4-Hydroxy-2-quinolones 166. Synthesis, isomerism, and antitubercular activity of 3-arylaminomethylene-quinoline-2,4-(1H,3H)-diones

Article abstract of DOI:10.1007/s10593-009-0356-x

Condensation of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes, thioglycolic acid (or methyl thioglycolate), and anilines does not lead to the synthesis of the corresponding thiazolidinylquinolones because the Schiff bases so formed exist exclusivel

Full text of DOI:10.1007/s10593-009-0356-x

Chemistry of Heterocyclic Compounds, Vol. 45, No. 7, 2009
4-HYDROXY-2-QUINOLONES
166*. SYNTHESIS, ISOMERISM,
AND ANTITUBERCULAR ACTIVITY
OF 3-ARYLAMINOMETHYLENE-
QUINOLINE-2,4-(1H,3H)-DIONES
I. V. Ukrainets1**, Liu Yangyang1, A. A. Tkach1, and A. V. Turov2
Condensation of 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes, thioglycolic acid (or methyl
thioglycolate), and anilines does not lead to the synthesis of the corresponding thiazolidinylquinolones
1
because the Schiff bases so formed exist exclusively in a form inert to enamine thioglycolates. H NMR
spectroscopy showed that the main components of the isolated 3-arylaminomethylenequinoline-
2,4-(1H,3H)-diones are E-isomers. The results of a study of the antitubercular properties of the
compounds obtained are presented.
Keywords: anilines, 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes, enamines, Schiff bases,
isomerism, antitubercular activity, tautomerism.
The search for novel biologically active compounds with antitubercular activity has gained special
urgency in the last 10-15 years. The reason for increased attention directed towards this problem has been the
widespread appearance and global distribution of resistant strains of the tubercular mycobacterium which are
stable to current medicinal preparations.
An interest in thiazolidin-4-ones has not diminished following the isolation in a pure state, structural
identification [2], and then the synthesis [3] of actithiazic acid as an antibiotic having highly specific activity
towards the mycobacterium. As a result, compounds based on this heterocycle were produced for the fight
against pathogens of different mycobacterial infections [4-6] including tuberculosis [7, 8].
4-Hydroxyquinol-2-ones posses a high potential for antimycobacterial properties hence their
combination with thiazolidin-4-ones in a single molecular system seems quite interesting and promising.
Thiazolidin-4-ones are obtained by a well known reaction of thioglycolic acid [9] or its esters [10] with
Schiff bases. Often more simple in use is a three component condensation of an aldehyde, thioglycolic acid
(alkyl thioglycolate) and primary amine [11]. The yields of the final products vary widely and this is fully
_______
* For Communication 165 see [1].
** To whom correspondence should be addressed, e-mail: uiv@kharkov.ua.
1National University of Pharmacy, Kharkiv 61002, Ukraine.
2Taras Shevchenko National University, Kiev 01033, Ukraine; e-mail: nmrlab@univ.kiev.ua.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1015-1022, July, 2009. Original
article submitted June 16, 2008.
802
0009-3122/09/4507-0802©2009 Springer Science+Business Media, Inc.

explained by structural features of the starting components. However, the corresponding thiazolidinylquinolones 2
could not be prepared at all from the 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes 1.
OH
O
H
N
R
1
O
1. H2N–Ar
2. HSCH2COOMe
R1
OH
OH
S
O
N
N
N
R
O
N
R
O
R1
3a–c
2
R1
R1
O
HN
O
O
H
O
H
N
H
N
R
N
R
4a–c (E-isomer)
4a–c (Z-isomer)
3, 4 a R = Me, R1 = OEt, b R = C5H11, R1 = F, c R = C5H11, R1 = Cl
The reason for this is evidently the somewhat unusual structure of the light-yellow substances obtained
1
in this way (Table 1). The H NMR spectra of these compounds (Table 2) clearly confirm the presence in their
structure of just quinolone and para-substituted aryl fragments. In addition, doubling of some signals (in the
spectra recorded with a working frequency of 400 MHz almost all of the signals are doubled) indicates that the
investigated compounds in DMSO solution form a mixture of two isomers (or tautomers) in the ratio 2:1 or 3:2.
The reaction products of the aldehydes 1 with anilines are undoubtedly Schiff bases. Hence it becomes clear that
we are dealing with a prototropic tautomerism typical of compounds with a carbon-nitrogen double bond, i.e.
azomethine–azomethine or indeed azomethine–enamine 3↔4 while each of these tautomers can exist further as
two geometrical Z- and E-isomers [12].
To resolve this question we carried out an intensive study of one of the synthesized compounds by the
1
1H NMR method. For this para-ethoxy derivative there were also measured 13C NMR spectra and H–13C
heteronuclear correlation spectra through one (HMQC) and through 2-3 (HMBC) chemical bonds. It was found
that doubling of the majority of the signals (see Experimental) also occurred in the carbon spectrum. Their
assignment in the main component of the isomeric mixture can be made via the heteronuclear correlation
spectra. The coordinates of the cross peaks found in the 2D HMQC and HMBC spectra are given in Table 3 for
the main component of the para-ethoxy derivative studied.
803

TABLE 1. Characteristics of the 3-Arylaminomethylenequinoline-
2,4-(1H,3H)-diones 4a-c
Antitubercular activity.
Inhibition of the growth
of M tuberculosis, %
Found, %
Calculated, %
H
——————
Com-
pound
Empirical
formula
mp, Yield,
°С
%
C
N
4a
4b
4c
C19H18N2O3
70.67 5.54
70.79 5.63
8.77 129-131 91
8.69
8.09 122-124 82
7.95
7.52 117-119 84
7.59
29
46
20
C21H21FN2O2 71.68 6.13
71.57 6.01
C21H21ClN2O2 68.51 5.88
68.38 5.74
TABLE 2. 1H NMR Spectra of Enamines 4a-c
Com-
pound
Chemical shifts, δ, ppm (200 MHz, DMSO-d6), (J, Hz)
4a
13.85 (0.63H, d, J = 13.6, NH Е-isomer); 12.73 (0.32H, d, J = 14.0, NH Z-isomer);
8.81 (0.66H, d, J = 13.6, =CH Е-isomer); 8.78 (0.34H, d, J = 14.0, =CH Z-isomer);
8.06 (1Н, d, J = 8.1, Н-5); 7.64 (1Н, td, J = 8.0 and J = 2.3, Н-7); 7.48 (2Н, m, Н-2',6');
7.36 (1Н, d, J = 8.4, Н-8); 7.19 (1Н, t, J = 7.6, Н-6); 6.96 (2Н, d, J = 8.8, Н-3',5');
4.03 (2Н, q, J = 7.2, ОСН2); 3.50 (1Н, s, NСН3 Z-isomer); 3.48 (2Н, s, NСН3 Е-isomer);
1.31 (3Н, t, J = 7.2, ОСН2СН3)
4b
4c
13.80 (0.59H, d, J = 13.5, NH Е-isomer); 12.72 (0.36H, d, J = 14.0, NH Z-isomer);
8.86 (0.61H, d, J = 13.5, =CH Е-isomer); 8.81 (0.39H, d, J = 14.0, =CH Z-isomer);
8.08 (1Н, dd, J = 8.0 and J = 1.5, Н-5); 7.71–7.59 (3Н, m, Н-7,2',6');
7.45-7.14 (4Н, m, Н-6,8,3',5'); 4.11 (2Н, t, J = 7.2, NСН2);
1.59 (2H, q, J = 6.9, NCH2CH2); 1.33 (4Н, m, (СН2)2СН3); 0.86 (3Н, t, J = 6.7, СН3)
13.74 (0.57H, d, J = 13.4, NH Е-isomer); 12.70 (0.38H, d, J = 13.8, NH Z-isomer);
8.89 (0.6H, d, J = 13.4, =CH Е-isomer); 8.83 (0.4H, d, J = 13.8, =CH Z-isomer);
8.08 (1Н, dd, J = 8.1 and J = 1.5, Н-5); 7.71–7.60 (3Н, m, Н-7,2',6');
7.49 (2Н, d, J = 9.0, Н-3',5'); 7.38 (1Н, d, J = 8.5, Н-8); 7.20 (1Н, t, J = 7.6, Н-6);
4.11 (2Н, t, J = 7.1, NСН2); 1.58 (2H, q, J = 6.7, NCH2CH2); 1.34 (4Н, m, (СН2)2СН3);
0.86 (3Н, t, J = 6.6, СН3)
1
TABLE 3. Full List of Heteronuclear H–13C Correlations found for the
Main Component of Enamine 4a
Cross peak positions in the 13C measurements
1Н signal, δ, ppm
НМQC
HMBC
13.84
8.78
8.05
7.63
7.48
7.35
7.19
6.97
4.00
3.47
1.30
—
154.2
126.4
134.5
120.9
115.8
122.3
116.1
64.1
154.2; 132.0; 120.9; 102.9
180.6; 163.3; 132.0; 121.4; 102.9
180.6; 142.7; 134.5
142.7; 126.4; 115.8
157.9; 132.0; 116.1
121.4; 122.3
134.5; 126.4; 121.4; 115.8
157.9; 132.0
157.9; 15.3
29.3
163.3; 142.7; 115.8
64.1
15.3
804

Assignment of the signals of the protonated carbon atoms can be made from their correlation with
proton signals in the HMQC spectrum and those for the quaternary carbon atoms via the existence of cross peaks
1
in the HMBC spectrum. H and 13C NMR signal assignments are given in the scheme below where the arrows
indicate the most significant HMBC correlations which served as the basis for carbon signal assignment. 2D
COSY and NOESY spectra were used for assignment of the proton signals.
H
1.30
H
157.9
O
H
64.1
8.78
H
8.05
H
15.3
O
7.19
H
126.4
116.1
154.2
H
180.6
122.3
134.5
H
4.00
132.0
N
H
120.9
121.4 102.9
142.7
6.97
163.3
H
13.84
H
7.48
H
N
O
115.8
7.63
29.3
H
7.35
H
H
H
3.47
For an understanding of the isomerization in this compound the most important feature is the correlation
of the NH proton signal with a chemical shift of 13.84 ppm with the carbon signal at 120.9 ppm which
corresponds to the C-2' atom of the para-ethoxyphenyl substituent. The presence of this correlation shows that
there are not more than three chemical bonds between these magnetic nuclei and this is possible only through
localization of the active proton on the nitrogen atom. It was interesting that an analogous correlation was found
in the minor component of the isomeric mixture. In this component the signal for the NH proton is observed at
12.72 ppm. The HMBC spectrum showed a correlation with the carbon signal at 120.8 ppm which corresponded
to the C-2' atom in this isomer.
Hence the investigation carried out shows that the compound studied is the enamine 4a which exists as a
Z- and E-mixture of isomers relative to the exocyclic double bond. This conclusion was also supported by the 1H
NMR spectra measured at increased temperature. Hence heating a solution of enamine 4a to 100ºC did not cause
a signal coalescence but, in fact, just to their broadening. This suggests that there is a high energetic barrier
between the isomers as is typical of Z- and E-isomers.
This is very interesting but the question as to which of these corresponds to the main isomer remains
1
open since direct confirmatory evidence could not be obtained. An attempt to determine the H–13C spin-spin
coupling for the carbonyl carbon atoms and the enamine =CH proton and so the answer to the question posed
also was unsuccessful because the values sought were hidden by other constants. In principle, such structural
problems can be resolved by comparison of intramolecular hydrogen bonds between the NH group proton and
carbonyl oxygen atoms in one isomer or the other. In this way, the signal placed at lower field must undergo
stronger hydrogen bonding. However, proof will not be straight forward in all cases.
With this consideration we selected another route to resolve the problem set, bearing in mind the good
solubility of enamine 4a in chloroform and also the presence such functional groups as NH and C=O in its
structure. In general these groups can coordinate efficiently with lanthanide shift reagents (LSR) leading to
1
induced signal shifts which are useful for structural assignments in the H NMR spectra. The addition of
1,1,1,2,2,3,3-heptafluoro-7,7-dimethyloctane-4,6-dionate europium (III) [Eu(FOD3)] to a solution of the
805

enamine 4a in deuterochloroform caused a low field lanthanide induced shift (LIS) for several signals. These
shifts were calculated as the difference between the chemical shifts of the corresponding sample signals with and
without the LSR.
The formulae below for the main and minor isomers of enamine 4a show these LIS values next to the
corresponding protons. As is seen in the data given, the main component of the mixture shows maximal shifts
for the =CH and NCH3 group signals and in the minor component these are found for the =CH and aromatic
quinolone H-5 proton. The closer the proton occurs to the coordination center of the molecule with the LSR the
greater the LIS value proves to be. For this reason the effects seen are best explained by the stipulation that LSR
coordination occurs at the carbonyl group of the heterocyclic ring which is sterically most accessible in the
given isomer. Hence the observed LIS unambiguously shows that the main component of the isomeric mixture
of enamine 4a has the E-configuration.
OEt
Eu(FOD)3
0.09
H
0.12
H
0.86
0.45
OEt
O
H
H
O
N
N
O
N
H
H
0.35
0.15
O
N
Eu(FOD)3
Me
Me
0.05
0.40
Z-4a (minor)
E-4a (main component)
The structure of the Schiff base obtained by reaction of 3-acyl-4-hydroxy-2-oxo-1,2-dihydroquinolines
with N-nucleophiles has repeatedly attracted the attention of investigators. As a result they have been reported as
a mixture of two tautomers azomethine 3 and enamine 4 with a predominance of the latter [13-16]. The
experiments we have carried out show a somewhat different picture. The 3-arylaminomethylenequinoline-
2,4-(1H,3H)-diones in DMSO solution exist only as the E- and Z-forms of just the enamine tautomeric form 4.
Confirmation of this conclusion comes from both the spectroscopic investigation and also from the fact that
these compounds do not take part in a reaction with methyl thioglycolate. According to a well studied
mechanism for the formation of thiazolidines [17] the first stage of such reactions is the addition of thioglycolate
esters at the carbon nitrogen double bond of the Schiff bases with initial formation of a C–S bond followed by
closing of a thiazolidine ring. In other words, should there be an equilibrium mixture, the presence of even a
small amount of azomethine 3 would certainly allow the reaction with methyl thioglycolate to occur
successfully. Enamines 4 are known not to react with thioglycolates since they do not have the required C=N
bond in their structure.
The antitubercular activity of the enamines 4a-c was studied in vitro by a radiometric method [18, 19].
The data in Table 1 shows that at a concentration of 6.25 µg/ml the compounds studied unfortunately show little
activity towards Mycobacterium tuberculosis H37Rv ATCC 27294. However, even in such a small series of
compounds the effect of a substituent in the aniline part of the molecule of enamines 4a-c on the biological
activity is clearly seen.
EXPERIMENTAL
1H NMR spectra for the compounds synthesized were recorded on a Varian Mercury VX-200 (200
13
1
MHz) instrument.1H and C NMR spectra for the enamine 4a, H COSY NMR 2D spectroscopic experiments,
806

homonuclear Overhauser NOESY-2D, and also heteronuclear HMQC and HMBC experiments were recorded on
1
a Varian Mercury-400 spectrometer (400 and 100 MHz for H and 13C respectively). All 2D experiments were
carried out with gradient selection of useful signals. Mixing times in the pulse sequences corresponded to 1JCH
=
2-3
140 and
J
CH
= 8 Hz. The number of increments in the COSY and HMQC spectra was 128 and 400 in the
HMBC spectra. The mixing time in the NOESY-2D experiment was 500 ms. The solvent was DMSO-d6 or
CDCl3 with TMS as internal standard. The synthesis of the starting 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-
3-carbaldehydes 1 was carried out according to method reported in [1].
3-(4-Ethoxyphenylaminomethylene)-1-methyl-quinoline-2,4-(1H,3H)-dione (4a). para-Phenetidine
(p-ethoxyaniline) (1.37 g, 0.01 mol) and methyl thioglycolate (0.89 ml, 0.01 mol) were added to a solution of
1-methyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1a, 2.03 g, 0.01 mol) in dry xylene (15 ml)
and refluxed for 20 h. The reaction mixture was cooled, diluted with hexane, and left for several hours in a
freezer cabinet. The light-yellow precipitate of enamine 4a was filtered off, washed with hexane, and dried.
1
Yield 2.96 g (92%). Crystallized from a mixture of 2-propanol and hexane. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm (J, Hz): 13.84 (0.65H, d, J = 13.6, NH E-isomer); 12.72 (0.29H, d, J = 14.0, NH Z-isomer);
8.78 (0.67H, d, J = 13.6, =CH E-isomer); 8.74 (0.33H, d, J = 14.0, =CH Z-isomer); 8.05 (1H, m, H-5); 7.63 (1H,
m, H-7); 7.48 (2H, m, H-2',6'); 7.38 (0.33H, d, J = 8.4, H-8 Z-isomer); 7.35 (0.6H, d, J = 8.4, H-8 E-isomer);
7.19 (1H, m, H-6); 6.97 (2H, m, H-3',5'); 4.00 (2H, q, J = 7.2, OCH2); 3.49 (1H, s, NCH3 Z-isomer); 3.47 (2H, s,
NCH3, E-isomer); 1.30 (3H, t, J = 7.2, OCH2CH3). 1H NMR spectrum (400 MHz, CDCl3), δ, ppm (J, Hz): 14.09
(0.68H, d, J = 11.6, NH E-isomer); 12.90 (0.22H, d, J = 12.4, NH Z-isomer); 8.96 (0.25H, d, J = 12.4, =CH
Z-isomer); 8.93 (0.75H, d, J = 11.6, =CH E-isomer); 8.29 (0.25H, d, J = 8.0, H-5 Z-isomer); 8.21 (0.75H, d,
J = 8.0, H-5 E-isomer); 7.59 (1H, m, H-7); 7.30-7.18 (4H, m, H-6,8,2',6'); 6.93 (2H, d, J = 8.8, H-3',5'); 4.03
1
(2H, q, J = 6.8, OCH2); 3.59 (3H, s, NCH3); 1.42 (3H, t, J = 6.8, OCH2CH3). H NMR spectrum (400 MHz,
CDCl3 + Eu(FOD)3), δ, ppm (J, Hz): 14.18 (0.49H, d, J = 10.2, NH E-isomer); 13.05 (0.19H, d, J = 11.5, NH
Z-isomer); 9.41 (0.25H, br. s, =CH, Z-isomer); 9.28 (0.75H, br. s, =CH E-isomer); 9.15 (0.25H, br. s, H-5
Z-isomer); 8.33 (0.75H, d, J = 7.2, H-5 E-isomer); 7.63 (1H, m, H-7); 7.40-7.24 (4H, m, H-6,8,2',6'); 6.93 (2H,
d, J = 8.0, H-3',5'); 4.05 (2H, q, J = 6.4, OCH2); 3.99 (2H, s, NCH3 E-isomer); 3.64 (1H, s, NCH3 Z-isomer);
1.43 (3H, t, J = 6.4, OCH2CH3). 13C NMR spectrum (DMSO-d6), δ, ppm: 180.64 (C-4 E); 178.34 (C-4 Z);
165.32 (C-2 Z); 163.31 (C-2 E); 157.88 (C-4' E); 157.69 (C-4' Z); 154.18 (=CHNH E); 152.68 (=CHNH Z);
142.65 (C-8a E); 142.34 (C-8a Z); 134.54 (C-7); 132.22 (C-1' Z); 132.03 (C-1' E); 126.93 (C-5 Z); 126.44 (C-5
E); 122.52 (C-6 Z); 122.27 (C-6 E); 122.25 (C-4a Z); 121.37 (C-4a E); 120.88 (C-2',6' E); 120.80 (C-2',6' Z);
116.11 (C-3',5' E); 116.07 (C-3',5' Z); 115.93 (C-8 Z); 115.78 (C-8 E); 102.91 (C-3 E); 102.26 (C-3 Z); 64.08
(OCH2); 29.30 (NCH3 E); 28.61 (NCH3 Z); 15.28 (OCH2CH3).
Enamines 4b,c (Table 1) were obtained by a similar method. Previously separated enamine 4a in the
pure state, in refluxing xylene, also does not react with either thioglycolic acid or its methyl ester.
The authors thank the US National Institute for Allergic and Infectious Diseases for studying the
antitubercular properties of the synthesized compounds within the scope of the TAACF program (Tuberculosis
Antimicrobial Acquisition and Coordination Facility) (contract No. 01-AI-45246).
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