SCHEME 3. Proposed Mechanism for Formation of 15 and
15c
exposure to catalytic MeLi (ca. 10 mol %) and microwave
irradiation, 2 was smoothly converted to the R-arylated bicyclo-
[5.3.0]decane system 3 as a 93:7 mixture of diastereomers in
76% isolated yield.
The cyclization-Claisen rearrangement sequence involving
5-aryl-substituted 4-pentyn-1-ols such as 2 is significant con-
sidering that the synthetically equivalent regioselective R-ary-
lation reaction of analogous hydroazuleneone systems is difficult
to achieve using existing methodology. In general, palladium-
catalyzed R-arylation reactions have not been widely applied
for the synthesis of highly substituted cycloheptanone deriva-
tives.13
The tandem process also works well with alcohols bearing
terminal triple bonds (Table 1, entries 2 and 5) and even alkyl-
substituted secondary alcohols react provided that the initial ring
closure is facilitated through operation of the Thorpe-Ingold
effect.14 Indeed, while simple alkyl-substituted acetylenic
alcohols were unreactive under the conditions investigated, the
secondary alcohol 22 bearing a gem-dimethyl moiety in the
flexible alkyl tether connecting to the alkyne unit gave the
expected bicyclic ring system 23 in 60% yield (Table 1, entry
11). The carbmethoxy derivative 20 also cyclized readily to
afford the known tetrahydrofuranyl system 21 exclusively as
the corresponding E-isomer; however, no formation of the
rearranged product was observed under these conditions (Table
1, entry 10).15
SCHEME 4. Isomerization of a Mixture of 17/17a under
Basic Conditions
The reaction involving enyne 10 also provided the expected
bicyclo[5.4.0]undecane ring system; however, the Claisen
rearrangement in this case was accompanied by isomerization
of the product (Table 1, entry 4). Results from these and other
experiments are summarized in Table 1.
Reactions involving terminally substituted 4-pentyn-1-ols
were found to be highly stereoselective, with R1 and R2 groups
(Scheme 1) showing a strong preference for trans orientation
in the final product. The observed stereochemical trends in these
processes may be justified by invoking a chairlike transition
state for the Claisen rearrangement and considering steric
interactions within the transition state structures 15a and 15b
(Scheme 3). It is reasonable to assume that the transition state
in which the phenyl group occupies a pseudoequatorial orienta-
tion (15a) is more favorable than that involving a pseudoaxial
phenyl group (15b).
under the high-temperature conditions employed and intercon-
vert via an endo-exo isomerization process,6,7,8h thereby serving
as precursors to either of the two transition state structures 15a
and 15b.
We have previously reported that the initial diastereomer ratio
of products obtained via the cyclization-Claisen rearrangement
processes could be significantly altered upon treatment with
alkoxide bases and heat (e.g., from 2.5:1 to 14.6:1).8g,h The same
trend was observed here. In the specific case examined, a
77:23 mixture of 17/17a, obtained directly from the cyclization-
Claisen rearrangement process, was subjected to NaOMe/MeOH
at reflux (65 °C). Analysis of the reaction mixture after 15 h of
heating revealed an 88:12 ratio of 17/17a (Scheme 4), represent-
ing a notable change from the initial product distribution. The
same ratio was obtained when a chromatographically enriched
92:8 mixture of the diastereomers was subjected to identical
conditions.17
In conclusion, we have shown that appropriately substituted
1-alkenyl-4-pentyn-1-ol systems, readily prepared from simple
starting materials, serve as useful precursors to a number of
substituted cyclohept-4-enone derivatives via a microwave-
assisted tandem oxyanionic 5-exo cyclization-Claisen rear-
rangement sequence.
Consistent with earlier reports regarding the configurational
lability of vinyl anions bearing aryl substituents,16 the Claisen
precursors 14a and 14b may be derived from isomerization of
the vinyl anion intermediates formed upon the initial base-
catalyzed 5-exo cyclization reaction involving 14. It is also
possible that neutral enol ethers 14a and 14b exist in equilibrium
(10) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
4467-4470.
(11) Brimble, M. A.; Pavia, G. S.; Stevenson, R. J. Tetrahedron Lett.
2002, 43, 1735-1738.
(12) Mancuso, A. J.; Swern, D. Synthesis 1981, 165-185.
(13) (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119,
11108-11109. (b) Fox J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J.
Am. Chem. Soc. 2000, 122, 1360-1370. (c) Hamann, B. C.; Hartwig, J. F.
J. Am. Chem. Soc. 1997, 119, 12382-12383.
Experimental Section
General Procedure for Preparation of 4-Alkyn-1-ol Deriva-
tives: Preparation of 1-Cyclopentenyl-5-(2,5-dimethoxyphenyl)-
pent-4-yn-1-ol (2). To a -78 °C solution of 1-iodocyclopentene
(776 mg, 4.00 mmol) in 15 mL of Et2O was added t-BuLi (1.7 M
(14) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. J. Chem. Soc. 1915,
107, 1080-1106.
(15) [3,3]-Sigmatropic rearrangement of 21 to afford 2-carbmethoxy-4-
cycloheptenone on prolonged heating has been previously observed; see:
Tsuji, J.; Kobayashi, Y.; Takahashi, T. Tetrahedron Lett. 1980, 21, 1475-
1476.
(16) Hunter, D. H.; Cram, D. J. J. Am. Chem. Soc. 1964, 86, 5478-
5490.
(17) All stereochemical assignments were unambiguously determined by
standard 1D NOSY techniques and through examination of the relevant
coupling constant between the benzylic proton and the adjacent bridgehead
proton in each case.
6626 J. Org. Chem., Vol. 72, No. 17, 2007