Synthesis of perspicamide A and related diverse analogues: Their bioevaluation as potent antileishmanial agents

Article abstract of DOI:10.1021/jo3025626

The first protocol for the synthesis of perspicamide A and related diverse analogues has been developed from economical and readily available starting materials. Furthermore, a few synthesized analogues, 24a, 24b, 24c, 24d, and 24l, exhibited potent activ

Full text of DOI:10.1021/jo3025626

Article
pubs.acs.org/joc
Synthesis of Perspicamide A and Related Diverse Analogues: Their
Bioevaluation as Potent Antileishmanial Agents
Anand Kumar Pandey,† Rashmi Sharma,† Rahul Shivahare,‡ Ashish Arora,§ Neeraj Rastogi,⊥
Suman Gupta,‡ and Prem M. S. Chauhan*,†
†Division of Medicinal and Process Chemistry, ‡Parasitology Division, §Molecular & Structural Biology Division, CSIR-Central Drug
Research Institute, Lucknow 226001, India
⊥Centre of Biomedical Magnetic Resonance (CBMR), Sanjay Gandhi Postgraduate Institute of Medical Sciences Campus, Lucknow
226014, India
S
* Supporting Information
ABSTRACT: The first protocol for the synthesis of perspicamide A and related diverse analogues has been developed from
economical and readily available starting materials. Furthermore, a few synthesized analogues, 24a, 24b, 24c, 24d, and 24l,
exhibited potent activity against Leishmania donovani with IC50 values ranging from 3.75 to 10.37 μM and a selectivity index (SI)
ranging from 9.58 to 53.12, which is improved compared to the standard drug Miltefosine (IC50 12.4 μM and SI 4.1).
sedative and anti-inflammatory peptide frangufoline,14 etc.
Perhaps even more importantly, quinoline-based molecules
INTRODUCTION
■
Throughout the history of medicinal chemistry and pharma-
ceutical drug development, small-molecule natural products
(SMNPs) have played and continue to play an invaluable role
in drug discovery and have inspired ingenuity owing to their
are landmarks for a broad range of biological activities including
antimalarial,15 antibacterial,16 cytotoxic,17 DNA binding prop-
erty,18 anti-inflammatory,19 and antileishmanial,20 etc. To the
best of our knowledge and belief, the synthesis and medicinal
drug like assets.1 Usually it is found that active SMNPs have
relatively poor drug properties,2 and thus some chemical
utility of perspicamide A and related analogues has not been
manipulations are required to address such defficiencies.3 In
reported yet. Our group has also been engaged in the synthesis
of small drug-like molecules using metal-catalyzed coupling
this context, several drugs have emerged, such as topotecan,
protocols,21 condensation reactions,22 and a multicomponent
irinotecan (from camptothecin), taxotere (from taxol), etopo-
side, teniposide (podophyllotoxin derivatives), etc. upon
approach.23 Thus, herein we disclose the first synthesis of
perspicamide A and a wide range of structurally related
analogues and their biological evaluation as potential
antileishmanial agent employing an efficient and flexible route
via Cu-mediated cross-coupling reaction under mild condition.
Retrosynthesis. The idea for the synthetic route to
perspicamide A (1) was developed by taking incremental
steps backward from the final structure (Figure 2), where the
synthons 7, 14, and 25 would be an obvious choice for the
modification of natural leads, and many more are in various
stages of research.4
The quinoline nucleus containing metabolite perspicamide A
(1) and B (2) (Figure 1), first isolated from the Australian
ascidian Botrylloides persipicuum in 2005 by Quinn et al.,5 has
attracted much attention as it is found in many drug-like
compounds.6 The presence of the quinoline and enamide
systems (separately) in a large number of functionalized
preparation of desired molecule. With regard to the
molecules with wide variety of applications including medicinal
chemistry,7 material science,8 and several reaction intermedi-
construction of the desired architecture, benzyl protection,
ates9 is well documented. From a medicinal point of view,
reduction, subsequent aza-Michael reaction, cyclization, benzyl
protection, amidation, and finally copper-mediated cross-
macrolactone bearing an enamide side chain, such as
coupling reaction followed by selective deprotection may lead
salicylihalamide A and B (3 and 4, inhibitors of mamalian
VATPases),10 CJ-12950 (5),11 and lobatamide A (6)12 (Figure
1) are well-known for their potent antitumor activity. Other
Received: November 30, 2012
Published: January 4, 2013
important enamides include protease inhibitor TMC-95-A-D,13
© 2013 American Chemical Society
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Figure 1. Perspicamide A and B (1, 2) and other biologically significant enamides (3−6).
Figure 2. Retrosynthetic analysis of perspicamide A (1).
Scheme 1. Synthesis of Quinoline Carboxamide (13)
to the formation of perspicamide A (1). The counterpart of the
excised fragment, e.g., styryl iodide (16), is easily accessible,
starting from 4-benzyloxy benzaldehyde (14).
Scheme 2. Synthesis of Styryl Iodide (16)
RESULTS AND DISCUSSION
■
The synthetic route for both the fragments is given in Schemes
1 and 2. 2-Nitrophenol (7), used as precursor, was protected
with benzyl bromide in presence of K2CO3 in DMF and
reduced with Fe/acetic acid to give the corresponding 2-
benzyloxy aniline (9) in overall 65% yield. This aniline 9 was
coupled to diethyl acetylenedicarboxylate (DEAD) in MeOH
via aza-Michael reaction to afford 10 in 84% yield.24 This early
stage of the synthesis provides our first diversification point
(Figure 2) and paves the way for the synthesis of perspicamide
A and related analogues.
The intermediate 10 was subsequently cyclized in
diphenylether (Ph2O) at 250 °C to get the desired skeleton,
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a
Table 1. Optimization of the Coupling Reaction of Quinoline 2-Carboxamide (13) and Styryl Iodide (16)
b
entry
catalyst
CuI
L
base
time (h)
yield (%)
c
1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
15
15
15
15
15
15
10
8
nr
c
2
nr
3
CuI
L1
L2
L2
L3
L4
L4
L4
L4
L5
L2
trace
62
4
CuI
c
5
CuI
nr
6
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
trace
74
7
CuI
8
Cu2O
CuTC
Cu(OAc)2
Cu2O
Cu(OTf)2
82
9
9
76
10
11
12
15
15
15
15
c
nr
c
nr
a
Reaction conditions: 13 (0.4 mmol), 16 (0.4 mmol), catalyst (15 mol %), ligand (20 mol %), base (1 mmol), and solvent (5 mL), under nitrogen
b
c
atmosphere at 85 °C. Isolated yield. No product formation.
a
Table 2. Deprotection of Benzylated Analogue to Perspicamide A (1)
b
entry
reagent
equiv
solvent
temp (°C)
time (min)
(%)1
c
1
2
3
4
5
6
7
8
Pd/C
Pd/C
Pd/C
BBr3
BBr3
BCl3
BCl3
BCl3
10
MeOH
MeOH
MeOH
DCM
DCM
DCM
DCM
DCM
rt
15
30
60
30
60
60
60
0
0
c
10
rt
c
10
rt
0
3
6
35
35
35
35
35
d
d
6
32
48
9
12
120
15
a
b
c
d
Reaction condition: substrate 17 (1.0 equiv), reagent, and solvent (5 mL) under argon atmosphere. Isolated yield. Weight percent used. Mixture
of uncharacterised product.
ethyl 4-hydroxyquinoline-2-carboxylate (11) in good yield
(69%),25 which upon a second benzyl protection followed by
amidation with aqueous ammonia in MeOH/THF (1:1) led to
the formation of the desired key intermediate 4,8-bis-
(benzyloxy)quinoline-2-carboxamide (13) in 79% yield. The
other excised fragment 16, e.g., styryl iodide, was prepared from
4-benzyloxy benzaldehyde (14) in two steps: (i) the
Knoevenagel condensation of malonic acid with 4-benzyloxy
benzaldehyde (14) using 10 mol % piperidine as catalyst in
pyridine at reflux conditions,26 and (ii) decarboxylative
iodination with N-iodosuccinamide (NIS) using 20 mol %
Et3N as catalyst in DCM at reflux conditions (inert
atmosphere) in overall 49% yield (Scheme 2).27
With both the key intermediates, 4,8-bis(benzyloxy)-quino-
line-2-carboxamide (13) and 4-benzyloxy styryl iodide (16) in
hand, we were ready to attempt the key coupling reaction with
concomitant construction of benzyl protected perspicamide A
(17). The coupling protocol for the desired molecule was
optimized to obtain the best reaction conditions so that the
efficiency of the protocol could be maintained. Several catalyst
and ligands along with bases were optimized and the results are
summarized in Table 1.
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a
Table 3. Synthesized Perspicamide A Related Analogues
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Table 3. continued
a
Reaction conditions: substrate A (2.47 mmol), substrate B (2.47 mmol), Cu2O (15 mol %), DMEDA (20 mol %), Cs2CO3 (6.17 mmol), and THF
b
(10 mL) under nitrogen atmosphere at 85 °C for 8−10 h. Isolated yield.
The Cu-catalyzed C−N coupling of amides with styryl
halides, the modified Goldberg reaction, is the most widely
applicable reaction for the synthesis of enamides framework of
natural products.28 The first enamide synthesis via metal-
catalyzed coupling was reported by Porco et al. where they used
CuTC as catalyst.29 Later Buchwald et al. used CuI as catalyst
and DMEDA as ligand to achieve the same.30 Further, Ma used
dimethyl glycine as ligand to promote a similar reaction.31
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Scheme 3. Synthesis of Perspicamide A Related Analogues 24a−24u
However, during optimization of catalyst, we found that Cu2O
is more effective and economic compared to CuI, along with
DMEDA as ligand and Cs2CO3 as base (entry 8, Table 1).
Thus, coupling of 4,8-bis(benzyloxy)quinoline-2-carboxamide
(13) with styryl halide (16) under the optimized reaction
conditions (entry 8, Table 1) led to the formation of benzyl-
protected perspicamide A, which upon subsequent depro-
tection led to the formation of perspicamide A in 48% yield
(Table 2). In the overall synthetic maneuver, relative
stereochemistry was found to be in favor of the desired trans-
diastereoisomer.
During the initial efforts of deprotection, the methylated
analogue of perspicamide A (24a, Table 3, entry 1) was
subjected to a deprotection reaction employing several Lewis
acids, such as BBr3, Br2 in acetic acid, etc., and unfortunately
this afforded a mixture of unidentified products (monitored by
TLC). This might be due to the sensitive nature of the enamide
catalyst was carried out, where CuTC was found as efficient
catalyst for the coupling of quinoline carboxamide with styryl
bromide (see Supporting Information Table S1). After
optimization of the catalytic system in the coupling reaction
with different styryl halides as iodide and less reactive bromide,
we were able to synthesize the related analogues of
perspicamide A bearing other funtionalities in excellent yields
(Table 4).
Biological Screening Results. All of the synthesized
compounds were evaluated for their antileishmanial activity
where analogues 24a, 24b, 24c, 24d, and 24l were found to be
potentially active with IC50 values or 4.16, 4.55, 3.75, 10.37,
and 6.98 μM and SI values or 9.58, 53.12, 25.27, 38.57, and
22.91, respectively, which seems more promising than values
for the standard drug Miltefosine (IC50 12.4 μM and SI 4.41)
(Table 5).
CONCLUSION
bond in such a functional system. Therefore, we opted to use a
■
protecting group that could be easily unmasked under mild
conditions. Even though the easily cleavable benzyl group is
used for protection, still the deprotection of O-benzylated
perspicamide was optimized (Table 2), where 9.0 equiv of BCl3
in DCM under argon atmosphere was found to be the best
reaction condition for deprotection.32
In conclusion, we have described the first synthesis of
perspicamide A and related analogues and their potential utility
as antileishmanial agents. A combination of well-optimized,
easy-to-operate methodologies and only a small number of
synthetic transformations increases both the practicability and
efficiency of the synthesis. This strategy would allow an
extremely valuable approach for a variety of substitution
patterns and offers the chance of a future bioactivity-directed
synthesis of defined perspicamide library.
The structure of the synthesized natural product was
1
confirmed by H and 13C NMR (see Supporting Information)
and HRMS and by comparison with literature.5 The synthetic
protocol for perspicamide A related analogues is delineated in
Scheme 3.
EXPERIMENTAL SECTION
■
The synthesis of these analogues was started with substituted
Material and Method for Biological Screening. Antiamasti-
gote Activity. To assess the activity of compounds against the
amastigote stage of the parasite, mouse macrophage cell line (J774A.1)
infected with WHO reference strain (MHOM//IN/80/Dd8) of
promastigotes (expressing luciferase firefly reporter gene) was used.
Cells were seeded in a 96-well plate (4 × 103 cell/100 μL/well) in
RPMI-1640 containing 10% fetal calf serum, and the plates were
incubated at 37 °C in a CO2 incubator. After 24 h, the medium was
replaced with fresh medium containing stationary-phase promastigotes
(4 × 104/100 μL/well). Promastigotes invade the macrophage and are
transformed into amastigotes. The test compounds were added at 2-
fold dilutions up to 7 points in complete medium starting from 40 μM
anilines, the first point of diversification in the designed library.
The second diversity point evolved during the syntheses of
styryl halides where different aromatic aldehydes were used as
precursor. Furthermore, during the hydroxyl protection a third
diversity point arose where different alkyl halides are used for
derivatization. Thus, the designed library holds several merits
with a high level of diversity in synthesized molecules (Table
3).
Unfortunately our catalytic system failed in the case of the
less reactive styryl bromide, and hence further screening of
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a
Table 4. Synthesized Perspicamide A Related Analogues via Styryl Bromide Substrate
a
Reaction conditions: substrate C (1.0 mmol), substrate D (1.1 mmol), CuTC (15 mol %), DMEDA (20 mol %), Cs2CO3 (2.5 mmol), and THF
b
(10 mL) or 1,4-dioxane (5 mL) under nitrogen atmosphere at 100 °C for 12 h, Isolated yield.
concentration after replacing the previous medium, and the plates were
incubated at 37 °C in a CO2 incubator for 72 h. After incubation, the
drug-containing medium was decanted, and 50 μL of PBS was added
in each well and mixed with an equal volume of Steady Glo reagent.
After gentle shaking for 1−2 min, the reading was recorded in a
luminometer.33 The values are expressed as relative luminescence units
(RLU), and the data were transformed into a graphic program (Excel).
The IC50 of antileishmanial activity was calculated by nonlinear
regression analysis of the concentration response curve using the four
parameter Hill equations.
cells/100 μL/well) were incubated with test compounds for 72 h. The
test compounds were added at 3-fold dilutions up to 7 points in
complete medium starting from 400 μM concentration and were
incubated at 37 °C in a humidified mixture of CO2 and 95% air in an
incubator. Podophyllotoxin was used as a reference drug, and control
wells containing dimethyl sulfoxide (DMSO) without compounds
were also included in the experiment. Stock solutions of compounds
were initially dissolved in DMSO and further diluted with fresh
complete medium. After incubation, 25 μL of MTT reagent (5 mg/
mL) in PBS medium, followed by syringe filtration, was added to each
well and incubated at 37 °C for 2 h. At the end of the incubation
period, the supernatant was removed by inverting the plate completely
Cytotoxicity Assay. The cell viability was determined using the
MTT assay.34 Exponentially growing cells (Vero Cell line) (1 × 105
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a
Table 5. In Vitro Antileishmanial Activity of Perspicamide Analogues against Intracellular Amastigotes and Their Cytotoxicity
compd antiamastigote activity IC50 cytotoxicity CC50
selectivity index
compd antiamastigote activity IC50 cytotoxicity CC50
selectivity index
b
b
no.
(μM)
(μM)
(SI)
no.
(μM)
(μM)
(SI)
1
>40
NA
NA
24l
6.98
ND
ND
toxic
toxic
ND
ND
>20
ND
ND
12.4
71.90
159.97
ND
22.91
NA
NA
NA
NA
NA
NA
NA
NA
NA
4.41
5.53
17
>40
NA
NA
24m
24n
24o
24p
24q
24r
24s
24t
24a
24b
24c
24d
24e
24f
24g
24h
24i
24j
24k
4.16
4.55
3.75
10.37
>40
39.86
241.74
94.77
>400
ND
9.58
53.12
25.27
>38.57
NA
ND
ND
ND
ND
ND
>40
ND
NA
ND
14.08
12.39
13.81
>20
ND
NA
ND
ND
NA
24u
MF
SSG
ND
ND
NA
54.75
398.26
ND
NA
20.73
ND
NA
a
MF (Miltefosine) and SSG (Sodium Stibo-gluconate): Standard antileishmanial drugs IC50 >15 μM = inactive; IC50 > 5−15 μM = moderately
b
active; IC50 < 5 μM = active compounds. ND = not done, NA = not available. SI for each compound was calculated as ratio between, CC50 and IC50
against Leishmania amastigotes.
without disturbing the cell layer, and 150 μL of pure DMSO was
added to each well. After 15 min of shaking the readings were recorded
as absorbance at 544 nm on a micro plate reader. The cytotoxic effect
were expressed as 50% lethal dose, i.e., as the concentration of a
compound that provoked a 50% reduction in cell viability compared to
cells in culture medium alone. CC50 values were estimated as described
by Huber and Koella.35
(1.80 mL, 11.23 mmol), and the reaction was allowed to stir for 6 h
at room temperature. After completion of the reaction, the solvent was
evaporated under reduced pressure followed by column chromatog-
raphy using 60−120 mesh silica gel using 2% ethyl acetate/hexane as
eluent to get intermediate 10 as yellow oil. Yield 2.90 g, 84%; IR
1
(cm−1) 3448, 1732, 1618, 1216, 768, 697, 668; H NMR (300 MHz,
CDCl3) δ 9.90 (s, 1H), 7.57 (d, J = 7.0 Hz, 2H), 7.49- 7.39 (m, 3H),
7.09 − 6.95 (m, 4H), 5.53 (s, 1H), 5.22 (s, 2H), 4.34 − 4.21 (m, 4H),
1.42 (t, J = 6.8 Hz, 3H), 1.21 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (50
MHz, CDCl3) δ 169.4, 164.3, 149.8, 148.0, 136.7, 130.2, 128.5, 127.8,
127.0, 124.4, 121.0, 120.7, 113.2, 93.2, 70.6, 61.8, 59.8, 14.4, 13.6 ppm;
HRMS (EI) calcd for [M + H]+ C21H24NO5 370.1576, found
370.1583.
Ethyl 8-(Benzyloxy)-4-oxo-1,4-dihydroquinoline-2-carboxy-
late (11). The above aza-Michael product (10) (2.90 g, 7.85 mmol)
was dissolved in diphenylether (DPE) and refluxed in a preheated oil
bath at 250 °C for 10 min to provide cyclized quinolone ester 11. The
crude reaction mixture was purified by column chromatography using
60−120 mesh silica gel with CHCl3 as eluent to get 11 as a red solid,
mp 118−122 °C. Yield 1.75 g, 69%; IR (cm−1) 3349, 1718, 1559,
1332, 1252; 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 8.1 Hz, 1H),
7.43- 7.36 (m, 4H), 7.26 (t, J = 7.8 Hz, 1H), 7.18 − 7.11 (m, 2H), 7.00
(s, 1H), 5.25 (s, 2H), 4.48 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H)
ppm; 13C NMR (50 MHz, CDCl3) δ 179.7, 162.5, 147.5, 136.1, 135.6,
130.7, 129.0, 128.7, 127.5, 127.0, 124.3, 117.6, 113.1, 111.6, 71.3, 63.4,
14.1 ppm; HRMS (EI) calcd for [M + H]+ C19H18NO4 324.1158,
found 324.1167.
Ethyl 4,8-Bis(benzyloxy)-quinoline-2-carboxylate (12). To a
stirring solution of quinolone 2-ester (11) (1.75 g, 5.41 mmol) in
DMF (5 mL), was added K2CO3 (1.50 g, 10.82 mmol), and the
mixture was allowed to stir for 15 min at room temperature, followed
by the addition of benzyl bromide (0.64 mL, 5.41 mmol). The reaction
mixture was heated at 70 °C for 6 h. After completion (monitored by
TLC), the reaction mixture was poured into water and extracted with
ethyl acetate (5 × 15 mL). The combined organic layers were washed
with saturated brine solution, dried over anhydrous Na2SO4, and
concentrated under reduced pressure to get the titled compound 12 as
a brown solid, mp 113−117 °C. Yield 1.81 g, 81%; IR (cm−1) 1718,
1508, 1258, 1220, 1045, 767, 697; 1H NMR (300 MHz, CDCl3) δ 7.85
(d, J = 8.3 Hz, 1H), 7.69 (s, 1H), 7.59 (d, J = 7.3 Hz, 2H), 7.51 (d, J =
7.1 Hz, 2H),7.44 - 7.29 (m, 7H), 7.12 (d, J = 7.5 Hz, 1H), 5.38 (s,
2H), 5.32 (s, 2H), 4.53 (q, J = 7.1 Hz, 2H), 1.51 (t, J = 7.0 Hz, 3H)
ppm; 13C NMR (75 MHz, CDCl3) δ 166.0, 162.2, 155.2, 148.3, 141.0,
137.0, 135.5, 128.8, 128.5, 127.9, 127.7, 127.2, 123.6, 114.0, 111.5,
101.6, 71.2, 70.7, 62.1, 14.3 ppm; HRMS (EI) calcd for [M + H]+
C26H24NO4 414.1627, found 414.1636.
General Chemistry. NMR spectra were recorded on 300, 400, or
600 MHz spectrometers for 1H NMR and 50, 75, 100, or 150 MHz for
13C NMR in CDCl3 or DMSO-d6 with TMS as internal reference
wherever mentioned. Chemical shifts (δ) are reported in parts per
million (ppm) for 1H and 13C NMR spectra. Coupling constants J are
reported in hertz (Hz). Multiplicities are reported as follows: singlet
(s), doublet (d), triplet (t), quartet (q), and multiplet (m). HRMS
analyses were carried out on an electrospray ionization (ESI)
apparatus using time-of-flight (TOF) mass spectrometry. The reaction
progress was routinely monitored by thin-layer chromatography
(TLC) on precoated silica gel plates. Column chromatography was
performed over silica gel (60−120) and (100−200) mesh. All
1
compounds were characterized by TLC, H and 13C NMR, IR, and
HRMS.
Experimental Procedure for the Synthesis of Fragment 13.
2-(Benzyloxy)nitrobenzene (8). To a stirred solution of 2-nitro
phenol (7) (2.0 g, 14.4 mmol) in DMF (5 mL) was added K2CO3 (4.0
g, 28.8 mmol) at room temperature, and the mixture was allowed to
stir for 15 min followed by the addition of benzyl bromide (1.71 mL,
14.4 mmol). The reaction was allowed to stir at room temperature for
2 h. After completion (monitored by TLC), the reaction mixture was
poured into water and extracted with ethyl acetate (4 × 20 mL). The
combined organic layers were washed with saturated brine solution,
dried over anhydrous Na2SO4, and concentrated under reduced
pressure to get the titled compound 8 as a brown solid. Yield 2.89 g,
88%.36
2-(Benzyloxy)aniline (9). To a solution of 2-benzyloxy nitro-
benzene (8) (2.89 g, 12.60 mmol) in acetic acid (10 mL) was added
iron powder (3.55 g, 63.00 mmol). The reaction mixture was heated at
90 °C for 40 min. After completion of reaction (monitored by TLC),
the reaction mixture was filtered through a Celite pad followed by
neutralization with 10% sodium bicarbonate solution and extracted
with ethyl acetate (3 × 20 mL). The combined organic layer was dried
over Na2SO4 and concentrated under reduced pressure, and the crude
product was purified by column chromatography using 60−120 mesh
silica gel with CHCl3/hexane (1:1) as eluent to get the intermediate 9
as a gummy solid. Yield 1.86 g, 74%.37
Diethyl 2-(2-(Benzyloxy)phenylamino)maleate (10). A sol-
ution of 2-benzyloxy aniline (9) (1.86 g, 9.36 mmol) in anhydrous
methanol was treated with diethylethylenedicarboxylate (DEAD)
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4,8-Bis(benzyloxy)-quinoline-2-carboxamide (13). To a stir-
ring solution of 12 (1.39 g, 10.0 mmol) in MeOH/THF (1:1) (10
mL) was added 10 mL of aq ammonia (30% solution). The reaction
mixture was allowed to stir at room temperature for 12 h (monitored
by TLC). Solvent was removed under reduced pressure and extracted
with ethyl acetate (3 × 20 mL). The combined organic layers were
washed with saturated brine solution and dried over anhydrous
Na2SO4. The crude product was purified by column chromatography
using 60−120 mesh silica gel with 1% MeOH/CHCl3 as eluent to get
13 as a brown solid, mp 167−170 °C. Yield 1.33 g, 79%; IR (cm−1)
11.25 (d, J = 12.8 Hz, 1H), 10.01 (s, 1H), 9.45 (S, 1H), 7.59−7.57 (m,
2H), 7.47−7.42 (m, 2H), 7.27 (d, J = 8.6 Hz, 2H), 7.15 (d, J = 7.6 Hz,
1H), 6.75 (d, J = 8.6 Hz, 2H), 6.54 (d, J = 14.2 Hz, 1H) ppm; 13C
NMR (150 MHz, DMSO-d6) δ 162.8, 161.5, 156.4, 153.5, 147.8,
138.2, 127.6, 127.2, 126.6, 122.1, 120.6, 115.7, 114.1, 111.8, 111.7,
102.0 ppm; HRMS (EI) calcd for [M + H]+ C18H15N2O4 323.1032,
found 323.1036.5
General Procedure for the Preparation of 19a−19e. Different
anilines (18a−18d) (20.0 mmol) were dissolved in 10 mL of
anhydrous methanol followed by dropwise addition of DEAD (24.0
mmol), and the reaction was allowed to run for 4 h at room
temperature. After completion of reaction as indicated by TLC, the
resulting mixture was evaporated under reduced pressure, and the
residue was purified by column chromatography using 60−120 mesh
silica gel (eluent hexane/EtOAc) affording the corresponding aza-
Michael product 19a−19d in 80−85% yield.40a−c
1
3387, 1632, 1553, 1457, 1041, 821; H NMR (300 MHz, CDCl3) δ
8.27 (s, 1H), 7.91- 7.86 (m, 2H), 7.55 − 7.43 (m, 11H), 7.18 (d, J =
6.2 Hz, 1H), 6.00 (s, 1H), 5.36 (s, 4H) ppm; 13C NMR (50 MHz,
CDCl3 + DMSO-d6) δ 171.8, 167.0, 159.2, 154.7, 144.7, 143.8, 141.7,
140.4, 133.4, 133.3, 133.1, 132.6, 132.3, 132.0, 128.0, 118.9, 116.2,
103.9, 75.6, 75.2 ppm; HRMS EI) calcd for [M + H]+ C24H21N2O3
385.1552, found 385.1567.
(E)-3-(4-(Benzyloxy)-phenyl)-acrylic Acid (15). This compound
was obtained by the condensation of 4-(benzyloxy) benzaldehyde (14)
(2.00 g, 9.43 mmol) and malonic acid (1.96 g, 18.86 mmol) with
piperidine (0.19 mL, 1.18 mmol) in pyridine (10 mL) solvent for 3 h
at 120 °C. After completion of reaction (monitored by TLC), the
reaction mixture was poured into a chilled solution of 10% aq
hydrochloric acid. The corresponding cinnamic acid appeared as a
white precipitate. The precipitate was filtered and washed with water
to get 15 as a white solid. Yield 1.07 g, 89%.38
(E)-1-(Benzyloxy)-4-(2-iodovinyl)-benzene (16). To a stirred
solution of (E)-3-(4-(benzyloxy)phenyl) acrylic acid (15) (1.07 g, 4.21
mmol) in DCM (10 mL) was added Et3N (0.13 mL, 0.84 mmol) over
a period of 10 min under argon atmosphere followed by the addition
of N-iodosuccinamide (NIS) (1.14 g, 5.05 mmol), and the reaction
mixture was allowed reaction for 30 min at 45 °C. The reaction was
cooled, and solvent was evaporated at low temperature under reduced
pressure. The crude product was purified by column chromatography
using 60−120 mesh silica gel with 2% EtOAc/hexane as eluent to get
the titled compound 16 as a white solid. Yield 0.78 g, 55%.39
(E)-4,8-Bis(benzyloxy)-N-(4-(benzyloxy)-styryl)-quinoline-2-
carboxamide (17). To a oven-dried double neck round-bottom flask
(rbf) equipped with magnetic stirring bar and 4,8-bis(benzyloxy)-
quinoline-2-carboxamide (13) (1.33 g, 3.46 mmol) in dry THF (10
mL) were added (E)-1-(benzyloxy)-4-(2-iodovinyl)benzene (16)
(1.16 g, 3.46 mmol), Cu2O (0.74 mg, 0.52 mmol), DMEDA (0.074
mL, 0.69 mmol), and Cs2CO3 (2.81 mg, 8.65 mmol) under an argon
atmosphere. Then reaction mixture was degassed and backfilled several
times with argon before being heated to 85 °C and allowed reaction to
reflux for 8 h. The flask was then cooled to room temperature, the
reaction mixture was filtered through a Celite pad, and the solution
was evaporated under reduced pressure followed by column
chromatography using 100−200 mesh silica gel with 15% EtOAc/
hexane as eluent to get the titled compound 17 as a yellow solid, mp
210−213 °C. Yield 1.68 g, 82%; IR (cm−1) 3458, 1643, 1502, 769; 1H
NMR (300 MHz, CDCl3) δ 10.31 (d, J = 11.3 Hz, 1H), 7.90−7.84 (m,
2H), 7.63−7.52 (m, 5H), 7.49−7.31 (m, 14H), 7.20 (d, J = 7.6 Hz,
1H), 6.96 (d, J = 8.4 Hz, 2H), 6.27 (d, J = 14.5 Hz, 1H), 5.38(s, 4H),
5.08 (s, 2H) ppm; 13C NMR (50 MHz, CDCl3) δ 162.7, 161.6, 157.8,
154.5, 149.0, 139.9, 137.0, 135.5, 129.3, 128.8, 128.7, 128.6, 128.5,
128.0, 127.9, 127.7, 127.4, 127.3, 127.1, 126.8, 123.6, 120.8, 115.1,
114.5, 114.1, 111.7, 111.4, 99.3, 71.1, 70.8, 70.0 ppm; HRMS (EI)
calcd for [M + H]+ C39H33N2O4 593.2440, found 593.2448.
Diethyl 2-(2-Bromophenylamino)-maleate (19d). Yellow oil.
Yield 83%; IR (cm−1) 3461, 3278, 1733, 1668, 1616, 1277, 1215, 1148,
1
1035, 760; H NMR (300 MHz, CDCl3) δ 9.71 (s, 1H), 7.57 (d, J =
7.5 Hz, 1H), 7.20 (t, J = 6.9 Hz, 1H), 6.95 (t, J = 7.2 Hz, 1H), 6.81 (d,
J = 7.6 Hz, 1H), 5.54 (s, 1H), 4.25−4.15 (m, 4H), 1.32 (t, J = 7.1 Hz,
3H), 1.13 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ
169.3, 164.1, 147.1, 139.1, 133.2, 127.8, 125.1, 121.6, 116.1, 96.4, 62.3,
60.4, 14.5, 13.8 ppm; HRMS (EI) calcd for [M + H]+ C14H17BrNO4
342.0341, found 342.0349.
General Procedure for the Preparation of 20a−20d. Different
substituted diethyl 2-(phenylamino) maleate (7.50 mmol) was added
to neat polyphosphoric acid (PPA) and allowed reaction to run for 2 h
at 135 °C. The reaction mixture was neutralized with sodium
bicarbonate, and the product was purified by simple washing with cold
water or extracted with CHCl3 from aqueous solution. The organic
layer was dried with Na2SO4 and evaporated under reduced pressure
provided 20a−20d in 75−85% yield.41
Ethyl 8-Bromo-4-oxo-1,4-dihydroquinoline-2-carboxylate
(20d). Brown solid, mp 150−153 °C. Yield 83%; IR (cm−1) 3367,
1719, 1634, 1523, 1272, 768, 600; 1H NMR (300 MHz, CDCl3) δ 9.39
(s, 1H), 8.30 (d, J = 8.1 Hz, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.27−7.22
(m, 1H), 6.99 (s, 1H), 4.54 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz,
3H) ppm; 13C NMR (50 MHz, CDCl3) δ 178.8, 162.2, 136.58, 136.56,
135.8, 127.3, 125.8, 124.7, 112.1, 111.7, 63.4, 14.0 ppm; HRMS (EI)
calcd for [M + H]+ C12H11BrNO3 295.9922, found 295.9924.
General Procedure for the Preparation of 21a−21g. To a
stirred solution of different substituted quinolone 2-ester (20a−20d)
(5.0 mmol) in DMF (5 mL) was added K2CO3 (10.0 mmol) followed
by addition of alkyl halide (methyl or ethyl iodide 10.0 mmol or benzyl
bromide 5.0 mmol), and the reaction allowed to run for 4−6 h. After
completion of reaction, the mixture was poured into water and
extracted with ethyl acetate, and the organic layer was dried with
Na2SO4 and evaporated under reduced pressure to provide a solid
mass of product (21a−21g) in 85−95% yield.42,43
Ethyl 8-Chloro-4-methoxy-quinoline-2-carboxylate (21c).
Brown solid, mp 125−128 °C. Yield 89%; IR (cm−1) 1718, 1626,
1276, 1070, 712, 756; 1H NMR (600 MHz, CDCl3) δ 8.13 (d, J = 8.4
Hz, 1H), 7.84 (d, J = 7.3 Hz, 1H), 7.59 (s, 1H), 7.48 (t, J = 8.1 Hz,
1H), 4.53 (q, J = 7.0 Hz, 2H), 4.11 (s, 3H), 1.50 (t, J = 7.1 Hz, 3H)
ppm; 13C NMR (150 MHz, CDCl3) δ 165.5, 163.6, 149.8, 144.8,
134.3, 130.6, 127.2, 123.5, 120.8, 100.8, 62.5, 56.3, 14.2 ppm; HRMS
(EI) calcd for [M + H]+ C13H13ClNO3 266.0584, found 266.0595.
Ethyl 8-Chloro-4-ethoxy-quinoline-2-carboxylate (21d).
Brown solid, mp 108 °C. Yield 88%; IR (cm−1) 1721, 1622, 1269,
(E)-4,8-Dihydroxy-N-(4-hydroxystyryl)-quinoline-2-carboxa-
mide (1). To a stirred solution of 17 (500 mg, 0.84 mmol) in dry
DCM (5 mL) at 0 °C was added BCl3 (1.0 M solution in methylene
chloride) (0.67 mL, 7.6 mmol) dropwise for 15 min under nitrogen
atmosphere, followed by stirring at room temperature for 1 h. After
completion (monitored by TLC), the reaction was quenched with
methanol (10 mL) followed by evaporation under vacuum on a
rotavapor and column chromatography using 100−200 mesh silica gel
with 2% MeOH/ CHCl3 as eluent to get the titled compound 1 as a
yellow solid, mp >250 °C. Yield 130 mg, 48%; IR (cm−1) 3435, 1641,
1
1068, 759, 686; H NMR (300 MHz, CDCl3) δ 8.19 (d, J = 7.9 Hz,
1H), 7.85 (d, J = 6.7 Hz, 1H), 7.58 (s, 1H), 7.50 (t, J = 7.7 Hz, 1H),
4.54 (q, J = 6.5 Hz, 2H), 4.39 (q, J = 6.5 Hz, 2H), 1.61 (t, J = 6.0 Hz,
3H), 1.50 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (150 MHz, CDCl3) δ
165.8, 163.2, 150.0, 145.0, 134.4, 130.8, 127.3, 123.8, 121.2, 101.6,
65.2, 62.7, 14.5, 14.4 ppm; HRMS (EI) calcd for [M + H]+
C14H15ClNO3 280.0740, found 280.0747.
Ethyl 4-(Benzyloxy)-8-methoxyquinoline-2-carboxylate
(21e). Creamy color solid, mp 157−153 °C. Yield 83%; IR (cm−1)
1714, 1268, 1228, 1068, 754, 698; 1H NMR (300 MHz, DMSO-d6) δ
1
1524, 1216, 766; H NMR (600 MHz, DMSO-d6) δ 11.88 (s, 1H),
1542
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7.74 (d, J = 7.8 Hz, 1H), 7.67 (s, 1H), 7.61−7.56 (m, 3H), 7.47−7.38
(m, 3H), 7.28 (d, J = 7.4 Hz, 1H), 5.46 (s, 2H), 4.45 (q, J = 7.0 Hz,
2H), 3.98 (s, 3H), 1.39 (t, J = 7.0 Hz, 3H) ppm; 13C NMR (50 MHz,
CDCl3) δ 165.7, 161.8, 156.3, 148.1, 140.3, 136.4, 129.1, 128.9, 128.7,
128.2, 123.1, 113.2, 110.1, 102.4, 70.6, 61.9, 56.2, 14.7 ppm; HRMS
(EI) calcd for [M + H]+ C20H20NO4 338.1392, found 338.1398.
Ethyl 4-(Benzyloxy)-8-bromo quinoline-2-carboxylate (21f).
Light brown solid, mp 152−155 °C. Yield 82%; IR (cm−1) 1715, 1629,
7.46−7.37 (m, 4H), 5.90 (s, 1H), 5.37 (s, 2H) ppm; 13C NMR (75
MHz, CDCl3) δ 166.8, 163.1, 151.2, 144.9, 135.3, 134.2, 128.9, 128.8,
127.9, 127.5, 125.1, 123.7, 122.1, 99.5, 71.3 ppm; HRMS (EI) calcd for
[M + H]+ C17H14BrN2O2 357.0239, found 357.0247.
4-Ethoxy-8-methoxyquinoline-2-carboxamide (22g). Brown
solid, mp 167−170 °C. Yield 88%; IR (cm−1) 3472, 1635, 1362, 743;
1H NMR (600 MHz, CDCl3) δ 8.20 (s, 1H), 7.81 (d, J = 8.3 Hz,
1H),7.68 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H),
5.83 (s, 1H), 4.36 (q, J = 6.9 Hz, 2H), 4.04 (s, 3H), 1.57 (t, J = 6.9 Hz,
3H) ppm; 13C NMR (150 MHz, CDCl3) δ 167.5, 162.9, 155.4, 149.8,
139.8, 127.3, 123.6, 114.0, 108.9, 99.2, 64.8, 56.2, 14.6 ppm; HRMS
(EI) calcd for [M + H]+ C13H15N2O3 247.1083, found 247.1087.
General Procedure for Styryl Iodide (16a−16e). Starting
material cinnamic acids are available commercially, although some of
the substrates used were prepared in our laboratory. Different
cinnamic acids (only substrates with electron-donating groups on
the aromatic ring) (4.0 mmol) were dissolved in dichloromethane (6
mL), subsequently Et3N (0.8 mmol) was added followed by addition
of N-iodosuccinamide (NIS) (4.80 mmol), and the reaction was
allowed to run for 15−30 min. After completion of reaction,
evaporated the solvent at low temperature on a rotavapor followed
by column chromatography using 60−120 mesh silica gel provided the
corresponding substituted (E)-styryl iodide (16a−16e) in 50−70%
yield.27
1
1259, 1064, 696; H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 8.0 Hz,
1H), 8.10 (d, J = 6.8 Hz, 1H), 7.72 (s, 1H), 7.51−7.42 (m, 6H), 5.36
(s, 2H), 4.56 (q, J = 6.6 Hz, 2H), 1.53 (t, J = 6.6 Hz, 3H) ppm; 13C
NMR (75 MHz, CDCl3) δ 165.5, 162.6, 150.1, 145.8, 135.1, 134.3,
128.8, 128.7, 127.8, 125.8, 123.6, 121.8, 101.8, 71.1, 62.4, 14.2 ppm;
HRMS (EI) calcd for [M + H]+ C19H17BrNO3 386.0392, found
386.0396.
Ethyl 4-Ethoxy-8-methoxy-quinoline-2-carboxylate (21g).
Brown solid, mp 132−135 °C. Yield 88%; IR (cm−1) 1719, 1633,
1257, 1053, 759, 682; 1H NMR (300 MHz, CDCl3) δ 7.81 (d, J = 8.4
Hz, 1H), 7.59 (s, 1H), 7.52 (t, J = 7.9 Hz 1H), 7.07 (d, J = 7.7 Hz,
1H), 4.54 (q, J = 6.9 Hz, 2H), 4.38 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H),
1.60 (t, J = 6.9 Hz, 3H), 1.52 (t, J = 7.1 Hz, 3H) ppm; 13C NMR (75
MHz, CDCl3) δ 165.6, 162.2, 155.5, 147.9, 140.1, 127.5, 123.1, 113.0,
108.1, 101.0, 64.3, 61.9, 55.6, 14.1, 14.0 ppm; HRMS (EI) calcd for [M
+ H]+ C15H18NO4 276.1236, found 276.1244.
General Procedure for the Preparation of 22a−22g. To a
stirred solution of different substituted quinoline 2-esters (5.0 mmol)
in MeOH/ THF (1:1) (10 mL) was added 30% NH4OH solution (15
mL) followed by stirring for 12 h at room temperature, converting the
ester to amide. Solvent was removed on a rotary evaporator and
extracted with ethyl acetate followed by washing with brine solution.
The combined organic layers dried over Na2SO4 provided substituted
quinoline 2-carboxamide. Purification through crystallization with
ethanol provided quinoline 2-carboxamides in 80−90% yield.44
4,8 Dimethoxy Quinoline-2-carboxamide (22a). Brown solid,
General Procedure for Styryl Bromide (23a−23c). Different
cinnamic acids (4.0 mmol) were dissolved in dichloromethane (6 mL),
subsequently Et3N (0.8 mmol) was added followed by addition of N-
bromosuccinamide (NBS) (4.80 mmol), and the reaction was allowed
to run for 15−30 min. Evaporattion of the solvent at low temperature
on a rotavapor followed by column chromatography using 60−120
mesh silica gel provided the corresponding substituted (E)-styryl
bromide (23a−23c) in 60−85% yield.27
General Procedure for Coupling Product (24a−24p). To a
oven-dried double-neck rbf equipped with magnetic stirring bar and
substituted quinoline-2-carboxamide (22a−22g) (2.47 mmol) in dry
THF (10 mL) were added different (E)-styryl iodides (16a−16e)
(2.47 mmol), Cu2O (0.37 mmol), DMEDA (0.49 mmol), and Cs2CO3
(6.17 mmol) under argon atmosphere. Then reaction mixture was
degassed and backfilled several times with argon before being heated
to 85 °C, and the reaction mixture was allowed to reflux for 8−10 h.
The flask was then cooled to room temperature and filtered through a
Celite pad, and sthe olution was evaporated under reduced pressure
followed by column chromatography using 100−200 mess silica gel
with 20% ethyl acetate/hexane as eluent to get the titled compounds
24a−24p as a yellow solids. Yield 75−91%.
1
mp 162−165 °C. Yield 90%; IR (cm−1) 3439, 1642, 1391, 767; H
NMR (CDCl3, 400 MHz): 8.25 (s, 1H), 7.80 (d, J = 8.4, 1H), 7.72 (s,
1H), 7.50 (t, J = 8, 1H), 7.09 (d, J = 7.7, 1H), 5.78(s, 1H), 4.11(s,
3H), 4.05(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 167.6, 163.9,
155.6, 150.0, 139.9, 127.6, 123.7, 114.0, 109.1, 98.9, 56.5, 56.37 ppm;
HRMS (EI) calcd for [M + H]+ C12H12N2O3 233.0848, found
233.0857.
8-Chloro-4-methoxyquinoline-2-carboxamide (22c). Brown
solid, mp 225−230 °C. Yield 89%; IR (cm−1) 3444, 1638, 1399, 770;
1H NMR (300 MHz, CDCl3) δ 8.23 (s, 1H), 8.18 (d, J = 8.4 Hz, 1H),
7.86 (d, J = 7.5 Hz, 1H), 7.75 (s, 1H), 7.50 (t, J = 8.3 Hz, 1H), 5.77 (s,
1H), 4.14 (s, 3H) ppm; 13C NMR (150 MHz, CDCl3 + DMSO-d6) δ
171.4, 168.7, 156.1, 148.6, 138.2, 135.2, 131.5, 128.2, 125.8, 103.2, 61.2
ppm; HRMS (EI) calcd for [M + H]+ C11H10ClN2O2 237.0431, found
237.0442.
(E)-4,8-Dimethoxy-N-(4-methoxy-styryl)-quinoline-2-car-
boxamide (24a). Yellow solid, mp 175−178 °C. Yield 88%; IR
1
(cm−1) 3471, 2366, 1653, 1504, 1074, 752; HNMR (CDCl3, 400
MHz): 10.11 (d, J = 11.0 Hz, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.76 (s,
1H), 7.63 (dd, J1 = 11.2 Hz, J2 = 14.5 Hz, 1H), 7.52 (t, J = 7.9 Hz,
1H),7.36 (d, J = 8.5, 2H), 7.12 (d, J = 7.7, 1H), 6.88 (d, J = 8.6, 2H),
6.46 (d, J = 14.6, 1H), 4.13 (s, 3H), 4.10 (s,3H), 3.81 (s, 3H) ppm;
13C NMR (CDCl3, 100 MHz): δ 164.4, 162.2, 158.9, 155.6, 149.6,
139.7, 129.4, 127.7, 127.2, 123.7, 121.1, 114.7, 114.5, 114.1, 109.2,
99.0, 56.6, 56.3, 55.6 ppm; HRMS (EI) calcd for [M + H]+
C21H21N2O4 365.1501, found 365.1501.
8-Chloro-4-ethoxyquinoline-2-carboxamide (22d). Dark
brown solid, mp 209−212 °C. Yield 88%; IR (cm−1) 3456, 1613,
1
1388, 774; H NMR (600 MHz, CDCl3) δ 8.23 (s, 1H), 8.17 (d, J =
8.3 Hz, 1H), 7.83 (d, J = 7.3 Hz, 1H), 7.70 (s, 1H), 7.46 (t, J = 8.0 Hz,
1H), 5.87 (s, 1H), 4.38 (q, J = 6.8 Hz, 2H), 1.58 (t, J = 6.9 Hz, 3H)
ppm; 13C NMR (150 MHz, CDCl3) δ 167.0, 163.4, 151.1, 144.1,
133.7, 130.6, 126.8, 123.8, 121.3, 99.1, 65.2, 14.6 ppm; HRMS (EI)
calcd for [M + H]+ C12H12ClN2O2 251.0587 found 251.0594.
4-(Benzyloxy)-8-methoxyquinoline-2-carboxamide (22e).
Light brown solid, mp 192−195 °C. Yield 82%; IR (cm−1) 3468,
1615, 1364, 748; 1H NMR (600 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.76
(s, 1H), 7.75−7.73 (m, 2H), 7.57−7.54 (m, 3H), 7.45 (t, J = 7.5 Hz,
2H), 7.39 (t, J = 7.3 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 5.46 (s, 2H),
3.99 (s, 3H) ppm; 13C NMR (150 MHz, DMSO-d6) δ 166.3, 161.6,
154.95, 150.1, 138.8, 135.8, 128.5, 128.1, 127.7, 127.5, 122.4, 112.9,
109.5, 99.4, 69.9, 55.7 ppm; HRMS (EI) calcd for [M + H]+
C18H17N2O3 309.1239, found 309.1243.
(E)-N-(4-(Benzyloxy)-styryl)-4,8-dimethoxy-quinoline-2-car-
boxamide (24b). Yellow solid, mp 157−159 °C. Yield 78%; IR
1
(cm−1) 3456, 1649, 1566, 1207, 784; HNMR (CDCl3, 300 MHz):
10.15 (d, J = 10.5 Hz, 1H), 7.84−7.79 (m, 2H), 7.67−7.36 (m, 9H),
7.15 (d, J = 7.1 Hz, 1H), 6.98 (d, J = 7.9 Hz, 2H), 6.48 (d, J = 14.4 Hz,
1H), 5.10 (s, 2H), 4.16 (s, 3H), 4.13 (s, 3H) ppm; 13C NMR (CDCl3,
100 MHz): δ 163.6, 161.8, 157.8, 155.2, 149.2, 139.4, 137.0, 129.3,
128.6, 127.9, 127.4, 126.8, 123.4, 120.8, 115.1, 114.4, 113.8, 108.9,
98.6, 70.0, 56.2, 56.0 ppm; HRMS (EI) calcd for [M + H]+
C27H25N2O4 441.1814, found 441.1811.
(E)-4,8-Dimethoxy-N-(2,5-dimethoxystyryl)-quinoline-2-car-
boxamide (24c). Yellow solid, mp 128−131 °C. Yield 84%; IR
(cm−1) 3408, 1667, 1547, 1222, 789; 1H NMR (CDCl3, 300 MHz): δ
10.20 (d, J = 11.1 Hz, 1H), 7.84−7.75 (m, 3H), 7.55 (t, J = 7.9 Hz,
4-(Benzyloxy)-8-bromo-quinoline-2-carboxamide (22f).
Creamy white solid, mp 185−188 °C. Yield 80%; IR (cm−1) 3464,
1
1628, 1365, 771; H NMR (300 MHz, CDCl3) δ 8.27 (d, J = 8.1 Hz,
2H), 8.07 (d, J = 7.3 Hz, 1H), 7.83 (s, 1H), 7.52 (d, J = 6.8 Hz, 2H),
1543
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1H), 7.15 (d, J = 7.7 Hz, 1H), 7.08 (d, J = 2.8 Hz, 1H), 6.86−6.72 (m,
3H), 4.16 (s, 3H), 4.14 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H) ppm; 13C
NMR (CDCl3, 75 MHz): δ 163.6, 161.9, 155.3, 153.8, 150.9, 149.2,
139.4, 127.4, 126.2, 123.4, 123.2, 113.7, 112.9, 112.3, 111.3, 109.7,
108.9, 98.6, 56.3, 56.2, 56.0, 55.8 ppm; HRMS (EI) calcd for [M + H]+
C22H23N2O5 395.1607, Found 395.1611.
11.1, 1H), 8.20 (d, J = 8.1, 1H), 7.89 (d, J = 7.4, 1H), 7.77 (s, 1H),
7.68 (dd, J1 = 11.4, J2 = 14.4, 1H), 7.52 (t, J = 7.9, 1H), 6.65 (s, 2H),
6.43 (d, J = 14.5, 1H), 4.18 (s, 3H), 3.91 (s,6H), 3.86 (s, 3H) ppm;
13C NMR (CDCl3, 75 MHz): δ 163.2, 160.3, 152.4, 149.3, 142.6,
136.3, 132.5, 130.8, 129.6, 125.9, 122.5, 120.6, 120.1, 114.0, 101.8,
97.5, 59.9, 55.5, 55.1 ppm; HRMS (EI) calcd for [M + H]+
C22H22ClN2O5 429.1217, found 429.1207.
(E)-4,8-Dimethoxy-N-(3,4,5-trimethoxystyryl)-quinoline-2-
carboxamide (24d). Yellow solid, mp 198−200 °C. Yield 88%, IR
(E)-8-Chloro-4-ethoxy-N-(4-(methylthio)-styryl)-quinoline-2-
1
(cm−1) 3344, 1676, 1469, 1234, 760; H NMR (CDCl3, 300 MHz):
carboxamide (24k). Yellow solid, mp 125−128 °C. Yield 86%; IR
1
(cm−1) 3426, 2367, 1652, 1587, 1435, 1023, 667; H NMR (CDCl3,
10.19 (d, J = 11.1 Hz, 1H), 7.85−7.78 (m, 2H), 7.71 (dd, J1 = 11.5 Hz,
J2 = 14.4 Hz, 1H), 7.56 (t, J = 8.0 Hz, 1H), 7.16 (d, J = 7.7 Hz, 1H),
6.66 (s, 2H), 6.46 (d, J = 14.5 Hz, 1H), 4.17 (s, 3H), 4.13 (s, 3H), 3.92
(s, 6H), 3.87 (s, 3H) ppm; 13C NMR (CDCl3, 75 MHz): δ 163.6,
162.0, 155.1, 153.3, 149.0, 132.1, 127.4, 123.4, 121.9, 114.7, 113.7,
108.8, 102.8, 98.5, 60.8, 56.1, 56.0 ppm; HRMS (EI) calcd for [M +
H]+ C23H25N2O6 425.1713, found 425.1722.
(E)-4-Methoxy-N-(4-methoxystyryl)-quinoline-2-carboxa-
mide (24e). Yellow solid, mp 124−127 °C. Yield 81%; IR (cm−1)
3447, 2357, 1663, 1544, 742; 1HNMR (CDCl3, 300 MHz): 10.08 (d, J
= 11.0 Hz, 1H), 8.25 (d, J = 8.1 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H),
7.78−7.72 (m, 2H), 7.64 (m, 2H), 7.37 (d, J = 8.5 Hz, 2H), 6.89 (d, J
= 8.6 Hz, 2H), 6.45 (d, J = 14.6 Hz, 1H), 4.14 (s, 3H), 3.82 (s, 3H)
ppm; 13C NMR (CDCl3, 75 MHz) δ 162.7, 160.6, 157.5, 149.2, 146.3,
129.4, 128.0, 127.8, 126.0, 125.8, 121.1, 121.0, 119.5, 113.2, 113.1,
96.8, 56.2, 54.2 ppm; HRMS (EI) calcd for [M + H]+ C20H19N2O3
335.1396, found 335.1407.
400 MHz): 10.19 (d, J = 11.2 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.88
(d, J = 7.3 Hz, 1H), 7.73 (s, 1H), 7.71 (dd, J1 = 11.5 Hz, J2 = 14.4 Hz,
1H), 7.50 (t, J = 7.9 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.23 (d, J = 8.1
Hz, 2H), 6.43 (d, J = 14.6 Hz, 1H), 4.43 (q, J = 6.8 Hz, 2H), 2.49 (s,
3H), 1.62 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ
163.8, 161.8, 150.7, 144.1, 137.0, 133.8, 133.6, 130.9, 127.4, 127.1,
126.4, 124.0, 122.1, 121.6, 114.6, 99.4, 65.5, 16.3, 14.7 ppm; HRMS
(EI) calcd for [M + H]+ C21H20ClN2O2S 399.0856, found 399.0859.
(E)-4-(Benzyloxy)-N-(4-(benzyloxy)-styryl)-8-methoxyquino-
line-2-carboxamide (24l). Yellow solid, mp 179−182 °C. Yield 75%,
IR (cm−1) 3422, 2306, 1639, 1541, 767; 1H NMR (CDCl3, 300 MHz)
10.14 (d, J = 11.1 Hz, 1H), 7.89 (s, 2H), 7.55−7.14 (m, 14H), 7.16 (d,
J=7.3 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.49 (d, J = 14.5 Hz, 1H),
5.41 (s, 2H), 5.10 (s, 2H), 4.14 (s, 3H) ppm; 13C NMR (CDCl3, 75
MHz): δ 162.7, 161.8, 157.8, 155.3, 149.2, 139.5, 137.0, 135.5, 129.3,
128.7, 128.6, 128.5, 127.9, 127.7, 127.4, 126.8, 123.5, 120.8, 115.2,
114.3, 114.0, 109.0, 99.6, 70.8, 70.1, 56.0 ppm; HRMS (EI) calcd for
[M + H]+ C33H29N2O4 517.2127, Found 517.2129.
(E)-N-(2,5-Dimethoxystyryl)-4-methoxyquinoline-2-carboxa-
mide (24f). Yellow solid, mp 144−147 °C. Yield 86%; IR (cm−1)
1
3449, 1663, 1563, 736; HNMR (CDCl3, 300 MHz): 10.17 (d, J =
(E)-4-(Benzyloxy)-8-methoxy-N-(4-methoxystyryl)-quino-
line-2-carboxamide (24m). Yellow solid, mp 155−158 °C. Yield
78%; Rf = 0.70 (30% EtOAc: Hexane); IR (cm−1) 3444, 2317, 1639,
1543, 759; 1H NMR (CDCl3, 400 MHz) δ 10.21 (d, J = 10.9 Hz, 1H),
7.87−7.85 (m, 2H), 7.63−7.33 (m, 9H), 7.12 (d, J = 7.6 Hz, 1H),
6.88−6.86 (d, 2H), 6.47 (d, J = 14.6 Hz, 1H), 5.37 (s, 2H), 4.10 (s,
3H), 3.81 (s, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 163.0, 162.1,
158.9, 155.5, 149.6, 139.9, 135.8, 129.4, 129.1, 128.8, 128.0, 127.7,
127.2, 123.8, 121.1, 114.7, 114.5, 114.3, 109.3, 100.0, 71.1, 56.3, 55.6
ppm; HRMS (EI) calcd for [M + H]+ C27H25N2O4 441.1814, Found
441.1811.
11.2 Hz, 1H), 8.52 (d, J = 8.1 Hz, 1H), 8.09 (d, J = 8.3 Hz, 1H), 7.82−
7.72 (m, 3H), 7.60 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 2.7 Hz, 1H), 6.84
(m, 3H), 4.14 (s, 3H), 3.85 (s, 3H), 3.81 (s, 3H) ppm; 13C NMR
(CDCl3, 75 MHz): δ 162.7, 160.7, 152.7, 149.8, 149.2, 146.4, 129.4,
128.1, 126.1, 124.9, 122.1, 121.2, 121.0, 111.9, 111.1, 110.2, 108.5,
96.8, 55.2, 54.8 ppm; HRMS (EI) calcd for [M + H]+ C21H21N2O4
365.1501, found 365.1490.
(E)-4-Methoxy-N-(4-(methylthio)-styryl)-quinoline-2-carbox-
amide (24g). Yellow solid, mp 139−142 °C. Yield 91%; IR (cm−1)
3474, 2196, 1661, 1542, 782; 1H NMR (CDCl3, 400 MHz) δ 10.05 (d,
J = 10.8 Hz, 1H), 8.17 (d, J = 8.1 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H),
7.98−7.65 (m, 3H), 7.60 (t, J = 14.9 Hz, 1H), 7.35 (d, J = 8.0 Hz, 2H),
7.23 (d, J = 8.0 Hz, 2H), 6.35 (d, J = 14.6 Hz, 1H), 4.06 (s, 3H), 2.41
(s, 3H) ppm; 13C NMR (CDCl3, 100 MHz) δ 164.1, 162.1, 150.5,
147.8, 137.0, 133.7, 130.8, 129.4, 127.4, 126.4, 122.6, 122.4, 122.3,
114.3, 98.2, 56.6, 16.4 ppm; HRMS (EI) calcd for [M + H]+
C20H19N2O2S 351.1167, found 351.1176.
(E)-4-(Benzyloxy)-8-bromo-N-(4-methoxystyryl)-quinoline-
2-carboxamide (24n). Yellow solid, mp 148−151 °C. Yield 76%; IR
1
(cm−1) 3429, 2298, 1634, 1504, 769; H NMR (CDCl3, 300 MHz):
10.17 (d, J = 11.1 Hz, 1H), 8.27 (d, J = 8.2 Hz, 1H), 8.11 (d, J = 7.3
Hz, 1H), 7.87 (s, 1H), 7.65−7.37 (m, 9H), 6.91 (d, J = 8.4 Hz, 2H),
6.46 (d, J = 14.5 Hz, 1H), 5.41 (s, 2H), 3.84 (s, 3H) ppm; 13C NMR
(CDCl3, 75 MHz): δ 163.1, 161.1, 158.7, 150.5, 144.5, 135.1, 134.2,
128.8, 128.6, 127.7, 127.4, 126.9, 124.8, 123.5, 122.0, 120.4, 114.6,
114.2, 99.4, 71.2, 55.3 ppm; HRMS (EI) calcd for [M + H]+
C26H22BrN2O3 489.0814, Found 489.0819.
(E)-8-Chloro-4-methoxy-N-(4-methoxystyryl)-quinoline-2-
carboxamide (24h). Yellow solid, mp 178−181 °C. Yield 82%; IR
1
(cm−1) 3434, 2372, 1656, 1477, 1219, 772; HNMR (CDCl3, 300
MHz): 10.15 (d, J = 11.4 Hz, 1H), 8.18 (d, J = 8.3 Hz, 1H), 7.88 (d, J
= 7.3 Hz, 1H), 7.77 (s, 1H), 7.64 (dd, J1 = 11.4 Hz, J2 = 14.5 Hz, 1H),
7.51 (t, J = 7.7 Hz, 1H), 7.38 (d, J = 8.5 Hz, 2H), 6.90 (d, J = 8.6 Hz,
2H), 6.45 (d, J = 14.6 Hz, 1H), 4.16 (s, 3H), 3.82 (s, 3H) ppm; 13C
NMR (CDCl3, 75 MHz): δ 164.2, 161.3, 158.7, 150.6, 133.5, 130.6,
128.8, 126.9, 126.8, 123.6, 121.1, 120.5, 114.7, 114.2, 98.6, 56.5, 55.3
ppm; HRMS (EI) calcd for [M + H]+ C20H18ClN2O3 369.1006, found
369.1012.
(E)-4-Ethoxy-8-methoxy-N-(4-(methylthio)-styryl)-quinoline-
2-carboxamide (24o). Yellow solid, mp 147−150 °C. Yield 88%; IR
1
(cm−1) 3458, 1685, 1647, 1349, 1069, 746; HNMR (CDCl3, 400
MHz): 10.25 (d, J = 11.1 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.71−7.65
(m, 2H), 7.51 (t, J = 7.9 Hz, 1H), 7.33−7.31 (m, 2H), 7.21−7.19 (m,
2H), 7.11 (d, J = 7.7 Hz, 1H), 6.45 (d, J = 14.6 Hz, 1H), 4.39 (q, J =
6.9 Hz, 2H), 4.09 (s, 3H), 2.48 (s, 3H), 1.60 (t, J = 6.9 Hz, 3H) ppm;
13C NMR (CDCl3, 100 MHz): δ 163.3, 162.4, 155.5, 149.5, 139.8,
136.8, 133.9, 127.6, 127.4, 126.4, 123.8, 122.4, 114.4, 114.3, 109.2,
99.5, 65.1, 56.3, 16.4, 14.7 ppm; HRMS (EI) calcd for [M + H]+
C22H23N2O3S 395.1429, found 395.1439.
(E)-8-Chloro-N-(2,5-dimethoxystyryl)-4-methoxyquinoline-
2-carboxamide (24i). Yellow solid, mp 221−224 °C. Yield 84%; IR
1
(cm−1) 3441, 2344, 1638, 1543, 742; HNMR (CDCl3, 300 MHz):
10.23 (d, J = 11.6 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.0
Hz, 1H), 7.82 (t, J = 12.4 Hz, 2H), 7.52 (t, J = 7.9 Hz, 1H), 7.07 (d, J
= 2.8 Hz, 1H), 6.85- 6.69 (m, 3H), 4.16 (s, 3H), 3.87 (s, 3H), 3.82 (s,
3H) ppm; 13C NMR (CDCl3, 75 MHz): δ164.1, 161.4, 153.7, 150.8,
150.4, 143.7, 139.2, 133.6, 130.6, 126.9, 125.8, 123.5, 123.0, 121.1,
114.0, 113.0, 112.1, 111.3, 110.0, 98.6, 56.5, 56.2, 55.8 ppm; HRMS
(EI) calcd for [M + H]+ C21H20ClN2O4 399.1112, found 399.1114.
(E)-8-Chloro-4-methoxy-N-(3,4,5-trimethoxystyryl)-
quinoline-2-carboxamide (24j). Yellow solid, mp 234−236 °C.
(E)-4-Ethoxy-8-methoxy-N-(4-methoxystyryl)-quinoline-2-
carboxamide (24p). Yellow solid, mp 107−110 °C. Yield 84%; IR
1
(cm−1) 3445, 2337, 1669, 1513, 738; HNMR (CDCl3, 400 MHz):
10.27 (d, J = 11.0 Hz, 1H), 7.83 (d, J = 8.4 Hz, 1H), 7.71 (s, 1H), 7.62
(dd, J1 = 11.2 Hz, J2 = 14.5 Hz, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.35−
7.33 (m, 2H), 7.11 (d, J = 7.7 Hz, 1H), 6.87 (m, 2H), 6.47 (d, J = 14.6
Hz, 1H), 4.39 (q, J = 6.9 Hz, 2H), 4.09 (s, 3H), 3.80 (s, 3H), 1.59 (t, J
= 6.9 Hz, 3H) ppm; 13C NMR (CDCl3, 100 MHz): δ 163.2, 162.3,
158.9, 155.5, 149.7, 139.8, 129.5, 127.5, 127.1, 123.8, 121.2, 114.7,
1
Yield 84%; mp 236 °C; HNMR (CDCl3, 300 MHz): 10.21 (d, J =
1544
dx.doi.org/10.1021/jo3025626 | J. Org. Chem. 2013, 78, 1534−1546

The Journal of Organic Chemistry
Article
114.5, 114.3, 109.2, 99.6, 65.1, 56.3, 55.6, 14.8 ppm; HRMS (EI) calcd
for [M + H]+ C22H23N2O4 379.1580, found 379.1592.
ASSOCIATED CONTENT
■
S
* Supporting Information
General Procedure for the Preparation of 24q−24u. To an
oven-dried double neck rbf equipped with magnetic stirring bar and
substituted quinoline-2-carboxamide (2.47 mmol) in 1,4-dioxane (5
mL) or dry THF (10 mL) were added different (E)-styryl bromides
(2.47 mmol), CuTC (0.37 mmol), DMEDA (0.49 mmol), and
Cs2CO3 (6.17 mmol) under argon atmosphere. Then reaction mixture
was degassed and backfilled several times with argon before being
heated to 100 °C, and the reaction mixture was allowed to reflux for
8−12 h. After consumption of starting material as indicated by thin
layer chromatography (TLC), the flask was then cooled to room
temperature and filtered through a Celite pad, and the solution was
evaporated under reduced pressure followed by column chromatog-
raphy using 100−200 mess silica gel with 20% ethyl acetate/exane as
eluent to afford the corresponding enamide products 24q−24u in 72−
77% yield.
(E)-4-Methoxy-N-styrylquinoline-2-carboxamide (24q). Yel-
low solid, mp 128−131 °C. Yield 72%; IR (cm−1) 3617, 1655, 1224,
761; 1H NMR (CDCl3, 600 MHz): δ 10.13 (d, J = 10.9 Hz, 1H), 8.24
(d, J = 8.2 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.77−7.70 (m, 3H), 7.59
(t, J = 7.5 Hz, 1H), 7.43 (d, J = 7.4 Hz, 2H), 7.34 (t, J = 7.3 Hz, 2H),
7.22 (t, J = 7.2 Hz, 1H), 6.47 (d, J = 14.5 Hz, 1H), 4.14 (s, 3H) ppm;
13C NMR (CDCl3, 150 MHz): δ 164.0, 162.0, 150.4, 147.6, 136.4,
1H and 13C NMR data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: prem_chauhan_2000@yahoo.com; premsc58@
hotmail.com.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.K.P. and R.S. are thankful to CSIR, NewDelhi for SRFs. We
thank SAIF division, CSIR-CDRI for the analytical facilities. We
also thank to Dr. Raja Roy for his valuable support in this
project. CDRI communication number is 8378.
REFERENCES
■
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130.7, 129.3, 128.8, 127.3, 126.9, 125.8, 122.5, 122.4, 122.2, 114.6,
98.1, 56.4 ppm; HRMS (EI) calcd for [M + H]+ C19H17N2O2
305.1290, found 305.1296.
(E)-N-(4-tert-Butylstyryl)-4-methoxyquinoline-2-carboxa-
mide (24r). Yellow solid, mp 142−145 °C. Yield 77%; IR (cm−1)
3628, 1649, 1222, 763; δ 1H NMR (CDCl3), 600 MHz): 10.10 (d, J =
11.2 Hz, 1H), 8.23 (d, J = 7.9 Hz, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.76
(t, J = 8.1 Hz, 1H), 7.72−7.67 (m, 2H), 7.58 (t, J = 7.2 Hz, 1H), 7.37
(q, J = 8.5 Hz, 4H), 6.45 (d, J = 14.6 Hz, 1H), 4.13 (s, 3H), 1.32 (s,
9H) ppm; 13C NMR (CDCl3, 150 MHz): δ 163.9, 161.9, 150.4, 150.0,
147.6, 133.6, 130.6, 129.2, 127.2, 125.8, 125.6, 122.4, 122.2, 121.8,
114.5, 98.0, 56.4, 34.7, 31.4 ppm; HRMS (EI) calcd for [M + H]+
C23H25N2O2 361.1838, found 361.1842.
(E)-8-Chloro-N-(4-isopropylstyryl)-4-methoxyquinoline-2-
carboxamide (24s). Yellow solid, mp 152−155 °C. Yield 74%; IR
1
(cm−1) 3622, 1661, 1212, 767; H NMR (CDCl3, 400 MHz): 10.16
(d, J = 11.1 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.3 Hz,
1H), 7.76 (s, 1H), 7.71 (dd, J1 = 11.5 Hz, J2 = 14.3 Hz, 1H), 7.50 (t, J
= 7.9 Hz, 1H), 7.38(m, 2H), 7.21 (m, 2H), 6.47 (d, J = 14.6 Hz, 1H),
4.16 (s, 3H), 2.94 (m, 1H), 1.27 (d, J = 6.8 Hz, 6H) ppm; 13C NMR
(CDCl3, 100 MHz): δ 164.5, 161.7, 150.8, 148.0, 144.1, 134.0, 133.9,
131.0, 127.2, 127.1, 126.1, 123.9, 121.7, 121.4, 115.2, 98.9, 56.9, 34.1,
24.2 ppm; HRMS (EI) calcd for [M + H]+ C22H22ClN2O2 381.1370,
found 381.1388.
(9) Larock, R. C. Comprehensive Organic Transformations: A Guide to
Functional Group Preparations; Wiley-VCH: New York, 1999.
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J. 2001, 7, 5286.
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(11) Dekker, K. A.; Aiello, R. J.; Hirai, H.; Inagaki, T.; Sakakibara, T.;
Suzuki, Y.; Thompson, J. F.; Yamauchi, Y.; Kojima, N. J. Antibiot.
1998, 51, 14.
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Boyd, M. R. J. Org. Chem. 1997, 62, 8968.
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Shimizu, R.; Ohnuki, T.; Komatsubara, S. J. Org. Chem. 2000, 65, 990.
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1993, 16, 289.
(E)-N-(4-tert-Butylstyryl)-8-chloro-4-ethoxyquinoline-2-car-
boxamide (24t). Yellow solid, mp 188−191 °C. Yield 76%; IR
1
(cm−1) 3616, 1654, 1216, 761; H NMR (CDCl3, 600 MHz): 10.17
(d, J = 11.3 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.87 (d, J = 7.4 Hz,
1H), 7.73 (s, 1H), 7.71 (dd, J1 = 11.5 Hz, J2 = 14.5 Hz, 1H), 7.48 (t, J
= 7.9 Hz, 1H), 7.39 (q, J = 8.4 Hz, 4H), 6.46 (d, J = 14.5 Hz, 1H), 4.41
(q, J = 6.9 Hz, 2H), 1.61 (t, J = 7.1 Hz, 3H), 1.33 (s, 9H) ppm; 13C
NMR (CDCl3, 150 MHz): δ 163.6, 161.6, 150.6, 150.1, 143.9, 133.6,
133.5, 130.7, 126.9, 125.8, 125.6, 123.8, 121.7, 121.4, 114.9, 99.2, 65.3,
34.7, 31.4, 14.6 ppm; HRMS (EI) calcd for [M + H]+ C24H26ClN2O2
409.1683, found 409.1680.
(15) Sharma, M.; Chauhan, K.; Chauhan, S. S.; Kumar, A.; Singh, S.
S.; Saxena, J. K.; Agarwal, P.; Srivastava, K.; Kumar, S. R.; Puri, S. K.;
Shah, P.; Siddiqi, M. I.; Chauhan, P. M. S. Med. Chem. Commun. 2012,
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Thomas, K. D. Eur. J. Med. Chem. 2010, 45, 3374.
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Wu, C. H.; Chang, C. Y.; Lai, W. Y.; Liou, J. P. J. Med. Chem. 2011, 54,
8517.
(E)-8-Chloro-4-ethoxy-N-styryl quinoline-2-carboxamide
(24u). Yellow solid, mp 152−155 °C. Yield 73%; IR (cm−1) 3618,
1655, 1216, 764; 1H NMR (CDCl3, 600 MHz): 10.17 (d, J = 11.1 Hz,
1H), 8.18 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 7.3 Hz, 1H), 7.73−7.69 (m,
2H), 7.48 (t, J = 7.7 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.34 (t, J = 7.5
Hz, 2H), 7.22 (t, J = 7.2 Hz, 1H), 6.46 (d, J = 14.5 Hz, 1H), 4.40 (q, J
= 6.9 Hz, 2H), 1.60 (t, J = 6.9 Hz, 3H) ppm; 13C NMR (CDCl3, 150
MHz): δ 163.6, 161.6, 150.5, 143.9, 136.4, 133.6, 131.6, 130.7, 128.8,
128.1, 126.96, 126.94, 125.9, 123.8, 122.3, 121.4, 121.2, 115.0, 104.4,
99.2, 65.3, 14.6 ppm; HRMS (EI) calcd for [M + H]+ C20H18ClN2O2
353.1057, found 353.1051.
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