Synthesis of pyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]quinolines, derivatives of a novel ring system

Article abstract of DOI:10.1515/hc-2014-0095

Several derivatives of the novel pyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]quinoline ring system have been synthesized through cyclocondensation of 5-amino-6-methylpyrimidine-4-thiols 5a,b and 2-chloroquinoline-3-carbaldehydes 6a-c in the presence of K₂ CO₃ in DMF.

Full text of DOI:10.1515/hc-2014-0095

Heterocycl. Commun. 2014; 20(5): 275–279
Azam Karimian, Hossein Eshghi*, Mehdi Bakavoli and Ali Shiri
Synthesis of pyrimido[4′,5′:2,3][1,4]thiazepino­
[
7,6­b]quinolines, derivatives of a novel ring
system
Abstract: Severalderivativesofthe novelpyrimido[4′,5′:2,3] halides with o-thiosalicylic acid esters as well as reduction
[
1,4]thiazepino[7,6-b]quinoline ring system have been and dehydration of the resulting products [5].
synthesized through cyclocondensation of 5-amino-
As part of our ongoing studies dealing with the
6
-methylpyrimidine-4-thiols 5a,b and 2-chloroquinoline- synthesis of new biologically active heterocyclic com-
3
-carbaldehydes 6a–c in the presence of K CO in DMF.
pounds [24–27], herein, we wish to report on the
synthesis and structural elucidations of various pyrimido-
2
3
Keywords: heterocyclization; pyrimidothiazepinoquino- [4′,5′:2,3][1,4]thiazepino[7,6-b]quinoline derivatives as a
line; quinoline; thiazepine.
novel heterocyclic system.
DOI 10.1515/hc-2014-0095
Received June 2, 2014; accepted August 28, 2014; previously pub-
lished online September 24, 2014
Results and discussion
2
,4-Dichloro-6-methyl-5-nitropyrimidine (1) was conveni-
Dedication: In memory of Professor Mohammad Rahimizadeh.
ently synthesized according to the published procedure
[
28]. The nitro group of this compound was reduced by treat-
Introduction
ment with iron powder in acetic acid at room temperature
to give 2,4-dichloro-6-methylpyrimidin-5-amine (2). Further
Heterocycles containing a 1,4-thiazepine moiety are impor- treatment of compound 2 with KSCN in boiling dimethyl for-
tant targets in synthetic and medicinal chemistry because mamide (DMF) gave 5-chloro-7-methylthiazolo[5,4-d]pyrimi-
of their presence in a wide range of natural and synthetic din-2-amine (3). Nucleophilic displacement of chlorine atom
active agents [1–4]. Among them, fused derivatives repre- in 2-position of the pyrimidine ring in compound 3 with
sent interesting pharmaceutical properties. For example, morpholine and piperidine as typical secondary amines
different alkyl derivatives of dihydro-1,4-benzothiazepine furnished the respective substituted derivatives 7-methyl-
are HIV-1 enzyme integrase inhibitor [5] and antitumor 5-morpholinothiazolo[5,4-d]pyrimidin-2-amine (4a) and
agents [6]. Several heteroannulated analogues of this core 7-methyl-5-piperidinothiazolo[5,4-d]pyrimidin-2-amine
fragment are also potent inhibitors of herpes simplex virus (4b). The synthesized compounds 4a,b were hydrolyzed in
type 1 replication [7], show antihistamine activity [8], and aqueous KOH solution to produce the respective 5-amino-
are vasoconstrictor agents [9]. Various methods for the syn- 6-methylpyrimidine-4-thiols 5a,b. Meanwhile, chloroqui-
thesis of fused 1,4-thiazepine derivatives have been reported noline-3-carbaldehydes 6a–c were conveniently prepared
in recent years with respect to their different structures according to the reported procedure [29]. Potassium carbon-
[10–18]. Synthetic approaches to these compounds involve ate catalyzed cyclocondensation reaction of compounds
addition [19], condensation [20], coupling [21], rearrange- 6a–c with compounds 5a,b in DMF under reflux pro-
ment [22], and thermolysis [23] reactions in multistep syn- ceeded smoothly and gave the first members of the hitherto
theses. These compounds have also been prepared through unknown 4-methylpyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]
the treatment of thioxanthen-9-ol with o-mesitylene sul- quinolines 7a–f. The progress of these reactions was moni-
fonyl hydroxylamine [4] or cyclization of o-nitrobenzene tored by thin layer chromatography (TLC) using n-hexane/
ethyl acetate (EtOAc) (8:1) as eluent (Scheme 1).
*
Corresponding author: Hossein Eshghi, Department of Chemistry,
All synthesized products were characterized by spectro-
scopic and microanalytical data. For instance, the IR spec-
trum of compound 7a did not show the stretching vibration
School of Sciences, Ferdowsi University of Mashhad, 91775-1436
Mashhad, Iran, e-mail: heshghi@um.ac.ir
Azam Karimian, Mehdi Bakavoli and Ali Shiri: Department of
Chemistry, School of Sciences, Ferdowsi University of Mashhad,
Mashhad, Iran
-1
bands of compounds 5a and 6a at 3336 and 3248 cm for
-
1
-1
the amino group, 2666 cm for the thiol, and at 1690 cm

2
76ꢀꢀꢀꢀꢁꢀA. Karimian et al.: Synthesis of pyrimidothiazepinoquinoline
Me
Me
Me
Me
O N
H N
2
i
2
ii
N
S
iii
N
S
N
N
N
N
H N
H N
2
2
Cl
N
Cl
Cl
N
Cl
N
Cl
N
R1
1
2
3
4a,b
iv
R2
CHO
Cl
Me
R2
N
Me
N
N
6a-c
H N
2
v
N
N
S
R1
HS
N
N
R1
7
a-f
5a,b
7
7
7
a: R1 = morpholino; R2 = H
b: R = morpholino; R2 = Cl
7d: R1 = piperidino; R2 = H
7e: R = piperidino; R = Cl
7f: R1 = piperidino; R2 = Me
4a, 5a: R1 = morpholino
4b, 5b: R1 = piperidino
1
1
2
c: R1 = morpholino; R2 = Me
Scheme 1ꢂReagents and conditions: (i) Fe powder, HOAc, rt, 2 h; (ii) KSCN, DMF, reflux, 3 h; (iii) morpholine or piperidine, EtOH, reflux, 6 h;
iv) KOH( , reflux, 10 h; (v) K CO , DMF, reflux, 8–12 h.
(
aq)
2
3
1
belonging to a carbonyl group. The H NMR spectrum of 7a system were synthesized for the first time by cycloconden-
does not show the signal for an aldehydic proton found in sation of 2-chloroquinoline-3-carbaldehydes and 5-amino-
the spectrum of compound 6a at 9.20 ppm. There are no 6-methylpyrimidine-4-thiols in the presence of K CO in
2
3
D O exchangeable signals, which indicates the absence of boiling DMF. Products 7a–f were obtained in high yields.
2
SH and NH groups present in the starting material 5a. The
2
spectrum shows a new sharp singlet signal at 8.71 ppm cor-
responding to the imino proton of the thiazepine ring of 7a.
Experimental
Melting points were recorded on an Electrothermal 9100 melting
point apparatus. The IR spectra were obtained in KBr pellets on an
Elimination of HCl is observed in the mass spectrum of 7a.
+
The molecular ion peak of 7a is observed at m/z 363 (M ),
which, together with the results of elemental analysis, fully
1
support the molecular formula of C H N OS. Analogous Avatar 370 FT-IR Thermo Nicolet spectrometer. The H NMR (400
19
17
5
1
3
results were obtained for the remaining products 7b–f. A MHz) and the C NMR (100 MHz) spectra were recorded on a Bruker
Avance DRX-400 spectrometer. The mass spectra were scanned on a
self-explanatory mechanism for the synthesis of 4-meth-
Varian Mat CH-7 instrument operating at 70 eV. Elemental analyses
ylpyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]quinoline deriva-
were performed on a Thermo Finnigan Flash EA microanalyzer.
tives 7a–f is proposed in Scheme 2.
2
,4­Dichloro­6­methylpyrimidin­5­amine (2)
Conclusion
A mixture of 2,4-dichloro-6-methyl-5-nitropyrimidine (1, 10 mmol, 2.1
Compounds 7a–f containing the previously unknown g) and iron powder (2.5 g) in acetic acid (50 mL) was stirred at room
temperature for 2 h. Af er completion of the reaction, the mixture was
pyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]quinoline
ring
filtered off and the filtrate was concentrated in vacuo. The resulting
solid was crystallized from ethyl acetate: yield 70% of a red powder;
1
mp 101–103°C; H NMR (CDCl ): δ 2.32 (s, 3H, CH ), 6.08 (s, 2H, NH ,
3
3
2
O
Me
R
N
Me
D O exchangeable); C NMR (CDCl ): δ 22.6, 115.2, 155.6, 159.6, 168.2;
1
3
R
H N
2
3
2
N
N
-1
+
+
H
IR: ν 3472, 3371, 1621, 1555 cm ; MS (m/z) 178 (M ), 180 (M +2). Anal.
Calcd for C H Cl N : C, 33.73; H, 2.83; N, 23.60. Found: C, 33.70; H, 2.81;
N
-
H O
R1
2
N
Cl
HS
N
N
Cl
HS
5
5
2
3
R1
N
N, 23.57.
R
Me
N
-HCl
5­Chloro­7­methylthiazolo[5,4­d]pyrimidin­2­amine (3)
N
S
N
R1
A mixture of 2,4-dichloro-6-methylpyrimidin-5-amine (2, 10 mmol,
1.7 g) and KSCN (10 mmol, 0.97 g) in DMF (15 mL) was heated under
Scheme 2ꢂ

A. Karimian et al.: Synthesis of pyrimidothiazepinoquinolineꢂꢁꢀꢀꢀꢂ277
reflux for 3 h. Af er completion of the reaction, the mixture was cooled 5-Amino-6-methyl-2-piperidinopyrimidine-4-thiolꢀ(5b)ꢀThis
and the resulting precipitate was collected by filtration and crystal- compound was obtained in 80% yield as yellow solid; mp 187–190°C;
1
1
lized from ethanol: yield 85% of a brown powder; mp 255–257°C; H
H NMR (DMSO-d ): δ 1.51–1.56 (m, 6H, 3CH ), 2.45 (s, 3H, CH ), 3.75–
6
2
3
NMR (DMSO-d ): δ 2.56 (s, 3H, CH ), 6.88 (s, 2H, NH , D O exchange- 3.77 (m, 4H, 2CH N), 6.81 (br s, 2H, NH , D O exchangeable), 6.40 (br
6
3
2
2
2
2
2
1
3
13
able); C NMR (DMSO-d ): δ 22.6, 115.2, 145.6, 159.6, 166.5 167.2; IR: ν s, 1H, SH, D O exchangeable); C NMR (DMSO-d ): δ 22.6, 24.3, 25.4,
6
2
6
-1
+
+
+
3
1
195, 3288, 2961, 1618 cm ; MS (m/z) 200 (M ), 202 (M +2), 170 (M -S), 56.8, 128.1, 162.5, 168.8, 170.1; IR: ν 3348, 3256, 2924, 2853, 2668, 1615
+
-1
+
+
+
26 (M -thiourea). Anal. Calcd for C H ClN S: C, 35.92; H, 2.51; N, 27.92; cm ; MS (m/z) 224 (M ), 192 (M -SH), 141 (M -piperidine). Anal. Calcd
6 5 4
S, 15.98. Found: C, 35.85; H, 2.47; N, 27.88; S, 15.93.
for C H N S: C, 53.54; H, 7.19; N, 24.98; S, 14.29. Found: C, 53.51; H,
10 16 4
.14; N, 24.92; S, 14.25.
7
General procedure for the preparation of compounds
4a,b
General procedure for the preparation of 4­methylpyrim­
ido[4′,5′:2,3][1,4]thiazepino[7,6­b]quinolines 7a­f
A mixture of 5-chloro-7-methylthiazolo[5,4-d]pyrimidin-2-amine (3,
0 mmol, 2.0 g) and the appropriate secondary amine (30 mmol) in To a mixture of 2-chloroquinoline-3-carbaldehyde (6a–c, 1 mmol)
CO (2 mmol, 0.13 g) in DMF (50 mL), the appropriate 5-amino-
1
ethanol (20 mL) was heated under reflux for 6 h. The progress of the and K
2
3
reaction was monitored by TLC using n-hexane/EtOAc (6:1) as eluent. 6-methylpyrimidine-4-thiol (5a,b, 1 mmol) was added, and the
Then, the solvent was removed under reduced pressure using rotary mixture was heated under reflux for 8–12 h according to the TLC mon-
evaporator. The crude residue was washed with ethanol (2 ꢀ× ꢀ2 0 mL) itoring using n-hexane/EtOAc (8:1) as eluent. Af er the completion of
and dried.
the reaction, water was added and the resulting solid was filtered off
and purified by column chromatography using n-hexane/EtOAc (8:1)
as mobile phase.
7
-Methyl-5-morpholinothiazolo[5,4-d]pyrimidin-2-amineꢀ(4a)ꢀ
This compound was obtained in 90% yield as a gray powder; mp 235–
1
4-(4-Methylpyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]quinolin-
2
37°C; H NMR (DMSO-d ): δ 2.36 (s, 3H, CH ), 3.65 (t, 4H, CH N, J ꢀ= ꢀ 5.2
6
3
2
Hz), 3.76 (t, 4H, CH O, J ꢀ= ꢀ 5.2 Hz), 6.9 (br s, 2H, NH , D O exchange- 2-yl)morpholine (7a)ꢀThis compound was obtained in 65% yield as
2
2
2
1
3
a pale yellow powder; mp 245–247°C;
1
H NMR (CDCl ): δ 2.53 (s, 3H,
3
able); C NMR (DMSO-d ): δ 22.6, 44.5, 62.3, 115.1, 145.4, 159.6, 166.8
6
-1
+
CH ), 3.75 (t, 4H, CH N, J ꢀ= ꢀ 5.2 Hz), 3.86 (t, 4H, CH O, J ꢀ= ꢀ 5.2 Hz), 7.61
1
67.1; IR: ν 3145, 3230, 2953, 2859, 1654 cm ; MS (m/z) 251 (M ), 221
3
2
2
+
+
+
(t, 1H, ArH, J ꢀ= ꢀ 8 Hz), 7.79 (t, 1H, ArH, J ꢀ= ꢀ 8 Hz), 7.88 (d, 1H, ArH, J ꢀ= ꢀ 8
C H N OS: C, 47.79; H, 5.21; N, 27.87; S, 12.76. Found: C, 47.74; H, 5.18; Hz), 8.12 (d, 1H, ArH, J ꢀ= ꢀ 8 Hz), 8.22 (s, 1H, ArH), 8.71 (s, 1H, HC ꢀ= ꢀN );
(
M -S), 177 (M -thiourea), 166 (M -morpholine). Anal. Calcd for
1
0
13
5
1
3
N, 27.84; S, 12.72.
C NMR (CDCl ): δ 22.0, 44.8, 66.8, 117.3, 127.0, 127.9, 128.1, 129.2, 130.2,
3
1
2
2
31.7, 138.2, 148.6, 149.0, 154.0, 155.1, 159.5, 166.1; IR: ν 3047, 3023, 2961,
-1
+
+
+
864, 1605, 1561, 1447 cm ; MS (m/z) 363 (M ), 365 (M +2), 333 (M -S),
7
-Methyl-5-piperidinothiazolo[5,4-d]pyrimidin-2-amineꢀ(4b)ꢀ
+
77 (M -morpholine). Anal. Calcd for C H N OS: C, 62.79; H, 4.71; N,
This compound was obtained in 90% yield as a gray powder; mp
19 17
5
1
19.27; S, 8.82. Found: C, 62.75; H, 4.67; N, 19.24; S, 8.85.
2
07–210°C; H NMR (DMSO-d ): δ 1.50–1.56 (m, 6H, 3CH ), 2.44 (s, 3H,
6
2
CH ), 3.73–3.75 (m, 4H, 2-CH N), 6.92 (br s, 2H, NH , D O exchange-
3
2
2
2
1
3
4-(10-Chloro-4-methylpyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]
quinolin-2-yl)morpholine (7b)ꢀThis compound was obtained in
able); C NMR (DMSO-d ): δ 22.6, 24.3, 26.4, 54.8, 125.1, 143.4, 160.5,
6
-
1
+
165.8, 168.1; IR: ν 3135, 3245, 2940, 2865, 1615 cm ; MS (m/z) 249 (M )
2
+
+
70% yield as a yellow powder; mp 305–307°C;
2.51 (s, 3H, CH ), 3.74 (t, 4H, 2CH N, J ꢀ= ꢀ 5.2 Hz), 3.85 (t, 4H, 2CH O,
2 2
1
H NMR (CDCl ): δ
19 (M -S), 166 (M -piperidine). Anal. Calcd for C H N S: C, 52.99; H,
3
1
1
15
5
6
.06; N, 28.09; S, 12.86. Found: C, 52.90; H, 6.04; N, 27.99; S, 12.82.
3
J ꢀ= ꢀ 5.2 Hz), 7.71 (dd, 1H, ArH, J ꢀ= ꢀ 8 Hz, J ꢀ= ꢀ 2.0 Hz), 7.85 (d, 1H, J ꢀ= ꢀ 2.0
Hz, ArH), 8.04 (d, 1H, ArH, J ꢀ= ꢀ 8 Hz), 8.12 (s, 1H, ArH), 8.71 (s, 1H,
1
3
HC ꢀ= ꢀN ); C NMR (CDCl ): δ 22.0, 44.4, 66.8, 126.6, 127.0, 130.7, 131.0,
3
General procedure for the preparation of compounds
a,b
1
32.5, 133.8, 137.0, 147.3, 151.7, 152.0, 153.6, 154.5, 159.6, 166.4; IR: ν
5
-1
3
3
076, 3019, 2953, 2868, 2839, 1607, 1555, 1491, 1449, 1311 cm ; MS (m/z)
+
+
+
+
97 (M ), 362 (M -Cl), 367 (M -S), 311 (M -morpholine). Anal. Calcd for
A mixture of 4a or 4b (10 mmol) in aqueous 15% KOH solution (20 C H ClN OS: C, 57.35; H, 4.05; N, 17.60; S, 8.06. Found: C, 57.31; H,
1
9
16
5
mL) was heated in a water bath for 10 h. The reaction mixture was 4.02; N, 17.56; S, 8.01.
then neutralized with acetic acid, and the separated solid was col-
lected by filtration and crystallized from water.
4
-(4,10-Dimethylpyrimido[4′,5′:2,3][1,4]thiazepino[7,6-b]quin-
olin-2-yl)morpholine (7c)ꢀThis compound was obtained in 55%
1
5
-Amino-6-methyl-2-morpholinopyrimidine-4-thiolꢀ(5a)ꢀThis yield as a yellow powder; mp 256–258°C; H NMR (CDCl ): δ 2.45 (s,
3
compound was obtained in 86% yield as yellow solid; mp 215–217°C; 3H, CH ), 2.61 (s, 3H, CH ), 3.66 (t, 4H, 2CH N, J ꢀ= ꢀ 4.4 Hz), 3.73 (t, 4H,
3
3
2
1
H NMR (DMSO-d ): δ 2.33 (s, 3H, CH ), 3.65 (t, 4H, CH N, J ꢀ= ꢀ 4.8 Hz), 2CH O, J ꢀ= ꢀ 4.4 Hz), 7.47 (d, 1H, ArH, J ꢀ= ꢀ 8Hz), 7.84 (s, 1H, ArH), 7.88
6
3
2
2
1
3
3
5
.75 (t, 4H, CH O, J ꢀ= ꢀ 4.8 Hz), 6.56 (br s, 2H, NH , D O exchangeable), (d, 1H, ArH, J ꢀ= ꢀ 8 Hz), 8.29 (s, 1H, ArH), 8.92 (s, 1H, HC ꢀ= ꢀN ); C NMR
2
2
2
13
.50 (br s, 1H, SH, D O exchangeable); C NMR (DMSO-d ): δ 23.6, (CDCl ): δ 21.3, 22.8, 45.1, 66.3, 117.4, 127.0, 127.5, 128.9, 129.2, 130.2,
2
6
3
4
1
6.5, 66.3, 115.8, 133.0, 147.9, 167.2; IR: ν 3336, 3248, 2940, 2865, 2666, 131.2, 137.3, 148.9, 150.7, 154.0, 155.2, 160.3, 165.4; IR: ν 3030, 2962,
-1
+
+
+
-1
+
610 cm ; MS (m/z) 226 (M ), 194 (M -SH), 141 (M -morpholine). Anal. 2904, 2855, 1617, 1579, 1538, 1507, 1494, 1444 cm ; MS (m/z) 377 (M ),
+
+
Calcd for C H N OS: C, 47.77; H, 6.24; N, 24.76; S, 14.17. Found: C, 47.70; 347 (M -S), 291 (M -morpholine). Anal. Calcd for C H N OS: C, 63.64;
9
14
4
20 19
5
H, 6.21; N, 24.72; S, 14.14.
H, 5.07; N, 18.55; S, 8.49. Found: C, 63.61; H, 5.01; N, 18.51; S, 8.45.

2
78ꢀꢀꢀꢀꢁꢀA. Karimian et al.: Synthesis of pyrimidothiazepinoquinoline
4
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diazepinylbenzoic acids. retinoid synergists which activate the
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quinoline (7d)ꢀThis compound was obtained in 65% yield as an
1
orange powder; mp 305–307°C; H NMR (CDCl ): δ 1.52–1.59 (m, 6H,
3
3
CH ), 2.44 (s, 3H, CH ), 3.71–3.73 (m, 4H, 2-CH N), 7.61 (t, 1H, ArH, J ꢀ= ꢀ
2
3
2
7
.8 Hz), 7.80 (t, 1H, ArH, J ꢀ= ꢀ 7.8 Hz), 7.9 (d, 1H, ArH, J ꢀ= ꢀ 8.0 Hz), 8.14
1
3
(
d, 1H, ArH, J ꢀ= ꢀ 8.0 Hz), 8.23 (s, 1H, ArH), 8.74 (s, 1H, HC ꢀ= ꢀN ); C NMR
(
CDCl ): δ 23.5, 24.7, 26.4, 54.8, 118.6, 126.3, 127.3, 127.8, 128.5, 129.1,
3
1
30.2, 137.1, 148.5, 160.8, 160.9, 161.4, 163.1, 163.6; IR: ν 3007, 2937,
-1
+
+
2
855, 1620, 1569, 1506, 1445 cm ; MS (m/z) 361 (M ), 331 (M -S), 377
+
(
M -piperidine). Anal. Calcd for C H N S: C, 66.46; H, 5.30; N, 19.37;
2
0
19
5
S, 8.87. Found: C, 66.50; H, 5.12; N, 19.4; S, 8.9.
1
0-Chloro-4-methyl-2-piperidinopyrimido[4′,5′:2,3][1,4]thia-
zepino[7,6-b]quinoline (7e)ꢀThis compound was obtained in 72%
1
yield as a yellow powder; mp 272–274°C; H NMR (CDCl ): δ 1.56–1.61
3
(
m, 6H, 3CH ), 2.50 (s, 3H, CH ), 3.79–3.82 (m, 4H, 2CH N), 7.16–7.21
2
3
2
(
m, 1H, ArH), 7.83 (d, 1H, ArH, J ꢀ= ꢀ 4 Hz), 8.1 (d, 1H, ArH, J ꢀ= ꢀ 4 Hz),
13
8
3
1
1
3
1
.23 (s, 1H, ArH), 8.74 (s, 1H, HC ꢀ= ꢀN ); C NMR (CDCl ): δ 25.8, 27.3, 27.6,
7.2, 125.6, 127.3, 131.1, 131.8, 132.5, 135.2, 137.0, 147.5, 150.3, 152.1, 153.6,
3
55.5, 159.4, 166.0; IR: ν 3024, 2990, 2926, 2831, 1629, 1611, 1593, 1500,
395, 1337 cm ; MS (m/z) 395 (M ), 397 (M +2), 360 (M -Cl), 365 (M -S),
-1
+
+
+
+
+
11 (M -piperidine). Anal. Calcd for C H ClN S: C, 60.67; H, 4.58; N,
[8] Cale, A. D.; Gero, T. W.; Walker, K. R.; Lo, Y. S.; Welstead, W. J.;
Jaques, L. W.; Johnson, A. F.; Leonard, C. A.; Nolan, J. C.;
Johnson, D. N. Benzo- and pyrido-1,4-oxazepin-5-ones and
-thiones: synthesis and structure-activity relationships of a new
series of H1-antihistamines. J. Med. Chem. 1989, 32, 2178–2199.
[9] Schlosser, K. M.; Krasutsky, A. P.; Hamilton, H. W.; Reed, J. E.;
Sexton, K. A highly efficient procedure for 3-sulfenylation of
indole-2-carboxylates. Org. Lett. 2004, 6, 819–821.
2
0
18
5
7.69; S, 8.10. Found: C, 60.65; H, 4.45; N, 17.50; S, 8.16.
4
,10-Dimethyl-2-piperidinopyrimido[4′,5′:2,3][1,4]thia-
zepino[7,6-b]quinoline (7f)ꢀThis compound was obtained in 70%
1
yield as a yellow powder; mp 294–295°C; H NMR (CDCl ): δ 1.55–1.61
3
(
2
m, 6H, 3CH ), 2.35 (s, 3H, CH ), 2.47 (s, 3H, CH ), 3.63–3.67 (m, 4H,
2
3
3
CH N), 7.40 (d, 1H, ArH, J ꢀ= ꢀ 8 Hz), 7.84 (s, 1H, ArH), 7.92 (d, 1H, ArH,
2
13
J ꢀ= ꢀ 8 Hz), 8.3 (s, 1H, ArH), 8.81 (s, 1H, HC ꢀ= ꢀN ); C NMR (CDCl ): δ 21.9, [10] Miki, T.; Kori, M.; Fujishima, A.; Mabuchi, H.; Tozawa, R.;
3
2
3.7, 28.4, 33.9, 66.1, 117.1, 124.2, 125.9, 127.3, 128.3, 129.2, 130.8, 131.2,
Nakamura, M.; Sugiyama, Y.; Yukimasa, H. Syntheses of fused
heterocyclic compounds and their inhibitory activities for
squalene synthase. Bioorg. Med. Chem. 2002, 10, 385.
1
1
36.3, 148.7, 150.7, 154.1, 162.3, 165.2; IR: ν 3020, 2940, 2835, 1616, 1562,
-1
+
+
+
+
501, 1445, 1363 cm ; MS (m/z) 375 (M ), 377 (M +2), (M -Cl), 345 (M -
+
S), 391 (M -piperidine). Anal. Calcd for C H N S: C, 67.17; H, 5.64; N, [11] Pei, Y. Z.; Lilly, M. J.; Owen, D. J.; D’Souza, L. J.; Tang, X. Q.;
2
1
21
5
18.65; S, 8.54. Found: C, 67.20; H, 5.70; N, 18.63; S, 8.78.
Yu, J. H.; Nazarbaghi, R.; Hunter, A.; Anderson, C. M.;
Glasco, S.; et al. Efficient syntheses of benzothiazepines as
antagonists for the mitochondrial sodium-calcium exchanger:
potential therapeutics for type II diabetes. J. Org. Chem. 2003,
Acknowledgments: The authors gratefully acknowledge
the Research Council of Ferdowsi University of Mashhad
for financial support of this project 25422/3.
68, 92–103.
[
[
12] Neo, A. G.; Marcos, C. F.; Marcaccinib, S.; Pepino, R. Studies
on isocyanides. A facile synthesis of 4,5-dihydro-1,4-benzothi-
azepin-3(2H)-ones via post-condensation modifications of the
Ugi reaction. Tetrahedron Lett. 2005, 46, 7977–7979.
13] Ilyn, A. P.; Loseva, M. V.; Vedensky, V. Y.; Putsykina, E. B.;
Tkachenko, S. E.; Kravchenko, D. V.; Khvat, A. V.; Krasavin, M.
Y.; Ivachtchenko, A. V. One-step assembly of carbamoyl-substi-
tuted heteroannelated [1,4]thiazepines. J. Org. Chem. 2006, 71,
2811–2819.
[14] Tu, S. J.; Cao, X. D.; Hao, W. J.; Zhang, X. H.; Yan, S.; Wu, S. S.;
Han, Z. G.; Shi, F. An efficient and chemoselective synthesis
of benzo[e][1,4]thiazepin-2(1H,3H,5H)-ones via a microwave-
assisted multi-component reaction in water. Org. Biomol.
Chem. 2009, 7, 557–563.
[15] Hui, C.; Daqing, S. Efficient one-pot synthesis of spiro[indoline-
3,4-pyrazolo[3,4-e][1,4]thiazepine]dione via three component
reaction. Tetrahedron 2011, 67, 5686–5692.
[16] Calvo, L. A.; Gonzalez-Ortega, A.; Marcos, R.; Perez, M.;
Sanudo, M. C. Synthesis of 2,3,4,7-tetrahydro[1,4]thiazepines
from thiazolidines and β-enaminonitriles. Tetrahedron 2008,
64, 3691–3700.
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