Some condensations of methyl 4-acetylphenylcarbamate

Article abstract of DOI:10.1134/S1070428010070031

Condensation of methyl 4-acetylphenylcarbamate with isatin in the presence of diethylamine afforded methyl 4-[(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl) acetyl]phenylcarbamate which was converted into the corresponding chalcone on heating in glacial acet

Full text of DOI:10.1134/S1070428010070031

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 7, pp. 971–975. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © A.V. Velikorodov, N.M. Imasheva, A.K. Kuanchalieva, O.Yu. Poddubnyi, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 7, pp. 975–979.
Some Condensations of Methyl 4-Acetylphenylcarbamate
A. V. Velikorodov, N. M. Imasheva, A. K. Kuanchalieva, and O. Yu. Poddubnyi
Astrakhan State University, pl. Shaumyana 1, Astrakhan, 414000 Russia
e-mail: avelikorodov@mail.ru
Received November 15, 2009
Abstract—Condensation of methyl 4-acetylphenylcarbamate with isatin in the presence of diethylamine
afforded methyl 4-[(3-hydroxy-2-oxo-2,3-dihydro-1H-indol-3-yl)acetyl]phenylcarbamate which was con-
verted into the corresponding chalcone on heating in glacial acetic acid in the presence of hydrochloric acid.
1,3-Dipolar cycloaddition to that chalcone of azomethine ylide generated from 2-phenacylisoquinolinium
bromide by the action of triethylamine gave methyl 4-(3′-benzoyl-2-oxo-1′,2,2′,3,3′,10b′-hexahydro-1H-spiro-
[indole-3,1′-pyrrolo[1,2-a]isoquinolin]-2′-ylcarbonyl)phenylcarbamate. Condensation of 2-hydroxy- and 2,4-di-
hydroxybenzaldehydes with methyl 4-acetylphenylcarbamate in the presence of gaseous hydrogen chloride
resulted in the formation of chromenium salts with a methoxycarbonylaminophenyl fragment on the C2 atom in
the heteroring.
DOI: 10.1134/S1070428010070031
Acetophenone and its derivatives are convenient
starting materials for the synthesis of various com-
pounds, including chalcones which can be converted
into various heterocycles [1–5]. Chalcones and flavo-
noids generally exhibit versatile biological activity, in
particular antituberculous [6]. The ability of chalcones
to inhibit leukocyte aggregation is completely lost
upon hydrogenation of the double bond [7]. Taking
into account the above stated, it seemed to be impor-
tant to examine condensations of new acetophenone
derivatives, specifically of those containing a carba-
mate moiety, with various carbonyl compounds.
Scheme 1). Compound III underwent dehydration with
formation of 79% of chalcone IV on heating in glacial
acetic acid in the presence of concentrated hydro-
chloric acid (Scheme 2). The structure of methyl
4-[(2-oxo-2,3-dihydro-1H-indol-3-ylidene)acetyl]-
phenylcarbamate (IV) was confirmed by IR and
1H NMR spectroscopy.
1,3-Dipolar cycloaddition to carbamate IV of azo-
methine ylide generated from 2-phenacylisoquino-
linium bromide by the action of triethylamine was
regio- and stereoselective, and the product was spiro-
compound V (yield 73%) which was identified as
methyl 4-(3′-benzoyl-2-oxo-1′,2,2′,3,3′,10b′-hexa-
hydro-1H-spiro[indole-3,1′-pyrrolo[1,2-a]isoquinolin]-
2′-ylcarbonyl)phenylcarbamate on the basis of the IR
and 1H NMR data (Scheme 3).
In order to obtain carbamate derivatives of chal-
cones, isatin (I) was reacted with methyl 4-acetyl-
phenylcarbamate (II) in anhydrous ethanol in the pres-
ence of diethylamine. The reaction mixture was heated
for 1 h at 95°C, and the product was isolated after
keeping the mixture for 4 days at 20°C. According to
the IR and 1H NMR data, the product was assigned the
structure of methyl 4-[(3-hydroxy-2-oxo-2,3-dihydro-
1H-indol-3-yl)acetyl]phenylcarbamate (III, yield 85%;
Derivatives of salicylaldehyde are widely used in
the synthesis of 2-phenylchromenium salts which
exhibit biological activity and are also used in laser
technologies [8]. We examined condensation of methyl
4-acetylphenylcarbamate (II) with salicylaldehyde and
Scheme 1.
O
H
O
HO
N
OMe
O
Et2NH, EtOH
+
O
MeO
Me
O
N
N
NH
H
H
O
O
I
II
III
971

VELIKORODOV et al.
972
Scheme 2.
H
AcOH, HCl
N
MeO
III
NH
O
O
O
IV
Scheme 3.
H
N
MeO
O
O
O
Et3N, CH2Cl2–CHCl3
O
IV
+
Br–
N
Ph
NH
N
O
V
2,4-dihydroxybenzaldehyde in glacial acetic acid
saturated with dry hydrogen chloride. As a result, we
obtained 2-phenylchromenium salts VI and VII having
a methoxycarbonylaminophenyl group attached to the
C2 atom (Scheme 4). The structure of 2-(4-methoxy-
carbonylaminophenyl)chromenium chlorides VI and
VII was confirmed by elemental analyses and IR, elec-
tronic absorption, and mass spectra. The mass spectra
of salts VI and VII contained no molecular ion peaks,
presumably due to their low stability, but ion peaks
with m/z 280 (VI) and 296 (VII) were present.
the whole molecule corresponds to the long-wave ab-
sorption band in the electronic spectra of 2-phenyl-
naphthopyrylium salts. Introduction of electron-donat-
ing groups into molecules of phenylchromenium salts
weakens negative inductive and mesomeric effects of
the chromenium fragment as a result of charge de-
localization. However, as shown in [10], due to high
degree of conjugation in the molecule mesomeric
effect of a substituent introduced into any fragment is
extended over both fragments (chromene and phenyl)
and affects the energy of both lowest unoccupied
orbital on the chromenium fragment and highest
occupied molecular orbital on the phenyl group.
It is known that phenylchromenium salts are π-iso-
electronic analogs of 2-phenylnaphthalene. Studies on
the electronic structure of such compounds showed
that all molecular orbitals therein are localized on the
bicyclic chromene fragment or phenyl ring. Therefore,
the electronic absorption spectra of phenylchromenium
salts should display three types of transitions corre-
sponding to three chromophores: chromenium, phenyl,
and entire molecule. In fact, three absorption maxima
were observed in the electronic spectra of compounds
VI and VII. As shown in [9], the transition involving
With a view to elucidate the effect of substituents
on the position of absorption maximum in the elec-
tronic spectrum we performed quantum-chemical cal-
culations of charge distribution in the molecules of
2-(4′-methoxycarbonylaminophenyl)chromenium
chlorides VI and VII. The geometric parameters were
optimized, and the charges on atoms in the ground
state were calculated, in terms of AM1 valence approx-
imation [11]. The results are collected in table; the data
Scheme 4.
H
N
OMe
CHO
AcOH, HCl
+
R
O
O
Me
O
R
OH
Cl–
VI, VII
N
OMe
O
H
II
VI, R = H; VII, R = HO.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

SOME CONDENSATIONS OF METHYL (4-ACETYLPHENYL)CARBAMATE
973
Absorption maxima in the electronic spectra and charges on some atoms in 2-(4-methoxycarbonylaminophenyl)chromenium
chlorides VI and VII and 2-phenylchromenium chloride
Charges on atoms in the ground state, e
Compound
λmax, nm
C2
C1′
Δq
2
1'
[9] 450 [9]
0.286
–0.153
0.439
O
Cl–
(VI)
455
0.289
0.283
–0.203
–0.198
0.494
0.481
O
Cl–
NHCOOMe
(VII)
490
HO
O
Cl–
NHCOOMe
for 2-phenylchromenium chloride are also given for
comparison. As follows from the calculated charge dis-
tribution, the main electronic interactions in phenyl-
chromenium cations are: mesomeric effect of the chro-
menium fragment on the phenyl substituent, inductive
effect of the charged bicyclic fragment on the phenyl
ring, and mesomeric substituent effects.
ence. The IR spectra were measured in the range from
4000 to 400 cm–1 on an InfraLUM FT-02 spectrometer
with Fourier transform from samples prepared as KBr
pellets. The mass spectra (electron impact, 70 eV)
were obtained on a Finnigan MAT INCOS 50 instru-
ment. The electronic absorption spectra were recorded
on an SF-103 spectrophotometer (cell path length
1 cm) from solutions in acetonitrile with a concentra-
tion of 3.6× 10–4 or 1.3 ×10–4 M. The purity of the
isolated compounds was checked by TLC on Silufol
UV-254 plates; spots were visualized by treatment with
iodine vapor.
According to [10], the parameter characterizing
π-charge transfer is linearly related to the difference
Δq in the total (σ+π) charges on the electrophilic (C2)
and nucleophilic (C1′) centers in the ground state. This
means that larger difference between the charges on
the molecular fragments corresponds to stronger
charge transfer upon excitation. Introduction of a car-
bamate group into the para-position of the benzene
ring increases the negative charge on the C2 atom in
chromenium salt VI. The difference Δq becomes
greater than that found for unsubstituted phenyl-
chromenium salt. Introduction of a hydroxy group into
position 7 (salt VII) leads to delocalization of positive
charge over the chromenium fragment and reduction of
Δq due to decrease of the charge on C2 and (in part) on
C1′ as a result of weakening of inductive effect of the
chromenium cation on the phenyl fragment (through
the C2–C1′ bond).
Methyl 4-acetylphenylcarbamate (II). Methyl
chloroformate, 7.7 ml (0.1 mol), was added dropwise
over a period of 1.5 h under stirring and cooling to
a solution of 13.5 g (0.1 mol) of p-aminoacetophenone
in 46 ml of anhydrous pyridine. The mixture was
stirred for 0.5 h, kept for 13 h at room temperature,
poured onto ice, and carefully acidified with concen-
trated hydrochloric acid (according to Congo Red).
The colorless crystals were filtered off and washed
with water. Yield 1.76 g (91%), mp 167°C (from
benzene); published data [12]: mp 167.5–168.0°C.
Methyl 4-[(3-hydroxy-2-oxo-2,3-dihydro-1H-in-
dol-3-yl)acetyl]phenylcarbamate (III). A mixture of
1.47 g (0.01 mol) of isatin, 1.93 g (0.01 mol) of methyl
4-acetylphenylcarbamate (II), and 0.5 ml of diethyl-
amine in 30 ml of anhydrous ethanol was heated for
1 h under reflux and was then left to stand for 96 h at
20°C. The light yellow crystals were filtered off and
EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian
VXR-400 spectrometer (400.13 MHz) from solutions
in DMSO-d6 using tetramethylsilane as internal refer-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

VELIKORODOV et al.
974
recrystallized from ethanol. Yield 2.2 g (85%),
mp 210–211°C. IR spectrum, ν, cm–1: 3340–3400,
3250 (NH, OH), 1710, 1685 (C=O), 1620, 1575, 1550
(C=Carom). H NMR spectrum (DMSO-d6), δ, ppm:
3.14 s (2H, CH2), 3.71 s (3H, NHCO2Me), 4.52 s (1H,
NH), 7.15 d (2H, Harom, J = 8.6 Hz), 7.28–7.38 m (3H,
J = 7.7 Hz), 7.20–7.89 m (13H, Harom), 7.97 d (1H,
arom, J = 7.6 Hz), 8.31 d (2H, Harom, J = 8.6 Hz),
8.42 s (1H, NH), 9.54 br.s (1H, NH). Found, %:
C 73.59; H 4.57; N 7.16. C35H27N3O5. Calculated, %:
C 73.73; H 4.74; N 7.37.
H
1
2-(4-Methoxycarbonylaminophenyl)chromenium
chloride (VI). Dry hydrogen chloride was passed over
a period of 1.5 h through a mixture of 1.93 g
(0.01 mol) of methyl 4-acetylphenylcarbamate (II) and
1 ml (0.01 mol) of freshly distilled salicylaldehyde in
7 ml of glacial acetic acid. Carbamate II dissolved, the
solution turned bright red, and red crystals separated.
The mixture was left to stand for 8 h at 20°C, 10 ml of
anhydrous diethyl ether was added, and the precipitate
was filtered off, dried in air, and purified by reprecip-
itation from acetic acid with diethyl ether. Yield 2.72 g
(86%), mp 128–129°C (decomp.). IR spectrum, ν,
cm–1: 3430 (NH), 1715 (C=O), 1610, 1575, 1545
H
H
arom), 7.55 d (1H, Harom, J = 7.8 Hz), 8.14 d (2H,
arom, J = 8.6 Hz), 9.20 s (1H, OH), 9.54 br.s (1H,
NH). Found, %: C 63.32; H 4.54; N 8.24. C18H16N2O5.
Calculated, %: C 63.53; H 4.71; N 8.07.
Methyl 4-[(2-oxo-2,3-dihydro-1H-indol-3-
ylidene)acetyl]phenylcarbamate (IV). A mixture of
1.7 g (5 mmol) of methyl 4-[(3-hydroxy-2-oxo-2,3-
dihydro-1H-indol-3-yl)acetyl]phenylcarbamate (III),
8 ml of glacial acetic acid, and 0.25 ml of concentrated
hydrochloric acid was heated for 30 min at 95°C,
10 ml of ethanol was added, the mixture was cooled
with an ice bath, and the orange crystals were filtered
off, dried in air, and recrystallized from ethanol–diox-
ane (1:2 by volume). Yield 1.27 g (79%), mp 237–
238°C. IR spectrum, ν, cm–1: 3340–3400 (NH), 1710,
(C=Carom), 1075. Electronic absorption spectrum, λmax
,
nm (ε, l mol–1 cm–1): 224 (7577), 284 (11438), 455
(3846). Mass spectrum, m/z (Irel, %): 280 (26), 279
(100), 248 (10), 131 (5), 118 (9), 89 (10), 76 (12).
Found, %: C 64.49; H 4.12; N 4.28. C17H14ClNO3.
Calculated, %: C 64.60; H 4.43; N 4.43.
1
1675 (C=O), 1620, 1575, 1555 (C=Carom). H NMR
spectrum (DMSO-d6), δ, ppm: 3.71 s (3H, CO2Me),
7.20–7.14 m (3H, Harom), 7.43 t (1H, Harom, J = 7.5 Hz),
7.70 t (1H, Harom, J = 7.5 Hz), 7.82 s (1H, CH), 8.16 d
(2H, Harom, J = 8.6 Hz), 8.30 d (1H, Harom, J = 8.2 Hz),
8.42 s (1H, NH), 9.56 br.s (1H, NH). Found, %:
C 66.85; H 4.27; N 8.53. C18H14N2O4. Calculated, %:
C 67.08; H 4.35; N 8.70.
7-Hydroxy-2-(4-methoxycarbonylaminophenyl)-
chromenium chloride (VII) was synthesized in a sim-
ilar way by reaction of 1.93 g (0.01 mol) of methyl
4-acetylphenylcarbamate (II) with 1.38 g (0.01 mol) of
2,4-dihydroxybenzaldehyde. Yield 2.49 g (75%), red
crystals (from glacial acetic acid), mp 189–191°C
(decomp.). IR spectrum, ν, cm–1: 3420–3510 (NH,
OH), 1715 (C=O), 1610, 1565 (C=Carom), 1095. Elec-
tronic absorption spectrum, λmax, nm (ε, l mol–1 cm–1):
229 (2000), 353 (530), 490 (614). Mass spectrum, m/z
(Irel, %): 296 (25), 295 (100), 264 (10), 263 (47), 235
(87), 206 (20), 165 (17), 153 (24), 152 (32), 131 (5),
118 (10), 89 (16), 77 (6). Found, %: C 61.37; H 4.25;
N 3.92. C17H14ClNO4. Calculated, %: C 61.54; H 4.22;
N 4.22.
Methyl 4-(3′-benzoyl-2-oxo-1′,2,2′,3,3′,10b′-
hexahydro-1H-spiro[indole-3,1′-pyrrolo[1,2-a]iso-
quinolin]-2′-ylcarbonyl)phenylcarbamate (V). A so-
lution of 0.5 ml of triethylamine in 10 ml of chloro-
form was added dropwise under stirring over a period
of 45 min to a suspension of 0.74 g (2.3 mmol) of
chalcone IV and 0.66 g (2 mmol) of 2-phenacyliso-
quinolinium bromide in 20 ml of methylene chloride,
and the mixture was stirred for 2 h more. The mixture
was then washed with water (2×20 ml), the organic
phase was dried over sodium sulfate, the solvent was
removed under reduced pressure, and the residue crys-
tallized. The product was purified by column chroma-
tography on silica gel (60–100 mesh) using acetone as
eluent, followed by recrystallization from chloroform–
hexane (2:1 by volume). Yield 0.75 g (57%), light
yellow crystals, mp 143–146°C. IR spectrum, ν, cm–1:
3340–3410 (NH), 1710, 1680, 1675 (C=O), 1620,
REFERENCES
1. Filler, R., Beaucaire, V.D., and Kang, H.H., J. Org.
Chem., 1975, vol. 40, p. 935.
2. Noyce, D.S. and Pryor, W.A., J. Am. Chem. Soc., 1955,
vol. 77, p. 1397.
3. Wagman, A.S., Wang, L., and Nuss, J.M., J. Org. Chem.,
1
1580, 1575 (C=Carom). H NMR spectrum (DMSO-d6),
2000, vol. 65, p. 9103.
δ, ppm: 3.71 s (3H, NHCO2Me), 4.12 d (1H, 4′-H,
J = 7.5 Hz), 5.57 d (1H, 3′-H, J = 7.5 Hz), 5.85 s (1H,
4. Cravotto, G., Demetri, A., Nano, G.M., Palmisano, G.,
Penoni, A., and Tagliapietra, S., Eur. J. Org. Chem., 2003,
p. 4438.
1′-H), 6.34 d (2H, J = 8.0 Hz), 7.07 t (1H, Harom
,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 7 2010

SOME CONDENSATIONS OF METHYL (4-ACETYLPHENYL)CARBAMATE
975
8. Comprehensive Organic Chemistry, Barton, D. and
Ollis, W.D., Eds., Oxford: Pergamon, 1979, vol. 5.
9. Deligeorgiev, T.G., Nikolov, P., and Tyutyukov, N.,
Z. Naturforsch., Teil A, 1986, vol. 42, p. 43.
10. Roshal’, A.D., Koval’, V.L., and Novikov, A.I., Opt.
Spektrosk., 1998, vol. 85, p. 772.
11. Dewar, M.J.S., Zoebich, E.G., Healy, E.F., and
Stewart, J.J.P., J. Am. Chem. Soc., 1985, vol. 107,
p. 3902.
12. Witek, S., Bielawski, J., and Bielawska, A., J. Prakt.
Chem., 1979, vol. 321, p. 804.
5. Edwards, M.L., Stemerick, D.M., and Sunkara, P.S.,
J. Med. Chem., 1990, vol. 33, p. 1948.
6. Lin, Y.M., Zhou, Y., Flavin, M.T., Zhou, L.M., Nie, W.,
and Chen, F.C., Bioorg. Med. Chem., 2002, vol. 10,
p. 2795.
7. Meng, C.Q., Zheng, X.S., Ni, L., Ye, Z., Simpson, J.E.,
Worsencroft, K.J., Hotema, M.R., Weingarten, M.D.,
Skudlarek, J.W., Gilmore, J.M., Hoong, L.K., Hill, R.R.,
Marino, E.M., Suen, K.L., Kunsch, C., Wasserman, M.A.,
and Sikorski, J.A., Bioorg. Med. Chem. Lett., 2004,
vol. 14, p. 1513.
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