Quinoline- and 1,8-naphthyridine-3-carboxylic acids using a self-catalyzed Friedl?nder approach

Article abstract of DOI:10.1016/j.tetlet.2014.04.010

One-step syntheses of 2-alkyl- and 2,4-dialkyl-substituted quinoline-3-carboxylic acids and 1,8-naphthyridine-3-carboxylic acids are reported using a catalyst-free Friedl?nder reaction. The reaction is carried out in one step by simple heating of 2-aminobenzaldehyde, 2-amino-5-chlorobenzaldehyde, 2-aminonicotinaldehyde, or 2-aminoacetophenone with a β-ketoester in toluene or xylene for 24 h. Under these conditions, the carboxylic acid product is isolated directly from the reaction mixture without need for further purification. The observation that the reaction starts slowly and accelerates as it proceeds suggests that the transformation is self-catalyzed. This hypothesis is also supported by the finding that attempts to extend the current reaction to diketones, which cannot hydrolyze to an acid, were generally unsuccessful.

Full text of DOI:10.1016/j.tetlet.2014.04.010

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Quinoline- and 1,8-naphthyridine-3-carboxylic acids using
a self-catalyzed Friedländer approach
⇑
Baskar Nammalwar, Maeghan Murie, Chelsea Fortenberry, Richard A. Bunce
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
One-step syntheses of 2-alkyl- and 2,4-dialkyl-substituted quinoline-3-carboxylic acids and 1,8-
naphthyridine-3-carboxylic acids are reported using a catalyst-free Friedländer reaction. The reaction
is carried out in one step by simple heating of 2-aminobenzaldehyde, 2-amino-5-chlorobenzaldehyde,
2-aminonicotinaldehyde, or 2-aminoacetophenone with a b-ketoester in toluene or xylene for 24 h.
Under these conditions, the carboxylic acid product is isolated directly from the reaction mixture without
need for further purification. The observation that the reaction starts slowly and accelerates as it pro-
ceeds suggests that the transformation is self-catalyzed. This hypothesis is also supported by the finding
that attempts to extend the current reaction to diketones, which cannot hydrolyze to an acid, were gen-
erally unsuccessful.
Received 13 March 2014
Revised 1 April 2014
Accepted 3 April 2014
Available online xxxx
Keywords:
Quinoline-3-carboxylic acid
1,8-Naphthyridine-3-carboxylic acid
Friedländer reaction
b-Ketoester
Ó 2014 Elsevier Ltd. All rights reserved.
Self-catalysis
The Friedländer synthesis of quinolines has generated consider-
able interest among researchers throughout the world. The reaction
most often involves condensation of a 2-aminoaryl-aldehyde or
ketone with a carbonyl compound containing an active methylene
group.1 The reaction is generally performed with a catalyst present
and has been promoted by acids, Lewis acids, and bases. Several
reports have also appeared where the transformation was
performed without catalyst, but the reaction required high temper-
atures (150–220 °C). Very recently, a paper describing the synthesis
of quinolines without added catalyst in water at 70 °C was
reported,2 but we have been unable to repeat this work as
published.
Quinolines display a wide range of biological activities and are
also present in various biologically active natural products such
as 20-(S)-camptothecin and luotonin A and F.3 More specifically,
derivatives of 2-alkylquinoline-3-carboxylic acids are currently
under investigation as drugs to treat cancer,4 HIV,5 and malaria6
as well as additives for helioprotective ointments.7 Finally, the pat-
ent literature is replete with reports of quinoline-3-carboxylic acid
derivatives as drugs for CNS disorders8 and as herbicides,9 while
the corresponding naphthyridine derivatives have attracted inter-
est as potential anti-HIV agents,10 antibacterials,11 antiasthmat-
ics,12 contrast agents for imaging myocardial perfusion13 and
herbicides.14
We have recently reported a synthesis of a-aminonitriles as
well as benzo-fused, five-membered heterocycles using a green
approach without expensive or corrosive catalysts.15 In a continu-
ation of our work in this area, we have undertaken the study of a
catalyst-free Friedländer reaction. An initial reaction of 2-amino-
benzaldehyde (1a) with methyl acetoacetate (2a) was performed
in benzene and the reaction was refluxed for a period of 12 h. A
tan solid appeared during the reaction and TLC indicated the com-
plete consumption of starting material with the formation of two
products. Analysis of the mixture revealed these products to be
quinoline-3-carboxylic acid (3a) and its corresponding methyl
ester 4a (Scheme 1). This observation piqued our curiosity, and
we decided to investigate the reaction in more detail. The same
transformation was repeated at a higher temperature in refluxing
toluene (or xylene) for 24 h and showed exclusive formation of acid
3a in high yield with none of the corresponding ester. To the best of
our knowledge, acids have not previously been observed directly
from this reaction.16 Ethyl acetoacetate showed similar reactivity.
Beyond these aromatic solvents, water, acetonitrile, and several
cyclic ethers were evaluated as media for the reaction and the
results are summarized in Figure 1. Of the solvents examined, tol-
uene and xylene furnished product 3a in the highest yield and pur-
ity. The product, obtained after cooling and filtration, was
chromatographically and spectroscopically clean, and further puri-
fication was unnecessary.
The results of our study are summarized in Schemes 2–4.
Aminobenzaldehydes 1a17 and 1b were reacted with a series of
b-ketoesters 2a–f18 in toluene at 110 °C for 24 h to give
⇑
Corresponding author. Tel.: +1 405 744 5952; fax: +1 405 744 6007.
E-mail address: rab@okstate.edu (R.A. Bunce).
http://dx.doi.org/10.1016/j.tetlet.2014.04.010
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Nammalwar, B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.010

2
B. Nammalwar et al. / Tetrahedron Letters xxx (2014) xxx–xxx
CO2Me
Me
CO2Me
R
CHO
CHO
CO2H
R
110 o
toluene
C
80 oC
+
+
O
benzene
N
NH2
N
N
O
NH2
5
2
6
1a
2a
CO2H
CO2Me
Me
Yield (%)
110 oC
toluene
or
2a
of 6
+
N
Me
N
a
(R = Me)
b (R = Et)
(R = n-Pr)
d (R = i-Pr)
(R = C4H7)
87
90
98
92
88
3a
4a
140 o
xylene
C
c
Scheme 1. Quinoline formation in aromatic solvents at reflux.
e
aC4H7 = 3-butenyl
Scheme 3. 1,8-Naphthyridine-3-carboxylic acids from 2-aminonicotinaldehyde
using the Friedländer reaction in refluxing toluene.
CH3
CH3
N
CO2Me
R
CO2H
R
140 oC
xylene
O
NH2
+
O
7
2
8
Yield (%)
2a
of 8
a (R = Me)
b (R = Et)
c (R = n-Pr)
d (R = i-Pr)
e (R = C4H7)
83
82
90
11
78
73
Figure 1. Effect of solvent on the yield of product 3a (the reaction was performed at
the reflux temperature of each solvent).
f
(R = CH2OPh)
CO2Me
R
X
CHO
X
CO2H
R
110 o
toluene
C
+
aC4H7 = 3-butenyl
O
NH2
N
1
2
3
Scheme 4. Quinoline-3-carboxylic acids from ketones using the Friedländer
reaction in refluxing xylene.
Yield (%)
1
2a
3a
of 3
a (X = H)
a (R = Me)
b (R = Et)
a
(X = H,
R = Me)
88
94
86
90
89
85
ether/hexane and dried to give the final product in pure form. Pre-
vious routes to these compounds utilized a Friedländer modifica-
tion promoted by piperidine in boiling ethanol to prepare the
ester, followed by saponification using aqueous NaOH and neutral-
ization with acid.19 Thus, the resulting products were likely con-
taminated with base, or the carboxylate or quinolinium salt of
the product. For example, compound 6a, prepared by this
sequence,19 gave a melting point nearly 100 °C lower than that
recorded in the current study, strongly suggesting the presence
of impurities. The reactions reported in this work were performed
in one step, without exogenous catalyst, and delivered the prod-
ucts with no residual contaminants. Compounds prepared by the
earlier route19 were not subjected to NMR analysis to establish
their purity. The products reported herein were characterized by
1H and 13C NMR (at 90 °C due to low solubility), which verified
both their structures and purities.
b (X = H
R = Et)
c (R = n-Pr)
d (R = i-Pr)
e (R = C4H7)
c
(X = H,
R = n-Pr)
d (X = H,
R = i-Pr)
e
(X = H,
R =C4H7)
(X = H,
f
(R = CH2OPh)
f
R = CH2OPh)
b (X = Cl)
a (R = Me)
b (R = Et)
g
(X = H,
R = Me)
87
85
90
86
90
h (X = H
R = Et)
c (R = n-Pr)
d (R = i-Pr)
e (R = C4H7)
i
(X = H,
R = n-Pr)
(X = H,
R = i-Pr)
j
k (X = H,
R =C4H7)
The current variant of the Friedländer reaction has been further
extended to include reactions between 2-aminoacetophenone (7)
and b-ketoesters (Scheme 4). In these cases, the cyclizations were
sluggish in refluxing toluene at 110 °C, and often failed to proceed
to completion. Therefore, the conditions were modified to use
refluxing xylene at 140 °C where the reaction occurred more effi-
ciently. Most products were isolated in high yields with the excep-
tion of 8d (R = i-Pr), indicating that the reaction is subject to steric
limitations. To date, there appear to be relatively few direct syn-
theses of 2,4-dialkylquinoline-3-carboxylic acids.16,20
aC4H7 = 3-butenyl
Scheme 2. Quinoline-3-carboxylic acids from aldehydes using the Friedländer
reaction in refluxing toluene.
2-alkylquinoline-3-carboxylic acids 3a–k (Scheme 2). The reaction
was also applied to 2-aminonicotinaldehyde (5) to yield 2-alkyl-
1,8-naphthyridine-3-carboxylic acids 6a–e (Scheme 3). During
the course of the reaction most of the acid product precipitated
from the mixture. When the reaction was complete, the mixture
was cooled, concentrated to one-half its volume, and filtered to
give the crude product. The isolated solid was washed with 1:1
Attempts to expand the scope of this reaction to other active
methylene substrates were generally not successful without added
Please cite this article in press as: Nammalwar, B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.010

B. Nammalwar et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
catalyst.21 Thus, we believe that the current reaction is self-cata-
References and notes
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gradually accelerated to completion over the 24 h reaction period.
At toluene reflux temperature, the reaction likely proceeds to ini-
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a small amount of the ester is hydrolyzed by water produced dur-
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of acid in the b-ketoesters.22 The product acid is only sparingly sol-
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In summary, we have demonstrated that the Friedländer reac-
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yields of 2-alkylquinoline-, 2-alkyl-1,8-naphthyridine-, and 2,4-
dialkylquinoline-3-carboxylic acids. The method is highly reliable
and avoids the use of additives, which can contaminate the final
products. The products, prepared as described here, are isolated
directly from the reaction mixture and require no further
purification.
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Acknowledgments
The authors would like to thank Dr. Dongtao Cui for assistance in
obtaining the high-temperature NMR spectra. M.M. wishes to thank
the Oklahoma State University for a Niblack scholarship to support
her undergraduate research. Funding for the 400 MHz NMR spec-
trometer of the statewide shared NMR facility was provided by
the NSF (BIR-95-12269), the Oklahoma State Regents for Higher
Education, the Keck foundation and Conoco Inc. Finally, the authors
wish to express their appreciation to the OSU College of Arts and Sci-
ences for funds to upgrade our departmental FT-IR instruments.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.04.
010.
Please cite this article in press as: Nammalwar, B.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.04.010