M. E. Jung, A. R. Novack / Tetrahedron Letters 46 (2005) 8237–8240
8239
8, since there is good literature precedent from Weiler
that anions cis to esters are more stable than those trans
to esters.7 This anion, if the ion pair is tight, can under-
go an intramolecular Michael addition to the enone to
ultimately produce the cyclohexenones 5 as we have
shown.1 However, if the ion pair is not as tight, presum-
ably a proton transfer can occur to convert the less sta-
ble carbanion 8, stabilized via the allylic ester, into the
more stable carbanion 9 stabilized by both the ketone
and the allylic ester. Also at some point, via enoliza-
tion–reprotonation, the double bond geometry of the
tetrasubstituted olefin must switch from E to Z (or a
mixture of the two since only the Z can react). Attack
of the enolate on the ester as shown in 10 gives 11, which
then ejects ethoxide to give the observed product, the
pyrone 6. There is some evidence for at least part of this
mechanism since Jeschke8 (Scheme 4) showed that sev-
eral keto esters 12, which are the protonated forms of
our suggested intermediates 9, gave the 2-pyrones 6 on
treatment with base. Thus, the anion of 12 (namely 9)
must lead to the pyrones. We have one additional piece
of evidence that suggests that the formation of pyrones
from the cyclobutanols proceeds as shown in Figure 1.
Treatment of the cyclobutanol 4a with sodium hydride
with the subsequent addition of an equiv of magnesium
chloride in THF at 22 °C for 48 h afforded two prod-
ucts, the expected pyrone 6a in 27% yield and the
dienone ester 12a in 28% yield (Scheme 5). Thus, we
have good evidence that the cyclobutanol 4a opens in
base to the diene ester 12, which has already been shown
to close to the pyrone in base.
CH3
EtO
OEt
EtO
OEt
H2C
C
CO2Et
2
H3C
Tol/110 oC/24 h
13
CO2Et
28%
O
14
aq TsOH
acetone
.
H3C
22 ˚C/1 h
CO2Et
81%
15
Scheme 6.
cyclobutanone ketal 14 in an unoptimized yield of 28%
(Scheme 6). Acidic hydrolysis of the ketal in aqueous
acetone afforded the 3-carboethoxyethylidene cyclo-
butanone 15 in 81% yield. Addition of nucleophiles to
this reactive ketone would generate the same alkoxide
intermediate shown in Figure 1 and thus should lead
to the same pyrones, thereby streamlining the process
somewhat.
In conclusion, we have developed a new method for the
synthesis of 6-substituted 3,4-dimethyl-2-pyrones 6,
which involves the base-promoted rearrangement of
3-carbo-ethoxyethylidene cyclobutanols 4 and affords a
series of pyrones in yields of 60–100%. A mechanism
for this unusual transformation has been proposed and
some evidence supporting it presented. Finally, a route
to the reactive cyclobutanone 15 has been developed.
Finally, we wish to report a new method for the forma-
tion of these compounds that does not utilize the initial
[2+2] cycloaddition of 2-silyloxydienes. Diethyl ketene
acetal, 13, prepared by the literature route,9 was heated
with the allene carboxylate 2 in toluene to give the
Acknowledgments
We thank the National Science Foundation (CHE
0314591) for generous support of this work.
Supplementary data
R"
O
O
R'
O
R'
Supplementary data associated with this article can be
base
R"
H3C
H3C
CH3
CH3
CO2Et
6
12
References and notes
Scheme 4.
1. Jung, M. E.; Nishimura, N.; Novack, A. R. J. Am. Chem.
Soc. 2005, 127, 11206–11207.
2. The yield of 3a is somewhat low because under these
conditions, the monoaryl substituted systems undergo
thermal [3,3]-sigmatropic rearrangement to the methylene
cyclohexenyl silyl ethers.
HO
CH3
NaH
MgCl2
CH3
H3C
THF
48 h
CO2Et
4a
3. (a) Fairlamb, I. J. S.; Marrison, L. R.; Dickinson, J. M.;
Lu, F.-J.; Schmidt, J. P. Bioorg. Med. Chem. 2004, 12,
4285–4299; (b) Fujinami, M. Japanese Patent 2002363174
(Chem. Abstr. 2004, 138, 24641); (c) Marrison, L. R.;
Dickinson, J. M.; Fairlamb, I. J. S. Bioorg. Med. Chem.
Lett. 2003, 13, 2667–2671.
4. (a) Shen, H. C.; Wang, J.; Cole, K. P.; McLaughlin, M. J.;
Morgan, C. D.; Douglas, C. J.; Hsung, R. P.; Coverdale, H.
A.; Gerasyuto, A. I.; Hahn, J. M.; Liu, J.; Sklenicka, H. M.;
Wei, L.-L.; Zehnder, L. R.; Zificsak, C. A. J. Org. Chem.
2003, 68, 1729–1735; (b) Shimizu, H.; Okamura, H.;
CH3
CH3
O
O
CH3
CH3
O
H3C
H3C
+
CH3
CH3
CO2Et
28%
27%
12a
6a
Scheme 5.