First Domino Mukaiyama-Aldol Cyclizations of 1,3-Bis(trimethylsiloxy)-1,3-butadienes with 1,2-Diketones

Article abstract of DOI:10.1021/ol005852i

(Matrix Presented) The first domino Mukaiyama-aldol cyclization of 1,3-bis(trimethylsiloxy)-1,3-dienes with enolizable 1,2-diketones provides a convenient and regioselective access to substituted cyclopent-2-en-1-ones.

Full text of DOI:10.1021/ol005852i

ORGANIC
LETTERS
2000
Vol. 2, No. 11
1597-1599
First Domino Mukaiyama-Aldol
Cyclizations of
1,3-Bis(trimethylsiloxy)-1,3-butadienes
with 1,2-Diketones
,†
Peter Langer* and Valentin Ko1hler
Institut fu¨r Organische Chemie der Georg-August-UniVersita¨t Go¨ttingen,
Tammannstrasse 2, 37077 Go¨ttingen, Germany
planger@uni-goettingen.de
Received March 23, 2000
ABSTRACT
The first domino Mukaiyama-aldol cyclization of 1,3-bis(trimethylsiloxy)-1,3-dienes with enolizable 1,2-diketones provides a convenient and
regioselective access to substituted cyclopent-2-en-1-ones.
The Diels-Alder reaction represents one of the most
convenient methods for generating molecular complexity in
the cyclohexane area.1 The obvious need to extend equally
efficient cycloaddition strategies to the construction of five-
membered carbocyclic ring systems has led to many elegant
studies of [3 + 2] annulation processes.2 Surprisingly, despite
the simplicity of the idea, only few reactions of 1,3-dianionic
synthons with 1,2-dielectrophiles have been reported so far.
Several drawbacks are possible for these reactions: on the
one hand, dianions are highly reactive compounds which can
react both as a nucleophile and a base; on the other hand,
1,2-dielectrophiles often represent rather labile compounds.
To the best of our knowledge, no cyclization reactions of
1,3-dianions with enolizable 1,2-diones have been reported
so far, presumably due to deprotonation of the latter by the
dianion.3,4 We have recently developed5 a Lewis acid-
catalyzed cyclization of oxalyl chloride with 1,3-bis(tri-
methylsiloxy)-1,3-dienes, synthons of 1,3-dicarbonyl-di-
anions,6 to give γ-alkylidene butenolides. Herein, we wish
to report the first domino Mukaiyama-aldol cyclization of
1,3-bis(trimethylsiloxy)-1,3-dienes with enolizable 1,2-di-
ketones.7,8 These reactions proceed not only with very good
chemoselectivities but also with very good regioselectivities.
The products, cyclo-2-penten-4-ones, are of pharmacological
relevance and represent versatile building blocks for the
synthesis of natural products.9
(4) For recent base-mediated cyclizations of nonenolizable aromatic 1,2-
diones, see: (a) Morgenroth, F.; Berresheim, A. J.; Wagner, M.; Mu¨llen,
K. Chem. Commun. 1998, 1139. For a cyclization reaction of the
nonenolizable homoadamantane-4,5-dione, see: (b) Eguchi, S.; Ishiura, K.;
Noda, T.; Sasaki, T. J. Org. Chem. 1987, 52, 496.
(5) (a) Langer, P.; Stoll, M. Angew. Chem. 1999, 111, 1919; Angew.
Chem., Int. Ed. 1999, 38, 1803. (b) Langer, P.; Schneider, T.; Stoll, M.
Chem. Eur. J., in press.
(6) (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun.
1979, 578. (b) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102,
3534. (c) Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115,
830.
(7) For the reaction of simple silyl enol ethers with ketones, see:
Mukaiyama, T. Angew. Chem. 1977, 89, 858; Angew. Chem., Int. Ed. Engl.
1977, 16, 817.
† FAX: 0049 (0) 551 399475.
(1) Review: Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 137;
Angew. Chem., Int. Ed. Engl. 1993, 32, 131.
(2) Trost, B. M. Angew. Chem. 1986, 98, 1; Angew. Chem., Int. Ed. 1986,
25, 1.
(3) For the reaction of 1,3,5-tricarbonyl compounds with glyoxal in
aqueous alkaline medium, see: Gawish, A.; Mitschka, R.; Cook, J. M.
Tetrahedron Lett. 1981, 211.
(8) For the reaction of 1,2-diones with 3-iodo-2-[(trimethylsilyl)methyl]-
propene, a synthon of the trimethylenemethane dianion, see: Molander, G.
A.; Shubert, D. C. J. Am. Chem. Soc. 1986, 108, 4683.
10.1021/ol005852i CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/06/2000

Because of deprotonation rather than nucleophilic attack,
all attempts to induce a cyclization reaction of dilithiated
ethyl acetoacetate with butane-2,3-dione 2a failed. Therefore,
we decided to react dione 2a with 1,3-bis(trimethylsiloxy)-
1,3-diene 1a, which was prepared from ethyl acetoacetate
in two steps, in the presence of a Lewis acid. Unfortunately,
only starting materials could be isolated when trimethylsilyl
trifluoromethanesulfonate (TMSOTf) or BF3‚OEt2 were used
as the Lewis acid. Similarly, only starting materials were
obtained when the reaction was carried out at -78 °C using
TiCl4. A complex mixture was formed when the reaction
temperature was 0 f 20 °C.
selective attack of the terminal carbon atom of the diene onto
the dielectrophile and regioselective cyclization via the
central carbon atom of the diene (Scheme 1). It is noteworthy
Scheme 1
Much to our satisfaction, a cyclization could be induced
when the reaction was carried out at -78 f 20 °C to give
the 1-hydroxycyclo-2-penten-4-one 3a. After much experi-
mentation (Table 1), optimal yields (up to 63%) were
Table 1. Optimization of the Reaction of Diene 1a with Dione
2a
entry Lewis acid
T [°C]
-78 f 20 6 + 2
BF3‚OEt2 -78 f 20 6 + 2
t [h]a
equiv of 1a yield [%]b
1
2
TMSOTf
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.5
1.0
0
0
0
that the TMSOTf-catalyzed cyclization of 1a with oxalyl
chloride proceeded via the oxygen rather than the central
carbon atom of the diene.5
To study the preparative scope of the reaction, the
substituents of the diene were systematically varied (Scheme
2, Table 2). Reaction of dione 2a with the 1,3-bis(trimethyl-
3
4
5
6
7
8
9
10
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
TiCl4
-78
-78
3
12
0
-78 f 20 6 + 0
-78 f 20 6 + 2
-78 f 20 6 + 12
-78 f 20 1 + 2
-78 f 20 6 + 2
0 f 20 2 + 2
38
63
26
18
41
0
a Reaction time (-78 f 20 °C) + reaction time at 20 °C. b Isolated
yields.
Scheme 2
obtained when the reaction mixture was warmed to ambient
during 6 h and when the mixture was stirred at 20 °C for 2
h.10 The success of this protocol can be explained by the
assumption that the initial condensation of the diene with
the 1,2-diketone takes place at low temperature and that the
cyclization step occurs at 20 °C. The product was formed
by a double Mukaiyama-aldol reaction and subsequent
elimination of water: the cyclization proceeded by regio-
siloxy)-1,3-dienes derived from ethyl acetoacetate, acetyl-
acetone, and 1-methoxyacetylacetone afforded the cyclo-2-
penten-4-ones 3a-c in good yields. Cyclization of 2a with
the dienes derived from methyl 3-oxopentanoate and ethyl
3-oxohexanoate afforded the cyclopentenones 3d-e. Reac-
tion of 2a with the dienes derived from methyl 4-methoxy-
acetoacetate and 1-methoxyacetylacetone (containing a meth-
oxy group at the terminal carbon atom) afforded the
methoxy-substituted cyclopentenones 3f and 3g, respectively.
Because of the similar steric demand of the methyl and the
hydroxy group, only low 1,2-stereoselectivities were ob-
served in the case of 3d and 3f-g. A moderate 1,2-
stereoselectivity was observed in the formation of cyclopen-
tenone 3e.
(9) (a) Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron
Lett. 1980, 1475. (b) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981,
103, 7550. (c) Filippini, M.-H.; Faure, R.; Rodriguez, J. J. Org. Chem.
1995, 60, 6872.
(10) Preparation of cyclopentenone 3a. To a CH2Cl2 solution (30 mL)
of dione 2a (1.5 mmol, 0.13 g) and 1,3-bis(trimethylsiloxy)-1,3-diene 1a
(1.5 mmol, 0.39 g) was added a CH2Cl2 solution (5 mL) of TiCl4 (3 mmol)
at -78 °C. The temperature of the reaction mixture was allowed to rise to
20 °C during 6 h. After 2 h of stirring at 20 °C, a saturated solution of
NaCl was added, the organic layer was separated, and the aqueous layer
was repeatedly extracted with ether. The combined organic extracts were
dried (MgSO4) and filtered, and the solvent of the filtrate was removed in
vacuo. The residue was purified by column chromatography (silica gel,
ether/petroleum ether ) 1/1). 1H NMR (acetone-d6, 200 MHz): δ 1.27 (t,
3 H, J ) 7, CH3), 1.45 (s, 3 H, CH3), 2.24 (s, 3 H, CH3), 2.55 (s, 2 H,
CH2), 4.21 (q, 2 H, J ) 7, OCH2), 4.62 (s, 1 H, OH). 13C NMR (acetone-
d6, 50 MHz): δc 11.68, 13.62, 25.31, 51.07, 60.22, 75.02, 131.57, 162.97,
182.60, 198.45. MS (70 eV): 198 (36, M+). Anal. Calcd for C10H14O4: C,
60.59; H, 7.12. Found.: C, 60.28; H, 7.36. All compounds were character-
ized by spectroscopic methods and gave correct elemental analyses and/ or
high-resolution mass spectra.
To vary the substituents of the 1,2-dione, cyclization
reactions of hexane-3,4-dione 2b were next studied. Reaction
of 2b with the 1,3-bis(trimethylsiloxy)-1,3-dienes derived
from ethyl acetoacetate and acetylacetone regioselectively
afforded the cyclopentenones 3h and 3i. Reaction of 2b with
1598
Org. Lett., Vol. 2, No. 11, 2000

compounds were isolated as the side products in the
formation of cyclopentenones 3j and 3k. These compounds
were isolated as the major products when the reactions were
quenched by addition of water directly after warming of the
reaction mixture to ambient. Reaction of diene 1a with
benzile resulted in formation of a complex mixture. Reaction
of pentane-2,3-dione 2c, an unsymmetrical 1,2-dione, with
the 1,3-bis(trimethylsiloxy)-1,3-dienes derived from ethyl
acetoacetate, 1-methoxy-2,4-pentanedione, and acetylacetone
afforded the cyclopentenones 3l-n in good yields. The
reactions leading to 3l and 3m proceeded with good
regioselectivities. This is noteworthy, since the two carbonyl
groups of 2c are very similar sterically.
Table 2. Synthesis of 1-Hydroxycyclo-2-penten-4-ones 3
a
3
R1
R2
R3
R4
%
selectivityb
a
H
H
H
Me
Et
OMe
OMe
H
OEt
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Et
Et
Et
Et
63
57
58
47
45
60
25
28
16
21
20
62
54
51
b
c
d
e
f
g
h
i
j
k
l
m
n
CH2OMe
OMe
OEt
OMe
Me
1.2:1
3.5:1
1:1.4
1:1.2
OEt
Me
H
Me
OMe
H
H
H
OMe
OMe
OEt
CH2OMe
Me
3:1
1:3
9:1
4:1
2:1
In summary, we have reported the first Lewis acid-
mediated domino Mukaiyama-aldol cyclizations of 1,3-bis-
(trimethylsiloxy)-1,3-dienes, 1,3-dicarbonyl dianion synthons,
with 1,2-diones. These reactions allow for a convenient and
regioselective preparation of cyclo-2-penten-4-ones which
are of pharmacological relevance and represent versatile
building blocks for the synthesis of natural products.
Et
Et
a
Isolated yields. b For 3d-g and 3j-k, diastereoselectivities in favor
of the drawn isomers. For 3l-n, regioselectivities in favor of the drawn
isomers. The ratios were determined by integration of the corresponding
1H NMR signals of the crude products.
the dienes derived from methyl 3-oxopentanoate and methyl
4-methoxyacetoacetate afforded the cyclopentenones 3j and
3k with diastereoselectivities of 5:1 and 3:1, respectively.
In the case of the cyclization reactions of dione 2b, the yields
were generally lower than in the case of 2a, presumably due
to the increased steric hindrance. In addition, extended
reaction times (6 + 12 h) were necessary. Open-chain
Acknowledgment. P.L. thanks Professor A. de Meijere
for his support. Financial support from the Fonds der
Chemischen Industrie (Liebig-scholarship and funds to P.L.)
and the Deutsche Forschungsgemeinschaft is gratefully
acknowledged.
OL005852I
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