Synthesis of novel 2-methyl-4-carboxyquinolines, the new by-products of the Doebner reaction

Article abstract of DOI:10.1080/00397911.2021.1912770

The Doebner reaction is the chemical reaction of an aniline with an aldehyde and pyruvic acid to form quinoline-4-carboxylic acids. Although Doebner reaction is a simple procedure for synthesis of 4-carboxyquinolines, which the product precipitates from the reaction mixtures with high purity, its yield is not high due to the formation of different reaction by-products. In the present study we found a new by-product (2-methylquinoline-4-carboxilic acid derivative), in Doebner reaction. We synthesized new 2-methylquinoline-4-carboxilic acid derivatives simply by stirring pyruvic acid and aromatic amine in ethanol with high purity. Generally, we found that aniline derivatives possessing electron donating groups are needed for the synthesis of 2-methylquinoline-4-carboxilic acid derivatives in ethanol. ¹H-NMR data of products revealed that this reaction is regioseletive and ring closure occurs on the position with less steric hindrance. The order of mixing of the reactants plays a key role in determining the type of products in the Doebner reaction.

Full text of DOI:10.1080/00397911.2021.1912770

Synthetic Communications
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Synthesis of novel 2-methyl-4-carboxyquinolines,
the new by-products of the Doebner reaction
Negar Omidkhah & Razieh Ghodsi
To cite this article: Negar Omidkhah & Razieh Ghodsi (2021) Synthesis of novel 2-methyl-4-
carboxyquinolines, the new by-products of the Doebner reaction, Synthetic Communications, 51:13,
1947-1955, DOI: 10.1080/00397911.2021.1912770
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SYNTHETIC COMMUNICATIONSV
2021, VOL. 51, NO. 13, 1947–1955
https://doi.org/10.1080/00397911.2021.1912770
Synthesis of novel 2-methyl-4-carboxyquinolines, the new
by-products of the Doebner reaction
Negar Omidkhah and Razieh Ghodsia,b
aBiotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical
b
Sciences, Mashhad, Iran; Department of Medicinal Chemistry, School of Pharmacy, Mashhad University
of Medical Sciences, Mashhad, Iran
ABSTRACT
ARTICLE HISTORY
Received 6 February 2021
The Doebner reaction is the chemical reaction of an aniline with an
aldehyde and pyruvic acid to form quinoline-4-carboxylic acids.
Although Doebner reaction is a simple procedure for synthesis of 4-
carboxyquinolines, which the product precipitates from the reaction
mixtures with high purity, its yield is not high due to the formation
of different reaction by-products. In the present study we found a
new by-product (2-methylquinoline-4-carboxilic acid derivative), in
Doebner reaction. We synthesized new 2-methylquinoline-4-carbox-
ilic acid derivatives simply by stirring pyruvic acid and aromatic
amine in ethanol with high purity. Generally, we found that aniline
derivatives possessing electron donating groups are needed for the
synthesis of 2-methylquinoline-4-carboxilic acid derivatives in etha-
KEYWORDS
Doebner reaction; 2-
methylquinoline-4-carboxilic
acid; pyruvic acid;
quinoline; synthesis
1
nol. H-NMR data of products revealed that this reaction is regiosele-
tive and ring closure occurs on the position with less steric
hindrance. The order of mixing of the reactants plays a key role in
determining the type of products in the Doebner reaction.
GRAPHICAL ABSTRACT
O
OH
O
Ethanol
OH
+
R
H
3C
NH2
O
R
N
CH3
Quinoline is an important scaffold for the lead compounds in drug discovery and plays
a key role in the field of medicinal chemistry.[1] Currently there are many articles
reporting synthesis of the quinoline derivatives for pharmaceutical activities. Interest in
the synthesis of compounds possessing the quinoline scaffold has increased in recent
years because of their various biological properties.[2–9] So far, a variety synthesis proce-
dures have been described in the literatures[10–20] for the formation of this scaffold. For
€
example, named reaction including Friedlander, Gould-Jacob, Pfitzinger, Doebner-von
Miller, Skraup, and Conrad-Limpach are traditional synthesis procedures were used for
the creation of the quinoline scaffold. The Doebner reaction is the chemical reaction of
CONTACT Razieh Ghodsi
ghodsir@mums.ac.ir
Biotechnology Research Center, Pharmaceutical Technology
Institute, Mashhad University of Medical Sciences, Mashhad, Iran.
ß 2021 Taylor & Francis Group, LLC

1948
N. OMIDKHAH AND R. GHODSI
Scheme 1. The products (4) and the by-products (5) of the Doebner reaction.
an aniline with an aldehyde and pyruvic acid to form quinoline-4-carboxylic acids.[21]
In 1887, Doebner reported the reaction of aromatic amines, aldehydes, and pyruvic acid
to afford quinolinic acid[22] which is now known as the “Doebner reaction.” The most
imperative reported procedures for the synthesis of the quinoline-4-carboxylic acids
involve the Pfitzinger reaction of isatin with a carbonyl compound in the presence of
an appropriate base and Doebner reactions of aromatic amines, aldehydes, and pyruvic
acid.[23] The Doebner reaction was initially reported by Doebner in 1887 for the synthe-
sis of cinchoninic acid or quinolinic acid derivatives. Although Doebner reaction is a
simple procedure for synthesis of 4-carboxyquinolines, which the product precipitates
from the reaction mixtures with high purity, its yield is not high due to the formation
of different reaction by-products. It is found that the formation of these by-products
depends on defined property combinations of the respective starting materials. We dis-
covered a new by-product (2-methyl-4-carboxyquinoline) in Doebner reaction which
encouraged us to examine the reaction of pyruvic acid with different aromatic amines
to synthesis of novel 2-methyl-4-carboxyquinolines.
Weber et al.[24] reported Doebner-type synthesis of quinoline from anilines, various
aldehydes and pyruvic acid derivatives. They found that, the reaction yielded not only
the expected substituted quinoline-4-carboxylic acids 4 but also 3-arylamino-dihydro-
pyrrol-2-ones 5 (4 component product) (Scheme 1).
They also described a full combinatorial library including anilines possessing electron
donating and withdrawing groups, aliphatic and aromatic aldehydes as well as various
pyruvic acid derivatives which provided additional products with diverse structures.
Recently, we synthesized various 2-aryl-4-carboxyquinolines using Doebner reaction and
different benzaldehyde and aniline derivatives and pyruvic acid as the starting
materials.[10–16,18–20,25] Generally, we found that aniline derivatives possessing electron
donating groups are needed for synthesis of quinolines in ethanol by Doebner
reaction.[20] We could not synthesize 2-aryl-4-carboxyquinolines by aniline or aniline
derivatives possessing electron withdrawing groups such as para chloroaniline.[20] For
synthesis of 2-aryl-4-carboxyquinolines possessing benzoyl group in position 4 or 6 of
quinoline ring, replacing ethanol (the solvent reaction) with acetic acid led to the for-
mation of these quinolines.[19] The quinolines which do not have any substitution in
positions 5–8 of quinoline ring or possessing electron withdrawing groups can be syn-
thesized by Pfitzinger reaction using isatin and isatins possessing electron withdrawing
groups respectively.[20] In one of our ongoing research, when we used 1-benzyl-2-
(methylthio)-1H-imidazole-5-carbaldehyde instead of benzaldehydes, the target product
2-(1-benzyl-2-(methylthio)-1H-imidazol-5-yl)benzo[h]quinoline-4-carboxylic acid 8 was
not achieved. 1H-NMR data revealed that 2-methylbenzo[h]quinoline-4-carboxylic

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Scheme 2. synthesis of the target product 2-(1-benzyl-2-(methylthio)-1H-imidazol-5-yl)benzo[h]quino-
line-4-carboxylic acid 8.
acid 9 was obtained instead. So we found a new by-product (2-methylquinoline-4-car-
boxilic acid derivative) in the Doebner reaction (Scheme 2).[15] For synthesis of the tar-
get product 2-(1-benzyl-2-(methylthio)-1H-imidazol-5-yl)benzo[h]quinoline-4-carboxylic
acid 8, at first we let pyruvic acid 3 and aldehyde 7 react, then we added aromatic
amine 6, which led to the formation of the target quinoline 8. So we can conclude that
the order of mixing of the reactants plays a key role in determining the type of product
in the Doebner reaction.
This finding encouraged us to examine the synthesis of 2-methylquinoline-4-carboxylic
acids using aromatic amines and pyruvic acid in ethanol under reflux conditions.
However, synthesis of some of the 2-methylquinoline-4-carboxylic acids using aromatic
amines and pyruvic acid were reported in the old literatures but they are not available or
the authors did not describe the details of their synthesis[26,27] or reported other prod-
ucts.[28,29] 2-Methylquinoline-4-carboxylic acids are widely used in organic synthesis for
the preparation of various derivatives possessing high biological activity.[30–39] These com-
pounds are usually obtained by the Pfitzinger reaction, by heating a mixture of substituted
isatin with acetone in the presence of alkali. Some researcher reported low yields for this
reaction. Apparently, the low yields of 2-methylquinoline-4-carboxylic acids prepared by
addition of alkali to a mixture of isatin derivatives with acetone is clarified by a consider-
able influence of the side reaction occurring by addition of acetone to isatin, which heads
opening of the isatin ring. The resulting unsaturated intermediate is probably undergoing
tarring at high temperature, thus, decreasing the yield of the target product.[39]
As we found 2-methylquinoline-4-carboxylic acids as the by-product of Doebner reac-
tion, we stirred different aniline derivatives with pyruvic acid in ethanol under reflux con-
ditions and we obtained pure 2-methylquinoline-4-carboxylic acids, then we let aniline
derivatives with pyruvic acid react at room temperature which led to precipitate highly
pure target product, so we reported the simple, soft, and efficient procedure for synthesis
of 2-methylquinoline-4-carboxylic acid derivatives. These compounds are usually obtained
by the Pfitzinger reaction, i.e., by heating a mixture of substituted isatin with acetone in
the presence of alkali and for synthesis of the target compounds by the Pfitzinger reaction,
we need special isatin which may not be available and we must synthesize them, but by
the procedure we reported, we just need aromatic amines which are usually available.
However, we could not synthesize 2-methyl-4-carboxyquinolines by aniline or aniline
derivatives possessing electron withdrawing group such as para chloroaniline. Generally,
we found that aniline derivatives possessing electron donating groups are needed for syn-
thesis of 2-methyl-4-carboxyquinolines in ethanol. We proposed the mechanism for the

1950
N. OMIDKHAH AND R. GHODSI
Scheme 3. Two possible cyclization pathways in the synthesis of 2-methylquinoline-4-carboxylic acid.
Scheme. 4. The proposed mechanism for formation of 2-methyl-4-carboxyquinoline using aromatic
amines and pyruvic acid.
formation of 2-methylquinoline-4-carboxylic acid derivatives (Scheme 3)[41] which it is not
reported in the literatures describing the mechanism of reaction between pyruvic acid and
aromatic amines.[27–29] According to the proposed mechanism, the amount of the pyruvic
1
acid was used stoichiometrically twice that of the aromatic amine. H-NMR data of prod-
ucts presented in entries 3,4, 5, and 8 of Table 1, revealed that this reaction is regioseletive.
As shown in Scheme 3, pyruvic acid and aromatic amine were stirred in ethanol to obtain
quinolines. In this condition, two cyclization ways were probable (Scheme 3); linear (2-
methyl-6,7-disubstutedquinolines, 10) or angular (2-methyl-5,6-disubstutedquinolines, 11).
1
The H NMR data showed three singlet signal for the product of entry 3,4 and 5 and con-
firmed that the only product of this reaction is compounds 10, however, the angular iso-
mer 11 was not obtained, and this finding can be due to the steric factors.

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Table 1. Starting materials and products, substituted anilines (a) and
2-methyl-4-carboxyquinoline (b).
Entry Compound
Anilines (a)
2-Methyl-4-
Ref
carboxyquinolines(b)
1
2
3
4
5
6
10a
10b
10c
10d
10e
10f
(40)
(41)
(26)
7
8
10g
10h
10i
9
10
11
10j
10k

1952
N. OMIDKHAH AND R. GHODSI
General procedure for preparation of 2-methylquinoline-4-carboxilic acid
derivatives
As elucidated in Table 1, various aromatic amines (1 mmol) and pyruvic acid (2 mmol)
were stirred in ethanol (10 ml) until the precipitate was formed (2–5 h). The obtained pre-
cipitate was filtered and washed with ethanol and recrystallized from ethanol to obtain qui-
nolines 10a–10k. The purity of all the products was determined by thin layer
chromatography using several solvent systems of different polarity. All compounds were
pure and stable.
6,7-Dimethoxy-2-methylquinoline-4-carboxylic acid (10d)
1
Cream solid; yield: 67%; mp: 280–285 ꢀC; H NMR (300 MHz, DMSO-d6) d 8.11 (s, 1H,
Ar-H), 7.70 (s, 1H, Ar-H), 7.39 (s, 1H, Ar-H), 3.95 (s, 3H, OCH3), 3.90 (s, 3H, OCH3),
2.65 (s, 3H, CH3). 13C NMR (76 MHz, DMSO) d 168.38, 156.11, 152.44, 150.18, 146.22,
134.14, 121.24, 118.98, 108.19, 103.73, 56.10, 55.89, 24.73. Anal. Calcd for C13H13NO4:
C, 63.15; H, 5.30; N, 5.67; Found: C, 63.21; H, 5.41; N, 5.69.
7-Methyl-2,3-dihydro-[1,4]dioxino[2,3-g]quinoline-9-carboxylic acid (10e)
1
Off white solid; yield: 60%; mp: 300 ꢀC; H NMR (300 MHz, DMSO-d6) d 8.11 (s, 1H,
Ar-H), 7.69 (s, 1H, Ar-H), 7.38 (s, 1H), 4.40 (s, 4H, OCH2), 2.64 (s, 3H, CH3). 13C
NMR (76 MHz, DMSO) d 168.05, 156.86, 147.19, 145.13, 145.01, 134.62, 121.82, 119.17,
113.24, 110.46, 64.77, 64.66, 24.72. Anal. Calcd for C13H11NO4: C, 63.67; H, 4.52; N,
5.71. Found: C, 63.71; H, 4.51; N, 5.62.
In conclusion in the present study, we found a new by-product (2-methylquinoline-4-
carboxilic acid derivative), in the Doebner reaction. The order of mixing of the reactants
plays a key role in determining the type of products in the Doebner reaction. We syn-
thesized new 2-methylquinoline-4-carboxilic acid derivatives by stirring pyruvic acid
and aromatic amine in ethanol.1H-NMR data of products revealed that this reaction is
regioseletive and ring closure occurs on the position with less steric hindrance.
1
Full experimental detail, H and 13C NMR spectra. This material can be found via
the “Supplementary Content” section of this article’s webpage.
Disclosure statement
The authors declare that there is no conflict of interests.
Funding
The authors are grateful to Research Deputy of Mashhad University of Medical Sciences for
financial support of this study as part of thesis of Negar Omidkhah.
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