Pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazines as a new heterocyclic system

Article abstract of DOI:10.3184/174751913X13738978141695

Six novel 2-substituted pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazines were prepared via a multistep synthetic sequence beginning with 5-bromo-2,4-dichloro-6-methylpyrimidine. Website

Full text of DOI:10.3184/174751913X13738978141695

JOURNAL OF CHEMICAL RESEARCH 2013
SEPTEMBER, 553–555
RESEARCH PAPER 553
Pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazines as a new heterocyclic
system
a
a
a
b
Hossein Eshghi *, Mohammad Rahimizadeh , Sattar Saberi , Khalil Abnous and
a
Mehdi Bakavoli
a
Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, 91775-1436 Mashhad, Iran
bPharmaceutical Research Center, Department of Medicinal Chemistry, School of Pharmacy, Mashhad University of Medical Sciences,
Mashhad, Iran
Six novel 2-substituted pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazines were prepared via a multistep synthetic
sequence beginning with 5-bromo-2,4-dichloro-6-methylpyrimidine.
Keywords: pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazine, heterocyclisation, 5-bromo-2,4-dichloro-6-methylpyrimidine, tetrazole
1
1
Pyrimidine derivatives have recently found wide applications
as drugs. These compounds have been synthesised and evalu-
mind, and in continuation of our recent studies on the enzyme
inhibitory activity of pyrimido[5,4-e][1,2,4]triazolo[3,4-b]-
[1,3,4]thiadiazines against soybean 15-lipoxygenase, we
considered the synthesis of pyrimidotetrazolothiadiazine
compounds where the biologically active pyrimido[4,5-e]-
[1,3,4]thiadiazine moiety is fused to a potent pharmacophoric
tetrazole ring across the 6,7-positions.
1
2
3
ated as anti-HIV-1, anticancer, and anti-inflammatory agents
4
and as RET kinase inhibitors. Moreover, these derivatives
can be used as precursors in the synthesis of fused ring com-
pounds like spiro[pyrimido[4,5-b]quinoline-5,5′-pyrrolo[2,3-d]-
5
6
pyrimidine] derivatives, pyrimido[4,5-b][1,4]benzothiazines,
7
thiazolo[4,5-d]pyridazines as antibacterial agents and pyrim-
ido-isoxazolidine as a selective hydride donor.
We now describe the synthesis of six novel 2-substituted
pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazines 5a–f.
8
Pyrimido[4,5-e][1,3,4]thiadiazines are a class of heterocy-
9
clic compounds that have been described as anti-hypertensive,
Results and discussion
anti-inflammatory, analgesic, antipyretic and anti-allergic
The starting material 5-bromo-2,4-dichloro-6-methylpyrimi-
10
agents. However, there are only a few reports for the synthe-
sis of pyrimidothiadiazines fused to other heterocyclic rings.
dine 1 was prepared according to our previously published
1
5
method. Treatment of compound 1 with sodium 1-amino-1H-
tetrazole-5-thiolate 2 which was prepared from the reaction of
1
1
Bakavoli and colleagues have recently described the synthe-
ses of pyrimido[5,4-e][1,2,4]triazolo[3,4-b][1,3,4]thiadiazines
and evaluated their 15-lipoxygenase inhibitory activity.
1
6,17
methyl dithiocarbazate (H NNHCS Me)
with sodium azide
2
2
afforded intermediate 3. Subsequent reaction of compound 3
with various secondary amines led to the selective replacement
of the C-2 chlorine function in the pyrimidine ring to produce
the corresponding diheteroaryl sulfide intermediates 4a–f. The
latter compounds subsequently underwent an intramolecular
S Ar reaction in the presence of NaNH in boiling acetonitrile
1
2
Santagati and colleagues synthesised some derivatives of
thieno[2′,3′:4,5]pyrimido[2,1-b][1,3,4]thiadiazine as analgesic,
anti-inflammatory and ulcerogenic agents.
In addition, tetrazole derivatives have been attracting atten-
tion due to their diverse pharmacological properties. For
N
2
1
3
example, Angiotensin II receptor blockers such as losartan
to give the desired tricyclic pyrimido[5,4-e]tetrazolo[5,1-b]-
[1,3,4]thiadiazines 5a–f. (Scheme 1)
14
and candesartan, contain a tetrazole ring. Keeping this in
Scheme 1
*
Correspondent. E-mail: heshghi@um.ac.ir

5
54 JOURNAL OF CHEMICAL RESEARCH 2013
The structural assignment of compounds 5a–f were based
on spectroscopic and micro analytical data. For example, the
H NMR spectrum of 5f showed one singlet peak at δ 2.41 in
(CDCl ): 24.7, 43.9, 66.4, 103.2, 147.2, 158.6, 163.3, 166.7; IR (KBr
3
1 +
−
disc): ν 3339, 3248, 2962, 1555, 771 cm ; MS (m/z) 356 (M ), 358
max
+
1
(M + 2). Anal. Calcd for C H BrN S: C, 33.62; H, 3.67; N, 31.37; S,
10 13
8
8
.98. Found: C, 33.58; H, 3.62; N, 31.30; S, 8.81%.
-[(5-Bromo-6-methyl-2-(piperidino)pyrimidin-4-yl)thio]-1H-
dimethyl sulfoxide-d , belonging to the methyl group of the
6
5
pyrimidine moiety. Whereas the spectrum of the precursor 4f
1
tetrazol-1-amine (4b): White powder; yield 81%; m.p. 180 °C; H
NMR (CDCl ): δ 1.49–1.65 (m, 6H, 3CH ), 2.42 (S, 3H, CH ), 3.42–
showed the NH signals at δ 5.58 that disappeared upon addi-
2
1
3
2
3
tion of D O, the H NMR spectrum of the cyclised product 5f
2
3
.58 (m, 4H, CH N), 5.59 (s, 2H, NH , D O exchangeable); IR (KBr
2 2 2
+
did not show this peak. Instead, an exchangeable broad singlet
−1
disc): ν 3325, 3235, 2929, 2847, 1559, 768 cm ; MS (m/z) 370 (M ),
372 (M + 2).
at 10.92 ppm in DMSO-d confirmed that heterocylisation of
+
6
5
f had occurred. The IR spectrum was devoid of the NH
5-[(5-Bromo-6-methyl-2-(4-methylpiperidin-1-yl)pyrimidin-4-
2
−
1
absorption bands at νmax 3331 and 3303 cm of the precursor,
but an absorption band at νmax 3348 cm− demonstrated the
existence of the NH group in the product 5f. The mass
yl)thio]-1H-tetrazol-1-amine (4c): White powder; yield 82%; m.p.
1
1
155–156 °C; H NMR (CDCl ): δ 0.87 (d, J = 9 Hz, 3H, CH ), 1.45–
3
3
1
.71 (m, 5H, CH and 2CH ), 2.42 (s, 3H, CH ), 2.51–2.82 (m, 2H,
2
3
+
equatorial hydrogens of CH N), 4.11–4.35 (m, 2H, axial hydrogens of
2
13
spectrum of 5f showed a molecular ion signal at m/z 291 (M )
CH N), 5.67 (s, 2H, NH , D O exchangeable); C NMR (CDCl ):
2
2
2
3
corresponding to the molecular formula C H N OS.
1
0
12
8
2
1.7, 24.7, 30.9, 33.7, 44.2, 101.9, 147.3, 158.4, 162.9, 166.6; IR
In summary, an interesting fused ring system containing the
pyrimido[5,4-e]tetrazolo[5,1-b][1,3,4]thiadiazine residue was
synthesised through the treatment of 5-bromo-2,4-dichloro-6-
methyl-pyrimidine 1 with sodium 1-amino-1H-tetrazole-5-
thiolate 2 which was subsequently reacted with secondary
amines and cyclised in presence of NaNH in boiling CH CN.
−
1
(
KBr disc): ν 3349, 3239, 2949, 1601,1552, 771 cm ; MS (m/z)
max
+ +
3
4
8
84 (M ), 386 (M + 2). Anal. Calcd for C H BrN S: C, 37.41; H,
12 17 8
.45; N, 29.08; S, 8.32. Found: C, 37.29; H, 4.41; N, 28.87; S,
.21%.
5
-[(5-Bromo-6-methyl-2-(4-methylpiperazin-1-yl)pyrimidin-4-yl)-
2
3
thio]-1H-tetrazol-1-amine (4d): White powder; yield 83%; m.p.
1
1
83 °C; H NMR (CDCl ) δ 2.27 (s, 3H, CH ), 2.31 (app. t, 4H,
3 3
2
CH N), 2.44 (s, 3H, CH ), 3.45 (app. t, 4H, 2CH N), 5.63 (s, 2H,
2
3
2
Experimental
NH , D O exchangeable); IR (KBr disc): ν 3304, 3247, 2937, 1551,
2
2
−
max
Melting points were taken on an Electrothermal type 9100 melting
point apparatus and are uncorrected. The IR spectra were obtained in
1
+
+
+
7
75 cm ; MS (m/z) 385 (M ), 387 (M + 2), 389 (M + 4). Anal. Calcd
for C H BrN S: C, 34.20; H, 4.18; N, 32.63; S, 8.30 Found: C, 34.05;
11
16
9
KBr disks on an Avatar 370 FT-IR Thermo-Nicolet spectrometer (ν
max
H, 4.01; N, 32.55; S, 7.98%.
-[(5-Bromo-6-methyl-2-(4-phenylpiperazin-1-yl)pyrimidin-4-yl)-
thio]-1H-tetrazol-1-amine (4e): White powder; yield 78%; m.p.
−1
1
in cm ). The H NMR (100 MHz) spectra were recorded on a Bruker
5
13
AC 100 spectrometer and C NMR (100 MHz) spectra were recorded
on a Bruker AV 400 MHz spectrometer for solutions in either CDCl3
or DMSO-d6 using TMS as internal standard. The Mass spectra
were obtained on a Varian Mat CH-7 and Agilent 5973 instruments at
1
1
95 °C; H NMR (CDCl ): δ 2.44 (s, 3H, CH ), 3.13 (app. t, 4H,
3
3
2
CH N), 3.59 (app. t, 4H, 2CH N), 5.58 (s, 2H, NH , D O exchangea-
2
2
2
2
13
ble), 6.84–6.95 (m, 3H, aromatic), 7.21–7.31 (m, 2H, aromatic;
NMR (CDCl ) 24.3, 43.4, 49.3, 103.1, 116.7, 120.8, 129.3, 147.2,
C
70 eV. Elemental analysis was performed on a Thermo Finnigan Flash
3
EA microanalyser.
1
50.4, 158.5, 163.3, 166.7; IR (KBr disc): ν 3376, 3219, 2949,
max
1 + +
Sodium 1-amino-1H-tetrazole-5-thiolate (2): Methyl dithiocarba-
−
16,17
1583, 1547, 1502, 1445, 797 cm ; MS (m/z) 447 (M ), 448 (M + 1),
zate
(27.5 g, 225 mmol) and sodium azide 97% (15.1 g, 225 mmol)
+
4
49 (M + 2).
-[(5-Bromo-6-methyl-2-morpholinopyrimidin-4-yl)thio]-1H-
were added to a mixture of ethanol (300 mL) and water (80 mL), and
the mixture was refluxed for 17 h. After the reaction, the mixture was
evaporated at 45 °C under reduced pressure to remove solvent. Then,
ethanol (150 mL) was added to the residue, and the resultant precipi-
tate was collected by filtration. The precipitate was washed with etha-
5
1
tetrazol-1-amine (4f): White powder; yield 89%; m.p. 193 °C; H
NMR (CDCl ): δ 2.44 (s, 3H, CH ), 3.31–3.45 (m, 4H, CH N), 3.51–
3
3
2
3
.63 (m, 4H, CH O), 5.58 (br. s, 2H, NH , D O exchangeable); IR
2 2 2
1
−
(
KBr disc): ν 3331, 3239, 2969, 1553, 771 cm ; MS (m/z) 372
max
+ + +
nol and then dried, whereby sodium 1-amino-1H-tetrazole-5-thiolate
1
(M ), 374 (M + 2), 376 (M + 4).
(
26.6 g, 85%) was obtained as white powder; m.p. 88–90 °C; H NMR
(
100 MHz, DMSO-d ): δ 10.1 (br. s, 2H, NH ); IR (KBr disc): ν
424, 3272, 1657, 1607 cm . The product was also characterised by
6
2
max
−
1
Synthesis of compounds (5a–f); general procedure
A mixture of each of compounds 4a–f (10 mmol), NaNH (1.2 g,
30 mmol) in dry acetonitrile (50 mL) was heated under reflux for
3
2
conversion to the free thiol by careful acidification with dilute H SO
2
4
8
1
to give 1-amino-1H-tetrazole-5-thiol, m.p. 160–161 °C (dec.) [lit.
m.p. 162–163 °C (dec.)].
1
5–60 min. Progress of the reaction was monitored by TLC using
chloroform–methanol (10:1) or ethyl acetate-n-hexane (1:1) as eluent.
The mixture was cooled and the solvent was removed under reduced
pressure. Then, a solution of acetic acid (1 mL) in water (20 mL) was
added to the residue and the resulting precipitant was filtered off and
recrystallised from ethanol.
5
-[(5-Bromo-2-chloro-6-methylpyrimidin-4-yl)thio]-1H-tetrazol-
1
1
-amine (3): Compound 1 (20 mmol, 4.88 g) and sodium 1-amino-
H-tetrazole-5-thiolate 2 (20 mmol, 2.78 g) were dissolved in DMF
40 mL). The mixture was stirred for 2 h at room temperature and then
(
poured into water (150 mL). The resulting precipitate was filtered off
and washed with water (2 × 50 mL) and diethyl ether (20 mL), respec-
tively. After drying the solid 3 (6.2 g) was obtained as a pure product.
8
-Methyl-6-pyrrolidino-9H-pyrimido[5,4-e]tetrazolo[5,1-b]-
[
1,3,4]thiadiazine (5a): White powder; yield 67%; m.p. 211 °C (dec.);
1
1
H NMR (DMSO-d ): δ 1.61–1.95 (m, 4H, 2CH ), 2.35 (s, 3H, CH ),
Yield 95%; m.p. 170–172 °C; H NMR (100 MHz, CDCl ): δ 2.65 (s,
3
νmax 3300, 3145, 2957, 1528, 750 cm ; MS (m/z) 321 (M ), 323 (M +
2
6
2
3
3
2
.78–3.52 (m, 4H, 2CH N), 10.82 (s, 1H, NH, D O exchangeable). IR
2 2
1 +
H, CH ), 5.73 (br. s, 2H, NH , D O exchangeable); IR (KBr disc):
3
2
2
−
−
1
+
+
(KBr disc): νmax 3268, 3080, 2989, 1617 cm ; MS (m/z) 276 (M ).
+
+
Anal. Calcd for C H N S: C, 43.47; H, 4.38; N, 40.55; S, 11.60.
), 324 (M + 3), 325 (M + 4).
10 12
8
Found: C, 43.59; H, 4.30; N, 40.35; S, 11.71%.
Synthesis of compounds (4a–f); general procedure
8-Methyl-6-piperidino-9H-pyrimido[5,4-e]tetrazolo[5,1-b]-
[1,3,4]thiadiazine (5b): White powder; yield 71%; m.p. 260 °C (dec.);
The appropriate secondary amine (30 mmol) was added to a stirred
mixture of compound 3 (10 mmol, 3.23 g) in ethanol (30 mL), and the
solution was heated under reflux for 10–60 min. Progress of the reac-
tion was monitored by TLC using chloroform–methanol (20:1) as
eluent. The solid obtained on cooling was filtered and recrystallised
from ethanol. Whilst 4b, 4e and 4f gave spectral data consistent with
homogenous compounds, completely satisfactory elemental analyses
could not be obtained; these compounds were, therefore, fully charac-
terised by conversion to the corresponding tricyclic derivative 5.
1
H NMR (DMSO-d ): δ 1.42–2.71 (m, 6H, 3CH ), 2.40 (s, 3H, CH ),
6
2
3
3.18–3.52 (m, 4H, CH N), 10.23 (s, 1H, NH, D O exchangeable);
2
2
13
C NMR (100 MHz, DMSO-d ): 21.5, 30.1, 33.2, 44.7, 115.6, 150.6,
152.1, 157.9, 165.6; IR (KBr disc): ν 3312, 2994, 1610 cm ; MS
(m/z) 290 (M ). Anal. Calcd for C H N S: C, 45.50; H, 4.86; N,
6
−1
max
+
11
14
8
38.59; S, 11.04. Found: C, 45.59; H, 4.75; N, 38.49; S, 11.11%.
8-Methyl-6-(4-methylpiperidin-1-yl)-9H-pyrimido[5,4-e]-tetra-
zolo[5,1-b][1,3,4]thiadiazine (5c): White powder; yield 74%; m.p.
1
5
-[(5-Bromo-6-methyl-2-(pyrrolidino)pyrimidin-4-yl)thio]-1H-
255 °C (dec.); H NMR (DMSO-d ): δ 0.83 (d, J = 8 Hz, 3H, CH ),
6
3
1
tetrazol-1-amine (4a): White powder; yield 80%; m.p. 177 °C; H
1.47–1.71 (m, 5H, CH and 2CH ), 2.33 (s, 3H, CH ), 2.51–2.91 (m,
2
3
NMR (CDCl ): δ 1.88–1.99 (m, 4H, 2CH ), 2.45 (s, 3H, CH ), 2.78–
2H, equatorial hydrogens of CH N), 3.83–4.41 (m, 2H, axial hydro-
3
2
3
3
2
1
3
.52 (m, 4H, 2CH N), 5.72 (s, 2H, NH , D O exchangeable); C NMR
gens of CH N), 11.52 (br. s, 1H, NH, D O exchangeable); IR (KBr
2
2
2
2
2

JOURNAL OF CHEMICAL RESEARCH 2013 555
−
1
+
disc): νmax 3333, 2948, 1600, 1546 cm ; MS (m/z) (M ) 304. Anal.
Calcd for C H N S: C, 47.35; H, 5.30; N, 36.81; S, 10.53. Found: C,
4
Received 30 April 2013; accepted 23 June 2013
Paper 1301917 doi: 10.3184/174751913X13738978141695
Published online: 6 September 2013
12
16
8
7.42; H, 5.33; N, 36.85; S, 10.61%.
-Methyl-6-(4-methylpiperazin-1-yl)-9H-pyrimido[5,4-e]tetra-
zolo[5,1-b][1,3,4]thiadiazine (5d): White powder; yield 75%; m.p.
8
1
References
2
4
1
55 °C (dec.); H NMR (DMSO-d ); δ 2.22 (s, 3H, CH ), 2.33 (app. t,
6
3
1
2
3
4
5
6
7
8
Y.P. Wang, F.E. Chen, E.D. Clercq, J. Balzarini and C. Pannecouque,
Eur. J. Med. Chem., 2009, 44, 1016.
Y.Y. Huang, L.Y. Wang, C.H. Chang, K. KuoKaneko, H. Takayama,
M. Kimura, S.H Juang and F.F. Wong, Tetrahedron, 2012, 68, 9658.
A.B.A. El-Gazzar, M.M. El-Enany and M.N. Mahmoud, Bioorg. Med.
Chem., 2008, 16, 3261.
P. Dinér, J.P. Alao, J. Söderlund, P. Sunnerhagen and M. Grøtli, J. Med.
Chem., 2012, 55, 4872.
K. Jadidi, R. Ghahremanzadeh and A. Bazgir, Tetrahedron, 2009, 65,
2005.
M. Bakavoli, M. Nikpour, M. Rahimizadeh, M.R. Saberi and H. Sadeghian,
Bioorg. Med. Chem., 2007, 15, 2120.
R. Kumar, R.R. Nair, S.S. Dhiman, J. Sharma and O. Prakash, Eur. J. Med.
Chem., 2009, 44, 2260.
I.A. Khan, V.M. Balaramnavar and K. Saxena, Tetrahedron, 2012, 68,
10122.
H, 2CH N), 2.43 (s, 3H, CH ), 3.42 (app. t, 4H, 2CH N), 10.66 (s,
H, NH, D O exchangeable); IR (KBr disc): ν 3247, 2948, 1549
cm ; MS (m/z) 305 (M ). Anal. Calcd for C H N S: C, 43.27; H,
.95; N, 41.28; S, 10.50. Found: C, 43.31; H, 4.93; N, 41.25; S,
0.61%.
-Methyl-6-(4-phenylpiperazin-1-yl)-9H-pyrimido[5,4-e]tetr-
azolo[5,1-b][1,3,4]thiadiazine (5e): White powder; yield 73%; m.p.
93–195 °C; H NMR (DMSO-d ): δ 2.36 (s, 3H, CH ), 2.45 (s, 3H,
6 3
CH ), 3.12 (m, 4H, 2CH N), 3.62 (m, 4H, 2CH N), 6.88–6.95 (m, 6H,
2
3
2
2
max
−1
+
11
15
9
4
1
8
1
1
3
2
2
aromatic), 7.25–7.35 (m, 4H, aromatic), 8.61 (s, 1H, NH, D O exchan-
geable). C NMR (DMSO-d ): 24.4, 43.2, 47.9, 115.7, 115.8, 119.2,
2
13
6
1
2
5
28.9, 150.7, 152.3, 157.9, 163.4, 166.8; IR (KBr disc): ν 3245,
max
1 +
−
954, 1585 cm ; MS (m/z) 367 (M ). Anal. Calcd for C H N S: C,
1
6
17
9
2.30; H, 4.66; N, 34.31; S, 8.73. Found: C, 52.37; H, 4.63; N, 34.33;
9
0
1
P.L. Anderson and R.E. Manning, US Patent 3 755 312 (1973).
T. Naka, T. Saijo and H. Satoh, EP Patent 1988/0307709 (1989).
M. Bakavoli, A. Shiri, S. Saberi, M. Gholami and H. Sadeghian, J. Chem.
Res., 2013, 37, 48.
A. Santagati, M. Modica, M. Antagati, V. Cutuli, D. Amore and A. Caruso,
Farmaco, 1995, 50, 605.
1
1
S, 8.81%.
8
[
-Methyl-6-morpholino-9H-pyrimido[5,4-e]tetrazolo[5,1-b]-
1,3,4]thiadiazine (5f): White powder; yield 70%; m.p. 195 °C (dec.);
H NMR (DMSO-d ): δ 2.03 (s, 3H, CH ), 3.42–3.75 (m, 4H, CH N
and 4H, CH O), 10.92 (br. s, 1H, NH, D O exchangeable); IR (KBr
disc): νmax 3248, 2966, 1642 cm ; MS (m/z) 291 (M ). Anal. Calcd for
C H N OS: C, 41.09; H, 4.14; N, 38.33; S, 10.97. Found: C, 41.15;
1
2
1
6
3
2
2
2
13 D.J. Carini, J.V. Duncia and P.C.B. Wong, US. Patent, 5 138 049 (1992).
14 K. Kubo, Y. Kohara, E. Imamiya, Y. Sugiura, Y. Inada and Y. Furukawa,
J. Med. Chem., 1993, 36, 2182.
−1
+
10
12
8
1
5
M. Bakavoli, M. Nikpour and M. Rahimizadeh, J. Heterocycl. Chem.,
006, 43, 1327.
S. Singh, P.K. Mandal, N. Singh, A. Misra, A.K. Saxena and S. Singh,
Bioorg. Med. Chem. Lett., 2010, 20, 2597.
W. Hu, Bioorg. Med. Chem. Lett., 2006, 16, 2213.
M.W. Urawa, S.H. Kawaguchi, T.Y. Urawa, S.O. Iwatsuki, US. Patent,
4 576 938, (1986).
H, 4.13; N, 38.39; S, 11.09%.
2
1
6
We are grateful to the Department of Chemistry, Ferdowsi
University of Mashhad, Iran for financial Support (Grant No.
1
1
7
8
3
/15421).

Copyright of Journal of Chemical Research is the property of Science Reviews 2000 Ltd. and
its content may not be copied or emailed to multiple sites or posted to a listserv without the
copyright holder's express written permission. However, users may print, download, or email
articles for individual use.