Efficient synthesis of functionalized 4,5-benzotropones by regioselective cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with phthalic dialdehyde

Article abstract of DOI:10.1055/s-2001-12330

The reaction of 1,3-bis(trimethylsiloxy)-1,3-butadienes with phthalic dialdehyde resulted in regioselective formation of functionalized 4,5-benzotropones.

Full text of DOI:10.1055/s-2001-12330

526
LETTER
Efficient Synthesis of Functionalized 4,5-Benzotropones by Regioselective
Cyclization of 1,3-Bis(trimethylsilyloxy)-1,3-butadienes with Phthalic
Dialdehyde
Peter Langer,* Uwe Albrecht
Institut für Organische Chemie der Georg-August-Universität Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
E-mail: planger@uni-goettingen.de
Received 19 January 2001
action of 2 with 1,3-bis(trimethylsilyloxy)-1,3-butadiene
Abstract: The reaction of 1,3-bis(trimethylsiloxy)-1,3-butadienes
1a, which was readily prepared from ethyl acetoacetate
with phthalic dialdehyde resulted in regioselective formation of
functionalized 4,5-benzotropones.
in two steps,4 resulted in formation of the 4,5-
benzotropone 3a, however, in only low yield. The Lewis
Key words: aldol reactions, benzotropones, cyclizations, regiose-
acid, temperature, reaction time, concentration and the
lectivity, silyl enol ethers
presence of molecular sieves (MS) proved important pa-
rameters during the optimization of the reaction condi-
tions (Table 1). After much experimentation (Table 1) we
Benzocycloheptanones and benzocycloheptatrienones
have found that best results (up to 72% yield) were ob-
(benzotropones) are present in a variety of pharmacologi-
tained when the Lewis acid TiCl4 (2.0 equiv.) and an ex-
cally relevant natural products including colchicone,
cess of the aldehyde were used. The reaction was carried
colchicine, allocolchicine or purpurogalline.1 4,5-Ben-
out in the presence of 4 Å MS at 78 °C 20 °C using a
zotropones have been previously prepared mainly by
relatively low concentration of 1a (0.01 mol/L).6
base-mediated cyclization of ketones with aromatic dial-
dehydes.2,3 Since tropones readily undergo base-mediated
Michael additions with the starting materials these reac-
O
tions are often problematic. In addition, a number of struc-
Me3SiO
OSiMe3
OEt
H
H
2.0 TiCl4
O
O
tural limitations exist: whereas 1,3,5-tricarbonyl
compounds generally react rather selectively, 1,3-dicar-
bonyl derivatives such as acetyl acetone and substrates
containing base-labile functional groups fail to give the
desired products.3c Acid-mediated cyclizations are
known,3d but require harsh conditions (the reactions have
to be carried out in neat 96-98% sulfuric acid). In addition,
only highly activated substrates, such as 1,3-dimethoxy-
carbonylacetone, can be successfully transformed into
4,5-benzotropones. Due to the pharmacological relevance
of benzotropone derivatives, we herein disclose our find-
ings related to a new synthesis of 4,5-benzotropones. Our
methodology is based on the Lewis-acid mediated cy-
clization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes 1,
electroneutral 1,3-dianion equivalents,4 with phthalic di-
aldehyde 2. Previously, cyclizations of dienes 1 with ali-
phatic 1,4-dicarbonyl compounds to give bridged
oxacycles have been reported by Molander and co-work-
ers.4b We have recently reported [3+2] cyclizations of
dienes 1 with 1,2-dielectrophiles such as oxalyl chloride,
1,2-diketones and epoxides.5 The reactions reported here-
in represent to our knowledge the first Mukaiyama-type
[4+3] cyclizations of bis-silyl enol ethers 1 with aromatic
1,4-dicarbonyl compounds to give 4,5-benzotropones.
+
CH2Cl, 4Å MS
_
O
1a
2
78
20 °C
3a
EtO
(1.8 eq.)
(1.0 eq.)
72%
+ 2 TiCl4
+ H2O, H+
OTiCl3
_
Me3SiCl
Cl3TiO
OSiMe3
O
O
O
H
_
Me3SiCl
OEt
Cl3TiO
O
Cl4Ti
EtO
A
B
Scheme 1 Mechanism of the formation of 4,5-benzotropone 3a
The formation of 4,5-benzotropone 3a can be explained
by a double Mukaiyama-aldol-reaction and subsequent
elimination of water. The cyclization proceeded by regio-
selective attack of the terminal carbon atom of the diene
onto the 1,4-dielectrophile and subsequent regioselective
cyclization via the central carbon atom of the diene
(Scheme 1).
In order to study the preparative scope of the reaction, the
substituents of the diene were systematically varied
(Scheme 2, Table 2). Reaction of phthalic dialdehyde 2
with the 1,3-bis(trimethylsiloxy)-1,3-dienes 1a-e derived
from ethyl-, methyl-, methoxyethyl-, benzyl-, and isobut-
yl acetoacetate afforded the 4,5-benzotropones 3a-e in
good yields and with very good regioselectivities. The cy-
clization of 2 with dienes 1f-h, containing an alkyl group
Our starting point was the reaction of the dianion of ethyl
acetoacetate with phthalic dialdehyde 2. Due to overaddi-
tion, polymerization and reduction of the aldehyde, only a
complex mixture was formed. The reaction of ethyl acet-
oacetate with 2 in the presence of KOH, NaOEt or sulfuric
acid were equally disappointing. The TiCl4-mediated re-
Synlett 2001, No. 4, 526–528 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Efficient Synthesis of Functionalized 4,5-Benzotropones by Regioselective Cyclization
527
Table 1 Optimization of the reaction of diene 1a with phthalic dialdehyde 2
a Reaction time: 12 h+2 h (20 °C). b 12 h+12 h (20 °C). c TiCl4: 2.0 equiv., Me3SiOTf: 0.3
equiv. d Isolated yield
at the terminal carbon atom, gave the methyl-, ethyl- and In conclusion, we have developed a new method for the
butyl-substituted 4,5-benzotropones 3f-h. The reaction of synthesis of a wide range of functionalized 4,5-ben-
2 with dienes 1i-k, which were prepared from acetyl ace- zotropones which are of pharmacological relevance and
tone, benzoyl acetone and 1-methoxyacetyl acetone, re- of interest for the synthesis of natural products. The cy-
gioselectively afforded the 4,5-benzotropones 3i-k. The clization products reported herein were not available by
methoxy-substituted 4,5-benzotropone 3l was obtained by base-mediated reactions. Our current work is directed to-
cyclization of 2 with diene 1l (a regioisomer of 1k).
wards exploring the preparative scope of our cyclization
reaction and towards its application to the synthesis of al-
kaloids.
R1
O
Me3SiO
R1
OSiMe3
R2
2.0 TiCl4
H
H
O
O
+
Acknowledgement
CH2Cl, 4Å MS
_
78
20 °C
O
2
P. L. thanks Professor A. de Meijere for his support. Financial sup-
port from the Fonds der Chemischen Industrie e. V. (Liebig-schol-
arship and funds for P. L.) and from the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
R2
1a-l
3a-l
Scheme 2 Cyclization of dienes 1a-l with phthalic dialdehyde 2
Table 2 Synthesis of 4,5-benzocycloheptatrien-1-ones 3a-l
References
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a Isolated yields.
Synlett 2001, No. 4, 526–528 ISSN 0936-5214 © Thieme Stuttgart · New York

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P. Langer, U. Albrecht
LETTER
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ether (100 mL). The combined organic extracts were extracted
with brine, dried (MgSO4), filtered and the solvent of the
filtrate was removed in vacuo. The residue was purified by
column chromatography (silica gel, ether/petroleum
(5) For cyclization reactions of 1,3-bis(trimethylsilyloxy)-1,3-
butadienes from our laboratory, see: (a) Langer, P.; Stoll, M.
Angew. Chem., Int. Ed. 1999, 38, 1803; (b) Langer, P.;
Schneider, T.; Stoll, M. Chem. Eur. J. 2000, 6, 3204; (c)
Langer, P.; Eckardt, T.; Stoll, M. Org. Lett. 2000, 2991; (d)
Langer, P.; Köhler, V. Org. Lett. 2000, 1597; (e) Langer, P.;
Krummel, T. Chem. Commun. 2000, 967; (f) Langer, P.;
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(6) General procedure for the preparation of 4,5-benzotropones 3:
A CH2Cl2-solution (110 mL) of 2 (2.0 mmol, 0.268 g) and
molecular sieves (4 Å, 1.0 g) was stirred for 15 min at 78 °C.
To the solution was added a CH2Cl2-solution (5 mL) each of
diene 1a (1.1 mmol, 0.301 g) and of TiCl4 (2.2 mmol, 0.417 g,
0.43 mL) at 78 °C. The temperature of the reaction mixture
was allowed to rise to 20 °C during 12 h. After stirring for 2 h
at 20 °C water and subsequently an aqueous solution of
hydrochloric acid (100 mL, 10%) was added. The organic
layer was separated and the aqueous layer was extracted with
ether = 5:1 2:1) to give 3a as a light yellow oil (0.180 g,
72%). For 3e, 3i and 3l: 1.0 equiv. of 2 was used. For 3f-g, 1.3
equiv. of 2 was used. 1H NMR (250 MHz, CDCl3): 1.34 (t,
J = 7 Hz, 3 H, OCH2CH3), 4.34 (q, J = 7 Hz, 2 H, OCH2CH3),
6.78 (d, J = 13 Hz, 1 H, CH=CHCO), 7.37 (d, J = 13 Hz, 1 H,
CH=CHCO), 7.56 7.61 (m, 4 H, Ar), 7.85 (s, 1 H, CH= );
13C NMR (200 MHZ, CDCl3): 13.99 (OCH2CH3), 61.60
(OCH2CH3), 130.4, 131.58, 133.55 (CH, Ar), 133.77 (C, Ar),
135.09, 135.24 (CH, Ar), 135.92, 137.26 (C, Ar), 140.28,
141.93 (CH, Ar), 167.42, 184.43 (C=O); IR (KBr): 3172
(w), 3059 (w), 2891 (w), 1726 (s), 1631 (s), 1596 (s), 1556
(m), 1426 (m), 1312 (s) cm−1; MS (EI, 70 eV): 228 (M+, 14),
200 (70), 183 (34), 155 (100), 127 (74); the exact molecular
mass m/z = 228.0786±2 mD (M+) was confirmed by HRMS
(EI, 70 eV). All new compounds gave satisfactory
spectroscopic and analytical and/ or high resolution mass data.
Article Identifier:
1437-2096,E;2001,0,04,0526,0528,ftx,en;L22200ST.pdf
Synlett 2001, No. 4, 526–528 ISSN 0936-5214 © Thieme Stuttgart · New York