SYNTHESIS OF 2-ARYL-3-HYDROXYQUINOLIN-4(1H)-ONES

Article abstract of DOI:10.1135/cccc19951357

Eight substituted phenacyl anthranilates have been prepared by reaction of sodium anthranilate with substituted phenacyl halides in dimethylformamide in the yields from 31 to 93percent.The phenacyl esters were cyclized in polyphosphoric acid or by mere heating to give the respective substituted 2-aryl-3-hydroxyquinolin-4(1H)-ones in the yields from 77 to 98percent.All the compounds prepared have been characterized by their 1H and 13C NMR spectra.

Full text of DOI:10.1135/cccc19951357

Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones
1357
SYNTHESIS OF 2-ARYL-3-HYDROXYQUINOLIN-4(1H)-ONES
a
b
Pavel HRADIL and Josef JIRMAN
a Farmakon s.p., 771 17 Olomouc, Czech Republic
b Research Institute of Organic Syntheses s.a., 532 18 Pardubice-Rybitvi, Czech Republic
Received March 9, 1995
Accepted May 13, 1995
Eight substituted phenacyl anthranilates have been prepared by reaction of sodium anthranilate with
substituted phenacyl halides in dimethylformamide in the yields from 31 to 93%. The phenacyl esters
were cyclized in polyphosphoric acid or by mere heating to give the respective substituted
2-aryl-3-hydroxyquinolin-4(1H)-ones in the yields from 77 to 98%. All the compounds prepared have
1
been characterized by their H and 13C NMR spectra.
Phenacyl bromides belong among very reactive substances and their reaction with so-
dium salts of lower organic acids giving the corresponding phenacyl esters is well
known and has been employed for identification of these acids1,2. The direct reaction of
anthranilic acid with bromomethyl phenyl ketone has also been described2,3. In boiling
ethanol in the absence of base, alkylation at amino group predominated to give N-phen-
acylanthranilic acid3. In the presence of base, phenacyl N-phenacylanthranilate was
formed2,3. Phenacyl anthranilates were prepared by reactions of 2-nitrobenzoic acid
with bromomethyl aryl ketones and subsequent reduction of the phenacyl 2-nitrobenzo-
ates formed with hydrogen on palladium4,5. The rates of reactions of bromomethyl aryl
ketones with nucleophiles are strongly affected by the solvent used. If amides are used
as the reaction medium, the reaction is smooth even at room temperature and is
exothermic6. When these conditions were adopted for the reactions of bromomethyl
phenyl ketones I with salts of anthranilic acid, the alkylation predominantly took place
at the oxygen atom to give phenacyl anthranilates II mostly in high yields (Scheme 1).
The substances prepared were identified by their 1H and 13C NMR spectra (Tables I and II).
Although quinolines represent an extensively studied class of heterocyclic compounds,
only few basic representatives of 2-aryl-3-hydroxyquinolin-4(1H)-ones have been de-
scribed in literature. The described method of preparation starting from the 2-nitro-
phenylethylene oxide prepared by the Darzens reaction7,8 is laborious and the yields of
whole synthesis are low. The method given by us for preparation of 3-hydroxyquinolin-
4(1H)-ones III was discovered during cyclizations of phenacyl anthranilates (Scheme 1).
Literature4,5 describes their cyclizations in polyphosphoric acid to give the respective
2-aryl-3H-benz[e][1,4]oxazepin-5-ones IV which are converted into the more stable
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1358
Hradil, Jirman:
2-aryl-1H-benz[e][1,4]oxazepin-5-ones. We have slightly modified this procedure with
regard to isolation of product and used it also for further phenacyl anthranilates not
1
described in refs4,5. By means of H and 13C NMR spectra it could be proved that the
reaction does not produce 2-aryl-3H-benz[e][1,4]oxazepin-5-ones IV but produces 2-aryl-
3-hydroxyquinolin-4(1H)-ones III (Scheme 1 and Tables III and IV). The correctness of
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones
1359
this structure was also confirmed by another reaction: alkylation of 2-phenyl-3-
hydroxyquinolin-4(1H)-one (IIIa) with dimethyl sulfate gave a mixture of two products
whose molecules were methylated with two methyl groups (Scheme 2). NMR spectra
showed that these products are 3-methoxy-1-methyl-2-phenyl-4-quinolone (Va) and
3,4-dimethoxy-2-phenylquinoline (VIa), which was also confirmed by the literature
data9,10 concerning these compounds.
The formation of 2-aryl-3-hydroxyquinolin-4(1H)-ones III is surprising though not
inexplicable. Lability of seven-membered ring compounds is well known. Hence the
transformation could consist in intramolecular cyclization giving 2-aryl-3H-
benz[e][1,4]oxazepin-5-ones IV (originally expected) immediately followed – due to
low stability of seven-membered ring at the given conditions – by decomposition of
lactone bond and formation of a new carbon–carbon bond with subsequent shift of
protons and aromatization of the molecule to give the quinoline nucleus. However, the
available data do not allow any decision about the reaction mechanism. Other cycliza-
TABLE I
1H NMR spectra of compounds II (δ, ppm)
Compound
NH2
H-3
H-4
H-5
H-6
H-8
H-2′ H-3′ H-4′ H-5′ H-6′
IIa
6.72
6.73
6.72
6.73
6.73
6.70
6.69
6.64
6.87
6.88
6.88
7.85
6.85
6.85
6.84
6.83
7.34
7.33
7.34
7.33
7.32
7.34
7.32
7.32
6.63
6.61
6.61
6.59
6.59
6.60
6.61
6.60
7.88
7.82
7.82
7.81
7.81
7.86
7.85
7.85
5.73
5.70
5.71
5.50
5.50
5.77
5.60
5.59
8.06
7.98
8.07
–
7.63
7.80
7.67
7.62
7.78
8.41
–
7.75
7.63
7.80
7.67
7.62
7.61
8.41
–
8.06
7.98
8.07
7.87
7.91
8.28
7.93
7.95
IIb
IIc
IId
IIe
IIf
–
–
7.54
–
–
8.28
7.93
7.95
–
IIg
IIha
–
–
–
–
a
δ(NH) = 4.93, δ(CH) = 4.20, δ(CH3) = 1.20.
SCHEME 2
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Hradil, Jirman:
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones
1361
tion conditions were also adopted with the aim to preserve the 2-aryl-3H-
benz[e][1,4]oxazepin-5-one or other intermediates formed but these attempts failed. No
reaction took place in toluene with piperidine as a catalyst. It was found that heating of
phenacyl anthranilates above their melting points – at about 180 °C – results in foaming
of the reaction mixture and escaping of water. After ca 15 min, the reaction mixture
solidified. Beside 2-aryl-3-hydroxyquinolin-4(1H)-ones III the reaction mixture con-
tained large amounts of the starting substance II. When the melt was heated more in-
tensively, the reaction became exothermic after reaching the temperature of 230 °C, the
temperature increased and the reaction mixture quickly solidified. In all the cases, how-
ever, the reaction mixture again contained 2-aryl-3-hydroxyquinolin-4(1H)-ones III. In
the cases of phenacyl anthranilates II with higher melting points, however, the reaction
mixture was strongly contaminated with decomposition products. For phenacyl an-
thranilates II with lower melting points the yields were acceptable though lower than
those of the cyclizations in polyphosphoric acid. The compounds obtained by the cycli-
zations in polyphosphoric acid were identical with those obtained by thermal cycliza-
tions, which was proved by determination of melting points, by TLC and NMR.
EXPERIMENTAL
The melting points were measured in capillaries in the Kofler apparatus and were not corrected. The
1H and 13C NMR spectra (δ, ppm) were measured with an AMX 360 (Bruker) apparatus at 360.13
and 90.57 MHz, respectively, using an inverse tunable 5 mm probe. Saturated solutions of the sub-
stances in hexadeuteriodimethyl sulfoxide (mixed with trifluoroacetic acid in the case of compound
IIIh) were prepared at 23 °C. The NMR spectra were interpreted and the signals of the parent com-
TABLE III
1H NMR spectra of compounds III (δ, ppm)
Compound
H-5
H-6
H-7
H-8
H-2′
H-3′
H-4′
H-5′
H-6′
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
8.24
8.21
8.21
8.23
8.21
8.21
8.16
8.15
7.33
7.31
7.32
7.32
7.32
7.32
7.29
7.28
7.64
7.63
7.64
7.63
7.61
7.66
7.61
7.60
7.80
7.77
7.77
7.64
7.61
7.76
7.75
7.72
7.87
7.88
7.89
–
7.59
7.79
7.54
7.59
7.79
7.87
7.88
7.89
7.70
7.69
8.14
7.83
7.94
–
7.68
a
–
a
7.68
a
–
7.90
8.44
–
–
–
–
–
7.65
8.44
–
8.14
7.83
–
IIIg
IIIhb
7.94
–
a
b
Unresolved multiplet from 7.53 to 7.67. δ(NH) = 4.47, δ(CH) = 4.02, δ(CH3) = 1.22.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

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Hradil, Jirman:
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones
1363
TABLE V
Characteristic data of compounds II and III
Calculated/Found
% H
M.p., °C
Formula
M.w.
Compound
Yield, %a
% C
% N
IIa
124.5–128ab C15H13NO3
74 255.3
70.64
70.58
5.02
5.13
5.77
5.49
IIb
136.5–140c C15H12BrNO3
53.55
53.91
3.58
3.62
4.20
4.19
83
334.2
IIc
136–138
93
C15H12ClNO3
289.7
62.16
62.19
4.26
4.18
4.89
4.83
IId
73.5–75.5
31d
C15H12ClNO3
289.7
61.72
61.19
4.18
4.18
4.87
4.83
IIe
85.5–87.5
58
C15H11Cl2NO3
324.2
55.37
55.58
3.40
3.42
4.29
4.32
IIf
155.5–158.5 C15H12N2O5
60.17
60.00
4.07
4.03
9.51
9.33
70
300.3
IIg
182–186
79
C15H12Cl2N2O3
339.2
52.49
53.12
3.62
3.57
8.18
8.26
IIh
111–114.5
82
C18H18Cl2N2O3
381.3
57.20
56.71
4.81
4.76
7.32
7.35
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
278–281e
C15H11NO2
237.3
76.00
75.94
4.72
4.67
6.39
5.90
95/75f
298–305g
97/72
C15H10BrNO2
316.2
56.60
56.99
3.15
3.19
4.45
4.43
291.5–294
98/71
C15H10ClNO2
271.7
66.63
66.31
3.78
3.71
5.26
5.16
291–295
93/64
C15H10ClNO2
271.7
65.88
66.31
3.69
3.71
5.19
5.16
298–304
95/68
C15H9Cl2NO2
306.2
58.34
58.85
2.96
2.96
4.58
4.58
329–332
95/65
C15H10N2O4
282.3
63.68
63.83
3.66
3.57
10.13
9.93
290–295.5
93/72
C15H10Cl2N2O2
321.2
55.45
56.10
3.46
3.14
8.32
8.72
237–242
98/75h
C18H16Cl2N2O2
363.2
59.93
59.52
4.23
4.44
8.10
7.71
a
b
c
For compounds III, yield for crude/crystalline product is given. Ref.4: m.p. 122–124 °C. Ref.4:
m.p. 133–134 °C. The yield is related to methyl-2-chlorophenyl ketone. Ref.4: 271–275 °C. f The
d
e
yields of the method B: 76/60. Ref.4: 297–300 °C. The yields of the method B: 80/61.
g
h
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1364
Hradil, Jirman:
pounds IIa and IIIa were assigned with the use of the following technique of measurement: H,H-ho-
monuclear correlated spectrum11, inverse H,C-heteronuclear correlated spectrum via heteronuclear
zero and double quantum coherence using BIRD sequence, phase sensitive using TPPI with decoup-
ling during acquisition12; inverse H,C-heterocorrelated spectrum via heteronuclear zero and double
quantum coherence optimized on long range couplings with low-pass J-filter to suppress one-bond
correlations without decoupling during acquisition13. For the other substances we only measured the
current unidimensional proton spectra and 13C J-modulated NMR spectra, and the assignment made
use of the substituent chemical shifts14,15. The 1H and 13C NMR spectra of compounds IIa–IIh are
given in Tables I and II. The 1H and 13C NMR spectra of compounds IIIa–IIIh are given in Tables
III and IV. The characteristics of compounds II and III are summarized in Table V. The IR spectra
were measured in KBr disc using a Genesis Series FTIR apparatus (ATI Mattson, U.S.A.). The
characteristic absorption bands are presented in Table VI.
Chemicals used. The bromomethyl phenyl ketones Ia–Ic were prepared from the corresponding
methyl phenyl ketones (Fluka) by known procedures16. Bromomethyl 2-chlorophenyl ketone Id was
prepared by the same procedure but, as the substance could not be obtained in crystalline state, the
oil layer washed with water and petroleum ether was used for the reaction, and the yield was calcu-
lated with respect to the starting methyl 2-chlorophenyl ketone. The bromomethyl phenyl ketones Ig
TABLE VI
–1
~
IR spectra of compounds II and III (ν, cm
)
~
~
~
Compound
ν(C=O)
ν(N−H)
ν(C=Carom)
IIa
1 615, 1 685
1 615, 1 689
1 616, 1 689
1 614, 1 687
1 615, 1 692
1 621, 1 685
1 615, 1 682
1 619, 1 692
1 631
3 368, 3 483
IIb
3 364, 3 485
IIc
3 364, 3 484
IId
3 362, 3 474
IIe
3 375, 3 464, 3 484
3 375, 3 480
IIf
IIg
3 374, 3 478
IIh
3 346–3 358, 3 460
IIIa
IIIb
IIIc
IIId
IIIe
IIIf
IIIg
IIIh
1 488, 1 549
1 488, 1 546
1 489, 1 547
1 490, 1 553
1 478, 1 569
1 486, 1 522
1 496, 1 555
1 489, 1 557
1 635
1 635
1 636
1 636
1 635
1 645
1 637
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Synthesis of 2-Aryl-3-hydroxyquinolin-4(1H)-ones
1365
and Ih were obtained from Chemopharma Usti nad Labem; bromomethyl 4-nitrophenyl ketone (If)
was obtained from Leciva s.a. Prague. Chloromethyl 2,4-dichlorophenyl ketone (Fluka) was used for
the synthesis of compound IIe. Anthranilic acid, pure (Lachema).
General Procedure of Preparation of Phenacyl Anthranilates II
Hydrogen carbonate (23.5 g, 0.28 mol) was added to a solution of anthranilic acid (32.9 g, 0.24 mol)
in dimethylformamide (350 ml), and the reaction mixture was heated at 90–100 °C until the foaming
ceased, whereupon it was cooled to 20 °C and treated with the respective substituted phenacyl bro-
mide I (0.2 mol). The temperature increased spontaneously to 25–28 °C. After 1 h stirring (while
monitoring the decrease of compound I in the reaction mixture by TLC), the mixture was poured
onto a mixture of 20 g Na2CO3 and 1.5 kg ice and water. The precipitated solid was collected by
suction and thoroughly washed with water and dried at 60 °C in a drying oven. In the case of com-
pound IId the product separated in a paste consistency after pouring the reaction mixture into water:
it was extracted with ethyl acetate, the extract was washed with distilled water, dried with sodium
sulfate, filtered, and evaporated until dry. The dried product or evaporation residue was dissolved in
boiling ethanol, filtered with 2.5 g charcoal, cooled to 0 °C, and the precipitated solid was collected
by filtration, washed with cold ethanol, and dried.
General Procedure of Preparation of 2-Aryl-3-hydroxyquinolin-4(1H)-ones III
A. Phenacyl anthranilate (II, 0.01 mol) was stirred with polyphosphoric acid (10 g, containing
88.4% P2O5) at 100 °C for 2 h. Then the reaction mixture was poured into 150 ml hot water, and the
precipitated product was hot filtered, and washed with 100 ml saturated NaHCO3 solution and with
hot water until neutral. After thorough suction and drying, the product was used as such in sub-
sequent synthesis or recrystallized from dimethylformamide and ethanol for analysis.
B. A melt of phenacyl anthranilate (II, 0.1 mol) was gradually heated to 230 °C. Foaming of the
reaction mixture began at a temperature of 170–190 °C with concomitant escaping of steam. After
reaching 230 °C, exothermic cyclization took place with concomitant spontaneous heating of reaction
mixture up to ca 250 °C, and after several minutes the mixture solidified. 15 min after reaching the
temperature of 200 °C, the reaction mixture was cooled to room temperature and treated with 75 ml
ethyl acetate. The solid was stirred and the mixture was refluxed 30 min, whereafter it was cooled to
0 °C and the solid was collected by filtration. After washing with cold ethyl acetate it was dried. For
analysis the product was recrystallized, for synthesis it was used without recrystallization.
3-Methoxy-1-methyl-2-phenyl-4-quinolone (Va) and 3,4-Dimethoxy-2-phenylquinoline (VIa)
Compound IIIa (3.64 g, 15.3 mmol) was added to a solution of NaOH (3.6 g, 90 mmol) in 30 ml
water. It did not dissolve until the temperature of 60 °C. Then the reaction mixture was cooled to 20 °C
and treated with dimethyl sulfate (5 ml, 52 mmol) added slowly drop by drop. During the addition,
the temperature increased and a precipitate separated. The reaction mixture was stirred at 25–30 °C
for 1 h, then 0.8 g NaOH was added and the solution was heated at 80 °C 20 min. After cooling to
0–5 °C, the reaction mixture was stirred ca 20 min and the solid was collected by filtration and
washed with water until neutral. Aqueous mother liquors were extracted with ethyl acetate, the ex-
tract was dried with sodium sulfate, filtered, and evaporated until dry. The evaporation residue was
added to the main product, mixed with 25 ml toluene, and refluxed 10 min. After cooling, the separ-
ated solid was collected by filtration, washed with toluene, and the mother liquors were filtered with
charcoal through a thin layer of silica. The filtrate was evaporated until dry in a vacuum rotary evap-
orator to give 0.2 g yellowish oil which crystallized on standing. This fraction was identified by
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1366
Hradil, Jirman:
NMR as 3,4-dimethoxy-2-phenylquinoline (VIa); yield 5%, m.p. 65 °C (ref.9 gives m.p. 62–64 °C).
13C NMR spectrum: 61.15, 61.36 (2 × OCH3). The solid portion was recrystallized from ethanol. The
isolated product was identified as 3-methoxy-1-methyl-2-phenyl-4-quinolone (Va). The yield inclu-
sive of the product from the mother liquors was 2.66 g, i.e. 65%, m.p. 227–231 °C (ref.9 gives m.p.
222–224 °C, ref.10 gives m.p. 220–222 °C). For C17H15NO2 (265.3) calculated: 76.96% C, 5.70% H,
5.28% N; found: 76.67% C, 5.76% H, 5.36% N. 13C NMR spectrum: 59.24 (OCH3), 37.18 (NCH3).
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