4-hydroxy-2-quinolones 165*. 1-R-4-hydroxy-2-oxo-1,2-dihydro- quinoline-3-carbaldehydes and their thiosemicarbazones. Synthesis, structure, and biological properties

Article abstract of DOI:10.1007/s10593-009-0327-2

Two variants are discussed of the synthesis of 1-R-4-hydroxy-2-oxo-1,2- dihydroquinoline-3-carboxylic acid β-N-tosylhydrazides which undergo a McFayden-Stevens reaction to give 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3- carbaldehydes in high yields. It was shown that the thiosemicarbazones prepared from them exist in the solid state exclusively in the syn-form while in solution a hydrazone ? enhydrazine tautomerism is observed. The results of a study of the antitubercular activity of the synthesized compounds are reported.

Full text of DOI:10.1007/s10593-009-0327-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 6, 2009
4-HYDROXY-2-QUINOLONES
165*. 1-R-4-HYDROXY-2-OXO-1,2-DIHYDRO-
QUINOLINE-3-CARBALDEHYDES AND THEIR
THIOSEMICARBAZONES. SYNTHESIS,
STRUCTURE, AND BIOLOGICAL PROPERTIES
I. V. Ukrainets1**, Liu Yangyang1, A. A. Tkach1, O. V. Gorokhova1, and A. V. Turov2
Two variants are discussed of the synthesis of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic
acid β-N-tosylhydrazides which undergo a McFayden-Stevens reaction to give 1-R-4-hydroxy-2-oxo-
1,2-dihydroquinoline-3-carbaldehydes in high yields. It was shown that the thiosemicarbazones
prepared from them exist in the solid state exclusively in the syn-form while in solution a hydrazone ↔
enhydrazine tautomerism is observed. The results of a study of the antitubercular activity of the
synthesized compounds are reported.
Keywords: 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehydes, thiosemicarbazones, isomeri-
zation, antitubercular activity, X-ray structural analysis.
Thiosemicarbazones have a broad spectrum of pharmacological activities. Amongst this class of
substances there are found compounds with antiproliferative [2] and antiamebal [3] activity. They are effective
in the fight against malaria [4], the herpes simplex virus [5], carcinoma of the prostate gland [6], hormone
dependent breast cancer [7], and other types of malignant neoplasms [8, 9]. However, the widest use of
thiosemicarbazones is actually found in the treatment of various microbial infections [10-16]. There is special
interest in their ability to inhibit the growth of the tubercular mycobacterium. Conditions of continuing
pandemic and the appearance of multiresistant strains of pathogen in this insidious illness serve as a reason for
the search for novel antimycobacterial agents in this series of compounds. The first antitubercular preparation in
the group discussed (p-acetamidobenzaldehyde thiosemicarbazone) has been used in medical practice for more
than 50 years under the trade name of thiacetazone (tibon) [17]. It shows clear bacteriostatic activity towards the
tubercular mycobacterium but, in view of its relatively high toxicity, it has limited use and is usually prescribed
in combination with other preparations for improving their therapeutic effect and to avoid the
_______
* For Communication 164 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. 6, pp. 883-894, June, 2009. Original
article submitted June 16, 2008.
0009-3122/09/4506-0705©2009 Springer Science+Business Media, Inc.
705

possible appearance of resistant forms [17, 18]. Chemical modification of the aldehyde part of the thiacetazone
molecule within broad limits has been used by many synthetic chemists in a search for improved analogs of this
preparation [18-22]. This was also the basic position in our work related to the synthesis and study of the
antitubercular properties of the 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carbaldehyde thiosemicarbazones
1a-f.
OH
O
OH
O
NH2
.
A. H2NNH2 H2O
OEt
N
H
N
R
O
N
R
O
5a–f
4a–f
B. H2NNH–Ts
Ts–Cl
OH
O
OH
N
O
O
HOCH2CH2OH,
160°С, Na2CO3
H
N
N
Ts
H
H
N
O
R
R
2a–f
3a–f
H2NNHC(=S)NH2
H2N
S
H2N
N
S
H2N
HN
S
H
HN
NH
H
NH
N
O
OH
O
H
N
R
O
N
R
O
N
R
O
1a–f
6a–f
7a–f
1–6 a R = Me, b R = Et, c R = Pr, d R = Bu, e R = C5H11, f R = C6H13
The obvious route for the synthesis of the starting 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-
3-carbaldehydes (4-hydroxy-3-formylcarbostyrils) 2a-f by Vilsmeier formylation of 4-hydroxy-2-quinolones is
not successful [23, 24]. Hence, for a long time, they were prepared by the Reimer-Tiemann method although the
yields of the target compounds did not exceed 40% [25]. More efficientl was basic hydrolysis of
3-arylaminomethylenequinoline-2,4-(1H,3H)-diones [32] which, in turn, were prepared also by reaction of
4-hydroxy-2-quinolones with triethylorthoformate and anilines [23, 26] or with formamidines [26, 27].
However, good yields were only basically achieved in this case in the final stage.
With this in mind we undertook an attempt to synthesize aldehydes 2a-f via the well known McFayden-
Stevens method from the 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid β-N-tosylhdrazides
3a-f. Decomposition of the tosylhydrazides 3a-f using sodium carbonate in ethylene glycol occurs readily and
the aldehydes 2a-f can be isolated in very good yields (87-96%). As is known [28], hydrazinolysis of the
706

TABLE 1.Characteristics of the Compounds Synthesized 1a-f and 3a-f
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С (solvent
Yield*, %
(method)
for crystallization)
C
H
N
1a
C12H12N4O2S
52.31
52.16
4.49
4.38
20.14
20.28
269-271 (DMF)
83
53.90
53.78
55.18
55.25
56.74
56.59
57.70
57.81
59.08
58.94
55.71
55.81
56.92
56.85
57.73
57.82
4.95
4.86
5.36
5.30
5.83
5.70
6.15
6.06
6.52
6.40
4.34
4.42
4.70
4.77
5.16
5.09
19.42
19.30
18.34
18.41
17.71
17.60
16.94
16.85
16.09
16.17
10.77
10.85
10.35
10.47
10.19
10.11
233-235(DMF)
238-240 (butanol)
222-224 (ethanol)
218-220 (ethanol)
225-227 (ethanol)
196-198
80
85
1b
1c
1d
1e
1f
C13H14N4O2S
C14H16N4O2S
C15H18N4O2S
C16H20N4O2S
C17H22N4O2S
C18H17N3O5S
C19H19N3O5S
C20H21N3O5S
82
76
77
96 (A)
92 (A)
3a
3b
3c
178-180
185-187
95 (A)
53 (B)
58.60
58.73
59.48
59.58
60.45
60.38
5.31
5.40
5.56
5.68
6.07
5.95
9.67
9.78
9.39
9.47
9.26
9.18
181-183
174-176
153-155
90 (A)
88 (A)
93 (A)
3d
3e
3f
C21H23N3O5S
C22H25N3O5S
C23H27N3O5S
_______
* Yields of thiosemicarbazones 1a-f calculated from the corresponding
β-N-tosylhydrazides 3a-f.
esters 4 occurs almost quantitatively. The hydrazides 5 formed can then be acylated very readily by tosyl
chloride (method A) and this allows us to recommend the overall synthetic scheme on a preparative scale.
In principle, the preparation of the intermediate tosylhydrazides 3a-f can be achieved in a single stage by
direct reaction of esters 4 with p-toluenesulfonylhydrazide (method B). However, as shown in the analogous
reaction for benzoic acid hydrazides [29], a temperature of around 140-160ºC is needed at which the
p-toluenesulfonylhydrazide undergoes marked decomposition. As a result, the yields of tosylhydrazides 3a-f by
this method are comparatively low while under milder conditions (e.g. refluxing in ethanol for 20 h) the esters 4
do not react with p-toluenesulfonylhydrazide at all.
Condensation of aldehydes 2a-f with thiosemicarbazide occurs in refluxing ethanol without the addition
of any kind of catalyst and gives the thiosemicarbazones 1a-f which are light-yellow, crystalline materials
(Table 1).
Because of the relatively rigid carbon–nitrogen double bond in the thiosemicarbazones 1a-f they can
potentially exist as the two geometrical syn- and anti-isomeric forms 1↔6 which are of interest for structural
investigation. According to our X-ray data (see Fig. 1 and Tables 2 and 3) the independent part of the unit cell of
the thiosemicarbazone 1c actually exists as two molecules (A and B), differentiated by certain geometrical
parameters. However, it turned out that this was in no way connected with the theoretically possible syn↔anti
isomerism in the compound studied but the difference is most significantly seen in the structure of the 1-N-
propyl substituent. Hence in molecule A all of the non-hydrogen atoms with the exclusion of atoms C(13) and
C(14) lie in a single plane to within 0.02 Å. It is likely that such a structure is stabilized by an intramolecular
hydrogen bond O(2a)–H(2Oa)···N(2a) (H···N 1.88 Å, O–H···N 137º). In the molecule B the plane of the
707

thiosemicarbazone substituent at atom C(8) is somewhat noncoplanar with that of the quinolone fragment
(torsional angle C(7)–C(8)–C(10)–N(2) 8.3(4)º despite the formation of the same hydrogen bond as in molecule
A: O(2b)–H(2Ob)···N(2b) (H···N 1.94 Å, O–H···N 144º). Formation of the rather strong hydrogen bonds leads to
Fig. 1. Structure of the thiosemicarbazone 1c with atomic numbering.
TABLE 2. Bond Lengths (l) in the Thiosemicarbazone 1c Structure
Bond
l, Å
Bond
N(1A)–C(9A)
l, Å
S(1A)–C(11A)
N(1A)–C(1A)
N(2A)–C(10A)
N(3A)–C(11A)
O(1A)–C(9A)
C(1A)–C(6A)
C(2A)–C(3A)
C(4A)–C(5A)
C(6A)–C(7A)
C(8A)–C(10A)
C(12A)–C(13A)
S(1B)–C(11B)
N(1B)–C(1B)
N(2B)–C(10B)
N(3B)–C(11B)
O(1B)–C(9B)
C(1B)–C(2B)
C(2B)–C(3B)
C(4B)–C(5B)
C(6B)–C(7B)
C(8B)–C(10B)
C(12B)–C(13B)
1.681(3)
1.403(3)
1.284(3)
1.349(3)
1.243(3)
1.397(4)
1.373(4)
1.375(4)
1.427(4)
1.449(4)
1.539(1)
1.670(3)
1.402(3)
1.282(3)
1.342(3)
1.236(3)
1.398(4)
1.372(4)
1.381(4)
1.432(3)
1.438(3)
1.536(1)
1.379(3)
1.469(3)
1.379(3)
1.317(4)
1.342(3)
1.408(4)
1.372(4)
1.409(3)
1.369(3)
1.450(3)
1.538(1)
1.382(3)
1.468(3)
1.375(3)
1.324(3)
1.332(3)
1.402(4)
1.375(4)
1.400(3)
1.374(3)
1.447(3)
1.535(1)
N(1A)–C(12A)
N(2A)–N(3A)
N(4A)–C(11A)
O(2A)–C(7A)
C(1A)–C(2A)
C(3A)–C(4A)
C(5A)–C(6A)
C(7A)–C(8A)
C(8A)–C(9A)
C(13A)–C(14A)
N(1B)–C(9B)
N(1B)–C(12B)
N(2B)–N(3B)
N(4B)–C(11B)
O(2B)–C(7B)
C(1B)–C(6B)
C(3B)–C(4B)
C(5B)–C(6B)
C(7B)–C(8B)
C(8B)–C(9B)
C(13B)–C(14B)
708

TABLE 3. Valence Angles (ω) in the Thiosemicarbazone 1c Structure
Angle
ω, deg
Angle
ω, deg
C(9A)–N(1A)–C(1A)
C(1A)–N(1A)–C(12A)
C(11A)–N(3A)–N(2A)
C(6A)–C(1A)–C(2A)
C(3A)–C(2A)–C(1A)
C(3A)–C(4A)–C(5A)
C(1A)–C(6A)–C(5A)
C(5A)–C(6A)–C(7A)
O(2A)–C(7A)–C(6A)
C(7A)–C(8A)–C(10A)
C(10A)–C(8A)–C(9A)
O(1A)–C(9A)–C(8A)
N(2A)–C(10A)–C(8A)
N(4A)–C(11A)–S(1A)
N(1A)–C(12A)–C(13A)
C(9B)–N(1B)–C(1B)
C(1B)–N(1B)–C(12B)
C(11B)–N(3B)–N(2B)
C(2B)–C(1B)–N(1B)
C(3B)–C(2B)–C(1B)
C(3B)–C(4B)–C(5B)
C(5B)–C(6B)–C(1B)
C(1B)–C(6B)–C(7B)
O(2B)–C(7B)–C(6B)
C(7B)–C(8B)–C(10B)
C(10B)–C(8B)–C(9B)
O(1B)–C(9B)–C(8B)
N(2B)–C(10B)–C(8B)
N(4B)–C(11B)–S(1B)
N(1B)–C(12B)–C(13B)
122.2(2)
120.4(2)
121.3(2)
118.7(2)
119.9(3)
119.8(3)
119.9(3)
121.5(3)
116.7(2)
122.7(2)
117.3(2)
122.0(2)
122.0(2)
123.1(2)
111.8(2)
122.5(2)
119.9(2)
120.7(2)
121.8(3)
120.4(3)
118.9(3)
119.6(2)
118.8(2)
116.4(2)
122.9(2)
117.0(2)
121.4(2)
121.3(2)
122.6(2)
113.1(3)
C(9A)–N(1A)–C(12A)
C(10A)–N(2A)–N(3A)
C(6A)–C(1A)–N(1A)
N(1A)–C(1A)–C(2A)
C(4A)–C(3A)–C(2A)
C(4A)–C(5A)–C(6A)
C(1A)–C(6A)–C(7A)
O(2A)–C(7A)–C(8A)
C(8A)–C(7A)–C(6A)
C(7A)–C(8A)–C(9A)
O(1A)–C(9A)–N(1A)
N(1A)–C(9A)–C(8A)
N(4A)–C(11A)–N(3A)
N(3A)–C(11A)–S(1A)
C(14A)–C(13A)–C(12А)
C(9B)–N(1B)–C(12B)
C(10B)–N(2B)–N(3B)
C(2B)–C(1B)–C(6B)
C(6B)–C(1B)–N(1B)
C(2B)–C(3B)–C(4B)
C(4B)–C(5B)–C(6B)
C(5B)–C(6B)–C(7B)
O(2B)–C(7B)–C(8B)
C(8B)–C(7B)–C(6B)
C(7B)–C(8B)–C(9B)
O(1B)–C(9B)–N(1B)
N(1B)–C(9B)–C(8B)
N(4B)–C(11B)–N(3B)
N(3B)–C(11B)–S(1B)
C(14B)–C(13B)–C(12B)
117.3(2)
115.9(2)
119.9(2)
121.3(3)
121.6(3)
120.1(3)
118.6(2)
122.0(2)
121.3(3)
120.0(2)
120.1(2)
117.9(2)
118.0(3)
118.9(2)
111.7(3)
117.6(2)
116.4(2)
118.6(2)
119.6(2)
121.6(3)
120.8(3)
121.6(2)
122.6(2)
121.1(2)
120.1(2)
120.7(2)
117.9(2)
117.7(3)
119.7(2)
111.4(3)
redistribution of electron density in the quinolone fragment as shown by the lengthened bond O(1)–C(9)
1.243(3) in molecule A and 1.236(3) Å in molecule B when compared with their mean value of 1.210 Å [30]
and the C(7)–C(8) bond 1.369(3) in A and 1.374(3) Å in B (mean value 1.326 Å) together with the shortened
bond O(2)–C(7) 1.342(3) in A and 1.332(3) Å in B (1.362 Å).
The strong repulsion between the atoms of the 1-N-propyl substituent in the quinolone fragment
[shortened intramolecular contacts H(2)···C(12) 2.55 in molecule A and 2.54 in B (sum of van der Waal radii
2.87 [31], H(2)···H(12b) 2.00 in A and 2.14 in B (2.34), H(12a)···C(2) 2.55 in A and 2.64 in B (2.87) and
H(12a)···O(1) 2.31 in A and 2.30 in B (2.46 Å)) lead to lengthening of the bond N(1)–C(9) 1.379(3) in A and
1.382(3) Å in B and also the bond N(1)–C(1) 1.403(3) in A and 1.402(3) in B when compared with the mean
values of 1.353 and 1.371 Å respectively, as was seen in previous studies of quinolone series compounds.
The propyl substituent on the N(1) atom is placed almost perpendicularly to the heterocyclic plane
(torsional angle C(1)–N(1)–C(12)–C(13) 84.0(3)º in molecule A and 78.7(3)º in B). The C(13)–C(14) bond in
the A molecule occurs in an ap position relative to the N(1)–C(12) bond (torsional angle N(1)–C(12)–C(13)–
C(14) = -175.0(3)º) and in molecule B it has a +sc orientation relative to this bond where the same torsional
angle is 61.4(4)º despite the repulsion between the methylene group in the substituent and a benzene ring atom
[shortened intramolecular contact H(2b)···H(13c) 2.25 Å (2.34Å)].
In the crystal the thiosemicarbazone 1c molecules form dimers via intermolecular hydrogen bonds:
N(3a)–H(3Na)···O(1b) (H···O 2.00 Å, N–H···O 166º) and N(3b)–H(3Nb)···O(1a) (H···O 2.11 Å. N–H···O 173º).
709

The dimer molecules do not lie in a single plane the angle between the planes of the bicyclic fragments being
13.9º. The crystal also shows intermolecular hydrogen bonds: N(4a)–H(4Na) ···S(1b)' (0.5+x, 1.5-y, 0.5+z) H···S
2.70 Å, N–H···S 159º; N(4a)–H(4Nb)···S(1b)' (0.5-x, 1.5-y, 1-z) H···S 2.84 Å, N–H···S 118º; and N(4b)–
H(4Nc)···S(1a)' (-0.5+x, 1.5-y, -0.5+z) H···S 2.46 Å, N–H···S 164º.
The overall results of the X-ray analysis confirm that in the crystalline state the thiosemicarbazone 1c
exists exclusively in the more stable isomeric syn form and this is a general characteristic for hydrazones [32].
As a rule, in solution there is established an equilibrium between the configurational partners and this
1
can usually be readily determined with the help of NMR spectroscopy [32, 33]. However, the H NMR spectra
of the thiosemicarbazones 1a-f (Table 4) show no kind of typical doubling of signals for such examples. Hence
TABLE 4. 1H NMR Spectra of the Compounds Synthesized 1a-f and 3a-f
Com-
pound
Chemical shifts δ, ppm (J, Hz)
1a
1b
11.61 (1H, s, OH); 11.43 (1H, s, NH); 8.58 (1Н, s, CH=N); 8.14 (2H, s, NH2);
8.01 (1Н, dd, J = 8.1 and J = 1.6, Н-5); 7.67 (1Н, td, J = 7.8 and J = 1.7, Н-7);
7.51 (1Н, d, J = 8.3, Н-8); 7.27 (1Н, t, J = 7.5, Н-6); 3.56 (3Н, s, СН3)
11.56 (1H, s, OH); 11.44 (1H, s, NH); 8.59 (1Н, s, CH=N); 8.10 (2H, s, NH2);
8.02 (1Н, dd, J = 8.2 and J = 1.5, Н-5); 7.69 (1Н, td, J = 7.9 and J = 1.6, Н-7);
7.54 (1Н, d, J = 8.4, Н-8); 7.27 (1Н, t, J = 7.5, Н-6); 4.26 (2Н, q, J = 7.2, NСН2);
1.19 (3Н, t, J = 7.2, NСН2СН3)
1c
1d
1e
1f
11.52 (1H, s, OH); 11.40 (1H, s, NH); 8.58 (1Н, s, CH=N); 8.12 (2H, s, NH2);
8.00 (1Н, dd, J = 8.2 and J = 1.6, Н-5); 7.66 (1Н, td, J = 7.8 and J = 1.6, Н-7);
7.52 (1Н, d, J = 8.3, Н-8); 7.28 (1Н, t, J = 7.4, Н-6); 4.13 (2Н, t, J = 7.5, NСН2);
1.60 (2Н, m, NСН2СН2); 0.91 (3Н, t, J = 7.4, NСН2СН2СН3)
11.54 (1H, s, OH); 11.41 (1H, s, NH); 8.58 (1Н, s, CH=N); 8.15 (2H, s, NH2);
7.98 (1Н, dd, J = 8.1 and J = 1.5, Н-5); 7.65 (1Н, td, J = 7.7 and J = 1.7, Н-7);
7.49 (1Н, d, J = 8.3, Н-8); 7.27 (1Н, t, J = 7.5, Н-6); 4.16 (2Н, t, J = 7.4, NСН2);
1.54 (2Н, q, J = 6.7, NСН2СН2); 1.35 (2Н, m, СН2СН3); 0.91 (3Н, t, J = 7.3, СН3)
11.53 (1H, s, OH); 11.41 (1H, s, NH); 8.59 (1Н, s, CH=N); 8.12 (2H, s, NH2);
8.01 (1Н, dd, J = 8.0 and J = 1.4, Н-5); 7.68 (1Н, td, J = 7.8 and J = 1.5, Н-7);
7.52 (1Н, d, J = 8.4, Н-8); 7.30 (1Н, t, J = 7.5, Н-6); 4.17 (2Н, t, J = 7.3, NСН2);
1.57 (2Н, q, J = 6.8, NСН2СН2); 1.32 (4Н, m, (СН2)2СН3); 0.85 (3Н, t, J = 6.6, СН3)
11.46 (1H, s, OH); 11.40 (1H, s, NH); 8.59 (1Н, s, CH=N); 8.06 (2H, s, NH2);
8.02 (1Н, d, J = 8.0, Н-5); 7.67 (1Н, t, J = 7.9, Н-7); 7.51 (1Н, d, J = 8.5, Н-8);
7.30 (1Н, t, J = 7.5, Н-6); 4.18 (2Н, t, J = 7.3, NСН2); 1.58 (2Н, q, J = 6.6, NСН2СН2);
1.30 (6Н, m, (СН2)3СН3); 0.84 (3Н, t, J = 6.3, СН3)
3a
3b
15.68 (1H, s, OH); 11.61 (1H, s, CONH); 10.27 (1H, s, SO2NH);
8.04 (1Н, d, J = 8.1, Н-5); 7.87–7.59 (4Н, m, Н-7,8,2',6'); 7.44–7.32 (3Н, m, Н-6,3',5');
3.58 (3Н, s, NСН3); 2.38 (3Н, s, Ar–СН3)
15.65 (1H, s, OH); 11.62 (1H, s, CONH); 10.26 (1H, s, SO2NH);
8.05 (1Н, dd, J = 8.0 and J = 1.5, Н-5); 7.84-7.60 (4Н, m, Н-7,8,2',6');
7.46-7.29 (3Н, m, Н-6,3',5'); 4.24 (2Н, q, J = 7.3, NСН2); 2.38 (3Н, s, Ar–СН3);
1.18 (3Н, t, J = 7.1, NСН2СН3)
3c
3d
3e
3f
15.68 (1H, s, OH); 11.60 (1H, s, CONH); 10.30 (1H, s, SO2NH);
8.04 (1Н, dd, J = 8.2 and J = 1.6, Н-5); 7.86–7.61 (4Н, m, Н-7,8,2',6');
7.50-7.32 (3Н, m, Н-6,3',5'); 4.15 (2Н, t, J = 7.7, NСН2); 2.37 (3Н, s, Ar–СН3);
1.59 (2Н, m, NСН2СН2); 0.91 (3Н, t, J = 7.4, NСН2СН2СН3)
15.66 (1H, s, OH); 11.67 (1H, s, CONH); 10.26 (1H, s, SO2NH);
8.02 (1Н, dd, J = 8.1 and J = 1.6, Н-5); 7.87–7.59 (4Н, m, Н-7,8,2',6');
7.48-7.33 (3Н, m, Н-6,3',5'); 4.18 (2Н, t, J = 7.5, NСН2); 2.38 (3Н, s, Ar–СН3);
1.56 (2Н, q, J = 6.9, NСН2СН2); 1.36 (2Н, m, СН2СН3); 0.90 (3Н, t, J = 7.1, СН3)
15.66 (1H, s, OH); 11.60 (1H, s, CONH); 10.28 (1H, s, SO2NH);
8.02 (1Н, dd, J = 8.2 and J = 1.5, Н-5); 7.84–7.59 (4Н, m, Н-7,8,2',6');
7.48-7.29 (3Н, m, Н-6,3',5'); 4.17 (2Н, t, J = 7.3, NСН2); 2.36 (3Н, s, Ar–СН3);
1.56 (2Н, q, J = 7.0, NСН2СН2); 1.30 (4Н, m, (СН2)2СН3); 0.84 (3Н, t, J = 6.9, СН3)
15.62 (1H, s, OH); 11.59 (1H, s, CONH); 10.31 (1H, s, SO2NH);
8.00 (1Н, dd, J = 8.1 and J = 1.6, Н-5); 7.82–7.58 (4Н, m, Н-7,8,2',6');
7.51-7.31 (3Н, m, Н-6,3',5'); 4.19 (2Н, t, J = 7.3, NСН2); 2.39 (3Н, s, Ar–СН3);
1.57 (2Н, q, J = 6.8, NСН2СН2); 1.31 (6Н, m, (СН2)3СН3); 0.86 (3Н, t, J = 6.5, СН3)
710

1
TABLE 5. Full List of H–13C Heteronuclear Correlations found for the
Thiosemicarbazone 1d
1Н Signal,
δ, ppm
Position of cross peaks in the 13C measurements
HMBC
НМQC
11.54
11.41
8.58
8.15
7.98
7.65
7.49
7.27
4.16
1.54
1.35
0.91
—
—
—
—
145.0
—
161.4; 102.6
—
124.6
133.4
115.4
122.7
41.9
30.0
20.3
14.4
139.5; 133.4
139.5; 124.6; 115.4
133.4; 122.7; 115.4
115.4
161.4; 139.4; 30.0; 20.3
41.9
14.4
30.3; 20.3
to identify the structural features of the synthesized compounds in solution we have measured the 13C NMR
spectrum of the 1-N-butyl derivative 1d. It was found that the 13C NMR spectrum of this compound recorded at
room temperature did not show the signals for the two quaternary carbon atoms which must be displaced to low
field. This did not allow us to carry out a safe assignment of the signals seen. Hence we also undertook
1
heteronuclear H–13C correlation experiments. Table 5 shows the cross peak coordinates found in these HMQC
and HMBC correlation spectra.
The assignment of the 13C signals on the basis of their heteronuclear correlations demands an initial
assignment of the signals in the proton spectrum. The aromatic proton signals of the thiosemicarbazone 1d occur
as an ABCD spin system and appear as two triplets and two doublets in the region 7.27-7.98 ppm. The
assignment needs the position of one of the doublets to be securely established. The remaining signals can then
be assigned on the basis of the spin-spin interactions occurring. Since at this step of the analysis of the spectrum
we have no full picture of the spin-spin interaction it will be assumed that the signal at lower field at 7.98 ppm is
the absorption of the H-5 proton signal. This assumption can be fully justified since, firstly, it agrees with
numerous data for previously studied 4-hydroxyquinol-2-ones and, secondly, the strongly anisotropic oxygen
atom of the 4-OH group is in a peri position to the proton indicated. We can subsequently confirm this
hypothesis through the heteronuclear spin-spin interactions. The scheme below shows the proton and carbon
signal assignments made.
The chemical shifts of the protonated carbon atoms follow from the presence of their correlation through
one chemical bond in the HMQC spectrum with the corresponding proton signal. The signals of the nodal
carbon atoms in the quinolone ring can be assigned on the basis of the 2-3 chemical bonds correlations in the
HMBC spectrum. Hence the assignment for the signal at 139.5 ppm to the C(8a) atom follows from its
correlation with the signal for the N–CH2 group protons of the butyl fragment at 4.16 ppm and also with the
signals for the H-5 and H-7 aromatic protons. Similarly, the signal at 115.4 ppm corresponds to the C(4a) atom
because it correlates with the H-5, H-6, and H-8 aromatic proton signals. It should be noted that the signals for
atoms C(4a) and C(8) coincide but in the spectrum recorded upon raising the temperature they appear separately.
Assignment of the signal at 161.4 ppm to the carbonyl C(2) atom follows from its correlation with the signal for
the 1-CH2 group of the N-butyl substituent and the exocyclic proton with chemical shift of 8.58 ppm assigned to
the hydrazone fragment in the molecule. From the scheme it follows that the assignments we have made for the
proton signals are indeed valid.
711

The conventional 13C NMR spectrum of the thiosemicarbazone 1d shows the absence of signals
corresponding to the C(4) atom and the carbon atom of the thiourea fragment. To reveal these we have measured
the carbon spectrum on heating to 90ºC. Under these conditions the spectrum shows two further
carbon signals with chemical shifts of 179.7 and 162.8 ppm which, from their chemical shift values must be
assigned to the carbon atom of the thiourea fragment and the quinolone C(4) atom respectively.
8.15
H2N
179.7
S
7.98
H
N
11.54
OH
N
H
11.41
7.27
162.8
124.6
145.0
H
H
102.6
161.4
8.58
122.7
133.4
115.4
139.5
H
N
O
115.4
41.9
7.65
H
H
H
7.49
4.16
H
H
1.54
30.0
20.3
H
H
1.35
14.4
H
H
H
0.91
Based on the observed broadening of the signal for the C(4) atom we can conclude that there exists in a
DMSO solution of the thiosemicarbazone 1d not the syn↔anti isomerism for 1↔6 we expected but rather a
hydrazone↔enhydrazine tautomerism 1↔7. Participation of the C(2)=O carbonyl in the tautomerism is very
unlikely since its signal is virtually unbroadened. As regards the carbon atom of the thio group, considering the
distance from the quinolone ring, the broadening of its signal is most likely caused by a totally independent type
of tautomerism, in fact typical of thiosemicarbazide derivatives [34].
Study of the antitubercular properties of the compounds synthesized showed that, against expectations,
both the thiosemicarbazones 1a-f and their synthetic precursor tosylhydrazides 3a-f were totally unable to
inhibit the growth of Mycobacterium tuberculosis H37Rv ATCC 27294.
EXPERIMENTAL
1
1
The H and 13C NMR spectra of the thiosemicarbazone 1d, the 2D H COSY NMR spectroscopic
experiments, the NOESY-2D Overhauser effect homonuclear, and HMQC and HMBC heteronuclear
correlations were recorded on a Varian Mercury-400 spectrometer (400 and 100 MHz respectively). All of the
2D experiments were carried out with gradient selection of useful signals. The mixing times in the pulse
1
2-3
sequences corresponded JCH = 140 and
J
CH
= 8 Hz. The number of increments in the COSY and HMQC
experiments was 128 and in the HMBC spectra 400. The mixing time in the NOESY-2D experiment was 500 ms.
712

The 1H NMR spectra of the remaining compounds were recorded on a Varian Mercury-VX-200 instrument (200
MHz) using DMSO-d6 with TMS as internal standard.
1-R-4-Hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acid hydrazides 5a-f were prepared using the
method in the report [28]. For the synthesis of the β-N-tosylhydrazides 3a-f commercial p-toluenesulfonyl chloride
was used from Merck, anhydrous DMF for peptide synthesis from Fluka, and p-toluenesulfonylhydrazide from
Aldrich.
4-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carboxylic acid β-N-Tosylhydrazide (3c). A. Triethyl-
amine (1.54 ml, 11 mmol) followed, with stirring, by p-toluenesulfonyl chloride (2.1 g, 11 mmol) were added to a
solution of the hydrazide 5c (2.61 g, 10 mmol) in dry DMF (20 ml) and the product was left for 10-12 h at room
temperature. The reaction mixture was treated with cold water and acidified to pH 5 using dilute HCl. The
precipitated β-N-tosylhydrazide 3c was filtered off, washed with water, dried, and crystallized from a mixture of
DMF and ethanol.
B. A mixture of the ester 4c (2.75 g, 10 mmol) and p-toluenesulfonylhydrazide (1.86 g, 10 mmol) in
DMF (1 ml) was vigorously stirred and held for 3-5 min at 140ºC. The still hot mixture was carefully treated
with ethanol (10-15 ml) and triturated. The precipitate was filtered off, washed with alcohol, and dried.
A mixed sample of the β-N-tosylhydrazide 3c prepared by the different methods did not show a
depressed melting point and their 1H NMR spectra were identical.
4-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline-3-carbaldehyde Thiosemicarbazide (1c). Anhydrous
Na2CO3 (3.18 g, 30 mmol) was added in one aliquot to a solution of the β-N-tosylhydrazide 3c (4.15 g,
10 mmol) in ethylene glycol (20 ml) heated to 160ºC (with care !, vigorous frothing). After several minutes the
gas evolution ceased. The reaction mixture was cooled, diluted with water, and acidified with diluted 1:1 HCl to
pH ~ 4. The aldehyde 2c formed was extracted with chloroform (3×20 ml). Solvent was distilled off (finally
under reduced pressure). Ethanol (10 ml) and thiosemicarbazide (0.83 g, 9.1 mmol) were added to the technical
aldehyde 2c (2.1 g, 9.1 mmol) and refluxed for 30 min. The yellow crystalline precipitate of the
thiosemicarbazone 1c formed on cooling was filtered off and dried.
Thiosemicarbazones 1a,b,d-f (Table 1) were prepared by a similar method.
X-ray Structural Investigation. Crystals of the thiosemicarbazone 1c are monoclinic (butanol), at
20ºC: a = 27.266(1), b = 13.057(1), c = 17.293(1) Å, β = 108.15(1)º, V = 5849.9(3) Å3, Mr = 304.37, Z = 16,
space group C2/c, dcalc = 1.382 g/cm3, µ(MoKα) = 0.231 mm-1, F(000) = 2560. The unit cell parameters and
intensities of 16147 reflections (5047 independent, Rint = 0.034) were measured on an Xcalibur-3 diffractometer
(MoKα radiation, CCD detector, graphite monochromator, ω-scanning to 2θmax = 50º).
The structure was solved by the direct method using the SHELXTL program package [35]. The positions of
the hydrogen atoms were revealed using electron density difference synthesis and refined using the "riding" model
with Uiso = nUeq (n = 1.5 for a methyl group and n = 1.2 for remaining hydrogen atoms). Hydrogen atoms taking part
in the formation of hydrogen bonds were refined in the isotropic approximation. In the refinement of the structure
limits were set on the length of the bonds in the propyl substituent (Csp3–Csp3 = 1.54 Å). The structure was refined
in F2 full-matrix least-squares analysis in the anisotropic approximation for non-hydrogen atoms to wR2 = 0.124
for 4983 reflections (R1 = 0.046 for 2637 reflections with F > 4σ(F), S = 0.869). The full crystallographic
information has been deposited in the Cambridge structural database (deposit No. CCDC 717533). Interatomic
distances and valence angles are given in Tables 2 and 3.
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