Synthesis of novel derivatives of (benz)imidazo[2,1-b]pyrimido[4,5-d][1,3] thiazine

Article abstract of DOI:10.3184/174751917X15132496997778

Several derivatives of the novel heterocyclic systems 2-substituted-imidazo- and benzimidazo-[2,1-b]pyrimido[4,5-d][1,3]thiazine have been synthesised through the one-pot cyclocondensation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine with imidazolidine-2thione and 1H-benzimidazole-2(3H)-thione and subsequently substituted by various secondary amines in moderately good yields.

Full text of DOI:10.3184/174751917X15132496997778

730 RESEARCH PAPER
VOL. 41 DECEMBER, 730–733
JOURNAL OF CHEMICAL RESEARCH 2017
Synthesis of novel derivatives of (benz)imidazo[2,1-b]pyrimido[4,5-d][1,3]
thiazine
Marzieh Akbarzadeh, Mehdi Bakavoli*, Hossein Eshghi and Ali Shiri
Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
Several derivatives of the novel heterocyclic systems 2-substituted-imidazo- and benzimidazo-[2,1-b]pyrimido[4,5-d][1,3]thiazine have
been synthesised through the one-pot cyclocondensation of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine with imidazolidine-2-
thione and 1H-benzimidazole-2(3H)-thione and subsequently substituted by various secondary amines in moderately good yields.
Keywords: pyrimidothiazine, imidazolidine, benzimidazole, one-pot cyclocondensation
The1,3-thiazinestructureplaysacrucialroleinpharmacological
and biologically active compounds.1–4 Among the 1,3-thiazine-
containing heteroaryl-fused structures, pyrimidothiazine
derivatives have attracted wide interest due to their considerable
biological activities, such as anti-inflammatory, antitumour,
antibacterial, antiallergic and antipyretic activity.5–9 Examples
of synthetic methods to prepare pyrimidothiazine-containing
compounds include the reaction of 4-methoxy- and 4-ethoxy-
5-amino-6-mercaptopyrimidines with diethyl bromomalonate
in the presence of potassium hydroxide,10 cyclisation of
mercaptopyrimidine with benzylidine malononitrile in ethoxide
solution,11 the treatment of ethyl-2-cyano-3,3-bis(methylthio)
acrylate and thiourea in the presence of potassium
carbonate in dimethylformamide,12 condensation reaction of
thioxopyrimidine derivatives and 3-bromopropionic acid,13
one-pot multicomponent reaction of aryl isocyanides, dialkyl
acetylenedicarboxylates and thiouracils14 and condensation of
5-amino-4-thiopyrimidines with desyl chloride in the presence
of sodium acetate.15
Moreover, imidazothiazines, as other thiazine-fused structures,
have often been used as scaffolds in medicinal chemistry. Some
medicinal properties of imidazothiazine derivatives consist
of anticancer, anti-leukemia, antifungal, anti-inflammatory
and antisecretory activities.16–19 There are various methods
reported for the synthesis of imidazothiazines, including the
reaction of 5,5-diphenyl-2-thiohydantoin with α,β-unsaturated
nitriles,20 cyclisation of 5,5-diphenyl-2-thiohydantoins with
1,3-dibromopropane under phase-transfer catalysis conditions,21
the reaction of 3,3-dichloro-2-phenylacryloyl chloride with
mercaptoimidazoles,22 one-step reaction of benzimidazoline-
2-thione with cinnamoyl chloride23 and cyclisation of
benzimidazolethiones with ethyl 3-chloro-but-2-enoate.24
Considering the pharmacological and biological activities
of pyrimidothiazines and imidazothiazines and as part of
our ongoing studies dealing with the synthesis of various
fused pyrimidines,25–31 we describe here a facile synthesis
and structural elucidation of 2-substituted-imidazo- and
benzimidazo-[2,1-b]pyrimido[4,5-d][1,3]thiazines 8a–e and
9a–e as novel heterocyclic systems that may be good candidates
in designing new biologically active compounds.
Results and discussion
Initially, the reaction of 6-methylpyrimidine-2,4-(1H,3H)-
dione 1 with formaldehyde in aqueous NaOH solution gave
5-(hydroxymethyl)-6-methylpyrimidine-2,4-(1H,3H)-dione
2, which was subsequently treated with POCl3 to produce
2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine 3.32 In
addition, imidazolidine-2-thione 4 and 1H-benzimidazole-
2(3H)-thione 5, used as binucleophiles, were prepared in
quantitative yield according to the previously published
methods.33,34 The reaction of 2,4-dichloro-5-(chloromethyl)-6-
methylpyrimidine 3 with binucleophiles 4 and 5 in CHCl3 at
−15 °C gave 2-chloro-4-methyl-8,9-dihydro-5H-imidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine
6 and 2-chloro-4-methyl-5H-
benzimidazo[2,1-b]pyrimido[4,5-d][1,3]thiazine
7 as new
heterocyclic systems (Scheme 1).
This reaction goes forward through combined nucleophilic
substitution and an addition–elimination reaction involving the
nitrogen and sulfur atoms in the binucleophiles followed by
elimination of two molecules of HCl. The evidence in support of
initial halide displacement from the chloromethyl group, rather
than the 4-Cl substituent was obtained from the comparison of
1
the H chemical shifts of methylene groups bonded to sulfur
in thiazine moieties with the SCH2–Ar function reported in
H
N
N
S
l
C
N
N
N
H
4
N
S
CHCl3 , -15 oC
Et3N
H
C
3
H
N
H
N
l
C
N
l
C
6
O
O
O
O
H
2CO
P
l
OC 3
H
N
N
l
C
HN
HN
H
O
S
N
H
C
3
H
H
3
C
C
N
3
l
C
N
N
H
5
1
2
3
N
S
CHCl3 , -15 oC
Et3N
H
C
3
7
Scheme 1
* Correspondent. E-mail: mbakavoli@um.ac.ir; mbakavoli@yahoo.com

JOURNAL OF CHEMICAL RESEARCH 2017 731
N
N
l
C
N
C
N
R2N
N
C
N
R2NH
N
N
S
EtOH, reflux
S
H
H
3
3
6
8a-e
N
N
l
C
N
N
R2N
N
N
R2NH
EtOH, reflux
N
N
S
S
H
C
H
C
3
3
7
9a-e
Entry
R2N-
8a,9a
8b,9b
8c,9c
8d,9d
3C
8e,9e
H
3C
H
Ph
O
N
N
N
N
N
N
N
Scheme 2
the literature (δ 3.8–4.2 ppm for CH2S).35–37 These literature
data are in accordance with the 1H chemical shifts of the CH2S
moiety in the synthesised compounds 6 and 7 (δ 3.93 and 4.07
ppm, respectively).
54.0, 66.9 and 98.5 ppm for the aliphatic carbons of the desired
compound 8b and four signals for its unsaturated carbons
appearing at 156.3, 159.9, 160.1 and 161.7 ppm. The mass
spectrum of compound 8b showed the molecular ion peak at
m/z 291 (M+) related to the molecular formula of C13H17N5OS.
The structural elucidation of these compounds was
accomplished from their physical, chemical and spectral
data. In the IR spectrum of the two synthesised compounds 6
Conclusion
1
and 7, the NH vibration of the precursors was absent. The H
We have successfully synthesised novel tri- and tetracyclic
2-substituted-imidazo- and benzimidazo-[2,1-b]pyrimido[4,5-d]
[1,3]thiazines 8a–e and 9a–e through the initial treatment of
2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine 3 with imid-
azolidine-2-thione 4 and 1H-benzimidazole-2(3H)-thione 5
to produce 2-chloro-4-methyl-8,9-dihydro-5H-imidazo[2,1-b]
NMR spectrum of compound 6 revealed two singlet signals
at δ 2.50 and 3.93 ppm due to methyl and thiomethylene
groups, respectively, and a multiplet signal at δ 4.02–4.12 ppm
attributed to the methylene group protons in the imidazole ring.
The 13C NMR spectrum plainly demonstrated nine signals for
the carbons of the desired compound.
pyrimido[4,5-d][1,3]thiazine
benzimidazo[2,1-b]pyrimido[4,5-d][1,3]thiazine
6
and 2-chloro-4-methyl-5H-
as new
Also, in the 1H NMR spectrum of compound 7, the presence
of two singlet signals at δ 2.59 and 4.07 ppm belonging to
methyl and methylene group protons and the multiplet signals
in the range 7.26–8.35 ppm corresponding to the aryl hydrogens
confirmed the structure of the new heterocyclic system. The
13C NMR spectrum showed two signals at δ 22.3 and 24.2
ppm assigned to the carbons of the methyl and methylene
carbons and eleven signals at δ 111.6, 115.6, 119.1, 124.6, 125.1,
132.5, 143.6, 148.4, 155.5, 158.9 and 167.1 ppm are attributed
to the unsaturated carbons. The mass spectrum also showed
the molecular ion peak at m/z 288 (M+) corresponding to the
molecular formula of C13H9ClN4S.
Further investigation was performed via nucleophilic
substitution of the 2-Cl substituent with various secondary
amines in boiling ethanol to synthesise substituted derivatives
of the new heterocyclic rings 8a–e and 9a–e in good to excellent
yields (Scheme 2).
7
heterocyclic systems, which were further substituted with various
sec-amines to obtain products 8a–e and 9a–e.
Experimental
Melting points were recorded on an Electrothermal type 9200 melting
point apparatus. The IR spectra were obtained on an Avatar 370 FTIR
Thermo Nicolet spectrophotometer and only noteworthy absorptions
1
are listed. The H NMR (300 MHz) and 13C NMR (75 MHz) spectra
were recorded on a Bruker Avance DRX-400 Fourier transform
spectrometer. Chemical shifts are 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.
Synthesis of 2-chloro-4-methyl-8,9-dihydro-5H-imidazo[2,1-b]pyrimido-
[4,5-d][1,3]thiazine (6)
Imidazolidine-2-thione 4 (1 mmol, 0.1g) in DMF (1 mL) was added
dropwise to a stirred solution of 2,4-dichloro-5-(chloromethyl)-6
methylpyrimidine 3 (1 mmol, 0.211g) and triethylamine (2 mmol,
0.2 g) in CHCl3 (2 mL) with vigorous stirring at −15 °C. After 4 h,
distilled water (10 mL) was added and the mixture was extracted with
chloroform (3 × 5 mL). The combined organic solvents were dried
over anhydrous sodium sulfate and concentrated to give compound 6
as a white powder; yield 85%; m.p. 190–192 °C; IR (KBr disc) (υmax
cm−1): 3007, 2966, 2944, 2864, 1593, 1568, 1544, 1474, 1365, 1299,
The structural assignments of the synthesised compounds
were confirmed by recording their elemental analyses and
1
spectral data. The H NMR spectrum of product 8b, as an
example, showed two singlet signals at δ 2.35 and 3.85 ppm
assigned to the hydrogens of the CH3 group of the pyrimidine
and CH2 unit of the thiazine rings and two multiple signals in
the regions δ 3.74–3.79 and 3.97–4.06 ppm due to protons from
the morpholine and imidazole rings, respectively. The 13C NMR
spectrum clearly showed seven signals at 21.9, 23.7, 44.2, 45.4,
1
1275, 1195, 1160, 1127; H NMR (300 MHz, CDCl3): δ 2.50 (s, 3H,

732 JOURNAL OF CHEMICAL RESEARCH 2017
CH3–pyrimidine), 3.93 (s, 2H, CH2–thiazine), 4.02–4.12 (m, 4H, CH2–
imidazole); 13C NMR (75 MHz, CDCl3): δ 21.6 (CH3), 23.4 (CH2–S),
45.7 (CH2–N), 54.4 (CH2–N), 108.0, 154.7, 157.1, 158.7, 163.4; MS
(m/z): 240 (M+). Anal. calcd for C9H9ClN4S: C, 44.91; H, 3.77; N,
23.28; S, 13.32; found: C, 44.87; H, 3.74; N, 23.15; S, 13.30%.
and CH2–thiazine), 4.74 (d, J = 13.2 Hz, 2H, equatorial hydrogens of
CH2–N); 13C NMR (75 MHz, CDCl3): δ 21.9 (CH3), 22.0 (CH3), 23.8
(CH), 31.3 (CH2), 34.1 (CH2–S), 44.1 (CH2–N), 45.4 (CH2–N), 54
(CH2–N), 97.4, 156.3, 157.2, 160.1, 161.6; MS (m/z): 303 (M+). Anal.
calcd for C15H21N5S: C, 59.38; H, 6.98; N, 23.08; S, 10.57; found: C,
69.41; H, 7.02; N, 23.15; S, 10.61%.
4-Methyl-2- (4-methylpiperazin-1-yl) - 8 ,9-dihydro-5H-
imidazo[2,1-b]pyrimido[4,5-d][1,3] thiazine (8d): White powder;
yield 72%; m.p. 146–148 °C; IR (KBr disc) (υmax cm−1): 3011, 2966,
2946, 2925, 2848, 2799, 2774, 1597, 1576, 1443, 1363, 1307, 1249,
1201, 1118, 1003; 1H NMR (300 MHz, CDCl3): δ 2.34 (br s, 6H,
CH3–pyrimidine and CH3–piperazine), 2.45 (t, J = 5.1 Hz, 4H, CH2–
piperazine), 3.81–3.84 (m, 6H, CH2–piperazine and CH2–thiazine),
4.00 (br s, 4H, CH2–imidazole); 13C NMR (75 MHz, CDCl3): δ 21.9
(CH3), 23.8 (CH2–S), 43.7 (CH3–N), 45.4 (CH2–N), 46.3 (CH2–N),
54.0 (CH2–N), 55.0 (CH2–N), 98.1, 156.3, 157.0, 160.1, 161.7; MS
(m/z): 304 (M+), 276 (M+ − C2H6). Anal. calcd for C14H20N6S: C,
55.24; H, 6.62; N, 27.61; S, 10.53; found: C, 55.21; H, 6.58; N, 27.54;
S, 10.49%.
Synthesis of 2-chloro-4-methyl-5H-benzimidazo[2,1-b]pyrimido-
[4,5-d][1,3]thiazine (7)
A solution of 1H-benzimidazole-2(3H)-thione 5 (1 mmol, 0.15 g) in
DMF (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 4 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 to give compound 7 as a white powder; yield 73%; m.p. 205–207
°C; IR (KBr disc) (υmax cm−1): 3088, 3019, 2962, 2925, 2855, 2789,
2692, 2606, 1567, 1549, 1479, 1462, 1415, 1323, 1298, 1238, 1183, 1150;
1H NMR (300 MHz, CDCl3): δ 2.59 (s, 3H, CH3–pyrimidine), 4.07 (s,
2H, CH2–thiazine), 7.26–7.34 (m, 2H, ArH), 7.59–7.61 (m, 1H, ArH),
8.32–8.35 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3): δ 22.3 (CH3),
24.2 (CH2–S), 111.6, 115.6, 119.1, 124.6, 125.1, 132.5, 143.6, 148.4,
155.5, 158.9, 167.1; MS (m/z): 288 (M+). Anal. calcd for C13H9ClN4S:
C, 54.07; H, 3.14; N, 19.40; S, 11.10; found: C, 54.04; H, 3.10; N, 19.31;
S, 11.04%.
4-Methyl-2- (4-phenylpiperazin-1-yl) - 8 ,9-dihydro-5H-
imidazo[2,1-b]pyrimido[4,5-d][1,3] thiazine (8e): White powder;
yield 84%; m.p. 242–246 °C; IR (KBr disc) (υmax cm−1): 3060, 2962,
2861, 2799, 2745, 1601, 1573, 1509, 1443, 1372, 1322, 1269, 1227, 1151,
1
1116; H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H, CH3–pyrimidine),
3.25 (t, J = 5.1 Hz, 4H, CH2–piperazine), 3.88 (s, 2H, CH2 of thiazine),
3.99 (t, J = 5.1 Hz, 4H, CH2 of piperazine), 4.05 (br s, 4H, CH2 of
imidazole), 6.92 (t, J = 7.2 Hz, 1H, phenyl), 7.01 (d, J = 8.1 Hz, 1H,
phenyl), 7.32 (t, J = 8.4 Hz, 2H, phenyl); 13C NMR (75 MHz, CDCl3):
δ 21.9 (CH3), 23.8 (CH2–S), 43.8 (CH2–N), 45.4 (CH2–N), 49.5
(CH2–N), 54.3 (CH2–N), 98.4, 116.6, 120.2, 129.2, 151.5, 156.4, 157.0,
160.1, 161.8; MS (m/z): 366 (M+). Anal. calcd for C19H22N6S: C, 62.27;
H, 6.05; N, 22.93; S, 8.75; found: C, 62.24; H, 6.03; N, 23.82; S, 8.71%.
Synthesis of 2-substituted-4-methyl-8,9-dihydro-5H-imidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine (8a–e); general procedure
A
mixture of 2-chloro-4-methyl-8,9-dihydro-5H-imidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine 6 (1 mmol, 0.24 g) and the appropriate
secondary amine (3 mmol) in ethanol (5 mL) was refluxed for
4 h. After reaction completion, which was monitored by TLC using
chloroform/methanol (30:1), the solvent was concentrated and the
resulting white precipitate was filtered. The resulting solid was
purified using silica gel column chromatography with hexane/ethyl
acetate (8:1) as eluent.
Synthesis of 2-substituted-4-methyl-5H-benzimidazo[2,1-b]pyrimido-
[4,5-d][1,3]thiazines (9a–e); general procedure
The appropriate secondary amine (3 mmol) was added to a stirred
solution of 2-chloro-4-methyl-5H-benzimidazo[2,1-b]pyrimido[4,5-d]
[1,3]thiazine (7) (1 mmol, 0.29 g) in EtOH (5 mL) and the solution was
refluxed for 4 h. After being cooled to room temperature, the resulting
precipitate was filtered off and washed with ethanol (3 mL).
4 - Methyl-2- (pyrrolidin-1-yl) -5 H- benzimidazo [2 ,1-b]
pyrimido[4,5-d][1,3]thiazine (9a): White powder; yield 91%;
m.p. 155–157 °C; IR (KBr disc) (υmax cm−1): 3052, 2962, 2861, 1614,
1583, 1540, 1447, 1341, 1272, 1220, 1169, 1112; 1H NMR (300 MHz,
CDCl3): δ 2.07 (t, J = 6.3 Hz, 4H, CH2–pyrrolidine), 2.50 (s, 3H,
CH3–pyrimidine), 3.70 (br s, 4H, CH2–N), 4.07 (s, 2H, CH2–thiazine),
7.31–7.36 (m, 2H, ArH), 7.68–7.72 (m, 1H, ArH), 8.47–8.53 (m,
1H, ArH); 13C NMR (75 MHz, CDCl3): δ 22.4 (CH3), 24.4 (CH2),
25.3 (CH2–S), 46.9 (CH2–N), 99.9, 115.3, 118.8, 123.5, 123.9, 133.1,
143.6, 149.8, 154.6, 158.5, 164.6; MS (m/z) 323 (M+). Anal. calcd for
C17H17N5S: C, 63.13; H, 5.30; N, 21.65; S, 9.91; found: C, 63.16; H, 5.32;
N, 21.73; S, 9.95%.
4-Methyl-2-(pyrrolidin-1-yl)-8,9-dihydro-5H-imidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine (8a): White powder; yield 75%; m.p.
158–160 °C; IR (KBr disc) (υmax cm−1): 2966, 2921, 2865, 1597,
1
1576, 1528, 1442, 1348, 1242, 1208, 1114; H NMR (300 MHz,
CDCl3): δ 1.96 (t, J = 6.4 Hz, 4H, CH2–pyrrolidine), 2.35 (s, 3H,
CH3–pyrimidine), 3.56 (t, J = 6.4 Hz, 4H, CH2–N), 3.86 (s, 2H, CH2–
thiazine), 4.02 (br s, 4H, CH2–imidazole); 13C NMR (70 MHz, CDCl3):
δ 21.9 (CH3), 23.9 (CH2), 25.5 (CH2–S), 45.4 (CH2–N), 46.5 (CH2–N),
54.0 (CH2–N), 97.2, 156.2, 157.3, 159.0, 161.5; MS (m/z): 275 (M+).
Anal. calcd for C13H17N5S: C, 56.70; H, 6.22; N, 25.43; S, 11.64; found:
C, 56.65; H, 6.19; N, 25.35; S, 11.61%.
4-(4-Methyl-8,9-dihydro-5H-imidazo[2,1-b]pyrimido[4,5-d]
[1,3]thiazin-2-yl) morpholine (8b): White powder; yield 81%; m.p.
172–174 °C; IR (KBr disc) (υmax cm−1): 3004, 2967, 2913, 2863, 1593,
1574, 1503, 1442, 1305, 1263, 1129, 1111; 1H NMR (300 MHz, CDCl3):
δ 2.35 (s, 3H, CH3–pyrimidine), 3.74–3.79 (m, 8H, CH2–morpholine),
3.85 (s, 2H, CH2–thiazine), 3.97–4.06 (m, 4H, CH2–imidazole);
13C NMR (75 MHz, CDCl3): δ 21.9 (CH3), 23.7 (CH2–S), 44.2
(CH2–N), 45.4 (CH2–N), 54.0 (CH2–N), 66.9 (CH2–O), 98.5, 156.3,
159.9, 160.1, 161.7; MS (m/z): 291 (M+), 205 (M+ − C9H9N4S). Anal.
calcd for C13H17N5OS: C, 53.59; H, 5.88; N, 24.04; S, 11.00; found: C,
53.61; H, 5.92; N, 24.11; S, 11.03%.
4-(4-Methyl-5H-benzimidazo[2,1-b]pyrimido[4,5-d][1,3]thiazin-
2-yl)morpholine (9b): White powder; yield 85%; m.p. 142–144 °C;
IR (KBr disc) (υmax cm−1): 2982, 2962, 2856, 1638, 1613, 1583, 1545,
1
1473, 1445, 1362, 1298, 1260, 1171, 1114, 1070, 1008; H NMR (300
MHz, CDCl3): δ 2.51 (s, 3H, CH3–pyrimidine), 3.84 (t, J = 3.9 Hz, 4H,
CH2–morpholine), 3.92 (t, J = 3.9 Hz, 4H, CH2–morpholine), 4.06 (s,
2H, CH2–thiazine), 7.31–7.37 (m, 2H, ArH), 7.68–7.72 (m, 1H, ArH),
8.29–8.33 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3): δ 22.5 (CH3),
24.4 (CH2–S), 44.5 (CH2–N), 66.8 (CH2–O), 101.7, 114.8, 118.9, 123.6,
124.1, 132.8, 143.6, 149.9, 154.8, 160.0, 165.0; MS (m/z): 339 (M+), 280
(M+ − Cl), 239 (M+ − C6H4). Anal. calcd for C17H17N5OS: C, 60.16; H,
5.05; N, 20.63; S, 9.45; found: C, 60.13; H, 5.02; N, 20.52; S, 9.41%.
4-Methyl-2-(4-methylpiperidin-1-yl)-5H-benzimidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine (9c): White powder; yield 87%; m.p.
110–112 °C; IR (KBr disc) (υmax cm−1): 2999, 2985, 2933, 2856, 2790,
2680, 1614, 1598, 1581, 1539, 1446, 1409, 1361, 1296, 1263, 1213,
4-Methyl-2- (4-methylpiperidin-1-yl) - 8 ,9- dihydro-5H-
imidazo[2,1-b]pyrimido[4,5-d][1,3] thiazine (8c): White powder;
yield 78%; m.p. 126–128 °C; IR (KBr disc) (υmax cm−1): 2998, 2952,
2919, 2867, 2844, 1597, 1578, 1553, 1442, 1374, 1313, 1250, 1219,
1
1121, 1079, 1023; H NMR (300 MHz, CDCl3): δ 0.97 (d, 3H, CH3–
piperidine), 1.08–1.21 (m, 3H, axial hydrogens of CH2 and CH of
piperidine), 1.60–1.72 (m, 2H, equatorial hydrogens of CH2), 2.34
(s, 3H, CH3–pyrimidine), 2.81 (t, J = 11.1 Hz, 2H, axial hydrogens of
CH2–N), 3.85 (s, 2H, CH2–imidazole), 4.01 (br s, 4H, CH2–imidazole

JOURNAL OF CHEMICAL RESEARCH 2017 733
1
2
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1169, 1141, 1003; H NMR (300 MHz, CDCl3): δ 0.9 (d, J = 6.3 Hz,
3H, CH3–piperidine), 1.05–1.17 (m, 2H, axial hydrogens of CH2),
1.57–1.70 (m, 3H, equatorial hydrogens of CH2 and CH–piperidine),
2.36 (s, 3H, CH3–pyrimidine), 2.86 (t, J = 12 Hz, 2H, axial hydrogens
of CH2–N), 3.92 (s, 2H, CH2–thiazine), 4.71 (d, J = 13 Hz, 2H,
equatorial hydrogens of CH2–N), 7.18–7.23 (m, 2H, ArH), 7.57–7.60
(m, 1H, ArH), 8.23–8.26 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3):
δ 21.9 (CH3), 22.6 (CH3), 24.5 (CH), 31.3 (CH2), 34.0 (CH2–S), 44.5
(CH2–N), 100.4, 114.9, 118.8, 123.5, 123.9, 132.9, 143.7, 150.0, 154.7,
159.9, 164.8. Anal. calcd for C19H21N5S: C, 64.93; H, 6.02; N, 19.93; S,
9.12; found: C, 64.96; H, 5.98; N, 20.02; S, 9.15%.
3
4
5
6
7
8
9
4-Methyl-2-(4-methylpiperazin-1-yl)-5H-benzimidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine (9d): White powder; yield 85%; m.p.
140–142 °C; IR (KBr disc) (υmax cm−1): 2999, 2958, 2933, 2856, 2790,
2680, 1614, 1598, 1581, 1539, 1446, 1361, 1296, 1274, 1213, 1169, 1142;
1H NMR (300 MHz, CDCl3): δ 2.38 (s, 3H, CH3–pyrimidine), 2.46
(s, 3H, CH3–piperazine), 2.53 (t, J = 4.8 Hz, 4H, CH2–piperazine),
3.94 (t, J = 4.8 Hz, 4H, CH2–piperazine), 4.00 (s, 2H, CH2–thiazine),
7.29–7.32 (m, 2H, ArH), 7.65–7.68 (m, 1H, ArH), 8.28–8.31 (m, 1H,
ArH); 13C NMR (75 MHz, CDCl3): δ 22.5 (CH3), 24.4 (CH2–S), 43.9
(CH3–N), 46.2 (CH2–N), 54.9 (CH2–N), 101.2, 114.8, 118.9, 123.5,
123.9, 132.8, 143.7, 149.9, 154.7, 159.9, 164.9; MS (m/z): 352 (M+), 276
(M+ − C6H4). Anal. calcd for C18H20N6S: C, 61.34; H, 5.72; N, 23.84; S,
9.10; found: C, 61.36; H, 5.75; N, 23.90; S, 9.14%.
4-Methyl-2-(4-phenylpiperazin-1-yl)-5H-benzimidazo[2,1-b]
pyrimido[4,5-d][1,3]thiazine (9e): White powder; yield 82%; m.p.
242–243 °C; IR (KBr disc) (υmax cm−1): 3052, 2974, 2896, 2853, 2827,
1617, 1597, 1544, 1490, 1445; 1H NMR (300 MHz, CDCl3): δ 2.53 (s,
3H, CH3–pyrimidine), 3.34 (t, J = 5.1 Hz, 4H, CH2–piperazine), 4.07
(s, 2H, CH2–thiazine), 4.11 (t, J = 5.1 Hz, 4H, CH2–piperazine), 6.94
(t, J = 7.2 Hz, 1H, ArH), 7.04 (d, J = 8.1 Hz, 2H, ArH), 7.32–7.40 (m,
4H, ArH), 7.69–7.74 (m, 1H, ArH), 8.35–8.41 (m, 1H, ArH); 13C NMR
(75 MHz, CDCl3): δ 22.6 (CH3), 24.4 (CH2–S), 44.0 (CH2–N), 49.4
(CH2–N), 101.5, 114.9, 116.6, 118.9, 120.3, 123.6, 124.1, 129.3, 132.8,
143.8, 149.9, 151.3, 154.8, 159.9, 165.0; MS (m/z): 414 (M+). Anal. calcd
for C23H22N6S: C, 66.64; H, 5.35; N, 20.27; S, 7.74; found: C, 66.61; H,
5.32; N, 20.19; S, 7.71%.
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Acknowledgement
The authors gratefully acknowledge the Research Council of
Ferdowsi University of Mashhad for financial support of this
project (3/25480).
Electronic Supplementary Information
1
The H and 13C NMR spectra for all new compounds are
available in the ESI through http://ingentaconnect.com/content/
stl/jcr/2017/00000041/00000012/art00014
Received 5 November 2017; accepted 13 December 2017
Paper 1705082
https://doi.org/10.3184/174751917X15132496997778
Published online: 18 December 2017
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