Polymer-supported thioanisole: a versatile platform for organic
Matthew Kwok Wai Choi and Patrick H. Toy*
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China
Received 8 December 2003; revised 12 January 2004; accepted 15 January 2004
Abstract—A new cross-linked polystyrene-supported thioanisole reagent is reported. This reagent incorporates the flexible JandaJelecross-linker and can be treated with methyl trifluoromethanesulfonate to form the corresponding sulfonium salt. This salt can in turn bedeprotonated to form a polymer-supported sulfur ylide that is able to react with aldehydes and ketones to form epoxides. The thioanisolereagent can also be oxidized to form an insoluble sulfoxide reagent that is useful in Swern oxidation reactions. In these reactions, thepolymer-supported thioanisole-based reagents can be recovered, regenerated and reused.
q 2004 Elsevier Ltd. All rights reserved.
Recent years have seen polymer-supported reagents and
Previously, cross-linked polymer-supported thioanisole has
catalysts become common tools for organic synthesis in
been prepared by bromination of preformed polystyrene
what is known as polymer-assisted synthesis since they can
beads followed by lithiation and trapping of the resulting
simplify product isolation and purification.In this context,
aryl lithium intermediate with dimethyl disulfide.Since
this procedure requires a sequence of three reactions that
support. The utility and power of such reagents has been
must proceed predictably in high yield with no side products
exquisitely demonstrated by Ley et al. in their syntheses of
being formed in order to obtain a homogeneous polymer-
several complex natural products using these reagents
supported reagent, we chose to incorporate the sulfide
exclusively.In order to broaden the range of reactions
moieties into our reagent by using a functional styrene
capable of being performed using such polymer-assisted
monomerin the polymerization process. Using this
techniques, new polymer-supported reagents are continually
strategy allows for the direct preparation of a maximally
loaded and homogeneous reagent in which all of the non-cross-linker aryl rings are derivatized with the desired
As part of our ongoing research into developing such
methyl sulfide groups. This is the method that we previously
reagents, we have recently reported some non-cross-linked
employed in the development of the JandaJele polystyrene
polystyrene-based sulfoxide reagents that are useful in
resinsincorporating a variety of functional monomers.
Swern oxidation reactions.Due to the fact that thesepolymeric reagents require a precipitation operation prior to
Therefore, we prepared thioanisole monomer 1 according to
their removal from reaction mixtures by filtration, we
the literature procedure from 4-bromostyrene
sought to prepare an insoluble analogous cross-linked
This was suspension co-polymerizedwith 2 mol% of the
reagent so that filtration can be performed directly. We
flexible JandaJele cross-linker to afford polymer-supported
also sought to examine the utility of such a polymer in the
thioanisole 2 (JandaJele-SMe). By preparing reagent 2 in
sulfide oxidation state by converting it to other organic
this manner, the loading level (5.9 mmol/g) could be
synthesis reagents. Herein we report our progress in
maximized and thereby reducing the amounts of polymeric
developing an insoluble polymer-supported thioanisole
reagent and solvent necessary for performing the subsequent
that can be converted into reagents for oxidation and
In order to examine the versatility of 2 as a platform forsulfur-based organic synthesis reagents, it was treatedseparately with MeOTf and tert-butyl hydroperoxide
Keywords: Thioanisole; JandaJele; Epoxide.
(TBHP) in the presence of p-TSA to afford sulfonium salt
Corresponding author. Tel.: þ852-2859-2167; fax: þ852-2857-1586;e-mail address: [email protected]
3 and sulfoxide 4, respectively (). Reagent 3 was
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879
Scheme 1. Synthesis of monomer 1 and polymers 2 – 4.
prepared in order to serve as a polymer-supported precursor
sulfoxide reagents have been used previously in Swern
to the Corey – Chaykovsky methylide reagentwhich can be
oxidation reactions.However, these reagents required
used to convert carbonyl groups into epoxide moieties.
multi-step synthesis to produce polymers that were not
Reagent 4 was prepared to serve as a polymer-supported
maximally functionalized with sulfoxide moieties, as is 4.
analog of dimethyl sulfoxide for use in Swern oxidationreactions.
Table 1. Epoxide synthesis reactions using 3
Reagent 3 was deprotonated with sodium hydride under
conditions similar to those reported by Fre´chet et fordeprotonation of sulfonium salts using potassium tert-butoxide, and the resulting ylide was allowed to react with a
range of aldehydes and ketones to afford the correspondingepoxides (In all cases, the starting carbonylcompound was completely consumed and product wasisolated in good to excellent yield. In the reaction of the
ylide from 3 with trans-cinnamaldehyde, only 1,2-additionwas observed (entry 5). Furthermore, reactionswith ketones afforded slightly higher yields (entries 6 – 8) than did reactions with aldehydes (
In order to examine the recyclability of the polymerrecovered from the epoxide synthesis reactions, the reaction
represented in entry 6 was performed five timesusing the same sample of 3. Since 3 was used as the excessreagent in these reactions, the polymer recovered at the endof the reaction was a mixture of 2 and 3. Therefore, at the
end of each reaction cycle, the polymer was recovered,washed and reacted with MeOTf in order to convert it topure 3. This was then reused for epoxide formation in a totalof 5 cycles (As can be seen, essentially identical
yields were observed for each reaction, clearly indicatingthat 3 can be regenerated and reused without any decrease ineffectiveness.
Swern oxidation reactions using polymer 4 were examinednext. A cross-linked polystyrene-based sulfoxide polymerrelated to 4 has been previously used in triphasic catalysis,
and in alcohol oxidation reactions involving chlorineactivation.
M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879
Table 2. Yields of 2-(4-bromophenyl)-2-methyloxirane from 40-bromo-
Table 4. Yields of 40-bromoacetophenone from 1-(4-bromophenyl)ethanol
Therefore, 4 should be more efficient to use since the nature
TBHP and p-TSA to regenerate homogeneous 4. As can be
of its functionalization is known precisely and its relatively
seen in , only a modest decrease in product yield was
higher concentration of sulfoxide moieties means that less
observed in each subsequent cycle. Regardless of this, the
reagent and solvent are required for the oxidation reactions.
results are acceptable because in each case the product wasisolated in a pure state, and in polymer-assisted synthesis,
A variety of secondary alcohols were oxidized using excess
generally product yield is of secondary importance to
4 and oxalyl chloride. The results of these reactions are
summarized in In these reactions, the startingmaterial was completely consumed and the yield reportedrepresents isolated product. In all cases, the desired product
could be isolated in essentially pure form from the reactionmixture in satisfactory yield after several filtration
In summary, we have developed a cross-linked polymer-
supported thioanisole platform (2) that can serve as afoundation for the preparation various sulfur-based reagents
To assess the reusability of the polymer recovered from the
for organic synthesis. We have used 2 to prepare a precursor
oxidation reactions, the reaction represented in
of a sulfur ylide (3) and a sulfoxide (4) for oxidation
entry 1 was performed five times using the same sample of
reactions. These reagents can be used repeatedly with only
4. Since the polymer recovered at the end of the reaction
modest decrease in their effectiveness. Furthermore, it is
was a mixture of 2 and 4, the sample was reoxidized with
expected that 2 can serve as the starting material foradditional polymer-supported reagents and studies directed
Table 3. Swern oxidation reactions using reagent 4
at developing these are currently underway.
All reagents were obtained from the Aldrich, Lancaster orAcros chemical companies and were used without further
purification. All moisture sensitive reactions were carriedout in dried glassware under a N2 atmosphere. Tetra-hydrofuran was distilled under a N2 atmosphere oversodium and benzophenone. Dichloromethane and dimethyl
sulfoxide were distilled under a N2 atmosphere and invacuo, respectively, over calcium hydride. Merck silica gel60 (230 – 400 mesh) was used for chromatography. Thinlayer chromatography analysis was performed using glass
plates coated with silica gel 60 F254. The NMR spectra wererecorded using a Bruker DRX 400 spectrometer. Chemicalshift data is expressed in ppm with reference to TMS.
EI-MS data was recorded on a Finnigan MAT 96 massspectrometer. Elemental analyses were conducted at the
Analytical and Testing Center of the Shanghai Institute ofOrganic Chemistry.
4.1.1. 4-Vinylphenyl methyl sulfide (1). Methyl disulfide(21.6 g, 229.0 mmol) was added slowly at 0 8C to a solutionof the Grignard reagent prepared from 4-bromostyrene
(28.0 g, 153.0 mmol) and Mg (7.4 g, 305.0 mmol) in dryTHF (200 mL). The mixture was stirred at rt for 3 h. At thistime, the reaction mixture was diluted with diethyl ether(500 mL), and then washed sequentially with water(250 mL), 10% aqueous HCl (250 mL), saturated aqueous
M. K. W. Choi, P. H. Toy / Tetrahedron 60 (2004) 2875–2879
NaHCO3 (250 mL) and brine (250 mL). The organic layer
dried over MgSO4, filtered and concentrated in vacuo. The
was dried over MgSO4, filtered and concentrated in vacuo.
crude residue was filtered through a plug of silica gel to
The crude product was purified by silica gel chromato-
provide the essentially pure epoxide product (
graphy (5% EtOAc/hexanes) to afford 1 as a clear, colorlessliquid (16.0 g, 106.5 mmol, 70%). 1H NMR (400 MHz,
4.3. Procedure for regeneration of polymer 3
CDCl3) d 2.45 (s, 3H), 5.21 (dd, 1H, J¼10.9, 0.9 Hz), 5.70(dd, 1H, J¼17.6, 0.9 Hz), 6.68 (dd, 1H, J¼17.6, 10.9 Hz),
The polymer mixture (2 with 3, ca. 1.0 g) recovered from
7.17 – 7.40 (m, 4H). 13C NMR (100 MHz, CDCl3) d 15.7,
the epoxide synthesis reaction was treated with MeOTf
113.1, 126.6 (4C), 134.5, 136.2, 138.0. HR EI-MS: calcd for
(1.5 g, 8.9 mmol) in CH2Cl2 (20 mL) and stirred for 24 h at
rt. The resin was recovered and washed sequentially withdichloromethane, methanol, diethyl ether and hexanes. The
4.1.2. JandaJele-SMe (2). A solution of acacia gum
shrunken beads 3 were dried in vacuo and reused in the
(6.0 g) and NaCl (3.8 g) in warm deionized water (45 8C,
epoxidation reaction. The same sample of 3 was used in all 5
150 mL) was placed in a 150 mL flanged reaction vessel
cycles reported in using this procedure.
equipped with a mechanical stirrer and deoxygenated bypurging with N2 for 2 hA solution of 1 (10.0 g,
4.4. General procedure for alcohol oxidation
6.7 mmol), cross-linker (0.4 g, 1.5 mmol) and AIBN(0.2 g, 1.3 mmol) in chlorobenzene (10 mL) was injected
A suspension of 4 (1.0 g, 4.8 mmol) in anhydrous CH2Cl2
into the rapidly stirred aqueous solution. The mixture was
(30 mL) was cooled to 270 8C and oxalyl chloride (0.6 g,
heated at 85 8C for 20 h. The crude polymer was collected
4.4 mmol) was added dropwise. After 30 min, a solution of
and washed with hot water (3£100 mL) and then placed in a
the alcohol (1.2 mmol) in anhydrous CH2Cl2 was added.
Soxhlet extractor and washed with THF for 1 day. The
The mixture was stirred at low temperature for 1 h and then
beads were recovered, washed with methanol (250 mL),
triethylamine (0.7 g, 7.2 mmol) was added. The solution is
diethyl ether (250 mL), and hexanes (250 mL). The
kept at 240 8C for 1 h more and then allowed to warm to rt.
shrunken beads 2 (9.0 g, 90%) were dried in vacuo.
The suspension was then filtered and the resin was washed
Elemental analysis was used to determine the sulfur content
with addition CH2Cl2 (3£10 mL). The combined filtrate was
(18.9%) and thus the loading level of 5.9 mmol S/g of 2.
concentrated in vacuo and the crude residue was filteredthrough a plug of silica gel to provide the essentially pure
4.1.3. JandaJele-S(Me)2OTf (3). To a magnetically
stirred suspension of 2 (3.0 g, 17.7 mmol) in CH2Cl2(30 mL) at rt was added MeOTf (4.4 g, 27.0 mmol). Stirring
4.5. Procedure for regeneration of polymer 4
was continued for 24 h at rt, at which time the resin wasfiltered off, and washed sequentially with dichloromethane,
The polymer mixture (2 with 4, ca. 1.0 g) recovered from
methanol, diethyl ether, and hexanes. The shrunken beads 3
the oxidation reaction was treated with 70% TBHP (3.1 g,
(6.0 g) were dried in vacuo. Elemental analysis was used to
24.0 mmol) and p-TSA (0.9 g, 4.8 mmol) in CH2Cl2
determine the sulfur content (18.3%) and thus the loading
(20 mL) and stirred at rt for 24 h. The beads were recovered,
and washed sequentially with dichloromethane, methanol,diethyl ether and hexanes. The shrunken beads 4 were dried
4.1.4. JandaJele-S(O)Me (4). To a magnetically stirred
in vacuo and reused in the oxidation reaction. The same
suspension of 2 (5.0 g, 29.5 mmol) in CH2Cl2 (40 mL) at rt
sample of 4 was used in all 5 cycles reported in
was added 70% TBHP (19.3 g, 150.0 mmol) and p-TSA
(5.6 g, 30.0 mmol). Stirring was continued for 24 h at rt, atwhich time the resin was filtered off and washedsequentially with dichloromethane, methanol, diethyl
ether, and hexanes. The shrunken beads 4 (5.5 g) weredried in vacuo. Elemental analysis was used to determine
This research was supported financially by the University of
the sulfur content (15.4%) and thus the loading level of
Hong Kong, and the Research Grants Council of the Hong
4.8 mmol S/g of 4. Previous reports using this oxidation
Kong Special Administrative Region, P. R. of China
system indicate that oxidation of the sulfide stops at the
(Project No. HKU 7112/02P). We also thank Mr. Bob
sulfoxide oxidation state and that no sulfone is formed.
Wandler of the Aldrich Chemical Co. for supplying many ofthe reagents used in this study.
4.2. General procedure for epoxide synthesis
A solution of the carbonyl compound (1.0 mmol) inanhydrous DMSO (4 mL) and anhydrous THF (1 mL) was
added to a mixture of 3 (1.0 g, 2.9 mmol) and 60% NaH(0.12 g, 3.0 mmol) in anhydrous THF (2 mL) that was
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