4-Hydroxy-2-quinolones. 93. Synthesis and biological properties of 2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic acid N-R-amides

Article abstract of DOI:10.1007/s10593-006-0114-2

Various methods of synthesizing amides of 2-hydroxy-4-imino-1,4- dihydroquinoline-3-carboxylic acids have been studied. Results of investigations on the antitubercular and antiinflammatory activity of the obtained compounds are discussed. 2006 Springer Sc

Full text of DOI:10.1007/s10593-006-0114-2

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
4-HYDROXY-2-QUINOLONES. 93*.
SYNTHESIS AND BIOLOGICAL PROPERTIES
OF 2-HYDROXY-4-IMINO-1,4-DIHYDROQUINOLINE-
3-CARBOXYLIC ACID N-R-AMIDES
I. V. Ukrainets1, L. V. Sidorenko1, O. V. Gorokhova1, and N. A. Jaradat2
Various methods of synthesizing amides of 2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic acids
have been studied. Results of investigations on the antitubercular and antiinflammatory activity of the
obtained compounds are discussed.
Keywords:
4-chloro-2-oxo-1,2-dihydroquinolines,
2-hydroxy-4-imino-1,4-dihydroquinolines,
amidation, intramolecular cyclization, enamine–imine tautomerism, antitubercular and anti-inflammatory
activity.
Amides are a class of organic compounds which are rightfully considered to be most convenient for
carrying out investigations devoted to the search for rules on structure–pharmacological activity links. The basis
for such a conclusion is the fact that the amide group is an important component of many biologically active
substances, both natural and synthetic. The enormous variety of methods and procedures used in the synthesis of
amides, and also the practically unlimited selection of starting materials, enables systematic changes to be
introduced into the structure of the final compounds, thereby purposefully changing their physicochemical and
biological properties.
Proceeding from this, one of the stages of our investigations was devoted to the amide of 4-amino-2-
oxoquinoline-3-carboxylic acids. As one of the proposed variants of obtaining such compounds we studied the
possibility of synthesizing amides of 1H-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1, which then
might be transformed into the 4-amino derivative by any suitable method.
Previous attempts to obtain amides 1 by the reaction of 4-chloro acid 2a with amines in the presence of
N,N'-dicyclohexylcarbodiimide were unsuccessful [2]. Activation of the acid component of acid 2a with
N,N'-carbonyldiimidazole (CDI) also gave no positive result. It turned out that on interacting 4-chloro-2-oxo-
1,2-dihydroquinoline-3-carboxylic acid (2a) with N,N'-carbonyldiimidazole in anhydrous DMF the vigorous
evolution of CO2 characteristic of this reaction was observed, obviously indicating the formation of
acylimidazole 3 (Scheme 1).
_______
* For Part 92 see [1].
__________________________________________________________________________________________
1
2
National Pharmaceutical University, Kharkov 61002, Ukraine; e-mail: uiv@kharkov.ua. An-Najah
National University College of Pharmacy, P.O. Box 7, Nablus, Palestine. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 4, pp. 542-555, April, 2006. Original article submitted September 14,
2004.
0009-3122/06/4204-0475©2006 Springer Science+Business Media, Inc.
475

Scheme 1
N
Cl
O
O
Cl
O
O
N
O
O
N
N
CDI
OH
N
N
N
CO2
+
+
N
H
N
H
N
H
N
H
3
4
5
2a
H2N–C8H17
H2N–R
HN
N
N
Cl
O
N
O
N
O
O
R
N
H
NHC8H17
N
N
H
O
N
H
O
N
H
6
1
7
It was assumed that further treatment of it with N-nucleophiles must lead to the corresponding amide of
1H-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1. On the basis of the attempts made, it was shown
that the acylimidazole obtained as a result of the reaction of 4-chloro acid 2a with N,N'-carbonyldiimidazole in
reality reacts smoothly with primary and with secondary aliphatic amines. However it was established by
methods of 1H NMR spectroscopy and chromato-mass spectrometry that the compounds synthesized in this way
are not the expected N-R-amides of 1H-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 1 but are alkyl
and dialkyl amides of 1H-4-(1-imidazolyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid 6 and 7 respectively. It
follows from this that the chlorine atom of the initially formed imidazide 3 is readily substituted under the
synthesis conditions by a residue of liberated imidazole 4, which leads to the imidazolide of
1H-4-(1-imidazolyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (5) and finally to amides 6 and 7.
Attempts to activate the carbonyl of the carboxyl group of 4-chloro acid 2a by converting it to an acid
halide were also unjustified. By the action of an excess of thionyl chloride 1H-4-chloro-2-oxo-1,2-
dihydroquinoline-3-carboxylic acid chloride (8) is indisputably formed, but regrettably the reaction failed to stop
at this stage, since in acid chloride 8 the 2-C=O group (more precisely its hydroxy tautomer) is also fairly readily
exchanged by chlorine, showing the activating influence of the neighboring acid chloride grouping. The extreme
ease of exchange of the 2-C=O group by halogen (which is exchanged first) was also noted for
1H-3-ethoxycarbonyl-4-hydroxy-2-oxo-1,2-dihydroquinoline in [3]. As a result, the final product of the
described reaction is in fact a mixture of the acid chlorides of 4-chloro-2-oxo- and 2,4-dichloroquinoline-3-
carboxylic acids 8 and 9 respectively (Scheme 2). For this reason the acid chloride method of obtaining
1H-4-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxamides also has no practical value.
It is understandable that the corresponding acid chlorides 10 are synthesized without complications from
1-substituted 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids (for example, 2b R = Pr), since the
possibility of forming 2-hydroxy forms with subsequent replacement of the hydroxy group by halogen is
excluded in such cases.
As was expected, acid chloride 10 readily acylates primary aromatic, aliphatic, and secondary amines
and the corresponding amides 11-13 are formed as a result. Reaction occurs with aminopyridines somewhat
unusually, at first sight. Thus, after interaction of the acid chloride of 4-chloro-2-oxo-1-propyl-1,2-
476

477

dihydroquinoline-3-carboxylic acid (10) with 4-aminopyridine in dry acetone, maintaining the reaction mixture
for 10 h at room temperature, and subsequently diluting with water, the initial 4-chloro-2-oxo-1-propyl-1,2-
dihydroquinoline-3-carboxylic acid (2b) was isolated. The obtained result is undoubtedly due to the formation
not of the amide but of the N-acylpyridylammonium salt 14. Such behavior on acylation with acid chlorides is
characteristic of many azaheterocyclic amines, including aminopyridines [4], although usually salts of the type
of 14 are far less stable and are rapidly rearranged into the corresponding acylamino derivatives, i.e. amides.
Aminopyridines, existing predominantly in the aromatic form, are acylated at the heteroatom in neutral medium,
since it is the nucleophilic center in just those conditions. This fact is explained from the position of the principle
of hard and soft acids and bases. An acid chloride is a relatively soft electrophile, consequently it attacks a more
soft reaction center bearing a more negative charge, i.e. the pyridine nitrogen atom [5].
Unlike the ethyl esters of 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids [6] the chlorine
atom in methoxyanilide 11 is readily exchanged by an amino group with the formation of the 4-imino derivative
15 on reaction with gaseous ammonia at normal pressure, although it would be more logical to expect a
reduction in reactivity, since the carbonyl in amides is superseded by ester in its activating effect [7]. A similar
effect, although less marked, is also observed in the case of diethylaminoethylamide 12. According to 1H NMR
data, after treatment of this compound with ammonia under the same conditions and for the same time
(Scheme 2), the exchange of halogen by an amino group occurs only to 60%, although this reaction goes readily
with diethylamine and the 4-diethylamino derivative 17 is formed practically quantitatively.
It is interesting that with other amines, the basicity of which is significantly less than ammonia (for
example, with anilines), the esters of 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids react without any
complications [1]. The same may be said about sterically hindered amines (isopropylamine, 1-phenylethylamine)
[8]. In reality the selective inertness noticed previously in [6] of the ethyl esters of 1-R-4-chloro-2-oxo-1,2-
dihydroquinoline-3-carboxylic acids in relation just to ammonia is caused not by the mobility of the chlorine
atom, but by other reasons, obstructing the specific mutual orientation of the reacting molecules and thereby not
permitting them to approach fairly close to one another. One of such reasons may be, for example, the formation
of complexes of 4-chloroquinoline-3-carboxylic acid ester with ammonia, as a result of which access to the
carbon atom in position 4 of the quinoline for nucleophilic attack becomes impossible.
A distinctive special feature of the structure of primary amides of 1-R-2-oxo-1,2-dihydroquinoline-3-
carboxylic acids [9-12], among them probably their 4-chloro substituted analogs 11 and 12, is the formation of a
stable intramolecular hydrogen bond 2-C=O···H-N(R)–CO(3), which evidently also prevents the formation of
unreactive compounds with ammonia. Confirmation of this conclusion is the fact that like the ester the
secondary amides of 1-R-4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids (for example 13), in which the
formation of the indicated intramolecular hydrogen bond is impossible, do not react with ammonia at normal
pressure.
It follows from the results presented that 1-R-4-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acids
are expedient for use only in the synthesis of 1-substituted 2-hydroxy-4-imino-1,4-dihydroquinoline-3-
carboxamides. The 1-H-derivative 19 regrettably was not successfully obtained by any of the methods
considered. The amidation of 1-H-4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (20, Scheme 3) was
also unsuccessful. Boiling equimolar quantities of acid and amine in DMF, used successfully in the synthesis of
alkylamides of 1-H-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid [13], was accompanied in this case
by the decarboxylation of the 4-aminoacid 20 with the formation of 1-H-4-amino-2-oxo-1,2-dihydroquinoline
(21).
Esters of 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 22 also do not react with alkylamines.
At the same time hydrazinolysis of these compounds was effected and hydrazides of 1-R-2-hydroxy-4-imino-
1,4-dihydroquinoline-3-carboxylic acids 23 may be isolated in good yield. Subsequent treatment of them with
aromatic aldehydes gives the corresponding arylidenehydrazides 24a-e.
478

Concerning the alkylamides of 1H-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic acid 19, a
different synthetic scheme to obtain them is completely justified, by forming the aminoquinolone nucleus just to
carry out amidation. As it turned out the ethyl ester of 2-cyanomalonic acid (25) is amidated fairly simply, and
the alkylamides 26 formed in this way may be obtained in the pure state or, after treatment with sodium
methylate in anhydrous methyl alcohol, are converted into the desired 1-H-2-hydroxy-4-imino-1,4-
dihydroquinoline-3-carboxamides 19a-l in high yield and without isolation from the reaction mixture (Table 1,
method A).
Scheme 3
OH
O
O
NH2
O
NH2
H2NR,
DMF
NHR
OH
N
H
N
H
O
N
H
O
27
21
20
10% HCl
NH
H2NR, DMF
H2NR
O
NH2
O
NHR
OH
OAlk
N
H
N
O
R
19a–l
22
B: H2NR, 15 h
MeONa, MeOH
N
N
A: H2NR, 4 h
NCOCH2COOEt
H
.
H2NNH2 H2O
NCOCH2CONHR
H
25
26a,b
O
NH
O
NH
O
R1
R1
N
H
N
NHNH2
OH
23a,b
H
N
OH
N
R
R
24a–e
19 a R = CH2CH=CH2, b R = Pr, c R = i-Bu, d R = i-C5H11, e R = C6H13, f R = C8H17,
g R = CH2Ph, h R = 2-picolyl, i R = 3-picolyl, j R = 4-picolyl, k R = furfuryl,
l R = CH2CH2NMe2; 23 a R = H, b R = C7H15; 24 a R = H, R1 = 2-FC6H4,
b R = H, R1 = 3-FC6H4, c R = C7H15, R1 = 2-pyridyl, d R = C7H15, R1 = 3-pyridyl,
e R = C7H15, R1 = 4-pyridyl; 26 a R = i-Bu, b R = CH2Ph
479

TABLE 1. Characteristics of Alkylamides of 1-H-2-Hydroxy-4-imino-1,4-
dihydroquinoline-3-carboxylic Acid 19a-l
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
Yield, %*
C
H
N
19a
19b
19c
19d
19e
19f
19g
19h
19i
C13H13N3O2
64.31
64.19
63.78
63.66
64.70
64.85
65.79
65.91
66.73
66.88
68.42
68.54
69.70
69.61
65.21
65.30
65.15
65.30
65.28
65.30
63.53
63.60
61.37
61.30
5.25
5.39
6.14
6.16
6.57
6.61
7.15
7.01
7.23
7.37
7.86
7.99
5.02
5.15
4.67
4.79
4.88
4.79
4.71
4.79
4.50
4.63
6.54
6.61
17.12
17.27
17.24
17.13
16.10
16.20
15.43
15.37
14.66
14.62
13.21
13.32
14.39
14.33
19.17
19.04
19.11
19.04
19.09
19.04
14.92
14.83
20.65
20.42
254-256
247-249
244-246
243-245
240-241
250-252
255-257
224-226
266-268
293-295
245-247
218-220
83
80
77
78
80
79
83
77
82
81
84
70
C13H15N3O2
C14H17N3O2
C15H19N3O2
C16H21N3O2
C18H25N3O2
C17H15N3O2
C16H14N4O2
C16H14N4O2
C16H14N4O2
C15H13N3O3
C14H18N4O2
19j
19k
19l
_______
* Yield is given for method A (compounds 19a-k) and B (compound 19l).
Being bases, alkylamines in principle are capable not only of amidating the acyclic ester 25, but also of
catalyzing its intramolecular cyclization. However the ethyl (or methyl as a possible product of
transesterification after carrying out the synthesis in methanol) ester of 4-amino-2-oxo-1,2-dihydroquinoline-3-
carboxylic acid was not detected in the reaction mixture. Nonetheless partial closure of the ring occurs, but after
amidation, which is indicated by the cyclic iso-butylamide 19c isolated after treatment of ester 25 with
iso-butylamine (method B). With the usual aliphatic amines the cyclization of amides of 2-cyanomalonanilic
acid 26 occurs fairly slowly, consequently to reduce the reaction time the need also arises to apply stronger
bases, such as sodium methylate. But on using alkylamines containing more basic groupings than a primary
aliphatic amino group (such as the tertiary amino group of dimethylaminoethylamine) the synthesis of the
corresponding cyclic compound 19l is effected efficiently and without adding sodium alcoholates.
1
A characteristic special feature of the H NMR spectra of acyclic alkylamides of 2-cyanomalonanilic
acid 26 is the singlet signal of the malonic acid methylene group protons of intensity 2H at 3.4 ppm. On closing
1
the quinoline ring this signal routinely disappears. A more detailed analysis of the H NMR spectra of cyclic
alkylamides and hydrazides 19, 23, 24 shows that, unlike 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic
acids and their esters, the amidated derivatives exist in the 2-hydroxy-4-imino form (Table 2). The imino group
is displayed in the spectrum by a broadened singlet forming, with the doublet of the aromatic quinoline H-5
proton, a general signal of integrated intensity 2H. The 2-hydroxy-4-imino-1,4-dihydroquinoline structure of
amides 19 is also confirmed by their chemical properties. On treatment with 10% HCl solution these compounds
are converted quantitatively into 4-hydroxy derivatives 27. It is necessary to take this circumstance into account
when isolating amides 19 and in order to avoid hydrolysis of the 4-amino group mineral acids are not used to
neutralize the excess of basic catalyst. Dilute acetic acid is completely suitable for this purpose.
480

481

The mass spectra of alkylamides of 1-H-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic acid 19
were interesting for the investigation, particularly in comparison with the mass spectra of their synthetic
precursors, the amides of 2-cyanomalonanilic acid 26, since they are isomers and their molecular masses are
identical. Under the action of electron impact the cyclic amides 19 form molecular ions, but the intensity of the
peaks did not exceed 10%. Further fragmentation is accompanied by fission of the amide bond and the
formation of two fragments, the peak of one of which has the maximum intensity in the spectrum, although for
amides with branched alkyl chains (such as iso-butylamide 19c) initial loss of an iso-propyl fragment is also
possible.
Comparison of the mass spectra of isomeric iso-butylamides of 2-cyano-malonanilic (26a) and
1-H-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic (19c) acids showed that they are practically
identical, differing only in the intensity of peaks of certain ions. Evidently in the mass spectrometer (rapid
heating in vacuum) the acyclic amide 26a is subject to intramolecular condensation and in fact the spectrum
recorded is of the already cyclic amide 19c, since such behavior at increased temperatures is characteristic of
many active-methylene nitriles having the structural prerequisites for this.
The structural similarity with derivatives of 4-hydroxy-2-oxo-1,2-dihydro-quinoline-3-carboxylic acids
which display marked antimycobacterial properties in experiments in vitro [15], served as a theoretical basis for
studying the antitubercular activity of some of the compounds synthesized by us, particularly the hydrazides and
arylidenehydrazides of 1-R-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic acids 23 and 24. The
microbiological screening was carried out at the National Institute of Allergy and Infectious Diseases in the USA
within the framework of the TAACF (Tuberculosis Antimicrobial Acquisition & Coordinating Facility) program
in relation to Mycobacterium tuberculosis H37Rv ATCC 27294 using nutrient medium BACTEC 12B and the
radiometric system BACTEC 460 [16-19]. Analysis of the experimental data obtained showed that replacement
of the 4-hydroxy-2-oxo-1,2-dihydroquinoline nucleus by 2-hydroxy-4-imino-1,4-dihydroquinoline leads
practically to complete loss of antimycobacterial properties, and in the plan of searching for new agents useful
for combating tuberculosis, such a modification is not expedient.
As a result of investigations of the anti-inflammatory activity of amides 19a-l carried out on the
carrageenan paw edema model in white rats [20], it was established that in the character of the action on the
course of the inflammatory reaction they were like the 2-oxo-1,2-dihydro-4-quinolinylaminocarboxylic acids
described previously in [1]. Intraperitoneal injection of these substances aids reduction of the inflammation, but
only for 1-2 h, after which a drop in activity and even the appearance of an inflammatory effect follows.
EXPERIMENTAL
The mass spectra of the synthesized compounds were recorded on a Kratos MS 890A magnetic mass
spectrometer, ionizing by electron impact (EI) at 70eV with direct insertion of samples, heating the coupling for
direct insertion with a heating chamber at 250°C, or on a Hewlett Packard 5890/5972 instrument in total
scanning mode for the range 35-700 m/z, ionization by electron impact (EI) at 70 eV; chromatographic column
Hewlett Packard 5MS, length 25 m, internal diameter 0.2 mm, stationary phase was a polysiloxane film
1
(5% diphenylpolysiloxane, 95% dimethylpolysiloxane) of thickness 0.33 µm, carrier gas helium. The H NMR
spectra were obtained on a Bruker WM 250 (250 MHz) instrument in DMSO-d6, internal standard was TMS.
4-Chloro-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 2 were obtained by the known procedure of [21].
Anhydrous DMF for peptide synthesis from Fluka was used in the synthesis of amides 6, 7, and 15.
Octylamide
of
1-H-4-(1-Imidazolyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic
Acid
(6).
N,N'-Carbonyldiimidazole (1.78 g, 0.011 mol) was added to a solution of acid 2a (2.23 g, 0.01 mol) in
anhydrous DMF (20 ml) and, while protected from the moisture of the air by a CaCl2 tube, was maintained for
~1 h at 90°C until CO2 evolution ceased. Octylamine (1.65 ml, 0.01 mol) was added, the reaction mixture was
heated to 90°C and maintained at this temperature for 2 h, after which the reaction mixture was cooled, and
482

diluted with water. The solid amide 6 which separated was filtered off, washed with water, and dried.
Yield 3.11 g (85%); mp 193-195°C (ethanol). Mass spectrum, m/z (Irel, %): 366 (5) [M]+, 298 (17)
[M-imidazole]+, 280 (93), 237 (37) [M-NHC8H17]+, 223 (82), 209 (100) [M-NHC8H17-CO-H]+, 154 (51), 127
(48), 68 (84). 1H NMR spectrum, δ, ppm (J, Hz): 12.41 (1H, t, J = 6.1, NHCH2); 11.20 (1H, s, NH); 8.21 (1H, s,
H-2 imidazole); 8.16 (1H, d, J = 8.9, H-5 quinolone); 7.64 (1H, d, J = 2.0, H-5 imidazole); 7.50 (1H, t, J = 7.2,
H-7 quinolone); 7.20 (1H, d, J = 8.4, H-8 quinolone); 7.09 (1H, t, J = 7.2, H-6 quinolone); 7.04 (1H, d, J = 2.0,
H-4 imidazole); 2.92 (2H, q, J = 6.1, NCH2); 1.49 (2H, m, NCH2CH2); 1.12 [10H, m, NCH2CH2(CH2)5]; 0.82
(3H, t, J = 6.1, CH3). Found, %: C 68.70; H 7.37; N 15.41. C21H26N4O2. Calculated, %: C 68.83; H 7.15;
N 15.29.
Piperidide of 1-H-4-(1-Imidazolyl)-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid (7) was obtained
by the procedure of the previous experiment. Yield 80%; mp 262-264°C (ethanol). Mass spectrum, m/z, (Irel, %):
322 (11) [M]+, 255 (100) [M-imidazole]+, 237 (22), 225 (23), 68 (73). 1H NMR spectrum, δ, ppm (J, Hz): 11,79
(1H, s, CONH); 8.33 (1H, s, H-2 imidazole); 7.83 (1H, d, J = 8.0, H-5 quinolone); 7.73 (1H, d, J = 1.9, H-5
imidazole); 7.59 (1H, t, J = 7.1, H-7 quinolone); 7.36 (1H, d, J = 7.3, H-8 quinolone); 7.25 (1H, t, J = 7.1, H-6
quinolone); 7.07 (1H, d, J = 1.9, H-4 imidazole); 3.00 [4H, s, N(CH2)2]; 1.60 [6H, s, NCH2(CH2)3]. Found, %:
C 67.22; H 5.50; N 17.47. C18H18N4O2. Calculated, %: C 67.07; H 5.63; N 17.38.
4-Methoxyanilide of 4-Chloro-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid (11).
Thionyl chloride (1.4 ml, 0.02 mol) was added to a solution of 4-chloro-2-oxo-1-propyl-1,2-dihydroquinoline-3-
carboxylic acid (2b) (2.65 g, 0.01 mol) in CH2Cl2 (40 ml) and the mixture boiled under reflux until cessation of
HCl evolution (about 3 h). The reflux condenser was changed to a condenser set for distillation and the solvent
and excess of SOCl2 were distilled off. The acid chloride 10 obtained was dissolved in dry acetone (20 ml) and a
solution of p-anisidine (1.23 g, 0.01 mol) and triethylamine (1.4 ml, 0.01 mol) in acetone (50 ml) was added
dropwise with stirring and cooling. After 4-5 h the reaction mixture was diluted with water, the separated solid
anilide 11 was filtered off, washed with water, and dried. Yield 3.07 g (83%); mp 207-209°C (ethanol). Mass
35
spectrum, m/z (Irel, %): 370 (34) [M]+, 248 (100), 206 (44), 162 (17), values of m/z are given only for the Cl
isotope. 1H NMR spectrum, δ, ppm (J, Hz): 13.80 (1H, s, NH); 8.04 (1H, d, J = 8.1, H-5 quinolone); 7.78 (1H, t,
J = 7.6, H-7 quinolone); 7.71 (1H, d, J = 8.2, H-8 quinolone); 7.56 (2H, d, J = 8.0, J = 8.6, H-3, 5 anilide); 7.42
(1H, t, J = 7.6, H-6 quinolone); 6.90 (2H, d, J = 8.6, H-2, 6 anilide); 4.22 (2H, t, J = 7.1, NCH2); 3.71 (3H, s,
OCH3); 1.62 (2H, m, CH2CH3); 0.93 (3H, t, J = 7.1, CH2CH3). Found, %: C 64.60; H 5.28; N 7.43.
C20H19ClN2O3. Calculated, %: C 64.78; H 5.16; N 7.55.
Compounds 12 and 13 were obtained by an analogous procedure.
2-Diethylaminoethylamide of 4-Chloro-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid
1
(12). Yield 74%; mp 112-113°C (ethanol). H NMR spectrum, δ, ppm (J,Hz): 8.31 (1H, t, J = 6.1, NH); 8.00
(1H, d, J = 8.0, H-5); 7.75 (1H, t, J = 7.7, H-7); 7.66 (1H, d, J = 8.2, H-8); 7.39 (1H, t, J = 7.7, H-6); 4.20 (2H, t,
J = 7.1, NCH2CH2CH3); 3,26 (2H, q, J = 6.2, NHCH2); 2.58 [6H, m, N(CH2)3]; 1.64 (2H, m, NCH2CH2CH3);
0.95 [9H, t, J = 7.6, NCH2CH2CH3 + N(CH2CH3)2]. Found, %: C 62.82; H 7.43; N 11.40. C19H26ClN3O2.
Calculated, %: C 62.71; H 7.20; N 11.55.
Morpholide of 4-Chloro-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic Acid (13). Yield 80%;
mp 97-99°C (ethanol). Mass spectrum, m/z (Irel, %): 334 (4) [M]+, 299 (54), 248 (50), 221 (47), 86 (100), values
35
1
of m/z are given only for the Cl isotope. H NMR spectrum, δ, ppm (J, Hz): 8.02 (1H, d, J = 7.9, H-5); 7.78
(1H, t, J = 7.5, H-7); 7.70 (1H, d, J = 8.1, H-8); 7.43 (1H, t, J = 7.5, H-6); 4.23, (2H, t, J = 7.1, NCH2CH2CH3);
3.64 (8H, m, 4CH2 morpholine); 1.65 (2H, m, NCH2CH2CH3); 0.95 (3H, t, J = 7.1, NCH2CH2CH3). Found, %:
C 60.85; H 5.76; N 8.44. C17H19ClN2O3. Calculated, %: C 60.99; H 5.72; N 8.37.
4-Methoxyanilide of 2-Hydroxy-4-imino-1-propyl-1,4-dihydroquinoline-3-carboxylic Acid (15). A
solution of compound 11 (3.7 g, 0.01 mol) in anhydrous DMF (20 ml) was heated to 90-100°C and a stream of
dry ammonia was passed through for 3 h. The reaction mixture was cooled, and diluted with water. The
precipitated solid anilide 14 was filtered off, washed with water, and dried. Yield 3.07 g (83%); mp 143-145°C
1
(ethanol). H NMR spectrum, δ, ppm (J, Hz): 12.89 (1H, s, CONH); 10.72 (1H, s, OH); 8.25 (2H, d, J = 8.1,
483

H-5 quinolone + 4-NH); 7.73 (1H, t, J = 7.1, H-7 quinolone); 7.56 (3H, d, J = 8.5, H-8 quinolone + H-3,
5 anilide); 7.33 (1H, t, J = 7.1, H-6 quinolone); 6.88 (2H, d, J = 8.5, H-2, 6 anilide); 4.20 (2H, t, J = 7.0, NCH2);
3.74 (3H, s, OCH3); 1.65 (2H, m, CH2CH3); 0.96 (3H, t, J = 7.0, CH2CH3). Found, %: C 68.48; H 6.17; N 11.82.
C20H21N3O3. Calculated, %: C 68.36; H 6.02; N 11.96.
2-Diethylaminoethylamide of 4-Diethylamino-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic
Acid (17). Diethylamine (1.65 ml, 0.025 mol) was added to a solution of compound 12 (3.63 g, 0.01 mol) in
ethyl alcohol (30 ml) and the mixture was boiled under reflux for 5 h. The excess of diethylamine and the
solvent were distilled off under reduced pressure. Water (50 ml) was added to the residue, and then a solution of
Na2CO3 to pH 8. The solid amide 17 was filtered off, washed with water, and dried. Yield 3.76 g (94%);
1
mp 72-73°C (hexane–2-propanol). H NMR spectrum, δ, ppm (J, Hz): 7.95 (1H, t, J = 6.1, NH); 7.90 (1H, d,
J = 7.9, H-5); 7.58 (1H, t, J = 7.3, H-7); 7.49 (1H, d, J = 8.0, H-8); 7.23 (1H, t, J = 7.3, H-6); 4.21 (2H, t, J = 7.1,
NCH2CH2CH3); 3.23 (2H, q, J = 6.2, NHCH2); 3.16 [4H, q, J = 6.0, 4-N(CH2CH3)2]; 2.45 [6H, m,
CH2N(CH2CH3)2]; 1.61 (2H, m, NCH2CH2CH3); 0.90-1.06 (15H, m, 5CH3). Found, %: C 68.80; H 9.14;
N 13.83. C23H36N4O2. Calculated, %: C 68.97; H 9.06; N 13.99.
4-Amino-2-oxo-1,2-dihydroquinoline (21). Benzylamine (1.09 ml, 0.01 mol) was added to a solution
of 4-amino-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (20) (2.04 g, 0.01 mol) in DMF (20 ml) and the
mixture was boiled under reflux for 4 h. The reaction mixture was cooled, diluted with water, and acidified with
AcOH. The separated crystals were filtered off, washed with water, and dried. Yield 1.52 g (95%);
mp 299-300°C (aqueous ethanol). Mass spectrum, m/z (Irel, %): 160 (100) [M]+, 132 (38) [M-CO]+, 118 (12), 104
(24), 77 (17). 1H NMR spectrum, δ, ppm (J, Hz): 10.78 (1H, s, NH); 7.86 (1H, d, J = 8.0, H-5); 7.43 (1H, t, J =
7.8, H-7); 7.22 (1H, d, J = 8.3, H-8); 7.08 (1H, t, J = 7.8, H-6); 6.56 (2H, s, NH2); 5.44 (1H, s, H-3). Found, %:
C 67.63; H 5.22; N 17.36. C9H8N2O. Calculated, %: C 67.49; H 5.03; N 17.49.
Hydrazide of 1H-2-Hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic Acid (23a). Hydrazine
hydrate (0.011 mole: calculated on the actual content) was added to a solution of the ethyl ester of 4-amino-2-
oxo-1,2-dihydroquinoline-3-carboxylic acid (22, R = H) [22] (2.32 g, 0.01 mol) in ethyl alcohol (20 ml), and the
mixture boiled under reflux for 5 h. After cooling, the solid hydrazide 23a was filtered off, washed with water,
1
and dried. Yield 1.91 g (88%); mp 313-315°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 13.85 (1H, s, NH);
11.16 (1H, s, NH); 10.60 (1H, s, OH); 8.10 (2H, d, J = 8.1, H-5 + 4-NH); 7.57 (1H, t, J = 7.2, H-7); 7.30 (1H, d,
J = 8.3, H-8); 7.19 (1H, t, J = 7.2, H-6); 4.57 (2H, s, NH2). Found, %: C 55.15; H 4.53; N 25.80. C10H10N4O2.
Calculated, %: C 55.04; H 4.62; N 25.67.
Hydrazide of 1-Heptyl-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic Acid (23b) was
obtained analogously from the methyl ester of 4-amino-1-heptyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid
(22, R = C7H15) [6]. Yield 90%; mp 154-156°C (ethanol). 1H NMR spectrum, δ, ppm (J, Hz): 11.19 (1H, s, NH);
10.62 (1H, s, OH); 8.18 (2H, d, J = 8.0, H-5 + 4-NH); 7.69 (1H, t, J = 7.1, H-7); 7.47 (1H, d, J = 8.3, H-8); 7.26
(1H, t, J = 7.1, H-6); 4.48 (2H, s, NH2); 4.17 (2H, t, J = 7.2, NCH2); 1.54 (2H, q, J = 6.9, NHCH2CH2); 1.30 [8H,
m, (CH2)4CH3]; 0.84 (3H, t, J = 6.9, CH3). Found, %: C 64.41; H 7.52; N 17.84. C17H24N4O2. Calculated, %: C
64.53; H 7.65; N 17.71.
2-Fluorobenzylidenehydrazide of 1H-2-hydroxy-4-imino-1,1-dihydro-quinoline-3-carboxylic Acid
(24a). 2-Fluorobenzaldehyde (1.25 ml, 0.012 mol) was added to a solution of hydrazide 23a (2.18 g, 0.01 mol)
in DMF (20 ml), and the mixture boiled under reflux for 2 h. After cooling, the solid hydrazide 24a was filtered
off, washed with water, and dried. Yield 2.75 g (85%); mp >340°C (DMF). 1H NMR spectrum, δ, ppm (J, Hz):
13.92 (1H, s, NH); 11.37 (1H, s, NH); 10.60 (1H, s, OH); 8.40 (1H, s, CH=); 7.11-8.16 (9H, m, H arom. +
4-NH). Found, %: C 62.84; H 4.16; N 17.17. C17H13FN4O2. Calculated, %: C 62.96; H 4.04; N 17.28.
Compounds 24b-e were obtained by an analogous method.
3-Fluorobenzylidenehydrazide of 1H-2-Hydroxy-4-imino-1,4-dihydro-quinoline-3-carboxylic Acid
1
(24b). Yield 92%; mp >340°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 13.91 (1H, s, NH); 11.38 (1H, s,
NH); 10.64 (1H, s, OH); 8.33 (1H, s, CH=); 7.15-8.18 (9H, m, H arom. + 4-NH). Found, %: C 62.87; H 4.09; N
17.20. C17H13FN4O2. Calculated, %: C 62.96; H 4.04; N 17.28.
484

2-Pyridylmethylidenehydrazide of 1-Heptyl-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic
1
Acid (24c). Yield 90%; mp 236-238°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 13.87 (1H, s, NH); 10.55
(1H, s, OH); the proton of the 4-imino group is displayed in the spectrum as a broad singlet in the region of 8-9
ppm; 8.60 (1H, d, J = 5.0, H-6 Py); 8.26 (1H, s, CH=); 8.19 (1H, d, J = 8.3, H-5 quinoline); 7.95 (1H, d, J = 7.9,
H-3 Py); 7.87 (1H, t, J = 8.4, H-5 Py); 7.73 (1H, t, J = 7.9, H-7 quinoline); 7.54 (1H, d, J = 9.0, H-8 quinoline);
7.41 (1H, t, J = 7.5, H-4 Py); 7.32 (1H, t, J = 7.9, H-6 quinoline); 4.20 (2H, t, J = 7.1, NCH2); 1.55 (2H, q,
J = 7.0, NHCH2CH2); 1.31 [8H, m, (CH2)4CH3]; 0.80 (3H, t, J = 7.0, CH3). Found, %: C 68.22; H 6.63; N 17.34.
C23H27N5O2. Calculated, %: C 68.13; H 6.71; N 17.27.
3-Pyridylmethylidenehydrazide of 1-Heptyl-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic
1
Acid (24d). Yield 92%; mp 217-219°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 13.90 (1H, s, NH); 10.61
(1H, s, OH); the proton of the 4-imino group is displayed in the spectrum as a broad singlet in the 8-9 ppm
region; 8.83 (1H, s, H-2 Py); 8.57 (1H, d, J = 4.7, H-6 Py); 8.40 (1H, s, CH=); 8.23 (1H, d, J = 8.3, H-5
quinoline); 8.09 (1H, d, J = 7.9, H-4 Py); 7.71 (1H, t, J = 7.9, H-7 quinoline); 7.53 (1H, d, J = 8.3, H-8
quinoline); 7.46 (1H, t, J = 6.1, H-5 Py); 7.31 (1H, t, J = 7.9, H-6 quinoline); 4.18 (2H, t, J = 7.1, NCH2); 1.53
(2H, q, J = 7.1, NHCH2CH2); 1.30 [8H, m, (CH2)4CH3]; 0.81 (3H, t, J = 7.1, CH3). Found, %: C 68.05; H 6.66;
N 17.38. C23H27N5O2. Calculated, %: C 68.13; H 6.71; N 17.27.
4-Pyridylmethylidenehydrazide of 1-Heptyl-2-hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic
1
Acid (24e). Yield 95%; mp 224-226°C (DMF). H NMR spectrum, δ, ppm (J, Hz): 14.00 (1H, s, NH); 10.63
(1H, s, OH); the proton of the 4-imino group is displayed in the spectrum as a broad singlet in the 8-9 ppm
region; 8.61 (2H, d, J = 5.4, H-2, 6 Py); 8.35 (1H, s, CH=); 8.24 (1H, d, J = 7.9, H-5 quinoline); 7.72 (1H, t,
J = 6.8, H-7 quinoline); 7.63 (2H, d, J = 5.4, H-3, 5 Py); 7.52 (1H, d, J = 8.6, H-8 quinoline); 7.30 (1H, t,
J = 6.8, H-6 quinoline); 4.17 (2H, t, J = 7.1, NCH2); 1.57 (2H, q, J = 7.1, NHCH2CH2); 1.33 [8H, m,
(CH2)4CH3]; 0.80 (3H, t, J = 7.1, CH3). Found, %: C 68.27; H 6.77; N 17.38. C23H27N5O2. Calculated, %:
C 68.13; H 6.7; N 17.27.
iso-Butylamide of 2-Cyanomalonanilic Acid (26a). iso-Butylamine (1.1 ml, 0.011 mol) was added to a
solution of the ethyl ester of 2-cyanomalonanilic acid (25) [22] (2.32 g, 0.01 mol) in absolute methyl alcohol
(20 ml) and the mixture was boiled under reflux for 4 h. The reaction mixture was then poured into water
(100 ml), and acidified with HCl to pH 4. The solid amide 26a was filtered off, washed with water, and dried.
Yield 2.12 g (82%). Colorless crystals of mp 110-112°C (ethanol). Mass spectrum, m/z (Irel, %): 259 (11) [M]+,
216 (25) [M-C3H7-i]+, 187 (60) [M-C4H9NH]+, 145 (36), 118 (100), 72 (40). 1H NMR spectrum, δ, ppm (J, Hz):
10.50 (1H, s, NH-Ar); 8.12 (1H, t, J = 5.1, NH-Alk); 7.21-7.86 (4H, m, H arom.); 3.40 (2H, s, COCH2CO); 2.90
(2H, t, J = 5.8, NCH2); 1.69 (1H, m, CH); 0.92 (6H, d, J = 6.4, 2CH3). Found, %: C 64.71; H 6.73; N 16.33.
C14H17N3O2. Calculated, %: C 64.85; H 6.61; N 16.20.
Benzylamide of 2-Cyanomalonanilic Acid (26b) was obtained analogously. Yield 87%. Colorless
1
crystals of mp 117-119°C (ethanol). H NMR spectrum, δ, ppm (J, Hz); 10.49 (1H, s, NH-Ar); 8.64 (1H, t,
J = 5.4, NH-Alk); 7.23-7.90 (9H, m, H arom.); 4.32 (2H, d, J = 6.1, NCH2); 3.45 (2H, s, COCH2CO). Found, %:
C 69.74; H 5.22; N 14.21. C17H15N3O2. Calculated, %: C 69.61; H 5.15; N 14.33.
iso-Butylamide of 1-H-2-Hydroxy-4-imino-1,4-dihydroquinoline-3-carboxylic Acid (19c). A.
iso-Butylamine (1.1 ml, 0.011 mol) was added to a solution of compound 25 (2.32 g, 0.01 mol) in absolute
methyl alcohol (20 ml) and the mixture was boiled under reflux for 4 h. A solution of sodium methylate [from
metallic sodium (0.23 g, 0.01 mol) and absolute methyl alcohol (10 ml)] was added, the reaction mixture was
boiled for 1 h on a water bath, after which the heating was stopped, and the mixture left for 7-8 h at room
temperature, The reaction mixture was diluted with water, and acidified with dilute acetic acid. The solid amide
19c was filtered off, washed with water, and dried. The product was crystallized from DMF. Mass spectrum, m/z
(Irel, %): 259 (9) [M]+, 216 (57) [M-C3H7-i]+, 187 (100) [M-C4H9NH]+, 145 (12), 118 (33), 72 (8).
Amides 19a-k (Table 1) were obtained analogously.
485

B. iso-Butylamine (2.2 ml, 0.22 mol) was added to a solution of compound 25 (2.32 g, 0.01 mol) in
absolute methyl alcohol (20 ml) and the mixture boiled for 15 h. The reaction mixture was diluted with water
and acidified with dilute acetic acid. The solid which separated was filtered off, dried, and then treated with
boiling ethanol (30 ml) and filtered hot. Amide 19c (0.72 g, 28%) was obtained on the filter. The acyclic amide
26a was isolated from the filtrate by dilution with water.
A mixing test of samples of amide 19c obtained by the various methods gave no depression of melting
point. Their 1H NMR spectra were identical.
Equimolar quantities of ester 25 and dimethylaminoethylamine were used when obtaining
dimethylaminoethylamide 19l. After completion of amidation and cyclization the reaction mixture was cooled
without acidification, the precipitated crystals of amide 19l were filtered off, washed with water, and dried.
Propylamide of 1-H-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (27). After dilution
with water (see example of obtaining amide 19c, method A) the reaction mixture was acidified with dilute HCl
to pH 3-4 and left at room temperature for 4-5 h. The solid amide 27, which precipitated, was filtered off,
washed with water, and dried. Yield 89%; mp 209-210°C (DMF). 1H NMR spectrum, δ, ppm (J, Hz): 17.37 (1H,
s, OH); 11.84 (1H, s, NH); 10.35 (1H, t, J = 5.4, NH-Alk); 7.97 (1H, d, J = 7.9, H-5); 7.70 (1H, t, J = 7.2, H-7);
7.40 (1H, d, J = 8.0, H-8); 7.31 (1H, t, J = 7.2, H-6); 3.37 (2H, q, J = 6.5, NHCH2); 1.62 (2H, m,
NCH2CH2CH3); 0.93 (3H, t, J = 6.8, CH3).
A mixing test with a sample of amide 27 obtained by amidation of the ethyl ester of 1-H-4-hydroxy-2-
oxo-1,2-dihydroquinoline-3-carboxylic acid with propylamine [13] gave no depression of melting point. The
1H NMR spectra of these compounds were identical.
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