N-bromosuccinimide and iodine catalyzed highly efficient deoxygenation of sulfoxides to thioethers using 3-mercaptopropionic acid under mild reaction conditions

Article abstract of DOI:10.1055/s-2003-40981

A variety of alkyl and aryl sulfoxides have been successfdlly deoxygenated using 3-mercaptopropionic acid as a reducing agent and a catalytic amount of either NBS or I₂ (5-10 mol%) in MeCN at ambient temperature. Under the described reaction condition, acid sensitive substrates such as acetals remained intact after several hours.

Full text of DOI:10.1055/s-2003-40981

SHORT PAPER
1875
N-Bromosuccinimide and Iodine Catalyzed Highly Efficient Deoxygenation
of Sulfoxides to Thioethers Using 3-Mercaptopropionic Acid under Mild
Reaction Conditions
D
eoxygenation o
a
S
ulfoxide
b
s
to Thioethe
a
rs
U
sing 3-
k
Mercaptopropioni
K
c
Acid arimi,* Daryoush Zareyee
Department of Chemistry, Institute for Advanced Studies in Basic Sciences (IASBS), P.O. Box 45195-159,GavaZang, Zanjan, Iran
Fax +98(241)4249023; E-mail: karimi@iasbs.ac.ir
Received 12 March 2003; revised 30 May 2003
the reduction of phenyl methyl sulfoxide (PMS) using the
Abstract: A variety of alkyl and aryl sulfoxides have been success-
thiols in the presence of NBS catalyst at room tempera-
fully deoxygenated using 3-mercaptopropionic acid as a reducing
ture. Although, all of the above-mentioned thiols worked
well as reducing agent, we chose 3-mercaptopropionic
agent and a catalytic amount of either NBS or I2 (5–10 mol%) in
MeCN at ambient temperature. Under the described reaction condi-
tion, acid sensitive substrates such as acetals remained intact after acid in the subsequent studies owing to the fact that the
several hours.
presence of the CO2H group in this molecule allows an
easier separation of the by-product disulfide during the
work-up stage through a simple aqueous NaOH washing
of the reaction mixture. On the other hand, though 2-TSA
has also the same property as 3-MPA, the latter is a su-
perior reducing agent than the former from an atom eco-
nomic point of view. Among different solvents such as
MeCN, CH2Cl2, CHCl3, and THF that we used for the re-
duction of PMS as a model substrate, MeCN turned out to
be the most suitable one. It is also worth mentioning that
in CH2Cl2 and CHCl3 the reactions are very sluggish. The
optimum ratios of the reacting species were also studied
by using both I2 and NBS as catalysts and PMS as sub-
strate. The optimum molar ratio was found to be
1:2.1:0.05; for PMS–3-MPA–catalyst, respectively, at
room temperature (Scheme 1, Table 1, entries 1, 2) (see
experimental section).
Key words: sulfoxides, deoxygenation, thioether, catalysis
Sulfoxides are important intermediates in a variety of syn-
thetic transformation, especially as chiral auxiliaries dur-
ing many asymmetric syntheses.1 However, in the
majority of their synthetic applications, it is necessary to
remove the residue of the sulfoxide moiety from the target
molecules. Such a transformations can be most easily
achieved by a two-step procedure that involves the deoxy-
genation of sulfoxides to the corresponding sulfides fol-
lowed by further reductive desulfurization by treatment
with either Raney nickel or dissolving metal systems such
as lithium in liquid ammonia. A survey of the literature re-
veals that though several methods have been reported for
the reduction of sulfoxides,2,3 there still remains important
problems with the reaction, i.e. many of them need rather
drastic conditions, long reaction times,3i or stoichiometric
amounts of expensive reagents.3j,k Among the reported
protocols, sulfur compounds such as thiols,4 sulfides,5 dis-
ulfides,6 thionyl chloride,7 elemental sulfur,8 and 1,3-
dithianes9 have been used for the conversion of sulfoxides
to thioethers. However, many of these methods suffer
from drawbacks such as long reaction time,4–6 harsh acidic
conditions,4,7 high temperature,8 or difficult work-up pro-
cedures.4,9 Therefore, there is still a demand for the devel-
opment of a new efficient method for this transformation
using inexpensive and common laboratory reagents. In the
development of new methods for functional group trans-
formations, we are especially interested in exploring the
potential use of neutral or nearly neutral catalysts.10 Along
this line, we have found that either N-bromosuccinimide
or iodine efficiently accelerates the reduction of sulfox-
ides using a thiol. Thiols that were utilized in this study
are thiophenol, butyl thiol, thiosalicylic acid (2-TSA), and
3-mercaptopropionic acid (3-MPA). We first examined
O
S
SH
(2.1-2.2 equiv.), Cat.
CH3CN, rt
HO2C
S
R1
R2
R1
R2
Cat. = NBS or I2 (5-10 mol%)
Method A = NBS; Method B = I2
Scheme 1
In a similar way, we have also discovered that the same ra-
tios work well for less hindered aryl alkyl and dialkyl sul-
foxides. Inspection of the data, which are summarized in
Table 1, clearly shows that various types of both dialkyl-
and aryl alkyl including benzylic and allylic sulfoxides are
rapidly deoxygenated to their sulfides in excellent yields
under similar reaction conditions (Table 1, entries 3–16).
Efficient deoxygenation of dibenzyl, benzyl phenyl, and
allyl phenyl sulfoxides to the corresponding thioethers in
excellent yields without the cleavage of the sensitive CS
bond, shows the usefulness of the present method
(Table 1, entries 9–14). On the other hand, it was found
that in the case of diaryl sulfoxides or those substrates car-
rying at least one bulky group, larger amounts of 3-MPA
(2.2 equiv) and the catalysts (0.1 equiv) are needed for
completion of the reactions (Table 1, entries 17–32).
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 30 07 2003.
Art Id.1437-210X,E;2003,0,12,1875,1877,ftx,en;Z03603SS.pdf.
DOI: 10.1055/s-2003-40981
© Georg Thieme Verlag Stuttgart · New York

1876
B. Karimi, D. Zareyee
SHORT PAPER
Table 1 NBS and Iodine Catalyzed Deoxygenation of Sulfoxides to
Thioethers Using 3-Mercaptopropionic Acid
However, substitution of one nitro group in the case of p-
nitrophenyl phenyl sulfoxide gave somewhat lower yields
together with the formation of unidentified products
(Table 1, entries 31, 32). This is presumably due to the re-
action of the 3-MPA–NBS system with the nitro group.
En- R1
try
R2
A or Ba/ Substrate/3-
time (min) MPA/Catalyst (%)b
Yield
1
2
Ph
Me
A
B
A
B
A
B
A
B
A
B
(10) 1:2.1:0.05
(20) 1:2.1:0.05
(15) 1:2.1:0.05
(22) 1:2.1:0.05
(15) 1:2.1:0.05
(25) 1:2.1:0.05
(90) 1:2.1:0.05
(90) 1:2.1:0.05
(80) 1:2.1:0.05
(90) 1:2.1:0.05
96
96
95
91
91
93
95
93
98
92
92
91
93
85
90
93
91
90
90
89
89
85
89
89
87
85
91
95
90
89
65
55
In order to further show the mildness of the method, we
have also conducted the reduction of PMS in the presence
of 2-phenyl-1,3-dioxane according to protocol A and B in
Scheme 2.
Ph
Me
3
Ph
Et
4
Ph
Et
O
5
Ph
Bu
S
S
SH
Ph
Me 100%
Ph
Me
HO2C
(2.1 equiv.)
6
Ph
Bu
O
NBS (5 mol%), CH3CN, rt, 15 min
Ph
Ph CHO
8%
7
Ph
PhCH2CH2
PhCH2CH2
PhCH2
PhCH2
PhCH2
PhCH2
Allyl
Allyl
Bu
O
8
Ph
O
S
S
9
PhCH2
PhCH2
Ph
SH
Ph
Me 100%
Ph
Me
HO2C
(2.1 equiv.)
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
I2 (5 mol%), CH3CN, rt, 20 min
Ph
Ph CHO
12%
A (100) 1:2.1:0.05
A (120) 1:2.1:0.05
O
Ph
Scheme 2 Conversions were determined using NMR of the crude
products
Ph
A
B
A
B
(15) 1:2.1:0.05
(60) 1:2.1:0.05
(20) 1:2.1:0.05
Ph
This result suggests that the protocols may be generally
useful for the conduction of similar chemoselective
deoxygenation reaction in poly-functional molecules.
Bu
Bu
Ph
Bu
(25)
1:2.1:0.05
In conclusion, we have demonstrated that either NBS or I2
are excellent catalysts for convenient deoxygenation of
various types of sulfoxides using 3-mercaptopropionic
acid (3-MPA). Owing to the special design of the reagent
system, the present protocols are superior to most of the
existing thiol-based sulfoxide reduction methods in re-
gard to its very simple work-up procedure. Moreover, the
present procedure also shows good chemoselectivity, and
the reaction conditions are quiet mild accompanied with
the short reaction times.
s-Bu
s-Bu
i-Pr
A (160) 1:2.1:0.05
B (180) 1:2.1:0.1
A (200) 1:2.2:0.1
B (240) 1:2.2:0.1
A (200) 1:2.2:0.1
B (240) 1:2.2:0.1
A (140) 1:2.2:0.1
B (140) 1:2.2:0.1
A (140) 1:2.2:0.1
B (240) 1:2.2:0.1
A (180) 1:2.2:0.1
B (300) 1:2.2:0.1
Ph
Ph
Ph
i-Pr
3-MeC6H4 i-Pr
3-MeC6H4 i-Pr
Ph
Ph
Ph
Ph
Ph
Ph
c-C5H9
c-C5H9
c-C6H11
c-C6H11
Ph
General Procedure for Deoxygenation of Sulfoxides
To a solution of sulfoxide (2 mmol) and 3-MPA (4.2–4.4 mmol) in
anhyd CH2Cl2 (10 mL), NBS or I2 (0.1–0.2 mmol) was added, and
the resulting solution was stirred at r.t. After completion of the re-
action (TLC), aq NaOH (5%, 25 mL) was added and the mixture
was extracted with Et2O (3 × 20 mL). The organic extracts were
washed successively with aq NaOH (5%, 15 mL), water (2 × 15
mL) and dried (Na2SO4). Evaporation of the solvent under reduced
pressure gave almost pure product(s). Further purification was
achieved by vacuum distillation or recrystallization in appropriate
solvent to afford pure thioether (Table 1).
Ph
4-MeC6H4 4-MeC6H4 A (180) 1:2.2:0.1
4-MeC6H4 4-MeC6H4 B (400) 1:2.2:0.1
p-NO2C6H4 Ph
p-NO2C6H4 Ph
A
B
(24)c 1:2.2:0.1
(24)c 1:2.2:0.1
Acknowledgments
The authors appreciate Institute for Advanced Studies in Basic sci-
ences (IASBS) Research Council for support of this work.
a Method A = NBS; Method B = I2.
b Isolated yields.
c Reaction time in hours.
Synthesis 2003, No. 12, 1875–1877 © Thieme Stuttgart · New York

SHORT PAPER
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Synthesis 2003, No. 12, 1875–1877 © Thieme Stuttgart · New York