TBHP/TBAI-mediated oxidation of thiophenols for the synthesis of tert-butyl arylsulfinates

Article abstract of DOI:10.1016/j.tetlet.2018.08.048

A novel and efficient TBHP/TBAI-mediated oxidation of thiophenols is described. The reactions proceeded smoothly to give tert-butyl arylsulfinates in up to 82% yield with good functional group compatibility under mild conditions.

Full text of DOI:10.1016/j.tetlet.2018.08.048

Accepted Manuscript
TBHP/TBAI-mediated oxidation of thiophenols for the synthesis of tert-butyl
arylsulfinates
Chunxiao Wen, Jiawei Wu, Yingcong Ou, Yulin Huang, Kun Zhang, Qian Chen
PII:
S0040-4039(18)31048-7
https://doi.org/10.1016/j.tetlet.2018.08.048
TETL 50223
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
22 July 2018
19 August 2018
24 August 2018
Please cite this article as: Wen, C., Wu, J., Ou, Y., Huang, Y., Zhang, K., Chen, Q., TBHP/TBAI-mediated oxidation
of thiophenols for the synthesis of tert-butyl arylsulfinates, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.08.048
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Chunxiao Wen, Jiawei Wu, Yingcong Ou, Yulin Huang, Kun Zhang, Qian Chen

1
Tetrahedron Letters
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TBHP/TBAI-mediated oxidation of thiophenols for the synthesis of tert-butyl
arylsulfinates
Chunxiao Wen†, Jiawei Wu†, Yingcong Ou, Yulin Huang, Kun Zhang* and Qian Chen∗
School of Chemical Engineering and Light Industry, Guangdong University of Technology, Guangzhou 510006, China
ARTICLE INFO
ABSTRACT
Article history:
Received
A novel and efficient TBHP/TBAI-mediated oxidation of thiophenols is described. The
reactions proceeded smoothly to give tert-butyl arylsulfinates in up to 82% yield with good
functional group compatibility under mild conditions.
Received in revised form
Accepted
© 2018 Published by Elsevier Ltd.
Available online
Keywords:
Thiophenols
Oxidation
Arylsulfinates
TBHP
TBAI
The sulfinyl groups can be found in a large number of organic
compounds, which have been widely employed in organic
synthesis, materials, and bioorganic chemistry.1 Among them,
sulfinate esters are highly valuable precursors as both
electrophiles and nucleophiles in organic synthesis.2 In addition,
sulfinate esters are widely regarded as sulfinylating reagents for
the synthesis of organosulfur compounds.2,3 Traditionally,
sulfinate esters are synthesized by the alkylation of sulfinic acids4
or sodium sulfinates,5 the substitution of sulfinyl chlorides with
alcohols,6 and the oxidative coupling of thiophenols or disulfides
with alcohols in the presence of transition metals7 or
phenyliodine bis(trifluoroacetate) (PIB).8 Recently, Wu and co-
workers reported the substitution of benzyl alcohols with
TosMIC (p-toluenesulfonylmethyl isocyanide) catalyzed by
bismuth(III) bromide.9 Prapurna and co-workers then reported
the synthesis of sulfinate esters from alcohols under Mitsunobu
conditions employing TosMIC as a sulfinyl source.10 In addition,
Most recently, our group developed the metal-free
construction of carbon–sulfur, phosphorus–sulfur, and sulfone–
sulfur bonds via an addition of nucleophiles or sulfonyl radicals
to disulfide intermediates.13 During our studies on the TBHP
(tert-butyl hydroperoxide)/NaI-mediated sulfonylation of thiols
with sulfonyl hydrazides,13d trace amounts of tert-butyl
arylsulfinates were occasionally observed. Hence, we became
interested in studying the synthesis of sulfinate esters through the
oxidation of thiophenols with TBHP in the presence of iodides.
To the best of our knowledge, this transformation has never been
reported. Herein, we report a practical method for the synthesis
of tert-butyl arylsulfinates through a TBHP/TBAI-mediated
oxidation of thiophenols.
The reaction conditions were tested by using a model reaction
of p-toluenethiol 1a with TBHP and iodides in solvents at room
temperature, and the results were shown in Table 1. We first
carried out a reaction of 1a with TBHP (3 equiv) in the presence
of NaI (0.5 equiv) in acetonitrile,13d leading to the formation of
disulfide 2a, the desired tert-butyl sulfinate 3a and thiosulfonate
4a in 12%, 32% and 55% yield, respectively (entry 1). The yield
of 3a was increased to 58% using KI instead of NaI (entry 2),
while the use of NH4I failed to give the desired product (entry 3).
When the reaction was carried out in the presence of TBAI, the
yield of 3a was increased to 68%, while only trace amounts of 2a
and 4a were observed (entry 4). We then turned to screen the
equivalent of TBHP. The use of 2.5 equiv of TBHP increased the
yield of 3a (74%, entry 5). However, the use of 2 equiv of TBHP
decreased the yield of 3a (51%, entry 6). When 3.5 equiv of
TBHP were employed, the yield of 3a was slightly decreased
(entry 7). In addition, the amounts of TBAI were also screened
a
copper-catalyzed aerobic oxidative reaction of sulfonyl
hydrazides and thiols with alcohols to afford sulfinate esters was
reported by Han, Pan and co-workers.11 Most recently, Han, Ma
and co-workers developed a Cu-catalyzed β-keto sulfones with
alcohols by using oxygen as an oxidant to synthesize sulfinate
esters.12 However, transition metals, moisture-sensitive reagents,
strong Lewis acids, high temperatures or long reaction times are
required in previous methods for the synthesis of sulfinate esters.
Moreover, the pre-functionalized starting materials are high-cost
and/or temperature- or moisture-sensitive. Thus, the development
of a convenient and efficient protocol for the synthesis of
sulfinate esters is still highly desirable.
———
∗ Corresponding author. Tel.: +86-20-3932-2231; fax: +86-20-3932-2235; e-mail addresses: qianchen@gdut.edu.cn (Q. Chen),
kzhang@gdut.edu.cn (K. Zhang)
† The first two authors contributed equally to this work

2
Tetrahedron
Table 2
(entries 8–10). When the reaction was carried out in the
Scope of thiophenolsa,b
presence of TBAI (0.75 equiv), 3a was obtained in 76% yield. To
our delight, both 2a and 4a were not detected (entry 10, see the
Supplementary data). Finally, we examined the solvent effects
for this reaction (entries 11–17). The desired 3a was also
obtained in good yield when the reaction was performed in
CH3NO2 (entry 11), while a poor yield of 3a was observed using
THF, toluene, DCM, DCE, DMSO or dioxane as the solvent.
Thus, we concluded that the optimized combination for the
oxidation of thiophenols was to use 3 equiv of TBHP as the
oxidant, 0.75 equiv of TBAI as the initiator, CH3CN as the
solvent, and the reaction was set at room temperature (entry 10).
R
O
O
S
O
S
OtBu
R
S
OtBu
OtBu
3a
3h
3i
3j
, R = Me, 73%
, R = OMe, 82%
, R = Et, 55%
, R = t-Bu, 64%
, R = -Pr, 56%
, R = Me, 71%
, R = OMe, 76%
, R = NH2, 25%
R
3b
3c
3d
3e
3n
3o
3p
3q
, R = Me, 79%
, R = F, 70%
, R = Cl, 71%
, R = CF3, 53%
3k
3l
3m
, R = F, 69%
, R = Br, 81%
i
3f
, R = F, 77%
, R = CF3, 62%
3g
, R = Br, 60%
R
O
Me
Cl
O
S
OtBu
Table 1
Optimization of reaction conditionsa,b
O
OtBu
Me
S
OtBu
Cl
S
3t
, 40%
3u
R
, 62%
3r
, R = Me, 75%
3s
, R = Cl, 50%
Cl Cl
O
O
S
I-
(equiv)
TBHP
(equiv)
2a
(%)
3a
(%)
4a
(%)
S
OtBu
OtBu
O
S
Entry
1
Solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3NO2
THF
S
OtBu
O
Me
3x
NaI
3w
, 65%
3
3
12
0
32
58
0
55
33
39
8
3v
, 63%
, 52%
(0.5)
O
S
KI
O
S
OtBu
2
OtBu
(0.5)
N
3y
NH4I
(0.5)
, 60%
3z
, 27%
3
3
58
9
a Reaction conditions: 1a (0.4 mmol), TBAI (0.3 mmol) and TBHP (1.2 mmol)
in CH3CN (2 mL) stirring at room temperature for 9 h.
b Isolated yield based on 1.
TBAI
(0.5)
4
3
68
74
51
69
19
42
76
75
38
18
36
32
27
43
TBAI
(0.5)
5
2.5
2
11
33
14
69
34
0
6
With the optimized reaction conditions in hand (Table 1, entry
10), we next explored the generality of this transformation, and
the results were summarized in Table 2. Pleasingly, the results
showed that thiophenols substrates bearing different groups such
TBAI
(0.5)
6
3
TBAI
(0.5)
t
i
7
3.5
2.5
2.5
3
0
as electron-donating groups (Me, Et, Bu, Pr and OMe) and
electron-withdrawing groups (F, Cl, Br and CF3) at the para,
meta or ortho or at both positions of aromatic rings were
tolerated. The desired tert-butyl arylsulfinates 3a–3i and 3k–3v
were isolated in moderate to good yields, indicating that the
electronic effects were not evident in this reaction. However, the
reaction of 3-aminobenzenethiol gave the desired 3j in only 25%
yield probably due to the effects of the amino group. The reaction
of heteroaromatic thiols such as thiophene-2-thiol, 2-
methylfuran-3-thiol and pyridine-4-thiol was also investigated,
and the desired products 3w-3y were isolated in moderate yields.
However, the oxidation of naphthalene-2-thiol afforded the
desired 3z in only 27% yield. It is noteworthy that the
corresponding disulfides 2 and thiosulfonates 4 were efficiently
inhibited in all cases. Unfortunately, the oxidation of aliphatic
thiols such as benzylthiol and cyclohexylthiol failed to afford the
desired products.
TBAI
(0.1)
8
11
23
0
TBAI
(0.25)
9
TBAI
(0.75)
10
11
12
13
14
15
16
17
TBAI
(0.75)
3
0
trace
10
10
19
12
21
0
TBAI
(0.75)
3
51
71
42
55
51
56
TBAI
(0.75)
3
toluene
DCM
TBAI
(0.75)
3
TBAI
(0.75)
3
DCE
TBAI
(0.75)
3
DMSO
dioxane
TBAI
(0.75)
3
a
Reaction conditions: 1a (0.4 mmol), TBHP, and iodides in solvents (2 mL)
stirring at room temperature for 9 h.
b
Yield based on 1a was determined by 1H NMR analysis of crude products
using an internal standard.
Scheme 1. Control experiments.

3
Supplementary data (these data include experimental details,
analytical data, 1H and 13C NMR spectra of compounds 3)
associated with this article can be found, in the online version, at
http://...
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Scheme 2. Proposed mechanism.
To gain more insight into the mechanism of this reaction, a
couple of control experiments were then conducted (Scheme 1).
In consideration of the generation of disulfides in all cases,13d the
reaction of disulfide 2a under the standard conditions was then
carried out (Scheme 1a). The reaction smoothly proceeded to
afford the desired 3a in 75% yield, demonstrating that the
disulfide might be an intermediate in the oxidation reaction.
When the radical scavenger TEMPO (2,2,6,6-tetramethyl-1-
piperidinyloxy), BHT (2,6-di-tert-butyl-4-methylphenol) or BQ
(1,4-benzoquinone) was employed under the standard conditions,
the desired oxidation of 1a was completely inhibited (Scheme
1b), suggesting that this transformation might proceed via a
radical pathway. In addition, the reaction of disulfide 2a with
tert-butanol was also carried out, while no reaction occurred
(Scheme 1c), indicating that the formation of S–OtBu bond in 3a
might not involve a nucleophilic attack of tert-butanol on S–S
bonds. Thus, the reaction might proceed by an addition of tert-
butoxyl radical to disulfides.13d,14
2.
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literatures,13d,14 a plausible mechanism is outlined in Scheme 2.
Initially, TBHP decomposes to generate tert-butoxyl and tert-
butylperoxy radicals in the presence of iodides. Under the
oxidative conditions, thiophenols 1 generate thiyl radicals, which
undergo a subsequent homocoupling to produce disulfides 2.
Next, tert-butoxyl radical reacts with disulfides 2 to form tert-
butoxyl aryl sulfides 5 via a radical propagation and regenerate
thiyl radicals, which could recombine to disulfides. Finally, the
oxidation of the sulfide intermediates 5 affords tert-butyl
arylsulfinates 3. Thus, the good functional group compatibility of
substiutents on the phenyl groups of 1 might be due to the
delocalization effect of aryl groups, which should stabilize thiyl
radicals.
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14. For selected examples of the addition of radicals to disulfides, see: (a)
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In summary, we have developed a novel and efficient
oxidation of thiophenols with TBHP/TBAI under mild conditions.
This method provides a simple and practical protocol for the
synthesis of tert-butyl arylsulfinates with good functional group
compatibility. We envision that the reaction mode outlined here
will have potential applications in organic synthesis. Further
studies on the transformations of thiols are ongoing and will be
reported in due course.
Acknowledgments
This work was supported by the Science and Technology
Planning Project of Guangdong Province (2015A020211026 and
2017A010103044), 100 Young Talents Programme of
Guangdong University of Technology (220413506), and the
National Undergraduate Training Program for Innovation and
Entrepreneurship (201811845097).
Supplementary data

4
Tetrahedron
Highlights
1. The TBHP/TBAI-mediated oxidation of
thiophenols has been achieved.
2. The reactions afford tert-butyl arylsulfinates
via a radical pathway.
3. The protocol is halogen-, metal-, and strong
oxidant-free.