Mendeleev Commun., 2020, 30, 427–429
5-fluoro-8-nitro-1,3-benzothiazin-4-ones 4a–f were detected,
while ultimate 2,5-bis(azacycloalk-1-yl)-1,3-benzothiazin-4-
ones 5a–f were formed in 70–91% yields (see Scheme 1).
F
O
F
F
O
F
S
S
C
i, ii
iii
N
N
2
H
Importantly, 2,6-difluoro-3-nitrobenzoyl intermediates
3
N
undergo intramolecular cyclization into under milder
4
Me
NO2
NO2
conditions than their 2,6-difluoro- and 2,3,4,5-tetrafluoro
counterparts. The presence of 8-positioned nitro group in
6
F
O
S
benzothiazinone intermediate
4
facilitates the amino-
5
8
defluorination process at C-5, so, at room temperature all stages
up to the formation of 2,5-bis(cycloalkylamino) derivative 5
proceed readily. Using less than 2 equiv. of amine or reducing
the duration of the process did provide pure 5-fluoro derivative
4; unfortunately, those reaction mixtures were impossible to be
resolved. When less amine was applied (1–1.5 equiv.), the
fluorine signal for the minor product 4 at –98.4 to –102.8 ppm
could be observed in the 19F NMR spectra.
6
N
7
NO2
N
Me
7 (84%)
Scheme 2 Reagents and conditions: i, SOCl2, PhMe, 90 °C; ii, NH4NCS,
MeCN, PhMe, room temperature; iii, 1-methylindole, MeCN, room
temperature.
The structural evidence for benzothiazinones 5a–f has been
obtained from the 1H and 13C NMR and mass spectra.
The 1H NMR spectra of all compounds are characterized by two
doublet signals of H-6 and H-7 at 7.16−7.21 and 8.27−8.32 ppm
(J 8.1−9.8 Hz) as well as signals for two azacycloalkyl residues;
no signals were observed in 19F NMR spectra. In the 13C NMR
spectra, signals for C-8 at 167.9–168.8 ppm and singlets for C-4
at 159.6–160.5 ppm were detected. Notably that in the case of
6,7,8-trifluoro- and 5-fluorobenzothiazinones the signals for
C(4) were located at 164–165 ppm.9 In the mass spectra of
compounds 5a–f, the peaks of molecular ions with 1−23%
intensity were observed.
one. In case of the 6-nitro isomer, only one cross-peak would
appear between C7H and nitro group. Additional evidence was
obtained from NOESY spectrum [Figure 1(b)] showing the cross
peak between C6H and piperazine CH2 group, which indicates
the formation of 5; in the case of the isomer such a peak would
be absent.
The addition of 1-methylindole (1.5 equiv.) as C-nucleophile
at the N=C bond of 2,6-difluoro-3-nitrobenzoyl isothiocyanate
occurred smoothly in acetonitrile at room temperature (Scheme 2).
According to the H and 19F NMR spectra, the reaction affords
1
In the case of participation of C6F of benzamides 3 in
intramolecular cyclisation instead of C2F, isomeric 6-nitro
analogues of products 5 could form (see Scheme 1). To provide
1,3-benzothiazin-4-one 7, the primary product 6 was not isolated,
and the 5-positioned fluorine atom was not replaced by the
nucleophile. Worthy of note, the intramolecular cyclization of 6
into 7 proceeded under milder conditions than in the case of
2,6-difluoro and 2,3,4,5-tetrafluoro counterparts (the refluxing in
MeCN or DMF in the presence of trimethylamine was reported as
suitable cyclization conditions for those intermediates10).
The positions of fluoro and nitro substituents in product 7
were proved by 19F NMR spectrum without the suppression of
spin–spin F–H interaction which contained a double doublet
signal with 3JF–H = 10.1 Hz and 4JF–H = 3.9 Hz, that justified the
formation of 5-fluoro-8-nitro isomer. The molecular ion peak in
the mass spectra of benzothiazinone 7 has a relative intensity of
16%. The ion IndCN+ (m/z 156) has 100% intensity, notably that
the elimination of RCN represent the typical fragmentation way
for 2-R-substituted 1,3-benzothiazin-4-ones.9
1
the evidence for structure 5, multibond heteronuclear H-15N
correlation HMBC spectrum for representative 5a was recorded
[Figure 1(a)]. The observed two cross-peaks justify that both
aromatic protons H-6 and H-7 correlate with nitrogen atoms,
namely, one of them with nitro group and another with amine
ꢈaꢉ
2 NꢈCꢊ2ꢉ2
EtOOCꢌNꢈCꢊ2ꢉ2
EtOOCꢌNꢈCꢊ2ꢉ2
ꢊꢋꢅ ꢊꢋꢄ
0
ꢁ0
2 NCOOEt
ꢃ00
ꢃꢁ0
NꢈC2ꢉ
NꢈCꢁꢉ
Benzothiazinone 5a exhibited higher tuberculostatic activity
towards M. tuberculosis H37Rv (MIC 4 mg ml–1) than previously
described9 5-fluoro derivative 7 (MIC 64 mg ml–1). For this
reason the provided way of fluorobenzothiazinone modification
is useful for the development of new antitubercular agents.
To sum up, we have found short and convenient synthetic
approach to 2,5-bis(azacycloalk-1-yl)-8-nitro-1,3-benzothiazin-
4-ones 5a–f and 5-fluoro-8-nitro-2-(1-methylindol-3-yl)-1,3-
benzothiazin-4-one 7. The proposed modification of fluoro-
benzothiazinones can be of great value for design of new
antitubercular agents.
200
2ꢁ0
ꢂ00
ꢂꢁ0
ꢀ00
ꢀꢁ0
NO2
ꢇ.0
ꢄ.0 ꢁ.0 ꢀ.0 ꢂ.0 2.0 ꢃ.0 0.0
ꢆ.0 ꢅ.0
ꢈbꢉ
ꢊꢋꢅ
ꢊꢋꢄ
0.0
0.ꢁ
ꢃ.0
ꢃ.ꢁ
2.0
2.ꢁ
ꢂ.0
2 Cꢊꢂ
The work was carried out with financial support from the
Ministry of Education and Science of the Russian Federation
(State Contract no. 0836-2020-0058). The authors are thankful
to V. Makarov (Federal Research Center ‘Fundamental Bases of
Biotechnology’ of Russian Academy of Sciences, Moscow) for
assistance with biological tests.
NꢈCꢊ2ꢉ2
ꢂ.ꢁ
ꢀ.0
2 NꢈCꢊ2ꢉ2
2 OCꢊ2
NꢈCꢊ2ꢉ2
ꢇ.ꢁ
ꢇ.0
ꢆ.ꢁ
ꢆ.0
ꢅ.ꢁ
ꢅ.0
ꢄ.ꢁ
Online Supplementary Materials
Figure 1 (a) HMBC 1H-15N and (b) NOESY spectra for 2,5-bis(4-
ethoxycarbonylpiperazin-1-yl)-8-nitro-1,3-benzothiazin-4-one 5a.
Supplementary data associated with this article can be found
in the online version at doi: 10.1016/j.mencom.2020.07.007.
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