reactions using milder Lewis3c-n or Brønsted3o,p acids were
reported, together with the first examples of asymmetric
induction.3e,k,l,n,o
Nazarov cyclization: stoichiometric SnCl4.6b-e Using these
conditions, complete polymerization of the sensitive substrate
was observed.8
When considering these recent successes in the Nazarov
reaction, we wondered if similar concepts could be successful
in other cyclization reactions to access larger ring systems.
A viable approach to access homologous rings via electro-
cyclic reactions is the substitution of a double bond by a
cyclopropyl group, as exemplified by the divinylcyclopropyl
rearrangement.4 Intra- and intermolecular ring-opening of
cyclopropyl ketones and diesters have been examined ex-
tensively.5 The reaction of vinyl-cyclopropyl ketones has
been less studied (B, Scheme 1).6 Tsuge has reported the
cyclization of vinyl-cyclopropyl ketones using an excess of
polyphosphoric acid at 80 °C, but this reaction was not
general and several other products were obtained beside the
desired cyclohexenones.6a More work has been done on
the related aryl-cyclopropyl ketones, first by Murphy for the
synthesis of tetralones using an excess of SnCl4 as
reagent.6b-d During completion of our work, Yadav also
demonstrated that diverse polycyclic heterocycles could be
accessed using 3 equivalents SnCl4 at 80 °C, but no vinyl-
cyclopropyl ketones were reported.6e Up to now, the harsh
conditions needed have limited the use of the homo-Nazarov
reaction in organic synthesis. Herein, we report the first
example of a catalytic formal homo-Nazarov process for non
aromatic substrates which lead to the formation of valuable
polycyclic cyclohexenones at room temperature as well as
preliminary experiments to probe the reaction mechanism.
Inspired by recent progress in the catalytic Nazarov
reaction,3j we decided to examine dihydropyran-derived
substrate 2a (Scheme 2). Substrate 2a was synthesized from
As most Lewis acid led to extensive polymerization, we
then turned toward Brønsted acid catalysts. The pKa value
of the catalyst had a strong influence on the outcome of the
reaction: sulfuric and toluenesulfonic acids were optimal.
Stronger acids led to decomposition of the starting material
and no full conversion could be achieved with weaker acids.
Examination of solvent effects showed that the reaction was
faster in noncoordinating solvents, like dichloromethane, but
polymerization was also difficult to suppress. Acetonitrile
finally offered the best compromise, with sufficient reactivity
but less pronounced polymerization. The cyclization of 2a
in acetonitrile with 20 mol % toluenesulfonic acid at room
temperature led to the formation of the desired cyclohex-
enone 3a in 70% isolated yield (Scheme 2).
The scope of the reaction was examined next (Table 1).
Variation of the aromatic substituent on the cyclopropane
confirmed the importance of its electron-donating ability;
whereas no reaction was observed with a simple phenyl
group (entry 2), a quantitative yield was observed with a
3,4- or 2,4- dimethoxyphenyl group (entries 3 and 4). This
result is noteworthy, as electron-rich aromatic substituents
are well represented in bioactive natural products9 and are
easily oxidized to the corresponding carboxylic acids.10
A
furan group was also tolerated at this position, although the
yield was moderate due to partial polymerization (entry 5).
Finally, the influence of a methyl group R to the ketone
was examined. Interestingly, a strong accelerating effect was
observed and cyclohexenone 3f was obtained in quantitative
yield after only 15 min (entry 6). A plausible explanation
would be a faster ring-opening of the cyclopropane ring due
to sterical strain release and the higher stability of the formed
enol intermediate.11 Importantly, this accelerating effect on
the formal homo-Nazarov cyclization has never been reported
before.
Scheme 2. Synthesis and Cyclization of Model Substrate 2a
We then examined variation of the electron-rich side of
the ketone. A dihydrofuran group proved to be more prone
to polymerization and the desired product was isolated only
in low yield with a 4-methoxyphenyl group on the cyclo-
propane (entry 7). The stronger stabilizing effect of the 2,4-
dimethoxyphenyl substituent allowed the isolation of the
desired 5-6 ring system in quantitative yield (entry 8).
Replacing the dihydropyran group with an electron-rich
N-methylindole heterocycle lead to an efficient cyclization
in quantitative yield (entry 9), but only polymerization was
observed with a benzofuran ring (entry 10). Interestingly,
similar results were obtained in the related Nazarov
cyclization.3i
Weinreb amide 1 via Corey-Chaykovsky cyclopropanation7
followed by addition of a lithiated nucleophile to afford 2a
in good yield (Scheme 2).
With our model substrate in hand, we began our studies
by examining the most frequently used procedure for homo-
(4) Piers, E. In ComprehensiVe Organic Synthesis; Trost, B. M., Ed.;
Pergamon Press: New York, 1991; Vol. 5, pp 971-998.
(5) For a few selected examples, see: (a) Stork, G.; Marx, M. J. Am.
Chem. Soc. 1969, 91, 2371. (b) Grieco, P. A.; Finkelhor, R. S. Tetrahedron
Lett. 1974, 527. (c) Pohlhaus, P. D.; Sanders, S. D.; Parsons, A. T.; Li, W.;
Johnson, J. S. J. Am. Chem. Soc. 2008, 130, 8642.
(8) Oligomerization, then polymerization was apparent in 1H NMR via
formation of broad signals in several regions of the spectra, see Supporting
Information (Figure S5).
(6) (a) Tsuge, O.; Kanemasa, S.; Otsuka, T.; Suzuki, T. Bull. Chem.
Soc. Jpn. 1988, 61, 2897. (b) Murphy, W. S.; Wattanasin, S. Tetrahedron
Lett. 1980, 21, 1887. (c) Murphy, W. S.; Wattanasin, S. J. Chem. Soc. Perkin
Trans. 1 1981, 2920. (d) Murphy, W. S.; Wattanasin, S. J. Chem. Soc.,
Perkin Trans. 1 1982, 1029. (e) Yadav, V. K.; Kumar, N. V. Chem.
Commun. 2008, 3774.
(9) For example in Podophyllotoxin natural products and their deriva-
tives: Bohlin, L.; Rosen, B. Drug DiscoV. Today 1996, 1, 343.
(10) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936. (b) Voight, E. A.; Rein, C.; Burke, S. D. J.
Org. Chem. 2002, 67, 8489.
(11) As an alternative explanation, a higher fraction of the more stable
enol tautomer could be envisaged to favor cyclization.
(7) Rodriques, K. E. Tetrahedron Lett. 1991, 32, 1275.
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