Synthesis of carbamate derivatives of coumarin and chromene

Article abstract of DOI:10.1134/S1070428008090212

Condensation of methyl (3-hydroxyphenyl)carbamate with ethyl acetoacetate and ethyl benzoylacetate at room temperature, as well as with L-2-hydroxysuccinic acid on heating, in the presence of concentrated sulfuric acid gave the corresponding methyl (4-R-2-oxo-2H-chromen-7-yl)carbamates (R = Me, Ph, H). Condensation of methyl (3-hydroxyphenyl)carbamate with benzylidenemalononitrile or with aromatic aldehydes and malononitrile on heating in propan-2-ol in the presence of piperidine led to the formation of the corresponding methyl (4-aryl-2-amino-3-cyano-4H-chromen-7-yl)carbamates.

Full text of DOI:10.1134/S1070428008090212

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 9, pp. 1374–1377. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.V. Velikorodov, N.M. Imasheva, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 9, pp. 1389–1392.
Synthesis of Carbamate Derivatives of Coumarin and Chromene
A. V. Velikorodov and N. M. Imasheva
Astrakhan State University, ul. Tatishcheva 20a, Astrakhan, 414056, Russia
e-mail: avelikorodov@mail.ru
Received December 13, 2007
Abstract—Condensation of methyl (3-hydroxyphenyl)carbamate with ethyl acetoacetate and ethyl benzoyl-
acetate at room temperature, as well as with L-2-hydroxysuccinic acid on heating, in the presence of concen-
trated sulfuric acid gave the corresponding methyl (4-R-2-oxo-2H-chromen-7-yl)carbamates (R = Me, Ph, H).
Condensation of methyl (3-hydroxyphenyl)carbamate with benzylidenemalononitrile or with aromatic alde-
hydes and malononitrile on heating in propan-2-ol in the presence of piperidine led to the formation of the
corresponding methyl (4-aryl-2-amino-3-cyano-4H-chromen-7-yl)carbamates.
DOI: 10.1134/S1070428008090212
It is well known that phenols are capable of react-
ing with various carbonyl compounds and that elec-
tron-rich phenols and naphthols react with α,β-unsatu-
rated nitriles. Among these transformations, the most
interesting are those leading to oxygen-containing het-
erocyclic compounds, in particular coumarins and
2-amino-4H-chromenes which are potential biological-
ly active substances. Some their derivatives exhibit
a strong antiproliferative activity, while others were
recommended for the treatment of immune disorders,
atrophic arthritis, atherosclerosis, cirrhosis, and cancer
[1]. Therefore, it seemed important to study the behav-
ior in analogous reactions of phenylcarbamates whose
chemical properties in many cases resemble those of
phenols and phenol ethers [2].
We examined the condensation of methyl phenyl-
carbamates having a hydroxy group in the aromatic
ring with ethyl acetoacetate and ethyl benzoylacetate
in the presence of concentrated sulfuric acid at room
temperature, as well as with L-2-hydroxysuccinic acid
at 110°C. We found that methyl (2-hydroxyphenyl)car-
bamate does not react with the above carbonyl-con-
taining compounds and that the corresponding para
isomer gives rise to carbamate coumarin derivatives in
a very poor yield (10–15%). On the other hand, the
condensation of methyl (3-hydroxyphenyl)carbamate
Scheme 1.
O
O
Me
Me
OEt
OEt
OH
O
O
O
MeO
MeO
MeO
N
H
O
O
O
O
II
OH
O
O
O
Ph
H2SO4
O
Ph
N
H
OMe
N
H
O
O
I
III
HO
HO
O
N
H
IV
1374

SYNTHESIS OF CARBAMATE DERIVATIVES OF COUMARIN AND CHROMENE
1375
Scheme 2.
OH
Ph
O
Piperidine
i-PrOH, Δ
CN
CN
O
O
+
Ph
CN
N
H
OMe
MeO
N
NH2
H
I
V
NH2
CN
Ph
O
MeO
N
O
H
VI
(I) with the same compounds gave the corresponding
4-substituted 7-methoxycarbonylaminocoumarins II–
IV in 23–87% yield (Scheme 1).
double bond of benzylidenemalononitrile to give iso-
meric Michael adduct and subsequent cyclization as
a result of electrophilic attack by the cyano carbon
atom on the carbon atom in the ortho-position with
respect to the oxygen atom.
The structure of coumarin derivatives II–IV was
1
confirmed by IR and H NMR spectroscopy. The
1H NMR spectra of II and III contained a singlet from
the 3-H proton at δ 6.22–6.24 ppm. In the spectrum of
IV the 3-H proton resonated as a doublet at δ 6.20 ppm
(J = 9.5 Hz), while the 4-H signal was overlapped by
signals from protons in the benzene ring. Unlike initial
carbamate I, the IR spectra of coumarins II–IV lacked
broad absorption band at 3385 cm–1, typical of phe-
nolic hydroxy group, stretching vibrations of the NH
group gave rise to absorption in the region 3280–
3287 cm–1, and absorption bands due to the carbamate
and lactone carbonyl groups were located at 1730 and
1690–1695 cm–1, respectively.
The product structure as 4H-chromene derivative V
1
was identified on the basis of the H NMR data. The
1H NMR spectrum contained a singlet at δ 4.67 ppm
from the 4-H proton linked to sp3-hybridized carbon
atom. It is well known that signals in the region δ 4.5–
5.0 ppm are typical of 4H-pyrans, 4H-thiopyrans, and
related structures [3, 4]. If the product were 2H-chro-
mene, the 2-H signal would appear in a stronger field.
We also examined the possibility for synthesizing
carbamate chromene derivatives by three-component
condensation of carbamate I with aromatic aldehydes
and malononitrile. Aromatic aldehydes should react
with malononitrile in isopropyl alcohol in the presence
of piperidine to give the corresponding arylmethyli-
denemalononitriles. In fact, we succeeded in obtaining
methyl (4-aryl-2-amino-3-cyano-4H-chromen-7-yl)-
carbamates V, VII, and VIII in good yield according
to one-pot procedure (Scheme 3). However, unlike
resorcinol, α- and β-naphthols, and some other substi-
tuted phenols [5], these one-pot syntheses required
more severe conditions (8 h under reflux).
The condensation of methyl (3-hydroxyphenyl)car-
bamate (I) with benzylidenemalononitrile on heating in
boiling isopropyl alcohol in the presence of piperidine
(reaction time 8 h) resulted in the formation of methyl
(2-amino-3-cyano-4-phenyl-4H-chromen-7-yl)carba-
mate (V) in 78% yield (Scheme 2). The structure of
1
chromene V was confirmed by the IR and H NMR
spectra and elemental analysis. Theoretically, this reac-
tion could give rise to 4H- and 2H-chromene deriva-
tives V and VI. The latter can be formed via attack by
the phenolic oxygen atom on the electron-deficient
Chromenes V, VII, and VIII are likely to be
formed via nucleophilic addition of hydroxyphenyl-
Scheme 3.
OH
Ar
O
Piperidine
i-PrOH, Δ
CN
O
O
+
ArCHO + CH2(CN)2
N
H
OMe
MeO
N
NH2
H
I
V, VII, VIII
V, Ar = Ph; VII, Ar = 4-MeOC6H4; VIII, Ar = 3,4-(MeO)2C6H3.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

VELIKORODOV, IMASHEVA
1376
Scheme 4.
H
H
HO
N
OMe
HN
NC
N
OMe
CN
I
NC
NC
V, VII, VIII
Ar
O
O
CN
Ar
Ar
A
B
carbamate I at the electron-deficient carbon atom of
arylmethylidenemalononitrile. The subsequent intra-
molecular cyclization of Michael adduct A gives inter-
mediate iminochromene B, and tautomerization of the
latter yields the final aminochromene (Scheme 4). The
structure of methyl (4-aryl-2-amino-3-cyano-4H-chro-
men-7-yl)carbamates V, VII, and VIII obtained by the
three-component condensation was confirmed by the
was obtained on a Kratos MS-30 instrument. The pu-
rity of the isolated compounds was checked by TLC on
Silufol UV-254 plates. Methyl (3-hydroxyphenyl)car-
bamate was synthesized according to the procedure re-
ported in [6], mp 94–95°C (from benzene); published
data [7]: mp 94.5–95.5°C.
Methyl (4-methyl-2-oxo-2H-chromen-7-yl)car-
bamate (II). A solution of 0.7 g (4 mmol) of methyl
(3-hydroxyphenyl)carbamate (I) in 0.55 ml (4 mmol)
of ethyl acetoacetate was added dropwise under stir-
ring to 4 ml of concentrated sulfuric acid cooled to 5°C
(the temperature of the reaction mixture should not
exceed 10°C). The mixture was left to stand for 24 h at
room temperature and poured into 50 ml of ice water.
The precipitate was filtered off, washed with 100 ml of
water on a filter, dried over concentrated sulfuric acid,
and recrystallized from ethanol. Yield 0.85 g (87%),
colorless crystals, mp 256–257°C. IR spectrum, ν,
cm–1: 3280 (NH); 1730, 1692 (C=O); 1620, 1584,
1
13
IR and H NMR data. In addition, C NMR and mass
spectra were recorded for compound V. Compounds
V, VII, and VIII displayed in the IR spectra absorp-
tion bands at 2200 and 3220–3210 cm–1 due to stretch-
ing vibrations of the C≡N and NH2 groups, respec-
tively; absorption bands at 1715 and 3410 cm–1 were
assigned to stretching vibrations of the carbonyl and
NH groups in the carbamate moiety. The 4-H proton
1
resonated in the H NMR spectra of V, VII, and VIII
at δ 4.67–4.52 ppm.
According to [5], analogous condensations with
resorcinol, naphthalene-1,5-diol and α- and β-naph-
thols were complete in 0.5–1 h; in our case, more
severe conditions are related to weaker electron-donat-
ing power the methoxycarbonylamino group as com-
pared to phenolic hydroxy group. Our attempts to in-
volve in analogous condensation arenecarbaldehydes
having electron-withdrawing substituents were unsuc-
cessful. Even after heating for 10 h under reflux, we
isolated from the reaction mixtures only the corre-
sponding arylmethylidenemalononitriles and initial
carbamate I.
1
1536, 1512 (C=C, C–Carom). H NMR spectrum
(500.13 MHz), δ, ppm: 2.38 s (3H, Me), 3.73 s (3H,
OMe), 6.22 s (1H, 3-H), 7.38 d.d (1H, 6-H, J = 2.0,
8.4 Hz), 7.54 s (1H, 8-H), 7.69 d (1H, 5-H, J =
8.4 Hz), 10.15 (1H, NH). Found, %: C 61.67; H 4.51;
N 5.58. C12H11NO4. Calculated, %: C 61.80; H 4.72;
N 6.01.
Methyl (4-phenyl-2-oxo-2H-chromen-7-yl)car-
bamate (III) was synthesized in a similar way from
0.7 g (4 mmol) of carbamate I and 0.69 ml (4 mmol) of
ethyl benzoylacetate. Yield 0.28 g (23%), colorless
crystals, mp 205–206°C (decomp.). IR spectrum, ν,
cm–1: 3287 (NH); 1730, 1695 (C=O); 1620, 1575, 1535
EXPERIMENTAL
1
1
(C=C, C–Carom). H NMR spectrum (400.13 MHz), δ,
The H NMR spectra were recorded on VXR-400
ppm: 3.73 s (3H, OMe), 6.24 s (1H, 3-H), 7.12–7.23 m
(2H, Harom), 7.43–7.64 m (6H, Harom), 9.65 (1H, NH).
Found, %: C 68.94; H 4.37; N 4.59. C17H13NO4. Cal-
culated, %: C 69.15; H 4.41; N 4.75.
(400.13 MHz) and Bruker DRX 500 (500.13 MHz)
spectrometers using DMSO-d6 as solvent and TMS as
internal reference. The 13C NMR spectrum was meas-
ured with complete decoupling from protons on
a Bruker DRX 500 instrument at 126 MHz using
DMSO-d6 as solvent. The IR spectra were recorded in
the spectral range from 4000 to 400 cm–1 on a Specord
M82 spectrometer from samples prepared as KBr
pellets. The mass spectrum (electron impact, 70 eV)
Methyl (2-oxo-2H-chromen-7-yl)carbamate (IV).
A solution of 0.58 g (4.3 mmol) of L-2-hydroxy-
succinic acid in 4 ml of concentrated sulfuric acid was
cooled to 15°C, 0.7 g (4.2 mmol) of carbamate I was
added, and the mixture was kept for 0.5 h at room
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008

SYNTHESIS OF CARBAMATE DERIVATIVES OF COUMARIN AND CHROMENE
1377
temperature and was then heated for 0.5 h at 110°C.
The mixture was cooled and poured into 50 ml of ice
water, and the precipitate was filtered off, washed with
water (2×50 ml), dried in air, and recrystallized from
ethanol. Yield 0.72 g (78%), colorless crystals,
mp 165–167°C (decomp.). IR spectrum, ν, cm–1: 3280
(NH); 1730, 1690 (C=O); 1620, 1578, 1535 (C=C,
(84%), light yellow crystals, mp 235–238°C. IR spec-
trum, ν, cm–1: 3410, 3210 (NH, NH2); 2200 (CN);
1715 (C=O); 1620, 1575, 1535 (C=C, C–Carom).
1H NMR spectrum (400.13 MHz), δ, ppm: 3.62 s (3H,
OMe), 3.73 s (3H, CO2CH3), 4.52 s (1H, 4-H), 6.52 d
(2H, 3′-H, 5′-H, J = 7.7 Hz), 6.61 s (2H, NH2), 6.75 d
(1H, 6-H, J = 7.9 Hz), 7.52–7.61 m (4H, 5-H, 8-H,
2′-H, 6′-H), 8.52 (1H, NH). Found, %: C 65.02;
H 4.62; N 12.14. C19H17N3O4. Calculated, %: C 64.96;
N 4.84; N 11.97.
1
C–Carom). H NMR spectrum (400.13 MHz), δ, ppm:
3.73 s (3H, OMe), 6.20 d (1H, 3-H, J = 9.5 Hz), 7.45 d
(1H, 6-H, J = 7.9 Hz), 7.56–7.62 m (3H, 4-H, 5-H,
8-H), 9.51 (1H, NH). Found, %: C 60.18; H 3.87;
N 6.18. C11H9NO4. Calculated, %: C 60.27; H 4.11;
N 6.39.
Methyl [2-amino-3-cyano-4-(3,4-dimethoxyphen-
yl)-4H-chromen-7-yl]carbamate (VIII). Yield 3.09 g
(81%), light yellow crystals, mp 243–245°C. IR spec-
trum, ν, cm–1: 3410, 3220 (NH, NH2); 2200 (CN);
1715 (C=O); 1620, 1570, 1535 (C=C, C–Carom).
1H NMR spectrum (400.13 MHz), δ, ppm: 3.65 s (6H,
OMe), 3.71 s (3H, CO2CH3), 4.42 s (1H, 4-H), 6.59 s
(2H, NH2), 6.75–6.78 m (2H, 6-H, 5′-H), 7.26–7.29 m
(2H, 2′-H, 6′-H), 7.52–7.62 m (2H, 5-H, 8-H),
8.51 (1H, NH). Found, %: C 62.82; H 5.02; N 10.87.
C20H19N3O5. Calculated, %: C 62.99; H 4.99; N 11.02.
Methyl (2-amino-3-cyano-4-phenyl-4H-chromen-
7-yl)carbamate (V). a. A mixture of 1.67 g (0.01 mol)
of carbamate I, 0.67 g (0.01 mol) of benzylidenemalo-
nonitrile, and 1 ml of piperidine in 30 ml of propan-2-
ol was heated for 8 h under reflux. The mixture was
cooled, and the precipitate was filtered off, dried in air,
and recrystallized from ethanol. Yield 2.5 g (78%),
light yellow crystals, mp 240–241°C.
b. Freshly distilled piperidine, 1 ml, was added to
a mixture of 0.01 mol of benzaldehyde, 0.01 mol of
carbamate I, and 0.01 mol of malononitrile in 30 ml of
propan-2-ol. The mixture was heated for 8 h under
reflux and cooled, and the precipitate was filtered off,
washed with 5 ml of ethanol on a filter, dried in air,
and recrystallized from ethanol. Yield 2.2 g (67%),
mp 240–241°C. IR spectrum, ν, cm–1: 3410, 3220 (NH,
NH2); 2200 (CN); 1715 (C=O); 1620, 1578, 1535
(C=C, C–Carom). 13C NMR spectrum, δC, ppm: 38.24
(C4), 51.79 (OCH3), 56.16 (C3), 105.13 (C8), 114.60
(CN), 117.18 (C6), 120.59 (C10), 126.78 (C5), 127.44
(Co), 128.68 (Cm), 129.47 (Co, Cp), 139.04 (C7), 146.10
(Ci), 148.44 (C2), 153.93 (C=O), 160.33 (C9). Mass
spectrum, m/z (Irel, %): [M]+ 321 (10), 288 (5), 244
(100), 212 (70), 185 (15), 158 (12), 77 (25), 59
(57), 51 (35). Found, %: C 67.14; H 4.53; N 12.94.
C18H15N3O3. Calculated, %: C 67.29; H 4.67; N 13.08.
REFERENCES
1. Melekhin, E.A., Bardasov, I.N., Ershov, O.V., and Kayu-
kov, Ya.S., Khimiya i biologicheskaya aktivnost’ sinteti-
cheskikh i prirodnykh soedinenii. Azotsoderzhashchie
geterotsikly (Chemistry and Biological Activity of Syn-
thetic and Natural Compounds. Nitrogen-Containing Het-
erocycles), Kartsev, V.G., Ed., Moscow: MBFNP, 2006,
vol. 2, p. 191.
2. Imasheva, N.M., Kovalev, V.B., and Velikorodov, A.V.,
Izv. Vyssh. Uchebn. Zaved., Ser. Khim. Khim. Tekhnol.,
2006, vol. 49, p. 23.
3. Elgemeie, G.E.H., Sallam, M.M.M., Sherif, S.M., and
Elnagdi, M.H., Heterocycles, 1985, vol. 23, p. 3107.
4. Elagamey, A.G.A., Sawllim, S.Z., El-Tawell, M.A., and
Elnagdi, M.H., Collect. Czech. Chem. Commun., 1988,
vol. 53, p. 1534.
5. Elagamey, A.G.A. and El-Tawell, M.A., Indian J. Chem.,
Sect. B, 1990, p. 29.
Compounds VII and VIII were synthesized in
a similar way according to method b.
6. Velikorodov, A.V., Bakova, O.V., and Mochalin, V.B.,
Russ. J. Org. Chem., 2002, vol. 38, p. 66.
Methyl [2-amino-3-cyano-4-(4-methoxyphenyl)-
7. Cross B., Aronti R.L. US Patent no. 3852332, 1974;
4H-chromen-7-yl]carbamate (VII). Yield 2.95 g
Chem. Abstr., 1974, vol. 82, no. 139732b.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 9 2008