Synthesis of multisubstituted quinolines from Baylis-Hillman adducts obtained from substituted 2-chloronicotinaldehydes and their antimicrobial activity

Article abstract of DOI:10.1016/j.bmc.2006.02.020

Baylis-Hillman acetates were synthesized from substituted 2-chloronicotinaldehydes and were conveniently transformed into multisubstituted quinolines and cyclopenta[g]quinolines on reaction with nitroethane or ethyl cyanoacetate via a successive S_N

Full text of DOI:10.1016/j.bmc.2006.02.020

Bioorganic & Medicinal Chemistry 14 (2006) 4600–4609
Synthesis of multisubstituted quinolines from
Baylis–Hillman adducts obtained from substituted
2-chloronicotinaldehydes and their antimicrobial activity
P. Narender,a U. Srinivas,a M. Ravinder,a B. Ananda Rao,a Ch. Ramesh,a
K. Harakishore,b B. Gangadasu,a U. S. N. Murthyb,* and V. Jayathirtha Raoa,*
aOrganic Chemistry Division-II, Indian Institute of Chemical Technology , Uppal Road, Tarnaka, Hyderabad 500007, India
bDivision of Biology, Indian Institute of Chemical Technology , Uppal Road, Tarnaka, Hyderabad 500007, India
Received 2 January 2006; revised 8 February 2006; accepted 9 February 2006
Available online 28 February 2006
Abstract—Baylis–Hillman acetates were synthesized from substituted 2-chloronicotinaldehydes and were conveniently transformed
into multisubstituted quinolines and cyclopenta[g]quinolines on reaction with nitroethane or ethyl cyanoacetate via a successive
SN20–SNAr elimination strategy. Thus, synthesized quinolines were evaluated for antimicrobial activity and found having substan-
tial antibacterial and antifungal activity.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
physiological and biological properties.8 Quinoline deriv-
atives have been developed for the treatment of many dis-
eases like malaria,9 HIV,10 tumor,11 and antibacterial
infections.12 Substituted quinolines have also been
reported to act as antagonists for endothelin,13 5HT3,14
NK-3,15 and leucotriene16,17 receptors. They also func-
tion as inhibitors of gastric (H+/K+)-ATPase,18 dihydro-
orotate dehydrogenase,19 and 5-lipoxygenase.20 In
addition to the medicinal importance, multisubstituted
quinolines are valuable synthons used for the preparation
of nano- and mesostructures with enhanced electronic
and photonic properties.21 Many methods for the synthe-
sis of quinoline derivatives are reported in the literature,22
but due to their interesting and important biological
properties, the development of new, simple, convenient,
and environmentally benign synthetic approaches using
mild conditions remains an active research area.23
The steadily increasing bacterial resistance to existing
drugs is a serious problem in antibacterial therapy and
necessitates continuing research into new classes of anti-
bacterials.1 Of particular concern are severe infections
caused by multidrug-resistant Gram-positive pathogens,
which cause high mortality rates especially in the hospi-
tal setting. The individual organisms responsible include
methicillin-resistant Staphylococcus aureus (MRSA),2,3
vancomycin-resistant Enterococcus faecalis (VRE),4,5
and penicillin-resistant Streptococcus pneumoniae.6,7
A
more controlled usage of these drugs may be a way to
partially counterbalance this challenge. In view of the
above, the design and synthesis of newer antimicrobials
is an area of immense significance and continues to at-
tract the attention of increasing number of medicinal
chemists.
The Baylis–Hillman (BH) reaction, a carbon–carbon
bond forming reaction between a carbonyl compound
and an activated olefin, is atom-economic and the
resulting products (BH adducts) are densely function-
alized molecules. These BH adducts have applications
in many organic stereoselective transformation meth-
odologies.24 Variety of natural, unnatural compounds,
several biologically important natural products have
been synthesized using BH adducts as precursors.25
Some publications have reported the formation of
Quinolines and their derivatives occur in numerous
natural products, many of which possess interesting
Keywords: Substituted 2-chloronicotinaldehydes; Baylis–Hillman
adducts; SN20–SNAr elimination reaction; Multisubstituted quinolines;
Antimicrobial evaluation.
*
Corresponding authors. Tel.: +91 40 27160123; fax: +91 40
27160757; e-mail: jrao@iict.res.in
IICT Communication No. 060203.
0968-0896/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.02.020

P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
4601
quinolines26 and dihydroquinolines27 from the BH ad-
ducts originating from aromatic aldehydes. Even
though many methodologies appeared on the applica-
tions of BH adducts in the literature, there are very
few reports for the applications of BH adducts derived
from the heterocyclic compounds. In continuation of
our work on bio-evaluation of heterocycles,28 we wish
to report herein the synthesis of new title quinolines
from the reaction of Baylis–Hillman acetates obtained
from substituted 2-chloronicotinaldehydes29 and
nitroethane or cyanoacetates in high yield and under
moderate conditions in order to study their antimicro-
bial activities.
a 2-chloro-3-pyridinyl moiety, it should undergo
aromatic nucleophilic substitution reaction (SNAr) fol-
lowed by aromatization, which would lead to the forma-
tion of substituted quinolines. The BH adducts obtained
from the reaction between substituted 2-chloronicotinal-
dehydes (1a–1f) and acyclic alkenes (2a–2h)31/cyclic
enones (2i–2l)32 were efficiently acetylated33 by treat-
ment with either AcCl/pyridine or Ac2O/Et3N, cat.
DMAP to give the corresponding BH acetates 3a–3h
(Scheme 1) in 80–92% yield and 3i–3l (Scheme 2) in
90–98% yield, respectively.
The reaction between Baylis–Hillman acetates (3a–3l)
and nitroethane was carried out via the successive
SN20–SNAr elimination strategy. Reaction of the Bay-
lis–Hillman acetates (3a–3h) in N,N-dimethylformam-
ide, in the presence of potassium carbonate and
nitroethane at 50–70 °C, afforded the desired substituted
8-methyl quinolines (4a–4h) in 80–92% yield in a short
time (3–4 h). Under the same reaction conditions the
acetates (3i–3l), obtained from the BH adducts with
2. Chemistry
BH acetates, resulting from BH adducts, have been used
to make c-lactams, c-keto-esters, and naphthalenes.30
We anticipated that, by analogy to the above work, if
the aromatic moiety of the Baylis–Hillman acetate were
OH
OAc
COOR
CHO
R2
R1
COOR
Ac2O/Et3N
R2
R1
COOR
R2
R1
DABCO
+
neat
10-15 min.
cat. DMAP
DCM, 0-5oC
N
Cl
N
3a-3h
82-95%
Cl
N
Cl
20-30 min.
2a-2h
~100%
1a-1f
1a: R1 = H, R2 = Me
1b: R1 = H, R2 = Ph
1c: R1 = H, R2 = p-OMe-Ph
1d: R1 = Ph, R2 = CH3
1e: R1 = COOMe, R2 = H
1f: R1 = Ph, R2 = COOEt
2a & 3a : R1 = H, R2 = Me, R = Me
2e & 3e: R1 = H, R2 = CH3, R = Et
2f & 3f: R1 = H, R2 = Ph, R = Et
2g & 3g: R1 = Ph, R2 = CH3, R = Et
2h & 3h: R1 = COOMe, R2 = H, R = Et
2b & 3b : R1 = H, R2 = p-OMe-Ph, R = Me
2c & 3c : R1 = COOMe, R2 = H, R = Me
2d & 3d : R1 = Ph, R2 =COOEt, R =Me
Scheme 1.
O
OH
Cl
OAc O
O
CHO
+
R2
R1
R2
R1
R2
R1
Ac2O/Et3N
imidazole
aq. MeOH
20-30 min.
cat. DMAP
N
Cl
DCM, 0-5oC
N
N
Cl
15-25 min.
3i-3l
2i-2l
1a,1b,1d,1e
90-98%
85-96%
2i & 3i : R1 = H, R2 = CH3
2j & 3j : R1 = H, R2 = Ph
2k & 3k: R1 = Ph, R2 = CH3
2l & 3l : R1 = COOMe, R2 = H
Scheme 2.
OAc
Cl
ROOC
COOR
R
R
CH CH NO
2
2
R
ROOC
R
R
3
2
2
2
K CO
2
3
CNCH COOEt
2
o
K CO
3
N
DMF, 50-60 C
3-4 h
2
1
R
N
N
1
1
o
DMF, 110-125
8-12 h
C
CN
5a-5c
80-92%
50-60%
CH
3
3a-3h
4a-4h
3a & 4a : R = H, R = CH , R = Me
1
2
3
3e & 4e : R = H, R = CH , R = Et
1 2 3
5a : R = H, R = CH , R = Me
1 2 3
3b & 4b: R = H, R = p-OMe-Ph,R = Me
1
2
3f & 4f : R = H, R = Ph, R = Et
1 2
5b: R = H, R = Ph, R = Et
1 2
3c & 4c : R = COOMe, R = H, R = Me
1
2
3g & 4g: R = Ph, R = CH , R = Et
1 2 3
5c: R = Ph, R = CH , R = Et
1 2 3
3d & 4d: R = Ph, R = COOEt, R = Me
1
2
3h &4h: R = COOMe, R = H, R = Et
1 2
Scheme 3.

4602
P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
Similarly, substituted 8-cyano quinolines were formed
O
OAc
Cl
O
via successive SN20–SNAr elimination–decarboxylation
and autooxidation reactions, respectively. In this case,
decarboxylation takes place at higher temperatures
and requires longer reaction times. To assign the stereo-
chemistry of the trisubstituted alkenes formed in this
reaction, one of the ester-containing trisubstituted
alkenes 7a was isolated (Scheme 5) with exclusive (E)-
stereoselectivity (ꢀ100%).35 The assignment of stereo-
chemistry of trisubstituted alkenes (e.g., 7a) was based
on spectroscopic evidence.36
CH3CH2NO2
K2CO3
R2
R1
R2
R1
DMF, 60-75oC
2h-3h
N
N
CH3
3i-3l
85-94%
6a-6d
3i & 6a: R1 = H, R2 = CH3
3j & 6b: R1 = H, R2 = Ph
3k & 6c: R1 = Ph, R2 = CH3
3l & 6d: R1 = COOMe, R = H
Scheme 4.
3. Antimicrobial activity
2-cyclopenten-1-ones (2i–2l), gave substituted 9-methyl
cyclopenta[g]quinoline-6-ones (6a–6d) in 85–94% yield
(Scheme 4). The same reaction was conducted at room
temperature for a longer time to obtain appreciable
amounts of 8-methyl quinolines along with (E)-3-(2-
chloropyridyl)-2-(2-nitropropyl)-2-propenoate (7a, tri-
substituted alkene, Scheme 5). Similarly, substituted
8-cyano quinolines (5a–5c) were obtained from the reac-
tion of BH acetates (3a–3h) and ethylcyano acetate in
50–60% yield (Scheme 3). In the case of ethyl cyanoace-
tate reaction at relatively higher temperatures (110–
125 °C) and longer times (ꢀ10 h), it is required to get
the substituted 8-cyano quinolines. Synthesized,
multisubstituted quinolines are arranged in Table 1
along with reaction conditions. As shown in Table 1,
the reaction proceeded irrespective of the electron-with-
drawing substituents on the pyridine moiety.
All the three series of newly synthesized novel quinolines
4a–4h, 5a–5c, and 6a–6d were tested for their in vitro
antibacterial activity against three representative
Gram-positive organisms, viz., Bacillus subtilis (MTCC
441), Bacillus sphaericus (MTCC 11), and S. aureus
(MTCC 96), and three Gram-negative organisms, viz.,
Chromobacterium violaceum (MTCC 2656), Klebsiella
aerogenes (MTCC 39), and Pseudomonas aeruginosa
(MTCC 741) by broth dilution method recommended
by National Committee for Clinical Laboratory
(NCCL) standards.39 Penicillin and streptomycin were
used as standard drugs whose minimum inhibitory con-
centration (MIC) values are provided in Table 2.
The quinolines 4a–4h, 5a–5c, and 6a–6d exerted a wide
range of broad spectrum of antibacterial activity, howev-
er, with a degree of variation. Compounds 4a–4h with a
methyl group at C-8 position are displaying notable in vi-
tro antibacterial activity against all the tested bacterial
organisms (MIC in the range of 6.25–25 lg/mL). In this
series of compounds, 4a and 4e with alkyl substituent at
C-3 position and carboalkoxy substituent at C-6 position
are showing substantial activity against Gram-negative
bacteria, P. aeruginosa and C. violaceum. Moderate
activity is observed against Gram-positive bacteria and
substantial activity against Gram-negative bacteria in
the case of compounds 4b and 4f where the phenyl group
at C-3 replaces the methyl group. By the introduction of
an electron-withdrawing group like methyl and ethyl es-
ters at C-2 and C-3 positions in compounds 4c, 4d, and
The mechanism of the reaction is depicted in Scheme 5.
Conjugate addition of carbananion of nitroalkane (tan-
dem nucleophilic addition–elimination reaction, SN20)34
in the presence of potassium carbonate in DMF to the
BH acetate 3a gives trisubstituted alkene 7a (methyl-
(E)-3-(2-chloropyridyl)-2-(2-nitropropyl)-2-propenoate)
with high stereoselectivity (step 1; Scheme 5). Intra-mo-
lecular aromatic nucleophilic substitution reaction
(SNAr) of trisubstituted alkene 7a gave the 7,8-dihydro
quinoline 8a (Scheme 5; step 2). Finally, 8-methyl-
substituted quinolines were formed via elimination of
nitrous acid (aromatization process), and the nitrous
acid was neutralized in situ by potassium carbonate.
OAc
Me
COOMe
CH CH NO /K CO
COOMe
Me
3
2
2
2
3
DMF, temperature
time
N
N
Cl
Me
3a
4a
SN2'
10-15 min
rt
-HNO2
H
Me
COOMe
Me
COOMe
NO2
SNAr
50-75 oC
3-4 h
N
O2N
N
Cl
CH3
7a
8a
CH3
trisubstituted alkene (E): ~100%
Scheme 5.

P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
Table 1. Conversion of Baylis–Hillman acetates into multisubstituted Quinolines
4603
Serial No.
Baylis–Hillman acetate
Conditions
Quinoline
Mp (°C)
Yield (%)
OAc
MeOOC
Me
Me
MeOOC
MeOOC
MeOOC
MeOOC
1
CH3CH2NO2 50 °C, 2 h
88
85
82
92
83
85
86
87
94
54
45
62
88
93
94
85
4a
N
N
N
N
3a
Me
Me
Me
Cl
N
OAc
MeOOC
MeOOC
P-OMe-Ph
p-OMe-Ph
2
3
CH3CH2NO2 70 °C, 3 h
CH3CH2NO2 50 °C, 2 h
CH3CH2NO2 50 °C, 2 h
CH3CH2NO2 50 °C, 2 h
CH3CH2NO2 50 °C, 3 h
CH3CH2NO2 75 °C, 3 h
CH3CH2NO2 80 °C, 3 h
NCCH2COOEt 125 °C, 8 h
NCCH2COOEt 125 °C, 12 h
NCCH2COOEt 110 °C, 10 h
CH3CH2NO2 80 °C, 5 h
CH3CH2NO2 80 °C, 5 h
CH3CH2NO2 80 °C, 5 h
CH3CH2NO2 80 °C, 5 h
102
112
79
4b
3b
Cl
N
OAc
4c
COOMe
COOEt
3c
COOMe
COOEt
Cl
N
OAc
MeOOC
EtOOC
EtOOC
EtOOC
EtOOC
4
4d
Ph
Me
3d
Cl
N
Me
Me
Me
Me
Me
Ph
OAc
Me
EtOOC
EtOOC
EtOOC
EtOOC
5
83
4e
4f
N
3e
3f
Cl
N
Ph
OAc
Ph
6
98
N
N
N
Cl
N
OAc
Me
Ph
Me
Ph
4g
7
98
3g
3h
Cl
N
OAc
4h
8
112
126
134
121
123
132
124
112
COOMe
Cl
N
COOMe
Me
OAc
MeOOC
EtOOC
Me
MeOOC
MeOOC
EtOOC
9
5a
3a
N
Cl
N
CN
CN
Ph
OAc
Ph
10
11
12
13
14
15
5b
3b
N
N
Cl
OAc
N
Me
EtOOC
Me
3g
Ph
5c
Ph
Cl
OAc
N
CN
O
O
O
O
O
Me
Me
6a
3i
3j
N
Cl
OAc
N
Me
O
Ph
Ph
6b
N
Cl
OAc
N
N
Me
O
Me
Ph
Me
Ph
6c
3k
3l
N
Cl
Cl
Me
Me
O
OAc
6d
COOMe
N
N
COOMe
Isolated yields; uncorrected mp.
4h, a slightly decreased activity is observed in both tested
Gram-positive and Gram-negative strains. On replace-
ment of the methyl group to cyano at C-8 (5a–5c), in-
creased antibacterial activity against all the tested
bacterial organisms is observed (MIC in the range of
6.25–12.5 lg/mL). In this series of compounds, 5b and
5c are displaying substantial activity against all the tested
strains. Compound 5a with methyl group at C-3 showing

4604
P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
Table 2. Antibacterial activity of substituted quinolines 4a–4h, 5a–5c, and 6a–6d
Quinoline compounds
Microorganisms (MIC)
Gram positive
Gram negative
Bacillus
subtilis
Bacillus
Staphylococcus
aureus
Pseudomonas
aeruginosa
Klebsiella
aerogenes
Chromobacterium
violaceum
sphaericus
4a
4b
25
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
12.5
25
12.5
25
6.25
12.5
25
12.5
12.5
12.5
25
6.25
12.5
12.5
12.5
6.25
6.25
6.25
12.5
12.5
6.25
12.5
12.5
12.5
12.5
25
6.25
12.5
25
4c
4d
25
12.5
25
25
4e
12.5
25
6.25
6.25
6.25
12.5
6.25
12.5
6.25
12.5
25
12.5
12.5
12.5
25
4f
4g
12.5
25
12.5
25
4h
5a
25
12.5
6.25
12.5
25
6.25
6.25
6.25
12.5
12.5
12.5
25
12.5
12.5
12.5
25
5b
5c
6a
6b
25
25
12.5
12.5
12.5
6.25
1.562
6c
6d
12.5
12.5
1.565
6.25
12.5
25
6.25
25
Penicillin
Streptomycin
3.125
12.5
1.565
6.25
12.5
3.125
12.5
3.125
Negative control (acetone), no activity.
Values are indicated in lg/mL.
Table 3. Antifungal activity of substituted quinolines 4a–4h, 5a–5c, and 6a–6d
Compound
Aspergillus niger
100 lg
Chrysosporium tropicum
30 lg 100 lg
Rhizopus oryzae
30 lg
30 lg
100 lg
4a
4b
8
9
8
9
8
9
9
8
9
8
9
9
8
9
7
7
9
11
9
7
9
7
9
9
8
8
8
8
8
8
9
6
11
12
9
6
8
7
7
9
9
9
8
8
7
7
8
9
8
6
8
11
8
4c
4d
8
8
9
9
4e
9
9
9
4f
4g
11
8
12
11
9
11
11
9
4h
5a
9
9
11
11
9
11
11
11
9
5b
5c
9
11
11
9
6a
6b
9
11
9
9
6c
6d
8
11
9
8
26
9
29
Clotrimazole
23
Negative control (DMSO). No activity.
Well or cup method; zone of inhibition is indicated in mm.
somewhat decreased activity is observed compared to 5b
and 5c. Compounds 6a–6d with cyclopentanone group
are showing the moderate antibacterial activity (MIC
in the range of 12.5–25 lg/mL). Overall, compound 5a
is showing the substantial antibacterial activity against
S. aureus, P. aeruginosa, and C. violaceum. Compounds
4a and 4e are showing notable antibacterial activity
and the remaining compounds exhibit moderate antibac-
terial activity.
(MTCC 262), Fusarium moniliforme (MTCC 1848), and
Curvularia lunata (MTCC 2030) by agar cup diffusion
method.40,41 and the strains were obtained from the
Institute of Microbial Technology, Chandigarh. Clo-
trimazole was used as a standard drug whose minimum
zone of inhibition values are presented in Table 3.
The investigation of antifungal screening data revealed
that all the tested compounds 4a–4h, 5a–5c, and 6a–6d
showed moderate to good antifungal activities against
the tested fungal strains. The compounds 4b, 4f, and
4g with the phenyl group displayed good antifungal
activity. Compound 4f was the most active compound
with a zone of inhibition value in the range of
The in vitro antifungal activity of the newly synthesized
quinolines 4a–4h, 5a–5c, and 6a–6d was studied against
the fungal strains, viz., Aspergillus niger (MTCC 282),
Chrysosporium tropicum (MTCC 2821), Rhizopus oryzae

P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
4605
11–12 mm at the concentration of 100 lg/mL. Modest
activity is shown by compounds 4c and 4h with methyl
ester at C-2 position. The effect of cyano group at C-8
position (5a–5c) did not increase the antifungal activity
but these are showing moderate activity. Compounds 6a
and 6b are exhibiting substantial activity against A. niger
and C. tropicum, moderately active against R. oryzae.
Rest of the compounds (6c and 6d) in this series having
a cyclopentanone group are showing moderate activity
against all the tested fungal strains. C. tropicum is inhib-
ited by most of our newly synthesized multisubstituted
quinolines. All the new compounds did not show any
activity against C. lunata and F. moniliforme fungal
strains.
5.1.2. Typical experimental procedure for the prepara-
tion of substituted quinolines from the Baylis–Hillman
acetates. To a stirred solution of pre-heated potassium
carbonate (3 mmol) in N,N-dimethylformamide (3 mL)
was added nitroethane (3 mmol) at room temperature
and stirred for about 10 min. A solution of Baylis–
Hillman acetate (1 mmol) in 2 mL of N,N-dimethyl-
formamide was stirred at room temperature for about
10–15 min to obtain (E)-trisubstituted alkene (pyridi-
nyl-4-cyano (or) nitro alkanoates). Further stirring of
the reaction mixture was done for about ꢀ3–4 h at
50–70 °C to obtain methyl-substituted quinoline and
for about ꢀ10–12 h at 110–120 °C to obtain cyano-
substituted quinoline. After completion of the reaction
(as judged by TLC), the reaction mixture was poured
into dilute hydrochloric acid solution and extracted
with chloroform thrice. The combined organic layer
was washed with brine solution thrice and concentrat-
ed to afford a residue. The residue was purified by
column chromatography using 10% ethyl acetate in
hexane as the eluent solvent to isolate 50–60% of
cyano-substituted quinoline and 75–92% of methyl-
substituted quinoline.
4. Conclusions
We have disclosed a facile and simple synthetic method
for multisubstituted quinolines and cyclopenta[g]quino-
line-6-ones from the Baylis–Hillman adducts via succes-
sive SN20–SNAr elimination reaction in excellent yields
under mild conditions in quicker timings. For the first
time, we introduced the Baylis–Hillman application
reactions to the heterocyclic compounds successfully.
The synthesis of multisubstituted quinolines is very effi-
cient and simple, especially the synthesis of 8-cyano-
substituted quinolines and cyclopenta[g]quinolines is
very easy compared to other methods for their synthesis.
The synthesized quinolines were evaluated for antibacte-
rial and antifungal activity and obtained good to moder-
ate values.
5.1.3. Typical experimental procedure for the prepara-
tion of methyl (E)-3-(2-chloro-5-methyl-3-pyridyl)-2-(2-
nitropropyl)-2-propenoate (7a). A solution of Baylis–
Hillman acetate (1 mmol) in 2 mL DMF was added
to the pre-stirred solution of potassium carbonate
(1.5 mmol) and nitroethane (3 mmol) in DMF solution
and stirred at room temperature for about 15 min.
After completion of the reaction (as evidenced by
TLC), the reaction mixture was poured into dilute
hydrochloric acid solution and extracted with ethyl
acetate twice. The organic layer was washed with brine
solution and concentrated to afford a residue. The res-
idue was purified by column chromatography using
5% ethyl acetate in hexane as eluent solvent. The tri-
substituted alkene (7a) was obtained as ꢀ100% of E-
isomer.
5. Experimental
5.1. General methods
The chemicals, nitroethane, ethyl cyanoacetate, triethyl
amine, acetic anhydride, DMAP, and all the solvents
were obtained commercially. All the melting points were
determined on a Mel-Temp apparatus and are uncor-
rected. IR were recorded with a Perkin-Elmer Model
5.2. Characterization data
1
1600 series FTIR spectrometer. All H NMR and 13C
5.2.1. Methyl 2-[(2-chloro-5-methylpyridine-3-yl)(hydroxy)-
methyl]acrylate (2a). Yield: 99.5%; white solid; mp: 98 °C;
1H NMR (200 MHz, CDCl3): dH 8.11 (s, 1H), 7.71 (s,
1H), 6.32 (s, 1H), 5.8 (s, 1H), 5.56 (s, 1H), 3.8 (s, 3H),
2.35 (s, 3H); 13C NMR (50 MHz, CDCl3): d 166.1,
148.2, 146.5, 140.2, 137.8, 134.8, 132.4, 126.7, 67.9, 51.7,
17.3; MS (EI), m/z: 241 [M+], 206, 156, 120, 92, 65; IR
(KBr): 3350, 2953, 1727, 1433, 1053, 972, 753 cmꢁ1; Anal.
Calcd for C11H12ClNO3: C, 54.68; H, 4.99; N, 5.80.
Found: C, 54.86; H, 5.10; N, 5.98.
NMR spectra were recorded on a Gemini 200 MHz
and 300 MHz. EIMS was detected on VG Micromass
7070 H (70 eV).
5.1.1. Typical experimental procedure for acetylation of
the Baylis–Hillman adducts. To a solution of the Baylis–
Hillman adduct (allylic alcohol derivative) (1 mmol) in
dry dichloromethane (CH2Cl2; 30 mL) was added trieth-
yl amine (Et3N) (1.2 mmol) followed by catalytic
amount of 4-(N,N-dimethylamino)pyridine (DMAP).
This solution was stirred at 0 °C and was added a solu-
tion of acetic anhydride (Ac2O) (1 mmol in 5 mL of
CH2Cl2) dropwise and stirred at 0–5 °C for about 20–
25 min. After completion of the reaction (as evidenced
by TLC), the solvent and triethyl amine were removed
under reduced pressure to afford the residue. Purifica-
tion of the residue by column chromatography on silica
gel and 20% ethyl acetate in hexane as eluent solvent fur-
nished 80–98% of acetyl derivative.
5.2.2. Methyl 2-{[2-chloro-5-(4-methoxyphenyl)-pyridine-
3-yl](hydroxy)methyl}acrylate (2b). Yield: 98%; light yel-
1
low solid; mp: 102 °C; H NMR (200 MHz, CDCl3): d
8.49 (s, 1H), 8.1 (s, 1H), 7.5 (m, 2H), 6.98 (m, 2H),
6.38 (s, 1H), 5.9 (s, 1H), 5.65 (s, 1H), 3.85 (s, 3H), 3.8
(s, 3H); 13C NMR (50 MHz, CDCl3): d 166.6, 160.0,
147.6, 146.2, 139.9, 135.7, 135.2, 135.0, 128.1, 127.5,
114.8, 114.6, 69.0, 60.3, 55.3, 52.1, 24.6; MS (EI), m/z:
333 [M+] (33), 298(33), 274(15), 248(22), 212(18),

4606
P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
99(33), 43(100); IR (KBr): 3295, 2927, 2835, 1727, 1664,
1434, 1258, 1152, 766; Anal. Calcd for C17H16ClNO4: C,
61.18; H, 4.83; N, 4.20. Found: C, 61.45; H, 4.99; N,
4.67.
1710, 1575, 1436, 1396, 1299, 1077, 634 cmꢁ1; Anal.
Calcd for C18H18ClNO3: C, 65.16; H, 5.47; Cl,
10.69; N, 4.22; O, 14.46. Found: C, 65.45; H, 4.56;
N, 4.44.
5.2.3. Methyl 6-chloro-5[1-hydroxy-2-(methoxycarbon-
yl)prop-2-en-1-yl]pyridine-2-carboxylate (2c). Yield:
99%; viscous oil; H NMR (200 MHz, CDCl3): d 8.12
5.2.8. Methyl 3,8-dimethyl-6-quinolinecarboxylate (4a)31.
Light yellow solid; yield: 82%; mp: 88 °C; 1H NMR
(200 MHz, CDCl3): d 8.81 (s, 1H), 8.30 (s, 1H),
8.02 (s, 1H), 7.93 (s, 1H), 3.98 (s, 3H), 2.81 (s,
3H), 2.54 (s, 3H); 13C NMR (50 MHz, CDCl3): d
166.9, 153.3, 147.5, 137.4, 136.1, 131.0, 128.4, 127.8,
127.6, 127.2, 52.2, 18.55, 18.0; MS (EI), m/z: 215
[M+] (100), 184(68), 156(54), 141(10), 128(10); IR
(KBr): 2922, 1715, 1619, 1446, 1270, 1226, 1106,
768 cmꢁ1; Anal. Calcd for C13H13NO2: C, 72.54;
H, 6.09; N, 6.51. Found: C, 72.63; H, 6. 36; N,
6.27.
1
(m, 2H), 6.32 (s, 1H), 5.82 (s, 1H), 5.52 (s, 1H), 3.98 (s,
3H), 3.78 (s, 3H); 13C NMR (50 MHz, CDCl3): d 166.4,
164.3, 149.6, 147.0, 139.4, 138.3, 127.8, 124.0, 69.1,
53.0, 52.2; MS (EI), m/z: 285 [M+] (2), 249(100),
217(70), 197(50), 164(20), 140(22), 115(18), 83(45),
59(60); IR (KBr): 3272, 2999, 1721, 14333, 1265,
1155, 1045, 764 cmꢁ1; Anal. Calcd for C12H12ClNO5:
C, 50.45; H, 4.23; N, 4.41. Found: C, 50.89; H, 4.44; N,
4.67.
5.2.4. Ethyl 6-chloro-5-(1-hydroxy-2-(methoxycarbon-
yl)allyl)-2-phenyl-nicotinate (2d). Yield: 98%; white solid;
mp: 85 °C; H NMR (200 MHz, CDCl3): d 8.8 (s, 1H),
5.2.9. Methyl 3-(4-methoxyphenyl)-8-methyl-6-quinoline-
carboxylate (4b). Light yellow solid; yield: 78%; mp:
102 °C; H NMR (200 MHz, CDCl3): d 9.18 (s, 1H),
1
1
7.62 (m, 2H), 7.4 (m, 3H), 6.41 (s, 1H), 5.98 (s, 1H),
5.78 (s, 1H), 4.2 (q, 2H), 3.68 (s, 3H), 1.25 (t, 3H); 13C
NMR (50 MHz, CDCl3): d 166.3, 165.6, 156.4, 149.4,
140.6, 139.6, 137.9, 133.1, 129.3, 129.0, 128.4, 128.3,
127.6, 67.9, 62.2, 52.1, 29.6, 13.5; MS (EI), m/z: 375
[M+] (15), 346(30), 330(33), 308(100), 262(23), 216(18);
Anal. Calcd for C19H18ClNO5: C, 60.73; H, 4.83; N,
3.72. Found: C, 60.89; H, 4.99; N, 3.87.
8.40 (s, 1H), 8.24 (s, 1H), 8.07 (s, 1H), 7.6 (m, 2H), 7.0
(m, 2H), 3.97 (s, 3H), 3.85 (s, 3H), 2.82 (s, 3H); 13C
NMR (50 MHz, CDCl3): d 166.7, 160.1, 150.3, 147.2,
137.1, 134.3, 134.0, 129.3, 129.0, 128.9, 128.4, 128.3,
128,2, 114.9, 55.4, 52.3, 18.0; MS (EI), m/z: 307 [M+]
(100), 292(15), 276(18), 248(10), 205(10); IR (KBr):
2958, 1720, 1445, 1252, 1029, 783 cmꢁ1; Anal. Calcd
for C19H17NO3: C, 74.25; H, 5.57; N, 4.56. Found: C,
74.53; H, 5.68; N, 4.78.
5.2.5. Ethyl 2-[(2-chloro-5-methylpyridine-3-yl)(hydroxy)-
methyl]acrylate (2e). Yield: 99.5%; white solid; mp: 78 °C;
1H NMR (200 MHz, CDCl3): d 8.06 (s, 1H), 7.66 (s, 1H),
6.28 (s, 1H), 5.76 (s, 1H), 5.55 (s, 1H), 4.16 (q, J = 6.69 Hz,
2H), 2.30 (s, 3H), 1.25 (t, J = 6.69 Hz, 3H); 13C NMR
(50 MHz, CDCl3): d 166.3, 148.8, 146.9, 140.1, 138.0,
134.5, 132.7, 127.4, 69.1, 61.2, 17.7, 14.1; MS EI, (m/z):
255 [M+] (10), 220(100), 192(60), 154(85), 146(45),
120(40), 92(10), 65(65); IR (KBr): 3429, 2926, 1721,
5.2.10. Dimethyl-8-methyl-2,6-quinolinedicarboxylate (4c).
Yellow solid; yield: 88%; mp: 112 °C; 1H NMR
(200 MHz, CDCl3): d 8.42 (s, 1H), 8.35 (d, 1H), 8.18
(d, 1H), 8.17 (s, 1H), 4.08 (s, 3H), 3.98 (s, 3H), 2.91 (s,
3H); 13C NMR (50 MHz, CDCl3): d 166.5, 165.8,
148.8, 148.5, 139.4, 138.7, 131.6, 129.4, 128.4, 127.5,
121.3, 53.0, 52.4, 17.8; MS (EI), m/z: 259 [M+] (58),
227(22), 199(100), 168(25), 140(35), 113(10); IR (KBr):
2958, 1720, 1441, 1341, 1228, 1141, 1099, 775 cmꢁ1; Anal.
Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found:
C, 65.12; H, 5.32; N, 5.55.
1627, 1465, 1168, 771 cmꢁ1
;
Anal. Calcd for
C12H14ClNO3: C, 56.35; H, 5.55; N, 5.48. Found: C,
56.66; H, 5.74; N, 5.62.
5.2.6. Ethyl 2-[(2-chloro-5-phenylpyridine-3-yl)(hydroxy)
methyl]acrylate (2f). Yield: 99.5%; viscous oil; H NMR
5.2.11. 3-Ethyl-6-methyl-2-phenyl-8-methyl-3,6-quinoline-
dicarboxylate (4d). Light yellow solid; yield: 78%; mp:
79 °C; 1H NMR (200 MHz, CDCl3): d 9.12 (s, 1H),
8.6 (s, 1H), 8.12 (s, 1H), 7.4 (m, 5H), 4.1 (q,
J = 6.79 Hz, 2H), 4.0 (s, 3H), 2.68 (s, 3H), 1.02 (t,
J = 6.79 Hz, 3H); MS (EI), m/z: 349 [M+] (70),
320(100), 304(65), 277(33), 216(25), 189(8); IR (KBr):
2928, 1706, 1552, 1295, 1132, 904, 770 cmꢁ1; Anal.
Calcd for C21H19NO4: C, 72.19; H, 5.48; N, 4.01.
Found: C, 72.44; H, 5.72; N, 4.23.
1
(200 MHz, CDCl3): d 8.5 (d, 1H), 8.12 (s, 1H), 7.35–7.6
(m, 5H), 6.34 (s, 1H), 5.88 (s, 1H), 5.62 (s, 1H), 4.3 (q,
J = 7.06 Hz, 2H), 3.88 (br, 1H), 1.3 (t, J = 7.06 Hz,
3H); 13C NMR (50 MHz, CDCl3): d 166.6, 148.9,
147.1, 140.6, 136.7, 136.5, 136.2, 135.6, 129.5, 128.9,
127.6, 127.5, 69.6, 61.7, 14.4; MS (EI), m/z: 317 [M+]
(12), 302(15), 282(70), 268(100), 254(50), 216(65),
182(12), 153(23), 127(40), 115(33); Anal. Calcd for
C17H16ClNO3: C, 64.26; H, 5.07; N, 4.40. Found: C,
64.53; H, 5.25; N, 4.62.
5.2.12. Ethyl 3,8-dimethyl-6-quinolinecarboxylate (4e).
White solid; yield: 84%; mp: 83 °C; 1H NMR (200 MHz,
CDCl3): d 8.81 (s, 1H), 8.30 (s, 1H), 8.06 (s, 1H), 7.94
(s, 1H), 4.44 (q, J = 6.79 Hz, 2H), 2.82 (s, 3H), 2.55 (s,
3H), 1.46 (t, J = 6.79 Hz, 3H); 13C NMR (50 MHz,
CDCl3): d 166.2, 153.0, 147.1, 137.0, 136.0, 130.8,
128.1, 127.8, 127.7, 127.0, 61.0, 18.4, 17.9, 14.2.; MS
(EI), m/z: 229 [M+] (100), 201 (65), 184 (63), 156 (60),
141 (10), 128 (10); IR (KBr): 2922, 1715, 1619, 1446,
5.2.7. Ethyl 2-[(2-chloro-5-methyl-6-phenylpyridine-3-
yl)(hydroxy) methyl]acrylate (2g). Yield: 99%; white
solid; mp: 104–106 °C; 1H NMR (200 MHz, CDCl3):
d 7.78 (s, 1H), 7.35–7.55 (m, 5H), 6.38 (s, 1H), 5.82
(s, 1H), 5.62 (s, 1H), 4.25 (q, J = 7.43 Hz, 2H), 2.4 (s,
3H), 1.33 (t, J = 7.43 Hz, 3H); MS (EI), m/z: 331
[M+], 302, 231, 165, 77; IR (KBr): 3274, 2981,

P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
4607
1270, 1226, 1106, 768 cmꢁ1; Anal. Calcd for C14H15NO2:
C, 73.34; H, 6.59; N, 6.11. Found: C, 73.51; H, 6.35; N,
6.66.
5.2.18. Ethyl 2-phenyl-3-methyl-8-cyano-6-quinolinecarb-
oxylate (5c). Light yellow solid; yield: 44%; mp: 121 °C;
1H NMR (200 MHz, CDCl3): d 9.6 (s, 1H), 8.8 (s, 1H),
8.13 (s, 1H), 7.68–7.74 (m, 2H), 7.4–7.5 (m, 3H), 4.51 (q,
J = 7.2 Hz, 2H), 2.6 (s, 3H), 1.5 (t, J = 7.2 Hz, 3H); MS
(EI), m/z: 316 [M+] (100), 273(64), 145(54), 141(10),
128(10); IR (KBr): 3015, 2965, 2246, 1709, 1656, 1496,
5.2.13. Ethyl 3-phenyl-8-methyl-6-quinolinecarboxylate
(4f). Light yellow solid; yield: 88%; mp: 98 °C; 1H
NMR (200 MHz, CDCl3): d 9.22 (s, 1H), 8.43 (s, 1H),
8.35 (s, 1H), 8.01 (s, 1H), 7.35–7.67 (m, 5H), 4.38 (q,
J = 6.65 Hz, 2H), 2.82 (s, 3H), 1.36 (t, J = 6.65 Hz,
3H); 13C NMR (50 MHz, CDCl3): d 166.2, 150.6,
148.0, 137.4, 137.3, 134.5, 134.1, 129.2, 129.0, 128.7,
128.4, 128.2, 127.3, 127.1, 61.2, 17.9, 14.3; MS (EI) m/
z: 291 [M+] (100), 276(10), 263(48), 256(33), 218(40),
189(10); IR (KBr): 3061, 2986, 1712, 1379, 1256, 1193,
1106, 1026, 768 cmꢁ1; Anal. Calcd for C19H17NO2: C,
78.33; H, 5.88; N, 4.81. Found: C, 78.54; H, 6.14; N,
5.05.
1270, 1226, 1078, 770 cmꢁ1
;
Anal. Calcd for
C20H16N2O2: C, 75.93; H, 5.10; N, 8.85. Found: C,
75.87; H, 4.96; N, 9.14.
5.2.19. 3,9-Dimethyl-7,8-dihydro-6H-cyclopenta[g]quino-
lin-6-one (6a)32. Yellow solid; yield: 74%; mp: 123 °C; 1H
NMR (200 MHz, CDCl3): d 8.82 (s, 1H), 8.02 (s, 1H),
8.01 (s, 1H), 3.28 (t, J = 6.79 Hz, 2H), 2.80(t,
J = 6.79 Hz, 2H), 2.78 (s, 3H), 2.56 (s, 3H); 13C NMR
(50 MHz, CDCl3): d 207.6, 154.0, 153.7, 137.5, 134.5,
133.7, 133.3, 130.5, 127.2, 121.0, 36.7, 24.8, 18.5, 13.0;
MS (EI) m/z: 211 [M+] (100), 182(95), 168(12); IR
(KBr): 2924, 1710, 1616, 1549, 1389, 1067 cmꢁ1; Anal.
Calcd for C14H13NO: C, 79.59; H, 6.2; N, 6.63. Found:
C, 79.89; H, 6.37; N, 6.78.
5.2.14. Ethyl 2-phenyl-3,8-dimethyl-6-quinolinecarboxy-
1
late (4g). White solid; yield: 84%; mp: 98 °C; H NMR
(200 MHz, CDCl3): d 8.34 (s, 1H), 8.06 (s, 1H), 8.06
(s, 1H), 7.67 (m, 2H), 7.48 (m, 3H), 4.45 (q,
J = 6.41 Hz, 2H), 2.82 (s, 3H), 2.55 (s, 3H), 1.48 (t,
J = 6.41 Hz, 3H); MS (EI), m/z: 305 [M+] (100),
276(70), 260(15), 231(25), 217(20), 129(10); IR (KBr):
3061, 2986, 1712, 1379, 1256, 1198, 1105, 1026,
764 cmꢁ1; Anal. Calcd for C20H19NO2: C, 78.86; H,
6.27; N, 4.59. Found: C, 78.99; H, 6.66; N, 4.64.
5.2.20. 3-Phenyl-9-methyl-7,8-dihydro-6H-cyclopenta[g]quin-
olin-6-one (6b)32. Light yellow solid; yield: 80%; mp:
1
132 °C; H NMR (200 MHz, CDCl3): d 9.21 (s, 1H),
8.38 (s, 1H), 8.18 (s, 1H), 7.67–7.42 (m, 5H), 3.24 (t,
J = 6.74 Hz, 2H), 2.8 (t, J = 6.72 Hz, 2H), 2.78 (s, 3H);
13C NMR (50 MHz, CDCl3): d 207.0, 150.8, 149.5,
148.1, 136.9, 135.4, 134.6, 133.7, 133.3, 129.2, 129.1,
129.0, 128.2, 127.1, 126.8, 121.2, 36.6, 24.8, 12.9.; MS
(EI) m/z: 273 [M+] (100), 245(78), 231(18), 164(15),
77(12); IR (KBr): 2919, 1708, 1611, 1481, 1261,
799 cmꢁ1; Anal. Calcd for C19H15NO: C, 83.49; H,
5.53; N, 5.12. Found: C, 83.64; H, 5.78; N, 5.36.
5.2.15. 6-Ethyl-2-methyl-8-methyl-2,6-quinolinedicarb-
1
oxylate (4h). White solid; yield: 85%; mp: 112 °C; H
NMR (200 MHz, CDCl3): d 8.38 (s, 1H), 8.3 (d,
1H), 8.18 (d, 1H), 8.17 (s, 1H), 4.4 (q, J = 7.55 Hz,
2H), 4.0 (s, 3H), 2.85 (s, 3H), 1.41 (t, J = 7.55 Hz.
3H); 13C NMR (50 MHz, CDCl3): d 166.4, 166.3,
149.1, 148.9, 139.7, 139.0, 130.2, 129.8, 128.8, 128.6,
121.7, 61.8, 53.4, 18.2, 14.7; MS (EI), m/z: 273 [M+]
(85), 241(33), 228(30), 213(100), 185(25), 165(25),
140(30); IR (KBr): 2962, 1726, 1440, 1339, 1267,
1228, 1196, 768 cmꢁ1; Anal. Calcd for C15H15NO4:
C, 65.93; H, 5.53; N, 5.13. Found: C, 66.19; H, 5.64;
N, 5.46.
5.2.21. 2-Phenyl-3-methyl-9-methyl-7,8-dihydro-6H-cy-
clopenta[g]quinolin-6-one (6c)32. White solid; yield:
1
85%; mp: 124 °C; H NMR (200 MHz, CDCl3): d 8.09
(s, 1H), 8.07 (s, 1H), 7.45–7.70 (m, 5H), 3.26 (t,
J = 6.76 Hz, 2H), 2.8 (t, J = 6.72 Hz, 2H), 2.78 (s, 3H);
13C NMR (50 MHz, CDCl3): d 207.6, 161.2, 149.1,
147.8, 140.5, 139.6, 134.3, 134.0, 129.4, 129.3, 129.2,
128.6, 128.1, 128.0, 126.4, 120.5, 36.8, 24.9, 20.6, 13.0.;
MS (EI) m/z: 287 [M+] (100), 245(78), 231(18),
164(15), 77(12); IR (KBr): 2923, 2362, 1718, 1616,
1478, 1057 cmꢁ1; Anal. Calcd for C19H15NO: C, 83.49;
H, 5.53; N, 5.12. Found: C, 83.63; H, 5.78; N, 5.21.
5.2.16. Methyl 3-methyl-8-cyano-6-quinolinecarboxylate
(5a). Light yellow solid; yield: 64%; mp: 126 °C; 1H
NMR (200 MHz, CDCl3): d 9.00 (s, 1H), 8.66 (s, 1H),
8.60 (s, 1H), 8.06 (s, 1H), 4.01 (s, 3H), 2.62 (s, 3H);
MS (EI), m/z: 226 [M+] (100), 211(48), 183(65),
137(10), 128(10); IR (KBr): 2922, 1715, 2226, 1619,
1446, 1270, 1226, 1106, 768 cmꢁ1; Anal. Calcd for
C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C,
69.18; H, 4.84; N, 12.57.
5.2.22. Methyl 9-methyl-6-oxo-7,8-dihydro-6H-cyclopen-
ta[g]quinoline-2-carboxylate (6d)32. Yellow solid; yield:
1
86%; mp: 112 °C; H NMR (CDCl3, 200 MHz): d 8.4
(d, 1H), 8.18 (s, 1H), 8.16 (d, 1H), 4.08 (s, 1H), 3.32
(t, J = 6.72 Hz, 2H), 2.9 (s, 3H), 2.84 (t, J = 6.72 Hz,
2H). MS (EI) m/z: 255 [M+] (70), 223(26), 196(100),
168(30), 139(25); Anal. Calcd for C15H13NO3: C,
70.58; H, 5.13; N, 5.49. Found: C, 70.72; H, 5.59; N,
5.64.
5.2.17. Ethyl 3-phenyl-8-cyano-6-quinolinecarboxylate
(5b). Light yellow solid; yield: 48%; mp: 134 °C; 1H
NMR (200 MHz, CDCl3): d 9.39 (s, 1H), 8.81 (s,
1H), 8.66 (s, 1H), 8.43 (s, 1H), 7.68–7.74 (m, 5H),
4.47 (q, 2H), 1.48 (t, 3H); MS (EI), m/z: 302 [M+]
(100), 273(64), 145(54), 141(10), 128(10); IR (KBr):
3015, 2965, 2246, 1709, 1656, 1496, 1270, 1226,
1078, 770 cmꢁ1; Anal. Calcd for C19H14N2O2: C,
75.48; H, 4.67; N, 9.27. Found: 75.76; H, 4.94; N,
9.58.
5.2.23. Methyl (E)-3-(2-Chloro-5-methyl-3-pyridyl)-2-(2-
nitropropyl)-2-propenoate (7a). White solid; yield: 96%;
mp: 154–158 °C; 1H NMR (200 MHz, CDCl3): d 8.2
(s, 1H), 7.72 (s, 1H), 7.3 (s, 1H), 4.93 (m, 1H), 3.86 (s,

4608
P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
16. Van Inwegan, R. G.; Khandwala, A.; Gordon, R.;
Sonnino, P.; Coutts, S.; Jolly, S. J. Pharmacol. Exp. Ther.
1987, 24, 117.
17. Gauthier, J. Y.; Jones, T.; Champion, E.; Charette, L.;
Dehaven, R.; Ford-Hutchinson, A. W.; Hoogsteen, K.;
Lord, A.; Masson, P.; Piechuta, H.; Pong, S. S.; Springer,
J. P.; Therien, M.; Zamboni, R.; Young, R. N. J. Med.
Chem. 1990, 33, 2841.
18. Ife, R. J.; Brown, T. H.; Keeling, D. J.; Leach, C. A.;
Meeson, M. L.; Parsons, M. E.; Reavill, D. R.; Theobald,
C. J.; Wiggall, K. J. Med. Chem. 1992, 35, 3413.
19. (a) Chen, S.-F.; Papp, L. M.; Ardecky, R. J.; Rao, G. V.;
Hesson, D. P.; Forbes, M.; Desxter, D. L. Biochem.
Pharmacol. 1990, 40, 709; (b) Zeevi, A.; Yao, G.-Z.;
Venkataramanan, R.; Duqesnoy, R. J.; Todo, S.; Fung, J.
J.; Starzl, T. E. Transplant. Proc. 1993, 25, 781.
20. Musser, J. H.; Chakraborty, U. R.; Sciortino, S.; Gordon,
R. J.; Khandawala, A.; Neiss, E. S.; Pruss, T. P.; Van
Inwegen, R.; Weinryb, I.; Coutts, S. M. J. Med. Chem.
1987, 30, 96.
3H), 2.91 (dd, 1H), 2.75 (dd, J = 8.21 Hz, 1H), 2.34 (s,
3H), 1.46 (d, J = 7.21 Hz, 3H); 13C NMR (50 MHz,
CDCl3): d 166.5, 148.8, 147.0, 139.0, 138.6, 132.4,
130.4, 129.2, 81.4, 52.6, 33.4, 18.9, 17.7; MS (EI), m/z:
298 [M+]; IR (KBr): 3021, 2959, 2362, 1709, 1549,
1438, 1416, 1265, 1215, 1133, 1070, 763 cmꢁ1; Anal.
Calcd for C13H15ClN2O4: C, 52.27; H, 5.06; N, 9.38.
Found: C, 52.46; H, 5.22; N, 9.48.
Acknowledgments
We thank Director, IICT and Head, Organic Chemistry
Division-II, for the continued encouragement. P.N. and
M.R. thank CSIR, U.S. and B.G. thank UGC for the
fellowship.
References and notes
21. (a) Aggarwal, A. K.; Jenekhe, S. A. Macromolecules 1991,
24, 6806; (b) Zhang, X.; Shetty, A. S.; Jenekhe, S. A.
Macromolecules 1999, 32, 7422; (c) Jenekhe, S. A.; Lu, L.;
Alam, M. M. Macromolecules 2001, 34, 7315.
22. (a) Balasubramanian, M.; Keay, J. G. In Comprehen-
sive Heterocyclic Chemistry II; Katritzky, A. R, Rees,
C. W., Scriven, E. F. V., Eds.; Pergamon Press:
Oxford, 1996; Vol. 5, pp 167–243; (b) Cheng, C.-C.;
Yan, S.-J. Org. React. 1982, 28, 37–200; (c) Jones, G..
In The Chemistry of Heterocyclic Compounds; Weiss
Berger, A., Taylor, A. C., Eds.; Wiley: New York,
1977; Vol. 32, p 93, Chapter 2.
23. (a) Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org.
Lett. 2005, 7, 763; (b) McNaughton, B. R.; Miller, B. L.
Org. Lett. 2003, 5, 4257; (c) Yadav, J. S.; Reddy, B. V. S.;
Sreedhar, P.; Rao, R. S.; Nagaiah, K. Synthesis 2004,
2381; (d) Demaude, T.; Knerr, L.; Pasau, P. J. Comb.
Chem. 2004, 6, 768; (e) De, S. K.; Gibbs, R. A.
Tetrahedron Lett. 2005, 46, 1647; (f) Patteux, C.; Levacher,
V.; Dupas, G. Org. Lett. 2003, 5, 3061.
24. (a) Baylis, A. B.; Hillman, M. E. D. German Patent
2155113, 1972; Chem. Abstr. 1972, 77, 34174q; (b) Drewes,
S. E.; Roos, G. H. P. Tetrahedron 1988, 44, 4653; (c)
Basavaiah, D.; Dharma Rao, P.; Suguna, Hy. Tetrahedron
1996, 52, 8001; (d) Ciganek, E. Org. React. 1997, 51, 201;
(e) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana,
T. Chem. Rev. 2003, 103, 811.
1. Woodford, N. Expert Opin. Investig. Drugs 2003, 12, 117.
2. Khare, M.; Keady, D. Expert Opin. Pharmacother. 2003,
4, 165.
3. Hamilton-Miller, J. M. Infection 2002, 30, 118.
4. Lam, S.; Singer, C.; Tucci, V.; Morthland, V. H.; Pfaller,
M. A.; Isenberg, H. D. Am. J. Infect. Control 1995, 23,
170.
5. Nicolau, D. J. Antimicrob. Chemother. 2002, 50, 61.
6. Adam, D. J. Antimicrob. Chemother. 2002, 50, 1.
7. Paladino, J. Am. J. Health Syst. Pharm. 2002, 59, 2413–
2425.
8. (a) Michael, J. P. Nat. Prod. Rep. 1997, 14, 605; (b)
Balasubramanian, M.; Keay, J. G. In Comprehensive
Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds.; Pergamon Press: Oxford,
1996; Vol. 5, pp 245–300; (c) Yates, F. S.. In
Comprehensive Hetercyclic Chemistry; Katritzky, A.
R., Rees, C. W., Eds.; Pergamon Press: Oxford, UK,
1984; Vol. 2, p 511.
9. (a) Lutz, R. E.; Bailey, P. S.; Clark, M. T.; Codington,
J. F.; Dinet, A. J.; Freek, J. A.; Harnest, G. H.; Leak,
N. H.; Martin, T. A.; Rowlett, R. J.; Salisbury, J. M.;
Shearer, N. H.; Smith, J. D.; Wilson, J. W. J. Am.
Chem. Soc. 1946, 68, 1813; (b) Surrey, A. E.; Hammer,
H. F. J. Am. Chem. Soc. 1950, 72, 1814; (c) Burck-
halter, J. H.; Brinigar, W. S.; Thompson, P. S. J. Org.
Chem. 1961, 26, 4070.
10. (a) Wilson, W. D.; Zhao, M.; Patterson, S. E.; Wydra, R.
L.; Janda, L.; Strekowski, L. Med. Chem. Res. 1992, 2,
102; (b) Strekowski, L.; Mokrosz, J. L.; Honkan, V. A.;
Czarny, A.; Cegla, M. T.; Wydra, R. L.; Patterson, S. E.;
Schinazi, R. F. J. Med. Chem. 1991, 34, 1739.
11. Atwell, G. J.; Baguley, B. C.; Denny, W. A. J. Med. Chem.
1989, 32, 393.
25. (a) Anand, R. V.; Bakthraman, S.; Singh, V. K. Tetrahe-
dron Lett. 1996, 52, 8001; (b) Mateus, C. R.; Feltrin, M.
P.; Costa, A. M.; Coelho, F.; Almedia, N.-P. Tetrahedron
2001, 57, 6901; (c) Iwabuchi, Y.; Sugihara, T.; Esumi, T.;
Hatakeyama, S. Tetrahedron Lett. 2001, 42, 7867; (d)
Iwabuchi, Y.; Furukawa, M.; Esumi, T.; Hatakeyama, S.
Chem. Commun. 2001, 2030; (e) Basavaiah, D.; Kumar-
agurubaran, N.; Sharada, D. S. Tetrahedron Lett. 2001,
42, 85.
12. Desai, P. K.; Desai, P.; Machhi, D.; Desai, C. M.; Patel,
D. Indian J. Chem. Sect. B. 1996, 35, 871.
13. Cheng, X.-M.; Lee, C.; Klutchko, S.; Winters, T.;
Reynolds, E. E.; Welch, K. M.; Flynn, M. A.; Doherty,
A. M. Bioorg. Med. Chem. 1996, 6, 2999.
14. Anzini, M.; Cappelli, A.; Vomero, S.; Giorgi, G.; Langer,
T.; Hamon, M.; Merahi, N.; Emerit, B. M.; Cagnotto, A.;
Skorupska, M.; Mennini, T.; Pinto, J. C. J. Med. Chem.
1995, 38, 2692.
15. Giardina, G. A. M.; Sarau, H. M.; Farina, C.; Medhurst,
A. D.; Grugni, M.; Raveglia, L. F.; Schmidt, D. B.;
Rigolio, R.; Luttmann, M.; Vecchietti, V.; Hay, D. W. P.
J. Med. Chem. 1997, 50, 1794.
26. (a) Basavaiah, D.; Reddy, R. M.; Kumaragurubaran, N.;
Sharada, D. S. Tetrahedron 2002, 58, 3693; (b) Kim, J. N.;
Chung, Y. M.; Im, Y. J. Tetrahedron Lett. 2002, 43, 6209;
(c) O’Dell, D. K.; Nicholas, K. M. J. Org. Chem. 2003, 68,
6427; (d) Chung, Y. M.; Lee, H. J.; Hwang, S. S.; Kim, J.
N. Bull. Korean Chem. Soc. 2001, 22, 799.
27. Kim, J. N.; Kim, H. S.; Gong, J. H.; Chung, Y. M.
Tetrahedron Lett. 2001, 42, 8341.
28. Srinivas, K.; Srinivas, U.; Rao, V. J.; Bhanuprakash, K.;
Kishore, K. H.; Murthy, U. S. N. Bioorg. Med. Chem.
Lett. 2005, 15, 112.
29. Gangadasu, B.; Chinaraju, B.; Jayathirtha Rao, V. U.S.
Patent 6,479,664, 2002; Chem. Abstr. 2002, 137, 352892.

P. Narender et al. / Bioorg. Med. Chem. 14 (2006) 4600–4609
4609
30. (a) Kim, J. M.; Im, Y. J.; Kim, I. H.; Kim, J. N. Bull.
Korean Chem. Soc. 2002, 23, 657; (b) Hbaieb, S.; Amri, H.
J. Soc. Chim. Tunis. 2000, 1, 671; (c) Chamakh, A.;
M’hirsi, M.; Villieras, J.; Lebreton, J.; Amri, H. Synthesis
2000, 0, 295; (d) Basavaiah, D.; Rao, J. S. Tetrahedron
Lett. 2004, 45, 1621; (e) Kim, J. N.; Im, Y. J.; Gong, J. H.;
Lee, K. Y. Tetrahedron Lett. 2001, 42, 4195.
31. Narender, P.; Srinivas, U.; Gangadasu, B.; Biswas, S.;
Jayathirtha Rao, V. Bioorg. Med. Chem. Lett. 2005, 15,
5378.
32. Narender, P.; Gangadasu, B.; Ravinder, M.; Srinivas, U.;
Swamy, G. Y. S. K.; Ravikumar, K.; Jayathirtha Rao, V.
Tetrahedron 2006, 62, 954.
33. Mason, P. L. H.; Emslie, N. D. Tetrahedron 1994, 50,
12001.
747; (c) Pascual, C.; Meier, J.; Simon, W. Helv. Chim.
Acta 1966, 49, 164; (d) Larson, G. L.; de Kaifer, C. F.;
Seda, R.; Torres, L. E.; Ramirez, J. R. J. Org. Chem.
1984, 49, 3385.
38. (a) Funabiki, T.; Hosomi, H.; Yoshida, S.; Tarama, K.
J. Am. Chem. Soc. 1982, 104, 1560; (b) Basavaiah, d.;
Bhavani, A. K. D.; Pandiaraju, S.; Sarma, P. K. S. Synlett
1995, 243; (c) Gruiec, A.; Foucaud, A. New J. Chem. 1991,
15, 943.
39. National Committee for Clinical Laboratory Stan-
dards (NCCLS). Standard methods for dilution
antimicrobial susceptibility tests for bacteria which
grow aerobically. Nat. Comm. Clini. Lab. Stands
Villanova, 1982; p 242.
40. Margery Linday, E. Practical Introduction to Microbiolo-
gy; E.& F.N. Spon: UK, 1962, p 177.
34. (a) Anderson, R. J.; Hendrick, C. A.; Sidall, J. B. J. Am.
Chem. Soc. 1970, 90, 735; (b) Goering, H. L.; Kantner, S.
S., ; Seitz, E. P., Jr. J. Org. Chem. 1985, 50, 5495.
35. In 1H NMR spectrum of the crude 3-aryl-(2-substitut-
ed)-prop-2-enoates, the b-vinylic proton cis to the ester
group [(E)-isomer] appears at abnormal downfield
d = 7.5–7.9 ppm, while the b-vinylic proton trans to
the ester group [(Z)-isomer] appears at d = 6.7–
6.9 ppm.37 In 13C NMR spectra of the same trisubsti-
tuted olefins, allylic carbon cis to aryl group appears
upfield, while the same carbon trans to aryl group
appears downfield.38.
41. The ready-made Potato Dextrose Agar (PDA) medium
(Himedia, 39 g) was suspended in distilled water
(1000 mL) and heated to boiling until it dissolved
completely, the medium and Petri dishes were autoclaved
at pressure of 15 lb/inc2 for 20 min. Agar cup bioassay was
employed for testing antifungal activity. The medium was
poured into sterile Petri dishes under aseptic conditions in
a laminar flow chamber. When the medium in the plates
solidified, 0.5 mL of (week old) culture of test organism
was inoculated and uniformly spread over the agar surface
with a sterile L-shaped rod. Solutions were prepared by
dissolving the compound in DMSO and different concen-
trations were made (30 and 100 lg/mL). After inoculation,
cups were scooped out with 6 mm sterile cork borer and
the lids of the dishes were replaced. To each cup different
concentrations of test solutions (30,100 lg/mL) were
added. Controls were maintained with acetone and
Clotrimazole (100 lg/mL). The treated and the controls
were kept at room temperature for 48 h. Inhibition zones
were measured and the diameter was calculated in
millimeter. Three to four replicates were maintained for
each treatment. Media. Potato Dextrose broth and Potato
Dextrose agar were procured from M/S Himedia Labora-
tories, Mumbai.
1
36. In H NMR spectrum of the crude methyl 3-(2-chloro-5-
methyl-3-pyridyl)-2-(2-nitropropyl)-2-propenoate, 7a, the
abnormal downfield shift of the vinylic proton at around
d = 7.79 with high intensity indicates the (E)-isomer, in
addition no peak at around d = 6.7–6.9 appeared even
with very low intensity which indicates the no (Z)-isomer.
In 13C NMR spectra of the same crude trisubstituted
alkene 7a, a peak at around d = 33.3 with high intensity
indicates the (E)-isomer, in addition no peak at around
d = 35–40 which indicates the no (Z)-isomer.
37. (a) Tanaka, K.; Yamagishi, N.; Tanikaga, R.; Kaji, A.
Bull. Chem. Soc. Jpn. 1979, 52, 3619; (b) Basavaiah, D.;
Panduraju, S.; Krishnamacharyulu, M. Synlett 1996,