Abstract
The
difluoromethyl
group
(CF2H)
can
function
as
a
lipophilic
hydrogen-bond
donor,
and
is
regarded
bioisostere
of
functional
groups
such
hydroxy
(-OH),
thiol
(-SH),
amino
(-NH2).
unique
physicochemical
properties
this
make
difluoromethylation
hot
topic
in
the
field
synthetic
organic
chemistry,
recent
decades,
various
methods
have
been
developed
for
constructing
C(sp3)—CF2H,
C(sp2)—CF2H,
C(sp)
—CF2H,
X—CF2H
(X
=
N,
O,
S,
Se,
B,
P,
etc.)
bonds.
This
review
summarizes
currently
available
reagents
performing
reactions,
well
other
approaches
installing
unit.
Nature Communications,
Journal Year:
2024,
Volume and Issue:
15(1)
Published: May 15, 2024
Abstract
Difluoromethyl
pyridines
have
gained
significant
attention
in
medicinal
and
agricultural
chemistry.
The
direct
C−H-difluoromethylation
of
represents
a
highly
efficient
economic
way
to
access
these
azines.
However,
the
meta-difluoromethylation
has
remained
elusive
methods
for
site-switchable
regioselective
meta-
para-difluoromethylation
are
unknown.
Here,
we
demonstrate
meta-C−H-difluoromethylation
through
radical
process
by
using
oxazino
pyridine
intermediates,
which
easily
accessed
from
pyridines.
selectivity
can
be
readily
switched
para
situ
transformation
pyridinium
salts
upon
acid
treatment.
preparation
various
para-difluoromethylated
this
approach
is
presented.
mild
conditions
used
also
allow
late-stage
or
containing
drugs.
Sequential
double
functionalization
presented,
further
underlines
value
work.
Nature Communications,
Journal Year:
2025,
Volume and Issue:
16(1)
Published: March 4, 2025
Nonlinear
effects
(NLEs)
serve
as
a
widespread
tool
in
the
study
of
asymmetric
catalytic
reactions.
However,
due
to
diversity
ligand-metal
coordination
modes,
information
obtained
solely
from
linear
relationship
between
ee
values
ligands
and
products
complex
systems
is
often
indirect.
Here,
we
report
precise
method
that
directly
connects
metal
complexes
products,
with
purpose
determining
active
species
occur
systems.
Through
an
in-depth
analysis
mechanism
our
previous
copper-catalyzed
esterification
reactions,
find
intrinsic
key
(LLCuI)
within
this
traditionally
non-linear
system.
This
holds
promise
powerful
for
exploration
catalysis
mechanisms,
heralding
new
avenues
understanding
application
processes.
ACS Catalysis,
Journal Year:
2024,
Volume and Issue:
14(14), P. 11087 - 11100
Published: July 9, 2024
Fluoroalkyl
fragments
have
played
a
critical
role
in
the
design
of
pharmaceutical
and
agrochemical
molecules
recent
years
due
to
enhanced
biological
properties
fluorinated
compared
their
non-fluorinated
analogues.
Despite
potential
advantages
conferred
by
incorporating
difluoromethyl
group
organic
compounds,
industrial
adoption
difluoromethylation
methods
lags
behind
fluorination
trifluoromethylation.
This
is
part
challenges
applying
common
sources
towards
applications.
We
report
here
nickel-catalyzed
cross-electrophile
coupling
(hetero)aryl
bromides
with
2-pyridyl
sulfone,
sustainably
sourced,
crystalline
reagent.
The
scope
this
reaction
demonstrated
24
examples
(67
±
16%
average
yield)
including
diverse
array
heteroaryl
precursors
difluoromethyl-containing
preclinical
pharmaceuticals.
can
be
applied
small-scale
parallel
synthesis
benchtop
scale-up
under
mild
conditions.
As
sulfone
reagents
are
uncommon
electrophiles
coupling,
mechanism
process
was
investigated.
Studies
confirmed
formation
•CF2H
instead
difluorocarbene.
A
series
modified
sulfones
revealed
that
reactivity
does
not
correlate
exclusively
reduction
coordination
cations
or
nickel
pyridyl
essential
reactivity,
setting
out
parameters
for
matching
coupling.
ACS Catalysis,
Journal Year:
2024,
Volume and Issue:
14(18), P. 13557 - 13566
Published: Aug. 28, 2024
The
incorporation
of
the
difluoromethyl
(CF2H)
group
into
arenes
has
increasingly
been
recognized
as
important
in
drug
discovery.
Herein,
we
report
a
divergent
cross-coupling
method
for
constructing
both
aryl
difluoromethanes
and
difluoroketones
from
thianthrenium
salts.
Site
selectivity
Negishi-type
coupling
C1
insertion
reactions
was
achieved
under
palladium
catalysis.
Both
transformations
proceed
with
broad
functional
tolerance,
enabling
late-stage
difluoromethylation
difluoromethylcarbonylation
complex
molecules.
synthetic
utility
this
demonstrated
by
synthesizing
four
pharmaceutical
analogues
same
precursor
applying
it
downstream
functionalization
difluoroketones.
Organic Letters,
Journal Year:
2023,
Volume and Issue:
25(3), P. 533 - 537
Published: Jan. 13, 2023
The
difluoromethyl
group
(CF2H)
is
of
great
importance
in
medicinal
chemistry.
We
report
herein
an
efficient
method
for
the
synthesis
diversified
α-difluoromethyl
amines
through
copper-catalyzed
hydroamination
gem-difluoroalkenes,
where
C-N
bond
formed
via
a
α-CF2H
transition-metal
intermediate.
This
new
reaction
proceeds
Cu-H
insertion
to
gem-difluoroalkenes
and
gives
valuable
alkyl-CF2H-containing
compounds,
which
overcome
much
more
challenged
β-F
elimination
from
α-fluoroalkyl
organocopper
species.
exhibits
broad
substrate
scope
with
readily
available
starting
materials
commercial
catalysis.
Chemical Communications,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 1, 2025
We
present
a
highly
efficient
and
versatile
nickel-catalyzed
protocol
for
the
reductive
cross-coupling
of
unactivated
CF2H-substituted
electrophiles
with
wide
variety
aryl
alkenyl
halides.
This
novel
approach
offers
high
catalytic
reactivity
broad
functional
group
compatibility,
enabling
late-stage
fluoroalkylation
drug
molecules.
The Journal of Organic Chemistry,
Journal Year:
2025,
Volume and Issue:
unknown
Published: Jan. 28, 2025
The
synthesis
of
perfluoroalkylated
fullerenes
(PFAFs)
holds
significant
importance
due
to
their
enhanced
molecular
stability,
increased
lipophilicity,
and
high
electron
affinity.
Herein,
we
report
a
copper-catalyzed
multicomponent
reaction
conducted
under
aerobic
conditions,
which
enables
the
production
highly
soluble
PFAFs
with
half-wave
reduction
potentials
similar
those
C60.
Furthermore,
challenges
posed
by
C-F
coupling
in
carbon
signal
assignment
were
addressed
through
fluorine-decoupled
spectroscopy,
facilitating
precise
structural
characterization
perfluoroalkyl
moieties.
ACS Catalysis,
Journal Year:
2025,
Volume and Issue:
unknown, P. 4644 - 4653
Published: March 4, 2025
A
copper-catalyzed
fluoroalkylation
of
lithium
aryl
nbutyl
borates
with
electrophilic
fluoroalkylating
reagent
YlideFluor
for
the
preparation
di-,
trifluoromethyl-,
and
monofluoroalkyl-substituted
(hetero)arenes
under
mild
conditions
was
described.
Control
experiments
indicated
that
a
fluoroalkyl
radical,
rather
than
difluorocarbene
intermediate,
is
involved
in
catalytic
process.
In
addition,
stoichiometric
reactions
demonstrated
transmetalation
copper
catalyst
borate
takes
place
before
single-electron-transfer
(SET)
oxidation
an
ate-type
Cu(I)
intermediate
[CuI(Ar)(SCN)]−
by
YlideFluor.
Based
on
these
mechanistic
results,
reasonable
cycle
proposed.
