Synthesis and biological activity of some new pyrazoline and pyrrolo[3,4-c]pyrazole-4,6-dione derivatives: Reaction of nitrilimines with some dipolarophiles

Article abstract of DOI:10.3390/molecules13041011

Several 1,3-diaryl-5-(cyano-, aminocarbonyl- and ethoxycarbonyl-)-2- pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione and 1,3,4,5-tetraaryl-2-pyrazoline derivatives were prepared by the reaction of nitrilimine with different dipolarophilic reagents. The new c

Full text of DOI:10.3390/molecules13041011

Molecules 2008, 13, 1011-1024
molecules
ISSN 1420-3049
© 2008 by MDPI
www.mdpi.org/molecules
Full Paper
Synthesis and Biological Activity of Some New Pyrazoline and
Pyrrolo[3,4-c]pyrazole-4,6-dione Derivatives: Reaction of
Nitrilimines with Some Dipolarophiles
Nada M. Abunada 1,*, Hamdi M. Hassaneen 2, Nadia G. Kandile 3 and Omar A. Miqdad 1
1 Department of Chemistry, Faculty of Applied Sciences, Al-Aqsa University, 76888 Gaza, Palestine;
E-mail: miqdadomar@hotmail.com (O. A. Miqdad)
2
Department of Chemistry, Faculty of Science, Cairo University, Egypt; E-mail:
hamdi_251@yahoo.com (H. M. Hassaneen)
3 Department of Chemistry, University College for Women, Ain Shams University, Heliopolis, Cairo,
Egypt; E-mail: nadiaghk@yahoo.com (N. G. Kandile)
*Author to whom correspondence should be addressed; E-mail: nadanadannrs@yahoo.com.
Received: 8 April 2008; in revised form: 22 April 2008 / Accepted: 22 April 2008 / Published: 29 April
2008
Abstract: Several 1,3-diaryl-5-(cyano-, aminocarbonyl- and ethoxycarbonyl-)-2-
pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione and 1,3,4,5-tetraaryl-2-pyrazoline derivatives
were prepared by the reaction of nitrilimine with different dipolarophilic reagents. The new
compounds were characterized using IR, 1H-NMR, 13C-NMR and mass spectra. Biological
screening of some compounds is reported.
Keywords: Pyrazoline, pyrrolo[3,4-c]pyrazole-4,6-dione, nitrilimine, dipolarophile,
biological activity.
Introduction
Considerable attention has been focused on pyrazolines and substituted pyrazolines due to their
interesting biological activities. They have found to possess antifungal [1], antidepressant [2-5]
anticonvulsant [4,5], anti-inflammatory [6], antibacterial [7] and anti-tumor [8] properties. Moreover,

Molecules 2008, 13
1012
many selectively fluoro-substituted organic compounds show peculiar pharmacological and agro-
chemical properties [9-14]. Several methods are employed in the synthesis of pyrazolines, including
the condensation of chalcones with hydrazine, hydrazine derivatives [15-19] and thiosemicarbazide
[20] under acidic [15,16] or basic [20] conditions, and the cycloaddition of nitrilimines, generated in
situ from the corresponding hydrazonoyl halides by the action of a suitable base, to carbon-carbon
double bonds of a suitable dipolarophile [21-24]. As a connection of our interest in the preparation of
heterocyclic compounds from hydrazonoyl halides [21-27] and the above-mentioned findings, the
work reported herein was aimed at the preparation of some new pyrazoline derivatives with anticipated
biological activities.
Results and Discussion
The reactivity of the nitrilimines 2a,b, generated in situ by base catalyzed elimination of hydrogen
bromide from hydrazonoyl bromides 1a,b, with various mono-, di- and tri-substituted dipolarophiles
was examined. Thus, heating of equimolar amounts of 1a,b and each of acrylonitrile, acrylamide or
ethyl acrylate in dry benzene in the presence of triethylamine gave exclusively 3-aryl-1-(4-
nitrophenyl)-5-substituted-2-pyrazolines 3a,b-5a,b, respectively, in good yields (Scheme 1).
Scheme 1.
_
+
Br
TEA
-HBr
N
Ar
+
H2C
C R
Ar'
Ar
Ar
N
H
N
NHAr'
2a,b
1a,b
Ar, a, 4-FC6H4; b, 2,4-Cl2C6H3;
Ar', 4-NO2C6H4
N
R
N
R; 3, -CN; 4, -CONH2; 5, -COOEt
Ar'
3a,b-5a,b
The assigned 5-substituted-2-pyrazoline structures 3-5 were supported by elemental analyses and
spectroscopic data (see Experimental). The chemical shifts of the methine and methylene hydrogens in
1
the H-NMR spectra of 3-5 compared favorably with those reported for the corresponding protons in
1-aryl-3-(2-naphthoyl)-5-substituted-2-pyrazolines [21]. Such similarity, while confirming the
assigned structures, indicates that both substituents, the 4-fluorophenyl- and 2,4-dichlorophenyl-, have
similar effects on the chemical shifts of the methylene protons at C-4 of substituted 2-pyrazoline
derivatives, compared with the 2-naphthoyl- group. The structures of 3a,b were also confirmed by the
absence of the nitrile absorption in the IR spectra, as observed in the case of aliphatic nitriles activated
by a nitrogen or an oxygen atom in the β-position [28,29]. The IR spectra of 4a,b showed the C=O
amide absorption band at υ 1680 cm-1 and NH2 absorption bands at υ 3420 and 3300 cm-1. The IR of
5a,b exhibited an ester carbonyl absorption band near υ 1730 cm-1. The 13C-NMR spectrum of 5b
displays the characteristic signals of the suggested structure. The signal for the carbonyl carbon of

Molecules 2008, 13
1013
ester group appears at δ 169.4 ppm, the signals for pyrazoline C-4 at δ 39.9, pyrazoline C-5 at δ 59.9,
the ester group methylene carbon at δ 61.6 and ester group methyl carbon at δ 13.8 ppm (see Figure 1
for the carbon numbering).
Figure 1.
4
3
2
N
5
1 N
Treatment of each of the hydrazonoyl bromides 1a and 1b with N-arylmaleimides 6a-g in refluxing
chloroform in the presence of triethylamine gave the corresponding cycloadducts 7a-n, respectively
(Scheme 2).
Scheme 2.
O
O
H
Ar
_
C6H4R
+
N
N
N
C6H4R
Ar
N
+
Ar'
N
N
O
H
O
6a-g
Ar'
2a,b
7a-n
Ar \ R
Ar \ R
Ar \ R
7a
7b
7c
7d
7e
a \ H
b \ H
a \ p-CH3
b \ p-CH3
a \ p-F
7k
7l
7m
7n
a \ p-NO2
b \ p-NO2
a \ p-C2H5
b \ p-C2H5
7f
b \ p-F
a \ p-Cl
b \ p-Cl
a \ p-Br
b \ p-Br
7g
7h
7i
7j
Ar = a, 4-FC6H4; b, 2,4-Cl2C6H3; Ar' = 4-NO2C6H4
The structure of the latter products was elucidated on the basis of their elemental analyses and the
study of their spectroscopic data (see Experimental). The IR spectra of products 7 exhibit characteristic
1
bands near υ 1720 cm-1, assignable to a carbonyl group. The H-NMR spectra of all compounds
showed, in each case, two doublets near δ 5.5 and 5.8 ppm, assignable to the protons at C-3a and C-6a,
respectively. The vicinal coupling constants have been shown to be diagnostic, Jtrans < (6 Hz), Jcis (9-12
Hz) [30,31], so the observed values of the coupling constants (J = 10.0-11.5 Hz) are compatible with
the expected cis-configuration. On the basis of these spectroscopic data, the products 7a-n were
assigned
3a,4,6,6a-tetrahydro-3,5-diaryl-1-(4-nitrophenyl)-1H,5H-pyrrolo[3,4-c]pyrazole-4,6-dione
13
structures. The C-NMR spectrum of 7m exhibited two signals at δ 171.49 and 170.59 for the two
amide carbonyl carbons. The signals at δ 66.54, 53.81, 27.33 and 14.78 are assignable to C-5
pyrazoline, C-4 pyrazoline (Figure 1) and the methylene and methyl carbons of the ethyl group
respectively. The mass spectra of all prepared compounds 7a-n displayed the correct molecular ion

Molecules 2008, 13
1014
peaks. All molecular ion fragments seem to go through similar fragmentation pattern since the
products with Ar = 4-FC6H4 show the same fragment signals at M+, 310, 283, 237 and the products
with Ar = 2,4-Cl2C6H3 show the same fragments at M+, 360, 333, 352. The fragmentation pattern of
compounds 7 are shown in Scheme 3.
Scheme 3.
.+
O
N Ar'
H
Ar
N
-ArNCOH
H
N
H
O
.+
Ar
.+
Ar'NCO
C=O
NO2
N
N
m/z, 7a, 7b, 119
m/z, 7c, 7d, 133
m/z, 7e, 7f, 153
m/z, 7g, 7h, 197
m/z, 7i, 7j, 137
m/z, 7a, 430, 7b, 480
m/z, 7c, 444, 7d, 494
m/z, 7e, 464, 7f, 514
m/z, 7g, 508, 7h, 558
m/z, 7i, 448, 7j, 498
m/z, 7k, 475, 7l, 525
NO2
m/z, 7a,c,e,g,i,k,m, 310,
7b,d,f,h,j,l,n, 360
m/z, 7m, 458, 7n, 508
+
.+
-NO2, -Cl
Ar
CH
CH
N
CH
CH
Cl
+
N
-CO, +H
Ar
N
CH
N
-NO2
CH
N
N
NO2
m/z, 7a,c,e,g,i,k,m, 283,
7b,d,f,h,j,l,n, 333
m/z, 7b,d,f,h,j,l,n, 252
m/z, 7a,c,e,g,i,k,m, 237,
7b,n, 287
Also, treatment of the hydrazonoyl bromides 1a,b with the appropriate α,β-unsatruated ketones 8a-c
in benzene in the presence of triethylamine afforded, in each case, one regioisomer, as evidenced by
TLC analysis. The structures of the products obtained were identified as 9a-f respectively (Scheme 4).
The structures of compounds 9 were assigned on the basis of their elemental analyses and
spectroscopic data (see Experimental). The 1H-NMR spectra of 9 were characterized, in each case, by
the presence of two doublets (J = 3.6-6.0 Hz) near δ 5.2 and 6.5 ppm, assignable to the protons at C-4
and C-5 of the pyrazoline ring respectively [32].

Molecules 2008, 13
1015
Scheme 4
_
+
YC6H4COCH=CHC6H4X
N
+
Ar'
Ar
N
8a-c
2a,b
C6H4X
H
Ar
Ar \Y \ X
COC6H4Y
9a a \ H \ H
9b b \ H \ H
9c a \ H \ p-Cl
9d b \ H \ p-Cl
9e a \ p-Br \ H
N
N
H
Ar'
9a-f
9f
b \ p-Br \ H
Ar = a, 4-FC6H4; b, 2,4-Cl2C6H3; Ar' = 4-NO2C6H4
On the basis of the coupling constant values [30,31], the cycloadducts 9 were assigned the trans-
configuration. The 13C-NMR spectra of compounds 9b and 9f revealed characteristic signals at δ
192.32 (191.71), 150.30 (150.29), 70.71 (70.63) and 56.54 (56.29) ppm, assignable to C=O, C=N, C-5
pyrazoline and C-4 pyrazoline, respectively. Also, the mass spectra of compounds 9 displayed
molecular ion peaks in accordance with the suggested structures. The base peaks occur from
elimination of benzoyl or bromobenzoyl at M+-105 or M+-183 respectively. Consequent loss of NO2
gives fragments at M+-(105+46) or M+-(183+46), respectively. Other characteristic fragments resulting
from cleavage β- to the carbonyl group also appeared at 105 or 183.
Antimicrobial activity
Four of the newly synthesized compounds were screened for their antibacterial activity against the
Gram –ve bacteria Escherchia coli and the Gram +ve bacteria Staphylococcus aureus, in addition to
their antifungal activity against Asperagillus flavus and Candida albicans using the agar diffusion
method [33,34] at a concentration 20 mg/mL using DMSO as a solvent. The results, recorded as
average diameter of inhibition zone in mm, are given in Table I.
Table 1. Antimicrobial screening results of the tested compounds*.
Comp. No. E. coli S. aureus A. flavus C. albicans
3a
7i
11
11
11
12
32
--
11
11
11
12
34
--
0.0
0.0
0.0
0.0
--
11
10
10
10
--
7n
9c
Tetracycline
Flucoral
Amphotricine
14
16
16
20
--
--
* Zone of inhibition in mm

Molecules 2008, 13
1016
Experimental
General
All melting points were measured on an Electrothermal melting point apparatus and are
uncorrected. The infrared spectra were recorded in potassium bromide disks on a Pye Unicam SP
1
13
3-300 or a Shimadzu FT-IR 8101 PC infrared spectrophotometer. The H-NMR (200 MHz) and C-
NMR (50 MHz) spectra were recorded in DMSO-d6 on a Varian Mercury VX 200 NMR using TMS as
the internal reference. Mass spectra were measured on a GCMS-QP 1000 EX spectrometer at 70 eV.
Elemental analyses were carried out at the Microanalytical Centre of Cairo University, Giza, Egypt.
Compounds 1a [35] and 1b [36] were prepared according to the methods reported in the literature.
Synthesis of 1,3,5-trisubstituted-2-pyrazoline derivatives 3a,b-5a,b
To a solution of hydrazonoyl bromides 1a,b (0.005 mol) and the appropriate monosubstituted
olefin (acrylonitrile, acrylamide and ethyl acrylate, 0.005 mol) in chloroform (50 mL) was added
triethylamine (0.7 mL, 0.005 mol) at room temperature. The mixture was refluxed for 4-6 h and then
cooled. The mixture was extracted with water and the organic layer was collected, dried (anhydrous
sodium sulfate) and then filtered. The solvent was evaporated and the residue was triturated with
methanol whereupon it solidified. The solid was collected and recrystallized from the indicated
solvents to give the corresponding cycloadducts 3-5 in good yield.
5-Cyano-3-(4-fluorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (3a). Yellowish brown solid; mp. 222-4 oC
(from acetic acid); yield 73 %; IR: ν/cm-1 3083.3 (CH-aromatic), 1596.5 (C=N); MS, m/z: 310 (M+,
60.4), 284 (50.8), 283 (100.0), 236 (17.4), 133 (12.4), 95 (21.6), 90 (27.1), 75 (25.7), 63 (33.2), 50
1
(25.1); H-NMR: δ/ppm 3.79-3.94 (dd, 1H, J = 18.0, 12.0 Hz), 3.96-4.07 (dd, 1H, J = 18.0, 6.0 Hz),
5.86-5.94 (dd, 1H, J = 12.0, 6.0 Hz), 7.29-8.27 (m, 8H, ArH's); Anal. Calcd. for C16H11FN4O2: C,
61.93; H, 3.57; N, 18.05; Found: C, 61.81; H, 3.63; N, 17.97.
o
5-Cyano-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (3b). Yellow solid; mp. 164-6 C
(from dioxane-ethanol); yield 63 %; IR: ν/cm-1 3091.3 (CH-aromatic), 1595.8 (C=N); MS, m/z: 362
(m++2, 27.8), 360 (M+, 45.3), 333 (78.5), 335 (37.9), 287 (14.7), 252 (23.3), 190 (10.0), 171 (18.1),
136 (20.7), 116 (32.5), 90 (63.8), 75 (59.9), 63 (100.0), 50 (74.6); 1H-NMR: δ/ppm 4.03 (d, 2H, J = 8.0
Hz), 5.94 (t, 1H, J = 8.0 Hz), 7.38-8.33 (m, 7 H, ArH's); Anal. Calcd. for C16H10Cl2N4O2: C, 53.20; H,
2.79; N, 15.51; Cl, 19.63; Found: C, 53.15; H, 2.87; N, 15.42; Cl, 19.60.
5-Aminocarbonyl-3-(4-fluorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (4a). Orange yellow solid; mp.
301-3 oC (from dioxane); yield 54 %; IR: ν/cm-1 3423.6, 3304.8 (NH2), 3185.3, 3078.3 (CH-aromatic),
1683.4 (C=O amide), 1598.2 (C=N); MS, m/z: 328 (M+, 11.3), 284 (100.0), 238 (56.6), 90 (12.9), 76
1
(16.3), 50 (14.9); H-NMR: δ/ppm 3.44-3.58 (dd, 1H, J = 17.4, 6.0 Hz), 3.76-3.91 (dd, 1H, J = 17.4,
12.4 Hz), 4.93-5.02 (dd, 1H, J = 12.4, 6.0 Hz), 7.06-8.19 (m, 10 H, ArH's, NH2); Anal. Calcd. for
C16H13FN4O3: C, 58.53; H, 3.99; N, 17.06; Found: C, 58.56; H, 3.87; N, 16.89.

Molecules 2008, 13
1017
5-Aminocarbonyl-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (4b). Orange yellow solid;
mp. 257-9 oC (from dioxane); yield 53 %; IR: ν/cm-1 3420.5, 3313.9 (NH2), 3074.8 (CH-aromatic),
1683.8 (C=O amide), 1595.1 (C=N); MS, m/z: 380 (M++2, 7.2), 378 (M+, 9.8), 336 (67.5), 334
1
(100.0), 290 (29.5), 288 (48.1), 90 (11.8), 76 (12.8), 63 (10.3), 50 (10.6); H-NMR: δ/ppm 3.44-3.57
(dd, 1H, J = 6.6, 18.4 Hz), 3.88-4.03 (dd, 1H, J = 18.4, 12.6 Hz), 4.94-5.04 (dd, 1H, J = 12.6, 6.6 Hz),
7.07-8.21 (m, 9H, ArH's, NH2); Anal. Calcd. for C16H12N4O3Cl2: C, 50.67; H, 3.18; N, 14.77; Cl,
18.69; Found: C, 50.66; H, 3.20; N, 14.78; Cl, 18.69.
5-Ethoxycarbonyl-3-(4-fluorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (5a). Yellow solid; mp. 184-6 oC
(from benzene); yield 58 %; IR: ν/cm-1 3071.9 (CH-aromatic), 2977.1, 2935.3 (CH-aliphatic), 1733.2
(C=O ester), 1593.4 (C=N); MS, m/z: 357 (M+, 18.7), 284 (100.0), 238 (57.4), 90 (10.2), 75 (12.6), 50
1
(7.4); H-NMR: δ/ppm 1.21 (t, 3H, J = 7.4 Hz, COOCH2CH3), 3.60-3.71 (dd, 1H, J = 18.2, 5.0 Hz),
3.82-3.97 (dd, 1H, J = 18.2, 12.4 Hz), 4.13-4.24 (q, 2H, J = 7.4 Hz, COOCH2CH3), 5.32-5.41 (dd, 1H,
J = 12.4, 5.0 Hz), 7.12-8.20 (m, 8H, ArH's); Anal. Calcd. for C18H16FN3O4: C, 60.49; H, 4.51; N,
11.75; Found: C, 60.52; H, 4.41; N, 11.64.
5-Ethoxycarbonyl-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl) -2-pyrazoline (5b). Orange yellow solid;
o
mp. 130-2 C (from acetic acid); yield 74 %; IR: ν/cm-1 3074.9 (CH-aromatic), 2997.8, 2980.4 (CH-
aliphatic), 1728.8 (C=O ester), 1594.8 (C=N); MS, m/z: 409 (M++2, 10.8), 407 (M+, 16.2), 335
1
(100.0), 334 (92.9), 289 (45.7), 288 (50.9), 117 (10.7), 90 (23.9), 76 (25.2), 63 (22.2), 50 (20.1); H-
NMR: δ/ppm 1.21 (t, 3H, J = 7.1 Hz, COOCH2CH3), 3.67-3.78 (dd, 1H, J = 18.0, 4.6 Hz), 3.94-4.09
(dd, 1H, J = 18.0, 12.8 Hz), 4.17-4.24 (q, 2H, J = 7.1 Hz, COOCH2CH3), 5.35-5.44 (dd, 1H, J = 12.8,
13
4.6 Hz), 7.14-8.21 (m, 7H, ArH's); C-NMR: δ/ppm 169.48 (C=O), 149.76 , 148.34 (C=N, C-NO2),
139.01, 134.60, 132.35, 131.85 (4C, ArC's), 130.47, 128.40, 127.63, 125.75, 112.28 (5C, ArCH's),
61.67 (CH2, ester), 59.93 (C-5, pyrazoline), 39.95 (C-4, pyrazoline), 13.86 (CH3); Anal. Calcd. for
C18H15Cl2N3O4: C, 52.95; H, 3.70; N, 10.29; Cl, 17.36; Found: C, 52.93; H, 3.62; N, 10.18; Cl, 17.29.
Synthesis of 3,5-diaryl-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]pyrazole-4,6-
dione derivatives 7a-n
Triethylamine (0.7 mL, 0.005 mol) was added to a solution of hydrazonoyl bromides 1a,b (0.005
mol) and the N-arylmaleimides 6a-g (0.005 mol) in benzene (50 mL). The mixture was refluxed for 2
h. The solid product was filtered off and washed with boiling ethanol (10 mL), then recrystallized from
the indicated solvents to give 7a-n.
3-(4-Fluorophenyl)-1-(4-nitrophenyl)-5-phenyl-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]pyrazole-
o
4,6-dione (7a). Yellow crystals; mp. 278-80 C (from dimethylformamide); yield 91 %; IR: ν/cm-1
3065.3 (CH-aromatic), 1721.0 (C=O), 1595.3 (C=N); MS, m/z: 430 (M+, 100.0), 310 (20.2), 283
(54.1), 237 (19.3), 237 (19.3), 119 (23.5), 91 (24.1), 63 (22.9), 50 (12.4); 1H-NMR: δ/ppm 5.46 (d, 1H,
J = 10.3 Hz), 5.83 (d, 1H, J = 10.3 Hz), 7.20-8.28 (m, 13H, ArH's); Anal. Calcd. for C23H15FN4O4: C,
64.18; H, 3.51; N, 13.01; Found: C, 63.99; H, 3.48; N, 12.98.

Molecules 2008, 13
1018
3-(2,4-Dichlorophenyl)-1-(4-nitrophenyl)-5-phenyl-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]-
pyrazole-4,6-dione (7b). Yellow crystals; mp. 206-7 oC (from toluene-ethanol); yield 94 %; IR: ν/cm-1
3072.0 (CH-aromatic), 1719.2 (C=O), 1594.8 (C=N); MS, m/z: 484 (M++4, 16.8), 482 (M++2, 68.6),
480 (M+, 100.0), 364 (5.2), 362 (20.6), 360 (33.0), 337 (13.6), 335 (60.9), 333 (74.8), 287 (15.1), 252
(29.9), 216 (13.2), 173 (14.9), 119 (49.8), 90 (79.4), 91 (68.2), 76 (51.0), 75 (48.0), 64 (65.6), 63
1
(89.6), 51 (33.7), 50 (42.2); H-NMR: δ/ppm 5.52 (d, 1H, J = 10.2 Hz), 5.86 (d, 1H, J = 10.2 Hz),
7.15-8.28 (m, 12H, ArH's); Anal. Calcd. for C23H14Cl2N4O4: C, 57.39; H, 2.93; N, 11.64; Cl, 14.73;
Found: C, 57.48; H, 3.02; N, 11.71; Cl, 14.71.
3-(4-Fluorophenyl)-1-(4-nitrophenyl)-5-(4-methylphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-
c]pyrazole-4,6-dione (7c). Yellow crystals; mp. 304-6 oC (from dimethylformamide); yield 92 %; IR:
ν/cm-1 3066.2 (CH-aromatic), 2952.9 (CH-aliphatic), 1718.8 (C=O), 1595.2 (C=N); MS, m/z: 444 (M+,
100.0), 310 (16.5), 283 (62.3), 237 (14.1), 133 (29.7), 117 (14.0), 104 (17.7), 90 (18.9), 63 (17.7), 50
(12.2); 1H-NMR: δ/ppm 2.33 (s, 3H, CH3), 5.44 (d, 1H, J = 10.9 Hz), 5.81 (d, 1H, J = 10.9 Hz), 7.18-
8.28 (m, 12H, ArH's); Anal. Calcd. for C24H17FN4O4: C, 64.86; H, 3.85; N, 12.60; Found: C, 64.65; H,
3.79; N, 12.57.
3-(2,4-Dichlorophenyl)-1-(4-nitrophenyl)-5-(4-methylphenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo-
[3,4-c]pyrazole-4,6-dione (7d). Yellow crystals; mp. 275-7 oC (from dimethylformamide); yield 91 %;
IR: ν/cm-1 3089.4 (CH-aromatic), 2952.4 (CH-aliphatic), 1720.1 (C=O), 1593.8 (C=N); MS, m/z: 498
(M++4, 16.6), 496 (M++2, 63.5), 494 (M+, 100.0), 335 (51.6), 333 (71.0), 252 (20.4), 133 (86.3), 132
(63.5), 117 (36.2), 116 (37.3), 105 (27.8), 104 (52.4), 91 (36.6), 90 (53.6), 89 (33.5), 78 (37.6), 77
(47.0), 76 (39.9), 75 (29.7), 63 (61.2), 51 (31.6), 50 (35.2); 1H-NMR: δ/ppm 2.34 (s, 3H, CH3), 5.55 (d,
1H, J = 10.8 Hz), 5.86 (d, 1H, J = 10.8 Hz), 7.15-8.29 (m, 11H, ArH's); Anal. Calcd. for
C24H16Cl2N4O4: C, 58.19; H, 3.25; N, 11.31; Cl, 14.31; Found: C, 58.19; H, 3.34; N, 11.32; Cl, 14.28.
5-(4-Chlorophenyl)-3-(4-fluorophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]-
pyrazole-4,6-dione (7e). Dark yellow crystals; mp. 298-300 oC (from dimethylformamide); yield 94 %;
IR: ν/cm-1 3064.7 (CH-aromatic), 1721.4 (C=O), 1595.1 (C=N); MS, m/z: 464 (M+, 92.1), 310 (25.0),
1
283 (100.0), 237 (20.4), 153 (26.8), 90 (38.1), 63 (34.7), 50 (16.2); H-NMR: δ/ppm 5.43 (d, 1H, J =
10.6 Hz), 5.81 (d, 1H, J = 10.6 Hz), 7.32-8.27 (m, 12H, ArH's); Anal. Calcd. for C23H14ClFN4O4: C,
59.42; H, 3.03; N, 12.05; Found: C, 59.39; H, 3.07; N, 11.98.
5-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo-
o
[3,4-c]pyrazole-4,6-dione (7f). Yellow crystals; mp. 268-70 C (from dimethylformamide); yield 90
%; IR: ν/cm-1 3091.3 (CH-aromatic), 1719.2 (C=O), 1590.9 (C=N); MS, m/z: 520 (M++6, 6.3), 518
(M++4, 28.6), 516 (M++2, 92.1), 514 (M+, 100.0), 362 (20.9), 360 (27.6), 335 (49.8), 333 (80.6), 254
(8.0), 252 (24.0), 188 (11.9), 153 (53.4), 125 (57.0), 117 (25.9), 116 (31.3), 90 (74.6), 63 (72.5), 50
1
(32.8); H-NMR: δ/ppm 5.55 (d, 1H, J = 11.3 Hz), 5.87 (d, 1H, J = 11.3 Hz), 7.16-8.29 (m, 11H,
ArH's); Anal. Calcd. for C23H13Cl3N4O4: C, 53.56; H, 2.54; N, 10.86; Cl, 20.62; Found: C, 53.64; H,
2.57; N, 10.90; Cl, 20.57.

Molecules 2008, 13
1019
5-(4-Bromophenyl)-3-(4-fluorophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-
o
c]pyrazole-4,6-dione (7g). Yellow crystals; mp. 306-8 C (from dimethylformamide); yield 96 %; IR:
ν/cm-1 3084.3 (CH-aromatic), 1721.7 (C=O), 1594.8 (C=N); MS, m/z: 510 (M++2, 60.6), 508 (M+,
69.9), 310 (27.2), 283 (100.0), 237 (26.9), 197 (22.7), 133 (13.9), 116 (25.5), 90 (69.1), 63 (50.5), 50
1
(22.5); H-NMR: δ/ppm 5.45 (d, 1H, J = 10.8 Hz), 5.81 (d, 1H, J = 10.8 Hz), 7.31-8.27 (m, 12H,
ArH's); Anal. Calcd. for C23H14BrFN4O4: C, 54.24; H, 2.77; N, 11.00; Found: C, 54.15; H, 2.84; N,
10.97.
5-(4-Bromophenyl)-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo-
[3,4-c]pyrazole-4,6-dione (7h). Yellow crystals; mp. 283-5 oC (from dimethylformamide); yield 93 %;
IR: ν/cm-1 3085.5 (CH-aromatic), 1719.2 (C=O), 1590.9 (C=N); MS, m/z: 564 (M++6, 14.7), 562
(M++4, 43.2), 560 (M++2, 96.4), 558 (M+, 73.5), 362 (26.7), 360 (40.3), 335 (59.7), 333 (88.2), 252
(30.7), 197 (35.3), 171 (31.8), 116 (40.0), 90 (100.0), 76 (42.9), 63 (81.2), 50 (34.1); 1H-NMR: δ/ppm
5.56 (d, 1H, J = 10.3 Hz), 5.87 (d, 1H, J = 10.3 Hz), 7.15-8.28 (m, 11H, ArH's); Anal. Calcd. for
C23H13BrCl2N4O4: C, 49.31; H, 2.33; N, 10.00; Cl, 12.65; Found: C, 49.50; H, 2.38; N; 10.06; Cl,
12.59.
3,5-Di-(4-fluorophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]pyrazole-4,6-
o
dione (7i). Yellow crystals; mp. 292-4 C (from dimethylformamide); yield 96 %; IR: ν/cm-1 3076.5
(CH-aromatic), 1721.6 (C=O), 1595.3 (C=N); MS, m/z: 448 (M+, 100.0), 310 (23.5), 283 (60.5), 237
(21.2), 137 (28.6), 117 (13.1), 109 (40.8), 90 (26.3), 63 (28.1), 50 (20.6), 1H-NMR: δ/ppm 5.48 (d, 1H,
J = 10.9 Hz), 5.87 (d, 1H, J = 10.9 Hz), 7.32-8.27 (m, 12H, ArH's); Anal. Calcd. for C23H14F2N4O4: C,
61.60; H, 3.14; N, 12.49; Found: C, 61.52; H, 3.20; N, 12.51.
3-(2,4-Dichlorophenyl)-5-(4-flurophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-
o
c]pyrazole-4,6-dione (7j). Yellow crystals; mp. 244-6 C (from dimethylformamide); yield 92 %; IR:
ν/cm-1 3081.6 (CH-aromatic), 1718.2 (C=O), 1590.0 (C=N); MS, m/z: 502 (M++4, 15.1), 500 (M++2,
68.0), 498 (M+, 100.0), 362 (17.0), 360 (26.8), 335 (37.5), 333 (56.3), 254 (4.7), 252 (16.2), 137
(34.7), 109 (46.7), 75 (16.6), 63 (24.0), 50 (14.8); 1H-NMR: δ/ppm 5.54 (d, 1H, J = 11.0 Hz), 5.85 (d,
1H, J = 11.0 Hz), 7.17-8.30 (m, 11H, ArH's); Anal. Calcd. for C23H13Cl2FN4O4: C, 55.32; H, 2.62; N,
11.22; Cl, 14.20; Found: C, 55.41; H, 2.65; N, 11.34; Cl, 14.13.
3-(4-Fluorophenyl)-1,5-di-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]pyrazole-4,6-
dione (7k). Yellow crystals; mp. 308-10 oC (from dimethylformamide); yield 98 %; IR: ν/cm-1 3079.4
(CH-aromatic), 1725.2 (C=O), 1595.2 (C=N); MS, m/z: 475 (M+, 100.0), 310 (25.2), 283 (60.2), 237
(20.1), 188 (10.5), 134 (12.9), 133 (11.1), 116 (19.2), 90 (46.7), 63 (38.2), 50 (15.6); 1H-NMR: δ/ppm
5.57 (d, 1H, J = 11.2 Hz), 5.87 (d, 1H, J = 11.2 Hz), 7.16-8.29 (m, 12H, ArH's); Anal. Calcd. for
C23H14FN5O6: C, 58.10; H, 2.96; N, 14.73; Found: C, 57.98; H, 3.06; N, 14.64.
3-(2,4-Dichlorophenyl)-1,5-di-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]pyrazole-
o
4,6-dione (7l). Yellow crystals; mp. 225-7 C (from acetic acid); yield 93 %; IR: ν/cm-1 3085.5 (CH-
aromatic), 1725.9 (C=O), 1591.9 (C=N); MS, m/z: 529 (M++4, 18.5), 527 (M++2, 58.2), 525 (M+)

Molecules 2008, 13
1020
(74.6), 362 (25.3), 360 (35.5), 335 (31.4), 333 (46.3), 254 (7.9), 252 (23.9), 189 (32.3), 188 (32.5), 171
(16.5), 158 (28.8), 116 (35.1), 90 (100.0), 76 (49.5), 63 (85.4), 50 (40.6); 1H-NMR: δ/ppm 5.57 (d, 1H,
J = 11.6 Hz), 5.87 (d, 1H, J = 11.6 Hz), 7.16-8.29 (m, 11H, ArH's); Anal. Calcd. for C23H13Cl2N5O6:
C, 52.48; H, 2.49; N, 13.30; Cl, 13.47; Found: C, 52.53; H, 2.51; N, 13.38; Cl, 13.34.
5-(4-Ethylphenyl)-3-(4-fluorophenyl)-1-(4-nitrophenyl)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-c]-
o
pyrazole-4,6-dione (7m). Yellow crystals; mp. 282-4 C (from dimethylformamide); yield 98 %; IR:
ν/cm-1 3074.3 (CH-aromatic), 2963.0 (CH-aliphatic), 1720.3 (C=O), 1594.5 (C=N); MS, m/z: 458 (M+,
100.0), 310 (16.6), 283 (64.9), 237 (11.6), 132 (38.1), 77 (11.3); 1H-NMR: δ/ppm 1.18 (t, 3H, J = 7.6
Hz, CH2CH3), 2.58 (q, 2H, J = 7.6 Hz, CH2CH3), 5.44 (d, 1H, J = 10.6 Hz), 5.81 (d, 1H, J = 10.6 Hz),
13
7.21-8.28 (m, 12H, ArH's); C-NMR: δ/ppm 171.49, 170.59 (two C=O amide), 165.24 (d, J = 248.7
Hz, C-F), 148.14 , 146.48 (C=N, C-NO2), 144.13, 139.38, 129.58 (d, J = 8.4 Hz, C-m-F), 128.89,
127.78, 126.37, 126.00 (d, J = 3.1 Hz, C-p-F), 125.04, 115.38 (d, J = 22.1 Hz, C-o-F), 112.81, 66.54
(C-5 pyrazoline), 53.81 (C-4 pyrazoline), 27.33 (CH2CH3), 14.78 (CH2CH3); Anal. Calcd. for
C25H19FN4O4: C, 65.49; H, 4.17; N, 12.22; Found: C, 65.48; H, 3.99; N, 12.18.
3-(2,4-Dichlorophenyl)-5-(4-ethylphenyl)-1-(4-nitrophenyl-)-3a,4,6,6a-tetrahydro-1H,5H-pyrrolo[3,4-
c]pyrazole-4,6-dione (7n). Yellow crystals; mp. 224-6 oC (from dimethylformamide); yield 95 %; IR:
ν/cm-1 3071.5 (CH-aromatic), 2958.8 (CH-aliphatic), 1719.1 (C=O), 1593.9 (C=N); MS, m/z: 512
(M++4, 9.8), 510 (M++2, 72.5), 508 (M+, 100.0), 360 (23.8), 333 (47.4), 287 (10.4), 252 (18.9), 132
(84.3), 90 (25.7), 77 (16.6), 63 (19.0), 50 (11.5); 1H-NMR: δ/ppm 1.22 (t, 3H, J = 7.6 Hz, CH2CH3),
2.67 (q, 2H, J = 7.6 Hz, CH2CH3), 5.58 (d, 1H, J = 10.4 Hz), 5.89 (d, 1H, J = 10.4 Hz), 7.21-8.32 (m,
11H, ArH's); Anal. Calcd. for C25H18N4O4Cl2: C, 58.95; H, 3.56; N, 11.00; Cl, 13.92; Found: C, 59.00;
H, 3.55; N, 10.98; Cl, 13.94.
Synthesis of 3,4,5-triaryl-1-(4-nitrophenyl)- 2-pyrazoline derivatives 9a-f
This reaction was carried out by the same method described for the preparation of pyrazolines 7
using the α,β-unsaturated ketone arylideneacetophenone derivatives 8a-c in place of N-arylmaleimides
6.
5-Benzoyl-3-(4-fluorophenyl)-1-(4-nitrophenyl)-4-phenyl-2-pyrazoline (9a). Yellow crystals; mp. 206-
8 oC (from benzene); yield 75 %; IR: ν/cm-1 3068.4 (CH-aromatic), 1698.5 (C=O), 1593.2 (C=N); MS,
m/z: 466 (M++1, 3.3), 465 (M+, 4.6), 361 (72.0), 360 (100.0), 315 (25.6), 314 (29.3), 105 (13.5), 77
1
(28.3), 51 (11.7); H-NMR: δ/ppm 5.23 (d, 1H, J = 3.0 Hz), 6.53 (d, 1H, J = 3.0 Hz), 7.13- 8.18 (m,
18H, ArH's); Anal. Calcd. for C28H20FN3O3: C, 72.24; H, 4.33; N, 9.02; Found: C, 72.71; H, 4.43; N,
9.13.
5-Benzoyl-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-4-phenyl-2-pyrazoline (9b). Yellow crystals; mp.
o
148-50 C (from benzene-ethanol); yield 71 %; IR: ν/cm-1 3064.3 (CH-aromatic), 1699.9 (C=O),
1593.8 (C=N), 1567.8 (C=C); MS, m/z: 517 (M++2, 2.9), 515 (M+) (3.5), 413 (55.2), 412 (59.4), 411
(91.7), 410 (100.0), 367 (18.9), 366 (20.0), 365 (26.1), 364 (30.3), 165 (14.4), 105 (50.9), 77 (82.1), 50

Molecules 2008, 13
1021
(16.4); 1H-NMR: δ/ppm 5.28 (d, 1H, J = 3.5 Hz), 6.58 (d, 1H, J = 3.5 Hz), 7.23- 8.19 (m, 17H, ArH's);
13C-NMR: δ/ppm 192.32 (C=O), 150.30 (C=N), 148.10, 138.68, 136.91, 134.09, 134.00, 132.48,
132.26, 132.01, 129.90, 128.97, 128.77, 128.62, 127.82, 127.18, 127.03, 126.95, 125.28, 112.33 (18C,
ArC's), 70.71 (C-5 pyrazoline), 56.54 (C-4 pyrazoline); Anal. Calcd. for C28H19Cl2N3O3: C, 65.12; H,
3.70; N, 8.13; Cl, 13.73; Found: C, 65.32; H, 3.68; N, 8.24; Cl, 13.67.
5-Benzoyl-4-(4-chlorophenyl)-3-(4-fluorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (9c). Yellow crystals;
mp. 230-2 oC ( from benzene-ethanol); yield 68 %; IR: ν/cm-1 3063.5 (CH-aromatic), 1692.4 (C=O),
1655.8 (C=N), 1595.2 (C=C); MS, m/z: 502 (M++2, 1.5), 500 (M+, 5.1), 397 (32.4), 395 (100.0), 351
(9.4), 350 (12.2), 349 (30.4), 348 (28.0), 105 (24.9), 77 (40.0), 51 (17.8); 1H-NMR: δ/ppm 5.31 (d, 1H,
J = 3.2 Hz), 6.52 (d, 1H, J = 3.2 Hz), 7.12- 8.17 (m, 17H, ArH's); Anal. Calcd. for C28H19ClFN3O3: C,
67.26; H, 3.83; N, 8.40; Found: C, 67.11; H, 3.86; N, 8.47.
5-Benzoyl-4-(4-chlorophenyl)-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-2-pyrazoline (9d). Yellowish
o
orange solid; mp. 204-6 C (from benzene-ethanol); yield 61 %; IR: ν/cm-1 3065.3 (CH-aromatic),
1686.4 (C=O), 1594.8 (C=N), 1557.2 (C=C); MS, m/z: 551 (M++2, 5.4), 549 (M+, 6.5), 515 (5.7), 513
(8.5), 449 (33.1), 447 (100.0), 445 (90.2), 402 (7.7), 401 (19.1), 400 (23.9), 399 (23.9), 105 (34.7), 77
(56.5); 1H-NMR: δ/ppm 5.41 (d, 1H, J = 3.0 Hz), 6.55 (d, 1H, J = 3.0 Hz), 7.28- 8.36 (m, 16H, ArH's);
Anal. Calcd. for C28H18Cl3N3O3: C, 61.05; H, 3.29; N, 7.62; Cl, 19.30; Found: C, 61.10; H, 3.36; N,
7.71; Cl, 19.19.
5-(4-Bromophenylcarbonyl)-3-(4-fluorophenyl)-1-(4-nitro-phenyl)-4-phenyl-2-pyrazoline (9e). Yellow
o
solid; mp. 224-6 C (from benzene); yield 53 %; IR: ν/cm-1 3068.6 (CH-aromatic), 1697.3 (C=O),
1655.4 (C=N), 1594.0 (C=N); MS, m/z: 543 (M+, 3.1), 361 (83.2), 360 (100.0), 315 (26.0), 314 (28.7),
183 (6.5), 91 (7.7), 76 (12.2), 50 (8.6); 1H-NMR: δ/ppm 5.22 (d, 1H, J = 3.3 Hz), 6.57 (d, 1H, J = 3.3
Hz), 7.13- 8.19 (m, 17H, ArH's); Anal. Calcd. for C28H19BrFN3O3: C, 61.77; H, 3.51; N, 7.71; Found:
C, 61.76; H, 3.55; N, 7.73.
5-(4-Bromophenylcarbonyl)-3-(2,4-dichlorophenyl)-1-(4-nitrophenyl)-4-phenyl-2-pyrazoline
(9f).
o
Yellow solid; mp. 211-3 C (from benzene); yield 51 %; IR: ν/cm-1 3072.7, 3030.9 (CH-aromatic),
1698.1 (C=O), 1592.2 (C=N); 1H-NMR: δ/ppm 5.27 (s, br., 1H, 4H-pyrazoline), 6.57 (s, br., 1H, 5H-
13
pyrazoline), 7.24-8.20 (m, 16H, ArH's); C-NMR: δ/ppm 191.71 (C=O), 150.29 (C=N), 148.08,
138.73, 136.82, 134.01, 132.29, 131.98, 131.71, 131.51, 130.69, 129.01, 128.49, 127.86, 127.82,
127.09, 127.00, 126.85 125.28, 112.35 (18C, ArC's), 70.63 (C-5 pyrazoline), 56.29 (C-4 pyrazoline);
Anal. Calcd. for C28H18N3O3BrCl2: C, 56.49; H, 3.04; N, 7.05; Cl, 11.91; Found: C, 56.48; H, 3.02; N,
7.0; Cl, 11.92.
References
1. Korgaokar, S. S.; Patil, P. H.; Shah, M. J; Parekh, H. H. Studies on Pyrazolines: Preparation and
Antimicrobial
Activity
of
3-(3'(P-Chlorophenyesulphonamidophenyl)-5-aryl-1H/acetyl
pyrazolines. Indian J. Pharm. Sci. 1996, 58, 222-225.

Molecules 2008, 13
1022
2. Palaska, E.; Aytemir, M.; Uzbay, IT.; Erol, D. Synthesis and Antidepressant Activities of Some
3,5-diphenyl-2-pyrazolines. Eur. J. Med. Chem. 2001, 36, 539-543.
3. Rajendra, P. Y.; Lakshmana, R. A.; Prasoona, L.; Murali, K.; Ravi, K. P. Synthesis and
Antidepressant Activity of Some 1,3,5-Triphenyl-2-pyrazolines and 3-(2''-Hydroxynaphthalen-1''-
yl)-1,5-diphenyl-2-pyrazolines. Bioorg. Med. Chem. Lett. 2005, 15, 5030-5034.
4. Ozdemir, Z.; Kandilici, HB.; Gumusel, B.; Calis, U.; Bilgin, AA. Synthesis and Studies on
Antidepressant and Anticonvulsant Activities of Some 3-(2-furyl)-pyrazoline Derivatives. Eur. J.
Med. Chem. 2007, 42, 373-379.
5. Ruhogluo, O.; Ozdemir, Z.; Calis, U.; Gumusel, B.; Bilgin, AA. Synthesis of and Pharmacological
Studies on The Antidepressant and Anticonvulsant Activities of Some 1,3,5-trisubstituted
Pyrazolines. Arzneimittelforschung 2005, 55, 431-436.
6. Udupi, R. H.; Kushnoor, A.S.; Bhat, A. R. Synthesis and Biological Evaluation of Certain
Pyrazoline Derivatives of 2-[6-methoxynaphthyl]-propionic Acid (Naproxen). Indian J.
Heterocycl. Chem. 1998, 8, 63-66.
7. Nauduri, D.; Reddy, G. B. Antibacterials and Antimycotics: Part 1: Synthesis and Activity of 2-
Pyrazoline Derivatives. Chem. Pharm. Bull. (Tokyo) 1998, 46, 1254-1260.
8. Taylor, E. C.; Patel, H. H. Synthesis of Pyrazol[3,4-d]pyrimidine Analogues of The Potent Agent
N-{4-[2-(2-amino-4(3H)-oxo-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl}-L-glutamic
acid
(LY231514). Tetrahedron 1992, 48, 8089-8100.
9. Koga, H.; Itoh, A.; Murayama, S.; Suzue, S.; Irikura, T. Structure-Activity Relationships of
Antibacterial 6,7- and 7,8-Disubstituted 1-Alkyl-1,4-dihydro-4-oxoquinoline-3-carboxylic acids.
J. Med. Chem. 1980, 23, 1358-1363.
10. Wilkinson, J. A. Recent Advances in the Selective Formation of the Carbon-Fluorine Bond.
Chem. Rev. 1992, 92, 505-519.
11. Wise, R.; Andrews, J. M.; Edwards, L. J. In Vitro Activity of Bay 09867, a New Quinoline
Derivative, Compared with Those of Other Antimicrobial Agents. Antimicrb. Agents Chemother.
1983, 23, 559-564.
12. Hagen, S. E.; Domagala, J. M.; Heifetz, C. L.; Johnson, J. Synthesis and Biological Activity of 5-
Alkyl-1,7,8-trisubstituted-6-fluoroquinoline-3-carboxylic Acids. J. Med. Chem. 1991, 34, 1155-
1161.
13. Matsumoto, J.; Miyamoto, T.; Minamada, A.; Mishimuna, Y.; Egawa, H.; Nisimira, H.
Pyridonecarboxylic Acids As Antibacterial Agents. 2. Synthesis and Structure-Activity
Relationships of 1,6,7-trisubstituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic Acids,
Including Enoxacin, a New Antibacterial Agent. J. Med. Chem. 1984, 27, 292-301.
14. Hayakawa, I.; Hiramitsu, T.; Tanaka, Y. Synthesis and Antibacterial Activities of Substituted 7-
oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acids. Chem. Pharm. Bull.
(Tokyo) 1984, 32, 4907-4913.
15. Azarifar, D.; Ghasemnejad, H. Microwave-Assisted Synthesis of Some 3,5-Arylated 2-
pyrazolines. Molecules 2003, 8, 642-648.
16. Azarifar, D.; Shaebanzadeh, M.; Synthesis and Characterization of New 3,5-Dinaphthyl
Substituted 2-Pyrazolines and Study of Their Antimicrobial Activity. Molecules 2002, 7, 885-895.

Molecules 2008, 13
1023
17. Ali, M. A., Siddiqui, M. S. A. A. Synthesis, Structural Activity Relationship and Anti-Tubercular
Activity of Novel Pyrazoline Derivatives. Eur. J. Med. Chem. 2007, 42, 268-275.
18. Amir, M., Kumar, H., Khan, S. A. Synthesis and Pharmacological Evaluation of Pyrazoline
Derivatives as New Anti-inflammatory and Analgesic Agents. Bioorg. Med. Chem. Lett. 2008, 18,
918-922.
19. Knorr, L. Notiz über die Pyrazolinreaction. Ber. Dt. Chem. Ges. 1893, 26, 100-103.
20. Patel, V. M.; Desai, K. R. Eco-friendly Synthesis of Fluorine-Containing Pyrazoline Derivatives
over Potassium Carbonate. Arkivoc (i) 2004, 123-129.
21. Hassaneen, H. M; Shawali, A. S.; Elwaln, N. M.; Abunada, N. M.; Algharib, M. S. Synthesis and
Cycloaddition Reactions of C-(2-naphthoyl)-N-arylmethanohydrazonylpyridinium Bromides.
Arch. Pharm. Res. 1992, 15, 292-297.
22. Hassaneen, H. M.; Hilal, R. H.; Elwan, N. M.; Harhash, A.; Shawali, A. S. The Regioselectivity in
the Formation of Pyrazolines and Pyrazoles from Nitrilimines. J. Heterocycl. Chem. 1984, 21,
1013-1016.
23. Hassaneen, H. M.; Mousa, H. A. H.; Shawali, A. S. Chemistry of C-Heteroarylnitrilimines.
Synthesis and Cycloaddition reactions of N-Phenyl-C-(2-thienyl)nitrilimine. J. Heterocycl. Chem.
1987, 24, 1665-1668.
24. Hassaneen, H. M.; Mousa, H. A. H.; Abed, N. M.; Shawali, A. S. Chemistry of C-
Heteroarylhydrazidoyl Halides. Synthesis and Reactions of N-(p-Nitrophenyl)-C-(2-thienyl)-
formohydrazidoyl Halides. Heterocycles 1988, 27, 695-706.
25. Hassaneen, H. M.; Harhash, A. E.; Abunada, N. M.; Abdallah, T. A.; Algharib, M. S. Cyano-(1-
methylbenzimidazol-2-yl)thioacetanilide in the Synthesis of 2,3-Dihydro-1,3,4-thiadiazole
Derivatives. J. Chem. Res. (S) 1993, 194-195.
26. Abunada, N. M.; Hassaneen, H. M. Cycloaddition Reactions of Nitrilimines with Some
Dipolarophiles and Thioxoanilide Derivatives. Hebron University Res. J. 2007 in press.
27. Abunada, N. M.; Hassaneen, H. M. Nitrilimines in 1,3-Dipolar Cycloaddition Reactions:
Synthesis of New Derivatives of Condensed 1,2,4-Triazolo- Heterocycle and Dithiatriaza-
spiro[4,4]non-2-enone Derivatives. Jordan. J. Chem. 2008 in press.
28. Butt, G.; Cilmi, J.; Hooben, P. M.; Topsom, R. D. The Transmission of Resonance Effects
Through a Methylene Group Spectroscopic Studies on Some -Substituted-Acetonitriles and p-
Toluonitriles. Spectrochim. Acta: Mol. Spectrosc. 1980, 36A, 521-524.
29. Jesson, J. P.; Thompson, H. W. Vibrational Band Intensities of the C N Group in Aliphatic
Nitriles. Spectrochim. Acta 1958, 13, 217-222.
30. Micetich, R. G. Studies in Isoxazole Chemistry. IV. Isoxazole via Isoxazolines. Can. J. Chem.
1970, 40, 3753-3755.
31. Oida, T.; Shimizu, T.; Hayashi, Y.; Termura, K. The Cycloaddition of Nitrilimines with 1,2-
Dibenzolethylenes. Bull. Chem. Soc. Jpn. 1981, 54, 1429-1433.
32. Sustmann, R.; Huisgen, R.; Huber, H. 1,3-Dipolare Cycloadditionen, XXX. Substituent-eneffekte
in den Kernresonanzspektren von 1,3-Diphenyl-Δ2-pyrazolinen und 3-Phenyl-Δ2-isoxazolinen.
Chem. Ber. 1967, 100, 1802-1813.
33. Grayer, R. J.; Harborne, J. B. A Survey of Antifungal Compounds from Higher Plants.
Phytochemistry 1994, 37, 19-42.

Molecules 2008, 13
1024
34. Irob, O. N.; Moo-Young, M.; Anderson, W. A. Antimicrobial Activity of Annatto Extract. Int. J.
Pharm. 1996, 34, 87-90.
35. Hegarty, A. F.; Scott, F. L. The kinetics of Bromination of Hydrazones. J. Chem. Soc. (B) 1966,
672-675.
36. Shawali, A. S.; Hassaneen, H. M. Reaction of Carbanions of β–Diketones and β–Keto Esters with
Hydrazidic Bromides. Tetrahedron 1972, 29, 121-124.
Sample Availability: Contact the authors.
© 2008 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.