Fluorine-containing heterocycles: XV. Reactions of polyfluorobenzoyl isothiocyanates with aminoazines and aminoazoles

Article abstract of DOI:10.1134/S1070428006100253

Reactions of tetra-and pentafluorobenzoyl isothiocyanates with aminoazoles and aminoazines led to the formation of fluorinated 1,3-benzothiazin-4-ones which reacted with cyclic amines in different ways. Replacement of the N=C=S fragment was observed in so

Full text of DOI:10.1134/S1070428006100253

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2006, Vol. 42, No. 10, pp. 1544–1550. © Pleiades Publishing, Inc., 2006.
Original Russian Text © E.V. Nosova, G.N. Lipunova, A.A. Laeva, V.N. Charushin, 2006, published in Zhurnal Organicheskoi Khimii, 2006, Vol. 42, No. 10,
pp. 1555–1561.
Fluorine-Containing Heterocycles: XV.*
Reactions of Polyfluorobenzoyl Isothiocyanates
with Aminoazines and Aminoazoles
E. V. Nosovaa, G. N. Lipunovaa, A. A. Laevaa, 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 June 24, 2005
Abstract—Reactions of tetra- and pentafluorobenzoyl isothiocyanates with aminoazoles and aminoazines led
to the formation of fluorinated 1,3-benzothiazin-4-ones which reacted with cyclic amines in different ways.
Replacement of the N=C=S fragment was observed in some reactions of polyfluorobenzoyl isothiocyanates
with nucleophiles.
DOI: 10.1134/S1070428006100253
Acyl isothiocyanates are characterized by high
reactivity toward nucleophiles, including difunctional
ones, so that such reactions are widely used in the
synthesis of heterocycles [2]. Due to the presence of
a halogen atom in the ortho-position of the benzene
ring in benzoyl isothiocyanates, nucleophilic attack on
the carbonyl or isothiocyanato group may be followed
by intramolecular replacement of the ortho-halogen
atom to give 2-substituted 1,3-benzothiazin-4-ones [3].
We previously showed that readily accessible poly-
fluorobenzoyl isothiocyanates I react with nucleo-
philes (e.g., cyclic amines and CH-active benzimid-
azoles), yielding fluorinated 1,3-benzothiazin-4-ones
[4, 5]. In the present work we examined reactions of
2,3,4,5-tetra- and pentafluorobenzoyl isothiocyanates
Ia and Ib with aminoazines and aminoazoles.
compounds IIIa, IIIc, IIIe, IIIg, IIIi, and IIIj was
typical of the tetrafluorobenzoyl moiety.
Polyfluorobenzoyl-substituted thioureas IIIa, IIIc,
and IIId underwent intramolecular cyclization to
1,3-benzothiazin-4-ones IVa, IVc, and IVd on heating
for 3 h in boiling toluene in the presence of triethyl-
amine; analogous transformation of azolylamino deriv-
atives IIIi and IIIj required a longer reaction time, 6 h.
The cyclization of pyridyl- and pyrimidinyl-substituted
thioureas IIIa–IIIh to the corresponding fluorinated
1,3-benzothiazin-4-ones IVa–IVh in boiling DMSO
was complete within 3 min (yield 84–90%), whereas
pyrazolyl derivatives IIIi and IIIj failed to react even
on prolonged heating in the same solvent.
The structure of 1,3-benzothiazin-4-ones IVa–IVj
1
was confirmed by the H and 19F NMR and mass
Polyfluorobenzoyl isothiocyanates Ia and Ib
smoothly reacted with 2-aminopyridines IIa and IIb,
2-aminopyrimidines IIc and IId, and 3-aminopyra-
zoles IIe and IIf in acetonitrile at room temperature
(reaction time 3 h) to give 69–89% of the correspond-
ing addition products IIIa–IIIj (Scheme 1). The
1H NMR spectra of IIIa–IIIj confirmed the presence
in their molecules of heterocyclic fragments and NH
groups (broadened signals at δ 11.5–13.9 ppm); a one-
proton multiplet at δ 7.61–7.69 ppm in the spectra of
1
spectra. The H NMR spectra of IVa–IVj contained
signals from protons in the heterocyclic fragment (as in
the spectra of the initial thioureas), one NH signal dis-
appeared from the spectra, and the multiplicity of the
5-H signal of IVa, IVc, IVe, IVg, IVi, and IVj
changed to a double doublet of doublets (δ 7.97–
8.02 ppm). In the 19F NMR spectra of these com-
pounds we observed multiplet signals from three (IVa,
IVe, IVg) or four fluorine atoms (IVb, IVf). The
molecular ion peaks in the mass spectra of 2-hetaryl-
amino-1,3-benzothiazin-4-ones IVa–IVj had a relative
* For communication XIV, see [1].
1544

FLUORINE-CONTAINING HETEROCYCLES: XV.
1545
Scheme 1.
Y
F
O
Y
O
S
S
F
F
C
F
F
Ht
N
N
N
+
Ht NH2
H
H
F
F
F
Ia, Ib
IIa–IIf
IIIa–IIIj
O
S
F
N
R
R
Y
O
N
N
F
R'
F
R'
N
Va, Vb
Ht
F
S
N
O
H
F
F
N
N
IVa–IVj
R
N
S
N
H
N
R'
F
VIa, VIb
I, Y = H (a), F (b); II, Ht = 2-pyridyl (a), 6-methylpyridin-2-yl (b), pyrimidin-2-yl (c), 4,6-dimethylpyrimidin-2-yl (d), 5-methyl-1H-
pyrazol-3-yl (e), 5-phenyl-1H-pyrazol-3-yl (f); III, IV, Ht = 2-pyridyl, Y = H (a), F (b); Ht = 6-methylpyridin-2-yl, Y = H (c), F (d);
Ht = pyrimidin-2-yl, Y = H (e), F (f); Ht = 4,6-dimethylpyrimidin-2-yl, Y = H (g), F (h); Ht = 5-methyl-1H-pyrazol-3-yl, Y = H (i);
Ht = 5-phenyl-1H-pyrazol-3-yl, Y = H (j); V, VI, RR'N = morpholino (a), 4-ethoxycarbonylpiperazin-1-yl (b).
position 2 of fluorine-containing 1,3-benzothiazin-4-
ones by morpholino and 4-ethoxycarbonylpiperazin-1-
yl groups was reported for the first time in [4].
Examples of replacement of an azolyl substituent in
thiazoles are well known (see, e.g., [6]).
intensity of 17–45%. The most abundant ions were
[HtNHCN]+ (IVa–IVd, IVg–IVj) or [M – HtNHCN]+
(m/z 190 or 208; IVe, IVf). It should be noted that
the base peak in the mass spectra of 2-substituted
6,7,8-trifluoro-1,3-benzothiazin-4-ones corresponded
to elimination of RCN from the molecular ion [4, 5];
elimination of the RNHCN fragment as the main
decomposition pathway of 2-aminopyrido[3,2-e]thia-
zin-4-ones under electron impact was reported in [3].
In the reactions of benzothiazinone IVe with
morpholine or ethyl piperazine-1-carboxylate in DMF,
only the 7-fluorine atom was replaced, while the pyri-
midin-2-ylamino group in position 2 remained un-
changed. The 1H NMR spectra of compounds VIa and
VIb thus formed contained signals from protons in the
pyrimidinylamino fragment and cyclic amine moiety,
as well as a doublet of doublets at δ 7.70–7.75 ppm
from the 5-H proton (as in the spectra of Va and Vb).
The reaction of benzothiazinones IVa and IVc with
morpholine in boiling DMF (5 h) involved replace-
ment of both fluorine atom in position 7 and the amino
group in position 2; as a result, 6,8-difluoro-2,7-dimor-
pholino-1,3-benzothiazin-4-one (Va) was obtained.
1
The product structure follows from the H NMR spec-
2,3,4,5-Tetrafluorobenzoyl isothiocyanate (Ia) re-
acted with 2-aminothiazole (VIIa), 2-aminobenzothia-
zole (VIIb), and 2-amino-5,6-difluorobenzothiazole
(VIIc) in acetonitrile at room temperature (3 h) in
a different way. Here, the products were benzamides
VIIIa–VIIIc rather than thioureas III (Scheme 2).
Compounds VIIIa–VIIIc were identical to those
obtained previously from 2,3,4,5-tetrafluorobenzoyl
chloride and aminothiazoles VIIa–VIIc [7]. Obvious-
ly, the reaction involves substitution of the N=C=S
group in Ia rather than nucleophilic addition of
trum which contained no signals from the pyridyl-
amino fragment, but those belonging to two morpho-
line residues were present. Compound Va showed the
molecular ion peak in the mass spectrum, and that
corresponding to loss of the O(CH2)4NCN fragment
from the molecular ion was the most intense, in
keeping with published data for fragmentation of
benzothiazinones. Likewise, benzothiazinones IVa and
IVc reacted with ethyl piperazine-1-carboxylate to
give compound Vb. Replacement of substituent in
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

NOSOVA et al.
1546
Scheme 2.
X
O
F
O
F
N
S
X
F
F
C
X
X
F
F
N
S
S
N
N
+
H
NH2
F
F
Ia
VIIa–VIIc
VIIIa–VIIIc
X = H (a); XX = –CH=CH–CH=CH– (b), –CH=CF–CF=CH– (c).
O
F
HN
O
F
S
HN
F
F
F
F
N
N
N
N
H
H
Ia
+
+
H
NH2
N
H
F
F
VIId
IX
X
2-aminothiazole at the N=C bond. Analogous replace-
ment of the N=C=S fragment in benzoyl isothio-
cyanate by methyl- and benzylhydrazine residues was
described in [8]. In the reaction of isothiocyanate Ia
with 2-aminobenzimidazole (VIId), a mixture of the
nucleophilic substitution and addition products IX and
X was formed at a ratio of 10:3 (according to the
1H NMR data). N-(2,3-Dihydro-1H-benzimidazol-2-
ylidene)-2,3,4,5-tetrafluorobenzamide (IX) was iden-
tical to the product obtained by reaction of tetrafluoro-
benzoyl chloride with aminobenzimidazole VIId [7].
[9]. Obviously, in this case the isothiocyanato group is
replaced by C-centered nucleophile, followed by intra-
molecular nucleophilic substitution of the ortho-
fluorine atom.
Thus we have demonstrated that 2-hetarylamino-
substituted fluorinated 1,3-benzothiazin-4-ones IV can
be synthesized from tetra(penta)fluorobenzoyl isothio-
cyanate and the corresponding hetarylamine and
revealed some specificity of the aminodefluorination
of compounds IV. In addition, examples of facile re-
placement of the isothiocyanato group by aminoazoles
have been described.
Likewise, the reaction of Ia with α-naphthylamine
(XI) followed the replacement rather than addition pat-
tern, leading to N-naphthylbenzamide XII (Scheme 3).
One more example of substitution of the N=C=S group
in tetrafluorobenzoyl isothiocyanate is the reaction of
Ia with acetoacetanilide (XIII), which was performed
in acetonitrile at room temperature (reaction time 3 h).
From the reaction mixture we isolated 6,7,8-trifluoro-
2-methyl-4-oxo-N-phenyl-4H-chromene-3-carbox-
amide (XIV); it was identical to the product obtained
from tetrafluorobenzoyl chloride and compound XIII
EXPERIMENTAL
1
The H NMR spectra were recorded on Bruker
WM-250 (250.14 MHz) and Bruker DRX-400 spec-
trometers (400.13 MHz). The 19F NMR spectra were
obtained on a Bruker DRX-500 instrument at
376.45 MHz. The chemical shifts were measured
relative to tetramethylsilane (1H) and hexafluoroben-
zene (19F) as intermal references; DMSO-d6 was used
Scheme 3.
NH2
O
F
O
O
MeCOCH2CONHPh
F
F
F
F
Ph
XIII
XI
N
N
H
Ia
H
O
Me
F
F
XII
XIV
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

FLUORINE-CONTAINING HETEROCYCLES: XV.
1547
as solvent. The mass spectra were run on a Varian
MAT 311A spectrometer (electron impact, 70 eV;
accelerating voltage 3 kV; cathode emission current
300 µA; direct sample admission into the ion source).
1-(Pyrimidin-2-yl)-3-(2,3,4,5-tetrafluoroben-
zoyl)thiourea (IIIe). Yield 84%, mp 190–192°C.
3
1H NMR spectrum, δ, ppm: 7.28 t (5-H, J = 4.8 Hz),
7.66 m (6'-H), 8.71 d (4-H, 6-H, 3J = 4.8 Hz), 12.1 br.s
(1H, NH), 13.0 br.s (1H, NH). Found, %: C 43.61;
H 1.79; N 17.01. C12H6F4N4OS. Calculated, %:
C 43.64; H 1.82; N 16.97.
1-(2-Pyridyl)-3-(2,3,4,5-tetrafluorobenzoyl)thio-
urea (IIIa). A solution of 0.23 g (3 mmol) of ammo-
nium thiocyanate in 7 ml of acetonitrile was added to
a solution of 0.64 g (3 mmol) of tetrafluorobenzoyl
chloride in 2.5 ml of toluene. The mixture was heated
for 5 min at 40°C and filtered from ammonium
chloride, the filtrate was added to a solution of 0.28 g
(3 mmol) of pyridin-2-amine in 5 ml of acetonitrile,
the mixture was stirred for 3 h at room temperature and
evaporated, and the residue was washed with ethanol
and recrystallized from ethanol. Yield 0.88 g (89%),
1-Pentafluorobenzoyl-3-(pyrimidin-2-yl)thiourea
1
(IIIf). Yield 69%, mp 242–244°C. H NMR spectrum,
3
δ, ppm: 7.30 t (5-H, J = 5.0 Hz), 8.76 d (4-H, 6-H,
3J = 5.0 Hz), 12.2 br.s (1H, NH), 13.2 br.s (1H, NH).
Found, %: C 41.41; H 1.39; N 16.06. C12H5F5N4OS.
Calculated, %: C 41.38; H 1.44; N 16.09.
1-(4,6-Dimethylpyrimidin-2-yl)-3-(2,3,4,5-tetra-
fluorobenzoyl)thiourea (IIIg). Yield 89%, mp 165–
1
1
mp 142–144°C. H NMR spectrum, δ, ppm: 7.22 d.d
167°C. H NMR spectrum, δ, ppm: 2.44 s (6H, CH3),
3
(5-H, J = 8.2, 5.0 Hz), 7.65 m (6'-H), 7.84 t.d (4-H,
6.99 s (5-H), 7.69 m (6'-H), 11.5 br.s (1H, NH),
13.8 br.s (1H, NH). Found, %: C 46.90; H 2.75;
N 15.66. C14H10F4N4OS. Calculated, %: C 46.93;
H 2.79; N 15.64.
3J = 8.2, 4J = 1.8 Hz), 8.38 d (6-H, 3J = 5.0 Hz), 8.73 m
(3-H), 11.9 br.s (1H, NH), 12.7 br.s (1H, NH). Found,
%: C 47.38; H 2.10; N 12.81. C13H7F4N3OS. Calculat-
ed, %: C 47.42; H 2.13; N 12.77.
1-(4,6-Dimethylpyrimidin-2-yl)-3-pentafluoro-
benzoylthiourea (IIIh). Yield 86%, mp 241–243°C.
1H NMR spectrum, δ, ppm: 2.43 s (3H, CH3), 2.47 s
(3H, CH3), 7.03 s (5-H), 11.7 br.s (1H, NH), 13.9 br.s
(1H, NH). Found, %: C 44.71; H 2.42; N 14.87.
C14H9F5N4OS. Calculated, %: C 44.68; H 2.39;
N 14.89.
Compounds IIIb–IIIj were synthesized in a similar
way.
3-Pentafluorobenzoyl-1-(2-pyridyl)thiourea
(IIIb). Yield 87%, mp 138–140°C. 1H NMR spectrum,
δ, ppm: 7.24 d.d (5-H, 3J = 7.3, 6.0 Hz), 7.86 t.d (4-H,
3J = 7.3, 4J = 2.3 Hz), 8.42 d (6-H, 3J = 6.0 Hz), 8.75 m
(3-H), 12.5 br.s (2H, NH). Found, %: C 45.00; H 1.76;
N 12.08. C13H6F5N3OS. Calculated, %: C 44.96;
H 1.73; N 12.10.
1-(5-Methyl-1H-pyrazol-3-yl)-3-(2,3,4,5-tetra-
fluorobenzoyl)thiourea (IIIi). Yield 87%, mp 202–
1
204°C. H NMR spectrum, δ, ppm: 2.34 s (3H, CH3),
6.82 s (4-H), 7.61 m (6'-H), 11.7 br.s (1H, NH),
12.3 br.s (1H, NH), 12.5 br.s (1H, NH). Found, %:
C 43.40; H 2.42; N 16.85. C12H8F4N4OS. Calculated,
%: C 43.37; H 2.41; N 16.87.
1-(6-Methylpyridin-2-yl)-3-(2,3,4,5-tetrafluoro-
benzoyl)thiourea (IIIc). Yield 82%, mp 120–122°C.
1H NMR spectrum, δ, ppm: 2.40 s (3H, CH3), 7.06 d
(5-H, J = 7.0 Hz), 7.64 m (6'-H), 7.70 t (4-H, J =
7.5 Hz), 8.63 m (3-H), 11.8 br.s (1H, NH), 12.6 br.s
(1H, NH). Found, %: C 46.84; H 2.54; N 11.68.
C14H9F4N3OS. Calculated, %: C 46.80; H 2.51;
N 11.70.
3
3
1-(5-Phenyl-1H-pyrazol-3-yl)-3-(2,3,4,5-tetra-
fluorobenzoyl)thiourea (IIIj). Yield 75%, mp 226–
1
228°C. H NMR spectrum, δ, ppm: 6.47 s (4-H),
7.34 m (1H, C6H5), 7.43 m (2H, C6H5), 7.68 m (6'-H),
7.72 m (2H, C6H5), 11.8 br.s (1H, NH), 12.7 br.s (1H,
NH), 13.2 br.s (1H, NH). Found, %: C 51.82; H 2.57;
N 14.18. C17H10F4N4OS. Calculated, %: C 51.78;
H 2.54; N 14.21.
1-(6-Methylpyridin-2-yl)-3-pentafluorobenzoyl-
1
thiourea (IIId). Yield 81%, mp 124–126°C. H NMR
3
spectrum, δ, ppm: 2.44 s (3H, CH3), 7.17 d (5-H, J =
3
7.0 Hz), 7.83 t (4-H, J = 7.9 Hz), 8.51 m (3-H),
12.3 br.s (1H, NH), 12.7 br.s (1H, NH). Mass spec-
trum, m/z (Irel, %): 361 [M]+ (21), 341 (22), 195 (100),
167 (42), 151 (14), 150 (22), 134 (37), 133 (95), 117
(22), 108 (70), 93 (12), 92 (66), 91 (16), 81 (29), 80
(26), 66 (13), 65 (40). Found, %: C 46.51; H 2.19;
N 11.66. C14H8F5N3OS. Calculated, %: C 46.54;
H 2.22; N 11.63.
6,7,8-Trifluoro-2-(pyridin-2-ylamino)-1,3-benzo-
thiazin-4-one (IVa). a. Thiourea IIIa, 0.25 g
(0.8 mmol), was dispersed in 6 ml of toluene, 0.22 ml
(1.6 mmol) of triethylamine was added, the mixture
was heated for 3 h under reflux and evaporated, and
the residue was washed with water and recrystallized
from ethanol. Yield 0.15 g (61%), mp 202–204°C.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

NOSOVA et al.
1548
3
1H NMR spectrum, δ, ppm: 7.16 d.d.d (5'-H, J = 8.0,
trum, m/z (Irel, %): 374 [M]+ (42), 185 (13), 184 (100),
162 (11), 77 (10). Found, %: C 54.51; H 2.38; N 14.96.
C17H9F3N4OS. Calculated, %: C 54.55; H 2.41;
N 14.97.
5.0, 4J = 0.5 Hz), 7.29 d.d (3'-H, 3J = 8.0, 4J = 0.5 Hz),
3
4
7.81 t.d (4'-H, J = 8.0, J = 1.5 Hz), 7.97 d.d.d (5-H,
3J = 9.8, 4J = 7.5, 5J = 2.3 Hz), 8.41 d.d (6'-H, 3J = 5.0,
4J = 1.5 Hz), 12.2 br.s (1H, NH). F NMR spectrum,
19
b. A solution of 0.3 g (0.9 mmol) of thiourea IIIa in
3 ml of DMSO was heated for 3 min at the boiling
point, and the precipitate of IVa was filtered off and
recrystallized from DMSO. Yield 0.25 g (90%).
δF, ppm: 10.12 m (1F), 26.20 m (1F), 27.37 m (1F).
Mass spectrum, m/z (Irel, %): 309 [M]+ (30), 308 (19),
190 (19), 162 (23), 119 (100), 78 (35). Found, %:
C 50.53; H 1.97; N 13.55. C13H6F3N3OS. Calculated,
%: C 50.49; H 1.94; N 13.59.
Compounds IVb–IVh were synthesized in a similar
way. Yield of IVc 87%, yield of IVd 88%.
Compounds IVc, IVd, IVi, and IVj were syn-
thesized in a similar way. In the synthesis of IVi and
IVj, the reaction mixture was heated under reflux for
6 h. Compounds IVd and IVj were recrystallized from
DMSO.
5,6,7,8-Tetrafluoro-2-(pyridin-2-ylamino)-1,3-
benzothiazin-4-one (IVb). Yield 88%, mp 220–
1
222°C. H NMR spectrum, δ, ppm: 7.14 d.d.d (5'-H,
3J = 7.8, 5.0, 4J = 0.8 Hz), 7.29 d.d (3'-H, 3J = 7.8, 4J =
3
0.8 Hz), 7.79 t.d (4'-H, J = 7.8, 4J = 1.5 Hz), 8.38 d.d
3
4
6,7,8-Trifluoro-2-(6-methylpyridin-2-ylamino)-
(6'-H, J = 5.0, J = 1.5 Hz), 12.2 br.s (1H, NH).
19F NMR spectrum, δF, ppm: 5.52 m (1F), 13.11 m
(1F), 20.97 m (1F), 25.40 m (1F). Mass spectrum, m/z
(Irel, %): 327 [M]+ (28), 326 (15), 208 (21), 180 (22),
120 (12), 119 (100), 78 (56), 51 (12). Found, %:
C 47.73; H 1.55; N 12.80. C13H5F4N3OS. Calculated,
%: C 47.71; H 1.53; N 12.84.
1,3-benzothiazin-4-one (IVc). Yield 70%, mp 216–
1
218°C. H NMR spectrum, δ, ppm: 2.42 s (3H, CH3),
3
3
7.00 d (5'-H, J = 7.8 Hz), 7.10 d (3'-H, J = 4.6 Hz),
3
3
7.69 d.d (4'-H, J = 7.8, 4.6 Hz), 7.97 d.d.d (5-H, J =
4
5
10.0, J = 7.6, J = 2.1 Hz), 11.7 br.s (1H, NH). Mass
spectrum, m/z (Irel, %): 323 [M]+ (21), 322 (14), 190
(9), 162 (13), 134 (9), 133 (100), 92 (24), 91 (10), 69
(11), 65 (14). Found, %: C 52.04; H 2.52; N 12.97.
C14H8F3N3OS. Calculated, %: C 52.01; H 2.48;
N 13.00.
6,7,8-Trifluoro-2-(pyrimidin-2-ylamino)-1,3-
benzothiazin-4-one (IVe). Yield 89%, mp 262–264°C.
3
1H NMR spectrum, δ, ppm: 7.27 t (5'-H, J = 4.9 Hz),
8.02 d.d.d (5-H, 3J = 10.0, 4J = 7.7, 5J = 2.2 Hz), 8.78 d
(4'-H, 6'-H, 3J = 4.9 Hz), 12.5 br.s (1H, NH). 19F NMR
spectrum, δF, ppm: 10.09 m (1F), 27.35 m (1F),
27.92 m (1F). Mass spectrum, m/z (Irel, %): 310 [M]+
(40), 191 (13), 190 (100), 162 (43), 120 (25). Found,
%: C 46.39; H 1.58; N 18.08. C12H5F3N4OS. Calculat-
ed, %: C 46.41; H 1.61; N 18.05.
5,6,7,8-Tetrafluoro-2-(6-methylpyridin-2-yl-
amino)-1,3-benzothiazin-4-one (IVd). Yield 73%,
1
mp 217–219°C. H NMR spectrum, δ, ppm: 2.46 s
(3H, CH3), 6.96 d (5'-H, 3J = 7.7 Hz), 7.17 d (3'-H, 3J =
4.5 Hz), 7.67 d.d (4'-H, 3J = 7.7, 4.5 Hz), 12.1 br.s (1H,
NH). Mass spectrum, m/z (Irel, %): 341 [M]+ (17), 133
(100), 92 (24), 65 (13). Found, %: C 49.31; H 2.08;
N 12.29. C14H7F4N3OS. Calculated, %: C 49.27;
H 2.05; N 12.32.
5,6,7,8-Tetrafluoro-2-(pyrimidin-2-ylamino)-1,3-
benzothiazin-4-one (IVf). Yield 87%, mp 279–281°C.
3
1H NMR spectrum, δ, ppm: 7.25 t (5'-H, J = 5.0 Hz),
3
6,7,8-Trifluoro-2-(5-methyl-1H-pyrazol-3-yl-
amino)-1,3-benzothiazin-4-one (IVi). Yield 66%,
8.75 d (4'-H, 6'-H, J = 5.0 Hz), 12.4 br.s (1H, NH).
19F NMR spectrum, δF, ppm: 6.05 m (1F), 13.78 m
(1F), 21.19 m (1F), 25.52 m (1F). Mass spectrum, m/z
(Irel, %): 328 [M]+ (40), 209 (12), 208 (100), 180 (38),
148 (12), 120 (54). Found, %: C 43.90; H 1.26;
N 17.05. C12H4F4N4OS. Calculated, %: C 43.87;
H 1.23; N 17.06.
1
mp >250°C. H NMR spectrum, δ, ppm: 2.27 s (3H,
CH3), 5.79 s (4'-H), 7.98 d.d.d (5-H, 3J = 9.8, 4J = 6.8,
5J = 2.0 Hz), 12.0 br.s (1H, NH), 12.2 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 312 [M]+ (45), 191 (13),
190 (13), 162 (15), 122 (100), 121 (11). Found, %:
C 46.13; H 2.22; N 17.99. C12H7F3N4OS. Calculated,
%: C 46.15; H 2.24; N 17.95.
2-(4,6-Dimethylpyrimidin-2-ylamino)-6,7,8-tri-
fluoro-1,3-benzothiazin-4-one (IVg). Yield 85%,
1
mp >250°C. H NMR spectrum, δ, ppm: 2.48 s (3H,
6,7,8-Trifluoro-2-(5-phenyl-1H-pyrazol-3-yl-
amino)-1,3-benzothiazin-4-one (IVj). Yield 66%,
CH3), 2.51 s (3H, CH3), 6.96 s (5'-H), 7.98 d.d.d (5-H,
1
4
5
mp >250°C. H NMR spectrum, δ, ppm: 6.43 s (4'-H),
3J = 9.8, J = 6.8, J = 2.0 Hz), 12.2 br.s (1H, NH).
19F NMR spectrum, δF, ppm: 9.45 m (1F), 25.27 m
(1F), 27.68 m (1F). Mass spectrum, m/z (Irel, %): 338
[M]+ (39), 190 (63), 162 (30), 149 (10), 148 (100), 107
7.32 m (1H, C6H5), 7.42 m (2H, C6H5), 7.72 m (2H,
C6H5), 7.98 d.d.d (5-H, 3J = 9.9, 4J = 7.8, 5J = 2.2 Hz),
11.8 br.s (1H, NH), 13.2 br.s (1H, NH). Mass spec-
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

FLUORINE-CONTAINING HETEROCYCLES: XV.
1549
1
(16), 68 (12), 67 (15). Found, %: C 49.73; H 2.68;
N 16.54. C14H9F3N4OS. Calculated, %: C 49.70;
H 2.66; N 16.57.
mp >250°C. H NMR spectrum, δ, ppm: 3.33 m (4H,
NCH2), 3.74 m (4H, OCH2), 3.83 m (4H, OCH2), 6.76 t
(5'-H, J = 4.9 Hz), 7.72 d.d (5-H, J = 12.3, J =
1.6 Hz), 8.47 d (4'-H, 6'-H, J = 4.9 Hz), 12.8 br.s
(1H, NH). Found, %: C 50.96; H 5.48; N 18.53.
C16H13F2N5O2S. Calculated, %: C 50.93; H 3.45;
N 18.57.
3
3
5
3
2-(4,6-Dimethylpyrimidin-2-ylamino)-5,6,7,8-
tetrafluoro-1,3-benzothiazin-4-one (IVh). Yield
1
84%, mp >250°C. H NMR spectrum, δ, ppm: 2.46 s
(3H, CH3), 2.62 s (3H, CH3), 6.95 s (5'-H), 12.2 br.s
(1H, NH). Mass spectrum, m/z (Irel, %): 356 [M]+ (31),
208 (65), 180 (21), 148 (100), 107 (15), 68 (12),
67 (16). Found, %: C 47.21; H 2.28; N 15.70.
C14H8F4N4OS. Calculated, %: C 47.19; H 2.25;
N 15.73.
Ethyl 4-[6,8-difluoro-4-oxo-2-(pyrimidin-2-yl-
amino)-4H-1,3-benzothiazin-7-yl]piperazine-1-car-
boxylate (VIb) was synthesized in a similar way. Yield
1
79%, mp >250°C. H NMR spectrum, δ, ppm: 1.22 t
(3H, CH3), 3.30 m (4H, NCH2), 3.52 m (4H, NCH2),
4.08 q (2H, OCH2), 6.77 t (5'-H, 3J = 4.9 Hz), 7.75 d.d
6,8-Difluoro-2,7-dimorpholino-1,3-benzothiazin-
4-one (Va). Benzothiazinone IVa, 0.28 g (0.89 mmol),
was dissolved in 5 ml of DMF, 0.35 ml (0.35 g,
4 mmol) of morpholine was added to the solution, the
mixture was heated for 5 h under reflux, cooled, and
diluted with water, and the precipitate was filtered off
and recrystallized from DMSO. Yield 0.25 g (77%),
3
5
(5-H, J = 12.3, J = 1.6 Hz), 8.43 d (4'-H, 6'-H,
3J = 4.9 Hz), 12.4 br.s (1H, NH). Found, %: C 50.86;
H 3.99; N 18.77. C19H18F2N6O3S. Calculated, %:
C 50.89; H 4.02; N 18.75.
2,3,4,5-Tetrafluoro-N-(1,3-thiazol-2-yl)benz-
amide (VIIIa). A solution of 3 mmol of isothiocyanate
Ia in acetonitrile (prepared as described above) was
added to a solution of 0.32 g (3 mmol) of 1,3-thiazol-
2-amine (VIIa) in 5 ml of acetonitrile, the mixture was
stirred for 3 h at room temperature and evaporated, and
the residue was recrystallized from ethanol. Yield
1
mp >250°C. H NMR spectrum, δ, ppm: 3.27 m (4H,
NCH2), 3.72 m (8H, NCH2, OCH2), 3.83 m (4H,
3
5
OCH2), 7.70 d.d (5-H, J = 12.5, J = 1.8 Hz). Mass
spectrum, m/z (Irel, %): 369 [M]+ (55), 327 (10), 257
(100), 215 (10), 199 (55). Found, %: C 51.94; H 4.58;
N 11.44. C16H17F2N3O3S. Calculated, %: C 52.03;
H 4.64; N 11.38.
1
0.60 g (71%), mp 128–130°C. H NMR spectrum, δ,
ppm: 7.35 d (1H, 5-H, 3J = 3.7 Hz), 7.58 d (1H, 4-H,
3J = 3.7 Hz), 7.85 m (1H, 6'-H), 12.9 br.s (1H, NH).
Mass spectrum, m/z (Irel, %): 276 [M]+ (19%), 257
(11), 248 (10), 177 (100), 149 (35), 99 (17). Found, %:
C 43.55; H 1.52; N 10.08. C10H4F4N2OS. Calculated,
%: C 43.49; H 1.46; N 10.14.
Diethyl 4,4'-(6,8-difluoro-4-oxo-4H-1,3-benzo-
thiazine-2,7-diyl)bis(piperazine-1-carboxylate) (Vb)
was synthesized in a similar way. Yield 67%, mp 245–
1
247°C. H NMR spectrum, δ, ppm: 1.23 t (3H, CH3),
1.25 t (3H, CH3), 3.28 m (4H, NCH2), 3.53 m (4H,
NCH2), 3.58 m (4H, NCH2), 3.87 m (4H, NCH2),
4.07 q (2H, OCH2), 4.11 q (2H, OCH2), 7.72 d.d (5-H,
Compounds VIIIb and VIIIc were synthesized in
a similar way.
5
3J = 12.5, J = 1.8 Hz). Mass spectrum, m/z (Irel, %):
511 [M]+ (35), 398 (14), 397 (24), 396 (43), 384 (15),
383 (71), 328 (21), 313 (14), 308 (17), 226 (18), 214
(21), 213 (17), 199 (22), 141 (17), 128 (16), 115 (15),
84 (12), 70 (14), 57 (11), 56 (100). Found, %: C 51.72;
H 5.37; N 13.61. C22H27F2N5O5S. Calculated, %:
C 51.66; H 5.32; N 13.69.
N-(1,3-Benzothiazol-2-yl)-2,3,4,5-tetrafluoro-
benzamide (VIIIb). Yield 75%, mp 170–172°C.
1H NMR spectrum, δ, ppm: 7.37 m (1H, benzothia-
zole), 7.79 m (1H, benzothiazole), 7.92 m (1H, 6'-H),
7.99 m (1H, benzothiazole), 8.04 m (1H, benzothia-
zole), 13.2 br.s (1H, NH). Mass spectrum, m/z (Irel, %):
326 [M]+ (27%), 298 (11), 177 (100), 149 (29). Found,
%: C 51.45; H 1.92; N 8.63. C14H6F4N2OS. Calculated,
%: C 51.54; H 1.85; N 8.58.
The reaction of benzothiazinone IVc with morpho-
line gave compound Va in 74% yield, and with ethyl
piperazine-1-carboxylate, compound Vb in 71% yield.
6,8-Difluoro-7-morpholino-2-(pyrimidin-2-yl-
amino)-1,3-benzothiazin-4-one (VIa). Morpholine,
0.35 ml (0.35 g, 4 mmol), was added to a solution of
0.31 g (1.0 mmol) of compound IVe in 5 ml of DMF,
the mixture was heated for 5 h under reflux, cooled,
and diluted with water, and the precipitate was filtered
off and recrystallized from DMSO. Yield 0.29 g (77%),
N-(5,6-Difluoro-1,3-benzothiazol-2-yl)-2,3,4,5-
tetrafluorobenzamide (VIIIc). Yield 70%, mp 180–
1
182°C. H NMR spectrum, δ, ppm: 7.91 d.d (1H, 4-H
3
4
or 7-H, J = 10.8, J = 7.1 Hz), 8.21 d.d (1H, 7-H or
3
4
4-H, J = 10.1, J = 8.2 Hz), 7.92 m (1H, 6'-H),
13.3 br.s (1H, NH). Mass spectrum, m/z (Irel, %): 362
(22) [M]+, 177 (100), 149 (25). Found, %: C 46.47;
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006

NOSOVA et al.
1550
3
3
H 1.09; N 7.65. C14H4F6N2OS. Calculated, %: C 46.42;
H 1.11; N 7.73.
5'-H, J = 8.5, 7.5 Hz), 7.65 m (2H, 2'-H, 6'-H, J =
4
3
4
8.5, J = 1.2 Hz), 7.83 d.d.d (1H, 5-H, J = 9.5, J =
7.7, 5J = 2.4 Hz), 11.32 br.s (1H, NH). Mass spectrum,
m/z (Irel, %): 333 (48) [M]+, 316 (10), 242 (12), 241
(100), 175 (10), 93 (42), 67 (99). Found, %: C 61.24;
H 3.05; N 4.32. C17H10F3NO3. Calculated, %: C 61.27;
H 3.02; N 4.20.
N-(2,3-Dihydro-1H-benzimidazol-2-ylidene)-
2,3,4,5-tetrafluorobenzamide (IX) and 1-(2,3-di-
hydro-1H-benzimidazol-2-ylidene)-3-(2,3,4,5-tetra-
fluorobenzoyl)thiourea (X). A solution of 3 mmol of
isothiocyanate Ia in acetonitrile (prepared as described
above) was added to a solution of 0.4 g (3 mmol) of
1H-benzimidazol-2-amine (VIId) in 5 ml of acetoni-
trile, the mixture was stirred for 3 h at room tempera-
ture, and the precipitate (a mixture of compounds IX
This study was performed under financial support
by the Russian Foundation for Basic Research (project
nos. 03-03-32254, 04-03-96107-Ural, 04-03-96011-
Ural), Ministry of Education and CRDF, Annex
BF4M05, EK-005-X2 [REC-005], and BRHE 2004
post-doctoral fellowship award Y2-C-05-01.
1
and X) was filtered off. Yield 0.62 g. H NMR spec-
trum, δ, ppm: 7.08 m (2H, 5-H, 6-H in X), 7.15 m (2H,
5-H, 6-H in IX), 7.29 m (2H, 4-H, 7-H in X), 7.41 m
(2H, 4-H, 7-H in IX), 7.56 m (1H, 6'-H in X), 7.75 m
(1H, 6'-H in IX), 12.4 br.s (2H, NH in IX), 12.8 br.s
(2H, NH in X), 14.1 br.s (1H, NH in X). Product ratio
IX:X = 10:3.
REFERENCES
1. Mochul’skaya, N.N., Nagibina, E.N., Volchenkova, Yu.S.,
Sidorova, L.P., and Charushin, V.N., Russ. J. Org. Chem.,
2005, vol. 41, p. 1694.
2,3,4,5-Tetrafluoro-N-(1-naphthyl)benzamide
(XII) was synthesized as described above for com-
pound VIIIa. Yield 78%, mp 174–176°C. H NMR
spectrum, δ, ppm: 7.49 m (3H, naphthyl), 7.77 m (1H,
6'-H), 7.80 m (2H, naphthyl), 7.93 m (1H, naphthyl),
8.05 m (1H, naphthyl), 10.4 br.s (1H, NH). Mass spec-
trum, m/z (Irel, %): 319 (44) [M]+, 177 (100), 149 (20),
144 (38), 142 (17), 115 (61). Found, %: C 63.98;
H 2.86; N 4.35. C17H9F4NO. Calculated, %: C 63.95;
H 2.82; N 4.39.
2. Comprehensive Organic Chemistry, Barton, D. and Ol-
lis, W.D., Eds., Oxford: Pergamon, 1979, vol. 3. Trans-
lated under the title Obshchaya organicheskaya khimiya,
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1
3. Koscik, D., Kristian, P., Gonda, J., and Dandarova, E.,
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skaya, N.N., and Charushin, V.N., Karbonil’nye soedine-
niya v sinteze geterotsiklov (Carbonyl Compounds in the
Synthesis of Heterocycles), Saratov: Nauchnaya Kniga,
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6. Rogoza, A.V. and Furin, G.G., Izv. Ross. Akad. Nauk, Ser.
Khim., 1997, p. 831.
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shin, V.N., Russ. J. Org. Chem., 2005, vol. 41, p. 1671.
6,7,8-Trifluoro-2-methyl-4-oxo-N-phenyl-4H-
chromene-3-carboxamide (XIV). A solution of
3 mmol of isothiocyanate Ia in acetonitrile (prepared
as described above) was added to a solution of 0.53 g
(3 mmol) of acetoacetanilide (XI) in 5 ml of aceto-
nitrile, the mixture was stirred for 3 h at room tempera-
ture and evaporated, and the residue was recrystallized
from ethanol. Yield 0.73 g (73%), mp 202–204°C.
1H NMR spectrum, δ, ppm: 3.04 s (3H, CH3), 7.13 t.t
8. Durant, G.J., J. Chem. Soc., 1967, p. 92.
9. Lipunova, G.N., Nosova, E.V., Kodess, M.I., and Charu-
3
4
(1H, 4'-H, J = 7.5, J = 1.2 Hz), 7.35 m (2H, 3'-H,
shin, V.N., Russ. J. Org. Chem., 2004, vol. 40, p. 1162.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 42 No. 10 2006