Synthesis, conformational assignment, and anti-inflammatory activities of N-arylidene-2-(4-chloro-2-(2-substituted phenoxy)phenyl)acetic acid hydrazides

Article abstract of DOI:10.1007/s00044-016-1656-1

A series of N-arylidene-2-(4-chloro-2-(2-fluoro or chlorophenoxy)phenyl)acetic acid hydrazides (16 or 17) was synthesized for their anti-inflammatory activity by the condensation of corresponding hydrazide and aromatic aldehydes. Characterization of these

Full text of DOI:10.1007/s00044-016-1656-1

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res
DOI 10.1007/s00044-016-1656-1
ORIGINAL RESEARCH
Synthesis, conformational assignment, and anti-inflammatory activities
of N-arylidene-2-(4-chloro-2-(2-substituted phenoxy)phenyl)acetic acid
hydrazides
Afraz Nakhostin1 Samaneh Mirseyyedhosein2 Mahsa Toolabi1
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Pariya Khodabakhsh2 Helia Aghamiri2 Soheila Ghaffari2 Hamed Shafaroodi2
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Alireza Shayesteh3 Mohsen Amini1 Abbas Shafiee1 Latifeh Navidpour1
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Received: 17 July 2015 / Accepted: 4 July 2016
© Springer Science+Business Media New York 2016
Abstract A series of N-arylidene-2-(4-chloro-2-(2-fluoro
or chlorophenoxy)phenyl)acetic acid hydrazides (16 or 17)
was synthesized for their anti-inflammatory activity by the
condensation of corresponding hydrazide and aromatic
aldehydes. Characterization of these compounds by proton
nuclear magnetic resonance showed most of the protons as
two separate peaks. The energy was calculated for each
possible configuration, and their stereochemical behavior
was studied using proton nuclear magnetic resonance
techniques. The results indicated that the most stable ste-
reoisomers are the two E geometrical isomers, which
undergo a rapid cis/trans amide equilibrium with the cis
conformer predominating. These analogs exhibited moder-
ate to excellent anti-inflammatory activity in carrageenan-
induced rat paw edema assay. Among them, N-(3,4-dime-
thoxybenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)phenyl)
acetic acid hydrazide (17k) showed the highest anti-
inflammatory activity relative to diclofenac sodium acid as
a reference drug (86 % vs. 61 % reduction in inflammation
post drug administration, respectively).
Introduction
Nonsteroidal anti-inflammatory drugs (NSAIDs) of the aryl-
(heteroaryl)acetic acid class (1–3, Fig. 1) exert their ther-
apeutic effects by inhibiting cyclooxygenase-derived pros-
taglandin synthesis. However, due to inhibition of the
constitutive cyclooxygenase-1 (COX-1) isozyme, chronic
use of these medications may cause several serious adverse
effects, the most important of which are gastric injury
(Huang et al., 2011; Go, 2006) and renal (Mounier
et al., 2006) or hepatic (Adebayo and Bjarnason,
2006) complications. Despite the safe profile of selective
cyclooxygenase-2 (COX-2) inhibitors in the gastro-
intestinal (GI) tract, they may increase risk of adverse car-
diovascular effects such as thrombosis and stroke in some
patients undergoing chronic treatment (Mukherjee et al.,
2001). Therefore, the discovery of new safer anti-
inflammatory drugs represents a challenging goal.
The two most important factors involved in GI damage
caused by NSAIDs are commonly considered to be local
irritation from direct contact of the free carboxylic acid
(COOH) moiety with GI mucosal cells (topical effect) and
the decrease of prostaglandin production in tissues (Smith
et al., 1998; Hawkey et al., 2000). Synthetic approaches
based on chemical modification of NSAIDs have been
considered to improve their safety profile and therapeutic
window. In this regard, several studies have described the
substitution of COOH moiety with derivatives featuring less
acidic hydrogens, such as amide or N-acylarylhydrazones
(4,5) (Fig. 2) (Bala et al., 2013). Alternatively, the hydra-
zone moiety has been suggested to have pharmacophoric
character for the inhibition of cyclooxygenase enzyme
(Simmons et al., 2004; Lacerda et al., 2012).
●
Keywords N-acylhydrazones Coalescence
Anti-inflammatory
* Latifeh Navidpour
navidpur@sina.tums.ac.ir
1
Department of Medicinal Chemistry, Faculty of Pharmacy and
Drug Design & Development Research Center, Tehran University
of Medical Sciences, Tehran 14176, Iran
2
Pharmacology and Toxicology Department, Pharmaceutical
Sciences Branch and Pharmaceutical Sciences Research Center,
Islamic Azad University, Tehran, Iran
3
In recent studies, niflumic acid-based N-acylhydrazones
or their 3-chloroanilino derivatives (7) showed significant
School of Chemistry, College of Science, University of Tehran,
Tehran, Iran

Med Chem Res
Fig. 1 Chemical structure of
some representative NSAIDs
from aryl-(or heteroaryl)acetic
acid class
COOH
CH3
COOH
H3CO
COOH
NH
Cl
Cl
N
O
Cl
(1) Indomethacin
(2) Ibuprofen
(3) Diclofenac sodium
COOH
Fig. 2 Chemical structure of
some representative
CH3
N
N-acylhydrazones, niflumic acid
and designed compounds
CH3
O
O
N
N
H
N
NH
N
O
O
S
N
H
H
N
N
H
CF3
(4)
(5)
(6) Niflumic acid
H
O
H
N
Y
2''
5''
6
1''
1
N
X
3''
4''
5
4
N
N
H
2
O
6''
H
Cl
O
N
NH
3
1'
X
6'
5'
2'
3'
X = F, Cl
4'
designed compounds (16,17)
(7) X = CF3, Cl
Y = H, F, OH, Cl, OCH3
anti-inflammatory and analgesic activities that were com-
parable to niflumic acid (6) as a reference drug (Kher-
admand et al., 2013; Navidpour et al., 2014). Hence, as a
part of our ongoing research (Kheradmand et al., 2013;
Navidpour et al., 2014; Moradi et al., 2010; Shekarchi et al.,
2011), we describe the synthesis and biological evaluation
of a novel diverse group of N-arylidene-4-chloro-2-(2-
fluoro or chlorophenoxy)phenylacetic acid hydrazides with
different substituents on the terminal phenyl ring as anti-
inflammatory agents.
prepared by refluxing sodium salts of 2,4-dichlorobenzoic
acid and 2-substituted phenols in dimethylformamide with a
catalytic amount of copper (Mashayekh et al., 2014; Haw-
kins et al., 1980). Benzoic acids 8a–b were esterified using
excess thionyl chloride (8 eq.) in ethanol. The reduction of
ethyl esters 9 with lithium aluminum hydride in tetra-
hydrofuran (THF) yielded alcohol derivatives (10)
(Mashayekh et al., 2014; Paduraru and Wilson, 2003). To
prepare the acetic acid derivative, the hydroxyl moiety
should primarily be substituted with cyano group. The
hydroxyl group was thus converted to chlorine as a suitable
leaving group using thionyl chloride in benzene in the
presence of pyridine. Then the substitution was approached
using sodium cyanide in dimethyl sulfoxide (DMSO).
Subsequent hydrolysis of the cyano compound 12 gave the
key intermediates, 2-(2-phenoxyphenyl)acetic acids (13)
(Mashayekh et al., 2014; Paduraru and Wilson, 2003). 2-(2-
Phenoxyphenyl)acetic acid hydrazides (15) were readily
prepared via esterification of the corresponding acetic acid
derivatives (13), followed by treatment with hydrazine
Results and discussion
Chemistry
The synthetic reactions leading to the substituted N-aryli-
dene-2-(4-chloro-2-(2-fluoro or chlorophenoxy)phenyl)
acetic acid hydrazides (16 and 17) are outlined in Scheme 1.
As starting materials, 2-phenoxybenzoic acids (8a–b) were

Med Chem Res
COOH
O
COOCH2CH3
CH2OH
c
a
b
Cl
Cl
O
Cl
O
X
X
X
8a, X=F
8b, X=Cl
10a, X=F
10b, X=Cl
9a, X=F
9b, X=Cl
CH2Cl
CH2CN
CH2COOH
f
e
d
Cl
O
Cl
O
Cl
O
X
X
X
13a, X=F
13b, X=Cl
11a, X=F
11b, X=Cl
12a, X=F
12b, X=Cl
O
Ar
H
CH2COOCH2CH3
CH2CNHN
CH2CONHNH2
h
Cl
O
Cl
O
g
Cl
O
X
X
X
14a, X=F
14b, X=Cl
15a, X=F
15b, X=Cl
16a-n, X=F
17a-k, X=Cl
Scheme 1 Reagents and conditions: a SOCl2, EtOH, reflux, 4 h; b
LiAlH4, THF, r.t., 24 h; c SOCl2, benzene, pyridine, r.t., 2 h; d NaCN,
DMSO, r.t., 24 h; e KOH, EtOH (for 12a) or n-BuOH (for 12b), reflux,
24 h; f SOCl2, EtOH, reflux, 4 h; j NH2NH2.H2O, EtOH, r.t. 24 h; k
ArCHO, EtOH, HCl (2 drops), r.t., 24 h
hydrate in methanol (Mashayekh et al., 2014; Shafiee et al.,
1995). Condensation of hydrazides with aromatic aldehydes
in ethanol with a catalytic amount of hydrochloric acid
(HCl) yielded N-arylidene-2-(4-chloro-2-(2-substituted-
phenoxy)phenyl) acetic acid hydrazides (16 and 17) in
yields of 22–91 %.
These results indicate that the compounds may exist as a
mixture of two stereoisomers at equilibrium at 298 K. The
intensities of H signals allow us to measure the ratio of
1
these isomers.
Hydrazone may exist as Z/E geometrical isomers about
the C=N double bond and cis/trans amide conformers, and
the different possible conformations (18–25) are shown in
Fig. 3 (Patorski et al., 2013; Palla et al., 1986). To deter-
mine the relative configurations of the two or three most
stable stereoisomers, the energy of each form was calcu-
lated. Systematic conformational analysis was carried out
using the AM1 (Austin Model 1) Hamiltonian. Further
optimization by density functional theory (DFT) methods
were applied to the conformations having the lowest ener-
gies shown in Fig. 3 (except for 20 and 24, which show
significant steric hindrance). The relative energy results are
shown in Table 1.
All final compounds were characterized by infrared (IR),
mass spectrometry (MS), proton nuclear magnetic reso-
nance (1H NMR), and 13C NMR spectroscopic data along
1
with elemental analyses. In the H NMR spectra, most of
the protons were seen as two or sometimes three separate
peaks. Two pairs of singlets associated with –CH=N– and
–CONH– protons were determined in the ranges of
7.86–8.42 and 11.27–11.75 ppm in DMSO-d6, or 7.71–8.64
and 8.98–9.80 ppm in CDCl3, respectively. Also, protons of
methylene residue were observed at about 3.70 and 4.08
ppm in DMSO-d6 or 3.80 and 4.21 ppm in CDCl3 as two
singlets.
Analysis of the results revealed that the E geometrical
isomers are more stable than their corresponding Z isomers.
Among the four possible conformations for the E geome-
trical isomer (Fig. 3, 18–21), the cis conformer (21) is
shown to be the most stable. The second lowest energy
In the 13C NMR spectra of the compounds, methylene
carbons were assigned at about 33.5 and 35.3 ppm, and the
carbon atom of the carbonyl group was determined at about
172 and 166 ppm.

Med Chem Res
Ar
Ar
H
N
H
N
H
H
N
N
N
N
H
C
O
N
C
O
N
Ar
C
H
C
O
H
Cl
O
Ar
H
O
Cl
O
Cl
O
Cl
O
Cl
Cl
Cl
Cl
cis-E (19)
trans-E (18)
trans-E (20)
cis-E (21)
H
H
H
N
Ar
Ar
O
N
H
Ar
N
N
N
H
C
N
C
H
N
C
C
O
N
H
O
O
O
Cl
O
Cl
O
Ar
H
Cl
Cl
O
Cl
Cl
Cl
Cl
cis-Z (25)
trans-Z (24)
cis-Z (23)
trans-Z (22)
Fig. 3 Different possible conformers for E (18–21) or Z (22–25) geometrical isomers
Table 1 Relative energies (in kcal mol−1) of the six stereoisomers,
calculated with the PBE0 functional and the def2-TZVPP basis set at
298 K
Finally, it can be concluded that the most stable stereo-
isomers are the E geometrical isomers 21 and 18 (Fig. 3),
which undergo a rapid cis/trans amide equilibrium with cis
conformer predominating.
ΔE
ΔG°
(298)
(298)
Anti-inflammatory activity
cis-E (21)
trans-E (18)
cis-E (19)
cis-Z (25)
trans-Z (22)
cis-Z (23)
0.0
1.4
3.7
4.3
5.7
10.8
0.0
2.5
5.4
5.9
7.1
12.9
The anti-inflammatory activity of the synthesized com-
pounds 16 and 17 was studied in vivo using carrageenan-
induced rat paw edema assay (Al-Haboubi and Zeitlin,
1983). The results are given in Table 1. Analysis of the
results shows that this group of N-arylidene-2-(4-chloro-2-
(2-substituted phenoxy)phenyl)acetic acid hydrazides exhi-
bits anti-inflammatory activity with moderate to excellent
activity range (25–86 % inhibition at their maximum inhi-
bition activity) in comparison with diclofenac sodium as a
reference drug (61 % inhibition).
Generally, most of 2-chlorophenoxy analogs (17a-k)
revealed noticeably better anti-inflammatory activities than
diclofenac sodium reference drug, while 2-fluorophenoxy
analogs (16a–n) mostly exhibited weaker to similar anti-
inflammatory activities to diclofenac sodium for intraper-
itoneal administration of the dose of 10 mg/kg, 30 min
before subcutaneous injection of the carrageenan.
The 2-chlorophenoxy analog with unsubstituted terminal
phenyl ring (17a) showed slightly better anti-inflammatory
activity than diclofenac sodium, whereas 2-fluorophenoxy
compound (16a) displayed weaker activity than reference
drug.
The influence on pharmacological activities was first
studied for substituents with different electronic and
physico-chemical parameters on the terminal phenyl moiety
attached to the imine functional group of title compounds.
1
corresponds to the trans conformation (18). The H signal
of methylene residue for the cis conformer (21) falls
downfield of the corresponding signal of trans conformer
(18), whereas the singlets due to –N=CH– and –CONH–
show a reverse pattern, and the upfield signals were
assigned to cis conformer (21). (Table 2)
For additional evidence about the relative configurations,
the assignment of 17i was followed by H NMR at several
1
temperatures. The coalescence of methylene, –CH=N– and
–CONH– group signals of the hydrazones in DMSO-d6
solution were studied at 330, 360 and 380 K. Each two sets
of signals were coalesced into one broad peak at about 360
K, which was sharpened at 380 K. The ratio of conformers
is the same as that measured at the same temperature at the
end of the experiment examining the coalescence tem-
perature. This is proof that the conversion of cis/trans amide
conformers is the only process of isomerization in the
DMSO-d6 solution of 17i.

Med Chem Res
Table 2 Anti-inflammatory activities of compounds 16 and 17
O
Ar
H
CH2CNHN
Cl
O
X
16a-n, X = F
17a-k, X = Cl
Compound
Ar
AI activity (%)a
at 30 min
cLogP
at 1 h
at 2 h
at 3 h
at 4 h
16a
Ph
20.61 10.82
29.84 9.65
12.41 11.07
16.63 5.66
26.89 1.65
24.18 10.58
48.06 16.31
32.98 3.19
60.71 22.68
15.43 7.58
22.35 27.38
32.28 10.10
29.96 9.07
10.13 1.49
8.83 5.56
51.96 14.85
24.20 15.18
32.24 3.59
45.70 8.89
20.11 18.22
43.98 15.34
44.99 7.98
25.77 13.85
77.26 8.83
42.07 18.96
26.02 24.15
43.77 7.42
36.24 8.28
45.37 2.81
14.18 9.52
28.74 12.53
10.51 8.94
19.02 6.66
23.03 14.05
40.27 13.39
35.52 4.92
22.13 14.97
24.90 10.80
38.52 7.94
46.99 3.82
41.32 13.00
37.79 9.88
26.28 4.88
52.70 4.26
52.06 9.63
54.02 3.96
45.10 7.51
44.13 6.29
26.90 13.43
59.98 7.54
50.09 9.68
22.80 12.01
19.47 11.53
41.30 10.41
46.47 2.56
35.81 7.61
58.51 6.96
50.05 4.62
38.76 9.78
29.08 10.79
59.68 7.68
62.58 8.37
56.60 6.12
52.52 7.83
67.36 5.01
71.52 7.35
53.99 4.91
39.04 7.98
44.95 6.06
61.20 4.28
44.95 6.06
45.18 2.90
60.23 4.58
31.57 8.16
34.33 2.26
44.64 6.24
44.97 7.58
19.23 7.89
26.96 6.79
33.61 6.99
37.92 8.12
47.92 8.77
65.40 6.8
51.67 8.46
52.31 4.39
67.01 3.63
52.31 4.39
53.91 5.42
64.80 4.02
40.28 0.05
58.01 4.45
44.97 6.13
54.71 3.87
49.30 4.47
36.02 7.32
46.88 3.97
52.30 5.45
63.31 6.41
71.72 7.26
61.56 6.81
49.64 8.71
25.56 10.90
49.37 5.50
84.36 0.64
67.76 4.00
73.53 7.01
78.90 3.19
86.94 2.67
61.26 2.29
6.169
6.359
6.322
6.798
6.761
5.898
5.861
6.162
6.125
6.116
5.8677
5.6105
4.936
4.937
6.608
6.798
6.761
7.237
7.20
16b
3-F-C6H4
16c
4-F-C6H4
16d
3-Cl-C6H4
16e
4-Cl-C6H4
16f
3-OH-C6H4
4-OH-C6H4
3-OMe-C6H4
4-OMe-C6H4
2,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
3,4,5-(OMe)3-C6H2
3-Pyridyl
16g
16h
16i
16j
16k
16l
16m
16n
4-Pyridyl
17a
Ph
17b
3-F-C6H4
4.67 2.71
17c
4-F-C6H4
29.28 14.44
11.10 6.91
12.49 6.33
25.35 15.70
16.24 3.38
13.41 12.25
9.51 5.90
45.88 6.22
42.77 9.42
17.31 12.47
42.02 6.58
78.38 2.96
57.35 2.34
64.74 6.50
76.01 2.97
80.05 6.76
55.76 4.34
17d
3-Cl-C6H4
17e
4-Cl-C6H4
17f
3-OH-C6H4
4-OH-C6H4
3-OMe-C6H4
4-OMe-C6H4
2,4-(OMe)2-C6H3
3,4-(OMe)2-C6H3
6.337
6.30
17g
17h
6.601
6.564
6.555
6.3067
4.231
17i
17j
16.58 16.24
19.91 6.60
35.05 18.42
17k
Diclofenac Sodium
a
The compounds are administered at the dose of 10 mg/kg.
The highest anti-inflammatory activity for each compound is shown as bold.
The study of substituent effects in the 2-fluorophenoxy
subgroup (16a–n) demonstrated that most of the sub-
stituents did not significantly change the activity relative to
the unsubstituted one (16a). Among the different analogs,
the substituents that produced compounds with improved
anti-inflammatory activities were C-4 fluoro (16c), methoxy
(16i), and C-3 hydroxy (16f) (67, 77, and 64 % reduction in
inflammation, respectively). This phenomenon can be
explained by a possible hydrogen bond formation between
the C-4 fluoro, methoxy or C-3 hydroxy substituents on the
phenyl ring with the amino acids of the target binding site.
Compounds with polymethoxy substituents (16j-l) had
weaker to similar activities (43–54 % reduction in inflam-
mation) relative to unsubstituted derivative (16a).
The effect of changing the position of substituents on the
phenyl ring was next investigated. Generally, most of the
meta substituted compounds (except for 16f-g) were pre-
ferred over para substituted ones.

Med Chem Res
The substitution of phenyl moiety with pyridyl (16m,n)
resulted in compounds with weaker or similar activities
(47–52 % reduction in inflammation).
showed the highest anti-inflammatory activity relative to
diclofenac sodium acid as a reference drug (86 % and 61 %
reduction in inflammation post drug administration,
respectively). The likely hydrogen-bond formation between
the substituents on the phenyl ring with amino acids of the
target-binding site may explain the potent anti-inflammatory
activity of the compounds with prominent activities. Since
these compounds do not have an acidic moiety, they pro-
vide a good framework for further modification to achieve
compounds with more potent anti-inflammatory activity and
weaker side effects.
In 2-chlorophenoxy subgroup (17a-k), comparison of the
paw edema assay results indicated that most of the sub-
stituents, except for the chloro (17d,e), resulted to com-
pounds with similar to significantly improved activity.
Among the different analogs, compounds with C-3 fluoro
(17b), methoxy (17h), C-4 hydroxy (17g), and methoxy
(17i) substituents revealed noticeably improved anti-
inflammatory activity (with 72, 67, 84, and 73 % reduc-
tion in inflammation, respectively) in comparison with the
diclofenac sodium reference drug.
Compounds with 2,4-(OMe)2 (17j) and 3,4-(OMe)2
(17k) substituents on the terminal phenyl ring showed
remarkable anti-inflammatory activities (78 and 86 %
reduction in inflammation). Again, the possible hydrogen
bond formation between fluoro, hydroxyl or methoxy sub-
stituents on the phenyl ring with the amino acids of the
target binding site might explain the potent anti-
inflammatory activity of these analogs.
Finally, among these analogs, N-(3,4-dimethox-
ybenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)phenyl)
acetic acid hydrazide (17k), exhibited 86 % reduction in
inflammation post drug administration, which was the
highest anti-inflammatory activity relative to diclofenac
sodium.
To investigate the possible mechanism of action of the
anti-inflammatory activity of similar analogs, we carried out
the in vitro assays on COX-1 and COX-2 enzymes (Moradi
et al., 2010). Those analogs displayed weak COX-2 inhi-
bitory activity, but moderate to good COX-1 inhibitory
activity. Thus, the potential mechanism of anti-
inflammatory activity of the synthesized analogs (16, 17)
could be COX-1 inhibition.
Experimental protocols
Chemistry
Melting points were determined with a Reichert-Jung hot-
stage microscope (Reichert-Jung, Germany) and are
uncorrected. IR spectra were recorded on a Nicolet Magna
550-fourier transform (FT) spectrometer (Nicolet, Madison,
WI, USA). 1H-NMR (500 MHz) spectra were measured
through a Bruker FT-500 MHz spectrometer (Bruker Bios-
ciences, USA) in DMSO-d6 with tetramethylsilane as the
internal standard, where J-values (coupling constant) are
estimated in Hertz. Spin multiplets are given as s (singlet), d
(doublet), dd (doublet of doublets), t (triplet), q (quartet), m
(multiplet), and b (broad). The coalescence temperature
studies were done by a Bruker 80 MHz spectrometer
(Bruker Analytische Messetechnik, Rheinstetten, Ger-
many). Mass spectra were obtained with an Agilent Tech-
nologies 5975C VL MSD spectrometer (Agilent
Technologies, USA) at 70 eV. The Elemental analyses were
carried out with a PerkineElmer model 240-C apparatus.
The results of elemental analyses (C, H, N) were within
0.4 % of the calculated values. Male Wistar rats used in
the anti-inflammatory screen were purchased from Pasteur
Institute (Karaj, Iran) and experiments were carried out
using protocols approved by the ethics committee of Tehran
University of Medical Sciences.
Conclusion
Various substituted N-arylidene-2-(4-chloro-2-(2-sub-
stituted phenoxy)phenyl)acetic acid hydrazide derivatives
were synthesized for their potential anti-inflammatory
General procedure for preparation of N-arylidene-2-(4-
chloro-2-(2-substituted phenoxy phenyl)acetic acid
hydrazide (16 and 17)
1
activities. In H NMR spectra, most of the protons were
seen as two separate peaks. The stereochemical behaviors
1
were studied by energy calculation and H NMR spectro-
scopy techniques. The results indicated that the most stable
stereoisomers are the E geometrical isomers, and the con-
version of cis/trans amide conformers was the only process
of isomerization.
In carrageenan-induced rat paw edema assay, the analogs
exhibited moderate to excellent anti-inflammatory activity.
Among them, N-(3,4-dimethoxybenzylidene)-2-(4-chloro-
2-(2-chlorophenoxy)phenyl)acetic acid hydrazide (17k),
A mixture of hydrazide 15 (1 mmol) and corresponding
aldehyde (1 mmol) in absolute ethanol (10 mL) in the pre-
sence of hydrochloric acid (2 drops) as the catalyst was
stirred at room temperature for 24 h. The completion of the
reaction was monitored by thin layer chromatography
(TLC). Then, water was added to the mixture, and the
precipitate was filtered, washed, and recrystallized from
ethanol or purified by preparative TLC to give 16 or 17.

Med Chem Res
N-benzylidene-2-(4-chloro-2-(2-fluorophenoxy)phenyl)
acetic acid hydrazide (16a)
134.0 (C, C-4), 137.1 (d, J = 6.25 Hz, CH, C-5′′), 141.9
(CH, =CH-), 143.1 (d, J = 11.25 Hz, C, C-1′), 153.6 (d, J =
245.0 Hz, C, C-2′), 156.0 (C, C-2), 162.8 (d, J = 242.5 Hz,
C, C-3′′), 171.8 (C=O); minor isomer (32 %): 33.3 (CH2),
113.5 (d, J = 22.5 Hz, CH, C-2′′), 116.2 (CH, C-3), 117.7
(d, J = 17.0 Hz, CH, C-3′), 117.8 (d, J = 17.5 Hz, CH, C-4′′),
122.4 (CH, C-5′), 123.6 (CH, C-5), 123.7 (d, J = 6.25 Hz,
C, C-1′′), 123.8 (C, C-1), 125.1 (CH, C-6′), 126.4 (d, J =
6.25 Hz, CH, C-4′), 131.3 (CH, C-6′′), 132.6 (CH, C-6),
133.8 (C, C-4), 137.2 (d, J = 6.25 Hz, CH, C-5′′), 145.3
(CH, =CH-), 153.8 (d, J = 245.0 Hz, C, C-2′), 156.2 (C,
C-2), 162.9 (d, J = 242.5 Hz, C, C-3′′), 166.3 (C=O); MS
m/z 402.1 (5.8), 400.2 (16.0), 296 (9.9), 262.1 (14.0), 237.1
(36.0), 236.1 (23.2), 235.1 (100), 233.1 (32.4), 217.1 (23.3),
215.1 (58.1), 201.1 (16.5), 200.1 (38.7), 199.1 (53.9), 185.1
(9.8), 172.1 (18.8), 171.1 (44.6), 170 (62.9), 169.1 (32.9),
168.1 (78.5), 167.1 (55.7), 165.1 (19.8), 153.1 (13.2), 152.1
(50.5), 137.1 (36.1), 133.1 (14.9), 125.1 (15.3), 123.1
(18.4), 111.1 (33.3), 110.1 (10.8), 109.1 (9.5), 107.1 (17.7),
95.1 (25.1), 83.1 (18.8), 77.4 (14.2), 75.1 (19.4), 63.1
(10.4), 51.1 (6.8), 43.1 (6.6).
Yield 43 %; m.p. 137–139 °C; IR (KBr) 3182 (NH), 1668
1
(C=O), 1273 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.68
(s, 0.66H, CH2), 4.08 (s, 1.34H, CH2), 6.71 (d, J = 1.9 Hz,
0.33H, H-3), 6.76 (d, J = 1.9 Hz, 0.67H, H-3), 7.03–7.09
(m, 0.67H, H-3′), 7.10–7.17 (m, 0.33H, H-3′), 7.18–7.26
(m, 3H), 7.28–7.34 (m, 0.67H, H-5′), 7.36–7.46 (m, 4.33H),
7.60 (dd, J = 1.9, 7.8 Hz, 1.34H, H-2′′, H-6′′), 7.65 (dd, J
= 1.9, 7.8 Hz, 0.66H, H-2′′, H-6′′), 7.95 (s, 0.67H, =CH),
8.15 (s, 0.33H, =CH), 11.43 (s, 0.67H, NH), 11.56 (s,
0.33H, NH); 13C NMR (DMSO-d6) δ major isomer (67 %):
33.5 (CH2), 116.8 (CH, C-3), 117.7 (d, J = 17.25 Hz, CH,
C-3′), 121.8 (CH, C-5′), 123.8 (CH, C-5), 123.8 (C, C-1),
125.2 (CH, C-6′), 126.1 (d, J = 6.25 Hz, CH, C-4′), 127.2
(CH, C-3′′, C-5′′), 129.2 (CH, C-2′′, C-6′′), 130.2 (CH,
C-4′′), 132.4 (CH, C-6), 134.0 (C, C-4), 134.6 (C, C-1′′),
143.3 (d, J = 11.25 Hz, C, C-1′), 143.4 (CH, =CH–), 153.7
(d, J = 245.0 Hz, C, C-2′), 156.1 (C, C-2), 171.8 (C=O);
minor isomer (33 %): 35.3 (CH2), 116.3 (CH, C-3), 117.8
(d, J = 17.0 Hz, CH, C-3′), 122.4 (CH, C-5′), 123.7 (CH,
C-5), 124.0 (C, C-1), 125.2 (CH, C-6′), 126.4 (d, J = 6.25
Hz, CH, C-4′), 127.5 (CH, C-3′′, C-5′′), 130.4 (CH, C-2′′,
C-6′′), 130.5 (C, C-4′′), 132.6 (CH, C-6), 133.8 (C, C-4),
134.7 (C, C-1′′), 143.1 (d, J = 11.25 Hz, C, C-1′), 146.8
(CH, =CH–), 153.8 (d, J = 245.0 Hz, C, C-2′), 156.2 (C, C-2),
166.2 (C=O); MS m/z 384.2 (4.2), 382.2 (11.4), 262.1
(12.7), 237.1 (25.9), 235.1 (73.6), 233.1 (33.3), 217.1
(18.0), 215.1 (47.3), 214.1 (11.4), 200.1 (34.3), 199.1
(50.2), 193.1 (17.2), 187.1 (11.5), 172.1 (18.3), 171.1
(43.2), 170.1 (70.4), 169.1 (39.8), 168.1 (100), 167.1 (71.1),
152.1 (47.9), 147.1 (31.9), 133.1 (15.2), 120.1 (43.3), 119.1
(42.9), 112.1 (11.7), 111.1 (35.1), 90.1 (12.8), 89.1 (28.9),
77.1 (23.3), 63.1 (11.3), 51.1 (10.4).
Anal. Calcd. for C21H15ClF2N2O2: C, 62.93; H, 3.77; N,
6.99. Found: C, 63.12; H, 3.56; N, 6.86.
N-(4-fluorobenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16c)
Yield 37 %; m.p. 161–163 °C; IR (KBr) 3171 (N–H), 1670
(C=O), 1228 (C–O) cm−1; 1H NMR (CDCl3): δ = 3.80
(s, 0.48H, CH2), 4.21 (s, 1.52H, CH2), 6.75 (s, 1H, H-3),
6.95–7.25 (m, 5H), 7.31 (d, J = 8.0 Hz, 0.76H, H-6), 7.38
(d, J = 8.0 Hz, 0.24H, H-6), 7.60–7.90 (m, 4H), 7.98 (s,
0.24H, =CH), 8.64 (s, 0.76H, =CH), 9.04 (s, 0.24H, NH),
9.61 (s, 0.76H, NH); 13C NMR (CDCl3) δ major isomer
(74 %): 33.5 (CH2), 115.8 (d, J = 21.25 Hz, CH, C-3′′, C-5′
′), 116.7 (CH, C-3), 117.7 (d, J = 17.5 Hz, CH, C-3′), 121.8
(CH, C-5′), 123.5 (CH, C-5), 124.0 (C, C-1), 124.8 (CH,
C-6′), 125.2 (CH, C-4′), 129.0 (d, J = 6.25 Hz, CH, C-2′′,
C-6′′), 131.2 (C, C-1′′), 132.4 (CH, C-6), 133.5 (C, C-4),
143.3 (d, J = 11.25 Hz, C, C-1′), 143.4 (CH, =CH–), 154.1
(d, J = 247.5 Hz, C, C-2′), 156.1 (C, C-2), 163.8 (d, J =
248.75 Hz, C, C-4′′), 171.8 (C=O); minor isomer (24 %):
35.3 (CH2), 115.9 (CH, C-3), 116.4 (d, J = 21.25 Hz, CH,
C-3′′, C-5′′), 117.4 (d, J = 17.0 Hz, CH, C-3′), 122.2 (CH,
C-5′), 123.7 (CH, C-5), 124.0 (C, C-1), 126.2 (d, J = 6.25
Hz, CH, C-4′), 126.3 (CH, C-6′), 129.0 (d, J = 6.5 Hz, CH,
C-2′′, C-6′′), 131.5 (C, C-1′′), 132.6 (CH, C-6), 134.5 (C,
C-4), 143.3 (CH, =CH–), 146.8 (d, J = 11.25 Hz, C, C-1′),
153.8 (d, J = 245.0 Hz, C, C-2′), 156.2 (C, C-2), 163.3 (d, J
= 245.0 Hz, C, C-4′′), 166.2 (C=O); MS m/z 402.1 (3.2),
400.1(9.6), 290.1 (10.0), 262.1 (25.1), 237.1 (41.2), 236.1
(29.8), 235.1 (100), 233.1 (41.0), 217.1 (28.5), 215.1 (39.2),
201.1 (10.2), 200.1 (33.9), 199.1 (47.2), 185.1 (15.2), 172.1
Anal. Calcd. for C21H16ClFN2O2: C, 65.89; H, 4.21; N,
7.32. Found: C, 66.12; H, 4.36; N, 7.14.
N-(3-fluorobenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16b)
Yield 42 %; m.p. 173–175 °C; IR (KBr) 3184 (N–H), 1670
1
(C=O), 1273 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.70
(s, 0.64H, CH2), 4.09 (s, 1.36H, CH2), 6.72 (d, J = 2.0 Hz,
0.32H, H-3), 6.78 (d, J = 2.0 Hz, 0.68H, H-3), 7.04–7.55
(m, 10H), 7.96 (s, 0.68H, =CH), 8.18 (s, 0.32H, =CH),
11.56 (s, 0.68H, NH), 11.60 (s, 0.32H, NH); 13C NMR
(DMSO-d6) δ major isomer (68 %): 33.5 (CH2), 113.0 (d, J
= 22.5 Hz, CH, C-2′′), 116.8 (CH, C-3), 117.5 (d, J =
17.25 Hz, CH, C-3′), 117.6 (d, J = 17.5 Hz, CH, C-4′′),
121.7 (CH, C-5′), 123.7 (d, J = 6.25 Hz, C, C-1′′), 123.9
(CH, C-5), 123.8 (C, C-1), 125.9 (CH, C-6′), 126.0 (d, J =
6.25 Hz, CH, C-4′), 131.2 (CH, C-6′′), 132.4 (CH, C-6),

Med Chem Res
(20.4), 171.1 (39.0), 170 (61.8), 169.1 (28.7), 168.1 (82.1),
167.1 (47.2), 165.1 (26.2), 153.1 (22.0), 152.1 (44.2), 137.1
(39.5), 133.1 (28.7), 125.1 (12.7), 123.1 (19.0), 111.1
(37.7), 110.1 (12.9), 109.1 (15.8), 107.1 (14.4), 83.1 (24.0),
77.1 (19.5), 75.1 (15.6), 63.1 (8.9), 51.1 (10.5).
(s, 0.44H, CH2), 4.21 (s, 1.56H, CH2), 6.74 (d, J = 2.2 Hz,
1H, H-3), 7.04–7.25 (m, 6H), 7.31 (d, J = 8.5 Hz, 0.78H),
7.34–7.37 (m, 1H, H-5′), 7.39 (d, J = 8.5 Hz, 0.22H), 7.55
(d, J = 8.5 Hz, 1.56H, H-2′′, H-6′′), 7.64 (d, J = 8.5 Hz,
0.44H, H-2′′, H-6′′), 7.97 (s, 0.22H, =CH), 8.62 (s, 0.78H,
=CH), 9.08 (s, 0.22H, NH), 9.80 (s, 0.78H, NH); 13C NMR
(DMSO-d6) δ major isomer (78 %): 33.6 (CH2), 116.9 (CH,
C-3), 117.7 (d, J = 17.25 Hz, CH, C-3′), 121.8 (CH, C-5′),
123.8 (CH, C-5), 123.9 (C, C-1), 125.9 (CH, C-6′), 126.2
(d, J = 6.25 Hz, CH, C-4′), 129.3 (CH, C-3′′, C-5′′), 129.4
(C, C-1′′), 132.5 (CH, C-6), 133.6 (CH, C-2′′, C-6′′), 134.1
(C, C-4), 134.6 (C, C-4′′), 142.1 (CH, =CH–), 143.3 (d, J
= 11.25 Hz, C, C-1′), 153.7 (d, J = 245.0 Hz, C, C-2′),
156.1 (C, C-2), 171.9 (C=O); minor isomers (22 %): 35.4
(CH2), 116.3 (CH, C-3), 117.8 (d, J = 17.25 Hz, CH, C-3′),
122.5 (CH, C-5′), 123.8 (CH, C-5), 124.2 (C, C-1), 125.8
(CH, C-4′), 126.5 (d, J = 6.25 Hz, CH, C-6′), 129.3 (CH, C-
3′′, C-5′′), 129.4 (C, C-1′′), 132.7 (CH, C-6), 133.7 (C, C-
4), 134.9 (C, C-4′′), 136.6 (CH, C-2′′, C-6′′), 143.0 (d, J =
11.25 Hz, C, C-1′), 145.5 (CH, =CH–), 153.9 (d, J = 245.0
Hz, C, C-2′), 156.3 (C, C-2), 166.40 (C=O); MS m/z 420.2
(5.6), 419.2 (4.0), 418.2 (10.8), 417.2 (4.2), 416.1 (12.3),
235.1 (55.2), 233.1 (20.8), 217.1 (14.8), 215.1 (48.4), 200.1
(34.5), 199.1 (47.3), 183.1 (10.9), 182.2 (22.1), 181.2
(53.1), 172.1 (21.6), 171.1 (40.5), 170.1 (55.3), 169.1
(38.5), 168.1 (100), 167.1 (56.5), 155.1 (12.0), 154.1 (16.3),
153.1 (18.1), 152.1 (62.3), 147.1 (28.3), 133.1 (15.6), 120.1
(14.7), 119.1 (30.8), 111.1 (35.1), 90.1 (15.6), 89.1 (20.2),
77.1 (17.4).
Anal. Calcd. for C21H15ClF2N2O2: C, 62.93; H, 3.77; N,
6.99. Found: C, 62.80; H, 3.93; N, 6.80.
N-(3-chlorobenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl) acetic acid hydrazide (16d)
Yield 68 %; m.p. 167–170 °C; IR (KBr) 3170 (N–H), 1673
1
(C=O), 1264 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.68
(s, 0.66H, CH2), 4.08 (s, 1.34H, CH2), 6.71 (d, J = 1.8 Hz,
0.33H, H-3), 6.76 (d, J = 1.8 Hz, 0.67H, H-3), 7.07 (dt, J =
2.0, 7.9 Hz, 0.67H, H-3′), 7.14 (dt, J = 2.0, 7.9 Hz, 0.33H,
H-3′), 7.18–7.26 (m, 3H), 7.30–7.36 (m, 0.66H), 7.36–7.46
(m, 3.34H), 7.61 (dd, J = 2.1, 7.5 Hz, 1.34H, H-6′′), 7.68
(dd, J = 2.1, 7.5 Hz, 0.66H, H-6′′), 7.96 (s, 0.67H, =CH),
8.16 (s, 0.33H, =CH), 11.44 (s, 0.67H, NH), 11.55 (s,
0.33H, NH); 13C NMR (CDCl3) δ major isomer (67 %):
33.7 (CH2), 116.6 (CH, C-3), 117.1 (d, J = 17.5 Hz, CH,
C-3′), 121.9 (CH, C-5′), 123.5 (CH, C-5), 123.6 (C, C-1),
124.8 (CH, C-6′′), 125.2 (d, J = 6.25 Hz, CH, C-4′), 125.6
(CH, C-2′′), 126.2 (CH, C-6′), 129.9 (CH, C-5′′), 130.0
(CH, C-4′′), 132.4 (CH, C-6), 133.6 (C, C-4), 134.8 (C, C-
1′′), 135.6 (C, C-3′′), 142.5 (d, J = 10.0 Hz, C, C-1′), 143.4
(CH, =CH-), 154.1 (d, J = 248.75 Hz, C, C-2′), 156.1 (C,
C-2), 173.4 (C=O); minor isomer (33 %): 37.0 (CH2), 115.9
(CH, C-3), 117.4 (d, J = 17.5 Hz, CH, C-3′), 122.2 (CH,
C-5′), 123.8 (C, C-1), 124.0 (CH, C-5), 124.8 (CH, C-6′′),
125.8 (CH, C-2′′), 126.3 (d, J = 6.0 Hz, CH, C-4′), 128.4
(CH, C-6′), 130.3 (CH, C-5′′), 130.8 (CH, C-4′′), 132.6
(CH, C-6), 133.5 (C, C-4), 134.2 (C, C-1′′), 136.2 (C, C-3′′),
143.1 (d, J = 11.25 Hz, C, C-1′), 143.8 (CH, =CH–), 153.1
(d, J = 245.0 Hz, C, C-2′), 155.5 (C, C-2), 166.2 (C=O);
MS m/z 420.1 (2.3), 419.1 (2.0), 418.1 (6.1), 417.2 (2.2),
416.1 (6.2), 379.1 (5.0), 262.1 (12.0), 237.1 (26.9), 235.1
(68.3), 233.1 (28.3), 217.1 (17.0), 215.1 (52.0), 200.1
(27.3), 199.1 (42.5), 193.1 (14.9), 183.1 (5.9), 182.2 (14.1),
181.2 (50.1), 172.1 (20.6), 171.1 (38.5), 170.1 (68.4), 169.1
(42.0), 168.1 (100), 167.1 (62.5), 155.1 (13.8), 154.1 (22.4),
153.1 (27.1), 152.1 (52.7), 147.1 (27.6), 133.1 (19.4), 120.1
(18.6), 119.1 (35.4), 112.1 (18.5), 111.1 (35.1), 90.1 (15.6),
89.1 (26.6), 77.1 (17.4), 63.1 (18.3).
Anal. Calcd. for C21H15Cl2FN2O2: C, 60.45; H, 3.62; N,
6.71. Found: C, 60.61; H, 3.40; N, 6.59.
N-(3-hydroxybenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16f)
Yield 41 %; m.p. 162–164 °C; IR (KBr) 3327 (N–H), 3214
(O–H), 1658 (C=O), 1265 (C–O) cm−1; 1H NMR (DMSO-
d6): δ = 3.68 (s, 0.72H, CH2), 4.08 (s, 1.28H, CH2), 6.71
(d, J = 1.8 Hz, 0.36H, H-3), 6.74 (d, J = 1.8 Hz, 0.64H, H-
1), 6.78–6.81 (m, 1H, H-4′′), 7.01 (t, J = 7.5 Hz, 1H, H-3′),
7.05–7.40 (m, 7H), 7.42 (t, J = 8.0 Hz, 1H, H-6), 7.89 (s,
0.64H, =CH), 8.07 (s, 0.36H, =CH), 8.31 (s, 0.36H, OH),
9.5 (s, 0.64H, OH), 11.40 (s, 0.64H, NH), 11.54 (s, 0.36H,
NH); 13C NMR (DMSO-d6) δ major isomer (64 %): 33.5
(CH2), 113.0 (CH, C-2′′), 116.2 (CH, C-3), 117.7 (d, J =
17.25 Hz, CH, C-3′), 118.6 (CH, C-4′′, C-6′′), 122.0 (CH,
C-5′), 123.7 (CH, C-5), 123.8 (C, C-1), 125.9 (CH, C-6′),
126.4 (d, J = 6.25 Hz, CH, C-4′), 130.2 (CH, C-5′′), 132.4
(CH, C-6), 134.0 (C, C-4), 135.8 (C, C-1′′), 143.1 (d, J =
11.25 Hz, C, C-1′), 143.4 (CH, =CH–), 153.7 (d, J =
246.25 Hz, C, C-2′), 156.2 (C, C-2, C-3′′), 171.6 (C=O);
minor isomer (36 %): 35.2 (CH2), 112.9 (CH, C-2′′), 115.6
(CH, C-3), 117.4 (d, J = 11.25 Hz, CH, C-3′), 119.2 (CH,
Anal. Calcd. for C21H15Cl2FN2O2: C, 60.45; H, 3.62; N,
6.71. Found: C, 60.59; H, 3.73; N, 6.54.
N-(4-chlorobenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16e)
Yield 56 %; m.p. 161–165 °C; IR (KBr) 3215 (N–H), 1670
(C=O), 1267 (C–O) cm−1; 1H NMR (CDCl3): δ = 3.80

Med Chem Res
C-4′′, C-6′′), 122.4 (CH, C-5′), 123.7 (CH, C-5), 125.2 (C,
C-1), 126.0 (CH, C-6′), 126.4 (d, J = 6.25 Hz, CH, C-4′),
130.2 (CH, C-5′′), 132.5 (CH, C-6), 133.8 (C, C-4), 135.9
(C, C-1′′), 142.9 (d, J = 11.25 Hz, C, C-1′), 146.7 (CH,
=CH–), 153.8 (d, J = 246.25 Hz, C, C-2′), 157.9 (C, C-2),
158.0 (C, C-3′′), 166.1 (C=O); MS m/z 400.2 (5.8), 398.8
(15.8), 280.1 (5.1), 240.1 (14.5), 236.1 (18.4), 235.1 (79.1),
233.1 (32.4), 217.1 (18.8), 215.1 (49.4), 201.1 (14.8), 200.1
(36.6), 199.1 (54.5), 181.1 (9.4), 172.1 (19.0), 171.1 (44.7),
170.1 (71.1), 169.1 (39.0), 168.1 (100), 167.1 (68.6), 163.1
(29.2), 153.1 (12.9), 152.1 (50.4), 136.1 (38.3), 135.1
(41.2), 133.1 (20.8), 120.1 (13.3), 111.1 (35.2), 77.1 (23.0).
Anal. Calcd. for C21H16ClFN2O3: C, 63.24; H, 4.04; N,
7.02. Found: C, 63.09; H, 4.22; N, 6.89.
N-(3-methoxybenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl) acetic acid hydrazide (16h)
Yield 26 %; m.p. 129–131 °C; IR (KBr) 3187 (N–H), 1669
1
(C=O), 1263 (C–O) cm−1; H NMR (CDCl3): δ = 3.81 (s,
0.5H, CH2) 3.83 (s, 3H, OCH3), 4.23 (s, 1.5H, CH2), 6.75
(d, J = 2.0 Hz, 0.75H, H-3), 6.78 (d, J = 2.0 Hz, 0.25H, H-
3), 6.85 (dd, J = 2.25, 8.0 Hz, 0.5H, H-4′′), 6.90–6.96 (m,
1.75H), 7.03–7.22 (m, 4.75H), 7.28–7.42 (m, 3H), 7.71 (s,
0.75H, =CH), 7.97 (s, 0.25H, =CH), 8.98 (s, 0.25H, NH),
9.39 (s, 0.75H, NH); 13C NMR (DMSO-d6) δ major isomer
(75 %): 33.6 (CH2), 55.6 (OCH3), 111.7 (CH, C-2′′), 116.2
(CH, C-4′′), 116.8 (CH, C-3), 117.7 (d, J = 17.25 Hz, CH,
C-3′), 121.8 (CH, C-6′′), 122.4 (CH, C-5′), 123.8 (CH, C-
5), 124.0 (C, C-1), 126.0 (CH, C-6′), 126.1 (d, J = 6.25 Hz,
CH, C-4′), 130.3 (CH, C-5′′), 132.4 (CH, C-6), 134.0 (C,
C-4), 136.0 (C, C-1′′), 142.0 (d, J = 11.25 Hz, C-1′), 143.2
(CH, =CH–), 153.6 (d, J = 246.25 Hz, C, C-2′), 156.1 (C,
C-2), 159.9 (C, C-3′′), 171.8 (C=O); minor isomer (25 %):
35.3 (CH2), 55.6 (OCH3), 110.8 (CH, C-2′′), 116.3 (CH, C-
3), 116.6 (CH, C-4′′), 117.8 (d, J = 11.25 Hz, CH, C-3′),
120.4 (CH, C-6′′), 122.4 (CH, C-5′), 123.7 (CH, C-5),
125.2 (C, C-1), 125.9 (CH, C-6′), 126.5 (d, J = 6.25 Hz,
CH, C-4′), 130.5 (CH, C-5′′), 132.6 (CH, C-6), 133.8 (C,
C-4), 136.1 (C, C-1′′), 143.3 (d, J = 11.25 Hz, C, C-1′),
146.7 (CH, =CH–), 153.7 (d, J = 246.25 Hz, C, C-2′),
156.2 (C, C-2), 160.1 (C, C-3′′), 166.2 (C=O); MS m/z
414.2 (2.6), 412.2 (6.8), 307.2 (29.5), 306.2 (100), 305.2
(85.7), 296.2 (12.0), 290.2 (14.3), 284.2 (14.5), 240.2
(19.9), 237.1 (11.0), 235.1 (29.9), 233.1 (13.1), 215.1
(18.3), 200.1 (15.4), 199.1 (23.3), 177.1 (15.7), 171.1
(21.9), 168.1 (49.6), 167.1 (32.7), 152.1 (22.8), 149.1
(20.3), 111.1 (16.2), 83.1 (20.3), 77.1 (18.5).
N-(4-hydroxybenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16g)
Yield 37 %; m.p. 182–184 °C; IR (KBr) 3217 (N–H), 3042
(O–H), 1654 (C=O), 1262 (C–O) cm−1; 1H NMR (DMSO-
d6): δ 3.64 (s, 0.7H, CH2), 4.04 (s, 1.3H, CH2), 6.70 (d, J =
1.9 Hz, 0.35H, H-3), 6.74 (d, J = 1.9 Hz, 0.65H, H-3), 6.76
(d, J = 3.6 Hz, 1.3H, H-3′′, H-5′′), 6.79 (d, J = 3.6 Hz,
0.7H, H-3′′, H-5′′), 7.08 (dt, J = 2.1, 7.5 Hz, 0.65H, H-3′),
7.12 (dt, J = 2.1, 7.5 Hz, 0.35H, H-3′), 7.17–7.27 (m, 3H),
7.35–7.45 (m, 3.35H), 7.48 (d, J = 8.6 Hz, 0.65H, H-6),
7.85 (s, 0.65H, =CH), 8.04 (s, 0.35H, =CH), 9.85 (s,
0.65H, OH), 9.88 (s, 0.35H, OH), 11.23 (s, 0.65H, NH),
11.35 (s, 0.35H, NH); 13C NMR (DMSO-d6) δ major
isomer (65 %): 33.5 (CH2), 116.2 (CH, C-3′′, C-5′′), 116.8
(CH, C-3), 117.7 (d, J = 17.25 Hz, CH, C-3′), 121.8
(CH, C-5′), 123.8 (CH, C-5), 123.8 (C, C-1), 125.5 (C, C-1′′),
125.9 (CH, C-6′), 126.1 (d, J = 6.25 Hz, CH, C-4′), 129.5
(CH, C-2′′, C-6′′), 132.4 (CH, C-6), 134.0 (C, C-4), 143.3
(d, J = 11.25 Hz, C, C-1′), 143.4 (CH, =CH-), 153.7 (d, J =
245.0 Hz, C, C-2′), 156.1 (C, C-2), 160.2 (C, C-4′′), 171.8
(C=O); minor isomer (35 %): 35.3 (CH2), 116.0
(CH, C-3′′, C-5′′), 116.3 (CH, C-3), 117.8 (d, J = 17.0 Hz,
CH, C-3′), 122.4 (CH, C-5′), 123.7 (CH, C-5), 125.2 (C, C-1),
125.7 (C, C-1′′), 126.4 (d, J = 6.25 Hz, CH, C-4′, C-6′),
129.5 (CH, C-2′′, -6′′), 132.6 (CH, C-6), 133.8 (C, C-4),
143.1 (d, J = 11.25 Hz, C, C-1′), 146.8 (CH, =CH–), 153.8
(d, J = 245.0 Hz, C, C-2′), 156.2 (C, C-2), 160.0 (C, C-4′′),
166.2 (C=O); MS m/z 400.4 (5.8), 398.6 (22.0), 263.2 (5.0),
236.0 (22.7), 235.0 (80.1), 233.1 (35.2), 217.1 (20.6),
215.1 (50.5), 201.1 (10.5), 200.1 (25.3), 199.1 (50.7),
172.1 (25.9), 171.1 (52.1), 170.1 (68.0), 169.1 (35.8), 168.1
(100), 167.1 (70.5), 163.1 (35.8), 153.1 (15.5), 152.1 (45.2),
135.1 (33.3), 133.1 (10.5), 120.1 (15.8), 111.1 (18.2),
77.1 (21.0).
Anal. Calcd. for C22H18ClFN2O3: C, 64.00; H, 4.39; N,
6.79. Found: C, 63.83; H, 4.54; N, 6.68.
N-(4-methoxybenzylidene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl) acetic acid hydrazide (16i)
Yield 60 %; m.p. 179–182 °C; IR (KBr) 3176 (N–H), 1652
1
(C=O), 1256 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.67
(s, 0.6H, CH2), 3.79 (s, 3H, OCH3), 4.07 (s, 1.4H, CH2),
6.71 (s, 0.3H, H-3), 6.76 (s, 0.7H, H-3), 6.94–7.65 (m,
10H), 7.91 (s, 0.7H, =CH), 8.10 (s, 0.3H, =CH), 11.32 (s,
0.7H, NH), 11.54 (s, 0.3H, NH); 13C NMR (DMSO-d6) δ
major isomer (70 %): 33.5 (CH2), 55.7 (OCH3), 114.6 (CH,
C-3′′, C-5′′), 116.8 (CH, C-3), 117.7 (d, J = 17.25 Hz, CH,
C-3′), 121.8 (CH, C-5′), 123.8 (CH, C-5), 124.0 (C, C-1),
126.0 (d, J = 6.25 Hz, CH, C-4′), 126.1 (CH, C-6′), 127.2
(C, C-1′′), 128.7 (CH, C-2′′, C-6′′), 132.4 (CH, C-6), 134.0
(C, C-4), 143.2 (CH, =CH–), 143.4 (d, J = 11.25 Hz, C, C-
1′), 153.6 (d, J = 245.0 Hz, C, C-2′), 156.1 (C, C-2), 161.0
(C, C-4′′), 171.5 (C=O); minor isomer (30 %): 35.3 (CH2),
Anal. Calcd. for C21H16ClFN2O3: C, 63.24; H, 4.04; N,
7.02. Found: C, 63.05; H, 3.96; N, 7.19.

Med Chem Res
55.8 (OCH3), 114.7 (CH, C-3′′, C-5′′), 116.3 (CH, C-3),
117.6 (d, J = 17.25 Hz, CH, C-3′), 122.4 (CH, C-5′), 123.7
(CH, C-5), 125.3 (C, C-1), 126.0 (CH, C-6′), 126.4 (d, J =
6.25 Hz, CH, C-4′), 129.1 (CH, C-2′′, C-6′′), 132.6 (CH, C-
6), 133.8 (C, C-4), 143.0 (d, J = 11.25 Hz, C, C-1′), 146.7
(CH, =CH–), 153.8 (d, J = 245.0 Hz, C, C-2′), 156.2 (C, C-
2), 161.2 (C, C-4′′), 166.0 (C=O); MS m/z 414.2 (9.7),
412.2 (26.7), 236.1 (9.5), 235.1 (44.1), 233.1 (15.8), 217.1
(9.5), 215.1 (24.2), 200.1 (25.2), 199.1 (39.1), 177.1 (31.0),
172.1 (15.2), 171.1 (36.7), 170.1 (68.6), 169.1 (37.3), 168.1
(100), 167.1 (63.9), 152.1 (38.9), 151.2 (16.2), 150.2 (67.8),
149.2 (45.1), 135.1 (13.6), 134.1 (36.0), 133.1 (28.9), 112.1
(10.6), 111.1 (32.0), 106.1 (12.7), 91.1 (15.0), 77.1 (22.3).
Anal. Calcd. for C22H18ClFN2O3: C, 64.00; H, 4.39; N,
6.79. Found: C, 64.18; H, 4.52; N, 6.67.
(30.3), 120.1 (36.1), 119.1 (15.2), 111.1 (26.6), 92.1 (16.7),
91.1 (14.1), 77.1 (18.1).
Anal. Calcd. for C23H20ClFN2O4: C, 62.38; H, 4.55; N,
6.33. Found: C, 62.20; H, 4.39; N, 6.17.
N-(3,4-dimethoxybenzylidene)-2-(4-chloro-2-(2-
fluorophenoxy)phenyl) acetic acid hydrazide (16k)
Yield 30 %; m.p. 196–198 °C; IR (KBr) 3205 (N–H), 1668
(C=O), 1255 (C–O) cm−1; 1H NMR (CDCl3): δ = 3.72,
3.89, 3.90, 3.92, 3.97 (all s, 6.8H, CH2, OCH3), 4.20 (s,
1.2H, CH2), 6.74 (d, J = 2.0 Hz, 0.4H, H-3), 6.85 (d, J =
2.0 Hz, 1.2 H, H-3), 6.94–7.65 (m, 9H), 7.63 (s, 0.6H,
=CH), 7.91 (s, 0.4H, =CH), 8.87 (s, 0.6H, NH), 9.07 (s,
0.4H, NH); 13C NMR (DMSO-d6) δ major isomer (55 %):
33.5 (CH2), 55.8 (OCH3), 56.0 (OCH3), 108.3 (CH, C-5′′),
111.9 (CH, C-2′′), 116.8 (CH, C-3), 117.7 (d, J = 17.25 Hz,
CH, C-3′), 121.6 (CH, C-6′′), 121.8 (CH, C-5′), 123.8 (CH,
C-5), 123.8 (C, C-1), 125.2 (CH, C-6′), 126.1 (d, J = 6.25
Hz, CH, C-4′), 127.4 (C, C-1′′), 132.4 (CH, C-6), 134.0 (C,
C-4), 143.3 (d, J = 11.25 Hz, C, C-1′), 143.4 (CH, =CH–),
149.4 (C, C-3′′), 150.8 (C, C-4′′), 153.7 (d, J = 245.0 Hz,
C, C-2′), 156.1 (C, C-2), 171.8 (C=O); minor isomer
(45 %): 35.3 (CH2), 55.9 (OCH3), 56.0 (OCH3), 109.9 (CH,
C-5′′), 111.8 (CH, C-2′′), 116.3 (CH, C-3), 117.8 (d, J =
17.0 Hz, CH, C-3′), 122.2 (CH, C-6′′), 122.4 (CH, C-5′),
123.7 (CH, C-5), 124.0 (C, C-1), 125.2 (CH, C-6′), 126.4
(d, J = 6.25 Hz, CH, C-4′), 126.9 (C, C-1′′), 132.6 (CH, C-
6), 133.8 (C, C-4), 143.1 (d, J = 11.25 Hz, C, C-1′), 146.8
(CH, =CH–), 149.5 (C, C-3′′), 151.1 (C, C-4′′), 153.8 (d,
J = 245.0 Hz, C, C-2′), 156.2 (C, C-2), 166.2 (C=O); MS
m/z 444.6 (4.1), 442.6 (8.4), 334.2 (5.0), 332.2 (5.0), 225.1
(14.2), 207.1 (30.3), 200.1 (12.6), 199.1 (17.1), 179.2
(14.6), 171.1 (25.3), 170.1 (45.9), 169.1 (20.1), 168.1
(60.0), 167.1 (42.4), 164.1 (44.6), 163.1 (100), 152.1 (12.5),
150.1 (15.2), 149.1 (66.7), 134.1 (19.5), 133.1 (23.8), 121.1
(22.5), 120.1 (28.2), 119.1 (12.9), 111.1 (19.5), 92.1 (12.9),
91.1 (17.1), 77.1 (10.5), 63.1 (10.4), 51.1 (6.8), 43.1 (6.6).
Anal. Calcd. for C23H20ClFN2O4: C, 62.38; H, 4.55; N,
6.33. Found: C, 62.55; H, 4.30; N, 6.46.
N-(2,4-dimethoxybenzylidene)-2-(4-chloro-2-(2-
fluorophenoxy)phenyl) acetic acid hydrazide (16j)
Yield 87 %; mp 162-163 °C; IR (KBr) 3213 (N–H), 1671
1
(C=O), 1267 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.84,
3.86, 3.87, 3.90 (all s, 6.66H, CH2, OCH3), 4.20 (s, 1.34H,
CH2), 6.44 (d, J = 2.2 Hz, 0.67H, H-3), 6.45 (d, J = 2.2 Hz,
0.33H, H-3), 6.50 (dd, J = 2.2, 8.6 Hz, 0.67H, H-3′′), 6.56
(dd, J = 2.2, 8.6 Hz, 0.33H, H-3′′), 6.73 (d, J = 1.8 Hz,
0.33H, H-5′′), 6.74 (d, J = 1.8 Hz, 0.67H, H-5′′), 7.02–7.27
(m, 5H), 7.31 (d, J = 8.0 Hz, 0.67H, H-6), 7.38 (d, J = 8.0
Hz, 0.33H, H-6), 7.82 (d, J = 8.6 Hz, 0.67H, H-6′′), 7.92 (d,
J = 8.6 Hz, 0.33H, H-6′′), 8.02 (s, 0.67H, =CH), 8.53 (s,
0.33H, =CH); 13C NMR (DMSO-d6) δ major isomer
(67 %): 33.5 (CH2), 55.8 (OCH3), 56.2 (OCH3), 98.6 (CH,
C-3′′), 106.8 (CH, C-5′′), 115.5 (C, C-1′′), 116.8 (CH,
C-3), 117.7 (d, J = 17.25 Hz, CH, C-3′), 121.8 (CH, C-5′),
123.8 (CH, C-5), 124.0 (C, C-1), 125.9 (CH, C-6′), 126.1
(d, J = 6.25 Hz, CH, C-6′), 126.9 (CH, C-6′′), 132.3 (CH,
C-6), 133.9 (C, C-4), 139.1 (CH, =CH–), 143.3 (d, J =
11.25 Hz, C, C-1′), 153.7 (d, J = 246.25 Hz, C, C-2′), 156.1
(C, C-2), 159.3 (C, C-2′′), 162.6 (C, C-4′′), 171.4 (C=O);
minor isomer (33 %): 35.3 (CH2), 55.9 (OCH3), 60.2
(OCH3), 98.7 (CH, C-3′′), 105.4 (CH, C-1′′, C-5′′), 116.3
(CH, C-3), 117.6 (d, J = 17.25 Hz, CH, C-3′), 117.8 (CH,
C-3), 122.4 (CH, C-5′), 123.7 (CH, C-5), 125.4 (C, C-1),
125.8 (CH, C-6′), 126.4 (d, J = 6.25 Hz, CH, C-4′), 127.1
(CH, C-6′′), 132.6 (CH, C-6), 133.7, C, C-4), 142.4 (CH,
=CH–), 143.0 (d, J = 11.25 Hz, C-1′), 153.8 (d, J = 246.25
Hz, C, C-2′), 156.2 (C, C-2), 159.5 (C, C-2′′), 162.5 (C, C-
4′′), 162.8 (C=O); MS m/z 444.2 (6.1), 442.2 (16.4), 310.1
(9.0), 308.1 (15.4), 235.1 (21.9), 215.1 (14.2), 207.1 (26.8),
200.1 (14.7), 199.1 (22.14), 180.1 (10.5), 179.1 (20.1),
171.1 (21.1), 170.1 (44.7), 169.1 (24.4), 168.1 (77.0), 167.1
(42.4), 164.1 (37.8), 163.1 (100), 152.1 (24.2), 150.1 (10.2),
149.1 (61.9), 147.1 (27.0), 134.1 (16.6), 133.1 (17.3), 121.1
N-(3,4,5-trimethoxybenzylidene)-2-(4-chloro-2-(2-
fluorophenoxy)phenyl) acetic acid hydrazide (16l)
Yield 31 %; m.p. 205–206 °C; IR (KBr) 3209 (N–H), 1668
1
(C=O), 1238 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.68,
3.69, 3.78, 3.84 (all s, 9.67H, CH2, OCH3), 4.09 (s, 1.34H,
CH2), 6.72 (d, J = 2.0 Hz, 0.33H, H-3), 6.78 (d, J = 2.0 Hz,
0.67H, H-3), 6.91 (s, 1.34H, H-2′′, H-6′′), 6.97 (s, 0.66H,
H-2′′, H-6′′), 7.05–7.55 (m, 6H), 7.88 (s, 0.67H, =CH),
8.09 (s, 0.33H, =CH), 11.48 (s, 0.67H, NH), 11.59 (s,
0.33H, NH); 13C NMR (DMSO-d6) δ major isomer (67 %):
33.7 (CH2), 56.3 (OCH3), 60.6 (OCH3), 104.3 (CH, C-2′′,

Med Chem Res
C-6′′), 116.9 (CH, C-3), 117.6 (d, J = 17.25 Hz, CH, C-3′),
121.8 (CH, C-5′), 123.9 (CH, C-5), 124.1 (C, C-1), 126.0
(d, J = 6.25 Hz, CH, C-4′), 126.1 (CH, C-6′), 130.2 (C, C-1′′),
132.4 (CH, C-6), 134.1 (C, C-4), 139.3 (C, C-4′′), 143.3 (d,
J = 11.25 Hz, C, C-1′), 153.6 (d, J = 246.25 Hz, C, C-2′),
153.6 (C, C-3′′, C-5′′), 156.1 (C, C-2), 171.8 (C=O); minor
isomer (33 %): 35.3 (CH2), 56.4 (OCH3), 60.6 (OCH3),
104.7 (CH, C-2′′, C-6′′), 116.3 (CH, C-3), 117.8 (d, J =
11.25 Hz, CH, C-3′), 122.5 (CH, C-5′), 123.8 (CH, C-5),
124.0 (C, C-1), 125.3 (CH, C-6′), 126.8 (d, J = 6.25 Hz,
CH, C-4′), 130.0 (C, C-1′′), 132.6 (CH, C-6), 133.8 (C, C-
4), 139.6 (C, C-4′′), 143.4 (d, J = 11.25 Hz, C, C-1′), 146.8
(CH, =CH–), 153.6 (C, C-3′′, C-5′′), 153.8 (d, J = 246.25
Hz, C, C-2′), 156.2 (C, C-2), 166.2 (C=O); MS m/z 475.2
(5.0), 474.2 (18.8), 473.3 (14.8), 472.2 (48.1), 237.1 (30.1),
235.1 (33.8), 215.1 (17.5), 210.2 (27.3), 209.2 (27.8), 200.1
(18.0), 199.1 (26.4), 195.2 (38.1), 194.2 (31.9), 193.2 (100),
179.1 (19.1), 178.1 (42.2), 171.1 (22.8), 170 (28.7), 168.1
(32.0), 167.1 (16.3), 163.1 (13.6), 152.1 (30.5), 151.1
(12.5), 133.1 (10.6), 84.1 (23.1), 77.1 (7.9).
(37.3), 199.1 (45.2), 193.1 (16.2), 188.1 (15.5), 172.1
(20.3), 171.1 (45.2), 170.1 (65.4), 169.1 (41.6), 168.1 (100),
167.1 (67.5), 152.1 (48.9), 148.1 (29.7), 133.1 (10.2), 121.1
(44.3), 120.1 (45.9), 112.1 (11.7), 111.1 (37.5), 91.1 (14.9),
89.1 (30.5), 77.1 (12.2), 63.1 (10.3), 51.1 (7.4).
Anal. Calcd. for C20H15ClFN3O2: C, 62.59; H, 3.94; N,
10.95. Found: C, 62.44; H, 4.12; N, 10.76.
(Pyridin-4-ylmethylene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16n)
Yield 22 %; m.p. 192–195 °C; IR (KBr) 3421 (N–H), 1685
1
(C=O), 1260 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.79
(s, 0.6H, CH2), 4.16 (s, 1.4H, CH2), 6.71 (d, J = 1.65 Hz,
0.3H, H-3), 6.77 (d, J = 1.65 Hz, 0.7H, H-3), 7.04–7.08 (m,
0.7H, H-3′), 7.10–7.16 (m, 0.3H, H-3′), 7.17–7.25 (m, 3H),
7.27–7.35 (m, 0.7H, H-5′), 7.35–7.42 (m, 0.3H, H-5′),
7.43–7.47 (m, 1H, H-6), 7.95–8.10 (m, 2.7H, H-3′′, H-5′′,
=CH), 8.34 (s, 0.3H, =CH), 8.81 (d, J = 6.2 Hz, 1.4H, H-2′′,
H-6′′), 8.83 (d, J = 6.2 Hz, 0.6H, H-2′′, H-6′′), 12.15 (s,
0.7H, NH), 12.44 (s, 0.3H, NH); 13C NMR (DMSO-d6) δ
major isomer (70 %): 33.7 (CH2), 116.8 (CH, C-3), 117.7
(d, J = 17.25 Hz, CH, C-3′), 121.9 (CH, C-5′), 123.1 (CH,
C-2′′, C-6′′), 124.0 (CH, C-5), 125.2 (C, C-1), 126.1 (CH,
C-6′), 126.2 (d, J = 6.25 Hz), 132.7 (CH, C-6), 133.5 (C, C-
4′′), 134.2 (C, C-4), 143.2 (d, J = 11.25 Hz), 146.8 (CH, C-
2′′, C-6′′), 153.6 (d, J = 250.0 Hz, C, C-2′), 156.1 (C, C-2),
172.7 (C=O); minor isomer (30 %): 35.6 (CH2), 116.2 (CH,
C-3), 117.9 (d, J = 11.25 Hz, CH, C-3′), 122.6 (CH, C-3′′,
C-5′′), 123.3 (CH, C-5′), 123.8 (CH, C-5), 124.8 (C, C-1),
126.0 (CH, C-6′), 126.6 (d, J = 6.25 Hz, CH, C-4′), 132.9
(CH, C-6), 133.6 (C, C-4′′), 134.0 (C, C-4), 142.4 (CH,
=CH–), 142.9 (d, J = 11.25 Hz, C, C-1′), 146.9 (CH, C-2′′,
C-6′′), 153.9 (d, J = 250.0 Hz, C, C-2′), 156.4 (C, C-2),
167.3 (C=O); MS m/z 385.2 (8.3), 383.2 (15.5), 262.1
(12.8), 237.1 (27.8), 235.1 (68.6), 233.1 (37.2), 217.1
(19.0), 215.1 (48.5), 200.1 (35.6), 199.1 (50.2), 172.1
(20.3), 171.1 (45.2), 170.1 (68.4), 169.1 (39.8), 168.1 (100),
167.1 (77.0), 152.1 (45.5), 148.1 (29.5), 133.1 (13.2), 121.1
(45.3), 120.1 (45.0), 111.1 (25.1), 91.1 (15.8), 77.1 (25.2),
63.1 (15.3), 51.1 (8.4).
Anal. Calcd. for C24H22ClFN2O5: C, 60.96; H, 4.69; N,
5.92. Found: C, 61.13; H, 4.51; N, 6.10.
(Pyridin-3-ylmethylene)-2-(4-chloro-2-(2-fluorophenoxy)
phenyl)acetic acid hydrazide (16m)
Yield 28 %; m.p. 147–149 °C; IR (KBr) 3424 (N–H), 1676
1
(C=O), 1267 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.71
(s, 0.60H, CH2), 4.10 (s, 1.4H, CH2), 6.73 (d, J = 2.0 Hz,
0.3H, H-3), 6.78 (d, J = 2.0 Hz, 0.7H, H-3), 7.04–7.10 (m,
0.7H, H-3′), 7.10–7.17 (m, 0.3H, H-3′), 7.18–7.27 (m, 3H),
7.28–7.37 (m, 0.7H, H-5′), 7.38–7.50 (m, 2.3H), 8.00 (m,
1H, H-5′′), 8.01–8.03 (m, 0.7H, H-4′′), 8.07–8.11 (m, 0.3H,
H-4′′), 8.07 (d, J = 8.0 Hz, 0.7H, H-6′′), 8.22 (d, J = 8.0 Hz,
0.3H, H-6′′), 8.57 (d, J = 3.25 Hz, 0.7H, H-2′′), 8.59 (d, J
= 3.25 Hz, 0.3H, H-2′′), 8.78 (s, 0.7H, =CH), 8.80 (s, 0.3H,
=CH), 11.60 (s, 0.7H, NH), 11.70 (s, 0.3H, NH); 13C NMR
(DMSO-d6) δ major isomer (70 %): 33.5 (CH2), 116.8 (CH,
C-3), 117.7 (d, J = 17.25 Hz, CH, C-3′), 121.8 (CH, C-5′),
123.8 (CH, C-5), 124.0 (C, C-1), 125.9 (CH, C-6′), 126.1
(d, J = 6.25 Hz, CH, C-4′), 127.2 (C, C-3′′, C-5′′), 132.4
(CH, C-6), 134.0 (C, C-4), 140.9 (CH, C-4′′), 142.6 (CH,
C-2′′), 143.3 (d, J = 11.25 Hz, C, C-1′), 143.4 (CH, =CH–),
143.5 (CH, C-6′′), 153.7 (d, J = 245.0 Hz, C, C-2′), 156.1
(C, C-2), 171.8 (C=O); minor isomer (30 %): 35.3 (CH2),
116.3 (CH, C-3), 117.8 (d, J = 11.0 Hz, CH, C-3′), 122.4
(CH, C-5′), 123.7 (CH, C-5), 125.2 (CH, C-6′), 126.4 (d, J
= 6.25 Hz, CH, C-4′), 126.9 (C, C-3′′, C-5′′), 132.6 (CH,
C-6), 133.8 (C, C-4), 140.3 (CH, C-4′′), 142.4 (CH, C-2′′),
143.1 (d, J = 11.25 Hz, C, C-1′), 143.5 (CH, C-6′′), 146.8
(CH, =CH–), 153.8 (d, J = 245.0 Hz, C, C-2′), 156.2 (C,
C-2), 166.2 (C=O); MS m/z 385.1 (6.2), 383.1 (14.4), 233.1
(34.5), 217.1 (19.0), 215.1 (48.3), 214.1 (12.4), 200.1
Anal. Calcd. for C20H15ClFN3O2: C, 62.59; H, 3.94;
N, 10.95. Found: C, 69.73; H, 4.08; N, 10.88.
N-benzylidene-2-(4-chloro-2-(2-chlorophenoxy)phenyl)
acetic acid hydrazide (17a)
Yield 40 %; m.p. 167–169 °C; IR (KBr) 3210 (N–H), 1664
1
(C=O), 1241 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.69
(s, 0.5H, CH2), 4.08 (s, 1.5H, CH2), 6.65 (s, 0.25H, H-3),
6.75 (s, 0.75H, H-3), 7.03 (d, J = 8.0 Hz, 0.75H, H-6′), 7.13
(d, J = 8.0 Hz, 0.25H, H-6′), 7.15–7.25 (m, 1.75H, H-5,
H-4′), 7.27 (t, J = 8.0 Hz, 0.25H, H-4′), 7.33–7.47 (m, 5H,

Med Chem Res
H-6, H-5′, H-3′′, H-4′′, H-5′′), 7.54 (d, J = 8.0 Hz, 0.75H,
H-3′), 7.55–7.65 (m, 1.75H, H-3′, H-2′′, H-6′′), 7.67 (d, J
= 8.0 Hz, 0.5H, H-2′′, H-6′′), 7.97 (s, 0.75H, =CH), 8.17 (s,
0.25H, =CH), 11.45 (s, 0.75H, NH), 11.59 (s, 0.25H, NH);
13C NMR (DMSO-d6) δ major isomer (75 %): 33.6 (CH2),
117.4 (CH, C-3), 121.0 (CH, C-6′), 124.1 (CH, C-5), 124.7
(C, C-1), 126.1 (CH, C-4′), 126.3 (CH, C-2′), 127.2 (CH,
C-3′′, C-5′′), 129.3 (CH, C-2′′, C-6′′), 129.4 (CH, C-5′),
130.3 (CH, C-4′′), 131.2 (CH, C-6), 132.5 (C, C-4), 134.2
(CH, C-3′), 134.6 (C, C-1′′), 143.4 (CH, =CH-), 151.9 (C,
C-1′), 155.7 (C, C-2), 171.9 (C=O); minor isomer (25 %):
35.4 (CH2), 116.6 (CH, C-3), 121.9 (CH, C-6′), 123.9
(CH, C-5), 125.2 (C, C-1), 125.4 (C, C-2′), 126.6 (CH, C-
4′), 127.6 (CH, C-3′′, C-5′′), 129.3 (CH, C-2′′, C-6′′),
129.6 (CH, C-5′), 130.5 (CH, C-4′′), 131.4 (CH, C-6),
132.7 (C, C-4), 134.0 (CH, C-3′), 134.7 (C, C-1′′), 146.8
(CH, =CH–), 151.6 (C, C-1′), 156.0 (C, C-2), 166.2 (C=O);
MS m/z 403.2 (2.3), 401.2 (12.2), 400.2 (13.2), 399.2
(19.1), 398.9 (19.0), 253.1 (14.3), 251.1 (24.2), 218.1
(13.6), 217.1 (40.9), 216.1 (45.6), 215.1 (100), 181.1 (36.6),
170.1 (18.3), 169.1 (23.6), 168.1 (58.9), 167.1 (55.4), 163.2
(11.1), 153.1 (13.5), 152.1 (45.9), 147.1 (12.6), 129.1
(11.5), 127.1 (35.5), 120.1 (29.4), 119.2 (37.3), 103.2
(10.2), 92.1 (23.7), 91.3 (10.5), 90.2 (16.8), 89.1 (31.9),
77.1 (30.8), 76.2 (15.0), 75.1 (18.8), 63.1 (21.8), 51.1
(23.3).
(C, C-2), 162.8 (d, J = 242.5 Hz, C, C-3′′), 171.9 (C=O);
minor isomers (29 and 21 %): 35.3 (CH2), 112.9 (d, J =
22.5 Hz, CH, C-2′′), 113.4 (d, J = 22.5 Hz, CH, C-2′′),
116.5 (CH, C-3), 117.0 (CH, C-3), 118.8 (d, J = 21.25 Hz,
CH, C-4′′), 121.2 (CH, C-6′), 121.7 (CH, C-6′), 123.8 (CH,
C-5, C, C-1′′), 124.0 (CH, C-5, C, C-1′′), 124.5 (C, C-2′),
124.7 (C, C-2′), 125.9 (C, C-4′), 126.4 (C, C-4′), 129.3
(CH, C-5′), 129.4 (CH, C-5′), 131.3, (d, J = 7.5 Hz, CH, C-
6′′), 131.3 (CH, C-6), 131.5 (d, J = 7.5 Hz, CH, C-6′′),
132.6 (C, C-4), 132.9 (C, C-4), 133.9 (CH, C-3′), 137.2 (d,
J = 6.25 Hz, CH, C-5′′), 137.3 (d, J = 6.25 Hz, CH, C-5′′),
145.3 (CH, =CH–), 151.2 (C, C-1′), 151.4 (C, C-1′), 155.6
(C, C-2), 155.8 (C, C-2), 161.2 (d, J = 242.5 Hz, C, C-3′′),
162.7 (d, J = 242.5 Hz, C, C-3′′), 166.2 (C=O), 166.3
(C=O); MS m/z 419.2 (12.1), 418.9 (12.3), 418.2 (14.7),
417.9 (14.8), 417.2 (20.0), 416.9 (20.2), 416.3 (17.6), 253.0
(18.9), 251.1 (13.4), 218.1 (14.6), 217.1 (40.3), 216.1
(47.8), 215.1 (100), 182.1 (8.1), 181.1 (35.0), 170.0 (13.3),
169.1 (18.0), 168.1 (43.3), 167.1 (42.7), 165.2 (9.3), 153.1
(12.9), 152.1 (44.3), 139.1 (8.9), 138.1 (22.9), 137.1 (24.5),
129.1 (8.4), 127.1 (27.0), 122.1 (8.3), 121.1 (8.2), 110.1
(12.7), 108.1 (10.4), 107.1 (16.6), 95.1 (13.6), 90.1 (10.9),
89.1 (15.8), 83.1 (16.5), 77.1 (10.8), 75.1 (23.9), 63.1
(15.9), 51.1 (11.6), 50.2 (10.2).
Anal. Calcd. for C21H15Cl2FN2O2: C, 60.45; H, 3.62; N,
6.71. Found: C, 60.31; H, 3.77; N, 6.55.
Anal. Calcd. for C21H16Cl2N2O2: C, 63.17; H, 4.04; N,
7.02. Found: C, 63.35; H, 3.90; N, 7.19.
N-(4-fluorobenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)
phenyl)acetic acid hydrazide (17c)
N-(3-fluorobenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)
phenyl)acetic acid hydrazide (17b)
Yield 55 %: m.p. 146–148 °C: IR (KBr) 3232 (N–H), 1667
1
(C=O), 1246 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.68
Yield 76 %; m.p. 152–154 °C; IR (KBr) 3188 (N–H), 1668
(s, 0.6H, CH2), 4.07 (s, 1.4H, CH2), 6.64 (d, J = 1.5 Hz,
0.3H, H-3), 6.74 (d, J = 1.5 Hz, 0.7H, H-3), 7.04 (d, J = 8.0
Hz, 0.7H, H-6′), 7.13 (d, J = 8.0 Hz, 0.3H, H-6′), 7.12-7.30
(m, 4H, H-5, H-4′, H-3′′, H-5′′), 7.35 (t, J = 8.0 Hz, 0.7H,
H-5′), 7.39 (t, J = 8.0 Hz, 0.3H, H-5′), 7.42 (d, J = 8.0 Hz,
0.7H, H-6), 7.43 (d, J = 8.0 Hz, 0.3H, H-6), 7.52 (d, J = 8.0
Hz, 0.7H, H-3′), 7.61 (d, J = 8.0 Hz, 0.3H, H-3′), 7.66 (dd,
J = 6.5, 7.5 Hz, 1.4H, H-2′′, H-6′′), 7.71 (dd, J = 6.5, 7.5
Hz, 0.6H, H-2′′, H-6′′), 7.95 (s, 0.7H, =CH), 8.17 (s, 0.3H,
=CH), 11.43 (s, 0.7H, NH), 11.57 (s, 0.3H, NH); 13C NMR
(DMSO-d6) δ major isomer (70 %): 33.4 (CH2), 116.2 (d, J
= 21.5 Hz, C, C-3′′, C-5′′), 117.4 (CH, C-3), 120.8 (CH, C-
6′), 124.0 (CH, C-5), 124.6 (C, C-1), 126.0 (CH, C-4′),
126.2 (CH, C-2′), 129.2 (d, J = 7.5 Hz, CH, C-2′′, C-6′′),
129.3 (CH, C-5′), 131.2 (C, C-1′′), 131.2 (CH, C-6), 132.4
(C, C-4), 134.1 (CH, C-3′), 142.1 (CH, =CH–), 151.8 (C,
C-1′), 155.6 (C, C-2), 163.3 (d, J = 245.0 Hz, C, C-4′′),
172.5 (C=O); minor isomer (30 %): 35.3 (CH2), 116.4 (d, J
= 21.5 Hz, CH, C-3′′, C-5′′), 116.5 (CH, C-3), 121.8 (CH,
C-6′), 123.8 (CH, C-5), 124.9 (C, C-1), 125.1 (C, C-2′),
126.5 (CH, C-4′), 129.5 (CH, C-5′), 129.6 (d, J = 7.5 Hz,
1
(C=O), 1241 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.71
(s, 0.58H, CH2), 3.74 (s, 0.42H, CH2), 4.09 (s, 1H, CH2),
6.66 (d, J = 2.0 Hz, 0.29H, H-3), 6.72 (d, J = 2.0 Hz, 0.21H,
H-3), 6.77 (d, J = 2.0 Hz, 0.5H, H-3), 7.02 (dd, J = 1.5, 8.0
Hz, 0.5H, H-6′), 7.06 (dd, J = 1.5, 8.0 Hz, 0.21H, H-6′),
7.13 (dd, J = 1.5, 8.0 Hz, 0.29H, H-6′), 7.20 (dt, J = 1.5,
8.0 Hz, 0.5H, H-4′), 7.22-7.32 (m, 2.5H, H-5, H-4′, H-4′′),
7.36 (dt, J = 1.5, 8.0 Hz, 0.5H, H-5′), 7.38-7.51 (m, 3.5H,
H-6, H-5′, H-2′′, H-5′′), 7.53 (d, J = 8.0 Hz, 0.5H, H-3′),
7.56–7.66 (m, 0.71H, H-3′, H-6′′), 7.68–7.72 (m, 0.29H, H-
6′′), 7.75 (d, J = 8.0 Hz, 0.5H, H-6′′), 7.96 (s, 0.29H,
=CH), 8.19 (s, 0.21H, =CH), 8.75 (s, 0.5H, =CH), 11.55 (s,
0.79H, NH), 11.75 (s, 0.21H, NH); 13C NMR (DMSO-d6) δ
major isomer (50 %): 33.4 (CH2), 114.8 (d, J = 22.5 Hz,
CH, C-2′′), 117.4 (CH, C-3), 118.8 (d, J = 21.25 Hz, CH,
C-4′′), 120.7 (CH, C-6′), 123.7 (C, C-1′′), 124.1 (CH, C-5),
124.7 (C, C-1), 126.2 (CH, C-4′), 126.5 (C, C-2′), 129.4
(CH, C-5′), 131.3 (CH, C-6), 131.5 (d, J = 7.5 Hz, CH, C-6′′),
132.4 (C, C-4), 134.1 (CH, C-3′), 136.5 (d, J = 6.25 Hz,
CH, C-5′′), 141.8 (CH, =CH–), 151.8 (C, C-1′), 155.5

Med Chem Res
CH, C-2′′, C-6′′), 131.3 (CH, C-6), 132.4 (C, C-4′), 133.6
(C, C-1′′), 133.9 (CH, C-3′), 145.6 (CH, =CH–), 151.4 (C,
C-1′), 155.9 (C, C-2), 163.3 (d, J = 245.0 Hz, C, C-3′′),
166.1 (C=O); MS m/z 419.1 (15.1), 418.5 (13.3), 418.1
(16.7), 417.5 (12.6), 416.5 (20.2), 416.0 (20.2), 253.0
(19.6), 251.1 (16.3), 218.1 (24.6), 217.1 (51.3), 216.1
(47.8), 215.1 (100), 181.1 (37.0), 169.1 (16.6), 168.1 (40.1),
167.1 (44.5), 165.2 (12.7), 153.1 (15.6), 152.1 (43.4), 139.1
(12.0), 138.1 (25.9), 137.1 (29.5), 129.1 (8.4), 127.1 (25.2),
110.1 (19.5), 108.1 (10.4), 107.1 (19.2), 89.1 (9.8), 77.1
(12.7), 75.1 (26.0), 63.1 (17.9), 51.1 (20.5).
(43.0), 216.1 (43.7), 215.1 (100), 183.2 (6.4), 182.2 (9.6),
181.2 (41.8), 171.2 (4.2), 170.1 (18.2), 169.1 (22.0), 168.1
(52.2), 167.1 (44.6), 155.2 (11.5), 154.1 (17.3), 153.1
(28.0), 152.2 (42.2), 151.2 (12.0), 149.2 (9.4), 139.2 (10.0),
137.2 (9.2), 30.1 (3.4), 129.1 (11.9), 128.1 (9.1), 127.1
(27.7), 126.2 (8.1), 125.2 (12.5), 111.2 (21.4), 109.2 (9.7),
99.2 (11.8), 97.2 (21.3), 95.2 (13.1), 89.1 (20.7), 85.2
(18.1), 84.2 (24.1), 83.2 (19.8), 81.2 (11.3), 71.2 (19.8),
66.1 (20.1), 57.2 (31.1), 55.2 (19.3).
Anal. Calcd. for C21H15Cl3N2O2: C, 58.15; H, 3.49; N,
6.46. Found: C, 58.02; H, 3.61; N, 6.30.
Anal. Calcd. for C21H15Cl2FN2O2: C, 60.45; H, 3.62; N,
6.71. Found: C, 60.29; H, 3.73; N, 6.99.
N-(4-chlorobenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)
phenyl)acetic acid hydrazide (17e)
N-(3-chlorobenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)
phenyl) acetic acid hydrazide (17d)
Yield 58 %; m.p. 165–167 °C; IR (KBr) 3180 (N–H), 1666
1
Yield 66 %; m.p. 130–132 °C; IR (KBr) 3208 (N–H), 1665
(C=O), 1241 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.69
1
(C=O), 1240 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.71
(s, 0.64H, CH2), 4.08 (s, 1.36H, CH2), 6.66 (d, J = 1.5 Hz,
0.32H, H-3), 6.77 (d, J = 1.5 Hz, 0.68H, H-3), 7.03 (d, J =
8.0 Hz, 0.68H, H-6′), 7.13 (d, J = 8.0 Hz, 0.32H, H-6′),
7.17–7.28 (m, 2H, H-5, H-4′), 7.36 (t, J = 8.0 Hz, 0.68H, H-
5′), 7.40 (d, J = 8.0 Hz, 0.32H, H-5′), 7.43–7.54 (m, 3H, H-
6, H-3′′, H-5′′), 7.56 (d, J = 8.0 Hz, 0.68H, H-3′),
7.62–7.67 (m, 1.68H, H-3′, H-2′′, H-6′′), 7.71 (d, J = 8.5
Hz, 0.64H, H-2′′, H-6′′), 7.95 (s, 0.68H, =CH), 8.20 (s,
0.32H, =CH), 11.53 (s, 0.68H, NH), 11.68 (s, 0.32H, NH);
13C NMR (DMSO-d6) δ major isomer (68 %): 33.6
(CH2), 117.4 (CH, C-3), 121.0 (CH, C-6′), 124.1 (CH, C-5),
127.4 (C, C-1), 125.2 (C, C-2′), 126.1 (CH, C-4′), 126.3
(CH, C-2′), 129.3 (CH, C-3′′, C-5′′), 129.4 (CH, C-5′),
129.5 (C, C-1′′), 131.2 (CH, C-6), 132.5 (C, C-4), 133.5
(CH, C-2′′, C-6′′), 134.2 (CH, C-3′), 134.6 (C, C-4′′),
143.4 (CH, =CH–), 151.9 (C, C-1′), 155.7 (C, C-2), 171.9
(C=O); minor isomer (32 %): 35.4 (CH2), 116.6 (CH, C-3),
121.9 (CH, C-6′), 123.9 (CH, C-5), 125.2 (C, C-1), 125.4
(CH, C-2′), 126.6 (C, C-4′), 129.3 (CH, C-3′′, C-5′′), 129.4
(C, C-1′′), 129.6 (CH, C-5′), 131.4 (CH, C-6), 132.7 (C, C-
4), (134.0 (CH, C-3′), 134.9 (C, C-4′′), 136.6 (CH, C-2′′,
C-6′′), 146.8 (CH, =CH–), 151.6 (C, C-1′), 156.0 (C, C-2),
166.2 (C=O); MS m/z 438.2 (0.5), 437.2 (0.8), 436.1
(2.3), 435.1 (2.0), 434.1 (6.1), 433.2 (2.2), 432.1 (6.2),
400.2 (1.5), 399.2 (3.3), 398.2 (2.3), 397.2 (4.6), 278.1
(7.9), 253.1 (27.6), 252.1 (10.4), 251.1 (43.0), 249.1
(7.4), 219.1 (6.2), 218.1 (19.3), 217.1 (52.0), 216.1 (50.2),
215.1 (100), 183.1 (5.9), 182.2 (14.1), 181.2 (50.1), 180.2
(6.0), 171.1 (4.5), 170.1 (25.2), 169.1 (28.3), 168.1 (67.0),
167.1 (52.4), 163.2 (7.9), 155.1 (10.7), 154.1 (22.4), 153.1
(33.1), 152.2 (45.2), 151.2 (10.0), 129.1 (10.2), 127.1
(29.0), 111.1 (11.6), 90.1 (10.6), 89.1 (25.5), 75.1 (13.4),
63.1 (9.7).
(s, 0.58H, CH2), 3.74 (s, 0.34H, CH2), 4.09 (s, 1.08H,
CH2), 6.66 (d, J = 2.0 Hz, 0.29H, H-3), 6.72 (d, J = 2.0 Hz,
0.17H, H-3), 6.78 (d, J = 2.0 Hz, 0.54H, H-3), 7.02 (dd, J =
1.0, 8.0 Hz, 0.54H, H-6′), 7.06 (dd, J = 1.0, 8.0 Hz, 0.17H,
H-6′), 7.13 (dd, J = 1.0, 8.0 Hz, 0.29H. H-6′), 7.20 (t, J =
8.0 Hz, 0.54H, H-4′), 7.22–7.29 (m, 1.46H, H-5, H-4′), 7.36
(t, J = 8.0 Hz, 0.54H, H-5′), 7.37–7.50 (m, 2.92H, H-6, H-
5′, H-4′′, H-5′′), 7.53 (dd, J = 1.5, 7.5 Hz, 0.54H, H-4′′),
7.56 (d, J = 8.0 Hz, 0.54H, H-3′), 7.58 (d, J = 8.0 Hz,
0.46H, H-3′), 7.62–7.65 (m, 1H, H-6′′), 7.66 (d, J = 1.5 Hz,
0.54H, H-2′′), 7.73 (d, J = 1.5 Hz, 0.46H, H-2′′), 7.87 (s,
0.29H, =CH), 7.95 (s, 0.54H, =CH), 8.18 (s, 0.17H, =CH),
11.57 (s, 0.54H, NH), 11.74 (s, 0.46H, NH); 13C NMR
(DMSO-d6) δ major isomer (54 %): 33.4 (CH2), 117.5 (CH,
C-3), 120.7 (CH, C-6′), 124.2 (CH, C-5), 124.7 (C, C-1),
126.1 (CH, C-4′), 126.2 (C, C-2′), 127.4 (CH, C-6′′), 128.3
(CH, C-2′′), 129.3 (CH, C-5′), 129.8 (CH, C-5′′), 131.2
(CH, C-6), 131.3 (CH, C-6), 131.6 (CH, C-4′′), 132.5 (C,
C-4), 133.9 (C, C-1′′), 134.2 (C, C-3′), 136.2 (C, C-3′′),
141.7 (CH, =CH–), 151.9 (C, C-1′), 155.5 (C, C-2), 171.9
(C=O); minor isomers (29 and 17 %): 33.5 (CH2), 35.3
(CH2), 116.5 (CH, C-3), 121.5 (CH, C-6′), 121.9 (CH, C-
6′), 124.0 (CH, C-5), 124.1 (CH, C-5), 125.0 (C, C-1),
125.2 (C, C-2′), 126.0 (CH, C-2′), 126.3 (CH, C-6′′), 126.4
(CH, C-4′), 126.7 (C, C-4′), 127.4 (CH, C-2′′), 128.3 (CH,
C-2′′), 129.5 (CH, C-5′), 130.0 (CH, C-5′′), 131.1 (CH, C-
4′′), 131.3 (CH, C-4′′), 131.4 (CH, C-6), 131.4 (CH, C-6),
132.5 (C, C-4), 133.9 (C, C-1′′), 134.0 (CH, C-3′), 136.8
(C, C-3′′), 137.0 (C, C-3′′), 145.2 (CH, =CH–), 145.8 (CH,
=CH–), 151.6 (C, C-1′), 155.7 (C, C-2), 161.1 (C=O),
166.3 (C=O); MS m/z 438.3 (0.74), 437.2 (1.1), 436.1 (2.7),
435.2 (2.4), 434.1 (7.2), 433.3 (2.8), 432.1 (7.7), 331.1
(6.5), 316.3 (4.8), 253.1 (29.1), 252.1 (9.9), 251.1 (42.0),
249.1 (7.3), 239.3 (9.0), 219.2 (4.6), 218.1 (15.9), 217.1
Anal. Calcd. for C21H15Cl3N2O2: C, 58.15; H, 3.49; N,
6.46. Found: C, 58.33; H, 3.34; N, 6.61.

Med Chem Res
N-(3-hydroxybenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)
phenyl) acetic acid hydrazide (17f)
0.37H, H-5′), 7.42–7.47 (m, 2.26H, H-6, H-2′′, H-6′′), 7.49
(d, J = 8.5 Hz, 0.74H, H-2′′, H-6′′), 7.55 (dd, J = 1.0, 8.0
Hz, 0.63H, H-3′), 7.62 (dd, J = 1.0, 8.0 Hz, 0.37H, H-3′),
7.86 (s, 0.63H, =CH), 8.05 (s, 0.37H, =CH), 9.79 (s,
0.37H, OH), 9.88 (s, 0.63H, OH), 11.27 (s, 0.63H, NH),
11.38 (s, 0.37H, NH); 13C NMR (DMSO-d6) δ major iso-
mer (68 %): 33.6 (CH2), 116.2 (CH, C-3′′, C-5′′), 117.4
(CH, C-3), 121.0 (CH, C-6′), 124.1 (CH, C-5), 124.7 (C, C-
1), 125.5 (C, C-1′′), 126.1 (CH, C-4′), 126.3 (CH, C-2′),
129.4 (CH, C-2′′, C-6′′), 129.5 (CH, C-5′), 131.2 (CH, C-
6), 132.5 (C, C-4), 134.2 (CH, C-3′), 143.4 (CH, =CH–),
151.9 (C, C-1′), 155.7 (C, C-2), 160.2 (C, C-4′′), 171.9
(C=O); minor isomer (32 %): 35.4 (CH2), 115.9 (CH, C-3′′,
C-5′′), 116.6 (CH, C-3), 121.9 (CH, C-6′), 123.9 (CH, C-5),
125.2 (C, C-1), 125.4 (CH, C-2′), 125.5 (C, C-1′′), 126.6
(C, C-4′), 129.6 (CH, C-2′′, C-6′′), 129.7 (CH, C-5′), 131.4
(CH, C-6), 132.7 (C, C-4) 134.0 (CH, C-3′), 146.8 (CH,
=CH–), 151.6 (C, C-1′), 156.0 (C, C-2), 160.2 (C, C-4′′),
166.2 (C=O); MS m/z 418.2 (1.1), 417.2 (1.5), 416.2 (5.2),
415.2 (2.4), 414.2 (8.2), 253.1 (15.3), 251.1 (25.8), 218.1
(14.3), 217.1 (42.9), 216.1 (41.3), 215.1 (100), 182.1 (10.7),
181.1 (43.2), 170.1 (28.3), 169.1 (28.1), 168.1 (81.9), 167.1
(59.5), 163.1 (16.9), 153.1 (14.7), 152.1 (48.6), 151.1 (9.8),
136.1 (55.1), 135.1 (40.9), 129.1 (12.0), 128.1 (10.1), 127.1
(35.6), 105.1 (10.4), 89.1 (12.1), 78.1 (10.7), 77.1
(21.1),75.1 (11.2), 65.1 (10.7), 63.1 (10.1), 51.1 (10.4).
Anal. Calcd. for C21H16Cl2N2O3: C, 60.74; H, 3.88; N,
6.75. Found: C, 60.56; H, 3.75; N, 6.90.
Yield 37 %: m.p. 166–168 °C; IR (KBr) 3322 (O–H), 3201
(N–H), 1665 (C=O), 1238 (C–O) cm−1; 1H NMR (DMSO-
d6): δ = 3.67 (s, 0.76H, CH2), 4.07 (s, 1.24H, CH2), 6.65 (d,
J = 2.0 Hz, 0.38H, H-3), 6.72 (d, J = 2.0 Hz, 0.62H, H-3),
6.78–6.83 (m, 1H, H-2′′), 7.01–7.08 (m, 1.62H, H-6′, H-4′′),
7.10–7.14 (m, 0.76H, H-6′), 7.18–7.24 (m, 2.86H, H-5, H-
4′, H-6′′), 7.26 (dt, J = 1.5, 8.0 Hz, 0.38H, H-4′), 7.29 (d, J
= 8.0 Hz, 0.38H, H-6′′), 7.37 (t, J = 8.0 Hz, 0.62H, H-5′),
7.40 (t, J = 8.0 Hz, 0.38H, H-5′), 7.44 (d, J = 8.0 Hz, 0.62H,
H-6), 7.45 (d, J = 8.0 Hz, 0.38H, H-6), 7.55 (dd, J = 1.5,
8.0 Hz, 0.62H, H-3′), 7.62 (dd, J = 1.5, 8.0 Hz, 0.38H, H-3′),
7.88 (s, 0.62H, =CH), 7.95 (s, 0.38H, OH), 8.08 (s, 0.38H,
=CH), 8.60 (s, 0.62H, OH), 11.38 (s, 0.62H, NH), 11.55 (s,
0.38H, NH); 13C NMR (DMSO-d6) δ major isomer (62 %):
33.5 (CH2), 113.0 (CH, C-2′′), 117.1 (CH, C-4′′), 117.4
(CH, C-3), 118.6 (CH, C-6′′), 121.1 (CH, C-6′), 123.9 (CH,
C-5), 124.8 (C, C-1), 126.1 (C, C-2′), 126.3 (CH, C-4′),
129.4 (CH, C-5′), 130.3 (CH, C-5′′), 131.2 (CH, C-6),
131.3, 132.4 (C, C-4), 134.2 (C, C-3′), 135.9 (C, C-1′′),
143.5 (CH, =CH–), 151.7 (C, C-1′), 155.8 (C, C-2), 158.0
(C, C-3′′), 171.6 (C=O); minor isomer (38 %): 35.4 (CH2),
112.9 (CH, C-2′′), 116.6 (CH, C-3), 117.8 (CH, C-4′′),
119.3 (CH, C-6′′), 121.8 (CH, C-6′), 123.8 (CH, C-5),
125.1 (C, C-1), 125.4 (CH, C-2′), 126.3 (CH, C-4′), 129.5
(CH, C-5′), 130.5 (CH, C-5′′), 131.4 (CH, C-6), 132.7 (C,
C-4), 133.9 (C, C-3′), 136.0 (C, C-1′′), 146.8 (CH, =CH–),
151.6 (C, C-1′), 155.9 (C, C-2), 158.0 (C, C-3′′), 166.1
(C=O); MS m/z 418.0 (2.6), 417.0 (3.1), 416.0 (13.3), 415.0
(10.5), 414.0 (12.2), 253.1 (25.3), 251.1 (17.7), 218.1
(10.5), 217.1 (45.8), 216.1 (37.5), 215.1 (100), 182.1 (12.7),
181.1 (52.1), 170.1 (33.3), 169.1 (25.1), 168.1 (75.9), 167.1
(50.5), 163.1 (10.3), 153.1 (16.7), 152.1 (50.6), 151.1
(12.8), 136.1 (57.1), 135.1 (44.9), 129.1 (9.4), 128.1 (8.5),
127.1 (33.6), 105.1 (15.4), 89.1 (17.1), 78.1 (16.7), 77.1
(27.1), 75.1 (15.2), 65.1 (9.7), 63.1 (12.1), 51.1 (13.4).
Anal. Calcd. for C21H16Cl2N2O3: C, 60.74; H, 3.88; N,
6.75. Found: C, 60.91; H, 4.05; N, 6.82.
N-(3-methoxybenzylidene)-2-(4-chloro-2-(2-
chlorophenoxy)phenyl) acetic acid hydrazide (17h)
Yield 34 %; m.p. 155-157 °C; IR (KBr) 3250 (N–H), 1678
1
(C=O), 1239 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.68
(s, 0.7H, CH2), 3.76 (s, 1.95H, OCH3), 3.79 (s, 1.05H,
OCH3), 4.08 (s, 1.3H, CH2), 6.65 (d, J = 1.5 Hz, 0.35H, H-3),
6.74 (d, J = 1.5 Hz, 0.65H, H-3), 6.95-7.01 (m, 1H, H-4′′),
7.03 (dd, J = 1.0, 8.0 Hz, 0.65H, H-6′), 7.12 (dd, J = 1.0,
8.0 Hz, 0.35H, H-6′), 7.15–7.25 (m, 3.65H, H-5, H-4′, H-2′′,
H-5′′), 7.26 (dt, J = 1.0, 8.0 Hz, 0.35H, H-4′), 7.30 (d, J =
8.0 Hz, 0.65H, H-5′), 7.32–7.38 (m, 1H, H-6, H-5′), 7.45
(dt, J = 1.0, 8.0 Hz, 0.35H, H-6), 7.45 (d, J = 8.0 Hz, 0.65H,
H-6′′), 7.46 (d, J = 8.0 Hz, 0.35H, H-6′′), 7.53 (dd, J = 1.0,
8.0 Hz, 0.65H, H-3′), 7.63 (dd, J = 1.0, 8.0 Hz, 0.35H, H-
3′), 7.93 (s, 0.65H, =CH), 8.15 (s, 0.35H, =CH), 11.45 (s,
0.65H, NH), 11.59 (s, 0.35H, NH); 13C NMR (DMSO-d6) δ
major isomer (65 %): 33.5 (CH2), 55.5 (OCH3), 111.6 (CH,
C-2′′), 116.2 (CH, C-4′′), 117.3 (CH, C-3), 120.9 (CH, C-6′′),
124.0 (C, C-4), 125.5 (C, C-2′), 126.0 (C, C-1), 126.2 (CH,
C-4′), 129.3 (CH, C-5′), 130.3 (CH, C-5′′), 131.1 (CH, C-
3′), 132.4 (CH, C-6), 134.1 (C, C-4), 136.0 (C, C-1′′),
143.1 (CH, =CH–), 151.8 (C, C-1′), 155.6 (C, C-2), 159.9
(C, C-3′′), 171.7 (C=O); minor isomer (35 %): 35.3 (CH2),
N-(4-hydroxybenzylidene)-2-(4-chloro-2-(2-chlorophenoxy)
phenyl)acetic acid hydrazide (10g)
Yield 38 %; m.p. 176–178 °C; IR (KBr) 3320 (O–H), 3216
(N–H), 1658 (C=O), 1238 (C–O) cm−1; 1H NMR (DMSO-
d6): δ = 3.65 (s, 0.74H, CH2), 4.04 (s, 1.26H, CH2), 6.65 (d,
J = 2.0 Hz, 0.37H, H-3), 6.74 (d, J = 2.0 Hz, 0.63H, H-3),
6.78 (d, J = 8.5 Hz, 1.26H, H-3′′, H-5′′), 6.81 (d, J = 8.5
Hz, 0.74H, H-3′′, H-5′′), 7.03 (d, J = 8.5 Hz, 0.63H, H-6′),
7.12 (d, J = 8.5 Hz, 0.37H, H-6′), 7.18–7.25 (m, 1.63H, H-
5, H-4′), 7.26 (dt, J = 1.0, 8.0 Hz, 0.37H, H-4′), 7.36 (dt, J
= 1.0, 8.0 Hz, 0.63H, H-5′), 7.40 (dt, J = 1.0, 8.0 Hz,

Med Chem Res
55.6 (OCH3), 111.6 (CH, C-2′′), 116.5 (CH, C-3), 116.5
(CH, C-4′′), 120.3 (CH, C-6′′), 121.7 (CH, C-6′), 123.8
(CH, C-5), 125.1 (C, C-1), 125.4 (CH, C-2′), 126.5 (C, C-
4′), 129.5 (CH, C-5′), 130.4 (CH, C-5′′), 131.3 (CH, C-6),
132.6 (C, C-4), 133.9 (CH, C-3′), 136.1 (C, C-1′′), 146.6
(CH, =CH–), 151.5 (C, C-1′), 155.9 (C, C-2), 159.9 (C, C-
3′′), 166.1 (C=O); MS m/z 432.0 (1.37), 431.0 (2.2), 430.0
(6.1), 428.0 (8.9), 260.0 (5.8), 253.0 (15.6), 251.0 (25.9),
218.0 (16.1), 217.1 (42.5), 216.1 (51.1), 215.1 (100), 182.1
(10.5), 181.1 (40.7), 177.1 (16.0), 170.0 (22.5), 169.1
(28.0), 168.1 (69.8), 167.1 (66.3), 153.1 (16.1), 152.1
(52.4), 151.1 (21.3), 150.1 (33.8), 149.1 (39.6), 134.1
(20.0), 133.1 (15.0), 129.1 (13.3), 128.1 (10.9), 127.1
(40.4), 119.1 (10.8), 107.1 (14.4), 106.1 (9.9), 92.1 (14.7),
91.1 (19.4), 90.2 (13.2), 89.1 (21.7), 78.1 (14.0), 77.1
(41.9), 76.2 (18.6), 75.1 (22.8), 65.1 (12.2), 64.1 (13.3),
63.1 (23.6), 57.1 (18.5), 55.1 (12.6), 51.1 (29.3), 50.2
(16.8).
(41.6), 249.1 (9.5), 242.1 (6.7), 219.2 (10.2), 218.1 (17.0),
217.1 (48.3), 216.1 (45.4), 215.1 (100), 214.2 (12.8), 181.2
(41.6), 176.2 (10.2), 170.1 (9.9), 169.1 (9.6), 168.1 (26.3),
167.1 (18.5), 155.2 (9.8), 153.2 (14.1), 152.2 (40.9), 151.2
(11.2), 127.1 (13.6), 89.1 (11.6), 77.1 (11.4), 75.1 (10.7).
Anal. Calcd. for C22H18Cl2N2O3: C, 61.55; H, 4.23; N,
6.53. Found: C, 61.42; H, 4.08; N, 6.37.
N-(2,4-dimethoxybenzylidene)-2-(4-chloro-2-(2-
fluorophenoxy)phenyl) acetic acid hydrazide (17j)
Yield 91 %; m.p. 174–176 °C; IR (KBr) 3206 (N–H), 1674
1
(C=O), 1234 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.64
(s, 0.74H, CH2), 3.81 (s, 1.89H, OCH3), 3.82 (s, 1.11H,
OCH3), 3.83 (s, 1.89H, OCH3), 3.84 (s, 1.11H, OCH3), 4.04
(s, 1.26H, CH2), 6.55 (dd, J = 1.0, 8.5 Hz, 0.63H, H-3′′,
H-5′′), 6.57–6.64 (m, 1.37H, H-3′′, H-5′′), 6.65 (d, J = 1.5
Hz, 0.37H, H-3), 6.74 (d, J = 1.5 Hz, 0.63H, H-3), 7.03 (d,
J = 8.0 Hz, 0.63H, H-6′), 7.12 (d, J = 8.0 Hz, 0.37H, H-6′),
7.18-7.23 (m, 1.37H, H-5, H-4′), 7.26 (t, J = 8.0 Hz, 0.63H,
H-4′), 7.38 (t, J = 8.0 Hz, 0.63H, H-5′), 7.40 (t, J = 8.0 Hz,
0.37H, H-5′), 7.44 (d, J = 8.0 Hz, 0.63H, H-6), 7.46 (d, J =
8.0 Hz, 0.37H, H-6), 7.55 (d, J = 8.0 Hz, 0.63H, H-3′), 7.62
(d, J = 8.0 Hz, 0.37H, H-3′), 7.63 (d, J = 8.5 Hz, 0.63H, H-
6′′), 7.72 (d, J = 8.0 Hz, 0.37H, H-6′′), 8.21 (s, 0.63H,
=CH), 8.42 (s, 0.37H, =CH), 11.28 (s, 0.63H, NH), 11.44
(s, 0.37H, NH); 13C NMR (DMSO-d6) δ major isomer (63
%) 33.5 (CH2), 55.3 (OCH3), 55.9 (OCH3), 98.5 (CH, C-3′
′), 106.8 (CH, C-5′′), 115.3 (C, C-1′′), 117.3 (CH, C-3),
120.9 (CH, C-6′), 124.0 (CH, C-5), 124.7 (C, C-1), 126.0
(CH, C-4′), 126.1 (C, C-2′), 126.8 (CH, C-6′′), 129.3 (CH,
C-5′), 131.2 (CH, C-6), 132.3 (C, C-4), 134.1 (CH, C-3′),
139.0 (CH, =CH–), 151.8 (C, C-1′), 155.6 (C, C-2), 159.3
(C, C-2′′), 163.1 (C, C-4′′), 171.3 (C=O); minor isomer
(37 %): 35.3 (CH2), 56.2 (OCH3), 60.2 (OCH3), 98.7 (CH,
C-3′′), 106.9 (CH, C-5′′), 115.4 (C, C-1′′), 116.6 (CH, C-
3), 121.7 (CH, C-6′), 123.8 (CH, C-5), 125.2 (C, C-1),
125.4 (CH, C-2′), 126.5 (C, C-4′), 127.0 (CH, C-6′′), 129.5
(CH, C-5′), 131.3 (CH, C-6), 132.5 (C, C-4), 133.8 (CH, C-
3′), 142.3 (CH, =CH–), 151.5 (C, C-1′), 155.8 (C, C-2),
159.5 (C, C-2′′, C-4′′), 165.6 (C=O); MS m/z 462.2 (1.1),
461.2 (1.6), 460.2 (5.5), 459.3 (2.7), 458 (8.0), 331.1 (12.5),
251.1 (14.2), 218.1 (8.6), 217.1 (24.8), 216.1 (25.8), 215.1
(55.0), 207.1 (19.1), 182.1 (8.2), 181.1 (28.4), 180.2 (13.7),
179.1 (20.8), 170.1 (25.3), 169.1 (24.5), 168.1 (73.8), 167.1
(60.3), 166.2 (12.1), 165.1 (12.2), 164.1 (33.9), 163.1 (100),
153.1 (9.9), 152.1 (32.0), 151.1 (18.3), 150.1 (16.1), 149.1
(86.8), 135.1 (11.4), 134.1 (15.3), 133.1 (13.6), 129.1
(12.7), 128.1 (9.9), 127.1 (34.2), 121.1 (33.1), 107.1 (10.9),
106.1 (9.9), 91.1 (12.4), 84.1 (63.3), 78.1 (10.4), 77.1
(25.7), 76.1 (14.5), 75.1 (12.5), 66.1 (77.4), 63.1 (12.5),
57.1 (11.5).
Anal. Calcd. for C22H18Cl2N2O3: C, 61.55; H, 4.23; N,
6.53. Found: C, 61.49; H, 4.34; N, 6.74.
N-(4-methoxybenzylidene)-2-(4-chloro-2-(2-
chlorophenoxy)phenyl) acetic acid hydrazide (17i)
Yield 55 %; m.p. 146–148 °C; IR (KBr) 3176 (N–H), 1664
1
(C=O), 1250 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.67
(s, 0.7H, CH2), 3.80 (s, 1.95H), 3.81 (s, 1.05H), 4.07 (s,
1.3H, CH2), 6.65 (d, J = 1.5 Hz, 0.35H, H-3), 6.74 (d, J =
1.5 Hz, 0.65H, H-3), 6.97 (d, J = 6.5 Hz, 1.3H, H-3′′, H-5′
′), 7.00 (d, J = 6.5 Hz, 0.7H, H-3′′, H-5′′), 7.04 (d, J = 8.0
Hz, 0.65H, H-6′), 7.13 (d, J = 8.0 Hz, 0.35H, H-6′),
7.15–7.25 (m, 1.65H, H-5, H-4′), 7.26 (t, J = 8.0 Hz, 0.35H,
H-4′), 7.37 (t, J = 8.0 Hz, 0.65H, H-5′), 7.41 (t, J = 8.0 Hz,
0.35H, H-5′), 7.43–7.48 (m, 1H, H-6), 7.50–7.58 (m,
1.95H, H-3′, H-2′′, H-6′′), 7.60–7.65 (m, 1.05H, H-3′, H-2′′,
H-6′′), 7.92 (s, 0.65H, =CH), 8.12 (s, 0.35H, =CH), 11.31
(s, 0.65H, NH), 11.45 (s, 0.35H, NH); 13C NMR (DMSO-
d6) δ major isomer (65 %): 33.5 (CH2), 55.8 (OCH3), 114.7
(CH, C-3′′, C-5′′), 117.3 (CH, C-3), 120.9 (CH, C-6′),
124.0 (CH, C-5), 124.7 (C, C-1), 126.1 (CH, C-4′), 126.3
(C, C-2′) 127.3 (C, C-1′′), 128.8 (CH, C-2′′, C-6′′), 129.4
(CH, C-5′), 131.2 (CH, C-6), 132.4 (C, C-4), 134.1 (CH,
C-3′), 143.2 (CH, =CH–), 151.8 (C, C-1′), 155.7 (C, C-2),
161.2 (C, C-4′′), 171.6 (C=O); minor isomer (35 %): 35.3
(CH2), 55.8 (OCH3), 114.8 (CH, C-3′′, C-5′′), 116.6 (CH,
C-3), 121.8 (CH, C-6′), 123.8 (CH, C-5), 125.2 (C, C-1),
125.5 (C, C-2′), 126.4 (CH, C-4′), 126.6 (C, C-1′′), 129.1
(CH, C-2′′, C-6′′), 129.5 (CH, C-5′), 131.3 (CH, C-6),
132.6 (C, C-4), 133.9 (CH, C-3′), 146.7 (CH, =CH–), 151.6
(C, C-1′), 155.9 (C, C-2), 161.3 (C, C-4′′), 166.0 (C=O);
MS m/z 432.3 (1.7), 431.3 (1.0), 430.3 (1.9), 429.3 (7.1),
428.3 (25.0), 280.1 (14.5), 278.1 (21.2), 274.2 (12.9), 273.2
(13.6), 272.2 (63.5), 253.1 (26.3), 252.1 (11.5), 251.1

Med Chem Res
Anal. Calcd. for C23H20Cl2N2O4: C, 60.14; H, 4.39; N,
6.10. Found: C, 60.29; H, 4.23; N, 5.92.
after intraperitoneal administration of the suspension of
compounds in vehicle (0.5 % methyl cellulose).
The paw thickness was measured from the ventral to the
dorsal surfaces using a dial caliper immediately before and
then 30 min, 1, 2, 3 and 4 h after carrageenan injection. The
edema was calculated as the thickness variation between
thickness of paw before and after carrageenan injection.
Anti-inflammatory activity was expressed as the percentage
of inhibition of the edema when compared with the control
group and was calculated using the following formula:
N-(3,4-dimethoxybenzylidene)-2-(4-chloro-2-(2-
chlorophenoxy)phenyl) acetic acid hydrazide (17k)
Yield 51 %; m.p. 180–182 °C; IR (KBr) 3204 (N–H), 1677
1
(C=O), 1237 (C–O) cm−1; H NMR (DMSO-d6): δ = 3.67
(s, 0.8H, CH2), 3.75, 3.79, 3.80 (all s, 6H, OCH3), 4.08 (s,
1.2H, CH2), 6.65 (d, J = 1.0 Hz, 0.4H, H-3), 6.74 (d, J =
1.0 Hz, 0.6H, H-3), 6.97 (d, J = 8.5 Hz, 0.6H, H-5′′), 7.01
(d, J = 8.5 Hz, 0.4H, H-5′′), 7.03 (d, J = 8.0 Hz, 0.6H, H-
6′), 7.07–7.32 (m, 4.4H, H-5, H-4′, H-6′, H-2′′, H-6′′), 7.36
(t, J = 8.0 Hz, 0.6H, H-5′), 7.40 (t, J = 8.0 Hz, 0.4H, H-5′),
7.48 (d, J = 8.0 Hz, 1H, H-6), 7.54 (d, J = 8.0 Hz, 0.6H, H-
3′), 7.62 (d, J = 8.0 Hz, 0.4H, H-3′), 7.85 (s, 0.6H, =CH),
8.08 (s, 0.4H, =CH), 11.35 (s, 0.6H, NH), 11.55 (s, 0.4H,
NH); 13C NMR (DMSO-d6) δ major isomer (60 %): 33.6
(CH2), 55.8 (OCH3), 56.0 (OCH3), 108.7 (CH, C-5′′), 111.9
(CH, C-2′′), 117.3 (CH, C-3), 121.0 (CH, C-6′), 121.6 (CH,
C-6′′), 124.0 (CH, C-5), 124.7 (C, C-1), 126.1 (CH, C-4′),
126.3 (C, C-2′), 127.4 (C, C-1′′), 129.4 (CH, C-5′), 131.2
(CH, C-6), 132.4 (C, C-4), 134.2 (CH, C-3′), 143.4 (CH,
=CH–), 149.4 (C, C-3′′), 150.8 (C, C-4′′), 151.9 (C, C-1′),
155.7 (C, C-2), 171.6 (C=O); minor isomer (40 %): 35.3
(CH2), 55.9 (OCH3), 56.0 (OCH3), 109.9 (CH, C-5′′), 111.8
(CH, C-2′′), 116.6 (CH, C-3), 121.8 (CH, C-6′), 122.2 (CH,
C-6′′), 123.9 (CH, C-5), 125.2 (C, C-1), 125.5 (CH, C-2′),
126.5 (CH, C-4′), 126.9 (C, C-1′′), 129.5 (CH, C-5′), 131.3
(CH, C-6), 132.6 (C, C-4), 133.9 (CH, C-3′), 147.0 (CH,
=CH–), 149.5 (C, C-3′′), 151.1 (C, C-4′′), 151.6 (C, C-1′),
155.9 (C, C-2), 166.0 (C=O); MS m/z 462.2 (2.0), 461.2
(2.9), 460.2 (10.2), 459.3 (4.7), 458.2 (14.6), 253.1 (12.1),
251.1 (16.0), 218.1 (9.0), 217.1 (24.8), 216.1 (25.9), 215.1
(56.2), 214.2 (9.1), 207.1 (13.5), 181.1 (29.9), 180.1 (34.7),
179.1 (29.7), 170.1 (14.7), 169.1 (14.3), 168.1 (42.5), 167.1
(34.6), 166.1 (10.5), 165.1 (19.7), 164.1 (20.5), 163.1 (100),
153.1 (10.8), 152.1 (29.7), 151.1 (13.3), 150.1 (9.6), 149.1
(30.5), 148.1 (9.4), 133.1 (11.7), 127.1 (19.7), 111.1 (11.6),
97.1 (14.5), 95.1 (10.5), 85.1 (17.6), 84.1 (86.1), 83.2
(19.1), 71.2 (18.6), 69.2 (16.3), 66.1 (91.5), 57.2 (29.7),
55.2 (18.2), 46.1 (18.3).
%Inhibition ¼ ð1 ꢀ Tt=TcÞ ´ 100
where Tt and Tc are defined as the thickness variation of test
group and control group, respectively.
Computational studies
All DFT calculations were performed using the ORCA
2.9.0 program (Neese, 2012), and the solvent effects were
included by the conductor-like screening model (Klamt,
1995). The structures were optimized in the DMSO solvent
using the tao-perdew-staroverov-scuseria (TPSS) density
functional (Tao et al., 2003) with the def2-TZVP basis set
(Weigend and Ahlrichs, 2005), and vibrational frequencies
were calculated for the thermochemical analyses. The
hybrid PBE0 functional (Perdew et al., 1996) with the def2-
TZVPP basis set was used for single point energy calcula-
tions on the optimized structures. The results for the PBE0
functional, including the thermal energy corrections and the
Gibbs free energies at 298 K, are reported in Table 1; all
energies are relative to the most stable conformer. Noticing
that the differences in relative energies were small, we
repeated our single point calculations while changing den-
sity functionals, basis sets and the solvent. Results of the
TPSS and PBE0 functionals were compared with PW6B95
(Zhao and Truhlar, 2005), and the basis set was changed to
def2-QZVPP (Weigend and Ahlrichs, 2005). In addition,
we optimized all the structures once again in the chloroform
solvent, and performed single point energy calculations
with the TPSS functional. All these calculations further
confirmed the relative stabilities of the conformers in
Table 1, and the differences in relative energies computed
with various density functionals were typically below 0.5
kcalmol−1.
Anal. Calcd. for C23H20Cl2N2O4: C, 60.14; H, 4.39; N,
6.10. Found: C, 60.03; H, 4.56; N, 6.19.
Anti-inflammatory assay
Acknowledgments This work was supported by grants from the
Medicinal Chemistry Center of Excellence and Research Council of
Tehran University of Medical Sciences (grant No: 92-03-33-24361).
The anti-inflammatory activity was determined in vivo
using the carrageenan-induced rat paw edema test (Al-
Haboubi and Zeitlin, 1983). Edema was induced in the right
hind paw of all rats by subcutaneous injection of 0.1 mL of
1 % (w/v) carrageenan in saline into their footpads 30 min
Compliance with ethical standards
Conflict of interest The authors declare that they have no com-
peting interests.

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