Iron-Mediated Chlorotrifluoromethylation of Alkenes with Sodium Trifluoromethanesulfinate

Article abstract of DOI:10.1002/cjoc.201500641

An iron-mediated three-component chlorotrifluoromethylation of both styrenes and aliphatic alkenes has been presented here. This reaction employs ferric chloride (FeCl₃) as the Cl source and the Langlois reagent (CF₃SO₂Na)

Full text of DOI:10.1002/cjoc.201500641

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DOI: 10.1002/cjoc.201500641
Iron-Mediated Chlorotrifluoromethylation of Alkenes with
Sodium Trifluoromethanesulfinate
Bin Yang,a Xiu-Hua Xu,a and Feng-Ling Qing*,a,b
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China
b College of Chemistry, Chemical Engineering and Biotechnology, Donghua University, Shanghai 201620, China
An iron-mediated three-component chlorotrifluoromethylation of both styrenes and aliphatic alkenes has been
presented here. This reaction employs ferric chloride (FeCl3) as the Cl source and the Langlois reagent (CF3SO2Na)
as the CF3 source. It provides a convenient pathway towards a wide range of chlorotrifluoromethylated compounds.
Keywords chlorotrifluoromethylation, alkene, Langlois reagent, radical
Introduction
Scheme 1 Chlorotrifluoromethylation of alkenes
Previous work:
visible light
The trifluoromethyl group is playing an increasing
important role in the fields of pharmaceuticals, agro-
chemicals, and materials due to its ability to enhance the
bioavailability, metabolic stability, and lipophilicity of
host molecule.[1] Therefore, a wide range of new and
efficient trifluoromethylation methods have been devel-
oped in the past decades.[2] Among them, difunctional-
ization-type trifluoromethylation of alkenes[3] including
hydrotrifluoromethylation,[4] oxtrifluoromethylation,[5]
Cl
Cl
Cl
photocatalyst
(a)
CF3SO2Cl
R = alkyl, COX
+
CF3
CF3
CF3
R
R
R
R
visible light
Ru(bpy)3(PF6)2
(b)
(c)
+
R
S
TMSCl
-
BF4
CF3
R = aryl
This work:
R
carbotrifluoromethylation,[6]
aminotrifluoromethyla-
FeCl3/K2S2O8
+
CF3SO2Na
tion,[6b,7] and halotrifluoromethylation[8] has emerged as
a powerful strategy for the preparation of various CF3-
bearing compounds. Despite these great achievements,
the chlorotrifluoromethylation of alkenes is relatively
scarce. Recently, Han,[8f] Dolbier,[8i] and Reiser[8j]
reported visible-light photocatalyzed chlorotrifluoro-
methylation of aliphatic alkenes or α,β-unsaturated
amides and esters using trifluoromethanesulfonyl chlo-
ride (CF3SO2Cl, b.p. 29－32 ℃) as the CF3 and Cl
source (Scheme 1a). Very recently, Masson reported a
visible-light photocatalyzed chlorotrifluoromethylation
of styrenes, using Umemoto reagent as CF3 source and
TMSCl as Cl source (Scheme 1b).[8k] In both of these
two protocols, the substrate scopes are relatively narrow.
Importantly, CF3SO2Cl is volatile and Umemoto reagent
is expensive, which limits their usage on a large scale.
Therefore, the development of practical chlorotrifluoro-
methylation of broader alkene substrates with operation-
ally simple and inexpensive trifluoromethylating rea-
gents is highly desirable.
R = alkyl, aryl
solid and inexpensive Langlois reagent (CF3SO2Na)[10]
as the CF3 source. In continuation of our research
interest in difunctionalization-type trifluoromethylation
of alkenes,[4a,5e,8h,9] herein we disclose an iron-mediated
chlorotrifluoromethylation of both styrenes and ali-
phatic alkenes with CF3SO2Na (Scheme 1c). This
protocol provides a convenient access to a variety of
chlorotrifluoromethylated compounds, which are useful
building blocks in organic synthesis.[11]
Experimental
A Schlenk tube equipped with a magnetic stir bar
was charged with FeCl3 (56.8 mg, 0.35 mmol),
CF3SO2Na (156.1 mg, 1.0 mmol), and K2S2O8 (264.9
mg, 1.35 mmol) in the glove-box. The tube was sealed
with a septum, evacuated and backfilled with Ar three
times. Then, freshly degassed CH3CN (2.0 mL) and the
alkene (0.5 mmol) were added. The reaction mixture
was stirred at 80 ℃ for 10 h. After the mixture was
cooled to room temperature, it was diluted with H2O.
Our group has recently developed a copper-catalyzed
oxytrifluoromethylation of alkenes[5e] and a copper-me-
diated bis(trifluoromethylation) of alkenes[9] using the
*
E-mail: flq@mail.sioc.ac.cn; Tel.: 0086-021-54925187; Fax: 0086-021-64166128
Received September 6, 2015; accepted October 13, 2015; published online November 13, 2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201500641 or from the author.
Chin. J. Chem. 2016, 34, 465—468
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465

Yang, Xu & Qing
COMMUNICATION
Then, the aqueous phase was extracted with Et2O. The
combined organic layer was dried over anhydrous
Na2SO4 and concentrated in vacuo. The residue was
purified by silica gel column chromatography to afford
the corresponding product.
ate to excellent yields. Notably, chloro, bromo, ester,
carboxy, and cyano containing substrates were compati-
ble with the reaction, enabling further transformations
(1e－1h, 1k). The substituent at the meta (2j) or ortho
(2k) position of the aromatic ring did not hinder the re-
action. To our delight, aliphatic alkenes 1m－1q pro-
ceeded smoothly to give products 2m－2q in good
yields, although larger amounts of CF3SO2Na and
K2S2O8 were needed.
Results and Discussion
We began our investigation by choosing styrene 1a
as the model substrate to react with CF3SO2Na and
K2S2O8 for the optimization of reaction conditions (Ta-
ble 1). The chlorotrifluoromethylation of styrene 1a
proceeded smoothly using CuCl2 as the initiator and Cl
source at 40 ℃ to give the desired product 2a in 43%
yield (Entry 1). Further screening of different metal salts
revealed that FeCl3 was optimal, giving 2a in 72% yield
(Entries 2－4). Switching of MeCN to DMF, DMSO or
NMP led to a sharp decrease of the yield (Entries 5－7).
On the other hand, slightly higher yield of 2a was ob-
served when the reaction temperature was increased
(Entries 8 and 9). Finally, the yield of 2a was improved
to 85% in the presence of FeCl3 (0.7 equiv.), CF3SO2Na
(2.0 equiv.), and K2S2O8 (2.7 equiv.) (Entry 10).
Table 2 Substrate scope of chlorotrifluoromethylation of al-
kenesa
FeCl3 (0.7 equiv.)
CF3SO2Na (2.0 equiv.)
K2S2O8 (2.7 equiv.)
R2
R2
Cl
CF3
R1
R1
MeCN, 80 oC, Ar
2
1
Cl
Cl
Cl
CF3
CF3
CF3
t-Bu
Ph
2a, 81%
2b, 71%
2c, 61%
Cl
Cl
Cl
CF3
CF3
CF3
MeO2C
Table 1 Screening of reaction conditionsa
AcO
HO2C
2d, 93%
2f, 71%
Cl
2e, 80%
metal salt (1.0 equiv.)
Cl
CF3SO2Na (3.0 equiv.)
CF3
Cl
Cl
K2S2O8 (4.0 equiv.)
CF3
CF3
CF3
Solvent, Temp., Ar
1a
2a
Cl
O2N
NC
2i, 51%
2g, 82%
2h, 61%
Entry
Metal salt
Solvent
MeCN
MeCN
MeCN
MeCN
DMF
Temp./℃
40
Yieldb/%
Cl
Br Cl
Cl
MeO
CF3
CF3
MeO2C
CF3
1
2
CuCl2
CuCl
FeCl2
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
FeCl3
43
22
61
72
20
24
13
78
83
85
40
2j, 87%
2k, 72%
2l, 91%
3
40
Ac
Cl
Cl
Cl
4
40
CF3
CF3
CF3
( )3
Ph
O
5
40
BzO
Cl
2o, 83%b
2m, 77%b
2n, 82%b
O2N
6
DMSO
NMP
40
NC
7
40
Cl
CF3
CF3
8
MeCN
MeCN
MeCN
60
( )3
2p, 83%b
O
( )3
2q, 82%b
O
9
10c
80
a
80
Reaction conditions: 1 (0.5 mmol), CF3SO2Na (1.0 mmol),
a Reaction conditions: 1a (0.25 mmol), CF3SO2Na (0.75 mmol),
K2S2O8 (1.0 mmol), metal salt (0.25 mmol), solvent (1 mL),
temperature, under argon. b Yield was determined by 19F NMR
K2S2O8 (1.0 mmol), FeCl3 (0.35 mmol), MeCN (2 mL), 80 ℃,
under argon, isolated yield. CF3SO2Na (1.25 mmol), K2S2O8
(1.7 mmol).
b
c
using benzotrifluoride as an internal standard. CF3SO2Na (0.5
Remarkably, this facile protocol could serve as an
efficient synthetic strategy to introduce CF3 and Cl
groups simultaneously to complex molecules, such as
vinylestrine 1r and vinyl-N-benzoyl-L-tyrosine ethyl
ester 1s (Scheme 2). The corresponding chlorotrifluoro-
methylated products were obtained in moderate to good
yields. These results showed that this method might be
applicable to “late-stage chlorotrifluoromethylation” of
natural products and drugs.
mmol), K2S2O8 (0.68 mmol), FeCl3 (0.18 mmol).
With the optimized reaction conditions in hand (Ta-
ble 1, Entry 12), we next investigated the substrate
scope of iron-mediated chlorotrifluoromethylation of
alkenes (Table 2). Styrenes bearing both electron-do-
nating groups (1b－1d, 1j) and electron-withdrawing
groups (1e－1i, 1k) reacted smoothly to afford the cor-
responding chlorotrifluoromethyled products in moder-
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Chin. J. Chem. 2016, 34, 465—468

Iron-Mediated Chlorotrifluoromethylation of Alkenes with Sodium Trifluoromethanesulfinate
Scheme 2 Iron-mediated chlorotrifluoromethylation of vinyles-
reine and vinyl-N-benzoyl-L-tyrosine ethyl ester (diastereomeric
ratios determined by 19F NMR analysis of crude mixtures)
onic intermediate B, which undergoes nucleophilic at-
tack by chloride anion to form the chlorotrifluoro-
methylated product 2.
O
Me
O
Me
Conclusions
H
standard
H
In conclusion, we have successfully accomplished a
practical and efficient method for chlorotrifluorometh-
ylation of both styrenes and aliphatic alkenes. This
transformation is highlighted by the use of simple and
inexpensive reagents FeCl3 and CF3SO2Na. It opens up
a new avenue for the synthesis of chlorotrifluoromethyl-
ated compounds.
conditions
H
H
H
H
F3C
Cl
1r
2r, 65% (dr > 99:1)
CO2Et
CO2Et
NHBz
standard
conditions
NHBz
F3C
1s
Cl
2s, 86% (dr = 98:2)
Acknowledgement
We are grateful to the National Natural Science
Foundation of China (Nos. 21421002, 21332010,
21272036), the National Basic Research Program of
China (No. 2012CB21600), and Shanghai City (No.
15PJ1410300) for funding this work.
To explore the mechanism of chlorotrifluoromethyl-
ation of alkenes, some preliminary control experiments
were conducted. When 2,2,6,6-tetramethyl-1-piperid-
inyloxy (TEMPO) was added in the standard reaction,
the desired transformation was almost inhibited
(Scheme 3a). Moreover, the reaction of compound 1d
and CF3SO2Na in the presence of catalytic FeCl3 (10
mol%) and Bu4NCl (3.0 equiv.) could also produce 2d
in 60% yield (Scheme 3b). The above results suggested
that a radical/cationic process was probably involved.
Based on the mechanistic experiments and previous re-
ports,[12] we proposed a plausible mechanism of this
chlorotrifluoromethylation reaction (Scheme 4). Firstly,
the trifluoromethyl radical is generated from CF3SO2Na
through a single electron transfer (SET) process under
the treatment of FeCl3 and K2S2O8.[12a,12c] Then, alkene
1 reacts with the trifluoromethyl radical to give the rad-
ical intermediate A. The intermediate A can be further
oxidized by FeCl3 and K2S2O8 to generate the cati-
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