An improved copper-mediated oxidative trifluoromethylation of terminal alkynes

Article abstract of DOI:10.1002/ejoc.201101550

An improved method for the efficient copper-mediated trifluoromethylation of terminal alkynes has been developed. This protocol highlights the convenient access to a variety of aryl-substituted trifluoromethylated alkynes by oxidative trifluoromethylation

Full text of DOI:10.1002/ejoc.201101550

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201101550
An Improved Copper-Mediated Oxidative Trifluoromethylation of Terminal
Alkynes
Ke Zhang,[a] Xiao-Long Qiu,[b] Yangen Huang,[a] and Feng-Ling Qing*[a,c]
Keywords: Fluorine / Alkynes / Copper
An improved method for the efficient copper-mediated tri-
fluoromethylation of terminal alkynes has been developed.
This protocol highlights the convenient access to a variety
of aryl-substituted trifluoromethylated alkynes by oxidative
trifluoromethylation with two equivalents of TMSCF3 at room
temperature.
aldehydes by the successful merger of an enamine and an
organometallic photoredox, whose mechanism relied on the
propensity of the trifluoromethyl radical (derived from the
reduction of trifluoromethyl iodide by a photoredox cata-
lyst) to combine with facially biased enamine intermediates
(derived from aldehydes and a chiral amine catalyst). Nu-
cleophilic trifluoromethylation has involved the generation
Introduction
Currently, organic chemists and medicinal chemists have
been paying attention to the introduction of fluorine
atom(s) or fluorine-containing groups into potentially bio-
logically active molecules because their introduction could
bring about remarkable and profound changes in physical,
chemical, and biological properties of the compounds.[1]
For example, over 100 fluorine-containing compounds have
been approved by the FDA in the United States for the
treatment of different diseases. In 2007, 9 of the top 20 best-
selling drugs in the world were fluorine-containing com-
pounds or mixtures of fluorine-containing compounds and
other compounds. Of all the fluorine-containing com-
pounds, trifluoromethylated compounds are widely used in
pharmaceuticals and agrochemicals.[2] Thus, the introduc-
tion of the strongly electron-withdrawing trifluoromethyl
group (CF3) into organic molecules, which has been shown
to greatly change the bioactivity, biostability, and lipophi-
licity[1,2] of these compounds, continues to be a hot topic in
current organic chemistry.
–
of CF3 or a trifluoromethyl metal complex. For example,
Amii’s group[6] and Buchwald’s group[7] described the Cu-
catalyzed and Pd-catalyzed trifluoromethylation of aryl hal-
ides, respectively. We[8] and Buchwald[9] reported the Cu-
mediated oxidative trifluoromethylation of boronic acids
with the nucleophilic trifluoromethylation agent TMSCF3
(Ruppert–Prakash reagent). Liu,[10] Sheng,[11] and Xiao[12]
documented the CuI-catalyzed trifluoromethylation of bor-
onic acids with electrophilic trifluoromethylation agents
(Umemoto reagent and Togni reagent). Noteworthy is that
Hartwig[13] and Grushin[14] recently prepared the trifluoro-
methylation Cu reagent [(phen)CuCF3] and [(phen)Cu-
(PPh3)(CF3)], respectively, both of which reacted with aryl
iodides to afford trifluoromethylated arenes in high yields.
Most of the aforementioned examples involved the prepara-
tion of CF3-substituted aryl compounds. In view of the im-
portance of trifluoromethylated olefins and alkynes, several
groups have recently developed efficient methodologies for
the direct trifluoromethylation of unactivated olefins and
alkynes. Buchwald[15] followed by Wang[16] described the
Cu-catalyzed trifluoromethylation of terminal olefins by
using the Togni electrophilic trifluoromethylation reagent.
Using Umemoto’s reagent and catalyzed by (thiophene-2-
carbonyloxy)copper in the presence of 2,4,6-collidine, Liu
and co-workers[17] reported another method for the trifluoro-
methylation of terminal alkenes. In 2010, our group[18] de-
scribed the first example of a Cu-mediated protocol for the
Csp–Csp3 oxidative trifluoromethylation of terminal alkynes
with TMSCF3. This method represented a straightforward
and functional group compatible approach to a broad
range of trifluoromethylated acetylenes in moderate to high
Generally, several methods have been utilized for the in-
corporation of the trifluoromethyl group into organic mole-
cules, including radical,[3] electrophilic,[4] and nucleophilic[5]
reactions. The efficient generation of the trifluoromethyl
radical is the key step in radical-mediated trifluoromethyl-
ation reactions. For example, MacMillan and co-workers[3c]
recently reported the asymmetric α-trifluoromethylation of
[a] College of Chemistry, Chemical Engineering and
Biotechnology, Donghua University
2999 North Renmin Road, Shanghai 201620, China
[b] Wisdom Pharmaceutical Co., Ltd.,
601 East Xiu-shan Road, Haimen, Jiangsu Province 226100,
China
[c] Key Laboratory of Organofluorine Chemistry,
Shanghai Institute of Organic Chemistry,
Chinese Academy of Science
345 Lingling Road, Shanghai 200032, China
E-mail: flq@mail.sioc.ac.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201101550.
58
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 58–61

Copper-Mediated Oxidative Trifluoromethylation of Terminal Alkynes
yields. However, reaction temperatures up to 100 °C and the to 90% yield (Table 1, Entry 4). Switching CuCl to other
requirement of 5.0 equivalents of TMSCF3 rendered this Cu salts, such as CuBr, CuI, and Cu(OAc)2, significantly
methodology less than ideal (Figure 1). We assume that this decreased the yield of 1b (Table 1, Entries 5–7). It was
oxidative trifluoromethylation reaction would be successful found that compound 1b was formed in low yield when KF
at room temperature by using fewer equivalents of was used as the base instead of tBuOK for the preparation
TMSCF3 if the (phen)Cu(CF3) generated in situ from of (phen)Cu(CF3) (Table 1, Entry 8). Thus, the optimal re-
[13]
TMSCF3 was used (Figure 1).
action conditions were established as follows: 2.0 equiv. of
CuCl, 2.0 equiv. of phen, 2.0 equiv. of tBuOK, 2.0 equiv. of
Ag2CO3, 2.0 equiv. of TMSCF3, and 1.0 equiv. of terminal
alkyne in DMF at room temperature.
With the optimal reaction conditions in hand, the scope
of the oxidative trifluoromethylation of terminal alkynes
was investigated (Table 2). Electron-rich terminal alkynes
could be smoothly trifluoromethylated to give the corre-
sponding products (i.e., 1b, 6b, 7b–10b) in moderate to good
yields. Trifluoromethylated aryl alkyne 3b with a meth-
oxycarbonyl substituent in the ortho position of the benzene
ring was also obtained in 71% yield. Noteworthy is that
ketone and ester groups were well tolerated (i.e., 3b, 4b, 11b,
12b) although substrates containing ketone groups were
problematic because of the competitive 1,2-addition of the
trifluoromethyl anion to the carbonyl group.[19]
Figure 1. Cu-mediated trifluoromethylation of terminal alkynes.
Results and Discussion
To test our assumption, 4-ethynylbiphenyl was selected
as a model substrate for direct trifluoromethylation; (phen)-
Cu(CF3) was in situ prepared by using TMSCF3
(2.0 equiv.), CuCl (2.0 equiv.), and tBuOK in DMF,[13] and
then 4-ethynylbiphenyl was added to the mixture in air at
room temperature. Analysis of the reaction mixture by 19F
NMR spectroscopy demonstrated that a trace amount of
the trifluoromethylation product was formed. GC–MS of
the reaction mixture showed that the major product was the
diyne. On the basis of the above experimental result, we
decided to replace the air with other oxidants. We were
happy to find that substitution of PhI(OAc)2 for air gave
desired product 1b in 53% yield (Table 1, Entry 2). The oxi-
dant tBuOOtBu gave almost the same yield (Table 1, En-
try 3). In view of the successful trifluoromethylation of bo-
ronic acids by using Ag2CO3 as an oxidant,[8] Ag2CO3 was
used instead of air for this oxidative trifluoromethylation.
Excitingly, the yield of desired compound 1b was improved
Table 2. Oxidative trifluoromethylation of terminal alkynes.[a,b]
Table 1. Optimization of the oxidative trifluoromethylation of 4-
ethynylbiphenyl (1a) at room temperature.[a]
Entry
Cu
Base (equiv.)
Oxidant
Yield [%][b]
1
2
3
4
5
6
7
8
CuCl
CuCl
CuCl
CuCl
CuI
CuBr
Cu(OAc)2
CuCl
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
tBuOK (2.0)
KF (2.0)
air
2
PhI(OAc)2
tBuOOtBu
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
53
50
90
30
37
13
31
[a] Reaction conditions: 1a (0.5 mmol), TMSCF3 (1.0 mmol), [Cu]
(1.0 mmol), phen (1.0 mmol), oxidant (1.0 mmol), and
base(1.0 mmol) in DMF (4 mL) at room temperature under N2.
[b] Yield was determined by 19F NMR spectroscopy with benzotri-
fluoride as an internal standard.
[a] Reactions were conducted with 0.5 mmol of the terminal alkyne
under the optimal conditions. [b] Isolated yields are given.
Eur. J. Org. Chem. 2012, 58–61
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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59

K. Zhang, X.-L. Qiu, Y. Huang, F.-L. Qing
SHORT COMMUNICATION
atmosphere. TMSCF3 (0.148 mL, 1.0 mmol, 2.0 equiv.) was slowly
added. The resulting mixture was further stirred at room tempera-
ture for 1 h. A solution of the terminal alkyne (0.5 mmol) in DMF
(2.0 mL) was slowly added to the reaction mixture over 3 h by using
a syringe pump under an atmosphere of N2. The reaction mixture
was kept for another 3 h at room temperature. The reaction mixture
was filtered through a plug of Celite on silica and eluted with di-
ethyl ether (50 mL). The combined solution was washed with water.
The water was extracted with ethyl ether. The combined organic
phase was washed with brine and then dried with magnesium sul-
Although Ag2CO3 was a suitable oxidant in this proto-
col, this method was limited by its high price. We turned
our attention to the development of an alternative oxidant.
Recently, Buchwald and co-workers described the oxidative
trifluoromethylation of aryl boronic acids by using oxygen
as an oxidant.[9] Accordingly, oxygen was used for the oxi-
dative trifluoromethylation of alkynes instead of expensive
Ag2CO3 (Table 3). The isolated yields of the trifluorometh-
ylated alkynes with the use of oxygen in the presence of 4 Å
powdered molecular sieves were similar to those obtained fate. After filtration and removal of solvent, the residue was puri-
fied by silica gel column chromatography to give the trifluorome-
thylated product.
with Ag2CO3.
Table 3. Oxidative trifluoromethylation of terminal alkynes by
using oxygen as an oxidant.[a,b]
General Procedure for the Oxidative Trifluoromethylation of Ter-
minal Alkynes Outside of the Glove Box with Oxygen as the Oxi-
dant: To a 25-mL three-necked round-bottomed flask equipped
with a magnetic stir bar was added 4 Å molecular sieves (250 mg).
The molecular sieves were activated by flame under vacuum. After
the molecular sieves were fully activated, the flask was allowed to
cool to room temperature under an atmosphere of N2. After it was
backfilled with dry oxygen (once), CuCl (99 mg, 1.0 mmol,
2.0 equiv.), tBuOK (112 mg, 1.0 mmol, 2.0 equiv.), and 1,10-phen-
anthroline (180 mg, 1.0 mmol, 2.0 equiv.) were added. Then, the air
in the flask was evacuated and dry oxygen was refilled (twice). Af-
ter that, DMF (2.0 mL) was added to the mixture, and the resultant
mixture was stirred at room temperature for 30 min under an atmo-
sphere of oxygen. TMSCF3 (0.148 mL, 1.0 mmol, 2.0 equiv.) was
slowly added. The resulting mixture was further stirred at room
temperature for 1 h. A solution of the terminal alkyne (0.5 mmol)
in DMF (2.0 mL) was slowly added to the reaction mixture over
3 h by using a syringe pump under an atmosphere of dry oxygen.
The reaction mixture was kept for another 3 h at room temperature.
The reaction mixture was filtered through a plug of Celite on silica
and eluted with diethyl ether (50 mL). The combined solution was
washed with water. The aqueous phase was extracted with ethyl
ether. The combined organic phase was washed with brine and then
dried with magnesium sulfate. After filtration and removal of the
solvent, the residue was purified by silica gel column chromatog-
raphy to give the trifluoromethylated product.
[a] CuCl (2.0 mmol), phen (2.0 mmol), tBuOK (2.0 mmol),
TMSCF3 (2.0 mmol), O2 (1 atm), and 4 Å MS (200 mg) in
DMF(2 mL) at room temperature; terminal alkyne/DMF (2.0 mL)
solution was slowly added to the mixture over 3 h by using a sy-
ringe pump. [b] Isolated yields are given.
Conclusions
Supporting Information (see footnote on the first page of this arti-
cle): General methods, experimental procedures, and characteriza-
tion data for all new compounds.
An improved procedure for the Cu-mediated oxidative
trifluoromethylation of terminal alkynes has been devel-
oped. By using (phen)Cu(CF3) generated in situ from
TMSCF3, this oxidative trifluoromethylation proceeded
smoothly at room temperature with a smaller amount of
TMSCF3. We believe that the milder and more efficient re-
action conditions described herein will be widely used for
oxidative trifluoromethylation.
Acknowledgments
The National Natural Science Foundation of China (21072028,
20832008) is greatly acknowledged for funding this work.
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60
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Eur. J. Org. Chem. 2012, 58–61

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Received: October 24, 2011
Published Online: November 29, 2011
Eur. J. Org. Chem. 2012, 58–61
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