Trifluoromethylation of aromatic alkenes by visible-light-driven photoredox catalysis: Direct conversion of alkenes to 3-trifluoromethyl-1-propenyl and 1,3-bis(trifluoromethyl)-1-propenyl derivatives

Article abstract of DOI:10.1016/j.jfluchem.2015.07.020

Photoredox-catalyzed trifluoromethylation of alkenes using Umemoto's reagent as a CF₃ source under visible light irradiation has been developed. A Ru photocatalyst, [Ru(bpy)₃](PF₆)₂ (bpy = 2,2′-bipyridine), is useful for the present trifluoromethylation and preferable formation of 3-trifluoromethyl-1-propenyl derivatives is observed. Use of an excess amount of Umemoto's reagent readily induces double trifluoromethylation of electron-rich alkenes, resulting in 1,3-bis(trifluoromethyl)-1-propenyl skeleton.

Full text of DOI:10.1016/j.jfluchem.2015.07.020

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Journal of Fluorine Chemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Trifluoromethylation of aromatic alkenes by visible-light-driven
photoredox catalysis: Direct conversion of alkenes to
3-trifluoromethyl-1-propenyl and 1,3-bis(trifluoromethyl)-
1-propenyl derivatives
a,
Masashi Asano b, Ren Tomita a, Takashi Koike a, , Munetaka Akita
*
*
a Chemical Resources Laboratory, Tokyo Institute of Technology, Japan
b Department of Chemistry, Faculty of Science, Tokyo University of Science, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Photoredox-catalyzed trifluoromethylation of alkenes using Umemoto’s reagent as a CF3 source under
visible light irradiation has been developed. A Ru photocatalyst, [Ru(bpy)3](PF6)2 (bpy = 2,20-bipyridine),
is useful for the present trifluoromethylation and preferable formation of 3-trifluoromethyl-1-propenyl
derivatives is observed. Use of an excess amount of Umemoto’s reagent readily induces double
trifluoromethylation of electron-rich alkenes, resulting in 1,3-bis(trifluoromethyl)-1-propenyl skeleton.
ß 2015 Elsevier B.V. All rights reserved.
Received 16 April 2015
Received in revised form 11 July 2015
Accepted 16 July 2015
Available online xxx
Keywords:
Trifluoromethylation
Transition metal catalyst
Allyl compound
Electrophilic CF3 reagent
Photoredox catalysis
Step-economical process
1. Introduction
Gouverneur and co-workers showed that photoredox-catalyzed
trifluoromethylation of allylsilanes using electrophilic CF3
For the past few years, catalytic trifluoromethylation of alkenes
has been recognized as one of the useful strategies for access to a
variety of organofluorine compounds bearing C(sp3)–CF3 bonds
[1,2]. In 2011, trifluoromethylation of simple unactivated aliphatic
alkenes via allylic C–H bond cleavage using electrophilic CF3
reagents such as Umemoto’s reagent 1a [3] and Togni’s regent 1b
[4] was reported by the groups of Buchwald, Fu, Liu and Wang
(Scheme 1(a)). These reactions are useful methods for synthesis of
linear allyl compounds bearing a CF3 group, but outcomes of the
reactions with respect to branched alkenes and aromatic alkenes
were not well-documented [5,6]. In 2012, the groups of Sodeoka
and Gouverneur developed the Cu-catalyzed desilylative trifluor-
omethylation of allylsilanes using Togni’s reagent 1b as a CF3
source, leading to branched alkenes and aromatic alkenes bearing a
CF3 group at the allylic position (Scheme 1(b)) [7]. Furthermore,
reagents yielded internal alkenes with a CF3 group at the allylic
position [8]. The CF3-allyl compounds are known as important
synthetic intermediates for further functionalization and biologi-
cally active molecules [9]. Thus, development of a simple method
for synthesis of CF3-allyl compounds is still of great value.
Recently, photoredox catalysis with well-defined ruthenium
polypyridine complexes (e.g., [Ru(bpy)3]2+: bpy = 2,20-bipyridine)
has become a powerful tool for redox reaction in synthetic
chemistry because it can easily promote single-electron-transfer
(SET) processesundervisiblelightirradiation [10,11]. Ourgroup has
extensively developed photoredox-catalyzed trifluoromethylation
of olefins using electrophilic CF3 reagents such as Umemoto’s
reagent 1a and Togni’s reagent 1b [12]. Electrophilic CF3 reagents
can serve both as an electron acceptor and as a CF3 radical source by
photoredoxcatalysis. Herein we will disclose photoredox-catalyzed
trifluoromethylation of aromatic alkenes, in particular a-alkylstyr-
enes, using Umemoto’s reagent 1a as a CF3 source. This protocol is
the first example to access CF3-allyl compounds directly from
aromatic alkenes. In addition, further trifluoromethylation of the
CF3-allyl compounds allows us an opportunity to readily construct
1,3-bis(trifluoromethyl)-1-propenyl scaffolds (Scheme 1(c)) [13].
*
Corresponding authors at: R1-27, 4259 Nagatsuta, Midori-ku, Yokohama 226-
8503, Japan.
E-mail addresses: koike.t.ad@m.titech.ac.jp (T. Koike), makita@res.titech.ac.jp
(M. Akita).
http://dx.doi.org/10.1016/j.jfluchem.2015.07.020
0022-1139/ß 2015 Elsevier B.V. All rights reserved.
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Scheme 1. Transition-metal-catalyzed trifluoromethylations of alkenes: synthesis of alkenes bearing a CF3 group at the allylic position.
2. Results and discussion
We initially examined the reaction of
Umemoto’s reagent 1a in the presence of 2.5 mol% [Ru(b-
py)3](PF6)2 in DMSO-d6 at room temperature under visible light
the dark or in the absence of photocatalyst (entries 8 and 9). The
photoexcited catalyst plays a key role in the present reaction.
The result of the present photocatalytic trifluoromethylation
in preparative scales is summarized in Table 2. The yield of 3a of
the preparative scale was lower than that of the NMR experiment
due to volatility of 3a (entry 1 in Table 2 and entry 7 in Table 1).
a
-methylstyrene 2a with
irradiation (
1-butene 3a was formed in a 53% yield together with
-trifluoromethylstyrene 4a as a by-product (entry 1 in Table 1).
lmax = 425 nm). As a result, 4,4,4-trifluoro-2-phenyl-
a
-methyl-
Then, the reactions of heavier
a-methylstyrene derivatives
b
bearing functional groups were examined. Reactions of terminal
t
Exploration of the solvent showed that DMSO was the best solvent
with respect to the yield of 3a (entries 1–4). To improve the yield of
3a, addition of base (1.2 equiv.), K2CO3, pyridine and 2,6-di-tert-
butylpyridine, was tested (entries 5–7). Bulkier base, 2,6-di-tert-
butylpyridine, resulted in slightly improvement of the yield of 3a
(60% yield). The selectivity of products 3a and 4a is determined at
the stage of the deprotonation process (see below). In addition, the
present photocatalytic reaction did not proceed at all either in
alkenes such as
groups on the benzene ring and 2-(
a
-methylstyrene bearing Br (2b) and Bu (2c)
-methylvinyl)naphthalene
a
(2d) afforded the corresponding CF3-allyl products (3b–d) in
moderate yields (44–49% NMR yields) together with CF3-alkenes
4 (entries 2–4 in Table 2). Electron-rich a-methylstyrenes bearing
MeO (2e) and methylenedioxy (2f) groups on the benzene ring
gave the allyl products in low yields (3e: 24%, 3f: 11% NMR yields)
because of not only formation of CF3-alkenes 4 but also further
Table 1
Photocatalytic trifluoromethylation of
a
-methylstyrene.a
Entry
Solvent
Base (1.2 equiv of 2a)
% Yield of 3ab
3a:4ab
1
2
DMSO-d6
Acetone-d6
CD2Cl2
–
53
32
7
2.1:1
6.4:1
2.3:1
–
–
3
–
4
CD3CN
–
0
5
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
K2CO3
47
46
60
0
2.9:1
1.3:1
2.5:1
–
6
Pyridine
7
2,6-di-tert-butylpyridine
2,6-di-tert-butylpyridine
2,6-di-tert-butylpyridine
8c
9d
0
–
a
Reaction conditions: a mixture of [Ru(bpy)3](PF6)2 (1.3
mmol, 2.5 mol%), 1a (60
mmol, 1.2 equiv), 2a (50
m
mol, 1.0 equiv), base (60
mmol, 1.2 equiv) and SiEt4 (an internal
standard) in a solvent (0.5 mL) was irradiated by 3 W blue LEDs (
l
= 425 ꢀ 15 nm) at room temperature.
b
Determined by 1H NMR spectroscopy.
c
In the dark.
d
No photocatalyst.
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Table 2
Scope of the present trifluoromethylation of alkenes in preparative scales.a
Entry
1
Substrate 2
Product 3
% Yield of 3
3a: 42b
3:4b
2.5:1
CF3
Me
2a
2
3
3b: 49b
2.6:1
2:1
Br
Br
CF3
Me
2b
3c: 44b
tBu
tBu
CF3
CF3
Me
Me
2c
4
5
3d: 44b
2.4:1
1:1.1
2d
3e: 24b
MeO
MeO
CF3
Me
2e
6
7
3f: 11b
1:1.4
O
O
O
O
CF3
Me
2f
3g: 48b,d
Only 3
Me
Me
CF3
Me
2g (E/Z = 1/4.5 )
8
3h: 30d(58c,d,e
)
Only 3
Only 3
Only 3
9
3i: 10b,d
10
3j: 23d (60d,e
)
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Table 2 (Continued )
Entry
11
Substrate 2
Product 3
% Yield of 3
3:4b
3k: 58d (83d,e
)
Only 3
a
Reaction conditions for preparative scales: see Section 4 and Supporting Information. Yields are lower than those obtained by NMR experiments because of the volatility
of the products. Products 3 and 4 were not separable by column chromatography.
b
Determined by 19F NMR spectroscopy using CF3C6H5 or (CF3O)C6H5 as an internal standard.
c
Reaction time = 4 h.
d
In the absence of base.
e
Experiments of NMR scale were conducted (reaction conditions, see the footnote in Table 1) and yields were determined by 1H NMR spectroscopy using SiEt4 as an
internal standard.
trifluoromethylation of the formed CF3-allyl products 5 (5e: 24%
NMR yield and 5f: 28% NMR yield, vide infra) (entries 5 and 6).
terminal C55C bonds in the CF3-ally products (3g–i) are more
reactive toward trifluoromethylation, compared to the starting
internal alkenes (2g–i). As expected, alkenes 2, which were
designed so as to give CF3-allyl products 3 bearing internal C55C
bond, suppressed further trifluoromethylation and formation of
CF3-alkene 4. Reactions of (E)-1-ethylidene-1,2,3,4-tetrahydro-
naphthalene (2j) and 1-phenylcyclohexene (2k) afforded the
Reactions of internal alkenes,
a,b-dimethylstyrenes (2g–i),
dramatically suppressed formation of CF3-alkenes 4, but further
trifluoromethylation of the products 3 occurred to some extent,
resulting in low to moderate yields of 3 (3g: 48% NMR yield, 3h:
30% isolated yield, 3i: 10% NMR yield [14]) (entries 7–9). Probably,
Scheme 2. Double trifluoromethylation of alkenes via CF3-allyl compound 3.
Scheme 3. A plausible reaction mechanism.
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CF3-allyl products (3j, k) in 23 and 58% isolated yields,
respectively. These results suggest that preferable formation of
the CF3-allyl product 3 can be attributed to (i) facile deprotonation
of protons at the allylic position of 2, which are less sterically
hindered and (ii) large steric hindrance of the C55C bond on the
formed CF3-allyl product 3.
from blue LED lamp: h
bath) for 2 h.
n
= 425 ꢀ 15 nm) at room temperature (water
4.2. General procedure for the photocatalytic trifluoromethylation of
alkenes (reaction conditions in Table 2)
As mentioned above, further trifluoromethylation of CF3-allyl
products 3 was observed, especially for the reactions of electron-
rich alkenes (2e, 2f, 2i). Therefore, reactions using an excess
amount of Umemoto’s reagent 1a were examined to attempt
double trifluoromethylation (Scheme 2). As a result, double
trifluoromethylation proceeded smoothly to yield new bis(tri-
fluoromethylated) products, 1,1,1,5,5,5-hexafluoro-3-phenyl-2-
pentene derivatives (5e: 34%, 5f: 21%, 5i: 35% [15] isolated yields).
Remarkably, the reactions of terminal alkenes 2e and 2f exhibited
high E selectivity. In contrast, predominant formation of Z isomer
was observed in the reaction of internal alkene 2i possibly due to
steric hindrance of the CHMeCF3 group.
A 20 mL Schlenk tube was charged with [Ru(bpy)3](PF6)2
(5.4 mg, 6.3
m
mol), Umemoto’s reagent (1a) (1.0 ꢃ 102 mg,
0.30 mmol), alkenes
(65
2 (0.25 mmol), 2,6-di-tert-butylpyridine
L, 0.30 mmol) and dry DMSO (2.5 mL) under N2. Then, the
m
mixture was degassed by three freeze-pump-thaw cycles and
refilled with N2. The tube was irradiated for 6 h at room
temperature (water bath) with stirring by 3 W blue LED lamps
(h
n
= 425 nm ꢀ 15 nm) placed at a distance of 2–3 cm. Then, H2O
was added to the reaction mixture, which was then extracted with
Et2O. The organic layer was washed with H2O, dried (Na2SO4), and
filtered. The filtrate was concentrated in vacuo. The residue was
treated by mCPBA (0.18 g, ca. 0.72 mmol) in CH2Cl2 to convert the
dibenzothiophene to sulfoxide, which was more easily separated
from the products. After the solution was stirred at room temperature
for 2 h, an aqueous solution of Na2S2O3ꢁ5H2O was added to the
solution, and the products were extracted with CH2Cl2. The organic
layer was washed with H2O, dried (Na2SO4), and filtered. The filtrate
was concentrated in vacuo. The residue was purified by chromatog-
raphy on silica gel (eluent: pentane) and further purification was
conducted by GPC. Yields of 3a–3g and 3i were determined by 19F
NMR spectroscopy using CF3C6H5 or (CF3O)C6H5 as an internal
standard before treatment with mCPBA in the above-mentioned
procedure.
A plausible reaction mechanism is shown in Scheme 3. First, Ru
photocatalyst, [Ru(bpy)3]2+, is excited by irradiation with visible
light to form the excited state, *[Ru(bpy)3]2+, which undergoes SET
to Umemoto’s reagent 1a to give a CF3 radical (ꢁCF3) and the highly
oxidized Ru species, [Ru(bpy)3]3+. The generated CF3 radical (ꢁCF3)
reacts with alkene 2 to afford the trifluoromethylated radical
intermediate 30. The second SET event between the highly oxidized
Ru species, [Ru(bpy)3]3+, and the trifluoromethylated radical
intermediate 30 generates
a-CF3-substituted carbocationic inter-
mediate 3+, which subsequently undergoes deprotonation. Steric
factors might induce selective deprotonation from the intermedi-
ate 3+, leading to preferable formation of the CF3-allyl product 3
(the left cycle in Scheme 3). The CF3-allyl product 3, especially
alkene with an electron donating group and a terminal C55C bond,
is further susceptible to the trifluoromethylation and deprotona-
tion process, [12f] leading to the bis(trifluoromethylated) product
5 (the right cycle in Scheme 3).
4.3. General procedure for the photocatalytic double
trifluoromethylation of alkenes
A 20 mL Schlenk tube was charged with [Ru(bpy)3](PF6)2
(5.5 mg, 6.3
0.63 mmol), alkenes
m
mol), Umemoto’s reagent (1a) (2.0 ꢃ 102 mg,
2 (0.25 mmol), 2,6-di-tert-butylpyridine
(1.4 ꢃ 102 mL, 0.63 mmol) and dry DMSO (2.5 mL) under N2. Then,
the mixture was degassed by three freeze-pump-thaw cycles and
refilled with N2. The tube was irradiated for 6 h at room
temperature (water bath) with stirring by 3 W blue LED lamps
3. Conclusions
In conclusion, we have developed the photoredox-catalyzed
trifluoromethylation of alkenes using Umemoto’s reagent, leading
to preferable formation of 3-trifluoromethyl-1-propenyl deriva-
tives. In particular, this method is useful for synthesis of the CF3-
allyl product from branched and internal aromatic alkenes. In
addition, use of an excess amount of Umemoto’s reagent induces
the double trifluoromethylation of electron-rich alkenes, resulting
in 1,3-bis(trifluoromethyl)-1-propenyl derivatives. Further devel-
opment of this protocol in the synthesis of organofluorine
molecules is a continuing effort in our laboratory.
(h
n
= 425 nm ꢀ 15 nm) placed at a distance of 2–3 cm. Then, H2O
was added into the reaction mixture, and the reaction mixture was
extracted with Et2O. The organic layer was washed with H2O, dried
(Na2SO4), and filtered. The filtrate was concentrated in vacuo. The
residue was purified by chromatography on silica gel and further
purification was conducted by GPC if necessary.
Appendix A. Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.jfluchem.2015.
07.020.
4. Experimental
Details of experimental procedures and spectral data for new
compounds (3h, 3j, 3k, 5e, 5f and 5i) are summarized in the
Supporting Information.
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´
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[14] Under these reaction conditions, double trifluoromethylated product 5i was
formed in 25% NMR yield.
[15] An NMR experiment gave a 69% yield of 5i, indicating that isolated yield was
reduced through purification process. Double trifluoromethylation of 2i gave a
better yield than reactions of 2e and 2f because the reaction of 2i did not
produce by-product 4. Reaction conditions for NMR experiment of double
trifluoromethylation of 2i: A mixture of [Ru(bpy)3](PF6)2 (1.3 mmol, 2.5 mol%),
1a (0.13 mmol, 2.5 equiv), 2i (50 mmol, 1.0 equiv) and SiEt4 (an internal
standard) in DMSO-d6 (0.5 mL) was irradiated by 3 W blue LEDs
(l = 425 ꢀ 15 nm) at room temperature for 4 h.
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Please cite this article in press as: M. Asano, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.07.020