A simple one-pot synthesis of quinoline-4-carboxylic acids by the Pfitzinger reaction of isatin with enaminones in water

Article abstract of DOI:10.1016/j.tetlet.2015.11.070

A simple one-pot method for synthesizing quinoline-4-carboxylic acids (3) by the reaction of enaminones (1) and isatin (2) using the Pfitzinger reaction conditions is described. Additionally, a plausible mechanism for this transformation is presented.

Full text of DOI:10.1016/j.tetlet.2015.11.070

Accepted Manuscript
A simple one-pot synthesis of quinoline-4-carboxylic acids by the Pfitzinger
reaction of isatin with enaminones in water
Ibrahim Elghamry, Yasair Al-Faiyz
PII:
S0040-4039(15)30378-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.11.070
TETL 47010
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
28 June 2015
17 October 2015
24 November 2015
Please cite this article as: Elghamry, I., Al-Faiyz, Y., A simple one-pot synthesis of quinoline-4-carboxylic acids
by the Pfitzinger reaction of isatin with enaminones in water, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.11.070
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Graphical Abstract
A simple one-pot synthesis of quinoline-4-
carboxylic acids by the Pfitzinger reaction of
isatin with enaminones in water
Leave this area blank for abstract info.
Ibrahim Elghamry and Yasair Al-Faiyz

Tetrahedron Letters
1
Tetrahedron Letters
A simple one-pot synthesis of quinoline-4-carboxylic acids by the Pfitzinger reaction
of isatin with enaminones in water
Ibrahim Elghamry and Yasair Al-Faiyz
King Faisal University, College of Science, Department of Chemistry, P. O. Box 380 Al-Hufuf, 31982 Al-Ahsa, Saudi Arabia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A simple one-pot method for synthesizing quinoline-4-carboxylic acids (3) by the reaction of
enaminones (1) and isatin (2) using the Pfitzinger reaction conditions is described. Additionally,
a plausible mechanism for this transformation is presented.
© 2015 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Pfitzinger reaction
Isatin
Enaminone
Quinoline-4-carboxylic acids
Introduction
acidic medium.15 To overcome these limitations, herein, we
report a one-step synthesis of these compounds by a simple one-
The quinoline ring system has attracted considerable interest
due to its important applications in various fields. Substituted
quinolones have industrial applications that include their use as
corrosion inhibitors,1 precursors of oil-soluble food colorants and
as chemosensors in luminescence chemistry.2 Quinolines also
have diverse biological and pharmacological activities such as,
antibacterial,3 antitumor,4 antileishmanial,5 antifungal,6 and
antiamoebic7 and chloroquinolines are widely used for the
treatment of malaria.8 Furthermore, quinoline-4-carboxamides
have been used as a pharmacophoric model with selective affinity
towards non-peptide human neurokinin-3 (hNK-3) receptors
which are implicated in a wide range of pathophysiological
conditions such as inflammatory and immunoregulatory
processes, skin disorders and various CNS disorders.9 Recently,
quinoline-4-carboxylic acid derivatives have also shown caspase-
3 enzymes inhibition10 which belongs to a family of cysteine-
dependent aspartate-directed proteases enzymes that play
important roles in apoptotic cell death.11
pot reaction of isatin and enaminones in the presence of aqueous
KOH or NaOH.
Results and Discussion
Isatins can react with α-methylene ketones or 1,3-dicarbonyl
compounds in different ways depending on the catalysts and
solvents used in the reaction. Generally, two main protocols have
been reported in the literature for this reaction. Firstly, an aldol-
type reaction gives 3-hydroxyindole adducts as the main products
from the reaction of isatins with α-methylene ketones or 1,3-
dicarbonyls when moderate to weak bases (DABCO, TEA, DBU,
proline, piperidine, imidazole, or DMAP) were used in organic
solvents.16 Secondly, the Pfitzinger-type reaction gives the
quionoline-4-carboxylic acid derivatives when the reaction takes
place in strong base (KOH) followed by acidification with
HCl.12,13 As previously reported, the latter protocol has
limitations when simple 1,3-dicarbonyls were reacted with isatins
under Pfitzinger conditions. Therefore, to overcome these
limitations and as a continuation of our interest in the chemistry
of enaminones and their utility as synthons for the synthesis of
biologically active and industrially important compounds,17
herein, we report the utility of enaminone building blocks for the
synthesis of quinoline-4-carboxylic acids.
The most common method for the synthesis of quinoline-4-
carboxylic acids is the Pfitzinger reaction which involve the
reaction of isatin or its derivatives with α-methylene ketones in
the presence of potassium hydroxide to yield quinolone-4-
carboxylic acids.12,13 However, when utilizing simple 1,3-
dicarbonyls, the corresponding quinoline-4-carboxylic acids were
obtained in low yield due to the formation of large amounts of
undesired by-products.14 Furthermore, the desired quinolone-4-
carboxylic acids have been obtained via a two-step protocol from
the in situ formation of the isatinate, as the basic hydrolysis
The reactivity and regioselectivity of enaminones can be
attributed to their ability to function both as nucleophiles or
electrophiles depending on the reaction conditions.18 Thus, we
expected that enaminones (1) could act as a suitable substitute for
1,3-dicarbonyls in the Pfitzinger reaction. Therefore, isatin (2)
product of isatin, followed by the addition of a 1,3-diketone in
———
 Corresponding author. Tel.: +966-135-89-9529; fax: +966-135-89-9557; e-mail: ielghamry@kfu.edu.sa

2
Tetrahedron Letters
was heated at reflux with enaminones (1a-e) in the presence of
deshielded proton at ~14.0 ppm which was assigned to the
carboxylic acid group was also observed. The 13CNMR spectra
revealed three down-field carbons in the ranges of 167.4-167.6
ppm, and 154.5-160.9 ppm and at 148 ppm which were assigned
to the carbonyl carbons of the carboxylic acid and ketone groups
and the C-2 position of the quinoline ring respectively.
Furthermore, mass spectra of the quinoline 4-carboxylic acids
(3a-e) revealed a characteristic fragment at m/z = 204 accounting
for loss of the aryl side chain at position three of the quinoline
ring.21
an aqueous solution of KOH or NaOH, followed by subsequent
acidification with dilute hydrochloric acid to give the quinoline-
4-carboxylic acids (3a-e) in good to excellent yields (75-90%
Table 1).
Table 1 Synthesis of quinoline-4-carboxylic acids (3a-e)
There are surprisingly few details reported for the mechanism
of the Pfitzinger reaction. Primarily, two types of reactions are
involved: Claisen condensation of the ketone group of isatinic
acid with the active methylene of the 1,3-dicarbonyl and Schiff
base formation between the amine group of isatinic acid and the
ketone carbonyl .13 In the present study a plausible mechanism
was suggested as depicted in Scheme 3.
Entry
Substrate
Ar
Producta
Yieldb % (m.p. C)c
90 (220)d
1
2
3
4
5
1a
1b
1c
1d
1e
Ph
3a
3b
3c
3d
3e
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-ClC6H4
75 (222)
86 (204)
90 (253)
80 (243)
a All new compounds gave elemental analysis for C, H, N, within 0.2% of the
1
calculated value and the structures were confirmed by IR, MS, and HNMR,
13CNMR spectroscopy .
b Yield of the crude product.
c
All products were crystallized from ethanol no further purification was
required.
d Decomposes 220 C.20
In order to evaluate this synthetic approach, the corresponding
1,3-dicarbonyl (4) was prepared20 and reacted with isatin under
the same reaction conditions. As expected the quinoline-4-
carboxylic acid (3a) was obtained in very poor yield (<10%
Scheme 1).
Scheme 3 Proposed mechanism for the formation of quinoline-4-
carboxylic acids (3a-e)
Thus, the reaction starts with hydrolysis of the five-membered
ring of isatin to give isatinate (5). Then, aldol-type nucleophilic
addition of the electron rich enaminone carbon (C-2) to the
ketone carbon of the isatinate (5) gives adduct 6. Under acidic
conditions, this intermediate undergoes cyclization via
dimethylamine elimination to give intermediate 7 which further
rearranges and aromatized by dehydration to give the final
quinoline-4-carboxylic acids (3a-e).
Scheme 1. Reaction of isatin (2) with 1,3-dicarbonyl (4)
Furthermore, the recently reported two-step synthetic route15
involving preparation of isatinate (5), as a basic hydrolysis
product of isatin followed by acidification with dilute HCl, then
addition of 1,3-dicarbonyl (4) or enaminone (1a) with
CuSO4•5H2O as a Lewis acid was examined (Scheme 2). The
desired quinoline-4- carboxylic acid (3a) was not detected using
either the 1,3-dicarbonyl (4) or enaminone (1a) after a period of
10 hours (TLC).
In conclusion, we report a new method for the synthesis of
quinoline-4-carboxylic acids using enaminones as a substitute for
1,3-dicarbonyl compounds in the Pfitzinger reaction. The high
yield coupled with the purity of the products makes this method
favorable over the previously reported methods for the synthesis
of such ring systems.
Acknowledgements
The authors are grateful to the Dean of Scientific Research at
King Faisal University for the financial support (project number
160032).
Scheme 2. Two-step, one pot reaction of isatin (2) with
enaminone (1a) and 1,3-dicarbonyl (4) under acidic conditions
Supplementary data
Supplementary data (1HNMR, 13CNMR, IR, and MS spectra) and
experimental information associated with this article can be
found in the online version at
The chemical structures of quinoline-4-carboxylic acids (3a-
e) were determined by spectroscopy (1HNMR, 13CNMR, MS, and
1
IR). Thus, the HNMR spectra of compounds 3a-e revealed a
singlet in the range of 8.42-8.50 ppm which was attributed to the
C-2 proton in the quinoline ring. A broad singlet for the more
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