Organic Letters
Letter
nonradioactive fluoropyridines and 18F radioligands through a
common intermediate is desirable.
Surprisingly, activation of 4-phenylpyridine N-oxide in the
presence of trimethylamine failed to produce isolable salt 2c.
Instead, a mixture of 4-phenylpyridin-2(1H)-one and 2-
chloro-4-phenylpyridine was observed in less than 30 min,
presumably derived from nucleophilic addition of trifluor-
oacetate and chloride12 to 2c generated in situ, respectively. In
contrast, activation of 4-phenylpyridine N-oxide in the
presence of excess pyridine over 48 h resulted in the
formation of pyridinium salt 2d in 69% isolated yield with
only trace amounts of chlorinated and hydrolyzed byproducts.
Failure to isolate 2c could be attributed to its relatively high
reactivity.
Alternative amine nucleophiles were selected on the basis of
either the lack of a β-proton (N,N-dimethylbenzylamine and
pyridine) or a conformational restriction to deprotonation
(quinuclidine and 1,4-diazabicyclo[2.2.2]octane [DABCO])
that would otherwise lead to rapid elimination and formation
of a neutral 2-(dialkylamino)pyridine. As expected, salts 2e−h
(Scheme 2) were isolated in good yields following either silica
gel or reversed-phase column chromatography.
Having demonstrated the synthesis and isolation of a small
number of pyridyltrialkylammonium salts, this approach was
applied to the synthesis of a variety of fluoropyridines from
their corresponding pyridine N-oxides assembled via an
assortment of synthetic transformations (e.g., Buchwald−
Hartwig, Suzuki, Sonogashira, and Pd-mediated N-oxide
couplings,13 aromatic substitution, and m-CPBA oxidation;
see the Supporting Information). A set of 2-substituted
pyridine N-oxides were converted into their corresponding
fluoropyridines 3a−e (Scheme 3) in good yields (37−87%),
with the exception of the electron-deficient ethyl picolinate N-
oxide 1f (25%). Notably, Lewis basic hetereocycles and
amines were tolerated in the reaction sequence.
The conversion of 3-substituted pyridine N-oxides proved
to be highly regioselective. In all cases, ammonium salt
formation and subsequent fluorination occurred exclusively
para to the existing substituent (i.e., 2-fluoro-5-phenylpyridine
3g was isolated in 84% yield, and 2-fluoro-3-phenylpyridine
was not detected). The observed site selectivity is noted to be
complementary to Hartwig’s AgF2-mediated C−H fluorination
process.4 Aryl and heteroaryl groups were all well tolerated,
producing the corresponding fluoropyridines 3g−j in
moderate to excellent yields (61−99%). 3-Morpholinyl- and
N-Boc-amino-substituted pyridine N-oxides were converted to
compounds 3k and 3l, albeit in lower yields. 5-Azetidin-3-yl-2-
fluoropyridine 3m was also prepared in 57% yield, and the
alkyne-containing dipyridyl derivative 3n was isolated in 72%
yield.
It has been demonstrated that a range of 2-substituted
pyridines can be prepared upon activation of pyridine N-
oxides in the presence of a wide variety of nucleophiles (Cl,
Br, CN, amine, etc.).8,9 There are a few reported examples of
preparing 2-pyridyltrimethylammonium salts from activated
pyridine N-oxides,10 though to our knowledge, a compre-
hensive study regarding the scope and use of these
ammonium salts has not been published. We hypothesized
that suitable activation of a pyridine N-oxide in the presence
of a tertiary amine would furnish a trialkylammonium salt that
would be reactive toward a fluoride nucleophile, thereby
allowing for a method to achieve the delivery of fluoride to
pyridine (Scheme 1, D).
Using 2-phenylpyridine N-oxide 1a as a model substrate, we
found that direct addition of fluoride (1 M tetrabutylammo-
nium fluoride [TBAF] in THF) to the reaction mixture of 2a,
formed in situ from the activation of 1a in the presence of
trimethylamine, resulted in the formation of (dimethylamino)-
pyridine instead of the desired fluoropyridine.11 It was
discovered that isolation of crude 2a by trituration from
Et2O/CH2Cl2 and exposure to fluoride resulted in the
formation of 2-fluoropyridine 3a. Further optimization
revealed that the fluorination reaction proceeded smoothly
in polar aprotic solvents (DMF and CH3CN), and 1 M TBAF
in THF was found to be an effective fluoride source (see the
Supporting Information).
Encouraged by the successful formation of 3a via 2a, we
identified preferred conditions for trimethylammonium salt
formation by screening a variety of reaction conditions
including activating electrophile and reaction solvent using
1a as a model substrate (3.0 equiv of trifluoroacetic anhydride
[TFAA] or p-toluenesulfonic anhydride [Ts2O] and 6.0 equiv
of NMe3 in CH2Cl2 [0.1 M], 0 °C - rt). For complete details,
see the Supporting Information. As shown in Scheme 2, we
Scheme 2. Preparation of Trialkylammonium and
Pyridinium Salts
Although conversions of various 4-monosubstituted pyr-
idine N-oxides were not successful (see the Supporting
Information), 2,4- and 3,4-disubstituted pyridine N-oxides
afforded trisubstituted pyridines 3o and 3p in good yields (51
and 74%). 2,5-Disubstituted pyridine N-oxides afforded 3q
and 3r in 68% and 23% yields, respectively. The yield of 3r
was improved to 50% when quinuclidine was used in place of
trimethylamine. Fused hetereocyclic N-oxides also participated
in the process, providing quinoline 3s, isoquinoline 3t, and
oxazolopyridine 3u. When both 2- and 2′-positions were
substituted, we observed addition of trimethylamine and
subsequent fluorination at the 4-position to furnish 4-fluoro-
2,6-diphenypyridine (3v) in 76% yield.
explored the ammonium salt formation of phenyl-substituted
pyridine N-oxides using a variety of amine nucleophiles. Both
2- and 3-phenylpyridine N-oxides reacted smoothly to give
trimethylammonium salts 2a and 2b in good yields and as
single regioisomers. We believe that the observed regiose-
lectivity could be explained by stereoelectronic (2- vs 4-
position) and steric (2- vs 6-position) effects as well as the
relatively mild reaction conditions.
Nonradioactive analogues of several PET tracers were
prepared from their parent N-oxides. AV-145114 (3w) was
B
Org. Lett. XXXX, XXX, XXX−XXX
Xiong, Hui
