A convenient synthesis of 5-fluorofuran-2-carboxylic acid

Article abstract of DOI:10.1016/j.tetlet.2011.07.087

A convenient synthesis of 5-fluorofuran-2-carboxylic acid has been achieved in two steps and 56% total yield. Fluorodenitration of commercially available benzyl 5-nitrofuran-2-carboxylate utilizing potassium fluoride and catalytic tetraphenylphosphonium b

Full text of DOI:10.1016/j.tetlet.2011.07.087

Tetrahedron Letters 52 (2011) 4965–4966
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Tetrahedron Letters
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A convenient synthesis of 5-fluorofuran-2-carboxylic acid
⇑
Renhua Song, Weimin Lin, Qin Jiang
AMRI, 26 Corporate Circle, PO Box 15098, Albany, NY 12212, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient synthesis of 5-fluorofuran-2-carboxylic acid has been achieved in two steps and 56% total
yield. Fluorodenitration of commercially available benzyl 5-nitrofuran-2-carboxylate utilizing potassium
fluoride and catalytic tetraphenylphosphonium bromide in sulfolane at 140 °C for 2 h furnished benzyl
5-fluorofuran-2-carboxylate. Hydrogenolysis of benzyl 5-fluorofuran-2-carboxylate gave the title
compound.
Received 12 July 2011
Accepted 20 July 2011
Available online 27 July 2011
Keywords:
Ó 2011 Elsevier Ltd. All rights reserved.
5-Fluorofuran-2-carboxylic acid
Benzyl 5-nitrofuran-2-carboxylate
Benzyl 5-fluorofuran-2-carboxylate
Synthesis
5-Fluorofuran-2-carboxylic acid (1) is a useful building block in
pharmaceutical research.1 The preparation of 1 was described in
the literature1a as shown in Scheme 1. The authors did not provide
a yield, and in our hands following the procedures provided only a
5% yield of 1 from 2. Fluorodenitration is a practical method for
introducing fluorine into the meta-position of an activated aro-
matic ring.2 Chambers3 reported a fluorodenitration strategy to
convert 5-nitrothiophene-2-carbonitrile (4) to 5-fluorothiophene-
2-carboxylic acid (6) (Scheme 2) in good yield. Therefore, we con-
sidered a similar strategy to prepare the furan analogue (1) and the
results are reported herein.
We first investigated Chambers’ method (KF, PPh4Br, 1,2-
Ph(COCl)2, sulfolane, 180 °C)3 to convert 5-nitrofuran-2-carbonitrile
(7) to 5-fluorofuran-2-carbonitrile (8), as well as 5-nitrofuran-2-
carboxylic acid (9) to 1 (Scheme 3). In both cases, we observed no
formation of the desired products. We investigated the fluorodeni-
tration of various esters of 9. The reactions were carried out with
or without phthaloyl chloride at various temperatures (Table 1).
Both methyl ester (10a) and tert-butyl ester (10b) gave complex
reaction profiles (entries 1 and 2), whereas the benzyl ester (10c)
gave the desired corresponding fluoride (11c) (entries 3–12). Our
investigation showed that the addition of phthaloyl chloride is not
necessary for the fluorodenitration of an activated furan ring and
reaction temperatures from 120 to 140 °C can be tolerated (entries
7–9). A significant reduction in yield was noted when the reaction
was conducted at 160 °C (entry 5). Considering the shorter reaction
time, we believe 140 °C is the best reaction temperature (entry 7).4
Different solvents were also investigated (entries 7 and 10–12) with
sulfolane providing the best results of those examined. Our
1. n-BuLi,
THF,-78 °C
NaHCO3
HO2C
F
F
O
O
O
Br
Br
CO2H
Selectfluor®
2. CO2
2
3
1
Scheme 1.
KF, PPh4Br
1. 1N NaOH
1,2-Ph(COCl)2
O2N
reflux
F
F
S
S
S
CN
CN
CO2H
sulfolane, 180 °C
76%
2. 1N HCl
4
5
6
82%
Scheme 2.
KF, PPh4Br
1,2-Ph(COCl)2, sulfolane
F
O2N
180 °C
O
O
x
X
X
(or)
KF, PPh4Br
7
: X = CN
8
: X = CN
sulfolane, 140 °C
9: X = CO2H
1: X = CO2H
Scheme 3.
fluorodenitration condition (KF, PPh4Br, sulfolane, 140 °C) was ap-
plied to convert 7 to 8 and 9 to 1. No desired corresponding fluorides
were observed (Scheme 3).
Hydrogenolysis of 11c gave the title compound (1) in 95% yield
(Scheme 4).5 Thus, starting from the commercially available ester
10c, 5-fluorofuran-2-carboxylic acid (1) has been achieved in two
steps and 56% total yield.
⇑
Corresponding author. Tel.: +1 518 512 2380; fax: +1 518 512 2079.
E-mail address: qin.jiang@amriglobal.com (Q. Jiang).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.087

4966
R. Song et al. / Tetrahedron Letters 52 (2011) 4965–4966
Table 1
Fluorodenitration of 5-nitrofuran-2-carboxylate
KF, PPh4Br
F
O2N
O
a: R = Me
O
CO2R
CO2R
b: R = t-Bu
c
: R = Bn
11
10
Entry
Compound
R
Phthaloyl Chloride
Solvent
T (°C)
t (h)
Product
Yield (%)a
1
2
3
4
5
6
7
8
9
10a
10b
10c
10c
10c
10c
10c
10c
10c
10c
10c
10c
Me
t-Bu
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
–
–
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
Sulfolane
DMSO
140
140
180
180
160
140
140
130
120
140
140
140
2
2
2
2
2
4
2
5
11a
11b
11c
11c
11c
11c
11c
11c
11c
11c
11c
11c
–
–
7
0.9 equiv
–
–
11
15
40
59
56
59
20
42
31
0.9 equiv
–
–
–
–
–
–
6
10
11
12
1.5
2.5
2
DMF
NMP
a
Isolated yield.
Miao, L.; Xiao, Y.; Hammond, P. S.; Miller, C. H.; Akireddy, S. R.; Murthy, V. S.;
Whitaker, R. C.; Breining, S. R.; Melvin, M. S. WO 2008057938.
2. (a) Adams, D. J.; Clark, J. H. Chem. Soc. Rev. 1999, 28, 225; (b) Suzuki, H.; Yazama,
N.; Yoshida, Y.; Furusawa, O.; Kimura, Y. Bull. Chem. Soc. Jpn. 1990, 63, 2010.
3. Chambers, R. J.; Marfat, A. Synth. Commun. 2000, 30, 3629.
F
Pd/C, H2 (1 atm)
F
O
O
CO2Bn
CO2H
MeOH, rt, 30 min
95%
11c
1
4. Standard procedure for fluorodenitration: A suspension of commercially available
benzyl 5-nitrofuran-2-carboxylate (10c, 0.793 g, 3.21 mmol), spray-dried
potassium fluoride (0.932 g, 16.0 mmol), and tetraphenylphosphonium
bromide (0.139 g, 0.330 mmol) in anhydrous sulfolane (10 mL) was heated at
140 °C under nitrogen for 2 h (reaction was monitored by TLC). The reaction
mixture was cooled to rt and diluted with water (10 mL). The resulting mixture
was extracted with diethyl ether (Â3). The combined extracts were washed with
brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced
pressure. The resulting residue was purified by flash column (5% MTBE/hexanes)
to give 11c (0.416 g, 59%) as a colorless oil: 1H NMR (300 MHz, CDCl3) d 7.40–
Scheme 4.
Acknowledgments
The authors would like to thank Professor Thomas R. Hoye, Dr.
Keith Barnes, Dr. R. Jason Herr, and Dr. P. Jolicia Gauuan for helpful
suggestions to this manuscript.
7.34 (m, 5H), 7.15 (t, J = 3.5 Hz, 1H), 5.62 (dd, J = 7.1, 3.6 Hz, 1H), 5.32 (s, 2H); 13
C
NMR (75 MHz, CDCl3) d 158.9 (d, J = 284 Hz), 157.7, 135.5, 135.0, 128.6, 128.5,
128.4, 120.6, 85.1 (d, J = 13.4 Hz), 66.6; 19F NMR (282 MHz, CDCl3) d 106.4.
5. Preparation of 1: To a solution of 11c (0.220 g, 1.00 mmol) in MeOH (10 mL) was
added 10% Pd/C (50% wet, 22 mg). The resulting suspension was stirred at rt
under hydrogen atmosphere (balloon, 1 atm) for 30 min (reaction was
monitored by TLC; prolonged reaction time resulted in de-fluoronation). The
reaction mixture was filtered through a short pad of diatomaceous earth and the
filter cake was washed with methanol (10 mL). The filtrate was concentrated
under reduced pressure. The residue was triturated with a mixture of hexanes
(4 mL) and methylene chloride (2 mL), filtered, and dried under high vacuum to
give 1 (0.123 g, 95%) as a white solid: 1H NMR (300 MHz, CD3OD) d 7.20 (t,
J = 3.5 Hz, 1H), 5.81 (dd, J = 7.0, 3.5 Hz, 1H); 13C NMR (75 MHz, CD3OD) d 160.7,
160.2 (d, J = 281 Hz), 137.1, 121.6, 86.0 (d, J = 13.6 Hz); 19F NMR (282 MHz,
CD3OD) d 110.8.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.087.
References and notes
1. (a) Neustadt, B. R.; Lindo, N. A.; Greenlee, W. J.; Tulshian, D.; Silverman, L. S.; Xia,
Y.; Boyle, C. D.; Chackalamannil, S. WO 2001092264 A1 2001.; (b) Shin, Y.; Chen,
W.; Habel, J.; Duckett, D.; Ling, Y. Y.; Koenig, M.; He, Y.; Vojkovsky, T.; LoGrasso,
P.; Kamenacka, T. M. Bioorg. Med. Chem. Lett. 2009, 19, 3344; (c) Mazurov, A.;