Heteroaromatic azo compounds as efficient and recyclable reagents for direct conversion of aliphatic alcohols into symmetrical disulfides

Article abstract of DOI:10.1016/j.tetlet.2012.10.013

4,4′-Azopyridine 1a and 5,5′-dimethyl-3,3′-azoisooxazole 1e are used for the efficient, direct, and selective conversion of aliphatic alcohols into their corresponding disulfides in high yields under Mitsunobu conditions in combination with PPh₃

Full text of DOI:10.1016/j.tetlet.2012.10.013

Tetrahedron Letters 53 (2012) 6913–6915
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Tetrahedron Letters
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Heteroaromatic azo compounds as efficient and recyclable reagents for
direct conversion of aliphatic alcohols into symmetrical disulfides
⇑
⇑
Nasser Iranpoor , Habib Firouzabadi , Dariush Khalili
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71454, Iran
a r t i c l e i n f o
a b s t r a c t
4,40-Azopyridine 1a and 5,50-dimethyl-3,30-azoisooxazole 1e are used for the efficient, direct, and selec-
tive conversion of aliphatic alcohols into their corresponding disulfides in high yields under Mitsunobu
conditions in combination with PPh3 and NH4SCN. The reaction with 1a occurs homogeneously, and 1e
heterogeneously. In both reactions, the produced N-cyanohydrazines are isolated and reoxidized to the
corresponding azo compounds easily.
Article history:
Received 13 June 2012
Revised 2 September 2012
Accepted 4 October 2012
Available online 12 October 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Disulfide
Mitsunobu reaction
4,40-Azopyridine
5,50-Dimethyl-3,30-azoisooxazole
Azo compounds
Organosulfur compounds, including disulfides, are attractive in
a variety of chemical1 and biological research fields.2 In addition,
acyclic disulfides are useful intermediates for the synthesis of ad-
sorbed monolayers.3,4 For the synthesis of disulfides, thiols serve
as the most frequently employed precursors. Various reagents, sys-
tems, and oxidants have been employed for the conversion of thi-
ols into disulfides, for example selenite ionic liquid,5a iron(III)
dichloronitrilotriacetate,5b Co–Fe magnetic composites,5c an acti-
vated carbon–air system,5d PhSeZnCl,5e SO2Cl2,5f solid anhydrous
potassium phosphate,5g molybdate sulfuric acid (MSA),5h NO2 gas,5i
and H3PW12O40–NaBrO3,5j under a range of experimental condi-
tions.5k–u However, apart from the very unpleasant odor of thiols
and their limited availability, most of these methods have certain
drawbacks such as expense, critical product isolation procedures
that may lead to contamination of the final products with traces
of transition metals, and difficulty in removal of side products.
Although alcohols can serve as suitable reagents for the synthesis
of disulfides, to the best of our knowledge, there are only a few
publications on the direct6 and indirect7 transformations of alco-
hols into disulfides. Since the first report in 1967,8 the Mitsunobu
reaction has become a widely used synthetic method for the con-
struction of carbon-heteroatom bonds. However, there is no exam-
ple dealing with the application of the Mitsunobu reaction for the
conversion of alcohols into disulfides. In this regard, and in contin-
uation of our interest on the use of heterocylic aromatic azo
compounds as new Mitsunobu reagents instead of DEAD or DIAD
(diisopropyl azodicarboxylate) in various organic transformations,8
herein, we report a selective and straightforward approach for the
synthesis of dialkyl disulfides from the corresponding alcohols
using heteroaromatic azo compounds and triphenylphosphine via
the Mitsunobu reaction.
As part of an investigation on the thiocyanation of alcohols un-
der modified Mitsunobu conditions, we studied the possibility of
using the previously reported heteroaromatic azo compounds
1a–e (Table 1),9 with NH4SCN in the presence of PPh3. Interest-
ingly, we observed no evidence for thiocyanate formation when
1-propanol was reacted with NH4SCN in the presence of these
azo compounds and PPh3. Instead, dipropyl disulfide was isolated
in 25–91% yield.10 Among the azo compounds studied, 4,40-azo-
pyridine 1a and 5,50-dimethyl-3,30-azoisooxazole (1e) were found
to be the most efficient reagents affording dipropyl disulfide in
the highest yields (Table 1, entries 1 and 5). The difference
between these two azo reagents is that the reactions with 1a are
performed under homogeneous conditions and those of 1e occur
heterogeneously. However, the N-cyanohydrazine tentatively
identified in the by-products obtained from both azo compounds
is insoluble in the reaction medium and can be easily isolated for
recycling.
The use of KSCN instead of its ammonium salt was not success-
ful due to its insolubility in the reaction media.
Next, we studied the effect of the solvents on the reaction.
Acetonitrile proved to be the most efficient (Table 1). Moreover,
in acetonitrile, the side products, the tentatively identified N-
cyanohydrazines obtained from 5,50-dimethyl-3,30-azoisooxazole
⇑
Corresponding authors. Tel.: +98 711 228 4822; fax: +98 711 228 0926.
E-mail addresses: iranpoor@susc.ac.ir (N. Iranpoor), firouzabadi@susc.ac.ir
(H. Firouzabadi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.10.013

6914
N. Iranpoor et al. / Tetrahedron Letters 53 (2012) 6913–6915
Table 1
sions of the starting materials into their corresponding disulfides
in high yields and with no evidence of thiocyanate formation.
The yield of the disulfide was found to be chain-length depen-
dent. Shorter carbon chain lengths led to increased disulfide forma-
tion (Table 2, entries 1 and 2) and longer carbon tethers (n = 8 or
12) produced the corresponding disulfides in lower yields (Table
2, entries 6, 7 and 8).
In comparison with aliphatic alcohols, under similar conditions,
benzylic alcohols gave the corresponding benzylic thiocyanates
without any disulfide formation.
Considering the literature reports on the conversion of thiocya-
nates into disulfides with a base (e.g., NaOH or NH3), our observa-
tions cannot be unsimilar.11 In order to find supporting evidence
for the mechanism of the reaction, we focused on the reaction of
n-propyl alcohol and azo compound 1a. In this reaction, we ob-
served the formation of a yellow precipitate tentatively identified
as 7 which was isolated. The 1H and 13C NMR spectra of this precip-
itate in DMSO-d6 showed the presence of the NH proton and the
N–CN carbon at 8.23 and 133.6 ppm, respectively, which are
indicative of the formation of 7 as a by-product.
Optimization of the reaction of n-propyl alcohol with different heteroaromatic azo
reagents
S
S
2a
ArN=NAr (1a-1e), PPh3
OH
+ NH4SCN
solvent
SCN
O
×
N
S
N
,
,
,
,
Ar =
N
N
N
Me
1a
1c
1e
1b
1d
Entry
Azo compound
Solvent
Conditions
Time (h)
Yield (%)a
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1a
1e
1a
1e
1a
1e
1a
1e
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
THF
Et2O
Et2O
CHCl3
CHCl3
Reflux
Reflux
Reflux
Reflux
Reflux
r.t.
3
7
10
6
3
10
10
5
88
62
25
77
91
32
28
70
68
28
29
63
60
The mass spectrum of 7 showed the molecular ion at m/z 211
(44%). The IR spectrum of this by-product showed two absorption
bands centered at 2085 and 3415 cmꢀ1 which were assigned to the
r.t.
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
9
5.5
15
15
9
m(C„N) and NH groups. Based on these observations and the liter-
10
11
12
13
ature reports for the conversion of thiocyanates into disulfides
with a base,11 and also the formation of Ph3PO, we presume that
our reagent system initially induces thiocyanation of the alcohol
to generate the corresponding alkyl thiocyanate intermediate 6
and then the 5 produced attack this intermediate to afford the
disulfide product (Scheme 1).
In conclusion, we have developed a new, direct, and efficient
method for selective disulfide formation from aliphatic alcohols
using heteroaromatic azo compounds under Mitsunobu conditions.
The use of these readily prepared azo compounds allows simple
product isolation compared to traditional methods. The diversity
of alcohols as widely available starting materials and recyclability
of these azo reagents are considered important advantages of this
method.
9
a
Isolated yield.
(1e) and 4,40-azopyridine (1a) were insoluble and could be easily
removed from the reaction mixture by filtration.
Applying the optimized conditions to other aliphatic alcohols
(Table 2) showed the general applicability of this reaction as a
high-yielding method for the preparation of symmetrical aliphatic
disulfides. Treatment of both primary and secondary acyclic and
cyclic aliphatic alcohols with ammonium thiocyanate in the pres-
ence of azo compounds 1a or 1e and PPh3 induced clean conver-
Table 2
Direct transformation of aliphatic alcohols into symmetrical disulfides under Mitsunobu conditionsa
1a or 1e
ROH
RS-SR
PPh3, NH4SCN, CH3CN, 80 °C
Entry
ROH
RS-SR
Time (h)
Yieldb (%)
Ref.
1a
1e
1a
1e
OH
OH
OH
1
2
3
(n-C3H7S–)2
(n-C4H9S–)2
(n-C5H11S–)2
2a
2b
2c
3
3
3
4
91
83
80
88
85
84
12a
12b
12c
3.5
3
OH
4
S
S
2d
5
6
83
80
12d
5
6
7
OH
S
S
2e
2f
6
5
6
6
4
5
81
85
77
79
82
81
12e
12c
12h
OH
OH
(n-C8H17S–)2
[CH3(CH2)5CH(CH3)S–]2
[CH3(CH2)10CH2S–]2
2g
8
9
OH
2h
2i
6
3
6
3
73
84
77
86
12e
12f
OH
(PhCH2CH2S–)2
OH
10
(PhCH2CH2CH2S–)2
2j
3
3
80
85
12g
a
The molar ratio of the reactants ROH/NH4SCN/1e (1a)/PPh3 in refluxing CH3CN was 1:2.5:1.8:1.8.
Isolated yield.
b

N. Iranpoor et al. / Tetrahedron Letters 53 (2012) 6913–6915
6915
H
ROH
1)
N
N N
N
+
PPh3
N
N
N
N
N
N N
N
PPh3
Ph3P OR
1a
3
4
H
H
2)
N
N
N
N
N
N
N
N
Ph3PO + RSCN
Ph3P
O
SCN
R
5
6
4
H
H
N
3)
+
N
RS-SR
N
N
N
N
N
N
+ NH4CN
CN
5
2a-j
7
6
N
C S R
6
N
C S R
+
NH4
Scheme 1. Proposed mechanism.
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Acknowledgement
We are grateful to Shiraz University for financial support of this
work.
References and notes
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disulfides (Caution: This procedure should be carried out in a well-ventilated
hood): The aliphatic alcohol (1 mmol) was added to
a solution of azo
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H
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20H), 0.95–0.85 (m, 6H); 13C NMR (62.9 MHz, CDCl3) d: 39.2, 31.8, 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, 66.38; H, 11.60; S, 22.19.
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6.55 (m, 4H, AA0XX0), 13C NMR (CDCl3, 62.9 MHz) d 116.3, 133.6, 151.5, 156.5.
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