Practical methods for the synthesis of trifluoromethylated alkynes: Oxidative trifluoromethylation of copper acetylides and alkynes

Article abstract of DOI:10.1002/adsc.201400057

Two practical and complementary methods are reported for the synthesis of trifluoromethylated alkynes. The first one, a mix-and-stir process, is based on the oxidative trifluoromethylation of readily available and bench-stable copper acetylides while the second one, which displays a broad substrate scope and has several advantages over existing procedures, is based on the oxidative copper-catalyzed direct trifluoromethylation of terminal alkynes. Both reactions provide user-friendly processes for the synthesis of trifluoromethylated acetylenes which can be easily obtained from readily available starting materials.

Full text of DOI:10.1002/adsc.201400057

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DOI: 10.1002/adsc.201400057
Practical Methods for the Synthesis of Trifluoromethylated
Alkynes: Oxidative Trifluoromethylation of Copper Acetylides
and Alkynes
Cꢀdric Tresse,a Cꢀline Guissart,b Stꢀphane Schweizer,a Yassine Bouhoute,b
Anne-Caroline Chany,a Mary-Lorꢁne Goddard,a Nicolas Blanchard,c,*
and Gwilherm Evanob,*
a
Laboratoire de Chimie Organique et Bioorganique, Universitꢀ de Haute-Alsace – ENSCMu, 3 rue A. Werner, 68093
Mulhouse cedex, France
b
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universitꢀ Libre de Bruxelles
(ULB), Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
Fax : (+32)-2-650-2798; phone: (+32)-2-650-3057; e-mail: gevano@ulb.ac.be
Laboratoire de Chimie Molꢀculaire, ECPM-CNRS UMR7509, Universitꢀ de Strasbourg, 25 rue Becquerel, 67087
c
Strasbourg, France
Fax : (+33)-3-8933-6860; phone: (+33)-3-8933-6824; e-mail: n.blanchard@unistra.fr
Received: January 16, 2014; Revised: February 22, 2014; Published online: && &&, 0000
Dedicated with much respect to Professor Alexandre Alexakis, an inspiring mentor.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400057.
Abstract: Two practical and complementary methods reactions provide user-friendly processes for the syn-
are reported for the synthesis of trifluoromethylated thesis of trifluoromethylated acetylenes which can be
alkynes. The first one, a mix-and-stir process, is easily obtained from readily available starting mate-
based on the oxidative trifluoromethylation of readi- rials.
ly available and bench-stable copper acetylides while
the second one, which displays a broad substrate
scope and has several advantages over existing pro- Keywords: copper; copper acetylides; oxidative
cedures, is based on the oxidative copper-catalyzed cross-coupling;
trifluoromethylated
alkynes;
direct trifluoromethylation of terminal alkynes. Both trifluoromethylation
AHCTUNGTRENNUNG
Introduction
the development of these new trifluoromethylation
processes, new trifluoromethylated building blocks
Trifluoromethylated compounds are of widespread are also emerging. Trifluoromethylated alkynes clear-
importance in nearly every sector of the chemical in- ly fall into this category and have recently found vari-
dustry as well as in pharmaceutical and agrochemical ous applications in medicinal chemistry.[1d,5] In addi-
sciences and for the preparation of liquid crystals, tion, they were shown to be excellent precursors for
dyes or polymers.[1] As with all fluorine-containing de- the synthesis of various trifluorinated building blocks
rivatives, the incorporation of the trifluoromethyl such as arenes,[6] alkenes,[7] allenes,[8] enones,[9] enol
motif, which is absent in Nature,[2] into an organic esters,[10] methyl ketones,[7g,8a] Pauson–Khand ad-
molecule results in deep modifications of its chemical ducts[11] or heterocycles.[12]
and physical properties including, among others, its
Despite their apparent simplicity, the preparation
basicity, hydrophobicity, conformation, binding selec- of these building blocks is however far from being
tivity or metabolic stability.[3] Because of these unique trivial. In most cases, they are indeed prepared by
properties of the trifluoromethyl group, tremendous a palladium-catalyzed cross-coupling reaction starting
efforts have been devoted recently to the develop- from trifluoropropynylmetal reagents[13] or by their
ment of new processes that allow for the introduction reaction with electrophiles,[14] by dehydrohalogenation
of a CF3 subunit – mostly to an aromatic ring – with from halogenated trifluoromethylalkenes[15] or by
surgical precision and remarkable efficiency.[4] Besides
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tions. While the second and third generation proce-
dures provided an improved access to trifluoromethy-
lated alkynes, they still suffer from important limita-
tions which make them less practical than one could
wish, especially on a larger scale.
Following these developments, alternative proce-
dures have been reported later on based either on the
use of alkyne surrogates such as potassium alkynyltri-
fluoroborates [Scheme 2, Eq. (1)],[22] and/or alterna-
tive trifluoromethylating agents such as Togniꢃs ben-
ziodoxole[20,23] [Scheme 2, Eqs. (1) and (2)] or Ume-
motoꢃs sulfonium [Scheme 2, Eq. (3)].[24] A remark-
able alternative process for the in situ generation of
trifluoromethylcopper was finally reported recently
based on the reaction of K[CuACHTUNRGTNEUNG(O-t-Bu)2] – generated
by reaction of copper(I) chloride and two equivalents
of potassium tert-butoxide – with trifluoroacetophe-
none [Scheme 2, Eq. (4)].[25] Quite impressively, the
reaction which, however, required the generation of
trifluoromethylcopper prior to its reaction with the
alkyne, provided the desired trifluoromethylated ace-
tylenes at room temperature within one hour, al-
though a slow addition of the alkyne was still required
in order to minimize its Glaser–Hay dimerization.
Scheme 1. Direct trifluoromethylation of alkynes with the
Ruppert–Prakash reagent.
a typically low-yielding electrophilic trifluoromethyla-
tion of lithium acetylides.[16]
The low efficiency of these reactions and/or the
limited availability of the starting materials required
have motivated many research groups to engage in
the development of more efficient and straightfor-
ward processes. This quest for direct methods for the
trifluoromethylation of alkynes recently resulted in
the development of innovative and more practical
routes to trifluoromethylated acetylenes. In this con-
text, Qing, capitalizing on Stahlꢃs oxidative cross-cou-
pling between terminal alkynes and amides,[17] report-
ed in 2010 the first direct trifluoromethylation of al-
kynes using a copper-mediated oxidative cross-cou-
pling with Ruppert–Prakash reagent [Scheme 1, Eq.
(1)].[18,19] By using stoichiometric amounts of copper
iodide and phenanthroline in the presence of potassi-
um fluoride in DMF at 1008C under air, various tri-
fluoromethylated alkynes could be obtained in good
yields provided that the alkyne was slowly added by
syringe pump. Although this protocol represented
a significant breakthrough, it still suffered from
severe limitations including the use of stoichiometric
amounts of both the copper salt and the ligand, of an
excess of TMSCF3, and the requirement for potassium
fluoride, high temperatures – which is quite critical
due to the volatility of most trifluoromethylated ace-
tylenes – and, of course, slow addition of the alkyne.
These limitations were next, at least partially, ad-
dressed by the same group who reported improved
procedures based on catalytic [Scheme 1, Eq. (2)][20]
or room temperature [Scheme 1, Eq. (3)][21] condi-
Scheme 2. Other copper-mediated syntheses of trifluorome-
thylated alkynes.
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Practical Methods for the Synthesis of Trifluoromethylated Alkynes
Scheme 3. Strategies for the development of practical pro-
cesses for the synthesis of trifluoromethylated alkynes.
While these developments reported in the last four
years clearly had a deep impact on the chemistry of
trifluoromethylated alkynes, which can now be pre-
pared by direct trifluoromethylation of alkynes or
synthetic equivalents,[26] all these procedures still dis-
play limitations, the most common one being the slow
addition of the alkyne, which renders these processes
less practical on a large scale, the use of complex re-
agents and/or the use of stepwise processes.
In an attempt to address some of the limitations as-
sociated with these procedures, we envisioned two
strategies as depicted in Scheme 3 for the design of
practical and user-friendly methods for the synthesis
of trifluoromethylated alkynes that could proceed at
room temperature and without the need for slow ad-
dition of the alkynyl partner.
Figure 1. Comparative efficiency of N-ligands for the tri-
fluoromethylation of para-biphenylylethynylcopper. Stan-
dard conditions: 0.5 mmol 1a, 2.0 mmol TMSCF3, 0.5 mmol
ligand (if bidentate) or 1.0 mmol ligand (if monodentate),
2 mL CH3CN, air, room temperature, 24 h. 19F NMR yields
determined using 0.5 mmol of 1H,1H,8H,8H-octafluoro-3,6-
dioxaoctane-1,8-diol as an internal standard.
The first one is based on the oxidative trifluorome-
thylation of readily available and bench-stable copper
acetylides while the second one relies on [CuACTHNUTRGNEUNG(CF3)] mediate species resulting from their oxidation should
species for the oxidative trifluoromethylation of ter- circumvent the need for the in situ activation of
minal alkynes.[27] Results obtained with these two TMSCF3 with a source of fluoride and the need for
complementary procedures are reported herein.
high temperatures. In addition, the slow dissolution of
these copper acetylides in the course of the reaction
should allow for the development of a mix-and-stir
process without slow addition of one reagent.
Results and Discussion
With this goal in mind, we first evaluated the effi-
Based on our recent interest in the reactivity of ciency of a set of nitrogen ligands to promote the tri-
copper acetylides under oxidative conditions,[28] we fluoromethylation of para-biphenylylethynyl-copper
envisioned that they could represent most useful re- 1a with Ruppert–Prakash reagent (Figure 1). At this
agents for the synthesis of trifluoromethylated al- first stage of the optimization, acetonitrile was arbi-
kynes. Indeed, we have shown during the last two trarily chosen as the solvent, the temperature was set
years that these remarkably stable polymeric reagents, at room temperature, molecular oxygen was chosen
which can be readily prepared on a multigram scale as the oxidant for obvious practical reasons (low cost,
by simply adding a terminal alkyne to a solution of generation of water as the by-product…) and an
copper(I) iodide in a mixture of ammonia/ethanol/ excess (four equivalents) of TMSCF3 was used to min-
water followed by filtration, can be activated in the imize the oxidative dimerization of 1a. Various repre-
presence of oxygen and a ligand and transfer their sentative mono- and bidentate ligands shown in
alkyne subunit to a wide range of nucleophiles. After Figure 1 were then evaluated under these standard
the success we met with this oxidative umpolung conditions and while all of them gave rather low
strategy for the preparation of ynamides,[28a] ynim- yields of the desired trifluoromethylated alkyne 2a
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
A
ACHTUNGTRENNUNG
benefits that we envisioned from the use of these al- used for this reaction using TMEDA as the ligand.
kynylcopper complexes, the high reactivity of inter- Various solvents with representative polarities (aceto-
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Figure 2. Comparative efficiency of solvents for the trifluor-
omethylation of para-biphenylylethynylcopper. Standard
conditions: 0.5 mmol 1a, 2.0 mmol TMSCF3, 0.5 mmol
TMEDA, 2 mL solvent, air, room temperature, 24 h.
19F NMR
yields
determined
using
0.5 mmol
of
1H,1H,8H,8H-octafluoro-3,6-dioxaoctane-1,8-diol as an in-
ternal standard.
Figure 3. Scope of the oxidative trifluoromethylation of
copper acetylides. Yields given correspond to isolated yields
of pure products unless otherwise stated.
nitrile, dichloromethane, toluene, dioxane, DMF, cy-
clohexane) were therefore first screened: as shown by
the results collected in Figure 2, toluene proved to be
by far the best solvent and allowed for the formation acetylides 1. Results of these studies are collected in
of the desired trifluoromethylated alkyne 2a in 80% Figure 3. As shown by these results, the corresponding
yield (19F NMR yield). While this solvent was shown trifluoromethylated alkynes 2 could be obtained in
to be remarkably efficient at this stage of the optimi- moderate to good yields in most cases, even though
zation, we were, however, concerned that its use with the homodimerization of the starting alkynylcopper
other copper acetylides would be problematic due to reagents 1 could not be completely suppressed.
the low boiling points of most trifluoromethylated al-
The reaction tolerates a wide range of substituents
kynes which are, in most cases, below that of toluene. on the starting copper acetylides and was found to be
To avoid problems associated with the isolation of the especially convenient for the preparation of aryl-sub-
desired trifluoromethylated alkynes, we therefore de- stituted trifluoromethylated alkynes (2a–2l), which
cided to switch to mixtures of petroleum ether and could be easily obtained regardless of the substitution
DMF. Among all mixtures evaluated, a 95/5 ratio of pattern of the starting reagent or the presence of elec-
petroleum ether/DMF was found to be optimal and tron-withdrawing/electron-donating substituents. The
allowed for the formation of 2a in 74% yield trifluoromethylation was also amenable to the prepa-
(19F NMR yield, 69% isolated yield), provided that ration of alkyl-substituted trifluoromethylated alkynes
the reaction was run under oxygen rather than air such as 2m–2q, which could also be obtained in mod-
(69% vs. 51% yield). While this yield was slightly erate to good yields. In some cases however, some of
lower than the one obtained in toluene, we decided to the corresponding copper acetylides were found to
stick with the use of a petroleum ether/DMF solvent lack the characteristic polymeric organization of these
mixture due to the easier isolation of trifluoromethy- reagents. In these cases, they were found to be highly
lated alkynes with this system.
sensitive to oxygen and to dimerize too rapidly to be
With the optimized conditions in hand, we next fo- used for the trifluoromethylation, which accounts for
cused on the scope of the reaction by studying the tri- the impossibility to form trifluoromethylated alkynes
fluoromethylation of various representative copper such as 2r and 2r’ using this procedure.
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Figure 4. 19F NMR (376 MHz) monitoring of the formation of [Cu(CF3)2]À and [Cu(CF3)4]À at 100 and 208C under nitrogen
ACTHNUTRGENNUG CAHTUNGTRENNUGN
or air, using trifluorotoluene as an internal standard.
Compared to previously reported procedures for ment our first generation synthesis, the goal of these
the synthesis of trifluoromethylated acetylenes, one of studies was to expand the scope of the direct trifluor-
the main advantages of the one reported here lies in omethylation of alkynes based on trifluoromethylcop-
its operational simplicity. Indeed, the reaction readily per complexes that would be readily prepared and
proceeds at room temperature without the need for that would show greater reactivity than the previously
purified solvents and slow addition of one reagent. reported phenanthroline ligated ones. Based on the
From a practical point of view, the completion of the remarkable efficiency of TMEDA, a much cheaper
trifluoromethylation is remarkably easy to detect due ligand than 1,10-phenanthroline, to promote the tri-
to the self-indicating nature of the reaction which fluoromethylation of copper acetylides, we envisioned
turns from a yellow heterogeneous suspension to that TMEDA-chelated trifluoromethylcopper com-
a deep green homogeneous solution upon completion. plexes could avoid the limitations met with phenan-
From a mechanistic perspective, it is also interest- throline.
ing to note that while all other copper-mediated tri-
Bearing in mind that a practical and functional
fluoromethylation of alkynes reported to date involve group-tolerant procedure was highly desirable, as in
the generation of a trifluoromethylcopper complex the first-generation method described above, the use
prior to its reaction with the alkyne, the order of the of a non-fluoride base such as K2CO3 was preferred.
elemental steps is reversed in this process, which Upon mixing a copper(I) salt, TMEDA, K2CO3 and
shows that coordination of the trifluoromethyl anion TMSCF3 in DMF, the formation of the active
to copper prior to the alkyne is not strictly required TMEDA-chelated trifluoromethylcopper complex was
for a clean cross-coupling.
monitored by 19F NMR (Figure 4). Extensive varia-
In parallel to these studies, we also investigated the tions of the nature of the copper(I) salt, of the reac-
possibility of generating trifluoromethylcopper com- tant stoichiometry and of the solvent concentration
plexes that could be used for the direct trifluorome- led to the optimal reaction conditions indicated in
thylation of terminal alkynes. In addition to comple- Figure 4. For the sake of conciseness, only the optimi-
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Cꢀdric Tresse et al.
zation of the reaction temperature is shown in spectra
Fair to good yields of the desired trifluoromethylat-
(b) to (e) starting from 1008C, under a nitrogen at- ed arylalkynes 2a, 2e, 2g, 2i and 2s–w were obtained
mosphere (spectrum b) or under air (spectrum c), by (Figure 5). Electron-poor and electron-rich aromatic
analogy with the reaction conditions reported by and heteroaromatic alkynes led to good yields of the
Qing.[18] After 5 min, all the Ruppert–Prakash reagent desired trifluoromethylated products, although the
has disappeared and two new sets of signals could be isolated yields of 2e, 2g, 2i and 2s–v were much lower
observed at À34.9 (s) and À80.4 (d, J=80.5 Hz, than their corresponding 19F NMR yields, due to their
CHF3) ppm. The origin of the former could be attrib- extreme volatility. Interestingly, diaryl ketones were
uted to the copper
is known to be a trifluoromethylation agent stable up 2w, which was however isolated in moderate yield.
to 1108C.[29c] Running the reaction under a nitrogen
Most interestingly, alkynes substituted by alkyl
atmosphere at 208C for 5 min led cleanly to a singlet groups led to excellent yields of the desired products
(CF3)2]À,[29] together even on a gram scale, thereby filling a major gap in
(CF3)4]À,[29] which also tolerated, as demonstrated by the synthesis of
ACHUTGTNREN(UNG III) complex [CuACHUTNGTRENNUGN
at À31.7 ppm, ascribed to [Cu
ACHTUNGTRENNUNG
with some remaining Ruppert–Prakash reagent (d= current trifluoromethylation processes (Figure 6).
À67.6 ppm, s) (spectrum d). Finally, under an air at- Linear alkyl substituents such as in 3x led to 92%
mosphere at room temperature, the 19F NMR profile yield of 2x. Silyl or benzyl ethers are also tolerated
was identical to the one recorded at 1008C (spectra (2y, 78% and 2z, 86%) as well as benzyl esters (2aa,
e and c, respectively), the copper
[Cu
(CF3)4]À resulting from the oxidation of the air-
sensitive [Cu
(CF3)2]À by oxygen.[29]
ACHTUNGTRENNUNG
G
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
These operationally very simple reaction conditions pargylic alcohol 3ad led to the desired product 2ad
were then used for the direct trifluoromethylation of (32%) demonstrating that free hydroxy groups are
a variety of terminal aryl- and alkylalkynes 3e–ag compatible with these reaction conditions. 1,3-Enynes
(Figure 5 and Figure 6). It should be noted here that
the alkyne was added in one portion a few minutes
after the formation of the trifluoromethylcopper com-
plex, in opposition to previous procedures requiring
a syringe pump addition of a DMF solution of the
alkyne over 4 h.[18]
Figure 6. Scope of the oxidative trifluoromethylation of ter-
Figure 5. Scope of the oxidative trifluoromethylation of ter-
minal aryl alkynes. Yields given correspond to isolated
yields of pure products unless otherwise stated.
minal alkyl alkynes. All reactions are run on a 0.5 mmol
scale unless otherwise stated. Yields given correspond to iso-
lated yields of pure products.
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Figure 7. Kinetic profile of the trifluoromethylation reaction of 3aa leading to 2aa and 4aa, determined by HPLC analysis of
triplicate experiments, using 1,2-dimethylnaphthalene as an internal standard.
are also suitable substrates, as shown with the synthe- fluoromethylation pathway, its yield remaining con-
sis of trifluoromethylated enyne 2ae (51%). Homo- stant over time.[30] Finally, it should be emphasized
propargylic sulfonamides such as 3af and 3ag were that no Glaser-type homocoupling of the terminal
also evaluated as substrates and delivered moderate alkyne 3aa could be detected during the reaction
to excellent yields of the corresponding trifluorome- course, thus enhancing the efficiency of the trifluoro-
thylated alkynes.
methylation process.
From a mechanistic perspective, recent DFT inves-
tigations by Maseras shed light on this oxidative cop-
per(I)-mediated trifluoromethylation reaction.[19] To Conclusions
gain insights into the product distribution as a function
of time, the kinetic profile of the reaction of alkyne Two practical methods for the oxidative copper(I)-
3aa, delivering the trifluoromethylated alkyne 2aa mediated trifluoromethylation reaction of copper ace-
and 1-iodoalkyne 4aa, was studied by HPLC. As can tylides and terminal alkynes are reported herein.
be seen in Figure 7, a very rapid consumption of ter- These processes are very simple to set up and proceed
minal alkyne 3aa is observed since only 40% remains at room temperature, under very mild conditions.
after 10 min. At the same time, less than 15% of the
Good to excellent yields of trifluoromethylated al-
trifluoromethylated alkyne 2aa is detected. The kynes were obtained, even on a large scale. The func-
amount of the latter slowly increases over time, reach- tional group tolerance is especially noteworthy since
ing 86% after 47 h. On the other hand, the amount of common protecting groups, such as silyl and benzyl
iodoalkyne 4aa (3%) remains constant throughout the ethers, and sensitive motifs (1,3-enynes, esters, ke-
reaction.
tones, unprotected alcohols) are not affected. This
Overall, these data support the fact that a syringe method should be a useful addition to the current ar-
pump addition of the alkyne is not mandatory for the senal of the synthetic community and as such, its ap-
success of the reaction at room temperature since the plication to the area of natural product total synthesis
build-up of the desired trifluoromethylated product is currently under investigations and will be reported
2aa is relatively slow. In addition, the formation of io- in due time.
doalkyne 4aa does not seem to be related to the tri-
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1H NMR (300 MHz, benzene-d6): d=7.19 (d, J=8.7 Hz,
2H), 6.81 (d, J=8.7 Hz, 2H), 4.32 (d, J=11.3 Hz, 1H), 4.15
(d, J=11.3 Hz, 1H), 3.29 (s, 3H), 2.95 (m, 1H), 2.01 (ddq,
J=17.4, 6.2, 3.8 Hz, 1H), 1.92 (ddq, J=17.4, 5.4, 3.9 Hz,
1H), 1.68 (septet of d, J=6.8, 5.3 Hz, 1H), 0.74 (d, J=
6.8 Hz, 3H), 0.69 (d, J=6.8 Hz, 3H); 13C NMR (100 MHz,
benzene-d6): d=160.2, 131.1, 129.8 (2C), 115.3 (q, J=
255.7 Hz, 1C), 114.4 (2C), 88.8 (q, J=6.4 Hz, 1C), 81.2,
72.5, 69.8 (q, J=51.6 Hz, 1C), 55.1, 32.1, 21.3, 18.6, 17.8;
19F NMR (376 MHz, benzene-d6): d =À44.6 (t, J=3.8 Hz);
HR-MS (APCI): m/z=323.1229, calcd. for C16H19F3NaO2
[M+Na]+: 323.1229.
Experimental Section
General Procedure for the Oxidative
Trifluoromethylation of Copper Acetylides
Users should be aware that the use of pure O2 with organic
solvents is potentially explosive.
A 5-mL round-bottom flask was successively charged with
the alkynylcopper reagent (0.5 mmol), petroleum ether
(1.9 mL), DMF (100 mL) and trifluoromethyltrimethylsilane
TMSCF3 (295 mL, 2.0 mmol). The resulting bright yellow
slurry was then treated with N,N,N’,N’-tetramethylethylene-
diamine (75 mL, 0.5 mmol) and the reaction mixture was vig-
orously stirred at room temperature and under an atmos-
phere of oxygen (balloon). After complete disappearance of
the alkynylcopper reagent (complete dissolution to a deep
blue/green homogeneous reaction mixture), 20 mL of water
were added to the crude reaction mixture. The resulting
mixture was extracted with diethyl ether, and the combined
organic layers were washed with water (three times) and
brine and then dried over magnesium sulfate, filtered and
concentrated at 408C at atmospheric pressure. The crude
product was then purified by flash chromatography (pen-
tane) to afford the desired trifluoromethylated alkyne.
Nonyltrifluoromethylacetylene (2n): This product was ob-
tained from undec-1-yn-1-ylcopper (216 mg, 1.00 mmol) to
afford 2n as a white solid; yield: 176 mg (0.80 mmol).
1H NMR (300 MHz, CDCl3): d=2.31 (m, 2H), 1.64–1.54 (m,
2H), 1.45–1.22 (m, 12H), 0.90 (t, J=7.1 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=114.2 (q, J=255.2 Hz), 89.3 (q, J=
6.2 Hz), 68.4 (q, J=51.9 Hz), 31.9, 29.4, 29.3, 29.0, 28.7, 27.3,
22.7, 18.1 (q, J=1.6 Hz), 14.0; 19F NMR (376 MHz, CDCl3):
d=À49.7 (t, J=3.7 Hz); IR: n=2927, 2858, 2266, 1285,
1136, 1024 cmÀ1.
Acknowledgements
Our work was supported by the Fondation Raoul Follereau,
the CNRS, the Universitꢀ de Strasbourg, the Universitꢀ de
Haute-Alsace, the Universitꢀ Libre de Bruxelles and the
FNRS (Incentive Grant for Scientific Research no.
F.4530.13). CT and CG respectively acknowledge the Univer-
sitꢀ de Haute-Alsace and the Universitꢀ Libre de Bruxelles
for graduate fellowships. Mrs. Rita D’Orazio, Pr. Michel
Luhmer (CIREM and RMN-HR, ULB) and Mr. Didier Le
Nouen (UHA) are gratefully acknowledged for their precious
assistance with 19F NMR.
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General Procedure for the Oxidative Trifluoro-
methylation of Terminal Alkynes
A 50-mL round bottom flask was charged with CuI (143 mg,
0.75 mmol), K2CO3 (207 mg, 1.5 mmol), N,N,N’,N’-tetrame-
thylethylenediamine (112 mL, 0.75 mmol) and DMF
(2.3 mL). The resulting deep blue mixture was vigorously
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an additional 5 min under air atmosphere, then cooled to
08C. A solution of terminal alkyne (0.5 mmol) and TMSCF3
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was stirred at 08C for 30 min, under air atmosphere, and al-
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the end of the reaction, water was added and the aqueous
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this direct trifluoromethylation reaction since only par-
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Practical Methods for the Synthesis of Trifluoromethylated
Alkynes: Oxidative Trifluoromethylation of Copper
Acetylides and Alkynes
11
Adv. Synth. Catal. 2014, 356, 1 – 11
Cꢀdric Tresse, Cꢀline Guissart, Stꢀphane Schweizer,
Yassine Bouhoute, Anne-Caroline Chany,
Mary-Lorꢁne Goddard, Nicolas Blanchard,*
Gwilherm Evano*
Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
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