A novel nickel-catalyzed domino method for the direct synthesis of symmetrical disulfides using potassium 5-methyl-1,3,4-oxadiazole-2-thiolate as a sulfurating reagent

Article abstract of DOI:10.1055/s-0034-1380141

A simple, one pot, efficient, and novel protocol has been developed for the direct synthesis of symmetrical organic disulfides using a domino reaction between an aryl/alkyl halide and potassium 5-methyl-1,3,4-oxadiazole-2-thiolate in the presence of NiCl₂ as catalyst. A variety of symmetrical aryl/alkyl disulfides can be obtained in moderate to excellent yields (up to 95%).

Full text of DOI:10.1055/s-0034-1380141

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 911–914
letter
911
M. Soleiman-Beigi, F. Mohammadi
Letter
Synlett
A Novel Nickel-Catalyzed Domino Method for the Direct Synthesis
of Symmetrical Disulfides Using Potassium 5-Methyl-1,3,4-oxadi-
azole-2-thiolate as a Sulfurating Reagent
Mohammad Soleiman-Beigi*
Fariba Mohammadi
N
N
NiCl2 (10 mol%), EG, KOH
DMF–H2O, 130 °C
RS-SR
2 RX
+ 3
S K
O
32–95%
Department of Chemistry, Basic of Sciences Faculty, Ilam University,
PO Box 69315-516, Ilam, Iran
R = alkyl and aryl
SoleimanBeigi@yahoo.com
m.soleimanbeigi@mail.ilam.ac.ir
Received: 07.12.2015
Accepted after revision: 14.01.2015
Published online: 18.02.2015
sulfur/sodium sulfide,12 and elemental sulfur.13,14 Although
these methods are very effective, they have drawbacks such
as the use of highly volatile, toxic, and foul-smelling thiols
or large amounts of copper salts as catalyst. To overcome
this disadvantage, attention has been directed towards the
direct synthesis of symmetrical disulfides in the presence
of catalytic amounts of nickel salts. In this regard, potassi-
um 5-methyl-1,3,4-oxadiazole-2-thiolate as a sulfur-trans-
fer reagent was used instead of a free thiol, for the direct
synthesis of organic disulfides from an alkyl/aryl halide in
the presence of NiCl2.
DOI: 10.1055/s-0034-1380141; Art ID: st-2014-d1010-l
Abstract A simple, one pot, efficient, and novel protocol has been de-
veloped for the direct synthesis of symmetrical organic disulfides using
a domino reaction between an aryl/alkyl halide and potassium 5-meth-
yl-1,3,4-oxadiazole-2-thiolate in the presence of NiCl2 as catalyst. A va-
riety of symmetrical aryl/alkyl disulfides can be obtained in moderate
to excellent yields (up to 95%).
Key words nickel-catalyzed, disulfides, cross-coupling, 1,3,4-oxadi-
azole, sulfur-transfer reagents
Our previous work utilized potassium 5-methyl-1,3,4-
oxadiazole-2-thiolate (1) as a new heterocyclic sulfur donor
for the direct synthesis of organic disulfides from aryl/alkyl
halides in the presence of a copper catalyst that effectively
led to the production of disulfides in high yield.15 In contin-
uation of our efforts towards the synthesis of organosulfur
compounds,16 we report for the first time a method for the
direct synthesis of symmetrical diaryl and dialkyl disulfides
from aryl/alkyl halides using nickel catalysis.
In this work, the reaction of iodobenzene with potassi-
um 5-methyl-1,3,4-oxadiazole-2-thiolate (1) in the pres-
ence of a nickel catalyst and KOH was studied under normal
atmospheric conditions in order to optimize the reaction
conditions in terms of temperature, amount of reagent, the
type of nickel source, ligand and solvent. According to the
results shown in Table 1 it was found that the ligand and
solvent significantly affected the rate of the reaction. Eth-
ylene glycol (EG) in DMF was the most effective solvent–li-
gand combination because increasing the amount of EG led
to an increased rate of reaction (Table 1, entries 10–14). It
seems EG behaves as a cosolvent in addition to acting as a
ligand during the reaction. In addition, the reaction yield
and reaction rate increased with increases in temperature
up to 130 °C. Furthermore, NiCl2·6H2O provided the best
yield when compared to other nickel salts tested in this in-
Nickel catalysis has been increasingly used in cross-cou-
pling chemistry as a reactive and cost-effective alternative
to other transition-metal catalysts.1 Several key properties
of nickel, such as its air stability, ease of preparation, and
low energy barriers for oxidative addition, have allowed the
development of a broad range of innovative reactions.2
Nickel-catalyzed C–S coupling reactions have been used
and investigated for efficient organic disulfide synthesis
from thiols.3
Organic disulfides are important intermediates in vari-
ous organic transformations.4 They are used in the sulfe-
nylation of enolates and other anions5 as well as being es-
sential moieties in biologically active compounds for pep-
tide and protein stabilization.6 As disulfides are relatively
more stable towards oxidation, alkylation, and acylation
when compared to their corresponding free thiols, the thiol
group can be conveniently protected as a disulfide.7
The oxidative coupling of thiols to their corresponding
disulfides is the most common method for disulfide forma-
tion.8 Derivatives can be obtained from the copper(I)-cata-
lyzed couplings of aryl/alkyl halides with various types of
sulfur-containing substrates involving thioacetamide,9
di(tri)thiocarbonate,10 thiourea and thiouronium salts,11
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 911–914

912
M. Soleiman-Beigi, F. Mohammadi
Letter
Synlett
vestigation (Table 2). A large number of symmetrical dia-
ryl/dialkyl disulfides was synthesized in the presence of
NiCl2·6H2O using three equivalents of potassium 5-methyl-
1,3,4-oxadiazole-2-thiolate (1) at 130 °C under normal at-
mospheric conditions (Table 3).
Table 2 Optimization of the Type and Amount of Nickel Source and
Temperaturea
Entry
Temp (°C) Nickel source (mol%)
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
25
80
NiCl2·6H2O (10)
NiCl2·6H2O (10)
NiCl2·6H2O (10)
NiCl2·6H2O (10)
NiCl2·6H2O (5)
24
24
6
n.r.
trace
54
Table 1 Optimization of the Reaction Conditionsa
110
130
130
130
130
130
130
N
N
4
92
NiCl2, ligand, KOH
PhS -SPh
2 PhI +
3
S K
24
4
50
O
solvent–H2O (20:1)
130 °C
NiCl2·6H2O (20)
Ni(OAc)2·4H2O (10)
Ni(SO4)2·6H2O (10)
Ni(NO3)2·6H2O (10)
94
1
24
24
24
trace
35
Entry
Solvent
Ligand (mol%)
Time (h)
Yield (%)
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
toluene
–
24
24
24
24
24
24
24
24
24
24
18
12
4
20
58
1,10-phenb (20)
EDc (20)
52
a Reaction conditions: PhI (2.0 mmol), potassium 5-methyl-1,3,4-oxadi-
azole-2-thiolate (1, 3 mmol), EG (200 mol%), KOH (36 mmol), DMF–H2O
(20:1; 2 mL), air.
3
trace
43
4
L-proline (20)
glycine (20)
acac (20)
glycerol (20)
glyoxime (20)
Ph3P (20)
EG (20)
5
48
Table 3 Direct Synthesis of Symmetrical Disulfides from Aryl/Alkyl Ha-
lides
6
34
7
31
NiCl2•6H2O (10 mol%)
EG (200 mol%), KOH
8
70
N
N
9
50
RS-SR
2 RX
+
3
S K
O
DMF–H2O, 130 °C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
72
2a–m
1
3a–m
EG (100)
EG (150)
EG (200)
EG (300)
EG (200)
EG (200)
EG (200)
EG (200)
EG (200)
EG (200)
EG (200)
EG (200)
–
85
89
Entry
RX
Product
Time (h)
Yield (%)a,b
92
1
2
PhI
3a
3b
3c
3d
3e
3f
4.0
5.0
8.0
8.0
4.5
3.0
3.0
4.0
1.5
2.5
24
9214
9014
70c,14
75c,14
7817
8915
8515
8215
4014
3215
47c,14
55c,14
908h
938h
959
4
95
PhBr
4
68
3
2-MeC6H4I
4
N.R
10
4
1-iodonaphthalene
4-BrC6H4I
1,4-dioxane
MeCN
PEG
4
5
4
25
6
2-iodothiophene
2-bromothiophene
2-chlorothiophene
4-NO2C6H4Br
2,4-(NO2)2C6H3Cl
3-MeOC6H4I
4
trace
trace
15
7
3f
EtOH
NMP
4
8
3f
4
9
3g
3h
3i
THF
4
32
10
11
12
13
14
15
EG
4
trace
a Reaction conditions: PhI (2.0 mmol), NiCl2·6H2O(10 mol%), potassium 5-
methyl-1,3,4-oxadiazole-2-thiolate (1, 3 mmol), KOH (36 mmol), solvent–
H2O (20:1; 2 mL), air.
4-MeOC6H4I
3j
24
PhCH2Cl
3k
3l
1.5
3.5
3.0
b 1,10-Phenanthroline.
c 1,2-Ethylenediamine.
Ph(CH2)2Br
Ph(CH2)3Br
3m
a All the products are known compounds and were characterized by com-
parison of NMR spectroscopic data and melting points with those reported
The reaction efficiency for the synthesis of diaryl disul-
fides from various aryl halides was examined. As can be
seen, aryl chlorides were not as reactive as aryl bromides
and aryl iodides with yields of 47–95% being obtained (Ta-
ble 3). Symmetrical diaryl disulfides bearing different func-
tional groups such as Me, OMe, NO2, and Br were also syn-
thesized in good to excellent yield.
in the literature.
b Isolated yield.
c Incomplete reaction.
As a general trend, under the optimal conditions deter-
mined above, a higher rate of reaction was obtained with
aryl substrates possessingelectron-withdrawing groups
such as NO2 (conversion 100%, time 1.5–2.5 h; Table 3, en-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 911–914

913
M. Soleiman-Beigi, F. Mohammadi
Letter
Synlett
tries 9 and 10) although several products were formed.
However, reactions were not complete after 24 hours in the
presence of electron-donating groups such as OMe (Table 3,
entries 11 and 12). The reaction efficiency for the synthesis
of symmetrical dialkyl disulfides was also examined and
was found to be as effective as aryl disulfides (Table 3, en-
tries 13–15).
Acknowledgment
We acknowledge financial support from the Ilam University Research
Council.
Supporting Information
Supporting information for this article is available online at
Although we cannot clearly determine the catalytic re-
action pathway for the synthesis of diaryl/dialkyl disulfides
from aryl/alkyl halides and potassium 5-methyl-1,3,4-oxa-
diazole-2-thiolate (1), the initial conversion of nickel(II) to
nickel(0) in the presence of EG is plausible.1d,e,m,18 The po-
tassium thiolate appears to be generated in the coupling re-
action between potassium 5-methyl-1,3,4-oxadiazole-2-
thiolate and the aryl/alkyl halide. The potassium thiolate
generated is then converted into the corresponding disul-
fide under the reaction conditions (Scheme 1).9
http://dx.doi.org/10.1055/s-0034-1380141.
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References and Notes
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Ni(II)
L(EG)
L2Ni(0)
ArX
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Ar
Ar
N
N
N
N
L2Ni
L2Ni
S K
S
O
O
X
OH
– KX
N
N
OH
S
N
N
Ar
Ar
O
S
O
N
N
HO
O
DMF–H2O, EG
NiCl2•6H2O
ArS-SAr
ArS
KOH,130 °C
Scheme 1 Proposed mechanism
In conclusion, we have developed a novel, simple and ef-
ficient method for the synthesis of diaryl/dialkyl disulfides,
that relies on a nickel-catalyzed coupling reaction.19 The
important feature of this method is the use of potassium 5-
methyl-1,3,4-oxadiazole-2-thiolate salt as the sulfurating
reagent, which is a new, inexpensive, and stable solid and
free of foul-smelling thiols. In this work NiCl2·6H2O (10
mol%) was used as an inexpensive, safe, readily available,
and more efficient catalyst. Therefore, this strategy pro-
vides a new method for the direct synthesis of symmetrical
diaryl and dialkyl disulfides from aryl/alkyl halides, which
is more economical and general than previous methods.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 911–914

914
M. Soleiman-Beigi, F. Mohammadi
Letter
Synlett
(9) Soleiman-Beigi, M.; Hemmati, M. Appl. Organomet. Chem. 2013,
27, 734.
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10.1155/2013/725265. (b) Fructuoso, B.; Fernando, R.; Belen, B.
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Synth. Commun. 2002, 32, 963.
1,3,4-oxadiazole-2-thiolate (1, 0.462 g, 3.0 mmol), NiCl2·6H2O
(10 mol%) and KOH (1.0 g, 18 mmol) were added to a flask con-
taining DMF–H2O (2 mL, 20:1) and EG (0.11 mL, 2 mmol). The
reaction mixture was heated at 130 °C under atmospheric con-
ditions until completion, monitored by TLC. The reaction
mixture was then filtered, the filtrate was evaporated under
reduced pressure, CH2Cl2 (20 mL) was added, and the mixture
was washed with H2O (2 × 15 mL). The organic layer was dried
over anhydrous Na2SO4, filtered, and the solvent was evapo-
rated to give the crude diaryl/alkyl disulfide, which was puri-
fied by preparative TLC (silica gel; n-hexane–EtOAc, 20:1).
Compound 3d was obtained as a creamy yellow solid in 75%
yield; mp 94–97 °C. 1H NMR (400 MHz, CDCl3): δ = 8.41–8.50
(m, 2 H), 7.82–7.95 (m, 4 H), 7.34–7.7 (m, 8 H). 13C NMR (100
MHz, CDCl3): δ = 134.1, 132.6, 130.3, 129.9, 128.6, 128.0, 126.8,
126.6, 125.9, 125.1. MS (EI): m/z = 318 [M+].
(13) Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S. Tetrahedron Lett.
2001, 42, 6741.
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Chem. 2013, 11, 2943.
(15) Soleiman-Beigi, M.; Mohammadi, F. Tetrahedron Lett. 2012, 53,
7028.
(16) (a) Soleiman-Beigi, M.; Arzehgar, Z.; Movassagh, B. Synthesis
2010, 392. (b) Movassagh, B.; Soleiman-Beigi, M. Synth.
Commun. 2010, 40, 3467. (c) Movassagh, B.; Soleiman-Beigi, M.
Monatsh. Chem. 2009, 140, 409.
(17) Barba, F.; Ranz, F.; Batanero, B. Tetrahedron Lett. 2009, 50, 6798.
(18) Shekhar, S.; Ryberg, P.; Hartwig, J. F.; Mathew, J. S.; Blackmond,
D. G.; Strieter, E. R.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128,
3584.
(19) Symmetrical Organic Disulfide Synthesis; Typical Experi-
mental Procedure
Compound 3f was obtained (EtOAc–n-hexane, 1:10) as a light
green solid in 89% yield; mp 54–55 °C. 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.38 (m, 2 H), 7.22–7.25 (m, 2 H), 6.97–7.00
(m, 2 H). 13C NMR (100 MHz, CDCl3): δ = 155.4, 129.7, 120.7,
115.4.
Compound 3j was obtained (EtOAc–n-hexane, 1:5) as a white
solid in 55% yield; mp 41–43 °C. 1H NMR (400 MHz, CDCl3): δ =
7.32 (d, J = 8.8 Hz, 4 H), 6.87 (d, J = 8.8 Hz, 4 H), 3.82 (s, 6 H). 13
NMR (100 MHz, CDCl3): δ = 159.0, 132.8, 127.4, 114.7, 55.4.
C
Compound 3k was obtained (EtOAc–n-hexane, 1:20) as a white
solid in 90% yield; mp 68–70 °C. 1H NMR (400 MHz, CDCl3): δ =
7.28–7.38 (m, 10 H), 3.63 (s, 4 H). 13C NMR (100 MHz, CDCl3): δ
= 137.4, 129.5, 128.5, 127.5, 43.3.
A mixture of iodobenzene (2.0 mmol), potassium 5-methyl-
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