Copper-catalyzed synthesis of thiosulfonates by oxidative coupling of thiols with sodium sulfinates

Article abstract of DOI:10.1002/ejoc.201402847

The copper-catalyzed sulfonylation of thiols was performed by using sodium sulfinates under an oxygen atmosphere. The procedure afforded thiosulfonates in good yields by using a CuI-Phen?H₂O (Phen = 1,10-phenanthroline) catalyst and tolerated numerous combinations of arene- and alkanethiols with sodium sulfinates. Furthermore, it was found that the coupling of diaryl disulfides with sodium arylsulfinates proceeded in air and both sulfide groups on the disulfide were available.

Full text of DOI:10.1002/ejoc.201402847

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402847
Copper-Catalyzed Synthesis of Thiosulfonates by Oxidative Coupling of Thiols
with Sodium Sulfinates
Nobukazu Taniguchi*[a]
Keywords: Synthetic methods / Oxidative coupling / Sulfur / Thiols / Sulfinates / Copper
The copper-catalyzed sulfonylation of thiols was performed
by using sodium sulfinates under an oxygen atmosphere.
The procedure afforded thiosulfonates in good yields by
using a CuI–Phen·H2O (Phen = 1,10-phenanthroline) catalyst
and tolerated numerous combinations of arene- and alka-
nethiols with sodium sulfinates. Furthermore, it was found
that the coupling of diaryl disulfides with sodium arylsulfin-
ates proceeded in air and both sulfide groups on the disulfide
were available.
Introduction
The development of organosulfur synthetic methodology
is an important field in organic chemistry, and various reac-
tions have been reported to date.[1] In particular, the transi-
tion-metal-catalyzed formation of carbon–sulfur bonds has
been well investigated.[2] The obtained compounds have
found widespread utilization as useful intermediates and
reagents.[3] In contrast, research on the useful construction
of sulfur–heteroatom bonds has been very restricted to date.
Similarly, the transition-metal-catalyzed synthesis of thios-
ulfonates with sulfur–sulfone bonds has been scarcely inves-
tigated, and these compounds have been prepared by tradi-
tional methods. However, they are convenient derivatives
that can be used in sulfenylation reactions that have been Figure 1. A general preparation of thiosulfonates.
employed for the formation of unsymmetrical disulfides, in-
cluding the immobilization of enzymes.[4,5a] Regrettably, an
efficient synthetic procedure has not been exploited yet.
As shown in Figure 1, thiosulfonates have been generally
In general, reaction performed with the use of thiols can-
prepared by oxidation of disulfides[5] or through sulfe-
nylation of sulfinic acid salts by using sulfenyl halides.[6]
The reaction of disulfides with sodium sulfinates has also
been performed in the presence of Lewis acids.[7,8] These
reactions often require the use of excess amounts of oxi-
dants. Unfortunately, the coupling of thiols with sulfonyl
chlorides has not yet been reported owing to the rapid for-
mation of disulfides from thiols with thiosulfonates.
not be controlled completely. Exploitation of a simple
method with the use of thiols is accordingly desired. To
achieve this, suppression or treatment of the disulfides pro-
duced from thiosulfinates with thiols becomes the impor-
tant process.
As an approach to solve this problem, it is considered
that the employment of transition-metal catalysts is appro-
priate, because transition metals have the ability to cleave
disulfide bonds.[9] For instance, it is well known that the
copper-catalyzed sulfenylation of various compounds can
be performed under oxidative conditions.[10,11] This shows
that the copper-catalyzed procedure is never affected by the
generation of disulfides, and therefore, disulfides can be uti-
lized (Figure 2).
[a] Department of Chemistry, Fukushima Medical University,
Fukushima 960-1295, Japan
E-mail: taniguti@fmu.ac.jp
http://www.fmu.ac.jp/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402847.
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N. Taniguchi
SHORT COMMUNICATION
96% yield (Table 1, entry 8). Regrettably, other additives
(NH4PF6 and Cs2CO3), solvents, and copper catalysts did
not adequately promote the reaction (Table 1, entries 9–15).
Thus, it became apparent that the copper-catalyzed cou-
pling of thiols with sodium sulfinates gave excellent results
under an oxygen atmosphere.
On the basis of the established results, various combina-
tions of thiols with sodium sulfinates were surveyed. A mix-
ture of thiol 1 (0.3 mmol), sodium sulfinate 2 (0.36 mmol),
NH4BF4 (0.15 mmol), and CuI–Phen·H2O (1:1, 5 mmol) in
DMA (0.3 mL) and water (0.1 mL) was stirred at 30 °C un-
der an oxygen atmosphere. As shown in Table 2, this pro-
cedure afforded the expected thiosulfonates in 41–96%
yields (Table 2, entries 1–17), and it also tolerated numerous
combinations of arenethiols with sodium sulfinates. How-
ever, the reaction performed with the use of 2-pyridinethiol
(2-PySH) did not proceed well (Table 2, entry 18). In the
sulfonylation reaction, not only arenethiols but also alka-
nethiols could be used. However, it was necessary to use
10 mol-% of the CuI–Phen·H2O catalyst and to prolong the
reaction time owing to the stability of alkanethiolate–cop-
per complexes (Table 2, entries 19 and 20).
To determine the reaction mechanism, some experiments
were next screened. Upon performing the reaction in the
absence of oxygen, the expected thiosulfonate was produced
in 2% yield (Scheme 1). This result supports the fact that
the coupling of thiols with sodium sulfinates requires the
presence of oxygen.
The reactivity of the phenylthiolate(I)–copper com-
plex,[12] which was considered to be the intermediate, was
also researched (Scheme 2). This reaction gave the corre-
sponding product in 49% yield. It is clear that oxidation of
thiolate–copper complexes promotes the synthesis of thios-
ulfonates.
Figure 2. Strategy for the synthesis of thiosulfonate from thiols
with sodium sulfinates.
Therefore, the copper-catalyzed oxidative coupling of thi-
ols with sodium sulfinates was investigated. It was found
that the procedure could produce the desired thiosulfonates
in excellent yields. In this paper, the methodology will be
described.
Results and Discussion
The evaluation of copper catalysts and ligands was com-
menced by using 4-toluenethiol (1a) and sodium 4-tolylsulf-
inate (2a) as starting materials (Table 1). Upon performing
the reaction in the absence of the CuI catalyst at 30 °C in
air, corresponding thiosulfonate 3aa was not obtained at all
and the disulfide was produced in 81% yield (Table 1, en-
try 1). Similarly, the CuI catalyst itself could not promote
the reaction (Table 1, entry 2). By examining the amine li-
gands, reactions performed by using N,N,NЈЈ,NЈЈ-tet-
ramethyl-1,2-ethylenediamine (TMEDA), bpy (bipyridyl),
and Phen·H2O (1,10-phenanthroline·H2O) provided the
product in about 10% yield (Table 1, entries 3–5). However,
upon adding water and NH4BF4 to improve the cationic
nature of the copper catalyst, the yield of 3aa increased to
43 and 59% yield, respectively (Table 1, entries 6 and 7).
Fortunately, the reaction that was performed under an oxy-
gen atmosphere proceeded satisfactorily and gave 3aa in
Table 1. Investigation of suitable conditions.
Entry
[Cu]
Solvent [mL][a]
Additive
Conditions
Yield 3aa [%][b]
1
2
3
4
5
6
7
8
none
CuI
CuI–TMEDA
CuI–bpy
DMA (0.3)
DMA (0.3)
DMA (0.3)
DMA (0.3)
none
none
none
none
none
none
NH4BF4
NH4BF4
NH4PF6
NH4BF4
NH4BF4
NH4BF4
NH4BF4
NH4BF4
NH4BF4
air
air
air
air
air
air
air
O2
O2
O2
O2
O2
O2
O2
O2
0
0
9
12
10
43
59
96
71
65
43
43
49
54
69
CuI–Phen·H2O
CuI–Phen·H2O
CuI–Phen·H2O
CuI–Phen·H2O
CuI–Phen·H2O
CuI–Phen·H2O
CuCl–Phen·H2O
CuBr–Phen·H2O
CuCl2–Phen·H2O
CuBr2–Phen·H2O
Cu(OAc)2–Phen·H2O
DMA (0.3)
DMA/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
DMF/H2O (0.3:0.1)
DMSO/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
DMA/H2O (0.3:0.1)
9
10
11
12
13
14
15
[a] DMA = dimethylacetamide.[a] Yield of isolated product after silica gel chromatography.
2
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Synthesis of Thiosulfonates by Oxidative Coupling
Table 2. Copper-catalyzed sulfonylation of thiols.[a]
Entry R1
R2
3 [%][b]
1
2
3
4
5
6
7
8
C6H5SH
4-MeC6H4SO2Na
C6H5SO2Na
85
85
96
81
4-MeC6H4SH
4-MeC6H4SH
4-MeC6H4SH
4-MeC6H4SH
4-MeC6H4SH
4-MeC6H4SH
4-MeC6H4SH
4-MeOC6H4SH
4-ClC6H4SH
4-BrC6H4SH
4-HOC6H4SH
4-H2NC6H4SH
2-MeC6H4SH
2-MeOC6H4SH
2-BrC6H4SH
2-naphthylSH
2-PySH
4-MeC6H4SO2Na
4-MeOC6H4SO2Na
4-AcHNC6H4SO2Na
4-ClC6H4SO2Na
4-FC6H4SO2Na
MeSO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
4-MeC6H4SO2Na
62
Figure 3. A plausible reaction mechanism.
76[c]
72[d]
87
From the described plausible mechanism, it was believed
that the coupling of disulfides with sodium sulfinates could
be performed. To date, an excess amount of the iodine oxi-
dant was necessary for the reaction. To solve this problem,
attention was focused on the coupling of disulfides with
sodium sulfinates. Notably, the reaction could be performed
at 30 °C in air, and the expected thiosulfonates were ob-
tained in excellent yields. Furthermore, both sulfide groups
of the disulfide were available to the reaction (Scheme 3).
Further investigation into the exact details of the conditions
and the mechanism are now in progress.
9
90
80
10
11
12
13
14
15
16
17
18
19
20
73
41[c]
42[c]
82
70
69
73
trace
68[c,e]
40[c,e]
nBuSH
iPrSH
[a] Reaction conditions: A mixture of thiol 1 (0.3 mmol), sodium
sulfinate 2 (0.36 mmol), NH4BF4 (0.15 mmol), and CuI–Phen·H2O
(1:1, 5 mol-%) in DMA (0.3 mL) and water (0.1 mL) at 30 °C under
an oxygen atmosphere. [b] Yield of isolated product after silica gel
chromatography. [c] 36 h. [d] 24 h. [e] The reaction was performed
by using CuI–Phen·H2O (1:1, 10 mol-%).
Scheme 3. Sulfonylation of disulfides.
Conclusions
In conclusion, the copper-catalyzed coupling of thiols
with sodium sulfinates was achieved under an oxygen atmo-
sphere. The procedure could be used to synthesize various
thiosulfonates in good yields. The coupling of disulfides
with sodium sulfinates also proceeded in air, and the two
sulfide groups on the disulfides were available.
Scheme 1. Reaction in the absence of oxygen.
Scheme 2. Reactivity of the copper–phenylthiolate complex.
Experimental Section
General Method: CuI (2.9 mg, 0.015 mmol) and Phen·H2O (3.0 mg,
0.015 mmol) were added to a mixture of benzenethiol (33.1 mg,
0.3 mmol), sodium 4-tolylsulfinate (64.1 mg, 0.36 mmol), and
NH4BF4 (15.7 mg, 0.15 mmol) in DMA (0.3 mL) and H2O
(0.1 mL), and the mixture was stirred at 30 °C for 18 h under an
oxygen atmosphere. After the residue was dissolved in Et2O, the
solution was washed with H2O and saturated sodium chloride and
dried with anhydrous magnesium sulfate. Chromatography on silica
From these investigations, a plausible reaction mecha-
nism is considered as follows (Figure 3). In cycle A, thio-
late–copper(I) complex 9 is formed from copper iodide and
the thiol or sodium sulfinate. Oxidation of 9 gives CuII
complex 10; and R1S(R2SO2)CuIILn 11 is produced by
transmetalation. Finally, thiosulfonate is produced by re-
ductive elimination and CuIX is regenerated.[11a] In cycle B,
after the formation of the disulfide by the oxidation of the gel (30% diethyl ether/hexane) gave PhS-SO2-4-MeC6H4 (67.5 mg,
thiol, reaction of CuIX with the disulfide and sodium sulf-
85%).
inate affords complex 12. Reductive elimination of 12 pro-
duces thiosulfinate and 9. Consequently, the oxidation of 9
affords 10, and 11 is reproduced.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, analytical data. and copies of the 1H
NMR and 13C NMR spectra.
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N. Taniguchi
SHORT COMMUNICATION
[6]
a) S. Oae, T. Takata, Y. H. Kim, Bull. Chem. Soc. Jpn. 1982,
55, 2484–2494; b) S. Oae, T. Tanaka, Y. H. Kim, Tetrahedron
1981, 37, 37–44; c) K. Fujiki, N. Tanifuji, Y. Sasaki, T. Yokoy-
ama, Synthesis 2002, 343–348; d) M.-L. Alcaraz, S. Atkinson,
P. Cornwall, A. C. Foster, D. M. Gill, L. A. Humphries, P. S.
Keegan, R. Kemp, E. Merifield, R. A. Nixon, A. J. Noble, D.
O’Beirne, Z. M. Patel, J. Perkins, P. Rowan, P. Sadler, J. T. Sin-
gleton, J. Tornos, A. J. Watts, I. A. Woodland, Org. Process
Res. Dev. 2005, 9, 555–569.
[1] a) B. M. Trost, I. Fleming (Eds.), Comprehensive Organic Syn-
thesis, Pergamon, New York, 1991, vol. 4; b) F. A. Davis, J.
Org. Chem. 2006, 71, 8993–9003.
[2] a) A. Krief, Comprehensive Organometallic Chemistry II (Eds.:
E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon, New
York, 1995, vol. 11, chapter 13; b) A. de Meijere, F. Diederich
(Eds.), Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH,
Weinheim, Germany, 2004; c) S. V. Ley, A. W. Thomas, Angew.
Chem. Int. Ed. 2003, 42, 5400–5449; Angew. Chem. 2003, 115,
5558–5607; d) T. Kondo, T. Mitsudo, Chem. Rev. 2000, 100,
3205–3220; e) I. P. Beletskaya, V. P. Ananikov, Chem. Rev. 2011,
111, 1596–1636; f) D. V. Partyka, Chem. Rev. 2011, 111, 1529–
1595.
[7]
[8]
[9]
a) E. Block, J. O’Connor, J. Am. Chem. Soc. 1974, 96, 3921–
3929; b) M. D. Bently, I. B. Douglass, J. A. Lacadie, J. Org.
Chem. 1972, 37, 333–334.
a) G. Liang, J. Chen, W. Li, J. Chen, H. Wu, Tetrahedron Lett.
2012, 53, 6768–6770; b) G. Liang, M. Liu, J. Chen, J. Ding, W.
Gao, H. Wu, Chin. J. Chem. 2012, 30, 1611–1616.
a) A. Bewick, J. M. Mellor, D. Milano, W. M. Owton, J. Chem.
Soc. Perkin Trans. 1 1985, 1045–1048; b) R. D. Bach, S. J. Ra-
jan, H. B. Vardhan, T. J. Lang, N. G. Albrecht, J. Am. Chem.
Soc. 1981, 103, 7727–7734; c) A. Ichimura, D. L. Nosco, E.
Deutsch, J. Am. Chem. Soc. 1983, 105, 844–850.
[3] P. Metzner, A. Thuillier, Sulfur Reagents in: Organic Synthesis
(Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees), Academic,
San Diego, USA, 1994.
[4] a) K. Sugata, L. Song, M. Nakamura, S. Ueki, P. G. Fajer, T.
Arata, J. Mol. Biol. 2009, 386, 626–636; b) B. Tiebel, N.
Radzwill, L. M. Aung-Hilbrich, V. Helbl, H.-J. Steinhoff, W.
Hillen, J. Mol. Biol. 1999, 290, 229–240.
[10] S. E. Allen, R. R. Walvoord, R. Padilla-Salinas, M. C. Kozlow-
[5] a) L. Field, T. F. Parsons, J. Org. Chem. 1965, 30, 657–659; b)
ski, Chem. Rev. 2013, 113, 6234–6458.
M. M. Chau, J. L. Kice, J. Am. Chem. Soc. 1976, 98, 7711– [11] a) N. Taniguchi, J. Org. Chem. 2007, 72, 1241–1245; b) N. Tani-
7716; c) M.-T. Cai, G.-S. Lv, J.-X. Chen, W.-X. Gao, J.-C. Ding,
H.-Y. Wu, Chem. Lett. 2010, 39, 368–369; d) N. Iranpoor, H.
Firouzabadi, A.-R. Pourali, Synlett 2004, 347–349; e) M. Kiri-
yama, S. Narito, Y. Ishizuka, H. Hanai, T. Noguchi, Tetrahe-
dron Lett. 2011, 52, 3086–3089; f) S. Sobhani, S. Aryanejad,
M. F. Maleki, Synlett 2011, 319–322; g) K. Bahrami, M. M.
Khodaei, D. Khaledian, Tetrahedron Lett. 2012, 53, 354–358.
guchi, Eur. J. Org. Chem. 2010, 2670–2673; c) N. Taniguchi,
Tetrahedron 2014, 70, 1984–1990; d) M. M. Kadooka, L. G.
Warner, K. Seff, J. Am. Chem. Soc. 1976, 98, 7569–7578.
[12] For the preparation of PhSCu, see: Organic Syntheses, Coll.
Vol. V, Wiley, New York, 1973, p. 107–110.
Received: July 1, 2014
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Synthesis of Thiosulfonates by Oxidative Coupling
Oxidative Coupling
The copper-catalyzed sulfonylation of thi-
ols is performed by using sodium sulfinates
under an oxygen atmosphere to afford the
corresponding thiosulfonates in good yi-
elds. The procedure tolerates numerous
combinations of arene- and alkanethiols
with sodium sulfinates. Phen = 1,10-phen-
anthroline.
N. Taniguchi* .................................... 1–5
Copper-Catalyzed Synthesis of Thiosulfon-
ates by Oxidative Coupling of Thiols with
Sodium Sulfinates
Keywords: Synthetic methods / Oxidative
coupling / Sulfur / Thiols / Sulfinates /
Copper
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