Carboxy pyridinium bromide perbromide reagents, part I: Selective oxidation of thiols and sulfides

Article abstract of DOI:10.1080/10426500701670683

Efficient and convenient oxidation of aliphatic and aromatic thiols to disulfides and of sulfides to sulfoxides with pyridinium hydrobromide perbromide (PHBP), nicotinic acid hydrobromide perbromide (NAHBP), and 2,6-dicarboxy pyridinium hydrobromide perbromide (DCPHBP) in a solvent or under solvent free conditions and at ambient temperature is introduced. Copyright Taylor & Francis Group, LLC.

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Phosphorus, Sulfur, and Silicon
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Carboxy Pyridinium Bromide
Perbromide Reagents, Part I:
Selective Oxidation of Thiols
and Sulfides
Moslem M. Lakouraj a & Keivan Ghodrati a
a Department of Chemistry, Mazandaran University,
Babolsar, Iran
Published online: 04 Jun 2008.
To cite this article: Moslem M. Lakouraj & Keivan Ghodrati (2008) Carboxy Pyridinium
Bromide Perbromide Reagents, Part I: Selective Oxidation of Thiols and Sulfides,
Phosphorus, Sulfur, and Silicon and the Related Elements, 183:6, 1432-1439
To link to this article: http://dx.doi.org/10.1080/10426500701670683
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Phosphorus, Sulfur, and Silicon, 183:1432–1439, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500701670683
Carboxy Pyridinium Bromide Perbromide Reagents,
Part I: Selective Oxidation of Thiols and Sulfides
Moslem M. Lakouraj and Keivan Ghodrati
Department of Chemistry, Mazandaran University, Babolsar, Iran
Efficient and convenient oxidation of aliphatic and aromatic thiols to disulfides
and of sulfides to sulfoxides with pyridinium hydrobromide perbromide (PHBP),
nicotinic acid hydrobromide perbromide (NAHBP), and 2,6-dicarboxy pyridinium
hydrobromide perbromide (DCPHBP) in a solvent or under solvent free conditions
and at ambient temperature is introduced.
Keywords Bromide perbromide; disulfide; thiols; oxidative coupling; solvent-free con-
dition; sulfoxides
INTRODUCTION
Disulfides are useful reagents in organic synthesis1,2 and essential
moieties of biologically active compounds for peptide and protein
stabilization.3 As disulfides are relatively more stable to organic re-
actions such as oxidation, alkylation and acylation compared to the
corresponding free thiols, the thiol group can conveniently be protected
as a disulfide.
So far, various reagents for the oxidative coupling of thiols
to disulfides have been described, e.g. iodine/hydrogen iodide,4
neat bromine,5a bromine/aqueous potassium hydrogen carbonate,5b
bromine/SiO2,5c FeCl3/NaCl,6 KMnO4/CuSO4,7 hydrogen perox-
ide in tetrafluoroethanol,8 Caro’s acid/SiO2,9 TMSCl and cya-
nuric chloride,10 HMDS/DMSO,11 Cu(NO3)2· N2O2,12 I2/morpholine,13
piperazinium dichromate,14 DMSO,15 and 2,6-dicarboxypyridinium
chlorochromate.16 However, most of these reagents suffer from disad-
vantages such as long reaction times and low yields, toxicity, availabil-
ity, difficult work-up, difficult preparation and instability.
Received 9 January 2007; accepted 8 September 2007.
Financial support of this work form the Research Council of Mazandaran University
is gratefully acknowledged.
Address correspondence to Moslem M. Lakouraj, Department of Chemistry, Faculty
of Basic Sciences, University of Mazandaran, P.O. Box 47416, Babolsar, Iran. E-mail:
lakouraj@umz.ac.ir
1432

Selective Oxidation of Thiols and Sulfides
1433
On the other hand, the chemistry of sulfoxides has attracted the
attention of organic chemists for a long time. The interest in this chem-
istry and in the preparation of sulfoxides is due to the fact, that sul-
foxides are often part of natural products and drugs, and also have
unique reactivity as a functional group for various transformations into
organosulfur compounds.17 The selective preparation of sulfoxides from
the corresponding sulfides was performed with a variety of reagents.
However, many of these reagents need a careful control of the reaction
conditions such as temperature and quantity of the reagent in order to
avoid the formation of sulfones as side products.18 Moreover, the ma-
jority of oxidizing reagents are incompatible with other sensitive func-
tionalities (e.g., hydroxy group, aldehyde, phenol ether) present in the
molecule of the organic substrate.
So far, a few amine based hydrobromide perbromide reagents have
been prepared and used for bromination of alkenes, activated aromatic
rings and aldehydes or ketones.19,20 The nature of the amine not only
affects the oxidation property of the perbromide ion but also determines
the stability of the reagent, which is inversely related to the donor
strength of the associated amine.
Pyridinium hydrobromide perbromide (PHBP) has been introduced
for selective bromination and oxidation/dehydration reactions.19,20 In
continuation of our previous investigations on the oxidative coupling
of thiols,9,14 we now present pyridinium hydrobromide perbromide
(PHBP), nicotinic acid hydrobromide perbromide (NAHBP), and 2,6-
dicarboxypyridinium hydrobromide perbromide (DCPHBP) as mild and
stable reagents for the selective oxidation of thiols to disulfides, and
of sulfides to sulfoxides in high to excellent yields. Both, nicotinic
acid hydrobromide perbromide (NAHBP) and 2,6-dicarboxypyridinium
hydrobromide perbromide (DCPHBP), are orange solids, which are
stable for several months in glass bottle at room temperature
(Scheme 1).
SCHEME 1

1434
M. M. Lakouraj and K. Ghodrati
RESULTS AND DISCUSSION
This paper describes the preparation and the synthetic potential of
PHBP, NAHBP and DCPHBP for the oxidation of aliphatic and aro-
matic thiols to disulfides under solvent-free conditions, as well as the
oxidation of sulfides to sulfoxides in THF/H2O.
The convenient oxidation of thiols to the corresponding disulfides is
achieved using these reagents both in an organic solvent and under
solvent free conditions at room temperature (Scheme 2).
SCHEME 2
The solvent-free procedure is very suitable for long chain aliphatic
thiols, which are usually insoluble in polar solvents, and therefore dif-
ficult to handle when using conventional methods (Table I). The results
presented in Table I indicate that this method is equally applicable for
the oxidative coupling of alkyl, aryl, and heterocyclic thiols. The re-
actions were preformed under mild conditions and proceed in high to
excellent yields. The reagents selectively oxidized the thiols to the cor-
responding disulfides without further oxidation or bromination of the
aromatic rings.
It is worth mentioning that, when 2-mercaptoethanol (Table I, o) was
treated with these reagents in a solvent or under solvent free conditions
only oxidative coupling took place and the corresponding disulfide was
obtained as the only product.

Selective Oxidation of Thiols and Sulfides
1435
TABLE I Oxidative Conversion of Thiols to Disulfides with
Hydrobromide Perbromide Reagentsa,b
PHBP
Time (min)
NAHBP
DCPHBP
Yield (%)
Yield (%)
Time (min)
Yield (%)
Time (min)
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
90
93
93
93
91
93
88
92
79
85
89
90
75
77
—
3
5
7
7
3
5
7
10
6
6
8
9
7
8
—
30
30
20
94
95
96
93
91
94
89
87
75
82
81
93
71
74
90
83
73
89
4
5
5
5
4
6
8
10
8
8
10
10
7
10
5
25
20
15
89
93
94
92
89
95
91
94
—
—
83
91
73
—
85
77
75
—
3
5
5
4
5
5
7
8
—
—
5
7
9
—
3
18
25
—
81
72
85
aYields refer to isolated products. bReactions were carried out under solvent-free
conditions.
Surprisingly, functional groups such as halogen, OH, CO2Me, and
heterocyclic rings are unaffected under the reaction conditions. In the
case of p-xylylene dithiol the corresponding polymer was obtained due
to intermolecular oxidation (Scheme 3).
SCHEME 3
Some experiments with thiophenol and p-chlorothiophenol were also
conducted in water as solvent and afforded the corresponding disulfides
in high yields.
Using these bromide perbromide reagents, organic sulfides can be
readily oxidized to the corresponding sulfoxides in THF/H2O at room
temperature in high to excellent yields (Scheme 4).
The results are summarized in the Table II. This reaction is applica-
ble to dialkylsulfides, alkylarylsulfides, and diarylsulfides. In addition,

1436
M. M. Lakouraj and K. Ghodrati
SCHEME 4
sulfides containing a strong electron-withdrawing group like NO2 react
readily to give the corresponding sulfoxide in high yield.
In order to show the advantages and drawbacks of these reagents
compared to some other oxidants, we have compared some of our
results with those reported in the literature for the oxidation of thiols
(Table III).
The tribromides PHBP, NAHBP, and DCPHBP were prepared from
hydrobromic acid (48%), bromine, and the respective pyridine deriva-
tive according to the method reported for PHBP.18 The tribromide con-
tent was determined by known iodometric methods. The reagents are
isolated as orange-red, stable crystals and can be stored in a glass bottle
for several months without any loss of activity.
Investigations about the possible use of these perbromide reagents
in further oxidation, bromination and deprotection reactions are
underway.
TABLE II Oxidation of Sulfides to Sulfoxides Using PHBP, NAHBP,
and DCPHBPa
PHBP
Yield (%)/Time
(h)
NAHBP
Yield (%)/Time
(h)
DCPHBP
Yield (%)/
Time (h)
R
Rꢀ
Ph
Ph
Me
Bn
Bn
Bn
89(1.5)
90(1.5)
88(1.5)
86(1.5)
94(1)
91(1)
92(1)
94(1)
89(1.5)
95(0.5)
82(2)
91(1)
89(1.5)
93(1.5)
92(1.5)
94(0.5)
78(2)
4-CH3C6H4
Bn
Ph
Ph
-CH2CH2OH
2,4-NO2C6H4
79(2)
-CH2CH2CH2CH2-
n-Bu
Ph
84(1.5)
88(1.5)
85(2)
87(1)
82(1)
83(1.5)
89(1)
81(1)
86(2)
n-Bu
-CH2CH2CN
aYields refer to isolated products.

Selective Oxidation of Thiols and Sulfides
1437
TABLE III Comparison of the Perbromide Reagents with Some
Other Reported for the Oxidation of Thiophenol
Reagent
Condition
Time (min)
Yield (%)
Reference
16
2,6-DCPCCa
Bu3SnMe/FeCl3
PCCb
(NH4)2S2O8
Caro’s acid/SiO2
Piperazinium dichromate
PHBP
CH3CN/r.t.
CH3CN/r.t.
CH2Cl2/r.t.
Solvent free
CH3CN/r.t.
CHCl3/reflux
Solvent free
Solvent free
Solvent free
8
120
114
10
270
210
3
93
99
97
79
93
92
90
94
89
21a
21b
21c
9
14
—
—
—
NAHBP
DCPHBP
4
3
a2,6-Dicarboxypyridinium chlorochromate; and bpyridinium chlorochromate.
EXPERIMENTAL
All products were identified by comparison of their physical and spectral
data with those of authentic samples. IR spectra were determined on a
Brucker FTIR-85 spectrometer. 1H NMR spectra were recorded with a
BRUKER DRX-500 AVANCE spectrometer at 500 MHz (1H) and with
a JEOL FT-NMR instrument at 90 MHz (1H) and at 22.4 MHz (13C).
General Procedure for the Preparation of NAHBP and DCPHBP
To a cooled solution (ice bath) of nicotinic acid or 2,6-dicarboxypyridine
(0.1 mol) in acetic acid (30 mL) was added with stirring (48%) HBr (10
mL). Then, a solution of bromine (0.1 mol) in acetic acid (5 mL) was
added dropwise and the mixture was stirred for 10 min at room tem-
perature. The resulting orange solid was filtered off, washed with acetic
acid (5 mL), and then dried in a desiccator to give a nonhygroscopic
powder.
NAHBP
m.p. = 140–142◦C, FT-IR (KBr): υ = 3499, 3379, 1720, 1607, 1390, 1240,
1
1214, 1179, 1120, 925, 746, 669 cm−1; H NMR (500 MHz, DMSO-d6):
δ = 7.49 (dd, J = 7.9 Hz, J = 4.8 Hz, 1H), 8.24 (dd, J = 7.9, J = 2.0 Hz,
1H), 8.75 (dd, J = 4.7 Hz, J = 1.6 Hz, 1H), 9.06 (dd, J = 2.0 Hz, J =
0.6 Hz, 1H), 13.30 (br, 2H).
DCPHBP
m.p. = 118–122◦C, FT-IR (KBr): υ = 2362, 1706, 1389, 1269, 1233, 916,
1
746, 669 cm−1; H NMR (500 MHz, DMSO-d6): δ = 8.16 (t,J = 7.3 Hz,
1H), 8.21 (d, J = 7.3 Hz, 2H), 13.30 (br, 3H).

1438
M. M. Lakouraj and K. Ghodrati
General Procedure for the Oxidation of Thiols by PHBPB,
NAHBP and DCPHBP under Solvent Free Conditions
The hydrobromide perbromide reagent (1 mmol) was added to the thiol
(1 mmol) in a mortar. The mixture was kept for the appropriate period
of time (Table I) at room temperature. The progress of the reaction was
followed by dissolving a sample in ether and using thin layer chromatog-
raphy on silica gel (petroleum ether). After completion of the reaction,
diethyl ether (20 mL) was added and the solid was separated by fil-
tration. The filtrate was washed with water (2 × 15 mL). The organic
layer was separated and dried (MgSO4). Finally, evaporation of the sol-
vent gave the disulfides in 71–96% yields in almost pure form. Further
purification was achieved by recrystallization from methanol.
General Procedure for the Oxidation of Thiols in Diethyl Ether
with PHBP
In a round-bottomed flask, a solution of the thiol (1 mmol) in di-
ethyl ether (10 mL) was treated with the hydrobromide perbromide
(1 mmol) and the resulting mixture was stirred at room temperature.
The progress of the reaction was monitored by TLC (petroleum ether).
On completion, the reaction mixture was filtered and the solid sepa-
rated was washed with diethyl ether (10 mL). The filtrate was washed
with water (2 × 10 mL), dried over MgSO4, and evaporated to give the
corresponding disulfide. Further purification was achieved by recrys-
tallization from methanol.
General Procedure for the Oxidation of Sulfides to Sulfoxides
In a round-bottomed flask a solution of the sulfide (1 mmol) in a mix-
ture of THF (10 mL) and H2O (5 mL) was treated with the perbromide
reagent (1 mmol) and the mixture was stirred at room temperature.
The progress of the reaction was monitored by TLC. The reaction mix-
ture was filtered and the solid separated was washed with diethyl ether
(25 mL). The filtrate was washed with water (2 × 10 mL) and dried over
MgSO4. Evaporation of the solvent gave the corresponding sulfoxide in
almost pure form.
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