Copper-mediated oxidative trifluoromethylthiolation of quinones

Article abstract of DOI:10.1016/j.tetlet.2015.09.117

A novel copper-mediated oxidative trifluoromethylthiolation of quinones was developed. This protocol provided an efficient and practical approach to a series of trifluoromethylthiolated quinones.

Full text of DOI:10.1016/j.tetlet.2015.09.117

Tetrahedron Letters 56 (2015) 6273–6275
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Tetrahedron Letters
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Copper-mediated oxidative trifluoromethylthiolation of quinones
a
a
b
a,b,
⇑
Chao Li , Ke Zhang , Xiu-Hua Xu , Feng-Ling Qing
a
College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, 2999 North Renmin Lu, Shanghai 201620, China
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Lu, Shanghai 200032, China
b
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel copper-mediated oxidative trifluoromethylthiolation of quinones was developed. This protocol
provided an efficient and practical approach to a series of trifluoromethylthiolated quinones.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 30 August 2015
Revised 23 September 2015
Accepted 25 September 2015
Available online 28 September 2015
Keywords:
Copper
Trifluoromethylthiolation
Quinones
C–H activation
Oxidization
Quinone motifs are prevalent in a number of naturally occurring
biologically active compounds. Many of natural or synthetic qui-
new protocol for the generation of SCF
3
radical from an easily pre-
1
14
pared and stable reagent AgSCF in the presence of an oxidant.
3
nones have found to exhibit a wide range of pharmacological prop-
erties. The quinone core is also very important in dye industry.
Shibata and co-workers reported a copper-catalyzed C–H trifluo-
romethylthiolation of enamines and indoles. Very recently, our
2
3
15
Furthermore, quinone derivatives are widely used as versatile oxi-
dizing reagents, ligands, and synthons in organic synthesis. Con-
group disclosed a copper-mediated oxidative trifluoromethylthio-
lation of unactivated alkenes with AgSCF (Scheme 1a). As an
3
4
16
sidering the high importance of quinones, there is obviously
significant interest in synthesizing new functionalized quinones.
It is well known that the incorporation of fluorine atom and/or
fluorine-containing groups into an organic molecule often changes
the chemical, physical, and biological properties of the parent com-
pound. The synthesis of fluorine-containing quinones, especially
trifluoromethylated quinones,7 has received increasing attention.
In contrast, the introduction of the trifluoromethylthio group
extension of our work, herein we report a copper-mediated oxida-
tive trifluoromethylthiolation of quinones with AgSCF
(Scheme 1b). To the best of our knowledge, this transformation
represents the first example of the direct introduction of trifluo-
romethylthio group into quinones.
3
5
6
Optimization of the reaction conditions was explored using
2-methylnaphthalene-1,4-dione (1a) as the model substrate
3
(Table 1). Initially, the reaction of 1a with AgSCF was investigated
(
SCF
3
) into quinones has not been reported yet, despite the SCF
3
using K as the oxidant, but none of the desired product 2a
2 2 8
S O
8
group having unique properties and thus is potentially useful in
was detected (entry 1). On the basis of our work of oxidative triflu-
9
16
pharmaceuticals and agrochemicals.
oromethylthiolation of unactivated alkenes, copper salt might be
In 2013, Szabó7 and Wang independently reported the
radical C–H trifluoromethylation of quinones with electrophilic
trifluoromethylation reagent. Inspired by their work, we wondered
if it was possible to synthesize trifluoromethylthiolated quinones
b
7c
helpful for the radical trifluoromethylthiolation. Accordingly, dif-
ferent Cu salts were added into the reaction mixture (entries
2–7). To our delight, Cu
It was noteworthy that the yield of compound 2a could not be
increased by using larger amounts of CuSO (entry 8). To further
improve the reaction yield, several oxidants (TBHP, (NH
NFSI, and O ) and solvents (DMSO, THF, and acetone) were
2
2
(OH) CO
3 2
ÁH O gave the best yield at 59%.
via the SCF
3
radical. Although radical trifluoromethylthiolation
4
10
reactions were developed half a century ago, normally toxic
4 2 2 8
) S O ,
1
1
and gaseous trifluoromethylthiolating reagents, such as CF
3
SH,
S radical sources, which
limited their applications. Recently, Wang and Yin developed a
2
1
2
13
CF
3
SCl, and CF
3
SSCF
3
,
were used as CF
3
screened (entries 9–15). However, no higher yield was obtained.
Only a trace amount of 2a was detected in the presence of catalytic
amounts of K
HMPA or K PO ,
3 4
2
S
2
O
8
(entry 16). The addition of a base, such as
could not improve the reaction yield (entries
1
4
16
⇑
Corresponding author. Tel.: +86 21 54925187; fax: +86 21 64166128.
E-mail address: flq@mail.sioc.ac.cn (F.-L. Qing).
1
7 and 18). Furthermore, either a higher or lower temperature
http://dx.doi.org/10.1016/j.tetlet.2015.09.117
040-4039/Ó 2015 Elsevier Ltd. All rights reserved.
0

6
274
C. Li et al. / Tetrahedron Letters 56 (2015) 6273–6275
previous work
O
O
O
2 2 3 2
Cu (OH) CO ·H O
K S O
2 2 8
MeCN, 65 o
C
overnight
H
AgSCF
3
H
SCF3
R
oxidant
R1
H
R1
(a)
+
AgSCF
3
SCF
3
R
this work
O
O
O
O
O
1
2
AgSCF3
oxidant
H
SCF
R2
3
O
O
O
(b)
SCF3
Me
SCF3
OMe
SCF3
R2
NMePh
O
O
O
Scheme 1. Oxidative trifluoromethylthiolation reactions.
b
2
a, 77%
2b, 43%
2c, 46%
O
O
O
led to a decrease in the reaction yield (entries 19 and 20). Finally,
SCF
3
SCF
3
SCF
3
the yield of compound 2a reached up to 84% by increasing the
amounts of AgSCF
tively (entry 21).
3
, Cu
2
(OH)
2
CO
3
ÁH
2 2 2 8
O, and K S O by 50%, respec-
O
O
O
d, 45%b
Me
2e, 61%b
OMe
Br
2
2f, 63%
With the optimized conditions (Table 1, entry 21) in hand, we
then investigated the substrate scope of copper-mediated trifluo-
romethylthiolation of quinones (Scheme 2). A number of quinone
derivatives proceeded smoothly to afford the corresponding triflu-
oromethylthiolated products in moderate to excellent yields. In the
cases of quinones bearing electron-donating groups, excess
O
O
O
SCF3
Cl
SCF3
Br
Me
SCF3
Me
O
O
O
2
g, 87%
2h, 78%
2i, 65%
amounts of AgSCF
3
, Cu
2
(OH)
2
CO
3
ÁH
2 2 2 8
O, and K S O were necessary
to achieve high yields (2c–e, 2j, 2n). The common functional
groups including ethers, amines, and esters were well tolerated
in this transformation. Notably, the substrates bearing chloro and
OMe O
OAc O
O
SCF3
Br
SCF3
Br
Br
SCF3
Br
O
O
O
2
j, 67%b
2k, 92%
2l, 72%
Table 1
a
O
O
O
O
Optimization of reaction conditions
SCF3
Br
Me
Me
SCF3
Me
O
O
O
SCF3
Me
Br
Cu salt, oxidant
+
AgSCF
3
solvent, 65 o
C
2n, 41%b
2
m, 55%
Me
overnight
O
a
Scheme 2. Substrate scope of C–H trifluoromethylthiolation of quinones. aReaction
conditions: 1 (0.2 mmol), AgSCF (0.6 mmol), Cu (OH) CO O (0.3 mmol), K
ÁH
1
2a
3
2
2
3
2
2 2 8
S O
Yieldb (%)
(0.6 mmol), MeCN (1.0 mL), 65 °C, under Ar atmosphere, overnight. Yields are those
Entry
Cu salt
Oxidant
Solvent
of isolated products. bAgSCF
(1.0 mmol).
(1.0 mmol), Cu
(OH)
CO
ÁH
3
2
2
3
2 2 2 8
O (0.5 mmol), K S O
1
2
3
4
5
6
7
—
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
K S
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
8
8
8
8
8
8
8
8
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
THF
Acetone
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
0
0
6
57
59
0
0
58
0
48
7
0
Trace
0
0
Trace
10
Trace
24
52
84
Cu(OAc)
2
Cu(OTf)
CuSO
Cu (OH)
CuCl
CuCN
2
4
bromo substituents were compatible with the reaction conditions,
thus providing opportunities for additional transformations (2f–h,
2j–m).
The reaction of naphthoquinone 1o under the optimized condi-
tions gave a mixture of mono- and bistrifluoromethylthiolated
products. To our delight, the selective mono- and bistrifluo-
romethylthiolation was accomplished by controlling the amounts
2
2
CO
3
ÁH
2
O
c
8
CuSO
4
9
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
2
2
2
2
2
2
2
2
2
2
2
2
2
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
(OH)
2
2
2
2
2
2
2
2
2
2
2
2
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
3
ÁH
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
TBHP
(NH
NFSI
10
11
12
13
14
15
16
17
18
19
20
21
4
)
2
2
S O
8
O
2
2
K S
2
K S
2
K S
2
O
2
O
2
O
8
8
8
3
of reagents (Scheme 3). The mono-SCF derivative 2o was pro-
duced in 46% yield in the presence of 2 equiv of AgSCF and
3
d
e
f
(NH )
4 2
2
S O
8
2
K S
2
K S
2
K S
2
K S
2
K S
2
O
2
O
2
O
2
O
2
O
8
8
8
8
8
O
g
h
i
AgSCF
Cu (OH)
(1.5 equiv)
3
(2.0 equiv)
SCF
CO ·H
3
2
O
3
2
2
K
2
S
2
O
8
(2.0 equiv)
o
a
O
O
Reaction conditions: 1a (0.2 mmol), AgSCF
3
(0.4 mmol), Cu salt (0.2 mmol),
MeCN, 65 C, overnight
O
oxidant (0.4 mmol), solvent (1.0 mL), 65 °C, under Ar atmosphere, overnight.
2
o, 46%
b
19
Yield was determined by F NMR analysis using (trifluoromethyl)benzene as
an internal standard.
O
AgSCF
Cu (OH)
(2.5 equiv)
K S O (5.0 equiv)
3
(5.0 equiv)
c
SCF
3
CuSO
4
(0.5 mmol).
(0.04 mmol).
2
2
CO ·H
3
2
O
d
e
f
K
2
S
2
O
8
1
o
HMPA (0.1 mmol) was added to the reaction mixture.
PO (0.2 mmol) was added to the reaction mixture.
2
2
8
SCF
3
o
MeCN, 65 C, overnight
K
3
4
O
g
h
i
The reaction was carried out at 80 °C.
The reaction was carried out at 5 0 °C.
AgSCF
3o, 65%
3
(0.6 mmol), Cu
2
(OH)
2
CO
3
ÁH
2 2 2 8
O (0.3 mmol), K S O (0.6 mmol).
Scheme 3. Selective mono- and bistrifluoromethylthiolation of 1o.

C. Li et al. / Tetrahedron Letters 56 (2015) 6273–6275
6275
O
O
TEMPO (1.0 equiv)
Cu (OH) CO ·H
O
References and notes
2
2
3
2
O
SCF
Me
3
(1.5 equiv)
+
AgSCF
3
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O
O
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2
S
2
O
8
-
HO
5
.
.
AgSCF
3
Cu
2
(OH)
2
3 2
CO ·H O
might be involved
R
2
H O
O
2
Scheme 4. Mechanistic investigation.
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K S
2 2
O
8
, despite part of 1o not being fully consumed. Using 5 equiv
of AgSCF and K , 1o was totally transformed to give the bistri-
3
2 2 8
S O
10784; (b) Miyamura, H.; Shiramizu, M.; Matsubara, R.; Kobayashi, S. Angew.
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TEMPO was added to the standard reaction and the desired trans-
formation was almost not observed (Scheme 4). This result showed
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b,c,14,16
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by K
radical underwent addition to
quinone 1 for the generation of intermediate A, which could be fur-
proposed in Scheme 4. Initially, the oxidation of AgSCF
3
2 2
S
O
8
7. (a) Lanfranchi, D. A.; Belorgey, D.; Müller, T.; Vezin, H.; Lanzer, M.; Davioud-
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1
4
3 3
gave SCF radical. Then the SCF
7
c
ther oxidized by Cu
Finally, deprotonation of intermediate B afforded the desired
product 2.
2
(OH)
2
CO
3
ÁH
2 3
O to form SCF intermediate B.
8
.
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In conclusion, we have developed a copper-mediated oxida-
tive trifluoromethylthiolation of quinones. This protocol provided
an efficient access to previously unknown trifluoromethylthio-
lated quinones. Future efforts will focus on probing the mecha-
nism and evaluating other oxidative trifluoromethylthiolation
reactions.
9.
Acknowledgments
1
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We thank the National Natural Science Foundation of China
(
21421002, 21332010, 21272036), the National Basic Research
Program of China (2012CB21600), and Shanghai City
15PJ1410300) for funding this work.
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Supplementary data associated with this article can be found, in
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1
17.
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