A study on the reactions of alkyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-3- ene-1-carboxylate and in vitro antioxidant activity of derivatives

Article abstract of DOI:10.1007/s00044-012-0304-7

New functionalized derivatives were prepared using alkyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-3-ene-1-carboxylate as a building block. Newly prepared compounds were well characterized using ¹H NMR, IR, and mass spectral data. All the synthesized products were screened for their antioxidant properties. Among the tested compounds, indazole derivatives exhibited noticeable DPPH radical scavenging activity and reducing power capacity in comparison with the standard Glutathione.

Full text of DOI:10.1007/s00044-012-0304-7

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2013) 22:3002–3011
DOI 10.1007/s00044-012-0304-7
ORIGINAL RESEARCH
A study on the reactions of alkyl 4,6-bis(4-fluorophenyl)-2-
oxocyclohex-3-ene-1-carboxylate and in vitro antioxidant
activity of derivatives
•
Seranthimata Samshuddin Badiadka Narayana
•
•
Balladka Kunhanna Sarojini Leelavathi Narayana Madhu
Received: 22 August 2012 / Accepted: 24 October 2012 / Published online: 9 November 2012
Ó Springer Science+Business Media New York 2012
Abstract New functionalized derivatives were prepared
using alkyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-3-ene-
1-carboxylate as a building block. Newly prepared com-
become interesting intermediates for the synthesis of a
variety of heterocyclic systems with diverse biological
activities (Yadav et al., 2011; Padmavathi et al., 2000;
Senguttuvan and Nagarajan, 2010; Vyas et al., 2009).
The search for new molecules with anti-oxidant prop-
erties is a very active domain of research, since they can
protect the human body from free radicals and retard the
progress of many chronic diseases, such as atherosclerosis,
stroke, diabetes, Alzheimer’s disease, some forms of can-
cer, and oxidative stress responsible for DNA, protein, and
membrane damage. Antioxidants are also believed to play
a very important role in the body defense system against
reactive oxygen species, which are the harmful byproducts
generated during normal cell aerobic respiration. Supple-
mentation with antioxidants may help to maintain an ade-
quate antioxidant status and therefore, the normal
physiological function of a living system (Van Acker et al.,
1996). Hence, there is considerable interest in the discov-
ery and development of efficient synthetic or natural anti-
oxidants. Many synthetic antioxidants, which are
characterized by a better antioxidant activity than natural
antioxidants and are more easily available, have been used
in a wide variety of food products. Butylated hydroxytol-
uene and butylated hydroxyanisole (BHA) were originally
developed to protect petroleum from oxidative gumming.
However, these compounds have been used as antioxidants
in human foods since 1954 and are perhaps the most
common antioxidants used in foods today (Sherwin, 1976).
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a strong
novel free radical scavenger, is used for treatment of patients
with acute brain infarction (Kokura et al., 2005). This has
attracted a great deal of research interest in synthetic
antioxidants.
1
pounds were well characterized using H NMR, IR, and
mass spectral data. All the synthesized products were
screened for their antioxidant properties. Among the tested
compounds, indazole derivatives exhibited noticeable
DPPH radical scavenging activity and reducing power
capacity in comparison with the standard Glutathione.
Keywords 4,40-Difluoro chalcone ꢀ Cyclohexenone ꢀ
Terphenyl ꢀ Indazole ꢀ Antioxidant activity
Introduction
The Michael addition reaction is widely recognized as one
of the key reaction for carbon–carbon bond formation
¨
(Krause and Hoffmann-Roder, 2001; Leonard et al., 1998;
Fan et al., 2002). Chalcone is used as a Michael acceptor in
organic synthesis. Michael addition reaction of 1,3-dicar-
bonyl compounds such as acetoacetic esters to chalcones
leads to the synthesis of cyclohexenone derivatives, which
S. Samshuddin ꢀ B. Narayana (&)
Department of Studies in Chemistry, Mangalore University,
Mangalagangotri, Mangalore 574199, Karnataka, India
e-mail: nbadiadka@yahoo.co.uk
B. K. Sarojini
Research Department of Chemistry, P.A College of Engineering,
Nadupadavu, Mangalore 574153, Karnataka, India
L. N. Madhu
Department of Allied Health Sciences, Nitte University,
Deralakatte, Mangalore 575018, India
A number of synthetic compounds such as, indazoles
(Hagihara et al., 2011), terphenyls (Wang and Pan, 2012),
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Med Chem Res (2013) 22:3002–3011
3003
´
benzodiazepines (Garcıa-Santos et al., 2004), quinazolines
Results and discussion
(Saravanan et al., 2010), and benzisoxazoles (Jain and
Kwon, 2003) have been extremely exploited for antioxi-
dant activity. Indazole derivatives have gained interest in
medicinal chemistry in view of their promising pharma-
cological properties including antioxidant activity. It is
noticed that by injecting 7-nitroindazole, malondialdehyde
(MDA), a major end product of lipid peroxidation, signif-
icantly decreased in epilepticus rats (Liu et al., 2007;
Thomas et al., 2008). The antioxidant study of some of the
terphenyl derivatives isolated from three edible and deli-
cious mushrooms (Thelephora ganbajun, T. aurantiotincta
and Boletopis grisea) indigenous to China, expressed
higher antioxidant activities than a-tocopherol or BHA
which are generally used as efficient free radical scav-
engers (Liu et al., 2004; Yang et al., 2004). Moreover, the
compounds having groups like –SH, –OH, or –NH2, which
are able to provide free electron either in the form of a
negative charge or in the form of a lone pair of electrons,
may show higher antioxidant activity due to their redox
properties (Flora, 2009). In view of above observations and
in continuation of our ongoing efforts on the synthesis of
large range of new compounds from a single precursor 4,40-
difluoro chalcone (Samshuddin et al., 2011a, b, c, d, 2012a,
b, c, d; Jasinski et al., 2010a, b, 2012a, b; Fun et al., 2010a,
2012; Baktir et al., 2011a, b, 2012), we converted the
chalcone into its cyclohexenone derivative and used that as
a key intermediate for the synthesis of new functionalized
derivatives. All these derivatives are characterized by
spectral data and screened for their antioxidant properties.
Chemistry
Syntheses of new functionalized derivatives were carried
out by reacting the cyclohexenone derivative of 4,40-
difluoro chalcone 2a/2b with various reagents according to
the reaction sequence depicted in Scheme 1, 2, 3, 4 5.
Cyclohexenones 2a/2b were prepared by the condensa-
tion of ethyl acetoacetate/methyl acetoacetate to the 4,40-
difluoro chalcone 1 by means of an intermediate Michael
adduct according to the method described in our previous
works (Fun et al., 2010b; Dutkiewicz et al., 2011). The
cyclocondensation of acetoacetic esters with chalcones led
to the generation of two chiral centers in cyclohexenones
which would result in a mixture of diastereomers. No
attempt was undertaken to separate the diastereomeric
cyclohexenones and used as such for further reaction.
Synthesis of terphenyl esters
Iodine in methanol is used as a good reagent for the
conversion of 2-cyclohexen-1-ones into the corresponding
anisole derivatives (Kotnis, 1990; Tamura and Yoshimoto,
1980). The method was successfully applied to the con-
version of cyclohexenones 2a and 2b to anisole deriva-
tives 3a and 3b. Hence, this reaction provides a simple
and good method for the synthesis of terphenyl deriva-
tives from chalcone via cyclohexenone intermediate
(Scheme 1).
Scheme 1 Synthesis of
terphenyl esters
R
O
O
O
CH3COCH2CO2R
O
F
F
1
F
: R = CH
2a
2b
3
F
: R = C H
2
5
I2 / MeOH
R
H3C
O
O
O
F
: R = CH
3a
3b
F
3
: R = C H
2
5
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Med Chem Res (2013) 22:3002–3011
Scheme 2 Synthesis of
indazole derivatives
R'
N
HN
R'-NH NH2
EtOH / H2SO4
O
R
O
O
O
F
F
: R' = H
4a
4b
: R' = 4-NO C H
6 5
2
C6H5
O
F
F
: R = CH
2a
2b
3
N
HN
: R = C H
2
5
Ph-NH NH2
AcOH / H2SO4
5
F
F
Scheme 3 Synthesis of
dibenzodiazepine derivative
R
O
O
HN
NH
H2N
H2N
O
H2SO4
AcOH
+
O
F
: R = CH
2a
2b
F
6
3
: R = C H
2
5
F
F
Scheme 4 Synthesis of oxime
and substituted guanidine
derivatives
OH
N
NH2OH. HCl
R
O
O
7
O
F
F
H2N
N
N
F
NH
.HCl
NH
F
: R = CH
2a
2b
3
NH2
NH2
: R = C H
2
5
H2N
8
F
F
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Med Chem Res (2013) 22:3002–3011
3005
Scheme 5 Synthesis of
aminated derivatives of
cyclohexenones
R
O
O
H2N
NH4OAc
F
R
O
: R = CH
9a
9b
F
3
O
O
: R = C H
2
5
H2N
O
F
F
HN
R
: R = CH
2a
2b
3
N
O
: R = C H
2
5
NH2 NH CO NH2
O
F
F
: R = CH
10a
10b
3
: R = C H
2
5
The structure of compounds 3a and 3b was confirmed
by their spectral data. In the IR spectrum of 3a, stretching
band due to ester carbonyl group was observed at
more doublet of doublet seen at d 4.17 ppm was due to a
proton attached to chiral carbon C-4. Similarly a singlet
observed at d 6.72 ppm could be due to methylene proton
of C-7. The mass spectrum showed a molecular ion peak at
m/z 324.9 (M? ? 1) which confirmed the structure. The
N-substituted indazole derivative 4b was obtained in similar
way when cyclohexenone 2a or 2b was treated with
4-nitrophenyl hydrazine. The structure was confirmed by IR,
1H NMR, and mass spectral data.
1
1,724 cm-1. The H NMR spectrum showed two singlets
integrating for three protons each at d 3.58 and 3.91 ppm
due to the protons of methoxy group and methyl group of
ester, respectively. Moreover, there was no signal other
than multiplets in the range d 7.20–7.86 ppm which were
due to the ten aromatic protons, hence confirming the
proposed structure of terphenyl derivative 3a. The mass
spectrum showed a molecular ion peak at m/z 355.1
(M? ? 1) which further confirmed the proposed structure.
Similarly, the spectral data of 3b was in good agreement
with the proposed structure.
In contrast to the above reaction, an indazole derivative
5 with aromatized ring-2 was obtained when cyclohexe-
none 2a or 2b was treated with phenyl hydrazine
(Scheme 2). The formation of aromatized product could be
due to the reaction carried out in acetic acid medium. In the
IR spectrum of 5, absorption bands appeared at 3,120 and
1,641 cm-1 were due to NH group and carbonyl group of
Synthesis of indazole derivatives
1
indazole ring, respectively. The H NMR spectrum sup-
Both the cyclohexenones 2a and 2b containing 1,3-dicar-
bonyl system reacted with hydrazine hydrate in acid medium
resulted in the formation of indazole derivative, 4,6-
bis(4-fluorophenyl)-1,2,4,5-tetrahydro-3H-indazol-3-one 4a
(Scheme 2). In the IR spectrum of 4a, the stretching band at
3,197 cm-1 was attributed to the presence of NH group of
indazole moiety. An absorption band due to carbonyl group
of indazole ring was seen at 1,718 cm-1. Two singlets at d
9.57 and 11.59 ppm appeared in the 1H NMR spectrum were
due to the two NH protons of indazole ring. Two doublet of
doublets at d 2.81 and 3.10 ppm were due to the two protons
attached to C-5 carbon, adjacent to chiral center C-4. One
ported the aromatization as there were no signals corre-
sponding to aliphatic protons. A singlet appeared at d
10.88 ppm was due to the NH proton of indazole ring. The
mass spectrum showed a molecular ion peak at m/z 399.0
(M? ? 1) which confirmed the structure of 5.
Synthesis of dibenzodiazepine derivative
A dibenzodiazepine derivative 6 was obtained when
cyclohexenone 2a or 2b was treated with o-phenylenedi-
amine (Scheme 3). The absorption bands in IR spectrum
showed stretching bands at 3,429 and 3,136 cm-1 due to
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Med Chem Res (2013) 22:3002–3011
NH group while strong stretching band at 1,712 cm-1
attributed to carbonyl of cyclic amide in dibenzodiazepine
ring, supported the structure. Two singlets at d 11.21 and
Synthesis of aminated derivatives of cyclohexenones
2-Aminated products 9a and 9b were obtained when cy-
clohexenones 2a and 2b treated with ammonium acetate in
ethanol (Scheme 5). Their spectral data proved the for-
mation of the products. In the IR spectrum of ethyl
2-amino-4,6-bis(4-fluorophenyl)cyclohexa-1,3-diene-1-car-
boxylate 9b, stretching bands appeared at 3,408,
3,311 cm-1 due to amino group and a strong stretching
1
8.71 ppm appeared in the H NMR spectrum were due to
the NH protons present in the dibenzodiazepine ring. Fur-
ther, multiplets in the range d 7.01–7.93 ppm appeared
were due to the aromatic protons, confirming the proposed
structure of dibenzodiazepine derivative 6. The mass
spectrum showed a molecular ion peak at m/z 399.1
(M? ? 1) which confirmed the proposed structure.
1
band at 1,649 cm-1 due to carbonyl group. The H NMR
spectrum showed a triplet and a multiplet at d 1.07 and
3.91 ppm integrating for three and two protons, respec-
tively, were due to ethyl chain of ester. A doublet of
doublet at d 2.77 ppm, a multiplet at d 3.04 ppm and also a
doublet observed at d 4.10 ppm integrating for one proton
each, were due to the two protons attached to C-5 carbon
and a proton attached to C-6 carbon, respectively. Two
amino protons resonated at d 7.85 ppm as a singlet.
The mass spectrum showed a molecular ion peak at m/z
355.9 (M? ? 1) corresponding to the molecular formula
C21H19F2NO2.
Synthesis of oxime and substituted guanidine derivatives
It was reported that, the reaction of cyclohexenone deriv-
atives with hydroxylamine hydrochloride yields benzisox-
azole derivative (Rajanarendar et al., 2009). But, the
cyclohexenone 2a or 2b with hydroxylamine hydrochloride
in the presence of strong base afforded decarboxylated
oxime derivative, (1E)-3,5-bis(4-fluorophenyl)-N-hydro-
xycyclohex-2-en-1-imine 7 (Scheme 4). The IR spectrum
of compound 7 showed an absorption band at 3,255 cm-1
1
Similarly, uncyclized products were obtained when cy-
clohexenones 2a and 2b reacted with semicarbazide
hydrochloride in the presence of a base (Scheme 5). The IR
spectrum of ethyl (2E)-2-(2-carbamoylhydrazinylidene)-
4,6-bis(4-fluorophenyl)cyclohex-3-ene-1-carboxylate 10b
showed stretching bands at 3,460, 3,313, and 3,178 cm-1
due to NH group. A band at 1,683 cm-1 was due to amide
carbonyl group, and another strong band at 1,734 cm-1
was due to ester carbonyl group. The presence of signals
corresponding to ethyl chain of ester in the 1H NMR
spectrum ruled out the formation of cyclized products.
due to hydroxyl group of oxime. The H NMR spectrum
showed a singlet at d 10.96 ppm corresponding to the
hydroxyl proton of oxime. A multiplet observed at d
2.32 ppm was due to a proton attached to C-5 carbon of
cyclohexene ring. Two mutiplets integrating for two pro-
tons each seen at d 2.73 and 3.07 ppm were due to the
protons attached to C-4 and C-6 carbon, respectively.
Similarly, a singlet observed at d 6.60 ppm was due to
methylene proton of C-2. The mass spectrum showed a
molecular ion peak at m/z 299.9 (M? ? 1) corresponding
to the molecular formula C18H15F2NO.
1
Furher, the H NMR spectrum of 10b showed a doublet at
It was aimed at the preparation of quinazoline derivative
by reacting cyclohexenones 2a or 2b with amino guanidine
hydrochloride (Senguttuvan and Nagarajan, 2009). But
instead of cyclization, decarboxylated uncyclized product,
N-[(1E)-3,5-bis(4-fluorophenyl)cyclohex-2-en-1-ylidene]car-
bonohydrazonic diamide 8 was obtained. The structure of the
product 8 formed was confirmed by the spectral data. In the
IR spectrum, the presence of absorption bands at 3,448,
3,313 cm-1 were due to amino groups present in the mole-
cule. The absence of absorption band due to ester carbonyl
group indicated the decarboxylation of the compound 8.
Further, in the 1H NMR spectrum, the presence of two
singlets at d 5.44 and 5.76 ppm integrating for two protons
each, revealed the presence of two different amino groups in
the compound. Two doublet of doublets observed at d 2.26
and 3.30 ppm were due to protons attached to C-4 carbon.
Similarly, signals at d 2.71 and 3.02 ppm were due to
the protons attached to C-6 and C-5 carbon, respectively.
The mass spectrum showed a molecular ion peak at m/z
340.9 (M? ? 1) corresponding to the molecular formula
C19H18F2N4.
d 2.73 ppm integrating for two protons was due to the
protons attached to C-5 carbon. A multiplet at d 3.36 ppm
integrating for one proton was due to a proton attached to
C-6 carbon, and a doublet at d 3.82 ppm integrating for one
proton was due to a proton attached to C-1 carbon. A broad
singlet resonated at d 6.07 ppm was observed due to the
protons of NH2 group while a singlet at d 10.15 ppm was
observed due to NH proton. A molecular ion peak seen at
m/z 413.8 (M? ? 1) in the mass spectrum confirmed the
structure of 10b.
Antioxidant activity
DPPH radical scavenging assay
A rapid, simple and inexpensive method to measure anti-
oxidant capacity of substances involves the use of the free
radical, 2,2-diphenyl-1-picrylhydrazyl (DPPH). DPPH is
widely used to test the ability of compounds to act as free
radical scavengers or hydrogen donors. Antioxidants tested
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Med Chem Res (2013) 22:3002–3011
3007
showed good reducing power capacity while compounds 4b,
5, 7, 8, and 9a exhibited moderate reducing power capacity in
comparison with the standard Glutathione. The good
reducing power capacity of these compounds was due to the
presence of free NH group in the molecules.
Table 1 Antioxidant activity of synthesized compounds
Compounds
% DPPH scavenging
Reducing power assay
3a
49.07 5.82
50.18 3.45
95.91 2.92
94.42 3.84
95.16 2.83
58.73 1.11
89.21 3.40
89.21 4.86
40.89 3.92
68.02 4.34
65.42 4.66
66.54 4.89
92.09 1.09
14.28 2.56
22.72 4.67
1.81 0.62
3.52 0.98
5.55 1.23
2.64 0.87
4.54 1.09
4.03 0.90
5.55 0.78
25.00 5.78
20.04 4.98
8.33 1.98
0.595 0.01
3b
4a
4b
5
Experimental section
6
7
Melting points were taken in open capillary tubes and are
uncorrected. The purity of the compounds was confirmed
by thin layer chromatography using Merck silica gel 60
8
9a
F254-coated aluminum plates using ethyl acetate:n-hexane
9b
(3:7, v/v) as solvent system. IR spectra were recorded
on Shimadzu-FTIR Infrared spectrometer in KBr
(mmax in cm-1). 1H NMR (400 MHz) spectra were recorded
on a Bruker AMX 400 spectrometer, with 5 mm PABBO
BB-1H TUBES with TMS as internal standard. LCMS were
obtained using Agilent 1200 series LC and Micromass zQ
spectrometer. Elemental analysis was carried out using
VARIO EL-III (Elementar Analysensysteme GmBH).
10a
10b
Glutathione
on DPPH were also found extremely effective in cell sys-
tems. This simple test further provides information on the
ability of a compound to donate electrons during antioxi-
dant action (Tiwari, 2004). The radical scavenging mech-
anism is based on the transfer of acidic H-atom from the
compound to DPPH radical to form DPPH-H. The results
are summarized in Table 1.
Synthesis of alkyl 4,6-bis(4-fluorophenyl)-2-
oxocyclohex-3-ene-1-carboxylate (2a, b)
Among the tested compounds, compounds 4a, 4b, and 5
showed very high radical scavenging capacity with con-
centration of 1 mg/mL in comparison with the standard
Glutathione. Such enhanced activity was due to the pres-
ence of acidic protons in the indazole moiety. Compounds
7 and 8 were also showing good activity due to the pres-
ence of oxime and guanidine functionalities in these mol-
ecules. Other compounds showed moderate activity.
Cyclohexenone derivatives of 4,40-difluoro chalcone viz.
methyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-3-ene-1-car-
boxylate 2a and ethyl 4,6-bis(4-fluorophenyl)-2-oxocyclo-
hex-3-ene-1-carboxylate 2b were prepared by the
condensation of 4,40-difluoro chalcone 1 with methyl aceto-
acetate and ethyl acetoacetate according to the method
described in our previous works (Fun et al., 2010b;
Dutkiewicz et al., 2011).
Reducing power assay
Synthesis of alkyl 4,400-difluoro-50-methoxy-1,10:30,100-
terphenyl-40-carboxylate (3a, b)
Reducing power is associated with antioxidant activity and
may serve as a significant reflection of the antioxidant
activity (Oktay et al., 2003). Compounds with reducing
power indicate that they are electron donors and can reduce
the oxidized intermediates of lipid peroxidation processes,
so that they can act as primary and secondary antioxidants
(Chanda and Dave, 2009). Substances, which have reduc-
tion potential, react with potassium ferricyanide to form
potassium ferrocyanide, which then reacts with ferric
chloride to form ferrous complex that has an absorption
maximum at 700 nm. Increased absorbance of the reaction
mixture indicates the increased reducing power. The results
are summarized in Table 1.
A mixture of methyl/ethyl 4,6-bis(4-fluorophenyl)-2-oxo-
cyclohex-3-ene-1-carboxylate 2a/2b (0.01 mol) and iodine
(0.025 mol) in 20 mL methanol was refluxed for 24 h with
stirring. The reaction mixture was cooled and poured into
ice-cold water (50 mL). Organic contents were extracted
with diethyl ether (25 mL) and washed with saturated
sodium thiosulphate solution (2 9 25 mL) followed by
water (25 mL). The precipitate obtained after evaporation
of solvent was collected and recrystallized from methanol.
Methyl 4,400-difluoro-50-methoxy-1,10:30,100-terphenyl-40-
carboxylate (3a)
Reducing power assay is expressed in effective concen-
tration (mg/mL) equivalent of 0.5 absorbance Glutathione.
Among the tested compounds, many compounds showed
significant reducing power capacity. Compounds 4a and 6
Yield: 70 %; m.p. 126–128 °C. IR (KBr, mmax in cm-1):
3051 (Ar–H), 2983, 2943 (CH), 1724 (C=O), 1222 (C–F).
1H NMR (400 MHz, DMSO-d6, d ppm): 3.58 (s, 3H,
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Med Chem Res (2013) 22:3002–3011
OCH3), 3.91 (s, 3H, CO2CH3), 7.20–7.86 (m, 10H, Ar–H).
LCMS: m/z 355.1 (M? ? 1). C H N Analysis; Calculated
for C21H16F2O3: C, 71.18; H, 4.55. Found: C, 71.15; H,
4.57 %.
for C25H17F2N3O3: C, 67.41; H, 3.85; N, 9.43. Found: C,
67.38; H, 3.84; N, 9.40 %.
Synthesis of 4,6-bis(4-fluorophenyl)-2-phenyl-1,2-
dihydro-3H-indazol-3-one (5)
Ethyl 4,400-difluoro-50-methoxy-1,10:30,100-terphenyl-40-
carboxylate (3b)
A mixture of ethyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-
3-ene-1-carboxylate 2b (3.56 g, 0.01 mol) and phenyl
hydrazine (1.08 g, 0.01 mol) in 20 mL glacial acetic acid
in the presence of concentrated sulfuric acid (0.5 mL) was
refluxed for 8 h. The reaction mixture was cooled and
poured into ice-cold water (50 mL). The precipitate
obtained after neutralization was collected by filtration and
recrystallized in ethanol. Yield: 58 %; m.p. 271–273 °C.
IR (KBr, mmax in cm-1): 3120 (NH), 3072 (Ar–H), 1641
(C=O), 1222 (C–F). 1H NMR (400 MHz, DMSO-d6, d
ppm): 7.23–7.91 (m, 15H, Ar–H), 10.88 (s, 1H, NH).
LCMS: m/z 399.0 (M? ? 1). C H N Analysis; Calculated
for C25H16F2N2O: C, 75.37; H, 4.05; N, 7.03. Found: C,
75.35; H, 4.06; N, 7.00 %.
Yield: 63 %; m.p. 108–110 °C. IR (KBr, mmax in cm-1):
3062 (Ar–H), 2898 (CH), 1709 (C=O), 1220 (C–F). H
1
NMR (400 MHz, DMSO-d6, d ppm): 0.98 (t, 3H, CH3),
3.62 (s, 3H, OCH3), 4.02 (q, 2H, CO2CH2), 7.18–7.81 (m,
10H, Ar–H). LCMS: m/z 369.1 (M? ? 1). C H N Analysis;
Calculated for C21H16F2O3: C, 71.73; H, 4.93. Found: C,
71.70; H, 4.92 %.
Synthesis of 4,6-bis(4-fluorophenyl)-1,2,4,5-tetrahydro-
3H-indazol-3-one (4a)
Amixtureofethyl4,6-bis(4-fluorophenyl)-2-oxocyclohex-3-
ene-1-carboxylate 2b (3.56 g, 0.01 mol) and hydrazine
hydrate (0.75 g, 0.015 mol) in 20 mL ethanol in the presence
of sulfuric acid (0.5 mL) was refluxed for 10 h. The reaction
mixture was cooled and poured into ice-cold water (50 mL).
The precipitate obtained after neutralization was collected by
filtration and recrystallized in ethanol. Yield: 71 %; m.p.
211–214 °C. IR (KBr, mmax in cm-1): 3197 (N–H), 3043 (Ar–
H), 2721 (C–H), 1718 (C=O), 1230 (C–F). 1H NMR
Synthesis of 1,3-bis(4-fluorophenyl)-5,10-dihydro-11H-
dibenzo[b,e][1,4]diazepin-11-one (6)
A mixture of ethyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-
3-ene-1-carboxylate 2b (3.56 g, 0.01 mol) and o-phenyl-
enediamine (1.3 g, 0.012 mol) in 20 mL glacial acetic acid
in the presence of concentrated sulfuric acid (0.5 mL) was
refluxed for 10 h. The reaction mixture was cooled and
poured into ice-cold water (50 mL). The precipitate
obtained after neutralization was collected by filtration and
recrystallized in ethanol. Yield: 47 %; m.p. 274–277 °C.
IR (KBr, mmax in cm-1): 3429, 3136 (NH), 3066 (Ar–H),
(400 MHz, DMSO-d6, d ppm): 2.81 (dd, 1H, HA, JAB
=
16.8 Hz, JAX = 3.6 Hz), 3.10 (dd, 1H, HB, JBA = 16.8 Hz,
JBX = 8.02 Hz), 4.17 (dd, 1H, HB, JXB = 8.02 Hz,
JXA = 3.8 Hz), 6.72 (s, 1H, CH), 7.00 -7.52 (m, 8H, Ar–H),
9.57 (s, 1H, NH), 11.59 (s, 1H, NH). LCMS: m/z 324.9
(M??1). C H N Analysis; Calculated for C19H14F2N2O: C,
70.36; H, 4.35; N, 8.64. Found: C, 70.33; H, 4.34; N, 8.62 %.
1
1712 (C=O), 1226 (C–F). H NMR (400 MHz, DMSO-d6,
d ppm): 7.01–7.93 (m, 14H, Ar–H), 8.71 (s, 1H, NH),
11.21 (s, 1H, NH). LCMS: m/z 399.1 (M? ? 1). C H N
Analysis; Calculated for C25H16F2N2O: C, 75.37; H, 4.05;
N, 7.03. Found: C, 75.36; H, 4.04; N, 7.01 %.
Synthesis of 4,6-bis(4-fluorophenyl)-2-(4-nitrophenyl)-
1,2,4,5-tetrahydro-3H-indazol-3-one (4b)
A mixture of ethyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-
3-ene-1-carboxylate 2b (3.56 g, 0.01 mol) and 4-nitro-
phenyl hydrazine (0.01 mol) in 20 mL ethanol in the
presence of concentrated sulfuric acid (0.5 mL) was
refluxed for 10 h. The reaction mixture was cooled and
poured into ice-cold water (50 mL). The precipitate was
collected by filtration and recrystallized in ethanol. Yield:
56 %; m.p. 204–206 °C. IR (KBr, mmax in cm-1): 3120
(NH), 3043 (Ar–H), 2924 (CH), 1724 (C=O), 1226 (C–F).
1H NMR (400 MHz, DMSO-d6, d ppm): 2.92 (broad d, 1H,
CH2-HA, JAB = 16 Hz), 3.20 (dd, 1H, CH2–HB,
JBA = 16.4 Hz), 4.40 (broad s, 1H, CH–HX), 6.91 (s, 1H,
CH), 7.03–8.40 (m, 12H, Ar–H), 11.98 (s, 1H, NH).
LCMS: m/z 445.8 (M? ? 1). C H N Analysis; Calculated
Synthesis of (1E)-3,5-bis(4-fluorophenyl)-N-
hydroxycyclohex-2-en-1-imine (7)
A mixture of ethyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-
3-ene-1-carboxylate 2b (3.56 g, 0.01 mol) and hydroxyl-
amine hydrochloride (1.03 g, 0.015 mol) in 20 mL ethanol
in the presence of 40 % NaOH (1 mL) was refluxed for
6 h. The reaction mixture was cooled and poured into ice-
cold water (50 mL). The precipitate was collected by fil-
tration and recrystallized in ethanol. Yield: 58 %; m.p.
164–166 °C. IR (KBr, mmax in cm-1): 3255 (OH), 3055
1
(Ar–H), 2900 (CH), 1600 (C=N), 1220 (C–F). H NMR
(400 MHz, DMSO-d6, d ppm): 2.32 (m, 1H, C-1 H), 2.73
(m, 2H, C-2 CH2), 3.07 (m, 2H, C-6 CH2), 6.60 (s, 1H,
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Med Chem Res (2013) 22:3002–3011
3009
CH), 7.13–7.64 (m, 8H, Ar–H), 10.96 (s, 1H, OH). LCMS:
m/z 299.9 (M? ? 1). C H N Analysis; Calculated for
C18H15F2NO: C, 72.23; H, 5.05; N, 4.68. Found: C, 72.20;
H, 5.06; N, 4.66 %.
1222 (C–F). 1H NMR (400 MHz, DMSO-d6, d ppm): 1.07
(t, 3H, CH3), 2.77 (dd, 1H, CH), 3.04 (m, 1H, CH), 3.91
(m, 2H, CH2), 4.10 (d, 1H, CH), 6.50 (d, 1H, CH),
6.97–7.47 (m, 8H, Ar–H), 7.85 (s, 2H, NH2). LCMS: m/z
355.9 (M? ? 1). C H N Analysis; Calculated for
C21H19F2NO2: C, 70.97; H, 5.39; N, 3.94. Found: C, 70.93;
H, 5.38; N, 3.91 %.
Synthesis of N-[(1E)-3,5-bis(4-fluorophenyl)cyclohex-
2-en-1-ylidene]carbonohydrazonic diamide (8)
A mixture of ethyl 4,6-bis(4-fluorophenyl)-2-oxocyclohex-3-
ene-1-carboxylate 2b (3.56 g, 0.01 mol) and aminoguanidine
hydrochloride (0.012 mol) in 20 mL ethanol in the presence
of 40 % NaOH (2 mL) was refluxed for 16 h. The reaction
mixture was cooled and poured into ice-cold water (50 mL).
The precipitate obtained after neutralization was collected by
filtration and recrystallized from ethanol. Yield: 66 %; m.p.
186–188 °C. IR (KBr, mmax in cm-1): 3448, 3313 (NH), 3037
(Ar–H), 1581 (C=N), 1234 (C–F). 1H NMR (400 MHz,
DMSO-d6, d ppm): 2.26 (dd, 1H, CH–HA, JAX = 12.4 Hz,
JAB = 16.4 Hz), 2.71 (m, 2H, CH2), 3.02 (m, 1H, CH–HX),
3.30 (dd, 1H, CH–HB, JXB = 12.4 Hz, JBA = 16.4 Hz), 5.44
(s, 2H, NH2), 5.76 (s, 2H, NH2), 6.66 (s, 1H, CH), 7.11–7.58
(m, 8H, Ar–H). LCMS: m/z 340.9 (M? ? 1). C H N Analysis;
Calculated for C19H18F2N4: C, 67.05; H, 5.33; N, 16.46.
Found: C, 67.01; H, 5.35; N, 16.42 %.
Synthesis of alkyl (2E)-2-(2-
carbamoylhydrazinylidene)-4,6-bis(4-
fluorophenyl)cyclohex-3-ene-1-carboxylate (10a, b)
A mixture of methyl/ethyl 4,6-bis(4-fluorophenyl)-2-oxo-
cyclohex-3-ene-1-carboxylate 2a/2b (0.01 mol) and semi-
carbazide hydrochloride (0.012 mol) in 20 mL ethanol in
the presence of 10 % NaOAc (1 mL) was refluxed for
10 h. The reaction mixture was cooled and poured into ice-
cold water (50 mL). The precipitate obtained after neu-
tralization was collected by filtration and recrystallized
from ethanol.
Methyl (2E)-2-(2-carbamoylhydrazinylidene)-4,6-bis(4-
fluorophenyl)cyclohex-3-ene-1-carboxylate (10a)
Yield: 64 %; m.p. 192–194 °C. IR (KBr, mmax in cm-1):
3468, 3311, 3116 (NH), 3080 (Ar–H), 2904 (CH), 1734
1
(ester C=O), 1662 (amide C=O), 1228 (C–F). H NMR
Synthesis of alkyl 2-amino-4,6-bis(4-
fluorophenyl)cyclohexa-1,3-diene-1-carboxylate (9a, b)
(400 MHz, DMSO-d6, d ppm): 2.68 (d, 2H, CH), 2.83 (m,
1H, CHA), 3.32 (m, 1H, CHB), 3.87 (d, 1H, CH), 4.04 (s,
3H, CO2CH3), 6.12 (s, 2H, NH2), 7.21–7.89 (m, 9H, Ar–
H), 10.21 (s, 1H, NH). LCMS: m/z 399.8 (M? ? 1). C H N
Analysis; Calculated for C21H19F2N3O3: C, 63.15; H, 4.80;
N, 10.52. Found: C, 63.13; H, 4.78; N, 10.50 %.
A mixture of methyl/ethyl 4,6-bis(4-fluorophenyl)-2-oxo-
cyclohex-3-ene-1-carboxylate 2a/2b (0.01 mol) and
ammonium acetate (0.02 mol) in 20 mL ethanol in the
presence of acetic acid (1 mL) was refluxed for 14 h. The
reaction mixture was cooled and poured into ice-cold water
(50 mL). The precipitate obtained after neutralization was
collected by filtration and recrystallized from ethanol.
Ethyl (2E)-2-(2-carbamoylhydrazinylidene)-4,6-bis(4-
fluorophenyl)cyclohex-3-ene-1-carboxylate (10b)
Methyl 2-amino-4,6-bis(4-fluorophenyl)cyclohexa-1,3-
diene-1-carboxylate (9a)
Yield: 68 %; m.p. 214–217 °C. IR (KBr, mmax in cm-1):
3460, 3313, 3178 (NH), 3074 (Ar–H), 2931 (CH), 1683
Yield: 68 %; m.p. 162–165 °C. IR (KBr, mmax in cm-1):
3298 (NH), 3068 (Ar–H), 2933 (CH), 1735 (C=O), 1228
(amide C=O), 1734 (ester C=O), 1220 (C–F). H NMR
1
(400 MHz, DMSO-d6, d ppm): 0.94 (t, 3H, CH3), 2.73 (d,
1H, CH), 2.84 (m, 1H, CHA), 3.36 (m, 1H, CHB), 3.82 (d, 1H,
CH), 3.89 (q, 2H, CH2), 6.07 (s, 2H, NH2), 7.12–7.95 (m, 9H,
Ar–H), 10.15 (s, 1H, NH). LCMS: m/z 413.8 (M? ? 1). C H
N Analysis; Calculated for C22H21F2N3O3: C, 63.91; H,
5.12; N, 10.16. Found: C, 63.88; H, 5.14; N, 10.14 %.
1
(C–F). H NMR (400 MHz, DMSO-d6, d ppm): 2.68 (dd,
1H, CH), 2.97 (m, 1H, CH), 3.98 (s, 3H, CO2CH3), 4.07 (d,
1H, CH), 6.45 (d, 1H, CH), 6.92–7.39 (m, 8H, Ar–H), 7.91
(s, 2H, NH2). LCMS: m/z 341.9 (M? ? 1). C H N Anal-
ysis; Calculated for C20H17F2NO2: C, 70.37; H, 5.02; N,
4.10. Found: C, 70.34; H, 5.04; N, 4.06 %.
Antioxidant activity
Ethyl 2-amino-4,6-bis(4-fluorophenyl)cyclohexa-1,3-diene-
1-carboxylate (9b)
DPPH radical scavenging assay
Yield: 70 %; m.p. 153–155 °C. IR (KBr, mmax in cm-1):
3408, 3311 (NH), 3049 (Ar–H), 2981 (CH), 1649 (C=O),
The DPPH assay was based on the reported method (Blois,
1958). In brief, 1 mM solution of DPPH in ethanol was
123

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Med Chem Res (2013) 22:3002–3011
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