Direct C-H trifluoromethylation of di- and trisubstituted alkenes by photoredox catalysis

Article abstract of DOI:10.3762/bjoc.10.108

Background: Trifluoromethylated alkene scaffolds are known as useful structural motifs in pharmaceuticals and agrochemicals as well as functional organic materials. But reported synthetic methods usually require multiple synthetic steps and/or exhibit lim

Full text of DOI:10.3762/bjoc.10.108

Direct C–H trifluoromethylation of di- and
trisubstituted alkenes by photoredox catalysis
Ren Tomita, Yusuke Yasu, Takashi Koike* and Munetaka Akita*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 1099–1106.
Chemical Resources Laboratory, Tokyo Institute of Technology,
R1-27, 4259 Nagatsuta, Midori-ku, Yokohama 226-8503, Japan
doi:10.3762/bjoc.10.108
Received: 23 January 2014
Accepted: 14 April 2014
Published: 12 May 2014
Email:
Takashi Koike* - koike.t.ad@m.titech.ac.jp; Munetaka Akita* -
makita@res.titech.ac.jp
This article is part of the Thematic Series "Organic synthesis using
photoredox catalysis".
* Corresponding author
Keywords:
Guest Editor: A. G. Griesbeck
electrophilic trifluoromethylating reagent; multi-substituted alkene;
photoredox catalysis; radical reaction; trifluoromethylation
© 2014 Tomita et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Background: Trifluoromethylated alkene scaffolds are known as useful structural motifs in pharmaceuticals and agrochemicals as
well as functional organic materials. But reported synthetic methods usually require multiple synthetic steps and/or exhibit limita-
tion with respect to access to tri- and tetrasubstituted CF3-alkenes. Thus development of new methodologies for facile construction
of Calkenyl–CF3 bonds is highly demanded.
Results: The photoredox reaction of alkenes with 5-(trifluoromethyl)dibenzo[b,d]thiophenium tetrafluoroborate, Umemoto’s
reagent, as a CF3 source in the presence of [Ru(bpy)3]2+ catalyst (bpy = 2,2’-bipyridine) under visible light irradiation without any
additive afforded CF3-substituted alkenes via direct Calkenyl–H trifluoromethylation. 1,1-Di- and trisubstituted alkenes were applic-
able to this photocatalytic system, providing the corresponding multisubstituted CF3-alkenes. In addition, use of an excess amount
of the CF3 source induced double C–H trifluoromethylation to afford geminal bis(trifluoromethyl)alkenes.
Conclusion: A range of multisubstituted CF3-alkenes are easily accessible by photoredox-catalyzed direct C–H trifluoromethyla-
tion of alkenes under mild reaction conditions. In particular, trifluoromethylation of triphenylethene derivatives, from which
synthetically valuable tetrasubstituted CF3-alkenes are obtained, have never been reported so far. Remarkably, the present facile
and straightforward protocol is extended to double trifluoromethylation of alkenes.
Introduction
The trifluoromethyl (CF3) group is a useful structural motif in highly efficient and selective incorporation of a CF3 group into
many bioactive molecules as well as functional organic ma- diverse skeletons has become a hot research topic in the field of
terials [1-6]. Thus, the development of new methodologies for organic synthetic chemistry [7-12]. Recently, radical trifluoro-
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Beilstein J. Org. Chem. 2014, 10, 1099–1106.
methylation by photoredox catalysis [13-23] with ruthenium(II) straightforward approach is direct C–H trifluoromethylation of
polypyridine complexes (e.g., [Ru(bpy)3]2+ (bpy: 2,2’-bipyri- alkenes (Scheme 2c). The groups of Loh, Besset, Cahard,
dine)), the relevant Ir cyclometalated complexes (e.g., fac- Sodeoka and Xiao showed that copper catalysts can induce a
Ir(ppy)3 (ppy: 2-phenylpyridine)) and organic dyes has been C–H trifluoromethylation of alkenes by electrophilic CF3
developed; the trifluoromethyl radical (·CF3) can be easily reagents (+CF3) [65-69]. In addition, Cho et al. reported that the
generated from conventional CF3 radical precursors such as reaction of unactivated alkenes with gaseous CF3I in the pres-
CF3I, CF3SO2Cl and CF3SO2Na through visible-light-induced ence of a Ru photocatalyst, [Ru(bpy)3]2+, and a base, DBU
single-electron transfer (SET) processes [24-32]. On the other (diazabicyclo[5,4,0]undec-7-ene) produced CF3-alkenes
hand, we have intensively developed trifluoromethylations of through iodotrifluoromethylation of alkenes followed by base-
olefins by the Ru and Ir photoredox catalysis using easy- induced E2 elimination [70]. To the best of our knowledge,
handling and shelf-stable electrophilic trifluoromethylating however, the development of synthetic methods for tri- and
reagents [33-36] (+CF3) such as Umemoto’s reagent (1a, tetrasubstituted CF3 alkenes through Calkenyl–H trifluoro-
5-(trifluoromethyl)dibenzo[b,d]thiophenium tetrafluoroborate) methylation of simple alkenes have been left much to be
and Togni’s reagents 1b (1-(trifluoromethyl)-1λ3,2-benz- desired.
iodoxol-3(1H)-one) and 1c (3,3-dimethyl-1,3-dihydro-1λ3,2-
benziodoxole) [37-41]. It was found that electrophilic trifluoro-
methylating reagents (+CF3) can serve as more efficient CF3
radical sources under mild photocatalytic reaction conditions. In
addition, the putative β-CF3 carbocation intermediate formed
through SET photoredox processes is playing a key role in our
reaction systems (vide infra).
Trifluoromethylated alkenes, especially multi-substituted CF3-
alkenes (3,3,3-trifluoropropene derivatives), have attracted our
attention as fascinating scaffolds for agrochemicals, pharma-
ceuticals, and fluorescent molecules (Scheme 1) [3,42-45].
Scheme 1: Representative examples of multisubstituted CF3-alkenes.
Scheme 2: Catalytic synthesis of CF3-alkenes via trifluoromethylation.
Conventional approaches to CF3-alkenes require multiple syn- Previously, we reported on the synthesis of CF3-alkenes via
thetic steps [46-54]. In contrast, “trifluoromethylation” is a sequential photoredox-catalyzed hydroxytrifluoromethylation
promising protocol to obtain diverse CF3-alkenes easily. and dehydration (Scheme 3a) [37] and photoredox-catalyzed tri-
Several catalytic synthetic methods via trifluoromethylation fluoromethylation of alkenylborates (Scheme 3b) [38]. These
have been developed so far [38,55-62]. Most of these reactions results prompted us to explore photoredox-catalyzed C–H tri-
require prefunctionalized alkenes as a substrate (Scheme 2a). fluoromethylation of di- and trisubstituted alkenes (Scheme 3c).
Additionally, only a limited number of examples for synthesis Herein we disclose a highly efficient direct C–H trifluoro-
of tri/tetra-substituted CF3-alkenes have been reported so far. methylation of di- and trisubstituted alkenes with easy-handling
Recently, the groups of Szabó and Cho described trifluoro- and shelf-stable Umemoto’s reagent 1a by visible-light-driven
methylation of alkynes, leading to trifluoromethylated alkenes photoredox catalysis under mild conditions. This photocatalytic
but the application to the synthesis of tetrasubstituted CF3- protocol allows us easy access to a range of multi-substituted
alkenes is not well documented (Scheme 2b) [63,64]. Another trifluoromethylated alkenes. In addition, our methodology can
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Beilstein J. Org. Chem. 2014, 10, 1099–1106.
be extended to a double trifluoromethylation of 1,1-disubsti- catalytic trifluoromethylation of 1,1-diphenylethene 2a with 1
tuted alkenes.
equivalent of Umemoto’s reagent 1a in the presence of 5 mol %
fac-Ir(ppy)3, a photoredox catalyst, and 2 equivalents of
K2HPO4, a base, in [D6]-DMSO under visible light irradiation
(blue LEDs: λmax = 425 nm) for 2 h. As a result, 3,3,3-trifluoro-
1,1-diphenylpropene (3a) was obtained in an 82% NMR yield
(Table 1, entry 1). The choice of +CF3 reagents turned out to be
crucial for the yield of 3a. Togni’s reagents 1b and 1c gave 3a
in lower yields (Table 1, entries 2 and 3). We also found that
DMSO is suitable for the present reaction (Table 1, entries 4–6).
Other solvent systems gave substantial amounts of the hydroxy-
trifluoromethylated byproduct, which we reported previously
[37]. In addition, the present C–H trifluoromethylation proceeds
even in the absence of a base (Table 1, entry 7). Another photo-
catalyst, [Ru(bpy)3](PF6)2, also promoted the present reaction,
providing the product 3a in an 85% NMR yield (Table 1, entry
8). The Ru catalyst is less expensive than the Ir catalyst; thus,
we chose the Ru photocatalyst for the experiments onward.
Notably, product 3a was obtained neither in the dark nor in the
absence of photocatalyst (Table 1, entries 9 and 10), strongly
supporting that the photoexcited species of the photoredox cata-
lyst play key roles in the reaction.
Scheme 3: Our strategies for synthesis of CF3-alkenes.
The scope and limitations of the present photocatalytic tri-
fluoromethylation of alkenes are summarized in Table 2. 1,1-
Diphenylethenes with electron-donating substituents, MeO
Results and Discussion
The results of investigations on the reaction conditions are (2b), and halogens, Cl (2c) and Br (2d), smoothly produced the
summarized in Table 1. We commenced examination of photo- corresponding trisubstituted CF3-alkenes (3b–d) in good yields.
Table 1: Optimization of photocatalytic trifluoromethylation of 1,1-diphenylethene 2a.a
Entry
Photocatalyst
CF3 reagent
Solvent
Base
NMR yield (%)
1
2
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
[Ru(bpy)3](PF6)2
none
1a
1b
1c
1a
1a
1a
1a
1a
1a
1a
[D6]-DMSO
[D6]-DMSO
[D6]-DMSO
CD3CN
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
none
82
17
47
57
22
29
81
85
0
3
4
5
CD2Cl2
6
[D6]-acetone
[D6]-DMSO
[D6]-DMSO
[D6]-DMSO
[D6]-DMSO
7
8
none
9
none
10b
[Ru(bpy)3](PF6)2
none
0
aFor reaction conditions, see the Experimental section. bIn the dark.
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Beilstein J. Org. Chem. 2014, 10, 1099–1106.
Table 2: The scope of the present trifluoromethylation of alkenes.a, b
Trifluoromethylated products 3a–m
3e: 70%c
E/Z = 89/11d
3a: 82%c
3b: 81%c
3c: 53%
3d: 70%
3f: 37%e
3g: 51%
3h: 78%
3i: 58%
E/Z = 91/9d
E/Z = 17/83d
E/Z = 33/67d
E/Z = 88/12d
3k: 59%
E/Z = 74/26d
3m: 53%
E/Z = 88/12d
3j: 82%
3l: 65%
aFor reaction conditions, see the Experimental section. bIsolated yields. cNMR yields. dE/Z ratios were determined by 19F NMR spectroscopy of the
crude product mixtures. e2,6-Lutidine (2 equiv) was added as a base.
In the reactions of unsymmetrically substituted substrates 1,2-disubsituted alkenes such as trans-stilbene provided compli-
(2e–h), products were obtained in good to moderate yields but cated mixtures of products.
consisted of mixtures of E and Z-isomers. Based on the experi-
mental results, the E/Z ratios are susceptible to the electronic Next, we extended the present C–H trifluoromethylation to
structure of the aryl substituent. Reactions afforded the major trisubstituted alkenes. The reactions of 1,1-diphenylpropene
isomers, in which the CF3 group and the electron-rich aryl derivatives 2j and 2k (E/Z = 1/1) afforded the corresponding
substituent are arranged in E-fashion. In addition, the present tetrasubstituted CF3-alkenes 3j and 3k in 82% and 59% (E/Z =
photocatalytic reaction can be tolerant of the Boc-protected 74/26) yields, respectively. Triphenylethenes 2l and 2m (only
amino group (2f) or pyridine (2h). Moreover, a substrate with E-isomer) are also applicable to this photocatalytic C–H tri-
an alkyl substituent, 2,4-diphenyl-4-methyl-1-pentene (2i), was fluoromethylation. Remarkably, the E-isomer of 3m is a key
also applicable to this transformation, whereas the reaction of intermediate for the synthesis of panomifene, which is known as
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Beilstein J. Org. Chem. 2014, 10, 1099–1106.
an antiestrogen drug [71,72]. These results show that the is made acidic by the strongly electron-withdrawing CF3
present protocol enables the efficient construction of a substituent, provides trifluoromethylated alkene 3. Preferential
Calkenyl–CF3 bond through direct C–H trifluoromethylation of formation of one isomer in the reaction of unsymmetrical
1,1-disubstituted and trisubstituted aryl alkenes.
substrates is attributed to the population of the rotational
conformers of the β-CF3 carbocation intermediate 3+. Our
During the course of our study on the C–H trifluoromethylation experimental result is consistent with the previous report [71],
of 1,1-diarylethenes 2, we found that a detectable amount of which described E-selective formation of the tetrasubstituted
bis(trifluoromethyl)alkenes 4 was formed through double C–H CF3-alkene 3m via a β-CF3 carbocation intermediate. In the
trifluoromethylation. In fact, the photocatalytic trifluoro- presence of an excess amount of CF3 reagent 1a, further C–H
methylation of 2a,b and d with 4 equivalents of Umemoto’s trifluoromethylation of CF3-alkene 3 proceeds to give bis(tri-
reagent 1a in the presence of 5 mol % of [Ru(bpy)3](PF6)2 with fluoromethyl)alkene 4.
irradiation from blue LEDs for 3 h gave geminal bis(trifluo-
romethyl)ethene (4a,b and d) in 45, 80 and 24% NMR yields,
respectively (Scheme 4). Substituents on the benzene ring
significantly affect the present double trifluoromethylation.
Reaction of the electron-rich alkene 2b afforded 1,1-anisyl-2,2-
bis(trifluoromethyl)ethene (4b) in a better yield than other
alkenes 2a and 2d. Additionally, we found that photocatalytic
trifluoromethylation of CF3-alkene 3d in the presence of an
excess amount of Umemoto’s reagent 1a produced bis(trifluo-
romethyl)alkenes 4d in a better yield (56% yield) compared to
the above-mentioned one-pot double trifluoromethylation of 2d.
Scheme 5: A possible reaction mechanism.
We cannot rule out a radical chain propagation mechanism, but
the present transformation requires continuous irradiation of
visible light (Figure 1), thus suggesting that chain propagation
is not a main mechanistic component.
Scheme 4: Synthesis of geminal bis(trifluoromethyl)alkenes.
A possible reaction mechanism based on SET photoredox
processes is illustrated in Scheme 5. According to our previous
photocatalytic trifluoromethylation [37-41], the trifluoromethyl
radical (·CF3) is generated from an one-electron-reduction of
electrophilic Umemoto’s reagent 1a by the photoactivated Ru
catalyst, *[Ru(bpy)3]2+. ·CF3 reacts with alkene 2 to give the
benzyl radical-type intermediate 3' in a regioselective manner.
Subsequent one-electron-oxidation by highly oxidizing Ru
Figure 1: Time profile of the photocatalytic trifluoromethylation of 2a
with 1a with intermittent irradiation by blue LEDs.
species, [RuIII(bpy)3]3+, produces β-CF3 carbocation intermedi-
ate 3+. Finally, smooth elimination of the olefinic proton, which
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Beilstein J. Org. Chem. 2014, 10, 1099–1106.
Conclusion
column chromatography on silica gel (eluent: hexane) to afford
We have developed highly efficient C–H trifluoromethylation the corresponding product 3. Further purification of 3c and 3d
of alkenes using Umemoto’s reagent as a CF3 source by visible- by GPC provided pure 3c and 3d.
light-driven photoredox catalysis. This reaction can be applied
Procedures for the photocatalytic double
to multi-substituted alkenes, especially, 1,1-disubstituted and
C−H trifluoromethylation of 1,1-bis(4-
methoxyphenyl)ethylene (2b)
trisubstituted aryl alkenes, leading to tri- and tetrasubstituted
CF3-alkenes. The present straightforward method for the syn-
thesis of multisubstituted CF3-alkenes from simple aryl alkenes
is the first report. In addition, we can extend the present photo-
catalytic system to double trifluoromethylation. Further devel-
opment of this protocol in the synthesis of bioactive organofluo-
rine molecules and fluorescent molecules is a continuing effort
in our laboratory.
A 20 mL Schlenk tube was charged with Umemoto’s reagent 1a
(340 mg, 1.0 mmol, 4 equiv), [Ru(bpy)3](PF6)2 (10.7 mg,
5 mol %), 2b (60 mg, 0.25 mmol), and DMSO (5 mL) under
N2. The tube was irradiated for 3 h at room temperature (water
bath) with stirring by 3 W blue LED lamps (hν = 425 ± 15 nm)
placed at a distance of 2–3 cm. After reaction, H2O was added.
The resulting mixture was extracted with Et2O, washed with
H2O, dried (Na2SO4), and filtered. The filtrate was concen-
trated in vacuo and the residue was purified by flash column
chromatography on silica gel (hexane→hexane/Et2O = 29:1) to
afford 4b as a product mixture with 3b. Further purification by
GPC provided pure 4b in 44% isolated yield (42 mg,
0.11 mmol). Isolated yield was much lower than the NMR yield
because of the difficulty of separation of 3b and 4b.
Experimental
Typical NMR experimental procedure (reac-
tion conditions in Table 1)
Under N2, [Ru(bpy)3](PF6)2 (1.1 mg, 1.3 μmol), Umemoto’s
reagent 1a (8.5 mg, 25 μmol), 1,1-diphenylethylene (2a, 4.3 μL,
25 μmol), SiEt4 (~1 μL) as an internal standard, and [D6]-
DMSO (0.5 mL) were added to an NMR tube. The reaction was
carried out at room temperature (water bath) under irradiation
of visible light (placed at a distance of 2–3 cm from 3 W blue
LED lamps: hν = 425 ± 15 nm).
Supporting Information
Supporting information features experimental procedures
and full spectroscopic data for all new compounds (3c, 3d,
3f, 3g, 3h, 3i, 3k, 4a, and 4d).
General procedure for the photocatalytic C−H
trifluoromethylation of alkenes (reaction
conditions in Table 2)
Supporting Information File 1
A 20 mL Schlenk tube was charged with Umemoto’s reagent 1a
(102 mg, 0.3 mmol, 1.2 equiv), [Ru(bpy)3](PF6)2 (4.3 mg,
2 mol %), alkene 2 (0.25 mmol), and DMSO (2.5 mL) under
N2. The tube was irradiated for 2 h at room temperature (water
bath) with stirring by 3 W blue LED lamps (hν = 425 ± 15 nm)
placed at a distance of 2–3 cm. After the reaction, H2O was
added. The resulting mixture was extracted with Et2O, washed
with H2O, dried (Na2SO4), and filtered. The filtrate was
concentrated in vacuo. The product was purified by the two
methods described below.
Experimental procedures and NMR spectra.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-10-108-S1.pdf]
Acknowledgements
This work was supported by a grant-in-aid from the Ministry of
Education, Culture, Sports, Scienece of the Japanese Govern-
ment (No 23750174), The Naito Foundation and the global
COE program (the GCOE) “Education and Research Center for
For products 3b, 3e, 3f, 3g, 3h, 3k and 3m, the residue was Emergence of New Molecular Chemistry”.
purified by column chromatography on silica gel (eluent:
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