Highly satisfactory alkynylation of alkenyl halides via Pd-catalyzed cross-coupling with alkynylzincs and its critical comparison with the sonogashira alkynylation

Article abstract of DOI:10.1021/ol030010f

(Matrix presented) The Pd-catalyzed alkynylation of various alkenyl halides and triflates with alkynylzincs proceeds well even with alkynyl derivatives containing electron-withdrawing groups. The reaction appears to be highly general. Noteworthy is that the corresponding Sonogashira reactions under various reported conditions are significantly less satisfactory in all cases performed in this study.

Full text of DOI:10.1021/ol030010f

ORGANIC
LETTERS
2003
Vol. 5, No. 10
1597-1600
Highly Satisfactory Alkynylation of
Alkenyl Halides via Pd-Catalyzed
Cross-Coupling with Alkynylzincs and
Its Critical Comparison with the
Sonogashira Alkynylation†
Ei-ichi Negishi,* Mingxing Qian, Fanxing Zeng, Luigi Anastasia, and
David Babinski
Herbert C. Brown Laboratories of Chemistry, Purdue UniVesity,
West Lafayette, Indiana 47907
negishi@purdue.edu
Received January 23, 2003
ABSTRACT
The Pd-catalyzed alkynylation of various alkenyl halides and triflates with alkynylzincs proceeds well even with alkynyl derivatives containing
electron-withdrawing groups. The reaction appears to be highly general. Noteworthy is that the corresponding Sonogashira reactions under
various reported conditions are significantly less satisfactory in all cases performed in this study.
Over the last quarter of a century, Pd-catalyzed alkynylation1
has emerged as a highly satisfactory method for the synthesis
of alkynes. It has been mainly performed either by Heck-
type reactions1a,2 with terminal alkynes, especially the
Sonogashira alkynylation cocatalyzed by Pd and Cu,1a,2b-e
or with preformed alkynylmetals,1b especially with those
containing Zn,3-6 Mg,3d,4,7 Sn,4,8 and B4,9 reported first by
the authors’ group.3a,4 Despite the fact that the Sonogashira
alkynylation has been the more frequently used of the two,
it has also become increasingly clear that this reaction fails
partially or totally in a large number of cases. Specifically,
it fails to produce terminal alkynes directly in useful yields
due to competitive disubstitution of ethyne.2,5c,d The use of
(3) For earlier contributions by the authors, see: (a) King, A. O.;
Okukado, N.; Negishi, E. J. Chem. Soc., Chem. Commun. 1977, 683. (b)
King A. O.; Negishi, E.; Villani, F. J., Jr.; Silveira, A., Jr. J. Org. Chem.
1978, 43, 358. (c) Negishi, E.; Bagheri, V.; Chatterjee, S.; Luo, F. T.; Miller,
J. A.; Stoll, A. T. Tetrahedron Lett. 1983, 24, 5181. (d) Negishi, E.;
Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem. 1984, 49, 2629.
(4) Negishi, E. In Aspects of Mechanism and Organometallic Chemistry;
Brewster, J. H., Ed.; Plenum Press: New York, 1978; pp 285-317. See
also: Negishi, E. Acc. Chem. Res. 1982, 15, 340.
(5) For recent papers by the authors, see: (a) Negishi, E.; Ay, M.;
Gulevich, Y. V.; Noda, Y. Tetrahedron Lett. 1993, 34, 1437. (b) Kotora,
M.; Negishi, E. Synthesis 1997, 121. (c) Negishi, E.; Xu, C.; Tan, Z.; Kotora,
M. Heterocycles 1997, 46, 209. (d) Kotora, M.; Xu, C.; Negishi, E. J. Org.
Chem. 1997, 62, 8957. (e) Negishi, E.; Alimardanov, A.; Xu, C. Org. Lett.
2000, 2, 65. (f) Negishi, E.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687. (g)
Negishi, E.; Tan Z.; Liou, S. Y.; Liao, B. Tetrahedron 2000, 56, 10197.
(h) Zeng, F.; Negishi, E. Org Lett. 2001, 3, 719. (i) Anastasia, L.; Negishi,
E. Org. Lett. 2001, 3, 3111.
† Dedicated to Prof. Marcial Moreno-Man˜as on the occasion of his 60th
birthday.
(1) For recent reviews, see: (a) Sonogashira, K. In Handbook of
Organopalladium Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-
Interscience: New York, 2002; pp 493-529. (b) Negishi, E.; Xu, C. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley-Interscience: New York, 2002; pp 531-549.
(2) (a) Dieck, H. A.; Heck, F. R. J. Organomet. Chem. 1975, 93, 259.
(b) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 4467.
(c) Sonogashira, K.; Yatake, T.; Tohda, Y.; Takahashi, S.; Hagihara, N. J.
Chem Soc., Chem. Commun. 1977, 291. (d) Tohda, Y.; Sonogashira, K.;
Hagihara, N. Synthesis 1977, 777. (e) Takahashi, S.; Kuroyama, Y.;
Sonogashira, K.; Hagihara, N. Synthesis 1980, 627.
10.1021/ol030010f CCC: $25.00 © 2003 American Chemical Society
Published on Web 04/22/2003

alkynes containing electron-withdrawing substituents has
been problematic.10 There have also been indications that
its scope appears to be more limited than that of the
alkynylation with preformed alkynylzincs in cases where
steric hindrance is significant.11 Two frequently encountered
side reactions in the Sonogashira alkynylation are alkyne
homodimerization and Michael-type addition reactions. On
the other hand, neither has been serious with preformed
alkynylzincs and related alkynylmetals.
Scheme 1
Herein reported are some synthetically useful results of
Pd-catalyzed alkynylation of alkenyl halides with alkynyl-
zincs that do not appear to be readily achieved by the
Sonogashira alkynylation. In conjunction with our recent
efforts to synthesize some natural products containing enynes,
it became desirable to develop an efficient and selective route
to a class of enynes represented by 1-3. The trienyne 3, for
example, may be envisioned as a potentially attractive
intermediate for the synthesis of stipiamide (4),12a,b 6,7-
dehydrostipiamide (5),12a,b and myxalamide (6).12c As desired,
1-3 were prepared in high yields by applying the Pd-
catalyzed alkynylation method reported recently by us for
the synthesis of alkynylated arenes5i (Scheme 1).13 In none
of the steps shown in Scheme 1 was the formation of any
stereoisomers detected by 1H and/or 13C NMR spectroscopy,
(6) For some other earlier contributions by others, see: (a) Vincent, P.;
Beaucount, J. P.; Pichat, L. Tetrahedron Lett. 1981, 22, 945. (b) Ruitenberg,
K.; Kleijn, H.; Westmijze, H.; Meijer, J.; Vermeer, P. Recl. TraV. Chim.
Pays-Bas 1982, 101, 405. (c) Andreini, B. P.; Carpita, A.; Rossi, R.
Tetrahedron Lett. 1986, 27, 5533; 1988, 29, 2239. (d) Tellier, F.; Sauveˆtre,
R; Normant, J. F. Tetrahedron Lett. 1986, 27, 3147. (e) Chen, Q. Y.; He,
Y. B. Tetrahedron Lett. 1987, 28, 2387.
(7) For other early contributions, see: (a) Dang, H. P.; Linstrumelle, G.
Tetrahedron Lett. 1978, 191. (b) Rossi, R.; Carpita, A.; Lezzi, A.
Tetrahedron 1984, 40, 2773.
(8) For early contributions, see: (a) Kashin, A. N.; Bumagina, I. G.;
Bumagin, N. A.; Beletskaya, I. P.; Reutov O. A. IzV. Akad. Nauk SSSR,
Ser. Khim. 1980, 479. (b) Scott, W. J.; Crisp, G. T.; Stille, J. K. J. Am.
Chem. Soc. 1984, 106, 4630. (c) Stille, J. K.; Simpson, J. H. J. Am. Chem.
Soc. 1987, 109, 2138.
(9) For other recent contributions, see: (a) Soderquist, J. A.; Matos, K.;
Rane, A. M.; Ramos, J. Tetrahedron Lett. 1995, 36, 2401. (b) Soderquist,
J. A.; Rane, A. M.; Matos, K.; Ramos, J. Tetrahedron Lett. 1995, 36, 6847.
(c) Fu¨rstner, A.; Seidel, G. Tetrahedron 1995, 51, 11165. (d) Fu¨rstner, A.;
Nikolakis, K. Liebigs Ann. Chem. 1996, 2107.
(10) See ref 5i and other pertinent papers cited therein.
(11) See, for example: Sonoda, M.; Inaba, A.; Itahashi, K.; Tobe, Y.
Org. Lett. 2001, 3, 2419.
(12) (a) Andrus, M. B.; Lepore, S. D.; Turner, T. M. J. Am Chem. Soc.
1997, 119, 12159. (b) Andrus, M. B.; Lepore, S. D. J. Am. Chem. Soc.
1997, 119, 2327. (c) Mapp, K.; Heathcock, C. H. J. Org. Chem. 1999, 64,
23.
(13) Ethyl (E,E)-2-Methyl-7-bromo-2,6-heptadien-4-ynoate (2). Rep-
resentative Procedure. To a solution of commercially available ethynyl-
magnesium bromide (0.5 M in THF, 4 mL, 2.0 mmol) was added a solution
of anhydrous ZnBr2 (450 mg, 2.0 mmol) in THF (2 mL) via cannula at 0
°C. The mixture was stirred at 0 °C for 30 min and added via cannula to
a solution of ethyl (E)-3-bromo-2-methyl-2-propenoate (386 mg, 2.0 mmol)
and Pd(PPh3)4 (116 mg, 0.1 mmol) in THF (2 mL). The reaction mixture
was stirred at 23 °C for 1 h, quenched with aqueous NH4Cl, extracted with
ether, washed with aqueous NaHCO3 and then with brine, dried over
MgSO4, filtered, and concentrated. Chromatography on silica gel (pentane/
EtOAc ) 95/5, v/v) gave 246 mg (89%) of ethyl (E)-2-methyl-2-penten-
4-ynoate. To a solution of this compound (138 mg, 1.0 mmol) in THF (1
mL) were successively added at -78 °C via cannula LDA (1.0 mmol) in
THF (3 mL) and a solution of anhydrous ZnBr2 (225 mg, 1.0 mmol) in
THF (1 mL). The mixture was stirred at 0 °C for 30 min and added via
cannula to a solution of (E)-1-iodo-2-bromoethylene (280 mg, 1.2 mmol)
and Pd(PPh3)4 (58 mg, 0.05 mmol) in THF (2 mL). After being stirred at
23 °C for 4 h, the mixture was quenched with aqueous NH4Cl, extracted
with ether, washed with aqueous NaHCO3 and then with brine, dried over
MgSO4, filtered, and concentrated. Chromatography on silica gel (pentane/
EtOAc ) 95/5, v/v) gave 209 mg (86%) of 2.
and the overall stereoisomeric purity may be claimed to be
g98-99%.14 The three-step synthesis of the C1-C9 moiety
(3) of 6,7-dehydrostipiamide (5) in 74% overall yield and
g98% isomeric purity from (E)-1-iodo-2-bromoethylene,
(E)-1-bromo-4-trimethylsilyl-1-buten-3-yne, and ethyl (E)-
3-bromo-2-methyl-2-propenoate is noteworthy.
In view of highly contrasting results observed in the Pd-
catalyzed alkynylation with alkynylzincs on one hand and
(14) For determination of stereoisomeric purities by 13C NMR, see: Zeng,
F.; Negishi, E. Org. Lett. 2002, 4, 703.
1598
Org. Lett., Vol. 5, No. 10, 2003

in the Sonogashira alkynylation on the other (vide supra),
the preparation of 1 and 2 by the Sonogashira alkynylation
was also attempted. However, these compounds were not
obtained in more than 28% yield, typical yield being less
than a few percent under various conditions reported15 for
the Sonogashira alkynylation. Thus, the reaction of (E)-1-
iodo-2-bromoethylene with ethyl propynoate in the presence
of Pd(PPh3)4 and CuI in Et2NH2b-e led to the formation of
ethyl (E)-3-diethylamino-2-propenoate in 92% yield. In the
reaction of (E)-1-iodo-2-bromoethylene with ethyl (E)-2-
methyl-2-penten-4-ynoate under various Sonogashira alkyn-
ylation conditions, the major product was always the
homodimer of the ethyl (E)-2-methyl-2-peten-4-ynoate, as
indicated by the results summarized in Table 1. Under the
23 °C led to the formation of 1,4-diphenyl-1,3-butadiyne in
50% yield without producing the desired product in detect-
able yield.
The scope of the Pd-catalyzed alkynylation of alkenyl
electrophiles with alkynylzincs appears to be very broad, and
the reaction is satisfactory even in those cases where the
Sonogashira alkynylation is problematic, as can be gleaned
from the results summarized in Table 2. No stereoisomer-
Table 2. Pd-Catalyzed Alkynylation of Alkenyl Halides and
Triflates as Well as Heteroaryl and Alkynyl Iodides:
Comparison of the Alkynylzinc Reaction and the Sonogashira
Reactiona
Table 1. Pd-Catalyzed Reaction of (E)-1-Iodo-2-bromoethylene
with Ethyl (E)-2-Methyl-2-penten-4-ynoate
homo-
temp, time,
2,
dimer,
a
a
base
solvent
catalyst
°C
h
%
%
Et2NH
Et2NH Pd(PPH3)4
23
23
23
65
23
23
23
5
16
41
72
d
d
d
Et2NHb
THF
THF
THF
DMF
Pd(PPH3)4
5
15
5
5
2
trace
trace
trace
trace
trace
28
c
K2CO3
K2CO3
K2CO3
piperidinee THF
PdCl2(PPH3)2
PdCl2(PPH3)2
PdCl2(PPH3)2
PdCl2(PPH3)2
Pd(PPH3)4
c
d
57
f
Cs2CO3
THF
8
a By GLC. b 3 molar equiv of Et2NH used. c Reference 15a. d The exact
amount was not determined, but it was substantial. 1 mol % of BHT added
as an antioxidant. e Reference 15b. f Reference 15c.
most favorable conditions involving the use of Pd(PPh3)4
and Cs2CO3 in THF,15c the yield of 2 was only 28%, the
major product being the alkyne homodimer accounting for
57% of ethyl (E)-3-bromo-2-methyl-2-propenoate even in
the presence of 2,6-di(tert-butyl)phenol used as an antioxi-
dant. In some cases, dialkynylation of (E)-1-iodo-2-bromo-
ethylene was also observed to the extent of e5-10%.
It should be noted that the difficulties associated with the
synthesis of 1-3 by the Sonogashira alkynylation appear to
be at least 2-fold. In addition to the previously noted
difficulties associated with the use of alkynes containing
electron-withdrawing substituents,5i the use of (E)-1-iodo-
2-bromoethylene in the Sonogashira alkynylation must be
problematic. Indeed, the reaction of phenylethyne with 1.1
molar equiv of (E)-1-iodo-2-bromoethylene in the presence
of 5 mol % of Pd(PPh3)4 and 10 mol % of CuI in Et2NH at
a Unless otherwise indicated, the alkynylzinc reactions were run in THF
in the presence of 3 mol % of Pd(PPh3)4 at 23 °C with alkynylzinc bromides
generated in situ by treatment of alkynes with LDA followed by addition
of dry ZnBr2. The Sonogashira alkynylation was run by using 3 mol % of
Cl2Pd(PPh3)2, 6 mol % of CuI, and 2 equiv of K2CO3 in THF under reflux.
The alkyne-to-alkenyl electrophile ratio was typically 1.2. b Isolated yield.
All stereodefined products are g98% stereoisomerically pure. c The yield
observed with 3% Cl2Pd(PPh3)2, 6% CuI, and Et2NH was <1%. d The yield
observed with 3% Cl2Pd(PPh3)2, 6% CuI, and Et3N was <1%. e Not
performed. f Cs2CO3 (2.0 equiv) was used in place of K2CO3. g A yield of
52% was observed with 2 equiv of the alkyne.
(15) (a) Eckert, T.; Ipaktschi, J. Synth. Commun. 1998, 28, 327. (b) Alami,
M.; Linstrumelle, G. Tetrahedron Lett. 1991, 32, 6109. (c) Yang, C.; Nolan,
S. P. Organometallics 2002, 21, 1020.
ization was detected in any of the reactions with potentially
isomerizable alkenyl iodides (entries 1-7 and 10), including
Org. Lett., Vol. 5, No. 10, 2003
1599

(Z)-1-iodo-1-hexene (entry 4). A few examples of the use
of heteroaryl and alkynyl halides are also included in Table
2. It should be noted that, in the reaction of iodopyrazine
with ethyl 3-bromozincopropynoate, the use of LDA to
generate the alkynylzinc reagent led to the formation of 7 in
68% yield along with the desired product 8 obtained only in
15% yield. On the other hand, a recently developed
procedure5i involving in situ generation of the alkynylzinc
reagent by using ZnBr2 (1.2 equiv) and Et3N (4.8 equiv) led
to clean formation of 8 in 82% yield (Scheme 2). The
coupling reactions, the “pair”-selectivity must be strongly
substrate dependent.16
With the use of (E)-1-iodo-2-bromoethylene as a two-
carbon synthon, a clean tandem dialkynylation can be
performed in one pot to produce (E)-3-ene-1,5-diynes in
excellent yields without the use of any reagent in excess, as
indicated by the results shown in Scheme 3.
Scheme 3
Scheme 2
Efforts are currently being made to apply new findings in
the Pd-catalyzed alkynylation reported herein to the synthesis
of stereodefined complex natural products and related
compounds.
Acknowledgment. We thank the National Science Foun-
dation (CHE-0080795), the National Institutes of Health (GM
36792), and Purdue University for support of this research.
Supporting Information Available: Experimental details
of representative reactions as well as spectral and analytical
data of isolated products including 1H and 13C NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
corresponding Sonogashira reaction with 1.5 equiv of the
alkyne provided 8 in 37% yield, which was elevated to 52%
by the use of 2 equiv of the alkyne. The Pd-catalyzed reaction
of 1-iodo-1-octyne with 3-bromozincopropynoate led to clean
formation of the desired diyne in 86% yield. However, the
corresponding reaction of 1-bromozinco-1-octyne with ethyl
3-iodo-2-propynoate gave a mixture of the same diyne (45%)
and the two symmetrically substituted diynes formed in 29%
and 15% yield. Thus, as in most of the other alkynyl-alkynyl
OL030010F
(16) For strictly “pair”-selective syntheses of conjugated diynes, see: (a)
Reference 3d. (b) Kende, A. S.; Smith, C. A. J. Org. Chem. 1988, 53, 2655.
(c) Reference 5e. (d) Reference 5f. (e) Qian, M.; Negishi, E. Org. Process
Res. DeV. In press. (f) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37,
2763. (g) Nishihara, Y.; Ikegashira, K.; Mori, A.; Hiyama, T. Tetrahedron
Lett. 1998, 39, 4075.
1600
Org. Lett., Vol. 5, No. 10, 2003