Facile and efficient generation of quinolone amides from esters using aluminum chloride

Article abstract of DOI:10.1016/j.tetlet.2010.12.108

Quinolone esters are readily converted into the corresponding amides using aluminum chloride at room temperature in excellent yields and purities. The method is both general and scalable to multi-kilogram quantities.

Full text of DOI:10.1016/j.tetlet.2010.12.108

Tetrahedron Letters 52 (2011) 1096–1100
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile and efficient generation of quinolone amides from esters using
aluminum chloride
⇑
Michael K. Schwaebe , David M. Ryckman, Johnny Y. Nagasawa, Fabrice Pierre, Anne Vialettes,
Mustapha Haddach
Cylene Pharmaceuticals, Inc., 5820 Nancy Ridge Dr. Suite 200, San Diego, CA 92121, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Quinolone esters are readily converted into the corresponding amides using aluminum chloride at room
temperature in excellent yields and purities. The method is both general and scalable to multi-kilogram
quantities.
Received 6 December 2010
Revised 17 December 2010
Accepted 21 December 2010
Available online 7 January 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Amide
Ester
Quinolone
Aluminum chloride
Direct conversion
Lewis acid
Acylation
Quinolones have a long and rich history as chemotherapeutic
antibacterial agents that eradicate bacteria by interfering with
DNA replication, transcription, and repair.1 Their broad spectrum
activity results from the inhibition of bacterial DNA gyrase and
topoisomerase IV.2 Certain sub-classes of quinolones have also
been reported to be active against cancer cells by means of inhib-
iting human Topoisomerases I and II.3 We have recently discov-
ered a new class of quinolones for the treatment of cancer,
which act through a novel mechanism of inhibition of the DNA
Polymerase I complex (Pol I).4 By replacing the carboxylic acid
moiety with amides in certain quinolones we have achieved
selective Pol I inhibition, allowing the discovery of several prom-
ising drug candidates for oncology. In the course of our work, we
encountered some challenging amide syntheses when utilizing
classical reaction conditions. We, therefore, sought to develop a
more versatile and practical synthesis of quinolone amides,
reported herein.
compound 3. Under thermal conditions, the decarboxylation was
also the prominent reaction. Without an efficient means to gener-
ate the carboxylic acid 2 in the desired quantities, we sought to
craft an alternate method to form the amide bond via a direct
conversion of ester 1 into amide 4 at an ambient temperature
(Scheme 1).
We examined a variety of conditions to directly affect the trans-
formation. Because the ester exhibits thermal instability any suc-
cessful reaction would require performance at or below room
temperature. While many mild Lewis acids proved ineffective, alu-
minum chloride emerged as an encouraging coupling reagent
(Scheme 1).6 With 1.5 equiv of both amine and aluminum chloride
in dichloromethane (DCM) at room temperature, the reaction
stalled at approximately 50% conversion and, therefore, yielded
only 15% of the corresponding amide 4.
In an effort to identify the optimal stoichiometry for comple-
tion of the reaction, we performed the transformation with a
model substrate, methyl-2-methoxy benzoate 5 (Scheme 2). We
envisioned that ester 5 might be activated by chelation of alumi-
num with the ester and the methoxy groups, mimicking the
dicarbonyl moiety present in quinolone esters. Another advantage
of using 5 resulted from the low molecular weight of amide 7,
allowing quick GC–MS monitoring of the reaction. The modeled
reactions were performed at room temperature in THF on a
1 mM scale by adding aluminum chloride as a 0.5 M solution in
THF. Both amine 6 and aluminum chloride were arrayed from
One substrate that could not be treated under classical condi-
tions was the naphthyridine benzimidazole ester 1 (Scheme 1).5
For closely related scaffolds we typically converted the ester into
acid 2 which could be subsequently treated with coupling agents
to afford the desired amide. However, hydrolysis of ester 1 under
both basic and acidic conditions led to decarboxylation, affording
⇑
Corresponding author. Tel.: +1 858 875 5112; fax: +1 858 875 5101.
E-mail address: mschwaebe@cylenepharma.com (M.K. Schwaebe).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.12.108

M. K. Schwaebe et al. / Tetrahedron Letters 52 (2011) 1096–1100
1097
O
N
O
N
O
N
O
N
O
OH
H+or Base, Δ
X
N
N
N
N
O
N
O
N
1
2
H+or Base, Δ
H2N
O
N
O
N
O
N
N
N
N
H
N
N
N
N
N
O
N
O
N
4
3
Scheme 1. Hydrolysis of quinolone ester 1.
O
O
O
O
ple 14) as well as anilines (example 5) and hydrazines (example
13) were also efficient coupling partners. Acid labile protecting
groups, such as the Boc group, also tolerated the reaction condi-
tions (example 11).
AlCl3
+
N
O
N
N
H2N
THF, rt
H
5
6
7
Moreover, we determined that the reaction could be success-
fully executed in a library format by the addition of aluminum
chloride as a dilute solution in THF. Under those conditions, we
have been able to prepare more than 2500 different amide analogs.
Additionally, the reaction performed well on a kilogram scale. The
exothermic nature of the reaction could be easily controlled either
by the rate of addition of the amine or by adding the aluminum
chloride in small portions. Due to the strong chelating effect of
the aluminum with the dicarbonyl group the workup utilizes
either a basic aqueous Rochelle’s Salt solution or a treatment with
a 50% sodium hydroxide solution and filtration of the resultant alu-
minum hydroxide.
While many of the substrates examined readily underwent
transformation, certain cases presented additional challenges
(Table 3). Reactions involving hindered and secondary amines or
which utilized scaffolds that contained basic nitrogen (such as in
examples 8 and 9) required an additional amount of base (Et3N,
DBU, or excess of coupling amine). For basic starting quinolones,
the additional amount of base was used to prevent the scaffold/
aluminum complex from precipitating out of the reaction mixture.
Indeed, in a separate experiment, the ester shown in example 8
when treated with 1.0 equiv of aluminum chloride in DCM precip-
itated out of the solution as a complex salt. The addition of 1 equiv
of base (Et3N, DBU or 1-(2-aminoethyl)pyrrolidine) induced disso-
lution of the complex and subsequent reaction with 1-(2-amino-
ethyl)pyrrolidine to yield the desired amide product. In many
instances, a confluence of factors, such as a strongly basic scaffold
and a weakly basic coupling amine mandated that an even greater
excess of base be used. In example 8 where 6 equiv of the coupling
basic amine was used, the reaction proceeded to completion and
the amide was isolated in 92% yield. On the contrary, in example
11 where only 1.5 equiv of amine was used without extra base,
the reaction stalled at 70% conversion.
Scheme 2. Methyl-2-methoxybenzoate as a model reagent for quinolone amide
synthesis.
1.0 to 3.0 equiv in 0.5 equiv increments with monitoring at 4, 8,
and 24 h.
As illustrated in Table 1, after 24 h at room temperature all
reactions using more than 1.5 equiv of the amine and aluminum
chloride went to completion. Additionally, the reaction could be
further accelerated using excess equivalents of the reagents such
that the reaction could be completed in a matter of a few hours.
However, it was important to maintain the balance of amine and
aluminum to avoid a dramatic decrease of the yield of amide 7 (Ta-
ble 1).
Application of the optimized conditions to a variety of quino-
lone scaffolds and amines (Tables 2 and 3) revealed that the reac-
tion was remarkably versatile, scalable, and capable of tolerating a
wide range of functionalities. The reaction was selective for pri-
mary amines over secondary amines (example 7) with none of
the tertiary amide detected in the product. Benzyl amines (exam-
Table 1
Influence of reagent stoichiometry and time on conversion of 5 to 7
Aluminum chloride equivalents
Amine equivalents
1
1.5
2
2.5
3
% Conversion at 4 h
1
1.5
2
2.5
3
37
44
41
4
35
50
56
47
54
25
71
78
77
80
10
53
89
92
89
6
48
79
89
100
2
% Conversion at 8 h
1
1.5
2
2.5
3
34
58
67
10
2
32
62
63
72
75
28
82
95
95
92
13
65
95
100
99
13
60
92
98
100
In the case of example 8, the reaction required 2 equiv of alumi-
num chloride, 2 equiv of the desired amine, and 4 equiv of DBU.
Alternately, we achieved the transformation with 6 equiv of the
desired amine. The reaction proceeded at 0 °C in DCM and was
complete in 2 h, resulting in a 92% yield of the product on a
200 g scale.7 The workup involved quenching the reaction with a
tartaric acid solution, discarding the organic layer then adjusting
the pH >13 with a 10% sodium hydroxide solution and extraction
by DCM.
% Conversion at 24 h
1
1.5
2
2.5
3
48
73
80
68
13
46
68
77
85
91
31
89
100
100
100
14
74
100
100
100
7
60
100
100
100

1098
M. K. Schwaebe et al. / Tetrahedron Letters 52 (2011) 1096–1100
Table 2
Reaction scale and yields of quinolone amides using 1.5 equiv each of the amine and aluminum chloridea
Ex.
Amide producta
Scale (g)
Isolated yield (%)
O
O
F
N
N
H
F
N
1
2.0
99
O
Cl
O
N
O
N
F
N
H
N
2b
458
98.5
O
N
N
O
N
O
F
N
N
H
N
3
5.9
74
O
N
O
Cl
O
N
O
N
F
N
H
4
0.99
0.06
74
60
Cl
N
S
O
N
O
N
N
H
5c
N
N
N
S
O
N
O
N
N
H
6
7
1.0
2.0
67
86
Cl
Cl
N
N
NH
O
N
O
N
N
H
H
S
a
b
c
1.5 equiv each of the amine and aluminum chloride unless otherwise noted.
1.2 equiv of the amine and 1.0 equiv of aluminum chloride.
2.0 equiv of each of the amine and aluminum chloride.
Thus we have demonstrated the utility of aluminum chloride
trialkylaluminum reagents, aluminum chloride is our reagent of
choice that could be used even on a kilogram scale. Although
this is clearly not an entirely novel synthetic approach to making
amides, we feel that the scope of possibilities for this approach
of general amide synthesis is greatly underrepresented in the
literature.
as a useful activating agent for the direct conversion of quino-
lone esters to their corresponding amides. In many cases the
reaction afforded products otherwise not obtainable through tra-
ditional amide bond formation from their corresponding carbox-
ylic acids. Due to its increased air handling stability over

M. K. Schwaebe et al. / Tetrahedron Letters 52 (2011) 1096–1100
1099
Table 3
Amide reactions with aluminum chloride requiring additional base
Ex.
Ester
Scale (g)
Amine
Equiv DBU
Equiv amine
Equiv AlCl3
Isolated yield (%)
O
N
O
N
H2N
N
O
8
200
0
6.0
2.0
92
87
82
70
65
70
61
N
N
O
N
O
N
O
N
N
H2
N
O
9
10
11
12
13
14
139.1
2.05
0.50
0.30
0.10
0.03
3.0
2.1
0
1.8
1.5
1.5
3.0
2.0
2.0
1.2
1.5
1.5
3.0
2.0
2.0
N
N
S
N
O
N
O
S
HN
F
N
O
N
N
O
O
N
O
H2N
N
O
N
N
N
N
N
N
Boc
O
N
O
O
HCl
F
NH
O
O
5.5
3.0
4.0
N
S
O
S
O
O
N
H2N
N
N
N
O
O
N
O
H2N
O
Cl
N
N
S
N
Omori, M.; Haddach, M.; Schwaebe, M.; Siddiqui-Jain, A.; Streiner, N.; Quin, J. E.;
Sanij, E.; Bywater, M. J.; Hannan, R. D.; Ryckman, D.; Anderes, K.; Rice, W. G.
Cancer Res. 2010, doi:10.1158/0008-5472.CAN-10-1728.; (c) Drygin, D.;
Siddiqui-Jain, A.; O’Brien, S.; Schwaebe, M.; Lin, A.; Bliesath, J.; Ho, C. B.;
Proffitt, C.; Trent, K.; Whitten, J. P.; Lim, J. K. C.; Von Hoff, D.; Anderes, K.; Rice,
W. G. Cancer Res. 2009, 69, 7653–7661.
Acknowledgements
The authors are grateful to Dr. George Yiannikouros for his in-
sight into the utilization of aluminum chloride for the direct ami-
dation of quinolone esters.
5. Chua, P. C.; Nagasawa, J. Y.; Pierre, F.; Schwaebe, M. K.; Vialettes, A.; Whitten, J.
P. Tetrahedron Lett. 2008, 49, 4437–4442.
6. (a) Gless, R. D., Jr. Synth. Commun. 1986, 16, 633–638; (b) Michael, F.; Lipton, M.
F.; Basha, A.; Weinreb, S. M. Org. Synth., Coll. 1988, 6, 492; (c) Barn, D. R.;
Morphy, J. R.; Rees, D. C. Tetrahedron Lett. 1996, 37, 3213–3215; (d) Lesimple, P.;
Bigg, D. C. H. Synthesis 1991, 306–308; (e) Barf, T.; Vallgårda, J.; Emond, R.;
Häggström, C.; Kurz, G.; Nygren, A.; Larwood, V.; Mosialou, E.; Axelsson, K.;
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H. Helv. Chim. Acta 2005, 88, 2951–2959; (g) Whitten, J. P.; Pierre, F.; Regan, C.;
Schwaebe, M.; Yiannikouros, G. P.; Jung, M. Methods for Converting Quinolone
Esters into Quinolone Amides. U.S. Patent 7652,134, January 26, 2010.
7. To a slurry of the ester 8 (200 g, 0.447 mol) and 1-(2-aminoethyl)-pyrrolidine
(306 g, 2.68 mol, 6.0 equiv) in methylene chloride (2.2 L) was added aluminum
chloride (90 g, 0.675 mol) at 0 °C portion-wise over 30 min maintaining the
temperature <15 °C. The mixture was stirred at 0 °C for 2 h then allowed to
References and notes
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Fox, J. A. PLoS ONE 5, e10186, doi:10.1371/journal.pone.0010186.
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1100
M. K. Schwaebe et al. / Tetrahedron Letters 52 (2011) 1096–1100
come to room temperature overnight. The reaction was cooled with the aid of an
ice bath and a saturated solution of -tartaric acid was added (1.5 L). The
removed in vacuo. The residual solids were co-evaporated with acetonitrile
L
(3 Â 200 mL). Acetonitrile was added (4.0 L) and the slurry was stirred at 40 °C
for 30 min then filtered and dried in a vacuum oven to afford the amide as a pale
off-white solid (212 g, 411.4 mmol, 92%). 1H NMR (400 MHz, CDCl3) d 9.75 (1H,
t, J = 5.6 Hz), 8.82 (1H, d, J = 7.6 Hz), 8.56 (1H, d, J = 8.4 Hz), 7.41 (3H, m), 8.83
(1H, d, J = 9.2 Hz), 3.89 (4H, br m), 3.82 (2H, br m), 3.81 (3H, s), 3.75 (2H, br m),
3.65 (2H, q, J = 7.2 Hz), 2.78 (2H, t, J = 7.2 Hz), 2.63 (4H, br t), 2.21 (3H, s), 1.81
(4H, br m); LC–MS (287 nm): Rt = 11.90 min (98.9%); EIMS (pos) m/z 516.5
[M+H]+.
mixture was allowed to stir until hydrolysis was complete. The organic layer
was removed and the aqueous layer was washed with DCM (500 mL). The
aqueous layer was then chilled in an ice bath and basified to pH >13 with a 1 N
solution of NaOH. A 9:1 mixture of DCM/methanol was added (200 mL) followed
by solid sodium chloride (3 kg). The aqueous layer was then separated from the
organic layer and extracted with the DCM/methanol mixture (200 mL Â 4). The
combined extracts were dried over sodium sulfate (300 g) and the solvent was