Journal of the American Chemical Society
Article
reactions through a short silica-filled pipet and evaporating the
solvent was sufficient to perform the subsequent SNAr
reactions. Yields of the SNAr reactions conducted after filtering
the fluorination reaction through Celite were low, due to the
presence of soluble Ag salts.
Convenient Protocols for Performing the Fluorination
of Pyridines and Diazines. For the fluorination−SNAr
sequence to be used broadly, procedures for conducting the
reaction without specialized equipment for excluding air and
moisture are needed. AgF2 is a hygroscopic solid that
decomposes in the presence of water. Therefore, during our
initial study, the fluorination reactions were assembled in a
glovebox with rigorously dried MeCN.10 However, despite the
water sensitivity of AgF2, simple procedures can be followed for
conducting the reactions without rigorous exclusion of air or
moisture.
dried over 5 wt % molecular sieves for 24 h is near 4 ppm, and
the water content further decreases with time.14 The water
content of commercial “anhydrous” MeCN is below 10 ppm
water and should be equally suitable for this reaction.
Finally, the same reaction was assembled in air with ACS
grade MeCN directly from a commercial bottle that had been
opened and used over the course of a year; a noticeable
decrease in yield to 65% was observed, but a substantial amount
of product was still formed. Together, these results demonstrate
that these fluorination reactions can be conveniently assembled
completely in air, without the use of a glovebox or air-free
techniques, and with MeCN dried over molecular sieves, even
though AgF2 is sensitive to water and should be stored under an
inert atmosphere. Reactions performed on the benchtop occur
in yields that are comparable to those performed under
rigorously anhydrous reaction conditions.
AgF2 is supplied as a black, microcrystalline solid, which
should be stored under an inert atmosphere. Because AgF2
undergoes decomposition with moisture, a noticeable color
change from black to yellow or brown is observed when it is
stored in air. For all reactions reported here, and in our
previous paper,10 AgF2 was used as received from Alfa Aesar
and stored under a nitrogen atmosphere in a plastic bottle. In
our experience, reactions with AgF2 supplied from Strem
occurred in comparable rates and yields to those performed
with AgF2 puchased from Alfa Aesar.
To assess the impact of water and oxygen on the yield of the
fluorination reaction of complex molecules, we performed a
series of experiments with (CO2Me)-vismodegib, a drug
recently approved for the treatment of basal-cell carcinoma
(Table 2). Assembling the fluorination reaction in a glovebox
Table 2. Assessing the Impact of Water and Air on the
a
Fluorination Reaction with AgF2
Scope of the Tandem C−H Fluorination and Nucleo-
philic Aromatic Substitution of Pyridines. Having
identified convenient methods for conducting both the
fluorination and SNAr reactions and having developed a
protocol to conduct the two reactions in sequence, we
investigated the scope of the C−H bond fluorination−SNAr
process. Representative examples illustrating the scope of the
combined reactions are shown in Tables 3 and 4. Yields given
are for isolated products starting from the heteroarene. The
yields for the fluorination step are also shown to illustrate how
the values for the two-step process compare to those of the first
step.
method of drying
MeCN
rxn vial
dried
solids
yield (%)
(NMR)
weighed
atmosphere
CaH2
yes
yes
no
no
no
in glovebox
in air
N2
N2
air
air
air
99
84
79
85
65
CaH2
CaH2
in air
molecular sieves
none
in air
in air
a
Reactions were performed with 0.2 mmol of (CO2Me)-vismodegib
with 2 mL of MeCN in 4 mL vials.
A variety of pyridines that are sterically hindered (2, 4, 11,
12, 14, 15) and/or electronically deactivated (2, 9, 13, 15)
toward SNAr reactions afforded the substitution products in
good yields. Substrates containing alkyl groups in the 2-position
reacted selectively at the 6-position (2, 4, 9, 14), while
analogous reactions with pyridine N-oxides are known to result
in substitution of a C−H bond on the alkyl group (Scheme
1B). A wide range of functional groups were tolerated,
including ethers, halides, ketones, acetals, esters, amides, ethyl
and t-butyl carbamates, nitriles, and sulfones. It is notable that
the azetidine in 11 (Table 4) did not undergo ring opening, a
competing reaction observed under acidic conditions.15
The reactions of chloropyridines 7 and 11 revealed a high
selectivity for substitution of a fluoride over a chloride under
conditions of the SNAr reactions shown in Table 1. This high
selectivity, along with the high functional group compatibility, is
attributed to the milder reaction conditions we developed for
the SNAr reaction at the 2-fluoro position, relative to the
conditions typically used to conduct substitutions with 2-
fluoropyridines. In sum, this work shows that fluoropyridines
undergo substitution reactions under conditions much milder
than previously reported and can be performed in the presence
of a wide range of functional groups, including those that are
electrophilic.
(oxygen and water content <1 ppm), in an oven-dried vial, with
MeCN that had been rigorously dried over CaH2, afforded the
fluorinated vismodegib derivative in 99% yield by 19F NMR
spectroscopy.
Since the use of a glovebox is not practical for all chemists,
we studied the effects of weighing the solid reagents in air and
assembling the reaction using standard air-free techniques. A
reaction was assembled by adding the pyridine substrate to a
dry vial in air and adding MeCN that had been dried over
CaH2. AgF2 was weighed quickly in air, added to the pyridine
solution, and the vial was sealed under an atmosphere of N2.
The reaction assembled in this manner afforded the 2-
fluoropyridine product in 84% yield, only a slight decrease in
yield compared to the reaction assembled entirely in the
glovebox. Performing the reaction in a similar manner with a
nondried vial and sealing the reaction under an atmosphere of
air (2 mL of MeCN in a 4 mL vial; 2 mL headspace of air)
resulted in a similar yield of the fluoropyridine product (79%).
Acetonitrile dried with 5 wt % of 3 Å molecular sieves for 24
h was a suitable solvent; the reaction of (CO2Me)-vismodegib
with AgF2 assembled by weighing the solid reagents in air in a
nondried vial sealed under an atmosphere of air afforded the
fluorinated product in 85% yield. The water content in MeCN
C
dx.doi.org/10.1021/ja5049303 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX