Synthesis of N-substituted pyrido[3,2-b][1,4]benzothiazepin-(11H)-one derivatives by denitrocyclisation reaction

Article abstract of DOI:10.1007/s11172-009-0212-2

A new approach to the synthesis of N-substituted pyrido[3,2-b][1,4] benzothiazepin- 10(11H)-one derivatives from 2-chloro-3-nitropyridine and thiosalicylic acid using denitro- cyclisation reaction for the tricycle-system formation is proposed.

Full text of DOI:10.1007/s11172-009-0212-2

Russian Chemical Bulletin, International Edition, Vol. 58, No. 7, pp. 1542—1545, July, 2009
1542
Synthesis of Nꢀsubstituted pyrido[3,2ꢀb][1,4]benzothiazepinꢀ(11H)ꢀone
derivatives by denitrocyclisation reaction
A. V. Sapegin,a T. A. Khristolyubova,a A. V. Smirnov,b M. V. Dorogov,a and A. V. Ivashchenkob
aLLC «Intellectual Dialogue»
108 Respublikanskay ul., 150000 Yaroslavl, Russian Federation.
Fax: (485) 230 5522. Eꢀmail: sapegin_yar@mail.ru
bInstitute of Chemogenomic Problems of Ushinsky Yaroslavl State Pedagogical University,
108 Respublikanskay ul., 150000 Yaroslavl, Russian Federation.
Fax: (485) 230 5522. Eꢀmail: mvdorogov@rambler.ru
A new approach to the synthesis of Nꢀsubstituted pyrido[3,2ꢀb][1,4]benzothiazepinꢀ
10(11H)ꢀone derivatives from 2ꢀchloroꢀ3ꢀnitropyridine and thiosalicylic acid using denitroꢀ
cyclisation reaction for the tricycleꢀsystem formation is proposed.
Key words: pyrido[3,2ꢀb][1,4]benzothiazepinꢀ10(11H)ꢀones, 2ꢀchloroꢀ3ꢀnitropyridine,
thiosalicylic acid, denitrocyclisation reaction, the Smiles rearrangement.
At the present, the number of investigations into methꢀ
presence of a twofold molar excess of triethylamine as the
base. 2ꢀ(3ꢀNitropyridinꢀ2ꢀylsulfanyl)benzamides 6a—g
were obtained in dioxane at room temperature starting
from acid 4 and primary amines 5a—g using N,Nꢀcarbonꢀ
yldiimidazole (CDI) for the activation of the carboxyl
group. Heating of benzamides 6a—g in DMF in the presꢀ
ence of a twofold molar excess of potassium carbonate,
most probably leads to the Smiles rearrangement,8,12 which
proceeds via intermediates 7a—g и 8a—g. Therefore, the
reactive benzenethiolate site is produced, which enters
denitrocyclisation reaction resulting in the pyridobenzothiꢀ
azepine system 9a—g. Ealier, we have shown that K2CO3
is more effective as the base in comparison with such
deprotonating agents as sodium hydride, sodium amide,
and potassium tertꢀbutoxide.6
ods of synthesis and introduction of functional groups into
original heterocyclic compounds possessing potentially
valuable biological properties and promising as drug canꢀ
didates is increasing constantly. Particularly, the benzoꢀ
thiazepinone heterocyclic system is of interest because
a plethora of known physiologically active compounds
contain structural fragments common to this heterocyclic
system.1—4
Previously, we have shown5 that the use of intramolecꢀ
ular nucleophlic aromatic substitution of a nitro group
(denitrocyclisation reaction) is one of the promising methꢀ
ods to obtain wide range of tricyclic systems with the genꢀ
eral formula 1 and their derivatives.6—10
1
Figures 1 and 2 represent NOESY Нꢀ1Н spectra of
compounds 9a and 9d. The spectra contain no crossꢀpeaks
in the region that is characteristic of the interaction of the
protons of the NCH3 group (δ 3.57) for 9a and the
NCH(CH3)2 group (δ 4.89, 1.65, 1.17) for 9d with the
aromatic proton of the pyridine ring (δ 8.00 and 8.01,
respectively, C(4)H). This fact confirms that it is comꢀ
pounds 9a,d that are obtained, rather than isomeric anaꢀ
In the present work, we applied this approach to the
synthesis of insufficiently studied pyrido[3,2ꢀb][1,4]ꢀ
benzothiazepinꢀ10(11H)ꢀone derivatives (Scheme 1),
which have previously been obtained by photochemical
rearrangement of pyridylbenzoylisothiazolones.11
2ꢀChloroꢀ3ꢀnitropyridine (2) readily undergoes nuꢀ
cleophilic aromatic substitution with thiosalicylic acid (3)
(both starting compounds are commercially available) reꢀ
sulting in 2ꢀ(3ꢀnitropyridinꢀ2ꢀylsulfanyl)benzoic acid (4).
The reaction was carried out in boiling propanꢀ2ꢀol in the
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 7, pp. 1497—1500, July, 2009.
1066ꢀ5285/09/5807ꢀ1542 © 2009 Springer Science+Business Media, Inc.

Synthesis of the pyridobenzothiazepinones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1543
Scheme 1
R = Me (a), Et (b), Pr (c), Pri (d), Ph (e), pꢀMeC6H4 (f), pꢀClC6H4 (g)
2ꢀ(3ꢀNitropyridinꢀ2ꢀylsulfanyl)benzoic acid (4). A mixture of
thiosalicylic acid (3) (0.25 mol), 2ꢀchloroꢀ3ꢀnitropyridine (2)
(0.25 mol), and triethylamine (0.5 mol) was heated in propanꢀ2ꢀ
ol (100 mL) at 80 °С for 3 h. The reaction mixture was poured
into water (500 mL) and acidified with conc. HCl to pH 1. The
precipitate that formed was recrystallized from ethanol.
logs 10a,d, the formation of which could be expected in
the case where the reaction proceeded without the Smiles
rearrangement.
δ
2.5
3.0
3.5
4.0
4.5
5.0
Thus, our investigations demonstrated the possibility
of the synthesis of earlier unknown Nꢀalkylꢀ and Nꢀarylꢀ
substituted pyrido[3,2ꢀb][1,4]benzothiazepinꢀ10(11H)ꢀ
ones using the denitrocyclisation reaction. Undoubtedly,
the advantage of this method is the possibility of the introꢀ
duction of a wide range of substituents to the amide fragꢀ
ment of compounds 6 prior to the formation of the tricyclic
system, which allows an access to the diverse compounds
of this class.
7.0
7.5
8.0
8.5
Experimental
1
H NMR and 2D correlation spectra NOESY 1Нꢀ1H for 5%
solutions of the samples in DMSOꢀd6 were recorded on a Bruker
MSLꢀ300 spectrometer at the Institute of chemogenomic probꢀ
lems of the Ushinsky Yaroslavl State Pedagogical University.
The yields, melting points, and elemental analysis data for
compounds 4, 6a—g and 9a—g are presented in Table 1, the
spectral characteristics of these compounds are listed in Table 2.
8.5 8.0 7.5 7.0 4.0 3.5 3.0 2.5
δ
Fig. 1. The 1Нꢀ1Н NOESY spectrum of compound 9a.

1544
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
Sapegin et al.
2ꢀ(3ꢀNitropyridinꢀ2ꢀylsulfanyl)benzamides 6a—g. Acid 4
(0.2 mol) and N,Nꢀcarbonyldiimidazole (0.2 mol) were suspendꢀ
ed in dioxane (100 mL). The mixture was stirred for 1 h and
amine 5e—g (0.2 mol) was added with cooling. The reaction
mixture was kept at room temperature for 4 h and poured into
water. In the case of compounds 6a and 6e—g, the precipitate
that formed was filtered off and recrystallized from ethanol. In
the case of compounds 6b—d, the oil that formed was dissolved
in chloroform (50 mL) and purified by column chromatography
(silica gel L40/100).
Pyrido[3,2ꢀb][1,4]benzothiazepinꢀ10(11H)ꢀones 9a—g. Calꢀ
cined K2CO3 (0.4 mol) was added to a solution of amide 6a—g
(0.2 mol) in DMF (100 mL). The reaction mixture was stirred at
75—80 °С for 1 h, cooled and poured into water. The precipitatꢀ
ed that formed was filtered off and recrystallized from a mixture
ethanol—DMF.
δ
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
The work was supported by the Federal Agency for
Science and Innovation within the Government contract
No 02.527.11.9002 for the research and development «Deꢀ
velopment of a series of highlyꢀeffective clinical candiꢀ
8.0 7.0 6.0 5.0 4.0 3.0
2.0 1.0 δ
Fig. 2. The 1Нꢀ1Н NOESY spectrum of compound 9d.
Table 1. Yields, melting points and elemental analysis data for the obtained compounds
Comꢀ
pound
R
Yield
(%)
M.p./°C
Found
Calculated
Molecular formula
(%)
C
H
N
4
—
Me
87
76
67
71
70
82
75
71
83
61
65
69
85
73
75
162—165
144—147
49—52
52.06
52.17
53.81
53.97
55.35
55.43
56.69
56.77
56.60
56.77
61.34
61.53
62.27
62.45
55.87
56.03
64.25
64.44
65.40
65.60
66.45
66.64
66.51
66.64
70.82
71.03
71.46
71.67
63.62
63.81
2.92
2.98
3.84
3.81
4.32
4.41
4.77
4.74
4.76
4.84
3.73
3.84
4.14
4.21
3.14
3.23
4.16
4.21
4.72
4.72
5.22
5.29
5.22
5.28
3.98
3.67
4.44
4.45
3.28
3.21
10.19
10.14
14.60
14.52
13.88
13.85
13.31
13.24
13.26
13.24
12.02
11.96
11.56
11.50
10.95
11.89
11.62
11.56
10.98
10.93
10.39
10.36
10.41
10.36
9.25
C12H8N2O4S
C13H11N3O3S
C14H13N3O3S
C15H15N3O3S
C15H15N3O3S
C18H13N3O3S
C19H15N3O3S
C18H12ClN3O3S
C13H10N2OS
C14H12N2OS
C15H14N2OS
C15H14N2OS
C18H12N2OS
C19H14N2OS
C18H11ClN2OS
6a
6b
6c
6d
6e
6f
Et
Pr
37—39
Pri
Oil
Ph
171—174
186—189
180—183
168—171
147—150
144—147
146—149
189—191
215—218
224—227
pꢀMePh
pꢀClPh
Me
6g
9a
9b
9c
9d
9e
9f
Et
Pr
Pri
Ph
9.20
8.84
8.80
8.31
pꢀMePh
pꢀClPh
9g
8.27

Synthesis of the pyridobenzothiazepinones
Russ.Chem.Bull., Int.Ed., Vol. 58, No. 7, July, 2009
1545
Table 2. 1H NMR spectra for the obtained compounds
Comꢀ
pound
δ (J/Hz)
4
12.78 (br.s, 1 H); 8.52—8.58 (m, 2 H, Ar); 0.99 (d, 1 H, Ar, J = 4.8); 7.52—7.59 (m, 3 H, Ar);
7.40 (d, 1 H, Ar, J = 4.7)
6a
6d
6c
8.52—8.58 (m, 2 H, Ar); 8.05 (br.s, 1 H, NHCH3); 7.45—7.55 (m, 4 H, Ar); 7.40 (d, 1 H, Ar,
J = 4.7); 2.62 (d, 3 H, NHCH3, J = 4.4)
8.53—8.58 (m, 2 H, Ar); 8.05 (br.s, 1 H, NHCH3); 7.45—7.59 (m, 4 H, Ar); 7.40 (d, 1 H, Ar,
J = 4.8); 3.10 (q, 2 H, NHCH2CH3); 0.93 (t, 3 H, NHCH2CH3, J = 7.4)
8.53—8.59 (m, 2 H, Ar); 8.07 (br.s, 1 H, NHCH2CH2CH3); 7.48—7.57 (m, 4 H, Ar); 7.39 (d,
1 H, Ar, J = 4.8); 3.04 (m, 2 H, NHCH2CH2CH3); 1.34 (m, 2 H, NHCH2CH2CH3); 0.79 (t,
3 H, NHCH2CH2CH3, J = 7.4)
6d
8.55—8.59 (m, 2 H, Ar); 7.05 (d, 1 H, NHCH(CH3)2, J = 7.7); 7.46—7.56 (m, 4 H, Ar); 7.40
(d, 1 H, Ar, J = 5.7); 3.86 (m, 1 H, NHCH(CH3)2); 0.97 (d, 6 H, NHCH(CH3)2)
8.53—8.58 (m, 2 H, Ar); 8.15 (br.s, 1 H, NH); 7.45—7.55 (m, 4 H, Ar); 7.28—7.40 (m, 6 H, Ar)
8.53—8.59 (m, 2 H, Ar); 7.51 (t, 1 H, Ar, J = 7.9); 7.43—7.58 (m, 4 H, Ar); 7.02—7.12 (m, 4 H,
Ar); 2.16 (s, 3 H, ArCH3)
6e
6f
6g
9a
8.58—8.65 (m, 2 H, Ar); 8.31 (t, 1 H, Ar, J = 7.9); 7.35—7.54 (m, 8 H, Ar)
8.44 (d, 1 H, Ar, J = 4.5); 8.00 (d, 1 H, Ar, J = 7.8); 7.64 (t, 1 H, Ar, J = 4.4); 7.40—7.51 (m,
3 H, Ar); 7.22 (d, 1 H, Ar, J = 4.8); 3.57 (s, 3 H, NCH3)
9b
9c
9d
8.46 (d, 1 H, Ar, J = 4.4); 8.01 (d, 1 H, Ar, J = 7.4); 7.61 (t, 1 H, Ar, J = 4.7); 7.39—7.50 (m,
3 H, Ar); 7.22 (d, 1 H, Ar, J = 4.8); 4.23 (dd, 2 H, NCH2CH3, J = 7.0); 1.26 (t, 3 H,
NCH2CH3, J = 7.0)
8.45 (d, 1 H, Ar, J = 3.7); 8.00 (d, 1 H, Ar, J = 7.3); 7.60 (t, 1 H, Ar, J = 4.1); 7.38—7.50 (m,
3 H, Ar); 7.21 (d, 1 H, Ar, J = 4.7); 4.34 (m, 1 H, NCH2CH2CH3); 4.13 (m, 1 H, NCH2CH2CH3);
1.64 (m, 2 H, NCH2CH2CH3); 0.91 (t, 1 H, NCH2CH2CH3, J = 7.4)
8.45 (d, 1 H, Ar, J = 4.1); 8.01 (d, 1 H, Ar, J = 8.1); 7.64 (t, 1 H, Ar, J = 4.5); 7.37—7.46 (m, 3 H,
Ar); 7.23 (d, 1 H, Ar, J = 4.7); 4.89 (m, 1 H, NCH(CH3)2); 1.65 (d, 3 H, NCH(CH3)2, J = 6.6);
1.17 (d, 3 H, NCH(CH3)2, J = 6.6)
9e
9f
8.28 (d, 1 H, Ar, J = 9.2); 8.17 (d, 1 H, Ar, J = 7.7); 7.88 (t, 1 H, Ar, J = 7.7); 7.47—7.61 (m, 4 H,
Ar); 7.29 (t, 2 H, Ar, J = 8.1); 7.11 (d, 2 H, J = 4.5)
8.23 (d, 1 H, Ar, J = 9.0); 8.15 (d, 1 H, Ar, J = 7.7); 7.90 (t, 1 H, Ar, J = 7.9); 7.43—7.59 (m, 4 H,
Ar); 7.02—7.12 (m, 4 H, Ar); 2.32 (s, 3 H, ArCH3)
9g
8.25 (d, 1 H, Ar, J = 8.7); 8.15 (d, 1 H, Ar, J = 7.8); 7.91 (t, 1 H, Ar, J = 7.8); 7.83 (d, 1 H, Ar,
J = 7.4); 7.35—7.52 (m, 7 H, Ar)
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dates for the treatment of infectious diseases based on
novel mechanisms of action using combinatorial synthesis
technologies and highꢀperformance screening».
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Received October 30, 2008;
in revised form April 27, 2009