1
Nickel
-
Catalyzed
Reductive Alkylation of Heteroaryl Imines
Raymond F. Turro
‡
, Marco Brandstätter
‡
and
Sarah E. Reisman
*
This paper is dedicated in memory of our colleague and friend Prof. Robert H. Grubbs.
[a]
R. F. Turro
‡
, M. Br
andst
ä
tter
‡
, Prof. S. E. Reisman
The Warren and Katharine Schlinger Laboratory for Chemistry and Chemical Engineering, Division of Chemistry and
Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, United States
E
-
mail:
reisman@caltech.edu
[
‡
]
These authors contributed equally to this work.
Supporting information for this
article is given via a link at the end of the document.
Abstract: A Ni
-
catalyzed
reductive cross
-
coupling of heteroaryl imines
with C(sp
3
) electrophiles for the preparation of heterobenzylic amines
is reported. This umpolung
-
type alkylation proceeds under mild
conditions, avoids the pre
-
generation of organometallic reagents, and
exhib
its good functional group tolerance. Mechanistic studies are
consistent with the imine substrate acting as a redox
-
active ligand
upon coordination to a low
-
valent
Ni
center. The resulting bis(2
-
imino)heterocycle·Ni complexes can engage in alkylation reacti
ons
with a variety of C(sp
3
) electrophiles, giving heterobenzylic amine
products in good yields.
Benzylic amines are common substructures in a variety of
natural products, agrochemicals, and pharmaceuticals.
1
In
particular, heterobenzylic amines serve as
important nitrogen
-
containing scaffolds in medicinal chemistry. Two representative
examples are Gilead’s Phase II/III HIV capsid inhibitor
Lenacapavir
2
and Pfizer’s commercial anticancer agent
Glasdegib
3
(Figure 1a). Due to broad interest in this struct
ural
motif, a variety of synthetic approaches to prepare benzylic
amines have been developed. Of these methods, the 1,2
-
addition
of organometallic reagents to imines is one of the most well
-
established;
4
however, pre
-
generation of sensitive and reactive
o
rganometallic reagents and use of activated imine derivatives is
typically required (Figure 1b). When simple
N
-
alkylimines are
employed, stoichiometric Lewis acid additives can be necessary
to enhance the reactivity. Moreover,
a
-
deprotonation of the imine
substrate by the basic nucleophiles can be problematic.
In order to improve access to benzylic amines, chemists have
explored complimentary single electron reactions of imines,
including the 1,2
-
addition of organic radicals to imines
5
,
6
,
7
and the
reductive alkylation of imines via
a
-
amino radicals.
8
These
reactions often exhibit improved functional group tolerance by
avoiding the use of organometallic reagents; however, they
typically
require activated imine derivatives (e.g. sulfinyl imi
nes,
N
-
arylimines, oximes, hydrazones, or phosphoryl imines)
to
stabilize the resulting
N
-
centered radicals or facilitate imine
reduction
. As part of our efforts to broaden the scope of
electrophiles for cross
-
electrophile coupling, we became
interested in
a mechanistically distinct transition metal
-
catalyzed
reductive alkylation of heterocyclic imines
9
,
10
that leverages the
redox non
-
innocence of 2
-
iminoheterocycles as ligands on first
-
row transition metals. This strategy allows for the mild activation
of
imines for single electron alkylation
and provides direct access
to
N
-
alkyl
heterobenzylic amines
. In this report, we describe the
development of this method, which provides access to a variety
of heterobenzylic
N
-
alkylamines in good yields
.
Figure 1.
Context for development of Ni
-
catalyzed reductive imine alkylation.
N
N
N
CF
3
N
H
N
H
F
F
O
N
N
F
3
C
F
F
H
H
S
Me
Lenacapavir (Gilead)
HIV capsid inhibitor
N
N
N
HN
alkyl
NiCl
2
·
dme (5 mol %)
Mn
0
(1.0 equiv)
TMSCl (2.0 equiv)
NMP,
23 ºC
R
3
X
+
R
3
alkyl
R
2
R
2
Het
Het
(a) Examples of pharmaceutically relevant heterobenzylic amines
direct access to
N
-alkyl amines
mild conditions
> 40 examples
N
Me
N
H
N
HN
O
N
H
CN
Glasdegib (Pfizer)
anticancer
R
1
N
R
2
SO
2
Me
Me
Me
(b) Approaches to imine alkylation
(c) This work: Ni-catalyzed cross-coupling of redox-active imines
Cl
O
O
M–R
3
2e
–
approach
R
1
N
R
2
1e
–
approach
R
3
R
1
HN
R
2
1e
–
approach
1,2-addition of
polar nucleophiles
1,2-addition of
radicals
reduction to
α
-amino
radical
X
R
3
R
2
= Ar, CO
2
R, PO(OR)
2
, SO
2
R, OR, NR
2
2
Conjugated nitrogen ligands such as diiminopyridines,
a
-
diimines, and bi
-
and terpyridines can be electronically non
-
innocent: their π
-
systems are able to accept one or two electrons
whe
n bound to first
-
row transition metals
.
11
For example,
spectroscopic, electrochemical, and computational investigations
conducted by Wieghardt and coworkers demonstrated that low
-
valent Cr, Mn, Fe, Co, Ni, and Zn bis(2
-
imino)pyridine complexes
possess liga
nd
-
centered radicals (Figure 2a).
12
Although the
alkylation of ligand backbones has been observed previously,
13
this reactivity has not been leveraged for a catalytic cross
-
coupling.
We hypothesized that these redox
-
active complexes could be
considered p
ersistent
α
-
amino radicals, which might react with
alkyl radicals to give metal
-
coordinated imine alkylation products
(Figure 2b,
I
to
II
). This process could be rendered catalytic if 1)
the alkylated product
-
metal complex
II
could activate a C(sp
3
)
electrophile to generate an alkyl radical, 2) the product could be
liberated from complex
III
by exchange with imine
1
, and 3) the
bis(2
-
imino
heterocycle)M
II
X
2
complex
IV
could be reduced by a
terminal reductant to regenerate the low
-
valent complex
I
. We
envisioned that turnover might be facilitated by a Brönsted acid
(H
–
X) or electrophilic reagent (E
–
X) able to sequester the anionic
nitrogen of
III
.
Figure 2. (a) Redox activity of bis(2
-
imino)pyridine
transition metal complexes
as candidates for catalysts. (b) Mechanistic framework for catalytic reaction
design.
Our investigations commenced with the coupling between
(
E
)
-
N
-
isopropyl
-
1
-
(pyridin
-
2
-
yl)methanimine
(
1a
) and benzyl bromide
(
2a
) in the presenc
e of Mn
0
as a stoichiometric reductant, NMP
as the solvent, and TMSCl as an additive. Product
3a
was formed
in varying yields for a series of metal dihalide salts (Table 1,
entries 1
–
6). Of the metal
s
evaluated, NiCl
2
·dme was found to be
optimal, providing
3a
in 87% yield (Table 1, entry 1).
Interestingly,
when TMSCl is used, the reaction proceeds in the absence of
Table 1. Optimization of Reaction Conditions
a
entry
M catalyst
deviation from standard conditions
yield
(%)
b
1
NiCl
2
·dme
none
87
2
CrCl
2
none
25
3
FeBr
2
none
50
4
ZnCl
2
none
62
5
CoCl
2
none
80
6
MnCl
2
none
68
7
none
none
66
8
none
no TMSCl
19
9
NiCl
2
·dme
no TMSCl
39
10
NiCl
2
·dme
NMP/HFIP (4:1), no TMSCl
67
11
NiCl
2
·dme
AcOH (1 eq), no TMSCl
69
12
NiCl
2
·dme
Zn
0
(2 eq), no
Mn
0
45
13
NiCl
2
·dme
TDAE (1.5 eq), no Mn
0
12
14
NiCl
2
·dme
1 mol % catalyst
83
15
NiCl
2
·dme
0.1 mol % catalyst
62
16
c,d
NiCl
2
·dme
Zn anode, RVC cathode, TBAPF
6
(1
eq), 20 mA, no Mn
0
or TMSCl
76
17
c,d
MnCl
2
Zn anode, RVC cathode, TBAPF
6
(1
eq), 20
mA, no Mn
0
or TMSCl
23
a
Reactions conducted under inert atmosphere on 0.3 mmol scale.
b
Determined
by
1
H NMR versus an internal standard.
c
1.2 mmol scale.
d
1.5 eq of
2a
.
exogenous catalyst (Table 1, entry 7).
It is likely that the
combination of
Mn0
and TMS
Cl generates MnCl
2
, which was
previously shown by Wieghardt
12
to form a redox
-
active complex
with a similar heteroaryl imine.
Use of
MnCl
2
gives no
improvement over just Mn
0
, and provides
3a
in lower yield than
NiCl
2
·dme
(entry 6).
12
,
14
,
15
When TMSCl was omitted from the
reaction,
3a
was formed in only 39% yield (entry 9). Protic
additives such as hexafluoroisopropanol (HFIP) (entry 10) and
AcOH (entry 11) were also beneficial, but inferior to TMSCl.
A
lternative
reductants
such as
Zn
0
and tetrakis(
N,N
-
dimethylamino)ethylene (TDAE) did not perform as well as Mn
0
(entries 12
–
13). The catalyst loading could be dropped to 1 mol %
with only a small decrease in yield (entry 14); however, lowering
the catalyst loading to 0.1 mol % significantly reduced the yield
and showed no improvement over the background Mn
-
mediated
reaction (entry 15 vs. entry 7).
To investigate the reaction in the
absence of Mn
0
, a constant current electrolysis protocol was
explored for both Ni and Mn salts. The Ni
-
catalyzed electrolysis
N
N
N
HN
i
Pr
M (5 mol %)
Mn
0
(1.0 equiv)
TMSCl (2.0 equiv)
NMP (0.4 M)
23 ºC
, 14 h
Ph
Br
+
Ph
i
Pr
1a
(1.0 equiv)
2a
(1.2 equiv)
3a
N
N
Ar
M
II
N
N
Ar
N
N
Ar
M
0
N
N
Ar
Ar =
i
Pr
i
Pr
M = Cr, Mn, Fe, Co, Ni, Zn
(a) Previously studied redox-active
α
-iminopyridine complexes
(b) Mechanistic hypothesis for catalytic reductive alkylation
2 e
–
2 X
–
I
M
II
N
N
N
X
X
R
1
N
R
1
IV
I
M
II
N
N
R
1
N
R
1
N
II
M
I
N
N
R
1
N
N
R
1
R
3
R
2
III
M
II
N
N
R
1
N
N
R
1
R
3
R
2
X
reduction
radical
addition
H
R
2
R
3
SET
X
R
2
R
3
1
+
E–X
3
–
E
ligand
exchange
3
Scheme 1. Substrate Scope
.
Reactions
were
conducted under inert atmosphere on 0.3 mmol scale with isolated yields reported as average of 2 runs.
b
1.0 mmol
scale.
c
50% yield of homocoupling product 1a’.
N
N
N
HN
R
1
NiCl
2
·
dme
(5 mol%)
Mn
0
(1.0 equiv)
TMSCl (2.0 equiv)
NMP (0.4 M)
23 °C, 14 h
+
R
3
R
1
Het
Het
1
(1.0 equiv)
2
(1.2 equiv)
3
or
4
imine substitution (X = Br)
3l
42% yield
N
HN
Bn
N
HN
Bn
Me
N
HN
Bn
Cl
3i
74% yield
3j
65% yield
3k
72% yield
3h
50% yield
N
HN
Bn
Me
MeO
HN
Bn
Me
HN
Bn
HN
Bn
3a
76% yield
(74% yield)
a
3b
74% yield
3d
67% yield
HN
Bn
3e
70% yield
HN
Bn
Me
3f
54% yield
1.8:1 dr
HN
Bn
Me
Me
Me
3c
76% yield
N
HN
Bn
3r
50% yield
HN
Bn
N
N
Me
HN
Bn
3p
52% yield
S
N
3o
74% yield
3q
48% yield
HN
Bn
N
N
N
N
N
N
N
N
pyridine substitution (X = Br)
N
HN
Bn
OMe
heteroaryl imines (X = Br)
ketimine
3g
37% yield
N
HN
Bn
Me
3m
44% yield
N
HN
Bn
3n
59% yield
N
HN
Bn
F
F
Me
Me
Me
Me
X
R
3
R
2
R
2
benzyl bromides (X = Br)
NH
4d
76% yield
N
Me
NH
4e
70% yield
N
Me
Me
NH
4f
67% yield
N
I
NH
4g
70% yield
N
Br
OMe
NH
4h
72% yield
N
NH
4i
46% yield
N
Br
OMe
CN
NH
Bn
3b
72% yield
N
benzyl chlorides (X = Cl)
NH
4j
76% yield
N
F
NH
4k
44% yield
1.4:1 dr
N
Ph
Me
N
NH
i
Pr
1a’
1:1 dr
benzyl bromides (X = Br)
NH
4a
72% yield
N
Cl
NH
4b
69% yield
N
CO
2
Me
NH
4c
67% yield
N
CN
CCDC 2079525
i
Pr
HN
N
R
1
=
i
Pr
R
1
=
n
Bu
X
O
X
X = I, R
1
=
n
Bu (
4l
), 57% yield
X = Br, R
1
=
n
Bu (
4l
), 32% yield
X = CONHP, R
1
=
n
Bu (
4l
), 44% yield
X = I, R
1
=
i
Pr (
4m
), 45% yield
b
X = CONHP, R
1
=
i
Pr (
4m
), 41% yield
NH
N
R
1
NH
N
R
1
O
BocN
X
NH
N
R
1
NBoc
X = I, R
1
=
n
Bu (
4n
),
30% yield
X = CONHP, R
1
=
i
Pr (
4o
),
52% yield
X
NH
N
4r
X = CONHP, 59% yield
X = I, R
1
=
n
Bu (
4p
),
80% yield
X = CONHP, R
1
=
i
Pr (
4q
),
51% yield
sec-alkyl electrophiles
O
O
4
provided
3a
in good yield (entry 16) while the Mn
-
cata
lyzed
reaction provided drastically lower yield of
3a
(entry 17).
Although
the reaction could be performed with just Mn
0
, the addition of
NiCl
2
·dme resulted in higher yields of the imine alkylation product.
As a result, the conditions from entry 1 were use
d to evaluate the
scope of the reaction
using Mn
0
as the terminal reductant
.
The scope of the heteroaryl imine coupling partner was
investigated using benzyl bromide as the electrophile (Scheme 1).
Sterically diverse
N
-
substitution on the imine was well to
lerated,
affording the products containing
n
Bu,
i
Pr, and
t
Bu groups in high
yields (
3a
–
3c
). Imines bearing cyclopropyl and cyclobutyl groups,
two increasingly popular fragments in drug development,
16
provided the coupled products in 67% yield (
3d
) and 70% yield
(
3e
), respectively. Use of the chiral imine derived from (
R
)
-
1
-
phenylethylamine gave product
3f
in good yield, albeit with poor
diastereoselectivity. The use of a ketimine substrate did result
in
product formation (
3g
); however, the yield was low, likely due to
the increased steric hindrance at the site of C
–
C bond formation.
Electron donating substituents at the 4
-
and 5
-
position of the
pyridine were tolerated, furnishing the desired products
in
generally good yields (
3i
–
3k
).
Substitution at the 6
-
position
afforded the products in lower yields (
3h
and
3m
), possibly
because the substituent hinders coordination of the imine to the
Ni
-
catalyst. In general, substrates bearing electron withdrawing
g
roups at the 5
-
position gave lower yields of the product.
In
addition to 2
-
iminopyridines, several other heterocyclic imines can
be employed, including the corresponding benzimidazole (
3o
),
thiazole (
3p
), pyrimidine (
3q
), and quinoline (
3r
).
A range of su
bstituted benzylic bromides could be coupled
with imine
1a
. Ortho
-
substituted benzylic bromides coupled
smoothly, affording products
4d
–
4g
in good yield. In addition, the
reaction exhibits chemoselectivity for the benzylic halide in the
presence of aryl i
odides and bromides (
4f
and
4g
); these
functionalities are frequently incompatible with standard
organometallic reagents. Benzylic chlorides perform comparably
under standard reaction conditions (
3b
, X = Cl and
4j
). A
secondary benzylic chloride also under
went the alkylation,
although in reduced yield and with poor diastereoselectivity (
4k
).
Non
-
benzylic alkyl halides were also investigated (Scheme 1),
which revealed that the reaction yield is influenced by the identity
of both the imine and the alkyl elect
rophile.
N
-
n
Bu imine
1b
could
be coupled with cyclohexyl iodide and cyclohexyl bromide to
furnish
4l
in 57% yield and 32% yield, respectively. Coupling of
the
N
-
i
Pr imine (
1a
) with cyclohexyl iodide gave
4m
in 45% yield;
however, it was accompanied by 50% yield of the imine
homocoupling product
1a’
.
17
In contrast, use of the corresponding
N
-
hydroxyphthalimide (NHP) ester
18
gave
4m
in 41% yield but
with minimal formation of
1a’
. Reaction of
1a
or
1b
with pyra
nyl
and piperdinyl electrophiles furnished products
4n
–
4q
in modest
to good yields. Taken together, these scope studies demonstrate
a generally high tolerance for nitrile, ketone, ester, and halide
functional groups, which are often incompatible with
organ
omagnesium and organolithium reagents.
Given
that
deleterious imine homodimerization
was observed
in some reactions when
Mn
0
was used as a reductant (Table S1),
we sought to drive the reaction electrochemically to eliminate the
need for Mn
0
.
Moreover, an
electroreductive system removes the
mechanistic ambiguity about the identity of the active catalyst (Ni
vs. Mn). Under
constant current electrolysis
using
reticulated
vitreous carbon (RVC) foam as the cathode and Zn
0
metal as a
sacrificial anode, alkylatio
n of
1a
with
2a
proceeded smoothly
(Scheme
2
). We were pleased to find that several substrates that
gave low yields under the
Mn
0
conditions performed better under
the electroreductive conditions. For example, when
1a
was
coupled with
iodocyclohexane under
standard conditions, product
4m
was formed in 45% yield and was accompanied by 50% yield
(Figure S2) of imine dimer
1a’
(see Scheme 1). Under the
electroreductive conditions,
4m
was produced in 59% yield on a
1.2 mmol scale; no
1a’
was observed.
Alkylation
products from
primary
(
4s
,
4v
, and
4w
)
and tertiary
(
4u
)
iodides, could also be
formed in good yield under the electroreductive conditions
(Scheme 2)
. Both reactions proceeded in <20% yield when Mn
0
was used as a reductant.
Scheme 2. Represe
ntative scope of electroreductive imine alkylation.
Reactions
conducted under inert atmosphere on a 1.2 mmol scale.
Since the electroreductive coupling demonstrates that Ni salts
can catalyze the alkylation of 2
-
iminopyridines, we carried out a
series of
mechanistic experiments studying the Ni system.
Initial
mechanistic investigations focused on the substrate
-
catalyst
complexes proposed to be key catalytic intermediates (Scheme
3
). Non
-
chelating substrates like
benzaldehyde
-
derived imine
5
and
isomeric py
ridyl imine
6
failed to couple under standard
conditions, demonstrating
the importance of forming a bidentate
substrate
-
metal complex
(Scheme
3
a).
Bis(2
-
iminopyridine)·Ni
complex
9
was prepared by the
addition of imine
1a
(2.0 equiv) to
Ni(cod)
2
(1.0
equiv);
12
subsequent addition of benzyl bromide
provided
3a
in 53% yield, providing support for reduced Ni
complex
9
as a competent species in the c
atalytic cycle (Scheme
3
b).
In agreement with Wieghardt and coworkers,
12
computational
studies suggest that the electronic structure of the formally
Ni
0
complex
9
is best described as a Ni
II
center with
antiferromagnetically coupled ligand
-
based radicals. DFT
calculations of
9
at the B3LYP/def2
-
TZVP level of theory show the
N
N
N
HN
i
Pr
+
TBAPF
6
(1.0 equiv)
NMP (0.4 M)
20 mA,
23 °C
, 6 h
1.2 mmol scale
NiCl
2
·dme (10 mol %)
Zn
RVC
i
Pr
1a or 1p
(1.0 equiv)
3a
X = Br
73% yield
Het
Het
N
HN
i
Pr
Ph
N
HN
i
Pr
4m
X = I
59% yield
N
HN
i
Pr
4s
X = I
51% yield
Ph
4u
X = I
53% yield
N
HN
i
Pr
2
(1.5 equiv)
3a or 4
Me
Me
Me
N
HN
i
Pr
NBoc
4o
X = I
43% yield
N
HN
i
Pr
4t
X = I
60% yield
S
S
X
R
2
R
1
R
1
R
2
N
HN
i
Pr
4v
X = I
53% yield
O
O
N
HN
i
Pr
CF
3
4w
X = I
49% yield
5
broken symmetry solution BS(2,2) being lower in energy than the
closed
-
shell or
high spin solutions (Scheme
3
c).
19
,
20
A qualitative
molecular orbital diagram of the magnetic orbitals reveals seven
orbitals with significant d contribution (Figure S30). Upon closer
examination of the electronic structure, there are two ligand
-
based SOM
Os as the imine
π
* orbitals (Scheme
3
d). Using the
Yamaguchi equation, the spin
-
spin coupling constant (
J
) between
the metal
-
based SOMOs and the ligand
-
based SOMOs was
calculated to be
J
=
–
777 cm
-
1
.
21
These data support our
hypothesis that the ligand non
-
innocence of reduced catalyst
-
substrate complexes such as
9
allows for facile access to
persistent
α
-
amino radical intermediates (Figure 2b).
Scheme
3
. Investigation of Ni
–
substrate complexes
.
a
Spin
density plot of
9
with
Loewdin spin population values for atoms with significant radical character.
b
Qualitative MO diagram of BS(2,2)
9
and corresponding magnetic orbitals with
corresponding spatial overlap (
S
) for orbitals with
S
< 0.999.
We sought to i
nvestigate the redox properties of (
1a
)
2
NiCl
2
(
10
) to confirm that reduction to the low
-
valent complex
9
is
possible under the reaction conditions. Using cyclic voltammetry
(CV), the reduction potential of free
1a
was compared to the
reduction potentials o
f corresponding
in situ
generated complexes
(
1a
)
2
NiCl
2
(
10
) and (
1a
)
2
MnCl
2
(
11
) (Figure 3a). Complex
11
(E
1/2
=
–
1.82 V vs. Fc/Fc
+
in NMP) is more challenging to reduce than
Ni complex
10
(E
1/2
=
–
1.43 V vs. Fc/Fc
+
in NMP). The free imine
1a
has a reduction potential (E
p/2
) of
–
2.65 V vs. Fc/Fc
+
in NMP,
which is significantly more negative than that of either complex
10
or
11
. Complexation of
1a
with a non
-
redox
-
active Lewis acid
such as MgBr
2
does not significantly
change the potential of imine
reduction (E
p/2
=
–
2.55 V vs. Fc/Fc
+
in NMP) (Figure 3a). The
significant anodic shift of the reduction potentials and the
increased reversibility of the redox events demonstrate that imine
coordination to Ni and Mn facilitat
es reduction and stabilizes the
ligand
-
centered radicals.
We note that reduction of
10
is
420 mV
more anodic than
11
indicating the formation of proposed
intermediate
I
(Figure 2b) is more thermodynamically favorable,
which may correlate with the improved
product yields when
catalytic Ni is included.
It was unclear from the CV alone whether the observed
reduction of (
1a
)
2
NiCl
2
(
10
) corresponded to a one
-
electron or a
two
-
electron process.
22
To investigate the identity of the species
generated upon reductio
n, UV/Vis spectroelectrochemical
analysis of
10
was performed at varying potentials (Figure S24).
At
–
1.4 V vs. Fc/Fc
+
, a species develops with a UV/Vis spectrum
that is consistent with that of an independently prepared sample
of (
1a
)
2
Ni (
9
)
(Figure 3b). A
lternatively, mixing 1 equiv each of
9
and
10
results in comproportionation to the Ni
I
complex; this
species has a different spectroscopic profile, and consistent with
Wieghardt’s prior studies,
12
computational and EPR studies
suggest that this complex does have not significant radical
character on the ligand backbone (Figure S3). These experiments
suggest that at potentials accessible under the catalytic reaction
conditions, complex
10
undergoes t
wo electron reduction to
generate
9
.
23
,
24
To probe whether reductively generated
9
can react with alkyl
electrophiles, CVs of complex
10
in the presence of benzyl
chloride were acquired. Scanning in the negative direction, the
CV of a mixture of
10
(1 equiv) and benzyl chloride (100 equiv)
shows a cathodic shift and increase in peak current relative to
complex
10
alone (Figure 3c). The ca
thodic shift indicates that,
upon reduction, complex
10
does not react with benzyl chloride
through a simple EC mechanism, but instead through a
mechanism that likely involves intermediate chemicals steps such
as loss of chloride ligands. Kinetic analysis
of the reaction with
benzyl chloride reveals a second order rate constant k = 1.8x10
-
1
M
-
1
s
-
1
(Supporting Information section 6.3).
25
Addition of AcOH
(150 equiv) and additional
1a
(50 equiv) results in a catalytic wave
(Figure 3c) that is not observed in
the absence of BnCl or excess
1a
(Figure S13). AcOH was used for these studies because it was
found to give reasonable alkylation yields (Table 1, entry 11) and
had greater stability than TMSCl in the electrochemical cell.
N
HN
i
Pr
Bn
3a
53% yield
(0.053 mmol)
BnBr
(1 equiv)
Ni(cod)
2
NMP, 23 ºC
0.1 mmol
1a
(2 equiv)
(
1a
)
2
Ni
9
in situ
23 ºC, 14 h
(b) Stoichiometric Ni
0
reaction
X
Y
N
X
Y
HN
i
Pr
Bn
NiCl
2
·
dme (5 mol %)
Mn
0
(1.0 equiv)
TMSCl (2.0 equiv)
NMP, 23 ºC, 20 h
Ph
Br
+
i
Pr
5
, X=Y=C
6
, X=C,Y=N
(1.0 equiv)
2a
(1.2 equiv)
7
, 0% yield
8
, 0% yield
(a) Probing the role of bidentate coordination
+ 1.25
- 0.10
- 0.08
-0.19
- 0.11
- 0.10
- 0.07
- 0.20
- 0.12
9
N
N
i
Pr
Ni
II
N
N
i
Pr
(c) Electronic structure of
9
as non-Innocent complex
a
9
N
N
i
Pr
Ni
0
N
N
i
Pr
S = 0.63
Ligand
π
*
(d) Metal and ligand-based SOMOs of
9
b
S = 0.35
6
Figure 3. Electroanalytical investigations. (a) CV of
1a
(blue) and complexes
with Ni (1 mM NiCl
2
·dme and 20 mM
1a
, purple), Mn (1 mM MnCl
2
and 20 mM
[
1
]
a)
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,
Cambridge University Press,
2004
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1a
, green) and Mg (2 mM
MgCl
2
and 100mM
1a
, orange). CVs measured with
0.1 M TBAPF
6
in NMP at 25°C with 100 mV/s scan rate. (b) UV/Vis spectra of
10
(blue);
10
after holding at
–
1.4 V (vs. Fc/Fc
+
; 0.1 M TBAPF
6
in NMP, purple)
for 2.5 minutes; independently synthesized
9
(teal); N
i
I
complex obtained from
comproportionation of
9
and
10
(orange,
9
ox
). Spectra were baseline corrected
to be zero at 860 nm, and * indicates signal saturation inherent to the light
source and detector used for the experiment. Inset: enlargement of 400
–
800
nm
region for
10
. See Supporting Information for individual spectra and calculations
of ε. (c)
10
(1.0 mM, blue);
10
with 100 mM benzyl chloride (green)
;
10
with 40
mM
1a
and 150 mM AcOH (purple).
CVs acquired with 0.1 M TBAPF
6
in NMP
at 25°C with
5
0 mV/s
scan rate.
In conclusion, the
Ni
-
catalyzed reductive cross
-
coupling of (2
-
imino)heterocycles
with C(sp
3
) alkyl electrophiles has been
reported. The reaction occurs under mild conditions and is
tolerant of a variety of functional groups, including
N
-
and
S
-
heterocyclic imine coupling partners. Mechanistic studies support
the formation of low
-
valent bis(2
-
imino)pyridine·Ni complexes as
persistent ligand
-
centered radical species that can react with alkyl
electrophiles and be leveraged for catalytic C
–
C bond fo
rmation.
Acknowledgements
Dr. Scott Virgil and the Caltech Center for Catalysis and Chemical
Synthesis are gratefully acknowledged for access to analytical
equipment. Fellowship support was provided by the Swiss
National Science Foundation (M. B.). S.E.R.
is a Heritage Medical
Research Institute Investigator and acknowledges financial
support from the NIH (R35GM118191). The authors would also
like to thank Dr. Nathan Dalleska and the Resnick Sustainability
Institute’s Water and Environmental Lab for elemen
tal analysis of
commercial manganese; Dr. Mona Shahgholi for assistance with
mass spectrometry measurements; Dr. Paul Oyala for assistance
with X
-
band EPR measurements; Dr. David E. Hill for invaluable
assistance with electroanalytical and spectroelectroc
hemical
experiments; as well as Z. Jaron Tong for helpful discussions on
DFT calculations and non
-
innocent ligand complexes.
Keywords:
imine alkylation
•
cross
-
electrophile coupling
•
nickel
-
catalyzed
•
electroredutive
•
redox non
-
innocent
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J.
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For a recent
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N
-
alkyliminium ions,
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Nature
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581
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420.
-0.035
-0.025
-0.015
-0.005
0.005
-1.7
-1.6
-1.5
-1.4
-1.3
-1.2
Current (mA)
Potential (V) vs Fc
+
/Fc
10
10 + BnCl
10 + BnCl + 1a + AcOH
0
2000
4000
6000
8000
10000
300
400
500
600
700
800
ε
(M^
-
1cm^
-
1)
λ
(nm)
10
9
9 + 10
10 at -1.4 V
0
10
20
30
40
50
400
500
600
700
800
ε
(M^
-
1cm^
-
1)
λ
(nm)
-3.0
-2.8
-2.6
-2.4
-2.2
-2.0
-1.8
-1.6
-1.4
-1.2
-1.0
Potential (V) vs Fc
+
/Fc
(a) Reduction potentials
(c) Change with reaction components
(b) UV/Vis spectroelectrochemistry
N
N
i
Pr
1a
E
p/2
= –2.60 V
1a
+ MgBr
2
1a
+ MnCl
2
1a
+ NiCl
2
•dme
E
p/2
= –2.55 V
E
1/2
= –1.82 V
E
1/2
= –1.43 V
10
11
*
*
7
[
8
]
For a review on the use of photoredox catalysis to generate
α
-
amino
radicals from imines, see:
J. A. Leitch, T. Rossolini, T. Rogova, J. A. P.
Maitland, D. J. Dixon,
ACS Catal.
2020
,
10
, 2009
–
2025.
[
9
]
For a complementary Ni
-
catalyzed imine alkylation, se
e
C. Heinz, J. P.
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]
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catalyzed addition of free radicals to glyoxylate
-
derived
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S. Ni, A. F. Garrido
-
Castro, R. R. Merchant, J. N.
de Gruyter, D. C. Schmitt, J. J. Mousseau, G. M. Gallego, S. Yang, M.
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Trace metal analysis by ICP
-
MS found that the Mn
0
source contains 54
ppm total Ni species. However, this would
represent a very low
concentration of Ni catalyst (<0.005 mol %). See Supporting Information
section 11 for ICP
-
MS sample preparation and calculations.
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[
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]
Less reactive alkyl halides with hindered imines produce varying
quantities of
1a’
(see Figure S2 for
1a’
production across several
substrates). Using a radical precursor that is more facile to reduce, like
NHP esters, enhances the rate of alkyl radical ge
neration and favors
cross
-
coupling over sp
2
–
sp
2
homocoupling. For examples, see: (a)
V.
Faugeroux, Y. Genisson,
Current Organic Chemistry
2008
,
12
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N. Yan, K. Yamanishi, Y.
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[
19
]
For additional investigations into the
electronic structure of redox
-
active
first
-
row transition metal bis
-
iminopyridine complexes, see reference 12
as well as: a
)
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,
53
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[
20
]
DFT calculations were performed using the ORCA software package at
the B3LYP/def2
-
TZVP level of theory. See Supporting Information for
optimization, frequency, broken symmetry, and property calculations.
[
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[
22
]
The peak
-
to
-
peak separation was determined to be ~106 mV for
10
.
Given this deviation from theoretical, we cannot draw a
conclusion from
the CV alone about whether the reduction is a one or two electron
process.
[
23
]
Mn
0
(S)
-
> Mn
II
(NMP)
is estimated to be ~
–
1.8 V vs. Fc/Fc
+
by converting
the known value of
–
1.185 V vs. SHE for Mn to Mn
II
. The reduction of
10
was found to occ
ur at
–
1.4 V vs. Fc/Fc
+
, and therefore should be in the
reducing window of Mn
0
. (a) For standard reduction potential values,
see:
W. M. Haynes,
CRC Handbook of Chemistry and Physics.
[Electronic Resource] : A Ready
-
Reference Book of Chemical and
Physical Data.
, CRC Press,
2018
.
b) For converting SCE potentials to
0.1 M TBAPF
6
in DMF vs. Fc/Fc
+
, see: Q. Lin, G. Dawson, T. Diao,
Synlett
2021
,
32
, 1606
–
1620.
[
24
]
The facile two electron reduction of
10
is in contrast to recent studies of
(Phen)NiBr
2
c
omplexes, which undergo one electron reduction at similar
potentials
:
Q. Lin, T. Diao,
J. Am. Chem. Soc.
2019
,
141
, 17937
–
17948.
[
25
]
C. Sandford, L. R. Fries, T. E. Ball, S. D. Minteer, M. S. Sigman,
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Chem. Soc.
2019
,
141
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–
18889.
Entry for the Table of Contents
A Ni
-
catalyzed
reductive cross
-
coupling of heteroaryl imines with
C(sp
3
) electrophiles for the preparation of heterobenzylic amines
is reported.
Mechanistic studies are consistent with the imine
substrate acting as a redox
-
active ligand upon coordination to a
low
-
valent
Ni
center.
Institute and/or researc
her Twitter usernames:
@
sarah_reisman
TOC Graphic
N
N
N
HN
R
1
R
3
X
R
3
R
1
R
2
R
2
Het
Het
Ni
II
N
R
1
N
Het
N
N
R
1
Het
+
harnessing ligand non-innonence for imine alkylation
abundant alkyl electrophiles
mild conditions
electroreductive variant