Formation of 3,4-dimethyl-2-pyrones from allene carboxylates and 2-silyloxydienes via 3-carboethoxyethylidene cyclobutanols

Article abstract of DOI:10.1016/j.tetlet.2005.09.091

The 3-carboethoxyethylidene cyclobutanols 4 are prepared in two steps via [2+2] cycloaddition of the 2-silyloxydienes 1 and the allene carboxylate 2 followed by acidic hydrolysis. Treatment of these cyclobutanols 4 with various bases affords good yields o

Full text of DOI:10.1016/j.tetlet.2005.09.091

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 8237–8240
Formation of 3,4-dimethyl-2-pyrones from allene carboxylates
and 2-silyloxydienes via 3-carboethoxyethylidene cyclobutanols
Michael E. Jung* and Aaron R. Novack
Department of Chemistry and Biochemistry, University of California, Los Angeles, CA 90095-1569, USA
Received 3 August 2005; revised 14 September 2005; accepted 14 September 2005
Available online 7 October 2005
Abstract—The 3-carboethoxyethylidene cyclobutanols 4 are prepared in two steps via [2+2] cycloaddition of the 2-silyloxydienes 1
and the allene carboxylate 2 followed by acidic hydrolysis. Treatment of these cyclobutanols 4 with various bases affords good yields
of the substituted 3,4-dimethyl-2-pyrones 6. The proposed mechanism involves ring opening of the metal alkoxide 7 to give the carb-
anion 8, which undergoes proton transfer to give the more stable carbanion 9 and double bond isomerization to give the enolate 10,
which then forms the pyrone ring 6 via attack on the ester via 11.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, we reported the formation (Scheme 1) of
1-alkenyl-3-carboethoxyethylidenecyclobutanols 4 via a
two-step procedure involving first [2+2] cycloaddition
of various 2-silyloxydienes 1 with ethyl 2-methylbuta-
2,3-dienoate 2 to give the cyclobutyl silyl ethers 3 and
then acidic hydrolysis of the silyl ethers to the alcohols
4.1 The dienes 2 were usually prepared from the corre-
sponding enones via standard silyl enol ether formation.
Treatment of these cyclobutanols 4 with lithium bases at
low temperature led to a highly stereoselective rear-
rangement of the cyclobutane systems to the cyclohexe-
nones 5. For example, the 2-silyloxydiene 1c derived
from 4-phenyl-3-buten-2-one on heating with the allene
carboxylate 2 in toluene at 130 °C for 5 h gave the [2+2]
cycloadduct 3c, which was hydrolyzed to the cyclobuta-
nol 4c in 38% overall yield for the two steps (Scheme 2).2
Treatment of 4c with lithium hexamethyldisilazide
(LiHMDS) in THF at ꢀ78 °C afforded a 5:1 mixture
of the endo and exo cyclohexenones 5cn and 5cx in
73% yield. We now report a different reaction pathway
for the cyclobutanols 4 on treatment with different bases
to produce not cyclohexenones 5 but rather the 6-substi-
tuted 3,4-dimethyl-2-pyrones 6 in good to excellent
yields (Scheme 3). Since substituted 2-pyrones are com-
pounds of interest both for their beneficial biological
properties3 and for their use in organic synthesis,4
several routes have been devised for their synthesis.5
CH3
TMSO
R'
R'
H2C
C
CO2Et
R"
R"
2
CH3
Tol/130 oC
TMSO
TsOH
CO2Et
1
CH3
OR
1)
H2C
3
Ph
C
HO
R' R"
R'
CO2Et
CH3
H
2
1.3 eq
MeLi
Ph
CH3
R"
Tol/130 oC/5 h
2) TsOH
38%
CO2Et
CH3
TMSO
EtOH
THF
THF
-78 oC
to 0 oC
CO2Et
O
CH3
1c
3c R = TMS
4c R = H
CO2Et
5
4
H
Ph
Ph H
CH3
CH3
Scheme 1.
LiHMDS
CO2Et
CO2Et
THF
-78 oC
73%
+
:
O
CH3
5
O
CH3
Keywords: 2-Pyrones; Cyclobutanols; Base-promoted rearrangement;
Cyclobutanones.
5cn
1
5cx
*
Corresponding author. Tel.: +1 3108257954; fax: +1 3102063722;
e-mail: jung@chem.ucla.edu
Scheme 2.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.09.091

8238
M. E. Jung, A. R. Novack / Tetrahedron Letters 46 (2005) 8237–8240
HO
CH3
We postulate that the formation of the 2-pyrones 6 from
R'
CH3
the cyclobutanols 4 proceeds via the mechanism shown
in Figure 1. Deprotonation of the alcohol would give
the alkoxide 7 with the metal counterion that was pres-
ent in the base. We have already shown that very tight
ion pairs are necessary for the ring opening-intramole-
cular Michael addition (or anionic [3,3]-sigmatropic
rearrangement) to give cyclohexenones 5.1 We propose
that the alkoxide opens the strained cyclobutane ring
regiospecifically to give the carbanion cis to the ester
base
R"
R"
CH3
R'
O
O
CO2Et
6
4
Scheme 3.
As reported herein, we have now developed a novel
route to 2-pyrones from allene esters and silyl enol
ethers via cyclobutanols.
_
The results are shown in Table 1. When the 1-(2-meth-
ylpropenyl)cyclobutanol 4a was treated with sodium
hydride, we isolated a 20% yield of the 2-pyrone 6a as
a white solid. The use of lithium hexamethyldisilazide
(LiHMDS) converted 4a into the pyrone 6a in 63%
yield. However, the best yield resulted when the cyclo-
butanol 4a was treated with sodium hydride and an
equiv of zinc dichloride was added; in this case a quan-
titative yield of the crystalline pyrone 6a was isolated.
The other 2,2-disubstituted alkenyl cyclobutanol 4b also
gave quite good yields of the pyrone 6b. Sodium hydride
afforded a 77% yield of 6b while the use of tert-butyl-
lithium as base furnished the desired pyrone as a white
solid in 94% yield. The two E monosubstituted alkenyl-
cyclobutanols 4c and 4d gave the corresponding pyrones
6c and 6d in yields of 60% and 64%, respectively. The
1-(cyclohexenyl)cyclobutanol 4e afforded the pyrone 6e
in 62% yield. Finally, we also looked at a simple case
in which no competing ring opening-intramolecular
Michael addition (or anionic [3,3]-sigmatropic rear-
rangement) to give cyclohexenone products would be
possible, namely the 1-phenyl derivative 4f. Treatment
of 4f with LiHMDSgave the pyrone 6f in 64% yield,
while the use of potassium hydride and 18-Crown-6
afforded 6f in 42% yield. Thus many different substituted
2-pyrones can be prepared by this route.6
O
HO
M+
R'
R'
_
M+ Base
R"
R"
CH3
CH3
CO2Et
CO2Et
7
4
O
R"
O
M+
_
proton
transfer
R'
R'
_
CH2
M+
CH3
CH3
CH3
R"
CO2Et
CO2Et
8
9
_
_
M+
M+
O
O
O
R'
O
R'
EtO
CH3
EtO
R"
O
R"
H
H
H3C
CH3
CH3
10
11
O
R'
R"
H3C
CH3
6
Figure 1. Mechanism for the conversion of the 3-carbo-ethoxyethy-
lidenecyclobutanols 4 into 2-pyrones 6.
Table 1. Formation of 6-substituted 3,4-dimethyl-2-pyrones 6 from cyclobutanols 4 on treatment with base
R"
HO
CH3
R'
H3C
O
base
THF
0 - 22 ˚C
R
R
H3C
R'
O
CO2Et
R"
6
4
Cyclobutanol
R
R0
R00
Base
NaH
LiHMDS
NaH/ZnCI2
NaH
t-BuLi
NaH
NaH
Pyrone
Yield (%)
4a
4a
4a
4b
4b
4c
4d
4e
CH3
CH3
CH3
CH3
CH3
H
CH3
CH3
CH3
Ph
Ph
Ph
H
H
H
H
H
H
H
6a
6a
6a
6b
6b
6c
6d
6e
20
63
100
77
94
60
H
H
CH3
64
62
–(CH2)4–
NaH
HO
CH3
Ph
LiHMDS
64
42
H3C
O
4f
H3C
Ph
O
KH 18-C-6
CO2Et
6f

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
found, in the online version, at doi:10.1016/j.tetlet.
2005.09.091.
base
R"
H3C
H3C
CH3
CH3
CO2Et
6
12
References and notes
Scheme 4.
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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
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O
CH3
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H3C
H3C
+
CH3
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28%
27%
12a
6a
Scheme 5.

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