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Nickel-Catalyzed Reductive Alkylation of Heteroaryl Imines
Raymond F. Turro
,
Marco Brandstätter
,
Sarah 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
Abstract
The preparation of heterobenzylic amines by a Ni-catalyzed reductive cross-coupling between
heteroaryl imines and C(sp
3
) electrophiles is reported. This umpolung-type alkylation proceeds
under mild conditions, avoids the pre-generation of organometallic reagents, and exhibits 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 reactions with a variety of C(sp
3
)
electrophiles, giving heterobenzylic amine products in good yields.
Graphical Abstract
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.
Keywords
cross-coupling; electrochemistry; imines; nickel-catalysis; alkylation
reisman@caltech.edu .
These authors contributed equally to this work.
This paper is dedicated in memory of our colleague and friend Prof. Robert H. Grubbs.
Institute and/or researcher Twitter usernames: @sarah_reisman
HHS Public Access
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. Author manuscript; available in PMC 2023 September 19.
Published in final edited form as:
Angew Chem Int Ed Engl
. 2022 September 19; 61(38): e202207597. doi:10.1002/anie.202207597.
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Introduction
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 structural 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 organometallic 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,
α
-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
α
-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 imines,
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 by the equivalent of a C(sp
3
)–
C(sp
3
) coupling reaction. In this report, we describe the development of this method, which
provides access to a variety of heterobenzylic
N
-alkylamines in good yields.
Conjugated nitrogen ligands such as diiminopyridines,
α
-diimines, and bi- and terpyridines
can be electronically non-innocent: their
π
-systems are able to accept one or two electrons
when 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 ligand-
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 persistent
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-iminoheterocycle)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
.
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Results and Discussion
Our investigations commenced with the coupling between (
E
)-
N
-isopropyl-1-(pyridin-2-
yl)methanimine (
1a
) and benzyl bromide (
2a
) in the presence of Mn
0
as a stoichiometric
reductant,
N-
methylpyrrolidone (NMP) as the solvent, and trimethylsilyl chloride (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 metals 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 exogenous catalyst (Table 1, entry 7). It is likely that
the combination of Mn
0
and TMSCl 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).
13
,
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.
16
Alternative 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 provided
3a
in good yield (entry 16) while the Mn-catalyzed
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 used 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
tolerated, 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,
17
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 groups 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
).
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A range of substituted 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 iodides
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 underwent 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 electrophile.
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’
.
18
19
In contrast, use of the corresponding
N
-hydroxyphthalimide
(NHP) ester
20
gave
4m
in 41% yield but with minimal formation of
1a’
. Reaction of
1a
or
1b
with pyranyl 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
organomagnesium 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, alkylation 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.
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 pyridyl imine
6
failed to couple under standard
conditions, demonstrating the importance of forming a bidentate substrate-metal complex
(Scheme 3a). 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
catalytic cycle (Scheme 3b).
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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 broken symmetry solution BS(2,2) being lower in
energy than the closed-shell or high spin solutions (Scheme 3c).
21
,
22
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 singly-occupied molecular orbitals (SOMOs) as the imine
π
* orbitals (Scheme 3d).
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
.
23
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).
We sought to investigate 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 of 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 facilitates 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.
24
To investigate the identity of
the species generated upon reduction, 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). Alternatively, 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 two electron reduction to generate
9
.
25
,
26
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 cathodic shift
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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 = 1.8×10
−1
M
−1
s
−1
(Supporting Information
section 6.3).
27
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.
Conclusion
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 formation.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
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. 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 elemental
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 spectroelectrochemical experiments; as well as Z. Jaron Tong for helpful discussions on DFT
calculations and non-innocent ligand complexes.
References
1. a)Lawrence SA, Amines
: Synthesis, Properties and Applications, Cambridge University Press,
2004;b)Lewis JR, Nat. Prod. Rep 2001, 18, 95–128; [PubMed: 11245403] c)Carey JS, Laffan D,
Thomson C, Williams MT, Org. Biomol. Chem 2006, 4, 2337–2347; [PubMed: 16763676] d)Hili R,
Yudin AK, Nat Chem Biol 2006, 2, 284–287. [PubMed: 16710330]
2. Link JO, Rhee MS, Tse WC, Zheng J, Somoza JR, Rowe W, Begley R, Chiu A, Mulato A, Hansen
D, Singer E, Tsai LK, Bam RA, Chou C-H, Canales E, Brizgys G, Zhang JR, Li J, Graupe M,
Morganelli P, Liu Q, Wu Q, Halcomb RL, Saito RD, Schroeder SD, Lazerwith SE, Bondy S, Jin
D, Hung M, Novikov N, Liu X, Villaseñor AG, Cannizzaro CE, Hu EY, Anderson RL, Appleby
TC, Lu B, Mwangi J, Liclican A, Niedziela-Majka A, Papalia GA, Wong MH, Leavitt SA, Xu Y,
Koditek D, Stepan GJ, Yu H, Pagratis N, Clancy S, Ahmadyar S, Cai TZ, Sellers S, Wolckenhauer
SA, Ling J, Callebaut C, Margot N, Ram RR, Liu Y-P, Hyland R, Sinclair GI, Ruane PJ, Crofoot
GE, McDonald CK, Brainard DM, Lad L, Swaminathan S, Sundquist WI, Sakowicz R, Chester AE,
Lee WE, Daar ES, Yant SR, Cihlar T, Nature 2020, 584, 614–618. [PubMed: 32612233]
3. Munchhof MJ, Li Q, Shavnya A, Borzillo GV, Boyden TL, Jones CS, LaGreca SD, Martinez-Alsina
L, Patel N, Pelletier K, Reiter LA, Robbins MD, Tkalcevic GT, ACS Med. Chem. Lett 2012, 3,
106–111. [PubMed: 24900436]
Turro et al.
Page 6
Angew Chem Int Ed Engl
. Author manuscript; available in PMC 2023 September 19.
Author Manuscript
Author Manuscript
Author Manuscript
Author Manuscript
4. a)Bloch R, Chem. Rev 1998, 98, 1407–1438; [PubMed: 11848938] b)Marcantoni E, Petrini M, in
Comprehensive Organic Synthesis (Second Edition) (Ed.: Knochel P), Elsevier, Amsterdam, 2014,
pp. 344–364.
5. For reviews on radical additions to imines under thermal conditions, see: a) Friestad GK,
Tetrahedron 2001, 57, 5461–5496;b)Miyabe H, Yoshioka E, Kohtani S, Current Organic Chemistry
2010, 14, 1254–1264.(c)Tauber J, Imbri D, Opatz T, Molecules 2014, 19, 16190–16222. [PubMed:
25310148]
6. For reviews on addition to imines under photoredox catalysis, see: a) Cullen STJ, Friestad GK,
Synthesis 2021, 53, 2319–2341;b)Zhao J-J, Zhang H-H, Yu S, Synthesis 2021, 53, 1706–1718.
7. For a recent method involving free radical addition to N-alkyliminium ions, see: Kumar R, Flodén
NJ, Whitehurst WG, Gaunt MJ, Nature 2020, 581, 415–420. [PubMed: 32268340]
8. For a review on the use of photoredox catalysis to generate
α
-amino radicals from imines, see:
Leitch JA, Rossolini T, Rogova T, Maitland JAP, Dixon DJ, ACS Catal 2020, 10, 2009–2025.
9. For a complementary Ni-catalyzed imine alkylation, see Heinz C, Lutz JP, Simmons EM, Miller
MM, Ewing WR, Doyle AG, J. Am. Chem. Soc 2018, 140, 2292–2300. [PubMed: 29341599]
10. For a Ni-catalyzed addition of free radicals to glyoxylate-derived sulfinnimines, see: Ni S, Garrido-
Castro AF, Merchant RR, de Gruyter JN, Schmitt DC, Mousseau JJ, Gallego GM, Yang S, Collins
MR, Qiao JX, Yeung K-S, Langley DR, Poss MA, Scola PM, Qin T, Baran PS, Angew. Chem. Int.
Ed 2018, 57, 14560–14565.
11. (a)Jacquet J, Desage-El Murr M, Fensterbank L, ChemCatChem 2016, 8, 3310–3316;b)Luca OR,
Crabtree RH, Chem. Soc. Rev 2013, 42, 1440–1459; [PubMed: 22975722] c)Praneeth VKK,
Ringenberg MR, Ward TR, Angew. Chem. Int. Ed 2012, 51, 10228–10234;d)Lyaskovskyy V, de
Bruin B, ACS Catal 2012, 2, 270–279;e)Chirik PJ, Wieghardt K, Science 2010, 327, 794–795.
[PubMed: 20150476]
12. Lu CC, Bill E, Weyhermüller T, Bothe E, Wieghardt K, J. Am. Chem. Soc 2008, 130, 3181–3197.
[PubMed: 18284242]
13. a)Bailey PJ, Dick CM, Fabre S, Parsons S, Yellowlees LJ, Dalton Trans 2006, 1602–1610;
[PubMed: 16547534] b)Riollet V, Copéret C, Basset J-M, Rousset L, Bouchu D, Grosvalet L,
Perrin M, Angew. Chem. Int. Ed 2002, 41, 3025–3027;c)Kaupp M, Stoll H, Preuss H, Kaim W,
Stahl T, Van Koten G, Wissing E, Smeets WJJ, Spek AL, J. Am. Chem. Soc 1991, 113, 5606–
5618.
14. (a)Solomon MB, Chan B, Kubiak CP, Jolliffe KA, D’Alessandro DM, Dalton Trans 2019, 48,
3704–3713; [PubMed: 30801575] b)Morrison MM, Sawyer DT, Inorg. Chem 1978, 17, 333–
337;c)Rao JM, Hughes MC, Macero DJ, Inorg. Chim. Acta 1976, 18, 127–131.
15. 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.
16. Alternative additives such as phenol, acetic anhydride, trifluoroacetic anhydride, and benzoic acid
led to no further improvement.
17. Talele TT, J. Med. Chem 2016, 59, 8712–8756. [PubMed: 27299736]
18. 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 generation and favors cross-coupling
over sp
2
–sp
2
homocoupling. For examples, see: a) Faugeroux V, Genisson Y, Current Organic
Chemistry 2008, 12, 751–773;b)Hulley EB, Wolczanski PT, Lobkovsky EB, J. Am. Chem. Soc
2011, 133, 18058–18061; [PubMed: 21999198] c)Inoue S, Yan Y-N, Yamanishi K, Kataoka Y,
Kawamoto T, Chem. Commun 2020, 56, 2829–2832;d)Pokhriyal D, Heins SP, Sifri RJ, Gentekos
DT, Coleman RE, Wolczanski PT, Cundari TR, Fors BP, Lancaster KM, MacMillan SN, Inorg.
Chem 2021, 60, 18662–18673. [PubMed: 34889590]
19. All data for X-ray crystal structures have been deposited in the CCDC, under the following
deposition numbers: 1a’ = 2079525, 10 = 2117478, 11 = 2117477
20. a)Huihui KMM, Caputo JA, Melchor Z, Olivares AM, Spiewak AM, Johnson KA, DiBenedetto
TA, Kim S, Ackerman LKG, Weix DJ, J. Am. Chem. Soc 2016, 138, 5016–5019; [PubMed:
27029833] b)Suzuki N, Hofstra JL, Poremba KE, Reisman SE, Org. Lett 2017, 19, 2150–2153;.
Turro et al.
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[PubMed: 28375631] For a recent review of Ni-catalyzed cross-couplings with NHP esters, see:
Konev MO, Jarvo ER, Angew. Chem. Int. Ed 2016, 55, 11340–11342.
21. For additional investigations into the electronic structure of redox-active first-row transition metal
bis-iminopyridine complexes, see reference
12
as well as: a) Lu CC, Bill E, Weyhermüller T,
Bothe E, Wieghardt K, Inorg. Chem 2007, 46, 7880–7889; [PubMed: 17715916] b)Mondal A,
Weyhermüller T, Wieghardt K, Chem. Commun 2009, 6098–6100;c)Tsvetkov NP, Chen C-H,
Andino JG, Lord RL, Pink M, Buell RW, Caulton KG, Inorg. Chem 2013, 52, 9511–9521;
[PubMed: 23909696] d)Sengupta D, Ghosh P, Chatterjee T, Datta H, Paul ND, Goswami S, Inorg.
Chem 2014, 53, 12002–12013. [PubMed: 25372948]
22. 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.
23. Soda T, Kitagawa Y, Onishi T, Takano Y, Shigeta Y, Nagao H, Yoshioka Y, Yamaguchi K, Chem.
Phys. Lett 2000, 319, 223–230.
24. 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.
25. Mn0(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 occur 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: Haynes WM, 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: Lin Q, Dawson G, Diao T, Synlett 2021, 32,
1606–1620.
26. The facile two electron reduction of 10 is in contrast to recent studies of (Phen)NiBr
2
complexes,
which undergo one electron reduction at similar potentials: Lin Q, Diao T, J. Am. Chem. Soc
2019, 141, 17937–17948. [PubMed: 31589820]
27. Sandford C, Fries LR, Ball TE, Minteer SD, Sigman MS, J. Am. Chem. Soc 2019, 141, 18877–
18889. [PubMed: 31698896]
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Figure 1.
Context for development of Ni-catalyzed reductive imine alkylation.
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Figure 2.
(a) Redox activity of bis(2-imino)pyridine transition metal complexes as candidates for
catalysts. (b) Mechanistic framework for catalytic reaction design.
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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
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); Ni
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 50 mV/s scan rate.
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