Abstract
We
report
an
optimized
synthetic
route
towards
a
functionalized
4,5,6,7-tetrahydrobenzo[c]thiophene
heterocycle
bearing
gem-difluoromethylene
moiety
in
4
steps
with
overall
yield
of
43%.
The
CF2
fragment
was
incorporated
using
building
block
approach,
by
coupling
appropriate
fluorinated
alcohol
C-3
sulfonyl
chloride,
synthesized
via
oxidative
chlorination
exocyclic
benzyl
thioether.
Visible-light-mediated
Smiles
rearrangement
the
resulting
fluorosulfonate
ester
then
furnishes
desired
thiophene
scaffold.
Angewandte Chemie,
Год журнала:
2024,
Номер
136(22)
Опубликована: Март 14, 2024
Abstract
Cyclic
β,β‐difluoro‐carbonyl
compounds
have
a
venerable
history
as
drug
discovery
leads,
but
limitations
in
the
synthesis
arsenal
continue
to
impede
chemical
space
exploration.
This
challenge
is
particularly
acute
arena
of
fluorinated
medium
rings
where
installing
difluoromethylene
unit
subtly
alters
ring
conformation
by
expanding
internal
angle
(∠C−CF
2
−C>∠C−CH
−C):
this
provides
handle
modulate
physicochemistry
(e.g.
p
K
).
To
reconcile
disparity,
highly
modular
expansion
has
been
devised
that
leverages
simple
α,β‐unsaturated
esters
and
amides,
processes
them
one‐carbon
homologated
with
concomitant
geminal
difluorination
(6
10
membered
rings,
up
95
%
yield).
process
rare
example
formal
an
alkene
enabled
sequential
I(III)‐enabled
O
‐activation.
Validation
enantioselective
catalysis
generation
unprecedented
scaffolds
reported
(up
93
:
7
e.r
.)
together
X‐ray
structural
analyses
product
derivatization.
Angewandte Chemie,
Год журнала:
2022,
Номер
135(1)
Опубликована: Ноя. 8, 2022
Abstract
A
catalysis‐based
regioselective
1,4‐fluorofunctionalization
of
trifluoromethyl
substituted
1,3‐dienes
has
been
developed
to
access
compact,
highly
functionalized
products.
The
process
allows
E
,
Z
‐mixed
dienes
be
processed
a
single
‐alkene
isomer,
and
leverages
an
inexpensive
operationally
convenient
I(I)/I(III)
catalysis
platform.
first
example
catalytic
1,4‐difluorination
is
disclosed
subsequently
evolved
enable
1,4‐hetero‐difunctionalization,
which
δ‐fluoro‐alcohol
amine
derivatives
forged
in
operation.
protocol
compatible
with
variety
nucleophiles
including
fluoride,
nitriles,
carboxylic
acids,
alcohols
even
water
thereby
allowing
products,
stereocenter
bearing
both
C(sp
3
)−F
)−CF
groups,
generated
rapidly.
Scalability
(up
mmol),
facile
post‐reaction
modifications
are
demonstrated
underscore
the
utility
method
expanding
organofluorine
chemical
space.
Abstract
We
report
an
optimized
synthetic
route
towards
a
functionalized
4,5,6,7-tetrahydrobenzo[c]thiophene
heterocycle
bearing
gem-difluoromethylene
moiety
in
4
steps
with
overall
yield
of
43%.
The
CF2
fragment
was
incorporated
using
building
block
approach,
by
coupling
appropriate
fluorinated
alcohol
C-3
sulfonyl
chloride,
synthesized
via
oxidative
chlorination
exocyclic
benzyl
thioether.
Visible-light-mediated
Smiles
rearrangement
the
resulting
fluorosulfonate
ester
then
furnishes
desired
thiophene
scaffold.
