Selective Oxidation of Sulfides in Flow Chemistry

Article abstract of DOI:10.1002/ejoc.201800339

A packed-bed reactor with oxone has been employed for selective oxidations of sulfur compounds. Various sulfides containing different functional groups are efficiently oxidized to the corresponding sulfoxides without formation of sulfones or other side products.

Full text of DOI:10.1002/ejoc.201800339

A Journal of
Accepted Article
Title: Selective Oxidation of Sulfides in Flow Chemistry
Authors: Filipa Silva, Alastair Baker, James Stansall, Weronika
Michalska, Mehkman Yusubov, Michael Graz, Robert
Saunders, Gareth J. S. Evans, and Thomas Wirth
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800339
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800339
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201800339
COMMUNICATION
Selective Oxidation of Sulfides in Flow Chemistry
[
a]
[a]
[a]
[a]
[b]
Filipa Silva, Alastair Baker, James Stansall, Weronika Michalska, Mehkman S. Yusubov,
[
c]
[c]
[c]
[a]
Michael Graz, Robert Saunders, Gareth J. S. Evans, and Thomas Wirth*
[
10]
[11]
Abstract: A packed bed reactor with oxone has been employed for
selective oxidations of sulfur compounds. Various sulfides containing
different functional groups are efficiently oxidized to the
corresponding sulfoxides without formation of sulfones or other side
products.
urea-hydrogen peroxide,
sodium hypochlorite,
and sodium
[
12]
periodate.
However, most of these methods either require
stoichiometric amounts of reagents or a transition metal catalyst.
Therefore, efficient, selective and environmentally benign
methods are still highly desired.
Oxone (2 KHSO
5
·KHSO
4
·K
2
SO
4
)
is
a
free-flowing and
commercially available peroxygen salt that provides powerful
non-chlorine oxidation in a stable, easy-to-handle manner. Due
to its high stability and efficiency, oxone has found many
Sulfoxides are very important moieties widely used in the
preparation of biologically and pharmaceutically significant
compounds. They constitute
a relevant motif in marketed
[
13]
[1]
[2]
applications that are well documented.
Li et al. reported a
therapeutics, such as Provigil and Nexium and in biologically
[
3]
selective oxidation of sulfides by employing oxone as the oxidant
without utilization of any catalyst/additive under mild conditions.
The degree of oxidation was achieved by solvent selection that
preferentially produced the sulfoxide. Although the yields are
active components of garlic extracts such as Allicin and Ajoene
Figure 1). Sulfide oxidation has also been utilized in the
extraction of sulfur-containing compounds from crude oil via
(
[
4]
catalytic oxidative desulfurization processes. Sulfoxides can
also serve as valuable oxo-transfer reagents in oxidation
[
14]
high, the reaction had to be performed at 60 ºC for 12 h.
Oxone in the presence of trifluoroacetic acid has been used for
[
5]
[6]
reactions and as versatile ligands in asymmetric catalysis.
[
15]
the oxidation of diarylacetylenes to 1,2-diketones, ketones or
[
16]
O
alkynes to carboxylic acids
and perfluoroalkyl iodides to the
N
O
O
S
[17]
S
N
corresponding bis(trifluoroacetoxy)iodo derivatives.
However,
Ph
H N
2
MeO
N
H
there are no reports regarding the oxidation of sulfur compounds
using these reaction conditions.
Ph
OMe
Provigil
O
Nexium
Microreactors have been used in many organic synthesis
transformations due to their efficiency, selectivity and high
[
18]
degree of safety.
Herein we describe the use of a simple
O
S
packed-bed reactor for the selective oxidation of sulfides. The
selective oxidation of sulfides in continuous-flow microreactors
S
S
S
S
[
19 ]
[ 20 ]
Allicin
Ajoene
using electrochemical
and photochemical
methods has
been reported. A simple protocol for the selective oxidation of
sulfides in flow chemistry utilizing a packed-bed reactor with
oxone in the presence of trifluoroacetic acid has been developed
Figure 1. Biologically active compounds containing sulfoxide moieties.
(
Scheme 1).
Research in sulfur chemistry has addressed the selective
oxidation of sulfides to sulfoxides without overoxidation to
S
R
R’
[
7]
+
Oxone
O
S
sulfones or other undesired side reactions. Several oxidants
have been reported for the selective oxidation of sulfur, such as
CF CO H
CH2Cl2
3
2
R
R’
[
8 ]
[ 9 ]
hydrogen peroxide,
nitric acid, m-chloroperbenzoic acid,
[a]
F. Silva, Dr. A. Baker, J. Stansall, W. Michalska, Prof. Dr. T. Wirth
School of Chemistry
Scheme 1. Flow setup for the oxidation of sulfur compounds using a packed-
bed reactor.
Cardiff University
Park Place, Main Building, Cardiff CF10 3AT (UK)
E-Mail: wirth@cf.ac.uk
Homepage: http://blogs.cardiff.ac.uk/wirth/
Prof. Dr. M. S. Yusubov
Tomsk Polytechnic University and Siberian State Medical University
For this study, thioanisole 1a was used as the model substrate
[
b]
c]
to find suitable reaction conditions. Initial reactions were carried
634050 Tomsk (Russia)
out by pumping
a
dichloromethane solution containing
[
Dr. M. Graz, Dr. R. Saunders, Dr. G. J. S. Evans
Neem Biotech
Roseheyworth Business Park North
Abertillery NP13 1SX (UK)
thioanisole 1a (0.05 M) and trifluoroacetic acid (TFA) (15 vol%)
through an Omnifit column packed with oxone (Table 1, entry 1).
The flow rate of 0.5 mL/min corresponds to a residence time of 4
1
minutes within the reactor. Upon collection,
H
NMR
spectroscopic analysis showed that 100% conversion was
achieved. Increasing the concentration of the sulfide solution to
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201800339
COMMUNICATION
either 0.1, 0.15 or 0.2 M (Table 1, entries 2-4) did not affect the
conversion of the reaction. Only when the concentration of the
sulfide solution was further increased to 0.4 M, the conversion
dropped to 55% (Table 1, entry 5). The volume percentage of
trifluoroacetic acid in dichloromethane was a crucial for obtaining
high conversion. Decreasing from 15 vol% to 10 vol% reduced
the conversion by a factor of 4 (Table 1, entries 4 and 6) when
performed at 0.5 mL/min. To improve the conversion when using
low concentration of TFA, longer reaction times were needed.
However, full conversion was not even obtained after 60 minutes
residence time while pumped at 0.03 mL/min (Table 1, entry 9).
Other researchers have also reported that TFA activates oxone
2 in good yields. Similarly, sulfide 1j bearing a ketone also
underwent efficient oxidation to afford the corresponding
sulfoxide 2j, where
a possible Baeyer-Villiger reaction
product was not observed. Moreover, the present protocol
was also applied to the oxidation of diallyl sulfide 1k. In the
case of allyl sulfides 1i and 1k no epoxide formation was
[22]
observed.
O
S
R
R’
Oxone
S
R
R’
CH Cl : CF CO H (85:15, v/v)
1
2
2
3
2
2
0.6 mL / min
4
min residence time
[
21]
in other oxidation reactions.
O
S
O
S
O
S
Table 1. Optimization of the reaction conditions in a solution of TFA
in dichloromethane.
Me
Ph
R’
2
2
g (R’ = n-Bu): 89%
h (R’ = Bn): 95%
R’’
O
O
S
S
Ph
Me
Oxone
Ph
Me
2a (R’’ = H): 98%
b (R’’ = Cl): 94%
2c (R’’ = F): 94%
O
2j 93%
2
CH Cl , CF CO H
S
1
a
2
2
3
2
2a
Ph
O
S
2
2
2
d (R’’ = Me): 90%
e (R’’ = CHO): 91%
f
2
i 89%
(R’’ = NO ): 92%
2
O
S
Entry Concentration
a [M]
TFA
Residence
Conversion
2
k 92%
a
Se
1
[vol%]
15
time [min]
[%]
Ph
Ph
1
2
3
4
5
6
7
8
9
0.05
0.10
0.15
0.20
0.40
0.20
0.20
0.20
4
4
100
100
100
100
55
2
l 76%
15
15
4
Scheme 2. Substrate scope for the oxidation of sulfides using flow
15
4
conditions.
15
4
10
4
20
10
17
30
60
33
Interestingly, compound 1l contains both a phenyl sulfide
and a phenyl selenide moiety (Scheme 2), but the only
product obtained was the sulfoxide 2l in 76% yield. To
demonstrate the chemoselectivity of this procedure, the
same substrate 1l was treated with one equivalent of
mCPBA (meta-chloroperbenzoic acid) under batch
conditions. The reaction now afforded sulfoxide 2l in very low
yield (7%), together with compound 1i (8%) and 2i (10%).
The starting material 1l was recovered in 43% yield. Under
the oxidizing conditions, also the selenide is partially oxidized
10
50
0.20
10
68
a
1
Determined by H NMR spectroscopic analysis.
The packed bed reactor with oxone contains approximately
.1 mmol oxone (5.6 g) and can be used to oxidize up to 10
9
mmol of sulfide without affecting the conversion and with no
change in residence time. The oxone in the packed bed
reactor can also be washed with dichloromethane allowing a
reuse of the reactor with a different substrate until the oxone
is fully consumed. In order to find an alternative solvent for
dichloromethane and TFA, other solvents such as acetone
and ethanol were investigated. However, the conversions
were not exceeding 45%. The temperature effect was also
briefly investigated. Generally, it was observed that an
increase in temperature leads to a lower selectivity (sulfoxide
vs. sulfone).
[
23 ]
to the selenoxide, which then undergoes elimination
generating the corresponding alkenes 1i and 2i (Scheme 3).
However, when the oxidation with mCPBA was carried out in
the presence of 10 vol% TFA, only compound 2l was
obtained in 70% yield. The cyclic voltammetry of compound
1l showed two different oxidation potentials (1.17 V and 1.70
V). In the presence of 10 vol% TFA a slight decrease in the
oxidation potentials (1.00 V and 1.50V) was observed.
Maybe protonation of the selenide prevents its oxidation in
the presence of TFA.
After optimization of the reaction conditions, the substrate
scope was explored (Scheme 2). Different sulfides were
reacted affording the desired sulfoxides in good to excellent
yields. Specifically, phenyl sulfides bearing aliphatic (1g),
benzyl (1h) and allyl (1i) substituents afforded the sulfoxides
in high yields. The yields were not affected by the electronic
structure of the phenyl sulfides. As it can be seen in Scheme
O
mCPBA
O
S
+
+
S
(1 eq)
Ph
Ph
S
Se
Se
Ph
Ph
Ph
Ph
2i 10%
CHCl3
S
1l
2l 7%
2
, para-substituted phenyl sulfides (1b-1f) with electron-
1
i 8%
donating or electron-withdrawing groups gave the sulfoxides
Scheme 3. Oxidation of compound 1l with mCPBA.
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European Journal of Organic Chemistry
10.1002/ejoc.201800339
COMMUNICATION
Using the optimal reaction conditions found for oxidizing
corresponding thiosulfinates 4e (72%) and 4f (59%), even in
the case of the hindered t-butyl disulfide 3e.
sulfides, different disulfides such as dibenzyl disulfide 3a
1
(
Table 2, entry 1) were investigated. The H NMR spectra of
the crude reaction mixture revealed the presence of disulfide
a (35%), thiosulfinate 4a (35%) and thiosulfonate 5a.
3
O
Further optimization studies were carried out using dibenzyl
disulfide 3a as a test substrate, in order to obtain the
thiosulfinate 4a selectively (Table 2). Decreasing the
concentration of disulfide to 0.1 M and 0.05 M, a slightly
increased conversion was observed but thiosulfonate 5a was
still detected (Table 2, entry 2). Only when the concentration
of 3a was reduced to 0.025 M, the conversion increased to
S
R
S
R
Oxone
R
S
R
S
CH2Cl2 : CF3CO2H
3
4
9:1 (v/v)
(
0.025 M)
(0.025 M)
0
.6 mL / min
min residence time
4a R = PhCH2: 91%
b R = 4-Br-C6H4-CH2: 89%
c R = PhCH=CHCH2: 69%
4d R = n-Pr: 72%
e R = t-Bu: 59%
R = allyl: 74%
4
4
4
4
4
8
2% (Table 2, entry 4). Reducing the percentage of TFA in
f
the mixture from 15% to 10%, resulted in almost full
Scheme 4. Substrate scope for the oxidation of disulfides 3 using
conversion to thiosulfinate 4a and thiosulfonate 5a was no
1
flow conditions.
longer detected by H NMR (Table 2, entry 5). Increasing the
concentration of disulfide 3a to 0.05 M and 0.1 M, while
using 10 vol% TFA lead to a diminished conversion (Table 2,
entries 6 and 7). Increasing the residence time barely
affected the conversion (Table 2, entry 8).
In conclusion, a rapid, versatile and selective oxidation
system is described for a variety of sulfides and disulfides.
The use of oxone as oxidant has the advantages of being
readily available, inexpensive and non-toxic. The packed-bed
reactor with oxone could be washed with dichloromethane
and reused. The method shows high functional group
tolerance. Compounds bearing both sulfur and selenium
atoms were selectively oxidized to the sulfoxides with no
formation of other products.
Table 2. Optimization of the reaction conditions of disulfide 3a in
dichloromethane / TFA.
O
Ph
Ph
S
S
Ph
Ph
4
a
Ph
S
S
Ph
Oxone
+
3
a
O O
S
CH2Cl2, CF3CO2H
S
Experimental Section
5
a
Entry Concentration
a [M]
TFA
Residence
Conversion
a
General Procedure for oxidation of sulfides:
3
[vol%] time [min]
[%]
3
a
4a 5a
1
2
3
4
5
6
7
8
0.200
0.100
0.050
0.025
0.025
0.050
0.100
0.100
15
15
15
15
10
10
10
10
4
4
4
4
4
4
4
8
35 35 30
23 50 27
20 53 27
Sulfide (2 mmol) dissolved in a solution of 15 vol% CF
3 2 2
COOH in CH Cl
(
10 mL, 0.2 M). After flushing the column with CH Cl , the reagent
2
2
solution was pumped through the column with a flow rate of 0.6 mL/min
by using Vapourtec E-series equipment (with a peristaltic pump).
Alternatively, a syringe pump can be used. The first column volume was
discarded, and the remaining solution collected. The solution was
8
3
7
82
97
87
8
0
6
6
28 66
3 4
washed with saturated solution of NaHCO (3 x 5 mL), dried over MgSO ,
14 70 16
filtered, and the solvent was removed in vacuo. The crude mixture was
purified by column chromatography.
a
1
Determined by H NMR spectroscopic analysis.
With optimized reaction conditions in hand, the oxidation of
various symmetric disulfides was examined to explore the
scope of the protocol (Scheme 4). The oxidation reaction
with disulfides proved to be more sensitive to overoxidation
and thiosulfinates are less stable when compared with the
corresponding sulfoxides. Benzyl disulfide with an electron-
withdrawing group 3b was oxidized to thiosulfinate 4b in
good yield (89%). Moreover, cinnamyl and allyl disulfides
were also oxidized in moderate yields. This system is also
applicable to the oxidation of dialkyl disulfides into the
General Procedure for oxidation of disulfides:
Disulfide (0.25 mmol) dissolved in a solution of 10 vol% CF
CH Cl (10 mL, 0.025 M). After flushing the column with CH
reagent solution was pumped through the column with a flow rate of 0.6
3
COOH in
2
2
2
Cl , the
2
mL/min by using a syringe pump. The first column volume was discarded,
and the remaining solution collected. The solution was washed with
3 4
saturated solution of NaHCO (3 x 5 mL), dried over MgSO , filtered, and
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European Journal of Organic Chemistry
10.1002/ejoc.201800339
COMMUNICATION
the solvent was removed in vacuo. The crude mixture was purified by
column chromatography.
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research grant from the Russian Science Foundation (RSF-16-
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European Journal of Organic Chemistry
10.1002/ejoc.201800339
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Filipa Silva, Alastair Baker, James
Stansall, Weronika Michalska, Mehkman
S. Yusubov, Michael Graz, Robert
Saunders, Gareth J. S. Evans, and
Thomas Wirth*
Page No. – Page No.
Fixed-bed oxone reactors achieve a selective sulfide oxidation in flow chemistry.
Selective Oxidation of Sulfides in
Flow Chemistry
Key Topic: Flow-Oxidation
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