Synthesis of aromatic carbamates derivatives with a chromen-2-one fragment

Article abstract of DOI:10.1134/S1070428014080077

Condensation of methyl N-(3-hydroxyphenyl)carbamate with ethyl trifluoromethylacetoacetate, 2-methoxyethyl acetoacetate in the presence of conc. sulfuric acid, and also with acetonedicarboxylic acid formed in situ from citric acid under the action of conc. sulfuric acid afforded chromene derivatives. The esterification of 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}acetic acid with methanol in the presence of TsOH provided the corresponding ester. The oxidation of its α-methylene group with selenium dioxide led to the formation of methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-2H-chromen-4-yl}-2-oxo-acetate entering into a condensation with o-phenylenediamine resulting in a derivative with a dihydroquinoxaline fragment. The reaction of phenyl N-(4-formylphenyl)carbamate with 3-acetyl-2H-chromen-2-one in butanol in the presence of catalytic quantity of piperidine and acetic acid furnished 4-[(E)-3-oxo-2H-chromen-3-yl)-1-propenyl]phenyl N-phenylcarbamate.

Full text of DOI:10.1134/S1070428014080077

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 8, pp. 1112–1116. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © A.V. Velikorodov, V.A. Ionova, E.A. Melent’eva, N.N. Stepkina, A.A. Starikova, 2014, published in Zhurnal Organicheskoi Khimii,
2014, Vol. 50, No. 8, pp. 1131–1135.
Synthesis of Aromatic Carbamates Derivatives
with a Chromen-2-one Fragment
A. V. Velikorodov, V. A. Ionova, E. A. Melent’eva, N. N. Stepkina, and A. A. Starikova
Astrakhan State University, pl. Shaumyana 1, Astrakhan, 414000 Russia
e-mail: avelikorodov@mail.ru
Received March 14, 2014
Abstract—Condensation of methyl N-(3-hydroxyphenyl)carbamate with ethyl trifluoromethylacetoacetate, 2-
methoxyethyl acetoacetate in the presence of conc. sulfuric acid, and also with acetonedicarboxylic acid formed
in situ from citric acid under the action of conc. sulfuric acid afforded chromene derivatives. The esterification
of 2-{7-[(methoxycarbonyl)amino]-2-oxo-2Н-chromen-4-yl}acetic acid with methanol in the presence of
TsOH provided the corresponding ester. The oxidation of its α-methylene group with selenium dioxide led to
the formation of methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-2Н-chromen-4-yl}-2-oxo-acetate entering into
a condensation with о-phenylenediamine resulting in a derivative with a dihydroquinoxaline fragment. The
reaction of phenyl N-(4-formylphenyl)carbamate with 3-acetyl-2Н-chromen-2-one in butanol in the presence of
catalytic quantity of piperidine and acetic acid furnished 4-[(E)-3-oxo-2Н-chromen-3-yl)-1-propenyl]phenyl
N-phenylcarbamate.
DOI: 10.1134/S1070428014080077
Coumarins and their derivatives exhibit a wide
range of biological action. Compounds found among
them possess antiphlogistic [1], anesthetic [2],
fungicidal [3], antibacterial [4], antiviral, neuroleptic
[5], tuberculocidal, anti-HIV, anticancer, and
antioxidant activity [6–8]. Insignificant changes in the
coumarin structure essentially alter its activity.
Therefore the synthesis of new coumarin derivatives
and their subsequent pharmaceutical screening are of
obvious interest.
N-(3-hydroxyphenyl)carbamate (I) with ethyl triflu-
oromethylacetoacetate (II), 2-methoxyethyl aceto-
acetate (III) in the presence of conc. sulfuric acid, and
also of acetonedicarboxylic acid (IV) formed in situ
from citric acid under the action of conc. sulfuric acid
[11]. Basing on the investigation of the structure of the
1
reaction products by IR, Н, 13С NMR spectroscopy,
and of the product of the reaction with ethyl
trifluoromethylacetoacetate also by mass spectrometry
we established that the reaction products were
chromene derivatives V–VII (Scheme 1).
In extension of research on the synthesis of new
chromen-2-one derivatives possessing a carbamate
function [9, 10] we studied the condensation of methyl
1Н NMR spectrum of compound VI contained the
singlet from proton Н3 in the region 6.22 ppm, in the
Scheme 1.
O
O
O
MeO2CHN
OH
O
I
O
HO2C
CO2H
CO2H
H3C
O
Me
O
III
IV
F3C
OEt
CH3
II
CF3
O
MeO2CHN
O
O
MeO2CHN
O
O
MeO2CHN
O
VI
VII
V
1112

SYNTHESIS OF AROMATIC CARBAMATES DERIVATIVES
1113
spectra of compounds V and VII this signal shifted
downfield (δ 6.84–6.85 ppm) due to the deshielding
effect of electron-acceptor groups.
group, and in its IR spectrum an additional absorption
band appears from the carbonyl group at 1680 cm−1.
In order to further functionalize compound X we
examined its reaction with о-phenylenediamine. The
reaction was carried out by boiling the reagents
mixture in butanol for 6 h.
The oxidation of the methyl group of compound VI
with selenium dioxide led to the formation of the
corresponding aldehyde VIII (Scheme 2).
Scheme 2.
We established proceeding from the data of IR and
1Н NMR spectra that the reaction led to the formation
of methyl N-[2-oxo-4-(3-oxo-3,4-dihydro-2-
quinoxalinyl)-2Н-chromen-7-yl]carbamate (XI)
(Scheme 4).
H
O
CH3
SeO2
xylene, Δ
MeO2CHN
O
O
MeO2CHN
O
O
The condensation of phenyl N-(4-formylphenyl)
carbamate (XII) [12] with 3-acetyl-2Н-chromen-2-one
(XIII) [13] in butanol in the presence of catalytic
quantities of piperidine and acetic acid yielded 4-
{[(E)-3-oxo-2Н-chromen-3-yl]-1-propenyl}phenyl N-
phenyl-carbamate (XIV) whose structure was
confirmed by IR and 1Н NMR spectra (Scheme 5).
VI
VIII
1
In the Н NMR spectrum of compound VIII in the
downfield region along with the singlet signal of the
NH group at 10.59 ppm a singlet is observed belonging
to a formyl group (δ 10.20 ppm), and the singlet of the
proton Н3 appears at 7.00 ppm.
The 1Н NMR spectrum of chalcone XIV along with
the signals of the aromatic protons and NH group
contained a singlet at 8.50 ppm corresponding to the
proton H4 of coumarin, and also a doublet from one
proton attached to the С=С group at 7.82 ppm (J
15.6 Hz), indicating the formation of the Е-isomer of
chalcone [14, 15].
The heating of 2-{7-[(methoxycarbonyl)amino]-2-
oxo-2Н-chromen-4-yl}acetic acid (VII) with methanol
in the presence of a catalytic quantity of p-
toluenesulfonic acid provided the corresponding ester
IX (Scheme 3).
1
In the Н NMR spectrum of ester IX unlike the
spectrum of compound VII the singlet signal of one
proton of the carboxy group at 10.07 ppm disappeared,
but a singlet appeared at 3.65 ppm belonging to three
protons of the methoxycarbonyl group.
EXPERIMENTAL
1Н NMR spectra were registered on a spectrometer
Bruker DRX-500 (500.13 MHz). 13С NMR spectra
were recorded on a spectrometer Bruker WM-400
(100 MHz) with a wide-band decoupling from protons,
solvent DMSO-d6. IR spectra were obtained on an IR
Fourier spectrophotometer Infra-LUM FT-02 in the
range 4000–400 cm–1 from pellets with KBr. Mass
spectra were measured on an instrument Finnigan
MAT INCOS 50 at ionizing electrons energy 70 eV.
The purity of compounds obtained was tested by TLC
The oxidation of the α-methylene group of the ester
with selenium dioxide afforded methyl 2-{7-
[(methoxycarbonyl)amino]-2-oxo-2Н-chromen-4-yl}-
2-oxoacetate (X) interesting for the syntheses of
polyheterocyclic compounds.
The 1Н NMR spectrum of α-ketoester X in contrast
to the spectrum of acid IX did not contain the singlet at
3.75 ppm belonging to two protons of the methylene
Scheme 3.
CO2Me
CO2Me
O
SeO2
MeOH
VII
p-TsOH
MeO2CHN
O
O
MeO2CHN
O
O
X
IX
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 8 2014

VELIKORODOV et al.
1114
Scheme 4.
NH
O
N
O
O
O
OMe
O
NH2
1-BuOH, Δ
+
MeO2CHN
O
NH2
MeO2CHN
O
X
XI
on Silufol UV-254 plates, development in iodine
vapor.
(4.2 mmol) of methyl N-(3-hydroxyphenyl)carbamate
(I) and 0.62 mL (4.2 mmol) of 2-methoxyethyl
acetoacetate (III). Yield 0.91 g (93%), colorless
crystals, mp 256–257°С (from ethanol) (mp 256–257°C
[9]. IR spectrum, ν, cm–1: 3280 (NH), 1730, 1692
Methyl N-[2-oxo-4-(trifluoromethyl)-2Н-chromen-
7-yl]carbamate (V). To 4 mL of conc. H2SO4 cooled
to 0–5°С was added at vigorous stirring 0.7 g
(4.2 mmol) of methyl N-(3-hydroxyphenyl)carbamate
(I) and 0.61 mL (4.2 mmol) of ethyl trifluoromethyl-
acetoacetate (II), maintaining the temperature below
10°С. The mixture was maintained at room tempera-
ture for 24 h, poured into 50 mL of ice water, the
separated precipitate was filtered off, thoroughly
washed with water on the filter, dried in desiccator,
1
(C=O), 1620, 1584, 1536, 1512 (C=C, С=Сarom). Н
NMR spectrum, δ, ppm: 2.38 s (3Н, Mе), 3.73 s (3Н,
ОMе), 6.22 s (1Н, Н3), 7.38 d.d (1Н, Н6, J 2.0, 8.4 Hz),
7.54 s (1Н, Н8), 7.69 d (1Н, Н5, J 8.4 Hz), 10.15 br.s (1Н,
NH). 13С NMR spectrum, δ, ppm: 18.5 (СН3), 52.42
(NHCO2Me), 105.60, 110.02, 113.14, 117.37, 127.56,
146.07, 152.14 (CAr), 154.86 (NHCO2Me), 155.78 (CAr),
159.58 (C=O). Found, %: С 61.72; Н 4.57; N 5.81.
C12H11NO4. Calculated, %: С 61.80; Н 4.72; N 6.01.
and recrystallized from chloroform. Yield 1.16
g
(96%), colorless crystals, mp 155–157°С. IR spectrum,
ν, cm–1: 3310 (NH), 1710, 1665 (C=O), 1610, 1575,
1565 (С=С, C=Carom). 1Н NMR spectrum, δ, ppm: 3.73 s
(3Н, NHCO2Me), 6.85 s (1Н, H3), 7.46 d.d (1H, Н6, J 2.0,
9.0 Hz), 7.65 d.d (1H, Н5, J 2.0, 9.0 Hz), 8.32 s (1H, Н8),
10.35 br.s (1Н, NH). 13С NMR spectrum, δ, ppm: 52.22
(NHCOCH3), 104.93, 107.55, 113.92, 115.09, 120.63
(CAr), 122.82 (CF3), 125.53, 143.87, 153.77 (CAr), 154.92
(NHCO2CH3), 158.67 (C=O). Mass spectrum, m/z (Irel, %):
289 (1.7) [M + 2]+, 288 (12) [M + 1]+, 287 (100) [M]+, 268
(5), 255 (17), 227 (37), 214 (40), 200 (20), 173 (8), 152
(12), 145 (7), 125 (3), 83 (5), 75 (3), 59 (17). Found, %: С
50.15; Н 2.80; N 4.75. C12H8F3NO4. Calculated, %: С
50.17; Н 2.79; N 4.88. M 287.
2-{7-[(Methoxycarbonyl)amino]-2-oxo-2Н-chro-
men-4-yl}acetic acid (VII). To 16 mL of conc.
sulfuric acid was added 0.96 g (5 mmol) of citric acid,
and the mixture was heated at 60–65°С under
continuous stirring for 30 min. The obtained solution
of acetonedicarboxylic acid (IV) in conc. sulfuric acid
was cooled to 0°С and was added thereto at vigorous
stirring within 1 h 0.85 g (5 mmol) of methyl N-(3-
hydroxyphenyl)carbamate (I) maintaining the
temperature at 0–5°С. The reaction mixture was stirred
for 2 h more at 5°С, then the reaction mixture was
slowly warmed to 30°С, left for 24 h at room
temperature, then poured in 50 g of crushed ice. The
separated precipitate was filtered off, dissolved in 20 mL
of saturated solution of sodium hydrogen carbonate,
2 g of activated carbon was added to remove colored
Methyl N-(4-methyl-2-oxo-2Н-chromen-7-yl)-
carbamate (VI) was obtained similarly from 0.7 g
Scheme 5.
O
O
O
O
AcOH,
Ph
O
H
piperidine
HN
CH3
+
O
1-BuOH, Δ
O
O
O
O
Ph
O
N
H
XII
XIII
XIV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 8 2014

SYNTHESIS OF AROMATIC CARBAMATES DERIVATIVES
1115
impurities, and after removal of the adsorbent the
filtrate was acidified with conc. hydrochloric acid. The
separater precipitate was filtered off and dried in air.
Yield 1.0 g (72%), colorless crystals, mp 249–250°С.
IR spectrum, ν, cm–1: 3330 (NH), 3250 (ОН), 1710,
Methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-
2Н-chromen-4-yl}-2-oxoacetate (X). To a mixture of
1.46 g (5 mmol) of ester IX in 5 mL of o-xylene
heated to 60-70 °С was added 0.72 g (6.5 mmol) of
selenium dioxide within 10 min, then the reaction
mixture was boiled for 6 h, filtered from selenium
formed in the course of the reaction, the filtrate was
cooled to 0°С, the precipitated crystals were filtered off
and recrystallized from a mixture dichloromethane–
hexane, 1 : 2 (v/v). Yield 1.3g (85%), light yellow
crystals, mp 190−191°С. IR spectrum, ν, cm–1: 3330
(NH), 1710, 1680, 1695 (C=O), 1610, 1570, 1565 (С=С,
1
1695 (С=O), 1612, 1575, 1565 (С=С, C=Carom). Н
NMR spectrum, δ, ppm: 3.71 s (3Н, NHCO2Me), 3.79
s (2H, СН2СО2Н), 6.84 s (1H, Н3), 7.22 d (1Н, Н6,
J 8.2 Hz), 7.59 s (1Н, Н8), 7.84 d (1Н, Н5, J 8.2 Hz),
10.07 br.s (1Н, СООН), 10.58 br.s (1Н, NHСО2Me).
13С NMR spectrum, δ, ppm: 44.17 (СН2), 52.31
(NHCO2CH3),105.25, 113.14, 113.81, 114.67, 128.18,
147.04, 152.81 (CAr), 154.94 (NHCO2CH3), 155.25
(СAr), 162.35 (O–С=О), 175.20 (СООН). Found, %: С
56.27; Н 4.01; N 4.87. C13H11NO6. Calculated, %: С
56.32; Н 3.97; N 5.05.
1
С=Сarom). Н NMR spectrum, δ, ppm: 3.67 s (3H,
СО2Me), 3.71 s (3Н, NHCO2Me), 7.07 s (1Н, H3), 7.22 d
(1Н, H6, J 8.2 Hz), 7.68 s (1Н, Н8), 7.74 d (1Н, Н5, J
8.2 Hz), 10.58 br.s (1Н, NHСО2Me). Found, %: С 54.96;
Н 3.65; N 4.38. C14H11NO7. Calculated, %: С 55.08; Н
3.61; N 4.59.
Methyl
carbamate (VIII). A mixture of 1.17 g (5 mmol) of
methyl N-(4-methyl-2-oxo-2Н-chromen-7-yl)carba-
N-(4-formyl-2-oxo-2Н-chromen-7-yl)-
Methyl N-[2-oxo-4-(3-oxo-3,4-dihydro-2-quino-
xalinyl)-2Н-chromen-7-yl]carbamate (XI) A mixture
of 0.31 g (1.02 mmol) of α-ketoester X, 0.1 g (1.1 mmol)
of о-phenylenediamine in 10 mL of n-butanol was
boiled for 6 h, cooled, the separated precipitate was
filtered off, washed on the filter with n-butanol (2 mL),
acetone (2 mL), and recrystallized from dioxane. Yield
0.32 g (87%), light yellow crystals, mp 352–353°С. IR
spectrum, ν, cm–1: 3330–3390 (NH), 1710, 1695, 1685
mate (VI), 0.72 g (6.5 mmol) of selenium dioxide was
boiled for 7 h, filtered from selenium formed in the
course of the reaction, the filtrate was cooled to 0°С,
and the precipitated crystals were filtered off and
recrystallized from
a
mixture hexane–dichloro-
methane, 4 : 1 (v/v). Yield 1.0 g (81%), yellow
crystals, mp 224−226° С. IR spectrum, ν, сm–1: 3327
(NH), 1710, 1705 (С=O), 1610, 1575, 1565 (C=C,
1
1
(С=O), 1610, 1575, 1565 (С=С, С=С arom). Н NMR
С=Сarom). Н NMR spectrum, δ, ppm: 3.71 s (3Н,
NHCO2Me),7.00 s (1Н, H3),7.28 d (1Н, H6, J 8.1 Hz),
7.68 s (1H, H8), 8.02 d (1Н, H5, J 8.1 Hz), 10.2 s (1Н,
СНО), 10.59 br.s (1Н, NHСО2Me). Found, %: С
58.34; Н 3.58; N 5.70 .C12H9NO5. Calculated, %: С
58.30; Н 3.64; N5.67.
spectrum, δ, ppm: 3.71 s (3Н, NHCO2Me), 7.05 s (1Н,
H3), 7.36–7.52 m (4Нarom),7.6 d (1Нarom, J 7.8 Hz), 7.82
s (1H, H8), 7.87 d (1Нarom, J 8.0 Hz ), 10.58 br.s (1Н,
NHCO2Me), 11.40 s (1H, NHCO). Found, %: С 62.79;
Н 3.55; N 11.54. C19H13N3O5. Calculated, %: С 6;2.81
Н 3.58; N 11.57.
Methyl 2-{7-[(methoxycarbonyl)amino]-2-oxo-
2Н-chromen-4-yl}acetate (IX). A mixture of 1.39 g
(5 mmol) of 2-{7-[(methoxycarbonyl)amino]-2-oxo-
2Н-chromen-4-yl}acetic acid (VII), 3.8 mL (0.09 mol)
of methanol, and 0.1 g of p-toluenesulfonic acid was
boiled for 6 h, cooled to 5-10 °С, the product was
filtered off, washed on the filter with 10 mL of 3%
solution of sodium hydrogen carbonate, with water,
dried in air, and recrystallized from methanol. Yield
1.3 g (90%), colorless crystals, mp 228–230°С. IR
spectrum, ν, cm–1: 3330 (NH), 1710, 1690 (С=O),
4-[(E)-3-Oxo-2Н-chromen-3-yl)-1-propenyl]phenyl
N-phenylcarbamate (XIV) A mixture of 2.89 g
(0.012 mol) of phenyl N-(4-formylphenyl)carbamate
(XII) and 1.74 g (0.01 mol) of 3-acetyl-2Н-chromen-
2-one (XIII) was dissolved in 10 mL of butanol-1 at
heating, cooled to room temperature, 0.3 mL of freshly
distilled piperidine and 0.3 mL of glacial acetic acid
was added, and the mixture was boiled for 4 h. The
reaction mixture was cooled to room temperature, 10 mL
of ethanol was added, the separated precipitate was
filtered off and recrystallized from 60% ethanol. Yield
3.66 g (89%), yellow crystals, mp 235–236°С. IR
spectrum, ν, cm–1: 3310 (NH), 1710, 1679, 1695,
1
1610, 156515, 75 (С=С, С=Сarom). Н NMR spectrum,
δ, ppm:3.6 s (3H, СО2Me),3.71 s (3Н, NHCO2Me),
3.75 s (2H, СН2СО2Me), 6.74 s (1Н, H3), 7.21 d (1Н,
H6, J 8.2 Hz), 7.63–7.67 m (2Н, Наrom.), 10.58 br.s (1Н,
NH). Found, %: С 57.59; Н 4.46; N 4.79. C14H13NO6.
Calculated, %: С 57.73; Н 4.47; N 4.81.
1
(C=O), 1610, 1585, 1565 (С=С, С=Сarom). Н NMR
spectrum, δ, ppm: 6.94–7.15 m (2Н, 1Hаrom., 1НHC=CH),
7.21–7.64 m (12Нarom), 7.82 d (1ННС=СН, J 15.6 Hz),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 8 2014

VELIKORODOV et al.
1116
8.50 s (1Н, H4 of coumarin), 10.59 br.s (1Н, NH).
Found, %: С 73.01; Н 4.1;2 N3.2 .3 C25H17NO5.
Calculated, %: С 72.99; Н 4.14; N 3.41.
and Raju, A., Int. J. Pharm. Sci. Res., 2012, vol. 3,
p. 474.
8. Arshad, A., Osman, H., Bagley, M.C., Lam, C.K.,
Mohamad, S., and Zahariluddin, A.S.M., Eur. J. Med.
Chem., 2011, vol. 46, p. 3788.
REFERENCES
9. Velikorodov, A.V., and Ishmaeva, N.M., Russ. J. Org.
Chem., 2008, vol. 44, p. 1374.
1. Symeonidis, T., Fylaktakidou, K.S., Hadjipavlou-Liti-
na, D.J., and Litinas, K.E., Eur. J. Med. Chem., 2009,
vol. 44, p. 5012.
2. Rajamanickam, V., Subburaju, T., Lakshminarayanan, B.,
and Pradeep Rajkumar, L.A., E.-J. Chem., 2010, vol. 7,
p. 383.
10. Ishmaeva, N.M., Velikorodov, A.V., and Krivosheev, O.O.,
Russ. J. Org. Chem., 2008, vol. 44, p. 1649.
11. Mashelkar, U.C., and Audi, A.A., J. Indian Chem. Soc.,
2006, vol. 45B, p. 967.
12. Habibi, D., Zolfigol, M.A., and Safaee, M., J. Chem.,
3. Mladenović, M., Vuković, N., Sukdolak, S., and
Solujić, S. Molecules, 2010, vol. 15, p. 4294.
4. Ajani, O.O., and Nwinyi, O.C., J. Heterocyclic Chem.,
2010, vol. 47, p. 179.
2013, p. 1.
13. Sahu, S.K., Mishra, A., and Behera, R.K., Indian J.
Heterocyclic. Chem., 1996, vol. 6, p. 91.
5. Kesten, S.R., Heffner, T.G., Johnson, S.J., Pugsley, T.A.,
Wright, J.L., and Wise, L.D., J. Med. Chemi., 1999,
vol. 42, p. 3718.
6. Kumar, P.V., and Rao, V.R., Indian J. Chem., 2008,
vol. 47B, p. 106.
14. Aragade, P., Maddi, V., Khode, S., Palkar, M.,
Ronad, P., Mamledesai, S., and Satyanarayana, D.,
Arch. Pharm. Chem. Life Sci., 2009, vol. 342,
p. 361.
15. Arbuzova, S.N., Glotova, T.E., Dvorko, M.Yu.,
Ushakov, I.A., Gusarova, N.K., and Trofimov, B.A.,
Arkivoc, 2011, vol. xi, p. 183.
7. LakshmiNarayanan, B., Pradeep Rajkumar, L.A.,
Arulanandham, A., Satheesh Babu, N., Gayathri, T.,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 8 2014