Synthesis of carbamate derivatives of 2,3-dihydro-4H-1,4-benzoxazine

Article abstract of DOI:10.1134/s107042800803010x

Alkylation of methyl 2-hydroxyphenylcarbamates with 1,2-dibromoethane in acetone in the presence of K₂CO₃ gave the corresponding methyl 6(7)-R-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate. Alkylation of methyl 2-hydroxyphenylcarbamat

Full text of DOI:10.1134/s107042800803010x

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 3, pp. 369–372. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © A.V. Velikorodov, N.M. Imasheva, 2008, published in Zhurnal Organicheskoi Khimii, 2008, Vol. 44, No. 3, pp. 375–378.
Synthesis of Carbamate Derivatives of 2,3-Dihydro-
4H-1,4-benzoxazine
A. V. Velikorodov and N. M. Imasheva
Astrakhan State University, ul. Tatishcheva 20 a, Astrakhan, 414056 Russia
e-mail: avelikorodov@mail.ru
Received April 9, 2007
Abstract—Alkylation of methyl 2-hydroxyphenylcarbamates with 1,2-dibromoethane in acetone in the
presence of K2CO3 gave the corresponding methyl 6(7)-R-2,3-dihydro-4H-1,4-benzoxazine-4-carboxylate.
Alkylation of methyl 2-hydroxyphenylcarbamates with chloromethyloxirane was accompanied by recyclization
of the oxirane ring with formation of methyl 6(7)-R-3-hydroxymethyl-2,3-dihydro-4H-1,4-benzoxazine-4-
carboxylates.
DOI: 10.1134/S107042800803010X
The chemistry of hydroxyphenylcarbamates has
been poorly studied. On the other hand, these com-
pounds, as well as their alkyl and acyl derivatives,
attract considerable interest as intermediate products in
the synthesis of nitrogen-containing heterocycles pos-
sessing a wide potential of biological activity. In con-
tinuation of our studies on the synthesis of O-alkyl
derivatives of aromatic carbamates [1, 2], in the pres-
ent work we examined alkylation of methyl 2-hy-
droxyphenylcarbamate (I), methyl 2-hydroxy-5-nitro-
phenylcarbamate (II), and dimethyl 2-hydroxyben-
zene-1,4-diyldicarbamate (IV) with 1,2-dibromoethane
and chloromethyloxirane.
tone in the presence of potassium carbonate afforded
the corresponding 2,3-dihydro-4H-1,4-benzoxazine
carbamate derivatives V–X whose structure was con-
1
sistent with their elemental compositions and H and
13C NMR and IR spectra (Scheme 3). For example,
1
the H NMR spectrum of benzoxazine V contained
a three-proton multiplet at δ 7.39–7.22 ppm due to
aromatic protons, a doublet at δ 6.68 ppm (J = 7.9 Hz)
from 5-H, a two-proton multiplet at δ 4.21–4.15 ppm
from 2-H, and a five-proton multiplet at δ 3.92–
3.76 ppm from the NCH2 and OCH3 protons.
Scheme 2.
ortho-Hydroxyphenylcarbamates I and II were
synthesized by acylation of the corresponding amino-
phenols with methyl chloroformate in pyridine
(Scheme 1). Dimethyl 2-hydroxybenzene-1,4-diyldi-
carbamate (IV) was obtained by hydrolysis of di-
methyl 2-acetoxybenzene-1,4-diyldicarbamate (III)
which was prepared in turn by reaction of dimethyl
cyclohexa-2,5-diene-1,4-diylidenedicarbamate [3] with
glacial acetic acid (Scheme 2).
NCOOMe
NHCOOMe
AcOH
OAc
NHCOOMe
III
NCOOMe
NHCOOMe
HCl, MeOH, Δ
The alkylation of carbamates I, II, and IV with
1,2-dibromoethane and chloromethyloxirane in ace-
OH
NHCOOMe
IV
Scheme 1.
MeOCOCl
pyridine
OH
OH
It is well known that 2,3-epoxypropyl phenylcar-
bamate is capable of undergoing recyclization through
intramolecular interaction between the epoxide and
carbamate moieties to produce oxazolidin-2-one deriv-
R
NH2
R
NHCOOMe
I, II
I, R = H; II, R = O2N.
369

VELIKORODOV, IMASHEVA
370
Scheme 3.
O
BrCH2CH2Br
R
N
K2CO3, Me2CO, Δ
COOMe
I, II, IV
V–VII
O
Cl
O
R
OH
N
COOMe
VIII–X
V, VIII, R = H; VI, IX, R = 6-O2N; VII, X, R = 7-MeOCONH.
atives having a hydroxymethyl substituent [4]
(Scheme 4). The results of our studies showed that
recyclization of the oxirane ring with participation of
the carbamate group in the ortho position with respect
to the oxiranylmethoxy group could give rise to 2,3-di-
hydro-4H-1,4-benzoxazine system.
1220 cm–1) were observed, while the spectrum con-
tained bands assignable to carbonyl group and benzene
ring. Compound VIII displayed in the H NMR spec-
trum a multiplet signal at δ 4.38 ppm (3-H) and multi-
plets at δ 3.76 and 3.70 ppm due to protons in the
3-CH2 and OH groups, respectively. In addition, sig-
nals from protons in the other molecular fragments
were present. The hydroxymethyl group in compounds
VIII–X gave a signal in the region δC 61.84–62.04 ppm
in the 13C NMR spectrum.
1
Scheme 4.
O
O
H
N
O
O
N
Δ
EXPERIMENTAL
O
OH
1
The H NMR spectra were measured on a Bruker
The alkylation of methyl 2-hydroxyphenylcarba-
mates I, II, and IV with chloromethyloxirane was also
accompanied by recyclization of the oxirane ring with
formation of methyl 6(7)-R-3-hydroxymethyl-2,3-di-
hydro-4H-1,4-benzoxazine-4-carboxylates VIII–X.
Presumably, in this case 1,4-benzoxazine system is
formed via intermediate 2,3-epoxypropoxyphenyl car-
bamate A which then undergoes heterocyclization.
DRX-500 spectrometer at 500.13 MHz from solutions
in DMSO-d6 using tetramethylsilane as internal refer-
ence. The 13C NMR spectra were recorded with com-
plete decoupling from protons on a Bruker WM-400
instrument (100 MHz) from solutions in acetone-d6.
The IR spectra (3800–400 cm–1) were obtained on
a Specord M82 spectrophotometer from samples pre-
pared as KBr pellets. The purity of the products was
checked by TLC on Silufol UV-254 plates.
O
O
Methyl 2-hydroxyphenylcarbamate (I). Methyl
chloroformate, 7.7 ml (0.1 mol), was added dropwise
over a period of 1.5 h to a solution of 10.9 g (0.1 mol)
of o-aminophenol in 46 ml of anhydrous pyridine
under stirring and cooling. The mixture was stirred for
an additional 0.5 h, left to stand for 13 h at room
temperature, poured onto ice, carefully acidified with
concentrated hydrochloric acid (according to Congo
Red), and extracted with ethyl acetate (4×50 ml). The
extract was washed with 100 ml of a saturated aqueous
solution of sodium chloride and water (2×50 ml) and
dried over sodium sulfate. The solvent was removed
under reduced pressure, and the residue crystallized.
The product was purified by reprecipitation from 2%
R
NHCOOMe
A
The heterocyclization involves nucleophilic attack
by the carbamate nitrogen atom on the positively
charged carbon atom in the oxirane ring. As a result,
six-membered heteroring having a hydroxymethyl sub-
stituent is built up. The IR spectrum of VIII lacked
NH absorption in the region 3400–3300 cm–1, but
a broad absorption band was present at 3200–3600 cm–1
due to stretching vibrations of the hydroxy group. No
absorption bands typical of oxirane ring (865, 910,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

SYNTHESIS OF CARBAMATE DERIVATIVES OF 2,3-DIHYDRO-4H-1,4-BENZOXAZINE
371
aqueous sodium hydroxide with 2% hydrochloric acid,
followed by recrystallization from ethanol. Yield 14.4 g
(86%), colorless crystals, mp 119–122°C. IR spectrum,
ν, cm–1: 3396, 3300 (NH, OH); 1704, 1680 (C=O);
pound I, 2.8 g (0.02 mol) of potassium carbonate,
1.7 ml (0.02 mol) of 1,2-dibromoethane, and 7 ml of
acetone was heated for 5 h at 70°C. The mixture was
cooled, diluted with 25 ml of water, and extracted with
diethyl ether (3×30 ml). The extract was washed with
100 ml of 10% aqueous sodium hydroxide and water
(2×50 ml) and dried over potassium carbonate. The
solvent was removed, and the residue crystallized. Re-
crystallization from ethyl acetate–hexane (1:3 by vol-
ume) gave 2.9 g (74%) of compound V as colorless
crystals, mp 172–173°C. IR spectrum, ν, cm–1: 1730,
1
1604, 1540, 1460 (C–Carom). H NMR spectrum, δ,
ppm: 9.65 s (1H, OH), 8.23 s (1H, NH), 7.50 d (1H,
6-H, J = 9.8 Hz), 6.91 t (1H, 4-H, J = 8.0 Hz), 6.84 d
(1H, 3-H, J = 8.0 Hz), 6.76 t (1H, 5-H, J = 8.0 Hz),
3.66 s (3H, OMe). Found, %: C 57.18; H 5.61; N 8.41.
C8H9NO3. Calculated, %: C 57.49; H 5.39; N 8.38.
Methyl 2-hydroxy-5-nitrophenylcarbamate (II)
was synthesized in a similar way from 15.4 g (0.1 mol)
of 2-amino-4-nitrophenol in 46 ml of anhydrous pyri-
dine and 7.7 ml (0.1 mol) of methyl chloroformate.
Yield 17.6 g (83%), light yellow crystals, mp 222–
223°C (from benzene). IR spectrum, ν, cm–1: 3384,
3248 (NH, OH); 1708 (C=O); 1628, 1596 (C–Carom);
1544, 1352 (NO2). 1H NMR spectrum, δ, ppm: 11.51 s
(1H, OH), 8.75 s (1H, NH), 8.62 s (1H, 6-H), 7.89 d
(1H, 4-H, J = 10.0 Hz), 7.02 d (1H, 3-H, J = 10.0 Hz),
3.70 s (3H, OMe). Found, %: C 44.99; H 3.82;
N 12.94. C8H8N2O5. Calculated, %: C 45.28; H 3.77;
N 13.21.
1
1760 (C=O); 1615, 1530 (C–Carom). H NMR spec-
trum, δ, ppm: 7.39–7.22 m (3H, Harom), 6.68 d (1H,
5-H, J = 7.9 Hz), 4.21–4.15 m (2H, OCH2), 3.92–
3.76 m (5H, NCH2, OMe). 13C NMR spectrum, δC,
ppm: 46.74 (C3), 54.24 (OCH3), 69.75 (C2), 112.77
(C8), 120.42 (C5), 123.30 (C7), 124.32 (C6), 132.52
(C10), 153.14 (C9), 154.28 (C=O). Found, %: C 61.94;
H 5.42; N 7.37. C10H11NO3. Calculated, %: C 62.18;
H 5.70; N 7.25.
Compounds VI–X were synthesized in a similar
way.
Methyl 6-nitro-2,3-dihydro-4H-1,4-benzoxazine-
4-carboxylate (VI) was synthesized using 2.12 g
(0.01 mol) of compound II, 1.40 g (0.01 mol) of potas-
sium carbonate, and 0.85 ml (0.01 mol) of 1,2-di-
bromoethane. Yield 1.86 g (78%), light yellow crys-
tals, mp 110–111°C (from chloroform). IR spectrum, ν,
cm–1: 1725, 1758 (C=O); 1610, 1575 (C–Carom); 1530,
Dimethyl 2-acetoxybenzene-1,4-diyldicarbamate
(III). Glacial acetic acid, 5 ml, was added to 0.5 g
(2.5 mmol) of N,N′-bis(methoxycarbonyl)-1,4-benzo-
quinone diimine [3]. The mixture spontaneously
warmed up and crystallized in a few minutes. Recrys-
tallization from chloroform gave 0.55 g (98%) of com-
pound III as a colorless crystalline substance, mp 205–
206°C. IR spectrum, ν, cm–1: 3300 (NH); 1720, 1690
(C=O); 1600, 1520 (C–Carom). Found, %: C 51.44;
H 4.83; N 10.13. C12H14N2O6. Calculated, %: C 51.06;
H 4.97; N 9.93.
1
1350 (NO2). H NMR spectrum, δ, ppm: 7.85 s (1H,
5-H), 7.69 d (1H, 7-H, J = 8.7 Hz), 7.21 d (1H, 8-H,
J = 8.7 Hz), 4.25–4.13 m (2H, OCH2), 3.89–3.73 m
(5H, NCH2, OMe). 13C NMR spectrum, δC, ppm: 46.73
(C3), 54.28 (OCH3), 69.68 (C2), 111.52 (C5), 114.25
(C8), 119.75 (C7), 134.01 (C10), 144.08 (C6), 150.65
(C9), 153.90 (C=O). Found, %: C 50.21; H 3.92;
N 11.34. C10H10N2O5. Calculated, %: C 50.42; H 4.20;
N 11.77.
Dimethyl 2-hydroxybenzene-1,4-diyldicarba-
mate (IV). A solution of 0.5 g (2.5 mmol) of com-
pound III in 20 ml of methanol containing 1 ml of
concentrated hydrochloric acid was heated for 40 min
under reflux. Excess alcohol was removed under
reduced pressure, and the residue was recrystallized
from ethanol. Yield 0.35 g (73%), colorless crystals,
mp 217°C. IR spectrum, ν, cm–1: 3356, 3295 (NH,
OH); 1712, 1684 (C=O); 1624, 1568, 1524 (C–Carom).
1H NMR spectrum, δ, ppm: 9.63 s (1H, OH), 8.45 s
and 8.18 s (1H each, NH), 7.32 d (1H, 5-H, J =
10.0 Hz), 7.12 s (1H, 3-H), 6.78 d (1H, 6-H, J =
10.0 Hz), 3.65 s (3H, OMe), 3.62 s (3H, OMe). Found,
%: C 49.87; H 4.89; N 12.01. C10H12N2O5. Calculated,
%: C 50.00; H 5.00; N 11.67.
Methyl 7-methoxycarbonylamino-2,3-dihydro-
4H-1,4-benzoxazine-4-carboxylate (VII) was ob-
tained using 2.40 g (0.01 mol) of bis-carbamate IV,
1.40 g (0.01 mol) of potassium carbonate, and 0.85 ml
(0.01 mol) of 1,2-dibromoethane. Yield 2.2 g (84%),
colorless crystals, mp 181–182°C (from ethyl acetate–
hexane, 1:3 by volume). IR spectrum, ν, cm–1: 3410
1
(NH); 1725 (C=O); 1610, 1530 (C–Carom). H NMR
spectrum, δ, ppm: 7.60 br.s (1H, NH), 7.51 s (1H,
8-H), 7.32 d (1H, 6-H, J = 8.2 Hz), 6.82 d (1H, 5-H,
J = 8.2 Hz), 4.15–4.24 m (2H, OCH2), 3.93 m (1H,
NCH2), 3.81 s (3H, 4-CO2Me), 3.76–3.73 m (1H,
Methyl 2,3-dihydro-4H-1,4-benzoxazine-4-car-
boxylate (V). A mixture of 3.34 g (0.02 mol) of com-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 3 2008

VELIKORODOV, IMASHEVA
372
13
NCH2), 3.71 (3H, NHCO2CH3). 13C NMR spectrum,
δC, ppm: 46.74 (C3), 52.68 (NHCO2Me), 54.24
(NCO2Me), 69.75 (C2), 112.05 (C8), 114.01 (C6),
115.49 (C5), 125.71 (C10), 136.61 (C7), 154.28
(NCO2Me), 155.18 (C9, NHCO2Me). Found, %:
C 54.41; H 5.07; N 10.26. C12H14N2O5. Calculated, %:
C 54.14; H 5.26; N 10.53.
(3H, OMe), 3.47 m (1H, OH). C NMR spectrum, δC,
ppm: 52.68 (OMe), 56.65 (C3), 61.84 (CH2OH), 63.24
(C2), 110.52 (C5), 113.73 (C8), 120.02 (C7), 133.38
(C10), 143.55 (C6), 149.50 (C9), 154.74 (C=O). Found,
%: C 49.01; H 4.56; N 10.31. C11H12N2O6. Calculated,
%: C 49.25; H 4.48; N 10.45.
Methyl 3-hydroxymethyl-7-methoxycarbonyl-
amino-2,3-dihydro-4H-1,4-benzoxazine-4-carbox-
ylate (X) was synthesized using 2.40 g (0.01 mol) of
carbamate IV, 1.4 g (0.01 mol) of potassium carbo-
nate, and 0.95 ml (0.01 mol) of chloromethyloxirane.
Yield 1.84 g (62%), white powder, mp 88–90°C (from
ethyl acetate–petroleum ether, 1:3 by volume). IR spec-
trum, ν, cm–1: 3200–3600 (OH); 1725 (C=O); 1610,
Methyl 3-hydroxymethyl-2,3-dihydro-4H-1,4-
benzoxazine-4-carboxylate (VIII) was synthesized
using 1.67 g (0.01 mol) of compound I, 1.4 g
(0.01 mol) of potassium carbonate, and 0.95 ml
(0.01 mol) of chloromethyloxirane. Yield 1.45 g
(65%), colorless crystals, mp 53–54°C (from hexane).
IR spectrum, ν, cm–1: 3200–3600 (OH); 1725 (C=O);
1
1
1610, 1540 (C–Carom). H NMR spectrum, δ, ppm:
1575 (C–Carom). H NMR spectrum, δ, ppm: 7.81 br.s
7.31–7.22 m (2H, 6-H, 7-H), 6.72 d (1H, 5-H, J =
7.8 Hz), 6.65 d (1H, 8-H, J = 7.8 Hz), 4.49 d.d (1H,
2-HA, J = 2.0, 12.0 Hz), 4.38 m (1H, 3-H), 3.94 m
(1H, 2-HB), 3.85 s (3H, OMe), 3.76 m (1H, CH2OH),
3.70 m (1H, OH), 3.61 m (1H, CH2OH). 13C NMR
spectrum, δC, ppm: 52.70 (OMe), 56.65 (C3), 62.02
(CH2OH), 63.24 (C2), 112.27 (C8), 119.24 (C5), 123.53
(C7), 123.80 (C6), 132.02 (C10), 152.03 (C9), 153.87
(C=O). Found, %: C 58.98; H 5.62; N 6.30. C11H13NO4.
Calculated, %: C 59.19; H 5.83; N 6.28.
(1H, NH), 7.40 s (1H, 8-H), 7.22 d (1H, 6-H, J =
7.8 Hz), 6.82 d (1H, 5-H, J = 7.8 Hz), 4.50–4.46 m
(2H, 2-H, 3-H), 3.94 m (1H, 2-H), 3.85 s (3H,
NCO2Me), 3.80–3.73 m (1H, CH2OH), 3.71 s (3H,
NHCO2Me), 3.70–3.61 m (2H, CH2OH). 13C NMR
spectrum, δC, ppm: 52.63 (NHCO2Me), 56.65 (C3),
52.70 (NCO2Me), 62.02 (CH2OH), 63.28 (C2), 111.54
(C8), 113.45 (C6), 114.35 (C5), 125.10 (C10), 136.85
(C7), 154.01 (C9), 154.76 (NCO2Me), 154.97
(NHCO2Me). Found, %: C 52.56; H 5.68; N 9.38.
C13H16N2O6. Calculated, %: C 52.70; H 5.41; N 9.46.
Methyl 3-hydroxymethyl-6-nitro-2,3-dihydro-
4H-1,4-benzoxazine-4-carboxylate (IX) was synthe-
sized using 2.12 g (0.01 mol) of carbamate II, 1.4 g
(0.01 mol) of potassium carbonate, and 0.95 ml
(0.01 mol) of chloromethyloxirane. Yield 1.85 g
(69%), light yellow crystals, mp 135–137°C (from
chloroform). IR spectrum, ν, cm–1: 3200–3600 (OH);
1740 (C=O); 1624, 1596 (C–Carom); 1544, 1348 (NO2).
1H NMR spectrum, δ, ppm: 8.69 s (1H, 5-H), 7.96 d
(1H, 7-H, J = 7.5 Hz), 7.25 d (1H, 8-H, J = 7.5 Hz),
4.51 d.d (1H, 2-HA, J = 2.0, 12.0 Hz), 4.35–4.05 m
(3H, 3-H, 2-HB, CH2OH), 3.76 m (1H, CH2OH), 3.73 s
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