Synthesis of fluorine-containing 2-(1-aryl-4-oxo-1,4-dihydrocinnolin-3-yl)- 2-oxoacetic Acids

Article abstract of DOI:10.1007/s11178-005-0349-x

Acid hydrolysis of ethyl 2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4- dihydrocinnolin-3-yl)-2-oxoacetates gives 2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1, 4-dihydrocinnolin-3-yl)-2,2-dihydroxyacetic acids which undergo dehydration on heating in toluene to afford

Full text of DOI:10.1007/s11178-005-0349-x

Russian Journal of Organic Chemistry, Vol. 41, No. 9, 2005, pp. 1374–1376. Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 9, 2005,
pp. 1402–1404.
Original Russian Text Copyright © 2005 by Fokin, Burgart, Saloutin, Chupakhin.
Dedicated to Full Member of the Russian Academy of Sciences
N.S. Zefirov on His 70th Anniversary
Synthesis of Fluorine-Containing 2-(1-Aryl-4-oxo-1,4-dihydro-
cinnolin-3-yl)-2-oxoacetic Acids
A. S. Fokin, Ya. V. Burgart, V. I. Saloutin, and O. N. Chupakhin
Institute of Organic Synthesis, Ural Division, Russian Academy of Sciences,
ul. S. Kovalevskoi 20, Yekaterinburg, 620219 Russia
fax: (343)3745954; e-mail: saloutin@ios.uran.ru
Received April 22, 2005
Abstract—Acid hydrolysis of ethyl 2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-yl)-2-oxo-
acetates gives 2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-yl)-2,2-dihydroxyacetic acids which
undergo dehydration on heating in toluene to afford 2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-
yl)-2-oxoacetic acids. Reactions of the latter with excess morpholine result in replacement of two fluorine
atoms in positions 5 and 7 by the amine residues.
Synthesis of new cinnoline systems attracts a keen
interest, for numerous cinnoline derivatives exhibit
biological activity [1]. Furthermore, fluorine-contain-
ing 4-oxo-1,4-dihydrocinnoline-3-carboxylic acids are
aza analogs of known fluoroquinolinone antibiotics
which are widely used in medicine [2].
and IIb. The latter are readily converted into oxo acids
IIIa and IIIb by heating in boiling toluene with
simultaneous removal of liberated water as azeotrope.
1
According to the IR and H NMR spectra, com-
pounds IIa and IIb are stable geminal diols formed via
addition of water at the α-carbonyl group of the oxalyl
fragment. No α-carbonyl absorption band was present
in the IR spectra of acids IIa and IIb, while the cor-
responding band in the spectra of oxo acids IIIa and
IIIb was observed at about 1700 cm–1. In addition, the
acid carbonyl band in the IR spectra of IIIa and IIIb
was displaced by ~20 cm–1 to lower frequencies, as
compared to dihydroxy compounds IIa and IIb: 1720–
1725 and 1740–1745 cm–1, respectively. This low-
frequency shift results from conjugation between the
carboxy and α-carbonyl groups in IIIa and IIIb. The
1H NMR spectra of compounds IIa and IIb contained
a broadened two-proton singlet at δ ~4–5 ppm due to
hydroxy protons.
We previously synthesized ethyl 2-(1-aryl-5,6,7,8-
tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-yl)-2-oxo-
acetates and their numerous derivatives [3–5]. The
goal of the present work was to obtain fluorine-con-
taining 2-(1-aryl-4-oxo-1,4-dihydrocinnolin-3-yl)-2-
oxoacetic acids. Acid hydrolysis of ethyl 2-(1-aryl-
5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-yl)-2-
oxoacetates Ia and Ib in a mixture of sulfuric and
acetic acids gives the corresponding acids IIIa and
IIIb (Scheme 1). However, unlike 2-[1-alkyl(aryl)-
5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-yl]-2-
oxoacetic acids synthesized previously [6], the isolated
hydrolysis products were dihydroxy derivatives IIa
Scheme 1.
F
O
O
F
O
OH
F
O
O
F
F
F
F
F
F
H+, H2O
Δ, toluene
COOEt
COOH
OH
COOH
N
N
N
N
N
N
F
C6H4R
F
C6H4R
F
C6H4R
Ia, Ib
IIa, IIb
IIIa, IIIb
R = H (a), 4-MeO (b).
1070-4280/05/4109-1374 © 2005 Pleiades Publishing, Inc.

SYNTHESIS OF FLUORINE-CONTAINING 2-(1-ARYL-4-OXO-1,4-DIHYDRO-...
1375
We also demonstrated that fluorine atoms in
EXPERIMENTAL
2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinno-
lin-3-yl)-2-oxoacetic acids IIIa and IIIb can be re-
placed by amino groups via reaction with dialkyl-
amines using morpholine as an example. According
to published data on transformations of structurally
related compounds, their reactions with alkylamines
usually give products of fluorine replacement in posi-
tion 5 or 7 of the heteroring while the fluorine atom in
position 8 is replaced in a few specific cases [7, 8].
The formation of 5,7-diamino derivatives occurs fairly
rarely. As a rule, the 6-fluorine atom is inactive in
these reactions [8].
The IR spectra were recorded on a Perkin–Elmer
Spectrum One Fourier spectrometer from samples
dispersed in mineral oil. The H NMR spectra were
obtained on a Bruker DRX-400 instrument (400 MHz)
using tetramethylsilane as reference. The 19F NMR
spectra were measured on Tesla BS-587A (75.3 MHz)
and Bruker DRX-400 instruments; the chemical shifts
were measured relative to C6F6. The elemental com-
positions were determined on a Carlo Erba CHNS-O
EA 1108 analyzer.
1
Ethyl 2-(1-aryl-5,6,7,8-tetrafluoro-4-oxo-1,4-dihy-
drocinnolin-3-yl)-2-oxoacetates Ia and Ib were syn-
thesized by the procedure described in [3].
We recently found conditions ensuring selective
replacement of fluorine atoms in ethyl 2-(1-aryl-
5,6,7,8-tetrafluoro-4-oxo-1,4-dihydrocinnolin-3-yl)-2-
oxoacetates and their 3-hetaryl-substituted analogs in
reactions with morpholine [5]. When these reactions
were performed in DMSO at room temperature,
7-monosubstituted products were mainly formed,
while heating in boiling pyridine favored formation of
5,7-disubstituted derivatives.
2,2-Dihydroxy-2-(5,6,7,8-tetrafluoro-4-oxo-1-
phenyl-1,4-dihydrocinnolin-3-yl)acetic acid (IIa).
A mixture of 2.7 ml of water, 3.5 ml of glacial acetic
acid, and 0.5 ml of concentrated sulfuric acid was
added to 597 mg (1.5 mmol) of ester Ia, the mixture
was heated for 30 min, 10 ml of water was added, the
mixture was cooled to 5°C, and the precipitate was
filtered off and washed with cold distilled water. Yield
446 mg (81%), yellow powder, mp 232–233°C. IR
spectrum, ν, cm–1: 3285, 3090 (OH); 1740 (CO2H);
By reacting acids IIIa and IIIb with excess mor-
pholine in boiling pyridine we obtained the corre-
sponding 5,7-dimorpholino derivatives IVa and IVb
(Scheme 2). However, we failed to obtain 7-monosub-
stituted compounds, presumably due to insignificant
difference in the reactivity of fluorine atoms in posi-
tions 5 and 7.
1
1640 (C=O); 1590 (C=C). H NMR spectrum
[(CD3)2CO], δ, ppm: 4.67 br.s (2H, OH); 7.52–7.73 m
(5Harom), 11.5 br.s (1H, COOH). 19F NMR spectrum
[(CD3)2CO], δF, ppm: 4.63 m (1F); 17.08 m (1F);
21.26 m (1F); 22.26 m (1F). Found, %: C 49.94;
H 1.93; F 19.86; N 7.18. C16H8F4N2O5. Calculated, %:
C 50.01; H 2.10; F 19.78; N 7.29.
Scheme 2.
O
2,2-Dihydroxy-2-[5,6,7,8-tetrafluoro-1-(4-meth-
oxyphenyl)-4-oxo-1,4-dihydrocinnolin-3-yl]acetic
acid (IIb) was synthesized in a similar way from
1.045 g (2.5 mmol) of ester Ib. Yield 654 mg (88%),
yellow powder, mp 122–123°C. IR spectrum, ν, cm–1:
3310, 3080 (OH); 1745 (COOH); 1640 (C=O); 1590
N
F
O
N
O
O
NH
F
COOH
Δ, pyridine
IIIa, IIIb
N
N
1
(C=C). H NMR spectrum (CDCl3), δ, ppm: 3.89 s
O
C6H4R
IVa, IVb
(3H, OCH3), 4.36 br.s (2H, OH), 7.19 m (4H, C6H4),
11.7 br.s (1H, COOH). 19F NMR spectrum (CDCl3), δF,
ppm: 6.98 m (1F), 19.58 m (1F), 21.76 m (1F), 23.75
m (1F). Found, %: C 49.20; H 2.53; F 18.25; N 6.56.
C17H10F4N2O6. Calculated, %: C 49.29; H 2.43;
F 18.34; N 6.76.
R = H (a), 4-MeO (b).
The site of substitution was established on the basis
of coupling constants in the 19F NMR spectra with
account taken of published data. In the spectra of acids
IVa and IVb, the coupling constant between fluorine
atoms in positions 6 and 8 (J6,8 = J8,6 = 6 Hz) was
typical of meta interaction in polyfluorinated aromatic
systems [9].
2-Oxo-2-(5,6,7,8-tetrafluoro-4-oxo-1-phenyl-1,4-
dihydrocinnolin-3-yl)acetic acid (IIIa). A solution of
1.152 g (3.0 mmol) of compound IIa in 30 ml of
toluene was heated for 3 h under reflux with simulta-
neous removal of liberated water. The solvent was
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 9 2005

FOKIN et al.
1376
distilled off under reduced pressure to isolate 1.043 g
(95%) of acid IIIa as a yellow powder with mp 145–
146°C. IR spectrum, ν, cm–1: 3070 (OH), 1720
(COOH), 1705 (α-C=O), 1640 (C=O), 1590 (C=C).
1H NMR spectrum [(CD3)2CO], δ, ppm: 7.44–7.65 m
(5H, Harom), 12.5 br.s (1H, COOH). 19F NMR spectrum
[(CD3)2CO], δF, ppm: 4.73 m (1F), 17.12 m (1F),
20.23 m (1F), 21.03 m (1F). Found, %: C 52.44;
H 1.73; F 20.86; N 7.58. C16H6F4N2O4. Calculated, %:
C 52.47; H 1.65; F 20.75; N 7.65.
acid (IVb) was synthesized in a similar way from
277 mg (0.7 mmol) of acid IIIb and 51 mg (3.5 mmol)
of morpholine. Yield 301 mg (81%), yellow powder,
mp 154–155°C. IR spectrum, ν, cm–1: 2714 (OH),
1721 (COOH), 1700 (α-C=O), 1640 (C=O), 1589
1
(C=C). H NMR spectrum [(CD3)2SO], δ, ppm: 3.27–
3.93 m (16H, CH2), 3.88 s (3H, OCH3), 7.17 m
(4H, Harom), 10.11 (1H, OH). 19F NMR spectrum
[(CD3)2SO], δF, ppm: 29.36 d (1F, J = 6.0 Hz) 31.29 d
(1F, J = 6.0 Hz). Found, %: C 56.52; H 4.68; F 7.45;
N 10.47. C25H24F2N4O7. Calculated, %: C 56.60; H 4.56;
F 7.16; N 10.56.
2-Oxo-2-[5,6,7,8-tetrafluoro-1-(4-methoxyphen-
yl)-4-oxo-1,4-dihydrocinnolin-3-yl]acetic acid (IIIb)
was synthesized in a similar way from 1.296 g
(3.1 mmol) of compound IIb. Yield 1.220 g (95%),
yellow powder, mp 118–119°C. IR spectrum, ν, cm–1:
3085 (OH); 1725 (COOH); 1700 (α-C=O); 1640
(C=O); 1590 (C=C). 1H NMR spectrum [(CD3)2SO], δ,
ppm: 3.86 s (3H, OCH3); 7.35 m (4Harom), 11.8 br.s
(1H, COOH). 19F NMR spectrum [(CD3)2SO], δF, ppm:
4.73 m (1F), 16.79 m (1F), 19.50 m (1F), 20.63 m
(1F). Found, %: C 51.77; H 2.11; F 18.73; N 7.03.
C17H8F4N2O5. Calculated, %: C 51.53; H 2.04;
F 19.18; N 7.07.
This study was performed under financial support
by the Russian Foundation for Basic Research (project
no. 03-03-33118), by the State Program for Support of
Leading Scientific Schools (project no. 1766.2003.3)
and by the Russian Foundation for Support of Russian
Science.
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pyridine, the mixture was heated for 30 min and evap-
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1
1595 (C=C). H NMR spectrum [(CD3)2SO], δ, ppm:
3.29–3.78 m (16H, CH2); 7.15–7.35 m (5H, Harom);
10.75 (1H, OH). 19F NMR spectrum [(CD3)2SO], δF,
ppm: 27.11 d (1F, J = 6.0 Hz); 33.51 d (1F, J =
6.0 Hz). Found, %: C 57.45; H 4.59; F 7.71; N 11.12.
C24H22F2N4O6. Calculated, %: C 57.60; H 4.40; F 7.59;
N 11.20.
2-[6,8-Difluoro-1-(4-methoxyphenyl)-5,7-dimor-
pholino-4-oxo-1,4-dihydrocinnolin-3-yl]-2-oxoacetic
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 41 No. 9 2005