Simple and selective oxidation of thiols to disulfides with dimethylsulfoxide catalyzed by dichlorodioxomolybdenum(VI)

Article abstract of DOI:10.1055/s-2002-28520

Selective and quantitative conversion of thiols to disulfides was effected by dimethyl sulfoxide under mild conditions catalyzed by dichlorodioxomolybdenum(VI).

Full text of DOI:10.1055/s-2002-28520

8
56
SHORT PAPER
Simple and Selective Oxidation of Thiols to Disulfides with Dimethylsulfoxide
Catalyzed by Dichlorodioxomolybdenum(VI)
S
R
elective
O
xidati
o
on of Thiols
b
to Disulfide
s
erto Sanz,* Rafael Aguado, María R. Pedrosa, Francisco J. Arnáiz*
Departamento de Química, Universidad de Burgos, 09001-Burgos, Spain
Fax +34(94)7258831; E-mail: farnaiz@ubu.es
Received 25 January 2002; revised 15 March 2002
this purpose as it can be readily prepared in a pure form
from easily available chemicals, is air stable and can be
Abstract: Selective and quantitative conversion of thiols to disul-
fides was effected by dimethyl sulfoxide under mild conditions cat-
alyzed by dichlorodioxomolybdenum(VI).
12
stored for months without special precautions. Here we
report the facile, selective and essentially quantitative
conversion of a number of thiols to disulfides by DMSO
catalyzed by such a dioxomolybdenum(VI) complex. The
overall oxidation process we propose could be written as
shown in the Scheme 1.
Key words: thiols, disulfides, molybdenum(VI) complexes, oxo-
transfer catalysis, sulfoxides
Selective oxidation of thiols to disulfides is of interest
1
from both a biological and a synthetic perspective. Thiols
MoO2Cl2(DMSO)2 cat.
are among functional groups that can be over oxidized so
2
RSH + DMSO
RSSR + H2O + Me2S
that many studies have been carried out for their con-
1a-n
2a-n
2
trolled oxidation. Thus, a wide number of oxidizing
a R=Ph
f
R=2-NH2C6H4
k R=t-C4H9
3
agents ranging from molecular oxygen, to halogens and
4
5
6
b R=2-ClC H
g R=2-CO HC H
l
R=2-pyridyl
6
4
2
6
4
derivatives, metal oxides, and oxo and peroxosalts,
have been used to oxidize thiols to disulfides. It is known
that the oxidation of mercaptans proceeds in dimethyl sul-
foxide (DMSO) solution, but the reaction requires high
c R=4-ClC6H4
h R=PhCH2
m R=2-CHOC6H4
i
j
R=C H
8
17
d R=4-MeC6H4
n R=2-CMe2OHC6H4
e R=4-MeOC6H4
R=C12H25
7
temperature and a prolonged reaction time. Recently, a
mild and efficient oxidation with hydrogen peroxide in Scheme 1
8
fluoroalcohols has been reported. Moreover, the air oxi-
dative coupling of thiols has been catalyzed in different
ways.
Commercially available and functionalized aromatic thi-
ols 1a–g were first chosen to test our procedure. The reac-
tions were carried out at room temperature, using DMSO
as solvent and 1 mol % of the catalyst. Under these condi-
tions, the mercaptans were selectively and quantitatively
oxidized to the corresponding disulfides (see Table) in 5–
9
However, most of the reported procedures involve the use
of strong oxidants that are also capable of reacting with
other oxidizable sites such as aldehyde and amino groups,
or severe conditions as happens with the mild oxidant
DMSO. Hence the interest in the search for new proce-
dures to transform thiols into disulfides while preserving
as much functionalities as possible.
3
0 minutes. It is worth noting that thiols having electron-
withdrawing substituents were oxidized within 10 min-
utes whereas, for instance, 4-methoxybenzenethiol (1e)
needed 30 minutes to afford the corresponding disulfide
On the other hand, it has been shown that dioxomolybde-
num(VI) complexes that mimic oxotransferases are able
2
e. This fact suggests that the rate of reaction is dependent
on the acidity of the mercaptan.
1
0
to oxidize some thiols to disulfides at room temperature.
In the oxotransfer processes it is assumed that oxomolyb-
denum(IV) species are formed, which in turn are readily
oxidized to the parent dioxomolybdenum(VI) complexes
by a number of oxidants including sulfoxides. The un-
availability of these complexes has precluded their use as
oxotransfer catalysts in oxygenation/deoxygenation pro-
cesses implying organic substrates. However, we have
Of these examples, the oxidation of o-aminothiophenol
(
1f) and thiosalicylic acid (1g) are remarkable due to the
low yields and problems found with these thiols in their
oxidation by other procedures.8
Next, we turned our attention to non-aromatic thiols and
so, phenylmethanethiol (1h) could be quantitatively oxi-
dized to dibenzyl disulfide. However, in this case we con-
sider it more appropriate to use 5% of the catalyst and
carrying out the reaction at 70 °C. Under these conditions
the reaction was complete after 6 hours and the disulfide
was isolated in 94% yield. In the same way, aliphatic thi-
ols 1i–k were completely oxidized in 24 hours and the
corresponding disulfides were isolated in good yields (see
Table).
found that MoO Cl and its addition compound with
2
2
DMSO, MoO Cl (DMSO) , are excellent catalysts for
2
2
2
oxotransfer reactions involving phosphines, thiols and
1
1
sulfoxides. MoO Cl (DMSO) is specially useful for
2
2
2
Synthesis 2002, No. 7, 21 05 2002. Article Identifier:
437-210X,E;2002,0,07,0856,0858,ftx,en;Z02302SS.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881
1
©

SHORT PAPER
Selective Oxidation of Thiols to Disulfides
857
Table Catalytic Oxidation of Thiols 1 to Disulfides 2
The mercaptan undergoes an oxidative coupling to the
corresponding disulfide by the dioxomolybdenum(VI)
complex which in turn is reduced to an oxomolybde-
num(IV) species. Then DMSO reoxidizes Mo(IV) to
Mo(VI) with the release of dimethyl sulfide. The follow-
ing observations are consistent with this proposal: (i) The
colorless solutions of thiols in DMSO become brown or
reddish upon addition of white MoO Cl (dmso) suggest-
Ra
Catalyst Conditions
Yield mp(ºC) or bp(ºC)/Torr
b
(
%) Temp/Time (%)
found
reported
6213
a
b
c
d
e
f
1
1
1
1
1
1
1
5
5
5
5
1
1
1
r.t./20 min
r.t./10 min
r.t./10 min
r.t./30 min
r.t./30 min
r.t./30 min
r.t./30 min
70 °C/6 h
70 °C/24 h
70 °C/24 h
70 °C/24 h
r.t./12 h
98
94
95
96
95
91
90
94
87
86
85
89
91
88
60–62
80–82
8414
2
2
1
2
1a
ing the formation of Mo(IV) species. (ii) The foul-
smelling dimethyl sulfide is always generated in the reac-
tion as proved by GC.
70–72
72–736a
46–48
47.513
42–444b
The catalyst is very resistant to degradation. Addition of
new batches of thiol to the resulting reaction mixture
showed that no significant loss of activity was produced.
This is probably due to the fact that dioxomolybde-
num(VI) species are unable to oxidize chloride ions under
mild conditions. Moreover, although water is generated in
the coupling process the catalyst is not noticeably affected
because water is miscible with DMSO and excess of this
is present in the reaction mixture. Indeed, we have proved
that MoO Cl (dmso) can be efficiently isolated from
42–43
88–89
91–927a
289–29015
g
h
i
288–290
70–71
71–729a
205/15
34–35
198–199/1016
33–347b
j
83–86/183c
56–586f
2
2
2
k
l
82–84/18
55–57
1
2
aqueous solutions, and that coordinated water in
MoO Br (H O) is immediately displaced by DMSO at
2
2
2
2
room temperature to yield the closely related complex
m
n
r.t./30 min
r.t./30 min
149–150
139–141
148–14918b
141–14319
20
MoO Br (dmso) .
2
2
2
The order of reactivity observed for thiols, Ar-
a
SH>ArCH SH>AlkSH, roughly correlates with their
For R, see Scheme.
Isolated yield.
2
b
acidity and is in agreement with other reports in the liter-
7b
ature. Thus, it is probable that a crucial, rate determining
step in the process is the protonation of the oxo ligands on
the dioxomolybdenum(VI) center.
The utility of this catalyst in the oxidation of heteroaro-
matic thiols was also tested. Thus 2-pyridinethiol (1l) was
quantitatively transformed to 2,2 -dipyridine disulfide (2l)
with DMSO in 12 hours at 20 °C in the presence of 1%
MoO Cl (dmso) . The disulfide, a very useful reagent in
The method here described could be carried out on a mul-
tigram scale and thus 0.2 mol of benzenethiol was quanti-
tatively oxidized to diphenyl disulfide with 0.22 mol of
DMSO catalyzed by 0.2 mmol (0.1%) of the catalyst in 30
minutes at room temperature. Addition of aqueous NaOH
to the mixture allowed the easy isolation of the disulfide
by filtration, as the decomposition products of the catalyst
2
2
2
peptide chemistry, could be isolated in 89% yield.
Finally, due to the easy selective oxidation of aromatic
thiols we decided to examine the reaction with other func-
tionalized arylthiols not commercially available. So, on
the basis of the method described for the regioselective
ortho-lithiation of benzenethiol, we synthesized thiosal-
icylaldehyde (1m) and 2-(1-hydroxy-1-methylethyl)ben-
zenethiol (1n). After carrying out the reactions of these
thiols under the conditions above described the corre-
–
sodium chloride and molybdate – remain in solution.
In summary, we have presented a mild, efficient and se-
lective oxidation of thiols to disulfides by DMSO cata-
lyzed by a dioxomolybdenum(VI) complex. The present
procedure, though involving the production of dimethyl
sulfide, is attractive because of its simplicity, general ap-
plicability and excellent yields of the products, making
this method a useful addition to the existing methodolo-
gies.
1
7
1
8
19
sponding disulfides 2m and 2n were isolated in 91%
and 88% yield respectively. The catalytic cycle involved
could be represented as shown in Scheme 2.
2
RSH
RSSR + H2O
MoOCl2(DMSO)2
DMSO
Thiols were obtained from Aldrich or Across Organics and used
without purification. Molybdenum(VI) oxide to prepare the
1
2
catalyst was obtained from Fluka. Commercial DMSO was re-
agent grade. Products were characterized by comparison of their
physical data with those of known samples. Melting points were de-
termined on a Electrothermal apparatus and are uncorrected. All
yields refer to isolated products. NMR spectra were recorded on a
Varian VXR 200 and Varian INOVA 400 spectrometer. The reac-
tion monitoring was accomplished by GC/MS on a HP 5890 Serie
II/5971-A.
MoO2Cl2(DMSO)2
Me2S
Scheme 2 Representation of the catalytic cycle in the oxidation of
thiols to disulfides
Synthesis 2002, No. 7, 856–858 ISSN 0039-7881 © Thieme Stuttgart · New York

8
58
R. Sanz et al.
SHORT PAPER
Oxidation of Thiophenol (1a) with DMSO Catalyzed by
(7) (a) Yiannios, C. N.; Karabinos, J. V. J. Org. Chem. 1963, 28,
3246. (b) Wallace, T. J. J. Am. Chem. Soc. 1964, 86, 2018.
(c) Wallace, T. J.; Mahon, J. J. J. Am. Chem. Soc. 1964, 86,
4099. (d) Wallace, T. J.; Mahon, J. J. J. Org. Chem. 1965,
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(f) Aida, T.; Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem.
Soc. Jpn. 1976, 49, 1441.
MoO Cl (DMSO) ; Diphenyl Disulfide (2a); Typical Procedure
2
2
2
A 50 mL Erlenmeyer flask was charged with DMSO (7.1 mL, 100
mmol) and MoO Cl (DMSO) (35 mg, 0.1 mmol). Then thiophenol
2
2
2
(
1.1 g, 10 mmol) was added and the resulting solution was stirred
for 30 min at 20 °C. The completion of the oxidation was ascer-
tained by GC/MS. The reaction mixture was treated with 2 M NaOH
(
25 mL). The precipitated diphenyl disulfide was collected by filtra-
(8) Kesavan, V.; Bonnet-Delpon, D.; Bégué, J.-P. Synthesis
2000, 223.
tion, washed with H O (3 20 mL), and dried under vacuum. In that
2
way crude diphenyl disulfide (1.07 g, 98%) was obtained, that was
pure by GC and NMR analysis (Table).
(9) (a) Iranpoor, N.; Zeynizadeh, B. Synthesis 1999, 49.
(b) Hirano, M.; Monobe, H.; Yakabe, S.; Morimoto, T. J.
Chem. Research (S) 1999, 374.
(
(
10) Harlan, E. W.; Berg, J. M.; Holm, R. H. J. Am. Chem. Soc.
Acknowledgement
1986, 108, 6992.
11) (a) Arnáiz, F. J.; Aguado, R.; Martínez-Ilarduya, J. M.
Polyhedron 1994, 13, 3257. (b) Arnáiz, F. J.; Aguado, R.;
Pedrosa, M. R. unpublished results.
We thank the Junta de Castilla y León (BU 14/98 and BU 09/99) for
financial support.
(
(
12) Arnáiz, F. J. Inorg. Synth. 1997, 31, 246.
13) Lide, D. R. CRC Handbook of Chemistry and Physics, 75 th
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Synthesis 2002, No. 7, 856–858 ISSN 0039-7881 © Thieme Stuttgart · New York