N-Phenyltriazolinedione as an efficient, selective, and reusable reagent for the oxidation of thiols to disulfides

Article abstract of DOI:10.1016/j.tetlet.2006.10.134

N-Phenyltriazolinedione is an efficient and chemoselective reagent for the oxidation of thiols to their corresponding symmetrical disulfides. The method is applicable to aromatic, aliphatic, and bi-functional thiols. The one-pot reaction takes a few minutes (in most cases studied) for completion and after a simple work-up affords the corresponding symmetrical disulfides in very good to excellent yields. Furthermore, the reaction could be performed with the same results in the absence of solvent for liquid thiols.

Full text of DOI:10.1016/j.tetlet.2006.10.134

Tetrahedron Letters 47 (2006) 9211–9213
N-Phenyltriazolinedione as an efficient, selective, and
reusable reagent for the oxidation of thiols to disulfides
Angelos Christoforou, Georgia Nicolaou and Yiannis Elemes*
Department of Chemistry, University of Ioannina, 45110 Ioannina, Greece
Received 7 September 2006; revised 16 October 2006; accepted 26 October 2006
Abstract—N-Phenyltriazolinedione is an efficient and chemoselective reagent for the oxidation of thiols to their corresponding sym-
metrical disulfides. The method is applicable to aromatic, aliphatic, and bi-functional thiols. The one-pot reaction takes a few min-
utes (in most cases studied) for completion and after a simple work-up affords the corresponding symmetrical disulfides in very good
to excellent yields. Furthermore, the reaction could be performed with the same results in the absence of solvent for liquid thiols.
Ó 2006 Elsevier Ltd. All rights reserved.
Oxidative coupling of thiols to disulfides under neutral
and mild conditions is of practical importance in
synthetic chemistry1 and biochemistry.2 Disulfides have
found industrial applications as vulcanizing agents3
and are important synthetic intermediates with many
applications in organic synthesis.4 Various reagents
and oxidants have been employed for the conversion
of thiols to disulfides, under a range of experimental
conditions.5 We report here a new, very simple, one-
pot, oxidation of a variety of thiols to their correspond-
ing symmetrical disulfides with good to excellent
isolated yields, after a simple work-up. In the case of
liquid thiols no solvent was necessary leading to the
same results.
presence of benzenethiol. Filtration of the white solid
product floating at the top of the solution, afforded
quantitatively, the parent N-phenylurazole, which was
identified by GC–MS (m/z = 178 amu). In addition, di-
phenyl disulfide was isolated from the filtrate, and iden-
tified spectroscopically. We decided then to further test
the applicability of disulfide formation with a variety
of thiols.
The procedure is based on the addition of solid PhTAD
to a solution of the corresponding thiol (twice the stoi-
chiometric ratio with regard to PhTAD) in dry toluene
at rt (Scheme 1). After decolorization of the red solution
(indication of completion of the reaction), the resulting
mixture was washed twice with 10% NaOH solution,
then with brine and the organic phase was dried over
Na2SO4. Removal of the volatile compounds and sol-
vent afforded solidified disulfides of a high purity, which
We have been involved in the chemistry of ene6 reactions
of triazolinediones (TADs)7 with alkenes.8 TADs are
powerful electrophiles and have been used in addition
reactions to various alkenes with synthetic importance,9
and have been extensively used in the synthesis of poly-
ureas.10 In addition, they are known for their dehydro-
genating properties,11 for their oxidation of alcohols to
aldehydes and ketones,12 and have been used for the
oxidation–aromatization of pyrazolines to pyrazoles.13
During an ongoing study in our laboratory dealing with
new synthetic applications of triazolinediones, we found
that a red solution of N-phenyltriazolinedione (PhTAD)
in toluene was decolorized almost instantaneously in the
1
gave correct H and 13C NMR spectroscopic, and FAB
MS spectrometric data.14 No further purification of the
‘crude’ product was needed except for recrystallization
from n-hexanes/EtOAc solvent mixtures (Table 1).
Ph
N
Ph
N
O
O
O
O
N
N
RS SR
2RSH
+
N N
PhMe, rt
or
no solvent
H
H
Keywords: N-Phenyltriazolinedione; Oxidation; Thiols; Disulfides.
*
Scheme 1. Synthesis of symmetrical disulfides, from the reaction of
N-phenyltriazolinedione with thiols.
Corresponding author. Tel.: +30 26510 98432; fax: +30 26510
98799; e-mail: yelemes@cc.uoi.gr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.134

9212
A. Christoforou et al. / Tetrahedron Letters 47 (2006) 9211–9213
Table 1. Synthesis of symmetrical disulfides from the reaction of
Ph
N
Ph
N
PhTAD with thiolsa
O
O
O
O
Entry
Substrate
(thiol)
Time
(min)
Product
Yield
(%)
N
N
N
N
H
(disulfide)
R
S
I
R
S H
δ
1
2
3
PhSH
5
5
5
(PhS)2
ꢀ100
ꢀ100b
ꢀ100
ꢀ100b
ꢀ100
ꢀ100b
72
δ
Ph
N
Ph
N
PhCH2SH
p-MeC6H4SH
(PhCH2S)2
(p-MeC6H4S)2
Ph
N
O
O
5
HO
O
O
O
R
S S R +
10
10
5
30
d
N
N
N
N
N
N
H
R
S
R
H
H
H
4
5
6
7
8
9
PhC(@O)SH
[PhC(@O)S]2
II
HO(CH2)2SH
HO(CH2)11SH
p-HOC6H4SH
CH3(CH2)15SH
CH3(CH2)17SH
[HO(CH2)2S]2
[HO(CH2)11S]2
(p-HOC6H4S)2
[CH3(CH2)15S]2
[CH3(CH2)17S]2
ꢀ100c
S
δ
H
δ
61c
10
10
d
ꢀ100c
ꢀ100
82
Scheme 2. A possible two step mechanism for the synthesis of
disulfides.
a In toluene at rt, unless otherwise stated.
b Reaction performed without solvent.
more, this method allows for the isolation of the parent
N-phenylurazole, by simple filtration from the reaction
mixture, which can be re-used in the regeneration of
PhTAD by known oxidation procedures.17
c Work-up: filtration through a pad of Celite (no extraction with basic
solution), and removal of the volatile compounds.
d Left overnight, until decolorization of the solution.
From Table 1 it can be seen that the present method is
of general applicability to aromatic (entries 1–3) and
aliphatic thiols (entries 8 and 9), and also showed
high efficiency and chemoselectivity in the case of
bi-functional thiols. As can be seen from entries 4–7,
hydroxyl- and carbonyl functionalities can be present
in the substrate thiols and remain intact during the
formation of the product disulfides. The observed inert-
ness of the acidic hydroxyl–hydrogen (entries 5–7) is
consistent with the higher acidity of S–H over O–H.15
Acknowledgements
Financial support from the Research Committee of the
University of Ioannina, Program ‘DAKAPHR II’ No.
1216 is gratefully acknowledged. We thank Dr. M.
Prodromidis for the donation of long chain alkyl-thiols.
Y.E. thanks Professor Dr. Andreas Hirsch from the
Institute of Organic Chemistry, University of Erlan-
gen-Nurnberg, Germany, for the hospitality and warm
¨
atmosphere during a sabbatical stay (February–July
2005). We thank the NMR and Mass Spectroscopy Cen-
ters of the University of Ioannina, Greece, for NMR
and ESI MS spectra. Special thanks to Dr. G. Kostakis
for the FT IR spectra.
The present work on the oxidation of thiols to disulfides
is the first involving a cis-locked diazo-compound as the
oxidant. Thiol additions to diethyl azodicarboxylate
(DEAD) are known.16 It is well documented that when
a 2:1 molar ratio of thiol/DEAD is used, the first
addition of one thiol molecule to DEAD results in the
formation of a diethyl N-alkylsulfenyl hydrazodicarb-
oxylate derivative (1:1 adduct), which undergoes a
subsequent nucleophilic displacement by a second thiol
molecule, resulting in the formation of the hydrazine
derivative (diethyl hydrazodicarboxylate) together with
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