Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives

Article abstract of DOI:10.1016/j.ejmech.2014.01.024

The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior. The systematic modification was done around the Part C to explore the structure activity relationship of antitubercular cinnamamide. All 52 compounds were evaluated for its antitubercular activity against Mycobacterium tuberculosis (M. tb) using Resazurin microtitre plate assay (REMA). Compound 11g with trifluoromethyl substitution exhibited good antitubercular activity of 3.125 μg/ml. The synthesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives showed promising activity against M. tb.

Full text of DOI:10.1016/j.ejmech.2014.01.024

European Journal of Medicinal Chemistry 75 (2014) 43e56
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Design, synthesis and antitubercular evaluation of novel series
of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives
*
Kavitkumar N. Patel, Vikas N. Telvekar
Department of Pharmaceutical Sciences & Technology, Institute of Chemical Technology, Matunga (E), Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular
hybridization approach in which part C of the designed molecule was linked through amide and
carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic
and pharmacodynamic behavior. The systematic modification was done around the Part C to explore the
structure activity relationship of antitubercular cinnamamide. All 52 compounds were evaluated for its
antitubercular activity against Mycobacterium tuberculosis (M. tb) using Resazurin microtitre plate assay
(REMA). Compound 11g with trifluoromethyl substitution exhibited good antitubercular activity of
Received 2 September 2013
Received in revised form
13 January 2014
Accepted 18 January 2014
Available online 25 January 2014
Keywords:
3.125
mg/ml. The synthesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives showed promising
Antitubercular
Cinnamic acid
Cinnamamide
Piperazine
REMA
activity against M. tb.
Ó 2014 Elsevier Masson SAS. All rights reserved.
1. Introduction
identified. However Yoya et al. [7] and Kakwani et al. [8] has
described the possible way of the mechanism of cinnamic acid
derivatives that may act on the fatty acid synthase type II (FAS-II)
pathway. The FAS-II pathway is unique in mycobacteria and is
essential for mycobacterial cell survival. Hence, the FAS-II biosyn-
thesis pathway represents a validated and promising target for
drug discovery [10]. Additionally it was reported that diphenyl
ethers, indols, benzofurans and recently cinnamic acid derivatives
have been acting through FAS-II system [7,8].
It was interesting to note that trans-cinnamic acid was used for
tubercular infection even before when the current therapy was not
discovered. Warbasse et al. and Corper et al. have reported the use
of ethyl cinnamate and sodium cinnamate in the treatment of pa-
tients with tuberculosis [11e13]. The synergistic activity of trans-
cinnamic acid in drug combinations with isoniazid, rifamycin,
have been reported against M. tuberculosis [14]. It was also
observed that the rifamycin SV, a hybrid derivative of cinnamic acid
and rifamycin has higher activity than its individual counterpart
[15].
Tuberculosis, or TB, the global epidemic caused by Mycobacte-
rium tuberculosis (M. tb) is infectious disease that has infected about
one-third of the world population. Around 19% cases were identi-
fied with MDR-TB that reached almost 60,000 in 2011. India and
China together account for almost 40% of the world’s TB cases, thus
the global burden of TB remains enormous [1].
The current therapy, first-line and second-line drugs for anti-TB
drugs are around 50 years old and nonetheless, it requires 6 months
of treatment and 20 months in the case of MDR-TB. Hence, new
drugs are required to shorten and simplify the treatment, to
improve the efficacy and tolerability of treatment for MDR-TB. In
the last four decades not a single molecule was introduced in the TB
therapy except US-FDA approves bedaquiline in December-2012, a
new antitubercular agent, as a part of combination therapy to treat
adults with MDR-TB [2].
In recent years, trans-cinnamic acid derivatives have attracted
much attention due to their antioxidative [3], antitumor [4], and
antimicrobial properties [5]. Though some of the research papers
on cinnamic acid derivatives were reported as antitubercular
agents [6e9], still they were not much explored and yet their
mechanism of action of antitubercular activity was not exactly
The importance of cinnamic acid moiety was also found from
natural product constituents as depicted in Fig. 1. The organic
extract of a native American plant Ipomoea leptophylla leaves
contain a resin glycoside Leptophyllin A with a trans-cinnamic acid
residue attached to one Rhamnose moiety which exhibited 13%
inhibition at 6.25 mg/ml [16]. Additionally, the bioassay of these
natural products revealed that Leptophyllin B, a glycoside from the
same plant without cinnamic acid residue, was having no in-vitro
* Corresponding author. Tel.: þ91 22 3361 2213; fax: þ91 22 3361 1020.
E-mail address: vikastelvekar@rediffmail.com (V.N. Telvekar).
0223-5234/$ e see front matter Ó 2014 Elsevier Masson SAS. All rights reserved.
http://dx.doi.org/10.1016/j.ejmech.2014.01.024

44
K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
carbamate with varying degree of lipophilicity. Moreover FAS-II
pathway was described as a possible way of mechanism for cin-
namic acid like derivatives. Hence, secondary amide bond and
carbamate linkage may help cinnamic acid derivatives to stabilize
drugereceptor interaction through H-bond formation. Based on
these preliminary reports, we have designed our cinnamic acid
derivatives into following three scaffolds as shown in Fig. 3 (Fig. 3).
As a part of our research to explore novel antitubercular agents,
we planned to synthesize the series of N-[4-(piperazin-1-yl)
phenyl]cinnamamide, with the hope that these novel compounds
would exhibit improved antitubercular activity. The all newly
synthesized derivatives were further evaluated for its antituber-
cular activity against M. tb H37Rv strain.
2. Results and discussion
Fig. 1. Antitubercular natural products containing cinnamic acid moiety (a) Lep-
tophyllin A, (b) Howiinin A, (c) Licochalcone A and (d) Pisoniamide.
2.1. Chemistry
activity. Recently, a styryllactone, Howiinin A, was isolated from
flowers of G. laoticus which showed promising activity at 6.25 mg/
The novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide
derivatives were synthesized according to Schemes 1e3. The in-
termediate amines, 4-(piperazine-1-yl)aniline, were synthesized as
depicted in Scheme 1. The starting material 4-Chloronitrobenzene
1a and 3,4-Difluoronitrobenzene 1b was reacted with different 4-
substituted piperazine derivatives 2aed in the presence of K2CO3
as a base and DMSO at 90 ꢀC to get the condensed nitro product 3ae
h in good yield. The 1-(4-nitrophenyl)piperazine derivatives were
further reduced to amines 4aeh with the help of Pd/C catalyst at
100 psi in quantitative yields. As described in Scheme 2, the cin-
namic acid derivatives 5a and 5b were converted to the acid
chloride using thionyl chloride in DCM which was added dropwise
to 0 ꢀC cooled solution of 4-(piperazine-1-yl)aniline derivatives in
dry pyridine to give product cinnamamide 7aep. (Table 1) The BOC
protected amines 7d, 7h, 7l and 7p were further treated with tri-
fluoroacetic acid to give deprotected piperazinyl amine 9aed.
The carbamate and amide derivatives were synthesized as
depicted in Scheme 3 by using triethyl amine as a base in dry DCM
at 0 ꢀC to afford corresponding cinnamamide in moderate to good
yields. Compounds 9aed were further reacted with alkyl/aryl
chloroformate to give corresponding carbamate derivatives 10ael
as shown in Table 2. For the synthesis of amide analogs, 9aed were
reacted with different acyl chloride in the presence of triethyl
amine as a base to give respective products 11aep as shown in
Table 2. The isonicotinoyl analogs 12aed were also prepared using
the same method as compound 11.
ml against M. tuberculosis [17]. Licochalcone A, extracted from
chinese licorice roots, exhibited promising antitubercular activity
[18]. The cinnamamide natural products Pisoniamide and N-trans-
(p-coumaroyl)tyramine isolated from Pisonia aculeate and Piper
sanctum respectively were also having antitubercular activity
[19,20].
Previously synthesized cinnamic acid derivatives were moder-
ately active may be due to poor bioavailability as log P value was
higher. Based on these findings, we decided to explore novel cin-
namic acid derivatives which can be easily bioavailable and have
promising antitubercular activity. Furthermore it was proved that
the addition of the piperazine ring to the first-generation quino-
lones led to a significant improvement in bioavailability of the
second-generation fluoroquinolones (norfloxacin and levo-
floxacin). Hence, the piperazine moiety might be helpful to adjust
the physicochemical properties and to improve the pharmacoki-
netic and pharmacodynamic behavior. Moreover LL-3858, a pyrrole
analog from Lupin Ltd., and SQ786 both were having piperazine
moiety showed promising antitubercular activity [8]. Thus
considering the above importance, we decided to hybridize cin-
namic acid derivatives with a piperazine ring as a 4-substituted
piperazinylaniline derivatives.
On the basis of these literature reports, we set out to explore our
promising drug candidate by molecular hybridization of common
pharmacophore of cinnamic acid derivatives with 4-substituted
piperazinylaniline. Our designed molecule was divided into three
parts: part A with cinnamic acid backbone having antitubercular
activity, part B with 4-piperazinyl aniline moiety having a prom-
ising antitubercular activity and part C with substitution at piper-
azinyl nitrogen to govern physicochemical, pharmacokinetic and
pharmacodynamic property (Fig. 2).
The structure of all newly synthesized N-[4-(piperazin-1-yl)
phenyl]cinnamamide derivatives were determined by IR, NMR and
Mass spectroscopic analysis and the results were in agreement with
the proposed structures. In 1H NMR spectra, the aromatic protons
resonated at
with two triplets around
of cinnamic acid showed two doublet of which CeH proton near to
aromatic ring (PheCH]CHCe) resonated around 7.8 while CeH
proton towards the carbonyl end (PheCH]CHeCO) resonated
around 6.6. The presence of proton of CONH group was confirmed
by one proton singlet between 9.10e10.85 ppm. However one
d
7.10e7.85 ppm. The piperazine ring proton resonated
d
3.1 and 3.9. The conjugated double bond
To explore the in depth physicochemical behavior of the cin-
namic acid derivatives, we designed a variety of substitutions at
part C with different type of functional groups like amide and
d
d
d
proton peak of NH group of piperazine in compounds 9aed could
not be able to resolve as a result they lack one proton peak. In 13C
NMR spectra aromatic carbon resonated between
many overlaps in that region while the C]O carbon resonated
around 160e165. In IR spectra, the C]O stretch of secondary
amide of synthesized cinnamic acid derivatives was demonstrated
by the appearance of the IR absorption band at 1690e1640 cmꢁ1
d 115e145 with
d
.
The presence of NO2 group of compounds was indicated by
the appearance of asymmetric and symmetric NO2 stretching
bands at 1560e1505 cmꢁ1 and 1385e1330 cmꢁ1 respectively. The
Fig. 2. Pictorial representation of designed cinnamic acid derivatives.

K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
45
Fig. 3. Designed scaffold of cinnamic acid derivatives.
synthesized compounds exhibited characteristic peak of cinnamic
acid double bond at 1680e1620 cmꢁ1
active even at 50 mg/ml. This may be attributed to the bulky nature
of the 2-pyridyl ring. The antitubercular activity of the carbamate
.
derivatives 10ael were not appreciable as none of the compounds
were active at 50 mg/ml.
2.2. Biological screening
All 52 novel N-[4-(piperazin-1-yl)phenyl]cinnamamide de-
rivatives were evaluated for its in-vitro antitubercular activity
against M. tb H37Rv strain using Resazurin microtitre plate assay
(REMA) [21]. All compounds were evaluated for its antitubercular
2.3. SAR of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives
2.3.1. SAR of alkyl/aryl derivatives
From the biological screening of alkyl or aryl derivatives of
cinnamamide, it was found that cinnamamide derivative of N-
activity at a concentration of 1.56e50
mg/ml. The serial dilution
technique was used to find out the minimum inhibitory concen-
tration (MIC) of the synthesized cinnamamide derivatives. Isoni-
azid was used as the standard drug.
The results of biological screening are summarized in
Tables 1and 2. From the antitubercular screening, it was found that
the highest active compounds 11g and 7a were having a MIC of
methyl piperazine 7a was active at 6.25
mg/ml. The other N-ethyl
piperazine derivatives were also active at 12.5
mg/ml. SAR of part A
showed that cinnamic acid and nitrocinnamic acid were equally
active against M. tb. In the design of part B, fluoro substitution at
aromatic ring has no effect on improvement of antitubercular ac-
tivity. However part C showed that smaller molecular weight
functional group substitutions were more active and exhibited
significant improvement in the antitubercular activity. It was also
found that compounds 7c, 7g, 7k and 7o with bulkier 2-pyridyl ring
substitution at piperazinyl nitrogen leads to decrease in the anti-
tubercular activity of cinnamic acid derivatives.
3.125 and 6.25 mg/ml respectively. The most active compound was
amide derivatives 11g with trifluoromethyl substitution at ortho
position of the benzene ring. The other compounds like 7b, 7d, 7f,
7i, 7j, 9a, 9d, 11f, 11h, 11i, 11m, 11n and 12d were having good
antitubercular activity of 12.5
amide derivatives were also having promising antitubercular ac-
tivity of 12.5e50 g/ml. The alkyl/aryl derivatives of the cinnama-
mg/ml against M. tb H37Rv strain. The
m
mide 7c, 7g, 7k and 7o contains 2-pyridyl ring which were not
a
Scheme 1. a: Synthesis of 4-(piperazine-1-yl)aniline derivatives. a Reagents: (a) K2CO3,
Scheme 2.
:
Synthesis of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives.
a
DMSO at 90 ꢀC for 12 h; (b) H2, 10% Pd/C, MeOH-EA at 100 PSI for 6 h.
Reagents: (a) SOCl2, MDC, reflux, 4 h; (b) amines 4aeh, pyridine at 0 ꢀC, 3 h.

46
K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
Scheme 3. Synthesis of carbamate and amide derivatives of N-[4-(piperazin-1-yl)phenyl]cinnamamide. Reagents: (a) TFA, MDC, rt, 12 h then 1 N NaOH; (b) alkyl/aryl Chlor-
oformate, TEA, MDC, 0 ꢀC, 0.5 h; (c) acyl chloride, TEA, MDC, 0 ꢀC, 0.5 h; (d) isonicotinoyl chloride, TEA, MDC, 0 ꢀC, 0.5 h.
2.3.2. SAR of carbamate derivatives
evidenced that compounds 11f, 11g, 11h, 11i, 11m and 11n were
containing fluoro substitution hence were active against M. tb. At
the 2-position of the part C aromatic ring, introduction of the tri-
fluoromethyl group leads to increase in the antitubercular activity.
At the 4-position of the part C, fluoro derivative was found to be
more active. The amide derivatives were also able to retain the
antitubercular activity even with the introduction of the bulkier
chloro atom at 3 and 5 position of the part C benzene ring.
We have postulated that carbamate derivatives may be active as
it contains carbamate functional group that may help by hydrogen
bonding with the receptor active site. But the SAR of part A and B
explained that the substitution of nitro or fluoro derivatives have
no effect on antitubercular activity. Furthermore it also explains
that any carbamate substitution at part C have resulted in com-
pounds that were not active at 50 mg/ml. The biological screening of
carbamate derivatives 10ael showed that carbamate moiety may
not be crucial for antitubercular activity in case of cinnamamide
derivatives.
Table 2
Antitubercular activity of N-(4-(piperazin-1-yl)phenyl)cinnamamide derivatives.
2.3.3. SAR of amide derivatives
Compd
R1
R2
R5
R6
MIC (mg/ml)
SAR of amide derivatives showed that nitrocinnamic acid de-
rivatives were more active as compared to cinnamic acid as it was
evidenced from the compound 11i, 11m, 11n and 12d.
But the most interesting thing found by SAR of part B was that
the compounds containing fluoro substitution at aromatic ring
were having higher activity than nonfluoro derivatives. It was
10a
10b
10c
10d
10e
10f
10g
10h
10i
H
H
H
H
H
H
NO2
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
H
H
H
F
F
F
H
H
H
F
F
F
H
H
H
H
F
F
F
F
H
H
H
H
F
F
F
F
H
F
CH3
C2H5
C6H5
CH3
C2H5
C6H5
CH3
C2H5
C6H5
CH3
C2H5
C6H5
e
e
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
>50
25
>50
50
>50
>50
12.5
3.125
12.5
12.5
>50
>50
>50
12.5
12.5
>50
>50
50
>50
>50
12.5
0.39
e
e
e
e
e
e
e
e
Table 1
10j
10k
10l
e
Antitubercular activity of N-(4-(piperazin-1-yl)phenyl)cinnamamide derivatives.
e
e
Compd
R1
R2
R4
MIC (
mg/ml)
11a
11b
11c
11d
11e
11f
11g
11h
11i
4-F
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
H
H
H
H
H
H
H
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
H
H
H
H
H
F
F
F
F
H
H
H
H
F
F
F
F
H
F
CH3
6.25
12.5
>50
12.5
25
12.5
>50
50
12.5
12.5
>50
12.5
25
>50
>50
50
12.5
25
50
12.5
e
3-Cl, 5-Cl
2-CF3
4-NO2
4-F
3-Cl, 5-Cl
2-CF3
4-NO2
4-F
3-Cl, 5-Cl
2-CF3
4-NO2
4-F
3-Cl, 5-Cl
2-CF3
4-NO2
e
C2H5
2-pyridyl
BOC
e
e
e
CH3
H
H
H
e
C2H5
2-pyridyl
BOC
e
e
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
H
e
CH3
11j
11k
11l
e
7j
7k
7l
C2H5
2-pyridyl
BOC
e
e
11m
11n
11o
11p
12a
12b
12c
12d
INH
e
7m
7n
7o
7p
9a
9b
9c
9d
CH3
e
C2H5
2-pyridyl
BOC
H
H
e
e
e
H
e
e
H
NO2
NO2
NO2
NO2
e
H
F
e
e
H
F
H
H
e
e
e
e
e

K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
47
2.4. In vitro cytotoxicity
4.3. General procedure for the synthesis of compounds 4aeh
Compounds 4aeh were synthesized as per literature [24].
The in vitro cytotoxicity study was carried out for five com-
pounds (7a, 7f, 11g, 11i, and 12d) in a mammalian Vero cell line on
three different concentrations. The tetrazolium salt, 3-(4,5-
dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT),
was used to measure cytotoxicity (IC50) in 96 well microtitre plate
[22,23]. After 72 h of exposure, the cell viability was assessed based
on conversion of yellow tetrazolium salt to its purple formazan
product. It was found that all the five compounds were having IC50
4.4. General procedure for the synthesis of compounds 6a and 6b
1 equiv of cinnamic acid derivatives 5a or 5b was dissolved in
DCM (20 ml/g) and a catalytic amount of DMF was added followed
by the addition of 1.2 equiv is SOCl2. The reaction mixture was
refluxed for 3 h and then solvent was evaporated under vacuum to
get the product 6a or 6b in the form of solid residue in quantitative
yield. The solid residue was used directly for second step without
further purification.
values more than 125
mg/ml indicating that the compounds were
nontoxic up to 125 g/ml. The in vitro cytotoxicity assay gives IC50
m
value which is used to calculate SI (Selectivity Index). The selec-
tivity index is defined as the ratio of the measured IC50
(mammalian cell toxicity) to the MIC (H37Rv M. tuberculosis). If the
SI value is ꢂ 10, then the compound may be considered for further
screening. The SI value of compound 11g was more than 40 indi-
cating that 11g is safe for further screening. The SI value of other
compounds like 7a, 7f,11i, and 12d were also found to be more than
10.
4.5. General procedure for the synthesis of compounds 7aep
1 equiv of piperazinyl amine was dissolved in pyridine (20 ml/g)
and stirred at 0 ꢀC under inert atmosphere. 1.2 equiv of cinnamoyl
chloride derivative was dissolved in dry DCM (10 ml/g) and added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
stirred for 3 h and was monitored by TLC. After completion of the
reaction, the reaction mixture was diluted with water (20 ml/g) and
ethyl acetate (30 ml/g) followed by 2 N HCl to make it acidic. The
precipitate came out which was filtered as yellow solid and further
washed with 2 N HCl and then water. The precipitate was sus-
pended in saturated bicarbonate solution and stirred vigorously to
remove acid impurities. The crude compound was purified either
by column chromatography or by recrystallization from ethyl ace-
tate and hexane.
3. Conclusion
The present study revealed that N-[4-(piperazin-1-yl)phenyl]
cinnamamide derivatives possess good to moderate activity against
M. tb. Out of 52 synthesized cinnamamide derivatives, compound
11g with trifluoromethyl substitution emerged with antitubercular
activity of 3.125 mg/ml. In case of alkyl/aryl derivatives, the com-
pounds with lower molecular weight with small functional group
substitutions were more active and exhibited significant improve-
ment in the antitubercular activity as compared to bulkier group.
Moreover cinnamamide containing fluoro group were more active
than nonfluoro derivatives. A further cytotoxicity study of five
compounds also revealed that they are safe for further screening as
the safety index was more than 10. The promising activity of the N-
[4-(piperazin-1-yl)phenyl]cinnamamide derivatives established
them as crucial pharmacophore which can be used as lead to design
further novel derivatives of cinnamic acid with better antituber-
cular activity. Considering this pharmacophore, the further
expansion of the cinnamamide series are underway to find a potent
antitubercular agent.
4.5.1. N-[4-(4-Methylpiperazin-1-yl)phenyl]cinnamamide (7a)
4-(4-Methylpiperazin-1-yl)aniline 4a (0.3 g, 1.57 mmol) was
dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6a (0.31 g, 1.88 mmol) was dis-
solved in 3 ml dry DCM and added dropwise to above stirred so-
lution at 0 ꢀC. The reaction mixture was worked up as per the
general procedure to afford 0.39 g of 7a. Light yellow solid; Yield
78%; mp 223e225 ꢀC; IR (KBr pellets, cmꢁ1): 3417, 3277, 3042,
2929, 2834, 1653, 1616, 1535, 1448, 1337, 1255, 967, 819, 755; 1H
NMR (400 MHz, CDCl3)
d (ppm): 2.39 (3H, s, CH3), 2.63 (4H, t,
J ¼ 3.51 Hz), 3.22 (4H, t, J ¼ 3.51 Hz), 6.58 (1H, d, J ¼ 15.1 Hz, Phe
CH]CHe), 6.96 (2H, d, J ¼ 7.4 Hz, AreH), 7.30e7.75 (7H, m, AreH),
7.78 (1H, d, J ¼ 15.1 Hz, PheCH]CHe), 9.65 (1H, s, CONH); 13C NMR
4. Experimental protocols
(100 MHz, CDCl3) d (ppm): 46.11, 49.37, 55.06, 116.53, 121.07, 121.32,
4.1. General
127.89, 128.81, 129.77, 130.46, 134.78, 141.74, 148.32, 163.74; HRe
MS m/z: 321.2086 (Mþ).
Starting materials were purchased from commercial sources
and were used without further purification. Solvents were dried
according to standard procedure. The reaction progress was
monitored by thin layer chromatography (TLC) on aluminum sheet
obtained from Merck. Silica gel 60e120 mesh was used for column
chromatography. Melting points were recorded on Thermomik
Campbell Melting Point apparatus having an oil bath system and
were uncorrected. IR spectrum was recorded on FTIR (Perkin Elmer
Spectrum RX1) by preparing KBr pellets.
4.5.2. N-[4-(4-Ethylpiperazin-1-yl)phenyl]cinnamamide (7b)
4-(4-Ethylpiperazin-1-yl)aniline 4b (0.3 g, 1.46 mmol) was
dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6a (0.29 g, 1.76 mmol) was dis-
solved in 3 ml dry DCM and added dropwise to above stirred so-
lution at 0 ꢀC. The reaction mixture was worked up as per the
general procedure to afford 0.31 g of 7b. Light yellow solid; Yield
65.96%; mp 224e226 ꢀC; IR (KBr pellets, cmꢁ1): 3350, 3254, 2948,
2827, 1631, 1602, 1542, 1428, 1261, 1194, 985, 761; 1H NMR
All 1H and 13C NMR were recorded on 400 MHz Varian Mercury
NMR instrument. All NMR spectra were recorded in CDCl3 or
DMSO-d6 solutions using TMS as an internal standard. Chemical
shifts are reported in ppm (
Agilent 7820A GC systems (SIS-Direct insertion probe) and LC-MS
TOF 6520A.
(400 MHz, CDCl3)
d
(ppm): 1.15 (3H, t, J ¼ 7.6 Hz, CH3), 2.43 (2H, q,
d
). Mass spectra were recorded on
J ¼ 7.6 Hz, CH2), 2.61 (4H, t, J ¼ 3.67 Hz), 3.21 (4H, t, J ¼ 3.69 Hz),
6.56 (1H, d, J ¼ 15.6 Hz, PheCH]CHe), 6.94 (2H, d, J ¼ 7.1 Hz Hz,
AreH), 7.20e7.59 (7H, m, AreH), 7.75 (1H, d, J ¼ 15.6 Hz, PheCH]
CHe), 9.69 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm):
4.2. General procedure for the synthesis of compounds 3aeh
Compounds 3aeh were synthesized as per literature [24].
12.43, 45.52, 49.81, 55.62, 112.27, 117.41, 119.54, 122.65, 125.73,
127.29, 128.73, 135.47, 141.82, 145.91, 165.11; HReMS m/z:
335.3234 (Mþ).

48
K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
4.5.3. N-{4-[4-(Pyridin-2-yl)piperazin-1-yl]phenyl}cinnamamide
(7c)
4.5.6. N-[4-(4-Ethylpiperazin-1-yl)-3-fluorophenyl]cinnamamide
(7f)
4-[4-(Pyridin-2-yl)piperazin-1-yl]aniline 4c (0.3 g, 1.18 mmol)
was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6a (0.24 g, 1.42 mmol) was dis-
solved in 3 ml dry DCM and added dropwise to above stirred so-
lution at 0 ꢀC. After completion of the reaction, the mixture was
diluted with water and ethyl acetate. The precipitate was filtered
and washed heavily with first cold water then tap water to remove
pyridine. The precipitate was suspended in saturated bicarbonate
solution and stirred vigorously to remove acid impurities. The
crude compound was purified by column chromatography to afford
0.34 g of 7c. Light yellow solid; Yield 75.56%; mp 218e220 ꢀC; IR
(KBr pellets, cmꢁ1): 3380, 3266, 1698, 1665, 1596, 1435, 1244, 987,
4-(4-Ethylpiperazin-1-yl)-3-fluoroaniline 4f (0.3 g, 1.35 mmol)
was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6a (0.27 g, 1.61 mmol) was dis-
solved in 3 ml dry DCM and added dropwise to above stirred solution
at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.31 g of 7f. Light yellow solid; Yield 60.78%; mp
194e196 ꢀC; IR (KBr pellets, cmꢁ1): 3366, 3266, 2952, 2857, 1630,
1602, 1510, 1339, 1258, 1191, 993, 876, 758; 1H NMR (400 MHz,
CDCl3)
d
(ppm): 1.07 (3H, t, J ¼ 7.15 Hz, CH3), 2.49 (2H, q, J ¼ 7.15 Hz,
CH2), 2.62 (4H, t, J ¼ 3.67 Hz), 3.32 (4H, t, J ¼ 3.69 Hz), 6.76 (1H, d,
J ¼ 15.2 Hz, PheCH]CHe), 6.99 (1H, d, J ¼ 8.2 Hz, AreH), 7.29e7.63
(7H, m, AreH), 7.70 (1H, d, J ¼ 15.2 Hz, PheCH]CHe), 10.29 (1H, s,
845, 789; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.17 (4H, t,
CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 12.89, 46.42, 49.24,
J ¼ 3.82 Hz), 3.59 (4H, t, J ¼ 3.85 Hz), 6.57 (1H, d, J ¼ 15.3 Hz, Phe
CH]CHe), 6.59e6.81 (4H, m, AreH), 7.21e7.58 (8H, m, AreH), 7.75
(1H, d, J ¼ 15.3 Hz, PheCH]CHe), 8.05 (1H, s, AreH), 9.11 (1H, s,
53.12, 111.78, 112.27, 118.29, 118.94, 121.15, 125.03, 127.90, 128.11,
134.41, 142.80, 145.22, 152.33, 165.11; HR-MS m/z: 353.3216 (Mþ).
CONH); 13C NMR (100 MHz, CDCl3)
d
(ppm): 45.52, 51.10,110.52,
4.5.7. N-{3-Fluoro-4-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}
cinnamamide (7g)
112.76, 118.93, 119.51,123.89, 127.10, 127.92, 128.31, 128. 34, 132.54,
139.41, 142.63, 144.21, 149.84, 156.20, 165.73; HReMS m/z:
384.2532 (Mþ).
3-Fluoro-4-[4-(pyridin-2-yl)piperazin-1-yl]aniline 4g (0.3 g,
1.1 mmol) was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC
under inert atmosphere. Cinnamoyl chloride 6a (0.22 g, 1.32 mmol)
was dissolved in 3 ml dry DCM and added dropwise to above stirred
solution at 0 ꢀC. After completion of the reaction, the mixture was
diluted with water and ethyl acetate. The precipitate was filtered
and washed heavily with first cold water then tap water to remove
pyridine. The precipitate was suspended in saturated bicarbonate
solution and stirred vigorously to remove acid impurities. The
crude compound was purified by column chromatography to afford
0.28 g of 7g. Light yellow solid; Yield 59.57%; mp 217e219 ꢀC; IR
(KBr pellets, cmꢁ1): 3436, 3312, 1622, 1514, 1431, 1336, 1256, 1155,
4.5.4. tert-Butyl 4-(4-cinnamamidophenyl)piperazine-1-
carboxylate (7d)
tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate 4d (3 g,
10.83 mmol) was dissolved in 40 ml of dry pyridine and stirred at
0
ꢀC under inert atmosphere. Cinnamoyl chloride 6a (2.16 g,
13 mmol) was dissolved in 20 ml dry DCM and added dropwise to
above stirred solution at 0 ꢀC. The reaction mixture was stirred for
3 h. After completion of the reaction, the reaction mixture was
diluted with 40 ml water and 60 ml ethyl acetate followed by 2 N
HCl to make it acidic. The organic layer was separated and again
washed with 2 N HCl followed by saturated bicarbonate solution
(2 ꢃ 50 ml) and brine solution. The organic layer was dried over
anhydrous sodium sulfate and was evaporated under reduced
pressure. The crude product was recrystallized from ethyl acetate
and hexane to afford 3.25 g of 7d. Off-white solid; Yield 73.86%; mp
186e188 ꢀC; IR (KBr pellets, cmꢁ1): 3335, 3106, 2976, 2822, 1689,
1624, 1521, 1423, 1232, 1173, 971, 827, 763; 1H NMR (400 MHz,
1021, 842, 754; 1H NMR (400 MHz, CDCl3)
d (ppm): 2.45 (4H, t,
J ¼ 4.71 Hz), 3.27 (4H, t, J ¼ 4.68 Hz), 6.79 (1H, d, J ¼ 15.9 Hz, Phe
CH]CHe), 6.89e7.01 (3H, m, AreH), 7.26e7.78 (8H, m, AreH), 7.85
(1H, d, J ¼ 15.9 Hz, PheCH]CHe), 8.11 (1H, s, AreH), 10.61 (1H, s,
CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 46.55, 50.18, 110.67,
111.06, 117.23, 118.31,122.19, 127.34, 128.22, 128.81, 129. 24, 131.14,
139.40, 143.73, 145.22, 149.34, 151.23, 156.21, 164.23; HR-MS m/z:
402.2125 (Mþ).
CDCl3)
d
(ppm): 1.41 (9H, s, CH3), 3.12 (4H, t, J ¼ 4.15 Hz), 3.71 (4H, t,
4.5.8. tert-Butyl 4-(4-cinnamamido-2-fluorophenyl)piperazine-1-
carboxylate (7h)
J ¼ 4.12 Hz), 6.75 (1H, d, J ¼ 14.8 Hz, PheCH]CHe), 7.09e7.45 (9H,
m, AreH), 7.71 (1H, d, J ¼ 14.8 Hz, PheCH]CHe), 8.61 (1H, s,
tert-Butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate
4h (4 g, 13.56 mmol) was dissolved in 40 ml of dry pyridine and
stirred at 0 ꢀC under inert atmosphere. Cinnamoyl chloride 6a
(2.7 g, 16.27 mmol) was dissolved in 20 ml dry DCM and added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
stirred for 3 h. After completion of the reaction, the reaction
mixture was diluted with 40 ml water and 60 ml ethyl acetate
followed by 2 N HCl to make it acidic. The organic layer was
separated and again washed with 2 N HCl followed by saturated
bicarbonate solution (2 ꢃ 50 ml) and brine solution. The organic
layer was dried over anhydrous sodium sulfate and was evaporated
under reduced pressure. The crude product was recrystallized from
ethyl acetate and hexane to afford 4.3 g of 7h. Light yellow solid;
Yield 70.15%; mp 183e185 ꢀC; IR (KBr pellets, cmꢁ1): 3305, 3059,
2911, 1621, 1527, 1333, 1285, 1201, 1027, 971, 812; 1H NMR
CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 28.37, 51.48, 80.43,
118.47, 121.14, 121.38, 127.97, 128.83, 129.84, 134.74, 141.93, 154.43,
164.33; HR-MS m/z: 407.2267 (Mþ).
4.5.5. N-[3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl]cinnamamide
(7e)
3-Fluoro-4-(4-methylpiperazin-1-yl)aniline
4e
(0.3
g,
1.44 mmol) was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC
under inert atmosphere. Cinnamoyl chloride 6a (0.29 g, 1.72 mmol)
was dissolved in 3 ml dry DCM and added dropwise to above stirred
solution at 0 ꢀC. The reaction mixture was worked up as per the
general procedure to afford 0.34 g of 7e. Light yellow solid; Yield
64.15%; mp 236e238 ꢀC; IR (KBr pellets, cmꢁ1): 3445, 3294, 2935,
2845, 1686, 1636, 1516, 1342, 12611, 1191, 920, 858, 766; 1H NMR
(400 MHz, CDCl3)
d
(ppm): 2.36 (3H, s, CH3), 2.60 (4H, t, J ¼ 3.39 Hz),
(400 MHz, CDCl3)
d
(ppm): 1.42 (9H, s, CH3), 2.99 (4H, t, J ¼ 3.46 Hz),
3.10 (4H, t, J ¼ 3.38 Hz), 6.49 (1H, d, J ¼ 15.3 Hz, PheCH]CHe), 6.90
(1H, d, J ¼ 7.1 Hz, AreH), 7.16e7.55 (7H, m, AreH), 7.73 (1H, d,
J ¼ 15.3 Hz, PheCH]CHe), 9.85 (1H, s, CONH); 13C NMR (100 MHz,
3.59 (4H, t, J ¼ 3.46 Hz), 6.45 (1H, d, J ¼ 15.5 Hz, PheCH]CHe), 6.91
(1H, d, J ¼ 7.7 Hz, AreH), 7.20e7.61 (7H, m, AreH), 7.79 (1H, d,
J ¼ 15.5 Hz, PheCH]CHe), 9.81 (1H, s, CONH); 13C NMR (100 MHz,
CDCl3)
d
(ppm): 48.16, 49.52, 53.26, 110.51, 116.20, 120.09, 121.95,
CDCl3) d (ppm): 28.43, 50.69, 79.91, 115.74, 119.30, 120.51, 127.95,
126.90, 128.32, 129.12, 131.46, 134.22, 141.04, 149.11, 151.71, 163.74;
128.89, 130.04, 134.54, 142.55, 154.11, 154.75, 163.94; HReMS m/z:
HR-MS m/z: 339.3642 (Mþ).
425.3239 (Mþ).

K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
49
4.5.9. N-[4-(4-Methylpiperazin-1-yl)phenyl]-3-(4-nitrophenyl)
acrylamide (7i)
17.33 mmol) was dissolved in 20 ml dry DCM and added dropwise
to above stirred solution at 0 ꢀC. The reaction mixture was stirred
for 3 h. After completion of the reaction, the reaction mixture was
diluted with 40 ml water and 60 ml ethyl acetate followed by 2 N
HCl to make it acidic. The organic layer was separated and again
washed with 2 N HCl followed by saturated bicarbonate solution
(2 ꢃ 50 ml) and brine solution. The organic layer was dried over
anhydrous sodium sulfate and was evaporated under reduced
pressure. The crude product was recrystallized from ethyl acetate
and hexane to afford 4.52 g of 7l. Light yellow solid; Yield 69.33%;
216e218 ꢀC (charred); IR (KBr pellets, cmꢁ1): 3425, 3105, 1666,
1604, 1544, 1514, 1427, 1342, 1220, 1141, 991, 844; 1H NMR
4-(4-Methylpiperazin-1-yl)aniline 4a (0.3 g, 1.57 mmol) was
dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6b (0.5 g, 1.88 mmol) was dis-
solved in 4 ml dry DCM and added dropwise to above stirred so-
lution at 0 ꢀC. The reaction mixture was worked up as per the
general procedure to afford 0.22 g of 7i. Light yellow solid; Yield
38.6%; mp 265e267 ꢀC (charred); IR (KBr pellets, cmꢁ1): 3400,
3238, 2957, 2683, 1597, 1516, 1415, 1339, 1250, 981, 827; 1H NMR
(400 MHz, CDCl3)
d
(ppm): 2.31 (3H, s, CH3), 3.05 (4H, t, J ¼ 3.34 Hz),
3.86 (4H, t, J ¼ 3.33 Hz), 6.50 (1H, d, J ¼ 16.3 Hz, PheCH]CHe), 6.88
(2H, d, J ¼ 7.4 Hz, AreH), 7.20e7.56 (4H, m, AreH), 7.73 (1H, d,
J ¼ 16.3 Hz, PheCH]CHe), 8.18 (2H, d, J ¼ 6.8 Hz, AreH), 9.95 (1H,
(400 MHz, CDCl3)
d
(ppm): 1.43 (9H, s, CH3), 3.10 (4H, t, J ¼ 3.79 Hz),
3.62 (4H, t, J ¼ 3.76 Hz), 6.71 (1H, d, J ¼ 16.5 Hz, PheCH]CHe), 6.98
(2H, d, J ¼ 7.2 Hz, AreH), 7.29e7.87 (4H, m, AreH), 7.89 (1H, d,
J ¼ 16.5 Hz, PheCH]CHe), 8.23 (2H, d, J ¼ 7.0 Hz, AreH), 9.24 (1H,
s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 46.90, 48.24, 54.36,
117.51, 121.15, 122.92, 127.34, 129.57, 131.49, 133.28, 141.10, 147.81,
148.25, 163.20; HR-MS m/z: 366.2082 (Mþ).
s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 28.76, 49.41, 51.48,
78.50, 112.10, 118.03, 121.31, 123.72, 126.08, 129.45, 141.79, 142.11,
4.5.10. N-[4-(4-Ethylpiperazin-1-yl)phenyl]-3-(4-nitrophenyl)
acrylamide (7j)
145.21, 147.29, 157.22, 167.52; HReMS m/z: 453.2067 (M þ 1).
4-(4-Ethylpiperazin-1-yl)aniline 4b (0.3 g, 1.46 mmol) was dis-
solved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert at-
mosphere. Cinnamoyl chloride 6b (0.46 g,1.76 mmol) was dissolved
in 4 ml dry DCM and added dropwise to above stirred solution at
4.5.13. N-[3-Fluoro-4-(4-methylpiperazin-1-yl)phenyl]-3-(4-
nitrophenyl)acrylamide (7m)
3-Fluoro-4-(4-methylpiperazin-1-yl)aniline
4e
(0.3
g,
1.44 mmol) was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC
under inert atmosphere. Cinnamoyl chloride 6b (0.45 g, 1.72 mmol)
was dissolved in 4 ml dry DCM and added dropwise to above stirred
solution at 0 ꢀC. The reaction mixture was worked up as per the
general procedure to afford 0.3 g of 7m. Light yellow solid; Yield
50%; mp 221e223 ꢀC; IR (KBr pellets, cmꢁ1): 3448, 2925, 2830,
1606, 1542, 1508, 1426, 1341, 1217, 1139, 988, 845; 1H NMR
0
ꢀC. The reaction mixture was worked up as per the general pro-
cedure to afford 0.32 g of 7j. Light yellow solid; Yield 58.18%; mp
228e230 ꢀC; IR (KBr pellets, cmꢁ1): 3428, 3100, 2945, 2828, 1664,
1604, 1544, 1515, 1427, 1342, 1221, 1140, 990, 846, 756; 1H NMR
(400 MHz, CDCl3)
d
(ppm): 1.19 (3H, t, J ¼ 6.8 Hz, CH3), 2.49 (2H, q,
J ¼ 6.8 Hz, CH2), 2.59 (4H, t, J ¼ 3.87 Hz), 3.10 (4H, t, J ¼ 3.89 Hz),
6.49 (1H, d, J ¼ 15.6 Hz, PheCH]CHe), 6.84 (2H, d, J ¼ 7.9 Hz, Are
H), 7.31e7.80 (4H, m, AreH), 7.75 (1H, d, J ¼ 15.6 Hz, PheCH]CHe),
8.10 (2H, d, J ¼ 6.4 Hz, AreH), 9.71 (1H, s, CONH); 13C NMR
(400 MHz, CDCl3)
d
(ppm): 2.41 (3H, s, CH3), 3.25 (4H, t, J ¼ 3.35 Hz),
3.81 (4H, t, J ¼ 3.36 Hz), 6.75 (1H, d, J ¼ 15.9 Hz, PheCH]CHe), 7.02
(1H, d, J ¼ 7.7 Hz, AreH), 7.26e7.45 (4H, m, AreH), 7.58 (1H, d,
J ¼ 15.9 Hz, PheCH]CHe), 8.01 (2H, d, J ¼ 6.8 Hz Hz, AreH), 10.85
(100 MHz, CDCl3)
d (ppm): 48.96, 51.90, 52.36, 115.92, 120.76,
123.70, 126.42, 127.98, 130.85, 137.08, 141.40, 147.46, 147.71, 162.56;
(1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 46.11, 48.42,
HR-MS m/z: 380.3129 (Mþ).
52.50, 111.14, 117.22, 121.03, 122.15, 128.12, 130.11, 131.06, 135.72,
142.01, 147.89, 148.45, 152.81, 165.28; HR-MS m/z: 384.3025 (Mþ).
4.5.11. 3-(4-Nitrophenyl)-N-{4-[4-(pyridin-2-yl)piperazin-1-yl]
phenyl}acrylamide (7k)
4.5.14. N-[4-(4-Ethylpiperazin-1-yl)-3-fluorophenyl]-3-(4-
nitrophenyl)acrylamide (7n)
4-[4-(Pyridin-2-yl)piperazin-1-yl]aniline 4c (0.3 g, 1.18 mmol)
was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6b (0.37 g, 1.42 mmol) was dis-
solved in 4 ml dry DCM and added dropwise to above stirred so-
lution at 0 ꢀC. After completion of the reaction, the mixture was
diluted with water and ethyl acetate. The precipitate was filtered
and washed heavily with first cold water then tap water to remove
pyridine. The precipitate was suspended in saturated bicarbonate
solution and stirred vigorously to remove acid impurities. The
crude compound was purified by column chromatography to afford
0.25 g of 7k. Light yellow solid; Yield 50%; mp 270e272 ꢀC (char-
red); IR (KBr pellets, cmꢁ1): 3462, 3327, 2834, 1653, 1600, 1510,
4-(4-Ethylpiperazin-1-yl)-3-fluoroaniline 4f (0.3 g, 1.35 mmol)
was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC under inert
atmosphere. Cinnamoyl chloride 6b (0.43 g, 1.61 mmol) was dis-
solved in 4 ml dry DCM and added dropwise to above stirred solu-
tion at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.25 g of 7n. Light yellow solid; Yield 43.1%; mp
217e219 ꢀC; IR (KBr pellets, cmꢁ1): 3421, 3100, 2945, 2832, 1664,
1602, 1542, 1514, 1421, 1341, 1225, 995, 847; 1H NMR (400 MHz,
CDCl3)
d
(ppm): 1.14 (3H, t, J ¼ 7.31 Hz, CH3), 2.32 (2H, q, J ¼ 7.31 Hz,
CH2), 3.44 (4H, t, J ¼ 3.68 Hz), 3.98 (4H, t, J ¼ 3.69 Hz), 6.37 (1H, d,
J ¼ 14.6 Hz, PheCH]CHe), 7.23e7.66 (5H, m, AreH), 7.68 (1H, d,
J ¼ 14.6 Hz, PheCH]CHe), 8.22 (2H, d, J ¼ 7.2 Hz, AreH), 9.62 (1H, s,
1434, 1339,1227, 1174, 951, 783; 1H NMR (400 MHz, CDCl3)
d (ppm):
3.11 (4H, t, J ¼ 3.37 Hz), 3.62 (4H, t, J ¼ 3.39 Hz), 6.65 (1H, d,
J ¼ 15.1 Hz, PheCH]CHe), 6.81e6.98 (4H, m, AreH), 7.23e7.71
(5H, m, AreH), 7.79 (1H, d, J ¼ 15.1 Hz, PheCH]CHe), 8.12 (3H, m,
CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 13.12, 46.40, 48.25,
52.19, 110.08, 113.21, 117.19, 118.55, 120.19, 125.82, 128.92, 134.20,
141.32, 145.67, 147.23, 152.12, 167.08; HR-MS m/z: 398.3010(Mþ).
AreH), 9.41 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm):
44.12, 46.01,111.42, 112.23, 118.13, 119.50,122.29, 127.11, 127.98, 128.
24, 131.64, 138.30, 141.94, 143.57, 147.56, 148.04, 155.93, 164.38; HR-
MS m/z: 429.2185 (Mþ).
4.5.15. N-{3-Fluoro-4-[4-(pyridin-2-yl)piperazin-1-yl]phenyl}-3-
(4-nitrophenyl)acrylamide (7o)
3-Fluoro-4-[4-(pyridin-2-yl)piperazin-1-yl]aniline 4g (0.3 g,
1.1 mmol) was dissolved in 5 ml of dry pyridine and stirred at 0 ꢀC
under inert atmosphere. Cinnamoyl chloride 6b (0.35 g, 1.32 mmol)
was dissolved in 4 ml dry DCM and added dropwise to above stirred
solution at 0 ꢀC. After completion of the reaction, the mixture was
diluted with water and ethyl acetate. The precipitate was filtered
and washed heavily with first cold water then tap water to remove
4.5.12. tert-Butyl 4-{4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate (7l)
tert-Butyl 4-(4-aminophenyl)piperazine-1-carboxylate 4d (4 g,
14.44 mmol) was dissolved in 40 ml of dry pyridine and stirred at
0
ꢀC under inert atmosphere. Cinnamoyl chloride 6b (4.45 g,

50
K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
pyridine. The precipitate was suspended in saturated bicarbonate
solution and stirred vigorously to remove acid impurities. The
crude compound was purified by column chromatography to afford
0.21 g of 7o. Light yellow solid; Yield 40.38%; mp 242e244 ꢀC
(charred); IR (KBr pellets, cmꢁ1): 3386, 3102, 2848, 1664, 1596,
1514, 1435, 1342, 1243, 986, 845, 789; 1H NMR (400 MHz, CDCl3)
4.6.2. N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide (9b)
tert-Butyl 4-(4-cinnamamido-2-fluorophenyl)piperazine-1-
carboxylate 7h (4 g, 12.31 mmol) was stirred at room tempera-
ture in a 20 ml mixture of TFA/DCM (1:1) for 12 h. The reaction
mixture was worked up as per the general procedure to afford
2.85 g of 9b. Light yellow solid; Yield 93.44%; mp 210e212 ꢀC; IR
(KBr pellets, cmꢁ1): 3400, 3327, 2834, 1667,1630, 1544, 1513,
d
(ppm): 2.97 (4H, t, J ¼ 3.45 Hz), 3.59 (4H, t, J ¼ 3.45 Hz), 6.58 (1H,
d, J ¼ 15.3 Hz, PheCH]CHe), 6.83e6.96 (3H, m, AreH), 7.21e7.57
(5H, m, AreH), 7.61 (1H, d, J ¼ 15.3 Hz, PheCH]CHe), 8.19 (3H, m,
1426, 1261, 1208, 1130, 869; 1H NMR (400 MHz, CDCl3)
d (ppm):
2.51 (4H, t, J ¼ 3.69 Hz), 3.34 (4H, t, J ¼ 3.70 Hz Hz), 6.71 (1H, d,
J ¼ 14.1 Hz, PheCH]CHe), 6.93 (1H, d, J ¼ 7.2 Hz, AreH), 7.23e
7.64 (7H, m, AreH), 7.69 (1H, d, J ¼ 14.1 Hz, PheCH]CHe), 9.78
AreH), 9.97 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm):
47.15, 49.01, 110.17, 111.23, 117.11, 118.56,122.30, 127.12, 128.11,
128.89, 129. 45, 131.22, 139.23, 143.12,145.72, 149.68,151.59,156.90,
165.54; HReMS m/z: 447.2128 (Mþ).
(1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 44.29, 53.94,
112.12, 113.84, 117.92,122.32, 127.13, 128.09, 129.18, 130.12,
135.38, 142.36, 147.78, 153.37, 167.14; HR-MS m/z: 325.3367
(Mþ).
4.5.16. tert-Butyl 4-{2-fluoro-4-[3-(4-nitrophenyl)acrylamido]
phenyl}piperazine-1-carboxylate (7p)
4.6.3. 3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide
tert-Butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate
4h (4 g, 13.56 mmol) was dissolved in 40 ml of dry pyridine and
stirred at 0 ꢀC under inert atmosphere. Cinnamoyl chloride 6b
(4.29 g, 16.27 mmol) was dissolved in 20 ml dry DCM and added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
stirred for 3 h. After completion of the reaction, the reaction
mixture was diluted with 40 ml water and 60 ml ethyl acetate
followed by 2 N HCl to make it acidic. The organic layer was
separated and again washed with 2 N HCl followed by saturated
bicarbonate solution (2 ꢃ 50 ml) and brine solution. The organic
layer was dried over anhydrous sodium sulfate and was evaporated
under reduced pressure. The crude product was recrystallized from
ethyl acetate and hexane to afford 4.42 g of 7p. Light orange solid;
Yield 65.19%; 205e207 ꢀC; IR (KBr pellets, cmꢁ1): 3452, 3273, 3065,
2863,1720, 1656,1594,1514, 1342,1215,1165, 975, 914, 838, 754; 1H
(9c)
tert-Butyl
4-{4-[3-(4-nitrophenyl)acrylamido]phenyl}pipera-
zine-1-carboxylate 7l (4 g, 11.36 mmol) was stirred at room tem-
perature in a 20 ml mixture of TFA/DCM (1:1) for 12 h. The reaction
mixture was worked up as per the general procedure to afford 2.7 g
of 9c. Light yellow solid; Yield 86.82%; mp 227e229 ꢀC (charred); IR
(KBr pellets, cmꢁ1): 3433, 3322, 2957, 2835, 1675, 1594, 1512, 1335,
1239, 1171, 901, 818; 1H NMR (400 MHz, CDCl3)
d (ppm): 2.43 (4H, t,
J ¼ 3.24 Hz), 3.37 (4H, t, J ¼ 3.24 Hz), 6.79 (1H, d, J ¼ 15.4 Hz, Phe
CH]CHe), 7.41e7.80 (6H, m, AreH), 7.92 (1H, d, J ¼ 15.4 Hz, Phe
CH]CHe), 8.09 (2H, d, J ¼ 6.9 Hz, AreH), 9.95 (1H, s, CONH); 13C
NMR (100 MHz, CDCl3)
d (ppm): 47.18, 53.25, 114.52, 118.17, 122.12,
126.10, 128.90, 131.17, 136.10, 141.11, 145.21, 147.01, 165.04; HR-MS
m/z: 352.2725 (Mþ).
NMR (400 MHz, CDCl3)
d (ppm): 1.39 (9H, s, CH3), 3.14 (4H, t,
J ¼ 3.50 Hz), 3.74 (4H, t, J ¼ 3.51 Hz), 6.82 (1H, d, J ¼ 15.9 Hz, Phe
CH]CHe), 7.01e7.68 (5H, m, AreH), 7.75 (1H, d, J ¼ 15.9 Hz, Phe
CH]CHe), 8.18 (2H, d, J ¼ 7.1 Hz, AreH), 9.92 (1H, s, CONH); 13C
4.6.4. N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)
acrylamide (9d)
tert-Butyl 4-{2-fluoro-4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate 7p (4 g, 10.81 mmol) was stirred at room
temperature in a 20 ml mixture of TFA/DCM (1:1) for 12 h. The
reaction mixture was worked up as per the general procedure to
afford 2.9 g of 9d. Light yellow solid; Yield 92.36%; mp 212e214 ꢀC
(charred); IR (KBr pellets, cmꢁ1): 3448, 3326, 2952, 1667, 1607, 1511,
NMR (100 MHz, CDCl3)
d (ppm): 26.22, 49.67, 50.12, 80.41, 116.44,
118.50, 119.31, 127.33, 131.21, 135.32, 141.95, 147.90, 154.56, 155.09,
166.23; HR-MS m/z: 470.3026 (Mþ).
1340, 1217, 1128, 910, 866; 1H NMR (400 MHz, CDCl3)
d (ppm): 2.62
4.6. General procedure for the synthesis of compounds 9aed
(4H, t, J ¼ 3.47 Hz), 3.45 (4H, t, J ¼ 3.47 Hz), 6.66 (1H, d,
J ¼ 14.8 Hz Hz, PheCH]CHe), 6.91 (1H, d, J ¼ 7.4 Hz, AreH), 7.27
(4H, m, AreH), 7.71 (1H, d, J ¼ 14.8 Hz Hz, PheCH]CHe), 8.24 (2H,
d, J ¼ 7.8 Hz, AreH), 9.88 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
The BOC protected amines were stirred at room temperature in
a mixture of TFA/DCM (1:1) for 12 h. The volatiles were removed in
vacuo, and the residue was scratched with little water to get yellow
solid. The solid was filtered and washed with water and ethyl ac-
etate to get product in the form of TFA salt. The TFA salt was sus-
pended in the 1 N NaOH solution and stirred for 10 min to get salt
free base form which was recrystallized from chloroform-Hexane
to get pure product.
d
(ppm): 46.19, 54.04, 111.78, 113.11, 117.73,121.28, 128.17, 129.75,
131.12, 135.68, 141.30, 147.10, 147.67, 154.37, 164.89; HReMS m/z:
370.2189 (Mþ).
4.7. General procedure for the synthesis of compounds 10ael
4.6.1. N-[4-(Piperazin-1-yl)phenyl]cinnamamide (9a)
1 equiv of cinnamamide was dissolved in dry DCM followed by
addition of 3 equiv of Et3N and stirred at 0 ꢀC under inert atmo-
sphere. 1.5 equiv of alkyl/aryl chloroformate derivative was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was stirred for 0.5 h. The reaction progress was monitored
by TLC. After completion of the reaction, the reaction mixture was
diluted with water (30 ml) and extracted with DCM twice. The
organic layer was washed successively with 2 N HCl (2 ꢃ 20 ml),
saturated bicarbonate solution (2 ꢃ 20 ml) and brine solution
(20 ml). The organic layer was dried over anhydrous sodium sulfate
and was evaporated under reduced pressure. The crude product
was recrystallized from ethyl acetate and hexane to afford the
desired product.
tert-Butyl 4-(4-cinnamamidophenyl)piperazine-1-carboxylate
7d (3 g, 9.77 mmol) was stirred at room temperature in a 20 ml
mixture of TFA/DCM (1:1) for 12 h. The reaction mixture was
worked up as per the general procedure to afford 2.1 g of 9a. Light
yellow solid; Yield 92.92%; mp 205e207 ꢀC; IR (KBr pellets, cmꢁ1):
3317, 3254, 2945, 2826,1665,1599,1316,1448,1338,1244,1177, 977,
820, 761; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.01e3.12 (8H, t,
J ¼ 3.89 Hz Hz), 6.59 (1H, d, J ¼ 15.2 Hz, PheCH]CHe), 6.91 (2H, d,
J ¼ 7.5 Hz, AreH), 7.21e7.59 (7H, m, AreH), 7.79 (1H, d, J ¼ 15.2 Hz,
PheCH]CHe), 9.84 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d
(ppm): 45.98, 52.38, 112.82, 117.37,121.40, 127.85, 128.11, 128.78,
131.33, 135.32, 141.36, 146.28, 165.93; HR-MS m/z: 307.2045 (Mþ).

K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
51
4.7.1. Methyl 4-(4-cinnamamidophenyl)piperazine-1-carboxylate
(10a)
995, 758; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.13 (4H, t,
J ¼ 4.28 Hz), 3.39 (4H, t, J ¼ 4.30 Hz Hz), 3.68 (3H, s, CH3), 6.79 (1H,
d, J ¼ 14.8 Hz, PheCH]CHe), 6.85 (1H, d, J ¼ 7.2 Hz, AreH), 7.12e
7.56 (7H, m, AreH), 7.81 (1H, d, J ¼ 14.8 Hz, PheCH]CHe), 9.85
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in 10 ml dry atmosphere. Methyl chloroformate
(0.04 g, 0.47 mmol) was directly added dropwise to above stirred
solution at 0 ꢀC. The reaction mixture was worked up as per the
general procedure to DCM followed by addition of Et3N (0.16 ml,
1.17 mmol) and stirred at 0 ꢀC under inert afford 0.089 g of 10a.
Light yellow solid; Yield 63.57%; mp 215e217 ꢀC; IR (KBr pellets,
cmꢁ1): 3229, 3105, 2919, 2821, 1695, 1612, 1532, 1449, 1341, 1248,
(1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 50.21, 52.78,
111.75, 112.55, 119.72, 121.06, 127.82, 127.98, 128.36, 128.24, 134.11,
142.23, 146.17, 152.09, 154.27, 165.10; HR-MS m/z: 383.2011 (Mþ).
4.7.5. Ethyl 4-(4-cinnamamido-2-fluorophenyl)piperazine-1-
carboxylate (10e)
1126, 995, 819, 757; 1H NMR (400 MHz, CDCl3)
d (ppm): 2.49 (4H, t,
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. Ethyl chloroformate (0.05 g, 0.44 mmol) was directly added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
worked up as per the general procedure to afford 0.11 g of 10e. Off-
white solid; Yield 78.57%; mp 226e228 ꢀC; IR (KBr pellets, cmꢁ1):
3335, 2975, 2822, 1689, 1512, 1422, 1233, 1123, 972, 826, 761; 1H
J ¼ 4.31 Hz), 3.34 (4H, t, J ¼ 4.32 Hz), 3.65 (3H, s, CH3), 6.76 (1H, d,
J ¼ 15.6 Hz, PheCH]CHe), 6.92 (2H, d, J ¼ 7.4 Hz, AreH), 7.36e7.62
(7H, m, AreH), 7.77 (1H, d, J ¼ 15.6 Hz Hz, PheCH]CHe),10.03 (1H,
s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 50.65, 52.02, 52.77,
112.56, 118.72, 121.86, 127.44, 127.92, 128.01, 128.78, 134.11, 142.02,
146.10, 154.30, 165.24; HReMS m/z: 365.2384 (Mþ).
4.7.2. Ethyl 4-{2-fluoro-4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate (10b)
NMR (400 MHz, CDCl3)
d
(ppm): 1.59 (3H, t, J ¼ 7.14 Hz, OeCH2e
CH3), 2.99 (4H, t, J ¼ 3.30 Hz), 3.61 (4H, t, J ¼ 3.29 Hz), 3.84 (2H, q,
J ¼ 7.14 Hz, OeCH2eCH3), 6.49 (1H, d, J ¼ 14.2 Hz, PheCH]CHe),
6.84 (1H, d, J ¼ 7.7 Hz, AreH), 7.18e7.59 (7H, m, AreH), 7.79 (1H, d,
J ¼ 14.2 Hz Hz, PheCH]CHe), 9.43 (1H, s, CONH); 13C NMR
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in 10 ml dry DCM followed by addition of Et3N
(0.16 ml, 1.17 mmol) and stirred at 0 ꢀC under inert atmosphere.
Ethyl chloroformate (0.05 g, 0.47 mmol) was directly added drop-
wise to above stirred solution at 0 ꢀC. The reaction mixture was
worked up as per the general procedure to afford 0.094 g of 10b.
Light yellow solid; Yield 67.14%; mp 206e208 ꢀC; IR (KBr pellets,
cmꢁ1): 3260, 3116, 2976, 2826, 1702, 1653, 1535, 1439, 1336, 1250,
(100 MHz, CDCl3) d (ppm): 28.53, 43.89, 50.63, 52.69, 119.37, 122.18,
122.47, 127.96, 128.91, 130.08, 134.53, 142.66, 156.12, 167.63; HR-MS
m/z: 397.3012 (Mþ).
1121, 990, 816; 1H NMR (400 MHz, CDCl3)
d (ppm): 1.22 (3H, t,
4.7.6. Phenyl 4-(4-cinnamamido-2-fluorophenyl)piperazine-1-
carboxylate (10f)
J ¼ 7.3 Hz, OeCH2eCH3), 3.05 (4H, t, J ¼ 4.78 Hz), 3.42 (4H, t,
J ¼ 4.78 Hz), 4.07 (2H, q, J ¼ 7.3 Hz, OeCH2eCH3), 6.66 (1H, d,
J ¼ 15.1 Hz, PheCH]CHe), 6.85 (2H, d, J ¼ 7.5 Hz, AreH), 7.40e7.59
(8H, m, AreH), 10.23 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. Phenyl chloroformate (0.07 g, 0.44 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.15 g of 10f. Light yellow solid; Yield 93.75%; mp 194e196 ꢀC; IR
(KBr pellets, cmꢁ1): 3258, 2918, 2855, 1692, 1516, 1428, 1222, 1197,
d
(ppm): 12.30, 50.35, 52.28, 63.37, 113.52, 118.26, 121.47, 127.19,
127.48, 128.71, 128.90, 135.10, 142.72, 145.16, 155.36, 165.20; HR-MS
m/z: 379.3461 (Mþ).
4.7.3. Phenyl 4-(4-cinnamamidophenyl)piperazine-1-carboxylate
(10c)
993, 748; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.10 (4H, t,
J ¼ 3.90 Hz), 3.81 (4H, t, J ¼ 3.92 Hz), 6.51 (1H, d, J ¼ 15.5 Hz, Phe
CH]CHe), 6.92 (1H, d, J ¼ 8.2 Hz, AreH), 7.11e7.60 (12H, m, AreH),
7.78 (1H, d, J ¼ 15.5 Hz, PheCH]CHe),10.11 (1H, s, CONH); 13C NMR
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in10 ml dry DCM followed by addition of Et3N
(0.16 ml, 1.17 mmol) and stirred at 0 ꢀC under inert atmosphere.
Phenyl chloroformate (0.07 g, 0.47 mmol) was directly added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
worked up as per the general procedure to afford 0.1 g of 10c. Light
yellow solid; Yield 62.5%; mp 219e220 ꢀC; IR (KBr pellets, cmꢁ1):
3240, 3038, 2919, 2857, 1723, 1651, 1540, 1418, 1343, 1248, 1072,
(100 MHz, CDCl3)
d (ppm): 52.11, 52.75, 111.45, 112.10, 118.73,
121.29, 121.49, 126.05, 127.37, 127.77, 128.16, 128.80, 129.90, 135.14,
141.22, 145.15, 151.05, 153.10, 155.26, 168.14; HR-MS m/z: 445.2251
(Mþ).
922, 822, 744; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.17e3.73 (8H,
4.7.7. Methyl 4-{4-[3-(4-nitrophenyl)acrylamido]phenyl}
m), 6.82 (1H, d, J ¼ 16.9 Hz, PheCH]CHe), 6.99 (2H, d, J ¼ 7.7 Hz,
piperazine-1-carboxylate (10g)
AreH), 7.13e7.51 (12H, m, AreH), 7.60 (1H, d, J ¼ 16.9 Hz, PheCH]
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. Methyl chloroformate (0.05 g, 0.41 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.11 g of 10g. Light yellow solid; Yield 84.62%; mp 267e269 ꢀC
(charred); IR (KBr pellets, cmꢁ1): 3262, 2954, 2834, 1705, 1652,
1622, 1514, 1446, 1339, 1232, 1119, 973, 819; 1H NMR (400 MHz,
CHe),10.06 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm):
49.10, 52.73, 112.29, 118.27, 121.18, 121.86, 126.04, 127.48, 127.86,
128.07, 128.78, 129.89, 134.11, 142.02, 146.10, 151.84, 154.04, 165.50;
HR-MS m/z: 427.2161 (Mþ).
4.7.4. Methyl 4-(4-cinnamamido-2-fluorophenyl)piperazine-1-
carboxylate (10d)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. Methyl chloroformate (0.04 g, 0.44 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.08 g of 10d. Off-white solid; Yield 57.14%; mp 210e212 ꢀC; IR (KBr
pellets, cmꢁ1): 3254, 2857, 1686, 1622, 1518, 1440, 1348, 1241,1124,
CDCl3)
d
(ppm): 3.19 (4H, t, J ¼ 4.11 Hz), 3.44 (4H, t, J ¼ 4.12 Hz), 3.95
(3H, s, CH3), 6.69 (1H, d, J ¼ 15.4 Hz, PheCH]CHe), 6.88 (2H, d,
J ¼ 7.8 Hz, AreH), 7.33e7.51 (4H, m, AreH), 7.71 (1H, d, J ¼ 15.4 Hz,
PheCH]CHe), 8.05 (2H, d, J ¼ 6.8 Hz, AreH), 9.43 (1H, s, CONH);
13C NMR (100 MHz, CDCl3)
d (ppm): 50.65, 52.80, 112.13, 118.43,
121.16, 127.23, 128.92, 128.71, 134.90, 142.22, 146.84, 147.43, 154.38,
165.64; HR-MS m/z: 410.2195 (Mþ).

52
K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
4.7.8. Ethyl 4-{4-[3-(4-nitrophenyl)acrylamido]phenyl}piperazine-
1-carboxylate (10h)
reaction mixture was worked up as per the general procedure to
afford 0.08 g of 10k. Light yellow solid; Yield 57.14%; mp 237e
239 ꢀC; IR (KBr pellets, cmꢁ1): 3448, 3266, 2861, 1699, 1597, 1515,
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. Ethyl chloroformate (0.06 g, 0.41 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.08 g of 10h. Light yellow solid; Yield 57.14%; mp 254e256 ꢀC; IR
(KBr pellets, cmꢁ1): 3447, 3290, 2820, 1699, 1621, 1517, 1342, 1248,
1342, 1246, 1147, 865; 1H NMR (400 MHz, CDCl3)
d (ppm): 1.28 (3H,
t, J ¼ 7.5 Hz, OeCH2eCH3), 3.09 (4H, t, J ¼ 4.45 Hz), 3.62 (4H, t,
J ¼ 4.47 Hz), 4.18 (2H, q, J ¼ 7.5 Hz, OeCH2eCH3), 6.54 (1H, d,
J ¼ 15.4 Hz, PheCH]CHe), 6.89 (1H, d, J ¼ 7.4 Hz, AreH), 7.35 (2H,
d, J ¼ 7.1 Hz, AreH), 7.50e7.54 (2H, m, AreH), 7.71 (1H, d,
J ¼ 15.4 Hz, PheCH]CHe), 8.21 (2H, d, J ¼ 6.8 Hz, AreH), 10.11 (1H,
s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 12.67, 50.15, 52.43,
1125, 991, 822; 1H NMR (400 MHz, CDCl3)
d
(ppm): 1.21 (3H, t,
62.27, 111.41, 112.02, 118.24, 121.27, 127.23, 128.84, 128.99, 135.89,
141.70, 145.06, 147.28, 154.36, 155.30, 165.10; HR-MS m/z: 442.2183
(Mþ).
J ¼ 7.2 Hz, OeCH2eCH3), 3.11 (4H, t, J ¼ 4.65 Hz), 3.61 (4H, t,
J ¼ 4.65 Hz), 4.19 (2H, q, J ¼ 7.2 Hz, OeCH2eCH3), 6.61 (1H, d,
J ¼ 15.8 Hz, PheCH]CHe), 6.92 (2H, d, J ¼ 7.8 Hz, AreH), 7.51 (2H,
d, J ¼ 7.1 Hz, AreH), 7.62 (2H, d, J ¼ 7.9 Hz, AreH), 7.79 (1H, d,
J ¼ 15.8 Hz, PheCH]CHe), 8.21 (2H, d, J ¼ 7.1 Hz, AreH), 10.11 (1H,
4.7.12. Phenyl 4-{2-fluoro-4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate (10l)
s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 13.30, 51.25, 51.32,
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM
followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred at 0 ꢀC
under inert atmosphere. Phenyl chloroformate (0.08 g, 0.39 mmol)
was directly added dropwise to above stirred solution at 0 ꢀC. The
reaction mixture was worked up as per the general procedure to
afford 0.08 g of 10l. Light yellow solid; Yield 53.33%; mp 269e
271 ꢀC; IR (KBr pellets, cmꢁ1): 3422, 3272, 2863, 1720, 1655, 1593,
1514, 1432, 1345, 1215, 1070, 914, 853, 754; 1H NMR (400 MHz,
62.37, 112.52, 118.51, 121.09, 127.13, 128.21, 128.87, 134.89, 141.72,
146.36, 147.68, 154.36, 167.19; HR-MS m/z: 424.3048 (Mþ).
4.7.9. Phenyl 4-{4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate (10i)
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. Phenyl chloroformate (0.08 g, 0.41 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.09 g of 10i. Light yellow solid; Yield 56.25%; mp 263e265 ꢀC; IR
(KBr pellets, cmꢁ1): 3447, 3269, 2833, 1719, 1621, 1515, 1414, 1340,
CDCl3)
d
(ppm): 3.13 (4H, t, J ¼ 4.56 Hz), 3.74 (4H, t, J ¼ 4.55 Hz),
6.69 (1H, d, J ¼ 15.9 Hz, PheCH]CHe), 6.91 (1H, d, J ¼ 7.2 Hz, Are
H), 7.32e7.67 (9H, m, AreH), 7.81 (1H, d, J ¼ 15.9 Hz, PheCH]CHe),
8.11 (2H, d, J ¼ 7.1 Hz, AreH), 10.18 (1H, s, CONH); 13C NMR
(100 MHz, CDCl3) d (ppm): 51.47, 52.01,110.27,112.19,118.03,121.20,
1203, 1046, 918, 751; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.32 (8H,
121.43, 126.25, 127.10, 128.37, 128.48, 129.87, 134.29, 141.15, 145.29,
147.07, 151.36, 154.29, 154.19, 164.28; HR-MS m/z: 490.3634 (Mþ).
m), 6.88 (1H, d, J ¼ 15.1 Hz, PheCH]CHe), 6.95 (2H, d, J ¼ 7.5 Hz,
AreH), 7.22e7.63 (9H, m, AreH), 7.72 (1H, d, J ¼ 15.1 Hz, PheCH]
CHe), 8.03 (2H, d, J ¼ 6.7 Hz, AreH), 9.23 (1H, s, CONH); 13C NMR
4.8. General procedure for the synthesis of compounds 11aep
(100 MHz, CDCl3) d (ppm): 51.19, 52.12,112.30,117.21,120.19,121.66,
127.68, 127.97, 128.27, 128.59, 130.19, 135.14, 141.02, 146.50, 147.28,
150.32, 155.04, 166.17; HR-MS m/z: 472.3141 (Mþ).
1 equiv of cinnamamide was dissolved in dry DCM followed by
addition of 3 equiv of Et3N and stirred at 0 ꢀC under inert atmo-
sphere. 1.5 equiv of acyl chloride derivative was directly added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
stirred for 0.5 h. The reaction progress was monitored by TLC. After
completion of the reaction, the reaction mixture was diluted with
water (30 ml) and extracted with DCM twice. The organic layer was
washed successively with 2 N HCl (2 ꢃ 20 ml), saturated bicar-
bonate solution (2 ꢃ 20 ml) and brine solution (20 ml). The organic
layer was dried over anhydrous sodium sulfate and was evaporated
under reduced pressure. The crude product was recrystallized from
ethyl acetate and hexane to afford the desired product.
4.7.10. Methyl 4-{2-fluoro-4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate (10j)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM
followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred at 0 ꢀC
under inert atmosphere. Methyl chloroformate (0.05 g, 0.39 mmol)
was directly added dropwise to above stirred solution at 0 ꢀC. The
reaction mixture was worked up as per the general procedure to
afford 0.07 g of 10j. Light yellow solid; Yield 53.85%; mp 238e
240 ꢀC (charred); IR (KBr pellets, cmꢁ1): 3380, 3266, 2848, 1698,
1665, 1596, 1514, 1435, 1342, 1244, 987, 845; 1H NMR (400 MHz,
CDCl3)
d
(ppm): 3.01 (4H, t, J ¼ 4.09 Hz), 3.65 (4H, t, J ¼ 4.07 Hz),
4.8.1. N-{4-[4-(4-Fluorobenzoyl)piperazin-1-yl]phenyl}
cinnamamide (11a)
3.72 (3H, s, CH3), 6.61 (1H, d, J ¼ 14.6 Hz, PheCH]CHe), 6.91 (1H, d,
J ¼ 7.5 Hz, AreH), 7.15 (2H, d, J ¼ 7.7 Hz, AreH), 7.59 (2H, d,
J ¼ 7.1 Hz, AreH), 7.80 (1H, d, J ¼ 14.6 Hz, PheCH]CHe), 8.25 (2H,
d, J ¼ 7.0 Hz, AreH), 9.87 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in 10 ml dry DCM followed by addition of Et3N
(0.16 ml, 1.17 mmol) and stirred at 0 ꢀC under inert atmosphere. 4-
fluoro benzoylchloride (0.07 g, 0.47 mmol) was directly added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
worked up as per the general procedure to afford 0.13 g of 11a. Off-
white solid; Yield 81.25%; mp 227e229 ꢀC; IR (KBr pellets, cmꢁ1):
3443, 3273, 2835, 1674, 1633, 1589, 1519, 1442, 1343, 1240, 1020,
d
(ppm): 49.21, 51.42, 111.05, 112.12, 119.74, 121.86, 127.32, 127.92,
128.23, 128.84, 134.51, 142.13, 146.10, 152.39, 154.07, 167.56; HR-MS
m/z: 428.2002 (Mþ).
4.7.11. Ethyl 4-{2-fluoro-4-[3-(4-nitrophenyl)acrylamido]phenyl}
piperazine-1-carboxylate (10k)
848; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.12e3.33 (8H, m), 6.76
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM
followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred at 0 ꢀC
under inert atmosphere. Ethyl chloroformate (0.05 g, 0.39 mmol)
was directly added dropwise to above stirred solution at 0 ꢀC. The
(1H, d, J ¼ 15.8 Hz, PheCH]CHe), 6.93 (2H, d, J ¼ 7.5 Hz, AreH),
7.26e7.61 (12H, m, AreH), 10.03 (1H, s, CONH); 13C NMR (100 MHz,
CDCl3)
d (ppm): 51.05, 53.20, 112.56, 115.72, 118.22, 122.97, 127.13,
127.71, 128.10, 128.52, 128.87, 130.67, 135.28, 141.63, 145.29, 159.60,
165.35, 169.30; HR-MS m/z: 429.2375 (Mþ).

K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
53
4.8.2. N-{4-[4-(3,5-Dichlorobenzoyl)piperazin-1-yl]phenyl}
cinnamamide (11b)
1017, 821, 765; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.13 (4H, t,
J ¼ 4.69 Hz), 3.56 (4H, t, J ¼ 4.66 Hz), 6.52 (1H, d, J ¼ 15.5 Hz, Phe
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in 10 ml dry DCM followed by addition of Et3N
(0.16 ml,1.17 mmol) and stirred at 0 ꢀC under inert atmosphere. 3,5-
dichloro benzoylchloride (0.1 g, 0.47 mmol) was directly added
dropwise to above stirred solution at 0 ꢀC. The reaction mixture was
worked up as per the general procedure to afford 0.15 g of 11b. Off-
white solid; Yield 83.33%; mp 194e196 ꢀC; IR (KBr pellets, cmꢁ1):
3449, 3311, 2804, 1659, 1630, 1515, 1415, 1285, 1176, 1018, 976, 769;
CH]CHe), 6.81 (1H, d, J ¼ 8.1 Hz, AreH), 7.21e7.60 (11H, m, Are
H), 7.80 (1H, d, J ¼ 15.5 Hz, PheCH]CHe), 9.11 (1H, s, CONH); 13
C
NMR (100 MHz, CDCl3) d (ppm): 50.14, 54.29,111.78, 113.56, 115.32,
117.21, 121.90, 127.10, 127.83, 128.38, 128.62, 128.98, 130.31, 132.37,
134.28, 142.63, 155.78, 159.98, 165.01, 168.90; HR-MS m/z:
447.3197 (Mþ).
4.8.6. N-{4-[4-(3,5-Dichlorobenzoyl)piperazin-1-yl]-3-
fluorophenyl}cinnamamide (11f)
1H NMR (400 MHz, CDCl3)
d
(ppm): 3.42 (4H, t, J ¼ 4.12 Hz), 3.57
(4H, t, J ¼ 4.10 Hz), 6.56 (1H, d, J ¼ 15.3 Hz, PheCH]CHe), 6.89 (2H,
d, J ¼ 7.7 Hz, AreH), 7.31e7.65 (10H, m, AreH), 7.78 (1H, d,
J ¼ 15.3 Hz, PheCH]CHe), 9.83 (1H, s, CONH); 13C NMR (100 MHz,
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. 3,5-dichloro benzoylchloride (0.09 g, 0.44 mmol) was
directly added dropwise to above stirred solution at 0 ꢀC. The re-
action mixture was worked up as per the general procedure to
afford 0.1 g of 11f. Light yellow solid; Yield 55.56%; mp 189e190 ꢀC;
IR (KBr pellets, cmꢁ1): 3366, 3058, 2817, 1622, 1527, 1446, 1334,
CDCl3)
d (ppm): 50.45, 54.25, 113.06, 118.74, 121.67, 125.13, 127.83,
128.45, 128.96, 130.60, 130.93, 135.17, 135.70, 138.21, 141.03, 145.58,
165.10, 169.97; HR-MS m/z: 479.2278 (Mþ).
4.8.3. N-{4-[4-(2-(Trifluoromethyl)benzoyl]piperazin-1-yl}
phenylcinnamamide (11c)
1258, 1029, 875, 604; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.56 (4H,
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in 10 ml dry DCM followed by addition of Et3N
(0.16 ml, 1.17 mmol) and stirred at 0 ꢀC under inert atmosphere. 2-
(trifluoromethyl)benzoylchloride (0.1 g, 0.47 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.16 g of 11c. Light yellow solid; Yield 88.89%; mp 201e203 ꢀC; IR
(KBr pellets, cmꢁ1): 3448, 2922, 1627, 1518, 1438, 1317, 1181, 1016,
t, J ¼ 4.27 Hz), 3.72 (4H, t, J ¼ 4.29 Hz), 6.69 (1H, d, J ¼ 15.4 Hz, Phe
CH]CHe), 6.83 (1H, d, J ¼ 7.9 Hz, AreH), 7.28e7.62 (10H, m, AreH),
7.75 (1H, d, J ¼ 15.4 Hz, PheCH]CHe), 9.92 (1H, s, CONH); 13C NMR
(100 MHz, CDCl3)
d (ppm): 47.15, 51.53, 111.26, 113.06, 118.84,
121.60, 124.24, 126.53, 127.44, 128.26, 129.60, 130.25, 135.10, 135.82,
138.31, 141.43, 145.10, 155.27, 165.69, 168.34; HR-MS m/z: 497.2092
(Mþ).
768; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.04e3.45 (8H, m), 6.76
4.8.7. N-{3-Fluoro-4-[4-(2-(trifluoromethyl)benzoyl)piperazin-1-
yl]phenyl}cinnamamide (11g)
(1H, d, J ¼ 16.1 Hz, PheCH]CHe), 6.92 (2H, d, J ¼ 7.9 Hz, AreH),
7.39e7.80 (11H, m, AreH), 7.85 (1H, d, J ¼ 16.1 Hz, PheCH]CHe),
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. 2-(trifluoromethyl)benzoylchloride (0.09 g, 0.44 mmol)
was directly added dropwise to above stirred solution at 0 ꢀC. The
reaction mixture was worked up as per the general procedure to
afford 0.13 g of 11g. Light yellow solid; Yield 72.22%; mp 192e
194 ꢀC; IR (KBr pellets, cmꢁ1): 3368, 2922, 1676, 1531, 1438, 1315,
10.04 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 50.62,
54.81, 113.16, 118.45, 121.47, 123.34, 127.37, 127.88, 127.97, 128.35,
128.17, 128.45, 130.28, 134.24, 135.22, 135.57, 141.03, 145.30, 164.32,
169.78; HR-MS m/z: 479.2183 (Mþ).
4.8.4. N-{4-[4-(4-Nitrobenzoyl)piperazin-1-yl]phenyl}
cinnamamide (11d)
N-[4-(Piperazin-1-yl)phenyl]cinnamamide
9a
(0.12
g,
1181, 1016, 767; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.11 (4H, t,
0.39 mmol) was dissolved in 10 ml dry DCM followed by addition
of Et3N (0.16 ml, 1.17 mmol) and stirred at 0 ꢀC under inert at-
mosphere. 4-nitrobenzoylchloride (0.09 g, 0.47 mmol) was
directly added portionwise to above stirred solution at 0 ꢀC. The
reaction mixture was worked up as per the general procedure to
afford 0.14 g of 11d. Light orange solid; Yield 82.35%; mp 218e
220 ꢀC; IR (KBr pellets, cmꢁ1): 3449, 3273, 2922, 2852, 1677, 1622,
1522, 1447, 1350, 1172, 1014, 849, 719; 1H NMR (400 MHz, CDCl3)
J ¼ 4.67 Hz), 3.38 (4H, t, J ¼ 4.69 Hz), 6.51 (1H, d, J ¼ 14.9 Hz, Phe
CH]CHe), 6.88 (1H, d, J ¼ 7.8 Hz, AreH), 7.19e7.69 (11H, m, AreH),
7.79 (1H, d, J ¼ 14.9 Hz, PheCH]CHe), 9.37 (1H, s, CONH); 13C NMR
(100 MHz, CDCl3)
d (ppm): 47.28, 50.32, 108.86, 109.14, 115.73,
119.42, 120.63, 125.00, 126.74, 126.78, 127.07, 127.25, 127.93, 128.84,
129.30, 129.98, 132.25, 134.01, 134.58, 135.77, 142.39, 154.25, 156.69,
164.08, 167.53; HR-MS m/z: 497.3178 (Mþ).
d
(ppm): 3.29 (4H, t, J ¼ 4.22 Hz), 3.44 (4H, t, J ¼ 4.25 Hz), 6.83
4.8.8. N-{3-Fluoro-4-[4-(4-nitrobenzoyl)piperazin-1-yl]phenyl}
cinnamamide (11h)
(1H, d, J ¼ 16.7 Hz, PheCH]CHe), 6.87 (2H, d, J ¼ 8.4 Hz, AreH),
7.28e7.84 (11H, m, AreH), 7.88 (1H, d, J ¼ 16.7 Hz, PheCH]CHe),
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. 4-nitrobenzoylchloride (0.08 g, 0.44 mmol) was directly
added portionwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.11 g of 11h. Light yellow solid; Yield 64.71%; mp 217e219 ꢀC; IR
(KBr pellets, cmꢁ1): 3323, 3058, 1648, 1556, 1417, 1316, 1020, 962,
10.12 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 47.05,
51.29, 111.56, 115.02, 117.21, 121.90, 127.14, 127.79, 128.23, 128.55,
128.93, 131.67, 133.20, 141.03, 145.59, 147.60, 166.30, 168.34; HR-
MS m/z: 456.2213 (Mþ).
4.8.5. N-{3-Fluoro-4-[4-(4-fluorobenzoyl)piperazin-1-yl]phenyl}
cinnamamide (11e)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. 4-fluoro benzoylchloride (0.07 g, 0.44 mmol) was directly
added dropwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford
0.12 g of 11e. Light yellow solid; Yield 75%; mp 212e214 ꢀC; IR (KBr
pellets, cmꢁ1): 3417, 3256, 2834, 1674, 1613, 1520, 1444, 1343, 1238,
748, 604; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.53 (4H, t,
J ¼ 4.02 Hz), 3.92 (4H, t, J ¼ 4.04 Hz), 6.43 (1H, d, J ¼ 15.5 Hz, Phe
CH]CHe), 6.85 (1H, d, J ¼ 8.2 Hz, AreH), 7.21e7.61 (9H, m, AreH),
7.77 (1H, d, J ¼ 15.5 Hz, PheCH]CHe), 8.23 (2H, d, J ¼ 6.9 Hz, Are
H), 9.45 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 49.25,
53.22, 112.52, 113.18, 115.71, 118.21, 122.91, 126.14, 127.25, 127.98,
128.45, 128.67, 131.60, 135.20, 142.03, 145.39, 146.61, 154.23, 165.11,
168.74; HR-MS m/z: 474.2052 (Mþ).

54
K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
4.8.9. N-{4-[4-(4-Fluorobenzoyl)piperazin-1-yl]phenyl}-3-(4-
nitrophenyl)acrylamide (11i)
afford 0.13 g of 11l. Light orange solid; Yield 76.47%; mp > 270 ꢀC; IR
(KBr pellets, cmꢁ1): 3270, 2923, 1667, 1635, 1521, 1444, 1367, 1283,
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. 4-fluoro benzoylchloride (0.08 g, 0.41 mmol) was
directly added dropwise to above stirred solution at 0 ꢀC. The re-
action mixture was worked up as per the general procedure to
afford 0.11 g of 11i. Light orange solid; Yield 68.75%; mp 267e
269 ꢀC; IR (KBr pellets, cmꢁ1): 3216, 2926, 1640, 1569, 1508, 1387,
1013, 767; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.13 (4H, t,
J ¼ 4.21 Hz), 3.67 (4H, t, J ¼ 4.19 Hz), 6.82 (1H, d, J ¼ 15.2 Hz, Phe
CH]CHe), 6.96 (2H, d, J ¼ 8.2 Hz, AreH), 7.22e7.54 (7H, m, AreH),
7.83 (1H, d, J ¼ 15.2 Hz, PheCH]CHe), 8.09 (2H, d, J ¼ 7.3 Hz, Are
H), 9.35 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 48.45,
52.53, 112.56, 114.92, 117.01, 121.55, 127.30, 128.23, 128.55, 128.86,
131.60, 132.20, 141.13, 144.50, 147.61, 148.41, 165.38, 169.80; HR-MS
m/z: 501.2182 (Mþ).
1233,1054, 801, 718; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.17 (4H, t,
J ¼ 4.38 Hz), 3.81 (4H, t, J ¼ 4.39 Hz), 6.69 (1H, d, J ¼ 16.7 Hz, Phe
CH]CHe), 6.86 (2H, d, J ¼ 7.6 Hz, AreH), 7.23e7.57 (8H, m, AreH),
7.82 (1H, d, J ¼ 16.7 Hz, PheCH]CHe), 8.12 (2H, d, J ¼ 7.1 Hz, Are
4.8.13. N-{3-Fluoro-4-[4-(4-fluorobenzoyl)piperazin-1-yl]phenyl}-
3-(4-nitrophenyl)acrylamide (11m)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM
followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred at 0 ꢀC
under inert atmosphere. 4-fluoro benzoylchloride (0.08 g,
0.39 mmol) was directly added dropwise to above stirred solution
at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.1 g of 11m. Light yellow solid; Yield 66.67%;
mp 245e247 ꢀC; IR (KBr pellets, cmꢁ1): 3448, 3323, 3110, 2921,
1678, 1604, 1515, 1429, 1342, 1226, 1155, 840, 756; 1H NMR
H),10.12 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 44.35,
47.38, 111.06, 116.70, 117.12, 121.46, 127.93, 128.37, 128.71, 128.90,
129.67,134.27,140.63,145.29,145.93,158.20,164.35,168.83; HR-MS
m/z: 474.2149 (Mþ).
4.8.10. N-{4-[4-(3,5-Dichlorobenzoyl)piperazin-1-yl]phenyl}-3-(4-
nitrophenyl)acrylamide (11j)
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. 3,5-dichloro benzoylchloride (0.11 g, 0.41 mmol) was
directly added dropwise to above stirred solution at 0 ꢀC. The re-
action mixture was worked up as per the general procedure to
afford 0.11 g of 11j. Light brown solid; Yield 64.71%; mp > 270 ꢀC; IR
(KBr pellets, cmꢁ1): 3414, 2832, 1635, 1522, 1332, 1238, 1169, 1024,
(400 MHz, CDCl3)
d
(ppm): 3.49 (4H, t, J ¼ 4.32 Hz), 3.87 (4H, t,
J ¼ 4.31 Hz), 6.56 (1H, d, J ¼ 15.5 Hz, PheCH]CHe), 6.89 (1H, d,
J ¼ 7.7 Hz, AreH), 7.24e7.73 (8H, m, AreH), 7.82 (1H, d, J ¼ 15.5 Hz,
PheCH]CHe), 8.07 (2H, d, J ¼ 7.6 Hz, AreH), 9.62 (1H, s, CONH);
13C NMR (100 MHz, CDCl3)
d (ppm): 49.10, 53.26,112.78, 113.02,
116.32, 118.23, 122.91, 127.86, 128.08, 128.77, 128.94, 130.50, 131.37,
135.28, 141.63, 146.64, 154.70, 158.98, 166.47, 169.92; HR-MS m/z:
492.2296 (Mþ).
830; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.22 (4H, t, J ¼ 4.24 Hz),
3.78 (4H, t, J ¼ 4.22 Hz), 6.73 (1H, d, J ¼ 15.8 Hz, PheCH]CHe), 6.82
(2H, d, J ¼ 7.9 Hz, AreH), 7.27e7.59 (7H, m, AreH), 7.88 (1H, d,
J ¼ 15.8 Hz, PheCH]CHe), 8.21 (2H, d, J ¼ 8.1 Hz, AreH),10.09 (1H,
4.8.14. N-{4-[4-(3,5-dichlorobenzoyl)piperazin-1-yl]-3-
fluorophenyl}-3-(4-nitrophenyl)acrylamide (11n)
s, CONH); 13C NMR (100 MHz, CDCl3)
d
(ppm): 50.90, 53.89, 112.26,
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM
followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred at 0 ꢀC
under inert atmosphere. 3,5-dichloro benzoylchloride (0.1 g,
0.39 mmol) was directly added dropwise to above stirred solution
at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.12 g of 11n. Light orange solid; Yield 70.59%;
mp 269e271 ꢀC; IR (KBr pellets, cmꢁ1): 3467, 3320, 2922, 1677,
1608, 1515, 1339, 1226, 1021, 840, 742; 1H NMR (400 MHz, CDCl3)
117.88, 121.07, 125.31, 127.45, 128.35, 130.48, 131.63, 135.87, 135.97,
138.51, 142.13, 145.28, 147.28, 165.35, 168.32; HR-MS m/z: 524.1016
(Mþ).
4.8.11. 3-(4-Nitrophenyl)-N-{4-[4-(2-(trifluoromethyl)benzoyl)
piperazin-1-yl]phenyl}acrylamide (11k)
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under
inert atmosphere. 2-(trifluoromethyl)benzoylchloride (0.11 g,
0.41 mmol) was directly added dropwise to above stirred solution
at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.12 g of 11k. Light orange solid; Yield 70.59%;
mp 249e251 ꢀC; IR (KBr pellets, cmꢁ1): 3352, 2923, 1648, 1613,
1517, 1488, 1390, 1268, 1133, 938, 755; 1H NMR (400 MHz, CDCl3)
d
(ppm): 3.59 (4H, t, J ¼ 4.17 Hz), 3.91 (4H, t, J ¼ 4.19 Hz), 6.81 (1H, d,
J ¼ 14.2 Hz, PheCH]CHe), 6.85 (1H, d, J ¼ 8.1 Hz, AreH), 7.27e7.78
(7H, m, AreH), 7.79 (1H, d, J ¼ 14.2 Hz, PheCH]CHe), 8.21 (2H, d,
J ¼ 6.7 Hz, AreH), 9.59 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d
(ppm): 46.45, 50.23, 111.67, 112.16, 118.26, 121.15, 125.22, 127.53,
128.19, 129.27, 130.14, 134.11, 135.16, 138.28, 141.23, 145.89, 147.29,
155.11, 166.21, 169.84; HR-MS m/z: 542.1288 (Mþ).
d
(ppm): 3.46 (4H, t, J ¼ 4.11 Hz), 3.82 (4H, t, J ¼ 4.13 Hz), 6.78 (1H, d,
J ¼ 15.5 Hz, PheCH]CHe), 6.80 (2H, d, J ¼ 7.4 Hz, AreH), 7.29e7.60
(8H, m, AreH), 7.71 (1H, d, J ¼ 15.5 Hz, PheCH]CHe), 8.19 (2H, d,
J ¼ 7.7 Hz, AreH),10.14 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
4.8.15. N-{3-Fluoro-4-[4-(2-(trifluoromethyl)benzoyl)piperazin-1-
yl]phenyl}-3-(4-nitrophenyl)acrylamide (11o)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM
followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred at 0 ꢀC
under inert atmosphere. 2-(trifluoromethyl)benzoylchloride (0.1 g,
0.39 mmol) was directly added dropwise to above stirred solution
at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.11 g of 11o. Light yellow solid; Yield 64.71%;
mp 252e254 ꢀC; IR (KBr pellets, cmꢁ1): 3447, 3335, 2926, 1635,
1605, 1510, 1336, 1284, 1177, 1015, 838, 776; 1H NMR (400 MHz,
d
(ppm): 47.29, 51.19, 113.52, 116.71, 118.24, 121.47, 123.64, 127.46,
128.45, 128.59, 128.99, 130.14, 135.47, 142.60, 145.24, 146.32, 147.89,
164.30, 168.88; HR-MS m/z: 525.1191 (M þ 1).
4.8.12. N-{4-[4-(4-Nitrobenzoyl)piperazin-1-yl]phenyl}-3-(4-
nitrophenyl)acrylamide (11l)
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. 4-nitrobenzoylchloride (0.09 g, 0.41 mmol) was
directly added portionwise to above stirred solution at 0 ꢀC. The
reaction mixture was worked up as per the general procedure to
CDCl3)
d
(ppm): 3.62e3.78 (8H, m), 6.69 (1H, d, J ¼ 14.1 Hz, Phe
CH]CHe), 6.93 (1H, d, J ¼ 7.8 Hz, AreH), 7.31e7.84 (8H, m, AreH),
7.88 (1H, d, J ¼ 14.1 Hz, PheCH]CHe), 8.24 (2H, d, J ¼ 7.1 Hz, Are
H), 9.78 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 49.32,

K.N. Patel, V.N. Telvekar / European Journal of Medicinal Chemistry 75 (2014) 43e56
55
53.27, 111.46, 115.73, 118.42, 121.63, 123.63, 125.10, 126.14, 127.17,
127.32, 128.43, 128.84, 129.21, 130.65, 131.27, 134.20, 135.71, 141.18,
147.61, 165.19, 169.33; HR-MS m/z: 542.2273 (Mþ).
of 12b. Off-white solid; Yield 66.67%; mp 252e254 ꢀC; IR (KBr
pellets, cmꢁ1): 3401, 3110, 2947, 1664, 1631, 1602, 1542, 1512, 1428,
1357, 1212, 1011, 997, 874, 761; 1H NMR (400 MHz, CDCl3)
d (ppm):
3.31 (4H, t, J ¼ 3.32 Hz), 3.57 (4H, t, J ¼ 3.30 Hz), 6.68 (1H, d,
J ¼ 16.9 Hz, PheCH]CHe), 6.93 (1H, d, J ¼ 7.9 Hz, AreH), 7.24e7.67
(9H, m, AreH), 7.73 (1H, d, J ¼ 16.9 Hz, PheCH]CHe), 8.56 (2H, d,
J ¼ 6.9 Hz, AreH), 10.08 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
4.8.16. N-{3-Fluoro-4-[4-(4-nitrobenzoyl)piperazin-1-yl]phenyl}-
3-(4-nitrophenyl)acrylamide (11p)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry
DCM followed by addition of Et3N (0.14 ml, 0.94 mmol) and stirred
at 0 ꢀC under inert atmosphere. 4-nitrobenzoylchloride (0.09 g,
0.39 mmol) was directly added portionwise to above stirred solu-
tion at 0 ꢀC. The reaction mixture was worked up as per the general
procedure to afford 0.13 g of 11p. Light yellow solid; Yield 81.25%;
mp 245e247 ꢀC; IR (KBr pellets, cmꢁ1): 3481, 3335, 3101, 2966,
1670, 1597, 1508, 1334, 1282, 1012, 844, 775; 1H NMR (400 MHz,
d
(ppm): 47.32, 51.22,111.26, 113.24, 117.09, 118.12, 121.19, 127.01,
127.29, 128.16, 128.34, 135.78, 142.10, 144.14, 145.52, 149.27, 155.24,
166.72, 168.10; HR-MS m/z: 430.2050 (Mþ).
4.9.3. N-[4-(4-Isonicotinoylpiperazin-1-yl)phenyl]-3-(4-
nitrophenyl)acrylamide (12c)
3-(4-Nitrophenyl)-N-[4-(piperazin-1-yl)phenyl]acrylamide 9c
(0.12 g, 0.34 mmol) was dissolved in 10 ml dry DCM followed by
addition of Et3N (0.14 ml, 1.02 mmol) and stirred at 0 ꢀC under inert
atmosphere. Isonicotinoyl chloride (0.07 g, 0.41 mmol) was directly
added portionwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford 0.09 g
of 12c. Reddish solid; Yield 60%; mp 262e264 ꢀC (charred); IR (KBr
pellets, cmꢁ1): 3394, 3239, 1637, 1562, 1542, 1449, 1261, 1185, 1038,
CDCl3)
d
(ppm): 3.44e3.57 (8H, m), 6.72 (1H, d, J ¼ 15.8 Hz, Phe
CH]CHe), 6.85 (1H, d, J ¼ 7.9 Hz, AreH), 7.27e7.78 (8H, m, AreH),
7.81 (1H, d, J ¼ 15.8 Hz, PheCH]CHe), 8.19 (2H, d, J ¼ 7.1 Hz, Are
H), 10.12 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 50.25,
54.12, 111.12, 112.18, 115.74, 118.83, 121.45, 125.14, 127.58, 128.40,
128.77, 132.61, 134.20, 141.03, 145.09, 146.21, 147.81, 154.27, 165.87,
169.34; HR-MS m/z: 519.2072 (Mþ).
802, 739; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.24 (4H, t,
J ¼ 4.56 Hz), 3.48 (4H, t, J ¼ 4.53 Hz), 6.62 (1H, d, J ¼ 15.5 Hz, Phe
CH]CHe), 6.83 (2H, d, J ¼ 7.8 Hz, AreH), 7.32e7.74 (8H, m, AreH),
7.76 (1H, d, J ¼ 15.5 Hz, PheCH]CHe), 8.89 (2H, d, J ¼ 7.1 Hz, AreH),
4.9. General procedure for the synthesis of compounds 12aed
1 equiv of cinnamamide was dissolved in dry DCM followed by
addition of 3 equiv of Et3N and stirred at 0 ꢀC under inert atmo-
sphere. 1.5 equiv of isonicotinoyl chloride dissolved in DCM was
directly added dropwise to above stirred solution at 0 ꢀC. The reac-
tion mixture was stirred for 0.5 h. The reaction progress was moni-
tored by TLC. After completion of the reaction, the reaction mixture
was diluted with water (30 ml) and extracted with DCM twice. The
organic layer was washed successively with saturated bicarbonate
solution (2 ꢃ 20 ml) and brine solution (20 ml). The organic layer was
dried over anhydrous sodium sulfate and was evaporated under
reduced pressure. The crude product was recrystallized from ethyl
acetate and hexane to afford the desired product.
9.85 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 50.35, 54.11,
113.89, 117.23, 121.38, 122.31, 127.30, 128.08, 128.18, 135.23, 141.41,
144.89, 145.19, 147.20, 148.32, 166.01, 168.48; HR-MS m/z: 458.1320
(Mþ1).
4.9.4. N-[3-Fluoro-4-(4-isonicotinoylpiperazin-1-yl)phenyl]-3-(4-
nitrophenyl)acrylamide (12d)
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]-3-(4-nitrophenyl)acryl-
amide 9d (0.12 g, 0.32 mmol) was dissolved in 10 ml dry DCM fol-
lowed by addition of Et3N (0.14 ml, 0.97 mmol) and stirred at 0 ꢀ
C
under inert atmosphere. Isonicotinoyl chloride (0.07 g, 0.39 mmol)
was directly added portionwise to above stirred solution at 0 ꢀC. The
reaction mixture was worked up as per the general procedure to
afford 0.11 g of 12d. Light brown solid; Yield 73.33%; mp 266e268 ꢀC
(charred); IR (KBr pellets, cmꢁ1): 3445, 3322,1623,1512,1430,1340,
4.9.1. N-[4-(4-Isonicotinoylpiperazin-1-yl)phenyl]cinnamamide
(12a)
N-[4-(Piperazin-1-yl)phenyl]cinnamamide 9a (0.12 g, 0.39 mmol)
was dissolved in 10 ml dry DCM followed by addition of Et3N
(0.16 ml, 1.17 mmol) and stirred at 0 ꢀC under inert atmosphere.
Isonicotinoyl chloride (0.07 g, 0.47 mmol) was directly added por-
tionwise to above stirred solution at 0 ꢀC. The reaction mixture was
worked up as per the general procedure to afford 0.12 g of 12a. Light
yellow solid; Yield 75%; mp 216e218 ꢀC; IR (KBr pellets, cmꢁ1):
3452, 3281, 3049, 2914, 1674, 1617,1522, 1447, 1289, 1165, 1015, 930,
1254,1020, 992, 843; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.12 (4H, t,
J ¼ 4.15 Hz), 3.53 (4H, t, J ¼ 4.16 Hz), 6.61 (1H, d, J ¼ 15.9 Hz, PheCH]
CHe), 6.92 (1H, d, J ¼ 7.3 Hz, AreH), 7.21e7.68 (6H, m, AreH), 7.75
(1H, d, J ¼ 15.9 Hz, PheCH]CHe), 8.22 (2H, d, J ¼ 7.1 Hz, AreH), 8.78
(2H, d, J ¼ 6.8 Hz, AreH), 10.14 (1H, s, CONH); 13C NMR (100 MHz,
CDCl3)
d (ppm): 51.32, 54.67, 112.30, 113.02, 117.15, 121.87, 122.54,
127.19, 128.28, 128.43, 135.78, 141.80, 144.33, 145.65, 147.29, 148.87,
155.90, 165.45, 169.12; HR-MS m/z: 475.2190 (Mþ).
829, 773; 1H NMR (400 MHz, CDCl3)
d (ppm): 3.11 (4H, t,
J ¼ 4.10 Hz), 3.59 (4H, t, J ¼ 4.12 Hz), 6.58 (1H, d, J ¼ 15.2 Hz, Phe
CH]CHe), 6.91 (2H, d, J ¼ 7.4 Hz, AreH), 7.21e7.59 (9H, m, AreH),
7.79 (1H, d, J ¼ 15.2 Hz, PheCH]CHe), 8.74 (2H, d, J ¼ 6.8 Hz, Are
4.10. Antitubercular assay
Resazurin Microtiter Assay (REMA) protocol was used to deter-
mine the minimum inhibitory concentration (MIC) of all the syn-
thesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives
[21]. The synthesized compounds were screened against M. tb.
H37Rv using serial dilution technique in middlebrook 7H9 broth
medium. Each compound (2 mg) was dissolved in 1 ml of DMSO.
The serial dilution of each compounds were prepared using 96-well
H), 10.15 (1H, s, CONH); 13C NMR (100 MHz, CDCl3)
d (ppm): 50.14,
54.39, 113.51, 117.12, 121.50, 121.47, 127.14, 127.34, 128.28, 128.92,
134.28, 141.12, 144.60, 145.39, 149.42, 165.09, 169.11; HR-MS m/z:
413.1490 (M þ 1).
4.9.2. N-[3-Fluoro-4-(4-isonicotinoylpiperazin-1-yl)phenyl]
cinnamamide (12b)
microtitre plate and 100
ml of M. tb. H37Rv cell suspension in
N-[3-Fluoro-4-(piperazin-1-yl)phenyl]cinnamamide 9b (0.12 g,
0.37 mmol) was dissolved in 10 ml dry DCM followed by addition of
Et3N (0.15 ml, 1.11 mmol) and stirred at 0 ꢀC under inert atmo-
sphere. Isonicotinoyl chloride (0.06 g, 0.44 mmol) was directly
added portionwise to above stirred solution at 0 ꢀC. The reaction
mixture was worked up as per the general procedure to afford 0.1 g
nutrient media was added to each well. After 7 days of incubation,
resazurin dye solution (0.02% w/v dissolved in distilled water) was
added to each well and again incubated for 1 day. The MIC was
determined by minimum concentration of compound that inhibits
the growth of M. tb. that is indicated by color change from non-
fluorescent blue to fluorescent pink color. The MIC values were

56
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KNP and VNT thanks University Grant Commission-Special As-
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financial support. The authors also thank Helix Diagnostic Micro-
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Appendix A. Supplementary data
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