Ultrasound-assisted three-component synthesis of 3-(5-amino-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en yl)indolin-2-ones in water

Article abstract of DOI:10.1016/j.ultsonch.2009.11.017

Indium(III) chloride was found to be an efficient catalyst for the synthesis of 3-(5-amino-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-en yl)indolin-2-ones by one-pot, three-component reaction of dimedone, 1H-pyrazol-5-amines and isatins in water under ultrasonic irradiation. The advantages of this method are the use of a readily available catalyst, easy workup, excellent 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.2009.11.017

Ultrasonics Sonochemistry 17 (2010) 587–591
Contents lists available at ScienceDirect
Ultrasonics Sonochemistry
journal homepage: www.elsevier.com/locate/ultsonch
Ultrasound-assisted three-component synthesis of 3-(5-amino-1H-pyrazol-4-yl)-
3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-ones in water
Afshin Rajabi Khorrami a, Fereshteh Faraji a, Ayoob Bazgir b,
*
a Department of Chemistry, Faculty of Sciences, Islamic Azad University, Karaj Branch, Tehran, Iran
b Department of Chemistry, Shahid Beheshti University, GC, 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
Article history:
Indium(III) chloride was found to be an efficient catalyst for the synthesis of 3-(5-amino-1H-pyrazol-4-
yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-ones by one-pot, three-component reac-
tion of dimedone, 1H-pyrazol-5-amines and isatins in water under ultrasonic irradiation. The advantages
of this method are the use of a readily available catalyst, easy workup, excellent yields, and the use of
water as a solvent that is considered to be relatively environmentally benign.
Received 7 September 2009
Received in revised form 1 November 2009
Accepted 23 November 2009
Available online 27 November 2009
Ó 2009 Elsevier B.V. All rights reserved.
Keywords:
Dimedone
Isatin
Pyrazole
Oxindol
Water
Ultrasound irradiation
1. Introduction
In recent years, indium(III) chloride has received considerable
attention as an inexpensive, nontoxic, readily available catalyst
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].
Isatin and its 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 [3]. Oxindoles are
well known amongst these compounds. Oxindoles are useful as
antibacterial, antiinflammatory, and laxatives [4,5]. Furthermore,
this heterocycle compounds were recently isolated from plant
[6]. The 3,3-substituted oxindoles have been shown to possess
mechanism-specific antiproliferative, antibacterial, antiprotozoal,
and antiinflammatory activities [7–10]. Therefore, recently, few
methods have been developed for the synthesis of 3,3-substituted
oxindoles [4,11–14]. Similarly, heterocycles containing the pyra-
zole ring are important targets in synthetic and medicinal chemis-
try because this fragment is a key moiety in numerous biologically
active compounds [15–17], among them such prominent drug
molecules as Celecoxib, Pyrazofurine, and many others.
for various transformations under mild and convenient conditions,
affording the corresponding products in excellent yields with high
selectivity [18].
Considering the above reports and in continuation of our previ-
ous works on synthesis of heterocyclic compounds [19–31], herein,
we report a simple and efficient method for the preparation of
oxindole derivatives in water under ultrasonic irradiation. In fact,
as clearly stated by Sheldon [32], it is generally recognized that
‘‘the best solvent is no solvent and if a solvent (diluent) is needed
it should preferably be water”. The use of water as the reaction
medium represent a remarkable benefit since this green solvent
is highly polar and therefore immiscible with most organic com-
pounds; moreover the water soluble catalyst resides and operates
in the aqueous phase and separation of the organic materials is
thus easy.
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 102 MB BOMEM apparatus. Mass spectra were
recorded on a FINNIGAN-MAT 8430 mass spectrometer operating
* 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.2009.11.017

588
A.R. Khorrami et al. / Ultrasonics Sonochemistry 17 (2010) 587–591
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
50 °C.
2.2.3. 3-(5-Amino-1,3-diphenyl-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-
dimethyl-6-oxocyclohex-1-enyl)-1-methylindolin-2-one (4d)
Cream powder (82%); mp: 294 °C dec. IR (KBr) (m
max/cmÀ1):
3333 (NH2 and OH), 3051, 1691 (C@O), 1624 (C@O). MS (EI,
70 eV) m/z (%): 500 (M+–H20, 50), 416 (100), 426 (26), 387 (45).
1H NMR (300 MHz, DMSO-d6): dH (ppm) 0.97 (3H, s, CH3), 1.01
(3H, s, CH3), 1.93 and 2.06 (2H, AB system, J = 24.3 Hz, CH2), 2.60
(2H, s, CH2), 2.62 (3H, s, CH3), 6.58–7.65 (16H, m, H–Ar and NH2),
9.93 (1H, s, OH). 13C NMR (DMSO-d6): dC (ppm) 25.9 (NCH3), 27.3
(CH3), 28.6 (CH3), 32.5 (C(CH3)2), 41.4 (CH2), 48.8 (C), 50.9 (CH2),
102.0 (C@COH), 107.7 (NH2–C@C), 108.2, 122.2, 123.8, 124.1,
127.6, 127.9, 128.0, 128.1, 128.9, 129.9, 133.0, 137.5 and 138.1
(Ar), 143.6 (C), 149.7 (NHÀ2CN), 153.5 (NC@O), 178.2 (COH),
193.4 (C@O). Anal. Calcd for C32H30N4O3: C, 74.11; H, 5.83; N,
10.80%. Found: C, 74.17; H, 5.77; N, 10.87%.
2.2. Typical procedure for the preparation of 3-(5-amino-1,3-diphenyl-
1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-
indolin-2-one (4a)
A 25 mL flask was charged with dimedone (1 mmol), 1,3-diphe-
nyl-1H-pyrazol-5-amine (1 mmol), isatine (1 mmol), InCl3
(10 mol%) and water (5 mL). The reaction mixture was sonicated
at 50 °C for 2 h (TLC). After completion of reaction, the reaction
mixture was filtered and the precipitate washed with water
(10 mL) and recrystallized from EtOH to afford the pure product
2.2.4. 3-(5-Amino-1,3-diphenyl-1H-pyrazol-4-yl)-5-bromo-3-(2-hydr-
oxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-1-methylindolin-2-one (4e)
Cream powder (80%); mp: 294 °C dec. IR (KBr) (m
max/cmÀ1):
3224 (NH2 and OH), 2957, 1722 (C@O), 1618 (C@O). MS (EI,
70 eV) m/z (%): 598 (M++2, 50), 596 (M+, 50), 580 (30), 496 (100).
1H NMR (300 MHz, DMSO-d6): dH (ppm) 0.99 (3H, s, CH3), 1.01
(3H, s, CH3), 2.03 (2H, s, CH2), 2.49 (2H, s, CH2), 2.61 (3H, s, CH3),
6.55–8.31 (13H, m, H–Ar and NH2), 9.98 (1H, s, OH). 13C NMR
(DMSO-d6): dC (ppm) 26.0 (NCH3), 27.7 (CH3), 28.2 (CH3), 32.6
(C(CH3)2), 41.2 (CH2), 48.9 (C), 50.7 (CH2), 101.3 (C@COH), 107.7
(NH2–C@C), 109.7, 113.9, 124.4, 126.0, 127.8, 128.2, 128.5, 128.8,
129.9, 130.5, 132.8, 137.4, 138.0 and 139.6 (Ar), 143.0 (C), 149.6
(NHÀ2CN), 153.8 (NC@O), 177.9 (COH), 193.8 (C@O). Anal. Calcd
for C32H29BrN4O3: C, 64.32; H, 4.89; N, 9.38%. Found: C, 64.20; H,
4.82; N, 9.31%.
4a as white powder (91%). mp: 290 °C dec. IR (KBr) (m
max/cmÀ1):
3305 (NH2, NH and OH), 3070, 1706 (C@O), 1618 (C@O). MS (EI,
70 eV) m/z (%): 504 (M+, 10), 489 (10), 402 (100). 1H NMR
(300 MHz, DMSO-d6): dH (ppm) 0.92 (3H, s, CH3), 1.01 (3H, s,
CH3), 1.95 and 2.10 (2H, AB system, J = 16.1 Hz, CH2), 2.56 (2H, s,
CH2), 6.48–7.60 (16H, m, H–Ar and NH2), 9.79 (1H, s, NH), 9.99
(1H, s, OH). 13C NMR (DMSO-d6): dC (ppm) 27.3 (CH3), 28.6 (CH3),
32.4 (C(CH3)2), 41.4 (CH2), 49.4 (C), 51.1 (CH2), 101.9 (C@COH),
108.7 (NH2–C@C), 109.1, 121.5, 123.6, 124.2, 127.6, 128.1, 128.2,
129.0, 129.9, 133.2, 137.4, 138.1, and 138.6 (Ar), 142.8 (C), 149.8
(NHÀ2CN), 153.0 (NC@O), 179.9 (COH), 193.5 (CO). Anal. Calcd for
C31H28N4O3: C, 73.79; H, 5.59; N, 11.10%. Found: C, 73.74; H, 5.55;
N, 11.17%.
2.2.5. 3-(5-Amino-1,3-diphenyl-1H-pyrazol-4-yl)-1-ethyl-3-(2-
hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-one (4f)
White powder (83%); mp: 235 °C dec. IR (KBr) (m
max/cmÀ1):
2.2.1. 3-(5-Amino-1,3-diphenyl-1H-pyrazol-4-yl)-5-bromo-3-(2-
hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-one (4b)
3214 (NH2 and OH), 2866, 1713 (C@O), 1608 (C@O). MS (EI,
70 eV) m/z (%): 532 (M+, 5), 514 (M+–H2O, 10), 430 (100), 471
(40). 1H NMR (300 MHz, DMSO-d6): dH (ppm) 0.78 (3H, t,
J = 6.1 Hz, CH3), 0.97 (3H, s, CH3), 1.01 (3H, s, CH3), 2.07 (2H, s,
CH2), 2.59 (2H, s, CH2), 3.06 (1H, m, CH2), 3.30 (1H, m, CH2),
6.53–7.60 (14H, m, H–Ar and NH2), 9.86 (1H, s, OH). 13C NMR
(DMSO-d6): dC (ppm) 11.9 (CH3), 27.2 (CH3), 28.6 (CH3), 31.1
(NCH2), 32.5 (C(CH3)2), 41.3 (CH2), 48.8 (C), 50.9 (CH2), 101.8
(C@COH), 108.0 (NH2–C@C), 108.6, 122.0, 123.5, 124.2, 127.7,
127.9, 128.0, 128.2, 128.9, 129.9, 133.2, 137.4, 137.8 and 138.1
(Ar), 143.2 (C), 149.7 (NHÀ2CN), 153.1 (NC@O), 177.7 (COH),
193.6 (C@O). Anal. Calcd for C33H32N4O3: C, 74.41; H, 6.06; N,
10.52%. Found: C, 74.49; H, 6.01; N, 10.45%.
Cream powder (86%); mp: 240 °C dec. IR (KBr) (m
max/cmÀ1):
3219 (NH2, NH and OH), 2957, 1714 (C@O), 1616 (C@O). MS (EI,
70 eV) m/z (%): 582 (M+À1, 7), 564 (5), 482 (100), 402 (45). 1H
NMR (300 MHz, DMSO-d6): dH (ppm) 0.98 (6H, s, 2CH3), 1.98 (2H,
s, CH2), 2.58 (2H, s, CH2), 6.40–7.65 (15H, m, H–Ar and NH2),
9.90 (1H, s, NH), 9.94 (1H, s, OH). 13C NMR (DMSO-d6): dC (ppm)
27.6 (CH3), 28.2 (CH3), 32.5 (C(CH3)2), 41.3 (CH2), 49.5 (C), 50.8
(CH2), 101.2 (C@COH), 108.1 (NH2–C@C), 111.0, 113.0, 124.5,
126.3, 127.8, 128.2, 128.3, 128.9, 129.9, 130.4, 133.0, 137.4, 138.0
and 140.7 (Ar), 142.1 (C), 149.8 (NHÀ2CN), 153.5 (NC@O), 179.6
(COH), 193.7 (C@O). IR (KBr) cmÀ1
: 3219.4, 2957.49 and
2859.91,1714.69, 1616.47. Anal. Calcd for C31H27BrN4O3: C,
63.81; H, 4.66; N, 9.60%. Found: C, 63.87; H, 4.61; N, 9.66%.
2.2.2. 3-(5-Amino-1,3-diphenyl-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-
2.2.6. 3-(5-Amino-1,3-diphenyl-1H-pyrazol-4-yl)-5-bromo-1-ethyl-3-
dimethyl-6-oxocyclohex-1-enyl)-5-nitroindolin-2-one (4c)
(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-one (4g)
Light brown powder (92%); mp: 215 °C dec. IR (KBr) (mmax
/
Cream powder (85%); mp: 330 °C dec. IR (KBr) (m
max/cmÀ1):
cmÀ1): 3224 (NH2, NH and OH), 2952, 1735 (C@O), 1617 (C@O).
MS (EI, 70 eV) m/z (%): 549 (M+, 5), 529 (20), 419 (100). 1H NMR
(300 MHz, DMSO-d6): dH 0.99 (6H, s, 2CH3), 2.05 (2H, s, CH2),
2.51 and 2.65 (2H, AB system, J = 24.7 Hz, CH2), 6.58–8.03 (15H,
m, H–Ar and NH2), 10.03 (1H, s, NH), 10.55 (1H, s, OH). 13C NMR
(DMSO-d6): dC (ppm) 27.8 (CH3), 28.0 (CH3), 32.6 (C(CH3)2), 41.2
(CH2), 49.3 (C), 50.7 (CH2), 100.8 (C@COH), 107.6 (NH2–C@C),
109.0, 118.8, 124.5, 125.4, 127.9, 128.2, 128.5, 129.0, 129.9,
132.8, 137.9, 139.1, 142.2 and 149.4 (Ar), 149.8 (C), (NHÀ2CN),
154.2 (NC@O), 180.6 (COH), 193.9 (C@O). Anal. Calcd for
C31H27N5O5: C, 67.75; H, 4.95; N, 12.74%. Found: C, 67.70; H,
4.89; N, 12.68%.
3437 (NH2 and OH), 2945, 1691 (C@O), 1626 (C@O). MS (EI,
70 eV) m/z (%): 612 (M++2, 15), 610 (M+, 15), 592 (43), 416 (100).
1H NMR (300 MHz, DMSO-d6): dH (ppm) 0.77 (3H, s, CH3), 0.99
(6H, s, 2CH3), 2.02 (2H, s, CH2), 2.59 (2H, s, CH2), 3.05 (1H, m,
CH2), 3.34 (1H, bs, CH2), 6.58–7.63 (13H, m, H–Ar and NH2), 9.94
(1H, s, OH). 13C NMR (DMSO-d6): dC (ppm) 11.7 (CH3), 27.6 (CH3),
28.3 (CH3), 32.5 (NCH2), 34.3 (C(CH3)2), 41.2 (CH2), 48.9 (C), 50.7
(CH2), 101.0 (C@COH), 107.9 (NH2–C@C), 109.9, 113.7, 124.4,
126.3, 127.8, 128.2, 128.3, 128.9, 129.9, 130.6, 133.0, 137.5, 138.0
and 138.3 (Ar), 142.5 (C), 149.6 (NHÀ2CN), 153.6 (NC@O), 177.4
(COH), 193.7 (C@O). Anal. Calcd for C33H31BrN4O3: C, 64.81; H,
5.11; N, 9.16%. Found: C, 64.71; H, 5.02; N, 9.07%.

A.R. Khorrami et al. / Ultrasonics Sonochemistry 17 (2010) 587–591
589
2.2.7. 3-(5-Amino-1-(4-nitrophenyl)-3-phenyl-1H-pyrazol-4-yl)-3-
(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-one (4h)
Yellow powder (83%); mp: 294 °C dec. IR (KBr) (
max/cmÀ1):
2.2.9. 3-(5-Amino-1-(4-nitrophenyl)-3-phenyl-1H-pyrazol-4-yl)-1-
ethyl-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)indolin-2-
m
one (4j)
3419 (OH), 3219 (NH2 and NH), 1705 (C@O), 1609 (C@O). MS (EI,
70 eV) m/z (%): 549 (M+, 25), 531 (40), 368 (70), 57 (100). 1H
NMR (300 MHz, DMSO-d6): dH 1.00 (3H, s, CH3), 1.02 (3H, s, CH3),
1.99 and 2.09 (2H, AB system, J = 15.0 Hz, CH2), 2.50 (2H, bs,
CH2), 6.47–8.48 (11H, m, H–Ar and NH2), 7.92 (2H, d, J = 8.6 Hz,
H–Ar), 8.42 (2H, d, J = 8.4 Hz, H–Ar), 9.82 (1H, s, NH),9.93 (1H, s,
OH). 13C NMR (DMSO-d6): dC 27.3 (CH3), 28.5 (CH3), 32.5
(C(CH3)2), 41.4 (CH2), 49.2 (C), 51.0 (CH2), 103.0 (C@COH), 109.1
(NH2–C@C), 109.2, 121.6, 123.6, 124.2, 125.5, 127.7, 127.9, 128.5,
128.9, 132.6, 138.0, 138.2, 142.8 and 143.1 (Ar), 146.0 (C), 151.5
(NHÀ2CN), 152.8 (NC@O), 179.6 (COH), 193.7 (C@O). Anal. Calcd
for C31H27N5O5: C, 67.75; H, 4.95; N, 12.74%. Found: C, 67.63; H,
4.86; N, 12.68%.
Yellow powder (87%); mp: 294 °C dec. IR (KBr) (m
max/cmÀ1):
3435 (OH), 3214 (NH2), 1714 (C@O), 1606 (C@O). MS (EI, 70 eV)
m/z (%): 577 (M+, 10), 552 (40), 368 (70), 57 (100). 1H NMR
(300 MHz, DMSO-d6): dH 0.78 (3H, bs, CH3), 0.99 (3H, s, CH3),
1.01 (3H, s, CH3), 1.93 and 2.06 (2H, AB system, J = 24.3 Hz, CH2),
2.54 (2H, bs, CH2), 3.06 (2H, s, CH2), 6.56–7.24 (11H, m, H–Ar
and NH2), 7.93 (2H, bs, H–Ar), 8.40 (2H, bs, H–Ar), 9.99 (1H, s,
OH). 13C NMR (DMSO-d6): dC 11.8 (CH3), 27.3 (CH3), 28.5 (CH3),
32.5 (C(CH3)2), 34.2 (NCH2), 41.4 (CH2), 48.7 (C), 50.8 (CH2),
102.8 (C@COH), 108.0 (NH2–C@C), 108.9, 122.1, 123.6, 124.2,
125.4, 127.8, 128.1, 128.5, 128.8, 132.6, 137.5, 138.0, 143.1 and
143.2 (Ar), 146.0 (C), 151.4 (NHÀ2CN), 152.9 (NC@O), 177.5
(COH), 193.7 (C@O). Anal. Calcd for C33H31N5O5: C, 68.62; H,
5.41; N, 12.12%. Found: C, 68.71; H, 5.34; N, 12.04%.
2.2.8. 3-(5-Amino-1-(4-nitrophenyl)-3-phenyl-1H-pyrazol-4-yl)-3-
(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-1-methylindolin-2-
one (4i)
2.2.10. 3-(5-Amino-1-(4-nitrophenyl)-3-phenyl-1H-pyrazol-4-yl)-3-
(2-hydroxy-4,4-dimethyl-6-oxocyclohex-1-enyl)-5-nitroindolin-2-one
(4k)
Yellow powder (89%); mp: >320 °C. IR (KBr) (m
max/cmÀ1): 3465
(OH), 3219 (NH2), 1714 (C@O), 1601 (C@O). MS (EI, 70 eV) m/z
(%): 563 (M+, 10), 538 (40), 368 (70), 57 (100). 1H NMR
(300 MHz, DMSO-d6): dH 0.99 (3H, s, CH3), 1.02 (3H, s, CH3), 1.95
and 2.09 (2H, AB system, J = 15.7 Hz, CH2), 2.61 (5H, s, CH2 and
CH3), 6.58–7.27 (11H, m, H–Ar and NH2), 7.94 (2H, d, J = 8.8 Hz,
H–Ar), 8.43 (2H, d, J = 8.9 Hz, H–Ar), 10.01 (1H, s, OH). 13C NMR
(DMSO-d6): dC 25.9 (NCH3), 27.4 (CH3), 28.5 (CH3), 32.6 (C(CH3)2),
41.4 (CH2), 48.7 (C), 50.9 (CH2), 103.0 (C@COH), 107.9 (NH2–
C@C), 108.7, 122.3, 123.4, 124.2, 125.5, 127.8, 128.1, 128.6,
128.8, 132.4, 137.2, 137.9, 143.1 and 143.6 (Ar), 146.1 (C), 151.4
(NHÀ2CN), 153.2 (NC@O), 177.9 (COH), 193.8 (C@O). Anal. Calcd
for C32H29N5O5: C, 68.19; H, 5.19; N, 12.43%. Found: C, 68.13; H,
5.24; N, 12.49%.
Cream powder (90%); mp: 299 °C dec. IR (KBr) (m
max/cmÀ1):
3415 (OH), 3256 (NH2 and NH), 1710 (C@O), 1626 (C@O). MS (EI,
70 eV) m/z (%): 594 (M+, 10), 576 (40), 57 (100). 1H NMR
(300 MHz, DMSO-d6): dH 0.97 (3H, s, CH3), 1.02 (3H, s, CH3), 2.03
(2H, bs, CH2), 2.51 (2H, bs, CH2), 6.53–7.25 (10H, m, H–Ar and
NH2), 7.94 (2H, bs, H–Ar), 8.38 (2H, bs, H–Ar), 9.81 (1H, s, NH),
9.99 (1H, s, OH). 13C NMR (DMSO-d6): dC 27.5 (CH3), 28.7 (CH3),
32.4 (C(CH3)2), 41.4 (CH2), 48.6 (C), 50.4 (CH2), 101.9 (C@COH),
108.1 (NH2–C@C), 108.4, 122.0, 123.7, 124.0, 125.4, 127.6, 128.3,
128.5, 129.4, 132.5, 137.1, 138.5, 143.3 and 143.8 (Ar), 146.1 (C),
151.9 (NHÀ2CN), 152.3 (NC@O), 177.8 (COH), 193.4 (C@O). Anal.
Calcd for C31H26N6O7: C, 62.62; H, 4.41; N, 14.13%. Found: C,
62.54; H, 4.49; N, 14.19%.
Table 1
Model reaction, conditions, and yield.a
HN
O
Ph
O
O
Ph
N
+
N
+
O
NH2
N
N
OH
H2N
N
H
O
O
Ph
2a
Ph
1
3a
4a
Entry
Conditions (°C)
Method
Catalyst (mol%)
Yield (%)
1
2
3
4
5
6
7
8
H2O/50
H2O/50
H2O/50
H2O/50
H2O/50
H2O/50
H2O/50
H2O/50
H2O/30
H2O/40
H2O/50
THF/50
THF/50
EtOH/50
EtOH/50
CH3CN/50
CH3CN/50
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
HOAc (15)
ZnCl2 (15)
LiClO4 (15)
p-TSA (15)
None
InCl3 (10)
InCl3 (15)
InCl3 (20)
InCl3 (15)
InCl3 (15)
InCl3 (15)
InCl3 (15)
InCl3 (15)
InCl3 (15)
InCl3 (15)
InCl3 (15)
InCl3 (15)
Trace
Trace
55
43
Trace
68
90
91
47
70
<30
75
<30
65
<30
69
<30
9
10
11
12
13
14
15
16
17
a
1H-pyrazol-5-amine (1 mmol), dimedone (1 mmol), isatin (1 mmol); reaction times = 2 h.

590
A.R. Khorrami et al. / Ultrasonics Sonochemistry 17 (2010) 587–591
RN
OH
X
O
Ph
O
O
Ph
H2O/ 50 oC
X
N
N
+
NH2
O
+
N
N
O
O
InCl3 (15 mol %)
H2N
4a-k
N
Ar
Ar
R
)))))
Ar= C6H5
2a
3a-g
1
Ar= 4-NO2-C6H4 2b
Scheme 1.
Table 2
Synthesis of oxindoles 4.
Table 3
Synthesis of 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-one 5.
Product 4
R
X
Ar
Time (h)
Yield (%)a
NR
a
b
c
d
e
f
g
h
i
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-NO2–C6H4
4-NO2–C6H4
4-NO2–C6H4
4-NO2–C6H4
2
90
86
92
82
80
83
85
83
89
87
90
O
O
X
Ph
Ph
N
Br
NO2
H
Br
H
Br
H
H
1.7
1.5
2
1.8
2
X
H2O/ 50 o
C
Ph
+
2
O
N
NH2
Me
Me
Et
Et
H
Me
Et
H
InCl3 (15 mol%)
))))
N
N
N
N
R
H2N
NH2
N
Ph
Ph
Ph
2
2
3
5
1.2
1.5
1.5
1
j
k
H
NO2
Product 5
R
X
Time (h)
Yield (%)
a
b
c
d
e
f
H
H
H
H
Br
Br
NO2
50
60
60
30
40
30
85
82
80
88
84
91
a
Isolated yields.
Me
Et
H
Me
H
3. Results and discussion
To achieve suitable conditions for the synthesis of 3-(5-ami
no-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-
1-enyl)indolin-2-ones 4, various reaction conditions and catalysts
have been investigated in the reaction of dimedone 1, 1,3-diphe-
nyl-1H-pyrazol-5-amine 2a, and isatin 3a as a model reaction (Ta-
ble 1). As could be seen in Table 1, the best result was obtained
with a 15 mol% of InCl3 as the catalyst in water at 50 °C under ultra-
sonic irradiation (entry 7). Using lower amount of catalyst resulted
in lower yields, while higher amount of catalyst did not affect reac-
tion times and yields (Table 1). When this reaction was carried out
without InCl3 or with other catalysts such as, ZnCl2, LiClO4, p-TSA,
HOAc, the yield of the expected product was very low (Table 1).
To study the effect of temperature on this synthesis, we also
performed three experiments in 30, 40, and 50 °C under ultrasonic
irradiation (Table 1). It was observed that a lower reaction temper-
ature led to a lower yield. To delineate the role of ultrasound and
solvent effect, the reaction was investigated with and without
ultrasonic irradiation at the same temperature (50 °C) in various
solvents. In all reactions it was found that the use of ultrasound
irradiation leads to a higher yield. Table 1 demonstrates that water
is 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 reaction
of dimedone 1, 1H-pyrazol-5-amines 2a and b, and various isatines
3a–g in the presence of InCl3 (15 mol%) proceeded rapidly in water
at 50 °C under ultrasonic irradiation and were complete after 1–2 h
to
afford
3-(5-amino-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-di-
methyl-6-oxocyclohex-1-enyl)indolin-2-ones 4a–k, in good yields
(Scheme 1 and Table 2). 1H and 13C NMR spectra of the crude prod-
ucts clearly indicated the formation of oxindol 4.
Ph
RN
N
NH2
X
O
N
Ar
Ph
1
2
OH
InCl3
N
NH2
N
Ar
InCl3
O
RN
O
X
O
X
O
Ph
N
N
R
N
OHH2N
RN
Ar
4
X
O
O
O
O
2
1
OH
InCl3
OH
Scheme 2.

A.R. Khorrami et al. / Ultrasonics Sonochemistry 17 (2010) 587–591
591
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ular ion peak at appropriate m/z values. Compounds 4a–k are sta-
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spectroscopy and elemental analysis.
To the best of our knowledge, this new procedure provides the
first example of an efficient and three-component method for the
synthesis of 3-(5-amino-1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-di-
methyl-6-oxocyclohex-1-enyl)indolin-2-ones. This method, based
on three-component InCl3-catalyzed reaction in water under ultra-
sonic irradiation, is the most simple and convenient and would be
applicable for the synthesis of different types of oxindoles.
We have not established an exact mechanism for the formation
of 3-(1H-pyrazol-4-yl)-3-(2-hydroxy-4,4-dimethyl-6-oxocyclohex-
1-enyl)indolin-2-one 4, however, a reasonable possibility is shown
in Scheme 2.
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zol-4-yl)indolin-2-ones 5 via a reaction of 1,3-diphenyl-1H-pyra-
zol-5-amine 2 with isatins 3 in the presence of p-TSA in refluxing
water within 4–8 h. To further explore the potential of InCl3-cata-
lyzed reaction under ultrasonic irradiation for oxindoles synthesis,
we investigated reaction of 1,3-diphenyl-1H-pyrazol-5-amine 2
with isatins 3 under similar conditions (InCl3/H2O/US) and ob-
tained 3,3-bis(5-amino-1H-pyrazol-4-yl)indolin-2-ones 5 in good
yields for 30–60 min (Table 3). As could be seen in Table 1, the
use of ultrasound irradiation leads to a higher yield.
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In conclusion, we have developed a facile, one-pot and three-
component procedure for the preparation of oxindole derivatives
in water under ultrasound radiations in the presence of InCl3 as a
nontoxic and available catalyst. The method is simple, starts from
readily accessible commercial starting materials, and provides bio-
logically interesting oxindol derivatives in good yields.
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