Facile synthesis of 2-(phenylthio)phenols by copper(I)-catalyzed tandem transformation of C-S coupling/C-H functionalization

Article abstract of DOI:10.1021/ja107758d

2-(Phenylthio)phenols were successfully synthesized from simple phenols and aromatic halides by using dimethyl sulfoxide as the oxidant. The transformation was accomplished via tandem copper(I)-catalyzed C-S coupling/C-H functionalization employing the CuI/L [L = (E)-3-(dimethylamino)-1-(2- hydroxyphenyl)prop-2-en-1-one] catalyst system. The mechanism of the reaction was elucidated based on an isotope labeling strategy.

Full text of DOI:10.1021/ja107758d

Published on Web 10/19/2010
Facile Synthesis of 2-(Phenylthio)phenols by Copper(I)-Catalyzed Tandem
Transformation of C-S Coupling/C-H Functionalization
Runsheng Xu,† Jie-Ping Wan,†,‡ Hui Mao,† and Yuanjiang Pan*,†
Department of Chemistry, Zhejiang UniVersity, Hangzhou, Zhejiang, P. R. China 310027 College of Chemistry and
Chemical Engineering, Jiangxi Normal UniVersity, Nanchang, Jiangxi, P. R. China 330022
Received September 2, 2010; E-mail: panyuanjiang@zju.edu.cn
Abstract: 2-(Phenylthio)phenols were successfully synthesized
from simple phenols and aromatic halides by using dimethyl
sulfoxide as the oxidant. The transformation was accomplished
via tandem copper(I)-catalyzed C-S coupling/C-H functional-
ization employing the CuI/L [L ) (E)-3-(dimethylamino)-1-(2-
hydroxyphenyl)prop-2-en-1-one] catalyst system. The mechanism
of the reaction was elucidated based on an isotope labeling
strategy.
These reactions were mainly based on the employment of the
ligand (E)-3-(dimethylamino)-1-(2-hydroxyphenyl)prop-2-en-1-one
(L4) which was previously discovered as an effective ligand for
the copper-catalyzed Ullmann C-N coupling reactions between aryl
halides and various azoles in our laboratories.6 The reaction
conditions were screened based on the model reaction of thiophenol
(1a) and iodobenzene (2a) by employing various copper(I) species
and ligands derived from L1 in different solvents (Table 1). It was
discovered that compound L4 was the ideal choice for this
transformation (entries 5-10). CuI exhibited superior catalytical
efficiency over all other examined Cu(I) catalysts (entries 1-5),
The development of selective hydroxylation of arenes is a
challenging process in organic synthesis.1 Transition-metal catalysis
has been significantly promoted for this purpose via direct C-H
functionalization of the arenes in the past decade. However, most
of the present C-H bond functionalization methods rely on the
use of noble metals such as palladium,2 rhodium, platinum, gold,
etc.3 which restricts large scale application of these methods.
Because of the good functional group tolerance and the economic
attractiveness, copper catalysts have been extensively employed in
the functionalization of C-H bonds and significant advancements
in this area have been achieved. However, expanding the application
scope of C-H bond functionalization is still highly desirable.4 For
example, exquisite methods have been developed for the oxidative
hydroxylation of the aromatic motifs bearing N atom (eq 1) or
carboxylic acid (eq 2) as an activation group, which are exemplified
by the latest reports from Yu’s group.5 The S atom has a similar
electronic profile pattern to that of the N atom; however, there are
no reports on the capability of an S-containing group to promote
the C-H bond functionalization.
Table 1. Optimization of the Reaction Conditionsa
Considering the significance of developing a direct C-H
functionalization reaction assisted by more diversified substituents,
we focused our attention toward the studies on the copper-catalyzed
C-H bond transformation of arenes. Here, we report our prelimi-
nary results on a new method for the synthesis of (2-hydroxylphe-
nyl) aryl thioethers 3 via the tandem copper-catalyzed reaction of
C-S coupling/C-H functionalization as shown in eq 3.
a Unless otherwise noted, reactions conditions were 1a (0.5 mmol),
2a (0.6 mmol), Cu salt (10 mol %), ligand (10 mol %), base (2 equiv),
protected by N2, in DMSO (2 mL) at 100 °C for 10 h. b Isolated yield.
c Reaction time for 5 h. d 80 °C. e In pure CH3CN (2 mL). f In pure
DMF (2 mL).
† Zhejiang University.
‡ Jiangxi Normal University.
9
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J. AM. CHEM. SOC. 2010, 132, 15531–15533 15531

C O M M U N I C A T I O N S
and Cs2CO3 turned out to be the proper base additive (entries
11-13). However, a reagent that played an indispensable role in
the reaction appears to be dimethyl sulfoxide (entries 15, 16).
As we found that the presense of dimethyl sulfoxide was critical
to the reaction, we decided to further understand how it was
involved. In most C-H functionalization reactions, the oxidants
are either O2 or other strong oxidative reagents. But in our reactions
O2 did not appear to be the oxidant because the reactions could be
performed in either open air or in a N2 atmosphere; in fact, the
open air operation afforded evidently even lower yields when 18O-
DMSO was used as the reaction medium, and the 18O labeled
products were obtained (Scheme 1).7 These results indicate that
dimethyl sulfoxide served as the main oxidant in this novel
transformation.
The scope of reaction was further investigated, and results are
summarized in Table 2. A wide array of thiophenols 1 and aryl
iodides 2 were subjected to the reaction, and the corresponding
products were in moderate to good yields. Thiophenol derivatives
bearing either an electron-withdrawing or -donating group reacted
smoothly with 2 to afford corresponding products. This transforma-
tion is applicable for both meta- and para-substituted thiophenols.
Aryl iodides bearing an electron-donating group showed better
reactivity than those with an electron-withdrawing group.
Scheme 1. Preliminary Mechanistic Studiesa
Table 2. Copper-Catalyzed C-S Coupling/C-H Functionalization
of Aryl Iodides with Thiolsa
entry
R1
R2
product
yield (%)b
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
4-CH3
3-CH3
3-CH3
4-Br
H
4-Cl
4-Br
2-CH3
4-CH3
4-OCH3
2-CF3
H
3a
3b
3c
3d
3e
3f
3g
3i
3j
67
78
75
56
62
69
76
68
82
80
66
71
64
84
77
73
55
63
70
81
a Unless otherwise noted, reactions conditions were CuI (10 mol %),
L4 (10 mol %), Cs2CO3 (2 equiv), at 100. °C for 10 h. Isolated yield. Isotope
product yield based on GC.
Given this isotope labeling result, we tentatively proposed a
reaction mechanism as shown in Scheme 2. The key intermediate
is complex II.8,9 Selective hydroxylation of the aromatic ring was
determined by the transitional state, complex IV.10 Reductive
elimination of complex IV produces complex V, which regenerates
complex I for the next catalytic cycle.11 However, how the ligand
promotes this transformation has not been made clear yet, and
further studies on this are ongoing.
9
4-Cl
4-Br
10
11
12
13
14
15
16
17
18
19
20
3k
3l
2-CH3
4-CH3
4-OCH3
2-CF3
4-Br
4-OCH3
H
4-CH3
4-Br
3m
3n
3o
3p
3q
3u
3v
3w
3x
4-Br
4-Br
4-Br
Scheme 2. Possible Mechanism
4-Cl
a Reactions conditions were 1 (0.5 mmol)2 (0.6 mmol), CuI (10 mol
%), L4 (10 mol %), Cs2CO3 (2 equiv), protected by N2, in DMSO (2
mL) at 100 °C for 10 h. b Isolated yield.
In addition, to our surprise, we found that aryl bromides were
also able to react with 1 smoothly, at 110 °C, and some typical
results are listed in Table 3. Interestingly, the aryl bromide
containing an electron-donating group also gave the corresponding
product in fair yield (entry 2).
In conclusion, we have found a novel hydroxylation reaction of
arenes at a position activated by an adjacent S group. The method
involves tandem conversion of C-S cross-coupling/C-H func-
tionalization. The preliminary investigation of the reaction mech-
anism suggests that dimethyl sulfoxide serves as the oxidant.
Table 3. Copper-Catalyzed C-S Coupling/C-H Functionalization
of Aryl Bromides with Thiolsa
entry
R1
R3
product
yield (%)b
1
2
3
4
5
6
7
8
9
H
H
H
4-CH3
4-CH3
4-Cl
4-Cl
4-Cl
4-Br
4-Br
H
3a
3f
3h
3i
3o
3r
3s
3t
3u
3w
52
45
63
47
62
51
60
57
40
55
4-OCH3
3-CF3
H
2-CF3
H
4-Cl
4-Br
H
Acknowledgment. We thank the National Natural Science
Foundation of China (Nos. 21025207, 20975092) for the financial
support.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
10
4-Br
a Reactions conditions were 1 (0.5 mmol), 2 (0.6 mmol), CuI (10 mol
%), L4 (10 mol %), Cs2CO3 (2 equiv), protected by N2, in DMSO (2
mL) at 110 °C for 10 h. b Isolated yield.
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