A simple synthetic route to methyl 3-fluoropyridine-4-carboxylate by nucleophilic aromatic substitution

Article abstract of DOI:10.3390/11020130

The nitro group of methyl 3-nitropyridine-4-carboxylate (1) has successfully been replaced by fluoride anion via nucleophilic aromatic substitution to give the 3-fluoropyridine-4-carboxylate 2.

Full text of DOI:10.3390/11020130

Molecules 2006, 11, 130-133
molecules
ISSN 1420-3049
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Short Communication
A Simple Synthetic Route to Methyl 3-Fluoropyridine-4-
carboxylate by Nucleophilic Aromatic Substitution
†
Freddy Tjosaas and Anne Fiksdahl *
Department of Chemistry, Norwegian University of Science and Technology, NTNU N-7491
†
Trondheim, Norway. E-mail: tjosas@chem.ntnu.no
*
To whom correspondence should be addressed; E-mail: Anne.Fiksdahl@chem.ntnu.no
Received: 25 January 2006 / Accepted: 24 February 2006 / Published: 25 February 2006
Abstract: The nitro group of methyl 3-nitropyridine-4-carboxylate (1) has successfully
been replaced by fluoride anion via nucleophilic aromatic substitution to give the 3-fluoro-
pyridine-4-carboxylate 2.
Keywords: Methyl 3-fluoropyridine-4-carboxylate, methyl 3-nitropyridine-4-carboxylate,
fluoride anion, nucleophilic aromatic substitution.
1
. Introduction
Compounds containing C-F bonds are rarely found in nature, in contrast to the abundant fluoride
anions [1,2]. The fluoride ion is extensively hydrated and therefore relatively unreactive as a
nucleophile, inhibiting C-F bond formation in nature. However, fluorinated organic compounds play
an important role and are widely used in the synthesis of pharmaceuticals and agrochemicals due to
their favourable chemical and biological properties.
In general, the introduction of a fluorine atom in a molecule does not result in a considerable
change in the size or the shape of the compound. Due to the minimal conformational effects, the
fluorinated molecule generally also fits in the active site of the receptor and the fluorine atom is thus a
suitable isosteric substitution of hydrogen. The incorporation of fluorine into organic molecules may
change the solubility properties and enhance the lipophilicity and thus increase the rate of cell
penetration and transport of a drug to an active site. The higher electronegativity of fluorine may also
alter the physical and chemical properties of a molecule, and the higher polarizability due to the new
C-F bond may give new possibilities for binding to the receptor. The C-F bond is stronger than the

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131
original C-H bond and fluorinated compounds are more resistant to metabolic degradation. On this
background, the development of new and efficient methods for the preparation of fluoroorganic
compounds has got increased attention in recent years.
As a general fact, aromatic substrates are very unreactive towards nucleophilic substitution.
However, substitution is accelerated by the presence of electron-withdrawing groups o- or p- to the
leaving group. A hetero-N atom in the ring is also activating. Surprisingly, the nitro group, which is
not generally lost in aliphatic systems, is a particularly good leaving group in nucleophilic aromatic
substitutions [3-5].
These effects and the synthetic potential for the replacement of a nitropyridine group have been
demonstrated by our results for the nucleophilic aromatic substitution of the nitro group in 3-nitro-4-
carboxylate (1) since the electron-poor pyridyl aromatic system in combination with the anion
stabilizing carbonyl group in the ortho position makes the 3-nitro substituent a good leaving group.
We have previously obtained promising results from the nucleophilic aromatic substitution of the nitro
group in methyl 3-nitropyridine-4-carboxylate (3-nitroisonicotinic acid methyl ester, 1) with
heteroatomic nucleophiles [6], since oxygen, nitrogen and sulphur nucleophiles yielded the new
products 2a-d as shown in Scheme 1.
Scheme 1.
CO Me
CO Me
2
2
NO2
R
i), ii), iii) or iv)
2a R = N3
50 %
2b
2c
2d
R = OMe 52 %
R = OPh
R = SPh
30 %
42 %
N
N
1
2a - d
i) NaN , DMSO, ii) NaOMe, MeOH, iii) PhOH, NaH, DMSO, iv) PhSH, NaH, THF
3
A number of substituted 3-nitropyridines have become readily available through an improved
nitration method [7,8] and an investigation of the chemistry of nitropyridines is now in progress in our
laboratories. Based on our experience with the good leaving group ability of the nitro group in
carboxylate 1, we have now investigated it as a potential substrate for the preparation of the 3-fluoro-
pyridine product 2 (see Scheme 2).
2
. Results and Discussion
We have succeeded in achieving the nucleophilic aromatic substitution of the nitro group in 3-nitro-
pyridyl carboxylate 1 with fluoride anion, thus obtaining methyl 3-fluoropyridine-4-carboxylate (2, see
1
Scheme 2) in 38 % yield. H-NMR showed complete conversion of the 3-nitro substrate 1 into the 3-
1
13
19
fluoro substitution product 2 after 1.5 hours reflux with CsF in dry DMSO. H-, C-, and F-NMR
spectra of the product 2 showed the characteristic features of fluorinated aryl compounds. Four signals
1
were observed in H-NMR for product 2 and the spectrum had the expected proton coupling patterns
3
4
and the J and J coupling constants were in accordance with the respective JHF observed in the
HF
HF
1
9
13
F- NMR spectrum. C-NMR confirmed the fluoropyridine structure, especially based on the most
1
2
characteristic observation represented by the large C-F coupling constants ( JCF = 268 Hz, JCF = 25.3
1
9
Hz). The shift values and the coupling patterns in the respective F-NMR spectra also supported the

Molecules 2006, 11
132
proposed structure 2. To our knowledge, the 3-fluoropyridyl compound 2 has not previously been
described.
Scheme 2.
CO Me
CO Me
CO Me
2
2
2
NO2
F
N O
2
5
CsF, DMSO
20 °C, 90 min
8 %
1
nitration [7,8]
N
N
1
N
2
3
For some purposes this direct nitro substitution may be a more convenient and rapid pathway than
the traditional three-step procedure via diazotization as shown in Scheme 3.
Scheme 3.
CO Me
CO Me
CO Me
CO Me
2
2
2
2
NO2
NH2
N2+
Nucl (F)
-
-)
Nucl (F
nucl. arom. subst.
red.
diazotization
N
N
N
N
2
1
3
. Conclusions
Methyl 3-fluoropyridine-4-carboxylate (2) is readily available from isonicotinic acid methyl ester in
two steps. The product 2 was prepared (in 38 % yield) by nucleophilic aromatic substitution of the
nitro group in methyl 3-nitro-4-pyridylcarboxylate (1) by fluoride anion after nitration of isonicotinic
acid methyl ester. The results confirm [6] the good leaving group ability of the nitro group in methyl 3-
nitropyridine-4-carboxylate (1) and demonstrate that the nitropyridine pathway may represent a
convenient strategy for the nucleophilic aromatic substitution of pyridines. This one-step nitro group
substitution reaction may be a superior alternative to the traditional three-step procedure going via the
amine and the standard substitution of a diazonium salt.
4
. Experimental
General
Chemicals: CsF (Acros); Solvents: pro analysi quality, distilled and stored under N over 4Å
2
1
13
19
molecular sieves. H-, C- and F-NMR: Bruker Avance DPX 300 and 400 MHz spectrometers,
chemical shifts are reported in ppm downfield from TMS. Hexafluorobenzene was used as reference
1
9
for F-NMR. J values are given in Hz. MS: Finnigan MAT 95 XL (EI / 70 eV). IR: Nicolet 20SXC
FT-IR spectrophotometer. Flash chromatography: Silica (sds, 60 Å, 40-63 µm). Methyl 3-nitro-4-
pyridinecarboxylate (1) was prepared from methyl 4-pyridinecarboxylate by nitration according to the
literature [7,8].

Molecules 2006, 11
133
Methyl 3-fluoropyridine-4-carboxylate (2).
Methyl 3-nitropyridine-4-carboxylate (1, 120 mg, 0,681 mmol) and CsF (517 mg, 3,406 mmol, 5
equivalents) was added to dry DMSO (6 mL) under N . The reaction mixture was heated at 120 °C for
2
9
0 minutes. TLC (4:1 EtOAc/pentane) showed complete conversion to the fluoro substituted product.
Distilled water (20 mL) was added to the reaction mixture, which was then extracted with EtOAc
3x20 mL) and concentrated in vacuo. The crude product was purified by flash chromatography (4:1
(
1
13
1
EtOAc/pentane) yielding 40 mg ( 38 %) of an oily product, pure by H- and C-NMR. H-NMR (400
4
MHz, CDCl ): δ 3.98 (d, J 2.0, 3H, OCH ), 7.77 (ddd, J 0.4, 4.8, J 6.0, 1H, H-5), 8.55 (dd, J 0.8,
3
HF
3
HF
3
13
3
4
.8, 1H, H-6), 8.62 (d, JHF 2.4, 1H, H-6); C-NMR (100 MHz, CDCl
3
): δ 53.0 (s), 124.4 (d, JCF 1.5
2
3
1
C5), 125.2 (d, JCF 8.0, C4), 140.4 (d, JCF 25.3, C2), 157.1 (d, JCF 268.0, C3), 163.3 (d, JCF 3.0,
1
9
C=O); F-NMR (376 MHz, C D ): δ -125.5 (dd, J 2.3, 6.0, F3); IR (film) υmax: 3020w, 2926m,
6
6
HF
-1
+
1
744s, 1538m, 1438w, 1352m, 1277m, 758s cm ; MS: m/z 155 (M , 24%), 149 (11), 124 (43), 111
(
13), 109 (13), 96 (23); Anal. Calcd. for C H FNO : C, 54.20; H, 3.90; N, 9.03. Found: C, 53.96; H,
7
6
2
3
.68; N, 8.86.
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