A general approach to the synthesis of substituted isoxazolo[4,3-c] quinolines via chalcones

Article abstract of DOI:10.1002/ejoc.200700268

A general and practical approach to the synthesis of substituted isoxazolo[4,3-c]quinolines from the substituted isoxazolines obtained by 1,3-dipolar cycloadditions between 2-nitrobenzonitrile oxide and chalcones is described. SnCl₂·2H₂O-mediated reduction of the nitro group, followed by intramolecular cyclization involving the amino and the keto groups in these substrates, furnished mixtures of isoxazolo[4,3-c] quinolines and 3,5-dihydroisoxazolo[4,3-c]-quinolines. In contrast, the reduction of these substrates with Fe/AcOH unexpectedly yielded 3-benzoylquinolin-4-yl-amine derivatives. Wiley-VCH Verlag GmbH & Co. KGaA, 2007.

Full text of DOI:10.1002/ejoc.200700268

FULL PAPER
DOI: 10.1002/ejoc.200700268
A General Approach to the Synthesis of Substituted Isoxazolo[4,3-c]quinolines
via Chalcones[‡]
Sudharshan Madapa,[a] Divya Sridhar,[a] Gaya P. Yadav,[b] Prakas R. Maulik,[b] and
Sanjay Batra*[a]
Keywords: Isoxazolo[4,3-c]quinolines / 3-Benzoylquinolin-4-ylamines / Reduction / Heterocyclization
A general and practical approach to the synthesis of substi-
tuted isoxazolo[4,3-c]quinolines from the substituted isoxaz-
olines obtained by 1,3-dipolar cycloadditions between
2-nitrobenzonitrile oxide and chalcones is described.
SnCl2·2H2O-mediated reduction of the nitro group, followed
by intramolecular cyclization involving the amino and the
keto groups in these substrates, furnished mixtures of
isoxazolo[4,3-c]quinolines and 3,5-dihydroisoxazolo[4,3-c]-
quinolines. In contrast, the reduction of these substrates with
Fe/AcOH unexpectedly yielded 3-benzoylquinolin-4-yl-
amine derivatives.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
recently, this approach resulted exclusively in the formation
of quinolin-4-ylamine derivatives.[24]
Introduction
Annulated heterocyclic systems have a variety of phar-
macological uses,[1,2] which provides incentive to synthetic
organic chemists to devise novel yet simple strategies for the
generation of these molecular frameworks. The develop-
ment of isoxazole-annulated ring systems has been a topic
of continuous research due to the synthetic and medicinal
importance of such scaffolds.[3–12] In one of the activities of
our research group, we have been involved in the develop-
ment of novel protocols for the synthesis of such ring sys-
tems and have reported the synthesis of furo[3,4-d]isoxazol-
4-one, 5H-isoxazolo[4,5-d]pyridazin-4-ones, 5,8-dihydro-
In our continuing efforts in this direction, we reasoned
that the synthesis of such ring systems might be ac-
complished from a substituted isoxazoline derivative con-
taining a 2-nitrophenyl group at the 3-position and a benz-
oyl moiety at the 4-position, obtainable through 1,3-dipolar
cycloadditions between 2-nitrobenzonitrile oxide and
chalcones. In principle, the reduction of the nitro group
would result in a 2-aminophenyl derivative, in which the
amino group should readily undergo intramolecular cycli-
zation with the keto moiety of the benzoyl group to furnish
isoxazolo[3,4-c]quinoline. The rationale for such a strategy
was based on reports by Rossi et al.[16] on the synthesis of
isoxazolo[4,5-c]quinolines from β-(2-aminophenyl)-α,β-
ynones and Kaye et al.[25a] on the generation of quinolines
by Baylis–Hillman chemistry. More recently, we have also
reported that the keto group has a preference for cyclization
with the amino moiety for the construction of the quinoline
ring.[25b] In order to explore our strategy we carried out the
synthesis of 2-isoxazoline derivatives from chalcones and
subjected them to reduction. Interestingly, the reduction of
the nitro group under catalytic hydrogenation conditions or
in the presence of SnCl2·2H2O yielded mixtures of substi-
tuted 3,5-dihydroisoxazolo[4,3-c]quinolines and substituted
isoxazolo[4,3-c]quinolines. In contrast, Fe/AcOH-mediated
reduction afforded 3-benzoylquinolin-4-ylamine derivatives.
These results prompted us to discuss the details of our
study in this paper.
isoxazolo[4,5-c]azepin-4-ones,
and isoxazolobenzazul-
enes.[13–15] During the program we became interested in the
synthesis of isoxazolo[4,3-c]quinolines. A literature survey
revealed that, although there exist a number of strategies
for the synthesis of isoxazolo[4,5-c]quinolines,[16–19] only
two reports[20–21] of the synthesis of isoxazolo[4,3-c]quino-
lines exist, despite their significance as structural compo-
nents of MRP-1 inhibitors.[22,23] Initially we reasoned that
such an architecture could be generated from 3-(2-ni-
trophenyl)isoxazole-4-carboxylate by reduction of the nitro
group to an amino group and subsequent cyclization with
the carboxylate or formyl function. However, as reported
[‡] CDRI Communication no. 7159
[a] Medicinal and Process Chemistry Division, Central Drug Re-
search Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405, -2623938
E-mail: batra_san@yahoo.co.uk
[b] Molecular and Structural Biology Division, Central Drug Re-
search Institute,
Results and Discussion
Initially, the substituted chalcones 1a–e and 2a–b were
synthesized in excellent yields through the reactions be-
P. O. Box 173, Lucknow 226001, India
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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S. Madapa, D. Sridhar, G. P. Yadav, P. R. Maulik, S. Batra
FULL PAPER
tween different aldehydes and acetophenones. The authen- tions we decided to employ it for our cause. Therefore, in
ticity of these chalcones was confirmed by comparing their the first instance we subjected 3a to hydrogenation in the
melting points with those reported in the literature.[26,27] presence of 10% Pd/C at 2.76 bar of H2 on a Parr assembly.
Treatment of chalcones 1a–e and 2a–b with 2-nitrobenzoni- Gratifyingly, the reaction was complete in 30 min, affording
trile oxide (generated from α-chloro-2-nitrobenzaldoxime) a mixture of products. Careful silica gel column chromatog-
in the presence of triethylamine in diethyl ether at –78 °C raphy resulted in the isolation of two products, and spectral
furnished the isoxazolines 3a–e and 4a–b, respectively, in 3– analysis of the less polar product, which was obtained in
4 h and in 54–64% yields (Scheme 1). Although the spectro- 11% yield, led us to establish the structure of the compound
scopic data supported the structural assignments for 3a–e as 5a. On the contrary, the polar product, which was iso-
and 4a–b, the structures were secured by X-ray crystallo- lated in 39% yield, was assigned the structure of 7a. The
graphic analysis of 3a (Figure 1).[28] Interestingly, this reac- formation of 5a may have resulted following the cyclization
tion was diastereoselective for the trans isomer, as only faint of the hydroxylamine intermediate with the keto group.
spots, probably attributable to the cis stereomers, were ob- This hydroxylamine intermediate would have resulted from
served by TLC.
partial reduction of the nitro group. On the other hand,
In the next stage of the synthesis, chemoselective re- product 7a would have formed through the intramolecular
duction of the nitro group was desired. Generally, this can cyclization taking place after the complete reduction of the
be achieved either by catalytic hydrogenation or by use of nitro group to an amino group.
metals including In, Fe, or Zn in the presence of additives
Subsequently, compound 3a was also subjected to treat-
or metal halides such as SnCl2. Catalytic hydrogenation is ment with SnCl2·2H2O in methanol at reflux temperature.
known to cause cleavage of the 2-isoxazoline ring, but in It was pleasing to note that here, too, the reaction was com-
the light of our recent results[24] in which we demonstrated plete within 30 min and that the obtained product was a
that a 2-isoxazoline ring bearing a nitrophenyl group at the mixture of only two compounds that could be readily sepa-
3-position is stable under catalytic hydrogenation condi- rated by column chromatography. The minor compound,
Scheme 1. Reagents and conditions: (i) aq. KOH, MeOH, 15–30 min. (ii) Et3N, diethyl ether, –78 °C to room temp., 14–16 h. (iii)
SnCl2·2H2O, MeOH, reflux, 80 °C, 30 min. (iv) Pd/C (10%), 2.76 bar of H2, room temp., 30 min. (v) Fe, AcOH, reflux, 110 °C, 30 min.
Figure 1. ORTEP diagram of compound 3a (probabilities of 30%), showing the atomic numbering scheme.
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Substituted Isoxazolo[4,3-c]quinolines via Chalcones
FULL PAPER
isolated here in 21% yield, was 5a, while the major product, these products were established as 9–10b. Although the for-
obtained in 57% yield, was 7a. In view of the better yields mation of quinoline N-oxide during the SnCl2·2H2O-pro-
and easy separation observed with this procedure, the other moted reduction of the nitro group and subsequent intra-
substrates 3b–e and 4a–b were also subjected to the molecular cyclization has literature precedence,[25a] the for-
SnCl2·2H2O-promoted reactions. Expectedly, these sub- mation of these products only in the cases of 3–4b is at
strates yielded the corresponding products 5b–e, 7b–e, 6a– present unexplainable. Nevertheless, the chemical evidence
b, and 8a–b. The unambiguous assignment of the structures for the assigned structure was obtained by treatment of 9b
of these compounds was achieved by carrying out X-ray with PBr3 in DMF to furnish 5a as reported earlier.[25a]
crystallographic analysis of representative compounds 5c
In the next stage of the study, our objective being to
avoid the formation of two products, we also investigated
and 7d (Figures 2 and 3).[29,30]
It is worth mentioning that the crystal of 7d used for the reduction of the nitro group with other metals. While
X-ray analysis was obtained from the recovered 13C NMR reduction with indium in the presence of HCl in water fur-
sample, because of which we observed entrapped (CH3)3Si– nished a complex mixture that was not characterized, sim-
Si(CH3)3.
ilar treatment with Fe/AcOH gave an interesting result.
Interestingly, during the reduction of 3–4b, third prod- Treatment of 3a with Fe/AcOH at reflux temperature re-
ucts, which were isolated in major yields, were invariably sulted in complete disappearance of the starting substrate
formed. On the basis of spectral evidence the structures of within 30 min. Subsequent purification led to isolation of a
Figure 2. ORTEP diagram of compound 5c (probability of 30%), showing the atomic numbering scheme.
Figure 3. ORTEP diagram of compound 7d (probability of 30%), showing the atomic numbering scheme. A solvent molecule
[(CH3)3Si–Si(CH3)3] has been omitted for clarity.
Eur. J. Org. Chem. 2007, 4343–4351
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S. Madapa, D. Sridhar, G. P. Yadav, P. R. Maulik, S. Batra
FULL PAPER
Figure 4. ORTEP diagram of compound 11b (probability of 30%), showing the atomic numbering scheme.
single compound, identified as 3-(4-chlorobenzoyl)-2-phen-
ylquinolin-4-ylamine (11a), in 65% yield. In order to exam-
Experimental Section
General: Melting points are uncorrected and were determined in
ine the general application of this reaction, isoxazolines 3b–
e and 4a–b were also treated with Fe in the presence of
AcOH. In all cases the corresponding quinolin-4-ylamines
11b–e and 12a–b, respectively, were isolated in good yields.
This is an unusual observation, since formation of quinolin-
4-ylamines can be explained on the basis of a cascade reac-
tion. It is believed that the reduction of the nitro group
would have occurred first, followed by intramolecular cycli-
zation of the amino group with the carbonyl functionality
to afford an isoxazolo[4,3-c]quinoline derivative and simul-
taneous cleavage of the isoxazoline ring. X-ray crystallo-
graphic analysis of a representative compound 11b (Fig-
ure 4)[31] unequivocally confirmed the assigned structure of
the product. Additional chemical evidence for the forma-
tion of these products was obtained by subjecting 5a to hy-
drogenation in the presence of Raney-Ni to furnish com-
pound 11a exclusively.
capillary tubes with an apparatus containing silicon oil. Infrared
spectra were recorded with a Perkin–Elmer RX I FTIR spectro-
1
photometer. H and 13C NMR spectra were recorded with Bruker
DPX 200 MHz or Bruker Avance 300 MHz FT spectrometers, with
TMS as an internal standard (chemical shifts in δ values, J in Hz).
The FAB mass spectra were recorded with JEOL/SX-102 spectrom-
eters, and the ES mass spectra were recorded with a MICROMASS
LCMS system. Elemental analyses were performed with a Carlo
Erba 1108 microanalyzer or an Elementar Vario EL III microana-
lyzer. Only representative data for the chalcones are provided. Hy-
drogenation was performed in the usual manner on a Parr as-
sembly. Compound 8a was insoluble in any solvent; therefore, no
NMR spectroscopic data are included. CAUTION: Round-bot-
tomed flasks containing α-chloro-2-nitrobenzaldoxime (around
5.0 g) exploded a few times during evaporation under vacuum with
a rotary evaporator; it should therefore be handled carefully.
Preparation of Chalcones 1a–e, 2a–b. General Procedure: Aq. KOH
(26 mmol, 1.43 g in 9.5 mL of water) was added dropwise at room
temperature to
a mixture of the appropriate benzaldehyde
(17 mmol) and the appropriate acetophenone (17 mmol) in meth-
anol (25 mL), and the reaction mixture was stirred for 15 min. Af-
ter completion, the reaction mixture was neutralized with dilute
HCl, filtered through a Büchner funnel, and washed freely with
water. The resultant solids 1a–e and 2a–b were dried over P2O5 in
a dessicator.
Conclusions
We have demonstrated a general and convenient synthe-
sis of isoxazolo[4,3-c]quinoline derivatives through the re-
duction of the nitro groups of (2-nitrophenyl)isoxazolines,
which in turn were afforded by chalcones. This synthetic
strategy is impressive because of easy availability of the
starting substrates, simple reaction conditions, and short re-
action times. The formation of quinolin-4-ylamine deriva-
tives bearing benzoyl moieties at the 3-position during re-
duction in the presence of Fe/AcOH provides an excellent
alternative for the synthesis of this important scaffold.
3-(4-Chlorophenyl)-1-p-tolylpropenone (2a): Yield: 82% (3.0 g from
3.66 g) as a white solid, m.p. 148–150 °C. Rf (10% EtOAc/hexanes)
= 0.56. 1H NMR (CDCl3, 200 MHz): δ = 2.43 (s, 3 H, CH3), 7.23–
7.28 (m, 4 H, ArH), 7.32–7.46 (m, 2 H, ArH and =CH), 7.54–7.58
(m, 2 H, ArH, and =CH), 7.93 (d, J = 8.2 Hz, 2 H, ArH) ppm.
13C NMR (CDCl3, 200 MHz): δ = 22.1, 122.8, 129.1, 129.6, 129.8,
130.0, 133.9, 135.8, 136.7, 143.3, 144.3, 190.1 ppm. IR (KBr): ν
˜
max
= 1659 (CO) cm–1. ESI-MS: m/z = 257.2 [M + 1]+.
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Substituted Isoxazolo[4,3-c]quinolines via Chalcones
FULL PAPER
Preparation of Isoxazolines 3a–e, 4a–b. General Procedure: The ap-
propriate chalcone 1a–e or 2a–b (15 mmol) was added to a solution
of α-chloro-2-nitrobenzaldoxime (10 mmol, 2.0 g) in dry diethyl
ether (10 mL), and the mixture was cooled to –78 °C. Et3N
(20 mmol, 2.8 mL) was added dropwise at this temperature with
stirring. After the addition was complete, the reaction was brought
to room temperature and the stirring was continued for 3–4 h.
Thereafter, the reaction mixture was extracted with ethyl acetate
(3ϫ50 mL) and water (100 mL). The organic layers were com-
bined, dried with Na2SO4, and concentrated under reduced pres-
sure. The crude product obtained was purified by column
chromatography on silica gel (60–120 mesh) with hexanes/EtOAc
(95:5, v/v) as solvent system to yield the desired product 3a–e or
4a–b.
(441.26): calcd. C 59.88, H 3.20, N 6.35; found C 60.11, H 3.30, N
6.51.
[5-(3,4-Dichlorophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl]-
(phenyl)methanone (3e): This compound was isolated in 58% yield
(1.92 g from 1.50 g) as a pale yellow solid, m.p. 141–142 °C. Rf
(20% EtOAc/hexanes) = 0.59. 1H NMR (CDCl3, 300 MHz): δ =
5.62 (d, J = 7.9 Hz, 1 H, CH), 6.04 (d, J = 7.9 Hz, 1 H, CH), 7.32–
7.47 (m, 3 H, ArH), 7.51–7.77 (m, 5 H, ArH), 8.09–8.17 (m, 2 H,
ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 64.4, 84.6, 124.6,
126.2, 127.3, 127.5, 128.2, 128.9, 129.5, 129.8, 130.2, 131.5, 131.9,
132.6, 132.9, 133.8, 135.0, 138.1, 146.7, 152.1, 192.4 ppm. IR
(KBr): ν
= 1688 (CO), 1521, 1350 (NO2) cm–1. ESI-MS: m/z =
˜
max
441 [M + 1]+. C22H14Cl2N2O4 (441.26): calcd. C 59.88, H 3.20, N
6.35; found C 59.91, H 3.16, N 6.43.
[5-(4-Chlorophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl]-
(phenyl)methanone (3a): This compound was isolated in 59% yield
(2.36 g from 2.0 g) as a yellow solid, m.p. 146–148 °C. Rf (20%
[5-(4-Chlorophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl](p-
tolyl)methanone (4a): This compound was isolated in 57% yield
(1.80 g from 1.50 g) as a white solid, m.p. 160–162 °C. Rf (20%
1
1
EtOAc/hexanes) = 0.5. H NMR (CDCl3, 300 MHz): δ = 5.65 (d,
EtOAc/hexanes) = 0.48. H NMR (CDCl3, 300 MHz): δ = 2.35 (s,
J = 8.2 Hz, 1 H, CH), 6.03 (d, J = 8.2 Hz, 1 H, CH), 7.31–7.36
(m, 2 H, ArH), 7.46 (s, 4 H, ArH), 7.49–7.57 (m, 2 H, ArH), 7.61–
7.66 (m, 4 H, ArH), 8.09 (d, J = 8.3 Hz, 1 H, ArH) ppm. 13C NMR
(CDCl3, 50 MHz): δ = 66.1, 87.5, 125.2, 128.5, 129.0, 129.3, 129.7,
131.3, 133.8, 134.4, 134.7, 135.4, 135.6, 137.9, 147.5, 153.8,
3 H, CH3), 5.62 (d, J = 8.2 Hz, 1 H, CH), 5.99 (d, J = 8.2 Hz, 1
H, CH), 7.13 (d, J = 8.1 Hz, 2 H, ArH), 7.45 (s, 4 H, ArH), 7.53–
7.57 (m, 3 H, ArH), 7.62–7.64 (m, 2 H, ArH), 8.10 (d, J = 8.1 Hz,
1 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 21.6, 65.5, 87.3,
124.8, 128.1, 128.7, 128.8, 129.2, 129.3, 129.6, 129.7, 130.8, 133.5,
194.7 ppm. IR (KBr): ν
= 1687 (CO), 1525, 1345 (NO2) cm–1.
˜
134.0, 134.8, 135.6, 138.4, 147.5, 153.8, 194.7 ppm. IR (KBr): ν
˜
max
max
ESI-MS: m/z = 407.0/409.0 [M + 1]+. C22H15ClN2O4 (406.82):
= 1694 (CO), 1525, 1350 (NO2) cm–1. FAB-MS: m/z = 421 [M +
1]+. C23H17ClN2O4·H2O (438.86): calcd. C 62.95, H 4.36, N 6.38;
found C 63.04, H 4.66, N 6.65.
calcd. C 64.95, H 3.72, N 6.89; found C 65.08, H 4.01, N 6.65.
[5-(4-Bromophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl]-
(phenyl)methanone (3b): This compound was isolated in 62% yield
(1.80 g from 1.30 g) as a brown solid, m.p. 155–157 °C. Rf (20%
EtOAc/hexanes) = 0.66. 1H NMR (CDCl3, 300 MHz): δ = 5.65 (d,
J = 8.1 Hz, 1 H, CH), 6.02 (d, J = 8.1 Hz, 1 H, CH), 7.31–7.41
(m, 4 H, ArH), 7.50–7.57 (m, 2 H, ArH), 7.60–7.66 (m, 6 H, ArH),
8.09 (d, J = 8.1 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 66.1, 87.5, 123.6, 125.3, 128.8, 129.0, 129.3, 130.1, 130.3, 131.3,
132.6, 133.8, 134.4, 134.8, 135.6, 138.4, 147.5, 153.8, 194.7 ppm.
[5-(4-Bromophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl](p-
tolyl)methanone (4b): This compound was isolated in 54% yield
(1.50 g from 1.20 g) as a yellow solid, m.p. 154–155 °C. Rf (20%
ethyl acetate/hexanes) = 0.53. 1H NMR (CDCl3, 200 MHz): δ =
2.34 (m, 3 H, ArH), 5.60 (d, J = 8.1 Hz, 1 H, CH), 5.96 (d, J =
8.1 Hz, 1 H, CH), 7.12 (d, J = 8.1 Hz, 2 H, ArH), 7.37 (d, J =
8.4 Hz, 2 H, ArH), 7.49–7.63 (m, 7 H, ArH), 8.09 (d, J = 7.8 Hz,
1 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 20.4, 64.2, 86.1,
121.8, 123.5, 127.1, 127.5, 128.4, 129.5, 130.9, 131.5, 132.2, 132.7,
IR (KBr): ν
= 1698 (CO), 1533, 1346 (NO2) cm–1. ESI-MS:
˜
max
136.8, 144.4, 145.9, 152.3, 192.6 ppm. IR (KBr): νmax = 1682 (CO),
˜
m/z = 451.1/453.0 [M + 1]+. C22H15BrN2O4 (451.27): calcd. C
1530, 1347 (NO2) cm–1. ESI-MS: m/z = 465.2/467.2 [M + 1]+.
C23H17BrN2O4 (465.29): calcd. C 59.37, H 3.68, N 6.02; found C
59.59, H 3.94, N 5.99.
58.55, H 3.35, N 6.21; found C 58.22, H 3.57, N 6.22.
[5-(2,3-Dichlorophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl]-
(phenyl)methanone (3c): This compound was isolated in 64% yield
(2.12 g from 1.50 g) as a yellow solid, m.p. 159–160 °C. Rf (20%
EtOAc/hexanes) = 0.67. 1H NMR (CDCl3, 300 MHz): δ = 5.49 (d,
J = 5.9 Hz, 1 H, CH), 6.58 (d, J = 5.9 Hz, 1 H, CH), 7.27–7.42
(m, 4 H, ArH), 7.46–7.54 (m, 4 H, ArH), 7.65–7.71 (m, 3 H, ArH),
8.05–8.08 (m, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz): δ =
65.5, 84.8, 124.7, 125.4, 126.2, 128.5, 128.8, 129.3, 129.7, 130.7,
131.4, 133.2, 133.7, 134.5, 134.6, 135.7, 140.3, 147.4, 153.4,
SnCl2·2H2O-Mediated Reduction of 3a–e or 4a–b. General Pro-
cedure: SnCl2·2H2O (6.15 mmol, 1.17 g) was added to a solution of
the appropriate isoxazoline 3a–e or 4a–b (1.23 mmol) in dry meth-
anol (15 mL), and the mixture was maintained at reflux tempera-
ture for 30 min. Thereafter, the reaction mixture was concentrated
to remove excess methanol and neutralized with saturated
NaHCO3 solution. It was then filtered through a Celite bed, and
the residue was washed with ethyl acetate. The water layer was fur-
ther extracted with ethyl acetate (3ϫ50 mL). The organic layers
were combined, washed with brine solution, dried with Na2SO4,
and concentrated under reduced pressure to provide a crude prod-
uct. The crude product was purified by column chromatography
on silica gel (60–120 mesh) with hexanes/EtOAc (98–97:2–3, v/v) to
provide 5a–e or 6a–b and with further elution with hexanes/EtOAc
(80–70:20–30, v/v) to provide 7a–e or 8a–b.
194.1 ppm. IR (KBr): ν
= 1696 (CO), 1523, 1345 (NO2) cm–1.
˜
max
ESI-MS: m/z = 441.0/443.0 [M + 1]+. C22H14Cl2N2O4 (441.26):
calcd. C 59.88, H 3.20, N 6.35; found C 60.03, H 3.45, N 6.65.
[5-(2,4-Dichlorophenyl)-3-(2-nitrophenyl)-4,5-dihydroisoxazol-4-yl]-
(phenyl)methanone (3d): This compound was isolated in 63% yield
(2.21 g from 1.60 g) as a white solid, m.p. 150–152 °C. Rf (20%
EtOAc/hexanes) = 0.58. 1H NMR (CDCl3, 300 MHz): δ = 5.50 (d,
J = 6.2 Hz, 1 H, CH), 6.52 (d, J = 6.2 Hz, 1 H, CH), 7.28–7.33
3-(4-Chlorophenyl)-4-phenylisoxazolo[4,3-c]quinoline (5a): This
(m, 2 H, ArH), 7.35–7.38 (m, 1 H, ArH), 7.42–7.54 (m, 5 H, ArH), compound was isolated in 21% yield (0.11 g from 0.60 g) as a pale
1
7.64–7.73 (m, 3 H, ArH), 8.06–8.09 (m, 1 H, ArH) ppm. 13C NMR
(CDCl3, 75 MHz): δ = 63.8, 82.5, 123.1, 123.7, 126.7, 127.1, 127.4,
127.6, 128.1, 129.7, 130.6, 131.6, 132.8, 132.9, 133.7, 134.1, 134.9,
yellow solid, m.p. 211–213 °C. Rf (20% EtOAc/hexanes) = 0.8. H
NMR (CDCl3, 200 MHz): δ = 7.20 (s, 4 H, ArH), 7.29–7.33 (m, 2
1
2
H, ArH), 7.38–7.49 (m, 3 H, ArH), 7.65 (dt, J = 1.2, J = 7.5 Hz,
= 1688 (CO), 1526, 1345 1 H, ArH), 7.81 (dt, J = 1.3, J = 7.2 Hz, 1 H, ArH), 8.12 (d, J
1
2
145.7, 151.8, 192.4 ppm. IR (KBr): ν
˜
max
(NO2) cm–1. FAB-MS: m/z = 441 [M + 1]+. C22H14Cl2N2O4
= 8.0 Hz, 1 H, ArH), 8.52 (dd, J = 1.2, J = 7.8 Hz, 1 H, ArH)
1
2
Eur. J. Org. Chem. 2007, 4343–4351
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4347

S. Madapa, D. Sridhar, G. P. Yadav, P. R. Maulik, S. Batra
FULL PAPER
ppm. 13C NMR (CDCl3, 50 MHz): δ = 108.7, 115.9, 123.8, 125.9,
128.5, 128.9, 129.0, 129.3, 130.2, 130.4, 131.2, 132.0, 137.5, 138.4,
145.7, 156.9, 157.8, 168.1 ppm. ESI-MS: m/z = 357.3/359.2 [M +
1]+. HR-EIMS: calcd. for C22H13ClN2O 356.0716; found 356.0711.
3-(4-Bromophenyl)-4-(p-tolyl)isoxazolo[4,3-c]quinoline (6b): This
compound was isolated in 18% yield (0.08 g from 0.50 g) as a yel-
low solid, m.p. 218–220 °C. Rf (20% EtOAc/hexanes) = 0.74. 1H
NMR (CDCl3, 200 MHz): δ = 2.38 (s, 3 H, CH3), 7.07–7.21 (m, 4
H, ArH), 7.33–7.39 (m, 4 H, ArH), 7.62 (t, J = 7.3 Hz, 1 H, ArH),
7.77 (t, J = 7.2 Hz, 1 H, ArH), 8.10 (d, J = 8.0 Hz, 1 H, ArH),
8.50 (d, J = 7.3 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 21.8, 108.8, 115.9, 123.8, 125.9, 126.4, 128.3, 129.3, 129.5,
130.3, 131.4, 131.8, 131.9, 135.6, 140.4, 145.8, 156.2, 157.87,
168.1 ppm. ESI-MS: m/z = 415.2/417.1 [M + 1]+. C23H15BrN2O
(415.28): calcd. C 66.52, H 3.64, N 6.75; found C 66.54, H 3.50, N
6.90.
3-(4-Bromophenyl)-4-phenylisoxazolo[4,3-c]quinoline (5b): This
compound was isolated in 19% yield (0.072 g from 0.42 g) as a
yellow solid, m.p. 132–133 °C. Rf (20% EtOAc/hexanes) = 0.82. 1H
NMR (CDCl3, 300 MHz): δ = 7.50–7.51 (m, 2 H, ArH), 7.52–7.53
(m, 3 H, ArH), 7.55–7.56 (m, 3 H, ArH), 7.58–7.62 (m, 2 H, ArH),
8.02–8.05 (m, 3 H, ArH) ppm. 13C NMR (CDCl3, 50 MHz): δ =
121.3, 123.5, 127.2, 127.4, 128.5, 130.9, 131.7, 132.5, 136.8, 142.1,
188.9 ppm. ESI-MS: m/z = 401.2/403.1 [M + 1]+. C22H13BrN2O
(401.25): calcd. C 65.85, H 3.27, N 6.98; found C 65.54, H 3.09, N
7.16.
3-(4-Chlorophenyl)-4-phenyl-3,5-dihydroisoxazolo[4,3-c]quinoline
(7a): This compound was isolated in 57% yield (0.30 g from 0.60 g)
as a yellow solid, m.p. 220–222 °C. Rf (20 % EtOAc/hexanes) =
0.32. 1H NMR (CDCl3, 300 MHz): δ = 6.69 (s, 1 H, CH), 7.07 (dd,
3-(2,3-Dichlorophenyl)-4-phenylisoxazolo[4,3-c]quinoline (5c): This
compound was isolated in 19% yield (0.081 g from 0.48 g) as a
light brown solid, m.p. 200–201 °C. Rf (20% EtOAc/hexanes) =
2
1J = 1.9, J = 6.5 Hz, 2 H, ArH), 7.11–7.17 (m, 1 H, ArH), 7.19
1
2
(dd, J = 1.8, J = 6.7 Hz, 2 H, ArH), 7.34–7.39 (m, 4 H, ArH),
7.42–7.48 (m, 3 H, ArH), 7.70 (dd, 1J = 1.1, 2J = 7.8 Hz, 1 H,
ArH), 10.20 (s, 1 H, NH) ppm. 13C NMR (CDCl3, 75 MHz): δ =
80.7, 111.5, 115.6, 116.6, 122.0, 123.1, 1215.8, 126.3, 126.8, 127.3,
127.7, 127.9, 128.7, 130.2, 131.4, 132.1, 135.6, 138.7, 139.3,
1
0.82. H NMR (CDCl3, 300 MHz): δ = 7.08–7.18 (m, 4 H, ArH),
7.30–7.32 (m, 1 H, ArH), 7.39–7.41 (m, 2 H, ArH), 7.53–7.56 (m,
1 H, ArH), 7.69 (t, J = 7.5 Hz, 1 H, ArH), 7.84 (t, J = 7.4 Hz, 1
H, ArH), 8.17 (d, J = 8.1 Hz, 1 H, ArH), 8.56 (d, J = 7.8 Hz, 1 H,
ArH) ppm. 13C NMR (CDCl3, 50 MHz): δ = 111.2, 116.0, 123.9,
124.6, 127.5, 128.2, 128.6, 128.7, 129.8, 130.0, 130.4, 130.5, 132.1,
132.9, 134.3, 137.7, 145.8, 156.8, 157.2, 166.0 ppm. ESI-MS: m/z =
391.2/393.2 [M + 1]+. C22H12Cl2N2O (391.24): calcd. C 67.54, H
3.09, N 7.16; found C 67.66, H 3.41, N 7.39.
150.5 ppm. IR (KBr): ν
= 3300 (NH) cm–1. ESI-MS: m/z =
˜
max
359.2/361.2 [M + 1]+. C22H15ClN2O (358.82): calcd. C 73.64, H
4.21, N 7.81; found C 73.53, H 4.40, N 7.65.
3-(4-Bromophenyl)-4-phenyl-3,5-dihydroisoxazolo[4,3-c]quinoline
(7b): This compound was isolated in 17 % yield (0.063 g from
0.42 g) as a yellow solid, m.p. 227–229 °C. Rf (20% EtOAc/hexanes)
= 0.4. 1H NMR (CDCl3, 200 MHz): δ = 6.68 (s, 1 H, CH), 7.01
(d, J = 8.0 Hz, 2 H, ArH), 7.14 (t, J = 7.3 Hz, 1 H, ArH), 7.32–
7.37 (m, 5 H, ArH), 7.43–7.46 (m, 3 H, ArH), 7.70 (d, J = 7.7 Hz,
1 H, ArH), 10.19 (s, 1 H, NH) ppm. 13C NMR (CDCl3, 50 MHz):
δ = 80.7, 111.5, 115.6, 116.6, 120.1, 122.0, 123.1, 126.8, 127.7,
128.2, 128.7, 130.2, 132.1, 135.6, 138.7, 139.7, 150.5 ppm. IR
3-(2,4-Dichlorophenyl)-4-phenylisoxazolo[4,3-c]quinoline (5d): This
compound was isolated in 17% yield (0.075 g from 0.50 g) as a pale
yellow solid, m.p. 128–129 °C. Rf (20% EtOAc/hexanes) = 0.81. 1H
NMR (CDCl3, 300 MHz): δ = 7.09–7.21 (m, 4 H, ArH), 7.30–7.36
1
2
(m, 1 H, ArH), 7.38–7.43 (m, 3 H, ArH), 7.67 (dt, J = 1.1, J =
7.8 Hz, 1 H, ArH), 7.82 (dt, J = 1.5, 2J = 7.3 Hz, 1 H, ArH), 8.15
1
(d, J = 8.3 Hz, 1 H, ArH), 8.54 (dd, 1J = 1.3, 2J = 7.8 Hz, 1 H,
ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 109.6, 114.3, 122.2,
125.7, 126.6, 126.9, 127.2, 127.4, 128.4, 128.5, 128.8, 130.4, 131.3,
133.7, 136.1, 136.4, 144.1, 155.1, 155.6, 163.9 ppm. ESI-MS: m/z =
391.2/393.1 [M + 1]+. C22H12Cl2N2O (391.24): calcd. C 67.54, H
3.09, N 7.16; found C 67.88, H 3.20, N 7.08.
(KBr): ν
= 3432 (NH) cm–1. ESI-MS: m/z = 403.2/405.1 [M +
˜
max
1]+. C22H15BrN2O (403.27): calcd. C 65.52, H 3.75, N 6.95; found
C 65.54, H 3.79, N 7.11.
3-(2,3-Dichlorophenyl)-4-phenyl-3,5-dihydroisoxazolo[4,3-c]quin-
oline (7c): This compound was isolated in 49% yield (0.21 g from
0.48 g) as a yellow solid, m.p. Ͼ250 °C. Rf (20% EtOAc/hexanes)
3-(3,4-Dichlorophenyl)-4-phenylisoxazolo[4,3-c]quinoline (5e): This
compound was isolated in 19% yield (0.085 g from 0.50 g) as a
yellow solid, m.p. 201–202 °C. Rf (20% EtOAc/hexanes) = 0.75. 1H
NMR (CDCl3, 300 MHz): δ = 7.15–7.18 (m, 1 H, ArH), 7.25–7.28
(m, 1 H, ArH), 7.33–7.38 (m, 3 H, ArH), 7.46–7.50 (m, 3 H, ArH),
7.68 (t, J = 7.5 Hz, 1 H, ArH), 7.82 (t, J = 7.5 Hz, 1 H, ArH), 8.15
(d, J = 8.1 Hz, 1 H, ArH), 8.53 (d, J = 7.8 Hz, 1 H, ArH) ppm.
13C NMR (CDCl3, 50 MHz): δ = 109.1, 115.8, 123.8, 127.0, 128.6,
128.8, 129.1, 129.2, 130.4, 130.6, 131.9, 132.2, 133.1, 135.7, 138.3,
145.6, 156.6, 157.8, 166.4 ppm. ESI-MS: m/z = 391.2/393.2 [M +
1]+. C22H12Cl2N2O·2H2O (427.28): calcd. C 64.56, H 3.45, N 6.84;
found C 64.80, H 3.41, N 6.79.
1
= 0.36. H NMR (CDCl3, 200 MHz): δ = 7.04 (s, 1 H, CH), 7.16–
7.19 (m, 3 H, ArH), 7.31–7.34 (m, 3 H, ArH), 7.40–7.47 (m, 5 H,
ArH), 7.69 (d, J = 7.8 Hz, 1 H, ArH), 10.36 (s, 1 H, NH) ppm.
13C NMR (CDCl3, 50.32 MHz): δ = 80.1, 112.5, 115.4, 117.9,
123.3, 124.3, 127.7, 128.6, 128.8, 129.9, 130.5, 131.5, 132.0, 133.3,
137.2, 139.9, 140.2, 152.1 ppm. IR (KBr): ν
= 3434 (NH) cm–1.
˜
max
ESI-MS: m/z = 393.1/395.1 [M + 1]+. C22H14Cl2N2O (393.26):
calcd. C 67.19, H 3.59, N 7.12; found C 67.34, H 3.66, N 7.01.
3-(2,4-Dichlorophenyl)-4-phenyl-3,5-dihydroisoxazolo[4,3-c]quin-
oline (7d): This compound was isolated in 52% yield (0.23 g from
0.50 g) as a yellow solid, m.p. 230–231 °C. Rf (20% EtOAc/hexanes)
3-(4-Chlorophenyl)-4-(p-tolyl)isoxazolo[4,3-c]quinoline (6a): This
compound was isolated in 14% yield (0.08 g from 0.65 g) as a yel-
low solid, m.p. 232–234 °C. Rf (20% EtOAc/hexanes) = 0.72. 1H
NMR (CDCl3, 200 MHz): δ = 7.09 (d, J = 7.8 Hz, 2 H, ArH), 7.22
(s, 4 H, ArH), 7.36 (d, J = 7.8 Hz, 2 H, ArH), 7.63 (t, J = 7.2 Hz,
1 H, ArH), 7.78 (t, J = 7.2 Hz, 1 H, ArH), 8.11 (d, J = 8.0 Hz, 1
H, ArH), 8.50 (d, J = 7.5 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
50 MHz): δ = 21.8, 108.8, 115.9, 123.8, 126.0, 128.3, 129.3, 129.5,
130.3, 131.3, 131.9, 135.7, 137.5, 140.4, 145.8, 156.9, 157.8,
168.0 ppm. ESI-MS: m/z = 370.2/372.1 [M + 1]+. C23H15ClN2O
(370.83): calcd. C 74.49, H 4.08, N 7.55; found C 74.54, H 4.19, N
7.35.
1
= 0.28. H NMR (CDCl3, 200 MHz): δ = 6.96 (s, 1 H, CH), 7.10–
7.21 (m, 3 H, ArH), 7.30–7.33 (m, 3 H, ArH), 7.37–7.46 (m, 5 H,
ArH), 7.67 (d, J = 7.7 Hz, 1 H, ArH), 10.30 (s, 1 H, NH) ppm.
13C NMR (CDCl3, 75 MHz): δ = 82.6, 116.0, 119.0, 121.5, 126.9,
127.9, 131.3, 131.5, 132.4, 133.5, 135.0, 135.3, 136.9, 137.1, 137.2,
140.4, 140.7, 143.5, 155.7 ppm. IR (KBr): ν
= 3421 (NH) cm–1.
˜
max
ESI-MS: m/z = 393.1/395.0 [M + 1]+. C22H14Cl2N2O (393.26):
calcd. C 67.19, H 3.59, N 7.12; found C 66.98, H 3.42, N 7.23.
3-(3,4-Dichlorophenyl)-4-phenyl-3,5-dihydroisoxazolo[4,3-c]quin-
oline (7e): This compound was isolated in 47% yield (0.21 g from
0.50 g) as a yellow solid, m.p. 195–197 °C. Rf (20% EtOAc/hexanes)
4348
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4343–4351

Substituted Isoxazolo[4,3-c]quinolines via Chalcones
FULL PAPER
1
= 0.33. H NMR ([D6]DMSO, 300 MHz): δ = 6.69 (s, 1 H, CH), with hexanes/EtOAc (90:10, v/v) as eluent to obtain the pure prod-
7.06–7.09 (m, 2 H, ArH), 7.11–7.21 (m, 3 H, ArH), 7.34–7.39 (m,
ucts.
4 H, ArH), 7.42–7.48 (m, 3 H, ArH), 7.70 (d, J = 7.8 Hz, 1 H,
(4-Amino-2-phenylquinolin-3-yl)(4-chlorophenyl)methanone (11a):
This compound was isolated in 66% yield (0.29 g from 0.50 g) as
a yellow solid, m.p. 249–250 °C. Rf (20% ethyl acetate/hexanes) =
0.57. 1H NMR (CDCl3, 300 MHz): δ = 6.45 (s, 2 H, NH2), 7.07
(d, J = 8.5 Hz, 2 H, ArH), 7.16–7.21 (m, 3 H, ArH), 7.34 (d, J =
8.5 Hz, 2 H, ArH), 7.48–7.58 (m, 3 H, ArH), 7.80 (t, J = 7.3 Hz,
ArH), 10.20 (s, 1 H, NH) ppm. IR (KBr): νmax = 3400 (NH) cm–1.
˜
ESI-MS: m/z = 393.2/395.2 [M + 1]+. C22H14Cl2N2O (393.26):
calcd. C 67.19, H 3.59, N 7.12; found C 73.64, H 4.21, N 7.81.
3-(4-Chlorophenyl)-4-(p-tolyl)-3,5-dihydroisoxazolo[4,3-c]quinoline
(8a): This compound was isolated in 61% yield (0.35 g from 0.65 g)
as a yellow solid, m.p. 260–262 °C. Rf (20 % EtOAc/hexanes) = 1 H, ArH), 7.90 (d, J = 8.3 Hz, 1 H, ArH), 8.13 (d, J = 8.4 Hz, 1
0.26. IR (KBr): ν
= 3352 (NH) cm–1. ESI-MS: m/z = 373.2 [M H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 119.5, 124.3,
˜
max
+ 1]+. C23H17ClN2O (372.84): calcd. C 74.09, H 4.60, N 7.51; found
126.7, 126.9, 127.5, 128.3, 128.9, 129.2, 130.1, 136.8, 158.6 ppm.
C 74.24, H 4.31, N 7.81.
IR (KBr): ν
= 1688 (C=O), 3424 (NH2) cm–1. ESI-MS: m/z =
˜
max
359.3/361.3 [M + 1]+. C22H15ClN2O (358.8): calcd. C 73.64, H 4.21,
3-(4-Bromophenyl)-4-(p-tolyl)-3,5-dihydroisoxazolo[4,3-c]quinoline
(8b): This compound was isolated in 16 % yield (0.072 g from
0.50 g) as a yellow solid, m.p. 200–202 °C. Rf (20% EtOAc/hexanes)
N 7.81; found C 73.47, H 4.10, N 7.77.
(4-Amino-2-phenylquinolin-3-yl)(4-bromophenyl)methanone (11b):
1
= 0.24. H NMR ([D6]DMSO, 300 MHz): δ = 2.30 (s, 3 H, CH3),
This compound was isolated in 56% yield (0.20 g from 0.40 g) as
1
6.45 (s, 1 H, CH), 6.95 (d, J = 8.3 Hz, 2 H, ArH), 7.04 (t, J =
6.8 Hz, 1 H, ArH), 7.10 (d, J = 8.0 Hz, 2 H, ArH), 7.20–7.24 (m,
4 H, ArH), 7.29–7.34 (m, 2 H, ArH), 7.68 (d, J = 7.9 Hz, 1 H,
ArH), 9.92 (s, 1 H, NH) ppm. 13C NMR ([D6]DMSO, 75 MHz): δ
= 20.2, 80.8, 111.4, 114.9, 116.6, 120.1, 121.7, 123.0126.6, 128.0,
128.1, 129.3, 129.9, 130.1, 135.8, 138.3, 138.6, 139.7, 150.7 ppm.
a yellow solid, m.p. Ͼ250 °C. Rf (20% EtOAc/hexanes) = 0.57. H
NMR ([D6]DMSO, 300 MHz): δ = 6.46 (br. s, 2 H, NH2), 7.16–
7.20 (m, 3 H, ArH), 7.22–28 (m, 4 H, ArH), 7.48–7.51 (m, 2 H,
ArH), 7.53–7.58 (m, 1 H, ArH), 7.77–7.83 (m, 1 H, ArH), 7.90 (d,
J = 8.2 Hz, 1 H, ArH), 8.13 (d, J = 8.2 Hz, 1 H, ArH) ppm. 13C
NMR (CDCl3, 75 MHz): δ = 108.7, 116.3, 122.3, 124.1, 125.3,
127.0, 127.4, 128.4, 130.0, 130.1, 130.3, 137.5, 140.6, 146.9, 150.6,
IR (KBr): ν
= 3402 (NH) cm–1. ESI-MS: m/z = 417.2/419.1 [M
˜
max
+ 1]+. C23H17BrN2O (417.29): calcd. C 66.20, H 4.11, N 6.71;
157.4, 196.1 ppm. IR (KBr): ν
= 1713 (CO), 3352 (NH2) cm–1.
max
˜
found C 66.30, H 4.19, N 6.77.
MS (ES+): m/z = 403.4/405.4 [M + 1]+. C22H15BrN2O (403.27):
calcd. C 65.52, H 3.75, N 6.95; found C 65.24, H 3.54, N 7.02.
3-(4-Bromophenyl)-4-phenylisoxazolo[4,3-c]quinoline 5-Oxide (9b):
This compound was isolated in 48% yield (0.19 g from 0.42 g) as
a yellow solid, m.p. 235–237 °C. Rf (20% EtOAc/hexanes) = 0.32.
(4-Amino-2-phenylquinolin-3-yl)(2,3-dichlorophenyl)methanone
(11c): This compound was isolated in 65 % yield (0.26 g from
1
2
1H NMR (CDCl3, 300 MHz): δ = 6.94 (dd, J = 1.7, J = 6.9 Hz,
0.45 g) as a pale yellow solid, m.p. 238–240 °C. Rf (20% EtOAc/
1
2 H, ArH), 727–7.37 (m, 4 H, ArH), 7.41–7.49 (m, 3 H, ArH), 7.82 hexanes) = 0.58. H NMR (CDCl3, 200 MHz): δ = 6.81–6.89 (m,
(dt, 1J = 1.1, 2J = 7.6 Hz, 1 H, ArH), 7.90 (dt, 1J = 1.4, 2J = 8.6 Hz,
2 H, ArH), 7.10–7.20 (m, 4 H, ArH), 7.34–7.37 (m, 2 H, ArH),
1
2
1
2
1 H, ArH), 8.52 (dd, J = 1.2, J = 7.7 Hz, 1 H, ArH), 8.83 (d, J
= 7.9 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 107.8,
116.2, 120.6, 122.5, 123.9, 124.0, 127.3, 128.7, 128.9, 129.0, 130.1,
131.0, 135.9, 140.2, 150.6, 163.8 ppm. ESI-MS: m/z = 417.2/419.1
[M + 1]+. C22H13BrN2O2 (417.25): calcd. C 63.33, H 3.14, N 6.71;
found C 63.29, H 3.42, N 6.88.
7.43 (brs, 2 H, NH2), 7.53 (dt, J = 1.0, J = 8.1 Hz, 1 H, ArH),
1
2
7.79 (dt, J = 1.0, J = 8.1 Hz, 1 H, ArH), 7.93 (d, J = 8.3 Hz, 1
H, ArH), 8.07 (d, J = 8.3 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3,
75 MHz): δ = 108.6, 115.7, 119.7, 124.4, 125.1, 126.7, 127.1, 127.8,
128.9, 130.0, 130.7, 132.3, 140.6, 141.2, 146.5, 152.4, 160.5,
194.9 ppm. IR (KBr): ν
= 1625 (CO), 3322 (NH2) cm–1. ESI-
˜
max
MS: m/z 393.3/395.2 [M + 1]+. C22H14Cl2N2O (393.26): calcd. C
3-(4-Bromophenyl)-4-(p-tolyl)isoxazolo[4,3-c]quinoline 5-Oxide
(10b): This compound was isolated in 52 % yield (0.24 g from
0.50 g) as a yellow solid, m.p. Ͼ250 °C. Rf (20% EtOAc/hexanes)
67.19, H 3.59, N 7.12; found C 66.89, H 3.81, N 7.22.
(4-Amino-2-phenylquinolin-3-yl)(2,4-dichlorophenyl)methanone
(11d): This compound was isolated in 59 % yield (0.25 g from
0.48 g) as a yellow solid, m.p. 200–201 °C. Rf (20% EtOAc/hexanes)
1
= 0.32. H NMR (CDCl3, 300 MHz): δ = 2.38 (s, 3 H, CH3), 6.94
(d, J = 8.5 Hz, 2 H, ArH), 7.13 (d, J = 8.1 Hz, 2 H, ArH), 7.29–
7.36 (m, J = 7.3 Hz, 4 H, ArH), 7.80 (t, J = 7.6 Hz, 1 H, ArH),
1
= 0.48. H NMR ([D6]DMSO, 300 MHz): δ = 7.00 (d, J = 8.2 Hz,
7.88 (t, J = 8.5 Hz, 1 H, ArH), 8.51 (d, J = 7.8 Hz, 1 H, ArH), 1 H, ArH), 7.10 (d, J = 8.2 Hz, 1 H, ArH), 7.18–7.26 (m, 6 H,
8.81 (d, J = 8.5 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz):
ArH), 7.55 (t, J = 7.2 Hz, 1 H, ArH), 7.76–7.88 (m, 2 H, ArH),
δ = 21.2, 107.9, 116.2, 120.6, 122.5, 123.8, 124.1, 125.8, 126.2, 8.36 (s, 2 H, NH2), 8.49 (d, J = 8.1 Hz, 1 H, ArH) ppm. 13C NMR
127.6, 127.9, 128.6, 128.8, 129.3, 129.9, 130.4, 130.7, 131.0, 136.3,
([D6]DMSO, 75 MHz): δ = 108.1, 116.5, 122.5, 124.3, 125.7, 126.8,
139.1, 140.2, 163.9 ppm. ESI-MS: m/z = 431.2/433.1 [M + 1]+.
127.2, 128.1, 128.4, 130.9, 131.0, 1345.1, 138.2, 141.3, 146.6, 153.1,
C23H15BrN2O2 (431.28): calcd. C 64.05, H 3.51, N 6.50; found C 159.8, 193.8 ppm. IR (KBr): ν
63.82, H 3.80, N 6.67.
= 1628 (CO) cm–1. ESI-MS: m/z
˜
max
= 393.2/395.1 [M + 1]+. C22H14Cl2N2O (393.26): calcd. C 67.19, H
3.59, N 7.12; found C 67.31, H 3.51, N 7.32.
Fe/AcOH-Mediated Reduction of 3a–e and 4a–b. General Procedure:
Fe powder (7.39 mmol, 0.41 g) was added to a solution of appropri-
(4-Amino-2-phenylquinolin-3-yl)(3,4-dichlorophenyl)methanone
ate isoxazoline 3a–e or 4a–b (1.23 mmol) in glacial acetic acid (11e): This compound was isolated in 62 % yield (0.30 g from
(10 mL), and the reaction mixture was heated at 110 °C for 30 min. 0.54 g) as a pale yellow solid, m.p. 160–162 °C. Rf (20% EtOAc/
Thereafter, the reaction mixture was concentrated to remove excess
acetic acid, neutralized with saturated aqueous NaHCO3 solution,
and then filtered through a Celite bed. The residue was washed
with ethyl acetate and the water layer was extracted with ethyl ace-
tate (2ϫ50 mL). The organic layers were combined, washed with
brine solution (50 mL), dried with Na2SO4, and concentrated un-
der reduced pressure to yield the crude product, which was further
purified by column chromatography on silica gel (60–120 mesh)
hexanes) = 0.59. IR (KBr): ν
= 1628 (CO), 3428 (NH2) cm–1.
˜
max
1H NMR (CDCl3, 200 MHz): δ = 6.63 (s, 1 H, NH), 7.11–7.19 (m,
5 H, ArH), 7.39–7.53 (m, 4 H, ArH), 7.71–7.93 (m, 2 H, ArH),
8.10 (d, J = 12.5 Hz, 1 H, ArH) ppm. 13C NMR ([D6]Py, 75 MHz):
δ = 110.8, 119.3, 124.7, 126.5, 129.2, 129.7, 130.0, 130.4, 131.1,
131.3, 132.3, 132.5, 142.0, 143.8, 154.7, 160.8, 197.3 ppm. ESI-MS:
m/z = 393.4/395.3 [M + 1]+. C22H14Cl2N2O (393.26): calcd. C
67.19, H 3.59, N 7.12; found C 67.44, H 3.81, N 7.29.
Eur. J. Org. Chem. 2007, 4343–4351
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4349

S. Madapa, D. Sridhar, G. P. Yadav, P. R. Maulik, S. Batra
FULL PAPER
[13]
A. K. Roy, B. Rajaraman, S. Batra, Tetrahedron 2004, 60,
2301–2310.
(4-Amino-2-p-tolylquinolin-3-yl)(4-chlorophenyl)methanone (12a):
This compound was isolated in 61% yield (0.28 g from 0.52 g) as
a yellow solid, m.p. 240–242 °C. Rf (20% EtOAc/hexanes) = 0.45.
1H NMR (CD3OD, 200 MHz): δ = 2.13 (s, 3 H, CH3), 6.91 (d, J
= 7.8 Hz, 2 H, ArH), 7.01–7.05 (m, 2 H, ArH), 7.16–7.26 (m, 4 H,
ArH), 7.44–7.48 (m, 1 H, ArH), 7.68–7.71 (m, 1 H, ArH), 7.85 (d,
J = 8.4 Hz, 1 H, ArH), 8.16 (d, J = 8.4 Hz, 1 H, ArH) ppm. 13C
NMR ([D5]Py, 75 MHz): δ = 21.8, 111.6, 119.2, 124.8, 126.2, 129.4,
129.9, 131.1, 131.2, 132.2, 136.7, 139.0, 139.5, 139.9, 153.9, 160.3,
[14]
[15]
[16]
S. Batra, A. K. Roy, Synthesis 2004, 2550–2554.
V. Singh, S. Batra, Tetrahedron Lett. 2006, 47, 7043–7045.
G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi, Eur. J. Org.
Chem. 2003, 1423–1427 and references cited therein.
G. Franco, R. Maria, P. Massimo, M. Maurizio, Heterocylces
1992, 34, 991–1004.
B. Venugopalan, C. P. Bapat, E. P. De Souza, N. J. De Souza,
J. Heterocycl. Chem. 1991, 28, 337–339.
B. Staskun, J. Org. Chem. 1966, 31, 2674–2676.
B. Purwono, R. K. Smalley, T. C. Porter, Synlett 1992, 231–
232.
[17]
[18]
198.7 ppm. IR (KBr): ν
= 1685 (CO), 3424 (NH2) cm–1. ESI-
˜
max
[19]
[20]
MS: m/z = 373.3/375.3 [M + 1]+. C23H17ClN2O (372.84): calcd. C
74.09, H 4.60, N 7.51; found C 73.93, H 4.76, N 7.65.
[21]
[22]
[23]
W. Stadelbauer, S. Prattes, W. Fiala, J. Heterocycl. Chem. 1998,
(4-Amino-2-p-tolylquinolin-3-yl)(4-bromophenyl)methanone (12b):
This compound was isolated in 61% yield (0.30 g from 0.55 g) as
a yellow solid, m.p. 210–212 °C. Rf (20% EtOAc/hexanes) = 0.52.
1H NMR (CDCl3, 300 MHz): δ = 2.23 (s, 3 H, CH3), 6.44 (s, 2 H,
NH2), 6.97 (d, J = 7.9 Hz, 2 H, ArH), 7.22–7.29 (m, 5 H, ArH),
7.38 (d, J = 8.0 Hz, 2 H, ArH), 7.48–7.53 (m, 1 H, ArH), 7.74–
7.79 (m, 1 H, ArH), 7.87 (d, J = 8.3 Hz, 1 H, ArH), 8.11 (d, J =
8.3 Hz, 1 H, ArH) ppm. 13C NMR (CDCl3, 75 MHz): δ = 19.9,
98.7, 108.9, 115.6, 119.5, 124.1, 125.5, 127.6, 128.3, 128.9, 129.3,
129.7, 130.0, 137.4, 137.5, 146.9, 150.2, 158.5, 196.9 ppm. IR
35, 627–636.
R. Bonjouklian, J. D. Cohen, PCT Int. Appl. WO 01 46,199,
1999 (Chem. Abstr. 2001, 135, 76865).
R. Bonjouklian, D. W. Johnson, P. A. Lander, V. F. Patel, S.
Vepachedu, Y. Xie, PCT Int. Appl. WO 01 27,116, 1999 (Chem.
Abstr. 2001, 134, 311201).
V. Singh, S. Madapa, G. P. Yadav, P. R. Maulik, S. Batra, Syn-
thesis 2006, 1995–2004.
Quinoline synthesis by reduction of a 2-nitrophenyl group with
SnCl2·2H2O, followed by intramolecular cyclization with a keto
group: a) O. B. Familoni, P. J. Klaas, K. A. Lobb, V. E. Pakade,
P. T. Kaye, Org. Biomol. Chem. 2006, 4, 3960–3965; b) S. Mad-
apa, V. Singh, S. Batra, Tetrahedron 2006, 62, 8740–8747 and
references cited therein.
[24]
[25]
(KBr): ν
= 1691 (CO), 3428 (NH2) cm–1. ESI-MS: m/z = 317.4/
˜
max
319.3 [M + 1]+. C23H17BrN2O (417.29): calcd. C 66.20, H 4.11, N
6.71; found C 65.98, H 4.31, N 6.66.
Supporting Information (see footnote on the first page of this arti-
[26]
H. H. Szmant, J. B. Arthur, J. Am. Chem. Soc. 1952, 74, 4397–
4400.
1
cle): Copies of H NMR, 13C NMR and mass spectra of represen-
[27]
[28]
G. Weygand, J. Chem. Soc. 1957, 1008–1014.
Crystal data for 3a (CHCl3/EtOH): C22H15ClN2O4, M =
tative compounds; copies of HSQC and HMBC spectra for com-
pounds 5a and 7a.
¯
406.81, triclinic, P1, a = 8.421(1), b = 10.709(1), c =
12.077(2) Å, α = 103.33(1), β = 101.24(1), γ = 110.090(1)°, V
Acknowledgments
= 949.5(2) Å3, Z = 2 Dcalcd. = 1.423 gcm–3, μ (Mo-Kα) =
0.23 mm–1, F2(000)
=
420, colorless block, dimensions
0.25ϫ0.20ϫ0.15 mm, 4008 reflections measured (Rint
=
Two of the authors (S. M. and G. P. Y.) gratefully acknowledge fin-
ancial assistance from Council of Scientific and Industrial Research
(CSIR), New Delhi in the form of fellowships. The authors
acknowledge Dr. Ashish Arora for carrying out the HMBC and
HSQC experiments.
0.0205), 3267 unique, wR2 = 0.111, conventional R = 0.0418
on F2 values of 2129 reflections with IϾ2σ(I), (Δ/σ) max = 000,
S = 1.022 for all data and 263 parameters. Structure solutions
by direct methods and refinements by full-matrix, least-squares
methods on F2. Programs: XSCANS (Siemens Analytical X-
ray Instrument Inc., Madison, WI, USA, 1996) for data collec-
tion and data processing; SHELXTL-NT (Bruker AXS Inc.,
Madison, Wisconsin, USA, 1997) for structure determination,
refinements and molecular graphics. CCDC-644536 contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif; for queries relating to X-ray data, please con-
tact maulik_prakas@yahoo.com).
[1] J. B. Sperry, D. L. Wright, Curr. Opin. Drug Discovery Dev.
2005, 8, 723–740.
[2] R. E. Ziegert, J. Toraeng, K. Knepper, S. Braese, J. Comb.
Chem. 2005, 7, 147–169.
[3] A few refs.[3–12] are provided only. T. M. V. D. Pinho Melo,
Curr. Org. Chem. 2005, 9, 925–958 and references cited therein.
[4] A. J. Manson, F. W. Stonner, H. C. Neumann, R. G. Chris-
tiansen, R. L. Clarke, J. H. Ackerman, D. F. Page, J. W. Dean,
D. K. Phillips, G. O. Potts, A. Arnold, A. L. Beyler, R. O. Clin-
ton, J. Med. Chem. 1963, 6, 1–9.
[29]
Crystal
data
for
compound
5c
(EtOAc/hexane):
C22H12Cl2N2O, M = 391.24, monoclinic, P21/c, a = 16.207(2),
b = 6.834(1), c = 17.281(2) Å, β = 107.57(1)°, V = 1824.7(4) Å3,
Z = 4, Dcalcd. = 1.424 gcm–3, μ (Mo-Kα) = 0.37 mm–1, F2(000)
= 800, colorless block, dimensions 0.3ϫ0.25ϫ0.2 mm, 4539
[5] P. Krogsgaard-Larsen, G. A. R. Johnston, D. Lodge, D. R.
Curtis, Nature 1977, 268, 53–55.
[6] L. Brehml, B. Ebert, U. Kristiansen, K. A. Wafford, J. A.
Kemp, P. Krogsgaard-Larsen, Eur. J. Med. Chem. 1997, 32,
357–363.
[7] F. Buttner, S. Bergemann, D. Guenard, R. Gust, G. Seitz, S.
Thoret, Bioorg. Med. Chem. 2005, 13, 3497–3511.
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M. Alessi, A. Piperno, G. Romeo, R. Romeo, Tetrahedron 1997,
53, 13855–13866.
[9] W. S. Laitonjam, T. S. Rajkumar, B. S. Chingakham, Steroids
2002, 67, 203–209.
[10] R. C. F. Jones, T. A. Pillainayagam, Synlett 2004, 2815–2817.
[11] D. Donati, S. Ferrini, S. Fusi, F. Ponticelli, Synthesis 2003,
2518–2524.
[12] M. F. A. Adamo, E. F. Duffy, D. Donati, P. Sarti-Fantoni, Tet-
rahedron 2007, 63, 2684–2688.
reflections measured (Rint = 0.0496), 3200 unique, wR2
=
0.1542, conventional R = 0.0626 on F values of 1543 reflections
with IϾ2σ(I), (Δ/σ)max = 000), S = 0.988 for all data and 244
parameters. CCDC-644537 contains the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
[30]
Crystal data for compound 7d ([D6]DMSO containing TMS):
¯
C22H14Cl2N2O·[(CH3)3Si]2, M = 466.44, triclinic, P1, a =
8.774(1), b = 11.963(1), c = 12.624(1) Å, α = 63.01, β =
76.76(1), γ = 72.69(1)°, V = 1120.36(2) Å3, Z = 2 Dcalcd.
=
1.383 gcm–3, μ (Mo-Kα) = 0.36 mm–1, F2(000) = 486, colorless
block, dimensions 0.275ϫ0.25ϫ0.15 mm, 4637 reflections
measured (Rint = 0.018), 3814 unique, wR2 = 0.1734, conven-
4350
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 4343–4351

Substituted Isoxazolo[4,3-c]quinolines via Chalcones
FULL PAPER
tional R = 0.0605 on F2 values of 2995 reflections with
IϾ2σ(I), (Δ/σ)max = 000, S = 1.022 for all data and 288 param-
eters. CCDC-644538 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
mensions 0.3ϫ0.25ϫ0.2 mm, 2096 reflections measured (Rint
= 0.0238), 1822 unique, wR2 = 0.0807, conventional R = 0.0476
on F2 values of 1269 reflections with IϾ2σ(I), (Δ/σ)max = 000,
S = 1.002 for all data and 235 parameters. CCDC-644535 con-
tains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
[31] Crystal data for compound 11b (CHCl3/EtOH): C22H15BrN2O,
M = 403.27, orthorhombic, Aba2, a = 12.616(2), b = 24.779(3),
c = 11.587(1) Å, V = 3622.2(8) Å3, Z = 8 Dcalcd. = 1.479 gcm–3,
μ (Mo-Kα) = 2.28 mm–1, F2(000) = 1640, colorless block, di-
Received: March 27, 2007
Published Online: July 10, 2007
Eur. J. Org. Chem. 2007, 4343–4351
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4351