Organic Letters
Letter
aromatic substrates bearing electron-donating or electron-
withdrawing groups, providing the desired products 3a−3l in
good yields. Specifically, a variety of biologically important
moieties, such as amide and sulphonamide segments, were
well-tolerated. Naphthalene analogues also delivered the
corresponding products 3m−3o in modest yields. Notably,
biologically relevant nitrogen-containing heterocycles 1p−1r
were also amenable to this difluorination process, which would
greatly broaden the versatility of this protocol in drug
discovery. Interestingly, this developed platform also provided
a new route to access the difluorination of styrylides 1s−1u,
significantly expanding the substrate scope of this strategy.
Unfortunately, substrates with methoxy and nitro groups were
unsuitable for this protocol. It should be noted that although
the traditional method for the synthesis of difluoromethylated
arenes through the deoxyfluorination of aldehydes provided a
powerful route to these molecules, the functional-group
compatibility was usually very poor due to the extremely
high reactivity of the fluorination reagent used, such as N,N-
diethylaminosulfur trifluoride (DAST).
type of deuteriomonofluorination protocol is greatly attractive
for medicinal studies.
Furthermore, noting the flexibility of this fluorination
protocol, we finally customized various reaction sequences to
demonstrate the practicality and versatility of this protocol
(Scheme 4). First, an alternative electrophile (MeI) was
Scheme 4. Programmable Sequences of the Developed
Fluorination Reaction
Encouraged by the above results, we subsequently evaluated
the potential of the monofluorination process (Scheme 3).
Scheme 3. Scope of the Monofluorination Transformation
employed to initially capture the deprotonated ylide 1a
(Scheme 4a). The newly generated methylated ylide could
be further fluorinated under the standard reaction conditions,
delivering the desired product 5a. The deuterated product 5a′
was similarly prepared utilizing CD3I and D2O. Additionally,
the in situ-generated fluorinated ylide reacted with an aldehyde
to undergo a Wittig-type pathway, giving the fluorine-
substituted styrene 6 (Scheme 4b). Ultimately, an alternative
one-pot procedure on a gram-scale starting from benzyl
bromide was also established to deliver the desired di- and
monofluorinated products (Scheme 4, c and d), leaving this
platform more synthetically adjustable.
In summary, by fully taking the advantage of reactivity of
phosphonium ylides, a programmable fluorination platform
was established. This platform has been proven to be highly
efficient and flexible, concurrently providing facile access to a
range of valuable di- and monofluoromethylarenes. Besides,
deuteriomonofluorinated arenes were also readily assembled
by simply using deuterium oxide. Moreover, customizable
sequences were also designed and realized by rationally
combining various valuable transformations, further expanding
the potential of this fluorination platform. Further exploration
on the use of the newly developed strategy in other
transformations is underway in our laboratory.
Noting that excess unreacted NFSI obstructed the workup step
in some cases, 1.95 equiv of PPh3 was added to quench NFSI
before the hydrolysis step. Under these conditions, a broad
range of substrates proceeded smoothly with the monofluori-
nation, providing the desired products 4a−4f. As for
heterocyclic substrates, comparably lower yields for the
monofluorinated products 4g−4h were obtained. Additionally,
the corresponding deuteriomonofluorinated products 4a′−4h′
were facilely prepared by simply switching H2O to D2O in the
final hydrolysis step. No deuteriomonofluorinated product was
detected during the difluoronation sequences in the presence
of D2O, presumably because the hydrolysis step for the
difluorinated ylide was too quick to be captured further by
other electrophiles. Notably, deuteration is an efficient tool to
alter drug pharmacokinetics.12 Considering the significance of
both the deuterated and fluorinated units, the success of this
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Org. Lett. 2021, 23, 2538−2542