Room-temperature direct alkynylation of arenes with copper acetylides

Article abstract of DOI:10.1021/ol502030y

C-H bond in azoles and polyhalogenated arenes can be smoothly activated by copper acetylides to give the corresponding alkynylated (hetero)arenes by simple reaction at room temperature in the presence of phenanthroline and lithium tert-butoxide under an oxygen atmosphere. These stable, unreactive, and readily available polymers act as especially efficient and practical reagents for the introduction of an alkyne group to a wide number of arenes under remarkably mild conditions.

Full text of DOI:10.1021/ol502030y

Letter
pubs.acs.org/OrgLett
Room-Temperature Direct Alkynylation of Arenes with Copper
Acetylides
Cedric Theunissen and Gwilherm Evano*
́
Laboratoire de Chimie Organique, Service de Chimie et PhysicoChimie Organiques, Universite
D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
́
Libre de Bruxelles (ULB), Avenue F.
S
* Supporting Information
ABSTRACT: C−H bond in azoles and polyhalogenated
arenes can be smoothly activated by copper acetylides to
give the corresponding alkynylated (hetero)arenes by simple
reaction at room temperature in the presence of phenanthro-
line and lithium tert-butoxide under an oxygen atmosphere.
These stable, unreactive, and readily available polymers act as
especially efficient and practical reagents for the introduction
of an alkyne group to a wide number of arenes under remarkably mild conditions.
n addition to being commonly found in naturally occurring/
Ibioactive molecules as well as organic materials and
polymers, alkynyl(hetero)arenes are also versatile building
blocks and intermediates in organic synthesis, notably due to
numerous possible synthetic transformations of the alkyne
subunit.1 The common method for the installation of an alkyne
into arenes is the Sonogashira−Linstrumelle cross-coupling2
which, despite its efficiency, requires the prefunctionalization of
the aromatic ring. Recently, the direct alkynylation of C−H
bonds in arenes has emerged as an especially straightforward
and appealing alternative and various reagents, in combination
Figure 1. Representative bioactive alkynylated azoles and polyfluor-
oarenes.
with different metals, have been used for such transformations.3
They include terminal alkynes,4 alkynyl halides,5 gem-
dihaloalkenes,6 arylsulfonylacetylenes,7 propiolic acids,8 or
benzodioxolone-based hypervalent alkynyl iodonium salts9
and can be used for the direct alkynylation of different classes
of arenes with varying efficiency.
We have indeed recently shown that copper acetylides can be
easily activated in the presence of molecular oxygen and simple
organic ligands and transfer their alkyne subunit to a wide range
of heteronucleophiles15 following an oxidative umpolung
strategy.16,17 On the basis of the success met with this strategy,
we envisioned that they might also be suitable reagents for the
direct room-temperature alkynylation of (hetero)arenes pos-
sessing relatively acidic C−H bonds such as azoles and
polyfluoroarenes, a strategy that was supported by results
from the Knochel group who demonstrated the possibility of an
oxidative copper-mediated cross-coupling between alkynyl
lithium and aryl magnesium reagents.17d
To test this hypothesis, we initiated our studies by examining
the oxidative cross-coupling between (p-tolylethynyl)copper 6a
and benzoxazole 5a, the latter being used in excess to minimize
the homocoupling of the former. For practical reasons, the
temperature was fixed at room temperature, and molecular
oxygen was chosen as the oxidant. Lithium tert-butoxide was
used to assist the cleavage of the acidic C−H bond in 5a, and a
brief solvent screen using TMEDA as the ligand revealed that
In the case of electron-deficient arenes such as azoles and
polyfluoroarenes (whose prefunctionalization is far from trivial)
several copper-,4c−e,5f,g,6a,b palladium-,4g−i,5i,6c nickel-,4d,5c and
iron-4f based systems have been reported for the direct
alkynylation of acidic C−H bonds in such systems. Due to
the importance of the resulting alkynylated arenes in medicinal
and agrochemical chemistry, as exemplified with representative
examples 1−4 shown in Figure 1,10−13 this C−H alkynylation
strategy is quite appealing. However, despite their efficiency, all
systems reported to date still suffer from major limitations, the
main ones being the requirement for high temperatures, lack of
practicability, and poor substrate scope. Alternative methods/
reagents that would allow for an efficient and practical direct
alkynylation of electron-deficient arenes under mild conditions
are therefore highly desirable. In this perspective, we report that
copper acetylides, readily available reagents that are known to
be remarkably stable and especially unreactive,14 can be
efficiently used for the direct alkynylation of azoles and
polyfluoroarenes at room temperature.
Received: July 11, 2014
© XXXX American Chemical Society
A
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Letter
the reaction was best performed in acetonitrile. The efficiency
of various ligands susceptible to promote the oxidative cross-
coupling was evaluated, and while electron-rich nitrogen ligands
were found to be somehow more efficient than the other ones
studied, the alkynylation turned out to be quite challenging
(Figure 2). Assuming that multiple chelation of the
obtained using a halogenation/Sonogashira sequence18 or with
other direct alkynylation procedures.4d,f−h,5c,g,j,6a,c The reaction
enabled the synthesis of aryl-substituted alkynyl-benzoxazoles
(7a−e,g) and benzothiazoles (7i) as well as their alkyl-
substituted congeners (7f,h,j), and benzoxazoles and benzo-
thiazole were found to be equally efficient. Interestingly, while
the homodimerization of the starting copper acetylides could
not be completely suppressed, the copper-mediated dimeriza-
tion of the starting azoles, which had been previously
documented,19 was found to be quite slow in our case.
Given the operational simplicity of this oxidative alkynyla-
tion, we then decided to evaluate the use of other azoles in this
procedure. Due to the importance of 1,3,4-oxadiazoles in
medicinal chemistry20 and in material sciences,21 we logically
decided to study their alkynylation using our standard
procedure. Results from these studies provide evidence that
the reaction proceeds quite smoothly in most cases, the
alkynylated 1,3,4-oxadiazoles 9 being easily isolated in
moderate to good yields (Figure 4). In the case of aryl-
Figure 2. Compared efficiency of ligands for the alkynylation of
benzoxazole.
deprotonated benzoxazole to the copper center might account
for the low yields obtained, we decided to check whether
increasing the amount of the ligand would have a beneficial
effect on the alkynylation. To our delight, the alkynylation
could indeed be improved when using an excess of TMEDA,
1,2-dimethylimidazole, or 1,10-phenanthroline, the latter being
superior in terms of efficiency. By using these optimized
conditions, the alkynylation could then be readily achieved by
simply adding the corresponding copper acetylide to a mixture
of the starting benzoxazole, lithium tert-butoxide, and 1,10-
phenanthroline in acetonitrile at room temperature. Upon
activation with molecular oxygen at room-temperature, the
alkynylation occurs, and the completion of the reaction can be
easily detected due to the self-indicating nature of the reaction
in which the starting bright-yellow polymeric copper acetylide
slowly dissolves to yield a brownish solution.
Figure 4. Direct alkynylation of 1,3,4-oxadiazoles.
substituted alkynylcopper reagents and oxadiazoles, the nature
of the substituents on both the oxadiazole 8 and the copper
acetylide 6 was found to have little influence on the outcome of
the reaction which proceeded with equal efficiency in the
presence of electron-donating and -withdrawing groups in the
ortho, meta, or para positions. Alkyl-substituted copper
acetylides could also be used for the oxidative alkynylation at
room temperature, yielding the corresponding alkyl-substituted
2-alkynyl-1,3,4-oxadiazoles (9g,i,l) with synthetically useful
yields under practical conditions.
We next moved to study other arenes possessing an activated
acidic C−H bond: polyfluoroarenes. The pKa value of its
C(sp2)−H bond being in the same range as those of azoles,22
pentafluorobenzene 10 was therefore reacted with various
copper acetylides 6 and was transformed to the corresponding
alkynyl-pentafluorobenzene derivatives 11, building blocks of
great interest for electronic and optoelectronic applications,23
with high efficiency (Scheme 1). Even an aromatic bromide was
well tolerated on the starting copper acetylide, therefore
providing an excellent starting point for further derivatization
starting from 11g. Importantly, the reaction could be
performed with alkyl-substituted alkynylcopper reagents,
products 11i−l resulting from the oxidative cross-coupling
being obtained in good yields with our procedure while they
could not be obtained using previously reported ones.3c,d
With these conditions in hand, we moved to the evaluation
of the scope and limitations of this oxidative alkynylation using
a set of representative benzoxazoles/benzothiazole 5 and
copper acetylides 6 (Figure 3). The reaction proceeded
smoothly in most cases, and the yields of the resulting
alkynylated azoles 7 were found to be comparable to the ones
Figure 3. Direct alkynylation of benzoxazoles and benzothiazole.
B
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Letter
efficient, as demonstrated by the reaction of ferrocene-,
benzocrown ether-, and estradiol-derived copper acetylides
with pentafluorobenzene which nicely provided the corre-
sponding alkynylated products 11m−o, further showing the
beneficial output of using copper acetylides for the direct
alkynylation of arenes under mild conditions.
Scheme 1. Direct Alkynylation of Pentafluorobenzene
We finally moved one step further and briefly investigated
the possibility of a double consecutive alkynylation. Octa-
fluorobiphenyl 14 was thus first monoalkynylated with 6a,
providing the corresponding alkynyl-octafluorobiphenyl 15
(Scheme 3). The remaining acidic C−H bond in this
Finally, it should be mentioned that the reaction can be
conveniently performed on a 2 g scale (for the synthesis of
11a) without significant decrease of yield.
Scheme 3. Consecutive Double Oxidative Alkynylations
The reaction could also be extended to the direct
alkynylation of tetrachloropyridine 12, in which the presence
of activated chlorine atoms, susceptible to undergoing
competitive nucleophilic aromatic substitution even with
weak nucleophiles, clearly rendered the direct alkynylation
more challenging. The oxidative alkynylation proceeded
smoothly upon reaction with various copper acetylides 6
under our standard conditions without competitive nucleophilic
aromatic substitution by the copper acetylide or lithium tert-
butoxide (Scheme 2). The corresponding alkynylated tetra-
Scheme 2. Direct Alkynylation of and Tetrachloropyridine
compound could then be used for the introduction of a
different alkyne, and a second oxidative alkynylation with 6b
could indeed be performed, yielding the desired diyne 16
resulting from two double consecutive alkynylations.
In conclusion, we have developed an efficient and general
procedure for the direct oxidative alkynylation of activated C−
H bonds in arenes. Upon reaction with readily prepared and
otherwise unreactive copper acetylides in the presence of
lithium tert-butoxide and phenanthroline, a wide variety of
arenes possessing an acidic C−H bond such as azoles and
polyhalogenated arenes could be smoothly alkynylated at room
temperature. Molecular oxygen is sufficient to trigger the
alkynylation which provides an efficient entry to numbers of
alkynyl-(hetero)arenes, versatile building blocks and inter-
mediates in organic synthesis, that are also at the core structure
of various naturally occurring and/or bioactive molecules as
well as organic materials and polymers. Major advantages of
this direct oxidative alkynylation, which does not require
prefunctionalization of the starting arene, are the mild and
practical conditions that do not require thermal activation, its
scope, its modularity, and its use for the alkynylation with
complex substrates and double consecutive alkynylations. This
reaction can in addition be performed without precautions or
inert atmosphere, does not require the use of expensive
chemicals, and typically affords the alkynylated (hetero)arenes
with improved yields, reaction conditions, or substrate scope in
most cases compared to previously reported catalytic direct
alkynylations. We envision great acceptance and applicability
for this oxidative cross-coupling reaction, and further studies
are underway in our laboratory to extend its scope.
chloropyridines 13, in which the activated chlorine atoms at C2
and C6 provide excellent starting points for further
derivatization by nucleophilic aromatic substitution or metal-
catalyzed cross-coupling reactions, could be isolated in good
yields.
To further test the synthetic potential of our oxidative
alkynylation, we next decided to investigate the possibility of
using our procedure for the alkynylation starting from more
complex arenes or copper acetylides. With this goal in mind,
the direct alkynylation of a cholic acid-derived 1,3,4-oxadiazole
was first evaluated and smoothly provided the corresponding
alkynylated derivative 9m in 46% yield, even by using 1.5 equiv
of the oxadiazole instead of the 4 equiv used for the scope and
limitation studies (Figure 5). Placing the molecular complexity
on the starting copper acetylide turned out to be even more
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental procedures, characterization, copies of H and
13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
Figure 5. Direct alkynylation with complex substrates.
C
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Letter
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AUTHOR INFORMATION
■
Corresponding Author
*gevano@ulb.ac.be
Notes
The authors declare no competing financial interest.
(12) Mitchell, M. L.; Roethle, P. A.; Xu, L.; Yang, H.; McFadden, R.;
Babaoglu, K. world patent WO/2012/145728(A1), October 26, 2012.
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ACKNOWLEDGMENTS
■
Our work was supported by the Universite
́
Libre de Bruxelles
and the FNRS (Incentive Grant for Scientific Research no.
F.4530.13). C.T. acknowledges the Fonds pour la formation a
la Recherche dans l’Industrie et dans l’Agriculture (F.R.I.A.) for
a graduate fellowship.
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