Fluorine-containing heterocycles: XVII. (Tetrafluorobrnzoyl)thioureas in the synthesis of fluorine-containing azaheterocycles

Article abstract of DOI:10.1134/S1070428008050199

Proceeding from (tetrafluorobenzoyl)thioureas fluorine-containing derivatives were synthesized of 1-aryl-2-ethylthioquinazolin-4-one, [1,3]benzothiazin-4-one, and also of thiazolidine and 1H-1,2,4-triazole.

Full text of DOI:10.1134/S1070428008050199

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2008, Vol. 44, No. 5, pp. 741−749. © Pleiades Publishing, Ltd., 2008.
Original Russian Text © G.N. Lipunova, E.V. Nosova, A.A. Laeva, T.V. Trashakhova, P.A. Slepukhin, V.N. Charushin, 2008, published in Zhurnal Organicheskoi
Khimii, 2008, Vol. 44, No. 5, pp. 749−757.
Fluorine-Containing Heterocycles:
XVII.* (Tetrafluorobrnzoyl)thioureas in the Synthesis
of Fluorine-Containing Azaheterocycles
G. N. Lipunovaa, E. V. Nosovaa, A. A. Laevaa, T. V. Trashakhovaa, P. A. Slepukhinb,
and V. N. Charushinb
aUral State Technical University, Yekaterinburg, Russia
bPostovsky Institute of Organic Chemistry, Ural Division, Russian Academy of Sciences, Yekaterinburg, 620219 Russia
e-mail: charushin@ios.uran.ru
Received April 4, 2006
Abstract—Proceeding from (tetrafluorobenzoyl)thioureas fluorine-containing derivatives were synthesized of
1-aryl-2-ethylthioquinazolin-4-one, [1,3]benzothiazin-4-one, and also of thiazolidine and 1H-1,2,4-triazole.
DOI: 10.1134/S1070428008050199
(Tetrafluorobenzoyl)thioureas are convenient syn-
thons for preparation of versatile fluorine-containing
heterocycles. We formerly reported on application of
(tetrafluorobenzoyl)thioureas for building up fluorine-
containing [1,3]benzothiazin-4-ones [1–5], but the syn-
thesis of derivatives of quinazolin-4-one did not succeed
[6]. Yet the interest to quinazoline derivatives, also to
fluorine-containing, considerably grew recently owing
to the wide range of biological activity inherent to this
class compounds [7–12]. For instance, in the series of
4-anilinoquinazolinone inhibitors are found of neuramini-
dase of smallpox virus [13] and highly selective inhibitors
of EGF receptor of thyrosine kinase [7, 8], 1-phenyl-
4(1H)quinazolinones are active with respect to the
receptor cholecystocholine [14], and 5-fluoro-3-(1,3,4-
thiadiazol-5-yl)quinazolin-4-ones are proved to be anti-
viral and antitumor agents [15]; 6-fluoro-3-(4-fluoro-
phenyl-ethyl)-quinazolin-4-ones are promising for
treating diseases originating from the disfunction of MC4-
R receptor, like obesity and diabetes [16].
Initial (tetrafluorobenzoyl)thioureas IIIa–IIIi were
obtained by the reaction of (tetrafluorobenzoyl) isothio-
cyanate (I) with aromatic or heterocyclic amines II in
acetonitrile at room temperature (Scheme 1). Synthesis
of thioureas IIIe–IIIi was described in [2]. We formerly
prepared compounds IIIa–IIIc from tetrafluorobenzoyl
chloride and the appropriate phenylthioureas [6], but the
synthesis of (tetrafluorobenzoyl)thioureas based on
(tetrafluorobenzoyl) isothiocyanate (I) proved to be more
feasible as seen from the higher yields of target products.
The structure of N-tetrafluorobenzoyl-N'-arylthioureas
IIIa–IIId was confirmed by NMR spectra (see
EXPERIMENTAL).
The attempt at S-alkylation of thioureas III and
cyclocondensation of the derivative obtained into 6,7,8-
trifluoroquinazolin-4-one was successful only in the case
of compound IIIb (Scheme 1). The reaction of com-
pound IIIb with ethyl iodide in ethanol in the presence
of sodium hydroxide at room temperature in 2 days led
to the formation S-ethyl derivative IV whose structure
was confirmed by 1H NMR spectrum, and heating of it
in toluene in the presence of triethylamine for 3 h resulted
in quinazolinone V. The reaction of compound IIIb with
ethyl iodide in the presence of NaOH at 800C for 5 h
also yielded quinazolinone V. The closure of the ring is
confirmed by the appearance in the 1H NMR spectrum
of compound V of a characteristic d.d.d signal at
7.43 ppm. In the 19F NMR spectrum of quinazolinone V
We were interested in developing conditions for
alkylation of N-tetrafluorobenzoyl-N'-arylthioureas at the
sulfur atom aiming at cyclizing the derivatives obtained
into 1-aryl-2-alkylthioquinazolin-4-ones for the prepara-
tion of 1-aryl-2-mercaptoquinazolin-4-ones by intra-
molecular cyclization of N-tetrafluorobenzoyl-N'-aryl-
thioureas under basic conditions proved to be difficult [6].
* For communication XVI, see [1].
741

LIPUNOVA et al.
742
Scheme 1.
CH3
O
F
O
S
O
F
S
R-NH2
IIa IIi
F
F
F
F
R
F
F
_
N C
S
N
N
H
C2H5I
NaOH
N
N
H
H
CH3CN,
20oC
F
F
F
F
IIIa_IIIi
H
I
IV
N
S
S
N
H
IX
NH
VI
HN
O
O
S
F
N
F
N
O
S
S
F
N
S
N
F
F
F
F
N
N
NH
H
F
X
F
O
F
VII
NEt3
CH3
F
F
V
N
S
S
N
NH
F
VIII
R = Ph (a), 4-CH3C6H4 (b), 2-ClC6H4 (c), 2,4-Cl2C6H3 (d), 2-pyridyl (e), 6-methyl-2-pyridyl (f), pyrimidin-2-yl (g), 4,6-
dimethylpyrimidin-2-yl (h), 5-methylpyrazol-3-yl (i).
the signals of three fluorine atoms are observed as d.d.d.
Mass spectrum of compound V contains a peak of
molecular ion (m/z 350) of low intensity (8%), and also
fragment peaks resulting from elimination from the
molecular ions of CO (m/z 322), SEt (m/z 289), and
EtSCN (m/z 263).
most abundant peak in the mass spectrum of benzothiazi-
none VIII m/z 258 corresponds to the fragment ion [M –
HSCN]+, and peak m/z 190 (63%) is consistent with the
data on fragmentation of 6,7,8-trifluoro-2-R-[1,3]benzo-
thiazin-4-ones [2].
The reaction of tetrafluorobenzoyl isothiocyanate (I)
with benzimidazole-2-thione IX in boiling acetone takes
another route leading to benzimidazo[2,1-b]benzothiazi-
none X that proved to be identical to the compound
obtained from tetrafluorobenzoyl chloride and thione IX
[17]. At keeping the dispersion of compounds IX and I
the yield of compound X is significantly lower due to
the low solubility of thione IX. Evidently the derivatives
of benzimidazole-2-thione do not react with the N=C
bond of isothiocyanate I but substitute the N=C=S
moiety. The replacement of the fragment N=C=S of
tetrafluorobenzoyl isothiocyanate by the residue of
2-aminothiazole was reported in [2].
In order to obtain new fluorine-containing derivatives
of [1,3]benzothiazin-4-one we investigated the reaction
between tetrafluorobenzoyl isothiocyanate (I) with
azolylthiones. The mixing of solutions of imidazolidine-
thione VI and isothiocyanate I initiated an addition
reaction resulting in benzamide VII (Scheme 1) (see
EXPERIMENTAL). The cyclization of compound VII
into [1,3]benzothiazin-4-one VIII occurred at boiling in
toluene in the presence of triethylamine for 2.5 h. The
structure of [1,3]benzothiazin-4-one VIII was confirmed
1
1
by H NMR and mass spectra. Thus in the H NMR
spectrum of compound VIII the signals of the protons
of imidazolidine fragment were conserved, one signal
of NH group disappeared, and the multiplicity of H5
signal simplified to d.d.d in the region δ 7.62 ppm. The
We also studied reactions of (tetrafluorobenzoyl)-
thioureas III proceeding without involvement of the
fluorine atom in the ortho-position to the benzoyl group.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

FLUORINE-CONTAINING HETEROCYCLES: XVII.
743
Actually, the reaction of thioureas IIIa, IIIb, IIIe–IIIi
with dimethyl acetylenedicarboxylate (XI) is a conveni-
ent procedure for preparation of new fluorine-containing
heterocycles (Scheme 2). The treatment of methanol
solutions of thioureas III with ester XI at room tempera-
ture for 12 h led to cyclocondensation providing thiazo-
lidinones XII in 73–82% yield.
1
In the H NMR spectra of reaction products of
thioureas III and ester XI appeared signals of protons
from aryl(heteryl) fragments, multiplet from the
tetrafluorobenzoyl fragment at δ 7.47–7.64 ppm, also
a singlet of the proton of thiazolidine moiety in the region
δ 6.98–7.07 ppm, and a three-proton singlet of the
methoxycarbonyl group at δ 3.88–3.90 ppm. The mass
spectra of compounds XII contain the peak of molecular
ion of intensity 9–29%, whereas the most abundant is
the peak of m/z 177 corresponding to the fluoroaryl
fragment C6HF4. Although published data indicated the
formation of 4-thiazolidinones derivatives in reaction of
thioureas (or thioamides) with ester XI [18–20], we
subjected compound XIIa to XRD analysis in order to
exclude the formation of an alternative product, methyl
3-aryl(heteryl)-4-oxo-2-(2,3,4,5-tetrafluorobenzoyl-
imino)-3,4-dihydro-2H-[1,3]thiazine-6-carboxylate XIII.
According to XRD data (see the figure) compound XIIa
really has a structure of a thiazolidinone.
Structure of methyl [4-oxo-3-phenyl-2-(2,3,4,5-tetrafluoro-
benzoylimino)thiazolidin-5-ylidene]acetate (XIIa).
located in the para-position to the amide group is sub-
stituted with a residue of cycloalkylamine thus preventing
the concurrent reaction at the fragment C(O)NHC(S) and
the fluorine atom in the aromatic ring. To this end by
boiling thioureas IIIc and IIId with pyrrolidine or
morpholine in DMF we obtained derivatives XIVa–XIVc
(Scheme 3). Thioureas IIIa and IIIb at heating in DMF
underwent cyclization giving a mixture of benzothiazi-
none and quinazolinone [6], and compound IIIe–IIIi
suffered cyclization into benzothiazinones [2]. The
The (tetrafluorobenzoyl)thioureas III can be also
involved into reactions at carbonyl and thiocarbonyl
groups situated in the β-position to each other. The
investigation of reactions between compounds III and
dinucleophiles, e.g., hydrazine, is more convenient to
perform using derivatives where the fluorine atom
1
structure of thioureas XIV was confirmed by H NMR
spectra.
Scheme 2.
R
O
F
O
N
F
F
N
S
O
F
S
MeOOC
COOMe
COOMe
F
F
R
F
XI
N
N
XIIa, XIIb, XIIe_XIIi
H
H
COOMe
O
S
F
F
F
N
IIIa, IIIb, IIIe_IIIi
N
F
R
O
F
XIII
R = Ph (a), 4-CH3C6H4 (b), 2-pyridyl (e), 6-methyl-2-pyridyl (f), pyrimidin-2-yl (g), 4,6-dimethylpyrimidin-2-yl (h), 5-methylpyrazol-
3-yl (i).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

LIPUNOVA et al.
744
Scheme 3.
XIV, XV, NR1R2 = pyrrolidin-1-yl, R3 = 2-ClC6H4 (a), 2,4-Cl2C6H3 (b); NR1R2 = morpholino, R3 = 2-ClC6H4 (c); XVI,
R3 = C6H5 (a), 4-CH3C6H4 (b).
In the reaction of thioureas XIVa–XIVc with
hydrazine hydrate within 2 h a closure 4H-1,2,4-triazole
ring occurred with the formation of derivatives XVa–
formation of dihydrazino derivative XVII. Thus also the
arylamino moiety in the position 3 of triazole ring is
capable of being replaced by hydrazine group. This was
confirmed by the reaction of compound XVIb with
hydrazine hydrate for 6 h that yielded derivative XVII.
Hydrazino derivative XVI and dihydrazino derivative
XVII on heating with acetylacetone in acetonitrile in
the presence of acetic acid were converted into
derivatives XVIII and XIX.
1
XVc whose structure is consistent with the H NMR
spectra. As expected, in the reaction of thioureas IIIa
and IIIb with hydrazine hydrate for 2 h occurred both
the closure of the triazole ring and the substitution of F4'
aton by the hydrazine group. The structure of obtained
compounds XVIa and XVIb was confirmed by spectral
data. In reaction with hydrazine hydrate of heteryl-
substituted thioureas IIIe and IIIg in 2 h occurred both
cyclization and substitution of the heteryl moiety by the
hydrazine as showed the lack in the 1H NMR spectrum
of derivative XVII the signals from protons of the
pyridine or pyrimidine moieties and appearance of
NHNH2 signals. Compound XVII was also obtained in
reaction of benzamide VII with hydrazine hydrate within
2 h. The prolongation of the reaction between thiourea
IIIb and hydrazine hydrate from 2 to 8 h resulted in the
Thus the study demonstrated that nucleophilic
reactions
of
N-tetrafluorobenzoyl-N'-aryl-
(heteryl)thioureas III involved the fluorine atom in the
ortho-position and also the C(O)–NH–C(S) fragment of
compounds III.
EXPERIMENTAL
1H NMR spectra were registered on spectrometers
Bruker WM-250 and Bruker DRX-400 at operating
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

FLUORINE-CONTAINING HETEROCYCLES: XVII.
745
frequencies 250.14 and 400.13 MHz (internal reference
TMS); 19F NMR spectra were recorded on a spectrometer
Bruker DRX-500 at operating frequency 376.45 MHz
(internal reference hexafluorobenzene). DMSO-d6 was
used as solvent. Mass spectra were measured on Varian
MAT 311Ainstrument at following parameters: acceler-
ating voltage 3 kV, cathode emission current 300 μA,
ionizing electrons energy 70 eV, direct admission of the
sample into the ion source. XRD analysis of compound
XIIa was performed on single-crystal X-ray diffractom-
eter Xcalibur 3 with a CCD-detector with the use of
software package SHELXL-97 [21]. The wavelength of
radiation λ 0.71073 (MoKα), temperature at the
experiment 295 K. Crystals 0.5 × 0.4 × 0.3 mm, colorless,
triclinic, space group P1 (pseudo P-1), unit cell param-
Atomic coordinates (in fractions of unit cell axes) and thermal
factors Uiso/Ueq for methyl [4-oxo-2-(2,3,4,5-tetrafluorobenzo-
ylimino)-3-phenylthiazolidin-5-ylidene]acetate (XIIa)
°
eters: a 10.6311(18), b 14.028(3), C 14.6841(13) A,
α 64.041(16), β 81.001(16), γ 76.935(16)°. The cell
includes 4 molecular units with a coplanar location of
thiazole and tetrafluorophenyl rings The structure was
solved by the direct method in isotropic approximation
and refined in anisotropic approximation. The atomic
coordinates and thermal factors are given in the table.
N-(2,3,4,5-Tetrafluorobenzoyl)-N'-phenylthiourea
(IIIa). To a solution of 6.0 g (28 mmol) of tetra-
fluorobenzoyl chloride in 6.5 ml of toluene was added
a solution of 2.17 g (28 mmol) of ammonium thiocyanate
in 35 ml of anhydrous acetonitrile. The mixture was
heated for 5 min at 40°C, the ammonium chloride was
filtered off, and the filtrate was added to the solution of
2.5 ml (2.55 g, 27.4 mmol) of aniline in 5 ml of anhydrous
acetonitrile. The reaction mixture was kept for 3 h at
room temperature, the separated precipitate was filtered
off and recrystallized from ethanol. Yield 8.2 g (91%),
1
mp 118–120°C. H NMR spectrum, δ, ppm: 7.09 m
(1Harom), 7.32 m (2Harom), 7.57 m (1H, H6'), 7.67 m
(1Harom), 10.4 br.s (1H, NH), 14.0–15.0 br.s (1H, NH).
Found, %: C 51.27; H 2.38; N 8.49. C14H8F4N2OS.
Calculated, %: C 51.22; H 2.46; N 8.53.
Compounds IIIb–IIId were prepared similarly.
N-(2,3,4,5-Tetrafluorobenzoyl)-N'-(p-tolyl)thio-
urea (IIIb). Yield 92%, mp 120–122°C. 1H NMR spec-
trum, δ, ppm: 2.31 s (3H, CH3), 7.11 m (2Harom), 7.54 m
(2Harom), 7.60 m (1H, H6'), 10.3 br.s (1H, NH), 14.0–
15.0 br.s (1H, NH). Found, %: C 52.58; H 2.99; N 8.23.
C15H10F4N2OS. Calculated, %: C 52.63, H 2.94, N 8.18.
N-(2,3,4,5-Tetrafluorobenzoyl)-N'-(2-chlorophenyl)-
1
thiourea (IIIc). Yield 89%, mp 123–125°C. H NMR
spectrum, δ, ppm: 7.24 m (1Harom), 7.36 m (1Harom),
7.49 m (1Harom), 7.65 m (1H, H6'), 7.85 m (1Harom),
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

LIPUNOVA et al.
746
9.9 br.s (1H, NH), 14.0–15.0 br.s (1H, NH). 19F NMR
spectrum, δ, ppm: 7.47 m (1F), 10.38 m (1F), 23.84 m
(2F). Found, %: C 46.39; H 2.09; N 7.53.
C14H7ClF4N2OS. Calculated, %: C 46.36; H 1.95; N 7.72.
N-(2-Thioxoimidazolidine-1-carbothioyl)-2,3,4,5-
tetrafluorobenzamide (VII). To a solution of 12 mmol
of imidazolidine-2-thione (VI) in a mixture of 15 ml of
dioxane and 15 ml of acetonitrile was added 24 mmol of
isothiocyanate solution in acetonitrile (the solution was
prepared as described in the procedure of the synthesis
of compound IIIa). The reaction mixture was maintained
at room temperature for 24 h. The yellow-green
precipitate was filtered off and recrystallized from
N-(2,4-Dichlorophenyl)-N'-(2,3,4,5-tetrafluoro-
benzoyl)thiourea (IIId). Yield 93%, mp 136–138°C.
1H NMR spectrum, δ, ppm: 7.18 d.d (1H, H4'', 3J 8.8, 4J
2.5 Hz), 7.41 m (1H, H6'), 7.52 d (1H, H3'', 3J 8.8 Hz),
4
8.35 d (1H, H6'', J 2.5 Hz), 9.2 br.s (1H, NH), 13.5–
1
acetonitrile. Yield 3.3 g (83%), mp 202–204°C. H NMR
14.0 br.s (1H, NH). Found, %: C 42.38; H 1.59; N 7.03.
C14H6Cl2F4N2OS. Calculated, %: C 42.32; H 1.51; N 7.05.
spectrum, δ, ppm: 3.56 m (2H, CH2), 4.44 m (2H, CH2),
7.62 m (1H, H6'), 10.4 br.s (1H, NH), 14.8 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 337 (35) [M]+, 278 (49)
[M – HSCN]+, 177 (100), 149 (28). Found, %: C 39.24;
H 2.13; N 12.42. C11H7F4N3OS2. Calculated, %: C 39.17;
H 2.08; N 12.46. M 337.32.
2-Ethyl-1-(2,3,4,5-tetrafluorobenzoyl)-3-(p-tolyl)-
isothiourea (IV). To a solution of 2.0 g (5.8 mmol) of
thiourea IIIb was added 1.8 ml of ethyl iodide and
1.8 ml of 30% NaOH solution. The reaction mixture was
left standing for 2 days at room temperature, then the
precipitate was filtered off, the mother liquor was
evaporated, and the residue was recrystallized from
2-(2-Thioxoimidazolidin-1-yl)-6,7,8-trifluoro-
[1,3]benzothiazin-4-one (VIII). To a dispersion of
0.7 g (2.1 mmol) of benzamide VII in 10 ml of toluene
was added 0.6 ml (4.2 mmol) of triethylamine. The
reaction mixture was boiled for 2.5 h, then it was
evaporated, the residue was washed with water and dilute
acetic acid, then it was recrystallized from ethanol. Yield
0.45 g (67%), mp 130–132°C. 1H NMR spectrum, δ,
1
ethanol. Yield 1.7 g (79%), mp 125–127°C. H NMR
spectrum, δ, ppm: 1.39 t (3H, CH3), 2.31 s (3H, CH3),
3
4.31 q (2H, SCH2), 7.10 d (2Harom, J 8.5 Hz), 7.32 m
(1H, H6'), 7.54 d (2Harom, 3J 8.5 Hz), 10.1 br.s (1H, NH).
Found, %: C 55.24; H 3.47; N 7.63. C17H13F4N2OS.
Calculated, %: C 55.28; H 3.52; N 7.59.
3
ppm: 3.95 m (4H, 2CH2), 7.62 d.d.d (1H, H5, J 10.3,
1-(p-Tolyl)-6,7,8-trifluoro-2-ethylsulfanyl-1H-
quinazolin-4-one (V). a. To a solution of 2.0 g (5.8 mmol)
of thiourea IIIb was added 1.8 ml of ethyl iodide and
1.8 ml of 30% NaOH solution. The reaction mixture was
for 5 h heated to 80°C, then it was evaporated, the residue
was washed with water, then with a mixture hexane–
ethanol, 2:1, and recrystallized from ethanol. Yield 1.35 g
4J 7.6, 5J 2.1 Hz ), 12.1 br.s (1H, NH). Mass spectrum,
m/z (Irel, %): 258 (100) [M – HSCN]+, 190 (63), 172
(13), 162 (18), 69 (22). Found, %: C 41.68; H 1.95;
N 13.20. C11H6F3N3OS2. Calculated, %: C 41.64; H 1.89;
N 13.25.
2,3,4-Trifluoro-6a,10a-dihydro-12H-benzo[e]-
benzo[4,5]imidazo[2,1-b][1,3]thiazin-12-one (X). To
1.2 g (8 mmol) of benzimidazole -2-thione (IX) in 15 ml
of anhydrous acetonitrile was added a solution of
12 mmol of tetrafluorobenzoyl isothiocyanate (I), the
reaction mixture was boiled for 2 h, then it was cooled.
The settled precipitate was filtered off and recrystallized
from DMSO.Yield 2.2 g (90%), mp 224–226°C. 1H NMR
spectrum, δ, ppm: 7.50 m (2H, H8, H9), 7.76 m (1H, H10),
1
(67%), mp 212–214°C. H NMR spectrum, δ, ppm:
1.29 t (3H, CH3), 3.00 s (3H, CH3), 3.07 q (2H, SCH2),
3
3
7.35 d (2Harom, J 8.5 Hz), 7.42 d (2Harom, J 8.5 Hz),
7.82 d.d.d (1H, H5, 3J 10.0, 4J 7.8, 5J 2.3 Hz). 19F NMR
spectrum, δ, ppm: 11.06 d.d.d (1F, F7, 3J 23.0, 3J 19.6,
4J 8.0 Hz), 20.46 d.d.d (1F, F8, 3J 19.6, 4J 4.0, 5J 2.5 Hz),
25.54 d.d.d (1F, F6, J 23.0, J 9.8, J 4.0 Hz). Mass
spectrum, m/z (Irel, %): 350 (8) [M]+, 322 (26), 321 (12),
289 (3), 264 (11), 263 (64), 262 (18), 234 (21), 173 (13),
120 (10), 119 (100). Found, %: C 58.30; H 3.81; N 8.04.
C17H13F3N2OS. Calculated, %: C 58.28; H 3.74; N 7.99.
M 350.36.
3
3
4
3
4
5
8.34 d.d.d (1H, H5, J 10.7, J 7.3, J 1.2 Hz), 8.48 m
(1H, H7). 19F NMR spectrum, δ, ppm: 12.78 d.d.d (1F,
F3, J 22.5, J 20.9, J 7.3 Hz), 28.83 d.d.d (1F, F2,
3J 22.5, 3J 10.7, 4J 5.6 Hz), 29.65 d.d.d (1F, F4, 3J 20.8,
4J 5.6, 5J 1.5 Hz). Mass spectrum, m/z (Irel, %): 306 (100)
[M]+, 274 (10), 190 (13), 162 (9). Found, %: C 55.00;
H 1.30; N 9.19. C14H5F3N2OS. Calculated, %: C 54.91;
H 1.65; N 9.15. M 306.26.
3
3
4
b. To a solution of 0.5 g (1.35 mmol) of compound
IV in 15 ml of anhydrous toluene was added 0.45 ml
(3 mmol) of triethylamine. The reaction mixture was
boiled for 3 h, then evaporated, the residue was washed
with water and recrystallized from ethanol. Yield 0.28 g
(60%).
Methyl [4-oxo-2-(2,3,4,5-tetrafluorobenzoyl-
imino)-3-phenylthiazolidin-5-ylidene]acetate (XIIa).
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FLUORINE-CONTAINING HETEROCYCLES: XVII.
747
3
To a solution of 0.45 g (1.37 mmol) of thiourea IIIa in
20 ml of methanol was added 0.3 ml (2.38 mmol) of
dimethyl acetylenedicarboxylate (XI). The reaction
mixture was stirred at room temperature for 12 h, the
separated colorless precipitate was filtered off and
recrystallized from DMSO. Yield 0.48 g (80%), mp 168–
(2H, H3', H5', J 4.9 Hz). Mass spectrum, m/z (Irel, %):
440 (22) [M]+, 297 (9), 291 (10), 177 (100), 149 (30),
144 (57), 116 (42), 85 (18). Found, %: C 46.29; H 1.84;
N 12.67. C17H8F4N4O4S. Calculated, %: C 46.37; H 1.83;
N 12.72.
Methyl [4-oxo-3-(4,6-dimethylpyrimidin-2-yl)-2-
(2,3,4,5-tetrafluorobenzoylimino)thiazolidin-5-
ylidene]acetate (XIIh). Yield 75%, mp 240–242°C.
1H NMR spectrum, δ, ppm: 2.59 s (6H, 2CH3), -3.89 s
(3H, COOMe), 7.05 s (1H, CH), 7.49 s (1H, H4'), 7.52 m
(1H, CHF4). Mass spectrum, m/z (Irel, %): 468 (29) [M]+,
325 (12), 177 (100), 149 (22), 144 (44), 116 (34), 85
(12). Found, %: C 48.66; H 2.58; N 11.87.
C19H12F4N4O4S. Calculated, %: C 48.72; H 2.58; N 11.96.
1
170°C. H NMR spectrum, δ, ppm: 3.89 s (3H, COOMe),
6.99 s (1H, CH), 7.54 m (2H, Ph), 7.57 m (4H, Ph, CHF4).
Mass spectrum, m/z (Irel, %): 438 (15) [M]+, 289 (11),
177 (100), 149 (19). Found, %: C 52.15; H 2.19; N 6.43.
C19H10F4N2O4S. Calculated, %: C 52.06; H 2.30; N 6.39.
M 438.35.
Compounds XIIb, XIIe–XIIi were analogously
obtained.
Methyl [4-oxo-3-(5-methylpyrazol-3-yl)-2-(2,3,4,5-
tetrafluorobenzoylimino)thiazolidin-5-ylidene]-
acetate (XIIi). Yield 75%, mp 218–220°C. H NMR
Methyl [4-oxo-2-(2,3,4,5-tetrafluoro-benzoyl-
imino)-3-(p-tolyl)thiazolidin-5-ylidene]acetate (XIIb).
Yield 82%, mp 155–157°C. 1H NMR spectrum, δ, ppm:
2.46 s (3H, CH3), 3.90 s (3H, COOMe), 6.98 s (1H, CH),
1
spectrum, δ, ppm: 2.37 s (3H, CH3), 3.88 s (3H,
-
COOMe), 6.09 s (1H, H4'), 6.99 s (1H, CH), 7.64 m (1H,
CHF4), 12.9 br.s (1H, NH). Mass spectrum, m/z (Irel, %):
442 (15) [M]+, 293 (7), 177 (100), 149 (19). Found, %:
C 46.20; H 2.32; N 12.62. C17H10F4N4O4S. Calculated,
%: C 46.16; H 2.28; N 12.67.
3
7.33 d (4Harom, J 2.8 Hz), 7.52 m (1H, CHF4). Mass
spectrum, m/z (Irel, %): 452 (15) [M]+, 303 (7), 177 (100),
149 (17). Found, %: C 53.09; H 2.62; N 6.15.
C20H12F4N2O4S. Calculated, %: C 53.10; H 2.67; N 6.19.
M 452.38.
N-(2,4-Dichlorophenyl)-N'-[4-(pyrrolidin-1-yl)-
2,3,5-trifluorobenzoyl]thiourea (XIVb). To 2.0 g
(5.0 mmol) of compound IIId in 12 ml of DMF was
added 1.7 g (24 mmol) of pyrrolidine, the mixture was
boiled for 5 h, on cooling the colorless precipitate was
filtered off and recrystallized from DMSO. Yield 1.9 g
Methyl [4-oxo-3-(2-pyridyl)-2-(2,3,4,5-tetra-
fluorobenzoylimino)thiazolidin-5-ylidene]acetate
(XIIe). Yield 79%, mp 205–210°C. 1H NMR spectrum,
δ, ppm: 3.89 s (3H, COOMe), 7.02 s (1H, CH), 7.47 m
(1H, CHF4), 7.60 m (2H, Py), 8.07 m (1H, Py), 8.65 (1H,
Py). Mass spectrum, m/z (Irel, %): 439 (10) [M]+, 407
(10), 290 (7), 262 (21), 177 (100), 149 (24), 144 (11),
116 (18), 85 (10), 78 (11). Found, %: C 49.18; H 2.12;
N 9.53. C18H9F4N3O4S. Calculated, %: C 49.19; H 2.06;
N 9.56. M 439.34.
1
(83%), mp 166–168°C. H NMR spectrum, δ, ppm:
1.93 m [4H, (CH2)2], 3.68 m [4H, N(CH2)2], 7.17 d.d
(1H, H4'', 3J 8.8, 4J 2.5 Hz), 7.34 d.d.d (1H, H6', 3J 14.0,
5
3
4J 7.1, J 2.0 Hz), 7.48 d (1H, H3'', J 8.8 Hz), 8.32 d
(1H, H6'', J 2.5 Hz), 9.2 br.s (1H, NH), 12.1 br.s (1H,
4
NH). Found, %: C 48.27; H 3.19; N 9.33.
C18H14Cl2F3N3OS. Calculated, %: C 48.21; H 3.13; N 9.38.
Methyl [4-oxo-3-(6-methyl-2-pyridyl)-2-(2,3,4,5-
tetrafluorobenzoylimino)thiazolidin-5-ylidene]-
acetate (XIIf). Yield 76%, mp 203–205°C. H NMR
1
Compounds XIVa and XIVc were obtained similarly
spectrum, δ, ppm: 2.58 s (3H, CH3), 3.90 s (3H, COOMe),
and recrystallized from ethanol.
7.01 s (1H, CH), 7.41 d.d (2H, H3', H5', 3J 7.8, 4J 4.6 Hz),
N-[4-(Pyrrolidin-1-yl)-2,3,5-trifluorobenzoyl]-N'-
(2-chlorophenyl)thiourea (XIVa). Yield 79%, mp 98–
100°C. 1H NMR spectrum, δ, ppm: 1.92 m [4H, (CH2)2],
3.66 m [4H, N(CH2)2], 7.17 m (1Harom), 7.34 m (1Harom),
3
7.51 m (1H, CHF4), 7.94 t (1H, H4', J 7.8 Hz). Mass
spectrum, m/z (Irel, %): 453 (9) [M]+, 421 (7), 276 (27),
177 (100), 149 (21), 116 (13). Found, %: C 50.44; H 2.36;
N 9.28. C19H11F4N3O4S. Calculated, %: C 50.34; H 2.45;
N 9.27. M 453.37.
3
5
7.36 d.d.d (1H, H6', J 14.2, 4J 7.2, J 2.2 Hz), 7.47 m
(1Harom), 8.13 m (1Harom), 9.2 br.s (1H, NH), 14.0 br.s
(1H, NH). Found, %: C 52.28; H 3.71; N 10.09.
C18H15ClF3N3OS. Calculated, %: C 52.24; H 3.65;
N 10.15.
Methyl [4-oxo-3-(pyrimidin-2-yl)-2-(2,3,4,5-
tetrafluorobenzoylimino)thiazolidin-5-ylidene]-
1
acetate (XIIg). Yield 73%, mp 210–212°C. H NMR
spectrum, δ, ppm:-3.90 s (3H, COOMe), 7.07 s (1H, CH),
N-(4-Morpholino-2,3,5-trifluorobenzoyl)-N'-(2-
chlorophenyl)thiourea (XIVc). Yield 77%, mp 111–
3
7.47 m (1H, CHF4), 7.81 t (1H, H4', J 4.9 Hz), 9.08 d
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

LIPUNOVA et al.
748
1
113°C. H NMR spectrum, δ, ppm: 3.31 m [4H,
(20 mmol) of hydrazine hydrate, the mixture was boiled
for 2 h, on cooling the precipitate was filtered off and
recrystallized from ethanol. Yield 0.25 g (86%), mp 183–
N(CH2)2], 3.75 m [4H, O(CH2)2], 7.20 m (1Harom),
7.36 m (1Harom), 7.47 d.d.d (1H, H6', J 13.9, J 7.1,
5J 2.2 Hz), 7.50 m (1Harom), 8.11 m (1Harom), 9.4 br.s
(1H, NH), 14.0 br.s (1H, NH). Found, %: C 50.34; H 3.49;
N 9.72. C18H15ClF3N3O2S. Calculated, %: C 50.29;
H 3.42; N 9.78.
3
4
1
185°C. H NMR spectrum, δ, ppm: 4.31 br.s (2H, NH2),
6.75 br.s (1H, NH), 7.02 m (1Harom), 7.16 d.d.d (1H, H6',
4
5
3J 12.5, J 6.2, J 2.2 Hz), 7.26 m (2Harom), 7.64 m
(2Harom), 9.8 br.s (1H, NH), 12.9 br.s (1H, NH). Found,
%: C 52.47; H 3.42; N 26.27. C14H11F3N6. Calculated,
%: C 52.50; H 3.46; N 26.24. Likewise was obtained
compound XVIb.
[4-(Pyrrolidin-1-yl)-5-(2,3,5-trifluorophenyl)-4H-
1,2,4-triazol-3-yl]-2-chlorophenylamine (XVa). To
0.2 g (0.48 mmol) of thiourea XIVa in 20 ml of ethanol
was added 1 ml (20 mmol) of hydrazine hydrate, the
mixture was boiled for 2 h, on cooling the precipitate
was filtered off and recrystallized from ethanol. Yield
0.16 g (84%), mp 109–111°C. 1H NMR spectrum, δ, ppm:
1.92 m [4H, (CH2)2], 3.65 m [4H, N(CH2)2], 7.13 m
(1Harom), 7.32 m (1Harom), 7.39 d.d.d (1H, H6', 3J 12.5,
4J 6.2, J 2.2 Hz), 7.48 m (1Harom), 8.24 m (1Harom),
9.1 br.s (1H, NH), 13.0 br.s (1H, NH). 19F NMR spectrum,
δ, ppm: 12.08 d.d (1F, F2', J 18.1, J 6.2 Hz),
22.58 d.d.d (1F, F3', 3J 18.1, 4J 6.6, 5J 2.2 Hz), 34.63 d.d
(1F, F5', 3J 12.3, 4J 6.6 Hz). Found, %: C 54.88; H 3.83;
N 17.73. C18H15ClF3N5. Calculated, %: C 54.85; H 3.81;
N 17.78.
[5-(4-Hydrazino-2,3,5-trifluorophenyl)-4H-1,2,4-
triazol-3-yl](p-tolyl)amine (XVIb). Yield 83%, mp
1
170–172°C. H NMR spectrum, δ, ppm: 2.31 C (3H,
CH3), 4.33 br.s (2H, NH2), 6.76 br.s (1H, NH), 7.08 d
(2Harom, 3J 8.8 Hz), 7.14 d.d.d (1H, H6', 3J 12.3, 4J 6.1,
5J 2.1 Hz), 7.54 d (2Harom, 3J 8.8 Hz), 9.7 br.s (1H, NH),
12.5 br.s (1H, NH). Found, %: C 53.93; H 3.96; N 25.09.
C15H13F3N6. Calculated, %: C 53.89; H 3.92; N 25.14.
5
3
4
[5-(4-Hydrazino-2,3,5-trifluorophenyl)-4H-1,2,4-
triazol-3-yl]hydrazine (XVII). To 0.5 g (1.5 mmol) of
thiourea IIIg in 20 ml of ethanol was added 2.5 ml
(50 mmol) of hydrazine hydrate, the mixture was boiled
for 2 h, on cooling the precipitate was filtered off and
recrystallized from ethanol. Yield 0.32 g (82%), mp
Compound XVb and XVc were similarly obtained.
1
195–197°C. H NMR spectrum, δ, ppm: 4.37 br.s
(2,4-Dichlorophenyl)-[4-(pyrrolidin-1-yl)-5-(2,3,5-
trifluorophenyl)-4H-1,2,4-triazol-3-yl]-amine (XVb).
(4H, 2NH2), 6.7 br.s (1H, NH), 7.14 d.d.d (1H, H6', 3J
12.5, 4J 7.1, 5J 2.5 Hz), 9.1 br.s (1H, NH), 12.4 br.s (1H,
NH). Found, %: C 37.11; H 3.14; N 37.78. C8H8F3N7.
Calculated, %: C 37.07; H 3.09; N 37.84.
1
Yield 81%, mp 178–180°C. H NMR spectrum, δ, ppm:
1.94 m [4H, (CH2)2], 3.68 m [4H, N(CH2)2], 7.15 d.d
(1H, H4'', 3J 8.8, 4J 2.5 Hz), 7.34 d.d.d (1H, H6', 3J 12.5,
Likewise compound XVII was obtained from thiourea
IIIe (yield 76%), benzamide VII (yield 74%), thiourea
IIIb at reaction duration 8 h (yield 71%) or compound
XVIb at reaction duration 6 h (yield 77%).
4J 6.4, J 2.1 Hz), 7.47 d (1H, H3'', J 8.8 Hz), 8.36 d
5
3
(1H, H6'', J 2.5 Hz), 9.1 br.s (1H, NH), 12.8 br.s (1H,
4
NH). 19F NMR spectrum, δ, ppm: 11.98 m (1F), 21.89 m
(1F), 34.64 m (1F). Found, %: C 50.51; H 3.32; N 16.31.
C18H14Cl2F3N5. Calculated, %: C 50.74; H 3.27; N 16.36.
{5-[4-(3,5-Dimethylpyrazol-1-yl)-2,3,5-
trifluorophenyl]-4H-1,2,4-triazol-3-yl}(p-tolyl)-amine
(XVIII). To a solution of 0.65 g (1.9 mmol) of compound
XVIb in 12 ml of anhydrous acetonitrile was added
0.39 ml (0.39 g, 3.8 mmol) of acetylacetone and 0.4 ml
of acetic acid. The reaction mixture was boiled for 2 h,
then it was evaporated, the residue was washed with
water and recrystallized from ethanol. Yield 0.55 g (73%),
[5-(4-Morpholino-2,3,5-trifluorophenyl)-4H-1,2,4-
triazol-3-yl](2-chlorophenyl)amine (XVc). Yield 79%,
mp 167–169°C. H NMR spectrum, δ, ppm: 3.30 m [4H,
N(CH2)2], 3.73 m [4H, O(CH2)2], 7.21 m (1Harom),
7.37 m (1Harom), 7.43 d.d.d (1H, H6' , J 12.3, J 6.5,
5J 2.0 Hz), 7.49 m (1Harom), 8.07 m (1Harom), 9.4 br.s
(1H, NH), 12.7 br.s (1H, NH). 19F NMR spectrum, δ,
ppm: 17.98 d.d (1F, F2', 3J 21.2, 4J 6.2 Hz), 21.66 d.d.d
(1F, F3', 3J 21.2, 4J 6.5, 5J 2.1 Hz), 37.89 d.d (1F, F5',
3J 12.7, 4J 6.5 Hz). Found, %: C 52.79; H 3.71; N 17.06.
C18H15ClF3N5O. Calculated, %: C 52.75; H 3.66; N 17.09.
1
3
4
1
mp 145–147°C. H NMR spectrum, δ, ppm: 2.22 s (6H,
2CH3), 2.64 s (3H, CH3), 6.06 s (1H, CH), 7.11 d (2Harom
,
3J 8.2 Hz), 7.52 m (1H, H6'), 7.57 d (2Harom, 3J 8.2 Hz),
10.3 br.s (1H, NH), 13.5 br.s (1H, NH). Found, %:
C 60.39; H 4.32; N 21.06. C20H17F3N6. Calculated, %:
C 60.33; H 4.27; N 21.11.
Phenyl[5-(4-hydrazino-2,3,5-trifluorophenyl)-4H-
1,2,4-triazol-3-yl]amine (XVIa). To 0.3 g (0.91 mmol)
of thiourea IIIa in 20 ml of ethanol was added 1 ml
3-(3,5-Dimethylpyrazol-1-yl)-5-[4-(3,5-dimethyl-
pyrazol-1-yl)-2,3,5-trifluorophenyl]-4H-1,2,4-triazole
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 44 No. 5 2008

FLUORINE-CONTAINING HETEROCYCLES: XVII.
749
(XIX). To a solution of 0.4 g (1.5 mmol) of compound
XVII in 12 ml of anhydrous acetonitrile was added
0.39 ml (0.39 g, 3.8 mmol) of acetylacetone and 0.4 ml
of acetic acid. The reaction mixture was boiled for 2 h,
then it was evaporated, the residue was dissolved in
5 ml of ethanol, the product was reprecipitated with
water, filtered off, and recrystallized from ethanol. Yield
0.4 g (69%), mp 120–122°C. 1H NMR spectrum, δ, ppm:
2.18 s (3H, CH3), 2.21 s (3H, CH3), 2.21 s (3H, CH3),
2.64 s (3H, CH3), 6.07 s (1H, CH), 6.24 s (1H, CH), 7.51
d.d.d (1H, H6', 3J 11.3, 4J 6.1, 5J 1.8 Hz), 12.5 br.s (1H,
NH). Found, %: C 55.75; H 4.17; N 25.24. C18H16F3N7.
Calculated, %: C 55.70; H 4.13; N 25.30.
(Achievements in Organic Synthesis), Ekaterinburg: Izd.
UrO RAN, 2003, p. 254.
7. Rocco, S.A., Barbarini, J.E., and Rittner, R., Synthesis,
2004, no. 3, p. 429.
8. Ciardiello, F., Drugs, 2000, vol. 60, p. 25.
9. Rewcastle, G.W., Denny, W.A., Bridges, A.J., Zhou, H.,
Cody, D.R., McMichael, A., and Fry, D.W., J. Med. Chem.,
1995, vol. 38, p. 3482.
10. Bridges, A.J., Zhou, H., Cody, D.R., Rewcastle, G.W.,
McMichael, A., Fry, D.W., and Denny, W.A., J. Med.
Chem., 1996, vol. 39, p. 267.
11. Rewcastle, G.W., Murray, D.K., Elliot, W.L., Fry, D.W.,
Howard, C.T., Nelson, J.A., Roberts, B.J., Vincent, P.W.,
Showalter, H.D.H., Winters, R.T., and Denny, W.A.,
J. Med. Chem., 1998, vol. 41, p. 742.
12. Szczepankiewicz, W., Suwiski, J., and Bujok, R.,
Tetrahedron, 2000, vol. 56, p. 9343.
13. Yang, H., Kim, S.K., Kim, M., Reche, P.A., More-
head, T.J., Damon, I.K., Welsh, R.M., and Reinherz, E.L.,
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The study was carried out under financial support of
the Russian Foundation for Basic research (grant no. 06-
03-32747); of grants from Ministry of Education of the
Russian Federation and from CRDF, Annex BF4M05,
EK-005-X2[REC-005]; “BRHE 2004 post-doctoral
fellowship award” Y2-C-05-01, and also NSh-
9178.2006.3.
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