Novel one-pot synthesis of new oxindole derivatives catalyzed by ptsa

Article abstract of DOI:10.1080/00397911.2010.515364

The one-pot synthesis of spirooxindoles via three-component reaction of urea, isatin, and 1,3-dicarbonyl compounds in the presence of a catalytic amount of p-toluenesulfonic acid in acetonitrile has been carried out. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.515364

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Novel One-Pot Synthesis of New Oxindole
Derivatives Catalyzed by PTSA
Maliheh Khorshidi a , Majid M. Heravi a , Yahia S. Beheshtia a & Bita
Baghernejad a
a Department of Chemistry, School of Science, Azzahra University,
Vanak, Tehran, Iran
Published online: 29 Jun 2011.
To cite this article: Maliheh Khorshidi , Majid M. Heravi , Yahia S. Beheshtia & Bita Baghernejad
(2011): Novel One-Pot Synthesis of New Oxindole Derivatives Catalyzed by PTSA, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:19, 2899-2904
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Synthetic Communications1, 41: 2899–2904, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515364
NOVEL ONE-POT SYNTHESIS OF NEW OXINDOLE
DERIVATIVES CATALYZED BY PTSA
Maliheh Khorshidi, Majid M. Heravi, Yahia S. Beheshtia, and
Bita Baghernejad
Department of Chemistry, School of Science, Azzahra University,
Vanak, Tehran, Iran
GRAPHICAL ABSTRACT
Abstract The one-pot synthesis of spirooxindoles via three-component reaction of urea,
isatin, and 1,3-dicarbonyl compounds in the presence of
p-toluenesulfonic acid in acetonitrile has been carried out.
a catalytic amount of
Keywords Isatin; spirooxindoles; p-toluenesulfonic acid
The indole skeleton occurs in many important natural products, pharmaceuticals,
and other synthetic materials exhibiting a variety of biological activities and other
properties.[1] Spiro compounds represent an important class of naturally occurring
substances characterized by highly pronounced biological properties. The spirooxin-
dole system is the core structure of many pharmacological agents and natural
alkaloids.[2–5] Spirooxindoles with fused chromenes have been found to have a wide
spectrum of activities such as antimicrobial,[6] antiviral,[7] mutagenicity,[8] antiproli-
ferative,[9] sex pheromone,[10] antitumor,[11] and central nervous system activities.[12]
One-pot multicomponent reactions (MCRs), by virtue of their convergence,
productivity, facile execution, and excellent yields, have attracted considerable
attention in recent years because they are performed without need to isolate the
any intermediate during the processes, and this reduces time and saves both energy
and raw materials.[13] There has been tremendous development in three- or four-
component reactions, especially the Bignelli,[14] Passerini,[15] Ugi,[16] and Mannich[17]
reactions, which have led to a renaissance of MCRs. MCRs have emerged as valu-
able tools for the preparation of structurally diverse chemical libraries of drug-like
Received May 24, 2010.
Address correspondence to Majid M. Heravi, Department of Chemistry, School of Science, Azzahra
University, Vanak, Tehran, Iran. E-mail: mmh1331@yahoo.com
2899

2900
M. KHORSHIDI ET AL.
heterocyclic compounds.[18–20] Nevertheless, great efforts have been and still are
being made to find and develop new MCRs.
As part of our program aimed at developing new methods for the preparation
of new compounds via MCRs,[21] herein, we describe the use of p-toluenesulfonic
acid (PTSA) as a catalyst for the synthesis of spirooxindoles 7 and 8 (Scheme 1).
In a typical procedure, urea (1 mmol), isatin (1 mmol), and dimedone (1 mmol)
in the presence of a catalytic amount of PTSA in CH3CN at reflux temperature
afforded the desired spirooxindoles (7a) in 90% yield after 6 h (entry 4, Table 1).
To the best of our knowledge, there are no reports on the synthesis of these
compounds.
The effect of temperature was studied by carrying out the reactions at different
temperatures. The yields of reactions increased as the reaction temperature was
raised.
From these results, it was decided that refluxing temperature would be the best
temperature for all reactions. In each reaction, the yield is a function of the reaction
time, and the best time for all reactions was completed after 6 h. The reaction
proceeds very cleanly under reflux condition and is free of side products.
To show the generality and scope of this new protocol, we used various isatines
with 1,3-dicarbonyl compounds in the presence of PTSA, and the results obtained
are summarized in Table 1. This reaction was carried out in various solvents such
as CH3CN, chloroform, ethanol, and CH2Cl2, and the best results in terms of yield
and time were obtained in CH3CN.
We evaluated the amount of PTSA required for this transformation and found
that as little as 5 mol% of PTSA catalyzed the reaction to some extent, but a longer
reaction time (>6 h) was required. The use of an increased amount of catalyst did not
improve the yield significantly.
The yields of the reactions decreased when mineral acids were used.
In conclusion, we have described a highly efficient procedure for the
preparation of spirooxindoles using PTSA as a catalyst in good yield. Moreover,
the procedure offers several advantages including excellent yields, operational
Scheme 1.

SYNTHESIS OF NEW OXINDOLE DERIVATIVES
2901
Table 1. Synthesis of spirooxindoles catalyzed by PTSA
Yield (%)a
40 ꢀC 82 ꢀC
Entry
X
H
1,3-Dicarbonyl compounds
Product
25 ꢀC
1
Dimedone
55
85
92
2
H
1,3-Cyclohexandione
50
75
91
3
H
Acetyl acetone
45
70
91
4
H
Ethyl acetoacetate
45
72
90
5
H
1,3-Diphenyl-1,3-propandione
50
79
90
6
Br
Dimedone
50
77
93
(Continued )

2902
M. KHORSHIDI ET AL.
Table 1. Continued
Yield (%)a
40 ꢀC 82 ꢀC
Entry
X
1,3-Dicarbonyl compounds
Product
25 ꢀC
7
Br
Acetyl acetone
43
70
92
aIsolated yields.
Table 2. Comparison of various catalysts for the synthesis of 7a
Entry
Catalyst
Yield (%)
1
2
3
4
PTSA
HClO4
H2SO4
HCl
92
80
85
82
simplicity, clean reaction, minimal environmental impact, and low cost, which make
it a useful and attractive process for the synthesis of these compounds.
EXPERIMENTAL
Preparation of Spirooxindoles: Typical Procedure
A mixture of the 1,3-dicarbonyl compounds (1 mmol), isatin (1 mmol), urea
(1 mmol), and PTSA (5 mol%) in acetonitrile (5 mL) was refluxed for 6 h. The
progress of the reaction was monitored by thin-layer chromatography (TLC; ethyl
acetate–hexane 1:3). On completion, the reaction mixture was washed with diethyl
ether, and the precipitate that formed was filtered to give the pure product.
Selected Data
Compound 7a. Mp: 183–185 ꢀC; GC=MS: 311 (Mþ). IR (KBr) (nmax, cmꢁ1):
1
3397, 3347, 3125, 1684, 1670, 1632; H NMR (CDC13, 500 MHz) dH (ppm): 1.02
(3H, CH3, s), 1.11 (3H, CH3, s), 2.12 (2H, CH2, s), 2.56 (2H, CH2, s), 7.03–7.65
(4H, m, arom), 7.89 (3H, s, NH). 13C NMR (CDC13, 125 MHz) dC (ppm): 23.45,
26.71, 36.81, 42.56, 52.68, 69.81, 111.26, 116.56, 117.23, 123.56, 140.68, 142.76,
143.62, 148.76, 168.22, 169.78, 170.22.
Compound 7b. Mp: 199–201 ꢀC; GC=MS: 283 (Mþ). IR (KBr) (nmax, cmꢁ1):
3367, 3354, 3200, 1655, 1642, 1629; 1H NMR (CDC13, 500 MHz) dH (ppm): 2.25 (2H,
CH2, m), 3.00 (2H, CH2, m), 3.51 (2H, CH2, m), 7.01–7.71 (4H, m, arom), 8.01 (3H, s,
NH). 13C NMR (CDC13, 125 MHz) dC (ppm): 32.47, 34.67, 38.97, 69.84, 112.55,
117.01, 118.22, 140.09, 142.38, 144.96, 145.77, 148.66, 169.33, 171.71, 174.98.

SYNTHESIS OF NEW OXINDOLE DERIVATIVES
2903
Compound 7c. Mp: 189–191 ꢀC; GC=MS: 390 (Mþ). IR (KBr) (nmax, cmꢁ1):
1
3387, 3366, 3205, 1674, 1665, 1622; H NMR (CDC13, 500 MHz) dH (ppm): 1.00
(3H, CH3, s), 1.10 (3H, CH3, s), 2.40 (2H, CH2, s), 3.01 (2H, CH2, s), 7.10–7.50
(3H, m, arom), 8.30 (3H, s, NH). 13C NMR (CDC13, 125 MHz) dC (ppm): 22.96,
27.88, 39.97, 43.68, 54.97, 69.96, 112.32, 117.66, 118.48, 140.56, 142.48, 144.96,
146.70, 149.71, 169.21, 172.70, 174.32.
Compound 8a. Mp > 300 ꢀC; GC=MS: 271 (Mþ). IR (KBr) (nmax, cmꢁ1):
1
3419, 3400, 3194, 1706, 1661, 1611; H NMR (CDC13, 500 MHz) dH (ppm): 2.29
(3H, CH3, s), 2.51 (3H, CH3, s), 7.11–7.40 (4H, m, arom), 7.51 (3H, s, NH). 13C
NMR (CDC13, 125 MHz) dC (ppm): 21.33, 25.71, 48.56, 110.16, 111.56, 116.53,
124.06, 140.48, 142.44, 143.55, 148.14, 168.28, 169.66, 170.10.
Compound 8b. Mp: 185–188 ꢀC; GC=MS: 273 (Mþ). IR (KBr) (nmax, cmꢁ1):
1
3448, 3361, 3267, 3199, 1702, 1673, 1632; H NMR (CDC13, 500 MHz) dH (ppm):
2.31 (3H, CH3, s), 7.16–7.53 (4H, m, arom), 8.07 (4H, s, NH, OH). 13C NMR
(CDC13, 125 MHz) dC (ppm): 22.93, 49.66, 110.48, 111.33, 117.28, 122.96, 141.08,
142.99, 143.67, 148.93, 168.84, 169.12, 172.17.
Compound 8c. Mp > 300 ꢀC; GC=MS: 395 (Mþ). IR (KBr) (nmax, cmꢁ1):
3448, 3459, 3229, 1729, 1671, 1639; 1H NMR (CDC13, 500 MHz) dH (ppm):
7.09–7.96 (14H, m, arom), 7.84 (3H, s, NH). 13C NMR (CDC13, 125 MHz) dC
(ppm): 48.56, 110.16, 111.57, 111.68, 112.56, 112.69, 112.98, 113.09, 114.01,
114.29, 114.56, 115.01, 115.29, 115.63, 116.12 116.41, 124.11, 140.93, 143.56,
144.65, 147.18, 169.36, 169.66, 171.52.
Compound 8d. Mp > 300 ꢀC; GC=MS: 350 (Mþ). IR (KBr) (nmax, cmꢁ1):
1
3425, 3412, 3199, 1716, 1669, 1622, 1252, 998. H NMR (CDC13, 500 MHz) dH
(ppm): 2.36 (3H, CH3, s), 2.77 (3H, CH3, s), 7.19–7.89 (3H, m, arom), 7.69 (3H, s,
NH). 13C NMR (CDC13, 125 MHz) dC (ppm): 21.55, 25.96, 48.96, 110.99, 111.27,
117.61, 127.19, 147.33, 144.57, 146.82, 149.93, 169.23, 171.66, 172.29.
ACKNOWLEDGMENT
The authors are thankful to the Alzahra Research Council for the partial
financial support.
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