Chiral Alkyl Amine Synthesis via Catalytic Enantioselective Hydroalkylation of Enecarbamates

Article abstract of DOI:10.1021/jacs.0c11630

Chiral alkyl amines are omnipresent as bioactive molecules and synthetic intermediates. The catalytic and enantioselective synthesis of alkyl amines from readily accessible precursors is challenging. Here we develop a nickel-catalyzed hydroalkylation method to assemble a wide range of chiral alkyl amines from enecarbamates (N-Cbz-protected enamines) and alkyl halides with high regio- and enantioselectivity. The method works for both nonactivated and activated alkyl halides and is able to produce enantiomerically enriched amines with two minimally differentiated α-alkyl substituents. The mild conditions lead to high functional group tolerance, which is demonstrated in the postproduct functionalization of many natural products and drug molecules, as well as the synthesis of chiral building blocks and key intermediates to bioactive compounds.

Full text of DOI:10.1021/jacs.0c11630

pubs.acs.org/JACS
Article
Chiral Alkyl Amine Synthesis via Catalytic Enantioselective
Hydroalkylation of Enecarbamates
Deyun Qian, Srikrishna Bera, and Xile Hu*
Cite This: J. Am. Chem. Soc. 2021, 143, 1959−1967
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Chiral alkyl amines are omnipresent as bioactive
molecules and synthetic intermediates. The catalytic and enantiose-
lective synthesis of alkyl amines from readily accessible precursors is
challenging. Here we develop a nickel-catalyzed hydroalkylation method
to assemble a wide range of chiral alkyl amines from enecarbamates (N-
Cbz-protected enamines) and alkyl halides with high regio- and
enantioselectivity. The method works for both nonactivated and
activated alkyl halides and is able to produce enantiomerically enriched
amines with two minimally differentiated α-alkyl substituents. The mild
conditions lead to high functional group tolerance, which is
demonstrated in the postproduct functionalization of many natural
products and drug molecules, as well as the synthesis of chiral building
blocks and key intermediates to bioactive compounds.
originating from activated alkyl electrophiles have been
reported.9 However, enantioselective hydroalkylation to
introduce a new stereocenter at the carbon originating from
the alkenes is challenging due to the tendency of Ni−H to
mediate chain walking of an internal alkene to form a terminal,
nonchiral Ni−alkyl species.10 By installing an α-directing group
such as boryl and aryl, our group11 and the Zhu group12 were
recently able to develop Ni-catalyzed enantioselective hydro-
alkylation and hydroarylation for the synthesis of chiral alkyl
boronates and 1,1-diarylalkanes, respectively. The electron-
withdrawing α-directing groups are essential in stabilizing the
branched alkyl−Ni intermediates against chain walking. In this
context, we envisioned enantioselective hydroalkylation of
enamine derivatives for the synthesis of chiral amines (Figure
1F). If successful, this approach would be general and efficient
in introducing a diverse set of alkyl groups at the α-position of
chiral amines, a task difficult to achieve using existing methods.
Moreover, because enamines can be easily prepared from
readily available alkyl aldehydes or other precursors,13 the
approach will have a wide scope or be more practical than
hydrogenation of imines, which requires less accessible dialkyl
ketones as reagents. However, an N-based α-substituent as in
enamine derivatives is typically considered an electron-
1. INTRODUCTION
Enantiomerically pure amines are frequently encountered in
natural products, pharmaceuticals, and agrochemicals (Figure
1A).1 They are also important building blocks and chiral
auxiliaries in asymmetric synthesis. General, catalytic, and
enantioselective assembly of chiral amines, especially those
with two minimally differentiated aliphatic substituents,
represents a synthetic challenge.1c Although chiral amines
can be prepared by the hydrogenation of imines, enamines, and
their derivatives using precious-metal catalysts (Figure 1B), the
catalysts are costly and the substrates typically have an α-aryl
or α-carboxyl substituent.2 Likewise, enantioselective addition
of an alkyl organometallic reagent1b,3 or an alkyl radical1b,4 to
imine derivatives is mostly applicable to the synthesis of chiral
amines with one α-aryl or α-carboxyl group, in addition to
requiring either highly activated substrates or high catalyst
loadings (Figure 1C,D). Recent breakthroughs in CuH-
catalyzed asymmetric hydroamination of internal alkenes
provide a new approach to chiral amine synthesis (Figure
1E).5 Nevertheless, trisubstituted, tetrasubstituted, and cis-
disubstituted alkenes and alkenes bearing electron-donating
substituents are still difficult substrates, limiting the types of
chiral amines that can be prepared from this approach.5a,6
Ni-catalyzed hydroalkylation of alkenes7 has emerged as an
attractive alternative to traditional alkyl−alkyl cross-coupling.8
By using stable and abundant alkenes as pro-nucleophiles
instead of reactive organometallic reagents, hydroalkylation
offers substantial advantages in practicality, scope, and
functional group compatibility over conventional cross-
coupling. Several elegant examples of asymmetric hydro-
alkylation to create a new stereocenter at the carbon
Received: November 5, 2020
Published: January 22, 2021
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967
© 2021 American Chemical Society
1959

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 1. Significance of chiral α-alkyl amines and representative methods of their synthesis.
donating group.2b When we started, there was no prior report
that such a group would stabilize a branched alkyl−Ni
intermediate to direct enantioselective hydroalkylation,
although a report of Ni-catalyzed enantioselective hydro-
arylation of N-vinyl amides appeared while we were writing
this manuscript.14
Table 1. Summary of the Effects of Key Reaction
a
Parameters
Here we describe the development of a modular method
based on this approach. The method allows the enantiose-
lective coupling of a wide range of N-Cbz-protected enamines
(Cbz = benzyloxycarbonyl) with both activated and non-
activated alkyl halides to give enantiomerically enriched α-alkyl
chiral amines. The method has high group tolerance and can
be used for the functionalization of many natural products and
bioactive compounds, as well as the synthesis of valuable chiral
intermediates.
b
entry
variant
L* = L*1
L* = L*2
L* = L*3
L* = L*4
yield (%)
er
1
2
3
4
5
6
7
91
83
41
97
84
85
27
90:10
65:35
55:45
70:30
82:18
92:8
2. RESULTS AND DISCUSSION
L* = L*5
HBpin instead of DEMS
HBcat instead of DEMS
DMPU instead of DMA
2.1. Reaction Development of Enantioselective
Hydroalkylation. We started the development by optimizing
the hydroalkylation of benzyl (Z)-N-(prop-1-en-1-yl)-
carbamate (1a, 1.0 equiv) using iodocyclohexane (2a, 1.5
equiv) as the alkylating agent, a silane or hydroborane (2.0
equiv) as the hydride source, and a nickel salt (10 mol %) in
combination with a chiral nitrogen-based ligand (15 mol %) as
the catalyst (Table 1). We chose Cbz as the N-protecting
group because this carbamate group could be easily removed,
unlike other acyl groups used in related studies.14 An initial
screening suggested room temperature and 40 h as appropriate
conditions. The influence of ligands, Ni salts, hydride sources,
bases, and solvents and the outcome of control experiments are
89:11
94:6
c
8
92 (87)
a
See section 2 in the the Supporting Information for experimental
details. All reactions were carried out in a 0.1 mmol scale with respect
to 1a, Corrected GC yields using n-dodecane as an internal standard
were reported. Definitions: DMA, dimethylacetamide; DEMS,
diethoxymethylsilane; DMPU, N,N′-dimethylpropyleneurea; Cbz,
b
benzyloxycarbonyl; rt, room temperature. The er values were
c
determined by HPLC analysis. Isolated yield.
described in Tables S1−S6 in the Supporting Information. A
key summary is shown in Table 1. With diethoxymethylsilane
1960
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Table 2. Scope of Ni-Catalyzed Enantioselective Hydroalkylation of Enecarbamates
a
Conditions unless noted otherwise: all reactions were carried out with NiBr2·diglyme (15 mol %), ligand L*1 (15 mol %), 1 (0.20 mmol), 2 (0.30
b
c
mmol), HBpin (0.40 mmol), KF (0.40 mmol), and DMPU (1.0 mL) at room temperature for 40 h. (OEt)2MeSiH instead of HBpin. The dr
value was determined by H NMR and HPLC analysis. DMA instead of DMPU. NiI2·xH2O, L*9, and DMA instead of the corresponding
standard parameters. 1i:2a = 1.5:1; NiI2·xH2O, L*9, (OEt)3SiH, and DMA instead of the corresponding standard parameters.
d
e
1
f
1961
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
a
Table 3. Reactions of Substrates Derived from Natural Products and Drugs
a
Conditions unless specified otherwise: all reactions were carried out with NiBr2·diglyme (15 mol %), ligand L*1 (15 mol %), 1 (0.20 mmol), 2
b
1
(0.30 mmol), HBpin (0.40 mmol), KF (0.40 mmol), and DMPU (1.0 mL) at room temperature for 40 h. The dr value was determined by H
c
d
NMR and HPLC analysis. DMA instead of DMPU. NiI2·xH2O, L*9, (OEt)3SiH, and DMA instead of the corresponding standard parameters.
e
ent-L*1 instead of L*1.
(DEMS) as the hydride source, 2,2-bis(2-oxazoline) (Bi-Ox)
and pyridine-oxazoline (Py-Ox) ligands were effective, giving
the desired product 3a in various yields and enantiomeric
ratios (ers), whereas bis-oxazoline (Box), pyridine bis-oxazo-
line (Pybox), and phosphinooxazoline (Phox) ligands gave no
product (Table S1 in the Supporting Information). A large
number of Bi-Ox ligands were screened, revealing the
sensitivity of the reaction outcome on the substituents of the
ligands. Aryl substituents typically gave higher ers than alkyl
substituents (entries 1−5, Table 1), and the best result was
obtained with the phenyl-substituted Bi-Ox ligand L*1, which
gave a yield of 91% and an er of 90:10 (entry 1, Table 1).
NiBr2·diglyme was the best Ni source among various Ni(II)
salts (Table S2 in the Supporting Information). Several
hydrosiloxanes could be used as the hydride source with
similar efficiency, but less electrophilic hydrosilanes such as
Et3SiH and Ph2MeSiH were inefficient (Table S3 in the
Supporting Information). The enantiomeric ratio was
increased to 92:8 using pinacolborane (HBpin) as the hydride
source (entry 6, Table 1), while the yield remained as high as
85%. A slightly lower er but much lower yield was obtained
using catecholborane (HBcat) (entry 7, Table 1). Different
bases gave similar enantioselectivities but very different yields,
and KF was the best base (Table S4 in the Supporting
Information). The yields and, to a lesser degree, the ers were
sensitive to the solvents (Table S5 in the Supporting
Information). A meticulous screening revealed N,N′-dimethyl-
propyleneurea (DMPU) to be the best solvent (entry 8, Table
1). Thus, the final optimized conditions were identified as
NiBr2·diglyme (10 mol %) plus Bi-Ox L*1 (15 mol %) as the
catalyst, HBpin (2.0 equiv) as the hydride source, KF (2.0
equiv) as the base, and DMPU as the solvent. Under these
conditions, 3a was obtained as a single regioisomer in 92% GC
(87% isolated) yield with an er of 94:6 (entry 8, Table 1). In
comparison to the Ni-catalyzed hydroalkylation of alkenyl
boronates,11 the best chiral ligand is the same while the
optimized Ni salt, hydride source, and solvent are all different,
indicating a strong influence of the directing group in the
reactivity. Two recent reports describe Ni-catalyzed enantio-
selective hydroarylation of alkenes where the best ligands were
based on bisimidazolines,14a,c a different class of ligands in
comparison to the Bi-Ox used here. This difference suggests a
mechanistic divergence in these related reactions.
2.2. Scope of Enantioselective Hydroalkylation. We
then explored the scope of this enantioselective hydro-
alkylation method (Table 2). The method worked well for
the coupling of various secondary alkyl iodides, including both
acyclic and cyclic substrates, to give the corresponding chiral
dialkyl amines with good yields and high enantioselectivity
(3a−i). These products would be difficult to access via
enantioselective cross-coupling,8b,c which is difficult for the
coupling of two secondary alkyl fragments.15 Cyclic groups
relevant to medicinal chemistry such as 2H-pyran, piperidine,
and oxetane were well tolerated (3e−g). Hydroalkylation with
2i had a good yield and er but moderate diastereoselectivity
(3i).
The hydroalkylation method worked for primary alkyl
iodides as well. Functional groups such as chloride (3l),
ether (3m), acetal (3n), ketone (3o), ester (3p), furan (3p),
phthalimide (3q), indole (3r), and amine (3r) were all
compatible. In addition to nonactivated alkyl halides, activated
halides such as benzylic bromides were also suitable substrates
for the hydroalkylation, yielding the corresponding chiral
amines in good yields and high enantioselectivity (3s−w). The
absolute configuration of 3s was determined as R by comparing
its optical rotation value to a reported compound (section 9 in
the Supporting Information). We assigned the same absolute
configuration to all analogous products. The reactions were
insensitive to the electronic properties of the substituents of
the benzylic bromides. An aryl bromide group was tolerated in
the reaction (3u), reserving a reaction site for further
downstream cross-coupling. The coupling of unactivated
tertiary alkyl iodides such as tert-butyl iodide was unsuccessful.
An array of enecarbamates could be used as the
pronucleophiles for the enantioselective hydroalkylation (4a−
j). Not only CbzNH but also BocNH (4c, Boc = tert-
butoxycarbonyl) was a viable directing group. The C−C bond
formation was regioselective at the carbon α to the RNH
group, even in the presence of an aryl group (4b,c). Functional
groups such as alkyl chlorides (4d,e) and esters (4f,g) on
1962
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
enecarbamates were tolerated. Coupling of a sterically
demanding β,β′-disubstituted enecarbamate had a modest
yield (48%) but a high er (94:6) (4i). Vinylamine, a
synthetically useful substrate that poses a challenge in
regioselectivity,16 was coupled to give a single regioisomer
(4j) with a high yield and high enantioselectivity with modified
reaction conditions. The reaction with a trisubstituted
enecarbamate was unsuccessful, however (end of section 6 in
the Supporting Information), probably due to steric hindrance
that blocked Ni−H insertion.
2.3. Functionalization of Natural Products and Drugs.
The enantioselective hydroalkylation method worked for alkyl
halide substrates derived from natural products and drugs,
generating chiral alkyl amines bearing the corresponding
complex or bioactive alkyl fragments (Table 3).17 Alkyl
iodides derived from cholestanol, a biomarker (5a),17a
nootkatone, a sesquiterpenoid (5b),17b and naproxen, a
nonsteroidal anti-inflammatory drug (5c),17c which contained
one or more stereocenters, reacted to give the corresponding
chiral alkyl amines in good yields, high enantioselectivity, and
modest to good diastereoselectivity. Alkyl iodides derived from
drugs such as gemfibrozil (5e), indomethacin (5f,g), and
adapalene (5h) as well as from the herbicide 2,4-D (5d) were
viable reaction partners. These results underscore the high
group tolerance of the hydroalkylation method and its
potential application in the synthesis of bioactive chiral amines.
2.4. Synthetic Applications. The chiral alkyl amines
produced from the above hydroalkylation method proved to be
useful synthetic intermediates.18 For example, simple silyl ether
deprotection of 3m afforded the amino alcohol 6 in high yield
(Figure 2). Compound 6 is a common synthon in asymmetric
organic synthesis because its OH moiety can be easily
converted to other functional groups without erosion in
enantiomeric excess: for instance, in the synthesis of a chiral
piperidine (7a)18a and a β-amino acid (7b).18b In another
example, a Finkelstein reaction of 3l followed by base
treatment provided a (R)-coniine analogue (8) in 53% yield
and 94:6 er. The chiral amine (−)-3s was a reported
intermediate to (R)-1,2,3,4-tetrahydroisoquinoline (11), an
inhibitor of phenylethanolamine N-methyltransferase. Previ-
ously (−)-3s was prepared in three steps from 10, which was in
turn prepared by organocatalytic conjugate addition of a
nitroalkane to vinylsulfone.18c With the current method,
(−)-3s was prepared in one step from enecarbamate 1a and
benzyl bromide. Deprotection of the Cbz moiety in (−)-3s by
Pd/C-catalyzed hydrogenation gave the primary amine, which
was converted without isolation into intermediate 9 with
perfect stereocontrol.
2.5. Mechanistic Investigation. Several experiments were
conducted to probe the origin of the enantioselectivity in the
present hydroalkylation reactions. When the E isomer of 1a
was subjected to the standard conditions (entry 8, Table 1), 3a
was produced just using (Z)-1a. The reaction of (E)-1a was
slightly slower and had a lower yield and enantioselectivity in
comparison to the reaction of (Z)-1a (Figure 3a). This result is
consistent with Ni−H insertion into the alkene as the
enantiodetermining step. If reductive elimination were the
enantiodetermining step, a similar er would be expected for
reactions using either (Z)-1a or (E)-1a.12,14,19 The reactions of
(Z)-1a and (E)-1a with DBpin gave diastereomerically pure D-
3h and D-3h′ (Figure 3b,c). Likewise, reactions of (Z)-1c and
its deuterated analogue, enecarbamate D-(Z)-1c, gave
diastereomerically pure D-4k and D-4k′, respectively (Figure
3d,e). These results again suggest that syn-hydrometalation of
NiH or NiD to N-Cbz enamine is the enantiodetermining step.
Otherwise, a diastereomeric mixture of deuterated products
would be formed. In the reactions involving deuterated
substrates, the enantioselectivity was not influenced by the
1
deuteration. The H NMR spectrum of D-4k′ indicated that
no H/D exchange occurred at the N α-position, suggesting
that the hydride insertion step was irreversible. Overall, the
above results indicate that a reaction pathway involving
reversible Ni−alkyl homolysis followed by stereoselective
reductive elimination12,14,19 can be excluded for the current
system.
When the allylic amine derivative 1a′ was used as the pro-
nucleophile, 3a was also produced, albeit in a lower yield and
er, together with other regioisomers (Figure 3f). This result
indicates chain walking of the distal alkenyl group mediated by
Ni−H to form an α-CbzHN-stabilized Ni−alkyl species.10
When the N-methyl enecarbamate (Z)-1a′′ was used as the
substrate, less than 5% hydroalkylation occurred (Figure 3g).
The low activity toward this tertiary carbamate might be due to
the conformational rigidity of a tertiary carbamate, which
precluded the Cbz group to act as a directing group for Ni−H
insertion (see below). To probe the possibility of Ni-catalyzed
hydroboration of enecarbamate followed by alkyl−alkyl Suzuki
cross-coupling, we treated the hydroboration product relevant
to the hydroalkylation reaction. However, no cross-coupling
occurred, ruling out the Suzuki coupling pathway (Figure 3h).
When 1.0 equiv of (2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO), a radical scavenger, was added to the reaction
mixture, the conversion decreased to 54% and the yield
decreased to 12% while the er remained the same (Figure 3i).
This result is consistent with the intermediate of an alkyl
Figure 2. Synthetic applications. See section 7 in the Supporting
Information for full details. TBAF = tetrabutylammonium fluoride.
Legend: (a) with ent-L*1.
1963
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 4. (a) Monitoring of the reaction progress of (Z)-1a with 2a
over time. (b) Nonlinear effect study.
enantiomeric excess of the product and catalyst followed a
linear relationship, indicating a monomeric nature of the active
catalyst (Figure 4b).
Following previous proposals on Ni-catalyzed hydroalkyla-
tion9,11 and considering the results above, we propose two
limiting catalytic cycles for the present enantioselective
hydroalkylation of N-protected enamines (Figure 5). In one
possibility (Figure 5a), under the reaction conditions, a chiral
L*NiI−X species (A) is formed as the actual catalyst, which
reacts with a hydride source and base (e.g, HBpin + KF) to
generate the Ni−H species L*NiI−H (C). The hydride species
inserts into the alkene moiety of the enamine.20 The resulting
NiI−alkyl species (D) reacts with an alkyl halide via a halogen
atom abstraction followed by alkyl radical trapping to give a
NiIII−bis(alkyl) intermediate (D to E to F).21 The last species
undergoes reductive elimination to give the coupling product
and regenerate the NiI−X catalyst (A). In another possibility
(Figure 5b), species A first abstracts a halogen atom from an
alkyl iodide to generate an alkyl radical and XL*NiII−I (B′).
The latter reacts with a hydride source (e.g, HBpin + KF) to
generate the Ni−H species XL*NiII−H (C′) that inserts into
the enamine. The resulting Ni−alkyl intermediate (D′) then
recombines with the alkyl radical to give a formal Ni(III)
complex (E′), which undergoes reductive elimination to give
the product and regenerate the Ni(I) catalyst. The key
difference between the two catalytic cycles is the Ni species
that activates the alkyl halide. In the first catalytic cycle, it is a
NiI−alkyl species; in the second catalytic cycle, it is a NiI−X
species. Both possibilities were proposed in the litera-
ture.7,9,14,21
Figure 3. Results of mechanistic experiments.
radical in the hydroalkylation reaction, which was inhibited by
TEMPO.9a Meanwhile, the hydrogenation product was
obtained in 31% yield, revealing that the Ni−alkyl species
formed upon Ni−H insertion underwent mostly C−H
reductive elimination instead of alkyl−alkyl coupling in the
presence of TEMPO. We cannot rule out the possibility that
TEMPO inhibited the reaction by abstracting an H atom from
a Ni−H species. Thus, we conducted additional reactions
using radical clock substrates. The reactions of 5-iodopent-1-
ene and an alkyl iodide containing a cyclopropyl ring gave ring-
closed and ring-opened products, respectively, albeit in low
yields (<10%) probably due to side reactions (see section 8.2
in the Supporting Information). This result supports the
intermediacy of alkyl radicals.21 However, direct addition of
alkyl radicals to alkenes is not a viable pathway, as indicated by
the regioselectivity of α-alkylation.
We expect that the coordination of the Cbz group of the
enecarbamate substrate to the Ni center facilitates regio- and
enantioselective Ni−H insertion into the alkene moiety.20 A cis
conformation of the carbamate is necessary for the Cbz group
to act as a directing group. The low activity toward a tertiary
carbamate substrate (Figure 3g) is likely due to a dominant
trans conformation of the substrate, which has a high rotational
barrier as well. The addition of hydride into the carbon β to
the NHCbz group is favored over the insertion into the α-
The reaction progress of (Z)-1a with 2a was monitored over
time (Figure 4a). While the yield increased gradually over the
course of the reaction, the er remained at about 94:6. This
result ruled out a kinetic resolution mechanism. Moreover, the
1964
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Figure 5. Proposed catalytic cycle: X = I, Br; RL = large group; RS = small group.
carbon due to the formation of a more stable five-membered
nickelacycle in comparison to a six-membered nickelacycle in
the latter case. The enantioselectivity of insertion is dictated by
the steric interaction of the phenyl substituent with the alkene
substituents (RL and RS). In the favored transition state, the
phenyl group is far from the RL group (TS-1a or TS-1a′). In
the opposite configuration, the phenyl group would experience
steric repulsion from the RL group (TS-1b or TS-1b′). A lower
enantioselectivity was observed for a Boc-protected enamine in
comparison to its Cbz-protected analogue (4b vs 4c). This
difference indicates an influence of the protecting group in the
stereoselectivity of the reaction, possibly due to steric effects
(Boc is bulkier than Cbz and might hinder metal coordination)
or a π−π stacking interaction (Cbz has a Ph group). The
details of the catalytic cycle will be subjected to a dedicated
study.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c11630.
Experimental procedures, mechanistic investigation,
characterization data, and H NMR, 13C NMR, and
1
HPLC spectra for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Xile Hu − Laboratory of Inorganic Synthesis and Catalysis,
Institute of Chemical Sciences and Engineering, École
Polytechnique Fédérale de Lausanne (EPFL), ISIC-LSCI,
BCH 3305, Lausanne 1015, Switzerland; orcid.org/
0000-0001-8335-1196; Email: xile.hu@epfl.ch
3. CONCLUSIONS
Authors
In summary, we have developed a method for the Ni-catalyzed
enantioselective hydroalkylation of enecarbamates. This
method allows the synthesis of a wide range of enantiomeri-
cally enriched chiral alkyl amines from readily available and
stable alkenes while avoiding sensitive organometallic reagents.
The method operates under mild conditions and has high
functional group tolerance. It has been applied for the
postfunctionalization of many natural products and drug
molecules.
Deyun Qian − Key Laboratory of Medicinal Chemistry for
Natural Resource, Ministry of Education and Yunnan
Province, Yunnan University, Kunming 650091, People’s
Republic of China; Laboratory of Inorganic Synthesis and
Catalysis, Institute of Chemical Sciences and Engineering,
École Polytechnique Fédérale de Lausanne (EPFL), Lausanne
1015, Switzerland
Srikrishna Bera − Laboratory of Inorganic Synthesis and
Catalysis, Institute of Chemical Sciences and Engineering,
1965
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Site-Selective Ni-Catalyzed Reductive Coupling of α-Haloboranes
with Unactivated Olefins. J. Am. Chem. Soc. 2018, 140, 12765−12769.
(d) 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.
(e) Bera, S.; Hu, X. Nickel-Catalyzed Regioselective Hydroalkylation
and Hydroarylation of Alkenyl Boronic Esters. Angew. Chem., Int. Ed.
2019, 58, 13854−13859. (f) Qian, D.; Hu, X. Ligand-Controlled
Regiodivergent Hydroalkylation of Pyrrolines. Angew. Chem., Int. Ed.
2019, 58, 18519−18523. (g) Sun, S.-Z.; Romano, C.; Martin, R. Site-
Selective Catalytic Deaminative Alkylation of Unactivated Olefins. J.
Am. Chem. Soc. 2019, 141, 16197−16201. (h) Wang, C.; Xi, Y.;
Huang, W.; Qu, J.; Chen, Y. Nickel-Catalyzed Regioselective
Hydroarylation of Internal Enamides. Org. Lett. 2020, 22, 9319−9324.
(8) (a) Hu, X. Nickel-catalyzed cross coupling of non-activated alkyl
halides: a mechanistic perspective. Chem. Sci. 2011, 2, 1867−1886.
(b) Choi, J.; Fu, G. C. Transition metal-catalyzed alkyl-alkyl bond
formation: another dimension in cross-coupling chemistry. Science
2017, 356, eaaf7230. (c) Fu, G. C. Transition-Metal Catalysis of
Nucleophilic Substitution Reactions: A Radical Alternative to SN1
and SN2 Processes. ACS Cent. Sci. 2017, 3, 692−700.
(9) (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 Remote Asymmetric 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 Hydroalkyla-
tion 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) Shi, L.; Xing, L.-L.; Hu, W.-B.; Shu, W. Regio- and
Enantioselective Ni-Catalyzed Formal Hydroalkylation, Hydrobenzy-
lation, and Hydropropargylation of Acrylamides to α-Tertiary Amides.
Angew. Chem., Int. Ed. 2021, 60, 1599.
École Polytechnique Fédérale de Lausanne (EPFL), Lausanne
1015, Switzerland
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c11630
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Swiss National Science
Foundation.
REFERENCES
■
(1) (a) Nugent, T. C. Chiral amine synthesis: methods, developments
and applications; Wiley: 2010. (b) Li, W.; Zhang, X. Stereoselective
formation of amines; Springer: 2014. (c) 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.
(2) (a) Nugent, T. C.; El-Shazly, M. Chiral Amine Synthesis -
Recent Developments and Trends for Enamide Reduction, Reductive
Amination, and Imine Reduction. Adv. Synth. Catal. 2010, 352, 753−
819. (b) Xie, J.-H.; Zhu, S.-F.; Zhou, Q.-L. Transition Metal-
Catalyzed Enantioselective Hydrogenation of Enamines and Imines.
Chem. Rev. 2011, 111, 1713−1760. (c) Seo, C. S. G.; Morris, R. H.
Catalytic Homogeneous Asymmetric Hydrogenation: Successes and
Opportunities. Organometallics 2019, 38, 47−65.
(3) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic
Enantioselective Formation of C-C Bonds by Addition to Imines and
Hydrazones: A Ten-Year Update. Chem. Rev. 2011, 111, 2626−2704.
(4) (a) Miyabe, H.; Ushiro, C.; Ueda, M.; Yamakawa, K.; Naito, T.
Asymmetric Synthesis of α-Amino Acids Based on Carbon Radical
Addition to Glyoxylic Oxime Ether. J. Org. Chem. 2000, 65, 176−185.
(b) Friestad, G. K.; Shen, Y.; Ruggles, E. L. Enantioselective Radical
Addition to N-Acyl Hydrazones Mediated by Chiral Lewis Acids.
Angew. Chem., Int. Ed. 2003, 42, 5061−5063. (c) Cho, D. H.; Jang, D.
O. Enantioselective radical addition reactions to the C−N bond
utilizing chiral quaternary ammonium salts of hypophosphorous acid
in aqueous media. Chem. Commun. 2006, 5045−5047. (d) Lee, S.;
Kim, S. Enantioselective radical addition reactions to imines using
binaphthol-derived chiral N-triflyl phosphoramides. Tetrahedron Lett.
2009, 50, 3345−3348.
(5) (a) Liu, R. Y.; Buchwald, S. L. CuH-Catalyzed Olefin
Functionalization: From Hydroamination to Carbonyl Addition.
Acc. Chem. Res. 2020, 53, 1229−1243. (b) Yang, Y.; Shi, S.-L.; Niu,
D.; Liu, P.; Buchwald, S. L. Catalytic asymmetric hydroamination of
unactivated internal olefins to aliphatic amines. Science 2015, 349,
62−66. (c) Niu, D.; Buchwald, S. L. Design of Modified Amine
Transfer Reagents Allows the Synthesis of α-Chiral Secondary Amines
via CuH-Catalyzed Hydroamination. J. Am. Chem. Soc. 2015, 137,
9716−9721.
(6) (a) Zhu, S.; Niljianskul, N.; Buchwald, S. L. Enantio- and
Regioselective CuH-Catalyzed Hydroamination of Alkenes. J. Am.
Chem. Soc. 2013, 135, 15746−15749. (b) Zhu, S.; Buchwald, S. L.
Enantioselective CuH-Catalyzed Anti-Markovnikov Hydroamination
of 1,1-Disubstituted Alkenes. J. Am. Chem. Soc. 2014, 136, 15913−
15916. (c) Shi, S.-L.; Buchwald, S. L. Copper-catalysed selective
hydroamination reactions of alkynes. Nat. Chem. 2015, 7, 38−44.
(d) Yu, L.; Somfai, P. Regio- and Enantioselective Formal
Hydroamination of Enamines for the Synthesis of 1,2-Diamines.
Angew. Chem., Int. Ed. 2019, 58, 8551−8555.
(10) (a) Vasseur, A.; Bruffaerts, J.; Marek, I. Remote functionaliza-
tion through alkene isomerization. Nat. Chem. 2016, 8, 209−219.
́
́
(b) Sommer, H.; Julia-Hernandez, F.; Martin, R.; Marek, I. Walking
Metals for Remote Functionalization. ACS Cent. Sci. 2018, 4, 153−
165.
(11) Bera, S.; Mao, R.; Hu, X. Enantioselective C(sp3)-C(sp3) cross-
coupling of non-activated alkyl electrophiles via nickel hydride
catalysis. Nat. Chem. 2020.
(12) He, Y.; Liu, C.; Yu, L.; Zhu, S. Enantio- and Regioselective
NiH-Catalyzed Reductive Hydroarylation of Vinylarenes with Aryl
Iodides. Angew. Chem., Int. Ed. 2020, 59, 21530−21534.
(13) (a) Mecozzi, T.; Petrini, M. A Stereoselective Synthesis of
Primary (Z)-Enecarbamates from α-Amidoalkylphenyl Sulfones.
Synlett 2000, 2000, 73−74. (b) Gooßen, L. J.; Salih, K. S. M.;
Blanchot, M. Synthesis of Secondary Enamides by Ruthenium-
Catalyzed Selective Addition of Amides to Terminal Alkynes. Angew.
Chem., Int. Ed. 2008, 47, 8492−8495. (c) Trost, B. M.; Cregg, J. J.;
Quach, N. Isomerization of N-Allyl Amides To Form Geometrically
Defined Di-, Tri-, and Tetrasubstituted Enamides. J. Am. Chem. Soc.
2017, 139, 5133−5139.
̈
(14) (a) Cuesta-Galisteo, S.; Schorgenhumer, J.; Wei, X.; Merino, E.;
Nevado, C. Nickel-Catalyzed Asymmetric Synthesis of α-Arylbenza-
mides. Angew. Chem., Int. Ed. 2021, 60, 1605−1609. (b) During the
review of this manuscript, there were several preprints on the
asymmetric reductive hydroarylation and hydroalkylation of enam-
ides: Jia-Wang, W.; Yan, L.; Wan, N.; Zhe, C.; Zi-An, Y.; Yi-Fan, Z.;
Xi, L.; Yao, F. Catalytic Asymmetric Reductive Alkylation of
Enamines to Chiral Aliphatic Amines. ChemRxiv, DOI: 10.26434/
chemrxiv.13102307.v1. (c) Yuli, H.; Huayue, S.; Shaolin, Z. NiH-
Catalyzed Asymmetric Hydroarylation of N-Acyl Enamines: Practical
Access to Chiral Benzylamines. ChemRxiv, DOI: 10.26434/
chemrxiv.13084946.v1. (d) Shan, W.; Tian-Yi, Z.; Jian-Xin, Z.;
Huan, M.; Bi-Hong, C.; Shu, W. Enantioselective Access to Dialkyl
(7) (a) 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. (b) Lu, X.; Xiao, B.; Liu, L.; Fu, Y. Formation of
C(sp3)-C(sp3) Bonds through Nickel-Catalyzed Decarboxylative
Olefin Hydroalkylation Reactions. Chem. - Eur. J. 2016, 22, 11161−
̈
11164. (c) Sun, S.-Z.; Borjesson, M.; Martin-Montero, R.; Martin, R.
1966
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967

Journal of the American Chemical Society
pubs.acs.org/JACS
Article
Amines and Alcohols via Ni-Catalyzed Reductive Hydroalkylations.
ChemRxiv, DOI: 10.26434/chemrxiv.13284416.v1.
(15) (a) Cordier, C. J.; Lundgren, R. J.; Fu, G. C. Enantioconvergent
Cross-Couplings of Racemic Alkylmetal Reagents with Unactivated
Secondary Alkyl Electrophiles: Catalytic Asymmetric Negishi α-
Alkylations of N-Boc-pyrrolidine. J. Am. Chem. Soc. 2013, 135,
10946−10949. (b) Mu, X.; Shibata, Y.; Makida, Y.; Fu, G. C. Control
of Vicinal Stereocenters through Nickel-Catalyzed Alkyl-Alkyl Cross-
Coupling. Angew. Chem., Int. Ed. 2017, 56, 5821−5824. (c) Huo, H.;
Gorsline, B. J.; Fu, G. C. Catalyst-controlled doubly enantioconver-
gent coupling of racemic alkyl nucleophiles and electrophiles. Science
2020, 367, 559−564.
(16) (a) Boyington, A. J.; Seath, C. P.; Zearfoss, A. M.; Xu, Z.; Jui,
N. T. Catalytic Strategy for Regioselective Arylethylamine Synthesis. J.
Am. Chem. Soc. 2019, 141, 4147−4153. (b) Wei, X.; Shu, W.; García-
Domínguez, A.; Merino, E.; Nevado, C. Asymmetric Ni-Catalyzed
Radical Relayed Reductive Coupling. J. Am. Chem. Soc. 2020, 142,
13515−13522.
(17) (a) Bethell, P. H.; Goad, L. J.; Evershed, R. P.; Ottaway, J. The
Study of Molecular Markers of Human Activity: The Use of
Coprostanol in the Soil as an Indicator of Human Faecal Material.
J. Archaeol. Sci. 1994, 21, 619−632. (b) Mander, L. Overview and
Introduction. Comprehensive natural products II 2010, 1−3. (c) Mitch-
ell, J. A.; Akarasereenont, P.; Thiemermann, C.; Flower, R. J.; Vane, J.
R. Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of
constitutive and inducible cyclooxygenase. Proc. Natl. Acad. Sci. U. S.
A. 1993, 90, 11693−11697.
(18) (a) Etxebarria, J.; Vicario, J. L.; Badía, D.; Carrillo, L. A general
and enantiodivergent method for the asymmetric synthesis of
piperidine alkaloids: concise synthesis of (R)-pipecoline, (S)-coniine
and other 2-alkylpiperidines. Tetrahedron 2007, 63, 11421−11428.
(b) Bahamonde, A.; Al Rifaie, B.; Martín-Heras, V.; Allen, J. R.;
Sigman, M. S. Enantioselective Markovnikov Addition of Carbamates
to Allylic Alcohols for the Construction of α-Secondary and α-
Tertiary Amines. J. Am. Chem. Soc. 2019, 141, 8708−8711. (c) Zhu,
Q.; Lu, Y. Enantioselective Conjugate Addition of Nitroalkanes to
Vinyl Sulfone: An Organocatalytic Access to Chiral Amines. Org. Lett.
2009, 11, 1721−1724.
(19) Gutierrez, O.; Tellis, J. C.; Primer, D. N.; Molander, G. A.;
Kozlowski, M. C. Nickel-Catalyzed Cross-Coupling of Photoredox-
Generated Radicals: Uncovering a General Manifold for Stereo-
convergence in Nickel-Catalyzed Cross-Couplings. J. Am. Chem. Soc.
2015, 137, 4896−4899.
(20) For the promotion of NiH insertion into olefins via
coordination of the directing group, see: Jeon, J.; Lee, C.; Seo, H.;
Hong, S. NiH-Catalyzed Proximal-Selective Hydroamination of
Unactivated Alkenes. J. Am. Chem. Soc. 2020, 142, 20470−20480.
(21) (a) Jones, G. D.; Martin, J. L.; McFarland, C.; Allen, O. R.;
Hall, R. E.; Haley, A. D.; Brandon, R. J.; Konovalova, T.; Desrochers,
P. J.; Pulay, P.; Vicic, D. A. Ligand Redox Effects in the Synthesis,
Electronic Structure, and Reactivity of an Alkyl-Alkyl Cross-Coupling
Catalyst. J. Am. Chem. Soc. 2006, 128, 13175−13183. (b) Breitenfeld,
J.; Ruiz, J.; Wodrich, M. D.; Hu, X. Bimetallic Oxidative Addition
Involving Radical Intermediates in Nickel-Catalyzed Alkyl-Alkyl
Kumada Coupling Reactions. J. Am. Chem. Soc. 2013, 135, 12004−
12012. (c) Yin, H.; Fu, G. C. Mechanistic Investigation of
Enantioconvergent Kumada Reactions of Racemic α-Bromoketones
Catalyzed by a Nickel/Bis(oxazoline) Complex. J. Am. Chem. Soc.
2019, 141, 15433−15440. (d) Richmond, E.; Moran, J. Recent
Advances in Nickel Catalysis Enabled by Stoichiometric Metallic
Reducing Agents. Synthesis 2018, 50, 499−513.
1967
https://dx.doi.org/10.1021/jacs.0c11630
J. Am. Chem. Soc. 2021, 143, 1959−1967