Nickel-Catalyzed Enantioselective α-Alkenylation of N-Sulfonyl Amines: Modular Access to Chiral α-Branched Amines

Article abstract of DOI:10.1021/jacs.1c00622

Chiral α-branched amines are common structural motifs in functional materials, pharmaceuticals, and chiral catalysts. Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in synthetic chemistry. Herein, we describe an atom-economical, modular method for a nickel-catalyzed enantioselective α-Alkenylation of readily available linear N-sulfonyl amines with alkynes to afford a wide variety of allylic amines without the need for exogenous oxidants, reductants, or activating reagents. The method provides a platform for constructing chiral α-branched amines as well as derivatives such as α-Amino amides and β-Amino alcohols, which can be conveniently accessed from the newly introduced alkene. Given the generality, versatility, and high atom economy of this method, we anticipate that it will have broad synthetic utility.

Full text of DOI:10.1021/jacs.1c00622

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Nickel-Catalyzed Enantioselective α‑Alkenylation of N‑Sulfonyl
Amines: Modular Access to Chiral α‑Branched Amines
Lun Li,§ Yu-Cheng Liu,§ and Hang Shi*
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ABSTRACT: Chiral α-branched amines are common structural motifs in functional materials, pharmaceuticals, and chiral catalysts.
Therefore, developing efficient methods for preparing compounds with these privileged scaffolds is an important endeavor in
synthetic chemistry. Herein, we describe an atom-economical, modular method for a nickel-catalyzed enantioselective α-alkenylation
of readily available linear N-sulfonyl amines with alkynes to afford a wide variety of allylic amines without the need for exogenous
oxidants, reductants, or activating reagents. The method provides a platform for constructing chiral α-branched amines as well as
derivatives such as α-amino amides and β-amino alcohols, which can be conveniently accessed from the newly introduced alkene.
Given the generality, versatility, and high atom economy of this method, we anticipate that it will have broad synthetic utility.
hiral α-branched amines are present in many agro-
concept introduced by Trost,36 this byproduct-free reaction is
atom-efficient in that chemical inputs besides the reaction
partners (the amine and alkyne) are used in less than
stoichiometric quantities. Moreover, the alkene motif, by
virtue of its synthetic versatility, allows the products to be
conveniently diversified into valuable targets, providing a
library of diversified building blocks that are prevalent in
bioactive natural products, pharmaceuticals, and chiral
catalysts.
In developing a strategy for achieving the above goal, we
drew upon a nickel-mediated oxidative cyclometalation,37−39
which has been successfully applied in the coupling reactions
between imines and compounds with unsaturated bonds.40−49
We hypothesized that, if an amine could perform a dual role in
a catalytic cycle by serving both as a precursor to the imine and
as a hydrogen donor via hydrogen transfer,50−63 a formal
insertion of an unsaturated motif into the α-C−H bond
adjacent to the nitrogen atom could be accomplished.
We selected benzylamine and diphenylacetylene to evaluate
the reaction feasibility by employing Ni(0), PPh3 (L1) as the
ligand, and K3PO4 (40 mol %) (Scheme 2a). We found that
amines masked with a carbonyl group failed to undergo the
desired alkenylation. Encouragingly, a substrate with a p-
tolylsulfonyl protecting group provided a low yield (36%) of
the desired alkenylation product. Varying the substituent on
the phenyl ring of the sulfonyl group revealed that neither an
electron-withdrawing group (−CF3) nor an electron-donating
group (−OMe) was beneficial. However, adding steric bulk
around the sulfur atom by using a mesitylen-2-sulfonyl (Mts)
C
chemicals and pharmaceuticals,1,2 and they are important
ligands for asymmetric catalysis3−5 (Scheme 1a). A topic of
long-standing interest in synthetic chemistry, transition-metal-
catalyzed C(sp3)−H bond functionalization reactions that
introduce substituents at an sp3-hybridized carbon center
adjacent to nitrogen are an efficient means of preparing
complex amines.6 α-Alkylation of amines with olefins catalyzed
by early transition metals was disclosed in the 1980s.7−9
Recent work from several groups dramatically improved the
efficiency of catalysis;10−16 however, the intrinsic properties of
these metals typically limit the reactivity to either benzylic or
primary C−H bonds, while offering narrow functional group
tolerance. In most cases, only monosubstituted olefins couple
efficiently (Scheme 1b, left). In a late-transition-metal catalysis,
a broader range of coupling reagents is compatible, allowing for
diversification of the α-metalated intermediates (Scheme 1b,
right).17−28 This strategy generally relies on directing
auxiliaries that are not prevalent in readily available reactants,
introducing practical limitations, particularly when considering
a large-scale synthesis and the step/atom economy. In
addition, except in rare cases, control over absolute stereo-
chemistry remains elusive.14,18,19,21,22,25,28 Unlike in the above-
described methods involving C−H bond metalation, oxidant-
or photoredox-catalyst-induced α-C−H bond functionaliza-
tions of amines have also been achieved in combination with
transition-metal catalysts,29−35 though the generality of these
methods, including the scope of amines and asymmetric
versions, remains to be extended. The above-described
challenges have motivated efforts to develop general, efficient,
atom-economical approaches for an enantioselective synthesis
of α-branched amines from abundant, simple materials.
Received: January 18, 2021
Published: March 10, 2021
Herein, we describe a novel method for nickel-catalyzed α-
alkenylation of a large array of primary amines protected with a
simple sulfonyl group (Scheme 1c). Enabled by a P-chiral
phosphine ligand, this practical method offers a high
enantioselectivity. From the standpoint of atom economy, a
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Scheme 1. Representative α-Branched Amines and Approaches to Their Syntheses
group markedly increased the yield (70%), whereas pyridine-2-
sulfonyl, a typical directing group, poisoned the catalysis.
Moreover, replacing the Mts with a methanesulfonyl group
slightly reduced the yield (62%).
(3j−3s) position regardless of the electronic properties of
these substituents. Multisubstituted benzylamines (3t−3x) and
heterocycles (3y, 3z) were also compatible, as were other
nonaromatic unsaturated motifs, such as alkenyl groups (3aa,
3ab). Next we evaluated aliphatic amines and found that linear
(3ac−3ah), β-branched (3ai−3am), and even sterically bulky
β,β-branched (3an−3aq) alkyl groups were all well-tolerated.
In addition, the reaction was suitable for substrates containing
various cyclic groups (three- to seven-membered and bridged
rings), which provided the corresponding products in yields up
to 99% (3ar−3bk). Notably, no obvious side reactions,
including double-bond migration, ring-opening reactions, or
rearrangements, were observed for substrates bearing reactive
motifs such as cyclic alkenes, heterocycles, a cyclic ketal, or
bridged rings.
We also evaluated the scope of alkynes by performing
reactions with amine 1a (Scheme 2d). Various symmetric
diaryl acetylenes bearing either ortho- (3bl−3bn), meta- (3bo−
3br), or para- (3bs−3bw) functionalized aromatic groups and
naphthalenes (3bx, 3by) were all suitable, providing the
desired products in 71−98% yields.64 The reactions of
unsymmetrical alkyl aryl acetylenes afforded products in yields
up to 99% with moderate to good regioselectivities, favoring
C−C bond formation proximal to the alkyl group (3bz−3cc).
Next we evaluated other ligands to obtain further insights
and improvements (Scheme 2b). Varying the electronic
properties of the aromatic rings of the phosphine resulted in
essentially unchanged (L2) or lower (L3, L4) yields. Replacing
a monodentate ligand with the bisphosphine 1,2-bis-
(diphenylphosphino)ethane (DPPE) inhibited the reaction
completely. A more strongly electron-donating ligand dramat-
ically improved the yield (PCy3, 95%; PPhCy2, 96%).
Increasing the steric bulk was deleterious (PtBu3, 2-
dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (XPhos)).
In addition, we also tested other privileged ligands: a σ-donor
N-heterocyclic carbene (NHC) (L10) gave a moderate yield,
whereas a typical N,N-bidentate ligand, bipyridine (L11), was
inactive (see the Supporting Information for additional
details).
The optimized protocol was then extended to other amines
with diphenylacetylene (2a) as the coupling partner (Scheme
2c). The desired branched products were obtained in 63−95%
yields from a wide range of benzylamines bearing a single
substituent at the ortho- (3b−3d), meta- (3e−3i), or para-
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a
Scheme 2. Nickel-Catalyzed α-Alkenylation of Amines
a
Conditions: amine 1 (0.1 mmol), alkyne 2 (0.2 mmol), 7 mol % Ni(cod)2, 14 mol % L7 (for 3a−3z, using L6), 40 mol % K3PO4, dioxane, 120 °C;
NMR yields are reported in (a, b); isolated yields are reported in (b, c). (*) 10 mol % Ni(cod)2, 20 mol % ligand. (†) 80 mol % K3PO4. (‡) Greater
than 20:1 rr. dr, diastereomeric ratio; rr, regioisomeric ratio.
Moreover, symmetric alkynes substituted with two identical
aliphatic groups were also compatible (3cd−3ch). Although
terminal alkynes were unsuitable, probably because of the
relatively high acidity of the C(sp)−H bond, silyl-containing
alkynes smoothly underwent the reaction, affording α-
alkenylated amines (3ci−3dh) with a broad range of functional
groups, including fluoro, methoxy, trifluoromethyl, carboxylate,
trifluoromethoxy, acetyl, cyano, and thienyl. Notably, reactions
with unsymmetrical silyl alkynes generally proceeded in a
highly regioselective manner with C−C coupling occurring
adjacent to silicon.
We next investigated whether the aforementioned strategy
could be applied to access enantioenriched allylic amines,
which are valuable and versatile synthetic building blocks, by
using a chiral ligand. We immediately encountered a significant
challenge in that bidentate ligands, which constitute the vast
majority of chiral ligands, completely failed to catalyze the
alkenylation reaction of amine 1a with diphenylacetylene (a
Josiphos-type ligand, (R)-BINAP, (S)-tBu-Phox in Table S5,
see the Supporting Information). Moreover, using either a
chiral NHC ligand or a monodentate phosphine, which bears a
chiral carbon center or a chiral axis, provided the desired
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Scheme 3. Nickel-Catalyzed Enantioselective α-Alkenylation of Amines and Applications
a
Conditions in (a, b): amine 1 (0.05 mmol), alkyne 2 (0.1 mmol), 10 mol % Ni(cod)2, 20 mol % L12, 80 mol % K3PO4, tetrahydrofuran (THF),
80 °C; isolated yields are reported. (*) 10 mol % Ni(cod)2, 25 mol % L12, 80 mol % NaOAc, dioxane, 140 °C. (†) Greater than 20:1 rr.
product with a low stereoselectivity (Table S5, entries 4−7).
We envisioned that, if the chiral information of the ligand was
closer to the nickel, the stereoselectivity would be enhanced.
To our delight, when a rigid P-chiral phosphine developed by
the Tang group65,66 was used, the reaction provided the
desired product with an enantiomeric ratio (er) of 88.0:12.0
(Table S5, entry 8). Further investigations revealed that steric
bulk near the phosphine atom reduced both the yield and the
enantioselectivity (Table S5, entries 9 and 10), whereas a more
rigid skeleton (L12) improved the er to 90.9:9.1 (Table S5,
entry 11). Further optimization of the conditions allowed us to
obtain 4a in 74% isolated yield with 94.1:5.9 er (Table S5,
entries 12−14).
With the optimal conditions in hand, we evaluated the scope
of the enantioselective α-alkenylation protocol by performing
reactions between diphenylacetylene and various sulfonyl
amines (Scheme 3a). Amines bearing monosubstituted aryl
rings (ortho-, 4b, 4c; meta-, 4d−4h; para-, 4i−4m), multi-
substituted aryl rings (4n−4q), a polyaromatic ring (4r), or a
thiophene (4s) were all compatible, providing the desired
products with good enantioselectivities (92.6:7.4 to 96.9:3.1
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Scheme 4. Mechanistic Studies
Scheme 5. Proposed Catalytic Cycle
as a handle for the introduction of various functional groups or
for ligation onto peptides. For example, an ozonolysis of
bromoalkene 6a and a subsequent condensation with an amino
ester produced amide 7 in 65% yield without epimerization.
Notably, the protocol was also successfully applied for a
homologation of an endorphin to afford peptide 8. Finally, in
light of the synthetic utility of the tert-butyloxycarbonyl (Boc)
protecting group, we utilized a convenient protocol for the
conversion of the Mts into the Boc group.
To gain insight into the reaction mechanism, we performed
mechanistic studies (Scheme 4). First, in the presence of a
stoichiometric amount of nickel catalyst, 1a was converted to
imine 10a (45% combined yield with corresponding aldehyde
10b) along with unreacted 1a. We also observed a Ni-hydride
species by 1H NMR spectroscopy.68 Moreover, in the presence
of alkyne 2b, besides imine (aldehyde), alkene 11a/b formed.
Given that the oxidative addition of Ni(0) into a N−H bond
has been reported,69 the above-described results suggest that
the amine is converted to an imine by an oxidative addition/β-
H elimination process. Second, we monitored the catalytic
reaction and found that the substrate 1a gradually converted to
the product 3ci without detecting any sulfonyl imine. Third,
when the reaction of α-deuterated substrate 1a-d2 was
terminated in 30 min, 93% deuterium incorporation at the
alkenyl position of the product (60% yield) was detected, and
the recovered substrate (37%) showed no loss of deuterium.
Moreover, when N-D substrate 1a−d′ was subjected, no
deuterium incorporation at the alkenyl position of the product
was observed. These results reveal that the alkenyl hydrogen is
derived from the α-position of the substrate amine. Notably,
the kinetic isotopic effect (kH/kD = 2.8) in the competitive
reaction suggests that the hydrogen at the α-position of amines
participates in the rate-determining step.
er).67 Moreover, the reaction tolerated aliphatic motifs,
including an isopropyl group (4t) and cyclic groups (4u−4y).
Next we evaluated alkynes (Scheme 3b) and found that both
symmetric alkynes (4z−4af) and unsymmetrical arylacetylenes
(4ag−4au) proved to be suitable, providing desired products
with good enantioselectivities (up to 98.5:1.5 er) and
regioselectivities. In addition, substituted benzylamines also
smoothly underwent enantioselective alkenylation with trime-
thylsilylphenylacetylene to afford 4av−4az.
The enantiomerically enriched amines were excellent
precursors for the synthesis of β-amino alcohols (Scheme
3c). Specifically, ozonolysis of allylic amines 4, followed by
reduction with NaBH4, afforded a series of cis-β-amino
alcohols in good yields with no loss of enantioselectivity
(5a−5g). In addition, the trimethylsilyl group of 4ai could be
readily converted to a bromine atom (6a), which could serve
On the basis of the aforementioned experiments and
previous reports on the nickel-catalyzed condensation of
imines and alkynes,42 we propose the mechanism outlined in
Scheme 5. The process is initiated by a protonation of the low-
valent nickel, which is followed by a β-H elimination and a
sequential hydrogen transfer to release a trace amount of the
sulfonyl imine along with the Ni(0) species. Subsequently, an
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oxidative cyclometalation and protonation generate the vinyl
Ni(II) intermediate II. The desired product is derived from
this intermediate through a β-H elimination/reductive
elimination process, completing the catalytic cycle.
and Physical Sciences at Westlake University for the assistance
work in measurement/data interpretation. We thank Prof. B.
Dang (Westlake University) and Prof. K. M. Engle (Scripps
Research Institute) for helpful discussion.
The general, modular method described herein for a nickel-
catalyzed enantioselective alkenylation is a valuable tool for
accessing chiral α-branched amines from linear primary
amines. Given the wide availability of primary amines and
coupling partner alkynes, as well as the varied functionality of
the products, this method can be expected to serve as a
platform for the synthesis of a diverse array of valuable
complex amines. The method features high enantioselectivity,
broad functional group tolerance, excellent atom economy, and
scalability for developing other functionalizations to build a
molecular complex from simple inputs.
REFERENCES
■
(1) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and
Applications; Wiley VCH: Weinheim, Germany, 2010; pp 1−478.
(2) Vitaku, E.; Smith, D. T.; Njardarson, J. T. Analysis of the
Structural Diversity, Substitution Patterns, and Frequency of Nitrogen
Heterocycles Among U.S. FDA Approved Pharmaceuticals. J. Med.
Chem. 2014, 57, 10257−10274.
(3) Wu, L.-l.; Salvador, A.; Dorta, R. Chiral Monodendate N-
Heterocyclic Carbene Ligands in Asymmetric Catalysis; Wiley VCH,
2014; pp 39−84.
(4) Wang, D.; Astruc, D. The Golden Age of Transfer Hydro-
genation. Chem. Rev. 2015, 115, 6621−6686.
(5) Shao, Q.; Wu, K.; Zhuang, Z.; Qian, S.-Q.; Yu, J.-Q. From
Pd(OAc)2 to Chiral Catalysts: the Discovery and Development of
Bifunctional mono-N-Protected Amino Acid Ligands for Diverse C-H
Functionalization Reactions. Acc. Chem. Res. 2020, 53, 833−851.
(6) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New Strategies for
the Transition-Metal Catalyzed Synthesis of Aliphatic Amines. Chem.
Rev. 2020, 120, 2613−2692.
(7) Clerici, M. G.; Maspero, F. Catalytic C-Alkylation of Secondary
Amines with Alkenes. Synthesis 1980, 1980, 305−306.
(8) Nugent, W. A.; Ovenall, D. W.; Holmes, S. J. Catalytic C-H
Activation in Early Transition-Metal Dialkylamides and Alkoxides.
Organometallics 1983, 2, 161−162.
(9) Buchwald, S. L.; Watson, B. T.; Wannamaker, M. W.; Dewan, J.
C. Zirconocene Complexes of Imines: General Synthesis, Structure,
Reactivity, and in Situ Generation to Prepare Geometrically Pure
Allylic Amines. J. Am. Chem. Soc. 1989, 111, 4486−4494.
(10) Herzon, S. B.; Hartwig, J. F. Direct, Catalytic Hydro-
aminoalkylation of Unactivated Olefins with N-Alkyl Arylamine. J.
Am. Chem. Soc. 2007, 129, 6690−6691.
(11) Herzon, S. B.; Hartwig, J. F. Hydroaminoalkylation of
Unactivated Olefins with Dialkylamines. J. Am. Chem. Soc. 2008,
130, 14940−14941.
(12) Kubiak, R.; Prochnow, I.; Doye, S. Titanium-Catalyzed
Hydroaminoalkylation of Alkenes by C-H Bond Activation at sp3
Centers in the α-Position to a Nitrogen Atom. Angew. Chem., Int. Ed.
2009, 48, 1153−1156.
(13) Bexrud, J. A.; Eisenberger, P.; Leitch, D. C.; Payne, P. R.;
Schafer, L. L. Selective C-H Activation α to Primary Amines. Bridging
Metallaaziridines for Catalytic, Intramolecular α-Alkylation. J. Am.
Chem. Soc. 2009, 131, 2116−2118.
(14) Reznichenko, A. L.; Hultzsch, K. C. The Mechanism of
Hydroaminoalkylation Catalyzed by Group 5 Metal Binaphtholate
Complexes. J. Am. Chem. Soc. 2012, 134, 3300−3311.
(15) Koperniku, A.; Foth, P. J.; Sammis, G. M.; Schafer, L. L.
Zirconium Hydroaminoalkylation. An Alternative Disconnection for
the Catalytic Synthesis of α-Arylated Primary Amines. J. Am. Chem.
Soc. 2019, 141, 18944−18948.
(16) Bahena, N.; Griffin, S. E.; Schafer, L. L. Zirconium-Catalyzed
Hydroaminoalkylation of Alkynes for the Synthesis of Allylic Amines.
J. Am. Chem. Soc. 2020, 142, 20566−20571.
(17) Jun, C.-H.; Hwang, D.-C.; Na, S.-J. Chelation-Assisted
Alkylation of Benzylamine Derivatives by Ru0 Catalyst. Chem.
Commun. 1998, 1405−1406.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.1c00622.
■
sı
Experimental procedures, characterization of new
compounds, and spectroscopic data (PDF)
Accession Codes
CCDC 2056486 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Hang Shi − Key Laboratory of Precise Synthesis of Functional
Molecules of Zhejiang Province, School of Science, Westlake
University, Hangzhou 310024, Zhejiang Province, China;
Institute of Natural Sciences, Westlake Institute for Advanced
Study, Hangzhou 310024, Zhejiang Province, China;
Email: shihang@westlake.edu.cn
Authors
Lun Li − Key Laboratory of Precise Synthesis of Functional
Molecules of Zhejiang Province, School of Science, Westlake
University, Hangzhou 310024, Zhejiang Province, China;
Institute of Natural Sciences, Westlake Institute for Advanced
Study, Hangzhou 310024, Zhejiang Province, China
Yu-Cheng Liu − Key Laboratory of Precise Synthesis of
Functional Molecules of Zhejiang Province, School of Science,
Westlake University, Hangzhou 310024, Zhejiang Province,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.1c00622
Author Contributions
§L.L. and Y.-C.L. contributed equally.
Notes
(18) Davies, H. W. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A.
Highly Regio-, Diastereo-, and Enantioselective C-H Insertions of
Methyl Aryldiazoacetates into Cyclic N-Boc-Protected Amines.
Asymmetric Synthesis of Novel C2-Symmetric Amines and threo-
Methylphenidate. J. Am. Chem. Soc. 1999, 121, 6509−6510.
(19) Axten, J. M.; Ivy, R.; Krim, L.; Winkler, J. D. Enantioselective
Synthesis of D-threo-Methylphenidate. J. Am. Chem. Soc. 1999, 121,
6511−6512.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (22071198) and the China
Postdoctoral Science Foundation (2020M671801). We thank
Instrumentation and Service Center for Molecular Sciences
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Communication
(20) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.;
Murai, S. Ru3(CO)12-Catalyzed Coupling Reaction of sp3 C-H Bonds
Adjacent to a Nitrogen Atom in Alkylamines with Alkenes. J. Am.
Chem. Soc. 2001, 123, 10935−10941.
(42) Ogoshi, S.; Ikeda, H.; Kurosawa, H. Formation of an Aza-
Nickelacycle by Reaction of an Imine and an Alkyne with Nickel(0):
Oxidative Cyclization, Insertion, and Reductive Elimination. Angew.
Chem., Int. Ed. 2007, 46, 4930−4932.
(43) Ohashi, M.; Kishizaki, O.; Ikeda, H.; Ogoshi, S. Ni(0)-
Catalyzed Formation of Azaaluminacyclopentenes via Azanickelacy-
clopentenes: a Unique Nickel/Aluminum Double Transmetalation
Reaction. J. Am. Chem. Soc. 2009, 131, 9160−9161.
(44) Zhou, C.-Y.; Zhu, S.-F.; Wang, L. X.; Zhou, Q.-L.
Enantioselective Nickel-Catalyzed Reductive Coupling of Alkynes
and Imines. J. Am. Chem. Soc. 2010, 132, 10955−10957.
(45) Karmakar, R.; Suneja, A.; Bisai, V.; Singh, V. K. Ni(II)-
Catalyzed Highly Stereo- and Regioselective Syntheses of Isoindoli-
nones and Isoquinolinones from in Situ Prepared Aldimines
Triggered by Homoallylation/Lactamization Cascade. Org. Lett.
2015, 17, 5650−5653.
(46) Xiao, L.-J.; Zhao, C.-Y.; Cheng, L.; Feng, B.-Y.; Feng, W.-M.;
Xie, J.-H.; Xu, X.-F.; Zhou, Q.-L. Nickel(0)-Catalyzed Hydro-
alkenylation of Imines with Styrene and Its Derivatives. Angew.
Chem., Int. Ed. 2018, 57, 3396−3400.
(47) Yao, W.-W.; Li, R.; Li, J.-F.; Sun, J.; Ye, M.-C. NHC Ligand-
Enabled Ni-Catalyzed Reductive Coupling of Alkynes and Imines
Using Isopropanol as a Reductant. Green Chem. 2019, 21, 2240−
2244.
(48) Shirataki, H.; Ono, T.; Ohashi, M.; Ogoshi, S. Ni(0)-Catalyzed
Three-Component Coupling Reaction of Tetraflfluoroethylene and
N-Sulfonyl-Substituted Imines with Silanes via Aza-Nickelacycles. Org.
Lett. 2019, 21, 851−856.
(49) Ashida, K.; Hoshimoto, Y.; Tohnai, N.; Scott, D. E.; Ohashi,
M.; Imaizumi, H.; Tsuchiya, Y.; Ogoshi, S. Enantioselective Synthesis
of Polycyclic γ-Lactams with Multiple Chiral Carbon Centers via
Ni(0)-Catalyzed Asymmetric Carbonylative Cycloadditions without
Stirring. J. Am. Chem. Soc. 2020, 142, 1594−1602.
(50) Ketcham, J. K.; Shin, I.; Montgomery, T. P.; Krische, M. J.
Catalytic Enantioselective C-H Functionalization of Alcohols by
Redox-Triggered Carbonyl Addition: Borrowing Hydrogen, Return-
ing Carbon. Angew. Chem., Int. Ed. 2014, 53, 9142−9150.
(51) Kim, S. W.; Zhang, W.; Krische, M. J. Catalytic Enantioselective
Carbonyl Allylation and Propargylation via Alcohol Mediated
Hydrogen Transfer: Merging the Chemistry of Grignard and Sabatier.
Acc. Chem. Res. 2017, 50, 2371−2380.
(52) Holmes, M.; Schwartz, L. A.; Krische, M. J. Intermolecular
Metal-Catalyzed Reductive Coupling of Dienes, Alkenes, and Enynes
with Carbonyl Compounds and Imines. Chem. Rev. 2018, 118, 6026−
6052.
(53) Gillena, G.; Ramón, D. J. Hydrogen Transfer Reactions; Springer:
Switzerland, 2016; pp 1−365.
(54) Schmitt, D. C.; Lee, J.; Dechert-Schmitt, A. M. R.; Yamaguchi,
E.; Krische, M. J. Ruthenium Catalyzed Hydroaminoalkylation of
Osoprene via Transfer Hydrogenation: Byproduct-Free Prenylation of
Hydantoins. Chem. Commun. 2013, 49, 6096−6098.
(55) Nakai, K.; Yoshida, Y.; Kurahashi, T.; Matsubara, S. Nickel-
Catalyzed Redox-Economical Coupling of Alcohols and Alkynes to
Form Allylic Alcohols. J. Am. Chem. Soc. 2014, 136, 7797−7800.
(56) Lu, X.; Xiao, B.; Zhang, Z.; Gong, T.; Su, W.; Yi, J.; Fu, Y.; Liu,
L. Practical Carbon-Carbon Bond Formation from Olefns through
Nickel-Catalyzed Reductive Olefn Hydrocarbonation. Nat. Commun.
2016, 7, 11129.
(21) Davies, H. W. L.; Venkataramani, C. Catalytic Enantioselective
Synthesis of 2-Amino Acids. Angew. Chem., Int. Ed. 2002, 41, 2197−
2199.
(22) Pan, S.-G.; Endo, K.; Shibata, T. Ir(I)-Catalyzed Enantiose-
lective Secondary sp3 C-H Bond Activation of 2-(Alkylamino)-
pyridines with Alkenes. Org. Lett. 2011, 13, 4692−4695.
(23) Dastbaravardeh, N.; Schnurch, M.; Mihovilovic, M. D.
̈
Ruthenium(0)-Catalyzed sp3 C-H Bond Arylation of Benzylic Amines
using Arylboronates. Org. Lett. 2012, 14, 1930−1933.
(24) Kumar, N. Y. P.; Jeyachandran, R.; Ackermann, L. C(sp3)-H
Bond Arylations Catalyzed by Well-Defined [Ru(O2CMes)2(p-
cymene)]. J. Org. Chem. 2013, 78, 4145−4152.
(25) Jain, P.; Verma, P.; Xia, G.; Yu, J.-Q. Enantioselective Amine α-
Functionalization via Palladium-Catalysed C-H Arylation of Thio-
amides. Nat. Chem. 2017, 9, 140−144.
(26) Tran, T.; Yu, J.-Q. Practical Alkoxythiocarbonyl Auxiliaries for
Iridium(I)-catalyzed C-H Alkylation of Azacycles. Angew. Chem., Int.
Ed. 2017, 56, 10530−10534.
(27) Xie, H.; Ye, Z.; Ke, Z.; Lan, J.; Jiang, H.; Zeng, W. Rh(III)-
catalyzed regioselective intermolecular N-methylene Csp3-H bond
carbenoid insertion. Chem. Sci. 2018, 9, 985−989.
(28) Reyes, R. L.; Sato, M.; Iwai, T.; Sawamura, M. Asymmetric
Synthesis of α-Aminoboronates via Rhodium-Catalyzed Enantiose-
lective C(sp3)-H Borylation. J. Am. Chem. Soc. 2020, 142, 589−597.
(29) Li, C.-J. Exploring C-C Bond Formations beyond Functional
Group Transformations. Acc. Chem. Res. 2009, 42, 335−344.
(30) Zuo, Z.; Ahneman, D. T.; Chu, L.; Terrett, J. A.; Doyle, A. G.;
MacMillan, D. W. C. Merging Photoredox with Nickel Catalysis:
Coupling of α-Carboxyl sp3-Carbons with Aryl Halides. Science 2014,
345, 437−440.
(31) Joe, C. L.; Doyle, A. G. Direct Acylation of C(sp3)-H Bonds
Enabled by Nickel and Photoredox Catalysis. Angew. Chem., Int. Ed.
2016, 55, 4040−4043.
(32) Shaw, M. H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.;
MacMillan, D. W. C. Native Functionality in Triple Catalytic Cross-
Coupling: sp3 C-H Bonds as Latent Nucleophiles. Science 2016, 352,
1304−1308.
(33) Thullen, S. M.; Rovis, T. A Mild Hydroaminoalkylation of
Conjugated Dienes Using a Unifified Cobalt and Photoredox
Catalytic System. J. Am. Chem. Soc. 2017, 139, 15504−15508.
(34) Rand, A. W.; Yin, H.-F.; Xu, L.; Giacoboni, J.; Martin-Montero,
R.; Romano, C.; Montgomery, J.; Martin, R. Dual Catalytic Platform
for Enabling sp3 α C-H Arylation and Alkylation of Benzamides. ACS
Catal. 2020, 10, 4671−4676.
(35) Shu, X.-M.; Huan, L.-T.; Huang, Q.; Huo, H.-H. Direct
Enantioselective C(sp3)-H Acylation for the Synthesis of α-Amino
Ketones. J. Am. Chem. Soc. 2020, 142, 19058−19064.
(36) Trost, B. M. The Atom Economy a Search for Synthetic
Efficiency. Science 1991, 254, 1471−1477.
(37) Eisch, J. J.; Galle, J. E. The Role of Nickelole Intermediates in
the Oligojmerization of Alkynes. J. Organomet. Chem. 1975, 96, C23−
C26.
(38) Eisch, J. J.; Damasevitz, G. A. Stereospecific Alkylation Alkynes
by bis(Ir-allyl) Nickel and the Mechanism of Oligomerization of
Alkynes by Nickel(0). J. Organomet. Chem. 1975, 96, C19−C22.
(39) Montgomery, J. Nickel-Catalyzed Reductive Cyclizations and
Couplings. Angew. Chem., Int. Ed. 2004, 43, 3890−3908.
(40) Patel, S. J.; Jamison, T. F. Asymmetric Catalytic Coupling of
Organoboranes, Alkynes, Imines with a Removable (Trialkylsiyloxy)-
ethyl Group-Direct Access to Enantiomerically Pure Primary Allylic
Amines. Angew. Chem., Int. Ed. 2004, 43, 3941−3944.
(41) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, S.; Tamaru, Y.
Highly Stereo- and Regioselective Ni-Catalyzed Homoallylation of
Aldimines with Conjugated Dienes Promoted by Diethylzinc. J. Am.
Chem. Soc. 2004, 126, 14360−14361.
(57) Chen, F.-L.; Chen, K.; Zhang, Y.; He, Y.-L.; Wang, Y.-M.; Zhu,
S.-L. Remote Migratory Cross-Electrophile Coupling and Olefin
Hydroarylation Reactions Enabled by in Situ Generation of NiH. J.
Am. Chem. Soc. 2017, 139, 13929−13935.
(58) Xiao, J.-C.; He, Y.-L.; Ye, F.; Zhu, S.-L. Remote sp3 C-H
Amination of Alkenes with Nitroarenes. Chem. 2018, 4, 1645−1657.
(59) Wang, Z.; Yin, H.; Fu, G. C. Catalytic Enantioconvergent
Coupling of Secondary and Tertiary Electrophiles with Olefns. Nature
2018, 563, 379−383.
4160
https://dx.doi.org/10.1021/jacs.1c00622
J. Am. Chem. Soc. 2021, 143, 4154−4161

Journal of the American Chemical Society
pubs.acs.org/JACS
Communication
(60) Zhou, F.; Zhang, Y.; Xu, X.; Zhu, S. NiH-Catalyzed Remote
Asymmetric Hydroalkylation of Alkenes with Racemic α-Bromo
Amides. Angew. Chem., Int. Ed. 2019, 58, 1754−1758.
(61) Bera, S.; Hu, X. Nickel-Catalyzed Regioselective Hydro-
alkylation and Hydroarylation of Alkenyl Boronic Esters. Angew.
Chem., Int. Ed. 2019, 58, 13854−13859.
(62) Cai, Y.; Zhang, J.-W.; Li, F.; Liu, J.-M.; Shi, S.-L. Nickel/N-
Heterocyclic Carbene Complex-Catalyzed Enantioselective Redox-
Neutral Coupling of Benzyl Alcohols and Alkynes to Allylic Alcohols.
ACS Catal. 2019, 9, 1−6.
(63) Bera, S.; Mao, R.; Hu, X. Enantioselective C(sp3)-C(sp3)
Cross-Coupling of Non-Activated Alkyl Electrophiles via Nickel
Hydride Catalysis. Nat. Chem. 2021, 13, 270.
(64) Because rotation of the C(alkenyl)-C(phenyl) σ-bond of the
products could be hindered by a bulky ortho-substituent on the
arenes, two diastereomers were obtained in the cases 3bl and 3bx.
(65) Nie, M.; Fu, W.; Cao, Z.; Tang, W. Enantioselective Nickle-
Catalyzed Alkylative Alkyne-Aldehyde Cross-Couplings. Org. Chem.
Front. 2015, 2, 1322−1325.
(66) Xu, G.; Senanayake, C. H.; Tang, W. P-Chiral Phosphorus
Ligands Based on a 2,3-Dihydrobenzo[d][1,3]oxaphosphole Motif for
Asymmetric Catalysis. Acc. Chem. Res. 2019, 52, 1101−1112.
(67) The absolute configuration of 4j was determined by X-ray
crystallography.
(68) Liu, D.; Li, B.-W.; Chen, J.-Z.; Gridnev, L. D.; Yan, D.-Y.;
Zhang, W.-B. Ni-Catalyzed Asymmetric Hydrogenation of N-Aryl
Imino Esters for the Efficient Synthesis of Chiral α-Aryl Glycines. Nat.
Commun. 2020, 11, 5935.
(69) Jonas, K.; Wilke, G. Hydrido and Alkyl(aryl)hydrido
Complexes of Nickel. Angew. Chem., Int. Ed. Engl. 1969, 8, 519−520.
4161
https://dx.doi.org/10.1021/jacs.1c00622
J. Am. Chem. Soc. 2021, 143, 4154−4161