Approach to the synthesis of 8-nitroquinoline-2-carboxylic acid in high yield

Article abstract of DOI:10.1007/s11172-016-1380-5

A synthesis of 8-nitroquinoline-2-carboxylic acid was optimized, using the following basic scheme of transformations: 1) nitration of 2-methylquinoline with subsequent separation of a mixture of isomeric 8-nitroand 5-nitro-2-methylquinolines; 2) oxidation of the methyl group in 2-methyl-8-nitroquinoline (including consecutive steps of bromination and hydrolysis in aqueous sulfuric acid). A new method for the separation of isomeric 8-nitroand 5-nitro-2methylquinolines was suggested. The optimal conditions for the final step of hydrolysis were selected, which gave almost quantitative yield of 8-nitroquinoline-2-carboxylic acid.

Full text of DOI:10.1007/s11172-016-1380-5

Russian Chemical Bulletin, International Edition, Vol. 65, No. 3, pp. 816—818, March, 2016
816
Approach to the synthesis of 8ꢀnitroquinolineꢀ2ꢀcarboxylic acid
in high yield
S. Ya. Gadomsky and I. K. Yakuschenko
Institute of Problems of Chemical Physics, Russian Academy of Sciences,
1 prosp. Akad. Semenova, 142432 Chernogolovka, Moscow Region, Russian Federation.
Eꢀmail: gadomsky@icp.ac.ru
A synthesis of 8ꢀnitroquinolineꢀ2ꢀcarboxylic acid was optimized, using the following basic
scheme of transformations: 1) nitration of 2ꢀmethylquinoline with subsequent separation of
a mixture of isomeric 8ꢀnitroꢀ and 5ꢀnitroꢀ2ꢀmethylquinolines; 2) oxidation of the methyl group
in 2ꢀmethylꢀ8ꢀnitroquinoline (including consecutive steps of bromination and hydrolysis in
aqueous sulfuric acid). A new method for the separation of isomeric 8ꢀnitroꢀ and 5ꢀnitroꢀ2ꢀ
methylquinolines was suggested. The optimal conditions for the final step of hydrolysis were
selected, which gave almost quantitative yield of 8ꢀnitroquinolineꢀ2ꢀcarboxylic acid.
Key words: 8ꢀnitroquinolineꢀ2ꢀcarboxylic acid, synthesis, separation of isomers, acid
hydrolysis.
8ꢀNitroquinolineꢀ2ꢀcarboxylic acid (1) is a useful
with subsequent oxidation of the methyl group in the inꢀ
reactant in the synthesis of a number of compounds imꢀ
portant for the development of highꢀtechnology productions,
pharmacy, and medicinal studies. For example, in the
patent1 it is indicated that acid 1 can be used in the synꢀ
thesis of efficient therapeutical agents, pharmaceutical
compositions, and antibiotics. A fluorescent chemosensor for
determination of anions in living organisms was develop
based on 8ꢀnitroquinolineꢀ2ꢀcarboxylic acid 4ꢀisobutoxy
derivative.2 Apart from that, the acid 1 itself and some
compounds derived from it showed high activity against the
causative agent of anthroponotic visceral leishmaniasis.3,4
There are known several approaches to the synthesis of
compound 1. Nitration of quinolineꢀ2ꢀcarboxylic acid
gives 8ꢀ and 5ꢀnitro isomers of compound 1 (see Ref. 1).
The difficulties in the separation of the isomers and the
expensive starting reagent are the main disadvantages of
this approach. The low yield (13%) and high cost characꢀ
terize another method for the preparation of 1 through the
oxidation of 10ꢀnitrobenzo[c]quinolisinium perchlorate
with potassium permanganate.5 Apart from that, comꢀ
pound 1 can be obtained by the reaction of oꢀnitroaniline
with some reagents (crotonic aldehyde in the presence of
arsenic pentoxide6 or phosphotungstic acid,7 vinyl nꢀbutyl
ether in the presence of nitrobenzene,8 paraldehyde9) with
subsequent oxidation of the methyl group in 2ꢀmethylꢀ8ꢀ
nitroquinoline obtained. However, these synthetic proceꢀ
dures also give low yields of 1 (15—45%), use expensive
and toxic starting reagents, laborious isolation of the
target product.
termediate 2ꢀmethylꢀ8ꢀnitroquinoline (3a) (Scheme 1).
Scheme 1
Procedures for the carrying out the first step (nitraꢀ
tion of compound 2) are considered in the works.3,10—13
They differ in the composition of the nitrating mixture
(concentrated sulfuric and nitric acids; sulfuric acid
and potassium or ammonium nitrate, etc.) and in the
method of separation of isomers 3a and 3b (fractional
The most convenient pathway for the preparation of 1
includes nitration of readily available 2ꢀmethylquinoline (2)
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 0816—0818, March, 2016.
1066ꢀ5285/16/6503ꢀ0816 © 2016 Springer Science+Business Media, Inc.

8ꢀNitroquinolineꢀ2ꢀcarboxylic acid
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 3, March, 2016
817
Table 1. Dependence of the yield of 1 on the mass
fraction of H2SO4 in the hydrolysis reaction of 4
crystallization from methanol or propanol, chromatoꢀ
graphic separation).
The yields of the isomers vary: 35—45% for 3a and
40—50% for 3b (see Refs 3 and 10—13).
Entry
ω (H2SO4) (%)
τ/h
Yield of 1 (%)
The final step in the preparation of 1 is the oxidation
reaction of the methyl group in 3a through the intermediate
bromination with the formation of compound 4 and subꢀ
sequent hydrolysis to the target product (see Scheme 1).8,10
The bromination step poses no problems, compound 4 is
formed in quantitative yield. However, the final step of
hydrolysis of 4 in 20% aqueous sulfuric acid leads to the
target product 1 in low (~16%) yield.8,10 The yield of the
target product 1 was increased to 50% by increasing
the reaction time and concentration of sulfuric acid
(to 27.5%).14 It is probable that varying such parameters
as the concentration of sulfuric acid and hydrolysis time,
the yield of 1 can be increase to the values close to 100%.
However, such studies have not been carried out earlier.
In this connection, the present work is directed on the
search of the optimal conditions for the final step of hyꢀ
drolysis of 4 (see Scheme 1) in order to increase the yield
of 1. An additional problem to be solved consisted in the
search for an alternative, more convenient method (as
compared to fractional crystallization and chromatograꢀ
phy) for the separation of isomers 3a and 3b, which would
considerably simplify the synthesis of 8ꢀnitroquinolineꢀ2ꢀ
carboxylic acid (1).
1
2
3
27.5
30.0
35.0
26
24
20
96.0
97.2
78.6
Note: τ is the hydrolysis time.
the reaction mixture completely homogenized (compound 4
dissolved). Thus, the yield of 1 was increase almost twoꢀ
fold as compared to the results reported in the work.14
Most likely, the reason for the moderate yield of 1 given in
the patent publication14 consists in the fact that the auꢀ
thors stopped hydrolysis before it reached completion, inꢀ
dicating that the reaction mixture contained unreacted
precipitate.
In other entries, we varied the concentration of sulfuꢀ
ric acid. It is seen from the data in Table 1 that an increase
in the concentration of H2SO4 decreases the hydrolysis
time (a criterion of the hydrolysis completion was the
time required for the dissolution of 4 in the reaction mixꢀ
ture). However, the entry with 35% aqueous H2SO4 led to
the formation of side products (a black precipitate) and a
considerable decrease in the yield of 1. The use of 30%
aqueous solution of H2SO4 for hydrolysis 4 turned out to
be the optimal.
Results and Discussion
In conclusion, we have developed a number of apꢀ
proaches allowing one to considerably lower the cost and
simplify the process of preparation of 8ꢀnitroquinolineꢀ2ꢀ
carboxylic acid. First, we suggested a simple (as compared
to the known) method for the isolation of the intermediate
2ꢀmethylꢀ8ꢀnitroquinoline (3a). Second, we optimized the
final step of hydrolysis of 2ꢀtribromomethylꢀ8ꢀnitroquinꢀ
oline (4), that increased the yield of the target 8ꢀnitroꢀ
quinolineꢀ2ꢀcarboxylic acid 1 from ~50% to almost quanꢀ
titative. We have developed a criterion of the hydrolysis
completion of 4: an entire dissolution of 2ꢀtribromomethꢀ
ylꢀ8ꢀnitroquinoline (4). We found an optimal concentraꢀ
tion of sulfuric acid (30%) for the most rapid proceeding
of the hydrolysis process and the formation of the miniꢀ
mum amount of side products.
Separation of 8ꢀ and 5ꢀnitro isomers 3a and 3b. One of
the methods for the separation of 8ꢀ and 5ꢀnitro isomers
3a and 3b is based on the different basicity of these comꢀ
pounds.15,16 In fact, it was shown17 that the nitro group at
position 5 can decrease the basicity of the quinoline moleꢀ
cule as compared to its 8ꢀnitro isomer by more than two
orders of magnitude (the equilibrium constant of the reacꢀ
tion of the corresponding quinolinium ion with hydroxide
ion with the formation of a "pseudobase" is given in the
work,17 the equilibrium constant of the reversed reaction
can be considered as the basicity of the "pseudobase" formed).
However, despite the large difference in the basic properꢀ
ties of compounds 3a and 3b, such a method for their
separation is not widely used, since the optimal pH values
for the precipitation of each of the isomers were not found.
In the present work, a controlled increase in the pH of the
solution (from 1 to 10) of a mixture of hydrochlorides of
isomers 3a and 3b was used to find out that 8ꢀnitro isomer 3a
precipitates as an individual compound within pH 2—4,
whereas 5ꢀnitro isomer 3b precipitates at pH 6—10.
Experimental
1
H NMR spectra were recorded on a Bruker DRX 500
spectrometer (500.13 MHz) at a temperature of 298 К, using
tetramethylsilane as an internal standard. Mass spectra were
recorded on a Finnigan MAT, INCOS 50 instrument with injecꢀ
tion of compounds in the localization area at the energy of ionizꢀ
ing electrons of 70 eV. Melting points were measured on a Boetius
PH MК 05 heating stage with an observation device and were
corrected. Elemental analysis was carried out on a Vario Micro
cube CHNS/O elemental analyzer.
Hydrolysis 2ꢀtribromomethylꢀ8ꢀnitroquinoline (4).
Table 1 summarizes the results of hydrolysis of 4 in soluꢀ
tions of sulfuric acid with different concentrations. In the
first entry (Table 1), we reproduced a procedure described
earlier14 with an increased time of hydrolysis. After 26 h,

818
Russ.Chem.Bull., Int.Ed., Vol. 65, No. 3, March, 2016
Gadomsky and Yakuschenko
Synthesis of 2ꢀmethylꢀ8ꢀnitroquinoline was based on the proꢀ
lution of 4, cooled to 80 °C, and poured into water (500 mL).
The reaction mixture was hot filtered from the side products and
poured into water (800 mL). After 10—12 h (at ~20 °C), a preꢀ
cipitate formed was filtered, washed with cold water (20 mL) on
the filter. An analytical sample was obtained by recrystallization
from isopropyl alcohol. The yields of compound 1 are given in
Table 1. Melting point of compound 1 was 176—177 °C. Found (%):
C, 55.02; H, 3.03; N, 12.71. C10H6N2O4. Calculated (%): C, 55.05;
H, 2.77; N, 12.84; O, 29.33. 1H NMR, δ: 7.90 (dd, 1 H, C(6)H,
J = 8.5 Hz, J = 9.0 Hz); 8.27 (d, 1 H, C(3)H, J = 9.0 Hz); 8.37
(d, 1 H, C(5)H, J = 8.5 Hz); 8.40 (d, 1 H, C(4)H, J = 9.0 Hz);
8.77 (d, 1 H, C(7)H, J = 9.0 Hz); 13.75 (br.s, 1 H, —COOH).
MS, m/z (I/Imax (%)): 218 [M] (20), 174 (100), 157 (18), 127 (40),
116 (45), 101 (30).
cedure described in the literature.16 Ammonium nitrate (48 g,
0.6 mol) was added in portions to a solution of 2ꢀmethylquinoꢀ
line bisulfate (120.6 g, 0.5 mol) in concentrated sulfuric acid
(200 mL) with stirring at 10—15 °C over 20 min. The mixture
was stirred for 1 h, then poured onto ice (800 g). The resulting
mixture was alkalized with 25% aqueous solution of ammonia to
pH 10—11, maintaining the temperature below 20 °C. A precipꢀ
itate formed was stirred for another 2 h, filtered, washed with
water (3×100 mL) on the filter. The mixture of 8ꢀnitroꢀ and
5ꢀnitroꢀ2ꢀmethylquinolines was suspended into water (700 mL),
followed by a gradual addition of concentrated hydrochloric acid
until a complete dissolution of the suspension (pH of the soluꢀ
tion <1). The resulting solution was filtered from a small amount
of the resinꢀlike impurities, the filtrate was gradually diluted
with a 30% solution of NaOH with stirring and a temperature
below 25 °C). A precipitate formed was collected within pH 2—4.
This precipitate was practically pure 2ꢀmethylꢀ8ꢀnitroquinoline.
For final purification, it was recrystallized from isopropyl alcohol
to obtain 2ꢀmethylꢀ8ꢀnitroquinoline (35.2 g, 37.4% on theoretiꢀ
cal), m.p. 138.5—139 °C. Found (%): C, 63.99; H, 4.45; N, 14.74.
C10H8N2O2. Calculated (%): C, 63.82; H, 4.28; N, 14.89; O, 17.00.
1H NMR, δ: 2.77 (s, 3 H, Me); 7.41 (d, 1 H, C(3)H, J = 9.0. Hz);
7.53 (dd, 1 H, C(6)H,,J = 9.0 Hz, J = 8.5. Hz); 7.94—7.97 (m, 2 H,
C(5)H + C(4)H); 8.11 (d, 1 H, C(7)H, J = 9.0 Hz). MS, m/z
(I/Imax (%)): 188 [M] (100), 158 (30), 142 (20), 130 (75), 115 (85),
103 (20), 89 (28).
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A precipitate collected at pH 6—10 was practically pure
2ꢀmethylꢀ5ꢀnitroquinoline. Its further purification from the tracꢀ
es of 8ꢀnitro isomer consisted in the extraction with hot hexane
(8ꢀnitro isomer is poorly soluble in hexane and remained in the
precipitate) to obtain 5ꢀnitro isomer (40.0 g, 42.5% on theoretiꢀ
cal). The fraction collected at pH 4—6 was a mixture of both
isomers.
Synthesis of 8ꢀnitroꢀ2ꢀtribromomethylquinoline.9 2ꢀMethylꢀ
8ꢀnitroquinoline (3a) (28.2 g, 0.15 mol) was suspended in glacial
acetic acid (600 mL) saturated with anhydrous sodium acetate
(~20 °C), followed by a dropwise addition of a solution of broꢀ
mine (80 g, 0.5 mol) in glacial acetic acid (200 mL) with stirring
over 5 h. The reaction temperature was maintained within
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stand at this temperature for 30 min and poured into water
(2.5 L). A precipitate formed was filtered and washed with cold
(10—12 °C) water (2×60 mL) on the filter to obtain practically
pure product. The yield was 62.85 g (98.6% on theoretical),
m.p. 118—118.5 °C. Found (%): C, 28.43; H, 1.40; N, 6.8.
C10H5Br3N2O2. Calculated (%): C, 28.27; H, 1.19; Br, 56.42;
N, 6.59; O, 7.53. 1H NMR, δ: 7.65—7.75 (m, 1 H, C(6)H); 8.09
(d, 1 H, C(5)H, J = 9.0 Hz); 8.13 (d, 1 H, C(4)H, J = 8.0 Hz);
8.36—8.38 (m, 2 H, C(3)H + C(7)H). MS, m/z (I/Imax (%)):
345 (100), 299 (20), 286 (20), 265 (15).
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Synthesis of 8ꢀnitroquinolineꢀ2ꢀcarboxylic acid. The syntheꢀ
sis was carried out with sulfuric acid of different concentrations
indicated in Table 1. 2ꢀTribromomethylꢀ8ꢀnitroquinoline (25.5 g,
60 mmol) was suspended in aqueous sulfuric acid (485 mL). The
reaction mixture was refluxed with stirring until complete dissoꢀ
Received July 8, 2015;
in revised form December 17, 2015