Communications
Table 2: Cyclobutane derivatives 7 from the zirconium-mediated reac-
tion of alkyllithium derivatives 4 and enol ethers 6.
hence the intramolecular migratory insertion process is
preferred.
E+
E
Product Yield [%][a]
Another surprising feature of these reactions is that the
orientation adopted by the enol ether during the insertion
process depends on the size of the enol ether ring. Although a
more detailed study is required, we believe that the orienta-
tion adopted by the five-membered enol ether 3 is governed
by electronic effects.[12] However, steric effects probably play
an important role in the opposite orientation adopted by the
pyran derivatives 6 during the insertion process. In fact, it has
been observed that the reaction of 6 and the sterically less-
demanding zirconacyclopropane 2 (R = H) (derived from the
reaction of EtLi and zirconocene dichloride) leads to an
approximately 1:1 mixture of the cyclobutyl derivative 7 f and
the alkene derivative 8 (Scheme 3 and Table 2). The forma-
tion of compound 8 could be explained by a mechanism
analogous to that described for the formation of 5 (Scheme 4)
where pyran 6 is oriented during the insertion step in a way
that is analogous to that adopted by the furans 3.
Alkyllithium
R
4a
4a
4a
4b
4c
4d
Et
Et
Et
H2O
D2O
H
D
7a
7b
69
63
53
70
60
66[c]
[b]
=
CH2 CHCH2Cl
allyl 7c
Pent H2O
Me
H
H
D
H
7d
7e
7 f
D2O
H2O
[a] Based on the amount of starting [Cp2ZrCl2]. Very small amounts
(<5%) of the corresponding compounds analogous to 8 were detected
in the crude pruduct of the reactions. [b] CuCl (5 mol%) and LiCl
(1 equiv) are also added. After 1 h at 258C, the reaction was stirred at
508C for 6 h. [c] The total yield corresponded to an approximately 1:1
inseparable mixture of 7 f and alkenol 8. Pure 7 f (33% yield) was
obtained after treating the mixture of 7 f and 8 with bromine and further
purification.
In summary, we have described the first coupling reaction
of cyclic enol ethers and alkene–zirconocene complexes. The
reactions described here followdifferent pathways compared
to previously reported results for acyclic enol ethers. The
reaction has been shown to be dependent on the ring size of
the enol ether, and thus, for five-membered enol ethers, the
reaction leads to alcohols or phenols containing a Z double
bond through an insertion/b-elimination process, while the
reaction with six-membered enol ethers generates cyclo-
butane derivatives through an unprecedented insertion/intra-
molecular migratory insertion reaction. Moreover, these
results firmly support the carbometalative ring-expansion
mechanism tentatively proposed by Marek and co-workers
for related reactions.
Scheme 4. Proposed mechanism for the formation of compounds 5
and 7.
phenol derivatives 5i–p from enol ether 3b follows a similar
pathway.
Moreover, the generation of cyclobutane derivatives 7
from the six-membered enol ether 6 can be explained by
insertion of the double bond of this enol ether into 2 to
produce the bicyclic intermediate 11. An intramolecular
migratory insertion process[11] generates intermediate 12,
which after reaction with an electrophile and hydrolysis
affords cyclobutane derivatives 7.[9] As before, this insertion
process is regioselective with respect to 2, with the reaction
Besides the important mechanistic aspects described, this
work is expected to have wide application in synthetic organic
chemistry since highly functionalized compounds can be
readily obtained from simple starting materials. Further
detailed investigations into the synthetic and mechanistic
aspects of these reactions, including experimental and theo-
retical calculations, are underway.[13]
occurring at the more substituted Zr C bond.[3d] The reaction
Received: March 1, 2004 [Z54151]
À
is also regioselective with respect to the enol ether 6 since the
double bond of this enol ether is oriented so that the oxygen
atom is close to the zirconocene moiety.
Keywords: insertion · organometallic reagents ·
.
small ring systems · synthetic methods · zirconium
The coupling products obtained firmly support the
carbometalative ring-expansion mechanism tentatively for-
mulated by Marek and co-workers for the reaction of the
Negishi reagent and acyclic enol ethers to give vinyl–
zirconocene complexes.[7,8] In fact, intermediate 11 is analo-
gous to I (see Scheme 1). However, in our case the elimi-
nation reaction leading to the vinyl–zirconocene complexes
(see Scheme 1) does not proceed and instead an intramolec-
ular migratory insertion process furnishes the cyclobutane
derivatives 7. According to model proposed by Marek and co-
workers for the formation of (E)-vinylzirconocenes,[8] an
isomerization at C1 in 11 should occur before the elimination
step. We believe that in our case this process is not favored
because of the rigidity of the bicyclic intermediate 11, and
[1] Titanium and Zirconium in Organic Synthesis (Ed.: I. Marek),
Wiley–VCH, Weinheim, 2002.
[2] E. Negishi, F. E. Cederbaum, T. Takahashi, Tetrahedron Lett.
1986, 27, 2829.
[3] For some leading reviews, see: a) T. Takahashi, M. Kotora, R.
Hara, Z. Xi, Bull. Chem. Soc. Jpn. 1999, 72, 2591; b) E. Negishi,
T. Takahashi, Bull. Chem. Soc. Jpn. 1998, 71, 755; c) E. Negishi,
D. Y. Kondakov, Chem. Soc. Rev. 1996, 25, 417; d) E. Negishi, T.
Takahashi, Acc. Chem. Res. 1994, 27, 124.
[4] a) J. Barluenga, R. Sanz, F. J. Faæanµs, Chem. Eur. J. 1997, 3,
1324; b) J. Barluenga, R. Sanz, F. J. Faæanµs, J. Org. Chem. 1997,
62, 5953; c) J. Barluenga, R. Sanz, F. J. Faæanµs, J. Chem. Soc.
Chem. Commun. 1995, 1009; d) J. Barluenga, R. Sanz, R.
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Angew. Chem. Int. Ed. 2004, 43, 3932 –3935