Iron(III)-Catalyzed Radical Cross-Coupling of Thiols with Sodium Sulfinates: A Facile Access to Thiosulfonates

Article abstract of DOI:10.1055/s-0035-1562101

A convenient and efficient synthesis of symmetrical and asymmetric thiosulfonates from thiols and sodium sulfinates is reported. The protocol involves iron(III)-catalyzed formation of sulfenyl and sulfonyl radicals in situ under aerobic conditions and their subsequent cross-coupling to afford thiosulfonates in 83-96% yield. The utilization of readily available, nontoxic, and inexpensive iron(III) as a catalyst and atmospheric oxygen as an oxidant is within the confines of green and sustainable chemistry.

Full text of DOI:10.1055/s-0035-1562101

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–E
letter
A
T. Keshari et al.
Letter
Synlett
Iron(III)-Catalyzed Radical Cross-Coupling of Thiols with Sodium
Sulfinates: A Facile Access to Thiosulfonates
Twinkle Keshari
Ritu Kapoorr
Lal Dhar S. Yadav*
Green Synthesis Lab, Department of Chemistry, University
of Allahabad, Allahabad 211 002, India
twinkle31081989@hotmail.com
ritukapoorr@yahoo.in
ldsyadav@hotmail.com
Received: 03.12.2015
Accepted after revision: 30.03.2016
Published online: 09.05.2016
greater stability and greater ease of handling compared
with sulfenyl chlorides and their stronger sulfenylating
power compared with disulfides, thiosulfonates have been
used extensively as sulfenylating reagents in organic syn-
thesis.9 Thiosulfonates have also found a wide range of in-
dustrial applications in polymer production and in photo-
graphic processes.8
DOI: 10.1055/s-0035-1562101; Art ID: st-2015-b0938-l
Abstract A convenient and efficient synthesis of symmetrical and
asymmetric thiosulfonates from thiols and sodium sulfinates is report-
ed. The protocol involves iron(III)-catalyzed formation of sulfenyl and
sulfonyl radicals in situ under aerobic conditions and their subsequent
cross-coupling to afford thiosulfonates in 83–96% yield. The utilization
of readily available, nontoxic, and inexpensive iron(III) as a catalyst and
atmospheric oxygen as an oxidant is within the confines of green and
sustainable chemistry.
Many methods for the synthesis of thiosulfonates have
been reported in the literature.10,11 Most of these transfor-
mations involve the direct oxidation of disulfides or thiols
to afford symmetrical thiosulfonates.12 These methods of-
ten require an excess of the oxidant, and they are not suit-
able for the synthesis of asymmetric thiosulfonates, as they
give mixtures of isomeric products in such cases. The syn-
thesis of asymmetrical thiosulfonates generally involves
formation of an S–S bond by sulfenylation of a sulfinic acid
or a sulfenic acid derivative.13–16 Alternatively, thiosulfon-
ates can be obtained by thiosulfonate exchange reactions of
sulfenamides,17 by the reduction of sulfonyl chlorides,18 by
oxidation of thiosulfinates,19 by the reaction of potassium
thiosulfonates with diaryliodonium salts,20 or by sponta-
neous desulfurization of sulfenic sulfonic thioanhydrides.21
However, these methods are limited because they demand
toxic and unstable sulfenylating reagents and/or require
cautious handling.
The literature records only a few methods that are ap-
plicable to the synthesis of either symmetric or asymmetric
thiosulfonates.15a,b,22 Two of these methods start from either
disulfides15a or N-(organolithio)succinimides,15b rather than
from thiols,22 and they require an additional step. A recent-
ly reported method starts from thiols and utilizes CuI with
1,10-phenanthroline as a ligand and water as a catalyst, but
it requires ten equivalents (with respect to the catalyst) of
NH4BF4 as an additive, which makes the method less eco-
nomical.22
Key words sulfonates, thiols, thiosulfonates, iron, catalysis, oxidation
Free-radical chemistry has played a crucial role in shap-
ing modern organic synthesis, including polymer synthe-
sis.1,2 Free-radical reactions generally require demanding
conditions, such as an inert atmosphere and anhydrous de-
gassed solvents, which make such reactions less economi-
cal and contrary to the requirements of green chemistry.
Consequently, any research directed to overcoming this sit-
uation would be warmly welcomed. One way of working
within the boundaries of green and sustainable chemistry
involves the use of inexpensive, readily available, and non-
toxic aerial dioxygen in synthetically useful free-radical re-
actions.3,4 There are numerous reports in the literature on
the activation of molecular oxygen by employing various
transition metals.5
The broad spectrum of biological activities and the wide
range of synthetic and industrial uses of thiosulfonates have
led to their identification as interesting organosulfur com-
pounds.6–9 Thiosulfonates exhibit antimicrobial and fungi-
cidal activities; their mode of action involves the blocking
the normal metabolism of the microorganism through
sulfenylation of thiol groups in enzymes.6 Because of their
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

B
T. Keshari et al.
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After a careful consideration of these points, and as part
of our continuing efforts to develop synthetically useful
radical reactions,23 we hypothesized that an iron(III)-cata-
lyzed radical cross-coupling of thiols with sodium sulfi-
nates under aerobic conditions might be a convenient and
economical method for preparing symmetric and asym-
metric thiosulfonates (Scheme 1).
Next, we assessed the reaction in the presence of vari-
ous transition-metal catalysts [CuI, ZnCl2, CuBr, CuCl2,
Mn(OAc)2, and FeCl3] in DMF, and we found that FeCl3 was
the best catalyst at r.t. in terms of yield and reaction time
(Table 2, entries 1–6). The variation in the efficiency of the
transition-metal catalysts might be attributable to their
various oxidizing powers under the present reaction condi-
tions. Moreover, the order of catalytic efficiency of CuI,
CuBr, and CuCl2 agreed with that reported by Taniguchi.22
When the loading of the catalyst was reduced from 20 mol%
to 15 mol%, the yield fell to 76% (entries 6 and 7). Note that
no thiosulfonate 3a was obtained in the absence of FeCl3
under air, even at a higher temperatures; instead, the disul-
fide was produced in 86% yield (entry 8).
R
FeCl3 (20 mol%)
S
R
SH
R1 SO2Na
R1
S
O
3
O
air, DMF, r.t., 30–60 min
1
2
Scheme 1 Oxidative sulfonylation of thiols
To realize our hypothesis and to optimize the reaction
conditions, we chose benzenethiol (1a) and sodium 4-tol-
uenesulfinate (2a) as model coupling partners, and their re-
action was conducted in DMF at r.t. in the presence of FeCl3
as a catalyst under an atmosphere of air (Table 1). Interest-
ingly, the reaction delivered the desired product S-phenyl
4-toluenethiosulfonate (3a) in an excellent yield of 96%.
Next, we probed the reaction in various solvents, and
we found that DMF was the best solvent, whereas CH2Cl2,
THF, MeCN, 1,4-dioxane, and DMSO were not suitable (Ta-
ble 1, entry 1 versus entries 2–6). Complete conversion of
benzenethiol (1a) into the thiosulfonate 3a in high yield
was observed in DMF (Table 1, entry 1). No byproduct was
obtained during the reaction, indicating that the reaction
has excellent chemoselectivity. When the reaction was car-
ried out in DMSO, the major product was the disulfide in-
stead of the thiosulfonate (entry 5).
Table 2 Oxidation of Benzenethiol with Iron(III) Chloride in the Pres-
ence of Various Catalysts at Room Temperaturea
SO2Na
SH
O
S
S
O
FeCl3 (20 mol%)
DMF, air (O2), r.t., 40 min
3a
2a
1a
Entry
Catalyst (mol%)
Time
Yield (%)b
1
2
3
4
5
6
7
8
CuI (20)
1 h
1 h
0
0
ZnCl2 (20)
CuBr (20)
CuCl2 (20)
Mn(OAc)2 (20)
FeCl3 (20)
FeCl3 (15)
–
1 h
32
49
42
96
76
0c
1 h
1 h
40 min
4 h
Table 1 Oxidation of Benzenethiol with Iron(III) Chloride in Various
1 h
Solvents at Room Temperaturea
a Reaction conditions: PhSH (1a; 0.5 mmol), 4-TolSO2Na (2; 1 mmol), cata-
lyst (20 mol%), DMF (3 mL), stirring, r.t., air.
SO2Na
SH
O
S
b Isolated yield of pure product.
FeCl3 (20 mol%)
c PhSSPh was produced in 86% yield at 80 °C.
S
O
DMF, air (O2), r.t., 40 min
Furthermore, only traces of product 3a were obtained
under a nitrogen atmosphere, which emphasizes the need
to perform the reaction under air (Scheme 2).
1a
2a
3a
Entry
Solvent
Time
40 min
Yieldb (%)
PhSH
FeCl3 (20 mol%)
1
2
3
4
5
6
DMF
96
0
(1 equiv)
PhS-SO2-4-MeC6H4
DMF, r.t., 45 min
THF
1 h
1 h
1 h
1 h
1 h
under N2
in traces
4-MeC6H4SO2Na
(2 equiv)
MeCN
1,4-dioxane
DMSO
CH2Cl2
0
0
Scheme 2 Reaction conducted in the absence of air
5c
0
The reaction also gave a 94% yield of S-phenyl 4-toluene-
thiosulfonate (3a) when diphenyl disulfide was used in-
stead of benzenethiol (Scheme 3).
a Reaction conditions: PhSH (1; 0.5 mmol), 4-TolSO2Na (2; 1 mmol), FeCl3
(20 mol%), solvent (3 mL), stirring, r.t., air atmosphere.
b Isolated yield of pure product 3a.
c PhSSPh was produced in 86% yield
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

C
T. Keshari et al.
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Table 3 Substrate Scope for the Synthesis of Thiosulfonatesa
SO2Na
O
S
S
O
FeCl3 (20 mol%)
R
S
FeCl3 (20 mol%)
S
DMF, air, r.t., 40 min
S
R
SH
R1 SO2Na
R1
S
O
3
O
air, DMF, r.t., 30–60 min
2a
3a
1
2
Scheme 3 Reaction with diphenyl disulfide
Entry
R
R1
Time
(min)
Yieldb,c
(%)
Next, we examined the effect of the ratio of the coupling
partners benzenethiol (1a) and sodium 4-toluenesulfinate
(2a). When the ratio of 1a to 2a was varied from 1:2 to 1:1
(equivalents), the yield of the desired product 3a decreased
considerably due to oxidation of benzenethiol (1a) to di-
phenyl disulfide in the presence of FeCl3. This demonstrates
that two equivalents of sodium thiosulfinate is the optimal
amount for complete conversion of thiols into thiosulfon-
ates. Moreover, the reaction was quenched by the radical
scavengers TEMPO and 2,2-diphenyl-1-picrylhydrazyl
(DPPH), indicating that it involves a radical intermediate
(Scheme 4).
1
2
Ph
4-MeC6H4
4-MeC6H4
4-FC6H4
40
40
45
30
50
45
50
60
40
60
40
40
30
96
89
92
95
90
92
94
91
89
93
83
85
88
4-MeC6H4
4-FC6H4
4-FC6H4
3
4
4-MeC6H4
4-MeC6H4
4-HOC6H4
4-ClC6H4
4-ClC6H4
2-pyridyl
1,3-benzoxazol-2-yl
s-Bu
5
3-O2NC6H4
4-HOC6H4
4-ClC6H4
4-O2NC6H4
2-pyridyl
1,3-benzoxazol-2-yl
s-Bu
6
7
8
9
10
11
12
13
PhSH
standard reaction conditions
TEMPO or DPPH (4 equiv)
(1 equiv)
PhS-SO2-4-MeC6H4
10%
Bu
Bu
Cy
Cy
4-MeC6H4SO2Na
(2 equiv)
a Reaction conditions: thiol 1 (0.5 mmol), sodium sulfinate 2 (1 mmol), FeCl3
(20 mol%), DMF (3 mL), stirring, r.t., air atmosphere.
b Isolated yield after flash chromatography.
Scheme 4 Evidence in support of the involvement of a radical interme-
diate
c All products 3 are known and were characterized by comparison of their
spectral data with those reported in the literature.22,24–27
With the optimized conditions in hand, various combi-
nations of the thiols and sodium sulfinates were surveyed
(Table 3).28 The reaction of benzenethiols 1 substituted
with electron-donating or electron-withdrawing groups
proceeded well and gave the corresponding thiosulfonates
3 in excellent yields (Table 3, entries 2–8). These results in-
dicate that an existing group on the aromatic ring has no
obvious effect on the yield of the reaction products. The re-
actions of the heterocyclic thiols pyridine-2-thiol and 1,3-
benzoxazole-2-thiol also delivered the desired products in
excellent yields (entries 9 and 10). The method also worked
well for the selective oxidation of aliphatic and cycloal-
iphatic thiols to the corresponding thiosulfonates (entries
11–13).
In summary, we have developed a convenient and cost-
effective one-pot method for the synthesis of a variety of
symmetrical and asymmetric thiosulfonates by a radical
cross-coupling of aryl, hetaryl, alkyl, or cycloaliphatic thiols
O
S
R1SH
R2
2
Fe3+
Fe2+
O
O2
1
O2
O2
O2
R1
O
S
O
S
R2
SH
R1S
R2
O
H+
4
O
5
III
II
On the basis of our investigations and precedents in the
literature,3f,h we propose the plausible reaction pathway for
the formation of thiosulfonates 3 that is shown in Scheme
5. Sulfinate anion 1 undergoes single-electron transfer with
dioxygen to form an oxygen-centered radical II, which reso-
nates with the sulfonyl radical III.3f Similarly, the thiol 2 un-
dergoes Fe3+-catalyzed oxidation to form the thiyl radical 5.
Cross-coupling of radicals III and 5 affords the desired thio-
sulfonate 3.
radical cross-coupling
R1
S
O
S
R2
O
3
Scheme 5 A plausible reaction pathway for the formation of thiosul-
fonate 3
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E

D
T. Keshari et al.
Letter
Synlett
with sodium sulfinates. The protocol efficiently uses Fe(III)
as an inexpensive and green catalyst to induce a radical
process, and it offers many desirable features, such as utili-
zation of air (O2) as a sustainable oxidant, room-tempera-
ture reaction, operational simplicity, short reaction times,
and high yields.
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Acknowledgment
We sincerely thank SAIF, Punjab University, Chandigarh, for providing
microanalyses and spectra. T.K. is grateful to the CSIR, New Delhi, for
the award of
a
senior research fellowship (File No.
09/001(0370)/2012-EMR-1), and R.K. is grateful to the Department of
Science and Technology (DST), New Delhi, for the award of a SERB-
Young Scientist position and for financial assistance (Registration No:
CS-271/2014)
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Srivastava, V. P.; Yadav, L. D. S. Tetrahedron Lett. 2015, 56, 2892.
(d) Tripathi, S.; Singh, S. N.; Yadav, L. D. S. Tetrahedron Lett. 2015,
56, 4211.
(24) (a) Iranpoor, N.; Firouzabadi, H.; Pourali, A.-R. Phosphorus,
Sulfur Silicon Relat. Elem. 2006, 181, 473. (b) Kim, Y. H.;
Shinhama, K.; Fukushima, D.; Oae, S. Tetrahedron Lett. 1978, 19,
1211.
(25) Meyers, C. Y.; Chan-Yu-King, R.; Hua, D. H.; Kolb, V. M.;
Matthews, W. S.; Parady, T. E.; Horii, T.; Sandrock, P. B.; Hou, Y.;
Xie, S. J. Org. Chem. 2003, 68, 500.
column chromatography using a gradient mixture of hexane
and EtOAc as eluent.
S-Phenyl 4-Toluenethiosulfonate (Table 3, Entry 1)
Colorless solid; yield: 126 mg (96%); mp 74–75 °C. IR (KBr):
1130, 1315 (SO2) cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 2.40
(s, 3 H) 7.31 (t, 2 H, J = 6.8 Hz), 7.34 (t, 2 H, J = 6.8 Hz), 7.40–7.44
(m, 2 H), 7.58 (d, 2 H, J = 8.4 Hz), 7.48 (d, 1 H, J = 8.8 Hz).
13C NMR (100 MHz, CDCl3, TMS): δ = 28.3, 127.4, 127.9, 128.8,
129.3, 131.5, 133.5, 136.6, 143.0. EIMS: m/z = 264 [M+]. Anal.
Calcd for C13H12O2S2: C, 59.06; H, 4.58. Found: C, 59.28; H, 4.45.
S-(4-Fluorophenyl) 4-Fluorobenzenethiosulfonate (Table 3,
Entry 3)
Colorless crystal; yield: 132 mg (92%); mp 68–70 °C. IR (KBr):
1229, 1330 (SO2) cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 7.10
(d, 2 H, J = 8.4 Hz), 7.16 (t, 2 H, J = 8.4 Hz), 7.35 (dd, 2 H, J = 5.2
Hz, J = 9.0 Hz), 7.63 (dd, 2 H, J = 4.8 Hz, J = 9.6 Hz). 13C NMR (100
MHz, CDCl3, TMS): δ = 116.4, 117.0, 123.2, 123.7, 130.1, 138.7,
163.9, 166.1. EIMS: m/z = 286 [M+]. Anal. Calcd for C12H8F2O2S2:
C, 50.34; H, 2.82. Found: C, 50.54; H, 2.76.
S-(3-Nitrophenyl) 4-Toluenethiosulfonate (Table 3, Entry 5)
Colorless crystal; yield: 139 mg (90%); mp 97–99 °C. IR (KBr):
1140, 1331 (SO2) cm–1
.
1H NMR (400 MHz, CDCl3, TMS): δ = 2.39 (s, 3 H), 7.24–7.28 (m,
2 H), 7.40–7.49 (m, 2 H), 7.64 (t, J = 8.0 Hz, 1 H), 7.83–7.86 (m, 1
H), 8.02 (s, 1 H), 8.32–8.39 (m, 1 H).
13C NMR (100 MHz, CDCl3, TMS): δ = 21.2, 125.6, 127.4, 129.8,
130.4, 130.5, 131.0, 139.5, 142.0, 145.7, 148.3. EIMS: m/z = 309
[M+]. Anal. Calcd for C13H11NO4S2: C, 50.47; H, 3.38; N, 4.53.
Found: C, 50.26; H, 3.49; N, 4.80.
(26) Kutsyuba, T. S.; Granchak, V. M.; Dilung, I. I. Theor. Exp. Chem.
(Engl. Transl.) 1997, 33, 26.
(27) Totani, I.; Okada, H. JP H0943760, 1997; Chem. Abstr. 1997, 126,
270336.
S-(4-Chlorophenyl) 4-Chlorobenzenethiosulfonate (Table 3,
Entry 7)
(28) Thiosulfonates 3; General Procedure
Colorless crystal; yield: 149 mg (94%); mp 134–136 °C. IR (KBr):
1140, 1330 (SO2) cm–1. 1H NMR (400 MHz, CDCl3, TMS): δ = 7.35
(d, 2 H, J = 8.4 Hz), 7.39 (d, 2 H, J = 8.8 Hz), 7.46 (d, 2 H, J = 9.2
Hz), 7.52 (d, 2 H, J = 8.8 Hz). 13C NMR (100 MHz, CDCl3, TMS):
δ = 128.8, 129.3, 130.0, 130.4, 137.7, 138.5, 140.5, 141.2. EIMS:
m/z = 318 [M+], 320 [M + 2]+, 322 [M + 4]+. Anal. Calcd for C12H8-
Cl2O2S2: C, 45.15; H, 2.53. Found: C, 45.00; H, 2.75.
A mixture of the appropriate thiol 1 (0.5 mmol), sodium thio-
sulfinate 2 (1.0 mmol), and FeCl3 (20 mol%) in DMF (3 mL) was
stirred at r.t. for 30–60 min under air in a round-bottomed flask.
When the reaction was complete (TLC), H2O (5 mL) was added
and the mixture was extracted with EtOAc (3 × 5 mL). The com-
bined organic phases were dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–E