metalation reactions of conjugated enynes and diynes includ-
alkynes are used as nucleophiles. On the other hand, BrCHd
CHBr used as E and Z mixtures has been associated with
chemo- and/or stereoselectivity problems as well as modest
12
13
14
ing those with B, Al, and Zr are generally complicated
by placement of metals in internal positions. Fortunately,
favorable results were obtained in the hydrozirconation-
cross coupling tandem reaction of 8. Thus, its hydrozircona-
tion generated 3 in 80% yield by NMR. The reaction of 3,
generated in situ from 8, with 2 in the presence of a Pd
1
7
product yields. We therefore chose (E)-ICHdCHBr as a
9
potentially superior alternative. The reported synthesis of
(E)-ICHdCHBr in 44% crude yield by treatment of acetylene
with I and Br in CHCl was improved by treatment of
2 2 3
catalyst prepared from 5 mol % of Cl
2
Pd(PPh
3
)
2
and 10 mol
acetylene with commercially available IBr at 0 °C over 48
h to provide pure (E)-ICHdCHBr in 73% yield. As expected,
its Pd-catalyzed selective monoalkynylation has proved to
be facile and high-yielding, as exemplified by the synthesis
of 2, 6, and 7, shown in Scheme 1. Furthermore, the second
Pd-catalyzed substitution with alkynyl- and alkenylmetals
can also be satisfactory, as shown in the synthesis of 8 and
9.
%
of DIBAH as well as ZnCl (0.6 equiv) afforded, after
2
chromatographic purification, 97% pure 9 in 95% yield based
on 2.
Third, unsymmetrically substituted conjugated diynes are
15a
commonly synthesized by the Cadiot-Chodkiewicz reaction
and its modification with Pd catalysts.15b These methods,
however, are often complicated by homocoupling leading
to diminished yields of the desired cross-coupling products.
We earlier introduced a strictly “pair-selective” alternative
Finally, the Pd-catalyzed cross coupling-lactonization
7
tandem procedure involving the use of 1 mol % of BHT
6
7c
procedure using (E)-ICHdCHCl. Although expected, the
and several cycles of freeze-thaw degassing was high-
feasibility of attaching the second carbon group to the
butadiyne unit via Pd-catalyzed cross coupling has not been
reported. The synthesis of 2 from 6 demonstrates not only
the feasibility of such transformations but also the inter-
changeability between (E)-ICHdCHBr and (E)-ICHdCHCl.
The scope of this method for the synthesis of conjugated
diynes needs to be further delineated. Nonetheless, we believe
it is a significantly more selective and potentially more
general method of comparable overall efficiency, as com-
yielding, stereoselective, and regioselective. Xerulin (1) was
formed in 70% yield as a >96% stereoisomerically pure
1
13
18
compound. The H and C NMR spectral data are in
excellent agreement with those reported in the literature.1
The extent of homocoupling of 5 was <5%. Neither the
formation of the corresponding pyrone nor other side
,2
7b
reactions, such as conjugate substitution of 1, were detect-
able.
1
5
Acknowledgment. We thank the National Institutes of
Health (GM 36792) and Purdue University for support of
this research and Johnson-Matthey for palladium compounds.
pared with the widely used procedures mentioned above.
Fourth, complications associated with the regiochemistry
and some other aspects of hydrometalation of conjugated
enynes and diynes have prompted us to develop highly
stereoselective modular approaches to the synthesis of
oligoenes and oligoenynes using (E)-1,2-dihaloethylenes. Of
three such compounds used thus far, Cl-containing com-
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 1, 4, 5, and
7
-9 as well as spectroscopic data for 2 and 6. This material
is available free of charge via the Internet at http://pubs.acs.org.
16
6
pounds, i.e., (E)-ClCHdCHCl and (E)-ICHdCHCl, suffer
from the generally low reactivity of the C-Cl bond in the
Pd-catalyzed cross coupling except for those cases where
OL990336H
(
16) (a) Rotovelomanana, V.; Linstrumelle, G. Tetrahedron Lett. 1981,
2
2, 315. (b) Alami, M.; Gueugnot, S.; Domingues, E.; Linstrumelle, G.
(
12) (a) Zweifel, G.; Polston, N. L. J. Am. Chem. Soc. 1970, 92, 4068.
b) For a review, see: Pelter, A.; Smith, K.; Brown, H. C. Borane Reagents;
Academic Press: New York, 1988; p 503.
Tetrahedron 1995, 51, 1209. (c) Ramaiandrasoa, P.; Br e´ hon, B.; Thivet,
A.; Alami, M.; Cahiez, G. Tetrahedron Lett. 1997, 38, 2447.
(17) (a) Carpita, A.; Rossi, R. Tetrahedron Lett. 1986, 27, 4351. (b)
Andreini, B. P.; Benetti, M.; Carpita, A.; Rossi, R. Tetrahedron 1987, 43,
4591.
(
(
13) Zweifel, G.; Miller, J. A. Org. React. 1984, 32, 375.
(14) (a) For a review, see: Labinger, J. A. In ComprehensiVe Organic
Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991;
Vol. 3, pp 667-702. (b) Fryzuk, M. D.; Bates, G. S.; Stone, C. Tetrahedron
Lett. 1986, 27, 1537. (c) Crombie, L.; Hobbs, A. J. W.; Horsham, M. A.;
Blade, R. J. Tetrahedron Lett. 1987, 28, 4875.
(18) Xerulin (1): 1H NMR (500 MHz, CDCl3) 1.84 (dd, J ) 6.8 and
1.9 Hz, 3 H), 5.61 (dqd, J ) 15.6, 1.9, and 1.1 Hz, 1 H), 5.76 (d, J ) 15.6
Hz, 1 H), 5.90 (d, J ) 11.8 Hz, 1 H), 6.18 (d, J ) 5.4 Hz, 1 H), 6.34 (dq,
J ) 15.8 and 7.0 Hz, 1 H), 6.4-6.55 (m, 3 H), 6.74-6.85 (m, 2 H), 7.37
13
(15) (a) Cadiot, P.; Chodkiewicz, W. In Chemistry of Acetylenes; Viehe,
(d, J ) 5.4 Hz, 1 H); C NMR (125 MHz, CDCl3) 18.99, 72.55, 79.40,
80.66, 83.36, 109.91, 112.15, 114.69, 118.89, 127.73, 135.07, 135.54,
137.81, 142.53, 143.79, 143.95, 149.46, 169.31.
H. G., Ed.; Marcel Dekker: New York, 1969; p 597. (b) See, for example:
Cai, C.; Vasella, A. HelV. Chim. Acta 1995, 78, 2053.
Org. Lett., Vol. 2, No. 1, 2000
67