Synthesis and reactions of some new heterocyclic carbohydrazides and related compounds as potential anticancer agents

Article abstract of DOI:10.3390/81000744

Acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) and hydrazine hydrate (7) with 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro[4.4]nona-2,6- dien-9-ones 5a,b gave the corresponding heterocyclic carbohydrazides 6a,b and 8a,b respectively. Conversion of compounds 8a,b into the versatile carbohydrazide derivatives 9a-g, 10, 13 and the related oxadiazoles 11, 12a,b was undertaken. A primary in vitro test of compound 8a (concentration 10 ^-4M) showed activity against leukemia cell lines (CCRF-CEM, K-256, MOLT-4, PRMI-8226, SR).

Full text of DOI:10.3390/81000744

Molecules 2003, 8, 744-755
molecules
ISSN 1420-3049
http://www.mdpi.org/
Synthesis and Reactions of Some New Heterocyclic
Carbohydrazides and Related Compounds as Potential
Anticancer Agents
Abdel Kader Mansour *,1, Mohga M. Eid 1 and Nasser S. A. M. Khalil 2
1 Department of Chemistry, Faculty of Science, Cairo University, Giza, Egypt.
2 Central Laboratory for Food and Feed, Agricultural Research Centre, 9 El Gamaa St., Giza, Egypt.
*Author to whom correspondence should be addressed; e-mail: nasserkhalil_23@hotmail.com
Received: 1 June 2003; in revised form: 20 August 2003/ Accepted: 25 August 2003 / Published: 31
October 2003
Abstract: Acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) and hydrazine
hydrate (7) with 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro[4.4]nona-2,6-dien-9-ones
5a,b gave the corresponding heterocyclic carbohydrazides 6a,b and 8a,b respectively.
Conversion of compounds 8a,b into the versatile carbohydrazide derivatives 9a-g, 10, 13
and the related oxadiazoles 11, 12a,b was undertaken. A primary in vitro test of
compound 8a (concentration 10-4 M) showed activity against leukemia cell lines (CCRF-
CEM, K-256, MOLT-4, PRMI-8226, SR).
Keywords: Synthesis, Pyrazoles, 2-Pyrazolines, Carbohydrazides.
Introduction
Hydrazides and related compounds have been described as useful building blocks for the assembly
of various heterocyclic rings [1]. A large number of aliphatic, alicyclic, aromatic and heterocyclic
carbohydrazides, their derivatives and related compounds are reported to present a plethora of
biological activities [2-15]. Thus, different carbohydrazides were found to be useful as medicaments
especially in the treatment of inflammatory and autoimmune diseases, osteoarthritis, respiratory

Molecules 2003, 8
745
diseases, tumors, cachexia, cardiovascular diseases, fever, hemorrhage and sepsis [11].
Carbohydrazides and related compounds exhibited antifungal [2], antiviral [14], bacteriostatic
[2,7,9,14], antiparasite [2,10], antituberculous [3-6], psychotropic [2], and insecticidal [15] activities.
Some heterocyclic carbohydrazides are useful as antifertility agents in rats and pigeons [13]. Other
carbohydrazides were reported to be components of deodorant compositions that can be used for
removal of offensive odor components [16]. The 1,3,4-oxadiazoles have been reported to be
biologically versatile compounds having bactericidal, fungicidal, analgesic, antiproteolytic,
hypoglycemic, tranquilizing and CNS depressant properties [2]. All these facts encouraged us to
synthesize some new 2-pyrazolin-3-carbohydrazides 8a,b, their derivatives 9a-g, 10, 13 and some
related oxadiazoles 11, 12a,b in anticipation of expected interesting biological activities.
Results and discussion
Acylation of 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2) with 4-arylidene-2-phenyl-oxazol-5(4H)-
ones (1a-d) has been previously reported [17] to give the corresponding N-(5,6-diphenyl-1,2,4-triazin-
3-yl)-carbohydrazides 3a-d (Scheme1).
Scheme 1
Ph
N
N
Ph
N
N
O
N
Ar
N
Ph
H2NHN
N
O
Ph
Ar-CH=C-CONHHN
2
3a-d
HN
Ph
Toluene
C=O
1a-d
Ph
Ar
C6H5
2-CH3OC6H4
4-CH3OC6H4
1,3
a
b
c
d
3,4-(CH3O)2C6H3
.
We have now studied the acylation of both compound 2 and hydrazine hydrate (7) with the 4-aryl-
1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro[4.4]nona-2,6-dien-9-ones 5a,b. Some chemical transformations
leading to new functionalities have also been achieved (Scheme 2). For example, acylation of 3-
hydrazino-5,6-diphenyl-1,2,4-triazine (2) with the spiro compounds 5a,b [19,20] gave the
corresponding
novel
N-(5,6-diphenyl-1,2,4-triazin-3-yl)-1,3-diphenyl-4-aryl-5-benzoylamino-2-
pyrazolin-5-carbohydrazides 6a,b. The structure of compounds 6a,b was assigned based on analytical
and spectral data. Thus, the IR spectra of these compounds showed bands at 3405-3396, 3277-3267

Molecules 2003, 8
746
(NH stretching), 3063-3059, 3038-3028 (aromatic CH stretching), 1709 (hydrazide C=O stretching ),
1685-1682 (amide C=O stretching), 1627 (C=N stretching) and 1601-1597 cm-1 (aromatic C=C
stretching).
Scheme 2
O
Ar
Ph
N
O
N
Ph
Ph
Ar
Ph
N+
N
N
PhC
N
1a,b
Ph
4
CONHHN
N
N
Refs. 19,20
H
NHCOPh
6a,b
2
Ph
N
Ph
Ar
Ph
C
N
O
N
Ph
N
CHAr'
N
N
H
N
O
Ph
Ar
Ph
N
Ar
N
OH
CONHNHCSNHPh
5a,b
Ph
H
NH2NH2.H2O
NHCOPh
7
13
PhNCS
( Ar =
2-
CH3O-C6H4 )
Ph
Ph
N
N
Ph
Ph
Ar'CHO
N
N
CONHNH2
Ar
H
CONHN
Ar
CHAr'
NHCOPh
9a-g
8a,b
CH3COOH
Ph
CS2 / EtOH / KOH
N
PhCOOH / POCl3
Ph
N
CONHNHCOCH3
Ar
Ph
N
N
Ph
Ar
H
Ph
N
N
Ph
N
N
N
N
( Ar =C H )
10
6
5
S
O
H
Ar
Ph
( Ar =C6H5 )
O
NHCOPh
11
12a,b
9
Ar'
Ar
1,5,6,8,12 Ar
C6H5
2-
C6H5
a
b
a
C6H5
C6H5
C6H5
C6H5
(OH)-C H
2-
6
4
CH3O-C6H4
b
CH -C H
CH O-C H
4-
4-
3
6
4
c
d
e
3
6
4
C6H5
2-
CH3O-C6H4
CH O-C H
CH O-C H
4
-(OH)-C H
f
g
2-
2-
3
6
4
2
6
4
3
6
-CH OC H
4
3
6
4
.

Molecules 2003, 8
747
1
Also, the H-NMR spectra of compounds 6a,b revealed signals at δ 11.31-10.28 (2s, hydrazide
NHNH), 7.97-7.72 (s, amide NH), 7.61-6.50 (m, ArH's), 5.87-5.64 (s, pyrazolinyl CH). Moreover, the
13C-NMR of compounds 6a,b showed signals consistent with their structures (cf. Experimental).
Similarly, acylation of hydrazine hydrate (7) with the spiro compounds 5a,b afforded the
corresponding 4-aryl-5-benzoylamino-1,3-diphenyl-2-pyrazoline-5-carbohydrazides 8a,b. The
1
structure of compounds 8a,b was established chemically and spectroscopically. Thus, the H-NMR
spectra of these compounds not only showed the presence of the pyrazolinyl proton at δ 5.59-5.32, but
also revealed the presence of NH2 protons at δ 4.61-4.54 [s, 2H (exchangeable)]. The mass spectra of
compounds 8a,b, also gave their correct parent ion peaks at m/z 475 (M+, 1.3%), and 505 (M+, 0.4%),
respectively.
Condensation of compounds 8a,b with aryl aldehydes and/or acetylation of compound 8a with
acetic acid was found to proceed concurrently with the elimination of a benzamide molecule to give
the corresponding N-arylidene and/or N-acetoxy-4-aryl-1,3-diphenyl-pyrazole-5-carbohydrazides 9a-g
and/or 10 respectively. The structures of these compounds were inferred from their analytical and
spectral data. Thus, the IR spectra of compounds 9a-g showed only one carbonyl function (hydrazide
C=O) at 1722-1670 cm-1 and that of compound 10 showed a carbonyl function at 1672 cm-1(hydrazide
C=O overlapped with acetyl C=O). The 1H-NMR spectra of 9a-g and 10 not only showed the absence
of both the pyrazolinyl proton at δ 5.59-5.32 and the NH2 protons at δ 4.61-4.54, but also the presence
of the N=CH in compounds 9a-g (δ 8.30-7.65) and the acetyl protons of compound 10 (δ 1.86). The IR
spectra of compounds 9a-g as well as their 1H-NMR spectra (relative proton integration ratio) showed
the presence of both hydrazide (25-63.3%) and hydrazole (36.7-75%) tautomeric structures. The mass
spectra of compounds 9a,c gave their correct parent ion peaks at m/z 442 (M+, 13.7%) and 456 (M+,
12%), respectively.
Treatment of compound 8a with benzoic acid and phosphorous oxychloride was found to proceed
via concurrent cyclocondensation and elimination of a benzamide molecule to give the 5-phenyl-2-
(1,3,4-triphenylpyrazol-5-yl)-1,3,4-oxadiazole (11). The mass spectrum of compound 11 showed its
correct parent ion peak at m/z 440 (M+, 49.9%).
Compounds 8a,b reacted with carbon disulfide in ethanolic KOH to yield the corresponding 2-(4-
aryl-1,3-diphenyl-5-benzoylamino-2-pyrazolin-5-yl)-1,3,4-oxadiazole-5(4H)-thiones (12a,b). The
absence of the characteristic weak S-H stretching bands at 2600-2550 and the appearance of the strong
C=S stretching bands at 1069-1064 cm-1 in the IR spectra of compounds 12a,b confirmed their thione
form and excluded the tautomeric thiol structure. The IR spectra of compounds 12a,b showed also
bands at 1199-1019 cm-1 (=C-O-C= stretching). The 1H-NMR spectra revealed the presence of the NH
oxadiazolyl proton at δ 14.60-14.52 and the CH pyrazolinyl proton at δ 6.32-5.90.
Reaction of compound 8b with phenyl isothiocyanate gave N-(N-phenylthiocarbamoyl)-5-
benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazolin-5-carbohydrazide (13). Elemental and
spectral data are consistent with the structure assigned to this compound (cf. Experimental).

Molecules 2003, 8
748
Biological Evaluation
A primary in vitro test of compound 8a (concentration 10-4 M) showed activity against Leukemia
cell lines (CCRF-CEM, K-562, MOLT-4, PRMI-8226, SR). Further investigation is in progress.
Experimental
General
All melting points are uncorrected. IR spectra (KBr disks) were recorded on a Perkin-Elmer 1430
spectrometer. The abbreviations str. and bend. are used to indicate stretching and bending bands,
1
13
respectively . H-NMR and C-NMR were measured with a Varian GEMINI 200 spectrometer (200
MHz for H-NMR; 50MHz for 13C-NMR). The abbreviation exch. is used to indicate exchangeable
1
protons. Mass spectra were recorded on a GCMS - QP 1000 EX (70EV) spectrometer. Elemental
analyses were carried out at the Microanalytical Center, Cairo University. Anticancer screening of
compound 8a was carried out at the National Cancer Institute – National Institutes of Health, Bethesda,
Maryland, United States of America. The starting materials 3-hydrazino-5,6-diphenyl-1,2,4-triazine (2)
[18] and 4-aryl-1,3,7-triphenyl-8-oxa-1,2,6-triazaspiro-[4.4]nona-2,6-dien-9-ones 5a,b [19,20] were
prepared as reported.
General procedure for the preparation of N-(5,6-diphenyl-1,2,4-triazin-3-yl)-4-aryl-5-benzoylamino-
1,3-diphenyl-2-pyrazoline-5-carbohydrazides (6a,b).
Each of compounds 5a,b (1 mmol) was added to a solution of compound 2 (1 mmol) in toluene (10
mL). The reaction mixture was then heated under reflux for 11/2 hour, concentrated, and diluted with
petroleum ether (bp. 40-60 ºC). After decantation, the residue obtained was boiled in ethanol (5 mL),
filtered, and cooled. The formed precipitate was collected by filtration and recrystallized from ethanol
giving colorless crystals of 6a,b.
N-(5,6-Diphenyl-1,2,4-triazin-3-yl)-5-benzoylamino-1,3,4-triphenyl-2-pyrazoline-5-carbohydrazide
(6a). Using the general procedure, 5a gave 6a (73%); mp. 218-219ºC; IR (cm-1): 3405, 3277 (NH str.),
3063, 3038 (aromatic CH str.), 2922, 2866, 2855 (pyrazolinyl aliphatic CH str.), 1709 (hydrazide C=O
str.), 1685 (amide C=O str.), 1627 (C=N str.), 1601 (aromatic C=C str.), 1505, 1480 (NH bend.), 1365,
1
1312, 1283, 1251 (C-N str.), 762, 697 (aromatic CH bend.); H-NMR (DMSO-d6) δ 11.31, 10.31 [2s,
2H (exch.), hydrazide NHNH], 7.72 [s, 1H (exch.), amide NH], 7.57-6.82 (m, 30H, ArH's), 5.64 (s,
1H, pyrazolinyl CH); 13C-NMR (DMSO-d6) δ 171.5, 164.8 (C=O), 157, 152, 146.5, 142.5 (C=N),
136.2, 134.6, 132.2, 131.5 (aromatic C), 130.5, 129.5, 129.4, 128.7, 128.6, 128.5, 128.2, 127.6, 127.3,
127.2, 127.0. 126.2 (aromatic CH), 81.6 (pyrazolinyl C), 63.5 (pyrazolinyl CH); Anal. for C44H34N8O2
Calcd.: C, 74.77; H, 4.85; N, 15.85. Found: C, 74.60; H, 5.00, N, 15.70.

Molecules 2003, 8
749
N-(5,6-Diphenyl-1,2,4-triazin-3-yl)-5-benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazoline-
5-carbohydrazide (6b). Using the general procedure, 5b gave 6b (41%); mp. 210-212ºC; IR (cm-1):
3396, 3267 (NH str.), 3059, 3028 (aromatic CH str.), 2964, 2932, 2883, 2833 (OCH3 and pyrazolinyl
aliphatic CH str.), 3059, 3028, 2997 (aromatic CH str.), 1709 (hydrazide C=O str.), 1682 (amide C=O
str.), 1597(aromatic C=C str.), 1495, 1473, 1445 (NH bend.), 1358, 1331, 1290, 1252 (C-N str.), 1067,
1
1028 (C-O str. of OCH3), 762, 692 (aromatic CH bend.); H-NMR (DMSO-d6) δ 11.23, 10.28 [2 brs,
2H (exch.), hydrazide NHNH], 7.97 [s, 1H (exch.), amide NH] 7.61-6.50 (m, 29H, ArH's), 5.87 (s, 1H,
pyrazolinyl CH), 3.60 (s, 3H, OCH3); 13C-NMR (DMSO-d6) δ 171.64, 164.30, (C=O), 157.28, 146.84,
142.78, 136.41 (C=N), 135.95, 134.76, 132.74, 132.49, 132.45, 132.41, 131.46 (aromatic C), 130.54,
129.70. 129.31, 129.20, 128.74, 128.64, 128.40, 128.29, 126.86, 126.08, 125.89, 121.68, 120.33,
115.15, 115.09, 114.99 (aromatic CH), 110.04 (pyrazolinyl C), 80.55 (pyrazolinyl CH), 55.04 (OCH3);
Anal. for C45H36N8O3 Calcd.: C, 73.35; H, 4.92; N, 15.21. Found: C, 73.50; H, 5.00; N, 15.40.
General procedure for the preparation of 4-aryl-5-benzoylamino-1,3-diphenyl-2-pyrazoline-5-
carbohydrazides (8a,b). To a suspension of each of compounds 5a,b (1 mmol) in methanol (20 mL)
was added 80% hydrazine hydrate (0.5 mL). While the reaction mixture of compound 8a was shaken
for ten minutes at room temperature, that of compound 8b was heated under reflux for one hour. The
reaction mixtures of each compound were then left overnight at room temperature. The colorless
precipitate formed was collected by filtration and recrystallized from methanol to give colorless
crystals of 8a,b.
5-Benzoylamino-1,3,4-triphenyl-2-pyrazoline-5-carbohydrazide (8a). Using the general procedure, 5a
gave 8a (73%); mp. 214-215ºC; IR (cm-1): 3400, 3325 (NH, NH2 str.), 3065, 3034 (aromatic CH str.),
2930 (pyrazolinyl CH str.), 1669 (C=O str.), 1625 (C=N str.), 1601 (aromatic C=C str.), 1503, 1480
(NH bend.), 1374, 1321, 1280, 1243 (C-N str.), 750, 696 (aromatic CH bend.); 1H-NMR (DMSO-d6) δ
10.05 [s, 1H (exch.), hydrazide NH], 8.07 [s, 1H (exch.), amide NH], 7.60-6.86 (m, 20H, ArH's), 5.32
(s, 1H, pyrazolinyl CH), 4.54[s, 2H (exch.), NH2]; MS m/z 475 (M+, 1.3%); Anal. for C29H25N5O2
Calcd.: C, 73.24; H, 5.30; N, 14.73. Found: C, 73.20; H, 5.25; N, 14.60.
5-Benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazoline-5-carbohydrazide (8b). Using the
general procedure, 5b gave 8b (74%); mp. 230ºC; IR (cm-1): 3384, 3334,3284 (NH, NH2 str.), 3061,
3025 (aromatic CH str.), 2954, 2942, 2901, 2835 (OCH3 and pyrazolinyl aliphatic CH str.), 1684
(hydrazide C=O str.), 1672 (amide C=O str.), 1636 (C=N str.), 1604 (aromatic C=C str.), 1497, 1475
(NH bend.), 1375, 1294, 1250 (C-N str.), 1167, 1028 (C-O str. of OCH3), 750, 692 (aromatic CH
1
bend.); H-NMR (DMSO-d6) δ 10.25 [s, 1H (exch.), hydrazide NH], 8.18 [s, 1H (exch.), amide NH],
7.56-6.49 (m, 19H, ArH's), 5.59 (s, 1H, pyrazolinyl CH), 4.61[s, 2H (exch.), NH2], 3.82 (s, 3H,
OCH3); MS m/z 505 (M+, 0.4%); Anal. for C30H27N5O3 Calcd.: C, 71.27; H, 5.38; N, 13.85. Found: C,
71.30; H, 5.50; N, 14.00.

Molecules 2003, 8
750
N-Arylidene-4-aryl-1,3-diphenylpyrazole-5-carbohydrazides (9a-g).
General Procedure A: To a solution of each of compounds 8a,b (1 mmol) in either acetic acid (12 mL)
or n-butanol (20 mL) was added the appropriate aryl aldehyde (1 mmol) and the reaction mixture was
then heated under reflux for a time as shown as in Table 1. The crystalline colorless precipitates of
compounds 9a-d,f were collected by filtration, washed with methanol, and recrystallized from the
appropriate solvent. Pure 9e,g were obtained from their reaction mixtures via dilution with water,
collection of the formed precipitate by filtration, and recrystallization from the appropriate solvent.
Table 1
9
a
b
c
d
e
f
Reaction Solvent Reflux Time Recrystallization Solvent
n-Butanol
3 hours
EtOH
Acetic acid
Acetic acid
Acetic acid
Acetic acid
Acetic acid
Acetic acid
20 minutes
11/2 hour
11/2 hour
2 hours
n-Butanol
Acetic acid
Acetic acid
Ethanol
11/4 hour
2 hours
Ethanol
Ethanol
g
General Procedure B: To compound 8a (1 mmol) was added 4-methylbenzaldehyde (1 mmol) and 3
drops of piperidene. The reaction mixture was then heated (oil bath) at 120 ºC till complete dissolution
which was followed by an immediate resolidification. The reaction mixture was allowed to cool to
room temperature, diluted with methanol, and the formed colorless crystalline product was collected
by filtration and recrystallized from ethanol giving colorless crystals of 9c, identical with the product
9c obtained from general procedure A (mp. and mixed mp. as well as analytical and spectral data).
N-Benzylidene-1,3,4-triphenylpyrazole-5-carbohydrazide (9a). Using general procedure A, 8a gave 9a
(34%); mp. 229-230ºC; IR (cm-1): 3584-3291 (OH str. of hydrazole tautomer), 3213 (NH str.), 3066,
3028 (aromatic CH str.), 1674 (hydrazide C=O str.) 1655 (C=N str.), 1597 (aromatic C=C str.), 1556,
1500 (NH bend.), 1365, 1313, 1275, 1246 (C-N str.), 760, 692 (aromatic CH bend.); 1H-NMR (CDCl3)
δ 10.03, 8.43 [ 2brs,1H (exch.), hydrazide (53.7%) - hydrazole (46.3%) tautomeric proton], 7.73-7.07
(m, 21H, ArH's, N=CH); Ms m/z 442 (M+, 13.7%); Anal. for C29H22N4O Calcd.: C, 78.71; H, 5.01; N,
12.66. Found: C, 78.80; H, 5.20; N, 12.80.
N-(2-Hydroxybenzylidene)-1,3,4-triphenylpyrazole-5-carbohydrazide (9b). Using general procedure A,
8a gave 9b (88%); mp.283-285ºC; IR (cm-1): 3200-2500 (OH str.), 3178 (NH str.), 3055, 3007
(aromatic CH str.), 1722 (hydrazide C=O str.), 1651(C=N str.), 1601 (aromatic C=C str.), 1545, 1499
(NH bend.), 1367, 1331, 1313, 1292, 1277, 1250, 1186, 1184, 1149 [C-N, C-O (phenolic) str.], 758,

Molecules 2003, 8
751
692 (aromatic CH bend.); 1H-NMR (DMSO-d6) δ 12.36 [s, 1H (exch.), 2-(OH)-C6H4] 10.70, 9.96 [2s,
1H (exch.), hydrazide (63.3%) - hydrazole (36.7%) tautomeric proton], 8.30 (s, 1H, N=CH), 7.72-6.73
(m, 19H, ArH's); Anal. for C29H22N4O2 Calcd.: C, 75.97; H, 4.83; N, 12.22. Found: C, 76.00; H, 4.76;
N, 12.00.
N-(4-Methylbenzylidene)-1,3,4-triphenylpyrazole-5-carbohydrazide (9c). Using the general procedures
A and/or B, 8a gave 9c (67%) and / or (70%), respectively; mp. 222-223ºC; IR (cm-1): 3342-2400 (OH
str. of hydrazole tautomer), 3197 (NH str.), 3052, 3000 (aromatic CH str.), 2947, 2919 (CH str. of
CH3), 1672 (hydrazide C=O str.) 1653 (C=N str.), 1603 (aromatic C=C str.), 1564, 1500 (NH bend.),
1372, 1335, 1322, 1311, 1292, 1279, 1256, 1211-1027 [C-O (of hydrazole tautomer), C-N str.],
1
765,757, 702, 684 (aromatic CH bend.); H-NMR (CDCl3) δ 10.45, 8.50 [2s, 1H (exch.), hydrazide
(61.0%) - hydrazole (39.0%) tautomeric proton], 7.65-7.08 (m, 20H, ArH's, N=CH), 2.33 (s, 3H, CH3);
MS m/z 456 (M+, 12.0%); Anal. for C30H24N4O Calcd.: C, 78.92; H, 5.30; N, 12.27. Found: C, 78.90;
H, 5.40; N, 12.40.
N-(4-Methoxybenzylidene)-1,3,4-triphenylpyrazole-5-carbohydrazide (9d). Using general procedure A,
8a gave 9d (83%); mp. 245-247ºC; IR (cm-1): 3713-2555 (OH str.of hydrazole tautomer), 3194 (NH
str.), 3055, 3006 (aromatic CH str.), 2967, 2927, 2838 (CH str. of OCH3), 1673 (hydrazide C=O str.),
1651 (C=N str.), 1604 (aromatic C=C str.), 1565, 1506 (NH bend.), 1369, 1306, 1251, 1172-1028 [C-
1
O, C-N str.), 762,701 (aromatic CH bend.); H-NMR (CDCl3) δ 9.93, 8.40 [2s, 1H (exch.), hydrazide
(52.2%) - hydrazole (47.8%) tautomeric proton], 7.69-6.83 (m, 20H, ArH's, N=CH), 3.84 (s, 3H,
OCH3); Anal. for C30H24N4O2 Calcd.: C, 76.25; H, 5.12; N, 11.86. Found: C, 76.40; H, 5.08; N, 12.00.
N-Benzylidene-1,3-diphenyl-4-(2-methoxyphenyl)-pyrazole-5-carbohydrazide (9e). Using general
procedure A, 8b gave 9e (80%); mp. 175-176ºC; IR (cm-1): 3200-2500 (OH str. of hydrazole
tautomer), 3196 (NH str.), 3067 (aromatic CH str.), 2987, 2930, 2856 (CH str. of OCH3), 1670
(hydrazide C=O str.) 1651 (C=N str.), 1612, 1595 (aromatic C=C str.), 1556, 1499 (NH bend.), 1364,
1
1273,1242-1074 (C-O, C-N str.), 760, 700, 692 (aromatic CH bend.); H-NMR (CDCl3) δ 9.83, 9.43
[2s, 1H (exch.), hydrazide (27.8%) - hydrazole (72.2%) tautomeric proton], 7.72-6.95 (m, 20H, ArH's,
N=CH), 3.85 (s, 3H, OCH3); Anal. for C30H24N4O2 Calcd.: C, 76.25; H, 5.12; N, 11.86. Found: C,
76.40; H, 5.10; N, 11.60.
N-(2-Hydroxybenzylidene)-1,3-diphenyl-4-(2-methoxyphenyl)-pyrazole-5-carbohydrazide (9f). Using
1
general procedure A, 8b gave 9f (81%); mp. 207-208ºC; H-NMR (CDCl3): δ 10.69 [s, 1H (exch.),
OH], 9.37 [s, 1H (exch.), NH], 7.89 (s, 1H, N=CH), 7.67-6.84 (m, 18H, ArH's), 3.84 (s, 3H, OCH3);
Anal. for C30H24N4O3 Calcd.: C, 73.75; H, 4.95; N, 11.47. Found: C, 73.80; H, 5.00; N, 11.62.
N-(4-Methoxybenzylidene)-1,3-diphenyl-4-(2-methoxyphenyl)-pyrazole-5-carbohydrazide (9g). Using
general procedure A, 8b gave 9g (85%); mp. 178-180ºC; IR (cm-1): 3645-3266 (OH str. of hydrazole

Molecules 2003, 8
752
tautomer), 3175 (NH str.), 3068, 3005 (aromatic CH str.), 2962, 2933, 2902, 2837(CH str. of OCH3),
1685 (hydrazide C=O str.) 1650 (C=N str.), 1603 (aromatic C=C str.), 1547, 1509 (NH bend.), 1366,
1307,1254 , 1170-1026 (C-O, C-N str.) 758, 694 (aromatic CH bend.); 1H-NMR (CDCl3): δ 9.74, 9.34
[2s,1H (exch.), hydrazide (25.0%) - hydrazole (75.0%) tautomeric proton], 7.72-6.86 (m, 19H, ArH's,
N=CH), 3.83(s, 6H, OCH3); Anal. for C31H26N4O3 Calcd.: C, 74.08; H, 5.21; N, 11.15. Found: C,
74.12; H, 5.10; N, 11.60.
N-Acetyl-1,3,4-triphenylpyrazole-5-carbohydrazide (10). To compound 8a (1 mmol) was added acetic
acid (15 mL) and the reaction mixture was heated under reflux for 11/4 hour. After cooling, the reaction
mixture was poured onto water and the formed precipitate was collected by filtration and recrystallized
from ethanol as colorless crystals of 10 (83%); mp. 237-238ºC; IR (cm-1): 3194 (NH str.), 3055, 3009
(aromatic CH str.), 2968, 2914, 2839 (CH str. of CH3), 1672 (C=O str.), 1651 (C=N str.), 1605
(aromatic C=C str.), 1564, 1512, 1500 (NH bend.), 1371, 1306, 1279, 1250 (C-N str.), 772, 768, 704,
1
690 (aromatic CH bend.); H-NMR (DMSO-d6): δ 10.76, 9.98 [2s, 2H (exch.), hydrazide NHNH],
7.97-7.26 (m, 15H, ArH's), 1.85 (s, 3H, CH3CO); Anal. for C24H20N4O2 Calcd.: C, 72.71; H, 5.08; N,
14.13. Found: C, 72.80; H, 5.10; N, 14.50.
2-(1,3,4-Triphenylpyrazol-5-yl)-5-phenyl-1,3,4-oxadiazole (11). A mixture of compound 8a (1 mmol),
benzoic acid (1 mmol), and phosphororus oxychloride (1 mmol) was heated under reflux for 11/2 hour.
After cooling to room temperature, the reaction mixture was poured onto crushed ice, stirred, decanted
and diluted with water. The residue obtained after a second decantation was boiled with methanol. The
solidified residue obtained on cooling was collected by filtration and recrystallized from N,N-
1
dimethylformamide as colorless crystals of 11 (23%); mp.185ºC; H-NMR (DMSO-d6): δ 7.69-7.34
(m, ArH's); MS m/z 440 (M+, 49.9); Anal. for C29H20N4O Calcd.: C, 79.07; H, 4.57; N, 12.72. Found:
C, 79.10; H, 4.62; N, 12.69.
General procedure for the preparation of 2-(4-Aryl-5-benzoylamino-1,3-diphenyl-2-pyrazolin-5-yl)-
1,3,4-oxadiazole-5(4H)-thiones (12a,b). To a solution containing 95% ethanol (5 mL) and potassium
hydroxide (1 mmol, dissolved in the least amount of water), were added compounds 8a,b (1 mmol)
followed by carbon disulfide (1.5 mmol). The reaction mixture was heated under reflux for 3 hours till
all the evolution of hydrogen sulfide ceased. After decantation, the supernatant solution was
evaporated, diluted with water (while a milky solution was obtained), and acidified with hydrochloric
acid containing ice. The reaction mixture was allowed to stand at room temperature for 15 minutes,
filtered, and the solid obtained was washed well with water and dried at room temperature. The crude
products were then recrystallized from ethanol as colorless crystals of 12a,b.
2-(5-Benzoylamino-1,3,4-triphenyl-2-pyrazolin-5-yl)-1,3,4-oxadiazole-5(4H)-thione (12a). Using the
general procedure, 8a gave 12a (81%); mp. 236-237ºC; IR (cm-1): 3421, 3157 (NH str.), 3063, 3030
(aromatic CH str.), 2945, 2926, 2852 (pyrazolinyl CH str.), 1683 (amide C=O str.), 1600 (aromatic

Molecules 2003, 8
753
C=C str.), 1507, 1489, 1469 (NH bend.), 1331, 1286, 1255 (C-N str.), 1199, 1153,1019 (=C-O-C=
1
str.), 1064 (C=S str.), 761, 649 (aromatic CH bend.); H-NMR (DMSO-d6): δ 14.60 [brs, 1H (exch.),
oxadiazolyl NH], 9.85 [s, 1H (exch.), amide NH], 7.83-7.10 (m, 20H, ArH's), 5.90 (s, 1H, pyrazolinyl
CH); Anal. for C30H23N5O2S Calcd.: C, 69.61; H, 4.48; N, 13.53; S,6.19. Found: C, 69.50; H, 4.50; N,
13.59; S, 6.15.
2-[5-Benzoylamino-1,3,-diphenyl-4-(2-methoxyphenyl)-2-pyrazolin-5-yl]-1,3,4-oxadiazole-5(4H)-
thione (12b). Using the general procedure, 8b gave 12b (81%); mp. 140ºC; IR ((cm-1): 3375, 3139
(NH str.), 3067 (aromatic CH str.), 2938, 2836 (OCH3 and pyrazolinyl aliphatic CH str.), 1682 (amide
C=O str.), 1602 (aromatic C=C str.), 1498, 1470, 1446 (NH bend.), 1343, 1328, 1293, 1253 (C-N str.),
1190, 1149, 1106, 1027 (=C-O-C= str., C-O str. of OCH3), 1069 (C=S str.), 759, 699 (aromatic CH
1
bend.); H-NMR (DMSO-d6): δ 14.52 [brs, 1H (exch.), oxadiazolyl NH], 9.69 [s, 1H (exch.), amide
NH], 7.78-6.78 (m,19H, ArH's), 6.32 (s, 1H, pyrazolinyl CH), 3.85 (s, 3H, OCH3); Anal. for
C31H25N5O3S Calcd.: C, 67.99; H, 4.60; N, 12.79; S,5.85. Found: C, 68.12 H, 4.62; N, 12.69; S,5.82.
N-(N-Phenylthiocarbamoyl)-5-benzoylamino-1,3-diphenyl-4-(2-methoxyphenyl)-2-pyrazoline-5-carbo-
hydrazide (13). To a suspension of 8b (1 mmol) in absolute ethanol (25 mL) was added phenyl
isothiocyanate (1.01 mmol), and the mixture was heated under reflux for 21/2 hours (all materials went
into solution after 45 minutes of heating under reflux). The reaction mixture was concentrated, allowed
to cool, and upon scratching, the product precipitated as colorless crystals. The crude product was
collected by filtration and recrystallized from ethanol as colorless crystals of 13 (75%) mp.145-146ºC;
IR (cm-1): 3371, 3327, 3150, 3110 (NH str.), 3059,3029 (aromatic CH str.), 2964, 2923, 2880, 2842
(OCH3 and pyrazolinyl aliphatic CH str.), 1718 (hydrazide C=O str.), 1678 (amide C=O str.), 1651,
1625 (C=N str.), 1599 (aromatic C=C str.), 1543,1497, 1473, 1442 (NH bend.), 1380, 1357, 1320,
1291, 1252 (C-N str.), 1210-1025 (C-O str.), 1070 (C=S str.), 758, 692 (aromatic CH bend.); 1H-NMR
(DMSO-d6): δ 10.79, 9.92, 9.34, 9.15 [3s, 1brs, 4H (exch.), 4NH], 7.80-6.55 (m, 24H, ArH's), 6.23 (s,
1H, pyrazolinyl CH), 3.76 (s, 3H, OCH3); Anal. for C37H32N6O3S Calcd.: C, 69.35; H, 5.03; N, 13.11;
S, 5.04. Found: C, 69.1, H, 5.30; N, 13.00; S, 5.10
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