Convenient Synthesis of Fluorine-Containing 2-Aryl-5H-[1,3,4]thiadiazolo[3,2-a]quinazolin-5-ones

Article abstract of DOI:10.1134/S1070428019010093

An efficient synthetic approach to new fluorine-containing [1,3,4]thiadiazolo[3,2-a]quinazolin-5-ones has been developed on the basis of intramolecular cyclization of N-(N′-benzoylhydrazinecarbothioyl)-benzamides obtained from tetrafluorobenzoyl isothiocy

Full text of DOI:10.1134/S1070428019010093

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 1, pp. 83–86. © Pleiades Publishing, Ltd., 2019.
Russian Text © E.V. Nosova, A.D. Poteeva, P.A. Slepukhin, 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 1, pp. 111–115.
Convenient Synthesis of Fluorine-Containing
2
-Aryl-5H-[1,3,4]thiadiazolo[3,2-a]quinazolin-5-ones
a, b
a
a, b
E. V. Nosova ,* A. D. Poteeva , and P. A. Slepukhin
a
Yeltsin Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: emily74@rambler.ru
*
b
Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620137 Russia
Received June 20, 2018; revised June 26, 2018; accepted July 4, 2018
Abstract—An efficient synthetic approach to new fluorine-containing [1,3,4]thiadiazolo[3,2-a]quinazolin-5-
ones has been developed on the basis of intramolecular cyclization of N-(N′-benzoylhydrazinecarbothioyl)-
benzamides obtained from tetrafluorobenzoyl isothiocyanate and benzohydrazides.
Keywords: fused quinazolines, fluorine-containing benzazines, hydrazides, benzoyl isothiocyanates, cyclo-
condensation.
DOI: 10.1134/S1070428019010093
Considerable interest in fluorine-containing
4a–4c were subjected to thermal cyclization in
[
a]-fused quinazolin-4-ones is determined by biologi-
Dowtherm A for 12 h to afford thiadiazoloquinazolines
1
19
cal activity of these compounds, in particular by their
ability to act as antipsychotic agents [1, 2] and CCK-B
cholecystokinin receptor antagonists [3] and anti-
leishmanial activity [4]. We previously described the
synthesis of 7,8,9-trifluoro-substituted [1,2,4]triazolo-
6a–6c whose structure was confirmed by H and
F
NMR and mass spectra, as well as by the X-ray dif-
1
fraction data for compound 6b (Fig. 1). The H NMR
spectra of 6a–6c lacked NH proton signals, and their
1
9
F NMR spectra showed three fluorine signals indicat-
[1,5-a]-, pyrazolo[1,5-a]-, and imidazo[1,2-a]quinazo-
ing formation of a benzo-fused heterocyclic derivative.
lin-5-ones by intramolecular cyclization of N-azolyl-
According to the X-ray diffraction data, compound
b crystallized in a non-centrosymmetric space group.
2
6
,3,4,5-tetrafluorobenzamides [5] and the synthesis of
,7,8-trifluorothiazolo[3,2-a]quinazolin-4-one [6].
6
The non-hydrogen atoms of the tetracyclic skeleton lie
in one plane within 0.1 Å; however, the plane sym-
metry of the molecule is distorted due to orientation of
protons of the methyl group. The bond lengths in the
pyrimidine ring suggest strong disruption of its
aromaticity and the lack of conjugation between the
π-systems of the thiadiazole and benzene rings. For
Only two methods of preparation of [1,3,4]thiadi-
azolo[3,2-a]quinazolin-5-ones have been reported so
far. These are the reaction of diazotized anthranilic
acid and its methyl ester with phenacyl thiocyanates in
the presence of sodium acetate [7] and cycloconden-
sation of 1,3,4-thiadiazol-2-amines with 2-halobenzoyl
chlorides [8]. It should be noted that 5-aryl-1,3,4-thia-
diazol-2-amines are difficultly accessible compounds.
Herein, we propose a convenient procedure for the
synthesis of new thiadiazoloquinazolinones from tetra-
fluorobenzoyl isothiocyanate and benzohydrazides.
1
9
instance, the C –C bond length (Fig. 1) is 1.489 Å,
which is typical of single Csp –Csp bonds, and this
2
2
3
10
bond is even longer than the exocyclic C –C bond
(1.466 Å). The C–S bonds in the thiadiazole ring
remain essentially symmetrical. The bond lengths in
1
1
3
2
2
,3,4,5-Tetrafluorobenzoyl isothiocyanate (2) reacted
the O =C –N =C fragment are typical for conjugated
systems involving a carbonyl group. Molecules 6b in
crystal are packed in stacks. Interestingly, there are
with hydrazides 3a–3e in boiling acetonitrile (1 h) to
give benzoylthiosemicarbazides 4a–4e in 91–94%
yield (Scheme 1). The structure of 4a–4e was con-
1
2
short intermolecular C ···F π-contacts [3.045 Å; x, y,
z –1] which are shorter by 0.125 Å than the sum of
1
19
sistent with their H and F NMR spectra. Compounds
8
3

8
4
NOSOVA et al.
Scheme 1.
O
F
O
F
O
F
S
F
F
NH SCN
MeCN
F
F
4-RC H C(O)NHNH (3a–3e)
MeCN
F
F
R
4
6
4
2
Cl
NCS
N
NH
HN
H
F
F
F
O
1
2
4a–4e
O
N
O
F
N
N
N
F
F
R
Dowtherm A, ∆
Dowtherm A, ∆
S
N
S
F
H
N
F
F
F
R
5
a–5c
6a–6c
3
, 4, R = H (a), Me (b), t-Bu (c), MeO (d), Cl (e); 5, 6, R = H (a), Me (b), t-Bu (c).
the van der Waals radii. These contacts are likely to be
formed via dipole–dipole interactions between the
boiling tetrahydrofuran, toluene, acetonitrile, or other
solvents in the presence of different bases (potassium
carbonate, triethylamine, sodium hydride, DBU) or in
Dowtherm A. Obviously, the reason is reduced reac-
tivity of the carbonyl group in compounds with +M
substituents.
polar Csp
2
–F and C=O groups.
4
-Chloro- and 4-methoxybenzoyl derivatives 4d
and 4e failed to undergo cyclization on heating in
1
O
We succeeded in isolating intermediate compound
3
F
8
5a by heating thiosemicarbazide 4a in Dowtherm A for
C
1
1
7
C
1
h. The H NMR spectrum of 5a contained a broad-
C
9
C
ened NH signal at δ 13.4 ppm, a multiplet signal of the
3
N
proton in the tetrafluorophenyl ring, and signals of the
1
9
6
C
phenyl protons. In the F NMR spectrum of 5a we
observed four fluorine signals. The mass spectrum
of 5a displayed a fragment ion peak with m/z 121
2
4
1
2
F
C
C
1
5
N
S
+
C
[PhCS] , indicating the presence of a thiadiazole ring
1
F
in its molecule.
2
N
3
C
Thus, we have synthesized new fluorine-containing
[1,3,4]thiadiazolo[3,2-a]quinazolin-5-ones by cycliza-
1
0
tion of tetrafluoro-N-(N′-benzoylhydrazinecarbo-
thioyl)benzamides in Dowtherm A. The synthesis of
C
1
5
1
1
C
C
2
,3,4,5-tetrafluorobenzoyl isothiocyanate (2) from
1
4
C
2,3,4,5-tetrafluorobenzoyl chloride (1) was described
in [9]. The procedure for the synthesis of compounds 4
and their characteristics are available from the authors.
1
2
C
1
3
C
EXPERIMENTAL
1
6
C
1
19
The H and F NMR spectra were recorded on
1
a Bruker Avance-400 spectrometer (400 MHz for H)
1
Fig. 1. Structure of the molecule of 7,8,9-trifluoro-2-(4-
methylphenyl)-5H-[1,3,4]thiadiazolo[3,2-a]quinazolin-5-one
in DMSO-d ; H chemical shifts were measured
6
relative to tetramethylsilane as internal standard. The
melting points were measured on a Boetius melting
point apparatus. The mass spectra (electrospray ioniza-
(
6b) according to the X-ray diffraction data. Non-hydrogen
atoms are shown as thermal vibration ellipsoids with a prob-
ability of 50%.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 1 2019

CONVENIENT SYNTHESIS OF FLUORINE-CONTAINING 2-ARYL-5H-[1,3,4]THIA...
85
4
5
19
tion) were recorded on a Bruker Daltonics MicrOTOF-
Q II instrument (Bremen, Germany). The elemental
analyses were obtained with a Perkin Elmer 2400
Series II CHN analyzer.
JHF = 7.7, J = 2.2 Hz). F NMR spectrum, δ , ppm:
HF
F
3
–133.10 d (1F, 8-F, J = 22.2 Hz), –140.05 d
(1F, 7-F, J = 16.1 Hz), –149.90 t (1F, 9-F, J
21.3 Hz). Mass spectrum, m/z (I , %): 333 (100) [M] ,
FF
3
3
=
FF
FF
+
rel
3
(
05 (28), 202 (14), 174 (22), 144 (94), 130 (11), 121
23), 103 (12), 77 (22), 76 (17), 75 (12), 69 (22), 51 (13).
Found, %: C 54.13; H 1.88; N 12.54. C H F N OS.
The X-ray diffraction data for compound 6b were
obtained on an Xcalibur E diffractometer (Cu K radia-
α
1
5
6
3
3
tion, λ = 154.184 pm, graphite monochromator, CCD
detector) from a 0.35×0.30×0.25-mm single crystal
Calculated, %: C 54.06; H 1.81; N 12.61.
(
brown prism) at 295(2) K. A correction for absorption
Compounds 6b and 6c were synthesized in
a similar way.
–
1
was applied empirically (μ = 2.499 mm ). Orthorhom-
bic crystal system, space group Pna2 ; C H F N OS;
unit cell parameters: a = 7.783(4), b = 28.50(3),
c = 6.301(3) Å; V = 1397.6(18) Å ; Z = 4. Total of
9
range 3.10 < θ < 66.73°, including 2145 independent
reflections (R = 0.0922) and 1125 reflections with
I > 2σ(I); completeness 98.8% for θ = 66.73°. The
structure was solved by the direct method and was
1
16
8
3
3
7,8,9-Trifluoro-2-(4-methylphenyl)-5H-[1,3,4]-
thiadiazolo[3,2-a]quinazolin-5-one (6b). Yield 88%,
3
1
mp 270–272°C. H NMR spectrum, δ, ppm: 2.95 s
3
905 reflection intensities were measured in the
(
3H, CH ), 7.42 d (2H, 3′-H, 5′-H, J = 8 Hz), 7.86 d
3
HH
3
(
2H, 2′-H, 6′-H, J = 8.2 Hz), 7.95 d.d.d (1H, 7-H,
JHF = 12.5, J = 4.9, J = 1.6 Hz). F–{ H} NMR
spectrum, δ , ppm: –133.21 d (1F, 8-F, J = 22.0 Hz),
F FF
–139.94 d (1F, 7-F, J = 18.5 Hz), –150.06 t (1F, 9-F,
HH
3
4
5
19
1
int
HF HF
3
3
FF
2
3
refined against F by the full-matrix least-squares
JFF = 21.8 Hz). Mass spectrum, m/z (I , %): 347
rel
+
method in anisotropic approximation for all non-hy-
drogen atoms using SHELXTL package. The positions
of hydrogen atoms were calculated according to the
riding model in isotropic approximation. Goodness of
fit 1.004; final divergence factors: R = 0.0498, wR =
(100) [M] , 319 (21), 202 (11), 174 (23), 158 (13), 144
(70), 135 (22), 130 (12), 117 (14), 116 (18), 91 (15),
90 (11), 89 (15), 69 (17), 63 (11). Found, %: C 55.33;
H 2.32; N 12.10. C H F N OS. Calculated, %:
1
6
8
3
3
1
2
C 55.28; H 2.25; N 12.15.
0
0
.1121 [reflections with I > 2σ(I)]; R = 0.0789, wR =
1 2
2
-(4-tert-Butylphenyl)-7,8,9-trifluoro-5H-[1,3,4]-
.1164 (all independent reflections); residual electron
thiadiazolo[3,2-a]quinazolin-5-one (6c). Yield 89%,
mp 232–234°C. H NMR spectrum, δ, ppm: 1.40 s
9H, CH ), 7.60 d (2H, 3′-H, 5′-H, J = 8.5), 7.87 d
2H, 2′-H, 6′-H, J = 8.5 Hz), 7.93 d.d.d (1H, 6′-H,
JHF = 11.5, J = 7.9, J = 2.1 Hz). F–{ H} NMR
spectrum, δ , ppm: –133.18 d.d (1F, 8-F, J = 22.3,
–
3
density peaks, max/min: 0.318/–0.308 ē Å .
,3,4,5-Tetrafluoro-N-(5-phenyl-1,3,4-thiadiazol-
-yl)benzamide (5a). A solution of compound 4a
1.1 g, 2.96 mmol) in Dowtherm A (1.5 mL) was
1
3
(
2
3
HH
3
(
2
(
HH
3
4
5
19
1
HF
HF
3
refluxed for 1 h. The mixture was cooled, and the
precipitate was filtered off, washed with ethanol
F
FF
4
3
4
J = 5.4 Hz), –140.01 d.d (1F, 7-F, J = 18.8, J =
FF
FF
FF
5
(
1
.4 Hz), –149.93 m (1F, 9-F). Mass spectrum, m/z
(
(
8 mL), and recrystallized from DMSO. Yield 0.89 g
85 %), mp 225–227°C. H NMR spectrum, δ, ppm:
+
1
I , %): 389 (23) [M] , 375 (22), 374 (100), 159 (12),
rel
16 (17), 41 (13). Found, %: C 58.67; H 3.71;
N 10.72. C H F N OS. Calculated, %: C 58.61;
H 3.62; N 10.79.
7
1
–
–
.51 m (3H, Ph), 7.74 m (1H, 6′-H), 7.93 m (2H, Ph),
1
9
3.4 br.s (1H, NH). F NMR spectrum, δ , ppm:
19 14
3
3
F
137.06 m (1F), –138.19 m (1F), –150.41 m (1F),
154.59 m (1F). Mass spectrum, m/z (I , %): 353 (25)
rel
+
ACKNOWLEDGMENTS
[
M ] , 177 (100), 149 (23), 121 (15). Found, %:
C 50.95; H 1.98; N 11.87. C H F N OS. Calculated,
1
5
7
4
3
This study was performed under financial support
by the Russian Science Foundation (project no. 15-
%
: C 50.99; H 2.00; N 11.89.
,8,9-Trifluoro-2-phenyl-5H-[1,3,4]thiadiazolo-
3,2-a]quinazolin-5-one (6a). A solution of compound
a (0.26 g, 0.73 mmol) in Dowtherm A (1.0 mL) was
7
1
3-00077P) and by the Ministry of Education and
[
5
Science of the Russian Federation (state contract
no. 4.6351.2017/8.9).
refluxed for 12 h. The mixture was cooled, and the
precipitate was filtered off, washed with ethanol
CONFLICT OF INTERESTS
(
(
7
5 mL), and recrystallized from DMSO. Yield 0.22 g
1
92%), mp 281–283°C. H NMR spectrum, δ, ppm:
The authors declare the absence of conflict of
interests.
3
.59–7.67 m (5H, Ph), 7.98 d.d.d (1H, 7-H, J = 9.9,
HF
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 1 2019

8
6
NOSOVA et al.
5. Lipunova, G.N., Nosova, E.V., Laeva, A.A., Ko-
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