Visible light induced Trifluoromethyl Migration: Easy Access to α-Trifluoromethylated Ketones from Enol Triflates

Article abstract of DOI:10.1002/adsc.201701051

Herein, we reported a novel method to synthesize α-trifluoromethylated ketones from enol triflates. Involving a cascade sulfur dioxide extrusion and a CF₃ (trifluoromethyl) radical addition process, this reaction proceeds at room temperature an

Full text of DOI:10.1002/adsc.201701051

Title: Visible light induced Trifluoromethyl Migration: Easy Access to α-
Trifluoromethylated Ketones from Enol Triflates
Authors: Shuyang Liu, Jiyang Jie, Jipan Yu, and Xiaobo Yang
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10.1002/adsc.201701051
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Visible light induced Trifluoromethyl Migration: Easy Access to
α-Trifluoromethylated Ketones from Enol Triflates
Shuyang Liu,a Jiyang Jie,a Jipan Yu,b Xiaobo Yang a*
a
Institute of Catalysis for Energy and Environment, College of Chemistry & Chemical Engineering, Shenyang Normal
University, Shenyang, Liaoning, 110034, P. R. China.
E-mail: bxy1223@gmail.com, yangxb@synu.edu.cn.
Key Laboratory of Nuclear Radiation and Nuclear Energy Technology and Key Laboratory for Biomedical Effects of
b
Nanomaterials and Nanosafety, Institute of High Energy Physics, Chinese Academy of Sciences, Beijing 100049, P. R.
China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
developed in the past decades.[2] α-CF3 ketone, as a
Abstract: Herein, we reported a novel method to
type of important fluorinated molecules, are
particlularly crucial because they can be used to
synthesize other CF3-containing compouds.[3]
Although various approaches to synthesize α-CF3
ketone have been developed,[4] unfortunately, most of
them suffer from some limitations such as the
requirement of external trifluoromethyl sources,
which include but not limited to either expensive or
harsh reagents: Umemoto reagent,[5] Togni reagent,[6]
Me3SiCF3,[7] MCF3,[8] CF3SO2Na,[9] CF3SO2Cl[10] and
CF3I[11] among others (Scheme 1a). Moreover in
synthesize α-trifluoromethylated ketones from enol
triflates. Involving a cascade sulfur dioxide extrusion and a
CF3 (trifluoromethyl) radical addition process, this reaction
proceeds at room temperature and is driven by visible light
irradiation. This protocol bears good functional group
compatibility, which can generate the desired products in
good to excellent yields even in gram scale. It is hoped that
this approach to generate CF3 radicals from enol triflates
can be used in other radical-involved reactions.
Keywords: visible light induced; radical; migration;
trifluoromethylation; enol triflate
order
to
produce
reasonable
yields,
superstoichiometric amound of trifluoromethylation
reagents (> 3 equiv) are necessary. Therefore,
developing more economic protocols to access these
-CF3 ketones are highly desirable. Recently, two
elegant methods to prepare α-CF3 ketones through a
radical process have been reported. These two
approaches feature employing enol triflates both as
the substrates and trifluoromethyl sources under mild
conditions. Interestingly, different radical initiators
were used to initiate the reactions, among which,
Introducing the trifluoromethyl group into the small
molecules can significantly change their properties,
which are beneficial for the drug discovery and the
development of new materials.[1] Therefore, due to
the prowess of trifluoromethyl group, different
methods for the trifluoromethylation have been
[12]
Kamimura and co-workers (Scheme 1b) used BEt3
Scheme 1. Previous strategies for the synthesis of α-CF3
Scheme 2. Visible light induced trifluoromethyl migration
ketones
1
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10.1002/adsc.201701051
Advanced Synthesis & Catalysis
[15]
while Li et al. introduced a catalytic amount of
AgNO3/(NH4)2S2O8 to generate the CF3 radical
(Scheme 1c).[13]
involvement of visible light.
To continue our
[16]
interest on photo-induced reactions
and optimize
the above UV light induced process into a visible
light driven one, herein we wish to report our
endeavor to develop such a visible light induced
trifluoromethyl migration process to generate α-
trifluoromethylated ketones from enol triflates under
mild conditions (Scheme 2c).
Recently, we have developed a method to convert
aryl triflates to aryl radicals via light irradiation.
During the investigation,[14] we found when aryl
triflates were converted to aryl iodides under UV
light, besides the desired aryl iodides, trace amount
of trifluoromethyl aryl ether was also detected by
GC-MS (Scheme 2a). The presence of this
unexpected product suggested the generation of CF3
radical following the loss of sulfur dioxide from the
triflate. Inspired by this observation, we decided to
As compiled in Table 1, to evaluate the feasibility
of the reaction under the visible light irradiation, we
commenced the study using the triflate 1c in the
presence of the photoinitiator Eosin Y (1 mol%) in
DMSO under visible-light irradiation (a 34 W blue
LED) at room temperature (ca. 25 ℃) for one hour.
Fortunately, the α-CF3-substituted ketone 2c was
formed in 39% yield with decent amounts of starting
material remaining (entry 1). Subsequently, five other
photoinitiators were examined (entries 2-6), among
explore the possibility of
a
photo-induced
trifluoromethyl migration to deliver the α-CF3 ketone
under the UV light. Fortunately, when 3,4-
dihydronaphthalen-1-yl
trifluoromethanesulfonate
was employed as the substrate (see ESI, part VI),
under the UV light (254 nm) and acetone as the
solvent, the corresponding α-CF3 ketone was obtained
in 99% yield (Scheme 2b). However, the generation
of UV light mandates the relatively expensive
equipment. It would be more ideal to employ visible
light as the energy input.
which
the
iridium
photoinitiator
Ir[dF(CF3)ppy]2(dtbbpy)PF6 gave the best result and
delivered the desired product in 84% yield. Notably,
the acridinium photoinitiator [Arc+-Mes]ClO4 was
-
Table 2. Visible light induced trifluoromethyl migrationa, b
Photo-redox catalysis, as an emerging tool to
generate radicals, has been very promising in the
context of solar energy utilization due to the
Table 1. Visible light induced trifluoromethyl migration of
1-(3-chlorophenyl)vinyl trifluoromethanesulfonate (1c):
optimization of conditionsa.
a) Reaction condition: N2 atmosphere (in a sealed tube) and
irradiation with visible light from a 34W blue LED, 1 (0.1
mmol), Ir complex (0.001 mmol), and DMSO (1 mL) were
stirred at room temperature (ca. 25 ℃) for 1 hour.
b) Isolated yield.
a) Reaction condition: N2 atmosphere (in a sealed tube) and
irradiation with visible light from a 34W blue LED, 1c (0.1
mmol), photoinitiator (0.001 mmol), and solvent (1 mL)
were stirred at room temperature (ca. 25 ℃) for 1 hour.
b) Isolated yield.
c) Under sunlight irradiation for 8 hours.
d) Reaction time is 2 hours.
c) 23 W compact fluorescent lamp (CFL)
d) Under dark.
e) 1 gram 1m was used as the substrate.
2
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10.1002/adsc.201701051
Advanced Synthesis & Catalysis
less effective since only trace amount of α-CF3-
substituted ketone could be detected. A survey of
common organic solvents revealed that DMSO
produced the highest yield (entries 7-9). Switching
the visible light source from blue LED to CFL
resulted in a slightly lower yield (entry 10). Further
control experiments showed that the reaction would
not occur without the photoinitiator or light
irradiation (entries 11 and 12).
process and the presence of CF3 radical (Figure 1a).
Besides the radical trapping experiment, to identify
the role of the iridium complex on this process, an
on/off visible light irradiation experiment from 1m to
2m was performed (Figure 1b). The results revealed
that the continuous light irradiation was crucial for
this transformation. Moreover, the quantum yield of
the reaction with 1m as the substrate was measured to
be 23, suggesting that this reaction involves a photo-
induced radical chain process. [18] Interestingly, during
the preparation of this manuscript, a similar work [17]
was reported by Li and co-workers.
With the optimized conditions in hand, various
enol triflates were subjected to examine the generality
of the current process. As depicted in Table 2, a wide
range of aromatic enol triflates performed well,
affording the corresponding products in excellent
Based on the above results and literature
12, 14, 17,
precedent[11,
18], a tentative mechanism is
yields
(2a-2p).
Notably,
halogen-substituted
depicted as follows (Scheme 3). In the initiation step,
with the help of the energy transfer from the excited
iridium complex to enol triflate 1, homolytic
decomposition occurs, delivering enol radical and
CF3 radical. Then CF3 radical reacts with another
enol triflate to afford the radical I. Subsequent β-
fission produces the desired α-CF3 ketone 2 and
trifluoromethanesulfonyl radical II, which could
substrates (2a−2c, 2k) and substituents bearing cyano
group (2f) or ester group (2g) were readily converted
to the corresponding ketones efficiently, offering a
good chance for further derivatization. Either
electron-rich (tBu) or electron-poor (CF3) substituents
are all suitable substrates to achieve desired products
in high yields (2e, 2i). Pyridyl enol triflate 1j is also
compatible to this reaction, delivering 2j in 85% yield. generate another CF3 radical with the loss of SO2 to
Cyclic enol triflates including five, six or seven
membered ring all showed good reactivity in this
transformation, providing 2l-2p in 86-92% yields.
The attempt to extend the substrate to aliphatic enol
triflates unfortunately proved futile since no
conversion of the substrates were observed (2q-2s)
under standard conditions or switching the
photoinitiator to other species (see ESI, part VII).
Gratifyingly, this protocol is so robust and efficient
that even the sunlight instead of the blue LED light
can serve as the energy input, to deliver the product
2c in 80% yield. Finally, scaling up the reaction to
gram-scale reaction caused no harmful effect on this
reaction and the product 2m could be isolated in 87%
yield.
initiate the chain process.
In order to further probe the reaction mechanism, a
control experiment with the addition of TEMPO (2
equiv) was conducted. The formation of 2c was
totally inhibited, and the radical adduct of TEMPO-
CF3 was detected by GC-MS, indicating a radical
Scheme 3. A tentative mechanism
In summary, we have developed a simple and
practical method to access α-trifluoromethylated
ketones from readily available enol triflates through a
visible light induced desulfur fragmentation and a
CF3 radical addition cascade process. This approach
provides a more sustainable and greener protocol to
synthesize α-CF3 ketone and related CF3-containing
compouds because it could be operated at room
temperature, and be scaled up and be promoted by the
sunlight. More importantly, it is expected that the
present visible light induced desulfur fragmentation is
helpful to inspire chemists to uncover other new
strategies for radical trifluoromethylation.
Figure 1. Mechanistic studies: a) A control experiment
with TEMPO. b) Visible light irradiation on/off
experiment.
3
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10.1002/adsc.201701051
Advanced Synthesis & Catalysis
Experimental Section
[3] a) Y. Itoh, M. Yamanaka, K. Mikami, Org. Lett. 2003,
5, 4807-4809; b) M. Schlosser, Angew. Chem. Int. Ed.
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Enol triflates (0.1 mmol), Ir[dF(CF3)ppy]2(dtbbpy)PF6
(0.0001 mmol, 1 mg) and DMSO (1mL) were added to a
10 mL Schlenk tube with a magnetic stirrer under nitrogen
atmosphere. The mixture was allowed to stir under
nitrogen atmosphere with illumination from a blue LED
(34W) at room temperature for an hour. Then the reaction
mixture was diluted with EtOAc (10 mL). The organic
layer was separated and the organic layer was washed with
saturated brines (10 mL×4). The organic layers were dried
over MgSO4. The solvent was removed under reduced
pressure and the residue was purified by flash column
chromatography on silica gel petroleum ether: ethyl acetate
(100:1, v:v) as the eluent.
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This work was supported by the National Natural Science
Foundation of China (21402126), the Engineering Technology
Research Center of Catalysis for Energy and Environment-Major
Platform for Science and Technology of the Universities in
Liaoning Province, Doctoral Fund of Shenyang Normal
University.
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5
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10.1002/adsc.201701051
Advanced Synthesis & Catalysis
COMMUNICATION
Visible light induced Trifluoromethyl Migration:
Easy Access to α-Trifluoromethylated Ketones
from Enol Triflates
Adv. Synth. Catal. Year, Volume, Page – Page
Shuyang Liu, Jiyang Jie, Jipan Yu, Xiaobo Yang*
6
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