The convenient synthesis and reaction of 2-(arylthio)phenols under ligand-free conditions: arylthioquinone preparation through cascade C–H functionalization and oxidation from arylthiols and aryl iodides

Article abstract of DOI:10.1016/j.tetlet.2016.10.028

A convenient and simple method for copper-catalyzed synthesis of 2-(arylthio)phenols through C–H functionalization of arylthiols and aryl iodides was developed under ligand-free conditions without nitrogen protection. In addition, arylthioquinone derivatives were very easily prepared for one more step of oxidation with moderate to good yields. This provide an alternative and efficient way to 2-(arylthio)phenols and arylthioquinone derivatives smoothly without using ligands and nitrogen protection or expensive arylboronic acids.

Full text of DOI:10.1016/j.tetlet.2016.10.028

Accepted Manuscript
The Convenient Synthesis and Reaction of 2-(Arylthio)phenols under Ligand-
free Conditions: Arylthioquinone Preparation Through Cascade C-H Function-
alization and Oxidation from Arylthiols and Aryl Iodides
Dawei Wang, Xiaoli Yu, Likui Wang, Wei Yao, Zhaojun Xu, Huida Wan
PII:
S0040-4039(16)31331-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.028
TETL 48198
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 August 2016
29 September 2016
8 October 2016
Please cite this article as: Wang, D., Yu, X., Wang, L., Yao, W., Xu, Z., Wan, H., The Convenient Synthesis and
Reaction of 2-(Arylthio)phenols under Ligand-free Conditions: Arylthioquinone Preparation Through Cascade C-
H Functionalization and Oxidation from Arylthiols and Aryl Iodides, Tetrahedron Letters (2016), doi: http://
dx.doi.org/10.1016/j.tetlet.2016.10.028
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The Convenient Synthesis and
Reaction of 2-(Arylthio)phenols under
Ligand-free
Conditions:
Arylthioquinone Preparation Through
Cascade C-H Functionalization and
Oxidation from Arylthiols and Aryl
Iodides
Dawei Wang*, Xiaoli Yu, Likui Wang, Wei Yao, Zhaojun Xu and Huida Wan*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering,
Jiangnan University, Wuxi 214122, Jiangsu Province, China.
An convenient and simple method for copper-catalyzed synthesis of 2-(arylthio)phenols through C-H functionaztion of
arylthiols and aryl iodides was developed under ligand-free conditions without nitrogen protection. In addition,
arylthioquinone derivatives were very easily prepared for one more step oxidation with moderate to good yields. This
provide an alternative and efficient way to 2-(arylthio)phenols and arylthioquinone derivatives smoothly without using
ligands and nitrogen protection or expensive arylboronic acids.

1
Contents lists available at ScienceDirect
Tetrahedron Letters
The Convenient Synthesis and Reaction of 2-(Arylthio)phenols under
Ligand-free Conditions: Arylthioquinone Preparation Through Cascade C-
H Functionalization and Oxidation from Arylthiols and Aryl Iodides
Dawei Wang*, Xiaoli Yu, Likui Wang, Wei Yao, Zhaojun Xu and Huida Wan*
The Key Laboratory of Food Colloids and Biotechnology, Ministry of Education, School of Chemical and Material Engineering, Jiangnan
University, Wuxi 214122, Jiangsu Province, China.
Email：wangdw@jiangnan.edu.cn, wanhuida@jiangnan.edu.cn, Tel./fax: +86 510 85917763
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
An convenient and simple method for copper-catalyzed synthesis of 2-
(arylthio)phenols through C-H functionaztion of arylthiols and aryl iodides was
developed under ligand-free conditions without nitrogen protection. In
addition, arylthioquinone derivatives were very easily prepared for one more
step oxidation with moderate to good yields. This provide an alternative and
efficient way to 2-(arylthio)phenols and arylthioquinone derivatives smoothly
without using ligands and nitrogen protection or expensive arylboronic acids.
Available online
Keywords:
C-H functionalization,
arylthiols,
2016 Elsevier Ltd. All rights reserved.
quinone,
2-(arylthio)phenols,
copper
synthesis in modern industry.6 Pan et al. described the
synthesis of 2-(phenylthio)phenols from phenols and aromatic
halides by using dimethyl sulfoxide as the oxidant with (E)-3-
1. Introduction
Arylthioquinone derivatives, which are widely distributed
in natural products, have exhibited practical and significant
pharmaceutical or biological activities.1 They are important
intermediates for the medicines, herbicides, insecticides, and
also show other special properties, like: antitumor, antiviral,
antibiotic, anticancer, antidiabetic and antimalarial.2 For
example, 2-methylsulfanyl-[1,4]naphtha quinones and 2,3-
bis(arylthio)-5-hydroxy-/5-methoxy-1,4-naphthoquin-ones
exhibited good fungistatic activity and resulted in a marked
increase in their activity profile (Scheme 1).3 Typical method
for arylthioquinones synthesis is the reaction of quinones and
thiophenol, however, it is difficult to avoid the reduction of
quinones to hydroquinones under thiophenol conditions and
often affected by the interference of byproduct
hydroquinones.4
(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one as a
ligand (Scheme 2).7 Based on the sulfur7,8 and disulfide6
directed C-H activation reaction,9 herein, we reported an
convenient and simple method for copper-catalyzed 2-
(arylthio)phenols synthesis through C-H functionaztion of
arylthiols and aryl iodides under ligand-free conditions
without dimethyl sulfoxide as the oxidant. In addition,
arylthioquinone derivatives were very easily prepared for one
pot two steps with moderate to good yields. This provide an
alternative and efficient way to synthesize 2-(arylthio)phenols
and arylthioquinone derivatives smoothly.
Scheme 1. Several biological arylthioquinones.
During the past several years, our interest in quinones
synthesis and reactions was initiated by the research of
borrowing hydrogen reactions and reduction of quinones,
which have attracted considerable attention due to their
unique properties and various applications, thus we
discovered several interesting transformations of quinones
derivatives.5 Recently, we reported thiophenol hydroxylation
and S-arylation to prepare arylthioquinones derivatives with
expensive arylboronic acids as the starting material, which
was difficult to tolerate for arylthioquinones derivatives

2
Tetrahedron Letters
Scheme 2. The synthesis of arylthioquinones and 2-
effect of substituents on the aryl iodides in the reaction. It was
(arylthio)phenols.
observed that fluoro, chloro, bromo, methyl, ethyl,
trifluoromethyl and methoxyl substituents were tolerated. In
most cases, the corresponding arylthioquinone derivatives
were achieved in moderate to good yields.
Table 2. Substrate expansion experiments a,b
Initially, this investigation began with the reaction of
mercaptophenol with iodobenzene in the presence of CuI (10
% mol), and Cs2CO3 (2.0 equiv.) in DMF (3.0 mL) at 90 °C,
then the reaction mixture was dealt with K2S2O8. To our great
joy, the phenylthioquinone was achieved moderate yield.
Consequently, a series of solvents were evaluated, wherein
DMF gave a better result. Then, a survey on several typical
bases indicated that Cs2CO3 was the best one, giving the
phenylthioquinone in a 65% yield. At the same time, other
copper salts were tested and CuI was found to produce the
best result. It should be noted that the reaction could not take
place in the absence of copper catalyst (Table 1, entry 16).
a
Conditions: 1 (1.0 mmol), 2 (1.5 mmol), CuI (10 mol%), Cs2CO3
(1.5 mmol), DMF (4 mL), 24 h, 90 oC, O2 (1atm); K2S2O8 (2.0
equiv.), 2 h. b Isolated yields.
Table 1. Screening of reaction conditions a
In addition, we were pleased to find that 3-methoxyarylthiol
was effective with this methodology (Table 3). The
experiments showed that arylthioquinone derivatives were
also achieved in moderate yields. The substituent group of
aryl iodides had a minimal influence on the transformation.
The yields of the corresponding arylthioquinones were
separated with 48% to 63%, which were a litter low than that
of mercaptophenols.
Entry
Catalyst
Pd(OAc)2
CuCl2
CuCl
CuBr
Base
Solvent
DMF
DMF
DMF
DMF
T/ oC
90
90
90
3a[%]b
<5
9
17
1
2
3
4
K2CO3
K2CO3
K2CO3
K2CO3
90
21
90
CuI
CuSO4
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
-
K2CO3
K2CO3
Cs2CO3
KOH
DMF
DMF
DMF
DMF
DMF
DMSO
DCE
Dioxane
Toluene
DMF
Table 3. Substrate expansion experiments of 3-methoxyarylthiols a,b
5
6
7
8
34
<5
65
52
63
90
90
90
90
90
90
80
90
rt
140
90
90
90
tBuOK
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
9
10
11
12
13
14
15
16
17
18
38
<5
<5
<5
<5
57
<5
56 c
47 d
DMF
DMF
DMF
DMF
CuI
CuI
a Conditions: 1a (1.0 mmol), 2a (1.5 mmol), catalyst (10 mol%), base
(1.5 mmol), solvent (4 mL), 24 h, O2 (1atm); K2S2O8 (2.0 equiv.), 2
h. b Isolated yields. c Under oxygen balloon. d Under air.
a Conditions: 4 (1.0 mmol), 2 (1.5 mmol), CuI (10 mol%), Cs2CO3
(1.5 mmol), DMF (4 mL), 24 h, 90 oC, O2 (1atm); K2S2O8 (2.0
equiv.), 2 h. b Isolated yields.
Having identified suitable reaction conditions (Table 1), the
substrate scope of arylthioquinone synthesis through cascade
C-H functionalization and oxidation from arylthiols and aryl
iodides was assessed (Table 2). We first set out to discuss the

3
At the same time, we also separated the 2-(arylthio)phenol
derivatives in this transdormation (Table 4). The reactions
were conducted with CuI as the catalyst, DMF as the solvent
and Cs2CO3 as the base. Compared to arylboronic acids, this
transformation almost produced nearly the same yields for
most cases. However, it provides an much cheaper and
alternative method10 for the synthesis of 2-(arylthio)phenol
derivatives.11
piperidinyloxy) as an radical scavenger. The result showed
that 2-(phenylthio)phenol was obtained with almost the same
yield, which indicated that the radical reaction process might
be not involved in this transformation (Scheme 4).
Scheme 4. The preliminary mechanism exploration experiment.
Table 4. Substrate expansion experiments a,b
Conclusions
In summary, we developed an convenient and simple
method for copper-catalyzed 2-(arylthio)phenols synthesis
through C-H functionaztion of arylthiols and aryl iodides
under ligand-free conditions without nitrogen protection. In
addition, arylthioquinone derivatives were very easily
prepared for one more oxidation with moderate yields. This
provide an alternative and efficient way to 2-(arylthio)phenols
and arylthioquinone derivatives smoothly.
Supporting Information
Supplementary data related to this paper is available free of
charge via the Internet.
Acknowledgements
We gratefully acknowledge financial support of this work
by the National Natural Science Foundation of China
(21401080, 51302109), the Natural Science Foundation of
Jiangsu Province of China (BK20130125), Jiangsu Talents
Project (2013-JNHB-027), China Postdoctoral Science
Foundation (2014M550262, 2015T80495), Postdoctoral
Science Foundation of Jiangsu (1401072C) and MOE &
SAFEA for the 111 Project (B13025).
a Conditions: 5 (1.0 mmol), 2 (1.5 mmol), CuI (10 mol%), Cs2CO3
(1.5 mmol), DMF (4 mL), 24 h, 90 oC, O2 (1atm). b Isolated yields. c
Under air.
Pan et al. revealed that the oxygen in product comes from
DMSO,7 while our previous reports indicated that oxygen is
from molecular oxygen.6 In this paper, we speculate oxygen
of 2-(arylthio)phenol may be from molecular oxygen (Scheme
3). The experiment showed that the reaction could not take
place in nitrogen condition. It should be noted that the desired
product was not detected with thioether as the starting
material under oxygen or nitrogen conditions, which was in
accordance with our previous results.6
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5

Arylthioquinones synthesis from arylthiols and aryl
iodides.


Without using ligands and nitrogen protection.
Without expensive arylboronic acids.