Immobilization of 1,4-diazabicyclo[2.2.2]octane (DABCO) over mesoporous silica SBA-15: An efficient approach for the synthesis of functionalized spirochromenes

Article abstract of DOI:10.1080/00397911.2013.789527

Immobilized 1,4-diazabicyclo[2.2.2]octane (DABCO) over mesoporous silica SBA-15 has been found to be an efficient heterogeneous base catalyst for the synthesis of biologically active functionalized spirochromene derivatives via three-component reaction of

Full text of DOI:10.1080/00397911.2013.789527

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Immobilization of 1,4-Diazabicyclo[2.2.2]Octane
(DABCO) over Mesoporous Silica SBA-15: An Efficient
Approach for the Synthesis of Functionalized
Spirochromenes
a
a
Robabeh Baharfar & Razieh Azimi
a
Department of Organic Chemistry, Faculty of Chemistry , University of Mazandaran ,
Babolsar , Iran
Accepted author version posted online: 15 Aug 2013.
To cite this article: Synthetic Communications (2013): Immobilization of 1,4-Diazabicyclo[2.2.2]Octane (DABCO)
over Mesoporous Silica SBA-15: An Efficient Approach for the Synthesis of Functionalized Spirochromenes,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2013.789527
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Immobilization Of 1,4-Diazabicyclo[2.2.2]Octane (DABCO) Over Mesoporous Silica
SBA-15: An Efficient Approach For The Synthesis Of Functionalized
Spirochromenes
Robabeh Baharfar , Razieh Azimi1
1
1
Department of Organic Chemistry, Faculty of Chemistry, University of Mazandaran,
Babolsar, Iran
Corresponding author: Tel: +98 11253 42350. E-mail: baharfar@umz.ac.ir
Abstract
Immobilization of 1,4-diazabicyclo[2.2.2]octane (DABCO) over mesoporous silica SBA-
1
5 has been found to be an efficient heterogeneous base catalyst for the synthesis of
biologically active functionalized spirochromene derivatives via three-component
reaction of isatins/acenaphthoquinone, activated methylene reagents and 1,3-dicarbonyl
compounds in the aqueous media. This eco-friendly protocol offers several advantages
such as a cost-effective procedure with excellent yield, short reaction time, simple work-
up, recovery, and reusability of catalyst, good functional group tolerance and broad scope
of usable substrates. [Supplementary materials are available for this article. Go to the
publisher’s online edition of Synthetic Communications® for the following free
supplemental resource(s): Full experimental and spectral details.]
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KEYWORDS: Mesoporous SBA-15; multi component reaction; spirochromenes;
heterogeneous catalyst
INTRODUCTION
Today, society with the new environment legislation demands more eco-friendly
alternative catalytic processes, which makes the current homogeneous systems
[
1]
environmentally unacceptable. The heterogenization of homogeneous catalysts has
received much attention in recent years, where the active phase of homogeneous catalysts
can be directly utilized and separation and recycling problems in the homogeneous
systems can be avoided; obviously, the development of green and sustainable catalytic
[
2]
processes is achievable. Normally this was afforded by supporting the active
[
3]
[4]
[5]
compounds on prefunctionalized solid materials such as carbon, silicates, alumina,
[
6]
[7]
zeolites and organic polymers. Among them, SBA-15 as a mesoporous silica material
is a promising candidate for the immobilization of organo-catalyst due to its high surface
area, porosity, uniform pore size distributions and thermal stability.[8]
On the other hand, using water as a solvent offers many advantages, such as simplicity of
reaction conditions, ease of work-up and product isolation, increasing the selectivity of a
[
9]
wide variety of organic reactions and accelerating reaction rates. Therefore, the
development of a catalyst that is not only stable toward water but also simply recyclable
seems highly desirable.
The heterocyclic spirooxindoles are attractive targets in organic synthesis because of their
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highly pronounced biological activities as well as wide-ranging utility as synthetic
intermediates for alkaloids, drug candidates, and clinical pharmaceuticals.[10] Among the
spirooxindole compounds, those with fused 4H-chromenes have immense importance due
to their diuretic, spasmolitic, anticoagulant, anticancer, and antinaphylactic activities.[11]
In recent years, several improved protocols for the synthesis of spirooxindoles with fused
chromenes have been reported by modification of three-component condensation of isatin
derivatives, activated methylene reagents, and 1,3-dicarbonyl compounds using various
catalysts such as InCl3,[12] triethylbenzyl ammonium chloride (TEBA),[13] electro-
generated base (NaBr/ROH),[14] NEt
,[15] NH Cl,[16] β-
3
4
cyclodextrin, ethylenediaminediacetate, surfactant metal carboxylates,[19] L-
[
17]
[18]
proline,[20] [BMIm]BF
,[21] HAuCl
.3H
O, MgO, SBA-pr-NH
,[24] and
[22]
[23]
4
4
2
2
MSNs.[25]Although all of these methods are effective, but some of them have drawbacks
such as, harsh reaction conditions,[12] long reaction times,[13,17] technical intricacy,[14] use
of expensive,[21,22] unsafe,[15] and unreusablecatalysts.[13,15,16,18,19] Therefore, the
development of a new and simple synthetic method for the preparation of spirooxindole
derivatives has become an interesting challenge.
1
,4-Diazabicyclo[2.2.2]octane (DABCO) has been applied as an inexpensive, eco-
friendly, high reactive and non-toxic base catalyst for various organic transformations,[26]
but in many of these cases it has not been recovered and eliminated as a residue. So
converting homogenous DABCO into heterogeneous DABCO catalyst is a better option
as it can be easily filtered as well as being recycled for several times.
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Due to the current challenges for developing environmentally benign synthetic processes
and in continuation of our investigations into the synthesis of biologically active
heterocyclic compounds,[27] we report a green and simple procedure for the synthesis of
some chromene derivatives using SBA-15@DABCO as a heterogeneous base catalyst in
water. The synthesis of spirooxindoles4a-y was achieved by the three-component
condensation of isatin derivatives 1a-h, activated methylene reagents 2a, b and 1,3-
dicarbonyl compounds 3a-e in the presence of SBA-15@DABCO (7 mol%) at 25 or 50
oC in water (Scheme 1).
RESULTS AND DISCUSSION
SBA-15@DABCO was synthesized according to the published procedure,[28] by
silylation/condensation of SBA-15 with 3-chloro propyltrimethoxysilane, which was then
reacted with DABCO to form DABCO-functionalized SBA-15 material (Scheme 2).
The catalyst structure was characterized by Fourier-transform infrared (FT-IR)
spectroscopy, elemental analysis (CHN), thermo gravimetric analysis (TGA), X-ray
diffraction and transmission electron microscopy (TEM). Potentiometric titration was
also used to confirm TGA and elemental analysis. The amount of DABCO in SBA-
1
5@DABCO was evaluated by the nitrogen content, 0.83 mmol/g, on the basis of
nitrogen content by elemental analysis (C: 9.26%; H: 1.07%; N: 2.23%). We also
determined the loading level of DAB-CO (0.82 mmol/g) based on the chlorine content
by potentiometric titration method, with employing recent procedure,[29] which is shown
to be in good agreement with results obtained from TGA and elemental analysis.
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To illustrate the efficiency of our catalyst, the three-component reaction between
isatin1a, malononitrile2a and dimedone3a in equimolar ratio as model substrates was
investigated. Initially, the model reaction was examined in the presence of different
amounts of SBA-15@DABCO in water at room temperature. The results are summarized
in Table 1.
As it is observed, when the amount of SBA-15@DABCO increases from 3 to 6, 7 and 9
mol%, the yields increase from 68 to 85, 96 and 95%, respectively, in appropriate times
(Table 1, entries 3-6). Using 7 mol% of SBA-15@DABCO in water at room temperature
is sufficient to push this reaction forward (Table 1, entry 5). More amount of catalyst did
not improve the product yields (Table 1, entry 6). Only a trace amount of the product was
formed in the absence of catalyst (Table 1, entry 1). The model reaction was also
checked in the presence of pure SBA-15, in which an increase in the reaction time
and a decrease in the yield were observed (Table 1, entry 2). The effect of temperature
was also studied. It was found that room temperature is appropriate for the SBA-
1
5@DABCO-catalyzed reaction. The high temperature could improve the reaction rate
and reduce the reaction time (Tabe 1, entry 9). The solvents also played an important role
in the SBA-15@DABCO catalyzed reactions. Several solvents, such as CHCl , THF,
3
CH CN, EtOAc, EtOH and CH OH were screened under similar reaction conditions
3
3
(
Table 1, entries 10–15). It is clear from Table 1, that water provided higher yield and
shorter reaction time than other organic solvents. Therefore, water was selected as the
reaction solvent in the following investigation.
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To study the scope of the reaction, a series of substituted isatins (substitution in aromatic
nucleus and at N1), different 1,3-dicarbonyl compounds (5,5-dimethyl-1,3-
cyclohexanedione 3a, 1,3-cyclohexane-dione 3b, 2-thiobarbituric acid 3c, 1,3-dimethyl-
barbituric acid 3d, and ethyl acetoacetate 3e) and malononitrile2a or ethyl
o
cyanoacetate2b were reacted using SBA-15@DABCO (7 mol%) in water at 25 or 50 C.
Under the optimized reaction conditions, a series of spiooxindoles4a-y were synthesized
in high yields within short reaction times (Table 2). Additionally, the reaction of
malononitrile or ethyl cyanoacetate proceeded smoothly, too.
In following further exploration of the potential of this protocol for spiro-heterocyclic
synthesis, we also examined three-component reactions using another reactant,
acenaphthoquinone instead of isatins under similar reaction conditions. Under these
conditions, a variety of desired spiroacenaphthylenes were also produced in excellent
yields within short reaction times (Table 3).
In order to compare the capability and efficiency of our catalyst with respect to the
previously reported catalysts for the preparation of spirooxindole derivatives, the results
for the synthesis of 4a are collected in Table 4.
On the basis of the results shown in Table 4, the use of homogenous catalysts in
water under heating conditions led to high product formation, while we designed a
convenient and reusable heterogeneous-catalytic methodology for the synthesis of
functionalized spirooxindoles at ambient temperature. Although the reaction proceeded
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more easily in [BMIm] BF , with its limitations in organic syntheses, naturally abundant
4
water appeared to be a better option as an environmentally benign reaction medium, due
to its inexpensive, non-toxic, non-corrosive, and non-inflammable nature.
In order to check the recyclability and stability of the catalyst, we designed a set of
experiments by conducting successive condensation reaction of isatin1a with
o
malononitrile2a and dimedone3a using SBA-15-DABCO catalyst (7 mol%) at 50 C.
After the completion of the first cycle, the reaction mixture was filtered, the residue was
dissolved in acetone and then filtered to separate the catalyst. The catalyst was
thoroughly washed with EtOH and finally dried at 80 °C for 3 h. It was found that the
catalyst could be used directly for six cycles (Table 5). However, a little drop was
observed in the product yield and catalytic activity after several cycles. It is obvious that
the amount of recovered catalyst is reduced after each cycle, therefore, the reactants were
taken with respect to the amount of the catalyst recovered after each reaction cycle.
A proposed mechanism for the synthesis of spirooxindole4a can be described as shown in
Scheme 3.[4b,4d] The process represents a typical cascade reaction in which the isatin1a is
firstly condensed with malononitrile2a in the presence of SBA-15@ DABCO to afford
isatylidenemalononitrile7. Then, enolate8 which is formed from dimedone3a usingSBA-
1
5@ DABCO, is added to intermediate 7 via Michael addition to produce adduct 9.
Finally, enolate oxygen of intermediate 10 attacks nucleophilically to nitrile group and
forms more stable product 4a, after tautomeric proton shift.
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CONCLUSION
In summary, a mild and efficient method for the synthesis of biologically active
functionalized spiro-heterocyclic compounds via three-component reaction catalyzed by
SBA-15@DABCO in the aqueous media is reported. The salient features of this atom
economical procedure are its reusability, inexpensiveness, environmentally benign
nature, high yield, short reaction times, tolerancy toward wide range of functional groups,
operational simplicity, and easy separation.
EXPERIMENTAL
The chemical materials used in this work were obtained from Merck and Aldrich and
used without purification. Mesoporous silica SBA-15 and DABCO functionalized SBA-
1
5 were synthesized in according to the reported procedures.[31,28] IR spectra were
determined on a Shimadzu instrument. Elemental analyses were carried out by Perkin-
1
13
Elmer CHN 2400 instrument. H and C NMR spectra were recorded on a Bruker DRX-
1
13
4
00 AVANCE spectrometer at 400.13 and 100.61 MHz, respectively. H and C NMR
spectra were obtained on solutions in DMSO-d using TMS as internal standard.
6
Chemical shifts are given in ppm (δ) relative to internal TMS, and coupling constants (J)
are reported in Hertz (Hz). Thermo gravimetric analysis (TGA) were recorded on a
Stanton Redcraft STA-780 (London, UK). Transmission electron microscopy (TEM)
images were obtained using a Phlips CM10 microscope operated at 200 kV. X-ray
powder diffraction (XRD) patterns of the PIs were recorded by an X-ray diffractometer
(
XRD, GBC MMA Instrument) with Be-filtered Cu Kα radiation. Melting points were
determined on a thermo scientific IA9200 and are uncorrected.
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General Procedure For The Synthesis Of Spirochromenes
A mixture of isatins or acenaphthoquinone (1 mmol), activated methylene reagents (1
mmol), 1,3-dicarbonyl compounds (1 mmol) and SBA-15@DABCO (0.085 g, 7 mol%)
o
in water was stirred at 25 or 50 C. Upon compilation, monitored by TLC (n-hexane/ethyl
acetate: 2/1), the reaction mixture was allowed to cool to room temperature. The
precipitate was filtered and dissolved in acetone. The catalyst was separated by filtration
of this solution. The solution was concentrated under vaccum to afford the product,
which was purified by recrystallization in the ethanol.
Compounds 4a-f, 4h, 4i, 4k, 4p, 4v, 4w, 4y, 6a- 6c and 6e are known compounds and
were characterized by comparison of their physical and spectroscopic data with those of
reported ones. [12–25,30,32] Physical properties and spectral data of new compounds are
reported in supplementary data.
SUPPLEMENTARY DATA AVAILABLE
Experimental procedure, characterization data for new compounds and catalyst. This
material is available free of charge via the Internet in an online version.
ACKNOWLEDGMENTS
We are thankful to the Research Council of Mazandaran University for the partial support
of this work.
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Table 1. Optimization of reaction conditions for the synthesis of 4a.
Entry Catalyst
Solvent Temp Time Yield(%)a
(
mol%)
(5ml)
(oC)
(min)
240
30
1
2
3
-
H
2
H
2
H
2
O
O
O
25
trace
25
b
SBA-15 (10)
25
SBA-15@DABCO
25
30
68
(3)
4
5
6
7
8
9
1
1
1
1
1
1
6
7
9
3
6
7
7
7
7
7
7
7
H
H
H
H
H
H
2
2
2
2
2
2
O
O
O
O
O
O
25
25
25
50
50
50
50
30
10
10
15
5
85
96
95
80
94
98
45
64
68
83
72
94
2
0
1
2
3
4
5
CHCl
CH
THF
EtOAC 50
CH OH 50
EtOH 50
3
60
60
60
60
30
30
3
CN 50
50
3
a
Yields refer to isolated products.
b
(10 wt% of isatin)
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Table 2. SBA-15@DABCO catalyzed synthesis of spirooxindoles 4a-y in
queousmedium.
Entr produ R1
R2
X
1,3-
Time
Yield Tim Yield
y
ct
dicarbonyl
compounds
(min)a
(%)a,c
e
(%)b,c
(min
)b
1
2
3
4
5
6
7
8
9
1
1
4a
4b
4c
4d
4e
4f
H
H
H
H
H
H
H
H
H
H
H
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
CN
3a
3b
3c
3d
3e
3a
3c
3e
3a
3d
3a
10
12
25
30
90
7
96
95
91
87
91
93
90
88
92
89
96
2
9816
9616
96 13
9120b
95 20a
97 20a
92
H
4
H
6
H
10
30
3
H
Br
Br
Br
Cl
Cl
4g
4h
4i
20
70
6
4
20
2
93 21
94 20a
92
0
1
4j
20
3
7
4k
NO H
<1
98 17
2
12
4l
NO H
CN
3c
10
94
3
93
2
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1
1
1
1
1
3
4
5
6
7
4m
4n
4o
4p
4q
H
H
H
H
H
Et
CN
3a
3b
3c
3a
3a
25
30
30
30
17
89
86
89
88
93
5
6
7
5
4
96
Et
CN
94
Et
CN
91
Bn
CH
CN
94 21
2
2
2
2
2
CO CN
97
2
Et
CH
Et
CH
Et
CH
Et
CH
Et
18
19
20
21
4r
4s
4t
H
CO CN
CO CN
CO CN
CO CN
3b
3c
3a
3b
20
30
13
15
91
90
94
92
5
5
3
4
96
93
97
95
2
H
2
Cl
Cl
2
4u
2
2
2
3
4v
H
H
H
H
CO
2
2
Et 3a
Et 3e
12
95
87
83
7
93 21
2
4w
CO
35
90
2
0a
2
4
4x
4y
H
CH
2
CO CO
2
2
Et 3a
Et 3b
20
8
84
91
7
5
92
2
Et
25
Br
H
CO
93 20a
a
At r.t.
b
o
At 50 C
c
Yields refer to isolated products.
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Table 3. SBA-15@DABCO catalyzed multicomponent synthesis of
spiroacenaphthylenes6a-e in aqueous medium.a
Entr Pro
X
1,3-
Tim Yield
y
duct
dicarbonyl
e
(%)b
compounds (min
)
1
2
6a
6b
CN
CN
3a
3
95
3
3
0b
3b
4
93
0b
3
4
5
6c
6d
6e
CO
CN
CN
2
Et 3a
3c
15
10
20
84 16
91
83
3d
3
0b
aReaction conditions: acenaphthoquinone (1 mmol); activated
methylene reagents (1 mmol); 1,3-dicarbonyl compounds (1 mmol);
catalyst: SBA-15@DABCO (7 mol%); solvent: H O (5 mL);
temperature: 50 C. Yields refer to isolated products.
2
◦
b
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0

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Table 4. Comparative the condensation of malononitrile with isatin and 5,5-dimethyl-
cyclohexane-1,3-dione using the reported catalysts versus SBA-15@DABCO.
Reagents and conditions
Time Yiel Ref.
(
min) d(%
)
InCl
TEBA, 20 mol%, H
NH Cl, 20 mol%, H
3
, 20 mol%, CH
3
CN, reflux
90
75
94
92
90
90
95
12
13
16
17
18
19
o
2
O, 60 C
120
10
o
4
2
O, 80 C
o
β-cyclodextrin, H
2
O, 60 C
300
60
o
EDDA, 10 mol%, H
2
O, 60 C
Sodium stearate, (10 mol %), H
2
O,
180
o
6
0 C
o
L-proline, 10 mol%, H
2
O, 70 C
20
3
94
94
96
20a
21
[
BMIm] BF , r.t.
4
HAuCl
4
, 3H
2
O, 5 mol%, PEG 400,
30
22
o
7
0 C
o
Nano MgO, 15 mol%, H
SBA-15@DABCO, 7 mol%, H
r.t.
SBA-15@DABCO, 7 mol%, H
0oC
2
O, 80 C
120
10
93
96
23
2
O,
This
work
This
work
2
O,
2
98
5
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Table 5. Recyclability of SBA-15@DABCO
Cycle
Yield
1
2
3
4
5
6
98 95 95 93 91 87
(
%)
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2

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Scheme 1. Synthesis of spirooxindoles4a-y using SBA-15@DABCO in aqueous
medium.
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3

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Scheme 2. Synhesis of SBA-15@DABCO.
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4

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Scheme 3. Plausible mechanism for the reaction of isatin and malononitrile with dime
done.
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5