Domino [3+2] cycloaddition/annulation reactions of β-(2-aminophenyl)-α,β-ynones with nitrile oxides: Synthesis of isoxazolo[4,5-c]quinolines

Article abstract of DOI:10.1002/ejoc.200390200

β-(2-Aminophenyl)-α,β-ynones react with nitrile oxides by domino [3+2] cycloaddition/annulation reactions giving rise to isoxazolo[4,5-c]quinolines in satisfactory yields. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390200

FULL PAPER
Domino [3؉2] Cycloaddition/Annulation Reactions of β-(2-Aminophenyl)-
α,β-ynones with Nitrile Oxides: Synthesis of Isoxazolo[4,5-c]quinolines
[a]
[b]
[b]
[a]
Giorgio Abbiati, Antonio Arcadi, Fabio Marinelli, and Elisabetta Rossi*
Keywords: Alkynes / Cycloaddition / Domino reactions / Polycycles
β-(2-Aminophenyl)-α,β-ynones react with nitrile oxides by
domino [3+2] cycloaddition/annulation reactions giving rise
to isoxazolo[4,5-c]quinolines in satisfactory yields.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
The readily available β-(2-aminophenyl/pyridinyl)-α,β- tors[5] and a new class of isoxazoloacridines and isoxazolo-
ynones are emerging as versatile building blocks for the quinolines was prepared as potential acetylcholinesterase
[
1]
[6]
construction of nitrogen-containing heterocyclic rings. In inhibitors. Despite their importance, the limited synthetic
particular, their domino cycloaddition/annulation reactions methodologies for their construction may represent the
could provide an interesting synthetic tool for building up bottleneck for further studies and developments in med-
fused mixed heteroaromatic compounds. Indeed, the dom- icinal chemistry. Thus, in analogy to our previous work,
ino [2ϩ2] cycloaddition/annulation reactions of β-(2- we are pleased to report that functionalized isoxazolo[4,5-
aminophenyl)-α,β-ynones 1 with enamines accomplished c]quinolines 3aϪg can be easily synthesised by slow drop-
the synthesis of quinolines, c-fused with different-size wise addition of a solution of the appropriate α-chloro-
[
2a]
carbocyclic rings.
Moreover, we reported, as a prelimi- oxime (1.2 mmol) in dry xylene to a boiling solution of β-
nary result, that sequential 1,3-dipolar cycloaddition/ (2-aminophenyl)-α,β-ynones 1aϪc (1.0 mmol) and triethyl-
annulation reactions of 1 with p-nitrophenyl azide and amine (TEA) (1.5 mmol) in dry xylene (Scheme 1, Table 1,
benzonitrile oxide can lead to triazolo[4,5-c]quinoline and method A). After usual work up, the reaction mixture was
isoxazolo[4,5-c]quinoline derivatives, respectively. The de- purified by flash chromatography on silica gel to yield the
velopment of new synthetic methods for the construction isoxazolo[4,5-c]quinolines in satisfactory yields.
of polycyclic quinoline ring systems is still an attractive re-
search area because these nuclei occur in pharmacologically
[
3]
active substances. Then, a further investigation on the re-
activity of β-(2-aminophenyl)-α,β-ynones 1 towards nitrile
oxides, derived from different substituted aldehydes, prom-
ises to provide a clean, mild, and general synthesis of func-
tionalised isoxazolo[4,5-c]quinolines and to overcome some
of the drawbacks caused by the drastic reaction conditions
required by traditional synthetic methods.[ It should be
pointed out that to date, only two reports dealing with the
synthesis of these derivatives have appeared in the literature,
both requiring harsh reaction conditions. For example,
4]
[
4a]
Staskun
prepared 3-methyl-4-phenylisoxazolo[4,5-c]qui-
noline by heating 2-phenyl-3-acetyl-4(1H)-quinolone oxime
above its melting point (290 °C). Recently, a number of
isoxazoloquinolines have been identified as MRP1 inhibi-
[
[
a]
b]
Istituto di Chimica Organica ‘ ‘A lessandro Marchesini’’, Facolt a`
di Farmacia, Universit a` degli Studi di Milano
Via Venezian 21, 20133 Milano, Italy
Scheme 1
Fax: (internat.) ϩ 39-02-50314476
E-mail: elisabetta.rossi@unimi.it
Dipartimento di Chimica, Ingegneria Chimica e Materiali,
Facolt a` di Scienze, Universit a` de L’Aquila
Via Vetoio, Coppito due, 67100 L’Aquila, Italy
The suggested reaction mechanism involves a regioselec-
tive [3ϩ2] cycloaddition reaction of the ynone with the ni-
Eur. J. Org. Chem. 2003, 1423Ϫ1427  2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0408Ϫ1423 $ 20.00ϩ.50/0
1423

G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi
FULL PAPER
lation[2b] of 1a promoted by the chloride ion gave 3j
Table 1. Isoxazolo[4,5-c]quinolines 3aϪl
(Scheme 3).
Scheme 3
With the aim to avoid or minimise the dimerization to
furoxanes of labile nitrile oxides, we carried out the reac-
tions involving alkanenitrile oxides 2gϪh in toluene at 40
°
C (Scheme 1, Table 1, method B). Under these milder con-
ditions the isoxazolo[4,5-c]quinoline 3h was isolated in 73%
yield, whereas the isoxazolo[4,5-c]quinoline 3i was isolated
as the main reaction product in 23% yield, beside several
unidentified products.
Finally, to keep the method as simple as possible and to
test the possibility to further improve the reaction yields, we
briefly investigated the development of a one-pot procedure
starting from 1 and generating the α-chloro oxime from the
corresponding oxime and, subsequently the nitrile oxide, in
the same reaction step. Thus, a solution of the crude α-
chloro oxime, obtained by treating the appropriate oxime
with N-chlorosuccinimide (NCS) at 0 °C in chloroform and
in the presence of a catalytic amount of pyridine (Py), was
added dropwise at 40 °C, over a period of 30 min, to a solu-
tion of 1d and triethylamine in toluene. Under these con-
ditions 1d reacts with 2e and 2h giving rise to the isox-
azolo[4,5-c]quinolines 3k and 3l in 57 and 41% yields,
respectively (Scheme 4, Table 1, method C).
trile oxide, generated in situ from the corresponding α-chlo-
rooxime, followed by an intramolecular addition/elimi-
nation reaction between the amino and carbonyl groups,
with loss of water. The observed regioselectivity is in agree-
ment with the results obtained in the cycloadditions of dis-
ubstituted electron-deficient alkynes with nitrile oxides giv-
ing rise to isoxazoles carrying the electron-withdrawing
group in the 4-position (Scheme 2).[
7]
Scheme 4
Scheme 2
In summary, we have shown that the sequential [3ϩ2]
Under these standard conditions the alkanenitrile oxides cycloaddition of readily available β-(2-aminophenyl)-α,β-
gϪh, generated in situ from the corresponding α-chloro ynones with nitrile oxides, followed by an annulation reac-
2
oxime, undergo dimerization to the corresponding furox- tion, leads in satisfactory yields to isoxazolo[4,5-c]quinol-
ans[ and the competitive nucleophilic addition/annu- ines.
8]
1424
Eur. J. Org. Chem. 2003, 1423Ϫ1427

Domino [3ϩ2] Cycloaddition/Annulation Reactions of β-(2-Aminophenyl)-α,β-ynones
FULL PAPER
1
18 2 3
67.5, 197.7 (one signal obscured) ppm. C25H N O (394.42):
Experimental Section
calcd. C 76.13, H 4.60, N 7.10; found C 76.02, H 4.57, N 7.13.
General Remarks: All chemicals and solvents are commercially
available and were used after distillation or treatment with drying
agents. Merck silica gel 60 F254 thin-layer plates were employed for
thin layer chromatography (TLC). Merck silica gel (230Ϫ400 mesh)
was employed for flash column chromatography. Melting points,
measured with a Stuart Scientific SMP3 apparatus, are uncor-
rected. Infrared spectra were recorded with an FT-IR
PerkinϪElmer SPECTRUM ONE spectrophotometer, using thin
films between NaCl plates in the cases of liquid samples and KBr
4-(4-Acetylphenyl)-3-(4-fluorophenyl)isoxazolo[4,5-c]quinoline (3c):
Reaction time: 5 h. Eluent for chromatography: PE/TEA (8:2).
Yield: 263 mg, 69%. Light yellow solid. M.p. 214Ϫ215 °C (dec.).
Ϫ1
1
IR (KBr): ν˜ ϭ 1680, 1603, 1516, 1438, 1267, 1226 cm . H NMR:
δ ϭ 2.63 (s, 3 H, CH CϭO), 6.93 (t, J ϭ 8.4 Hz, 2 H, arom.), 7.27
3
(m, 2 H, arom.), 7.54 (d, J ϭ 8.1 Hz, 2 H, arom., AAЈ part of an
AAЈBBЈ system), 7.82 (d, J ϭ 8.1 Hz, 2 H, arom., BBЈ part of an
AAЈBBЈ system), 7.84 (m, 1 H, arom.), 7.98 (t, J ϭ 7.3 Hz, 1 H,
arom.), 8.29 (d, J ϭ 8.1 Hz, 1 H, arom.), 8.53 (d, J ϭ 7.4 Hz, 1 H,
1
13
2
tablets for solid samples. H NMR spectra were recorded at room
arom.) ppm. C NMR: δ ϭ 26.8, 111.8, 114.4, 115.1 (d, J
C,F
ϭ
4
temp. in CDCl
sidual chloroform as the internal reference (δ
NMR spectra were recorded at room temp. in CDCl
same spectrometer, at 50.3 MHz, using the central peak of chloro-
form as the internal reference (δ ϭ 77.3 ppm). Low-resolution
3
, with a Varian-Gemini 200 at 200 MHz, using re-
21 Hz), 121.6, 124.0 (d, J
(d, J ϭ 8 Hz), 131.8, 137.4, 142.0, 147.4, 154.3, 157.9, 131.5 (d,
JC,F ϭ 248 Hz), 167.6, 197.5 ppm (one signal obscured).
C,F
ϭ 4 Hz), 128.0, 128.1, 130.0, 131.5
1
3
3
H
ϭ 7.27 ppm).
C
C,F
1
3
, with the
C H FN O (382.39): calcd. C 75.38, H 3.95, N 7.33; found C
2
4
15
2
3
C
75.49, H 4.00, N 7.31.
mass spectra were run with a Fisons MD 800 spectrometer using
4
-(4-Chlorophenyl)-3-(4-nitrophenyl)isoxazolo[4,5-c]quinoline (3d):
the EI method. α,β-Ynones 1aϪd were prepared according to a
Reaction time: 8 h. Eluent for chromatography: PE/EtOAc (9:1).
Yield: 309 mg, 77%. Yellowish solid. M.p. 184Ϫ185 °C. IR (KBr):
ν˜ ϭ 1633, 1605, 1590, 1540, 1380 cm . H NMR: δ ϭ 7.23 (d,
J ϭ 8.3 Hz, 2 H, arom., AAЈ part of an AAЈBBЈ system), 7.39 (d,
J ϭ 8.3 Hz, 2 H, 2 H, arom., BBЈ part of an AAЈBBЈ system), 7.51
[
9]
described method. Oximes and α-chloro oximes were synthesised
according to literature procedures or purchased from standard
chemical suppliers. ‘‘PE’’ refers to the fraction of petroleum ether
with boiling range of 40Ϫ60 °C. ‘‘EtOAc’’ means ethyl acetate.
Ϫ1
1
(
(
d, J ϭ 8.4 Hz, 2 H, arom., AAЈ part of an AAЈBBЈ system), 7.82
m, 1 H, arom.), 7.98 (dt, J ϭ 7.7, 1.1 Hz, 1 H, arom.), 8.17 (d,
Reactions of α,β-Ynones 1a؊c with Nitrile Oxides 2a؊h (Method
A): A solution of the appropriate α-chloro oxime (1.2 mmol) in dry
xylene (5 mL) was slowly added to a boiling, nitrogen-flushed and
well-stirred solution of the α,β-ynone 1aϪc (1.0 mmol) and TEA
J ϭ 8.4 Hz, 2 H, 2 H, arom., BBЈ part of an AAЈBBЈ system), 8.36
d, J ϭ 8.0 Hz, 1 H, arom.), 8.54 (d, J ϭ 8.5 Hz, 1 H, arom) ppm.
(
1
3
C NMR: δ ϭ 111.3, 114.1, 121.6, 123.4, 128.2, 128.5, 130.0,
(1.5 mmol) in dry xylene (5 mL). The reaction mixture was stirred
1
1
1
30.6, 130.8, 132.1, 134.5, 136.1, 136.2, 147.5, 148.7, 153.8, 157.1,
68.0 ppm. C22H12ClN O (401.80): calcd. C 65.76, H 3.01, N
3 3
0.46; found C 65.65, H 3.05, N 10.39.
under reflux for 3Ϫ24 h, until no more α,β-ynone was detectable
by TLC. The solvent was then removed in vacuo, the residue taken
up in EtOAc and washed twice with a solution of 0.1  HCl. Fi-
nally, the organic layer was dried with anhydrous sodium sulfate
and freed from solvent under reduced pressure at 40 °C. The crude
product was purified by flash chromatography on a silica gel col-
umn.
4
-(4-Chlorophenyl)-3-styrylisoxazolo[4,5-c]quinoline (3e): Reaction
time: 5 h. Eluent for chromatography: PE/EtOAc (95:5). Yield:
1
1
7
72 mg, 45%. Yellow solid. M.p. 168Ϫ173 °C. IR (KBr): ν˜ ϭ 1632,
Ϫ1 1
590 cm
. H NMR: δ ϭ 6.76 (d, J ϭ 16.1 Hz, 1 H, ϭCH),
.30Ϫ7.46 (m, 5 H, arom.), 7.50 (d, J ϭ 16.1 Hz, 1 H, ϭCH), 7.60
4-(4-Chlorophenyl)-3-phenylisoxazolo[4,5-c]quinoline (3a): Reaction
(
(
d, J ϭ 8.4 Hz, 2 H, arom., AAЈ part of an AAЈBBЈ system), 7.76
m, 1 H, arom.), 7.78 (d, J ϭ 8.4 Hz, 2 H, 2 H, arom., BBЈ part of
time: 6 h. Eluent for chromatography: PE/EtOAc (98:2). Yield:
2
1
2
7
53 mg, 71%. Yellowish solid. M.p. 186Ϫ188 °C. IR (KBr): ν˜ ϭ
Ϫ1 1
an AAЈBBЈ system), 7.93. (dt, J ϭ 6.9, 1.4 Hz, 1 H, arom.), 8.33
d, J ϭ 8.0 Hz, 1 H, 1 H, arom.), 8.48 (d, J ϭ 6.9 Hz, 1 H, arom.)
650, 1630, 1590, 1090 cm . H NMR: δ ϭ 7.15 (d, J ϭ 8.5 Hz,
H, arom., AAЈ part of an AAЈBBЈ system), 7.26 (m, 4 H, arom.),
.34 (d, J ϭ 8.5 Hz, 2 H, 2 H, arom., BBЈ part of an AAЈBBЈ
(
1
3
ppm. C NMR: δ ϭ 112.2, 113.7, 114.4, 121.6, 127.3, 127.8, 128.9,
1
1
29.0, 129.5, 129.8, 131.1, 131.6, 135.5, 136.2, 136.9, 137.6, 147.3,
54.4, 155.4, 167.2 ppm. C24 15ClN O (382.84): calcd. C 75.29, H
system), 7.42 (m, 1 H, arom.), 7.76 (m, 1 H, arom.), 7.91 (m, 1 H,
arom.), 8.31 (d, J ϭ 8.3 Hz, 1 H, arom.), 8.48 (dd, J ϭ 8.1, 1.1 Hz,
H
2
H, arom) ppm. 1 C NMR: δ ϭ 112.2, 114.7, 121.9, 128.1, 128.3,
3
3.95, N 7.32; found C 75.41, H 3.91, N 7.36.
1
1
1
28.5, 128.7, 129.9, 130.2, 130.3, 131.3, 132.0, 135.9, 136.5, 147.7,
Ethyl 4-(4-Acetylphenyl)isoxazolo[4,5-c]quinoline-3-carboxylate (3f):
Reaction time: 3 h. Eluent for chromatography: PE/EtOAc (98:2).
Yield: 198 mg, 55%. Yellow solid. M.p. 107Ϫ108 °C. IR (KBr): ν˜ ϭ
ϩ
54.9, 159.2, 167.9 ppm. EI-MS: m/z (%) ϭ 358 (37) [M ϩ 2], 356
ϩ
(
2
100) [M ]. C22H13ClN O (356.80): calcd. C 74.16, H 3.68, N 7.87;
found C 74.20, H 3.65, N 7.82.
Ϫ1 1
1
736, 1684, 1677, 1633, 1383, 1282, 1289, 1211 cm . H NMR:
δ ϭ 1.05 (t, J ϭ 7.0 Hz, 3 H, CH ), 2.69 (s, 3 H, CH ), 4.08 (q,
J ϭ 7.0 Hz, 2 H, CH ), 7.82 (m, 1 H, arom.), 7.86 (d, J ϭ 8.1 Hz,
H, arom., AAЈ part of an AAЈBBЈ system), 7.98 (t, J ϭ 6.9 Hz,
H, arom.), 8.15 (d, J ϭ 8.1 Hz, 2 H, arom., BBЈ part of an
3
3
4
-(4-Acetylphenyl)-3-(4-methoxyphenyl)isoxazolo[4,5-c]quinoline
2
(
(
(
3b): Reaction time: 24 h. Eluent for chromatography: PE/TEA
2
1
8:2). Yield: 248 mg, 63%. Yellow solid. M.p. 151Ϫ152 °C. IR
Ϫ1
1
KBr): ν˜ ϭ 1673, 1609, 1514, 1356, 1268, 1251 cm . H NMR:
CϭO), 3.89 (s, 3 H, CH O), 6.73 (d, J ϭ
.8 Hz, 2 H, arom., AAЈ part of an AAЈBBЈ system), 7.19 (d, J ϭ
AAЈBBЈ system), 8.37 (d, J ϭ 7.8 Hz, 1 H, arom.), 8.50 (d, J ϭ
δ ϭ 2.62 (s, 3 H, CH
3
3
1
3
8
1
1
.0 Hz, 1 H, arom.) ppm. C NMR: δ ϭ 13.7, 27.2, 63.3, 110.7,
8
8
8
8
13.8, 121.6, 128.6, 128.7, 129.4, 130.3, 132.5, 138.0, 143.2, 147.5,
52.0, 153.6, 160.1, 167.5, 197.7 ppm. C21H N O (360.36): calcd.
16 2 4
.8 Hz, 2 H, arom., BBЈ part of an AAЈBBЈ system), 7.56 (d, J ϭ
.2 Hz, 2 H, arom., AAЈ part of an AAЈBBЈ system), 7.82 (d, J ϭ
.2 Hz, 2 H, arom., BBЈ part of an AAЈBBЈ system), 7.84 (m, 1 H,
C 69.99, H 4.48, N 7.77; found C 69.84, H 4.46, N 7.80.
arom.), 7.95 (ddd, J ϭ 8.4, 7.2, 1.6 Hz, 1 H, arom.), 8.35 (d, J ϭ
Ethyl 4-[3-(Trifluoromethyl)phenyl]isoxazolo[4,5-c]quinoline-3-car-
boxylate (3g): Reaction time: 3 h. Eluent for chromatography: PE/
1
3
8.0 Hz, 1 H, arom.), 8.52 (d, J ϭ 7.8 Hz, 1 H, arom.) ppm.
C
NMR: δ ϭ 26.8, 55.5, 111.9, 113.8, 114.5, 120.0, 121.6, 127.9, EtOAc (98:2). Yield: 185 mg, 48%. Yellow wax. IR (NaCl): ν˜ ϭ
Ϫ1
1
129.9, 130.0, 130.9, 131.6, 137.2, 142.1, 147.3, 154.6, 158.4, 161.0,
1739, 1633 cm . H NMR: δ ϭ 1.14 (t, J ϭ 7.3 Hz, 3 H, CH
3
),
Eur. J. Org. Chem. 2003, 1423Ϫ1427
1425

G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi
FULL PAPER
4
.19 (q, J ϭ 7.3 Hz, 2 H, CH
2
), 7.71 (t, J ϭ 7.3 Hz, 1 H, arom.),
containing the α,β-ynone 1d (239 mg, 0.81 mmol) and triethyl-
7
.82 (m, 2 H, arom.), 8.00 (m, 3 H, arom.), 8.37 (d, J ϭ 8.7 Hz, 1 amine (197 mg, 1.95 mmol) in toluene (6 mL). The mixture was
13
H, arom.), 8.51 (d, J ϭ 8.1 Hz, 1 H, arom.) ppm. C NMR: δ ϭ then stirred at 40 °C overnight, concentrated to dryness, taken up
1
1
3.6, 63.2, 110.6, 113.8, 121.6, 123.9 (q, JC,F ϭ 272 Hz), 125.8 (q, in EtOAc (60 mL) and washed twice with a solution of 0.1  HCl
3
3
J
C,F ϭ 4 Hz), 126.5 (q, JC,F ϭ 4 Hz), 128.4, 129.2, 130.1, 131.1 (2 ϫ 40 ml). The organic layer was finally dried with anhydrous
2
(q, JC,F ϭ 32 Hz), 132.1, 132.3, 139.6, 147.5, 151.7, 153.2, 159.8, sodium sulfate, freed from the solvent under reduced pressure and
1
67.6 ppm. C20
H
13
F
3
N
2
O
3
(386.32): calcd. C 62.18, H 3.39, N 7.25;
the crude product was purified by flash chromatography on a silica
gel column [PE/EtOAc (95:5)].
found C 62.05, H 3.36, N 7.28.
4
-Chloro-2-(4-chlorophenyl)quinoline (3j): Reaction time: 18 h. Elu-
Ethyl 4-(3-Styrylisoxazolo[4,5-c]quinolin-4-yl)benzoate (3k): Yield:
194 mg, 57%. Yellow solid. M.p. 159Ϫ160 °C. IR (KBr): ν˜ ϭ 1716,
ent for chromatography: PE/EtOAc (95:5). Yield: 238 mg, 87%.
Ϫ1
1
Yellowish solid. M.p. 125Ϫ126 °C. IR (KBr): ν˜ ϭ 1588, 1571, 1544, 1600, 1438 cm . H NMR: δ ϭ 1.48 (t, J ϭ 7.0 Hz, 3 H, CH
3
),
), 6.74 (d, J ϭ 16.5 Hz, 1 H, ϭCH),
7.33 (m, 5 H, arom.), 7.54 (d, J ϭ 16.5 Hz, 1 H, ϭCH), 7.78 (t,
H, arom.), 7.82 (ddd, J ϭ 8.4, 6.9, 1.4 Hz, 1 H, arom.), 7.96 [s, 1 J ϭ 7.0 Hz, 1 H, arom.), 7.90 (m, 3 H, arom.), 8.30 (m, 3 H, arom.),
Ϫ1
1
1
486, 1091 cm . H NMR: δ ϭ 7.53 (d, J ϭ 8.6 Hz, 2 H, arom.,
4.49 (q, J ϭ 7.0 Hz, 2 H, CH
2
AAЈ part of an AAЈBBЈ system), 7.66 (ddd, J ϭ 8.4, 6.9, 1.2 Hz, 1
1
3
H, 3-H, arom.), 8.13 (d, J ϭ 8.6 Hz, 2 H, 2 H, arom., BBЈ part of 8.45 (d, J ϭ 6.5 Hz, 1 H, arom.) ppm. C NMR: δ ϭ 14.4, 61.4,
an AAЈBBЈ system), 8.19 (m, 1 H, arom.), 8.25 (dd, J ϭ 8.4, 1.2 Hz,
113.6, 114.4, 121.5, 127.3, 127.9, 28.9, 129.4, 129.8, 131.6, 131.7,
H, arom.) ppm. 13C NMR: δ ϭ 118.7, 124.1, 125.4, 127.5, 128.8, 135.5, 137.6, 142.4, 147.1, 154.5, 155.4, 166.2, 167.2 (3 signals ob-
1
1
ϩ
29.2, 130.1, 130.8, 136.2, 137.1, 143.4, 149.1, 156.0 ppm. EI-MS:
20 2 3
scured) ppm. EI-MS: m/z (%) ϭ 420 (100) [M ]. C27H N O
ϩ
ϩ
ϩ
m/z (%) ϭ 275 (58) [M ϩ 2], 273 (92) [M ], 238 (100) [M Ϫ Cl], (420.47): calcd. C 77.13, H 4.79, N 6.66; found C 76.32, H 4.75,
ϩ
2
03 [M Ϫ 2 Cl] (58). C15
H
9
Cl
2
N (274.14): calcd. C 65.72, H 3.31,
N 6.52.
N 5.11; found C 65.64, H 3.29, N 4.99.
Ethyl 4-(3-Ethylisoxazolo[4,5-c]quinolin-4-yl)benzoate (3l): Yield:
Reactions of α,β-Ynone 1a with Nitrile Oxides 2g؊h (Method B): A 126 mg, 45%. Yellow solid. M.p. 122Ϫ124 °C. IR (KBr): ν˜ ϭ 1716,
Ϫ1
1
solution of the appropriate α-chloro oxime (1.2 mmol) in dry tolu-
ene (5 mL) was slowly added to a nitrogen-flushed and well-stirred
solution of the α,β-ynone 1aϪc (1.0 mmol) and TEA (1.5 mmol)
1600, 1570 cm . H NMR: δ ϭ 1.05 (t, J ϭ 7.2 Hz, 3 H, CH
1.48 (t, J ϭ 7.0 Hz, 3 H, CH ), 2.80 (q, J ϭ 7.2 Hz, 2 H, CH
4.47 (q, J ϭ 7.2 Hz, 2 H, CH
3
),
),
3
2
2
O), 7.78 (m, 3 H, arom.), 7.93 (t,
in dry toluene (5 mL). The reaction mixture was stirred at 40 °C J ϭ 6.9 Hz, 1 H, arom.), 8.28 (d, J ϭ 8.4 Hz, 2 H, arom.), 8.36 (d,
for 24 h. The solvent was then removed in vacuo, the residue taken
up in EtOAc and washed twice with a solution of 0.1  HCl. Fi-
nally, the organic layer was dried with anhydrous sodium sulfate
and freed from solvent under reduced pressure at 40 °C. The crude
product was purified by flash chromatography on a silica gel col-
umn [PE/EtOAc (98:2)].
J ϭ 8.5 Hz, 1 H, arom.), 8.46 (d, J ϭ 6.9 Hz, 1 H, arom.) ppm.
1
3
C NMR: δ ϭ 11.8, 14.4, 20.6, 61.5, 112.9, 114.5, 121.6, 127.9,
129.0, 129.7, 128.9, 131.6, 142.8, 147.0, 154.9, 159.8, 166.2,
167.0 ppm (one signal obscured). C21 (346.38): calcd. C
72.82, H 5.24, N 8.09; found C 72.32, H 5.20, N 7.99.
18 2 3
H N O
4
-(4-Chlorophenyl)-3-(1-ethylpropyl)isoxazolo[4,5-c]quinoline (3h):
Yield: 256 mg, 73%. Yellowish oil. IR (NaCl): ν˜ ϭ 1634, 1600, Acknowledgments
Ϫ1
1
1
558, 1520, 1090 cm . H NMR: δ ϭ 0.77 (t, J ϭ 7.3 Hz, 6 H,
CH ), 1.70 (m, 4 H, CH ), 2.78 (m, 1 H, CH), 7.58 (m, 4 H, arom.),
.75 (m, 1 H, arom.), 7.89 (m, 1 H, arom.), 8.28 (d, J ϭ 8.4 Hz, 1
The authors gratefully acknowledge the Ministero dell’Istruzione,
dell’Universit a` e della Ricerca (MIUR) for financial support.
3
2
7
13
H, arom.), 8.46 (d, J ϭ 8.1 Hz, 1 H, arom) ppm. C NMR: δ ϭ
1
1
1.7, 26.9, 40.2, 113.6, 114.6, 121.6, 127.6, 128.8, 129.7, 130.4,
31.3, 135.7, 137.5, 147.0, 154.9, 131.8, 166.6 ppm. C21 19ClN
H
2
O
[
1]
G. Abbiati, A. Arcadi, F. Marinelli, E. Rossi, Synthesis 2002,
3, 1912Ϫ1916 and references therein.
(350.84): calcd. C 71.89, H 5.46, N 7.98; found C 71.67, H 5.49,
1
N 8.02.
[2] [2a]
E. Rossi, G. Abbiati, A. Arcadi, F. Marinelli, Tetrahedron
Lett. 2001, 42, 3705Ϫ3708. [ A. Arcadi, F. Marinelli, E.
Rossi, Tetrahedron 1999, 55, 13233Ϫ13250.
3] [3a]
2b]
4
7
1
-(4-Chlorophenyl)-3-ethylisoxazolo[4,5-c]quinoline (3i): Yield:
1 mg, 23%. Yellow solid. M.p. 124Ϫ125 °C. IR (KBr): ν˜ ϭ 1634,
596, 1556, 1088 cm . H NMR: δ ϭ 1.15 (t, J ϭ 7.5 Hz, 3 H,
), 1.70 (q, J ϭ 7.5 Hz, 2 H, CH ), 7.57 (d, J ϭ 8.8 Hz, 2 H,
[
K. Gorlitzer, J. Fabian, P. Froheberg, G. Drutkowski, Phar-
Ϫ1
1
[3b]
mazie 2002, 57, 243Ϫ247.
lerano, W. Filippelli, G. Falcone, Farmaco, Ed. Sci. 2001, 56,
39Ϫ956.
L. Savini, L. Chiasserini, C. Pel-
CH
3
2
arom., AAЈ part of an AAЈBBЈ system), 7.66 (d, J ϭ 8.8 Hz, 2 H,
arom., BBЈ part of an AAЈBBЈ system), 7.74 (m, 1 H, arom.), 7.89
9
[
[
4] [4a]
B. Staskun, J. Org. Chem. 1966, 31, 2674Ϫ2676. [4b] B.
(m, 1 H, arom.), 8.29 (d, J ϭ 8.4 Hz,, 1 H, arom.), 8.43 (d, J ϭ
Venugopalan, C. P. Bapat, E. P. de Souza, N. J. de Souza, J.
Heterocycl. Chem. 1991, 28, 337Ϫ339.
13
8
1
1
.1 Hz, 1 H, arom) ppm. C NMR: δ ϭ 12.0, 20.8, 113.0, 114.6,
5] [5a]
R. Bonjouklian, J. S. York, PCT Int. Appl. WO
21.7, 127.8, 129.0, 129.9, 130.5, 131.6, 136.1, 137.6, 147.4, 154.9,
59.9, 167.1 ppm. C18H13ClN O (308.76): calcd. C 70.02, H 4.24,
2
5b]
2
002000624, 2002; Chem. Abstr. 2002, 136, 69745. [ R. Bon-
jouklian, J. D. Cohen, J. M. Gruber, D. W. Johnson, L. N.
Jungheim, J. S. Kroin, P. A. Lander, H. Lin, M. C. Lohman,
B. S. Muehl, B. H. Norman, V. F. Patel, M. E. Richett, K. J.
Thrasher, S. Vepachedu, W. T. White, Y. Xie, J. S. York, B. L.
Parkhurst, PCT Int. Appl. WO 2001046199, 2001; Chem.
Abstr. 2001, 135, 76865. [ R. Bonjouklian, D. W. Johnson, P.
A. Lander, M. C. Lohman, V. F. Patel, S. Vepachedu, Y. Xie,
N 9.07; found C 70.05, H 4.24, N 9.06.
One-Pot Reactions of α,β-Ynone 1d with Nitrile Oxides 2e,h
(Method C): To a well-stirred solution of 3-phenylpropenal oxime
or propionaldehyde oxime (1.63 mmol) in chloroform (4 mL) and
pyridine (0.02 mL), cooled to 0 °C, N-chlorosuccinimide (217 mg,
5c]
1.63 mmol) was added portionwise over a period of 30 min. The
PCT Int. Appl. WO 2001027116, 2001; Chem. Abstr. 2001, 134,
mixture was treated at room temperature for 2 h, until the starch-
iodide paper test was negative, then diluted with toluene (10 mL)
and added dropwise at 40 °C, over a period of 4 h, to a solution
[5d]
311201.
B. Buettelmann, T. Godel, L. Gross, M-P. Heitz
Niedhart, C. Riemer, R. Wyler, PCT Int. Appl. No WO
9532205, 1995; Chem. Abstr. 1996, 124, 232481.
1426
Eur. J. Org. Chem. 2003, 1423Ϫ1427

Domino [3ϩ2] Cycloaddition/Annulation Reactions of β-(2-Aminophenyl)-α,β-ynones
FULL PAPER
[
[
6]
7]
F. Gatta, M. R. Del Giudice, M. Pomponi, M. Marta, Hetero-
cycles 1992, 34, 991Ϫ1004.
P. Gr ünanger, P. Vita-Finzi, in The Chemistry of Heterocyclic
Compounds (Eds.: A. Weissberger, E. C. Taylor), John Wiley,
New York, 1999, vol. 49.
try (Ed.: A. L. Katritzky), Academic, Orlando, 1981, vol. 29.
[8b]
W. Sliwa, A. Thomas, Heterocycles 1985, 23, 399Ϫ416.
[9]
S. Cacchi, G. Fabrizi, F. Marinelli, Synlett 1999, 4, 401Ϫ404.
Received December 23, 2002
[Ø02658]
[
8] [8a]
A. Gasco, A. J. Bulton in Advances in Heterocyclic Chemis-
Eur. J. Org. Chem. 2003, 1423Ϫ1427
1427