Three-component oxytrifluoromethylation of alkenes: Highly efficient and regioselective difunctionalization of C=C bonds mediated by photoredox catalysts

Article abstract of DOI:10.1002/anie.201205071

Here comes the sun: A facile vicinal difunctionalization of alkenes, oxytrifluoromethylation, was established by visible-light-driven photoredox catalysis. Judicious choice of the CF₃ source is key. Nucleophiles such as water, alcohols, and carboxylic acids can be used in this highly efficient (2-4 h) and regioselective (100 %) transformation using light-emitting diode (LED) lamps and natural sunlight. SET=single-electron transfer. Copyright

Full text of DOI:10.1002/anie.201205071

Angewandte
Chemie
DOI: 10.1002/anie.201205071
Synthetic Methods
Three-component Oxytrifluoromethylation of Alkenes: Highly
=
Efficient and Regioselective Difunctionalization of C C Bonds
Mediated by Photoredox Catalysts**
Yusuke Yasu, Takashi Koike,* and Munetaka Akita*
Organofluorine compounds continue to increase in impor-
tance in the pharmaceutical and agrochemical fields as well as
in the materials science field.[1] In particular, the trifluoro-
methyl (CF3) group is considered to be a useful structural
motif in many biologically active molecules because it can
often influence chemical and metabolic stability, lipophilicity,
and binding selectivity.[2] Thus, the development of new
methodologies for highly efficient and selective incorporation
of a CF3 group into diverse skeletal structures has attracted
great interest of synthetic chemists.[3] The strategies for
trifluoromethylation can be classified into three types, that
is, nucleophilic, electrophilic, and radical trifluoromethyla-
tion. The electrophilic and radical transformations using
Umemotoꢀs reagent 1a (S-(trifluoromethyl)dibenzothiophe-
nium tetrafluoroborate),[4] and Togniꢀs reagents 1b (1-tri-
fluoromethyl-1,2-benziodoxol-3-(1H)-one) and 1c (1-tri-
fluoromethyl-1,3-dihydro-3,3-dimethyl-1,2-benziodoxole)[5]
have attracted attention because the reagents are easy to
handle in terms of shelf-stable solid chemicals at room
temperature.[6]
Trifluoromethylation of aromatic compounds is a hot
Scheme 1. Transition-metal-catalyzed trifluoromethylation of alkenes
with electrophilic trifluoromethylating reagents (1a–c). a) CuI-mediated
allylic trifluoromethylation reported by Parsons and Buchwald,[8a] Liu
et al.,[8b] and Wang et al.[8c]. b) CuI-mediated benzoyloxytrifluoromethy-
lation reported by Szabꢀ and co-workers.[11] c) This work: three-
component oxytrifluoromethylation by photoredox catalysis
research area and effective methods have been established.[7]
In contrast, it is apparent that trifluoromethylation of simple
alkenes is still developing.[8–11] Recently, Parsons and Buch-
wald,[8a] Liu et al.[8b] and Wang et al.[8c] reported copper-
mediated allylic trifluoromethylation with electrophilic tri-
fluoromethylating reagents, thus leading to allylic CF3 com-
pounds (Scheme 1a). The detailed reaction mechanism
involving a Cu/CF3 species, and the question as to whether
they proceed through a radical or nonradical pathway, is open
to further discussion. During preparation of this manuscript,
Szabꢁ and co-workers reported a copper-catalyzed benzoyl-
oxytrifluoromethylation with Togniꢀs reagent 1b (Sche-
me 1b).[11] In contrast, recent studies by the groups of
MacMillan,[12a,b] Stephenson,[9d,e] and others[12c,d] proved the
conversion of CF3I and CF3SO2Cl into the CF3 radical (CCF3)
by photoredox catalysis. For the past few years, photoredox
catalysis using the well-defined ruthenium(II) polypyridine
derivatives (e.g. [Ru(bpy)3]2+) and the relevant cyclometa-
lated iridium(III) complexes has been regarded as a valuable
synthetic tool for redox reactions on the basis of their visible-
light-driven single-electron transfer (SET).[13–15] We envi-
sioned that electrophilic trifluoromethylating reagents such as
Umemotoꢀs reagent 1a and Togniꢀs reagents (1b, c) could also
serve as precursors to the CF3 radical in the presence of
photoredox catalysts. In addition, we expected difunctional-
ization of alkenes through a SET photoredox process
(Scheme 1c). Although it is known that selective difunction-
alization of an alkene is an extremely powerful chemical
transformation, only a limited number of reports involving
trifluoromethylation have been shown.[9–11] Herein, we report
novel three-component intermolecular oxytrifluoromethyla-
tion of alkenes. Highly efficient (usually 2–4 h) and regiose-
lective incorporation of a CF3 group and a variety of
O functionalities such as hydroxy, alkoxy, and carboxy
[*] Y. Yasu, Dr. T. Koike, Prof. Dr. M. Akita
Chemical Resources Laboratory, Tokyo Institute of Technology
4259 Nagatsuta, Midori-ku, Yokohama 226-8503 (Japan)
E-mail: koike.t.ad@m.titech.ac.jp
makita@res.titech.ac.jp
Homepage: http://www.res.titech.ac.jp/~smart/smart_e.html
[**] This work was supported by a Grant-in-Aid from the Ministry of
Education, Culture, Sports, Science of the Japanese Government
(No 23750174) and the global COE program (the GCOE) through
the “Education and Research Center for Emergence of New
Molecular Chemistry”.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205071.
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Table 2: Photocatalytic oxytrifluoromethylation of styrene 2a.[a,b]
=
groups to C C bonds has been achieved by photoredox
catalysis under visible-light irradiation (Blue LEDs) and
sunlight at room temperature.
We initially examined the photocatalytic hydroxytri-
fluoromethylation of styrene (2a) with 1.2 equivalents of 1a
or 1b, c using 5 mol% of the photoredox catalyst [fac-
Ir(ppy)3][16] in a mixture of [D6]acetone and D2O (9:1) under
visible-light irradiation (Blue LEDs: lmax = 425 nm; Table 1,
Entry
4
R
Yield [%][c]
1
2
3
4
4a
4b
4c
4d
Me
Et
nPr
iPr
3aa: 78 (99[d])
3ab: 75
3ac: 76
Table 1: Optimization of photocatalytic hydroxytrifluoromethylation of
styrene (2a).[a]
3ad: 84
5
4e
3ae: 51
6
7
4 f
3af: 72
3ag: 74
4g
Yield [%][b]
8
4h
3ah: 87 (1:1 d.r.)
Entry
CF3 reagent
Photocatalyst
9
10
4i
4j
COMe
COEt
3ai: 74
3aj: 72
1
2
3
4
1a
1b
1c
1a
1a
1a
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
[fac-Ir(ppy)3]
[Ru(bpy)3](PF6)2
[fac-Ir(ppy)3]
none
97 (88[c])
62
4
96
0
0
[a] For reaction conditions, see the Supporting Information. [b] Yields of
the isolated products are lower than those determined by NMR
spectroscopy because of the volatility of the products. [c] Yield of isolated
5[d]
6
1
products. [d] Yield was determined by H NMR spectroscopy using
tetraethylsilane as an internal standard.
[a] Reaction conditions as indicated. [b] Yield determined by NMR
spectroscopy. [c] Yield of isolated product from preparative scale
reaction; see the Supporting Information. [d] In the dark. bpy=2,2’-
bipyridine, LED=light-emitting diode, ppy=2-phenylpyridine.
The reaction of 1-methoxy-2-propanol (4h) gave the product
in 87% yield as a mixture of two diastereomers (1:1; entry 8).
Acetic acid (4i) and propionic acid (4j) afforded the
corresponding CF3-containing esters 3ai and 3aj in 74 and
72% yield, respectively (entries 9 and 10). These results
indicate that the present photocatalytic oxytrifluoromethyla-
tion leads to the efficient and regioselective reactions,
regardless of the O nucleophiles.
entries 1–3). The experiments confirmed the formation of
deuterated 3,3,3-trifluoro-1-phenyl-1-propanol (3a) in every
case, however, the choice of the trifluoromethylating reagent
turned out to be crucial for efficiency and chemoselectivity.
Umemotoꢀs reagent 1a afforded the alcohol 3a with high
chemo- and regioselectivity in 97% yield as determined by
1H NMR spectroscopy (entry 1). Even when the catalyst
loading was reduced to 0.5 mol% in a preparative scale
experiment, 3a was obtained in 88% yield upon isolation. In
contrast, Togniꢀs reagents 1b, c provided a mixture of 3a and
olefinic by-products. Another photocatalyst, [Ru(bpy)3]-
(PF6)2, also promoted the present reaction in a manner
similar to [fac-Ir(ppy)3] (entry 4). Notably, the product 3a was
not obtained either in the dark or in the absence of the
photoredox catalyst (entries 5 and 6), thus strongly support-
ing the involvement of the photoexcited species of the
photoredox catalyst in the reaction.
Next, we investigated other O nucleophiles (ROH; 4)
such as alcohols and carboxylic acids (Table 2). All reactions
were conducted in dry CH2Cl2/ROH because the present
hydroxytrifluoromethylation is so efficient that it can be
promoted by a trace amount of water in the acetone
solvent.[17] As a result, alkoxytrifluoromethylation and car-
boxytrifluoromethylation smoothly proceeded not only to
introduce a CF3 group to an alkene but also to construct ether
and ester functionalities. Reactions of 2a with primary (4a–c
and 4g) and secondary (4d,f) alcohols produced the expected
CF3-substituted ethers 3aa–ad, 3af, and 3ag in good yields
(entries 1–4, 6, and 7). The sterically hindered tertiary alcohol
tert-amyl alcohol (4e), resulted in a low yield of 3ae (entry 5).
The scope and limitations of the present photocatalytic
hydroxytrifluoromethylation are summarized in Scheme 2.
Styrenes with the electron-donating substituent MeO (2b) on
the benzene ring smoothly produced the corresponding three-
component coupling product 3b in 96% yield after 2.5 hours.
In addition, this reaction can be applied to styrenes bearing
halogen atoms such as F (2c), Cl (2d), and Br (2e), an ester
group such as AcO (2 f), a boronic acid ester such as Bpin
(2h), and an acetal group (2l). The corresponding alcohol
products 3c–f,h[18] and l were obtained in good yields (84–
98%) without any loss of the functional groups. In particular,
the Br and Bpin functionalities can serve as potential handles
for additional transformations. In contrast, substrates with
a strongly electron-withdrawing group such as CF3 (2g) on the
benzene ring resulted in a low yield. Styrenes with a-alkyl and
a-aryl substituents (2i and j) afforded the corresponding
alcohols 3i (82%) and 3j (90%), respectively. Next, to
expand the scope, internal alkenes were examined. The
reaction of trans-b-methylstyrene (2k) gave the single regio-
isomer 3k as a mixture of two diastereomers (1:1 d.r.) in 88%
yield, and has the 1,1,1-trifluoroisopropyl skeleton used as
modifications of amino acids and biologically active com-
pounds.[19] Remarkably, the reaction of the trisubstituted
alkene 1-phenylcyclohexene (2m) proceeded in a highly
regio- and diastereoselective manner (1:10 d.r.), that is, the
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Scheme 3. Studies on diastereoselective oxytrifluoromethylation of
trans-stilbene (2n).
Scheme 2. The scope and limitations of the present hydroxytrifluoro-
methylation. Yield are given as yields of isolated products. For reaction
conditions, see the Supporting Information. [a] Yield was determined
by 1H NMR spectroscopy using tetraethylsilane as an internal stan-
dard. [b] Irradiation time=8 h.
Scheme 4. Application to synthesis of CF3-containing tetrasubstituted
alkene: panomifene.
CF3 and hydroxy groups were introduced in an anti fashion, in
95% yield. The reactions of trans-stilbene (2n) and indene
(2o) also showed a moderate diastereoselectivity. Further-
more, the electron-rich alkene 3,4-dihydro-2H-pyran (2p) can
be used in this photocatalytic system. However, the simple
linear alkene 1-octene did not react at all.[20] These results
show that the present hydroxytrifluoromethylation is regio-
specific for both terminal and internal electron-rich alkenes.
In addition, the featured effectiveness of styryl substrates and
electron-rich alkenes supports the involvement of the elec-
tron-deficient CF3 radical in this reaction.
Stereoselective difunctionalization of alkenes is the next
stage for this work. Before advancing to stereocontrolled
reactions, we tested diastereocontrolled reactions by changing
the O nucleophiles. Based on the results summarized in
Scheme 2, 2n was chosen as a substrate because diastereose-
lective hydroxytrifluoromethylation of 2n was observed to
a certain extent. As a result, oxytrifluoromethylation with
O nucleophiles such as MeOH, EtOH, iPrOH, and AcOH
exhibited similar d.r. values (1:4.6–5.3) as shown in Scheme 3.
These results suggest the reactions proceed through the
common 3,3,3-trifluoro-1,2-diphenylpropyl intermediate
having the same configuration.
key intermediate 5 for the preparation of panomifene, which
is reported to exhibit antiestrogenic activity and is a well-
known drug for the treatment of breast cancer.[21] Indeed, the
CF3-containing tetrasubstituted alkene 5 was obtained in
35% yield. This result suggests we can easily access to the
corresponding CF3-containing alkenes by the consecutive
hydroxytrifluoromethylation and dehydration processes.
Finally, it was found that the present photocatalytic
hydroxytrifluoromethylation can harness sunlight as a light
source. It should be noted that sunlight induced the reaction
with an efficiency and selectivity similar to that for the
irradiation with Blue LEDs [Eq. (1)].
On the basis of the experimental results, a plausible
reaction mechanism is shown in Scheme 5. First, irradiation of
visible light excites [fac-IrIII(ppy)3] to [fac-IrIII(ppy)3]*. Lumi-
nescence quenching experiments support the SET process
between [fac-IrIII(ppy)3]* and 1a (see the Supporting Infor-
mation). Choice of the CF3 source is key in the present
photocatalytic transformation. We showed that use of 1b, c
instead of 1a leads to loses in efficiency and selectivity.
Encouraged by the highly efficient and selective hydroxy-
trifluoromethylation of the trisubstituted alkene 2m, we
expanded this transformation to the reaction of the 1,1,2-
triphenylethylene derivative 2q (Scheme 4). The hydroxytri-
fluoromethylation of 2q and sequential dehydration gave the
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mograms for 1a,b, and c contain irreversible reduction waves
at À0.75 V, À1.34 V, and À1.49 V (vs Cp2Fe in CH3CN),
respectively. These data indicate that 1a is reduced more
easily than 1b and c, thus leading to generation of CCF3.
Addition of CCF3 to the alkenes 2 gives the alkyl radical
intermediate, which is oxidized by the [fac-IrIV(ppy)3] formed
by the SET process (path a in Scheme 5). Subsequent
nucleophilic attack of 4 on the carbocation intermediate
produces the three-component coupled product 3. We cannot
rule out radical chain propagation mechanism (path b), but
the present transformation requires continuous irradiation of
visible light (see Figure S8 in the Supporting Information),
thus suggesting that chain propagation is not a main mech-
anistic component.
In conclusion, we have developed the first visible-light-
driven three-component oxytrifluoromethylation of alkenes
using the photoredox catalyst [fac-Ir(ppy)3]. This highly
efficient (usually 2–4 h) and regioselective (100% in all
cases) radical transformation of alkenes proceeds even at
room temperature under sunlight (under mild reaction
conditions) and makes use of a broad range of O nucleophiles
such as alcohols, carboxylic acids, and water. In addition,
these reactions are operationally easy. Furthermore, this
photocatalytic reaction was used in the synthesis of the
antiestrogen drug panomifene from the corresponding triar-
ylalkene. Importantly, Umemotoꢀs reagent turns out to be
crucial for efficient and selective reaction. The additional
development of this method in the directed synthesis of
pharmaceuticals and agrochemicals is a continuing effort in
our laboratory.
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Received: June 28, 2012
Revised: July 27, 2012
Published online: && &&, &&&&
´
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Keywords: fluorine · homogeneous catalysis · photochemistry ·
radical reactions · synthetic methods
.
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[15] a) T. Koike, M. Akita, Chem. Lett. 2009, 38, 166 – 167; b) Y. Yasu,
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Koike, Y. Yasu, M. Akita, Chem. Lett. 2012, in press.
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[20] These scope of this reaction complements that of the iodoper-
fluoroalkylation by
a photoredox process as reported by
Stephenson and co-workers.[9d,e]
[17] In fact, the reaction in nondehydrated acetone provided the
alcohol product 3a in a manner similar to the reaction in the
acetone/water system.
[18] The molecular structure of 3h is shown in the Supporting
Information. CCDC 887925 contains the supplementary crystal-
[21] For the synthesis of panomifene, see: a) G. Nemeth, R. Kapiller-
Dezsofi, G. Lax, G. Simig, Tetrahedron 1996, 52, 12821 – 12830;
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for the bioactivity therein.
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Communications
Synthetic Methods
Y. Yasu, T. Koike,*
M. Akita*
&&&& — &&&&
Three-component
Oxytrifluoromethylation of Alkenes:
Highly Efficient and Regioselective
=
Difunctionalization of C C Bonds
Here comes the sun: A facile vicinal
difunctionalization of alkenes, oxytri-
fluoromethylation, was established by
visible-light-driven photoredox catalysis.
Judicious choice of the CF3 source is key.
Nucleophiles such as water, alcohols, and
carboxylic acids can be used in this highly
efficient (2–4 h) and regioselective
(100%) transformation using light-emit-
ting diode (LED) lamps and natural sun-
light. SET=single-electron transfer.
Mediated by Photoredox Catalysts
6
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