4-Hydroxy-2-quinolones 132. Synthesis, chemical, and biological properties of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2-nitrobenzylidenehydrazides

Article abstract of DOI:10.1007/s10593-007-0221-8

1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2-nitrobenzylidenehydrazides are reduced to the corresponding quinoline-3-carboxamides by zinc in glacial acetic acid but in refluxing triethylphosphite they are converted to the symmetrical N,N′-di(4-hydroxy- 2-oxo-1,2-dihydro-3-quinolinoyl)hydrazines. A study of the antitubercular activity of the synthetic compounds has been carried out.

Full text of DOI:10.1007/s10593-007-0221-8

Chemistry of Heterocyclic Compounds, Vol. 43, No. 11, 2007
4-HYDROXY-2-QUINOLONES
132*. SYNTHESIS, CHEMICAL,
AND BIOLOGICAL PROPERTIES
OF 1-R-4-HYDROXY-2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBOXYLIC ACIDS
2-NITROBENZYLIDENEHYDRAZIDES
I. V. Ukrainets, L. V. Sidorenko, and O. S. Golovchenko
1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2-nitrobenzylidenehydrazides are
reduced to the corresponding quinoline-3-carboxamides by zinc in glacial acetic acid but in refluxing
triethylphosphite they are converted to the symmetrical N,N'-di(4-hydroxy-2-oxo-1,2-dihydro-
3-quinolinoyl)hydrazines. A study of the antitubercular activity of the synthetic compounds has been
carried out.
Keywords: hydrazides, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, amidation,
reduction, antitubercular activity.
In carrying out a systematic search for novel, potential medicinal preparations suitable for treatment of
microbacterial infections we have repeatedly noted the high antitubercular activity of 1-R-4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylic acids benzylidenehydrazides [2-4]. The 2-nitrobenzylidene derivatives 1 are
interesting objects of study in this area. Such compounds can also serve as the basis for the synthesis of different
heterocyclic compounds through reactions of the ortho-positioned nitro groups.
The starting 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2-nitrobenzylidene-
hydrazides 1 were prepared by reaction of the corresponding quinoline-3-carboxylic acid hydrazides 2 with
ortho-nitrobenzaldehyde in refluxing ethanol. They are light yellow, crystalline materials with sharp melting
points (Table 1), soluble in DMF and DMSO, of low solubility in ethanol, and virtually insoluble in water, ether,
and hexane.
A reliable confirmation of the formation of the acylhydrazones 1 is the singlet signal for the methine
1
protons in the H NMR spectra (Table 2). The assignment of the signals of each of the eight aromatic protons
without special NMR experiments is made difficult or, in the extreme, impossible because they are localized in a
narrow spectral range and frequently overlapped.
_______
* For Communication 131 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine, e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1687-1692, November, 2007. Original article submitted
June 25, 2006.
1434
0009-3122/07/4311-1434©2007 Springer Science+Business Media, Inc.

As is known, carboxylic acids hydrazides are reduced with somewhat greater difficult than derivatives
with a C=N bond [5]. This feature opens up the possibility of a selective hydrogenation of acylhydrazones with
retention of the acyl group and this is often used in the pharmaceutical industry in the synthesis of medicinal
compounds [6, 7].
OH
O
OH
O
.
H2NNH2 H2O
NHNH2
OEt
O
N
O
N
R
R
4a–i
2a–i
O
NH3
O2N
OH
O
O
OH
O
O
N
N
Zn, AcOH
NH2
H
NO2
N
N
R
R
3b,e
1a–i
P(OEt)3
OH
O
O
OH
O
O
O
OH
N
N
N
N
N
H
H
H
N
R
N
R
O
N
R
6e
5e
a R = H, b R = Me, c R = Et, d R = CH2CH=CH2, e R = Pr, f R = Bu, g R = i-Bu,
h R = C5H11, i R = C6H13
Reducing agents used are hydrogen, hydrides, complex hydrides, metals, organometallic compounds etc.
As a rule, this type of reaction occurs without particular difficulty and gives good results [6-8]. Only in certain
examples is a partial fission of the N–N bond observed [5]. However, in the reduction of the acylhydrazones 1
using zinc dust in glacial acetic acid this process becomes predominant and gives high yields of 1-R-4-hydroxy-
2-oxo-1,2-dihydroquinoline-3-carboxamides 3 in the end, even though the preparation of the amine derivatives
from hydrazines normally needs catalytic hydrogenation under pressure over Raney nickel or platinum catalysts
[5].
The structure of the amides 3 obtained was confirmed by a counter synthesis via the amidation of the
ethyl esters 4 (readily soluble in alcohols). At first glance this may be a trivial reaction but it proved also to have
specific features.
Thus when solutions of esters 4 in methanol or ethanol were saturated with gaseous ammonia the
corresponding quinoline-3-carboxamides 3 were formed with unexpectedly high difficulty and occurred to no
more than 20% over 24 h despite a large excess of the amine. It was of interest that, in methanol, the strongly
1435

predominating process is that of trans esterification and not amidation. However, in the case of 2-propanol,
immediately after addition of ammonia to the reaction mixture white precipitates formed which proved, after
filtering and drying, to be the unexpected starting esters 4. It is likely that the initial products of this reaction are
the ammonium 1-R-3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolin-4-olates. Their formation may account for the
extremely low rate of amidation, completion of which could not be achieved in the poorly solvating 2-propanol,
even after increasing the reaction time to 10 days.
TABLE 1. Characteristics of 2-Nitrobenzylidenehydrazides 1a-i
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
C
H
N
1a
1b
1c
1d
1e
1f
C17H12N4O5
57.87
57.96
59.12
59.02
59.94
60.00
61.16
61.22
60.97
60.91
61.66
61.76
61.80
61.76
62.50
62.55
3.36
3.43
3.95
3.85
4.28
4.24
4.16
4.11
4.52
4.60
4.85
4.94
4.88
4.94
5.33
5.25
15.97
15.90
15.20
15.29
14.81
14.73
14.35
14.28
14.17
14.21
13.82
13.72
13.79
13.72
13.20
13.26
310-312
274-276
249-251
204-206
177-179
151-153
170-172
191-193
185-187
90
91
87
83
88
85
90
86
82
C18H14N4O5
C19H16N4O5
C20H16N4O5
C20H18N4O5
C21H20N4O5
C21H20N4O5
C22H22N4O5
C23H24N4O5
1g
1h
1i
63.35
63.29
5.59
5.54
12.93
12.84
TABLE 2. 1H NMR Spectra of the 2-Nitrobenzylidenehydrazides 1a-i
Chemical shifts, δ, ppm. (J,Hz)
Com-
pound
4-OH
(1H, s)
NH–N
(1H, s)
N=CH
(1H, s)
Н arom.
(8Н, m)
R
1a
1b
1c
16.33
16.45
16.37
13.47
13.50
13.53
8.75
8.81
8.82
8.12-7.26 12.06 (1Н, s, NН)
8.19-7.35 3.69 (3Н, s, СН3)
8.19-7.36 4.32 (2Н, q, J = 7.2, NCH2);
1.03 (3Н, t, J = 7.2, СН3)
1d
16.39
13.45
8.76
8.14-7.29 5.97 (1H, m, CH=СН2);
5.16 (1H, dd, J = 10.8
and J = 1.3, NСН2СН=СН-cis);
5.03 (1H, dd, J = 17.3
and J = 1.3, NСН2СН=СН-trans);
4.94 (2H, d, J = 4.8, NСН2)
1e
1f
16.44
16.40
13.42
13.49
8.80
8.82
8.17-7.34 4.18 (2Н, t, J = 7.1, NCH2);
1.62 (2Н, m, NCH2СН2);
0.97 (3Н, t, J = 7.0, СН3)
8.17-7.35 4.28 (2Н, t, J = 7.3, NCH2);
1.63 (2Н, m, NCH2СН2);
1.42 (2Н, m, СН2СН3);
0.93 (3Н, t, J = 7.2, СН3)
1g
1h
1i
16.47
16.36
16.30
13.50
13.44
13.48
8.82
8.81
8.81
8.18-7.35 4.19 (2Н, d, J = 7.5, NCH2);
2.16 (1Н, m, CH); 0.92 (6Н, d,
J = 6.7, 2СН3)
8.16-7.30 4.25 (2Н, t, J = 7.2, NCH2);
1.65 (2Н, m, NCH2СН2); 1.36 (4Н, m,
(СН2)2СН3); 0.90 (3Н, t, J = 7.1, СН3)
8.17-7.29 4.26 (2Н, t, J = 7.2, NCH2);
1.66 (2Н, m, NCH2СН2); 1.33 (6Н, m,
(СН2)3СН3); 0.87 (3Н, t, J = 7.0, СН3)
1436

A similar inertness towards nucleophiles, including amines, has also been demonstrated in sodium and
potassium 1-R-3-ethoxycarbonyl-2-oxo-1,2-dihydroquinolin-4-olates [9]. The ammonium salts differ in their
formation from a weak acid and weak bases (the 4-OH group in the ethyl 1-R-4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carboxylates 4 having a pKa of about 8.6 [10]), their separation from the reaction
mixture occurring with rapid decomposition by the action of atmospheric moisture and carbon dioxide (as
observed experimentally). The high reactivity of the ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylates
4 has often been noted. However, only with ammonia (one of about 200 aliphatic, aromatic, and heterocyclic
amines used by us to this time in the synthesis of the corresponding quinoline-3-carboxamides) do they take part
in the reaction with such difficulty. It is possible that the unique steric structure of the ammonia molecule has an
importance in this case and thanks to which they can form stable adducts in solution with 3-ethoxycarbonyl-
2-oxo-1,2-dihydroquinolines. As a result, the approach to the quinolone reaction center (in particular the ester
carbonyl carbon atom) is blocked to a marked extent. A similar selective inertness towards ammonia has already
been discussed by us in the case of ethyl 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylates [11].
Meanwhile, amidation of esters 4 by ammonia can also be brought about by carrying out the synthesis in
refluxing DMF to give the amides 3 in good yields.
The 2-nitrobenzylidenehydrazides 1 also behave unusually in reaction with triethylphosphite, at least the
expected [12] reductive cyclization to the indazolyl-2-amides proved to be impossible. Under experimentally
similar conditions to the 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids ethoxymethylidene-
hydrazides [13] the acylhydrazones 1 gave the symmetrical N,N'-di(1-R-4-hydroxy-2-oxo-1,2-dihydro-
3-quinoinoyl)hydrazines 6. In this case it is most likely that the triethylphosphite merely behaves as a high
boiling solvent since, for example, such a conversion can be brought about in the inert bromobenzene.
The antimicrobial activity of all of the synthesized 2-nitrobenzylidenehydrazides 1 was studied
radiometrically [14, 15]. It was quite clear that the single 1-N-amyl derivative 1h inhibits the in vitro growth of
Mycobacterium tuberculosis H37RvATCC27294 by 99% at a concentration of 12.5 µg/ml. In the following step
of microbial screening where the minimum inhibitory concentration (MIC) is determined it was found that, in
terms of antitubercular properties, the 2-nitrobenzylidenehydrazide 1h and its 2-fluoro substituted analog [3]
were identical (for both compounds the MIC was 3.13 µg/ml). In all other examples, fluoro derivatives have
proved much more active.
EXPERIMENTAL
1
The H NMR spectra of the synthesized compounds were recorded on a Varian Mercury VX-200 (200
MHz) instrument for DMSO-d6 solutions with TMS as internal standard.
1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acids Hydrazides 2 were prepared by the
method in [16].
1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acids 2-Nitrobenzylidenehydrazides 1a-i
(General Method). The 2-nitrobenzaldehyde (1.66 g, 0.011 mol) was added to a solution of the corresponding
quinoline-3-carboxylic acid hydrazide 2 (0.01 mol) in ethanol (50 ml) and refluxed for 30 min (in the
preparation of the 1-H and 1-CH3 derivatives the solvents used were respectively DMF and DMF–ethanol (1:1)).
The reaction mixture was cooled, and the target 2-nitrobenzylidenehydrazide 1 was filtered off, washed with
ether or ethanol, dried, and crystallized from DMF or ethanol.
4-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxamide (3e). A. A refluxing solution of the
4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic acid 2-nitrobenzylidenehydrazide (1e) (3.94 g,
0.01 mol) in glacial acetic acid (70 ml) with intensive stirring was treated with zinc powder (5 g) added in small
portions at such a rate that that the evolution of hydrogen was not too vigorous. After addition of all of the zinc it
was stirred with heating for 3 h. The reaction mixture was cooled, filtered, and the residue on the filter
1437

washed several times with ethanol. The solvent from the filtrate was distilled in vacuo to a volume of about
15 ml. The residue was diluted with cold water. The precipitated solid amide 3e was filtered off, washed with
1
water, and dried. Yield 2.02 g (82%); mp 189-191ºC (aqueous ethanol). H NMR spectrum, δ, ppm (J, Hz):
16.11 (1H, s, OH); 9.67 (1H, s, NH); 8.58 (1H, s, NH); 8.09 (1H, dd, J = 7.9, 1.5, H-5); 7.79 (1H, td, J = 6.9,
1.7, H-7); 7.63 (1H, d, J = 8.0, H-8); 7.34 (1H, td, J = 7.0, 1.5, H-6); 4.19 (2H, t, J = 7.1, NCH2); 1.62 (2H, m,
NCH2CH2); 0.95 (3H, t, J = 7.1, CH3). Found, %: C 63.46; H 5.80; N 11.29. C13H14N2O3. Calculated, %:
C 63.40; H 5.73; N 11.38.
B. A solution of ethyl 4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylate (4e) in DMF
(15 ml) was saturated, with ammonia and refluxed for 30 min. After cooling, the operation was repeated. The
reaction mixture was diluted with cold water and acidified with dilute HCl to pH 5.0. The precipitated amide 3e
was filtered off, washed with water, and dried. Yield 2.06 g (84%). A mixed sample with that from that obtained
by method A did not give a melting point depression and their 1H NMR spectra were identical.
4-Hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamide (3b) was prepared as in the
1
previous experiment (method A). Yield 80%; mp 207-209ºC (aqueous ethanol). H NMR spectrum, δ, ppm (J,
Hz): 16.07 (1H, s, OH); 9.65 (1H, s, NH); 8.54 (1H, s, NH); 8.06 (1H, dd, J = 7.9, 1.6, H-5); 7.77 (1H, td,
J = 7.0, 1.8, H-7); 7.56 (1H, d, J = 8.2, H-8); 7.33 (1H, td, J = 7.0, 1.6, H-6); 3.59 (3H, s, NCH3). Found, %:
C 60.48; H 4.57; N 12.75. C11H10N2O3. Calculated, %: C 60.55; H 4.62; N 12.84.
N,N'-Di(4-hydroxy-2-oxo-1-propyl-1,2-dihydro-3-quinolinoyl)hydrazine (6e). A solution of the
2-nitrobenzylidenehydrazide 1e (3.94 g, 0.01 mol) in triethylphosphite (50 ml) was refluxed for 2 h and the
triethylphosphite distilled off in vacuo. The residue was treated with ethanol (30 ml). The precipitate was filtered
1
off, washed with ethanol and then water, and dried. Yield 1.83 g (75%); mp 326-328ºC (DMF). The H NMR
spectra of the diacylhydrazine 6e obtained and a known sample [13] are identical.
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