An efficient approach to the synthesis of 2,3,4,5-tetrafluorophenol

Article abstract of DOI:10.1007/s11172-021-3178-3

A new method for the preparation of 2,3,4,5-tetrafluorophenol from 2-[(2,3,4,5,6-pentafluorophenyl)thio]acetic acid has been proposed. It included the intramolecular cyclization of the salt of this acid in the presence of K₂CO₃ with the substitution of the ortho fluorine atom and the formation of a lactone, which under the reaction conditions underwent the ring-opening with the formation of the potassium salt of 2-[6-hydroxy(2,3,4,5-tetrafluorophenyl)-thio]acetic acid. The resulting salt was converted into methyl ester and desulfurized with Raney nickel to 2,3,4,5-tetrafluorophenol. The proposed method is a simple and efficient way to obtain poorly available 2,3,4,5-tetrafluorophenol in ～58% total yield based on 2-[(2,3,4,5,6-pentafluorophenyl)thio]acetic acid.

Full text of DOI:10.1007/s11172-021-3178-3

Russian Chemical Bulletin, International Edition, Vol. 70, No. 5, pp. 995—998, May, 2021
995
Brief Communications
An efficient approach to the synthesis of 2,3,4,5-tetrafluorophenol*
E. V. Tretyakov,a A. M. Maksimov, P. V. Nikul´shin, and T. V. Mezhenkova
b
b
b
aN. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
4
7 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. E-mail: tretyakov@ioc.ac.ru
b
N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences,
9
prosp. Akad. Lavrentґeva, 630090 Novosibirsk, Russian Federation.
Fax: +7 (383) 330 9752. E-mail: maksimov@nioch.nsc.ru
A new method for the preparation of 2,3,4,5-tetrafluorophenol from 2-[(2,3,4,5,6-penta-
fluorophenyl)thio]acetic acid has been proposed. It included the intramolecular cyclization of
the salt of this acid in the presence of K CO with the substitution of the ortho fluorine atom
2
3
and the formation of a lactone, which under the reaction conditions underwent the ring-
opening with the formation of the potassium salt of 2-[6-hydroxy(2,3,4,5-tetrafluorophenyl)-
thio]acetic acid. The resulting salt was converted into methyl ester and desulfurized with Raney
nickel to 2,3,4,5-tetrafluorophenol. The proposed method is a simple and efficient way to obtain
poorly available 2,3,4,5-tetrafluorophenol in ~58% total yield based on 2-[(2,3,4,5,6-penta-
fluorophenyl)thio]acetic acid.
Key words: organofluorine compounds, aromatic nucleophilic substitution reaction, poly-
fluorinated aromatic sulfides, reduction of sulfide, fluorinated phenols.
Systematic research directed at revealing the struc-
ture—property relationship is the essence of the search for
materials with the required characteristics. In the field of
organofluorine derivatives, there is a demand for system-
atic series of compounds with certain groups and varied
number and arrangement of fluorine atoms.1 As a rule,
the materialization of such series is limited by the presence
during the development of methods for the preparation of
chelating organic radicals containing fluorinated 2-hydr-
9
oxyphenyl groups, researchers faced the problem with
availability of such a reagent as 2,3,4,5-tetrafluorophenol.
One of the known approaches to the synthesis of this
partially fluorinated compound is based on the oxidation
of organoelement derivatives of 1,2,3,4-tetrafluorobenz-
ene. An example is the preparation of the target tetrafluoro-
phenol in 47% yield by the reaction of lithium derivative
of 1,2,3,4-tetrafluorobenzene with trimethyl borate and
subsequent treatment of the resulting organoboron com-
—7
8
of basic mono-, di- and polyfluorinated reagents. Thus,
*
Dedicated to Academician of the Russian Academy of Sciences
V. N. Charushin on the occasion of his 70th birthday.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 5, pp. 995—998, May, 2021.
066-5285/21/7005-0995 © 2021 Springer Science+Business Media LLC
1

9
96
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
Tretyakov et al.
Scheme 1
pound with 45 or 85% hydrogen peroxide (Scheme 1).10—13
This approach can be used to synthesize 2,3,4,5-tetra-
fluorophenol in 14—32% yield from trimethylsilyl ester of
tetrafluorobenzoic acid by reacting it with anhydrous zinc
salts or zinc oxide to form a zinc-containing organic de-
rivative, which was further oxidized in the presence of
copper(I) halide. The oxidation was carried out with
such peroxide compounds as tert-butyl peroxybenzoate,
as an approach to the preparation of tetrafluorosalicylic
1
8
acid, in the present study, we developed a simple labor-
atory method for the synthesis of 2,3,4,5-tetrafluoro-
phenol. It also includes intramolecular cyclization with
substitution of the ortho-fluorine atom. In our case, the
cyclization of 2-[(2,3,4,5,6-pentafluorophenyl)thio]acetic
acid (1) in the presence of K CO in DMF proceeded with
2
3
the formation of lactone (A), which underwent ring-
opening under the reaction conditions to give potassium
salt of 2-[(2,3,4,5-tetrafluoro-6-hydroxyphenyl)thio]
acetic acid (B) (Scheme 2). This salt was converted into
methyl ester 2 (~74% yield), which was then desulfurized
by the reaction with Raney nickel in ethanol to obtain
2,3,4,5-tetrafluorophenol (3) in ~79% yield.
1
4
-
acetate, -trifluoroacetate, or hydroperite. The second
approach consisted in thermal (T > 240 °C) decarboxyl-
ation of polyfluorinated salicylic acids,1
5,16
including the
tetrafluoro derivative to form 2,3,4,5-tetrafluorophenol.
Another approach, which was specially developed for
industrial use, involves heating 2,3,4,5-tetrafluorobromo-
benzene with aqueous KOH in sulfolane in the presence
of Raney nickel or Pd/C at 120—180 °C and a pressure of
In conclusion, we proposed a simple and efficient
method for the synthesis of 2,3,4,5-tetrafluorophenol in
58% total yield starting from perfluorophenylthioacetic
acid 1, which can be easily obtained by the reaction of
pentafluorothiophenol with bromoacetic (chloroacetic)
acid in an aqueous medium. Since polyfluorophenols are
widely used in various fields, including in the preparation
0
.8—1.0 MPa.17 All the approaches considered above have
a significant disadvantage of being multistep and labor-
consuming processes, especially if to consider a prelimi-
nary synthesis of the starting reagents.
Taking into account the work of the Ural chemists who
proposed using the substitution of the ortho-fluorine atom
1
9
of polymers with unique properties, amino acids, pep-
Scheme 2

Synthesis of 2,3,4,5-tetrafluorophenol
Russ. Chem. Bull., Int. Ed., Vol. 70, No. 5, May, 2021
997
tides, and nucleosides serving as intermediates in the
F, 28.30; S, 12.08. C9H6O3F4S. Calculated (%): C, 40.01;
2
0,21
H, 2.24; F, 28.12; S, 11.87.
synthesis of antitumor agents, HIV inhibitors,
catalytic
systems for the polymerization of olefins,22 the proposed
2,3,4,5-Tetrafluorophenol (3)
10. Raney nickel (obtained from
Raney alloy (20.04 g)) was added portionwise (~1/3 part each
with a ~24 h interval) to a solution of compound 2 (1.86 g) in
ethanol (120 mL) with continuous stirring at room temperature.
At the end of the experiment, the reaction mixture was centrifuged
to separate excess Raney nickel, then ethanol was evaporated at
atmospheric pressure. Dichloromethane (~20 mL) was added to
the residue and the organic layer was separated, which was dried
simple method for obtaining 2,3,4,5-tetrafluorophenol,
undoubtedly, will be useful and will open up the possibil-
ity of active use of this partially fluorinated phenol in the
synthesis of various substances and materials.
Experimental
with CaCl . Evaporation of CH Cl at atmospheric pressure gave
2
2
2
a liquid residue (2.47 g, ~79%) with the phenol 3 content of about
In the work, we used commercially available reagents and
solvents without additional purification. Perfluorophenylthioacetic
1
3
6.6% ( H NMR data). The filtrate (2.38 g) was distilled in a flow
of argon at atmospheric pressure to obtain compound 3 (0.65 g)
2
3
acid 1 was obtained according to a known procedure. NMR
1
with a purity of ~91.6% ( H NMR data), the rest was ethanol.
1
19
spectra were recorded on Bruker AV-300 ( H, 300.13 MHz; F,
1
H NMR (acetone-d ), δ: 6.81 (dtd, Н(6), J
= 11.9 Hz,
6
H—F(5)
1
3
2
82.40 MHz) or Bruker DRX-500 ( C, 125.76 MHz) spectro-
meters. All experiments were carried out according to the standard
Bruker procedures. Chemical shifts are given relative to Me Si
for H and C) or C F (for F). Samples for NMR spectro-
scopy were prepared in CDCl or acetone-d . IR spectra were
19
JH—F(2),F(4) = 7.6 Hz, JH—F(3) = 2.6 Hz); 9.57 (s, OH). F NMR
acetone-d ), δ: –9.4 (tm, F(4), J = 21.2 Hz);
(
6
F(4)—F(3),F(5)
4
4.4 (br.t, F(3), JF(3)—F(2),F(4) = 20.4 Hz), –0.3 (m, F(2)); 21.1
1
13
19
(
6 6
(ddd, F(5), JF(5)—F(4) = 21.2 Hz, JF(5)—H = 12 Hz, JF(5)—F(2) =
3
6
= 9.1 Hz).
recorded on a Bruker Vector 22 IR spectrometer, samples were
prepared in KBr pellets. UV spectra were recorded on a Hewlett
Packard 8453 UV instrument (solutions in hexane). Mass spec-
tra were recorded on a Thermo Electron Corporation DFS in-
strument, ionization energy 70 eV. Melting points were measured
on a Mettler Toledo Thermosystem FP-900 apparatus. Elemental
analysis (C, H, N) was performed on a Euro EA 3000 analyzer.
Methyl 2-[(2,3,4,5-tetrafluor-6-hydroxyphenyl)thio]acetate
The work was carried out in the framework of the
Russian state assignment АААА-А21-121011490017-5
for N. N. Vorozhtsov Novosibirsk Institute of Organic
Chemistry of the Siberian Branch of the Russian Academy
of Sciences. The authors of the work are grateful to the
Chemical Service Center for Collective Use of the Siberian
Branch of the Russian Academy of Sciences for carrying
out spectral and analytical measurements.
(
2). Potassium carbonate (1.94 g, 14.04 mmol) was added to
a solution of 2-[(2,3,4,5,6-pentafluorophenyl)thio]acetic acid (3.57 g,
3.83 mmol) in DMF (75 mL) K CO . The reaction mixture was
1
This paper does not contain descriptions of studies on
animals or humans.
2
3
heated to 100—105 °C and kept at this temperature for 6 h.
Dimethylformamide was evaporated in vacuo at ~15 Torr and
The authors declare no competing interest.
~
55 °C. The remaining precipitate was washed with CHCl3
(
(
~80 mL) from residual DMF to obtain a solid compound
3.87 g), which was dissolved in anhydrous MeOH (~45 mL).
References
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concentrated to obtain the product (4.44 g), which was purified
by chromatography on silica gel 0.035—0.07 mm in the
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1
M.p. 72.3—72.9 °C. H NMR (CDCl ), δ: 3.53 (s, 2 H, CH );
3
2
1
3
3
.76 (s, 3 H, Me); 8.08 (s, 1 H, OH). C (CDCl ), δ: 38.0
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(
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= 20 Hz,
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JСF = 3 Hz); 134.7 (ddd, С(Ar), J = 248 Hz, J = 18 Hz,
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1
СF
2
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JСF = 13 Hz); 137.6 (ddd, С(Ar), J = 249, J = 12 Hz,
СF
СF
1
2
JСF = 4 Hz); 143.1 (dtd, С(Ar), J = 254 Hz, J = 14 Hz,
СF
СF
1
JСF ~5 Hz); 144.3 (m, С(6)); 148.1 (dddd, С(Ar), J = 250 Hz,
СF
3
4
19
JСF = 10 Hz, J ~5 Hz, J ~4 Hz); 171.7 (s, CO). F NMR
СF
СF
(
=
CDCl ), δ: –5.7 (ddd, F(3), J
= 25 Hz, JF(3)—F(4)
=
3
F(3)—F(2)
21 Hz, JF(3)—F(5) ~4 Hz); 1.8 (ddd, F(5), JF(5)—F(4) = 20.5 Hz,
JF(5)—F(2) = 10 Hz, JF(5)—F(3) ~4 Hz); 10.2 (ddd, F(4), JF(4)—F(3)
=
=
21 Hz, JF(4)—F(5) = 20.5 Hz, JF(4)—F(2) ~4 Hz); 29.1 (ddd,
F(2), JF(2)—F(3) = 25 Hz, JF(2)—F(5) = 10 Hz, JF(2)—F(4) = 4 Hz).
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1
(
1
1
5
489, 1441, 1410, 1398, 1309, 1281, 1232, 1198, 1180, 1136,
092, 1016, 980, 933, 856, 795, 750, 700, 667, 642, 629, 586,
+
13, 447, 426, 417. МS: found m/z 269.9973 [M] ; calculated
+
for C H O F S 269.9968. Found (%): С, 40.42; H, 2.43;
9
6
3 4

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Received February 25, 2021;
in revised form March 10, 2021;
accepted March 12, 2021
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