Research Square (Research Square),
Journal Year:
2023,
Volume and Issue:
unknown
Published: April 18, 2023
Abstract
The
nucleophilic
substitution
reaction
(S
N
2)
is
one
of
the
oldest,
yet
very
useful
organic
transformations
and
has
found
widespread
applications
for
synthesis
drugs
natural
products.
Typically,
cyanide,
oxygen,
nitrogen,
sulfur,
or
phosphorous
nucleophiles
replace
a
halogen
sulfonyl
ester
leaving
group
to
form
new
bond
between
nucleophile
electrophile.
Isocyanides
display
an
unusual
versatile
chemistry
based
on
their
C-centered
lone
pair
s
p
*
frontier
orbitals
leading
radical,
multicomponent
reactions.
Surprisingly,
character
isocyanides
never
been
explored
in
S
2
We
discovered
that
react
as
reactions
with
alkyl
halides
general
manner
afford
highly
substituted
secondary
amides
by
situ
hydrolysis
intermediate
nitrilium
ion.
innovative
3-component
broad
scope
regarding
structures
isocyanide
electrophile
components,
functional
compatibility,
scalability,
use
late-stage
modification
drug
complex
compounds
otherwise
not
easily
accessible
from
simple
precursors.
chemical
space
only
different
but
nearly
doubled
size
compared
classical
amid
coupling.
Significantly,
comprises
Umpolung
amide
carbanion
synthon
R-NHC(-)=O,
alternative
Organic Letters,
Journal Year:
2025,
Volume and Issue:
unknown
Published: March 7, 2025
Although
aryl
chlorides
are
among
the
most
abundant
and
stable
aromatic
electrophiles,
coupling
of
with
isocyanides
has
remained
an
unsolved
challenge.
Herein,
we
report
a
general
transformation
chlorides,
isocyanides,
thiocarboxylates
to
synthesize
thioamides.
The
sterically
hindered
electron-rich
Josiphos
ligand
significantly
facilitates
rate-determining
oxidative
addition
step
reduces
toxicity
toward
metal
center.
combination
thiocarboxylate
as
nucleophile
ligands
enabled
coupling-tolerated
various
1°,
2°,
3°
which
provides
rapid,
efficient,
versatile
method
for
synthesis
large
quantities
thioamides,
including
those
pharmaceutical
relevance.
The Journal of Organic Chemistry,
Journal Year:
2022,
Volume and Issue:
88(1), P. 198 - 210
Published: Dec. 22, 2022
A
Mn(III)-mediated
radical
addition/cyclization
reaction
of
isocyanides
with
aryl
boronic
acids/diarylphosphine
oxides
has
been
developed.
series
11-arylated/-phosphorylated
dibenzodiazepines
were
efficiently
constructed
in
moderate
to
excellent
yields
under
mild
conditions
via
imidoyl
process.
The
present
protocol
offers
novel
access
functionalized
seven-membered
N-heterocycles.
Chemical Communications,
Journal Year:
2023,
Volume and Issue:
59(89), P. 13309 - 13312
Published: Jan. 1, 2023
This
study
describes
an
iron-catalyzed
divergent
oxidation
of
styrene
into
β-hydroxylmethylketone
and
ketone
under
photo-irradiation.
divergence
is
ascribed
to
the
use
with
various
substituents.
More
importantly,
methanol
oxidized
formaldehyde
in
reaction
serves
as
a
C1
synthon.
Mechanism
investigations
show
that
initiated
by
oxidative
SET
transfer
cation
radical.
The
pathway
undergoes
HAT
β-hydride
elimination
well
concerted
cyclization.
Particularly,
several
drug-like
molecules,
such
melperone
analogue,
lenperone
haloperidol
are
synthesized.
In
addition,
this
method
also
applicable
synthesis
natural
product
(R)-atomoxetine.
The Journal of Organic Chemistry,
Journal Year:
2024,
Volume and Issue:
89(14), P. 10223 - 10233
Published: June 28, 2024
A
photo-induced
cascade
sulfone
alkylation/cyclization
of
2-isocyanoaryl
thioethers
is
explored.
This
visible-light-triggered
reaction
not
only
occurs
under
extremely
mild
conditions
but
also
does
require
the
presence
a
photosensitizer.
The
photocatalytic
process
triggered
by
photochemical
activity
in
situ-generated
electron
donor–acceptor
complexes,
arising
from
association
and
α-iodosulfones.
radical
pathway
was
confirmed
UV–vis
spectroscopy,
trapping,
Job's
plot,
on/off
irradiation
experiments.
Nature Communications,
Journal Year:
2023,
Volume and Issue:
14(1)
Published: Sept. 19, 2023
Abstract
The
S
N
2
nucleophilic
substitution
reaction
is
a
vital
organic
transformation
used
for
drug
and
natural
product
synthesis.
Nucleophiles
like
cyanide,
oxygen,
nitrogen,
sulfur,
or
phosphorous
replace
halogens
sulfonyl
esters,
forming
new
bonds.
Isocyanides
exhibit
unique
C-centered
lone
pair
σ
π*
orbitals,
enabling
diverse
radical
multicomponent
reactions.
Despite
this,
their
potential
in
reactions
remains
unexplored.
We
have
uncovered
that
isocyanides
act
as
versatile
nucleophiles
with
alkyl
halides.
This
yields
highly
substituted
secondary
amides
through
situ
nitrilium
ion
hydrolysis
introducing
an
alternative
bond
break
compared
to
classical
amide
novel
3-component
process
accommodates
various
isocyanide
electrophile
structures,
functional
groups,
scalability,
late-stage
modifications,
complex
compound
greatly
expands
chemical
diversity,
nearly
doubling
the
amid
coupling’s
space.
Notably,
nucleophile
presents
unconventional
Umpolung
carbanion
synthon
(R-NHC(-)
=
O),
couplings.
Chemical Communications,
Journal Year:
2023,
Volume and Issue:
59(70), P. 10540 - 10543
Published: Jan. 1, 2023
An
unprecedented
route
for
the
preparation
of
indole–isoindole
derivatives
was
developed
and
proceeds
via
a
palladium-catalyzed
[3+2]
cyclization
isocyanides
with
alkynyl
imines.
Organic & Biomolecular Chemistry,
Journal Year:
2022,
Volume and Issue:
20(47), P. 9272 - 9281
Published: Jan. 1, 2022
Radical
annulation
has
emerged
as
one
of
the
most
efficient
and
straightforward
methods
for
synthesizing
cyclic/polycyclic
compounds
core
structures
can
be
constructed
through
a
single
procedure
comprising
multiple
bond-forming
steps.
Particularly,
radical
using
reagent
cyclization
partner
two-carbon
unit
greatly
expands
diversity
cyclic
skeletons
functionality
reagents.
We
herein
have
highlighted
representative
processes
reported
in
past
decade
unit,
including
[2
+
2
2],
[3
[4
[5
2]
modes,
with
an
emphasis
on
their
reaction
mechanisms.
These
studies
not
only
pave
way
toward
but
also
provide
insight
into
exploration
new
mode
chemistry.
Organic Letters,
Journal Year:
2023,
Volume and Issue:
25(34), P. 6272 - 6277
Published: Aug. 21, 2023
An
unprecedented
route
for
the
preparation
of
fused
tetracyclic
N-heterocycles
is
presented
through
palladium-catalyzed
cyclization
isocyanides
with
alkyne-tethered
aryl
iodides.
In
this
transformation,
a
novel
amino-to-alkyl
1,5-palladium
migration/intramolecular
C(sp3)-C(sp2)
coupling
sequence
was
observed
first.
More
importantly,
isocyanide
exhibited
three
roles,
serving
simultaneously
as
C1
synthon,
C1N1
and
donor
C(sp3)
coupling,
reaction
sole
successful
example
that
achieved
C(sp3)-H
activation
isocyanide.
