A simple and efficient one-step synthesis of 3-substituted-4- hydroxyquinolin-2-one derivatives

Article abstract of DOI:10.1016/j.tetlet.2012.01.140

A new simple and efficient one-step procedure for the preparation of 3-substituted-4-hydroxyquinolin-2-one derivatives was developed. Product isolation is simple, isolated yields are good to excellent and this method tolerates a variety of substitution pa

Full text of DOI:10.1016/j.tetlet.2012.01.140

Tetrahedron Letters 53 (2012) 1920–1923
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Tetrahedron Letters
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A simple and efficient one-step synthesis of 3-substituted-4-hydroxyquinolin-2-
one derivatives
⇑
Jérôme Toum, Alexandre Moquette, Yann Lamotte, Olivier Mirguet
Lipid Metabolism Discovery Performance Unit, GlaxoSmithKline R&D, 25 avenue du Québec, 91951 Les Ulis Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
A new simple and efficient one-step procedure for the preparation of 3-substituted-4-hydroxyquinolin-2-
one derivatives was developed. Product isolation is simple, isolated yields are good to excellent and this
method tolerates a variety of substitution patterns.
Received 22 December 2011
Revised 28 January 2012
Accepted 31 January 2012
Available online 8 February 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
4-Hydroxyquinolinone
Quinolinone
Cyclization
One-step procedure
The 4-hydroxyquinolin-2-one motif is found in a variety of
biologically active compounds and in particular, 3-substituted-4-
hydroxyquinolin-2-one derivatives are known as selective non-
competitive agonists of NMDA receptors1,2 and antagonists of
AMPA receptors.3,4 Some compounds are of utility in the treatment
of convulsions, schizophrenia and in the prevention of neurode-
generative disorders, such as Alzheimer’s disease, Huntington’s
disease and Parkinsonism.5 Recently, this scaffold was also de-
scribed as type I fatty acid synthase inhibitors.6
Initially, the quinoline-2-one derivatives were prepared follow-
ing a classical two-step synthesis6,7 shown in Scheme 1. Acylation
in the presence of HATU in DCM at rt was followed by cyclization
induced by either LiHMDS at À78 °C or KHMDS at rt in THF. In gen-
eral, the overall yields over two steps were moderate, especially
when R2 was an O-alkyl group. Although these conditions allowed
us to generate a number of 3-O-substituted quinolinones, we spec-
ulated that it might be possible to improve this synthesis by com-
bining the two reactions in a single step.
There are several approaches for the preparation of these com-
pounds all of which require a multistep synthesis. The most com-
monly found routes used in the literature is a two-step procedure
involving acylation reaction of an anthranilic ester derivative with
substituted acetate followed by the formation of the pyridinone via
an intramolecular Claisen condensation in the presence of a base.
(Scheme 1).6,7
Several literature references describe the synthesisof 4-hydroxy-
quinolin-2-one with diverse substitutions at the C3-position.
Carbonyl, phenyl, and alkyl groups are common but there are very
few reports describing O-substitution.8 To the best of our knowl-
edge, a convenient and high-yielding method for the synthesis of
N-unsubstituted 4-hydroxyquinolin-2-ones with C3 O-substitu-
tion8 is still lacking. Herein, we report a simple one-step synthesis
of these compounds of interest from commercially available starting
materials (Scheme 1).
As a model system, we investigated the reaction of methyl 2-
amino-4-chlorobenzoate and methyl 2-(2-methoxyethoxy) ace-
tate. Table 1 describes the conditions used for the direct cyclization
reaction. These results revealed that there were substantial differ-
ences between the conditions used. Among the bases utilized,
t
KHMDS was superior to some other bases such as BuOK, LDA, or
NaH and even better than LiHMDS under the same reaction condi-
tions. In addition, THF appeared to be the solvent of choice. The use
of KHMDS in THF at room temperature provided the intended
quinolinone in a high yield with no detectable trace of by-products.
O
O
OH
3
R2
O
cyclization
acylation
O
O
R1
R1
R1
NH2
NH
N
H
O
R2
This work
Scheme 1. Synthesis of 3-substituted-4-hydroxyquinolin-2-one derivatives.
⇑
Corresponding author.
E-mail address: olivier.x.mirguet@gsk.com (O. Mirguet).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2012.01.140

J. Toum et al. / Tetrahedron Letters 53 (2012) 1920–1923
1921
Table 1
Firstly the protocol was repeated with ethyl 2-phenoxyacetate
(entry 1). As expected, the quinolinone was isolated in excellent
yield within 10 min after simple work-up. It turned out that, as
outlined in the examples of Table 2, the electronic nature of the
substituents on the phenyl ring played a limited role on the reaction
outcome. Thus for anthranilic ester bearing mildly electron-with-
drawing groups (entries 1, 7, 8, 10) or those with electron-donating
substituents (entries 5, 6, 9) the reactions were completed within
30 min. A slight adjustment of the reaction conditions was required
in some cases in which more KHMDS was added to achieve full con-
version (entries 5, 6, 9, 12). However, the reaction yield with phenyl
substituted at the C3-position suggests a marked role of steric fac-
tors on the completion of the reaction. In these specific cases,
microwave irradiation was used. While no reaction occurred with
nitro moiety (entry 3), these stronger conditions allowed us to get
the 8-OMe substituted compound (entry 4) in a moderate yield.
The anthranilic ester could also be replaced by certain heterocycles
(entries 11–13). Even though longer reaction time was required, the
protocol allowed us to generate the desired products in every cases,
either in a low yield for thiophene moiety (entry 13) or in good
yields for pyridine and tetrahydropyridine starting materials
(entries 11 and 12).
Optimization of a one-step quinolinone synthesisa
OH
O
O
O
O
O
Base
Solvent
Time
O
O
O
+
O
Cl
N
H
Cl
Entry
NH2
Base
Solvent
Time
Conv./intended productb (%)
1
2
3
4
5
6
7
8
tBuOK
Cs2CO3
NaH
DMSO
DMSO
THF
2 h
2 h
2 h
100/0
100/0
100/0
100/0
82/30
87/30
100/15
LDA
THF
3 h
LiHMDS
LiHMDS
KHMDS
KHMDS
THF
THF
Toluene
THF
3 h
24 h
2 h
20 min
100/100 (67%)c
a
Reaction conditions: 1.0:1.2 equiv anthranilic ester/acetate, 3.0 equiv base,
0.13 M solvent, rt (reaction with Cs2CO3 was performed at 90 °C).
b
Determined by HPLC.
Isolated yield.
c
Noteworthy, the difference between the conversion and the iso-
lated yield (entry 8) is certainly due to the loss of material during
isolation and purification.
The scope of this methodology to other substitutions at C-3 on
the pyridinone was then enlarged. Examples in Table 3 show that
N-phenyl (entry 2), S-phenyl (entry 3), O-alkyl (entry 4), or O-pyr-
idyl acetates (entry 1) are tolerated.
The feasibility of the one-step reaction is being now demon-
strated, this procedure was further evaluated for its scope and gen-
eral applicability. To this end, a variety of anthranilic esters were
examined and the results are presented in Table 2.
Table 2
Synthesis of quinolinone from various anthranilic estersa
OH
O
R1
R1
EtOOC
O
O
KHMDS
OR
+
THF, RT
N
H
O
NH2
Entry
1
Anthranilic ester
Product
Time (min)
Yieldb (%)
92
COOMe
NH2
OH
O
O
10
10
Cl
Cl
N
H
COOMe
OH
O
O
2
3
91
NH2
N
H
OH
COOMe
NH2
120
15c
—
—
O
O
N
H
NO2
NO2
COOMe
NH2
OH
O
O
4
15c
33
O
N
H
O
O
COOMe
OH
O
5
6
7
30d
30d
20
79
80
O
NH2
N
H
OH
O
O
O
COOMe
NH2
O
O
O
O
N
H
OH
I
COOMe
NH2
I
O
98
Cl
Cl
N
H
O
(continued on next page)

1922
J. Toum et al. / Tetrahedron Letters 53 (2012) 1920–1923
Table 2 (continued)
Entry
Anthranilic ester
Product
Time (min)
10
Yieldb (%)
80
Br
COOMe
NH2
OH
Br
O
O
8
N
H
OH
COOMe
O
9
60e
60
96
68
67
76
25
NH2
N
H
OH
O
F
F
COOMe
O
O
10
11
12
NH2
N
H
OH
COOMe
O
20
N
NH2
N
N
H
O
Bn
COOMe
OH
N
S
Bn
O
O
N
S
60f
10c
NH2
N
H
OH
COOEt
NH2
O
O
13
N
H
a
Reaction conditions: 1.0:1.2 equiv anthranilic ester/acetate, 3.0 equiv KHMDS 1.0 M in THF, 0.13 M THF, rt.
Isolated yields.
Microwave irradiation, 130 °C.
0.5 equiv of KHMDS was added after 20 min.
0.5 equiv of KHMDS was added after 60 min.
b
c
d
e
f
Reaction performed at 60 °C. 1 equiv of KHMDS was added after 60 min.
Table 3
Heteroatom and phenyl replacementa
OH
O
X
KHMDS
THF, RT
R2
ROOC
X
O
R2
N
H
Cl
O
Cl
NH2
Entry
1
Acetate
Product
Time (min)
20
Yieldb (%)
66
OH
O
O
N
EtOOC
O
N
N
Cl
N
H
OH
N
O
EtOOC
2
3
4
20
67
24
81
Cl
Cl
Cl
N
H
OH
S
MeOOC
S
10c
40d
N
H
OH
O
O
O
EtOOC
O
N
H
a
b
c
Reaction conditions: 1:1.2 equiv anthranilic ester/acetate, 3 equiv KHMDS 1.0 M in THF, 0.13 M THF, rt.
Isolated yields.
Microwave irradiation, 130 °C.
1 equiv of KHMDS was added after 40 min.
d
In conclusion we have developed an efficient and high yielding
one-step synthesis of 4-hydroxyquinolin-2-one substituted at the
3-position by a heteroatom directly from anthranilic esters and
heteroatom-substituted acetates. The short reaction time, mild

J. Toum et al. / Tetrahedron Letters 53 (2012) 1920–1923
1923
reaction conditions, and high isolated yields render this method
Supplementary data
more attractive in comparison to the existing synthetic route cur-
rently found in the literature.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2012.01.140. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
Typical procedure
To a solution of methyl 2-amino-4-chlorobenzoate (300 mg,
1.6 mmol) and ethyl 2-phenoxyacetate (320 mg, 1.8 mmol) in
anhydrous THF (9 mL) was added KHMDS (4.8 mL, 1.0 M in THF,
4.8 mmol) in one portion with vigorous stirring under a nitrogen
atmosphere. The reaction mixture was stirred at rt until comple-
tion of the reaction (10 min) then MeOH was added. The reaction
mixture was concentrated under reduced pressure and the result-
ing residue was taken up in water and acidified with 1 N HCl until
precipitation occurred. The precipitate was filtered, washed with
EtOH then dried to give 7-chloro-4-hydroxy-3-phenoxyquinolin-
2(1H)-one (Table 2, entry 1) as a pale pink powder (449 mg,
92%). 1H NMR (300 MHz, DMSO-d6) d 11.74 (s, 1H), 11.37 (s, 1H),
7.88 (s, 1H), 7.49–7.13 (m, 4H), 7.10–6.78 (m, 3H). 13C NMR
(75 MHz, DMSO-d6) d 158.8 (s), 157.4 (s), 152.2 (s), 137.2 (s),
134.4 (s), 129.2 (d), 125.3 (s), 124.8 (d), 121.7 (d), 121.6 (d),
115.2 (d), 114.3 (s and d). MS(EI) m/z 288 (MH+).
References and notes
1. Rowley, M.; Kulagowski, J. J.; Watt, A. P.; Rathbone, D.; Stevenson, G. I.; Carling,
R. W.; Baker, R.; Marshell, G. R.; Kemp, J. A.; Foster, A. C.; Grimwood, S.;
Hargreaves, R.; Hurley, C.; Saywell, K. L.; Tricklebank, M. D.; Leeson, P. D. J. Med.
Chem. 1997, 40, 4053–4068.
2. Fuchigami, T.; Haradahira, T.; Fujimoto, N.; Nojiri, Y.; Mukai, T.; Yamamoto, F.;
Okauchi, T.; Maeda, J.; Suzuki, K.; Suhara, T.; Yamaguchi, H.; Ogawa, M.; Magata,
Y.; Maeda, M. Bioorg. Med. Chem. 2009, 17, 5665–5675.
3. 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, 3423–3425.
4. Hicks, C. A.; Ward, M. A.; Ragumoorthy, N.; Ambler, S. J.; Dell, C. P.; Dobson, D.;
O’Neill, M. J. Brain Res. 1999, 819, 65–74.
5. Park, N. S.; Seong, C. M.; Jung, Y. S.; Choi, J. I.; Lee, C. W.; Chung, Y. J.; Choi, S. W.;
Kong, J. Y.; Park, W. K. Eur. Pat. Appl. EP 869122, 1998.
6. Rivkin, A.; Kim, Y. R.; Goulet, M. T.; Bays, N.; Hill, A. D.; Kariv, I.; Krauss, S.;
Ginanni, N.; Strack, P. R.; Kohl, N. E.; Chung, C. C.; Varnerin, J. P.; Goudreau, P. N.;
Chang, A.; Tota, M. R.; Munoz, B. Bioorg. Med. Chem. Lett. 2006, 16, 4620–4623.
7. (a) Goulet, M. T.; Munoz, B.; Rivkin, A. A. PCT Int Appl. WO2007089634, 2003.;
(b) Walser, A.; Silverman, G.; Flynn, T.; Fryer, R. I. J. Heterocycl. Chem. 1975, 12,
351–358.
8. (a) Pongratz, E.; Kappe, T. Monatsh. Chem. 1984, 115, 231–242; (b) Freeman, G.
A., ; Andrews, C. W., III; Hopkins, A. L.; Lowell, G. S.; Schaller, L. T.; Cowan, J. R.;
Gonzales, S. S.; Koszalka, G. W.; Hazen, R. J.; Boone, L. R.; Ferris, R. G.; Creech, K.
L.; Roberts, G. B.; Short, S. A.; Weaver, K.; Reynolds, D. J.; Milton, J.; Ren, J.; Stuart,
D. I.; Stammers, D. K.; Chan, J. H. J. Med. Chem. 2004, 47, 5923–5936; (c) Coppola,
G. M. J. Heterocycl. Chem. 1985, 22, 1087–1088; (d) Cuny, G. D.; Lee, K.; Choi, S.
Lett. Org. Chem. 2006, 3, 68–72; (e) Jeon, M.-K.; Laa, H. J.; Hab, D.-C.; Gong, Y.-D.
Synlett 2007, 1431–1435.
Acknowledgments
Dr. Dominique Amans and Dr. Matthew Popkin are gratefully
acknowledged for providing useful feedback during manuscript
revisions.