Copper-Catalyzed Reaction Cascade of Thiophenol Hydroxylation and S-Arylation through Disulfide-Directed C-H Activation

Article abstract of DOI:10.1002/chem.201600597

Copper-catalyzed thiophenol C-H activation is described. Through an initial attempt to conduct C-arylation with arylboronic acid, a rather surprising sequential C-H activation and S-arylation was discovered. Mechanistic investigation revealed the disulfide intermediate as the key component in directing C-H oxidation. The overall reaction proceeded under mild conditions with molecular oxygen as the oxidant. Discovery of disulfide as the directing group provides a potential new direction for catalytic C-H functionalization under mild conditions.

Full text of DOI:10.1002/chem.201600597

DOI: 10.1002/chem.201600597
Communication
&
CÀH Activation |Hot Paper|
Copper-Catalyzed Reaction Cascade of Thiophenol Hydroxylation
and S-Arylation through Disulfide-Directed CÀH Activation
Dawei Wang,*[a] Xin Yu,[a] Wei Yao,[a] Wenkang Hu,[a] Chenyang Ge,[a] and Xiaodong Shi*[b]
Abstract: Copper-catalyzed thiophenol CÀH activation is
described. Through an initial attempt to conduct C-aryla-
tion with arylboronic acid, a rather surprising sequential
CÀH activation and S-arylation was discovered. Mechanis-
tic investigation revealed the disulfide intermediate as the
key component in directing CÀH oxidation. The overall re-
action proceeded under mild conditions with molecular
oxygen as the oxidant. Discovery of disulfide as the direct-
ing group provides a potential new direction for catalytic
CÀH functionalization under mild conditions.
One aspiration for chemists is to search for effective, new reac-
tions or methodologies for challenging functional group con-
structions, including the chemo-, regio-, or stereoselective syn-
thesis of multifunctional intermediates or natural products
from simple starting materials.[1] Over the past two decades,
direct CÀH activation has been applied as one of the most ef-
fective strategies for the introduction of functional groups on
the selected target.[2] The directing group plays an important
role because it guides the specific CÀH bond toward activa-
tion.[3] However, successful examples of CÀH activation pro-
moted by the sulfur directing group are rare.[4] This is due to
the strong coordination between sulfur and metal cations,
which quenches the catalyst reactivity. Thus, an effective new
strategy with which to facilitate the CÀH activation of sulfur-
containing molecules is of general interest for synthetic
chemistry.[5]
Scheme 1. Thioether as directing group in CÀH activation.
palladium-catalyzed arene arylation with thioether as the di-
recting group, as reported by Zhang et al. (Scheme 1A).[6a] In
that case, Ag2CO3 (3 equiv) was applied as the oxidant. Subse-
quently, Shi and co-workers reported the Rh-catalyzed benzyl
thioether CÀH arylation using a combination of Cu(OAc)2
(3 equiv) and a catalytic amount of AgOAc (0.3 equiv) as oxi-
dant.[7a] More recently, the same group extended the strategy
to the synthesis of biaryl compounds through benzyl thioeth-
er-directed CÀH activation and sequential condensation with
benzylic acid.[7b] These pioneering works demonstrated the fea-
sibility of thioether as the directing group. One interesting ob-
servation is that benzylthiol seems crucial. In the arene aryla-
tion example, no reaction occurred on the thiophenol ortho
position, thus suggesting that the formation of the six-
member transition state is crucial for thioether-directed CÀH
activation. Considering that thiophenol could be easily oxi-
dized to disulfide with molecular oxygen and a similar six-
member transition state will be produced, we postulated
whether thiophenol could be viable as a substrate with which
to produce the desired CÀH activation with simple molecular
oxygen as the oxidant. Herein, we report the successful synthe-
sis of 2-(phenylthio)phenol derivatives through the copper-cat-
alyzed thiophenolortho-hydroxylation followed by direct thio-
larylation (Scheme 1B).
In addition to the concern of quenching catalyst reactivity,
sulfur directing groups must face the challenge of oxidation,
thereby forming sulfoxide or sulfone. Thus the choice of oxi-
dant is limited. According to the literature, one of the first suc-
cessful sulfur-directed CÀH functionalization examples was the
[a] Prof. Dr. D. Wang, X. Yu, W. Yao, W. Hu, C. Ge
The Key Laboratory of Food Colloids and Biotechnology
Ministry of Education
School of Chemical and Material Engineering
Jiangnan University
Wuxi 214122 (China)
E-mail: wangdw@jiangnan.edu.cn
[b] Prof. Dr. X. Shi
Department of Chemistry
University of South Florida
Tampa, FL 33620 (USA)
E-mail: xmshi@usf.edu
Supporting information for this article can be found under http://
dx.doi.org/10.1002/chem.201600597.
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Communication
The choice of metal complexes is important for catalysis in
general. Considerable effort has been made to use base metal
(Fe, Ni, Cu, etc.) to replace much more expensive noble metals.
Given this concern, we prepared disulfide 1a to react with vari-
ous base-metal salts. Unfortunately, no conversion was ob-
served, with 1a remaining unreacted in most cases. Surprising-
ly, during our attempt to incorporate aryl group using CuI as
catalyst with the addition of boronic acid 2a, an unexpected
aryl hydroxylation product 4a was observed. Notably, the di-
sulfide hydroxylation product 3a was not obtained. Moreover,
no CÀH arylation product (3b and 3c) was observed. A signifi-
cantly lower yield of 4a was observed while conducting the re-
action under O2-free conditions (Figure 1).
Table 1. Optimization of reaction conditions.[a,b]
Entry Cat. [%]
Base
T
[oC]
Solvent Convn. Yield of 4a Yield of
[%]
[%]
5a [%]
1
2
3
4
5
6
7
CuSO4(10) Cs2CO3 90 DMF
CuCl (10) Cs2CO3 90 DMF
CuBr (10) Cs2CO3 90 DMF
>95
>95
>95
>95
>95
>95
86
<5
40
49
70
<5
18
<5
43
<5
<5
52
41
63
55
60
17
<5
91
53
45
21
78
69
81
52
83
89
36
43
29
38
31
76
93
CuI (10)
Cs2CO3 90 DMF
Cu2O (10) Cs2CO3 90 DMF
CuCl2 (10) Cs2CO3 90 DMF
PdCl2(5) Cs2CO3 90 DMF
8
9
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuI (5)
CuI (10)
CuI (10)
Cs2CO3 90 DMSO >95
Cs2CO3 90 Toluene >95
10
11
12
13
14
15
16
KOH
KOH
90 THF
90 DMF
>95
>95
>95
>95
>95
>95
>95
>95
K2CO3 90 DMF
Cs2CO3 90 DMF
Cs2CO3 120 DMF
Cs2CO3 60 DMF
Cs2CO3 25 DMF
Cs2CO3 90 DMF
17[c] CuI (10)
[a] Conditions: 6a (0.6 mmol), 2a (0.5 mmol, 1.0 equiv), cat. (10%), base
(2 equiv), solvent (2 mL), 12 h, O2. [b] Isolated yields based on 2a. [c] N2.
best catalyst. Solvent experiments showed that this reaction is
highly solvent-dependent. For DMSO, the yield is low even
with a longer reaction time. For other solvents, this reaction
could happen. Additionally, the evaluation of the activity with
a range of bases was conducted. The results revealed that
Cs2CO3 was superior to other bases. It should be noted that
the reaction cannot take place under the conditions of a nitro-
gen atmosphere (Entry 17, Table 1).
Figure 1. Unexpected CÀH hydroxylation with copper catalyst.
The other important observation was that thiolether 5a
could not promote this reaction under identical conditions.
This result clearly suggests that the formation of disulfide is
crucial for this CÀH activation, as we proposed in our initial hy-
pothesis (Scheme 1B).
Having established the optimal conditions of DMF as the sol-
vent, Cs2CO3 as the base, and CuI as the catalyst, we explored
the scope of hydroxylation/CÀS coupling from thiophenol with
arylboronic acids. The results are summarized in Table 2.
Generally, a series of 2-(phenylthio)phenol derivatives 4 was
obtained with moderate to good yields. Substrates with vari-
ous electron-donating groups or electron-withdrawing groups,
such as Me-, MeO-, tBu-, and F-moieties, can be tolerated and
will give the corresponding products in all cases. The structure
of 4 was unambiguously confirmed by single-crystal X-ray dif-
fraction (4q). In addition, the product was also supported by
Pan and co-workers, and DMSO was proposed as an oxidant.[3e]
When we attempted a much more challenging reaction, with
compound 6t as the substrate, it was very interesting to find
that the bromide group remained in the product (4t). It
should be noted that the experiment using a substrate that
contained boronic acid or an iodine functional group showed
that 2-((4-iodophenyl)thio)phenol (4u) was separated with
66% yield, which implied that the reaction of thiophenols with
boronic acids occurs prior to the reaction of thiophenols with
aryl iodide (4u).
This new reaction is interesting because it will offer an effec-
tive new strategy by which to prepare 1,2-thio-phenol deriva-
tives under mild conditions. Generally, 2-(phenylthio)phenol
derivatives are difficult to prepare, owing to over oxidation to
sulfone or sulfoxide by-products. Thus the selective synthesis
of 2-(phenylthio)phenols is of great interest, particularly one in-
volving readily accessible starting materials.[8] As discussed in
the introduction, disulfide can be formed from simple thiol oxi-
dation. Therefore, to make the reaction more practical, we put
our efforts into investigating the direct thioarylation and CÀH
oxidation. The thiophenol 6a and boronic acid 2a were ap-
plied to explore this proposed cascade process. The results are
summarized in Table 1.
According to the literature, copper-catalyzed thiophenol S-
arylation could be achieved under proper conditions. Thus the
formation of 5a is expected with the use of thiophenol 6a as
the starting material. However, as demonstrated in Figure 1,
the thioether 5a would not be an effective directing group for
the desired CÀH oxidation. This has been observed in the
screening table and formation of 5a was observed in most of
the cases. To obtain better yield for this reaction, we evaluated
the effects of catalyst factors and it was found CuI was the
Thus, with these new conditions worked out, we want to
further investigate the compatibility of oxidation to thiophe-
nol-substituted quinone derivatives.
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Table 2. Substrate expansion experiments.[a]
Table 3. Substrate expansion for the synthesis of quinones.[a]
[a] Conditions: 1) 1 (0.6 mmol), 2 (0.5 mmol, 1.0 equiv), Cs2CO3 (2 equiv),
CuI (10%), DMF (2 mL), 12 h, 908C, O2; 2) K2S2O8 (2.0 equiv), 2 h.
[a] Conditions: 1 (0.6 mmol), 2 (0.5 mmol, 1.0 equiv), Cs2CO3 (2 equiv), CuI
(10%), DMF (2 mL), 12 h, 908C.
Quinones are important building blocks and synthetic inter-
mediates for chemical, biological, and pharmaceutical re-
search.[9] In particular, quinones have been used as pigments,
anticancer reagents, dyes, and antibiotics, owing to their spe-
cial biological activities. With the discovery of this new
method, a one-pot quinone synthesis is proposed through se-
quential CÀH hydroxylation and oxidation. After screening of
various oxidants, K2S2O8 was identified as the optimal reagent
to promote the phenol oxidation without oxidizing thioether.
Based on these results, a two-step one-pot condition was de-
veloped through sequential CÀH activation and phenol oxida-
Figure 2. Preliminary mechanistic investigations.
The competing reactions between different thiophenols re-
vealed a faster reaction with electron-rich substrate (Fig-
ure 2A). The use of the 18O isotope-labeled water with regular
O2 gave the product with only 16O on the phenol (Figure 2B).
Considering that the reaction could not proceed under N2 pro-
tection, it is highly likely that the hydroxyl oxygen originated
from molecular oxygen. Clearly, the keys to understand the
mechanism of this new reaction were: 1) determining the type
of copper complex formed in the reaction with CuI and
ArB(OH)2, and 2) how the oxidation occurred between the
copper intermediate and molecular oxygen. A significant
degree of mechanistic investigation is required to fully eluci-
date this new catalytic system. Nevertheless, the fact that disul-
fide was successfully applied as the directing group and effec-
tive oxidation was achieved without further thiol oxidation
greatly highlighted the significance of this new catalytic
system.
tion. The desired thiophenol-substituted quinone
8 (see
Scheme 2) was observed in good yields. The reaction scope is
summarized in Table 3. Generally, all the substrates could be
smoothly converted to the corresponding quinone derivatives
with moderate to high yields.
Some preliminary mechanistic studies have also been per-
formed, as shown in Figure 2.
In conclusion, we report herein a ligand-free and copper-cat-
alyzed tandem one-step hydroxylation/CÀS coupling of thio-
phenols. The disulfide intermediate is used as the directing
group toward CÀH activation. Aryl boronic acid was crucial for
formation of actual copper catalyst. Various 2-(phenylthio)phe-
Scheme 2. Proposed synthesis of thiophenol-substituted quinone.
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We acknowledge the NSF (CHE-1362057), NSFC (21401080),
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Keywords: CÀH activation
·
disulfide
·
homogeneous
catalysis · hydroxylation · S-arylation
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Received: February 8, 2016
Published online on March 9, 2016
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