Synthesis of 3-pyrrol-3′-yloxindoles with a carbamate function

Article abstract of DOI:10.1134/S1070428011110108

By the reaction of methyl {4(3)-[2-(2-oxo-1,2-dihydro-3H-indol-3-ylidene) acetyl]phenyl} carbamates with ethyl 3-aminocrotonate at boiling in the mixture toluene-anhydrous ethanol, 2: 1, ethyl 5-{3(4)-[(methoxycarbonyl)amino]phenyl}- 2-methyl-4-(2-oxo-2,3

Full text of DOI:10.1134/S1070428011110108

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2011, Vol. 47, No. 11, pp. 1715−1717. © Pleiades Publishing, Ltd., 2011.
Original Russian Text ©A.V. Velikorodov, A.K. Kuanchalieva, V.A. Ionova, 2011, published in Zhurnal Organicheskoi Khimii, 2011, Vol. 47, No. 11, pp. 1679−1681.
Synthesis of 3-Pyrrol-3'-yloxindoles
with a Carbamate Function
A. V. Velikorodov, A. K. Kuanchalieva, and V. A. Ionova
Astrakhan State University, Astrakhan, 414000 Russia
e-mail: avelikorodov@mail.ru
Received January 24, 2011
Abstract—By the reaction of methyl {4(3)-[2-(2-oxo-1,2-dihydro-3Н-indol-3-ylidene)acetyl]phenyl}
carbamates with ethyl 3-aminocrotonate at boiling in the mixture toluene–anhydrous ethanol, 2 : 1, ethyl
5-{3(4)-[(methoxycarbonyl)amino]phenyl}-2-methyl-4-(2-oxo-2,3-dihydro-1Н-indol-3-yl)-1Н-pyrrole-3-
carboxylates were obtained. The condensation of methyl {3(4)-[2-(2-oxo-1,2-dihydro-3Н-indol-3-ylidene)acetyl]
phenyl}carbamates with ethyl acetoacetate in the presence of ammonium acetate and 20 mol% of 1-methyl-3-
butylimidazolium chloride or 1-methyl-3-octylimidazolium tetrafluoroborate at boiling in anhydrous ethanol led
to the formation of the corresponding 3-pyrrol-3'-yloxindoles with a carbamate function.
DOI: 10.1134/S1070428011110108
α,β-Unsaturated ketones are widely used in the syn-
thesis of diverse heterocyclic compounds [1–3].
the reagents in the mixture toluene–anhydrous ethanol,
2 : 1, v/v. The study of the structure of the reaction
products by IR, Н NMR spectroscopy, and mass
spectrometry established that the reaction products
were ethyl 5-[3(4)-methoxycarbonylaminophenyl]-
2-methyl-4-(2-oxo-2,3-dihydro-1Н-indol-3-yl)-1Н-
pyrrole-3-carboxylates (III, IV) formed in 88–91%
yield.
1
Aiming at the synthesis of new biologically active
compounds possessing a carbamate function we
studied the reactions of methyl {4(3)-[2-(2-oxo-1,2-
dihydro-1Н-indol-3-ylidene)acetyl]phenyl}carbamates
(I, II) with ethyl 3-aminocrotonate. The process was
performed by boiling over 5 h of equimolar amounts of
H
O
N
CO2Et
NHCO2Me
H2N
NHCO2Me
CO2Et
Me
NH
PhMe_EtOH, Δ
O
Me
+
O
H2N
Me
CO2Et
O
O
N
N
H
H
NHCO2Me
III, IV
I, II
A
The 3-acetonylideneoxindole is known to react
with methyl(ethyl) 3-amino-, methyl 3-(methyl-amino)
crotonates with the formation of pyrroloindoles which
according to the 1Н NMR data exist as keto-enol tauto-
mers [4].
The formation of 3-pyrrole-3'-yloxindoles III, IV oc-
curred apparently as a result of the primary attack of the
electron-excessive β-carbon atom of the enamine on the
electron-deficient carbon atom of compound I, II leading
to the formation of intermediate compounds А further
suffering the heterocyclization.
1
Yet the Н NMR data showed that 3-pyrrole-3’-yl-
1715

VELIKORODOV et al.
1716
oxindoles III, IV existed in the keto form apparently due
to the π-stacking between the oxindole and the phenyl ring
[5]. In the keto form the atom С3' is sp3-hybridized thus
permitting the rotation of the phenyl ring in the direction
of the oxindole providing the possibility of π-stacking.
In the enol form the atom С3' becomes sp2-hybridized
favoring the location of the indole and pyrrole rings in
the same plane with this atom. This molecular geometry
increases strains ant reduces the possibility of π-stacking
between the phenyl ring and the oxindole.
imidazolium tetrafluoroborate in these reactions also
provides pyrroloindoles III, IV in high yields (88, 89%
respectively), but the required reaction time increased
to 4 h. The increase in the ionic liquid concentration to
30 mol% did not result in higher yield or shorter reac-
tion time.
EXPERIMENTAL
1Н NMR spectra were registered on a spectrometer
Varian VXR-500 (500.13 МHz) in DMSO-d6, internal
reference TMS. IR spectra were recorded on a spec-
trophotometer Specord M82 in the frequency range
4000–400 cm–1 from pellets with KBr. Mass spectra
were measured on an instrument Finnigan MAT INCOS
50 at the ionizing electrons energy 70 eV. The purity of
compounds obtained was checked by TLC on Silufol
UV-254 plates.
1
The appearance of a singlet signal in the Н NMR
spectra in the region of 4.53–4.55 ppm belonging to the
proton Н3', and the presence in the IR spectrum of the
absorption band of the amide carbonyl group confirm the
structure of compounds III, IV.
NHCO2Me
Methyl {3-[2-(2-oxo-1,2-dihydro-1Н-indol-3-
ylidene)acetyl]phenyl}carbamate (II) was obtained
by isatin condensation with methyl N-(3-acetylphenyl)
carbamate by procedure [8]. Yield 1.35 g (84%), red-
orange crystals, mp 227–229°С (from dioxane). IR
spectrum, ν, cm–1: 3410–3340 (NH), 1710 (C=O), 1620,
O
O
N
H
I, II
1
1575, 1550 ( С−Сarom). Н NMR spectrum, δ, ppm:
3.71 s (3H, NHCO2Me), 6.89 d (1Нarom, J 7.5 Hz), 6.96 t
H
O
N
O
O
CO2Et
Et
(1Нarom, J 7.5 Hz), 7.35 t (1Нarom, J 7.5 Hz), 7.52 t (1Нarom
,
,
Me
O
Me
NH
J 8.0 Hz), 7.67 s (1Н, СН), 7.70 d (1Нarom, J 8.0 Hz),
7.79 d (1Нarom, J 8.0 Hz), 8.01 d (1Нarom, J 7.5 Hz),
8.21 s (1Нarom), 9.93 br.s (1Н, NHCO2Me), 10.80 br.s
(1Н, NHCO). Mass spectrum, m/z (Irel, %): 323 (11)
[M + 1]+·, 322 (83) [M]+·, 294 (43), 261 (25), 234 (35),
220 (22), 200 (1.7), 178 (23), 172 (44), 150 (10), 144
(78), 135 (34), 116 (100), 89 (43), 77 (13). Found, %:
С 66.85; Н 4.32; N 8.57. С18Н14N2O4. Calculated, %:
С 67.08; Н 4.35; N 8.70.
,
AcONH4 EtOH, Δ
[bmim][Cl]
NHCO2Me
III, IV
Recently an information appeared on a successful
reaction between ethyl acetoacetate and chalcones in the
presence of ammonium acetate and 10 mol% of ionic liq-
uid, 1-methyl-3-cyanomethylimidazolium chloride [6, 7].
Ethyl 5-(4-methoxycarbonylaminophenyl)-2-
methyl-4-(2-oxo-2,3-dihydro-1Н-indol-3-yl)-1Н-
pyrrole-3-carboxylate (III). (a) A mixture of 1.61 g
(5 mmol) of compound I, 0.64 ml (5 mmol) of ethyl
3-aminocrotonate in 15 ml of a mixture toluene–anhy-
drous ethanol, 2:1, was boiled for 5 h. On cooling the
separated crystals were filtered off, washed on the filter
with ethyl ether (5 ml), and recrystallized from dioxane.
Yield 1.8 g (85%), colorless crystals, mp 194–195°С.
IR spectrum, ν, cm–1: 3400–3320 (NH), 1715, 1687
(C=O), 1620, 1560, 1555 (С−Сarom). 1Н NMR spectrum,
δ, ppm: 1.05 t (3Н, СО2СН2СН3, J 7.0 Hz), 2.42 s (3Н,
СН3), 3.75 q (2Н, OСН2CH3, J 7.0 Hz), 3.65 s (3Н,
We investigated the reactions of chalcones I, II with
ethyl acetoacetate, ammonium acetate in the presence of
10–30 mol% 1-methyl-3-butylimidazolium chloride or
1-methyl-3-octylimidazolium tetrafluoroborate. The pro-
cess was carried out by boiling the reagents in anhydrous
ethanol.
It was found that the shortest process (3 h) and the
highest yields of 3-pyrrole-3'-yloxindoles (III, IV)
were observed at the use of 20 mol% of 1-methyl-3-
butylimidazolium chloride. The use of 1-methyl-3-octyl-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011

SYNTHESIS OF 3-PYRROL-3'-YLOXINDOLES
1717
NHCO2Me), 4.53 s (1Н, Н3'), 6.80–6.84 m (3Нarom),
7.10–7.14 m (1Нarom), 7.43 d (2Нarom, J 8.5 Hz), 7.54 d
(2Нarom, J 8.5 Hz), 9.75 br.s (1Н, NHCO2Me), 10.30 br.s
(1Н, NH), 11.52 s (1H, NH). Mass spectrum, m/z (Irel, %):
434 (0.5) [M + 1]+·, 433 (10) [M]+·, 387 (80), 355 (60), 328
(40), 300 (20), 285 (21), 272 (15), 257 (18), 194 (15), 154
(16), 128 (10), 77 (8). Found, %: С 66.27; Н 5.27; N 9.53.
C24H23N3O5. Calculated, %: С 66.51; Н 5.31; N 9.70.
(1Н, NHCO2Me), 10.31 br.s (1Н, NH), 11.60 br.s (1H,
NH). Found, %: С 66.35; Н 5.41; N 9.44. C24H23N3O5.
Calculated, %: С 66.51; Н 5.31; N 9.70.
Compound IV was obtained by method b reacting
1.86 mmol of compound II, 1.86 mmol of ethyl acetoac-
etate, 1.86 mmol of ammonium acetate, in the presence
of 20 mol% of 1-methyl-3-butylimidazolium chloride.
Yield 0.73 g (91%), co;orless crystals, mp 214–215°С
(from dioxane). Found, %: С 66.42; Н 5.27; N 10.04.
C24H23N3O5. Calculated, %: С 66.51; Н 5.31; N 9.70.
(b) A mixture of 0.6 g (1.86 mmol) of compound
I, 0.24 ml (1.86 mmol) of ethyl acetoacetate, 0.14 g
(1.86 mmol) of ammonium acetate, 20 mol% of 1-methyl-
3-butylimidazolium chloride in 15 ml anhydrous ethanol
was boiled for 3 h, the reaction mixture was cooled and
poured into 50 ml of distilled water, the separated pre-
cipitate was filtered off, washed with water on the filter
(20 ml), dried in air, and recrystallized from dioxane.
Yield 0.74 g (92%), colorless crystals, mp 194–195°С.
Found, %: С 66.33; Н 5.20; N 9.47. C24H23N3O5.
Calculated, %: С 66.51; Н 5.31; N 9.70.
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Ethyl 5-(3-methoxycarbonylaminophenyl)-2-
methyl-4-(2-oxo-2,3-dihydro-1Н-indol-3-yl)-1Н-
pyrrole-3-carboxylate (IV) was obtained by procedure
а reacting 5 mmol of compound II with 5 mmol of
ethyl 3-aminocrotonate. Yield 1.86 g (86%), colorless
crystals, mp 214–215°С (from dioxane). IR spectrum,
ν, cm–1: 3410–3300 (NH), 1710, 1690 (C=O), 1610,
1565, 1550 (С−Сarom). 1Н NMR spectrum, δ, ppm: 1.06 t
(3Н, СО2СН2СН3, J 7.0 Hz), 2.43 s (3Н, СН3), 3.73 q
(2Н, OСН2CH3, J 7.0 Hz), 3.65 s (3Н, NHCO2Me),
4.55 s (1Н, Н3'), 6.82 t (2Нarom, J 8.0 Hz), 7.10–7.16 m
(3Нarom), 7.19–7.44 m (2Нarom), 7.62 s (1Нarom), 9.75 br.s
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 47 No. 11 2011