New synthesis of nitro-substituted 3,1-benzoxazines

Article abstract of DOI:10.1134/S1070428013060158

A new one-step procedure has been proposed for the synthesis of nitro derivatives of 3,1-benzoxazines from substituted N-[2-(cyclopent-2-en-1-yl) phenyl]acetamides.

Full text of DOI:10.1134/S1070428013060158

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 6, pp. 890–894. © Pleiades Publishing, Ltd., 2013.
Original Russian Text © O.A. Andriyanova, D.A. Skladchikov, R.R. Gataullin, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 6,
pp. 904–908.
New Synthesis of Nitro-Substituted 3,1-Benzoxazines
O. A. Andriyanova, D. A. Skladchikov, and R. R. Gataullin
Institute of Organic Chemistry, Ufa Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
e-mail: gataullin@anrb.ru
Received May 25, 2012
Abstract—A new one-step procedure has been proposed for the synthesis of nitro derivatives of 3,1-benzox-
azines from substituted N-[2-(cyclopent-2-en-1-yl)phenyl]acetamides.
DOI: 10.1134/S1070428013060158
3,1-Benzoxazine derivatives exhibit a high antiviral
activity [1] and are used as markers in biochemical
studies [2]. Macrocyclic compounds containing
3,1-benzoxazine fragments were isolated from natural
sources [3]. Benzoxazines can also be used as inter-
mediate products in the synthesis of some receptor
agonists [4]. In view of the above stated, heterocyclic
compounds of the 3,1-benzoxazine series attract inter-
est of many researchers [5].
Benzoxazine structures are commonly synthesized
from derivatives of aminobenzyl alcohol [6], o-vinyl-
anilines [7], or o-cyclopropylanilines [8, 9]. We now
report on the synthesis of nitro-substituted 3,1-benzox-
azines by reaction of acetanilides Ia and Ib with sul-
furic acid in the presence of sodium nitrate (Scheme 1).
The reactions were complete almost instantaneously.
Presumably, the process includes several protonation–
deprotonation steps. Carbocation II loses a proton to
give compound III which is protonated again and
undergoes intramolecular cyclization with formation of
benzoxazine structure IV. The process is accompanied
by nitration of the benzene ring to produce 8-nitro
derivative Va or 6-nitro isomer Vb. The presence of
an electron-withdrawing nitro group in the aromatic
ring reduces the basicity of the endocyclic nitrogen
atom in molecules Va and Vb. Therefore, these com-
pounds can readily be extracted with chloroform from
strongly acidic solution. The structure of benzoxazines
Va and Vb was determined on the basis of their ele-
mental compositions and spectral data.
Treatment of acetanilide Ia with 98% sulfuric acid
at room temperature led to the formation of 3,1-benz-
oxazine VI (Scheme 2). The product turned out to be
unstable, and it fairly rapidly decomposed during
Scheme 1.
R3
R3
R3
R2
R2
R2
NaNO3, H2SO4
20°C
–H+
NHAc
NHAc
NHAc
R1
Ia, Ib
R1
R1
IIa, IIb
IIIa, IIIb
R3
(1) H+
R2
(2) NO2+
O
N
Me
R1
IVa, IVb, Va, Vb
I–IV, R1 = R3 = H, R2 = Me (a), R1 = R3 = Me, R2 = H (b); V, R1 = O2N, R2 = Me, R3 = H (a), R1 = R3 = Me, R2 = O2N (b).
890

NEW SYNTHESIS OF NITRO-SUBSTITUTED 3,1-BENZOXAZINES
891
Scheme 2.
H2SO4
Silica, PhH
Me
Me
Me
O
NHAc
N
Me
NH2
Ia
VI
VII
chromatography on silica gel to afford a considerable
amount of cyclopentenylaniline VII (Scheme 2). The
latter was identified by comparison with published
data [10].
cyclopentene rings gave rise to well distinguishable
signals. Multiplet signals at δ 1.83–1.89, 1.95–2.03,
and 2.25–2.32 ppm due to methylene protons were
assigned to benzoxazine XI by comparing with the
spectrum of compound Va. By analogy with the spec-
tral parameters of compound VII, the quintet at
δ 2.05 ppm and two signals at δ 2.56–2.64 and 2.66–
2.72 ppm (triplets of quartets) were assigned to cyclo-
pentene derivative X. Only singlets were observed in
the aromatic region. Compound XII showed only one
one-proton singlet in the aromatic region, indicating
the presence of five substituents in the benzene ring.
The reaction of carbamate VIII with sulfuric acid
in the presence of sodium nitrate was not selective. By
crystallization from ethanol we isolated 3,1-benzoxa-
zin-2-one IX, and chromatographic separation of the
mother liquor on silica gel gave (according to the
1H NMR data) a mixture of nitro derivative X and
2-ethoxy-3,1-benzoxazine XI at a ratio of 1 :1 in
a poor yield (Scheme 3). We failed to improve the
yield of IX by increasing the time of treatment with
sulfuric acid to 1 h and adding afterward NaNO3,
followed by prolonged keeping of the reaction mixture
in water. However, in this case, after precipitation of
compound IX from ethanolic solution, crystals of
dinitro derivative XII separated from the solution in 4–
5 days. Increased time of contact of compound VIII
with sulfuric acid favored complete consumption of
The nitration of alkenylanilide XIII under analo-
gous conditions afforded benzoxazine XIV which was
isolated by chromatography in 70% yield (Scheme 4).
The mass spectrum of XIV (atmospheric pressure
chemical ionization) contained the molecular ion peak
with m/z 263 [M + H]+ and abundant ion peak with
m/z 304 [M + H + CH3CN]+ due to solvate with aceto-
nitrile. In the negative ion chemical ionization mass
spectrum of XIV the molecular ion was represented by
a peak with m/z 261 [M – H]–.
1
carbamate X. The H NMR spectrum of a mixture of
solid components of the mother liquor obtained after
crystallization of nitro derivatives IX and XII lacked
signal at δ 6.05 ppm typical of the 2′-H olefinic proton.
Thus the reactions of N-[2-(cyclopent-2-en-1-yl)-
phenyl]- and N-{4-methyl-2-[(3E)-pent-3-en-2-yl]-
phenyl}acetamides with sulfuric acid in the presence
of sodium nitrate lead to the formation of 8- or 6-nitro-
3,1-benzoxazine derivatives. Under analogous con-
ditions, ethyl [2-(cyclopent-2-en-1-yl)-4-methyl-
phenyl]carbamate is converted into a mixture of
8-nitro-substituted 3,1-benzoxazin-2-one and 2-eth-
oxy-3,1-benzoxazine. Prolonged contact with excess
nitrating mixture favors formation of dinitro-substi-
tuted 3,1-benzoxazin-2-one.
1
Isomer mixture X/XI displayed in the H NMR
spectrum two sets of signals. The presence of a charac-
teristic triplet (δ 6.05 ppm, J = 2.0 Hz) from 2′-H at the
double bond in the cyclopentene ring and a broadened
singlet from the NH proton (δ 8.75 ppm) allowed us to
presume that this mixture contains carbamate X. Two
quartets at δ 4.24 and 4.37 ppm and two triplets typical
of methyl protons indicated that both isomers X and
XI contain ethoxy group. Spirocyclopentane and
Scheme 3.
R
NaNO3, H2SO4
20°C
Me
Me
Me
Me
+
+
O
O
NHCOOEt
N
O
NHCOOEt
N
OEt
H
NO2
NO2
NO2
XI
VIII
IX, XII
X
1 : 1
IX, R = H; XII, R = O2N.
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ANDRIYANOVA et al.
892
Scheme 4.
Me
Me
Me
NaNO3, H2SO4
70%
Me
Me
Me
O
NHAc
N
Me
NO2
XIV
XIII
EXPERIMENTAL
2′-H), 6.99 d (1H, Harom, J = 7.6 Hz), 7.00 s (1H, NH),
7.01 d (1H, Harom, J = 7.6 Hz). Found, %: C 78.48;
H 8.26; N 6.04. C15H19NO. Calculated, %: C 78.56;
H 8.35; N 6.11.
The IR spectra were recorded on a Shimadzu IR
Presstige-21 spectrometer with Fourier transform. The
1H and 13C NMR spectra were obtained on a Bruker
Avance III 500 instrument at 500.13 and 125.73 MHz,
respectively, using tetramethylsilane as internal refer-
ence. The elemental compositions were determined on
a Hewlett Packard M-185B CHN analyzer. The mass
spectra of Va and XIV were recorded on a Shimadzu
LCMS-2010EV instrument [atmospheric pressure
chemical ionization; eluent methanol–water (50:50) or
acetonitrile (100%)]. The mass spectra of Va, Vb, IX,
and XII were obtained on a ThermoFinnigan MAT 95
XP mass spectrometer with direct sample admission
into the ion source under standard conditions. The
purity of liquid products was checked by GLC on
a Khromos GKh-1000 gas chromatograph (flame
ionization detector, carrier gas helium, 1 m×3-mm
column packed with 5% of SE-30 on Chromaton
N-AW). Qualitative TLC analysis was performed using
Sorbfil PTSKh-AF-V-UF plates (Sorbpolimer closed
corporation, Krasnodar, Russia); spots were detected
under UV light (λ 254 nm) or by treatment with iodine
vapor.
2,6-Dimethyl-8-nitrospiro[3,1-benzoxazine-4,1′-
cyclopentane] (Va). Compound Ia, 2.6 g (10 mmol),
was dissolved in 25 ml of 98% sulfuric acid, and 1.0 g
(11.7 mmol) of sodium nitrate was added. When the
salt dissolved, the mixture was poured onto 200 g of
ice and extracted with chloroform (150 ml). The
aqueous phase was neutralized with NaHCO3 and
treated with chloroform (50 ml). The organic extracts
were combined, washed with a saturated solution of
NaHCO3 until CO2 no longer evolved and with water
(50 ml), dried over Na2SO4, and evaporated under
reduced pressure. The residue was purified by column
chromatography on silica gel using benzene as eluent.
Yield 2.15 g (83%), yellow crystals, mp 111–113°C.
1H NMR spectrum (CDCl3), δ, ppm: 1.83–2.00 m (6H,
CH2, 2′-H, 5′-H), 2.10 s (3H, CH3), 2.21–2.26 m (2H,
2′-H, 5′-H), 2.55 s (3H, CH3), 6.97 s (1H, Harom), 7.70 s
(1H, Harom). 13C NMR spectrum (CDCl3), δC, ppm:
20.3 and 21.9 (CH3), 24.0 (C3′, C4′), 41.3 (C2′, C5′),
88.3 (C4), 119.7 and 126.5 (C5, C7); 131.0, 134.1,
138.2 (C4a, C6, C8a); 148.5 (C8), 161.4 (C2). Mass spec-
trum, m/z: 261 [M + H]+, 260.1165 [M]+. Found, %:
C 64.51; H 6.15; N 10.69. C14H16N2O3. Calculated, %:
C 64.50; H 6.20; N 10.76. M 260.1155.
N-[2-(Cyclopent-2-en-1-yl)-3,6-dimethylphenyl]-
acetamide (Ib). Acetic anhydride, 4.2 g (40 mmol),
was added to a solution of 3.3 g (17.6 mmol) of
2-(cyclopent-2-en-1-yl)-3,6-dimethylaniline in 20 ml
of anhydrous chloroform. The mixture was left to
stand for 12 h at room temperature, washed with
a saturated solution of NaHCO3 until CO2 no longer
evolved, and extracted with chloroform. The extract
was dried over Na2SO4 and evaporated on a rotary
evaporator, and the residue was purified by column
chromatography on silica gel using first benzene and
then benzene–ethyl acetate (9:1) as eluent. Yield 2.9 g
(72%), Rf 0.14 (C6H6–EtOAc, 9:1). 1H NMR spectrum
(CDCl3), δ, ppm: 1.67–1.75 m (2H, CH2), 2.07 s (3H,
CH3), 2.15 s (3H, CH3), 2.33 s (3H, CH3), 2.34–2.42 m
(2H, CH2), 2.46–2.60 m (2H, CH2), 4.26–4.32 m (1H,
1′-H), 5.78–5.81 m (1H, 3′-H), 5.94–5.97 m (1H,
2,5,8-Trimethyl-6-nitrospiro[3,1-benzoxazine-
4,1′-cyclopentane] (Vb) was synthesized in a similar
way from 0.458 g (2 mmol) of amide Ib and 0.2 g
(2.35 mmol) of NaNO3 in 5 ml of 98% H2SO4. Yield
0.467 g (85%), Rf 0.8 (C6H6–EtOAc, 9:1), mp 99–
1
103°C. H NMR spectrum (CDCl3), δ, ppm: 1.84–
2.02 m (6H, CH2, 2′-H, 5′-H), 2.11 s (3H, CH3), 2.14–
2.22 m (2H, 2′-H, 5′-H), 2.31 s (3H, CH3), 2.36 s (3H,
CH3), 7.55 s (1H, Harom). Mass spectrum: m/z 274.1321
[M]+. Found, %: C 65.63; H 6.57; N 10.13.
C15H18N2O3. Calculated, %: C 65.68; H 6.61; N 10.21.
M 274.132.
2,6-Dimethylspiro[3,1-benzoxazine-4,1′-cyclo-
pentane] (VI). Compound Ia, 0.43 g (2 mmol), was
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NEW SYNTHESIS OF NITRO-SUBSTITUTED 3,1-BENZOXAZINES
893
added at room temperature to 2 ml of 98% sulfuric
acid. After 30 min, the mixture was poured onto 50 g
of ice, neutralized with NaHCO3, and extracted with
chloroform (100 ml). The extract was washed with
water, dried over Na2SO4, and evaporated on a rotary
evaporator. Yield of crude product VI 0.42 g (98%).
Thin-layer chromatography revealed no any impurity.
N 10.61. C13H14N2O4. Calculated, %: C 59.54; H 5.38;
N 10.68. M 262.0948.
The mother liquor was evaporated, and the residue
was subjected to column chromatography on silica gel
using benzene as eluent to isolate 0.09 g (18%) of
a mixture containing (according to the spectral data)
carbamate X and ethoxybenzoxazine XI at a ratio
of ~1:1.
1
Rf 0.4 (C6H6–EtOAc, 9 : 1). H NMR spectrum
(CDCl3), δ, ppm: 1.82–1.88 m (2H, 2′-H, 5′-H), 1.94–
2.01 m (4H, CH2), 2.19–2.26 m (2H, 2′-H, 5′-H),
2.11 s (3H, CH3), 2.34 s (3H, CH3), 6.89 s (1H, 5-H),
7.02 d (1H, Harom, J = 8.0 Hz), 7.06 d.d (1H, Harom, J =
1.2, 8.0 Hz). Compound VI partly decomposed with
formation of amine VII during chromatographic isola-
tion on silica gel.
6-Methyl-5,8-dinitrospiro[3,1-benzoxazine-4,1′-
cyclopentane]-2(1H)-one (XII). A solution of 0.49 g
(2 mmol) of compound VIII in 5 ml of 98% sulfuric
acid was stirred for 1 h, 0.22 g (2.58 mmol) of sodium
nitrate was added, and the mixture was stirred for 2 h
and poured onto ice. The mixture was then treated as
described above for compound Va. Crystals of IX
separated from the alcoholic solution, 0.1 g, were
filtered off. After 5 days, crystals of dinitro derivative
XII separated from the mother liquor. Yield 0.126 g
Ethyl [2-(cyclopent-2-en-1-yl)-4-methylphenyl]-
carbamate (VIII). A solution of 2 g of ethyl chloro-
formate in 5 ml of methylene chloride was added
dropwise under stirring to a solution of 1.73 g
(10 mmol) of 4-methyl-2-(cyclopent-2-en-1-yl)-
aniline in 10 ml of anhydrous methylene chloride, and
2 g of K2CO3 was then added at room temperature.
When the reaction was complete, the mixture was
treated with 10 ml of water, stirred for 20 min, and
extracted with 50 ml of methylene chloride. The
organic phase was separated, washed with water, dried
over MgSO4, and evaporated, and the residue was
purified by column chromatography on silica gel.
Yield 2.32 g (95%); the product was a gradually crys-
tallizing material, mp 74–76°C, Rf 0.8 (C6H6–EtOAc,
1
(20%), mp 203–205°C (from EtOH). H NMR spec-
trum (CDCl3), δ, ppm: 1.90–2.17 m (6H, CH2, 2′-H,
5′-H), 2.38 s (3H, CH3), 2.40–2.41 m (2H, 2′-H, 5′-H),
7.40 s (1H, Harom), 9.20 s (1H, NH). Mass spectrum:
m/z: 307.0782 [M]+. Found, %: C 59.49; H 5.33;
N 10.61. C13H13N3O6. Calculated, %: C 50.82; H 4.26;
N 13.68. M 307.0799.
2,4,6-Trimethyl-8-nitro-4-propyl-4H-3,1-benzox-
azine (XIV) was synthesized as described above for
compound Va from 0.434 g (2 mmol) of amide XIII
and 0.2 g (2.35 mmol) of NaNO3 in 5 ml of 98%
H2SO4. The product was isolated by column chroma-
tography on silica gel using benzene as eluent. Yield
0.367 g (70%), yellow viscous material, Rf 0.8 (C6H6–
1
9:1). H NMR spectrum (CDCl3), δ, ppm: 0.81 t (3H,
CH3, J = 7.0 Hz), 1.56–1.75 m (1H, 5′-H), 2.26 s (3H,
CH3), 2.49–2.60 m (3H, 5′-H, 4′-H), 3.95 m (1H,
1′-H), 4.20 q (2H, CH2, J = 7.0 Hz), 5.72–5.74 m (1H,
2′-H), 6.01–6.04 m (1H, 3′-H), 6.53 br.s (1H, Harom),
6.94 s (1H, 3-H), 7.02 d (1H, Harom, J = 7.9 Hz),
7.62 br.s (1H, NH). Found, %: C 73.36; H 7.16; N 5.68.
C15H19NO2. Calculated, %: C 73.44; H 7.21; N 5.71.
1
EtOAc, 9:1). H NMR spectrum (CDCl3), δ, ppm:
0.88 t (3H, CH3, J = 7.0 Hz), 1.18–1.42 m (2H, CH2),
1.61 s (3H, CH3), 1.78–2.03 m (2H, CH2), 2.12 s (3H,
CH3), 2.57 s (3H, CH3), 6.92 s (1H, Harom), 7.70 s (1H,
H
arom). 13C NMR spectrum (CDCl3), δC, ppm: 14.0,
20.3, 21.7, 27.9 (CH3); 16.8, 44.1 (CH2); 80.8 (C4);
118.8, 127.3 (C5, C7); 131.0, 134.1, 137.6 (C4a, C6,
C8a); 148.5 (C8), 161.7 (C2). Mass spectrum, m/z: 263
[M + H]+, 304 [M + H + CH3CN]+. Found, %: C 64.05;
H 6.86; N 10.62. C14H18N2O3. Calculated, %: C 64.10;
H 6.92; N 10.68. M 262.3044.
6-Methyl-8-nitrospiro[3,1-benzoxazine-4,1′-cy-
clopentane]-2(1H)-one (IX) was synthesized as de-
scribed above for compound Va from 0.49 g (2 mmol)
of amide VIII and 0.2 g (2.35 mmol) of NaNO3 in
5 ml of 98% H2SO4. The residue obtained after treat-
ment of the reactions mixture and removal of the
solvent was crystallized from ethanol, and the yellow
crystals were filtered off. Yield 0.1 g (19%), mp 247–
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