New route to pyrimido[4,5- e][1,3,4]thiadiazine derivatives

Article abstract of DOI:10.1002/jhet.5570440230

(Chemical Equation Presented) 5-Bromo-2-chloro-4-methyl-6-(1- methylhydrazino)pyrimidine is readily obtained from the recently reported 5-bromo-2,4-dichloro-6-methylpyrimidine by treatment with methylhydrazine in chloroform. Treatment of this compound wit

Full text of DOI:10.1002/jhet.5570440230

Mar-Apr 2007
463
New Route to Pyrimido[4,5- e][1,3,4]thiadiazine Derivatives
M. Rahimizadeh, M. Nikpour and M. Bakavoli*
Department of Chemistry, School of Sciences, Ferdowsi University, Mashhad, 91775-1436, Iran.
*Corresponding author: email:mbakavoli@yahoo.com
Received April 5, 2006
Cl
N
N
Cl
N
N
S
1-CS2, EtOH, R-X
2-CH3CN, (Et)3N
NH2
N
N
N
Br
SR
5-Bromo-2-chloro-4-methyl-6-(1-methylhydrazino)pyrimidine is readily obtained from the recently
reported 5-bromo-2,4-dichloro-6-methylpyrimidine by treatment with methylhydrazine in chloroform.
Treatment of this compound with carbon disulfide and several alkyl halides gave an intermediate which
was successfully converted to its corresponding 3-(alkylsulfanyl)-7-chloro-1,5-dimethyl-1H-pyrimido[4,5-
e][1,3,4]thiadiazine derivatives in basic acetonitrile. The latter compounds were reacted with secondary
amines in boiling ethanol to afford the related 7-amino derivatives.
J. Heterocyclic Chem., 44, 463 (2007).
H
N
INTRODUCTION
MeO2S
N
Cl
Br
MeO2S
N
S
Ph
DMF, TEA
N
+
Our interest in pyrimido[4,5-e][1,3,4]thiadiazine
synthesis emerges from few reports on their diverse
biological activities. These compounds have been
described as being nucleoside analogues [4,5], antiinflam-
matory, hypotensive, diuretic [1,2], and phosphodiesterase
inhibitor [2] agents. Despite their importance from
pharmacological and synthetic point of views,
comparatively few methods for their preparation have
been reported.
N
N
NH
S
Ph
H2N
H
N
H
H
O
O H2N
O
HN
N
N
NH
N
+
HN
Br
S
NH2
S
NH2
O
O
Figure 3
Pyrimido[4,5-e][1,3,4]thiadiazines have been solely
synthesized from pyrimidines. Previous routes to such
systems have involved condensation of 2,4-dichloro-5-
nitro-6-methylpyrimidine with dithizone [6] via Smiles
Rearrangement (Figure 1), heterocyclization of 6- hyra-
zinosubstituteduracils with isothiocyanates and N-
bromosuccinimide [1-5] (Figure 2), reaction of thio-
hyrazides with 4,5- dihalopyrimidines [7] and cyclo-
condensation of thiosemicarbazide with 5-bromo-
barbituric acid [8](Figure 3).
The current route is also based upon intramolecular
heterocyclization of new hydrazinecarbodithioate
derivatives 3 a-e (Scheme I) The latter compounds were
easily synthesized from the new 5-bromo-2-chloro-4-
methyl-6-(1-methylhydrazino)pyrimidine (2) which in
turn is readily obtainable from 5-bromo-2,4-dichloro-6-
methylpyrimidine [9].
RESULTS AND DISCUSSION
5-Bromo-2-chloro-4-methyl-6-(1-methylhydrazino)-
pyrimidine 2 was reacted with carbon disulfide and
several alkyl halides in basic ethanol to afford the key
intermediates hydrazinocarbodithioates 3a-e. These
intermediates, which are air sensitive, were subjected to
intramolecular heterocyclization in basic acetonitrile
without further purification to give the cyclized products
4a-e. The latter compounds were further reacted with
secondary amines to give the amino derivatives 5a-d.
The structure of new derivatives 4a-e and 5a-d were
confirmed by their spectral and microanalytical data. For
example, the IR spectrum of 4a was devoid of the
stretching vibration bands at 3280 and 3360 cm-1 due to
NH2 functionality of the precursor 2 but exhibits vibration
bands at 800, 2900, 2940 cm-1 due to 7-chloro and methyl
Ph
N
Cl
Cl
S
N2Ph
Cl
N
N
CH3CN , TEA
N
+
N
N
NH
NO
N2Ph
S
2 HN
Ph
Figure 1
R1
N
R1
R3
R3
NNH2
O
1- R4NCS , EtOH
2- NBS , EtOH
O
N
N
N
N
N
R4
R2
R2
S
NH
O
O
R1, R2, R3 = H, variety alkyl groups
R
4 = alky aryl and sugar groups
1
groups respectively. The H NMR spectrum of 4a was
Figure 2

464
M. Rahimizadeh, M. Nikpour and M. Bakavoli
Vol 44
S
Cl
N
Cl
Br
Cl
N
N
N
N
Cl
N
N
S
Cl
R
CS2, EtOH, R-X
CH3CN, (Et)3N
NH,
NH2
N
N
Me-NH-NH2
S
H
N
N
N
N
Br
Br
SR
heat
, R2
H
1
2
4a-e
O
3a-e
Et
R2N
N
N
S
R= 4a: Me, 4b: Et, 4c: Pr, 4d: Bu, 4e: CH2Ph
R2N= Morpholine, R= 5a: Et, 5b: Pr, 5c: CH2Ph
R2N=Pyrrolidine, R= 5d: CH2Ph
N
N
SR
5a-f
for 12 hours. Then the solvent was removed under reduced
pressure, the residue was dissolved in 20 ml of acetonitril,
triethylamine (1.01 g, 10mmoles) was added and the resulting
solution was refluxed under nitrogen atmosphere for 4 hours.
The solvent was evaporated and the residue was purified by
column chromatography over silica gel eluted with chloroform:
hexane (1: 1) to give products 4a-e.
7-Chloro-1,5-dimethyl-3-(methylsulfanyl)-1H-pyrimido-
[4,5-e][1,3,4]thiadiazine (4a) was obtained as a green powder in
35% yield, mp 90-92 °C, IR: 800, 2900, 2940 cm-1 ; 1HNMR:
(CDCl3) ꢀ, 2.2 (s, 3H, 5-CH3), 2.41 (s, 3H, S-CH3), 3.34 (s, 3H,
1-CH3); ms: m/z, 260 (60), 262 (20), 184 (100%). Anal. Calcd.
for C8H9ClN4S2: C, 36.85; H, 3.48; N, 21.49; S, 24.59. Found:
C, 36.73; H, 3.44; N, 21.35; S,24.38.
also devoid of the broad NH2 signal at ꢀ 4.2 ppm of the
precursor but showed a singlet at ꢀ 2.41 ppm assignable to
3 protons for the SMe group which indicates the
formation of compound 4a. The molecular ions of 4a (M:
M+2) was observed at 260 and 262 (60%:20%)
corresponding to the molecular formula C8H9ClN4S2. It is
worth noting that the IR spectra of 5a-d were devoid of
the C-Cl bond stretching vibration in the range of 780-
840 cm-1 which is a clear indication of its replacement
with nucleophiles. In conclusion, the sequential treatment
of the newly reported 5-bromo-2-chloro-4-methyl-6-(1-
methylhydrazino)pyrimidine (2) with carbondisulfide and
alkylhalides in basic ethanol which was followed by
subsequent intramolecular heterocyclization in basic
acetonitrile is a new, efficient and general access to
pyrimido[4,5-e][1,3,4]thiadiazine derivatives.
7-Chloro-3-(ethylsulfanyl)-1,5-dimethyl-1H-pyrimido[4,5-e]-
[1,3,4]thiadiazine (4b) was obtained as a green powder in 30%
1
yield, mp 50 °C, IR: 820, 2900, 2950 cm-1; HNMR: (CDCl3) ꢀ,
1.35(t, 3H,CH3),2.2 (s, 3H, 5-CH3), 3.05 (q, 2H, S-CH2), 3.4 (s,
3H, 1-CH3); ms: m/z, 274 (79), 276 (25), 184 (100%). Anal.
Calcd. for C9H11ClN4S2: C, 39.34; H, 4.03; N, 20.39; S, 23.34.
Found: C, 39.50; H, 4.1; N, 20.25; S,23.20.
EXPERIMENTAL
7-Chloro-1,5-dimethyl-3-(propylsulfanyl)-1H-pyrimido-
[4,5-e][1,3,4]thiadiazine (4c) was obtained as a green powder
in 36% yield, mp 43-45 °C, IR: 840, 2880, 2920 cm-1; 1HNMR:
(CDCl3) ꢀ, 1.03 (t, 3H,CH3), 1.6 (sextet, 2H,CH2), 2.2 (s, 3H, 5-
CH3), 3.01(t, 2H,S-CH2), 3.32 (s, 3H, 1-CH3); ms: m/z, 288 (70),
290 (23), 184 (100). Anal. Calcd. for C10H13ClN4S2: C, 41.59; H,
4.54; N, 19.40; S, 22.20. Found : C, 41.42; H, 4.38; N, 19.51;
S,22.10.
3-(Butylsulfanyl)-7-chloro-1,5-dimethyl-1H-pyrimido[4,5-e]-
[1,3,4]thiadiazine (4d) was obtained as a green powder in 30%
yield, mp 45-47 °C, IR: 800, 2900, 2950 cm-1; 1HNMR: (CDCl3)
ꢀ,0.95 (t, 3H,CH3), 1.2-1.7 (multiplet, 4H, 2CH2), 2.25 (s, 3H, 5-
CH3), 3.05 (t, 2H, S-CH2), 3.4 (s, 3H, 1-CH3); ms: m/z, 302 (50),
304 (17), 184 (100). Anal. Calcd. for C11H15ClN4S2: C, 43.63; H,
4.99; N, 18.50; S, 21.18. Found : C, 43.71; H, 4.85; N, 18.59; S,
21.03.
Melting points were recorded on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a 4300
Shimadzu Spectrometer. The H 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 new compounds synthesized
was tested by TLC using chloroform as mobile phase.
1
5-Bromo-2-chloro-4-methyl-6-(1-methylhydrazino)pyrim-
A solution of 5-bromo-2,4-dichloro-6-methyl-
idine (2).
pyrimidine (2.42 g, 10 mmoles) and triethylamine (1.01 g, 10
mmoles) in chloroform (20 ml), was added at once to a solution
of methylhydrazine (0.46 g, 10 mmoles) in chloroform (10 ml).
The resulting solution was stirred for 15 minutes at room
temperature. The solvent was removed under reduced pressure
and the residue was washed with water and recrystallized from
ethanol as an orange powder in 80% yield, mp 99-101°C, IR:
3-(Benzylsulfanyl)-7-chloro-1,5-dimethyl-1H-pyrimido-
[4,5-e][1,3,4]thiadiazine (4e) was obtained as a green powder in
1
35% yield, mp 97-99 °C, IR: 780, 2910, 2960 cm-1; HNMR:
1
840, 2900, 2960, 3280, 3360 cm-1, HNMR: (CDCl3) ꢀ, 2.52 (s,
(CDCl3) ꢀ, 2.25 (s, 3H, 5-CH3), 3.4 (s, 3H, 1-CH3), 4.25 (t, 2H,
S-CH2), 7.4 (multiplet,5H),; ms: m/z, 336 (46), 338 (15), 299
(100). Anal. Calcd. for C14H13ClN4S2: C, 49.92; H, 3.89; N,
16.63; S, 19.04. Found : C, 50.05; H, 3.95; N, 16.55; S,18.93.
General procedure for the reaction of 3-alkylthio-7-
chloro-1,5-dimethylpyrimido[4,5-e][1,3,4]thiadiazines with
morpholine or pyrrolidine. 3-Alkylthio-7-chloro-1,5-dimethyl-
pyrimido[4,5-e][1,3,4]thiadiazines 4b-c,e (2 mmoles) in ethanol
(10 ml) was heated under reflux with either morpholine (2.0 g)
3H, CH3), 3.38 (s, 3H, N- CH3), 4.2 (s, 2H, NH2); ms:m/z, 250
(58%), 252 (75%), 254 (19%), 234 (100%).
General procedure for preparation of 3-alkylthio-7-
chloro-1,5-dimethyl- pyrimido[4,5-e] 1,3,4 thiadiazines. A
solution of 1-(5-bromo-2-chloro-6-methylpyrimidin-4-yl)-1-
methylhydrazine (2.51 g, 10 mmoles), triethylamine (1.01 g, 10
mmoles), carbondisufide (0.76 g, 10 mmoles) and alkylhalide
(iodomethane, bromoethane, 1-bromopropane, 1-bromobutane
or benzylchloride) (10 mmoles) in ethanol (20 ml) was stirred

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New Route to Pyrimido[4,5- e][1,3,4]thiadiazine Derivatives
465
or pyrrolidine (1.8 g) for 4 hours. The solvent was removed and
the residue was washed with water and then recrystallized from
ethanol to give products 5a-d.
as a green powder in 70% yield, mp 101-103 °C, IR: 2900, 2940
cm-1; 1HNMR: (CDCl3) ꢀ, 1.93(t, 4H, 2 ((CH2)-CH2N),2.17 (s,
3H, 5-CH3), 3.40 (s, 3H, 1-CH3), 3.51(t,4H, 2(CH2N)), 4.23 (S,
2H, S-CH2), 7.4 (multiplet,5H); ms: m/z, 371. Anal. Calcd. for
C18H21N5S2: C, 58.19; H, 5.70; N, 18.85; S, 17.26. Found: C,
58.28; H, 5.75; N, 18.81; S,17.2.
4-[3-(Ethylsulfanyl)-1,5-dimethyl-1H-pyrimido[4,5-e]-
[1,3,4]thiadiazin-7-yl]morpholine (5a) was obtained as a green
powder in 85% yield, mp 81-83 °C, IR: 2880, 2930 cm-1;
1HNMR: (CDCl3) ꢀ, 1.35(t, 3H,CH3), 2.1(s, 3H, 5-CH3), 2.9(q,
2H, S-CH2), 3.3(s, 3H, 1-CH3), 3.65(m, 8H, CH2-(O&N)); ms:
m/z, 325. Anal. Calcd. for C13H19N5OS2: C, 47.98; H, 5.88; N,
21.52; S, 19.70. Found : C, 48.1; H, 5.79; N, 21.45; S,19.61.
4-[1,5-Dimethyl-3-(propylsulfanyl)-1H-pyrimido[4,5-e]-
[1,3,4]thiadiazin-7-yl]morpholine (5b) was obtained as a green
powder in 70% yield, mp 79°C, IR: 2910, 2940 cm-1; 1HNMR:
(CDCl3) ꢀ, 0.98(t, 3H,CH3), 1.6(sextet, 2H,CH2), 2.1(s, 3H, 5-
CH3), 2.9(t, 2H,S-CH2), 3.29 (s, 3H, 1-CH3), 3.65(m, 8H, CH2-
(O&N)); ms: m/z, 339. Anal. Calcd. for C14H21N5OS2: C, 49.53;
H, 6.24; N, 20.63; S, 18.89. Found : C, 49.61; H, 6.30; N,
20.55; S,18.75
4-[3-(Benzylsulfanyl)-1,5-dimethyl-1H-pyrimido[4,5-e][1,3,4]-
thiadiazin-7-yl]morpholine (5c) was obtained as a green
powder in 80% yield, mp 134-136 °C, IR: 2890, 2930 cm-1;
1HNMR: (CDCl3) ꢀ, 2.16 (s, 3H, 5-CH3), 3.39 (s, 3H, 1-CH3),
3.73 (m, 8H, CH2-(O&N)), 4.23 (s, 2H, S-CH2), 7.4
(multiplet,5H),; ms: m/z, 387. Anal. Calcd. for C18H21N5OS2: C,
55.79; H, 5.46; N, 18.07; S, 16.55. Found : C, 55.68; H, 5.40;
N, 18.20; S,16.41.
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