An alternate approach to quinoline architecture via Baylis-Hillman chemistry: SnCl2-mediated tandem reaction toward synthesis of 4-(substituted vinyl)-quinolines

Article abstract of DOI:10.1016/j.tet.2006.06.098

An alternate approach to densely substituted quinolines from the products of S_N2 nucleophilic substitution reaction between the acetyl derivatives of the Baylis-Hillman adducts obtained from 2-nitrobenzaldehydes and the carbonyl group containin

Full text of DOI:10.1016/j.tet.2006.06.098

Tetrahedron 62 (2006) 8740–8747
An alternate approach to quinoline architecture via
Baylis–Hillman chemistry: SnCl2-mediated tandem reaction
toward synthesis of 4-(substituted vinyl)-quinolines
,y
*
Sudharshan Madapa, Virender Singh and Sanjay Batra
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow 226001, India
Received 28 April 2006; revised 13 June 2006; accepted 29 June 2006
Available online 24 July 2006
Abstract—An alternate approach to densely substituted quinolines from the products of SN2 nucleophilic substitution reaction between the
acetyl derivatives of the Baylis–Hillman adducts obtained from 2-nitrobenzaldehydes and the carbonyl group containing carbon nucleophiles
is described. Treatment of these compounds with SnCl2, triggers a tandem reaction wherein reduction of the nitro group is followed by a
remarkably regioselective intramolecular cyclization and subsequent dehydrogenation to afford 4-(substituted vinyl)-quinolines.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Substituted quinolines are one of the oldest known classes of
pharmaceutical agents and their relevance in chemotherapy
especially against malaria is widely known.1 Beside anti-
malarials, a spectrum of other pharmacological activities2
has been the major reason for the development of novel
and efficient syntheses of this heterocycle. As a result, the
recent past has witnessed the publication of several simple
and elegant syntheses of substituted quinolines.3 Neverthe-
less, a new mild one-pot method, from readily accessible
starting materials, which would permit delivery of this motif
decorated with functional groups amenable to further diver-
sification, should be of great synthetic relevance.
In the recent times, Baylis–Hillman adducts have been illus-
Figure 1. Summary of synthesis of quinoline motif from Baylis–Hillman
adducts or their derivatives. Numbers on the arrows indicate the correspond-
ing reference no. (also see Ref. 16).
trated as suitable starting materials for the synthesis of vari-
ety of heterocyclic systems.4 The generation of substituted
quinolines either directly from the Baylis–Hillman adducts
or their derivatives has therefore received considerable
attention. Historically, since the first such synthesis reported
by Familoni et al. in 1998, several variants of this approach
have been demonstrated.5–16 A summary of these methods is
provided in Figure 1.
occurred to us that substrates resulting from the SN2 nucleo-
philic substitution reaction between the acetyl derivatives of
Baylis–Hillman adducts of 2-nitrobenzaldehydes and a nu-
cleophile containing a keto group or an ester group would
represent an interesting carbon framework for the construc-
tion of a quinoline architecture. In these compounds beside
the three carbon chain originating from the Baylis–Hillman
reaction, which generally participates in the intramolecular
cyclization toward construction of the quinoline, there would
also be another three carbon chain containing a terminal keto
or an ester group, which could also undergo cyclization. In
the latter case cyclization would result in a dihydroquinoline
derivative with a vinyl chain at the 4-position, which could
be dehydrogenated to yield the desired quinoline. We have
With our ongoing interest in the synthesis of heterocycles
employing derivatives of Baylis–Hillman adducts,17 it
Keywords: Quinolines; Baylis–Hillman; 2-Nitrobenzaldehyde; Reduction;
SnCl2; Regioselective.
* Corresponding author. Tel.: +91 522 2262411–18x4368; fax: +91 522
2623405/938; e-mail: batra_san@yahoo.co.uk
CDRI Communication no. 6991.
y
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.06.098

S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
8741
therefore carried out SN2 reactions of the acetates of the
Baylis–Hillman adducts of 2-nitrobenzaldehydes and sub-
stituted 2-nitrobenzaldehydes with nucleophiles such as
acetyl acetone, benzoyl acetone, methylacetoacetate, and
benzoylacetoacetate and subjected the resulting products to
chemoselective reduction in the presence of SnCl2. Interest-
ingly, the chemoselective reduction led to a tandem reaction
wherein the reduction, a regioselective cyclization involving
the carbonyl group of the added nucleophile dehydrogena-
tion occurred in a single step to furnish the 4-(substituted
vinyl)-quinolines. This observation prompted us to disclose
the details of results of our study in this paper.
Accordingly, compound 6a was prepared and subjected to
similar reduction. However, instead of the desired product
8a, a complex mixture of products was formed, which could
not be characterized.
In the next step we decided to investigate the same reaction
sequence by replacing the nucleophile with benzoyl acetone.
Thus, the SN2 nucleophilic substitution reaction of benzoyl
acetone with the acetate 3a in the presence of DABCO in
a THF/H2O system led to the synthesis of compound 9a as
a diastereoisomeric mixture in good yield. The nitro group
in 9a was then chemoselectively reduced with anhydrous
SnCl2. Gratifyingly this reaction proceeded smoothly to
yield a product, which was established as the quinoline
16a via spectroscopic analysis. The change in the chemical
shift of the protons of methyl group indicated that the acetyl
group of the nucleophile was involved in the intramolecular
cyclization with the amino group. The isolation of quinoline
16a implied that the SnCl2 had triggered a tandem reaction
wherein the reduction of the nitro group was followed by
cyclization and subsequent dehydrogenation. This reaction
was found to be general in nature since substrates 9b,c
also furnished the quinolines 16b,c. During optimization it
was observed that replacing anhydrous SnCl2 with
SnCl2$2H2O did not have any effect on the outcome of
the reaction. Encouraged with these results we decided to
evaluate the reaction with compounds 10a–c, which were
synthesized from 4a–c, respectively, following a similar
synthetic route to that for the preparation of 9a–c. Interest-
ingly when 10a was subjected to SnCl2-promoted reaction,
unlike compound 9a–c, the dihydroquinoline derivative
17a was isolated. 1H NMR analysis of product 17a showed
2. Results and discussion
Preparation of the starting materials, the acetates 3a–c,4a–c,
was accomplished by acetylating the corresponding Baylis–
Hillman adducts 1a–c,2a–c in the presence of acetyl chloride
and pyridine in dichloromethane at room temperature
(Scheme 1). Initially, the SN2 reaction of acetyl acetone
was carried out with the acetate 3a following the reported
procedure to obtain product 5a.17d The chemoselective
reduction of the nitro group employing anhydrous SnCl2 in
compound 5a, instead of yielding the desired dihydroquino-
line 7a, resulted in an inseparable mixture of products. It is
likely that both the carbonyl group of the added nucleophile
and the ester group originally present in the substrate could
have participated in the cyclization reaction leading to a
complex mixture. In principle, if the acetate 4a is used
as the starting substrate for a similar reaction then the pos-
sibility of simultaneous cyclizations could be eliminated.
Scheme 1. Reagents and conditions: (a) CH2]CHEWG, DABCO, rt, 15 min to 1 h; (b) AcCl, pyridine, CH2Cl2, rt, 2–3 h; (c) DABCO, MeCOCH2COMe,
THF/H2O (1:1), rt, 30 min; (d) SnCl2, MeOH, reflux, 1 h; (e) DABCO, PhCOCH2COMe, THF/H2O (1:1), rt, 30 min; (f) DABCO, MeCOCH2CO2Et, THF/
H2O (1:1), rt, 30 min; (g) DABCO, PhCOCH2CO2Et, THF/H2O (1:1), rt, 30 min; (h) DABCO, CO2EtCH2CO2Et, THF/H2O (1:1), rt, 30 min.

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S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
the presence of peaks for the NH and the CH protons and 13
C
were recorded using a Perkin–Elmer RX I FTIR spectro-
1
NMR exhibited the CH carbon instead of the signal for
tertiary carbon. The mass spectrum supported the assigned
structure. Treatment of compound 10b with SnCl2 also
yielded the dihydroquinoline 17b but substrate 10c gave
the usual quinoline 18c.
photometer. H NMR and 13C NMR spectra were recorded
on either a 300 or a 200 MHz FT spectrometer, using TMS
as an internal standard (chemical shifts are expressed as
d values, J in hertz). FABMS were recorded on a JEOL/
SX-102 spectrometer and ESMS were recorded using a
Micromass LC–MS system. Elemental analyses were per-
formed on a Carlo Erba 1108 microanalyzer or Elementar’s
Vario EL III microanalyzer. All yields are the isolated yields
from column chromatography. Spectroscopic data of com-
pounds 9–13 are reported as diastereoisomeric mixtures
unless otherwise stated.
The results generated interest in studying the outcome of re-
actions with other carbonyl group containing carbon nucleo-
philes in order to further explore the scope of this strategy.
Therefore, compounds 11a–c,12a–c were synthesized using
ethylacetoacetate as the nucleophile in the SN2 reaction of
the acetates 3a–c,4a–c, respectively. We were pleased to ob-
serve that the SnCl2 reduction of the nitro group proceeded
smoothly in these compounds to furnish the quinolines
19a–c, 20a,c in good yields. Like compounds 10a,b, com-
pound 12b also yielded dihydroquinoline 21b exclusively.
These results indicated that the acetyl carbonyl introduced
through the SN2 reaction reacts in preference to other acti-
vated carbonyl moieties present in the molecule with the
amine generated during the reduction reaction.
4.2. General procedure for the SN2 nucleophilic
substitution reaction with the acetyl derivatives
To a stirred solution of appropriate acetate (1.0 equiv) in
THF/H2O (50:50, v/v) was added DABCO (1.5 equiv)
at room temperature and the reaction was allowed to con-
tinue for 20 min. Thereafter, the appropriate nucleophile
(1.2 equiv) was added to the reaction mixture, and was fur-
ther stirred for 30 min at room temperature. The organic sol-
vent was removed and the residue diluted with water and
extracted with EtOAc (3ꢀ50 mL). Combined organic layer
was washed with brine solution (70 mL), dried (Na2SO4),
and evaporated to yield a crude product, which was purified
via silica gel column chromatography using hexanes/EtOAc
(85:15, v/v) as eluent to furnish pure products in 62–85%
yield.
We next examined the reduction in compound 13a. Gratify-
ingly treatment with SnCl2 yielded the quinoline 22a in good
yield. This result again indicated that the carbonyl group are
more reactive in the cyclization reaction and precedes the
ester moiety. In our quest to find out whether the ester group
can at all participate in the intramolecular cyclization, diethyl-
malonate was selected as nucleophile for the SN2 reaction.
Hence, compounds 14a and 15a generated by the reaction of
compounds 3a and 4a, respectively, with diethylmalonate in
the presence of DABCO, were treated with SnCl2. The reac-
tion led to isolation of products, which were established to be
tetrahydro quinolin-2-ones 23a, 24a. Interestingly, this cycli-
zation was found to be diastereoselective in favor of trans
isomer, as evident from the NOE correlations for H-3 and
H-4 protons. Thus in the absence of a ketone moiety, the ester
group can also participate in the intramolecular cyclization.
However, the subsequent dehydrogenation does not occur.
4.2.1. 4-Acetyl-2-methylene-3-(2-nitro-phenyl)-5-oxo-
hexanoic acid methyl ester (5a). Ref. 17d.
4.2.2. 4-Acetyl-2-methylene-3-(2-nitro-phenyl)-5-oxo-
hexanenitrile (6a). Yield 78% (0.9 g from 1.0 g) as a brown
solid; mp 135–137 ꢁC; nmax (KBr) 1707 (2ꢀCO), 2227 (CN)
cmꢂ1; 1H NMR (CDCl3, 200 MHz) d 1.98 (s, 3H, CH3), 2.35
(s, 3H, CH3), 4.69 (d, 1H, J¼11.8 Hz, CH), 5.21 (d, 1H,
J¼11.8 Hz, CH), 6.02 (s, 1H, ]CH), 6.19 (s, 1H, ]CH),
7.45–7.65 (m, 3H, ArH), 7.87 (d, 1H, J¼7.4 Hz, CH); 13C
NMR (CDCl3, 50 MHz) d 29.3, 30.0, 42.6, 72.0, 117.0,
121.4, 125.8, 129.0, 129.6, 131.3, 135.7, 150.3, 200.0,
200.3; mass (ES+) m/z 309 (M++Na); Anal. Calcd for
C15H14N2O4: C, 62.93; H, 4.93; N, 9.79. Found: C, 63.04;
H, 4.96; N, 9.65.
3. Conclusions
In summary, we have demonstrated a new alternate strategy
for the synthesis of highly functionalized quinolines from
easily accessible derivatives of Baylis–Hillman adducts,
which has general applicability. The SnCl2-mediated reduc-
tion of the nitro group initiates a highly regioselective intra-
molecular cyclization between the amino group and the
carbonyl moiety from the nucleophile introduced through
the SN2 substitution reaction. This study indicates that the
preference of the activated carbonyl group COR for cycliza-
tion has the following order: R¼Me>Ph>O-alkyl. We
believe that the quinoline derivatives generated during the
present study would serve as good building blocks for the
synthesis of quinoline-annulated ring systems.
4.2.3. 4-Benzoyl-2-methylene-3-(2-nitro-phenyl)-5-oxo-
hexanoic acid methyl ester (9a). Yield 81% (1.1 g from
1.0 g) as a brown solid; mp 102–104 ꢁC; nmax (KBr) 1679
(CO), 1724 (CO and CO2Me) cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 2.09 (s, 3H, CH3), 2.19 (s, 3H, CH3), 3.57 (s,
3H, CO2CH3), 3.71 (s, 3H, CO2CH3), 5.55–5.82 (m, 5H,
4ꢀCH and ]CH), 5.99 (s, 1H, ]CH), 6.18 (s, 1H,
]CH), 6.39 (s, 1H, ]CH), 7.21–7.72 (m, 16H, ArH),
7.92 (d, 1H, J¼11.8 Hz, ArH), 8.08 (d, 1H, J¼11.8 Hz,
ArH); 13C NMR (CDCl3, 75 MHz) d 26.8, 27.0, 40.1,
40.8, 50.7, 50.8, 64.8, 65.3, 123.4, 123.6, 126.6, 126.9,
127.4, 127.5, 127.7, 128.3, 128.6, 129.5, 131.0, 131.1,
131.8, 132.6, 132.8, 135.1, 135.3, 136.8, 137.5, 149.0,
149.1, 152.4, 164.7, 165.0, 189.7, 192.5, 200.7, 200.8;
mass (ES+) m/z 382.1 (M++1), 404.1 (M++Na); Anal. Calcd
for C21H19NO6: C, 66.13; H, 5.02; N, 3.67. Found: C, 66.10;
H, 4.97; N, 3.66.
4. Experimental
4.1. General
Melting points are uncorrected and were determined using
a hot stage apparatus containing silicon oil. IR spectra

S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
8743
4.2.4. 4-Benzoyl-3-(5-chloro-2-nitro-phenyl)-2-methyl-
ene-5-oxo-hexanoic acid methyl ester (9b). Yield 63%
(0.5 g from 0.6 g) as a brown semisolid; nmax (Neat) 1680
4.2.8. 4-Benzoyl-2-methylene-3-(6-nitro-benzo[1,3]-
dioxol-5-yl)-5-oxo-hexanenitrile (10c). Yield 81% (0.75 g
from 0.8 g) as a yellow solid; mp 189–191 ꢁC; nmax (KBr)
1
(CO), 1721 (CO and CO2Me) cmꢂ1; H NMR (CDCl3,
1676 (CO), 1722 (CO and CO2Me) cmꢂ1 1H NMR
;
300 MHz) d 2.11 (s, 3H, CH3), 2.17 (s, 3H, CH3), 3.59 (s,
6H, 2ꢀCO2CH3), 5.45–5.60 (m, 4H, 4ꢀCH), 5.65 (s, 2H,
2ꢀ]CH), 5.75 (s, 1H, ]CH), 6.22 (s, 1H, ]CH), 7.34
(d, 2H, J¼6.8 Hz, ArH), 7.49–7.76 (m, 10H, ArH), 8.07
(d, 4H, J¼7.2 Hz, ArH); 13C NMR (CDCl3, 50 MHz)
d 29.6, 30.0, 42.6, 43.2, 53.6, 53.7, 67.2, 67.7, 127.6,
127.7, 129.5, 127.5, 129.3, 129.9, 130.1, 130.3, 130.5,
131.7, 132.2, 135.5, 135.7, 136.3, 138.8, 139.6, 140.1,
149.9, 167.2, 167.5, 195.0, 202.9; mass (ES+) m/z 415.9
(M++1); Anal. Calcd for C21H18ClNO6: C, 60.66; H, 4.36;
N, 3.37. Found: C, 60.69; H, 4.44; N, 3.67.
(CDCl3, 300 Hz) d 1.99 (s, 3H, CH3), 5.42 (d, 1H,
J¼12.0 Hz, CH), 5.61 (s, 1H, J¼12.0 Hz, CH), 5.92 (s,
1H, ]CH), 6.17 (s, 3H, ]CH, CH2), 7.14 (s, 1H, ArH),
7.44 (s, 1H, ArH), 7.54–7.71 (m, 3H, ArH), 8.13 (d, 2H,
J¼9.0 Hz, ArH); 13C NMR (CDCl3, 50 MHz) d 28.5, 29.4,
43.0, 43.4, 66.1, 66.9, 103.6, 103.8, 106.8, 108.2, 117.3,
121.3, 121.7, 127.6, 128.6, 129.1, 129.5, 129.6, 134.8,
135.0, 135.7, 136.6, 144.4, 148.1, 152.3, 192.7, 200.1;
mass (ES+) m/z 393.0 (M++1), 415.0 (M++Na); Anal. Calcd
for C21H16N2O6: C, 64.28; H, 4.11; N, 7.14. Found: C,
64.21; H, 4.19; N, 7.31.
4.2.5. 4-Benzoyl-2-methylene-3-(6-nitro-benzo[1,3]-
dioxol-5-yl)-5-oxo-hexanoic acid methyl ester (9c). Yield
69% (0.9 g from 1.0 g) as a brown solid; mp 127–129 ꢁC;
4.2.9. 2-Acetyl-4-methylene-3-(2-nitro-phenyl)-pentane-
dioic acid 1-ethyl ester 5-methyl ester (11a). Yield 85%
(0.80 g from 0.75 g) as a brown oil; nmax (Neat) 1722 (CO,
1
nmax (KBr) 1680 (CO), 1721 (CO and CO2Me) cmꢂ1; H
CO2Me, CO2Et) cmꢂ1 1H NMR (CDCl3, 300 MHz)
;
NMR (CDCl3, 300 MHz) d 2.12 (s, 3H, CH3), 2.19 (s, 3H,
CH3), 3.62 (s, 3H, CO2CH3), 3.75 (s, 3H, CO2CH3), 5.58–
5.79 (m, 4H, 3ꢀCH and ]CH), 5.96–6.03 (m, 2H, CH
and ]CH), 6.10 (s, 4H, 2ꢀOCH2O), 6.20 (s, 1H, ]CH),
6.40 (s, 1H, ]CH), 7.01 (s, 1H, ArH), 7.06 (s, 1H, ArH),
7.28–7.30 (m, 4H, ArH), 7.43–7.62 (m, 6H, ArH), 7.97 (d,
1H, J¼12.0 Hz, ArH), 8.08 (d, 1H, J¼12.0 Hz, ArH); 13C
NMR (CDCl3, 50 MHz) d 14.6, 21.4, 28.5, 28.7, 41.5,
42.3, 52.5, 60.8, 66.7, 67.1, 103.2, 103.4, 106.1, 106.3,
109.8, 127.9, 129.2, 129.5, 130.1, 134.6, 136.9, 139.4,
144.8, 151.6, 166.5, 194.2, 202.7; mass (ES+) m/z 425.9
(M++1), 448.1 (M++Na); Anal. Calcd for C22H19NO8: C,
62.12; H, 4.50; N, 3.29. Found: C, 62.00; H, 4.41; N, 3.11.
d 1.03 (t, 3H, J¼7.5 Hz, CH3), 1.26 (t, 3H, J¼7.5 Hz,
CH3), 2.18 (s, 3H, CH3), 2.31 (s, 3H, CH3), 3.68 (s, 3H,
CO2CH3), 3.69 (s, 3H, CO2CH3), 3.98 (q, 2H, J¼7.0 Hz,
CH2), 4.20 (q, 2H, J¼7.0 Hz, CH2), 4.57 (d, 1H,
J¼12.0 Hz, CH), 4.63 (d, 1H, J¼9.0 Hz, CH), 5.32 (d, 2H,
J¼12.0 Hz, CH), 5.88 (s, 1H, ]CH), 5.92 (s, 1H, ]CH),
6.35 (s, 1H, ]CH), 6.36 (s, 1H, ]CH), 7.35–7.41 (m, 2H,
ArH), 7.51–7.62 (m, 4H, ArH), 7.74–7.79 (m, 2H, ArH);
13C NMR (CDCl3, 50 MHz) d 14.0, 14.4, 29.6, 29.8, 41.0,
41.1, 50.5, 52.5, 62.2, 62.3, 63.4, 63.5, 125.0, 125.1,
128.2, 128.6, 129.1, 130.4, 130.6, 132.8, 133.7, 138.8,
139.2, 150.7, 166.3, 166.7, 167.6, 168.1, 210.2, 201.3;
mass (ES+) m/z 349.9 (M++1); Anal. Calcd for
C17H19NO7: C, 58.45; H, 5.48; N, 4.01. Found: C, 58.36;
H, 5.44; N, 3.98.
4.2.6. 4-Benzoyl-2-methylene-3-(2-nitro-phenyl)-5-oxo-
hexanenitrile (10a). Yield 78% (1.1 g from 1.0 g) as a brown
solid; mp 102–104 ꢁC; nmax (KBr) 1674 (CO), 1724 (CO),
2221 (CN) cmꢂ1; 1H NMR (CDCl3, 200 Hz) d 1.95 (s, 3H,
CH3), 2.25 (s, 3H, CH3), 5.41–5.53 (m, 4H, 4ꢀCH), 5.91
(s, 1H, ]CH), 6.09 (s, 1H, ]CH), 6.17 (s, 1H, ]CH),
6.30 (s, 1H, ]CH), 7.43–8.11 (m, 16H, ArH), 8.12–8.15
(d, 2H, J¼7.2 Hz, ArH); 13C NMR (CDCl3, 50 MHz)
d 28.9, 29.6, 43.1, 43.5, 65.8, 66.7, 117.4, 117.5, 121.3,
121.7, 125.7, 128.6, 129.1, 129.3, 129.5, 129.6, 131.3,
133.6, 133.7, 134.8, 135.1, 135.7, 135.9, 136.5, 150.4,
192.5, 192.8, 199.9, 200.2; mass (ES+) m/z 349.0 (M++1);
Anal. Calcd for C20H16N2O4: C, 68.96; H, 4.63; N, 8.04.
Found: C, 69.15; H, 4.55; N, 7.90.
4.2.10. 2-Acetyl-3-(5-chloro-2-nitro-phenyl)-4-methyl-
ene-pentanedioic acid 1-ethyl ester 5-methyl ester
(11b). Yield 75% (1.0 g from 0.9 g) as a brown oil; nmax
(Neat) 1720 (CO, CO2Me, CO2Et) cmꢂ1
;
1H NMR
(CDCl3, 200 MHz) d 1.06 (t, 3H, J¼7.0 Hz, CH2CH3),
1.24 (t, 3H, J¼7.0 Hz, CH2CH3), 2.20 (s, 3H, CH3), 2.26
(s, 3H, CH3), 3.68 (s, 3H, CO2CH3), 3.69 (s, 3H,
CO2CH3), 3.99–4.21 (2q merged, 4H, 2ꢀCH2CH3), 4.15
(d, 1H, J¼12.0 Hz, CH), 4.19 (d, 1H, J¼12.0 Hz, CH),
5.34 (dd, 2H, J1¼12.0 Hz, J1¼3.4 Hz, 2ꢀCH), 5.90 (s,
1H, ]CH), 5.96 (s, 1H, ]CH), 6.38 (s, 2H, 2ꢀ]CH),
7.32 (d, 2H, J¼8.4 Hz, ArH), 7.53 (d, 2H, J¼9.6 Hz,
ArH), 7.75 (dd, 2H, J1¼8.4 Hz, J2¼2.2 Hz, ArH); 13C
NMR (CDCl3, 50 MHz) d 14.1, 14.4, 26.1, 29.7, 30.0,
40.9, 42.6, 58.1, 61.9, 62.4, 63.0, 63.3, 126.6, 128.6,
128.9, 129.6, 130.4, 131.0, 135.7, 136.1, 138.2, 138.6,
139.1, 148.4, 166.2, 166.5, 167.4, 167.8, 200.7, 200.8;
mass (ES+) m/z 383.9 (M++1); HR-EIMS calculated for
C17H18ClNO7: 383.0772, found: 383.0770.
4.2.7. 4-Benzoyl-3-(5-chloro-2-nitro-phenyl)-2-methyl-
ene-5-oxo-hexanenitrile (10b). Yield 71% (1.1 g from
1.15 g) as a white solid; mp 183–185 ꢁC; nmax (KBr) 1672
(CO), 1723 (CO), 2221 (CN) cmꢂ1 1H NMR (CDCl3,
;
200 Hz) d 1.99 (s, 3H, CH3), 2.25 (s, 3H, CH3), 5.36–5.50
(m, 4H, 4ꢀCH), 5.94 (s, 1H, ]CH), 6.13 (s, 1H, ]CH),
6.18 (s, 1H, ]CH), 6.32 (s, 1H, ]CH), 7.48–7.91 (m,
14H, ArH), 8.15 (d, 2H, J¼7.6 Hz, ArH); 13C NMR
(CDCl3, 50 MHz) d 29.4, 29.9, 42.9, 43.3, 65.5, 66.4,
117.3, 120.6, 121.1, 127.2, 129.1, 129.3, 129.6, 133.9,
134.5, 135.0, 135.2, 136.2, 136.5, 140.0, 140.2, 148.6,
192.3, 192.5, 199.3, 199.7; mass (ES+) m/z 405.0
(M++Na); Anal. Calcd for C20H15ClN2O4: C, 62.75; H,
3.95; N, 7.32. Found: C, 62.95; H, 4.02; N, 7.33.
4.2.11. 2-Acetyl-4-methylene-3-(6-nitro-benzo[1,3]-
dioxol-5-yl)-pentanedioic acid 1-ethyl ester 5-methyl
ester (11c) (single diastereoisomer). Yield 77% (0.75 g
from 0.8 g) as a white solid; mp 125–127 ꢁC; nmax (KBr)
1710 (CO, CO2Me, CO2Et) cmꢂ1 1H NMR (CDCl3,
;
200 MHz) d 1.10 (t, 3H, J¼7.0 Hz, CH2CH3), 2.28 (s, 3H,
CH3), 3.68 (s, 3H, CO2CH3), 4.01 (q, 2H, J¼7.0 Hz,

8744
S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
CH2CH3), 4.49 (d, 1H, J¼11.8 Hz, CH), 5.38 (d, 1H,
J¼11.8 Hz, CH), 5.86 (s, 1H, ]CH), 6.07 (s, 2H,
OCH2O), 6.34 (s, 1H, ]CH), 6.97 (s, 1H, ArH), 7.31 (s,
1H, ArH); 13C NMR (CDCl3, 50 MHz) d 14.1, 29.7, 40.9,
52.8, 62.2, 63.4, 103.4, 106.0, 109.0, 128.9, 130.3, 138.9,
144.6, 147.2, 151.6, 166.7, 167.6, 201.3; mass (ES+) m/z
393.9 (M++1); Anal. Calcd for C18H19NO9: C, 54.96; H,
4.87; N, 3.56. Found: C, 55.12; H, 4.99; N, 3.67.
(M++Na); HR-EIMS calculated for C17H16N2O7:
360.0958, found: 360.0961.
4.2.15. 2-Benzoyl-4-methylene-3-(2-nitro-phenyl)-pentane-
dioic acid 1-ethyl ester 5-methyl ester (13a). Yield 82%
(1.2 g from 1.0 g) as a brown oil; nmax (Neat) 1691 (CO),
1729 (CO2Me and CO2Et) cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 0.94 (t, 3H, J¼6.0 Hz, CH2CH3), 1.15 (t, 3H,
J¼6.0 Hz, CH2CH3), 3.60 (s, 3H, CH3), 3.72 (s, 3H, CH3),
3.82 (q, 2H, J¼6.0 Hz, CH2CH3), 4.11 (q, 2H, J¼6.0 Hz,
CH2CH3), 5.43–5.63 (m, 3H, 3ꢀCH), 5.72 (d, 1H,
J¼12.0 Hz, CH), 5.81 (s, 1H, ]CH), 6.06 (s, 1H, ]CH),
6.26 (s, 1H, ]CH), 6.39 (s, 1H, ]CH), 7.37–7.62 (m,
11H, ArH), 7.69–7.72 (m, 1H, ArH), 7.76–7.78 (m, 2H,
ArH), 7.97–8.00 (m, 2H, ArH), 8.08–8.11 (m, 2H, ArH);
13C NMR (CDCl3, 50 MHz) d 13.9; 14.3, 42.1, 43.1, 52.4,
57.6, 60.8, 62.3, 125.0, 125.1, 128.2, 128.5, 128.8, 129.1,
129.2, 130.3, 131.2, 132.7, 133.3, 133.4, 134.3, 136.4,
136.6, 138.1, 138.8, 150.9, 166.6, 167.6, 168.0, 192.7;
mass (ES+) m/z 411.9 (M++1), 434.1 (M++Na); Anal. Calcd
for C22H21NO7: C, 64.23; H, 5.14; N, 3.40. Found: C, 64.22;
H, 5.01; N, 3.32.
4.2.12. 2-Acetyl-4-cyano-3-(2-nitro-phenyl)-pent-4-enoic
acid ethyl ester (12a). Yield 78% (1.0 g from 1.0 g) as
a brown solid; mp 85–87 ꢁC; nmax (KBr) 1723 (CO and
1
CO2Et), 2226 (CN) cmꢂ1; H NMR (CDCl3, 200 MHz)
d 0.96 (t, 3H, J¼7.0 Hz, CH2CH3), 1.31 (t, 3H, J¼7.0 Hz,
CH2CH3), 2.12 (s, 3H, CH3), 2.39 (s, 3H, CH3), 3.92 (q,
2H, J¼7.0 Hz, CH2CH3), 4.25 (q, 2H, J¼7.0 Hz,
CH2CH3), 4.41 (d, 1H, J¼6.8 Hz, CH), 4.47 (d, 1H,
J¼6.8 Hz, CH), 5.06 (d, 2H, J¼11.8 Hz, 2ꢀCH), 6.05 (s,
1H, ]CH), 6.06 (s, 1H, ]CH), 6.24 (s, 1H, ]CH), 6.28
(s, 2H, 2ꢀ]CH), 7.42–7.48 (m, 2H, ArH), 7.56–7.65 (m,
4H, ArH), 7.83–7.88 (m, 2H, ArH); 13C NMR (CDCl3,
75 MHz) d 14.5, 30.1, 42.5, 63.0, 63.1, 117.6, 121.6,
125.7, 128.3, 129.3, 132.1, 133.7, 135.5, 166.6, 199.2;
mass (ES+) m/z 317.1 (M++1), 339.1 (M++Na); Anal. Calcd
for C16H16N2O5: C, 60.75; H, 5.10; N, 8.86. Found: C,
60.88; H, 5.18; N, 8.99.
4.2.16. 2-Ethoxycarbonyl-4-methoxycarbonyl-3-(2-
nitro-phenyl)-pent-4-enoic acid ethyl ester (14a). Yield
74% (1.0 g from 1.0 g) as brown oil; nmax (Neat) 1727
(CO2Me and 2ꢀCO2Et) cmꢂ1
;
1H NMR (CDCl3,
4.2.13. 2-Acetyl-3-(5-chloro-2-nitro-phenyl)-4-cyano-
pent-4-enoic acid ethyl ester (12b). Yield 64% (0.8 g
from 1.0 g) as a white solid; mp 119–121 ꢁC; nmax (KBr)
300 MHz) d 0.85 (t, 3H, J¼7.0 Hz, CH2CH3), 1.05 (t, 3H,
J¼7.0 Hz, CH2CH3), 3.68 (s, 6H, CO2CH3), 4.01 (q, 2H,
J¼7.0 Hz, CH2CH3), 4.20 (q, 2H, J¼7.0 Hz, CH2CH3),
4.41 (d, 1H, J¼12.0 Hz, CH), 5.27 (d, 1H, J¼12.0 Hz,
CH), 5.89 (s, 1H, ]CH), 6.38 (s, 1H, ]CH), 7.35–7.41
(m, 1H, ArH), 7.51–7.62 (m, 2H, ArH), 7.76 (d, 1H,
J¼7.5.0 Hz, ArH); 13C NMR (CDCl3, 50 MHz) d 14.0,
14.3, 41.4, 52.5, 55.9, 62.1, 124.9, 126.7, 128.0, 128.5,
130.4, 132.8, 133.4, 139.4, 150.7, 166.2, 167.4, 167.7;
mass (ES+) m/z 379.9 (M++1), 402.0 (M++Na); Anal. Calcd
for C18H21NO8: C, 56.99; H, 5.58; N, 3.69. Found: C, 57.17;
H, 5.66; N, 3.85.
1708 (CO), 1738 (CO2Et), 2228 (CN) cmꢂ1 1H NMR
;
(CDCl3, 200 MHz) d 1.03 (t, 3H, J¼7.0 Hz, CH2CH3),
1.32 (t, 3H, J¼7.0 Hz, CH2CH3), 2.17 (s, 3H, CH3), 2.41
(s, 3H, CH3), 3.97 (q, 2H, J¼7.0 Hz, CH2CH3), 4.29 (q,
2H, J¼7.0 Hz, CH2CH3), 4.37 (d, 1H, J¼8.2 Hz, CH),
4.43 (d, 1H, J¼8.0 Hz, CH), 5.10 (dd, 2H, J1¼11.6 Hz,
J2¼3.6 Hz, 2ꢀCH), 6.08 (s, 2H, 2ꢀ]CH), 6.25 (s, 1H,
]CH), 6.28 (s, 1H, ]CH), 7.39–7.44 (m, 2H, ArH), 7.52
(s, 1H, ArH), 7.59 (s, 1H, ArH), 7.85 (dd, 2H, J1¼8.8 Hz,
J2¼2.8 Hz, 2ꢀCH); 13C NMR (CDCl3, 50 MHz) d 14.0,
14.4, 30.1, 30.9, 41.8, 42.2, 62.7, 62.8, 63.0, 63.1, 117.1,
120.7, 121.1, 127.0, 127.2, 128.5, 129.1, 129.4, 134.5,
135.8, 136.6, 140.0, 148.6, 148.7, 165.8, 166.3, 198.8,
199.0; mass (ES+) m/z 351.1 (M++1), 373.0 (M++Na);
HR-EIMS calculated for C16H15ClN2O5: 350.0670, found:
350.0671.
4.2.17. 2-[2-Cyano-1-(2-nitro-phenyl)-allyl]-malonic acid
diethyl ester (15a). Yield 85% (1.25 g from 1.0 g) as a white
solid; mp 78–80 ꢁC; nmax (KBr) 1739 (2ꢀCO2Et), 2226
1
(CN) cmꢂ1; H NMR (CDCl3, 200 MHz) d 0.99 (t, 3H,
J¼7.0 Hz, CH2CH3), 1.30 (t, 3H, J¼7.0 Hz, CH2CH3),
3.93 (q, 2H, J¼7.0 Hz, CH2CH3), 4.10–4.30 (m, 3H,
CH2CH3 and 1ꢀCH), 5.01 (d, 1H, J¼12.0 Hz, CH), 6.07
(s, 1H, ]CH), 6.26 (s, 1H, ]CH), 7.43–7.51 (m, 1H,
ArH), 7.65 (d, 2H, J¼4.0 Hz, ArH), 7.87 (m, 1H,
J¼8.0 Hz, ArH); mass (ES+) m/z 347.2 (M++1), 369.1
(M++Na); Anal. Calcd for C17H18N2O6: C, 58.96; H, 5.24;
N, 8.09. Found: C, 59.08; H, 5.49; N, 7.87.
4.2.14. 2-Acetyl-4-cyano-3-(6-nitro-benzo[1,3]dioxol-5-
yl)-pent-4-enoic acid ethyl ester (12c). Yield 79% (0.68 g
from 0.7 g) as a yellow solid; mp 130–132 ꢁC; nmax (KBr)
1710 (CO), 1743 (CO2Et), 2225 (CN) cmꢂ1 1H NMR
;
(CDCl3, 300 MHz) d 1.07 (t, 3H, J¼7.0 Hz, CH2CH3),
1.32 (t, 3H, J¼7.0 Hz, CH2CH3), 2.16 (s, 3H, CH3), 2.39
(s, 3H, CH3), 4.00 (q, 2H, J¼7.0 Hz, CH2CH3), 4.26 (q,
2H, J¼7.0 Hz, CH2CH3), 4.32 (d, 1H, J¼9.0 Hz, CH),
4.45 (d, 1H, J¼9.0 Hz, CH), 5.19 (d, 2H, J¼12.0 Hz,
2ꢀCH), 6.04 (s, 1H, ]CH), 6.08 (s, 1H, ]CH), 6.14 (s,
4H, 2ꢀOCH2O), 6.22 (s, 1H, ]CH), 6.28 (s, 1H, ]CH),
6.95 (s, 1H, ArH), 7.02 (s, 1H, ArH), 7.39 (s, 1H, ArH),
7.41 (s, 1H, ArH); 13C NMR (CDCl3, 50 MHz) d 14.0,
14.4, 29.9, 30.8, 41.9, 42.6, 62.9, 63.2, 103.7, 106.4,
106.7, 107.1, 117.3, 121.2, 121.6, 128.3, 135.2, 136.1,
147.8, 152.2, 165.9, 166.6, 199.1; mass (ES+) m/z 383.1
4.3. General procedure for SnCl2-mediated reactions
To a solution of an appropriate nitro derivative (1.0 equiv) in
methanol (10 mL) was added anhydrous SnCl2 (5.0 equiv)
and the reaction mixture was heated at reflux in a nitrogen
atmosphere for 1.0 h. The excess solvent was removed and
the residue was made basic with NaHCO3 solution and taken
in EtOAc (50 mL). The resultant suspension was passed
through a bed of Celite and the organic layer separated, dried
(Na2SO4), and evaporated to yield the crude product, which

S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
8745
was purified by silica gel column chromatography using
hexanes/EtOAc (80–70:20–30, v/v) to yield corresponding
products in 50–86% yield.
7.29 (m, 1H, ArH), 7.35 (d, 1H, J¼3.0 Hz, ArH), 7.42–
7.52 (m, 5H, ArH), 9.62 (s, 1H, NH); 13C NMR
(CDCl3+DMSO-d6, 50 MHz) d 20.6, 43.2, 102.4, 107.3,
111.6, 117.1, 118.6, 122.8, 125.9, 126.8, 127.9, 128.3,
128.8, 129.6, 131.0, 136.0, 142.7, 149.7, 194.4; mass
(ES+) m/z 335.1 (M++1); Anal. Calcd for C20H15ClN2O:
C, 71.75; H, 4.52; N, 8.37. Found: C, 72.01; H, 4.20;
N, 8.55.
4.3.1. 2-(3-Benzoyl-2-methyl-quinolin-4-yl)-acrylic acid
methyl ester (16a). Yield 67% (0.35 g from 0.6 g) as a white
solid; mp 164–166 ꢁC; nmax (KBr) 1661 (CO), 1727
1
(CO2Me) cmꢂ1; H NMR (CDCl3, 300 MHz) d 2.61 (s,
3H, CH3), 3.54 (s, 3H, CO2CH3), 5.81 (d, 1H, J¼0.6 Hz,
]CH), 6.66 (d, 1H, J¼0.6 Hz, ]CH), 7.43 (t, 2H,
J¼8.6 Hz, ArH), 7.54–7.59 (m, 2H, ArH), 7.66–7.68 (m,
1H, ArH), 7.74–7.79 (m, 3H, ArH), 8.13 (d, 1H,
J¼6.0 Hz, ArH); 13C NMR (CDCl3, 75 MHz) d 22.7, 50.9,
123.7, 124.0, 125.5, 127.4, 127.6, 128.4, 129.1, 131.3,
132.1, 132.8, 134.1, 135.3, 139.8, 145.9, 153.4, 164.0,
195.9; mass (FAB+) m/z 332 (M++1); HR-EIMS calculated
for C21H17NO3: 331.1208, found: 331.1210.
4.3.6. 2-(7-Benzoyl-6-methyl-[1,3]dioxolo[4,5-g]quinolin-
8-yl)-acrylonitrile (18c). Yield 64% (0.36 g from 0.65 g) as
a yellow solid; mp 188–190 ꢁC; nmax (KBr) 1664 (CO), 2223
1
(CN) cmꢂ1; H NMR (CDCl3, 200 MHz) d 2.53 (s, 3H,
CH3), 6.02 (s, 1H, ]CH), 6.17 (s, 2H, OCH2O), 6.32 (s,
1H, ]CH), 7.18 (s, 1H, ArH), 7.42–7.53 (m, 3H, ArH),
7.61–7.64 (m, 1H, ArH), 7.76 (d, 2H, J¼9.4 Hz, ArH); 13C
NMR (CDCl3, 50 MHz) d 24.0, 100.2, 102.7, 106.4, 116.9,
117.9, 120.4, 129.6, 130.0, 131.2, 135.0, 136.0, 137.0,
139.1, 146.9, 149.4, 152.2, 153.1, 197.1; mass (ES+) m/z
343.3 (M++1); HR-EIMS calculated for C21H14N2O3:
342.1004, found: 342.1009.
4.3.2. 2-(3-Benzoyl-6-chloro-2-methyl-quinolin-4-yl)-
acrylic acid methyl ester (16b). Yield 61% (0.12 g from
0.25 g) as a white solid; mp 134–136 ꢁC; nmax (KBr) 1660
1
(CO), 1714 (CO2Me) cmꢂ1; H NMR (CDCl3, 200 MHz)
d 2.57 (s, 3H, CH3), 3.56 (s, 3H, CO2CH3), 5.81 (s, 1H,
]CH), 6.67 (s, 1H, ]CH), 7.40–7.47 (m, 2H, ArH),
7.57–7.77 (m, 5H, ArH), 8.04 (d, 1H, J¼9.0 Hz, ArH); 13C
NMR (CDCl3, 50 MHz) d 24.5, 52.8, 126.2, 129.2, 130.1,
131.1, 131.6, 133.1, 133.8, 134.2, 134.7, 135.3, 136.9,
140.6, 146.3, 155.5, 165.4, 197.2; mass (ES+) m/z 366.2
(M++1); HR-EIMS calculated for C21H16ClNO3:
365.0819, found: 365.0820.
4.3.7. 4-(1-Methoxycarbonyl-vinyl)-2-methyl-quinoline-
3-carboxylic acid ethyl ester (19a). Yield 86% (0.44 g
from 0.6 g) as a brown oil; nmax (Neat) 1727 (CO2Me and
1
CO2Et) cmꢂ1; H NMR (CDCl3, 300 MHz) d 1.34 (t, 3H,
J¼7.2 Hz, CH2CH3), 2.82 (s, 3H, CH3), 3.73 (s, 3H,
CO2CH3), 4.34 (q, 2H, J¼7.2 Hz, CH2CH3), 5.81 (d, 1H,
J¼0.6 Hz, ]CH), 6.81 (s, 1H, ]CH), 7.52–7.56 (m, 1H,
ArH), 7.70–7.79 (m, 2H, ArH), 8.09 (d, 1H, J¼8.2 Hz,
ArH); 13C NMR (CDCl3, 50 MHz) d 14.3, 24.6, 52.9,
62.1, 125.3, 126.1, 126.9, 127.1, 129.3, 131.06, 137.2,
143.1, 147.9, 155.7, 166.0, 168.1; mass (ES+) m/z 300.3
(M++1), 322.0 (M++Na); HR-EIMS calculated for
C17H17NO4: 299.1158, found: 299.1160.
4.3.3. 2-(7-Benzoyl-6-methyl-[1,3]dioxolo[4,5-g]quinolin-
8-yl)-acrylic acid methyl ester (16c). Yield 50% (0.26 g
from 0.6 g) as a white solid; mp 188–189 ꢁC; nmax (KBr)
1665 (CO), 1723 (CO2Me) cmꢂ1 1H NMR (CDCl3,
;
200 MHz) d 2.51 (s, 3H, CH3), 3.54 (s, 3H, CO2CH3),
5.76 (s, 1H, ]CH), 6.12 (s, 2H, OCH2O), 6.60 (s, 1H,
]CH), 6.89 (s, 1H, ArH), 7.39–7.45 (m, 3H, ArH), 7.54–
7.60 (m, 1H, ArH), 7.75 (d, 2H, J¼7.4 Hz, ArH); 13C
NMR (CDCl3, 50 MHz) d 24.1, 52.6, 101.1, 102.3, 106.0,
122.2, 129.0, 130.1, 134.3, 137.4, 140.3, 146.5, 148.6,
151.6, 152.7, 165.7, 198.0; mass (FAB+) m/z 376 (M++1);
HR-EIMS calculated for C22H17NO5: 375.1107, found:
375.1108.
4.3.8. 6-Chloro-4-(1-methoxycarbonyl-vinyl)-2-methyl-
quinoline-3-carboxylic acid ethyl ester (19b). Yield 68%
(0.36 g from 0.6 g) as a brown solid; mp 124–126 ꢁC; nmax
1
(KBr) 1729 (CO2Me and CO2Et) cmꢂ1; H NMR (CDCl3,
300 MHz) d 1.33 (t, 3H, J¼7.2 Hz, CH2CH3), 2.78 (s, 3H,
CH3), 3.75 (s, 3H, CO2CH3), 4.35 (q, 2H, J¼7.2 Hz,
CH2CH3), 5.81 (s, 1H, ]CH), 6.82 (s, 1H, ]CH), 7.65–
7.68 (m, 2H, ArH), 7.99 (d, 1H, J¼9.6 Hz, ArH); 13C
NMR (CDCl3, 50 MHz) d 13.8, 24.1, 52.5, 61.7, 124.4,
125.6, 127.1, 130.6, 131.1, 131.4, 132.5, 136.2, 141.6,
145.9, 155.6, 165.2, 167.3; mass (ES+) m/z 334.1 (M++1);
HR-EIMS calculated for C17H16ClNO4: 333.0768, found:
333.0770.
4.3.4. 2-(3-Benzoyl-2-methyl-1,4-dihydro-quinolin-4-yl)-
acrylonitrile (17a). Yield 71% (0.12 g from 0.2 g) as a white
solid; mp 188–189 ꢁC; nmax (KBr) 1664 (CO), 2226
1
(CO2Me) cmꢂ1; H NMR (CDCl3, 200 MHz) d 2.51 (s,
3H, CH3), 5.02 (s, 1H, CH), 5.68 (s, 1H, ]CH), 5.73 (s,
1H, ]CH), 6.76 (s, 1H, NH exchangeable with D2O),
6.80–6.83 (m, 1H, ArH), 7.08–7.11 (m, 1H, ArH), 7.20–
7.24 (m, 2H, ArH), 7.39–7.44 (m, 3H, ArH), 7.45–7.49 (m,
2H, ArH); mass (ES+) m/z 301.1 (M++1); Anal. Calcd for
C20H16N2O: C, 79.98; H, 5.37; N, 9.33. Found: C, 80.09;
H, 5.45; N, 9.55.
4.3.9. 8-(1-Methoxycarbonyl-vinyl)-6-methyl-[1,3]di-
oxolo[4,5-g]quinoline-7-carboxylic acid ethyl ester (19c).
Yield 68% (0.36 g from 0.6 g) as a pale yellow oil; nmax
(Neat) 1727 (CO2Me and CO2Et); 1H NMR (CDCl3,
200 MHz) d 1.31 (t, 3H, J¼7.0 Hz, CH2CH3), 2.73 (s, 3H,
CH3), 3.74 (s, 3H, CO2CH3), 4.31 (q, 2H, J¼7.0 Hz,
CH2CH3), 5.76 (s, 1H, ]CH), 6.10 (s, 2H, CH2), 6.74 (s,
1H, ]CH), 6.95 (s, 1H, ArH), 7.33 (s, 1H, ArH); 13C
NMR (CDCl3, 50 MHz) d 14.3, 24.3, 52.9, 61.9, 101.4,
102.4, 105.9, 122.1, 130.7, 137.8, 144.4, 148.5, 152.0,
153.7, 166.1; mass (ES+) m/z 344.1 (M++1); Anal. Calcd
for C18H17NO6: C, 67.30; H, 4.76; N, 6.20. Found: C,
67.03; H, 4.95; N, 5.95.
4.3.5. 2-(3-Benzoyl-6-chloro-2-methyl-1,4-dihydro-qui-
nolin-4-yl)-acrylonitrile (17b). Yield 65% (0.28 g from
0.5 g) as a yellow solid; mp 192–194 ꢁC; nmax (KBr) 1665
1
(CO), 2227 (CN) cmꢂ1; H NMR (DMSO-d6, 300 MHz)
d 2.50 (s, 3H, CH3), 4.92 (s, 1H, CH), 5.74 (s, 1H, ]CH),
5.83 (s, 1H, ]CH), 6.99 (d, 1H, J¼9.0 Hz, ArH), 7.27–

8746
S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
4.3.10. 4-(1-Cyano-vinyl)-2-methyl-quinoline-3-carb-
oxylic acid ethyl ester (20a). Yield 65% (0.35 g from
0.65 g) as a brown oil; nmax (Neat) 1728 (CO2Me), 2228
CH), 4.13–4.20 (q merged with d, 3H, CH2CH3 and CHC–
C]CH2), 5.37 (d, 1H, J¼0.6 Hz, ]CH), 6.40 (d, 1H,
J¼0.6 Hz, ]CH), 7.05–7.12 (m, 1H, ArH), 7.37–7.45 (m,
2H, ArH), 7.51 (d, 1H, J¼7.5 Hz, ArH), 8.98 (br s, 1H,
NH); 13C NMR (CDCl3, 75 MHz) d 12.7, 40.0, 50.8, 51.0,
60.8, 112.8, 121.6, 123.4, 126.7, 127.5, 127.9, 135.7,
136.8, 159.4, 166.0, 166.4; mass (ES+) m/z 304 (M++1);
Anal. Calcd for C16H17NO5: C, 63.36; H, 5.65; N, 4.62.
Found: C, 63.52; H, 5.67; N, 4.70.
1
(CN) cmꢂ1; H NMR (CDCl3, 300 MHz) d 1.43 (t, 3H,
J¼7.2 Hz, CH2CH3), 2.80 (s, 3H, CH3), 4.45 (q, 2H,
J¼7.2 Hz, CH2CH3), 6.13 (s, 1H, ]CH), 6.55 (s, 1H,
]CH), 7.59–7.66 (m, 1H, ArH), 7.70–7.85 (m, 1H, ArH),
7.93 (d, 1H, J¼8.4 Hz, ArH), 8.09 (d, 1H, J¼8.4 Hz,
ArH); 13C NMR (CDCl3, 50 MHz) d 14.4, 24.4, 30.1,
62.7, 116.9, 118.6, 123.5, 125.0, 128.1, 129.8, 131.6,
137.3, 148.1, 155.7, 165.6; mass (ES+) m/z 267.2 (M++1),
289.0 (M++Na); HR-EIMS calculated for C16H14N2O2:
266.1105, found: 266.1107.
4.3.15. 4-(1-Cyano-vinyl)-2-oxo-1,2,3,4-tetrahydro-quino-
line-3-carboxylic acid ethyl ester (24a). Yield 51%
(0.3 g from 0.85 g) as a brown oil; nmax (Neat) 1671
(CONH), 1739 (CO2Et), 2227 (CN) cmꢂ1 1H NMR
;
4.3.11. 8-(1-Cyano-vinyl)-6-methyl-[1,3]dioxolo[4,5-g]-
quinoline-7-carboxylic acid ethyl ester (20c). Yield 50%
(0.07 g from 0.18 g) as a pale yellow solid; mp 128–
(CDCl3, 300 MHz) d 1.18 (t, 3H, J¼7.2 Hz, CH2CH3),
3.96 (d, 1H, J¼7.5 Hz, CHCO2Et), 4.17 (q, 2H, J¼7.1 Hz,
CH2CH3), 4.28 (d, 1H, J¼7.5 Hz, CHC–C]CH2), 5.73 (d,
1H, J¼0.6 Hz, ]CH), 6.14 (s, 1H, ]CH), 7.18–7.21 (m,
2H, ArH), 7.40–7.44 (m, 1H, ArH), 7.52 (d, 1H,
J¼8.0 Hz, ArH), 9.21 (br s, 1H, NH); 13C NMR (CDCl3,
75 MHz) d 12.7, 42.4, 49.9, 61.3, 113.1, 115.2, 118.3,
119.8, 123.7, 126.5, 128.5, 132.9, 135.4, 158.7, 165.5;
mass (ES+) m/z 271.1 (M++1); Anal. Calcd for
C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C,
66.68; H, 5.45; N, 10.19.
1
130 ꢁC; nmax (KBr) 1710 (CO2Et), 2225 (CN) cmꢂ1; H
NMR (CDCl3, 200 MHz) d 1.43 (t, 3H, J¼7.2 Hz,
CH2CH3), 2.72 (s, 3H, CH3), 4.42 (q, 2H, J¼7.2 Hz,
CH2CH3), 6.07 (s, 1H, ]CH), 6.15 (s, 2H, OCH2O), 6.49
(s, 1H, ]CH), 7.15 (s, 1H, ArH), 7.35 (s, 1H, ArH); 13C
NMR (CDCl3, 50 MHz) d 14.3, 24.0, 62.5, 100.3, 102.7,
106.2, 117.0, 119.0, 120.5, 125.3, 136.9, 147.0, 149.3,
152.4, 153.5, 167.8, 183.7; mass (ES+) m/z 311.1 (M++1);
Anal. Calcd for C17H14N2O4: C, 65.80; H, 4.55; N, 9.03.
Found: C, 65.77; H, 4.49; N, 8.81.
Acknowledgements
4.3.12. 6-Chloro-4-(1-cyano-vinyl)-2-methyl-1,4-dihy-
dro-quinoline-3-carboxylic acid ethyl ester (21b). Yield
60% (0.15 g from 0.3 g) as a white solid; mp 127–129 ꢁC;
Two of the authors (S.M. and V.S.) gratefully acknowledge
the financial support from CSIR, N. Delhi in the form of
fellowship. This work was supported by the grant under
DST project.
1
nmax (KBr) 1717 (CO2Me), 2218 (CN) cmꢂ1; H NMR
(CDCl3, 300 MHz) d 1.30 (t, 3H, J¼7.2 Hz, CH2CH3),
2.44 (s, 3H, CH3), 4.19 (q, 2H, J¼7.2 Hz, CH2CH3), 4.85
(s, 1H, CH), 5.69 (s, 1H, ]CH), 5.75 (s, 1H, ]CH), 6.39
(s, 1H, NH exchangeable with D2O), 6.68 (d, 1H,
J¼9.0 Hz, ArH), 7.11–7.15 (m, 2H, ArH); 13C NMR
(CDCl3, 50 MHz) d 14.8, 20.9, 43.9, 60.23, 93.4, 116.5,
118.8, 122.2, 127.1, 128.4, 128.6, 128.7, 129.2, 135.5,
150.1, 167.4; mass (ES+) m/z 303.1 (M++1); Anal. Calcd
for C16H15ClN2O2: C, 63.47; H, 4.99; N, 9.25. Found: C,
63.47; H, 4.99; N, 9.25.
References and notes
1. (a) Rosenthal, P. J. Antimalarial Chemotherapy: Mechanisms
of Action, Resistance, and New Directions in Drug
Discovery; Humana: Totowa, NJ, 2001; (b) Bhattacharjee,
A. K.; Karle, J. M. J. Med. Chem. 1996, 39, 4622–4629; (c)
De, D.; Krogstad, F. M.; Byers, L. D.; Krogstad, D. J. J. Med.
Chem. 1998, 41, 4918–4926; (d) Stocks, P. A.; Raynes, K. J.;
Bray, P. G.; Park, B. K.; O’Neill, P. M.; Ward, S. A. J. Med.
Chem. 2002, 45, 4975–4983; (e) Vennerstrom, J. L.; Ager,
A. L., Jr.; Dorn, A.; Andersen, S. L.; Gerena, L.; Ridley,
R. G.; Milhous, W. K. J. Med. Chem. 1998, 41, 4360–4364;
(f) Kaschula, C. H.; Egan, T. J.; Hunter, R.; Basilico, N.;
Parapini, S.; Taramelli, D.; Pasini, E.; Monti, D. J. Med.
Chem. 2002, 45, 3531–3539; (g) Delarue, S.; Girault, S.;
Maes, L.; Debreu-Fontaine, M.-A.; Labaeid, M.; Grellier, P.;
Sergheraert, C. J. Med. Chem. 2001, 44, 2827–2833.
2. (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.;
Blackwell Science: Oxford, 2000; pp 121–150; (b) Roth,
H. J.; Fenner, H. Arzneistoffe, 3rd ed.; Deutscher Apotheker:
Stuttgart, 2000; pp 51–114; (c) Balasubramanian, M.; Keay,
J. G. Comprehensive Heterocyclic Chemistry II; Katritzky,
A. R., Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford,
1996; Vol. 5, pp 245–265; (d) Chen, Y. L.; Fang, K. C.; Sheu,
J. Y.; Hsu, S. L.; Tzeng, C. C. J. Med. Chem. 2001, 44, 2374–
2377; (e) Roma, G.; Braccio, M. D.; Grossi, G.; Mattioli, F.;
Ghia, M. Eur. J. Med. Chem. 2000, 35, 1021–1035; (f)
Shinkai, H.; Ito, T.; Iida, T.; Kitao, Y.; Yamada, H.; Uchida, I.
4.3.13. 4-(1-Methoxycarbonyl-vinyl)-2-phenyl-quino-
line-3-carboxylic acid ethyl ester (22a). Yield 58%
(0.25 g from 0.5 g) as a white solid; mp 107–109 ꢁC; nmax
1
(KBr) 1727 (CO2Me and CO2Et) cmꢂ1; H NMR (CDCl3,
300 MHz) d 1.05 (t, 3H, J¼7.2 Hz, CH2CH3), 3.79 (s, 3H,
CO2CH3), 4.10 (q, 2H, J¼7.2 Hz, CH2CH3), 5.88 (d, 1H,
J¼0.6 Hz, ]CH), 6.87 (d, 1H, J¼0.6 Hz, ]CH), 7.43–
7.50 (m, 3H, ArH), 7.56–7.62 (m, 1H, ArH), 7.64–7.74
(m, 4H, ArH), 8.09 (d, 1H, J¼8.2 Hz, ArH); 13C NMR
(CDCl3, 50 MHz) d 14.3, 24.6, 52.9, 62.1, 125.3, 126.1,
126.9, 127.1, 129.3, 131.06, 137.2, 143.1, 147.9, 155.7,
166.0, 168.1; mass (ES+) m/z 362.2 (M++1); HR-EIMS
calculated for C22H19NO4: 361.1314, found: 361.1318.
4.3.14. 4-(1-Methoxycarbonyl-vinyl)-2-oxo-1,2,3,4-tetra-
hydro-quinoline-3-carboxylic acid ethyl ester (23a). Yield
62% (0.2 g from 0.4 g) as a low melting white solid; nmax
1
(Neat) 1674 (CONH), 1739 (CO2Et), 3205 (NH) cmꢂ1; H
NMR (CDCl3, 300 MHz) d 1.15 (t, 3H, J¼7.2 Hz,
CH2CH3), 3.81 (s, 3H, CO2CH3), 4.08 (d, 1H, J¼6.0 Hz,

S. Madapa et al. / Tetrahedron 62 (2006) 8740–8747
8747
J. Med. Chem. 2000, 43, 4667–4677; (g) van Straten, N. C. R.;
van Berkel, T. H. J.; Demont, D. R.; Karstens, W.-J. F.; Merkx,
R.; Oosterom, J.; Schulz, J.; van Someren, R. G.; Timmers,
C. M.; van Zandvoort, P. M. J. Med. Chem. 2005, 48, 1697–
1700; (h) Boschelli, D. H.; Wang, Y. D.; Johnson, S.; Wu, B.;
Ye, F.; Barrios Sosa, A. C.; Golas, J. M.; Boschelli, F. J. Med.
Chem. 2004, 47, 1599–1601.
Kim, H. R.; Ryu, E. K. Bull. Korean Chem. Soc. 2001, 22,
135–136.
7. (a) Chung, Y. M.; Lee, H. J.; Hwang, S. S.; Kim, J. N. Bull.
Korean Chem. Soc. 2001, 22, 799–800; (b) Kim, J. N.; Lee,
H. J.; Lee, K. Y.; Kim, H. S. Tetrahedron Lett. 2001, 42,
3737–3740; (c) Kim, J. N.; Chung, Y. M.; Im, Y. J.
Tetrahedron Lett. 2002, 43, 6209–6211; (d) O’Dell, D. K.;
Nicholas, K. M. J. Org. Chem. 2003, 68, 6427–6430; (e) Lee,
K. Y.; Kim, S. C.; Kim, J. N. Bull. Korean Chem. Soc. 2005,
26, 1109–1110.
8. Kim, J. N.; Kim, H. S.; Gong, J. H.; Chung, Y. M. Tetrahedron
Lett. 2001, 42, 8341–8344.
9. Lee, K. Y.; Kim, J. M.; Kim, J. N. Tetrahedron 2003, 59,
385–390.
10. (a) Basavaiah, D.; Reddy, R. M.; Kumaragurubaran, N.;
Sharada, D. S. Tetrahedron 2002, 58, 3693–3697; (b) Lee,
K. Y.; Kim, J. M.; Kim, J. N. Bull. Korean Chem. Soc. 2002,
23, 1493–1494; (c) Lee, K. Y.; Kim, J. N. Bull. Korean
Chem. Soc. 2002, 23, 939–940.
11. Lee, C. G.; Lee, K. Y.; GowriSankar, S.; Kim, J. N. Tetrahedron
Lett. 2004, 45, 7409–7413.
12. Basavaiah, D.; Rao, J. S.; Reddy, R. J. J. Org. Chem. 2004, 69,
7379–7382.
3. (a) Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron Lett. 2006,
47, 3127–3130; (b) Sakai, N.; Aoki, D.; Hamajima, T.;
Konakahara, T. Tetrahedron Lett. 2006, 47, 1261–1265; (c)
Sakai, N.; Annaka, K.; Konakahara, T. J. Org. Chem. 2006,
71, 3653–3655; (d) Tanaka, S.-y.; Yasuda, M.; Baba, A.
J. Org. Chem. 2006, 71, 800–803; (e) Wang, G.-W.; Jia, C.-S.;
Dong, Y.-W. Tetrahedron Lett. 2006, 47, 1059–1063; (f)
Wang, X.; Dixon, S.; Kurth, M. J.; Lam, K. S. Tetrahedron
Lett. 2005, 46, 5361–5364; (g) De, S. K.; Gibbs, R. A.
Tetrahedron Lett. 2005, 46, 1647–1649; (h) Taguchi, K.;
Sakaguchi, S.; Ishii, Y. Tetrahedron Lett. 2005, 46, 4539–
4542; (i) Kobayashi, K.; Yoneda, K.; Miyamoto, K.;
Morikawa, O.; Konishi, H. Tetrahedron 2004, 60, 11639–
11645; Zhang, X.; Campo, M. A.; Yao, T.; Larock, R. C. Org.
Lett. 2004, 7, 763–766.
4. (a) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T.
Chem. Rev. 2003, 811–890; (b) Basavaiah, D.; Reddy, R. J.;
Rao, J. S. Tetrahedron Lett. 2006, 47, 73–77; (c) Sreedhar,
B.; Reddy, P. S.; Kumar, N. S. Tetrahedron Lett. 2006, 47,
3055–3058; (d) Coelho, F.; Veronese, D.; Pavam, C. H.; de
Paula, V. I.; Buffon, R. Tetrahedron 2006, 62, 4563–4572; (e)
Chandrasekhar, S.; Basu, D.; Rambabu, Ch. Tetrahedron Lett.
2006, 47, 3059–3063; (f) Shi, Yong-Ling; Shi, Min Synlett
2005, 2623–2626; (g) Lee, K. Y.; Gowrisankar, S.; Kim, J. N.
Bull. Korean Chem. Soc. 2005, 26, 1481–1490; (h)
Shanmugam, P.; Rajasingh, P. Tetrahedron Lett. 2005, 46,
3369–3372; (i) Mix, S.; Blechert, S. Org. Lett. 2005, 7,
2015–2018; (j) Du, Y.; Feng, J.; Lu, X. Org. Lett. 2005, 7,
1987–1989; (k) Nair, Vijay; Abhilash, K. G. Synthesis 2005,
12, 1967–1970 (only a few examples are covered herein).
5. Familoni, O. B.; Kaye, P. T.; Klaas, P. J. Chem. Commun. 1998,
2563–2564.
13. (a) Lee, C. G.; Lee, K. Y.; Lee, S.; Kim, J. N. Tetrahedron 2005,
61, 1493–1499; (b) Kim, S. C.; Gowrisankar, S.; Kim, J. N.
Bull. Korean Chem. Soc. 2005, 26, 1001–1004.
14. Narender, P.; Srinivas, U.; Ravinder, M.; Rao, B. A.; Ramesh,
Ch.; Harakishore, K.; Gangadasu, B.; Murthy, U. S. N.; Rao,
V. J. Bioorg. Med. Chem. 2006, 14, 4600–4609.
15. See Ref. 4b.
16. These papers appeared after the communication of this manu-
script. (a) Hong, W. P.; Lee, K.-J. Synthesis 2006, 963–968; (b)
Yi, H.-W.; Park, H. W.; Song, Y. S.; Lee, K.-J. Synthesis 2006,
1953–1960.
17. (a) Singh, V.; Saxena, R.; Batra, S. J. Org. Chem. 2005, 70,
353–356; (b) Pathak, R.; Roy, A. K.; Batra, S. Synlett 2005,
848–850; (c) Pathak, R.; Roy, A. K.; Kanojiya, S.; Batra, S.
Tetrahedron Lett. 2005, 46, 5289–5292; (d) Singh, V.; Batra,
S. Synthesis 2006, 63–72; (e) Nag, S. N.; Pathak, R.; Kumar,
M.; Shukla, P. K.; Batra, S. Bioorg. Med. Chem. Lett. 2006,
16, 3824–3828.
6. (a) Kim, J. N.; Lee, K. Y.; Kim, H. S.; Kim, T. Y. Org. Lett.
2000, 2, 343–345; (b) Kim, J. N.; Lee, K. Y.; Ham, H.-S.;