N-(2-Aminobenzoyl)benzotriazole mediated and t-BuOK promoted synthesis of 2-substituted quinolone 3-carboxylates

Article abstract of DOI:10.1016/j.tetlet.2015.09.109

2-Substituted quinolone 3-carboxylates were obtained in moderate to good yields by the reaction of N-(2-aminobenzoyl)benzotriazoles with β-ketoesters in the presence of t-BuOK in THF.

Full text of DOI:10.1016/j.tetlet.2015.09.109

Accepted Manuscript
N-(2-aminobenzoyl)benzotriazole mediated and t-BuOK promoted synthesis of
2-substituted quinolone 3-carboxylates
Şule Kökten, İlhami Çelik
PII:
S0040-4039(15)30151-9
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.109
TETL 46781
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
26 June 2015
11 September 2015
24 September 2015
Please cite this article as: Kökten, Ş., Çelik, İ., N-(2-aminobenzoyl)benzotriazole mediated and t-BuOK promoted
synthesis of 2-substituted quinolone 3-carboxylates, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/
j.tetlet.2015.09.109
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N-(2-aminobenzoyl)benzotriazole mediated
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substituted quinolone 3-carboxylates
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Şule Kökten and İlhami Çelik

1
Tetrahedron Letters
N-(2-aminobenzoyl)benzotriazole mediated and t-BuOK promoted synthesis of 2-
substituted quinolone 3-carboxylates
Şule Köktena and İlhami Çelik a, 
aDepartment of Chemistry, Faculty of Science, Anadolu University, Eskişehir 26470, Turkey
ARTICLE INFO
ABSTRACT
Article history:
Received
2-Substituted quinolone 3-carboxylates were obtained in moderate to good yields by the reaction
of N-(2-aminobenzoyl)benzotriazoles with β-ketoesters in the presence of t-BuOK in THF.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Quinolone
Quinolone 3-carboxylate
N-(2-aminobenzoyl)benzotriazole
Anthranilic acid
Benzotriazole
———
 Corresponding author. Tel.: +90-222-335-0580; fax: +90-222-320-4910; e-mail: ilcelik@anadolu.edu.tr

2
Tetrahedron Letters
Quinolones are a widely employed series of synthetic
antibacterial agents which have also been shown to possess
various pharmacological activities such as anticonvulsant,
antitumor and antiviral. These compounds have been widely used
to treat genitourinary infections, prostatitis, respiratory diseases,
gastroenteritis, sexually transmitted diseases, as well as skin and
soft tissue infections.1,2
Table 1.Screening of reaction conditions.
Yield of 3a
(%)
Entry Solvent
Base
Time (temp)
1
2
3
4
5
6
THF
DMF
THF
DMF
THF
THF
t-BuOK
t-BuOK
t-BuOK
t-BuOK
Na2CO3
NEt3
Overnight (rt)
Overnight (rt)
2 h (reflux)
2 h (reflux)
2 h (reflux)
2 h (reflux)
30
39
68
55
23
25
Most quinolone drugs contain the carboxylic acid moiety at
the 3-position and the hydrolysis of 2-substituted quinolone-3-
carboxylate derivatives 3 provides potential access to other
analogues. In addition to being useful for the preparation of
biologically important compounds, some activity studies have
shown that the ester group at the 3-position of a quinolone ring is
required for antibacterial activity3 and replacement of this group
with another group caused a decrease or loss in activity.4a,b
Additionally, there have been reports that 2-substituted
quinolone-3-carboxylates 3 are promising leads for the treatment
of cancer5 and AIDS.6
Having established the optimal reaction conditions, we then
started to explore the generality of this reaction for the
preparation of related quinolone carboxylates bearing different
substituents (Table 2).
This motif has been synthesized using various methodologies
including the reaction of i) anilines with various malonates;7a-d ii)
benzonitriles with keto phosphorus ylides;8 iii) isatoic anhydride
with β-ketoesters;7a, 9a,b iv) o-isocyanobenzoates with magnesium
enolates;10 v) anthranilic acid with various reagents;11a,b vi) N-
arylimines with various carbon nucleophiles12a,b and vii) 2-
nitrobenzoic acid, activated by thionyl chloride13a or oxalyl
chloride,13b with 1,3-dicarbonyl compounds (Scheme 1). These
literature methods have several drawbacks such as long reaction
times, multiple steps, toxic reagents, and starting materials which
are difficult to synthesize. In the case of intramolecular
electrophilic substitution, the regioselectivity of the reaction
becomes a problem when using unsymmetrical substituted
aniline derivatives.
Scheme 3. Preparation of 2-substituted quinolone-3-carboxylates
Scheme 1. Selected literature methods for the synthesis of 2-
bearing different substituents.
substituted quinolone-3-carboxylates. See text for a description
N-(2-Aminobenzoyl)benzotriazoles,
prepared
from
of (i) – (vii).
anthranilic acids and containing both free amino and active
carbonyl groups, are stable reagents that have been utilised as
versatile intermediates for the synthesis of anthranilic acid
amides,14 esters and thioesters15 as well as heterocycles.16 Similar
to
other
N-acylbenzotriazole
derivatives,
N-(2-
aminobenzoyl)benzotriazoles are easily prepared in crystalline
form and are stable to moisture. As a continuation of our efforts
to utilise N-(2-aminobenzoyl)benzotriazoles in synthesis, we
herein describe a new protocol for the synthesis of 2-substituted
quinolone-3-carboxylates 3.
We
initially
synthesized
a
series
of
N-(2-
aminobenzoyl)benzotriazoles from suitable anthranilic acids by
stirring with benzotriazole in the presence of DCC at room
temperature, according to the procedure developed by our
group14,15 (Scheme 3). To develop the optimum conditions, the
reaction of N-(2-aminobenzoyl)benzotriazole 1a with ethyl
acetoacetate 2a was chosen as a model system (Scheme 2) and a
variety of reaction conditions were screened (Table 1). Initially,
the reaction was carried out at RT and reflux in THF and DMF. It
was found that in THF the yield increased from 30% at room
temperature (Table 1, Entry 1) to 68% at reflux (Table 1, Entry
3). Next, we examined the effect of different bases and it was
concluded that the use of t-BuOK in THF at reflux provided
product 3a in the highest yield.
Table 2.Synthesis of various 2-substituted quinolone-3-
carboxylates.
Yield
Entry Substrate
R
R1
Product
(%)
68 (67)8a
45
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a Me
2b 4-MeOC6H4 3-Me
-
3a
3b
3c
3d
3e
3f
2c 4-NO2C6H4 4-Me
42
65
48
72
67
72
19
2a Me
2d 4-BrC6H4
2e Ph
2f 4-MeC6H4
2g 4-ClC6H4
2a Me
5-Me
4-F
4-Cl
5-Br
5-I
1g
1h
1i
3g
3h
3i
Scheme 2. Model reaction of N-(2-aminobenzoyl)benzotriazole
3,5-Cl2
with ethyl acetoacetate.
8a: Literature yield.

3
6.
7.
Stevens, M.; Pollicita, M.; Pannecouque, C.; Verbeken, E.;
All 2-substituted quinolone-3-carboxylates were successfully
synthesized in moderate to good yields, except 3i which was
isolated in only 19% yield (Table 2, entry 9). The reason for the
low yield of 3i may be due to the electronic effects of the
chlorides in the aromatic ring. Except 3a, all obtained
compounds were novel and their structures identified by NMR
spectroscopy. Because of the free acidic proton, these compounds
have two possible tautomeric structures: 4-oxoquinoline and 4-
hydroxyquinoline. In the 1H-NMR spectra, a characteristic singlet
resonance was observed around 12 ppm for all compounds,
which could be assigned to either the NH or enolic OH proton.
Tabarrini, O.; Cecchetti, V.; Aquaro, S.; Perno, C. F.; Fravolini,
A.; De Clercq, E.; Schols, D.; Balzarini, J. Antimicrob. Agents Ch.
2007, 51, 14071413.
(a) Goncalves, V.; Brannigan, J. A:; Whalley, D.; Ansell, K. H.;
Saxty, B.; Holder, A. A.; Wilkinson, A. J.; Tate, E. W.;
Leatherbarrow, R. J. J. Med. Chem. 2012, 55, 3578. (b) Höglund,
I. P. J.; Silver, S.; Engström, M. T.; Salo, H; Tauber, A.;
Kyyrönen, H-K.; Saarenketo, P.; Hoffren, A-M.; Kokko, K.;
Pohjanoksa, K.; Sallinen, J.; Savola, J-M.; Wurster, S.; Kallatsa,
O. A. J. Med. Chem. 2006, 49, 6351-6363. (c) Fryer, R. I.; Zhang,
P.; Rios, R.; Gu, Z-Q.; Basile, A. S.; Skolnickt, P. J. Med. Chem.
1993, 36, 1669-1673. (d) Chen, S.; Chen, R.; He, M.; Pang, R.;
Tan, Z.; Yang, M. Bioorg. Med. Chem. 2009, 17, 1948-1956.
Abdou, W. M.; Ganoub, N. A. F.; Fahmy, A. F. M.; Shaddy, A. A.
M. Phosphorus Sulfur 2004, 180, 2373-2390.
(a) Pidathala, C.; Amewu, R.; Pacorel, B.; Nixon, G. L.; Gibbons,
P.; Hong, W. D.; Leung, S. C.; Berry, N. G.; Sharma, R.; Stocks,
P. A.; Srivastava, A.; Shone, A. E.; Charoensutthivarakul, S.;
Taylor, L.; Berger, O.; Mbekeani, A.; Hill, A.; Fisher, N. E.;
Warman, A. J.; Biagini, G. A.; Ward, S. A.; O’Neill, P. M. J. Med.
Chem. 2012, 55, 1831-1843. (b) Mai, A.; Rotili, D.; Tarantino, D.;
Ornaghi, P.; Tosi, F.; Vicidomini, C.; Sbardella, G.; Nebbioso, A.;
Miceli, M.; Altucci, L.; Filetici, P. J. Med. Chem. 2006, 49, 6897-
6907.
In previously reported work, 3a was prepared with two other
examples of quinolone-3-carboxylates containing a free NH in
the product, using N-hydroxysuccinimide as an activating
agent.11b The products prepared in the literature work gave only
poor to fair yields (13-34%) while all of the examples in the
current work were considerably better in yield (19-72%) The ease
and convenience of both methodologies are approximately the
8.
9.
same and the current work represents
a complementary
alternative to prepare N-unsubstituted-2-substituted quinolone-3-
carboxylates.
10. Kobayashi, K.; Nakashima, T.; Mano, M.; Morikawa, O.; Konishi,
H. Chem. Lett. 2001, 7, 602-603.
Consequently, we have developed a new method for the
synthesis of 2-substituted quinolone-3-carboxylates using N-
acylbenzotriazoles. This appears to be a suitable method for the
preparation of quinolones with a variety of substituents at the 2-
position and the benzene ring. Easily accessible starting
compounds, mild reaction conditions and short reaction times are
the advantages of the developed method.
11. (a) Tsantrizos, Y. S.; Bailey, M D.; Bilodeau, F.; Carson, R. J.;
Fader, L.; Halmos, T.; Kawai, S.; Landry, S.; Laplante, S.;
Simoneau, B. PCT Int. Appl. WO2009062289 (A1), 2009. (b)
Mitsos, C.; Zografos, A.; Igglessi-Markopoulou, O. Chem. Pharm.
Bull. 2000, 48, 211-214.
12. (a) Uneyama, K.; Morimoto, O.; Yamashita, F. Tetrahedron Lett.
1989, 30, 4821-4824. (b) Isobe, A.; Takagi, J.; Katagiri, T.;
Uneyama, K. Org. Lett. 2008, 10, 2657-2659.
13. (a) Jung, J-C.; Jung, Y-J.; Park, O-S. J. Heterocyclic Chem. 2001,
38, 61-67. (b) Bunce, R. A.; Nammalwar, B. Org. Prep. and
Proced. Int. 2010, 42, 557-563.
Acknowledgments
14. Kanışkan, N.; Kökten, Ş.; Çelik, İ. Arkivoc 2012, viii, 198.
15. Kökten, Ş.; Çelik, İ. Synthesis 2013, 45, 2551.
This work is dedicated to Professor Alan Roy Katritzky, who
died on 10th February, 2014. It is gratefully acknowledged that
this work was supported financially by Anadolu University
(Project No: 1306F110).
16. Chaturvedi, A. K.; Rastogi, N. Synthesis 2015, 47, 249-255.
17. Typical procedure for ethyl 4-hydroxy-2-methylquinoline-3-
carboxylate (3a): N-(2-Aminobenzoyl)benzotriazole 1a (238 mg,
1 mmol) and ethyl acetoacetate 2a (0.128 ml, 1 mmol) were
stirred in anhydrous THF at room temperature for 1 h. t-BuOK
(123 mg, 1.1 mmol) was added and the resulting mixture heated at
reflux for two hours. Upon reaction completion, the THF was
evaporated to provide the crude product which was first washed
with water, then purified by flash column chromatography (silica
gel, hexanes / EtOAc) to afford the desired product 3a (156 mg,
68%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.98
(br s, 1H), 8.03 (dd, J = 8.0, 1.4 Hz, 1H), 7.67 – 7.63 (m, 1H),
7.51 (d, J = 8.2 Hz, 1H), 7.33 (t, J = 7.6 Hz, 1H), 4.21 (q, J = 7.2
Hz, 2H), 2.37 (s, 3H), 1.24 (t, J = 7.0 Hz, 3H); 13C NMR (400
MHz, DMSO-d6): δ 173.9, 167.2, 149.4, 139.5, 132.7, 125.5,
124.9, 124.3, 118.4, 115.2, 60.8, 18.5, 14.5. Anal. Calcd. for
C13H13NO3: C, 67.52; H, 5.67; N, 6.06; found: C, 66.92; H, 5.74;
N, 6.09.
References and notes
1.
2.
3.
4.
Boteva, A. A.; Krasnykh, O. P. Chem. Het. Comp. 2009, 45, 757-
785.
Oliphant, C. M.; Green, G. M. Am. Fam. Physician 2002, 65, 455-
464.
Chu, D. T. W.; Fernandes, P. B. Antimicrob. Agents Ch. 1998, 33,
131 – 135.
(a) Yanagisawa, H.; Nakao, H.; Ando, A. Chem. Pharm. Bull.
1973, 21, 1080-1089; (b) Kondo, H.; Sakamoto, F.; Kawakami,
K.; Tsukamoto, G. J. Med. Chem. 1988, 31, 221-225.
Xu, J.; Cole , D. C.; Chang, C-P. B.; Ayyad, R.; Asselin, M.; Hao,
W.; Gibbons, J.; Jelinsky, S. A.; Saraf, K. A.; Park, K. J. Med.
Chem. 2008, 51, 4115-4121.
5.