A strictly "pair"-selective synthesis of conjugated diynes via Pd-catalyzed cross coupling of 1,3-diynylzincs: A superior alternative to the Cadiot-Chodkiewicz reaction

Article abstract of DOI:10.1021/ol000270m

(matrix presented) A strictly "pair"-selective synthesis of conjugated diynes via Pd-catalyzed cross coupling of 1,3-diynylzincs is described. This method, like the Cadiot-Chodkiewicz reaction, requires three steps for the synthesis of R¹C≡CC≡CR² from R¹C≡CH, R²X, and HC≡CH. However, the high "pair"-selectivity permitting high-yield production of the desired conjugated diynes without separation of symmetrical diynes promises to make the present protocol superior to the Cadiot-Chodkiewicz reaction in many cases.

Full text of DOI:10.1021/ol000270m

ORGANIC
LETTERS
2000
Vol. 2, No. 23
3687-3689
A Strictly “Pair”-Selective Synthesis of
Conjugated Diynes via Pd-Catalyzed
Cross Coupling of 1,3-Diynylzincs: A
Superior Alternative to the
Cadiot−Chodkiewicz Reaction
Ei-ichi Negishi,* Mitsuhiro Hata, and Caiding Xu
Herbert C. Brown Laboratories, Purdue UniVersity, West Lafayette, Indiana 47907
negishi@purdue.edu
Received September 14, 2000
ABSTRACT
A strictly “pair”-selective synthesis of conjugated diynes via Pd-catalyzed cross coupling of 1,3-diynylzincs is described. This method, like the
1
2
1
2
Cadiot−Chodkiewicz reaction, requires three steps for the synthesis of R CtCCtCR from R CtCH, R X, and HCtCH. However, the high
“pair”-selectivity permitting high-yield production of the desired conjugated diynes without separation of symmetrical diynes promises to
make the present protocol superior to the Cadiot−Chodkiewicz reaction in many cases.
The Cadiot-Chodkiewicz reaction1,2 represents the current
benchmark for the synthesis of conjugated diynes. However,
it is known that the reaction is plagued with the formation
of one or both of the undesired homocoupling diynes, often
leading to low yields of the desired products and technical
difficulties associated with the delicate product separation.
We report herein a strictly “pair”-selective synthesis of
conjugated diynes containing one or two aryl, alkenyl, and/
or alkyl groups via Pd-catalyzed cross coupling of 1,3-
diynylzincs. Both the Cadiot-Chodkiewicz protocol and that
reported herein require three steps for the synthesis of R1Ct
CCtCR2 from one alkyne (R1CtCH), one organyl halide
or related electrophile (R2X), and ethyne (Scheme 1).
However, the high “pair”-selectivity permitting high-yield
production of the desired conjugated diynes without oft
Scheme 1
(1) (a) Chodkiewicz, W. Ann. Chim. Paris 1957, 2, 819. (b) Cadiot, P.;
Chodkiewicz, W. In Chemistry of Acetylenes; Viehe, H. G., Ed.; Marcel
Dekker: New York, 1969; pp 597-647. (c) Brandsma L.; Vasilevski, S.
F.; Verkruijsse, H. D. Application of Transition Metal Catalysts in Organic
Synthesis; Springer-Verlag: Berlin, Heidelberg, 1999; pp 49-105.
(2) For other syntheses of conjugated diynes via stoichiometric or
catalytic alkynyl-alkynyl coupling, see: (a) Sinclair, J. A.; Brown, H. C. J.
Org. Chem. 1976, 41, 1078. (b) Pelter, A.; Hughes, R.; Smith, K.; Tabata,
M. Tetrahedron Lett. 1976, 4385. (c) Zweifel, G.; Stracker, E. C.
Tetrahedron Lett. 1990, 31, 6815. (d) Wityak, J.; Chan, J. B. Synth.
Commun. 1991, 21, 977. (e) Cai, C.; Vasella, A. HelV. Chim. Acta 1995,
78, 2053. (f) Alami, M.; Ferri, F. Tetrahedron Lett. 1996, 37, 2763.
10.1021/ol000270m CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/24/2000

tedious separation of symmetrical diynes promises to make
the present protocol vastly superior to the Cadiot-Chod-
kiewicz reaction in many cases.
Scheme 3
We earlier reported a convenient and strictly “pair”-
selective synthesis of conjugated diynes with the use of (E)-
chloroiodoethylene.3,4 However, the feasibility of incorpo-
rating unsaturated organic groups, such as aryl and alkenyl,
via Pd-catalyzed cross coupling of 1,3-diynylmetals was not
investigated. We recently required such a method in the
synthesis of various natural products, such as xerulin5 and
found that the reaction of (E)-5-hepten-1,3-diynylzinc bro-
mide with (E)-bromoiodoethylene in the presence of 2 mol
% of Pd(PPh3)4 provided (1E,7E)-1-bromo-1,7-nonadiene-
3,5-diyne1 in 65% yield.6
The favorable results mentioned above prompted us to
further explore the scope of the conjugated diyne synthesis
based on the Pd-catalyzed cross coupling vis-a`-vis the
Cadiot-Chodkiewicz reaction.1 Typically, the reaction of
(E)-3-penten-1-yne (2) with 2-bromo-1-phenylethyne under
the Cadiot-Chodkiewicz conditions was reported to give (E)-
1-phenyl-5-heptene-1,3-diyne (3) in 30% yield after repeated
chromatography.7,8 In contrast, the reaction of (E)-5-hepten-
1,3-diynylzinc bromide, generated in situ by the treatment
of (1E,5E)-1-bromo-1,5-heptadien-3-yne (4) with LDA and
then ZnBr2, with iodobenzene in the presence of 2 mol %
of Pd(PPh3)4, cleanly produced 3 in 78% yield after simple
short-path chromatography (Scheme 2).
arylenyne derivatives (5) in excellent yields by the Pd-
catalyzed yne-ene coupling of the corresponding aryl-
ethynylzinc bromides with (E)-chloroiodoethylene. After in
situ generation of conjugated diynylzinc derivatives by
successive treatment of 5 with n-BuLi and ZnBr2, their Pd-
catalyzed cross-coupling with four p-substituted aryl iodides
containing Me, OMe, F, and NO2 in the p-position was
carried out by using 2 mol % of Pd(PPh3)4 as a catalyst. As
indicated by the results shown in Scheme 3, the yields of
the desired products were uniformly high (73-88%) regard-
less of the p-substituents in either organozinc reagents or
Scheme 2
(9) 1-Phenyl-1, 3-decadiyne. Representative Procedure Using (E)-
Chloroiodoethylene (Procedure A). (a) (E)-1-Chloro-1-decen-3-yne. To
a solution of 1-octyne (1.1 g, 10 mmol) in THF (15 mL) was added n-BuLi
(4.0 mL of a 2.5 M hexane solution, 10 mmol) at -78 °C. The reaction
mixture was stirred at -78 °C for 30 min and treated with a solution of
anhydrous ZnBr2 (3.0 g, 13 mmol) in THF (10 mL). (E)-Chloroiodoethylene
[Van de Walle, H.; Henne, A. Bull. Cl. Sci., Acad. R. Belg. 1925, 11, 360]
(1.9 g, 10 mmol) and Pd(PPh3)4 (231 mg, 2 mol %) were added to the
reaction mixture at 0 °C, which was then stirred at 25 °C for 1 h. The
reaction mixture was quenched with aqueous NH4Cl, extracted with ether,
dried over MgSO4, and concentrated. Purification by column chromatog-
raphy (silica gel, pentane) afforded 1.46 g (86%) of the title product
[Kodaira, K.; Okuhara, K. Bull. Chem. Soc. Jpn. 1988, 61, 1625] as a
colorless liquid. (b) Conversion of (E)-1-Chloro-1-decen-3-yne into
1-Phenyl-1,3-decadiyne. To a solution of (E)-1-chloro-1-decen-3-yne (171
mg, 1.0 mmol) in THF (3 mL) was added n-BuLi (0.8 mL of a 2.5 M
hexane solution, 2.0 mmol) at -78 °C. The reaction mixture was stirred
first at -78 °C for 30 min and then at -30 °C for 30 min and treated with
anhydrous ZnBr2 (270 mg, 1.2 mmol) in THF (1 mL). Iodobenzene (204
mg, 1.0 mmol) and Pd(PPh3)4 (23 mg, 2 mol %) were added to the reaction
mixture at 0 °C. After 3 h of stirring at 25 °C, analysis of the reaction
mixture indicated the formation of the title compound in 93% yield. The
reaction mixture was quenched with aqueous NH4Cl, extracted with ether,
dried over MgSO4, and concentrated. Purification by column chromatog-
raphy (silica gel, pentane) afforded 152 mg (72%) of the title product
[Ziegler, C. B.; Harris, S. M.; Baldwin, J. E. J. Org. Chem. 1987, 52, 443].
Representative Procedure Using (E)-Bromoiodoethylene (Procedure B).
(a) (E)-1-Bromo-1-decen-3-yne. This compound [Andreini, B. P.; Benetti,
M.; Carpita, A.; Rossi, R. Tetrahedron 1987, 43, 4591] was obtained in
74% yield in a manner similar to the preparation of (E)-1-chloro-1-decen-
3-yne except that (E)-bromoiodoethylene was used. (b) Conversion of (E)-
1-Bromo-1-decen-3-yne into 1-Phenyl-1,3-decadiyne. To a solution of
(E)-1-bromo-1-decen-3-yne (215 mg, 1.0 mmol) in THF (3 mL) was added
LDA (1.1 mL of a 2.0 M heptane/ethylbenzene solution, 2.2 mmol) at -78
°C. The reaction mixture was stirred at -78 °C for 30 min, treated with
anhydrous ZnBr2 (270 mg, 1.2 mmol) in THF (1 mL), and warmed to 0
°C. The reaction of 1,3-decadiynylzinc bromide thus generated with
iodobenzene (1.0 mmol) was performed as described in Procedure A to
give 189 mg (90%) of the title compound.
To see if the vastly different product yields observed with
the two protocols shown in Scheme 2 represent a general
trend or an exception, three p-substituted arylethynes con-
taining Me, F, and CF3 in the p-position were converted to
(3) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem.
1984, 49, 2629.
(4) For a subsequent related study, see: Kende, A. S.; Smith, C. A. J.
Org. Chem. 1988, 53, 2655.
(5) Kuhnt, D.; Anke, T.; Besl, H.; Bross, M.; Herrmann, R.; Mocek, U.;
Steffan, B.; Steglich, W. J. Antibiot. 1990, 43, 1413.
(6) Negishi, E.; Alimardanov, A.; Xu, C. Org. Lett. 2000, 2, 65.
(7) Fairbrother, J. R. F.; Jones, E. R. H.; Thaller, V. J. Chem. Soc. C
1967, 1035.
(8) Although no information about the two possible symmetrical diynes
was given in the paper, the results and the experimental description suggest
their formation to significant extents.
3688
Org. Lett., Vol. 2, No. 23, 2000

convenient procedure (procedure A), but bromoiodoethylene
used in conjunction with LDA as a base (procedure B) is
also satisfactory. It appears that a wide variety of carbon
groups can be the substituents in haloenynes, although only
some alkyl, aryl, and alkenyl groups are used in this study.
(E)-1-Chloro-1-decen-3-yne and its bromo analogue were
prepared in 86% and 74% yields from 1-octyne by using
chloroiodoethylene and bromoiodoethylene, respectively. In
each structure shown in Scheme 4, the substituent on the
right is introduced last as part of a halide. In cases where an
organic bromide is used, it is indicated by Br in parentheses,
and A and B represent procedures A and B, respectively.
The apparent general applicability, the uniformly high
product yields, and the strict “pair”-selectivity discussed
above appear to be totally unprecedented in the synthesis of
conjugated diynes containing two aryl and/or alkenyl groups,10
and these favorable features combine to make the present
method a superior alternative to the Cadiot-Chodkiewicz1
and other related reactions2,10 in many cases.
Scheme 4
aryl iodides. Equally important is the essential absence of
any byproducts that might interfere with isolation of the
products as pure compounds.
Acknowledgment. We thank the National Institutes of
Health (GM 36792) and Purdue University for support of
this research. Palladium compounds are kindly supplied by
Johnson-Matthey.
Under the Cadiot-Chodkiewicz conditions employing
CuCl (0.1 equiv), NH2OH‚HCl (0.8 equiv), PrNH2 (1.8
equiv), and EtOH, the yields of 6a-c obtained by the
reaction of R1-containing arylethynes with R2-containing
arylethynyl bromides were 34% (6a, R1 ) F, R2 ) OMe),
34% (6b, R1 ) Me, R2 ) F), 48% (6b, R1 ) F, R2 ) Me),
and 38% (6c, R1 ) CF3, R2 ) F). In each case, at least one
of the two symmetrical diynes was formed in the range of
(20 ( 5)%.
The generality and uniform dependability of the protocol
reported herein are further reinforced by the additional results
shown in Scheme 4.9 In most cases, the use of chloroiodo-
ethylene and n-BuLi (as a base) may be recommended as a
Supporting Information Available: Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL000270M
(10) For other syntheses of conjugated diynes via 1,3-diynes and their
derivatives, see: (a) Adams, S.; Potts, K. T. Synthesis 1988, 375. (b) De
Graaf, W.; Smits, A.; Boersma, J.; Van Koten, G.; Hoekstra, W. P. M.
Tetrahedron 1988, 44, 6699. (c) Lo¨ffler, A.; Himbert, G. Synthesis 1991,
232. (d) Alami, M.; Crousse, B.; Linstrumelle, G. Tetrahedron Lett. 1995,
36, 3687.
Org. Lett., Vol. 2, No. 23, 2000
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