Synthesis of the first novel pyrazole thioglycosides as deaza ribavirin analogues

Article abstract of DOI:10.1080/15257770.2017.1378817

This study reports a novel and efficient method for the synthesis of the first reported novel class of thiopyrazoles and their corresponding thioglycosides. These series of compounds were designed through the reaction of hydrazine derivatives with sodium dithiolate salt 2 in EtOH at ambient temperature to give the corresponding sodium 5-amino-4-cyano-1H-pyrazole-3-thiolates 4a-d. The latter compounds were treated with α-acetobromoglucose 6a and α-acetobromogalactose 6b in DMF at ambient temperature to give in an excellent yields the corresponding pyrazole S-glycosides 7a-h. Ammonolysis of the pyrazole thioglycosides 7a-h afforded the corresponding free thioglycosides 8a-h.

Full text of DOI:10.1080/15257770.2017.1378817

Nucleosides, Nucleotides and Nucleic Acids
ISSN: 1525-7770 (Print) 1532-2335 (Online) Journal homepage: http://www.tandfonline.com/loi/lncn20
Synthesis of the first novel pyrazole thioglycosides
as deaza ribavirin analogues
Mamdouh A. Abu-Zaied & Galal H. Elgemeie
To cite this article: Mamdouh A. Abu-Zaied & Galal H. Elgemeie (2017): Synthesis of the first
novel pyrazole thioglycosides as deaza ribavirin analogues, Nucleosides, Nucleotides and Nucleic
Acids, DOI: 10.1080/15257770.2017.1378817
To link to this article: https://doi.org/10.1080/15257770.2017.1378817
Published online: 07 Dec 2017.
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Date: 08 December 2017, At: 07:50

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
, VOL. , NO. , –
https://doi.org/./..
Synthesis of the first novel pyrazole thioglycosides as deaza
ribavirin analogues
Mamdouh A. Abu-Zaieda and Galal H. Elgemeieb
aGreen Chemistry Department, National Research Centre, Dokki, Giza, Egypt; bChemistry Department,
Faculty of Science, Helwan University, Helwan, Cairo, Egypt
ABSTRACT
ARTICLE HISTORY
Received  October 
Accepted  November 
This study reports a novel and efficient method for the synthesis
of the first reported novel class of thiopyrazoles and their
corresponding thioglycosides. These series of compounds were
designed through the reaction of hydrazine derivatives with
sodium dithiolate salt 2 in EtOH at ambient temperature to
give the corresponding sodium 5-amino-4-cyano-1H-pyrazole-
3-thiolates 4a-d. The latter compounds were treated with
α-acetobromoglucose 6a and α-acetobromogalactose 6b in
DMF at ambient temperature to give in an excellent yields the
corresponding pyrazole S-glycosides 7a-h. Ammonolysis of the
pyrazole thioglycosides 7a-h afforded the corresponding free
thioglycosides 8a-h.
KEYWORDS
Pyrazole thioglycosides;
ribavirin; Hepatitis C virus
(HCV); Ledipasvir; Harvoni;
sodium ,-dicyanoethene-
,-bis(thiolate); hetrocyclic
thioglycosides
Introduction
Hepatitis C virus (HCV) incurs a major disease burden worldwide. Ribavirin is a
triazole nucleoside approved for HCV treatment. Recently, another HCV drug, a
combination of sofosbuvir and ledipasvir called Harvoni, was approved by the FDA.
This combination drug with or without ribavirin offered further treatment options
for HCV patients.[1] Ribavirin can cause a potentially severe hemolytic anemia
and can cause remarkable embyocidal effects, associated with possible birth death
and defects.[2] Ribavirin is proscribed during pregnancy for women.[3] Some other
effects have been noticed with ribavirin, such as nausea, rash, itching and fatigue. In
view of the facts mentioned, design and synthesis of ribavirin analogues as bioac-
tive lead compounds continue to be of interest.[4] As a part of our current project
aimed towards exploring synthetic methods for the preparation of S-glycosylated
derivatives of heterocyclic nitrogen bases, we have recently reported the synthesis
and antiviral activity of a series of heterocyclic S-glycosides that have interesting
cytotoxic activity as pyridine S-glcosides,[5,6] pyrimidine S-glycosides,[7,8] imida-
zole S-glycosides.[9] oxadiazole S-glycosides.[10] thiophene S-glycosides.[11] quino-
line S-glycosides.[12] thienopyrazole S-glycosides.[13] and purine S-glycosides,[14,15]
CONTACT Galal H. Elgemeie
University, Helwan, Cairo, Egypt.
elgemeie@yahoo.com
Chemistry Department, Faculty of Science, Helwan
©  Taylor & Francis Group, LLC

2
M. A. ABU-ZAIED AND G. H. ELGEMEIE
O
NH2
N
N
N
HO
O
H
H
H
H
OH
OH
Figure . Structure of ribavirin.
We had mentioned that the dihydropyridine S-glycosides showed a potent P-
glycoprotein antagonist effect and revealed activity against human cancer cells.[16]
In the light of these findings and our previous researches.[17] the aim of the present
work was to design, prepare and investigate the biological activity of pyrazole thio-
glycosides carrying carbohydrate residues through S-glycosidic bond formation. To
our knowledge, this is the first reaction to be reported for the synthesis of thiopyra-
zoles and their corresponding thioglycosides.
Results and discussion
The synthesis was initiated by the condensation of malononitrile 1 and carbon
disulfide in ethanolic sodium ethoxide in a simple one-step protocol to give the
sodium dithiolate salt 2 (Scheme 1). Compound 2 reacts easily with one equivalent
of hydrazine derivatives in ethanol at room temperature for 24 h to afford the
expected sodium 5-amino-4-cyano-1H-pyrazole-3-thiolate derivatives 4a–d in
good yields. Acidification of the latter with HCl solution (30%) has resulted in
the formation of the corresponding 3-mercaptopyrazoles 5a-d. Compounds 4a–d
reacted with α-acetobromoglucose 6a and α-acetobromogalactose 6b in DMF at
ambient temperature to give in a quntitative yields the corresponding pyrazole
thioglycosides 7a-h (Scheme 1). It has been suggested that the cis-(α) sugars react
through a simple SN2 mechanism to give the β-glycoside compounds.[18] The
structures of 7a-h were proved according to their spectral analysis (13C NMR, 1H
NMR, IR). The 1H NMR spectrum for 7a showed a doublet at δ 5.62–5.63 ppm for
the anomeric proton with a spin-spin coupling constant of 10.74 Hz indicating the
β-configuration. The remaining six glucose protons appeared at δ 3.96–5.14 ppm.
Compounds 7a–h can also be prepared by reaction of the pyrazole-3-thiole deriva-
tives 5a-d with halo sugars 6a,b in DMF-sodium hydride at room temperature.
When thioglycosides 7a-h were reacted with NH3-MeOH at ambient temperature

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
3
for 5 minutes, the free deprotected thioglycosides 8a-h were obtained in good yields,
the structures of compounds 8a-h were proved according to their spectral data.
Thus, The 1H NMR spectrum for 8a revealed the anomeric proton as a doublet at δ
4.55–4.56 (J1,2 = 10.78 Hz), indicating the existance of just the β-D-configuration.
Scheme . Synthetic pathway for pyrazole thioglycosides a-h.
Conclusion
In conclusion, a new preparation of an interesting novel class of thiopyrazoles and
their corresponding thioglycosides has been developed. The results represent a
new, simple and economically effective method for the synthesis of the ribavirin
analogues. The ambient temperature reaction conditions, and clean and high yield
reaction products, render this method as innovative to the existing preparation
methods for synthesis of pyrazole glycosides. Further investigations on the appli-
cation of this preparation method for the synthesis of other biologically interesting
active glycosides will be investigated. These thioglycosides can be used as starting
compounds for the preparation of other interesting carbohydrates.

4
M. A. ABU-ZAIED AND G. H. ELGEMEIE
7a-h
MeOH - NH3
RT - 5 min
R
NH2
N
N
CN
HO
X
S
O
OH
H
Y
H
H
OH
8a-h
Scheme . Synthetic pathway for pyrazole thioglycosides a-h.
3,4,5
a
R
H
C6H5
b
c
4-NO2-C6H4
2,4-di NO2-C6H3
d
X
7
a
7
e
f
R
R
Y
X
H
Y
OAc
H
H
OAc
OAc
H
H
C6H5
C6H5
b
OAc
H
4-NO2-C6H4
g
c
H
H
OAc
OAc
4-NO2-C6H4
OAc
OAc
H
H
d
2,4-di NO2-C6H3
h
2,4-di- NO2-C6H3
8
e
8
a
R
X
X
Y
Y
R
H
H
H
OH
OH
H
OH
H
H
b
c
C6H5
f
C6H5
OH
g
4-NO2-C6H4
4-NO2-C6H4
OH
OH
H
H
OH
OH
H
H
2,4-di NO2-C6H3
h
d
2,4-di NO2-C6H3
Scheme . List of synthesized derivatives ,,a-d, a-h, a-h.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
5
Experimental
All melting points were measured on a Gallenkamp melting point apparatus. The
1H NMR and 13C NMR spectra were measured on a Jeol-500 MHz spectrome-
ter in DMSO-d6 or CDCl3 using Si(CH3)4 as an internal standard at the National
Research Centre, Cairo, Egypt. Progress of the reactions was monitored by TLC
using aluminum sheets coated with silica gel F254 (Merck). Viewing under a
short-wavelength UV lamp effected detection. Tetra-O-acetyl-α-D-glucopyranosyl
bromide 6a and tetra-O-acetyl-α-D-galactopyranosyl bromide 6b were prepared
according to literature procedures.[19]
General procedure for the synthesis of (4a-d)
To a solution of sodium 2,2-dicyanoethene-1,1-bis(thiolate) 2 (10 mmol) in absolute
ethanol (20 ml) was added hydrazine derivatives (10 mmol), the reaction mixture
was stirred at room temperature until completion (TLC, 24 h), then the solution was
evaporated and the formed solid product was collected and recrystallized from the
appropriate solvent to give compounds 4a-d.
Sodium -amino--cyano-H-pyrazole--thiolate (a)
Yellow solid; (EtOH); yield (92%); mp >300°C; IR (KBr, cm−1) υ 3383 (NH2), 3364
(NH), 2206 (CN). C4H3N4NaS (162.15).
Sodium -amino--cyano--phenyl-H-pyrazole--thiolate (b)
Yellow solid; (EtOH); yield (88%); mp >300°C; IR (KBr, cm−1) υ 3391 (NH2), 3027
=
(aromatic CH), 2211 (CN), 1594 (C N). C10H7N4NaS (238.24).
Sodium -amino--cyano--(-nitrophenyl)-H-pyrazole--thiolate (c)
Yellow solid; (EtOH); yield (90%); mp >300°C; IR (KBr, cm−1) υ 3388 (NH2), 3032
=
(aromatic CH), 2209 (CN), 1602 (C N). C10H6N5NaO2S (283.24).
Sodium -amino--(,-dinitrophenyl)-H-pyrazole--thiolate (d)
White solid; (EtOH); yield (82%); mp >300°C; IR (KBr, cm−1) υ 3392 (NH2), 3041
=
(aromatic CH), 2213 (CN), 1589 (C N). C10H5N6NaO4S (328.24).
General procedure for the synthesis of (5a-d)
Method A
To a solution of 2,2-dicyanoethene-1,1-bis(thiolate) 2 (10 mmol) in absolute ethanol
(20 ml) containing glacial acetic acid (2 ml) was added hydrazine derivatives (10
mmol). The reaction mixture was stirred at room temperature for 10 h. A precipi-
tate was formed, filtered off and recrystallized from the appropriate solvent to give
compounds 5a-d.

6
M. A. ABU-ZAIED AND G. H. ELGEMEIE
Method B
To a solution of compound 4a-d (10 mmol) in water (10 ml), HCl solution (30%)
was dropped at room temperature (25 oC). After an additional stirring, a precipitate
thus formed was filtered off and crystallized from methanol to give 5a-d as yellow
solid.
-Amino--mercapto-H-pyrazole--carbonitrile (a)
Yellow solid; (EtOH); yield (86%); mp 249°C; IR (KBr, cm−1) υ 3411, 3328 (NH2),
3164 (NH), 2206 (CN); 1H NMR (500 MHz, DMSO): δ 7.22 (brs, D2O exch., 2H,
NH2), 10.68 (s, D2O exch., 1H, NH), 11.78 (s, D2O exch., 1H, SH). Anal. Calcd. for.
C4H4N4S (140.17): C, 34.28; H, 2.88; N, 39.97; S, 22.88. Found: C, 34.25; H, 2.86; N,
39.89; S, 22.76%.
-Amino--mercapto--phenyl-H-pyrazole--carbonitrile (b)
Yellow solid; (EtOH); yield (81%); mp 265°C; IR (KBr, cm−1) υ 3421, 3335 (NH2),
3046 (aromatic CH), 2213 (CN); 1H NMR (500 MHz, DMSO): δ 7.26 (s, D2O exch.,
2H, NH2), 7.36-7.78 (m, 5H, C6H5), 13.27(s, D2O exch., 1H, SH); Anal. Calcd. for.
C10H8N4S (216.26): C, 55.54; H, 3.73; N, 25.91; S, 14.83. Found: C, 55.52; H, 3.68;
N, 25.85; S, 14.78%.
-Amino--mercapto--(-nitrophenyl)-H-pyrazole--carbonitrile (c)
Yellow solid; (EtOH); yield (77%); mp 248°C; IR (KBr, cm−1) υ 3442, 3353 (NH2),
3022 (aromatic CH), 2208 (CN); 1H NMR (500 MHz, DMSO): 7.19 (s, D2O exch.,
2H, NH2), 8.164-8.72 (m, 4H, C6H4), 14.54 (s, D2O exch., 1H, SH). Anal. Calcd. for.
C10H7N5O2S (261.26): C, 45.97; H, 2.70; N, 26.81; S, 12.27. Found: C, 45.82; H, 2.64;
N, 26.72; S, 12.19%.
-Amino--(,-dinitrophenyl)--mercapto-H-pyrazole--carbonitrile (d)
Yellow solid; (EtOH); yield (84%); mp 226°C; IR (KBr, cm−1) υ 3454, 3354 (NH2),
1
=
3028 (aromatic CH), 2209 (CN), 1601 (C N); H NMR (500 MHz, DMSO): δ 7.46
(s, D2O exch., 2H, NH2), 8.24-8.99 (m, 3H, C6H3), 13.77 (s, 1H, SH); 13C NMR: δ
99.28 (C-4), 116.45 (CN), 122.61-149.82 (7C, Ar-C, C-3), 154.51 (C-5). Anal. Calcd.
for. C10H6N6O4S (306.26): C, 39.22; H, 1.97; N, 27.44; S, 10.47. Found: C, 39.10; H,
1.78; N, 27.32; S, 10.35%.
General procedure for the synthesis of (7a-h)
Methode A
To a solution of 4a-d (10 mmol) in dry DMF (20 ml) a solution of 2,3,4,6-tetra-O-
acetyl-α-D-gluco- or galactopyronosyl bromide 6a,b (10 mmol) was dropped within
30 min. Stirring was continued for 8 h. After completion, the reaction mixture was
poured into ice water and the resulting precipitate was collected by filtration, dried
and recrystaiized by using an appropriate solvent to give compounds 7a-h.

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
7
Methode B
To a solution of 5a-d (10 mmol) in dry DMF (20 ml), NaH (15 mmol) was added por-
tion wise through 15 min and the solution stirred at room temperature for another
30 min. Then a solution of 2,3,4,6-tetra-O-acetyl-α-D-gluco- or galactopyronosyl
bromide 6a,b in DMF (10 mmol) was dropped within 30 min and the reaction mix-
ture was stirred at room temperature until completion (TLC, 3–8 h). After comple-
tion, the reaction mixture was poured on ice water and the resulting precipitate was
collected by filtration, dried and recrystallized by using an appropriate solvent to
give compounds 7a-h.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-glucopyranosylthio)-H-pyrazole--
carbonitrile (a)
White solid; (EtOH); yield (method a: 80%, method b: 67%); mp 217oC; IR (KBr,
−1
1
=
=
cm ) υ 3446, 3362 (NH2), 3144 (NH), 2216 (CN), 1755 (4C O), 1603 (C N); H
NMR (500 MHz, DMSO): δ 1.98–2.14 (4s, 12H, 4xOAc), 3.96 (m, 2H, 2H-6ꢀ), 4.13
(m, 1H, H-5ꢀ), 4.29 (t, 1H, J = 9.2 Hz, H-4ꢀ), 4.57 (t, 1H, J = 9.1 Hz, H-3ꢀ), 5.14
(t, 1H, J = 9.3 Hz H-2`), 5.62–5.63 (d, 1H, J 1`-2` = 10.74 Hz, H-1`), 7.26 (s, D2O
exch., 2H, NH2), 11.85 (s, D2O exch., 1H, NH); 13C NMR: δ 21.64 (4xOAc), 62.33
(C-6`), 69.48 (C-5`), 70.62 (C-4`), 73.66 (C-3`), 74.71 (C-2`), 82.86 (C-1`), 103.44
=
(C-4), 116.46 (CN), 140.25 (C-3), 158.11 (C-5), 172.69 (4C O). Anal. Calcd. for
C18H22N4O9S (470.45): C, 45.95; H, 4.71; N, 11.91; S, 6.82. Found: C, 45.84; H, 4.66;
N, 11.79; S, 6.69%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-glucopyranosylthio)--phenyl-H-
pyrazole--carbonitrile (b)
White solid; (EtOH); yield (method a: 85%, method b: 78%); mp 225 ◦C; IR (KBr,
=
cm−1) 3432, 3359 (NH2), 3023 (aromatic CH), 2211 (CN), 1748 (4C O), 1599
1
=
(C N); H NMR (500 MHz, DMSO): δ 2.02–2.18 (4s, 12H, 4xOAc), 3.88 (m, 2H,
2H-6`), 4.16 (m, 1H, H-5`), 4.38 (t, 1H, J = 9.2 Hz, H-4`), 4.55 (t, 1H, J = 9.4 Hz,
H-3`), 4.86 (t, 1H, J = 9.5 Hz H-2`), 5.65–5.66 (d, 1H, J 1`-2` = 10.66 Hz, H-1`), 7.27
(s, D2O exch., 2H, NH2), 7.35–7.78 (m, 5H, C6 H5); Anal. Calcd. for C24H26N4O9S
(546.55): C, 52.74; H, 4.79; N, 10.25; S, 5.87. Found: C, 52.68; H, 4.64; N, 10.12; S,
5.74%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-glucopyranosylthio)--(-nitrophenyl)-H-
pyrazole--carbonitrile (c)
White solid; (EtOH); yield (method a: 82%, method b: 75%); mp 229 oC; 1H NMR
(500 MHz, DMSO): δ 2.02–2.19 (4s, 12H, 4xOAc), 4.16 (m, 2H, 2H-6`), 4.29 (m,
1H, H-5`), 4.54 (t, 1H, J = 9.2 Hz, H-4`), 4.68 (t, 1H, J = 9.4 Hz, H-3`), 4.77 (t, 1H,
J = 9.3 Hz H-2`), 5.66–5.67 (d, 1H, J 1`-2` = 10.49 Hz, H-1`), 7.62 (s, D2O exch., 2H,
NH2), 8.19–8.72 (m, 4H, C6 H4); 13C NMR: δ 21.68 (4xOAc), 62.48 (C-6`), 67.34
(C-5`), 70.45 (C-4`), 72.46 (C-3`), 74.78 (C-2`), 82.66 (C-1`), 102.21 (C-4), 117.52
=
(CN), 120.24-148.41 (7C, Ar-C, C-3), 156.04 (C-5), 172.42 (4C O). Anal. Calcd.

8
M. A. ABU-ZAIED AND G. H. ELGEMEIE
for C24H25N5O11S (591.55): C, 48.73; H, 4.26; N, 11.84; S, 5.42. Found: C, 48.64; H,
4.14; N, 11.72; S, 5.31%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-glucopyranosylthio)--(,-
dinitrophenyl)-H-pyrazole--carbonitrile (d)
White solid; (EtOH); yield (method a: 80%, method b: 70%); mp 208 oC; IR (KBr,
−1
=
cm ) 3439, 3372 (NH2), 3025 (aromatic CH), 2217 (CN), 1757 (4C O), 1597
1
=
(C N); H NMR (500 MHz, DMSO): δ 1.97–2.17 (4s, 12H, 4xOAc), 3.94 (m, 2H,
2H-6`), 4.16 (m, 1H, H-5`), 4.22 (t, 1H, J = 9.2 Hz, H-4`), 4.43 (t, 1H, J = 9.1 Hz,
H-3`), 4.54 (t, 1H, J = 9.2 Hz H-2`), 5.43–5.44 (d, 1H, J 1`-2` = 9.64 Hz, H-1`), 7.65 (s,
D2O exch., 2H, NH2), 8.26–8.99 (m, 3H, C6 H3); 13C NMR: δ 22.35 (4xOAc), 62.42
(C-6`), 66.13 (C-5`), 69.42 (C-4`), 72.35 (C-3`), 78.48 (C-2`), 82.82 (C-1`), 102.34
=
(C-4), 116.47 (CN), 124.22-149.55 (7C, Ar-C, C-3), 153.26 (C-5), 172.24 (4C O).
Anal. Calcd. for C24H24N6O13S (636.54): C, 45.28; H, 3.80; N, 13.20; S, 5.04. Found:
C, 45.16; H, 3.72; N, 13.13; S, 4.90%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-galactopyranosylthio)-H-pyrazole--
carbonitrile (e).
White solid; (EtOH); yield (method a: 80%, method b: 70%); mp 232oC; IR (KBr,
−1
=
=
cm ) υ 3423, 3354 (NH2), 3139 (NH), 2212 (CN), 1753 (4C O), 1605 (C N);
1H NMR (500 MHz, DMSO): δ 2.04–2.16 (4s, 12H, 4xOAc), 3.88 (m, 2H, 2H-6`),
4.05 (m, 1H, H-5`), 4.18 (t, 1H, J = 9.4 Hz, H-4`), 4.35(t, 1H, J = 9.1 Hz, H-3`),
4.53 (t, 1H, J = 9.3 Hz H-2`), 5.56–5.57 (d, 1H, J 1`-2` = 10.02 Hz, H-1`), 7.42 (s,
D2O exch., 2H, NH2), 10.59 (s, D2O exch., 1H, NH); 13C NMR: δ 21.55 (4xOAc),
62.46 (C-6`), 67.66 (C-5`), 68.47 (C-4`), 73.57 (C-3`), 79.22 (C-2`), 82.68 (C-1`),
=
102.56 (C-4),115.81 (CN), 139.43 (C-3), 158.54 (C-5), 172.28(4C O). Anal. Calcd.
for C18H22N4O9S (470.45): C, 45.95; H, 4.71; N, 11.91; S, 6.82. Found: C, 45.84; H,
4.66; N, 11.79; S, 6.69%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-galactopyranosylthio)--phenyl-H-
pyrazole--carbonitrile (f)
White solid; (EtOH); yield (method a: 85%, method b: 77%); mp 225 ◦C; 1H NMR
(500 MHz, DMSO): δ 2.04–2.16 (4s, 12H, 4xOAc), 3.92 (m, 2H, 2H-6`), 4.26 (m,
1H, H-5`), 4.41 (t, 1H, J = 9.1 Hz, H-4`), 4.52 (t, 1H, J = 9.3 Hz, H-3`), 4.74 (t, 1H,
J = 9.2 Hz H-2`), 5.52–5.53 (d, 1H, J 1`-2` = 9.48 Hz, H-1`), 7.24 (s, D2O exch., 2H,
NH2), 7.34–7.79 (m, 5H, C6 H5); Anal. Calcd. for C24H26N4O9S (546.55): C, 52.74;
H, 4.79; N, 10.25; S, 5.87. Found: C, 52.68; H, 4.64; N, 10.12; S, 5.74%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-galactopyranosylthio)--(-nitrophenyl)-
H-pyrazole--carbonitrile (g)
White solid; (EtOH); yield (method a: 82%, method b: 75%); mp 226 oC; IR (KBr,
=
cm−1) 3408, 3325 (NH2), 3029 (aromatic CH), 2207 (CN), 1753 (4C O), 1599
1
=
(C N); H NMR (500 MHz, DMSO): δ 2.04–2.24 (4s, 12H, 4xOAc), 3.96 (m, 2H,

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
9
2H-6`), 4.18 (m, 1H, H-5`), 4.28 (t, 1H, J = 9.4 Hz, H-4`), 4.53 (t, 1H, J = 9.3 Hz, H-
3`), 4.68 (t, 1H, J = 9.1 Hz H-2`), 5.61–5.62 (d, 1H, J 1`-2` = 10.22 Hz, H-1`), 7.41 (s,
D2O exch., 2H, NH2), 8.02–8.54 (m, 4H, C6 H4); 13C NMR: δ 22.02 (4xOAc), 62.62
(C-6`), 66.19 (C-5`), 69.26 (C-4`), 75.43 (C-3`), 78.56 (C-2`), 82.85(C-1`), 103.62(C-
=
4), 117.44 (CN), 122.16-149.52 (7C, Ar-C, C-3), 155.46 (C-5), 171.57 (4C O). Anal.
Calcd. for C24H25N5O11S (591.55): C, 48.73; H, 4.26; N, 11.84; S, 5.42. Found: C,
48.64; H, 4.14; N, 11.72; S, 5.31%.
-Amino--(ꢀ,ꢀ,ꢀ,ꢀ-tetra-O-acetyl-β-D-galactopyranosylthio)--(,-
dinitrophenyl)-H-pyrazole--carbonitrile (h)
White solid; (EtOH); yield (method a: 80%, method b: 69%); mp 208 oC; 1H NMR
(500 MHz, DMSO): δ 1.99–2.15 (4s, 12H, 4xOAc), 3.99 (m, 2H, 2H-6`), 4.14 (m,
1H, H-5`), 4.25 (t, 1H, J = 9.1 Hz, H-4`), 4.37 (t, 1H, J = 9.4 Hz, H-3`), 4.48 (t, 1H,
J = 9.3 Hz H-2`), 5.66–5.67 (d, 1H, J 1`-2` = 10.44 Hz, H-1`), 7.28 (s, D2O exch., 2H,
NH2), 8.02–8.52 (m, 3H, C6 H3); 13C NMR: δ 21.22 (4xOAc), 62.55 (C-6`), 64.54
(C-5`), 67.62 (C-4`), 69.42 (C-3`), 79.63 (C-2`), 83.44 (C-1`), 104.23 (C-4), 116.57
=
(CN), 123.34-149.32 (7C, Ar-C, C-3), 151.66 (C-5), 172.49 (4C O). Anal. Calcd.
for C24H24N6O13S (636.54): C, 45.28; H, 3.80; N, 13.20; S, 5.04. Found: C, 45.16; H,
3.72; N, 13.13; S, 4.90%.
General procedure for the synthesis of (8a-h)
Dry gaseous of ammonia was passed through a solution of protected nucleoside
7a-h (10 mmol) in dry methanol (20 ml) for 5 minutes with cooling and stirring,
then the reaction mixture was stirred at room temperature until the reaction was
judged complete by TLC (9-10 h) using (CHCl3/MeOH 9:1) (Rf, 0.54-0.56). The
resulting mixture was concentrated under reduced pressure to afford a solid residue
which washed several times by boiling chloroform. The residue was dried, purified
by column chromatography using chloroform/methanol (9:1) and crystallized from
appropriate solvent to give the corresponding compounds 8a-h.
-Amino--(β-D-glucopyranosylthio)-H-pyrazole--carbonitrile (a)
White solid; (EtOH); yield (77%); mp 155 oC; IR (KBr, cm−1) υ 3533-3382 (OH),
3364, 3338 (NH2), 3249 (NH), 2934 (CH), 2205 (CN); 1H NMR (500 MHz, CDCl3)
δ 3.54-3.62 (m, 2H, 2H-6`), 3.71 (m.1H, H-5`), 3.85 (m, 1H, H-4`), 4.22 (t, 1H, J3`-2` =
6.74 Hz, J3`-4` = 5.93 Hz, H-3`), 3.96 (t, 1H, J2`-1` = 6.54 Hz, J2`-3` = 5.77 Hz, H-2`),
4.55-4.56 (d, 1H, J1 -2 = 10.78 Hz, H-1ꢀ), 4.76 (br, s, D2O exch., 1H, 6ꢀ-OH), 4.99-
5.04 (s, D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and 4ꢀ-OH), 7.48 (s, D2O exch., 2H, NH2),
11.52 (s, D2O exch., 1H, NH); 13C NMR: δ 62.24 (C-6ꢀ), 66.52 (C-5`), 69.34 (C-4ꢀ),
71.53 (C-3ꢀ), 78.62 (C-2ꢀ), 85.44 (C-1ꢀ), 101.36 (C-4), 115.24 (CN), 145.73 (C-3),
157.63 (C-5). Anal. Calcd. for C10H14N4O5S (302.31): C, 39.73; H, 4.67; N, 18.53; S,
10.61. Found: C, 39.82; H, 4.54; N, 18.39; S, 10.47%.
ꢀ
ꢀ

10
M. A. ABU-ZAIED AND G. H. ELGEMEIE
-Amino--(β-D-glucopyranosylthio)--phenyl-H-pyrazole--carbonitrile (b)
White solid; (EtOH); yield (80%); mp 165 oC; IR (KBr, cm−1) υ 3510-3378 (OH),
3367, 3346 (NH2), 3046 (aromatic CH), 2209 (CN); 1H NMR (500 MHz, CDCl3) δ
3.42-3.51 (m, 2H, 2H-6`), 3.64 (m,1H, H-5`), 3.78 (m, 1H, H-4`), 4.38 (t, 1H, J3`-2` =
5.86 Hz, J3`-4` = 6.48 Hz, H-3`), 4.42 (t, 1H, J2`-1` = 6.66 Hz, J2`-3` = 5.84 Hz, H-2`),
4.98-4.99 (d, 1H, J1 -2 = 10.84 Hz, H-1ꢀ), 5.04 (s, D2O exch., 1H, 6ꢀ-OH), 5.11-5.21 (s,
D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and 4ꢀ-OH), 7.42 (s, D2O exch., 2H, NH2), 7.38–7.78
(m, 5H, C6H5); 13C NMR: δ 62.21 (C-6ꢀ), 72.44 (C-5`), 75.62 (C-4ꢀ), 76.27 (C-3ꢀ),
77.35 (C-2ꢀ), 85.43 (C-1ꢀ), 104.41 (C-4), 116.74 (CN), 124.22-142.38 (7C, Ar-C, C-
3), 153.33 (C-5). Anal. Calcd. for C16H18N4O5S (378.40): C, 50.78; H, 4.79; N, 14.81;
S, 8.47. Found: C, 50.80; H, 4.66; N, 14.72; S, 8.32%.
ꢀ
ꢀ
-Amino--(β-D-glucopyranosylthio)--(-nitrophenyl)-H-pyrazole--carbonitrile
(c)
White solid; (EtOH); yield (68%); mp 182 oC; IR (KBr, cm−1) υ 3500-3340 (OH),
3371, 3258 (NH2), 3029 (aromatic CH), 2937 (CH), 2209 (CN); 1H NMR (500 MHz,
CDCl3) δ 3.44-3.51 (m, 2H, 2H-6`), 3.57 (m, 1H, H-5`), 3.66 (t, 1H, J4`-3` = 6.36 Hz,
J4`-5` = 6.22 Hz, H-4`), 4.23 (t, 1H, J3`-2` = 5.48 Hz, J3`-4` = 6.45 Hz, H-3`), 4.35 (t,
1H, J2`-1` = 5.33 Hz, J2`-3` = 5.63 Hz, H-2`), 4.26-4.27 (d, 1H, J1 -2 = 10.67 Hz, H-1ꢀ),
4.77 (br, s, D2O exch., 1H, 6ꢀ-OH), 4.86-4.91 (s, D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and
4ꢀ-OH), 7.42 (s, D2O exch., 2H, NH2), 7.97–8.58 (m, 4H, C6H4). Anal. Calcd. for
C16H17N5O7S (423.40): C, 45.39; H, 4.05; N, 16.54; S, 7.57. Found: C, 45.26; H, 4.00;
N, 16.42; S, 7.43%.
ꢀ
ꢀ
-Amino--(β-D-glucopyranosylthio)--(,-dinitrophenyl)-H-pyrazole--
carbonitrile (d)
White solid; (EtOH); yield (72%); mp 186 oC; 1H NMR (500 MHz, CDCL3) 3.51-
3.62 (m, 2H, 2H-6`), 3.77 (m.1H, H-5`), 3.91 (t, 1H, J4`-3` = 7.92 Hz, J4`-5` = 8.43 Hz,
H-4`), 4.02 (t, 1H, J4`-3` = 6.48 Hz, J4`-5` = 5.95 Hz, H-3`), 4.24 (t, 1H, J4`-3` = 6.97 Hz,
J4`-5` = 5.74 Hz, H-2`), 4.63-4.64 (d, 1H, J1 -2 = 10.7 Hz, H-1ꢀ), 4.79 (s, D2O exch., 1H,
6ꢀ-OH), 4.86-4.92 (s, D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and 4ꢀ-OH), 7.16 (s, D2O exch.,
2H, NH2), 8.27–8.99 (m, 3H, C6H3); 13C NMR: δ 62.45 (C-6ꢀ), 68.27 (C-5`), 73.33
(C-4ꢀ), 77.41 (C-3ꢀ), 79.46 (C-2ꢀ), 85.44 (C-1ꢀ), 101.62 (C-4), 117.48 (CN), 122.55-
150.24 (7C, Ar-C, C-3), 154.71 (C-5). Anal. Calcd. for C16H16N6O9S (468.40): C,
41.03; H, 3.44; N, 17.94; S, 6.85. Found: C, 41.12; H, 3.32; N, 17.81; S, 6.72%.
ꢀ
ꢀ
-Amino--(β-D-galactopyranosylthio)-H-pyrazole--carbonitrile (e)
White solid; (EtOH); yield (79%); mp 186 oC; 1H NMR (500 MHz, CDCl3) δ 3.42-
3.56 (m, 2H, 2H-6`), 3.68 (m.1H, H-5`), 3.84 (m, 1H, H-4`), 4.04 (t, 1H, J3`-2` = 7.21
Hz, J3`-4` = 6.65 Hz, H-3`), 4.25 (t, 1H, J2`-1` = 6.33 Hz, J2`-3` = 5.61 Hz, H-2`), 4.41-
4.42 (d, 1H, J1 -2 = 10.29 Hz, H-1ꢀ), 4.88 (br, s, D2O exch., 1H, 6ꢀ-OH), 5.04-5.12
(s, D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and 4ꢀ-OH), 7.36 (s, D2O exch., 2H, NH2), 10.18
ꢀ
ꢀ

NUCLEOSIDES, NUCLEOTIDES AND NUCLEIC ACIDS
11
(s, D2O exch., 1H, NH); 13C NMR: δ 62.33 (C-6ꢀ), 69.24 (C-5`), 70.46 (C-4ꢀ), 75.64
(C-3ꢀ), 79.45 (C-2ꢀ), 85.84 (C-1ꢀ), 103.24 (C-4), 116.73 (CN), 144.89 (C-3), 155.68
(C-5). Anal. Calcd. for C10H14N4O5S (302.31): C, 39.73; H, 4.67; N, 18.53; S, 10.61.
Found: C, 39.66; H, 4.58; N, 18.41; S, 10.58%.
-Amino--(β-D-galactopyranosylthio)--phenyl-H-pyrazole--carbonitrile (f)
White solid; (EtOH); yield (79%); mp 192 oC; IR (KBr, cm−1) υ 3410-3367 (OH),
3354, 3346 (NH2), 3034 (aromatic CH), 2207 (CN); 1H NMR (500 MHz, CDCL3) δ
3.48-3.57 (m, 2H, 2H-6`), 3.69 (m.1H, H-5`), 3.83 (m, 1H, H-4`), 4.06 (t, 1H, J3`-2` =
5.46 Hz, J3`-4` = 6.88 Hz, H-3`), 4.25 (t, 1H, J2`-1` = 6.23 Hz, J2`-3` = 5.64 Hz, H-2`),
4.76-4.77 (d, 1H, J1 -2 = 10.98 Hz, H-1ꢀ), 4.86 (s, D2O exch., 1H, 6ꢀ-OH), 5.04-5.15 (s,
D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and 4ꢀ-OH), 7.22 (s, D2O exch., 2H, NH2), 7.36–7.84
(m, 5H, C6H5); 13C NMR: δ 62.71 (C-6ꢀ), 73.82 (C-5`), 74.51 (C-4ꢀ), 77.44 (C-3ꢀ),
79.43 (C-2ꢀ), 85.63 (C-1ꢀ), 104.62 (C-4), 117.26 (CN), 123.52-144.52 (7C, Ar-C, C-
3), 151.64 (C-5). Anal. Calcd. for C16H18N4O5S (378.40): C, 50.78; H, 4.79; N, 14.81;
S, 8.47. Found: C, 50.72; H, 4.70; N, 14.64; S, 8.36%.
ꢀ
ꢀ
-Amino--(β-D-galactopyranosylthio)--(-nitrophenyl)-H-pyrazole--
carbonitrile (g)
White solid; (EtOH); yield (73%); mp 187 oC; IR (KBr, cm−1) υ 3500-3366 (OH),
3342, 3336 (NH2), 3036 (aromatic CH), 2942 (CH), 2213 (CN); 1H-NMR (500 MHz,
CDCL3) δ 3.46-3.54 (m, 2H, 2H-6`), 3.65 (m, 1H, H-5`), 3.82 (t, 1H, J4`-3` = 6.84 Hz,
J4`-5` = 7.63 Hz, H-4`), 4.16 (t, 1H, J3`-2` = 7.74 Hz, J3`-4` = 6.28 Hz, H-3`), 4.26 (t,
1H, J2`-1` = 6.84 Hz, J2`-3` = 5.22 Hz, H-2`), 4.33-4.34 (d, 1H, J1 -2 = 10.41 Hz, H-1ꢀ),
4.82 (br, s, D2O exch., 1H, 6ꢀ-OH), 5.04-5.16 (s, D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and
4ꢀ-OH), 7.48 (s, D2O exch., 2H, NH2), 7.68–8.35 (m, 4H, C6H4). Anal. Calcd. for
C16H17N5O7S (423.40): C, 45.39; H, 4.05; N, 16.54; S, 7.57. Found: C, 45.31; H, 4.14;
N, 16.45; S, 7.46%.
ꢀ
ꢀ
-Amino--(β-D-galactopyranosylthio)--(,-dinitrophenyl)-H-pyrazole--
carbonitrile (h)
White solid; (EtOH); yield (78%); mp 202 oC; 1H NMR (500 MHz, CDCl3) 3.42-
3.56 (m, 2H, 2H-6`), 3.62 (m.1H, H-5`), 3.84 (t, 1H, J4`-3` = 6.93 Hz, J4`-5` = 5.44 Hz,
H-4`), 4.06 (t, 1H, J3`-4` = 6.77 Hz, J3`-5` = 5.62 Hz, H-3`), 4.23 (t, 1H, J2`-3` = 6.74
Hz, J2`-4` = 5.92 Hz, H-2`), 4.58-4.89 (d, 1H, J1 -2 = 10.46 Hz, H-1ꢀ), 4.88 (s, D2O
exch., 1H, 6ꢀ-OH), 5.21-5.34 (s, D2O exch., 3H, 2ꢀ-OH, 3ꢀ-OH, and 4ꢀ-OH), 7.37 (s,
D2O exch., 2H, NH2), 8.17–8.79 (m, 3H, C6H3); 13C NMR: δ 62.67 (C-6ꢀ), 69.37
(C-5`), 74.28 (C-4ꢀ), 76.54 (C-3ꢀ), 78.85 (C-2ꢀ), 85.83 (C-1ꢀ), 103.46 (C-4), 117.57
(CN), 123.61-152.16 (7C, Ar-C, C-3), 153.64 (C-5). Anal. Calcd. for C16H16N6O9S
(468.40): C, 41.03; H, 3.44; N, 17.94; S, 6.85. Found: C, 41.09; H, 3.40; N, 17.86; S,
6.70%.
ꢀ
ꢀ

12
M. A. ABU-ZAIED AND G. H. ELGEMEIE
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