4-Hydroxy-2-quinolones. 149*. Synthesis, chemical transformations, and biological properties of β-N-acylhydrazides of 1-R-4-hydroxy-2-oxo-1,2- dihydro-quinoline-4-carboxylic acids

Article abstract of DOI:10.1007/s10593-009-0198-6

Two methods of preparation have been proposed and the synthesis has been effected of a large series of β-N-acylhydrazides of 1-R-4-hydroxy-2-oxo-1, 2-dihydroquinoline-3-carboxylic acids. The possibility of using various condensing agents for converting them into the corresponding 1,3,4-oxa-diazoloquinolines has been studied. Results are given of an investigation of the antitubercular activity of the synthesized compounds.

Full text of DOI:10.1007/s10593-009-0198-6

Chemistry of Heterocyclic Compounds, Vol. 44, No. 11, 2008
4-HYDROXY-2-QUINOLONES. 149*. SYNTHESIS,
CHEMICAL TRANSFORMATIONS, AND BIOLOGICAL
PROPERTIES OF β-N-ACYLHYDRAZIDES
OF 1-R-4-HYDROXY-2-OXO-1,2-DIHYDRO-
QUINOLINE-4-CARBOXYLIC ACIDS
I. V. Ukrainets, A. A. Tkach, and Liu Yang Yang
Two methods of preparation have been proposed and the synthesis has been effected of a large series of
β-N-acylhydrazides of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids. The possibility of
using various condensing agents for converting them into the corresponding 1,3,4-oxa-
diazoloquinolines has been studied. Results are given of an investigation of the antitubercular activity of
the synthesized compounds.
Keywords: acylhydrazines, 4-hydroxy-2-oxoquinoline-3-carboxylic acids, 1,3,4-oxadiazoles, anti-
tubercular activity.
A characteristic feature of the search for new medicinal agents under modern conditions is purpose-
directed synthesis based on developing, accumulating, and systematizing empirical data on the relation between
chemical structure and the biological properties of substances. It is impossible in principle to develop rules of
such a type from the example of any one compound. It is necessary to study a series of related structures [2].
The present communication is the investigation of just such a series, the aim of which is the definition in the
structure of previously described benzylidenehydrazides of 1-R-4-hydroxy-2-oxo-1,2-dihydro-quinoline-
3-carboxylic acids [3-5] of functional groups strengthening or, on the other hand, weakening the antitubercular
activity of these substances.
To carry out the projected aim we obtained, and then subjected to microbiological screening, β-N-acyl-
hydrazides of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 1-4, which are formally derivatives of
the acylhydrazones indicated above. The subjects of the investigation were synthesized by the two methods given
in the scheme: by hydrazinolysis of the ethyl esters of quinoline-3-carboxylic acids 5 with subsequent acylation of
the intermediate hydrazides 6 (method A) or by the direct reaction of esters 5 with previously obtained
benzoylhydrazines (method B). Both methods are fairly simple in use, are readily reproduced, and give good yields
of the desired 1,2-diacylhydrazines 1-4 (see Table 1). At first sight method B appears preferable since it is possible to
form the final compounds in one step. At the same time each of the reactions in method A is distinguished by high
_______
* For Communication 148 see [1].
__________________________________________________________________________________________
National University of Pharmacy, Kharkiv 61002, Ukraine; e-mail: uiv@kharkov.ua. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1655-1663, November, 2008. Original article submitted
November 30, 2006.
0009-3122/08/4411-1347©2008 Springer Science+Business Media, Inc.
1347

efficiency. In fact the main criterion when selecting one or other of the methods of obtaining 1,2-diacyl-
hydrazines 1-4 in each actual case is the availability of the respective reactants, viz. the presence of the prepared
hydrazides of aromatic carboxylic acids using method B, or in the absence of them using the linear synthetic
scheme A.
CONHNH2
O
OH
B: R1
OEt
O
N
R
5a–d
O
O
OH
H
N
N
.
H
R1
A: H2NNH2 H2O
O
N
R
COCl
O
O
OH
1–4 a–m
R1
NHNH2
N
R
6a–d
1a–m, 5,6 a R = H, 2a–m, 5,6 b R = Me, 3a–m, 5,6 c R = Et, 4a–m, 5,6 d R = Pr;
1–4 a R1 = H, b R1 = 2-F, c R1 = 2-Cl, d R1 = 3-Cl, e R1 = 2-Br, f R1 = 4-Br, g R1 = 2,4-Cl2,
h R1 = 2-NO2, i R1 = 3-NO2, j R1 = 4-NO2, k R1 = 3,5-(NO2)2, l R1 = 3-Me, m R1 = 4-Me
All the synthesized 1,2-diacylhydrazines 1-4 (Table 1) were colorless crystalline substances practically
1
insoluble in water and weakly soluble in alcohols. In their H NMR spectra (Table 2) signals of 7-9 protons
close in properties were concentrated in the fairly narrow section from 7.25 to 8.18 ppm in the "aromatic" region
of the spectrum. Consequently precise assignment was difficult if not impossible in the majority of cases without
using special NMR procedures. Only in the spectra of the 3,5-dinitrobenzoyl derivatives 1k-4k, thanks to the
two possessing the powerful magnetic anisotropy nitro groups, were the signals of the protons of the β-N-acyl
residues strongly displaced towards low field and overlap with the signals of the quinolone protons was not
observed.
The microbiological testing carried out showed that in vitro none of the obtained 1,2-diacylhydrazines
1-4 at a concentration of 6.25 µg/ml was capable of inhibiting to a significant degree the growth of
Mycobacterium tuberculosis H37Rv ATCC 27294. The negative effect on antitubercular activity of replacing
the azomethine grouping in benzylidenehydrazines of 1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic
acids by an amide fragment similar in structure has therefore been confirmed experimentally.
N
N
OH
OH
Cl
SOCl2
P2O5 or PPA
O
1–4
Cl
O
O
N
N
R
Pr
7
8a,b
8 a R = Et, b R = Pr
1348

TABLE 1. Characteristics of 1,2-Diacylhydrazines 1-4
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
mp, °C
C
3
H
4
N
5
A
7
B
8
1
1a
1b
1c
1d
1e
1f
2
6
C17H13N3O4
C17H12FN3O4
C17H12ClN3O4
C17H12ClN3O4
C17H12BrN3O4
C17H12BrN3O4
C17H11Cl2N3O4
C17H12N4O6
C17H12N4O6
C17H12N4O6
C17H11N5O8
C18H15N3O4
C18H15N3O4
C18H15N3O4
C18H14FN3O4
C18H14ClN3O4
C18H14ClN3O4
C18H14BrN3O4
C18H14BrN3O4
C18H13Cl2N3O4
C18H14N4O6
C18H14N4O6
C18H14N4O6
C18H13N5O8
C19H17N3O4
C19H17N3O4
C19H17N3O4
C19H16FN3O4
C19H16ClN3O4
C19H16ClN3O4
C19H16BrN3O4
63.21
63.16
59.75
59.83
57.00
57.08
57.03
57.08
50.85
50.77
50.82
50.77
52.01
52.06
55.51
55.44
55.49
55.44
55.53
55.44
49.35
49.40
64.17
64.09
64.16
64.09
64.13
64.09
60.94
60.85
58.08
58.15
58.17
58.15
51.98
51.94
51.87
51.94
53.15
53.22
56.63
56.55
56.61
56.55
56.50
56.55
50.55
50.59
64.86
64.95
64.88
64.95
64.87
64.95
61.85
61.79
59.13
59.15
59.23
59.15
53.11
53.04
4.12
4.05
3.47
3.54
3.29
3.38
3.33
3.38
3.11
3.01
3.08
3.01
2.89
2.83
3.20
3.28
3.36
3.28
3.32
3.28
2.60
2.68
4.54
4.48
4.41
4.48
4.56
4.48
4.03
3.97
3.71
3.80
3.83
3.80
3.46
3.39
3.44
3.39
3.19
3.23
3.74
3.69
3.77
3.69
3.62
3.69
3.01
3.07
4.80
4.88
4.82
4.88
4.80
4.88
4.32
4.37
4.22
4.18
4.27
4.18
3.80
3.75
13.08
13.00
12.41
12.31
11.83
11.75
11.81
11.75
10.54
10.45
10.51
10.45
10.83
10.71
15.17
15.21
15.15
15.21
15.28
15.21
17.03
16.94
12.53
12.46
12.55
12.46
12.40
12.46
11.89
11.83
11.37
11.30
11.39
11.30
10.04
10.10
10.17
10.10
10.41
10.34
14.70
14.65
14.62
14.65
14.57
14.65
16.47
16.39
12.03
11.96
11.90
11.96
12.04
11.96
11.46
11.38
10.94
10.89
10.97
10.89
9.83
9.77
323-325
295-297
326-328
318-320
330-332
392-394
376-378
339-341
321-323
355-357
220 (dec.)
334-336
328-330
137-139
192-194
170-172
153-155
189-191
197-199
279-281
243-245
234-236
215-217
218 (dec.)
224-226
205-207
102-104
188-190
174-176
115-117
196-198
90
93
91
95
84
92
1g
1h
1i
85
82
88
87
90
93
1j
1k
1l
1m
2a
2b
2c
2d
2e
2f
91
88
91
90
93
87
90
2g
2h
2i
86
83
87
88
85
89
2j
2k
2l
2m
3a
3b
3c
3d
3e
90
92
86
94
95
96
89
1349

TABLE 1 (continued)
1
2
3
4
5
6
7
8
3f
C19H16BrN3O4
C19H15Cl2N3O4
C19H16N4O6
C19H16N4O6
C19H16N4O6
C19H15N5O8
C20H19N3O4
C20H19N3O4
C20H19N3O4
C20H18FN3O4
C20H18ClN3O4
C20H18ClN3O4
C20H18BrN3O4
C20H18BrN3O4
C20H17Cl2N3O4
C20H18N4O6
C20H18N4O6
C20H18N4O6
C20H17N5O8
C21H21N3O4
C21H21N3O4
53.09
53.04
54.24
54.30
57.51
57.58
57.68
57.58
57.63
57.58
51.65
51.71
65.83
65.74
65.81
65.74
65.70
65.74
62.74
62.66
60.15
60.08
60.02
60.08
54.13
54.07
54.10
54.07
55.25
55.31
58.47
58.54
3.82
3.75
3.52
3.60
4.00
4.07
4.16
4.07
4.14
4.07
3.36
3.43
5.31
5.24
5.27
5.24
5.19
5.24
4.79
4.73
4.50
4.54
4.47
4.54
4.16
4.08
4.13
4.08
3.86
3.95
4.34
4.42
9.85
9.77
10.11
10.00
14.05
14.14
14.19
14.14
14.10
14.14
15.80
15.87
11.62
11.50
11.55
11.50
11.45
11.50
11.03
10.96
10.53
10.51
10.58
10.51
9.51
9.46
9.55
9.46
9.74
9.68
13.60
13.65
222-224
227-229
243-245
271-273
188-190
223 (dec.)
190-192
182-184
96-98
91
3g
3h
3i
88
85
90
92
87
88
3j
3k
3l
3m
4a
4b
4c
4d
4e
4f
91
86
89
172-174
161-163
120-122
184-186
205-207
209-211
231-233
217-219
166-168
222 (dec.)
151-153
144-146
85
90
87
84
4g
4h
4i
86
80
85
90
85
87
58.48
58.54
58.62
58.54
52.67
52.75
66.55
66.48
4.47
4.42
4.49
4.42
3.66
3.76
5.64
5.58
13.58
13.65
13.73
13.65
15.29
15.38
11.13
11.07
4j
4k
4l
4m
66.57
66.48
5.65
5.58
11.02
11.07
89
The most convenient method of obtaining 2,5-disubstituted 1,3,4-oxadiazoles is the intramolecular
cyclization of 1,2-diacylhydrazines. Closing of the oxadiazole ring may be effected thermally or even by the
action of acid catalysts [6, 7]. For some time past a great number of new dehydrating agents have appeared
[8-11]. However the already well-known agents have not lost their value. Moreover POCl3, P2O5, and SOCl2 are
inexpensive and available [7, 12]. Treatment of diacylhydrazines 1-4 with POCl3 assuredly leads to the
formation of 4-chloro (or 2,4-dichloro in the case of derivatives unsubstituted at position 1) quinolines. For this
reason POCl3 was not considered by us as a possible condensing agent for converting 1,2-diacylhydrazines 1-4
into the corresponding 4-hydroxy-3-(1,3,4-oxadiazol-2-yl)-2-oxo-1,2-dihydroquinolines 7. The use of phosphorus
pentoxide in anhydrous carbon tetrachloride and also PPA was not justified. As it turned out, on interaction with
these reagents 1,2-diacylhydrazines 1-4 were readily decomposed and form 1-R-4-hydroxy-2-oxo-1,2-dihydro-
quinolines 8. It is interesting that under such conditions 2-sulfamylanilides of 1-R-4-hydroxy-2-oxo-1,2-dihydro-
quinoline-3-carboxylic acids behave in an analogous manner [13]. But here in thionyl chloride 1,3,4-oxa-
diazolylquinolines 7 are formed without any complications. The high yield of the desired compounds, the
simplicity of carrying out the experiment, the ease of separating the excess of cyclodehydrating reagent, and its
accessibility on the whole enable this method to be recommended as preparative.
1350

TABLE 2. 1H NMR Spectra of the Synthesized Compounds
Com
pound
Chemical shifts, δ, ppm (J, Hz)*
Н arom.
N- quinolone substituent
1
2
3
1a
8.03-7.25 (9H)
8.04-7.26 (8H)
8.03-7.28 (8H)
8.02-7.26 (8H)
8.04-7.27 (8H)
8.03-7.24 (8H)
8.04-7.28 (7H)
8.02-7.24 (8H)
12.06 (1H, s, NH)
12.07 (1H, s, NH)
12.00 (1H, s, NH)
12.09 (1H, s, NH)
11.98 (1H, s, NH)
12.02 (1H, s, NH)
12.04 (1H, s, NH)
12.01 (1H, s, NH)
12.08 (1H, s, NH)
1b
1c
1d
1e
1f
1g
1h
1i
8.74 (1H, s, H-2'); 8.48-7.25 (7H, m)
1j
8.26 (2Н, d, J = 8.8, H-3',5'); 8.15-8.09 (3H, m, Н-2',6',5); 12.06 (1H, s, NH)
7.80 (1Н, td, J = 7.9 and J = 1.3, Н-7);
7.67 (1Н, d, J = 8.4, Н-8); 7.36 (1Н, td, J = 7.5 and J = 1.3, Н-6)
1k
9.09 (2Н, d, J = 2.3, Н-2',6'); 8.99 (1Н, t, J = 2.3, Н-4');
7.94 (1Н, dd, J = 8.4 and J = 1.5, Н-5);
12.10 (1Н, s, NH)
7.66 (1Н, td, J = 7.9 and J = 1.8, Н-7);
7.35 (1Н, d, J = 8.5, Н-8); 7.25 (1Н, t, J = 7.7, Н-6)
1l
8.03-7.25 (8H)
12.05 (1H, s, NH)
12.08 (1H, s, NH)
1m
8.00 (1Н, dd, J = 8.1 and J = 1.4, Н-5);
7.86-7.75 (3Н, m, Н-2',6',7); 7.44 (1Н, d, J = 8.5, H-8);
7.31 (1Н, t, J = 7.4, Н-6); 7.23 (2Н, d, J = 8.3, Н-3',5')
2a
2b
2c
2d
2e
2f
8.11-7.30 (9H)
3.66 (3H, s, CH3)
3.67 (3Н, s, CH3)
3.66 (3Н, s, CH3)
3.67 (3Н, s, CH3)
3.66 (3Н, s, CH3)
3.67 (3Н, s, CH3)
3.67 (3Н, s, CH3)
3.68 (3Н, s, CH3)
3.66 (3Н, s, CH3)
8.12-7.27 (8H)
8.14-7.35 (8H)
8.13-7.22 (8H)
8.17-7.35 (8H)
8.15-7.32 (8H)
2g
2h
2i
8.16-7.34 (7H)
8.16-7.36 (8H)
8.80 (1H, s, H-2'); 8.51-7.30 (7H, m)
2j
8.38 (2Н, d, J = 8.9, H-3',5'); 8.19-8.13 (3H, m, Н-2',6',5); 3.67 (3Н, s, CH3)
7.87 (1Н, td, J = 7.8 and J = 1.3, Н-7);
7.73 (1Н, d, J = 8.3, Н-8); 7.41 (1Н, td, J = 7.6 and J = 1.2, Н-6)
2k
9.10 (2Н, d, J = 2.3, H-2',6'); 9.01 (1Н, t, J = 2.3, H-4');
8.11 (1Н, dd, J = 8.2 and J = 1.4, H-5);
3.68 (3Н, s, CH3)
7.80 (1Н, td, J = 7.8 and J = 1.7, H-7);
7.67 (1Н, d, J = 8.4, H-8); 7.38 (1Н, t, J = 7.7, H-6)
2l
8.15-7.28 (8H)
3.67 (3Н, s, CH3)
3.66 (3Н, s, CH3)
2m
8.10 (1Н, dd, J = 8.1 and J = 1.4, Н-5);
7.89-7.78 (3Н, m, Н-2',6',7); 7.64 (1Н, d, J = 8. 5, Н-8);
7.39 (1Н, t, J = 7.4, Н-6); 7.30 (2Н, d, J = 8.3, Н-3',5')
3a
3b
3c
3d
3e
3f
8.17-7.34 (9H)
8.16-7.28 (8H)
8.15-7.33 (8H)
8.16-7.26 (8H)
8.18-7.36 (8H)
8.17-7.33 (8H)
4.34 (2Н, q, J = 7.0, NCH2);
1.25 (3H, t, J = 7.0, CH3)
4.34 (2Н, q, J = 7.1, CH2);
1.24 (3H, t, J = 7.1, CH3)
4.33 (2Н, q, J = 7.1, NCH2);
1.25 (3H, t, J = 7.1, CH3)
4.35 (2Н, q, J = 7.0, NCH2);
1.25 (3H, t, J = 7.0, CH3)
4.35 (2Н, q, J = 7.1, NCH2);
1.25 (3H, t, J = 7.0, CH3)
4.34 (2Н, q, J = 7.0, NCH2);
1.26 (3H, t, J = 7.0, CH3)
3g
3h
8.18-7.33 (7H)
8.15-7.32 (8H)
4.34 (2Н, q, J = 7.0, NCH2);
1.24 (3H, t, J = 7.0, CH3)
4.33 (2Н, q, J = 7.1, NCH2);
1.25 (3H, t, J = 7.0, CH3)
1351

TABLE 2 (continued)
1
2
3
3i
3j
8.81 (1H, s, H-2'); 8.52-7.33 (7H, m)
4.34 (2Н, q, J = 7.0, NCH2);
1.26 (3H, t, J = 7.0, CH3)
8.37 (2Н, d, J = 8.9, H-3',5'); 8.18-8.10 (3H, m, Н-2',6',5); 4.35 (2Н, q, J = 7.0, NCH2);
7.85 (1Н, td, J = 7.8 and J = 1.4, Н-7); 7.71 (1Н, d, J = 8.5, Н-8); 1.25 (3H, t, J = 7.0, CH3)
7.40 (1Н, td, J = 7.6 and J = 1.3, Н-6)
3k
9.08 (2Н, d, J = 2.3, Н-2',6'); 9.00 (1Н, t, J = 2.3, Н-4');
8.08 (1Н, dd, J = 8.3 and J = 1. 3, Н-5);
4.36 (2Н, q, J = 7.1, NCH2);
1.24 (3H, t, J = 7.1, CH3)
7.77 (1Н, td, J = 7.7 and J = 1.6, Н-7);
7.65 (1Н, d, J = 8.5, Н-8); 7.38 (1Н, t, J = 7.6, Н-6)
3l
8.16-7.27 (8H)
4.34 (2Н, q, J = 7.1, NCH2);
1.25 (3H, t, J = 7.0, CH3)
3m
8.13 (1Н, dd, J = 8.0 and J = 1.2, Н-5);
7.90-7.79 (3Н, m, Н-2',6',7); 7.70 (1Н, d, J = 8.6, Н-8);
7.41 (1Н, t, J = 7.6, Н-6); 7.31 (2Н, d, J = 8.2, Н-3',5')
4.34 (2Н, q, J = 6.8, NCH2);
1.25 (3H, t, J = 6.9, CH3)
4a
4b
4c
4d
4e
4f
8.18-7.31 (9H)
4.26 (2Н, t, J = 7.4, NCH2);
1.65 (2H, m, СH2CH3);
0.97 (3H, t, J = 7.4, CH3)
8.17-7.26 (8H)
4.26 (2Н, t, J = 7.5, NCH2);
1.67 (2H, m, СH2CH3);
0.99 (3H, t, J = 7.4, CH3)
8.18-7.35 (8H)
4.25 (2Н, t, J = 7.5, NCH2);
1.66 (2H, m, СH2CH3);
0.97 (3H, t, J = 7.5, CH3)
8.13-7.29 (8H)
4.27 (2Н, t, J = 7.4, NCH2);
1.69 (2H, m, СH2CH3);
0.99 (3H, t, J = 7.4, CH3)
8.15-7.34 (8H)
4.25 (2Н, t, J = 7.4, NCH2);
1.66 (2H, m, СH2CH3);
0.97 (3H, t, J = 7.5, CH3)
8.17-7.32 (8H)
4.24 (2Н, t, J = 7.3, NCH2);
1.65 (2H, m, СH2CH3);
0.98 (3H, t, J = 7.4, CH3)
4g
4h
4i
8.16-7.36 (7H)
4.27 (2Н, t, J = 7.5, NCH2);
1.66 (2H, m, СH2CH3);
0.99 (3H, t, J = 7.4, CH3)
8.17-7.35 (8H)
4.26 (2Н, t, J = 7.6, NCH2);
1.67 (2H, m, СH2CH3);
0.98 (3H, t, J = 7.5, CH3)
8.79 (1H, s, H-2'); 8.53-7.36 (7H, m)
4.25 (2Н, t, J = 7.5, NCH2);
1.66 (2H, m, СH2CH3);
0.98 (3H, t, J = 7.4, CH3)
4j
8.40 (2Н, d, J = 8.8, H-3',5'); 8.19-8.10 (3H, m, Н-2',6',5); 4.27 (2Н, t, J = 7.4, NCH2);
7.86 (1Н, td, J = 7.7 and J = 1.4, Н-7);
7.70 (1Н, d, J = 8.4, Н-8);
1.68 (2H, m, СH2CH3);
0.97 (3H, t, J = 7.4, CH3)
7.42 (1Н, td, J = 7.7 and J = 1.3, H-6)
4k
9.09 (2Н, d, J = 2.3, H-2',6'); 9.00 (1Н, t, J = 2.3, H-4');
8.13 (1Н, dd, J = 8.3 and J = 1.5, H-5);
7.84 (1Н, td, J = 7.9 and J = 1.9, H-7);
4.26 (2Н, t, J = 7.2, NCH2);
1.67 (2H, m, СH2CH3);
0.98 (3H, t, J = 7.3, CH3)
7.70 (1Н, d, J = 8. 3, Н-8); 7.39 (1Н, t, J = 7.6, Н-6)
4l
8.15-7.29 (8H)
4.25 (2Н, t, J = 7.3, NCH2);
1.66 (2H, m, СH2CH3);
0.99 (3H, t, J = 7.3, CH3)
4m
8.16 (1Н, dd, J = 8.2 and J = 1.3, Н-5);
7.89-7.77 (3Н, m, Н-2',6',7);7.70 (1Н, d, J = 8.6, Н-8);
7.39 (1Н, t, J = 7.5, Н-6); 7.30 (2Н, d, J = 8.1, Н-3',5')
4.25 (2Н, t, J = 7.4, NCH2);
1.67 (2H, m, СH2CH3);
0.96 (3H, t, J = 7.5, CH3)
_______
* Signals of the protons of the 4-OH groups are displayed as singlets at
16.27-16.05, of the NH groups of hydrazine fragments as two singlets at
12.31-11.87 and 11.63-10.93, and of the methyl groups in β-N-acyl
residues of 1,3-diacylhydrazines 1l,m-4l,m as singlets of intensity 3H at
2.37-2.36 ppm respectively.
1352

EXPERIMENTAL
1
The H NMR spectra of all the synthesized compounds were recorded on a Varian Mercury-VX-200
(200 MHz) spectrometer, solvent was DMSO-d6, and internal standard TMS. The chromato-mass spectrum of
1,3,4-oxadiazolylquinolone 7 was recorded on a Hewlett Packard 5890/5972 instrument in total scanning mode
over the range 35-700 m/z, ionization by electron impact 70 eV; the chromatographic column was a Hewlett
Packard-5MS, length 25 m, internal diameter 0.2 mm, stationary phase was a polysiloxane film (5%
diphenylpolysiloxane, 95% dimethylpolysiloxane) of thickness 0.33 µ, carrier gas was helium. Hydrazides of
1-R-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic acids 6a-d were obtained by the procedure of [14].
β-N-Benzoylhydrazide of 1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylic Acid (3a).
A. Triethylamine (1.54 ml, 0.011 mmol) was added to a solution of hydrazide 6c (2.47 g, 0.01 mol) in dry
dioxane (20 ml), and then benzoyl chloride (1.28 g, 0.011 mol) was added with cooling and stirring. The
mixture was left for 4 h at room temperature. The reaction mixture was diluted with cold water, and acidified
with dilute HCl to pH 5. The precipitated solid diacylhydrazine 3a was filtered off, washed with water, and
dried.
B. A mixture of ester 5c (2.61 g, 0.01 mol), benzoic acid hydrazide (1.36 g, 0.01 mol), and DMF (1 ml)
was stirred and maintained at 160°C for 3-5 min. Initially the reactants dissolved, and then after violent
evolution of ethanol the final diacylhydrazine 3a crystallized out. Ethanol (10-15 ml) was carefully added to the
still hot reaction mixture, which was thoroughly triturated. The solid was filtered off, washed with alcohol, and
dried. A mixing test of samples of diacylhydrazine 3a obtained by the different methods gave no depression of
melting point, and their 1H NMR spectra were identical.
3-[5-(2,4-Dichlorophenyl)-1,3,4-oxadiazol-2-yl]-4-hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline
(7). A solution of 2,4-dichlorobenzoylhydrazide 4g (4.34 g, 0.01 mol) in SOCl2 (50 ml) was boiled for 3.5 h.
The reflux condenser was changed for distillation and the SOCl2 was removed from the reaction mixture (in
vacuum at the end). The residue was treated with cold water, the isolated solid oxadiazoloquinolone 7 was
filtered off, washed with water, and dried. Yield was 3.78 g (91%); mp 170-172°C (ethanol). 1H NMR spectrum,
δ, ppm (J, Hz): 13.06 (1H, br. s, OH); 8.20-7.54 (6H, m, H arom); 7.34 (1H, t, J = 7.6, H-6 quinolone); 4.23
(2H, t, J = 7.3, NCH2); 1.67 (2H, m, CH2CH3); 0.97 (3H, t, J = 7.3, CH3). Mass spectrum, m/z (Irel, %): 415 [M]+
(27), 373 [M-C3H6]+ (77), 188 (42), 173 (58), 132 (100), 77 (22), m/z values are given for the 35Cl isotope only.
Found, %: C 57.79; H 3.72; N 10.02. C20H15Cl2N3O3. Calculated, %: C 57.71; H 3.63; N 10.09.
1-Ethyl-4-hydroxy-2-oxo-1,2-dihydroquinoline (8a). Phosphorus pentoxide (4.2 g, 0.03 mol) was
added to a solution of diacylhydrazine 3a (3.51 g, 0.01 mol) in anhydrous CCl4 (50 ml) and the mixture boiled
with a CaCl2 tube fitted to protect from moisture of the air for 3h. The reaction mixture was cooled, the organic
layer separated from the solid by decantation, after which the CCl4 was distilled off in vacuum. The residue was
treated with cold water, and then Na2CO3 was added to pH 5. The solid was filtered off, washed with water, and
dried. Yield was 1.56 g (83%); mp 274-276oC (ethanol).
A mixing test with an authentic sample of 3H-quinolone 8a [15, 16] gave no depression of melting
point, and the 1H NMR spectra of these compounds were identical.
4-Hydroxy-2-oxo-1-propyl-1,2-dihydroquinoline (8b). A mixture of diacylhydrazine 4a (3.65 g,
0.01 mol) and PPA (polyphosphoric acid) (20 g) was maintained at 100°C for 2 h. The mixture was cooled, an
ice-water mixture was added, and carefully stirred. The reaction mixture was then treated as in the previous
experiment. Yield was 1.50 g (74%); mp 221-222oC (ether).
A mixing test with an authentic sample of the 1-propyl substituted 3H-quinoline 8b [13] gave no
depression of melting point, the 1H NMR spectra of these compounds were identical.
1353

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1354