Combining photoredox-catalyzed trifluoromethylation and oxidation with dmso: Facile synthesis of α-trifluoromethylated ketones from aromatic alkenes

Article abstract of DOI:10.1002/anie.201403590

Trifluoromethylated ketones are useful building blocks for organic compounds with a trifluoromethyl group. A new and facile synthesis of ketones with a trifluoromethyl substituent in the α-position proceeds through a one-pot photoredox-catalyzed trifluoromethylation-oxidation sequence of aromatic alkenes. Dimethyl sulfoxide (DMSO) serves as a key and mild oxidant under these photocatalytic conditions. Furthermore, an iridium photocatalyst, fac[Ir(ppy)₃] (ppy=2-phenylpyridine), turned out to be crucial for the present photoredox process. Valuable α-CF₃-substituted ketones can be synthesized from aromatic alkenes by combining photoredox-catalyzed trifluoromethylation and oxidation with DMSO. The iridium photocatalyst fac-[Ir(ppy)₃] (ppy=2-phenylpyridine) plays key roles in this keto-trifluoromethylation. SET=single electron transfer.

Full text of DOI:10.1002/anie.201403590

Angewandte
Chemie
DOI: 10.1002/anie.201403590
Keto-Trifluoromethylation
Combining Photoredox-Catalyzed Trifluoromethylation and Oxidation
with DMSO: Facile Synthesis of a-Trifluoromethylated Ketones from
Aromatic Alkenes**
Ren Tomita, Yusuke Yasu, Takashi Koike,* and Munetaka Akita*
Dedicated to Dr. Teruo Umemoto
Abstract: Trifluoromethylated ketones are useful building
blocks for organic compounds with a trifluoromethyl group. A
new and facile synthesis of ketones with a trifluoromethyl
substituent in the a-position proceeds through a one-pot
photoredox-catalyzed trifluoromethylation–oxidation se-
quence of aromatic alkenes. Dimethyl sulfoxide (DMSO)
serves as a key and mild oxidant under these photocatalytic
conditions. Furthermore, an iridium photocatalyst, fac-
[Ir(ppy)3] (ppy = 2-phenylpyridine), turned out to be crucial
for the present photoredox process.
T
he trifluoromethyl group prevails in pharmaceutical and
agrochemical compounds as well as in functional organic
materials.[1,2] Therefore, the development of new methods for
the efficient and selective incorporation of a CF3 group into
diverse molecular architectures has become an important
research topic in synthetic organic chemistry.[3] Trifluorome-
thylated carbonyl compounds are versatile building blocks for
the synthesis of a wide variety of fluorinated compounds.[4] In
general, electrophilic or radical trifluoromethylation of eno-
lates, which were prepared from the corresponding carbonyl
compounds in advance, provides access to valuable
a-trifluoromethylated carbonyl compounds.[5] A few other
unique methods have also been reported,[6–9] but examples of
the “direct” oxidative trifluoromethylation (keto-trifluoro-
methylation) of alkenes, which are abundant and commonly
used feedstocks, have been limited thus far.[10] Xiao and co-
workers reported the keto-trifluoromethylation of styrenes
with an S-(trifluoromethyl)diphenylsulfonium salt and air in
the presence of an excess amount of the reducing agent,
HOCH2SO2Na. However, the a-CF3-substituted ketones
were obtained in low yields (Scheme 1a). More recently,
Maiti et al. described a catalytic system consisting of AgNO3
and K2S2O8 that is effective for the oxidative trifluoromethy-
Scheme 1. Keto-trifluoromethylation of alkenes.
lation of alkenes with the Langlois reagent, CF3SO2Na, and
air (Scheme 1b). For both processes, the involvement of
a trifluoromethyl radical (CCF3) was proposed, and it was
implied that the outcome of the reaction is significantly
affected by the methods that are used for the generation of
the CF3 radical and oxidation.
Recently, radical trifluoromethylation by photoredox
catalysis has emerged; visible-light-driven single-electron
transfer (SET) processes are enabled by the well-known
ruthenium(II) polypyridine complexes (e.g., [Ru(bpy)3]2+;
bpy = 2,2’-bipyridine) and the corresponding cyclometalated
iridium(III) derivatives (e.g., fac-[Ir(ppy)3]; ppy = 2-phenyl-
pyridine).[5k,m,11–13] Our efforts have been devoted to the
development of a photoredox-catalyzed difunctionalization
of C C bonds[13] in the presence of electrophilic trifluorome-
=
thylating reagents (+CF3),[5g, 14] such as Togniꢀs reagent (1a) or
Umemotoꢀs reagent (1b). In these reactions, a key inter-
mediate is the b-CF3-substituted carbocation that is generated
from SET photoredox processes, and which undergoes
subsequent nucleophilic attack to produce difunctionalized
products. This is a powerful method for the difunctionaliza-
tion of alkenes without isolation of the intermediate. We
hypothesized that combining the photoredox-catalyzed tri-
fluoromethylation and Kornblum (DMSO) oxidation[15] of the
b-CF3-substituted carbocation would enable the development
of a facile and new approach to the synthesis of a-trifluoro-
methylated ketones by keto-trifluoromethylation (Sche-
me 1c), which is the subject of the present contribution.
[*] R. Tomita, Dr. Y. Yasu, Dr. T. Koike, Prof. Dr. M. Akita
Chemical Resources Laboratory, Tokyo Institute of Technology
R1-27, 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
(23750174) and the Naito Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403590.
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Our strategy provides us with an operationally simple
procedure as well as a highly regioselective and efficient
transformation. Furthermore, it has been revealed that an
alkoxysulfonium species, which is a well-known intermediate
in DMSO oxidation,[16] smoothly produces an a-CF3-substi-
tuted ketone without treatment with any base under photo-
redox reaction conditions.
The scope of the present photocatalytic keto-trifluorome-
thylation is summarized in Table 2. Styrene (2a) and styrene
derivatives bearing CO2Me (2b) and NHBoc groups (2c;
Boc = tert-butoxycarbonyl) on the aryl ring produced the a-
Table 2: Scope of the photocatalytic keto-trifluoromethylation.[a,b]
We initially examined the photocatalytic reaction of
styrene (2a) with Togniꢀs reagent 1a (1.05 equiv) and the
iridium photoredox catalyst fac-[Ir(ppy)3][17] (5 mol%) in
[D6]DMSO under visible-light irradiation (blue LEDs: lmax
=
425 nm) for two hours. To our surprise, the a-CF3-substituted
ketone 3a was directly formed in 58% yield together with
b-trifluoromethylstyrene (4a, 35% yield; entry 1, Table 1).
3a: 60%
3d: 69%
3b: 36%
3e: 78%
3h: 81%[d]
3c: 46%
3 f: 75%
3i: 60%[d]
Table 1: Optimization of the photocatalytic keto-trifluoromethylation of
styrene (2a).[a]
Entry CF3
reagent
Photocatalyst
Yield of 3a [%][b] Yield of 4a [%][b]
3g: 87%,
84% (gram scale)[c]
1
2
3
4
1a
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
[Ru(bpy)3](PF6)2
58
59
5
35
22
0
20
0
1b
1a
1b
1a
1a
[Ru(bpy)3](PF6)2 76 (5a); 38[c]
3j: 71%[d]
3k: 60%[d]
3n: 45%[e]
3l: 65%[d]
3o: 45%[d]
5[d]
6
fac-[Ir(ppy)3]
–
0
0
0
[a] For detailed reaction conditions, see the Supporting Information.
[b] Yields were determined by 1H NMR spectroscopy using Si(Et)4 as an
internal standard. [c] Yield after treatment of the product mixture with
NEt3 (10 equiv). [d] In the dark. bpy=2,2’-bipyridine, LED=light-emit-
ting diode, ppy=2-phenylpyridine.
3m: 84%[d]
3p: 55%[d]
3s: 46%[d]
3q: 56%[d]
3t: 28%[f]
3r: 74%[d]
3u: 56%[f]
When Umemotoꢀs reagent 1b was used in place of 1a,
a similar product mixture (3a: 59%, 4a: 22%) to that of the
reaction with Togniꢀs reagent 1a (entry 2) was obtained. The
ruthenium photoredox catalyst [Ru(bpy)3](PF6)2[18], in con-
trast, did not promote the present direct keto-trifluorome-
thylation of 2a very well (entries 3 and 4). The use of Togniꢀs
reagent 1a resulted in low conversion (12%; entry 3).
Remarkably, the use of Umemotoꢀs reagent 1b gave alkox-
ysulfonium salt 5a in 76% yield instead of 3a with concom-
itant formation of b-trifluoromethylstyrene (4a) in 20% yield
(entry 4). When the salt 5a, the key intermediate of the
DMSO oxidation,[16] was treated with NEt3, the desired
a-CF3-substituted ketone 3a was formed in 38% yield
(entry 4). For entries 1 and 2, ketone 3a was formed in the
absence of a base, as is the case in the Kornblum oxidation.
On the basis of these results, we have developed the direct
keto-trifluoromethylation of alkenes using the iridium photo-
catalyst without addition of a base. Notably, product 3a was
not obtained either in the dark or in the absence of the
photocatalyst (entries 5 and 6), strongly supporting that the
photoexcited species of the photoredox catalyst plays key
roles in the reaction.
[a] For detailed reaction conditions, see the Supporting Information.
[b] Yields of isolated products. [c] Reaction conducted on a gram scale.
For details, see the Supporting Information. [d] 1a (1.30 equiv) was
used. [e] fac-[Ir(ppy)3] (5 mol%) and 1a (1.5 equiv) were used. [f] fac-
[Ir(ppy)3] (5 mol%), 1a (2.0 equiv), 5 h.
CF3-substituted ketones (3a–3c) in moderate yields (36–
60%) because of concomitant formation of b-trifluorome-
thylstyrene derivatives 4. In contrast, styrenes with electron-
donating substituents, such as methyl (2d) and acetoxy groups
(2e), and (E)-b-methylstyrene (2 f) suppressed the formation
of the side product 4 to a significant extent. As a result, the
corresponding CF3-substituted ketones were obtained in good
yields (3d–f; 69–78%).
Furthermore, b-methylstyrene derivatives with electron-
donating groups on the aromatic ring (2g and 2h) smoothly
afforded the corresponding products 3g and 3h in a regiose-
2
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lective fashion and in 87% and 81% yield, respectively. To
demonstrate the scalability of the present photocatalytic
reaction, the keto-trifluoromethylation of 2g was carried out
on a gram scale, and the product 3g was isolated in 84% yield
(1.31 g). Halogen (2i–2k), hydroxy (2l), boronic ester (Bpin;
2m), and pyridyl groups (2n) did not hinder the reaction (45–
84%). Alkenes with bulky mesityl or cyclohexyl substituents
(2o and 2p), cyclic alkenes (2q and 2r), and trans-stilbene
(2s) were also suitable substrates for this transformation (45–
74%). Furthermore, the present catalytic system was ame-
nable to the reaction of b-disubstituted alkenes (2t and 2u).
The corresponding a-CF3-substituted ketones that bear
a quaternary carbon atom were obtained in 28% and 56%
yield, respectively (3t and 3u). The reactions of some alkenes,
such as 1-octene and vinylcyclohexane, resulted in an
inseparable mixture of products. These results show that
aromatic alkenes with a variety of functional groups, such as
halogen, ester, acetal, boronic ester, hydroxy, and pyridyl
groups, can be applied to the present photocatalytic keto-
trifluoromethylation, leading to the corresponding a-CF3-
substituted ketones in a highly regioselective fashion.
To gain insight into the reaction mechanism, we con-
ducted some control experiments. As mentioned above, the
reaction of (E)-b-methylstyrene 2 f gave a better yield than
that of styrene 2a because formation of CF3-substituted
alkene 4 was suppressed. Therefore, we conducted the
reaction of 2 f with Umemotoꢀs reagent 1b in the presence
of [Ru(bpy)3](PF6)2 (5 mol%). As a result, quantitative
formation of a diastereomeric mixture of alkoxysulfonium
salt 5 f was observed by NMR spectroscopy. In light of these
results, side product 4 is possibly formed before formation of
5. Subsequent treatment of 5 f with sodium benzoate
(2.0 equiv; method A) or further photoreaction with addition
of fac-[Ir(ppy)3] (5 mol%; method B) provided 3 f in 78%
and 84% yield, respectively (yields determined by NMR
spectroscopy; Scheme 2a). When fac-[Ir(ppy)3] (5 mol%)
was added at the beginning of the reaction, a product mixture
of 3 f (31% NMR yield) and 5 f (49% NMR yield) was
obtained after ten minutes, and elongated reaction times
(30 min) enabled the formation of 3 f in 74% yield as the sole
product. A cyclic voltammogram for alkoxysulfonium salt 5 f
exhibited a broad irreversible reduction wave at À1.07 V (vs.
[Cp2Fe] in MeCN; Cp = cyclopentadienyl), which is close to
the reduction potential of the photoexcited [Ru(bpy)3]2+,
indicating that 5 f cannot be easily reduced by the photo-
excited [Ru(bpy)3]2+, but only by the photoexcited fac-
[Ir(ppy)3].[17,18] These results suggest that the action of
benzoate or the iridium photocatalyst can induce the for-
mation of the corresponding ketones 3 from the alkoxysulfo-
nium intermediates 5. Furthermore, to our surprise, the
reactions of a-cyclohexylstyrene 2v and a-methylstyrene 2w
afforded 3a in 79% and 44% yield, respectively; these
À
transformations proceed through a C C bond cleavage
process. In the case of the reaction of 2v, the eliminated
alkyl group was detected as the cyclohexyldimethylsulfonium
À
salt 6v (Scheme 2b). These remarkable C C bond cleavage
processes likely stem from b-scission of the tertiary alkoxy
radical intermediate. These results suggest that photoredox
catalysis is playing two crucial roles in the present photo-
catalytic keto-trifluoromethylation: 1) formation of the
b-CF3-substituted carbocation intermediate,[13] and 2) forma-
tion of the reactive alkoxy radical intermediate from the
alkoxysulfonium intermediate 5.
On the basis of these results, a possible reaction mecha-
nism was proposed by combining photoredox-catalyzed
trifluoromethylation and oxidation with DMSO (Scheme 3).
First, irradiation with visible light excites fac-[IrIII(ppy)3]
(IrIII) into fac-[IrIII(ppy)3]* (*IrIII), which undergoes SET
reduction of the electrophilic trifluoromethylating reagent
(+CF3) 1 to generate the CF3 radical (CCF3), accompanied by
formation of the highly oxidized fac-[IrIV(ppy)3]+ (IrIV)
species. Addition of the CF3 radical to alkene 2 provides
radical intermediate 5’. A second SET oxidation event of 5’
Scheme 2. Control experiments. [a] Method A: Sodium benzoate
(2 equiv) was added at RT, and the reaction mixture stood for two
hours; method B: fac-[Ir(ppy)3] (5 mol%) was added, and the reaction
mixture was irradiated with visible light (425 nm blue LEDs) at RT for
one hour. Yields were determined by 1H NMR spectroscopy using
Si(Et)4 as an internal standard.
Scheme 3. A proposed reaction mechanism.
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should occur concurrently with reduction of IrIV to the IrIII
ground state, leading to the b-CF3-substituted carbocationic
intermediate 5+. Nucleophilic attack of DMSO to 5+ affords
alkoxysulfonium intermediate 5. In the reaction with Togniꢀs
reagent 1a, o-iodobenzoate, which is the byproduct of the
reduction of 1a, should serve as the base. A reaction similar to
Kornblum oxidation proceeds to give product 3 (path a).[19]
On the other hand, the strong reducing agent *IrIII can affect
the reduction of 5, which leads to the formation of alkoxy
radical 3’ (path b), especially in the reaction with Umemotoꢀs
reagent 1b. Subsequent SET oxidation preceded by 1,2-
hydrogen atom shift[20] or b-scission of the alkoxy radical 3’
furnishes the product 3. In the reactions of 2v and 2w, the
alkyl groups (R) cannot be removed with the help of a base.
This observation is therefore regarded as unequivocal evi-
dence for the hypothesis that at least in the case of
a-substituted styrene derivatives, the photoredox mechanism
is operating for the conversion of 5 into 3 via 3’.
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In conclusion, we have developed a new method for the
synthesis of a-CF3-substituted carbonyl compounds by com-
bining photoredox-catalyzed trifluoromethylation and oxida-
tion mediated by an alkoxysulfonium ion. The iridium
photocatalyst fac-[Ir(ppy)3], which can be a strong reducing
agent, plays key roles in achieving the direct keto-trifluor-
=
omethylation of a C C bond in a regioselective manner.
Furthermore, this iridium-catalyzed reaction is a new type of
base-free DMSO oxidation. The present method also enabled
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Received: March 22, 2014
Published online: && &&, &&&&
Keywords: carbocations · fluorine · homogeneous catalysis ·
.
oxidation · photochemistry
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11840 – 11843; d) Y. Ashikari, A. Shimizu, T. Nokami, J.-i.
Yoshida, J. Am. Chem. Soc. 2013, 135, 16070 – 16073.
[17] The photoexcited state of fac-[Ir(ppy)3] is a stronger reductant
(E1/2 = À2.14 V vs. [Cp2Fe]) than that of [Ru(bpy)3]2+; see: L.
Flamigni, A. Barbieri, C. Sabatini, B. Ventura, F. Barigelletti,
Top. Curr. Chem. 2007, 281, 143 – 203.
[18] The photoexcited state of [Ru(bpy)3]2+ is a strong reductant
(E1/2=À1.24 V vs. [Cp2Fe]); see: K. Kalyanasundaram, Coord.
Chem. Rev. 1982, 46, 159 – 244.
[19] The control experiment (method A, Scheme 2a) suggested that
the reaction in the presence of 1a (entry 1 in Table 1 and
Table 2) mainly proceeds through path a.
[20] The reaction in the presence of 1b (entry 2 in Table 1; method B
in Scheme 2a and Scheme 2b) can proceed through path b. We
cannot exclude other possibilities. This 1,2-hydrogen atom shift
might be induced by adventitious H2O or O2 in DMSO; see:
K. G. Konya, T. Paul, S. Lin, J. Lusztyk, K. U. Ingold, J. Am.
Chem. Soc. 2000, 122, 7518 – 7527.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Keto-Trifluoromethylation
R. Tomita, Y. Yasu, T. Koike,*
M. Akita*
&&&& — &&&&
Combining Photoredox-Catalyzed
Trifluoromethylation and Oxidation with
DMSO: Facile Synthesis of a-
Trifluoromethylated Ketones from
Aromatic Alkenes
Valuable a-CF3-substituted ketones can
be synthesized from aromatic alkenes by
combining photoredox-catalyzed
DMSO. The iridium photocatalyst fac-
[Ir(ppy)3] (ppy=2-phenylpyridine) plays
key roles in this keto-trifluoromethylation.
SET=single electron transfer.
trifluoromethylation and oxidation with
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!