Fluorine-containing heterocycles: Xix. * synthesis of fluorine-containing quinazolin-4-ones from 3,1-benzoxazin-4-ones

Article abstract of DOI:10.1134/S1070428009060190

Reactions of fluorine-containing 3,1-benzoxazin-4-ones with ammonium acetate, hydrazine, and heteroaromatic amines gave new 3H-, 3-amino-, and 3-hetarylquinazolin-4-ones, respectively. Differences in the conditions of formation of benzoxazinones from anthranilic acids with different fluorination patterns and in the reactions of fluorinated 3,1-benzoxazinones with nitrogen-centered nucleophiles were revealed. Pleiades Publishing, Ltd., 2009.

Full text of DOI:10.1134/S1070428009060190

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 913–920. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © A.A. Laeva, E.V. Nosova, G.N. Lipunova, A.V. Golovchenko, N.Yu. Adonin, V.N. Parmon, V.N. Charushin, 2009, published in
Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 6, pp. 925–932.
Dedicated to Full Member of the Russian Academy of Sciences
O.N. Chupakhin on his 75th anniversary
Fluorine-Containing Heterocycles:
XIX.* Synthesis of Fluorine-Containing Quinazolin-4-ones
from 3,1-Benzoxazin-4-ones
A. A. Laevaa, E. V. Nosovaa, G. N. Lipunovab, A. V. Golovchenkoa, N. Yu. Adoninc,
V. N. Parmonc, and V. N. Charushinb
a Ural State Technical University, Yekaterinburg, Russia
b Postovskii Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 22, Yekaterinburg, 620219
e-mail: charushin@ios.uran.ru
c Boreskov Institute of Catalysis, Siberian Division, Russian Academy of Sciences, Novosibirsk, Russia
Received October 15, 2008
Abstract—Reactions of fluorine-containing 3,1-benzoxazin-4-ones with ammonium acetate, hydrazine, and
heteroaromatic amines gave new 3H-, 3-amino-, and 3-hetarylquinazolin-4-ones, respectively. Differences in
the conditions of formation of benzoxazinones from anthranilic acids with different fluorination patterns and in
the reactions of fluorinated 3,1-benzoxazinones with nitrogen-centered nucleophiles were revealed.
DOI: 10.1134/S1070428009060190
Due to unique properties of fluorine atoms (which
ensure solubility in lipids and the ability to inhibit spe-
cific enzymes and penetrate through cell membranes)
fluorine-containing organic compounds, including het-
erocyclic ones, have found wide application in medic-
inal chemistry; in particular, 20% of pharmaceuticals
contain fluorine [2]. In the recent years, extensive
studies have been performed on compounds of the
quinazolinone series with a view to obtain highly ef-
ficient medicines [3–6]. In this respect, strong attention
is given to 2,3-disubstituted quinazolin-4-ones, some
of which were found to be useful in the treatment of
obesity, diabetes, tumors, viral infections, and degener-
ative pathologies of central nervous system, including
epilepsy and Parkinson’s disease [7–9]. 2,3-Disubsti-
tuted quinazolin-4-ones can be synthesized in several
ways [10–14], among which the procedure based on
the transformation of 3,1-benzoxazin-4-ones by the ac-
tion of amines or hydrazines [15–17] seems to be quite
promising and fairly convenient.
and acetic anhydride or benzoyl chloride. The choice
of this synthetic route was determined by high reac-
tivity of 3,1-benzoxazin-4-ones, which makes it pos-
sible to vary substituent in the 3-position of the target
quinazolinone. Published data on the synthesis of 5- or
6-fluoro-substituted quinazolin-4-ones according to the
above procedure (Scheme 1) are very scanty [16, 17],
whereas derivatives containing two or more fluorine
atoms were not obtained in such a way.
We previously reported on the synthesis and prop-
erties of a series of 6,7,8-trifluoroquinazolin-4-ones,
some of which were found to exhibit fairly strong
tuberculostatic activity [18]. Taking into account that
the presence of several fluorine atoms generally in-
creases the toxicity, in the present work we synthesized
a number of new 2- and 2,3-substituted quinazolin-4-
ones having one to three fluorine atoms in the benzene
fragment with a view to test the products for biological
activity.
The procedures developed by us previously for the
synthesis of fluorine-containing quinazolin-4(1H)-ones
via cyclocondensation of o-fluorobenzoyl chloride
with S-alkylisothioureas [18] or of 2-amino-5-fluoro-
2-Methyl- and 2-phenyl-3,1-benzoxazin-4-ones can
readily be synthesized from anthranilic acid derivatives
* For communication XVIII, see [1].
913

LAEVA et al.
914
Scheme 1.
N
N
N
F
O
N
O
N
N
R
R
NH2
S
S
N
Me
F
F
O
N
COOH
NH2
Ac2O
O
NH2
H
N
O
F
Me
O
NH
N
Me
O
O
N
O
O
H
F
F
F
N
ArSO2NHNH2
NHNHSO2Ar
NHCOR
N
SO2Ar
R
N
R
benzamide with carboxylic acid chlorides or aldehydes
[19] are difficult to apply to the preparation of 6,7-di-
fluoro derivatives. The reason is that the required
initial compounds, such as 2,4,5-trifluorobenzoic acid
and 2-amino-4,5-difluorobenzonitrile are difficultly
accessible. Therefore, development of a convenient
procedure for the synthesis of 6,7-difluoro-1H-quinaz-
olin-4-one from accessible building blocks seems to be
an important problem.
product. Trifluoroanthranilic acid Ib reacted with ben-
zoyl chloride in the presence of triethylamine at room
temperature (4 h) to give the corresponding 2-phenyl-
benzoxazinone IId, as in the reaction with 4,5-di-
fluoroanthranilic acid. Like trifluoro derivative IIc,
5-fluoro-3,1-benzoxazin-4-one (IIe) was synthesized
by heating 6-fluoroanthranilic acid (Ic) with acetic an-
hydride in the presence of anhydrous sodium acetate.
The reaction in the absence of sodium acetate lead to
exclusive formation of 2-acetylamino-6-fluorobenzoic
acid A. Thus, the condensation with acetic anhydride
occurs most readily with 4,5-difluoroanthranilic acid,
while the condensation of 3- and 6-fluoro-substituted
anthranilic acids requires the presence of a base.
2-Methyl- and 2-phenyl-6,7-difluoro-4H-3,1-benz-
oxazin-4-ones IIa and IIb were synthesized by heating
4,5-difluoroanthranilic acid (Ia) with acetic anhydride
for 1 h (IIa) or by reaction of Ia with benzoyl chloride
in the presence of triethylamine in anhydrous methyl-
ene chloride (IIb, Scheme 2). According to the
1H NMR data, the condensation of 3,4,5-trifluoroan-
thranilic acid (Ib) with acetic anhydride in the absence
of a base gave a mixture of acid A and benzoxazinone
IIc at a ratio of 27:73. When the reaction was per-
formed by heating compound Ib with acetic anhydride
in the presence of anhydrous sodium acetate (reaction
time 2 h), benzoxazinone IIc was formed as the only
3,4,5-Trifluoroanthranilic acid (Ib) was synthesized
by nitration of 3,4,5-trifluorobenzoic acid [20] with
a mixture of concentrated nitric and sulfuric acids,
followed by reduction of the nitro group with hydrogen
over Pd/C.
The formation of oxazine ring in compounds IIa
1
and IIb follows from the absence in their H NMR
spectra of broadened signals typical of protons in
Scheme 2.
R1
R1
R1
O
5
R2
R3
COOH
NH2
R2
R3
COOH
R2
R3
4
Ac2O or BzCl, NEt3
3O
6
2
1
NHCOR5
N
R5
7
8
R4
Ia–Ic
R4
R4
IIa–IIe
A
I, R1 = R4 = H, R2 = R3 = F (a); R1 = H, R2 = R3 = R4 = F (b); R1 = F, R2 = R3 = R4 = H (c); II, R1 = R4 = H, R2 = R3 = F, R5 = Me (a),
Ph (b); R1 = H, R2 = R3 = R4 = F, R5 = Me (c), Ph (d); R1 = F, R2 = R3 = R4 = H, R5 = Me (e).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

FLUORINE-CONTAINING HETEROCYCLES: XIX.
915
Scheme 3.
gous protons in benzoxazinones IIa and IIb. In the
spectrum of 3-amino-6,7-difluoro-2-phenylqunazolin-
4(3H)-one (IVb), the 5-H and 8-H signals are dis-
placed downfield to δ 7.9 and 8.8 ppm, respectively.
The amino group in position 3 of IVb gives rise to
a broadened singlet at δ 12.9 ppm; the corresponding
signal of 2-methyl derivative IVa is located in a much
stronger field, at δ 5.7 ppm.
O
N
O
(1) NH4OAc
(2) NaOH
F
F
F
F
O
NH
R
N
R
IIa, IIb
IIIa, IIIb
R = Me (a), Ph (b).
The reaction of 6,7,8-trifluoro-4H-3,1-benzoxazin-
4-one (IIc) with hydrazine hydrate was accompanied
by replacement of one fluorine atom in the benzene
ring by hydrazino group, and the product was 3-amino-
6,8-difluoro-7-hydrazino-2-methylquinazolin-4(3H)-
one (IVc) whose structure was determined on the basis
of its 1H and 19F NMR and mass spectra. The observed
multiplicity of the 5-H signal in the 1H NMR spectrum
carboxy and amino groups, as well as from the pres-
ence of signals from protons in the methyl or phenyl
group in position 2. Signals from the 5-H and 8-H
protons in the benzene fragment appear as doublets of
doublets at δ 7.5–7.6 and 8.0 ppm, respectively. In the
1H NMR spectra of 6,7,8-trifluoro-3,1-benzoxazin-4-
ones IIc and IId, the 5-H proton resonated as a double
doublet of doublets. The IR spectra of IIa–IId con-
tained an absorption band at 1746–1767 cm–1, which is
typical of stretching vibrations of the C4=O carbonyl
group. Benzoxazin-4-ones IIa and IIb displayed mo-
lecular ion peaks in the mass spectra.
3
5
of IVc (δ 7.40 ppm, d.d, J = 11.7, J = 1.4 Hz)
indicated that fluorine atom in position 7 was replaced.
19
The F NMR spectrum of IVc contained signals as-
signable to two fluorine atoms. Compound IId reacted
with hydrazine hydrate under analogous conditions to
give 3-amino-6,7,8-trifluoro-2-phenylquinazolin-
4(3H)-one (IVd) which displayed signals from three
fluorine atoms (d.d.d) in the 19F NMR spectrum. In the
mass spectra of IVa–IVd we observed the correspond-
ing molecular ion peak. Stretching vibrations of the
carbonyl group in compounds IVa and IVc gave rise to
IR absorption at 1673–1681 cm–1, and bands in the
region 3206–3342 cm–1 were assigned to stretching vi-
brations of amino and hydrazino groups. The reaction
of 5-fluoro-2-methyl-3,1-benzoxazin-4-one (IIe) with
hydrazine hydrate in boiling ethanol stopped at the
stage of formation of the corresponding hydrazide B.
We also examined reactions of benzoxazinones IIa
and IIb with some heteroaromatic amines with a view
to obtain quinazolin-4-one derivatives having a phar-
macophoric heterocyclic substituent in the 3-position
(Scheme 5). The reactions smoothly occurred on
fusion of the reactants at 170–180°C over a period of
20–40 min, and the yield of 3-hetaryl-6,7-difluoroquin-
azolin-4(3H)-ones Va–Vf thus obtained ranged from
By fusion of benzoxazinones IIa and IIb with am-
monium acetate and subsequent treatment of the reac-
tion mixture with 5% aqueous sodium hydroxide on
heating we obtained previously unknown 2-methyl-
and 2-phenyl-6,7-difluoroquinazolin-4(3H)-ones IIIa
and IIIb (Scheme 3). Their fluorine-free analogs were
described in [10]. The structure of IIIa and IIIb was
confirmed by the 1H NMR and mass spectra.
Benzoxazin-4-ones IIa–IIe were brought into reac-
tion with hydrazine hydrate as nucleophile (Scheme 4).
Reactions of benzoxazinones IIa and IIb with hydra-
zine hydrate in boiling ethanol (reaction time 3 h) gave
3-amino-6,7-difluoroquinazolin-4(3H)-ones IVa and
IVb, respectively. It is known that the transformation
of benzoxazinones into quinazolinones involves inter-
mediate N-acylanthranilic acid hydrazides B which un-
der-go intramolecular cyclization to the corresponding
2,3-disubstituted quinazolin-4-ones IV [13]. The 5-H
and 6-H protons in 2-methyl derivative IVa resonate in
1
the same region of the H NMR spectra as do analo-
Scheme 4.
R1
O
R1
O
R1
O
R2
R3
R2
R3
R2
R3
NH2
R5
H2NNH2 · H2O
O
NHNH2
COR5
N
N
R5
N
H
N
R4
IIa–IIe
R4
R4
IVa–IVd
B
IV, R1 = R4 = H, R2 = R3 = F, R5 = Me (a), Ph (b); R1 = H, R2 = R4 = F, R3 = NH2NH, R5 = Me (c), R3 = F, R5 = Ph (d).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

LAEVA et al.
916
Scheme 5.
R1
O
N
R1
O
R1
O
N
R2
R3
R2
R3
Ht
R2
R3
Ht
H2N–Ht
O
N
N
H
R5
NHCOR5
R5
R4
IIa–IIc
R4
VIa, VIb
R4
Va–Vg
V, R1 = R4 = H, R2 = R3 = F: R5 = Me, Ht = 5-tert-butyl-1,2-oxazol-3-yl (a), 1,3-thiazol-2-yl (b), 1H-1,2,4-triazol-5-yl (c), 3-methyl-
1H-pyrazol-5-yl (d), pyridin-2-yl (e); R5 = Ph, Ht = 5-tert-butyl-1,2-oxazol-3-yl (f); R1 = F, R2 = R3 = R4 = H, R5 = Me, Ht = 5-tert-
butyl-1,2-oxazol-3-yl (g); VI, R1 = R4 = H, R2 = R3 = F, R5 = Me, Ht = 4,6-dimethylpyrimidin-2-yl (a); R1 = F, R2 = R3 = R4 = H,
R5 = Me, Ht = pyridin-2-yl (b).
60 to 80%. The product structure was determined by
1H NMR and mass spectrometry. The mass spectra of
Va–Vf characteristically contained strong molecular
ion peaks, as well as a peak with m/z 153 (Vb, Vc),
belonging to the [M – R1 – NCO]+ ion. In the IR spec-
tra of quinazolinones Vb and Ve the carbonyl absorp-
tion band appeared at 1678–1687 cm–1.
Thus we have studied the possibility of using
mono-, di-, and trifluoroanthranilic acids in the synthe-
sis of fluorinated 2- and 2,3-substituted quinazolin-
4(3H)-ones through intermediate 3,1-benzoxazin-
4-ones. Di- and trifluorobenzoxazin-4-ones were found
to fairly readily undergo transformation into the cor-
responding quinazolin-4-ones, while reactions of tri-
fluorobenzoxazin-4-ones with nitrogen-centered nu-
cleophiles can be accompanied by replacement of the
7-fluorine atom by nucleophile residue, which makes it
possible to introduce pharmacophoric groups into the
7-position of quinazolin-4(3H)-one.
Quinazolinones Vb, Vd, and Ve can also be syn-
thesized by heating benzoxazinone IIa with the corre-
sponding hetarylamines in boiling DMF (1 h), but in
this case the yield was lower than under solvent-free
conditions. Weaker nucleophiles such as 2-aminopy-
rimidines failed to react with benzoxazinone IIa with
formation of desired quinazolin-4-ones. The only prod-
uct isolated in the reaction of compound IIa with
4,6-dimethylpyrimidin-2-amine was anthranilic acid
amide VIa which did not undergo intramolecular cy-
clization to the corresponding quinazolinone, presum-
ably due to steric hindrances created by the bulky
4,6-dimethylpyrimidinyl substituent. In the reaction of
IIa with 2-aminopyrimidine, the former was recovered
from the reaction mixture. The structure of VIa was
confirmed by the 1H NMR and mass spectra.
EXPERIMENTAL
1
The H NMR spectra were recorded from solutions
in DMSO-d6 on Bruker WM-250 and Bruker DRX-
400 spectrometers at 250.14 and 400.13 MHz, respec-
tively. The 19F NMR spectra were measured on Bruker
Avance 400 and Bruker DRX-500 instruments at
376.43 and 470.51 MHz, respectively. The chemical
shifts were determined relative to tetramethylsilane
(1H) and CFCl3 (19F; C6F6 was used as secondary refer-
ence, δF –162.9 ppm). The mass spectra were obtained
on a Varian MAT 311A mass spectrometer (electron
impact, 70 eV; accelerating voltage 3 kV, cathode
emission current 300 μA; direct sample admission into
the ion source), as well as on a Shimadzu LCMS-2010
instrument (positive and negative ion detection; spe-
cified a.m.u. range scan, selected ion monitoring,
profile scan; atmospheric pressure chemical ioniza-
tion). The IR spectra were recorded on a Perkin–Elmer
Spectrum One spectrometer with Fourier transform
equipped with a diffuse reflectance adapter. The purity
of the products was checked by TLC.
Fusion of 5-fluoro-2-methylbenzoxazin-4-one (IIe)
with 5-tert-butyl-1,2-oxazol-3-amine (reaction time
1 h) resulted in the formation of a mixture of amide
VIc (R1 = F, R2 = R3 = R4 = H, R5 = Me, Ht = 5-tert-
butyl-1,2-oxazol-3-yl) and quinazolinone Vg at a ratio
1
of 1:1 (according to the H NMR data). The reaction
of 2-aminopyridine with 5-fluorobenzoxazinone IIe
gave amide VIb as the only product. Compound VIb
failed to undergo cyclization to the corresponding
quinazolinone on heating in boiling anhydrous pyri-
dine for 10 h or in DMF for 1 h. We can conclude that
the presence of fluorine atom in position 5 of benzox-
azinone hampers cyclization of intermediate benz-
amides to quinazolinones.
4,5-Difluoroanthranilic acid (Ia) was synthesized
from 3,4-difluoroaniline according to the procedure
described in [21] for 4-chloro-5-fluoroanthranilic acid
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

FLUORINE-CONTAINING HETEROCYCLES: XIX.
917
and was identical to commercially available product.
3,4,5-Trifluorobenzoic acid was prepared by hydro-
defluorination of pentafluorobenzoic acid [20].
washed with water and recrystallized from ethanol.
Yield 0.98 g (86%), mp 164–166°C. IR spectrum:
ν 1755 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 2.44 s
3
4
(3H, CH3), 7.53 d.d (1H, 8-H, J = 10.7, J = 7.0 Hz),
3,4,5-Trifluoroanthranilic acid (Ic). Fuming nitric
acid (d = 1.54 g/cm3), 15 ml, was carefully added
under continuous stirring to 15 ml of concentrated
sulfuric acid, 5 g (28.4 mmol) of 3,4,5-trifluorobenzoic
acid was added in small portions, and the mixture was
heated for 1 h on an oil bath at 90°C in a flask
equipped with a reflux condenser. The mixture was
then cooled to 20°C and poured onto 750 g of ice.
When the ice melted, the mixture was extracted with
methylene chloride (5×30 ml), the extracts were com-
bined and dried over magnesium sulfate, and the sol-
vent was distilled off to isolate 4.6 g (20.8 mmol, 73%)
of 3,4,5-trifluoro-2-nitrobenzoic acid as colorless crys-
3
4
8.00 d.d (1H, 5-H, J = 9.7, J = 8.7 Hz). Mass spec-
trum, m/z (Irel, %): 197 (100) [M]+, 182 (86) [M – CH3]+,
155 (75), 153 (64) [M – CO2]+, 112 (37) [C6H2F2]+.
Found, %: C 54.71; H 2.56; N 6.96. C9H5F2NO2. Cal-
culated, %: C 54.83; H 2.56; N 7.10. M 197.15.
6,7-Difluoro-2-phenyl-4H-3,1-benzoxazin-4-one
(IIb). 4,5-Difluoroanthranilic acid (Ia), 0.7 g
(4.1 mmol), was dissolved in 8 ml of anhydrous meth-
ylene chloride, 1.3 ml (8.2 mmol) of triethylamine and
0.6 ml (4.1 mmol) of benzoyl chloride were added, and
the mixture was stirred for 4 h at room temperature
using a magnetic stirrer. The precipitate was filtered
off, washed with water, and recrystallized from etha-
nol. Yield 0.87 g (82%), mp 132–134°C. IR spectrum:
1
tals with mp 185–187°C. H NMR spectrum, δ, ppm:
3
4
5
7.84 d.d.d (1H, JHF = 9.8, JHF = 7.3, JHF = 2.0 Hz),
1
ν 1755 cm–1 (C=O). H NMR spectrum, δ, ppm: 7.5–
7.36 s (1H, COOH). 19F NMR spectrum, δF, ppm:
3
4
3
4
5
7.7 m (4H, 8-H, Ph), 8.04 d.d (1H, 5-H, J = 9.7, J =
8.7 Hz), 8.20 m (2H, Ph). Mass spectrum, m/z (Irel, %):
259 (44) [M]+, 215 [M – CO2]+ (26), 105 (100)
[C6H5CO]+, 77 [C6H5]+ (78). Found, %: C 64.70;
H 2.75; N 5.44. C14H7F2NO2. Calculated, %: C 64.87;
H 2.72; N 5.40. M 259.21.
–145.0 d.d.d (1F, 3-F, JFF = 19.6, JFF = 9.9, JHF
=
=
2.0 Hz), –148.2 d.d.d (1F, 4-F, 3JFF = 19.6, 19.8, 4JHF
3
4
7.3 Hz), –127.5 d.d.d (1F, 5-F, JFF = 19.8, JFF = 9.9,
3JHF = 9.8 Hz). Found, %: C 38.05; H 0.95; N 6.22.
C7H2F3NO4. Calculated, %: C 38.03; H 0.91; N 6.34.
A 100-ml round-bottom flask equipped with a mag-
netic stirrer was charged with 2.6 g (12 mmol) of
3,4,5-trifluoro-2-nitrobenzoic acid, 366 mg of palladi-
um on Sibunit (1.8 wt %) and 25 ml of methanol were
added, and the flask was triply evacuated to a residual
pressure of 100–150 mm and filled with hydrogen. The
flask was then connected to a gasholder filled with
hydrogen, and the mixture was stirred until a required
amount of hydrogen was absorbed (~810 ml). The
catalyst was filtered off and washed with 5 ml of meth-
anol, and the filtrate was evaporated under reduced
pressure (water-jet pump) to isolate 1.61 g (8.42 mmol,
70%) of acid Ic as colorless crystals which gradually
6,7,8-Trifluoro-2-methyl-4H-3,1-benzoxazin-
4-one (IIc). Anhydrous sodium acetate, 1.4 g
(17.1 mmol), was added to a solution of 0.7 g
(3.7 mmol) of 3,4,5-trifluoroanthranilic acid (Ib) in
5 ml of acetic anhydride, and the mixture was heated
for 2 h under reflux and evaporated. The residue was
treated with 25 ml of water and extracted with ethyl
acetate, the extract was dried over Na2SO4, and evap-
orated, and the residue was recrystallized from ethanol.
Yield 0.56 g (71%), mp 125–127°C. IR spectrum:
ν 1767 cm–1 (C=O). 1H NMR spectrum, δ, ppm: 2.44 s
(3H, CH3), 7.89 d.d.d (1H, 5-H, 3J = 9.5, 4J = 7.9, 5J =
2.1 Hz). Mass spectrum, m/z (Irel, %): 215 (95) [M]+,
200 (66) [M – CH3]+, 171 (100) [M –CO2]+, 130 (63)
[M – CO2 – CH3 – CN]+. Found, %: C 50.34; H 1.93;
N 6.44. C9H4F3NO2. Calculated, %: C 50.25; H 1.87;
N 6.51. M 215.31.
1
darkened on exposure to air. H NMR spectrum, δ,
3
4
5
ppm: 7.47 d.d.d (1H, JHF = 11.1, JHF = 8.6, JHF
=
2.3 Hz). 19F NMR spectrum, δF, ppm: –153.3 d.d.d
3
3
4
(1F, 5-F, JFF = 21.7, JHF = 11.3, JFF = 2.3 Hz),
–154.8 d.d.d (1F, 4-F, 3JFF = 21.7, 18.1, 4JHF = 8.6 Hz),
3
4
5
–156.7 d.d.d (1F, 3-F, JFF = 18.1, JFF = 2.3, JHF
=
6,7,8-Trifluoro-2-phenyl-4H-3,1-benzoxazin-4-
one (IId) was synthesized as described above for com-
pound IIb. Yield 0.81 g (79%), mp 191–193°C. IR
2.0 Hz). Found, %: C 44.03; H 2.13; N 7.30.
C7H4F3NO2. Calculated, %: C 43.99; H 2.11; N 7.33.
1
6,7-Difluoro-2-methyl-4H-3,1-benzoxazin-4-one
(IIa). Acetic anhydride, 4 ml, was added to 1 g
(5.8 mmol) of 4,5-difluoroanthranilic acid (Ia), and the
mixture was heated for 1 h under reflux. The mixture
was cooled and evaporated, and the residue was
spectrum: ν 1746 cm–1 (C=O). H NMR spectrum, δ,
3
ppm: 7.5–7.7 m (3H, Ph), 7.94 d.d.d (1H, 5-H, J =
4
5
10.0, J = 7.8, J = 2.1 Hz), 8.25 m (2H, Ph). Mass
spectrum, m/z (Irel, %): 277 (34) [M]+, 105 (100)
[C6H5CO]+, 77 (71) [C6H5]+. Found, %: C 60.55;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

LAEVA et al.
918
H 2.12; N 5.03. C14H6F3NO2. Calculated, %: C 60.66;
H 2.18; N 5.05. M 277.20.
N2H2], 112 (43) [C6H2F2]+. Found, %: C 51.17; H 3.25;
N 19.90. C9H7F2N3O. Calculated, %: C 51.19; H 3.34;
N 19.90. M 211.17.
5-Fluoro-2-methyl-4H-3,1-benzoxazin-4-one
(IIe) was synthesized as described above for com-
pound IIc from 2-amino-6-fluorobenzoic acid (Ic).
Compounds IVb–IVd were synthesized in a similar
way from the corresponding benzoxazinones II and
hydrazine hydrate.
1
Yield 92%, mp 111–113°C (from ethanol). H NMR
spectrum, δ, ppm: 2.50 s (3H, CH3), 7.24–7.35 m (2H,
3-Amino-6,7-difluoro-2-phenylquinazolin-4(3H)-
one (IVb). Yield 89%, mp 201–203°C (from ethanol).
1H NMR spectrum, δ, ppm: 7.57 m (3H, Ph), 7.88 d.d
3
4
7-H, 8-H), 7.84 d.d.d (1H, 6-H, J = 7.4, 10.7, J =
2.5 Hz). Mass spectrum, m/z (Irel, %): 179 (59) [M]+,
164 (100) [M – CH3]+, 135 (68) [M – CO2]+, 94 (33)
[C6H3F]+. Found, %: C 60.25; H 3.22; N 7.73.
C9H6FNO2. Calculated, %: C 60.34; H 3.38; N 7.82.
M 179.15.
3
4
(1H, 5-H, J = 12.0, J = 8.7 Hz), 8.0 m (2H, Ph),
3
4
8.76 d.d (1H, 8-H, J = 13.8, J = 7.9 Hz), 12.9 br.s
(2H, NH2). Mass spectrum, m/z (Irel, %): 273 (6) [M]+,
103 (100) [C6H5CN]+, 77 (79) [C6H5]+. Found, %:
C 57.36; H 3.71; N 14.24. C14H9F2N3O·H2O. Calculat-
ed, %: C 57.73; H 3.81; N 14.43. M 273.24.
6,7-Difluoro-2-methylquinazolin-4(3H)-one
(IIIa). A mixture of 1.7 g (8.5 mmol) of benzoxazin-
one IIa and 1.3 g (17 mmol) of anhydrous ammonium
acetate was fused at 160°C over a period of 15 min,
15 ml of ethanol and 2.5 ml of a 30% solution of
sodium hydroxide were added, and the mixture was
heated for 15 min under reflux. The mixture was
cooled and neutralized to pH 7.0 with dilute acetic
acid, and the precipitate was filtered off and recrystal-
lized from DMSO. Yield 1.27 g (76%), mp 232–
3-Amino-6,8-difluoro-7-hydrazino-2-methyl-
quinazolin-4(3H)-one (IVc). Yield 0.81 g (79%),
mp 202–204°C. IR spectrum, ν, cm–1: 3342 (NH2),
1
3275 (NH2), 3206 (NH), 1681 (C=O). H NMR spec-
trum, δ, ppm: 2.59 s (3H, CH3), 4.38 br.s (2H, NH2),
5.61 br.s (2H, NH2), 6.70 br.s (1H, NH), 7.41 d.d (1H,
3
5
5-H, J = 11.7, J = 1.4 Hz). 19F NMR spectrum, δF,
ppm: –143.43 m (1F), –126.85 m (1F). Mass spectrum,
m/z (Irel, %): 241 (100) [M]+, 196 (44) [M – CH3 – N2 –
H2]+, 142 (21) [M – CH3 – CN – N2 – H2 – CO]+.
Found, %: C 44.70; H 3.62; N 28.60. C9H9F2N5O. Cal-
culated, %: C 44.82; H 3.76; N 29.04. M 241.20.
1
234°C. H NMR spectrum, δ, ppm: 2.35 s (3H, CH3),
7.64 d.d (1H, 5-H or 8-H, J = 11.6, 7.2 Hz), 7.97 d.d
(1H, 8-H or 5-H, J = 10.0, 9.2 Hz), 12.4 br.s (1H, NH).
Mass spectrum: m/z 195 (Irel 100%) [M – H]+. Found,
%. C 55.11; H 3.09; N 14.23. C9H6N2F2O. Calculated,
%: C 55.11; H 3.08; N 14.28. M 196.16.
3-Amino-6,7,8-trifluoro-2-phenylquinazolin-
4(3H)-one (IVd). Yield 0.81 g (79%), mp 180–181°C.
1H NMR spectrum, δ, ppm: 7.40–7.59 m (4H, 5-H,
6,7-Difluoro-2-phenylquinazolin-4(3H)-one
(IIIb) was synthesized in a similar way. Yield 72%,
19
Ph), 7.98 m (2H, Ph), 10.37 br.s (2H, NH2). F NMR
1
spectrum, δF, ppm: –157.11 m (1F), –137.34 m (1F),
–136.27 m (1F). Mass spectrum, m/z (Irel, %): 291
(100) [M]+, 290 (90) [M – H]+, 262 (37) [M – H – N2]+,
130 (28) [C6HF3]+, 77 (66) [C6H5]+. Found, %:
C 58.05; H 2.82; N 14.43. C14H8F3N3O. Calculated, %:
C 57.74; H 2.77; N 14.43. M 291.23.
mp 225–227°C. H NMR spectrum, δ, ppm: 7.50 m
(3H, Ph), 7.57 d.d (1H, 5-H or 8-H, J = 11.2, 7.2 Hz),
7.95 d.d. (1H, 8-H or 5-H, J = 9.6, 9.2 Hz), 12.7 br.s
(1H, NH). Mass spectrum, m/z (Irel, %): 257 [M – H]+
(89), 276 [M + H2O]+ (100). Found, %: C 65.00;
H 3.07; N 10.89. C14H8N2F2O. Calculated, %: C 65.12;
H 3.12; N 10.85. M 258.23.
2-Acetylamino-6-fluorobenzohydrazide (B) was
synthesized as described above for compound IV from
benzoxazinone IIc and hydrazine hydrate. Yield 86%,
3-Amino-6,7-difluoro-2-methylquinazolin-4(3H)-
one (IVa). Benzoxazinone IIa, 0.4 g (2 mmol), was
dissolved in 10 ml of ethanol, 0.2 ml (4 mmol) of
98% hydrazine hydrate was added, and the mixture
was heated for 3 h under reflux. After cooling, the pre-
cipitate was filtered off and recrystallized from etha-
nol. Yield 0.4 g (95%), mp 217–219°C. IR spectrum, ν,
1
mp 150–152°C. H NMR spectrum, δ, ppm: 2.05 s
(3H, CH3), 5.5 br.s (2H, NH2), 6.68 m (1H, Harom),
7.16 m (1H, Harom), 8.16 m (1H, Harom), 11.5 br.s (1H,
NH), 12.1 br.s (1H, NH). Found, %: C 51.05; H 4.62;
N 19.83. C9H10FN3O2. Calculated, %: C 51.18; H 4.77;
N 19.90.
1
cm–1: 3303 (NH2), 1673 (C=O). H NMR spectrum, δ,
ppm: 2.49 s (3H, CH3), 5.72 s (2H, NH2), 7.45 d.d (1H,
6,7-Difluoro-2-methyl-3-(1,3-thiazol-2-yl)quinaz-
olin-4(3H)-one (Vb). a. A mixture of 0.5 g (2.6 mmol)
of benzoxazinone IIa and 0.4 g (3.4 mmol) of 1,3-thi-
azol-2-amine was heated for 30 min at 170–180°C.
3
4
3
8-H, J = 11.3, J = 7.5 Hz), 7.97 d.d (1H, 5-H, J =
4
10.2, J = 8.6 Hz). Mass spectrum, m/z (Irel, %): 211
(100) [M]+, 182 (81) [M – 29]+, 153 (38) [M – CO –
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FLUORINE-CONTAINING HETEROCYCLES: XIX.
919
4
The mixture was cooled, 4 ml of ethanol was added,
and the product was recrystallized. Yield 75%,
mp 226–228°C. IR spectrum: ν 1687 cm–1 (C=O).
1H NMR spectrum, δ, ppm: 2.25 s (3H, CH3), 7.58 d.d
(1H, 8-H, 3J = 11.1, 4J = 7.6 Hz), 7.86 d (1H, thiazole,
3J = 3.1 Hz), 7.9–8.0 m (2H, 5-H, thiazole). Mass
spectrum, m/z (Irel, %): 279 (100) [M]+, 179 (27), 153
(32) [M – C3H2NS – NCO]+, 112 (83) [C6H2F2]+.
Found, %: C 51.48; H 2.49; N 14.98. C12H7F2N3OS.
Calculated, %: C 51.61; H 2.53; N 15.05. M 279.27.
3J = 11.3, J = 7.6 Hz), 12.8 br.s (1H, NH). Mass
spectrum, m/z (Irel, %): 276 (100) [M]+, 261 (34) [M –
CH3]+, 235 (29) [M – CH3 – CN ]+, 112 (54) [C6H2F2]+.
Found, %: C 56.61; H 3.57; N 20.10. C13H10F2N4O.
Calculated, %: C 56.52; H 3.65; N 20.28. M 276.25.
6,7-Difluoro-2-methyl-3-(pyridin-2-yl)quinazo-
lin-4(3H)-one (Ve). a. Reaction time 40 min, yield
73%; b. Yield 68%. mp 208–210°C (from DMSO). IR
spectrum: ν 1678 cm–1 (C=O). H NMR spectrum, δ,
1
ppm: 2.14 s (3H, CH3), 7.55–7.62 m (3H, pyridine),
3
4
Compounds Va and Vc–Vf were synthesized in
a similar way from benzoxazinone IIa and 5-tert-
butyl-1,2-oxazol-3-amine, 1H-1,2,4-triazol-5-amine,
3-methyl-1H-pyrazol-5-amine, and pyridin-2-amine,
respectively.
7.96 m (1H, 8-H), 8.06 d.d (1H, 5-H, J = 9.7, J =
8.5 Hz), 8.66 m (1H, pyridine). Mass spectrum, m/z
(Irel, %): 273 (32) [M]+, 272 (100) [M – H]+, 112 (22)
[C6H2F2]+, 78 (62) [C4H4N]+. Found, %: C 61.31;
H 3.52; N 15.27. C14H9F2N3O. Calculated, %: C 61.54;
H 3.32; N 15.38. M 273.24.
b. A solution of 0.7 g (3.6 mmol) of benzoxazinone
IIa and 0.56 g (5.5 mmol) of 1,3-thiazol-2-amine in
7 ml of DMF was heated for 1 h under reflux. The
mixture was cooled and diluted with 6 ml of water, and
the precipitate was filtered off and recrystallized from
ethanol. Yield 68%.
3-(5-tert-Butyl-1,2-oxazol-3-yl)-6,7-difluoro-
2-phenylquinazolin-4(3H)-one (Vf). Reaction time
20 min. Yield 83%, mp 181–183°C (from ethanol).
1H NMR spectrum, δ, ppm: 1.27 s (9H, t-Bu), 6.38 s
(1H, 4′-H), 7.29–7.45 m (5H, Ph), 7.72 d.d (1H, 8-H,
4
3
3J = 10.7, J = 7.0 Hz), 8.07 d.d (1H, 5-H, J = 10.3,
4J = 8.8 Hz). Mass spectrum, m/z (Irel, %): 381 (27)
[M]+, 324 (43) [M – C(CH3)3]+, 296 (100) [M –
C(CH3)3 – CO]+, 57 (53) [C(CH3)3]+. Found, %:
C 65.65; H 4.39; N 10.95. C21H17F2N3O2. Calculated,
%: C 66.14; H 4.49; N 11.02. M 381.39.
Compounds Vd and Ve were synthesized in a simi-
lar way.
3-(5-tert-Butyl-1,2-oxazol-3-yl)-6,7-difluoro-2-
methylquinazolin-4(3H)-one (Va). Reaction time
20 min. Yield 80%, mp 140–142°C (from ethanol).
1H NMR spectrum, δ, ppm: 1.43 s (9H, t-Bu), 2.29 s
3
(3H, CH3), 6.45 s (1H, 4′-H), 7.56 d.d (1H, 8-H, J =
2-Acetylamino-N-(5-tert-butyl-1,2-oxazol-3-yl)-6-
fluorobenzamide (VIc) and 3-(5-tert-butyl-1,2-oxa-
zol-3-yl)-5-fluoro-2-methylquinazolin-4(3H)-one
(Vg) (1:1 mixture) were synthesized as described
above (method a) from benzoxazinone IIe and 5-tert-
butyl-1,2-oxazol-3-amine (reaction time 1 h).
4
3
4
11.1, J = 7.3 Hz), 7.96 d.d (1H, 5-H, J = 10.2, J =
8.5 Hz). Mass spectrum, m/z (Irel, %): 319 (74) [M]+,
262 (85) [M – C(CH3)3]+, 112 (31) [C6H2F2]+, 57 (100)
[C(CH3)3]+. Found, %: C 59.99; H 4.64; N 13.10.
C16H15F2N3O2. Calculated, %: C 60.18; H 4.74;
N 13.16. M 319.31.
1
Compound Vg. H NMR spectrum, δ, ppm: 1.37 s
(9H, t-Bu), 2.28 s (3H, CH3), 6.67 s (1H, CH), 7.21 m
(1H, 6-H), 7.78 m (1H, 8-H).
6,7-Difluoro-2-methyl-3-(1H-1,2,4-triazol-5-yl)-
quinazolin-4(3H)-one (Vc). Reaction time 40 min.
Yield 64% (from ethanol), mp > 300°C (from DMSO).
1H NMR spectrum, δ, ppm: 2.18 s (3H, CH3), 7.59 d.d
1
Compound VIc. H NMR spectrum, δ, ppm: 1.32 s
3
4
(9H, t-Bu), 2.06 s (3H, CH3), 6.45 s (1H, 4′-H), 6.98–
7.75 m (3H, Harom), 9.60 br.s (1H, NH2), 11.30 br.s
(1H, NH2).
(1H, 8-H, J = 11.0, J = 7.0 Hz), 7.99 m (1H, 5-H),
8.67 s (1H, 3′-H), 14.5 br.s (1H, NH). Mass spectrum,
m/z (Irel, %): 263 (100) [M]+, 236 (20) [M – CN]+, 153
(28) [M – C2H2N3 – NCO]+, 112 (53) [C6H2F2]+.
Found, %: C 49.82; H 2.68; N 26.64. C11H7F2N5O.
Calculated, %: C 50.20; H 2.68; N 26.61. M 263.21.
2-Acetylamino-N-(4,6-dimethylpyrimidin-2-yl)-
4,5-difluorobenzamide (VIa). Yield 79%, mp 190–
192°C (from DMSO). H NMR spectrum, δ, ppm:
1
2.21 s (3H, CH3), 2.30 s (6H, CH3), 6.30 s (1H, 5′-H),
6,7-Difluoro-2-methyl-3-(3-methyl-1H-pyrazol-
5-yl)quinazolin-4(3H)-one (Vd). a. Reaction time
35 min, yield 78%; b. Yield 74%. mp 200–202°C
(from ethanol). 1H NMR spectrum, δ, ppm: 2.37 s (3H,
CH3), 2.50 s (3H, CH3), 6.03 s (1H, 4′-H), 7.52 d.d
3
4
6.37 br.s (1H, NH), 7.86 d.d (1H, 5-H, J = 11.3, J =
3
4
9.5 Hz), 8.56 d.d (1H, 8-H, J = 13.8, J = 7.7 Hz),
11.43 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 155
(83) [M – HtNH – COCH3]+, 123 (100) [HtNH]+, 112
(21) [C6H2F2]+. Found, %: C 56.30; H 4.48; N 17.42.
3
4
(1H, 5-H, J = 10.3, J = 8.8 Hz), 7.94 d.d (1H, 8-H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

LAEVA et al.
920
4. Fray, M.J., Allen, P., and Bradley, P.R., Heterocycles,
2006, vol. 67, p. 489.
5. Rocco, S.A., Barbarini, J.E., and Ritter, R., Synthesis,
C15H14F2N4O2. Calculated, %: C 56.25; H 4.41;
N 17.49. M 320.30.
2-Acetylamino-6-fluoro-N-(pyridin-2-yl)benz-
amide (VIb) was synthesized from benzoxazinone
IIc and pyridin-2-amine. Yield 81% (a), 76% (b);
mp >250°C.
2004, p. 429.
6. Ciardiello, F., Drugs, 2000, vol. 60, p. 25.
7. Boyce, R.S., Aurrecoechea, N., Chu, D., and Smith, A.,
WO Patent Appl. no. 0399818, 2003; Chem. Abstr.,
2004, vol. 140, no. 16739f.
c. Pyridin-2-amine, 0.3 g (3 mmol), was added to
a solution of 0.3 g (1.8 mmol) of compound IIc in 6 ml
of anhydrous pyridine, the mixture was heated for 10 h
under reflux and cooled, and the precipitate was fil-
tered off and recrystallized from DMSO. Yield 0.51 g
8. Abdel-Jalil, R.J., Aldoqum, H.M., Ayoub, M.T., and
Voelter, W., Heterocycles, 2005, vol. 65, p. 2061.
9. Na, Y.H., Hong, S.H., Lee, J.H., Park, W.K., Back, D.J.,
Koh, H.Y., Cho, Y.S., Choo, H., and Pae, A.N., Bioorg.
Med. Chem., 2008, vol. 16, p. 2570.
10. Connoly, D.J., Cusack, D., O’Sullivan, T.P., and
Cuiry, P.J., Tetrahedron, 2005, vol. 61, p. 1153.
11. Xue, S., Mckenna, J., Shich, W.C., and Repic, O.,
1
(91%), mp 210–212°C. H NMR spectrum, δ, ppm:
3
2.22 s (3H, CH3), 7.16 d.d.d (1H, 5′-H, J = 8.0, 5.0,
4J = 0.5 Hz), 7.29 d.d (1H, 3′-H, 3J = 8.0, 4J = 0.5 Hz),
3
4
7.81 t.d (1H, 4′-H, J = 8.0, J = 1.5 Hz), 7.87 m
(1H, FC6H3), 8.08 m (1H, FC6H3), 8.41 d.d (1H, 6′-H,
J. Org. Chem., 2004, vol. 69, p. 6474.
12. Shi, D., Rong, L., Wang, J., Zuang, Q., Wang, X., and
4
3J = 5.0, J = 1.5 Hz), 9.08 m (1H, FC6H3), 11.5 br.s
(1H, NH), 13.7 br.s (1H, NH). Found, %: C 61.45;
H 4.32; N 15.43. C14H12FN3O2. Calculated, %:
C 61.53; H 4.43; N 15.38.
Hu, H., Synth. Commun., 2004, vol. 34, p. 1759.
13. Larksarp, C. and Alper, H., J. Org. Chem., 2000,
vol. 65, p. 2773.
14. Reddy, P.S., Reddy, P.P., and Vasantha, T., Heterocycles,
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 06-03-32 791), by the Council for Grants at
the President of the Russian Federation (project
no. NSh-9178.2006.3), by the CRDF (BRHE, grant
no. BP2M05), and by the Presidium of Siberian Divi-
sion of the Russian Academy of Sciences (Program for
Complex Integration Projects, project no. 5.8.5).
2003, vol. 60, p. 183.
15. Undheim, T. and Benneche, T., Comprehensive Hetero-
cyclic Chemistry II, Katritzky, A.R., Rees, C.W., and
Scriven, E.F.V., Oxford: Pergamon, 1996, vol. 6, p. 93.
16. Zhou, Y., Murphy, D.E., Sun, Z.-X., and Gregor, V.E.,
Tetrahedron Lett., 2004, vol. 45, p. 8049.
17. Parkanyi, C., Yuan, H.L., Stromberg, B.H.E., and Even-
zahav, A., J. Heterocycl. Chem., 1992, vol. 29, p. 749.
18. Layeva, A.A., Nosova, E.V., Lipunova, G.N., Trasha-
khova, T.V., and Charushin, V.N., J. Fluorine Chem.,
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19. Laeva, A.A., Nosova, E.V., Lipunova, G.N., Trasha-
khova, T.V., and Charushin, V.N., Izv. Ross. Akad. Nauk,
Ser. Khim., 2007, p. 1758.
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