A novel one-pot synthesis of spirooxindole derivatives catalyzed by nano ZnO

Article abstract of DOI:10.4314/bcse.v27i2.17

Nano zinc oxide was explored as a heterogeneous and reusable catalyst for the one-pot synthesis of spirooxindoles via three-component reaction between urea, isatin, and 1,3-dicarbonyl compounds.

Full text of DOI:10.4314/bcse.v27i2.17

Bull. Chem. Soc. Ethiop. 2013, 27(2), 309-314.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v27i2.17
ISSN 1011-3924
 2013 Chemical Society of Ethiopia
SHORT COMMUNICATION
A NOVEL ONE-POT SYNTHESIS OF SPIROOXINDOLE DERIVATIVES
CATALYZED BY NANO ZnO
Bita Baghernejad* and Maliheh Khorshidi
Department of Chemistry, School of Sciences, Payame Noor University (PNU), 19395-3697,
Iran
(Received June 15, 2012; revised January 24, 2013)
ABSTRACT. Nano zinc oxide was explored as a heterogeneous and reusable catalyst for the one-pot synthesis
of spirooxindoles via three-component reaction between urea, isatin, and 1,3-dicarbonyl compounds.
KEY WORDS: Nano-ZnO, Spirooxindoles, Isatin
INTRODUCTION
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 spirooxindole 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], antiproliferative [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 high yield have attracted considerable attention in recent years since they
are performed without need to isolate the any intermediate during their processes and this
reduces time saves both energy and raw materials [13]. There has been tremendous development
in three or four component reaction specially the Bignelli [14], Passerini [15], Ugi [16] and
Mannich [17] reactions, which have further led to renaissance of MCRs. MCRs have emerged
as valuable tools for the preparation of structurally diverse chemical libraries of drug-like
heterocyclic compounds [18-20]. Nevertheless, great efforts have been and still are being made
to find and develop new MCRs. Zinc oxide is a non-hygroscopic, inexpensive, non-toxic [LD50
= 7950 mg/kg (mouse)] material, which has been utilized as a heterogeneous catalyst for
number of organic reactions [21]. Of late, catalysis by nano materials has become an area of
interest, as these materials exhibit better catalytic activity compared their bulk sized counterparts
[22].
As part of our program aimed at developing new methods for the preparation of new
compounds via MCRs [23], Herein, we used nano-ZnO as a catalyst for the synthesis of
spirooxindoles 7 and 8 via three-component reaction between urea, isatin, and 1,3-dicarbonyl
compounds (Scheme 1).
__________
*Corresponding author. E-mail: bitabaghernejad@yahoo.com

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Bita Baghernejad and Maliheh khorshidi
Scheme 1. Nano ZnO catalyzed synthesis of spirooxindoles.
RESULTS AND DISCUSSION
In connection with our recent interested aimed at the development of efficient protocols for the
preparation of biological active heterocycles, herein, we selected nano-ZnO as a new catalyst to
synthesis of these compounds.
In a typical procedure, urea (1 mmol), isatin (1 mmol), and dimedone (1 mmol) in the
presence of a catalytic amount of nano-ZnO in CH3CN at reflux temperature afforded the
desired spirooxindoles (7a) in 93% yield after 6 h (entry 1, Table 1). Similar trend was also
observed with bulk ZnO but the yields were comparatively lower than that for nano-ZnO (82%)
(entry 2, Table 2). This more yield with nano-ZnO may be attributed to the more surface area due to size
reduction.
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 5 h. The reaction proceeds very cleanly under reflux condition and free of side
products.
In order 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 obtained in CH3CN.
We evaluated the amount of nano-ZnO required for this transformation and found that as
little as 5 mol% of nano-ZnO catalyzed the reaction to some extent, but a longer reaction time
(> 5 h) was required. The use of an increased amount of catalyst did not improve the yield
significantly.
In order to show the merit of the present work, we compared the result of the synthesis of
these compounds in the presence of various catalysts but the best results obtained with nano-
ZnO (Table 2).
In conclusion, we have described a highly efficient procedure for the preparation of
spirooxindoles using nano-ZnO as a catalyst in good yield. Moreover, the procedure offers
several advantages including high yields, operational simplicity, cleaner reaction, minimal
environmental impact, and low cost, which make it a useful and attractive process for the
synthesis of these compounds.
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Table 1. Synthesis of spirooxindoles catalyzed by nano-ZnO.
Entry
1
X
H
1,3-Dicarbonyl
compounds
Product
Yield (%)a
40 ˚C
25 ˚C
55
82 ˚C
Dimedone
85
93
H
N
O
HN
O
O
N
H
7a
2
H
1,3-Cyclohexandione
50
76
92
H
N
O
HN
O
O
O
N
H
7b
3
H
Acetyl acetone
H
N
45
70
91
O
NH
O
N
H
8a
H
N
4
5
H
H
Ethyl acetoacetate
45
50
72
79
91
91
O
O
HO
NH
O
N
H
8b
Ph
O
1,3-Diphenyl-1,3-
propandione
H
N
O
Ph
NH
O
N
H
8c
6
7
Br Dimedone
50
45
77
70
93
93
H
N
O
HN
O
O
N
H
Br
7c
H
N
Br Acetyl acetone
O
O
NH
O
N
H
Br
8d
a Isolated yields.
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Table 2. Comparision of various catalysts for the synthesis of 7a.
Entry
Catalyst
Nano-ZnO
Bulk-ZnO
HClO4
Yield (%)
1
93
82
80
85
82
2
3
4
H2SO4
5
HCl
a Isolated yields.
Preparation of catalysts
Bulk zinc oxide was prepared by simple precipitation method wherein aqueous ammonia
solution (30%) was added dropwise to zinc nitrate solution under vigorous stirring (till pH of
solution reached (7.5–8). The white precipitate of Zn(OH)2 was filtered and washed several
times with distilled water till the washings were neutral. The precipitate was then dried
overnight at 100 °C in an oven and calcined at 600 °C for 3 h. Nano zinc oxide catalyst was
prepared by the gel combustion method as described by Riahi-Noori et al. [24]. An appropriate
molar ratio of citric acid and zinc nitrate (2:1) were mixed in a minimum amount of distilled
water. The aqueous solution was homogenized and further concentrated on a hot plate to a
viscous liquid, which was further heated at 100 °C for complete removal of water to obtain a
dry mass. This mass was then further heated gradually till its combustion occurred giving a
white fluffy powder. The powder obtained was annealed at 600 °C for 3 h to give nano-ZnO.
The oxide was further characterized by various analytical techniques to confirm its structural
properties. External morphology and particle size of the catalyst was determined by TEM image
(Figure 1). It is clear from TEM image that the zinc oxide has polymorphic geometry and the
size of the particles is in the range of 50-70 nm.
Figure 1. Transmission electron microscopy (TEM) image of nano-ZnO at 100 nm.
Preparation of spirooxindoles
Typical procedure. A mixture of the 1,3-dicarbonyl compounds (1 mmol), isatin (1 mmol), urea
(1 mmol) and nano-ZnO (5 mol%) in acetonitrile (5 mL) was refluxed for 6 h. The progress of
the reaction was monitored by TLC (ethyl acetate-hexane 1:3). On completion, the reaction
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313
mixture was washed with diethyl ether and the precipitate formed was filtered to give pure
product.
7a. M.p. 183-185 ºC; GC/MS: 311 (M+). IR (KBr) (νmax, cm−1): 3397, 3347, 3125, 1684, 1670,
1
1632; H NMR (CDC13, 500 MHz) δH (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) δC (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.
7b. M.p. 199-201 ºC; GC/MS: 283 (M+). IR (KBr) (νmax, cm−1): 3367, 3354, 3200, 1655, 1642,
1629; 1H NMR (CDC13, 500 MHz) δH (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) δC (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.
7c. M.p. 189-191 ºC; GC/MS: 390 (M+). IR (KBr) (νmax, cm−1): 3387, 3366, 3205, 1674, 1665,
1
1622; H NMR (CDC13, 500 MHz) δH (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) δC (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.
8a. M.p. > 300 ºC; GC/MS: 271 (M+). IR (KBr) (νmax, cm−1): 3419, 3400, 3194, 1706, 1661,
1
1611; H NMR (CDC13, 500 MHz) δH (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) δC (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.
8b. M.p. 185-188 ºC; GC/MS: 273 (M+). IR (KBr) (νmax, cm−1): 3448, 3361, 3267, 3199, 1702,
1
1673, 1632; H NMR (CDC13, 500 MHz) δH (ppm): 2.31 (3H, CH3, s), 7.16-7.53 (4H, m,
arom), 8.07 (4H, s, NH, OH). 13C NMR (CDC13, 125 MHz) δC (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.
8c. M.p. > 300 ºC; GC/MS: 395 (M+). IR (KBr) (νmax, cm−1): 3448, 3459, 3229, 1729, 1671,
1639; 1H NMR (CDC13, 500 MHz) δH (ppm): 7.09-7.96 (14H, m, arom), 7.84 (3H, s, NH). 13
C
NMR (CDC13, 125 MHz) δC (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.
8d. M.p. > 300 ºC; GC/MS: 350 (M+). IR (KBr) (νmax, cm−1): 3425, 3412, 3199, 1716, 1669,
1
1622, 1252, 998. H NMR (CDC13, 500 MHz) δH (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) δC (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.
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