Synthesis of 2-fluorotetronic acid

Article abstract of DOI:10.1016/S0022-1139(97)00028-6

Fluorination of 2-bromotetronic acid (7) in ethanol produces 2-bromo-3-ethoxy-2-fluoro-γ-butyrolactone (8). Tributyltin hydride reduction of 8 gives 2-fluorotetronic acid in good yield.

Full text of DOI:10.1016/S0022-1139(97)00028-6

Journal of Fluorine Chemistry 84 (1997) 45–47
Synthesis of 2-fluorotetronic acid
Ping Ge, Kenneth L. Kirk U
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,
Bethesda, MD 20892, USA
Received 20 November 1996; accepted 25 February 1997
Abstract
Fluorination of 2-bromotetronic acid (7) in ethanol produces 2-bromo-3-ethoxy-2-fluoro-g-butyrolactone(8).Tributyltinhydridereduction
of 8 gives 2-fluorotetronic acid in good yield.
Keywords: 2-Fluorotetronic acid
1. Introduction
attempted fluorination of the sodium salt of 1 resulted mostly
in degradation of the starting material. This result suggests
that electrophilic fluorination of 1 in CH3CN or THF is a slow
process, possibly owing to the low nucleophilicity of the
enolic double bond of the acidic 1 (pKas3.76) [11]. In
contrast, when fluorination was attempted in EtOH, a 2,2-
difluoro hemiacetal derivative 5 was the only isolated prod-
uct. The structural assignment of 5 was based on its 1H and
13C NMR spectra. In the presence of ethanol, formation of
the hemiacetal at C-3 may permit lactone enolization
(C1_C2 double bond) that is subject to electrophilic fluori-
nation. In this case, rapid enolization of the monofluoro prod-
uct apparently is followed by further fluorination to produce
5 in a process too rapid to allow detection of the monofluoro
intermediate.
Based on these results, a strategy was devised to take
advantage ofthisapparentrapidfluorinationofthehemiacetal
intermediate. In contrast to our experience with fluorination,
monobromination is a facile process (Scheme 1). Therefore,
tetronic acid was first brominated to 2-bromotetronic acid
(7) in quantitative yield, using NBS. Consistent with our
rationalization for formation of 5, fluorination of 7 by 6,
without isolation, rapidly gave 2-bromo-2-fluoro hemiacetal
(8). Saturation of the 2,3 double bond introduced two chiral
centers, and, as expected, the NMR spectrum revealed that 8
was present as a mixture of diastereoisomers. The bromine
in compound 8 proved to be quite reactive and reduction by
n-tributyltin hydride, followed by treatment with aqueous
acetic acid, gave the target compound 4 in overall yield of
45%.
Increasing interest in tetronic acid (1) in recent years has
been prompted in part by the fact that a number of natural
products and synthetic derivatives that contain this moiety
have been shown to have important biological activities [1–
3]. We have investigated fluorination of this small but chem-
ically versatile molecule in anticipation of the significant and
potentially useful alterations in physical and chemical prop-
erties that should result.
Halogenation of tetronic acid was reported decades ago
[4,5], but fluorination of 1 has not been reported. Kitazume
described a synthesis of 2-fluoro-4-substituted tetronic acids
by ultrasound-promoted Reformatsky-type reactions
between O-trimethylsilylated cyanohydrins (2) and ethyl
a-fluorobromoacetate (3) [6,7]. Recently, several stable
electrophilic fluorinating reagents have become available,
including the N-F reagents such as N-fluorobenzenesulfon-
imide (NFSi) and selectfluorTM reagent (6) [8–10].
These convenient and easily handled fluorinating agentshave
made many electrophilic fluorinations routine procedures.
We now wish to report a facile synthesis of 2-fluorotetronic
acid (4) from 1, based on a key electrophilic fluorination
step using 6.
2. Results and discussion
When 6 was added to the solution of 1 in CH3CN or THF,
only trace amounts of 4 were detected (Scheme 1), whereas
Our synthesis of 4 completes the series of 2-halo-tetronic
acids. We are now applying the strategy reported here to
U Corresponding author. Fax: q1 301 402 4182.
0022-1139/97/$17.00 q 1997 Elsevier Science S.A. All rights reserved
PII S0022-1139(97)00028-6

46
P. Ge, K.L. Kirk / Journal of Fluorine Chemistry 84 (1997) 45–47
(5% solution in ethanol) with heating. Fluorine analysis was
carried out by Galbraith Laboratories, Inc., Knoxville, TN.
selectfluorTM reagent 6 was a gift from Air Products and
Chemicals, Inc.
3.1. 2,2-Difluoro-3-ethoxy-3-hydroxy-g-butyrolactone (5)
To a solution of tetronic acid (1) (50 mg, 0.5 mmol) in
ethanol (2 ml) was added 6 (180 mg, 0.5 mmol). The result-
ing mixture was stirred at room temperature for 10 h and then
filtered. The filtrate was evaporated and the residue was puri-
fied by column chromatography (silica gel, eluting with 25%
EtOAc in petroleum ether) to give the product as a colorless
oil (30 mg, 67%). 1H NMR (DMSO-d6) d ppm: 1.18 (t, 3H,
Js6.9 Hz, CH3), 3.60–3.78 (m, 2H, CH2), 4.30–4.51 (m,
2H, 4-H), 7.69 (s, 3-OH), 8.04 (d, Js1.5Hz, 3-OH). 13C
NMR (DMSO-d6) d ppm: 15.50 (s, CH3), 58.45 (s, CH2),
72.41, 72.45 (s, C-4), 91.91, 94.67 (t, Js20.2 Hz, C-3),
110.18 (dd, Js261.2 and 264.1 Hz, C-2), 110.11 (dd,
Js254.4 and 260.0 Hz, C-2), 164.86 (t, Js31.87 Hz, C-1).
Scheme 1.
3.2. 2-Bromo-3-ethoxy-2-fluoro-3-hydroxy-g-butyrolactone
(8)
fluorination of more complex tetronic acid derivatives,
including 2-deoxy-l-ascorbic acid [12].
To a solution of tetronic acid (500 mg, 5 mmol) in ethanol
(5 ml) was added N-bromosuccinimide (885 mg, 5 mmol)
at room temperature. The resulting solution was stirred for
10 min. TLC and 1H NMR showed that 7 had been formed
quantitatively. 1H NMR (DMSO-d6) d ppm: 4.78 (s, 4-H).
To this solution was then added 6 (1.8 g, 5 mmol). The
resulting mixture was stirred at room temperature for 10 h
then filtered. The filtrate was evaporated and the residue was
purified by column chromatography (silica gel, eluting with
25% EtOAc in petroleum ether) to give the product as a
colorless liquid (1.06 g, 87%). 1H NMR (DMSO-d6) d ppm:
1.19 (t, 3H, Js6.9 Hz, CH3), 3.64–3.79 (m, 2H, CH2),
4.16–4.36 (m, 2H, 4-H), 7.98 (s, 1H, 3-OH). MS-EI m/e:
242 (Mq).
3. Experimental details
The melting point was determined in an open-end capillary
tube on a Thomas Hoover capillary melting point apparatus
and is uncorrected. Proton and carbon-13 NMR spectra were
recorded on a Varian Gemini 300 spectrometer and chemical
shifts are reported in ppm relative to tetramethylsilane. TLC
analyses were performed on Uniplate GHLF silica gel (Anal-
tech). Solvents and reagents were purchased from Aldrich or
Fluka. Chromatographic separations were performed by flash
column chromatographyonsilicagel.Chromatographicspots
on TLC were visualized by UV or by phosphomolybdic acid

P. Ge, K.L. Kirk / Journal of Fluorine Chemistry 84 (1997) 45–47
47
3.3. 2-Fluorotetronic acid (4)
C-1), 166.23 (d, Js25.1 Hz, C-3). MS-EI m/e: 118 (Mq).
Analysis calculated for C4H3O3F: F, 15.81. Found: F, 16.09.
To a solution of compound 8 (400 mg, 1.65 mmol) in
THF (1.5 ml) was added n-tributyltin hydride (0.9 ml, 3.2
mmol) under nitrogen at 0 8C. The resulting solution was
stirred at rom temperature for 10 h, and then evaporated to
remove THF. The residue was stirred in 50% HOAc (2 ml)
and petroleum ether (4 ml) for 30 min. The acetic acid layer
was separated, washed with petroleum ether (3=4 ml), and
evaporated to dryness. The residue was then dissolved in
sodium carbonate solution (1 N, 5 ml), and the solution was
washed with 25% EtOAc in petroleum ether (3=4 ml). The
aqueous solution was acidified to pH 1 with 2 N hydrochloric
acid, and extracted with EtOAc (5 ml). The organic layer
was separated, dried and evaporated to give the product as
light yellow solid (95 mg, 49%), mp 145–147 8C. 1H NMR
(DMSO-d6) d ppm: 4.68 (d, 2H, Js3.9 Hz), 12.60 (br, 1H,
3-OH). 13C NMR (DMSO-d6) d ppm: 64.10 (d, Js5.7 Hz,
C-4), 124.82 (d, Js244.1 Hz, C-2), 155.65 (d, Js2.3 Hz,
References
[1] D. Desmaele, Tetrahedron 48 (1992) 2925 and references cited
therein.
[2] S.V. Ley, M.L. Trudell, D.J. Wadsworth, Tetrahedron47(1991)8258.
[3] G. Kohr, U. Heinemann, Neurosci. Lett. 112 (1990) 43.
[4] W.D. Kumler, J. Am. Chem. Soc. 60 (1938) 855.
[5] W.D. Kumler, J. Am. Chem. Soc. 60 (1938) 857.
[6] T. Kitazume, Synthesis (1986) 855.
[7] T. Kitazume, J. Fluorine Chem. 35 (1987) 287.
[8] V. Snieckus, F. Beaulieu, K. Mohri, W. Han, C.K. Murphy, F.A. Davis,
Tetrahedron Lett. 35 (1994) 3465.
[9] G.S. Lal, J. Org. Chem. 58 (1993) 2791.
[10] R.E. Banks, N.J. Lawrence, A.L. Popplewell, J. Chem. Soc. Chem.
Commun. (1994) 343.
[11] W.D. Kumler, J. Am. Chem. Soc. 60 (1938) 859.
[12] P. Ge, K.L. Kirk, J. Org. Chem., 61 (1996) 8671.