Synthesis of Some Novel Thiadiazaphosphole, Oxazaphospholothiadiazaphosphole, Thiadiazaphosphinine, and Phosphonates Containing a 1,2,4-Triazine Moiety

Article abstract of DOI:10.1002/jhet.3567

Synthesis of some novel organophosphorus compounds bearing 1,2,4-triazinone moiety was achieved. The methodology depended on simple reactions between 4-amino-6-methyl-3-sulfanyl-1,2,4-triazin-5(4H)-one (1) and variable phosphorus reagents such as phosphorus halides and phosphorus sulfides as well as phosphorous acid and its esters. These reactions were performed in proper solvents under mild conditions giving good yields of phosphorylated 1,2,4-triazinones.

Full text of DOI:10.1002/jhet.3567

Month 2019
Synthesis of Some Novel Thiadiazaphosphole,
Oxazaphospholothiadiazaphosphole, Thiadiazaphosphinine, and
Phosphonates Containing a 1,2,4-Triazine Moiety
Somaia M. Abdel-kariem*
Department of Chemistry, Faculty of Education, Ain Shams University, Roxy, Cairo, Egypt
*
E-mail: somaia.abdelkariem@yahoo.com
Received January 24, 2019
DOI 10.1002/jhet.3567
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
Synthesis of some novel organophosphorus compounds bearing 1,2,4-triazinone moiety was achieved.
The methodology depended on simple reactions between 4-amino-6-methyl-3-sulfanyl-1,2,4-triazin-5(4H)-
one (1) and variable phosphorus reagents such as phosphorus halides and phosphorus sulfides as well as
phosphorous acid and its esters. These reactions were performed in proper solvents under mild conditions
giving good yields of phosphorylated 1,2,4-triazinones.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
RESULTS AND DISCUSSION
Over the last decades, a variety of 1,2,4-triazine
derivatives were synthesized and studied for their
biological activities. They were used as adenosine A2A
antagonists [1], antimalarial, anti-inflammatory [2], and
anticancer drugs [3]. Moreover, Lamotrigine, one of the
most important 1,2,4-triazine derivatives, which sold as
the brand name Lamictal, is used as anticonvulsant agent
In the present article, the synthesis of some novel
phosphorylated
performed. Thus, 4-amino-6-methyl-3-sulfanyl-1,2,4-
triazin-5(4H)-one (1) was prepared from
1,2,4-triazinone
derivatives
was
cyclocondensation reaction of sodium pyruvate and
thiocarbohydrazide according to the reported method in
literature [14] (Scheme 1).
[
4]. On the other hand, organophosphorus compounds
Refluxing of starting material 1 with benzaldehyde in
absolute ethanol afforded the corresponding Schiff base
2. When Schiff base 2 was reacted with phosphorous
acid (phosphonic acid) in dry toluene in the presence of
4-TsOH as a catalyst under Pudovic reaction conditions
have received much attention whether linear or cyclic.
They were demonstrated to be pesticides [5], herbicides
[6], antifungal [7], anti-inflammatory [8], anti-HIV [9],
anticancer [10], and good cytotoxic on K562 and colo205
cancerous cells [11]. These aforementioned reasons with
our interest in organophosphorus chemistry [12,13]
encouraged us to synthesize new organophosphorus
compounds incorporating 1,2,4-triazinone moiety through
reaction of 4-amino-6-methyl-3-sulfanyl-1,2,4-triazin-
[15],
2-hydroxy-7-methyl-3-phenyl-3,4-dihydro-2,6H-
[1,2,4]triazino[4,3-e][1,4,5,2]thiadiazaphosphinin-6-one-2
-oxide (3) was isolated as a sole product (Scheme 2).
Also, the latter product 3 was authentically obtained
through three-component one-pot reaction under
Kabachnik–Fields reaction conditions [16] (Scheme 2).
5
(4H)-one (1) with different phosphorus reagents.
©
2019 Wiley Periodicals, Inc.

S. M. Abdel-kariem
Vol 000
Scheme 1. Preparation of 4-amino-6-methyl-3-sulfanyl-1,2,4-triazin-
(4H)-one (1).
Scheme 3. Reaction of compound 1 with HP(O)(OEt)
2 3
and (EtO) P(O)
5
CH COOEt.
2
Scheme 2. Reaction of compound 1 with a mixture of PhCHO and HP(O)
OH)
(
2
.
6
1.9 ppm as well as the carbon atom C-3 of triazine ring at
δ 150.0 ppm. The mass spectrum also proved the suggested
structure.
Moreover, the unexpected diethyl {2-[(6-methyl-5-oxo-
3
-sulfanyl-1,2,4-triazin-4(5H)-yl)amino]-2-oxo-ethyl}pho-
sphonate (5) was prepared from direct reaction of 1,2,4-
triazinone 1 and ethyl 2-(diethoxyphosphoryl)acetate in
ethanolic sodium ethoxide. Compound 5 existed as two
enantiomers, and the spectral data confirmed their
existence due to a duplication of chemical shifts of
hydrogen and carbon atoms. The occurrence of
duplication here was due to the presence of phosphorus
1
The H-NMR spectrum of compound 3 showed a doublet
signal at δ 2.78 (J = 63 Hz) ppm for CH–P of
thiadiazaphosphinine ring while the P–OH appeared at δ
3
.34 ppm.
Diethyl phosphite is a versatile intermediate used in the
atom adjacent to CH (have two asymmetrical hydrogen
2
production of various phosphorus-based heterocycles.
When diethyl phosphate reacted with bi-functionalized
atoms) that gave rise to Enantiotopic phenomenon [18].
The IR spectrum of compound 5 showed two peaks for
each P¼O (1277 and 1249) and P–O–C (1051 and
1,2,4-triazine 1, it was expected to give new fused
ꢀ
1
1
heterocyclic system containing phosphorus, but it gave
the more interesting {4-(ethylamino)-6-methyl-5-oxo-4,5-
dihydro-1,2,4-triazin-3-yl}phosphonothioate (4) as a sole
product (Scheme 3). This novel product was formed via a
nucleophilic attack of thiol group at the α-carbon atom of
the ethoxy group to give the corresponding ethyl
ammonium salt of the monoethyl ester of phosphonic
acid as shown in Scheme 3. This result based on amine
promoted reactions of dialkyl H–Phosphonates, which
prefer the dealkylation process over than the
deprotonation according to the lower ΔG value of
dealkylation over than the deprotonation [17]. The IR
spectrum of compound 4 showed the absorption bands of
1028) cm . Also, its H-NMR spectrum confirmed the
structure by appearance of four methyl and four OCH2
groups at δ 1.16–1.33 and δ 3.99–4.12 ppm with
J = 6.9 Hz confirming the asymmetry of the two ethoxy
groups. Also, the protons of P–CH moiety appeared as
2
two separated doublets at δ 2.96 and 3.08 ppm with
coupling constants of 29.2 and 28.4 Hz. Moreover, the
13
carbon atom of P–CH group appeared in C-NMR
spectrum as two doublets at δ 33.9 (J = 130.4 Hz) and
52.7 ppm (J = 144.8 Hz).
In the same manner, fusion of trimethyl phosphate with
compound 1 for 6 h afforded the corresponding
thiadiazaphospholotriazine system
6 in 64% yield
ꢀ
1
NH at 3414 and 3147 cm . Also, the functional P–H
(Scheme 4). Its IR spectrum showed the presence of NH
2
ꢀ
1
ꢀ1
and P¼O appeared at 2426 and 1220 cm , respectively.
and P¼O at 3168 and 1217 cm , respectively. Also, its
1
1
Its H-NMR spectrum revealed the presence of P–H
H-NMR spectrum displayed the OCH3 protons at δ
proton at δ 6.67 ppm with coupling constant 644 Hz. The
NH2 appeared as a broad peak around δ 7.00 ppm.
Furthermore, the C-NMR spectrum of compound 4
2.77 ppm with disappearance of SH group as an evidence
for cyclization process. Moreover, the methoxy group
1
3
13
appeared in its C-NMR spectrum at δ 52.7 ppm. The
showed the carbon atoms of CH and CH at δ 17.1 and
mass spectrum exhibited the molecular ion peak of
3
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Some Novel Thiadiazaphosphole, Oxazaphospholothiadiazaphosphole,
Thiadiazaphosphinine, and Phosphonates Containing a 1,2,4-Triazine Moiety
3 2 2 3
Scheme 4. Reaction of compound 1 withP(O)(OMe) and P (OCH CH Cl) .
compound 6 at m/e 234, which agree with the proposed
structure.
osphinic amide (9) (Scheme 5). The suggested mechanism
for the synthesis of triazinylphosphinic amide 9 was
occurred through formation of non-isolable intermediate
A with the liberation of triethylammonium chloride salt,
followed by hydrolysis giving intermediate B. The latter
intermediate B underwent rearrangement to furnish the
isolated product 9 (Scheme 5). The IR spectrum of
compound 9 revealed the presence of two broad peaks
The
interesting
3-methyl-7,8-dihydro-4H-[1,3,2]
0
0
oxazaphospholo[2 ,3 :2,3][1,3,4,2]thiadiazaphospholo[5,4-
c][1,2,4]triazin-4-one (7) was constructed via fusion of
triazine 1 with tris(2-chloroethyl)phosphite at 70–80°C for
6
h (Scheme 4). The importance of compound 7 lied in the
presence of phosphorus atom as a bridgehead atom, which
has great and various biological activities [19]. The
suggested mechanism for the formation of compound 7
forwarded through two nucleophilic substitution steps by
sulfur then nitrogen at phosphorus(III) with loss of two
molecules of 2-chloroethanol. Then an intramolecular
heterocyclization was caused by attack of nitrogen atom at
ꢀ
1
for NH groups at 3296 and 3216 cm , while C¼S and
ꢀ
1
P¼O were appeared at 1380 and 1214 cm . Also, its
1
H-NMR spectrum confirmed its structure due to the
presence of two NH groups that were exchangeable with
D O at δ 6.30 and 13.70 ppm, respectively. Moreover,
2
the P–H proton appeared as a doublet at δ 7.30 ppm with
coupling constant of 630 Hz.
On the other hand, refluxing of phosphorus
oxychloride with compound 1 in dry dioxane in the
CH Cl with removal of HCl forming the final product 7
2
1
(
Scheme 4). The IR and H-NMR spectra for compound 7
confirmed the proposed structure due to the absence of SH
1
and NH groups. Also, the H-NMR proved the presence of
presence of three equivalent amounts of Et N afforded
3
one NCH moiety and one OCH moiety at range δ 3.06–
the product 10. The reaction pathway proceeded as
shown in Scheme 6. The IR spectrum of compound 10
showed signal at 3220 cm for NH group and another
2
2
4.49 ppm.
ꢀ
1
On the other hand, phosphorus halides are extremely
reactive reagents that can react easily with different bi-
nucleophiles forming new heterocycles containing
phosphorus atom [20]. Thus, reaction of 4-amino-6-
methyl-3-sulfanyl-1,2,4-triazin-5(4H)-one (1) with PBr3
2
Scheme 5. Reaction of compound 1 with PhPCl in dioxane.
and PCl was performed. Both reactions took place at the
3
same conditions in dry dioxane containing a few drops of
triethylamine for 6–8 h. Unfortunately, we failed to
isolate the products in pure cases to identify them.
Neatly, P,P-dichlorophenylphosphine was reacted with
triazine 1 in dry dioxane containing a few drops of
triethylamine. The reaction was expected to give the
system thiadiazaphosphole 8 as a result of thiol attack
followed by amino group, but actually, the attack
occurred by only amino group leading to N-(6-methyl-5-
oxo-3-thioxo-2,5-dihydro-1,2,4-triazin-4(3H)-yl)phenylph
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. Abdel-kariem
Vol 000
Scheme 6. Reaction of compound 1 with POCl
3
in dioxane.
EXPERIMENTAL
The melting point was determined in an open capillary
tube on a digital Stuart SMP-3 apparatus. Infrared spectra
were
measured
on
FT-IR
(Nicolet
IS10)
spectrophotometer using KBr disks and Perkin-Elmer 293
1
spectrophotometer using KBr disks. H-NMR spectra
were measured on Gemini-300BB spectrometer
(
300 MHz), using DMSO-d as a solvent and TMS (δ) as
6
13
an internal standard. C-NMR spectra were measured on
Mercury-300BB (75 MHz), using DMSO-d as a solvent
6
and TMS (δ) as an internal standard. Mass spectra were
recorded on a Gas Chromatographic GCMSqp 1000 ex
Shimadzu instrument at 70 eV and in Thermo scientific
GCMS model ISQ at the Regional Center for Mycology
and Biotechnology (RCMB), Alazhar University.
Elemental microanalyses were performed on Perkin-
Elmer 2400II at the Chemical War Department, Ministry
of Defense. The purity of the synthesized compounds
was checked by thin-layer chromatography.
ꢀ
1
1
one at 1244 cm special for P¼O group. Also, its H-
NMR spectrum revealed the presence of
triethylammonium moiety at δ 1.14 and 3.05 ppm for
CH3 and CH2 protons, respectively, while the NH
proton appeared δ 10.09 ppm as exchangeable with D O.
2
The novel thiadiazaphospholotriazine systems 11 and
1
2 were obtained from refluxing of compound 1 with
each P4S10 (Berzelius reagent) and Lawesson’s reagent
LR) in dry dioxane for 6–8 h, respectively, which
were classified as the most efficient thionating agents
21,22]. A reasonable mechanism for the latter products
was the nucleophilic attack of SH at phosphorus atom
forming the non-isolable intermediates A and B, which
underwent an intramolecular cyclization via amino
group forming the desired compounds 11 and 12, in
high yields (Scheme 7). Their IR spectra showed the
Synthesis of 2-hydroxy-7-methyl-2-oxido-3-phenyl-3,4-
dihydro-2,6H-[1,2,4]triazino[4,3-e][1,4,5,2]
(
thiadiazaphosphinin-6-one (3).
A mixture of phos-
phorous acid (0.133 g, 1.6 mmol) and 6-methyl-
4-{[phenyl-methylidene]amino}-3-sulphanyl-1,2,4-triazin-
[
5
(4H)-one (0.3 g, 1.2 mmol) was heated under reflux in
toluene in presence of p-toluenesulphonic acid as a
catalyst for 4 h. The reaction mixture was left in air for
2
4 h for evaporation of solvent. The obtained solid was
filtered off and crystallized from diluted ethanol to give
brown solid in 36% yield; mp 197–200°C. IR (KBr) (νmax
ꢀ
1
C¼O groups at 1694 and 1663 cm , respectively,
giving rise to the absence of thionation process. Also,
,
ꢀ
1
1
cm ): 3429 (br, OH, NH), 3060 (C–Harom.), 2925 (C–
their H-NMR spectra revealed the presence of
1
exchangeable protons at δ 13.68 and 13.75 ppm
attributed to NH protons for compounds 11 and 12,
respectively, with the appearance of one exchangeable
signal of SH of compound 11 at δ 7.55 ppm.
Furthermore, the C-NMR spectrum of compound 11
displayed the characteristic carbon atoms C-3, C-5, and
C-6 at δ 163.4, 169.7, and 150.8 ppm, respectively.
H
aliph.), 1633 (C¼O), 1490 (C¼C), 1163 (P¼O). H-
NMR (300 MHz, DMSO-d ): 2.26 (s, 3H, CH ), 2.78 (d,
H, J = 63 Hz, CH–P), 3.34 (br, 1H, P–OH exchangeable
6
3
1
with D
O), 7.07–7.46 (m, 5H, aromatic protons), 7.90 (s,
2
+
1
3
1H, NH exchangeable with D
O). MS (m/z, I%): 310 (M ,
2
5
%). Anal. Calcd for C H N O PS (230.18): C, 42.58;
11 11
4 3
H, 3.57; N, 18.06; S, 10.33. Found C, 42.58; H, 3.55; N,
1
8.02; S, 10.01%.
Synthesis of {4-(ethylamino)-6-methyl-5-oxo-4,5-dihydro-
4
Scheme 7. Reaction of compound 1 with P S10 and LR in dioxane.
1
,2,4-triazin-3-yl}phosphono-thioate (4).
Compound 1
(
(
0.8 g, 5 mmol) was fused with diethylphosphite
1.95 mL, 15 mmol) for 3 h at 70–80°C. After cooling, a
dark brown solid was obtained. The solid was filtered off
and crystallized from diluted ethanol in 90% yield. IR
ꢀ
1
(
(
KBr) (νmax, cm ): 3414, 3147 (br, NH ), 2986, 2934
2
1
C–Haliph.), 2426 (P–H), 1690 (C¼O), 1220 (P¼O). H-
NMR (400 MHz, DMSO-d ): 1.14 (t, 3H, J = 7.2 Hz,
6
CH ), 2.04 (s, 3H, CH ), 3.83(q, 2H, J = 7.2 Hz, CH ),
3
3
2
6
.67 (d, JPH = 644 Hz, 1H, P–H), 7–7.10 (br, 2H, NH
2
13
exchangeable with D O).
C-NMR (75 MHz,
2
DMSO-d ): 16.4 (CH ), 17.1 (CH ), 61.9 (CH ), 146.0
6
3
3
2
(C-6), 150.0 (C-3), 206.9 (C-5). MS (m/z, I%): 250.9
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Synthesis of Some Novel Thiadiazaphosphole, Oxazaphospholothiadiazaphosphole,
Thiadiazaphosphinine, and Phosphonates Containing a 1,2,4-Triazine Moiety
+
+
(
M , 5%). Anal. Calcd for C H N O PS (250.21): C,
230 (M , 1%). Anal. Calcd for C H N O PS (230.18): C,
6
11
4
3
6 7 4 2
28.80; H, 4.43; N, 22.39; S, 12.81. Found C, 28.55; H,
31.31; H, 3.07; N, 24.34; S, 13.93. Found C, 31.0; H,
4.38; N, 22.33; S, 12.77%.
3.03; N, 24.32; S, 13.89%.
Synthesis of diethyl {2-[(6-methyl-5-oxo-3-sulfanyl-1,2,4-
Synthesis of N-(6-methyl-5-oxo-3-thioxo-2,5-dihydro-1,2,4-
triazin-4(3H)-yl)phenyl-phosphinic amide (9). A solution
triazin-4(5H)-yl)amino]-2-oxo-ethyl}phosphonate (5).
A
mixture of compound 1 (0.79 g, 5 mmol) and
ethyl 2-(diethoxyphosphoryl)acetate (1.57 mL, 7 mmol)
in ethanolic sodium ethoxide (0.116-g Na in 20-mL
EtOH) was heated under reflux for 10 h. After cooling,
the mixture was neutralized with diluted HCl to give
the solid that was filtered off and crystallized from
ethanol to give a beige semisolid in 52% yield.
of P,P-dichlorophenylphosphine (0.7 mL, 5 mmol) in dry
dioxane (5 mL) was added dropwise to a solution of
triazine (0.79 g, 5 mmol) in dry dioxane (50 mL) in the
presence of a catalytic amount of triethylamine (1.4 mL,
10 mmol) at 5–10°C for 30 min. The mixture was heated
under reflux for 6 h. The solution was evaporated, and
the formed solid was filtered off, washed with distilled
water, and crystallized from diluted ethanol to give pale
yellow crystalline solid in 88% yield; mp 75–77°C. IR
ꢀ
1
IR (KBr) (νmax, cm ): 3314, 3207 (br, NH), 2983,
2
934 (C–Haliph.), 1738 (C¼O ), 1686 (C¼O), 1538
ester
1
ꢀ1
(C¼N), 1277, 1249 (P¼O), 1051, 1028 (P–O–C). H-
(KBr) (νmax, cm ): 3296, 3216 (br, NH), 3099 (C–
NMR (300 MHz, DMSO-d ): 1.16–1.33 (m,
Harom), 2700 (P–H), 2959 (C–Haliph.), 1663 (C¼Oamide),
6
1
J = 6.9 Hz, 12H, 4CH ), 2.11, 2.22 (ss, 3H, CH ),
1597 (C¼N), 1380 (C¼S), 1214 (P¼O). H-NMR
3
3
2.96 (d, 1H, J = 29.2 Hz, P–CH), 3.08 (d, 1H,
(300 MHz, DMSO-d ): 2.17 (s, 3H, CH ), 6.30 (br s, 1H,
6
3
J = 28.4 Hz, P–CH), 3.99–4.12 (m, J = 6.9 Hz, 8H,
NH exchangeable with D O), 7.30 (d, 1H, P–H,
2
4
1
OCH ), 6.61 (s, 1H, NH exchangeable with D O),
J = 630 Hz), 7.47–7.73 (m, 5H, aromatic protons), 13.70
2
2
1
3
2.4 (br s, 1H, SH exchangeable with D O). C-NMR
(s, 1H, NH exchangeable with D O). MS (m/z, I%): 282
2
2
+
(75 MHz, DMSO-d ): 12.8, 14.4 (2CH ), 17.2, 17.3
(M , 0.5%). Anal. Calcd for C H N O PS (282.25): C,
6
3
10 11 4 2
(2CH3), 33.9 (d,
J
=
130.4 Hz, P–CH), 52.7
42.55; H, 3.93; N, 19.85; S, 11.36. Found C, 42.34; H,
(
d, J = 144.8 Hz, P–CH), 61.2, 62.3 (2 OCH CH ),
3.90; N, 19.77; S, 11.34%.
2 3
1
1
45.2 (C-3triazine), 148.2 (C-4triazine), 166.2 (C¼O),
Synthesis of 2-triethylammonium {6-methyl-2-oxido-1,7a-
dihydro-[1,3,4,2]thiadiza-phospholo[5,4-c][1,2,4]triazin-
+
67.7 (C¼O). MS (m/z, I%): 336 (M , 1%). Anal.
7
(2H)-one}chloride (10).
A solution of phosphorus
Calcd for C H N O PS (336.304): C, 35.71; H, 5.10;
10 17 4 5
N, 16.66; S, 9.53. Found C, 35.66; H, 5.08; N, 16.61;
S, 9.49%.
oxychloride (0.5 mL, 5 mmol) in dry dioxane (5 mL) was
added dropwise to a solution of compound 1 (0.79 g,
5
mmol) in dry dioxane (50 mL) in the presence of
Synthesis of 2-methoxy-6-methyl-2-oxido-1,2-dihydro-7H-
[
1,3,4,2]thiadiazaphospholo[5,4-c][1,2,4]triazin-7-one (6).
triethylamine (2.08 mL, 15 mmol) at 5–10°C for 30 min.
The mixture was heated under reflux for 6 h. During
heating, a solid was formed that was filtered off, washed
with distilled water, and crystallized from diluted ethanol
to give beige solid in 53% yield; mp 177–180°C. IR
Compound 1 (0.79 g, 5 mmol) was fused with
trimethylphosphate (0.70 mL, 5 mmol) for 6 h at 70–
8
0°C. The product was separated as a viscous brown
ꢀ
1
liquid in 64% yield. IR (KBr) (νmax, cm ): 3168 (br,
NH), 2956 (C–H
), 1679 (C¼O), 1217 (P¼O), 1046
ꢀ
1
(KBr) (νmax, cm ): 3220 (br, NH), 2978, 2944 (C–
aliph.
1
1
(
P–O–C). H-NMR (300 MHz, DMSO-d ): 2.12 (s, 3H,
H
aliph), 1691 (C¼O), 1613 (C¼N), 1244 (P¼O). H-
6
NMR (300 MHz, DMSO-d ): 1.14 (t, 9H, CH ), 2.16 (s,
CH ), 2.77 (s, 3H, OCH ), 12.0 (s, 1H, NH exchangeable
with D O). C-NMR (75 MHz, DMSO-d ): 17.0 (CH ),
5
(
C H N O PS (234.17): C, 25.64; H, 3.01; N, 23.93; S,
1
6
3
3
3
13
3H, CH
exchangeable with D
), 3.05 (q, 12H, NCH
), 10.09 (s, 1H, NH
3
2
2
6
3
+
2.7 (OCH ), 157.0 (C-6
), 168.9 (C¼N), 173.1
2
O). MS (m/z, I%): 325 (M ꢀ Me,
3
triazine
+
1
.4%) Anal. Calcd for C H N O PSCl (339.7): C,
C¼O). MS (m/z, I%): 234 (M , 2.50%). Anal. Calcd for
10 19 5 2
35.29; H, 5.58; N, 20.58; S, 9.41. Found C, 35.10; H,
5.56; N, 20.53; S, 9.01%.
5
7 4 3
3.69. Found C, 25.62; H, 3.04; N, 23.88; S, 13.67%.
Synthesis
oxazaphospholo[2 ,3 :2,3][1,3,4,2]thiadiaza-phospholo[5,4-c]
1,2,4]triazin-4-one (7). Compound 1 (0.79 g, 5 mmol)
was fused with tris(2-chloroethyl)phosphite (0.97 mL,
mmol) for 6 h at 70–80°C. The reaction mixture was
of
3-methyl-7,8-dihydro-4H-[1,3,2]
Synthesis of 6-methyl-2-sulfanyl-2-sulfido-1,2-dihydro-7H-
[1,3,4,2]-thiadiazaphospholo[5,4-c][1,2,4]triazin-7-one (11).
0
0
[
A mixture of phosphorus decasulfide (1.12 g, 5 mmol) and
compound 1 (0.8 g, 5 mmol) in dry dioxane (30 mL) was
heated under reflux for 6–8 h. The reaction mixture was
left to cool. The product was filtered off and
recrystallized from diluted ethanol to give yellow solid in
5
treated with ethanol to give the precipitate that was
filtered off and dried to give beige solid in 75% yield; mp
ꢀ
1
ꢀ1
2
1
(
32–235°C. IR (KBr) (νmax, cm ): 2925 (C–Haliph.),
86% yield; mp 127–130°C. IR (KBr) (νmax, cm ): 3445
1
698 (C¼O), 1665 (C¼N), 1068 (P–O–C). H-NMR
(br, NH), 2985 (C–Haliph), 2800 (SH), 1694 (C¼O), 1645
1
400 MHz, DMSO-d ): 2.16 (s, 3H, CH ), 3.06–3.27 (m,
(C¼N), 1515 (C¼C), 809 (P¼S). H-NMR (300 MHz,
6
3
2
H, NCH ), 4.10–4.49 (m, 2H, OCH ). MS (m/z, I%):
DMSO-d ): 2.08 (s, 3H, CH ), 7.55 (s, 1H, SH
2
2
6
3
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

S. M. Abdel-kariem
Vol 000
exchangeable with D O), 13.68 (s, 1H, NH exchangeable
[2] Anu, A.; Srivastava, K.; Purib, S. K.; Chauhan, P. M. S.
Bioorg Med Chem Lett 2005, 15, 531.
2
13
with D O). C-NMR (75 MHz, DMSO-d ): 21.9 (CH ),
2
6
3
[3] Sztanke, K.; Pasternak, K.; Rzymowska, J.; Sztanke, M.;
1
50.8 (C-6), 163.4 (C-3), 169.7 (C-5). MS (m/z, I%): 254
Kandefer-Szerszen, M. Eur J Med Chem 2008, 43, 1085.
+
(M , 1%). Anal. Calcd for C H N OPS (252.27): C,
[4] Bowden, C. L.; Singh, V. Expert Opin Pharmacother 2012, 13,
4
5
4
3
2
2
2
4
565.
1
2
9.04; H, 2.00; N, 22.21; S, 38.13. Found C, 19.00; H,
.03; N, 22.02; S, 38.00%.
[
5] Nivsarkar, M.; Gupta, A. K.; Kaushik, M. P. Tetrahedron Lett
004, 45, 6863.
[6] Yu, Z. H.; Shi, D. Q. Phosphorus, Sulfur Silicon Relat Elem
010, 185, 2316.
Synthesis of 2-(4-methoxyphenyl)-6-methyl-2-sulfido-1,2-
dihydro-7H-[1,3,4,2]thiadiaza-phospholo[5,4-c][1,2,4]triazin-
-one (12). Lawesson’s reagent (1.27 g, 3 mmol) was
[
7] Ali, H. M.; Ali, M. K. Bull Environ Contam Toxicol 2000, 65,
7
15.
added to a solution of compound 1 (0.5 g, 3 mmol) in
dry dioxane (30 mL). The mixture was heated under
reflux for 8–10 h. The crude material was washed with
diethyl ether. The obtained solid was filtered off and
crystallized from diluted ethanol to give yellow solid in
[
8] Sharma, D.; Narasimhan, B.; Kumar, P.; Judge, V.; Narang,
R.; Clercq, E. D.; Balzarini, J. Eur J Med Chem 2009, 44, 2347.
9] Mulato, A. S.; Cherrington, J. M. Antiviral Res 1997, 36, 91.
10] Demkowicz, S.; JanuszRachon, J.; Dasko, M.; Kozak, W. RSC
Adv 2016, 6, 7101.
[
[
[
11] Reddy, C. B.; Kumar, K. S.; Kumar, M. A.; Reddy, M. V. N.;
Krishna, B. S.; Naveen, M.; Arunasree, M. K.; Reddy, C. S.; Raju, C. N.;
Reddy, C. D. Eur J Med Chem 2012, 47, 553.
12] Ali, T. E.; Abdel-Aziz, S. A.; El-Edfawy, S. M.; Mohamed, E.
A.; Abdel-Kariem, S. M. Synth Commun 2014, 44, 3610.
[13] Abdel-Aziz, S. A.; Ali, T. E.; El-Mahdy, K. M. Eur J Chem
011, 2, 25.
14] Dornow, A.; Menzel, H.; Marx, P. Chem Ber 1964, 97, 2173.
15] Wang, X.; Cai, Y.; Chen, J.; Verpoort, F. Phosphorus, Sulfur,
Silicon Relat Elem 2016, 191, 1268.
ꢀ
1
7
3
1% yield; mp 158–160°C. IR (KBr) (νmax, cm ): 3296,
218 (br, NH), 3069 (C–Harom), 2973 (C–Haliph), 1663
[
(
(
C¼O), 1600 (C¼N), 1570 (C¼C), 1026 (O–C), 829
1
P¼S). H-NMR (300 MHz, DMSO-d ): 2.17 (s, 3H,
6
2
CH ), 3.92 (s, 3H, OCH ), 7.00 (d, J = 8.7 Hz, 2H, C-
3
NH exchangeable with D O). MS (m/z, I%): 326.35 (M ,
3
3
[
[
0
0
0
0
,5 ), 7.60 (m, J = 8.7 Hz, 2H, C-2 ,6 ), 13.75 (s, 1H,
+
2
[
[
16] Keglevich, G.; Bálint, E. Molecules 2012, 17, 12821.
17] Troev, K. D. Chemistry and application of H–Phosphonates;
Elsevier, 2006.
1
4
3
5%). Anal. Calcd for C H N O PS (326.33): C,
0.49; H, 3.40; N, 17.17; S, 19.65. Found C, 40.40; H,
.20; N, 17.14; S, 19.61%.
11 11 4 2 2
[
18] Saba, S.; Ciaccio, J. A.; Espinal, J.; Aman, C. E. J Chem Educ
2007, 84, 1011.
[19] Bauer, I.; Hadicher, W. D. Collect Czech Chem Commun
2
004, 69, 1190.
REFERENCES AND NOTES
[20] Haribabu, Y.; Srinivasulu, K.; Reddy, C. S.; Reddy, C. D.
Arkivoc 2006, xv, 95.
[
1] Congreve, M.; Andrews, S. P.; Doré, A. S.; Hollenstein, K.;
[
[
21] Berzelius, J. Libigs Ann Chem 1843, 46, 251.
22] Curphey, T. J. J Org Chem 2002, 67, 6461.
Hurrell, E.; Langmead, C. J.; Mason, J. S.; Ng, I. W.; Tehan, B.; Zhukov,
A.; Weir, M. H.; Marshall, F. H. J Med Chem 2012, 55, 1898.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet