Copper-catalyzed endo-type trifluoromethylarylation of alkynes

Article abstract of DOI:10.1039/c4cc05692b

A new copper-catalyzed trifluoromethylarylation reaction of alkynes has been developed. The transformation represents the first example of endo-type carbotrifluoromethylation of unsaturated carbon-carbon bonds and provides efficient access to a variety of

Full text of DOI:10.1039/c4cc05692b

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Copper-catalyzed endo-type
trifluoromethylarylation of alkynes†
Cite this:DOI: 10.1039/c4cc05692b
Jun Xu, Yun-Long Wang, Tian-Jun Gong, Bin Xiao and Yao Fu*
Received 23rd July 2014,
Accepted 24th August 2014
DOI: 10.1039/c4cc05692b
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A new copper-catalyzed trifluoromethylarylation reaction of alkynes
has been developed. The transformation represents the first example of
endo-type carbotrifluoromethylation of unsaturated carbon–carbon
bonds and provides efficient access to a variety of CF3-substituted
dihydronaphthalenes and chromenes.
Transition metal-catalyzed difunctionalization of unsaturated
carbon–carbon bonds represents an efficient and step-economical
strategy for the synthesis of complex organic molecules, because it
provides access to multiple carbon–carbon/carbon–heteroatom
bonds in a single step from readily available starting materials.1,2
As trifluoromethyl containing compounds are widely used in
pharmaceutical, agrochemical, and material industries,3 the
development of efficient difunctionalization-type trifluoromethyla-
tion of unsaturated carbon–carbon bonds is of particular interest.
Scheme 1 (a) exo-Type aryltrifluoromethylation of terminal alkenes.
(b) This work: endo-type trifluoromethylarylation of alkynes.
Since the establishment of Cu(I)-catalyzed deprotonative trifluoro- trifluoromethylation of alkynes would not only expand the concept
methylation of simple alkenes by Buchwald, Wang, and our group in and scope of trifluoromethylation of unsaturated carbon–carbon
2011,4 significant progress has been made in the development bonds, but would also provide new approaches for the synthesis of
of difunctionalization-type trifluoromethylation of alkenes5 to CF3-containing tetra-substituted alkenes. However, among all the
generate diverse bioactive molecules. In particular, the use of processes involving an alkyne and a trifluoromethylating reagent,5g,8
the intramolecular carbon atom as a reaction partner is effective for no example of catalytic trifluoromethylarylation of alkynes has been
building CF3-containing carbocyclic and heterocyclic compounds described. A possible reason is that the addition of the CF3 radical to
(Scheme 1a). For example, Liu et al. developed Pd-catalyzed aryltri- the CRC bond has a higher activation energy barrier relative to the
fluoromethylation of activated alkenes for the synthesis of a variety CQC bond.8a Therefore, the development of a mild and efficient
of CF3-containing oxindoles.6 Sodeoka7 et al. reported an method for trifluoromethylarylation of alkynes is still a challenge.
elegant method of copper(I)-catalyzed carbotrifluoromethylation
Inspired by recent findings on copper-catalyzed carboarylation of
of unactivated alkenes, which provides diverse carbocyclic and alkynes reported by Gaunt9 and co-workers, herein, we describe
heterocyclic compounds bearing a trifluoromethyl group. Note an unprecedented copper-catalyzed trifluoromethylarylation
that the above two processes proceed through exo-cyclization, reaction of alkynes that produces CF3-containing cyclic tetra-
and they are only suitable for terminal alkenes.
substituted alkenes10 in one step (Scheme 1b).11 Remarkably, the
To address another important category of unsaturated carbon– reaction regioselectively gives the endo-type cyclization products.
carbon bonds, the development of the difunctionalization-type Various CF3-substituted dihydronaphthalenes and chromenes,
which are widely found in biologically active compounds,12 were
Department of Chemistry & Collaborative Innovation Center of Chemistry for
synthesizable by the new method.
The feasibility of the trifluoromethylarylation reaction of
alkynes was first examined using alkyne 1a as a test substrate
Energy Materials, University of Science and Technology of China, Hefei 230026,
China. E-mail: fuyao@ustc.edu.cn
† Electronic supplementary information (ESI) available: Detailed experimental
(Table 1). Initially we examined our previous reaction conditions,
procedures and compound characterization data. CCDC 1015427. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc05692b which were developed for Cu-catalyzed trifluoromethylation of
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Table 1 Optimization of the reaction conditionsa,f
reagent, 2c, did not afford the desired product 3a (entry 14).
Finally, we only detected a trace amount of 3a in the absence of
Cu, even at a higher temperature (entry 15).
With the optimized conditions established, we next examined
the scope of trifluoromethylarylation of alkynes. An array of
alkynes bearing different aryl nucleophilic groups were found
to undergo the desired reaction smoothly. Both the electron-
donating methoxy, methyl, and ether groups (3a–3d, 3m and 3n)
as well as the electron-withdrawing trifluoromethyl and carbonyl
groups (3j, 3k and 3o) on aromatic rings could be well tolerated
in the reaction. Moreover, halogen-substituted arene rings were
also compatible with the reaction, enabling additional modifica-
tions at the halogenated positions (3e–3i). Notably, the meta-
substituent led to isomeric mixtures of products (3h and 3n),
while the aryltrifluoromethylation of 1d regioselectively gave the
product 3d in 81% yield. Besides, in addition to the ethylene
linkage, oxygen linked substrates could also be used to provide
the trifluoromethylated chromene derivatives (3l–3o). To our
delight, a seven-membered ring could also be formed albeit in
a relatively low yield (3p). Complicated mixtures were observed
when we tried to construct the corresponding indene derivative
(3q). Furthermore, heterocyclic and polycyclic compounds could
be introduced as the nucleophiles, which further extends the
[Cu]
(10 mol%)
Additive
(2 equiv.)
Yield of
3a (%)
Entry
Solvent (1 mL)
1b
2
3
4
5
6
7
8
9
10
11
12
13c
14d
15e
CuTc
CuCl
Cu(OTf )2
Cu
Cu
Cu
Cu
Cu
Cu
Cu
CuCl
Cu(OTf )2
Cu
Cu
—
L1
L1
L1
L1
—
—
—
—
DMAc
DMAc
DMAc
DMAc
DMAc
DCE
6
10
5
22
21
15
26
37
DMF
DCE/DMF (1 : 1)
DCE/DMF (20 : 1)
DCE
DCE
DCE
DCE
DCE
DCE
—
62
DMF
DMF
DMF
DMF
DMF
DMF
86 (81%)b
82
80
84
0
Trace
a
Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), [Cu] (10 mmol%),
and additive (2 equiv.) in the solvent (1.0 mL) for 24 h under an Ar
atmosphere, unless otherwise noted. The yield of 3a was determined by
Table 2 Scope of the arene nucleophile and the link unita
b
19F NMR spectroscopy with PhCF as the internal standard. Yield of the
isolated product in the parentheses. c 2b was added instead of 2a. d 2c was
e
added instead of 2a. The reaction was conducted at 110 1C. f CuTc =
(thiophene-2-carbonyloxy)copper, DMAc = N,N-dimethylacetamide. DMF =
N,N-dimethylformamide. DCE = 1,2-dichloroethane.
terminal alkenes5c (Table 1, entry 1). The desired product (3a)
could be detected with a very low yield (6%). Thus, further tests
were conducted to improve the reaction. First, we tested the
effect of different Cu catalysts. To our surprise, Cu powder13
gave a higher yield (entry 4), whereas the other Cu(I) and Cu(II)
salts afforded lower yields of products (entries 2 and 3).
Notably, when additive L1, was not added in the reaction, the
yield of the reaction did not significantly decrease (entry 5). It
was found that the solvent has an important effect on the yield
of target product 3a (entries 6–9). The optimal solvent system
was found to be as follows: only 2 equiv of DMF as an additive
in primary solvent DCE to achieve the desired product 3a in
86% 19F NMR yield (entry 10). Although we could not determine
the actual role of DMF in the reaction in the present study, it is
known that the DMF additives can increase the solubility of the
trifluoromethyl electrophilic reagent in DCE. Besides, it may
also be responsible for stabilization of the CF3 reactive species
which is produced in the reaction. Further studies on the actual
role of DMF are in progress in our lab. Under the optimal
solvent system, we next re-examined the effect of different Cu
a
Reaction conditions: 1 (0.2 mmol, 1 equiv.), 2a (0.24 mmol, 1.2 equiv.), Cu
powder (10 mmol%), and DMF (0.4 mmol, 2 equiv.) in the DCE (1.0 mL)
for 24 h under an Ar atmosphere. Yields are those of the isolated products.
catalysts14 and found that Cu(I) and Cu(II) salts could also PMP = p-methoxyphenyl. b The reaction was carried out with 2 equiv. of 2a
at 100 1C. c The reaction was carried out with 2.5 mol% Cu powder,
afford the product in good yield (entries 11 and 12). Different
1 (2 equiv.) and 2b (0.2 mmol, 1 equiv.) at 100 1C. d The reaction was carried
trifluoromethyl electrophilic reagents15 were also tested, use of
out with 2.5 mol% Cu powder, 1 (2 equiv.) and 2b (0.2 mmol, 1 equiv.) at
2b led to a similar yield (entry 13), whereas the use of Togni’s 110 1C. e The ratio of regioisomers.
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Scheme 2 Further conversion of the product.
Scheme 5 Proposed mechanism (EDG: electron-donating group).
utility of this process (3r and 3s). In addition, we also investigated
the electronic effect of substituents on the carbon–carbon triple
bond. We found that it is essential to have a functional group that
can sufficiently stabilize an alkenyl radical or a cation intermediate
generated in the reaction. For instance, simple phenyl groups,
styryl groups, naphthalene groups, and the electron-rich thiophene
substituted alkynes are adequately reactive (3t–3w). Besides, the
heteroatom functional group directly linked to the alkynes is also a
good substrate (3x) (Table 2).
To demonstrate the synthetic utility of this method, a range
of more complex CF3-containing compounds was synthesized. As
shown in Scheme 2, product 3a could readily be oxidized to
polyaromatic naphthalene 4a.16 3a could also be epoxidized to give
the tetra-substituted epoxide 5a.17 Finally, 3a could be hydrogenated
to produce a trifluoromethyl-substituted benzocyclohexane derivative
6a.18 These functionalized CF3-containing compounds are otherwise
difficult to prepare by previous methods. Besides, we also developed
an efficient route toward the synthesis of CF3 derivatives of the
anticancer agent nafoxidine19 (Scheme 3).
and the inhibition experiment were conducted with the addition of
TEMPO, product 3a was obtained in only 26% 19F NMR yield
together with TEMPO adduct 9 in 45% 19F NMR yield (Scheme 4a).
These observations are consistent with a mechanism involving
in situ generation of the CF3 radical species.12 Furthermore, the
low KH/KD values of intramolecular and intermolecular20 isotope
labeling experiments indicated that the intramolecular cyclization
is a quick step (Scheme 4b).
On the basis of the above observations, we proposed a possible
mechanism shown in Scheme 5. First, a CF3 electrophilic active
species would be generated by the single electron transfer (SET) of
2a and the copper catalyst,5d,e which would then react with the
carbon–carbon triple bond of 1 to give intermediate A. Second,
intermediate A may undergo either direct radical electrophilic
cyclization (path I), or further oxidation to give the cation inter-
mediate B, followed by cyclization to furnish the target product D
(path II). Based on a recently reported mechanism that was
proposed for Cu-catalyzed alkyne difunctionalization,9 we suggest
that path II, which involves the vinyl cation intermediate B, is more
plausible. Further investigation will be required to reveal the nature
of this trifluoromethylarylation process (Scheme 5).
A series of experiments were performed to investigate the
mechanism of the reaction. The capture of CF3 radicals (see ESI†)
In conclusion, we have reported an unprecedented copper-
catalyzed trifluoromethylarylation reaction of alkynes with
high regioselectivity. This highly efficient transformation extends
the concept and scope of the recently popularized transition metal-
catalyzed difunctionalization-type trifluoromethylation reactions,
which previously only occurred on more reactive alkenes. Further-
more, the existence of an olefin moiety in the product also enables
subsequent transformations to more complex trifluoromethylated
compounds. Our next challenge is to exploit other nucleophiles for
expanding the scope of the reaction.
Scheme 3 Synthesis of the nafoxidine derivative.
This work was financially supported by the NSFC (21325208,
21302178, 21172209 and 21361140372), 973 Program (2012-
CB215305), SRFDP (20123402110051), FRFCU (WK2060190025),
CAS (KJCX2-EW- J02) and Fok Ying Tung Education Foundation,
China Postdoctoral Science Fundation (2013M540516).
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