Unambiguous structure elucidation of the reaction products of 3-acyl-4-methoxy-1-methylquinolinones with hydroxylamine via NMR spectroscopy

Article abstract of DOI:10.1016/j.tet.2007.08.108

Reaction of 3-acyl-4-methoxy-1-methylquinolinones 2a,b with hydroxylamine has been investigated under different experimental conditions. Whereas compound 2a gives rise selectively and exclusively to the regioisomeric isoxazolo[4,5-c]- or isoxazolo[4,3-c]q

Full text of DOI:10.1016/j.tet.2007.08.108

Tetrahedron 63 (2007) 11656–11660
Unambiguous structure elucidation of the reaction products
of 3-acyl-4-methoxy-1-methylquinolinones with hydroxylamine
via NMR spectroscopy
*
Stefano Chimichi, Marco Boccalini and Alessandra Matteucci
*
Dipartimento di Chimica Organica ‘U. Schiff’ and Laboratorio di Progettazione, Sintesi e Studio di Eterocicli
Biologicamente Attivi (HeteroBioLab), Via della Lastruccia 13, I-50019 Sesto F.no, Firenze, Italy
Received 21 June 2007; revised 8 August 2007; accepted 30 August 2007
Available online 5 September 2007
Abstract—Reaction of 3-acyl-4-methoxy-1-methylquinolinones 2a,b with hydroxylamine has been investigated under different experimen-
tal conditions. Whereas compound 2a gives rise selectively and exclusively to the regioisomeric isoxazolo[4,5-c]- or isoxazolo[4,3-c]quino-
lin-4(5H)one (compound 3a or 4a, respectively), reaction of 2b always led to a mixture of the required isoxazole together with the oxazole
derivative. Structural elucidation of all products has been independently achieved by multinuclear (13C and 15N) magnetic resonance spec-
troscopy.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
We report here the synthesis of the title compounds together
with a discussion on the reaction mechanism under different
experimental conditions; unambiguous structure elucidation
of the isomeric products being achieved by 13C and 15N
NMR spectroscopies.
Recently, we devoted our attention to the reaction of 1,2-bis-
nucleophiles with quinolinylenaminones with the aim of
synthesizing new 3-isoxazolyl- or pyrazolyl-substituted
4-hydroxy-2(1H)-quinolinones of type A.1 Following our
research in the chemistry of heterocycles, we became inter-
ested in the synthesis of new fused isoxazolo[4,5-c]- (B) or
isoxazolo[4,3-c]quinolin-4(5H)ones (C)2–5 as biologically
attractive tricyclic systems that could act as P-38 mitogen-
activated protein (MAP) kinase inhibitors,6,7 benzodiaze-
pine ligand receptors8 or selective multidrug resistance
protein inhibitors.9
2. Results and discussion
Reaction of 3-acetyl-4-methoxy-1-methylquinolin-2(1H)-
one (2a), easily obtained as a single product by treatment
of compound 1a1 with dimethyl sulfate in acetone, with
hydroxylamine could, in theory, give rise to three different
products, namely compounds 3a–5a (Scheme 1) depend-
ing on the experimental conditions. Thus, if the reaction
is carried out with hydroxylamine hydrochloride or
hydroxylamine free base, two different products are obtained
(see Table 1). Structural assignment of the product
C12H10N2O2 deriving from the reaction of 2a with
hydroxylamine hydrochloride can be achieved as follows:
(a) the oxazole structure 5a was excluded on the basis
of the presence of a three-bond connectivity between
C-3a and the methyl group at position 3 in the 13C NMR
spectra (HMBC experiments) of compounds 3a and 4a;
(b) distinction between the two regioisomeric isoxazole
structures was then tentatively based on the chemical shift
of the C-3 atom that in the compound under examination
is more similar to that of a 3-substituted isoxazole with
respect to a 5-substituted one (Dd ca. 10 ppm). The
[4,5-c] structural attribution to this product (compound
3a) was then confirmed by long-range 1H–15N
OH
R1
R
N
N
O
N
R=
,
N
O
A
O
N
N
O
3
9b
3a
R
9
6
R
8
7
9a
5a
N
4
N
R"
O
O
R'
R'
R"
B
C
Keywords: Isoxazolo[4,5-c]quinolin-4(5H)ones; 3-Acyl-4-methoxy-1-
methylquinolinones; Structure determination; 13C NMR; HMBC;
15N NMR.
* Corresponding authors. Tel.: +39 055 4573537; fax: +39 055 4573568
(S.C.); e-mail: stefano.chimichi@unifi.it
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.08.108

S. Chimichi et al. / Tetrahedron 63 (2007) 11656–11660
11657
OH
N
O
O
i or ii
R
Yield 70%
1a,b
R
O
N
N
O
N
O
O
3
3
9b
3a
9b
3N
O
9b
3a
a R=Me
b R=Ph
3a
9
6
9
6
9
6
9a
5a
8
7
8
7
R
R
9a
5a
8
7
9a
5a
and/or
and/or
4
4
4
N
O
N
3a,b
4a,b
5a,b
OMe O
R
i or ii
N
O
2a,b
Scheme 1. Reagents and conditions: (i) NH2OH$HCl, Et3N, ethylene glycol, reflux; (ii) NH2OH$HCl, ethylene glycol, reflux.
heteronuclear shift correlation studies. Thus, not only the
isoxazole nature of the compound can be confirmed
through the chemical shift value of the nitrogen atom
but we may also unambiguously solve the ambiguity
between the [4,3-c] or [4,5-c] ring fusion (compounds 4a
and 3a, respectively) on the basis of the three-bond corre-
lation between the nitrogen atom (d ꢀ4.0 ppm) and the
methyl group resonating at d 2.68 ppm (Tables 2 and 4).
From a mechanistic point of view this product may be
considered the ‘normal’ one arising from the attack of
the nitrogen atom of the nucleophile on the acetyl group;
this hypothesis was confirmed by the isolation of the cor-
responding oxime when the reaction was carried out in
ethanol at reflux (quantitative yield, see Section 4). Subse-
quently heating this oxime in xylene or ethylene glycol at
reflux gave compound 3a. The reaction of 2a with
hydroxylamine free base gave a different but very similar
On the other hand, the behavior of 1a in the reactions with
hydroxylamine or hydroxylamine hydrochloride is the
same in both cases: the reactions gave a C12H10N2O2 com-
pound different from 3a and 4a. The oxazole nature of this
product was easily confirmed by 13C NMR, the product
showing in the gHMBC experiments only one correlation
between the quaternary carbon resonating at d 162.7 ppm
(C-2) with the C-methyl group and the absence of correla-
tions for C-3a (d 128.8 ppm); once again 15N NMR data
are in perfect agreement with the assigned structure 5a
(Table 4). The structure of this compound, previously chem-
ically proved by Stadlbauer by a different synthetic proce-
dure,5,10 can be rationalized on the basis of a Beckmann
rearrangement of the intermediate oxime.
Reaction of 2b with hydroxylamine or hydroxylamine hy-
drochloride under the same conditions gave a mixture of
two products in different amounts: whereas with the free
base the ratio of the products is 1:1, when the reaction
is carried out with the hydrochloride there is a predomi-
nant compound (92:8, see Table 1). In both cases, the
obtained compounds have been separated by flash
chromatography and then carefully examined by NMR
spectroscopy. Once again 15N NMR experiments allowed
us to ascertain the oxazole nature of one of the two
reaction products in both the reactions. In particular for
the reaction with hydroxylamine hydrochloride the minor
compound was proved to be the oxazolo[4,5-c] derivative
5b, whereas the predominant one was an isoxazole deriv-
ative whose structure was determined on the basis of the
chemical shifts of C-3 and C-9b and of their long-range
C–H connectivities. On this basis analysis of the gHMBC
spectra led us to attribute the signal at d 160.9 ppm to the
quaternary carbon at position 3 owing to its correlation
peak with the ortho protons of the phenyl group and
therefore structure 3b was assigned to this compound.
On the other hand, carbon atom at position 9b resonates
now at d 168.3 ppm, according to the properties of
a [4,5-c] fused isoxazole ring (see compounds 3a and
4a, Table 3). As for the different isoxazole originating
from the reaction of 2b with the free base, the gHMBC
spectra show a correlation peak between the ortho protons
of the phenyl group with the quaternary carbon resonating
1
(mp, IR, and H NMR spectra) compound C12H10N2O2;
once again this product has an isoxazole nature (presence
of the three-bond connectivity between the 3-CH3 and C-
3a), but now differently from compound 3a the nitrogen
atom did not show any long-range correlation in the pro-
ton-detected 1H–15N HMBC experiments. Moreover, the
13C NMR chemical shifts of 4a are in perfect agreement
with a 5-substituted isoxazole (Table 3). Although the
mechanism of the reaction was not ascertained, no inter-
mediates having been isolated, it is reasonable to hypo-
thesize as the first step of the reaction a nucleophilic
attack of the reagent on the methoxy group at position 4
of the quinoline ring with a subsequent elimination of
methanol. Following this hypothesis, we reacted 2a with
a primary amine in ethanol, thus obtaining the expected
substitution product 6 (see Scheme 2).
Table 1. Cyclization reaction of 2a,b with hydroxylamine
Compd
R
Ratio 3:4:5 (Yield %)
NH2OH NH2OH$HCl
i
ii
3a, 4a, 5a
3b, 4b, 5b
Me
Ph
0:100:0 (100)
0:50:50 (50)
100:0:0 (80)
92:0:8 (50)

11658
Table 2. 1H NMR (CDCl3, 400 MHz) chemical shifts (d, ppm) of oxazoloquinolinone derivatives 3–5
Compd H-6 H-7 H-8 H-9
S. Chimichi et al. / Tetrahedron 63 (2007) 11656–11660
H-20/60
H-30/40/50 CH3 N–CH3
2.68 3.72
3a
4a
5a
3b
4b
5b
7.44, dd,
J¼8.6, 1.0 Hz
7.68, ddd, J¼8.6, 7.2, 1.6 Hz 7.35, ddd, J¼7.8, 7.2, 1.0 Hz 8.08, dd, J¼7.8, 1.6 Hz
7.61, ddd, J¼8.6, 7.2, 1.6 Hz 7.28, ddd, J¼7.6, 7.2, 1.0 Hz 8.21, dd, J¼7.6, 1.6 Hz
7.58, ddd, J¼8.6, 7.2, 1.6 Hz 7.33, ddd, J¼7.8, 7.2, 1.0 Hz 7.89, dd, J¼7.8, 1.6 Hz
7.33, dd,
J¼8.6, 1.0 Hz
7.46, dd,
2.89 3.60
2.68 3.80
J¼8.6, 1.0 Hz
7.49, dd,
J¼8.8, 0.9 Hz
7.33, dd,
7.72, ddd, J¼8.8, 7.9, 1.5 Hz 7.40, ddd, J¼8.8, 7.9, 0.9 Hz 8.19, dd, J¼7.9, 1.5 Hz 8.24–8.28 7.50–7.55
7.60, ddd, J¼8.6, 7.2, 1.6 Hz 7.30, ddd, J¼7.6, 7.2, 1.0 Hz 8.27, dd, J¼7.6, 1.6 Hz 8.56–8.62 7.52–7.58
7.64, ddd, J¼8.6, 7.2, 1.5 Hz 7.40, ddd, J¼7.8, 7.2, 1.0 Hz 8.06, dd, J¼7.8, 1.5 Hz 8.35–8.30 7.56–7.50
3.78
3.67
3.87
J¼8.6, 1.0 Hz
7.56–7.50
Table 3. 13C NMR (CDCl3, 100 MHz) chemical shifts (d, ppm) of oxazolo-
quinolinone derivatives 3–5
confirmed by the obtainment of 5b from 1b with hydroxyl-
amine in ethylene glycol (see Scheme 1).
Carbon
3a
4a
5a
3b
4b
5b
2
3
3a
4
5a
6
7
8
9
9a
9b
10
20/60
30/50
40
CH3
N–CH3
—
—
162.7
—
—
—
162.6
—
3. Conclusions
158.6
108.75
158.6
140.3
115.4
132.4
122.8
123.3
110.65
167.2
—
—
—
—
10.8
29.1
174.3
107.1
158.7
140.4
115.5
131.95
123.0
124.8
112.2
156.3
—
—
—
—
12.85
28.7
160.9
107.5
158.0
140.2
115.3
132.7
122.8
123.4
110.4
168.3
127.2
129.6
128.4
130.6
—
172.4
105.9
158.1
140.1
115.5
132.05
123.0
124.7
112.1
157.4
126.5
129.1
128.7
131.9
—
128.8
157.3
138.2
115.2
130.1
122.45
121.4
111.3
152.3
—
—
—
—
14.2
29.6
130.0
157.75
138.6
115.4
130.5
122.7
121.75
111.5
152.2
126.5
127.45
129.0
131.6
—
We have investigated the reaction of hydroxylamine with
3-acyl-4-methoxy-1-methylquinolinones 2a,b and unambi-
guously determined the structure of the obtained products
under different reaction conditions. Whereas from the reaction
of 2a with hydroxylamine both the regioisomeric isox-
azolo[4,5-c] and -[4,3-c] (compounds 3a and 4a) can be se-
lectively and exclusively obtained, reaction of 2b always
gave rise to a mixture of the required isoxazole together
with the oxazole derivative. The same reaction carried out
on the 4-hydroxy substituted quinolinones 1a,b gave rise
uniquely to the oxazoles 5a,b. All the structures of the
obtained products have been elucidated by the combined
use of 13C and 15N NMR experiments.
29.5
29.35
29.8
at d 172.4 ppm, in agreement with a carbon linked to the
oxygen atom of the isoxazole moiety, thus allowing us to
attribute the structure 4b to this product.
4. Experimental
4.1. General
The formation of compound 5b could be rationalized by pos-
tulating a partial conversion of compound 2b into 1b thus
allowing the formation of the corresponding oxime and its
subsequent Beckmann rearrangement. This hypothesis is
€
Melting points were taken on a Buchi 510 apparatus and are
uncorrected. IR spectra were obtained with a Perkin–Elmer
881 spectrophotometer for dispersion in KBr. Elemental
analyses were obtained by Elemental Analyzer Perkin–
Elmer 240C Apparatus. Mass spectra were registered with
a Carlo Erba QMD 1000 instrument at 70 eV. Compounds
1a,b were obtained as reported in the literature.1,11 Silica
gel plates (Merck F254) and silica gel 60 (Merck 230–
400 mesh) were used for analytical TLC and for column
chromatography, respectively. Solvents were removed under
reduced pressure. All 1D- and 2D-NMR experiments were
performed on a Varian Mercuryplus-400 spectrometer
Ph
O
O
OMe
N
O
O
NH
i
N
2a
6
(399.95 MHz for H, 100.57 MHz for 13C, and 40.54 for
1
Scheme 2. Reagents and conditions: (i) 1-phenylethanamine, ethanol,
reflux.
15N), with a 5 mm indirect detection probe equipped with
a gradient coil, at 298 K. Chemical shifts (d in parts per mil-
lion) were referenced to the solvent CDCl3, 7.26 for 1H and
77.00 for 13C, and external nitromethane (0.00) for 15N
NMR. All coupling constants are in hertz. Assignments are
Table 4. Chemical shifts (CDCl3, d, ppm, 40.54 MHz) of five-membered
ring nitrogen atom in compounds 3–5
made using H, 13C, DEPT and NOESY 1D experiments
1
Compd
d (15N)
and gHSQC, gHMBC, gHMQC, and gCOSY 2D experi-
ments. All pulse sequences were used as provided by Varian
and processing was done using standard Varian methods. 1H
NMR spectra were acquired using 4.6 kHz spectral width
with 32K data points (4.5 ms 90ꢁ pulse width, 0.28 Hz/point
digital resolution).
3a
4a
5a
3b
4b
5b
ꢀ4.0
ꢀ16.0
ꢀ135.0
ꢀ7.3
ꢀ21.4
ꢀ140.4

S. Chimichi et al. / Tetrahedron 63 (2007) 11656–11660
11659
4.2. Synthesis of 3-acyl-4-methoxy-1-methylquinolin-
2(1H)-ones (2a,b)
3J¼8.6 Hz, 4J¼1.0 Hz, H-8), 7.22 (1H, ddd, 3J¼8.1,
4
7.2 Hz, J¼1.0 Hz, H-6), 3.96 (3H, s, O–Me), 3.66 (3H, s,
N–Me), 2.26 (3H, s, 3-Me); 13C NMR (100.57 MHz,
CDCl3) d 163.1 (s, C-2), 160.9 (s, C-4), 153.2 (s, C]N),
139.2 (s, C-8a), 131.4 (d, C-7), 124.6 (d, C-5), 122.0 (d, C-
6), 117.6 (s, C-4a), 113.9 (d, C-8), 112.8 (s, C-3), 61.3 (q,
O–Me), 29.5 (q, N–Me), 16.5 (q, CNMe); EIMS m/z (%):
246 (M+, 33), 229 (100), 215 (67), 200 (37), 117 (11), 77
(26), 51 (17). Anal. Calcd for C13H14N2O3: C, 63.40; H,
5.73; N, 11.38. Found: C, 63.18; H, 6.00; N, 11.59.
To a solution of 3-acetyl(benzoyl)-4-hydroxy-1-methylqui-
nolin-2(1H)-one 1a,b (2.17 g or 2.79 g, 10 mmol) and
dimethyl sulfate (11.1 mmol) in acetone (100 mL) potassium
carbonate (11.1 mmol) was added and the mixture was
heated at reflux for 5 h. Removal of the solvent left a yellow
solid which was suspended in water (100 mL), collected by
filtration, and dried. The obtained material was purified
by flash chromatography (ethyl acetate/petroleum ether
40/70¼1:1 as eluant for 2a and ethyl acetate/petroleum ether
4.4. Synthesis of 3,5-dimethylisoxazolo[4,5-c]quinolin-
4(5H)-one (3a)
1
40/70¼2:3 as eluant for 2b). H and 13C NMR data for
compounds 3a,b–5a,b are reported in Tables 2 and 3,
respectively.
To a stirred solution of 3-acetyl-4-methoxy-1-methylquino-
lin-2(1H)-one (2a) (0.208 g, 0.9 mmol) in ethylene glycol
(10 mL) hydroxylamine hydrochloride (0.076 g, 1.1 mmol)
was added in one portion and the reaction mixture heated
at reflux for 1 h. After cooling, the yellow precipitate was
collected by filtration, dried, and recrystallized from ethanol
(mp 190–191 ꢁC, 0.154 g, yield 80%); IR (KBr) 2947, 1670,
1570, 1413, 1315 cmꢀ1; EIMS m/z (%): 214 (M+, 100), 185
(31), 104 (57), 77 (39), 63 (19), 51 (31). Anal. Calcd for
C12H10N2O2: C, 67.08; H, 4.71; N, 13.08. Found: C,
66.74; H, 4.60; N, 13.17.
4.2.1. 3-Acetyl-4-methoxy-1-methylquinolin-2(1H)-one
(2a). Colorless needles; 1.62 g (70%); mp 84–85 ꢁC; Rf (eth-
yl acetate/petroleum ether 40/70¼1:1) 0.42; IR (KBr) 2971,
1682, 1610, 1502, 1358 cmꢀ1; 1H NMR (400 MHz, CDCl3)
d 7.97 (1H, dd, 3J¼8.0 Hz, 4J¼1.6 Hz, H-5), 7.59 (1H, ddd,
3J¼8.6, 7.2 Hz, 4J¼1.6 Hz, H-7), 7.32 (1H, dd, 3J¼8.6 Hz,
4J¼1.0 Hz, H-8), 7.24 (1H, ddd, 3J¼8.0, 7.2 Hz,
4J¼1.0 Hz, H-6), 3.95 (3H, s, O–Me), 3.65 (3H, s, N–Me),
2.65 (3H, s, 3-Me); 13C NMR (100.57 MHz, CDCl3)
d 201.6 (s, C]O), 161.7 (s, C-2), 159.9 (s, C-4), 139.5 (s,
C-8a), 131.9 (d, C-7), 124.7 (d, C-5), 122.2 (d, C-6), 117.6
(s, C-3), 117.1 (s, C-4a), 114.0 (d, C-8), 61.6 (q, O–Me),
32.35 (q, COMe), 29.1 (q, N–Me); EIMS m/z (%): 231
(M+, 51), 216 (100), 201 (39), 105 (24), 77 (23). Anal. Calcd
for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.78;
H, 5.45; N, 6.30.
4.5. Synthesis of 3,5-dimethylisoxazolo[4,3-c]quinolin-
4(5H)-one (4a)4
A solution of hydroxylamine hydrochloride (0.042 g,
0.6 mmol) and Et3N (0.08 mL, 0.6 mmol) in ethylene glycol
(6 mL) was stirred for 10 min at room temperature. 3-Ace-
tyl-4-methoxy-1-methylquinolin-2(1H)-one (2a) (0.092 g,
0.4 mmol) was subsequently added and the solution was
heated at 200 ꢁC for 30 min. After cooling, the white precip-
itate was collected by filtration, dried, and recrystallized
from ethanol [mp 193–194 ꢁC, lit.4 mp 205–206 ꢁC (from
dioxane), 0.086 g, quantitative yield].
4.2.2. 3-Benzoyl-4-methoxy-1-methylquinolin-2(1H)-one
(2b). Yellow needles; 2.08 g (71%); mp 172–173 ꢁC; Rf (eth-
yl acetate/petroleum ether 40/70¼2:3) 0.38; IR (KBr) 3009,
1670, 1619, 1441, 1361 cmꢀ1; 1H NMR (400 MHz, CDCl3)
3
4
d 8.06 (1H, dd, J¼8.1 Hz, J¼1.2 Hz, H-5), 8.00 (2H, m,
H-20), 7.64 (1H, ddd, 3J¼8.5, 7.2 Hz, 4J¼1.7 Hz, H-7),
7.57 (1H, m, H-40), 7.47 (2H, m, H-30), 7.38 (1H, dd,
3J¼8.5 Hz, 4J¼1.0 Hz, H-8), 7.64 (1H, ddd, 3J¼8.1,
4.6. Synthesis of 2,5-dimethyl[1,3]oxazolo[4,5-c]quino-
lin-4(5H)-one (5a)5
4
7.2 Hz, J¼1.0 Hz, H-6), 3.89 (3H, s, O–Me), 3.66 (3H, s,
N–Me); 13C NMR (100.57 MHz, CDCl3) d 194.38 (s,
C]O), 162.2 (s, C-2), 159.8 (s, C-4), 139.55 (s, C-8a),
138.0 (s, C-10), 133.5 (d, C-40), 131.9 (d, C-7), 129.4 (d,
C-20), 128.8 (d, C-30), 124.7 (d, C-5), 122.2 (d, C-6), 117.0
(s, C-4a), 114.1 (d, C-8), 113.1 (s, C-3), 60.5 (q, O–Me),
29.2 (q, N–Me); EIMS m/z (%): 293 (M+, 53), 264 (100),
216 (25), 105 (37), 77 (80). Anal. Calcd for C18H15NO3:
C, 73.71; H, 5.15; N, 4.78. Found: C, 73.98; H, 4.95; N, 5.06.
To a stirred solution of 3-acetyl-4-methoxy-1-methylquino-
lin-2(1H)-one (2a) (0.304 g, 1.4 mmol) in ethylene glycol
(10 mL) hydroxylamine hydrochloride (0.118 g, 1.7 mmol)
was added in one portion and the reaction mixture heated
at reflux for 2 h. After cooling, water was added and the solid
obtained was filtered and purified by column chromato-
graphy with ethyl acetate as eluant, Rf 0.50 [mp 190–
191 ꢁC, lit.5 mp 191 ꢁC (from toluene/hexane), 0.210 g,
yield 70%].
4.3. Synthesis of 4-methoxy-3-(N-hydroxyethanimi-
doyl)-4-methoxy-1-methylquinolin-2(1H)-one
4.7. Synthesis of 3-acetyl-1-methyl-4-[(1-phenylethyl)-
amino]quinolin-2(1H)-one (6)
To a stirred solution of 3-acetyl-4-methoxy-1-methylquino-
lin-2(1H)-one (2a) (0.208 g, 0.9 mmol) in ethanol (10 mL)
hydroxylamine hydrochloride (0.076 g, 1.1 mmol) was
added in one portion and the reaction mixture heated at reflux
for 3 h. Removal of the solvent left a yellow solid (mp 149–
150 ꢁC, quantitative yield); IR (KBr) 3300, 1650, 1620,
1604, 1587 cmꢀ1; 1H NMR (400 MHz, CDCl3) d 8.70 (1H,
To a stirred solution of 3-acetyl-4-methoxy-1-methylquino-
lin-2(1H)-one (2a) (0.231 g, 1.0 mmol) in ethanol (10 mL)
1-phenylethanamine (0.153 mL, 1.2 mmol) was added and
the reaction mixture was heated at reflux for 3 h. Removal
of the solvent left a yellow solid (mp 140–141 ꢁC, quantita-
tive yield); IR (KBr) 2978, 2246, 1612, 1563, 1440,
3
4
br s, OH), 7.98 (1H, dd, J¼8.1 Hz, J¼1.5 Hz, H-5), 7.56
1300 cmꢀ1
;
1H NMR (400 MHz, CDCl3) d 11.98 (1H,
3
4
3
3
4
(1H, ddd, J¼8.6, 7.2 Hz, J¼1.5 Hz, H-7), 7.31 (1H, dd,
d, J¼6.6 Hz, NH), 7.76 (1H, dd, J¼8.4 Hz, J¼1.5 Hz,

11660
S. Chimichi et al. / Tetrahedron 63 (2007) 11656–11660
H-5), 7.52 (1H, ddd, 3J¼8.4, 7.0 Hz, 4J¼1.4 Hz, H-7), 7.40–
(0.041 g, yield 25%). Analytical samples were obtained by
recrystallization from ethanol: 4b mp 173–174 ꢁC (lit.5 mp
177.5–178 ꢁC from ethanol) and 5b mp 194–195 ꢁC (lit.5
mp 246 ꢁC from toluene/hexane and lit.12 199 ꢁC from eth-
anol). Anal. Calcd for C17H12N2O2: C, 73.90, H, 4.38; N,
10.14. Found: C, 73.98; H, 4.22; N, 10.21 and C, 74.11; H,
4.24; N, 10.19, for 4b and 5b, respectively.
7.28 (5H, m, Ar–H), 7.24 (1H, dd, 3J¼8.4 Hz, 4J¼1.0 Hz, H-
3
4
8), 6.96 (1H, ddd, J¼8.4, 7.0 Hz, J¼1.0 Hz, H-6), 5.18
3
(1H, dq, J¼6.6 Hz, H-10), 3.58 (3H, s, N–Me), 2.75 (3H,
s, COMe), 1.63 (3H, d, 3J¼6.6 Hz); 13C NMR
(100.57 MHz, CDCl3) d 202.6 (s, C]O), 162.6 (s, C-2),
159.8 (s, C-4), 143.7 (s, C-100), 141.5 (s, C-8a), 132.7 (d,
C-7), 129.1 (d, C-300), 128.4 (d, C-5), 127.5 (d, C-400),
125.6 (d, C-200), 120.35 (d, C-6), 114.55 (d, C-8), 114.5 (s,
C-4a), 105.65 (s, C-3), 58.1 (d, C-10), 33.4 (q, COMe),
29.45 (q, N–Me), 26.7 (q, 10-Me); EIMS m/z (%): 320
(M+, 49), 305 (38), 215 (67), 229 (28), 215 (41), 201 (67),
105 (100), 77 (48). Anal. Calcd for C20H20N2O2: C, 74.98;
H, 6.29; N, 8.74. Found: C, 74.71; H, 6.45; N, 8.50.
Acknowledgements
The authors wish to thank MIUR for financial support and
Ente Cassa di Risparmio di Firenze, Italy for granting
a 400 MHz NMR spectrometer. Mrs. Brunella Innocenti
and Mr. Maurizio Passaponti (Dipartimento di Chimica
ꢀ
Organica ‘Ugo Schiff’, Universita di Firenze) are acknowl-
edged for technical assistance.
4.8. Reaction of 3-benzoyl-4-methoxy-1-methylquinolin-
2(1H)-one (2b) with hydroxylamine hydrochloride
To a stirred solution of 3-benzoyl-4-methoxy-1-methylqui-
nolin-2(1H)-one (2b) (0.117 g, 0.4 mmol) in ethylene glycol
(5 mL) hydroxylamine hydrochloride (0.035 g, 0.5 mmol)
was added in one portion and the reaction mixture heated
at reflux for 4 h. After cooling, the reaction mixture was
poured into water (15 mL) and the solid obtained was fil-
tered and dried. The crude product consisting of the isomeric
5-methyl-3-phenylisoxazolo[4,5-c]quinolin-4(5H)-one (3b)
and 5-methyl-2-phenyl[1,3]oxazolo[4,5-c]quinolin-4(5H)-
one (5b)5 was separated by column chromatography with
ethyl acetate/petroleum ether 40/70¼1:3 as eluant; the first
fraction, Rf 0.41, afforded a white solid (0.051 g, yield
46%) which was identified as 3b whereas the second eluted
fraction, Rf 0.15, gave a small amount of compound 5b
(0.0044 g, yield 4%). An analytical sample of 3b obtained
by recrystallization from ethyl acetate had mp 153–
154 ꢁC; IR (KBr) 3017, 1666, 1219, 1207 cmꢀ1; EIMS m/z
(%): 276 (M+, 100), 247 (37), 104 (59), 77 (42), 51 (38).
Anal. Calcd for C17H12N2O2: C, 73.90, H, 4.38; N, 10.14.
Found: C, 74.01; H, 4.18; N, 10.29.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tet.2007.
08.108.
References and notes
1. Chimichi, S.; Boccalini, M.; Hassan, M. M. M.; Viola, G.;
Dall’Acqua, F.; Curini, M. Tetrahedron 2006, 62, 90–96.
2. Norman, B. H.; Lander, P. A.; Gruber, J. M.; Kroin, J. S.;
Cohen, J. D.; Jungheim, L. N.; Starling, J. J.; Law, K. L.;
Self, T. D.; Tabas, L. B.; Williams, D. C.; Paul, D. C.;
Dantzig, A. H. Bioorg. Med. Chem. Lett. 2005, 15, 5526–5530.
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823.
5. Steinschifter, W.; Fiala, W.; Stadlbauer, W. J. Heterocycl.
Chem. 1994, 31, 1647–1652.
6. Melese, T.; Perkins, E.; Nguyen, A. T. Q.; Sun, D. PCT Int.
Appl. WO 0335618, 2003; Chem. Abstr. 138, 353971.
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W. Heterocycl. Commun. 1995, 1, 341–352.
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4.9. Reaction of 3-benzoyl-4-methoxy-1-methylquinolin-
2(1H)-one (2b) with hydroxylamine
3-Benzoyl-4-methoxy-1-methylquinolin-2(1H)-one
(2b)
(0.176 g, 0.6 mmol) was added at room temperature under
stirring to a solution of hydroxylamine hydrochloride
(0.055 g, 0.8 mmol) and Et3N (0.11 mL, 0.8 mmol) in ethyl-
ene glycol (5 mL) and the solution was then heated at reflux
for 3 h. After cooling, the reaction mixture was poured into
water (15 mL) and exhaustively extracted with dichlorome-
thane. Evaporation to dryness of the organic layer afforded
a crude product consisting of the isomeric 5-methyl-3-phe-
nylisoxazolo[4,3-c]quinolin-4(5H)-one (4b) and 5b in the
ratio 1:1. Compounds were separated by column chromato-
graphy with ethyl acetate/petroleum ether 40/70¼1:3 as
eluant; the first band, Rf 0.67, afforded a white solid
(0.041 g, yield 25%) which was identified as 4b whereas
the second eluted fraction, Rf 0.15, gave the derivative 5b