Copper-catalyzed coupling of alkynes with alkenyl halides

Article abstract of DOI:10.1055/s-0031-1290502

The synthesis of enynes from the coupling of terminal alkynes with alkenyl iodides and bromides is described. This system employs 1.0-5.0 mol% of CuI(Xantphos) as a catalyst. A variety of alkenyl iodides and bromides are coupled smoothly with terminal alkynes, affording enynes in good to excellent yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290502

930
LETTER
Copper-Catalyzed Coupling of Alkynes with Alkenyl Halides
C
opper-Catalyzed
u
Coupling of
n
A
lkyne
s
w
ith
-
Alkeny
Y
l
Halides ung Lin, Yu-Jen Wang, Jun-Hao Cheng, Chin-Fa Lee*
Department of Chemistry, National Chung Hsing University, Taichung, Taiwan 402, Republic of China
Fax +886(4)22862547; E-mail: cfalee@dragon.nchu.edu.tw
Received 1 December 2011
ligand) loading, and greater variety of substrates are de-
sired in the preparation of enynes.
Abstract: The synthesis of enynes from the coupling of terminal
alkynes with alkenyl iodides and bromides is described. This sys-
tem employs 1.0–5.0 mol% of CuI(Xantphos) as a catalyst. A vari-
ety of alkenyl iodides and bromides are coupled smoothly with
terminal alkynes, affording enynes in good to excellent yields.
Recently, we communicated a catalytic system compris-
ing of a copper salt with Xantphos as a very efficient
method of coupling aryl iodides with alkynes.7a Herein,
we report that the well-defined CuI(Xantphos) complex10
also represents a powerful catalyst for the coupling reac-
tion of alkynes with alkenyl halides, affording the enynes
in good to excellent yields.
Key words: copper, cross-coupling, terminal alkyne, alkenyl ha-
lide, enyne
Enynes are important skeletons in organic synthesis, ma-
terials science, and the pharmaceutical industry.1,2 Many
strategies have been achieved for preparing enynes, but
the transition-metal-catalyzed dimerization of two termi-
nal alkynes is one of the more popular methods.3 This
method is an excellent example of the atom-economy con-
cept, however, it sometimes suffers from a lack of regi-
oselectivity, leading to undesirable regioisomers.3a,e,g,i
The metal-catalyzed coupling reaction of alkynyl halides
with organometallic alkenes is another route to enynes
and eliminates the ailment of regioselectivity,4 however,
tedious procedures are required for synthesizing alkynyl
halides and organometallic alkenes limiting the popularity
of this approach. The Sonogashira coupling reaction of
aryl and alkenyl halides with alkynes in the presence of
palladium and copper as the co-catalyst is well known and
has been widely applied for the formation of Csp2–Csp
bond.5,6 Indeed, adding a copper salt as the sole metal
source has gained significant attention in the Sonogashira-
type reaction because of the low cost of copper.7 As a re-
sult, the copper-catalyzed coupling reaction of alkynes
and alkenyl halides is an alternative way for constructing
enynes.8,9 For example, the combination of CuI (5 mol%)
with Ph3P (10 mol%) has been reported as the first exam-
ple of a copper-catalyzed coupling reaction of terminal
alkynes with alkenyl halides, however, few cases have
been described by this work.8f Elegant work published by
Venkataraman et al. using 10 mol% of well-defined cop-
per complex [Cu(bipy)PPh3Br] as the catalyst has also
been described.8d More recently, Bao et al. demonstrated
that a system using 15 mol% of CuI and 30 mol% of 1,10-
phenanthroline (30 mol%) is reactive for coupling the (E)-
b-bromostyrene derivatives with alkynes, however, no
alkyl alkynes were presented in their work.8a Despite
these recent advances, lower catalyst (and ancillary
Table 1 Optimization of the Copper-Catalyzed Coupling Reaction
of 1-(Iodomethylidene)-4-tert-butyl-cyclohexane (1a) with Phenyl-
acetylenea
I
t-Bu
CuI(xantphos)
(1.0 mol%)
1a
+
t-Bu
base, solvent
135 °C, 12 h
3a
2a
Entry
1
Base
Solvent
DMSO
NMP
Yield (%)b
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
44
68
–
2
3
DMF
4
DME
83
99
42
–
5
dioxane
toluene
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
6
7c
8
75
74
–
9
K2CO3
10
11
12
KOt-Bu
Na2CO3
Cs2CO3
43
72d
a Reaction conditions (unless otherwise stated): CuI(Xantphos) (0.005
mmol, 1.0 mol%), base (1.0 mmol), phenylacetylene (0.75 mmol), 1-
(iodomethylidene)-4-tert-butylcyclohexane (0.5 mmol) in solvent
(0.5 mL).
b Isolated yield.
c No catalyst.
d 120 °C
SYNLETT 2012, 23, 930–934
x
x.
x
x.
2
0
1
2
Advanced online publication: 15.03.2012
DOI: 10.1055/s-0031-1290502; Art ID: W74011ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Copper-Catalyzed Coupling of Alkynes with Alkenyl Halides
931
Initially, 1-(iodomethylidene)-4-tert-butylcyclohexane entry 5), amino (Table 2, entry 6), and nitro (Table 2, en-
and phenylacetylene were selected as the substrates to op- try 7) all tolerated the reaction conditions. Sterically de-
timize the reaction conditions. The results are summarized manding aryl alkynes also underwent the cross-coupling
in Table 1. After screening the effect of solvent (Table 1, reaction, affording the products in good to excellent yields
entries 1–6), dioxane was found to be the best (Table 1, (Table 2, entries 3 and 11). (E)-b-bromostyrene can also
entry 5). Lower yield of product was observed when the be coupled using this catalytic system (Table 2, entries
reaction was carried out without catalyst (Table 1, entry 24–27).
7). Other bases such as K3PO4, K2CO3, KOt-Bu, and
Na2CO3 could not give satisfying results (Table 1, entries
In summary, we have demonstrated that the CuI(Xant-
phos) is an active catalyst for the coupling reaction of
8–11). Lower temperature will decrease the yield of the
alkynes with alkenyl iodides and bromides; a variety of
product (Table 1, entry 12).
alkyl and aryl alkynes with substituted aromatics are in-
In order to explore the scope of the system, a variety of volved, giving the corresponding enynes in good to excel-
alkyl and aryl alkynes were reacted with alkenyl iodides lent yields.
(Table 2, entries 1–23), giving the corresponding enynes
in good to excellent yields. The results are summarized in
Table 2. Functional groups such as free amine (Table 2,
Table 2 Copper-Catalyzed Coupling Reaction of Alkenyl Halides with Alkynesa
R2
CuI(xantphos) (1.0–5.0 mol%)
I
Cs2CO3, 1,4-dioxane
R1
R2
+
R1
135 °C, 12–24 h
3
1
2
Entry
1
1
2
Product
Yield (%)b Ratio (E/Z)d
I
3b
3c
3d
3e
76
Bu
Bu
t-Bu
1a
2
3
4
1a
77
81
99
C8H17
C8H17
t-Bu
1a
1a
t-Bu
NH2
t-Bu
5
6
1a
1a
3f
97
94
H2N
Me2N
Me2N
O2N
S
t-Bu
3g
O2N
t-Bu
7
8
1a
1a
3h
3i
78
86
S
t-Bu
© Thieme Stuttgart · New York
Synlett 2012, 23, 930–934

932
Y.-Y. Lin et al.
LETTER
Table 2 Copper-Catalyzed Coupling Reaction of Alkenyl Halides with Alkynesa (continued)
R2
CuI(xantphos) (1.0–5.0 mol%)
I
Cs2CO3, 1,4-dioxane
R1
R2
+
R1
135 °C, 12–24 h
3
1
2
Entry
1
2
Product
Yield (%)b Ratio (E/Z)d
MeO
F3C
MeO
t-Bu
t-Bu
9
1a
1a
1a
3j
3k
3l
97
F3C
10
11
99
98
OMe
t-Bu
OMe
I
12
13
3m
3n
67
Ph
Ph
Ph
1b
1b
76c
Bu
Bu
I
14
15
3o
3p
79
1c
1c
98c
Bu
Bu
I
MeO
16
3q
92
4.6:1
MeO
1d
17
18
1d
3r
3s
90
8.2:1
6.5:1
MeO
MeO
Bu
Bu
1d
90c
C8H17
C8H17
F3C
MeO
MeO
19
20
21
1d
1d
3t
99
99
67
4.3:1
7.6:1
CF3
S
3u
3v
S
I
1e
1e
22
23
3w
3x
68
1e
98c
Bu
Bu
Synlett 2012, 23, 930–934
© Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Coupling of Alkynes with Alkenyl Halides
933
Table 2 Copper-Catalyzed Coupling Reaction of Alkenyl Halides with Alkynesa (continued)
R2
CuI(xantphos) (1.0–5.0 mol%)
I
Cs2CO3, 1,4-dioxane
R1
R2
+
R1
135 °C, 12–24 h
3
1
2
Entry
24
1
2
Product
Yield (%)b Ratio (E/Z)d
3v
3y
98c
Br
1f
1f
S
S
25
88c
F3C
26
27
1f
1f
3z
3x
90c
75c
CF3
Bu
Bu
a Reaction conditions (unless otherwise stated): CuI(Xantphos) (0.005 mmol, 1.0 mol%), Cs2CO3 (1.0 mmol), alkenyl halide (0.5 mmol), alkyne
(0.75 mmol) in dioxane (0.5 mL).
b Isolated yield.
c CuI(Xantphos) (0.025 mmol, 5.0 mol%), 24 h.
d The ratios of E/Z were determined by GC–MS and 1H NMR techniques. The starting 1-(2-iodovinyl)-4-methoxybenzene (1d) contains a ratio
of E/Z = 8:1; 1-(2-iodovinyl)benzene (1e) contains a ratio of E/Z = 9:1; 1-(2-bromovinyl)benzene (1f) contains a ratio of E/Z = 10:1. Only the
E products were detected in entries 21–27.
Akamatsu, K.; Ozawa, F. Macromolecules 2004, 37, 13.
(h) Nishiura, M.; Hou, Z.; Makatsuki, Y.; Yamaki, T.;
Miyamoto, T. J. Am. Chem. Soc. 2003, 125, 1184. (i)Yang,
C.; Nolan, S. P. J. Org. Chem. 2002, 67, 591. (j) Rubina,
M.; Gevorgyan, V. J. Am. Chem. Soc. 2001, 123, 11107.
(k) Trost, B. M.; Sorum, M. T.; Chan, C.; Harms, A. E.;
Rühter, G. J. Am. Chem. Soc. 1997, 119, 698. (l) Trost, B.
M.; Chan, C.; Ruhter, G. J. Am. Chem. Soc. 1987, 109, 3486.
(4) (a) Hoshi, M.; Nakayabu, H. H.; Shirakawa, K. Synthesis
2005, 1991. (b) Silveira, C. C.; Braga, A. L.; Vieira, A. S.;
Zeni, G. J. Org. Chem. 2003, 68, 662. (c) Stang, P. J.;
Kitamura, T. J. Am. Chem. Soc. 1987, 109, 7561.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
Financial support by the National Science Council, Taiwan
(NSC99-2113-M-005-004-MY2) and the National Chung Hsing
University are gratefully acknowledged. We thank Prof. Fung-E.
Hong for generously sharing his GC–MS instruments. C.F.L. is a
Golden-Jade Fellow of Kenda Foundation, Taiwan.
(5) (a) Sonogashira, K. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley:
New York, 2002, 493–529. (b) Negishi, E.; Xu, C. In
Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E., Ed.; Wiley: New York, 2002, 531–
549.
(6) For reviews, see: (a) Heravi, M. M.; Sadjadi, S. Tetrahedron
2009, 65, 7761. (b) Chinchilla, R.; Nájera, C. Chem. Rev.
2007, 107, 874. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah,
D. Angew. Chem. Int. Ed. 2005, 44, 4442. (d) Negishi, E.;
Anastasia, L. Chem. Rev. 2003, 103, 1979. (e) Littke, A. F.;
Fu, G. C. Angew. Chem. Int. Ed. 2002, 41, 4176.
(f) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew.
Chem. Int. Ed. 2000, 39, 2632. (g) Martin, R. E.; Diederich,
F. Angew. Chem. Int. Ed. 1999, 38, 1350. (h) Grissom, J.
W.; Gunawardena, G. U.; Klingberg, D.; Huang, D.
Tetrahedron 1996, 52, 6453. (i) Nicolaou, K. C.; Dai,
W.-M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1387.
(7) For selected examples, see: (a) Lin, C.-H.; Wang, Y.-J.;
Lee, C.-F. Eur. J. Org. Chem. 2010, 4368. (b) Monnier, F.;
Turtaut, F.; Duroure, L.; Taillefer, M. Org. Lett. 2008, 10,
3203. (c) Li, J.-H.; Li, J.-L.; Wang, D.-P.; Pi, S.-F.; Xie,
Y.-X.; Zhang, M.-B.; Hu, X.-C. J. Org. Chem. 2007, 72,
References
(1) For reviews, see: (a) Chinchilla, R.; Nájera, C. Chem. Rev.
2007, 107, 874. (b) Doucet, H.; Hierso, J.-C. Angew. Chem.
Int. Ed. 2007, 46, 834. (c) Saito, S.; Yamamoto, Y. Chem.
Rev. 2000, 100, 2901. (d) Trost, B. M. Angew. Chem. Int.
Ed. 1995, 34, 259.
(2) Nicolaou, K. C.; Smith, A. L. In Modern Acetylene
Chemistry; Stang, P. J.; Diederich, F., Eds.; VCH:
Weinheim, 1995.
(3) For examples, see: (a) Bassetti, M.; Pasquini, C.; Raneri, A.;
Rosato, D. J. Org. Chem. 2007, 72, 4558. (b) Chen, X.;
Xue, P.; Sung, H. H. Y.; Williams, I. D.; Peruzzini, M.;
Bianchini, C.; Jia, G. Organometallics 2005, 24, 4330.
(c) Lee, C.-C.; Lin, Y.-C.; Liu, Y.-H.; Wang, Y.
Organometallics 2005, 24, 136. (d) Komeyama, K.;
Kawabata, T.; Takehira, K.; Takaki, K. J. Org. Chem. 2005,
70, 7260. (e) Katayama, H.; Yari, H.; Tanaka, M.; Ozawa, F.
Chem. Commun. 2005, 4336. (f) Ogoshi, S.; Ueta, M.; Oka,
M.; Kurosawa, H. Chem. Commun. 2004, 2732.
(g) Katayama, H.; Nakayama, M.; Nakano, T.; Wada, C.;
© Thieme Stuttgart · New York
Synlett 2012, 23, 930–934

934
Y.-Y. Lin et al.
LETTER
2053. (d) Xie, Y.-X.; Deng, C.-L.; Pi, S.-F.; Li, J.-H.; Yin,
D.-L. Chin. J. Chem. 2006, 24, 1290. (e) Saejueng, P.;
Bates, C. G.; Venkataraman, D. Synthesis 2005, 1706.
(f) Wang, Y. F.; Deng, W.; Liu, L.; Guo, Q. X. Chin. Chem.
Lett. 2005, 16, 1197. (g) Ma, D.; Liu, F. Chem. Commun.
2004, 1934. (h) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315. (i) Okuro, K.;
Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org.
Chem. 1993, 58, 4716.
K.; Furuune, M.; Miura, M.; Nomura, M. Tetrahedron Lett.
1992, 33, 5363.
(9) Other methods for preparing enynes, see: (a) Zhou, L.; Ye,
F.; Ma, J.; Zhang, Y.; Wang, J. Angew. Chem. Int. Ed. 2011,
50, 3510. (b) Sakai, N.; Komatsu, R.; Uchida, N.; Ikeda, R.;
Konakahara, T. Org. Lett. 2010, 12, 1300. (c) Hatakeyama,
T.; Yoshimoto, Y.; Gabriel, T.; Nakamura, M. Org. Lett.
2008, 10, 5341. (d) Kang, B.; Kim, D.-h.; Do, Y.; Chang, S.
Org. Lett. 2003, 5, 3041. (e) Shi, J.-c.; Zeng, X.; Negishi,
E.-i. Org. Lett. 2003, 5, 1825.
(8) (a) Liu, Y.; Yang, J.; Bao, W. Eur. J. Org. Chem. 2009,
5317. (b) Xie, X.; Xu, X. B.; Li, H. F.; Xu, X. L.; Yang, J.
Y.; Li, Y. Z. Adv. Synth. Catal. 2009, 351, 1263. (c) Wu,
M.; Mao, J.; Guo, J.; Ji, S. Eur. J. Org. Chem. 2008, 4050.
(d) Bates, C. G.; Saejueng, P.; Venkataraman, D. Org. Lett.
2004, 6, 1441. (e) Okuro, K.; Furuune, M.; Enna, M.; Miura,
M.; Nomura, M. J. Org. Chem. 1993, 58, 4716. (f) Okuro,
(10) Huang, J.; Chan, J.; Chen, Y.; Borths, C. J.; Baucom, K. D.;
Larsen, R. D.; Faul, M. M. J. Am. Chem. Soc. 2010, 132,
3674.
Synlett 2012, 23, 930–934
© Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or
emailed to multiple sites or posted to a listserv without the copyright holder's express written permission.
However, users may print, download, or email articles for individual use.