Angewandte
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synthesis of only difluoromethyl aryl ethers starting from
a-fluoro acids has been disclosed, and just one report of this
transformation has been published.[14a] On the basis of our
previous fluorination with the relatively inexpensive and
readily available AgF2,[18] we envisioned that oxidative
fluorination to form aryl trifluoromethyl ethers could be
conducted with AgF2 as a reagent (Scheme 1).[19]
We report a facile decarboxylative fluorination reaction
for the synthesis of trifluoromethyl ethers. The reactions
occur with either AgF2 or a combination of AgF2 and AgF
under mild reaction conditions with a broad range of aryl
groups. The reactivity of AgF2 was tuned by an electron-poor
pyridine additive, thus enabling the synthesis of products with
a broad substrate scope. We also found that the addition of
AgF increased the yields, presumably, by serving as a source
of CF during the early stages of the reaction.
To identify reaction conditions for the decarboxylative
fluorination to form aryl trifluoromethyl ethers, we conducted
a series of reactions with the a-phenoxy-a,a-difluoro acetic
acid 1a (see Table 1) We initially investigated the decarbox-
ylation of 1a by methods reported by the groups of Li,[15a]
Sammis and Paquin,[14b] MacMillan,[14c] and Groves[16] but
these methods gave less than 5% of the trifluoromethyl ether
(see the Supporting Information). Based on the ability of
AgF2 to act as a source of fluorine and oxidant,[18,19] we
conducted reactions of 1a with AgF2 in acetonitrile under
various reaction conditions (Table 1). An excess of AgF2 was
used because of the background decomposition from inter-
action with the solvent.[18] In the absence of any additional
source of fluorine, the reaction gave the trifluoromethoxyar-
ene 2a in 49% yield, along with the difluoromethyl ether 3a
in 2% yield (entry 1). This result showed that either AgF2 or
AgF, or both, could function as the source of the fluorine
atom to quench a putative alkyl radical. However, large
amounts of 1a decomposed during this reaction. We hypothe-
sized that this decomposition results from rapid oxidative
decarboxylation to generate high concentrations of the alkyl
radical and that this high concentration leads to intermolec-
À
ular processes that compete with C F bond formation.
Copper difluoride, NFSI, and Selectfluor were investigated
as alternative sources of CF (entries 2–4), but reactions
conducted with AgF2 and these reagents generated low
yields (< 5 to 12%) of 2a. However, reactions conducted
with added AgF occurred in a significantly increased yield of
71% (entry 5). The AgF added or present in the commercial
samples of AgF2 could serve as a base to generate the
carboxylate anion from the carboxylic acid or a source of
fluorine to quench the alkyl radical, or both.
Studies of additional reaction parameters further
increased the yield. Reactions at slightly lower or higher
temperatures (08C and 408C) gave lower yields than those at
room temperature (Table 1, entries 6 and 7). Reactions in
propionitrile as the solvent occurred in lower yields than
those in acetonitrile and with a significant increase in the
formation of the byproduct 3a (entry 8). Reactions in
pivalonitrile gave no trifluoromethyl ether product
(entry 9), even though this solvent might suppress the
À
formation of byproducts because of a lack of weak C H
bonds a to the cyano group. Ultimately, we found that the
addition of pyridines to coordinate the AgF2 (initially to
reduce its oxidizing potential)[8i,18] led to higher yields of 2a.
A series of reactions with added pyridines (entries 10–14)
showed that the reaction conducted with 2,6-difluoropyridine
as an additive occurred in 95% yield (entry 14).
Table 1: Evaluation of the effects of reaction parameters.[a]
In addition to adding AgF to increase the availability of FC,
we controlled the concentration of radical intermediates by
adding 1a slowly with a syringe pump (Table 1, entry 15).
Under these reaction conditions, the concentration of AgF
generated in situ should be sufficient to quench the alkyl
radical. Indeed, the reaction conducted in this fashion with
AgF2 alone generated 1a in 96% yield, as determined by
19F NMR spectroscopy, and gave 91% yield of the isolated
product (entry 15). The reaction of 1a under these conditions
on a 1 mmol scale occurred in a comparable yield of 86%
(isolated). Therefore, both sets of reaction conditions were
used to evaluate the substrate scope. Although we conducted
most reactions in a glovebox, we also conducted the reaction
of 1a using standard Schlenk techniques, which gave 60%
yield of 2a. For detailed procedures, see the Supporting
Information.
Entry Additives
Solvent Yield of 2a [%][b] Yield of 3a [%][b]
1
2
3
4
5
–
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
EtCN
49
12
<5
12
71
44
2
<5
<5
3
5
12
8
CuF2
NSFI
Selectfluor
AgF
6[c] AgF
7[d] AgF
49
<5
8
9
AgF
AgF
18
tBuCN
n.r.
n.r.
10[e] AgF, A1 (50 mL) MeCN
11[e] AgF, A2 (50 mL) MeCN
12[e] AgF, A3 (50 mL) MeCN
13[e] AgF, A4 (50 mL) MeCN
14[e] AgF, A4 (100 mL) MeCN
58
73
5
2
13
83
95
96
<1
<1
<1
<1
15[e,f] A4 (100 mL)
MeCN
(91)[g] (86)[h]
The substrate scope of this decarboxylative reaction with
a series of substrates containing distinct substitution patterns
and a range of functional groups is shown in Table 2. These
reactions were generally conducted with the combination of
AgF2, AgF, and 2,6-difluoropyridine. The acid was generally
added manually, without a syringe pump, but when the yields
from reactions conducted by this procedure were low,
a syringe pump was used to add the acid to AgF2 without
[a] 1a (0.1 mmol) in 1 mL MeCN was added to a mixture containing AgF2
(3.0 equiv), F source (2.0 equiv), and additive in 1 mL MeCN at RT. The
reaction was stirred for an additional 1 h. [b] Yield determined by
19F NMR spectroscopy using trifluorotoluene as an internal standard.
[c] 08C. [d] 408C. [e] Used 5.0 equiv of AgF2. [f] 1a in MeCN was added
by syringe pump over 1 h. [g] Yield of isolated product. [h] Yield of
isolated product from reaction run on 1 mmol scale. A1=2,6-dimeth-
oxypyridine, A2=2-fluoro-6-methylpyridine, A3=2-(trifluoromethyl)pyr-
idine, A4=2,6-difluoropyridine.
2
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
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