One-pot efficient synthesis of disulfides from alkyl halides and alkyl tosylates using thiourea and elemental sulfur without contamination by higher polysulfides

Article abstract of DOI:10.1007/s13738-012-0141-0

An efficient and odorless synthesis of disulfides from alkyl halides using thiourea and elemental sulfur in the presence of sodium carbonate in wet polyethylene glycol (PEG 200) at 40 C without contamination by higher polysulfides has been developed. This procedure was then extended to preparation of disulfides from alkyl tosylates at 70 C.

Full text of DOI:10.1007/s13738-012-0141-0

J IRAN CHEM SOC (2013) 10:201–205
DOI 10.1007/s13738-012-0141-0
ORIGINAL PAPER
One-pot efficient synthesis of disulfides from alkyl halides
and alkyl tosylates using thiourea and elemental sulfur
without contamination by higher polysulfides
•
Mohammad Abbasi Mohammad Reza Mohammadizadeh
•
Zeinab Khatoon Taghavi
Received: 16 April 2012 / Accepted: 10 July 2012 / Published online: 7 August 2012
Ó Iranian Chemical Society 2012
Abstract An efficient and odorless synthesis of disulfides
from alkyl halides using thiourea and elemental sulfur in
the presence of sodium carbonate in wet polyethylene
glycol (PEG 200) at 40 °C without contamination by
higher polysulfides has been developed. This procedure
was then extended to preparation of disulfides from alkyl
tosylates at 70 °C.
Compared with the thiols, alkyl halides are odorless and
more easily available. Furthermore, thiols are generally
prepared from the corresponding alkyl halides; hence, the
one-pot production of disulfides from the corresponding
alkyl halides which also saves both time and cost is more
suitable. Several procedures using such reagents as disul-
fide dianion [8–14], tetrathiomolybdate and tetrathiotung-
state complexes [15, 16], a combination of borohydride
reducing agents with sulfur [17, 18] and sulfur element in
strong alkaline media [19, 20] have been developed for the
conversion of alkyl halides to disulfides. Recently, two
odorless procedures for one-pot conversion of alky halides
to disulfides according to the reaction presented in
Scheme 1 have been developed [21, 22].
Keywords Disulfide Á Alkyl halide Á Alkyl tosylate Á
Sulfur Á Thiourea
Introduction
The synthesis of disulfide is an essential transformation in
modern research because it has several applications and
potential abilities in organic synthesis [1–6]. Disulfides can
be obtained by various methods using different substrates,
but they are generally prepared by thiol oxidation because
many alternative methods are limited by their conditions,
substrates or reagents (for a review see ref. [7]). Many
thiols are toxic and foul-smelling compounds; hence, the
extension of straightforward disulfide synthetic methods by
use of non-thiolic, commercially available and inoffensive
precursors and reagents is important.
According to this strategy, disulfide is formed from
oxidation of in situ generated thiol. Many reagents for the
conversion of thiols to disulfides are known at present, but
selection of a proper oxidant for the reaction presented in
Scheme 1 is crucial due to the high oxidation capability of
thiourea and thiol over-oxidation in alkaline reaction
media. In this regard, MnO2 and BaMnO4 as suitable
oxidizing reagents have been previously introduced [21,
22]. We now wish to introduce another efficient procedure
for one-pot preparation of disulfides from alkyl halides or
tosylated alcohols using thiourea and elemental sulfur.
Results and discussion
M. Abbasi (&)
Fisheries and Aquaculture Department, College of Agriculture
and Natural Resources, Persian Gulf University,
75169 Bushehr, Iran
Oxidation of thiols to disulfides can take place with ele-
mental sulfur and a basic catalyst (Scheme 2) [23].
e-mail: abbassi@pgu.ac.ir
A major problem with the method was that significant
amounts of other higher polysulfides may be produced. It
has been found that the formation of polysulfides can be
avoided by employing a co-catalyst [23]. In terms of
M. R. Mohammadizadeh Á Z. K. Taghavi
Chemistry Depatment, Faculty of Sciences,
Persian Gulf University, 75169 Bushehr, Iran
123

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J IRAN CHEM SOC (2013) 10:201–205
(3 mmol) in wet polyethylene glycol (2 mL PEG-
200 ? 0.2 mL H2O) was stirred for 3 h at 40 °C. Under
these conditions, the reaction proceeded well and the cor-
responding disulfide was produced purely in 91 % isolated
yield (Table 1, entry 6). This reaction was easily scaled up to
50 mmol (6.33 g) of the substrate without affecting the rate
and the yield of the reaction. This protocol was then applied
for the preparation of different symmetric disulfides. The
results have been shown in Table 2.
S
Base, Oxidant
RX
H2N
NH2
+
RSSR
Scheme 1 One-pot formation of disulfides from alkyl halides using
thiourea and oxidizing reagents
RSSR + H2S
2 RSH + 1/8 S8
Scheme 2 Oxidative coupling of thiols to disulfides by elemental
sulfur
As the results show, benzylic, allylic, primary and sec-
ondary halides were easily transformed into their corre-
sponding disulfides after appropriate reaction times
(Table 2, entries 1–13). In all experiments, formation of
polysulfide by-products was not observed.
benefits, elemental sulfur is cheap, abundant and stable,
and easy to store and handle. It has low chemical reactivity
toward organic compounds and a wide range of reactive
functionalities remain intact in the presence of sulfur.
Accordingly, we were interested in exploring a modified
procedure for the synthesis of disulfides from alkyl halides
under mild conditions using elemental sulfur. To optimize
the reaction conditions, conversion of benzyl chloride to
dibenzyl disulfide in wet polyethylene glycol (PEG-200)
was studied. The results have been summarized in Table 1.
As the results show, the best yield was obtained when a
mixture of benzyl chloride (2 mmol), thiourea (2.5 mmol),
octasulfur (48 mg, 1.5 mmol sulfur atoms) and Na2CO3
Production of disulfides from alkyl tosylates is syn-
thetically valuable, since they can be readily prepared in
one step from alcohols. In this regard, we extended our
studies and disulfides were successfully prepared from
alkyl tosylates without contamination with polysulfide by-
products (Table 2, entries 14–19). A proposed reaction
pathway has been presented in Scheme 3.
The alkyl halide or tosylate undergoes nucleophilic
substitution reaction with thiourea by an SN2 mechanism to
Scheme 3 A proposed reaction
mechanism for conversion of
alkyl halides or tosylates to
disulfides
H2O, CO2,
NaX
Na2CO3
SR
H2N
H N
X
2
S
R
X
+
SR
HN
NH2
H2N
H2N
S-alkylisothiouronium salt
OH
urea
SR
O
SR
S2-
S8
H2N
NH2
HN
NH2
SR
RS-SR
OH
Table 1 Conversion of benzyl chloride to dibenzyl disulfide under different conditions
wet PEG-200
PhCH2Cl + Thiourea + S + Na2CO3
1a 1b
PhCH2S-SCH2Ph
1c
1d
Entry
mol ratios
1a:1b:1c:1d
T (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6
7
8
2:2:1:3
rt
8
77
77
81
82
81
91
80
91
2:2.5:1:3
rt
5.5
5.5
5
2:2.5:1.5:3
2:2:1:3
rt
40
40
40
40
40
2:2.5:1:3
3
2:2.5:1.5:3
2:2.5:1.5:2.5
2:2.5:1.5:3.5
3
3
3
Each reaction was carried out in a medium consisting of 2 mL PEG-200 and 0.2 mL H2O
123

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203
Table 2 One-pot synthesis of disulfides from alkyl halides and tosylates using thiourea and elemental sulfur
Entry
1
Reactant
Producta
Time (h)
3
Isolated Yield (%)
91
CH2Cl
CH2Br
CH2Cl
CH2S
CH2S
2
2
2
3
2.5
3
93
89
CH2S
2
4
4
91
Cl
S
2
5
6
n-C8H17Br
11.5
9
86
86
n-C8H17S
2
CH2CH2Br
Br
CH2CH2S
2
7
3.45
85
S
2
8
C2H5Br
3
12
4.3
36
84
91
90
80
C2H5S
2
9
n-C10H21I
n-C10H21S
2
10
11
n-C4H9Br
n-C4H9S
2
Br
Br
S
2
12
13
36
36
81
84
S
2
Br
S
2
14b
15b
16b
17b
18b
CH3OTs
3
4
84
87
91
87
92
H3CS
2
C2H5OTs
n-C3H7OTs
C2H5S
2
6
n-C3H7S
2
n-C8H17OTs
12
5
n-C8H17S
2
CH2OTs
CH2S
2
123

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J IRAN CHEM SOC (2013) 10:201–205
Table 2 continued
Entry
Reactant
Producta
Time (h)
5
Isolated Yield (%)
90
19b
CH2=CHCH2OTs
CH2=CHCH2S
2
a
The products were identified by spectroscopic techniques (1H NMR and 13C NMR), elemental analysis and comparison to authentic samples
b
The reaction was conducted at 70 °C
give S-alkylisothiouronium salt intermediate. Next, the thiol
(s, 6H); 13CNMR (62.5 MHz, CDCl3): d 137.2, 134.4,
129.4, 129.3, 42.7, 21.3; anal. calcd for C16H18S2: C,
70.02; H, 6.61; S, 23.37 %. Found: C, 70.09; H, 6.58; S,
23.33 %.
moiety is gradually generated in situ due to alkaline hydro-
lysis of the salt that subsequently undergoes oxidation by
elemental sulfur producing the corresponding disulfide.
Bis(2-methyl-2-propenyl) disulfide (3) Colorless oil;
1HNMR (250 MHz, CDCl3): d 4.89–4.80 (m, 4H), 3.22 (s,
4H), 1.76 (s, 6H); 13CNMR (62.5 MHz, CDCl3): d 140.7,
114.9, 46.4, 20.9; anal. calcd for C8H14S2: C, 55.12; H,
8.09; S, 36.79 %. Found: C, 55.03; H, 8.06; S, 36.91 %.
Conclusion
In conclusion, we have introduced an efficient, versatile
and odorless protocol for direct preparation of disulfides
from non-thiolic precursors under mild and eco-friendly
conditions. In this protocol, a mixture of an alkyl halide or
alkyl tosylate, thiourea, elemental sulfur and sodium car-
bonate in wet PEG-200 produced the related pure disulfide
in good to excellent yields. These substrates are readily
available and their synthesis is much easier than the cor-
responding thiols and so the preparation of structurally
diverse disulfides becomes more practical using this pro-
tocol. This protocol is easily applicable for large-scale
operation. Moreover, this method is important because it
provides a short synthetic route to the disulfides from non-
commercially available thiols.
1
Dioctyl disulfide (4) Colorless oil; HNMR (250 MHz,
CDCl3): d 2.61 (t, J = 7.3 Hz, 4H), 1.66–1.54 (m, 4H),
1.30-1.21 (broad band, 20H), 0.84–0.79 (m, 6H); d
13CNMR (62.5 MHz, CDCl3): 39.2, 31.8, 29.2, 29.2, 29.1,
28.5, 22.6, 14.1; Anal. Calcd for C16H34S2: C, 66.14; H,
11.79; S, 22.07 %. Found: C, 66.07; H, 11.81; S, 22.12 %.
1
Didecyl disulfide (8) Colorless oil; HNMR (250 MHz,
CDCl3): d 2.63 (t, J = 7.3 Hz, 4H), 1.76–1.61 (m, 4H),
1.21 (broad band, 28H), 0.84–0.79 (m, 6H); 13CNMR
(62.5 MHz, CDCl3): d 39.2, 31.9, 29.6, 29.5, 29.3, 29.3,
29.2, 28.5, 22.7, 14.1; anal. calcd for C20H42S2: C, 69.29;
H, 12.21; S, 18.50 %. Found: C, 69.40; H, 12.23; S,
18.37 %.
Dicyclohexyl disulfide (12) Colorless oil; 1H NMR
(250 MHz, CDCl3): d 2.69–2.61 (m, 2H) 2.03-1.97 (m, 4H)
1.80-1.72 (m, 4H) 1.63–1.55 (m, 2H) 1.34–1.14 (m, 10H);
13C NMR (62.5 MHz, CDCl3): 49.9, 32.8, 26.1, 25.7; anal.
calcd for C12H22S2: C, 62.55; H, 9.62; S, 27.83. Found: C,
62.70; H, 9.55; S, 27.75 %.
Experimental
General procedure
To a stirred solution of thiourea (2.5 mmol) in wet PEG-200
(2 mL PEG ? 0.2 mL H2O) at 40 °C, an alkyl halide or
alkyl tosylate (2 mmol), Na2CO3 (3 mmol) and elemental
sulfur (0.048 g, 1.5 mmol sulfur atoms) were added. The
reaction was monitored by TLC or GC. After complete
consumption of the halide or tosylate, the stirring was con-
tinued for another 2 h at the same temperature. Then H2O
(2 mL) was added to the reaction mixture and the mixture
was extracted with EtOAc (3 9 2 mL). The organic layers
were decanted, combined, dried over Na2SO4, filtered, and
concentrated to yield the crude product, which was further
purified by silica gel chromatography using low-boiling
petroleum ether as eluent to provide the desired disulfides in
good to excellent yields (Table 1).
Typical large-scale procedure for one-pot preparation
of dibenzyl disulfide (1) from benzyl chloride (Table 1,
entry 1)
To a stirred solution of thiourea (62.5 mmol) in wet PEG-
200 (50 mL PEG ? 5 mL H2O) at 40 °C, benzyl chloride
(50 mmol), Na2CO3 (75 mmol) and elemental sulfur
(1.2 g, 37.5 mmol sulfur atoms) were added. The progress
of the reaction was monitored by TLC until the starting
halide was completely consumed (1 h). The stirring was
continued for another 2 h at the same temperature. Then,
H2O (50 mL) was added to the reaction mixture and the
mixture was extracted with EtOAc (3 9 20 mL). The
organic layers were decanted, combined, dried over
Na2SO4, filtered and concentrated. The crude product was
1
Bis(4-methylbenzyl) disulfide (2) Colorless oil; HNMR
(250 MHz, CDCl3): d 7.05 (s, 8H), 3.52 (s, 4H), 2.25
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