Efficient synthesis of functionalised 4-hydroxycyclopent-2-en-1-ones by cyclisation of 1,3-bis(silyl) enol ethers and 1,3-dicarbonyl dianions with 1,2-diketones

Article abstract of DOI:10.1002/ejoc.200400553

The cyclisation of 1,3-bis(silyl) enol ethers and 1,3-dicarbonyl dianions with 1,2-diketones provides convenient access to functionalised 4-hydroxycyclopent-2-en-1-ones. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005.

Full text of DOI:10.1002/ejoc.200400553

FULL PAPER
Efficient Synthesis of Functionalised 4-Hydroxycyclopent-2-en-1-ones by
Cyclisation of 1,3-Bis(silyl) Enol Ethers and 1,3-Dicarbonyl Dianions
with 1,2-Diketones
Edith Holtz,[a] Valentin Köhler,[a] Bettina Appel,[a] and Peter Langer*[a][‡]
Keywords: Aldol reactions / Cyclisations / Dianions / Regioselectivity / Silyl enol ethers
The cyclisation of 1,3-bis(silyl) enol ethers and 1,3-dicarbonyl
dianions with 1,2-diketones provides convenient access to
functionalised 4-hydroxycyclopent-2-en-1-ones.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2005)
Introduction
Functionalised 4-hydroxycyclo-2-penten-1-ones are of
pharmacological relevance and are present in a number of
natural products such as prostaglandins[14,15] and industrial
compounds for crop protection.[14,16] For example, (ϩ)-pyr-
ethrolon, (ϩ)-cinerolon and (ϩ)-jasmolon represent the ac-
tive compounds of the insecticide pyrethrum isolated from
Chrysanthemum plants.[14] The development of methods for
the synthesis of analogues, which are less harmful towards
humans and animals, is of considerable interest.
Despite their simplicity, the synthetic applicability of
cyclisation reactions of 1,3-dicarbonyl dianions[1,2] with di-
electrophiles is often limited by side reactions such as poly-
merisation, decomposition,[3] formation of open-chain
products,[4] elimination[5] or SET reactions.[6] Lewis acid
mediated reactions of 1,3-bis(silyl) enol ethers, which can
be regarded as masked 1,3-dicarbonyl dianions, have been
developed to overcome these problems.[7,8] During the past
years, we have studied cyclisation reactions[9] of free and
masked 1,3-dicarbonyl dianions with a variety of 1,2-dielec-
trophiles.[10] In this context, reactions of 1,2-dicarbonyl de-
rivatives such as 1,2-diketones, 2-formylketones, glyoxal or
2-formylketals are of special synthetic relevance. Base-me-
diated cyclisation reactions of ketones with 1,2-diketones
have been studied for a long time[11] but they are often lim-
ited to the use of nonenolisable (e.g. aromatic) substrates.
Molander et al. developed the Lewis acid mediated cyclis-
ation of an electroneutral equivalent of the trimethyleneme-
thane dianion with enolisable 1,2-diketones to give 1,2-di-
hydroxy-4-methylenecyclopentanes[12] and we have recently
reported[13] the cyclisation of enolisable 1,2-diketones with
1,3-bis(silyl) enol ethers. These reactions allow the chemose-
lective synthesis of a variety of functionalised 4-hydroxy-
cyclo-2-penten-1-ones. Herein, we wish to report full details
of this methodology. With regards to our preliminary re-
port, we have extended the preparative scope to the use of
1,2-formylketals. In addition, we report what are, to the best
of our knowledge, the first cyclisations of free 1,3-dicar-
bonyl dianions with enolisable 1,2-diketones to give cyclo-
pentenones.
One-Pot Cyclisation of 1,3-Bis(silyl) Enol Ethers with 1,2-
Diketones
The reaction of 1,3-bis(silyl) enol ether 1a with butane-
2,3-dione (2a) afforded the 4-hydroxycyclo-2-penten-1-one
3a (Scheme 1). The best yields were obtained when the
Lewis acid TiCl4 (2 equiv.) was employed. The use of Me3-
SiOTf or BF3·OEt2 proved unsuccessful. The presence of
˚
molecular sieves (4 A) and a proper tuning of the concen-
tration, reaction time and temperature also proved ex-
tremely important during the optimisation. The success of
the reaction depended very much on the reaction conditions
and on the quality of the reagents and solvents.
The formation of 3a can be explained by the occurrence
of a double MukaiyamaϪaldol-reaction[17] and subsequent
elimination of water. The reaction proceeds by regioselec-
tive attack of the terminal carbon of the diene on 2a and
subsequent cyclisation via the central carbon atom. In con-
trast, a cyclisation via the carbon and the oxygen atom was
observed in the reactions of 1a with oxalyl chloride due
to stereoelectronic effects (Baldwin rules). The change from
C,O- to C,C-cyclisation in the reaction of 1a with 2a can
be explained by reversible formation of a labile hemiketal
[a]
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt
Universität Greifswald,
Soldmannstr. 16, 17487 Greifswald, Germany
Fax: (internat.) ϩ 49-3834-864373
E-Mail: peter.langer@uni-greifswald.de
[‡]
New address: Institut für Chemie der Universität Rostock,
Albert-Einstein-Str. 3a, 18051 Rostock, Germany
532
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400553
Eur. J. Org. Chem. 2005, 532Ϫ542

Synthesis of Functionalised 4-Hydroxycyclopent-2-en-1-ones
FULL PAPER
oxohexanoate, gave the cyclopentenones 3dϪe. The reaction
of 2a with 1fϪg, prepared from methyl 4-methoxyace-
toacetate and 1-methoxyacetylacetone, afforded the meth-
oxy-substituted cyclopent-2-en-1-ones 3f and 3g, respec-
tively. The 1,2-stereoselectivities observed for 3d and 3fϪg
were low. A moderate 1,2-stereoselectivity was observed in
the case of 3e.
The reaction of 3,4-hexanedione (2b) with 1,3-bis(trime-
thylsilyloxy)-1,3-butadienes 1a and 1b afforded the cyclo-
pentenones 3h and 3i, respectively. Cyclopentenone 3j was
prepared from diene 1d with good diastereoselectivity (5:1).
The structure of the major component could not be unam-
biguously assigned, however, due to signal overlap. The
yields obtained from the reactions of 2b were lower than
those obtained from the reactions of the respective cyclisa-
tions of 2a. In addition, longer reaction times were required
(6 ϩ 12 h). The reactions of 1a and 1c with the unsymmetri-
cal pentane-2,3-dione (2c) afforded the cyclo-2-penten-1-
ones 3kϪl with good and moderate regioselectivities,
respectively.
Scheme 1. Cyclisation of 1,3-bis(silyl) enol ether 1a with 2,3-but-
˚
anedione, a: 2.0 TiCl4, CH2Cl2, 4-A mol. sieves, Ϫ78 Ϫ 20 °C,
6Ϫ12 h, 20 °C, 2Ϫ6 h
The reaction of 1-ethoxy-2-methyl-1,3-bis(trimethylsilyl-
oxy)-1,3-butadiene (1h) with butane-2,3-dione afforded the
open-chained product 4 as a mixture of diastereomers
(Scheme 3). No cyclisation could be induced, presumably
due to the steric effect of the methyl group.
(C,O-cyclisation) which was subsequently opened and
irreversibly transformed into 3a.
To study the preparative scope of the reaction, the sub-
stituents were systematically varied (Scheme 2, Table 1).
The reaction of 2a with 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes 1aϪc, prepared from ethyl acetoacetate, acetyl-
acetone and 1-methoxyacetylacetone, afforded the cyclo-
pent-2-en-1-ones 3aϪc. The cyclisation of 2a with dienes
1dϪe, derived from methyl 3-oxopentanoate and ethyl 3-
˚
Scheme 3. Reaction of 1h with 2a, a: 2.0 TiCl4, CH2Cl2, 4-A mol.
sieves, Ϫ78 °C Ϫ 20 °C, 12 h, 20 °C, 2 h, 53%
The diastereomers of 3f were separated and analysed by
NOESY measurements. For one of the isomers, an interac-
tion was detected between hydrogen atom 5-H and the
methyl group attached to C-4. This supports the presence
of a cis relationship between the hydroxy and the methoxy
groups which is also supported by a comparison of the
chemical shifts of the CH groups of the isomers. For one
isomer, the corresponding resonance at δ ϭ 3.92 ppm ap-
pears at significantly lower field than for the other (δ ϭ 3.53
ppm). This can be explained by deshielding of the proton
located cis to the neighbouring hydroxy group.
Scheme 2. Synthesis of 4-hydroxycyclopent-2-en-1-ones 3, a: 2.0
˚
TiCl4, CH2Cl2, 4-A mol. sieves, Ϫ78 °C Ϫ 20 °C, 12 h, 20 °C, 2 h
Table 1. Products and yields
3
R1
R2
R3 R4 (%)[a] δ (multiplicity)[b]
ds[c]
a
b
c
d
e
f
g
h
i
H
H
H
Me
Et
OMe OMe
OMe Me
H
H
Me
H
OEt
Me
Me Me 50
Me Me 38
2.24 (s) 1.47 (s)
2.25 (s) 1.45 (s)
2.29 (s) 1.46 (s)
2.26 (s) 1.45 (s) 1.2:1
2.30 (s) 1.49 (s) 3.5:1
2.28 (s) 1.46 (s) 1:1.4
2.36 (s) 1.36 (s) 1:1.2
2.60 (m) 1.78 (m)
2.60 (m) 1.70 (m)
2.68 (m) 1.79 (m) 5:1
2.67 (m) 1.53 (s) 5:1
2.76 (m) 1.52 (s) 4:1
Ϫ
Ϫ
Ϫ
CH2OMe Me Me 40
OMe
OEt
Me Me 32
Me Me 34
Me Me 42
Me Me 25
Et Et 28
Et Et 16
Et Et 21
Me Et 45
OEt
Me
OMe
OEt
Ϫ
Ϫ
j
k
l
H
CH2OMe Me Et 35
The configurations of the isomers of 3dϪe could not be
established by NOESY experiments due to a severe signal
overlap. However, comparisons of the chemical shifts of the
endocyclic CH-signals and of the alkyl groups R1 (Me, Et)
of the isomers and comparisons with the signals of com-
pounds with known configurations[18] supported the exist-
[a]
[b]
Isolated yields.
chemical shifts (1H NMR) of the CH3 and
CH2 groups attached to carbons C-3 and C-4; for 3dϪg and 3jϪl
[c]
the signals of the major isomers are given.
for 3dϪg and 3j:
diastereomeric ratio (by 1H NMR), for 3kϪl: regioisomeric ratio
1
(by H NMR spectroscopy).
Eur. J. Org. Chem. 2005, 532Ϫ542
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
533

E. Holtz, V. Köhler, B. Appel, P. Langer
FULL PAPER
ence of a trans configuration in the main isomers of 3dϪe. minal carbon of the diene on the aldehyde and subsequent
The configurations of the unsymmetrically substituted com- cyclisation by attack of the central carbon atom on the ke-
pounds 3kϪl were established by analysis of the chemical tal. The cyclisation of 5 with dienes 1iϪm, prepared from
shifts: the signals of the CH3 and CH2 groups of substituent methyl, methoxyethyl, isobutyl, benzyl and isopropyl ace-
R4 generally appear at lower field than those of R3 toacetate, afforded the cyclopentenones 6aϪe (Scheme 4,
(Table 1). Characteristic singlets and multiplets were ob- Table 2). The cyclisation of 1-phenyl-1,3-bis(trimethyl-
served for the CH3 and the CH2 groups, respectively.
silyloxy)-1,3-butadiene (1n) with 5 afforded the correspond-
ing product 6f. The 4-hydroxycyclopent-2-en-1-ones 6gϪh
were prepared from dienes 1d and 1e with good trans-
diastereoselectivities. The relative configurations were es-
tablished from spectroscopic data (comparison of chemical
shifts as outlined above).[21]
One-Pot Cyclisation of 1,3-Dicarbonyl Dianions with 1,2-
Diketones
The reaction of the dianion of ethyl acetoacetate (7a)
with butane-2,3-dione (2a) and subsequent aqueous
workup afforded the open-chained β-keto ester 8a as the
crude product (Scheme 5, Table 3). All attempts to induce
a cyclisation by heating a solution of 8a failed. Interestingly,
chromatographic purification (silica gel) of 8a resulted in
complete cyclisation and formation of the 4-hydroxycyclo-
2-penten-1-one 9a in 92% yield. Based on this observation,
a one-pot cyclisation was developed for the reaction of the
dianion of 7a with hexane-3,4-dione (2b). After warming
the reaction mixture to 20 °C, silica gel (0.5 g/1 mmol of
2b) was added and the mixture was stirred for 19 h at reflux.
Aqueous workup and chromatographic purification af-
forded the desired cyclopentenone 9b. The one-pot pro-
cedure outlined above allowed the synthesis of 9b in a sig-
nificantly higher yield (61%) than by the use of 1,3-bis(silyl)
enol ether 1a (Table 1, 28%). The open-chained product 8b
could be isolated in 37% yield when no silica gel was added
to the reaction mixture. The one-pot reaction presumably
proceeded by initial condensation of the dianion with 2 to
give a dilithiated intermediate. The latter then became pro-
tonated upon addition of the (slightly acidic) silica gel and
the cyclopentenone 9 was subsequently formed by silica gel
mediated cyclisation.
2,2-Dimethoxy-2-phenylacetaldehyde
The cyclisations of 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes with 2-ketoaldehydes were studied next although the
use of 2-oxo-2-phenylacetaldehyde proved unsuccessful.
Based on the pioneering work of Chan et al., the desired
cyclisation could be induced when 2,2-dimethoxy-2-phenyl-
acetaldehyde (5)[19] was employed.[20] The reaction of diene
1a with 5 afforded the 4-hydroxycyclo-2-penten-1-one 6a
with very good regioselectivity (Scheme 4). The reaction
proceeded by chemo- and regioselective attack of the ter-
Scheme 4. Cyclisation of dienes 1 with 2,2-dimethoxy-2-phenylacet-
˚
aldehyde, a: 2.0 TiCl4, CH2Cl2, 4-A mol. sieves, Ϫ78 °C Ϫ 20 °C,
12 h, 20 °C, 2 h
Table 2. Synthesis of 4-hydroxycyclopent-2-en-1-ones 6aϪh
6
R1
R2
Yield (%)[a]
ds[b]
a
b
c
d
e
f
H
H
H
H
H
H
Me
Et
OMe
17
16
16
5
10
14
55
48
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
Ϫ
3:1
15:1
O(CH2)2OMe
O(iBu)
OCH2Ph
O(iPr)
Ph
OMe
OEt
g
h
Scheme 5. Cyclisation of 1,3-dicarbonyl dianions with 1,2-dike-
tones, a: 1) 2.3 LDA, THF, 0 °C, 7, 1 h, 2) 2, Ϫ78 °C Ϫ 20 °C,
12 h, b: addition of SiO2, THF, reflux, 19Ϫ26 h
[a] Isolated yields. [b] Diastereoselectivity in favour of the trans-iso-
mer.
534
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2005, 532Ϫ542

Synthesis of Functionalised 4-Hydroxycyclopent-2-en-1-ones
Table 3. Products and yields
FULL PAPER
ate with 2b afforded 9m as a separable mixture of dia-
stereomers. The cyclisation of the dianion of N,N-diethyl-
acetylacetamide with 2a and 2b afforded the cyclopen-
tenones 9n and 9o, respectively. In the case of 9o, the open-
chained product 10 was isolated as a side product.
A brief comparison of the two reported methods for the
synthesis of cyclopentenones seems to be appropriate. Simi-
lar yields were obtained for cyclisations of 2a with dianions
or 1,3-bis(silyl) enol ethers derived from simple β-keto es-
ters. The aryl-substituted cyclopentenones 9e and 9j could
not be prepared by application of the TiCl4-mediated cyclis-
ation reaction. The amide-substituted products 9n and 9o
are also not available by TiCl4-mediated cyclisations since
β-ketoamide-derived 1,3-bis(silyl) enol ethers undergo a ra-
pid 1,5-silyl migration.[22] The cyclisations of hexane-3,4-
dione (2b) generally proceeded in higher yields when the
dianion method was employed. Similar regio- and dia-
stereoselectivities were observed for both the dianion and
the silyl enol ether methodologies. For both methods, the
yields decreased for cyclopentenones containing a substitu-
ent at carbon C-5.
In summary, we have reported two convenient methods
for the synthesis of cyclopentenones. Each method offers
specific advantages.
[a] Isolated yields. [b] Formed from pure 8a during chromatographic
[c]
[d]
purification.
Mixture of regioisomers: rs ϭ 3:1.
Mixture
[e]
of diastereomers: ds ϭ 4:1.
Diastereomers were separated.
[f]
Experimental Section
General Procedure for the Cyclisation of 1,2-Diketones with 1,3-Bis-
(trimethylsilyloxy)-1,3-butadienes: To a CH2Cl2 solution (40 mL) of
1,3-bis(trimethylsilyloxy)-1-ethoxy-1,3-butadiene
(1a)
(0.52 g,
1.9 mmol) and 2,3-butanedione (0.17 mL, 0.17 g, 2.0 mmol, 1.0
equiv.) was added TiCl4 (0.42 mL, 0.72 g, 2.0 equiv.) at Ϫ78 °C in
the presence of molecular sieves (4 A). The reaction mixture was
warmed to 20 °C over 6Ϫ12 h. After stirring for 2Ϫ6 h at 20 °C, a
saturated aqueous NaHCO3 solution (20 mL) was added, the or-
The cyclisation of the dianion of 7a with cyclohexane-
1,2-dione (2d) afforded the desired bicyclic product 9c in up
to 25% yield. During optimisation of this reaction, the use
˚
of an excess of 7a (2 equiv.) and removal of the silica gel by ganic layer was separated and the aqueous layer was extracted with
diethyl ether (4 ϫ 50 mL). The combined organic layers were dried
(MgSO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by chromatography (silica gel, diethyl ether/
petroleum ether, 1:1) to give 3a as a colourless oil (188 mg, 50%).
The results of our earlier work are substituted by the results re-
ported herein.
filtration proved to be important. The addition of water to
the suspension of silica gel also proved unsuccessful. The
cyclisation of dilithiated 7a with (unsymmetrical) hexane-
2,3-dione (2e) afforded 9d as a 3:1 mixture of its regioiso-
mers. The major product was formed by attack of the ter-
minal carbon of the dianion on the sterically less encum-
bered side of the diketone. The cyclisation of dilithiated 7a
with benzile (2f) afforded the phenyl-substituted cyclopen-
tenone 9e in 69% yield. The reaction of the dianion of 7a
with 3,4,5,6-tetrachloro-1,2-benzoquinone, acenaphtenequi-
none and 1,2-naphthoquinone resulted in the formation of
complex mixtures due to competing SET-processes. The
cyclopentenones 9fϪh were prepared by cyclisation of the
dianions of methyl, methoxyethyl and tert-butoxy ace-
toacetate (7bϪd) with hexane-3,4-dione (2b). The cyclis-
Ethyl
3-Hydroxy-2,3-dimethyl-5-oxocyclopent-1-enecarboxylate
(3a): 1H NMR ([D6]acetone, 250 MHz, ppm): δ ϭ 1.27 (t, J ϭ
7.1 Hz, 3 H, CH3CH2), 1.47 (s, 3 H, 3-CH3), 2.24 (s, 3 H, 2-CH3),
2.53 (s, 2 H, 4-H), 4.22 (q, J ϭ 7.1 Hz, 2 H, CH2O), 4.62 (s, 1 H,
OH). 13C NMR ([D6]acetone, 62.9 MHz, ppm): δ ϭ 11.68, 13.62
(CH3CH2, 3-CH3), 25.31 (2-CH3), 51.07 (C-4), 60.22 (CH3CH2),
75.02 (C-3), 131.57 (C-1), 162.97 (CO2Et), 182.60 (C-2), 198.45
(CϭO). MS (70 eV, EI): m/z (%) ϭ 198 (43) [Mϩ], 183 (60), 154
(46), 152 (64), 137 (100); the exact molecular mass for C10H14O4
m/z ϭ 198.0892Ϯ2 ppm [Mϩ] was confirmed by HRMS (EI,
ation of dilithiated tert-butoxy acetoacetate with benzile 70 eV).
and phenanthrene-9,10-dione afforded the cyclopentenones
2-Acetyl-4-hydroxy-3,4-dimethylcyclopent-2-enone (3b): Following
9i and 9j, respectively. The cyclisation of the dianions of
benzyloxy acetoacetate with 2b afforded the cyclopentenone
9k, albeit in low yield. The cyclisation of dilithiated ethyl 3-
oxohexanoate with 2b gave 9l as a mixture of diastereomers.
the general procedure, 2,3-butanedione (0.20 mL, 0.19 g, 2.2 mmol,
1 equiv.) was treated with 2,4-bis(trimethylsilyloxy)-1,3-pentadiene
(0.53 g, 2.2 mmol, 1 equiv.) and TiCl4 (0.48 mL, 0.82 g, 4.3 mmol,
2 equiv.). The product was purified by chromatography to give 3b
The reaction of the dianion of methyl 4-methoxyacetoacet- as a colourless solid (140 mg, 38%). 1H NMR ([D6]acetone,
Eur. J. Org. Chem. 2005, 532Ϫ542
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© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
535

E. Holtz, V. Köhler, B. Appel, P. Langer
FULL PAPER
250 MHz, ppm): δ ϭ 1.45 (s, 3 H, 4-CH3), 2.25 (s, 3 H, 3-CH3), butanedione (0.16 g, 0.16 mL, 1.9 mmol) was treated with 1,3-bi-
2.34 (s, 3 H, CH3CϭO), 2.56 (s, 2 H, 5-H), 4.61 (s, 1 H, OH). 13C
NMR ([D6]acetone, 50.3 MHz, ppm): δ ϭ 12.72, 26.22, 30.89 (4-
s(trimethylsilyloxy)-1,4-dimethoxybuta-1,3-diene (0.55 g, 1.9 mmol,
1 equiv.) and TiCl4 (0.42 mL, 0.72 g, 2 equiv.). The product was
CH3, 3-CH3, CH3CϭO), 51.97 (C-5), 75.76 (C-4), 137.56 (C-2), purified by chromatography to give 3f as a colourless oil (171 mg,
185.17 (C-3), 197.63, 202.00 (2 ϫ CϭO). MS (70 eV, EI): m/z (%) ϭ 42%, ds ϭ 1:1.4). The diastereomers could be separated by repeated
168 (65) [Mϩ], 153 (22), 125 (22), 85 (59), 43 (100). C9H12O3 chromatography to give (cis-3f) (46 mg, 11%) and (trans-3f) (19 mg,
(168.2): calcd. C 64.26, H 7.20; found C 64.01, H 7.11.
5%) as yellowish solids.
1
cis-3f: H NMR ([D6]acetone, 250 MHz, ppm): δ ϭ 1.46 (s, 3 H, 3-
4-Hydroxy-2-(2-methoxyethanoyl)-3,4-dimethylcyclopent-2-enone
(3c): Following the general procedure, 2,3-butanedione (0.18 g, 0.18
mL, 2.1 mmol) was treated with 2,4-bis(trimethylsilyloxy)-5-meth-
oxy-1,3-pentadiene (0.56 g, 2.0 mmol) and TiCl4 (0.45 mL, 0.78 g,
4.1 mmol, 2 equiv.). The product was purified by chromatography
to give 3c as a colourless oil (160 mg, 40%). 1H NMR ([D6]acetone,
250 MHz, ppm): δ ϭ 1.46 (s, 3 H, 4-CH3), 2.29 (s, 3 H, 3-CH3),
2.56 (s, 2 H, 5-H), 3.33 (s, 3 H, CH3O), 4.39 (s, 2 H, CH2O), 4.66
(s, 1 H, OH). 13C NMR (CDCl3, 62.9 MHz, ppm): δ ϭ 12.05, 25.42
(3-CH3, 4-CH3), 50.99 (C-5), 58.28 (CH3O), 75.43 (C-4), 135.21
(C-2), 186.26 (C-3), 196.19, 201.13 (CϭO). MS (70 eV, EI):
m/z (%) ϭ 198 (10) [Mϩ]; the exact molecular mass for C10H14O4
m/z ϭ 198.0892Ϯ2 ppm [Mϩ] was confirmed by HRMS (EI,
70 eV).
CH3), 2.28 (s, 3 H, 2-CH3), 3.53 (s, 1 H, 4-H), 3.59 (s, 3 H,
CH3OCH), 3.75 (s, 3 H, CH3OCϭO), 4.12 (s, 1 H, OH). 13C NMR
([D6]acetone, 50.3 MHz, ppm): δ ϭ 13.10 (3-CH3), 24.77 (2-CH3),
51.85 (CH3OCϭO), 59.63 (CH3OCH), 75.53 (C-3), 85.24 (C-4),
130.59 (C-1), 164.04 (CO2Me), 182.99 (C-2), 197.82 (CϭO). IR
(neat): ν˜ ϭ 3469 (br), 2956 (m), 2936 (m), 1746 (s), 1721 (s), 1629
(m), 1438 (s), 1377 (s), 1348 (m), 1323 (m), 1232 (s), 1127 (s), 1102
(s). MS (70 eV, EI): m/z (%) ϭ 214 (16) [Mϩ], 199 (10), 184 (12),
182 (100); the exact molecular mass for C10H14O5 m/z
ϭ
214.0841Ϯ2 ppm [Mϩ] was confirmed by HRMS (EI, 70 eV).
1
trans-3f: H NMR ([D6]acetone, 250 MHz, ppm): δ ϭ 1.27 (s, 3 H,
3-CH3), 2.30 (s, 3 H, 2-CH3), 3.63 (s, 3 H, CH3OCH), 3.74 (s, 3 H,
CH3OCϭO), 3.92 (s, 1 H, 4-H), 4.96 (s, 1 H, OH). 13C NMR
([D6]acetone, 75.5 MHz, ppm): δ ϭ 12.79 (3-CH3), 22.30 (2-CH3),
51.79 (CH3OCϭO), 59.91 (CH3OCH), 78.92 (C-3), 91.23 (C-4),
129.27 (C-1), 163.76 (CO2Me), 182.49 (C-2), 196.14 (CϭO). MS
(70 eV, EI): m/z (%) ϭ 214 (32) [Mϩ], 199 (16), 182 (100).
Methyl 3-Hydroxy-2,3,4-trimethyl-5-oxocyclopent-1-enecarboxylate
(3d): Following the general procedure, 2,3-butanedione (0.18 g, 0.18
mL, 2.1 mmol) was treated with 1,3-bis(trimethylsilyloxy)-1-meth-
oxypenta-1,3-diene (0.56 g, 2.0 mmol, 1 equiv.) and TiCl4 (0.45 mL,
0.78 g, 2 equiv.). The product was purified by chromatography to
give 3d as a colourless oil (128 mg, 32%, ds ϭ 1.2:1). 1H
2-Acetyl-4-hydroxy-5-methoxy-3,4-dimethylcyclopent-2-enone (3g):
Following the general procedure, 2,3-butanedione (0.15 g, 0.15 mL,
1.8 mmol) was treated with 2,4-bis(trimethylsilyloxy)-1-methoxy-
1,3-pentadiene (0.50 g, 1.8 mmol) and TiCl4 (0.69 g, 0.40 mL,
3.6 mmol). The product was purified by chromatography to give 3g
as a colourless oil (88 mg, 25%, ds ϭ 1:1.2). 1H NMR (CDCl3,
250 MHz, ppm): δ ϭ 1.36 (s, 3 H, 4-CH3), 2.36 (s, 3 H, 3-CH3),
2.45 (s, 3 H, CH3CϭO), 3.72 (s, 3 H, CH3O), 3.96 (s, 1 H, 5-H).
13C NMR (CDCl3, 62.9 MHz, ppm): δ ϭ 12.15, 21.64, 29.99 (4-
CH3, 3-CH3, CH3CϭO), 59.11 (CH3O), 78.20 (C-4), 90.32 (C-5),
134.05 (C-2), 182.17 (C-3), 195.90, 198.08 (2 ϫ CϭO). MS (70 eV,
EI): m/z (%) ϭ 198 (4) [Mϩ]; the exact molecular mass for
C10H14O4 m/z ϭ 198.0892Ϯ2 ppm [Mϩ] was confirmed by HRMS
(EI, 70 eV).
NMR ([D6]acetone, 250 MHz, ppm): δ ϭ 1.00Ϫ1.10 (d,
J ϭ
7.4 Hz, 3 H, 4-CH3), overlapped by 1.05 (d, J ϭ 7.4 Hz, 3 H, 4-
CH3), 1.25 (s, 3 H, 3-CH3), 1.45 (s, 3 H, 3-CH3), 2.26 (s, 3 H, 2-
CH3), 2.29 (s, 3 H, 2-CH3), overlapped by 2.32 (q, J ϭ 7.4 Hz,
1 H, 4-CH3), 2.54 (q, J ϭ 7.4 Hz, 1 H, 4-H), 3.74 (s, 3 H, CH3O),
overlapped by 3.74 (s, 3 H, CH3O), 4.32 (s, 1 H, OH), 4.64 (s, 1 H,
OH). 13C NMR (CDCl3, 62.9 MHz, ppm): δ ϭ 8.25, 9.38, 11.88,
11.99 (2 ϫ 4-CH3, 2 ϫ 3-CH3), 22.07, 24.58 (2 ϫ 2-CH3), 50.90,
50.93, 51.41, 54.39 (2 ϫ C-4, 2 ϫ CH3O), 76.48, 78.18 (2 ϫ C-3),
129.85, 130.50 (2 ϫ C-1), 163.42, 163.73 (2 ϫ CO2Me), 181.37,
183.53 (2 ϫ C-2), 199.44, 202.13 (2 ϫ CϭO). IR (neat): ν˜ ϭ 3446
(br), 2978 (m), 2954 (m), 2940 (m), 1720 (s), 1632 (m), 1438 (s),
1376 (s), 1347 (s), 1330 (m), 1234 (s), 1106 (m), 1053 (s) cmϪ1. MS
(70 eV, EI): m/z (%) ϭ 198 (12) [Mϩ], 183 (22), 166 (100), 151 (72);
the exact molecular mass for C10H14O4 m/z ϭ 198.0892Ϯ2 ppm
[Mϩ] was confirmed by HRMS (EI, 70 eV).
Ethyl 2,3-Diethyl-3-hydroxy-5-oxocyclopent-1-enecarboxylate (3h):
Following the general procedure, 3,4-hexanedione (0.24 g, 0.26 mL,
2.1 mmol) was treated with 1,3-bis(trimethylsilyloxy)-1-ethoxy-1,3-
butadiene (0.55 g, 2.0 mmol, 1 equiv.) and TiCl4 (0.44 mL, 0.76 g,
4.0 mmol, 2 equiv.). The product was purified by chromatography
to give 3h as a colourless oil (125 mg, 28%). 1H NMR ([D6]acetone,
250 MHz, ppm): δ ϭ 0.85 (t, J ϭ 7.3 Hz, 3 H, CH3CH2COH),
1.19 (t, J ϭ 7.6 Hz, 3 H, CH3CH2CϭC), 1.28 (t, J ϭ 7.0 Hz, 3 H,
Ethyl 4-Ethyl-3-hydroxy-2,3-dimethyl-5-oxocyclopent-1-enecarbox-
ylate (3e): Following the general procedure, 2,3-butanedione (0.16
mL, 0.16 g, 1.9 mmol) was treated with 1,3-bis(trimethylsilyloxy)-
1-ethoxy-1,3-hexadiene (0.56 g, 1.8 mmol) and TiCl4 (0.41 mL,
0.70 g, 3.7 mmol, 2 equiv.). The product was purified by chroma-
tography to give 3e as a colourless oil (104 mg, 34%, ds ϭ 3.5:1).
1H NMR (CDCl3, 250 MHz, ppm): δ ϭ 1.10 (t, J ϭ 7.4 Hz, 3 H,
CH3CH2CH), 1.32 (t, J ϭ 7.1 Hz, 3 H, CH3CH2O), 1.49 (s, 3 H,
3-CH3), 1.51Ϫ1.79 (m, 4 H, 4-H, CH3CH2CH), 2.30 (s, 3 H, 2-
CH3), 4.29 (q, J ϭ 7.1 Hz, 2 H, CH3CH2O). 13C NMR (CDCl3,
62.9 MHz, ppm): δ ϭ 12.69, 12.80, 14.09 (CH3CH2CH, CH3CH2O,
2-CH3), 20.08 (CH2CH), 26.41 (3-CH3), 58.01 (C-4), 60.99 (CH2O),
77.26 (C-3), 130.66 (C-1), 163.42 (CO2Et), 182.42 (C-2), 202.71
(CϭO). MS (70 eV, EI): m/z (%) ϭ 226 (5) [Mϩ], 211 (12), 197 (10),
184 (18), 180 (100); the exact molecular mass for C12H18O4 m/z ϭ
226.1205Ϯ2 ppm [Mϩ] was confirmed by HRMS (EI, 70 eV).
CH3CH2O), AB-signal (δA ϭ 1.68, δB ϭ 1.91, JA,B ϭ 14.6, JA,X
JB,X ϭ 7.3 Hz, 2 H, CH3CH2COH), AB-signal (δA ϭ 2.41, δB
ϭ
ϭ
2.60, JA,B ϭ 18.3 Hz, 2 H, 4-H), overlapped by 2.48Ϫ2.74 (m, 2 H,
CH2CϭC), 4.23 (q, J ϭ 7.0 Hz, 2 H, CH2O), 4.54 (s, 1 H, OH).
13C NMR ([D6]acetone, 62.9 MHz, ppm): δ ϭ 8.64, 13.54, 14.39
(CH3CH2COH, CH3CH2CϭC, CH3CH2O), 20.65, 31.62
(CH2COH, CH2CϭC), 48.96 (C-4), 61.16 (CH2O), 79.86 (C-3),
133.69 (C-1), 164.13 (CO2Et), 185.76 (C-2), 199.68 (CϭO). MS
(70 eV, EI): m/z (%) ϭ 226 (12) [Mϩ], 197 (59), 181 (14), 151 (100);
the exact molecular mass for C12H18O4 m/z ϭ 226.1205Ϯ2 ppm
[Mϩ] was confirmed by HRMS (EI, 70 eV).
2-Acetyl-3,4-diethyl-4-hydroxycyclopent-2-enone (3i): Following the
general procedure 3,4-hexanedione (0.28 mL, 0.26 g, 2.2 mmol, 1
equiv.) was treated with 2,4-bis(trimethylsilyloxy)-1,3-pentadiene
Methyl 3-Hydroxy-4-methoxy-2,3-dimethyl-5-oxocyclopent-1-ene-
carboxylate: (cis-3f, trans-3f) Following the general procedure, 2,3-
536
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 532Ϫ542

Synthesis of Functionalised 4-Hydroxycyclopent-2-en-1-ones
(0.53 g, 2.3 mmol, 1 equiv.) and TiCl4 (0.48 mL, 0.83 g, 2 equiv.).
FULL PAPER
3-Ethyl-4-hydroxy-2-(2-methoxyethanoyl)-4-methylcyclopent-2-
enone (3l) and 4-Ethyl-4-hydroxy-2-(2-methoxyethanoyl)-3-methyl-
The product was purified by chromatography to give 3i as a colour-
1
less oil (70 mg, 16%). H NMR (CDCl3, 250 MHz, ppm): δ ϭ 0.88 cyclopent-2-enone (3lЈ): Following the general procedure, 2,3-
(t, J ϭ 7.5 Hz, 3 H, CH3CH2COH), 1.22 (t, J ϭ 7.5 Hz, 3 H, pentanedione (0.26 mL, 0.25 g, 2.4 mmol, 1 equiv.) was treated
CH3CH2CϭC), 1.70, 1.94 (2 ϫ m, 2 ϫ 1 H, CH2COH), overlapped with 2,4-bis(trimethylsilyloxy)-5-methoxy-1,3-pentadiene (0.65 g,
by 1.98 (s, 1 H, OH), 2.47 (s, 3 H, CH3CO), 2.54, 2.66 (2 ϫ m, 2
2.4 mmol, 1 equiv.) and TiCl4 (0.52 mL, 0.90 g, 4.8 mmol, 2 equiv.).
ϫ 1 H, CH3CH2CϭC), overlapped by AB-signal (δA ϭ 2.52, δB ϭ The product was purified by chromatography to give 3l as a colour-
2.69, JA,B ϭ 18.4 Hz, 2 H, 5-H). 13C NMR (CDCl3, 62.9 MHz, less oil (180 mg, 35%, 3l/3lЈ ϭ 4:1). 3 l: 1H NMR (CDCl3,
ppm): δ ϭ 8.31, 13.48 (CH3CH2COH, CH3CH2CϭC), 20.51, 250 MHz, ppm): δ ϭ 1.22 (t, J ϭ 7.5 Hz, 3 H, CH3CH2CϭC), 1.52
31.24, 31.34 (CH2CϭC, CH2COH, CH3CO), 48.63 (CH2), 79.71
(COH), 137.82 (CH2CϭC), 188.00 (CH2CϭC), 197.47, 201.56 (2 overlapped by 2.65Ϫ2.87 (m, 2 H, CH2CϭC), 3.44 (s, 3 H, OCH3),
ϫ CϭO). IR (Film): ν˜ ϭ 3428 (br), 2974 (m), 2940 (m), 2882 (m),
4.40Ϫ4.60 (m, 2 H, 2 ϫ CH2OMe). 13C NMR (CDCl3, 50 MHz,
(s, 3 H, 4-CH3), 1.60Ϫ1.95 (m, 2 H, CH2COH), 2.65 (s, 2 H, 5-H),
1711 (s), 1692 (s), 1601 (m), 1463 (m), 1361 (m), 1331 (m), 1299 ppm): δ ϭ 13.43 (CH3CH2CϭC), 20.77 (CH2CϭC), 26.12 (4-CH3),
(m), 1189 (m), 1034 (m) cmϪ1. MS (70 eV, EI): m/z (%) ϭ 196 (10) 51.23 (C-5), 59.01 (CH3O), 76.32 (C-4), 78.05 (CH2OMe), 133.95
[Mϩ]; the exact molecular mass for C11H16O3 m/z ϭ 196.1099Ϯ2
(C-2), 193.04 (C-3), 195.50, 202.26 (CϭO).
ppm [Mϩ] was confirmed by HRMS (EI, 70 eV).
1
3lЈ: H NMR (CDCl3, 250 MHz, ppm): δ ϭ 0.83 (t, J ϭ 7.4 Hz, 3
Methyl
2,3-Diethyl-3-hydroxy-4-methyl-5-oxocyclopent-1-enecar-
H, CH3CH2COH), 1.60Ϫ1.95 (m, 2 H, CH2COH), 2.33 (s, 3 H, 3-
CH3), 2.64 (s, 2 H, 5-H), overlapped by 3.44 (s, 3 H, CH3O),
4.40Ϫ4.60 (m, 2 H, CH2OMe). 13C NMR (CDCl3, 50 MHz, ppm):
δ ϭ 8.02, 13.15 (CH3CH2COH, 3-CH3), 30.63 (CH2COH), 47.95
(C-5), 59.01 (CH3O), 77.98 (CH2OMe), 79.00 (C-4), 135.47 (C-2),
187.81 (C-3), 195.43, 201.77 (CϭO). MS (70 eV, EI): m/z (%) ϭ
212 (48) [Mϩ], 183 (29), 167 (92), 99 (100); the exact molecular
mass for C11H16O4 m/z ϭ 212.1049Ϯ2 ppm [Mϩ] was confirmed
by HRMS (EI, 70 eV).
boxylate (3j): Following the general procedure, 3,4-hexanedione
(0.27 mL, 0.25 g, 2.1 mmol, 1 equiv.) was treated with 1,3-bis(tri-
methylsilyloxy)-1-methoxy-1,3-pentadiene (0.55 g, 2.1 mmol,
1
equiv.) and TiCl4 (0.46 mL, 0.79 g, 4.2 mmol, 2 equiv.). The prod-
uct was purified by chromatography to give 3j as a colourless oil
(100 mg, 21%, ds ϭ 5:1). The main isomer 3j could be separated
by a second chromatographic procedure as a colourless oil (19 mg,
4%). 1H NMR (CDCl3, 250 MHz, ppm): δ ϭ 0.90 (t, J ϭ 7.4 Hz,
3 H, CH3CH2COH), 1.16 (d, J ϭ 7.6 Hz, 3 H, 4-CH3), 1.23 (t,
J ϭ 7.6 Hz, 3 H, CH3CH2CϭC), AB-signal (δA ϭ 1.66, δB ϭ 1.92,
JA,B ϭ 14.8, JA,X ϭ JB,X ϭ 7.4 Hz, 2 H, CH3CH2COH), 2.48 (q,
J ϭ 7.6 Hz, 1 H, 4-H), 2.56Ϫ2.82 (m, 2 H, CH3CH2CϭC), 3.84 (s,
3 H, CH3O). Besides 3j an open-chain minor component was iso-
lated (22 mg, 4%). Methyl 5-ethyl-5-hydroxy-4-methyl-3,6-dioxooc-
tanoate: 1H NMR (CDCl3, 250 MHz, ppm): δ ϭ 0.74 (t, J ϭ
7.4 Hz, 3 H, CH3CH2COH), 1.06 (d, J ϭ 7.2 Hz, 3 H, CH3CH),
overlapped by 1.08 (t, J ϭ 7.2 Hz, 3 H, 8-H), AB-signal (δA ϭ 1.61,
δB ϭ 1.80, JA,B ϭ 14.8, JA,X ϭ JB,X ϭ 7.4 Hz, 2 H, CH3CH2COH),
2.53 (q, J ϭ 7.2 Hz, 1 H, 7-H), overlapped by 2.54 (q, J ϭ 7.2 Hz,
1 H, 7-H), 3.01 (q, J ϭ 7.2 Hz, 1 H, 4-H), AB-signal (δA ϭ 3.57,
δB ϭ 3.68, JA,B ϭ 16.4 Hz, 2 H, 2-H), overlapped by 3.73 (s, 3 H,
CH3O), 4.04 (s, 1 H, OH). 13C NMR (CDCl3, 62.9 MHz, ppm):
δ ϭ 7.28, 7.55, 11.65 (C-8, CH3CH2COH, 4-CH3), 30.44, 30.78 (C-
7, CH2COH), 47.93 (C-2), 52.14, 53.00 (C-4, CH3O), 82.59 (C-5),
167.44 (CO2Me), 206.38, 213.57 (2 ϫ CϭO). MS (DCI, NH3):
Ethyl 5-Hydroxy-2,5-dimethyl-3,6-dioxoheptanoate (4): Following
the general procedure, 2,3-butanedione (0.18 mL, 0.18 g, 2.0 mmol,
1 equiv.) was treated with 1,3-bis(trimethylsilyloxy)-1-ethoxy-2-
methyl-1,3-butadiene (0.57 g, 2.0 mmol, 1 equiv.) and TiCl4 (0.44
mL, 0.76 g, 4.0 mmol, 2 equiv.). The product was purified by chro-
matography to give 4 as a colourless oil (0.22 g, 53%, ds: A/B ϭ
1:1). 1H NMR (CDCl3, 250 MHz, ppm): δ ϭ 1.24Ϫ1.32 (dia-
stereomer A, 2 ϫ t, 2 ϫ 3 H, 2 ϫ CH3CH2O, 2 ϫ d, 2 ϫ 3 H, 2
ϫ 2-CH3, 2 ϫ s, 2 ϫ 3 H, 2 ϫ 5-CH3), 2.26 (diastereomer B, s,
3 H, CH3CϭO), overlapped by 2.27 (A, s, 3 H, CH3CϭO), AB-
signal (A, δA ϭ 2.81, δB ϭ 2.88, JA,B ϭ 5.4 Hz, 2 H, 4-H), AB-sig-
nal (B, δA ϭ 3.25, δB ϭ 3.28, JA,B ϭ 16.1 Hz, 2 H, 4-H), 3.51 (B,
q, J ϭ 7.1 Hz, 1 H, 2-H), overlapped by 3.55 (A, q, J ϭ 7.2 Hz,
1 H, 2-H), 4.14Ϫ4.24 (A and B, m, 2 ϫ H, 2 ϫ CH3CH2). Dia-
stereomer B:13C NMR (CDCl3, 62.9 MHz, ppm): δ ϭ 13.91, 23.86,
25.16 (CH3CH2, 2-CH3, 5-CH3), 49.37 (C-4), 61.47 (CH2O), 77.61
(C-5), 169.82 (CO2Et), 206.01, 211.59 (CH3CϭO, C-3). Dia-
stereomer A: 3C NMR (CDCl3, 62.9 MHz, ppm): δ ϭ 12.23, 23.75,
24.79 (CH3CH2, 2-CH3, 5-CH3), 49.65 (C-4), 61.47 (CH2O), 78.08
(C-5), 169.78 (CO2Et), 207.00, 212.46 (CH3CϭO, C-3). MS (70 eV,
EI): m/z (%) ϭ 214 (12) [Mϩ]; the exact molecular mass for
C11H18O4 m/z ϭ 214.1205Ϯ2 ppm [Mϩ] was confirmed by HRMS
(EI, 70 eV).
m/z (%) ϭ 279 (99) [M ϩ NH4 ϩ NH3], 262 (100) [M ϩ NH4ϩ].
C12H20O5 (244.3): calcd. C 58.98, H 8.26; found C 59.32, H 8.12.
ϩ
Ethyl 2-Ethyl-3-hydroxy-3-methyl-5-oxocyclopent-1-enecarboxylate
(3k) and Ethyl 3-Ethyl-3-hydroxy-2-methyl-5-oxocyclopent-1-ene-
carboxylate (3kЈ): Following the general procedure, 2,3-pentane-
dione (0.24 mL, 0.23 g, 2.2 mmol, 1 equiv.) was treated with 1,3-
bis(trimethylsilyloxy)-1-ethoxy-1,3-butadiene (0.60 g, 2.2 mmol, 1
equiv.) and TiCl4 (0.48 mL, 0.83 g, 4.4 mmol, 2 equiv.). The prod-
uct was purified by chromatography to give 3k as a colourless oil
and as a mixture of regioisomers (210 mg, 45%, 3k/3kЈ, 5:1, crude
product: 9:1). H NMR (CDCl3, 250 MHz, ppm): δ ϭ 1.24 (t, J ϭ the 1,3-bis(trimethylsilyloxy)-1,3-butadiene 1 (1.0 equiv.) at Ϫ78
7.6 Hz, 3 H, CH3CH2CϭC), 1.33 (t, J ϭ 7.2 Hz, 3 H, CH3CH2O), °C. A CH2Cl2 solution (5 mL) of TiCl4 (3.0 equiv.) was then added
General Procedure for the Cyclisation of 1,3-Bis(trimethylsilyloxy)-
1,3-butadienes with 2,2-Dimethoxy-2-phenylethanal: To a CH2Cl2
solution of 2,2-dimethoxy-2-phenylethanal (0.9 equiv.) was added
1
1.53 (s, 3 H, 3-CH3), 2.54Ϫ2.79 (2 ϫ m, 2 ϫ 2 H, CH2CϭC, 4-H),
4.30 (q, J ϭ 7.2 Hz, 2 H, CH2O). 13C NMR (CDCl3, 62.9 MHz, time and at the temperature indicated and was subsequently poured
ppm): δ ϭ 13.37, 13.86 (CH3CH2CϭC, CH3CH2O), 20.36 (CH2Cϭ into a saturated aqueous solution of sodium hydrogencarbonate
C), 26.01 (3-CH3), 51.24 (C-4), 60.90 (CH2O), 76.02 (C-3), 130.74 (150 mL). The organic layer was separated and the aqueous layer
(C-1), 163.11 (CO2Et), 188.30 (C-2), 200.48 (CϭO). MS (70 eV, was repeatedly extracted with diethyl ether (4 ϫ 80 mL). The com-
EI): m/z (%) ϭ 212 (44) [Mϩ], 197 (8), 183 (40), 167 (46), 166 (100); bined organic layers were dried (MgSO4), filtered and the filtrate
to the reaction mixture. The solution was stirred for the required
the exact molecular mass for C11H16O4 m/z ϭ 212.1049Ϯ2 ppm
was concentrated in vacuo. The residue was purified by repeated
chromatography.
[Mϩ] was confirmed by HRMS (EI, 70 eV).
Eur. J. Org. Chem. 2005, 532Ϫ542
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
537

E. Holtz, V. Köhler, B. Appel, P. Langer
FULL PAPER
Methyl 3-Hydroxy-5-oxo-2-phenylcyclopent-1-enecarboxylate (6a):
To a CH2Cl2 solution (25 mL) of 2,2-dimethoxy-2-phenylethanal
C-1), 200.18 (C-5). IR (neat): ν˜ ϭ 3436 (br, OH), 2962 (w, Ar-H),
2876 (w), 1733 (s, CϭO), 1621 (m), 1469 (m), 1446 (m), 1379 (m),
(292 mg, 1.62 mmol) was added 1,3-bis(trimethylsilyloxy)-1-meth- 1348 (m), 1236 (s), 1199 (m), 1014 (s), 798 (w), 729 (m). 695 (w).
oxy-1,3-butadiene (482 mg, 1.85 mmol) at Ϫ78 °C. A solution of MS (EI, 70 eV): m/z (%) ϭ 274 (3) [Mϩ], 256 (5), 220 (6), 219 (33),
TiCl4 (1.15 g, 6.06 mmol) in CH2Cl2 (5 mL) was then added and
the reaction mixture was stirred for 75 min at Ϫ78 °C. The tem-
perature was raised to 0 °C within 20 min. The product was puri-
fied by chromatography (50 g silica gel, column 2.5 ϫ 25 cm, petro-
leum ether/diethyl ether, 3:1) to give 6a as an orange oil (62 mg,
201 (100); the exact molecular mass for C16H18O4 m/z
ϭ
274.1205Ϯ2 ppm [Mϩ] was confirmed by HRMS (EI, 70 eV).
Benzyl 3-Hydroxy-5-oxo-2-phenylcyclopent-1-enecarboxylate (6d):
To a CH2Cl2 solution (10 mL) of 2,2-dimethoxy-2-phenylethanal
(535 mg, 2.97 mmol) was added 1-benzyloxy-1,3-bis(trimethylsily-
loxy)-1,3-butadiene (1.11 g, 3.30 mmol) at Ϫ78 °C. A solution of
TiCl4 (2.04 g, 10.8 mmol) was then added and the mixture was
stirred for 2 h at Ϫ78 °C. The temperature was raised within 20 min
to 0 °C. The product was purified by chromatography (50 g silica
gel, 2.5 ϫ 25 cm, petroleum ether/diethyl ether, 1:2) to give 6d
(43 mg, 5%) as a slightly brownish solid. 1H NMR (250 MHz,
1
17%). H NMR (250 MHz, CDCl3, ppm): δ ϭ 2.56 (dd, 2J ϭ 12,
2
3J ϭ 2 Hz, 1 H, 4-H), 2.68 [m, 1 H, CH(OH)], 2.98 (dd, J ϭ 12,
3
3
3J ϭ 4 Hz, 1 H, 3-H), 3.73 (s, 3 H, OCH3), 5.42 (dd, J ϭ 2, J ϭ
4 Hz, 1 H, CH2ϪCH(OH)), 7.42Ϫ7.56 (m, 5 H, Ph). 13C NMR
(62.9 MHz, CDCl3, DEPT, ppm): δ ϭ 44.42 (C-4), 52.43 (CH3,
OCH3), 69.49 (C-3), 128.41, 128.84, 131.42 (5 ϫ CH, 5 ϫ Ph-CH),
131.34 (Ph-C), 133.10 (C-2), 164.76 (CO2), 172.186 (C-1), 200.07
(C-5). IR (neat): ν˜ ϭ 3445 (br, OH), 2953 (m, Ar-H), 1738 (s, Cϭ
O), 1707 (s), 1620 (s), 1495 (w), 1436 (m), 1350 (s), 1238 (s), 1062
2
3
CDCl3, ppm): δ ϭ 2.54 (dd, J ϭ 12, J ϭ 2 Hz, 1 H, 4-H), 2.98
(dd, 2J ϭ 12, 3J ϭ 4 Hz, 1 H, 4-H), 5.22 (s, 2 H CH2-Ph), 5.38 (dd,
3J ϭ 2, J ϭ 4 Hz, 1 H, 3-H), 7.16Ϫ7.51 (m, 10 H, Ph). 13C NMR
3
(s), 1017 (m), 928 (w), 800 (w), 780 (m), 728 (m), 694 (w) cmϪ1
.
(62.9 MHz, CDCl3, DEPT, ppm): δ ϭ 44.43 (C-4), 67.32 (CH2,
CH2-Ph), 69.67 (C-3), 128.39, 128.49, 131.62, 128.91 (Ph-CH),
131.28 (C, PhCϪCϭC), 133.86 (C, PhCϪCH2), 134.70 (C-2),
164.02 (CO2), 171.64 (C-1), 199.56 (C-5). IR (neat): ν˜ ϭ 3450 (br),
2925 (w, Ar-H), 1731 (s, CϭO), 1695 (m), 1621 (w), 1456 (w), 1381
(m), 1227 (m), 1188 (m), 1058 (w), 903 (m), 750 (m), 696 (w), 602
(w) cmϪ1. MS (EI, 70 eV): m/z (%) ϭ 308 (1) [Mϩ], 280 (2), 235
(1), 217 (2), 202 (39), 184 (78), 91 (100).
MS (EI, 70 eV): m/z (%) ϭ 232 (100) [Mϩ], 200 (58), 198 (20), 172
(44), 171 (22), 145 (18), 144 (42), 129 (71); the exact molecular
mass for C13H12O4 m/z ϭ 232.0735Ϯ2 ppm [Mϩ] was confirmed
by HRMS (EI, 70 eV).
2-Methoxyethyl 3-Hydroxy-5-oxo-2-phenylcyclopent-1-enecarboxyl-
ate (6b): To a CH2Cl2 solution (10 mL) of 2,2-dimethoxy-2-phenyl-
ethanal (438 mg, 2.43 mmol) was added 1,3-bis(trimethylsilyloxy)-
1-(2-methoxyethoxy)-1,3-butadiene (822 mg, 2.70 mmol) at Ϫ78
°C. A CH2Cl2 solution (5 mL) of TiCl4 (1.67 g, 8.80 mmol) was
then added and the solution was stirred for 75 min at Ϫ78 °C. The
temperature was raised to 0 °C within 20 min. The product was
purified by chromatography (50 g silica gel, 2.5 ϫ 25 cm, petroleum
ether/diethyl ether, 3:1 to pure ether) to give 6b as a deep yellow
oil (112 mg, 16%). 1H NMR (250 MHz, CDCl3, ppm): δ ϭ 2.46
Isopropyl
3-Hydroxy-5-oxo-2-phenylcyclopent-1-enecarboxylate
(6e): To a CH2Cl2 solution (10 mL) of 2,2-dimethoxy-2-phenyle-
thanal (498 mg, 2.76 mmol) was added 1,3-bis(trimethylsilyloxy)-
1-isopropyloxy-1,3-butadiene (627 mg, 2.17 mmol) at Ϫ78 °C. A
solution of TiCl4 (1.39 g, 7.33 mmol) was then added and the mix-
ture was stirred for 105 min at Ϫ78 °C. The temperature was raised
within 20 min to 0 °C. The product was purified by chromatogra-
phy (50 g silica gel, 2.5 ϫ 25 cm, petroleum ether/diethyl ether, 1:2)
to give 6e (51 mg, 10%) as a yellow oil. 1H NMR (250 MHz,
CDCl3, ppm): δ ϭ 1.14 [d, 3J ϭ 8 Hz, 3 H, CH(CH3)2], 1.16 [d,
2
3
2
3
(dd, J ϭ 12, J ϭ 2 Hz, 1 H, 4-H), 2.91 (dd, J ϭ 12, J ϭ 4 Hz,
1 H, 4-H), 3.21 (s, 3 H, OCH3), 3.48 (m, 2 H, CH2-OCH3), 4.32
(m, 2 H, CO2CH2), 5.54 (dd, 3J ϭ 2, 3J ϭ 4 Hz, 1 H, 3-H),
7.36Ϫ7.58 (m, 5 H, Ph). 13C NMR (62.9 MHz, CDCl3, DEPT,
ppm): δ ϭ 44.45 (C-4), 58.62 (CH3, OCH3), 64.11 (CH2, CH2-
OCH3), 69.37 (CO2CH2), 69.80 (C-3), 128.54, 128.68, 131.18 (5 ϫ
CH, 5 ϫ Ph-CH), 131.45 (Ph-C), 133.13 (C-2), 164.25 (CO2),
171.90 (C-1), 199.97 (C-5). IR (neat): ν˜ ϭ 3429 (br, OH), 2932 (w,
Ar-H), 1737 (s, CϭO), 1707 (s), 1621 (m), 1447 (m), 1734 (m), 1339
(m), 1236 (m), 1196 (m), 1128 (m), 1031 (m), 864 (w), 757 (m), 695
(w) cmϪ1. MS (EI, 70 eV): m/z (%) ϭ 276 (2) [Mϩ].
2
3
3J ϭ 8 Hz, 3 H, CH(CH3)2], 2.49 (dd, J ϭ 12, J ϭ 2 Hz, 1 H, 4-
H), 2.96 (dd, 2J ϭ 12, 3J ϭ 4 Hz, 1 H, 4-H), 3.15Ϫ3.41 (br. s, 1 H,
3
3
OH), 5.12 [m, 1 H, CH(CH3)2], 5.38 (dd, J ϭ 2, J ϭ 4 Hz, 1 H,
3-H), 7.22Ϫ7.58 (m, 5 H, Ph). 13C NMR (62.9 MHz, CDCl3,
DEPT, ppm): δ ϭ 21.23, 21.53 (2 ϫ CH3, 2 ϫ CH3), 44.49 (C-4),
69.50 (C-3), 128.46, 128.70, 131.14 (3 ϫ CH, 3 ϫ Ph-CH), 131.57
(Ph-C), 134.29 (C-2), 163.93 (CO2), 171.01 (C-1), 200.07 (C-5). IR
(neat): ν˜ ϭ 3437 (br, OH), 2982 (w, Ar-H), 1732 (s, CϭO), 1621
(m), 1447 (w), 1372 (m), 1238 (m), 1202 (m), 1104 (m), 1004 (w),
910 (w), 833 (w), 695 (m) cmϪ1. MS (EI, 70 eV): m/z (%) ϭ 260
(22) [Mϩ], 246 (3), 218 (100), 201 (52).
Isobutyl 3-Hydroxy-5-oxo-2-phenylcyclopent-1-enecarboxylate (6c):
To a CH2Cl2 solution (10 mL) of 2,2-dimethoxy-2-phenylethanal
(483 mg, 2.68 mmol) was added 1,3-bis(trimethylsilyloxy)-1-isobu-
toxy-1,3-butadiene (958 mg, 3.17 mmol) at Ϫ78 °C. A solution of
TiCl4 (1.84 g, 9.70 mmol) was then added and the reaction mixture
2-Benzoyl-4-hydroxy-3-phenylcyclopent-2-enone (6f): To a CH2Cl2
solution (10 mL) of 2,2-dimethoxy-2-phenylethanal (178 mg,
was stirred for 1.5 h at Ϫ78 °C. The temperature was raised within 0.99 mmol) was added 1,3-bis(trimethylsilyloxy)-1-phenyl-1,3-buta-
20 min to 0 °C. The product was purified by chromatography (50 g
silica gel, 2.5 ϫ 25 cm, petroleum ether/diethyl ether, 1:2) to give
6c (120 mg, 16%, Rf ϭ 0.45 in petroleum ether/diethyl ether, 1:2)
diene (336 mg, 1.10 mmol) at Ϫ78 °C. A solution of TiCl4 (686 mg,
3.61 mmol) was then added and the mixture was stirred for 1 h at
Ϫ78 °C. The temperature was raised to 0 °C within 30 min. The
product was purified by chromatography (50 g silica gel, 2.5 ϫ
1
as an orange oil. H NMR (250 MHz, CDCl3, ppm): δ ϭ 0.78 (d,
3J ϭ 3 Hz, 6 H, 2 ϫ CH3), 1.68Ϫ1.89 [m, 1 H, CH(CH3)2], 2.46 25 cm, petroleum ether/diethyl ether, 1:2) to give 6f (37 mg, 14%,
2
3
2
3
1
(dd, J ϭ 12, J ϭ 2 Hz, 1 H, 4-H), 2.92 (dd, J ϭ 12, J ϭ 4 Hz, Rf ϭ 0.38 in petroleum ether/diethyl ether, 1:1) as a yellow oil. H
1 H, 4-H), 3.42Ϫ3.78 (br. s, 1 H, OH), 3.88 [d, 3J ϭ 3 Hz, 2 H, NMR (250 MHz, CDCl3, ppm): δ ϭ 2.56 (dd, J ϭ 12, J ϭ 2 Hz,
2
3
CH2ϪCH(CH3)2], 5.34 (dd, 3J ϭ 2, 3J ϭ 4 Hz, 1 H, 3-H),
7.38Ϫ7.54 (m, 5 H, Ph). 13C NMR (62.9 MHz, CDCl3, DEPT,
1 H, 5-H), 2.98 (dd, J ϭ 12, 3J ϭ 4 Hz, 1 H, 5-H), 3.24Ϫ3.82 (br.
2
s, 1 H, OH), 5.42 (dd, 3J ϭ 2, 3J ϭ 4 Hz, 1 H, 4-H), 7.18Ϫ7.84 (m,
ppm): δ ϭ 18.70, 18.71 (CH3, 2 ϫ CH3), 27.24 [CH(CH3)2], 44.45 10 H, Ph). 13C NMR (62.9 MHz, CDCl3, DEPT, ppm): δ ϭ 44.81
(C-4), 69.38 (C-3), 71.56 (CO2CH2), 128.28, 128.68, 131.04 (5 ϫ (C-5), 69.43 (C-4), 128.72, 128.84, 128.92, 129.29, 131.20, 134.27
Ph-CH), 131.64 (Ph-C), 133.40 (C-2), 164.44 (CO2CH2), 172.06 (C, (6 ϫ CH, 6 ϫ Ph-CH), 131.37 (C, PhCϪCϭO), 135.36 (C,
538
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 532Ϫ542

Synthesis of Functionalised 4-Hydroxycyclopent-2-en-1-ones
FULL PAPER
PhCϪCϭC), 139.81 (C-3), 170.17 (C-2), 194.59 (OϭCPh), 201.94
added and the aqueous layer was repeatedly extracted with diethyl
(C-1). IR (neat): ν˜ ϭ 3430 (br), 3061 (w, Ar-H), 2926 (w, Ar-H), ether. The combined organic layers were dried (Na2SO4), filtered
1710 (s, CϭO), 1660 (s), 1597 (s), 1579 (s), 1494 (w), 1448 (s), 1344
(w), 1238 (s), 1177 (s), 1160 (m), 1060 (m), 1001 (m), 980 (w), 912
(w), 841(w), 779 (m), 736 (s), 689 (m), 647 (m) cmϪ1. MS (EI,
70 eV): m/z (%) ϭ 278 (23) [Mϩ], 122 (38), 105 (100), 86 (65), 84
(100), 77 (68).
and the filtrate was concentrated in vacuo.
Ethyl 5-Ethyl-5-hydroxy-3,6-dioxooctanoate (8b): Starting with
ethyl acetoacetate (143 mg, 1.1 mmol, 1.1 equiv.), diisopropylamine
(253 mg, 2.5 mmol, 2.5 equiv.), n-butyllithium (2.5 mmol,
2.5 equiv.) and hexane-3,4-dione (114 mg, 1.0 mmol), 8b was iso-
lated by chromatography (petroleum ether /diethyl ether, 1.5:1,
Rf ϭ 0.30, 40 g silica gel, Ø ϭ 2.0 cm) as a yellow oil (91 mg, 37%).
Reaction time: 35 min. 1H NMR (250 MHz, CDCl3, ppm): δ ϭ
Methyl 3-Hydroxy-4-methyl-5-oxo-2-phenylcyclopent-1-enecarbox-
ylate (6g): To a CH2Cl2 solution (10 mL) of 2,2-dimethoxy-2-phen-
ylethanal (269 mg, 1.49 mmol) was added 1,3-bis(trimethylsilyl-
oxy)-1-methoxy-4-methyl-1,3-butadiene (455 mg, 1.66 mmol) at
Ϫ78 °C. A solution of TiCl4 (1.04 g, 5.48 mmol) was then added
and the mixture was stirred for 1 h at Ϫ78 °C. The temperature
was raised within 30 min to 0 °C and the mixture was stirred for
30 min at 0°. The product was purified by chromatography (40 g
silica gel, 3 ϫ 20 cm, petroleum ether/diethyl ether, 1:2) to give 6g
(201 mg, 55%, trans/cis ϭ 3:1) as a yellow oil. 1H NMR (250 MHz,
CDCl3, ppm): δ ϭ 1.22 (d, 3J ϭ 4 Hz, 3 H, CH3), 1.31 (d, 3J ϭ
4 Hz, 1 H, CHCH3), 2.62Ϫ2.81 (m, 1 H, OH), 3.78 (s, 3 H, OCH3),
3
3
0.74 (t, J ϭ 7 Hz, 3 H, CH3), 1.01 (t, J ϭ 7 Hz, 3 H, CH3), 1.21
3
3
(t, J ϭ 7 Hz, 3 H, CH3), 1.57 (q, J ϭ 7 Hz, 2 H, CH2), 2.55 (q,
3J ϭ 7 Hz, 2 H, CH2), 2.88 (d, 2J ϭ 17 Hz, 1 H, CH2), 3.13 (d,
2J ϭ 17 Hz, 1 H, CH2), 3.41 (s, 2 H, CH2), 4.12 (q, 3J ϭ 7 Hz, 2 H,
OϪCH2). 13C NMR (50.3 MHz, CDCl3, ppm): δ ϭ 7.10, 7.41,
13.93 (CH3), 29.64, 31.42 (CH2, ethyl), 49.84, 49.94 (CH2,
HOCϪCH2, OϪCH2), 61.38 (CH2, COϪCH2ϪCO), 80.32 (C,
COH), 166.62 (C, CO, ester), 203.03, 214.09 (C, CO, ketone). IR
(neat): ν˜ ϭ 3466 (w) cmϪ1, 2979 (m), 2940 (m), 1742 (s), 1713 (s),
1650 (m), 1461 (m), 1372 (m), 1180 (m), 1142 (m), 1031 (m), 808
(w). MS (EI, 70 eV): 187 (39), 141 (68), 99 (35), 57 (100). MS (CI,
NH3, 70 eV): m/z (%) ϭ 506 (84) [2M ϩ NH4]ϩ , 262 (100) [M ϩ
NH4]ϩ. C12H20O5 (244.29): calcd. C 59.00, H 8.25; found C 59.18,
H 7.97.
3
5.32 (d, J ϭ 4 Hz, 1 H, 3-H), 7.24Ϫ7.60 (m, 5 H, Ph). 13C NMR
(62.9 MHz, CDCl3, DEPT, ppm): δ ϭ 10.06 (CH3, CH3), 45.47 (C-
4), 52.43 (CH3, OCH3), 71.83 (C-3), 128.46, 128.51, 128.82 (3 ϫ
CH, 3 ϫ Ph-CH), 131.25 (Ph-C), 131.89 (C-2), 165.11 (CO2),
170.29 (C-1), 203.78 (C-5). IR (KBr): ν˜ ϭ 3373 (br, OH-stretch-
ing), 3062 (m), 2924 (w, Ar-H), 1736 (s, CϭO), 1707 (s), 1622 (m),
1437 (m), 1350 (m), 1234 (m), 1120 (m), 1033 (m), 846 (w), 696 (m)
cmϪ1. MS (EI, 70 eV): m/z (%) ϭ 246 (36) [Mϩ], 214 (25), 129 (19),
121 (90), 105 (100), 77 (42).
One-Pot Synthesis of Ethyl 2,3-Diethyl-3-hydroxy-5-oxocyclopent-1-
enecarboxylate (9b): The reaction was carried out following the
general procedure vide infra. Starting with ethyl acetoacetate
(140 mg, 1.1 mmol), diisopropylamine (273 mg, 2.7 mmol), n-butyl-
lithium (2.7 mmol) and hexane-3,4-dione (1.0 mmol), 9b was iso-
lated by chromatography as a colourless oil (61%). For spectro-
scopic data, see 3h.
Ethyl 4-Ethyl-3-hydroxy-5-oxo-2-phenyl-1-enecarboxylate (6h): To a
CH2Cl2 solution (10 mL) of 2,2-dimethoxy-2-phenylethanal
(339 mg, 1.88 mmol) was added 1,3-bis(trimethylsilyloxy)-1-ethoxy-
1,3-hexadiene (617 mg, 2.04 mmol) at Ϫ78 °C. A solution of TiCl4
(1.19 mg, 6.27 mmol) was then added and the mixture was stirred
for 1 h at Ϫ78 °C. The temperature was raised within 20 min to 0
°C. The product was purified by chromatography (50 g silica gel,
2.5 ϫ 25 cm, petroleum ether/diethyl ether, 1:2) to give 6h (250 mg,
Ethyl
3-Hydroxy-2,3-dimethyl-5-oxocyclopent-1-enecarboxylate
(9a): For spectroscopic data of 9a, see 3a (vide supra).
Ethyl 3,3a,4,5,6,7-Hexahydro-3a-hydroxy-2-oxoinden-1-carboxylate
(9c): Starting with ethyl acetoacetate (281 mg, 2.2 mmol,
2.0 equiv.), diisopropylamine (546 mg, 5.4 mmol, 5.0 equiv.), n-bu-
tyllithium (5.4 mmol, 5.0 equiv.) and cyclohexane-1,2-dione
(121 mg, 1.1 mmol), 9c was isolated by chromatography (petroleum
ether/diethyl ether, 1:2, Rf ϭ 0.20, Ø ϭ 2.0 cm) as a yellow oil
(62 mg, 25%). Reaction time: 20 h. 1H NMR (250 MHz, CDCl3,
1
48%, trans/cis ϭ 15:1) as a slight yellow oil. H NMR (250 MHz,
CDCl3, ppm): δ ϭ 1.12Ϫ1.38 (m, 6 H, 2 ϫ CH3), 1.52 (m, 2 H, 4-
H2), 2.56 (m, 1 H, 4-H), 3.42Ϫ3.53 (m, 1 H, OH), 4.18Ϫ4.30 (m,
2 H, OCH2CH3), 5.39 (d, 3J ϭ 3 Hz, 1 H, 3-H), 7.31Ϫ7.64 (m,
5 H, Ph). 13C NMR (62.9 MHz, CDCl3, DEPT, ppm): δ ϭ 12.46
(CϪCH2CH3), 13.87 (CH3, OϪCH2CH3), 18.74 (CϪCH2CH3),
52.33 (C-4), 61.62 (OCH2), 71.64 (C-3), 128.46, 128.79, 130.07 (3
ϫ CH, 3 ϫ Ph-CH), 131.17 (Ph-C), 134.24 (C-2), 164.64 (CO2),
169.33 (C-1), 203.02 (C-5). IR (neat): ν˜ ϭ 3444 (br), 3062 (m),
3029 (m), 2974 (w, Ar-H), 1734 (s, CϭO), 1706 (s), 1624 (m), 1496
(w), 1449 (m), 1372 (m), 1343 (m), 1230 (m), 1113 (m), 1023 (m),
860 (w), 763 (w), 698 (m) cmϪ1. MS (CI, NH3, 70 eV): m/z (%) ϭ
566 (12) [2 M ϩ NH4ϩ], 292 (100) [M ϩ NH4ϩ].
3
2
3
ppm): δ ϭ 1.34 (t, J ϭ 7 Hz, 3 H, CH3), 1.45 (dt, J ϭ 13, J ϭ
4 Hz, 1 H, CH2), 1.57 (dd, 2J ϭ 13, 3J ϭ 4 Hz, 1 H, CH2),
1.60Ϫ1.75 (m, 2 H, CH2), 1.87 (ddt, 2J ϭ 3Jtrans ϭ 13, 3Jcis ϭ 4 Hz,
1 H, CH2), 2.00Ϫ2.15 (m, 1 H, CH2), 2.20Ϫ2.40 (m, 1 H, CH2),
2
2
2.51 (d, J ϭ 19 Hz, 1 H, HϪHCϪCO), 2.51 (d, J ϭ 19 Hz, 1 H,
3
HϪHCϪCO), 3.20Ϫ3.35 (m. 1 H, ϭCϪCH2), 4.31 (q, J ϭ 7 Hz,
2 H, OϪCH2). 13C NMR (50.3 MHz, CDCl3, ppm): δ ϭ 14.04
(CH3), 20.68, 26.33, 27.05, 39.99, 50.32 (CH2), 61.01 (OϪCH2),
74.13 (C, COH), 128.88 (C, CϭCϪCO), 162.94 (C, CO, ester),
186.30 (C, CϭCϪCO), 200.51 (C, CO, ketone). IR (neat): ν˜ ϭ
3423 (m) cmϪ1, 2934 (s), 2859 (m), 1740 (s), 1719 (s), 1645 (s), 1447
(m), 1375 (s), 1318 (s), 1263 (s), 1207 (s), 1132 (m), 1028 (s), 854
(w), 619 (w), 591 (w). MS (EI, 70 eV): m/z (%) ϭ 224 (34) [Mϩ],
178 (95), 151 (45), 150 (100), 43 (62), 41 (46); the exact molecular
mass for C12H16O4 m/z ϭ 224.1049Ϯ2 ppm [Mϩ] was confirmed
by HRMS (EI, 70 eV). C12H16O4 (224.26): calcd. C 64.27, H 7.19;
found C 63.95, H 6.97.
General Procedure for the One-Pot Cyclisation of 1,3-Dicarbonyl
Dianions with 1,2-Diketones: A THF solution (15 mL, 25 mL for
liquid starting materials) of diisopropylamine (2.3 equiv.) and n-
butyllithium (2.3 equiv., solution in n-hexane) was stirred at 0 °C
for 30 min. The 1,3-dicarbonyl compound 7 was added (1.1 equiv.,
solids were dissolved in 10 mL of THF) and the mixture was stirred
for 1 h. To the solution was added the 1,2-diketone (1.0 equiv.,
solids were dissolved in 10 mL of THF) at Ϫ78 °C. The solution
was stirred for 1 h and was then slowly warmed to 20 °C. To the
solution was added silica gel (0.5 g/ 1 mmol of 1,2-diketone) and
the mixture heated to refluxed (TLC control). After cooling the
mixture, hydrochloric acid (5 mL, 10%), a saturated aqueous solu-
tion of sodium chloride (10 mL) and diethyl ether (50 mL) were
Ethyl
3-hydroxy-3-methyl-3-propylcyclopent-1-ene-1-carboxylate
and Ethyl 3-Hydroxy-3-methyl-5-oxo-2-propylcyclopent-1-ene-1-car-
boxylate (9d): Starting with ethyl acetoacetate (143 mg, 1.1 mmol,
1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol, 2.5 equiv.), n-bu-
Eur. J. Org. Chem. 2005, 532Ϫ542
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
539

E. Holtz, V. Köhler, B. Appel, P. Langer
FULL PAPER
tyllithium (2.5 mmol, 2.5 equiv.) and hexane-2,3-dione (114 mg,
ν˜ ϭ 3440 (s) cmϪ1, 2945 (s), 2884 (m), 1741 (s), 1718 (s), 1627 (s),
1.0 mmol), 9d was isolated by chromatography (petroleum ether/ 1439 (s), 1355 (s), 1308 (s), 1221 (s), 1152 (m), 1028 (s), 794 (w),
diethyl ether, 1:3, Rf ϭ 0.29, 40 g silica gel, Ø ϭ 2.0 cm) as a yellow
oil (86 mg, 37%). Reaction time: 26 h. Isomeric ratio: 4-methyl iso-
mer (major)/3-methyl isomer (minor), 3:1. 1H NMR (250 MHz,
591 (w). MS (EI, 70 eV): m/z (%) ϭ 212 [Mϩ] (12), 183 (79), 151
(100), 125 (40).
Compound 9g: Starting with 2-(methoxyethyl)acetoacetate (176 mg,
1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol,
2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and hexane-3,4-
dione (114 mg, 1.0 mmol), 9g was isolated by chromatography
(pentane/diethyl ether, 1:3, Rf ϭ 0.22, 40 g silica gel, Ø ϭ 2.0 cm)
as a yellow oil (109 mg, 42%). Reaction time: 25 h. 1H NMR
3
CDCl3, ppm): δ ϭ 0.95 (t, J ϭ 7 Hz, 3 H, CH3, minor), 1.03 (t,
3J ϭ 7 Hz, 3 H, CH3, major), 1.10Ϫ1.30 (m, 1 H, minor and
major), 1.34 (t, 3J ϭ 7 Hz, 2 H, CH3, minor and major), 1.53 (s,
3 H, CH3, major), 1.55Ϫ1.75 (m, 2 H, major), 1.75Ϫ1.90 (m, 2 H,
minor), 2.29 (s, 3 H, CH3, minor), 2.45Ϫ2.75 (m, 3 H, minor and
3
major), 4.31 (q, J ϭ 7 Hz, 2 H, OϪCH2, minor and major). 13C
3
(200 MHz, CDCl3, ppm): δ ϭ 0.90 (t, J ϭ 7 Hz, 3 H, CH3), 1.25
NMR (50.3 MHz, CDCl3, ppm): δ ϭ 13.02, 14.15, 14.26 (CH3,
minor), 14.08, 14.82, 26.27 (CH3, major), 17.45, 40.14 (CH2,
minor), 22.91, 29.48 (CH2, major), 48.75 (COϪCH2, minor), 51.43
(COϪCH2, major), 61.13 (OϪCH2, minor and major) 76.27 (C,
COH, major), 78.38 (C, COH, minor), 131.41 (C, CϭCϪCO,
major), 131.95 (C, CϭCϪCO, minor), 163.06 (C, CO, ester, minor),
163.35 (C, CO, ester, major), 184.07 (C, CϭCϪCO, minor), 186.49
(C, CϭCϪCO, major), 200.07 (C, CO, ketone, minor), 200.43 (C,
CO, ketone, major). IR (neat): ν˜ ϭ 3439 (m) cmϪ1, 2971 (s), 2945
(m), 2876 (m), 1741 (s), 1629 (m) 1463 (m), 1375 (s), 1304 (m), 1201
(s), 1102 (m), 1032 (s), 955 (w), 598 (w). MS (EI, 70 eV): m/z (%) ϭ
226 (28) [Mϩ], 183 (69), 181 (52), 180 (98), 162 (45), 137 (100), 43
(41); the exact molecular mass for C12H18O4 m/z ϭ 226.1205Ϯ2
ppm [Mϩ] was confirmed by HRMS (EI, 70 eV).
(t, 3J ϭ 8 Hz, 3 H, CH3), 1.72 (dq, 3J ϭ 7, 2J ϭ 14 Hz, 1 H,
HϪHCϪCOH), 1.91 (dq, 3J
ϭ
8, 2J
ϭ
14 Hz, 1 H,
HϪHCϪCOH), 2.52 (d, 2J ϭ 18 Hz, 1 H, HϪHCϪCO), partly
overlapped by 2.45Ϫ2.80 (m. 2 H, CϭCϪCH2), overlapped by 2.70
(d, 2J ϭ 18 Hz, 1 H, HϪHCϪCO), 3.39 (s, 3 H, OϪCH3), 3.67
3
3
3
3
(dd, J1 ϭ J2 ϭ 5 Hz, 2 H, OϪCH2), 4.40 (dd, J1 ϭ J2 ϭ 5 Hz,
2 H, COOϪCH2). (dd, 3J1 ϭ 3J2 ϭ 5 Hz, 2 H, OϪCH2). 13C NMR
(50.3 MHz, CDCl3, ppm): δ ϭ 8.36, 13.37 (CH3), 20.50, 31.10
(CH2), 48.49 (COϪCH2), 58.85 (OϪCH3), 63.79, 70.14 (OϪCH2),
79.51 (C, OϪC), 132.11 (C, CϭCϪCO), 163.01 (C, CO, ester),
187.11 (C, CϭCϪCO), 199.69 (C, CO, ketone). IR (neat): ν˜ ϭ
3436 (s) (cmϪ1), 2974 (s), 2940 (s), 1742 (s), 1721 (s), 16.29 (m),
1461 (s), 1380 (s), 1305 (s), 1198 (s), 1131 (s), 1097 (s), 1036 (s),
864 (w), 590 (w). MS (EI, 70 eV): m/z (%) ϭ 256 (50) [Mϩ], 181
(63), 180 (70), 151 (100), 59 (79), 58 (77), 45 (55), 43 (42); the exact
molecular mass for C13H20O5 m/z ϭ 256.1311Ϯ2 ppm [Mϩ] was
confirmed by HRMS (EI, 70 eV). C13H20O5 (256.30): calcd. C
60.92, H 7.87; found C 60.72, H 7.64.
Ethyl 3-Hydroxy-5-oxo-2,3-diphenylcyclopent-1-ene-1-carboxylate
(9e): Starting with ethyl acetoacetate (159 mg, 1.2 mmol,
1.1 equiv.), diisopropylamine (280 mg, 2.8 mmol, 2.5 equiv.), n-bu-
tyllithium (2.8 mmol, 2.5 equiv.) and benzil (232 mg, 1.1 mmol), 9e
was isolated by chromatography (petroleum ether/diethyl ether,
1.5:1, Rf ϭ 0.20, 40 g silica gel, Ø ϭ 2.0 cm) as a yellow solid
Compound 9h: Starting with tert-butyl acetoacetate (174 mg,
1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol,
2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and hexane-3,4-
dione (114 mg, 1.0 mmol), 9h was isolated by chromatography
(petroleum ether/diethyl ether, 1:1.5, Rf ϭ 0.29, 40 g silica gel, Ø ϭ
2.0 cm) as a yellow oil (78 mg, 31%). Reaction time: 25 h. 1H NMR
1
(263 mg, 73%). Reaction time: 26 h. H NMR (250 MHz, CDCl3,
2
ppm): δ ϭ 1.16 (t, 3J ϭ 7 Hz, 3 H, CH3), 3.00 (d, J ϭ 18 Hz, 1 H,
HϪHCϪCO), 3.12 (d, 2J ϭ 18 Hz, 1 H, HϪHCϪCO), 4.24 (q,
3J ϭ 7 Hz, 2 H, OϪCH2), 7.10Ϫ7.50 (m, 10 H, Ph). 13C NMR
(50.3 MHz, CDCl3, ppm): δ ϭ 13.83 (CH3), 55.05 (COϪCH2),
61.61 (OϪCH2), 80.84 (C, COH), 124.50, 128.35, 128.63, 128.91
(CH, Ph, ortho and meta), 127.78, 130.48 (CH, Ph, para), 131.24,
134.31, 142.56 (C, Ph, CϭCϪCO), 163.84 (C, CO, ester), 173.82
(C, CϭCϪCO), 199.86 (C, CO, ketone). IR (neat): ν˜ ϭ 3463 (s)
cmϪ1, 3062 (w), 2979 (m), 2931 (m), 1737 (s), 1712 (s), 1618 (m),
1447 (m), 1373 (m), 1336 (s), 1211 (s), 1102 (m), 1026 (m), 772 (m),
701 (m). MS (EI, 70 eV): m/z (%) ϭ 322 (59) [Mϩ], 276 (100), 105
(59); the exact molecular mass for C20H18O4 m/z ϭ 322.1205Ϯ2
ppm [Mϩ] was confirmed by HRMS (EI, 70 eV). Analysis: calcd.
for: C20H18O4 (322.36): calcd. C 74.52, H 5.63; found C 74.43, H
5.36.
3
(250 MHz, CDCl3, ppm): δ ϭ 0.90 (t, J ϭ 7 Hz, 3 H, CH3), 1.25
(t, 3J ϭ 7 Hz, 3 H, CH3), 1.55 (s, 9 H CH3), overlapped by
1.50Ϫ2.00 (AB system, additional splitting by 3J-coupling, 2 H,
2
HOCϪCH2), 2.47 (d, J ϭ 18 Hz, 1 H, HϪHCϪCO), partly over-
lapped by 2.45Ϫ2.80 (m, 2 H, ϭCϪCH2), partly overlapped by
2.68 (d, 2J ϭ 18 Hz, 1 H, HϪHCϪCO). 13C NMR (50.3 MHz,
CDCl3, ppm): δ ϭ 8.38, 13.49 (CH3), 20.23, 31.08 (CH2), 48.46
(COϪCH2), 28.09 (3 ϫ CH3, C(CH3) 3), 79.64, 82.34 (C, OϪC),
133.77 (C, CϭCϪCO), 162.01 (C, CO, ester), 184.28 (C, Cϭ
CϪCO), 200.04 (C, CO, ketone). IR (neat): ν˜ ϭ 3438 (s) (cmϪ1),
2976 (s), 2938 (s), 1735 (s), 1714 (s), 1621 (s), 1461 (s), 1369 (s),
1158 (s), 1095 (s), 1016 (s), 896 (m), 843 (s), 810 (m), 736 (w), 589
(m). MS (EI, 70 eV): m/z (%) ϭ 86 (100), 58 (51), 57 (65), 44 (58),
43 (52). MS (CI, NH3, 70 eV): m/z (%) ϭ 526 [2M ϩ NH4ϩ] (56),
272 (71) [M ϩ NH4ϩ], 216 (100). C14H22O4 (254.33): calcd. C
66.12, H 8.72; found C 65.86, H 8.45.
Compound 9f: Starting with methyl acetoacetate (128 mg,
1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol,
2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and hexane-3,4-
dione (114 mg, 1.0 mmol), 9f was isolated by chromatography
(petroleum ether/diethyl ether, 1:3, Rf ϭ 0.25, 40 g silica gel, Ø ϭ
Compound 9i: Starting with tert-butyl acetoacetate (178 mg,
2.0 cm) as a yellow oil (91 mg, 44%). Reaction time: 19 h. 1H NMR 1.1 mmol, 1.1 equiv.), diisopropylamine (259 mg, 2.6 mmol,
3
(250 MHz, CDCl3, ppm): δ ϭ 0.92 (t, J ϭ 7 Hz, 3 H, CH3), 1.24
2.5 equiv.), n-butyllithium (2.6 mmol, 2.5 equiv.) and benzil
(316 mg, 1.0 mmol), 9i was isolated by chromatography (petroleum
3
(t, J ϭ 8 Hz, 3 H, CH3), 1.50Ϫ2.10 (AB system, additional split-
ting by 3J-coupling, 2 H, HOCϪCH2), 2.40Ϫ2.80 (m. 2 H, ϭ ether/diethyl ether, 3:1, Rf ϭ 0.22, Ø ϭ 1.5 cm) as a slight yellow
CϪCH2), partly overlapped by 2.52 (d, 2J
ϭ
19 Hz, 1 H, solid 163 mg (45%). Reaction time: 19 h. 1H NMR (250 MHz,
HϪHCϪCO) and 2.72 (d, 2J ϭ 19 Hz, 1 H, HϪHCϪCO), 3.85 (s, CDCl3, ppm): δ ϭ 1.37 (s, 9 H, CH3), 2.85 (br, 1 H, OH), 2.99 (d,
3 H, OϪCH3). 13C NMR (50.3 MHz, CDCl3, ppm): δ ϭ 8.28, 2J ϭ 18 Hz, 1 H, HϪHCϪCO), 3.08 (d, 2J ϭ 18 Hz, 1 H,
13.26 (CH3), 20.50, 30.98 (CH2), 48.41 (COϪCH2), 51.99 HϪHCϪCO), 7.10Ϫ7.45 (m, 10 H, Ph). 13C NMR (50.3 MHz,
(OϪCH3), 79.63 (C, COH), 131.71 (C, CϭCϪCO), 163.71 (C, CO,
CDCl3, ppm): δ ϭ 27.79 (CH3), 54.96 (CH2), 80.70, 82.98 (C,
ester), 188.43 (C, CϭCϪCO), 200.24 (C, CO, ketone). IR (neat): OϪC), 124.58, 128.17, 128.56, 128.81 (CH, Ph, ortho and meta),
540
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2005, 532Ϫ542

Synthesis of Functionalised 4-Hydroxycyclopent-2-en-1-ones
127.68, 130.11 (CH, Ph, para), 131.64 (C, CϭCϪCO), 135.39, 14.06 (CH3, major), 17.21, 20.25, 29.09 (CH2, minor), 20.50, 21.35,
FULL PAPER
142.65 (C, Ph), 162.93 (C, CO, ester), 172.81 (C, CϭCϪCO),
32.13 (CH2, major), 54.96 (CH, major), 60.88 (OϪCH2, minor),
200.10 (C, CO, ketone). IR (KBr): ν˜ ϭ 3465 (m) (cmϪ1), 2975 (m), 61.01 (OϪCH2, major), 61.20 (CH, minor), 81.22 (C, OϪC,
1748 (s), 1450 (m), 1361 (s), 1250 (m), 1160 (s), 1057 (m), 702 (m), major), 83.00 (C, OϪC, minor), 131.28 (C, CϭCϪCO, minor),
538 (w). MS (CI, NH3, 70 eV): m/z (%) ϭ 368 [M ϩ NH4]ϩ (42), 131.66 (C, CϭCϪCO, major), 163.09 (C, CO, ester, minor), 163.40
312 (100).
(C, CO, ester, major), 184.70 (C, CϭCϪCO, minor), 185.82 (C,
CϭCϪCO, major), 199.51 (C, CO, ketone, minor), 203.4 (C, CO,
ketone, major). IR (neat): ν˜ ϭ 3467 (s) (cmϪ1), 2974 (s), 2939 (s),
1736 (s), 1715 (s), 1630 (m), 1463 (s), 1375 (s), 1306 (s), 1211 (s),
1096 (m), 1025 (s), 895 (w), 797 (w), 592(w). MS (EI, 70 eV): m/z
(%) ϭ 254 (3) [Mϩ], 225 (67), 179 (100), 57 (37); the exact molecu-
lar mass for C14H22O4 m/z ϭ 254.1518Ϯ2 ppm [Mϩ] was confirmed
by HRMS (EI, 70 eV).
Compound 9j: Starting with tert-butylacetoacetate (178 mg,
1.1 mmol, 1.1 equiv.), diisopropylamine (259 mg, 2.6 mmol,
2.5 equiv.), n-butyllithium (2.6 mmol, 2.5 equiv.) and phen-
anthrene-9,10-dione (213 mg, 1.0 mmol), 9j was isolated by chro-
matography (petroleum ether/diethyl ether, 1:1, Rf ϭ 0.33, 40 g sil-
ica gel, Ø ϭ 1.5 cm) as a colourless solid (109 mg, 31%). Reaction
time: 18 h. 1H NMR (250 MHz, [D6]DMSO, ppm): δ ϭ 0.60 (s,
2
9 H, CH3), 1.63 (s, 1 H, OH), 2.05 (d, J ϭ 18 Hz, 1 H, CH2), 2.45
Compound 9m: Starting with methyl 4-methoxyacetoacetate
(161 mg, 1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg,
2.5 mmol, 2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and
hexane-3,4-dione (114 mg, 1.0 mmol), 9m was isolated by chroma-
tography (40 g silica gel, Ø ϭ 2.0 cm). Reaction time: 22 h. Dia-
stereomer 1 (petroleum ether/diethyl ether, 2:1, Rf ϭ 0.29): Yield:
(d, 2J ϭ 18 Hz, 1 H, CH2), 6.50Ϫ6.70 (m, 4 H, CH, Ar), 6.70Ϫ6.80
3
3
(m, 2 H, CH, Ar), 7.17 (d, J ϭ 7 Hz, 1 H, CH, Ar), 7.27 (d, J ϭ
7 Hz, 1 H, CH, Ar). 13C NMR (50.3 MHz, [D6]DMSO, ppm): δ ϭ
27.59 (CH3), 47.63 (CH2), 73.51 (C, CϪOϪCϭO), 82.64 (C,
COH), 124.44, 124.68, 127.50, 128.01, 128.46, 128.99. 129.10,
132.40 (CH, Ar), 126.43 (C, CϭCϪCO), 131.39, 131.52, 133.48,
137.70 (C, Ar), 163.40 (C, CO, ester), 166.34 CϭCϪCO), 200.40
(C, CO, ketone). IR (KBr): ν˜ ϭ 3466 (s) (cmϪ1), 2983 (w), 1716
(s), 1701 (s), 1637 (s), 1451 (m), 1353 (s), 1228 (s), 1159 (s), 1051
(m), 998 (m), 759 (m), 734 (m). MS (EI, 70 eV): m/z (%) ϭ 248
(75) [Mϩ], 292 (96), 275 (100), 274 (70), 202 (50), 57 (50); the exact
molecular mass for C22H20O4 m/z ϭ 348.1362Ϯ2 ppm [Mϩ] was
confirmed by HRMS (EI, 70 eV).
1
29 mg (12%) as a yellow oil. H NMR (300 MHz, CDCl3, ppm):
3
3
δ ϭ 0.83 (t, J ϭ 8 Hz, 3 H, CH3), 1.19 (t, J ϭ 8 Hz, 3 H, CH3),
3
2
3
1.55 (dq, J ϭ 8, J ϭ 14 Hz, 1 H, HϪHCϪCOH), 1.91 (dq, J ϭ
2
3
2
8, J ϭ 14 Hz, 1 H, HϪHCϪCOH), 2.57 (dq, J ϭ 8, J ϭ 12 Hz,
1 H, HϪHCϪCϭ), 2.81 (dq, 3J 8, 2J
ϭ
ϭ
12 Hz, 1 H,
HϪHCϪCϭ), 3.37 (s, 1 H, CH), 3.62 (s, 3 H, OϪCH3), 3.81 (s,
3 H, OϪCH3). 13C NMR (50.3 MHz, CDCl3, ppm): δ ϭ 7.99,
13.55 (CH3), 21.20, 29.92 (CH2), 51.98, 59.07 (OϪCH3), 78.00 (C,
OϪC), 81.12 (CH), 129.66 (C, CϭCϪCO), 163.15 (C, CO, ester),
189.63 (C, CϭCϪCO), 197.41 (C, CO, ketone). IR (neat): ν˜ ϭ
3486 (m) (cmϪ1), 2971 (m), 2940 (m), 1744 (s), 1722 (s), 1626 (m),
1461 (m), 1439 (m), 1308 (m), 1220 (s), 1105 (m), 1024 (m), 790
(w). MS (EI, 70 eV): m/z (%) ϭ 213 (40), 210 (55), 57 (100), 43
(48). MS (CI, NH3, 70 eV): m/z (%) ϭ 502 (100) [2M ϩ NH4ϩ],
260 (45) [M ϩ NH4ϩ]. Diastereomer 2 (petroleum ether/diethyl
ether, 1:1.5, Rf ϭ 0.29): Yield: 79 mg (33%) as a yellow oil. 1H
NMR (300 MHz, CDCl3, ppm): δ ϭ 0.65 (t, 3J ϭ 8 Hz, 3 H, CH3),
Compound 9k: Starting with benzyl acetoacetate (212 mg,
1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol,
2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and hexane-3,4-
dione (114 mg, 1.0 mmol), 9k was isolated by chromatography
(petroleum ether/diethyl ether, 1:2, Rf ϭ 0.28, 40 g silica gel, Ø ϭ
1.5 cm) as a yellow oil (38 mg, 13%). Reaction time: 25 h. 1H NMR
3
(200 MHz, CDCl3, ppm): δ ϭ 0.89 (t, J ϭ 7 Hz, 3 H, CH3), 1.17
3
(t, J ϭ 8 Hz, 3 H, CH3), 1.60Ϫ2.00 (AB system, additional split-
2
2
ting by J؊coupling, 2 H, HOCϪCH2), 2.51 (d, J ϭ 18 Hz, 1 H,
HϪHCϪCO), partly overlapped by 2.50Ϫ2.80 (m, 2 H,
ϭCϪCH2), partly overlapped by 2.68 (d, 2J ϭ 18 Hz, 1 H,
HϪHCϪCO), 5.30 (s, 2 H, OϪCH2), 7.30Ϫ7.50 (m, 5 H, CH, Ph).
13C NMR (75.5 MHz, CDCl3, ppm): δ ϭ 8.34, 13.39 (CH3), 20.43,
31.07 (CH2), 48.46 (COϪCH2), 66.74 (OϪCH2), 79.71 (C, OϪC),
128.23, 128.50 (CH, Ph, ortho and meta), 128.26 (CH, Ph, para),
131.96, 135.28 (C, Ph, CϭCϪCO), 162.87 (C, CO, ester), 187.47
(C, CϭCϪCO), 199.78 (C, CO, ketone). IR (neat): ν˜ ϭ 3441 (s)
(cmϪ1), 3037 (w), 2976, (m), 2939 (m), 1736 (s), 1715 (s), 1633 (m),
1458 (m), 1384 (m), 1305 (m), 1196 (m), 1097 (m), 1024 (m), 749
(w), 699 (w). MS (EI, 70 eV): m/z (%) ϭ 288 (2) [Mϩ], 164 (35), 91
(100); the exact molecular mass for C16H18O4 m/z ϭ 288.1362Ϯ2
ppm [Mϩ] was confirmed by HRMS (EI, 70 eV).
3
3
2
1.20 (t, J ϭ 8 Hz, 3 H, CH3), 1.72 (dq, J ϭ 8, J ϭ 14 Hz, 1 H,
HϪHCϪCOH), 1.99 (dq, 3J
ϭ
8, 2J
ϭ
14 Hz, 1 H,
3
HϪHCϪCOH), 2.54 (dq, J ϭ 8, 2J ϭ 12 Hz, 1 H, HϪHCϪCϭ),
2.83 (dq, 3J ϭ 8, 2J ϭ 12 Hz, 1 H, HϪHCϪCϭ), 3.68 (s, 3 H,
OϪCH3), 3.81 (s, 3 H, OϪCH3), 3.91 (s, 1 H, CH). 13C NMR
(50.3 MHz, CDCl3, ppm): δ ϭ 9.16, 13.16 (CH3), 20.57, 29.55
(CH2), 52.00, 60.29 (OϪCH3), 82.57 (C, OϪC), 90.00 (CH), 129.52
(C, CϭCϪCO), 162.84 (C, CO, ester), 183.65 (C, CϭCϪCO),
196.27 (C, CO, ketone). IR (neat): ν˜ ϭ 3460 (s) (cmϪ1), 2977 (s),
2943 (s), 1741 (s), 1726 (s), 1618 (m), 1440 (s), 1310 (s), 1221 (s),
1129 (s), 1028 (s), 841 (w), 787 (w), 732 (m). MS (EI, 70 eV): m/z
(%) ϭ 242 (24) [Mϩ], 213 (97), 210 (100); the exact molecular mass
for C12H18O5 m/z ϭ 242.1154Ϯ2 ppm [Mϩ] was confirmed by
HRMS (EI, 70 eV).
Compound 9l: Starting with ethyl 3-oxohexanoate (174 mg,
1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol, Compound 9n: Starting with N,N-diethylacetylacetamide (173 mg,
2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and hexane-3,4-
dione (114 mg, 1.0 mmol), 9l was isolated by chromatography (pen-
1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg, 2.5 mmol,
2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and butane-2,3-di-
tane/diethyl ether, 2:1, Rf ϭ 0.21, 40 g silica gel, Ø ϭ 2.0 cm) as a one (86 mg, 1.0 mmol), 9n was isolated by chromatography (diethyl
yellow oil (124 mg, 49%, two diastereomers, dr ϭ 4:1). Reaction
ether/acetone, 10:1, Rf ϭ 0.21, 40 g silica gel, Ø ϭ 2.0 cm) as a yel-
low oil (146 mg, 65%). Reaction time: 19 h. H NMR (250 MHz,
1
1
time: 25 h. H NMR (300 MHz, CDCl3, major, ppm): δ ϭ 0.82 (t,
3
3
3J ϭ 8 Hz, 3 H, CH3), 1.03 (t, J ϭ 7 Hz, 3 H, CH3), 1.18 (t, J ϭ CDCl3, ppm): δ ϭ 1.08 (t, 3J ϭ 7 Hz, 3 H, CH3), 1.18 (t, 3J ϭ
8 Hz, 3 H, CH3), 1.30 (t, 3J ϭ 7 Hz, 3 H, CH3), 1.50Ϫ1.70 (m, 2 H, 7 Hz, 3 H, CH3), 1.48 (s, 3 H, CH3), 2.06 (s, 3 H, CH3), 2.58 (d,
CH2), 1.70Ϫ1.95 (m, 2 H, CH2), 2.25 (t, 3J ϭ 7 Hz, 1 H, CH), 2J ϭ 18 Hz, 1 H, CH2), 2.68 (d, 2J ϭ 18 Hz, 1 H, CH2), 3.14 (q,
3
3
2.40Ϫ2.60 (m, 1 H, CH2), 2.60Ϫ2.80 (m, 1 H, CH2), 4.26 (q, J ϭ
7 Hz, 2 H, OϪCH2). 13C NMR (50.3 MHz, CDCl3, ppm): δ ϭ 8.29 (50.3 MHz, CDCl3, ppm): δ ϭ 11.18, 13.01, 14.36, 25.67 (CH3),
(CH3, major, minor), 9.55, 13.19, 13.20 (CH3, minor) 12.47, 13.47, 39.21, 42.88 (CH2), 51.19 (COϪCH2), 77.63 (C, COH), 137.76 (C,
3J ϭ 7 Hz, 2 H, CH2), 3.46 (q, J ϭ 7 Hz, 2 H, CH2). 13C NMR
Eur. J. Org. Chem. 2005, 532Ϫ542
www.eurjoc.org
© 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
541

E. Holtz, V. Köhler, B. Appel, P. Langer
FULL PAPER
A. Maercker, A. Groos, Angew. Chem. 1996, 108, 216; Angew.
Chem. Int. Ed. Engl. 1996, 35, 210.
For the extrusion of carbon monoxide in reactions of oxalic
acid dielectrophiles, see for example: [3a] T. Iida, T. Itaya, Tetra-
hedron 1993, 49, 10511. [3b] M. P. Sibi, M. Marvin, R. Sharma,
J. Org. Chem. 1995, 60, 5016.
K. G. Hampton, J. J. Christie, J. Org. Chem. 1976, 41, 2772.
J. R. McClure, J. H. Custer, H. D. Schwarz, D. A. Lill, Synlett
2000, 710.
CϭCϪCO), 164.39 (C, CO, ester), 175.76 (C, CϭCϪCO), 200.65
(C, CO, ketone). IR (neat): ν˜ ϭ 3397 (s), 2978 (s), 2937 (s), 1711
(s), 1611 (s), 1442 (s), 1379 (s), 1326 (s), 1273 (s), 1226 (s), 1200 (s),
1089 (s), 949 (m), 651 (w), 589 (m) cmϪ1. MS (EI, 70 eV): m/z
(%) ϭ 225 (6) [Mϩ], 72 (100); the exact molecular mass for
C12H19NO3 m/z ϭ 225.1365Ϯ2 ppm [Mϩ] was confirmed by
HRMS (EI, 70 eV).
[3]
[4]
[5]
[6]
[7]
Compound 9o and E-10: Starting with N,N-diethylacetylacetamide
(173 mg, 1.1 mmol, 1.1 equiv.), diisopropylamine (253 mg,
2.5 mmol, 2.5 equiv.), n-butyllithium (2.5 mmol, 2.5 equiv.) and
hexane-3,4-dione (114 mg, 1.0 mmol), 9o was isolated by chroma-
tography (diethyl ether, 40 g silica gel, Ø ϭ 2.0 cm). Reaction time:
20 h. Yield of 10: 26 mg (10%) of a yellow oil. 1H NMR (300 MHz,
CDCl3, ppm): δ ϭ 0.78 (t, 3J ϭ 8 Hz, 6 H, CH3), 1.09 (t, 3J ϭ
7 Hz, 3 H, CH3), 1.19 (t, 3J ϭ 7 Hz, 3 H, CH3), 1.74 (q, 3J ϭ 8 Hz,
K. G. Hampton, R. J. Light, C. R. Hauser, J. Org. Chem. 1965,
30, 1413.
[7a] T.-H. Chan, P. Brownbridge, J. Chem. Soc., Chem. Commun.
[7b]
1979, 578.
T.-H. Chan, P. Brownbridge, J. Am. Chem. Soc.
[7c]
1980, 102, 3534.
Chem. Soc. 1993, 115, 830.
G. A. Molander, K. O. Cameron, J. Am.
[8]
For a review of 1,3-bis(silyl) enol ethers, see: P. Langer, Syn-
thesis 2002, 441.
[9]
Review: P. Langer, Chem. Eur. J. 2001, 7, 3858.
For a review of cyclisations of free dianions, see: P. Langer, W.
Freiberg, Chem. Rev. 2004, 104, 4125.
3
3
[10]
4 H, CH2), 3.31 (q, J ϭ 7 Hz, 2 H, CH2), 3.37 (q, J ϭ 7 Hz, 2 H,
CH2), 3.56 (s, 2 H, COϪCH2ϪCO), 5.54 (s, 1 H, HCϭC). 13C
NMR (50.3 MHz, CDCl3, ppm): δ ϭ 7.14 (2 Χ CH3), 12.74, 14.29
(CH3), 28.76 (2 ϫ CH2), 36.30, 40.41, 42.59 (CH2), 95.23 (C, Cϭ),
106.09 (CH), 165, 07 (C, CO, amide), 186.07, 206.72 (C, CO, ke-
tone). IR (neat): ν˜ ϭ 2974 (m) (cmϪ1), 1699 (m), 1649 (s), 1595
(m), 1460 (m), 1439 (m), 1382 (m), 1259 (w), 1138 (m), 1100 (m),
975 (w), 802 (w). MS (EI, 70 eV): 253 [Mϩ] (2), 225 (46), 100 (91),
72 (50), 58 (100), 43 (54). MS (CI, NH3, 70 eV): m/z (%) ϭ 507
(37) [2M ϩ NH4ϩ], 271 (52) [M ϩ NH4]ϩ, 254 (100) [M ϩ H]ϩ;
the exact molecular mass for C14H23NO3 m/z ϭ 253.1678Ϯ2 ppm
[Mϩ] was confirmed by HRMS (EI, 70 eV). Yield of 9o (Rf ϭ 0.16):
[11]
For base-mediated cyclisations of 1,2-diones with ketone
[11a]
monoanions, see:
F. Morgenroth, A. J. Berresheim, M.
[11b]
Wagner, K. Müllen, Chem. Commun. 1998, 1139.
S. Egu-
chi, K. Ishiura, T. Noda, T. Sasaki, J. Org. Chem. 1987, 52,
[11c]
496.
A. Gawish, R. Mitschka, J. M. Cook, Tetrahedron
[11d]
Lett. 1981, 211.
D. Yang, J. M. Cook, J. Org. Chem. 1976,
[11e]
41, 1903.
J. Oehldrich, J. M. Cook, Can. J. Chem. 1977,
F. R. Japp, G. D. Lander, J. Chem. Soc. 1897, 71,
F. R. Japp, A. Findlay, J. Chem. Soc. 1899, 75, 1017.
[11f]
55, 82.
[11g]
139.
[11h] A. C. Cope, D. W. H. MacDowell, J. Am. Chem. Soc. 1958,
80, 5513. [11i] L. A. Cort, M. A. Mahesar, J. Chem. Soc., Perkin
[11j]
1
Trans. 1 1979, 2034, and references cited therein.
W. Ried,
80 mg (32%) of a yellow solid. H NMR (300 MHz, CDCl3, ppm):
C. Gürsan, Chem. Ber. 1968, 101, 2598; for related cyclopen-
3
¸
δ ϭ 0.83 (t, J ϭ 7 Hz, 3 H, CH3), 1.00Ϫ1.40 (m, 9 H, CH3), 1.66
[11k]
tene syntheses, see:
K. Okano, Y. Mizuhara, H. Suemune,
(dq, 3J ϭ 8, 2J ϭ 14 Hz, 1 H, HϪHCϪCOH), 1.88 (dq, 3J ϭ 8,
2J ϭ 14 Hz, 1 H, HϪHCϪCOH), 2.30Ϫ2.55 (m, 2 H, CϭCϪCH2),
H. Akita, K. Sakai, Chem. Pharm. Bull. 1988, 36, 1358. [11l] K.
Okano, H. Suemune, Kiyoshi Sakai, Chem. Pharm. Bull. 1988,
2
partly overlapped by 2.49 (d, J ϭ 18 Hz, 1 H, HϪHCϪCO), 2.60
[11m]
36, 1385.
H. Suemune, Y. Miyao, Kiyoshi Sakai, Chem.
(d, 2J ϭ 18 Hz, 1 H, HϪHCϪCO), 3.14 (q, 3J ϭ 7 Hz, 2 H,
NCH2), 3.25Ϫ3.50 (m, 2 H, NCH2). 13C NMR (50.3 MHz, CDCl3,
ppm): δ ϭ 8.46, 12.06, 12.54, 14.01 (CH3), 20.21, 30.70 (CH2),
38.84, 42.89 (NϪCH2), 48.21 (COϪCH2), 79.95 (C, OϪC), 138.16
(C, CϭCϪCO), 164.84 (C, CO, ester), 179.36 (C, CϭCϪCO),
201.26 (C, CO, ketone). IR (KBr): ν˜ ϭ 3269 (m) (cmϪ1), 2977 (m),
2936 (m), 1707 (s), 1653 (m), 1603 (s), 1466 (m), 1383 (m), 1322
(m), 1174 (m), 1043 (m), 822 (w), 718 (w), 677 (w). MS (EI, 70 eV):
253 (15) [Mϩ], 72 (100). C14H23NO3 (253.34): calcd. C 66.37, H
9.15, N 5.53; found C 66.39, H 8.95, N 5.37.
[11n]
Pharm. Bull. 1989, 37, 2523.
K. Okano, H. Suemune, Ki-
yoshi Sakai, Chem. Pharm. Bull. 1989, 37, 1995. [11o] K. Okano,
H. Suemune, Kiyoshi Sakai, Chem. Pharm. Bull. 1990, 38, 532.
G. A. Molander, D. C. Shubert, J. Am. Chem. Soc. 1986, 108,
4683.
[12]
[13]
[14]
P. Langer, V. Köhler, Org. Lett. 2000, 1597.
Römpp Lexikon Naturstoffe (Eds.: B. Fugmann, S. Lane-Fug-
mann, W. Steglich), Thieme, Stuttgart, 1997.
[15]
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis,
Wiley-VCH, Weinheim, 1996, p. 137ff.
[16] [16a]
ACS Syp. Ser. 591 (Molecular Action of Insecticides on
[16b]
Ion Channels), 1995, p. 26Ϫ43.
Handbook of Pesticide
Toxicology (Ed.: W. J. Hayes), New York, Academic Press,
1991, p. 585.
T. Mukaiyama, Angew. Chem. 1977, 89, 858; Angew. Chem. Int.
Ed. Engl. 1977, 16, 817.
For a related discussion, see: G. Adembri, C. Anselmi, A. Cam-
parini, A. M. Celli, M. Scotton, Gazz. Chim. Ital. 1983, 113,
489.
N. De Kimpe, R. Verhe, L. De Buyck, N. Schamp, J. Org.
Chem. 1980, 45, 2803.
An example of this transformation has been previously re-
ported: T. H. Chan, M. A. Brook, Tetrahedron Lett. 1985, 26,
2943.
For reactions of silyl enol ethers with aldehydes, see for ex-
ample: [21a] K. Mikami, S. Matsukawa, J. Am. Chem. Soc. 1993,
115, 7039. [21b] I. Mori, K. Ishihara, L. A. Flippin, K. Nozaki,
H. Yamamoto, P. A. Bartlett, C. H. Heathcock, J. Org. Chem.
1990, 55, 6170.
[17]
[18]
Acknowledgments
Financial support from the Deutsche Forschungsgemeinschaft is
gratefully acknowledged.
[19]
[20]
[1]
[1a]
Reviews:
A. Maercker, Methoden Org. Chem. (Houben-
[1b]
Weyl), 4th ed., vol. E19d, 1993, 448.
C. M. Thompson, D.
Green, Tetrahedron 1991, 47, 4223. [1c] E. M. Kaiser, J. D. Petty,
P. L. A. Knutson, Synthesis 1977, 509. [1d] T. M. Harris, C. M.
[1e]
[21]
[22]
Harris, Tetrahedron 1977, 33, 2159; see also:
Am. Chem. Soc. 1970, 92, 6702.
L. Weiler, J.
[2]
For cyclisations of other than 1,3-dicarbonyl dianions, see for
example: [2a] K. G. Bilyard, P. J. Garratt, R. Hunter, E. Lete, J.
[2b]
Org. Chem. 1982, 47, 4731.
R. B. Bates, B. Gordon, T. K.
[2c]
Highsmith, J. J. White, J. Org. Chem. 1984, 49, 2981.
K.
P. Langer, T. Schneider, Synlett 2000, 497.
Received August 4, 2004
Tanaka, H. Horiuchi, H. Yoda, J. Org. Chem. 1989, 54, 63. [2d]
542
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