Letter
Using ACF in combination with THT, 1,1-difluorodecane
1m) could be monoactivated to generate the salt [1m-
(
THT][NTf ] in a 90% yield. In contrast to reports of the
2
activation of 1m with stoichiometric amounts of P(o-Tol) and
3
7a
ACF that required elevated temperatures, the reaction of 1m
using THT proceeded at room temperature with an improved
yield. 1,1-Difluoroalkanes 1n and 1o (R-152a) generated the
products [1n-THT][NTf ] and [1o-THT][NTf ] in respec-
2
2
tive yields of 28% and 46%.
Finally, we applied selective fluoride activation to equivalent
distal C−F positions (challenge 2, Figure 1B). 1,3-Difluor-
opropane (R-272fa) (1p) gave the monoactivated products
[
1p-THT][NTf ] in a 60% NMR yield and [1p-TPPy][NTf ]
2
2
in a 52% isolated yield. This concept also worked when an
aromatic system was separated from the distal fluoride
positions, with 1,4-bis(fluoromethyl)benzene (1q) and 1,4-
bis(difluoromethyl)benzene (1r) generating [1q-THT][NTf2]
and [1r-THT][NTf ] in over 95% and 70% yields,
2
respectively, while [1r-TPPy][NTf ] was generated in an
2
12
8
0% yield. Thus, FLP-mediated C−F activation is effective
even for distal difluorides separated by modest intramolecular
distances.
It must be noted that a second C−F activation was possible
in some instances where excess amounts of reagents were used.
For example, 3 equiv of THT and Me SiNTf reacted with 1q
3
2
to generate [1q-(THT) ][NTf ] in a 92% isolated yield (see
2
2 2
SI). Thus, the incorporation of a neutral base allows
monoactivation by reordering the relative kinetic barriers
rather than completely preventing over-reaction.
With the demonstration of selective C−F activation for a
range of aliphatic polyfluorocarbons, we turned our attention
to postactivation functionalization. In a similar manner to that
Figure 2. Reaction scope of FLP-mediated monoselective C−F bond
activation in a range of polyfluorides using THT and TPPy as the base
1
9
components. Yields were determined by F NMR spectroscopy after
2 h, and isolated yields given in brackets. *Reaction was performed
1
reported α,α-difluorobenzylic TPPy salts (i.e., [ArCF TPPy]-
2
#
+
at 40 °C. ACF was used as the catalyst. Reaction was performed for
7
[NTf ]), we found that α-fluoroalkyl THT and TPPy salts
2
2 h.
readily underwent S 2-type nucleophilic substitutions (Figure
N
7b
3
A). Indeed, THT appeared to be a better leaving group
than TPPy, in agreement with its lower basicity. For instance,
1 equiv of TPPy reacted with [1a-THT][NTf ] to form [1a-
10
9
5% yield. Heteroaromatics such as 1g were also susceptible to
selective activation with THT, and [1g-THT][NTf ] gen-
2
2
erated in a 67% yield.
Selective activation with THT also worked with non-
aromatic difluoromethylene groups. Difluoromethoxybenzene
TPPy][NTf
TPPy][NTf
2
] in a 56% yield after 48 h, whereas [1a-
] reacted with an equivalent of free THT to
2
generate [1a-THT][NTf
must be stated that due to the slow reaction rate for these
reactions [1a-THT][NTf ] began to decompose in solution
] in only a 27% yield after 48 h. It
2
1
h could be activated to generate [1h-THT][NTf ] in an 86%
2
yield; however, the inclusion of an electron-withdrawing
bromide group in the aromatic para-position greatly reduced
the reactivity, resulting in only a 42% yield of [1i-THT]-
2
after 48 h, preventing the determination of an equilibrium
constant. However, assuming that both these reactions proceed
[
NTf ]. TPPy gave a slightly improved yield of 45% to
via an S
follows that [1a-TPPy][NTf
compared to [1a-THT][NTf
The substitution of THT in [(1a−f)-THT][NTf
found to occur readily with a range of nucleophiles to give
N
2 mechanism with a common transition state, it
] is thermodynamically preferred
].
2
generate [1i-TPPy][NTf ]. The thioether difluorothiomethox-
ybenzene (1j) was also selectively activated to give [1j-
THT][NTf ] in a moderate yield of 78%.
Internal difluoromethylene groups were selectively activated
with THT. 1,1-Difluoroethylbenzene (1k) reacted with THT
2
2
2
] was
2
2
13
products 2a−m. Notably, secondary amine (piperidine) and
sulfide (phenylsulfide) donors reacted with THT salts to give
good yields of products 2f and 2i (Figure 3A), whereas we
found that amine and sulfide reactions with TPPy salts also
give rise to redox side-products that compromised the yields of
to generate [1k-THT][NTf ] in an over 95% yield. However,
2
substrate 1l could only be selectively activated in a 30% yield,
with the HF elimination being a dominant side reaction that
formed large amounts of the corresponding fluoroolefin.
Attempts to selectively activate difluoroalkanes possessing α-
hydrogen using P(o-Tol)3 gave primarily HF elimination
products. In contrast, THT largely avoided HF elimination
7b,14
the substituted products.
Neutral nucleophiles such as
pyridine, triphenyl phosphine, and triethylamine also displaced
THT to give excellent yields of 2a, 2e, 2g, and 2m,
respectively. Triphenylphosphine was also found to substitute
products (as compared to TPPy and P(o-Tol) ), which we
3
attribute to the higher pK of sulfonium acids compared to
THT in [1h-THT][NTf ] in an 86% yield to give 2o,
a
2
10
those of pyridinium and phosphonium acids.
More challenging gem-difluoroalkanes required the use of
providing a practical way to access this salt (avoiding HF
elimination) for further functionalization reactions (described
below).
11
the more fluorophilic catalyst [Al(C F ) ·0.5(C H )] (ACF).
6
5 3
7
8
1
917
Org. Lett. 2021, 23, 1915−1920
Gupta, Richa
