Synthesis of cyclic disulfides using didecyldimethylammonium bromide as phase transfer catalyst

Article abstract of DOI:10.1016/j.tetlet.2007.11.075

A convenient, practical and general method for the synthesis of symmetrical and unsymmetrical cyclic disulfides based on the reaction of sulfur with sodium sulfide in the presence of didecyldimethylammonium bromide (DDAB) as a phase transfer catalyst is described.

Full text of DOI:10.1016/j.tetlet.2007.11.075

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 520–522
Synthesis of cyclic disulfides using didecyldimethylammonium
bromide as phase transfer catalyst
Sachin U. Sonavane, Mandan Chidambaram, Sanaa Khalil,
Joseph Almog and Yoel Sasson*
Casali Institute of Applied Chemistry, Hebrew University of Jerusalem, 91904, Israel
Received 28 September 2007; revised 5 November 2007; accepted 14 November 2007
Available online 19 November 2007
Abstract—A convenient, practical and general method for the synthesis of symmetrical and unsymmetrical cyclic disulfides based on
the reaction of sulfur with sodium sulfide in the presence of didecyldimethylammonium bromide (DDAB) as a phase transfer
catalyst is described.
Ó 2007 Published by Elsevier Ltd.
The disulfide moiety occurs in proteins and is also found
in a variety of small molecule natural products and
pharmacologically active compounds.1 In addition,
cyclic and acyclic disulfides are useful intermediates in
the synthesis of biologically-active compounds, both in
pharmaceutical and agrochemical intermediates2 and
in the preparation of self-assembled monolayers on gold
nanoparticles.3 Acyclic disulfides are typically prepared
through oxidation of thiols.4 Similarly, cyclic disulfides
are typically prepared by the oxidative dimerization of
a,x-dithiol using reagents such as I2, NEt3,5 Br2,6
K3Fe(CN)6,7 H2O2/KI/AcOH,8 lead thiolates9 and
supported silica gel.10 More recently, reactions of
a,x-bisthiocyanates with samarium diiodide,11 tetrathio-
molybdate12 or tetrabutylammonium fluoride13 have
been reported for the synthesis of cyclic disulfides.
recently developed to assess the polysulfide distribution
in various sulfur/sulfide mixtures.16 Hase used Li2S2 for
the preparation of dialkyldisulfides.17 The same reagent
was later used for the synthesis of cyclic disulfides.18
Despite the plethora of processes available in the litera-
ture for the synthesis of cyclic disulfides, the preferred
method varies with ring size. The most common proce-
dures involve the oxidation of a dithiol by various
oxidizing agents. Cyclic disulfides have also been
obtained by steam distillation of an appropriate Bunte
salt.19 The reaction of 1,3-dielectrophiles with S24À
followed by desulfurization with copper is a method to
produce 1,2-dithiolanes, usually in moderate yields.20
Harpp et al. have reported the high-yield preparation
of cyclic disulfides by oxidation of alkyltin thiolates
using iodine or bromine without the need for high
dilution.6
The most commonly used method for the direct conver-
sion of aryl/acyl halides to disulfides involves the use of
Na2S/S.14 However, the methods currently available for
the preparation of disulfides often involve several steps
and the transformation is usually effected at 70–90 °C
over a long period of time (20–30 h)14 giving only mod-
erate yields of the corresponding disulfide. Aliphatic
polysulfides were prepared by PTC reaction of Na2S
with dibromoalkanes.15 Disulfide and other polysulfide
anions are easily obtained by mixing aqueous solutions
of S2À with sulfur. Several analytical methods were
We recently showed that DDAB is quite effective as a
phase transfer catalyst and in bringing about the forma-
tion of disulfides from alkyl halides.21 It was of interest
to us to find out whether cyclic disulfides could be
formed efficiently from 1,n-dihalo compounds at higher
dilution using the same methodology. For forensic
chemistry applications, we were interested in making
ninhydrin derivatives substituted by long aliphatic
chains bearing cyclic disulfides at the end. 4-Hydroxydi-
thiane, a potential building block (entry 2), has been
prepared in the past via a relatively complicated proce-
dure involving oxidative cyclization of 1,4-dithio-2-
butanol with FeCl3Æ6H2O, and the process took several
*
Corresponding author. Tel./fax: +972 2 6528250; e-mail: ysasson@
huji.ac.il
0040-4039/$ - see front matter Ó 2007 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2007.11.075

S. U. Sonavane et al. / Tetrahedron Letters 49 (2008) 520–522
521
OH
ponding cyclic disulfide was high (90%) with complete
conversion of the starting dihalide.
OH
DDAB, Na2S, S
CHCl3, H2O, 30 ºC, 4 h
To explore the utility of this catalytic system further,
several dibromides were reacted under the optimized
reaction conditions (Table 1). All were converted into
the corresponding cyclic disulfides with excellent yields.
Dibromides were preferred to dichlorides due to their
higher reactivity as described in our earlier report.21
1,3-Dibromopropane reacted readily at room tempera-
ture (30 °C, 2 h). However, attempts to isolate pure
1,2-dithiolane always led to polymeric material. This is
in accordance with the earlier observation that unsubsti-
tuted dithiolanes are prone to fast polymerization.6,23
Br
S
S
Br
Conversion = 100%, Yield = 90%
Scheme 1.
days.22 Our pathway afforded the same compound in
91% yield, at 30 °C (Scheme 1, Table 1).
As a part of a program directed towards the synthesis of
functionalized cyclic disulfides for monolayer adsorp-
tion studies, we required a simple route to disulfides
from dihalides that would not affect base-sensitive func-
tionalities (specifically esters) and which did not require
specialist reagents or reaction conditions. Herein we
report that DDAB catalyzes the formation of cyclic
disulfides from the corresponding 1,n-dibromo com-
pounds (Scheme 1) in moderate to excellent yields under
mild conditions. The process affords symmetrical as well
as unsymmetrical cyclic disulfides. The reaction is fast,
and is carried out at room temperature.
Treatment of 1,3-dibromobutane at room temperature
initially posed a few problems. A polymer was obtained
instead of the desired 3-methyl-1,2-dithiolane. Possible
reasons could be the higher reactivity of the primary
bromide compared to the secondary bromide, as well
as the electron donating nature of the methyl substitu-
ent. This problem, however, was somewhat overcome
by carrying out the reaction in the dark and in a more
dilute solution. In this case the 1,2-dithiolane was
obtained in 35% isolated yield along with an unknown
by-product, perhaps a polymer. To find out whether
the present methodology could be extended effectively
to the synthesis of higher cyclic dithianes, 1,4-dibromo-
butane and 1,5-dibromopentane were reacted in a simi-
lar manner and produced the corresponding dithianes.
In a generalized procedure 1,4-dibromo-2-butanol (in
chloroform) was stirred with aqueous sodium sulfide
and sulfur in the presence of DDAB as a phase transfer
catalyst at room temperature. The yield of the corres-
Table 1. Synthesis of cyclic disulfides using didecyldimethylammonium bromide as a phase transfer catalyst
Entry
Reactant
T (h)
Product
% Conversiona
% Yieldb (mp/bp)
1
3
96
80 (34–37 °C)
Br Br
S
S
OH
OH
2
4
100
91 (42–45 °C)
Br Br
S
S
S
S
3
4
3
5
80
86
71 (oily gel)
Br Br
n
62 (59–63 °C, bp)
Br Br
S
S
5
4
88
35 (46–53 °C, bp)
Br
Br
S
S
Br
Br
S
S
6
4
71
63 (76–80 °C)
Reaction conditions: A mixture of sulfur powder (10 mmol), sodium sulfide (10 mmol) and water (25 ml) was stirred at 50 °C for 30 min. The solution
was cooled to RT, DDAB (4 mol %) was added, followed by substrate (5 mmol) and chloroform (50 ml) and stirring continued at 30 °C.
a Conversion based on GC analysis with area minimization.
b Isolated yields.

522
S. U. Sonavane et al. / Tetrahedron Letters 49 (2008) 520–522
References and notes
Na2S2 (aq)
Q2S2 (org) + 2NaBr(aq)
Na2S(aq) + S(aq)
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In conclusion, a simple, convenient and practical method
has been developed for the synthesis of symmetrical and
unsymmetrical cyclic disulfides using DDAB as a phase
transfer catalyst.
General procedure:
A mixture of sulfur powder
(10 mmol), sodium sulfide (10 mmol) and water (25 ml)
was stirred for 30 min at 50 °C. After dissolution, the
reaction mixture was cooled to room temperature and
DDAB (4 mol %) was added. A mixture of substrate
(5 mmol) and chloroform (50 ml) was added and the
reaction mixture was stirred for the appropriate period
of time at 30 °C. The progress of the reaction was mon-
itored by GC and GC–MS. After completion of the
reaction, the product was extracted twice with diethyl
ether. The combined organic layers were washed with
water and dried over sodium sulfate. The organic layer
was concentrated under reduced pressure to afford a
crystalline (or liquid) dialkyl disulfide. The pure solid
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Acknowledgement
M.C. is grateful to the Pikovski-Valazzy Fund for finan-
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