Manganese(III)-mediated direct Csp2-H radical trifluoromethylation of coumarins with sodium trifluoromethanesulfinate

Article abstract of DOI:10.1039/c3cc49689a

Mn(OAc)₃-mediated direct C_sp2-H radical trifluoromethylation of coumarins with CF₃SO₂Na (Langlois reagent) to afford selective 3-trifluoromethyl coumarins in moderate to good yields is described. This methodology can also be applied to the trifluoromethylation of quinolinones and pyrimidinones. The Royal Society of Chemistry 2014.

Full text of DOI:10.1039/c3cc49689a

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Manganese(III)-mediated direct Csp2–H radical
trifluoromethylation of coumarins with sodium
trifluoromethanesulfinate†
Cite this:DOI: 10.1039/c3cc49689a
Received 21st December 2013,
Accepted 3rd February 2014
Xiao-Hui Cao,a Xiangqiang Pan,a Peng-Jun Zhou,a Jian-Ping Zou*ab and
Olayinka Taiwo Asekunc
DOI: 10.1039/c3cc49689a
www.rsc.org/chemcomm
Mn(OAc)3-mediated direct Csp2–H radical trifluoromethylation
of coumarins with CF3SO2Na (Langlois reagent) to afford selective
3-trifluoromethyl coumarins in moderate to good yields is described.
This methodology can also be applied to the trifluoromethylation of
quinolinones and pyrimidinones.
Trifluoromethylation has gained increasing interest in recent
years as fluorinated compounds possess wide and specific
bioactivities and have good solubility and lipophilicity which
leads to better membrane permeability and bioavailability than
their non-fluorinated analogues, otherwise, they are more stable
in the metabolic process because they are more difficult to
oxidize.1 Along with the transition metal-mediated or catalyzed
coupling reaction of trifluoromethyl reagents with functionalized
substrates,2,3 radical trifluoromethylation plays an important role
in this area.4
Scheme 1
Sodium trifluoromethanesulfinate (CF3SO2Na, Langlois reagent)
is one of the CF3 radical sources, it was first applied in trifluoro-
Coumarins are significant natural products, which display
methylation of aromatic compounds by Langlois in 1991,5a later wide and interesting pharmacological properties such as anti-
extended to enol ethers and disulfides (Scheme 1),5b–d and recently breast cancer,10 anti-HIV,11 anti-Alzheimer,12 vasorelaxant and
to biaryls.5e Baran reported the trifluoromethylation of nitrogen- platelet antiaggregatory activities.13 In coumarin derivatives,
containing heteroarenes with the CF3SO2Na/t-BuOOH system 3-trifluoromethyl coumarins were not easily accessible as
(Scheme 1);6 Nicewicz described the hydrotrifluoromethylation of 4-trifluoromethyl coumarins.14 In general, introduction of fluorine
alkenes with CF3SO2Na using N-Me-9-mesityl acridinium as a atoms into medicinal molecules will increase their bioactivities,
photoredox catalyst7 (Scheme 1). In recent years, Cu-mediated or so we became interested in exploring direct trifluoromethylation.
catalyzed coupling reactions of CF3SO2Na with aryl-/vinylboronic In our recent studies, we reported the direct phosphonylation of
acids and unsaturated organotrifluoroborates4h,8 and copper-/iron- arenes,15 heteroarenes16 and alkenes17 with dialkylphosphites
catalyzed decarboxylative trifluoromethylation of a,b-unsaturated and the diphenylphosphine oxide/Mn(OAc)3 system. Our goal is
carboxylic acids have been reported.9
to develop a novel, selective and efficient method for direct
trifluoromethylation of coumarins and other heteroarenes. Herein,
we report a general, straightforward method for trifluoromethyl-
ation of coumarins with CF3SO2Na mediated by Mn(OAc)3
(Scheme 1). Based on the ease of use, safety, environment-
friendly nature and cost, we evaluated CF3I, CF3SO2Cl, CF3SO2SPh,
the Togni reagent, the Langlois reagent and Me3SiCF3, which are
potent sources of CF3 radicals, eventually, the Langlois reagent
(CF3SO2Na, a benchtop stable and inexpensive solid) was selected
as the CF3 radical source. Initially, when CF3SO2Na/t-BuOOH
a Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry and
Chemical Engineering, Soochow University, 199 Renai Street, Suzhou,
Jiangsu 215123, China. E-mail: jpzou@suda.edu.cn
b Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of Science, China
c Department of Chemistry, University of Lagos, Akoka, Yaba, Nigeria
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c3cc49689a
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Table 1 Optimization of the reaction conditionsa
Table 2 Reactions of coumarin 1 and sodium trifluoromethanesulfinate 2a
Entry Oxidant
1a : oxidant Solvent
Temp (1C) Yieldb
1
2
3
4
5
6
7
8
t-BuOOH
t-BuOOH
t-BuOOH–cat 1 : 5
CAN
FeCl3
1 : 5
1 : 5
CH2Cl2 : H2O 25
HOAc 25
CH2Cl2 : H2O 25
N.R.c
N.R.
N.R.c,d
N.R.
10
12
26
50
16
25
15
56
46
45
43
Entry
1
Coumarin 1
Products 3 and yieldb
1 : 1
1 : 1
1 : 1
1 : 1
1 : 3
1 : 3
1 : 3
1 : 3
1 : 4
1 : 5
1 : 4
1 : 4
1 : 4
HOAc
HOAc
HOAc
HOAc
HOAc
MeCN
CH2Cl2
EtOH
HOAc
HOAc
HOAc
HOAc
HOAc
25
25
25
25
25
25
25
25
25
25
50
60
80
MnO2
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
Mn(OAc)3
9
2
3
10
11
12
13
14
15
16
4
5
30
a
Reaction conditions: coumarin (0.1 mmol) and CF3SO2Na (0.3 mmol),
b
c
24 h. Isolated yield. The ratio of CH2Cl2 : H2O is 3 : 1, N.R. indicates
no reaction. Using 20% mmol CuSO4 as catalyst.
d
and CF3SO2Na/t-BuOOH/cat. Cu(II) systems were applied to the
trifluoromethylation of coumarin (1a), no reaction was
observed (Table 1, entries 1–3). Then, the other metal oxidants
such as CAN, FeCl3, MnO2 and Mn(OAc)3 were employed for the
reaction, the results indicated that Mn(OAc)3 gave only one
trifluoromethylated product in 26% yield (Table 1, entries 4–7), its
structure was characterized to be 3-trifluoromethyl coumarin (3a)
6
7
1
by H, 13C, 19FNMR and HRMS spectral analyses (Scheme 2).
It showed that this reaction is regioselective, the trifluoro-
methylation occurred only at the a-position of the carbonyl
group in the pyranone ring, so Mn(OAc)3 was selected as an
oxidant for trifluoromethylation. When using 3 equivalents
of Mn(OAc)3 for the reaction, the yield reached 50% (Table 1,
entry 8). Solvents such as MeCN, CH2Cl2, HOAc and EtOH were
screened; HOAc gave the best yield (Table 1, entries 8–11). The
ratio of 1a : 2 : Mn(OAc)3 was optimized, and it was found that
1 : 3 : 4 is good for the reaction (Table 1, entries 12 and 13).
Raising temperature caused yield reduction, it may be attributed
to self-coupling of CF3 radicals at higher temperatures (Table 1,
entries 14–16). Eventually, the optimal reaction conditions were
determined to be: a mixture of coumarin (0.1 mmol), CF3SO2Na
(0.3 mmol) and Mn(OAc)3 (0.4 mmol) in HOAc (3 mL), stirred at
25 1C for 24 h.
Subsequently, different coumarins were used for the reaction
and it was found that coumarins bearing electron-donating groups
like Me and OMe on the phenyl ring afforded the expected
3-trifluoromethylated coumarins in 50–56% yields (Table 2,
entries 1–5). However, when CH3 groups occupied the 8-position
of coumarins, the yield was lowered to 44–45%, this was attributed
to the formation of a di-trifluoromethylated by-product (Table 2,
entries 6 and 7). In contrast, coumarins bearing electron-withdrawing
8
9
10
11
12
13
14
15
16
Scheme 2
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Table
3
Reactions of heteroarene
4
and sodium trifluoromethane-
Table 2 (continued)
sulfinate 2a
Entry
Heteroarene 4
Product 5 and yieldb
Entry
Coumarin 1
Products 3 and yieldb
1
2
17
a
Reaction conditions: coumarin (0.5 mmol), CF3SO2Na (1.5 mmol),
3
4
b
Mn(OAc)3Á2H2O (2.0 mmol) in HOAc (10 mL), 25 1C, 24 h. Isolated
c
yield. Detected by LC-MS.
5
a
Reaction conditions: coumarin (0.5 mmol), CF3SO2Na (1.5 mmol) and
b
Mn(OAc)3Á2H2O (2.0 mmol) in HOAc (10 mL), 25 1C, 24 h. Isolated
yield.
JPZ thanks the National Natural Science Foundation of China
for financial support (No. 20772088 and 21172163) and A Project
Funded by the Priority Academic Program Development of
Jiangsu Higher Education Institutions.
Scheme 3
groups like Cl and NO2 on the phenyl ring gave the products in
good yields (up to 70%) (Table 2, entries 8–11). In addition, the
electronic and steric effects of the 4-substituent of coumarins
were explored, this revealed that both of them played a less
significant role in the reaction (Table 2, entries 12–17).
A mechanism for the reaction of coumarins (1) with
CF3SO2Na (2) is proposed in Scheme 3. Trifluoromethyl radical
6 derived from 2 is selectively added to the 3-position of 1 to
form intermediate radical 7, which is oxidized by Mn(OAc)3 to
form carbocation 8, and deprotonation of 8 gives product 3.
We extended this method to other heteroarenes such as
2-quinolinone derivatives 4a and 4b, as expected, the CF3
radical was selectively added to the 3-position of 4a and 4b to
afford 3-trifluoromethyl quinolinone-2 (5a and 5b) in 58% and
53% yields, respectively (Table 3, entries 1 and 2). Furthermore,
when pyrimidinones (4c–4e) were exploited for the reaction,
5-trifluoromethyl pyrimidinones (5c–5e) were obtained in
57–63% yields (Table 3, entries 3–5).
In conclusion, a novel method for direct Csp2–H radical
trifluoromethylation of coumarins was developed through
the reaction of sodium trifluoromethanesulfinate (CF3SO2Na,
Langlois reagent) with coumarins in the presence of Mn(OAc)3.
The reaction proceeded under mild conditions in air to afford
selective 3-trifluoromethyl coumarins in moderate to good yields,
this methodology is straightforward and provides a general,
effective and cheap way for the synthesis of 3-trifluoromethyl
coumarins and other trifluoromethylated heteroarenes such
as 3-trifluoromethyl quinolinone-2 and 5-trifluoromethyl
pyrimidinones.
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