Highly efficient and selective synthesis of conjugated triynes and higher oligoynes of biological and materials chemical interest via palladium-catalyzed alkynyl-alkenyl coupling

Article abstract of DOI:10.1021/ol0623825

(Diagram presented) Iteration of a Pd-catalyzed reaction of alkynyl- and oligoynylzincs with (E)-ICH=CHCl followed by metalation-termination with electrophiles(E) has provided a linear route to conjugated tri- and tetraynes, and Pd-catalyzed monoalkynylation of 1,1-dibromoenynes accompanied by dehydrobromination has provided a convergent route to conjugated tri-, tetra-, and pentaynes. Both display unprecedented high efficiency and selectivity.

Full text of DOI:10.1021/ol0623825

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5773-5776
Highly Efficient and Selective Synthesis
of Conjugated Triynes and Higher
Oligoynes of Biological and Materials
Chemical Interest via
Palladium-Catalyzed Alkynyl
−Alkenyl
Coupling†
Estelle Me´tay, Qian Hu, and Ei-ichi Negishi*
Herbert C. Brown Laboratories of Chemistry, Purdue UniVersity, 560 OVal DriVe,
West Lafayette, Indiana 47907-2084
negishi@purdue.edu
Received September 27, 2006
ABSTRACT
Iteration of a Pd-catalyzed reaction of alkynyl- and oligoynylzincs with (E)-ICH
d
CHCl followed by metalation−termination with electrophiles(E)
has provided a linear route to conjugated tri- and tetraynes, and Pd-catalyzed monoalkynylation of 1,1-dibromoenynes accompanied by
dehydrobromination has provided a convergent route to conjugated tri- , tetra- , and pentaynes. Both display unprecedented high efficiency
and selectivity.
A large number of naturally occurring conjugated diynes and
oligoynes exhibiting antibacterial, antifungal, antiinflamma-
tory, antiangiogenic, antimicrobial, cytotoxic, larvicidal, and
other biological activities are known.1 Additionally, a grow-
ing number of nonnatural oligo- and polyynes of optical,
electrical, and other materials as well as structural chemical
interest have been prepared and investigated.2 The parent
polyynes of high degrees of polymerization represent the
hypothetical sp carbon allotrope “carbyne” of considerable
current interest.2b,3
Although various Cu-mediated4 and Pd-catalyzed5,6 meth-
ods for the synthesis of unsymmetrically substituted conju-
gated diynes via alkynyl-alkynyl coupling are known, the
(2) See, for example: (a) Ye, F.; Orita, A.; Yaruva, J.; Hamada, T.; Otera,
J. Chem. Lett. 2004, 33, 528. (b) Gibtner, T.; Hampel, F.; Grisselbrecht,
J.-P.; Hirsch, A. Chem. Eur. J. 2002, 8, 408.
(3) For a recent paper reporting on an explosion of conjugated polyynes,
see: Baughman, R. H. Science 2006, 312, 1009.
† Warning! Upon concentration and exposure to air, 1-trimethylsilyl-
1,3,5,7-nonatetrayne spontaneously ignited in a manner of fireworks.
Although the exact nature of the phenomenon remains unclear, it is advisable
to exercise appropriate precautions in handling conjugated oligoynes.3.
(1) For reviews, see: (a) Bohlmann, F.; Burkhardt, H.; Zdero, C.
Naturally Occurring Acetylenes; Academic Press: New York, 1973; pp
547. (b) Shi Shun, A. L. K.; Tykwinski, R. R. Angew. Chem., Int. Ed. 2006,
45, 1043.
(4) (a) Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe,
H. G., Ed.; Marcel Dekker: New York, 1969; pp 597-647. (b) Brandsma,
L.; Vasilevski, S. F.; Verkruijsse, H. D. Application of Transition Metal
Catalysis in Organic Synthesis; Springer-Verlag: Berlin, 1999; pp 49-
105.
(5) For a recent review summarizing the reported results of the
Pd-catalyzed alkynyl-alkynyl coupling reactions, see: Negishi, E.; Anas-
tasia, L. Chem. ReV. 2003, 103, 1979.
10.1021/ol0623825 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/15/2006

Scheme 1
available data indicate that none appear to be widely and
and alkynyl-alkynyl coupling. It is clearly desirable to
develop protocols requiring just one step for each homolo-
gation or even less, i.e., homologation by two or more
ethynyl units in one step.
predictably satisfactory, the major side reaction being
competitive formation of the two homodimers derivable from
the two starting alkynes presumably via alkynyl ligand
scrambling. For example, we recently reported a highly cross-
selective reaction of BrZnCtCCO2Me with nHexCtCI
We report herein a highly efficient and strictly “pair-
selective”11 linear iterative protocol for the synthesis of con-
jugated tri- and tetraynes (Schemes 1 and 2). Also reported
are some results for the development of a complementary
convergent protocol for the synthesis of tri- and higher
oligoynes (Schemes 3 and 4) through application of a strictly
pair-selective Pd-catalyzed alkynyl-alkenyl coupling.
Since 1984, we have reported a series of pair-selective
syntheses of conjugated diynes via Pd-catalyzed alkynyl-
alkenyl coupling reactions12-15 with (E)-1-iodo-2-chloro-
ethylene,12,13 (E)-1-iodo-2-bromoethylene,13 and vinylidene
dichloride.14 However, their applicability to the synthesis
of higher oligoynes has not been investigated. In the
initial search for a highly favorable ethynyl synthon, con-
version of PhCtCH to PhCtCCtCMe was performed
with (E)-ICHdCHCl,12,16 (E)-ICHdCHBr,13,17 Cl2CdCH2
($6.6/mol, Aldrich), and ClCHdCCl2 ($1.2/mol, Aldrich) as
ethynyl synthons. The yields of PhCtCCtCMe were 84,
76, 72, and 55%, respectively. Despite the lower product
n
producing HexCtCCtCCO2Me in 86% yield7 but still
failed to develop it into a predictably general and satisfactory
route to conjugated diynes. An ingenious application of the
Fritsch-Buttenberg-Wiechell rearrangement8 by Tykwinski
et al.1b,9 provides an alternative convergent route to conju-
gated oligoynes. However, application of these basically
convergent protocols to the synthesis of tetra- and higher
conjugated oligoynes requires one or two shorter oligoynyl
intermediates. In this context, a recent modification of the
Cadiot-Chodkiewicz reaction permitting its iterative use by
Kim et al.10 is noteworthy, but each homologation cycle
requires two steps, namely, halogenation of alkynylsilanes
(6) For papers reporting the use of Sonogashira alkynyl-aklynyl
coupling, see: (a) Wityak, J.; Chan, J. B. Synth. Commun. 1991, 21, 977.
(b) Alzeer, J.; Vasella, A. HelV. Chim. Acta 1995, 78, 177. (c) Amatore,
C.; Blart, E.; Geneˆt, J. P.; Jutand, A.; Lemaire-Audoire, S.; Savignac, M.
J. Org. Chem. 1995, 60, 6829. (d) Alami, M.; Ferri, F. Tetrahedron Lett.
1996, 37, 2763.
(7) Negishi, E.; Qian, M.; Zeng, F.; Anastasia, L.; Babinski, D. Org.
Lett. 2003, 5, 1597.
(8) (a) Fritsch, P. Liebigs Ann. Chem. 1894, 279, 319. (b) Buttenberg,
W. P. Liebigs Ann. Chem. 1894, 279, 327. (c) Wiechell, H. Liebigs Ann.
Chem. 1894, 279, 332.
(9) (a) Eisler, S.; Tykwinski, R. R. J. Am. Chem. Soc. 2000, 122, 10737.
(b) Shi Shun, A. L. K.; Tykwinski, R. R. J. Org. Chem. 2003, 68, 6810. (c)
Luu, T.; Shi, W.; Lowary, T. L.; Tykwinski, R. R. Synthesis 2005, 3167.
(d) For an application of the Tykwinski protocol to the synthesis of
(-)-ichthyothereol, see: Mukai, C.; Miyakoshi, N.; Hanaoka, M. J. Org.
Chem. 2001, 66, 5875.
(11) In place of “pair-selective”, a Greek-derived term “couploselective”
may be used along with “stereoselective”, “regioselective”, and so on.
(12) Negishi, E.; Okukado, N.; Lovich, S. F.; Luo, F. T. J. Org. Chem.
1984, 49, 2629. See also: Kende, A. S.; Smith, C. A. J. Org. Chem. 1988,
53, 2655.
(13) Negishi, E.; Hata, M.; Xu, C. Org. Lett. 2000, 2, 3687.
(14) Qian, M.; Negishi, E. Org. Process Res. DeV. 2003, 1, 412.
(15) For a recent review, see: Negishi, E.; Hu, Q.; Huang, Z.; Qian,
M.; Wang, G. Aldrichimica Acta 2005, 38, 71. See also ref 5.
(16) (a) Van de Walle, H.; Henne, A. Bull. Clin. Sci., Acad. R. Belg.
1925, 11, 360 [Chem. Abstr. 1926, 20, 1050]. (b) For a detailed procedure,
see ref 12.
(10) Kim, S.; Kim, S.; Lee, T.; Ko, H.; Kim, D. Org. Lett. 2004, 6,
3601.
5774
Org. Lett., Vol. 8, No. 25, 2006

Scheme 2
yields, the significantly lower costs of Cl2CdCH2 and
ClCHdCCl2 might appear to favor their use in cases where
the starting alkynes are relatively inexpensive.
and used in the subsequent steps. For their full identification,
however, they were chromatographically purified and iso-
lated. This additional operation, however, led to an overall
yield of 30% for the synthesis of 8. Omission of purification
of intermediates was also applied to the synthesis of
1-phenyl-1,3,5-heptatrieyne (5c). Even though the overall
yield of 67% from PhCtCH is only comparable to that
shown in entry c (68%), the overall process is simpler and
more efficient.19 In all of the other cases shown in Scheme
1, however, all indicated intermediates were isolated and
purified primarily for their full identification.
During the development of the above-described linear
iterative protocol, it occurred to us that 1,1-dibromo-1-
alkenes should be used not as mere precursors to 1-alkynes
(routes II in Schemes 1 and 2) but for devising a convergent
protocol shown in Scheme 3 for the synthesis of triynes
and higher oligoynes by combining two shorter monoynyl
and/or oligoynyl intermediates, the latter of which are now
efficiently and selectively preparable, as discussed above.
The critical step involves the Pd-catalyzed trans-selective
monoalkynylation of 1,1-dibromo- and 1,1-dichloro-1-
alkenes developed recently by us.20
For the proof of principle, 7-phenyl-2,4,6-heptatriyn-1-ol
(10) was prepared in 45% overall yield in four steps from
PhCtCH and HCtCCH2OTBS, as shown in eq 2 of Scheme
3.21,22 Application of the convergent protocol shown in
Scheme 3 to the synthesis of conjugated tetraynes, however,
was complicated by competitive formation of the expected
monobromotriynes and the eventual target tetraynes. Specif-
ically, the reaction of 4-phenyl-1,1-dibromo-1-buten-3-yne
with 1.1 equiv of an enediynylzinc derivative 11, generated
in situ by treating (E,E)-1-chloro-1,5-heptadien-3-yne, in the
However, their cross-coupling reactions require several-
fold excesses of them, which complicates their iterative use
for the synthesis of oligoynes. In view of the higher product
yield and cleaner reaction profile, (E)-ICHdCHCl was
chosen in this study. As an ethynyl synthon, (E)-ICHdCHBr
does not generally offer any notable advantage over (E)-
ICHdCHCl. Some representative results of the syntheses of
tri- and tetraynes from the corresponding monoynes (1) or
aldehydes (2) in three and four steps, respectively, are
summarized in Scheme 1. Specifically, several triynes (5)
were prepared in 34-62% overall yields from 1, and a couple
of tetraynes (7) were prepared in 43 and 45% overall yield.
Many of the requisite starting terminal alkynes are
commercially available. In cases where appropriately struc-
tured aldehydes are economically available, as in the case
of (E)-crotonaldehyde, 2-furylaldehyde, and (E)-3-(2-furyl)-
acrolein, the corresponding alkynylzinc reagents can be
readily generated via Corey-Fuchs18 and other carbonyl
alkynylation reactions and used in situ for the preparation
of 3 in one pot (route II in Scheme 1). An efficient synthe-
sis of a dienetriyne derivative (8) from (E)-crotonaldehyde,
(E)-ICHdCHCl, and (E)-ICHdCHCH2OTBS in 42% overall
yield shown in Scheme 2 is exemplary. In this case, the
dienemonoyne (3d) and dienediyne (9) intermediates were
obtained as crudely worked-up materials without purification
Scheme 3
(17) (a) Negishi, E.; Alimardanov, A.; Xu, C. Org. Lett. 2000, 2, 65. (b)
Negishi, E.; Zeng, X. Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons, Inc.: New York, 2002. (c)
Bartlome, A.; Stampfli, U.; Neuschwander, M. Chimia 1991, 45, 346.
(18) Corey, E. J.; Fuchs, P. L. Tetrahedron Lett. 1972, 36, 3769.
(19) For the synthesis of oligoenynes via the Pd-catalyzed alkynylation
through the use of ICHdCHBr involving the formation of two or more
C-C bonds without isolation/purification, see: (a) Negishi, E.; Alimar-
danov, A.; Xu, C. Org. Lett. 2000, 2, 65. (b) Ghasemi, H.; Antunes, L. M.;
Organ, M. G. Org. Lett. 2004, 6, 2913.
(20) (a) Shi, J.; Zeng, X.; Negishi, E. Org. Lett. 2003, 5, 1825. (b)
Negishi, E.; Shi, J.; Zeng, X. Tetrahedron 2005, 61, 9886.
(21) For related syntheses of conjugated diynes, see: (a) Bryant-Friedrich,
A.; Neidlein, R. Synthesis 1995, 1506. (b) Shen, W.; Thomas, S. A. Org.
Lett. 2000, 2, 2857.
(22) A recent synthesis of 10 from PhCtCH and HOCH2CtCCH2OH
was achieved in 17% overall yield over seven steps.9c
Org. Lett., Vol. 8, No. 25, 2006
5775

Scheme 4
presence of 5 mol % of Pd(DPEphos)Cl2 at 23 °C gave 12
cessfully applied to the synthesis of 14 in 68% yield from
4-(p-tolyl)-1,1-dibromo-1-buten-3-yne and bis(4-phenyl-1,3-
butadiynyl)zinc (eq 2 of Scheme 4) as well as three con-
jugated pentaynes 15a-c (eq 3 of Scheme 4).
Although further condition optimization is needed to im-
prove the modest yields of 43-55%, these examples appear
to represent the first set of pair-selective syntheses of unsym-
metrically substituted conjugated pentaynes.
and 13 in <10 and 32% yields, respectively, with 49% of
the starting dibromide remaining unreacted. Only traces, if
any, of the stereoisomer of 12 and the dialkynylated product
were present. Although the precise mechanism of formation
of 13 is unclear, 11 must have been partially consumed as a
mere base to neutralize HBr. As expected, the use of 2 equiv
of 11 produced 13 in 66% yield along with only traces of
12 and the starting dibromide. Although this reaction is clean,
it is not synthetically attractive, as it requires 1.0 molar equiv
(or a 2-fold excess) of the alkynylzinc reagent. Our recent
development of the Pd-catalyzed alkynylation with free
terminal alkynes in the presence of NEt3 and ZnBr2,23
however, provided a handy solution. Thus, a combination
of 11 (0.55 molar equiv) and NEt3 (1.0 equiv) in place of a
2-fold excess (1.0 molar equiv) of 11 cleanly produced 13
in 66% yield (eq 1 of Scheme 4). This procedure was suc-
Acknowledgment. We thank the National Science Foun-
dation (CHE-0309613), 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.
(23) Anastasia, L.; Negishi, E. Org. Lett. 2001, 3, 3111.
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