A lewis acid-promoted cyclization of ethenetricarboxylate derivative aromatic compounds. Novel syntheses of oxindoles and benzofuranones via friedel-crafts intramolecular michael addition

Article abstract of DOI:10.1039/b408728c

A novel cyclization reaction of ethenetricarboxylate derivative aromatic compounds in the presence of various Lewis acids gave benzo-annulated cyclic compounds such as oxindole and benzofuran derivatives via Friedel-Crafts intramolecular Michael addition

Full text of DOI:10.1039/b408728c

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A R T I C L E
A Lewis acid-promoted cyclization of ethenetricarboxylate
derivative aromatic compounds. Novel syntheses of oxindoles and
benzofuranones via Friedel–Crafts intramolecular Michael addition†
Shoko Yamazaki,* Satoshi Morikawa, Yuko Iwata, Machiko Yamamoto and Kaori Kuramoto
Department of Chemistry, Nara University of Education, Takabatake-cho, Nara 630-8528,
Japan. E-mail: yamazaks@nara-edu.ac.jp
Received 10th June 2004, Accepted 17th August 2004
First published as an Advance Article on the web 24th September 2004
A novel cyclization reaction of ethenetricarboxylate derivative aromatic compounds in the presence of various
Lewis acids gave benzo-annulated cyclic compounds such as oxindole and benzofuran derivatives via Friedel–Crafts
intramolecular Michael addition in high yields. For example, the reaction of diethyl 2-[(N-methyl-N-phenyl-
carbamoyl)methylene]malonate (1a) in the presence of ZnCl2 at room temperature gave diethyl 2-(1-methyl-2-
oxoindolin-3-yl)malonate (2a) in 98% yield. The reactions also proceeded with a catalytic amount of a Lewis acid
such as AlCl3, ZnCl2, ZnBr2, Sc(OTf)3, or InBr3.
Table 1 Lewis acid-promoted cyclization of 1a
Benzo-annulated heterocyclic compounds such as oxindoles and
oxybenzofurans,areimportantmotifsfoundinbiologicallyactive
compounds and are useful synthetic intermediates.1,2 Although
various methods for the synthesis of oxindoles are known,3 they
are limited in scope and the development of general methodology
for the synthesis of these heterocycles is an important objective.
Lewis acids have been demonstrated to promote numerous
ring-forming reactions,4 including: Diels–Alder,5 [2 + 2]
cycloaddition,6 ene,7 and alkene–alkene cyclization reactions.8
On the other hand, known cyclization methods to give benzo-
annulated heterocycles using Lewis acids are quite limited,9
although selective and catalytic Lewis acid-promoted Friedel–
Crafts intermolecular Michael additions have been reported.10
Recently, we reported Lewis acid-promoted intramolecular C–C
bond forming reactions of tricarbonyl-substituted enynes.11 As
part of efforts to demonstrate the synthetic potential of highly
reactive tricarbonyl-substituted olefins, Lewis acid-promoted
intramolecular aromatic cyclizations to afford heterocycles
were examined. It was considered that the enhanced reactivity
of tricarbonyl-substituted olefins such as ethenetricarboxylate
derivative units might lead to highly efficient intramolecular
Michael acceptors. Herein, we report a novel cyclization reaction
of ethenetricarboxylate derivative aromatic compounds in the
presence of various Lewis acids to afford benzo-annulated cyclic
products. The reactions also proceeded with a catalytic amount
of various Lewis acids which makes the process highly valuable.
Diester-amides 1 were prepared by condensation of the 1,1-
diester of 2-hydrogen ethenetricarboxylate (prepared from the
1,1-diester of 2-tert-butyl ethenetricarboxylate upon treatment
with CF3CO2H) with 1-hydroxybenzotriazole (HOBT) and 1-
[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride
(EDCI), followed by reaction with the corresponding N-alkyl
anilines (eqn 1).12
Entry
Lewis acid
Equiv.
2a(yield)
1
2
3
4
5
6
7
8
9
ZnCl2
ZnBr2
ZnCl2
ZnBr2
AlCl3
GaCl3
InBr3
SnCl4
Zn(OTf)2
Sc(OTf)3
1.2
1.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
98
90
82
76
79
75
91
98
79
72
10
The reaction of diethyl 2-[(N-methyl-N-phenylcarbamoyl)-
methylene]malonate (1a) in the presence of ZnCl2 (1.2
equivalents) in CH2Cl2 at room temperature for 16 h gave
diethyl 2-(1-methyl-2-oxoindolin-3-yl)malonate (2a) in 98%
yield (eqn 2, Table 1). The reaction also proceeded with catalytic
amounts (0.2 equivalents) of Lewis acids such as AlCl3, ZnCl2,
ZnBr2, Sc(OTf)3, and InBr3.
(2)
As shown in Table 2, a variety of substrates underwent
cyclization to afford oxindoles in high yields. meta-Me
substituted substrate 1f gave a 1 : 1 mixture of 4-Me and 6-
Me regioisomers, demonstrating that steric hindrance from
the methyl group at the 4-position for 2f does not influence
selectivity (entries 8–9). Chloro-substituted substrate 1h also
gave cyclized product 2h in 86–87% yield (entries 13–14).
(1)
(3)
† Electronic supplementary information (ESI) available: additional
experimental procedures and spectral data and copies of 1H and 13C
NMR spectra for selected compounds. See http://www.rsc.org/suppdata/
ob/b4/b408728c/
The reaction of triester-substituted substrates was also
examined for comparison. The substrates 3 were prepared by
3 1 3 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 3 4 – 3 1 3 8
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

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Table 2 Lewis acid-promoted cyclization of 1b–ga
Entry
1
Substrate
Lewis acid
ZnCl2
Equiv.
1.2
2 (yield)
2b (80)
1b
2
3
4
1b
1b
1c
ZnCl2
Sc(OTf)3
ZnBr2
0.2
0.2
1.2
2b (74)b,c
2b (67)
2c (76)
5
6
1d
1e
ZnBr2
ZnCl2
1.2
1.2
2d (72)
2e (98)
7
8
1e
1f
ZnBr2
ZnCl2
1.2
1.2
2e (65)
2f-4-Me
2f-6-Me (79)d
9
1f
ZnBr2
ZnCl2
1.2
1.2
2f-4-Me
2f-6-Me (83)d
2g (91)b
10
1g
11
12
13
1g
1g
1h
SnCl4
SnCl4
SnCl4
0.2
1.2
1.2
2g (86)
2g (90)
2h (87)
14
1h
SnCl4
0.2
2h (86)
a The reactions were carried out at room temperature for 16 h, unless otherwise noted. b Reaction time, 44 h. c 6% of 1b remained.d Total yield.
Regioisomer ratio 1:1.
reaction of 1,1-diethyl 2-hydrogen ethenetricarboxylate with
the corresponding phenols in the presence of DEAD and PPh3.
The reaction of 1,1-diethyl 2-phenyl ethene-1,1,2-tricarboxylate
(3a) with ZnBr2 in CH2Cl2 at room temperature did not
proceed, however, reaction with the stronger Lewis acid FeCl3
(1.2 equiv.) gave diethyl 2-(2,3-dihydro-2-oxobenzofuran-3-yl)-
malonate (4a) in 65% yield (eqn 4).13 Various substrates were
thus examined to determine the scope of this benzofuran ring
formation. Substrates without OMe at the meta-position of the
phenyl ring did not react with ZnX2 but only reacted with FeCl3
(eqn 5, Table 3, entries 1–2). On the other hand, the reaction
of m-methoxyphenyl esters 3d–f with ZnCl2 or Sc(OTf)3 gave
benzofuran-2-one derivatives in high yields and regioselectivity
(entries 3–9).
(4)
(5)
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 3 4 – 3 1 3 8
3 1 3 5

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Table 3 Lewis acid-promoted cyclization of phenyl esters 3b–f
Entry
1
Substrate
Lewis Acid
FeCl3
equiv.
1.2
4 (Yield)
4b-6-Me
3b
4b-4-Me (53)a
4c (26)
2
3
3c
3d
FeCl3
ZnBr2
1.2
1.2
4d (67)b
4
5
6
3d
3d
3e
ZnCl2
ZnCl2
ZnCl2
1.2
0.2
1.2
4d (84)b
4d (84)b
4e (61)c
7
8
9
3e
3e
3e
3f
ZnBr2
Sc(OTf)3
FeCl3
1.2
0.2
1.2
1.2
4e (89)c
4e (87)c
4e (92)c
4f (88)
10
ZnCl2
11
12
13
14
15
16
17
3f
3f
3f
3f
3f
3f
3f
ZnCl2
ZnBr2
FeCl3
0.2
1.2
1.2
0.2
0.2
0.2
0.2
4f (64)
4f (91)
4f (68)
4f (73)
4f (94)
4f (89)
4f (82)
FeCl3
Sc(OTf)3
Zn(OTf)2
AlCl3
a Total yield. The regioisomer ratio for 6-Me and 4-Me is 3:1. b Almost entirely a single regioisomer (6-OMe) by NMR. A trace amount of a minor
product, believed to be the 4-OMe isomer, was present but not characterized. c Single regioisomer (5,6-diOMe).
The reaction of diester substrates was also examined. The
reaction of diethyl 2-(3-phenylpropylidene)malonate (5a) with
ZnBr2 or FeCl3 in CH2Cl2 at room temperature did not proceed.
The substrate with OMe at the meta-position of the phenyl ring
5b did not react with ZnX2 but reacted with FeCl3 (1.2 equiv.) to
give the indane derivative 6b in lower yield (eqn 6).
ester substrate 10a did not give cyclized products with ZnBr2, FeCl3
or AlCl3 at room temperature. The substrate with two OMe groups
at the meta-positions of the phenyl ring, 10b reacted with AlCl3
(1.2 equiv.) to give cyclized product 11b in 65% yield (eqn 8).
(6)
Six-membered ring formation was examined next. Reaction
of benzyl amide 7 with ZnCl2 at room temperature gave only
recovered starting material. Reaction with AlCl3, SnCl4, or FeCl3
(1.2 equiv.) at room temperature gave 8 in 26–64% yields along with
noncyclizedH2Oadduct9(eqn7).Incontrast,unsubstitutedbenzyl
(7)
3 1 3 6
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 3 4 – 3 1 3 8

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organic synthesis has been demonstrated in this study. Further
elaboration of the products and development of the use of chiral
Lewis acids is under investigation.
Experimental
General methods
Melting points are uncorrected. IR spectra were recorded in
the FT-mode. 1H NMR spectra were recorded at 400 MHz. 13
C
(8)
NMR spectra were recorded at 100.6 MHz. 1H chemical shifts
are reported in ppm relative to Me4Si. 13C chemical shifts are
reported in ppm relative to CDCl3 (77.1 ppm). 13C mutiplicities
were determined by DEPT and HSQC. Mass spectra were
recorded at an ionizing voltage of 70 eV by EI or FAB. All
reactions were carried out under a nitrogen atmosphere.
The probable aromatic substitution mechanism for ring
formation exemplified for 3a is shown in Scheme 1. Nucleophilic
attack of the aromatic carbon to the vinyl carbon (C2) of the
electrophilic olefin complexed with Lewis acid in A gives
a zwitterionic intermediate B (r-complex intermediate for
aromatic substitution). Deprotonation at aromatic hydrogen
and subsequent protonation of C1 may lead to intermediate
C. Dissociation of Lewis acid from the intermediate C yields
the cyclized product 3. The nitrogen atom in diester-amide-
substituted olefins 1 increases the electron density of the
aromatic ring and facilitates the cyclization. For substrate 1f, the
nitrogen atom strongly activates both ortho-positions on the ring
electronically. Therefore, steric differentiation was not observed
compared to substrate 3b (Table 2 entries 8–9 (regioisomer
ratio 1:1), Table 3, entry 1 (regioisomer ratio 3:1)). Triester
substrates need meta-methoxy substituents on the aromatic ring
in order to react in this catalytic process. For a meta-methoxy
group compared to a meta-methyl group, higher para/ortho
selectivity was observed (Table 2, entries 8–9, Table 3, entries
1 and 3–9, eqn 6). Determination of detailed electronic effects
towards regioselectivity are under investigation.
Typical cyclization procedure (Table 1, entry 1)
To a solution of 1a (132 mg, 0.43 mmol) in dichloromethane
(0.8 ml) was added ZnCl2 (68 mg, 0.50 mmol) at 0 °C. The
mixture was allowed to warm to room temperature and stirred
for 16 h. The reaction mixture was quenched by water at 0 °C.
The mixture was extracted with dichloromethane and the
organic phase was washed with saturated aqueous NaHCO3,
dried (Na2SO4), and evaporated in vacuo. The residue was
purified by column chromatography over silica gel eluting with
hexane–ether (2:1) to give to give 2a (129 mg, 98%).
1
Compound 2a. (Rf = 0.4, hexane–ether = 1:4) Yellow oil; H
NMR (400 MHz, CDCl3) d (ppm) 0.988 (t, J = 7.1 Hz, 3H),
1.29 (t, J = 7.1 Hz, 3H), 3.24 (s, 3H), 3.92–4.06 (m, 2H), 4.02
(d, J = 3.7 Hz, 1H), 4.22 (d, J = 3.7 Hz, 1H), 4.21–4.34 (m, 2H),
6.83 (d, J = 7.9 Hz, 1H), 7.03 (td, J = 7.6, 1.0 Hz, 1H), 7.29 (tt,
J = 7.8, 1.1 Hz, 1H), 7.40 (d, J = 7.5 Hz, 1H). Selected NOEs
are between d 3.24 and 6.83, d 4.02 and 7.40, and d 4.22 and
7.40; 13C NMR (100.6 MHz, CDCl3) d (ppm) 13.73 (q), 14.07
(q), 26.45 (q), 44.65 (d), 52.39 (d), 61.63 (t), 61.93 (t), 107.99 (d),
122.58 (d), 124.96 (d), 125.63 (s), 128.68 (d), 144.76 (s), 166.98
(s), 168.11 (s), 175.36 (s); IR (neat) 2982, 2916, 1719, 1613, 1479,
1323, 1294, 1270, 1093, 1050 cm−1; MS (EI) m/z 305; exact mass
M+ 305.1259 (calcd for C16H19NO5 305.1263); Anal. calcd for
C16H19NO5: C, 62.94; H, 6.27; N, 4.59. Found: C, 62.62; H, 6.31;
N, 4.55%.
Compound 2b. (Table 2) (Rf = 0.2, hexane–ether = 1:1) Yellow
oil; 1H NMR (400 MHz, CDCl3) d (ppm) 2.93 (s, 3H), 4.02 (d,
J = 3.5 Hz, 1H), 4.34 (d, J = 3.5 Hz, 1H), 4.90 (d, J = 12.0 Hz,
1H), 4.92 (d, J = 12.0 Hz, 1H), 5.21 (d, J = 12.2 Hz, 1H), 5.23
(d, J = 12.2 Hz, 1H), 6.65 (d, J = 7.7 Hz, 1H), 6.98 (td, J = 7.6,
1.0 Hz, 1H), 7.05–7.08 (m, 2H), 7.23–7.35 (m, 10H). Selected
NOEs are between d 2.93 and 6.65, d 4.02 and 7.23–7.35, and
d 4.34 and 7.23–7.35; 13C NMR (100.6 MHz, CDCl3) d (ppm)
26.16 (q), 44.65 (d), 52.36 (d), 67.60 (t), 67.83 (t), 108.26 (d),
122.61 (d), 124.92 (d), 125.32 (s), 128.43 (d), 128.52 (d), 128.56
(d), 128.59 (d), 128.66 (d), 134.76 (s), 135.08 (s), 144.62 (s),
166.77 (s), 167.92 (s), 175.10 (s); IR (neat) 3066, 3036, 2946,
1715, 1613, 1495, 1470, 1379, 1156 cm−1; MS (EI) m/z 429; exact
mass M+ 429.1573 (calcd for C26H23NO5 429.1576).
Scheme 1
Six-membered ring formation was not achieved for Lewis
acid-promoted HX-incorporative triester or diester/amide enyne
cyclization, as studied previously.11 In this aromatic substitution
case, six-membered ring products were obtained, although their
formation is a less efficient process compared to five-membered
ring formation, mainly because nitrogen or oxygen are not
directly connected to aromatic rings. Tricarbonyl structures as
Michael acceptors are also effective for this cyclization.
In summary, we have shown a novel and efficient Lewis acid-
promoted cyclization reaction yielding benzo-annulated cyclic
compounds. The reaction proceeds with mild Lewis acids and
in catalytic amounts and the procedure is straightforward.
The present reaction should provide an efficient cyclization
method for diverse benzo-annulated heterocycles. The highly
functionalized cyclized products are suitable for further
elaboration to products which are difficult to obtain by known
methods. A new utility of tricarbonyl-substituted olefins in
Compound 4a. (eqn 4) (Rf = 0.2, CH2Cl2) Yellow oil; 1H
NMR (400 MHz, CDCl3) d (ppm) 1.05 (t, J = 7.1 Hz, 3H), 1.29
(t, J = 7.1 Hz, 3H), 4.02–4.10 (m, 2H), 4.22–4.35 (m, 3H), 4.22
(d, J = 3.5 Hz, 1H), 7.11–7.15 (m, 2H), 7.33 (tt, J = 7.7, 1.2 Hz,
1H), 7.42 (d, J = 7.5 Hz, 1H). Selected NOEs are between d 4.22
and 7.42 and d 4.22–4.35 and 7.42.; 13C NMR (100.6 MHz,
CDCl3) d (ppm) 13.70 (q), 14.04 (q), 42.99 (d), 52.78 (d), 62.34
(t), 62.38 (t), 110.76 (d), 124.21 (s), 124.40 (d), 125.32 (d), 129.69
(d), 154.33 (s), 166.31 (s), 167.26 (s), 174.88 (s); IR (neat) 2986,
1808, 1745, 1620, 1481, 1464, 1373, 1340, 1288, 1234, 1180,
1054, 1033 cm−1; MS (EI) m/z 292; exact mass M+ 292.0938
(calcd for C15H16O6 292.0947).
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 3 4 – 3 1 3 8
3 1 3 7

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5 (a) W. Oppolzer, Angew. Chem., Int. Ed. Engl., 1984, 23, 876;
Compound 4e. (Table 3) (Rf = 0.2, CH2Cl2) Yellow crystals;
mp 76–79 °C; H NMR (400 MHz, CDCl3) d (ppm) 1.08 (t,
1
(b) S. Masamune, W. Choy, J. S. Petersen and L. R. Sita, Angew.
Chem., Int. Ed. Engl., 1985, 24, 1; (c) D. M. Birney and K. N. Houk,
J. Am. Chem. Soc., 1990, 112, 4127; (d) W. Carruthers, in
Cycloaddition Reactions in Organic Synthesis, Pergamon Press,
Oxford, 1991, pp. 140–208.
J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 3.85 (s, 3H), 3.89
(s, 3H), 4.02–4.10 (m, 2H), 4.19 (d, J = 3.5 Hz, 1H), 4.24 (dd,
J = 3.5, 0.7 Hz, 1H), 4.26–4.34 (m, 2H), 6.73 (s, 1H), 7.03 (d,
J = 0.7 Hz, 1H). Selected NOEs are between d 3.85 and 6.73, d
3.89 and 7.03, d 4.19 and 7.03, and d 4.24 and 7.03; 13C NMR
(100.6 MHz, CDCl3) d (ppm) 13.73 (q), 14.03 (q), 43.48 (d), 52.91
(d), 56.30 (q), 56.62 (q), 62.20 (t), 62.26 (t), 95.78 (d), 108.70 (d),
114.13 (s), 146.09 (s), 148.36 (s), 150.37 (s), 166.30 (s), 167.50 (s),
175.50 (s); IR (KBr) 2994, 2940, 1794, 1742, 1723, 1630, 1504,
1464, 1317, 1241, 1228, 1160, 1089 cm−1; MS (EI) m/z 352; exact
mass M+ 352.1161 (calcd for C17H20O8 352.1158).
6 (a) T. Takeda, T. Fujii, K. MoritaandT. Fujiwara, Chem. Lett., 1986,
1311; (b) K. Narasaka, Y. Hayashi, H. Shimadzu and S. Niihata, J.
Am. Chem. Soc., 1992, 114, 8869; (c) W. Srisiri, A. B. Padias and
H. K. Hall, Jr., J. Org. Chem., 1994, 59, 5424; (d) R. D. Clark and
K. G. Untch, J. Org. Chem., 1979, 44, 248, 253; (e) M. R. Baar,
P. Ballesteros and B. W. Roberts, Tetrahedron Lett., 1986, 27,
2083; (f) T. Okauchi, T. Kakiuchi, N. Kitamura, T. Utsunomiya,
J. Ichikawa and T. Minami, J. Org. Chem., 1997, 62, 8419.
7 (a) B. B. Snider, Acc. Chem. Res., 1980, 13, 426; (b) K. Narasaka,
Y. Hayashi and S. Shimada, Chem. Lett., 1988, 1609; (c) L. F. Tietze,
U. Beifuss, M. Ruther, A. Rühlmann, J. Antel and G. M. Sheldrick,
Angew. Chem., Int. Ed. Engl., 1988, 27, 1186; (d) L. F. Tietze and
U. Beifuß, Synthesis, 1988, 359; (e) T. Minami, T. Utsunomiya,
S. Nakamura, M. Okubo, N. Kitamura, Y. Okada and J. Ichikawa,
J. Org. Chem., 1994, 59, 6717.
8 (a) B. B. Snider and D. M. Roush, J. Org. Chem., 1979, 44, 4229;
(b) L. F. Tietze and M. Ruther, Chem. Ber., 1990, 123, 1387;
(c) L. F. Tietze and C. Schünke, Eur. J. Org. Chem., 1998, 2089.
9 (a) M. Agnusdei, M. Bandini, A. Melloni and A. Umani-Ronchi,
J. Org. Chem., 2003, 68, 7126; (b) A. H. Beckett, R. W. Daisley and
J. Walker, Tetrahedron, 1968, 24, 6093.
10 (a) W. Zhuang, T. Hansen and K. A. Jørgensen, Chem. Commun.,
2001, 347; (b) J. Zhou and Y. Tang, J. Am. Chem. Soc., 2002, 124,
9030; (c) N. Gathergood, W. Zhuang and K. A. Jørgensen, J. Am.
Chem. Soc., 2000, 122, 12517; (d) K. B. Jensen, J. Thorhauge,
R. G. Hazell and K. A. Jørgensen, Angew. Chem., Int. Ed., 2001, 40,
160; (e) A. Ishii, V. A. Soloshonok and K. Mikami, J. Org. Chem.,
2000, 65, 1597, and references therein; (f) Y. Yuan, X. Wang, X. Li
and K. Ding, J. Org. Chem., 2004, 69, 146.
Compound 4f. (Table 3) (Rf = 0.4, CH2Cl2) Pale yellow
1
crystals; mp 96–99 °C; H NMR (400 MHz, CDCl3) d (ppm)
1.13 (t, J = 7.1 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 3.799 (s, 3H),
3.803 (s, 3H), 3.98–4.08 (m, 1H), 4.11–4.19 (m, 1H), 4.30–4.35
(m, 2H), 4.35 (d, J = 4.0 Hz, 1H), 4.41 (d, J = 4.0 Hz, 1H), 6.19
(d, J = 2.0 Hz, 1H), 6.33 (d, J = 2.0 Hz, 1H). Selected NOEs
are between d 4.41 and 3.799 or 3.803, d 6.19 and 3.799, 3.803,
and d 6.33 and 3.799 or 3.803.; 13C NMR (100.6 MHz, CDCl3) d
(ppm) 13.84 (q), 14.08 (q), 41.99 (d), 51.33 (d), 55.72 (q), 55.83
(q), 61.84 (t), 62.37 (t), 89.69 (d), 94.28 (d), 103.30 (s), 155.69 (s),
156.53 (s), 162.32 (s), 166.63 (s), 167.10 (s), 174.69 (s); IR (KBr)
2988, 1812, 1740, 1729, 1632, 1613, 1510, 1468, 1348, 1156,
1048 cm−1; MS (EI) m/z 352; exact mass M+ 352.1154 (calcd for
C17H20O8 352.1158); Anal. calcd for C17H20O8: C, 57.95; H, 5.72.
Found: C, 57.70; H, 5.71%.
Acknowledgements
11 (a) S. Yamazaki, K. Yamada, S. Yamabe and K. Yamamoto,
J. Org. Chem., 2002, 67, 2889; (b) S. Yamazaki, K. Yamada and
K. Yamamoto, Org. Biomol. Chem., 2004, 2, 257.
This work was supported by the Ministry of Education, Culture,
Sports, Science, and Technology of the Japanese Government.
We are grateful to Prof. S. Umetani (Kyoto University) and Prof.
K. Kakiuchi (Nara Institute of Science and Technology) for
measurement of mass spectra and elemental analysis. We thank
Dr S. Hamanaka for helpful discussions.
12 The optimized reaction conditions are as follows. The 1,1-
diester of 2-hydrogen ethenetricarboxylate was reacted with
1-hydroxybenzotriazole (HOBT) in the presence of EDCI for 1 h
at 0 °C, then the corresponding N-alkyl aniline was added and the
resulting mixture stirred at room temperature overnight. When all
the reagents were mixed at once (see Electronic supplementary
information†), considerable amounts of byproducts 12 were
produced and the yields of 1 decreased. Probably Michael addition
of the corresponding N-alkyl anilines to 1,1-diester of 2-hydrogen
ethenetricarboxylate occurred before condensation of the carboxyl
group and the aniline.
References and notes
1 (a) G. A. Cordell, Introduction to Alkaloids—A Biogenetic Ap-
proach, Wiley-Interscience, New York, 1981; (b) J. S. Bindra,
Oxindole Alkaloids in The Alkaloids—Chemistry and Physiology,
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The reaction with N-unsubstituted aniline under the conditions gave
diester amide 1 only in very low yield.
13 The yield (65%) contains small amounts of unidentified byproducts
which could not be removed by column chromatography. Pure 4a
was isolated in 36% yield.
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3 1 3 8
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2 , 3 1 3 4 – 3 1 3 8