NiH-Catalyzed Proximal-Selective Hydroamination of Unactivated Alkenes

Article abstract of DOI:10.1021/jacs.0c10333

Reported herein is a modular, NiH-catalyzed system capable of proximal-selective hydroamination of unactivated alkenes with diverse amine sources. The key to the successful implementation of this approach is the promotion of NiH insertion into even highly substituted olefins via coordination of the bidentate directing group to the nickel complex. A wide range of primary and secondary amines can be installed in both internal and terminal unactivated alkenes with excellent regiocontrol under the optimized reaction conditions. This protocol is flexible and general for the preparation of a variety of valuable β- and γ-amino acid building blocks that would otherwise be difficult to synthesize. The utility of this transformation was further demonstrated by the site-selective late-stage modification of complex and medicinally relevant molecules. Combined experimental and computational studies illuminate the detailed reaction mechanism.

Full text of DOI:10.1021/jacs.0c10333

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NiH-Catalyzed Proximal-Selective Hydroamination of Unactivated
Alkenes
Jinwon Jeon, Changseok Lee, Huiyeong Seo, and Sungwoo Hong*
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ABSTRACT: Reported herein is a modular, NiH-catalyzed system
capable of proximal-selective hydroamination of unactivated alkenes
with diverse amine sources. The key to the successful implementation
of this approach is the promotion of NiH insertion into even highly
substituted olefins via coordination of the bidentate directing group
to the nickel complex. A wide range of primary and secondary amines
can be installed in both internal and terminal unactivated alkenes
with excellent regiocontrol under the optimized reaction conditions.
This protocol is flexible and general for the preparation of a variety of valuable β- and γ-amino acid building blocks that would
otherwise be difficult to synthesize. The utility of this transformation was further demonstrated by the site-selective late-stage
modification of complex and medicinally relevant molecules. Combined experimental and computational studies illuminate the
detailed reaction mechanism.
olefins.7d,10 Moreover, the regioselectivity in the hydroamina-
INTRODUCTION
The catalytic hydroamination of alkenes is a powerful synthetic
■
tion of unactivated internal olefins has been typically governed
by their steric7a and electronic properties,6b−f,7g,8 generating
tool for the direct installation of amino groups across alkenes to
products in an only moderately regioselective manner, thus
enable the rapid buildup of molecular complexity from abundant
limiting the generality and synthetic utility of these reactions.11
The Hartwig group demonstrated that the regioselectivity in the
hydroamination of unsymmetrical internal alkenes could be
controlled by the electronic inductive effect of a polar group on
the alkene (Scheme 1b, up).12 Nevertheless, the presence of a
polar group at the homoallylic position was required to achieve a
high regioselectivity, and the inherent inductive effect
diminished significantly at different locations, which limits the
broad applicability of this method.13 Engle et al. reported a Pd-
catalyzed regiocontrolled hydroamination utilizing an amide-
linked aminoquinoline (AQ) directing group, allowing a distal-
selective installation of various nucleophilic amino groups at the
γ-position (Scheme 1b, down).14
The NiH catalytic system has been used as a powerful tool to
enable the hydrofunctionalization of alkenes.15 For example, Fu
and Liu reported NiH-catalyzed reductive olefin hydrocarbo-
nation with anti-Markovnikov selectivity.15a In addition, the Zhu
group employed NiH catalysis to enable remote 1,n-hydro-
amination of olefins by using nitroso electrophiles.15c Despite
recent advances, proximal-selective hydroamination methods
and readily available alkenes.1 Consequently, various catalytic
systems have been developed to diversify molecular frameworks
via C−N bond-forming processes, and notable breakthroughs
have been reported in the catalytic assembly of synthetically
valuable aliphatic amines.2 Hydroamination of alkenes using
transition-metal catalysis through an intramolecular3 and
intermolecular4 manner was extensively investigated for
decades. For the efficient formation of C−N bonds, considerable
efforts have been directed toward searching various aminating
agents. The Yu group reported that electrophilic O-benzoylhy-
droxylamine reagents could be employed in Pd-catalyzed C−H
amination reactions via oxidative amination of the carbon−Pd
bond.5 Recently, Miura6 and Buchwald7 independently
demonstrated intermolecular alkene hydroamination reactions
with high levels of enantiocontrol using catalytic CuH
complexes and electrophilic aminating reagents, which is a
powerful tool to convert alkenes to primary or secondary
aliphatic amines. Despite the utility of being applicable to
styrenes,6b,7g,8 vinylsilanes,7c 1,1-disubstituted alkenes,7b un-
activated terminal alkenes,4h,7a and strained internal alkenes,6a,9
only a few examples of intermolecular hydroamination using
unactivated internal alkenes have been reported with a high level
of regioselectivity. Several factors have disturbed the advance-
ment of hydrofunctionalization of unactivated internal alkenes
using metal hydride catalysis. In particular, the hydrometalation
of unactivated internal alkenes is slower than terminal olefin
substrates by several orders of magnitude, which can cause slow
and undesired chain-walking isomerization to terminal
Received: September 28, 2020
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© XXXX American Chemical Society
A

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to convert unactivated terminal and internal alkenes into
valuable β- and γ-amino acid building blocks, and the amination
occurs at proximal sites with excellent regiocontrol (Scheme 1c).
This method has attractive features such as the use of a broad
range of amine sources and mild reaction conditions, allowing
the effective installation of various amines into challenging
olefins, including even trisubstituted alkenes. Furthermore, this
new protocol is highly effective for the site-selective late-stage
modification of complex, medicinally relevant molecules to
allow new retrosynthetic disconnections that would otherwise
be difficult to achieve.
Scheme 1. Strategies for the Site-Selective Hydroamination
of Unactivated Alkenes
RESULT AND DISCUSSION
■
To check the feasibility of the above scenario, we initiated our
studies on the regioselective hydroamination of 4-pentenoic acid
substrate 1a containing an 8-aminoquinoline (AQ) directing
group with morpholino benzoate 2a in the presence of
(EtO)2MeSiH as the hydride source (Table 1). To our delight,
a
Table 1. Optimization of the Reaction Conditions
b
Ni catalyst (10
mol %)
hydride source
(3.0 equiv)
solvent
(0.2 M)
yield
(%)
entry
1
2
3
4
5
6
7
8
NiBr2·DME
Ni(OTf)2
Ni(COD)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(acac)2
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(EtO)2MeSiH
(MeO)2MeSiH
(EtO)3SiH
THF
THF
THF
THF
MeCN
1,2-DCE
toluene
THF
THF
THF
50
79
80
90 (86)
15
65
59
64
80
65
0
that are applicable to a wide range of unactivated olefins have
proven elusive. In particular, the site-selective hydrofunctional-
ization of unactivated trisubstituted alkenes poses formidable
challenges in terms of reactivity and regiocontrol, and the
unproductive reduction of the electrophilic reagent with the
metal hydride is a common side reaction.8,9,16 In this context, it
is highly desirable to develop a general catalytic platform to
enable the proximal-selective hydroamination of various classes
of alkene and amine substrates in a predictable and controllable
manner under mild conditions. Such an approach has not been
reported, presumably due to the following issues: (1) the low
binding affinity of internal alkenes to metal centers, (2) the
difficult discrimination of similar chemical environments, and
(3) undesired chain-walking isomerization. Recently, the Zhao
and Engle groups demonstrated NiH-catalyzed Markovnikov or
anti-Markovnikov hydroarylation by using a combination of
AQ-tethered nickellacycle17b,18 and ligands.15h,18b In addition,
the carboamination of AQ-tethered olefins was successfully
achieved using electrophilic aminating reagents by the Engle
group.18c Inspired by the versatility of metal hydride chemistry
and coordinating directing groups,17 we envisioned a strategy
that takes advantage of the coordination of a bidentate directing
group on a nickel complex to promote nickel hydride insertion
into highly substituted olefins. We believe that this process is the
key to the success of our proposed proximal-selective hydro-
amination and will significantly expand the scope of alkene
substrates. In addition, the formation of a coordinated complex
would prevent the undesired competitive reduction of the
aminating reagents, making this strategy applicable to a broad
range of primary and secondary amine sources. Herein, we
report a NiH-catalyzed, regioselective hydroamination strategy
9
10
11
12
PMHS
(EtO)2MeSiH
THF
THF
THF
Ni(acac)2
Ni(acac)2
0
0
c
13
(EtO)2MeSiH
a
Reactions were performed by using 1a (0.1 mmol), 2a (0.15 mmol),
Ni catalyst (10 mol %), hydride source (0.3 mmol), Cs2CO3 (0.2
mmol), and solvent (0.5 mL) at room temperature for 24 h in a
b
silicon-septa capped test tube under Ar. Yields were determined by
c
1H NMR spectroscopy. Isolated yield in the parentheses. No
Cs2CO3. PMHS = poly(methylhydrosiloxane).
the reaction in the presence of NiBr2·DME (DME =
dimethoxyethane) as the catalyst and Cs2CO3 in tetrahydrofur-
an (THF) afforded the desired γ-amino product 3a in 50% yield
with excellent regioselectivity, and the distal δ-amino product
was not detected (entry 1). These observations suggest that the
Ni species and the hydride were regioselectively added to the γ
and δ positions of the olefin, respectively. Further screening of
other nickel(II) salts showed that Ni(acac)2 (acac =
acetylacetonate) is the superior catalyst, delivering product 3a
in 86% yield at room temperature (entry 4). The choice of
solvent was also critical for the reaction efficiency, and THF was
optimal for this reaction (entries 4−7). Among the silanes
screened, (EtO)2MeSiH was the most effective hydride source
for promoting this reaction (entries 8−10). As anticipated,
control experiments demonstrated that the nickel catalyst, silane
B
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a
Table 2. Substrate Scope of Hydroamination
a
Reactions were performed by using 1 (0.1 mmol), 2 (0.15 mmol), Ni(acac)2 (10 mol %), (EtO)2MeSiH (0.3 mmol), and Cs2CO3 (0.2 mmol) in
b
c
THF (0.5 mL) at room temperature for 24 h in a silicon-septa capped test tube under Ar. Yields of isolated products. 60 °C. Ni(acac)2 20 mol %
was used at 40 °C. NiI2 (10 mol %) and cinnamaldehyde (1.0 equiv) were used instead of Ni(acac)2 at 40 °C. 4-NMe2BzO was used instead of
BzO for 2.
d
e
C
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Table 3. Late-Stage Proximal-Selective Functionalization of
Biorelevant Molecules
Table 4. Substrate Scope of Picolinamide-Directed
Hydroamination
a
a
a
Reactions were performed by using 6 (0.1 mmol), 2 (0.15 mmol),
Ni(acac)2 (10 mol %), (EtO)2MeSiH (0.3 mmol), and Cs2CO3 (0.2
mmol) in THF (0.5 mL) at room temperature for 24 h in a silicon-
a
Reactions were performed by using 1 (0.1 mmol), 2 (0.15 mmol),
Ni(acac)2 (10 mol %), (EtO)2MeSiH (0.3 mmol), and Cs2CO3 (0.2
mmol) in THF (0.5 mL) at room temperature for 24 h in a silicon-
b
septa capped test tube under Ar. Yields of isolated products. 80 °C.
b
septa capped test tube under Ar. Yields of isolated products. 60 °C.
c
4-NMe2BzO was used instead of BzO for 2.
alkene and obtained the desired product 3k. As we have been
interested in the stereochemistry of this method to probe the
mechanism, we applied the current reaction conditions to cis-
locked cyclic alkenes. In contrast to the trans products
previously reported by the Hartwig group,12 the syn-isomeric
products were exclusively obtained using our protocol (3l, 3m,
3v, and 3w). The syn-configuration of 3m and 3w was
unambiguously confirmed by X-ray crystallographic analysis
(details are given in the Supporting Information). These results
indicate that the syn-configuration is determined by the
coordination of the directing group to the nickel hydride
intermediate in the alkene migratory insertion step via the inner-
sphere installation of the amino group. Therefore, this protocol
provides a potentially useful strategy for the synthesis of syn-
amino acid derivatives, which is complementary to the existing
method.
On the basis of the success of the proximal-selective
hydroamination of γ,δ-alkenes, we continued our survey by
applying the chemistry to β,γ-alkenes. Pleasingly, a variety of
unactivated terminal and internal β,γ-alkenes underwent
hydroamination to selectively provide β-amino products under
the optimized conditions (3n−3r). Trisubstituted alkene
substrates can also be employed, yielding the corresponding
product 3s. Notably, substitution at the β-position did not
hamper addition across the olefin, demonstrating the ability of
this approach to forge a β-amino quaternary carbon center (3t).
Similarly, the effect of substitution at the α-position was also
investigated, and a substrate bearing a benzyl group at the α-
source, and Cs2CO3 were all essential for the reaction to proceed
(entries 11−13).
With these optimized reaction conditions, we set out to
examine the reaction scope of the hydroamination for the γ,δ-
alkene substrates, as outlined in Table 2. We were pleased to find
that mono-, di-, and trisubstituted alkenes containing various
functional groups were tolerated and successfully afforded γ-
amino products. Notably, this reaction is highly proximal-
selective, providing γ-amino products from both terminal and
internal alkenes. Likewise, both trans-alkenes and cis-alkenes
were effective in this reaction, delivering the desired products
(3b).
An internal alkene bearing a relatively long alkyl chain (3c)
was also a suitable substrate for this reaction. One of the most
significant synthetic challenges for a transition-metal catalyzed
hydroamination is the functionalization of trisubstituted alkene
substrates. In this respect, we were particularly interested in the
use of trisubstituted alkenes that have proven unreactive in
previous studies. Gratifyingly, a broad range of trisubstituted
alkenes could successfully participate in this transformation with
excellent proximal selectivity (3d−3g), highlighting the
potential utility of this chemistry. Next, the suitability of more
sterically hindered alkenes was examined. Interestingly, for
alkene substrates bearing a methyl and dimethyl group at the α-
and β-positions, desired products 3h, 3i, and 3j were obtained.
We tested the hydroamination of a conjugated styrene-based
D
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Scheme 2. Control Experiments
position was suitable under the optimized reaction conditions
(3u). As mentioned above, we found that the reaction with β,γ-
cyclic alkenes proceeded smoothly to give syn-isomeric products
3v and 3w. With respect to the distance between the alkene and
the directing group, we investigated the chemoselectivity of
substrates containing multiple carbon−carbon double bonds.
With substrates containing pendant olefins, the reaction proved
to be chemoselective and preferentially functionalized the β,γ-
olefin to generate only β-amino products with δ,ε-terminal
alkene moieties remaining intact (3x and 3y). The chemo-
selectivity originates from the competition in the relative rates of
formation of the five- versus seven-membered nickellacycles
from the directing group.
Figure 1. (A) Same-excess experiment of hydroamination reaction. (B)
Different-excess experiment of hydroamination reaction.
We then turned our attention to the O-benzoylhydroxylamine
electrophile sources and were pleased to find a broad substrate
scope. The reactivities of various disubstituted amine transfer
agents were investigated for the synthesis of tertiary amines. We
observed that cyclic amine sources were tolerated with five-, six-,
and seven-membered rings, affording the desired products 4a,
4b, and 4c regardless of the size of the cyclic amine. Amine
sources containing a series of privileged heterocyclic scaffolds,
including piperazine (4d), pyrimidine (4e), and ester group
(4g), which are frequently found in bioactive molecules, were
well tolerated due to the mild reaction conditions. Similarly,
substrates bearing an acetal (4f) and acetate group (4h)
underwent the hydroamination reaction, yielding the corre-
sponding products. After deprotection, these substrates can
provide ketone and alcohol functional groups, which can be
easily further functionalized to access complex molecules. In
addition to cyclic amines, an acyclic amine such as diethylamine
was a competent substrate under the optimized conditions (4i).
Furthermore, an N-phthalimide group could be introduced
under slightly modified reaction conditions, producing 4j. We
then explored the scope of monosubstituted amine transfer
agents for the synthesis of secondary amines, which has been
shown to be difficult due to the unproductive reduction of the
electrophilic reagent in previous metal hydride systems.1d,8 In
the current system, monoalkyl-substituted amine transfer
sources were well tolerated regardless of the bulkiness of the
E
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́
Figure 2. Bures graphical rate analysis for (A) Ni catalyst and (B) alkene 1a. Details of the kinetic analysis based on initial rates are presented in the
Supporting Information (see Figures S5−S10).
Figure 3. Computed energy profile of NiH-catalyzed hydroamination of an unactivated alkene 1a with morpholino benzoate (2a).
alkyl groups (4k−4n). In addition, amine sources bearing acetyl-
(4o), benzoyl- (4p), Boc- (4q), and Cbz- (4r) protecting groups
could also be employed, providing an opportunity for further
functionalization and application.
To further underscore the generality of this methodology, this
approach was applied to the late-stage modification of complex,
pharmaceutically relevant molecules, as shown in Table 3.
Structurally complex amines, including estrone (5a), loratadine
F
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(5b), pentoxifylline (5d), and fluoxetine (5e) effectively
underwent hydroamination, affording corresponding desired
products. This methodology was also applied to more complex
alkene substrates derived from docosahexaenoic acid (DHA)
(5c) and cholesterol (5f and 5g), and these substrates could
undergo hydroamination with a loratadine-derived amine
transfer reagent and a monoalkyl-substituted amine source to
yield corresponding desired products.
As amines are ubiquitous and the most versatile functional
groups for subsequent transformations and diversification, we
subsequently turned our attention to the scope of amine-derived
picolinamide (PA) alkenes to demonstrate the synthetic utility
of the current method.14e To our delight, the desired aminated
products were obtained with comparable reactivity under the
standard conditions, which enabled the proximal selective
hydroamination of various classes of δ,ε-unsaturated alkenes, as
shown in Table 4. Beyond the δ,ε-unsaturated alkenes, this
method could be expanded to the γ,δ-unsaturated alkenes,
effectively yielding the corresponding product. In addition,
structurally complex loratadine could be effectively installed to
afford the desired product 7k. Therefore, this NiH-catalyzed
system significantly broadens its potential and general utility by
providing a new platform to deal with the challenging and broad
substrates with excellent levels of site selectivity and reactivity
under the mild reaction conditions.
To elucidate the mechanism, control experiments were
conducted, as depicted in Scheme 2. First, to investigate the
features of the hydrometalation step, we performed deuterium
labeling experiments by subjecting δ,δ-dideuterated alkene d2-1a
to the standard reaction conditions (Scheme 2a). The analysis of
1H NMR spectroscopy confirmed that the deuterium atoms at
the δ-position remained intact, and no H/D exchange was
observed at the γ-position. Additionally, we performed a
crossover experiment with 1j and deuterium-labeled olefin d2-
1a as substrates and observed that products 3j and d2-3a were
produced (Scheme 2b). These results indicate that olefin
dissociation may not occur prior to the formation of the desired
product.19 Next, to investigate the origin of the hydrogen atom
source, an isotope labeling experiment was conducted with
Ph2SiD2 under the standard reaction conditions (Scheme 2c).
Importantly, we observed deuterium incorporation at the δ-
position, which supports that the hydrogen is provided by silyl
hydride from the generated NiH species. Next, kinetic isotope
effect (KIE) experiments were performed with Ph2SiH2 and
Ph2SiD2, in which the observed kH/kD value was found to be 1.57
(Scheme 2d). Moreover, an inverse secondary KIE was observed
with 1a and d2-1a, in which the kH/kD ratio was 0.86 (Scheme
2e). These results indicate that the migratory insertion step is
involved in the turnover-limiting step.
To further investigate the reaction mechanism in the catalytic
system, in-depth kinetic studies using reaction progress kinetic
analysis (RPKA) experiments20 were conducted, and reaction
progress data in the NiH-catalyzed hydroamination reaction are
presented in Figure 1. First, we established standard conditions
for RPKA using 4-pentenoic acid derivatives 1a, morpholino
benzoate (2a), and diethoxymethylsilane with dimethyl
terephthalate as an internal standard. The initial concentration
of alkene 1a in the same-excess 1 represents the situation where
alkene 1a reached a 50% conversion at standard conditions. In
the same-excess 2, product 3a was added to the reaction mixture
of the same-excess 1. On the one hand, in our experiments, the
rate profiles of the same-excess case 1 and 2 overlapped, which
indicates that the generated product does not inhibit the
reaction in a significant way. On the other hand, there was no
overlay at the rate profile between a standard run condition and a
same-excess 2 when time-adjusted, indicating that the
concentration of the on-cycle catalyst is decreased in this
catalytic reaction.
Next, different-excess experiments were conducted to
determine the rate orders of the reaction components. On the
one hand, different initial concentrations of morpholino
benzoate (2a) and silane did not change the reaction rate,
indicating zero-order kinetics (see Supporting Information for
detail). On the other hand, there is no overlap between the
different initial concentrations of Ni catalyst and alkene 1a in the
plotted graph over a function of time (Figure 1B). To visualize
the direct comparison of profiles between the reaction rate and
́
concentration of Ni catalyst and alkene 1a, the Bures graphical
rate analysis21 was employed by plotting the concentration of
the product over normalized time·[component]n, as shown in
Figure 2. Notably, there are significant overlaps with different
loading changes of each Ni catalyst and alkene 1a (Ni: n = 0.62
and 1a: n = 0.42), which means that this reaction has a rate order
of 0.62 for Ni catalyst and 0.42 for alkene 1a, respectively. The
observed fractional order of Ni and alkene 1a (near 0.5) showed
the possibility of the presence of dimeric nickel complex Ni-1a as
an inactive off-cycle resting state, and NiH dimer would undergo
reversible dissociation to the corresponding active NiH
monomer prior to turnover-limiting migratory insertion.20b,22
To further support the generation of off-cycle bridged NiH
dimers, we conducted density functional theory (DFT)
calculations, which supported the possibility for the mono-
mer−dimer equilibrium, as illustrated in Figure 3.
We next turned our attention to investigate the electronic
effects of the amine electrophile components on the reaction
rate via Hammett parameter analysis.23 A series of amine
electrophiles bearing different para-substituted benzoates were
prepared and subjected to the standard reaction conditions.
Similar reaction rates were observed, regardless of the electronic
properties of benzoates, indicating that the oxidative addition
step and NiH regeneration step are not significantly involved in
the turnover-limiting step of this transformation (see the
Supporting Information for details). The zero-order depend-
ence on the silane concentration as shown in Figure 1B is also
consistent with these observed results.24
To gain further insight into the mechanism and the regio-
determining step, DFT calculations were performed using
alkene 1a and morpholino benzoate (2a) as the model reactants,
and the calculated reaction energy profiles of the Ni-catalyzed
hydroamination are illustrated in Figure 3. Regarding redox
manifolds of Ni catalysis, Ni(0)/Ni(II) and Ni(I)/Ni(III)
catalytic systems could be considered as possible pathways.
However, the energy barrier of the reductive elimination step in
the Ni(0)/Ni(II) system is too high to be mechanistically
plausible in this current reaction (>50 kcal/mol), ruling out the
reaction pathway involving Ni(0)/Ni(II) catalysis. Therefore,
we performed a DFT calculation based on the Ni(I)/Ni(III)
catalytic system. The catalytic cycle is initiated by the formation
of active Ni(I) hydride species A from the A-dimer, which is
generated from hydrosilane and the bidentate directing group-
tethered alkene 1a.22c,25 The intermediate A then undergoes
migratory insertion to form alkylnickel intermediate B. Our
calculations support that this migratory insertion step is the
regio-determining step, leading to the formation of two possible
nickellacycles. The transition state A-TS that leads to the six-
membered nickellacycle B is found to be 10.0 kcal/mol lower in
G
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energy than A-TS2, indicating that a penalty is derived from a
more structural distortion in A-TS2 associated with the hydride
insertion into the internal position of the alkene. The decisive
difference in transition-state energy is in good agreement with
the experimentally observed excellent regioselectivity. The
migratory insertion step is assigned as a turnover-limiting step
on the basis of the reaction energy profile, which is in good
agreement with the experimental kinetic data (Scheme 2d,e).
The generated alkylnickel intermediate B subsequently under-
goes oxidative addition with the amination reagent to form
intermediate C. Next, the highly stabilized intermediate D can
be readily generated through the reductive elimination of C with
an activation energy barrier of 19.8 kcal/mol. Finally, the Ni(I)
hydride species E is regenerated in situ by the hydrosilane
reagent, and the desired product F is furnished through the
subsequent ligand exchange with alkene substrate.
Changseok Lee − Department of Chemistry, Korea Advanced
Institute of Science and Technology, Daejeon 34141, Korea;
Center for Catalytic Hydrocarbon Functionalizations, Institute
for Basic Science, Daejeon 34141, Korea; orcid.org/0000-
0001-8925-1479
Huiyeong Seo − Department of Chemistry, Korea Advanced
Institute of Science and Technology, Daejeon 34141, Korea;
Center for Catalytic Hydrocarbon Functionalizations, Institute
for Basic Science, Daejeon 34141, Korea; orcid.org/0000-
0002-0445-8719
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c10333
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
CONCLUSIONS
■
This research was supported financially by the Institute for Basic
Science (IBS-R010-A2). We thank Dr. D. Kim (IBS) for the
XRD analysis.
We have developed a NiH-catalyzed, proximal-selective hydro-
amination of unactivated alkenes to provide a new and
complementary retrosynthetic method for valuable β- and γ-
amino acid building blocks. The strong coordination of the
directing group to the NiH species enabled the functionalization
of both unactivated terminal and challenging internal alkenes,
enabling the installation of structurally diverse amino groups
with excellent compatibility of diverse substitution patterns and
functional groups. Interestingly, the reactions with internal
alkenes led to the formation of syn-isomeric products enabled by
the coordination of the directing group to the NiH species. The
synthetic utility of this method was further demonstrated by the
late-stage modification of complex and medicinally relevant
molecules. Combined mechanistic and computational studies
are conducted to clarify that the migratory insertion step is the
turnover-limiting step.
REFERENCES
■
(1) For selected recent reviews for a catalytic hydroamination, see:
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c10333.
■
sı
Experimental procedures, characterization data, copies of
NMR spectra for new products; computed energy
components, Cartesian coordinates, and vibrational
frequencies of all of the DFT-optimized structures
(PDF)
X-ray crystallographic data (3m) (CIF)
X-ray crystallographic data (3w) (CIF)
AUTHOR INFORMATION
Corresponding Author
Sungwoo Hong − Center for Catalytic Hydrocarbon
Functionalizations, Institute for Basic Science, Daejeon 34141,
Korea; Department of Chemistry, Korea Advanced Institute of
Science and Technology, Daejeon 34141, Korea; orcid.org/
0000-0001-9371-1730; Email: hongorg@kaist.ac.kr
■
́
Reagents. Nat. Commun. 2019, 10, 4117. (i) Zheng, S.; Gutierrez-
́
Bonet, A.; Molander, G. A. Merging Photoredox PCET with Ni-
Catalyzed Cross-Coupling: Cascade Amidoarylation of Unactivated
Olefins. Chem. 2019, 5, 339. (j) He, J.; Xue, Y.; Han, B.; Zhang, C.;
Wang, Y.; Zhu, S. Nickel-Catalyzed Asymmetric Reductive 1,2-
Carboamination of Unactivated Alkenes. Angew. Chem., Int. Ed. 2020,
59, 2328. (k) Moon, Y.; Lee, W.; Hong, S. Visible-Light-Enabled Ortho-
Selective Aminopyridylation of Alkenes with N-Aminopyridinium
Ylides. J. Am. Chem. Soc. 2020, 142, 12420.
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olefin, see: (a) Han, X.; Widenhoefer, R. A. Gold(I)-Catalyzed
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Authors
Jinwon Jeon − Department of Chemistry, Korea Advanced
Institute of Science and Technology, Daejeon 34141, Korea;
Center for Catalytic Hydrocarbon Functionalizations, Institute
for Basic Science, Daejeon 34141, Korea; orcid.org/0000-
0002-2185-086X
H
https://dx.doi.org/10.1021/jacs.0c10333
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

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