Reactions of 1-aryl(alkyl)-3-ethoxalyl-5,6,7,8-tetrafluoro-1,4-dihydrocinnolin(quinolin)-4-on es with aromatic dinucleophiles

Article abstract of DOI:10.1023/A:1011325215083

The title compounds react with o-phenylenediamine and o-aminophenol at the ethoxalyl fragment to form heteryl-substituted quinoxalones and benzooxazinones, respectively. o-Amino-benzenethiol acts as both an S-nucleophile replacing the F atom and an N-nucleophile replacing the carbonyl group in the ethoxalyl fragment. Under more drastic conditions, cyclization proceeds to form benzothiazinones.

Full text of DOI:10.1023/A:1011325215083

Russian Chemical Bulletin, International Edition, Vol. 50, No. 4, pp. 689—692, April, 2001
689
Reactions of 1-aryl(alkyl)-3-ethoxalyl-5,6,7,8-tetrafluoro-
1,4-dihydrocinnolin(quinolin)-4-ones with aromatic dinucleophiles
A. S. Fokin, Ya. V. Burgart, O. V. Ryzhkov, and V. I. Saloutin«
Institute of Organic Synthesis,
Ural Branch of the Russian Academy of Sciences,
20 ul. S. Kovalevskoi, 620219 Ekaterinburg, Russian Federation.
Fax: +7 (343 2) 74 5954. E-mail: saloutin@ios.uran.ru
The title compounds react with o-phenylenediamine and o-aminophenol at the ethoxalyl
fragment to form heteryl-substituted quinoxalones and benzooxazinones, respectively. o-Amino-
benzenethiol acts as both an S-nucleophile replacing the F atom and an N-nucleophile
replacing the carbonyl group in the ethoxalyl fragment. Under more drastic conditions,
cyclization proceeds to form benzothiazinones.
Key words: 5,6,7,8-tetrafluorocinnolones, 5,6,7,8-tetrafluoroquinolones, o-phenylenedi-
amine, o-aminophenol, o-aminobenzenethiol, quinoxalones, benzooxazinones, benzo-
thiazinones.
Owing to the presence of the α-dicarbonyl fragment,
1-aryl-3-ethoxalyl-5,6,7,8-tetrafluoro-1,4-dihydrocinno-
lin-4-ones (1)1 and 1-aryl(alkyl)-3-ethoxalyl-5,6,7,8-
tetrafluoro-1,4-dihydroquinolin-4-ones (2)2 prepared re-
cently have considerable prospects for their subsequent
modifications and can be used for the construction of
new heterocyclic systems based on them. Reactions with
nucleophilic reagents can involve either one carbonyl
group or simultaneously two groups. In addition, aro-
matic nucleophilic substitution of the F atoms can occur
in these heterocycles.
aromatic dinucleophiles, viz., to o-phenylenediamine,
o-aminophenol, and o-aminobenzenethiol.
Results and Discussion
Refluxing of cinnolones 1a,b and quinolones 2a,b in
alcohols with a twofold excess of o-phenylenediamine or
Table 1. Principal characteristics of compounds 3, 4a,b, 5a,b,
6a,b, and 7—10
Com- M.p. Yield
pound/ °C (%)
Found
Calculatedformula
Molecular
In the present work, we studied the reactivities of
cinnolones 1a,b and quinolones 2a,b with respect to
(%)
Ñ
H
F
N
Scheme 1
3
>300 80 59.10 2.57 16.06 12.11 Ñ23H13F4N4O3
58.98 2.58 16.23 11.96
H2N
4à
4b
5à
5b
6à
6b
7
210 82 58.83 2.44 16.14 8.86 Ñ23H11F4N3O4
58.87 2.36 16.19 8.95
224 70 60.13 1.94 16.95 9.73 C22H9F4N3O3
60.15 2.07 17.30 9.57
255 64 63.74 2.86 16.87 9.27 C24H13F4N3O2
63.86 2.90 16.84 9.31
>300 73 59.85 2.78 18.62 10.32 C20H11F4N3O2
59.86 2.76 18.94 10.47
240 82 63.75 2.69 16.75 6.21 C24H12F4N2O3
63.72 2.69 16.80 6.19
195 83 59.47 2.60 18.44 6.87 C20H10F4N2O3
59.71 2.51 18.98 6.96
194 97 58.25 3.58 9.31 8.79 Ñ31H23F3N4O4S2
58.48 3.64 8.95 8.80
125— 82 61.75 3.80 9.05 6.76 Ñ32H24F3N3O3S2
O
O
OEt
HY
n
F
MeOH (Bu OH),
∆
X
O
N
R
1a,b; 2a,b
O
N
Y
F
X
O
N
R
8*
9
127
62.02 3.90 9.20 6.78
>300 98 58.76 2.68 10.02 9.37 Ñ29H17F3N4O3S2
58.98 2.90 9.65 9.49
3; 4a,b; 5a,b; 6a,b
10
164— 89 58.72 3.58 14.66 10.83 C25H18N4O4F4
X = N, R = C6H4OMe-p (1à), Y = NH (3), O (4a);
R = Ph (1b), Y = O (4b);
166
58.37 3.53 14.77 10.89
X = CH, R = C6H4Me-î (2à), Y = NH (5a), Î (6à);
R = cyclo-Pr (2b), Y = NH (5b), Î (6b)
* The compound was present as two isomeric forms.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 4, pp. 662—665, April, 2001.
1066-5285/01/5004-689 $25.00 © 2001 Plenum Publishing Corporation

690
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
Fokin et al.
Table 2. Data from IR and 1H and 19F NMR spectroscopy of compounds 3, 4a,b, 5a,b, 6a,b, and 7—10
–1
Com-
pound
IR, ν/cm
NMR spectrum,
(DMSO-d6, δ, J/Hz)
1H
19F
3
2700, 1605 (NH);
3.84 (s, 3 H, OCH3);
7.88—7.03 (m, 8 H, 2 C6H4);
12.76 (br.s, 1 H, NH)
3.84 (s, 3 H, OCH3);
7.82—7.05 (m, 8 H, 2 C6H4)
19.08 (m, 2 F); 15.58 (m, 1 F);
1.70 (m, 1 F)
1670 (C=O amide); 1630 (C=O);
1500, 1480 (C=C, Ñ=N)
1740 (C=O lactone); 1635 (C=O);
1595, 1550, 1500, 1480
4a
19.33 (m, 2 F); 16.05 (m, 1 F);
2.55 (m, 1 F)
(Ñ=N, C=C)
4b
5a
1740 (C=O lactone);
7.40—7.93 (m, 9 H, C6H4, C6H5)
2.72 (m, 1 F); 16.26 (m, 1 F);
19.20 (m, 1 F); 20.16 (m, 1 F)
–0.41 (m, 1 F); 11.73—12.96
(m, 2 F); 18.48—19.03 (m, 1 F)
1650, 1640 (C=O, C=N)
3320, 2780, 2720 (NH);
3040 (CH); 1670 (C=O amide);
1635 (C=O); 1610 (C=N)
3290, 3060, 2760, 2700 (NH);
3045 (CH); 1675 (C=O amide);
1640 (C=O); 1595 (C=N)
2.29 (s, 1 H, CH3);
7.20—7.83 (m, 8 H, 2 C6H4,);
8.09 (s, 1 H, CH); 12.43 (s, NH)
1.12—1.19 (m, 4 H, 2 CH2);
3.83—4.16 (m, 1 H, CH);
7.11—7.83 (m, 4 H, C6H4);
8.26 (s, 1 H, CH);
5b
–0.66 (m, 1 F); 11.33 (m, 1 F);
16.47 (m, 1 F); 18.38 (m, 1 F)
12.41 (br.s, 1 H, NH)
6a
6b
7
3055 (CH); 1765 (C=O lactone);
1645 (C=O); 1610 (C=N);
1590, 1580, 1520, 1510, 1500,
1490 (C=C)
3040 (CH); 1765 (C=O lactone);
1640 (C=O); 1600 (C=C)
2,19 (s, 3 H,CH3);
7.40—7.84 (m, 8 H, 4 Ñ6H4);
8.08 (s, 1 H, CH)
–0.41 (m, 1 F); 11.73—12.96
(m, 2 F); 18.48—19.03 (m, 1 F)
1.13—1.30 (m, 4 H, 2 CH2);
3.74—4.20 (m, 1 H, CH);
7.41—7.89 (m, 4 H, C6H4);
8.30 (s, 1 H, CH)
1.12 (t, 3 H, OCH2CH3,
J = 7.0); 3.83 (s, 3 H, OCH3);
5.38 (br.s, 2 H, NH2);
4.14 (q, 2 H, OCH2CH3,
J = 7.0); 6.43—7.53
0.18 (m, 1 F); 12.01 (m, 1 F);
17.07 (m, 1 F); 18.57 (m, 1 F)
3450, 3350 (NH); 1730 (COOEt);
1620 (C=O); 1570, 1500, 1480
(C=N, C=C)
16.33 (dd, 1 F, F(5));
25.67 (d, 1 F, F(6));
53.78 (d, 1 F, F(8));
J5,8 = J8,5 = 17.2;
J5,6 = J6,5 = 21.5;
(m, 13 H, 3 C6H4, SH)
1.11, 1.13 (both t, 3 H,
OCH2CH3, J = 7.1);
1.88, 1.96 (both s, 3 H, CH3);
4.10, 4.12 (both q, 2 H,
OCH2CH3, J = 7.1);
5.28 (br.s, 2 H, NH2);
6.40—7.41 (m, 12 H, 3 C6H4,);
7.34 (br.s, 1 H, SH);
J6,8 = J8,6 = 0
16.73, 17.02 (both dd, 1 F, F(5));
24.63, 24.66 (both d, 1 F, F(6));
8*
3450, 3340 (NH); 3050 (CH);
1740 (C(=O)OEt); 1630 (C=O);
1610, 1580 (C=N, C=C)
46.18, 46.47 (both d, 1 F, F(8));
J5,8 = J8,5 = 17.1;
J5,6 = J6,5 = 22.0;
J6,8 = J8,6 = 0
7.72, 7.74 (both s, 1 H, CH)
3.84 (s, 3 H, CH3);
5.37 (m, 2 H, NH2);
9
3450 (NH); 1640 (C(=O)S);
1610 (C=O); 1500, 1490, 1470
(C=N, C=C)
17.97 (dd, 1 F, F(5));
28.36 (d, 1 F, F(6));
54.58 (d, 1 F, F(8));
J5,8 = J8,5 =17.2;
6.50—8.17 (m, 5 H, C6H5)
J5,6 = J6,5 = 20.1;
J6,8 = J8,6 = 0
10
3240, 1600 (NH); 1680 (CO2Et);
1640, 1630, 1620 (C=O, C=N);
1520—1490 (C=C arom.)
1.23 (t, 3 H, OCH2CH3,
J = 7.1); 3.89 (s, 3 H, OCH3);
4.32 (q, 2 H, OCH2CH3,
J = 7.1); 7.04—7.69
20.24 (m, 2 F); 15.11 (m, 1 F);
0.76 (m, 1 F)
(m, 9 H, C6H4, C6H5);
12.32 (br.s, 1 H, NH)
* The compound was present as two isomeric forms.
o-aminophenol afforded the corresponding heterocyclic
ensembles, viz., quinoxalonylcinnolone (3), cinnolonyl-
benzooxazinones (4a,b), quinolonylquinoxalones (5a,b),
and quinolonylbenzooxazinones (6a,b) (Scheme 1,
Tables 1 and 2).
It is of note that the reactions of cinnolones 1 with
aromatic dinucleophiles proceed more readily than those
of quinolones 2. Apparently, this is due to the fact that
the former are more electron-deficient compounds. Thus,
the reactions with quinolones 2 require a substantial

Reactions of cinnolin(quinolin)ones with dinucleophiles Russ.Chem.Bull., Int.Ed., Vol. 50, No. 4, April, 2001
691
increase in the reaction time or the use of higher-boiling
n-butanol instead of methanol. The course of the reac-
tions was monitored by TLC.
It should be noted that quinoxalonylcinnolones of
the type 3 can be prepared from 3-[(1-arylhydrazo-2-
oxo-2-(pentafluorophenyl)ethyl]-1,2-dihydroquinoxalin-
2-ones by thermal intramolecular cyclization.2
Unlike o-phenylenediamine and o-aminophenol,
o-aminobenzenethiol reacted with heterocycles 1a and
2a to form products 7 and 8, respectively (Scheme 2, see
Tables 1 and 2), due to the replacement of the carbonyl
group in the ethoxalyl fragment by the amino group of
o-aminobenzenethiol and the nucleophilic replacement
of the F(7) atom in the aromatic ring by the 2-amino-
phenylthio group. The direction of the replacement was
established taking into account the published data3 and
based on the spin-spin coupling constants for the F
atoms (see Table 2). Apparently, the nucleophilic substi-
tution in the fluoroaromatic ring occurs due to the high
nucleophilicity of the S atom of this reagent.
The reactions with phenylhydrazine provided addi-
tional evidence for the higher reactivities of cinnolones 1
compared to quinolones 2. It appeared that the reaction
of cinnolone 1a with phenylhydrazine afforded readily
phenylhydrazone (10) upon refluxing in diethyl ether
(Scheme 3, see Tables 1 and 2). Under these conditions,
quinolone 2b did not enter into the reaction, while in
boiling alcohols it gave a mixture of nonidentified
products.
Scheme 3
O
N
NNHPh
OEt
PhNHNH2
1a
F
∆, Et2O
N
O
C6H4OMe-p
10
Upon refluxing in xylene for 10 h, compound 7
underwent intramolecular cyclization to form substituted
cinnolonylbenzothiazinone (9) (see Scheme 2, Tables 1
and 2). Under analogous conditions, quinolone 8 gave a
mixture of products, which was difficult to separate,
instead of the expected quinolonylthiazinone. It should
be noted that attempts to perform cyclization of com-
pounds 7 and 8 in boiling n-butanol failed.
Thus, 1-aryl(alkyl)-3-ethoxalyl-5,6,7,8-tetrafluoro-
1,4-dihydrocinnolones(quinolones) are convenient sub-
strates in the synthesis of a wide range of novel hetero-
cyclic compounds.
Experimental
The IR spectra were recorded on a Specord IR-75 spec-
–1
trometer in the range of 400—4000 cm in Nujol mulls. The
Scheme 2
1H NMR spectra were measured on Tesla BS-587 A (80 MHz)
and Bruker DRX-400 (400 MHz) spectrometers relative to
Me4Si. The 19F NMR spectra were recorded on a Tesla
BS-587 A spectrometer (75 MHz) relative to C6F6. Elemental
analyses were carried out on a Carlo Erba CHNS-O EA 1108
instrument.
HS
SH
O
N
OEt
NH2
The starting compounds 1a,b and 2a,b were prepared ac-
cording to known procedures.1,2
1a, 2a
MeOH, ∆
F
X
O
5,6,7,8-Tetrafluoro-1-(4-methoxyphenyl)-3-(2-oxo-1,2-di-
hydroquinoxalin-3-yl)-1,4-dihydrocinnolin-4-one (3). A solu-
tion of o-phenylenediamine (0.216 g, 2 mmol) in MeOH (5 mL)
was added to a solution of cinnolone 1a (0.424 g, 1 mmol) in
MeOH (5 mL). The reaction mixture was refluxed for 1 min.
The precipitate that formed was filtered off and washed with
MeOH. Compound 3 was obtained in a yield of 0.375 g (see
Tables 1 and 2).
S
N
R
NH2
7, 8
3-(5,6,7,8-Tetrafluoro-1-(4-methoxyphenyl)-4-oxo-1,4-di-
hydrocinnolin-3-yl)-1,2-dihydrobenzooxazin-2-one (4a). A so-
lution of o-aminophenol (0.218 g, 2 mmol) in MeOH (7 mL)
was added to a solution of cinnolone 1a (0.422 g, 1 mmol) in
MeOH (7 mL). The reaction mixture was refluxed for 3 h and
then cooled to ∼20 °C. The precipitate that formed was filtered
off and recrystallized from MeOH. Compound 4a was obtained
in a yield of 0.238 g (see Tables 1 and 2).
O
N
N
S
7
Xylene, ∆
F
N
O
S
3-(5,6,7,8-Tetrafluoro-4-oxo-1-phenyl-1,4-dihydrocinnolin-
3-yl)-1,2-dihydrobenzooxazin-2-one (4b). Analogously, com-
pound 4b was obtained from cinnolone 1b (0.4 g, 1.2 mmol)
and o-aminophenol (0.222 g, 2.4 mmol) in a yield of 0.312 g
(see Tables 1 and 2).
NH2
R
9
3-[5,6,7,8-Tetrafluoro-4-oxo-1-(2-tolyl)-1,4-dihydro-
quinolin-3-yl]-1,2-dihydroquionoxalin-2-one (5a). Analogously,
X = N, R = C6H4OMe-p (7, 9)
X = CH, R = C6H4Me-î (8)

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Fokin et al.
compound 5a was obtained from quinolone 2a (0.407 g, 1 mmol)
and o-phenylenediamine (0.218 g, 2 mmol) in a yield of 0.372 g
(the reaction time was 2 h; see Tables 1 and 2).
3-(1-Cyclopropyl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydro-
quinolin-3-yl)-1,2-dihydroquionoxalin-2-one (5b). Analogously,
compound 5b was obtained from quinolone 2b (0.365 g, 1 mmol)
and o-phenylenediamine (0.216 g, 2 mmol) in a yield of 0.293 g
(the reaction time was 3h; see Tables 1 and 2).
3-[5,6,7,8-Tetrafluoro-4-oxa-1-(2-tolyl)-1,4-dihydro-
quinolin-3-yl]-1,2-dihydrobenzooxazin-2-one (6a). A solution
of o-aminophenol (0.216 g, 2 mmol) in BunOH (20 mL) was
added to a solution of quinolone 2a (0.407 g, 1 mmol) in
BunOH (20 mL). The reaction mixture was refluxed for 1 h and
poured into water. The precipitate that formed was filtered off
and recrystallized from BunOH. Compound 6a was obtained in
a yield of 0.289 g (see Tables 1 and 2).
3-(1-Cyclopropyl-5,6,7,8-tetrafluoro-4-oxa-1,4-dihydro-
quinolin-3-yl)-1,2-dihydrobenzooxazin-2-one (6b). Analogously,
compound 6b was obtained from quinolone 2b (0.356 g, 1 mmol)
and o-aminophenol (0.220 g, 2 mmol) upon refluxing in MeOH
for 10 h in a yield of 0.332 g (see Tables 1 and 2).
3-[7-(2-Aminophenylthio)-5,6,8-trifluoro-1-(4-methoxy-
phenyl)-4-oxo-1,4-dihydrocinnolin-4-on-3-yl]-1,2-dihydro-
benzothiazin-2-one (9). A solution of ester 7 (0.250 g, 0.4 mol)
was refluxed in m-xylene (10 mL) for 10 h. Then the reaction
mixture was poured into hexane (100 mL). The precipitate that
formed was filtered off and washed with hexane. Compound 9
was obtained in a yield of 0.236 g (see Tables 1 and 2).
Ethyl 2-[5,6,7,8-tetrafluoro-1-(4-methoxyphenyl)-4-oxo-
1,4-dihydrocinnolin-3-yl]-2-phenylhydrazonoacetate (10). Phe-
nylhydrazine (0.098 mL, 1 mmol) was added to a solution of
cinnolone 1a (0.423 g, 1 mmol) in Et2O (20 mL). The reaction
mixture was refluxed for 10 h and the solvent was evaporated.
After recrystallization from MeOH, hydrazone 10 was obtained
in a yield of 0.560 g (see Tables 1 and 2).
This work was financially supported by the Russian
Foundation for Basic Research (Project No. 00-03-
32767a).
References
Ethyl 2-[7-(2-aminophenylthio)-5,6,8-trifluoro-1-(4-meth-
oxyphenyl)-4-oxo-1,4-dihydrocinnolin-3-yl]-(2-mercapto-
phenylimino)glyoxylate (7). A solution of cinnolone 1a (0.270 g,
0.64 mmol) and o-aminobenzenethiol (0.137 mL, 1.28 mmol)
in MeOH (7 mL) was refluxed for 4 h and then cooled to
∼20 °C. After recrystallization from MeOH, compound 7 was
obtained in a yield of 0.302 g (see Tables 1 and 2).
Ethyl 2-[7-(2-aminophenylthio)-5,6,8-trifluoro-4-oxo-1-(2-
tolyl)-1,4-dihydroquionolin-3-yl]-2-(2-mercaptophenylimi-
no)acetate (8). o-Aminobenzenethiol (0.674 mL, 6.3 mmol)
was added to a solution of quinolone 2a (0.845 g, 2.1 mmol) in
MeOH (20 mL). The reaction mixture was refluxed for 10 h and
poured into water (100 mL). The precipitate that formed was
filtered off and recrystallized from BunOH. Compound 8 was
obtained in a yield of 0.332 g (see Tables 1 and 2).
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Khim., 1999, 35, 309 [Russ. J. Org. Chem., 1999, 35 (Engl.
Transl.)].
2. G. A. Obanin, A. S. Fokin, Ya. V. Burgart, O. V. Ryzhkov,
Z. E. Skryabina, V. I. Saloutin, and O. N. Chupakhin, Izv.
Akad. Nauk, Ser. Khim., 2000, 1234 [Russ. Chem. Bull., Int.
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3. G. A. Mokrushina, S. G. Alekseev, V. N. Charushin, and
O. N. Chupakhin, Zh. Vsesoyuz. Khim. Obshch. im. D. I.
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(Engl. Transl.)].
Received October 16, 2000