Ultrasound-assisted one-pot, three-component synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(1′H)-diones in water

Article abstract of DOI:10.1016/j.ultsonch.2009.09.009

A simple, facile, efficient and three-component procedure for the synthesis of spiro[indoline-3,4′-pyrazolo[3,4-b]pyridine]-2,6′(1′H)-diones by the reaction of 4-hydroxycumarin, isatins and 1H-pyrazol-5-amines in water under ultrasonic irradiation is reported. The advantages of this method are the use of an inexpensive and readily available catalyst, easy work-up, good yields, and the use of water as a solvent that is considered to be relatively environmentally benign.

Full text of DOI:10.1016/j.ultsonch.2009.09.009

Ultrasonics Sonochemistry 17 (2010) 447–452
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound-assisted one-pot, three-component synthesis
of spiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-diones in water
*
Ayoob Bazgir , Somayeh Ahadi, Ramin Ghahremanzadeh, Hamid Reza Khavasi, Peiman Mirzaei
Department of Chemistry, Shahid Beheshti University G.C., P.O. Box 19396-4716, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
A simple, facile, efficient and three-component procedure for the synthesis of spiro[indoline-3,40-pyraz-
olo[3,4-b]pyridine]-2,60(10H)-diones by the reaction of 4-hydroxycumarin, isatins and 1H-pyrazol-5-
amines in water under ultrasonic irradiation is reported. The advantages of this method are the use of
an inexpensive and readily available catalyst, easy work-up, good yields, and the use of water as a solvent
that is considered to be relatively environmentally benign.
Article history:
Received 17 May 2009
Received in revised form 19 September
2009
Accepted 21 September 2009
Available online 26 September 2009
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Cumarin
Isatin
Pyrazole
Spirooxindole
Water
Ultrasound irradiation
1. Introduction
3-position, have shown high biological activity [7,8]. The spiroox-
indole system is the core structure of many pharmacological
Recently published comprehensive books [1] and papers [2]
indicate chemical applications of ultrasounds. ‘‘Sonochemistry”,
is a new trend in organic chemistry, offering a versatile and facile
pathway for a large variety of syntheses. Thus, a large number of
organic reactions can be carried out under ultrasonic irradiation
in high yields, short reaction times and mild conditions [1,2].
Multi-component reactions (MCRs) are of increasing impor-
tance in organic and medicinal chemistry, because the strategies
of MCR offer significant advantages over conventional linear-type
syntheses. MCRs leading to interesting heterocyclic scaffolds are
particularly useful for the creation of diverse chemical libraries
of ‘drug-like’ molecules for biological screening, since the combi-
nation of three or more small molecular weight building blocks in
a single operation leads to a high combinatorial efficacy [3,4].
Designing of multi-component reactions in water is another
attractive area in chemistry [5], because water is a cheap, safe
and environmentally benign solvent. There is need for developing
multi-component reactions in water with a suitable catalyst and
without the use of any harmful organic solvents.
agents and natural alkaloids [9,10]. Therefore, a number of meth-
ods have been reported for the preparation of spirooxindole fused
heterocycles [11–17].
Pyrazolopyridines are very interesting compounds and have re-
ceived considerable attention as a result of their biological activity
and structural relationship to indoles. A number of pyrazolopyri-
dines display interesting anxiolytic activity [18] (e.g. tracazolate
Ref. [19]), are potentially biologically active compounds as new
inhibitors of xantine oxidases [20] have proved to be active against
Gram positive and Gram negative bacteria [21] and as cholesterol
formation-inhibiting compounds [22] and are also promising for
the treatment of cataracts associated with diabetes [23].
As part of our continuing efforts on the development of new
routes for the synthesis of biologically active heterocyclic
compounds [24–32], we recently described an efficient synthesis
of spiro[pyrimido[4,5-b]quinoline-5,50-pyrrolo[2,3-d]pyrimidine]
and spiro[indoline-pyrido[2,3-d:6,5-d0]dipyrimidine] derivatives
via a condensation reaction between amino-uraciles and isatines
[33,34]. We have also developed an efficient synthesis of spiro[chro-
meno[2,3-d]pyrimidine-5,30-indoline]tetraones and spiro [indoline-
pyrazolopyrido[2,3-d]pyrimidine]triones via a reaction between
barbituric acids, isatins and cyclohexane-1,3-diones or amino-pyra-
zoles in water [35,36].
Indole and indoline fragments are important moieties of a large
number of a variety of natural products and medicinal agents [6],
and some of indolines, spiro-annulated with heterocycles in the
Considering the important biological properties of spirooxin-
doles fused heterocycles, we report herein a novel and clean
* Corresponding author. Fax: +98 21 2403041.
E-mail address: a_bazgir@sbu.ac.ir (A. Bazgir).
1350-4177/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.ultsonch.2009.09.009

448
A. Bazgir et al. / Ultrasonics Sonochemistry 17 (2010) 447–452
synthesis of spiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-
dione 4 through a three-component condensation reaction of 4-
hydroxycumarin 1, isatines 2 and 1H-pyrazol-5-amines 3 in the
presence of p-toluenesulfonic acid (p-TSA) as an inexpensive cata-
lyst in water under ultrasonic irradiation (Scheme 1).
2.2.1. 50-(2-Hydroxybenzoyl)-1-methyl-10,30-diphenyl-50,70-dihydrospiro
[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4b)
White powder (68%); mp 289 °C (dec); IR (KBr) (m
max, cmꢀ1):
3352, 1716, 1637; 1H NMR (300 MHz, DMSO-d6): dH = 3.28 (3H, s,
CH3), 6.10 (1H, s, CH), 6.51–7.92 (18H, m, H-Ar), 11.23 (1H, s,
NH), 11.29 (1H, bs, OH). 13C NMR (75 MHz, DMSO-d6): dC = 26.8,
47.9, 57.6, 102.3, 108.7, 118.0, 119.7, 122.2, 122.4, 123.5, 123.7,
127.5, 127.8, 128.0, 129.1, 129.8, 131.7, 132.4, 136.7, 138.1,
140.9, 145.6, 148.7, 160.5, 168.2, 176.3, 198.8. MS (EI, 70 eV) m/z
(%): 540 (M+). Anal. Calcd for C33H24N4O4: C, 73.32; H, 4.48; N,
10.36%. Found: C, 73.28; H, 4.53; N, 10.44%.
2. Experimental
2.1. Chemicals and apparatus
The chemical used in this work were obtained from Fluka and
Merck and were used without purification. Melting points were
measured on an Electrothermal 9200 apparatus. IR spectra were
recorded on a FT-IR 102MB BOMEM apparatus. Mass spectra were
recorded on a FINNIGAN-MAT 8430 mass spectrometer operating
at an ionization potential of 70 eV. 1H and 13C NMR spectra were
recorded on a BRUKER DRX-300 AVANCE spectrometer at 300.13
and 75.47 MHz. 1H and 13C NMR spectra were obtained on solu-
tions in DMSO-d6 using TMS. Ultrasonication was performed in a
EUROSONICÒ 4D ultrasound cleaner with a frequency of 50 kHz
and an output power of 350 W. The reaction flask was located in
the maximum energy area in the cleaner, where the surface of
reactants (reaction vessel) is slightly lower than the level of the
water, and the temperature of the water bath was controlled at
60 °C.
2.2.2. 1-Ethyl-50-(2-hydroxybenzoyl)-10,30-diphenyl-50,70-dihydrospiro-
[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione(4c)
Yellow powder (69%); mp 287 °C (dec); IR (KBr) (m
max, cmꢀ1):
3229, 1726, 1678; 1H NMR (300 MHz, DMSO-d6): dH = 1.30 (3H, t,
J = 6.2 Hz, CH3), 3.87 (2H, m, CH2), 6.09 (1H, s, CH), 6.50–7.94
(18H, m, H-Ar), 11.26 (1H, s, NH), 11.29 (1H, bs, OH). MS (EI,
70 eV) m/z (%): 554 (M+). Anal. Calcd for C34H26N4O4: C, 73.63; H,
4.73; N, 10.10%. Found: C, 73.67; H, 4.77; N, 10.16%.
Due to very low solubility of the product 4c, we can not report
the 13C NMR data for this product.
2.2.3. 1-Benzyl-50-(2-hydroxybenzoyl)-10,30-diphenyl-50,70-dihydrospiro-
[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4d)
Cream powder (71%); mp 237 °C (dec); IR (KBr) (m
max, cmꢀ1):
3440, 3055, 2921, 1724, 1712; 1H NMR (300 MHz, DMSO-d6):
dH = , 4.91 and 5.10 (2H, ABSystem, J = 15.1 Hz, CH2), 6.15 (1H, s,
CH), 6.46–7.96 (23H, m, H-Ar), 11.28 (1H, s, NH), 11.33 (1H, bs,
OH). 13C NMR (75 MHz, DMSO-d6): dC = 43.3, 48.0, 57.5, 102.2,
109.3, 118.0, 119.8, 122.5, 123.7, 127.4, 127.6, 127.7, 128.0,
128.8, 129.0, 129.8, 131.7, 136.9, 138.1, 141.0, 144.8, 160.6,
168.2, 176.4, 199.1. MS (EI, 70 eV) m/z (%): 616 (M+). Anal. Calcd
for C39H28N4O4: C, 75.96; H, 4.58; N, 9.09%. Found: C, 75.90; H,
4.51; N, 9.02%.
2.2. Typical procedure for the preparation of 50-(2-hydroxybenzoyl)-
10,30-diphenyl-50,70-dihydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-
2,60 (10H)-dione (4a)
A 25 mL flask was charged with 4-hydroxycumarin (0.16 g,
1 mmol), isatin (0.15 g, 1 mmol), 1,3-diphenyl-1H-pyrazol-5-
amine (0.24 g, 1 mmol), p-TSA (0.1 g) and water (5 mL). The reac-
tion mixture was sonicated at 60 °C for 6 h (TLC). After completion
of reaction, the reaction mixture was filtered and the precipitate
washed with water (10 mL) and recrystallized by EtOH to afford
the pure product 4a as white powder (70%). mp 280 °C (dec); IR
2.2.4. 50-(2-Hydroxybenzoyl)-5-nitro-10,30-diphenyl-50,70-
dihydrospiro- [indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione
(4e)
(KBr) (m
max, cmꢀ1): 3409, 3157, 3070, 1726, 1647; 1H NMR
(300 MHz, DMSO-d6) dH = 6.07 (1H, s, CH), 6.43–7.97(18H, m, H-
Ar), 10.66 (1H, s, NH), 11.22 (1H, s, NH), 11.31 (1H, bs, OH). 13C
NMR (75 MHz, DMSO-d6): dC = 48.5, 57.3, 102.6, 109.8, 118.0,
119.7, 121.7, 122.1, 123.7, 123.9, 127.8, 128.0, 128.2, 129.0,
129.8, 131.7, 132.5, 136.8, 138.2, 140.9, 144.2, 148.7, 160.6,
168.3, 178.22, 199.29. MS (EI, 70 eV) m/z (%): 526 (M+). Anal. Calcd
for C32H22N4O4: C, 72.99; H, 4.21; N, 10.64%. Found: C, 72.93; H,
4.17; N, 10.58%.
Cream powder (73%); mp 234 °C (dec); IR (KBr) (m
max, cmꢀ1):
3347, 1734, 1611; 1H NMR (300 MHz, DMSO-d6): dH = 6.30 (1H, s,
CH), 6.87–7.89 (17H, m, H-Ar), 11.15 (1H, s, NH), 11.32 (1H, s,
NH), 11.40 (1H, bs, OH). 13C NMR (75 MHz, DMSO-d6): dC = 48.1,
57.6, 101.6, 110.0, 118.0, 119.7, 120.4, 122.2, 123.7, 126.4, 127.9,
128.1, 128.2, 129.1, 131.7, 132.5, 136.9, 138.1, 140.7, 142.0,
148.7, 150.8, 160.4, 167.9, 178.7, 198.8. MS (EI, 70 eV) m/z (%):
R2
OH
H
N
O
Ph
N
N
R
O
i
O
+
+
N
H2N
Ph
N
N
R1
O
O
R
O
O
HO
N
R1
R2
1
2
3
4
i
: H2O, 60 oC, US,
p-TSA, 6 h.
R=H, Br, NO2, Me; R1= H, Me, Et, CH2Ph ; R2= H, NO2
Scheme 1.

A. Bazgir et al. / Ultrasonics Sonochemistry 17 (2010) 447–452
449
571 (M+). Anal. Calcd for C32H21N5O6: C, 67.25; H, 3.70; N, 12.25%.
Found: C, 67.31; H, 3.63; N, 12.17%.
(M+), 632 (M+). Anal. Calcd for C34H25BrN4O4: C, 64.46; H, 3.98;
N, 8.84%. Found: C, 64.41; H, 3.93; N, 8.90%.
2.2.5. 50-(2-Hydroxybenzoyl)-1-methyl-5-nitro-10,30-diphenyl-50,70-dihy-
2.2.10. 50-(2-Hydroxybenzoyl)-5-methyl-10,30-diphenyl-50,70-dihydro-
drospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4f)
spiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4k)
White powder (71%); mp 226 °C (dec); IR (KBr) (
m
max, cmꢀ1):
White powder (76%); mp 290 °C (dec); IR (KBr) (m
max, cmꢀ1):
3419, 3265, 1735, 1728; 1H NMR (300 MHz, DMSO-d6): dH = 3.39
(3H, s, CH3), 6.33 (1H, s, CH), 6.68–7.94 (17H, m, H-Ar), 11.09
(1H, s, NH), 11.38 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6):
dC = 27.3, 47.4, 57.8, 101.2, 109.1, 118.1, 119.7, 119.9, 122.2,
123.7, 126.4, 128.0, 128.1, 128.2, 128.4, 129.8, 131.7, 132.3,
136.8, 138.1, 140.8, 142.5, 148.7, 151.6, 160.3, 162.7, 167.8,
177.0, 198.5. MS (EI, 70 eV) m/z (%): 585 (M+). Anal. Calcd for
C33H23N5O6: C, 67.69; H, 3.96; N, 11.96%. Found: C, 67.63; H,
3.92; N, 11.91%.
3025, 1730, 1678; 1H NMR (300 MHz, DMSO-d6): dH = 1.77 (3H, s,
CH3), 5.99 (1H, s, CH), 6.57–7.96 (17H, m, H-Ar), 10.52 (1H, s,
NH), 11.18 (1H, s, NH), 11.30 (1H, s, OH). 13C NMR (75 MHz,
DMSO-d6): dC = 20.7, 48.4, 57.3, 102.8, 109.6, 118.0, 119.7, 122.2,
123.7, 127.6, 128.0, 128.2, 129.1, 129.8, 130.4, 131.7, 132.6,
136.7, 138.2, 140.7, 141.7, 148.8, 160.5, 168.3, 178.1, 199.1. MS
(EI, 70 eV) m/z (%): 540 (M+). Anal. Calcd for C33H24N4O4: C,
73.32; H, 4.48; N, 10.36%. Found: C, 73.26; H, 4.53; N, 10.31%.
2.2.11. 50-(2-Hydroxybenzoyl)-10-(4-nitrophenyl)-30-phenyl-50,70-dih-
2.2.6. 1-Ethyl-50-(2-hydroxybenzoyl)-5-nitro-10,30-diphenyl-50,70-dihy-
ydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4l)
drospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4g)
Brown powder (80%); mp 285 °C (dec); IR (KBr) (m
max, cmꢀ1):
Cream powder (78%); mp 224 °C (dec); IR (KBr) (
m
max, cmꢀ1):
3413, 3193, 1730, 1724; 1H NMR (300 MHz, DMSO-d6): dH = 6.12
(1H, s, CH), 6.44–8.45 (17H, m, H-Ar), 10.68 (1H, s, NH), 11.27
(1H, s, NH), 11.46 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6):
dC = 48.3, 57.1, 104.0, 109.9, 118.0, 119.8, 121.8, 122.0, 123.7,
125.5, 127.9, 128.0, 128.1, 129.1, 131.6, 136.9, 141.5, 143.1,
144.2, 146.0, 150.2, 160.5, 168.4, 178.0, 198.9. MS (EI, 70 eV) m/z
(%): 571 (M+). Anal. Calcd for C32H21N5O6: C, 67.25; H, 3.70; N,
12.25%. Found: C, 67.31; H, 3.76; N, 12.34%.
3445, 3394, 3234, 1725, 1673; 1H NMR (300 MHz, DMSO-d6):
dH = 1.36 (3H, bs, CH3), 3.94 (2H, bs, CH2), 6.34 (1H, s, CH), 6.83–
7.90 (17H, m, H-Ar), 11.14 (1H, s, NH), 11.39 (1H, s, OH). 13C
NMR (75 MHz, DMSO-d6): dC = 12.4, 35.3, 47.5, 57.8, 101.2, 109.1,
118.0, 119.8, 120.2, 122.1, 123.7, 126.4, 127.9, 128.1, 128.2,
129.8, 131.7, 132.4, 136.9, 138.1, 140.8, 142.3, 148.7, 150.8,
160.4, 167.8, 176.6, 198.7. MS (EI, 70 eV) m/z (%): 599 (M+). Anal.
Calcd for C34H25N5O6: C, 72.99; H, 4.21; N, 10.64%. Found: C,
73.03; H, 4.26; N, 10.58%.
2.2.12. 50-(2-Hydroxybenzoyl)-1-methyl-10-(4-nitrophenyl)-30-pheny
l-50,70-dihydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-
dione (4m)
2.2.7. 5-Bromo-50-(2-hydroxybenzoyl)-10,30-diphenyl-50,70-dihydrospiro-
[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4h)
Brown powder (81%); mp 276 °C (dec); IR (KBr) (m
max, cmꢀ1):
Cream powder (78%); mp 260 °C (dec); IR (KBr) (
m
max, cmꢀ1):
3625, 3183, 1728, 1685, 1642; 1H NMR (300 MHz, DMSO-d6):
dH = 3.28 (3H, s, CH3), 6.15 (1H, s, CH), 6.50–8.48 (17H, m, H-Ar),
11.2 (1H, s, NH), 11.54 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6):
dC = 26.8, 47.8, 57.4, 103.7, 108.8, 118.0, 119.7, 122.1, 122.4,
123.5, 123.7, 125.5, 127.1, 127.9, 128.0, 128.1, 129.3, 131.6,
131.8, 136.8, 141.6, 143.1, 145.6, 146.1, 150.2, 160.5, 168.4,
176.2, 198.5. MS (EI, 70 eV) m/z (%): 585 (M+). Anal. Calcd for
C33H23N5O6: C, 67.69; H, 3.96; N, 11.96%. Found: C, 67.62; H,
4.04; N, 11.89%.
3347, 3260, 3065, 1719, 1638; 1H NMR (300 MHz, DMSO-d6):
dH = 6.10 (1H, s, CH), 6.63–7.92 (17H, m, H-Ar), 10.79 (1H, s, NH),
11.24 (2H, bs, OH and NH). 13C NMR (75 MHz, DMSO-d6):
dC = 48.4, 57.3, 102.2, 111.7, 113.3, 118.0, 119.8, 122.1, 123.6,
127.1, 127.8, 128.0, 129.8, 130.4, 131.7, 132.5, 136.8, 138.1,
140.6, 143.5, 148.7, 160.5, 168.1, 177.8, 199.0. MS (EI, 70 eV) m/z
(%): 606 (M+), 604 (M+). Anal. Calcd for C32H21BrN4O4: C, 63.48;
H, 3.50; N, 9.25%. Found: C, 63.41; H, 3.56; N, 9.17%.
2.2.8. 5-Bromo-50-(2-hydroxybenzoyl)-1-methyl-10,30-diphenyl-50,70-
dihydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione
(4i)
2.2.13. 5-Bromo-50-(2-hydroxybenzoyl)-10-(4-nitrophenyl)-30-phenyl-
50,70-dihydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-
dione (4n)
White powder (81%); mp 270 °C (dec); IR (KBr) (
m
max, cmꢀ1):
Brown powder (72%); mp 285 °C (dec); IR (KBr) (m
max, cmꢀ1):
3024, 1730, 1678; 1H NMR (300 MHz, DMSO-d6): dH = 3.27 (3H, s,
CH3), 6.12 (1H, s, CH), 6.68–7.89 (17H, m, H-Ar), 11.17 (1H, s,
NH), 11.30 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): dC = 26.9,
47.8, 57.5, 101.8, 110.7, 114.1, 118.0, 119.6, 119.7, 122.1, 123.6,
126.8, 128.0, 128.9, 129.5, 129.8, 131.3, 131.6, 132.3, 136.4,
138.8, 138.1, 1403.7, 144.9, 148.7, 160.4, 168.0, 176.0, 198.5. MS
(EI, 70 eV) m/z (%): 620 (M+), 618 (M+). Anal. Calcd for
C33H23BrN4O4: C, 63.98; H, 3.74; N, 9.04%. Found: C, 64.03; H,
3.70; N, 9.10%.
3394, 3219, 1740, 1688, 1638; 1H NMR (300 MHz, DMSO-d6):
dH = 6.18 (1H, s, CH), 6.64–8.45 (16H, m, H-Ar), 10.89 (1H, s, NH),
11.24 (1H, s, NH), 11.53 (1H, bs, OH). 13C NMR (75 MHz, DMSO-
d6): dC = 48.4, 57.2, 103.6, 111.8, 113.4, 118.1, 113.4, 118.1, 119.8,
122.1, 123.7, 125.5, 127.2, 127.9, 128.1, 130.1, 131.8, 131.9,
136.9, 141.3, 143.1, 143.6, 148.1, 150.3, 160.5, 168.3, 177.7,
198.6. MS (EI, 70 eV) m/z (%): 651 (M+), 649 (M+). Anal. Calcd for
C32H20BrN5O6: C, 59.09; H, 3.10; N, 10.77%. Found: C, 59.15; H,
3.14; N, 10.71%.
2.2.9. 5-Bromo-1-ethyl-50-(2-hydroxybenzoyl)-10,30-diphenyl-50,70-di-
2.2.14. 50-(2-Hydroxybenzoyl)-5-nitro-10-(4-nitrophenyl)-30-phenyl-
50,70-dihydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-di-
one (4o)
hydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (4j)
Cream powder (75%); mp 263 °C (dec); IR (KBr) (m
max, cmꢀ1):
3399, 3219, 3065, 1716, 1637; 1H NMR (300 MHz, DMSO-d6):
dH = 1.29 (3H, t, J = 8.9 Hz, CH3), 3.85 (2H, m, CH2), 6.14 (1H, s,
CH), 6.85–7.88 (17H, m, H-Ar), 11.22 (1H, s, NH), 11.33 (1H, s,
OH). 13C NMR (75 MHz, DMSO-d6): dC = 12.4, 34.8, 47.9, 57.5,
101.8, 110.7, 113.9, 118.1, 119.8, 122.1, 123.7, 123.8, 127.1,
127.8, 128.1, 129.7, 129.9, 131.7, 132.4, 136.9, 138.1, 140.8,
143.9, 148.7, 160.5, 175.5, 198.8. MS (EI, 70 eV) m/z (%): 634
Brown powder (79%); mp 287 °C (dec); IR (KBr) (m
max, cmꢀ1):
3383, 3224, 1744, 1690, 1628; 1H NMR (300 MHz, DMSO-d6):
dH = 6.14 (1H, s, CH), 6.65–8.43 (16H, m, H-Ar), 10.88 (1H, s, NH),
11.25 (1H, s, NH), 11.56 (1H, bs, OH). 13C NMR (75 MHz, DMSO-
d6): dC = 48.1, 57.5, 102.9, 110.2, 118.1, 119.8, 120.4, 122.2, 123.7,
125.5, 126.5, 128.1, 128.3, 128.8, 131.6, 131.9, 136.9, 141.4,
142.1, 143.0, 146.2, 150.2, 150.8, 160.4, 168.1, 178.7, 198.5. MS

450
A. Bazgir et al. / Ultrasonics Sonochemistry 17 (2010) 447–452
(EI, 70 eV) m/z (%): 616 (M+). Anal. Calcd for C32H20N6O8: C, 62.34;
Table 2
Synthesis of spiro[indolinepyrazolopyridine]-diones.
H, 3.27; N, 13.63%. Found: C, 62.40; H, 3.22; N, 13.54%.
Product 4
R
R1
R2
Yield (%)a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
H
H
H
H
NO2
NO2
NO2
Br
Br
Br
Me
H
H
Br
NO2
NO2
H
H
H
H
H
H
H
H
H
H
H
H
NO2
NO2
NO2
NO2
NO2
70
68
69
71
73
71
70
78
81
75
76
80
81
72
79
73
2.2.15. 1-Ethyl-50-(2-hydroxybenzoyl)-5-nitro-10-(4-nitrophenyl)-30-
phenyl-50,70-dihydrospiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,6-
0(10H)-dione (4p)
Me
Et
Bz
H
Me
Et
H
Me
Et
H
H
Me
H
H
Et
Yellow powder (73%); mp 281 °C (dec); IR (KBr) (m
max, cmꢀ1):
3380, 3234, 1738, 1692, 1628; 1H NMR (300 MHz, DMSO-d6):
dH = 1.3 (3H, t, J = 7.1 Hz, CH3), 3.85 (2H, m, CH2), 6.18 (1H, s,
CH), 6.50–8.50 (17H, m, H-Ar), 11.28 (1H, s, NH), 11.58 (1H, s,
OH). 13C NMR (75 MHz, DMSO-d6): dC = 12.4, 34.5, 49.4, 57.2,
103.7, 113.7, 118.0, 122.0, 123.7, 125.5, 127.3, 128.0, 128.8,
128.9, 132.2, 138.3, 141.6, 143.4, 143.7, 144.6, 146.0, 146.1,
152.4, 159.3, 160.5, 168.4, 175.6, 176.7, 198.79. MS (EI, 70 eV) m/
z (%): 644 (M+). Anal. Calcd for C34H24N6O8: C, 63.35; H, 3.75; N,
13.04%. Found: C, 63.28; H, 3.69; N, 13.13%.
a
Isolated yields.
2.2.16. 50-(2-Hydroxybenzoyl)-10,30-diphenyl-50,70-dihydro-2H-spiro-
acenaphthylene-1,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-dione (8)
3. Results and discussion
Cream powder (66%); mp 241 °C (dec); IR (KBr) (m
max, cmꢀ1):
3316, 3224, 3044, 1721, 1632; 1H NMR (300 MHz, DMSO-d6):
dH = 6.40 (1H, s, CH), 6.31–8.19 (20H, m, H-Ar), 10.98 (1H, s, NH),
11.37 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): dC = 52.8, 59.1,
103.4, 118.0, 119.7, 121.0, 122.0, 122.2, 123.6, 127.2, 127.7,
128.0, 128.7, 129.1, 129.8, 130.4, 131.7, 132.3, 137.5, 138.1,
140.5, 142.4, 149.1, 160.4, 168.5, 198.6, 202.81. MS (EI, 70 eV) m/
z (%): 561 (M+). Anal. Calcd for C36H23N3O4: C, 76.99; H, 4.13; N,
7.48%. Found: C, 77.03; H, 4.18; N, 7.40%.
To achieve suitable conditions for the synthesis of spirooxindole
4, various reaction conditions and catalysts have been investigated
in the reaction of 4-hydroxycumarin 1, isatin 2a and 1H-pyrazol-5-
amines 3 as a model reaction (Table 1). As could be seen in Table 1,
the best result was obtained with p-TSA as a catalyst in water un-
der ultrasonic irradiation for 6 h at 60 °C. Apparently, lower reac-
tion time resulted in lower yield; while higher reaction time did
Table 1
Effect of reaction conditions.a
Ph
N
OH
H
N
O
Ph
N
O
O
+
+
N
H2N
Ph
N
N
H
O
O
Ph
O
O
HO
N
H
1
2a
3
4a
Entry
Conditions
Method
Catalyst
Yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H2O/60 °C
H2O/60 °C
H2O/50 °C
H2O/40 °C
H2O/60 °C
H2O/60 °C
H2O/60 °C
H2O/60 °C
H2O/60 °C
H2O/50 °C
H2O/60 °C
THF/60 °C
THF/60 °C
EtOH/60 °C
EtOH/60 °C
CH3CN/60 °C
CH3CN/60 °C
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
Ultrasound
High speed stirring
Ultrasound
High speed stirring
Ultrasound
High speed stirring
Ultrasound
High speed stirring
None
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
HOAc
ZnCl2
LiClO4
FeCl3
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
p-TSA
<30
70
45
<30
61b
72c
50
Trace
Trace
Trace
<30
40
<30
50
<30
47
<30
a
b
c
4-Hydroxycumarin (1 mmol), isatin (1 mmol) and 1H-pyrazol-5-amines (1 mmol), cat. (0.3 mmol), reaction times = 6 h.
Reaction times = 5 h.
Reaction times = 8 h.

A. Bazgir et al. / Ultrasonics Sonochemistry 17 (2010) 447–452
451
O
O
OH
O
Ph
O
O
OH
Ph
i
+
N
+
NH2
N
Ph
N
O
N
H
O
N
Ph
1
5
7
8
66%
i: H2O, 60 oC, US, p-TSA, 6 h
Scheme 3.
to afford spiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-
diones 4, in good yields (Table 2). 1H and 13C NMR spectra of
the crude products clearly indicated the formation of spirooxin-
dole fused pyrazolopyridine 4.
The nature of these compounds as 1:1:1 adducts was appar-
ent from their mass spectra, which displayed, in each case, the
molecular ion peak at appropriate m/z values. Compounds 4a–
p are stable solids whose structures were established by IR, 1H
and 13C NMR spectroscopy and elemental analysis. The structure
of 4 h was confirmed by a single-crystal X-ray analysis [37]
(Fig. 1).
To the best of our knowledge, this new procedure provides the
first example of an efficient and three-component method for the
synthesis of spiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-
diones. This method, based on three-component p-TSA-catalyzed
reaction in water under ultrasonic irradiation, is the most simple
and convenient and would be applicable for the synthesis of differ-
ent types of spiroindolinepyrazolopyridine-diones. Moreover, it is
worth noting that two C–C and one C–O bonds were formed with
concomitant creation of a spirooxindole fused pyrazolopyridine in
this one-pot, three-component process.
We have not established an exact mechanism for the formation
of spiro[indoline-3,40-pyrazolo[3,4-b]pyridine]-2,60(10H)-diones 4,
however, two reasonable possibilities are indicated in Scheme 2.
Addition of 4-hydroxycumarin 1 to isatin 3 leads to highly reactive
intermediate 5 via a standard nucleophilic addition. Interception of
5 by 1H-pyrazol-5-amines 3 and followed by cyclization produces
the corresponding spirooxindole 4 (Pathway A). Isatin 2 and
1H-pyrazol-5-amines 3 would react to produce highly reactive
intermediate 6, followed by a nucleophilic addition with 4-
Fig. 1. X-ray crystal structure of 4 h.
not affect the reaction yield (Table 1). When this reaction was car-
ried out without p-TSA or with other catalysts such as, ZnCl2, Li-
ClO4, FeCl3, TLC and 1H NMR spectra of the reaction mixture
showed a combination of starting materials and numerous prod-
ucts, the yield of the expected product was very poor (Table 1).
To study the effect of temperature on this synthesis, we also
performed three experiments in 40, 50, and 60 °C under ultra-
sonic irradiation (Table 1). It was observed that a lower reaction
temperature leads to a lower yield. To delineate the role of ultra-
sound and solvent effect, the reaction was investigated with and
without ultrasonic irradiation at the same temperature (60 °C) in
various solvents. In all reactions it was found that the use of
ultrasound irradiation leads to a higher yield. Table 1 demon-
strates that water was the best choice of solvent and the use
of ultrasound radiation in water improves the yield of the
product.
Therefore, the one-pot, three-component condensation reac-
tion of 4-hydroxycumarin 1, various isatines 2 and 1H-pyrazol-
5-amines 3 in the presence of p-TSA proceeded rapidly in water
at 60 °C under ultrasonic irradiation and were complete after 6 h
OH
R1
N
R
HO
O
O
O
1
OH
3
R1
N
O
5
H+
O
R
A
O
Ph
N
O
O
Ph
4
R
N
O
O
N
O
R1
N
NH2
NH2
N
N
R1
2
R
B
O
Ph
R2
OH
R2
1
H+
N
3
N
NH2
6
R2
Scheme 2.

452
A. Bazgir et al. / Ultrasonics Sonochemistry 17 (2010) 447–452
[13] R.Gr. Redkin, L.A. Shemchuk, V.P. Chernykh, O.V. Shishkin, S.V. Shishkina,
Tetrahedron 63 (2007) 11444.
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Chem. 12 (2004) 2483.
[17] A.A. Mohammadi, M. Dabiri, H. Qaraat, Tetrahedron 65 (2009) 3804.
[18] H. Hoehn, T. Denzel, US Patent, 3,755,340, August 28, 1973.
[19] B.A. Meiners, A.I. Salama, Eur. J. Pharmacol. 78 (1982) 315.
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hydroxycumarin 1 and cyclization to afford spirooxindole 4 (Path-
way 5).
As expected, when the isatin 2 was replaced by acenaphthylene-
1,2-dione 7, 50-(2-hydroxybenzoyl)-10,30-diphenyl-50,70-dihydro-2H-
spiro[acenaphthylene-1,40-pyrazolo [3,4-b]pyridine]-2,60(10H)-dione
8 was obtained under the same reaction conditions (Scheme 3).
4. Conclusion
[22] Y. Fujikama, M. Suzuki, H. Iwasaki, M. Sakashita, M. Kitahara, European Patent
Applied, EP 339,358, 1989.
[23] A. Abdel Hafed, I. Awad, R. Ahmed, Collect. Czech. Chem. Commun. 58 (1993)
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8790.
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2375.
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(2007) 1009.
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In conclusion, we have developed a facile, one-pot and three-
component procedure for the preparation of spiro[indoline-3,40-
pyrazolo[3,4-b]pyridine]-2,60(10H)-dione derivatives in water un-
der ultrasound radiations. The method is simple, starts from read-
ily accessible commercial starting materials, and provides
biologically interesting spirooxindole derivatives in good yields.
Moreover, it is worth noting that two C–C and one C–O bonds were
formed with concomitant creation of a spirooxindole fused pyraz-
olopyridine in this one-pot, three-component process.
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K
a
) = 1.495 mmꢀ1
,
structure was solved by using SHELXS. The structure refinement and data
reduction was carried out with SHELXL of the X-Step32 suite of programs [38].
The non-hydrogen atoms were refined anisotropically by full matrix least-
squares on F2 values to final R1 = 0.0876, wR2 = 0.1798 and S = 1.100 with 409
parameters using 7675 independent reflection (h range = 1.64–29.23°).
Hydrogen atoms were located from expected geometry and were not
refined. Crystallographic data for 4 h have been deposited with the
Cambridge Crystallographic Data Centre. Copies of the data can be obtained,
free of charge, on application to The Director, CCDC 746761, Union Road,
Cambridge CB2 1EZ, UK. Fax: +44 1223 336033 or e-mail:
deposit@ccdc.cam.ac.
[38] X-STEP32 Version 1.07b, X-ray Structure Evaluation Package, 2000, Stoe and
Cie, Darmstadt,Germany.