SYNTHESIS AND ANTITUBERCULAR EVALUATION OF FLUORINATED 2-CYCLOALKYLIMINO SUBSTITUTED 1,3-BENZOTHIAZIN-4-ONES

Article abstract of DOI:10.1016/j.jfluchem.2019.02.009

Novel fluorinated 2-substituted 1,3-benzothiazin-4-ones were obtained through the addition of N-nucleophiles to ortho-fluorobenzoylisothiocyanates, followed by cyclization of fluorobenzoyl-thioureas. Synthetic approaches to original 2-cycloalkylimino- and 2-carbonylpiperazino- substituted benzothiazinones, bearing different number of fluorine atoms in the benzene ring have been found. 2-Ethoxycarbonylpiperazino-5-fluoro-1,3-benzothiazin-4-one proved to exhibit a high tuberculostatic activity in vitro (MIC 0.7 microgram/mL), thus indicating that a search of biologically active compounds in this family of heterocycles appears to be a reasonable approach.

Full text of DOI:10.1016/j.jfluchem.2019.02.009

Accepted Manuscript
Title: SYNTHESIS AND ANTITUBERCULAR
EVALUATION OF FLUORINATED
2
1
-CYCLOALKYLIMINO SUBSTITUTED
,3-BENZOTHIAZIN-4-ONES
Authors: Emiliya V. Nosova, Olga A. Batanova, Galina N.
Lipunova, Svetlana K. Kotovskaya, Pavel A. Slepukhin,
Marionella A. Kravchenko, Valery N. Charushin
PII:
S0022-1139(19)30004-1
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2019.02.009
FLUOR 9292
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
4 January 2019
20 February 2019
22 February 2019
Please cite this article as: Nosova EV, Batanova OA, Lipunova GN,
Kotovskaya SK, Slepukhin PA, Kravchenko MA, Charushin VN, SYNTHESIS
AND
ANTITUBERCULAR
EVALUATION
OF
FLUORINATED
2-
CYCLOALKYLIMINO SUBSTITUTED 1,3-BENZOTHIAZIN-4-ONES, Journal of
Fluorine Chemistry (2019), https://doi.org/10.1016/j.jfluchem.2019.02.009
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SYNTHESIS AND ANTITUBERCULAR EVALUATION
OF FLUORINATED 2-CYCLOALKYLIMINO SUBSTITUTED
1
,3-BENZOTHIAZIN-4-ONES
a,b
a
b
a,b
Emiliya V. Nosova,* Olga A. Batanova, Galina N. Lipunova, Svetlana K. Kotovskaya,
a,b
c
a,b
Pavel A. Slepukhin, Marionella A. Kravchenko and Valery N. Charushin
aDepartment of Organic and Biomolecular Chemistry, Ural Federal University, 19 Mira st.,
Ekaterinburg 620002, Russia. E-mail: emily74@rambler.ru
b
Postovsky Institute of Organic Synthesis, Ural Branch of the Russian Academy of Sciences
2
2 S. Kovalevskaya st. /20 Akademicheskaya st., Ekaterinburg 620137, Russia
Ural Research Institute for Phthisiopulmonology, 50 XXII Parts’ezda St.,
c
Ekaterinburg 620039, Russia
*
The corresponding author
Highlights




Interaction of o-fluorobenzoyl isothiocyanates with cycloalkylimines was studied
Synthesis of novel 5-fluoro- and 6,7,8-trifluoro-1,3-benzothiazin-4-ones was developed
X-ray data for 6,7,8-trifluoro-2-(thiomorpholin-4-yl)-1,3-benzothiazin-4-one were obtained
Fluorinated benzothiazinones exhibit a good level of antimycobacterial activity
Abstract
Novel fluorinated 2-substituted 1,3-benzothiazin-4-ones were obtained through the addition of N-
nucleophiles to ortho-fluorobenzoylisothiocyanates, followed by cyclization of fluorobenzoyl-
thioureas. Synthetic approaches to original 2-cycloalkylimino- and 2-carbonylpiperazino-
substituted benzothiazinones, bearing different number of fluorine atoms in the benzene ring have
been found. 2-Ethoxycarbonylpiperazino-5-fluoro-1,3-benzothiazin-4-one proved to exhibit a
high tuberculostatic activity in vitro (MIC 0.7 microgram/mL), thus indicating that a search of
biologically active compounds in this family of heterocycles appears to be a reasonable approach.
Keywords: fluorinated benzothiazinones, o-fluorobenzoylisothiocyanates, 4-ethoxycarbonyl-
piperazine, tuberculosis, multi-drug-resistant tuberculosis, in vitro activity.

1
. Introduction
Tuberculosis (TB) is one of the most urgent problems for modern world community, and
it is recognized by World Health Organization (WHO) as a disease, which demands a number of
active measures to prevent distribution of this danger over the world. Among main problems
associated with treatment of TB the following ones have to be mentioned: a restricted arsenal of
efficient anti-tuberculosis drugs; a fast appearance of stable forms of TB mycobacteria in the
course of treatment; and, as a result, a wide spread of patients with multi-drug resistant (MDR-
TB) and extensively drug-resistant M. tuberculosis (XDR-TB) strains [1, 2].
Benzothiazinone derivatives are of particular interest due to their recently discovered
ability to be active against TB mycobacteria by blocking decaprenylphosphoryl-beta-D-ribose-2-
epimerase (DprE1), the enzyme catalyzing transformation of decaprenylphosphoryl substituted
ribose into its epimere, the corresponding arabinose, and this conversion proved to be the key step
in biosynthesis of arabinane, as a building block for TB mycobacteria cell wall [3]. Indeed,
benzothiazinones BTZ043 and PBTZ169, bearing the trifluoromethyl group in position 6 and the
nitro group at C-8 proved to be the most promising in this respect (Figure 1) [4, 5]. It is quite
understandable that 6-trifluoromethyl-8-nitro-1,3-benzothiazin-4-ones, bearing not only
piperidine or piperazine fragments, but a variety of cycloalkylimino substituents, have been
intensively studied during the last decade [6-11].
Figure 1. Structures of the known DprE1 inhibitors.
In general, several approaches are considered to be suitable to obtain 2-amino-1,3-
benzothiazin-4-ones: a) cyclocondensation of 2-mercaptobenzoic acid with the appropriate
cyanamides [12]; b) the reaction of 2-chlorobenzcarboxamide with sodium salt of dithiocarbamate
[
13, 14]; c) addition of primary or secondary amines to 2-halo substituted benzoylisothiocyanates
with subsequent intramolecular cyclizations [6, 15, 16]. In this respect benzoylisothiocyanates,
bearing an additional fluorine atom in the ortho-position of the benzene ring seem to be the most
suitable intermediates for the synthesis of fluorinated 2-cycloalkylimino-1,3-benzothiazin-4-ones
[
17].

It has been shown that the reaction of tetrafluorobenzoylisothiocyanates with amino-azines
provides a convenient approach to 2-heterylamino-6,7,8-trifluoro-1,3-benzothiazin-4-ones [17];
and a number of compounds from the obtained family of fluorine-containing benzo-thiazinones
have demonstrated a high antitubercular activity [18].
The aim of this communication is to describe the synthesis of 2-cycloalkylimino-1,3-
benzothiazin-4-ones, bearing one or several fluorine atoms in the benzene ring, and to study their
antimicrobial activity, including that relative to multi-drug resistant strains of M. tuberculosis, to
expand synthetic opportunities for the development of anti-tuberculosis agents.
2
. Results and discussion
Fluorinated benzoyl isothiocyanates 2a-d have been found to react smoothly with some
cycloalkylimines 3 in acetonitrile at room temperature (reaction time 3 h) to give the corresponding
addition products 4a–p in 76–89% yields (Scheme 1). Fluorobenzoyl substituted derivatives 4
1
13
19
were characterized by H, C and F NMR data.
1
The H NMR spectra of compounds 4a–p confirm the presence in their molecules of
cycloalkylamino fragments and NH groups (broadened signals at δ 10.7–11.4 ppm), while proton
multiplet at δ 7.55–7.61 ppm in the spectra of compounds 4a-f is a typical one for the
1
tetrafluorobenzoyl moiety. The H NMR spectra of 2,6-difluorobenzoyl compounds 4g-n contain
a two-proton signal of Н-3 and Н-5 at 7.03–7.11 ppm and one-proton triplet of triplets of H-4 at
7
.47–7.52 ppm. Multiplets of three benzene ring protons in the range of 7.11–7.78 ppm were
1
observed in the H NMR spectra of 2,4-difluoro and 2,3-difluoro derivatives 4o,p.
1
9
The F NMR spectra of compounds 4a-f proved to exhibit four signals of C
6
HF
4
fragment:
at -137.68– (-137.84) ppm, -138.73– (-138.83) ppm, -151.61– (-151.78) ppm and -155.29– (-
1
9
1
55.37) ppm. In the F NMR spectra of symmetrical 2,6-difluorobenzoyl derivatives 4g-n a
singlet at -112.74 – (-113.06) ppm was observed. 2,4-Difluorobenzoyl compound 4o was
characterized by two doublets, originating from these fluorine atoms at -107.58 and -104.49 ppm
4
19
with J= 11 Hz, whereas two doublets in the F NMR spectra of 2,3-difluoro analogue 4p were
3
shifted upfield (-139.26 and -133.35 ppm with J 18.5 = Hz).
Tetrafluorobenzoyl substituted thioureas 4a-f have been shown to undergo intramolecular
cyclization into 1,3-benzothiazin-4-ones 5a-f (yields 59–84%); this conversion takes place
smoothly on heating for 3−6 hours in boiling toluene in the presence of triethylamine (Scheme 1).
Attempts to perform cyclization of difluorobenzoyl compounds 4g-p into the corresponding 1,3-
benzothiazin-4-ones 5g-p under the same conditions (reflux in toluene, the presence of
triethylamine), have failed. However, heating of compounds 4g-p in DMF in the presence of
triethylamine (reaction time 6-8 hours) proved to be an effective procedure for the synthesis of 5-

fluoro-1,3-benzothiazin-4-ones 5g-p (Scheme 1). Compounds 5g-j,l-p were obtained in 78-85%
yields, whereas the yield of 4-(t-butoxycarbonyl)piperazin-1-yl derivative (5k) was only 45%. It
has been found that 4k undergoes cyclization into benzothiazinone 5k in refluxing acetonitrile in
the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in 81% yield.
1
13
19
The structure of 1,3-benzothiazin-4-ones 5a–p has been confirmed by H, С, F NMR
1
and mass spectra. The H NMR spectra of 5a–f have exhibited signals from protons of
1
cycloalkylimino fragments (similar to the H NMR spectra of the starting thioureas), and the
multiplicity of H-5 signal has changed to a double doublet of doublets (δ 7.99–8.01 ppm), while
1
9
NH signal has disappeared expectedly. In the F NMR spectra of compounds 5a–f multiplet
signals from three fluorine atoms were observed, while spectra of 4-(2-fluorophenyl)piperazinyl
derivative 5e exhibited one more signal from the C
mass spectra of 2-cycloalkylamino-1,3-benzothiazin-4-ones 5a–f have relative intensities of 2–
2%. The ion m/z 190 with 100% intensity was observed for benzothiazinone 5a, whereas the most
6
4
H F fragment. The molecular ion peaks in
3
abundant peak was observed in case of 2-heterylamino-6,7,8-trifluoro-1,3-benzothiazin-4-ones
due to elimination of HetNHCN fragment from its molecular ion [11].
1
2
3
4
1
2
3
4
1
4
, 2: X = H, X = X = X = F (a); X = F, X = X = X = H (b);
3
1
2
4
4
1
2
3
X = F, X = X = X = H (c); X = F, X = X = X = H (d);
1
2
3
4
, 5: X = H, X = X = X = F, cycloalkylimino = morpholin-4-yl (a), thiomorpholin-4-yl (b),
1
4
,4-dioxa-8-azaspiro[4.5]decane-8-yl (c), 4-ethoxycarbonylpiperazin-1-yl (d),
-(2-fluorophenyl)piperazin-1-yl (e), 4-(t-butoxycarbonyl)piperazin-1-yl (f);
1
2
3
4
X = F, X = X = X = H, cycloalkylimino = morpholin-4-yl (g), thiomorpholin-4-yl (h),
4
4
-ethoxycarbonylpiperazin-1-yl (i), 4-(2-fluorophenyl)piperazin-1-yl (j),
-(t-butoxycarbonyl)piperazin-1-yl (k), 4-acetylpiperazin-1-yl (l),

4
-cyclopropylcarbonylpiperazin-1-yl (m), 4-(2-furoyl)piperazin-1-yl (n),
3
1
2
4
X = F, X = X = X = H, cycloalkylimino = 4-ethoxycarbonylpiperazin-1-yl (o);
4
1
2
3
X = F, X = X = X = H, cycloalkylimino = 4-ethoxycarbonylpiperazin-1-yl (p).
: Z = N-COOEt, Y = O (a); Z = Y = O (b); Z = Y = N-COOEt (c).
6
Scheme 1
According to the XRD data, compound 5b is crystallized in the centrosymmetric space
group of the monoclinic system (Figure 2). The benzothiazine part of the molecule is planar. The
bond distances for double and single bonds of the thiazinone moiety are well distinguished (the
distances N(2)-C(3) = 1.370(3) Å, N(2)-C(1) = 1.303(3) Å). The thiomorpholino fragment has a
“chair” conformation with (pseudo)axial position of the substituent at N(1) atom. The N(1) atom
has a planar trigonal configuration and strong conjugation with the thiazine ring (the bond
distances N(1)-C(1) = 1.338(3) Å, N(1)-C(2) = N(1)-C(12) = 1.465(4) Å). The crystal packing is
presented by stacks with shortened intermolecular contacts (with interatomic distances more when
3
.35 Å). Also, the F…F contacts are observed between stacks with distances F(2)…F(2) [1-x, 1-
y, 3-z] 2.711 Å. The shortened F…H and O…H contacts with participation of CH -groups of the
2
thiomorpholino moiety are induced probably by other interatomic contacts.
Figure 2. The molecule of benzothiazinone 5b according to the XRD data
in the thermal ellipsoids of the 50% probability level.
1
The H NMR spectra of 5-fluorobenzothiazinones 5g-n exhibit three groups of signals for
the benzene ring protons: Н-6 signals are observed in the region of 7.18−7.30 ppm, Н-8 at
1
9
1
7
.32−7.47 ppm, and triple doublets of Н-7 at 7.58−7.65 ppm. In the F NMR { H} spectra of
compounds 5g-n singlets at -107.86−(-108.95) ppm belong to fluorine atoms of the benzene ring.
1
9
In the F NMR spectra of 7-fluoro-1,3-benzothiazin-4-one 5o the signal of 7-fluoro atom is
observed at -106.44 ppm, whereas in case of its 8-fluoro analogue 5p it resonates at -115.94 ppm.

The mass spectra of mono-fluorinated 2-cycloalkylimino-1,3-benzothiazin-4-ones 5g-p contain
peaks of molecular ions with intensities 3–23%, and the most abundant for benzothiazinones 5g-
i,l,o,p peak m/z 154, corresponding to the fragment [M-R
NCN]+.
2
Nucleophilic substitution of F(7) atom by morpholine 3a or 1-ethoxycarbonylpiperazine
d in benzothiazinones 5а,d, proceeding in refluxing DMSO, afforded 6,8-difluoro-1,3-
3
benzothiazin-4-ones 6а-с, bearing cycloalkylimino substituents in positions 2 and 7 (Scheme 1).
1
The H NMR spectra of 6,8-difluorobenzothiazinones 6a–c exhibit proton resonances of
1
9
cycloalkylimino fragment, as well as H-5 signals at 7.73–7.74 ppm. In the F NMR spectra of
compounds 6 signals of two fluorine atoms were observed at -120.4–(-120.9) ppm and -124.0–(-
1
24.5) ppm. The mass spectra of fluorinated 1,3-benzothiazin-4-ones 6 contain peaks of molecular
ions with intensities 32–44%, while for compounds 6a,b the most abundant was the peak m/z 257,
+
corresponding to the fragment [M-R
2
NCN] . It is worth noting that compounds 6b,c proved to be
identical to products obtained from the reaction of 2-(2-pyridylamino)-6,7,8-trifluoro-1,3-
benzothiazin-4-one due to replacement of 7-fluoro and the amino group in position 2 [17].
Modification of the piperazine fragment in compound 5f was performed through
deprotection of Boc and subsequent aroylation (Scheme 2) under the same reaction conditions, as
described for 4-carbonyl piperazine substituted 6-trifluoromethyl-8-nitro-1,3-benzothiazin-4-ones
[
7]. Deprotection of Boc, proceeding in trifluoroacetic acid, afforded the intermediate 7 in 70%
yield. To get target compounds 8, benzothiazinone 7 was condensed with the corresponding
carboxylic acids or acyl chlorides, respectively. Compound 7 proved to react with carboxylic acids
catalyzed by combination of HATU and DIPEA at room temperature, or could directly be
condensed with aroyl chlorides for 4 hours at 55 °C, thus giving benzothiazinones 8a-e. The
1
19
19
structures of compounds 8a-e were determined by H NMR, F NMR and MS. In the F NMR
spectra of benzothiazinones 8a-e the signals of F-6 were observed at -134.40−(-134.61) ppm, F-8
in the range of -136.17−(-136.24) ppm, and double doublets of F-7 were exhibited at -153.38−(-
1
53.49) ppm.
8
: Ar = 4-tBuC
6
H
4
(a), Ph (b), 2,6-diFC
6
H
3
(c), 4-EtC
6
H
4
(d), 3-FC
6
4
H (e).
Scheme 2

Fluorinated benzothiazinones 5, 6, 8 were screened to estimate the level of their activity
against Mycobacterium tuberculosis H37 strain, and the influence of two factors (a number and
R
v
positions of fluorine atoms in the benzene ring, as well as the nature of the substituent at the
position 2) on their activity was considered. 5-Fluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-
benzothiazin-4-one (5i) exhibited the highest activity (MIC 0.7 g/mL) [19], transfer from 5i to 7-
fluoro (5o, MIC 12.5 g/mL), 8-fluoro (5p, MIC 12.5 g/mL), 6,8-difluoro (6a-c, MIC 12.5

g/mL) or 6,7,8-trifluoro (5d, MIC 12.5 g/mL) derivatives led to a decrease of activity.
Replacement of ethoxycarbonylpiperazinyl fragment (5i, MIC 0.7 g/mL) with thiomorpholino
5h, MIC 3.1 g/mL), morpholino (5g, MIC 12.5 g/mL), 4-(2-fluorophenyl)piperazino (5j, MIC
2.5 g/mL), 4-acylpiperazino (5l,m, MIC 12.5 g/mL) or 4-(2-furoyl)piperazino (5n, MIC 12.5
g/mL) also led to a decrease of activity. In the series of 6,7,8-trifluoro-1,3-benzothiazin-4-ones
a-f, 8 only 2-thiomorpholinyl compound 5b proved to exhibit MIC 6.2 g/mL, the rest of
(
1

5
derivatives demonstrated a lower activity (5a,c-f, 8, MIC 12.5 g/mL).
It is worth noting that compound 5i exhibits the highest activity (MIC 0.7 g/mL) not only
against M. tuberculosis H37R , but also against M. avium, M. terrae and MDR strains (Table). It is
v
important that, unlike the known anti-tuberculosis drug Isoniazide, benzothiazinone 5i was active
against MDR strains, while its acute toxicity in mice LD50 was found to be 600 mg/kg.
Table
In vitro antimycobacterial activity of 5-fluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-
1
,3-benzothiazin-4-one 5i and its acute in vivo toxicity in mice
Com-
Pound
Antimycobacterial activity against different strains
of M. tuberculosis (MIC in g/mL)
LD50 in mice
(mg/kg)
H
37
R
V
M. avium
0.7
M. terrae
0.7
MDR-TB a
5
i
0.7
0.7
n.d.
–
600
0.5 b
0.1
n.d.
n.d.
1500-2000 b
149 151d
LEV
INH
c
0.1
0.1
n.d. – not determined; INH – Izoniazid; LEV – Levofloxacin;
a
MDR-TB – Rifampin and Izoniazid resistant Mycobacterium tuberculosis strain having
Beijing genotype with a combination of mutations Ser 531-Leu 315 and Ser-Thr in rpoB and
katC genes, respectively.
LD50 oral administration in mice and rats [20].
LD50 i.v. administration in mice [20].
b
c
d
LD50 i.p. administration in mice [20].
3
. Conclusion

In summary, an efficient synthetic approach to fluorine-containing 2-cycloalkylimino
substituted 1,3-benzothiazin-4-ones has been developed. It is based on addition of N-nucleophiles
to o-fluorobenzoyl substituted isothiocyanates and subsequent intramolecular cyclizations of
intermediates. As a result, novel 1,3-benzothiazin-4-ones, with varying number and positions of
fluorine atoms in the benzene ring have been obtained.
In the series of novel fluorinated benzothiazinones a number of compounds have been
discovered which exhibit a good level of antimycobacterial activity. These compounds can
possibly be modified further to reach a better potency than the reference drugs. The results
obtained show that some fluorobenzothiazinones can be regarded as promising anti-M.
tuberculosis agents. Further studies are necessary to be done to get more detailed data concerning
structure–activity relationships (QSAR).
4
. Experimental
4
.1. General
Unless otherwise indicated, all common reagents and solvents were used from commercial
suppliers without further purification.
1
19
The Н NMR (400.13 МHz) and F NMR (376.45 MHz) spectra were obtained on a Bruker
1
Avance II DMX400 spectrometer using DMSO-d
6
as the solvent. The Н NMR experiments were
1
9
carried out using trimethylsilane as the internal standard and the F NMR spectra were recorded
1
3
with CFCl
3
(C
6
F
6
was used as secondary reference, δ
F
–162.9 ppm). C (125.7 MHz) NMR spectra
solution.
were recorded on the AVANCE-500 spectrometer in DMSO-d
6
Mass spectra were recorded on a SHIMADZU GCMS-QP2010 Ultra instrument with
electron ionization (EI) of the sample. Microanalyses (C, H, N) were performed using a Perkin–
Elmer 2400 elemental analyzer. Melting points were measured on the instrument Boetius.
Microanalyses (C, H, N) were performed using the Perkin–Elmer 2400 elemental analyzer.
The structure of compound 5b was determined on an Xcalibur E X-ray diffractometer. The
single crystal (colorless prism, 0.25×0.20×0.15) of compound 5b (C12
H F
9 3
N
2
OS ) was used for
2
X-ray analysis. Analysis was performed at 295(2) K on an automated “Xcalibur 3” diffractometer
on standard procedure (graphite monochromated MoK irradiation (λ= 71.073 pm), ω-scans with
1o step, CCD detector). An empirical absorption correction was applied ( = 0.437 mm ). Crystal
-1
is monoclinic, space group P2 /n with a = 6.7672(12), b = 18.952(2), c = 10.4881(14) Å, β =
1
o
3
1
02.592(16) , V = 1312.8(3) Å , Z = 4. On the angles 2.26 <  ° 5056 reflections were
measured, among them 2849 unique reflections (Rint = 0.0297), 1952 reflections with I>2(I).
Completeness to  = 26.00 is 98.30%. The structure was solved by direct method and refined by

2
1
full-matrix least squares at F using the SHELXTL program package. All non-hydrogen atoms
were refined anisotropically, the positions of the hydrogen atoms were calculated as a riding model
2
in isotropic approximation. Goodness to fit at F 1.061; final R values [I>2(I)]: R
1
= 0.0586, wR
2
=
0.1550; R value (all reflections): R
1
= 0.0837, wR
2
= 0.1835. Largest difference peak and hole
-3
were 0.498 and -0.309 ēÅ .
CCDC 1875321 contains the supplementary crystallographic data for this paper. These data
can be obtained free of charge from the Cambridge Crystallographic Data Center via
http://www.ccdc.cam.ac.uk.
Commercially
purchased
2,3,4,5-tetrafluorobenzoylchloride
1a,
2,6-difluoro-
benzoylchloride 1b, 2,4-difluorobenzoylchloride 1c and 2,3-difluorobenzoylchloride 1d were used
for the preparation of intermediates 2a-d.
4
.2. Procedure for the Synthesis of o-fluorosubstituted N-(cycloalkylimino-4-
carbothioyl)benzamides (4a-p)
General Procedure
To o-fluorobenzoylchloride 1 (4.5 mmol) a solution of ammonium thiocyanate (0.35 g, 4.5 mmol)
º
in acetonitlile (13 mL) was added. Reaction mixture was stirred at 40 C for 5 min, the precipitate
of NH Cl was filtered off, and cycloalkylimine 3 (4.5 mmol) was added to a solution of o-
4
fluorobenzoylisothiocyanate 2. Mixture was stirred at room temperature for 3 h, the precipitate
was filtered off and recrystallized from ethanol.
2
,3,4,5-Tetrafluoro-N-(morpholine-4-carbothioyl)benzamide (4a)
1
Yield 76%, mp 201−203 °C. Н NMR (DMSO-d
6
): 3.72 (m, 6H, N(CH
2
)
2
, OCH
): -137.79 (m, 1F), -138.83
): 42.92 (s, NCH ), 50.64 (s,
), 112.11 (d, C-6, 2JCF = 19.9 Hz), 129.84 (m, C-1), 139.81
dt, C-3, 1JCF = 249.8, 2JCF = 15.0 Hz), 141.36 (dt, C-4, 1JCF = 253.6, 2JCF = 13.4 Hz), 145.12 (dd,
2
), 4.14 (m, 2H,
1
9
OCH
m, 1F), -151.71 (m, 1F), -155.37 (m, 1F). C NMR (DMSO-d
NCH ), 63.31 (s, OCH ), 65.48 (s, OCH
2
), 7.60 (m, 1H, C
6
HF
4
), 11.1 (br. s, 1H, NH). F NMR (DMSO-d
6
1
3
(
6
2
2
2
2
(
C-2, 1JCF = 246.6, 2JCF = 13.4 Hz), 146.03 (dd, C-2, 1JCF = 246.6, 2JCF = 11.8 Hz), 159.21 (s, CO),
+
1
5
78.48 (s, CS). MS, m/z (rel. int.): 322 (19) [M] , 177 (31), 149 (19), 99 (13), 86 (100), 58 (12),
6 (11). Calcd for C12
H F
10 4
N
2
O S: C 44.72; H 3.13; N 8.69. Found: C 44.61; H 3.07; N 8.78.
2
2
,3,4,5-Tetrafluoro-N-(thiomorpholine-4-carbothioyl)benzamide (4b)
1
Yield 81%, mp 154−156 °C. Н NMR (DMSO-d
6
): 2.78 (m, 4H, S(CH
2
)
2
), 3.92 (m, 2H, NCH
2
),
1
9
4
.39 (m, 2H, NCH
2
), 7.57 (m, 1H, C
6
HF
4
), 11.1 (br. s, 1H, NH). F NMR (DMSO-d ): -137.68
6

(m, 1F), -138.73 (m, 1F), -151.67 (m, 1F), -155.33 (m, 1F). Calcd for C12
H
10
F
4
N
2
OS : C 42.60; H
2
2
.98; N 8.28. Found: C 42.49; H 2.87; N 8.36.
2
,3,4,5-Tetrafluoro-N-(1,4-dioxa-8-azaspiro[4.5]decane-8-carbothioyl)benzamide (4c)
1
Yield 79%, mp 156−158 °C. Н NMR (DMSO-d
6
): 1.83 (m, 4H, (CH
), 10.9 (br. s, 1H, NH). F NMR (DMSO-d
37.72 (m, 1F), -138.78 (m, 1F), -151.78 (m, 1F), -155.37 (m, 1F). Calcd for C15 S: C
7.62; H 3.73; N 7.40. Found: C 42.51; H 3.64; N 7.48.
2
)
2
), 3.96 (m, 6H, N(CH
2
)
2
,
1
9
OCH
2
), 4.20 (m, 2H, OCH
2
), 7.56 (m, 1H, C
6
HF
4
6
): -
1
4
H
14
F
4
N
2
O
3
2
,3,4,5-Tetrafluoro-N-(4-ethoxycarbonylpiperazine-1-carbothioyl)benzamide (4d)
1
Yield 82%, mp 153−155 °C. Н NMR (DMSO-d
6
): 1.26 (t, 3H, CH
), 7.61 (m, 1H, C HF ), 11.2 (br. s, 1H, NH). F NMR
): -137.84 (m, 1F), -138.82 (m, 1F), -151.69 (m, 1F), -155.37 (m, 1F). Calcd for
S: C 45.80; H 3.84; N 10.68. Found: C 45.70; H 3.83; N 10.74.
3
), 3.57 (m, 4H, N(CH
2
)
2
), 3.70
1
9
(
m, 2H, NCH
2
), 4.10 (m, 4H, OCH
2
, NCH
2
6
4
(DMSO-d
6
C
15
H
15
F
4
N
3
O
3
2
,3,4,5-Tetrafluoro-N-[(4-(2-fluorophenyl)piperazine-1-carbothioyl]benzamide (4e)
1
Yield 77%, mp 99−101 °C. Н NMR (DMSO-d
6
): 3.21 (m, 4H, N(CH
F), 7.09 (m, 3H, C F), 7.61 (m, 1H, C
): -122.71 (s, 1F), -137.72 (m, 1F), -138.79 (m, 1F), -151.69
OS: C 52.05; H 3.40; N 10.12. Found: C 51.94; H
2
)
2
), 3.83 (m, 2H, NCH
2
),
4
1
.30 (m, 2H, NCH
2
), 7.00 (m, 1H, C
6
H
4
6
H
4
6
HF ), 10.8 (br. s,
4
1
9
1
H, NH). F NMR { H} (DMSO-d
6
(
m, 1F), -155.34 (m, 1F). Calcd for C18
H
14
F
5
N
3
3
.33; N 10.19.
2
,3,4,5-Tetrafluoro-N-(4-t-butoxycarbonylpiperazine-1-carbothioyl)benzamide (4f)
1
Yield 82%, mp 144−146 °С. Н NMR (DMSO-d
6
): 1.45 (s, 9H, C(CH
)), 7.55 (m, 1H, C HF ), 11.1 (br. s, 1H, NH). F NMR
): -137.56 (s, 1F); -138.73 (м, 1F); -151.61 (m, 1F); -155.29 (m, 1F). Calcd for
S: C 48.45; H 4.54; N 9.97. Found: C 48.50; H 4.56; N 9.90.
3
)
3
), 3.54 (m, 4H, N(CH
2
) ),
2
1
9
3
.68 (m, 2H, N(CH
2
)), 4.10 (m, 2H, N(CH
2
6
4
{1
H} (DMSO-d
6
C
17
H
19
F
4
N
3
O
3
2
,6-Difluoro-N-(morpholine-4-carbothioyl)benzamide (4g)
1
Yield 84%, mp 177−179 °C. Н NMR (DMSO-d
6
): 3.74 (m, 6H, N(CH
2
)
2
, OCH ), 4.13 (m, 2H,
2
OCH
Hz), 11.3 (br. s, 1H, NH). F NMR { H} (DMSO-d
s, NCH ), 50.16 (s, NCH ), 65.53 (s, O(CH
), 111.93 (dd, C-3, C-5, 2JCF = 23.3, 4JCF = 6.2 Hz),
14.04 (t, C-1, 2JCF = 21.8 Hz), 132.57 (t, C-4, 3JCF = 9.5 Hz), 157.70 (s, C(O)Ar), 158.83 (dd, C-
2
), 7.08 (ddd, 2H, H-3, H-5, J = 10.8, J = 8.0, J = 2.6 Hz), 7.50 (tt, 1H, H-4, J = 8.4, J = 6.6
1
9
1
13
6
): -113.06 (s). C NMR (DMSO-d ): 50.26
6
(
2
2
)
2 2
1

2
9
, C-6, 1JCF = 249.5, 3JCF = 7.9 Hz), 178.94 (C=S). Calcd for C12
H
12
F
2
N
2
2
O S: C 50.34; H 4.22; N
.78. Found: C 50.27; H 4.16; N 9.84.
2
,6-Difluoro-N-(thiomorpholine-4-carbothioyl)benzamide (4h)
1
Yield 82%, mp 115−117 °C. Н NMR (DMSO-d
6
): 2.79 (m, 4H, S(CH
2
)
2
), 3.96 (m, 2H, NCH ),
2
4
8
d
.38 (m, 2H, NCH
.4, J = 6.5 Hz), 11.3 (br. s, 1H, NH). F NMR { H} (DMSO-d
): 26.37 (s, SCH ), 26.75 (s, SCH ), 52.69 (s, N(CH
), 111.94 (dd, C-3, C-5, 2JCF = 24.6, 4JCF
4.1 Hz), 114.07 (t, C-1, 2JCF = 21.8 Hz), 132.56 (t, C-4, 3JCF = 9.5 Hz), 157.59 (s, C(O)Ar),
2
), 7.08 (ddd, 2H, H-3, H-5, J = 10.9, J = 8.0. J = 2.6 Hz), 7.49 (tt, 1H, H-4, J =
1
9
1
13
6
): -112.98 (s). C NMR (DMSO-
6
2
2
)
2 2
=
1
4
58.82 (dd, C-2, C-6, 1JCF = 249.5, 3JCF = 8.1 Hz), 178.40 (C=S). Calcd for C12
H
12
F
2
N
2
OS : C
2
7.67; H 4.00; N 9.26. Found: C 47.59; H 3.94; N 9.31.
2
,6-Difluoro-N-(4-ethoxycarbonylpiperazine-1-carbothioyl)benzamide (4i)
1
Yield 83%, mp 154−156 °C. Н NMR (DMSO-d
6
): 1.26 (t, 3H, CH
3
), 3.57 (m, 4H, N(CH
2
)
2
), 3.72
(
m, 2H, NCH
2
), 4.10 (m, 4H, OCH
2
, NCH ), 7.11 (ddd, 2H, H-3, H-5, J = 10.8, J = 7.9. J = 2.5),
2
1
9
1
7
.50 (tt, 1H, H-4, J = 8.4, J = 6.5 Hz), 11.3 (br. s, 1H, NH). F NMR { H} (DMSO-d
6
): -113.01
1
3
(
s). C NMR (DMSO-d
6
): 14.50 (s, CH
3
), 42.34 (s, N(CH
2
)
2
), 49.61 (s, N(CH
)
2 2
), 61.01 (s,
OCH
), 111.93 (dd, C-3, C-5, 2JCF = 26.3, 4JCF = 5.0 Hz), 114.03 (t, C-1, 2JCF = 21.2 Hz), 132.59
2
(
t, C-4, 3JCF = 9.7 Hz), 154.53 (s, COO), 157.86 (s, C(O)Ar), 158.85 (dd, C-2, C-6, 1JCF = 250.7,
S: C 50.41; H 4.79; N 11.76. Found: C
3JCF = 8.5 Hz), 178.38 (C=S). Calcd for C15
H
17
F
2
N
3
O
3
5
0.35; H 4.71; N 11.83.
2
,6-Difluoro-N-[(4-(2-fluorophenyl)piperazine-1-carbothioyl]benzamide (4j)
1
Yield 77%, mp 155−157 °C. Н NMR (DMSO-d
6
): 3.22 (m, 4H, N(CH
F), 7.07 (m, 5H, C F, H-3, H-5), 7.52 (m, 1H, H-4),
1.3 (br. s, 1H, NH). F NMR { H} (DMSO-d ): -112.96 (s, 2F), -122.60 (s, 1F). Calcd for
OS: C 56.98; H 4.25; N 11.08. Found: C 56.86; H 4.14; N 11.17.
2
)
2
), 3.85 (m, 2H, NCH ),
2
4
1
.31 (m, 2H, NCH
2
), 6.98 (m, 1H, C
6
H
4
6
H
4
1
9
1
6
C
18
H
16
F
3
N
3
2
,6-Difluoro-N-(4-t-butoxycarbonylpiperazine -1-carbothioyl)benzamide (4k)
1
Yield 76%, mp 130−132 °С. Н NMR (DMSO-d
6
): 1.45 (s, 9H, C(CH
3
)
3
), 3.54 (m, 4H, N(CH
2
2
) ),
3
3
4
.70 (m, 2H, N(CH
2
)), 4.10 (m, 2H, N(CH
2
)), 7.06 (t, 2H, Н-3, H-5, J = 8.0 Hz), 7.51 (m 1Н, Н-
1
9
1
), 11.3 (br. s, 1H, NH). F NMR { H} (DМSO-d
6
): -112.93 s. Calcd for C17
H
21
F
2
N
3
3
O S: C 52.98;
H 5.49; N 10.90. Found: C 52.90; H 5.45; N 10.85.
2
,6-Difluoro-N-(4-acetylpiperazin-1-carbothioyl)benzamide (4l)

1
Yield 89%, mp 189−191 °С. Н NMR (DMSO-d
6
): 2.05 (s, 3H, CH
3
), 3.71–4.09 (m, 8H,
3
5
3
2
1
N(CH
2
)
2
), 7.03 (ddd, 2Н, H-3, H-5, 3JHF = 13.5, J = 8.6, JHF = 1.6 Hz), 7.47 (tt, 1H, H-4, J =
2.8, 4JHF = 4.8 Hz), 11.3 (br. s, 1H, NH). F NMR { H} (DМSO-d
): 21.19 (s, CH ), 44.24 (s, NCH ), 44.65 (s, NCH ), 49.67 (s, NCH
12.02 (dd, C-3, C-5, 2JCF = 23.8, 4JCF = 4.6 Hz), 114.03 (t, C-1, 2JCF = 21.8 Hz), 132.60 (t, C-4,
19
1
): -112.79 s. C NMR
13
6
(DMSO-d
6
3
2
2
2
), 50.08 (s, NCH ),
2
1
3JCF = 10.6 Hz), 157.80 (s, C(O)Me), 158.82 (dd, C-2, C-6, 1JCF = 253.4, 3JCF = 8.7 Hz), 168.64 (s,
C(O)Ar), 178.23 (C=S). Calcd for C14 S: C 51.37; H 4.62; N 12.84. Found: C 51.44; H
H
15
F
2
N
3
O
2
4
.68; N 12.79.
2
,6-Difluoro-N-(4-cyclopropylcarbonylpiperazin-1-carbothioyl)benzamide (4m)
1
3
Yield 88%, mp 148−150 °С. Н NMR (DMSO-d
6
): 0.82 (m, 4Н, 2CH
2
), 1.91 (dd, 1H, CH, J 10.2,
3J = 5.5 Hz), 3.79 (m, 8H, 2N(CH
)
2
), 7.07 (dt, 2Н, H-3, H-5, 3JHF = 6.1, J = 8.2 Hz), 7.47 (m,
3
2
1
9
1
1
5
H, H-4), 10.7 (s, 1H, NH). F NMR { H} (DМSO-d
6
): -112.92 s. Calcd for C16
H
17
F
2
N
3
2
O S: C
4.38; H 4.85; N 11.89. Found: C 54.45; H 4.91; N 11.83.
2
,6-Difluoro-N-[4-(2-furoyl)carbonylpiperazin-1-carbothioyl]benzamide (4n)
1
Yield 81%, mp 192−194 °C. Н NMR (DMSO-d
6
): 3.89–4.19 (m, 8H, 2N(CH
2
)
2
), 6.56 (dd, 1Н,
4
’
3
3
3
4
H , J 3.4, J 1.7 Гц), 7.04 (m, 3H, H-3, H-5, H-3’), 7.50 (tt, 1H, H-4, J = 12.9, JHF = 8.6 Hz),
3
19
1
7
.68 (d, 1Н, H-5’, J = 5.0 Hz), 11.4 (s, 1H, NH). F NMR { H} (DМSO-d
6
), δ, м.д.: -112.74 s.
Calcd for C17 S: C 53.82; H 3.99; N 11.08. Found: C 53.90; H 4.05; N 11.02.
H
15
F
2
N
3
O
3
2
,4-Difluoro-N-(4-ethoxycarbonylpiperazine-1-carbothioyl)benzamide (4o)
1
Yield 85%, mp 162−164 °C. Н NMR (DMSO-d
6
): 1.26 (t, 3H, CH
), 7.11 (m, 2H, C
): -107.58 (d, 1F, 4JFF = 11 Hz), -104.49 (d, 1F, 4JFF
): 14.50 (s, CH ), 42.32 (s, N(CH ), 49.59 (s, N(CH ), 60.99 (s,
), 104.64 (t, C-3, 2JCF =26.2 Hz), 111.80 (dd, C-5, 2JCF =29.4, 4JCF =4.6 Hz), 119.71 (dd, C-
, 2JCF =14.5, 4JCF =3.4 Hz), 132.15 (m, C-6), 154.54 (s, COO), 160.19 (dd, C-2, 1JCF =255.8, 4JCF
3
), 3.57 (m, 4H, N(CH
2
)
2
), 3.66
(
m, 2H, NCH
2
), 4.08 (m, 4H, OCH
2
, NCH
2
6
H
3
F
2
), 7.72 (m, 1H, C
6
H
3 2
F
), 10.9
1
9
1
(
br. s, 1H, NH). F NMR { H} (DMSO-d
6
=
1
3
1
1 Hz). C NMR (DMSO-d
6
3
2
)
2
)
2 2
OCH
2
1
=
14.3 Hz), 161.16 (s, C(O)Ar), 164.02 (dd, C-4, 1JCF =252.8, 4JCF =12.0 Hz), 179.19 (C=S). Calcd
for C15
H
17
F
2
N
3
O
3
S: C 50.41; H 4.79; N 11.76. Found: C 50.32; H 4.68; N 11.84.
2
,3-Difluoro-N-(4-ethoxycarbonylpiperazine-1-carbothioyl)benzamide (4p)
1
Yield 83%, mp 135−137 °C. Н NMR (DMSO-d
m, 2H, N(CH )), 4.13 (q, 2H, CH ), 7.26 (m, 1Н, Н-5), 7.47 м (m, 1Н, Н-4), 7.78 (m, 1Н, Н-6),
1.3 (br. s, 1Н, NH). F NMR { H} (DMSO-d
6
): 1.21 (t, 3H, CH
3
), 3.32 (m, 2H, N(CH
2
)), 3.86
(
2
2
1
9
1
): -139.26 (d, 1F, 3JFF = 18.5 Hz), -133.35 (d, 1F,
1
6

3JFF = 18.5 Hz). Calcd for C15
H
17
F
2
N
3
3
O S: C 50.41; H 4.79; N 11.76. Found: C 50.36; H 4.73; N
1
1.82.
4
1
.3. Procedure for the Synthesis of fluorinated 2-cycloalkylimino-
,3-benzothiazin-4-ones (5a-p)
General Procedure for the synthesis of 6,7,8-trifluoro-2-cycloalkylimino-1,3-benzothiazin-4-ones
5a-f)
(
To a suspension of 2,3,4,5-tetrafluoro-N-(cycloalkylimino-4-carbothioyl)benzamide (4a-f) (4.5
mmol) in toluene (20 mL) triethylamine (1.25 mL, 9 mmol) was added. Reaction mixture was
refluxed during 37 h (control by TLC), and then cooled. The precipitate was filtered off, washed
with water (20 mL) and recrystallized from ethanol.
6
,7,8-Trifluoro-2-(morpholin-4-yl)-1,3-benzothiazin-4-one (5a)
1
Yield 59%, mp 208−210 °C. Н NMR (DMSO-d
6
): 3.75 (m, 4H, N(CH
2
)
2
), 3.88 (m, 4H, O(CH
): -134.66 (dd, 1F,
F-6, J = 21.4, J = 4.8 Hz), -136.31 (dd, 1F, F-8, J = 20.6, J = 4.8 Hz), -153.56 (dd, 1F, F-7, J =
2
) ),
2
3
4
5
19
1
8
.00 (ddd, 1H, H-5, J = 10.5, J = 7.5, J = 2.2 Hz). F NMR { H} (DMSO-d
6
1
3
2
1
0.8, J = 21.3 Hz). C NMR (DMSO-d
6
): 50.26 (s, NCH
2
), 50.16 (s, NCH
2
), 65.53 (s, O(CH ) ),
2
2
11.13 (d, C-5, 2JCF = 22.8 Hz), 113.11 (d, C-4a, 3JCF = 18.9 Hz), 118.33 (m, C-8a), 141.49 (dt,
C-7, 1JCF = 257.8, 2JCF = 18.2 Hz), 145.44 (dd, C-8, 1JCF = 249.4, 2JCF = 14.6 Hz), 149.54 (dd, C-
6
, 1JCF = 247.6, 2JCF = 13.0 Hz), 159.27 (s, C-2), 164.48 (s, C(O)). MS, m/z (rel. int.): 302 (16)
+
[
M] , 259 (13), 245 (17), 191 (11), 190 (100), 162 (43), 144 (11), 93 (12), 55 (11). Calcd for
C
12
H
9
F
3
N
2
2
O S: C 47.68; H 3.00; N 9.27. Found: C 47.81; H 3.07; N 9.19.
6
,7,8-Trifluoro-2-(thiomorpholin-4-yl)-1,3-benzothiazin-4-one (5b)
1
Yield 84%, mp 210−212 °C. Н NMR (DMSO-d
6
): 2.78 (m, 4H, S(CH
2
)
2
), 4.18 (m, 2H, (NCH
): -134.57 (dd, 1F, F-6,
J = 21.6, J = 4.8 Hz), -136.28 (dd, 1F, F-8, J = 20.0, J = 4.8 Hz), -153.50 (t, 1F, F-7, J = 20.8 Hz).
13C NMR (DMSO-d ), 110.48 (d, C-5, 2JCF = 23.2 Hz),
): 26.44 (s, S(CH ), 49.14 (s, N(CH
13.09 (d, C-4a, 3JCF = 19.7 Hz), 118.37 (m, C-8a), 141.51 (dt, C-7, 1JCF = 258.5, 2JCF = 19.2 Hz),
2
)
2
),
3
4
5
19
1
7
.99 (ddd, 1H, H-5, J = 9.9, J = 7.5, J = 2.1). F NMR { H} (DMSO-d
6
6
2
)
2
)
2 2
1
1
1
1
45.44 (dd, C-8, 1JCF = 248.9, 2JCF = 15.0 Hz), 149.50 (dd, C-6, 1JCF = 248.9, 2JCF = 13.2 Hz),
+
59.32 (s, C-2), 164.58 (s, C(O)). MS, m/z (rel. int.): 318 (20) [M] , 245 (42), 218 (13), 191 (12),
90 (58), 162 (38), 144 (10), 127 (14), 93 (11), 69 (100), 68 (11), 55 (14), 46 (19), 45 (11), 42
(15). Calcd for C12
H
9
F
3
N
2
OS : C 45.28; H 2.85; N 8.80. Found: C 45.20; H 2.77; N 8.89.
2

6
,7,8-Trifluoro-2-(1,4-dioxa-8-azaspiro[4.5]decane-8-yl)-1,3-benzothiazin-4-one (5c)
1
Yield 73%, mp 203−205 °C. Н NMR (DMSO-d
6
): 1.79 (m, 4H, (CH
2
)
2
), 3.94 (m, 8H, N(CH
2
2
) ,
3
4
5
19
1
O(CH
2
)
2
), 7.99 (ddd, 1H, H-5, J = 9.9, J = 7.5, J = 2.1 Hz). F NMR { H} (DMSO-d
6
): -134.78
(dd, 1F, F-6, J = 21.7, J = 4.7 Hz), -136.39 (dd, 1F, F-8, J = 20.4, J = 4.8 Hz), -153.67 (t, 1F, F-7,
1
3
J = 21.0 Hz). C NMR (DMSO-d
OCH CH
O), 105.63 (s, C-4’), 111.44 (d, C-5, 2JCF = 22.3 Hz), 113.14 (d, C-4a, 3JCF = 24.8 Hz),
18.17 (m, C-8a), 141.46 (dt, C-7, 1JCF = 251.7, 2JCF = 12.4 Hz), 145.37 (dd, C-8, 1JCF = 244.6,
6
): 33.88 (s, CH
2
), 34.33 (s, CH
2
), 48.27 (s, N(CH
2
)
2
), 63.95 (s,
2
2
1
2JCF = 13.6 Hz), 149.45 (dd, C-6, 1JCF = 247.8, 2JCF = 12.4 Hz), 154.46 (s, C-2), 164.51 (s, C(O)).
+
MS, m/z (rel. int.): 358 (32) [M] , 289 (71), 258 (21), 245 (31), 191 (25), 190 (82), 162 (36), 100
(15), 99 (100), 87 (14), 86 (35), 56 (11), 55 (37), 43 (11), 42 (24). Calcd for C15
H
13
F
3
N
2
3
O S: C
5
0.28; H 3.66; N 7.82. Found: C 50.19; H 3.57; N 7.93.
6
,7,8-Trifluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-one (5d)
1
Yield 74%, mp 173−175 °C. Н NMR (DMSO-d
6
): 1.27 (t, 3H, CH
3
), 3.58 (m, 4H, N(CH
2
)
2
), 3.91
3
4
5
19
(
m, 4H, N(CH
2
)
2
), 4.12 (q, 2H, OCH
2
), 8.00 (ddd, 1H, H-5, J = 9.6, J = 7.5, J = 1.5 Hz). F
1
NMR { H} (DMSO-d
6
): -134.62 (dd, 1F, F-6, J = 21.7, J = 4.7 Hz), -136.28 (dd, 1F, F-8, J = 20.3,
1
3
J = 4.6 Hz), -153.52 (dd, 1F, F-7, J = 21.2, J = 20.9). C NMR (DMSO-d
s, N(CH ), 45.49 (s, N(CH ), 61.07 (s, OCH
), 111.44 (d, C-5, 2JCF = 22.3 Hz), 113.10 (d, C-
a, 3JCF = 25.1 Hz), 118.15 (m, C-8a), 141.44 (dt, C-7, 1JCF = 252.6, 2JCF = 12.6 Hz), 145.36 (dd,
6
): 14.51 (s, CH
3
), 42.47
(
2
)
2
2
)
2
2
4
C-8, 1JCF = 244.2, 2JCF = 13.9 Hz), 149.48 (dd, C-6, 1JCF = 248.4, 2JCF = 12.6 Hz), 154.48 (s, C-2),
+
1
1
4
59.76 (s, COO), 164.48 (s, C(O)). MS, m/z (rel. int.): 373 (9) [M] , 258 (42), 245 (15), 190 (45),
62 (21), 157 (10), 128 (72), 69 (42), 56 (100), 55 (20), 42 (31). Calcd for C15
8.26; H 3.78; N 11.25. Found: C 48.19; H 3.69; N 11.33.
H
14
F
3
N
3
3
O S: C
6
,7,8-Trifluoro-2-[(4-(2-fluorophenyl)piperazin-1-yl]-1,3-benzothiazin-4-one (5e)
1
Yield 77%, mp 191−193 °C. Н NMR (DMSO-d
6
): 3.21 (m, 4H, N(CH
2
)
2
), 4.06 (m, 4H, N(CH
2
2
) ),
3
4
5
19
1
6
.98-7.12 (m, 4H, C
6
H
4
F), 8.01 (ddd, 1H, H-5, J = 9.6, J = 7.5, J = 1.6 Hz). F NMR { H}
(DMSO-d
6
): -122.67 (s, 1F), -134.61 (dd, 1F, F-6, J = 21.6, J = 4.7 Hz), -136.28 (dd, 1F, F-8, J =
1
3
2
4
0.3, J = 4.7 Hz), -153.55 (t, 1F, F-7, J = 21.0 Hz). C NMR (DMSO-d
6
): 45.49 (s, N(CH
2
)
2
),
9.37 (s, N(CH
2
)
2
), 111.29 (d, C-5, 2JCF = 21.8 Hz), 113.12 (d, C-4a, 3JCF = 23.8 Hz), 116.28 (d,
C-3’, 2JCF = 22.6 Hz), 118.15 (m, C-8a), 119.64 (d, C-6’, 3JCF = 2.4 Hz), 123.02 (d, C-1’, 2JCF
=
8
1
1
1
.7 Hz), 124.87 (d, C-5’, 4JCF = 4.9 Hz), 139.04 (d, C-4’, 3JCF = 7.3 Hz),
41.42 (dt, C-7, 1JCF = 251.4, 2JCF = 12.6 Hz), 145.36 (dd, C-8, 1JCF = 245.2, 2JCF = 13.7 Hz),
49.45 (dd, C-6, 1JCF = 248.4, 2JCF = 12.6 Hz), 154.48 (s, C-2), 154.91 (d, C-2’, 1JCF = 244.7 Hz),
+
64.48 (s, C(O)). MS, m/z (rel. int.): 395 (2) [M] , 151 (10), 150 (100), 138 (33), 137 (24), 123

(34), 122 (69), 95 (11). Calcd for C18
H
13
F
4
3
N OS: C 54.68; H 3.31; N 10.63. Found: C 54.59; H
3
.20; N 10.71.
6
,7,8-Trifluoro-2-(4-t-butoxycarbonylpiperazine)-1,3-benzothiazin-4-one (5f)
1
Yield 79 %, mp 193−195 °C. Н NMR (DMSO-d
6
): 1.46 (m, 9Н, С(CH
3
)
3
), 3.54 (m, 4H, N(CH
2
2
) ),
1
9
1
): -134.40 (d, 1F, F-6, 3JFF
3
.90 (m, 4H, N(CH
2
)
2
), 8.00 (m, 1H, Н-5). F NMR { H} (DМSO-d
6
=
21.3 Hz), -136.25 (d, 1F, F-8, 3JFF = 19.9 Hz); -153.47 (dd, 1F, F-7, 3JFF = 21.3, 3JFF = 19.9 Hz).
13C NMR (DMSO-d
): 27.51 (s, (CH ), 42.52 (s, N(CH ), 45.64 (s, N(CH ), 71.48 (s,
OCMe
), 111.42 (d, C-5, 2JCF = 22.1 Hz), 113.12 (d, C-4a, 3JCF = 25.5 Hz), 118.17 (m, C-8a),
41.43 (dt, C-7, 1JCF = 249.8, 2JCF = 13.1 Hz), 145.36 (dd, C-8, 1JCF = 248.6, 2JCF = 13.5 Hz),
6
3
)
3
2
)
2
)
2 2
3
1
1
50.04 (dd, C-6, 1JCF = 249.7, 2JCF = 12.8 Hz), 154.51 (s, C-2), 159.74 (s, COO), 164.39 (s, C(O)).
+
MS, m/z (rel. int.): 401 (2) [M] , 190 (13), 69 (36), 57 (100), 56 (25), 42 (11), 41 (21). Calcd for
C
17
H
18
F
3
N
3
3
O S: C 50.87; H 4.52; N 10.47. Found: C 50.82; H 4.56; N 10.39.
General Procedure for the synthesis of monofluorinated 2-cycloalkylimino-1,3-benzothiazin-4-
ones (5g-p)
Method A. To a solution of difluoro-N-(cycloalkylimino-4-carbothioyl)benzamide (4g-p) (1.16
mmol) in DMF (3 mL) triethylamine (0.33 mL, 2.32 mmol) was added. Reaction mixture was
refluxed during 6 h, and then cooled. The precipitate was filtered off, washed with water (20 mL)
and recrystallized from ethanol.
Method B. To a solution of difluoro derivative (4k) (0.347 g, 0.9 mmol) in MeCN (15 mL) DBU
(0.3 mL, 1.99 mmol) was added. Reaction mixture was refluxed during 3 h, and then cooled. The
precipitate was filtered off, suspended in water (20 mL), and pH was adjusted to 5 by addition of
acetic acid. Colorless product 5k was filtered off and recrystallized from ethanol.
5
-Fluoro-2-(morpholin-4-yl)-1,3-benzothiazin-4-one (5g)
1
Yield 81%, mp 193−195 °C. Н NMR (DMSO-d
6
): 3.71 (m, 4H, N(CH
2
)
2
), 3.77 (m, 4H, O(CH
2
2
) ),
3
3
4
3
4
7
.30 (ddd, 1H, H-6, J = 11.2, J = 8.2, J = 0.9 Hz), 7.47 (dd, 1H, H-8, J = 8.0, J = 0.9 Hz), 7.65
3
4
19
1
13
(
td, 1H, H-7, J = 8.1, J = 5.0 Hz). F NMR { H} (DMSO-d
): 50.22 (s, NCH ), 51.34 (s, NCH ), 65.58 (s, O(CH
), 112.42 (d, C-4a, 2JCF = 13.1 Hz), 116.34
d, C-6, 2JCF = 24.6 Hz), 122.38 (d, C-8, 4JCF = 5.7 Hz), 133.62 (d, C-7, 3JCF = 7.9 Hz), 134.43 (s,
6
): -108.95 (s). C NMR (DMSO-
d
6
2
2
)
2 2
(
C-8a), 154.53 (s, C-2), 161.78 (d, C-5, 1JCF = 259.4 Hz), 165.01 (d, C(O), 3JCF = 5.9 Hz). MS, m/z
+
(
rel. int.): 266 (11) [M] , 155 (11), 154 (100), 126 (21), 110 (16), 81 (16), 69 (30). Calcd for
C
12
H11FN
2
2
O S: C 54.13; H 4.16; N 10.52. Found: C 54.04; H 4.08; N 10.63.

5
-Fluoro-2-(thiomorpholin-4-yl)-1,3-benzothiazin-4-one (5h)
1
Yield 85%, mp 182−184 °C. Н NMR (DMSO-d
6
): 2.79 (m, 4H, S(CH
2
)
2
), 4.12 (m, 2H, (NCH
2
2
) ),
3
3
3
3
7
8
4
.20 (dd, 1H, H-6, J = 10.6, J = 8.7 Hz), 7.34 (d, 1H, H-8, J = 8.0 Hz), 7.60 (td, 1H, H-7, J =
4
19
1
.1, J = 5.0 Hz). F NMR { H} (DMSO-d
6
): -108.21 (s). NMR (DMSO-d
6
): 26.41 (s, S(CH
2
2
) ),
8.86 (s, N(CH
2 2
)
), 112.37 (d, C-4a, 2JCF = 12.8 Hz), 116.27 (d, C-6, 2JCF = 23.9 Hz), 122.30 (d,
C-8, 4JCF = 5.2 Hz), 133.47 (d, C-7, 3JCF = 7.6 Hz), 134.35 (s, C-8a), 154.44 (s, C-2), 161.86 (d,
C-5, 1JCF = 258.4 Hz), 165.03 (d, C(O), 3JCF = 5.5 Hz). MS, m/z (rel. int.): 282 (23) [M] , 209 (42),
+
1
6
5
82 (13), 180 (11), 155 (18), 154 (100), 152 (15), 127 (25), 126 (46), 110 (34), 108 (13), 94 (15),
9 (91), 46 (17), 45 (12), 42 (14). Calcd for C12
0.97; H 3.85; N 10.01.
H11FN
2
OS : C 51.05; H 3.93; N 9.92. Found: C
2
5
-Fluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-one (5i)
1
Yield 78%, mp 172−174 °C. Н NMR (DMSO-d
6
): 1.27 (t, 3H, CH
3
), 3.56 (m, 4H, N(CH
2
2
) ), 3.84
3
3
4
(
m, 4H, N(CH
2
)
2
), 4.11 (q, 2H, OCH
2
), 7.20 (ddd, 1H, H-6, J = 10.7, J = 8.9, J = 0.5 Hz), 7.36
3
4
3
4
19
1
(
dd, 1H, H-8, J = 8.0, J = 0.5 Hz), 7.65 (td, 1H, H-7, J = 8.1, J = 5.0). F NMR { H} (DMSO-
1
3
d
6
8
6
): -108.25 (s). C NMR (DMSO-d
1.04 (s, OCH
), 112.39 (d, C-4a, 2JCF = 13.0 Hz), 116.29 (d, C-6, 2JCF = 24.2 Hz), 122.32 (d, C-
, 4JCF = 5.4 Hz), 133.58 (d, C-7, 3JCF = 7.8 Hz), 134.39 (s, C-8a), 154.49 (s, C-2), 160.20 (s,
6
): 14.53 (s, CH
3
), 42.56 (s, N(CH
2
)
2
), 45.18 (s, N(CH
2
)
2
),
2
COO), 161.83 (d, C-5, 1JCF = 262.3 Hz), 165.00 (d, C(O), 3JCF = 5.9 Hz). MS, m/z (rel. int.): 337
+
(
8) [M] , 269 (16), 222 (41), 209 (40), 182 (14), 157 (17), 155 (18), 154 (100), 128 (19), 126 (22),
1
10 (20), 69 (14), 56 (34), 55 (11), 42 (16). Calcd for C15
H16FN
3
3
O S: C 53.40; H 4.78; N 12.45.
Found: C 53.35; H 4.71; N 12.53.
5
-Fluoro-2-[(4-(2-fluorophenyl)piperazin-1-yl]-1,3-benzothiazin-4-one (5j)
1
Yield 81%, mp 177−179 °C. Н NMR (DMSO-d
6
): 3.19 (m, 4H, N(CH
2
)
2
), 3.99 (m, 4H, N(CH
2
2
) ),
3
3
3
6
.97−7.12 (m, 4H, C
6
H
4
F), 7.20 (dd, 1H, H-6, J = 10.6, J = 8.8 Hz), 7.36 (d, 1H, H-8, J = 8.0
3
4
19
1
Hz), 7.60 (td, 1H, H-7, J = 8.0, J = 5.1 Hz). F NMR { H} (DMSO-d
6
): -108.27 (s, 1F), -122.66
1
3
), 112.43 (d, C-4a, 2JCF = 9.2
(
s, 1F). C NMR (DMSO-d
6
): 45.58 (s, N(CH
2
)
2
), 49.65 (s, N(CH
)
2 2
Hz), 116.01 (d, C-6, 2JCF = 20.7 Hz), 116.28 (d, C-3’, 2JCF = 22.6 Hz), 119.64 (d, C-6’, 3JCF = 2.4
Hz), 122.35 (d, C-8, 4JCF = 5.5 Hz), 123.02 (d, C-1’, 2JCF = 8.8 Hz), 124.87 (d, C-5’, 4JCF = 4.9
Hz), 133.58 (d, C-7, 3JCF = 10.7 Hz), 134.43 (s, C-8a), 139.04 (d, C-4’, 3JCF = 7.3 Hz), 154.92 (d,
C-2’, 1JCF = 245.9 Hz), 160.07 (s, C-2), 161.84 (d, C-5, 1JCF = 263.8 Hz), 165.13 (d, C(O), 3JCF
=
+
6
.3 Hz). MS, m/z (rel. int.): 359 (3) [M] , 222 (31), 154 (15), 150 (100), 123 (37), 122 (70). Calcd
for C18
H
15
F
2
3
N OS: C 60.16; H 4.21; N 11.69. Found: C 60.04; H 4.11; N 11.83.

5
-Fluoro-2-(4-t-butoxycarbonylpiperazine)-1,3-benzothiazin-4-one (5k)
1
Yield 45% (method A), 81% (method B), mp 158−160 °С. Н NMR (DMSO-d
6
): 1.45 (s, 9H,
), 7.18 (dd, 1H, Н-6, 3JHF = 10.6, J = 8.9
3
C(CH
3
)
3
), 3.51 (m, 4H, N(CH
2
)
2
), 3.83 (m, 4H, N(CH
2
)
2
3
3
4
19
1
Hz), 7.32 (d, 1Н, Н-8, J = 8.0 Hz), 7.58 (td, 1H, H-7, J = 8.0, JHF = 4.9 Hz). F NMR { H}
1
3
(
DМSO-d
N(CH ), 71.44 (s, OCMe
22.34 (d, C-8, 4JCF = 5.3 Hz), 133.55 (d, C-7, 3JCF = 7.6 Hz), 134.37 (s, C-8a), 154.46 (s, C-2),
6
): -108.04 (s). C NMR (DMSO-d
6
): 27.54 (s, (CH
3
)
3
), 45.57 (s, N(CH
2
) ), 49.63 (s,
2
2
)
2
3
), 112.42 (d, C-4a, 2JCF = 12.8 Hz), 116.26 (d, C-6, 2JCF = 23.7 Hz),
1
1
60.24 (s, COO), 161.81 (d, C-5, 1JCF = 262.3 Hz), 165.02 (d, C(O), 3JCF = 5.9 Hz). MS, m/z (rel.
+
int.): 365 (7) [M] , 292 (13), 222 (26), 210 (19), 209 (13), 197 (34), 155 (11), 154 (52), 126 (11),
1
10 (12), 69 (32), 57 (100), 56 (17), 41 (18). Calcd for C17
H
20FN
3
3
O S: C 55.88; H 5.52; N 11.50.
Found: C 55.81; H 5.48; N 11.53.
5
-Fluoro-2-(4-acetylpiperazin-1-yl)-1,3-benzothiazin-4-one (5l)
1
Yield 78 %, mp 206−208 °С. Н NMR (DMSO-d
6
): 2.08 (s, 3H, CH
3
), 3.63 (m, 4H, N(CH
2
2
) ),
), 7.19 (dd, 1H, H-6, 3JHF = 10.4, J = 8.5 Hz), 7.33 (d, 1H, H-8, J = 8.0
3
3
3
.84 (m, 4H, N(CH
2
)
2
3
4
19
1
13
Hz), 7.58 (td, 1H, H-7, J = 8.1, J = 4.9 Hz). F NMR { H} (DМSO-d
DMSO-d ): 21.19 (s, CH ), 44.66 (s, N(CH ), 45.42 (s, N(CH
), 112.43 (d, C-4a, 2JCF = 10.1
Hz), 116.29 (d, C-6, 2JCF = 24.0 Hz), 122.34 (d, C-8, 4JCF = 5.4 Hz), 133.58 (d, C-7, 3JCF = 12.5
6
): -108.15 (s). C NMR
(
6
3
2
)
2
)
2 2
Hz), 134.42 (s, C-8a), 160.23 (s, C-2), 161.83 (d, C-5, 1JCF = 263.2 Hz), 165.02 (d, C(O), 3JCF
=
+
4
.8 Hz), 168.56 (s, C(O)Me). MS, m/z (rel. int.): 307 (5) [M] , 223 (10), 222 (27), 209 (25), 182
(
13), 180 (11), 155 (21), 154 (100), 152 (12), 127 (24), 126 (31), 110 (28), 108 (10), 69 (23), 56
32), 55 (12), 43 (47), 42(16). Calcd for C14 S: C 54.71, H 4.59, N 13.67. Found: С 54.78,
(
H14FN O
3 2
Н 4.63, N 13.61.
5
-Fluoro-2-(4-cyclopropylcarbonylpiperazin-1-yl)-1,3-benzothiazin-4-one (5m)
1
Yield 85 %, mp 164−166 °С. Н NMR (DMSO-d
6
): 0.76 (m, 4Н, 2CH
2
), 1.94 (m, 1H, CH), 3.68
), 7.20 (ddd, 1H, H-6, 3JHF = 11.0, J = 8.1, J = 1.7 Hz),
3
4
(
m, 4H, N(CH
2
)
2
), 3.86 (m, 4H, N(CH
2 2
)
3
3
4
5
19
7
.33 (d, 1H, H-8, J = 8.0 Hz), 7.58 (ddd, 1H, H-7, J = 8.1, J = 4.9, JHF = 2.2 Hz). F NMR
{1
H} (DМSO-d
), 43.90 (s, NCH
23.1 Hz), 122.32 (d, C-8, 4JCF = 5.9 Hz), 133.56 (d, C-7, 3JCF = 10.3 Hz), 134.42 (s, C-8a), 160.22
): -108.12 (s). C NMR (DMSO-d
13
): 7.19 (s, (CH
) ), 10.31 (s, CH), 40.73 (s,
6
6
2
2
NCH
2
2
), 45.33 (s, N(CH
2 2
)
), 112.41 (d, C-4a, 2JCF = 9.8 Hz), 116.28 (d, C-6, 2JCF
=
(
s, C-2), 161.84 (d, C-5, 1JCF = 259.5 Hz), 169.99 (d, C(O), 3JCF = 4.8 Hz), 171.36 (s, C(O)Alk).
+
MS, m/z (rel. int.): 333 (5) [M] , 265 (15), 223 (15), 222 (27), 209 (28), 182 (16), 180 (14), 155
(17), 154 (73), 153 (24), 152 (14), 126 (27), 124 (11), 110 (26), 108 (11), 69 (100), 56 (18), 55

(11), 42 (16), 41 (64), 39 (20). Calcd for C16
H16FN
3
2
O S: C 57.64, H 4.84, N 12.60. Found: С
5
7.71, Н 4.90, N 12.55.
5
-Fluoro-2-[4-(2-furoyl)carbonylpiperazin-1-yl]-1,3-benzothiazin-4-one (5n)
1
Yield 81%, mp 202−204 °C. Н NMR (DMSO-d
6
): 3.92 (m, 8H, 2N(CH
2
2
) ), 6.57 (dd, 1Н, H-4’,
3
3
3
3
4
5
J = 3.2, J = 1.6 Hz), 7.04 (d, 1Н, Н-3’, J = 3.4 Hz), 7.18 (ddd, 1H, H-6, J = 8.1, J = 4.9, JHF
3
4
3
2
7
4
.9 Hz), 7.32 (dd, 1H, H-8, J = 8.1, JHF = 4.9 Hz), 7.58 (dd, 1H, H-7, 3JHF = 10.5, J = 8.4 Hz),
1
9
1
13
.71 м (m, 1Н, H-5’). F NMR { H} (DМSO-d
6
), δ, м.д.: -107.86 (s). C NMR (DMSO-d ):
6
5.21 (s, N(CH
2 2
)
), 111.41 (s, C-4’), 112.43 (d, C-4a, 2JCF = 9.1 Hz), 116.10 (s, C-3’), 116.31 (d,
C-6, 2JCF = 23.1 Hz), 122.35 (d, C-8, 4JCF = 4.4 Hz), 133.59 (d, C-7, 3JCF = 10.6 Hz), 134.41 (s, C-
8
a), 145.06 (s, C-5’), 146.65 (s, C-2’), 158.48 (s, C(O)-furoyl), 160.25 (s, C-2), 161.85 (d, C-5,
1JCF = 262.9 Hz), 165.01 (d, C(O), 3JCF = 4.8 Hz). MS, m/z (rel. int.): 359 (14) [M] , 291 (10), 209
+
(
17), 182 (10), 180 (11), 163 (10), 155 (14), 154 (72), 126 (24), 110 (21), 95 (100), 94 (12), 81
11), 69 (14), 56 (13), 39 (18). Calcd for C17 S: C 56.82, H 3.93, N 11.69. Found: С
(
H14FN
3
O
3
5
6.88, Н 4.00, N 11.63.
7
-Fluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-one (5o)
1
Yield 80%, mp 166−168 °C. Н NMR (DMSO-d
6
): 1.27 (t, 3H, CH
3
), 3.57 (m, 4H, N(CH
2
2
) ), 3.86
3
3
4
(
m, 4H, N(CH
2
)
2
), 4.11 (q, 2H, OCH
2
), 7.28 (ddd, 1H, H-6, J = 8.6, J = 6.0, J = 2.5 Hz), 7.48
3
4
3
3
19
1
(
dd, 1H, H-8, J = 8.8, J = 2.5 Hz), 8.27 (dd, 1H, H-5, J = 8.8, J = 6.0). F NMR { H} (DMSO-
1
3
d
6
4
1
6
): -106.44 (s). C NMR (DMSO-d
6
): 14.52 (s, CH
3
), 42.52 (s, N(CH
2
)
2
), 45.14 (s, N(CH
2
2
) ),
1.04 (s, OCH
2
), 112.67 (d, C-6, 2JCF = 26.4 Hz), 116.02 (d, C-8, 2JCF = 22.0 Hz), 118.98 (d, C-
a, 4JCF = 2.3 Hz), 132.40 (d, C-5, 3JCF = 7.4 Hz), 134.57 (d, C-8a, 3JCF = 9.9 Hz), 154.50 (s, COO),
61.33 (s, C-2), 163.58 (d, C-7, 1JCF = 253.4 Hz), 166.44 (s, C(O)). MS, m/z (rel. int.): 337 (15)
+
[
M] , 269 (27), 223 (14), 222 (58), 209 (47), 182 (17), 157 (15), 155 (22), 154 (100), 128 (32),
1
26 (37), 69 (19), 56 (43), 55 (11), 42 (17). Calcd for C15
H16FN
3
3
O S: C 53.40; H 4.78; N 12.45.
Found: C 53.30; H 4.67; N 12.59.
8
-Fluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-one (5p)
1
Yield 84%, mp 173−175 °C. Н NMR (DMSO-d
6
): 1.27 (m, 3H, CH
3
), 3.58 (m, 4H, N(CH
2
2
) ),
3
.92 (m, 4H, N(CH
2
)
2
), 4.13 (q, 2H, OCH
2
), 7.50 (m, 2H, H-5, Н-7), 8.08 (td, 1H, H-6, 3JHН = 8.7,
4JHF = 2.1 Hz). F NMR { H} (DMSO-d
19
1
): -115.94 (s). C NMR (DMSO-d
13
): 14.53 (s, CH ),
6
6
3
4
2.53 (s, N(CH
d, C-8a, 2JCF = 9.1 Hz), 121.75 (d, C-5, 4JCF = 4.4 Hz), 132.46 (d, C-6, 3JCF = 7.3 Hz), 134.41 (s,
C-4a), 154.50 (s, COO), 161.33 (s, C-2), 162.69 (d, C-8, 1JCF = 252.1 Hz), 166.44 (s, C(O)). MS,
2
)
2
), 45.15 (s, N(CH
2
)
2
), 61.03 (s, OCH
), 112.69 (d, C-7, 2JCF = 26.1 Hz), 116.68
2
(

+
m/z (rel. int.): 337 [M] (10), 269 (16), 223 (10), 222 (45), 209 (40), 182 (12), 180 (10), 154 (100),
28 (28), 126 (46), 108 (12), 69 (24), 56 (53), 55 (15), 42 (27). Calcd for C15 S: C 53.40;
H 4.78; N 12.45. Found: C 53.34; H 4.71; N 12.53.
1
H16FN
3
O
3
4
1
.4. Procedure for the Synthesis of 2,7-bis(cycloalkylimino)-6,8-difluoro-
,3-benzothiazin-4-ones (6a-c)
General Procedure
To a solution of benzothiazinone (5a,d) (1.19 mmol) in DMSO (2 mL) cycloalkylimine
morpholine or 1-ethoxycarbonylpiperazine) (3.17 mmol) was added. Reaction mixture was
(
refluxed during 8 h, and then cooled. The precipitate of compound 6 was filtered off and
recrystallized from DMSO.
6
,8-Difluoro-2-(4-ethoxycarbonylpiperazin-1-yl)-7-(morpholin-4-yl)-1,3-benzothiazin-4-one (6a)
1
Yield 73%, mp 255−257 °C. Н NMR (DMSO-d
6
): 1.27 (t, 3H, CH
3
), 3.29 (m, 4H, (CH
2
2
) ), 3.56
(
m, 4H, (CH
2
)
2
), 3.73 (m, 4H, (CH
2
)
2
), 3.88 (m, 4H, (CH
2
)
2
), 4.11 (q, 2H, OCH ), 7.73 (dd, 1H,
2
3
3
19
1
): -120.64 (d, 1F, 4JFF = 8.8 Hz), -124.40
), 42.55 (s, N(CH ), 43.95 (s,
), 66.56 (s, OCH
), 112.24 (d, C-5, 2JCF = 25.7
Hz), 115.92 (м, C-4a), 117.43 (m, C-8a), 130.99 (d, C-7, 2JCF = 12.8 Hz), 140.24 (d, C-8, 1JCF
57.8 Hz), 148.53 (d, C-6, 1JCF = 257.8 Hz), 154.56 (s, COO), 160.29 (s, C-2), 165.34 (s, C(O)).
H-5, J = 12.4, J = 1.5 Hz). F NMR { H} (DMSO-d
6
13
(
d, 1F, 4JFF = 8.8 Hz). C NMR (DMSO-d
6
): 14.49 (s, CH
3
)
2 2
N(CH
2
)
2
), 45.26 (s, N(CH
2
)
2
), 50.68 (s, O(CH
2
)
2
2
=
2
+
MS, m/z (rel. int.): 440 (33) [M] , 372 (16), 326 (21), 325 (68), 313 (14), 312 (78), 283 (13), 258
(
32), 257 (100), 256 (14), 200 (14), 199 (90), 171 (14), 170 (12), 141 (18), 139 (17), 128 (17), 57
18), 56 (34), 42 (22). Calcd for C19 S: C 51.81; H 5.03; N 12.72. Found: C 51.70; H
(
H
22
F
2
N
4
O
4
4
.92; N 12.84.
6
,8-Difluoro-2,7-bis(morpholin-4-yl)-1,3-benzothiazin-4-one (6b)
°
1
Yield 68%, mp 271−273 C. Н NMR (DMSO-d
6
): 3.29 (m, 4H, N(CH
2
)
2
), 3.74 (m, 8H, N(CH
2
2
) ,
3
19
1
O(CH
2
)
2
), 3.86 (m, 4H, O(CH
2
)
2
), 7.73 (d, 1H, H-5, J = 12 Hz). F NMR { H} (DMSO-d
6
): -
20.88 (d, 1F, 4JFF = 8.9 Hz), -124.47 (d, 1F, 4JFF = 8.9 Hz). C NMR (DMSO-d
13
): 42.55 (s,
1
6
NCH
2
), 43.95 (s, NCH
2
), 66.56 (s, O(CH
2
)
), 112.26 (d, C-5, 2JCF = 25.8 Hz), 115.90 (м, C-4a),
2
1
6
2
5
17.46 (m, C-8a), 130.94 (d, C-7, 2JCF = 12.8 Hz), 140.26 (d, C-8, 1JCF = 257.5 Hz), 148.51 (d, C-
1
+
, JCF = 257.5 Hz), 160.26 (s, C-2), 165.32 (s, C(O)). MS, m/z (rel. int.): 369 (44) [M] , 258 (16),
57 (100), 199 (71), 171 (12), 170 (10), 139 (14), 57 (13), 42 (12). Calcd for C16
2.03; H 4.64; N 11.38. Found: C 51.94; H 4.58; N 11.44.
H
17
F
2
N
3
3
O S: C

6
,8-Difluoro-2,7-bis(4-ethoxycarbonylpiperazin-1-yl)-1,3-benzothiazin-4-one (6c)
1
Yield 79%, mp 245−247 °C. Н NMR (DMSO-d
6
): 1.27 (t, 6H, 2CH
3
), 3.27 (m, 4H, (CH
2
)
2
), 3.56
3
3
(
m, 8H, 2(CH
2
)
2
), 3.89 (m, 4H, (CH
2
)
2
), 4.11 (m, 4H, 2OCH
2
), 7.74 (dd, 1H, H-5, J = 12.2, J =
19
1
13
1
.2 Hz). F NMR { H} (DMSO-d
6
): -120.49 (d, 1F, J = 8.7 Hz), -124.07 (d, 1F, J = 8.7 Hz). C
NMR (DMSO-d
0.08 (s, N(CH
C-4a), 117.46 (m, C-8a), 131.91 (d, C-7, 2JCF = 12.9 Hz), 140.25 (d, C-8, 1JCF = 259.7 Hz), 148.51
6
): 14.49 (s, CH
3
), 42.55 (s, N(CH
2
)
2
), 43.95 (s, N(CH
2
)
2
), 45.27 (s, N(CH
2
)
2
),
5
2
)
2
), 60.84 (s, OCH
2
), 61.02 (s, OCH
2
), 111.98 (d, C-5, 2JCF = 26.5 Hz), 115.94 (м,
(
d, C-6, 1JCF = 259.7 Hz), 154.56 (s, COO), 154.67 (s, COO), 160.30 (s, C-2), 165.20 (s, C(O)).
+
MS, m/z (rel. int.): 511 (37) [M] , 443 (14), 397 (24), 396 (46), 384 (15), 383 (72), 381 (12), 328
(
15), 313 (15), 308 (13), 226 (13), 214 (15), 213 (13), 199 (13), 141 (25), 128 (13), 115 (16), 70
17), 69 (11), 56 (100), 44 (11), 43 (12), 42 (31). Calcd for C22 S: C 51.66; H 5.32; N
(
H
27
F
2
N
5
O
5
1
3.69. Found: C 51.72; H 5.37; N 13.61.
4
4
.5. Procedures for the Synthesis of 2-Piperazino-substituted 6,7,8-trifluoro-1,3-benzothiazin-
-ones (7, 8)
6
,7,8-Trifluoro-2-(piperazin-1-yl)-1,3-benzothiazin-4-one (7)
Trifluoroacetic acid (0.15 mL, 1.3 mmol) was added to a solution of 6,7,8-trifluoro-2-(4-t-
butoxycarbonylpiperazine)-1,3-benzothiazin-4-one 5f (0.19 g, 0.46 mmol) in dichloromethane
(1.5 mL) at 0 °С. Reaction mixture was stirred at 0 °C for 5 min, then at room temperature during
3
h. Solvent was removed in vacuum, saturated solution of sodium hydrocarbonate (10 ml) was
added to the residue, and then product 7 was filtered off and used for the synthesis of compounds
1
8
a-e without further purification. Yield 0.1 g (70%), mp 229−231 °C. Н NMR (DMSO-d
6
): 2.92
1
9
1
(
m, 4H, N(CH
2
)
2
), 3.85 (m, 4H, N(CH
2
)
2
), 4.9 (s, 1Н, NH), 8.00 (m, 1H, H-5). F NMR { H}
(DМSO-d
6
): -134.80 (dd, 1F, F-6, 3JFF = 21.5, 4JFF = 4.9 Hz), -136.49 (dd, 1F, F-8, 3JFF = 20.1,
4JFF = 4.9 Hz), -153.80 (dd, 1F, F-7, 3JFF = 21.5, 3JFF = 20.1 Hz). MS, m/z (rel. int.): 301 (16) [M]+,
2
5
1
46 (15), 245 (10), 233 (11), 218 (15), 191 (14), 190 (31), 162 (23), 144 (12), 69 (100), 68 (12),
7 (24), 56 (85), 55 (26), 51 (12), 45 (31), 42 (30). Calcd for C12
3.95. Found: C 47.79; H 3.40; N 13.90.
H
10
F
3
3
N OS: C 47.84; H 3.35; N
General Procedure for the Synthesis of 1,3-Benzothiazin-4-ones 8a-c
Aroylchloride (0.74 mmol) was added to a solution of 6,7,8-trifluoro-2-(piperazin-1-yl)-1,3-
benzothiazin-4-one 7 (0.2 g, 0.66 mmol) in dichloromethane (15 mL). Reaction mixture was

stirred at 55 °C for 4 h, and then concentrated in vacuum; the precipitate was filtered off and
recrystallized from ethanol.
6
,7,8-Trifluoro-2-(4-t-butylbenzoylpiperazino)-1,3-benzothiazin-4-one (8a)
1
Yield 87%, mp 265−267 °C. Н NMR (DMSO-d
6
): 1.36 (s, 9H, C(CH
3
)
3
), 3.71 (m, 4H, N(CH
2
2
) ),
3
3
3
.97 (m, 4H, N(CH
2
)
2
), 7.38 (d, 2H, H-3’, H-5’, J = 8.2 Hz), 7,45 (d, 2Н, Н-2’, H-6’, J = 8.3
Hz), 8.00 (m, 1H, H-5). F NMR { H} (DМSO-d
): -134.51 (dd, 1F, F-6, 3JFF = 21.5, 4JFF = 4.6
1
9
1
6
Hz), -136.24 (dd, 1F, F-8, 3JFF = 20.0, 4JFF = 4.6 Hz), -153.49 (dd, 1F, F-7, 3JFF = 21.5, 3JFF 20.0
+
=
Hz). MS, m/z (rel. int.): 461 (7) [M] , 190 (6), 162 (17), 161 (100), 146 (15), 118 (14), 69 (15).
Calcd for C23
H
22
F
3
N
3
2
O S: C 59.86; H 4.80; N 9.10. Found: C 59.81; H 4.82; N 9.05.
6
,7,8-Trifluoro-2-(4-benzoylpiperazino)-1,3-benzothiazin-4-one (8b)
1
Yield 85%, mp 153−155 °C. Н NMR (DMSO-d
6
): 3.71 (m, 4H, N(CH
2
)
2
), 3.96 (m, 4H, N(CH
2
)
2
),
7
.45 (s, 3H, H-3’, H-4’, Н-5’), 7.59 (m, 1Н, Н-6’), 8.00 (m, 1H, H-5), 8.11 (m, 1Н, Н-2’). 19F
NMR { H} (DМSO-d
): -134.46 (dd, 1F, F-6, 3JFF = 21.6, 4JFF = 4.9 Hz), -136.24 (dd, 1F, F-8,
1
6
3JFF = 20.1, 4JFF = 4.9 Hz), -153.46 (dd, 1F, F-7, 3JFF = 21.6, 3JFF = 20.1 Hz). MS, m/z (rel. int.):
+
4
1
05 (3) [M] , 190 (8), 105 (100), 77 (44), 69 (23). Calcd for C19
0.37. Found: C 56.32; H 3.41; N 10.42.
H
14
F
3
N
3
2
O S: C 56.29; H 3.48; N
6
,7,8-Trifluoro-2-[4-(2,6-difluorobenzoyl)piperazino)-1,3-benzothiazin-4-one (8c)
1
Yield 82%, mp 229−231 °C. Н NMR (DMSO-d
6
): 3.49 (m, 2Н, N(CH
2
)), 3.89 (m, 4H, N(CH
2
2
) ),
19
4
.02 (m, 2H, N(CH
2
)), 7.13 (m, 2H, H-3’, H-5’), 7.55 м (m, 1Н, Н-4’), 8.00 (m, 1H, H-5). F
): -113.21 (s, 2F, С
), -134.40 (d, 1F, F-6, 3JFF = 21.4 Hz), -136.17 (d,
1
NMR { H} (DМSO-d
6
6
H F
3 2
1
F, F-8, 3JFF = 16.1 Hz), -153.38 (dd, 1F, F-7, 3JFF = 21.4, 3JFF = 16.1 Hz). MS, m/z (rel. int.): 441
+
(
2) [M] , 286 (29), 258 (17), 190 (26), 162 (12), 141 (100), 113 (15), 69 (12), 56 (10). Calcd for
C
19
H
12
F
5
N
3
O
2
S: C 51.70; H 2.74; N 9.52. Found: C 51.75; H 2.39; N 9.45.
General Procedure for the Synthesis of 1,3-Benzothiazin-4-ones 8d,e
HATU (0.27 g, 0.71 mmol) was added to a solution of substituted benzoic acid (0.63 mmol) in
dichloromethane (24 mL), then DIPEA (0.12 mL, 0.71 mmol) and 6,7,8-trifluoro-2-(piperazin-1-
yl)-1,3-benzothiazin-4-one 7 (0.2 g, 0.63 mmol) were added. Reaction mixture was stirred at room
temperature for 24 h, and then water (47 mL) was added. The organic layer was separated, the
product was extracted from water layer with dichloromethane (3×10 mL), dichloromethane
solution was washed with brain, dried over Na
The residue was recrystallized from ethanol.
2
SO and then the solvent was removed in vacuum.
4

6
,7,8-Trifluoro-2-[4-(3-fluorobenzoyl)piperazino]-1,3-benzothiazin-4-one (8d)
1
Yield 84%, mp 213−215 °C. Н NMR (DMSO-d
6
): 3.73 (m, 4H, N(CH
2
)
2
), 3.99 (m, 4H, N(CH
2
2
) ),
1
9
1
7
d
2
.26 (m, 3H, H-4’, H-5’, Н-6’), 7.49 (m, 1Н, Н-2’), 8.00 (m, 1H, H-5). F NMR { H} (DМSO-
): -111.78 (s, 1F, С =
F), -134.45 (dd, 1F, F-6, 3JFF 21.2, 4JFF 4.7), -136.23 (dd, 1F, F-8, 3JFF
6
6
H
4
0.0, 4JFF = 4.7 Hz), -153.46 (dd, 1F, F-7, 3JFF = 21.2, 3JFF = 20.0 Hz). MS, m/z (rel. int.): 423 (8)
+
[
M] , 258 (18), 245 (11), 218 (12), 190 (23), 162 (12), 123 (100), 95 (35), 69 (33), 56 (11). Calcd
for C19
H
13
F
4
N
3
2
O S: C 53.90; H 3.09; N 9.92. Found: C 53.85; H 3.02; N 9.85.
6
,7,8-Trifluoro-2-[4-(4-ethylbenzoyl)piperazino]-1,3-benzothiazin-4-one (8e)
1
, 3J 7.9 Hz), 2.71 (q, 2H, CH
,
Yield 83%, mp 226−228 °C. Н NMR (DMSO-d
6
): 1.28 (t, 3H, CH
3
2
3J = 7.6 Hz), 3.71 (m, 4H, N(CH
)
2
), 3.97 (m, 4H, N(CH
)
2
), 7.27 (d, 2H, H-3’, H-5’, J = 7.9 Hz),
3
2
2
3
19
1
7
1
1
.38 (d, 2Н, Н-2’, H-6’, J = 7.9 Hz), 8.00 (m, 1H, H-5). F NMR { H} (DМSO-d
6
), δ, м.д.: -
34.46 (dd, 1F, F-6, 3JFF = 21.5, 4JFF = 4.6 Hz), -136.21 (dd, 1F, F-8, 3JFF = 20.1, 4JFF = 4.6 Hz), -
53.47 (dd, 1F, F-7, 3JFF = 21.5, 3JFF = 20.1 Hz). MS, m/z (rel. int.): 433 (5) [M] , 190 (4), 133
+
(100), 105 (10), 69 (13). Calcd for C21
H
18
F
3
3
N OS: C 58.19; H 4.19; N 9.69. Found: C 58.11; H
4
.12; N 9.65.
4
.6. Antimycobacterial assay
To evaluate the inhibitory efficiency of molecules on Mycobacterium tuberculosis (MTB), M.
tuberculosis H37 , which is susceptible to all classical antituberculosis drugs, was used. The
minimal inhibitory concentration (MIC) for M. tuberculosis H37 for each compound was
R
v
R
v
determined by a micro broth dilution method. All molecules tested were dissolved in
dimethylsulfoxide and their 1/2 dilutions were prepared in 5 mL tubes using Löwenstein-Jensen
medium. A few colonies from freshly grown M. tuberculosis H37
v
R were suspended in Löwenstein-
Jensen medium to obtain 1.0 McFarland turbidity and diluted ten times using the same medium
and the tubes were incubated at 37 °C medium with a different concentration of the tested molecule
and to a positive control tube containing only clear growth medium. After 24 hours the tubes were
placed in a vertical position and the free edge of the buried 0.3 mL of the substance in the test
compounds concentrations: 12.5, 6.25, 3.1, 1.5, 0.7, 0.37, 0.15 μg/mL. The tubes were then placed
in thermostat at a temperature of 37 °C and incubated for 10 days. Growth estimate for the MTB
were determined by standard methods, where the appearance of zones of growth retardation MTB
(over 10 mm) indicated the presence of tuberculostatic properties in concentration of the
compounds under study. Penetration size stunting MTB (in mm) is proportional to the degree of
tuberculostatic activity. Growth delay of 100 mm or more is considered as a complete growth

inhibition MTB. The multi-drug-resistant (MDR) tuberculosis strain has been isolated from
tuberculosis patients in Ural Research Institute for Phthisiopulmonology (Russia). The minimal
inhibitory concentrations against Mycobacterium tuberculosis avium, Mycobacterium tuberculosis
terrae, and MDR tuberculosis strains were evaluated similarly.
4
.7. Evaluation of acute toxicity in vivo
All experimental protocols were conducted in accordance to the standard protocol approved by the
Committee of the Ethical Use of Animals of the Ural Research Institute for Phthisiopulmonology
(CEUA/URIP). The synthesized compounds were evaluated for their approximate LD50 in white
healthy mice (17−20 g body weight) divided into 3 groups of 5 animals each for testing of one
compound [21, 22]. Toxicity tests were carried out via a single per oral introduction of compound
in a 1 % starch aqueous solution. The volume introduced did not exceed 0.5 mL for mice. The
observation period was 14 days. The median lethal doses LD50 were used as the criteria of toxicity.
Acknowledgment
The work was carried out with financial support from the Russian Scientific Foundation
(grant 15-13-00077-P) and from the Ministry of Education of Russian Federation (State Contract
4
.6351.2017/8.9, research of 1,3-benzothiazinones 8).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j. jfluchem.
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