A facile parallel synthesis of trifluoroethyl-substituted alkynes

Article abstract of DOI:10.1002/anie.201202372

Trifluoroethylation made easy: The ease of execution of the reaction (see scheme), which runs under mild conditions and without the need for additional base or ligands, allows for the rapid parallel synthesis of a broad variety of trifluoroethylated alkynes. Both experimental and theoretical analyses indicate that the trifluoromethylcarbene could undergo concerted insertion into the C_sp-H bond of the alkyne. Copyright

Full text of DOI:10.1002/anie.201202372

Angewandte
Chemie
DOI: 10.1002/anie.201202372
Fluorine Chemistry
A Facile Parallel Synthesis of Trifluoroethyl-Substituted Alkynes**
Cui-Bo Liu, Wei Meng, Feng Li, Shuai Wang, Jing Nie, and Jun-An Ma*
The physicochemical and biological properties of an organic
compound are profoundly modified by the presence of
fluorine functional groups, which alter the steric, electronic,
lipophilic, and metabolic characteristics of the compound.
The incorporation of fluorinated moieties into organic
molecules has captured the attention of synthetic chemists
over the past decades.[1] As a reactive intermediate, 2,2,2-
trifluorodiazoethane is an attractive C2 synthon for the
construction of fluorine-containing building blocks. The ear-
lier studies involving this reagent primarily focused on
noncatalytic reactions.[2] These methods usually suffer from
relatively harsh reaction conditions and limited substrate
scope. To overcome these problems, recent research has paid
more attention to metal-catalyzed transformations of 2,2,2-
trifluorodiazoethane. For instance, the Simonneaux and
Komarov groups reported metal-catalyzed cyclopropanation
reactions of gaseous F3CCHN2 with various olefins.[3] Carreira
and co-workers demonstrated the catalytic generation of
2,2,2-trifluorodiazoethane in situ from CF3CH2NH2·HCl.[4]
Several metal catalysts have been found to be compatible
with the diazotization reaction, allowing a tandem trans-
formation to take place in aqueous media. However, the
Scheme 1. Synthesis of trifluoroethyl-substituted alkynes. NMP=
N-methyl-2-pyrrolidone, OTf=trifluoromethanesulfonate.
lated alkynes. These products, which bear a CH2CF3 group in
the propargyl position, are versatile precursors for the
synthesis of other types of fluorinated molecules. Addition-
ally, both experimental and theoretical analyses indicate that
À
this trifluoroethylation could proceed by a concerted Csp
insertion process.
H
À
À
generation of Csp3 CH2CF3 or Csp2 CH2CF3 bonds has been
the focus of nearly all such studies.[5] In sharp contrast, the
In general, reactions of terminal alkynes with diazo
[7]
À
À
formation of Csp CH2CF3 bonds through simple trifluoroe-
compounds lead to cyclopropenation or Csp H insertion.
thylation of terminal alkynes has not been reported to date,
and still remains an interesting challenge.
The reaction course strongly depends on the nature of the
metal and the catalyst structure. For example, the groups of
Pꢀrez[8a] and Doyle[8c] described cyclopropenation reactions of
alkynes with diazoesters catalyzed by CuI or RhII complexes,
whereas the groups of Fu,[8b] Fox,[8d] and Wang[8e–i] reported
the cross-coupling of alkynes with diazo compounds catalyzed
by CuI or PdII to afford the corresponding products. Very
recently, Morandi and Carreira disclosed a rhodium-catalyzed
cyclopropenation of alkynes by CF3CHN2 generated in situ
from CF3CH2NH2·HCl in aqueous media.[4b] Based on these
important precedents, we examined the ability of various CuI
and CuII salts to catalyze the trifluoroethylation of phenyl-
acetylene 1a using gaseous CF3CHN2. A preliminary result
was obtained using CuI as a catalyst under mild conditions to
provide the corresponding trifluoroethylated product 2a in
63% yield without the use of extra base or ligands. However,
a disadvantage of this method is that it requires the use of
a large excess of CF3CH2NH2·HCl (5–8 equiv). In order to use
gaseous CF3CHN2 more efficiently, we needed to set up
a recycling system. After the reactor, a storage balloon was
placed to trap and reuse the escaping gaseous CF3CHN2.
Gratifyingly, examination of the same test reaction with the
recycling system in place revealed that the yield can be
significantly improved to 85% and that the amount of
CF3CH2NH2·HCl can be lowered to three equivalents.
Furthermore, a multireactor setup has been designed to
provide an integrated system for simultaneously running
A survey of the literature reveals that the use and
preparation of trifluoroethyl-substituted alkynes is extremely
rare, which likely correlates with the absence of practical
general methods for their synthesis. Only one recent report by
Shibata and co-workers has addressed the trifluoromethyla-
tion of 3-(4’-nitrophenyl)propargyl bromide with [CuCF3]
species, which were generated in situ from an electrophilic
trifluoromethylating reagent and a stoichiometric amount of
copper, but the desired product was obtained in only 36%
yield (Scheme 1a).[6] Herein, we report our efforts in devel-
oping a direct catalytic trifluoroethylation of terminal alkynes
by using 2,2,2-trifluorodiazoethane (Scheme 1b). This cross-
coupling reaction can be conducted under mild conditions
without the need for additional base or ligands. Furthermore,
the ease of preparation and workup allows for the quick and
efficient parallel synthesis of a broad variety of trifluoroethy-
[*] C.-B. Liu, W. Meng, F. Li, S. Wang, J. Nie, Prof. J.-A. Ma
Department of Chemistry, Tianjin University
Tianjin 300072 (China)
E-mail: majun_an68@tju.edu.cn
[**] This work was financially supported by the NSFC (20972110 and
21002068).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201202372.
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is noteworthy that the reactions are very clean; in all cases,
side products, such as cyclopropenes from alkynes and
CF3CHN2, self-coupling products of alkynes, and allene
isomers of the trifluoroethylated adducts, were not observed.
Trifluoroethylated alkynes are also versatile synthetic
intermediates and can be readily transformed into highly
functionalized organofluorine compounds that are otherwise
difficult to access (Scheme 3). For example, direct hydro-
genation of 2 f and 2o using a Pd/C catalyst and H2 at
atmospheric pressure gave rise to the corresponding fluori-
nated alkanes 3 and 4 in high yields. Reaction of 2k with ethyl
phenyldiazoacetate in the presence of AgOTf delivered the
Figure 1. Setup for the catalytic cross-coupling trifluoroethylation of
terminal alkynes.
multiple reactions. Using such a system, trifluoroethylated
alkyne 2a was obtained in 83–92% yield (Figure 1).
Based on the studies described above, we explored the
scope of the cross-coupling reaction of gaseous CF3CHN2
with terminal alkynes 1a–x. Thus, constructing a flow setup
(as shown in Figure 1, four reactors in parallel) for the
continuous gaseous CF3CHN2 generation/trifluoroethylation
sequence, we could prepare a series of trifluoroethylated
alkynes 2a–x (Scheme 2). Although a standard reaction time
of 10 h was chosen, most of the reactions were complete
within 4 h. Alkynes with aryl, alkyl, phenylthio, or silyl
substituents are all suitable substrates, providing the isolated
trifluoroethylated products 2a–l in 80–96% yield. Further-
more, we found that various terminal 1,3-diynes react
smoothly with gaseous CF3CHN2 under the same reaction
conditions to furnish the corresponding products 2m–v in
excellent yields. Two enynes also worked well in the cross-
coupling reactions to afford the desired adducts 2w and 2x. It
Scheme 3. Further synthetic transformation of products.
Scheme 2. Scope of the Cu-catalyzed trifluoroethylation of terminal alkynes with CF3CHN2. Reactions conducted in four parallel stirred reactors. Yields
shown are of isolated products from an average of two runs. TIPS=triisopropylsilyl.
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1
highly substituted cyclopropene 5 in 68% yield. Also, treat-
ment of trifluoroethylated alkyne 2b with Ce(SO4)2 and
concentrated H2SO4 at 708C afforded the corresponding
ketone 6 in moderate yield. These promising results indicate
that the present protocol provides a reliable and rapid
approach for the synthesis of diverse CH2CF3-containing
compounds.
shown to be homogeneous by H NMR analysis in CD3CN,
copper acetylide was not detected on the timescale of the
NMR experiment. Moreover, we did not observe any
incorporation of deuterium at the propargyl position when
D2O or CD3OD were used as additives (Scheme 4, bottom).
These experimental results provide supportive evidence that
À
the trifluoroethylation could proceed by a Csp H insertion
The reaction mechanism of the trifluoroethylation could
process.
À
involve the insertion of a carbene into a Csp H bond, a key
To shed some light on the mechanism, we carried out
a frontier molecular orbital analysis[9] for the model reactants
of propyne (pp) and copper carbenoid (cc; Figure 2a). The
energy gap of HOMOpp–LUMOcc is much smaller than that of
HOMOcc–LUMOpp (11.9 vs. 17.2 eV), which indicates that
the most favored orbital interaction is between the ethyne
process in this type of cross-coupling that has been reasonably
implicated, but remains largely unproven.[7] To obtain more
information about our reaction, we conducted the CuI-
catalyzed cross-coupling of deuterium-labeled terminal
alkynes with gaseous CF3CHN2 under the standard reaction
conditions (Scheme 4, top). It was found that the ratio of
=
moiety of the propyne and the p* orbital of the Cu C
coordinate bond in the copper carbenoid. DFT calculations
using the B3LYP/6-31G(d) method[10] were also performed
with a view to delineating the details of the putative insertion
À
of carbenes into the Csp H bond. The computed path of the
model reaction is shown in Figure 2b. The barrierless [2+2]
cycloaddition between copper carbenoid and propyne was
found to be strongly exothermic, indicating that the gener-
ation of metallacyclobutene intermediate (IN-1) is more
favorable than that of TS in the cyclopropenation. This
prediction is consistent with our experimental results. From
IN-1, the critical four-membered-ring transition state (TS-1)
is identified with an energy barrier of 26.8 kcalmolÀ1
.
Although significant, this energy requirement is more than
compensated for by the energy released in the preceding
steps. Through TS-1, the intermediate IN-2 is generated.
Finally, the formation of the cross-coupling product from the
intermediate IN-2 proceeds through a concerted 1,2-hydride
shift (TS-2) with an energy barrier of 15.0 kcalmolÀ1. There-
fore, the overall process for the cross-coupling is exothermic
and thermodynamically favorable.
Scheme 4. Isotopic labeling and control experiments.
deuterium to hydrogen at the propargyl positions in the
corresponding products is identical to that in the alkyne
substrates. Subsequently, we performed several control
experiments. While a mixture of substrate 1o and CuI was
In summary, we have disclosed a direct and efficient
copper(I)-catalyzed trifluoroethylation of terminal alkynes
employing gaseous CF3CHN2 under mild conditions without
Figure 2. Calculations for the model reaction of a copper carbenoid with propyne. a) Frontier molecular orbital diagram. Orbital coefficients are given in
italics. b) DFT-computed energy surfaces. Reaction coordinate calculated using the B3P86/CPCM basis set: SDD for Cu, Lanl2DZ for I, and 6-311+G(2d,p)
for other atoms.
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is the ease of execution, which enables the rapid synthesis of
a wide number of trifluoroethylated alkynes in parallel. The
presence of an ethyne moiety in the products also allows for
subsequent conversion to more functionalized trifluoroethy-
lated compounds. Moreover, we present the first piece of
evidence for the mechanism of the insertion of a carbene into
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À
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À
a Csp H bond in a copper-catalyzed cross-coupling of terminal
alkynes with diazo compounds.
Received: March 26, 2012
Published online: May 8, 2012
Keywords: alkynes · cross-coupling · diazo compounds ·
.
homogeneous catalysis · trifluoroethylation
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