Synthesis of dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepines; derivatives of a novel ring system

Article abstract of DOI:10.3184/174751915X14401726334645

Several derivatives of the novel dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepine ring system have been synthesised through the initial heterocyclisation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine with o-aminothiophenol followed by treatment with various secondary amines in boiling ethanol.

Full text of DOI:10.3184/174751915X14401726334645

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 SEPTEMBER, 531–534
RESEARCH PAPER 531
Synthesis of dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepines; derivatives of a
novel ring system
Marzieh Akbarzadeh, Mehdi Bakavoli*, Hossein Eshghi, Ali Shiri and Javad Tajabadi
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
Several derivatives of the novel dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepine ring system have been synthesised through the initial
heterocyclisation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine with o-aminothiophenol followed by treatment with various
secondary amines in boiling ethanol.
Keywords: dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepine, heterocyclisation, 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine
Nitrogen-containing heterocycles are important targets in
synthesis because of their biological properties and their roles
as pharmacophores of many biologically active compounds.1
Among them, 1,4-benzothiazepine exhibit important biological
activities in the central nervous system2-5 which are considered
as antipsychotic,3-5 antihypertensive and antidepressant
agents.6 1,4-Benzothiazepines have also emerged as privileged
structures with cardioprotective effect for the treatment of
sudden cardiac death and myocardial infarction.7-9
They also act as angiotensin converting enzyme inhibitors,
calmodulin antagonists, bradykinin receptor agonists and Ca2+
antagonists.10 Some of the widely used benzo[b][1,4]thiazepine
drugs are shown in Fig. 1.
Various methods have been reported for the synthesis
of benzo[b][1,4]thiazepines. Some of the more recent
ones involve Cu-catalysed coupling of 2-iodoanilines and
2-mercaptoacetate,11 reductive ring expansion reactions of cyclic
ketoximes using dichloroaluminum hydride,12 diethylamine
promoted α-sulfenylation reaction followed by subsequent acid
catalysed condensation reaction13 and coupling–isomerisation
reaction of an electron poor (hetero)aryl halide with a terminal
propargyl alcohol followed by cyclocondensation with
2-mercapto anilines.14
The literature survey reveals that only a few synthetic
procedures have been reported for the synthesis of
pyrimidobenzothiazepines. These methods include the
condensation of 5-amino-4,6-bis-(arylthio)pyrimidines and
carboxylic acids through Bischler–Napieralski-type reactions,15
Mannich-type cyclisation of 6-[(2-aminophenyl)thio]uracils
followed by alkylation at N1 by a one-pot Vorbruggen reaction16
and rearrangement of an azide compounds.17
Due to our interest in the synthesis of various fused
heterocyclic derivatives with pyrimidine core,18-24 we now
report a convenient method for the synthesis of 2-substituted-
4-methyl-5,11-dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepine
derivatives (6a–g) as members of a new heterocyclic system.
Results and discussion
The precursor, 6-methylpyrimidine-2,4-(1H,3H)-dione (1),
was prepared by treatment of thiourea and ethylacetoacetate
according to the previously published method.25 The reaction of
(1) with formaldehyde in aqueous 5% NaOH solution at room
temperature gave 5-(hydroxymethyl)-6-methylpyrimidine-
2,4(1H,3H)-dione (2)26 which was subsequently converted
with a little modification into 2,4-dichloro-5-(chloromethyl)-
6-methylpyrimidine (3) in boiling POCl3 and N(i-Pr)2Et.27 The
compound (3) was treated with o-aminothiophenol (4) as a
binucleophile at –15 ºC in CHCl3. (Scheme 1)
The evidence which confirms both 4-Cl and the chloromethyl
group on the pyrimidine core were substituted by sulfur
and amino groups of o-aminothiophenol, respectively, and
formation of compound (5) can be deduced from previously
1
published methods. The comparison of the H chemical shifts
of methylene group bonded to sulfur or nitrogen in thiazepine
moieties with the similar ones in the reported literatures (δ 3.98
ppm for CH2S 28, δ 4.26 ppm for CH2N 29) revealed that the
data are in accordance with the 1H chemical shifts of the CH2 in
compound (5) (δ 3.90 ppm) confirming the SNAr displacement
of the 4-Cl function with the thiol group of compound (4).
Moreover, computational evaluations can be used for the
elucidation of ambiguity in the structure of the seven membered
heterocycle (5). First, compound (5) and its regioisomer which
H
O
N
N
O
N
N
O
O
O
O
O
O
N
S
N
S
N
O
N
S
N
l
C
S
O
O
(a)
(b)
(c)
(d)
Fig. 1 Examples of some clinically used benzothiazepine derivatives: (a) clentiazem (calcium channel blocker); (b) diltiazem (calcium channel
blocker); (c) thiazesim (antidepressant); (d) quetiapine (antipsychotic agent).
* Correspondent. E-mail: mbakavoli@um.ac.ir; mbakavoli@yahoo.com

532 JOURNAL OF CHEMICAL RESEARCH 2015
H
H
N
l
C
N
l
C
N
O
O
O
O
P
l
OC 3
H
C
2O
N
l
C
HN
HN
H
O
NaOH(aq)
(1)
(2)
(3)
NH2
H
l
C
C 3
-15oC
H
S
(4)
H
H
N
N
R2N
N
l
C
N
R2NH
EtOH, reflux
N
N
S
S
(6a-g)
6c
(5)
6a
6b
6d
6e
6f
6g
entry
Me
Me
Et
Ph
R2N
N
N
N
N
O
N
N
N
N
N
N
Scheme 1
Fig. 2 The optimised structures of (5) and (5’).
we named it (5′) were optimised at mPW1PW91/6-31G(d) level
of theory in the gas phase (Fig. 2).
The stationary points were characterised by frequency
calculations. The comparison of Gibbs energy difference in the
gas phase indicated that isomer (5) was more thermodynamically
stable than isomer (5’) (15.9 kcal mol-1).
doublet and a triplet signals between 7.07–7.13 ppm and 7.29–
7.49 ppm assignable to the hydrogens of aryl group as well as
a broad singlet signal at δ 8.22 ppm due to NH moiety confirm
the structure (5). The IR spectrum of (5) displays the stretching
vibration bands at 3468 cm-1 due to NH group.
Compound 5 on treatment with excess amount of various
secondary amines in boiling ethanol underwent the chlorine
substitution to give derivatives of the new heterocyclic ring
system, dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepines (6a–g)
in good to excellent yields. All the physical, chemical and spectral
data were in agreement with the newly proposed structures. The
1H NMR spectrum of product (6a), as an example, showed a
triplet signal at 1.97 and 3.57 ppm due to the methylene protons
of pyrrolidine ring, a singlet signal at 2.37 ppm indicating the
presence of methyl group on the pyrimidine ring and a singlet
signal at δ 3.89 ppm attributed to CH2S hydrogens. The signals
of the aryl hydrogens and D2O exchangeable broad peak of
NH moiety were also appeared around 6.9–7.41 and 7.28 ppm,
As we recently applied GIAO/13C NMR calculations for
elucidation of organic compound structures,30, 31 therefore, the
GIAO 13C chemical shifts for (5) and (5′) were computed by
Sarotti and Pellegrinet method 32 at the mPW1PW91/6-31G(d)//
mPW1PW91/6-31G(d) level of theory. The experimental and
unscaled GIAO 13C chemical shifts of compounds (5) and (5′)
using multistandard approach (MSTD) have been represented in
Table 1. As shown in Table 1, the differences between calculated
and experimental chemical shifts demonstrated that the
formation of compound (5) is preferred. The 1H NMR spectrum
of compound (5) shows two singlet signals at δ 2.56 and 3.90
ppm, attributed to CH3 and CH2S hydrogens, respectively. The

JOURNAL OF CHEMICAL RESEARCH 2015 533
Table 1 Experimental and unscaled GIAO 13C chemical shift values (δ), in ppm, for structures (5) and (5′) (atom numbering is according to Fig. 2)
a
a
a
No. of carbon
5(C16)
Exp.
No. of carbon
5(C9)
Exp.
No. of carbon
5(C6)
Exp.
δ
Δδ
δ
Δδ
δ
Δδ
22.36
22.25
35.21
42.42
114.64
113.88
120.53
115.86
1.13
121.84
118.08
128.41
129.25
130.47
133.71
134.13
135.4
–2.02
–5.78
0.43
1.27
1.42
4.66
0.82
2.09
140.01
142.74
156.33
164.25
164.51
166.26
165.15
174.82
–0.42
2.31
0.67
8.59
4.44
6.19
21.23
123.86
140.43
1.02
2.45
9.66
0.01
–0.75
–1.63
–6.3
5′(C16)
5(C3)
5′(C10)
5(C10)
5′(C5)
5(C1)
32.76
127.98
129.05
155.66
160.07
5′(C3)
5(C2)
5′(C9)
5(C5)
5′(C15)
5(C15)
114.63
5′(C6)
5(C11)
5′(C2)
5(C8)
5′(C13)
5(C13)
1.42
11.09
122.16
133.31
163.73
5′(C8)
5′(C11)
5′(C1)
a
Dδ, the difference between the calculated and experimental (Exp.) 13C chemical shifts.
solution was refluxed. After the completion of the reaction which was
monitored by TLC using chloroform: methanol (30:1), the solvent was
concentrated and the resulting white precipitate was filtered, washed
with water (2 × 20 mL) and dried.
respectively. The IR spectrum of compound (6a) revealed
the existence of the stretching vibration band of CH2 around
2800–2900 cm–1 in the product confirming the occurrence of
substitution.
4-Methyl-2-(pyrrolidin-1-yl)-5,11-dihydrobenzo[b]pyrimido[4,5-e]
o
[1,4]thiazepine (6a): Yield 74%; white powder; m.p. 178–180 C, IR
Conclusion
(KBr disc) 3384, 3056, 2951, 2859, 1597, 1548, 1472, 1400, 1336, 1275,
1175, 1127 cm-1, 1H NMR (300 MHz, CDCl3) δ 1.97 (t, J = 6.9 Hz, 4H,
CH2), 2.37 (s, 3H, CH3), 3.57 (t, J = 6.9 Hz, 4H, CH2–N), 3.89 (s, 2H,
CH2), 6.92 (td, J = 7.5 Hz, J = 1.2 Hz, 1H, ArH), 6.97 (dd, J = 7.5 Hz,
J = 1.2 Hz, 1H, ArH), 7.21 (td, J = 7.5 Hz, J = 1.2 Hz, 1H, ArH), 7.28 (s,
1H, NH), 7.39 (d, J = 7.5 Hz, J = 1.2 Hz, 1H, ArH), 13C NMR (75 MHz,
CDCl3) δ 22.5, 25.5, 32.9, 54.4, 105.8, 120.9, 121.9, 127.0, 128.3, 133.2,
142.2, 159.1, 159.5, 163.5, MS (m/z) 298 (M+), 228 (M - C4H8N). Anal.
calcd for C16H18N4S: C, 64.40; H, 6.08; N, 18.78, 10.74; found: C, 64.34;
H, 5.98; N, 18.71; S, 10.63%.
4-(4-Methyl-5,11-dihydrobenzo[b]pyrimido[4,5-e][1,4]thiazepin-
2-yl)morpholine (6b): Yield 68%; white powder; m.p. 189–191 oC,
IR (KBr disc) 3329, 3060, 2983, 2944, 2889, 2844, 1598, 1573, 1557,
1476, 1405, 1357, 1301, 1262, 1190, 1102, 1071 cm-1, 1H NMR (300
MHz, CDCl3) δ 2.34 (s, 3H, CH3), 3.75–3.88 (m, 10H, CH2, CH2–O,
CH2–N), 6.94–6.95 (m, 2H, ArH), 7.21 (t, J = 7.5 Hz, 1H, ArH), 7.31 (s,
1H, NH), 7.88 (d, J = 7.5 Hz, 1H, ArH), 8.05 (s, 1H, NH) , 13C NMR (75
MHz, CDCl3) δ 22.5, 32.9, 43.4, 66.9, 105.9, 121.0, 121.9, 127.1, 128.3,
133.2, 142.2, 159.0, 159.5, 163.6, MS (m/z) 314 (M+), 257 (M – C3H7O).
Anal. calcd for C16H18N4OS: C, 61.12; H, 5.77; N, 17.82; S, 10.20;
found: C, 61.05; H, 5.71; N, 17.74; S, 10.12%.
4-Methyl-2-(piperidin-1-yl)-5,11-dihydrobenzo[b]pyrimido[4,5-e]
[1,4]thiazepine (6c): Yield 82%; white powder; m.p. 150–153oC,
IR (KBr disc) 3260, 3072, 3015, 2925, 2859, 1605, 1576, 1549, 1525,
1474, 1400, 1361, 1259, 1192, 1135 cm-1, 1H NMR (300 MHz, CDCl3)
δ 1.60–1.67 (m, 6H, CH2), 2.35 (s, 3H, CH3), 3.15 (t, J = 7.5 Hz, 4H,
CH2–N), 3.76 (t, J = 5.3 Hz, 4H, CH2–N), 3.88 (s, 2H, CH2), 6.90–6.97
(m, 2H, ArH), 7.24 (td, J = 7.9 Hz, J = 1.5 Hz, 1H, ArH), 7.26 (s, 1H,
NH), 7.4 (dd, J = 7.5 Hz, J = 1.2 Hz, 1H, ArH), 13C NMR (75 MHz,
CDCl3) δ 22.5, 24.9, 25.8, 32.9, 44.7, 104.8, 120.9, 121.6, 126.9, 128.2,
133.1, 142.4, 158.9, 159.6, 163.5, MS (m/z) 312 (M+), 228 (M – C5H10N).
Anal. calcd for C17H20N4S: C, 65.35; H, 6.45; N, 17.93; S, 10.26; found:
C, 65.27; H, 6.39; N, 17.88; S, 10.19%.
In conclusion, we have developed a novel and efficient
synthetic method for the preparation of 5,11-dihydrobenzo[b]
pyrimido[4,5-e][1,4]thiazepine derivatives (6a–g). The initial
treatment of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine
(3) with o-aminothiophenol in CHCl3 leads to simultaneous
substitution and heterocyclisation. The reaction of the synthesised
compound (5) with various sec-amines led to the substitution
of the 2-Cl atom to give the derivatives of a new ring system
(6a–g). Further investigation towards construction of other novel
heterocyclic ring systems is underway in our laboratory.
Experimental
Melting points were recorded on an Electrothermal type 9100 melting
point apparatus. The IR spectra were obtained on Avatar 370 FT-IR
Thermo Nicolet and only noteworthy absorptions were listed. The
1H NMR (300 MHz) and the 13C NMR (75 MHz) spectra were recorded
on a Bruker Avance DRX-400 Fourier transformer spectrometer.
Chemical shifts were reported in ppm downfield from TMS as internal
standard. The mass spectra were scanned on a Varian Mat CH-7 at 70
eV. Elemental analyses were performed on a Thermo Finnigan Flash
EA microanalyser.
2-Chloro-4-methyl-5,11-dihydrobenzo[b]pyrimido[4,5-e][1,4]
thiazepine (5): A solution of o-aminothiophenol (4) (1 mmol, 0.12 g) in
CHCl3(1 mL) was added dropwise to a cooled (–15°C) stirred solution
of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine (3) (1 mmol,
0.21 g) and Et3N (2 mmol, 0.2 g) in CHCl3 (5 mL). The resulting
mixture was allowed to warm to room temperature for 5 h, then water
(10 mL) was added and the mixture was extracted with CHCl3 (3× 10
mL). The combined organic solvents were dried over anhydrous sodium
sulfate and concentrated. The resulting solid was purified using silica
gel column chromatography CHCl3: methanol (30:1) as eluent. Yield
74%; white powder; m.p. 200–203 oC, IR (KBr disc) 3468, 3068, 3002,
2917, 2847, 1608, 1544, 1524, 1478, 1446, 1332, 1310, 1222, 1159 cm-1,
1H NMR (300 MHz, CDCl3) δ 2.56 (s, 3H, CH3), 3.90 (s, 2H, CH2),
7.7–7.13 (m, 2H, ArH), 7.32 (td, J = 6.9 Hz, J = 1.1 Hz, 1H, ArH), 7.48
(dd, J = 6.9 Hz, J = 1.1 Hz, 1H, ArH), 8.22 (s, 1H, NH), 13C NMR (75
MHz, CDCl3) δ 22.2, 32.8, 114.6, 122.2, 123.9, 127.9, 129.1, 133.3, 140.4,
155.7, 160.1, 163.7, MS (m/z) 263.8 (M+), 228 (M - Cl), 187 (M – C6H4).
Anal. calcd for C12H10ClN3S: C, 54.65; H, 3.82; N, 15.93; S, 12.16; found:
C, 54.56; H, 3.74; N, 15.87; S, 12.00%.
4-Methyl-2-(4-methylpiperidin-1-yl)-5,11-dihydrobenzo[b]
pyrimido[4,5-e][1,4]thiazepine (6d): Yield 62%; white powder; m.p.
o
130–132 C, IR (KBr disc) 3267, 3064, 3011, 2962, 2949, 2916, 2850,
1602, 1575, 1523, 1473, 1452, 1366, 1358, 1303, 1255, 1191, 1131 cm-1,
1H NMR (300 MHz, CDCl3) δ 0.95 (d, J = 4.5, 3H, CH3), 1.10–1.19 (m,
1H, CH), 1.59–1.69 (m, 2H, CH), 2.33 (s, 1H, CH3), 2.78 (m, 2H, CH–N),
3.84 (s, 2H, CH2), 4.69 (m, 2H, CH–N), 6.88–6.93 (m, 3H, ArH), 7.18
(t, J = 5.7 Hz, 1H, ArH), 7.26 (s, 1H, NH), 7.37 (d, J = 5.7 Hz, 1H, ArH),
13C NMR (75 MHz, CDCl3) δ 22.0, 22.5, 31.4, 32.9, 34.1, 44.1, 104.9,
120.9, 121.7, 126.9, 128.2, 133.1, 142.4, 158.9, 159.6, 163.5, MS (m/z)
326 (M+), 271 (M – C4H10N). Anal. calcd for C18H22N4S: C, 66.22; H,
6.79; N, 17.16; S, 9.82; found: C, 66.17; H, 6.71; N, 17.12; S, 9.74%.
4-Methyl-2- (4-methylpiperazin-1-yl)-5,11-dihydrobenzo[b]
pyrimido[4,5-e][1,4]thiazepine (6e): Yield 89%; white powder; m.p.
Synthesis of 2-substituted-4-methyl-5,11-dihydrobenzo[b] pyrimido-
[4,5-e][1,4]thiazepine (6a–g); general procedure
The appropriate secondary amine (5 mmol), was added to a stirred
solution of 2-chloro-4-methyl-5,11-dihydrobenzo[b]pyrimido[4,5-e]
[1,4]thiazepine (5) (1 mmol, 0.26 g) in EtOH (10 mL) and the

534 JOURNAL OF CHEMICAL RESEARCH 2015
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5
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M. A. Di Cesare, D. Mastroianni, N. Scafetta, B. Galletti, M. A. Stasi, M.
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2009, 4, 126.
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Schmitto, F. A. Schoendube, N. Kaneko, C. M. Loughrey, G. L. Smith, G.
Hasenfuss and T. Seider, Basic Res. Cardiol., 2010, 105, 279
160–163 C, IR (KBr disc) 3397, 2956, 2925, 2869, 2833, 2787, 2760,
2733, 1598, 1548, 1527, 14775, 1445, 1401, 1356, 1323, 1298, 1260,
1196, 1143, 1048 cm-1, 1H NMR (300 MHz, CDCl3) δ 2.35 (s, 3H,
CH3–N), 2.40 (s, 3H, CH3), 2.54 (t, J = 5 Hz, 4H, CH2–N), 3.85–3.87
(m, 6H, CH2, CH2–N), 6.91–9.96 (m, 2H, ArH), 7.21 (td, J = 5.7 Hz,
J = 1.5 Hz, 1H, ArH), 7.3 (s, 1H, NH), 7.39 (d, J = 5.7 Hz, 1H, ArH),
13C NMR (75 MHz, CDCl3) δ 22.5, 32.9, 43.5, 46.1, 54.9, 105.7, 120.9,
121.9, 126.7, 128.3, 133.1, 142.2, 158.9, 159.5, 163.6), MS (m/z) 327
(M+), 228 (M – C5H11N2). Anal. calcd for C17H21N5S: C, 62.36; H, 6.46;
N, 21.39; S, 9.79; found: C, 62.31; H, 6.37; N, 21.32; S, 9.71%.
2- (4-Ethylpiperazin-1-yl) -4-methyl-5,11-dihydrobenzo[b]
pyrimido[4,5-e][1,4]thiazepine (6f): Yield 74%; white powder; m.p.
157–159 oC, IR (KBr disc) 3272, 3060, 2970, 2925, 2864, 2794, 2761,
1675, 1603, 1574, 1547, 1521, 1472, 1401, 1354, 1354, 1294, 1254, 1123
cm-1, 1H NMR (300 MHz, CDCl3) δ 1.16 (t, J = 7.5 Hz, 3H, CH3), 2.36
(s, 1H, CH3), 2.46–2.54 (m, 6H, CH2, CH2–N), 3.84 (t, J = 7.5 Hz, 4H,
CH2–N), 3.88 (s, 2H, CH2), 6.91–6.97 (m, 2H, ArH), 7.22 (td, J = 8.5
Hz, J = 1.5 Hz, 1H, ArH), 7.23 (s, 1H, NH), 7.40 (dd, J = 7.8 Hz, J = 1.5
Hz, 1H, ArH), 13C NMR (75 MHz, CDCl3) δ 13.3, 22.4, 32.9, 43.3, 48.7,
52.9, 105.8, 120.7, 122.0, 126.8, 128.2 133.2, 142.3, 158.9, 159.5, 163.6,
MS (m/z) 341 (M+), 270 (M – C4H9N). Anal. calcd for C18H23N5S: C,
63.31; H, 6.79; N, 20.51; S, 9.39; found: C, 63.25; H, 6.71; N, 20.43; S,
9.22%.
4-Methyl-2- (4-phenylpiperazin-1-yl)-5,11-dihydrobenzo[b]
pyrimido[4,5-e][1,4]thiazepine (6g): Yield 87%; white powder; m.p.
130–132 oC, IR (KBr disc) 3387, 3064, 2966, 2900, 2810, 2676, 1596,
1575, 1552, 1524, 1476, 1405, 1368, 1266, 1229, 1188, 1041, 1000 cm-1,
1H NMR (300 MHz, CDCl3) δ 2.34 (s, 3H, CH3), 3.22 (t, 4H, J = 5 Hz,
CH2), 3.85 (s, 2H, CH2), 3.93 (t, J = 5 Hz, 4H, CH2–N), 6.86–7.39 (m,
10H, ArH, NH), 13C NMR (75 MHz, CDCl3) δ 22.4, 32.9, 43.8, 49.5,
105.8, 116.5, 120, 120.9, 121.9, 127.1, 128.3, 129.2, 133.2, 142.2, 151.5,
159.0, 159.5, 163.6, MS (m/z) 389 (M+), 252 (M – C7H7NS). Anal. calcd
for C22H23N5S: C, 67.84; H, 5.95; N, 17.98; S, 8.23; found: C, 67.78; H,
5.88; N, 17.93; S, 8.18%.
6
7
8
9
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Received 17 May 2015; accepted 10 August 2015
Paper 1503368 doi: 10.3184/174751915X14401726334645
Published online: 1 September 2015
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