An efficient route to 3-aryl-substituted quinolin-2-one and 1,8-naphthyridin-2-one derivatives of pharmaceutical interest

Article abstract of DOI:10.1021/jo0340051

Reaction of arylacetic ester enolates with 2-alkoxy-4H-3,1-benzoxazin-4-ones offers a short and versatile synthetic route to 3-aryl-4-hydroxyquinolin-2(1H)-ones, through the cyclization of the β-ketoesters produced. Similar reactions of 4H-pyrido[2,3-d][1

Full text of DOI:10.1021/jo0340051

A series of 3-aryl-4-hydroxyquinolin-2(1H)-one deriva-
tives, stimulating bone formation, have been synthesized
as potent osteoporosis drugs.5 Furthermore, the structur-
ally similar 3-aryl- and 3-alkyl-4-hydroxy-1,8-naphthy-
ridin-2(1H)-ones have been reported as potent antiallergy
agents displaying inhibitory activity against the slow-
reacting substance of anaphylaxis (SRS-A).6 To date
3-aryl-4-hydroxyquinolin-2(1H)-ones have been prepared
mainly by two methods: (i) the Dieckman reaction of
suitable N-acylated anthranilate esters7 and (ii) the
condensation of anilines with arylmalonates.8 In the
continuation of our studies on the synthesis of nitrogen-
fused heterocycles,9 we wish to report a new methodology
for the synthesis of the 3-aryl-substituted quinolin-2-one
and 1,8-naphthyridin-2-one class of compounds.
An Efficien t Rou te to 3-Ar yl-Su bstitu ted
Qu in olin -2-on e a n d 1,8-Na p h th yr id in -2-on e
Der iva tives of P h a r m a ceu tica l In ter est
Christos A. Mitsos, Alexandros L. Zografos, and
Olga Igglessi-Markopoulou*
National Technical University of Athens,
School of Chemical Engineering, Laboratory of Organic
Chemistry, Zografou Campus, Athens 15773, Greece
ojmark@orfeas.chemeng.ntua.gr
Received J anuary 3, 2003
Abstr act: Reaction of arylacetic ester enolates with 2-alkoxy-
4H-3,1-benzoxazin-4-ones offers a short and versatile syn-
thetic route to 3-aryl-4-hydroxyquinolin-2(1H)-ones, through
the cyclization of the â-ketoesters produced. Similar reac-
tions of 4H-pyrido[2,3-d][1,3]oxazin-4-ones with ester eno-
lates afford 1-acyl-4-hydroxy-1,8-naphthyridin-2(1H)-ones in
a convenient two-step, one-pot procedure.
This new route, illustrated in Scheme 1, is based on
the electrophilicity of 2-alkoxy-4H-3,1-benzoxazin-4-ones
(1, X ) CH), which constitute activated derivatives of
anthranilic acids, analogous to isatoic anhydrides. The
nucleophilic ring opening of benzoxazinones 1a (R1
)
OMe, R2 ) H) and 1b (R1 ) OEt, R2 ) Cl) by enolates of
arylacetic esters 2 (R3 ) Ph, 3-MeOPh, or 4-MeOPh),
generated with LDA in THF, proceeded smoothly at -78
°C, affording the o-amino-functionalized benzoyl acetates
of type 3. Ketoesters 3, obtained as oily mixtures with
the starting ester 2, were used for the preparation of
3-aryl-4-hydroxyquinolin-2(1H)-ones without further pu-
During the past few years considerable interest has
been attracted by the pharmaceutical properties of 3-
aryl-4-hydroxyquinolin-2(1H)-ones. Antagonistic activity
against the glycine site of the N-methyl-D-aspartate
(NMDA) subtype of excitatory amino acid receptor has
been reported for these compounds,1 as well as for their
nonacidic derivatives.2 The excitation of NMDA receptors
is associated with glutamate excitotoxicity, hence such
antagonists constitute promising pharmaceutical agents
for the treatment of various central nervous system
disorders, including global cerebral ischaemia, Parkin-
son’s disease, head injury, epilepsy, and Alzheimer’s
disease. Recently, 3-aryl-4-hydroxyquinolin-2(1H)-ones
have been used as precursors of a new class of nonpep-
tidyl gonadotropine releasing hormone (GnRH) receptor
antagonists.3 Antagonists of this type have been used for
the clinical treatment of sex hormone-related conditions.4
1
rification. As estimated from the H NMR spectra of the
crude compounds 3, when a 2-fold excess of the ester
enolate was used the conversion of 1 was nearly quan-
titative. Deprotection of the amine group of 3 was
expected to induce the spontaneous cyclization to the
desired quinolinones 4. Actually, treatment of 3 with
excess sodium methoxide in boiling toluene effected this
transformation providing 3-aryl-4-hydroxyquinolin-2(1H)-
ones 4a -f in very good yields (75-93% from 1, see Table
1).
Having established the feasibility of this approach for
the synthesis of quinolinones 4, the production of 3-aryl
-or 3-alkyl-1,8-naphthyridine analogues was a straight-
forward extension. Incorporation of 4H-pyrido[2,3-d][1,3]-
oxazin-4-ones (1, X ) N) as acylating agents of esters 2
was expected to result in ketoesters of type 5, which
would be easily transformed to 1,8-naphthyridinones.
However, reactions of 2-methyl- and 2-phenyl-4H-pyrido-
[2,3-d][1,3]oxazin-4-ones (1c and 1d ) with ethyl phenyl-
acetate (2a ) and ethyl propionate (2d ) afforded 1-acyl-
4-hydroxy-1,8-naphthyridin-2(1H)-ones 6 as the sole
products, instead of the intermediate ketoesters 5, which
* To whom correspondence should be addressed. Phone: +30
2107723074. Fax: +30 2107723072.
(1) (a) McQuaid, L. A.; Smith, E. C. R.; Lodge, D.; Pralong, E.; Wikel,
J . H.; Calligaro, D. O.; O’Malley, P. J . J . Med. Chem. 1992, 35, 3423-
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Mawer, I. M.; Ridgill, M. P.; Rowley, M.; Smith, J . D.; Stansfield, I.;
Stevenson, G. I.; Foster, A. C.; Kemp, J . A. Bioorg. Med. Chem. Lett.
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Yaowu Huaxue Zazhi 1995, 5, 122-126 (CA 124: 289213).
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10.1021/jo0340051 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/02/2003
J . Org. Chem. 2003, 68, 4567-4569
4567

SCHEME 1 a
SCHEME 2 a
a
Method C: NaH, THF, rt.
To overcome this drawback, a modification of the
methodology was attempted targeting the synthesis of a
nonenolizable analogue of intermediate 5, which we
hoped could be isolated. As a preliminary attempt in this
direction, pyridoxazinone 1c was employed as an acylat-
ing agent of a substituted malonate or acetoacetate 7, as
shown in Scheme 2. Despite our expectations, this
procedure resulted in the direct formation of 3-alkyl
naphthyridinones 6b and 6e instead of the intermediate
ketoesters 8. Apparently, this transformation involves
cyclization of 8 toward the 3,3-disubstituted 1,8-naph-
thyridinones 9, which undergo decarboxylation or deacety-
lation during the aqueous workup to afford naphthyri-
dinones 6.
In conclusion, an efficient method for the synthesis of
3-aryl-4-hydroxyquinolin-2(1H)-ones and its extension to
similar 1,8-naphthyridine derivatives have been devel-
oped. Further investigations concerning the application
of substituted malonate carbanions as alternative nu-
cleophiles in this sequence are currently under way.
a
Method A: (i) LDA, THF, -78 °C, (ii) MeONa, toluene, reflux.
Method B: LDA, THF, -78 °C.
TABLE 1. 4-Hyd r oxyqu in olin -2(1H)-on es 4 a n d
1-Acyl-4-h yd r oxy-1,8-n a p h th yr id in -2(1H)-on es 6 Obta in ed
product
method
yield (%) product
method
yield (%)
4a
4b
4c
4d
4e
4f
A
A
A
A
A
A
B
89
75
79
83
87
93
57
6b
B
C
C
B
B
C
14
38
41
41
13
27
6ba
6bb
6c
Exp er im en ta l Section
P r ep a r a tion of Ben zoxa zin on es 1a ,b a n d P yr id oxa zi-
n on es 1c,d . Compounds 1a -d were prepared according to
literature procedures.9
6d
6e
6a
Gen er a l P r oced u r e for th e P r ep a r a tion of 3-Ar yl-4-
h yd r oxyqu in olin -2(1H)-on es 4 (Meth od A). A solution of the
appropriate arylacetic ester 2 (4.0 mmol) in anhydrous THF (10
mL) was added dropwise, under argon, to a solution of LDA (2.0
M solution in THF/ethylbenzene/heptane; 4.0 mmol, 2.0 mL) in
anhydrous THF (20 mL), at -78 °C. The addition was completed
in 20 min, the mixture stirred at -78 °C for 10 min, and then a
solution of benzoxazinone 1a (or 1b) (2.0 mmol) in anhydrous
THF (20 mL) was added dropwise over 30 min and the mixture
stirred at -78 °C for 30-40 min. After being quenched with 10%
hydrochloric acid (10 mL) the mixture was diluted with diethyl
ether (15 mL), the organic phase was separated, and the aqueous
layer was extracted further with diethyl ether (15 mL). The
mixture of the organic extracts was diluted with light petroleum
(20 mL), the water was separated and removed, and the organic
phase was dried over sodium sulfate and concentrated in vacuo
to afford the crude acylated arylacetic ester 3 as a viscous oil. A
solution of crude compound 3 in anhydrous toluene (5 mL) was
a
b
From diethyl methylmalonate. From methyl 2-methylac-
etoacetate. c From diethyl butylmalonate.
undergo spontaneous cyclization under the conditions
employed. This remarkable transformation of the amide
functionality in 5 into the imide one in 6 has been
observed previously and was ascribed to the formation
of a reactive ketene intermediate.10 This route represents
an attractive one-pot procedure for the preparation of
4-hydroxy-1,8-naphthyridin-2(1H)-ones, although very
low yields were obtained in the case of 3-alkyl naphthy-
ridinones 6b and 6d (see Table 1).
(10) Zografos, A. L.; Mitsos, C. A.; Igglessi-Markopoulou, O. J . Org.
Chem. 2001, 66, 4413-4415.
4568 J . Org. Chem., Vol. 68, No. 11, 2003

added to a suspension of sodium methoxide [generated by the
addition of methanol to a suspension of sodium hydride (60% in
oil; 4.5 mmol, 0.18 g) in anhydrous toluene (20 mL)] and the
mixture was heated at reflux for 3 h. The insoluble salt was
dissolved by the addition of water (ca. 40 mL), the aqueous layer
separated, and the organic phase extracted further with water
(10 mL). After being washed with a small amount of light
petroleum the mixture of aqueous extracts was acidified with
10% hydrochloric acid under cooling at 0 °C and the fine
precipitate formed was filtered and washed with ice-cold water.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-Acyl-4-
h yd r oxy-1,8-n a p h th yr id in -2(1H)-on es 6 (Meth od B). The
appropriate ester 2 (3.0 mmol) was added dropwise, under argon,
to a stirred solution of LDA (2.0 M solution in THF/ethylbenzene/
heptane; 3.0 mmol, 1.5 mL) in anhydrous THF (10 mL), at -78
°C, and the mixture was stirred for 30 min. A solution of
pyridoxazinone 1c (or 1d ) (2.2 mmol) in anhydrous THF (10 mL)
was added dropwise over 15 min and the mixture was stirred
at -78 °C for 1 h, then allowed to reach rt and stirred for an
additional 1 h. The solvent was evaporated in vacuo, the residue
dissolved in water, and the aqueous mixture washed with diethyl
ether. The aqueous solution was acidified with 10% hydrochloric
acid and the precipitated solid collected by filtration.
Gen er a l P r oced u r e for th e Rea ction s of P yr id oxa zin on e
1c w ith Alk yl-Su bstitu ted â-Dica r bon yl Com p ou n d s 7
(Meth od C). The appropriate malonate or acetoacetate 7 was
added dropwise to a suspension of sodium hydride (55-60% in
oil; 22 mmol, 0.88 g) in anhydrous THF (20 mL) and the mixture
was stirred at room temperature for 30 min. Pyridoxazinone 1c
(5.5 mmol, 0.89 g) was added, the mixture stirred at room
temperature for 3 h, and the solvent evaporated in vacuo. The
residue was dissolved in water and the aqueous mixture was
washed with diethyl ether and acidified with 10% hydrochloric
acid. The acidified mixture was extracted with dichloromethane
and the mixture of the extracts was dried over anhydrous sodium
sulfate and evaporated in vacuo. The oily residue was treated
with diethyl ether and the solid formed collected by filtration.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectroscopic data for all compounds synthesized.
This material is available free of charge via the Internet at
http://pubs.acs.org.
J O0340051
J . Org. Chem, Vol. 68, No. 11, 2003 4569