Controlled trifluoromethylation reactions of alkynes through visible-light photoredox catalysis

Article abstract of DOI:10.1002/anie.201308735

The control of a reaction that can form multiple products is a highly attractive and challenging concept in synthetic chemistry. A set of valuable CF₃-containing molecules, namely trifluoromethylated alkenyl iodides, alkenes, and alkynes, were selectively generated from alkynes and CF ₃I by environmentally benign and efficient visible-light photoredox catalysis. Subtle differences in the combination of catalyst, base, and solvent enabled the control of reactivity and selectivity for the reaction between an alkyne and CF₃I. Variety through selectivity: Highly valuable trifluoromethylated alkenyl iodides, alkenes, and alkynes were selectively generated from alkynes and CF₃I by environmentally benign and efficient visible-light photoredox catalysis. A suitable choice of catalyst, base, and solvent was crucial for the reactivity and selectivity of these processes.

Full text of DOI:10.1002/anie.201308735

Angewandte
Chemie
DOI: 10.1002/anie.201308735
Trifluoromethylation
Controlled Trifluoromethylation Reactions of Alkynes through Visible-
Light Photoredox Catalysis**
Naeem Iqbal, Jaehun Jung, Sehyun Park, and Eun Jin Cho*
Abstract: The control of a reaction that can form multiple
products is a highly attractive and challenging concept in
synthetic chemistry. A set of valuable CF3-containing mole-
cules, namely trifluoromethylated alkenyl iodides, alkenes, and
alkynes, were selectively generated from alkynes and CF3I by
environmentally benign and efficient visible-light photoredox
catalysis. Subtle differences in the combination of catalyst,
base, and solvent enabled the control of reactivity and
selectivity for the reaction between an alkyne and CF3I.
T
he control of a chemical reaction to selectively produce
Figure 1. Controlled trifluoromethylation reactions using an unacti-
vated alkyne and CF3I under visible-light irradiation.
a set of distinct valuable compounds from the same starting
material is a highly attractive concept, but represents
a significant synthetic challenge.[1] Selective trifluoromethy-
lation[2,3] processes could be of great benefit as the trifluor-
omethyl group is widely utilized, for example, in pharma-
ceuticals and agrochemicals.[4] Recently, visible-light photo-
redox catalysis has attracted substantial attention because of
its environmental compatibility and versatility in promoting
a large number of synthetically important reactions.[5] Visible-
light photoredox catalysis has also been applied to trifluor-
omethylations,[6] and further applications of this method will
continue to yield important trifluoromethylation reactions.
Herein, an environmentally benign and efficient method for
controlled trifluoromethylation reactions was exploited to
selectively obtain three different valuable alkenyl–CF3 and
alkynyl–CF3 compounds from the same starting materials,
namely an alkyne and CF3I, by the judicious choice of
reaction conditions using different photoredox catalysts,
bases, and solvents (Figure 1).
processes and can be converted into a set of distinct
compounds depending on the reaction conditions.[8] Subtle
differences in the combination of catalyst and base led to
totally different outcomes; iodotrifluoromethylation,[9,10]
hydrotrifluoromethylation,[11] and trifluoromethylation[12] of
alkynes have been described.
We started our investigation of controlled trifluorome-
thylations using phenyl acetylene (1a) as a model compound
with CF3I. First, iodotrifluoromethylation and hydrotrifluor-
omethylation were studied with different catalysts and bases.
A range of iridium and ruthenium photocatalysts, including
fac-[Ir(ppy)3], [Ir(ppy)2(dtb-bpy)]PF6, [Ru(bpy)3]Cl2, and
[Ru(phen)3]Cl2, efficiently generated the iodotrifluoromethy-
lation product 2a in high yields with E/Z ratios ranging from
17:1 to 20:1 with TMEDA in MeCN under visible-light
irradiation (Table 1, entries 3–6). [Ru(phen)3]Cl2 was chosen
as the catalyst for iodotrifluoromethylation because it is
inexpensive and displayed a cleaner reaction profile. Both the
photocatalyst and visible light were required for the trans-
formation, as demonstrated by control experiments (entries 1
and 2).
For the hydrotrifluoromethylation of 1a to form the
alkenyl–CF3 product 3a, iridium catalysts were found to be
more effective than ruthenium catalysts. The choice of base
was critical for this process, as the base acts not only as
a reductive quencher of the activated photocatalyst, but also
as a hydrogen donor.[13] For the reaction of 1a catalyzed by
fac-[Ir(ppy)3], the highest reactivity was observed with DBU
to yield the alkenyl–CF3 compound 3a (Table 1, entries 11–
15). The use of THF as a co-solvent improved the reactivity,
and 3a was isolated in a higher yield after a shorter reaction
time (entry 18).
Whereas the formation of aryl–CF3 bonds has been
extensively studied, trifluoromethylation reactions for the
synthesis of alkenyl–CF3 and alkynyl–CF3 compounds are
rather underdeveloped; this prompted us to prepare alkenyl–
CF3 and alkynyl–CF3 compounds from alkynes.[2,3,7] Alkynes
are highly reactive towards atom-transfer radical addition
[*] N. Iqbal, Prof. Dr. E. J. Cho
Department of Chemistry and Applied Chemistry
Hanyang University
55 Hanyangdaehak-ro, Sangnok-gu Ansan, Kyeonggi-do 426-791
(Republic of Korea)
E-mail: echo@hanyang.ac.kr
J. Jung, S. Park, Prof. Dr. E. J. Cho
Department of Bionanotechnology
Hanyang University (Republic of Korea)
[**] This work was supported by the National Research Foundation of
Korea (NRF; NRF-2011-0013118 and NRF-2012M3A7B4049657;
Nano Material Technology Development Program).
With optimized conditions in hand, we next evaluated the
iodotrifluoromethylation of a variety of aromatic and ali-
phatic alkynes (Scheme 1). The mild conditions allowed for
the iodotrifluoromethylation of alkynes that contain a range
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308735.
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Table 1: Catalyst and base screening with phenyl acetylene (1a) for iodo- and
of functional groups. Notably, excellent E/Z stereo-
selectivity was observed with selective formation of
the E isomers, especially in reactions of phenyl
acetylene derivatives (2a–2e).[8b] Alkynes with
directing groups at the propargylic position, such as
2 f and 2g, however, underwent selective iodotri-
fluoromethylation to exclusively give the Z isom-
ers.[14]
hydrotrifluoromethylation.[a]
Entry Photocatalyst
(mol%)
Base
(2 equiv)
Yield[b] [%]
2a (E/Z) 3a (E/Z)
The substrate scope of the hydrotrifluoromethy-
lation of alkynes was also investigated (Scheme 2).
Reactions in the presence of fac-[Ir(ppy)3] (3 mol%)
and DBU (10 equiv) in MeCN (0.1m) or MeCN/THF
(1:1) under visible-light irradiation provided a mix-
ture of the E and Z alkenyl–CF3 compounds in good
to excellent yields. In general, aliphatic alkynes,
except for those with a heteroatom at the propargylic
position, did not readily undergo hydrotrifluorome-
thylation under these conditions.
1
2
3
4
5
6
7
8
–
TMEDA
TMEDA
TMEDA
trace
trace
–
–
[Ru(phen)3]Cl2 (no light)
fac-[Ir(ppy)3] (0.5)
[Ir(ppy)2(dtb-bpy)]PF6 (0.5) TMEDA
92 (19:1)
93 (18:1)
90 (17:1)
95 (18:1)
trace
80 (8:1)
60 (17:1)
67
71 (11:1)
79 (11:1)
86 (11:1)
84 (12:1)
trace
trace
trace
trace
–
–
11 (1:3.8)
24 (1:4.0)
17 (1:2.8)
14 (1:6.4)
7 (1:2.8)
11 (1:3.1)
[Ru(bpy)3]Cl2 (0.5)
[Ru(phen)3]Cl2 (0.5)
[Ru(phen)3]Cl2 (0.5)
[Ir(ppy)2(dtb-bpy)]PF6 (0.5)
[Ru(phen)3]Cl2 (3.0)
[Ru(phen)3]Cl2 (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
fac-[Ir(ppy)3] (3.0)
TMEDA
TMEDA
–
–
DBU
DBU (5 equiv)
TMEDA
DIPEA
nBu3N
TEA
9
10
11
12
13
14
15
16
17[c]
18[d]
A plausible mechanism for the hydrotrifluoro-
methylation of alkynes is proposed in Figure 2.
Photoexcitation of [Ir(ppy)3] by visible light provides
*[Ir(ppy)3], which is then reductively quenched by
DBU to produce [Ir(ppy)3]CÀ and the ammonium
radical cation. The radical anion [Ir(ppy)3]CÀ in turn
DBU
DBU (5 equiv)
DBU (10 equiv) trace
DBU (10 equiv) trace
53 (only E) 36 (1:2.2)
trace
55 (1:2.3)
70 (1:2.3)
75 (1:1.3)
À
performs a single-electron reduction of the F3C I
[a] Reaction conditions: 1a (0.2 mmol), CF3I (0.6 mmol). [b] The yield and the E/Z
ratio were determined by gas chromatography and 19F NMR spectroscopy with
internal standards, namely dodecane and 4-fluorotoluene, respectively. [c] 2.0 mL of
MeCN (0.1m). [d] MeCN/THF (1:1; 0.1m). DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene, DIPEA=diisopropylethylamine, dtb-bpy=4,4’-di-tert-butyl-2,2’-bipyridine,
phen=1,10-phenanthroline, ppy=2-phenylpyridine, TEA=triethylamine,
TMEDA=N,N,N’,N’-tetramethylethylenediamine.
bond, which leads to the regeneration of [Ir(ppy)3]
and the formation of a carbon-centered *CF3 radical.
Addition of this electron-deficient radical species to
an alkyne 1 generates the vinyl radical. The desired
alkenyl–CF3 product 3 is finally generated through
direct hydrogen abstraction by the vinyl radical.
Scheme 2. Scope of the hydrotrifluoromethylation of alkynes. Reaction
conditions: 1 (0.5 mmol), CF3I (1.5 mmol). The given yields either
correspond to the yield of isolated product or were determined by
19F NMR spectroscopy because of the volatility of the products. The
E/Z ratios were determined by gas chromatography and 1H NMR and
19F NMR spectroscopy of the crude products.
Scheme 1. Scope of the iodotrifluoromethylation of alkynes. Reaction
conditions: 1 (1.0 mmol), CF3I (3.0 mmol). Yields of isolated products
that are based on the average of two runs are given. The E/Z ratios
were determined by gas chromatography and 1H NMR spectroscopy of
the crude products.
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cesses. Phenyl acetylene (1a) was converted into the alkynyl–
CF3 compound 4a when inorganic bases, such as KOtBu and
Cs2CO3, were used (Table 2). Although this process was less
efficient than the iodo- and hydrotrifluoromethylation reac-
tions, the alkynyl–CF3 product 4a was obtained in a reason-
able yield with fac-[Ir(ppy)3] and KOtBu in DMF (0.1m). The
process also produced approximately 10–20% of the bis(tri-
fluoromethylated) product 5a and 5% of the alkynyl iodide
as side products (entry 2). The process required both a visible-
light source and the photocatalyst to give the trifluoromethy-
lated alkyne 4a, as without light or catalyst, only the alkynyl
iodide was formed (entries 7 and 8).[18]
Various aromatic alkynes 1 were transformed into the
desired alkynyl–CF3 compounds 4 under the optimized
conditions, which was accompanied by the formation of the
bis(trifluoromethylated) products 5 (5–20%; Scheme 3).
Reactions of both electron-rich (4b, 4c, 4o) and electron-
poor (4d) phenyl acetylene derivatives yielded trifluorome-
thylated alkynes in reasonable yields. Unfortunately, aliphatic
alkynes were not suitable substrates for this reaction.
Figure 2. Proposed mechanism for the formation of trifluoromethy-
lated alkenes.
However, the reaction could also proceed by competitive
iodide abstraction from CF3I by the vinyl radical to give the
alkenyl iodide 2 as an intermediate, that is, hydrotrifluoro-
methylation of alkynes might occur through a cascade process
where iodotrifluoromethylation is followed by de-iodination
of the trifluoromethylated alkenyl iodide intermediate 2. De-
iodination could proceed with the same catalytic system;
[Ir(ppy)3]CÀ performs a single-electron reduction of the
À
alkenyl I bond to give a vinyl radical that undergoes hydro-
gen abstraction to provide the alkenyl–CF3 product 3.[15] This
was confirmed by an additional experiment; the alkenyl
iodide 2 was transformed into 3 under the conditions for the
hydrotrifluoromethylation of 1 to yield 3.[16] Furthermore, the
fact that alkenyl iodide 2 was present during the course of the
reaction[17] also supports the idea that cascade catalysis
through de-iodination of 2 is involved in this hydrotrifluor-
omethylation.
Next, we investigated the trifluoromethylation reaction
that yields trifluoromethylated alkynes (Table 2). The reac-
tion conditions for this process were quite different to the
conditions for the iodo- and hydrotrifluoromethylation pro-
Scheme 3. Scope of the trifluoromethylation of alkynes. Reaction
conditions: 1 (0.5 mmol), CF3I (1.5 mmol). The given yields either
correspond to the yield of isolated product or were determined by
19F NMR spectroscopy because of the volatility of the products.
[a] With TMEDA (instead of KOtBu) in MeCN after 3 h.
Table 2: Optimization of the reaction conditions for the synthesis of
trifluoromethylated alkynes.[a]
In conclusion, three different CF3-substituted compounds,
namely trifluoromethylated alkenyl iodides, alkenes, and
alkynes, were selectively generated from alkynes under
similar reaction conditions. Subtle differences in the choice
of catalyst and base enabled the control of reactivity and
selectivity in the reaction between an alkyne and CF3I.
Trifluoromethylated alkenyl iodides were selectively obtained
as the E isomers in the presence of [Ru(phen)3]Cl2 and
TMEDA under visible-light irradiation, whereas alkenyl–CF3
compounds were obtained with fac-[Ir(ppy)3] and DBU by
the hydrotrifluoromethylation of alkynes. Alkynyl–CF3 com-
pounds were generated with fac-[Ir(ppy)3] and KOtBu in
DMF under visible-light irradiation. These environmentally
friendly and mild reaction conditions enabled the trifluoro-
methylation of alkynes that bear a variety of functional
groups to efficiently provide a highly valuable set of CF3-
containing molecules.
Entry
Photocatalyst
(2 mol%)
Base
(3 equiv)
Solvent
(0.1m)
Yield[b] [%]
4a
5a
1
2
3
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
fac-[Ir(ppy)3]
[Ru(phen)3]Cl2
[Ir(dFppy)3]
–
Cs2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
DMF
DMF
MeCN
DMSO
DMF
DMF
DMF
DMF
58
64
trace
–
trace
15
–
4[c]
5
–
–
–
6
60
–
16
–
7[c]
8[c]
[Ir(dFppy)3] (no light)
–
–
[a] Reaction conditions: 1a (0.2 mmol), CF3I (0.6 mmol), 7 h. [b] The
yield was determined by gas chromatography and 19F NMR spectrosco-
py. [c] The alkynyl iodide was formed. dFppy=2-(2,4-difluorophenyl)-
pyridine, DMF=N,N-dimethylformamide, DMSO= dimethyl sulfoxide.
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Received: October 7, 2013
Revised: October 30, 2013
Published online: November 20, 2013
Keywords: iridium · radical reactions · ruthenium ·
.
trifluoromethylation · visible light
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[16] Isolated 2a (Scheme 1) was subjected to the conditions de-
scribed in Scheme 2. See the Supporting Information,
Scheme S1.
[17] Alkenyl iodide 2a was detected during the reaction of 1a, see
the Supporting Information, Figure S1 (kinetic studies of the
reaction with 1a).
[18] It is likely that the reaction proceeded through an alkynyl iodide
as the intermediate. For experimental details, see the Supporting
Information, Scheme S2. A plausible mechanism for the tri-
fluoromethylation of alkynes is proposed in Figure S2.
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