Polyfunctional 4-quinolinones. Synthesis of 2-substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines

Article abstract of DOI:10.1016/j.tetlet.2016.01.077

We present here two new methods based on rearrangement reactions to obtain novel 2-substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines, an important family of heterocycles with potential applications. Alkyl 3-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylates were obtained by alkoxide promoted rearrangement of alkyl isatinacetates. A second synthetic route involves the alkoxide promoted reaction of both isatin and N-methylisatin, with alkylating agents having acidic methylenes. This reaction leads to the formation of spiroepoxyoxindoles via Darzens' condensation. When phenacyl bromides are used, the initially obtained benzoyl substituted spiroepoxyoxindoles were smoothly transformed into the corresponding 2-benzoyl-3-hydroxy-4-quinolinones with good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2016.01.077

Accepted Manuscript
Polyfunctional 4-quinolinones. Synthesis of 2-substituted 3-hydroxy-4-
oxo-1,4-dihydroquinolines
María S. Shmidt, Isabel A. Perillo, Alicia Camelli, María A. Fernández, María
M. Blanco
PII:
S0040-4039(16)30076-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.077
TETL 47241
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
17 December 2015
11 January 2016
20 January 2016
Please cite this article as: Shmidt, M.S., Perillo, I.A., Camelli, A., Fernández, M.A., Blanco, M.M., Polyfunctional
4-quinolinones. Synthesis of 2-substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines, Tetrahedron Letters (2016),
doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.077
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Polyfunctional 4-quinolinones. Synthesis of
2-substituted 3-hydroxy-4-oxo-1,4-
dihydroquinolines
Leave this area blank for abstract info.
María S. Shmidt, Isabel A. Perillo, Alicia Camelli, María A. Fernández and María M. Blanco*

1
Tetrahedron Letters
Polyfunctional 4-quinolinones. Synthesis of 2-substituted 3-hydroxy-4-oxo-1,4-
dihydroquinolines
María S. Shmidt, Isabel A. Perillo, Alicia Camelli, María A. Fernández and María M. Blanco 
Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Orgánica, Junín 956 (1113) Buenos Aires, Argentina
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
We present here two new methods based on rearrangement reactions to obtain novel 2-
substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines, an important family of heterocycles with
potential applications. Alkyl 3-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylates were
obtained by alkoxide promoted rearrangement of alkyl isatinacetates. A second synthetic route
involves the alkoxide promoted reaction of both isatin and N-methylisatin, with alkylating
agents having acidic methylenes. This reaction leads to the formation of spiroepoxyoxindoles
via Darzens’ condensation. When phenacyl bromides are used, the initially obtained benzoyl
substituted spiroepoxyoxindoles were smoothly transformed into the corresponding 2-benzoyl-
3-hydroxy-4-quinolinones with good to excellent yields.
Available online
Keywords:
Rearrangement
Ring expansion
Spiro compounds
Heterocycles
Epoxidation
2009 Elsevier Ltd. All rights reserved.
1. Introduction
compounds that have enormous potential in medicine. 1-Alkyl-4-
oxo-1,4-dihydroquinoline-3-carboxylic acids, appropriately
Hydroxypyridonecarboxylic acid derivatives containing an
aromatic or heteroaromatic fused ring (A, B) represent a type of
compounds which has been the subject of interest of many
researchers (Figure 1). This group includes hydroxy derivatives
of quinolinone (A, Ar= C6H4),1 isoquinolinone (B, Ar= C6H4)2
and different type of naphthyridinones (A and B, Ar= C5H3N).3
Some of these compounds display interesting biological activities
substituted on the benzene nucleus (such as Norfloxacin and
Ciprofloxacin8) belong to a synthetic broad spectrum antibiotics
family, including also second-line drugs for treatment of
tuberculosis9
and
antimycobacterial
agents.10
Also
hypoglycemic11 and citotoxic12 biological activities have been
reported.
such
as
immunomodulating
and
antiangiogenic,1a-d,3d
Table 1.
antiinflamatory,2c,d,3d gastric antisecretory3b,c and PAI-1
inhibitory1f among others. These compounds have also been used
as synthetic intermediaries,2d,4 models to study tautomerism,5
analytical and spectroscopic applications.6
2-Substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines 1 synthesized
Compound
X
R
1a
OH
H
1b
OCH3
H
1c
1d
1e
1f
OC2H5
OCH(CH3)2
OC(CH3)3
C6H5
H
H
H
H
Figure 1. Hydroxypyridonecarboxylic acid derivatives
1g
[a]
H
1h
1i
1j
1k
4-ClC6H4
C6H5
4-ClC6H4
4-CH3C6H4
H
Following our ongoing research on the synthesis of
polyfunctional compounds containing the hydroxypyridone
moiety2b,e,3a,g-k we were interested in the synthesis of 3-hydroxy-
4-oxo-1,4-dihydroquinoline-2-carboxylic acid derivatives (1,
Table 1), a family of scarcely explored 4-quinolinones.7 This type
of compounds has interesting structural features which would
result in possible applications. Bearing the chromophore 4-
CH3
CH3
CH3
[a] COX = 4-NO2C6H4
Moreover, these compounds should have good chelating
properties due to their polyfunctionality and therefore can also
find applications in analytical chemistry, i.e. in metal ion analysis
quinolinone, they are an important class of biologically active
———
 Corresponding author. Tel.: +54-114-964-8350; fax: +54-114-964-8250; e-mail: mblanco@ffyb.uba.ar

2
Tetrahedron Letters
by complexation. Metal ion interactions play an important role
3b-e were obtained with excellent yields by N-alkylation of isatin
employing the corresponding haloester, Cs2CO3 as base and a
few drops of DMF as solvent under MW irradiation (Scheme 2).
in the solubility, pharmacokinetic, and bioavailability of
compounds and, in many cases, they are involved in the drug’s
mechanism of action.6b-d
We present herein the synthesis of a series of 2-substituted 3-
hydroxy-4-oxo-1,4-dihydroquinolines 1 most of which are new
compounds (Table 1). We have used three different synthetic
approaches to determine their scope and limitations. The
precursors used were 4-oxo-1,4-dihydroquinoline-2-carboxylic
acid (2a, kynurenic acid), N-substituted isatins
spiroepoxyoxindoles 4 (Figure 2).
3 and
Figure 2. Precursors for the synthesis of hydroxyquinolinones 1
Scheme 1. Synthesis of esters1b,c from kynurenic acid 2a
[a] 1) K2S2O8, NaOH, H2O, r.t., 12 h, 2)HCl, 100 °C, 1 h. [b] MeOH or
EtOH/MsOH/alumina, 60 °C, 12 h. [c] MeOH or EtOH/HCl(g). [d] 1)
K2S2O8, NaOH, H2O, r.t., 12 h, 2)AcOH, 100 °C, 1 h, or 1) NBS/H2O, -10 °C,
3 h, 2) NaOH reflux or MW.
2. Results and discussion
We were initially interested in the synthesis of alkyl 3-
hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylates 1 (X= OR),
which are potentially valuable synthetic intermediaries. The first
option was to employ a precursor with the 4-quinolinone nucleus
preformed. Thus, we used the commercially available kynurenic
acid 2a as starting material, which through C-3 hydroxylation
and esterification would lead to the desired compounds (Scheme
1). Oxidation using peroxydisulfate in basic medium (Elbs´
reaction)13 afforded poor yields of the 3-hydroxy derivative 1a
(28%). Furthermore, esterification of the acid 1a proved to be
difficult due to its insolubility and low reactivity. The best results
were obtained using methanesulfonic acid/alumina as catalyst
(1b, 37%, 1c, 42%). Alkylating reactions in neutral or basic
media yielded mixtures of N- and O-alkylated derivatives.14
Inverting the sequence of reactions, esters 2b,c were easily
obtained with good yields (Scheme 1). Nevertheless C-3
hydroxylation, employing Elbs´ oxidation or the sequence
halogenation-hydrolysis15, failed.
Reactions of alkyl isatinacetates 3b-e with 4 equivalents of
alkoxide in the corresponding anhydrous alcohol followed a
common behavior. At room temperature only isatinacetic acid 3a
was obtained. At 100-120 °C a reddish-black syrup was formed
and, by acidification with HCl-ice, mixtures of alkyl 3-hydroxy-
4-oxo-1,4-dihydroquinoline-2-carboxylates 1b-e (43-65%) were
isolated together with variable amounts of acid 3a, the
corresponding 3-hydroxy-2-oxindoles 5b-e and traces of 3-
hydroxykynurenic acid 1a (Scheme 2).
3-Hydroxy-2-oxindoles
5b-e,
(3-hydroxy-2-oxo-2,3-
dihydroindol-1-yl)acetic acid alkyl esters, result from reduction
of the 3-carbonyl of the isatin nucleus. The formation of
compounds 5 can be explained by the carbonyl reductive ability
of alkoxides derived from metals with low ionization potentials
(Meerwein-Ponndorf-Verley type reductions) and which
probably proceeds through radical intermediates.7b
Given the poor results achieved by the methods described
above, we explored other approaches based on rearrangement
reactions. In 2007 we described the synthesis of novel 3-
hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxamides (1, X=
NR1R2) by alkoxide promoted rearrangement of isatinacetamides
(3, X= NR1R2).7b However, to the best of our knowledge, the sole
attempts of rearrangement of alkyl isatinacetates (3, X= OR) with
hot sodium ethoxide date from the first half of the past century.
In 1934, Ainley and Robinson unsuccessfully attempted to obtain
ethyl 3-hydroxy-4-oxo-1,4-dihydroquinoline-2-carboxylate (1c)
from ethyl isatinacetate (3c).16 By the same time and exploring
the same reaction, Putokhin obtained isatinacetic acid (3a) and
the hydroxyacid 1a identified as silver salt and as the O,O-diethyl
derivative.7a
Many attempts to increase yield of esters 1b-e under various
conditions were poor due to the hydrolysis of the ester. However,
even though yields were low, the results for the transformation
isatin → 1b-e can be considered satisfactory, taking into account
the polyfunctionality of the 4-quinolinones 1 obtained, and that
precursors 3 were obtained with excellent yields.
Unlike other families of compounds with enolic OH
(isoquinolinones,2 naphthyridinones3), hydroxyquinolinones 1b-e
do not give positive reaction with FeCl3. Structures were
confirmed by spectral analysis (1H- and 13C-NMR, IR and MS).
With the focus on the synthesis of alkyl 3-hydroxy-4-oxo-1,4-
dihydroquinoline-2-carboxylates (1, X= OR), we studied the
reaction of alkyl isatinacetates with alkoxides. Starting products
Scheme 2. Reaction of N-substituted isatins 3b-e with alkoxides.
[a] ClCH2COX/Cs2CO3/DMF, MW.20 [b] NaOR/ROH, 100-120 °C, 5-10 min

3
By analogy with the proposed mechanism for rearrangement
of isatinacetamides7b the rearrangement 3  1 should involve
nucleophilic attack of the alkoxide with opening of the isatin
ring, isomerization of the resultant anion (I) and subsequent
Dieckmann cyclization (Scheme 3).
Scheme 3. Proposed mechanism for the alkoxide promoted rearrangement
of alkyl isatinacetates 3b-e
To determine the behavior of N-substituted isatins with other
electron-withdrawing substituents, we explored the performance
of N-phenacylisatin 3f (3, X= C6H5). This reaction was studied
by Rekhter in 1993.17 Employing 3 equivalents of sodium
methoxide at room temperature and further acidification the
author obtained 2-benzoylindole-3-carboxylic acid 6.
Bearing this in mind, we decided to study this reaction in
different conditions. Under mild conditions 2-benzoylindole-3-
carboxylic acid (6) was obtained as main product together with 2-
benzoylindole (7) and methyl 2-benzoylindole-3-carboxylate (8).
Under more drastic conditions indoles 6 and 7 were the sole
products isolated (Scheme 4, route a). 2-Benzoyl-3-hydroxy-4-
oxo-1,4-dihydroquinoline (1f) could only be obtained with poor
yields (25%) by treatment of 3f with sodium methoxide (ratio
1:1) at 90 °C, 1-2 min (Scheme 4, route b), together with acid 6
as main product (66%).
Scheme 4. Proposed mechanism for the alkoxide promoted
rearrangements of N-phenacylisatin (3f)
We also studied the reaction of N-4-nitrobenzylisatin 3g (3,
COX= 4-NO2C6H4) with alkoxides under different conditions. In
all cases isatin was obtained as a major product. The N-
dealkylation would be the result of nucleophilic attack of
alkoxide on the benzylic methylene. In no case compounds with
indole structure or 4-quinolinone 1g could be isolated. This
indicates that the presence of a carbonyl to stabilize the
intermediate carbanion I is required in such alkoxide promoted
rearrangements.
For the transformation 3f → 6-8, we propose a reaction
mechanism in which the indole nucleus would be generated
through an addition-elimination reaction by nucleophilic attack
of the intermediate carbanion I on the keto carbonyl. The ester 8
formed, would be transformed into acid 6 (probably by alkoxide
promoted O-alkylester cleavage).18 Finally, decarboxylation of 6
would result in compound 7 (Scheme 4, route a).
Finally, we decided to use
a new approach using
spiroepoxyoxindoles 4 as intermediaries. Recently we reported a
study of reactions of alkylation of isatin19 where we observed that
reaction path depends on the nature of the alkylating agent and
the reaction conditions. Employing NaOEt/EtOH at low
temperatures (0-5 °C), alkylating agents having acidic
methylenes (such as nitrobenzyl bromide or phenacyl bromide)
lead to spiroepoxyoxindoles 4f,g via Darzens’ condensation12
(Scheme 5, Table 2). At room temperature (20-25 °C)
compounds 4 were transformed into the corresponding 3-
hydroxy-4-oxo-1,4-dihydroquinolines 1f and 1g with good to
excellent yields (92% and 73% respectively). The proposed
mechanism involves as fundamental step a 1,2 nucleophilic
migration of the carbon attached to the electron-withdrawing
group (R') (Scheme 6).
When comparing the behavior of alkyl isatinacetates 3b-e (see
above), and isatinacetamides (3, X= NR1R2)7b with the behavior
of the N-phenacyl derivative 3f, the observed differences could
be justified taking into account the intermediate carbanion I
stabilization. The phenacyl group, a strong electron acceptor,
causes a strongly stabilized carbanion I, that preferentially
attacks the more electrophilic carbonyl mainly leading to
compounds with indole nucleus (6-8) (Scheme 4, route a).
However, esters and amides of isatinacetic acid (3, X= OR,
NR1R2) have the alkoxycarbonyl or carboxamido group, with less
electron acceptor effect, thus originating less stable intermediate
carbanions, that preferentially attack the ester carbonyl leading to
The same behavior was observed employing isatin and 4-
chlorophenacyl bromide as starting products. According to the
reaction conditions the corresponding epoxide 4h and the 4-
3-hydroxy-4-oxo-1,4-dihydroquinolines
(Scheme 3).
1 as main products

4
Tetrahedron
quinolinone 1h were obtained with good yields (93% and 81%
important in the case of compounds 4 when R'= COAr, CO2CH3,
respectively).
in which carbonyl groups interactions would destabilize the Z
diastereomers. This interaction could be reduced in the 4-
nitrophenyl derivative 4m as a result of a suitable orientation of
the aryl group by rotation of the Ar-C bond thus explaining why
both diastereomers are obtained.
Scheme 5. Synthetic route to hydroxyquinolinones 1f-k via
spiroepoxyoxindoles 4
[a] XCH2R’/NaOC2H5, 0-5 °C. [b] NaOC2H5, 25 °C
Table 2.
Spiroepoxyoxindoles 4f-m synthesized
Compound 4
R
R’
Figure 3. (Z, E)-4m diastereomers
f [Ref. 19]
H
C6H5CO
g [Ref. 19]
h
i
j
k
l
H
H
4-NO2C6H4
4-ClC6H4CO
C6H5CO
4-ClC6H4CO
4-CH3C6H4CO
CO2CH3
Finally, in order to force the rearrangement of 4 to 1, the
previously isolated E,Z-4m and E-4l epoxides, were subjected to
the reaction with alkoxides under more drastic conditions. We
were not able to achieve the rearrangement, demonstrating the
importance of a strong electron withdrawing benzoyl group for
the rearrangement to occur. However, the stereochemistry of the
epoxide was crucial to its behavior under the reaction conditions.
When E-4l,m isomers were treated at different temperatures (40-
70 °C) a mixture of compounds was obtained, being N-
methylisatin the main product. In contrast, under similar
conditions, the diastereomer Z-4m remained unchanged. The
different behavior of spiroepoxyoxindoles with nucleophiles has
been reported.20b In this case, it could be explained considering
that for E diastereomers, the oxirane ring carbon (C-3') would be
the sterically favored site for nucleophilic attack by the alkoxide,
CH3
CH3
CH3
CH3
CH3
m
4-NO2C6H4
regenerating N-methylisatin (in
a "retro-epoxidation" type
reaction). In the Z isomer, that attack would be prevented by the
steric hindrance caused by R' (Scheme 7).
Scheme 6. Mechanism for rearrangement of 4→1
To extend the scope of the reaction above to the synthesis of
N-substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines we studied
the reaction of N-methylisatin with various alkylating agents.
Reactions using methyl chloroacetate or 4-nitrobenzyl bromide in
the presence of sodium ethoxide at room temperature led to the
corresponding epoxides 4l (77%) and 4m (66%) as final
products. However, when using phenacyl halides under similar
conditions the initially formed spiroepoxyoxindoles 4i-k were
slowly consumed by transforming into the corresponding 2-
Scheme 7. Behavior of spiroepoxyoxindoles (Z)-4m and (E)-4l,m towards
alkoxides
aroyl-3-hydroxy-1-methyl-4-oxo-1,4-dihydroquinolines
1i-k
(Scheme 5). Considering the proposed mechanism, the 4  1
rearrangement (Scheme 6) would be favored by the carbanionic
character acquired by the migratory carbon due to the stability
conferred by the strong electron acceptor group (ArCO).
3. Conclusion
In summary, we have presented here the synthesis of a series
of 2-substituted 3-hydroxy-4-oxo-1,4-dihydroquinolines (1), an
important class of heterocyclic compounds for their potential
applications. We have used three different synthetic approaches
and have determined their scope and limitations. The use of a
compound with the preformed 4-quinolinone nucleus (kynurenic
acid) as a precursor gave poor results. However, two methods
based on rearrangement reactions allowed us to obtain properly
substituted 4-quinolinones 1. The alkoxide promoted
rearrangement of alkyl isatinacetates led to 2-alkoxycarbonyl
derivatives 1b-e as the main products. 2-Benzoyl derivatives
1f,h-k were obtained with good to excellent yields by the
alkoxide promoted reaction of isatin (or N-methylisatin) with
It was interesting to analyze the stereochemical results of the
epoxidation reaction. Epoxides 4i-l were obtained in the form of
E diastereomer. On the other hand, in the case of epoxide 4m,
both stereoisomers were isolated by chromatographic methods
with similar yields (Figure 3; Z, 30% and E, 36%). Confirmation
of the structures was performed by 2D spectroscopy (HSQC,
HMBC and NOESY, see Supplementary material).
Regarding epoxides, it is accepted that E isomers are generally
the most stable,20 because the interactions between the R' group
and the isatin carbonyl are minimal. In particular, this is

5
Fischer, J. P.; Hendricks, R. T.; Spencer, S. R.; Stengel, P. J.
WO Pat. 117 306, 2006; Chem. Abstr. 2006, 145, 489244q.
a) Mphahlele, M. J.; El-Nahas, A. M. J. Mol Struct. 2004, 688,
129. b) Frank, J.; Mészáros, Z.; Kömives, T.; Márton, A.; Dutka,
phenacyl halides at room temperature. This reaction led initially
to the benzoyl substituted spiroepoxyoxindoles 4 (via Darzens’
condensation) which were smoothly transformed into the
corresponding 2-benzoylquinolinones 1. The determination of the
configuration of the spiroepoxioxindoles 4 by spectroscopic
methods allowed us to correlate their chemical behavior to their
stereochemical features.
5.
F. J. Chem. Soc. Perkin II 1980, 401. c) Elguero, J.; Katritzky; A.;
Denisko, O. Adv. Het. Chem. 2000, 76, 1. d) Ito, H.; Matsuoka,
M.; Ueda, Y.; Takuma, M.; Kudo, Y.; Iguchi, K. Tetrahedron
2009, 65, 4235. e) Elguero, J.; Martínez, A.; Singh, S. P.; Grover,
M.; Tarar, L. S. J. Heterocycl. Chem. 1990, 27, 865. f) De la Cruz,
A.; Elguero, J.; Goya, P.; Martínez, A. Pfleiderer, W. Tetrahedron
1992, 48, 6135.
6.
a) Katritzky, A.; Ellison, J.; Frank, J.: Rákóczy, P.; Radics, L.;
Gács-Baitz, E. Org. Magn. Res. 1981, 16, 280. b) Motyka, K.;
Hlaváč, J.; Soural, M.; Funk, P. Tetrahedron Lett. 2010, 51, 5060.
c) Pileni, M. P.; Giraud, M.; Santus, R. Photochem. Photobiol.
1979, 30, 251. d) Ito, H.; Matsuoka, M.; Ueda, Y.; Takuma, M.;
Kudo, Y.; Iguchi, K. Tetrahedron 2009, 65, 4235.
Acknowledgments
This work was financially supported by the Universidad de
Buenos Aires.
7.
8.
a) Putokhin, N. I. J. Gen. Chim. 1935, 5,1176, Chem. Abstr. 1935,
30, 1055. b) Blanco, M. M.; Dal Maso, M.; Shmidt, M. S.; Perillo,
I. A. Synthesis 2007, 829.
Among others a) Uivarosi, V. Molecules 2013, 18, 11153. b)
Appelbaum, P.C.; Hunter, P.A. Int. J. Antimicrob. Agents 2000,
16, 5. c) Hooper, D.C. Biochim. Biophys. Acta-Gene Struct.
Express. 1998, 1400, 45. d) Mitscher, L. A. Chem. Rev. 2005, 105,
559.
References and notes
1.
Among others: (a) Khan, S. R.; Mhaka, A.; Pili, R.; Isaacs, J. T.
Bioorg. Med. Chem. Lett. 2001, 11, 451. (b) Shi, J.; Xiao, Z.;
Ihnat, M. A.; Kamat, C.; Pandit, B.; Hu, Z.; Li, P.-K. Bioorg. Med.
Chem. Lett. 2003, 13, 1187. (c) Jönsson, S.; Andersson, G.; Fex,
T.; Fristedt, T. Hedlund, G.; Jansson, K.; Abramo, L.; Fritzson, I.;
Pekarski, O.; Runström, A.; Sandin, H.; Thuvesson, I.; Björk, A.
J. Med. Chem. 2004, 47, 2075 and references cited therein. (d)
Brunmark, C.; Runström, A.; Ohlsson, L.; Sparre, B.; Brodin, T.;
Aström, M.; Hedlund, G. J. Neuroimmun. 2002, 130, 163. (e)
Tsuji, K.; Spears, G. W.; Nakamura, K.; Tojo, T.; Seki, N.;
Sugiyama, A.; Matsuo, M. Bioorg. Med. Chem. Lett. 2002, 12, 85.
(f) Folkes, A.; Brown, S. D.; Canne, L. E.; Chan, J.; Engelhardt,
E.; Epshteyn, S.; Faint, R.; Golec, J.; Hanel, A.; Kearney, P.;
Leahy, J. W.; Mac, M.; Matthews, D.; Prisbilla, M. P.; Sanderson,
J.; Simon, R. J.; Tesfai, Z.; Vicker, N.; Wang, S.; Webb, R. R.;
Charlton, P. Bioorg. Med. Chem. Lett. 2002, 12, 1063. (g)
Ukrainets, I. V.; Taran, S. G.; Gorokhova, O. V.; Taran, E. A.;
Jaradat, N. A.; Petukhova, I. Y. Chem. Heterocyclic Compounds
2000, 36, 166 and references cited therein. (h) Kugalowski, J. J.;
Baker, R.; Curtis, N. R.; Leeson, P. D.; Mawer, I. M.; Moseley, A.
M.; Ridgill, M. P.; Rowley, M.; Stansfield, I.; Foster, A. C.;
Grimwood, S.; Hill, R. G.; Kemp, J.A.; Marshall, J. R.; Saywell,
K. L.; Tricklebank, M. D. J. Med. Chem. 1994, 37, 1402.
9.
a) O’Brien, R. Am. J. Respir. Crit. Care Med. 2003, 168, 1266. b)
Janin, Y. L. Bioorg. Med. Chem. 2007, 15, 2479.
10. Wube, A. A.; Bucar, F.; Hochfellner, C.; Blunder, M.; Bauer, R.;
Hüfner, A. Eur. Bioorg. Med. Chem. 2011, 46, 2091.
11. Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Bioorg. Med.
Chem. Lett. 2000, 10, 1831.
12. Among others: a) Huang, L-J.; Hsieh, M-C.; Teng C-M.; Lee, K-
H.; Kuo, S-C. Bioorg. Med. Chem. 1998, 6, 1657. b) Traxler, P.;
Green, J.; Mett, H.; Sequin, U.; Furet, P. J. Med. Chem. 1999, 42,
1018. c) Hadjeri, M.; Barbier, M.; Ronot, X.; Mariotte, A-M.;
Boumendjel, A.; Boutonnat, J. J. Med. Chem. 2003, 46, 2125. d)
Xiao, Z-P.; Li, H-Q.; Shi, L.; Lv, P-C.; Song, Z-C.; Zhu, H-L.
ChemMedChem 2008, 3, 1077. e) Jin, G. H.; Ha, S. K.; Park, H.
M.; Kang, B.; Kim, S. Y.; Kim, H-D.; Ryu, J-H.; Jeon, R. Bioorg.
Med. Chem. Lett. 2008, 18, 4092. f)Kuo, S. C.; Lee, H. Z.; Juang,
J. P.; Lin, Y-T.; Wu, T-S.; Chang, J-J.; Lednicer, D.; Paull, K. D.;
Lin, C. M. J. Med. Chem. 1993, 36, 1146.
13. a) Behrman, E. J. Beilstein J. Org. Chem. 2006, 2 (22) 1. b)
Behrman, E. J.; Kiser, R. L.; Garas, W. F.; Behrman, E. C.; Pitt,
B. M. J. Chem. Res.(S) 1995, 164.
14. Shmidt, M. S.; Blanco, M. M. PhD thesis: Síntesis y estudio de
derivados del ácido 3-hidroxi-4-quinolinona-2-carboxílico con
potencial actividad biológica, 2014, Library of Pharmacy and
Biochemistry Faculty, Buenos Aires University, Argentina.
15. Coppini, D. Gazz. Chim. Ital. 1950, 80, 36.
16. Ainley, A. D.; Robinson, R. J. Chem. Soc. 1934, 1508.
17. Rekhter, M.A. Khim. Geterotsikl. Soedin. 1993, 29, 642.
18. Perillo, I.; Schapira, C.; Lamdan, S. J. Heterocycl. Chem. 1983,
20, 155.
19. Shmidt, M. S.; Perillo, I. A.; González, M.; Blanco, M. M.
Tetrahedron Lett. 2012, 53, 2514.
20. a) Fu, Q.;Yan, Ch-G. Beilstein J. Org. Chem. 2013, 9, 918. b)
Dandia, A.; Singh, R.; Saha, M.; Shivpuri, A. Pharmazie 2002, 9,
602. c) Boucherif, A.; Yang, Q-Q.; Wang, Q.; Chen, J-R.; Lu, L-
Q.; Xiao, W-J. J. Org. Chem. 2014, 79, 3924.
2.
Among others: (a) Lombardino, J. G. J. Heterocycl. Chem. 1970,
7, 1057. (b) Schapira, C. B.; Abasolo, M. I.; Perillo, I. A. J.
Heterocycl. Chem. 1985, 22, 577 and references cited therein. (c)
Kadin, S. B.; Wiseman, E. H. Nature 1969, 222, 275. (d) Lazer,
E.; Miao, C. K.; Cywin, C. L.; Sorcek, R.; Wong, H.-C.; Meng, Z.;
Potocki, I.; Hoermann, M.; Snow, R. J.; Tschantz, M. A.; Kelly, T.
A.; McNeil, D. W.; Coutts, S. J.; Churchill, L.; Graham, V; David,
E.; Grob, P. M.; Engel, W.; Meier, H.; Trummlitz, G. J. Med.
Chem. 1997, 40, 980. e) Blanco, M. M.; Shmidt, M. S.; Schapira,
C. B.; Perillo, I. A. Synthesis 2006, 1971.
3.
Among others: (a) Blanco, M. M.; Schapira, C. B.; Levin, G.;
Perillo, I. A. J. Heterocycl. Chem. 2005, 42, 493 and references
cited therein. (b) Scotese, A. C.; Santilli, A. A. S. African ZA
8000631, 1981; Chem. Abstr. 1982, 96, 6706. (c) Scotese, A. C.;
Morris, R. L.; Santilli, US Patent 4301281, 1981; Chem. Abstr.
1982, 97, 23815. (d) Armitage, B.J.; Leslie, B.W. PCT Int. Appl.
WO 199611199, 1996; Chem.Abstr. 1996, 125, 114712. (e)
Nuebling, C.; Von Deyn, W.; Theobald, H.; Westphalen, K.-O.;
Kardorff, U.; Helmut, W. Kappe, T.; Gerber, M. Ger. Offen. DE
4227747, 1993; Chem. Abstr. 1994, 120, 323554z. f) Kobayashi,
K; Litsuka, D; Fukamachi, S; Konishi, H. Synthesis 2009, 375. g)
Blanco, M. M.; Lorenzo, M. G.; Perillo, I. A.; Schapira, C. B. J.
Heterocycl. Chem. 1996, 33, 361. h) Blanco, M. M; Perillo, I. A.;
Schapira, C. B. J. Heterocycl. Chem. 1999, 36, 979. i) Blanco, M.
M.; Buldain, G. Y.; Schapira, C. B.; Perillo, I. A. J. Heterocycl.
Chem. 2002, 39, 341. j) Santo, M.; Giacomelli, L.; Catanna,
R.;Silber, J.; Blanco, M. M.; Schapira, C.; Perillo, I. A.
Supplementary Material
Supplementary material that may be helpful in the review
process should be prepared and provided as a separate electronic
file. That file can then be transformed into PDF format and
submitted along with the manuscript and graphic files to the
appropriate editorial office.
Spectrochimica Acta Part A 2003, 59, 1399. k) Perillo, I. A.;
Kremenchuzky, L. D.; Blanco, M. M. J. Mol. Struct. 2009, 307.
a) Coppola, G. M.; Fraser, J. D.; Hardtmann, G. E.; Shapiro, M. J.
J. Heterocycl. Chem. 1985, 22, 193. b) Fujisawa Pharmaceutical
Co., Ltd. Japan. Japan Kokai Tokyo Koho JP Pat. 07252228,
1995; Chem. Abstr. 1996, 124, 117079c. c) Blake, J. F.; Fell, J. B.;
4.
Click here to remove instruction text...