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J.-F. Peyrat et al. / Tetrahedron Letters 44 (2003) 6703–6707
Acknowledgements
case, it should be noted that only 0.6 equiv. of ZnCl2
were necessary to provide 2a in excellent yield (entry
11). All our efforts to perform this coupling reaction
in the presence of a catalytic amount of ZnCl2 (10
mol%) resulted, however, in a disappointing 20%
yield (entry 12).
The CNRS is gratefully thanked for support of this
research. We would like to thank Olivia Casajus for
carrying out some experiments.
Another parameter that should have a significant
influence on the course of the reaction was phosphine
ligands around palladium catalyst. Consequently, we
examined the catalytic activity of palladium catalysts
bearing commercial bidentate phosphines on the
course of the zinc chloride promoted coupling of 1a
with n-octylmagnesium bromide. The use of palla-
dium catalysts coordinated with bidentates phosphines
such as dppe or dppp was almost inactive however,
the addition of PdCl2(dppb) was found to catalyze
the coupling process efficiently offering the coupling
product 2a in a similar yield (90%) than that achieved
with PdCl2(dppf). Finally, the influence of cosolvent
additive was also briefly examined and no modifica-
tion of the yield of 2a was observed when the reac-
tion was carried out in THF with Et3N (8 equiv.) as
cosolvent, whereas the addition of NMP or DMPU9
dramatically decreased the yield of the reaction (10–
15%).
References
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6. PdCl2(dppf) is well-known to depress side reactions partic-
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In order to demonstrate the efficiency of this new
palladium–zinc chloride mediated coupling reaction of
1 with Grignard reagents, a variety of functionalized
polyunsaturated molecules were thus synthesized in
good to excellent yields. As shown in Table 2, the
coupling reaction was successful from various func-
tionalized unsaturated vinyl chlorides and allows to
introduce efficiently aryl substituents as well as pri-
mary and secondary alkyl substituents without forma-
tion of side products arising from b-elimination
process (isomerization in the case of secondary alkyl
groups and/or reduction/dimerization of the vinyl
chloride). Interestingly, these reactions are highly
stereoselective (>97%) since the cross coupling reac-
tions with either (E)- or (Z)-chloroenynes furnishes
either (E)- or (Z)-coupling products in excellent yields
(entries 1–6). In addition, it should be noted that the
cross coupling reaction tolerates sensitive functional
groups in the substrates and is even successful with
conjugated alkenyl chlorides having a free hydroxyl
group (entry 12) or a homopropargyl acetate or ben-
zoate (entries 8–10).
7. Alami, M.; Gueugnot, S.; Domingues, E.; Linstrumelle, G.
Tetrahedron 1995, 51, 1209–1220.
8. (a) Harada, T.; Kotani, Y.; Katsuhira, T.; Oku, A.
Tetrahedron Lett. 1991, 32, 1573–1576; (b) Vaughan, A.;
Singer, R. D. Tetrahedron Lett. 1995, 36, 5683–5686; (c)
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9. The beneficial influence of DMPU has already been
demonstrated for the Mn-catalyzed alkylation of
chloroenynes with Grignard reagents, see: Alami, M.;
Ramiandrasoa, P.; Cahiez, G. Synlett 1998, 325–327.
10. Typical procedure: To a mixture containing a THF solution
of ZnCl2 (0.5 M, 0.6 mmol, 1.2 mL), alkenyl chloride 1 (1
mmol) and PdCl2(dppf) (5 mol%) in 2 mL of THF, was
added, at 65°C, Grignard reagent (1.5 mmol). The reaction
was stirred at 65°C and monitored by TLC until complete
consumption of starting materials (3.5–4 h). The reaction
In summary, we have demonstrated for the first time
that organozincate reagents generated in situ by reac-
tion of Grignard compounds with less than molar
amounts of zinc chloride lead to an efficient car-
bonꢀcarbon bond formation reaction with various
functionalized conjugated alkenyl chlorides. The use
of these substrates for the elaboration of polyunsatu-
rated molecules appears to be interesting since they
are less photosensitive and thus more stable than the
corresponding iodo and bromo analogs.