Copper-catalyzed 2:1 Coupling reaction of arynes with alkynes

Article abstract of DOI:10.1021/ol802609j

(Chemical Equation Presented) A formal insertion reaction of two molar amounts of arynes into a C-H bond of terminal alkynes is efficaciously catalyzed by copper(1) chloride, giving 2-alkynylbiaryls in one step.

Full text of DOI:10.1021/ol802609j

ORGANIC
LETTERS
2009
Vol. 11, No. 2
373-376
Copper-Catalyzed 2:1 Coupling Reaction
of Arynes with Alkynes
Hiroto Yoshida,* Takami Morishita, Hiromi Nakata, and Joji Ohshita
Department of Applied Chemistry, Graduate School of Engineering, Hiroshima
UniVersity, Higashi-Hiroshima 739-8527, Japan
yhiroto@hiroshima-u.ac.jp
Received November 12, 2008
ABSTRACT
A formal insertion reaction of two molar amounts of arynes into a C-H bond of terminal alkynes is efficaciously catalyzed by copper(I)
chloride, giving 2-alkynylbiaryls in one step.
Transition-metal-catalyzed transformations of arynes have
recently received much attention as an efficient method for
constructing benzo-annulated structures or multisubstituted
arenes that are otherwise difficult to be synthesized.1 Since
the pioneering work on the transformations, that is, pal-
ladium-catalyzed trimerization of arynes, was disclosed by
Pen˜a,2 most of the effort has been hitherto devoted to
developing catalysis of palladium or nickel complexes.3
During our ongoing studies on element-element σ-bond
addition reactions4,5 and three-component coupling6 utilizing
highly electrophilic character of arynes, we envisaged that
copper acetylides of sufficient nucleophilicity, being readily
producible from terminal alkynes and a catalytic amount of
copper(I) salts, should be suitable reagents for capturing
arynes, which leads to new catalytic transformations for
constructing aromatic compounds and opens up copper
catalysis in aryne chemistry.7,8 We report herein that arynes
can be coupled with alkynes by the use of a copper(I) salt
in a totally different manner from those observed in the
palladium- or nickel-catalyzed reactions,9 giving diverse
(5) (a) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247. (b) Yoshida, H.; Terayama, T.; Ohshita, J.;
Kunai, A. Chem. Commun. 2004, 1980. (c) Yoshida, H.; Watanabe, M.;
Ohshita, J.; Kunai, A. Chem. Commun. 2005, 3292. (d) Yoshida, H.; Minabe,
T.; Ohshita, J.; Kunai, A. Chem. Commun. 2005, 3454. (e) Yoshida, H.;
Watanabe, M.; Ohshita, J.; Kunai, A. Tetrahedron Lett. 2005, 46, 6729. (f)
Yoshida, H.; Watanabe, M.; Ohshita, J.; Kunai, A. Chem. Lett. 2005, 34,
1538. (g) Yoshida, H.; Watanabe, M.; Morishita, T.; Ohshita, J.; Kunai, A.
Chem. Commun. 2007, 1505. (h) Yoshida, H.; Mimura, Y.; Ohshita, J.;
Kunai, A. Chem. Commun. 2007, 2405.
(1) For reviews, see: (a) Pellissier, H.; Santelli, M. Tetrahedon 2003,
59, 701. (b) Dyke, A. M.; Hester, A. J.; Lloyd-Jones, G. C. Synthesis 2006,
4093.
(6) (a) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai, A. Angew. Chem.,
Int. Ed. 2004, 43, 3935. (b) Yoshida, H.; Fukushima, H.; Ohshita, J.; Kunai,
A. Tetrahedron Lett. 2004, 45, 8659. (c) Yoshida, H.; Fukushima, H.;
Ohshita, J.; Kunai, A. J. Am. Chem. Soc. 2006, 128, 11040. (d) Yoshida,
H.; Fukushima, H.; Morishita, T.; Ohshita, J.; Kunai, A. Tetrahedron 2007,
63, 4793. (e) Yoshida, H.; Morishita, T.; Fukushima, H.; Ohshita, J.; Kunai,
A. Org. Lett. 2007, 9, 3367. (f) Morishita, T.; Fukushima, H.; Yoshida, H.;
Ohshita, J.; Kunai, A. J. Org. Chem. 2008, 73, 5452.
(2) Pen˜a, D.; Escudero, S.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Angew.
Chem., Int. Ed. 1998, 37, 2659.
(3) For recent examples, see: (a) Liu, Z.; Zhang, X.; Larock, R. C. J. Am.
Chem. Soc. 2005, 127, 15716. (b) Henderson, J. L.; Edwards, A. S.; Greaney,
M. F. J. Am. Chem. Soc. 2006, 128, 7426. (c) Quintana, I.; Boersma, A. J.;
Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Org. Lett. 2006, 8, 3347. (d) Bhuvaneswari,
S.; Jeganmohan, M.; Cheng, C.-H. Org. Lett. 2006, 8, 5581. (e) Jayanth,
T. T.; Cheng, C.-H. Chem. Commun. 2006, 894. (f) Liu, Z.; Larock, R. C.
J. Org. Chem. 2007, 72, 223. (g) Liu, Z.; Larock, R. C. Angew. Chem., Int.
Ed. 2007, 46, 2535. (h) Jayanth, T. T.; Cheng, C.-H. Angew. Chem., Int.
Ed. 2007, 46, 5921. (i) Henderson, J. L.; Edwards, A. S.; Greaney, M. F.
Org. Lett. 2007, 9, 5589.
(7) Copper-catalyzed reactions of arynes have recently been reported.
(a) Xie, C.; Liu, L.; Zhang, Y.; Xu, P. Org. Lett. 2008, 10, 2393. (b)
Bhuvaneswari, S.; Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2008,
5013
.
(8) Palladium-catalyzed three-component coupling of arynes, alkynes,
and allylic electrophiles using cuprous iodide has recently been reported:
Bhuvaneswari, S.; Jeganmohan, M.; Yang, M.-C.; Cheng, C.-H. Chem.
(4) For a review, see: Pen˜a, D.; Pe´rez, D.; Guitia´n, E. Angew. Chem.,
Int. Ed. 2006, 45, 3579
.
Commun. 2008, 2158.
10.1021/ol802609j CCC: $40.75
Published on Web 12/11/2008
2009 American Chemical Society

Scheme 1
.
Copper-Catalyzed 2:1 Coupling of Arynes with
Alkynes
Scheme 2
.
Copper-Catalyzed 2:1 Coupling of Substituted
Arynes
2-alkynylbiaryls straightforwardly (Scheme 1). Recently, a
similar coupling reaction promoted by a Au(I)-Cu(I) co-
catalytic system has been reported.10
Initially, a reaction of benzyne, generated in situ from 1a11
and a fluoride ion, with phenylacethylene (2a) was examined
with various copper catalysts (Table 1). By use of copper(I)
chloride, two molar amounts of benzyne were found to be
formally inserted into a C(sp)-H bond of 2a to afford a 64%
yield of 2-(phenylethynyl)biphenyl (3aa) containing a small
portion of diphenylacetylene 4aa (entry 1). Increasing the
amount of 1a improved the selectivity for the formation of
Table 1. Reaction of Benzyne with Phenylacetylenea
(entry 7), and the reaction using AgCl or NiCl2 resulted in
the formation of a complex mixture (entries 8 and 9), which
demonstrates the vital role of the copper catalysis in the 2:1
coupling reaction.
We next conducted the reaction of various alkynes using
CuCl as a catalyst (Table 2). Aryl alkynes bearing a n-butyl
(2b), fluoro (2c), or methyl (2d) substituent smoothly reacted
with benzyne in a manner similar to 2a, producing the
respective 2-alkynylbiphenyls (3ab-3ad) in 68%, 54%, or
53% yield (entries 1-4). Preferential formation of 2:1
coupling products was also observed with 1-naphthylacety-
lene (2e), 2-naphthylacetylene (2f), or dimethoxypheny-
entry
catalyst
CuCl
CuCl
CuBr
time (h)
3aa (%)b
4aa (%)b
1
2c
3
4
5
6
7
8
9
4
4
1
1
1
3
5
15
27
64
77
37
24
34
24
-
4
trace
20
54
28
14
CuI
(Ph3P)3CuCl
Cu(OAc)2
none
AgCl
NiCl2
-
-
-
-
a The reaction was carried out in THF (0.5 mL) at 50 °C using 1a (0.20
mmol), 2a (0.10 mmol), KF (0.40 mmol), and 18-crown-6 (0.40 mmol) in
the presence of a catalyst (0.01 mmol). b Isolated yield based on 2a. c 1a )
0.44 mmol, 2a ) 0.20 mmol, KF ) 0.88 mmol, 18-crown-6 ) 0.88 mmol,
CuCl ) 0.01 mmol, THF ) 2 mL.
(9) Cocyclization of arynes with alkynes generally occurs by use of a
palladium or nickel catalyst. For examples, see: (a) Pen˜a, D.; Pe´rez, D.;
Guitia´n, E.; Castedo, L. J. Am. Chem. Soc. 1999, 121, 5827. (b)
Radhakrishnan, K. V.; Yoshikawa, E.; Yamamoto, Y. Tetrahedron Lett.
1999, 40, 7533. (c) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. Synlett
2000, 1061. (d) Pen˜a, D.; Pe´rez, D.; Guitia´n, E.; Castedo, L. J. Org. Chem.
2000, 65, 6944. (e) Hsieh, J.-C.; Cheng, C.-H. Chem. Commun. 2005, 2459.
(f) Caeiro, J.; Pen˜a, D.; Cobas, A.; Pe´rez, D.; Guitia´n, E. AdV. Synth. Catal.
2006, 348, 2466. (g) Sato, Y.; Tamura, T.; Kinbara, A.; Mori, M. AdV.
Synth. Catal. 2007, 349, 647. (h) Hsieh, J.-C.; Cheng, C.-H. Chem. Commun.
2008, 2992.
3aa (77% yield), and only a trace of 4aa was detected (entry
2). Other copper salts including CuBr, CuI, (Ph3P)3CuCl,
and Cu(OAc)2 also exhibited catalysis toward the present
aryne-alkyne coupling, albeit at the cost of product selectiv-
ity (entries 3-6). In marked contrast, none of the coupling
products were produced in the absence of a copper catalyst
(10) Xie, C.; Zhang, Y.; Yang, Y. Chem. Commun. 2008, 4810.
(11) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983, 1211.
374
Org. Lett., Vol. 11, No. 2, 2009

Table 2. Copper-Catalyzed 2:1 Coupling of Benzyne with
Scheme 3. Plausible Catalytic Cycle
Alkynesa
ratio, which confirms that the present reaction proceeds
through an aryne intermediate.
Scheme 4. Reaction Using Phenylacetylene-d
A plausible catalytic cycle for the present 2:1 coupling
reaction is depicted in Scheme 3. First a copper acetylide
(5), generated from a terminal alkyne and CuCl, attacks an
aryne to give an aryl copper species (6).12 Subsequent
nucleophilic attack of 6 to a second aryne produces biaryl
copper 7, which then reacts with an alkyne (or HCl) to
furnish product 3 with regeneration of 5 (or CuCl). In all
cases, neither 3:1 coupling products nor higher oligomers
were produced. At present, the reason why the 2:1 coupling
products form preferentially is unclear.
a The reaction was carried out in THF (2 mL) at 50 °C using 1a (0.44
mmol), 2 (0.20 mmol), KF (0.88 mmol), and 18-crown-6 (0.88 mmol) in
the presence of CuCl (0.01 mmol). b Isolated yield based on 2.
lacetylene (2g), and moreover, a 63% yield of 3ah was
generated in the reaction of enyne 2h (entries 5-8). In
addition, aliphatic alkynes (2i or 2j) or methyl propargyl ether
(2k) were found to be convertible into 2:1 coupling products
3ai-3ak as well (entries 9-11).
To gain insight into a catalytic cycle, we also performed
the reaction using a labeled alkyne (2a-d) (Scheme 4) and
observed that deuterium-incorporated biphenyl (3aa-d) was
produced in 45% yield (deuterium incorporation ratio )
57%), which supports a hydrogen-transfer process between
an alkyne and biaryl copper 7 (see Scheme 3).13 The
Multisubstituted biaryl frameworks could be constructed
by the reaction of substituted arynes as shown in Scheme 2.
Thus, 2,3-naphthalyne (from 1b) or 4,5-dimethylbenzyne
(from 1c) underwent the reaction with 2a to provide 2,2′-
binaphthyl 3ba or tetramethylbiphenyl 3ca in 48% or 55%
yield, respectively. The reaction of an unsymmetrical aryne
such as 4-methylbenzyne (from 1d) also took place smoothly,
giving a mixture of four regioisomers in an almost equal
(12) Nucleophilic attack of organocuprates to arynes has been disclosed.
See: Meyers, A. I.; Pansegrau, P. D. J. Chem. Soc., Chem. Commun. 1985,
690.
Org. Lett., Vol. 11, No. 2, 2009
375

moderate incorporation ratio may be ascribable to fluoride
ion-induced D-H exchange between 2a-d and contaminated
water.
In conclusion, we have demonstrated that a copper(I) salt
exhibits the characteristic catalysis on a coupling reaction
of arynes with alkynes, which is completely distinct from
that of nickel or palladium complexes. Upon the basis of
the present 2:1 coupling reaction, diverse 2-alkynylbiaryls
of great synthetic usefulness14 are synthesized straightfor-
wardly via formal insertion of two molar amounts of arynes
into a C(sp)-H bond of alkynes. Further studies on copper-
catalyzed transformations of arynes as well as on the detailed
catalytic cycle are in progress in our laboratory.
(13) A preliminary experiment revealed that the reaction using ethyl
propiolate (2l) gave ethyl 2-(9H-fluoren-9-ylidene)-2-phenylacetate (8) as
the major product, which should arise from 5-Exo-Dig cyclization of
intermediate 7. This result strongly supports the intermediacy of 7 in the
present 2:1 coupling and demonstrates that the intramolecular cyclization
of 7 takes place with an electron-deficient alkyne. Thus, it would be
reasonable to assume that protonation of 7 is much faster than the
intramolecular cyclization in the cases of the reactions using electron-rich
alkynes (2a-2k). Detailed results of the reaction using electron-deficient
alkynes will be reported in due course.
Acknowledgment. We thank Central Glass Co Ltd. for a
generous gift of trifluoromethanesulfonic anhydride.
Supporting Information Available: Experimental pro-
cedure and characterization of products. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL802609J
(14) Various carbocyclic compounds can be readily synthesized by
intramolecular cyclizations of 2-alkynylbiaryls. For example, see: (a)
Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Am. Chem. Soc. 1997,
119, 4578. (b) Goldfinger, M. B.; Crawford, K. B.; Swager, T. M. J. Org.
Chem. 1998, 63, 1676. (c) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002,
67, 6264. (d) Fu¨rstner, A.; Mamane, V. Chem. Commun. 2003, 2112. (e)
Mamane, V.; Hannen, P.; Fu¨rstner, A. Chem.-Eur. J. 2004, 10, 4556. (f)
Yao, T.; Campo, M. A.; Larock, R. C. Org. Lett. 2004, 6, 2677. (g) Yao,
T.; Campo, M. A.; Larock, R. C. J. Org. Chem. 2005, 70, 3511. (h)
Chernyak, N.; Gevorgyan, V. J. Am. Chem. Soc. 2008, 130, 5636.
376
Org. Lett., Vol. 11, No. 2, 2009