Organic Letters
Letter
aldehydes, and alcohols that bear aryl, heteroaryl, and alkyl
functional groups were smoothly transformed into their
corresponding acyl fluorides in good yields. The method can
be applied to the late-stage functionalization of natural
products and drug molecules. Significantly, the combination
of TCCA and CsF is essential, and TCCA acts as both a
chlorine source and an oxidation agent (in the case of
alcohols) while CsF is a suitable fluoride source to partner with
TCCA.
Scheme 2. Synthesis of Acyl Fluorides from Carboxylic
Acids 2
a
Initially, we chose benzoic acid (2a) as the model substrate,
and we found that a combination of 2 equiv of TCCA and 8
equiv of CsF in acetonitrile (MeCN) (0.2 M) at room
temperature for 24 h provided benzoyl fluoride (1a) in 92%
19F NMR yield (Table 1, entry 1). Interestingly, gas evolution
Table 1. Optimization of the Reaction Conditions for the
a
Conversion of 2a to 1a
yield
b
entry
deviation from the standard conditions
(%)
1
2
3
4
5
6
none
no TCCA
no CsF
92
0
0
0−23
0−30
0−49
using KF, LiF, NaF, or KHF2 instead of CsF
using NCS, Ph3PCl2, or DCDMH instead of TCCA
using DMF, THF, toluene, acetone, or DCM instead of
MeCN
a
Standard conditions: 2a (0.1 mmol), TCCA (0.2 mmol), and CsF
(0.8 mmol) in MeCN (0.5 mL, 0.2 M) at room temperature for 24 h.
b
Determined by 19F NMR spectroscopy.
was observed in the reaction by the naked eye. Several
examples of variations from the standard conditions are listed
in Table 1 (for an extensive list of reaction conditions, see
conducted without TCCA or CsF confirmed that they were
necessary to obtain the target product 1a (Table 1, entries 2
and 3). Alkali fluoride alternatives to CsF, such as KF, LiF,
NaF, or KHF2, were less effective (Table 1, entry 4). Chlorine
sources such as N-chlorosuccinimide (NCS), triphenylphos-
phine dichloride (Ph3PCl2), and 1,3-dichloro-5,5-dimethylhy-
dantoin (DCDMH) produced 1a in low yields (0−30%; Table
1, entry 5). Replacement of acetonitrile with other common
solvents such as dimethylformamide (DMF), tetrahydrofuran
(THF), toluene, acetone, or dichloromethane (DCM) afforded
1a in 0−49% yield (Table 1, entry 6). The time course of the
reaction of 2a to give 1a was also investigated, as shown in SI
section 6. The yield of 1a dramatically increased to 77%
between 8 and 12 h and then gradually reached a maximum
(up to 92%) at 20−24 h.
With the optimized conditions in hand, we next turned our
attention to the scope of substrates tolerated under these
conditions (Scheme 2). The transformation tolerated sub-
strates bearing common functional groups at the para position
of the phenyl ring. For example, substrates with electron-
withdrawing groups such as F, Cl, Br, NO2, and CF3 (2b−f) as
well as electron-donating groups such as Me, MeO, Ph, tBu,
nBu, or Cy (2g−l) reacted well and afforded the corresponding
products in good to excellent yields (68−99%). The meta-
substituted aryl carboxylic acid 2m and ortho-substituted aryl
carboxylic acids 2n−p still afforded the desired products (1m−
p) in high to excellent yields (83−94%). 1-Naphthoic acid and
2-naphthoic acid derivatives (2q and 2r) furnished the desired
products (1q and 1r) in good yields (61−67%). A
a
Reaction conditions: 2 (0.2 mmol), TCCA (0.4 mmol, 2.0 equiv),
and CsF (1.6 mmol, 8.0 equiv) in MeCN (1.0 mL, 0.2 M) at room
temperature for 24 h. Yields in parentheses were determined by 19F
NMR spectroscopy. The large differences in the NMR and isolated
yields in certain cases are due to instability and/or volatility issues.
b
c
2.0 equiv of PPh3 was added. Using 2d on a 1.0 mmol scale.
disubstituted substrate also furnished the desired product 1s
in 99% yield. Heteroaryl groups (2t and 2u) and an alkyl group
(2v) were tolerated and gave the corresponding products (1t−
v) in good yields (70−81%). Meanwhile, some druglike
derivatives, such as probenecid derivative 1w and estrone
derivative 1x, can also be obtained from the corresponding
carboxylic acids 2w and 2x in good yields (64−84%). We
should note that in some cases substrates with electron-
donating groups on the benzene ring gave low yields. We thus
again optimized the reaction conditions (Table S2). The
addition of 2 equiv of triphenylphosphine (PPh3) was found to
be effective to improve the yield, and the reaction mechanism
should be somewhat different, as discussed below. Moreover, a
1 mmol scale reaction was also performed for the preparation
of 4-bromobenzoyl fluoride (1d) without a major loss of yield.
We were excited to find that it was possible to synthesize
acyl fluorides from aldehydes under the same reaction
conditions and that the reactivity of some aldehydes even
848
Org. Lett. 2021, 23, 847−852