Synthesis of 5-and 7-fluoroquinazolin-4(1H)-ones

Article abstract of DOI:10.1007/s11172-007-0283-x

5-Fluoroquinazoline-2,4-diones and their 2-thio analogs were obtained from 6-fluoroanthranilic acid. Two convenient routes to 5-fluoroquinazolin-4-ones involved cyclocondensation of 6-fluoroanthranilamide with acid chlorides (anhydrides) or with aromatic (heterocyclic) aldehydes. A method for the synthesis of 7-fluoroquinazolin-4-one from 2,4-difluorobenzoic acid was proposed.

Full text of DOI:10.1007/s11172-007-0283-x

Russian Chemical Bulletin, International Edition, Vol. 56, No. 9, pp. 1821—1827, September, 2007
1821
Synthesis of 5ꢀ and 7ꢀfluoroquinazolinꢀ4(1H )ꢀones*
A. A. Layeva,a E. V. Nosova,a G. N. Lipunova,a T. V. Trashakhova,a and V. N. Charushinb
ꢀ
aUral State Technical University,
19 ul. Mira, 620002 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 740 458. Eꢀmail: ndvd@unets.ru
bInstitute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Eꢀmail: charushin@ios.uran.ru
5ꢀFluoroquinazolineꢀ2,4ꢀdiones and their 2ꢀthio analogs were obtained from 6ꢀfluoroꢀ
anthranilic acid. Two convenient routes to 5ꢀfluoroquinazolinꢀ4ꢀones involved cycloꢀ
condensation of 6ꢀfluoroanthranilamide with acid chlorides (anhydrides) or with aromatic
(heterocyclic) aldehydes. A method for the synthesis of 7ꢀfluoroquinazolinꢀ4ꢀone from 2,4ꢀdiꢀ
fluorobenzoic acid was proposed.
Key words: fluoroꢀcontaining quinazolinꢀ4ꢀones, quinazolineꢀ2,4ꢀdione, 2ꢀaminoꢀ6ꢀ
fluorobenzonitrile, 6ꢀfluoroanthranilamide, 6ꢀfluoroanthranilic acid, 2,4ꢀdifluorobenzonitrile,
cyclocondensation, Schiff bases.
Quinazolinꢀ4(1H )ꢀones constitute an important class
of heterocyclic compounds. Some of them can inhibit
various enzymes and show antiviral or other biological
activity.1—10 In turn, many fluoroꢀcontaining azaheteroꢀ
cycles are superior to nonfluorinated analogs in physioꢀ
logical effect.11—15 For instance, some quinazolinone deꢀ
rivatives monofluorinated at the benzene ring are promisꢀ
ing for use in medicinal chemistry: 6ꢀfluoroquinazolinones
are efficient for treatment of obesity and diabetes16,17 and
are neuroprotectors and inhibitors of the AMPA recepꢀ
tor,18—22 5ꢀ and 7ꢀfluoroquinazolinones show antitumor
activity,23,24 and 8ꢀfluoroquinazolinones are effective
against human cytomegalovirus.25
acetic anhydride into 5ꢀfluoroꢀ2ꢀmethylꢀ3,1ꢀbenzoxazinꢀ
4ꢀone; the reactions of the latter with 2ꢀaminoꢀ1,3,4ꢀ
thiadiazoles and DLꢀαꢀaminoꢀεꢀcaprolactam lead to
3ꢀsubstituted 5ꢀfluoroquinazolinꢀ4(3H )ꢀones.30 In addiꢀ
tion, treatment of 2ꢀaminoꢀ3ꢀfluorobenzonitrile with forꢀ
mic acid in the presence of sulfuric acid affords 8ꢀfluoroꢀ
quinazolinꢀ4(1H )ꢀone in 88% yield (see Ref. 31).
The goal of the present work was to search for simple
synthetic routes to 5ꢀ and 7ꢀfluoroquinazolinꢀ4ꢀones conꢀ
taining various substituents in position 2, which is of inꢀ
terest for revealing correlations between the structures
and biological activities of fluoroꢀcontaining quinazoꢀ
linones.
Despite numerous publications concerned with the
synthesis of quinazolinꢀ4(1H )ꢀones,26 a search for novel
approaches to their design remains of current interest in
heterocyclic chemistry. In particular, the synthesis of
monofluorinated quinazolinꢀ4(1H )ꢀones is illustrated
with only few examples. For instance, monofluorinated
2ꢀstyrylquinazolinꢀ4(3H )ꢀones have been obtained by
reactions of fluoroꢀcontaining 2ꢀaminobenzonitriles with
3ꢀphenylacryloyl chloride followed by baseꢀcatalyzed oxiꢀ
dative cyclization of intermediate amides.27,28 4ꢀBenzylꢀ
aminoꢀ5ꢀfluoroquinazoline has been synthesized from
N´ꢀ(2ꢀcyanoꢀ3ꢀfluorophenyl)ꢀN,Nꢀdimethylformamidine
and benzylamine under microwave radiation.29 Another
known route to 5ꢀfluoroquinazolinones involves a transꢀ
formation of 6ꢀfluoroanthranilic acid under the action of
Earlier, we have obtained 6ꢀfluoroꢀ and 6,7,8ꢀtriꢀ
fluoroquinazolinꢀ4(1H )ꢀones from 2ꢀfluorobenzoyl chloꢀ
rides and Sꢀethylisothiourea as a N,N´ꢀdinucleophile.32
This method was successfully employed for the synthesis
of 2ꢀethylthioꢀ7ꢀfluoroquinazolinone (Scheme 1). For this
purpose, we treated 2,4ꢀdifluorobenzoic acid (1) with
thionyl chloride to give 2,4ꢀdifluorobenzoyl chloride 2.
A roomꢀtemperature reaction of chloride 2 with Sꢀethylꢀ
isothiourea hydroiodide in CH2Cl2 in the presence of
triethylamine afforded NꢀaroylꢀSꢀethylisothiourea 3 in
81% yield. Reflux of (2ꢀfluorobenzoyl)thiourea 3 in
dry DMF for 5 h gave 2ꢀethylthioꢀ7ꢀfluoroquinazolinꢀ
1
4(1H )ꢀone (4). The H NMR spectrum of compound 4
shows signals for aromatic protons, a broadened oneꢀ
proton singlet for the NH group, and signals for the ethyl
group. The mass spectrum of compound 4 contains a
100%ꢀintensity peak with m/z 137 corresponding to the
ion [M – EtS – CN]+; the intensity of the molecular ion
* Dedicated to Academician G. A. Abakumov on the occasion
of his 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 9, pp. 1758—1764, September, 2007.
1066ꢀ5285/07/5609ꢀ1821 © 2007 Springer Science+Business Media, Inc.

1822
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 9, September, 2007
Layeva et al.
peak with m/z 224 was 82%. The structure of 2ꢀ(ethylꢀ
thio)quinazolinꢀ4ꢀone was additionally confirmed by the
peak of the ion [M – EtS – CN – CO]+.
ing was required and the yields of products were lower.
The structures of compounds 6 and 7 were proved by
1H NMR spectroscopy and mass spectrometry. Having
the electronꢀwithdrawing F atom, the starting anthranilic
acid 5 is more reactive than nonfluorinated anthranilic
acid and hence reacts under milder conditions (shorter
reaction time and lower temperature).
Scheme 1
We studied the possibility of obtaining monofluoriꢀ
nated quinazolinꢀ4ꢀones from 2ꢀaminoꢀ6ꢀfluorobenzoꢀ
nitrile (8). In fact, treatment of compound 8 with formic
acid in the presence of H2SO4 gave 5ꢀfluoroquinazolinꢀ4ꢀ
one 9 (Scheme 3). However, this reaction is applicable
only to the synthesis of 2ꢀunsubstituted quinazolinꢀ4(1H )ꢀ
ones. Acid hydrolysis of nitrile 8 yielded 2ꢀaminoꢀ6ꢀ
fluorobenzamide (10), which allows wide variation of the
substituent in position 2 of quinazolinones. For instance,
2ꢀ(quinolinꢀ2ꢀyl)quinazolinꢀ4ꢀone has been synthesized
by acylation of 2ꢀaminobenzamide with quinolineꢀ2ꢀcarꢀ
bonyl chloride followed by cyclization.34
Analogously,34 starting from 6ꢀfluoroanthranilamide
(10), we obtained fluoroꢀcontaining quinazolinꢀ4(1H )ꢀ
ones 12a—d (Scheme 3). Compound 10 was refluxed with
acetic anhydride for 3 h or kept with benzoyl, nicotinoyl,
and isonicotinoyl chlorides at room temperature in the
presence of triethylamine. Intermediates 11a—d were not
characterized; they underwent in situ cyclization on shortꢀ
time reflux (5—10 min) in 5% KOH. The structures of
2ꢀAminoꢀ6ꢀfluorobenzoic acid is another easily acꢀ
cessible synthon for construction of monofluorinated
heterocycles. It is known that quinazolineꢀ2,4ꢀdiones and
their 2ꢀthio analogs are most simply obtained by condenꢀ
sation of anthranilic acid with urea and thiourea derivaꢀ
tives.26,33 This approach was successfully employed for
the synthesis of 5ꢀfluoroquinazolinꢀ4ꢀones: fusion of
6ꢀfluoroanthranilic acid (5) with thiourea, phenylthioꢀ
urea, and urea at 160—170 °C gave quinazolinꢀ4ꢀones
6a,b and 7, respectively (Scheme 2). Phenylthiourea reꢀ
acted most readily; in the reactions of 6ꢀfluoroanthranilic
acid with unsubstituted urea and thiourea, prolonged heatꢀ
1
compounds 9 and 12a—d were confirmed by H NMR
and mass spectra. In the mass spectra of compounds 9
and 12a, the intensity of the molecular ion peak was 100%.
For compounds 12b—d, the peak with m/z 137 correꢀ
sponding to the ion [M – RCN]+ (where R is the subꢀ
Scheme 3
Scheme 2
R = H (6a), Ph (6b)
11, 12: R = Me (a), Ph (b), 4ꢀpyridyl (c), 3ꢀpyridyl (d).

5ꢀ and 7ꢀfluoroquinazolinꢀ4(1H )ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 9, September, 2007
1823
stituent in position 2 of the quinazolinone) has a 100%
intensity.
benzaldehyde and 4ꢀtrifluoromethylbenzaldehyde under
the same conditions for 40 min gave quinazolinꢀ4(1H )ꢀ
ones 12k,l.
2ꢀAminoꢀ6ꢀfluorobenzamide (10) was also used for
the synthesis of bis(4ꢀoxoquinazolinꢀ2ꢀyl)pyridine 13. For
this purpose, pyridineꢀ2,6ꢀdicarbonyl dichloride was kept
with 2ꢀaminobenzamide 10 in the presence of NEt3 and
then the intermediate was heated in 5% KOH. The resultꢀ
ing 2,6ꢀbis(5ꢀfluoroꢀ4ꢀoxoꢀ1,4ꢀdihydroquinazolinꢀ2ꢀ
yl)pyridine 13 is a structural analog of 1,3ꢀbis(4ꢀoxoꢀ1,4ꢀ
dihydroquinazolinꢀ2ꢀyl)benzene, which exhibits a broad
spectrum of antibacterial activity.35 The structure of prodꢀ
uct 13 was confirmed by 1H NMR spectroscopy and mass
spectrometry.
Scheme 4
12,14: R — 2ꢀfuryl (12e, 14a), 2ꢀpyridyl (12f, 14b),
2ꢀhydroxyphenyl (12g, 14c), 2ꢀhydroxyꢀ5ꢀnitrophenyl (12h, 14d),
4ꢀmethoxyphenyl (12i, 14e), 2,4ꢀdihydroxyphenyl (12j),
4ꢀfluorophenyl (12k), 4ꢀtrifluoromethylphenyl (12l)
To extend the range of substituents in position 2 of
5ꢀfluoroquinazolinꢀ4ꢀones, we used aromatic and heteroꢀ
cyclic aldehydes in the reaction with 2ꢀaminoꢀ6ꢀfluoroꢀ
benzamide. Note that the synthesis of 2ꢀsubstituted
quinazolinones from 2ꢀaminobenzamide and aldehydes
has been first proposed by AbdelꢀJalil et al.36
1
The H NMR spectra of compounds 12e—l are conꢀ
sistent with their structures. Their mass spectra contain a
characteristic intense peak of the ion [M – RCN – CO]+.
In an earlier1,37 described reaction of 2ꢀaminobenzoꢀ
nitrile with phenyl isothiocyanate, 4ꢀphenylaminoꢀ
quinazolineꢀ2ꢀthiol has been obtained via rearrangement
of intermediate 4ꢀiminoꢀ3ꢀphenylquinazoline for 12 h.
We found that a reaction of 2ꢀaminoꢀ6ꢀfluorobenzoꢀ
nitrile (8) with phenyl isothiocyanate at 100 °C for 3 h
gives 5ꢀfluoroꢀ4ꢀphenylaminoquinazolineꢀ2ꢀthiol (15)
(Scheme 5). The 1H NMR spectrum of compound 15
shows signals for the aromatic protons, a broadened sinꢀ
glet at δ 12.74 for the SH group, and a doublet at δ 9.01
A reaction of 2ꢀaminoꢀ6ꢀfluorobenzamide (10) with
furfural in boiling ethanol easily gave the Schiff base 14a;
its structure was confirmed by 1H NMR data (Scheme 4).
When heated in methanol in the presence of CuCl2
for 3 h, aldimine 14a underwent oxidative cyclization
into quinazolinꢀ4ꢀone 12e. The 1H NMR spectrum of
compound 12e shows no signals for the amide group and
the N=CH group; instead, a broadened singlet for the
NH group appears at δ 12.37. The "one pot" synthesis of
quinazolinꢀ4ꢀone 12e can be carried out by refluxing
2ꢀaminoꢀ6ꢀfluorobenzamide (10) and furfural in ethanol
in the presence of CuCl2. A reaction of 2ꢀaminoꢀ6ꢀ
fluorobenzamide (10) with pyridineꢀ2ꢀcarboxaldehyde
gave compound 14b undergoing cyclization into 2ꢀ(pyriꢀ
dinꢀ2ꢀyl)quinazolinꢀ4ꢀone 12f on heating in acetonitrile
in the presence of DDQ.
Scheme 5
To obtain monofluorinated quinazolinꢀ4ꢀones conꢀ
taining various aryl substituents in position 2, we carried
out reactions of 2ꢀaminoꢀ6ꢀfluorobenzamide (10) with
salicylaldehyde, 5ꢀnitrosalicylaldehyde, and anisaldehyde.
The resulting Schiff bases 14c—e easily underwent cyꢀ
clization into the corresponding quinazolinones 12g—i
on heating with CuCl2 for 40 min. 2ꢀ(2,4ꢀDihydroxyꢀ
phenyl)ꢀ5ꢀfluoroꢀ1Hꢀquinazolinꢀ4ꢀone (12j) was syntheꢀ
sized by heating 2ꢀaminoꢀ6ꢀfluorobenzamide (10) with
benzeneꢀ1,3ꢀdicarbaldehyde in the presence of CuCl2
for 2 h. Reactions of benzamide 10 with 4ꢀfluoroꢀ

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Layeva et al.
Compounds 6b and 7 were obtained analogously from
2ꢀaminoꢀ6ꢀfluorobenzoic acid (5) and phenylthiourea or urea,
respectively.
(JH,F = 15.3 Hz) for the NH proton. In the mass spectrum
of compound 15, the peak of the ion [M – H]+ has the
intensity I = 100%. As with quinazolinones 6, 7, and 12,
the main fragmentation pathway of quinazoline 15 inꢀ
volves detachment of the fragment [RCN] (R = S)
from [M]+. Introduction of a fluorine atom into 2ꢀaminoꢀ
benzonitrile, as well as into anthranilic acid, makes it
possible to obtain the corresponding quinazolines under
milder conditions (at lower temperature and shorter reacꢀ
tion time).
5ꢀFluoroꢀ4ꢀoxoꢀ3ꢀphenylꢀ1,2,3,4ꢀtetrahydroquinazolineꢀ2ꢀ
thione (6b). The reaction mixture was heated for 1 h. Yield 70%,
m.p. 250—252 °C (from ethanol). 1H NMR (DMSOꢀd6), δ:
6.99 (t, H (7), 3J = 8.4 Hz); 7.19 (d, 2 H, Ph, 3J = 6.7 Hz); 7.28
3
(d, 1 H, H(8), J = 8.2 Hz); 7.37—7.52 (m, 3 H, Ph); 7.69 (m,
1 H, H(6)); 12.99 (br.s, 1 H, N(1)H). MS, m/z (Irel (%)):
272 [M]+ (84), 271 [M – H]+ (100), 137 [M – Ph – NCS]+
(43), 110 [(M + H) – PhNCS – CO]+ (56), 77 [C6H5]+ (49).
Found (%): C, 61.55; H, 3.39; N, 10.97. C14H9FN2OS. Calcuꢀ
lated (%): C, 61.75; H, 3.34; N, 10.29.
5ꢀFluoroquinazolineꢀ2,4(1H,3H )ꢀdione (7). The reaction
mixture was heated for 3 h. Yield 50%, m.p. 320—322 °C (from
ethanol). 1H NMR (DMSOꢀd6), δ: 6.80 (dd, 1 H, H(7), 3J =
8.3 Hz, 3J = 10.3 Hz); 6.98 (d, 1 H, H(8), 3J = 8.3 Hz); 7.52
(ddd, 1 H, H(6), 4J = 2.8 Hz, 3J = 6.8 Hz, 3J = 11.0 Hz); 11.11
(br.s, 2 H, N(1)H, N(3)H). MS, m/z (Irel (%)): 180 [M]+ (85),
137 [M – CO – NH]+ (98), 110 [M – OCN – CO]+ (100), 82
(30). Found (%): C, 53.15; H, 2.89; N, 15.53. C8H5FN2O2.
Calculated (%): C, 53.33; H, 2.80; N, 15.55.
To sum up, the methods we proposed for the design of
various 2ꢀsubstituted fluoroquinazolinꢀ4ꢀones extend the
scope of the synthesis of fluoroꢀcontaining azaheteroꢀ
cycles.
Experimental
1
H NMR spectra were recorded on Bruker WMꢀ250 and
Bruker DRXꢀ400 spectrometers (250.14 and 400.13 MHz, reꢀ
spectively) with Me4Si as the internal standard. Mass spectra
were recorded on a Varian MAT 311A spectrometer (acceleratꢀ
ing voltage 3 kV, cathode emission current 300 µA, ionizing
energy 70 eV, direct inlet probe).
2,4ꢀDifluorobenzoyl chloride (2) was prepared from 2,4ꢀdiꢀ
fluorobenzoic acid (1) and thionyl chloride in toluene as deꢀ
scribed earlier.38
5ꢀFluoroquinazolinꢀ4(1H )ꢀone (9). A suspension of 2ꢀaminoꢀ
6ꢀfluorobenzonitrile (8) (2 g, 14.6 mmol) in 85% HCOOH
(15 mL) was added in portions to a mixture of conc. H2SO4
(0.8 mL) and 85% HCOOH (5 mL). The reaction mixture was
heated at 105—115 °C for 50 min. On cooling, the mixture was
poured onto ice and kept for 15 min. The precipitate that formed
was filtered off, washed with water, and recrystallized from ethaꢀ
nol. The yield of quinazolinone 9 was 1.51 g (64%), m.p.
210—212 °C. 1H NMR (DMSOꢀd6), δ: 6.70 (br.s, 1 H, NH);
7.22 (t, 1 H, H(7), 3J = 8.3 Hz); 7.51 (d, 1 H, H(8), 3J =
8.3 Hz); 7.79 (m, 1 H, H(6)); 8.31 (s, 1 H, H(2)). MS,
m/z (Irel (%)): 164 [M]+ (100), 163 [M – H]+ (35), 137
[M – CN]+ (22), 136 [M – HCN]+ (36), 110 [M – RCN – CO]+
(29), 108 (30). Found (%): C, 58.55; H, 3.09; N, 17.13.
C8H5FN2O. Calculated (%): C, 58.53; H, 3.08; N, 17.07.
2ꢀAminoꢀ6ꢀfluorobenzamide (10). A solution of 2ꢀaminoꢀ6ꢀ
fluorobenzonitrile (8) (1.5 g, 11.0 mmol) in conc. H2SO4
(7.5 mL) was stirred with a magnetic stirring bar at 50—55 °C
for 2 h. The reaction mixture was poured into water (300 mL)
and neutralized with soda. The product was extracted with
CH2Cl2 and the extract was dried over Na2SO4. The solvent was
removed and the residue was recrystallized from hexane. The
yield of compound 10 was 0.9 g (54%), m.p. 87—89 °C. 1H NMR
(DMSOꢀd6), δ: 5.77 (br.s, 1 H, NH); 6.11 (br.s, 2 H, NH2);
1ꢀ(2,4ꢀDifluorobenzoyl)ꢀ2ꢀethylisothiourea (3). Triethylꢀ
amine (2.7 mL, 19.4 mmol) and a solution of 2,4ꢀdifluorobenzoyl
chloride 2 (19.6 mL, 9.7 mmol) in toluene (6 mL) were added to
a stirred suspension of Sꢀethylisothiourea hydroiodide (2.3 g,
9.7 mmol) in anhydrous CH2Cl2 (20 mL). The reaction mixture
was kept at room temperature for 24 h and then concentrated.
The residue was washed with water and recrystallized from
ethanol. The yield of compound 3 was 1.92 g (81%), m.p.
1
3
144—146 °C. H NMR (DMSOꢀd6), δ: 1.32 (t, 3 H, CH3, J =
3
7.4 Hz); 3.11 (q, 2 H, SCH2, J = 7.4 Hz); 7.13, 8.07 (both m,
2 H and 1 H, C6H3F2); 9.52 (br.s, 2 H, HN=C—NH—).
Found (%): C, 48.89; H, 4.13; N, 11.39. C10H10F2N2OS. Calꢀ
culated (%): C, 49.16; H, 4.13; N, 11.47.
2ꢀEthylthioꢀ7ꢀfluoroquinazolinꢀ4(1H )ꢀone (4). A solution of
isothiourea 3 (0.7 g, 2.9 mmol) in anhydrous DMF (6 mL) was
refluxed for 4 h and then concentrated. The residue was recrysꢀ
tallized from ethanol. The yield of quinazolinone 4 was 0.23 g
(35%). 1H NMR (DMSOꢀd6), δ: 1.40 (t, 3 H, CH3, 3J = 7.5 Hz);
3.19 (q, 2 H, SCH2, 3J = 7.5 Hz); 7.13 (m, 2 H, H(5) and H(8));
8.07 (m, 1 H, H(6)); 12.37 (br.s, 1 H, NH). MS, m/z (Irel (%)):
224 [M]+ (82), 196 [M – CO]+ (37), 137 [M – EtS – CN]+
(100), 108 (96). Found (%): C, 53.25; H, 4.09; N, 12.93.
4
3
3
6.35 (ddd, 1 H, H(4), J = 1.0 Hz, J = 7.8 Hz, J = 13.2 Hz);
6.45 (d, 1 H, H(3), 3J = 8.5 Hz); 6.65 (br.s, 1 H, NH); 7.12
(ddd, 1 H, H(5), 4J = 2.0 Hz, 3J = 7.5 Hz, 3J = 14.5 Hz).
5ꢀFluoroꢀ2ꢀmethylquinazolinꢀ4(1H )ꢀone (12a). A solution of
2ꢀaminoꢀ6ꢀfluorobenzamide (10) (0.7 g, 4.5 mmol) in acetic
anhydride (3 mL) was refluxed for 3 h. The reaction mixture was
cooled and neutralized with a solution of soda to pH 6—7.
Intermediate 11a was extracted with ethyl acetate. The extract
was dried over Na2SO4. The solvent was removed and the resiꢀ
due was dissolved in ethanol (6 mL). The solution was refluxed
with 5% KOH (13 mL) for 5 min. On cooling, the reaction
mixture was neutralized with dilute acetic acid and the product
was extracted with chloroform. The extract was dried over
Na2SO4 and concentrated and the residue was recrystallized
from ethanol. The yield of quinazoline 12a was 0.65 g (92%),
C
10H9FN2OS. Calculated (%): C, 53.55; H, 4.05; N, 12.49.
5ꢀFluoroꢀ4ꢀoxoꢀ1,2,3,4ꢀtetrahydroquinazolineꢀ2ꢀthione (6a).
A mixture of 2ꢀaminoꢀ6ꢀfluorobenzoic acid 5 (0.24 g, 3.2 mmol)
and thiourea was heated at 160—170 °C for 2 h. On cooling,
ethanol (3 mL) was added and the product was recrystallized. The
yield of quinazolinone 6a was 0.25 g (47%), m.p. 102—104 °C.
1H NMR (DMSOꢀd6), δ: 6.92, 7.18, 7.38 (all m, 1 H each,
H(6), H(8), H(7)); 7.81 (br.s, 2 H, N(1)H, N(3)H). Found (%):
C, 49.04; H, 2.59; N, 14.23. C8H5FN2OS. Calculated (%):
C, 48.97; H, 2.57; N, 14.28.

5ꢀ and 7ꢀfluoroquinazolinꢀ4(1H )ꢀones
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 9, September, 2007
1825
m.p. 251—253 °C. 1H NMR (DMSOꢀd6), δ: 2.36 (s, 3 H, CH3);
1H NMR (DMSOꢀd6), δ: 5.68 (s, 1 H, NH); 6.29—6.37 (m,
3 H, NH and 2 H, furyl); 6.58 (d, 1 H, H(3), 3J = 8.3 Hz); 7.15,
7.38, 7.51 (all m, 1 H each, H(4), H(5) and Hfuryl); 8.25 (s, 1 H,
N=CH). Found (%): C, 62.10; H, 3.89; N, 12.13. C12H9FN2O2.
Calculated (%): C, 62.06; H, 3.91; N, 12.07.
Compounds 14b—e were obtained analogously from
amide 10 and pyridineꢀ2ꢀcarboxaldehyde, salicylaldehyde,
2ꢀhydroxyꢀ5ꢀnitrobenzaldehyde, or 4ꢀmethoxybenzaldehyde, reꢀ
spectively.
3
3
7.08 (dd, 1 H, H(7), J = 8.0 Hz, J = 10.8 Hz); 7.34 (d, 1 H,
H(8), 3J = 8.3 Hz); 7.67 (m, 1 H, H(6)); 12.16 (br.s, 1 H, NH).
MS, m/z (Irel (%)): 178 [M]+ (100), 163 [M – NH]+ (25), 137
[M – MeCN]+ (19), 110 [M – MeCN – CO]+ (27), 108 (33).
Found (%): C, 60.65; H, 3.99; N, 16.00. C9H7FN2O. Calcuꢀ
lated (%): C, 60.66; H, 3.97; N, 15.73.
5ꢀFluoroꢀ2ꢀphenylquinazolinꢀ4(1H )ꢀone (12b). Benzoyl
chloride (0.63 mL, 4.5 mmol) and triethylamine (1.4 mL,
9 mmol) were added to a suspension of amide (10) (0.7 g,
4.5 mmol) in dry CH2Cl2 (8 mL). The reaction mixture was
stirred with a magnetic stirring bar for 2 h. The precipitate of
compound 11b was filtered off and refluxed with 5% KOH
(18 mL) in ethanol (6 mL) for 10 min. On cooling, the reaction
mixture was neutralized with dilute acetic acid. The precipitate
that formed was filtered off and recrystallized from DMSO. The
yield of quinazoline 12b was 0.65 g (90%), m.p. 308—310 °C.
1H NMR (DMSOꢀd6), δ: 7.13 (t, 1 H, H(7), 3J = 8.6 Hz);
7.45—7.54 (m, 1 H, H(8) and 3 H, Ph); 7.73 (ddd, 1 H, H(6),
4J = 2.1 Hz, 3J = 6.9 Hz, 3J = 9.9 Hz); 8.22 (m, 2 H, Ph); 12.42
(br.s, 1 H, NH). MS, m/z (Irel (%)): 240 [M]+ (63), 137
[M – PhCN]+ (100), 108 (20), 77 [C6H5]+ (33). Found (%):
C, 70.00; H, 3.80; N, 11.73. C14H9FN2O. Calculated (%):
C, 69.99; H, 3.78; N, 11.66.
2ꢀFluoroꢀ6ꢀ[(pyridinꢀ2ꢀylmethylidene)amino]benzamide
(14b). Yield (85%), m.p. 202—204 °C (from ethanol). 1H NMR
(DMSOꢀd6), δ: 5.65 (s, 1 H, NH); 6.28 (dd, 1 H, H(4), 3J =
8.4 Hz); 6.57 (d, 1 H, H(3’), 3J = 4.3 Hz); 7.11 (dd, 1 H, H(3),
3J = 8.0 Hz); 7.30 (m, 1 H, H(5´)); 7.37 (s, 1 H, NH); 7.53 (d,
1 H, H(5), 3J = 7.8 Hz); 7.78 (m, 1 H, H(4´)); 8.14 (s, 1 H,
N=CH); 8.54 (d, 1 H, H(6´), 3J = 4.4 Hz). Found (%): C, 64.15;
H, 4.19; N, 17.23. C13H10FN3O. Calculated (%): C, 64.18;
H, 4.15; N, 17.28.
2ꢀFluoroꢀ6ꢀ(2ꢀhydroxybenzylideneamino)benzamide (14c).
Yield 96%, m.p. 200—202 °C (from ethanol). 1H NMR
(DMSOꢀd6), δ: 6.95 (m, 2 H, C63H4OH); 7.09 (t, 1 H, H(4),
3J = 8.5 Hz); 7.23 (d, 1 H, H(5), J = 8.4 Hz); 7.36—7.45 (m,
1 H, H(3) and 1 H, C6H4OH); 7.54 (s, 1 H, NH); 7.59—7.65
(m, 1 H, NH and 1 H, C6H4OH); 7.79 (s, 1 H, N=CH); 8.87
(s, 1 H, OH). Found (%): C, 64.95; H, 4.39; N, 10.73.
C14H11FN2O2. Calculated (%): C, 65.10; H, 4.30; N, 10.85.
2ꢀFluoroꢀ6ꢀ(2ꢀhydroxyꢀ5ꢀnitrobenzylideneamino)benzamide
(14d). Yield 95%, m.p. 240—242 °C (from ethanol). 1H NMR
(DMSOꢀd6), δ: 5.97 (s, 1 H, NH); 6.35 (m, 1 H, H(4)); 6.62 (d,
1 H, H(5), 3J = 8.2 Hz); 7.00—7.12 (m, 1 H, NH and 1 H,
C6H3OH(NO2)); 7.15 (m, H(6)); 7.90 (s, 1 H, N=CH); 8.05,
8.26 (both m, 1 H each, C6H3OH(NO2)). Found (%): C, 55.35;
H, 3.39; N, 13.83. C14H10FN3O4. Calculated (%): C, 55.44;
H, 3.33; N, 13.86.
Compounds 12c,d and 13 were obtained analogously from
2ꢀaminoꢀ6ꢀfluorobenzamide (10) and isonicotinoyl, nicotinoyl,
and pyridineꢀ2,6ꢀdicarbonyl chlorides, respectively.
5ꢀFluoroꢀ2ꢀ(pyridinꢀ4ꢀyl)quinazolinꢀ4(1H )ꢀone (12c). Yield
1
86%, m.p. 310—312 °C (from DMSO). H NMR (DMSOꢀd6),
δ: 7.19 (m, 1 H, H(7)); 7.53 (d, 1 H, H(8), 3J = 7.8 Hz);
4
7.77 (m, 1 H, H(6)); 8.12 (dd, 2 H, H(3´), H(5´), J = 1.4 Hz,
3J = 4.6 Hz); 8.73 (d, 2 H, H(2´), H(6´), 3J = 6.0 Hz); 12.66
(br.s, 1 H, N(1)H). MS, m/z (Irel (%)): 241 [M]+ (73), 137
[M – RCN]+ (100), 110 [(M + H) – RCN – CO]+ (25),
108 (26), 78 (21). Found (%): C, 64.65; H, 3.39; N, 17.33.
C13H8FN3O. Calculated (%): C, 64.72; H, 3.35; N, 17.42.
5ꢀFluoroꢀ2ꢀ(pyridinꢀ3ꢀyl)quinazolinꢀ4(1H )ꢀone (12d). Yield
2ꢀFluoroꢀ6ꢀ(4ꢀmethoxybenzylideneamino)benzamide (14e).
Yield 94%, m.p. 205—207 °C (from ethanol). 1H NMR
(DMSOꢀd6), δ: 3.78 (s, 3 H, CH3); 5.63 (s, 1 H, NH); 6.31 (td,
1
4
3
3
88%, m.p. 311—313 °C (from DMSO). H NMR (DMSOꢀd6),
1 H, H(4), J = 7.5 Hz, J = 8.3 Hz); 6.54 (d, 1 H, H(5), J =
8.3 Hz); 6.90 (d, 2 H, C6H4(OCH3), 3J = 8.8 Hz); 7.09—7.18
(m, 2 H, H(3) and NH); 7.41 (d, 2 H, C6H4(OCH3), 3J =
8.4 Hz); 7.93 (s, 1 H, N=CH). Found (%): C, 66.15; H, 4.89;
N, 10.23. C15H13FN2O2. Calculated (%): C, 66.16; H, 4.82;
N, 10.29.
δ: 7.19 (ddd, 1 H, H(7), 4J = 1.0 Hz, 3J = 8.3 Hz, 3J = 10.5 Hz);
7.53 (m, 2 H, H(8) and H(5´)); 7.76 (ddd, 1 H, H(6), 4J =
2.3 Hz, 3J = 6.7 Hz, 3J = 10.2 Hz); 8.51, 8.72, 9.32 (all m,
1 H each, H(6´), H(4´), H(2´)); 12.62 (br.s, 1 H, NH). MS,
m/z (Irel (%)): 241 [M]+ (67), 137 [M – RCN]+ (100), 110
[(M + H) – RCN – CO]+ (25), 78 (22). Found (%): C, 64.65;
H, 3.39; N, 17.53. C13H8FN3O. Calculated (%): C, 64.72;
H, 3.35; N, 17.42.
5ꢀFluoroꢀ2ꢀ(furanꢀ2ꢀyl)quinazolinꢀ4(1H )ꢀone (12e). A. Cuꢀ
pric chloride (0.35 g, 2.6 mmol) was added to a suspension of
compound 14a (0.4 g, 1.7 mmol) in methanol (6 mL). The
mixture was refluxed for 3 h and then partially concentrated.
The precipitate that formed was filtered off and recrystallized
from CH2Cl2—hexane (1 : 1). The yield of quinazolinꢀ4ꢀone
12e was 0.2 g (52%), m.p. 200—202 °C.
B. Furfural (0.4 mL, 5 mmol) and CuCl2 (0.62 g, 4.5 mmol)
were added to a suspension of 2ꢀaminoꢀ6ꢀfluorobenzamide 10
(0.7 g, 4.5 mmol) in ethanol (10 mL). The mixture was refluxed
for 3 h and then partially concentrated. The precipitate that
formed was filtered off and recrystallized from CH2Cl2—hexane
(1 : 1). The yield of quinazolinꢀ4ꢀone 12e was 0.4 g (63%), m.p.
200—202 °C. 1H NMR (DMSOꢀd6), δ: 6.66 (m, 1 H, furyl);
7.10 (m, 1 H, H(7)); 7.49 (m, 1 H, furyl); 7.62 (d, 1 H, H(8),
3J = 8.3 Hz); 7.70 (m, 1 H, H(6)); 7.81 (m, 1 H, furyl);
12.37 (br.s, 1 H, NH). MS, m/z (Irel (%)): 230 [M]+ (100),
231 [M+H]+ (22), 138 [(M + H) – RCN]+ (20), 110
2,6ꢀBis(5ꢀfluoroꢀ4ꢀoxoꢀ1,4ꢀdihydroquinazolinꢀ2ꢀyl)pyridine
(13). Yield 76%, m.p. 352—354 °C (from DMSO). 1H NMR
(DMSOꢀd6), δ: 7.29 (t, 2 H, H(7´), H(7″), 3J = 9.8 Hz); 7.61 (d,
2 H, H(8´), H(8″) 3J = 8.3 Hz); 7.82 (m, 2 H, H(6´), H(6″));
8.30 (m, 1 H, H(4)); 8.72 (m, 2 H, H(3), H(5)); 13.22 (br.s,
2 H, N(1´)H and N(1″)H). MS, m/z (Irel. (%)): 403 [M]+ (100),
404 [M + H]+ (26), 375 [M – CO]+ (29), 137 (61), 110 (49), 108
(43). Found (%): C, 61.95; H, 2.79; N, 17.33. C21H11F2N5O2.
Calculated (%): C, 62.53; H, 2.75; N, 17.37.
2ꢀFluoroꢀ6ꢀ[(furanꢀ2ꢀylmethylidene)amino]benzamide (14a).
Furfural (0.72 mL, 8.7 mmol) was added to a suspension of
2ꢀaminoꢀ6ꢀfluorobenzamide (10) (0.9 g, 5.8 mmol) in ethanol
(10 mL). The reaction mixture was refluxed for 3 h. On cooling,
the precipitate was filtered off and recrystallized from ethanol.
The yield of compound 14a was 0.82 g (82%), m.p. 195—197 °C.

1826
Russ.Chem.Bull., Int.Ed., Vol. 56, No. 9, September, 2007
Layeva et al.
[(M + H) – RCN – CO]+ (21), 108 (26), 94 (37). Found (%):
C, 62.15; H, 2.89; N, 12.23. C12H7FN2O2. Calculated (%):
C, 62.60; H, 3.07; N, 12.17.
1H NMR (DMSOꢀd6), δ: 6.38 (m, 2 H, C6H3(OH)2); 7.14 (td,
4
3
3
1 H, H(7), J = 7.3 Hz, J = 8.0 Hz); 7.45 (d, 1 H, H(8), J =
8.0 Hz); 7.66 (m, 1 H, H(6)); 8.08 (m, 1 H, C6H3(OH)2); 9.98
(br.s, 2 H, 2OH); 12.15 (br.s, 1 H, NH). MS, m/z (Irel (%)):
272 [M]+ (67), 137 [M – RCN]+ (100), 110 [M – RCN – CO]+
(41), 108 (13). Found (%): C, 61.65; H, 3.39; N, 10.23.
5ꢀFluoroꢀ2ꢀ(pyridinꢀ2ꢀyl)quinazolinꢀ4(1H )ꢀone
(12f).
2,3ꢀDichloroꢀ5,6ꢀdicyanoꢀ1,4ꢀbenzoquinone (2.1 g, 9.3 mmol)
was added to a suspension of compound 14b (1.4 g, 5.8 mmol) in
dry acetonitrile (86 mL). The mixture was refluxed for 2 h. On
cooling, the precipitate was filtered off and recrystallized from
ethanol. The yield of compound 12f was 0.7 g (51%), m.p.
190—192 °C. 1H NMR (DMSOꢀd6), δ: 7.21 (td, 1 H, H(7), 4J =
7.3 Hz, 3J = 8.0 Hz); 7.58 (d, 1 H, H(8), 3J = 7.9 Hz); 7.64 (m,
1 H, H(5´)); 7.80 (ddd, 1 H, H(6), 4J = 2.9 Hz, 3J = 7.0 Hz, 3J =
11.1 Hz); 8.05 (m, 1 H, H(4´)); 8.50 (d, 1 H, H(3´), 3J =
7.9 Hz); 8.74 (d, 1 H, H(6´), 3J = 4.9 Hz); 11.31 (br.s, 1 H,
NH). MS, m/z (Irel (%)): 241 [M]+ (86), 242 [M + H]+
(13), 213 [M – CO]+ (25), 137 [M – RCN]+ (100), 110
[M – RCN – CO]+ (39), 108 (28), 78 (37). Found (%): C, 64.75;
H, 3.39; N, 17.39. C13H8FN3O. Calculated (%): C, 64.72;
H, 3.35; N, 17.42.
C14H9FN2O3. Calculated (%): C, 61.76; H, 3.34; N, 10.29.
Compounds 12k and 12l were obtained analogously from
2ꢀaminoꢀ6ꢀfluorobenzamide (10) and 4ꢀfluorobenzaldehyde or
4ꢀtrifluoromethylbenzaldehyde, respectively.
5ꢀFluoroꢀ2ꢀ(4ꢀfluorophenyl)quinazolinꢀ4(1H )ꢀone (12k). The
reaction mixture was refluxed for 40 min. The yield was 94%,
m.p. 320—322 °C (from DMSO). 1H NMR (DMSOꢀd6), δ: 7.14
(td, 1 H, H(7), 4J = 7.4 Hz, 3J = 8.2 Hz); 7.25 (d, 2 H, C6H4F,
3
3J = 5.6 Hz); 7.49 (d, 1 H, H(8), J = 8.2 Hz); 7.74 (ddd, 1 H,
3
H(6), J = 15.2 Hz, 3J = 7.0 Hz, 4J = 2.7 Hz); 8.30 (dd, 2 H,
C6H4F, 3J = 5.5 Hz, 3J = 2.0 Hz); 12.60 (br.s, 1 H, NH).
Found (%): C, 64.99; H, 3.10; N, 11.00. C14H9FN2O3. Calcuꢀ
lated (%): C, 65.12; H, 3.12; N, 10.85.
5ꢀFluoroꢀ2ꢀ(2ꢀhydroxyphenyl)quinazolinꢀ4(1H )ꢀone (12g).
Cupric chloride (0.36 mL, 2.7 mmol) was added to a suspension
of compound 14c (0.7 g, 2.7 mmol) in ethanol (8 mL). The
mixture was refluxed for 40 min. On cooling, the precipitate
was filtered off and recrystallized from DMSO. The yield of
quinazolinꢀ4ꢀone 12g was 0.60 g (83%), m.p. 322—324 °C.
1H NMR (DMSOꢀd6), δ: 6.89 (m, 2 H, C6H4OH), 7.13 (dd,
5ꢀFluoroꢀ2ꢀ(4ꢀtrifluoromethylphenyl)quinazolinꢀ4(1H )ꢀone
(12l). The reaction mixture was refluxed for 40 min. The yield was
1
96%, m.p. 290—292 °C (from DMSO). H NMR (DMSOꢀd6),
3
3
δ: 7.17 (dd, 1 H, H(7), J = 9.6 Hz, J = 8.1 Hz); 7.53 (d, 1 H,
H(8), 3J = 8.2 Hz); 7.74 (m, 1 H, H(6)); 7.80 (d, 2 H, C6H4CF3,
3J = 8.5 Hz); 8.42 (d, 2 H, C6H4CF3, 3J = 8.3 Hz); 12.65 (br.s,
1 H, NH). Found (%): C, 58.41; H, 2.60; N, 9.00. C14H9FN2O3.
Calculated (%): C, 58.45; H, 2.62; N, 9.09.
4
1 H, H(7), J = 7.4 Hz, 3J = 8.2 Hz); 7.37 (m, 1 H, C6H4OH);
7.46 (d, 1 H, H(8), 3J = 8.2 Hz); 7.73 (ddd, 1 H, H(6), 4J =
2.9 Hz, 3J = 6.8 Hz, 3J = 11.0 Hz); 8.18 (m, 1 H, C6H4OH);
12.40 (br.s, 1 H, NH or OH); 13.43 (br.s, 1 H, NH or OH). MS,
m/z (Irel (%)): 256 [M]+ (100), 137 [M – RCN]+ (91), 110
[M – RCN – CO]+ (41), 108 (11), 91 (13). Found (%): C, 65.75;
H, 3.59; N, 10.93. C14H9FN2O2. Calculated (%): C, 65.62;
H, 3.55; N, 10.93.
4ꢀAnilinoꢀ5ꢀfluoroquinazolineꢀ2ꢀthiol (15). A mixture of
2ꢀaminoꢀ6ꢀfluorobenzonitrile (8) (0.5 g, 3.6 mmol) and phenyl
isothiocyanate (1 mL, 7.2 mmol) was heated at 100 °C for 3.5 h.
On cooling, the precipitate was filtered off and recrystallized
from DMSO. The yield of compound 15 was 0.93 g (95%), m.p.
260—262 °C. 1H NMR (DMSOꢀd6), δ: 7.02 (dd, 1 H, H(7),
3J = 7.9 Hz, 3J = 12.5 Hz); 7.17 (m, 1 H, Ph); 7.28 (d, 1 H,
H(8), 3J = 8.6 Hz); 7.39 (m, 2 H, Ph); 7.61 (ddd, 1 H, H(6),
4J = 2.1 Hz, 3J = 7.2 Hz, 3J = 11.4 Hz); 7.82 (m, 2 H, Ph); 9.01
(d, 1 H, NH, JH,F = 15.3 Hz); 12.74 (br.s, 1 H, SH). MS,
m/z (Irel (%)): 271 [M]+ (87), 270 [M – H]+ (100), 213
[M – SCN]+ (56), 93 [C6H5NH2]+ (34), 77 [C6H5]+ (56), 272
[M + H]+ (20). Found (%): C, 61.55; H, 3.39; N, 10.23.
Products 12h and 12i were obtained analogously from comꢀ
pounds 14d and 14c, respectively.
5ꢀFluoroꢀ2ꢀ(2ꢀhydroxyꢀ5ꢀnitrophenyl)quinazolinꢀ4(1H )ꢀone
(12h). Yield 80%, m.p. > 320 °C (from DMSO). 1H NMR
(DMSOꢀd6), δ: 7.16 (d, 1 H, H(3´), 3J = 9.2 Hz); 7.24 (m, 1 H,
H(7)); 7.58 (d, 1 H, H(8), 3J = 8.1 Hz); 7.82 (m, 1 H, H(6));
8.28 (dd, 1 H, H(4´), 3J = 9.0 Hz, 4J = 2.3 Hz); 9.33 (d, H(6´),
4J = 2.8 Hz); 12.38 (br.s, 1 H, NH). MS, m/z (Irel (%)): 301 [M]+
(100), 271 (58), 137 [M – RCN]+ (50), 110 [M – RCN – CO]+
(54). Found (%): C, 55.75; H, 2.69; N, 13.93. C14H8FN3O4.
Calculated (%): C, 55.81; H, 2.68; N, 13.95.
5ꢀFluoroꢀ2ꢀ(4ꢀmethoxyphenyl)quinazolinꢀ4(1H )ꢀone (12i).
Yield 91%, m.p. 288—290 °C (from DMSO). 1H NMR
(DMSOꢀd6), δ: 3.90 (s, 3 H, CH3); 6.96—7.10 (m, 1 H, H(7)
and 2 H, C6H4(OCH3)); 7.45 (m, 1 H, H(8)); 7.67 (m, 1 H,
H(6)); 8.22 (m, 2 H, C6H4(OCH3)); 12.25 (br.s, 1 H, NH). MS,
m/z (Irel (%)): 270 [M]+ (79), 137 [M – RCN]+ (100), 110
[M – RCN – CO]+ (16), 108 (15). Found (%): C, 67.00; H, 4.19;
N, 10.23. C15H11FN2O2. Calculated (%): C, 66.65; H, 4.11;
N, 10.37.
C14H10FN3S. Calculated (%): C, 61.76; H, 3.34; N, 10.29.
This work was financially supported by the Civilian
Research and Development Foundation (BRHE Program,
CRDF Grant BP2M05 "Advanced Organic Materials for
Medical and Biological Application"), the Russian Founꢀ
dation for Basic Research (Project No. 06ꢀ03ꢀ32791),
and the Council on Grants of the President of the Rusꢀ
sian Federation (Program for State Support of Leading
Scientific Schools of the Russian Federation, Grant
NShꢀ9178.2006.3).
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in revised form August 2, 2007