Synthesis and antimicrobial evaluation of novel pyrazolones and pyrazolone nucleosides

Article abstract of DOI:10.1080/15257770.2012.732250

The synthesis of a novel series of 4-Arylhydrazono-5-methyl-1,2- dihydropyrazol-3-ones 4a-h, and their N ²-Alkyl and acyclo, glucopyranosyl, and ribofuranosyl derivatives is described. K₂CO ₃ catalyzed alkylation of 4a-h with allyl bromide, propargyl bromide, 4-bromobutyl acetate, 2-Acetoxyethoxymethyl bromide, and 2,3,4,6-tetra-O- Acetyl-D-glucopyranosyl bromide proceeded selectively at the N ²-position of the pyrazolinone ring. Glycosylation of 4a with 1,2,3,5-tetra-O-Acetyl-D-ribofuranose under Vorbruggen glycosylation conditions gave the corresponding N ²-4-Arylhydrazonopyrazolone ribofuranoside 9a in good yield. Conventional deprotection of the acetyl protected nucleosides furnished the corresponding 4-Arylhydrazonopyrazolone nucleosides in good yields. Selected numbers of the newly synthesized compounds were screened for antimicrobial activity. Compounds 4b, 12a, and 14d showed moderate activities against Aspergillus flavus, Penicillium sp., and Escherichia coli.

Full text of DOI:10.1080/15257770.2012.732250

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Synthesis and Antimicrobial Evaluation
of Novel Pyrazolones and Pyrazolone
Nucleosides
Abdalla E. A. Hassan a b , Ahmed H. Moustafa a , Mervat M. Tolbah a
Hussein F. Zohdy c & Abdelfattah Z. Haikal a d
,
a Department of Chemistry, Faculty of Science, Zagazig University,
Zagazig, Egypt
b Applied Nucleic Acids Research Center, Zagazig University, Zagazig,
Egypt
c Department of Chemistry, Faculty of Science, Cairo University,
Cairo, Egypt
d Chemistry Department, Faculty of Science, Islamic University, Al
Madina Al Munawara, Kingdom of Saudi Arabia
Version of record first published: 12 Nov 2012.
To cite this article: Abdalla E. A. Hassan , Ahmed H. Moustafa , Mervat M. Tolbah , Hussein F. Zohdy
& Abdelfattah Z. Haikal (2012): Synthesis and Antimicrobial Evaluation of Novel Pyrazolones and
Pyrazolone Nucleosides, Nucleosides, Nucleotides and Nucleic Acids, 31:11, 783-800
To link to this article: http://dx.doi.org/10.1080/15257770.2012.732250
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Nucleosides, Nucleotides and Nucleic Acids, 31:783–800, 2012
Copyright ꢀC Taylor and Francis Group, LLC
ISSN: 1525-7770 print / 1532-2335 online
DOI: 10.1080/15257770.2012.732250
SYNTHESIS AND ANTIMICROBIAL EVALUATION OF NOVEL
PYRAZOLONES AND PYRAZOLONE NUCLEOSIDES
Abdalla E. A. Hassan,1,2 Ahmed H. Moustafa,1 Mervat M. Tolbah,1
Hussein F. Zohdy,3 and Abdelfattah Z. Haikal1,4
1Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt
2Applied Nucleic Acids Research Center, Zagazig University, Zagazig, Egypt
3Department of Chemistry, Faculty of Science, Cairo University, Cairo, Egypt
4Chemistry Department, Faculty of Science, Islamic University, Al Madina Al Munawara,
Kingdom of Saudi Arabia
The synthesis of a novel series of 4-arylhydrazono-5-methyl-1,2-dihydropyrazol-3-ones 4a–h,
2
and their N2-alkyl and acyclo, glucopyranosyl, and ribofuranosyl derivatives is described. K2CO3
catalyzed alkylation of 4a–h with allyl bromide, propargyl bromide, 4-bromobutyl acetate, 2-
acetoxyethoxymethyl bromide, and 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide proceeded se-
lectively at the N2-position of the pyrazolinone ring. Glycosylation of 4a with 1,2,3,5-tetra-O-
acetyl-β-D-ribofuranose under Vorbruggen glycosylation conditions gave the corresponding N2-4-
arylhydrazonopyrazolone ribofuranoside 9a in good yield. Conventional deprotection of the acetyl
protected nucleosides furnished the corresponding 4-arylhydrazonopyrazolone nucleosides in good
yields. Selected numbers of the newly synthesized compounds were screened for antimicrobial activity.
Compounds 4b, 12a, and 14d showed moderate activities against Aspergillus flavus, Penicillium
sp., and Escherichia coli.
Keywords Pyrazolinone; pyrazolono nucleosides; acyclic nucleosides; N 2-alkyl pyra-
zolones; antimicrobial activity
INTRODUCTION
Structural modifications at the nucleobase moiety of nucleosides have
resulted in a plethora of nucleosides with interesting chemical and bio-
logical properties.[1,2] For instance, ribavirin (1), a triazolyl ribonucleo-
side, has shown a wide range of activity against DNA and RNA viruses.[3]
Received 10 August 2012; accepted 17 September 2012.
We thank Dr. Ashraf A. Sabry of the Microbiology Department, Faculty of Science, Zagazig University
for determining the antimicrobial activity reported in the manuscript.
Address correspondence to Abdalla E. A. Hassan, Department of Chemistry, Faculty of Science,
Zagazig University, Zagazig, Egypt. E-mail: abdallaelsayed@zu.edu.eg
783

784
A. E. A. Hassan et al.
The current standard care of hepatitis C virus (HCV) infection is based
on the combination of ribavirin and pegylated interferon-α (PEG-INF)[4]
,
or most recently, as a triple therapy (ribavirin/PEG-INF/protease in-
hibitor; telaprevir or boceprevir).[5] In another instance, bredinine (2) is
an imidazolyl ribonucleoside antibiotic[6] with immunosuppressant,[7] anti-
rheumatism,[8] and antitumor[9] activities. Pyrazolones have attracted con-
siderable attention because of their interesting structural features and ap-
plications in diverse areas.[10] Pyrazolone derivatives are reported to have
analgesic,[11] anti-inflammatory,[12] antiviral,[13] and antimicrobial activi-
ties.[14,15] Anchoring a 3-methyl-1-phenyl-2-pyrazolin-5-one moiety at the
5-position of 2ꢁ-deoxyuridine has been shown to produce anti-orthopox
virus activity.[16] 4-Arylhydrazono-pyrazolones were disclosed to have in-
hibitory activities against glycogen synthase kinase-3 (GSK-3), Aurora-2
protein kinase, and cyclin-dependent kinase-2 (CDK-2) with the poten-
tial use for prevention and treatment of disorders such as diabetes and
Alzheimer’s disease.[17] 4-Hydrazonopyrazolones have an interesting struc-
tural feature, that the 4-arylhydrazino group most likely forms an inter-
nal hydrogen bond with the pyrazolone carbonyl forming a pseudobi-
cyclic 6,5-ring system,[18] mimicking the shape-structure of a 1-substituted
purine. N 1-3-fluorophenylinosine (3) and N 1-3-fluorophenylhypoxanthine
have been reported to show interesting anti-Hantaan virus activ-
ity.[19] It is of interest to check whether nucleosides derived from 4-
hydrazonopyrazolones 4a–h would exert desirable biological properties. In
continuation of our efforts to search for nucleosides with biological ac-
tivities,[20] we wish to report on the synthesis of novel 4-arylhydrazono-3-
methylpyrazolin-5-ones 4a–h; their N 2–alkyl derivatives 5a–d; 6a,c,f; and
N 2-nucleosides derivatives 8b,c,g; 10; 12a,b,f; 14b,e,g,h and the antimi-
crobial evaluation of selected number of newly synthesized compounds
(Figure 1).
FIGURE 1 Biologically active nucleobase modified nucleosides.

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
Ar
785
Ar
N
H3C
N
N
H3C
N
H
H
N
O
N
O
H
N
H
N
(I)
(II)
Ar
Ar
N
N
H3C
N
H3C
N
H
H
N
N
O
O
H
N
N
H
(IV)
(III)
FIGURE 2 Possible tautomeric structures of 3-methyl-4-(arylhydrazono)-1H-pyrazol-5(4H)-one.
RESULTS AND DISCUSSION
Chemistry
1H-3-Methylpyrazolo-5-one[21] was coupled with aryldiazonium chlo-
rides, according to the published procedure,[22–24] to give the cor-
responding 4-arylhydrazono-3-methylpyrazolo-5-one derivatives 4a–h. 4-
Arylhydrazonopyrazolo-5-one derivatives 4 may exist, in solution, in four
tautomeric forms: I, II, III, and IV (Figure 2).[25] Literature reports con-
clude that, both in solid and liquid state (DMSO, CHCl3, and pyridine), the
equilibrium is in favor of the arylhydrazono tautomers.[26] Consequently,
N 1, N 2, and O-alkylation is anticipated and the regioselectivity could be
manipulated by altering the reaction conditions.
Khalil reported that Et3N-assisted coupling of a 1H-3-trifluoromethyl-4-
arylhydrazonopyrazolo-5-one with 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl
bromide in DMF gave a mixture of N 2and bis-N 1-O-glycosylated products.[14]
N- versus O- Chemoselective alkylation of amides is largely dependent on the
nature of the cation of the base, where alkali metals’ [K+ and Na+] cations
favor the N -alkylation.[27] Thus, treatment of 4a–c with allyl bromide or
propargyl bromide in the presence of K2CO3 in dry acetone gave the corre-
sponding N 2-propargyl/allyl pyrazolone derivatives 5a–d, and 6a,e, f, respec-
tively in good yields (Scheme 1). Spectroscopic data of compounds 5a–d and
6a,e,f support the N 2-alkylation site and the compounds exist in the hydrazo-
keto form I rather than other possible tautomers (Figure 2). IR spectra of
5a, for instance, showed absorption bands at 3480, 1645 cm−1 characteristic

786
A. E. A. Hassan et al.
SCHEME 1 aReagents and conditions. (a) K2CO3, dry acetone, 15 minutes, r.t., then BrCH2CCH,
6 hours, reflux temp.; (b) K2CO3, dry acetone, 15 minutes, r.t., then BrCH2CHCH2, 8 hours, reflux
temp.; (c) K2CO3, dry acetone, 30 minutes, r.t., then 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bro-
mide, overnight, r.t.; (d) (i) Silylation of 4a [HMDS, (NH4)2SO4, dry CH2Cl2, 12 hours, 80◦C], (ii)
SnCl4, 1,2,3,4,6-tetra-O-acetyl-β-d-ribofuranose, CH2Cl2, overnight, r.t.; (e) K2CO3, dry DMF, 15 min-
utes, r.t., then BrCH2(CH2)2CH2OAc, 0 C◦-r.t, 12 hours; (f) K2CO3, dry DMF, 15 minutes, r.t., then
BrCH2OCH2CH2OAc, 0◦C, 12 hours, r.t.; (g) Et3N, MeOH, r.t.
for ν NH of the hydrazo moiety, and the ν C = O of the pyrazolone ring.
1H NMR spectrum of 5a showed a signal at δ 12.24 ppm (exchangable with
D2O, hydrazono NH) and its 13C NMR spectra showed a signal at 164.8 ppm
(C = O, pyrazolone ring). In a similar manner, treatment of 4b,c,g with
2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide in the presence of K2CO3
in dry acetone gave the corresponding N 2-[(4-arylhydrazono)-3-methyl-1-
(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-1H-pyrazol-5(4H)-one 7b,c,g, re-
spectively, in good yields (Scheme 1). The N 2-β-D-configuration of the gly-
ꢁ
ꢁ
cosides 7b,c,g was supported by the large J 1 ,2 = 8.28–8.62 Hz, and the
appearance of the C-5 pyrazolone ring signals at δ 160.5–160.7 ppm in their
13C-NMR spectra.
IR spectra of compounds 7b,c,g showed absorption bands (ν C = O)
at 1660–1669 cm−1 supporting their hydrazo-keto structures. Silylation of
the pyrazolin-3-one derivative, 4a followed by treatment with 1,2,3,5-tetra-
O-acetyl-β-D-ribofuranose in the presence of SnCl4 gave the N 2-pyrazolone
1
ribofuranosyl derivative 9a in good yield (Scheme 1). The H NMR signal

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
787
ꢁ
ꢁ
of the anomeric proton of 9a appeared at δ 6.19 ppm (d, J 1 ,2 5.8 Hz), in-
dicating the β-configuration of the nucleoside analogue. The IR spectrum
showed absorption bands at 3480 cm−1 (ν NH, hydrazo) and 1653 cm−1
(ν C = O, pyrazolone) supporting the keto-hydrazo structure of the nucle-
obase. Treatment of 4a,b,f with 4-bromobuty acetate[28] in the presence of
K2CO3 in DMF afforded N 2-acyclonucleosides 11a,b,f, respectively, in high
yields (Scheme 1). Spectroscopic analysis of these compounds supports the
N 2, keto-hydrazo structure (Figure 2, structure II) of the alkylated pyra-
zolone derivatives 11. For instance, the 1H-NMR spectrum of 11b showed
the hydrazo-NH signal at δ 13.23 ppm, the C-5 pyrazolone signal appeared
at δ 164.5 ppm in the13C-NMR spectrum, and a characteristic (ν C = O) IR
absorption band appeared at 1649 cm−1. Reaction of the 4-arylhydrazono-
pyrazolones, 4b,e,g,h with 2-acetoxyethoxymethyl bromide[29] gave the cor-
responding N 2-acyclonuclosides 13b,e,g,h, respectively, in good yields. The
1
structures of 13b,e,g,h were confirmed by their H NMR and 13C NMR, IR
and elemental analysis. Conventional deprotection of 7b,c,g; 9a; 11a,b,f,
and 13b,e,g,h using Et3N in methanol gave the corresponding nucleosides
8b,c,g; 10a; 12a,b,f, and 14b,e,g,h, respectively, in good yields (Scheme 1).
Biology
The antimicrobial activities of 4b,d,e,f,g, 7b,c, 8a, 110a, 12a,b, 13b and
14a,d were assessed against Aspergillus flavus, Penicillium sp., and Escherichia
coli according to published procedures.[30] The antimicrobial activity of the
tested compounds is expressed by the diameter of inhibition zone (cm)
TABLE 1 Antimicrobial activity of compounds 4b,d,e,f,g; 7b,c; 8a; 12a,b; 13b, and 14a,d against
Aspergillus flavus, Penicillium sp., and Escherichia coli
Compd.
Escherichia coli
Penicillium sp.
Aspergillus flavus
4b
4d
4e
4f
4g
7b
7c
8a
11a
12a
11b
13b
14a
0.4
0.3
0.4
0.2
0.1
0.3
0.4
0.7
0.3
0.5
0.4
0.2
0.4
0.3
NA
0.8
0.7
0.5
0.3
0.1
ND
0.4
0.3
0.6
0.1
0.5
0.3
0.2
0.3
0.4
0.9
NA
0.8
0.4
0.5
ND
ND
0.3
0.5
0.7
0.3
0.8
0.4
0.5
0.4
0.8
1.2
NA
14d
Griseofulvin
Ampicillin

788
A. E. A. Hassan et al.
around the well. 3-Methyl-4-arylhydrazono-pyrazolones 4d, 4e, the glucopy-
ranoside 7c, and the acyclic nucleoside derivative 13b showed moderate in-
hibitory effect on the growth of Aspergillus flavus and Penicillium sp.(0.5 cm)
compared with griseofulvin. Significant antifungal activity against Aspergillus
flavus and penicillium sp. was observed with 4b, 8a, 12a, and 14a,d (Table 1).
A significant antibacterial activity against Escherichia coli was observed with 6a
while compounds 4b, 4e, 7c, 12a,b showed moderate inhibitory activity.
Conclusions
We have synthesized a series of 3-methyl-4-(arylhydrazono)-1H-pyrazol-
5(4H)-one, bearing electron donating/electron withdrawing substituents on
the aryl moiety, their N 2-alkyl, N 2-glycosyl derivatives, and evaluated their an-
timicrobial activity against Aspergillus flavus and penicillium sp. and Escherichia
coli. Among the tested compounds, 3-methyl-4-(arylhydrazono)-1H-pyrazol-
5(4H)-one (4b), bearing electron donating and lipophilic substituent on
the aryl moiety, showed the highest antimicrobial activity. However, the pat-
tern was reversed with the acylic nucleosides 13a and 14d. Further biological
antiviral and anticancer evolutions of the synthesized compounds are under
way and will be published in due course.
EXPERIMENTAL
General Procedures
All melting points are uncorrected and were measured using an Elec-
trothermal IA 9100 apparatus. The IR spectra (KBr disc) were recorded on a
Pye Unicam Sp-3-300 and Shimadzu FTIR 8101 PC infrared spectrophotome-
ter. The 1H and 13C NMR spectra were recorded on Varian Mercury VX-NMR
300 MHz spectrometer. Chemical shifts are expressed δ (ppm) scale using
TMS as internal reference and coupling-constant values are given in Hz.
Elemental analysis was determined on a Perkin Elmer 240.
Antimicrobial Evaluation
The antimicrobial evaluation was conducted with minor modifications
to the published procedure.[29] The tested compounds were dissolved in
dimethylsulfoxide to obtain a solution of 1 μg/mL concentration. After
seeding of the ceded-solid medium by the microbial suspension (10 mL/250
medium), the plates were incubated overnight for germination, then 500 μL
of each tested compound were pipetted to the wells of the plate cultures.
Blanks of dissolving solvent were done for each organism. The cultures were
incubated for 7 days at 30◦C for fungal growth and for 2 days at 37◦C for
bacterial growth. The antimicrobial activity was expressed by the diameter

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
789
of inhibitory zone around the wells compared to griseofulvin and ampicillin
as standard antifungal and antibacterial agents, respectively.
General Procedure for Preparation of Pyrazolone Derivatives (4a–h)
To a solution of ethyl acetoacetate (10.1 mL, 0.1 mol) in absolute ethanol
(100 mL) was added hydrazine hydrate (3.5 mL, 0.1 mol) in absolute ethanol
(15 mL) dropwise at room temperature. Then the mixture was heated for
30 minutes at 60◦C. The mixture was cooled to room temperature and
the precipitate was filtered, washed with ice-cold ethanol to give (7.46 g,
76%) of 1H-3-methylpyrazolo-5-one[19] as pale yellow solid. To a solution of
1H-3-methylpyrazolo-5-one (0.98 g, 10 mmol) and sodium acetate (1.64 g,
20 mmol) in ethanol (50 mL) was added an aqueous solution of aryl diazo-
nium salt (10 mmol) dropwise at 0◦C. The reaction mixture was stirred at
room temperature for 3 hour and the formed precipitate was collected by fil-
tration, washed several times with cold water, dried, and recrystallized from
ethanol to give the corresponding 4-arylhydrazonopyrazolones 4a–h.[31]
3-Methyl-4-(2-phenylhydrazono)-1H-pyrazol-5(4H)-one (4a)[31a]
1
Orange crystals, 80% yield; mp 198–199◦C (lit. > 200◦C); H NMR δH
(CDCl3, 300 MHz) 2.27 (3H, s, CH3), 7.14-7.44 (5H, m, Ar-H), 9.23 (1H,
s, NH-pyrazolinone ring), 13.36 (1H, br s, NH-hydrazone). Anal. Calcd. for
C10H10N4O: C, 59.40; H, 4.98; N, 27.71. Found: C, 59.35; H, 4.89; N, 27.59.
3-Methyl-4-(2-p-tolylhydrazono)-1H-pyrazol-5(4H)-one (4b)[31b]
Orange crystals, 77% yield; mp 196–197◦C (lit 195–196◦C); 1H NMR δH
(CDCl3, 300 MHz) 2.24 (3H, s, CH3), 2.35 (3H, s, CH3), 7.17 (2H, d, J =
8.6 Hz, Ar-H), 7.29 (2H, d, J = 8.6 Hz, Ar-H), 9.17 (1H, s, NH-pyrazolinone
ring), 13.39 (1H, br s, NH-hydrazone). Anal. Calcd for C11H12N4O: C, 61.09;
H, 5.59; N, 25.91. Found: C, 60.97; H, 5.48; N, 25.79.
4-[2-(4-Methoxyphenyl)hydrazono]-3-methyl-1H-pyrazol-5(4H)-one (4c)[31c]
Yellow crystals, 89% yield; mp 195–197◦C; 1H NMR δH (CDCl3,300 MHz)
2.25 (3H, s, CH3), 3.75 (3H, s, OCH3), 5.66 (1H, s, NH-pyrazolinone ring),
6.90 (2H, d, J = 8.8 Hz, Ar-H), 7.31 (2H, d, J = 8.8 Hz, Ar-H), 13.51 (1H, br,
NH-hydrazone). Anal. Calcd for C11H12N4O2: C, 56.89; H, 5.21; N, 24.12.
Found: C, 56.74; H, 5.18; N, 24.09.
4-[2-(3-Chlorophenyl)hydrazono]-3-methyl-1H-pyrazol-5(4H)-one (4d)[31a]
Orange crystals; 84% yield; mp 213–214◦C; 1H NMR δH (CDCl3,
300 MHz) 2.27 (3H, s, CH3), 5.67 (1H, s, NH-pyrazolinone ring), 7.05–7.82
(4H, m, Ar-H), 13.54 (1H, s, NH, hydrazone). Anal. Calcd for C10H9ClN4O:
C, 50.75; H, 3.83; N, 23.67. Found: C, 50.67; H, 3.79; N, 23.60.

790
A. E. A. Hassan et al.
4-[2-(4-Bromophenyl)hydrazono]-3-methyl-1H-pyrazol-5(4H)-one (4e)[31c]
Orange crystals; 89% yield; mp 229–230◦C (lit 231–232◦C); 1H NMR δH
(CDCl3, 300 MHz) 2.24 (3H, s, CH3), 7.26 (2H, d, J = 8.8 Hz, Ar-H), 7.49
(2H, d, J = 8.8 Hz, Ar-H), 7.70 (1H, s, NH-pyrazolinone), 13.35 (1H, brs,
NH-hydrazone). Anal. Calcd for C10H9BrN4O: C, 42.73; H, 3.23; N, 19.93.
Found: C, 42.76; H, 3.20; N, 19.88.
3-Methyl-4-[2-(4-nitrophenyl)hydrazono]-1H-pyrazol-5(4H)-one (4f)[31c]
1
Orange crystals; 81% yield; mp 259–260◦C (Lit. 260◦C); H NMR δH
(DMSO-d6, 300 MHz) 2.18 (3H, s, CH3), 7.76 (2H, d, J = 9.0 Hz, Ar-H), 8.26
(2H, d, J = 9.0 Hz, Ar-H), 13.26 (1H, brs, NH-hydrazone). Anal. Calcd for
C10H9N5O3: C, 48.58; H, 3.67; N, 28.33. Found: C, 48.46; H, 3.72; N, 28.39.
4-[2-(4-Fluorophenyl)hydrazono]-3-methyl-1H-pyrazol-5(4H)-one (4g)
1
Yellow crystals; 90% yield; mp 212–214◦C; H NMR δH (DMSO-d6,
300 MHz) 2.14 (3H, s, CH3), 7.26 (2H, m, Ar-H), 7.59 (2H, m, Ar-H),
11.53 (1H, s, NH-hydrazone). Anal. Calcd for C10H9FN4O: C, 54.54; H, 4.12;
N, 25.44. Found: C, 54.67; H, 4.09; N, 25.37.
3-Methyl-4-[2-(3-(trifluoromethyl)phenylhydrazono]-1H-pyrazol-5(4H)-one
(4h)
1
Yellow crystals; 89% yield; mp 203–205◦C; H NMR δH (DMSO-d6,
300 MHz) 2.15 (3H, s, CH3), 7.47 (1H, d, J = 7.5 Hz, Ar-H) 7.61 (1H,
t, J = 7.5 Hz, Ar-H), 7.89 (2H, m, Ar-H), 11.59 (1H, s, NH-hydrazone). Anal.
Calcd for C11H9F3N4O: C, 48.89; H, 3.36; N, 20.73. Found: C, 49.01; H, 3.29;
N, 20.68.
3-Methyl-4-(2-phenylhydrazono)-1-(prop-2-ynyl)-1H-pyrazol-5(4H)-one (5a)
A mixture of 4a (1.2 g, 5.94 mmol) and K2CO3 (1.23 g, 8.9 mmol)
in dry acetone (15 mL) was stirred for 30 minutes at room temperature.
Propargyl bromide (80 wt.% in toluene, 1.1 mL, 7.1 mmol) was added and
the reaction mixture was heated for 6 hours at reflux temperature. The
mixture was cooled down to room temperature and poured onto ice water,
the precipitate was collected by filtration and crystallized from ethanol to
1
give 5a (1.11 g, 78% yield) as yellow crystals; mp 121–122◦C; H NMR δH
(DMSO-d6, 300 MHz) 2.59 (3H, s, CH3), 3.35 (1H, s, ≡CH), 4.94 (2H, d, J =
7.2 Hz, N CH2CCH), 7.42–7.70 (5H, m, Ar-H), 11.30 (1H, s, NH-hydrazone);
13C NMR δC (DMSO-d6, 75 MHz) 10.7, 56.5, 76.8, 78.5, 121.8, 123.4, 129.6,
130.1, 139.3, 153.5, 154.4; Anal. Calcd for C13H12N4O: C, 64.99; H, 5.03; N,
23.32. Found: C, 65.01; H, 4.96; N, 23.21.

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
791
3-Methyl-1-(prop-2-ynyl)-4-(2-p-tolylhydrazono)-1H-pyrazol-5(4H)-one (5b)
Compound 5b was synthesized from 4b in a similar manner as described
1
for 5a, 85% yield; yellow crystals; mp 110–112◦C; H NMR δH (DMSO-d6,
300 MHz) 2.32 (3H, s, CH3), 2.57 3H, (s, CH3), 3.32 (1H,s, ≡CH), 4.81
(2H, s, NCH2), 7.22 - 7.90 (4H, m, Ar-H), 11.50 (1H, s, NH). 13C NMR δC
(DMSO-d6, 75 MHz) 10.8, 21.4, 56.5, 76.7, 78.5, 96.6, 116.1, 121.8, 130.1,
130.5, 151.2, 160.9. Anal. Calcd for C14H14N4O (245.29): C, 66.21; H, 5.62;
N, 22.03. Found: C, 66.28; H, 5.94; N, 21.96.
4-[2-(4-Methoxyphenyl)hydrazono]-3-methyl-1-(prop-2-ynyl)-1H-pyrazol-5
(4H)-one (5c)
Compound 5c was synthesized from 4c (1.2 g, 5.94 mmol) in a similar
manner as described for the synthesis of 5a, in 83% yield: yellow crystals;
mp 108–110◦C; 1H NMR δH (DMSO-d6, 300 MHz) 2.59 (3H,brs, CH3), 3.33
(1H, s, C≡CH), 3.82 (3H, s, OCH3), 4.93 (2H, d, J = 7.23 Hz, NCH2), 7.04
(2H,d, J = 8.8 Hz, Ar-H), 7.70 (2H, d, J = 8.9 Hz, Ar-H), 11.35 (1H, s, NH).
13C NMR δC (DMSO-d6, 75 MHz) 10.77, 55.9, 56.5, 76.7, 79.7, 99.9, 114.8,
123.5, 138.4, 147.6, 154.4, 161.1. Anal. Calcd for C14H14N4O2: C, 62.21; H,
5.22; N, 20.73. Found: C, 62.35; H, 5.18; N, 20.68.
4-[2-(3-Chlorophenyl)hydrazono]-3-methyl-1-(prop-2-ynyl)-1H-pyrazol-5
(4H)-one (5d)
Compound 5d was synthesized from 4d in a similar manner as described
1
for 5c, 83% yield; yellow crystals; mp 148–150◦C; H NMR δH (DMSO-d6,
300 MHz) 2.61 (3H,s, CH3), 3.60 (1H, d, J = 2.4 Hz, C≡CH), 4.97 (2H, s,
NCH2), 7.41–7.61 (4H, m, Ar-H), 12.9 (1H, s, NH-hydrazone). 13C NMR δC
(DMSO-d6, 75 MHz) 11.3, 56.8, 76.9, 78.6, 101.9, 117.4, 124.7, 128.3, 130.8,
132.8, 137.5, 149.3, 156.2. Anal. Calcd. for C13H11ClN4O (274.71): C, 56.84;
H, 4.04; N, 20.40. Found: C, 56.85; H, 4.02; N, 20.43.
1-Allyl-3-methyl-4-(2-phenylhydrazono)-1H-pyrazol-5(4H)-one (6a)
A mixture of 4a (1.0 g, 4.95 mmol) and K2CO3 (1.0 g, 8.9 mmol) in
dry acetone (10 mL) was stirred for 30 minutes at room temperature. Allyl
bromide (0.5 mL, 5.45 mmol) was added and the reaction mixture was
heated for 8 hours at reflux temperature. The mixture was cooled down to
room temperature and poured onto ice water. EtOAc (40 mL) was added
to the mixture and the organic phase was separated, dried over MgSO4,
and evaporated. The residue was purified by a silica gel column (eluate;
1
7% MeOH in CH2Cl2) to give 6a (1.g, 85%) as a yellow foam; H NMR δH
(DMSO-d6, 300 MHz) 2.25 (3H, s, CH3), 4.66 (1H, m, CH2aCH = CH2), 4.77
(1H, m, CH2bCH = CH2), 5.00 – 5.49 (m, 2H, CH2CH = CH2), 6.06 (m,
1H, CH2CH = CH2), 7.36–7.69 (m, 5H, Ar-H), 12.24 (1H, s, NH); 13C NMR
δC (DMSO-d6, 75 MHz) 11.6, 32.8, 113.9, 117.5, 122.5, 128.7, 129.5, 132.8,

792
A. E. A. Hassan et al.
143.5, 148.4, 164.8; Anal. Calcd. for C13H14N4O: C, 64.45; H, 5.82; N, 23.13.
Found: C, 64.39; H, 5.71; N, 22.91.
1-Allyl-4-[2-(4-methoxyphenyl)hydrazono]-3-methyl-1H-pyrazol-5(4H)-one (6c)
Compound 6c was synthesized from 4c, in a similar manner as described
for the synthesis of 6a, in 78% yield: yellow foam; IR (KBr) 3480 cm−1 (ν
1
NH), 1645 cm−1 (ν C = O); H NMR δH (DMSO-d6, 300 MHz) 2.55 (3H,
s, CH3), 3.81 (3H, s, OCH3), 4.69 (2H, m, CH2CH = CH2), 4.97–5.42 (2H,
m, CH2CH = CH2), 6.04 (1H, m, CH2CH = CH2), 7.04 (2H, d, J = 8.4 Hz,
Ar-H), 7.67 (2H, d, J = 8.44 Hz, Ar-H), 12.35 (1H, s, N-H); Anal. Calcd. for
C14H16N4O2: C, 61.75; H, 5.92; N, 20.58. Found: C, 61.64; H, 5.87; N, 20.42.
1-Allyl-3-methyl-4-[2-(4-nitrophenyl)hydrazono]-1H-pyrazol-5(4H)-one (6f)
Compound 6f was synthesized from 4f, in a similar manner as described
1
for the synthesis of 6a, in 75% yield: yellow foam; H NMR δH (DMSO-d6,
300 MHz) 2.55 (3H, s, CH3), 4.68 (1H, d, CH2aCH = CH2, J = 5.1 Hz), 4.77
(1H, d, J = CH2bCH = CH2, 5.1 Hz), 5.02–5.47 (2H, m, CH2CH = CH2),
6.00 (1H, m, CH2CH = CH2), 7.83 (2H, d, Ar-H, J = 8.42 Hz), 8.35 (2H,
d, Ar-H, J = 8.4 Hz), 12.21 (1H, s, NH); 13C NMR δC (DMSO-d6, 75 MHz)
11.6, 32.9, 113.4, 117.3, 124.6, 128.8, 132.5, 137.8, 148.5, 149.4, 164.8; Anal.
Calcd. for C13H13N5O3: C, 54.35; H, 4.56; N, 24.38. Found: C, 54.29; H, 4.48;
N, 24.31.
4-[2-(4-Fluorophenyl)hydrazono]-3-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-
glucopyranosyl)-1H-pyrazol-5(4H)-one (7g)
Dry K2CO3 (0.56 g, 5.45 mmol) was added to a solution of 4g (1.0 g,
4.54 mmol) in dry acetone (15 mL) and the mixture was stirred for
30 minutes at room temperature. A solution of 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide (3.32 g, 8.18 mmol) in dry acetone (20 mL), was
added and the reaction mixture was further stirred overnight at room tem-
perature. The solvent was evaporated under reduced pressure and the
residue was crystallized from EtOH to give 7g (2.25 g, 75% yield) as yel-
low crystals; mp 130–131◦C; IR (KBr) 3476 cm−1 (ν NH), 1747 cm−1 (ν C =
O, ester), 1670 cm−1 (ν C = O, amide); 1H NMR δH (DMSO-d6, 300 MHz)
1.89, 1.99, 2.00, and 2.03 (12H, 4s, Ac), 2.13 (3H, s, CH3-pyrazolinone), 3.98
ꢁ
ꢁ
ꢁ
(1H, m, H-5’a), 4.2 (1H, dd, H-6’, J 5 ,6 = 4.55, J 6 ,6” = 11.89 Hz), 4.32 (1H,
dd, H-6”, J 5 ,6 = 3.55, J 6 ,6”11.89 Hz), 5.18 (2H, m, H-2ꢁ, H-4ꢁ), 5.98 (1H, d,
ꢁ
ꢁ
ꢁ
J 1 ,2 = 8.62 Hz, H-1ꢁ), 7.21 (d, 2H, Ar-H, J = 8.9 Hz), 7.62 (2H, d, Ar-H, J =
8.9 Hz), 11.5 (1H, s, NH); 13C NMR δC (DMSO-d6, 75 MHz) 12.0, 20.7, 20.8,
20.9, 21.1, 69.6, 70.5, 71.8, 72.1, 73.6, 81.2, 116.6, 116.9, 117.9, 118.0, 160.5,
169.2, 169.5, 169.7, 169.8, 170.2, 170.4; Anal. Calcd. for C24H27FN4O10: C,
52.36; H, 4.94; N, 10.18. Found: C, 52.27; H, 4.87; N, 10.02.
ꢁ
ꢁ

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
793
4-[2-(4-(Methoxyphenyl)hydrazono]-3-methyl-1-(2,3,4,6-tetra-O-acetyl-
β-D-glucopyranosyl)-1H-pyrazol-5(4H)-one (7c)
Compound 7c was synthesized from 4c and 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide, in a similar manner described for 7f, in 69% yield;
yellow crystals; mp 148–150◦C; 1H NMR δH (DMSO-d6, 300 MHz) 1.99 (3H,
s, Ac), 2.00 (3H, s, Ac), 2.07 (3H, s, Ac), 2.14 (3H, s, Ac) 2.18 (3H, s, CH3),
ꢁ
ꢁ
3.78 (3H, s, OCH3), 3.9 (1H, m, H-5’), 4.14 (1H, dd, H-6’, J 5 ,6 = 4.62,
ꢁ
ꢁ
ꢁ
ꢁ
ꢁ
J 6 ,6 = 11.72 Hz), 4.21 (1H, dd, H-6”, J 5 ,6 = 2.76, J 6 ,6 = 11.72 Hz), 4.95
(2H, m, H-2’and H-4’), 5.44 (1H,t, H-3’, J 9.58 Hz), 5.96 (1H, d, H-1’), 7.02
(2H, d, Ar-H, J = 8.9 Hz), 7.48 (2H, d, Ar-H, J = 8.9 Hz), 11.50 (1H, s, NH,
J = 8.3 Hz); 13C NMR δC (DMSO-d6, 75 MHz) 12.0, 20.7, 20.8, 20.9, 30.8,
61.8, 68.1, 69.1, 70.5, 71.8, 72.1, 81.4, 126.0, 122.1, 128.3, 135.4, 157.5, 160.7,
169.2, 169.5, 169.7, 169.9, 170.4; Anal. Calcd. for C25H30N4O11: C, 53.38; H,
5.38; N, 9.69. Found: C, 53.27; H, 5.26; N, 9.54.
4-[2-(p-Tolylhydrazono)-3-methyl-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-
1H-pyrazol-5(4H)-one (7b)
Compound 7b was synthesized from 4b and 2,3,4,6-tetra-O-acetyl-α-D-
glucopyranosyl bromide, in a similar manner described for 7f, in 83% yield;
yellow crystals; mp 139–141◦C; IR (KBr) 3470 cm−1(ν NH), 1745 cm−1 (ν C =
O, ester), 1660 cm−1 (ν C = O, amide); 1H NMR δH (DMSO-d6, 300 MHz)
1.87 (3H, s, Ac), 1.97 (3H, s, Ac), 1.99 (3H, s, Ac), 2.04 (3H, s, Ac), 2.35 (3H,
ꢁ
s, CH3), 2.45 (3H,s, CH3), 3.98 (1H, m, H-5ꢁ), 4.18 (1H, dd, H-6ꢁ, J 5 ,6”
4.68, J 6 ,6” = 11.72 Hz), 4.21(1H, dd, H-6”, J 5 ,6” = 2.76, J 6 ,6” = 11.72 Hz,),
5.93 (1H, d, H-1ꢁ, J = 8.29 Hz), 12.80 (1H, brs, NH); Anal. Calcd. for
C25H30N4O10: C, 54.94; H, 5.53; N, 10.25. Found: C, 54.82; H, 5.47; N, 10.17.
=
ꢁ
ꢁ
ꢁ
4-(2-(4-Fluorophenyl)hydrazono)-1-(β-D-glucopyranosyl)-3-methyl-1H-pyrazol-
5(4H)-one (8g)
Triethylamine (0.5 mL, 3.63 mmol) was added to a solution of 7g
(2 g, 3.63 mmol) in MeOH (15 mL). The mixture was stirred overnight at
room temperature and the volatiles were evaporated and co-evaporated with
MeOH under reduced pressure. The residue was crystallized from ethanol
1
to give 8g (1.1 g, 83% yield) as yellow crystals; mp 178–180◦C; H NMR δH
(DMSO-d6, 300 MHz) 2.27 (3H,s, CH3), 3.13–3.34 (6H, m, H-6,” H-6,” H-
5, H-4’, H-3’and H-2’), 4.50 (1H, brt, 6’-OH), 5.00 (1H, brd, 4ꢁ-OH), 5.20
(1H, brd, 3ꢁ-OH), 5.47 (1H, brd, 2’-OH), 5.61 (1H, d, H-1ꢁ, J 1 ,2 = 7.83 Hz),
7.23–7.69 (4H, m, Ar-H), 11.53 (1H, s, NH); Anal. Calcd. for C16H19FN4O6:
C, 50.26; H, 5.01; N, 14.65. Found: C, 50.21; H, 4.98; N, 14.52.
ꢁ
ꢁ
1-(β-D-Glucopyranosyl)-4-[2-(4-methoxy)phenylhydrazono]-3-methyl-1H-
pyrazol-5(4H)-one (8c)
Compound 7c (0.8 g, 1.42 mmol) was deprotected, in a similar man-
ner described for 8g, to give 8c (0.4 g, 83% yield) as yellow crystals; mp

794
A. E. A. Hassan et al.
172–173◦C; 1H NMR δH (DMSO-d6, 300 MHz) δ 2.16 (3H,s, CH3), 3.02–3.35
(6H, m, H-6ꢁ, H-6”, H-5ꢁ, H-4ꢁ, H-3ꢁ and H-2ꢁ), 3.67 (3H, s, OCH3), 4.32 (1H,
t, 6ꢁ-OH), 4.81(1H, d, 4ꢁ-OH), 4.90 (1H, d, 3ꢁ-OH), 5.01 (1H, d, 2ꢁ-OH),
5.30 (1H, d, H-1ꢁ, J 1 ,2 8.0 Hz), 7.01 (2H, d, Ar-H, J = 8.8 Hz), 7.50 (2H, d,
ꢁ
Ar-H, J 8.8 Hz), 11.50 (1H, s, NH); Anal. Calcd. for C17H22N4O7: C, 51.77;
H, 5.62; N, 14.21. Found: C, 51.45; H, 5.52; N, 14.19.
1-(β-D-Glucopyranosyl)-3-methyl-4(2-p-tolylhydrazono)-1-H-pyrazol-5(4H)-one
(8b)
Compound 7b (0.85 g, 1.55 mmol) was deprotected, in a similar man-
ner described for 7f, to give 7b (0.5 g, 85% yield) as yellow crystals; mp
160–162◦C; 1H NMR δH (DMSO-d6, 300 MHz) 2.14 (3H, s, CH3), 2.35 (3H,
s, CH3), 3.10–3.64 (6H, m, H-6ꢁ, H-6ꢁꢁ, H-5ꢁ, H-4ꢁ, H-3ꢁ, and H-2ꢁ), 4.54 (1H,
t, 6ꢁ-OH), 4.90 (1H, d, 4ꢁ-OH), 5.10 (1H, d, 3ꢁ-OH), 5. 21 (1H, d, 2ꢁ-OH),
5.56 (1H, d, H-1ꢁ, J 1 ,2 7.98 Hz), 7.26 (2H, d, Ar-H, J 8.4 Hz), 7.60 (2H, d,
ꢁ
Ar-H, J = 8.4 Hz), 12.50 (br s, 1H, NH); Anal. Calcd. for C17H22N4O6: C,
53.96; H, 5.89; N, 14.81. Found: C, 53.89; H, 5.77; N, 14.79.
3-Methyl-1-(2ꢀ,3ꢀ,5ꢀ-tri-O-acetyl-β-D-ribofuranolyl)-4-(2-phenylhydrazono)-1H-
pyrazol-5(4H)-one (9a)
A mixture of 4a (1.4 g, 6.92 mmol), ammonium sulfate (0.1 g), and
of HMDS (30 mL) was heated for 12 hours at 80◦C. The excess of HMDS
evaporated and co-evaporated (dry xylene) under reduced pressure. A mix-
ture of the silylated pyrazolone and 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose
(3.3 g, 10.4 mmol) was dissolved in dry CH2Cl2 (50 mL), and treated with a
solution of SnCl4 (1M in CH2Cl2; 13.84 mL) at room temperature. The reac-
tion mixture was stirred for 18 hours at room temperature and then diluted
with CH2Cl2 (100 mL), washed with saturated aqueous solution of NaHCO3
(50 mL) and water (2 × 50 mL). The organic phase was separated, dried over
(Na2SO4), and evaporated under reduced pressure. The residue was puri-
fied by a silica gel column chromatography (eluate; 4% MeOH in CH2Cl2)
to give 9a (2.3 g, 73% yield) as a pale yellow foam; IR (KBr) 3480 cm−1 (ν
NH), 1749 cm−1 (ν C = O, Ac), 1653 cm−1 (ν C = O, amide); 1H NMR δH
(DMSO-d6, 300 MHz) 2.07 (3H,s, Ac), 2.10 (3H, s, Ac), 2.12 (3H, s, Ac),
2.27 (3H, s, CH3), 3.43 (1H, m, H-4ꢁ), 4.19 (1H, dd, H-5ꢁ, J 4 ,5’ = 3.5, J 5 ,5”
=
ꢁ
ꢁ
ꢁ
ꢁ
11.8 Hz), 4.30 (1H, dd, H-5”, J 4 ,5” = 2.9, J 5 ,5” = 11.8 Hz), 5.34 (2H, m,
H-2ꢁand H-3ꢁ), 6.19 (1H, d, H-1’, J 1 ,2 6.9 Hz), 7.26–7.42 (5H, m, Ar-H), 13.4
ꢁ
(1H, br s, NH); Anal. Calcd. for C21H24N4O8: C, 54.78; H, 5.25; N, 12.17.
Found: C, 54.59; H, 5.14; N, 12.10.
3-Methyl-1-(β-D-ribofuranosyl)-4-(2-phenylhydrazono)-1H-pyrazol-5(4H)-one
(10a)
Compound 9a (2 g, 4.34 mmol) was deprotected, in a similar manner
1
described for 7d, to give 10a (1.15 g, 79% yield) as a pale yellow foam; H

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
795
NMR δH (DMSO-d6, 300 MHz) 2.27 (3H, s, CH3), 3.31 (5H, m, H-2ꢁ, H-3’,
H-4’, H-5’ and H-5”), 4.12 (1H, t, 5’-OH, J = 5.4 Hz), 4.26 (1H, d, 3’-OH),
4.30 (1H, d, 2ꢁ-OH), 5.52 (1H, d, H-1ꢁ, J 1 ,2 = 6.6 Hz), 7.17–7.69 (5H, m,
Ar-H), 11.53 (1H, s, NH); Anal. Calcd. for C15H18N4O5: C, 53.98; H, 5.43;
N, 16.76. Found: C, 53.86; H, 5.39; N, 16.58.
ꢁ
ꢁ
4-[3-Methyl-5-oxo-4(2-phenylhydrazono)-4,5-dihydro-1H-pyrazol-1-yl]butyl
acetate (11a)
A solution of 4a (1 g, 4.95 mmol), and dry K2CO3 (0.61 g, 5.93 mmol)
in dry DMF (15 mL) was stirred for 15 minutes at room temperature. 4-
Bromobutylacetate (0.6 mL, 5.94 mmol) was added at 0◦C and the mix-
ture was stirred overnight at room temperature. The insoluble material
was filtered off and the filterate was evaporated under reduced pressure.
The residue was then chromatographic on a silica gel column (eluate: 5%
1
MeOH in CH2Cl2) to give 11a (1.1 g, 72% yield) as orange foam; H-NMR
δH (DMSO-d6, 300 MHz) 1.52 (2H, m, CH2), 1.76 (2H, m, CH2), 1.98 (3H, s,
Ac), 2.53 (3H, s, CH3), 3.99 (2H, m, CH2N), 4.22 (2H, t, CH2O), 6.66–7.38
(5H, m, Ar-H), 11.83 (1H, s, NH); 13C NMR δC (DMSO-d6. 75 MHz) 11.6,
20.7, 21.6, 26.0, 34.3, 64.6, 113.9, 122.4, 128.7, 129.5, 143.1, 148.2, 163.1,
170.2; Anal. Calcd. for C16H20N4O3: C, 60.75; H, 6.37; N, 17.71. Found: C,
60.74; H, 6.28; N, 17.69.
4-[3-Methyl-4-(2-p-tolylhydrazono]-4,5-dihydro-1H-pyrazol-1-yl)butyl acetate
(11b)
Compound 11b was synthesized from 1c, in a similar manner as described
for the synthesis of 11a, in 85% yield; yellow foam; 1H NMR δH (DMSO-d6,
300 MHz) 1.52 (2H, m, CH2), 1.78 (2H, m, CH2), 1.88 (3H, s, CH3), 1.98
(3H, s, Ac), 2.53 (3H, s, CH3), 3.99 (2H, m, CH2N), 4.22 (2H, t, CH2O),
7.27 (2H, d, Ar-H, J = 8.1 Hz), 7.58 (2H, d, Ar-H, J = 8.1 Hz), 12.48 (1H, s,
NH); 13C NMR δC (DMSO-d6) 11.6, 20.7, 21.3, 21.6, 26.1, 34.3, 64.7, 116.2,
128.7, 129.8, 131.2, 140.0, 148.2, 163.0, 170.3; Anal. Calcd. for C17H22N4O3:
C, 61.80; H, 6.71; N, 16.96. Found: C, 61.69; H, 6.67; N, 16.82.
4-[3-Methyl-4-(2-(4-nitrophenyl)hydrazono]-5-oxo-4,5-dihydro-1H-pyrazol-1-
yl)butyl acetate (11f)
Compound 11f was synthesized from 4f, in a similar manner as described
for the synthesis of 11a, in 80% yield; yellow foam; IR (KBr) 1739 cm−1 (C
1
= O, ester), 1649 cm−1 (C = O, amide); H NMR (DMSO-d6) δ 1.58 (2H,
m, CH2), 1.79 (2H, m, CH2), 1.98 (3H, s, COCH3), 2.56 (3H, s, CH3), 3.99
(2H, m, CH2N), 4.24 (2H, t, CH2O), 7.81 (2H, d, Ar-H, J = 8.7 Hz), 8.33
(2H, d, Ar-H, J = 8.7 Hz); Anal. Calcd for C16H19N5O5 (361.35): C, 53.18;
H, 5.30; N, 19.38. Found: C, 53.20; H, 5.28; N, 19.37.

796
A. E. A. Hassan et al.
1-(4-Hydroxybutyl)-3-methyl-4-(2-phenylhydrazono)-1H-pyrazol-5(4H)-one
(12a)
Compound 11a (0.95 g, 3 mmol) in MeOH (15 mL) was treated with
Et3N (0.5 mL, 3.2 mmol) and the mixture was stirred for 2 hours at room
temperature. The volatiles were removed under reduced pressure and the
residue was purified by silica gel column chromatography (eluate: 6% MeOH
1
in CH2Cl2) to give 12a (0.61g, 75% yield) as a yellow foam; H NMR δH
(DMSO-d6, 300 MHz) 1.42–1.78 (4H, m, CH2CH2), 2.25 (3H, s, CH3), 3.49
(2H, m, CH2N), 3.96–4.21 (2H, m, CH2O), 4.50 (1H, t, OH), 7.48–7.66 (5H,
m, Ar-H); Anal. Calcd. for C14H18N4O2: C, 61.30; H, 6.61; N, 20.42. Found:
C, 61.28; H, 6.59; N, 20.33.
1-(4-Hydroxybutyl)-3-methyl-4-(2-p-tolylhydrazono)-1H-pyrazol-5(4H)-one
(12b)
Compound 11b (0.75 g, 2.27 mmol) was deprotected, in a similar manner
described for 11a, to give 12b (0.54 gm, 82% yield) as a yellow foam; 1H NMR
δH (DMSO-d6, 300 MHz) 1.25 (2H, m, CH2), 2.04 (2H, m, CH 2), 2.36 (3H,
s, CH3), 2.57 (3H, s, CH3), 3.97 (2H, t, CH2N), 4.22 (2H, t, CH2O), 4.49
(1H, t, OH), 7.25 (2H, d, Ar-H, J 8.4 Hz), 7.69 (2H, d, J 8.4 Hz, Ar-H). Anal.
Calcd. for C15H20N4O2: C, 62.48; H, 6.99; N, 19.43. Found: C, 62.39; H, 6.88;
N, 19.38.
1-(4-Hydroxybutyl)-3-methyl-4-(2-(4-nitrophenyl)hydrazono)-1H-pyrazol-
5(4H)-one (12f)
Compound 11f (0.8 g, 2.21 mmol) was deprotected, in a similar manner
described for 11a, to give 12f (0.56 g, 79% yield) as a yellow foam; 1H NMR δH
(DMSO-d6, 300 MHz) 1.40–1.79 (4H, m, CH2-CH2), 2.54 (3H, s, CH3), 3.47
(2H, m, CH2N), 3.97–4.24 (2H, m, CH2O), 4.49 (brt, 1H, OH, exchanged
with D2O), 7.78 (2H, d, Ar-H, J = 8.8 Hz), 8.29 (2H, d, Ar-H, J = 8.8 Hz).
Anal. Calcd. for C14H17N5O4: C, 52.66; H, 5.37; N, 21.93. Found: C, 52.64;
H, 5.29; N, 21.87.
2-[4-(2-(4-Fluorophenyl)hydrazono)-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-
yl)methoxy]ethyl acetate (13g)
A mixture of 4g (1.25 g, 5.68 mmol) and dry K2CO3 (0.88 g, 8.5 mmol)
in dry DMF (15 mL) was stirred for 15 minutes at room temperature. (2-
acetoxyethoxy)methyl bromide (1.45 g, 7.4 mmol) was added at 0◦C and the
mixture was stirred overnight at room temperature. The insoluble material
was filtered off and the filtrate was evaporated under reduced pressure. The
residue was purified by a silica gel column chromatography (eluate; 5%
MeOH in CH2Cl2) to give 13g (1.4 g, 75% yield) as a yellow syrup; IR (KBr)
3260 cm−1 (ν NH), 1740 cm−1 (ν C = O, ester), 1669 cm−1 (ν C = O, amide);

Evaluation of Novel Pyrazolones and Pyrazolone Nucleosides
797
1H NMR δH (DMSO-d6, 300 MHz) 1.99 (3H, s, CH3CO), 2.58 (3H, s, CH3),
4.38 (2H, t, OCH2), 4.76 (2H, t, CH2OCO), 4.98 (2H, s, NCH2O), 7.23–7.73
(4H, m, Ar-H), 12.58 (1H, s, NH). 13C NMR δC (DMSO-d6, 75 MHz) 11.9,
21.2, 62.8, 66.2, 66.9, 116.2, 116.6, 116.9, 117.9, 118.0, 118.2, 118.3, 123.7,
137.1, 138.6, 147.3, 150.3, 157.9, 161.7; Anal. Calcd. for C15H17FN4O4: C,
53.57; H, 5.09; N, 16.66. Found: C, 53.47; H, 5.02; N, 16.54.
2-[(3-Methyl-5-oxo-4-(2-p-tolylhydrazono)-4,5-dihydro-1H-pyrazol-1-yl)
methoxy]ethyl acetate (13b)
Compound 13b was synthesized from 4b, in a similar manner as described
for 13g, in 85% yield; yellow foam; IR (KBr) 3230 cm−1 (ν NH), 1742 cm−1 (ν
C = O, ester), 1657 cm−1 (ν C = O, amide); 1H NMR δH (CDCl3, 300 MHz)
1.32 (3H, s, CH3), 2.06 (3H, s, CH3CO), 2.63 (1H, s, CH3), 4.18 (2H, t,
CH2), 4.50 (2H, m, CH2OCO), 5.24 (2H, s, NCH2O), 7.25 (2H, d, Ar-H, J =
8.4 Hz), 7.69 (2H, d, Ar-H, J = 8.4 Hz). 13C NMR δC (DMSO-d6, 75MHz)
11.6, 20.8, 63.3, 66.2, 83.2, 116.4, 128.5, 129.7, 131.8, 140.3, 148.5, 164.1,
170.5; Anal. Calcd. for C16H20N4O4 (332.35): C, 57.82; H, 6.07; N, 16.86.
Found: C, 57.71; H, 5.96.08; N, 16.77.
2-[4-(2-(4-Bromophenyl)hydrazono]-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-
yl)methoxy]ethyl acetate (13e)
Compound 13e was synthesized from 4e, in a similar manner as described
for 13g, in 83% yield; yellow foam; IR (KBr) 1735 cm−1 (ν C = O, ester),
1666 cm−1 (ν C = O, amide), 1235 cm−1 (ν C-O, ether); 1H NMR δH (CDCl3,
300 MHz) 2.05 (3H, s, Ac), 2.62 (3H,s, CH3-pyrazolinone ring), 3.75 (2H, t,
OCH2), 4.21 (2H, t, CH2OCO), 5.18 (2H, s, NCH2O), 7.26 (2H, d, Ar-H, J =
8.3 Hz), 7.52 (2H, d, Ar-H, J = 8.3 Hz), 13.26 (1H, brs, NH). Anal. Calcd.
for C15H17BrN4O4: C, 45.35; H, 4.31; N, 14.10. Found: C, 45.39; H, 4.27; N,
14.06.
2-[(3-Methyl-5-oxo-4-(2-(3-trifluoromethyl)phenyl)hydrazono)-4,
5-dihydro-1H-pyrazol-1-yl)methoxy]ethyl acetate (13h)
Compound 13h was synthesized from 4h, in a similar manner as described
for 13g, in 80% yield; yellow crystals; m. p 145–146◦C; IR (KBr) 3301 cm−1(ν
NH), 1740 cm−1 (ν C = O, ester), 1668 cm−1 (ν C = O, amide). 1H NMR
δH (DMSO-d6, 300 MHz) 2.04 (3H, s, Ac), 2.58 (3H, s, CH3-pyrazolinone
ring), 4.41 (2H, t, OCH2), 4.72 (2H, t, CH2OCO), 4.98 (2H, s, NCH2O),
7.23–7.72 (4H, m, Ar-H), 13.12 (1H, brs, NH). 13C NMR δC (DMSO-d6,
300 MHz) 12.0, 34.7, 62.8, 66.2, 66.9, 99.9, 112.9, 120.1, 121.6, 129.6, 130.4,
130.8, 131.2, 142.9, 147.1, 157.6; Anal. Calcd. for C16H17F3N4O4: C, 49.74;
H, 4.44; N, 14.50. Found: C, 49.84; H, 4.41; N, 14.42.

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A. E. A. Hassan et al.
1-[(2-Hydroxyethoxy)methyl)-3-methyl-4-(2-p-tolylhydrazono]-1H-pyrazol-
5(4H)-one (14b)
Compound 13b (0.48 g, 1.44 mmol) was deprotected, in a similar manner
described for 11a, to give 14b (0.34 g, 82% yield) as a yellow foam; 1H NMR
δH (DMSO-d6, 300 MHz) 2.33 (3H, s, CH3), 2.55 (3H, s, Ac), 3.74 (2H, t,
CH2OH), 4.25 (2H, t, OCH2), 4.75(1H, t, OH), 4.98 (2H, s, NCH2O), 7.28
(2H, d, Ar-H, J 8.32 Hz), 7.58 (2H, d, Ar-H, J 8.3 Hz), 12.52 (1H, s, NH).
Anal. Calcd. for C14H18N4O3: C, 57.92; H, 6.25; N, 19.30. Found: C, 57.69;
H, 6.36; N, 19.21.
4-(2-(4-Fluorophenyl)hydrazono)-1-[(2-hydroxyethoxy)methyl]-3-methyl-1H-
pyrazol-5(4H)-one (14g)
Compound 13g (0.54 g, 1.36 mmol) was deprotected in a similar manner
described for 11a, to give 14g (0.3 g, 73% yield) as a yellow foam; 1H NMR
δH (DMSO-d6, 300 MHz) 2.56 (3H, s, CH3), 3.68 (2H, t, CH2OH), 4.19
(2H, t, OCH2), 4.52 (1H, t, OH), 5.16 (2H, s, NCH2O), 7.29 (2H, d, Ar-
H, J = 8.43 Hz), 7.49 (2H, d, Ar-H), 13.2 (1H, brs, NH). Anal. Calcd. for
C13H15FN4O3: C, 53.06; H, 5.14; N, 19.04. Found: C, 52.96; H, 5.03; N, 14.94.
4-[2-(4-Bromophenyl)hydrazono)-1-(2-hydroxyethoxy)methyl]-3-methyl-1H-
pyrazol-5(H)-one (14e)
Compound 13e (0.42 g, 1.1 mmol) was deprotected, in a similar manner
described for 11a, to give 14e (0.29 g, 78% yield) as a yellow foam; 1H NMR
δH (CDCl3, 300 MHz) 2.26 (3H, s, CH3), 3.69 (2H, t, CH2OH), 4.21(2H, t,
OCH2), 4.49 (1H, brt, OH), 5.18 (2H, s, NCH2O), 7.26 (2H, d, Ar-H), 7.52
(2H, d, Ar-H), 13.26 (1H, brs, NH). 13C NMR δC (DMSO-d6, 75 MHz) 11.7,
61.2, 69.5, 84.6, 116.8, 118.0, 128.5, 132.7, 142.0, 148.5, 164.5; Anal. Calcd.
for C13H15BrN4O3: C, 43.96; H, 4.26; N, 15.77. Found: C, 43.95; H, 4.19; N,
15.61.
1-[(2-Hydroxyethoxy)methyl)-3-methyl-4-(2-(3-trifluoromethyl)-
phenyl)hydrazono)-1H-pyrazol-5(4H)-one (14h)
Compound 13h (0.51 g, 1.32 mmol) was deprotected, in a similar manner
described for 11a, to give 14h (0.3 g, 68% yield) as a yellow foam; 1H NMR δH
(DMSO-d6, 300 MHz) 2.54 (3H, s, CH3), 3.70 (2H, t, CH2OH), 4.23 (2H, t,
OCH2), 4.51 (1H, brt, OH), 5.28 (2H, s, NCH2O), 7.23–7.85 (4H, m, Ar-H),
12.50 (1H, brs, NH). Anal. Cald. for C14H15F3N4O3: C, 48.84; H, 4.39; N,
16.27. Found: C, 48.71; H, 4.27; N, 16.12.
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