Fluorine-containing heterocycles: Xviii. * monofluoro derivatives of quinazolines and 1,3-benzothiazin-4-ones

Article abstract of DOI:10.1134/S1070428009060189

5- and 7-Fluoro-substituted quinazolines and 1,3-benzothiazin-4-ones were synthesized starting from 2-amino-6-fluorobenzonitrile and mono- and difluoro-substituted benzoic acid derivatives. The reactivities of di- and tetrafluoro-substituted benzoyl chlorides and benzoyl isothiocyanates in cyclocondensations leading to fluorinated quinazolines and 1,3-benzothiazines were compared. Pleiades Publishing, Ltd., 2009.

Full text of DOI:10.1134/S1070428009060189

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2009, Vol. 45, No. 6, pp. 904–912. © Pleiades Publishing, Ltd., 2009.
Original Russian Text © E.V. Nosova, A.A. Laeva, T.V. Trashakhova, A.V. Golovchenko, G.N. Lipunova, P.A. Slepukhin, V.N. Charushin, 2009, published in
Zhurnal Organicheskoi Khimii, 2009, Vol. 45, No. 6, pp. 916–924.
Dedicated to Full Member of the Russian Academy of Sciences
O. N. Chupakhin on his 75th anniversary
Fluorine-Containing Heterocycles: XVIII.* Monofluoro
Derivatives of Quinazolines and 1,3-Benzothiazin-4-ones
E. V. Nosovaa, A. A. Laevaa, T. V. Trashakhovaa, A. V. Golovchenkoa, G. N. Lipunovab,
P. A. Slepukhinb, 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 Russia
e-mail: charushin@ios.uran.ru
Received October 15, 2008
Abstract—5- and 7-Fluoro-substituted quinazolines and 1,3-benzothiazin-4-ones were synthesized starting
from 2-amino-6-fluorobenzonitrile and mono- and difluoro-substituted benzoic acid derivatives. The reactiv-
ities of di- and tetrafluoro-substituted benzoyl chlorides and benzoyl isothiocyanates in cyclocondensations
leading to fluorinated quinazolines and 1,3-benzothiazines were compared.
DOI: 10.1134/S1070428009060189
2-Substituted quinazolin-4-ones were classed with
the base structural fragment of new drugs for the treat-
ment of strokes, traumatic brain damages, and Parkin-
son’s disease, which were reported at the XVIIth Inter-
national Symposium on Medicinal Chemistry [2].
Compounds promising from the viewpoint of medici-
nal chemistry were found among quinazolinones and
their derivatives containing a fluorine atom in the ben-
zene ring. In particular, 5- and 7-fluoroquinazolin-4-
ones exhibit antitumor activity [3, 4]. 4-Alkylsulfanyl-
and 4-alkylaminoquinazolines having a fluorine atom
in the 6-position were found to possess fungicidal
and other kinds of biological activity [5, 6]. 5- and
7-Fluoro-1,3-benzothiazin-4-ones also attract interest
[7] as sulfur analogs of monofluoro-substituted quinaz-
olin-4-ones, but these compounds were poorly studied.
On the other hand, we previously synthesized 6,7,8-tri-
fluoro-1,3-benzothiazin-4-ones from polyfluoroben-
zoyl isothiocyanates and CH-active benzimidazoles or
pyridines, and some of the products were found to
exhibit moderate to high tuberculostatic activity [8].
Synthesis of their analogs having only one fluorine
atom in the benzene ring seems to be promising from
the viewpoint of reducing the toxicity of potential
tuberculostatics.
We previously showed that 2-amino-6-fluorobenzo-
nitrile (I) is a convenient starting compound for the
synthesis of 2-substituted 5-fluoroquinazolin-4(1H)-
ones [9]. The reaction of compound I with phenyl
isothiocyanate was studied (Scheme 1). The product
obtained by heating the reactants for 3 h at 100°C was
1
characterized by H NMR and mass spectra. The
1H NMR spectrum contained signals from aromatic
protons, a doublet from NH proton in the arylamino
Scheme 1.
F
F
NH
N
F
NHPh
N
F
NHPh
NHPh F
CN
Ph
N
N
N
PhN=C=S
NH2
SH
N
H
S
N
S
S
N
I
IIa
IIb
* For communication XVII, see [1].
904

FLUORINE-CONTAINING HETEROCYCLES: XVIII.
905
4
C27
group (δ 9.05 ppm, J = 14.9 Hz), and a one-proton
signal at δ 12.7 ppm, which may be assigned to the
thioamide NH proton. In the electron-impact mass
spectrum of the product, the base peak was that with
m/z 270; also, a strong fragment ion peak resulting
from elimination of SCN from the former was present
(m/z 213). These findings led us to assign the structure
of 5-fluoro-4-phenylaminoquinazoline-2(1H)-thione
(IIa) to the isolated compound [9]. However, more
recent X-ray diffraction data showed that this com-
pound in crystal has the structure of disulfide IIb
(Fig. 1). Molecule IIb consists of two quinazoline
fragments linked through a disulfide bridge. One quin-
azoline fragment is planar (deviations of its atoms
from the mean-square plane do not exceed 0.035 Å),
whereas the phenylamino group in the second quinaz-
oline fragment declines from the quinazoline plane
(the dihedral angle between the mean-square planes of
the corresponding rings is 30.3°). The observed differ-
ence is related to paired π–π interaction involving the
quinazoline ring in one part of the molecule (the dis-
tance between the interacting planes [x, y, z] and [1 – x,
1 – y, –z] is 3.5 Å), which does not occur in the second
part. In all other respects, the quinazoline fragments
are characterized by similar structures (the correspond-
ing bond lengths and bond angles are almost equal,
and they approach standard values). The C2–C3 and
C16–C17 bonds are appreciably extended [1.446(2) Å]
due to electron-withdrawing effect of nitrogen atoms
in the quinazoline ring and negative inductive effect of
the nitrogen atom in the phenylamino group. The
structure of molecule IIb is shown in Fig. 1, and
a fragment of crystal packing is shown in Fig. 2.
C28
C23 N6
F2
C26
C18 C19
C20
C17
C16
C24
N5
C25
N4
C22 C21
S1
C15
S2
N1
C8
C1
N2
N3
C7
C14
C13
C2
C6
C9
C12
C3
C4
C11
C5
F1
C10
Fig. 1. Structure of the molecule of 2,2′-dithiobis(5-fluoro-4-
phenylaminoquinazoline) (IIb) according to the X-ray dif-
fraction data.
445 cm–1, which is likely to arise from vibrations of
the disulfide group (as in the IR spectrum of IIb).
Compound IVb displayed the molecular ion peak
(m/z 543) in the chemical ionization mass spectrum,
and the main fragmentation pathway was cleavage of
the S–S bond (m/z 271).
1
Summarizing the H NMR, IR, X-ray diffraction,
and mass spectral data for compounds II and IV, we
can conclude that the disulfide structure in solution is
The IR spectrum of disulfide IIb contained an ab-
sorption band at 440 cm–1, which may be assigned to
vibrations of the disulfide group [10]. Compound IIb
displayed in the chemical ionization mass spectrum the
molecular ion peak with m/z 541 and a peak from ion
with m/z 271, resulting from cleavage of the disulfide
S–S bond.
Likewise, the structure of 5-fluoro-3-phenyl-2-
thioxo-2,3-dihydroquinazolin-4(1H)-one (IVa) was
assigned to the product obtained by us previously by
reaction of 2-amino-6-fluorobenzoic acid with N-phen-
ylthiourea [9] (Scheme 2). The 1H NMR spectrum of
this compound, apart from signals belonging to aro-
matic protons, contained a signal at δ 13.0 ppm, which
may be attributed to NH proton in the thiolactam
fragment. However, the IR and mass spectral data led
us to presume disulfide structure IVb. In the IR
spectrum of IVb we observed an absorption band at
Fig. 2. A fragment of crystal packing of 2,2′-dithiobis-
(5-fluoro-4-phenylaminoquinazoline) (IIb).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

NOSOVA et al.
906
Scheme 2.
F
F
O
F
O
N
O
N
F
Ph Ph
H2NC(=S)NHPh
160–170°C
COOH
NH2
Ph
N
N
N
N
H
S
S
S
III
IVa
IVb
fairly labile; in proton-donor solvent (or in the pres-
ence of traces of water) it is converted into thiol form
which exists in equilibrium with the thione tautomer.
chloride with S-alkylisothioureas as N,N-binucleo-
philes (Scheme 3). By carrying out the reactions of
benzoyl chlorides Va and Vb with S-alkylisothiuro-
nium iodides at room temperature in methylene chlo-
ride in the presence of triethylamine we succeeded in
isolating S-alkyl-N-aroylisothioureas VIa and VIb in
good yield. Subsequent heating of thioureas VI in boil-
ing anhydrous DMF for 4 h gave compounds VIIa and
VIIb (Scheme 3).
The presence of an alkylsulfanyl group in position
2 of quinazolinones makes the formation of disulfide
structure impossible; Moreover, 2-alkylsulfanyl deriva-
tives can be readily modified at the 2-position via nu-
cleophilic substitution reactions. We have synthesized
5-fluoro-2-methylsulfanyl- and 2-ethylsulfanyl-7-
fluoroquinazolin-4(1H)-ones VIIa and VIIb according
to the procedure described previously [9], which was
based on cyclocondensation of tetrafluorobenzoyl
1
Compounds VII displayed in the H NMR spectra
signals from aromatic protons, a broadened one-proton
singlet from the NH group, and signals from protons in
Scheme 3.
NH2
F
O
NH
F
O
I–, Et3N
SMe
H2N
DMF, Δ
N
SMe
N
H
F
N
H
SMe
VIa
VIIa
NH2
SEt
Y
O
NH
O
I–, Et3N
COCl
F
H2N
DMF, Δ
N
SEt
N
H
X
F
F
F
N
SEt
H
Va, Vb
VIb
VIIb
F
O
N
N
Y
O
F
IXa
N
NH2
N
H
N
O
X
N
VIIIa, VIIIb
F
N
IXb
V, VIII, Y = F, X = H (a); Y = H, X = F (b).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

FLUORINE-CONTAINING HETEROCYCLES: XVIII.
907
Scheme 4.
O
F
N
S
CN
NH
S
CN
HN
N
O
CH2CN
Y
X
NH
F
N
H
NH
Et3N
XIIa
HN
O
N
S
CN
Y
O
F
XIa, XIb
NH
NCS
HN
F
X
Xa, Xb
XIIb
O
F
N
S
CN
CN
N
HN
XIIIa
the alkyl group. In the mass spectrum of VIIb, the base
peak was that with m/z 137 [M – EtS – CN]+, while the
molecular ion peak (m/z 224) had an intensity of 82%.
In addition, the [M – EtS – CN – CO]+ ion peak was
present in support of the 2-ethylsulfanylquinazolin-4-
one structure. The most abundant ion in the mass spec-
trum of VIIa was [M – H]+, m/z 209.
2,4- and 2,6-Difluorobenzoyl chlorides Va and Vb
are also convenient starting compounds for the syn-
thesis of monofluoro-substituted 1,3-benzothiazin-4-
ones that are thia analogs of quinazolin-4-ones. For
this purpose, benzoyl chlorides Va and Vb were con-
verted into the corresponding isothiocyanates Xa and
Xb, and the latter were brought into reactions with
C-nucleophiles, 2-cyanomethylpyridine and 2-cyano-
methylbenzimidazole (Scheme 4). The addition of
2-cyanomethylbenzimidazole at the N=C bond of iso-
thiocyanates Xa and Xb occurred in acetonitrile at
room temperature. The cyclization of addition products
XIa and XIb to 1,3-benzothiazin-4-ones XIIa and
XIIb was effected by heating in boiling toluene in the
presence of triethylamine. According to published data
[7], a 1:1 mixture of the addition product and 1,3-ben-
zothiazin-4-one was formed in the reaction of tetra-
fluorobenzoyl isothiocyanate with 2-cyanomethylbenz-
imidazole even at room temperature.
The yield in the cyclization VIb → VIIb was con-
siderably lower than in the formation of 5-fluoro
analog VIIa and 2-ethylsulfanyl-6,7,8-trifluoroquinaz-
olin-4(1H)-one [11].
Difluoro-substituted benzoyl chlorides were also
used as starting materials in the synthesis of mono-
fluoropyrido[1,2-a]quinazolinones. By heating pyri-
din-2-amine with benzoyl chlorides Va and Vb over
a period of 2 h we obtained the corresponding acyla-
tion products only at the exocyclic nitrogen atom
(compounds VIIIa and VIIIb), whereas in the reaction
with tetrafluorobenzoyl chloride both nitrogen atoms
in 2-aminopyridine (endo- and exocyclic) were acylat-
ed with formation of bis-aroyl derivatives [12]. The
structure of compounds VIII was confirmed by the
1H NMR data (see Experimental). Benzamides VIIIa
and VIIIb underwent intramolecular ring closure to
tricyclic derivatives IXa and IXb on heating in boiling
toluene in the presence of triethylamine. Their 1H NMR
and mass spectra were consistent with the structure of
6H-pyrido[1,2-a]quinazolin-6-ones (IX).
The reaction of another C-nucleophile, 2-cyano-
methylpyridine, with 2,6-difluorobenzoyl isothiocya-
nate (Xa) was as facile as with tetra- and pentafluoro-
benzoyl isothiocyanates [8], and it led to the formation
of 2-substituted 5-fluoro-1,3-benzothiazin-4-one
(XIIIa) at room temperature.
To conclude, we have synthesized new monofluoro-
substituted quinazoline and 1,3-benzothiazin-4-one
derivatives which attract interest as potential biologic-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

NOSOVA et al.
908
Table 1. Coordinates of atoms (in fractions of unit cell axes, × 104) and their thermal parameters Ueq in the molecule of
2,2′-dithiobis(5-fluoro-4-phenylaminoquinazoline) (IIb)
Atom
x
y
z
Ueq ×103
Atom
x
y
z
Ueq ×103
S1
S2
N5
F2
0778(1)
2191(1)
3833(2)
7893(1)
2143(2)
5097(2)
4822(2)
0050(2)
6299(2)
2401(2)
3806(2)
6112(2)
1026(2)
3396(2)
5053(2)
2296(2)
7660(2)
1316(2)
0201(2)
2359(1)
0889(1)
1769(2)
1461(1)
3695(2)
2603(2)
00–55(2)–
4786(2)
0780(2)
7337(1)
0878(2)
00–96(2)–
3778(1)
4743(2)
1734(2)
4781(2)
0627(2)
6000(2)
5937(2)
2956(1)
2590(1)
3586(1)
4634(1)
1084(1)
4474(2)
2931(2)
1878(2)
3804(2)
–1414(1)–
3104(2)
3278(2)
1826(2)
0–505(2)–
3952(2)
0270(2)
4128(2)
0215(2)
1064(2)
69(1)
68(1)
55(1)
91(1)
57(1)
68(1)
66(1)
68(1)
56(1)
102(1)0
57(1)
61(1)
57(1)
70(1)
55(1)
57(1)
67(1)
62(1)
66(1)
C23
C4
C9
C19
C21
C20
C10
C24
C7
3966(2)
1352(3)
4477(2)
8767(2)
7264(3)
8562(3)
5457(3)
2809(2)
0–782(3)–
4102(3)
0400(3)
1771(3)
4614(3)
3051(4)
6664(3)
5712(3)
1886(3)
0–672(3)–
6546(3)
3527(2)
7231(2)
3698(2)
0–301(2)–
–1061(2)–
–1157(2)–
4017(3)
4135(2)
7077(3)
3838(3)
8337(2)
5056(3)
2425(3)
4761(3)
1792(3)
1485(3)
5363(3)
8244(3)
3055(3)
4769(2)
0–571(2)–
0–648(2)–
3961(2)
67(1)
77(1)
65(1)
81(1)
N2
N6
N4
N1
C17
F1
C15
C22
C1
N3
C16
C2
C18
C3
C8
3101(2)
78(1)
3442(2)
85(1)
–1547(2)–
4135(2)
87(1)
73(1)
1084(2)
84(1)
C28
C5
5737(2)
86(1)
0–546(2)–
4457(2)
91(1)
C25
C14
C27
C12
C13
C26
C6
89(1)
0031(2)
89(1)
6044(3)
106(1)0
94(1)
–1091(3)–
0–190(3)–
5408(3)
100(1)0
105(1)0
98(1)
0296(3)
C11
–1761(2)–
100(1)0
Table 2. Bond lengths (d) in the molecule of 2,2′-dithiobis(5-fluoro-4-phenylaminoquinazoline) (IIb)
Bond
d, Å
Bond
d, Å
Bond
d, Å
Bond
d, Å
S1–C1
S1–S2
1.769(2)
2.0101(8)
1.778(2)
1.321(2)
1.333(2)
1.364(3)
1.316(2)
1.338(2)
1.351(3)
1.418(3)
0.814(19)
1.307(2)
1.375(3)
1.300(2)
1.366(3)
1.397(3)
C17–C22
C17–C16
F1–C4
C22–C21
N3–C2
N3–C9
N3–H3
C2–C3
1.406(3)
1.446(3)
1.360(3)
1.407(3)
1.348(3)
1.414(3)
0.869(19)
1.446(3)
1.352(3)
1.396(3)
1.410(3)
1.400(3)
1.360(3)
1.386(3)
1.360(3)
C9–C14
C9–C10
1.369(3)
1.380(3)
1.386(3)
0.9300
C5–C6
C5–H5A
1.376(4)
0.9300
1.358(4)
0.9300
1.377(3)
0.9300
1.367(4)
0.9300
1.361(4)
1.359(4)
0.9300
0.9300
0.9300
0.9300
0.9300
S2–C15
N5–C16
N5–C15
F2–C18
N2–C2
N2–C1
N6–C16
N6–C23
N6–H4
N4–C15
N4–C22
N1–C1
N1–C8
C17–C18
C19–C20
C19–H19A
C21–C20
C21–H21A
C20–H20A
C10–C11
C10–H10A
C24–C25
C24–H24A
C7–C6
C25–C26
C25–H25A
C14–C13
C14–H14A
C27–C26
C27–H27A
C12–C13
C12–C11
C12–H12A
C13–H13A
C26–H26A
C6–H6A
1.361(3)
0.9300
0.9300
1.385(3)
0.9300
C18–C19
C3–C4
C3–C8
1.381(3)
0.9300
C8–C7
1.358(4)
0.9300
C23–C24
C23–C28
C4–C5
C7–H7A
C28–C27
C28–H28A
1.3810(3)
0.9300
C11–H11A
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

FLUORINE-CONTAINING HETEROCYCLES: XVIII.
909
Table 3. Bond angles (ω) in the molecule of 2,2′-dithiobis(5-fluoro-4-phenylaminoquinazoline) (IIb)
Angle
ω, deg
Angle
ω, deg
Angle
ω, deg
Angle
ω, deg
C1S1S2
105.16(7)
105.25(7)
117.08(17)
116.66(18)
128.5(2)
N5C16N6
N5C16C17
N6C16C17
N2C2N3
N2C2C3
N3C2C3
F2C18C19
F2C18C17
C19C18C17
C4C3C8
118.15(19)
120.64(18)
121.21(19)
118.8(2)
120.8(2)
120.4(2)
117.9(2)
118.5(2)
123.6(2)
116.3(2)
127.7(2)
116.0(2)
118.6(2)
121.73(19)
119.6(2)
119.7(2)
123.5(2)
116.8(2)
117.7(3)
118.3(2)
123.9(3)
118.9(2)
125.1(2)
115.9(2)
C18C19C20
C18C19H19A
C20C19H19A
C20C21C22
C20C21H21A
C22C21H21A
C21C20C19
C21C20H20A
C19C20H20A
C9C10C11
C9C10H10A
C11C10H10A
C23C24C25
C23C24H24A
C25C24H24A
C6C7C8
119.1(2)
120.4
C26C25C24
C26C25H25A
C24C25H25A
C9C14C13
120.7(3)
119.7
C15S2S1
C16N5C15
C2N2C1
120.4
119.7
120.3(2)
119.8
120.1(2)
120.0
C16N6C23
C16N6H6
C23N6H6
C15N4C22
C1N1C8
C18C17C22
C18C17C16
C22C17C16
N4C15N5
N4C15S2
N5C15S2
N4C22C17
N4C22C21
C17C22C21
N1C1N2
N1C1S1
C9C14H14A
C13C14H14A
C26C27C28
C26C27H27A
C28C27H27A
C13C12C11
C13C12H12A
C11C12H12A
C12C13C14
C12C13H13A
C14C13H13A
C25C26C27
C25C26H26A
C27C26H26A
C7C6C5
113.2(16)
117.5(15)
114.56(17)
115.01(19)
116.49(19)
127.6(2)
119.8
120.0
120.5(2)
119.8
120.9(3)
119.6
119.8
119.6
120.1(3)
120.0
119.1(3)
120.4
C4C3C2
115.96(18)
129.62(19)
111.54(15)
118.84(15)
122.11(18)
117.8(2)
C8C3C2
120.0
120.4
N1C8C7
N1C8C3
C7C8C3
120.2(2)
119.9
121.2(3)
119.4
119.9
119.4
C24C23C28
C24C23N6
C28C23N6
F1C4C5
F1C4C3
C5C4C3
C14C9C10
C14C9N3
C10C9N3
120.8(3)
119.6
119.4(3)
120.3
C6C7H7A
C8C7H7A
C27C28C23
C27C28H28A
C23C28H28A
C6C5C4
120.0(2)
119.6
120.3
129.7(2)
119.2(3)
120.4
120.9(3)
119.5
111.32(16)
118.92(16)
131.5(2)
C7C6H6A
C5C6H6A
C12C11C10
C12C11H11A
C10C11H11A
N2C1S1
C2N3C9
C2N3H3
C9N3H3
120.4
119.5
118.4(3)
120.8
120.6(3)
119.7
114.1(12)
114.4(12)
C6C5H5A
C4C5H5A
120.8
119.7
ally active substances. 2,6-Difluorobenzoyl derivatives
were shown to be more reactive than their 2,4-sub-
stituted analogs in the cyclocondensation process.
A simple one-step procedure for the synthesis of
fluorine-containing bis(quinazolinyl) disulfide was
described. Some of the synthesized compounds were
tested for tuberculostatic activity at the Research Insti-
tute of Phthisiopulmonology, Ministry of Health Pro-
tection and Social Development of the Russian Federa-
tion. Compounds IVb and VIIb showed relatively
high activity against Micobacterium tuberculosis
H37RV (minimal inhibitory concentration 0.36 μg/ml).
relative to tetramethylsilane (1H) or hexafluorobenzene
(19F); DMSO-d6 was used as solvent. The mass spectra
were obtained on a Varian MAT 311A spectrometer
(electron impact, 70 eV; accelerating voltage 3 kV;
cathode emission current 300 μA; direct sample admis-
sion into the ion source), as well as on a Shimadzu
LCMS-2010 instrument (positive and negative ion
detection, atmospheric pressure chemical ionization;
selected ion monitoring, profile scan mode).
The X-ray diffraction data for a single crystal of
compound IIb were acquired at 293 K on an Xcalibur
3 diffractometer (CCD detector; MoKα irradiation,
λ 0.71073 Å). Colorless crystals, 0.5×0.6×0.9 mm,
triclinic crystal system, space group P0 (pseudo-P-1);
unit cell parameters: a = 9.8095(11), b = 11.2052(9),
c = 12.359(2) Å; α = 70.047(12), β = 82.411(11), γ =
75.528(9)°. The structure was solved by the direct
method in isotropic approximation and was refined in
anisotropic approximation using SHELXL-97 software
package [13]. The coordinates of atoms and their ther-
EXPERIMENTAL
1
The H NMR spectra were recorded on Bruker
WM-250 and Bruker DRX-400 spectrometers at 250.14
and 400.13 MHz, respectively. The 19F NMR spectra
were measured on a Bruker DRX-500 instrument at
376.45 MHz. The chemical shifts were determined
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

NOSOVA et al.
910
1
mal parameters are collected in Table 1, and the bond
lengths and bond angles are listed in Tables 2 and 3,
respectively.
mp 64–66°C. H NMR spectrum, δ, ppm: 2.37 s (3H,
CH3), 6.98 m (2H, Harom), 7.44 m (1H, Harom), 9.54 br.s
(2H, NH). Found, %: C 46.99; H 3.44; N 12.30.
C9H8F2N2OS. Calculated, %: C 46.95; H 3.50; N 12.17.
2,2′-Dithiobis(5-fluoro-4-phenylaminoquinazo-
line) (IIb). A mixture of 0.5 g (3.6 mmol) of 2-amino-
6-fluorobenzonitrile (I) and 1 ml (7.2 mmol) of phenyl
isothiocyanate was heated for 3.5 h at 100°C. The
mixture was cooled, and the precipitate was filtered off
and recrystallized from DMSO. Yield 0.93 g (95%). IR
spectrum, ν, cm–1: 440 (S–S), 1100 (C–F), 1500–1640
N-(2,4-Difluorobenzoyl)-S-ethylisothiourea (VIb)
was synthesized in a similar way. Yield 81%, mp 144–
146°C. H NMR spectrum, δ, ppm: 1.32 t (3H, CH3),
3.11 q (2H, SCH2), 7.13 m (2H, Harom), 8.07 m (1H,
arom), 9.52 br.s (2H, NH). Found, %: C 48.89; H 4.13;
N 11.39. C10H10F2N2OS. Calculated, %: C 49.16;
H 4.13; N 11.47.
1
H
1
(C=C, C=N), 3420 br (NH). H NMR spectrum, δ,
3
ppm: 7.02 d.d (1H, 7-H, J = 7.9, 12.5 Hz), 7.17 m
5-Fluoro-2-methylsulfanylquinazolin-4(1H)-one
(VIIa). A solution of 0.7 g (2.9 mmol) of isothiourea
VIa in 6 ml of anhydrous DMF was heated for 4 h
under reflux. The mixture was evaporated, and the
residue was recrystallized from ethanol. Yield 67%,
3
(1H, Ph), 7.28 d (1H, 8-H, J = 8.6 Hz), 7.39 m
4
3
(2H, Ph), 7.61 d.d.d (6-H, J = 2.1, J = 7.2, 11.4 Hz),
7.82 m (2H, Ph), 9.01 d (1H, NH, JHF = 15.3 Hz),
12.7 br.s (1H, NH). Mass spectrum (EI), m/z (Irel, %):
272 (20) [M/2 + 2H]+, 270 (100) [M/2]+, 213 (56) [M/2 –
SCN]+, 93 (34) [C6H5NH2]+, 77 (56) [C6H5]+. Mass
spectrum (APCI), m/z (Irel, %): 542 (31) [M + H]+, 541
(73) [M]+, 271 (43) [M/2 + H]+, 256 (100) [M/2 – 14]+.
Found, %: C 61.55; H 3.39; N 10.23. C28H18F2N6S2.
Calculated, %: C 62.21; H 3.36; N 10.29. M 540.61.
1
mp 188–190°C. H NMR spectrum, δ, ppm: 2.56 s
(3H, CH3), 7.01 d.d (7-H, J = 8.1, 10.2 Hz), 7.29 d
3
3
4
3
(8-H, J = 8.1 Hz), 7.63 d.d.d (1H, 6-H, J = 2.7, J =
6.6, 10.8 Hz), 12.44 br.s (1H, NH). Mass spectrum
(APCI), m/z (Irel, %): 210 (16) [M]+, 209 (100) [M – H]+.
Found, %: C 51.45; H 3.39; N 13.33. C9H7FN2OS.
Calculated, %: C 51.42; H 3.36; N 13.32. M 210.23.
2,2′-Dithiobis[5-fluoro-3-phenylquinazolin-
4(3H)-one] (IVb). A mixture of 0.5 g (3.2 mmol) of
benzoic acid III and 0.49 g (3.2 mmol) of N-phenyl-
thiourea was heated for 1 h at 160–170°C. The melt
was cooled, 10 ml of water was added, and the precip-
itate was filtered off and recrystallized from ethanol.
Yield 70%, mp 250–252°C. IR spectrum, ν, cm–1: 445
(S–S), 1180 (C–F), 1540–1680 (C=C, C=N, C=O).
2-Ethylsulfanyl-7-fluoroquinazolin-4(1H)-one
(VIIb) was synthesized in a similar way. Yield 35%,
mp 188–190°C. H NMR spectrum, δ, ppm: 1.40 t
(3H, CH3), 3.19 q (2H, SCH2), 7.13 m (2H, 5-H, 8-H),
8.07 m (1H, 6-H), 12.37 br.s (1H, NH). Mass spectrum
(EI), m/z (Irel, %): 224 (82) [M]+, 196 (37) [M – CO]+,
137 (100) [M – EtS – CN]+, 108 (96). Found, %:
C 53.25; H 4.09; N 12.93. C10H9FN2OS. Calculated,
%: C 53.55; H 4.05; N 12.49. M 224.25.
1
3
1H NMR spectrum, δ, ppm: 6.99 t (1H, 7-H, J =
8.4 Hz), 7.19 d (2H, Ph, 3J = 6.7 Hz), 7.28 d (1H, 8-H,
3J = 8.2 Hz), 7.37–7.52 m (3H, Ph), 7.69 m (1H, 6-H),
13.0 br.s (1H, NH). Mass spectrum (EI), m/z (Irel, %):
271 (84) [M/2]+, 271 (100) [M/2 – H]+, 137 (43)
[M/2 – Ph – NCS]+, 110 (56) [M/2 – Ph – NCS – CO]+,
77 (49) [C6H5]+. Mass spectrum (APCI), m/z (Irel, %):
543 (31) [M]+, 544 (13) [M + H]+, 272 (18) [M/2 +
H]+, 271 (33) [M/2]+. Found, %: C 61.55; H 3.39;
N 11.97. C28H16F2N4O2S2. Calculated, %: C 61.98;
H 2.97; N 10.32. M 542.58.
2,6-Difluoro-N-(pyridin-2-yl)benzamide (VIIIa).
2,6-Difluorobenzoyl chloride, 1.87 g (10.6 mmol), was
added to a solution of 0.5 g (5.3 mmol) of 2-amino-
pyridine in 15 ml of anhydrous toluene. The mixture
was heated for 1.5 h under reflux and cooled, and the
precipitate was filtered off and recrystallized from
ethanol. Yield 1.06 g (85%), mp 228–230°C. 1H NMR
spectrum, δ, ppm: 7.52 d.d (1H, 5-H, J = 8.1, 6.8 Hz),
7.6–7.8 m (2H, 3′-H, 5′-H), 8.11 m (1H, 4′-H), 8.28 m
(1H), 8.57 m (1H), 9.55 d (1H, 6-H, J = 6.8 Hz),
10.8 br.s (1H, NH). Found, %: C 61.48; H 3.39;
N 12.01. C12H8F2N2O. Calculated, %: C 61.54; H 3.44;
N 11.96.
N-(2,6-Difluorobenzoyl)-S-methylisothiourea
(VIa). Triethylamine, 2.7 ml (19.4 mmol), and a solu-
tion of 19.6 ml (9.7 mmol) of 2,6-difluorobenzoyl
chloride (Va) in 6 ml of toluene were added in succes-
sion under stirring to a solution of 2.3 g (9.7 mmol) of
S-ethylthiourea in 20 ml of anhydrous methylene chlo-
ride. The mixture was kept for 24 h at room tempera-
ture and evaporated, and the residue was washed with
water and recrystallized from ethanol. Yield 84%,
2,4-Difluoro-N-(pyridin-2-yl)benzamide (VIIIb)
was synthesized in a similar way. Yield 60%, mp 276–
278°C. H NMR spectrum, δ, ppm: 7.61 d.d (1H, 5-H,
J = 7.1, 6.8 Hz), 7.77 m (1H, 3′-H), 7.91 d (1H, 3-H,
J = 8.4 Hz), 8.37 d.d (1H, 4-H, J = 8.4, 7.1 Hz), 8.46 m
1
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

FLUORINE-CONTAINING HETEROCYCLES: XVIII.
911
(1H, 5′-H), 8.81 m (1H, 6′-H), 9.62 d (1H, 6-H, J =
6.8 Hz), 10.9 br.s (1H, NH). Found, %: C 61.46;
H 3.37; N 12.02. C12H8F2N2O. Calculated, %: C 61.54;
H 3.44; N 11.96.
was synthesized in a similar way from 2,4-difluoroben-
zoyl chloride and 2-cyanomethylbenzimidazole. Yield
90%, mp 175–177°C. H NMR spectrum, δ, ppm:
7.17 m (2H, C6H3F2), 7.34 m (2H, C6H4), 7.68 m
(2H, C6H4), 7.81 m (1H, C6H3F2), 10.28 br.s (1H, NH),
13.74 br.s (2H, NH). Found, %: C 57.33; H 2.84;
N 15.75. C17H10F2N4OS. Calculated, %: C 57.30;
H 2.83; N 15.72.
1
7-Fluoro-6H-pyrido[1,2-a]quinazolin-6-one
(IXa). Triethylamine, 0.2 g (2.0 mmol), was added to
a suspension of 0.23 g (1.0 mmol) of amide VIIIa in
10 ml of toluene, the mixture was heated for 3 h under
reflux, cooled, and evaporated, and the residue was
washed with water and recrystallized from ethanol.
(2,3-Dihydro-1H-benzimidazol-2-ylidene)-
(5-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)acetoni-
trile (XIIa). Triethylamine, 0.5 ml (3.4 mmol), was
added to a solution of 0.6 g (1.7 mmol) of compound
XIa in 10 ml of anhydrous toluene, and the mixture
was heated for 3 h under reflux. The mixture was
cooled, and the precipitate was filtered off, washed
with water, and recrystallized from DMSO. Yield 0.5 g
1
Yield 0.17 g (78%), mp 258–260°C. H NMR spec-
3
4
trum, δ, ppm: 6.99 d.d.d (1H, 2-H, J = 7.5, 6.6, J =
3
4
1.2 Hz), 7.21 d.d (1H, 4-H, J = 9.1, J = 1.2 Hz),
7.42 m (1H, FC6H3), 7.74 d.d.d (1H, 3-H, 3J = 8.9, 6.6,
4J = 1.2 Hz), 7.90 m (1H, FC6H3), 8.27 m (1H, FC6H3),
8.99 d (1H, 1-H, 3J = 7.5 Hz). Mass spectrum (APCI),
m/z (Irel, %): 256 (100) [M + CH3CN]+, 215 (53) [M +
H]+. Found, %: C 67.33; H 3.36; N 13.02. C12H7FN2O.
Calculated, %: C 67.29; H 3.30; N 13.08. M 214.20.
1
(82%), mp >300°C. H NMR spectrum, δ, ppm: 7.19–
7.28 m (3H, 7-H, C6H4), 7.43 d (1H, 8-H, 3J = 8.1 Hz),
7.57–7.7.1 m (3H, 6-H, C6H4), 13.42 br.s (2H, NH).
Mass spectrum (ACPI), m/z (Irel, %): 335 (100)
[M – H]+, 336 (43) [M]+. Found, %: C 61.00; H 2.68;
N 16.64. C17H9FN4OS. Calculated, %: C 60.71;
H 2.70; N 16.66. M 336.34.
9-Fluoro-6H-pyrido[1,2-a]quinazolin-6-one
(IXb) was synthesized in a similar way. Yield 57%,
1
mp >300°C. H NMR spectrum, δ, ppm: 7.04 d.d.d
3
4
(1H, 2-H, J = 7.0, 6.3, J = 1.5 Hz), 7.23 d (1H, 4-H,
3J = 9.1 Hz), 7.56 m (1H, FC6H3), 7.78 d.d.d (1H, 3-H,
3J = 9.1, 6.3, 4J = 1.4 Hz), 8.32 m (1H, FC6H3), 8.42 m
(2,3-Dihydro-1H-benzimidazol-2-ylidene)-
(7-fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)acetoni-
trile (XIIb) was synthesized in a similar way. Yield
3
(1H, FC6H3), 8.99 d (1H, 1-H, J = 7.0 Hz). Mass
1
spectrum (ACPI), m/z (Irel, %): 256 (100) [M +
MeCN]+, 215 (52) [M + H]+. Found, %: C 67.30;
H 3.38; N 13.04. C12H7FN2O. Calculated, %: C 67.29;
H 3.30; N 13.08. M 214.20.
85%, mp >300°C. H NMR spectrum, δ, ppm: 7.20–
7.29 m (3H, 5-H or 8-H, C6H4), 7.51–7.59 m (3H, 8-H
or 5-H, C6H4), 8.30 m (1H, 6-H), 13.53 br.s (2H, NH).
Mass spectrum (ACPI), m/z (Irel, %): 336 (32) [M]+,
335 (100) [M – H]+. Found, %: C 60.83; H 2.718;
N 16.70. C17H9FN4OS. Calculated, %: C 60.71;
H 2.70; N 16.66. M 336.34.
N-[2-Cyano-2-(2,3-dihydro-1H-benzimidazol-2-
ylidene)ethanethioyl]-2,6-difluorobenzamide (XIa).
A solution of 0.4 g (5 mmol) of ammonium thiocya-
nate in 5 ml of anhydrous acetonitrile was added to
a solution of 0.6 ml (5 mmol) of 2,6-difluorobenzoyl
chloride in 3 ml of anhydrous acetonitrile. The mixture
was heated for 5 min at 40°C, the precipitate of NH4Cl
was filtered off, and a suspension of 0.8 g (5 mmol) of
2-cyanomethylbenzimidazole in 5 ml of acetonitrile
was added to the filtrate containing isothiocyanate Xa.
The mixture was kept for 1 h at room temperature, and
the precipitate was filtered off and recrystallized from
(5-Fluoro-4-oxo-4H-1,3-benzothiazin-2-yl)[pyri-
din-2(1H)-ylidene]acetonitrile (XIII). A solution of
5 mmol of isothiocyanate Xa in 12 ml of anhydrous
acetonitrile was added to 0.84 g (7 mmol) of (pyridin-
2-yl)acetonitrile in 10 ml of acetonitrile. The mixture
was kept for 24 h at room temperature and evaporated,
and the residue was washed with ethanol and recrys-
tallized from DMSO. Yield 0.7 g (82%), mp 255–
257°C. 1H NMR spectrum, δ, ppm: 7.07 m (2H, 7-H,
pyridine), 7.46 m (2H, 8-H, pyridine), 7.75 m (1H,
6-H), 8.24 m (1H, pyridine), 8.55 m (1H, pyridine),
10.87 br.s (1H, NH). Mass spectrum (ACPI), m/z
(Irel, %): 297 (19) [M]+, 296 (100) [M – H]+. Found, %:
C 60.59; H 2.73; N 14.18. C15H8FN3OS. Calculated,
%: C 60.60; H 2.71; N 14.13. M 297.31.
1
ethanol. Yield 1.6 g (92%), mp 160–162°C. H NMR
spectrum, δ, ppm: 7.04 m (2H, C6H3F2), 7.32 m (2H,
C6H4), 7.48 m (1H, C6H3F2), 7.68 m (2H, C6H4),
10.82 br.s (1H, NH), 13.74 br.s (2H, NH). Found, %:
C 57.30; H 2.88; N 15.77. C17H10F2N4OS. Calculated,
%: C 57.30; H 2.83; N 15.72.
N-[2-Cyano-2-(2,3-dihydro-1H-benzimidazol-2-
ylidene)ethanethioyl]-2,4-difluorobenzamide (XIb)
This study was performed under financial support
by the CRDF (BRHE program, grant no. BP2M05), by
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 45 No. 6 2009

NOSOVA et al.
912
7. Kawada, A., Nakayama, Y., and Kimura, H., EU Patent
no. 1424336, 2004; Chem. Abstr., 2004, vol. 138,
no. 238199.
8. Nosova, E.V., Lipunova, G.N., Laeva, A.A., and Charu-
shin, V.N., Sovremennye problemy teoreticheskoi i eks-
perimental’noi khimii (mezhvuzovskii sbornik nauch-
nykh trudov) [Current Problems of Theoretical and
Experimental Chemistry (An Interinstitution Collection
of Scientific Papers)], Saratov: Nauchnaya Kniga, 2005,
p. 80.
the Russian Foundation for Basic Research (project no.
06-03-32791), and by the Council for Grants at the
President of the Russian Federation (project no. NSh-
9178.2006.3).
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