Synthesis of fluorinated 1,3,4-oxadiazino[6,5,4-i.j]quinolines

Article abstract of DOI:10.1023/A:1013814014098

3-(2-Acylhydrazino)-2-tetra(penta)fluorobenzoylacrylates are readily converted to acylamino-substituted quinolones and, under more forcing conditions, annelation of oxadiazine ring occurs. We have identified the possible cyclization of the mentioned acrylates to 4,5-substituted pyrazoles.

Full text of DOI:10.1023/A:1013814014098

Chemistry of Heterocyclic Compounds, Vol. 37, No. 10, 2001
SYNTHESIS OF FLUORINATED
i j
1,3,4-OXADIAZINO[6,5,4- , ]QUINOLINES
G. N. Lipunova, E. V. Nosova, V. N. Charushin, and O. M. Chasovskikh
3-(2-Acylhydrazino)-2-tetra(penta)fluorobenzoylacrylates are readily converted to acylamino-
substituted quinolones and, under more forcing conditions, annelation of oxadiazine ring occurs. We
have identified the possible cyclization of the mentioned acrylates to 4,5-substituted pyrazoles.
Keywords: hydrazides of aromatic and pyridinecarboxylic acids, 1,3,4-oxadiazino[6,5,4-i,j]quinolines,
reactivity, spectral characteristics.
Derivatives of 6-fluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylic acids (fluoroquinolones) have
presented themselves as efficient antibacterial agents [1-3]. Tri- and tetracyclic fluoroquinolones are particularly
promising in this series and, along with their antibacterial activity, they possess antiviral and antitumor activity.
The most important representatives of these polycyclic fluoroquinolones, having use in clinical practice, are the
preparations ofloxacin (A), levofloxacin (the optically active S-isomer of ofloxacin), and marbofloxacin (B),
and also the compound KB-5246 (C) which is under development [4-6].
O
O
8
7
COOH
F
COOH
F
9
6
10
N
5
N 4
N
N
N
N
O
N
O
*
1
Me
Me
Me
3
Me
2
B
A
O
N
F
COOH
S
N
N
O
Me
C
In compounds A and C the quinolone residue is annelated at the [i,j] edge by the oxazine and in
compound B by the 1,3,4-oxadiazine ring. Construction of the oxadiazine ring in compound B is carried out as
in Scheme 1, but the given method allows one to obtain only derivatives which do not have a substituent at the
position 2 [7].
__________________________________________________________________________________________
Ural State Technical University, Yekaterinburg 620002, Russia; e-mail: charushin@prm.uran.ru,
azine@htf.rcupi.e-burg.su. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1396-1406,
October, 2001. Original article submitted July 20, 1999; revision submitted June 5, 2000.
1278
0009-3122/01/3710-1278$25.00©2001 Plenum Publishing Corporation

Scheme 1
O
O
F
F
COOEt
F
COOEt
CH2O, H2O
B
N
F
N
N
F
NHMe
F
Me
OH
Synthesis of [i,j]-annelated quinolones can be brought about if there are substituents at the quinoline
nitrogen atom which contain a nucleophilic center in the -position [8, 9]. Hence cyclization of quinolones
γ
containing thiosemicarbazide fragment permits the preparation of 1,3,4-thiadiazino[i,j]-annelated systems [9].
By the reaction of ethyl 3-ethoxy-2-polyfluorobenzoylacrylates 1a,b with the hydrazides of benzoic,
m-nitrobenzoic, and acetic acids 2a,b,e in ethanol or pyridinecarboxylic acids 2e,d in toluene at room
temperature, we have synthesized 3-(2-acylhydrazino)-2-tetra(penta)fluorobenzoylacrylates 3a-h (Scheme 2) in
71-97% yields and have studied their cyclization. Like the starting acrylates 1a,b, compounds 3a-c,h exist in
solution as a mixture of two isomers (3' and 3'') relative to the C=C bond of the side chain and this is indicated
by the presence of a double set of proton signals in their 1H NMR spectra (Table 1).
Scheme 2
X
O
F
X
O
F
F
F
COOEt
F
F
COOEt
R
O
NHNH2
2a–f
O
+
OEt
NH-NH-C
R
F
1a,b
F
3a–i
X
5
O
X
O
O
4
F
F
COOEt
8
7
3
F
COOEt
EtOOC
9
6
6
5
1
F10
N
N 3
2
N
7
4
F8
NH
C
O
R
1
R2
4a–i
5a–g
EtOOC
N
N
F
F
F
F
N
N
H
3d,f
F
O
F
N
F
F
7
6
1a X = H, b X = F; 2a-5a X = H, R = Ph; 2b-5b X = H, R = C6H4,NO2-3;
3c–5c X = F, R = C6H4NO2-3; 2c, 3d-5d X = H, R = 4-pyridyl;
3e-5e X = F, R = 4-pyridyl; 2d, 3f–5f X = H, R = 3-pyridyl, 3g-5g X = F,
R = 3-pyridyl; 2e, 3h, 4h X = H, R = Me; 2f, 3i, 4i X = H, R = CH2CN
1279

TABLE 1. 1H NMR Spectral Characteristics of Ethyl 3-(2-Acylhydrazino-1)-2-[tetra(penta)fluorobenzoyl]acrylates 3a-h,
δ, ppm, spin-spin coupling constants (J), Hz
=CHNH
NHCO, br. s
3' 3''
=CHNH
Com-
Solvent
Isomer ratio 3':3''*
pound
3'
3''
3'
3''
CD3CN
CDCl3
11.90, br. d,
10.45, br. d,
9.70
8.31, d,
8.11, d,
3:1
5:2
3а
3JHH = 11.0
3JHH = 11.0
3JHH = 11.0
3JHH = 11.0
12.0, br. d,
11.1, br. d,
9.99
10.1
10.4
10.7
8.71, d,
3b
3JHH = 11.4
3JHH = 11.4
J
HH = 11.4
CDCl3
12.3, br. s
11.1, br. s
8.37, s
8.24, s
8.64, s
7.83, s
5:2
—
—
—
—
4:3
3c
3d*2
3e
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
DMSO-d6
12.3, br. s
11.5, br. s
12.3, br. s
11.2, br. s
11.0
11.5
11.0
11.2
8.4, s
8.4, s
8.3, s
8.4, s
3f *3
3g
13.60, br. s
10.15
11.05
3h

TABLE 1 (continued)
COOEt
R
6-H
Com-
CH2, q
CH3, t
pound
3'
3''
3'
3''
3'
3''
3'
3''
7.87 (2H, m, 2'- and 6'-H), 7.56 (3Н, m, 3'-,4'- and 5'-H)
7.19, m
7.02, m
4.04, 3JHH = 7.1
1.09, 3JHH = 7.1
3a
3b
8.2-8.5 (3Н, m, 2'-, 4'- and 6'-H), 7.72 (1Н, dd, 5'-H, 3JHH = 8.0)
4.05
4.12
1.07
1.24
3JHH = 7.0
3JHH = 7.0
3JHH = 7.0
3JHH = 7.0
8.72 (1Н, m, 2'-H),
8.70 (1Н, m, 2'-H),
—
4.06
4.11
1.09
1.01
3c
8.44 (1Н, m, 4'-H or 6'-H),
8.27 (1Н, m, 4'-H or 6'-H),
7.72 (1Н, t, 5'-H, 3JHH = 7.9)
8.41 (1Н, m, 4'-H or 6'-H),
8.23 (1Н, m, 4'-H or 6'-H),
7.68 (1Н, t, 5'-H, 3JHH = 7.9)
3JHH = 7.0
3JHH = 7.0
3JHH = 7.0
3JHH = 7.0
8.9 (2Н, m, 3'- and 5'-Н); 7.8 (2Н, m, 2'- and 6'-H)
7.5, m
—
7.5, m
—
4.1, 3JHH = 7.1
1.1, 3JHH = 7.1
3d
3e
3f
3g
3h
8.8 (2Н, m, 3'- and 5'-Н); 7.8 (2Н, m, 2'- and 6'-H)
9.1 (1Н, m, 2'-Н); 8.8 (1Н, m, 4'-Н); 7.7 (1Н, m, 6'-Н); 7.5 (1Н, m, 5'-H)
9.1 (1Н, m, 2'-Н); 8.7 (1Н, m, 4'-Н); 8.3 (1Н, m, 6'-Н); 7.6 (1Н, m, 5'-H)
4.0, 3JHH = 7.1
4.1, 3JHH = 7.2
4.1, 3JHH = 7.2
1.1, 3JHH = 7.1
1.1, 3JHH = 7.2
1.1, 3JHH = 7.2
2.12 (3H, s, CH3CO)
1.93 (3H, s, CH3CO)
7.41, m
4.14
3.94
1.20
0.99
6.95, m
3JHH = 7.0
3JHH = 7.0
3JHH = 7.0
3JHH = 7.0
_______
* Measurement based on the intensity of the doubled signals
*
*
2 19F NMR spectrum (DMSO-d6): 157.6 (1F, m); 156.2 (1F, m); 143.4 (1F, m); 140.1 (1F, m).
3 19F NMR spectrum (DMSO-d6): 157.7 (1F, m); 156.2 (1F, m); 142.3 (1F, m); 140.2 (1F, m).

TABLE 2. 1H NMR Spectral Characteristics of Ethyl 5-X-1-Acylamino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-
quinolinecarboxylates 4a-e,g,h,i, δ, ppm, spin-spin coupling constants (J), Hz
Compound
Solvent
CD3CN
NH, br. s
2-H, s
5-H
R
OCH2, q
CH3, t
10.75
10.9
8.50
8.54
7.66 m
7.97 (3Н, m); 7.58 (2Н, m)
4.24
4.26
1.30
1.31
4а
4b
CD3CN
8.01 (ddd,
3JHF = 10.4,
4JHF = 8.2,
5JHF = 2.2)
8.76 (1H, dd, 4JHH = 1.7, 2'-H,); 8.49 (1H, ddd, 3JHH = 8.3,
4JHH = 2.4, 4JHH = 1.1, 4'- or 6'-H); 8.30 (1H, m, 4'- or 6'-H);
7.83 (1H, dd, 3JHH = 8.1, 5'-H)
CDCl3
12.4
12.9
8.54
8.81
8.98 (1H, dd, 4JHH = 1.8, 2'-H); 8.45 (2H, m, 4'-, 6'-H);
7.73 (1H, dd, 3JHH = 7.9, 5'-H)
4.09
4.26
1.19
1.30
4c
—
DMSO-d6
8.04 (ddd,
3JHF = 10.2,
4JHF = 8.0,
5JHF = 2.1)
8.87 (2H, dd, 4JHH = 4.4, 5JHH = 1.5, 3'-, 5'-H);
7.87 (2H, dd, 4JHH = 4.4, 5J = 1.5, 2'-, 6'-H)
4d
DMSO-d6
DMSO-d6
12.85
12.6
8.72
8.56
8.87 (2H, dd, 4JHH = 4.4, 5JHH = 1.5, 3'-, 5'-H);
7.85 (2H, dd, 4JHH = 4.4, 5J = 1.5, 2'-, 6'-H)
4.23
4.27
1.29
1.34
4e
4g
—
9.09 (1H, dd, 4JHH = 1.5, 5JHH = 0.9, 2'-H);
8.80 (1H, dd, 3JHH = 4.9, 4JHH = 2.1, 4'-H);
—
8.26 (1H, ddd, 3JHH = 7.9, 4JHH = 2.1, 4JHH = 1.5, 6'-H);
7.58 (1H, ddd, 3JHH = 7.9, 3JHH = 4.9, 5JHH = 0.9, 5'-H)
CDCl3
11.68
12.4
8.45
8.61
7.71 (ddd,
3JHF = 10.5,
4JHF = 8.1,
5JHF = 2.1)
2.33 (3H, s, COCH3)
3.99 (2H, s, CH2CN)
4.09
4.26
1.24
1.29
4h
4i
DMSO-d6
8.0 m

Cyclization of acrylates 3 can occur by two routes. Refluxing compounds 3a-e,g,h in benzene (toluene)
for 1 h gives the 1-acylamino-substituted quinolones 4a-e,g,h in 40-92% yields. With more prolonged heating of
acrylates 3a-g in toluene in the presence of K2CO3 (3-4 h), the formation of the quinolone moiety is followed by
cyclization involving the oxygen atom of the amide group to give compounds 5a-g in 56-87% yields. The
acylhydrazides 3d,e,f,g can be converted to the tricyclic compounds 5d,e,f,g in refluxing toluene in the absence
of base. Acrylate 3f is cyclized to quinolone 5f so readily that it is not possible to separate the compound 4f.
The bicyclic quinolones 4a-e are converted to the tricyclic derivatives 5a-e upon heating in toluene in the
presence of K2CO3. Compounds 5e,g are also obtained by refluxing the corresponding acrylates 3e,g in
acetonitrile in the presence of KF for 3 h.
Quinolones 4h,i can also be obtained without separation of the intermediate hydrazidoacrylates 3h,i.
Hence holding a mixture of acetic acid hydrazide 2e and 3-ethoxy-2-tetrafluorobenzoylacrylate 1a in ethanol at
room temperature for 5 h and subsequent refluxing of the residue (after removal of solvent) in toluene for 4 h
gave the product 4h in 91% yield. Heating a mixture of cyanoacetic acid hydrazide 2f and acrylate 1a in toluene
for 1.5 h at 80°C gave quinolone 4i in 63% yield.
The reaction of 4h,i to 5h,i could not be carried out either in toluene with K2CO3 or in dioxane with
NaH. When compound 4h was heated in acetonitrile in the presence of diazabicycloundec-7-ene the cyclization
1
product was recorded spectroscopically using 1H NMR. The H NMR spectrum of the product showed a signal
4
for the proton of the polyfluorobenzene fragment as a double doublet (3J = 10.2, J = 7.6 Hz) whereas in
quinolone 4h it appeared as a double doublet of doublets. Isolation of a pure product and the proof of structure
for the product of this reaction were not achieved.
The structures of the synthesized ethyl 5-X-1-acylamino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-
carboxylates 4a-e,g,h,i and ethyl 2-R-8-X-9,10-difluoro-7-oxo-7-H-[1,3,4]-oxadiazino[6,5,4-i,j]quinoline-6-
1
19
carboxylates 5a-g were established on the basis of their H, F NMR, and mass spectroscopic data. Hence the
1H NMR spectra of quinolones 4a-e,g,h,i show a singlet signal for the 2-H proton, a double doublet of doublets
for the 5-H proton in the case of compounds 4a,b,d,h,i, signals for the protons of the ethyl group and the R
substituent, and also a broadened singlet for the NH group proton in the region of 10.7-12.9 ppm (Table 2). The
19F NMR spectra show signals for all the fluorine atoms.
The mass spectra of the compounds 4 are characterized by a low intensity molecular ion peak (3-4% in
the case of quinolones 4d,h,i) or the absence of the same, with the presence of intense peaks [M-HF]+ for
compounds 4a,b,e since, under mass spectrum scanning conditions, the given quinolones readily lose HF to give
the tricyclic derivatives 5. Subsequent fragmentation is evidently associated with elimination of ethoxy and
carbethoxy groups and also with the destruction of the oxadiazine ring (Table 3).
TABLE 3. Mass Spectral and 19F NMR Spectral Characteristics of Ethyl
5-X-1-Acylamino-6,7,8-trifluoro-4-oxo-1,4-dihydro-3-quinolinecarboxylates
4a-e,g,h,i
19F NMR spectra (DMSO-d6), δF, ppm, spin-spin
coupling constants, (J), Hz
Com-
pound
Mass spectrum,
m/z (Irel, %)
1
2
3
[M–HF]+ 370 (20),
325 (21), 298 (100),
222 (14), 195 (42)
151.31 (ddd, 3JFF = 23.1, 3JFF = 19.5, 4JHF = 8.3, 7-F);
148.48 (ddd, 3JFF = 19.5, 4JFF = 4.9, 5JHF = 2.0, 8-F);
136.45 (ddd, 3JFF = 23.1, 3JHF = 10.5, 4JFF = 4.9, 6-F)
4a
[M–HF]+ 415 (11),
370 (13), 343 (100),
324 (15), 297 (14),
222 (9), 195 (22)
151.14 (ddd, 3JFF = 23.1, 3JFF = 19.4, 4JHF = 8.2, 7-F);
148.71 (ddd, 3JFF = 19.4, 4JFF = 4.9, 5JHF = 2.2, 8-F);
136.36 (ddd, 3JFF = 23.1, 3JHF = 10.4, 4JFF = 4.9, 6-F)
4b
4c
[M–HF]+ 434 (18),
388 (23), 361 (100),
342 (17), 315 (12),
240 (24), 213 (38)
160.11 (dd, 3JFF = 21.7, 3JFF = 20.2, 7-F);
154.12 (dd, 3JFF = 20.2, 4JFF = 13.9, 5-F);
147.15 (ddd, 3JFF = 21.7, 3JFF = 20.2, 4JFF = 9.2, 6-F);
142.82 (ddd, 3JFF = 20.2, 4JFF = 13.9, 4JFF = 9.2, 8-F)
1283

TABLE 3 (continued)
1
2
3
M+ 391 (4), 371 (100),
326 (100), 300 (98),
299 (100), 222 (38)
151.13 (ddd, 3JFF = 23.2, 3JFF = 19.2, 4JHF = 8.0, 7-F);
148.66 (ddd, 3JFF = 19.2, 4JFF = 4.6, 5JHF = 2.1, 8-F);
136.32 (ddd, 3JFF = 23.2, 3JHF = 10.2, 4JFF = 4.6, 6-F)
4d
4e
[M–HF]+ 389 (63),
344 (48), 317 (100),
240 (24)
160.75 (dd, 3JFF = 22.6, 3JFF = 21.6, 7-F);
155.89 (dd, 3JFF = 21.6, 4JFF = 13.3, 5-F);
148.65 (ddd, 3JFF = 21.6, 3JFF = 22.6, 4JFF = 8.5, 6-F);
143.17 (ddd, 3JFF = 21.6; 4JFF = 13.3; 4JFF = 8.5, 8-F)
[M–HF]+ 390 (30), 34 (27), 160.81 (dd, 3JFF = 22.2, 3JFF = 21.5, 7-F);
4g
317 (100), 240 (24), 213
(42), 185 (31)
155.91 (dd, 3JFF = 21.5, 4JFF = 13.3, 5-F);
148.68 (ddd, 3JFF = 21.5, 3JFF = 22.2, 4JFF = 8.5, 6-F);
143.22 (ddd, 3JFF = 21.5, 4JFF = 13.3, 4JFF = 8.5, 8-F)
M+ 328 (3%), 308 (27),
263 (56), 236 (100),
222 (30), 195 (46)
151.53 (ddd, 3JFF = 23.3, 3JFF = 19.4, 4JHF = 8.6, 7-F);
148.73 (ddd, 3JFF = 19.4, 4JFF = 4.3, 5JHF = 2.2, 8-F);
136.60 (ddd, 3JFF = 23.3, 3JHF = 10.8, 4JFF = 4.3, 6-F)
4h
4i
M+ 353 (3%), 333 (13),
308 (4), 288 (32), 261
(100), 223 (36), 195 (6)
151.29 (ddd, 3JFF = 23.2, 3JFF = 19.3, 4JHF = 7.8, 7-F);
148.29 (ddd, 3JFF = 19.3, 4JFF = 4.9, 5JHF = 2.0, 8-F);
136.42 (ddd, 3JFF = 23.2, 3JHF = 10.5, 4JFF = 4.9, 6-F)
The 1H NMR spectra of the tricyclic fluoroquinolone derivatives 5 are characterized by the presence of a
singlet for the 2-H proton, a double doublet for the 8-H proton (5a,b,d,e), and also signals for the protons of the ethyl
group and the substituent R (Table 4). The 19F NMR spectra also correspond to the proposed structure 5. In the
mass spectra of quinolones 5 intense molecular ion peaks are observed. The peak with 100% intensity corresponds
to fission of carbethoxy group and this underlines the high thermal stability of the tricyclic system 5 (Table 5).
1
TABLE 4. H NMR Spectral Characteristics of Ethyl 2-R-8-X-9,10-
Difluoro-7-oxo-7-H-[1,3,4]oxadiazino[6,5,4-i,j]quinolinecarboxylates 5a-g*,
, ppm, spin-spin coupling constants (J), Hz
δ
Com-
5-H, s
8-H
R
OCH2, q CH3, t
pound
8.48
8.72
7.63 m
7.59 dd
8.02 (2Н, m); 7.63 (3Н, m)
4.27
4.26
1.33
1.35
5a
5b
7.90 (dd, 1H, 3JHH = 7.9, 5'-H);
(3JHF = 10.5, 8.37 (m, 1H, 4'- or 6'-H);
4JHF = 7.6)
8.48 (m, 1H, 4'- or 6'-H);
8.54 (m, 1H, 2'-H)
8.46
—
7.89 (dd, 1H, 3JHH = 8.1, 5'-H);
8.34 (m, 1H, 4'- or 6'-H);
8.51 (m, 1H, 4'- or 6'-H);
8.68 (m, 1H, 2'-H)
4.24
1.34
5c
8.56
8.47
8.57
7.63 dd
7.88 (dd, 2H, 3JHH = 4.5, 4JHH = 1.5,
4.23
4.22
4.23
1.30
1.28
1.30
5d
5e
5f
(3JHF =11.0, 2'- and 6'-H); 8.85 (dd, 2H, 3JHH = 4.5,
4JHF = 7.5)
4JHH = 1.5, 3'- and 5'-H)
—
7.85 (dd, 2H, 3JHH = 4.6, 4JHH = 1.5,
2'- and 6'-H); 8.84 (dd, 2H, 3JHH = 4.6,
4JHH = 1.5, 3'- and 5'-H)
7.64 dd
7.67 (ddd, 1H, 3JHH = 8.1, 3JHH = 4.9,
(3JHF = 10.4, 5JHH = 0.8, 5'-H); 8.32 (ddd, 1H, 3JHH = 8.1,
4JHF = 7.6)
4JHH = 2.3, 4JHH = 1.5, 6'-H); 8.85 (dd, 1H,
3JHH = 4.9, 4J = 2.3, 4'-H); 9.14 (dd, 1H,
4JHH = 1.5, 5JHH = 0.8, 2'-H)
8.50
—
7.65 (ddd, 1H, 3JHH = 8.1, 3JHH = 4.8,
5JHH = 0.9, 5'-H); 8.32 (ddd, 1H,
4.23
1.29
5g
3JHH = 8.1, 4JHH = 2.3, 4JHH = 1.5, 6'-H);
8.86 (dd, 1H, 3JHH = 4.8, 4JHH = 2.3, 4'-H);
9.12 (dd, 1H, 4JHH = 1.5, 5JHH = 0.9, 2'-H)
_______
* Spectrum of compound 5a recorded in CD3CN, the reminder in DMSO-d6
1284

TABLE 5. Mass Spectral and 19F NMR Spectral Characteristics of Ethyl
2-R-8-X-9,10-Difluoro-7-oxo-7-H-[1,3,4]oxadiazino[6,5,4-i,j]quinoline-6-
carboxylates 5a-g
19F NMR spectra (DMSO-d6), δ, ppm,
Com-
Mass spectrum, m/z (Irel, %)
spin-spin coupling constants, (J), Hz
pound
M+ 370 (23), 325 (24), 298 (100),
222 (17), 195 (51)
154.65 (dd, 3JFF = 22.0, 4JHF = 7.3, 10-F);
134.91 (dd, 3JFF = 22.0, 3JHF = 10.7, 9-F)
5a
M+ 415 (14), 370 (16), 343 (100),
324 (20), 297 (16), 222 (11),
195 (26)
154.65 (dd, 3JFF = 22.1, 4JHF = 7.8, 10-F);
134.59 (dd, 3JFF = 22.1, 3JHF = 10.5, 9-F)
5b
M+ 433.6 (16), 389 (14), 362 (100),
160.58 (dd, 3JFF = 19.5, 3JFF = 20.5, 9-F);
5c
42 (13), 315 (8), 240 (12), 213 (29), 151.45 (dd, 3JFF = 20.5, 4JFF = 5.5, 10-F);
185 (23)
146.25 (dd, 3JFF =19.5, 4JFF = 5.5, 8-F)
M+ 371 (50), 326 (51), 299 (100)
154.24 (dd, 3JFF = 22.0, 4JHF = 7.5, 10-F);
134.51 (dd, 3JFF = 22.0, 3JHF = 11.0, 9-F)
5d
5e
M+ 389 (40), 344 (45), 317 (100),
240 (36), 213 (34), 185 (34)
160.59 (dd, 3JFF = 20.2, 3JFF = 21.4, 9-F);
151.43 (dd, 3JFF = 21.4, 4JFF = 6.0, 10-F);
146.19 (dd, 3JFF = 20.2, 4JFF = 6.0, 8-F)
M+ 371 (82), 326 (73), 299 (100)
154.24 (dd, 3JFF = 22.0, 4JHF = 7.6, 10-F);
134.66 (dd, 3JFF = 22.0, 3JHF = 10.4, 9-F)
5f
M+ 389 (34), 344 (30), 317 (100),
240 (29), 213 (33), 185 (27)
160.77 (dd, 3JFF = 20.2, 3JFF = 21.3, 9-F);
151.42 (dd, 3JFF = 21.3, 4JFF = 5.5, 10-F);
146.31 (dd, 3JFF = 20.2, 4JFF = 5.5, 8-F)
5g
In the case of acrylates 3d,f it was found that, when refluxed in acetonitrile in the presence of KF for
4 h, cyclization by a second route occurred involving carbonyl group and that this led to the 4,5-substituted
pyrazoles 6,7.
This reaction is accompanied by hydrolysis of the amide group (Scheme 2), while in the case of acrylate
1
3f only pyrazole 7 was isolated. The structure of the products 6,7 was confirmed by H and 19F NMR
spectroscopic data (see Experimental).
In conclusion, we should mention that the derivatives 5 are important synthetic intermediates and can be
used to prepare a wide range of novel tricyclic fluoroquinolone carboxylic acid derivatives in order to study
their biological activity.
TABLE 6. Characteristics of the Compounds Synthesized
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
Yield, %
(method)
mp, °С
C
3
H
4
N
5
1
3a
3b
3c
3d
3e
3f
2
6
7
C19H14F4N2O4
55.84
55.62
3.35
3.44
7.01
6.83
148-150
68-70
74 (A)
90 (A)
79 (A)
97 (B)
89 (B)
93 (B)
97 (B)
C19H13F4N3O6
C19H12F5N3O6
C18H13F4N3O4
C18H12F5N3O4
C18H13F4N3O4
C18H12F5N3O4
49.98
3.08
9.41
50.12
2.88
9.23
47.74
48.12
2.76
2.56
8.96
8.88
79-81
52.47
3.59
9.62
111-113
125-127
127-129
117-119
52.56
3.19
10.22
50.20
50.36
3.00
2.89
10.03
9.79
52.61
3.35
10.03
10.22
10.40
52.56
3.19
49.97
50.36
3.00
2.82
3g
9.79
1285

TABLE 6 (continued)
1
2
3
4
5
6
7
C14H12F4N2O4·H2O
C19H13F3N2O4·H2O
C19H12F3N3O6·H2O
C19H11F4N3O6·0.5H2O
45.92
45.91
3.60
3.85
7.81
7.65
133-135
82-84
71 (A)
91 (D)
82 (D)
96 (D)
40 (C)
56 (C)
78 (D)
3h
56.06
3.77
6.80
4a
4b
4c
4d
4e
4g
4h
55.89
3.70
6.86
50.43
50.34
3.23
3.11
9.15
9.27
124-126
176-178
140-142
136-138
112-114
172-174
49.70
2.85
9.12
49.38
2.62
9.05
C18H12F3N3O4·C2H5OH 55.10
54.92
4.22
4.15
9.58
9.61
C18H11F4N3O4·H2O
C18H11F4N3O4·H2O
C14H11F3N2O4·H2O
51.14
3.09
9.86
50.60
3.07
9.83
50.81
50.60
3.38
3.07
9.78
9.83
49.13
3.48
8.22
84 D),
91 (E)
48.56
3.78
8.09
C15H10F3N3O4
C19H12F2N2O4
50.96
51.00
3.02
2.85
12.77
11.90
213-215
209-211
63 (F)
4i
60.90
3.31
7.39
85 (I),
95 (J)
5a
61.63
3.27
7.56
C19H11F2N3O6·0.5H2O
C19H10F3N3O6·0.5H2O
C18H11F2N3O4
54.08
53.81
2.94
2.85
9.83
9.91
256-258
248-250
244-246
238-240
216-218
226-228
76 (I),
5b
5c
5d
5e
5f
89 (J)
51.79
2.65
9.46
71 (I),
83 (J)
51.62
2.51
9.51
58.10
58.23
2.99
2.99
10.86
11.32
69 (I), 78 (J),
61 (G)
C18H10F3N3O4
55.67
2.71
11.17
87 (I), 81 (J),
72 (H), 87 (G)
55.54
2.59
10.79
C18H11F2N3O4
58.42
58.23
2.89
2.99
11.11
11.32
67 (I),
58 (G)
C18H10F3N3O4
55.38
2.67
10.57
56 (I), 76 (H),
64 (G)
5g
55.54
2.59
10.79
C18H11F4N3O3·H2O
C12H8F4N2O2
52.53
52.56
3.10
3.19
10.07
10.22
143-145
140-142
47
6
7
50.41
3.15
9.89
38
50.09
2.80
9.72
EXPERIMENTAL
1H NMR spectra were obtained on a Bruker WP-250 (250 MHz) instrument using DMSO-d6, CDCl3,
and CD3CN as solvents and TMS as internal standard. 19F NMR spectra were recorded on a Bruker WP-80
(80 MHz) instrument using DMSO-d6 solvent and hexafluorobenzene as internal standard. Mass spectra were
taken on a Varian MAT 311A spectrometer. Scanning conditions: accelerating voltage 3 kV, cathode emission
current 300 microamperes, and electron ionization energy 70 eV; direct introduction of samples into the source.
The characteristics for the compounds synthesized are given in Table 6.
Ethyl 3-[2-(R-Carbonyl)hydrazino-1]-2-[tetra(penta)fluorobenzoyl]acrylates (3a-h). A. Ethyl
2-tetra(penta)fluorobenzoyl-3-ethoxyacrylate 1a,b (4 mmol) was added to suspension of hydrazide 2a,b,e
(3.9 mmol) in ethanol (15 ml). The reaction mixture was stirred at room temperature for 2-3 h, the precipitated
product filtered off, and recrystallized from ethanol to give the compounds 3a-c,h.
B. Ethyl 2-tetra(penta)fluorobenzoyl-3-ethoxyacrylate 1a,b (7 mmol) was added to suspension of
pyridinylhydrazide 2c,d (1 g, 7 mmol) in absolute toluene (15 ml). The reaction mixture was stirred at room
temperature for 2-3 h and the precipitate obtained was filtered and washed with n-hexane to give compounds
3d-g.
1286

Ethyl 5-X-1-Acylamino-6,7,8-trifluoro-4-oxo-1,4-dihydroquinoline-3-carboxylates (4a-e,g,h,i). C.
Solution of compound 3d (0.8 g, 1.9 mmol) in absolute toluene (12 ml) was refluxed for 1 h and the reaction
mixture was filtered hot and the product 4d recrystallized from isopropanol. Yield 0.3 g. Acylhydrazide 3e gave
compound 4e similarly.
D. Solution of acrylate 3b (0.7 g, 1.5 mmol) in absolute benzene (10 ml) was held at 80°C for 2 h. After
cooling, the precipitated compound 4b was filtered off and recrystallized from ethanol. Compounds 4a,c,g,h
were obtained similarly.
E. Ethyl ester 1a (2.2 g, 6.8 mmol) was added to suspension of acylhydrazide 2e (0.5 g, 6.76 mmol) in
ethanol (15 ml). The reaction mixture was stirred at room temperature for 5 h and then cooled. Absolute toluene
(12 ml) was added to the residue and the solution was refluxed for 4 h. The precipitated compound 4h was
filtered off and recrystallized from ethanol.
F. Ethyl 3-ethoxy-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (3.2 g, 10 mmol) was added to suspension of
cyanoacetic acid hydrazide 2f (1 g, 10 mmol) in absolute toluene (15 ml). The reaction product was held at 80°C
for 1.5 h, cooled, and the precipitated compound 4i was filtered off and recrystallized from acetonitrile.
Ethyl 2-R-8-X-9,10-difluoro-7-oxo-7-H-[1,3,4]oxadiazino[6,5,4-i,j]quinoline-6-carboxylates (5a-g).
G. Solution of compound 3e (0.5 g, 1.2 mmol) in absolute toluene (20 ml) was refluxed for 2 h. After cooling,
the precipitated product 5e was filtered off and recrystallized from isopropanol. Compounds 5d,f,g were
obtained similarly.
H. Solution of compound 3g (0.5 g, 1.2 mmol) and potassium fluoride (0.14 g, 2.4 mmol) in absolute
acetonitrile (10 ml) was refluxed for 2 h. After cooling, the reaction product 5g was filtered off, washed with
water, and recrystallized from ethanol. Compound 5e was obtained similarly.
I. Potassium carbonate (0.3 g, 2.4 mmol) was added to suspension of acrylate 3g (0.5 g, 1.2 mmol) in
absolute toluene (8 ml). The reaction mixture was refluxed for 2 h and then cooled. The precipitated compound
5g was filtered off, washed with water, and recrystallized from ethanol. Compounds 5a-f were obtained
similarly.
J. Potassium carbonate (0.1 g, 0.7 mmol) was added to solution of quinolone derivative 4b (0.3 g,
0.7 mmol) in absolute toluene (8 ml). The reaction mixture was refluxed for 3 h and then cooled. The
precipitated product 5b was filtered off, washed with water, and recrystallized from DMF. Compounds 5a,c,d,e
were obtained similarly.
4-Carbethoxy-1-(pyridin-4-yl)carbonyl-5-(2,3,4,5-tetrafluorophenyl)pyrazole (6) and 1-H-4-carbethoxy-
5-(2,3,4,5-tetrafluorophenyl)pyrazole (7). Potassium fluoride (0.14 g, 2.4 mmol) was added to solution of
acrylate 3d (0.5 g, 1.2 mmol) in absolute acetonitrile (12 ml). The reaction mixture was refluxed for 4 h and
then cooled. The precipitated pyrazole 6 was filtered off, washed with water, and recrystallized from ethanol.
The mother liquor was diluted with water and the precipitated compound 7 was filtered off and recrystallized
from ethanol.
1
4
5
Compound 6. H NMR spectrum (DMSO-d6), , ppm, J (Hz): 8.73 (2H, dd, JHH = 4.4, JHH = 1.5,
δ
3'- and 5'-H); 8.39 (1H, s, 3-H); 7.78 (2H, dd, 4JHH = 4.4, 5JHH = 1.5, 2'- and 6'-H); 7.54 (1H, m, 6''-H); 4.20 (2H,
q, CH2); 1.10 (3H, t, CH3). 19F NMR spectrum (DMSO-d6), , ppm: 117.6 (1F, m); 116.5 (1F, m); 100.9 (1F, m);
δ
99.3 (1F, m).
Compound 7. 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 13.77 (1H, br. s, NH); 8.40 (1H, s, 3-H);
δ
7.54 (1H, m, 6''-H); 4.10 (2H, q, CH2); 1.20 (3H, t, CH3). 19F NMR spectrum (DMSO-d6), , ppm: 157.7 (1F, m);
δ
156.7 (1F, m); 141.1 (1F, m); 139.4 (1F, m). Mass spectrum, m/z (%): M+ 288 (26), 260 (17), 243 (100),
240 (65), 216 (22), 18 (21).
This work was carried out with the financial support of the special technical science federal program
"Research and Development on Prioritising Progress in the Science and Technology of Civic Growth" in the
project scheme "Basic Problems in Contemporary Chemistry" (9.1.06).
1287

REFERENCES
1.
2.
D. C. Hoope and J. S. Wolfson (editors), Quinolone Antibacterial Agents, ASM, Washington (1993).
G. A. Mokrushina, S. G. Alekseev, V. N. Charushin, and O. N. Chupakhin, Zh. Vses. Khim. O-va., 36,
447 (1991).
3.
4.
5.
D. Bouzard, Antibiotics and Antiviral Compounds (editors K. Krohn, H. A. Kirst, and H. Maag), VCH,
Weinheim (1993).
M. Taguchi, H. Kondo, Y. Inoue, Y. Kawahata, Y. Jinbo, F. Sakamoto, and G. Tsukamoto, J. Med.
Chem., 35, 94 (1992).
S. Atarashi, S. Yokohama, K. Yamazaki, K. Sakano, M. Imamuro, and I. Hayakawa, Chem. Pharm.
Bull., 35, 1896 (1987).
6.
7.
8.
R. J. Dogan ad D. W. Gottschall, WO Patent 9727201; Chem. Abstr., 127, 176444 (1997).
S. L. Dax and C. C. Wei, J. Org. Chem., 57, 744 (1992).
G. N. Lipunova, G. A. Mokrushina, E. V. Nosova, L. I. Rusinova, and V. N. Charushin, Mendeleev
Commun., 109 (1997).
9.
G.N. Lipunova, E. V. Nosova, V. N. Charushin, L. P. Sidorova, and O. M. Chasovskikh, Mendeleev
Commun., 131 (1998).
1288