Synthesis of β-Trifluoromethylated Ketones from Propargylic Alcohols by Visible Light Photoredox Catalysis

Article abstract of DOI:10.1002/ejoc.201500031

Regioselective trifluoromethylation at a remote position represents an important challenge in the development of biologically active molecules and functional materials. A practical method to access β-trifluoromethyl ketones from readily available propargylic alcohols by visible light photocatalysis has been developed. Trifluoromethylation of propargylic alcohols with CF₃I in the presence of Ru(bpy)₃Cl₂ as the photocatalyst followed by double-bond migration/keto-enol tautomerization provides β-trifluoromethyl ketones as the final product. β-Trifluoromethyl ketones are synthesized from readily available propargylic alcohols by visible light photocatalysis. Trifluoromethylation followed by double-bond migration/keto-enol tautomerization provides β-trifluoromethyl ketones as the final product.

Full text of DOI:10.1002/ejoc.201500031

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201500031
Synthesis of β-Trifluoromethylated Ketones from Propargylic Alcohols by
Visible Light Photoredox Catalysis
Sehyun Park,[a] Jung Min Joo,*[b] and Eun Jin Cho*[c]
Keywords: Photocatalysis / Radical reactions / Trifluoromethylation / Propargylic alcohols / Ketones
Regioselective trifluoromethylation at a remote position rep-
resents an important challenge in the development of biolo-
gically active molecules and functional materials. A practical
method to access β-trifluoromethyl ketones from readily
available propargylic alcohols by visible light photocatalysis
has been developed. Trifluoromethylation of propargylic
alcohols with CF3I in the presence of Ru(bpy)3Cl2 as the pho-
tocatalyst followed by double-bond migration/keto-enol tau-
tomerization provides β-trifluoromethyl ketones as the final
product.
Introduction
Incorporation of trifluoromethyl substituents is one of
the most important strategies for modulating properties of
organic molecules in drug discovery, agrochemical research,
and materials science. In general, trifluoromethylated com-
pounds show superior bioavailability, metabolic stability,
and lipophilicity compared with those of their non-tri-
fluoromethylated analogue.[1] A number of new methods
have been developed to produce aryl–, alkenyl–, and alkyl–
CF3 bonds, yet it is a significant challenge to introduce a
trifluoromethyl group at a remote position in a regioselec-
tive manner.[2] For example, while α-trifluoromethylation of
carbonyl compounds can be readily carried out through
electrophilic and radical processes,[3] there are few methods
that directly install a trifluoromethyl group at the β-position
of a carbonyl compound.[4] The electron-withdrawing na-
ture of the trifluoromethyl group makes its introduction by
direct nucleophilic addition into the electron-deficient β-po-
sition of α,β-unsaturated ketones challenging.[5] Conse-
quently, the preparation of β-trifluoromethyl ketones has
relied on multi-step syntheses that consist of the generation
of the trifluoromethylated alkene followed by a change in
oxidation state [Figure 1, (1)].[6,7]
Figure 1. Synthesis of β-trifluoromethylated ketones. Compared to
(1) a stepwise synthesis consisting of trifluoromethylation followed
by an oxidation state change, (2) a one-pot trifluoromethylation of
propargyl alcohols followed by isomerization directly provides β-
CF3 ketones.
Recently, we have developed a visible-light-induced
hydrotrifluoromethylation reaction of alkynes[8] in which we
observed a tendency of the trifluoromethylated alkene to
undergo allylic migration.[9] In this previous work, a prop-
argyl alcohol, 1-phenylprop-2-yn-1-ol, in the presence of
fac-Ir(ppy)3 generated the β-trifluoromethylated ketone as
the final product in moderate yield, rather than the corre-
sponding trifluoromethylated alkene product.[8] This find-
ing prompted us to develop a general and efficient one-step
protocol to access β-trifluoromethyl ketones from readily
available propargylic alcohols and trifluoroiodomethane by
visible-light photoredox catalysis[10,11] [Figure 1, (2)].
[a] Department of Bionanonotechnology, Hanyang University
Ansan, Kyeonggi-do 426-791, Republic of Korea
[b] Department of Chemistry and Chemistry Institute of
Functional Materials, Pusan National University,
Busan 609-735, Republic of Korea
E-mail: jmjoo@pusan.ac.kr
http://chemlab.pusan.ac.kr/jmjoo
[c] Department of Chemistry Chung-Ang University,
Seoul 156-756, Republic of Korea
Results and Discussion
E-mail: ejcho@cau.ac.kr
http://ejcho.cau.ac.kr
Based on our early observation, we tested a range of
ruthenium, iridium, and platinum[11n] photocatalysts for the
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500031.
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S. Park, J. M. Joo, E. J. Cho
SHORT COMMUNICATION
transformation with 1-phenylprop-2-yn-1-ol (1a) (Table 1, Table 2. Substrate scope for the synthesis of β-trifluoromethylated
ketones.[a]
Entries 1–7). While Ru(bpy)3Cl2 and fac-Ir(ppy)3 gave com-
parable results, Ru(bpy)3Cl2 was selected due to its lower
cost and clean reaction profile. Solvent screening experi-
ments found that DMF was more efficient than other polar
solvents (Entries 1 and 8–12). It was critical to use DBU as
a base for the process; the β-CF3 ketone 2a was obtained
in low yield with TMEDA, TEA, or DIPEA (Entries 13–
15). The [NR3]·+ intermediate formed by the photocatalytic
pathway can be a good hydrogen atom donor in the trans-
formation.[12] It is likely that the rigid structure of DBU
allows for efficient overlap between the half-vacant nitrogen
p-orbital and the α-C–H bond, thus rendering DBU the
more reactive hydrogen atom donor than TEA and DI-
PEA.[8] The reaction performed best in 0.1 m DMF solution
with 10 equiv. of DBU to generate 2a in 78% yield (En-
try 17). The use of less DBU lowered the yield (Entry 19).
The results of control experiments showed that both the
photocatalyst and visible light were required for the process
to take place (Entries 20 and 21) as the absence of either
light or photocatalyst resulted in the recovery of starting
material 1a.
Table 1. Optimization of reaction conditions for the synthesis of β-
trifluoromethylated ketone 2a.[a]
[a] Reaction conditions: 1 (0.5 mmol), CF3I (1.5 mmol), 16–24 h.
[a] Reaction conditions: 1a (0.2 mmol), CF3I (0.6 mmol), 20 h. [b]
Yields were determined by gas chromatography and 19F NMR
spectroscopy with internal standards dodecane and 4-fluorotolu-
ene, respectively.
[b] The given yields are isolated yields obtained from an average of
two runs. [c] The trifluoromethylated allylic alcohol, the product
before migration, was also produced (5–20%). [d] During the reac-
tion, the tert-butyldimethylsilyl group was removed.
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β-Trifluoromethylated Ketones
With optimized conditions in hand, we evaluated the tri-
In addition, internal propargyl alcohols were not good
fluoromethylation of a variety of propargylic alcohols. substrates for the selective synthesis of β-CF3 ketones. Re-
Propargylic alcohols connected to an aromatic ring ef- actions of an internal propargyl alcohol with aryl substitu-
ficiently underwent the cascade catalysis to provide the cor- tion at the triple bond (6) generated a mixture of alkenyl-
responding β-CF3 ketones 2 (Table 2). The substrate with a CF3 compounds from trifluoromethylation at both sites of
substituent at the ortho position of the aromatic ring was the alkyne (7 and 9) and their migration product ketones (8
also suitable for the process (Entry 3). Fluoro-, chloro-, and and 10) along with some unidentified byproducts
bromo-substituted aromatic β-CF3 ketones can also be syn- [Scheme 2, (1)].[13] Changing the aryl substituent to an ali-
thesized by this process, albeit in moderate yields (Entries 8, phatic group (11) did not improve the selectivity or reactiv-
9, and 10).
ity of the process and generated mixtures of unidentified
One of the limitations of our protocol is that the isomer- compounds [Scheme 2, (2)].
ization to ketones was efficient only with aromatic proparg-
These results led us to propose a radical-chain process
ylic alcohols. For example, the reaction with aliphatic to account for the formation of the β-trifluoromethylated
alcohol 1l resulted in the formation of trifluoromethylated ketone. First, photoexcitation of [RuII(bpy)3]2+ by visible
allylic alcohol 3l as the major product [Scheme 1, (1)]. A light produces [RuIII(bpy)2(bpy)·–]2+, which is oxidatively
conjugated system, cinnamylpropargyl alcohol 1m, was not quenched by single-electron transfer to CF3I to produce the
·
suitable for this process as a mixture of unidentified com- key intermediate CF3, [RuIII(bpy)3]2+, and iodide ion.[14]
·
pounds was produced [Scheme 1, (2)]. An aromatic homo- Addition of the CF3 radical to the alkyne generates the
alkynyl alcohol 4 provided the trifluoromethylated alkene 5 trifluoromethylated vinyl radical species 1Ј. Hydrogen ab-
in 65% yield [Scheme 1, (3)].
straction by 1Ј from the amminium radical cation [NR3]·+,
Scheme 1. β-Trifluoromethylation of aliphatic propargylic alcohols.
Scheme 2. Reactions of internal propargylic alcohols.
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S. Park, J. M. Joo, E. J. Cho
SHORT COMMUNICATION
Figure 2. Proposed mechanism for the formation of β-trifluoromethylated ketones.
and argon backfill.
A
solution of Ru(bpy)3Cl2 (2.0 mol-%,
produced by one-electron transfer from the tertiary amine
DBU to [RuIII(bpy)3]2+, generates the allylic alcohol 3.[8,12]
During the reaction, a small amount of 3 was also detected
by NMR spectroscopy as well as by GC analysis, along
with the final product 2. While transition-metal-catalyzed
isomerization of allylic alcohols often proceeds by metal
hydride addition-elimination,[9] an alternative mechanism
can be postulated for the Ru complex with strongly coordi-
nating bipyridine ligands. We propose the formation of a
0.01 mmol) in DMF (5.0 mL, 0.1 m) and DBU (5.0 mmol) were
then added to the tube under argon. CF3I (1.5 mmol) was added
to the reaction mixture by using a gas-tight syringe. The test tube
under argon was irradiated with blue LEDs (7 W) at room tem-
perature. The reaction was allowed to proceed for 16–24 h, and its
progress was monitored by thin-layer chromatography (TLC) and
gas chromatography (GC). The reaction mixture was then diluted
with diethyl ether and washed with 1 n HCl. The organic layer was
dried with MgSO4, concentrated in vacuo, and purified by flash
resonance-stabilized allyl radical 1Љ by hydrogen abstraction column chromatography to give the β-CF3 ketone.
from 3 by radical intermediates of the process, such as 1Ј
and CF3 radical.[15,16] Ultimately, the allyl radical is termin-
ated by hydrogen abstraction to give the enol species 2Ј,
Acknowledgments
and keto-enol tautomerization affords the final product β-
trifluoromethylated ketone 2 (Figure 2).
This work was supported by the National Research Foundation
of Korea [NRF-2014R1A1A1A05003274, NRF-2014-011165, and
NRF-2012M3A7B4049657] and the TJ Science Fellowship of the
POSCO TJ Park Foundation.
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Experimental Section
An oven-dried resealable test tube equipped with a magnetic stir
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β-Trifluoromethylated Ketones
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Received: January 9, 2015
Published Online: May 27, 2015
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