bazgir@sbu.ac.ir
Abstract – A clean and efficient method has been reported for the condensation
of 1,3-diphenyl-1H-pyrazol-5-amine with isatines in aqueous media to afford the
corresponding 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-one derivatives in good
yields.
Polyfunctionalized heterocyclic compounds play important roles in the drug discovery process, and
analysis of drugs in late development or on the market shows that 68% of them are heterocycles.1
Therefore, it is not surprising that research in the field of synthesis of heterocyclic compounds has
received special attention.
Isatine and derivatives have proved to be versatile starting materials for the synthesis of heterocyclic, and
non-cyclic, natural products, and analogues, as well as for the synthesis of potentially important
compounds with biological activities.2 Oxindoles are well known amongst these compounds. Oxindoles
are useful as antibacterial, antiflammatory, and laxatives.3 Furthermore, this heterocycle compounds were
recently isolated from plant. For example, the marine alkaloid convolutamydine A, isolated from the
marine bryozoan Amathia convolute was found to show potent activity in the differentiation of HL-60
human promyelocytic leukenie cell.4 Therefore, a number of methods have been reported for the synthesis
of oxindole derivatives.5
Heterocycles containing the pyrazole ring are important targets in synthetic and medicinal chemistry
because this fragment is a key moiety in numerous biologically active compounds,6 among them such
prominent drug molecules as Celecoxib, Pyrazofurine, and many others. Recently, they have also
emerged as potential atypical antipsychotics.7
Considering the above reports and in continuation of our previous works on synthesis of heterocyclic
compounds,8 we wish to report an efficient, and clean method for the preparation of
3,3-bis(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)indolin-2-one derivatives (3) in aqueous media (Scheme
1).

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HETEROCYCLES, Vol. 75, No. 9, 2008
R
N
O
O
Ph
Ph
X
Ph
X
H2O/ reflux/ p-TSA
+
O
N
2
N
NH2
N
N
N
N
NH2
H2N
N
R
Ph
Ph
Ph
1
2a-g
3a-g
Scheme 1
To achieve suitable conditions for above transformation, we tested the reaction of 1,3-
diphenyl-1H-pyrazol-5-amine (1) and isatine (2a) as a simple model substrate in different solvents in the
presence of p-TSA as an inexpensive and available catalyst at reflux conditions. The results are shown in
Table 1. It was found that water was a solvent of choice for the reaction and the desired product obtained
in good yield in water. In organic solvent the product obtained in low to moderate yield. In the absence of
solvent, the reaction was very slow and the yield of product was 50% at 100 oC after 8 h (entry 7).
Table 1. Solvent effect on the reactiona
Entry
1
Solvent
EtOH (reflux)
Yield (%)
53
Time ( h)
6
2
3
4
5
6
7
MeOH (reflux)
CHCl3 (reflux)
MeCN (reflux)
H2O (reflux)
57
trace
45
75
trace
50
6
6
6
4
10
8
toluene (reflux)
b
―
a 1,3-diphenyl-1H-pyrazol-5-amine (2 mmol), isatine (1 mmol),
p-TSA (0.1 mmol). b The reaction was run under solvent-free
conditions at 100 oC.
To study the generality of this process, several examples illustrating this method for the synthesis of
polyfunctionalized 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-one (3) were studied. The results are
summarized in Table 2. Varying the substituents on the isatine did not detrimentally affect the yields. The
condensation reaction proceeded smoothly under reflux in water to give the corresponding products (3) in
good yields.
Finally, it should be mentioned when reactions were carried out in the absence of catalyst for long period
of time (15-17 h) and under reflux in water the yields of products were low (<30%).
Compound (3) apparently result from the initial addition of 1,3-diphenyl-1H-pyrazol-5-amine (1) to the
isatines (2) to yield intermediate (4), which after dehydration reacted further with another molecule of

HETEROCYCLES, Vol. 75, No. 9, 2008
2295
1,3-diphenyl-1H-pyrazol-5-amine (1) to afford the corresponding 3,3-bis(5-amino-1H-pyrazol-4-
yl)indolin-2-one (3) (Scheme 2).
Table 2. Synthesis of 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-one 3a-g
Product 3
Compound 2
isatine (2a)
R
H
Me
Et
PhCH2
H
Me
H
X
H
H
H
H
Br
Br
NO2
Time (h)
Yield (%)
a
b
c
d
e
f
4
8
6
7
6
5
4
75
70
72
80
82
80
83
N-methylisatine (2b)
N-ethylisatine (2c)
N-benzylisatine (2d)
5-bromoisatine (2e)
5-bromo-N-methylisatine (2f)
5-nitroisatine (2g)
g
When we extended this reaction to ninhydrin (5), product of 9a-(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)-
4a-hydroxy-1,3-diphenyl-1,4,4a,9a-tetrahydro-9H-indeno[2',1':4,5]pyrrolo[3,2-c]pyrazol-9-one (6) was
generated in 68% yield after 7 h (Scheme 3). To the best of our knowledge, this paper is the first report in
the synthesis of 9a-(5-amino1H-pyrazol-4-yl)-4a-hydroxy-tetrahydro-9H-indeno[2',1':4,5]pyrrolo[3,2-c]-
pyrazol-9-one (6).
R
R
N
N
O
O
O
Ph
X
X
Ph
X
H+
OH
H+
+
Ph
O
N
NH2
N
- H2O
N
N
N
NH2
R
N
+
Ph
NH2
N
1
2a-g
4a-g
Ph
Ph
R
1
N
O
Ph
X
Ph
N
N
N
NH2 H2N
N
Ph
3a-g
Ph
Scheme 2
When we extended this reaction to ninhydrin (5), product of 9a-(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)-
4a-hydroxy-1,3-diphenyl-1,4,4a,9a-tetrahydro-9H-indeno[2',1':4,5]pyrrolo[3,2-c]pyrazol-9-one (6) was
generated in 68% yield after 7 h (Scheme 3). To the best of our knowledge, this paper is the first report in
the synthesis of 9a-(5-amino1H-pyrazol-4-yl)-4a-hydroxy-tetrahydro-9H-indeno[2',1':4,5]pyrrolo[3,2-c]-
pyrazol-9-one (6).

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HETEROCYCLES, Vol. 75, No. 9, 2008
O
OH
NH
Ph
Ph
O
H2O/ reflux/ p-TSA
O
+
2
N
N
NH2
N
N
Ph
NH2
O
N
Ph
N
Ph
Ph
68%
1
5
6
Scheme 3
In summary, we have described a clean, efficient and simple method for the preparation of 3,3-bis(5-
amino-1,3-diphenyl-1H-pyrazol-4-yl)indolin-2-one derivatives (3) in condensation reaction of 1,3-
diphenyl-1H-pyrazol-5-amine (1) and isatines (2) under reflux in water. Furthermore, a novel synthesis
of 9a-(5-amino1H-pyrazol-4-yl)-4a-hydroxy-tetrahydro-9H-indeno[2',1':4,5]pyrrolo[3,2-c]pyrazol-9-one
(6) was reported.
ACKNOWLEDGMENT
We gratefully acknowledge financial support from the Research Council of Shahid Beheshti University.
EXPERIMENTAL
Melting points were measured on an Electrothermal 9200 apparatus. IR spectra were recorded on FT-IR
1
13
102MB BOMEM apparatus. H NMR and C NMR spectra were determined on a BRUKER DRX-300
AVANCE spectrometer at 300.13 and 75.47 MHz, respectively. MS spectra were recorded on a Shimadzu
QP 1100EX mass spectrometer operating at an ionization potential of 70 eV. Elemental analyses were
performed using a Heracus CHN-O-Rapid analyzer.
Typical procedure for the preparation of 3,3-bis(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)-
indolin-2-one (3a-g): A mixture of 1,3-diphenyl-1H-pyrazol-5-amine (2 mmol), isatines (1 mmol) and
p-TSA (0.1 mmol) in water (5 mL) was stirred at reflux for appropriate time according to Table 1. After
completion of reaction (monitored by TLC) the reaction mixture was filtered and the precipitate washed
with water (15 mL) and then recrystallized from EtOH/ H2O (1:2) to afford the pure product (3).
Spectral data for products:
3a: White powder, mp180 oC (decomp.); IR (KBr) (νmax, cm-1): 3404, 3315, 1710, 1605; MS (m/z, %):
599 (M+, 35), 554 (38), 402 (100), 77 (50); 1H NMR (DMSO-d6) δH: 4.51 (2H, s, NH2), 4.91 (2H, s, NH2),
13
6.39-7.52 (24H, m, H-Ar.), 10.48 (1H, s, NH); C NMR (DMSO-d6) δC: 50.2, 98.5, 98.9, 109.8, 121.9,
123.8, 124.2, 126.3, 127.1, 127.2, 127.4, 128.6, 128.9, 129.1, 129.4, 129.5, 132.5, 135.3, 135.4, 138.8,
139.0, 141.3, 145.6, 145.7, 150.7, 150.8, 179.4. Anal. Calcd for C38H29N7O: C, 76.11; H, 4.87; N, 16.35%.
Found: C, 76.16; H, 4.83; N, 16.28%.

HETEROCYCLES, Vol. 75, No. 9, 2008
2297
o
3b: White powder, mp 218 C (decomp.); IR (KBr) (νmax, cm-1): 3400, 3294, 1701, 1605; MS (m/z, %):
613 (M+, 40), 521 (30), 402 (45), 235 (100), 77 (65); 1H NMR (DMSO-d6) δH: 2.78 (3H, s, Me), 3.91 (2H,
13
s, NH2), 4.82 (2H, s, NH2), 6.41-7.62 (24H, m, H-Ar.); C NMR (DMSO-d6) δC: 26.1, 49.6, 97.4, 98.8,
107.5, 122.6, 124.2, 124.4, 126.5, 127.0, 127.2, 127.3, 127.4, 127.6, 127.8, 128.1, 128.7, 129.1, 129.4,
129.5, 131.5, 134.2, 134.5, 138.0, 138.4, 142.2, 144.1, 145.8, 151.3, 178.2. Anal. Calcd for C39H31N7O: C,
76.33; H, 5.09; N, 15.98%. Found: C, 76.27; H, 5.03; N, 15.90%.
3c: White powder, mp 177 oC (decomp.); IR (KBr) (νmax, cm-1): 3447, 3310, 1705, 1603; MS (m/z, %):
1
627 (M+, 51), 402 (37), 235 (100), 77 (60); H NMR (DMSO-d6) δH: 1.16 (3H, bs, Me), 3.22 (2H, bs,
CH2), 4.11 (2H, bs, NH2), 4.64 (2H, bs, NH2), 6.40-7.75 (24H, m, H-Ar.); 13C NMR (DMSO-d6) δC: 12.6,
34.7, 49.5, 98.5, 108.9, 122.5, 123.9, 124.3, 125.9, 126.1, 127.4, 127.5, 127.7, 128.5, 128.8, 129.1, 129.6,
131.8, 134.7, 138.1, 138.4, 138.8, 141.7, 145.7, 146.3, 150.3, 150.7, 176.5. Anal. Calcd for C40H33FN7O:
C, 76.53; H, 5.30; N, 15.62%. Found: C, 76.59; H, 5.35; N, 15.54%.
o
3d: Yellow powder, mp 182 C (decomp.); IR (KBr) (νmax, cm-1): 3423, 1713, 1610; MS (m/z, %): 689
1
(M+, 20), 567 (48), 456 (25), 235 (45), 91 (100), 77 (40); H NMR (DMSO-d6) δH: 4.03 (2H, s,. NH2),
13
4.08 and 4.68 (2H, AB system, J= 15.1 Hz, CH2), 4.60 (2H, s, NH2), 6.40-7.76 (24H, m, H-Ar.); C
NMR (DMSO-d6) δC: 43.8, 49.7, 97.9, 98.9, 108.7, 122.7, 124.3, 124.4, 124.6, 125.8, 126.2, 126.5, 127.2,
127.3, 127.4, 127.6, 127.7, 127.9, 128.0, 128.5, 128.8, 129.3, 129.4, 129.5, 129.7, 131.3, 135.8, 141.4,
144.4, 145.5, 151.3, 178.1. Anal. Calcd for C45H35N7O: C, 78.35; H, 5.11; N, 14.21%. Found: C, 78.40; H,
5.17; N, 14.14%.
o
3e: White powder, mp 203 C (decomp.); IR (KBr) (νmax, cm-1): 3423, 3314, 1700, 1598; MS (m/z, %):
677 (M+, 30), 634 (42), 235 (100), 77 (85); 1H NMR (DMSO-d6) δH: 4.62 (2H, s, NH2), 5.07 (2H, s, NH2),
13
6.72-7.55 (23H, m, H-Ar.), 10.61 (1H, s, NH); C NMR (DMSO-d6) δC: 50.4, 97.7, 98.2, 111.7, 114.0,
123.8, 124.2, 127.1, 127.4, 127.6, 127.8, 128.7, 128.9, 129.5, 129.6, 131.4, 134.5, 135.1, 135.2, 138.8,
139.0, 140.7, 145.8, 146.0, 150.6, 150.7, 179.3. Anal. Calcd for C38H28BrN7O: C, 67.26; H, 4.16; N,
14.45%. Found: C, 67.31; H, 4.11; N, 14.52%.
3f: White powder, mp 215 oC (decomp.); IR (KBr) (νmax, cm-1): 3423, 3314, 1709, 1602; MS (m/z, %):
691 (M+, 30), 634 (40), 235 (60), 77 (100); 1H NMR (DMSO-d6) δH: 2.74 (3H, s, Me), 4.55 (2H, s, NH2),
13
5.26 (2H, s, NH2), 6.73-7.63 (23H, m, H-Ar.); C NMR (DMSO-d6) δC: 26.6, 49.7, 96.6, 98.3, 110.7,
114.8, 123.8, 124.3, 127.1, 127.6, 127.9, 128.7, 128.9, 129.1, 129.6, 129.7, 131.5, 133.9, 134.9, 135.1,
138.8, 139.1, 142.1, 145.7, 146.6, 150.6, 151.6, 176.9. Anal. Calcd for C39H30BrN7O: C, 67.63; H, 4.37;
N, 14.16%. Found: C, 67.69; H, 4.31; N, 14.22%.
3g: White powder, mp 228 oC (decomp.); IR (KBr) (νmax, cm-1): 3429, 1713, 1605; MS (m/z, %): 644 (M+,
1
34), 597 (65), 235 (100), 77 (90); H NMR (DMSO-d6) δH: 4.56 (2H, s, NH2), 5.11 (2H, s, NH2),
13
6.74-7.92 (23H, m, H-Ar.), 11.14 (1H, s, NH); C NMR (DMSO-d6) δC: 50.2, 97.1, 97.3, 110.0, 123.6,

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123.9, 124.3, 125.9, 127.1, 127.3, 127.6, 127.8, 128.5, 128.8, 128.9, 129.5, 129.6, 132.7, 134.9, 135.2,
138.6, 138.8, 142.3, 146.2, 147.7, 150.4, 150.6, 180.0. Anal. Calcd for C38H28N8O3: C, 70.80; H, 4.38; N,
17.38%. Found: C, 70.75; H, 4.32; N, 17.46%.
Synthesis
of
9a-(5-amino-1,3-diphenyl-1H-pyrazol-4-yl)-4a-hydroxy-1,3-diphenyl-1,4,4a,9a-
(6): mixture of
tetrahydro-9H-indeno[2',1':4,5]pyrrolo[3,2-c]pyrazol-9-one
A
1,3-diphenyl-1H-pyrazol-5-amine (2 mmol), ninhydrine (1 mmol), and p-TSA (0.1 mmol) in water (5
mL) was stirred at reflux for 7 h. After completion of reaction (monitored by TLC) the reaction mixture
was filtered and the precipitate washed with water (15 mL) and then recrystallized from MeOH/H2O (1:2)
to afford the pure product 6. White powder (68%), mp 162 oC (decomp.); IR (KBr) (νmax, cm-1): 3417,
1
3324, 1696, 1609; MS (m/z, %): 612 (M+, 40), 594 (54), 364 (100), 262 (87), 77 (85); H NMR
(DMSO-d6) δH: 7.00 (2H, bs, NH2), 7.12-8.00 (24H, m, H-Ar.), 10.33 (1H, s, OH), 12.44 (1H, s, NH).
Anal. Calcd for C39H28N6O2: C, 76.45; H, 4.61; N, 13.72. Found: C, 76.50; H, 4.55; N, 13.78.
Due to very low solubility of the product (6), we can not report the 13C NMR data for this product.
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