Synthesis and reactions of 2-hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4- methoxyphenyl)-but-2-enoic acid methyl ester

Article abstract of DOI:10.1016/S0022-1139(03)00031-9

2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-but-2-enoic acid methyl ester (1) was synthesized by the reaction of pentafluoroacetophenone with dimethyl oxalate in the presence of sodium methylate. Subsequently, reactions of compound 1 with anil

Full text of DOI:10.1016/S0022-1139(03)00031-9

Journal of Fluorine Chemistry 121 (2003) 201–204
Synthesis and reactions of 2-hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-
4-methoxyphenyl)-but-2-enoic acid methyl ester
Elena V. Pimenovaa, Olga P. Krasnycha, Elena A. Gounb, D. Howard Milesb,*
aDepartment of Chemistry, Perm State University, Bukireva St., Perm 614 000, Russia
bDepartment of Chemistry, University of Central Florida, Orlando, FL 32816, USA
Received 11 May 2002; received in revised form 23 December 2002; accepted 2 January 2003
Abstract
2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-but-2-enoic acid methyl ester (1) was synthesized by the reaction of penta-
fluoroacetophenone with dimethyl oxalate in the presence of sodium methylate. Subsequently, reactions of compound 1 with aniline,
o-phenylenediamine, and o-aminophenol were investigated. In addition, the thermal cyclization of ester 1 was studied and led to the formation
of 5,6,8-trifluoro-7-methoxy-4-oxo-4H-chromene-2-carboxylic acid methyl ester (6) due to nucleophilic substitution of the 3-fluoro
group. Hydrolysis of compound 1 and subsequent cyclization by treatment with SOCl2 gave 5-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-
furan-2,3-dione (3). Thermal decarbonylation of compound 3 under mild conditions resulted in the formation of 3-(2,3,5,6-tetrafluoro-
4-methoxyphenyl)-propene-1,3-dione (4) which dimerized to pyranone 5.
# 2003 Elsevier Science B.V. All rights reserved.
Keywords: 2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-but-2-enoic acid methyl ester; 5-(2,3,5,6-Tetrafluoro-4-methoxyphenyl)-furan-2,3-
dione; 3-(2,3,5,6-Tetrafluoro-4-methoxyphenyl)-propene-1,3-dione
1. Introduction
The goal of this research was to provide a novel synthesis
of 2-hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphe-
nyl)-but-2-enoic acid methyl ester (1) and to prepare novel
derivatives by thermal cyclization and by reaction with
aniline, o-phenylenediamine, and o-aminophenol.
Pyruvic acid is a natural metabolite, which plays an
important role in biochemistry. In addition, substituted
benzoylpyruvic acids and their derivatives are convenient
synthons for the synthesis of various acyclic and hetero-
cyclic compounds [1–5]. For example, they have been
utilized by Andreichikov et al. [2] for the synthesis of highly
reactive five member 2,3-dioxoheterocylic compounds such
as furandiones [3], pyrrolediones [4], and pyrazolediones
[5].
Substituted benzoylpyruvic acids and their derivatives are
also known as an important source of biologically active
compounds. The analgesic activity of aroylpyruvic acids has
been widely studied [6–8]. Substituted benzoylpyruvic acids
and their derivatives have also demonstrated antiviral [9],
antibacterial [10,11], and anti-inflammatory [7,9,12] acti-
vity.
2. Results and discussion
As previously mentioned, substituted benzoylpyruvic
acids and their derivatives have been of interest due to their
biological activity. Therefore, this research has two goals: to
provide a novel synthetic route to new synthons by the
introduction of aroyl fragments containing four fluorine
atoms at C-3, which would provide opportunities to produce
additional synthons due to the ease of nucleophilic substitu-
tion of fluorine atoms that are ortho to acyl groups; to use
this synthetic route to provide additional analogs for further
biological studies.
As shown in Scheme 1, pentafluoroacetophenone under-
went condensation with dimethyl oxalate in the presence of
sodium methylate (ratio 1:1:2) to give compound 1. This
occurred due to a Claisen reaction that was accompanied by
nucleophilic substitution of the fluorine atom at position 4 by
a methoxy group which resulted in the formation of
As the result of our previous work several novel deriva-
tives of benzoylpyruvic acids were found to be active against
Mycobacterium tuberculosis [13] and human myeloma
(ATCC CCL155) [14].
* Corresponding author. Tel.: þ1-407-823-0142; fax: þ1-407-823-2252.
E-mail address: hmiles@mail.ucf.edu (D.H. Miles).
0022-1139/03/$ – see front matter # 2003 Elsevier Science B.V. All rights reserved.
doi:10.1016/S0022-1139(03)00031-9

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E.V. Pimenova et al. / Journal of Fluorine Chemistry 121 (2003) 201–204
Scheme 1.
2-hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-
but-2-enoic acid methyl ester (1). The structure of com-
pound 1 was confirmed by elemental analysis, IR, and H
reaction to give 4-hydroxy-3-(2,3,5,6-tetrafluoro-4-methoxy-
benzoyl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-pyran-
2-one (5).
1
and 19F NMR spectroscopy. 2-Hydroxy-4-oxo-4-(2,3,5,6-
tetrafluoro-4-methoxyphenyl)-but-2-enoic acid (2) was pre-
pared by hydrolysis of ester 1 with a solution of sodium
hydroxide in ethanol. Acid 2 underwent cyclization in a
manner analogous to non-fluorinated substituted benzoyl-
pyruvic acids [2,3] into 5-(2,3,5,6-tetrafluoro-4-methoxy-
phenyl)-furan-2,3-dione (3) by heating at 50–60 8C with
SOCl2. Thermal decarboxylation of 3 at temperatures
greater than 65 8C resulted in the formation of a 3-
(2,3,5,6-tetrafluoro-4-methoxyphenyl)-propene-1,3-dione 4
which underwent dimerization due to a [4þ2] cycloaddition
Compounds 1 and 2 exist in the 1,3-ketoenol forms, which
is stabilized by intramolecular hydrogen bonds and is typical
for substituted benzoylpyruvic acids and their ester deriva-
tives [1,4,15]. This allows for the thermal cyclization of ester
1 into 5,6,8-trifluoro-7-methoxy-4-oxo-4H-chromene-2-car-
boxylic acid methyl ester (6) due to the nucleophilic sub-
stitution of the fluorine atom that is ortho to the 1,3-diketone
enol group as was observed earlier for pentafluorobenzoyl-
pyruvic acids and their esters [16,17]. However the ability
of the fluorine atom to undergo nucleophilic substitution
is considerably reduced when meta to the methoxy

E.V. Pimenova et al. / Journal of Fluorine Chemistry 121 (2003) 201–204
203
group. Therefore cyclization of 1 into 6 proceeds only by
heating in DMSO at temperature 100 8C.
added in small portions to a mixture of 6.35 g (10 mmol)
pentafluoroacetophenone and 3.54 g (10 mmol) of dimethyl
oxalate. The reaction was maintained at room temperature
for 24 h and then was stirred with 50 ml of water and
acidified with a solution of HCl (1:4). The resulting ester
1 was extracted with ether (240 ml), washed by a solution of
soda and water, and then dried with anhydrous Na2SO4. The
solvent was removed in vacuum and solid 1 was crystallized
from methanol to obtain 2.25 g (73% yield) of colorless
crystals with mp 92–93 8C. 1H NMR (300 MHz, CDCl3): d
3.87 (s, 3H, CO2CH3), 4.19 (s, 3H, CH3O), 6.68 (s, 1H, CH),
13.24 (s, 1H, OH). 19F NMR (CDCl3): d 156.27 (dd, 2F,
J ¼ 13 Hz), 136.49 (dd, 2F, J ¼ 13 Hz). IR: n 1732, 1645,
1610 cmꢀ1. Anal. Calcd for C12H8F4O5: C, 46.77; H, 2.62.
Found: C, 46.83; H, 2.83.
Under mild conditions ester 1 reacts with aniline to give
(Z)-4-oxo-2-phenylamino-4-(2,3,5,6-tetrafluoro-4-methoxy-
phenyl)-but-2-enoic acid methyl ester (7). The reaction
of ester 1 with o-phenylenediamine and o-aminophenol
results in the formation of (Z)-3-[2-oxo-2-(2,3,5,6-tetra-
fluoro-4-methoxyphenyl)-ethylidene]-3,4-dihydro-1H-qui-
noxalin-2-one (8) and the mixture of (Z)-3-[2-oxo-2-(2,3,5,
6-tetrafluoro-4-methoxyphenyl)-ethylidene]-3,4-dihydro-
benzo[1,4]oxazin-2-one (9), and (Z)-3-[2-oxo-2-(2,3,5-tri-
fluoro-6-hydroxy-4-methoxyphenyl)-ethylidene]-3,4-dihydro-
benzo[1,4]oxazin-2-one (10), respectively.
Formation of products analogous to compounds 8–10 is
typical for non-fluorinated and pentafluorinated benzoyl-
pyruvic acids [1,16–18]. Evidence that compounds 8–10 are
in the Z-form is the deshielding in the NMR spectrum of the
NH proton due to intermolecular hydrogen bonding with the
NH proton.
In summary, the Claisen reaction of pentafluoroacetophe-
none with dimethyl oxalate and the sodium methylate as the
condensing agent leads to 2-hydroxy-4-oxo-4-(2,3,5,6-tetra-
fluoro-4-methoxyphenyl)-but-2-enoic acid methyl ester (1)
instead of the expected pentafluorobenzoylpyruvic acid or its
esters. The ease of substitution of the fluorine atom which is
ortho to the 1,3-diketone enol group in this compound is
reduced in comparison with pentafluorobenzoylpyruvic acids
and their esters due to the presence of a para methoxy
group. This is confirmed by the fact that more severe condi-
tions are required for the thermal cyclization of ester 1 to
compound 6. In reactions of compounds 1 and 2 with mono-
and dinucleophiles the C-2 carbonyl group is attacked pre-
ferentially to the C-4 carbonyl group. Cyclization of acid 2 by
SOCl2 and its further decarboxylation leads to 3-(2,3,5,
6-tetrafluoro-4-methoxyphenyl)-propene-1,3-dione (4) is an
effective way of generation of polyfluorinated arylketenes.
Further dimerization of compound 4 leads to the formation
of 4-hydroxy-3-(2,3,5,6-tetrafluoro-4-methoxy-benzoyl)-6-
(2,3,5,6-tetrafluoro-4-methoxyphenyl)-pyran-2-one (5).
3.1.2. 2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-
4-methoxyphenyl)-but-2-enoic acid (2)
To a solution of 3.08 g (10 mmol) of ester 1 in absolute
ethanol (10 ml) a saturated solution of NaOH in ethanol
was added with stirring. After 1 h the reaction mixture was
diluted with water and acidified with H2SO4 (10%) to
obtain a pH of 1–2. The resulting precipitate of 2 was
filtered and recrystallized from toluene to give 2.38 g (81%
yield) in the form of white–yellow crystals, mp 155–
1
156 8C (decomp.). H NMR (300 MHz, CDCl3): d 4.15
(s, 3H, CH3O), 6.66 (s, 1H, CH), 10.40 (s, 1H, OH). 19F
NMR (DMSO-d6): d 157.95 (dd, 2F), 143.54 (dd, 2F). IR:
n 3500–3400, 3100–3000, 1730, 1650, 1630 cmꢀ1. Anal.
Calcd for C11H6F4 O5: C, 44.92; H, 2.06. Found: C, 45.03;
H, 1.83.
3.1.3. 5-(2,3,5,6-Tetrafluoro-4-methoxyphenyl)-furan-
2,3-dione (3)
A solution of 5.88 g (20 mmol) of acid 2 and 1.51 ml
(21 mmol) of SOCl2 in absolute benzene (8 ml) and absolute
hexane (4 ml) was heated on a water bath at a temperature of
50–60 8C for 1 h. The solution was cooled and the resulting
precipitate of 3 was filtered and recrystallized from absolute
benzene–hexane (1:1) to give 1.93 g (35% yield) of orange
1
crystals, mp 113–114 8C (decomp.). H NMR (300 MHz,
3. Experimental
CDCl3): d 4.19 (s, 3H, CH3O), 6.31 (s, 1H, CH). IR: n 1830,
1722, 1645, 1590 cmꢀ1. Anal. Calcd for C11H4F4O4: C,
47.85; H, 1.46. Found: C, 48.03; H, 1.53.
3.1. General experimental procedures
Infrared spectra (Nujol oil) were obtained on UR-20
1
3.1.4. 4-Hydroxy-3-(2,3,5,6-tetrafluoro-4-methoxy-
benzoyl)-6-(2,3,5,6-tetrafluoro-4-methoxyphenyl)-
pyran-2-one (5)
spectrometer, H NMR spectra were recorded on a Bruker
AC-300 (300 MHz) referenced to tetramethylsilane. 19F
NMR spectra were obtained on Bruker WP 80 SY at
75.398 MHz, where a C6F6 internal standard has been
utilized. All d values are given relative to CFCl3.
A solution of 1.38 g (5 mmol) of furandione 3 in absolute
toluene (10 ml) was refluxed for 2 h, cooled and the pre-
cipitate was filtered and recrystallized from toluene to give
0.88 g (71% yield) of colorless crystals 5, mp 204–205 8C.
1H NMR (300 MHz, DMSO-d6): d 4:20 þ 4:26 (2s, 6H,
2CH3O), 7.15 (s, 1H, CH). IR: n 3085, 1765, 1650,
1630 cmꢀ1. Anal. Calcd for C20H8F8O6: C, 48.41; H,
1.62. Found: C, 48.49; H, 1.23.
3.1.1. 2-Hydroxy-4-oxo-4-(2,3,5,6-tetrafluoro-
4-methoxyphenyl)-but-2-enoic acid methyl ester (1)
A solution of sodium methylate, prepared from 0.46 g
(20 mmol) of sodium and 30 ml absolute methanol, was

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E.V. Pimenova et al. / Journal of Fluorine Chemistry 121 (2003) 201–204
3.1.5. 5, 6,8-Trifluoro-7-methoxy-4-oxo-4H-
chromene-2-carboxylic acid methyl ester (6)
6.40 (s, 1H, CH), 7.20 (m, 3H, C6H3), 7.70 (d, 1H, C5–H),
12.52 (s, 1H, NH). IR: n 1750, 1630, 1610 cmꢀ1. Anal.
Calcd for C17H9F4NO4: C, 55.60; H, 2.47; N, 3.81. Found:
C, 56.03; H, 2.53. MS (70 eV), m/z (%): 367 (11) [Mþ], 325
(16), 207 (91) [p-CH3OC6F4CO], 187 (16), 160 (100)
[Mþꢀ207], 159 (63) [Mþꢀ207-H], 132 (45).
A solution of 1.54 g (5 mmol) of ester 1 in DMSO (5 ml)
was heated at reflux on a water bath for 20 min, cooled, and
the resulting solid (5) was filtered to give 1.27 g (88% yield)
1
of colorless crystals, mp 154–156 8C. H NMR (300 MHz,
DMSO-d6): d 3.92 (s, 3H, CH3COO), 4.20 (s, 3H, CH3O),
6.87 (s, 1H, CH). 19F NMR (DMSO-d6): d 156.43 (d, 1F,
J ¼ 22 Hz), 154.36 (dt, 1F, J ¼ 17 Hz), 146.51 (dd, 1F,
J ¼ 22 Hz). IR: n 3044, 1742, 1656 cmꢀ1. Anal. Calcd
for C12H7F3O5: C, 50.01; H, 2.45. Found: C, 50.09; H, 2.57.
Solvent was evaporated in vacuo and the resulting mate-
rial was recrystallized from ethanol to yield 0.083 g (2%
yield) of compound 10 in the form of yellow crystals, mp
230–232 8C. 1H NMR (300 MHz, DMSO-d6): d 4.13 (s, 3H,
CH3O), 6.77 (s, 1H, CH), 7.20 (m, 4H, C6H3), 7.65 (d, 1H,
C5–H), 12.56 (brs, 2H, NH, OH). IR: n 3200, 1760,
1635 cmꢀ1. Anal. Calcd for C17H10F3NO5: C, 55.90; H,
2.76; N, 3.83. Found: C, 55.79; H, 2.85; N, 3.90.
3.1.6. (Z)-4-Oxo-2-phenylamino-4-(2,3,5,6-tetrafluoro-
4-methoxyphenyl)-but-2-enoic acid methyl ester (7)
A solution of 1.54 g (5 mmol) of ester 1 and 0.47 ml
(5 mmol) aniline in 10 ml benzene was refluxed for 2 h. The
solvent was removed and the residue was recrystallized from
CCl4 to give 1.90 g (99% yield) of yellow crystals 7, mp
References
1
115–116 8C. H NMR (300 MHz, CDCl3): d 3.59 (s, 3H,
CH3COO), 3.99 (s, 3H, CH3O), 5.76 (s, H, CH), 7.12 (m, 5H,
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Russia (1994).
C6H5), 11.59 (s, 1H, NH). IR: n 3200, 1740, 1650 cmꢀ1
.
Anal. Calcd for C18H13F4NO4: C, 56.40; H, 3.42; N, 3.65.
Found: C, 56.08; H, 3.18; N, 3.52.
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3.1.7. (Z)-3-[2-Oxo-2-(2,3,5,6-tetrafluoro-4-methoxy-
phenyl)-ethylidene]-3,4-dihydro-1H-quinoxalin-
2-one (8)
[5] E.V. Pimenova, Yu.S. Andreichikov, Zh. Org. Khim. 28 (1992)
376–389.
[6] A.V. Milyutin, R.R. Makhmudov, Yu.S. Andreichikov, A.F. Golene-
va, G.A. Tul’bovich, T.I. Kovina, Khim. Farm. Zh. 30 (1996) 20–22.
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To a solution of 0.62 g (2 mmol) of ester 1 in 5 ml benzene
a solution of 0.25 g (2 mmol) o-phenylenediamine in 10 ml
benzene was added. The reaction mixture was maintained
for 24 h at room temperature and the resulting solid was
filtered and recrystallized from CHCl3 to give 0.72 g (98%
yield) of orange crystals (8), mp 259–260 8C (decomp.). 1H
NMR (300 MHz, DMSO-d6): d 3.89 (s, 3H, CH3O), 6.69
(s, 1H, CH), 7.08 (m, 4H, C6H4), 8.56 (s, 1H, NHCO), 13.03
(s, 1H, NH). IR: n 1690, 1615 cmꢀ1. Anal. Calcd for
C17H10F4N2 O3: C, 55.75; H, 2.75; N, 7.66. Found: C,
55.83; H, 2.88; N, 7.94.
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Drovosekova, Yu.S. Andreichikov, Khim. Farm. Zh. 32 (1998) 24–26.
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Kolla, Z.N. Semenova, Yu.S. Andreichikov, Khim. Farm. Zh. 26
(1992) 28–31.
[10] Yu.S. Andreichikov, A.N. Maslivets, O.P. Krasnykh, G.A. Aleksan-
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30 (1996) 47–49.
3.1.8. (Z)-3-[2-Oxo-2-(2,3,5,6-tetrafluoro-4-methoxy-
phenyl)-ethylidene]-3,4-dihydro-benzo[1,4]oxazin-
2-one (9) and 3-[2-oxo-2-(2,3,5-trifluoro-6-hydroxy-
4-methoxyphenyl)-ethylidene]-3,4-dihydro-
[13] UCF-303A United States Provisional Application Serial No.
60/292,985 filed 23 May 2001.
[14] UCF-311C United States Provisional Application Serial No.
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benzo[1,4]oxazin-2-one (10)
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A solution of 3.08 g (10 mmol) of ester 1 and 1.09 g
(10 mmol) of o-aminophenol in 30 ml ethanol was refluxed
for 30 min and cooled to give compound 9 which was
filtered and recrystallized from ethyl acetate to give
3.13 g (85% yield) of orange crystals, mp 183–184 8C.
1H NMR (300 MHz, DMSO-d6): d 4.15 (s, 3H, CH3O),
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