A new silica-supported organocatalyst based on L-proline: An efficient heterogeneous catalyst for one-pot synthesis of spiroindolones in water

Article abstract of DOI:10.1016/j.molcata.2013.07.009

A simple and practical synthetic strategy for the synthesis of a novel silica-supported organocatalyst system based on L-proline (SSLP) has been developed. First, silica was treated with trimethoxy(vinyl)silane to produced a vinyl-silica (VS) substrate. T

Full text of DOI:10.1016/j.molcata.2013.07.009

Accepted Manuscript
Title: A new silica-supported organocatalyst based on
L-proline: An efficient heterogeneous catalyst for one-pot
synthesis of spiroindolones in water
Author: Ali Khalafi-Nezhad Elham Shaikhi Shahidzadeh
Samira Sarikhani Farhad Panahi
PII:
S1381-1169(13)00271-9
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.molcata.2013.07.009
MOLCAA 8809
To appear in:
Journal of Molecular Catalysis A: Chemical
Received date:
Revised date:
Accepted date:
18-4-2013
19-7-2013
20-7-2013
Please cite this article as: A. Khalafi-Nezhad, S. Sarikhani, F. Panahi, A new silica-
supported organocatalyst based on L-proline: An efficient heterogeneous catalyst
for one-pot synthesis of spiroindolones in water, Journal of Molecular Catalysis A:
Chemical (2013), http://dx.doi.org/10.1016/j.molcata.2013.07.009
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A new silica-supported organocatalyst based on L-proline: An efficient
heterogeneous catalyst for one-pot synthesis of spiroindolones in water
Ali Khalafi-Nezhad,* Elham Shaikhi Shahidzadeh, Samira Sarikhani and Farhad Panahi*
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran.
Corresponding authors: Fax +98(711)2280926. E-mails: khalafi@chem.susc.ac.ir,
panahi@shirazu.ac.ir
Abstract
A simple and practical synthetic strategy for the synthesis of a novel silica-supported
organocatalyst system based on L-proline (SSLP) has been developed. First, silica was
treated with trimethoxy(vinyl)silane to produced a vinyl-silica (VS) substrate. Then, VS
was oxidized using H O to generate the silica-oxiran (SO) material. Finally, ring-
2
2
opening of oxiranes in SO substrate with L-proline was resulted the production of SSLP
catalyst. The catalytic performance of SSLP was evaluated in the three-component
synthesis of spirooxindole derivatives via the condensation reaction of isatins and
dicarbonyl compounds in water. All reactions were completed in short times and all
products were obtained in good to excellent yields. Besides, SSLP could be recovered for
8
times without any additional treatments.
Keywords: silica-supported organocatalyst; L-proline; heterogeneous catalyst;
spiroindolones; water
1
Page 1 of 28

1
. Introduction
In the recent years, organocatalysis has emerged as a powerful methodology in
organic synthesis for the construction of new materials. The application of
organocatalytic systems for fine chemical synthesis, provides some advantages such as
lack of sensitivity to moisture and oxygen, ready availability, low cost, and low toxicity
[1-3]. The most interest to the organocatalytic systems is attributed from this fact that
they possesses huge direct benefits in organic synthesis, when compared with other
catalytic systems [4-6]. However, the capability and applicability of an organocatalyst in
organic transformations can be improved if its recovery and reuse procedure become
more and more facile [7-9]. So briefly the recycling capability of an organocatalyst has
the following advantages: simpilicity in the practical separation of the catalyst from the
products and reaction mixture, economical impacts (in several cases organocatalysts are
used up to 30 mol %), avoiding wastes and potential for the application in large-scale
operations [10-12]. Considering these points, development of a recyclable organocatalyst
with high catalytic performance is the main subject of much current studies [13, 14].
There are various reported methods for the preparation of recyclabale organocatalytic
systems [15-25]. Among the used strategies, preparation of solid-supported
organocatalysts are potentially highly useful method for the preparation of more efficient
catalytic systems for the synthesis of fine chemicals under especially simple, mild and
more environmentally benign conditions [26]. So far, amino acids and their derivatives,
pyridines, alkaloids, pyrrolidine, biguanidine, and piperidine are the most supported on
solid substrates organocatalysts [27-32]. This is noteworthy that L-proline and its
derivatives have shown considerable catalytic efficiency in different organic
2
Page 2 of 28

transformations [33]. Nowadays, there are widespread interest to the development of new
heterogeneous organocatalysts based on L-proline [34]. Also, among the various
materials used as a support for the preparation of heterogeneous organocatalysts, silica
has particular importance because of its abundant availability, high stability and the fact
that organic groups can adjoin to the silica surface with strong connection that lead to the
generation of more stable catalytic sites [35].
In the current study, we would like to report a new and easy access to a new silica-
supported organocatalyst based on L-proline. Our main purpose for the design of this
reusable organocatalyst is preparation of a heterogeneous and more convenient catalytic
system for the application in multicomponent reactions (MCRs). MCRs have gained
considerable interest in both academia and industry, owing to exceptional synthetic
efficiency, intrinsic atom-economy, and simplicity [36, 37]. MCRs avoiding the
complicated purification operations and allowing save of both materials and energy [38].
On the other hand, isatin and its derivatives possess a broad range of biological and
pharmacological properties and are widely used as starting materials in MCRs for the
synthesis of a broad range of heterocyclic compounds [39]. Drugs containing the isatin
skeleton are used for the treatment of various diseases such as epilepsy, tuberculosis, and
bulimia [40-42]. Therefore the need to create novel isatin derivatives for emerging drug
targets is an active area of medicinal chemistry [43, 44]. Herein, we disclosed an efficient
one-pot access to spirooxindole derivatives using a three-component reaction of isatins
and dicarbonyl compounds in water catalyzed by a highly efficient silica-supported
organocatalyst based on L-proline (SSLP) as a new entry of heterogeneous
organocatalysts.
3
Page 3 of 28

2
. Experimental
2
.1. General
All chemicals were purchased from Fluka and Aldrich chemical companies and used
without further purification. Known products were characterized by comparison of their
1
13
spectral and physical data with those reported in the literature. H (250 MHz) and C
NMR (62.9 MHz) spectra were recorded on a Bruker Avance spectrometer in CDCl and
3
DMSO-d solutions with tetramethylsilane (TMS) as an internal standard. FT-IR
6
spectroscopy (Shimadzu FT-IR 8300 spectrophotometer) was employed for the
characterization of the catalyst and obtained products. The Raman spectrum was also
taken using the Nicolet Almega Dispersive Raman (Thermo Scientific, USA)
spectrometer. The thermogravimetry analysis (TGA) of the samples was analyzed using a
hand-made TGA instrument. Melting points were determined in open capillary tubes with
a Barnstead Electro-thermal 9100 BZ circulating oil melting point apparatus. The
reaction monitoring was accomplished by TLC on silica gel PolyGram SILG/UV254
plates.
2
.2. Experimental procedure for the synthesis of silica-supported organocatalyst
based on L-proline (SSLP)
2
.2.1. The synthesis of vinyl silica (VS)
Silica (10 g) was charged to a 100 mL three-necked flask containing anhydrous
chloroform (70 mL). Trimethoxy(vinyl)silane (3.54 g, 0.02 mol) was added drop-wise to
the obtained mixture over a period of 5 min at room temperature. When the addition was
completed, the mixture was stirred magnetically and refluxed for 12 h. After this time,
the reaction mixture was filtered and the obtained solid was washed with chloroform (20
4
Page 4 of 28

mL, two times), dried in vacuum at 50 °C for 24 h and vinyl silica was obtained as a
white powder.
2
.2.2. The synthesis of silica oxirane (SO)
The mixture of vinyl silica (5 g) and H O 30% (20 mL) in a round-bottomed flask
2
2
was stirred at 50 °C for 12 h. The resulting white precipitate was filtered through a celite
pad, washed with water (10 mL, 2 times), dried in vacuum for 24 h to afford the SO
substrate as a white solid.
2
.2.3. The preparation of silica supported N-Boc-protected L-proline (SSNBLP)
The N-Boc-protected L-proline (0.6 g) was added to a suspension of SO (5g) in
chloroform (40 mL). Then, Et N (0.5 mL) was added to the reaction mixture.
3
Subsequently, the mixture was stirred for 20h under reflux condition. The resulting
precipitate was filtered through a celite pad, washed with water (10 mL, 2 times), dried in
vacuum to afford the silica supported N-Boc-protected L-proline (SSNBLP) as a white
product.
2
.2.4. The synthesis of SSLP via N-Boc deprotection of SSNBLP
N-Boc deprotection of SSNBLP was performed based on a reported procedure [45].
To a round-bottomed flask containing water (5 mL), SSNBLP (5g) is added and the
obtained mixture was stirred and refluxed for 1 h. Then, the reaction mixture was cooled
down to room temperature, filtered through a celite pad and washed with water (15 mL,
two times) and EtOH (10 mL, two times) and the obtained solid was dried in vacuum for
overnight to give SSLP as a white powder.
2
.3. General procedure for the SSLP-catalyzed multicomponent synthesis of
spirooxindolones
5
Page 5 of 28

A mixture of isatin (1 mmol), dicarbonyl compound 1 (1 mmol), dicarbonyl
compound 2 (1 mmol) and SSLP (0.1g, 4.8 mol %) was added to a 25 mL canonical flask
contained water (5 mL) and was stirred at 80 °C for appropriate time. After completion of
the reaction as indicated by TLC, the reaction mixture was filtered and washed with
acetone (25 mL, two times) to separate the catalyst. The obtained organic phase was
evaporated and the residue was recrystallized from ethanol to obtain the pure products.
2
2
.4. Spectral data of the selected compounds
.4.1. Compound 4b
Yield: 95% black solid, mp: 305-310 °C. IR (KBr): 3402, 3209, 2816, 2361, 1705, 1612,
-
1 1
1
466, 1358, 1319, 1204, 1103, 1026, 756, 664, 617, 540, 447 cm . H NMR (250 MHz,
DMSO-d /TMS): δ = 2.98 (s, 3H), 3.37 (s, 1H), 6.91 (t, J = 4.9 Hz, 1 H), 6.96 (s, 1 H),
.12 (s, 1 H), 7.24-7.28(m, 1 H), 9.11 (s, 1 NH), 10.59 (s, 1NH), 11.55 (s, 1 NH). C
NMR (62.9 MHz, DMSO-d /TMS): δ = 18.0, 24.4, 34.3, 60.4, 87.0, 109.7, 121.2, 121.8,
25.9, 126.8, 130.0, 141.4, 151.1, 164.4, 175.4, 191.5. Anal. Cal. C18 (365.33):
C, 59.18; H, 3.04; N, 11.50; found: C, 59.29; H, 3.13; N, 11.67.
.4.2. Compound 4d
Yield: 95% cream solid, mp: 288-298 °C. IR (KBr): 3348, 3086, 2955, 1705, 1651, 1504,
6
1
3
7
6
1
11 3 6
H N O
2
-1 1
1
373, 1327, 1242, 1204, 1103, 1057, 941, 895, 748, 679, 617, 517, 440 cm . H NMR
(
250 MHz, DMSO-d /TMS): δ = 0.90 (s, 3 H), 1.00 (s, 3 H), 2.48 (t, J = 1.8 HZ, 2H),
6
2
6
.58 (s, 2H), 2.96 (s, 3 H), 3.45 (s, 3 H), 6.60-6.74 (m, 2 H), 6.86 (d, J = 6.8 Hz, 1 H),
1
3
.99 (dt, J = 7.5, 1.2 Hz, 1 H), 8.94 (s, 1 NH), 10.05 (s, 1 H). C NMR (62.9 MHz,
DMSO-d /TMS): δ = 26.4, 27.4, 28.3, 30.4, 31.8, 50.5, 82.6, 107.9, 110.8, 120.3, 122.6,
6
6
Page 6 of 28

1
27.2, 135.7, 143.3, 144.0, 150.1, 150.2, 159.2, 179.7, 193.4. Anal. Cal. C22
406.43): C, 65.01; H, 5.46; N, 13.78; found: C, 65.14; H, 5.52; N, 13.89.
.4.3. Compound 4e
22 4 4
H N O
(
2
Yield: 96%, brown solid, mp: >350 °C. IR (KBr): 3263, 3094, 1767, 1736, 1681, 1612,
-
1
543, 1443, 1358, 1319, 1257, 1219, 1173, 1111, 1018, 972, 856, 756, 663, 517, 424 cm
1
1
.
6
H NMR (250 MHz, DMSO-d /TMS): δ = 2.99 (s, 3 H), 3.37 (s, 3 H), 6.90 (t, J = 4.9
Hz, 2H), 7.12 (s, 1 H), 7.24-7.31 (m, 1H), 9.11 (s, 1 NH), 10.48 (s, 1NH), 10.59 (s, 1
1
3
NH), 11.55 (s, 1 NH). C NMR (62.9 MHz, DMSO-d /TMS): δ = 27.0, 31.2, 50.0, 82.0,
6
8
1
5
2
7.0, 97.1, 116.1, 120.8, 123.1, 126.4, 128.2, 135.2, 146.0, 149.9, 151.0, 152.0, 156.8,
62.0, 181.2. Anal. Cal. C18
4.91; H, 3.64; N, 21.39.
.4.4. Compound 4h
14 6 5
H N O (394.34): C, 54.82; H, 3.58; N, 21.31; found: C,
Yield: 91% white solid, mp: 159-170 °C. IR (KBr): 3078, 2970, 2878, 2847, 1689, 1620,
1
7
597, 1520, 1489, 1443, 1396, 1342, 1273, 1227, 1165, 1126, 1057,988, 957, 926, 848,
-1 1
6
56, 717, 687, 594, 532, 455 cm . H NMR (250 MHz, DMSO-d /TMS): δ = 1.19 (s, 6
H), 1.54 (s, 3 H), 2.22-251 (m, 4H), 6.93-7.06 (m, 3 H), 7.25 (dd, J = 10.0, 7.4 Hz, 2 H),
1
3
7
.41 (t, J = 7.9 Hz, 2 H), 7.76 (dd, J = 8.5, 1.1 Hz, 2 H), 9.19 (s, 1 NH). C NMR (62.9
MHz, CDCl /TMS): δ (ppm) = 12.2, 17.0, 27.1, 33.1, 33.8, 38.9, 48.6, 54.4, 54.9, 55.0,
0.5, 69.4, 81.7, 104.6, 105.6, 108.2, 108.6, 109.3, 110.5, 115.1, 120.9, 122.7, 123.4,
26.0, 128.9, 129.0, 132.4. Anal. Cal. C26 (425.48): C, 73.39; H, 5.45; N, 9.88;
3
6
1
23 3 3
H N O
found: C, 73.45; H, 5.51; N, 9.97.
.4.5. Compound 4l
2
7
Page 7 of 28

Yield: 95% white solid, mp: 263-270 °C. IR (KBr): 3418, 3148, 1713, 1682, 1612, 1458,
-
1 1
1
404, 1365, 1311, 1180, 1080, 887, 818, 756, 687, 555, 501, 440 cm . H NMR (250
MHz, DMSO-d /TMS): δ = 1.89 (s, 3 H), 6.87 (td, J = 8.9, 2.5 Hz, 1 H), 7.18 (s, 1 H),
.32 (d, J = 2.4 Hz, 1 H), 7.35 (t, J = 2.3 Hz, 1 H), 7.40 (s, 1 H), 7.64 (s, 2 H), 8.32 (s, 1
6
7
1
3
H), 9.86 (s, 1 NH), 10.97 (s, 1 NH), 14.85 (s, 1 NH). C NMR (62.9 MHz, DMSO-
d6/TMS): δ = 17.9, 24.2, 34.2, 60.6, 86.8, 111.2, 119.1, 125.0, 125.8, 126.1, 128.6, 128.7,
1
5
2
28.8, 129.8, 140.4, 151.1, 165.4, 173.4, 175.1. Anal. Cal. C H ClN O (447.83): C,
22 14 5 4
9.00; H, 3.15; N, 15.64; found: C, 59.12; H, 3.21; N, 15.77.
.4.6. Compound 4m
Yield: 93% white solid, mp: 250-258 °C. IR (KBr): 3302, 3171, 2831, 2199, 1728, 1689,
1
4
1
651, 1535, 1473, 1404, 1335, 1242, 1219, 1165, 1119, 1003, 903, 818, 779, 687, 571,
-1 1
40 cm . H NMR (250 MHz, DMSO-d
6
/TMS): δ = 2.48 (s, 1 NH), 6.78 (d, J = 8.2 Hz,
H), 7.19 (dt, J = 8.2, 1.1 Hz, 1 H), 7.32 (s, 1 H), 7.43 (s, 2 NH), 10.60 (s, 1 NH), 11.14
1
3
(
s, 1 NH). C NMR (62.9 MHz, DMSO-d
24.1, 125.8, 128.2, 135.5, 141.0, 149.2, 153.5, 158.3, 161.5, 177.5. Anal. Cal.
ClN (357.71): C, 50.37; H, 2.25; Cl, 9.91; N, 19.58; found: C, 50.44; H, 2.29;
N, 19.65.
.4.7. Compound 4o
Yield: 95%, white solid, mp: >300 °C. IR (KBr): 3412, 2955, 1736, 1713, 1666, 1620,
6
/TMS): δ = 46.9, 57.0, 86.2, 110.6, 116.8,
1
C
15
H
8
5 4
O
2
-1
1
1
512, 1481, 1342, 1227, 1173, 1072, 1034, 841 cm . H NMR (250 MHz, DMSO-
d6/TMS): δ = 1.06 (s, 6H), 1.13 (s, 6H), 2.22 (q, J = 29.0, 16.3 Hz, 4H), 2.56 (t, J = 19.0
Hz, 4H), 6.86 (d, J = 8.6, 1H), 7.79 (d, J = 2.1 Hz, 1H), 8.11 (q, J = 8.6, 2.3 Hz, 1H), 8.73
1
3
(
s, 1NH). C NMR (62.9 MHz, DMSO-d /TMS): δ = 27.7, 28.5, 32.1, 41.2, 50.8, 109.1,
6
8
Page 8 of 28

1
12.8, 118.1, 125.9, 134.5, 143.0, 148.8, 164.6, 178.8, 195.9. Anal. Cal. C24
24 2 6
H N O
(
436.46): C, 66.04; H, 5.54; N, 6.42; found: C, 66.13; H, 5.60; N, 6.52.
3
. Results and Discussions
3
.1. Catalyst preparation and characterization
Applied strategy for the preparation of SSLP catalyst is shown in Scheme 1.
Scheme 1. Synthetic route for the preparation of SSLP catalyst
As shown in Scheme 1, VS was prepared via the reaction of silica and
trimethoxy(vinyl)silane. Then, synthesized VS was reacted with H to obtain SO
2
O
2
substrate and obtained SO was treated with N-Boc protected L-proline followed by N-Boc
deprotection of obtained material that leads to the preparation of SSLP catalyst. The
presence of vinyl group on the surface of silica was recognized using bromine test [46].
The amount of supported vinyl groups on the surface of silica was determined using
9
Page 9 of 28

elemental analysis which was in good agreement with the value that estimated with an
iodine test [47]. The results showed that there are 5.1 mmol/g ethylene groups on the
surface of silica. The presence of ethylene oxide group on the silica substrate was
detected by the bright pink color of the phenolphthalein (as indicator) when air passed
through an aqueous solution of NaCl. The quantitative amount of oxirane group on the
substrate was identified to be 4.9 mmol/g using elemental analysis which it showed that
practically all vinyl groups is converted to oxirane under applied conditions. The
chemical structure of VS and SO substrates were investigated using FT-IR spectroscopy
-1
(
Fig. 1). According to the FT-IR spectrum, the peak located at 1627 cm is related to the
stretching of C=C bond in VS substrate. Also, the oxirane ring in SO substrate is
-1
characterized by the FT-IR absorption peaks. The peak positioned at 3054 cm shows the
-1
C-H stretching in oxirane ring. Also, the peak near to 1250 cm indicates the stretching
of C-O-C bond.
1
0
Page 10 of 28

Figure 1. A comparison between the FT-IR spectrum of the VS and SO substrates
Because, SO substrate can react with a large number of reagents in order to generate a
wide range of functional groups and catalytic sites on the surface of silica, it seems that
SO is a good substrate for the synthesis of new materials based on silica (Scheme 2).
Scheme 2. Generation of catalytic sites on the silica surface using SO substrate
To reveal the importance of this substrate for the generation of different catalytic sites
on the surface of silica, herein some of the most important reactions of oxiranes were
mentioned. Addition of water, alcohols, carboxylic acids and their derivatives, ammonia
and amines, halides, metalorganic reagents, hydrogen cyanide, hydrogen sulfide and
mercaptans, nitrous and nitric acids, active methylene groups, aromatic compounds,
isomerization, reduction reaction, oxidation and etc. are a summarized list of reactions
which can performed by an oxiran ring [48-50]. Thus, with the application of each of
these reactions SO can convert to a desired functionalized substrate for the designing new
materials based on silica. In this study we decided to react it with N-Boc protected L-
proline for the preparation of a new heterogeneous organocatalyst.
The SSLP catalyst was characterized using FT-IR, Raman and TGA techniques. In
accordance with the FT-IR spectra (Fig. 2), peaks that positioned around 1095, 802 and
-1
4
s
63 cm are related to asymmetric stretching (νas), symmetric stretching (ν ), and bending
-1
modes of Si-O-Si, respectively [35]. The peak at ~1628 cm is confirmed the presence of
L-proline in the structure of SSLP catalyst because this peak attributed to the C=O bond
1
1
Page 11 of 28

-1
[
51]. Also, distinguished peaks at ~2361, 950, 851 and 644 cm establish the presence of
L-proline moiety in the structure of synthesized catalyst.
Figure 2. A comparison between the FT-IR spectrum of the SSLP catalyst and L-proline
-1
According to the Raman spectrum (Fig. 3), the weak asymmetric band near 3249 cm
-
is due to the O-H stretching vibration of hydroxyl groups. Also, the weak peak at 977 cm
1
can be due to Si-OH stretching [52]. The asymmetric CH
2
stretching band is observed at
-1
-1
3
046 cm [51]. The band at 1643 cm is assigned to a C=O band. According to the
-1
-1
Raman spectrum (Fig. 3), two peaks positioned at 1227 cm and 1510 cm belong to the
-1
C-O and N-H bonds, respectively. The band observed at 1455 cm is ascribed to the
δCH scissoring [51].
2
1
2
Page 12 of 28

Figure 3. The Raman spectrum of SSLP catalyst
The TGA curve of SSLP catalyst (Fig. 4) shows three main weight losses. The first
one is accounted for adsorbed water in the structure of catalyst. The seconded one which
is occurred at ~180-220 ºC is related to the decomposition of grafted L-proline from the
silica substrate. This part of the thermogram reveals the amounts of supported L-proline
on silica which is estimated to be ~5.5%, (W/W). The reduction in the weight percentage
of the catalyst at ~250-350 °C is related to decomposition of carbon chain from the
surface of silica. So, the elevated temperature for grafted organic group removal indicates
the high thermal stability for SSLP catalyst which establishes the covalent bonding of
these groups to the surface of silica. These results confirm that our applied strategy can
be considered as a good and practical method for the modification of the SO substrate by
various functional groups such as L-proline. The pH value of the catalyst was obtained
7
.8 representing that the SSLP catalyst in nature is basic.
1
3
Page 13 of 28

Figure 4. A typical TGA curve of the SSLP catalyst
The porous character of the SSLP catalyst was obviously proved by the BJH method. The
BJH curve clearly displayed three peaks with the pore size centered at about 1.6, 2.1, and
2
.7 nm, for three types of pores. The enhanced active site of the SSLP catalyst was
investigated using the nitrogen adsorption–desorption isotherms from the BET analysis.
The specific surface area and pore volume of the mesoporous catalyst were calculated as
2
-1
3
-1
3
53.33 m g and 0.55 cm g , respectively (Fig. 5).
Figure 5. a) N2 adsorption–desorption analysis, b) Brunauer–Emmett–Teller (BET)
analysis and c) Barrett–Joyner–Halenda (BJH) analysis of SSLP catalyst.
.2. The one-pot synthesis of spiroindolones using SSLP catalyst
3
1
4
Page 14 of 28

After preparation and characterization of SSLP catalyst, its catalytic activity was
evaluated in a multicomponent reaction between isatin and dicarbonyl compounds for the
preparation of a library of spirooxindole derivatives under more green conditions. To
obtain best conditions for the synthesis of titled compounds, the reaction of isatin (1a),
barbituric acid (2a) and malononitrile (3a) was selected as a model reaction and was
studied in the presence of different catalysts as well as solvents at different temperatures
and the obtained results are summarized in Table 1.
►
Table 1◄
First, the model reaction was checked in the absence of catalyst in water as a solvent
and desired product was obtained in 51% after 5h (Table 1, entry 1). We used L-proline
as a catalyst and compound 4a was obtained in 80% isolated yield (Table 1, entry 2). The
results were shown that a decreasing in the amount of L-proline lead to a reduction in
product yield (Table 1, entry 3). This experiment is confirmed that L-proline acts as a
catalyst for this process. The reaction was also checked in the presence of SiO , but no
2
remarkable reactivity difference was observed (Table 1, entry 4). In the presence of
2
SiO /L-proline mixture, the yield of the product was 79% (Table 1, entry 5). When SSLP
was used as a catalyst, compound 4a was obtained in 95% isolated yield (Table 1, entry
6
7
). With increasing the temperature to 80 ºC, the yield enhanced to 98% (Table 1, entry
). However, at room temperature the yield decreased to 71% (Table 1, entry 8). These
tests revealed that temperature has a significant effect on the progress of the reaction.
Then, the effect of solvent was investigated and the best results were obtained in water as
a solvent (Table 1, entries 7, 9 & 10). This is probably due to the organic-inorganic
nature of SSLP catalyst. Subsequently, the catalyst quantity was also optimized, and 4.8
1
5
Page 15 of 28

mol% of the catalyst was selected as optimum amount (Table 1, entries 11 & 12).
According to the data which were obtained from optimizing study, the three-component
reaction properly carried out in water in the presence of 4.8 mol% SSLP catalyst (entry
7
). It is noteworthy that, SSLP catalyst is a heterogeneous catalyst and can be easily
separated from the reaction mixture by a simple filtration. After the optimization of
reaction conditions the versatility of the catalyst was studied and the substrate scope of
this MCR was investigated using reagents which are shown in Fig. 6.
Figure 6. Diversity of reagents
The obtained results using above reagents in the presence of SSLP catalyst are
summarized in Fig. 7.
1
6
Page 16 of 28

Figure 7. Products of tree-component coupling reaction catalyzed by SSLP catalyst
1
7
Page 17 of 28

As shown in Fig.6, various isatins efficiently reacted with dicarbonyl compounds and
malononitriles to afford the desired spirooxindole products in high yields (Fig. 6,
compounds 4a-4o). All the examined substrates gave the corresponding products in high
yields under the same reaction conditions in a relatively short reaction time. The
structures of the prepared compounds were characterized by spectroscopic methods. We
proposed a plausible mechanism for the reaction in the presence of SSLP catalyst
according to the literature (Scheme 3) [53, 54].
Scheme 3. Proposed mechanism for the synthesis of spirooxindole derivatives using
SSLP catalyst
1
8
Page 18 of 28

Activation of the isatin can be achieved by grafted L-proline on the surface of silica
via the iminium formation. The grafted L-proline can act as a bifunctional organocatalyst
in the activation of substrates [55]. We believe that the hydroxyl group of the catalytic
site is engaged in substrate activation process using hydrogen bond formation [56]. SSLP
catalyst can also acts as a Brönsted acid/base which assists the enolization of the
dicarbonyl compound which reacts with activated isatin. Although, grafted L-proline on
silica plays a key role in this reaction, unfortunately, it does not affect the generation of a
chiral center and as a result there is not stereoselectivity during the synthesis of titled
compounds in the presence of SSLP.
For the establishment of the practical applicability of this heterogeneous
organocatalyst the level of reusability was also evaluated. The possibility of recycling of
the catalyst was examined using the model reaction under optimized conditions. After the
completion of the reaction, heterogeneous catalyst was separated with a simple filtration,
washed with acetone, dried under reduced pressure and recycled catalyst was saved for
the next operation. The recycled catalyst could be reused more than 8 times without any
treatment (Fig. 8).
1
9
Page 19 of 28

Figure 8. Reusability of SSLP catalyst in the reaction of isatin and dimedone under
optimized reaction conditions; reaction time was 1 h.
To confirm this point that the catalyst activity of SSLP did not change remarkably
during the reaction process, the nitrogen content of recycled catalyst after 8 cycles of
themodel reaction was estimated using elemental analysis method and results shown that
only about 0.5% of nitrogen was lost. These results are in good agreement with the
stability of the catalytic behavior of SSLP after each recovery.
The possibility of SSLP as a catalyst for the synthesis of titled compounds in large
scales also was investigated. For this, the reaction between isatin (10 mmol), dimedone
(
10 mmol) and malononitrile (10 mmol) was evaluated using different amount of SSLP
catalyst to optimum the catalyst loading for a scaled up procedure (10 mmol) and
obtained results are summarized in Table 2. The obtained results were shown that the
optimum catalyst loading for this process is about 0.8 g (Table 2, entry 2).
►
Table 2◄
2
0
Page 20 of 28

In comparison with the micro-scaled experiment (Table 1, entry 7) additional time, 4
h, was required to achieve desired isolated yield of product. The slight decrease in
efficiency and unimportant increase in the time could be due to the fact that the orbital
shaking is less efficient when the reaction is performed with a higher volume of a vessel
[57].
4
. Conclusions
So briefly, a new heterogeneous organocatalyst based on silica supported L-proline
has been developed and efficiently catalyzed the one-pot synthesis of spiroindolone
derivatives under more green conditions. The novel organocatalyst was efficient for a
broad variety of isatins and dicarbonyl compounds, leading to the corresponding
spiroindolones in good to excellent yields (up to 90%). In the structure of SSLP catalyst
there are L-proline moieties which are covalently connected to the silica. These groups
provide active catalytic sites on the surface of silica. The reusability of presented catalytic
system and easy workup are two other advantages of presented methodology. Moreover,
a new strategy for the synthesis of new materials based on silica using reaction of silica
oxirane and different reagents for the preparation of a wide range of functional groups
and catalytic sites on the surface of silica was disclosed. The SSLP catalyst provides
great promise toward further useful applications in other organic transformations,
especially asymmetric synthesis in the future.
Acknowledgements
We acknowledge Shiraz University for partial support of this work.
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2
5
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Table 1. Optimization of reaction condition between isatin, barbituric acid,
a
malononitrile
b
Entry
Catalyst (mol%)
-
Solvent
T/ºC
80
80
80
80
80
60
80
r.t.
80
60
80
80
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
5
1
1
2
2
1
1
5
1
5
1
2
51
80
72
L-proline (20)
L-proline (10)
c
SiO
2
2
55
d
SiO
/L-proline
79
SSLP (4.8)
SSLP (4.8)
SSLP (4.8)
SSLP (4.8)
SSLP (4.8)
SSLP (5.8)
SSLP (3.8)
95
98
71
90
75
98
87
H
2
O
H
2
O
EtOH
CHCl
1
0
1
2
3
1
H
2
2
O
O
1
H
a
Reaction conditions: isatin (1 mmol), barbituric acid (1 mmol), malononitrile (1 mmol),
b
c
d
solvent (5 mL) and SSLP (0.1g, 4.8 mol%). Isolated yield. 0.05 g silica was used.
0
.05 g silica and 10 mol% L-proline were used.
2
6
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Table 2. Optimization of catalyst loading for large-scale synthesis of spiroindolones
a
using SSLP catalyst
b
Entry
Catalyst loading (g)
Time (h)
Yield (%)
1
1.0
2
91
5
92
2
0.8
2
90
5
91
3
4
0.5
0.2
-
5
12
24
81
72
51
5
a
b
Reaction conditions: isatin (10 mmol), dimedone (20 mmol), H
Isolated Yield.
2
O (20 mL), SSLP.
2
7
Page 27 of 28

Highlights
Preparation of a new heterogeneous organocatalyst based on L-proline
L-proline moieties covalently connected to the silica using silica-oxiran substrate
Introduction of new strategy for synthesis of new materials based on silica
Efficient synthesis of spiroindolones under green conditions
2
8
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