Copper-catalyzed alkyne-aryne and alkyne-alkene-aryne coupling reactions

Article abstract of DOI:10.1021/ol800651h

(Chemical Equation Presented) The efficient copper-catalyzed two-component coupling reaction of alkynes with arynes and the three-component coupling reaction of alkynes with allylic chlorides and arynes have been developed. Copper acetylide was postulated as a transient intermediate for the initiation of the coupling reactions.

Full text of DOI:10.1021/ol800651h

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2393-2396
Copper-Catalyzed Alkyne-Aryne and
Alkyne-Alkene-Aryne Coupling
Reactions
Chunsong Xie, Leifang Liu, Yuhong Zhang,* and Peixin Xu
Department of Chemistry, Zhejiang UniVersity,
Hangzhou 310027, People’s Republic of China
yhzhang@zju.edu.cn
Received March 21, 2008
ABSTRACT
The efficient copper-catalyzed two-component coupling reaction of alkynes with arynes and the three-component coupling reaction of alkynes
with allylic chlorides and arynes have been developed. Copper acetylide was postulated as a transient intermediate for the initiation of the
coupling reactions.
Alkynes have been widely used as substrates in transition
metal-mediated C-C bond-formation processes.1 However,
arynes are seriously limited as components of catalytic
reactions due to their high reactivity and the harsh conditions
required to prepare them. In 1983, a mild method for the
preparation of arynes in situ at moderate temperatures from
commercially available o-silyl aryl triflates2 promoted the
exploration of the reactions with arynes as substrates,3 and
the transition metal-catalyzed reaction sequences indeed
occurred with arynes in high efficiency.4 For example, the
cyclotrimerization of arynes,5 the cocyclization of arynes with
alkynes,6 and the multicomponent reactions involving arynes7
have been reported in the presence of palladium catalysts,
which have demonstrated great potential in organic synthesis
with selectivities. Copper is one of the most efficient catalysts
for the construction of carbon-carbon and carbon-heteroatom
bonds,8 and in particular, the copper acetylide species are
active intermediates in organic transformations.9 However,
to the best of our knowledge, there is no report based on the
copper-catalyzed strategy of arynes.10 Our ongoing research
program on employing arynes as useful substrates in organic
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Ramtohul, Y. K.; Chartrand, A. Org. Lett. 2007, 9, 1029–1032. (i) Yoshida,
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128, 2782–2783. (c) Murakami, M.; Ashida, S.; Matsuda, T. J. Am. Chem.
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Chem., Int. Ed. 2006, 45, 1945–1949. (e) Zhang, L.; Chen, X.; Xue, P.;
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10.1021/ol800651h CCC: $40.75
Published on Web 05/17/2008
2008 American Chemical Society

synthesis11 prompted us to explore the function of copper
in the reaction of arynes. Herein, we report the first example
of a copper-catalyzed two-component coupling reaction of
alkynes with arynes and a three-component coupling reaction
of alkynes with allylic chlorides and arynes.
Initially, we performed the reaction of benzyne generated
in situ from 2-(trimethylsilyl)phenyl triflate2 and phenyl
acetylene in the presence of copper catalysts. After certain
optimization work on the reaction, to our delight, the
coupling product of diphenyl acetylene was obtained in an
87% yield without the use of any ligands (Table 1, entry 1).
entries 2-5). A good yield was obtained for ethyl propiolate
(Table 1, entry 6) and the substituted benzyne gave compa-
rable yields with benzyne (Table 1, entries 7 and 8).
Quite interestingly, the cyclotrimerization of benzyne took
place in the absence of alkynes, and a high yield of
triphenylene was isolated in the presence of 20 mol % CuI
in refluxing CH3CN for 24 h (Scheme 1). This result implied
Scheme 1
Table 1. The Copper-Catalyzed Two-Component Coupling
Reaction
that the copper acetylide, which was possibly generated in
situ under the reaction conditions, might be a very active
intermediate for the initiation of the coupling reaction of
alkynes and arynes. A tentative mechanism was proposed
for the above coupling reaction as presented in Scheme 2.
Scheme 2
a Reaction conditions: benzyne precursor (1.2 mmol), terminal alkyne
(1.0 mmol), CsF (365 mg, 2.4 mmol), CuI (19 mg, 0.05 mmol), toluene:
CH3CN ) 3:3 mL, 110 °C (bath temperature), 24 h. b Isolated yield.
A trace of self-coupling product from phenyl acetylene was
observed, but the cocyclization product of arynes and alkynes
that often form in palladium catalysis6a,b was not detected.
Both alkyl and aryl alkynes afforded the desired coupling
products in good yields, and the various aryl substituents in
aryl alkynes tolerated well the reaction conditions (Table 1,
First, the copper acetylide 1 is formed from the terminal
alkyne and copper(I), and the subsequent insertion of benzyne
into the copper acetylide 1 produces the carbocopper
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2394
Org. Lett., Vol. 10, No. 12, 2008

intermediate 2, which undergoes protonolysis to liberate the
coupling product and copper catalyst.
intermediate 2. In conclusion, the optimal reaction conditions
for this three-component reaction utilized 10 mol % CuI, 10
mol % dppe, 1.5 equiv of CsF, and 2 equiv of K2CO3 in
CH3CN solvent at 60 °C for 12 h.
It should be noted that the carbocopper intermediate 2
should also be active and might react with another suitable
reagent. Therefore, allyl acetate, allyl chloride, and allyl
bromide, which are general allylating reagents used in metal
catalysis, were chosen as the third component for the
reaction. We were very delighted to find that both allyl
chloride and allyl bromide underwent the three-component
coupling reaction and yielded the useful 1,6-enyne product
(Table 2, entries 1 and 2), while allyl acetate was inactive
The scope and limitations of this copper-catalyzed three-
component coupling reaction were studied as shown in Table
3. Under the standard reaction conditions, a variety of
Table 3. Copper-Catalyzed Three-Component Couplingsa
Table 2. Screen for Reaction Conditionsa
entry
X
cat.
CuI
CuI
CuI
CuCl
CuBr
CuCl2
CuBr2
-
yield (%)b
1
2
3
4
5
6
7
8
Cl
73
58
trace
53
57
60
61
NR
Br
OAc
Cl
Cl
Cl
Cl
Cl
a Reaction conditions: 4,5-dimethyl-2-(trimethylsilyl)phenyl triflate (163
mg, 0.5 mmol), phenyl acetylene (51 mg, 0.5 mmol), allyl chloride (76
mg, 1.0 mmol), CsF (228 mg, 1.5 mmol), copper catalysts (0.05 mmol),
ligands (0.05 mmol), CH3CN (5 mL), 60 °C (bath temperature), 12 h
b Isolated yields.
(Table 2, entry 3). A number of Cu sources were tested,
including CuCl, CuBr, CuCl2, and CuBr2, and CuI showed
the best reactivity (Table 2, entries 4-7). In these cases,
however, the phosphine ligands such as 1,3-bis(diphe-
nylphosphino)propane (dppp) and 1,2-bis(diphenylphosphi-
no)ethane (dppe) were required. No reaction was observed
in the absence of copper catalysts (Table 2, entry 8). When
the substituted internal alkynes were used as the substrates,
a small amount of triphenylene was isolated. Phenanthrene
derivatives, which were formed in palladium-catalyzed
systems,6a,b were not found.
a Reaction conditions: benzyne precursors (0.5 mmol); 4-methoxy phenyl
acetylene (66 mg, 0.5 mmol), allylic chlorides (2.0 mmol), CsF (228 mg,
1.5 mmol), CuI (10 mg, 0.05 mmol), dppe (25 mg, 0.05 mmol), K2CO3
(138 mg, 1.0 mmol), CH3CN (5 mL), 60 °C (bath temperature), 12 h.
b Isolated yields. c Two isomers are nearly 1:1.
During further studies, we found that a trace of two-
component coupling products from alkynes and arynes was
always formed in the three-component coupling product as
determined by GC-MS analysis, and it was very difficult to
separate these byproducts. We felt that we might be able to
suppress it by adjusting the reaction conditions, for example,
using a base or increasing the amount of allyl chloride to
promote the ensuing transformations over the protonolysis
of intermediate 2 (Scheme 2). We then performed the
reaction using 4 equiv of allyl chloride, and the amount of
the two-component coupling product from alkynes and
arynes was indeed decreased. The coupling product from
alkynes and arynes was fully suppressed by using 2 equiv
of K2CO3, which probably retarded the protonolysis of
substituted allylic chlorides underwent the reaction smoothly
and delivered good yields (Table 3, entries 1-4). Interest-
ingly, we found that the reaction of 3-chlorobut-1-ene
afforded the same product as that of chlorobut-2-ene with
high regioselectivity at the less substituted carbon in 67%
yield (Table 3, entry 4). Benzyne with two methyl groups
on the phenyl ring showed comparable reactivity with
benzyne and gave the three-component coupling product in
71% yield (Table 3, entry 5). It should be noted that
4-methyl-substituted aryne led to two regioisomers in a ratio
of 1:1, indicating that the reaction process was through
Org. Lett., Vol. 10, No. 12, 2008
2395

4-methylbenzyne (Table 3, entry 6). Similarly, a mixture of
regioisomers was obtained in the case of 5-fluoro-substituted
benzyne precursor (Table 3, entry 7).
Scheme 3. Proposed Mechanism and Intermediates
The optimized reaction conditions could be applied to a
variety of terminal alkynes (Table 4). Electronic variation
Table 4. Copper-Catalyzed Three-Component Couplingsa
of allyl chloride to carbocopper intermediate 2 results in the
intermediate 3, which might rearrange to allylcopper complex
4.13 The reductive elimination of intermediate 3 or 4 affords
the 1,6-enyne product. In the case of substituted allylic
chlorides, the reductive elimination of intermediate 4 deter-
mines the regiochemistry, and the elimination takes place at
the less hindered end of the π-allylic system. Accordingly,
3-chlorobut-1-ene afforded the same product as that of
chlorobut-2-ene in the reaction (Table 3, entries 2 and 4). In
addition, the phosphine ligands should play a role in the
reactivity of intermediate 2, 3, and 4. One other possible
pathway is that the nucleophilic attack of carbocopper
intermediate 2 to allyl chloride generates the final 1,6-enyne
product via an SN2 or SN2′ reaction due to the allylic
rearrangement.
In summary, the present process demonstrates the first
example of aryne reactions with copper catalysts and terminal
alkynes. The efficient copper-catalyzed three-component
coupling of arynes with terminal alkynes and allylic chlorides
provides a facile and novel route for the synthesis of 1,6-
enynes. Further studies to elucidate the reaction mechanism
and extend the scope of the reactions are in progress.
a Reaction conditions are the same as for Table 3. b Isolated yield.
on aryl acetylenes causes no appreciable change in the
efficiency of the three-component couplings (Table 4, entries
1-4). The conjugated enyne readily participated in the
reaction (Table 4, entry 5). The aliphatic terminal alkynes
exhibited comparable reactivity with phenylacetylene (Table
4, entries 6 and 7). Methyl propiolate, which is inactive in
some of the coupling reactions,12 underwent this three-
component aryne coupling process, and a 46% yield was
obtained (Table 4, entry 8). However, no product was found
for TMS acetylene and 2-methylbut-3-yn-2-ol.
Acknowledgment. Funding from Natural Science Foun-
dation of China (No. 205710631) is acknowledged.
Supporting Information Available: The experimental
procedure and spectroscopic data (1H NMR, 13C NMR, and
HRMS) for the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL800651H
On the basis of these results, we proposed a plausible
mechanism for this useful 1,6-enyne synthesis (Scheme 3).
Initially, the copper acetylide 1 is formed from the terminal
alkyne and copper(I), following insertion of benzyne gener-
ated in situ from o-(trimethylsilyl)phenyl triflate to afford
carbocopper intermediate 2. Subsequent oxidative addition
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15258.
2396
Org. Lett., Vol. 10, No. 12, 2008