Organic Letters
Letter
these AAFs should serve as soluble, anhydrous fluoride sources
that could be exploited for room temperature SNAr reactions.
Importantly, acid fluorides are available from inexpensive
carboxylic acid chlorides and HF or KF,11 making them
relatively affordable fluoride sources.12 In addition, a
straightforward route to 18F-labeled acyl fluorides has recently
been reported,13 which could ultimately enable the translation
of this chemistry to PET tracer synthesis.
Our initial studies focused on the use of AAFs for the SNAr
fluorination of 4,5-dichloropicolinate 1. For comparison, we
have previously shown that 1 reacts with 4 equiv of TBAFanh to
form the difluorinated product 3 in 79% yield within 24 h at 25
°C in DMF.7 We first examined the reaction of 1 with the AAF
generated from the combination of benzoyl fluoride and
carbene A9 (eq 1). Benzoyl fluoride, A, and 1 were combined in
We reasoned that the nitrogen substituents of the NHC
might also impact the reaction, possibly by modulating the
solubility and/or stability of the AAF intermediate. Indeed,
changing from 2,6-di-iPr phenyl substituents (in A) to iPr
substituents (in C) led to a substantial increase in the yield of 2
(from 5% to 44%). The best results were obtained with carbene
D, which bears methyl groups on the imidazolium ring and iPr
substituents on the nitrogens. With D, the starting material 1
was completely consumed, and the difluorinated product 3 was
formed in 57% yield, along with 10% of 2.
Further optimization was carried out using the 5-
chloropicolinate 4. Substrate 4 is considerably less reactive
than 1 toward SNAr fluorination. For example, 4 does not react
at all with carbenes A−C/benzoyl fluoride over 16 h at room
temperature. However, the reaction of 1 equiv of 4 with 3 equiv
of D and 3 equiv of benzoyl fluoride afforded a 75% yield of the
fluorinated product 5 after 16 h at 25 °C in DMF (Table 1,
Table 1. Effect of Acid Fluoride Structure on Conversion of
4 to 5
a
entry
R
equiv of D
equiv ArC(O)F
yield of 5
1
2
3
4
5
H
3
3
3
2
1
3
3
3
2
1
75%
9%
CF3
anhydrous DMF, and the resulting deep red solution was
stirred for 16 h at room temperature. Analysis of the crude
reaction mixture by 19F NMR spectroscopy showed the
formation of the monofluorinated product 2 in 5% yield as
an approximately 1:1 mixture of isomers. The difluorinated
product 3 was not detected. The experiment suggests that
AAFs can participate in room temperature SNAr reactions.
We hypothesized that reactivity could be enhanced by
changing the structure of the NHC. Several literature reports
have shown that the hydrogens on the imidazolium ring (H1 in
Figure 1) can serve as hydrogen bond donors.10,14 A hydrogen
OMe
OMe
OMe
99%
89%
81%
a
Yields determined by 19F NMR analysis of the crude reaction
mixtures.
entry 1). Analysis of the reaction mixture by GCMS showed
that the mass balance is unreacted 4. Changing the acid fluoride
to the more electrophilic p-trifluoromethylbenzoyl fluoride led
to a dramatic decrease in the yield of 5 (to 9%, entry 2). In
contrast, the use of the more electron-rich p-methoxybenzoyl
fluoride resulted in quantitative conversion and the formation
of 5 in 99% yield as determined by 19F NMR spectroscopy
(entry 3). Using the combination of D and p-methoxybenzoyl
fluoride, the loading of carbene and acid fluoride could be
reduced to 2 equiv or even 1 equiv relative to 4 with minimal
drop-off in yield (89% and 81%, respectively). For comparison,
the SNAr fluorination of 4 with NBu4Cl/KF (2 equiv/2 equiv)
affords an 86% yield after 24 h at 130 °C.15 Using NBu4CN/
C6F6 (2 equiv/0.33 equiv), 4 is converted to 5 in 86% yield in
30 min at room temperature.7
With optimal conditions in hand, we next explored the
combination of carbene D and p-methoxybenzoyl fluoride as an
anhydrous fluoride source for the SNAr fluorination of different
substrates. As summarized in Figure 2, a variety of 5- and 4,5-
substituted chloropicolinate derivatives underwent fluorination
to form products 3 and 5−9 in modest to excellent isolated
yields. The modest yields with 4,5-dichloropicolinate substrates
are due to the formation of byproduct 21 (Figure 3).16
Methoxy, cyano, and trifluoromethyl substituents were
compatible with the reaction conditions (see products 7, 9,
12, 15, 17, and 20). In addition, other aryl halide substituents
(Cl, Br, and I) were well tolerated at less activated sites in the
molecule (see products 6, 8, 10, 14, 18, and 19). Ethyl 3,6-
Figure 1. Impact of NHC structure on the SNAr fluorination of 1 to
form 2 and 3. Conditions: 3 equiv of NHC, 3 equiv of benzoyl
fluoride, 1 equiv of 1, 16 h, 25 °C in DMF (0.2 M). Yields and product
ratios determined by 19F NMR analysis of the crude reaction mixtures.
bonding interaction with fluoride would be expected to
significantly lower its nucleophilicity. Thus, we next examined
carbene B, in which the backbone hydrogens are replaced with
methyl groups. Under otherwise identical conditions, B
provided an enhancement in the yield of the monofluorinated
product 2 (21%, Figure 1).
B
Org. Lett. XXXX, XXX, XXX−XXX