Facile oxidation of electron-poor benzo[b]thiophenes to the corresponding sulfones with an aqueous solution of H2O2 and P 2O5

Article abstract of DOI:10.1039/b924333j

A facile oxidation for the clean conversion of benzo[b]thiophenes to their corresponding sulfones is described employing an aqueous solution of H ₂O₂ and P₂O₅; the solution can be prepared and stored on a multi-

Full text of DOI:10.1039/b924333j

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Facile oxidation of electron-poor benzo[b]thiophenes to the corresponding
sulfones with an aqueous solution of H2O2 and P2O5w
Dyeison Antonow, Teresa Marrafa, Irfaan Dawood, Tauheed Ahmed, Mohammad R. Haque,
David E. Thurston and Giovanna Zinzalla*
Received (in Cambridge, UK) 19th November 2009, Accepted 21st December 2009
First published as an Advance Article on the web 25th January 2010
DOI: 10.1039/b924333j
A facile oxidation for the clean conversion of benzo[b]thiophenes
to their corresponding sulfones is described employing an
aqueous solution of H2O2 and P2O5; the solution can be
prepared and stored on a multi-gram scale with a shelf-life of
up to two weeks.
is also an issue for storage purposes; reactions cannot be
carried out at temperatures higher than 35 1C as the trifluoro-
peracetic acid degrades.12 Finally, the use of DMD is
problematic in reactions of more than 100 mg scale, as the
complex preparation20 of this reagent limits its scalability.
Thus, we focused on developing an oxidation method that
would allow the conversion of benzo[b]thiophenes to benzo[b]-
thiophene 1,1-dioxides in a facile manner, and on a multi-
gram scale for potential industrial applications. We report
here the use of an aqueous solution of H2O2 (60%) and
P2O5 that involves inexpensive and enviromentally friendly
reagents. A further advantage of this oxidizing system is
that it does not need to be freshly prepared in situ, but can
be prepared on a mutli-gram scale as a single reagent
containing the reactive species peroxymonophosphoric acid21
(0.88 M aq.). The solution has a shelf-life of up to two weeks
when stored at 4 1C.22
To evaluate the versatility of this reagent we investigated the
oxidation of benzo[b]thiophenes bearing EWGs, where the
sulfur atom is more difficult to oxidize. In particular, we
selected the more challenging benzo[b]thiophene carboxamides
(Table 1) whose oxidation to 1,1-dioxides has not been
reported. For each of these derivatives, the carboxamide
group is at the 2-, 3- or 5-positions of the benzo[b]thiophene
system, and the phenyl ring of the amide possesses an EDG or
EWG. For comparison purposes two other oxidative methods
were investigated alongside involving a novel H2O2/TFAA
procedure employing non-explosive 60% aq. H2O2, and
DMD.20 For these preliminary investigations we used the
benzo[b]thiophene 1 (Scheme 1).
Benzo[b]thiophene 1,1-dioxides are an emerging class of
heterocyclic compounds with synthetic and medicinal
chemistry applications. These unsaturated sulfones are
dipolarophiles that have been shown to undergo a number
of synthetically useful cycloaddition reactions1,2 and to be
useful synthons for various chemical transformations.3–5 Also,
this class of cyclic sulfones possesses a variety of biological
activities.6–11 Nevertheless, their potential is under-exploited
due to a lack of synthetic methods to prepare derivatives with
a wide range of substituents. Benzo[b]thiophene 1,1-dioxides
are commonly obtained from benzo[b]thiophenes using
synthetic methods based on a small number of reagents
capable of oxidizing thiophenes bearing electron-donating
groups (EDGs). Fewer reagents are available for the more
challenging derivatives bearing electron-withdrawing groups
(EWG).12–15 The sulfur atom of the benzo[b]thiophene ring
system is even more difficult to oxidize to 1,1-dioxides and few
methods have been explored.16–18 In particular, no general
methods have been reported for the direct synthesis of
benzo[b]thiophene 1,1-dioxides possessing EWGs by oxidation
of the corresponding benzo[b]thiophenes. Based on studies
in the literature for thiophenes and benzo[b]thiophenes,
oxidizing systems that could be successfully exploited include
the use of hydrogen peroxide (30% aqueous solution) at room
temperature with metal-based salts such as MoO2Cl2,19
The reactions were carried out in parallel at room tempera-
ture in acetonitrile using 2 equivalents of the oxidizing agent.
Clean sulfone formation (i.e., no by-products) allowed efficient
isolation of the products in excellent yields. Longer reaction
times were required for substrates possessing a nitro group.
Only in the case of entry 3 was the desired product not formed
and starting material fully recovered. 60% aq. H2O2 and
TFAA afforded the desired compounds in lower yields when
compared to H2O2–P2O5, which was particularly noticeable
for the nitro-substituted substrates. The use of DMD afforded
the oxidized products in comparable yields to the H2O2–P2O5
ZrCl4 or binuclear manganese,16 the use of 98% hydrogen
18
peroxide with trifluoroacetic anhydride,12 or the use of
dimethyl dioxirane (DMD).15 Metal-free catalysis is desirable
from an environmental viewpoint, and 98% hydrogen
peroxide is highly explosive, has to be produced ‘‘in loco’’
and then the oxidizing species (i.e., trifluoroperacetic acid)
formed in situ by mixing the H2O2 with TFAA.12 Its instability
Cancer Research UK Protein-Protein Interactions Drug Discovery
Research Group, The School of Pharmacy, University of London,
29-39 Brunswick Square, London, UK.
E-mail: giovanna.zinzalla@pharmacy.ac.uk;
Fax: +44 (0)207753 5964; Tel: +44 (0)207 7753 5932
w Electronic supplementary information (ESI) available: Experimental
details for preparation of the aqueous H2O2–P2O5 reagent and for all
the reactions described here. Full characterisation of all starting
materials and products is also included. See DOI: 10.1039/b924333j
Scheme 1 Oxidation of 1 with aqueous H2O2–P2O5.
Chem. Commun., 2010, 46, 2289–2291 | 2289
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Table 1 Conversion of benzo[b]thiophene carboxamides to benzo[b]-
thiophene carboxamide 1,1-dioxides with the H2O2–P2O5 reagent
Table 2 The effect of temperature variation on the oxidation of
benzo[b]thiophene-3-carboxamides with the H2O2–P2O5 reagenta
Entry
Temperatureb
Timec
Productd
Yielde (%)
1
2
60 1C
60 1C
130 1C
60 1C
10 min
10 min
1 min
4 h
4g
4k
98
98
98
40
3
4i
a
b
H2O2–P2O5 reagent (2.0 eq), CH3CN (see ESIw for details). Oil
Entry Oxidizing agent Time Producta,b
Yield (%)
bath. Monitored by LC–MS. Characterized by 1H- and 13C-NMR,
c
d
e
f
IR, MS, HRMS. Isolated yield. Additional 2.0 eq of H2O2–P2O5
were added after 3 h.
benzo[b]thiophene-2-carboxamides
c
1
2
3
4
5
6
H2O2–P2O5
9 h
98d
94d
98d
98d
91d
98g
—
H2O2–TFAAe 5 h
DMDf
H2O2–P2O5
10 min
8 h
c
room temperature. We found that reactions were significantly
faster upon heating to 60 1C while affording the same yields
for 4g and 4h. For the nitro-derivative 4i a lower yield was
observed due to degradation of the product during the reaction.
The highly efficient and facile sulfone formation observed
prompted us to extend the reaction to other types of
bennzo[b]thiophenes, and to representatives of classes of
sulfur-containing compounds such as thiophenes, and acyclic
and aromatic sulfides (Table 3).
H2O2–TFAAe 4 h
DMDf
H2O2–P2O5
10 min
72 h
c
H2O2–TFAAe 72 h
—
—
DMDf
H2O2–P2O5
48 h
4 h
92d
91d
98d
95d
79d
98d
98d
98d
98d
c
H2O2–TFAAe 2 h
DMDf
H2O2–P2O5
10 min
4 h
c
H2O2–TFAAe 1.5 h
DMDf
H2O2–P2O5
10 min
7 h
The H2O2–P2O5 oxidizing reagent again allowed formation
of the desired sulfones in excellent yields, and, as anticipated,
shorter reaction times were required than for the benzo[b]-
thiophenes carboxamides.
c
H2O2–TFAAe 1 h
DMDf
20 min
benzo[b]thiophene-3-carboxamides
H2O2–P2O5
7
32 h
98d
78d
98g
h
In summary, a novel oxidizing method using a H2O2–P2O5
reagent has been developed for the preparation of sulfones
from their corresponding sulfides. This reagent allows facile
and efficient oxidation in a parallel manner, and also allows
large scale oxidations. The H2O2–P2O5 aqueous solution can
be prepared as a single reagent that can be stored on a mutli-
gram scale with a shelf-life of up to two weeks. Furthermore, it
is able to oxidize challenging substrates such as benzo[b]-
thiophene derivatives bearing EWGs to afford the corresponding
sulfones in excellent yields. This allows access to a wide range
H2O2–TFAAe 4 h
DMDf
10 min
h
8
9
H2O2–P2O5
48 h
82d
78d
98g
H2O2–TFAAe 5 h
DMDf
10 min
H2O2–P2O5
72 h
80d
47d
96d
h
H2O2–TFAAe 3 h
DMDf
40 min
benzo[b]thiophene-5-carboxamides
10
H2O2–P2O5
10 h
95d
98d
98g
c
H2O2–TFAAe 8 h
DMDf
10 min
6 h
Table 3 Examples of oxidation of other sulfur-containing substrates
with the H2O2–P2O5 reagenta
11
12
a
H2O2–P2O5
94d
90d
98g
c
Entry
Timeb
1.5 h
Productc
Yield (%)
96e
H2O2–TFAAe 2 h
DMDf
10 min
1
H2O2–P2O5
30 h
87d
66d
96d
c
H2O2–TFAAe 4 h
DMDf
40 min
2
3
1.5 h
18 h
98e
91e
Monitored by LC-MS. Characterized by 1H- and 13C-NMR, IR,
b
c
MS, HRMS, CHN. H2O2–P2O5 reagent (2.0 eq), CH3CN (see ESIw
for details). Isolated yield. TFAA (10 eq), 60% aq. H2O2 (10 eq),
d
e
f
CH3CN (see ESIw for details). 0.07–0.09 M DMD in acetone
g
h
15 minf
10 min
80d
98e
(2.4 eq), DCM (see ESIw for details). As indicated by LC-MS. An
additional equivalent of H2O2–P2O5 reagent (3.0 eq overall) was added
after 24 h (see ESIw for details).
4
5
reagent and with a higher reaction rate. However, the
reactions could not be performed in parallel due to the
limitations of manufacturing the DMD.20
6
10 min
75e
a
b
H2O2–P2O5 reagent (2.0 eq), (see ESIw for details). Monitored by
To address the reaction time of the H2O2–P2O5 reagent, we
varied the temperature for the formation of compounds 4g, k
and 4i (Table 2) that required the longest reaction times at
LC-MS. Characterized by 1H- 13C-NMR, IR, MS, HRMS, CHN.
d
c
e
As indicated by LC-MS. Isolated yield. H2O2–P2O5 reagent (3.0 eq).
f
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of benzo[b]thiophene 1,1-dioxides. A final advantage is
that the reagent does not employ enviromentally-damaging
materials such as metal ions, and is thus attractive for
industrial applications. To further exploit the potential of
aq. H2O2–P2O5, the oxidation of alcohols and unsaturated
carbon bonds is under investigation, in parallel with its
application to a wider range of sulfur–containing derivatives.
The authors would like to thank Cancer Research UK for
financial support (DA, TM, ID, TA, DET, GZ - C18/A9327),
and the Commonwealth Commission is acknowledged for
providing a studentship to MRH.
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22 Titration indicated a 50% reduction in the oxidizing properties of
the reagent after three weeks, which demanded larger volumes of
the H2O2–P2O5 reagent for complete conversion to sulfone.
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