The selective ortho-methoxylation of pentafluorobenzoic acid - A new way to tetrafluorosalicylic acid and its derivatives

Article abstract of DOI:10.1016/S0022-1139(98)00316-9

A simple and efficient preparation of tetrafluorosalicylic acid has been developed which involves a selective substitution of fluorine in pentafluorobenzoic acid with methoxyl group by magnesium methoxide. The synthesis of 2,6-dimethoxy-3,4,5-trifluorobenzoic acid, 4,5,6-trifluororesorcinol and its dimethoxy ether is described.

Full text of DOI:10.1016/S0022-1139(98)00316-9

Journal of Fluorine Chemistry 94 (1999) 11±13
The selective ortho-methoxylation of penta¯uorobenzoic acid ± a new
way to tetra¯uorosalicylic acid and its derivatives
I.T. Bazyl', S.P. Kisil', Y.V. Burgart, V.I. Saloutin*, O.N. Chupakhin
Institute of Organic Synthesis, Urals Division, Russian Academy of Sciences, Kovalevskoy Str. 20, 620219, Ekaterinburg, GSP-147, Russia
Received 5 August 1998; accepted 12 October 1998
Abstract
A simple and ef®cient preparation of tetra¯uorosalicylic acid has been developed which involves a selective substitution of ¯uorine in
penta¯uorobenzoic acid with methoxyl group by magnesium methoxide. The synthesis of 2,6-dimethoxy-3,4,5-tri¯uorobenzoic acid, 4,5,6-
tri¯uororesorcinol and its dimethoxy ether is described. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: Penta¯uorobenzoic acid; Tetra¯uorosalicylic acid; 4,5,6-tri¯uororesorcinol
1. Introduction
of ¯uorine atoms in penta¯uorobenzoic acid due to the para-
orientation effect of the carbonyl substituent. Hitherto meth-
ods for the preparation of tetra¯uorosalicylic acid involved
splitting of ¯uorinated heterocycles [8,9] and tetra¯uoro-
benzene metallation [10]. In this connection, the develop-
ment of a simple and effective method for synthesis of
tetra¯uorosalicylic acid will open a way to its active use
in organic synthesis.
Nucleophilic substitution is the most typical reaction for
¯uoroaromatic compounds. Its direction and rate are deter-
mined by the presence of electron-withdrawing (or donat-
ing) substituents in the benzene ring. Electron-withdrawing
groups orientate an attack of a nucleophile mainly to the
para-position [1,2]. Ortho-substituted products (in a mixture
with para-) may be obtained when the acceptor substituent
forms hydrogen bonds with the attacking nucleophile. The
reaction must be carried out in a low-polar solvent to
stabilize the complex. Examples of these are the reactions
of nitropenta¯uorobenzene, methylpenta¯uorophenylsul-
phone and ethylpenta¯uorobenzoate with sodium ethylate
in diethyl ether [2,3]. Penta¯uorobenzoic acid reacts simi-
larly with magnesium benzyl(methyl)halides to form ortho-
substituted products [4], while the reaction of this acid with
alkali metal alkoxides gives only para-derivatives [5].
We have studied the selective ortho-substitution of ¯uor-
ine atoms in penta¯uorobenzoic acid with magnesium meth-
oxide with a purpose to prepare ¯uoroaromatic synthons, in
particular, tetra¯uorosalicylic acid. Non¯uorinated salicylic
acid is widely used in organic chemistry for the preparation
of heterocyclic compounds. The use of tetra¯uorosalicylic
acid and its derivatives is emphasized by the synthesis of
quinolone class of antibiotics on the basis of ortho-methoxy-
tetra¯uorosalicylic acid [6,7]. Tetra¯uorosalicylic acid and
its alkoxy derivatives are not obtained by direct substitution
2. Experimental details
Infrared spectra were measured on a Specord 75 IR
1
spectrophotometer. H NMR spectra were recorded on a
Tesla BS-567A instrument (1H: 100 MHz) using TMS as an
internal standard. 19F NMR spectra were recorded on a Tesla
BS-587A instrument (19F: 75 MHz) using CFCl3 as an
internal standard. Microanalyses were performed with a
Carlo Erba CHNS-O EA 1108 elemental analyzer. Melting
points were measured in open capillaries and are reported
uncorrected.
2.1. Tetrafluorosalicylic acid (3)
A stirred suspension of Mg (shavings) (6.7 g, 27.6 mmol)
in absolute MeOH (55 ml) was warmed to 608C. To the
suspension was added anhydrous diglyme (50 ml) at 60±
808C. The reaction mass was stirred to fully dissolve the Mg
at 60±808C after 3±4 h. Methanol was removed at 1608C
from the reaction mixture. After cooling to 1008C the
*Corresponding author. Fax: +7-3432-745954.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
P I I : S 0 0 2 2 - 1 1 3 9 ( 9 8 ) 0 0 3 1 6 - 9

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I.T. Bazyl' et al. / Journal of Fluorine Chemistry 94 (1999) 11±13
C9H7F3O4: C, 45.78; H, 2.99; F, 24.14. Found: C, 45.51;
H, 2.99; F, 24.27%.
2.3. 4,5,6-Trifluororesorcinol dimethoxy ether (5) (nc)
A mixture of 4 (1 g, 4.23 mmol) and Bu3N (20 ml) was
re¯uxed for 2 h, then distilled under reduced pressure. The
distillate was cooled to room temperature. The precipitated
solid was collected by ®ltration, washed with the saturated
solution of NaHCO3 (50 ml), recrystallized from heptane to
give 5 (0.15 g, 18.5%) as colorless crystals (mp 92±948C).
1H NMR (acetone-d6) (ꢀ (ppm) ˆ 3.93 (6H, s, 2CH3), 6.73
(1H, td, CH, J(H±Fmetha) ˆ 8 Hz, J(H±Fpara) ˆ 2.6 Hz). 19F
NMR (acetone-d6) (ꢀ (ppm) ˆ 167.53 (2F, dd, F4, F6,
J(F±F) ˆ 19.5 Hz, J(H±Fmetha) ˆ 8 Hz), 160.24 (1F, dt, F5,
J(F±F) ˆ 19.5 Hz, J(H±Fpara) ˆ 2.6 Hz). IR (cm 1): 1510
(C=C); 1060 (CF) Anal. Calc. for C8H7F3O2: C, 50.01;
H, 3.67; F, 29.66. Found: C, 50.09; H, 3.58; F, 29.63%.
2.4. 4,5,6-Trifluororesorcinol (6) (nc)
A mixture of 4 (1.1 g, 4.66 mmol) and 40% HBr (25 ml)
was re¯uxed for 12 h, than poured into water (30 ml). The
product was extracted with Et2O (3 Â 50 ml). The extract
was washed with the saturated solution of NaHCO3
(100 ml). The solvent was evaporated, the residue was
recrystallized from CCl4 to give 6 (0.4 g, 52%) as color-
less crystals (mp 128±128.58C). 1H NMR (acetone-d6)
Scheme 1.
mixture was added to a solution of penta¯uorobenzoic acid
(1) (5 g, 23.6 mmol see Scheme 1) in anhydrous diglyme
(30 ml). The reaction mixture was stirred at 1008C for 2 h.
The solvent was removed in vacuo, the residue was treated
with 10% HCl (190 ml). The resulting solution was
extracted with CHCl3 (3 Â 50 ml) and Et2O (100 ml).
The extracts were combined, dried (over MgSO4) and the
solvents were removed in vacuo. The oily residue was
re¯uxed in 40% HBr (50 ml) for 12 h. The mixture was
cooled and the precipitate ®ltered off, recrystallized from
H2O to give 3 (2.1 g, 42%) as colorless crystals (mp 170±
1738C) ([1], 169±1728C). 1H NMR and IR spectra matched
literature values [1].
(ꢀ (ppm)ˆ6.47 (1H, td, CH, J(H±Fmetha)ˆ7.8 Hz, J(H±Fpara)
ˆ
2.3 Hz), 8.78 (1H, s, OH). 19F NMR (acetone-d6) (ꢀ
(ppm) ˆ 170.01 (2F, dd, F4, F6, J(F±F) ˆ 20 Hz,
J(H±Fmetha) ˆ 7.8 Hz), 160.67 (1F, td, F5, J(F±F) ˆ 20 Hz,
J(H±Fpara) ˆ 2.3 Hz). IR (cm 1): 3355 (OH); 1630, 1510
(C=C); 1060 (CF). Anal. Calc. for C6H3F3O2: C, 43.92;
H, 1.84; F, 34.73. Found: C, 43.98; H, 1.73; F, 34.65%
3. Results and discussion
2.2. 2,6-dimethoxy-3,4,5-trifluorobenzoic acid (4) (nc)
In present work, it has been found that interaction of
penta¯uorobenzoic acid (1) with magnesium methoxide in
benzene, toluene, bis(2-methoxyethyl)ether (diglyme) or
methanol leads to selective ortho-substitution of a ¯uorine
atom by methoxyl group to form 2-methoxy-3,4,5,6-tetra-
¯uorobenzoic acid (2). Compound 2 was not isolated from
the reaction mass as a pure sample, but in the 19F spectrum
of the resulting mixture four equivalent multiple resonance
signals at ꢀ ˆ 142.08, 145.00, 155.50 and 163.17 ppm
were attributed to the ¯uorine atoms of 2.
Treatment of 2 with 40% hydrogen bromide affords
tetra¯uorosalicylic acid (3) (Scheme 1). Incomplete con-
version of starting 1 does not allow preparation of 3 in good
yield. Increase of the reaction time and/or temperature leads
to displacement of the second ¯uorine atom to form 2,6-
dimethoxy-3,4,5-tri¯uorobenzoic acid (4) (via intermediate
C) (Scheme 1). Optimal conditions for preparative synthesis
To a well-stirred suspension of magnesium methoxide
(6.7 g, 27.6 mmol) prepared by the procedure described
above was added a solution of 1 (5 g, 23.6 mmol) in
anhydrous diglyme (30 ml) at 1308C. The stirred reaction
mixture was heated at 1308C for 4 h. The solvent was
removed in vacuo. The residue was treated with 10%
HCl (190 ml). The resulting solution was cooled to 08C
and stored for 2 h. The precipitate was ®ltered off and
washed with H2O. The crude product was crystallized from
heptane and dried to give 4 (2.1 g, 57%) as colorless crystals
1
(mp 107±1098C). H NMR (acetone-d6) (ꢀ (ppm) ˆ 4.10
(6H, d, 2CH3, J(H±F) ˆ 1.9 Hz,), 11.22 (1H, s, COOH). 19
F
NMR (acetone-d6) (ꢀ (ppm) ˆ 157.12 (2F, dq, F3, F5,
J(F±F) ˆ 19.5 Hz, J(H±F) ˆ 1.9 Hz), 154.26 (1F, t, F4,
J(F±F) ˆ 19.5 Hz). IR (cm 1): 2750±2450 (OH); 1700
(C=O); 1490 (C=C); 1060 (CF). Anal. Calc. for

I.T. Bazyl' et al. / Journal of Fluorine Chemistry 94 (1999) 11±13
13
Thus, the present reactions provide a useful method for
preparation of tetra¯uorosalicylic acid and its derivatives.
Acknowledgements
The authors wish to thank the Russian Foundation of
Fundamental Researches for ®nancial support of this
work.
References
Scheme 2.
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and for 2,6-dimethoxy-3,4,5-tri¯uorobenzoic acid (4)
diglyme at 1308C, 4 h.
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4,5,6-tri¯uororesorcinol (6) and its dimethoxy ether (5)
(Scheme 2).
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probably due to its decarboxylation, which is possible when
acid exists in keto-form (E2) and occurs like decarboxyla-
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