Catalytic Asymmetric Hydroalkylation of α,β-Unsaturated Amides Enabled by Regio-Reversed and Enantiodifferentiating syn-Hydronickellation

Article abstract of DOI:10.1021/acscatal.1c02299

Here, we report an enantioselective nickel-hydride catalyzed hydroalkylation of readily accessible β-alkyl-α,β-unsaturated amides to form structurally diverse β-chiral amides. This process was proposed to proceed through an enantiodifferentiating syn-hydrometalation of nickel hydride, forming chiral alkylnickel at the β-position in which the regioselectivity is different from that with copper hydride. This regio-reversed hydronickellation process provides a complementary approach to access enantioenriched β-functionalization amides with a stereocenter at the β-position.

Full text of DOI:10.1021/acscatal.1c02299

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Letter
Catalytic Asymmetric Hydroalkylation of α,β-Unsaturated Amides
Enabled by Regio-Reversed and Enantiodifferentiating syn-
Hydronickellation
Fang Zhou and Shaolin Zhu*
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ABSTRACT: Here, we report an enantioselective nickel-hydride
catalyzed hydroalkylation of readily accessible β-alkyl-α,β-unsaturated
amides to form structurally diverse β-chiral amides. This process was
proposed to proceed through an enantiodifferentiating syn-hydro-
metalation of nickel hydride, forming chiral alkylnickel at the β-position
in which the regioselectivity is different from that with copper hydride.
This regio-reversed hydronickellation process provides a complemen-
tary approach to access enantioenriched β-functionalization amides with
a stereocenter at the β-position.
KEYWORDS: alkenes, alkylation, asymmetric catalysis, nickel, nickel-hydride
o improve the clinical success in drug discovery, an
attractive approach is to increase C(sp3) fraction of drug
manner consistent with the electronic requirements which
limited the subsequent functionalization to the α-position
(Figure 1b, left).10,11 To overcome the electronic effect and
reverse the classical regioselectivity of hydrometalation, we
questioned if the coordination effect of a certain metal hydride
with a carbonyl group could predominate and whether the
stereoselectivity could be simultaneously controlled.8h−o In such
a case, a wide range of structurally diverse, enantiopure β-
functionalized carbonyl compounds could be obtained (Figure
1b, right). As shown in Figure 1c, we speculated that the amide
group could serve as a good directing group for an appropriately
ligated NiH species to undergo a regio-reversed syn-hydro-
nickellation and then form a five-membered nickellacycle.8h−o
In terms of enantiomeric control, such a hydrometalation step
with an appropriate chiral ligand could be enantioselective
producing enantioenriched β-alkylnickel intermediates, which
could undergo subsequent stereospecific cross-coupling with
alkyl iodides to produce the enantioenriched β-alkylation
product.12 Successful implementation of this transformation
will also require that the obtained oxidative addition Ni(III)
intermediates obtained in this way will not undergo homolysis
and recombination before reductive elimination to form the final
product.8f,g,i,j,p This is essential, because, otherwise, a loss of
T
candidates to avoid flat molecules.1 Construction of the most
common C(sp3)−C(sp3) bond with stereochemical control has
long been a goal in organic synthesis.2 As a catalyst, low-cost
nickel has many advantages, such as its easy access to diverse
oxidation states and its ability to allow facile oxidative addition
with alkyl electrophiles. Over the past two decades, it has
emerged as a powerful catalyst in enantioselective C(sp3) cross-
coupling reactions.3
Generation of alkyl organometallic reagents in situ by catalytic
hydrometalation of alkenes with metal hydrides is an attractive
strategy that avoids the special preparation of organometallic
reagents.4 It also circumvents another issue encountered in
conventional cross-coupling, that the basic and nucleophilic
nature of pregenerated organometallic reagents can often lead to
limited functional-group compatibility, rendering it unable to
handle sensitive functionality. Recently, nickel hydride5−9 has
proved to be an efficient catalyst for enantioselective reductive
hydrofunctionalization,8 especially in hydroalkylation reactions
(Figure 1a). In this process, chiral induction could occur in one
of two possible steps: (i) enantioconvergent alkylation with
racemic 2° or 3° alkyl halide to form enantioenriched Ni(III)
intermediates, constructing stereocenter at the carbon originat-
ing from racemic electrophile;8a−d or (ii) enantioselective syn-
hydrometalation of NiH with an alkene to form enantioenriched
alkylnickel species, constructing a stereocenter at the carbon
originating from achiral olefin.8e−p
Received: May 21, 2021
Revised: June 29, 2021
Published: July 2, 2021
Previously, when electron-deficient alkenes such as β-alkyl-
α,β-unsaturated carbonyl compounds were used in hydro-
cupration reactions, an α-copper intermediate was produced in a
https://doi.org/10.1021/acscatal.1c02299
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Table 1. Variation of Reaction Parameters
a
Yields were determined by GC using n-tetradecane as the internal
Figure 1. Enantioselective regio-reversed hydroalkylation of α,β-
unsaturated amides.
standard, the yield in parentheses is the isolated yield and is an
average of two runs (0.20 mmol scale). Regioisomeric ratio
b
represents the ratio of the major product to the sum of all other
isomers, as determined by GC analysis. Enantiomeric excess (ee) was
determined by chiral-stationary-phase HPLC analysis. ND = not
determined. PMHS, polymethylhydrosiloxane; DMA, N,N-dimethy-
lacetamide; DME, dimethoxyethane.
c
enantiomeric purity would result. In this communication, we
report a mild and robust protocol for such a strategy and
demonstrate that by using a chiral PyrOx-nickel complex as the
sole catalyst, a highly enantioselective hydroalkylation of α,β-
unsaturated amides can be realized through such an
enantioselective regio-reversed hydrometalation step (Figure
1c).
results were obtained when the reaction was conducted at 0 °C
(Table 1, entry 12). An alkyl bromide was less reactive when 1-
bromohexane was used (Table 1, entry 13). The E,Z-
configuration of the α,β-unsaturated amide governs the
stereochemistry of the product. When (Z)-1a was used, the
opposite enantiomer was obtained, albeit in significantly lower
yield and with only moderate ee (Table 1, entry 14). A slightly
diminished yield was obtained when the catalyst loading was
reduced to 5 mol % (Table 1, entry 15), and the reaction was
found to be not highly sensitive to small amounts of water and air
(Table 1, entries 16 and 17).
With these optimal conditions in hand, we examined the
scope of the alkyl iodide reaction partner. As shown in Table 2,
both primary (2a−2d′) and secondary (2e′−2i′) alkyl iodides
reacted. Methyl-d3 iodide (2c) was also compatible, providing
the β-methyl-d3 substituted amide smoothly. Under these mild
conditions, not only were a nitrile (2f), esters (2h, 2w), a
phosphonate (2i), ethers (2j−2l, 2z, 2b′, 2f′), an acetal (2m), a
N-Boc carbamate (2n), and a phthaloyl imide (2o) tolerated,
but a trisubstituted alkene (2c′) and easily reduced ketones (2p,
2x) remained intact. Notably, the reaction is orthogonal to alkyl
chlorides (2g) and aryl chlorides (2u), providing coupling
handles that can be used for further derivatization. Various
medicinally relevant heterocycles including furan (2v), thio-
phene (2w), pyrrole (2x), indole (2y), pyridine (2z), pyrazole
(2a′), and benzothiazole (2b′) were also found to be
This catalytic regio-reversed hydroalkylation was first
evaluated by using α,β-unsaturated amide (1a) and 1-
iodohexane (2a) as model substrates (see Table 1). After
examination of the reaction parameters and evaluation of
different ligands, it was determined that Ni(NO3)2·6H2O and
the C6-substituted PyrOx ligand (L1)8b,13 could generate the
desired β-selective hydroalkylation product as a single
regioisomer [rr (β-product: all other isomers) > 99:1] in 90%
isolated yield with excellent enantioselectivity (Table 1, entry 1).
Other nickel sources such as NiI2·xH2O led to significantly lower
yields and a moderate rr (Table 1, entry 2). Screening of ligands
revealed that ligands lacking the C4-methoxy substituent gave
similar results (Table 1, entry 3), while a ligand with a tert-butyl
group on its oxazoline ring shown the highest ee (Table 1, entry
3 vs entries 4 and 5). Ligands with different C6-substituents on
the pyridyl ring were screened, and a ligand with sterically
bulkier C6-substituent gave the best ee and yield (Table 1, entry
3 vs entries 6 and 7). Evaluation of other hydride sources showed
that diethoxy(methyl)silane (DEMS) and pinacolborane
(HBpin) were equally effective (Table 1, entries 8 and 9).
Polymethylhydrosiloxane (PMHS), which is an inexpensive,
environmentally friendly, and common silicone industry by-
product was used in subsequent investigations. NaF was shown
to be an unsuitable base (Table 1, entry 10) and DME was
shown to be an unsuitable solvent (Table 1, entry 11). Similar
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compatible. However, for unsymmetrical racemic secondary
alkyl iodide substrate (2i′), the stereocenter at the carbon
originating from this alkyl electrophile could not be well-
controlled in this protocol.
Scheme 1. Gram-Scale, Versatile Transformations, Isotopic
Labelling, and Directing Group Experiments
The optimized conditions also proved efficient for the various
α,β-unsaturated amide components (Table 3). Both β-alkyl
(1b−1i) and β-aryl (1j) substituted acrylamides were readily
accommodated, but in the case of the β-aryl acrylamide (1j), a
slightly decreased enantioselectivity was observed. Under these
exceptionally mild reaction conditions, a variety of functional
groups were readily accommodated, including an alkyl chloride
(1e), esters (1g, 1p), ethers (1h, 1i, 1n), an aryl chloride (1o), a
free alcohol (1f), and an unprotected phenol (1m). Notably,
α,β-disubstituted acrylamides (1k, 1l) could also undergo
reversed hydroalkylation to afford the enantioenriched amides
as a single diastereoisomer with two stereocenters, although a
marginal erosion in the ee was observed. The absolute
configuration of 4l was unambiguously determined by X-ray
diffraction analysis, and supports our hypothesis that syn-
hydronickellation is the enantio-determining step. β,β-Disub-
stituted α,β-unsaturated amide produced no desired product
under the current reaction conditions. Moreover, α,β-unsatu-
rated amides with aryl (1m−1p, 1v) or alkyl (1q, 1t)
substituents on the nitrogen atom all were found to be
compatible. α,β-Unsaturated amides bearing electron-donating
(1m, 1n) or electron-withdrawing (1o, 1p) substituents on the
N-aryl ring were well-tolerated. Finally, α,β-unsaturated amide
with a stereocenter adjacent to the nitrogen atom proceeded
with excellent catalyst control (1t).
The model reaction proceeded smoothly on a 6 mmol scale
without any decrease of yield or enantioselectivity, demonstrat-
ing the scalability of this process (Scheme 1a). As illustrated in
Scheme 1b, the obtained enantiopure β-substituted amides
could be transformed to versatile enantioenriched motifs
including an amine (5), a primary amide (6), an ester (7), or
a ketone (8). To shed light on the hydrometalation process, an
isotope labeling experiment was performed (Scheme 1c). With
deuteropinacolborane as a hydride source, the desired
deuteroalkylation product (3a-D) was obtained as only one
diastereoisomer,14 together with the partial hydroalkylation
product (3a), indicating the amide-directed regio-reversed syn-
hydronickellation is the enantio-determining step, which is also
consistent with previous reports.8e,h,k−n This conclusion was
also supported by the observation of diastereoisomerically pure
products in the case of 4k or 4l (see Table 3). Finally, the amide
directing group also plays an important role. As illustrated in
Scheme 1d, α,β-unsaturated carbonyl compounds with a weak
directing group such as α,β-unsaturated ester (4w) gave the
desired β-alkylation product with poor selectivity and low yield.
And a trace amount of desired product was obtained in the case
of using α,β-unsaturated ketone (4x) or α,β-unsaturated
aldehyde (4y) as a substrate.
In conclusion, we have developed an enantioselective
reductive NiH-catalyzed strategy for regio-reversed hydro-
functionalization of α,β-unsaturated amides to form enantiopure
β-alkylated carbonyl compounds. This reversed hydrometala-
tion of nickel hydride differs from the regioselectivity of
hydrocupration of β-alkyl-α,β-unsaturated carbonyls, and allows
access to β-selective hydroalkylation products. A preliminary
isotope labeling experiment indicated that the syn-hydro-
metalation of NiH is the enantio-determining step. With an
olefin as a nucleophile, broad substrate scope, and mild
conditions of this protocol have been demonstrated. Studies
directed toward the development of a migratory enantioselective
version of this transformation are currently in progress.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.1c02299.
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Full experimental data, details on methods and starting
materials, copies of spectral data (PDF)
Crystallographic data of 4c (CIF)
Crystallographic data of 4l (CIF)
AUTHOR INFORMATION
Corresponding Author
■
Shaolin Zhu − State Key Laboratory of Coordination
Chemistry, Jiangsu Key Laboratory of Advanced Organic
Materials, Chemistry and Biomedicine Innovation Center
(ChemBIC), School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing 210093, China; orcid.org/
0000-0003-1516-6081; Email: shaolinzhu@nju.edu.cn
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(c) Sommer, H.; Juliá-Hernández, F.; Martin, R.; Marek, I. Walking
Author
Metals for Remote Functionalization. ACS Cent. Sci. 2018, 4, 153−165.
Fang Zhou − State Key Laboratory of Coordination Chemistry,
Jiangsu Key Laboratory of Advanced Organic Materials,
Chemistry and Biomedicine Innovation Center (ChemBIC),
School of Chemistry and Chemical Engineering, Nanjing
University, Nanjing 210093, China
(d) Janssen-Muller, D.; Sahoo, B.; Sun, S.-Z.; Martin, R. Tackling
̈
Remote sp3 C−H Functionalization via Ni-Catalyzed “chain-walking”
Reactions. Isr. J. Chem. 2020, 60, 195−206. (e) Ning, Y.; Chen, F.-E.
Transition Metal-Catalyzed Branch-Selective Hydroformylation of
Olefins in Organic Synthesis. Green Synth. Catal. 2021,
DOI: 10.1016/j.gresc.2021.04.008.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.1c02299
(6) For selected examples about Ni(I)H, see: (a) Cornella, J.; Gómez-
Bengoa, E.; Martin, R. Combined Experimental and Theoretical Study
on the Reductive Cleavage of Inert C−O Bonds with Silanes: Ruling
out a Classical Ni(0)/Ni(II) Catalytic Couple and Evidence for Ni(I)
Intermediates. J. Am. Chem. Soc. 2013, 135, 1997−2009. (b) Kuang, Y.;
Anthony, D.; Katigbak, J.; Marrucci, F.; Humagain, S.; Diao, T. Ni(I)-
Catalyzed Reductive Cyclization of 1,6-Dienes: Mechanism-Controlled
trans Selectivity. Chem. 2017, 3, 268−280. (c) Wang, X.-X.; Lu, X.; Li,
Y.; Wang, J.-W.; Fu, Y. Recent Advances in Nickel-Catalyzed Reductive
Hydroalkylation and Hydroarylation of Electronically Unbiased
Alkenes. Sci. China: Chem. 2020, 63, 1586−1600.
Author Contributions
F.Z. and S.Z. designed the project. F.Z. performed the
experiments. All authors cowrote the manuscript, analyzed the
data, discussed the results and commented on the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(7) For recent NiH-catalyzed reductive (remote) hydrofunctionaliza-
tion, see: (a) Buslov, I.; Becouse, J.; Mazza, S.; Montandon-Clerc, M.;
Hu, X. Chemoselective Alkene Hydrosilylation Catalyzed by Nickel
Pincer Complexes. Angew. Chem., Int. Ed. 2015, 54, 14523−14526.
(b) Lu, X.; Xiao, B.; Zhang, Z.; Gong, T.; Su, W.; Yi, J.; Fu, Y.; Liu, L.
Practical Carbon−Carbon Bond Formation from Olefins through
Nickel-Catalyzed Reductive Olefin Hydrocarbonation. Nat. Commun.
2016, 7, 11129. (c) Green, S. A.; Matos, J. L. M.; Yagi, A.; Shenvi, R. A.
Branch-Selective Hydroarylation: Iodoarene-Olefin Cross-Coupling. J.
Am. Chem. Soc. 2016, 138, 12779−12782. (d) He, Y.; Cai, Y.; Zhu, S.
Mild and Regioselective Benzylic C−H Functionalization: Ni-
Catalyzed Reductive Arylation of Remote and Proximal Olefins. J.
Am. Chem. Soc. 2017, 139, 1061−1064. (e) Juliá-Hernández, F.;
Moragas, T.; Cornella, J.; Martin, R. Remote Carboxylation of
Halogenated Aliphatic Hydrocarbons with Carbon Dioxide. Nature
2017, 545, 84−88. (f) Gaydou, M.; Moragas, T.; Juliá-Hernández, F.;
Martin, R. Site-Selective Catalytic Carboxylation of Unsaturated
Hydrocarbons with CO2 and Water. J. Am. Chem. Soc. 2017, 139,
12161−12164. (g) Chen, F.; Chen, K.; Zhang, Y.; He, Y.; Wang, Y.-M.;
Zhu, S. Remote Migratory Cross-Electrophile Coupling and Olefin
Hydroarylation Reactions Enabled by in situ Generation of NiH. J. Am.
Chem. Soc. 2017, 139, 13929−13935. (h) Zhou, F.; Zhu, J.; Zhang, Y.;
Zhu, S. NiH-Catalyzed Reductive Relay Hydroalkylation: A Strategy for
the Remote C(sp3)−H Alkylation of Alkenes. Angew. Chem., Int. Ed.
2018, 57, 4058−4062. (i) Xiao, J.; He, Y.; Ye, F.; Zhu, S. Remote sp3
C−H Amination of Alkene with Nitroarenes. Chem. 2018, 4, 1645−
1657. (j) Peng, L.; Li, Y.; Li, Y.; Wang, W.; Pang, H.; Yin, G. Ligand-
Controlled Nickel-Catalyzed Reductive Relay Cross-Coupling of Alkyl
Bromides and Aryl Bromides. ACS Catal. 2018, 8, 310−313.
(k) Shevick, S. L.; Obradors, C.; Shenvi, R. A. Mechanistic
Interrogation of Co/Ni-Dual Catalyzed Hydroarylation. J. Am. Chem.
Soc. 2018, 140, 12056−12068. (l) Sun, S.-Z.; Börjesson, M.; Martin-
Montero, R.; Martin, R. Site-Selective Ni-Catalyzed Reductive
Coupling of α-Haloboranes with Unactivated Olefins. J. Am. Chem.
Soc. 2018, 140, 12765−12769. (m) Zhang, Y.; Xu, X.; Zhu, S. Nickel-
Catalysed Selective Migratoryhydrothiolation of Alkenes and Alkynes
with Thiols. Nat. Commun. 2019, 10, 1752. (n) Nguyen, J.; Chong, A.;
Lalic, G. Nickel-Catalyzed anti-Markovnikov Hydroarylation of
Alkenes. Chem. Sci. 2019, 10, 3231−3236. (o) Bera, S.; Hu, X.
Nickel-Catalyzed Regioselective Hydroalkylation and Hydroarylation
of Alkenyl Boronic Esters. Angew. Chem., Int. Ed. 2019, 58, 13854−
13859. (p) Zhang, Y.; Han, B.; Zhu, S. Rapid Access to Highly
Functionalized Alkyl Boronates by NiH-Catalyzed Remote Hydro-
arylation of Boron-Containing Alkenes. Angew. Chem., Int. Ed. 2019, 58,
13860−13864. (q) Qian, D.; Hu, X. Ligand-Controlled Regiodivergent
Hydroalkylation of Pyrrolines. Angew. Chem., Int. Ed. 2019, 58, 18519−
18523. (r) Sun, S.-Z.; Romano, C.; Martin, R. Site-Selective Catalytic
Deaminative Alkylation of Unactivated Olefins. J. Am. Chem. Soc. 2019,
141, 16197−16201. (s) Qian, C.; Tang, W. NiH-Catalyzed Migratory
Defluorinative Olefin Cross-Coupling: Trifluoromethyl-Substituted
Support was provided by NSFC (Nos. 21822105 and
21772087), NSF of Jiangsu Province (No. BK20201245), and
programs for high-level entrepreneurial and innovative talents
introduction of Jiangsu Province (group program). F. Zhou
thanks the “Nanjing University Innovation and Creative
Program for PhD candidate” (No. CXCY19-41) for support.
We thank Dr. Yuanzheng Cheng, Jingjie Yang, and Yuhang Xue
for providing some substrates. We gratefully acknowledge Dr.
Penglong Wang (Professor Congqing Zhu group) for acquiring
X-ray crystal structure.
REFERENCES
■
(1) (a) Lovering, F.; Bikker, J.; Humblet, C. Escape from Flatland:
Increasing Saturation as an Approach to Improving Clinical Success. J.
Med. Chem. 2009, 52, 6752−6756. (b) Chiral Drugs: Chemistry and
Biological Action. Lin, G.-Q.; You, Q.-D.; Cheng, J.-F., Eds.; Wiley−
VCH: Hoboken, NJ, 2011.
(2) de Meijere, A.; Diederich, F. In Metal-Catalyzed Cross-Coupling
Reactions, 2nd Edition; Wiley−VCH: Weinheim, Germany, 2004.
(3) For selected reviews on nickel catalysis, see: (a) Netherton, M. R.;
Fu, G. C. Nickel-Catalyzed Cross-Couplings of Unactivated Alkyl
Halides and Pseudohalides with Organometallic Compounds. Adv.
Synth. Catal. 2004, 346, 1525−1532. (b) Hu, X. Nickel-Catalyzed
Cross Coupling of Non-Activated Alkyl Halides: A Mechanistic
Perspective. Chem. Sci. 2011, 2, 1867−1886. (c) Montgomery, J.
Organonickel Chemistry. In Organometallics in Synthesis; Lipshutz, B.
H., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ, 2013; pp 319−428.
(d) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Recent Advances in
Homogeneous Nickel Catalysis. Nature 2014, 509, 299−309. (e)
Nickel Catalysis in Organic Synthesis; Ogoshi, S., Ed.; Wiley−VCH:
Weinheim, Germany, 2020. (f) Poremba, K. E.; Dibrell, S. E.; Reisman,
S. E. Nickel-Catalyzed Enantioselective Reductive Cross-Coupling
Reactions. ACS Catal. 2020, 10, 8237−8246.
(4) For selected reviews on metal-hydride chemistry, see: (a) Liu, R.
Y.; Buchwald, S. L. CuH-Catalyzed Olefin Functionalization: From
Hydroamination to Carbonyl Addition. Acc. Chem. Res. 2020, 53,
1229−1243. (b) Eberhardt, N. A.; Guan, H. Nickel Hydride
Complexes. Chem. Rev. 2016, 116, 8373−8426. (c) Crossley, S. W.
M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Mn-, Fe-, and Co-
Catalyzed Radical Hydrofunctionalizations of Olefins. Chem. Rev. 2016,
116, 8912−9000. (d) Chen, J.; Guo, J.; Lu, Z. Recent Advances in
Hydrometallation of Alkenes and Alkynes via the First Row Transition
Metal Catalysis. Chin. J. Chem. 2018, 36, 1075−1109.
(5) For selected reviews on metal hydride-catalyzed chain-walking,
see: (a) Larionov, E.; Li, H.; Mazet, C. Well-Defined Transition Metal
Hydrides in Catalytic Isomerizations. Chem. Commun. 2014, 50, 9816−
9826. (b) Vasseur, A.; Bruffaerts, J.; Marek, I. Remote Functionalization
through Alkene Isomerization. Nat. Chem. 2016, 8, 209−219.
8771
https://doi.org/10.1021/acscatal.1c02299
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pubs.acs.org/acscatalysis
Letter
Alkenes as Acceptor Olefins to Form gem-Difluoroalkenes. Youji
Huaxue 2020, 40, 1076−1077. (t) Gao, Y.; Yang, C.; Bai, S.; Liu, X.;
Wu, Q.; Wang, J.; Jiang, C.; Qi, X. Visible-Light-Induced Nickel-
Catalyzed Cross-Coupling with Alkylzirconocenes from Unactivated
Alkenes. Chem. 2020, 6, 675−688. (u) Kumar, G. S.; Peshkov, A.;
Brzozowska, A.; Nikolaienko, P.; Zhu, C.; Rueping, M. Nickel-
Catalyzed Chain-Walking Cross-Electrophile Coupling of Alkyl and
Aryl Halides and Olefin Hydroarylation Enabled by Electrochemical
Reduction. Angew. Chem., Int. Ed. 2020, 59, 6513−6519. (v) Zhang, Y.;
He, J.; Song, P.; Wang, Y.; Zhu, S. Ligand-Enabled NiH-Catalyzed
Migratory Hydroamination: Chain Walking as a Strategy for
Regiodivergent/Regioconvergent Remote sp3 C−H Amination. CCS
Chem. 2020, 2, 2259−2268. (w) Jeon, J.; Lee, C.; Seo, H.; Hong, S.
NiH-Catalyzed Proximal-Selective Hydroamination of Unactivated
Alkenes. J. Am. Chem. Soc. 2020, 142, 20470−20480.
W.-M.; Li, M.-L.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)-Catalyzed
Hydroarylation of Styrenes and 1,3-Dienes with Organoboron
Compounds. Angew. Chem., Int. Ed. 2018, 57, 461−464. (d) Cheng,
L.; Li, M.-M.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)-Catalyzed
Hydroalkylation of 1,3-Dienes with Simple Ketones. J. Am. Chem. Soc.
2018, 140, 11627−11630. (e) Chen, Y.-G.; Shuai, B.; Xu, X.-T.; Li, Y.-
Q.; Yang, Q.-L.; Qiu, H.; Zhang, K.; Fang, P.; Mei, T.-S. Nickel-
Catalyzed Enantioselective Hydroarylation and Hydroalkenylation of
Styrenes. J. Am. Chem. Soc. 2019, 141, 3395−3399. (f) Lv, X.-Y.; Fan,
C.; Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. Ligand-Enabled Nickel-Catalyzed
Enantioselective Hydroarylation of Styrenes and 1,3-Dienes with
Arylboronic Acids. CCS Chem. 2019, 1, 328−334. (g) Zhang, W.-B.;
Yang, X.-T.; Ma, J.-B.; Su, Z.-M.; Shi, S.-L. Regio- and Enantioselective
C−H Cyclization of Pyridines with Alkenes Enabled by a Nickel/N-
Heterocyclic Carbene Catalysis. J. Am. Chem. Soc. 2019, 141, 5628−
5634. (h) Li, Y.; Luo, Y.; Peng, L.; Li, Y.; Zhao, B.; Wang, W.; Pang, H.;
Deng, Y.; Bai, R.; Lan, Y.; Yin, G. Reaction Scope and Mechanistic
Insights of Nickel-Catalyzed Migratory Suzuki−Miyaura Cross-
Coupling. Nat. Commun. 2020, 11, 417. (i) He, Y.; Liu, C.; Yu, L.;
Zhu, S. Ligand-Enabled Nickel-Catalyzed Redox-Relay Migratory
Hydroarylation of Alkenes with Arylborons. Angew. Chem., Int. Ed.
2020, 59, 9186−9191. (j) Marcum, J. S.; Taylor, T. R.; Meek, S. J.
Enantioselective Synthesis of Functionalized Arenes by Nickel-
Catalyzed Site-Selective Hydroarylation of 1,3-Dienes with Aryl
Boronates. Angew. Chem., Int. Ed. 2020, 59, 14070−14075. (k) Shao,
W.; Besnard, C.; Guénée, L.; Mazet, C. Ni-Catalyzed Regiodivergent
and Stereoselective Hydroalkylation of Acyclic Branched Dienes with
Unstabilized C(sp3) Nucleophiles. J. Am. Chem. Soc. 2020, 142,
16486−16492. (l) Yu, R.; Rajasekar, S.; Fang, X. Enantioselective
Nickel-Catalyzed Migratory Hydrocyanation of Nonconjugated
Dienes. Angew. Chem., Int. Ed. 2020, 59, 21436−21441. (m) Li, Z.-
Q.; Fu, Y.; Deng, R.; Tran, V. T.; Gao, Y.; Liu, P.; Engle, K. M. Ligand-
Controlled Regiodivergence in Nickel-Catalyzed Hydroarylation and
Hydroalkenylation of Alkenyl Carboxylic Acids. Angew. Chem., Int. Ed.
2020, 59, 23306−23312.
(10) β-Selective hydrometalation of CuH only happened for styrene
type carbonyl (β-aryl-α,β-unsaturated carbonyl), two similar reports,
see: (a) Guo, S.; Zhu, J.; Buchwald, S. L. Enantioselective Synthesis of
β-Amino Acid Derivatives Enabled by Ligand-Controlled Reversal of
Hydrocupration Regiochemistry. Angew. Chem., Int. Ed. 2020, 59,
20841−20845. (b) Zhang, G.; Liang, Y.; Qin, T.; Xiong, T.; Liu, S.;
Guan, W.; Zhang, Q. Copper-Catalyzed Asymmetric Hydroamination:
A Unified Strategy for the Synthesis of Chiral β-Amino Acid and its
Derivatives. CCS Chem. 2020, 2, 1737−1745.
(11) One elegant example of reversed hydrometalation of β-alkyl-α,β-
unsaturated carbonyl using RhH, see: Gao, T.-T.; Zhang, W.-W.; Sun,
X.; Lu, H.-X.; Li, B.-J. Stereodivergent Synthesis through Catalytic
Asymmetric Reversed Hydroboration. J. Am. Chem. Soc. 2019, 141,
4670−4677.
(8) For NiH-catalyzed enantioselective reductive hydrofunctionaliza-
tion of olefins, see: (a) Wang, Z.; Yin, H.; Fu, G. C. Catalytic
Enantioconvergent Coupling of Secondary and Tertiary Electrophiles
with Olefins. Nature 2018, 563, 379−383. (b) Zhou, F.; Zhang, Y.; Xu,
X.; Zhu, S. NiH-Catalyzed Asymmetric Remote Hydroalkylation of
Alkenes with Racemic α-Bromo Amides. Angew. Chem., Int. Ed. 2019,
58, 1754−1758. (c) He, S.-J.; Wang, J.-W.; Li, Y.; Xu, Z.-Y.; Wang, X.-
X.; Lu, X.; Fu, Y. Nickel-Catalyzed Enantioconvergent Reductive
Hydroalkylation of Olefins with α-Heteroatom Phosphorus or Sulfur
Alkyl Electrophiles. J. Am. Chem. Soc. 2020, 142, 214−221. (d) Yang,
Z.-P.; Fu, G. C. Convergent Catalytic Asymmetric Synthesis of Esters of
Chiral Dialkyl Carbinols. J. Am. Chem. Soc. 2020, 142, 5870−5875.
(e) 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, 270−277. (f) He, Y.; Liu, C.; Yu, L.;
Zhu, S. Enantio- and Regioselective NiH-Catalyzed reductive Hydro-
arylation of Vinylarenes with Aryl Iodides. Angew. Chem., Int. Ed. 2020,
59, 21530−21534. (g) Liu, J.; Gong, H.; Zhu, S. Nickel-Catalyzed,
Regio- and Enantioselective Benzylic Alkenylation of Olefins with
Alkenyl Bromide. Angew. Chem., Int. Ed. 2021, 60, 4060−4064. (h) Shi,
L.; Xing, L.-L.; Hu, W.-B.; Shu, W. Regio- and Enantioselective Ni-
Catalyzed Formal Hydroalkylation, Hydrobenzylation and Hydro-
propargylation of Acrylamides to α-Tertiary Amides. Angew. Chem., Int.
Ed. 2021, 60, 1599−1604. (i) Cuesta-Galisteo, S.; Schörgenhumer, J.;
Wei, X.; Merino, E.; Nevado, C. Nickel-Catalyzed Asymmetric
Synthesis of α-Arylbenzamides. Angew. Chem., Int. Ed. 2021, 60,
1605−1609. (j) He, Y.; Song, H.; Chen, J.; Zhu, S. NiH-Catalyzed
Asymmetric Hydroarylation of N-Acyl Enamines: Practical Access to
Chiral Benzylamines. Nat. Commun. 2021, 12, 638. (k) Qian, D.; Bera,
S.; Hu, X. Chiral Alkyl Amine Synthesis via Catalytic Enantioselective
Hydroalkylation of Enecarbamates. J. Am. Chem. Soc. 2021, 143, 1959−
1967. (l) Wang, J.-W.; Li, Y.; Nie, W.; Chang, Z.; Yu, Z.-A.; Zhao, Y.-F.;
Lu, X.; Fu, Y. Catalytic Asymmetric Reductive Hydroalkylation of
Enamides and Enecarbamates to Chiral Aliphatic Amines. Nat.
Commun. 2021, 12, 1313. (m) Wang, X.-X.; Yu, L.; Lu, X.; Zhang,
Z.-L.; Liu, D.-G.; Tian, C.; Fu, Y. NiH-Catalyzed Reductive
Hydrocarbonation of Enol Esters and Ethers. CCS Chem. 2021, 3,
727−737. (n) Wang, S.; Zhang, J.-X.; Zhang, T.-Y.; Meng, H.; Chen, B.-
H.; Shu, W. Enantioselective Access to Chiral Aliphatic Amines and
Alcohols via Ni-Catalyzed Hydroalkylations. Nat. Commun. 2021, 12,
2771. (o) Zhou, F.; Zhu, S. Enantioselective Hydroalkylation of α,β-
Unsaturated Amides through Reversed syn-Hydrometallation of NiH.
ChemRxiv. 2021, DOI: 10.26434/chemrxiv.13681579.v1. (p) Jiang, X.;
Han, B.; Xue, Y.; Duan, M.; Gui, Z.; Wang, Y.; Zhu, S. Nickel-Catalysed
Migratory Hydroalkynylation and Enantioselective Hydroalkynylation
of Olefins with Bromoalkynes. Nat. Commun. 2021, 12, 3792.
(12) For selected examples of nickel-catalyzed β-alkylation of α,β-
unsaturated carbonyls, see: (a) Shrestha, R.; Weix, D. J. Reductive
Conjugate Addition of Haloalkanes to Enones to form Silyl Enol Ethers.
Org. Lett. 2011, 13, 2766−2769. (b) Shrestha, R.; Dorn, S. C. M.; Weix,
D. J. Nickel-Catalyzed Reductive Conjugate Addition to Enones via
Allylnickel Intermediates. J. Am. Chem. Soc. 2013, 135, 751−762.
(c) Huihui, K. M. M.; Shrestha, R.; Weix, D. J. Nickel-Catalyzed
Reductive Conjugate Addition of Primary Alkyl Bromides to Enones to
Form Silyl Enol Ethers. Org. Lett. 2017, 19, 340−343. (d) Subburaj, K.;
Montgomery, J. A New Catalytic Conjugate Addition/Aldol Strategy
that Avoids Preformed Metalated Nucleophiles. J. Am. Chem. Soc. 2003,
125, 11210−11211.
(9) For recent NiH-catalyzed redox-neutral (remote) hydrofunction-
alization, see: (a) Lee, W.-C.; Wang, C.-H.; Lin, Y.-H.; Shih, W.-C.;
Ong, T.-G. Tandem Isomerization and C−H Activation: Regioselective
Hydroheteroarylation of Allylarenes. Org. Lett. 2013, 15, 5358−5361.
(b) Bair, J. S.; Schramm, Y.; Sergeev, A. G.; Clot, E.; Eisenstein, O.;
Hartwig, J. F. Linear-Selective Hydroarylation of Unactivated Terminal
and Internal Olefins with Trifluoromethyl-Substituted Arenes. J. Am.
Chem. Soc. 2014, 136, 13098−13101. (c) Xiao, L.-J.; Cheng, L.; Feng,
(13) For examples of using 6-substituted PyrOx ligands in Pd-
catalyzed asymmetric transformations, see: (a) Qi, X.; Chen, C.; Hou,
C.; Fu, L.; Chen, P.; Liu, G. Enantioselective Pd(II)-Catalyzed
Intramolecular Oxidative 6-Endo Aminoacetoxylation of Unactivated
Alkenes. J. Am. Chem. Soc. 2018, 140, 7415−7419. (b) Chen, C.;
Pfluger, P. M.; Chen, P.; Liu, G. Palladium(II)-Catalyzed Enantiose-
̈
lective Aminotrifluoromethoxylation of Unactivated Alkenes using
CsOCF3 as a Trifluoromethoxide Source. Angew. Chem., Int. Ed. 2019,
8772
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ACS Catalysis
pubs.acs.org/acscatalysis
Letter
58, 2392−2396. (c) Li, X.; Qi, X.; Hou, C.; Chen, P.; Liu, G.
Palladium(II)-Catalyzed Enantioselective Azidation of Unactivated
Alkenes. Angew. Chem., Int. Ed. 2020, 59, 17239−17244. (d) Chen, C.;
Hou, C.; Chen, P.; Liu, G. Palladium(II)-Catalyzed Aminotrifluor-
omethoxylation of Alkenes: Mechanistic Insight into the Effect of N-
Protecting Groups. Chin. J. Chem. 2020, 38, 346−350.
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(14) Because of the partial overlap of H NMR signals at α- and β-
positions, there may be a trace amount of deuterium at the β-position.
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ACS Catal. 2021, 11, 8766−8773