Hydroxysulfenylation of electron-deficient alkenes through an aerobic copper catalysis

Article abstract of DOI:10.1021/acs.orglett.5b00112

A copper-catalyzed hydroxysulfenylation of α,β-unsaturated esters/amides is reported. The method presents a selective and efficient synthesis of β-hydroxysulfides bearing electron-withdrawing groups. The synthetic utility of this method is demonstrated by the concise synthesis of the anticancer drug bicalutamide.

Full text of DOI:10.1021/acs.orglett.5b00112

Letter
pubs.acs.org/OrgLett
Hydroxysulfenylation of Electron-Deficient Alkenes through an
Aerobic Copper Catalysis
Hui Xi, Bicheng Deng, Zhenzhen Zong, Shenglin Lu, and Zhiping Li*
Department of Chemistry, Renmin University of China, Beijing 100872, China
S
* Supporting Information
ABSTRACT: A copper-catalyzed hydroxysulfenylation of α,β-unsatu-
rated esters/amides is reported. The method presents a selective and
efficient synthesis of β-hydroxysulfides bearing electron-withdrawing
groups. The synthetic utility of this method is demonstrated by the
concise synthesis of the anticancer drug bicalutamide.
he addition of organosulfurs to C−C unsaturated bonds is
one of the powerful synthetic tools toward sulfur-
Scheme 2. Strategies for Hydroxysulfenylation of Electron-
Deficient Alkenes
T
containing compounds.1,2 Hydroxysulfenylation (thiol−oxygen
co-oxidation) of alkenes with thiols provides an excellent route to
introduce vicinal heteroatomic substituents, affording β-hydrox-
ysulfides in one step. Although the strategy is well-suited for
electron-rich alkenes,3 hydroxysulfenylation of electron-deficient
alkenes has remained largely underdeveloped for a long time. It is
not surprising that the greatest difficulty is attributed to the
selectivity of the reaction (Scheme 1).4 The formation of the
Scheme 1. Outline for Hydroxysulfenylation of Electron-
Deficient Alkenes
effectively overcomes the selective issue of the reactions of α,β-
unsaturated esters/amides with thiols (Scheme 2b).
The reaction of p-toluenethiol 5a and methyl methacrylate 6a
under oxygen atmosphere was chosen as a model to investigate
the reaction conditions (Table 1). The desired β-hydroxysulfide
4a was obtained in 30% yield, while the hydroxyl sulfoxide 2a was
formed as a major product along with trace amounts of the
hydrothiolation product 1a without catalyst (entry 1). To our
delight, metal catalysts greatly prevented the formation of 2a.
Accordingly, we performed an extensive survey of a variety of
metal salts (entries 2−10). It turned out that the copper catalysts
were beneficial to the formation of 4a in the terms of efficiency
and selectivity (entries 7−10). Importantly, although benzoic
acid as an additive showed no obvious influence (entries 11−13),
a 98% yield of 4a was achieved by using Cu(OAc)2 as catalyst
(entry 14). These results indicated that the efficiency of
hydroxysulfenylation heavily depends on both the copper
anion and the extra proton source. Further studies showed that
the acidity of carboxylic acid slightly affected the efficiency and
selectivity of the reaction (entries 15 and 16). Significantly, 4a
could be obtained in an excellent yield without benzoic acid by
prolonging the reaction time (entry 17). On the basis of the
hydrothiolation product 1 is favored for the alkene with an
electron-withdrawing group in both radical and nucleophilic
mechanisms.1 In addition, the hydroxyl sulfoxide 2 is also feasibly
generated via an intramolecular oxygen transfer of 3 (or B).5 We
anticipate that the desired β-hydroxysulfide product 4 can be
favored by pushing the radical equilibrium to generate the
hydroperoxide 3 and reducing the peroxyl bond simultaneously
(blue arrows in Scheme 1).
In 2008, Naito and co-workers creatively applied α,β-
unsaturated imines as the thiyl radical acceptors by enhancing
the stability of the intermediate radical A and reducing the ability
of the Michael acceptor (Scheme 2a).6 Despite the success of this
method, the selective hydroxysulfenylation of simple α,β-
unsaturated esters/amides still remained an important challenge.
Herein, we present a practical hydroxysulfenylation of electron-
deficient alkenes based on an aerobic copper catalysis that
Received: January 13, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Scope of Substrates 5
b
NMR yield (%)
entry
cat.
FeCl2
additive
4a
1a
2a
1
2
30
36
34
25
40
30
64
74
46
20
70
40
49
98
67
90
97
4
10
6
66
3
3
FeCl3
6
4
Fe(OAc)2
CoCl2
15
5
15
5
5
6
Mn(OAc)2
CuCl
3
3
7
13
4
3
8
CuBr
6
9
CuCl2
3
5
10
11
12
13
14
15
16
Cu(OAc)2
CuCl
1
1
PhCOOH
15
15
9
5
CuBr
PhCOOH
3
CuCl2
PhCOOH
2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
PhCOOH
1
1
4-NO2-PhCOOH
4-MeO-PhCOOH
3
3
5
5
c
17
1
1
a
Reaction conditions: 5 (2.0 mmol), 6a (0.5 mmol), Cu(OAc)2 (0.025
a
b
Reaction conditions: 5a (2.0 mmol), 6a (0.5 mmol), cat. (0.025
mmol), additive (1.0 mmol), DCE (5.0 mL), 50 °C, 3 h, unless
mmol), PhCOOH (1.0 mmol), DCE (5.0 mL), 50 °C, 3 h. NMR
yields; isolated yields are given in parentheses.
b
c
otherwise noted. NMR yields were based on 6a. 12 h.
ysulfenylation of alkenes, overcoming limitations of the previous
reports.
results, we rationalized that (1) copper catalysis could be an easy
to accomplish approach for hydroxysulfenylation of electron-
deficient alkenes, which was one of the unsettled problems in
synthetic chemistry, and (2) Brønsted acid greatly accelerated
the process.
The utility of this catalytic system was demonstrated by the
synthesis of bicalutamide,7 which is the leading nonsteroidal
androgen receptor inhibitor used for the treatment of prostate
cancer. We successfully completed the synthesis of bicalutamide
through a two-step strategy, hydroxysulfenylation and oxidation
(Scheme 3). Although the efficiency of the hydroxysulfenylation
step is unsatisfactory, this synthetic route is attractive because the
starting materials are easily available and both reactions are
feasible.8
To rationalize the possible mechanism of this hydroxysulfe-
nylation reaction, the controlled experiments were carried out.
First, a radical inhibition test was examined. The formation of 4a
was completely suppressed, and the TEMPO adduct 8 was
obtained by reaction of 5a and 6a in the presence of TEMPO
under the standard conditions (eq 1). The result supports that
The applicability of the method was subsequently explored by
using the conditions of entry 14 in Table 1 as the standard
reaction conditions. First, the scope of thiols was investigated
(Table 2). Thiophenol and its derivatives 5b−5f were applied,
and the corresponding β-hydroxysulfides 4b−4f were obtained
in good to excellent yields (entries 1−5). The results indicated
that the electronic effect of thiophenols shows no obvious
influence on the efficiency of the desired transformation, while
the steric hindrance reduced the yields of 4 (entries 4 and 5).
Thionaphthol 5g also reacted smoothly with 6a to afford 4g in
85% yield (entry 6). However, aliphatic thiols, for an example of
benzyl mercaptan 5h, could not be used under the standard
reaction conditions, indicating that the stable thiyl radicals
generated by the oxidation of thiols were required for the present
transformation.
Next, the scope of alkenes 6 was surveyed by the use of 5a as a
test substrate (Figure 1). To our satisfaction, a broad range of
alkenes was applied smoothly for the hydroxysulfenylation under
the standard conditions, including α,β-unsaturated esters, amides
and ketone, styrenes, and the conjugated diene. More
importantly, a variety of functional groups of alkenes were
well-tolerated, such as allyl 4j, hydroxy 4k, and free amino 4q. It
should be noted that the internal alkene also led to the desired
product 4y under the standard reaction conditions, albeit in a low
yield due to the steric hindrance, which could be improved by
prolonging the reaction time. These results demonstrated that
this copper catalysis presents a general method for hydrox-
the hydroxysulfenylation is initiated by a thiyl radical. Second, the
reaction of 1,2-di-p-tolyldisulfane 9 and 6a did not generate the
desired product 4a (eq 2). The result excluded one of the
B
DOI: 10.1021/acs.orglett.5b00112
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 4. Cu-Catalyzed Hydroxysulfenylation
the valence of copper is unclear, a sulfur-containing ligand10 to
the copper catalyst might assist the activation of O2 and generate
a peroxy-copper species C.11,12 Finally, the reduction of 3 by the
copper catalyst leads to the desired product 4 (red arrow).13
Overall, the Cu-mediated pathway (A → D → 3 → 4) favors the
generation of both 3 and 4 and avoids the formation of the other
products 1 and 2 accordingly. However, the possibility of the
direct conversion of D into 4 could not be fully excluded in the
present copper catalysis (dotted arrow).14
In conclusion, we have developed a general and practical
method for hydroxysulfenylation of alkenes through an aerobic
copper catalysis. A great feature of the methodology is to realize
the hydroxysulfenylation of simple α,β-unsaturated esters/
amides for the first time. The developed method was successfully
applied for the selective and concise synthesis of bicalutamide.
Efforts to understand the reaction mechanism and apply this
catalytic system to other substrates are underway and will be
reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Figure 1. Scope of the substrates 6: 5a (2.0 mmol), 6 (0.5 mmol),
Cu(OAc)2 (0.025 mmol), PhCOOH (1.0 mmol), DCE (5.0 mL), 50
°C, 3 h. NMR yields; isolated yields are given in parentheses. a4-MeO-
PhCOOH instead of PhCOOH. bThe debenzoylation product 4x′ was
obtained in 45% yield (see SI). c24 h.
AUTHOR INFORMATION
Corresponding Author
■
Scheme 3. Two-Step Synthesis of Bicalutamide
*E-mail: zhipingli@ruc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support was from the National Science Foundation of
China (21272267), State Key Laboratory of Heavy Oil
Processing (SKLOP201401001), the Fundamental Research
Funds for the Central Universities, the Research Funds of
Renmin University of China (10XNL017), and Beijing National
Laboratory for Molecular Sciences (BNLMS).
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