Synthesis of new pyrazoline-nucleoside analogue derivatives

Article abstract of DOI:10.1080/15257770.2013.786834

In this work, a synthesis of pyrazoline nucleosides analogues is presented, using the stereospecific sodium salt glycosylation procedure. In the first step, chalcones were prepared using Claisen Schmidt reaction by reacting benzaldehyde with enolizable ketones in ethanolic NaOH solutions. Next, these chalcones were immediately reacted with hydrazine hydrochloridein the presence of dry methanol to obtain the corresponding 2-pyrazolines. Finally, the coupling of the pyrazolines with 1-chloro-arabinofuranose leads to different β-nucleosides as the major product (13-17) in good yields. The structures of these derivatives were characterized by infrared and 1HNMR spectroscopy and mass spectrometry.

Full text of DOI:10.1080/15257770.2013.786834

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Synthesis of New Pyrazoline-Nucleoside
Analogue Derivatives
a
a
b
b
M. Azouz , K. Lammara , M. Benallia & H. Guenane
a
Department of Chemistry , Oum-El-Bouaghi University , Oum-El-
Bouaghi , Algeria
b
Laboratory of Synthesis and Characterization and Natural Product
Synthesis and Synthetic Process Engineering Department , Amar
Telidji University , Laghouat , Algeria
Published online: 02 May 2013.
To cite this article: M. Azouz , K. Lammara , M. Benallia & H. Guenane (2013) Synthesis of New
Pyrazoline-Nucleoside Analogue Derivatives, Nucleosides, Nucleotides and Nucleic Acids, 32:6,
294-305, DOI: 10.1080/15257770.2013.786834
To link to this article: http://dx.doi.org/10.1080/15257770.2013.786834
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Nucleosides, Nucleotides and Nucleic Acids, 32:294–305, 2013
Copyright © University of Souk-Ahras, Algeria
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2013.786834
SYNTHESIS OF NEW PYRAZOLINE-NUCLEOSIDE ANALOGUE
DERIVATIVES
1
1
2
2
M. Azouz, K. Lammara, M. Benallia, and H. Guenane
1
Department of Chemistry, Oum-El-Bouaghi University, Oum-El-Bouaghi, Algeria
Laboratory of Synthesis and Characterization and Natural Product Synthesis and Synthetic
2
Process Engineering Department, Amar Telidji University, Laghouat, Algeria
GRAPHICAL ABSTRACT
2
In this work, a synthesis of pyrazoline nucleosides analogues is presented, using the stere-
ospecific sodium salt glycosylation procedure. In the first step, chalcones were prepared using
Claisen–Schmidt reaction by reacting benzaldehyde with enolizable ketones in ethano-
lic NaOH solutions. Next, these chalcones were immediately reacted with hydrazine hydrochloride
in the presence of dry methanol to obtain the corresponding 2-pyrazolines. Finally, the coupling of
the pyrazolines with 1-chloro-arabinofuranose leads to different β-nucleosides as the major product
(
13–17) in good yields.
The structures of these derivatives were characterized by infrared and HNMR spectroscopy and
1
mass spectrometry.
ꢀ
Keywords α,α -Bis(substituted benzylidene) cycloalkanones; ketones enolization; aldol
condensation; nucleosides; glycosylation
Received 9 May 2012; accepted 11 March 2013.
Address correspondence to Dr. Azouz Mounir, University Mohamed Ch e´ rif Messaadia of Soukahras,
B.P/1553, Route de Aannaba, 41000, Soukahras, Algeria. E-mail: mounir.azouz@cu-soukahras.dz
2
94

Synthesis of New Pyrazoline-Nucleoside Analogue Derivatives
295
INTRODUCTION
Natural nucleosides and nucleotides play a key role in many biosyntheses
[1]
and regulatory processes in the living cell. The purine and pyrimidine
nucleotides are very important building blocks that can be found in RNA and
DNA, an energy transcription (ATP); parts of coenzymes (AMP); acceptors
for oxidative phosphorylation (ADP); allosteric regulators of enzyme activity;
and as second messengers, the cyclic adenosine -3,5-monophosphate (cAMP)
[2]
and cyclic guanosine-3,5-monophosphate.
Nucleoside and nucleoside analogues are from a pharmacological family
of molecules that have been synthesized and used for cytotoxic, antiviral, and
[3]
immunosuppressive therapy. Particularly, adenosine, a purine nucleoside,
is increasingly being found to play an important role in tumor growth and
[
4]
metastasis. The pharmacological approach in the synthesis of novel drugs
suggests that the use of purine nucleoside analogues in which the hetero-
cyclic structure or sugar moiety can cause toxic effects when incorporated in
different part of the cell. Various compounds used for chemotherapy differ
[5]
in their chemical structure and mechanism of action.
RESULTS AND DISCUSSION
The present investigation involves the synthesis of some chalcones from
the preparation of starting material aromatic aldehydes on the basis of direct
Claisen–Schmidt reaction.[ Benzaldehyde is subjected to react with a series
of substituted acetophenones to give enones (1–2) in a quantitative yield
6]
(
Scheme 1).
SCHEME 1
The ketone PhCOMe reacts with 4-nitrobenzaldehyde in aqueous
ethanol under NaOH catalysis to give a quantitative yield of an enone. On
ꢀ
the other hand, the α,α -bis(substituted benzylidene) cycloalkanones (3–5)
are prepared by the condensation of benzaldehyde with cyclohexanone and
cyclopentanone, using mole ratios (1:2), in the presence of alkali in aque-
ꢀ
ous ethanol to give a good yield. The α,α -bis(substituted benzylidene) cy-
cloalkanones served as the starting compounds for the synthesis of pyrazoles
(Scheme 2). Cycloalkanones are an interesting class of compounds because

2
96
M. Azouz et al.
SCHEME 2
of their use as precursors to potentially bioactive pyrimidine derivatives.[7]
Cross aldol-type reaction is available for these preparations. However, tradi-
[
8]
tional acid- or base-catalyzed reaction suffers from the reverse reaction.
[
9]
Direct cross aldol condensation of cycloalkanones with aldehydes is a very
attractive route to prepare α,α -bis(substituted benzylidene) cycloalkanones.
ꢀ
The condensation of cyclopentanone and cyclohexanone with an aldehyde
ꢀ
leads to the α,α -bis(substituted benzylidene) cycloalkanones (3), (4), and
(
5), in good yields
The results obtained for condensation of cyclohexanone and different
ketones are shown in Table 1.
In the last step, chalcones (1 and 2) were immediately reacted with
[10]
hydrazine hydrochloride in the presence of dry methanol
to obtain the
corresponding (6 and 7) 2-pyrazolines, respectively, in acceptable yields, as
shown in Scheme 3.
SCHEME 3
The reaction of diarylidenecycloalkanones with hydrazine hydrate
[7]
was studied by Oszbach and Szabo,
who reported that with 2,6-
diarylidenecyclohexanones the reaction afforded bicyclic pyrazolines. Our
compound intermediates (Scheme 4) were obtained by refluxing 2,6-
diarylidenecyclohexanone (3), (4), and 2,6-diarylidenecyclopentanone (5)
with hydrazine in methanol to give the corresponding 2-pyrazolines (8), (9),
and (10) respectively, in acceptable yields.

Synthesis of New Pyrazoline-Nucleoside Analogue Derivatives
297
SCHEME 4
The formation of dihydropyrazoles (8), (9), and (10) occurs stereospecif-
ically. These compounds were isolated in only one diastereoisomeric form
with trans-orientation of the hydrogen atoms H-3 and H-8 of the dihydropy-
razole ring, which was confirmed by 1H and 13C NMR spectral data. Thus,
chemical shifts for the protons H-3 in (8), (9), and (10) are, δ ppm = 4.69;
3
4
.62, and 4.56 and the spin–spin coupling constants J
are equal to 11.5;
H-3,H-8
11.2, and 11, respectively. These values are characteristic of trans-isomers.
N-Glycosylation of Pyrazoline
For the synthesis of various nucleoside analogues, 1-O-acetyl-2,3,5-O-
benzoylribofuranose (11)—which is commercially available—was converted
[
12]
to a mixture of α and β chlorosugars (12) utilizing TiCl4.
Treatment of
the chlorosugar mixture with the sodium salt of pyrazoline in acetonitrile
gave the corresponding nucleosides (13–17).
Deprotonation of pyrazoline (2.0 eq) with NaH (2.1 eq) in anhydrous
[8]
acetonitrile, according to the procedure of Kandasamy. et al., was followed
by a treatment with 1-chloro-arabinofuranose (12) (2.0 eq). The reaction
mixture was stirred at room temperature (r.t.) for 12 hours under a nitrogen
atmosphere and filtered to remove a small amount of insoluble material.
Evaporation of the filtrates gave a crude product, which was purified by flash
chromatography using toluene: ethyl acetate (1:25, v/v) as an eluent to yield
the β nucleosides as the major products (13)–(17) in good yields (51–67%)
TABLE 1 Results obtained for condensation of cyclohexanone and different ketones
◦
Compound
Form
Yield (%)
Mp ( C)
Eluant
1
2
3
4
5
Yellow crystal
Yellow crystal
Yellow crystal
Yellow crystal
Yellow crystal
77.5
77.4
74.7
61
56–58 (Lit.[10] 84–86).
87–89
AcOEt/n-hexane: 8/2
AcOEt/n-hexane: 8/2
AcOEt/n-hexane: 7/3
AcOEt/n-hexane: 7/3
AcOEt/n-hexane: 7/3
121–122 (Lit.[7] 121–122).
133–134
68
142–145 (Lit.[11] 143–146).

2
98
M. Azouz et al.
as white foams (Scheme 5). In all cases, a small amount of starting material
was observed by thin layer chromatography (TLC).
The anomeric configuration of the isolated pyrazoline ribonucleosides
13–17) was assigned as β on the basis of H NMR data. The H NMR spec-
1
1
(
trum of 13 in CDCl exhibited a much smaller coupling constant (J
.01 Hz) than that of 14 (J1
ꢀ
ꢀ
=
3
1 −2
1
6
ꢀ
−2ꢀ
= 4.15 Hz). Moreover, the H NMR of 15–17
in CDCl revealed the anomeric doublet centered at δ (6.03–6.04) ppm with
3
a small coupling constant between (J1
ꢀ
ꢀ
= 2 Hz) and (J
1ꢀ−2ꢀ
= 4.15 Hz),
−2
which is within the acceptable limits for β-ribonucleosides.
IR spectra of compounds 13–17 show absorption bands stretching for
–
1
benzoyl carbonyl group at 1725 cm , the C C bonds of compounds 15,
–1
1
6, and 17 at 1640–1645 cm , The presence of the imine function C N
was confirmed by the infrared spectrum, which revealed a sharp absorption
–
1
band at 1595 cm .
1H NMR spectra of the compounds are characterized by the presence
of signals for the aromatic protons together and the associated methoxy
group singlet at 1.79–2.15 ppm for compounds 14, 16, and 17, a dou-
ꢀ
blet at 5.02–6.04 ppm, (J 1
ꢀ
−2ꢀ
4.10–6.01 Hz) for the H-1 proton, double
doublets in the regions 5.94–6.00, coupling constant (J = 6.01, 4.15 Hz),
(
J = 4.70, 4.15 Hz), and (J = 6.99, 6.01 Hz) and triplet at 5,95 ppm cou-
ꢀ
pling constant 8 Hz for the H-2 , double doublets, respectively, at 5.79, 5.89,
and 6.09 ppm coupling constant (J = 5.60, 4.70 Hz), (J = 8.50,6.99 Hz),
and (J = 8.2, 5.00 Hz) and triplet at 6.12 ppm coupling constant 6.01 Hz
ꢀ
for the H-3 and as well characterized by the presence of signals of the pyra-
1
13
zolinic ring protons. H and C NMR confirmed the structure of compounds
1
3–17.
EXPERIMENTAL
General
1
13
1
H NMR and C NMR spectra were recorded at 300 MHz ( H: 300 MHz,
3C: 75.5 MHz) or 250 MHz (1H: 250 MHz, 13C: 62.9 MHz), using CDCl3
1
as internal reference. The chemical shifts (δ) and coupling constants (J )
are expressed in ppm and hertz (Hz), respectively. IR spectra were recorded
on a PerkinElmer Paragon 1000 FTIR spectrophotometer as neat films on
NaCl windows or as KBr pellets. Melting points (mp) were determined
by using a B u¨ chi Totolli apparatus and are uncorrected Merck silica gel
(
0.043–0.063 mm) was used for flash chromatography.
All reactions were carried out under nitrogen atmosphere. Acetonitrile,
was distilled over potassium carbonate. All reagent-grade chemicals were
obtained from commercial suppliers and were used as received, unless oth-
erwise stated.

2
99

3
00
M. Azouz et al.
Synthesis
General Procedure for the Preparation of 4-Hydroxyphenyl Chalcones 1–2
An aqueous solution of potassium hydroxide (20%, 10 mL) was added
under stirring overnight to a solution of the appropriate aryl aldehyde
30 mmol) and 4-hydroxyacetophenone (30 mmol) in 96% ethanol (75 mL)
(
at r.t. The reaction mixture was then poured into water (100 mL) and after
neutralization with hydrochloric acid (5%) a yellow solid was recrystallized
from ethanol.
(
2E)-1,3-Diphenylprop-2-en-1-one (1). Compound 1 was prepared in a
7.5% yield (14.52 g) from 10.81 g (10.6 mL, 0.09 mol) acetophenone
and 9.55 g (9.14 mL, 0.09 mol) of benzald e´ hyde, pale yellow powder; mp
7
◦
[9]
◦
5
6–58 C (Lit. mp 56–57 C).
–
1
IR spectrum (KBr) ν, cm : 3050; 1685 (C O); 1640 (C C); 1600; 1495.
2E)-1,3-Bis(3-methoxyphenyl)prop-2-en-1-one (2). Compound 2 was pre-
(
pared in a 77.4% yield (14.52 g) from (13.5 g, 0.09 mol) 3-m e´ thoxyac e´ to-
ph e´ none and (12.15 g, 0.09 mol) of 3-m e´ thoxybenzald e´ hyde, pale yellow
◦
powder; mp 87–89 C.
–
1
IR spectrum (KBr) ν, cm : 3066; 2939; 1685 (C O); 1640 (C C); 1601;
1574; 1489; 1248.
Distyryl Ketones (3)–(5), General Procedure
These compounds were synthesized using a conventional procedure
[
8]
from cyclohexanone, cyclopentanone, and benzaldehyde or m-anisaldehyde
in the presence of alkali in aq EtOH and purified by column chromatography
on alumina (eluent, hexane–CHCl , 3:1).
3
(
2E,6E)-2,6-Bis(phenylmethylidene)cyclohexan-1-one (3). Compound 3 was
prepared in a 74.7% yield (25.6 g) from 26.53 g (25.4 mL, 0.25 mol) of
benzaldehyde and 12.27 g (12.91 mL, 0.125 mol) of cyclohexanone, pale
◦
–
[13]
◦
yellow powder; mp 121–122 C (Lit.
mp 121–122 C).
IR spectrum (KBr) ν, cm : 3033; 2935; 1685 (C O); 1640 (C C); 1600;
493; 1465.
2E,6E)-2,6-Bis[(3-methoxyphenyl)methylidene]cyclohexan-1-one (4). Com-
1
1
(
pound 4 was prepared in a 61% yield (25.6 g) from (33.75 g, 0.25 mol)
of 3-m e´ thoxybenzald e´ hyde and (12.25 g, 0.125 mol) of cyclohexanone, pale
◦
yellow powder; mp 133–134 C
–1
IR,νmax (cm ), (KBr): 3055; 2995; 1685 (C O); 1635 (C C); 1600; 1524;
465; 1200
2E,5E)-2,5-Bis[(3-methoxyphenyl)methylidene]cyclopentan-1-one (5). Co-
mpound 5 was prepared in a 68% yield (27.2 g) from (33.75 g, 0.25 mol) of
-m e´ thoxybenzald e´ hyde and (10.5 g, 0.125 mol) of cyclopentanone, pale
1
(
3
◦
[11]
◦
yellow powder, mp 142–145 C (Lit.
mp 143–146 C).

Synthesis of New Pyrazoline-Nucleoside Analogue Derivatives
301
–1
IR,νmax (cm ), (KBr): 3020; 2995; 1689 (C O); 1645 (C C); 1600; 1554;
466; 1200.
1
General Procedure for the Synthesis of 2-Pyrazoline (6)–(7)
These compounds were synthesized by a standard procedure from the
[
9]
chalcones 6 and 7 and hydrazine hydrate in EtOH. The solid precipitate that
formed on cooling was collected by filtration and recrystallized from ethanol
3,5-Diphenyl-4,5-dihydro-1H-pyrazole (6). Compound 6 was prepared in
a 66.6% yield (1.48 g) from (2.08 g, 0.01 mol) of benzylid e` neac e´ toph e´ none
◦
and (2.41 mL, 0.05 mol) of hydrazine, pale yellow powder; mp 79–81 C
[
14]
◦
(
Lit.
IR,ν
mp 80 C).
–
1
(cm ), (KBr): 3300; 3057; 2912; 1603; 1595 (C N);1530.
max
1
H NMR spectrum, δ, ppm (J , Hz): 7.03–7.29 (m,10H, H ); 5.25 (dd,1H,
ar
J = 10.4, J = 4.8 Hz, H ); 3.80 (dd, 1H, J = 17.6 et 4.8, H ); 3.20 (dd,1H,
5
4a
J = 17.6 et 10.3, H ).
4
b
+
Found: m/z 223.1235 [M+H] . C H N . Calculated: M = 223.1235
15
15
2
3,5-Bis(3-methoxyphenyl)-4,5-dihydro-1H-pyrazole (7). Compound 7 was
prepared in a 53% yield (1.5 g) from (2.68 g, 0.01 mol) of 3-
methoxybenzylideneacetophenone and (2.41 mL, 0.05 mol) of hydrazine,
◦
pale yellow powder; mp 114–116 C.
–1
IR,ν
(cm ), (KBr): 3300; 3057; 2912; 1603; 1595 (C N), 15 = 30; l200
max
1
H NMR spectrum, δ, ppm (J , Hz): 6.83–7.32 (m,8H, H ); 4.97 (dd, 1H,
ar
J = 9.2, 4.8, H ); 3.81 (s, 3H, OMe); 3.71 (s, 3H, OMe); 3.60 (dd, 1H, J =
5
1
5.8, 4.6, H ); 3.20 (dd 1H, J = 15.8, 9.2, H ).
4
a
4b
+
Found: m/z 283.1444 [M+H] . C H N O . Calculated: M = 283.1447
17
19
2
2
Dihydropyrazoles (8)–(10)
These compounds were synthesized by a standard procedure
[
13]
from
the chalcones 3–5 and hydrazine hydrate in EtOH. The precipitated dihy-
dropyrazoles were filtered, washed with EtOH on a filter, and dried over
P O .
2
5
(
7E)-3-Phenyl-7-(phenylmethylidene)-3,3a,4,5,6,7-hexahydro-2H-indazole (8).
The general procedure was employed using dibenzylid e` necycloh e´ xanone
◦
[13]
(
2.74 g, 0.01 mol), yield 2.16 g (74%), colorless powder, mp 84–86 C (Lit.
◦
mp 84–86 C).
–
1
IR,νmax (cm ), (KBr): 3043; 2927; 1640; 1600; 1590 (C N);1493;1465.
H NMR spectrum, δ, ppm (J , Hz): 7.25–7.31 (m, 10H, H ); 6.75 (s, 1H,
ar
Hvinyl); 4.69 (d,1H, J = 11.5, H ); 3.35 (td, 1H, J = 11.5, 4.5, H ); 2.05–2.50
3
4
(
m, 6H, CH
).
-cyclox
2
+
Found: m/z 311.1526 [M+Na] . C H N Na. Calculated: M = 311.1522
20
20
2
(
7E)-3-(3-Methoxyphenyl)-7-[(3-methoxyphenyl)methylidene]-3,3a,4,5,6,7-
hexahydro-2H-indazole (9). The general procedure was employed using

3
02
M. Azouz et al.
(
(
3.34 g, 0.01 mol) of 3-methoxydibenzylidenecyclohexanone, yield 2.66 g
◦
76%), colorless powder, mp 112–114 C.
–1
IR,νmax (cm ), (KBr): 3300; 3043; 2927; 1640; 1600; 1590 (C N);
1
493; 1421; 1250.
H NMR spectrum, δ, ppm (J , Hz): 6.70–7.34 (m, 8H, H ); 6.70 (s, 1H,
ar
Hvinyl); 4.62 (d, 1H, J = 11.2, H ); 3.81 (s, 3H, OMe); 3.7 (s, 3H, OMe); 3.30
3
(
td, 1H, J = 11.7 3.5, H ); 1.96–2.49 (m, 6H, CH
).
2-cyclox
4
+
Found: m/z 371.1740 [M+Na] . C H N O Na. Calculated: M =
22
24
2
2
3
71.1735
6E)-3-(3-Methoxyphenyl)-6-[(3-methoxyphenyl)methylidene]-2H,3H,3aH,4H,
H,6H-cyclopenta[c]pyrazole (10). The general procedure was employed
(
5
using 3-methoxydibenzylidenecyclopentanone (3.20 g, 0.01 mol), yield
◦
2
.30 g (69%), colorless powder, mp 101–104 C.
–1
IR,νmax (cm ), (KBr): 3300; 3033; 2922; 1643; 1600; 1595 (C N);
1
490; 1434; 1250.
H NMR spectrum, δ, ppm (J , Hz): 7.33–6.61 (m, 8H, H ); 6.50 (s, 1H,
ar
H ); 4.56 (d, 1H, J = 11, H ); 3.80 (s, 3H, OMe); 3.73 (s, 3H, OMe), (m,
vin
3
1
H, H ); 2.60–2.56 (m, 2H, H ); 2.09–2.04 (m, 1H, H ); 1.88–1.78 (m, 1H,
4 7 6
H ).
6
+
Found: m/z 357.1571 [M+Na] . C H N O Na. Calculated: M =
21
22
2
2
3
57.1579
[
3,4-Bis(benzoyloxy)-5-chlorooxolan-2-yl]methylbenzoate (12)
β-1-O-Acetyl-2,3,5-O-benzoylribofuranose (11) (9, 5.91 g, 11.71 mmol) in
[
12]
CH Cl (70 mL) was added a solution of TiCl4 in CH Cl (13 mL, 1.0 M).
2
2
2
2
◦
The reaction was stirred at 23 C for 2 hours, followed by quenching with
deionized H O (75 mL). The organic layer was separated, washed with deion-
2
ized H O (1 × 75 mL), dried over anhydrous MgSO , and concentrated in
2
4
vacuo. The crude material 1-chloro-2,3,5-tri-O-benzyl-α-D-arabinofuranose
(
11) was dissolved in CH CN (20 mL) and used without further purification
3
in the subsequent coupling step.
General Procedure for Nucleosides Preparation
To a stirred solution of pyrazoline (5 mmol) in dry acetonitrile (35 mL)
was added sodium hydride (60% in oil, 0.2 g, 5 mmol) in small portions
[
15]
at r.t.
0 minutes and then chloro ribofuranose (12) (5 mmol) in dry acetonitrile
35 mL) was added. The reaction mixture was stirred at r.t. for 12 hours
After the addition of sodium hydride, the mixture was stirred for
3
(
under a nitrogen atmosphere and filtered to remove a small amount of
insoluble material. Evaporation of the filtrate gave crude product, which was
purified by flash chromatography using toluen:ethylacetate (1:25, v/v) as
eluant to yield of β nucleosides as the major product (13)–(17) as a white
foam.

Synthesis of New Pyrazoline-Nucleoside Analogue Derivatives
303
4
-(Benzoyloxy)-5-[(benzoyloxy)methyl]-2-(3,5-diphenyl-4,5-dihydro-1H-pyrazol-
1
5
3
-yl)oxolan-3-yl Benzoate (13). By the synthesis of pyrazoline 6 (1.11 g,
mmol), according to the general procedure, nucleoside 13 (2.23 g,
.35 mmol, 67%) was obtained as a white foam.
–
1
IR,νmax (cm ), (KBr): 3066; 2947; 1725 (C O); 1603; 1595 (C N);
493; 1266.
1
1
H NMR spectrum, δ, ppm (J , Hz): base: 4.22 (dd, 1H, J = 14.00, J =
1.75, H ); 3.44 (dd, 1H, J = 15.00, J = 11.75, H ); 2.88 (dd, 1H, J = 15.00,
5
4b
J = 14.00, H ) sugar: 6.00 (dd, 1H, J = 6.99, J = 6.01 Hz, H
ꢀ
); 5.89 (dd,
2
4
a
1
H
H, J = 8.50, J = 6.99, H
ꢀ
); 5.09–5.11 (m, 1H, H
ꢀ
4
); 5.02 (d, 1H, J = 6.01,
3
ꢀ
); 4.88 (dd, 1H, J = 12.4, J = 3.4 Hz, H ); 4.60 (dd, 1H, J = 12.4, J =
ꢀ
1
5 b
2.5, H
ꢀ
); benzoyle + H
: 7.16–7.99 (m, 25 H, H
).
aroma
5
a
aroma
13
C NMR (100 MHz, CDCl3, δ (ppm): sugar: 92.50 (C
ꢀ
); 77.00 (C4
); base: 155.70 (C ); 67.40 (C ); 39.50
ꢀ
);
1
7
4.90 (C3
ꢀ
); 74.11 (C2
ꢀ
); 65.19 (C5
ꢀ
3
5
(
(
4
ro-1H-pyrazol-1-yl]oxolan-3-yl Benzoate (14). By synthesis of pyrazoline 7
1.41 g, 5 mmol) according to the general procedure, nucleoside 14 (1.85 g,
.55 mmol, 51%) was obtained as a white foam.
(
2
1
1
–
1
IR,νmax (cm ), (KBr): 3067; 2955; 1725 (C O); 1603; 1595 (C N);
494; 1266; l200.
H NMR spectrum, δ, ppm (J , Hz): base: 4.29 (dd, 1H, J = 14.00, J =
1.50, H ); 3.84 (s, 3H, OMe); 3.77 (s, 3H, OMe); 3.40 (dd, 1H, J = 15.00,
5
J = 11.50, H ); 2.87 (dd, 1H, J = 15.00, J = 14.00, H ); sugar: 6.00 (dd, 1H,
4b
4a
J = 4.70, J = 4.15, H
ꢀ
); 5.79 (dd, 1H, J = 5.60, J = 4.70, H
ꢀ
); 5.06 (d, 1H,
2
3
J = 4.15, H
ꢀ
); 4.98–5.03 (m, 1H, H
ꢀ
); 4.69–4.81 (m, 1H, H
ꢀ
); 4.69–4.81
1
4
5 a
(m, 1H, H
ꢀ
); benzoyle + Haroma: 6.70–7.97 (m, 23 H, H
).
5
b
aroma
13
C NMR (100 MHz, CDCl3, δ (ppm): sugar: 93.09 (C
ꢀ
); 76.49 (C4
ꢀ
);
1
7
4.90 (C3
ꢀ
); 74.11 (C2
ꢀ
); 64.99 (C5
ꢀ
); base: 156.90, 153.50 (C–OMe); 154.89
(
1
C ); 66.70 (C5); 56.03, 54.99 (OMe), 39.89 (C4); benzoyles group:
3
67.03,165.30,164.50 (C O)
; 121.80–136.50 (Caroma).
Benzoyle
+
Found: m/z 727.2656 [M+H] . C H N O . Calculated: M = 727.2656.
43
39
2
9
4-(Benzoyloxy)-5-[(benzoyloxy)methyl]-2-[(7E)-3-phenyl-7-(phenylmethylidene)
-3,3a,4,5,6,7-hexahydro-2H-indazol-2-yl]oxolan-3-yl Benzoate (15). By synthesis
of pyrazoline 8 (1.44 g, 5 mmol) according to the general procedure,
nucleoside 15 (2.24 g, 3.05 mmol, 61%) was obtained as a white foam.
–
1
IR,νmax (cm ), (KBr): 3066; 2931; 1725 (C O); 1640 (C C); 1603; 1595
C N); 1490; 1465; 1275.
(
H NMR spectrum, δ, ppm (J , Hz): base: 6.94 (s, 1H, Hvinyl); 4.76 (d, 1H,
J = 11.5, H ); 3.51 (td,1H, J = 12.20, J = 11.50, H ); 1.99–2.42 (m, 6H,
5
4
CH
; sugar: 6.12 (t, 1H, J = 6.01, H
ꢀ
); 6.04 (d, 1H, J = 4.15, H
ꢀ
);
1
2
Cycloh e´ xan)
3
5.94 (dd, 1H, J = 6.01, J = 4.15, H
ꢀ
); 5.07–5.093 (m, 1H, H );4.67–4.77 (m,
4
ꢀ
2

3
04
M. Azouz et al.
); benzoyle + Haroma: 7.29–7.93 (m, 25 H,
1
H
H, H5 a
aroma
ꢀ
); 4.67–4.77 (m, 1H, H
ꢀ
5 b
).
13
C NMR (100 MHz, CDCl3, δ (ppm): sugar: 91.80 (C
ꢀ
); 77.70 (C4
ꢀ
);
1
7
6.29 (C3
ꢀ
); 74.20 (C2
ꢀ
); 65.80 (C5
ꢀ
); base: 170.60 (C ); 134.10 (C ); 119.70
3
9
(
C ); 78.29 (C ); 49.09 (C ); 29.20 (C ); 27.09 (C ); 23.44 (C ), benzoyles
10
5
4
8
6
7
group: 166.50, 165.70, 164.10 (C O)Benzoyle; 122.70–138.89 (Caroma).
+
Found: m/z 733.2917 [M+H] . C H N O . Calculated: M = 733.2912.
46
41
2
7
4
-(Benzoyloxy)-5-[(benzoyloxy)methyl]-2-[(7E)-3-(3-methoxyphenyl)-7-[(3-met-
hoxyphenyl)methylidene]-3,3a,4,5,6,7-hexahydro-2H-indazol-2-yl]oxolan-3-ylbenz-
oate (16). By the synthesis of pyrazoline 9 (1.74 g, 5 mmol) according
to the general procedure, nucleoside 16 (2.34 g, 2.95 mmol, 59%) was
obtained as a white foam.
–1
IR,νmax (cm ), (KBr): 3066; 2931; 1725 (C O); 1645 (C C); 1600; 1595
C N); 1496; 1465; 1275; 1200
(
H NMR spectrum, δ, ppm (J , Hz): base: 6.69 (1H, s, Hvinyl); 4.79 (d, 1H,
J = 11.5, H ); 3.86 (s, 3H, OMe), 3.73 (s, 3H, OMe); 3.47 (td, 1H, J = 11.7,
5
J = 3.50, H ); 1.67–2.30 (m, 6H, CH
; sugar: 6.09 (dd, 1H, J =
4
2Cyclohexan)
8
.2, J = 5.00 Hz, H
ꢀ
); 6.03 (d, 1H, J = 4.10, H
ꢀ
); 5.95 (t, 1H, J = 8, H
ꢀ
);
);
3
1
2
5.06–5.12 (m, 1H, H
ꢀ
); 4.66–4.80 (m, 1H, H
ꢀ
); 4.66–4.80 (m, 1H, H
ꢀ
4
5 a
5 b
benzoyle + Haroma: 7.10–7.98 (m, 23 H, Haroma).
13
C NMR (100 MHz, CDCl3, δ (ppm): sugar: 91.80 (C
ꢀ
); 78.19 (C4
ꢀ
);
1
7
6.19 (C3
ꢀ
); 74.10 (C2
ꢀ
); 66.19 (C5
ꢀ
); base: 170.60 (C ); 157.00, 152.99
3
(
C–OMe); 134.10 (C ); 119.80 (C ); 78.90 (C ); 56.03 (OMe); 48.70 (C );
9
10
5
4
2
9.20 (C ); 27.49 (C ); 23.29 (C ), benzoyles group: 167.06, 166.87, 166.20
8 6 7
(
C O)Benzoyle; 121.19–138.09 (Caroma).
+
Found: m/z 815.2938 [M+Na] . C H N O Na. Calculated: M =
48
44
2
7
815.2945.
4-(Benzoyloxy)-5-[(benzoyloxy)methyl]-2-[(6E)-3-(3-methoxyphenyl)-6-[(3-met-
hoxyphenyl)methylidene]-2H,3H,3aH,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]oxol-
an-3-yl Benzoate (17). By synthesis of pyrazoline 10 (1.67 g, 5 mmol)
according to the general procedure, nucleoside 17 (2.45 g, 3.15 mmol,
6
3%) was obtained as a white foam.
–1
IR,νmax (cm ), (KBr): 3056; 2938; 1725 (C O); 1645 (C C); 1605; 1595
(
C N); 1495; 1460; 1275.
H NMR spectrum, δ, ppm (J , Hz): base: H NMR spectrum, δ, ppm (J ,
Hz): base: 6.81 (s, 1H, Hvinyl); 4.66 (d, 1H, J = 11.2, H ); 3.57–3.53 (m, 1H,
5
H ); 3.82 (s, 3H, OMe), 3.75 (s, 3H, OMe); 2.56–2.53 (m, 2H, H ); 1.67–1.64
4
7
ꢀ
(
1
(
m, 1H, H ), 1.37–1.34 (m, 1H, H ); sugar: (t, 1H, J = 2.4, H ); 6.03 (d,
6
6
3
ꢀ
ꢀ
ꢀ
H, J = 2.0, H ); 5.96 (t, 1H, J = 2.5, H ); 5.10–5.08 (m, 1H, ); 4.85–4.71
1
2
4
ꢀ
m, 1H, H
); benzoyle + H
: 8.05–6.67 (m, 23 H, H
).
5
a+b
aroma
aroma
13
C NMR (100 MHz, CDCl3, δ (ppm): sugar: 91.56 (C
ꢀ
); 78.50 (C4 );
ꢀ
1
7
5.50 (C3
ꢀ
); 73.80 (C2
ꢀ
); 64.60 (C5 ); base: 167.86 (C ); 120.56 (C ); 76.50
ꢀ
3 9
(
1
C ); 48.90 (C ); 141.66 (C ); 27.51 (C ); 25.39 (C ), benzoyles group:
64.04, 165.35, 166.82 (C O)Benzoyle; 121.06–135.72 (Caroma).
5 4 8 6 7

Synthesis of New Pyrazoline-Nucleoside Analogue Derivatives
305
+
Found: m/z 801.2796 [M+Na] . C H N O Na. Calculated: M =
47
42
2
9
8
01.2788.
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1. Marry, R.; Cranner, D.; Mayes, D.; Well, V. Harper’s Biochemistry 23rd ed., Prentice-Hall International,
London, 1993, p. 333.
2
3
. Bohinski, R.; Modern Concepts In Biochemistry 5th ed., Allyn and Bacon, Boston, 1987, p. 236.
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4
. Baldwin, S.; Mackey, J.; Cass, C. Nucleoside transporters: Molecular biology and implications for
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oncology. 2001, 9(3), 155.
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6
7
. Szel, T.; Sohar, L. New nitsochalcones. IX, Can. J. Chem. 1969, 47, 1254.
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8
. Hathaway, B.A. An aldol condensation experiment using a number of aldehydes and ketones. J.
Chem. Educ. 1987, 64, 367.
ꢀ
9. Zheng, M.; Wang, L. A facile synthesis of α,α -bis(substituted benzy1idene) cycloalkanones catalyzed
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27(2), 351–354.
1
1
1
1
1
1
0. Vogel, A.I.; Tatchell, A.R.; Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G. Vogel’s Textbook of Practical
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1. Esmaili, A.A. Solvent-Free crossed aldol condensation of cyclic ketones with aromatic aldehydes
assisted by microwave irradiation. Monatshefte fur Chemie 2005, 136, 571–576.
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strates. U.S. Patent 6379911, 2002.
3. Barth, J.; Leipzig, A. Syntheses and spectroscopic characterisation of some new 3,5-bisaryl-2-
pyrazoline derivatives. J. Prakt. Chemie. Band. 1980, 322(5), 716–722.
ꢀ
ꢀ
ꢀ
4. Czarnecki, S.; Le Diguarher, T. Synthesis of 1-(3 -azido-2 ,3 -dideoxy-α-L-threo-pentofuranosyl)
thymine as a potential anti-HIV agent. Synthesis 1991, 683.
5. Kandasamy, R.; Roland, K.; Robins, J. Direct synthesis of pyrrol nucleosides by the stereospecific
sodium salt glycosysation procedure. Heterocyclic Chem. 1987, 24, 863.