of 11
Mechanistic
Investigation
of Ni-Catalyzed
Reductive
Cross-Coupling
of Alkenyl
and Benzyl
Electrophiles
Raymond
F. Turro,
Julie L.H. Wahlman,
Z. Jaron Tong,
Xiahe Chen,
Miao Yang, Emily P. Chen,
Xin Hong,
Ryan G. Hadt, K. N. Houk,
Yun-Fang
Yang,
*
and Sarah E. Reisman
*
Cite This:
J. Am. Chem.
Soc.
2023,
145, 14705−14715
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ABSTRACT:
Mechanistic
investigations
of
the
Ni-catalyzed
asymmetric
reductive
alkenylation
of
N
-hydroxyphthalimide
(NHP)
esters
and
benzylic
chlorides
are
reported.
Investigations
of
the
redox
properties
of
the
Ni-bis(oxazoline)
catalyst,
the
reaction
kinetics,
and
mode
of
electrophile
activation
show
divergent
mechanisms
for
these
two
related
transformations.
Notably,
the
mechanism
of C(sp
3
) activation
changes
from
a Ni-
mediated
process
when
benzyl
chlorides
and
Mn
0
are
used
to a
reductant-mediated
process
that
is gated
by a Lewis
acid
when
NHP
esters
and
tetrakis(dimethylamino)ethylene
is used.
Kinetic
experiments
show
that
changing
the
identity
of the
Lewis
acid
can
be used
to tune
the
rate
of NHP
ester
reduction.
Spectroscopic
studies
support
a Ni
II
alkenyl
oxidative
addition
complex
as
the
catalyst
resting
state.
DFT
calculations
suggest
an
enantiodetermining
radical
capture
step
and
elucidate
the
origin
of enantioinduction
for
this
Ni-BOX
catalyst.
1. INTRODUCTION
Ni-catalyzed
reductive
cross-couplings
(RCCs)
of
organic
electrophiles
have
emerged
as useful
reactions
for
C(sp2)
C(sp3)
bond
formation.
1
These
reactions
provide
direct
access
to
cross-coupled
products
from
readily
available
organic
electrophiles,
such
as
halides,
precluding
the
need
to
pregenerate
an organometallic
coupling
partner.
The
use
of a
metal
powder
(Mn
0
, Zn
0
) or an organic
electron
donor
such
as
tetrakis(dimethylamino)ethylene
(TDAE)
2
provides
reducing
equivalents
to render
the
system
catalytic
in Ni.
Ni-catalyzed
RCC
reactions
can
also
be
driven
electrochemically
using
either
sacrificial
anodes
or paired
electrolysis
systems.
3
A key
challenge
in the
development
of these
reactions
is achieving
selectivity
for
the
cross-coupled
product
over
possible
homo-
coupling
products;
this
requires
a catalyst
that
oxidatively
adds
each
electrophile
in
sequence
or
a catalyst
system
with
mechanistically
distinct
modes
of
activating
each
coupling
partner.
Despite
this
challenge,
several
different
Ni
catalysis
systems
have
been
developed
that
afford
high
selectivity
for
cross-coupled
products.
1,4,5
Our
lab
has
developed
several
Ni-catalyzed
asymmetric
reductive
alkenylation
(ARA)
reactions
(Figure
1),
which
leverage
the
intermediacy
of
C(sp
3
) radicals
to
enable
stereoconvergent,
enantioselective
bond
formation.
6
8
In
2014,
we
reported
an
ARA
between
benzylic
chlorides
and
alkenyl
bromides
using
cyclopropyl-containing
IndaBOX
ligand
L1
and
Mn
0
as the
terminal
reductant
(Figure
1a).
6
We
subsequently
developed
a related
ARA
that
uses
the
same
ligand
(
L1
),
but
employs
redox-active
N
-hydroxyphthalimide
(NHP)
esters
as the
C(sp
3
) coupling
partner.
7
In this
case,
Received:
March
13,
2023
Published:
June
26,
2023
Figure
1.
Ni-catalyzed
asymmetric
reductive
cross-coupling
between
alkenyl
and
benzylic
electrophiles.
Article
pubs.acs.org/JACS
© 2023
The Authors.
Published
by
American
Chemical
Society
14705
https://doi.org/10.1021/jacs.3c02649
J. Am. Chem.
Soc.
2023,
145, 14705
14715
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TDAE
was
used
as the
reductant,
and
trimethylsilyl
bromide
(TMSBr)
was
identified
as a key
additive
(Figure
1b).
In
addition
to chiral
ligand
L1
being
optimal
for
both
reactions,
the
use
of DMA
as solvent
and
NaI
as an additive
was
shared
between
the
two
transformations.
Given
their
similarities,
we
identified
this
pair
of
transformations
as
well
suited
for
investigating
the
mechanism
of Ni-catalyzed
RCCs
and
how
the
mechanism
might
change
depending
on
the
C(sp
3
)
coupling
partner.
Since
many
RCCs
use
heterogeneous
terminal
reductants,
the
mechanisms
of
these
reactions
have
been
difficult
to
elucidate.
Nonetheless,
insightful
studies
of reductive
arylation
have
been
disclosed
by the
groups
of Weix
9
and
Diao;
10
these
systems
have
primarily
focused
on
reactions
in
which
catalytically
relevant
Ni
II
(aryl)X
complexes
can
be
isolated
and
characterized.
Diao
and
coworkers
have
also
recently
investigated
bi(oxazoline)
10a,b
and
pyridine-oxazoline
10c
li-
gands
in reductive
arylation;
however,
mechanistic
studies
of
reductive
alkenylation
and
of Ni-catalysts
supported
by chiral
bis(oxazolines)
such
as
L1
are
lacking.
11
Here,
we
report
our
mechanistic
investigations
of
two
L1
·
Ni-catalyzed
ARA
reactions.
In
this
study,
we
sought
to
(1)
determine
the
kinetic
driving
forces
and
resting
state
for
the
homogeneous
reaction
of
alkenyl
bromide
1a
with
NHP
ester
2b
;
(2)
investigate
the
redox
properties
of the
L1
·
Ni
II
X
2
precatalysts
and
determine
whether
L1
·
Ni
0
is accessible
using
common
reductants;
(3)
interrogate
the
mechanism
of
electrophile
activation
for
both
2a
and
2b
;
(4)
use
computational
methods
to understand
the
enantioselectivity
determining
step.
These
studies
have
revealed
that
chloride
2a
and
NHP
ester
2b
are
activated
through
distinct
mechanisms
and
provide
insights
that
can
guide
the
optimization
of reaction
conditions
for
Ni-
catalyzed
RCC
reactions.
2. RESULTS
AND DISCUSSION
2.1. Reaction
Kinetics
of TDAE-Mediated
RCC.
Since
the
TDAE-driven
L1
·
Ni-catalyzed
ARA
6
is homogeneous
and
does
not
suffer
from
an
induction
period,
we
initiated
our
mechanistic
investigation
by determining
the
kinetic
orders
in
1a
,
2b
,
and
Ni under
standard
reaction
conditions
(Figure
2a).
For
this,
we
employed
variable
time
normalization
analysis
12
(VTNA)
to analyze
the
results
of different
excess
experiments
(Figure
2b
d).
These
experiments
revealed
a first
order
rate
dependence
on
the
concentration
of NHP
ester
2b
(Figure
2c).
The
rate
dependence
on
[
1a]
appears
to be 0th
order
at
concentrations
similar
to the
standard
conditions
(0.1
and
0.2
M
1a
,
Figure
2b);
however,
a fractional
inverse
rate
dependence
is observed
at higher
concentrations
of
1a
(Figure
2b,
Figure
S27).
Moreover,
at higher
[
1a]
,
minor
amounts
of
dienyl
homodimer
are
observed;
the
slight
inverse
rate
dependence
is proposed
to derive
from
this
off-cycle
pathway.
We
note
that
inverse
order
in C(sp
2
) electrophile
has
been
observed
previously
by
Weix
et al.
for
a related
(bpy)Ni-
catalyzed
RCC
of aryl
and
alkyl
halides.
9a
Interestingly,
there
is
an
apparent
0th
order
rate
dependence
on
L1
·
NiBr
2
at
loadings
similar
to the
optimized
conditions
(5 and
10 mol
%,
Figure
2d);
however,
a positive
rate
dependence
develops
at
low
catalyst
loadings
(<1
mol
%).
The
observation
that
the
catalyst
loading
does
not
influence
the
rate
of
product
formation
has
not
been
previously
reported
for
Ni-catalyzed
RCC
reactions.
9b,10a
Figure
2.
(a)
Standard
conditions
for
different
excess
experiments
on
TDAE-mediated
ARA.
Different
excess
VTNA
experiments
with
varying
initial
concentrations
of (b)
alkenyl
bromide
1a
,
(c)
NHP
ester
2b
,
and
(d)
catalyst
L1
·
NiBr
2
. Impact
of [
L1
·
NiBr
2
] on the
rate
of conversion
of
(e)
alkenyl
bromide
1a
,
(f)
NHP
ester
2b
,
and
(g)
byproduct
4
. Concentrations
determined
vs dodecane
internal
standard
using
GC-FID.
Journal
of the American
Chemical
Society
pubs.acs.org/JACS
Article
https://doi.org/10.1021/jacs.3c02649
J. Am. Chem.
Soc.
2023,
145, 14705
14715
14706