Oxetane synthesis via cyclisation of aryl sulfonate esters on polystyrene and PEG polymeric supports

Article abstract of DOI:10.1016/j.tetlet.2004.11.138

The addition of suitably protected pentaerythritols to polymer supported sulfonyl chloride with subsequent alkoxide formation and intramolecular cyclisation to generate oxetanes is described. This convenient method for the preparation of oxetanes has seve

Full text of DOI:10.1016/j.tetlet.2004.11.138

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 643–645
Oxetane synthesis via cyclisation of aryl sulfonate esters
on polystyrene and PEG polymeric supports
a
Jonathan M. Behrendt, Kason Bala, Peter Golding and Helen C. Hailes
b
b
a,
*
a
Department of Chemistry, University College London, 20 Gordon Street, London WC1H OAJ, UK
b
AWE, Aldermaston, Reading, Berks RG7 4PR, UK
Received 16 July 2004; revised 15 November 2004; accepted 26 November 2004
Available online 13 December 2004
Abstract—The addition of suitably protected pentaerythritols to polymer supported sulfonyl chloride with subsequent alkoxide for-
mation and intramolecular cyclisation to generate oxetanes is described. This convenient method for the preparation of oxetanes has
several advantages over analogous solution phase reactions and the methodology is extended to the preparation and use of a novel
PEG-sulfonyl chloride.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Oxetanes are an important group of cyclic ethers that
3
can be used in synthesis as equivalents for the a -syn-
OR
OR
RO
OR
thon, and undergo a wide range of chemical transforma-
tions. As with their three membered ring analogues, the
epoxides, they can be self-polymerised under Lewis acid
Support
Linker
O
Base + cyclisation
Support
O
HO
Linker
OH
1
–4
conditions,
5
or polymerised through anionic ring
opening, to give a range of polyether architectures.
They have also been converted into cage molecules for
Scheme 1. Solid support cyclisation strategy to oxetanes.
6
the selective complexation of cations and oxetane moi-
7
,8
due to the emergence of combinatorial chemistry, which
has enabled the parallel synthesis of large libraries of
compounds. SPOS has also led to the development
of automated synthetic procedures, where the purifica-
tion following each synthetic step can be achieved using
resin-washing procedures. When designing a synthesis
on solid support one key consideration is selection of the
linker through which the substrate is attached to the
support, as well as the type of support. For an applica-
tion in oxetane synthesis a polymer bound sulfonyl chlo-
ride was selected. Herein we describe the use of a
polystyrene (PS) resin and the synthesis of a novel
PEG-sulfonyl resin for the synthesis of oxetanes.
eties are found in many natural products. The synthe-
sis of oxetanes has been reported using a number of
1
4
9
different strategies, for example, via a [2+2]-photocy-
0
1
cloaddition of an alkene and aldehyde, or more fre-
1
1,12
quently the dehydration of 1,3-diols.
approach, yields are often moderate at best, particularly
with acyclic diols.
For the later
1
4
1
3
With the intense interest in these compounds there is a
continuing desire to develop facile procedures requiring
the minimal purification of products. Therefore, the use
of a solid support for the synthesis of sterically hindered,
functionalised oxetanes, using the support as a leaving
group during the cyclisation step was considered
Sulfonyl chloride (PS bound) is most often used as a
nucleophile scavenger (e.g., for amines or alcohols),
allowing the simple purification of solution phase reac-
tions. However, as a linker it can also provide a conve-
nient method of attaching a substrate through a free
amine or alcohol functionality, which can then be re-
(
Scheme 1).
Solid phase organic synthesis (SPOS) has become of
increasing importance in the last 10–15 years, largely
1
5–17
leased and modified by nucleophilic attack.
To the
Keywords: Oxetanes; Solid-phase reactions; PEG supported reactions.
*
Corresponding author. Tel.: +44 20 7679 4654; fax: +44 20 7679
463; e-mail: h.c.hailes@ucl.ac.uk
best of our knowledge, there are no reported examples
of the cleavage of molecules from this linker via an
7
0
040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.138

644
J. M. Behrendt et al. / Tetrahedron Letters 46 (2005) 643–645
intramolecular nucleophilic attack, to form cyclic prod-
ucts. Two pentaerythritol analogues were selected as
suitable compounds to investigate this approach: di-
tert-butyldimethylsilyl pentaerythritol 1 and the mono-
benzylidene protected pentaerythritol 2. In order to
obtain a direct comparison with the solution phase reac-
tion, the equivalent non-SPOS reaction was initially per-
formed. The monotosylate 3 was readily prepared
although the synthesis of 4 proved to be low yielding
due to decomposition under the reaction conditions
Interestingly, when the polymer bound alcohols 7 and 8
were treated with sodium hydride no reaction was ob-
served. However, the use of potassium tert-butoxide to
generate the alkoxide gave 5 and 6 in 96% and 62%
yields, respectively, over the two steps. The only purifi-
cation step required was to remove trace impurities from
1
8
2
0
5 and 6 by filtration through a short pad of silica.
Whilst the use of a polystyrene resin has many advanta-
ges, reactions on the beads are often nontrivial to mon-
itor in detail. In addition, we predicted that a support
with a polar environment could influence stabilisation
of the alkoxide and the subsequent cyclisation favour-
ably. The synthesis of a sulfonyl chloride linker on a
PEG polymer (average mass 3400) was therefore inves-
tigated. Soluble polymeric supports of this nature, with
applications in liquid-phase organic synthesis (LPOS),
can have several advantages over polystyrene based sup-
(
Scheme 2). Also, as with all such desymmetrisation
reactions, the ditosylated compounds together with
unreacted starting material were also present in the
crude product mixture, and purification by flash column
chromatography was required. The alkoxide was then
generated in situ, which subsequently formed the oxe-
tane, and was isolated and purified. The use of sodium
hydride gave 5 in higher yields, whilst the optimal base
to give the oxetane 6 was potassium tert-butoxide. The
conversion of 1 and 2 into 5 and 6 was achieved in
2
1
ports: solubility in solvents such as dichloromethane
and methanol gives a more solution-like environment
for reactions, and also enables the monitoring of poly-
5
9% and 6% yield over two steps.
1
mer bound intermediates by solution H NMR spectros-
With the results of the solution based oxetane synthesis in
hand, we set about modifying the procedure for use on a
solid support. Both diols were successfully loaded onto
the PS support to give 7 and 8 (A is PS, Scheme 3), using
pyridine as base and heating at reflux for 16 h, as indi-
copy. However, their low solubility in other solvents,
such as propan-2-ol and diethyl ether, allows ease of
purification using simple recrystallisation techniques.
The synthesis of the PEG-sulfonyl chloride resin 9 was
carried out as detailed below in 64% overall yield, and
all steps were readily monitored using solution
1
9
1
cated by a positive result from a bead-staining test.
H
NMR spectroscopy. The dimesylation of PEG3400
was carried out as previously reported and then conver-
sion to the corresponding dibromide achieved under
RO
OR
RO
OR
RO
OR
a
b
R = TBDMS
22,23
standard conditions (Scheme 4).
Reaction with 4-
O
OH OH
OH OTs
hydroxybenzenesulfonic acid and sodium hydroxide,
then treatment with thionyl chloride gave the difunc-
1
3
5
2
3
tionalised PEG-sulfonyl chloride resin 9.
Ph
Ph
Ph
O
O
O
O
O
O
The loading of the pentaerythritol 2 onto 9 required the
use of DMAP (stoichiometric) in toluene and the reac-
tion was stirred at rt for 16 h to give 10 (A is
PEG3400, Scheme 3) containing approximately 30% of
c
d
O
6
OH OH
OH OTs
2
4
1
a bridged side product, by H NMR spectroscopy.
Scheme 2. Reagents and conditions: (a) TsCl, pyridine, reflux, 24 h,
The use of alternative reaction conditions led to lower
loading levels onto 9. Despite this, cyclisation and cleav-
age were readily achieved using potassium tert-butoxide
to give 6 in 63% yield over the two steps, reflecting the
problem with the bridged side products, but highlighting
that the cyclisation occurred with 10 in almost quantita-
tive yield. Again, trace impurities were removed from 6
by filtration through a short pad of silica. Since the over-
all yield was comparable to that for the loading and cyc-
7
1
1%; (b) NaH, THF, rt, 3 h, 83%; (c) TsCl, DMAP, pyridine, rt, 16 h,
t
0%; (d) KO Bu, THF, rt, 3 h, 57%.
TBDMSO
O
OTBDMS
O
S
A
Cl
O
b
1
A
S
O
OH
5
a
O
7
(A = PS resin)
a,b
3%
O
Ph
O
PEG3400
Br
Br
9
n
O
O
S
6
9% c,d
A
Cl
O
O
S
O
S
O
O
O
b
2
A
S
O
OH
6
Cl
O
O
n
Cl
9
a
O
O
8
1
(A = PS resin)
0 (A = PEG3400)
Scheme 4. Reagents and conditions: (a) MsCl, Et
acetone, reflux, 16 h; (c) 4-hydroxybenzenesulfonic acid, NaOH,
3
N, rt, 16 h; (b) LiBr,
i
Scheme 3. Reagents and conditions: (a) pyridine, reflux, 16 h; (b)
t
KO Bu.
2 3 2 2
PrOH/H O, reflux, 16 h; (d) CH CN, Soxhlet, CaC , 5 h then SOCl ,
DMF, rt, 16 h.

J. M. Behrendt et al. / Tetrahedron Letters 46 (2005) 643–645
645
lisation of 2 using the PS resin, it was concluded that the
nature of the solid support was not a key issue in this
synthesis, however, detailed reaction monitoring was
extremely easy using the PEG resin 9.
added 2 (224 mg, 1.00 mmol), and the reaction mixture
was heated at reflux for 16 h. The resin was collected by
filtration, washed with CH Cl (3 · 5 mL), DMF
2
2
(
3 · 5 mL), DMF/H
and CH Cl
(3 · 5 mL), and dried in vacuo to give 8
102mg). Unreacted 2 was fully recovered from the
filtrate. To a suspension of the loaded resin 8 (50 mg,
.07 mmol; assuming full loading of 2) in THF (2mL) was
2
O (5:1, 3 · 5 mL), THF (3 · 5 mL),
2
2
(
In summary, we have developed a straightforward, and
synthetically useful method for the formation of oxe-
tanes via a sulfonyl linker on different polymeric sup-
ports. This method of forming oxetanes has
advantages over the analogous solution phase reactions,
both in terms of yield and ease of purification of inter-
mediates and products. The PEG-sulfonyl resin 9 dem-
onstrated clear advantages over PS-supports in terms
of reaction monitoring to generate the cyclic ether. Also,
these procedures could be used with higher loading res-
0
added potassium tert-butoxide (24 mg, 0.21 mmol), and
the reaction mixture was shaken at room temperature for
3 h. The resin was collected by filtration, and washed with
THF/H
(
(
2
O (5:1, 3 · 5 mL), THF (3 · 5 mL), and CH
3 · 5 mL). The combined filtrates were washed with water
5 mL), dried and evaporated. The crude product was
2 2
Cl
filtered through a short pad of silica in ethyl acetate/
hexane (2:3) to give 6 (9 mg, 62%). d (300 MHz; CDCl
.89 (2H, d, J 11.0 Hz), 4.27 (2H, s), 4.56 (2H d, J
1.0 Hz), 4.77 (2H, s), 5.43 (1H s, CH–Ph), 7.31–7.38 (5H,
(75 MHz; CDCl ) 38.0 (C(CH ), 73.1, 73.8,
1.3, 101.3 (CH–Ph), 126.0, 128.3, 129.0, 137.7.
H
3
)
3
1
2
4
ins, expanding the synthetic utility further. It is likely
that the methodology can be applied to other 1,3-diols,
and for the synthesis of alternative ring sizes.
m, Ph); d
C
3
2 4
)
8
2
2
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999, 64, 5188–5192.
23. Procedure for the formation of 9: PEG3400 dimesylate
10.0 g, 2.81 mmol) in acetone (50 mL), and lithium
We thank the AWE for studentships (K.B. and J.M.B.).
(
bromide (1.47 g, 16.9 mmol) were heated at reflux for
16 h. The solution was cooled and a white solid removed
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cooled to 5 ꢁC. The precipitate formed was collected by
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1
propan-2-ol (10 mL), Et
afford PEG3400 disulfonic acid sodium salt as a white
solid (8.25 g, 93%). d (300 MHz; CDCl ) 3.40–3.85 (m,
PEG CH ), 4.14 (4H, t, J 5.1 Hz, CH OAr), 6.85 (4H, d, J
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1
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1
1
1
1
1
1
9
for 5 h under an atmosphere of N . The reaction mixture
2
was cooled to rt and thionyl chloride (4.01 mL,
61.8 mmol), and DMF (5 mL) were added and it was
stirred for 16 h at rt. The solvent was removed in vacuo
and the crude product dissolved in hot propan-2-ol
(100 mL). The solution was cooled to 5 ꢁC, and the
precipitate formed collected by filtration. The precipita-
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dried in vacuo to afford 9 as a white solid (21.6 g, 93%). d
(300 MHz; CDCl ) 3.38–3.90 (m, PEG CH ), 4.23 (4H, t, J
4.6 Hz, CH OAr), 7.07 (4H, d, J 9.0 Hz, Ar–H), 7.96 (4H,
2
O (50 mL), and then
H
6
9. http://www.argotech.com/products.
0. Procedure for the formation of 8 and cyclisation and
cleavage to generate 6: To a suspension of PS sulfonyl
chloride resin (100 mg, 0.20 mmol) in pyridine (5 mL), was
79–680.
3
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