of 12
Enantioselective
C(sp
2
)
C(sp
3
) Bond
Construction
by Ni Catalysis
Published
as part of the Accounts
of Chemical
Research
special
issue “Cross-Coupling
with First-Row
Transition
Metals”.
Li-Ming
Chen
and Sarah
E. Reisman
*
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2024,
57, 751−762
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CONSPECTUS:
After decades
of palladium
dominating
the realm of
transition-metal-catalyzed
cross-coupling,
recent years have witnessed
exciting
advances
in the development
of new nickel-catalyzed
cross-coupling
reactions
to form C(sp
3
) centers.
Nickel possesses
distinct
properties
compared
with
palladium,
such as facile single-electron
transfer
to C(sp
3
) electrophiles
and
rapid C
C reductive
elimination
from Ni
III
. These properties,
among
others,
make nickel particularly
well-suited
for reductive
cross-coupling
(RCC)
in
which two electrophiles
are coupled
and an exogenous
reductant
is used to turn
over the metal catalyst.
Ni-catalyzed
RCCs use readily
available
and stable
electrophiles
as starting
materials
and exhibit good functional
group tolerance,
which makes them appealing
for applications
in the synthesis
of complex
molecules.
Building
upon the foundational
work in Ni-catalyzed
RCCs by the
groups of Kumada,
Durandetti,
Weix, and others, as well as the advancements
in Ni-catalyzed
enantioselective
redox-neutral
cross-couplings
led by Fu and co-workers,
we initiated
a program
to explore
the
feasibility
of developing
highly enantioselective
Ni-catalyzed
RCCs.
Our research
has also been driven by a keen interest
in
unraveling
the factors
contributing
to enantioinduction
and electrophile
activation
as we seek new avenues
for advancing
our
understanding
and further
developing
these reactions.
In the first part of this Account,
we organize
our reported
methods
on the basis of the identity
of the C(sp
3
) electrophiles,
including
benzylic
chlorides,
N
-hydroxyphthalimide
(NHP)
esters, and
α
-chloro
esters and nitriles.
We highlight
how the selection
of specific
chiral ligands plays a pivotal role in achieving
high cross-selectivity
and enantioselectivity.
In addition,
we show that reduction
can be
accomplished
not only with heterogeneous
reductants,
such as Mn
0
, but also with the soluble
organic
reductant
tetrakis(dimethylamino)ethylene
(TDAE),
as well as electrochemically.
The use of homogeneous
reductants,
such as TDAE,
is
well suited for studying
the mechanism
of the transformation.
Although
this Account
primarily
focuses
on RCCs, we also highlight
our work using trifluoroborate
(BF
3
K) salts as radical precursors
for enantioselective
dual-Ni/photoredox
systems.
At the end of this Account,
we summarize
the relevant
mechanistic
studies of two closely related asymmetric
reductive
alkenylation
reactions
developed
in our laboratory
and provide
a context
between
our work and related mechanistic
studies by others. We discuss
how the ligand properties
influence
the rates and mechanisms
of electrophile
activation
and how understanding
the mode of C(sp
3
)
radical generation
can be used to optimize
the yield of an RCC. Our research
endeavors
to offer insights
on the intricate
mechanisms
at play in asymmetric
Ni-catalyzed
RCCs with the goal of using the rate of electrophile
activation
to improve
the substrate
scope of
enantioselective
RCCs. We anticipate
that the insights
we share in this Account
can provide
guidance
for the development
of new
methods
in this field.
1. KEY REFERENCES
Cherney,
A. H.; Kadunce,
N. T.; Reisman,
S. E. Catalytic
Asymmetric
Reductive
Acyl Cross-Coupling:
Synthesis
of Enantioenriched
Acyclic
α
,
α
-Disubstituted
Ketones.
J.
Am. Chem.
Soc.
2013
,
135
, 7442
7445.
1
We reported
the
first Ni-catalyzed
enantioselective
reductive
cross-coupling
reaction
with acyl chlorides
and benzylic
chlorides
as
coupling
partners
.
Poremba,
K. E.; Kadunce,
N. T.; Suzuki,
N.; Cherney,
A.
H.; Reisman,
S. E. Nickel-Catalyzed
Asymmetric
Reductive
Cross-Coupling
To Access 1,1-Diarylalkanes.
J. Am. Chem.
Soc.
2017
,
139
, 5684
5687.
2
We reported
the first Ni-catalyzed
enantioselective
reductive
cross-
Received:
December
15, 2023
Revised:
January
10, 2024
Accepted:
January
16, 2024
Published:
February
12,
2024
Article
pubs.acs.org/accounts
© 2024
The Authors.
Published
by
American
Chemical
Society
751
https://doi.org/10.1021/acs.accounts.3c00775
Acc. Chem.
Res.
2024,
57, 751
762
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coupling
to prepare
diarylalkanes,
which
necessitated
the
development
of the 4-heptyl-BiOX
ligand
.
DeLano,
T. J.; Reisman,
S. E. Enantioselective
Electro-
reductive
Coupling
of Alkenyl
and Benzyl
Halides
via
Nickel Catalysis.
ACS Catal.
2019
,
9
, 6751
6754.
3
We
reported
the first Ni-catalyzed
enantioselective
reductive
cross-coupling
driven
by electrochemistry
.
Turro, R. F.; Wahlman,
J. L. H.; Tong, Z. J.; Chen, X.;
Yang, M.; Chen, E. P.; Hong, X.; Hadt, R. G.; Houk, K.
N.; Yang, Y.-F.; Reisman,
S. E. Mechanistic
Investigation
of Ni-Catalyzed
Reductive
Cross-Coupling
of Alkenyl
and Benzyl Electrophiles.
J. Am. Chem.
Soc.
2023
,
145
,
14705
14715.
4
Mechanistic
studies
of enantioselective
reductive
alkenylation
reactions
developed
by our lab. This
study demonstrates
the distinct
activation
of the electro-
philes,
catalyst
resting
state, and the origin
of enantioin-
duction
.
2. INTRODUCTION
The development
of enantioselective
reactions
is a challenging
but important
discipline
within
organic
chemistry
with
applications
in natural
product
synthesis,
drug development,
and materials
science.
Amidst
the array of methods
to generate
stereogenic
centers
through
C
C bond formation,
transition-
metal-catalyzed
cross-coupling
has emerged
as a powerful
tool.
Whereas
early efforts
to develop
redox-neutral
palladium-
catalyzed
cross-coupling
reactions
of either C(sp
3
) nucleo-
philes or electrophiles
were plagued
by challenges,
such as slow
transmetalation
and
β
-hydride
elimination,
nickel has emerged
as a versatile
metal to catalyze
C(sp
3
) bond formation.
5
Nickel,
compared
with palladium,
offers distinct
reactivity
that is
advantageous
for constructing
C(sp
3
) centers,
including
facile
oxidative
addition
(Ni
0/II
,
E
0
=
0.26 V vs SHE versus Pd
0/II
,
E
0
= 0.95 V vs SHE), slower
β
-hydride
elimination,
and a range
of accessible
oxidation
states (Ni
0/I/II/III/IV
) that enable diverse
modes of electrophile
activation.
6
In pioneering
studies,
Fu and
co-workers
reported
the first examples
of Ni-catalyzed
enantioconvergent
cross-couplings
in 2005 in which racemic
secondary
alkyl halides
could be coupled
with aryl zinc
nucleophiles
with high enantioselectivity
(Figure
1a).
5,7
9
Since these initial reports,
complementary
strategies,
such as
enantioselective
dual-Ni/photoredox
catalysis
(Figure
1b)
10
and enantiospecific
Ni-catalyzed
transformations
(Figure
1c)
11,12
have been developed
to stereoselectively
cross-couple
C(sp
3
) partners.
Many of these transformations
are redox-
neutral
as they involve
the use of both an electrophilic
and a
nucleophilic
fragment
without
a net change
in the oxidation
state of the reaction
partners.
In addition
to redox-neutral
cross-coupling,
Ni has emerged
as a particularly
good catalyst
for reductive
cross-coupling
(RCC)
in which two electrophilic
fragments
are coupled,
and
an exogenous
reductant
is used to turn over the catalyst.
13
15
The ability
to replace
organometallic
nucleophiles
with
electrophiles
is advantageous,
since they are generally
more
commercially
available,
are stable, and exhibit
greater
func-
Figure
1.
Seminal
reports
and schematic
representations
of (a) Ni-catalyzed
enantioselective
cross-coupling,
(b) dual-Ni/metallaphotoredox
for
asymmetric
cross-coupling,
(c) Ni-catalyzed
enantiospecific
cross-coupling,
(d) Ni-mediated
reductive
homocoupling,
(e) Ni-catalyzed
RCCs, and
(f) Ni-catalyzed
enantioselective
RCCs.
Accounts
of Chemical
Research
pubs.acs.org/accounts
Article
https://doi.org/10.1021/acs.accounts.3c00775
Acc. Chem.
Res.
2024,
57, 751
762
752
tional group tolerance
compared
with their organometallic
counterparts.
Although
there has been a resurgence
in interest
in Ni-
catalyzed
RCCs over the past decade,
these reactions
were first
reported
in the 1970s. Following
initial reports
of stoichio-
metric Ni-mediated
reactions
of allylic
16
and aryl halides,
17,18
in 1977, Kumada
and co-workers
described
the Ni-catalyzed
homodimerization
reaction
of aryl bromides
where
Zn
0
powder
was used to generate
the active catalyst
in situ
and
promote
turnover
(Figure
1d).
19
Nevertheless,
because
of the
challenges
associated
with achieving
cross-selectivity
between
distinct
aryl electrophiles,
the use of redox-neutral
cross-
couplings
has remained
the prevalent
focus of research
for
several
decades.
Following
initial development
of electro-
reductive
Ni-catalyzed
cross-couplings
between
α
-chloroesters
and aryl bromides,
20,21
in 2007, Durandetti
and co-workers
demonstrated
that Mn
0
could be used as the chemical
reductant
to synthesize
α
-aryl esters (e.g.,
8
, Figure 1e).
22
In
2010, Weix and co-workers
reported
the first Ni-catalyzed
RCC of unactivated
C(sp
3
) electrophiles
(e.g.,
9
) with aryl
iodides,
also by utilizing
Mn
0
as the stoichiometric
chemical
reductant
(Figure
1e).
23
In the decade
since, research
on Ni-
catalyzed
RCC has flourished,
thereby
expanding
its scope to
include
a plethora
of activated
and unactivated
C(sp
3
)
electrophiles.
In 2011, our laboratory
initiated
a program
focused
on the
development
of Ni-catalyzed,
enantioselective
reductive
cross-
coupling
(RCC)
reactions.
1
Although
the detailed
mechanisms
of RCC reactions
are complex
and were poorly understood
when we began our studies,
we recognized
that activation
of
the C(sp
3
) electrophile
likely proceeded
through
radical
intermediates,
in analogy
to many of the redox-neutral
Ni-
catalyzed
cross-couplings
developed
by Fu and others.
24
As a
result, we became
interested
in the possibility
of using chiral Ni
complexes
to cross-couple
sec
-alkyl
electrophiles
by stereo-
convergent
processes
(Figure
1f). Indeed,
our initial foray into
Ni catalysis
was driven by a challenge
encountered
in our total
synthesis
program,
which required
an enantioselective
syn-
thesis of an
α
,
α
-disubstituted
carbonyl
compound
(vide infra).
We were drawn to acyl cross-coupling
as an alternative
to
auxiliary-based
enolate
alkylation
methods.
25,26
Moreover,
we
anticipated
that the functional
group compatibility
of these
reactions
would
make them well-suited
for downstream
applications
in total synthesis.
In this Account,
we provide
an overview
of our work in Ni-
catalyzed
enantioselective
cross-coupling.
The discussion
will
be organized
according
to the identity
of the C(sp
3
) coupling
partner
and will close with a discussion
of mechanism.
3. SYNTHETIC
METHOD
DEVELOPMENT
3.1. Benzylic
Chlorides
as C(sp
3
) Electrophiles
Our interest
in Ni-catalyzed
enantioselective
RCC methods
was inspired
by a challenge
encountered
during the synthesis
of the natural
product
maoecrystal
Z,
27
where we required
an
enantiopure
alkyl iodide
building
block (
11
, Figure
2).
Although
we ultimately
resorted
to a chiral auxiliary
approach,
our brainstorming
during
this project
prompted
us to
investigate
catalytic
alternatives
that obviate
the use of a
stoichiometric
stereocontrol
element
and cryogenic
reaction
temperatures.
Motivated
by this synthetic
challenge,
we began investigating
the Ni-catalyzed
reductive
cross-coupling
between
acyl
chloride
12
and benzylic
chloride
13
using chiral nitrogen-
based ligands.
1
Preliminary
studies
identified
that the phenyl-
substituted
bis(oxazoline)
(BOX)
ligand
L2
provided
promis-
ing enantioselectivity,
although
the yield of
α
-phenylketone
14a
was very low (Figure
3).
1
Extensive
investigations
of
reaction
parameters
revealed
that a mixed tetrahydrofuran
(THF)
dimethylacetamide
(DMA)
solvent
system
delivered
the optimal
balance
between
the reactivity
and enantioselec-
tivity. Furthermore,
the addition
of dimethylbenzoic
acid
(DMBA)
proved
to be crucial
for suppressing
undesired
homocoupling
of the benzylic
electrophiles.
Under the final
conditions,
acyl chloride
12
and benzylic
chloride
13
could be
cross-coupled
to give enantioenriched
ketone
14a
in 85% yield
and 92% ee. Several
aspects
of this transformation
are
noteworthy.
(1) The mild conditions
avoid racemization
of
the
α
-arylketone
products,
which is a challenge
faced in other
transition-metal-mediated
arylation
reactions
that employ
strong base or high temperatures.
(2) The reaction
tolerates
functional
groups like primary
alkyl halides (
14h
and
14i
) and
can provide
β
-siloxy
ketone
products
(
14e
), which would be
prone to elimination
under strongly
basic conditions.
(3) This
catalyst-controlled
method
can provide
diastereoselective
access to products
with remote
stereocenters,
as observed
in
the coupling
of a
β
-stereogenic
acid chloride
to give either
diastereomer
of
14j
with high diastereomeric
ratio (dr).
Although
our initial interest
in Ni-catalyzed
asymmetric
RCC derived
from the need to synthesize
α
,
α
-disubstituted
carbonyl
derivatives,
we recognized
that this general
mode of
reactivity
could potentially
be extended
to broad classes
of
electrophiles.
For example,
stereogenic
aryl-substituted
tertiary
allylic alkenes
are valuable
but challenging
compounds
to
synthesize
using traditional
asymmetric
allylic substitution
methods.
28
To address
this challenge,
we developed
a Ni-
catalyzed
asymmetric
reductive
alkenylation
(ARA)
between
alkenyl
bromides
and racemic
benzylic
chlorides,
which
provided
products
bearing
aryl-substituted
tertiary
allylic
stereogenic
centers
in excellent
yields and enantiomeric
excess
under relatively
mild conditions
(Figure
4).
29
Similar
to the
acyl cross-coupling,
BOX ligands
were identified
as promising
candidates
for inducing
enantioselectivity.
Further
ligand
development
identified
the cyclopropyl-linked
indanyl-derived
BOX ligand
L3
as optimal
for both ee and enhanced
cross-
coupling
selectivity;
increased
formations
of homodimer
derived
from
13
were observed
with other ligands.
In contrast
to acyl coupling,
ethereal
cosolvents
led to reduced
Figure
2.
Schematic
representation
of initial thought
process
for
methodology
development.
Accounts
of Chemical
Research
pubs.acs.org/accounts
Article
https://doi.org/10.1021/acs.accounts.3c00775
Acc. Chem.
Res.
2024,
57, 751
762
753