Oxidative transformation of thiols to disulfides promoted by activated carbon-air system

Article abstract of DOI:10.1016/j.tetlet.2010.10.070

Efficient oxidative transformation of thiols to disulfides took place in the presence of activated carbon under an oxygen (or air) atmosphere. The present oxidation method is available not only for a variety of thiols such as simple aromatic and aliphatic thiols but also for 3,4-dihydropyrimidin-2(1H)- thiones and N-Boc-l-cysteine.

Full text of DOI:10.1016/j.tetlet.2010.10.070

Tetrahedron Letters 51 (2010) 6734–6736
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Tetrahedron Letters
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Oxidative transformation of thiols to disulfides promoted by activated
carbon–air system
⇑
Masahiko Hayashi , Ken-ichi Okunaga, Shunsuke Nishida, Kenjiro Kawamura, Kazuo Eda
Department of Chemistry, Graduate School of Science, Kobe University, Kobe 657-8501, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient oxidative transformation of thiols to disulfides took place in the presence of activated carbon
under an oxygen (or air) atmosphere. The present oxidation method is available not only for a variety
of thiols such as simple aromatic and aliphatic thiols but also for 3,4-dihydropyrimidin-2(1H)-thiones
Received 6 September 2010
Revised 9 October 2010
Accepted 13 October 2010
Available online 20 October 2010
and N-Boc-L-cysteine.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Activated carbon
Oxidation
Thiol
Disulfide
Transformation of thiols to disulfides is an important process in
organic synthesis. Hydrogen peroxide is the most common oxidiz-
ing reagent.1 Actually, Kirihara et al. recently reported oxidation of
thiols to disulfides by the combination of NaI and 30% H2O2.2 Other
oxidizing agents, such as KMnO4/CuSO4, Me2SO–I2, Br2, t-BuOOH/
VO(acac)2, SmI2, MnO2, and PCC have been also reported.3 Recently
Leino and Lönnqvist reported the use of stoichiometric amount of
SO2Cl2 as an oxidizing agent, however, in this reaction equimolar
amount of gaseous SO2 and HCl were evolved.4 Shirini et al. re-
ported oxidative coupling using (NH4)2Cr2O7 in the presence of sil-
ica chloride and wet SiO2.5 Sasson reported oxidative coupling of
thiols to disulfides using a solid anhydrous potassium phosphate
catalyst.6 Montazerozohori et al. also reported molybdate sulfuric
acid (MSA) worked as a solid acid reagent for the oxidation of thiols
to symmetrical disulfides.7 In this case, the preparation of MSA is
necessary in advance. Furthermore, Naimi-Jamal and Kaupp re-
ported oxidative dimerization of 2-benzthiazolethiol and 2-pyri-
midinethiol with NO2 gas.8 Very recently, Shaabani’s group
reported H3PW12O40–NaBrO3 system for the formation of disul-
fides from thiols.9 Therefore, development of mild and environ-
mentally friendly method for transformation of thiols into
disulfides has been required till now. We have discovered some
activated carbons work as promoter of oxidative aromatization of
dihydroaromatic compounds.10 Among them, a variety of function-
alized 3,4-dihydropyrimidin-2(1H)-ones were converted into the
corresponding pyrimidin-2(1H)-ones using activated carbon–
molecular oxygen system.11 During the course of this study, we
discovered activated carbon also promotes the conversion of thiols
into the corresponding symmetric disulfides. In this Letter, we will
report general synthesis of disulfides from thiols using activated
carbon–air (or oxygen) system.
At first, we examined the oxidation of functionalized 3,4-dihy-
dropyrimidin-2(1H)-thiones. We expected the corresponding
pyrimidin-2(1H)-thiones were obtained, however, as shown in
Table 1, all the products were symmetrical disulfides. The combi-
nation of xylene as a solvent, at 140 °C under an air atmosphere
using 100 wt% of activated carbon was the best choice we
examined.12
The structure was confirmed by MS spectra and X-ray diffrac-
tometry (Fig. 1).
It should be mentioned that in this system, the use of aliphatic
group of R1 and/or R2 was available giving the product in moderate
yields (entries 9 and 10) that was in contrast with the case of 3,4-
dihydropyrimidin-2(1H)-ones. We proposed the mechanism of the
formation of disulfides as shown in Scheme 2 based on the result of
Scheme 1.
The alternative mechanism is also plausible. That is, tautome-
ization may occur at dihydropyrimidin-2(1H)-thiones stage, fol-
lowed by oxidation with activated carbon–air system to form the
tetrahydrodisulfide, then finally oxidation may take place again
to afford functionalized bis(2-pyrimidyl) disulfides.
Reduction of functionalized bis(2-pyrimidyl) disulfide with
NaBH4 afforded pyrimidin-2(1H)-thiones (not 3,4-dihydro pyrimi-
din-2(1H)-thiones). This was confirmed by comparison with the
compound that was prepared by the reaction of pyrimidin-2(1H)-
ones with Lawesson’s reagent as shown in Scheme 3.
⇑
Corresponding author. Tel.: +81 78 803 5687; fax: +81 78 803 5688.
E-mail address: mhayashi@kobe-u.ac.jp (M. Hayashi).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.070

M. Hayashi et al. / Tetrahedron Letters 51 (2010) 6734–6736
6735
Table 1
Oxidation of functionalized 3,4-dihydropyrimidin-2(1H)-thiones
R1
O
O
R1
O
O
air
air
100 wt% activated
carbon
100 wt% activated
carbon
EtO
N
EtO
N
EtO
N
EtO
NH
N
R2
O
N
S
Ph
O
S
xylene, 140 ºC
xylene, 140 ºC
R2
S
S
Ph
N
N
R2
S
Ph
N
H
N
H
S
OEt
N
OEt
N
R1
Entry
R1
R2
Time (h)
Yielda (%)
96%
Scheme 1. Oxidation of pyrimidin-2(1H)-thiones.
1
2
3
4
5
6
7
8
9
10
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Me
45
46
50
43
43
55
48
41
67
36
85
79
66
83
82
82
56
91
54
57
4-ClC6H4
4-NO2C6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
3-HOC6H4
1-Naphthyl
C6H5
R1
air
O
O
R1
100 wt% activated
carbon
EtO
N
EtO
EtO
NH
Me
Me
R2
R2
N
H
N
H
S
S
a
Isolated yield after silica-gel chromatography.
tautomerization
O
R1
N
O
R1
N
oxidation
S
N
R2
O
R2
S
EtO
N
N
OEt
R2
N
SH
R1
Scheme 2. Oxidation of functionalized 3,4-dihydropyrimidin-2(1H)-thiones.
R1
R1
O
O
0.5 equiv.
Lawersson's reagent
EtO
N
EtO
N
benzene
R2
N
H
R2
N
H
S
O
reflux, 4 h
R = Ph; 82%
R = 1-naphthyl; 82%
R1
O
R1
O
N
EtO
EtO
N
S
N
R2
O
NaBH4
R2
N
S
R2
N
H
S
MeOH/t-BuOH
(1/10)
N
OEt
Figure 1. ORTEP diagram of 2,20-dithiobis[4-(1-naphthyl)-6-phenyl-5-(ethoxycar-
bonyl)pyrimidine] with ellipsoids set at 50% probability.
R = Ph; 79%
R = 1-naphthyl; 79%
20 ºC, overnight
R1
Scheme 3. Synthesis of functionalized pyrimidin-2(1H)-thiones.
Therefore, in order to obtain substituted pyrimidin-2(1H)-thi-
ones, there are two methods. One is the reaction of pyrimidin-
2(1H)-ones with Lawesson’s reagent. The other method is the
reduction of substituted bis(2-pyrimidyl) disulfide with NaBH4.1
These two methods are general. Two examples to prepare func-
tionalized pyrimidin-2(1H)-thiones are shown Scheme 4.
Then we examined the generality of this activated carbon–air
(or oxygen) system promoted oxidation of aromatic and aliphatic
thiols to disulfides. Tables 2 and 3 show the results of the oxidation
of 4-tert-butylbenzenethiol, 4-isopropylbenzenethiol, 4-bromo-
benzenethiol and 1-undecanethiol, 1-dodecanethiol, 1-tetradeca-
nethiol, respectively. In all cases, in the absence of activated
carbon, no reaction took place even at 140 °C. While, in the pres-
ence of activated carbon the reaction proceeded smoothly to give
the corresponding disulfides in good to high yield (72–98% yield).
Finally, we applied this method to the amino acid. That is,
air
NHBoc
O
O
100 wt% activated
carbon
HO
S
S
OH
NHBoc
HS
OH
NHBoc
xylene
140 ºC, 2 h
O
75%
Scheme 4. Oxidation of N-Boc-
L-cysteine.
L
-cystine using activated carbon under an air atmosphere in 75%
yield.
In conclusion, we revealed oxidative conversion of thiols into
disulfides was promoted by activated carbon–air (or oxygen) sys-
tem. The present method is applicable to both aromatic and ali-
phatic thiols. This method is not only operationally simple and
inexpensive but also environmentally friendly.
N-Boc-L-cysteine was converted into the corresponding disulfide

6736
M. Hayashi et al. / Tetrahedron Letters 51 (2010) 6734–6736
Table 2
elementary analyses for all new compounds, and the CIF file of
Oxidation of aromatic thiols to disulfidesa
2,20-dithiobis[4-(1-naphthyl)-6-phenyl-5-(ethoxycarbonyl)pyrimi-
dine]). CCDC 769416 contains the supplementary crystallographic
data. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_re-
quest/cif.
O2 or air
100 wt% activated
carbon
X
X
S
xylene
S
SH
X
Acknowledgment
X
O2 or air
Temperature (°C)
Time (h)
Yield (%)
t-Bu
O2
Air
O2
Air
O2
Air
O2
Air
O2
Air
30
30
60
24
48
12
24
6
4
3
3
4
97
98
93
96
94
98
72
76
97
94
This work was supported by Grants-in-Aid for Scientific
Research on Priority Areas ‘Advanced Molecular Transformations
of Carbon Resources’ and No. B17340020 from the Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan.
60
120
140
120
140
120
140
i-Pr
Br
References and notes
1. For reviews, see: Capozzi, G.; Modena, G. In The Chemistry of the Thiol Group,
part 2, Patai, S., Ed., Wieley: NY, pp 785–839.
4
a
In the absence of activated carbon; 0% yield (O2, 140 °C, 4 h).
2. Kirihara, M.; Asai, Y.; Ogawa, S.; Noguchi, T.; Hirai, Y. Synthesis 2007, 3278–
3289.
3. Smith, M.; March, J. March’s Advanced Organic Chemistry: Reactions, Mechanism,
and Structure, 6th ed.; John Wiley & Sons, 2007. pp 1785–1786, and references
cited thererin.
4. Leino, R.; Lönnqvist, J.-E. Tetrahedron Lett. 2004, 45, 8489–8491.
5. Shirini, F.; Zolfigol, M. A.; Khaleghi, M. Mendeleev Commun. 2004, 14, 34–35.
6. Joshi, A. V.; Baidossi, M.; Qafisheh, N.; Sasson, Y. Tetrahedron Lett. 2005, 46,
3583–3586.
7. Montazerozohori, M.; Karami, B.; Azizi, M. Arkivoc 2007, 99–104.
8. Naimi-Jamal, M. R.; Hazeali, H.; Mokhtari, J.; Boy, J.; Kaupp ChemSusChem 2009,
2, 83–88.
Table 3
Oxidation of aliphatic thiols to disulfidesa
O2 or air
100 wt% activated
carbon
H3C
SH
H3C
S
S
CH3
n
xylene
n
n
n
O2 or air
Temperature (°C)
Time (h)
Yield (%)
9. Shaabani, A.; Behnam, M.; Rezayan, A. H. Catal. Commun. 2009, 10, 1074–1078;
Other examples using Et3N in DMF inder sonication, see: Ruano, J. L. G.; Parra,
A.; Alemán, J. Green Chem. 2008, 10, 83–88; Using NaI-Fe(CF3CO2)3-air system,
see: Adibi, H.; Samimi, H. A.; Iranpoor, N. Chin. J. Chem. 2008, 26, 2086–2092.
10. Hayashi, M. Chem. Rec. 2008, 8, 252–267.
10
O2
Air
O2
Air
O2
Air
120
140
120
140
120
140
4
9
6
8
5
5
89
92
86
89
93
95
11
13
11. Okunaga, K.; Nomura, Y.; Kawamura, K.; Nakamichi, N.; Eda, K.; Hayashi, M.
Heterocycles 2008, 76, 715–726.
12. A general experimental procedure is as follow: A mixture of functionalized 3,4-
dihydropyrimidin-2(1H)-thiones (5 mmol), 100 wt% of activated carbon
(Charcoal Activated, Tokyo Chemical Industry Co., Ltd (TCI)), and anhydrous
xylene (20 mL) was placed in a three-necked flask under an air atmosphere. The
whole mixture was heated to 140 °C and stirred for 36–67 h at this temperature.
After confirmation of the completion of the reaction by TLC analysis (hexane/
EtOAc = 1:2), activated carbon was filtered off using celite. The filtrate was
evaporated then recrystalized or silica-gel column chromatographed. The
obtained solid was vacuum-dried to give functionalized bis(2-pyrimidyl)
disulfides.
a
In the absence of activated carbon; 0% yield (O2, 140 °C, 6 h).
Supplementary data
Supporting Information Available: Details of experimental pro-
cedures and characterization data (1H, 13C, IR, mass spectrometry,