at high temperatures.7 Anhydrous tetrabutylammonium fluo-
ride (TBAF) has also previously been shown to promote
fluorodenitration for a limited number of nitrobenzenes.8 In
this communication, we disclose our own efforts in this area
and expand the scope of the tetrabutylammonium salt
promoted denitration to include nitropyridines as substrates.
Several substituted 2-,3-, and 4- nitropyridines were
subjected to fluorodenitration with commercially available
TBAF (1 M in THF) in DMF9 to yield fluoropyridines in
good yield.10 In some instances, decreased yields were
observed and these results are attributable to the volatility
of the corresponding fluoropyridine products. As the data
in Table 1 indicate, pyridines with nitro groups at the 2- or
in entry 1. Fluorodenitration of 3-nitropyridines appears
limited to substrates containing electron-withdrawing groups
(entry 6), since no reaction was seen with electron-rich
examples (entries 4 and 5).13
To illustrate the practicality of our protocol, the fluoro-
denitration of aniline-containing nitropyridine 1 was carried
out to afford desired product 2 in one operation (64% yield,
unoptimized) (Scheme 1). Our methodology obviates the
protection-deprotection of the aniline nitrogen necessitated
by the Balz-Schiemann process to access 2.
Scheme 1
Table 1. Fluorodenitration of Pyridinesa
Although there is some precedence for the fluorodenitra-
tion of nitropyridines, the reported reaction conditions involve
high temperatures and the use of KF as the fluoride source.14
An important stipulation in these examples is that it is
essential for the fluoride salt to be anhydrous, since the
presence of water retards the reaction.15 Similarly, the TBAF-
promoted fluorodenitration of nitrobenzenes, required 5 equiv
of anhydrous TBAF to effect the reaction. 8,16 In the present
case, anhydrous conditions are not essential. Indeed, the
commercially available solutions of TBAF in THF contain
approximately 5% water. In fact, the use of anhydrous TBAF
(6) Finger, G. C.; Kruse, C. W. J. Am. Chem. Soc. 1956, 78, 6034.
(7) Attina, M.; Cacace, F.; Wolf, A. P. J. Chem. Soc., Chem. Comm.
1983, 108.
(8) Clark, J. H.; Smith, D. K. Tetrahedron Lett. 1985, 26, 2233.
(9) The fluorodenitration reaction can be carried out in THF and CH2Cl2
with equal facility. DMF is the solvent of choice since the competing
hydroxydenitration is suppressed (vide infra).
(10) General Procedure. To a solution of 2-cyano-3-nitropyridine (468
mg, 3.14 mmol) in 6 mL of DMF was added 6.3 mL (2 equiv) of a 1 M
solution TBAF in THF (Aldrich). After 30 min, the dark red-brown reaction
mixture was poured into 50 mL of a 1:1 mixture of water and EtOAc. The
organic layer was washed twice with water and brine. The extracts were
dried over sodium sulfate, filtered, and concentrated. The residue was
purified by chromatography on silica gel using 5% to 10% ethyl acetate in
hexane to afford 244 mg (63%) of volatile 2-cyano-3-fluoropyridine, which
1
exhibited satisfactory H, 19F, and 13C magnetic resonance spectra.
(11) Microwave heating was not beneficial in promoting the reaction.
For example, the fluorodenitration of 3-ethoxy-2-nitropyridine (Table 1,
entry 3) affords 3-ethoxy-2-fluoropyridine among a mixture of products in
low yield (µw conditions: 180 °C, 30 min, <10%; 250 °C, 30 min, ∼
20%).
a All reactions were carried out in DMF with 2.0 equiv of TBAF (1 M
in THF).
(12) Adams, D. J.; Clark, J. H.; Nightingale, D. J. Tetrahedron 1999,
55, 7725.
(13) In the case of entry 4, addition of TBAF produced a bright red
reaction mixture. This is indicative of deprotonation of the 2-amino group
by the highly basic TBAF.
(14) For example, see: Dolle, F.; Vallette, H.; Bottlander, M.; Hinnen,
F.; Vaufre, F.; Guenther, I.; Crouzel. C. J. Labelled Compd. Radiopharm.
1998, 41, 451.
(15) In our experience, spray-dried KF in dry DMSO or CsF in DMF
does promote fluorodenitration, albeit much more slowly than TBAF in
DMF. Addition of 1 equiv of water to CsF in DMF inhibits the
fluorodenitration.
(16) Cox, D. P.; Terpinski, J.; Lawrynowicz, W. J. Org. Chem. 1984,
49, 3216-3219. The authors dried commercial TBAF‚3H2O at 40 °C under
high vacuum overnight and reported 0.1-0.3 equiv of water in the anhydrous
product.
4-position (entries 1-3, 7, and 8) underwent smooth de-
nitration to afford the corresponding fluoropyridines after a
few hours either at room temperature or at 70 °C.11 While
pyridines with electron-donating groups required both heating
and prolonged reaction times to go to completion (entry 3),
the observation that they participate under these conditions
is unique since the fluorodenitration of nitrobenzenes is
limited to electron-deficient substrates.12 It is also notable
that the fluorodenitration reaction is highly chemoselective
since the nitro is displaced in preference to the ortho bromide
578
Org. Lett., Vol. 7, No. 4, 2005