Oxidative coupling of thiols to disulfides with Ti(IV) in the presence of NaI under air atmosphere

Article abstract of DOI:10.1002/jccs.200300118

Ti(IV) as TiCl₃(O₃SCF₃) and TiO(O ₂CCF₃)₂ are used as efficient catalysts for oxidative coupling of aliphatic, aromatic and heteroaromatic thiols to their disulfides in the presence of NaI under air atmosphere.

Full text of DOI:10.1002/jccs.200300118

Journal of the Chinese Chemical Society, 2003, 50, 849-852
849
Oxidative Coupling of Thiols to Disulfides with Ti(IV) in the Presence of
NaI under Air Atmosphere
Behzad Zeynizadeha* and Nasser Iranpoorb
aDepartment of Chemistry, Faculty of Sciences, Urmia University, Urmia 57159-165, Iran
bDepartment of Chemistry, Faculty of Sciences, Shiraz University, Shiraz 71454, Iran
Ti(IV) as TiCl3(O3SCF3) and TiO(O2CCF3)2 are used as efficient catalysts for oxidative coupling of
aliphatic, aromatic and heteroaromatic thiols to their disulfides in the presence of NaI under air atmosphere.
Keywords: Thiol; Disulfide; Oxidative coupling; Ti(IV); Sodium iodide.
INTRODUCTION
Oxidative coupling of thiols to disulfides under neutral
refluxing acetonitrile. Therefore, different aliphatic, aro-
matic and heteroaromatic thiols were reacted with these two
Ti(IV) catalysts under air atmosphere (Scheme I).
and mild conditions is an important reaction from both bio-
logical and practical points of view.1 Some of the reported re-
agents known to convert thiols to disulfides include, I2/HI,2
Br2/KHCO3,3 Br2,4 Sm/BiCl3,5 Tl(OAc)3,6 NaBO3,7 Zn(BiO3)2,8
Pb(OAc)4,9 Ba(MnO4)2,10 [Ce(NO3)3]2CrO4,11 pyridinium
chlorochromate (PCC),11 [Ce(NO3)3]3H2IO6,12 Cu(NO3)2·
N2O4,13 Fe(III)/NaI,14 KMnO4/CuSO4,15 Fe(III)16 or Ca(OCl)2/
montmorillonite,17 (PhCH2PPh3)2Cr2O7,18 30% H2O2 in fluo-
roalcohols,19 silica sulfuric acid/NaNO2,20 wet HIO3,21
HMDS/DMSO22 and MoO2Cl2(dmso)2.23 With the aim to ex-
plore new synthetic methodologies and continue our recent
work for oxidative coupling of thiols to disulfides with iodine
in wet acetonitrile,24 we now wish to report an alternative
procedure for this transformation.
Scheme I
Ti(IV) cat., NaI, CH3CN
RSH
RSSR
Air, Reflux, 45-99%
1(a-j)
2(a-j)
Entry
R groups
Entry
R groups
1a
1b
1c
1d
1e
C6H5
3-MeC6H4
4-MeC6H4
4-MeOC6H4
PhCH2
1f
n-Butyl
C2H5
1g
1h
1i
Cyclohexyl
HS(CH2)3
N
1j
S
The possibility of performing this coupling reaction
with catalytic amounts of Ti(IV) as TiCl3(O3SCF3) and
TiO(O2CCF3)2 was studied. It was observed that 0.1-0.3 mo-
lar equivalents of Ti(IV) are enough to complete the di-
merization of thiols accompanied by 2 molar equivalents of
NaI. The results obtained from the reaction of different thiols
under air atmosphere are listed in Table 1.
RESULTS AND DISCUSSION
In our investigation on some new applications of Ti(IV)
in organic synthesis,25 it was observed that TiCl4 in the pres-
ence of NaI can catalyze the coupling reaction of thiols to di-
sulfides but the yields of the reactions are low.26 In order to
overcome the low efficiency, the handling problem of TiCl4
and to increase the Lewis acidity of Ti(IV), we decided to pre-
pare two known compounds of Ti(IV) as TiCl3(O3SCF3)27 and
TiO(O2CCF3)2 28 which are both solid and stable compounds
and their handling is easy. It was also observed that these two
Ti(IV) compounds are more efficient catalysts than TiCl4 for
coupling reaction of thiols in the presence of sodium iodide in
Commercially available and functionalized aromatic
thiols 1a-d were first chosen to test our procedure. The reac-
tions were carried out under reflux condition and air atmo-
sphere, using CH3CN as a solvent. Under these conditions,
the mercaptans efficiently oxidized to the corresponding di-
sulfides (Table 1). Next we turned our attention to aliphatic
* Corresponding author. Fax: +98 441 2776707; e-mail: b.zeynizadeh@mail.urmia.ac.ir

850 J. Chin. Chem. Soc., Vol. 50, No. 4, 2003
Zeynizadeh and Iranpoor
Table 1. Catalytic Oxidative Coupling of Thiols to Disulfides with TiCl3(O3SCF3) and TiO(O2CCF3)2 in the Presence of NaI under Air
Atmospherea
TiCl3(O3SCF3)
Molar Ratio
TiO(O2CCF3)2
Molar Ratio
Mp or Bp (°C)14,18,20,23
Entry Thiol Disulfide
Time (h) Yield (%)b
Time (h) Yield (%)b
Found
Reported
Cat./NaI/Thiol
Cat./NaI/Thiol
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
1g
1h
1i
2a
2b
2c
2d
2e
2f
2g
2h
2i
0.1/2/1
0.1/2/1
0.1/2/1
0.2/2/1
0.1/2/1
0.2/2/1
0.2/2/1
0.2/2/1
0.2/2/1
0.2/2/1
0.3
1.3
1.4
2.3
4
2.5
2.2
8
95
93
94
94
93
93
94
96
45
96
0.2/2/1
0.3/2/1
0.1/2/1
0.3/2/1
0.1/2/1
0.2/2/1
0.2/2/1
0.2/2/1
----
2.5
3
3.1
10
6
5
6
10
--
24
94
95
96
93
93
94
92
94
--
59-60
45-46
45-46
43
60
45-47
45-46
43-44
72
71-72
224-226(760) 226(760)
153-154(760) 154(760)
124-129
----
8
125-130
----
182-183
9c
10
12
2
1j
2j
0.3/2/1
15
180-182
a All reactions were performed in CH3CN under reflux conditions. b Yields referred to isolated products. c The reaction was performed
between 1,3-propanedithiol (1 mmol), TiCl3(O3SCF3) (0.2 mmol) and NaI (2 mmol) in acetonitrile (100 mL) under reflux condition.
After 12 h, 1,2-dithiacyclopentane was isolated according to the procedure and identified by its spectral data.
thiols 1e-h, and these compounds could also be efficiently
oxidized to their disulfides under the mentioned conditions
for 2.2-10 hrs. The ability of this procedure for conversion of
heteroaromatic thiols was demonstrated by the oxidation of
2-benzothiazolthiol (1j) to 2,2¢-benzothiazol disulfide (2j)
by two Ti(IV) compounds in 15-96% yields.
the yields of disulfides after 3 hrs were 10-50%. (Entries 7,8).
The presence of I2 and absence of NaI with two Ti(IV) cata-
lysts in the formation of diphenyl disulfide were also studied
(Entries 5,6). After 4-5 hrs, the disulfides have 0-45% yields.
So, from the obtained results in Table 2, it can be concluded
the presence of TiCl3(O3SCF3) or TiO(O2CCF3)2 as catalyst
and NaI are necessary for completion of the reaction. The ac-
tual mechanism of the present protocol and the precise role of
Ti(IV) are not clear at this stage, but it could be proposed that
the following catalytic cycle may play a role in formation of
the disulfides (Scheme II).
In order to show the necessity of Ti(IV), the role of NaI
and air oxygen in this transformation, a set of experiments
was undertaken by performing the coupling reaction of
thiophenol under different reaction conditions (Table 2). The
reaction of thiophenol with an equimolar amount of sodium
iodide was carried out in refluxing acetonitrile. After 4 h,
unreacted starting material was recovered (Entry 9). The pos-
sibility of formation of disulfides was also examined by using
I2 or I2/NaI in refluxing acetonitrile. Under these conditions
Although oxidative coupling of thiols has been widely
studied, the reports on coupling of dithiols due to the ready
polymerization are rare.29 We studied the possibility of cou-
pling 1,3-propanedithiol (1i) with our method under high di-
Table 2. Oxidative Coupling of Thiophenol under Different Reaction Conditionsa
Entry
Reaction Components
TiCl4/NaI/thiol
Molar Ratio
Time (h)
Conversion (%)b
1
0.1/1/1
0.1/1/1
0.1/2/1
0.2/2/1
0.2/2/1
0.1/1
1/1
1/0.5/1
1/1
10
4
0.3
2.5
4
5
3
3
4
40
30
100
100
45
0
50
10
0
2
TiCl4/I2/thiol
3c
4c
5
TiCl3(O3SCF3)/NaI/thiol
TiO(O2CCF3)/NaI/thiol
TiCl3(O3SCF3) or TiO(O2CCF3)2/I2/thiol
TiCl3(O3SCF3) or TiO(O2CCF3)2/thiol
I2/thiol
6
7
8
9
NaI/I2/thiol
NaI/thiol
a All reactions were performed in CH3CN under reflux conditions. b Conversions referred to GC yields.
c When these reactions were performed in oxygen free solvent under N2 atmosphere, only 6-8% of conversion
to disulfide were observed after 3 hrs.

Coupling of Thiols with Ti(IV)/NaI/Air Atmosphere
J. Chin. Chem. Soc., Vol. 50, No. 4, 2003 851
tractive because of a new application of Ti(IV), simplicity,
general applicability and high to excellent yields of the prod-
ucts, thus making this method a useful addition to the existing
methodologies.
Scheme II
2I-
H2O
2Ti(IV)
O2
2Ti(III)
I2 + 2Ti(III)
2H+
EXPERIMENTAL SECTION
2RSH
2I-
+
RSSR
Products were characterized by comparison of their
physical data with those of authentic samples (IR, NMR, mp
or bp). All yields refer to isolated pure products. TLC accom-
plished the purity determination of the substrates, products
and reactions monitoring over silica gel PolyGram SILG/UV
254 plates. Compounds 2a, 2b, 2c, 2d, 2e, 2f, 2g, 2h, 2i and 2j
are known and their mp or bp are listed in Table 1.
.
2RSH +
lution conditions (Table 1, footnote c). Although some poly-
meric materials were formed, 1,2-dithiacyclopentane (2i)
was also obtained in 45% yield (Table 1, entry 9). In order to
see the efficiency of other Lewis acids for this catalytic trans-
formation, different metal halides such as Fe(III), Ni(II),
Cr(III), Zn(II), Al(III), Ce(III), Pb(II), Mn(II), Hg(I), Co(II),
Nb(VI), Sn(II), Cd(II), Mg(II), Zr(IV) and W(IV) were stud-
ied. In addition to Ti(IV) which was found to be very effi-
cient, Fe(III), Ni(II), Cr(III), Co(II) and Sn(II) also showed
this catalytic activity.26 For showing the advantage and limi-
tation of our method, we compared some of our results with
those reported for other reagents (Table 3).
Preparation of Diphenyl Disulfide with TiCl3(O3SCF3);
A Typical Procedure
A round bottom flask was charged with thiophenol (10
mmol, 1.1 g) (1a), acetonitrile (30 mL), NaI (20 mmol, 3 g)
and TiCl3(O3SCF3) (1 mmol, 0.303 g). The resulting mixture
was stirred under reflux condition for 18 min. After comple-
tion of the reaction, a solution of 1% aqueous sodium thio-
sulfate (30 mL) was added and the mixture was stirred for 10
min. The mixture was extracted with CH2Cl2 (3 ´ 40 mL) and
dried over anhydrous Na2SO4. The organic solution was
evaporated to dryness and the residue was chromatographed
on a short column of silica gel using n-hexane as eluent. The
pure diphenyl disulfide (2a) was obtained as colorless crys-
tals (1.03 g, 95% yield). Mp. 59-60 °C (Ref. 14, 60 °C); IR
(KBr) n/cm-1: 3051, 1572, 1475, 1435, 734, 688, 459;
The results show that the oxidative couplings of thiols
to their disulfides with Ti(IV)/NaI/air oxygen system, with
respect to the rates and efficiencies of the reactions, have
good to excellent results and between two Ti(IV) catalysts,
TiCl3(O3SCF3) is more efficient than TiO(O2CCF3)2.
In summary, we have presented a mild, catalytic and ef-
ficient method for oxidation of thiols to disulfides by Ti(IV)/
NaI/air oxygen system. The present procedure could be at-
Table 3. Comparison of Oxidative Coupling of Thiols to Their Disulfides with Ti(IV)/NaI/Air Atmosphere and some other Reported
Reagents
Molar Ratio of Reaction Components/Time (h)/Yields (%)
Entry
Thiol Disulfide
I
II
III22
IV23
V13
VI20
VII10
VIII11
(2/1)
(4)(80-90) (2)(82-92)
(2/1) (1/1)
(1.5)(95) (9)(55-60) (2)(67)
(2/1) (2/1) (1/1)
(2.5)(88) (8)(70-80) (2)(75)
(2/1) (2/1) (1/1)
(0.17)(92) (1.5)(98) (2)(85) (6)(80-85) (4)(45-50)
(0.2/1) (2/2/1) (2/1) (1/1)
(2.17)(95) (3)(99) (6)(75-80) (120)(0)
IX11,a
1
2
3
4
5
1a
1b
1e
1f
2a
2b
2e
2f
(0.1/2/1) (0.1/2/1) (1.2/3/1) (0.01/1/1) (0.2/1)
(2/2/1)
(1/1)
(1/1)
(0.3)(95) (2.5)(94) (0.75)(96) (0.3)(98) (0.17)(98) (0.75)(95) (2)(92)
(0.1/2/1) (0.3/2/1) (1.2/3/1) (0.01/1/1) (0.2/1)
(1.3)(93) (3)(95) (1.3)(90) (0.5)(96) (0.12)(98)
(0.1/2/1) (0.1/2/1) (1.2/3/1) (0.05/1/1) (0.2/1)
(4)(93) (6)(93) (1.5)(97) (6)(94)
(0.2/2/1) (0.2/2/1) (1.2/3/1)
(2.5)(93) (5)(94) (4.2)(82)
(0.2/2/1) (0.2/2/1) (1.2/3/1)
(8)(96) (10)(94) (1.6)(96)
(2/1)
----
(2/2/1)
(0.08)(96) (2)(97)
(0.2/1) (2/2/1)
----
----
1h
2h
----
I TiCl3(O3SCF3)/NaI/Thiol; II TiO(O2CCF3)2/NaI/Thiol; III HMDS/DMSO/Thiol; IV MoO2Cl2(dmso)2/DMSO/Thiol; V Cu(NO3)2.3H2O;
VI Silica sulfuric acid/NaNO2/Thiol; VII Ba(MnO4)2; VIII [Ce(NO3)3]2CrO4/Thiol; IX PCC/Thiol; a Time as minutes.

852 J. Chin. Chem. Soc., Vol. 50, No. 4, 2003
Zeynizadeh and Iranpoor
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ACKNOWLEDGEMENT
We are grateful to Urmia and Shiraz Universities Re-
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