Purine and Guanine Thioglycoside Analogs: Novel Synthesis of a New Class of Pyrazolo[1,5-a][1,3,5]Triazine-4-Thioglycoside Derivatives under Microwave Activation

Article abstract of DOI:10.1080/15257770.2015.1078470

A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogues from readily available starting materials has been described. The key step of this protocol is the formation of sodium pyrazolo[1,5-a][1,3,5]triazine-4-thiolates via condensation of 5-amino-1H-pyrazoles with sodium cyanocarbonimidodithioate salt under microwave irradiation, followed by coupling with halo sugars to give the corresponding purine thioglycoside analogues. Further studies on the application of this method for the synthesis of other highly functionalized biologically active glycosides are underway.

Full text of DOI:10.1080/15257770.2015.1078470

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
Purine and Guanine Thioglycoside Analogs:
Novel Synthesis of a New Class of Pyrazolo[1,5-A]
[1,3,5]Triazine-4-Thioglycoside Derivatives under
Microwave Activation
Galal Elgemeie & Mamdouh Abu-Zaied
To cite this article: Galal Elgemeie & Mamdouh Abu-Zaied (2015): Purine and Guanine
Thioglycoside Analogs: Novel Synthesis of a New Class of Pyrazolo[1,5-A][1,3,5]Triazine-4-
Thioglycoside Derivatives under Microwave Activation, Nucleosides, Nucleotides and Nucleic
Acids, DOI: 10.1080/15257770.2015.1078470
To link to this article: http://dx.doi.org/10.1080/15257770.2015.1078470
Published online: 23 Sep 2015.
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Date: 08 October 2015, At: 23:07

Nucleosides, Nucleotides and Nucleic Acids, 00:1–14, 2015
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2015.1078470
PURINE AND GUANINE THIOGLYCOSIDE ANALOGS: NOVEL
SYNTHESIS OF A NEW CLASS OF
PYRAZOLO[1,5-A][1,3,5]TRIAZINE-4-THIOGLYCOSIDE DERIVATIVES
UNDER MICROWAVE ACTIVATION
Galal Elgemeie1 and Mamdouh Abu-Zaied2
1Chemistry Department, Faculty of Science, Helwan University, Helwan, Cairo, Egypt
2Green Chemistry Department, National Research Centre, Dokki, Cairo, Egypt
A first microwave-assisted synthesis of a new class of novel purine thioglycoside analogues from
2
readily available starting materials has been described. The key step of this protocol is the formation of
sodium pyrazolo[1,5-a][1,3,5]triazine-4-thiolates via condensation of 5-amino-1H-pyrazoles with
sodium cyanocarbonimidodithioate salt under microwave irradiation, followed by coupling with
halo sugars to give the corresponding purine thioglycoside analogues. Further studies on the appli-
cation of this method for the synthesis of other highly functionalized biologically active glycosides are
underway.
Keywords Microwave synthesis; purine thioglycoside analogues; thioglycosides; sodium
cyanocarbonimidodithioate salt; anti-metabolites
INTRODUCTION
6-Mercaptopurine (6-MP) is commonly referred by pharmacists as
purinethol. It is listed as an anti-neoplastic and immunosuppressant. 6-MP
is a DNA anti-metabolite. This means that it mimics the substance necessary
in DNA synthesis.[1] In the body, 6-MP is converted into the corresponding
ribonucleotide. 6-MP ribonucleotide is a potent inhibitor of the conversion
of the compound called inosinic acid to adenylic acid. Without adenylic acid,
DNA cannot be synthesized. 6-MP also works by being incorporated into nu-
cleic acids as thioguanosine, rendering the resulting nucleic acids (DNA,
RNA) unable to direct proper protein synthesis.[2] 6-Thioguanine (6-TG) is
closely related to 6-MP in both structure and metabolism. Similar to 6-MP,
6-TG is a purine anti-metabolite. Thioguanine inhibits purine biosynthesis as
does 6-MP, albeit at different steps.[3] 6-MP and 6-TG are the only two purine
Received 29 January 2015; accepted 27 July 2015.
Address correspondence to Prof. Galal Elgemeie, Chemistry Department, Faculty of Science, Helwan
University, Helwan, Cairo, Egypt. E-mail: elgemeie@yahoo.com
1

2
G. Elgemeie and M. Abu-Zaied
anti-metabolites that are currently used in chemotherapy.[4] 6-MP and 6-TG
have certain therapeutic disadvantages, which have continued to stimulate
the search for purine analogs enhancing therapeutic efficacy.[5] Consider-
able efforts have been made to prepare other novel mercaptopurine and
thioguanine analogs and their nucleosides to improve anti-tumor efficacy;
very few examples are reported for the synthesis of purine and guanine thio-
glycosides. In recent reports from our laboratory, we described the prepa-
ration of different novel functionalized heterocyclic thioglycosides.[6–12] In
an earlier brief communication, we had already reported the use of dihy-
dropyridine thioglycosides as substrates or inhibitors in the protein glyco-
sylation process.[13,14] These common features encouraged us to develop a
new straightforward route for the synthesis of guanine and purine thiogly-
cosides. Continuing our efforts for the development of simple, eco-friendly
and cost-effective methodologies,[15] we report here in this research a novel
microwave-assisted synthesis of thioguanine and mercaptopurine analogues
and their thioglycosides as anti-metabolic agents. As far as we know, this is
the first method to be reported for the preparation of such a novel ring
system.
RESULTS AND DISCUSSION
It has been found that reaction of cyanamide with carbon disulfide in the
presence of sodium ethoxide gives sodium cyanocarbonimidodithioate salt
2. Compounds 2 are readily reacted with one equivalent of 5-aminopyrazoles
1a-e in the presence of acetic acid under microwave activation for 10 min to
give the corresponding pyrazolo[1,5-a][1,3,5]triazine-4-thiol derivatives 4a-e
in good yields. The structures of 4a-e were established on the basis of its ele-
mental analysis and spectral data (IR, 1H NMR, and 13C NMR). Compounds
4a-e can also be prepared through the reaction of cyanocarbonimidodithioic
acid 3 with 5-aminopyrazoles 1a-e under the same reaction conditions. Com-
pounds 4a-e reacted with halosugars 5 in dimethylformamide at room tem-
perature to give in high yield the corresponding S-glycosides 6a-j (Scheme 1).
It has been suggested that the cis-(α) sugars react by a simple SN2 reaction
to give the β-glycoside products.[16] The structures of 6a-j were established
1
on the basis of their elemental analysis and spectral data (IR, H NMR,
and 13C NMR). For example, the analytical data for 6a revealed a
molecular formula C25H28N8O9S, its 1H NMR spectrum showing the
anomeric proton as a doublet at δ 5.29–5.32 ppm with a spin–spin cou-
pling constant of 11.25 Hz indicating the β-configuration. The other
six glucose protons resonated at δ 3.73–4.82 ppm. When glycosides
6a-j were treated with methanolic ammonia at room temperature for
10 min, the deprotected derivatives 7a-j were obtained in almost quan-
titative yields (Scheme 2), the structures of which were established

Synthesis of Purine and Guanine Thioglycoside Analogs
3
SCHEME 1 Synthetic pathway for 4-(2ꢁ,3ꢁ,4ꢁ,6ꢁ-Tetra-O-acetyl-β-D-glycopyranosylthio)-pyrazolo[1,5-
a][1,3,5]triazines 6a-j
on the basis of elemental analysis and spectral data. Thus, the an-
alytical data for 7a reveal the molecular formula C17H20N8O5S. The
1H NMR spectrum shows the anomeric proton as a doublet at δ 4.52–4.54 (J 1,2
= 9.95 Hz), indicating the presence of only β-D configuration. The other six-
glucose protons appear as a multiplet at δ 3.34–4.41, while the four hydroxy
groups of glucose moiety resonated at δ 5.14–5.23 (exchangeable by D2O).
Encouraged by these results, methylation of compounds 4a-e with methyl io-
dide in sodium ethoxide gave the 4-methylthiopyrazolo[1,5-a][1,3,5]triazine

4
G. Elgemeie and M. Abu-Zaied
SCHEME 2 Synthetic pathway for 4-(β-D-Glycopyranosylthio)-pyrazolo[1,5-a][1,3,5]triazines 7a-j
products 9a-e.[10] Compounds 9a-e can also be prepared by the reaction
of 1a-e with dimethyl N -cyanodithioiminocarbonate 8 in acetic acid un-
der microwave activation for 10 min. When compounds 6a-j and 9a-e were
subjected to reaction with aniline, the corresponding 4-anilinopyrazolo[1,5-
a][1,3,5]triazine derivatives 10a-e were obtained [17] (Scheme 3). The struc-
ture of compound 10 was established on the basis of elemental analysis and
spectral data (MS, 1H NMR, and IR).
CONCLUSIONS
We have developed a new and simple method for the synthesis of purine
and guanine thioglycoside analogues under microwave activation. The mild
reaction conditions, clean reaction profiles, zero side product, and cost-
efficiency render this approach as a useful and innovative one to the existing

Synthesis of Purine and Guanine Thioglycoside Analogs
5
SCHEME 3 Synthetic pathway for pyrazolo[1,5-a][1,3,5]triazines 4a-e, 9a-e, 10a-e
methods for glycoside formation. Further studies on the application of this
method for the synthesis of other highly functionalized biologically active
glycosides are underway.

6
G. Elgemeie and M. Abu-Zaied
EXPERIMENTAL
All melting points were measured on a Gallenkamp melting point appa-
ratus. The 1H NMR spectra were measured on a Jeol-500 MHz spectrometer
for solutions DMSO-d6 and CDCl3 using Si(CH3)4 as an internal standard at
National Research Centre, Cairo, Egypt. Progress of the reactions was mon-
itored by TLC using aluminum sheets coated with silica gel F254 (Merck).
Viewing under a short-wavelength UV lamp effected detection. Microwave
reactions were conducted using microwave.
General Procedure for Synthesizing 4a-e
A mixture of 4-(Aryldiazenyl)-1H-pyrazole-3,5-diamine 1a-e (10 mmol)
and sodium cyanocarbonimidodithioate 2 or cyanocarbonimidodithioic acid
3 (10 mmol) in a glacial acetic acid (20 mL), irradiated in a microwave oven
for 10 min at 150◦C, the reaction mixture was cooled to room temperature
and triturated with MeOH to afford 4a-e, which was collected by filtration,
and recrystallized from the appropriate solvent.
2,7-Diamino-8-(phenyldiazenyl)pyrazolo[1,5-a][1,3,5]triazine-4-thiol (4a)
Yellow solid (MeOH) yield 82%: m.p. 210◦C; IR (KBr, cm−1) υ 3447,
3438, 3325 (NH2), 1610 (C N), 1599 (C C). 1H NMR (500 MHz, DMSO-
d6): δ 6.34 (s, 2H, NH2), 6.65 (s, 2H, NH2), 7.23–7.47 (m, 5H, C6H5), 12.27
(s, 1H, SH); 13C NMR: δ 94.2 (C-8), 129.5 (4C, Ar-C), 129.8 (2C, Ar-C), 136.1
(C-8a), 155.7 (C-7), 180.1 (C-2), 201.2 (C-4); MS. m/z (%) [M+ 286]. Anal.
Calcd. for C11H10N8S (286.32): C, 46.14; H, 3.52; N, 39.14; S, 11.20. Found:
C, 46.16; H, 3.45; N, 39.18; S, 11.15.
2,7-Diamino-8-(4-methoxyphenyldiazenyl)pyrazolo[1,5-a][1,3,5]
triazine-4-thiol (4b)
Yellow solid (MeOH) yield 82%: m.p. 224◦C; IR (KBr, cm−1) υ 3443,
3438, (NH2), 1609 (C N), 1599 (C C). 1H NMR (500 MHz, DMSO-d6): δ
4.01 (s, 3H, OCH3), 6.62 (s, 2H, NH2), 6.68 (s, 2H, NH2), 7.23–7.49 (m,
4H, C6H4), 12.13 (s, 1H, SH); 13C NMR: δ 57.2 (CH3), 96.4 (C-8), 115.9
(2C, Ar-C), 129.8 (2C, Ar-C), 122.5 (Ar-C), 162.1 (Ar-C), 137.5 (C-8a), 157.8
(C-7), 182.6 (C-2), 200.7 (C-4). Anal. Calcd. for C12H12N8OS (316.34): C,
45.50; H, 3.80; N, 35.42; S, 10.14. Found: C, 45.56; H, 3.82; N, 35.40; S, 10.10.
2,7-Diamino-8-(p-tolyldiazenyl)pyrazolo[1,5-a][1,3,5]triazine-4-thiol (4c)
Yellow solid (MeOH) yield 85%: m.p. 202◦C; IR (KBr, cm−1) υ 3456,
1
3443 (NH2), 1606 (C N). H NMR (500 MHz, DMSO-d6): δ 2.59 (s, 3H,
CH3), 6.42 (s, 2H, NH2), 6.77 (s, 2H, NH2), 7.34–7.56 (m, 4H, C6H4), 12.32
(s, 1H, SH); 13C NMR: δ 22.5 (CH3), 94.3 (C-8), 127.8 (Ar-C), 129.2 (2C,
Ar-C), 130.2 (2C, Ar-C), 138.4 (Ar-C), 133.6 (C-8a), 155.2 (C-7), 180.2 (C-2),

Synthesis of Purine and Guanine Thioglycoside Analogs
7
199.8 (C-4). Anal.Calcd. for C12H12N8S (300.34): C, 47.99; H, 4.03; N, 37.31;
S, 10.68. Found: C, 47.90; H, 4.12; N, 37.25; S, 10.56.
2,7-Diamino-8-(4-chlorophenyldiazenyl)pyrazolo[1,5-a][1,3,5]triazine-4-thiol
(4d)
Yellow solid (MeOH) yield 85%: m.p. 220◦C; IR (KBr, cm−1) υ 3457,
1
3422 (NH2). H NMR (500 MHz, DMSO-d6): δ 6.52 (s, 2H, NH2), 6.68
(s, 2H, NH2), 7.50–7.81 (m, 4H, C6H4), 13.12 (s, 1H, SH); 13C NMR: δ 93.8
(C-8), 128.2 (Ar-C), 129.6 (2C, Ar-C), 131.4 (2C, Ar-C), 135.3 (Ar-C), 134.2
(C-8a), 156.4 (C-7), 180.6 (C-2), 200.1 (C-4). Anal.Calcd. for C11H9ClN8S
(320.76): C, 41.19; H, 2.83; N, 34.93; S, 10.00. Found: C, 41.21; H, 2.90; N,
34.90; S, 10.11.
2,7-Diamino-8-(4-bromophenyldiazenyl)pyrazolo[1,5-a][1,3,5]triazine-4-thiol
(4e)
Yellow solid (MeOH), yield 80%: m.p. 215◦C; IR (KBr, cm−1) υ 3472,
3423, 3328 (NH2). 1H NMR (500 MHz, DMSO-d6): δ 6.58 (s, 2H, NH2), 6.66
(s, 2H, NH2), 7.43–7.68 (m, 4H, C6H4), 12.54 (s, 1H, SH). Anal.Calcd. for
C11H9BrN8S (365.21): C, 36.18; H, 2.48; N, 30.68; S, 8.78. Found: C, 36.20;
H, 2.40; N, 30.65; S, 8.76.
General Procedures for synthesizing (6a-j)
To a solution of 4a-e (10 mmol) in dry DMF (20 mL), NaH (15 mmol)
was added portion-wise through 15 min, and the solution was stirred at
room temperature for another 1 h, a cooled solution of 2,3,4,6-tetra-O-
acetyl-α-D-gluco (or galacto)pyronosyl bromide (10 mmol) 5 was dropped
within 30 min and the reaction mixture was stirred at room temperature until
completion (TLC, 6–8 h). After completion, the reaction mixture was poured
on ice water. A solid product precipitate was filtered off. Dried, purified on
silica gel column using petroleum ether 40–60◦C: ethyl acetate (4:1) as an
eluent and recrystallized from appropriate solvent to give compounds 6a-j.
4-(2’,3’,4’,6’-Tetra-O-acetyl-β-D-glucopyranosylthio)-8- (phenyldiazenyl)pyra
zolo[1,5a][1,3,5]triazine-2,7-diamine (6a)
1
Yellow solid (MeOH); yield 79%; m.p. 185◦C; H NMR (500 MHz,
CDCl3): δ 1.96–2.12 (4s, 12H, 4xOAc), 3.73, 4.04 (m, 2H, 2H-6’), 4.25 (m, H,
H-4’), 4.50 (m, 1H, H-5’), 4.59 (t, J = 9.2 Hz, 1H, H-3’), 4.82 (t, J = 9.1 Hz,
1H, H-2’), 5.29–5.32 (d, J 1’–2’ = 11.25 Hz, 1H, H-1’), 6.37 (s, D2O exch., 2H,
NH2), 6.31 (s, D2O exch., 2H, NH2). 13C NMR: δ 62.4 (C-6’), 67.4 (C-4’),
69.4 (C-2’), 70.8 (C-3’), 75.6 (C-5’), 81.2 (C-1’), 94.2 (C-8), 128.7 (4C, Ar-C),
129.1 (2C, Ar-C), 135.3 (C-8a), 155.4 (C-7), 170.4 (4CO), 181.2 (C-2), 183.2
(C-4). Anal. Calcd. for C25H28N8O9S (616.60): C, 48.70; H, 4.58; N, 18.17; S,
5.20. Found: C, 48.65; H, 4.50; N, 18.10; S, 5.25.

8
G. Elgemeie and M. Abu-Zaied
8-(4-Methoxyphenyldiazenyl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-D- glucopyranosyl
thio)pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine (6b)
Yellow solid (MeOH); yield 75%; m.p. 190◦C; IR (KBr, cm−1) υ 3454,
3433, 3332 (NH2), 1736 (CO). 1H NMR (500 MHz, DMSO-d6): δ 1.97–2.21
(4s, 12H, 4xOAc), 3.78 (s, 3H, OCH3), 3.92–4.02 (m, 2H, 2H-6’), 4.16 (m,
1H, H-5’), 4.23 (t, J = 9.1 Hz, 1H, H-4’), 4.42 (t, J = 9.3 Hz, 1H, H-3’),
5.18 (t, J = 9.2, 1H, H-2’), 5.23–5.24 (d, J1’–2’ = 5.01, 1H, Hz, H-1’), 6.32
(s, 2H, NH2), 6.53 (s, 2H, NH2), 7.23–7.52 (m, 4H, C6H4).13C NMR: δ 22.0
(4CH3CO), 57.6 (CH3), 62.6 (C-6’), 69.6 (C-4’), 70.4 (C-2’), 74.2 (C-3’), 77.1
(C-5’), 84.2 (C-1’), 93.8 (C-8), 116.5 (2C, Ar-C), 124.1 (Ar-C), 131.5 (2C, Ar-
C), 135.3 (C-8a), 156.6 (C-7), 162.4 (Ar-C), 170.4 (4CO), 182.4 (C-2), 184.5
(C-4). Anal.Calcd. for C26H30N8O10S (646.63): C, 48.29; H, 4.68; N, 17.33;
S, 4.96. Found: C, 48.25; H, 4.62; N, 17.35; S, 4.90.
4-(2’,3’,4’,6’-Tetra-O-acetyl-β-D-glucopyranosylthio)-8-(p-tolyldiazenyl)pyra
zolo[1,5-a][1,3,5]triazine-2,7-diamine (6c)
Yellow solid (MeOH); yield 80%; m.p. 177◦C; IR (KBr, cm−1) υ 3431,
3380, 3332 (NH2), 1743 (CO). 1H NMR (500 MHz, DMSO-d6): δ 1.97–2.21
(4s, 12H, 4xOAc), 2.99 (s, 3H, CH3), 3.95 (m, 2H, 2H-6’), 4.14 (m, 1H,
H-5’), 4.41 (t, J = 9.3 Hz, 1H, H-4’), 4.56 (t, J = 9.1 Hz, 1H, H-3’), 4.79 (t, J
= 9.2, 1H, H-2’), 5.09–5.12 (d, J1’–2’ = 5.70, 1H, Hz, H-1’), 6.43 (s, 2H, NH2),
6.51 (s, 2H, NH2), 7.26–7.34 (m, 4H, C6H4).13C NMR: δ 21.9 (4CH3.CO),
24.2 (CH3), 62.2 (C-6’), 68.8 (C-4’), 70.6 (C-2’), 75.5 (C-3’), 76.6 (C-5’), 82.1
(C-1’), 90.9 (C-8), 130.4 (2C, Ar-C), 125.0 (Ar-C 1321.8 (2C, Ar-C), 140.2
(Ar-C), 136.5 (C-8a), 155.5 (C-7), 170.8 (4CO), 180.3 (C-2), 182.4 (C-4).
Anal.Calcd. for C26H30N8O9S (630.63): C, 49.52; H, 4.79; N, 17.77; S, 5.08.
Found: C, 49.50; H, 4.75; N, 17.80; S, 5.15.
8-(4-Chlorophenyldiazenyl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-D-glucopyranosyl
thio)pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine (6d)
Pale yellow solid (MeOH); yield 72%; m.p. 179◦C; IR (KBr, cm−1) υ 3434,
3396, 3342 (NH2), 1736 (CO). 1H NMR (500 MHz, DMSO-d6): δ 1.95–2.16
(4s, 12H, 4xOAc), 3.92 (m, 2H, 2H-6’), 4.15 (m, 1H, H-5’), 4.73 (t, J =
9.5 Hz, 1H, H-4’), 4.95 (t, J = 9.4 Hz, 1H, H-3’), 5.35 (t, J = 9.2, 1H, H-2’),
5.55–5.57 (d, J1’–2’ = 9.20, 1H, Hz, H-1’), 6.58 (s, 2H, NH2), 6.81 (s, 2H,
NH2), 7.36–7.68 (m, 4H, C6H4). Anal. Calcd. for C25H27ClN8O9S (651.05):
C, 46.12; H, 4.18; N, 17.21; S, 4.93. Found: C, 46.15; H, 4.20; N, 17.25; S,
4.90.
8-(4-Bromophenyldiazenyl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-D-glucopyranosyl
thio)pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine (6e)
Pale yellow solid (MeOH); yield 71%; m.p. 185◦C; IR (KBr, cm−1) υ 3447,
3384, 3339 (NH2), 1739 (CO). 1H NMR (500 MHz, DMSO-d6): δ 2.09–2.16
(4s, 12H, 4xOAc), 3.90 (m, 2H, 2H-6’), 4.15–4 24 (m, 2H, H-5’, H-4’), 4.64

Synthesis of Purine and Guanine Thioglycoside Analogs
9
(t, J = 9.5 Hz, 1H, H-3’), 4.92 (t, J = 9.2, 1H, H-2’), 5.47–5.49 (d, J1’–2’
=
9.11, 1H, Hz, H-1’), 6.65 (s, 2H, NH2), 6.88 (s, 2H, NH2), 7.33–7.63 (m,
4H, C6H4). Anal. Calcd. for C25H27BrN8O9S (695.50): C, 43.17; H, 3.91; N,
16.11; S, 4.61. Found: C, 43.15; H, 3.90; N, 16.8; S, 4.55.
4-(2’,3’,4’,6’-Tetra-O-acetyl-β-D-galactopyranosylthio)-8-(phenyldiazenyl)pyra
zolo[1,5-a][1,3,5]triazine-2,7-diamine (6f)
Yellow solid (MeOH); yield 80%; m.p. 191◦C; IR (KBr, cm−1) υ 3434,
3395, 3341 (NH2), 1745 (CO). 1H NMR (500 MHz, DMSO-d6): δ 1.84–2.08
(4s, 12H, 4xOAc), 4.02 (m, 2H, 2H-6’), 4.37 (m, H, H-5’), 5.11 (t, J = 9.3 Hz,
1H, H-4’), 5.22 (t, J = 9.2, 1H, H-3’), 5.24 (t, J = 9.1 Hz, H-2’), 6.21 (d,
J1’–2’ = 10.35, 1H, Hz, H-1’), 6.57 (s, 2H, NH2), 6.85 (s, 2H, NH2), 7.34–7.88
(m, 5H, C6H5). Anal. Calcd. for C25H28N8O9S (616.60): C, 48.70; H, 4.58;
N, 18.17; S, 5.20. Found: C, 48.65; H, 4.50; N, 18.20; S, 5.25.
8-(4-Methoxyphenyldiazenyl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-D- galactopyranos
ylthio)pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine (6g)
Yellow solid (MeOH); yield 79%; m.p. 174◦C; IR (KBr, cm−1)
υ
3437, 3396, 3339 (NH2), 1741 (CO). 1H NMR (500 MHz,
CDCl3):
δ
1.93–2.12 (4s, 12H, 4xOAc), 3.82 (s, 3H, OCH3),
3.92–4.28 (m, 3H, 2H-6’, H-5’), 4.02 (m, 1H, H-4’), 4.63 (t, J =
9.22, H, H-3’), 5.14 (t, J = 9.5, 1H, H-2’), 5.42 (d, J 1’–2’
=
8.56 Hz, 1H, H-1’), 6.64 (s, 2H, NH2), 6.81 (s, 2H, NH2), 7.34–7.89 (m,
4H, C6H4). 13C NMR: δ 20.6 (4CH3.CO), 58.1 (s, 3H, CH3O), 62.3 (C-6’),
63.3 (C-5’), 67.6 (C-4’), 72.2 (C-3’), 74.0 (C-2’), 79.6 (C-1’), 93.6 (C-8), 116.4
(2C, Ar-C), 132.2 (2C, Ar-C), 123.4 (Ar-C), 164.2 (Ar-C), 136.2 (8a), 158.4
(C-7), 170.2 (4CO), 177.2 (C-2), 185.1 (C-4). Anal. Calcd. for C26H30N8O10S
(646.63): C, 48.29; H, 4.68; N, 17.33; S, 4.96. Found: C, 48.30; H, 4.70; N,
17.30; S, 4.90.
4-(2’,3’,4’,6’-Tetra-O-acetyl-β-D-galactopyranosylthio)-8-(p-tolyldiazenyl)
pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine (6h)
Yellow solid (MeOH); yield 70%; m.p. 172◦C.; IR (KBr, cm−1) υ 3427,
1
3301 (NH2), 1745 (CO). H NMR (500 MHz, CDCl3): δ 2.12 (4s, 12H,
4xOAc), 3.02 (s, 3H, CH3), 3.95–4.21 (m, 3H, 2H-6’, H-5’), 4.15 (m, 1H,
H-4’), 4.35 (t, J = 9.5, H, H-3’), 3.82 (t, J = 9.2, 1H, H-2’), 5.53 (d, J 1’–2’
=
9.64 Hz, 1H, H-1’), 6.72 (s, 2H, NH2), 6.84 (s, 2H, NH2), 7.34–7.56 (m, 4H,
C6H4). Anal. Calcd. for C26H30N8O9S (630.63): C, 49.52; H, 4.79; N, 17.77;
S, 5.08. Found: C, 49.50; H, 4.70; N, 17.50; S, 5.20.

10
G. Elgemeie and M. Abu-Zaied
8-(4-Chlorophenyldiazenyl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-D-galactopyranosyl
thio)pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine (6i)
Yellow solid (DMF); yield 75%; m.p. 187◦C; 1H NMR (500 MHz, DMSO-
d6): δ 2.03 (4s, 12H, 4CH3CO), 3.82–4.01 (m, 3H, H-6’, H-5’), 4.24 (m, 1H,
H-4’), 4.75 (t, J = 9.3, 1H, H-3’), 5.03 (t, J = 9.2, 1H, H-2’), 5.58 (d, 1H, J1’–2’
=
8.9 Hz, H-1’), 6.79 (s, 2H, NH2), 6,84 (s, 2H, NH2), 7.34–7.51 (m, 4H,
C6H4).13C NMR: δ 22.2 (4CH3.CO), 62.6 (C-6’), 67.4 (C-4’), 68.2 (C-2’),
71.1 (C-3’), 72.3 (C-5’), 81.0 (C-1’), 95.21 (C-8), 128.6 (Ar-C), 130.4 (2C,
Ar-C), 131.2 (2C, Ar-C), 134.8 (C-8a), 136.2 (Ar-C), 157.4 (C-7), 178.4 (C-
2), 171.0 (4CO), 179.1 (C-4). Anal. Calcd. for C25H27ClN8O9S (651.05): C,
46.12; H, 4.18N, 17.21S, 4.93. Found: C, 46.22; H, 4.10; N, 17.10; S, 4.80.
8-(4-bromophenyldiazenyl)-4-(2’,3’,4’,6’-tetra-O-acetyl-β-D-galactopyranosyl
thio)pyrazolo[1,5-a][1,3,5]triazine-2,7-diamine(6j)
Yellow solid (MeOH); yield 72%; m.p. 186◦C; IR (KBr, cm−1) υ 3444,
1
3315 (NH2), 1743 (CO). H NMR (500 MHz, DMSO-d6): δ 2.08–2.13 (4s,
12H, 4xOAc), 3.92 (m, 2H, 2H-6’), 4.21–4.23 (m, 2H, H-5’, H-4’), 4.44 (t, J
= 9.5 Hz, 1H, H-3’), 4.62 (t, J = 9.2, 1H, H-2’), 5.52–5.50 (d, J 1’–2’ = 9.10,
1H, Hz, H-1’), 6.78 (s, D2O exch., 2H, NH2), 6.84 (s, 2H, NH2), 7.34–7.72
(m, 4H, C6H4). Anal. Calcd. for C25H27BrN8O9S (695.50): C, 43.17; H, 3.91;
N, 16.11; S, 4.61. Found: C, 43.10; H, 3.77; N, 16.6; S, 4.50.
Ammonolysis of (6a-j)
Dry gaseous ammonia was passed through a solution of protected gly-
cosides 6a-j (10 mmol) in dry methanol (20 mL) at room temperature for
10 min. The mixture was further stirred at room temperature until the reac-
tion was judged complete by TLC (10–12 h) using (CHCl3/MeOH 9:1) (Rf,
0.67–0.69). The resulting mixture was then evaporated under reduced pres-
sure to afford a solid residue that was crystallized from appropriate solvent
to give compounds 7a-j.
4-(β-D-Glucopyranosylthio)-8-(phenyldiazenyl)pyrazolo[1,5-a][1,3,5]triaz
ine-2,7-diamine (7a)
Yellowish white solid (MeOH); yield 75%; m.p. 211◦C; IR (KBr, cm−1)
1
υ 3620 (OH), 3415, 3342, (NH2), 1618 (C N), 1569 (C C); H NMR
(500 MHz, DMSO-d6): δ 3.34 (m, 2H, 2H-6’), 3.41 (m, 1H, H-5’), 3.53 (t,
J 4’–3’ = 9.2 Hz, 1H, H-4’), 3.74 (t, J 3’–2’ = 9.2 Hz, J 3’–4’ = 9.1 Hz, 1H, H-3’),
4.41 (t, J 2’–1’ = 9.1 Hz, J 2’–3’ = 9.5, 1H, H-2’), 4.52–4.54 (d, 1H, J 1’–2’
=
9.95 Hz, H-1’), 5.14 (s, 1H, 2’-OH), 5.23 (m, 3H, 3’-OH, 4’-OH, and 6’-OH),
6.81 (s, 2H, NH2), 6.88 (s, 2H, NH2), 7.33–7.52 (m, 5H, C6H5). 13C NMR: δ
62.4 (C-6’), 72.5 (C-4’), 75.1 (C-5’), 80.2 (C-3’), 82.1 (C-2’), 91.2 (C-1’), 94.4
(C-8), 130.2 (4C, Ar-C), 131.2 (2C, Ar-C), 135.6 (C-8a), 157.6 (C-7), 183.8

Synthesis of Purine and Guanine Thioglycoside Analogs
11
(C-2), 184.8 (C-4). Anal. Calcd. for C17H20N8O5S (448.46): C, 45.53; H, 4.50;
N, 24.99; S, 7.15. Found: C, 45.45; H, 4.35; N, 24.85; S, 7.20.
8-(4-Methoxyphenyldiazenyl)-4-(β-D-glucopyranosylthio)pyrazolo[1,5-a][1,3,
5]triazine-2,7-diamine (7b)
Yellowish white solid (MeOH); yield 75%; m.p. 203◦C; IR (KBr, cm−1) υ
1
3610 (OH), 3420, 3349, (NH2); H NMR (500 MHz, DMSO-d6): δ 3.21 (s,
3H, OCH3), 3.72–4.21 (m, 3H, 2H-6’, H-5’), 4.32 (m, 2H, H-4’, H-3’), 4.44
(t, J = 9.2 Hz, 1H, H-2’), 4.52 (s, 1H, 2’-OH), 4.84 (m, 3H, 3’OH, 4’-OH,
and 6’-OH), 5.62 (d, 1H, J 1’–2’ = 9.98 Hz, H-1’), 6.85 (s, 2H, NH2), 6.88 (s,
2H, NH2), 7.21–7.42 (m, 4H, C6H4). 13C NMR: δ 58.2 (CH3O), 61.2 (C-6’),
69.6 (C-4’), 71.5 (C-5’), 75.6 (C-3’), 77.5 (C-2’), 82.2 (C-1’), 96.4 (C-8), 117.3
(2C, Ar-C), 125.4 (Ar-C), 132.5 (2C, Ar-C), 136.5 (C-8a), 156.5 (C-7), 165.2
(Ar-C), 181.9 (C-2), 183.6 (C-4). Anal. Calcd. for C18H22N8O6S (478.48): C,
45.18; H, 4.63; N, 23.42; S, 6.70. Found: C, 45.30; H, 4.50; N, 23.30; S, 6.60.
4-(β-D-Glucopyranosylthio)-8-(p-tolyldiazenyl)pyrazolo[1,5-a][1,3,5]tria
zine-2,7-diamine (7c)
Yellowish white solid (MeOH); yield 75%; m.p. 198◦C; IR (KBr, cm−1) υ
3520–3601 (OH), 3433, 3351 (NH2); 1H-NMR (500 MHz, DMSO-d6): δ 2.89
(s, 3H, CH3), 3.91–4.23 (m, 3H, 2H-6’, H-5’), 4.41 (m, 2H, H-4’, H-3’), 4.44
(t, J = 9.5 Hz, 1H, H-2’), 4.51 (s, 1H, 2’-OH), 4.61 (m, 3H, 3’OH, 4’-OH,
and 6’-OH), 5.41 (d, 1H, J 1’–2’ = 8.27 Hz, H-1’), 6.83 (s, 2H, NH2), 6.86 (s,
2H, NH2), 7.34–7.45 (m, 4H, C6H4). 13C NMR: δ 24.3 (CH3), 60.5 (C-6’),
65.6 (C-4’), 68.3 (C-5’), 70.4 (C-3’), 74.6 (C-2’), 81.1 (C-1’), 94.3 (C-8), 124.3
(Ar-C), 131.3 (2C, Ar-C), 132.5 (2C, Ar-C), 135.7 (Ar-C), 135.3 (C-8a), 152.5
(C-7), 180.2 (C-2), 181.4 (C-4). Anal. Calcd. for C18H22N8O5S (462.48): C,
46.75; H, 4.79; N, 24.23; S, 6.93. Found: C, 46.60; H, 4.90; N, 24.10; S, 6.70.
8-(4-Chlorophenyldiazenyl)-4-(β-D-glucopyranosylthio)pyrazolo[1,5-a][1,3,
5]triazine-2,7-diamine (7d)
Yellow solid (MeOH); yield 75%; m.p. 213◦C; IR (KBr, cm−1) υ
1
3515–3600 (OH), 3456, 3349 (NH2); H NMR (500 MHz, DMSO-d6): δ
3.88–4.16 (m, 3H, 2H-6’, H-5’), 4.28 (m, 2H, H-4’, H-3’), 4.34 (t, J = 9.2 Hz,
1H, H-2’), 4.39 (s, 1H, 2’-OH), 4.52 (m, 3H, 3’OH, 4’-OH, and 6’-OH),
5.35 (d, 1H, J 1’–2’ = 9.275 Hz, H-1’), 6.79 (s, 2H, NH2), 6.84 (s, 2H, NH2),
7.33–7.52 (m, 4H, C6H4). Anal. Calcd. for C17H19ClN8O5S (482.09): C, 42.28;
H, 3.97; N, 23.20; S, 6.64. Found: C, 42.10; H, 3.82; N, 23.25; S, 6.52.
8-(4-Bromophenyldiazenyl)-4-(β-D-glucopyranosylthio)pyrazolo[1,5-a][1,3,
5]triazine-2,7-diamine (7e)
Yellowish white solid (MeOH); yield 75%; m.p. 205◦C; IR (KBr, cm−1) υ
3578 (OH), 3431, 3339 (NH2); 1H NMR (500 MHz, DMSO-d6): δ 3.79–4.01

12
G. Elgemeie and M. Abu-Zaied
(m, 3H, 2H-6’, H-5’), 4.22 (m, 2H, H-4’, H-3’), 4.31 (t, J = 9.3 Hz, 1H, H-2’),
4.30 (s, 1H, 2’-OH), 4.42 (m, 3H, 3’OH, 4’-OH, and 6’-OH), 5.24 (d, 1H,
J 1’–2’ = 7.54, Hz, H-1’), 6.81 (s, 2H, NH2), 6.82 (s, 2H, NH2), 7.33–7.46 (m,
4H, C6H4). Anal. Calcd. for C17H19BrN8O5S (527.35): C, 38.72; H, 3.63; N,
21.25; S, 6.08. Found: C, 38.60; H, 3.50; N, 21.30; S, 6.28.
4-(β-D-Galactopyranosylthio)-8-(phenyldiazenyl)pyrazolo[1,5-a][1,3,5]tria
zine-2,7-diamine (7f)
Yellowish white solid (MeOH); yield 75%; m.p. 188◦C; IR (KBr, cm−1)
1
υ 3574 (OH), 3453, 3382, 3354 (NH2); H-NMR (500 MHz, DMSO-d6):
δ 3.32 (m, 2H, 2H-6’), 3.52 (m, 1H, H-5’), 3.64 (t, J 4’–3’ = 9.6 Hz, 1H,
H-4’), 3.76 (t, J 3’–2’ = 9.3 Hz, J 3’–4’ = 9.6 Hz, 1H, H-3’), 4.12 (t, J 2’–1’
=
10:2 Hz, J 2’–3’ = 9:3 Hz, 1H, H-2’), 4.42 (br, D2O-exchangeable IH, OH),
4.63 (s, br, IH, OH), 4.78 (d, J 1’–2’ = 10.35, 1H, Hz, H-1’), 4.92 (s, br, IH,
OH), 5.43 (dd, J = 5.2, 7.5 Hz, IH, OH), 6.57 (s, 2H, NH2), 6.85 (s, 2H,
NH2), 7.34–7.88 (m, 5H, C6H5). Anal. Calcd. for C17H20N8O5S (448.46): C,
45.53; H, 4.50; N, 24.99; S, 7.15. Found: C, 45.45; H, 4.35; N, 24.88; S, 7.10.
8-(4-Methoxyphenyldiazenyl)-4-(β-D-galactopyranosylthio)pyrazolo[1,5-a][1,
3,5]triazine-2,7-diamine (7g)
Yellowish white solid (MeOH); yield 75%; m.p. 196◦C; IR (KBr, cm−1) υ
3600–3517 (OH), 3453, 3382, 3354 (NH2); 1H NMR (500 MHz, DMSO-d6):
δ 3.34 (s, 3H, OCH3), 3.41 (m, 2H, 2H-6’), 3.54 (m, 1H, H-5’), 3.65 (t, J 4’–3’
= 9.4 Hz, 1H, H-4’), 3.76 (t, J 3’–2’ = 9.2 Hz, J 3’–4’ = 9.5 Hz, 1H, H-3’), 4.12
(t, J 2’–1’ = 10.1 Hz, J 2’–3’ = 9.5 Hz, 1H, H-2’), 4.52 (s, br, IH, OH), 4.65 (s,
br, IH, OH), 4.92 (d, J 1’–2’ = 10.35, 1H, Hz, H-1’), 5.23 (s, br, IH, OH),
5.45 (dd, J = 5.2, 7.5 Hz, IH, OH), 6.67 (s, 2H, NH2), 6.84 (s, 2H, NH2),
7.33–7.82 (m, 4H, C6H4). Anal. Calcd. for C18H22N8O6S (478.48): C, 45.18;
H, 4.63; N, 23.42; S, 6.70. Found: C, 45.25; H, 4.55; N, 10.42; S, 6.75.
4-(β-D-Galactopyranosylthio)-8-(p-tolyldiazenyl)pyrazolo[1,5-a][1,3,5]tr
iazine-2,7-diamine (7h)
Yellowish white solid (MeOH); yield 75%; m.p. 201◦C; IR (KBr, cm−1) υ
3600–3500 (OH), 3443, 3362, 3344 (NH2); 1H NMR (500 MHz, DMSO-d6):
δ 2.95 (s, 3H, CH3), 3.22 (m, 2H, 2H-6’), 3.36 (m, 1H, H-5’), 3.54 (t, J 4’–3’
= 9.6 Hz, 1H, H-4’), 3.66 (t, J 3’–2’ = 9.5 Hz, J 3’–4’ = 9.6 Hz, 1H, H-3’), 4.00
(t, J 2’–1’ = 9.7 Hz, J 2’–3’ = 9.4 Hz, 1H, H-2’), 4.51 (d, J 1’–2’ = 10.35, 1H,
Hz, H-1’), 4.61 (s, br, IH, OH), 4.71 (s, br, IH, OH), 5.42 (s, br, IH, OH),
5.48 (dd, J = 5.2, 7.5 Hz, IH, OH), 6.82 (s, 2H, NH2), 6.89 (s, 2H, NH2),
7.33–7.54 (m, 4H, C6H4). Anal. Calcd. for C18H22N8O5S (462.48): C, 46.75;
H, 4.79; N, 24.23; S, 6.93. Found: C, 45.20; H, 4.42; N, 10.35; S, 6.68.

Synthesis of Purine and Guanine Thioglycoside Analogs
13
8-(4-Chlorophenyldiazenyl)-4-(β-D-galactopyranosylthio)pyrazolo[1,5-a][1,3,
5]triazine-2,7-diamine (7i)
Yellowish white solid (MeOH); yield 75%; m.p. 203◦C; IR (KBr, cm−1) υ
3600–3500 (OH), 3465, 3375, 3357 (NH2), 3129 (CH). 1H NMR (500 MHz,
DMSO-d6): δ 3.33 (m, 2H, 2H-6’), 3.37 (m, 1H, H-5’), 3.64 (t, J 4’–3’ = 9.4 Hz,
1H, H-4’), 3.68 (t, J 3’–2’ = 9.3 Hz, J 3’–4’ = 9.5 Hz, 1H, H-3’), 4.31 (d, J 1’–2’
= 10.35, 1H, Hz, H-1’), 4.42 (t, J 2’–1’ = 9.6 Hz, J 2’–3’ = 9.5 Hz, 1H, H-2’),
4.65 (t, J OH-6’ = 5.8 Hz, 6’-OH), 4.84 (d, J = 5.5 Hz, IH, OH), 5.12 (d, J =
5.2 Hz, IH, OH), 5.35 (d, J = 5.4 Hz, IH, OH), 6.79 (s, 2H, NH2), 6.87 (s, 2H,
NH2), 7.33–7.56 (m, 4H, C6H4). Anal. Calcd. for C17H19ClN8O5S (482.90):
C, 42.28; H, 3.97; N, 23.20; S, 6.64. Found: C, 42.16; H, 3.84; N, 23.35; S,
6.50.
8-(4-Bromophenyldiazenyl)-4-(β-D-galactopyranosylthio)pyrazolo[1,5-a][1,3,
5]triazine-2,7-diamine(7j)
Yellowish white solid (MeOH); yield 75%; m.p. 188◦C; 1H NMR
(500 MHz, DMSO-d6): δ 3.31 (m, 2H, 2H-6’), 3.35 (m, 1H, H-5’), 3.60
(t, J 4’–3’ = 9.6 Hz, 1H, H-4’), 3.62 (t, J 3’–2’ = 9.4 Hz, J 3’–4’ = 9.6 Hz, 1H,
H-3’), 4.021 (d, J 1’–2’ = 10.35, 1H, Hz, H-1’), 4.40 (t, J 2’–1’ = 9.5 Hz, J 2’–3’
= 9.3 Hz, 1H, H-2’), 4.55 (t, J OH-6’ = 5.7 Hz, 6’-OH), 4.62 (d, J = 5.8 Hz,
IH, OH), 5.23 (d, J = 5.5 Hz, IH, OH), 5.25 (d, J = 5.2 Hz, IH, OH), 6.64
(s, 2H, NH2), 6.82 (s, 2H, NH2), 7.34–7.48 (m, 4H, C6H4). Anal. Calcd.
for C17H19BrN8O5S (527.35): C, 38.72; H, 3.63; N, 21.25; S, 6.08. Found: C,
38.62; H, 3.75; N, 21.12; S, 6.15.
8-Arylazo-2,7-diamino-4-(methylthio)pyrazolo[1,5-a]-1,3,5-triazines (9a-e)
Method A
A solution of compounds 1a-e (10 mmol) and dimethyl N -
cyanodithioiminocarbonate 8 (10 mmol) in DMF (20 mL) was heated at
150◦C under microwave 600 W for 10 min. The reaction mixture was mon-
itored by TLC (petroleum ether 60–80 – EtOAc 3:1) until the reactants
disappeared. The solvent was then evaporated and the resulting residue was
triturated with MeOH to afford compounds 9a-e, which were recrystallized
from the appropriate solvent.
Method B
A solution of compounds 4a-e (10 mmol) in sodium ethoxide (10 mmol)
was refluxed for 30 min and allowed to cool to room temperature; methyl
iodide (10 mmol) was then added to the reaction mixture, and refluxed for
3 h. The formed solid product was collected by filtration and recrystallized
from the appropriate solvent.

14
G. Elgemeie and M. Abu-Zaied
4-Anilino-8-arylazo-2,7-diaminopyrazolo[1,5-a]–1,3,5-triazines (10a-e) [17]
A solution of 6a-j or 9a-e (10 mmol) and aniline (10 mmol) in ethanol
(20 mL) containing a few drops of triethylamine was refluxed for 3 h, cooled,
the precipitate was filtered off, and crystallized from the appropriate solvent.
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