have been exploited for these processes. However, the use
of copper catalysts remains quite rare4c,8 despite the clear
advantage in cost-effectiveness. An attractive, yet unexplored,
approach would be the direct alkenylation of oxazoles and
related electron-rich heterocycles with vinyl halides. At the
outset of our studies, there was limited literature precedent
for the direct alkenylation of (hetero)aromatics with bro-
moalkenes, and in particular copper-catalyzed direct alkeny-
lation was unknown. Oi and Inoue have reported the ortho-
selective direct alkenylation of 2-aryloxazolines with various
alkenyl bromides by ruthenium complexes.9 Daugulis et al.
described the coupling of 3-haloacrylates with anilides.10
During the preparation of our manuscript, two notes on direct
alkenylation with bromoalkenes were published. Daugulis
et al. have shown copper-catalyzed direct alkenylation of
pentafluorobenzene with ꢀ-bromostyrene in high yield.8b
Doucet et al. described the use of alkenyl bromides for a
palladium-catalyzed C-H bond activation of benzoxazole
and benzothiazole with moderate to good yields.11
amine as ligand, and lithium tert-butoxide in dioxane at 100
°C for 4 h. Product 3a was isolated in 81% yield as the pure
E stereoisomer. Crucially, formation of 3a was not observed
if CuI was omitted from the reaction mixture. Also, the use
of 2.1 equiv of t-BuOLi was found to be optimal since
reactions with K3PO4, Cs2CO3, Ag2CO3, LiH, and t-BuOK
were much slower or did not proceed. Commercial grade
dioxane proved to be the better solvent, as reaction in toluene
resulted in significantly reduced product yields (39% in 2 h,
58% overnight). Further, the use of the less expensive N,N′-
dimethylethylene-1,2-diamine ligand resulted in lower con-
version to product (76%). As a byproduct of the reaction,
the dimer of 5-phenyloxazole was obtained in up to 11%
yield resulting from the oxidative homocoupling of the
organocopper oxazole intermediate. The reactivity of
dimethoxystyrene iodide and the corresponding chloride13
was also studied in the direct alkenylation. Reaction of
iodostyrene (entry 5, Table 1) with 5-phenyloxazole 1a gave
E-2-alkenyl-5-aryloxazole 3f in comparable yield (80%),
whereas no product was formed when using the chlorostyrene
derivative (entry 7).
This optimized protocol was subsequently used to inves-
tigate the scope of the direct alkenylation of 5-phenyloxazole
1a with various readily accessible E-ꢀ-bromostyrenes (Table
1).14 Both electron-rich (entries 1-6) and electron-deficient
(entries 8-11) ꢀ-bromostyrenes reacted regioselectively at
the C-2 position of 5-phenyloxazole in very good yields.
Substitutions at the ortho-, meta-, or para-positions of the
styrene were tolerated. Moreover, these conditions are
compatible with a range of functional groups including nitro,
cyano, and halides which may be used for further transfor-
mations. In addition, the reactivity of isocrotyl bromide was
evaluated in the direct alkenylation with 1a (entry 13) giving
compound 3l in good yield (76%). This result shows the
potential scope of the method beyond the bromostyrenes.
The E-isomers 3 were obtained exclusively. However, in
the 1H NMR of the crude product mixture from the reaction
of 1a with E-ꢀ-paramethylbromostyrene (Table 1, entry 1),
the Z-isomer could be detected and was isolated in 4% yield.
There is strong evidence to suggest that the Z-isomer comes
from the coupling of E-ꢀ-bromostyrene and not from traces
of Z-ꢀ-bromostyrene contained in the starting material. First,
when the reaction was run with pure Z-ꢀ-bromostyrene, no
coupling product 3b was observed. Furthermore, the starting
material was fully recovered in stereoisomerically pure form
when compound 3b was subjected to the reaction conditions
for several hours (overnight).
Herein, we report a novel method for the direct copper-
catalyzed alkenylation of 5-phenyloxazoles and related
compounds with various styryl halides. This approach
provides straightforward and efficient access to a wide variety
of 2-E-alkenyloxazoles in a stereoselective manner and is
illustrated by an expedient three-step synthesis of the alkaloid
annuloline.
Initially, the coupling of 5-phenyloxazole 1a with E-ꢀ-
bromostyrene 2a was investigated (Scheme 1).
Scheme 1. Optimized Coupling Conditions
Compound 1a was readily prepared in one step in 85%
yield by the van Leusen reaction of benzaldehyde with
p-toluenesulfonylmethylisocyanide (TosMIC) and K2CO3 in
refluxing MeOH.12 Screening of the conditions for the
coupling reaction involved varying the solvent, ligand, metal
source, and base. The best results were obtained using
copper(I) iodide, trans-N,N′-dimethylcyclohexane-1,2-di-
These new conditions were also successfully applied to
substituted 5-phenyloxazoles and related azoles (Table 2).
Both electron-rich (entries 1-2) and electron-poor (entry 3)
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Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006,
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(14) (a) Das, J. P.; Roy, S. J. Org. Chem. 2002, 67, 7861, and references
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Org. Lett., Vol. 10, No. 18, 2008