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,
Год журнала:
2024,
Номер
15(1)
Опубликована: Май 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,
Год журнала:
2025,
Номер
16(1)
Опубликована: Март 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,
Год журнала:
2024,
Номер
14(18), С. 13557 - 13566
Опубликована: Авг. 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.
ACS Catalysis,
Год журнала:
2024,
Номер
14(14), С. 11087 - 11100
Опубликована: Июль 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,
Год журнала:
2025,
Номер
unknown, С. 4644 - 4653
Опубликована: Март 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.
Organic Letters,
Год журнала:
2023,
Номер
25(3), С. 533 - 537
Опубликована: Янв. 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.
The Journal of Organic Chemistry,
Год журнала:
2024,
Номер
89(4), С. 2525 - 2537
Опубликована: Фев. 1, 2024
Difluoromethylated
compounds
usually
act
as
bioisosteres
for
alcohol
functional
groups
and
show
unique
physicochemical
biological
properties.
The
cyano-difluoromethylation
of
alkenes
using
5-((difluoromethyl)sulfonyl)-1-phenyl-1H-tetrazole
a
CF2H
radical
difluoromethyl
precursor
was
developed
to
afford
nitriles
including
group.
A
low-cost,
stable,
easily
handled
5-((difluoromethyl)sulfonyl)-1-methyl-1H-tetrazole
(DFSMT)
synthesized
applied
the
reagent.
Using
DFSMT
precursor,
oxyl-difluoromethylation
obtain
difluoromethylated
ether
products.
All
reactions
showed
good
group
tolerability.
Initial
mechanistic
experiments
indicated
that
involved
key
active
intermediate.
