A preparation of 3,3-difluoropyruvate from trifluoroacetic anhydride

Article abstract of DOI:10.1016/j.jfluchem.2009.03.013

Difluoropyruvate was prepared from trifluoroacetic anhydride via 3 steps (Friedel-Crafts type addition, reductive defluorination, and ozonolysis) in 30% yield.

Full text of DOI:10.1016/j.jfluchem.2009.03.013

Journal of Fluorine Chemistry 130 (2009) 682–683
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Journal of Fluorine Chemistry
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Short communication
A preparation of 3,3-difluoropyruvate from trifluoroacetic anhydride
*
Toshimasa Katagiri , Fumiya Ozaki, Yasuhiro Tanaka
Department of Applied Chemistry, Faculty of Engineering, Okayama University, Tsushimanaka 3-1-1, Okayama, 700-8530, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
Difluoropyruvate was prepared from trifluoroacetic anhydride via 3 steps (Friedel–Crafts type addition,
reductive defluorination, and ozonolysis) in 30% yield.
Received 12 March 2009
Received in revised form 31 March 2009
Accepted 31 March 2009
Available online 8 April 2009
ß 2009 Elsevier B.V. All rights reserved.
Keywords:
3,3-Difluoropyruvate
Trifluoroacetic anhydride
Reductive defluorination
Ozonolysis
The importance of fluorinated synthetic building blocks for
preparation of biologically active compounds would need no
repeated description here [1]. Trifluoropyruvate is commercially
available and one of the well-studied fluoro-building blocks for
preparation of trifluoromethylated amino acids and heterocycles
[2]. In contrast, there has been reported only a few reactions of
difluoropyruvates [3–5]. The poor chemistry of the difluoropyr-
uvate would be due to its low availability.
resulted in cleavage of C–C bond to give difluoroacetic acid. Among
examined oxidations, ozonolysis in MeOH at low temperature gave
the methyl difluoropyruvate hemiacetal 3 with itsderivatives (4 and
5) in the best yield [7]. Here, a slightly excess amount of O3 depress
the over oxidation, of which amount could be observed by the
slightly greenish yellow color of the reacting solution. Use of excess
amount ofO3 withbluecoloredsolutionresultedinoveroxidation to
give difluoroacetic acid.
Conventionally, difluoropyruvates were prepared by reduction
of trifluoropyruvates followed by dehydrofluorination [3], reduc-
tive enolization of trifluoropyruvates followed by defluorosilyla-
tion [4], or oxidative fluorination of the corresponding fluoroenols
[5]. Drawbacks of these preparations are the use of expensive
substrates. Therefore, a new preparation of difluoropyruvates from
cheaper starting material has been demanded.
Further esterification and hydrolysis of the hemiacetal 3 in
MeOH with sulfuric acid gave the acetal 4 in ca. 55% yield from the
difluoroacetylfuran 2 (3 stages). Ketonization of acetal unit with
P2O5 gave the methyl 3,3-difluoropyruvate 5 in ca. 84% yield. The
total yield of the difluoropyruvate 5 from the trifluoroacetic
anhydride was 30% (3 steps, 6 stages).
A similar procedure produced trifluoropyruvate by ozonolysis
of trifluoroacetylfuran 1 followed by esterification, hydrolysis, and
ketonization in 41% yield from trifluoroacetic anhydride.
This laboratory scale preparation of the difluoropyruvate 4
enables the compound to use in preparation of biologically active
compounds, such as difluoromethyl-amino acids and difluoro-
methyl-heterocycles with its application to the reactions instead of
trifluoropyruvates [2].
Here we report
a laboratory scale synthesis of methyl
difluoropyruvate 5 from commercially available trifluoroacetic
anhydride. Optimized synthetic route is illustrated in Scheme 1.
Preparation of the 2-trifluoroacetyl-5-methylfuran 1 and the
magnesium promoted defluorination of the furan 1 to difluor-
oacetyl furan 2 were described in our previous report [6].
Successive oxidation of the furan 2 was the key-step of this
preparation. Because of low lying HOMO of the molecule, fluori-
nated compounds would need strong oxidant for its oxidation [1].
Meanwhile, the C–C bond between the carbonyl carbons of the
pyruvate is easily cleaved by a strong oxidant. Actually, the Ru-
catalyzed oxidation with NMO oxidant (TPAP oxidation), which was
a successful oxidation in the preparation of difluorolactate [6],
1. Experimental
1.1. General
1.1.1. Spectroscopic measurements
1.1.1.1. NMR spectra. All NMR spectra were recorded as CDCl3
solutions. 1H, and 19F NMR spectra were recorded at 300 and
282 MHz respectively with Varian MERCURY 300 instrument. The
* Corresponding author. Tel.: +81 86 251 8605; fax: +81 86 251 8021.
E-mail address: tkata@cc.okayama-u.ac.jp (T. Katagiri).
0022-1139/$ – see front matter ß 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2009.03.013

T. Katagiri et al. / Journal of Fluorine Chemistry 130 (2009) 682–683
683
Scheme 1.
chemical shifts are reported in
d
(ppm) related to the CHCl3
J = 299, 55 Hz, 1H) ppm [5]); GC–MS m/z (rel. Int.) 153 (2), 119 (5),
111 (100), 91 (24), 63 (43), 51 (42).
(7.26 ppm for 1H NMR) and C6F6 (0 ppm for 19F NMR: the relative
chemical shift of C6F6 to CFCl3 is À162.2 ppm). Coupling constants
(J) are reported in hertz (Hz).
Hemiacetal 3 was mixed with THF/H2O (=1/1, 90 ml) and
stirred. The solution was added by saturated brine (15 ml),
separated, and extracted by ethyl ether (80 ml). Combined organic
layer was dried over MgSO4, and concentrated under a reduced
pressure to give crude hydrate of difluoropyruvate 4. When the
product was submitted to GC–MS, it converted completely to
methyl difluoropyruvate in vaporizing chamber.
1.1.1.2. IR spectra. Infrared spectra were recorded on a Hitachi
270-30 spectrometer. Only selected absorbances are reported
(n
in cmÀ1).
1.1.1.3. MS analysis. MS analyses were performed on a Shimadzu
GCMS-QP5050A.
1.1.5. Hydrate of methyl difluoropyruvate (4)
[
19F] NMR (282 MHz, CDCl3)
d
26.4 (d, J = 54 Hz, 2F) (lit.
(d, J = 55 Hz, 2F) [5]); 1H NMR (300 MHz, CDCl3)
5.87 (t,
J = 54.6 Hz, 1H), 3.94 (s. 3H) (lit. 5.88 (t, J = 54.7 Hz, 1H) (no
d 27.4
1.1.2. Chemicals
d
Hexane was dried over MS 4A for 1 day and used without further
purification. THFwas dried overbenzophenoneNaketylanddistilled
just prior to use. Trifluoroacetic anhydride (TFAA: Aldrich) was
distilled and stored in Schlenk tube. 2-Methylfuran (Aldrich) was
used without further purification. Chlorotrimethylsilane (TMSCl:
TCI) was distilled and stored in a glass tube. Mg turnings for Grignard
reagent grade (Nacalai) were used without further treatment.
Ozone (O3) was prepared from pure O2 by ED-OG-R2+ Ozone
Gas Generator equipped with SD-158-11 Silent Electric Discharge
Tube (Eco Design Co.).
d
description of chemical shift of methyl group in literature) [5]).
Hydrate 4 was mixed with P2O5 (6.5 g) then sonicated for 5 min.
Distillation gave methyl difluoropyruvate 5 (1.54 g, 11.1 mmol) in
46% yield from the difluoroacetylfuran 2.
1.1.6. Methyl difluoropyruvate (5)
[
19F] NMR (282 MHz, CDCl3)
d
31.1 (d, J = 54 Hz, 2F) (lit.
(d, J = 53 Hz, 2F) [5]); 1H NMR (300 MHz, CDCl3)
6.40 (t,
J = 52.8 Hz, 1H), 3.98 (s. 3H) (lit. 6.40 (t, J = 52.7 Hz, 1H), 3.99
d 32.0
d
d
Preparations of 2-trifluoroacetyl-5-methylfuran 1 and 2-difluor-
oacetyl-5-methylfuran 2 were reported in our previous report [6].
(s, 3H) [5]); GC–MS m/z (rel. Int.) 94 (1), 81 (10), 79 (5), 59 (57), 51
(100), 44 (2), 43 (18).
1.1.3. Ozonolysis of 2-difluoroacetyl-5-methylfuran (2)
References
In a 200 ml flask, 2-difluoroacetyl-5-methylfuran 2 (3.87 g,
24 mmol), was dissolved in MeOH (120 ml) and cooled to
À80–100 8C. The O3/O2 gas (0.15 L/min) was bubbled into the
solution for 90 min (until the solution became greenish yellow).
The excess O3 was purged by 10 min of Ar bubbling. The solution
was added by sulfuric acid (0.5 ml) and stirred for 20 min at
À50 8C, followed by addition of MS 3A (1.5 g) and 15 h refluxing.
Removal of sulfuric acid by filtration through silica gel, followed by
evapolation of MeOH under a reduced pressure, and difluoroacetic
acid was removed by silica gel column chromatography to give
crude hemiacetal of methyl difluoropyruvate 3, which was
submitted for hydrolysis without further purification. Further
removal of MeOH gave a mixture of 3 and 5.
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