Ionic liquid catalyzed one-pot synthesis of novel spiro-2-amino-3- phenylsulfonyl-4H-pyran derivatives

Article abstract of DOI:10.1016/j.tetlet.2013.02.073

A series of novel spiro-2-amino-3-phenylsulfonyl-4H-pyran derivatives were synthesized via the three component, one pot reaction of phenylsulfonylacetonitrile and 1,3-dicarbonyl compounds with isatins or acenaphthenequinone in ethanol with a novel basic ionic liquid 2-hydroxyethyl ammonium acetate [H₃N⁺CH₂CH₂OH] [CH₃COO^-] (HEAA) as catalyst. HEAA was found to be a suitable and efficient catalyst for this condensation. This method has some distinct advantages such as mild reaction conditions, short reaction time, and environmental friendliness.

Full text of DOI:10.1016/j.tetlet.2013.02.073

Tetrahedron Letters 54 (2013) 2353–2356
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ionic liquid catalyzed one-pot synthesis of novel
spiro-2-amino-3-phenylsulfonyl-4H-pyran derivatives
⇑
Shuai-Shuai Jin, Hong Wang, Hong-Yun Guo
College of Chemical Engineering and Materials, Zhejiang University of Technology, Hangzhou 310014, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of novel spiro-2-amino-3-phenylsulfonyl-4H-pyran derivatives were synthesized via the three
component, one pot reaction of phenylsulfonylacetonitrile and 1,3-dicarbonyl compounds with isatins
or acenaphthenequinone in ethanol with a novel basic ionic liquid 2-hydroxyethyl ammonium acetate
[H3N+CH2CH2OH][CH3COOÀ] (HEAA) as catalyst. HEAA was found to be a suitable and efficient catalyst
for this condensation. This method has some distinct advantages such as mild reaction conditions, short
reaction time, and environmental friendliness.
Received 21 December 2012
Revised 22 January 2013
Accepted 22 February 2013
Available online 1 March 2013
Keywords:
One pot
Ó 2013 Elsevier Ltd. All rights reserved.
Phenylsulfonylacetonitrile
Basic ionic liquid
HEAA
Environmental friendliness
Introduction
being found in a number of alkaloids like horsifiline, spirotryprost-
atin, and (+)-elacomine.23
Sulfones and sulfoxides are important intermediates in organic
synthesis1 and additionally have a wide applicability in diverse
fields including agrochemicals,2 pharmaceuticals,3 and polymers.4
Especially, sulfones and sulfoxides are important intermediates in
the synthesis of many interesting biologically active com-
pounds.5,1,6–8 Omeprazole and Fipronil pesticide are two typical
examples of extensive application of these intermediates in phar-
maceutical and fine chemical industries.9 Sulfones are notable as
‘chemical chameleons’10 due to the ability of the sulfonyl group
to serve as a temporary transformer of chemical reactivity. The
group RSO2 can function as a nucleofuge producing a sulfinate
anion11 and powerfully stabilize adjacent carbanions.12,13 Although
lacking inherent asymmetry, the sulfonyl group can also function
as a potential stereoinducer.14
Poly-functionalized oxindole derivatives are also a very impor-
tant class of heterocyclic compounds and are the core structure of
many pharmacological agents and natural alkaloids.15–17 Several
spiroheterocycles, containing both indole and pyran heterocycles,
possess anticonvulsant and analgesic,18 herbicidal,19 and antibac-
terial activities.20 Furthermore, it has been reported that sharing
of the indole 3-carbon atom in the formation of spiroindoline
derivatives, highly enhances biological activity.21,22 The derivatives
of spirooxindole ring systems are useful as antimicrobial and anti-
tumor agents, and as inhibitors of the human NKI receptor, besides
Recently, ionic liquids (ILs) are receiving considerable attention
because they offer a unique medium for chemistry, biocatalysis,
separation science, material synthesis, and electrochemistry.24
The implementation of task specific ionic liquids (TSILs) further
enhances the versatility of classical ionic liquids where both
reagent and medium are coupled.25 Their dual organic and ionic
nature allows them to establish nearly all kinds of interactions
with the reacting species including transition states, and hence
sometimes give rise to improved yields and rate increase.26 Struc-
tural variation of ionic liquids gives more flexibility to their appli-
cations due to the possibility of fine tuning their miscibility to
merit phase-separation from products.27 Moreover, functionalized
ionic liquids offer specific types for catalysis applications and
served as solution phase supports in combinatorial syntheses.28
Due to the potential biological and pharmacological activities of
fused spiro-2-amino-3-phenylsulfonyl-4H-pyran derivatives, and
our interest in the synthesis of heterocyclic compounds,29 we
report a simple and efficient method for the preparation of pyrim-
idine-fused heterocycles in ethanol using HEAA as the catalyst in
the multi-component reaction of phenylsulfonylacetonitrile and
1,3-dicarbonyl compounds with acenaphthenequinone or isatins.
Results and discussion
First, phenylsulfonylacetonitrile 2 was synthesized according to
previous work30 by means of reaction between sodium benzene-
sulfinate and 2-chloroacetonitrile (Scheme 1).
⇑
Corresponding author. Tel.: +86 571 88320417.
E-mail address: guohy63@163.com (H.-Y. Guo).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.073

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S.-S. Jin et al. / Tetrahedron Letters 54 (2013) 2353–2356
Table 2
HEAA-catalyzed reaction of isatins, phenylsul-fonylacetonitrile,
and 5,5-dimethyl-cyclohexane-1,3-dione in different solvents
Entry
Solvent
Time (h)
Yielda (%)
Scheme 1. Preparation of phenylsulfonylacetonitrile 2.
1
2
3
4
5
6
7
8
EtOH
H2O
CH3CN
CHCl3
DMF
THF
DMSO
CH3COCH3
2
2
2
2
2
2
2
2
90
30
55
34
35
14
21
38
Then, the three-component reaction of isatins 1 (1 mmol),
phenylsulfonylacetonitrile 2 (1 mmol), and 5,5-dimethyl-cyclohex-
ane-1,3-dione 3b (1 mmol) was carried out as the model reaction
to optimize the reaction condition. Different catalysts such as
[Bmim]PTSA, [Bmim]Cl, Et3N, HEAA and the loading of the HEAA
were investigated. The results were summarized in Table 1. We
found that without catalyst or acidic ionic liquid this reaction can-
not be catalyzed, and the neutral ionic liquids can promote the
reaction but the yield is lower than 50% (Table 1, entries 1–4). In
contrast, we found that basic catalyst can catalyze this reaction,
and the basic ionic liquid (HEAA) gave the highest yield (90%) with
10% loading (Table 1, entries 6–10). And the outcomes displayed
that 10% mmol catalyst was sufficient to complete this reaction.
Larger amounts of the catalyst did not improve the yields. And
we also found that this reaction was completed in 2 h, and reflux
temperature is the most suitable temperature for this reaction.
The reaction medium has been recognized to be one of the most
important factors influencing the reaction. Several solvents were
tested for the reaction, the results are shown in Table 2. It can be
observed ethanol was the most efficient medium to promote this
reaction. (Table 2, entry 1) Other solvents, such as THF, MeCN,
DMSO, DMF, CH3COCH3, and CHCl3 led to lower yields (Table 2, en-
try 2–8). The reaction hardly proceeded in THF. Therefore, ethanol
was selected as the reaction solvent in the following investigation.
With the optimal conditions in hand, the multicomponent reac-
tion was carried out by stirring a mixture of isatins 1, phenylsulfo-
nylacetonitrile 2, and 1,3-dicarbonyl compounds 3 in the presence
of HEAA in refluxing ethanol for 2 h, afforded spiro-2-amino-3-
phenylsulfonyl-4H-pyrans derivatives 4 in good yields (Scheme 2).
The results were good in terms of yields and product purity in the
presence of HEAA, while without HEAA the reaction cannot proceed.
Using this method, twelve new compounds 4 were selectively syn-
thesized by the three-component condensation of two different isa-
tins 1 (isatin and 5-chloroisatin), phenylsulfonylacetonitrile 2, and
1,3-dicarbonyl compounds 3 (3a–3h) in good yields. However, we
found that the three-component reaction of phenylsulfonylaceto-
nitrile 2 and ethyl 3-oxobutanoate 3h with isatins 1 cannot proceed,
which is probably due to the lower reactivity of ethyl 3-oxobutano-
ate (Table 3, entry 8). The results are summarized in Table 3.
To the best of our knowledge, this new procedure provides the
first example of a three-component reaction for the synthesis of
spiro-2-amino-3-phenylsulfonyl-4H-pyran derivatives. This meth-
od, based on a three-component HEAA-catalyzed reaction in EtOH,
a
Yields refer to isolated products.
Scheme 2. Three-component synthesis of spiro-2-amino-3-phenylsulfonyl-4H-
pyran derivatives 4.
Table 3
Three-component synthesis of spiro-2-amino-3-phenylsulfonyl-4H-pyran derivatives
4
Entry
R
Compound 3
Products
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
Cl
3a
3b
3c
3d
3e
3f
3g
3h
3a
3b
3d
3e
3g
4a
4b
4c
4d
4e
4f
4g
4h
4i
2
2
3
2.5
2.5
3
3
5
2
2
3
3
93
92
86
91
90
87
83
Trace
91
90
89
85
89
9
10
11
12
13
4j
4k
4l
4m
3
a
Yields refer to isolated products
is simple and convenient and would be applicable for the synthesis
of different types of spiro-2-amino-3-phenylsulfonyl-4H-pyrans. In
addition, we have proposed the mechanism which is shown in
Scheme 3.
To further explore the potential of this protocol for spiro-hetero-
cycle synthesis, we investigated the reaction of acenaphthylene-
1,2-dione 5 instead of isatin 2 and obtained spiroacenaphthylene
derivatives. Using this protocol, another five new compounds 4
were synthesized by the one-pot, three-component condensation
of acenaphthylene-1,2-dione 5, phenylsulfonylacetonitrile 2, and
1,3-dicarbonyl compound 3, in good yields (Scheme 4). The results
are summarized in Table 4.
Table 1
Optimization of the reaction conditionsa
Entry
Catalyst
Catalyst (%)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
—
—
5
5
5
5
2
2
2
2
2
2
2
Trace
Trace
49
46
72
67
89
81
90
[Bmim]PTSA
[Bmim]Cl
[Bmim]Br
Et3N
10
10
10
10
10
10
5
10
15
20
C5H10
HEAA
HEAA
HEAA
HEAA
HEAA
N
9
10
11
88
89
In the next phase of study the viability of catalysis by the recy-
cled ionic liquid was evaluated. In this regard preparation of 4b
was chosen as the model. After completion of the reaction the fil-
trate was extracted with diethyl ether several times to remove
a
Reaction conditions: isatins (1 mmol), phenylsulfonylacetonitrile (1 mmol), 5,5-
dimethyl-cyclohexane-1,3-dione (1 mmol), EtOH (5 ml), HEAA (0.1 mmol), 80 °C.
b
Yields refer to isolated products.

S.-S. Jin et al. / Tetrahedron Letters 54 (2013) 2353–2356
2355
Scheme 3. Possible mechanism for the formation of products 4.
Experimental
Melting points were determined with an X-4 microscopic melt-
ing-point apparatus and were uncorrected. IR spectra were
recorded on a NEXUS 670 spectrometer in KBr. 1H NMR and 13C
NMR spectra were measured on a BRUKER AVANCE-II 500 and
125 MHz, respectively, spectrometer using TMS as internal stan-
dard and DMSO-d6 as solvent. Mass spectra were documented on
an Agilent Technology (HP) mass spectrometer operating at an ion-
ization potential of 70 eV.
The synthesis of this task-specific ionic liquid has been carried
out from a similar method in the literature.31 The ionic liquid
was formed quantitatively and in high purity as assessed by 1H
NMR. All other chemicals (AR grade) were commercially available
and used without further purification.
Scheme 4. Three-component synthesis of spiroacenaphthylene derivatives 4.
Table 4
Three-component synthesis of spiroacenaphthylene derivatives 4
Entry
Compound 3
Products
Time (h)
Yielda (%)
1
2
3
4
5
3a
3b
3d
3e
3g
4n
4o
4p
4q
4r
2
2
3
3
3
94
92
91
90
88
General procedure for the synthesis of compounds 4
The mixture of aromatic isatins 1 (1 mmol), phenylsulfonyl-
acetonitrile 2 (1 mmol), 1,3-dicarbonyl compounds 3 (1 mmol),
and HEAA (0.1 mmol) in EtOH (5 ml) was stirred at 80 °C for about
2 h (monitored by thin-layer chromatography [TLC]). After comple-
tion of the reaction, the resulting mixture was cooled to room tem-
perature and poured into water (10 ml). The solid product was
collected by filtration and recrystallized from ethanol to give the
pure compound 4. The same reaction procedure was carried out
by using other materials.
a
Yields refer to isolated products.
Table 5
Recyclability of the HEAAa
Entry
Cycle
Yield (%)
1
2
3
4
5
Fresh
93
92
90
89
89
First recycle
Second recycle
Third recycle
Fourth recycle
Acknowledgement
This work was financially supported by the Research Founda-
tion of Zhejiang Provincial Education Department (No. 20060811).
a
Yields refer to isolated products.
Supplementary data
unreacted starting materials and other organic contaminations.
Then the water was evaporated under reduced pressure and dried
to recover the ionic liquid for subsequent use. Table 4 displays sim-
ilar high conversions obtained after consecutive recycling of the io-
nic liquid (Table 5).
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
073.
References and notes
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In conclusion, we herein report the HEAA-catalyzed one-pot
reaction for the synthesis of novel spiro-2-amino-3-phenylsulfo-
nyl-4H-pyran derivatives, which are compounds of major syn-
thetic, biological, and medicinal importance. This reaction can be
carried out under mild conditions and covers a great range of sub-
strates with excellent yields of spirooxindole products. This novel
protocol provides an efficient, easy to separate, environmental
friendly synthetic route for synthesis of novel spiro-2-amino-3-
phenylsulfonyl-4H-pyran derivatives.

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