Synthesis of 1,2,4-triazol-3-ylmethyl-, 1,3,4-oxa-, and -thiadiazol-2-ylmethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones

Article abstract of DOI:10.1007/s00706-007-0649-7

1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]triazolo[4,5-d]pyrimidine-5,7(4H, 6H)-dione was synthesized and treated with hydrazine hydrate to give the corresponding hydrazide. The latter hydrazide was treated either with phenylisothiocyanate or with carbon

Full text of DOI:10.1007/s00706-007-0649-7

Monatshefte fu¨r Chemie 138, 777–785 (2007)
DOI 10.1007/s00706-007-0649-7
Printed in The Netherlands
Synthesis of 1,2,4-Triazol-3-ylmethyl-, 1,3,4-Oxa-, and -Thiadiazol-2-ylmethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones
ꢀ
Farag A. El-Essawy, Ahmed F. Khattab, and Adel A.-H. Abdel-Rahman
Faculty of Science, Department of Chemistry, Menoufia University, Shebin El-Koam, Egypt
Received December 15, 2006; accepted (revised) January 3, 2007; published online May 31, 2007
# Springer-Verlag 2007
Summary. 1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]tri-
azolo[4,5-d]pyrimidine-5,7(4H,6H)-dione was synthesized
and treated with hydrazine hydrate to give the corresponding
hydrazide. The latter hydrazide was treated either with
phenylisothiocyanate or with carbon disulfide=alc. KOH to
in medicine, the synthesis of new compounds is of
vital importance due to increasing drug resistance.
Moreover, it is important to obtain therapeutical
compounds having less toxic effects. A number of
syntheses for substituted derivatives of these het-
erocyclic systems have been developed. Arylthio-
semicarbazides are versatile intermediates for the
synthesis of substituted triazoles, oxa-, and thiadia-
zoles [15–18]. The retrosynthetic analysis leads to
the conclusion that arylthiosemicarbazides can have
ambident sites for cyclization, which readily afford
these heterocycles carrying various substituents as
shown in Scheme 1. In addition, several compounds
containing the 1,2,3-triazolo[4,5-d]pyrimidine residue
are considered as potential purine antagonists [19].
Therefore, we wanted to develop an efficient proce-
dure for the synthesis of new heterocyclic systems
containing 1,2,4-triazoles, 1,3,4-oxa-, and -thiadia-
zoles linked with 1,2,3-triazolo[4,5-d]pyrimidines.
Our interest in the synthesis of such compounds
was to shed some light on their biological study as
antiviral agents as a part of our program aimed at the
development of new heterocyclic compounds as anti-
viral agents [20–23].
afford the corresponding thiosemicarbazide and oxadiazole
derivatives. Alkylation of 2-mercapto-1,3,4-oxadiazole with
dimethyl sulfate or ethyl chloroacetate gave the corresponding
2-methylthio-, and 2-ethylthioglycolate derivatives. Formation
of 1,3,4-thiadiazole, 5-mercapto-1,2,4-triazole, and 1,3,4-oxa-
diazole were carried out by treating of the latter thiosemicar-
bazide with conc. H2SO4, NaOH=HCl, and HgO. Treating of
5-mercapto-1,2,4-triazole with ethyl chloroacetate afforded
the thioglycolate ester. Hydrolysis of the latter with hydrazine
hydrate afforded the hydrazide derivatives. Condensation of
these hydrazides with monosaccharide aldoses gave the corre-
sponding sugar hydrazones. The novel compounds were tested
for antiviral activity against hepatitis B virus and showed mod-
erate activities.
Keywords. 1,2,4-Triazole; 1,3,4-Oxadiazole; 1,3,4-Thiadia-
zole; 6-Azido-1,3-dimethyuracil; Triazolopyrimidines.
Introduction
Triazoles, oxa-, and thiadiazoles have been the sub-
ject of chemical and biological studies on account of
their interesting pharmacological properties, such as
antimicrobial, antiinflammatory, analgesic, and an-
titumoral activities [1–7]. In addition, several 1,3,4-
oxadiazole derivatives have been reported to possess
biological activities [8–14]. Although there are a
number of antibiotics, which are commercially used
Results and Discussion
Synthesis
The starting material 1-carbethoxymethyl-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione
(1) [24] was synthesized by refluxing 6-azido-1,3-
ꢀ
Corresponding author. E-mail: adelnassar63@hotmail.com

778
F. A. El-Essawy et al.
Scheme 1
dimethyluracil [25] with ethyl chloroacetate in dry
DMF containing anhydrous potassium carbonate.
Treatment of 1 with hydrazine hydrate in ethanol
gave the corresponding hydrazide derivative 2 in
89% yield. The IR spectrum shows the characteristic
band for N–CO at 1660–1685 cmꢁ1. The hydrazide
2 was treated with phenylisothiocyanate in absolute
ethanol under reflux to afford 1-{4,6-dimethyl-1H-
[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}-
acetyl-4-phenyl thiosemicarbazide (3) in 92% yield.
Compound 3 shows a characteristic carbonyl fre-
quency at 1680–1695 cmꢁ1. Treatment of the hydra-
zide 2 with carbon disulfide in alcoholic potassium
hydroxide at reflux temperature afforded the corre-
sponding mercaptooxadiazole derivative 4 in 83%
yield. Compound 4 shows a characteristic SH fre-
quency at 2570 cmꢁ1. Methylation of 4 with dimethyl
sulfate afforded the corresponding methylthio de-
1
rivative 5 in 88% yield. The H NMR spectrum
showed a singlet at ꢀ ¼ 2.52 ppm for the SMe which
indicated that S-alkylation had taken place. Reaction
of 4 with ethyl chloroacetate=OHꢁ gave the corre-
sponding ethyl thioglycolate 6 in 78% yield. Its IR
spectrum shows a characteristic C¼O absorption at
1
1690–1700 cmꢁ1 and its H NMR spectrum agrees
with the structure. Treatment of 6 with hydrazine
hydrate in ethanol gave the corresponding hydrazide
derivative 7 in 81% yield (Scheme 2).

Synthesis of 1,2,4-Triazol-3-ylmethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones
779
Scheme 2
When the thiosemicarbazide 3 was treated with sul-
furic acid, 1,3,4-thiadiazole derivative 8 was formed
in 80% yield. The preferred formation of the thia-
diazole ring under such acidic conditions can be due
to the loss of nucleophilicity of N-4 as a result of
its protonation leading to an increase in the nucleo-
philicity of the sulfur atom towards the attack of
the carbonyl carbon. On the other hand, when the
cyclization of 3 was carried out under alkaline con-
ditions, the nucleophilicity of N-4 is enhanced and
leads to cyclization with the carbonyl carbon atom
to give the 1,2,4-triazole derivative 9 in 85% yield.
When the cyclization was performed by mercuric
oxide, the 1,3,4-oxadiazole derivative 10 was formed
in 71% yield. The mode of cyclization includes de-
sulfurization by mercuric oxide, which introduces

780
F. A. El-Essawy et al.
the oxygen atom in the cyclization process. Reaction
of 9 with ethyl chloroacetate=OHꢁ gave the corre-
sponding ethyl thioglycolate 11 in 80% yield. Treat-
ment of 11 with hydrazine hydrate in ethanol gave
the corresponding hydrazide derivative 12 in 79%
yield (Scheme 3).
and a doublet at ꢀ ¼ 7.20–7.50 ppm corresponding to
the proton at C-1 of the sugar. The assignments of NH
and OH groups in these compounds were achieved
by D2O exchange.
Testing
Condensation of the hydrazides 2, 7, and 12 with
L-arabinose, D-ribose, D-xylose, D-glucose, D-galac-
tose, and D-mannose gave the corresponding sugar
hydrazones 13a–13f (70–85%), 14a–14f (68–80%),
Preliminary viral screening against HBV (Hep G2
2.2.15 cell method) [26–28] indicated that com-
pounds 2, 4, 7, 9, 12, 16, 17, 21–23, and 26–29
are active against HBV replication with IC50 83–
99 ꢁM and CC50 88–95 ꢁM, while compounds 3,
5, 6, 8, 10, 11, 13–15, 18–20, 24, 25, and 30 showed
1
and 15a–15f (66–77%) – Scheme 4. The H NMR
spectra of the hydrazones 13–15 confirmed the pres-
ence of sugar protons in the range 3.14–4.23 ppm
Scheme 3

Synthesis of 1,2,4-Triazol-3-ylmethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones
781
Scheme 4
Egypt, and were found to agree favourably with the calculated
values. Viral screening against HBV was conducted at the
National Liver Institute, Menoufia University, Egypt.
moderate viral replication inhibition and moderate
cytotoxicity.
1-Carbethoxymethyl-4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione (1)
Conclusions
1,2,4-Triazol-3-ylmethyl, 1,3,4-oxa-, and -thiadiazol-
2-ylmethyl-1-[1,2,3]-triazolo[4,5-d]pyrimidindiones
were synthesized in order to increase the number of
tested compounds screened for anti-HBV activity.
A mixture of 18.1g 6-azido-1,3-dimethyluracil [25] (0.1mol),
14.7g ethyl chloroacetate (0.12 mol), and 13.8g anhydrous
K2CO3 (0.1mol) in 30cm3 dry DMF was refluxed for 2 h
(TLC). The solvent was removed in vacuo and the residue
was diluted with H2O and extracted with CH2Cl2. The com-
bined organic layers were dried (Na2SO4) and the solvent
was evaporated. The residue was recrystallized from ethanol
to afford 12g 1 (45%) (Ref. [24] 21%). Mp: 165–166ꢂC;
1H NMR (DMSO-d6, 250 MHz): ꢀ ¼ 1.22 (t, J ¼ 6.1 Hz,
CH3CH2O), 3.41 (s, N6–CH3), 3.62 (s, N4–CH3), 4.25 (q,
J ¼ 6.1 Hz, CH3CH2O), 5.44 (s, N1–CH2) ppm; 13C NMR
(DMSO-d6, 62.5MHz): ꢀ ¼ 14.0 (CH3CH2O), 27.8 (N6–CH3),
29.8 (N4–CH3), 48.3 (N1–CH2), 61.3 (CH3CH2O), 110.6
(C-7a), 150.2 (C-3a), 150.9 (C-5), 153.3 (C-7), 166.1 (C¼O)
ppm; MS: m=z (%) ¼ 267 (Mþ, 20).
Experimental
Melting points were determined using a Kofler block instru-
ment. IR spectra were recorded with a Perkin-Elmer model
1720 FTIR (KBr), 1H NMR spectra were recorded with
Bruker AC 250 FT NMR spectrometer at 250 MHz with TMS
as an internal standard. EIMS and FABMS spectra were
recorded with a Finnigen MAT 312=AMD. The microanalyses
were performed at the microanalytical unit, Cairo University,

782
F. A. El-Essawy et al.
to afford 3.26 g 5 (88%). Mp: 174–175ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 2.52 (s, SMe), 3.38 (s, N6–CH3), 3.55 (s, N4–
CH3), 5.76 (s, N1–CH2) ppm; MS: m=z (%) ¼ 309 (Mþ, 33).
1-Acetylhydrazine-4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione (2, C8H11N7O3)
A mixture of 2.67g 1 (10 mmol) and 1.25 g N2H4 ꢃ H2O
(25 mmol) in 30 cm3 ethanol was heated under reflux for 3 h.
The excess of ethanol was removed under reduced pressure
and the resulting precipitate was filtered off, washed with etha-
nol, and recrystallized from ethanol to give 2.25 g 2 (89%).
Mp: 145–146ꢂC; IR (KBr): ꢂꢀ¼ 3310 and 3210 (NH), 2950
Ethyl {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-(1,3,4-oxadiazol-2-yl)methyl}-
thioglycolate (6, C13H15N7O5S)
A solution of 2.95g 4 (10 mmol) was refluxed with 0.23g Na
(10 mmol) in 10cm3 absolute ethanol for 1 h. Then 1.22g
ethyl chloroacetate (10 mmol) were added and refluxed for
an additional 6 h. After evaporation under reduced pressure, a
solid appeared. This was recrystallized from EtOH:H2O (1:1)
to afford 2.97 g 6 (78%). Mp: 170–172ꢂC; IR (KBr): ꢂꢀ¼
(C–H), 1660–1685 (C¼O) cmꢁ1
;
1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.40 (s, N6–CH3), 3.60 (s, N4–CH3), 4.82
(br, s, NHNH2), 5.14 (s, N1–CH2), 9.45 (br, s, NHNH2) ppm;
13C NMR (DMSO-d6, 62.5MHz): ꢀ ¼ 27.7 (N6–CH3), 29.9
(N4–CH3), 49.9 (N1–CH2), 111.7 (C-7a), 150.5 (C-5), 153.1
(C-3a), 154.9 (C-7), 168.0 (C¼O) ppm; MS: m=z (%) ¼ 254
(Mþ þ 1, 14).
1
1690–1700 (C¼O) cmꢁ1; H NMR (DMSO-d6, 250 MHz):
ꢀ ¼ 1.20 (t, J ¼ 6.1 Hz, CH3CH2O), 3.40 (s, N6–CH3), 3.63
(s, N4–CH3), 3.78 (s, SCH2), 4.15 (q, J ¼ 6.1 Hz, CH3CH2O),
5.74 (s, N1–CH2) ppm; 13C NMR (DMSO-d6, 62.5MHz):
ꢀ ¼ 14.0 (CH3CH2O), 27.5 (N6–CH3), 29.9 (N4–CH3), 41.9
(SCH2), 44.9 (N1–CH2), 61.9 (CH3CH2O), 110.2 (C-7a), 149.0
(C-3a), 150.5 (C-5), 152.1 (C-7), 168.7 (C¼O), 169.2, 170.9
(oxadiazole carbons) ppm; MS: m=z (%) ¼ 381 (Mþ, 25).
1-{4,6-Dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7-
(4H,6H)-dione}acetyl-4-phenyl thiosemicarbazide
(3, C15H16N8O3S)
To a solution of 2.53 g 2 (10 mmol) in 10 cm3 ethanol, 1.35g
phenylisothiocyanate (10 mmol) were added. The reaction
mixture was heated under reflux for 1 h. The product that sep-
arated on cooling was filtered off, washed with ethanol, and
dried well to give 3.57 g 3 (92%). Mp: 170–171ꢂC; IR (KBr):
ꢂꢀ¼ 1680–1695 (C¼O) cmꢁ1; 1H NMR (DMSO-d6, 250 MHz):
ꢀ ¼ 3.47 (s, N6–CH3), 3.63 (s, N4–CH3), 5.20 (s, N1–CH2),
7.20–7.32 (m, Ph-H), 7.48–7.7.53 (m, Ph-H), 7.94 (br, s, NH)
ppm; 13C NMR (DMSO-d6, 62.5MHz): ꢀ ¼ 27.8 (N6–CH3),
29.8 (N4–CH3), 50.6 (N1–CH2), 111.8 (C-7a), 125.9, 128.3,
139.0 (Ph-C), 150.5 (C-5), 153.1 (C-3a), 155.0 (C-7), 163.1
(C¼O), 181.1 (C¼S) ppm; MS: m=z (%) ¼ 388 (Mþ, 22).
{5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-
5,7(4H,6H)-dione]-(1,3,4-oxadiazol-2-yl)methyl}-
thioglycolylhydrazide (7, C11H13N9O4S)
A solution of 3.81 g 6 (10 mmol) in 30 cm3 ethanol was re-
fluxed with 1.25 g N2H4 ꢃ H2O (25 mmol) for 4 h. After cool-
ing it to room temperature, a white solid appeared. This was
recrystallized from ethanol to afford 2.97 g 7 (81%). Mp:
295–296ꢂC; 1H NMR (DMSO-d6, 250MHz): ꢀ ¼ 3.41 (s,
N6–CH3), 3.64 (s, N4–CH3), 3.88 (s, SCH2), 4.90 (br, s,
NHNH2), 5.74 (s, N1–CH2), 9.40 (br, s, NHNH2) ppm; MS:
m=z (%) ¼ 368 (Mþ þ 1, 11).
1-(2-Mercapto-1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione
(4, C9H9N7O3S)
1-[(5-Phenylamino-1,3,4-thiadiazol-2-yl)methyl]-4,6-
dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-
dione (8, C15H14N8O2S)
A mixture of 2.53 g 2 (10 mmol) and 0.6 cm3 CS2 (10 mmol)
was added to a solution of 0.56 g KOH (10 mmol) in 50cm3
H2O and 50 cm3 ethanol. The reaction mixture was refluxed
for 4 h. After evaporating it to dryness under reduced pressure,
a solid was obtained. This was dissolved in 50cm3 H2O and
acidified with conc. HCl. The precipitate was filtered off,
washed with H2O, and recrystallised from ethanol to afford
2.45g 4 (83%). Mp: 283–285ꢂC; IR (KBr): ꢂꢀ¼ 2570 (SH),
1670–1685 (C¼O), 1590 and 1540 (–C¼N), 1170 (–C¼S)
cmꢁ1; 1H NMR (DMSO-d6, 250 MHz): ꢀ ¼ 3.40 (s, N6–CH3),
3.67 (s, N4–CH3), 5.66 (s, N1–CH2), 13.40 (br, s, SH) ppm;
13C NMR (DMSO-d6, 62.5MHz): ꢀ ¼ 27.6 (N6–CH3), 29.9
(N4–CH3), 43.6 (N1–CH2), 110.0 (C-7a), 147.0 (C-3a), 151.1
(C-5), 152.3 (C-7), 162.4, 171.2 (oxadiazole carbons) ppm;
MS: m=z (%) ¼ 295 (Mþ, 15).
A solution of 1.94g 3 (5mmol) in 10 cm3 cold conc. H2SO4
was stirred until dissolution and then left at room temperature
for 2 h. The reaction mixture was poured onto crushed ice and
the precipitated product was filtered off, washed with H2O,
and recrystallized from ethanol to give 1.48g 8 (80%). Mp:
205–207ꢂC; 1H NMR (DMSO-d6, 250MHz): ꢀ ¼ 3.40 (s, N6–
CH3), 3.59 (s, N4–CH3), 5.70 (s, N1–CH2), 6.99 (m, Ph-H),
7.33 (m, Ph-H), 7.52 (m, Ph-H), 11.99 (br, s, NHPh) ppm;
MS: m=z (%) ¼ 370 (Mþ, 34).
1-[(5-Mercapto-4-phenyl-1,2,4-triazol-3-yl)methyl]-4,6-
dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-
dione (9, C15H14N8O2S)
A solution of 3.88 g 3 (10 mmol) in 50 cm3 2 N NaOH was
heated under reflux for 3 h. The reaction mixture was cooled
and acidified with 2 N HCl. The resulting precipitate was
filtered off, washed with ethanol and recrystallized from eth-
anol to give 3.14 g 9 (85%). Mp: 213–215ꢂC; 1H NMR
(DMSO-d6, 250 MHz): ꢀ ¼ 3.38 (s, N6–CH3), 3.61 (s, N4–
CH3), 5.81 (s, N1–CH2), 7.23–7.34 (m, Ph-H), 13.69 (br, s,
SH) ppm; MS: m=z (%) ¼ 370 (Mþ, 22).
1-(2-Methythio-1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione
(5, C10H11N7O3S)
A solution of 3.54g 4 (12 mmol) in 10cm3 10% KOH solution
was stirred for 1 h. The reaction mixture was treated dropwise
with 1.76 g Me2SO4 (14 mmol). The precipitated solid was
filtered off, washed with H2O, and recrystallized from ethanol

Synthesis of 1,2,4-Triazol-3-ylmethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones
783
4ꢄOH), 5.14 (s, N1–CH2), 7.50 (d, J ¼ 2.5 Hz, H-10), 8.90
(br, s, NH) ppm; MS: m=z (%) ¼ 385 (Mþ, 22).
1-[(5-Phenylamino-1,3,4-oxadiazol-2-yl)methyl]-4,6-
dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-
dione (10, C15H14N8O3)
D-(ꢁ)-Ribose {4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione}acetylhydrazone
(13b, C13H19N7O7)
Yield: 81%. Mp: 150–152ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.14–3.52 (m, H-20, H-30, H-40, H-50, N6–
CH3), 3.65 (m, N4–CH3), 3.99–4.21 (br, s, 4ꢄOH), 5.43 (s,
N1–CH2), 7.30 (d, J ¼ 2.5 Hz, H-10), 8.88 (br, s, NH) ppm;
MS: m=z (%) ¼ 385 (Mþ, 18).
HgO (2.37 g, 11 mmol) was added to a solution of 3.88 g 3
(10 mmol) in 20 cm3 methanol and the resulting mixture was
refluxed for 3 h. The precipitated HgS was filtered off and
washed with hot methanol. The filtrate on cooling gave a pre-
cipitate which was recrystallized from ethanol to give 2.51g
1
10 (71%). Mp: 199–201ꢂC; H NMR (DMSO-d6, 250 MHz):
ꢀ ¼ 3.41 (s, N6–CH3), 3.64 (s, N4–CH3), 5.73 (s, N1–CH2),
6.97 (m, Ph-H), 7.32 (m, Ph-H), 7.72 (m, Ph-H), 9.14 (br, s,
NHPh) ppm; MS: m=z (%) ¼ 355 (Mþ þ 1, 19).
D-(þ)-Xylose {4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione}acetylhydrazone
(13c, C13H19N7O7)
Yield: 77%. Mp: 173–174ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.41–3.69 (br, m, H-40, H-50, N4–CH3, N6–
CH3), 3.59–3.61 (s, H-20, H-30), 4.42–4.92 (br, s, 4ꢄOH),
5.30 (s, N1–CH2), 7.20 (d, J ¼ 2.5 Hz, H-10), 8.98 (br, s,
NH) ppm; MS: m=z (%) ¼ 385 (Mþ, 26).
Ethyl {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-
5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)methyl}
thioglycolate (11, C19H20N8O4S)
A solution of 3.70g 9 (10 mmol) was refluxed with 0.23 g Na
(10 mmol) in 10cm3 absolute ethanol for 1 h. Then 1.22g
ethyl chloroacetate (10 mmol) were added and refluxed for
an additional 6 h. After evaporation under reduced pressure,
a solid appeared. This was recrystallized from EtOH:H2O
(1:1) to afford 3.65 g 11 (80%). Mp: 183–185ꢂC; 1H
NMR (DMSO-d6, 250 MHz): ꢀ ¼ 1.25 (t, J ¼ 6.1 Hz,
CH3CH2O), 3.41 (s, N6–CH3), 3.60 (s, N4–CH3), 3.89 (s,
SCH2), 4.17 (q, J ¼ 6.1 Hz, CH3CH2O), 6.00 (s, N1–CH2),
7.25 (m, Ph-H), 7.49 (m, Ph-H) ppm; MS: m=z (%) ¼ 456
(Mþ, 10).
D-(þ)-Glucose {4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione}acetylhydrazone
(13d, C14H21N7O8)
Yield: 85%. Mp: 145–147ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.44–3.89 (m, H-30, H-40, H-50, H-60, N4–
CH3, N6–CH3), 4.27 (s, H-20), 4.40–4.90 (br, s, 5ꢄOH),
5.34 (s, N1–CH2), 7.40 (d, J ¼ 2.5Hz, H-10), 8.99 (br, s, NH)
ppm; MS: m=z (%) ¼ 415 (Mþ, 23).
{5-[4,6-Dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7-
(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)methyl}
thioglycolylhydrazide (12, C17H18N10O3S)
D-(þ)-Galactose {4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione}acetylhydrazone
(13e, C14H21N7O8)
Yield: 70%. Mp: 159–161ꢂC; 1H NMR (DMSO-d6, 250 MHz):
ꢀ ¼ 3.34–3.93 (m, H-50, H-60, N4–CH3, N6–CH3), 4.12–4.23
(br, s, H-20, H-30, H-40), 4.33–4.80 (br, s, 5ꢄOH), 5.39 (s,
N1–CH2), 7.43 (d, J ¼ 2.5 Hz, H-10), 8.92 (br, s, NH) ppm;
MS: m=z (%) ¼ 415 (Mþ, 10).
A solution of 4.56 g 11 (10 mmol) in 30 cm3 ethanol was
refluxed with 1.25 g N2H4 ꢃ H2O (25 mmol) for 4 h. After
cooling it to room temperature, a white solid appeared.
This was recrystallized from ethanol to afford 3.49 g 12
1
(79%). Mp: 268–269ꢂC; H NMR (DMSO-d6, 250 MHz):
ꢀ ¼ 3.41 (s, N6–CH3), 3.62 (s, N4–CH3), 3.84 (s, SCH2), 4.95
(br, s, NHNH2), 6.04 (s, N1–CH2), 7.28 (m, Ph-H), 7.39 (m,
Ph-H), 9.34 (br, s, NHNH2) ppm; MS: m=z (%) ¼ 443
(Mþ þ 1, 7).
D-(þ)-Mannose {4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione}acetylhydrazone
(13f, C14H21N7O8)
Sugar {4,6-Dimethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidine-
5,7(4H,6H)-dione}acetylhydrazones 13–15
Yield: 80%. Mp: 182–184ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.44–3.78 (m, H-20, H-30, H-40, H-50, H-60,
N4–CH3, N6–CH3), 4.36–4.47 (br, s, 5ꢄOH), 5.43 (s, N1–
CH2), 7.45 (d, J ¼ 2.5 Hz, H-10), 8.96 (br, s, NH) ppm; MS:
m=z (%) ¼ 415 (Mþ, 6).
A solution of the sugar (10 mmol) in 3 cm3 H2O was treated
with a solution of 2, 7, and 12 (10 mmol) in 100 cm3 ethanol,
and a few drops of glacial acetic acid. The mixture was boiled
under reflux for 3–5 h (TLC). The excess of ethanol was re-
moved under reduced pressure and the residue was triturated
with 15cm3 diethyl ether. The product was filtered off, washed
with ether, and recrystallized from ethanol.
L-(þ)-Arabinose {(1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}
thioglycolylhydrazone (14a, C16H21N9O8S)
Yield: 79%. Mp: 155–157ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.14–3.38–3.50 (m, H-30, H-40, H-50, N6–
CH3), 3.60–3.85 (m, H-20, N4–CH3, SCH2), 4.44–4.58 (br,
s, 4ꢄOH), 5.66 (s, N1–CH2), 7.40 (d, J ¼ 2.5 Hz, H-10),
8.88 (br, s, NH) ppm.
L-(þ)-Arabinose {4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione}acetylhydrazone
(13a, C13H19N7O7)
Yield: 80%. Mp: 177–178ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.14–3.40 (m, H-40, H-50, N6–CH3), 3.49
(s, H-30), 3.60–3.65 (m, H-20, N4–CH3), 4.39–4.51 (br, s,

784
F. A. El-Essawy et al.
D-(ꢁ)-Ribose {(1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}
thioglycolylhydrazone (14b, C16H21N9O8S)
Yield: 80%. Mp: 190–192ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.30–3.62 (m, H-20, H-30, H-40, H-50, N4–
CH3, N6–CH3), 3.90–4.22 (br, s, 4ꢄOH, SCH2), 5.63 (s,
N1–CH2), 7.34 (d, J ¼ 2.5 Hz, H-10), 8.89 (br, s, NH) ppm.
D-(þ)-Xylose {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)-
methyl}thioglycolylhydrazone (15c, C22H26N10O7S)
Yield: 70%. Mp: 180–181ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.41–3.99 (br, m, H-20, H-30, H-40, H-50, N4–
CH3, N6–CH3, SCH2), 4.49–4.90 (br, s, 4ꢄOH), 5.80 (s, N1–
CH2), 7.20–7.40 (m, H-10, Ph-H), 8.92 (br, s, NH) ppm.
D-(þ)-Xylose {(1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}
thioglycolylhydrazone (14c, C16H21N9O8S)
Yield: 77%. Mp: 203–204ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.40–4.02 (br, m, H-20, H-30, H-40, H-50, N4–
CH3, N6–CH3, SCH2), 4.55–4.90 (br, s, 4ꢄOH), 5.70 (s, N1–
CH2), 7.23 (d, J ¼ 2.5 Hz, H-10), 8.95 (br, s, NH) ppm.
D-(þ)-Gluose {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)-
methyl}thioglycolylhydrazone (15d, C23H28N10O8S)
Yield: 77%. Mp: 150–152ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.42–3.97 (m, H-20, H-30, H-40, H-50, H-60,
N4–CH3, N6–CH3, SCH2), 4.47–4.90 (br, s, 5ꢄOH), 5.74 (s,
N1–CH2), 7.32–7.49 (m, H-10, Ph-H), 8.94 (br, s, NH) ppm.
D-(þ)-Glucose {(1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}
thioglycolylhydrazone (14d, C17H23N9O9S)
Yield: 80%. Mp: 195–197ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.44–4.12 (br, m, H-20, H-30, H-40, H-50, H-
60, N4–CH3, N6–CH3, SCH2), 4.40–4.70 (br, s, 5ꢄOH), 5.74
(s, N1–CH2), 7.40 (d, J ¼ 2.5 Hz, H-10), 8.90 (br, s, NH) ppm.
D-(þ)-Galactose {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)-
methyl}thioglycolylhydrazone (15e, C23H28N10O8S)
Yield: 66%. Mp: 169–171ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.44–4.00 (m, H-50, H-60, N4–CH3, N6–CH3,
SCH2), 4.19–4.33 (m, H-20, H-30, H-40), 4.50–4.87 (br, s,
5ꢄOH), 5.79 (s, N1–CH2), 7.32–7.49 (m, H-10, Ph-H), 8.93
(br, s, NH) ppm.
D-(þ)-Galactose {(1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}
thioglycolylhydrazone (14e, C17H23N9O9S)
Yield: 68%. Mp: 177–179ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.44–4.23 (br, m, H-20, H-30, H-40, H-50, H-
60, N4–CH3, N6–CH3, SCH2), 4.33–4.80 (br, s, 5ꢄOH), 5.66
(s, N1–CH2), 7.41 (d, J ¼ 2.5 Hz, H-10), 8.90 (br, s, NH) ppm.
D-(þ)-Mannose {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)-
methyl}thioglycolylhydrazone (15f, C23H28N10O8S)
Yield: 75%. Mp: 144–145ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.44–4.03 (br, m, H-20, H-30 H-40, H-50, H-60,
N4–CH3, N6–CH3, SCH2), 4.44–4.67 (br, s, 5ꢄOH), 5.83 (s,
N1–CH2), 7.33–7.50 (m, H-10, Ph-H), 8.98 (br, s, NH) ppm.
D-(þ)-Mannose {(1,3,4-oxadiazol-5-ylmethyl)-4,6-dimethyl-
1H-[1,2,3]-triazolo[4,5-d]pyrimidine-5,7(4H,6H)-dione}
thioglycolylhydrazone (14f, C17H23N9O9S)
Yield: 73%. Mp: 162–163ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.40–3.98 (br, m, H-20, H-30, H-40, H-50, H-
60, N4–CH3, N6–CH3, SCH2), 4.40–4.52 (br, s, 5ꢄOH), 5.63
(s, N1–CH2), 7.42 (d, J ¼ 2.5 Hz, H-10), 8.97 (br, s, NH) ppm.
References
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[7] Demirbas N, Alpay Karaoglu S, Demirbas A, Sancak K
(2004) Eur J Med Chem 39: 793
L-(þ)-Arabinose {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)-
methyl}thioglycolylhydrazone (15a, C22H26N10O7S)
Yield: 74%. Mp: 211–212ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.33–3.54 (m, H-30, H-40, H-50, N6–CH3),
3.60–3.85 (m, H-20, N4–CH3, SCH2), 4.44–4.58 (br, s,
4ꢄOH), 5.84 (s, N1–CH2), 7.30–7.44 (m, H-10, Ph-H), 8.90
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D-(ꢁ)-Ribose {5-[4,6-dimethyl-1H-[1,2,3]-triazolo[4,5-d]-
pyrimidine-5,7(4H,6H)-dione]-4-phenyl-(1,2,4-triazol-3-yl)-
methyl}thioglycolylhydrazone (15b, C22H26N10O7S)
Yield: 71%. Mp: 139–141ꢂC; 1H NMR (DMSO-d6,
250 MHz): ꢀ ¼ 3.33–3.82 (br, m, H-20, H-30, H-40, H-50 N4–
CH3, N6–CH3, SCH2), 4.11–4.28 (br, s, 4ꢄOH), 5.83 (s, N1–
CH2), 7.20 (d, J ¼ 2.5 Hz, H-10), 7.37–7.48 (m, Ph-H), 8.89
(br, s, NH) ppm.
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Synthesis of 1,2,4-Triazol-3-ylmethyl-1H-[1,2,3]-triazolo[4,5-d]pyrimidinediones
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