Synthesis and 1,3-dipolar cycloaddition reactions of N-aryl-C,C-dimethoxycarbonylnitrones

Article abstract of DOI:10.1002/jhet.5570400116

Arylnitroso compounds 1-3 easily reacted with dimethyl bromomalonate to give the corresponding N-aryl-C,C-dimethoxycarbonylnitrones (4-6). Treatment of C,C-dimethoxycarbonyl-N-(1-naphthyl)nitrone (4) with acetylene compounds (dimethyl acetylenedicarboxylate, methyl 2-butynoate or ethyl phenylpropiolate) caused 1,3-dipolar cycloaddition to furnish the corresponding 1H-benz[g]indolines (7a-c). In a similar manner, the reactions of nitrones 5 and 6 with acetylene compounds afforded the corresponding indolines 9a-c and 11a-c together with 4-oxazolines 13a-c and 14a-c.

Full text of DOI:10.1002/jhet.5570400116

Jan-Feb 2003
Synthesis and 1,3-Dipolar Cycloaddition Reactions of N-Aryl-C,C-
dimethoxycarbonylnitrones
121
Yukihiko Tomioka*, Chie Nagahiro, Yumiko Nomura and Hiroshi Maruoka
Faculty of Pharmaceutical Sciences, Fukuoka University,
8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
Received July 26, 2002
Arylnitroso compounds 1-3 easily reacted with dimethyl bromomalonate to give the corresponding N-
aryl-C,C-dimethoxycarbonylnitrones (4-6). Treatment of C,C-dimethoxycarbonyl-N-(1-naphthyl)nitrone (4)
with acetylene compounds (dimethyl acetylenedicarboxylate, methyl 2-butynoate or ethyl phenylpropiolate)
caused 1,3-dipolar cycloaddition to furnish the corresponding 1H-benz[g]indolines (7a-c). In a similar man-
ner, the reactions of nitrones 5 and 6 with acetylene compounds afforded the corresponding indolines 9a-c
and 11a-c together with 4-oxazolines 13a-c and 14a-c.
J. Heterocyclic Chem., 40, 121 (2003).
In recent years much attention has been focused on syn-
troso compounds. We also describe a new route to indolines
from nitrones with acetylene compounds by their using 1,3-
dipolar cycloaddition.
thesis and reactions of nitrones because of their importance
as synthetic tools in organic chemistry [1-4]. In fact, many
reports have appeared, especially concerning 1,3-dipolar
cycloaddition reactions. 1,3-Dipolar cycloaddition of
nitrones occupies a uniquely important position due to their
synthetic significance [5-10]. In general, nitrones react
energetically with alkynes to form 2,3-dihydroisoxazoles as
intermediates and products [11,12]. However, the situation
is complicated by the instability of the isoxazoles produced
and by the variety of different decomposition pathways.
The 2,3-dihydroisoxazole system, which was associated
with the presence of the weak nitrogen-oxygen bond and
the carbon-carbon π system, goes through many types of
rearrangements. In this respect, our interest in the chemistry
of nitrone-alkyne cycloaddition stems from the exploitation
of indolines and indoles showing biological interest [13-
21]. This work presents an efficient method for the synthe-
sis of N-aryl-C,C-dimethoxycarbonylnitrones from arylni-
The starting compounds N-aryl-C,C-dimethoxycarbonyl-
nitrones (4-6) were prepared by the reaction of the corre-
sponding arylnitroso compounds 1-3 [22] with dimethyl
bromomalonate and sodium hydroxide in moderate yields
(4: 49%, 5: 81%, 6: 82%). When a mixture of 4 and acety-
lene compounds (dimethyl acetylenedicarboxylate, methyl
2-butynoate or ethyl phenylpropiolate) in benzene was
refluxed, 1H-benz[g]indolines 7a-c were obtained in good
yields (7a: 89%, 7b: 81%, 7c: 92%). Fortunately, it was fur-
ther found that dimethyl 3-methoxalyl(and 3-ethoxalyl)-
1H-benz[g]indoline-2,2-dicarboxylates (8b and 8c) were
also obtained in 3 and 2% yield, respectively. The ir spectra
-1
of 7a-c and 8b,c display bands near 3350 cm due to an
-1
amino group and in the range of 1660~1760 cm due to
1
carbonyl groups. The H nmr spectrum of 7a exhibits four
three-proton singlets near δ 3.80 attributable to methoxy-

122
Y. Tomioka, C. Nagahiro, Y. Nomura and H. Maruoka
Vol. 40
such as the 2,3-dihydroisoxazoles 15b,c could not be iso-
lated at room temperature or another conditions. These
results make us believe that the key intermediate 2,3-dihy-
droisoxazoles 15b,c are more stable than those of the reac-
tions of 4 and/or 5 with acetylene compounds. Compounds
15b,c were easily converted to 11b,c (11b: 76%, 11c: 63%)
and 14b,c (14b: 22%, 14c: 35%) in refluxing benzene. The
formation of 9, 11, 13 and 14 can be explained in terms of
Scheme 2. A 1,3-dipolar cycloaddition of nitrones 5 and 6
to acetylene compounds gives the intermediate 2,3-dihy-
droisoxazole C, which undergoes ring transformation to
afford the indolines 9 and 11. On the other hand, a ring
contraction of the intermediate C to the aziridine D easily
occurs, which could then undergo ring expansion to give
4-oxazolines 13 and 14. The structures of 9a-c, 10b,c, 11a-
c, 12b,c, 13a-c, 14a-c and 15b,c were confirmed by ele-
mental analyses and spectral data.
Finally, we have examined the aromatization of 7a and
11a with triethylamine, hydrogen chloride and 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) in order to
confirm their structures (Scheme 3). The reactions of 7a
and 11a with triethylamine gave the corresponding
trimethyl indoline-2,2,3-tricarboxylates 16a,b (16a: 90%,
16b: 99%). Treatment of 16a,b with hydrogen chloride
caused demethoxycarbonylation to afford dimethyl cis-
and trans-indoline-2,3-dicarboxylates 17a,b (cis-17a:
11%, trans-17a: 50%, cis-17b: 13%, trans-17b: 29%).
These diastereomers of 17a,b could be separated by silica
gel chromatography (see experimental section).
Compounds cis- and trans-17a,b reacted with DDQ to
yield the corresponding dimethyl indole-2,3-dicarboxy-
carbonyl groups and a broad one-proton singlet at δ 5.63
assignable to a secondary amino group. The H nmr spec-
1
trum of 7b shows three singlets near δ 3.80 for methoxycar-
bonyl groups and a singlet at δ 2.31 for an acetyl group,
whereas 8b appears as three singlets near δ 3.80 for
methoxycarbonyl groups and a singlet at δ 1.76 for a
methyl group. Elemental analyses and spectral data of 7a-c
and 8b,c are consistent with the proposed structures. These
findings suggest the possibility that this reaction occurs via
1,3-dipolar cycloaddition of 4 and acetylene compounds to
form the intermediate 2,3-dihydroisoxazole A (path a)
rather than B (path b), which undergoes ring transformation
to give 7a-c (Scheme 1). These observations indicate that
the structure of the intermediate is susceptible to electronic
influence of the methoxy(or ethoxy)carbonyl group of
dipolarophiles as electron-withdrawing.
Subsequently, the reactions of 5 and 6 with acetylene
compounds under the same conditions gave the corre-
sponding indolines 9a-c (9a: 43%, 9b: 48%, 9c: 58%) and
11a-c (11a: 69%, 11b: 56%, 11c: 59%) together with 10b,c
(10b: 3%, 10c: 2%) and 12b,c (12b: 6%, 12c: 3%) as by-
products. In the case of this reaction, 4-oxazolines 13a-c
(13a: 25%, 13b: 15%, 13c: 16%) and 14a-c (14a: 17%,
14b: 15%, 14c: 29%) were also obtained as rearrangement
products (Scheme 2). Furthermore, we found the reaction
condition under which the key intermediate 2,3-dihy-
droisoxazoles 15b,c could be isolated. Treatment of 6 with
methyl 2-butynoate or ethyl phenylpropiolate at room tem-
perature gave the corresponding 15b,c in 65 and 59%
yield, respectively. However, in the case of the reaction of
4 and/or 5 with acetylene compounds, the intermediate C

Jan-Feb 2003
Synthesis and 1,3-Dipolar Cycloaddition Reactions
123
nmr (deuteriochloroform): δ 3.64 (s, 3H, CO Me), 3.97 (s, 3H,
lates 18a,b (18a: 85% from cis-17a, 81% from trans-17a;
18b: 77% from cis-17b, 85% from trans-17b), which were
identical with authentic samples prepared according to the
method of Mitchell et al. [23] or prepared according to the
method of Diels et al. [24].
2
CO Me), 7.37-7.56 (m, 3H, aromatic H), 7.79-7.91 ppm (m, 4H,
2
+
aromatic H); ms: m/z 287 (M ).
Anal. Calcd. for C
H NO : C, 62.72; H, 4.56; N, 4.88.
15 13 5
Found: C, 62.78; H, 4.50; N, 4.88.
C,C-Dimethoxycarbonyl-N-phenylnitrone (6).
EXPERIMENTAL
This compound was obtained as yellow prisms (5.83 g, 82%),
mp 74-75°; ir (potassium bromide): ν 1738 (C=O) cm ; H nmr
All melting points are uncorrected. The ir spectra were recorded
on a JASCO A-302 spectrometer or a JASCO FT/IR-230 spec-
trometer. The H nmr spectra were recorded on a HITACHI R-90
-1
1
(deuteriochloroform): δ 3.67 (s, 3H, CO Me), 3.96 (s, 3H,
2
1
+
CO Me), 7.30-7.52 ppm (m, 5H, aromatic H); ms: m/z 237 (M ).
2
H spectrometer (90 MHz) or a JEOL JNM-MH-100 (100 MHz)
spectrometer. Chemical shifts (δ) are reported in parts per million
(ppm) relative to tetramethylsilane as internal standard. Mass (70
eV, electron impact ionization) spectra were obtained on a JEOL
JMS-D 300 spectrometer. Elemental analyses were performed on
a HERAUS CHNO-RAPID analyzer or a YANACO MT-6 CHN
analyzer. Nitrosobenzene was obtained from Aldrich Chemical
Company, Inc. 1- and 2-Nitrosonaphthalene were prepared
according to the method of Earl Brill [22].
Anal. Calcd. for C
Found: C, 55.56; H, 4.68; N, 5.64.
H NO : C, 55.70; H, 4.67; N, 5.91.
11 11 5
General Procedure for the Preparation of 7a-c, 8b,c, 9a-c, 10b,c,
11a-c, 12b,c, 13a-c and 14a-c from 4-6 and Acetylene
Compounds.
A mixture of 4-6 (5 mmoles) and dimethyl acetylenedicarboxy-
late (0.71 g, 5 mmoles), methyl 2-butynoate (0.49 g, 5 mmoles) or
ethyl phenylpropiolate (0.87 g, 5 mmoles) in benzene (5 ml) was
refluxed for 2 hours (in the case of dimethyl acetylenedicarboxy-
late) or 8 hours (methyl 2-butynoate and ethyl phenylpropiolate).
After removal of the solvent in vacuo, the residue was recrystal-
lized from an appropriate solvent (a fractional recrystallization) to
give 7a-c, 9a-c, 11a-c, 13a-c and 14a-c. The mother solvent was
purified by silica gel chromatography using an ethyl acetate-
hexane (1:4) as the eluent to give 8b,c, 10b,c and 12b,c.
General Procedure for the Preparation of N-Aryl-C,C-dimethoxy-
carbonylnitrones 4-6.
To an ice-cooled and stirred solution of arylnitroso com-
pounds 1-3 (30 mmoles) in tetrahydrofuran (30 ml) were added
dimethyl bromomalonate (6.96 g, 33 mmoles) and a solution of
sodium hydroxide (1.32 g, 33 mmoles) in water (3 ml). After the
mixture was stirred for 3 hours with ice-cooling, cold water was
added to the reaction mixture. The precipitate was collected by
filtration, washed with water, dried and recrystallized from
diethyl ether to yield 4-6.
Trimethyl 3-Methoxalyl-1H-benz[g]indoline-2,2,3-tricarbox-
ylate (7a).
This compound was obtained as orange prisms (1.91 g, 89%),
mp 149-150° (acetone-diethyl ether); ir (potassium bromide): ν
C,C-Dimethoxycarbonyl-N-(1-naphthyl)nitrone (4).
-1
1
3380 (NH), 1760, 1725 (C=O) cm ; H nmr (deuteriochloro-
form): δ 3.75 (s, 3H, CO Me), 3.82 (s, 6H, 2xCO Me), 3.83 (s,
This compound was obtained as yellow prisms (4.19 g, 49%),
2
2
-1
1
mp 187-188°; ir (potassium bromide): ν 1730 (C=O) cm ; H
nmr (DMSO-d ): δ 3.54 (s, 3H, CO Me), 3.99 (s, 3H, CO Me),
3H, CO Me), 5.63 (br s, 1H, NH), 7.35-7.47 (m, 4H, aromatic
2
+
6
2
2
H), 7.70-7.83 ppm (m, 2H, aromatic H); ms: m/z 429 (M ).
7.58-7.73 (m, 5H, aromatic H), 8.02-8.18 ppm (m, 2H, aromatic
Anal. Calcd. for C
H NO : C, 58.74; H, 4.46; N, 3.26.
21 19 9
+
H); ms: m/z 287 (M ).
Found: C, 58.72; H, 4.44; N, 2.96.
Anal. Calcd. for C
H NO : C, 62.72; H, 4.56; N, 4.88.
15 13 5
Trimethyl 3-Acetyl-1H-benz[g]indoline-2,2,3-tricarboxylate (7b).
Found: C, 63.01; H, 4.58; N, 5.06.
This compound was obtained as colorless prisms (1.56 g,
81%), mp 174-177° (acetone-diethyl ether); ir (potassium bro-
C,C-Dimethoxycarbonyl-N-(2-naphthyl)nitrone (5).
This compound was obtained as yellow prisms (6.97 g, 81%),
-1
1
mide): ν 3385 (NH), 1745, 1715 (C=O) cm ; H nmr (deuterio-
chloroform): δ 2.31 (s, 3H, COMe), 3.76 (s, 3H, CO Me), 3.80
-1
1
mp 101-103°; ir (potassium bromide): ν 1735 (C=O) cm ; H
2

124
Y. Tomioka, C. Nagahiro, Y. Nomura and H. Maruoka
Vol. 40
(s, 3H, CO Me), 3.81 (s, 3H, CO Me), 5.50 (br s, 1H, NH), 7.33-
aromatic H), 7.74 (d, J = 8.5 Hz, 1H, 5-H), 7.69-7.79 ppm (m,
1H, aromatic H); ms: m/z 385 (M ).
2
2
+
7.56 (m, 4H, aromatic H), 7.72-7.85 ppm (m, 2H, aromatic H);
+
ms: m/z 385 (M ).
Anal. Calcd. for C
H NO : C, 62.33; H, 4.97; N, 3.64.
20 19 7
Anal. Calcd. for C
H NO : C, 62.33; H, 4.97; N, 3.64.
20 19 7
Found: C, 62.36; H, 5.13; N, 3.85.
Found: C, 62.17; H, 4.92; N, 3.49.
Dimethyl 1-Benzoyl-1-ethoxycarbonyl-3H-benz[e]indoline-2,2-
dicarboxylate (9c).
Dimethyl 3-Benzoyl-3-ethoxycarbonyl-1H-benz[g]indoline-2,2-
dicarboxylate (7c).
This compound was obtained as pale yellow prisms (1.34 g,
58%), mp 160-161° (acetone-petroleum ether); ir (potassium bro-
This compound was obtained as yellow prisms (2.12 g, 92%),
-1
1
mp 182-183° (acetone); ir (potassium bromide): ν 3320 (NH),
mide): ν 3330 (NH), 1745, 1670 (C=O) cm ; H nmr (deuteri-
ochloroform): δ 1.06 (t, J = 7 Hz, 3H, CO CH CH ), 3.34 (s, 3H,
-1
1
1757, 1742, 1660 (C=O) cm ; H nmr (deuteriochloroform): δ
1.22 (t, J = 7 Hz, 3H, CO CH CH ), 3.64 (s, 3H, CO Me), 3.76
2
2
3
CO Me), 3.82 (s, 3H, CO Me), 4.10 (q, J = 7 Hz, 2H,
2
2
3
2
2
2
(s, 3H, CO Me), 4.24 (q, J = 7 Hz, 2H, CO CH CH ), 5.61 (br s,
CO CH CH ), 5.37 (s, 1H, NH), 7.06-7.76 ppm (m, 11H, aro-
matic H); ms: m/z 461 (M ).
Anal. Calcd. for C H NO : C, 67.67; H, 5.02; N, 3.04.
26 23 7
2
2
2
3
2 2 3
+
1H, NH), 7.22-7.87 ppm (m, 11H, aromatic H); ms: m/z 461
+
(M ).
Anal. Calcd. for C
H
NO : C, 67.67; H, 5.02; N, 3.04.
Found: C, 67.55; H, 4.83; N, 2.82.
26 23
7
Found: C, 67.47; H, 5.19; N, 2.80.
Dimethyl 1-Methoxalyl-1-methyl-3H-benz[e]indoline-2,2-dicar-
boxylate (10b).
Dimethyl 3-Methoxalyl-3-methyl-1H-benz[g]indoline-2,2-dicar-
boxylate (8b).
This compound was obtained as yellow prisms (58 mg, 3%),
mp 147-148° (ethyl acetate-hexane); ir (potassium bromide): ν
3345 (NH), 1739, 1711 (C=O) cm ; H nmr (deuteriochloro-
This compound was obtained as orange prisms (58 mg, 3%),
-1
1
mp 129-130° (acetone); ir (potassium bromide): ν 3390 (NH),
-1
1
form): δ 1.90 (s, 3H, 1-Me), 3.42 (s, 3H, CO Me), 3.79 (s, 3H,
1753, 1730, 1712 (C=O) cm ; H nmr (deuteriochloroform): δ
2
CO Me), 3.81 (s, 3H, CO Me), 5.22 (s, 1H, NH), 7.05-7.52 (m,
1.76 (s, 3H, 3-Me), 3.52 (s, 3H, CO Me), 3.76 (s, 3H, CO Me),
2
2
2
2
4H, aromatic H), 7.66-7.75 ppm (m, 2H, aromatic H); ms: m/z
385 (M ).
3.84 (s, 3H, CO Me), 5.60 (br s, 1H, NH), 7.06 (d, J = 8 Hz, 1H,
2
+
4-H), 7.33 (d, J = 8 Hz, 1H, 5-H), 7.40-7.88 ppm (m, 4H, aro-
+
matic H); ms: m/z 385 (M ).
Anal. Calcd. for C H NO : C, 62.33; H, 4.97; N, 3.64.
20 19 7
Anal. Calcd. for C
H
NO : C, 62.33; H, 4.97; N, 3.64.
Found: C, 62.16; H, 5.03; N, 3.89.
20 19
7
Found: C, 62.23; H, 4.97; N, 3.66.
Dimethyl 1-Ethoxalyl-1-phenyl-3H-benz[e]indoline-2,2-dicar-
boxylate (10c).
Dimethyl 3-Ethoxalyl-3-phenyl-1H-benz[g]indoline-2,2-dicar-
boxylate (8c).
This compound was obtained as orange prisms (46 mg, 2%),
mp 212-213° (ethyl acetate-hexane); ir (potassium bromide): ν
3360 (NH), 1750, 1732, 1721 (C=O) cm ; H nmr (deuteriochlo-
This compound was obtained as orange prisms (46 mg, 2%),
-1 1
mp 181-182° (acetone-diethyl ether); ir (potassium bromide): ν
-1
1
roform): δ 0.69 (t, J = 7 Hz, 3H, CO CH CH ), 2.99 (s, 3H,
3360 (NH), 1738 (C=O) cm ; H nmr (deuteriochloroform): δ
1.03 (t, J = 7 Hz, 3H, CO CH CH ), 3.05 (s, 3H, CO Me), 3.93
2
2
3
CO Me), 3.67-3.96 (m, 2H, CO CH CH ), 3.90 (s, 3H, CO Me),
2
2
2
3
2
2
2
3
2
5.34 (s, 1H, NH), 6.87-7.87 ppm (m, 11H, aromatic H); ms: m/z
461 (M ).
(s, 3H, CO Me), 4.03 (q, J = 7 Hz, 2H, CO CH CH ), 5.46 (br s,
2
2
2
3
+
1H, NH), 7.30-7.93 ppm (m, 11H, aromatic H); ms: m/z 461
+
(M ).
Anal. Calcd. for C H NO : C, 67.67; H, 5.02; N, 3.04.
26 23 7
Anal. Calcd. for C
H
NO : C, 67.67; H, 5.02; N, 3.04.
Found: C, 67.48; H, 5.17; N, 3.05.
26 23
7
Found: C, 67.62; H, 5.05; N, 3.12.
Trimethyl 3-Methoxalylindoline-2,2,3-tricarboxylate (11a).
Trimethyl 1-Methoxalyl-3H-benz[e]indoline-1,2,2-tricarboxylate
(9a).
This compound was obtained as yellow prisms (1.31 g, 69%),
mp 129-130° (methylene chloride-diethyl ether); ir (potassium
bromide): ν 3380 (NH), 1767, 1750, 1730 (C=O) cm ; H nmr
-1
1
This compound was obtained as red prisms (0.92 g, 43%), mp
(deuteriochloroform): δ 3.75 (s, 3H, CO Me), 3.82 (s, 6H,
162-164° (acetone-petroleum ether); ir (potassium bromide): ν
3370 (NH), 1755, 1741, 1726 (C=O) cm ; H nmr (deuteriochlo-
2
-1 1
2xCO Me), 3.83 (s, 3H, CO Me), 5.15 (br s, 1H, NH), 6.72-7.36
2
2
+
ppm (m, 4H, aromatic H); ms: m/z 379 (M ).
roform): δ 3.70 (s, 3H, CO Me), 3.76 (s, 6H, 2xCO Me), 3.81 (s,
2
2
3H, CO Me), 5.40 (s, 1H, NH), 7.02-7.39 (m, 4H, aromatic H),
7.68-7.77 ppm (m, 2H, aromatic H); ms: m/z 429 (M ).
Anal. Calcd. for C NO : C, 53.83; H, 4.52; N, 3.69.
Found: C, 53.75; H, 4.52; N, 3.40.
H
2
17 17
9
+
Anal. Calcd. for C
Found: C, 58.71; H, 4.46; N, 3.07.
H NO : C, 58.74; H, 4.46; N, 3.26.
21 19 9
Trimethyl 3-Acetylindoline-2,2,3-tricarboxylate (11b).
This compound was obtained as colorless prisms (0.94 g,
Trimethyl 1-Acetyl-3H-benz[e]indoline-1,2,2-tricarboxylate
(9b).
56%), mp 148-149° (acetone); ir (potassium bromide): ν 3345
-1
1
(NH), 1742, 1729, 1714 (C=O) cm ; H nmr (deuteriochloro-
form): δ 2.28 (s, 3H, COMe), 3.75 (s, 3H, CO Me), 3.79 (s, 6H,
This compound was obtained as colorless prisms (0.92 g,
48%), mp 148-151° (acetone-petroleum ether); ir (potassium bro-
2
2xCO Me), 5.04 (br s, 1H, NH), 6.73 (d, J = 8 Hz, 1H, 4-H), 6.85
2
-1
1
(dd, J = 1, 8 Hz, 1H, 5 or 6-H), 7.12 (dd, J = 1, 8 Hz, 1H, 5 or 6-
mide): ν 3340 (NH), 1758, 1745, 1730, 1703 (C=O) cm ; H
nmr (deuteriochloroform): δ 2.51 (s, 3H, COMe), 3.69 (s, 3H,
CO Me), 3.75 (s, 3H, CO Me), 3.82 (s, 3H, CO Me), 5.20 (s,
+
H), 7.35 ppm (d, J = 8 Hz, 1H, 7-H); ms: m/z 335 (M ).
Anal. Calcd. for C
H NO : C, 57.31; H, 5.11; N, 4.18.
16 17 7
2
2
2
1H, NH), 7.09 (d, J = 8.5 Hz, 1H, 4-H), 7.17-7.41 (m, 3H,
Found: C, 57.41; H, 5.15; N, 4.16.

Jan-Feb 2003
Synthesis and 1,3-Dipolar Cycloaddition Reactions
125
Dimethyl 3-Benzoyl-3-ethoxycarbonylindoline-2,2-dicarbox-
ylate (11c).
2xCO Me), 4.00 (q, J = 7 Hz, 2H, CO CH CH ), 7.36-8.13 ppm
2 2 2 3
(m, 12H, aromatic H); ms: m/z 461 (M ).
+
Anal. Calcd. for C NO : C, 67.67; H, 5.02; N, 3.04.
Found: C, 67.75; H, 4.93; N, 3.03.
H
26 23
7
This compound was obtained as pale yellow prisms (1.21 g,
59%), mp 115-116° (acetone-diethyl ether); ir (potassium
-1
1
bromide): ν 3345 (NH), 1752, 1739, 1663 (C=O) cm ; H nmr
(deuteriochloroform): δ 1.22 (t, J = 7.5 Hz, 3H, CO CH CH ),
Tetramethyl 3-Phenyl-4-oxazoline-2,2,4,5-tetracarboxylate
(14a).
2
2
3
3.63 (s, 3H, CO Me), 3.73 (s, 3H, CO Me), 4.23 (q, J = 7.5 Hz,
2
2
This compound was obtained as colorless prisms (0.32 g,
17%), mp 95-97° (diethyl ether-petroleum ether); ir (potassium
2H, CO CH CH ), 4.60 (br s, 1H, NH), 6.64-6.83 (m, 2H,
2
2
3
aromatic H), 7.05-7.65 ppm (m, 7H, aromatic H); ms: m/z 411
-1
1
bromide): ν 1758, 1744, 1720 (C=O) cm ; H nmr (deuterio-
chloroform): δ 3.68 (s, 3H, CO Me), 3.69 (s, 6H, 2xCO Me),
+
(M ).
2
2
Anal. Calcd. for C
H NO : C, 64.23; H, 5.15; N, 3.41.
22 21 7
3.86 (s, 3H, CO Me), 7.30 ppm (s, 5H, aromatic H); ms: m/z
2
Found: C, 63.96; H, 5.10; N, 3.31.
+
379 (M ).
Dimethyl 3-Methoxalyl-3-methylindoline-2,2-dicarboxylate
(12b).
Anal. Calcd. for C
H NO : C, 53.83; H, 4.52; N, 3.69.
17 17 9
Found: C, 53.80; H, 4.39; N, 3.77.
This compound was obtained as yellow prisms (0.10 g, 6%),
Trimethyl 5-Methyl-3-phenyl-4-oxazoline-2,2,4-tricarboxylate
(14b).
mp 110-111° (diethyl ether); ir (potassium bromide): ν 3350
-1
1
(NH), 1743, 1710 (C=O) cm ; H nmr (deuteriochloroform): δ
1.68 (s, 3H, 3-Me), 3.61 (s, 3H, CO Me), 3.76 (s, 3H, CO Me),
This compound was obtained as colorless plates (0.25 g, 15%),
mp 100° (diethyl ether-petroleum ether); ir (potassium bromide):
2
2
3.80 (s, 3H, CO Me), 4.96 (br s, 1H, NH), 6.68-7.25 ppm (m, 4H,
2
-1
1
ν 1770, 1746, 1706 (C=O) cm ; H nmr (deuteriochloroform): δ
2.41 (s, 3H, 5-Me), 3.60 (s, 3H, CO Me), 3.63 (s, 6H, 2xCO Me),
+
aromatic H); ms: m/z 335 (M ).
2
2
Anal. Calcd. for C
H NO : C, 57.31; H, 5.11; N, 4.18.
16 17 7
+
7.06-7.26 ppm (m, 5H, aromatic H); ms: m/z 335 (M ).
Found: C, 57.25; H, 5.10; N, 4.29.
Anal. Calcd. for C NO : C, 57.31; H, 5.11; N, 4.18.
H
16 17
7
Dimethyl 3-Ethoxalyl-3-phenylindoline-2,2-dicarboxylate (12c).
This compound was obtained as orange oil (62 mg, 3%); ir
Found: C, 57.20; H, 5.16; N, 4.15.
Dimethyl 4-Ethoxycarbonyl-3,5-diphenyl-4-oxazoline-2,2-dicar-
boxylate (14c).
-1
1
(neat): ν 3370 (NH), 1740 (C=O) cm ; H nmr (deuteriochloro-
form): δ 1.12 (t, J = 7.5 Hz, 3H, CO CH CH ), 3.07 (s, 3H,
2
2
3
This compound was obtained as pale yellow prisms (0.60 g,
29%), mp 92-93° (diethyl ether-petroleum ether); ir (potassium
CO Me), 3.89 (s, 3H, CO Me), 4.10 (q, J = 7.5 Hz, 2H,
2
2
CO CH CH ), 5.04 (br s, 1H, NH), 6.76-6.91 (m, 2H, aromatic
2
2
3
-1
1
bromide): ν 1760, 1740, 1710 (C=O) cm ; H nmr (deuterio-
chloroform): δ 0.91 (t, J = 7.5 Hz, 3H, CO CH CH ), 3.66 (s, 6H,
H), 7.16-7.55 ppm (m, 7H, aromatic H); high-resolution ms:
Calcd. for C NO 411.1318, found 411.1334.
H
2
2
3
22 21
7
2xCO Me), 4.02 (q, J = 7.5 Hz, 2H, CO CH CH ), 7.08-7.46 (m,
2
2
2
3
Tetramethyl 3-(2-Naphthyl)-4-oxazoline-2,2,4,5-tetracarboxylate
(13a).
8H, aromatic H), 7.94-8.05 ppm (m, 2H, aromatic H); ms: m/z
+
411 (M ).
Anal. Calcd. for C
H NO : C, 64.23; H, 5.15; N, 3.41.
22 21 7
This compound was obtained as colorless prisms (0.54 g,
25%), mp 154-156° (diethyl ether); ir (potassium bromide): ν
Found: C, 63.99; H, 5.06; N, 3.13.
-1
1
1777, 1753, 1740, 1720 (C=O) cm ; H nmr (deuteriochloro-
form): δ 3.64 (s, 3H, CO Me), 3.67 (s, 6H, 2xCO Me), 3.87 (s,
General Procedure for the Preparation of 15b,c from 6 and
Methyl 2-Butynoate or Ethyl Phenylpropiolate.
2
2
3H, CO Me), 7.33-7.52 (m, 3H, aromatic H), 7.70-7.79 ppm (m,
2
+
A mixture of 6 (1.19 g, 5 mmoles) and methyl 2-butynoate
(0.49 g, 5 mmoles) or ethyl phenylpropiolate (0.87 g, 5 mmoles)
in benzene (5 ml) was stirred at room temperature for 6 days.
After removal of the solvent in vacuo, the residue was purified by
silica gel chromatography using an ethyl acetate-hexane (1:4) as
the eluent to afford 15b,c. The second fraction gave 14b (34 mg,
2%) and 14c (12 mg, 3%). The third fraction gave 12b (0.10 g,
6%) and 12c (0.16 g, 8%). The last fraction gave 11b (0.18 g,
11%) and 11c (0.21 g, 10%). The melting points and ir spectra of
11b,c, 12b and 14b,c coincided with those of authentic samples
prepared from 6 and methyl 2-butynoate or ethyl phenylpropio-
late. The ir spectrum of 12c coincided with that of authentic sam-
ple prepared from 6 and ethyl phenylpropiolate.
4H, aromatic H); ms: m/z 429 (M ).
Anal. Calcd. for C
H NO : C, 58.74; H, 4.46; N, 3.26.
21 19 9
Found: C, 58.82; H, 4.52; N, 3.49.
Trimethyl 5-Methyl-3-(2-naphthyl)-4-oxazoline-2,2,4-tricar-
boxylate (13b).
This compound was obtained as colorless prisms (0.29 g,
15%), mp 127-130° (diethyl ether-petroleum ether); ir (potassium
–1
1
bromide): ν 1760, 1710 (C=O) cm
; H nmr (deuteriochloro-
form): δ 2.44 (s, 3H, 5-Me), 3.57 (s, 3H, CO Me), 3.59 (s, 6H,
2
2xCO Me), 7.36-7.46 (m, 3H, aromatic H), 7.60-7.77 ppm (m,
2
+
4H, aromatic H); ms: m/z 385 (M ).
Anal. Calcd. for C
H NO : C, 62.33; H, 4.97; N, 3.64.
20 19 7
Found: C, 62.13; H, 5.03; N, 3.41.
Trimethyl 2,3-Dihydro-5-methyl-2-phenylisoxazole-3,3,4-tricar-
Dimethyl 4-Ethoxycarbonyl-3-(2-naphthyl)-5-phenyl-4-oxazo-
boxylate (15b).
line-2,2-dicarboxylate (13c).
This compound was obtained as colorless needles (1.09 g,
This compound was obtained as pale yellow prisms (0.37 g,
16%), mp 123-125° (diethyl ether-petroleum ether); ir (potassium
65%), mp 116° (ethyl acetate-hexane); ir (potassium bromide): ν
-1
1
1753, 1694 (C=O) cm ; H nmr (deuteriochloroform): δ 2.41 (s,
3H, 5-Me), 3.61 (s, 6H, 2xCO Me), 3.73 (s, 3H, CO Me), 7.08-
-1
1
bromide): ν 1757, 1713 (C=O) cm ; H nmr (deuteriochloro-
form): δ 0.84 (t, J = 7 Hz, 3H, CO CH CH ), 3.63 (s, 6H,
2
2
+
7.42 ppm (m, 5H, aromatic H); ms: m/z 335 (M ).
2
2
3

126
Y. Tomioka, C. Nagahiro, Y. Nomura and H. Maruoka
Vol. 40
Anal. Calcd. for C
Found: C, 57.40; H, 5.12; N, 4.40.
H
NO : C, 57.31; H, 5.11; N, 4.18.
sodium sulfate and concentrated in vacuo. The residue was puri-
fied by silica gel chromatography using a 10% ethyl acetate in
hexane as the eluent to yield cis-17a,b. Further the elution
afforded trans-17a,b.
16 17
7
Dimethyl 4-Ethoxycarbonyl-2,3-dihydro-2,5-diphenylisoxazole-
3,3-dicarboxylate (15c).
Dimethyl cis-1H-Benz[g]indoline-2,3-dicarboxylate (cis-17a).
This compound was obtained as colorless needles (1.21 g,
59%), mp 90-91° (ethyl acetate-hexane); ir (potassium bromide):
This compound was obtained as colorless needles (0.19 g,
-1
1
ν 1757, 1742, 1726 (C=O) cm ; H nmr (deuteriochloroform): δ
1.15 (t, J = 7 Hz, 3H, CO CH CH ), 3.64 (s, 6H, 2xCO Me),
11%), mp 94-95° (diethyl ether); ir (potassium bromide): ν 3370
-1
1
(NH), 1752, 1735 (C=O) cm ; H nmr (deuteriochloroform): δ
2
2
3
2
4.16 (q, J = 7 Hz, 2H, CO CH CH ), 7.08-7.52 (m, 8H, aromatic
3.86 (s, 6H, 2xCO Me), 4.71 (d, J = 5 Hz, 1H, 3-H), 4.98 (br s,
2
2
3
2
+
H), 7.83-7.94 ppm (m, 2H, aromatic H); ms: m/z 411 (M ).
Anal. Calcd. for C NO : C, 64.23; H, 5.15; N, 3.41.
1H, NH), 5.15 (d, J = 5 Hz, 1H, 2-H), 7.27-7.50 (m, 4H, aromatic
+
H
H), 7.72-7.86 ppm (m, 2H, aromatic H); ms: m/z 285 (M ).
22 21
7
Found: C, 64.22; H, 5.23; N, 3.59.
Anal. Calcd. for C
H NO : C, 67.36; H, 5.30; N, 4.91.
16 15 4
Found: C, 67.65; H, 5.30; N, 5.18.
The Preparation of 11b,c and 14b,c from 15b,c.
Dimethyl trans-1H-Benz[g]indoline-2,3-dicarboxylate (trans-
17a).
A mixture of 15b,c (10 mmoles) in benzene (3 ml) was refluxed
for 3 hours. After removal of the solvent in vacuo, the residue was
purified by silica gel chromatography using an ethyl acetate-
hexane (1:4) as the eluent to yield 14b (0.37 g, 22%) and 14c (0.72
g, 35%). Further the elution gave 11b (1.27 g, 76%) and 11c (1.29
g, 63%), respectively. The melting points and ir spectra of 11b,c
and 14b,c coincided with those of authentic samples prepared from
6 and methyl 2-butynoate or ethyl phenylpropiolate.
This compound was obtained as colorless needles (0.85 g,
50%), mp 118-120° (diethyl ether); ir (potassium bromide): ν
-1
1
3360 (NH), 1738 (C=O) cm ; H nmr (deuteriochloroform): δ
3.67 (s, 3H, CO Me), 3.80 (s, 3H, CO Me), 3.92 (br s, 1H, NH),
2
2
4.58 (d, J = 10 Hz, 1H, 3-H), 4.86 (d, J = 10 Hz, 1H, 2-H), 7.33-
7.47 (m, 4H, aromatic H), 7.69-7.83 ppm (m, 2H, aromatic H);
+
ms: m/z 285 (M ).
General Procedure for the Preparation of 16a,b from 7a and 11a.
Anal. Calcd. for C
H NO : C, 67.36; H, 5.30; N, 4.91.
16 15 4
A mixture of 7a or 11a (1 mmole) and triethylamine (0.30 g, 3
mmoles) in methanol (5 ml) was refluxed for 2 hours. After
removal of the solvent in vacuo, cold water was added to the
residue. The resulting mixture was extracted with chloroform.
The extract was dried over anhydrous sodium sulfate and concen-
trated in vacuo. The residue was recrystallized from an appropri-
ate solvent to give 16a,b.
Found: C, 67.38; H, 5.39; N, 4.97.
Dimethyl cis-Indoline-2,3-dicarboxylate (cis-17b).
This compound was obtained as colorless prisms (0.18 g,
13%), mp 74-77° (diethyl ether-petroleum ether); ir (potassium
-1
1
bromide): ν 3410 (NH), 1730, 1713 (C=O) cm ; H nmr
(DMSO-d ): δ 3.70 (s, 3H, CO Me), 3.74 (s, 3H, CO Me), 4.37
6
2
2
(d, J = 6.5 Hz, 1H, 3-H), 4.73 (dd, J = 2.5, 6.5 Hz, 1H, 2-H), 6.32
(d, J = 2.5 Hz, 1H, NH), 6.55-6.70 (m, 2H, aromatic H), 6.98-
7.19 ppm (m, 2H, aromatic H); ms: m/z 235 (M ).
Trimethyl 1H-Benz[g]indoline-2,2,3-tricarboxylate (16a).
This compound was obtained as colorless prisms (0.31 g,
90%), mp 127-128° (acetone-diethyl ether); ir (potassium bro-
+
Anal. Calcd. for C
H NO : C, 61.27; H, 5.57; N, 5.95.
-1
1
12 13 4
mide): ν 3400 (NH), 1755, 1740 (C=O) cm ; H nmr (deuteri-
ochloroform): δ 3.69 (s, 3H, CO Me), 3.79 (s, 3H, CO Me), 3.82
Found: C, 61.12; H, 5.60; N, 5.89.
2
2
(s, 3H, CO Me), 5.18 (s, 1H, 3-H), 5.47 (br s, 1H, NH), 7.33-7.52
Dimethyl trans-Indoline-2,3-dicarboxylate (trans-17b).
2
(m, 4H, aromatic H), 7.73-7.84 ppm (m, 2H, aromatic H); ms:
This compound was obtained as colorless prisms (0.41 g,
+
m/z 343 (M ).
29%), mp 72-74° (diethyl ether); ir (potassium bromide): ν 3370
Anal. Calcd. for C
H NO : C, 62.97; H, 4.99; N, 4.08.
18 17 6
-1
1
(NH), 1735 (C=O) cm ; H nmr (DMSO-d ): δ 3.60 (s, 3H,
6
Found: C, 63.15; H, 5.10; N, 4.15.
CO Me), 3.63 (s, 3H, CO Me), 4.50 (d, J = 10 Hz, 1H, 3-H), 4.72
2
2
Trimethyl Indoline-2,2,3-tricarboxylate (16b).
(dd, J = 2.5, 10 Hz, 1H, 2-H), 6.13 (d, J = 2.5 Hz, 1H, NH), 6.52-
6.67 (m, 2H, aromatic H), 6.95-7.10 ppm (m, 2H, aromatic H);
This compound was obtained as colorless prisms (0.29 g,
99%), mp 70-72° (diethyl ether-petroleum ether); ir (potassium
+
ms: m/z 235 (M ).
-1 1
Anal. Calcd. for C
H NO : C, 61.27; H, 5.57; N, 5.95.
12 13 4
bromide): ν 3420 (NH), 1738 (C=O) cm ; H nmr (deuteriochlo-
Found: C, 60.90; H, 5.62; N, 5.86.
roform): δ 3.63 (s, 3H, CO Me), 3.76 (s, 3H, CO Me), 3.77 (s,
2
2
3H, CO Me), 4.77 (br s, 1H, NH), 4.96 (s, 1H, 3-H), 6.68-7.16
ppm (m, 4H, aromatic H); ms: m/z 293 (M ).
2
General Procedure for the Preparation of 18a,b from cis- or
trans-17a,b.
+
Anal. Calcd. for C
H NO : C, 57.34; H, 5.16; N, 4.78.
14 15 6
A mixture of cis- or trans-17a,b (1 mmole) and 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (0.23 g, 1 mmole) in 1,4-dioxane
(2 ml) was refluxed for one hour. After removal of the deposited
crystals by filtration, the filtrate was concentrated in vacuo. The
residue was purified by column chromatography on silica gel
with chloroform as the eluent to give dimethyl 1H-benz[g]indole-
2,3-dicarboxylate (18a) [(0.24 g, 85%, from cis-17a), (0.23 g,
81%, from trans-17a)] and dimethyl indole-2,3-dicarboxylate
(18b) [(0.18 g, 77%, from cis-17b), (0.20 g, 85%, from trans-
17b)]. The melting points and ir spectra of 18a,b coincided with
Found: C, 57.44; H, 5.21; N, 4.83.
General Procedure for the Preparation of cis- and trans-17a,b
from 16a,b.
Dry hydrogen chloride was bubbled into an ice-cooled and
stirred solution of 16a,b (6 mmoles) in anhydrous methanol (40
ml) for one hour, and then the mixture was refluxed for 8 hours.
After removal of the solvent in vacuo, the residue was basified
with saturated sodium bicarbonate. The resulting mixture was
extracted with chloroform. The extract was dried over anhydrous

Jan-Feb 2003
Synthesis and 1,3-Dipolar Cycloaddition Reactions
127
York, 1977, p 207.
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diphenylhydrazine and dimethyl acetylenedicarboxylate [24].
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