Copper-catalyzed synthesis of 1,3-enynes

Article abstract of DOI:10.1021/ol049706e

We report a copper(I)-catalyzed procedure for the synthesis of 1,3-enynes. This method affords a variety of enynes in good to excellent yields. This method can tolerate a variety of functional groups, does not require the use of expensive additives, and is palladium-free.

Full text of DOI:10.1021/ol049706e

ORGANIC
LETTERS
2
004
Vol. 6, No. 9
441-1444
Copper-Catalyzed Synthesis of
,3-Enynes
1
1
Craig G. Bates, Pranorm Saejueng, and D. Venkataraman*
Department of Chemistry, UniVersity of Massachusetts-Amherst,
710 North Pleasant Street, Amherst, Massachusetts 01003
dV@chem.umass.edu
Received February 18, 2004
ABSTRACT
We report a copper(I)-catalyzed procedure for the synthesis of 1,3-enynes. This method affords a variety of enynes in good to excellent yields.
This method can tolerate a variety of functional groups, does not require the use of expensive additives, and is palladium-free.
1
,3-Enynes can be found in many naturally occurring and
terminal organometallic alkyne (Cu, Mg, Si, Zn, Sn)6a,7 and
an alkene or the alkynylation of alkenylmetals (Al, B, Cu,
1
biologically active compounds. Terbinafine, which is com-
monly known as Lamisil, contains the 1,3-enyne moiety and
is a pharmaceutically important compound used in the
treatment of superficial fungal infections. Another pharma-
ceutically important compound is Calicheamicin γ
has been shown to be an effective antitumor antibiotic. 1,3-
Enynes are also important precursors to polysubstituted
benzenes and conjugated dienes via hydroboration-proto-
nolysis.5
6
a,8
Mg, Zr).
The latter methods do suffer from some
drawbacks such as toxic reagents, the need to prepare an
organometallic alkyne or alkene, poor functional group
tolerance, and undesired side-products resulting in low
2
I
1
, which
3
9
yields.
The use of copper has also been shown to mediate the
synthesis of conjugated enynes. Marshall and co-workers
synthesized 1,3-enynes by coupling trimethylsilyl alkynes
4
1
0
Among the methods developed to synthesize 1,3-enynes,
the Pd-Cu-catalyzed Sonogashira coupling reaction between
an alkyne and a vinyl halide is most prevalent. Other
with vinyl iodides. However, this procedure requires the
use of a greater than stoichiometric amount of CuCl and is
limited to propargylic alcohol derivatives. Hoshi synthesized
6
methods include the Pd-catalyzed coupling between a
(
7) For alkynylcopper, see: (a) Masuda, Y.; Murata, M.; Sato, K.;
(
1) (a) El-Jaber, N.; Estevez-Braun, A.; Ravelo, A. G.; Mu n˜ oz- Mu n˜ oz,
Watanabe, S. Chem. Commun. 1998, 807. For alkynylmagnesium, see: (b)
Dang, H. P.; Linstrumelle, G. Tetrahedron Lett. 1978, 191. For alkynyl-
silicon, see: (c) Hatanaka, Y.; Hiyama, T. J. Org. Chem. 1988, 53, 918.
For alkynyltin, see: (d) Siesel, D. A.; Staley, S. W. Tetrahedron Lett. 1993,
34, 3679. (e) Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 9,
2138. (f) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984,
106, 4630. For alkynylzinc, see: (g) Negishi, E. I.; Qian, M. X.; Zeng, F.
X.; Anastasia, L.; Babinski, D. Org. Lett. 2003, 5, 1597. (h) Stracker, E.
C.; Zweifel, G. Tetrahedron Lett. 1991, 32, 3329.
(8) For alkenylaluminum and alkenylzirconium, see: (a) Negishi, E.;
Okukado, N.; King, A. O.; Vanhorn, D. E.; Spiegel, B. I. J. Am. Chem.
Soc. 1978, 100, 2254. For alkenylboranes, see: (b) Miyaura, N.; Yamada,
K.; Suginome, H.; Suzuki, A. J. Am. Chem. Soc. 1985, 107, 972. For
alkenylcopper, see: (c) Stang, P. J.; Kitamura, T. J. Am. Chem. Soc. 1987,
109, 7561. (d) For alkenylmagnesium, see: (e) Ramiandrasoa, P.; Brehon,
B.; Thivet, A.; Alami, M.; Cahiez, G. Tetrahedron Lett. 1997, 38, 2447.
(9) For a critical comparison between the Sonogashira alkynylation and
the Pd-catalyzed cross-coupling of alkenyl halides and alkynylzincs see:
ref 7g and refs therein.
O.; Rodriguez-Afonso, A.; Murguia, J. R. J. Nat. Prod. 2003, 66, 722. (b)
Fontana, A.; d'Ippolito, G.; D’Souza, L.; Mollo, E.; Parameswaram, P. S.;
Cimino, G. J. Nat. Prod. 2001, 64, 131. (c) Rudi, A.; Schleyer, M.;
Kashman, Y. J. Nat. Prod. 2000, 63, 1434. (d) Spande, T. F.; Jain, P.;
Garraffo, H. M.; Pannell, L. K.; Yeh, H. J. C.; Daly, J. W.; Fukumoto, S.;
Imamura, K.; Tokuyama, T.; Torres, J. A.; Snelling, R. R.; Jones, T. H. J.
Nat. Prod. 1999, 62, 5.
(
(
2) Iverson, S. L.; Uetrecht, J. P. Chem. Res. Toxicol. 2001, 14, 175.
3) Zein, N.; Sinha, A. M.; McGahren, W. J.; Ellestad, G. A. Science
1
988, 240, 1198.
4) (a) Saito, S.; Yamamoto, Y. Chem. ReV. 2000, 100, 2901. (b)
Bergman, R. G. Acc. Chem. Res. 1973, 6, 25.
(
(
(
5) Zweifel, G.; Polston, N. L. J. Am. Chem. Soc. 1970, 92, 4068.
6) (a) Negishi, E.; Anastasia, L. Chem. ReV. 2003, 103, 1979 and
references therein. (b) Alami, M.; Crousse, B.; Ferri, F. J. Organomet. Chem.
2
001, 624, 114. (c) Sonogashira, K. ComprehensiVe Organic Chemsitry;
Pergamon Press: 1991; Vol. 3, pp 521-549. (d) Alami, M.; Linstrumelle,
G. Tetrahedron Lett. 1991, 32, 6109. (e) Nwokogu, G. C. J. Org. Chem.
1
985, 50, 3900. (f) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
(10) Marshall, J. A.; Chobanian, H. R.; Yanik, M. M. Org. Lett. 2001,
3, 4107.
Lett. 1975, 4467.
1
0.1021/ol049706e CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/01/2004

conjugated enynes through the coupling of alkenyldialky-
lboranes and (trimethylsilyl)ethynyl bromide using strong
bases such as NaOMe and LiOH and a catalytic amount of
Table 1. Comparison of Well-Defined Copper(I) Complexes,
Copper(I) Salts, and Additives as Catalysts for the
Cross-Coupling of Phenylacetylene and
11
2
Cu(acac) .
(Z)-Ethyl-3-iodoacrylatea
In recent years, there has been a resurgence in the
development of copper-based protocols for a variety of cross-
1
2-14
coupling reactions.
These newly developed protocols
have been shown to be mild and tolerate a wide variety of
functional groups and substrates. On the basis of these
precedences, we now report a Cu(I)-catalyzed cross-coupling
reaction of vinyl iodides and acetylenes for the synthesis of
catalyst
w ell-d efin ed com p lexes
[Cu(phen)(PPh3)2]NO3
GC yield
1
,3-enynes.15
To optimize the reaction protocol we chose the cross-
76%
74%
69%
51%
34%
21%
7%
[
[
[
[
[
[
Cu(bipy)PPh3Br]
Cu(phen)PPh3Br]
Cu(PPh3)3Br]
Cu(neocup)PPh3Br]
Cu(acac)(PPh3)2]
Cu(neocup)2Br]H2O
coupling of phenylacetylene and (Z)-ethyl-3-iodoacrylate as
the test reaction. We examined a variety of copper(I)
complexes, copper(I) salts, and copper(I) salts with certain
additives in toluene at 110 °C with 2.0 equiv of Cs
the base (Table 1). It was found that both [Cu(phen)(PPh
NO and [Cu(bipy)PPh Br] were effective at catalyzing the
reaction.
2
CO
3
as
3 2
) ]-
3
3
[Cu(CH CN) ]PF
3
4
6
4%
cop p er (I) sa lts
Using these two complexes as potential catalysts, we then
screened a variety of bases for the cross-coupling of
phenylacetylene and (Z)-ethyl-3-iodoacrylate in toluene at
CuCl
CuI or CuBr or Cu O
2%
0%
2
cop p er (I) sa lts/a d d itives
1
(
10 °C for 24 h. It was found that the optimal base for [Cu-
phen)(PPh ]NO remained to be Cs CO . This afforded
the desired product with a yield of 76% by GC. However,
with [Cu(bipy)PPh Br] as the catalyst and K CO as the base,
CuI/phen/PPh3 (1:1:2)
CuI/phen (1:1)
CuI/bipy (1:1)
53%
36%
16%
3
)
2
3
2
3
3
2
3
a
Reaction Conditions: 1.00 mmol phenyl acetylene, 1.00 mmol (Z)-
ethyl-3-iodoacrylate, 10 mol % Cu(I) catalyst, 2.0 equiv Cs2CO3, toluene,
10 °C, 24 h (phen ) 1,10-phenanthroline, bipy ) 2,2′-bipyridine, neocup
2,9-dimethyl-1,10-phenanthroline, acac ) acetylacetonate).
the yield was improved to 99%. Lowering the amount of
base to 1.5 equiv resulted in lower yields. Other bases such
as K PO , Na CO , KOtBu, NaOtBu, Et N, and DBU were
3 4 2 3 3
1
)
ineffective with this reaction. When this reaction was
monitored over a period of time, it was discovered that the
reaction was complete within 8 h. Lowering the catalytic
using 2.0 equiv of K
2 3
CO as the base decreased the yield to
51% in 24 h. When the reaction was run either in the absence
of catalyst or in the absence of base, the product was not
observed by GC. On the basis of the results of the
optimization and control experiments, we decided to use 10
loading of [Cu(bipy)PPh
3
Br] to 2.5 mol % for the cross-
coupling of phenylacetylene and (Z)-ethyl-3-iodoacrylate
(
11) Hoshi, M.; Shirakawa, K. Synlett 2002, 1101.
mol % [Cu(bipy)PPh
3
Br] as the catalyst and 2.0 equiv of
(12) (a) Van Allen, D.; Venkataraman, D. J. Org. Chem. 2003, 68, 4590.
K
2
CO as the base in toluene at 110 °C for the standard
3
(
b) Gujadhur, R. K.; Venkataraman, D. Tetrahedron Lett. 2003, 44, 81. (c)
Bates, C. G.; Gujadhur, R. K.; Venkataraman, D. Org. Lett. 2002, 4, 2803.
d) Bates, C. G.; Saejueng, P.; Murphy, J. M.; Venkataraman, D. Org. Lett.
002, 4, 4727. (e) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315. (f) Gujadhur, R.; Venkataraman, D.; Kintigh, J. T.
Tetrahedron Lett. 2001, 42, 4791. (g) Gujadhur, R.; Venkataraman, D. Synth.
Comm. 2001, 31, 2865.
protocol for synthesizing 1,3-enynes.
(
2
We first chose to examine the efficacy of coupling a
variety of acetylenes to (Z)-ethyl-3-iodoacrylate (Table 2).
It was found that a wide-range of aryl acetylenes could be
coupled in good to excellent yields with complete retention
of stereochemistry. This method tolerated both electron-rich
and electron-poor aryl acetylenes. Sterically hindered aryl
acetylenes (Table 2, entries 3 and 13) are also successfully
coupled in good to excellent yields. Notably, base-sensitive
functional groups such as methyl ketones (Table 2, entry
11) and methyl esters (Table 2, entries 12 and 13) are also
tolerated by this method. A free aniline group (Table 2, entry
(13) (a) Jiang, L.; Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett.
2
5
003, 5, 3667. (b) Gelman, D.; Jiang, L.; Buchwald, S. L. Org. Lett. 2003,
, 2315. (c) Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2003, 5, 793. (d)
Kwong, F. Y.; Buchwald, S. L. Org. Lett. 2002, 4, 3517. (e) Wolter, M.;
Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett. 2002, 4, 973. (f)
Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (g)
Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 7727. (h) Marcoux, J. F.; Doye, S.; Buchwald, S. L. J. Am.
Chem. Soc. 1997, 119, 10539.
(14) (a) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (b) Ley,
S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400. (c) Ma, D.
W.; Cai, Q.; Zhang, H. Org. Lett. 2003, 5, 2453. (d) Fagan, P. J.; Hauptman,
E.; Shapiro, R.; Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043. (e)
Kalinin, A. V.; Bower, J. F.; Riebel, P.; Snieckus, V. J. Org. Chem. 1999,
6), a terminal alkene (Table 2, entry 7), and a bromine (Table
2, entry 17) all proved to be compatible functional groups.
Heterocyclic acetylenes such as a pyridine moiety and a
thiophene (Table 2, entries 15 and 16, respectively) were
also compatible substrates with this protocol. However, for
6
(
2
4, 2986. (f) Goodbrand, H. B.; Hu, N. X. J. Org. Chem. 1999, 64, 670.
g) Zhang, S. J.; Zhang, D. W.; Liebeskind, L. S. J. Org. Chem. 1997, 62,
312.
15) We are aware of only one account of a copper(I)-catalyzed cross-
(
3
-ethynylpyridine, the use of [Cu(phen)(PPh
3 2 3
) ]NO as the
coupling of vinyl iodides and acetylenes. However, this method requires
the use of DMF or DMSO as the solvent at 120 °C. Furthermore, the scope
and limitations of this reaction have not been fully explored. See: Okuro,
K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993,
catalyst and Cs CO as the base was needed to obtain the
2
3
cross-coupled product in a moderate yield. The cross-
5
8, 4716.
coupling of n-octyne and (Z)-ethyl-3-iodoacrylate demon-
1442
Org. Lett., Vol. 6, No. 9, 2004

Table 2. Copper-Catalyzed Cross-Coupling of Various
Acetylenes with (Z)-Ethyl-3-iodoacrylate Using the Standard
Protocol
Table 3. Copper-Catalyzed Cross-Coupling of Phenylacetylene
with Various Vinyl Iodides Using the Standard Protocol
a
Reaction run for 24 h.
strated that this procedure was not specific to aryl acetylenes
(Table 2, entry 9).
We then chose to examine cross-coupling of phenyl
acetylene to a variety of vinyl iodides (Table 3). The standard
protocol worked well for a variety of â-(Z)-iodo-R,â-
unsaturated esters (Table 3). When (E)-ethyl-3-iodoacrylate
was used as the vinyl iodide, the reaction yield after 8 h
3
was only 55% when [Cu(bipy)PPh Br] was used as the
catalyst and K CO was used as the base. However, allowing
2
3
the reaction continue for 24 h improved the yield to 81%. A
similar observation was made when (E)-1-iodo-octene was
Table 4. Copper-Catalyzed Cross-Coupling of Phenylacetylene
with Various Vinyl Iodides Using 10 Mol %
3 2 3 2 3
[Cu(phen)(PPh ) ]NO as the Catalyst and Cs CO as the Base
a
Reaction run for 12 h. b [Cu(phen)(PPh3)2NO3] (10 mol %) as catalyst
c
and 2.0 equiv of Cs2CO3 used as base. Reaction run for 20 h.
a
GC yield. b Reaction run for 24 h.
Org. Lett., Vol. 6, No. 9, 2004
1443

used as the vinyl iodide (Table 3, entry 5). This reaction
also required 24 h to afford the desired product in excellent
yield.
For reactions that were difficult using our standard
protocol, we found that when the catalyst was changed to
the vinyl halide is an (E)-alkene, we recommend the use of
[Cu(phen)(PPh ]NO as the catalyst and Cs CO as the
3
)
2
3
2
3
base. Our protocol tolerates a wide-range of substrates and
functional groups affording the desired enynes in high yields.
The cross-coupled products retain the stereochemistry of the
starting vinyl iodides. Furthermore, this protocol is pal-
ladium-free, does not rely on the use of expensive and air-
sensitive additives, and eliminates the need for an organo-
metallic alkene or alkyne species.
3 2 3 2 3
[Cu(phen)(PPh ) ]NO and the base changed to Cs CO , the
yields were greatly improved (Table 4). We were now able
to successfully couple electron-rich vinyl iodides in excellent
yields. (E)-Ethyl-3-iodoacrylate can now be coupled to
phenyl acetylene with a near quantitative yield in 8 h (Table
Acknowledgment. D.V. gratefully acknowledges a Cam-
ille and Henry Dreyfus New Faculty Award and an NSF
CAREER Award (CHE-0134287). P.S. thanks the Royal
Thai Government for financial support. C.G.B. thanks Proctor
4
, entry 1). The cross-coupling of both (E)-1-iodo-octene
and (Z)-1-iodo-octene to phenyl acetylene (Table 4, entries
and 3, respectively) were complete in 8 h with retention
2
of stereochemistry. We did find that the use of a cyclic vinyl
iodide resulted in slightly lower yields and longer reaction
times (Table 4, entry 4).
In conclusion, we have developed a mild protocol for the
synthesis of 1,3-enynes via a copper(I)-catalyzed cross-
coupling reaction between an acetylene and a vinyl iodide.
For most substrates, we recommend the use of [Cu(bipy)-
&
Gamble for a graduate research fellowship.
Supporting Information Available: Synthetic procedures
and complete characterization data for entries in Tables 2-4.
This material is available free of charge via the Internet at
http://pubs.acs.org.
PPh
3
Br] as the catalyst and K
2
CO
3
as the base. In cases where
OL049706E
1444
Org. Lett., Vol. 6, No. 9, 2004