Cobalt-Catalyzed Radical Hydrotrifluoroethylation of Styrenes with Trifluoroethyl Iodide

Article abstract of DOI:10.1021/acs.orglett.0c02300

The cobalt-catalyzed radical trifluoroethylation of styrenes with CF3CH2I under mild conditions is described. By controlling the reaction conditions, we realized both radical trifluoroethylation self-coupling and hydrotrifluoroethylation of styrenes. The

Full text of DOI:10.1021/acs.orglett.0c02300

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Letter
Cobalt-Catalyzed Radical Hydrotrifluoroethylation of Styrenes with
Trifluoroethyl Iodide
Bin He, Qijun Pan, Yong Guo, Qing-Yun Chen,* and Chao Liu*
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ABSTRACT: The cobalt-catalyzed radical trifluoroethylation of
styrenes with CF3CH2I under mild conditions is described. By
controlling the reaction conditions, we realized both radical
trifluoroethylation self-coupling and hydrotrifluoroethylation of
styrenes. The standard conditions are also suitable for other
fluoroalkyl halides, generating the corresponding hydrofluoroalkyla-
tion products in good yields.
F3-containing compounds have broad applications in
fluorinated agrochemicals, pharmaceuticals, and func-
C
tional materials because their introduction into an organic
compound can significantly improve its activity, lipophilicity,
and metabolic stability.1 Thus, synthetic methodologies of
CF3-containing compounds, including the construction of C−
CF3 bonds2 and CF3 introduction via versatile CF3-containing
building blocks,3 have attracted a great deal of attention and
have been extensively developed in recent years. Among them,
CF3 introduction via direct trifluoroethylation reactions,3b,c
with readily available CF3CH2-containing starting materials,
such as CF3CH2I,4 CF3CH2N2,5 CF3CHCl2,6 CF3CH2SO2Cl,7
(CF3CH2)2Zn,8 [ArI(CH2CF3)]+(OTf)−,9 CF3COOH,10
[Ph2S(CH2CF3)]+(OTf)−,11 etc., is highly valuable. Specifi-
cally, CF3CH2I is an important and popular trifluoroethylation
building block due to its inexpensive price and ease of use.
Radical 1,2-difunctionalization type fluoroalkylation of
various unsaturated carbon−carbon bonds for simultaneous
and efficient incorporation of one fluoroalkyl group and the
other important functional group in one step has been a hot
research field.12 Radical trifluoroethylation of a CC bond
serves as a powerful synthetic strategy for CF3CH2-containing
compounds. For examples, an elegant photochemical trifluor-
oethylation of styrene derivatives with CF3CH2I has been
reported by Carreira, Martin, and co-workers to efficiently
provide various trifluoroethylated alkenes (Figure 1a).13 The
Xiang group disclosed a copper/silver co-mediated oxidative
coupling of styrenes with CF3CH2I to afford β-CF3-substituted
ketones (Figure 1d).14 Trifluoroethylstyrenes were efficiently
produced by copper-catalyzed decarboxylative trifluoroethyla-
tion of cinamic acid derivatives with CF3CH2I (Figure 1e).15
We have long-standing interest in inert C−X bond activation
and radical reactions of CF3CH2I and its analogues via a single-
electron transfer (SET) process. The reductive cleavage of
unactivated carbon−chlorine bond of various fluoroalkyl
halides, such as perfluoroalkyl chlorides (RFCl),16 2-chloro-
Figure 1. Radical trifluoroethylation of styrenes with CF3CH2I.
Received: July 13, 2020
https://dx.doi.org/10.1021/acs.orglett.0c02300
© XXXX American Chemical Society
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1,1,1-trifluoroethane (CF3CH2Cl),17 and 1,1-dichloro-2,2,2-
trifluoroethane (CF3CHCl2),6,18 via a single-electron transfer
(SET) process has been achieved. Notably, we have already
realized the sulfinatodehalogenation of CF3CH2I to generate
the CF3CH2 radical and its subsequent reactions with various
unactivated alkenes.19 Moreover, the photocatalytic activation
of CF3CH2I can efficiently afford the corresponding CF3CH2
radical, which can react with styrenes to afford the desired γ-
trifluoromethyl alcohols in the presence of an oxygen source
(Figure 1b),20 or with aryl silyl enol ethers to produce the
corresponding β-CF3-substituted ketones (Figure 1c).21 As a
continuation of our research interest in the activation and
radical reactions of CF3CH2I, we have currently investigated
the activation of CF3CH2I and its subsequent radical reactions
with styrenes under a cobalt catalyst. Without the addition of
an extra hydrogen source, addition of the generated CF3CH2
radical to styrenes proceeded smoothly to produce a new
radical intermediate and its self-coupling finished the
corresponding trifluoroethylation self-coupling products in
high yields. Interestingly, in the presence of both thiophenol
and tris(trimethylsilyl)silane as an extra hydrogen source, high
yields of the desired hydrotrifluoroethylated products were
obtained.
Our study commenced by using 4-vinylbiphenyl (1a) as the
model substrate, CF3CH2I as the trifluoroethyl source, and
zinc powder as the reductant at room temperature for 6 h in
acetone. Initially, we investigated the influence of different
metal salts as a catalyst with the assistance of PPh3 as the
ligand (see Table S1 for details). However, instead of the
desired hydrotrifluoroethylation product, trifluoroethylation
self-coupling product 2a was obtained. We tested the effect of
CF3CH2I loading, various catalysts, and their loadings and
found that 0.6 equiv of CoCl2 combined with 1.5 equiv of
CF3CH2I afforded the best yield of 2a.
of 4-vinylbiphenyl (1a) as the substrate resulted in a good yield
of 2a of 82%, which is a 1:1 mixture of two diastereomers.
After repeat flash column chromatography and preparative thin
layer chromatography on silica gel, they can be successfully
separated and diastereomer 2a″ was unambiguously assigned
by X-ray crystallographic analysis.22 Other substrates contain-
ing various groups, including methyl, methoxy, and fluorine, on
the aromatic ring are all applicable to the reactions, affording
the target products in nice yields.
Aiming at hydrotrifluoroethylation of vinylbiphenyl 1a, we
continued to examine screening conditions by adding an extra
hydrogen source (see Tables S4−S7 for details). Notably,
CoBr2 and PPh3 stood out as the best catalyst combination and
were used in the radical hydrotrifluoroethylation reactions (see
Tables S2 and S3 for details), and the first choice of an extra
hydrogen source that came to our mind was thiol because it is
known that an alkyl radical can readily abstract a hydrogen
from thiol.23 After examining various thiols, we found
thiophenol (PhSH) performed best and the desired hydro-
trifluoroethylation product 3a was successfully obtained (see
Table S4 for details). To our delight, the use of 1.0 equiv of
thiophenol efficiently suppressed the formation of self-coupling
product 2a, but another byproduct 4 was generated obviously
due to the combination of benzyl radical and phenylthio
radical generated in the reaction system (Figure 5). A further
increase in thiophenol loading resulted in more byproduct 4,
and the same yield of desired product 3a was observed (see
Tables S5 and S6 for details). Additionally, it is worth
mentioning that the direct reaction of the CF3CH2 radical with
PhSH to give PhSCH2CF3 in the reaction mixture was
observed by 19F NMR spectroscopy.
Next, we considered adding a second extra hydrogen source
to transfer the phenylthio radical back to thiophenol to
suppress the formation of side product 4. We chose
tris(trimethylsilyl)silane [(Me3Si)3SiH] because the alkyl
radical generated from addition of the CF3CH2 radical with
styrene is not prone to abstracting the hydrogen from
(Me3Si)3SiH, while the phenylthio radical can readily abstract
the hydrogen of (Me3Si)3SiH. We then investigated the
influence of its loading (see Table S7 for details). Fortunately,
it was observed that (Me3Si)3SiH did effectively suppress the
production of 4. The more (Me3Si)3SiH we used, the less
byproduct 4 we obtained. Although utilization of 1.0 equiv of
(Me3Si)3SiH almost completely eliminated byproduct 4, it was
found that some starting styrene was still not consumed. To
improve the yield of desired product 3a, we further
investigated the loading of CF3CH2I and Zn powder used
(see Table S7 for details). We found that 1.5 equiv of Zn
powder and 3.0 equiv of CF3CH2I afforded the best yield of
88%. On the basis of all of the screening results mentioned
above, the optimized conditions for the cobalt-catalyzed radical
trifluoroethylation of styrenes were set as follows: styrene (1.0
equiv), CF3CH2I (3.0 equiv), CoBr2 (0.2 equiv), PPh3 (0.8
equiv), Zn (1.5 equiv), PhSH (1.0 equiv), (Me3Si)3SiH (1.0
equiv), acetone, Ar atmosphere, room temperature, 12 h.
With optimized reaction conditions established, we then
investigated the scope of various styrenes for the cobalt-
catalyzed radical hydrotrifluoroethylation reactions (Figure 3).
We first studied the hydrotrifluoroethylation of substrates 1c−
1j bearing electron-donating substituents on the aromatic ring.
Compounds bearing methyl, tert-butyl, methoxy, hydroxyl,
amino, and acetoxy substituents on the benzene core at meta or
para positions afforded the desired products in moderate to
With the optimal conditions for product 2 in hand, several
styrenes were subjected to the cobalt-mediated trifluoroethy-
lation self-coupling reactions. As shown in Figure 2, utilization
Figure 2. Trifluoroethylation self-coupling reactions of various
styrenes. Reaction conditions: 1 (0.5 mmol, 1.0 equiv), CF3CH2I
(0.75 mmol, 1.5 equiv), Zn (1.0 mmol, 2.0 equiv), CoCl2 (0.3 mmol,
0.6 equiv), PPh3 (1.2 mmol, 2.4 equiv), acetone (5 mL), rt, 12 h, Ar
a
atmosphere. Isolated yields are shown. The yield was determined by
19F NMR spectroscopy with trifluorotoluene as an internal standard
and 1H NMR spectroscopy using dibromomethane as an internal
standard.
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Figure 4. Substrate scope with respect to fluoroalkyl halides for the
cobalt-catalyzed radical hydrofluoroalkylation of various styrenes with
RFX. Reaction conditions: 1 (0.5 mmol, 1.0 equiv), RFX (1.5 mmol,
3.0 equiv), Zn (0.75 mmol, 1.5 equiv), CoBr2 (0.1 mmol, 0.2 equiv),
PPh3 (0.4 mmol, 0.8 equiv), PhSH (0.5 mmol, 1.0 equiv),
(Me3Si)3SiH (0.5 mmol, 1.0 equiv), acetone (5 mL), rt, 12 h, Ar
atmosphere. Isolated yields are shown.
Figure 3. Substrate scope with respect to styrenes for the cobalt-
catalyzed radical hydrotrifluoroethylation reactions of styrenes with
CF3CH2I. Reaction conditions: 1 (0.5 mmol, 1.0 equiv), CF3CH2I
(1.5 mmol, 3.0 equiv), Zn (0.75 mmol, 1.5 equiv), CoBr2 (0.1 mmol,
0.2 equiv), PPh3 (0.4 mmol, 0.8 equiv), PhSH (0.5 mmol, 1.0 equiv),
(Me3Si)3SiH (0.5 mmol, 1.0 equiv), acetone (5 mL), rt, 12 h, Ar
atmosphere. Isolated yields are shown.
good yields (49−92%). As for the substrates with electron-
withdrawing groups (1k−1p), the transformation was
amenable under standard conditions to halogen substitution
with fluorine, chlorine, and bromine as well as a cyano
substituent. Moreover, vinylnaphthalenes 1s and 1t were
suitable substrates for this protocol, resulting in good yields of
the corresponding hydrotrifluoroethylation products. 1-Sub-
stituted styrenes 1u and 1v were subjected to the standard
conditions and delivered good yields of the corresponding
products in 76−84% yields. Unfortunately, internal alkenes are
not suitable for the transformation, and no desired products
are observed, which might be due to their steric hindrance
effect. Furthermore, a structurally complicated biologically
active steroid derivative 1w was selected as a candidate for this
transformation, producing desired product 3w in 70% yield.
Gram-scale synthesis of 3f was carried out, and an excellent
yield of 90% was achieved, demonstrating the good scalability
of the reaction. Notably, the structure of 3a was unambigu-
ously assigned by X-ray crystallographic analysis.22
To further expand the substrate scope of this transformation,
we also decided to explore the substrate scope with respect to
various fluoroalkyl halide derivatives, and the results are
summarized in Figure 4. A range of fluoroalkyl halides
participated in the cobalt-cataylzed hydrofluoroalkylation
reactions of styrenes to successfully lead to the corresponding
hydrofluoroalkylation products in good yields.
On the basis of the experimental results described above and
the literature,16b,17c we proposed a possible mechanism for the
cobalt-catalyzed radical trifluoroethylation of various styrenes
(Figure 5). The catalyst CoBr2 or CoCl2 is reducted into active
catalyst species Co(PPh3)4 in the presence of Zn and PPh3,
Figure 5. Proposed mechanism for the cobalt-catalyzed radical
fluoroalkylation of various styrenes.
which can efficiently activate CF3CH2I and generate the
CF3CH2 radical. Its addition to styrenes results in new alkyl
radical species A. In the absence of an extra hydrogen source,
self-coupling of intermediate A occurred to produce the
corresponding trifluoroethylation self-coupling products. With
thiophenol and tris(trimethylsilyl)silane as the extra hydrogen
source, subsequent hydrogen abstraction of intermediate A
from thiophenol finishes the desired hydrofluoroalkylation
products and phenylthio radical. The resulting phenylthio
radical abstracts a hydrogen atom from tris(trimethylsilyl)-
silane to regenerate thiophenol, avoiding the side reaction of
alkyl radical species A with phenylthio radical. The radical
character of this transformation was further supported by the
radical inhibition experiments with a radical scavenger [2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO)] and an electron
transfer scavenger (1,4-dinitrobenzene) (see Table S8 for
details).
In conclusion, styrenes make up a challenging class of
substrates for current radical hydrotrifluoroethylation reactions
because of the potentially serious side reactions. We have
successfully developed a mild and efficient cobalt-catalyzed
radical trifluoroethylation reaction of styrenes with CF3CH2I
to produce hydrotrifluoroethylated products in the presence of
thiophenol and tris(trimethylsilyl)silane, while trifluoroethyla-
tion self-coupling products were obtained in their absence.
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Notably, a variety of other fluoroalkyl halides is also
compatible with a current transformation to afford the
corresponding hydrofluoroalkylation products in good yields.
Given the overall practicality and scope, this diverse trans-
formation may provide a good route for the introduction of
important fluoroalkyl groups, including the CF3 group, into
organic compounds.
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AUTHOR INFORMATION
■
Corresponding Authors
Chao Liu − School of Chemical and Environmental Engineering,
Shanghai Institute of Technology, Shanghai 201418, China;
Key Laboratory of Organofluorine Chemistry, Shanghai
Institute of Organic Chemistry, University of Chinese Academy
of Sciences, Chinese Academy of Sciences, Shanghai 200032,
China; orcid.org/0000-0003-1968-031X;
Email: chaoliu@sit.edu.cn
Qing-Yun Chen − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China; Email: chenqy@sioc.ac.cn
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Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
Qijun Pan − School of Chemical and Environmental
Engineering, Shanghai Institute of Technology, Shanghai
201418, China
Yong Guo − Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry, University of Chinese
Academy of Sciences, Chinese Academy of Sciences, Shanghai
200032, China
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Complete contact information is available at:
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge the financial support from
the National Natural Science Foundation of China (21421002,
21871283, 21737004, and 21672239).
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