4-hydroxy-2-quinolones. 95. Synthesis, structure, and antitubercular properties of hetarylamides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3- carboxylic acid

Article abstract of DOI:10.1007/s10593-006-0159-2

The optimal conditions for obtaining hetarylamides of 4-hydroxy-2-oxo-1,2, 5,6,7,8-hexahydroquinoline-3-carboxylic acid are suggested on the basis of derivatographic investigations. The ¹H NMR spectra of the synthesized compounds, their spatial

Full text of DOI:10.1007/s10593-006-0159-2

Chemistry of Heterocyclic Compounds, Vol. 42, No. 6, 2006
4-HYDROXY-2-QUINOLONES. 95*. SYNTHESIS,
STRUCTURE, AND ANTITUBERCULAR PROPERTIES
OF HETARYLAMIDES OF 4-HYDROXY-2-OXO-
1,2,5,6,7,8-HEXAHYDROQUINOLINE-3-CARBOXYLIC ACID
I. V. Ukrainets1, E. V. Kolesnik1, L. V. Sidorenko1, O. V. Gorokhova1, and A. V. Turov2
The optimal conditions for obtaining hetarylamides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-
1
3-carboxylic acid are suggested on the basis of derivatographic investigations. The H NMR spectra of
the synthesized compounds, their spatial structure, and also the results of a study of their antitubercular
properties are discussed.
Keywords: amides, 4-hydroxy-2-oxoquinoline-3-carboxylic acids, antitubercular activity, X-ray
structural analysis, thermolysis.
More recently tuberculosis was considered to be an illness already finally conquered, but today it has
become the most widespread infectious disease in the world. The reason for the position established now is
concealed in the reduction of the set of antitubercular measures in the majority of developing and economically
highly developed countries. As a result tuberculosis has emerged from being under control and at the beginning
of the nineties of the last century approached a crisis point, in place of an annual fall in morbidity an impetuous
deterioration in the epidemiological situation began [2, 3]. In addition, seriously complicating the problem, the
ability of Mycobacterium tuberculosis to mutate actively, has given it the possibility of producing resistance
(frequently multiple) against many well-known antitubercular preparations. As a result there are now in the
world several million people for whom classical medical treatment is no help. In connection with this the search
for new medicinal agents with antimycobacterial action is a problem of paramount importance in contemporary
international public health.
Of undoubted interest in this project are anilides [4], hetarylamides [5-7], and hydrazides [8] of
1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids, which show, in experiments in vitro, high
activity in relation not only to Mycobacterium tuberculosis, but also to inducers of nontubercular mycobacterial
disease, the Mycobacterium avium complex. With the aim of clarifying the rules of the chemical structure–
antitubercular action in the series of compounds being studied we have effected the synthesis and carried out
microbiological screening of hydrogenated analogs of the compounds described previously and of the hetaryl-
amides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acids 1a-u.
_______
* For Part 94 see [1].
__________________________________________________________________________________________
1
2
National Pharmaceutical University, Kharkov 61002, Ukraine; e-mail: uiv@kharkov.ua. Kiev Taras
Shevchenko National University, Kiev 01033, Ukraine; e-mail: nmrlab@univ.kiev.ua. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 6, pp. 874-886, June, 2006. Original article submitted November 8, 2004.
0009-3122/06/4206-0765©2006 Springer Science+Business Media, Inc.
765

O
O
O
ClOCCH2COOEt
NH3
OEt
OEt
NH2
2
3
O
OH
O
O
AlkONa,
AlkOH
OEt
OAlk
N
H
NHCOCH2COOEt
4
5a,b
H2N–R
OH
230 oC
OH
O
O
NHR
N
H
O
N
H
1a–-u
6
1 a R = Py-4, b R = Py-3, c R = Py-2, d R = 3-Me-Py-2, e R = 4-Me-Py-2, f R = 5-Me-Py-2,
g R = 6-Me-Py-2, h R = 4-picolyl, i R = 3-picolyl, j R = 2-picolyl, k R = 3-OH-Py-2,
l R = 2-thiazolyl, m R = 4-(1-adamantyl)-2-thiazolyl, n R = 2-benzothiazolyl,
o R = 6-Me-2-benzothiazolyl, p R = 6-Br-2-benzothiazolyl, q R = 1,3,4-thiadiazol-2-yl,
r R = 5-Me-1,3,4-thiadiazol-2-yl, s 5-Et-1,3,4-thiadiazol-2-yl, t 5-Pr-1,3,4-thiadiazol-2-yl,
u 5-Isopropyl-1,3,4-thiadiazol-2-yl; 5 a Alk = Me; b Alk = Et
The ethyl ester of cyclohexanone-2-carboxylic acid (2) served as starting material for obtaining amides
1a-u, and is readily converted on treatment with gaseous ammonia into enamine 3. Subsequent acylation with
the ethyl ester of chlorocarbonylacetic acid, and then intramolecular cyclization of the resulting diester 4 under
the action of alkali metal alcoholates gave the esters of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-
carboxylic acid 5a,b.
It was shown previously that thermolysis at 160-200°C is most rational for the amidation of esters of
1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids with anilines or hetarylamines [4-7]. Evidently
such a method is also right for their hydrogenated analogs. Consequently to select optimum conditions for
obtaining amides 1a-u we studied the thermal behavior of ester 5a. From the derivatograms shown in Fig. 1 it
follows that methyl ester 5a is stable to 175°C. On further increase of temperature a smooth loss of mass begins,
which sharply increases from 185°C. A break is observed at this temperature on curve 4 changing into a peak at
220°C. The rapid loss of mass stops at 250°C and then only a uniform volatilization of the compound occurs.
The overall loss of mass in the temperature range 180 to 230°C was 25% of the initial, which calculated on each
molecule of ester 5a corresponds to 56 atomic mass units. In other words, under conditions of dry heat the ester
group of compound 5a decomposes (as indicated by the endothermal peak at 220°C on curve 2) with the
formation of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline (6), the structure of which was confirmed by
1H NMR and mass spectra. It is interesting that under analogous conditions esters of 1-R-4-hydroxy-2-oxo-1,2-
dihydroquinoline-3-carboxylic acids behave differently. They are practically quantitatively condensed into
5,9-di-R-6,7,8-trioxodiquinolino[3,4-b;3',4'-e]-4H-pyranes [9].
The derivatographic investigation therefore shows that amidation of esters 5 with hetarylamines under
thermolysis conditions must be carried out at a temperature no greater than 175°C. In addition we noted that
carrying out the synthesis in the presence of a small amount of a high-boiling solvent (DMF or bromobenzene)
766

M, mg
Fig. 1. Derivatograms of methyl ester 5a: 1) thermal analysis curve; 2) differential thermal analysis curve;
3) thermogravimetric curve; 4) differential thermogravimetric curve. Sample weight 100 mg.
gives the best results, which provides better mixing of reactants and prevents local overheating of the reaction
mixture. The hetarylamides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid 1a-u obtained
in this way contain less contaminants while retaining high yields (Table 1).
All of the proton-containing functional groups of the synthesized compounds were identified in the
1H NMR spectra fairly simply (Table 2). Difficulties arose only on assigning signals for the hydroquinolone
methylene groups. In all cases they were displayed by three multiplets of intensity 2, 2, and 4H. It is apparent
that the last of the signals mentioned is caused by the similar CH2 groups in positions 6 and 7 together. The
methylene groups in positions 5 and 8 are magnetically non-equivalent and for the precise assignment of their
signals we used the nuclear Overhauser effect (NOE) [10]. In ester 5b the only protons which may help in the
assignment of the signals of the cyclohexene fragment by the NOE method are the protons of the NH and OH
groups. Their assignment follows from comparison with the spectrum of the N-alkyl-substituted analog of esters
5 [11] in which the signal of the NH group is displayed at higher field (at 11.20 ppm). Saturation of this signal in
the NOE experiment led to an increase of 2% for the signal at 2.45 ppm. Consequently this signal corresponds to
the proton at C(8) and the remaining signal at 2.30 ppm to the methylene proton at C(15). The small size of the
NOE is linked most likely with the presence of a fairly rapid exchange of the NH group proton of the quinoline
with water, which also reduces the size of the effect.
Interesting features of the spatial structure of amides 1a-u became apparent in the X-ray structural
investigation of one of these compounds. In the symmetrically independent portion of the unit cell of the crystal
of 4-(1-adamantyl)-2-thiazolylamide 1m two molecules were detected (A and B) differing in the conformation of
the cyclohexene ring. In the molecule it was possible to distinguish two fragments planar to a precision of 0.02
Å. One of them includes the pyridine ring and the O(1), O(2), O(3), and C(10) atoms. The second contains the
thiazole ring and the N(2) and C(14) atoms. The two planar fragments are folded somewhat relative to one another
by an angle of 11.9 (molecule A) and 15.8° (B), which is probably caused by the shortened intramolecular
contact O(3)···S(1) 2.81 in A and 2.86 Å in molecule B (the sum of the van der Waals radii is 3.09 Å [12]). The
repulsion between these atoms also leads to an increase in the valence angle C(11)–N(2)–C(10) to 125.0(5) A,
127.3(4)° B. The adamantyl substituent is disposed in such a way that one of the C–C bonds is practically in the
plane of the thiazole nucleus [torsion angle C(13)–C(12)–C(14)–C(15) is 9(1) in A and 17(1)° in B]. The cyclohexene
767

TABLE 1. Characteristics of N-R-Amides of 4-Hydroxy-2-oxo-1,2,5,6,7,8-
hexahydroquinoline-3-carboxylic Acids (1a-u)
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °С
(dec.)
Antitubercular
activity*
Yield, %
C
H
N
C15H15N3O3
C15H15N3O3
C15H15N3O3
C16H17N3O3
C16H17N3O3
C16H17N3O3
C16H17N3O3
C16H17N3O3
C16H17N3O3
C16H17N3O3
C15H15N3O4
C13H13N3O3S
C23H27N3O3S
C17H15N3O3S
C18H17N3O3S
63.22
63.15
63.25
63.15
63.06
63.15
64.11
64.20
64.15
64.20
64.33
64.20
64.10
64.20
64.14
64.20
64.32
64.20
64.30
64.20
59.92
59.80
53.55
53.60
64.98
64.92
59.73
59.81
60.89
60.83
5.41
5.30
5.39
5.30
5.40
5.30
5.62
5.72
5.75
5.72
5.84
5.72
5.80
5.72
5.78
5.72
5.66
5.72
5.81
5.72
5.13
5.02
4.63
4.50
6.54
6.40
4.34
4.43
4.95
4.82
3.47
3.36
14.60
14.73
14.78
14.73
14.80
14.73
14.00
14.04
14.16
14.04
14.13
14.04
14.02
14.04
14.15
14.04
14.17
14.04
14.14
14.04
13.88
13.95
14.51
14.42
9.76
9.87
12.40
12.31
11.72
11.82
10.14
10.00
307-309
270-272
277-279
225-227
262-264
293-295
303-305
222-224
241-243
232-234
271-273
302-304
331-333
325-327
318-320
310-312
283-285
297-299
288-290
274-276
255-257
0
90
93
85
76
87
90
92
88
84
83
78
86
89
90
87
92
80
82
77
81
80
1a
1b
1c
1d
1e
1f
1
14
13
14
0
0
1g
1h
1i
33
21
6
1j
33
19
10
14
29
36
8
1k
1l
1m
1n
1o
1p
1q
1r
1s
1t
C17H14BrN3O3S 48.60
48.58
C12H12N4O3S
C13H14N4O3S
C14H16N4O3S
C15H18N4O3S
C15H18N4O3S
49.45
49.31
50.84
50.97
52.40
52.49
53.97
53.88
4.26
4.14
4.70
4.61
5.15
5.03
5.55
5.43
19.25
19.17
18.38
18.29
17.40
17.49
16.64
16.75
24
4
8
53.94
53.88
5.50
5.43
16.79
16.75
98
1u
_______
* Depression of growth (%) of Mycobacterium tuberculosis H37Rv ATCC
27294 at a concentration of 6.25 µg/ml.
ring is randomized with two equally probable conformations. In the case of molecule A this is an asymmetric
half-chair. The deviation of the C(3) and C(4) atoms from the plane of the remaining atoms of the ring was 0.15,
-0.56 Å for one conformer (C), and -0.44, 0.28 Å for the other (D). In molecule B the tetrahydro ring is
randomized with a half-chair (deviations of atoms C(3) and C(4) were 0.41 and -0.53 Å) and a sofa conformation
(atom C(4) deviates from the plane of the remaining atoms by 0.54 Å).
Molecules A and B also differ in the character of their intramolecular hydrogen bonds. In both molecules
bonds N(2)–H···O(1) are formed with close geometric characteristics (H···O 1.90 Å in A and B,
N–H···O 140 in A, 141° in B). This leads to a significant lengthening of the C(9)=O(1) bond to 1.257(8) (A) and
768

769

770

1.254(5) Å (B) in comparison with a mean value of 1.210 Å [13]. In molecule B a hydrogen bond is also formed
at O(2)–H···O(3) (H···O 1.80 Å, O–H···O 147°). In molecule A such a bond is very weak (H···O 1.98 Å, O–H···O
122°), which is also confirmed by the absence of lengthening of the C(10)=O(3) bond at 1.219(8) Å, in comparison
with molecule B [1.250(6) Å].
In the crystal of the 1m amide molecule centrosymmetric dimers are formed as a result of hydrogen
bonds N(1)–H···O(1), (-x, -y, -z): H···O 1.90 (A), 1.94 Å (B), N–H···O 177 (A), 169° (B).
The antitubercular properties of the hetarylamides of 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-
3-carboxylic acid 1a-u were studied by the radiometric method of [14]. From the data of the first microbiological
screening (Table 1) it follows that hydrogenation of the benzene portion of the quinolone is accompanied by a
significant fall in activity. From all the groups of substances investigated only 5-isopropyl-1,3,4-thiadiazolyl-2-
amide 1u deserves attention. At a concentration of 6.25 µg/ml it was able to suppress the
TABLE 3. Bond Lengths (l) in the Structure of Amide 1m
Bond
l, Å
Bond
l, Å
S(1A)–C(11A)
O(1A)–C(9A)
O(3A)–C(10A)
N(1A)–C(1A)
N(2A)–C(11A)
N(3A)–C(12A)
C(1A)–C(2A)
C(2A)–C(3D)
C(4C)–C(5A)
C(4D)–C(5A)
C(6A)–C(7A)
C(8A)–C(9A)
C(12A)–C(13A)
C(14A)–C(19A)
C(14A)–C(20A)
C(16A)–C(17A)
C(17A)–C(18A)
C(18A)–C(19A)
C(21A)–C(22A)
S(1B)–C(13B)
O(1B)–C(9B)
O(3B)–C(10B)
N(1B)–C(1B)
N(2B)–C(11B)
N(3B)–C(12B)
C(1B)–C(2B)
C(2B)–C(3F)
C(4E)–C(5B)
C(4F)–C(5B)
C(6B)–C(7B)
C(8B)–C(9B)
C(12B)–C(13B)
C(14B)–C(20B)
C(14B)–C(15B)
C(16B)–C(17B)
C(17B)–C(18B)
C(18B)–C(19B)
C(21B)–C(23B)
1.698(6)
1.257(8)
1.219(8)
1.388(8)
1.432(6)
1.391(6)
1.476(9)
1.524(9)
1.53(1)
S(1A)–C(13A)
O(2A)–C(7A)
N(1A)–C(9A)
N(2A)–C(10A)
N(3A)–C(11A)
C(1A)–C(6A)
C(2A)–C(3C)
C(3C)–C(4C)
C(3D)–C(4D)
C(5A)–C(6A)
C(7A)–C(8A)
C(8A)–C(10A)
C(12A)–C(14A)
C(14A)–C(15A)
C(15A)–C(16A)
C(16A)–C(22A)
C(18A)–C(23A)
C(20A)–C(21A)
C(21A)–C(23A)
S(1B)–C(11B)
O(2B)–C(7B)
N(1B)–C(9B)
N(2B)–C(10B)
N(3B)–C(11B)
C(1B)–C(6B)
C(2B)–C(3E)
C(3E)–C(4E)
C(3F)–C(4F)
1.723(5)
1.29(1)
1.381(7)
1.358(8)
1.293(7)
1.31(1)
1.498(9)
1.52(1)
1.53(1)
1.48(1)
1.43(1)
1.489(8)
1.521(7)
1.504(8)
1.59(1)
1.53(2)
1.49(1)
1.60(1)
1.51(1)
1.726(5)
1.351(6)
1.357(6)
1.363(6)
1.300(6)
1.361(7)
1.54(1)
1.54(1)
1.54(1)
1.546(8)
1.396(7)
1.479(7)
1.509(6)
1.480(9)
1.61(1)
1.50(1)
1.58(2)
1.582(9)
1.49(1)
1.513(8)
1.45(1)
1.39(1)
1.336(7)
1.501(9)
1.54(1)
1.46(1)
1.49(1)
1.594(8)
1.51(2)
1.721(5)
1.254(5)
1.250(6)
1.378(6)
1.395(6)
1.387(7)
1.502(8)
1.544(9)
1.538(9)
1.56(1)
C(5B)–C(6B)
C(7B)–C(8B)
C(8B)–C(10B)
C(12B)–C(14B)
C(14B)–C(19B)
C(15B)–C(16B)
C(16B)–C(23B)
C(18B)–C(22B)
C(20B)–C(21B)
C(21B)–C(22B)
1.417(8)
1.428(7)
1.356(7)
1.477(9)
1.59(1)
1.46(2)
1.47(2)
1.62(1)
1.45(1)
771

Fig. 2. Structure of amide 1m molecule with atom numbering.
growth of Mycobacterium tuberculosis H37Rv ATCC 27294 by 98%. All the remaining hetarylamides of
4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic acid 1a-t in antimycobacterial properties were
surpassed by their nonhydrogrenated analogs [5-7] and consequently such a structural modification must be
acknowledged to be inexpedient.
TABLE 4. Valence Angles (ω) in the Structure of Amide 1m
Valence angle
1
ω, deg
2
Valence angle
3
ω, deg
4
C(11A)–S(1A)–C(13A)
C(10A)–N(2A)–C(11A)
C(6A)–C(1A)–N(1A)
N(1A)–C(1A)–C(2A)
C(2A)–C(3C)–C(4C)
C(2A)–C(3D)–C(4D)
C(6A)–C(5A)–C(4D)
C(1A)–C(6A)–C(5A)
O(2A)–C(7A)–C(8A)
C(8A)–C(7A)–C(6A)
C(9A)–C(8A)–C(10A)
O(1A)–C(9A)–N(1A)
N(1A)–C(9A)–C(8A)
O(3A)–C(10A)–C(8A)
N(3A)–C(11A)–N(2A)
N(2A)–C(11A)–S(1A)
C(13A)–C(12A)–C(14A)
C(12A)–C(13A)–S(1A)
C(19A)–C(14A)–C(12A)
C(19A)–C(14A)–C(20A)
C(12A)–C(14A)–C(20A)
C(17A)–C(16A)–C(22A)
C(22A)–C(16A)–C(15A)
C(23A)–C(18A)–C(17A)
C(17A)–C(18A)–C(19A)
C(14A)–C(20A)–C(21A)
C(22A)–C(21A)–C(20A)
87.3(3)
125.0(5)
121.4(6)
115.8(7)
101(2)
C(9A)–N(1A)–C(1A)
125.1(7)
109.2(4)
122.6(6)
120(1)
C(11A)–N(3A)–C(12A)
C(6A)–C(1A)–C(2A)
C(1A)–C(2A)–C(3C)
C(3C)–C(4C)–C(5A)
C(5A)–C(4D)–C(3D)
C(6A)–C(5A)–C(4C)
C(7A)–C(6A)–C(5A)
O(2A)–C(7A)–C(6A)
C(9A)–C(8A)–C(7A)
C(7A)–C(8A)–C(10A)
O(1A)–C(9A)–C(8A)
O(3A)–C(10A)–N(2A)
N(2A)–C(10A)–C(8A)
N(3A)–C(11A)–S(1A)
C(13A)–C(12A)–N(3A)
N(3A)–C(12A)–C(14A)
C(19A)–C(14A)–C(15A)
C(15A)–C(14A)–C(12A)
C(15A)–C(14A)–C(20A)
C(14A)–C(15A)–C(16A)
C(17A)–C(16A)–C(15A)
C(16A)–C(17A)–C(18A)
C(23A)–C(18A)–C(19A)
C(14A)–C(19A)–C(18A)
C(22A)–C(21A)–C(23A)
C(23A)–C(21A)–C(20A)
117(2)
102(1)
118(2)
120(1)
105(1)
123.2(6)
122.1(6)
119.9(8)
122.9(6)
119.4(6)
115.1(6)
122.7(7)
118.4(5)
124.0(4)
127.3(5)
111.9(4)
111.8(4)
104.4(6)
109.0(6)
113.3(8)
100(1)
119.3(8)
117.9(7)
120.7(6)
116.3(7)
125.5(5)
121.8(5)
115.5(7)
117.6(4)
114.0(5)
118.6(5)
113.1(7)
112.6(5)
105.4(7)
112.0(5)
110.2(6)
112.8(8)
105.5(6)
111.8(4)
111(1)
114.6(6)
104.9(5)
112.7(8)
106.5(8)
102.1(6)
772

TABLE 4 (continued)
1
2
3
4
C(21A)–C(22A)–C(16A)
C(13B)–S(1B)–C(11B)
C(10B)–N(2B)–C(11B)
C(6B)–C(1B)–N(1B)
N(1B)–C(1B)–C(2B)
C(4E)–C(3E)–C(2B)
C(4F)–C(3F)–C(2B)
113.6(6)
87.8(2)
C(18A)–C(23A)–C(21A)
C(9B)–N(1B)–C(1B)
C(11B)–N(3B)–C(12B)
C(6B)–C(1B)–C(2B)
C(1B)–C(2B)–C(3E)
C(3E)–C(4E)–C(5B)
C(3F)–C(4F)–C(5B)
113.2(6)
125.1(4)
110.7(4)
123.3(5)
107(1)
127.3(4)
120.9(5)
115.7(5)
111(1)
103(1)
113(1)
117(1)
C(6B)–C(5B)–C(4F)
C(1B)–C(6B)–C(5B)
O(2B)–C(7B)–C(8B)
C(8B)–C(7B)–C(6B)
C(7B)–C(8B)–C(10B)
O(1B)–C(9B)–N(1B)
N(1B)–C(9B)–C(8B)
O(3B)–C(10B)–C(8B)
N(3B)–C(11B)–N(2B)
N(2B)–C(11B)–S(1B)
C(13B)–C(12B)–C(14B)
C(12B)–C(13B)–S(1B)
C(20B)–C(14B)–C(12B)
C(20B)–C(14B)–C(15B)
C(12B)–C(14B)–C(15B)
C(17B)–C(16B)–C(23B)
C(23B)–C(16B)–C(15B)
C(17B)–C(18B)–C(22B)
C(22B)–C(18B)–C(19B)
C(14B)–C(20B)–C(21B)
C(23B)–C(21B)–C(20B)
C(21B)–C(22B)–C(18B)
110(1)
C(1B)–C(6B)–C(7B)
C(7B)–C(6B)–C(5B)
O(2B)–C(7B)–C(6B)
C(7B)–C(8B)–C(9B)
C(9B)–C(8B)–C(10B)
O(1B)–C(9B)–C(8B)
O(3B)–C(10B)–N(2B)
N(2B)–C(10B)–C(8B)
N(3B)–C(11B)–S(1B)
C(13B)–C(12B)–N(3B)
N(3B)–C(12B)–C(14B)
C(20B)–C(14B)–C(19B)
C(19B)–C(14B)–C(12B)
C(19B)–C(14B)–C(15B)
C(14B)–C(15B)–C(16B)
C(17B)–C(16B)–C(15B)
C(16B)–C(17B)–C(18B)
C(17B)–C(18B)–C(19B)
C(14B)–C(19B)–C(18B)
C(23B)–C(21B)–C(22B)
C(22B)–C(21B)–C(20B)
C(21B)–C(23B)–C(16B)
116.5(5)
120.3(5)
116.0(4)
119.6(4)
121.7(4)
125.0(5)
120.9(5)
116.9(4)
115.9(4)
113.6(4)
118.1(4)
118.6(7)
111.3(4)
103.9(7)
107(1)
123.2(5)
121.7(4)
122.3(4)
118.6(4)
119.3(4)
115.6(4)
122.2(4)
120.0(4)
124.1(3)
128.2(5)
111.9(4)
111.7(4)
103.6(6)
106.3(6)
110(1)
110(1)
103.9(7)
114(1)
114(1)
101(1)
108.4(8)
112.9(6)
104.2(8)
109(1)
110.1(5)
115(1)
104.9(6)
116(1)
EXPERIMENTAL
The derivatographic investigation of ester 5a was carried out on a Derivatograf Q-1500 D complex
1
thermochemical instrument in a platinum crucible with a lid, rate of heating was 5°C/min. The H NMR
spectrum of ester 5b and the NOE experiment were carried out on a Varian Mercury 400 (400 MHz)
spectrometer by the standard 1D-NOE procedure with the mathematical provision for this problem. The
1H NMR spectra of the remaining compounds were recorded on a Varian Mercury VX 200 (200 MHz)
instrument. In all cases the solvent was DMSO-d6, internal standard was TMS. The mass spectrum of 3-H
quinolone 6 was recorded on a Varian 1200L spectrometer in total scanning mode for the range 45-550 m/z,
ionization was by electron impact at 70 eV, with direct insertion of samples. Commercial cyclohexanone-2-
carboxylic acid from Fluka was used in the work.
2-Aminocyclohex-1-enecarboxylic Acid Ethyl Ester (3). Gaseous ammonia was passed for 3.5-4 h into
cyclohexanone-2-carboxylic acid ethyl ester (68.9 ml, 0.5 mol), heated to 50°C. The reaction mixture was left at
room temperature for 8-10 h, and was then diluted with cold water. The crystalline solid of amino ester 3 was
1
filtered off, washed with water, and dried. Yield 79.4 g (94%); mp 73-75°C (diethyl ether). H NMR spectrum,
δ, ppm (J, Hz): 7.04 (2H, br. s, NH2); 4.04 (2H, q, J = 7.0, OCH2); 2.15 (4H, m, 3,6-CH2); 1.51 (4H, m, 4,5-
CH2); 1.16 (3H, t, J = 7.0, OCH2CH3). Found, %: C 63.72; H 8.80; N 8.41. C9H15NO2. Calculated, %: C 63.88;
H 8.93; N 8.28.
773

4-Hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic
Acid
Methyl
Ester
(5a).
Triethylamine (14.4 ml, 0.11 mol) was added to a solution of amino ester 3 (16.9 g, 0.1 mol) in CH2Cl2 (100 ml),
and then (chlorocarbonyl)acetic acid ethyl ester (16.56 g, 0.11 mol) was added dropwise with stirring and
cooling. The mixture was left at room temperature for 4-5 h. The reaction mixture was diluted with water, the
organic layer separated, and dried over anhydrous CaCl2. The solvent was distilled (under reduced pressure at
the end), and to the residue (diester 4) was added a solution of sodium methylate [from metallic sodium (3.45 g,
0.15 mol) and absolute methyl alcohol (150 ml)]. The mixture was boiled on a water bath for 30 min, 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 1:1 HCl to pH 4.5-5. The solid ester 5a was filtered off, washed with water,
1
and dried. Yield 18.52 g (83%). After recrystallization from ethanol mp (capillary) 214-216°C (decomp.). H
NMR spectrum, δ, ppm (J, Hz): 13.30 (1H, s, OH); 11.16 (1H, s, NH); 3.78 (3H, s, OCH3); 2.46 (2H, m, 8-CH2);
2.31 (2H, m, 5-CH2); 1.64 (4H, m, 6,7-CH2). Found, %: C 59.31; H 5.96; N 6.20. C11H13NO4. Calculated, %: C
59.19; H 5.87; N 6.27.
4-Hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic Acid Ethyl Ester (5b) was obtained
analogously. In the cyclization of diester 4 sodium ethylate in absolute ethanol was used as basic catalyst.
Yield 80%. After recrystallization from ethanol mp (capillary) 222-224°C (decomp.). 1H NMR spectrum, δ, ppm
(J, Hz): 13.50 (1H, s, OH); 11.20 (1H, s, NH); 4.29 (2H, q, J = 8.0, OCH2); 2.45 (2H, m, 8-CH2); 2.30 (2H, m, 5-
CH2); 1.65 (4H, m, 6,7-CH2); 1.28 (3H, t, J = 8.0, CH3). Found, %: C 60.80; H 6.48; N 5.81. C12H15NO4.
Calculated, %: C 60.75; H 6.37; N 5.90.
4-Hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline (6). Compound 5a (2.23 g, 0.01 mol) was
maintained at 230°C for 10 min, then cooled. The 3-H derivative 6 (1.97 g, 96%) was obtained; mp 355-357°C
(DMF). Mass spectrum, m/z (Irel, %): 165 (100) [M]+, 137 (16) [M-CO]+, 109 (42) [M-CO-CO]+, 95 (44), 81
1
(94), 67 (76), 54 (52). H NMR spectrum, d, ppm (J, Hz); 10.70 (1H, s, OH); 10.46 (1H, s, NH); 5.40 (1H, s,
H-3); 2.36 (2H, m, 8-CH2); 2.21 (2H, m, 5-CH2); 1.60 (4H, m, 6,7-CH2). Found, %: C 65.35; H 6.60; N 8.53.
C9H11NO2. Calculated, %: C 65.44; H 6.71; N 8.48.
Hetarylamides of 4-Hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylic Acid 1a-u
(General Procedure). A mixture of compound 5a (2.23 g, mol), the appropriate hetarylamine (0.01 mol), and
DMF (1-2 ml) was stirred and maintained at 160-170°C for 3 min. The reactants dissolved and practically
straight away amide 1 began to crystallize from the reaction mixture. The mixture was cooled, alcohol (30 ml)
was added, the mixture was thoroughly stirred, and filtered. The amide 1 obtained was washed with alcohol, and
dried. The product was crystallized from DMF.
X-ray Structural Investigation. Crystals of amide 1m were triclinic, at 20°C a = 6.498(1),
b = 15.476(4), c = 22.411(6) Å; α = 71.92(2), β = 89.58(2), γ = 88.24(2)°; V = 2141.4(9) Å3; Mr = 430.58; Z = 4;
space group P1; dcalc = 1.336 g/cm3; µ(MoKα) = 0.182 mm-1; F(000) = 924. The parameters of the unit cell and
the intensities of 6821 reflections (6195 independent, Rint = 0.04) were measured on a Siemens P3/PC automatic
four-circle diffractometer (λMoKα, graphite monochromator, 2θ/θ scanning, 2θmax = 50°).
The structure was solved by the direct method with the SHELX97 set of programs [15]. The position of
the hydrogen atoms was calculated geometrically and refined by the rider model with Uiso = 1.2 × Ueq for the
nonhydrogen atom linked to a given hydrogen. The disordered fragments were refined with the imposition of
limitations on the C–C bond length of 1.54(1) Å. The structure was refined on F2 with the full matrix least
squares method in anisotropic approximation for the nonhydrogen atoms to wR2 = 0.282 for 6195 reflections
(R1 = 0.086 for 3122 reflections with F >4σ (F), S = 0.998). All the crystallographic information has been
deposited in the Cambridge Structural Data Bank (deposit No. CCDC 257524). Interatomic distances and
valence angles are given in Tables 3 and 4.
774

The authors are grateful to the National Institute of Allergy and Infectious Diseases of the USA for
carrying out the study of the antitubercular properties of the compounds synthesized by us in conformity with
the TAACF program (Tuberculosis Antimicrobial Acquisition & Coordinating Facility) (contract No. 01-A1-
45246).
REFERENCES
1.
I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, and O. V. Shishkin, Khim. Geterotsikl. Soedin., 718
(2006).
2.
3.
4.
A. G. Khomenko, Probl. Tuberkuleza, No. 2, 2 (1994).
A. G. Khomenko, Probl. Tuberkuleza, No. 1, 4 (1995).
I. V. Ukrainets, Abdel Naser Kh. N. Dakkakh, P. A. Bezuglyi, O. V. Gorokhova, L. V. Sidorenko, and
T. V. Alekseeva, Vestn. Farm., No. 1(25), 9 (2001).
5.
6.
I. V. Ukrainets, M. Amer, P. A. Bezugly, O. V. Gorokhova, L. V. Sidorenko, and A. V. Turov, Khim.
Geterotsikl. Soedin., 654 (2002).
I. V. Ukrainets, Amzhad Abu Sharekh, P. A. Bezuglyi, L. V. Sidorenko, and O. V. Gorokhova, Farm.
Zh., No. 5, 52 (2002).
7.
I. V. Ukrainets, S. A. El Kayal, O. V. Gorokhova, L. V. Sidorenko, and T. V. Alekseeva, Vestn. Farm.,
No. 1(37), 12 (2004).
8.
I. V. Ukrainets, O. S. Prokopenko, L. V. Sidorenko, and O. V. Gorokhova, Vestn. Farm., No. 3(39), 3
(2004).
9.
I. V. Ukrainets, E. A. Taran, O. V. Shishkin, O. V. Gorokhova, S. G. Taran, Jaradat Nidal Amin, and
A. V. Turov, Khim. Geterotsikl. Soedin., 516 (2000).
10.
11.
H. Gunther, NMR Spectroscopy: Basic Principles, Concepts, and Applications in Chemistry, John Wiley
& Sons, Chichester (1995).
I. V. Ukrainets, L. V. Sidorenko, O. V. Gorokhova, V. B. Rybakov, V. V. Chernishev, and
E. V. Kolesnik, Vestn. Farm., No. 2(38), 7 (2004).
12.
13.
14.
Yu. V. Zefirov and P. M. Zorkii, Usp. Khim., 58, 713 (1989).
H.-B. Burgi and J. D. Dunitz, Structure Correlation, Vol. 2, VCH, Weinheim (1994), p. 741.
S. H. Siddiqui in H. D. Isenberg (editor), Clinical Microbiology Procedures Handbook, Vol. 1,
American Society for Microbiology, Washington D. C. (1992), p. 5.14.2.
G. M. Sheldrick, SHELX97. PC Version. A System of Computer Programs for Crystal Structure Solution
and Refinement, Rev. 2, (1998).
15.
775