Mendeleev
Communications
Mendeleev Commun., 2008, 18, 284–285
Convenient synthesis of new
pyrimido[4,5-e][1,3,4]thiadiazine derivatives
Mohsen Nikpour,*a Mehdi Bakavoli,b Mohammad Rahimizadeh,b
Ali Javid Sabbaghiana and Mohammad Reza Bigdelia
a Department of Chemistry, School of Sciences, Islamic Azad University, Ahvaz Branch, Ahvaz, 61349-68875, Iran.
Fax: +98 611 332 8200; e-mail: nikpour_m@yahoo.com
b Department of Chemistry, School of Sciences, Ferdowsi University of Mashhad, Mashhad, 91775-1436, Iran
DOI: 10.1016/j.mencom.2008.09.020
New 3-alkylsulfanyl-7-chloro-5-methyl-1-phenyl-1H-pyrimido[4,5-e][1,3,4]thiadiazines were synthesized via the cyclocondensa-
tion of alkyl-2-phenylhydrazinecarbodithioates with 5-bromo-2,4-dichloro-6-methylpyrimidine in basic acetonitrile.
The biological activities of pyrimido[4,5-e][1,3,4]thiadiazines
persuaded us to search for efficient synthetic methods for this
class of heterocyclic compounds, which have been described as
nucleoside analogues,1,2 antiinflammatory, hypotensive, diuretic,3,4
and phosphodiesterase inhibitor2 agents.
at d 6.0 and 9.0 ppm for NH groups of precursors 2 and showed
further downfield shifts for aromatic protons and a signal at
2.35 ppm for the methyl group of precursor 1 indicating the
construction of a thiadiazine ring around the 4- and 5-positions
of the pyrimidine ring. Further proofs came from their IR
spectra, which lacked the N–H stretching frequencies of their
precursors 2 and confirm the presence of the methyl group and
the chlorine atom in compounds 3 by two stretching frequencies
at about 2900 and 850 cm–1, respectively. Mass spectra showed
the expected molecular ion peak and the fragmentation pattern
indicated the loss of alkylthio groups from compounds 3a–e,
which is in line with the proposed structure as shown in Scheme 2.
Microanalytical data for compounds 3 had no significant
difference with the expected data. We also found that the
chlorine atom in the 7-position of the products can be easily
Pyrimido[4,5-e][1,3,4]thiadiazines have been synthesized from
pyrimidines. Previous routes to such a system involved the
heterocyclization of 6-hydrazino-substituted uracils with isothio-
cyanates and N-bromosuccinimide,1–5 condensation of 2,4-di-
chloro-5-nitro-6-methylpyrimidine with dithizone6 via the Smiles
rearrangement, reaction of thiosemicarbazide with 4,5-dihalo-
pyrimidines,7 cyclocondensation of thiosemicarbazide with
5-bromobarbituric acid8 and condensation of 5-bromo-2-chloro-
6-methyl-4-(1-methylhydrazino)pyrimidine with carbon disulfide
and alkyl halides9 or isothiocyanates.10 Previously, we described the
formation of 1-phenyl-1H-[1,3,4]thiadiazino[5,6-b]quinoxalines.11
The synthesis involved heterocyclization of alkyl-2-phenylhydra-
zinecarbodithioates as bifunctional nucleophiles with 2,3-dichloro-
quinoxaline as an electrophile. To extend the scope of this
strategy, we explored other electrophilic species that could
successfully undergo similar reaction.
†
The melting points were recorded on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu
Spectrometer. The 1H NMR (100 MHz) spectra were recorded on a
Bruker AC 100 spectrometer. The mass spectra were scanned on a Varian
Mat CH-7 instrument at 70 eV. Elemental analysis was obtained on a
Thermo Finnigan Flash EA microanalyzer. The purity of all of the new
compounds was tested by TLC using chloroform as a mobile phase.
General procedure for the preparation of pyrimido[4,5-e][1,3,4]thia-
diazines 3a–e. A mixture of compound 1 (2.5 mmol, 0.61 g), alkyl-
2-phenylhydrazinecarbodithioate 2 (2.5 mmol) and triethylamine (1 ml)
in acetonitrile (10 ml) was refluxed under an atmosphere of nitrogen for
3 h. After the reaction was completed, the mixture was cooled to room
temperature and then evaporated under reduced pressure. The residue
was washed with water and crystallized from ethanol prior to washing
with light petroleum 40–60 to give products 3a–e.
As shown in Scheme 1, starting alkyl-2-phenylhydrazine-
carbodithioates 2 underwent heterocyclization with 5-bromo-
2,4-dichloro-6-methylpyrimidine 112 in boiling acetonitrile in
the presence of triethylamine to afford 7-chloro-5-methyl-
1-phenylpyrimido[4,5-e][1,3,4]thiadiazines 3.
The structures assigned to compounds 3 were substantiated
by spectral data.† The 1H NMR spectra were devoid of the signals
Ph
7-Chloro-5-methyl-3-(methylsulfanyl)-1-phenyl-1H-pyrimido[4,5-e]-
[1,3,4]thiadiazine 3a: yellow powder, yield 64%, mp 160 °C. IR (KBr,
n/cm–1): 850, 1550, 2900, 2940. 1H NMR (CDCl3) d: 2.35 (s, 3H, 8-Me),
2.52 (s, 3H, S–Me), 7.2–7.6 (m, 5H). 13C NMR (CDCl3) d: 15.570,
21.343, 107.500, 123.695, 126.416, 128.622, 141.305, 143.492, 158.437,
158.523, 164.141. MS, m/z: 324, 323, 322, 321, 277, 275, 46. Found
(%): C, 48.44; H, 3.50; N, 17.20; S, 19.69. Calc. for C13H11ClN4S2 (%):
C, 48.36; H, 3.43; N, 17.35; S, 19.86.
Cl
N
Cl
Br
Cl
N
N
S
S
N
R
NEt3
+
N
N
R
NH
MeCN,
reflux
S
S
HN
Ph
2a–e
d R = Bu
e R = CH2Ph
Me
Me
1
3a–e
EtOH,
reflux
a R = Me
b R = Et
c R = Pr
2, 3:
4:
R'2NH
7-Chloro-3-(ethylsulfanyl)-5-methyl-1-phenyl-1H-pyrimido[4,5-e][1,3,4]-
thiadiazine 3b: yellow powder, yield 58%, mp 106–108 °C. IR (KBr,
Ph
1
n/cm–1): 870, 1600, 2900, 2950. H NMR (CDCl3) d: 1.35 (t, 3H, Me,
'
a R = Et, R = (CH ) O(CH )
b R = Et, R2 = (CH2)4
c R = Pr, R2 = (CH2)2O(CH2)2
d R = Pr, R2 = (CH2)4
e R = CH2Ph, R2 = (CH2)2O(CH2)2
f R = CH2Ph, R2 = (CH2)4
'
R2N
N
N
N
2
2 2
2 2
J 7.5 Hz), 2.35 (s, 3H, 8-Me), 3.1 (q, 2H, S–CH2, J 7.5 Hz), 7.2–7.6 (m,
5H). MS, m/z: 338, 337, 336, 335, 277, 275, 60. Found (%): C, 49.80;
H, 3.90; N, 16.75; S, 18.88. Calc. for C14H13ClN4S2 (%): C, 49.92; H,
3.89; N, 16.63; S, 19.04.
For characteristics of compounds 3c–e, see Online Supplementary
Materials.
'
'
'
N
R
S
S
'
'
Me
4a–f
Scheme 1
– 284 –
© 2008 Mendeleev Communications. All rights reserved.
Nikpour, Mohsen
