Regioselective synthesis of 4-acyl-1-hydroxy-2,3-benzodioates by chelation-controlled [3+3] annulation of 3-acyl-4-ethoxy-2-oxo-3-enoates with 1,3-bis(trimethylsilyloxy)-1,3-butadienes

Article abstract of DOI:10.1039/b905556h

4-Acyl-1-hydroxy-2,3-benzodioates were regioselectively prepared by chelation-controlled [3+3] cyclization of 1,3-bis(trimethylsilyloxy)-1,3- butadienes with 3-acyl-4-ethoxy-2-oxo-3-enoates.

Full text of DOI:10.1039/b905556h

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Regioselective synthesis of 4-acyl-1-hydroxy-2,3-benzodioates by
chelation-controlled [3+3] annulation of 3-acyl-4-ethoxy-2-oxo-3-enoates
with 1,3-bis(trimethylsilyloxy)-1,3-butadienes†
Abdolmajid Riahi,a,b Mohanad Shkoor,a Olumide Fatunsin,a Rasheed Ahmad Khera,a Christine Fischera and
Peter Langer*a,b
Received 19th March 2009, Accepted 3rd July 2009
First published as an Advance Article on the web 11th August 2009
DOI: 10.1039/b905556h
4-Acyl-1-hydroxy-2,3-benzodioates were regioselectively prepared by chelation-controlled [3+3]
cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3-acyl-4-ethoxy-2-oxo-3-enoates.
4-acyl-1-hydroxy-2,3-benzodioates by [3+3] cyclization of 1,3-
Introduction
(bis)trimethylsilyloxy-1,3-butadienes with 3-acyl-4-ethoxy-2-oxo-
Highly functionalized benzene derivatives, such as hydroxylated
3-enoates. Although several electrophilic sites are present in
benzoates and benzodioates, are of considerable interest as
the starting materials, the cyclizations proceed with excellent
lead structures and synthetic building blocks in medicinal and
regioselectivity, which can be explained by the regiodirecting effect
agricultural chemistry.1,2 Classical syntheses of such compounds
are based on electrophilic substitution and oxidation reactions.
Despite their great utility, electrophilic substitutions have several
drawbacks (e.g., low regioselectivity and low reactivity of electron-
poor substrates). Oxidations of toluene to benzoic acid derivatives
often require drastic conditions. Transition metal-catalyzed func-
tionalizations of functionalized benzene derivatives proceed under
relatively mild conditions.3 However, the synthesis of the required
starting materials, highly functionalized or sterically encumbered
benzene derivatives, can be a difficult task.
of the 2-oxoester moiety (chelation-control).10,11 The products
reported herein are not readily available by other methods.
Results and discussion
3-Acyl-4-ethoxy-2-oxo-3-enoates 3a–f were prepared in good yield
by reaction of the known 2,4-diketoesters 2a–f, available from
diethyl oxalate, with triethyl orthoformate and acetic anhydride
(Scheme 1, Table 1).
Functionalized benzene derivatives have also been prepared
by application of a ‘building block’ strategy. Examples in-
clude base-mediated cyclizations of acetone-1,3-dicarboxylates,4
condensations of 1,3-dicarbonyl dianions with carboxylic acid
derivatives and subsequent intramolecular aldol reactions of the
polyketides thus formed,5 and [4+2] cycloadditions.6 Chan and
Brownbridge were the first to report7 the synthesis of salicylates
by formal [3+3] cyclizations of 1,3-bis(silyloxy)-1,3-butadienes8
with 3-silyloxy-2-en-1-ones. This strategy has been widely applied
in recent years.9 However, its scope is mainly limited to 3-silyloxy-
2-en-1-ones derived from symmetrical 1,3-diketones. Although a
few exceptions have been reported,7 cyclizations of 3-silyloxy-2-en-
1-ones derived from unsymmetrical 1,3-diketones often proceed
with low regioselectivity, due to TiCl4-mediated isomerization of
the 3-silyloxy-2-en-1-one.
In their early work, Chan and Brownbridge reported7 an isolated
example of a regioselective cyclocondensation of a 3-alkoxy-
rather than a 3-silyloxy-2-en-1-one. Based on this observation,
we recently started a program directed towards the development
of new cyclizations of acceptor-substituted 3-alkoxy-2-en-1-ones.
Herein, we report, for the first time, a convenient synthesis of
Scheme 1 Synthesis of 3a–f; i: diethyl oxalate (1.0 equiv.), 1a–f (1.0
equiv.), NaOEt (1.0 equiv.), ii: 2a–f (1.0 equiv.), HC(OEt)3 (1.2 equiv.),
Ac2O, reflux, 2–4 h, products exist as mixtures of E/Z isomers.
The TiCl4-mediated cyclization of 3a with 4a afforded the
4-acetyl-1-hydroxy-2,4-benzodioate 5a with excellent regioselec-
tivity (Scheme 2). The best yield was obtained when the reaction
was carried out in a highly concentrated solution. The formation
of 5a can be explained by reaction of 3a with TiCl4 to give
oxocarbenium ion A. The attack of the terminal carbon atom
of 4a onto A resulted in the formation of intermediate B.
The elimination of (ethoxy)trimethylsilane (intermediate C) and
subsequent cyclization gave intermediate D. The elimination of
titanium hydroxide and aromatization resulted in the formation
of product 5a.
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059
Rostock, Germany. E-mail: peter.langer@uni-rostock.de; Fax: 00 49 381
49864112; Tel: 0049 381 4986410
bLeibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-
Einstein-Str. 29a, 18059 Rostock, Germany
† Electronic supplementary information (ESI) available: Experimental
details and NMR spectra. See DOI: 10.1039/b905556h
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Table 1 Synthesis of 3a–f
yield (Scheme 3, Table 2). The best yields are obtained for aroyl
derivatives 5g–ai and for ester derivative 5l.
1,2,3
R
% (2)a
% (3)a
a
b
c
d
e
f
Me
Ph
4-MeC6H4
4-MeOC6H4
4-BrC6H4
OEt
76
79
80
82
75
74
97
96
98
95
92
99
a Yields of isolated products.
Scheme 3 Synthesis of 5a–al.
Treatment of 5n with conc. sulfuric acid resulted in an in-
tramolecular Friedel–Crafts acylation to give the anthraquinone
6 (Scheme 4).
In conclusion, we have reported the regioselective synthesis of 4-
acyl-1-hydroxy-2,3-benzodioates by the first chelation-controlled
[3+3] cyclizations of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
3-acyl-4-ethoxy-2-oxo-3-enoates.
Table 2 Synthesis of 5a–al
4
3
5
R
R1
R2
% (5)a
a
b
c
d
f
g
a
b
c
d
f
g
h
i
a
b
d
f
g
h
i
a
b
c
e
f
h
i
a
b
c
e
f
a
a
a
a
a
a
b
b
b
b
b
b
b
b
c
c
c
c
c
c
c
d
d
d
d
d
d
d
e
e
e
e
e
e
e
f
a
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
4-BrC6H4
OEt
H
Me
Et
nBu
nHex
nOct
H
Me
Et
nBu
nHex
nOct
nNon
nDec
H
Me
Me
Et
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Et
48
50
50
58
59
59
65
67
62
65
65
66
67
66
69
70
70
65
64
66
65
62
63
56
64
61
63
64
63
66
65
66
70
68
69
68
69
69
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
Me
q
nBu
nHex
nOct
nNon
nDec
H
Me
Et
nPen
nHex
nNon
nDec
H
Me
Et
nPen
nHex
nNon
nDec
H
r
s
t
u
v
w
x
Scheme 2 Possible mechanism of the formation of 5a.
y
z
The regioselectivity of the first step (A→B) might be explained
by the low steric hindrance and by the high positive charge density
of the allylic carbon atom attached to the ethoxy group. The
regioselectivity of the cyclization (C→D) might be explained by
selective activation of the 2-oxoester moiety rather than the acetyl
group, due to the formation of a chelate complex with TiCl4
(intermediates A, B and C). An alternative explanation is just that
the cyclization occurs onto the most electrophilic ketone carbonyl
(which is the one adjacent to the ester group).
aa
ab
ac
ad
ae
af
ag
ah
ai
aj
ak
al
Me
Me
Me
Me
Me
Me
Me
h
i
a
b
e
f
OEt
OEt
Me
nPent
f
The TiCl4-mediated cyclization of 3-acyl-4-ethoxy-2-oxo-3-
enoates 3a–f with 1,3-bis(trimethylsilyloxy)-1,3-butadienes 4a–i
afforded the 4-acyl-1-hydroxy-2,3-benzodioates 5a–al in 48–70%
a Yields of isolated products.
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solution was allowed to warm to 20 ◦C during 14 h with stirring.
To the solution was added hydrochloric acid (10%, 20 mL) and
the organic and the aqueous layers were separated. The latter was
extracted with CH2Cl2 (3 ¥ 20 mL). The combined organic layers
were dried (Na2SO4), filtered and the filtrate was concentrated in
vacuo. The residue was purified by chromatography (silica gel,
heptanes/EtOAc) to give 5a–al.
2-Ethyl 1-methyl 3-acetyl-6-hydroxyphthalate (5a). Starting
with 3a (0.321 g, 1.5 mmol) and 4a (0.429 g, 1.65 mmol), 5a was
isolated after chromatography (silica gel,◦n-heptane/EtOAc) as a
yellowish solid (0.191 g, 48%), mp. 95–97 C. 1H NMR (300 MHz,
CDCl3): d = 1.17 (t, 3J = 7.2 Hz, 3 H, OCH2CH3), 2.32 (s, 3 H,
CH3), 3.72 (s, 3 H, OCH3), 4.20 (q, 3J = 7.7 Hz, 2 H, OCH2CH3),
Scheme 4 Synthesis of 6; i: conc. sulfuric acid, 1 h.
Experimental section
General comments
3
3
6.87 (d, J = 9.0 Hz, 1 H, CHAr), 7.73 (d, J = 9.0 Hz, 1 H,
CHAr), 11.37 (s, 1 H, OH). 13C NMR (CDCl3, 75 MHz): d = 14.0,
27.5 (CH3), 53.2 (OCH3), 61.8 (OCH2), 110.5 (CCOOCH3), 118.5
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C
NMR spectra the deuterated solvents indicated were used. Mass
spectrometric data (MS) were obtained by electron ionization
(EI, 70 eV), chemical ionization (CI, isobutane) or electrospray
ionization (ESI). For preparative scale chromatography silica gel
60 (0.063–0.200 mm, 70–230 mesh) was used.
(CHAr), 126.9 (CCOCH3), 136.2 (CHAr), 137.4 (CCOOC2H5),
-1
˜
164.9 (COH), 168.3, 169.4, 195.7 (CO). IR (neat, cm ): n = 3119
(w), 3076 (w), 2981 (w), 2919 (w), 2850 (w), 1729 (m), 1674 (s),
1580 (m), 1470 (w), 1443 (m), 1389 (w), 1362 (m), 1328 (m), 1304
(m), 1248 (s), 1207 (s), 1155 (m), 1137 (s), 1100 (m), 1026 (m), 965
(m), 937 (m), 872 (m), 847 (m), 811 (m), 757 (m), 733 (m), 706
(m), 688 (m), 647 (m), 598 (m), 580 (m), 540 (m). GC-MS (EI, 70
eV): m/z (%) = 266 ([M]+, 24), 251 (11), 221 (27), 220 (33), 192
(10), 191 (100), 190 (18), 189 (42), 188 (15), 162 (39), 120 (12), 119
(29), 43 (10). HRMS (EI): Calcd. for C13H14O6 ([M]+): 266.07849;
found: 266.079233.
General procedure for the synthesis of 2a–f. To a suspension
of sodium ethoxide (1.0 equiv.) in benzene (0.5 mL/1.0 mmol
EtONa), was dropwise added diethyl oxalate (1.0 equiv.) at 0 C
◦
followed by dropwise addition (during 30 min) of 1a–f (1.0 equiv.).
The temperature of the solution was allowed to warm to 20 ◦C
during 14 h with stirring. To the solution was added hydrochloric
acid (10%, 20 mL) and the organic and the aqueous layers
were separated. The latter was extracted with ether (3 ¥ 20 mL)
and washed with brine. The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo to give
products 2. The synthesis of 2a–f has been previously reported.
Acknowledgements
Financial support by the State of Mecklenburg-Vorpommern
(scholarship for M. S.) is gratefully acknowledged.
General procedure for the synthesis of 3a–f. To a solution
of 2a–f (1.0 equiv.) in acetic anhydride (2.0 equiv.) was added
triethylorthoformate (1.2 equiv.). The mixture was heated under
reflux for 2 h at 120 ◦C and for further 4 h at 140 ◦C. The mixture
was concentrated in vacuo to give 3 (92–99%).
Notes and references
1 Ro¨mpp Lexikon Naturstoffe, (W. Steglich, B. Fugmann, S. Lang-
Fugmann, eds.), Thieme, Stuttgart, 1997.
2 (a) S. Cabiddu, C. Fattuoni, C. Floris, G. Gelli, S. Melis and F. Sotgiu,
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Koziski, J. Org. Chem., 1987, 52, 183; (i) R. K. Hill and R. M. Carlson,
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Ethyl 3-(ethoxymethylene)-2,4-dioxopentanoate (3a). Starting
with 2a (4.30 g, 27.2 mmol), triethyl orthoformate (5.16 g,
32.6 mmol), and acetic anhydride (8.60 g, 54.4 mmol), 3a was
isolated as a red oil (5.64 g, 97%). 1H NMR (300 MHz, CDCl3):
3
3
d = 1.28 (t, J = 7.2 Hz, 3 H, OCH2CH3), 1.40 (t, J = 7.1 Hz,
3
3 H, OCH2CH3), 2.36 (s, 3 H, CH3), 4.24 (q, J= 7.2 Hz, 2 H,
3
OCH2CH3), 4.35 (q, J= 7.1 Hz, 2 H, OCH2CH3), 7.85 (s, 1 H,
CHOlf). 13C NMR (CDCl3, 75 MHz): d = 13.7, 15.0, 30.4 (CH3),
61.8, 74.4 (OCH2), 117.4 (COCCO), 164.5 (CO), 169.4 (CHOlf),
-1
˜
186.8, 195.8 (CO). IR (neat, cm ): n = 2984 (w), 2940 (w), 2255
(w), 1780 (w), 1732 (m), 1661 (m), 1577 (m), 1473 (w), 1389 (w),
1367 (w), 1312 (m), 1255 (m), 1224 (m), 1172 (m), 1097 (m), 1022
(m), 907 (s), 862 (w), 725 (s), 684 (w), 648 (m), 601 (w). GC-MS
(EI, 70 eV): m/z (%) = 214 ([M]+, 1.4), 141 (100), 113 (55), 99 (23),
71 (82), 43 (48), 29 (20). HRMS (EI): Calcd. for C10H14O5 ([M]+):
214.08358; found: 214.083886.
3 Metal-Catalyzed Cross-Coupling Reactions, (eds: A. de Meijere,
F. Diederich), Wiley-VCH, Weinheim, 2004.
4 (a) V. Prelog, J. Wu¨rsch and K. Ko¨nigsbacher, Helv. Chim. Acta, 1951,
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Minabi, Tetrahedron Lett., 1986, 27, 2401; for the cyclization of a 1,3-
dicarbonyl dianion with 3-(N,N-dimethylamino)-2-ethylacrolein, see:
(e) D. H. R. Barton, G. Dressaire, B. J. Willis, A. G. M. Barrett and M.
Pfeffer, J. Chem. Soc., Perkin Trans. 1, 1982, 665.
General procedure for the synthesis of 5a–al. To a CH2Cl2 solu-
tion (2 mL/1 mmol of 3a–f) of 3a–f was added 4a–i (1.1 mmol) and,
subsequently, TiCl4 (1.1 mmol) at -78 ◦C. The temperature of the
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5 For a review, see: (a) T. M. Harris and C. M. Harris, Tetrahedron, 1977,
33, 2159; (b) T. P. Murray and T. M. Harris, J. Am. Chem. Soc., 1972, 94,
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and T. M. Harris, J. Am. Chem. Soc., 1988, 110, 6172.
6 (a) I. Hussain, M. A. Yawer, B. Appel, M. Sher, A. Mahal, A. Villinger
and P. Langer, Tetrahedron, 2008, 64, 8003; (b) M. Sher, H. Reinke and
P. Langer, Tetrahedron, 2007, 63, 4080.
7 T.-H. Chan and P. Brownbridge, J. Am. Chem. Soc., 1980, 102, 3534.
8 For a review of 1,3-bis(silyloxy)-1,3-butadienes, see: P. Langer, Synthe-
sis, 2002, 441.
9 H. Feist and P. Langer, Synthesis, 2007, 327.
10 For reviews of chelation control in Lewis acid-mediated reactions, see:
(a) H. Yamamoto, Lewis Acid Chemistry: A Practical Approach, Oxford
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eds.; Pergamon: Oxford, 1991; Vol. 1, pp. 283–324.
11 Chelation control has been reported for the [4+3] annulation reaction
of benzyloxy-substituted 1,4-dicarbonyl compounds with bis(silyl enol
ethers): (a) G. A. Molander and P. R. Eastwood, J. Org. Chem., 1996,
61, 1910; recently, we have reported chelation control in the [3+3]
annulation of alkoxy-substituted 1,1-diacylcyclopropanes: (b) J. Hefner
and P. Langer, Tetrahedron Lett., 2008, 49, 4470.
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The Royal Society of Chemistry 2009
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