Regio- and Enantioselective Ni-Catalyzed Formal Hydroalkylation, Hydrobenzylation, and Hydropropargylation of Acrylamides to α-Tertiary Amides

Article abstract of DOI:10.1002/anie.202011339

The development of enantioselective alkyl–alkyl cross-couplings with coinstantaneous formation of a stereogenic center without the use of sensitive organometallic species is attractive yet challenging. Herein, we report the intermolecular regio- and enantioselective formal hydrofunctionalizations of acrylamides, forging a stereogenic center α-position to the newly formed C_sp3–C_sp3 bond for the first time. The use of a newly developed chiral ligand enables the electronically-reversed formal hydrofunctionalizations, including hydroalkylation, hydrobenzylation, and hydropropargylation, offering an efficient way to access diverse enantioenriched amides with a tertiary α-stereogenic carbon center which is facile to racemize. This operationally simple protocol allows for the anti-Markovnikov enantioselective hydroalkylation, and unprecedented hydrobenzylation, hydropropargylation under mild conditions with excellent functional group compatibility, delivering a wide range of amides with excellent levels of enantioselectivity.

Full text of DOI:10.1002/anie.202011339

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Regio- and Enantioselective Ni-Catalyzed Formal
Hydroalkylation, Hydrobenzylation and Hydropropargylation of
Acrylamides to α-Tertiary Amides
Authors: Wei Shu and Lou Shi
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011339
Link to VoR: https://doi.org/10.1002/anie.202011339

10.1002/anie.202011339
Angewandte Chemie International Edition
COMMUNICATION
Regio- and Enantioselective Ni-Catalyzed Formal Hydroalkylation,
Hydrobenzylation and Hydropropargylation of Acrylamides to α-
Tertiary Amides
Lou Shi,[a] Ling-Ling Xing,[a] Wen-Bo Hu,[a] and Wei Shu*[a]
Dedicated to Shanghai Institute of Organic Chemistry on the occasion of its 70th anniversary
[a]
Dr. L. Shi, L.-L. Xing, W.-B. Hu, Prof. Dr. W. Shu
Shenzhen Grubbs Institute, Department of Chemistry, and Guangdong Provincial Key Laboratory of Catalysis
Southern University of Science and Technology
Shenzhen 518055, Guangdong, P. R. China
*E-mail: shuw@sustech.edu.cn
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
a) Enantioselective cross-coupling of electrophiles with nucleophiles
Abstract: To develop enantioselective alkyl-alkyl cross-couplings
with coinstantaneous formation of a stereogenic center without the
use of sensitive organometallic species is attractive yet challenging.
Herein, we report the intermolecular regio- and enantioselective
formal hydrofunctionalizations of acrylamides, forging a stereogenic
center α-position to the newly formed Csp3-Csp3 bond for the first time.
The use of a new developed chiral ligand enables the electronically-
reversed formal hydrofunctionalizations, including hydroalkylation,
hydrobenzylation, and hydropropargylation, offering an efficient way
X
alkyl
EWG
TM/chiral ligand
+
alkyl
M
EWG
M = Zn, B, Mg
-stereogenic center
-C-C bond-forming
b) Enantioselective cross-coupling of -bromoelectrophiles with alkenes
R
H
X
Ni/chiral ligand
Si-H
R
+
EWG
EWG
X = Br
Ni
via
-stereogenic center
R

-C-C bond-forming
c) Enantioselective hydrofunctionalizations of alkenes (This work)
to access diverse enantioenriched amides with
a tertiary α-

stereogenic carbon center which is facile to racemize. This
operationally simple protocol allows for the anti-Markovnikov
alkyl
H
[Ni] L*
+
alkyl
X
 EWG

EWG
Si-H
X = Br, I
-stereogenic center
enantioselective
hydroalkylation,
and
unprecedented

-C-C bond-forming
H
Ni
Ni
H
hydrobenzylation, hydropropargylation under mild conditions with
excellent functional group compatibility, delivering a wide range of
amides with excellent levels of enantioselectivity.
Ni
H


EWG
EWG
sterically
favored
I
II
Ni
H


electronically
favored
hydroalkylation
hydrobenzylation
hydropropargylation



Scheme 1. Alkyl-alkyl cross-coupling strategies to construct stereogenic carbon
center.
As a privileged substructure, α-stereogenic amides are found in a
wide range of bioactive molecules, such as peptides, and serve
as versatile precursors for many other functional groups.[1,2] As a
result, the development of methods to access such stereogenic
centers in a highly enantioselective manner is significant and
highly desirable.[3] Early efforts have focused on the use of
stoichiometric chiral auxiliaries to control the stereochemistry.[4]
Recent studies have been increasingly paid to asymmetric
catalytic alkyl-alkyl cross-coupling transformations.[5] Over the
past decade, extensive progress has been made in transition
metal-catalyzed, in particular, nickel-catalyzed enantioselective
alkyl-alkyl cross-coupling reactions from racemic secondary alkyl
electrophiles with organometallic reagents (Scheme 1a).[6] To
circumvent the use of stoichiometric, reactive, and often sensitive
organometallic reagents, which usually require time-consuming
preformation, one attractive alternative is hydrometallation of
alkenes through metal hydride insertion to generate alkylmetallic
intermediate in situ.[7] Direct use of readily available alkenes as a
surrogate of carbon nucleophile to form alkyl-alkyl carbon bonds
to phosphates and ethers.[10] The current strategy could only be
applied to monosubstituted aliphatic alkenes, resulting in a non-
enantioselective Ni-H insertion, followed by an enantioselective
cross-coupling with activated secondary alkyl bromides adjacent
to electron-withdrawing groups to form a stereogenic carbon-
center at the newly-formed alkyl-alkyl bond. Unactivated alkyl
halides and activated alkenes are unsuccessful substrates with
this strategy. Buchwald group discovered that Cu-H could
undergo enantioselective insertion into alkenes to form alkyl
copper species with a tertiary β-stereogenic carbon center,
followed by C-N bond formation to give β-stereogenic amines.[11]
We questioned whether Ni-H could undergo enantioselective
hydride insertion into alkenes to form an alkyl-Ni species with a
tertiary stereogenic center (II) over electronically favored
intermediate (I), followed by
Csp3-Csp3 cross-coupling of
unactivated alkyl halides, benzyl halides, and propargyl halides to
realize enantioselective hydrofunctionalization of substituted
acrylamides. In particular, enantioselective hydrobenzylation,[12]
hydropropargylation[13] of acrylamides remains unknown. Herein,
we demonstrate the first intermolecular regio- and
enantioselective formal hydrofunctionalizations of alkenes
enabled by Ni-H insertion into acylamides, followed by a Csp3-Csp3
bond-forming process to forge a stereogenic carbon center α-
with
aliphatic
stereogenic
carbon-centers
remains
underdeveloped.[8] Fu group reported a seminal work on Ni-H
catalyzed enantioselective alkyl-alkyl cross-couplings of 1-
substituted alkenes with secondary alkyl bromides adjacent to
amides and esters (Scheme 1b).[9] More recently, the same
strategy was further extended to secondary alkyl bromides next
1
This article is protected by copyright. All rights reserved.

10.1002/anie.202011339
Angewandte Chemie International Edition
COMMUNICATION
position to the newly formed alkyl-alkyl bond (Scheme 1c). This
modular process allows for enantioselective hydroalkylation,
hydrobenzylation, hydropropargylation of acrylamides to afford a
wide range of enantioenriched amides with an α-tertiary
stereogenic carbon center that is facile to racemize.
We set out to explore the hypothesis using N-
phenylmethacrylamide 1a and 3-phenyl-1-bromopropane 2a as
the stereotype substrates (Table 1). After extensive evaluation of
preliminary conditions, we found that use of NiBr2ꞏglyme (10
mol%), nitrogen-coordination ligand (L, 12 mol%), in the presence
of TBAI (2 equiv), trimethoxylsilane (3 equiv), potassium
phosphate monohydrate (3 equiv), and t-butanol (4 equiv) in
diethyl ether delivered optimal yield of 3a. Using the identified
condition, we evaluated the reaction outcome by using different
scaffolds of chiral ligands. First, pyridine bisoxazolidine (L1) or
With the optimized conditions in hand, we turned to explore the
scope of enantioselective formal hydrofunctionalization reaction.
The reaction tolerates a wide variety of functional groups and
substitution patterns for diverse hydrofunctionalization processes
(Tables 2 and 3). Initially, we tested the scope of acrylamides
(Table 2). N-Aryl acrylamides with electron-withdrawing or
electron-donating groups are well tolerated under the reaction
conditions, affording corresponding hydroalkylated chiral amides
in good yields (46-76% yield) with excellent enantioselectivity (93-
95% ee) (3b-3g). Functional groups such as halides (3c), ketones
(3d and 3e), and esters (3f) do not affect the outcome of the
reaction, delivering the chiral amides in excellent enantiomeric
excess (93-94% ee), leaving an opportunity for further elaboration
of the products. Notably, free O-H is also compatible in this
reaction, furnishing the desired product 3h in 60% yield with 94%
pyridine oxazolidine (L2) led to no formation of desired product 3a. ee. meta- and ortho-Substituted anilines were successful
The use of bisoxazolidine ligand with indanyl substituent (L3) only
gave trace amount of 3a. The reaction underwent smoothly in the
presence of Bn-BOX ligand (L4), delivering the anti-Markovnikov
hydroalkylation product 3a in 45% yield with 30% ee. The use of
Ph-BOX ligand derivatives (L5 or L6) improved the results, giving
3a in moderate efficiency with 61% and 70% ee, respectively.
Notably, L7 further improved the enantiomeric excess to 87%.
Modification the sidearm of L7 from methyl to benzyl (L8)
decreased the enantioselectivity of 3a to 77%. To our delight,
further modification of the chiral BOX ligand by introducing alkyl
substituents onto 5-position of oxazolidine ring substantially
improved the efficiency and enantioselectivity of the reaction (L9-
L12). Increasing the steric hindrance of the chiral ligand at 5-
position improved both the yield and enantioselectivity of the
desired product, furnishing 3a in 64% yield with 92% ee with L12
as an anchoring ligand. Chiral amide 3a was obtained in 75%
yield and 93% ee when 3-phenyl-1-iodopropane 2b was used
substrates for the reaction, delivering the desired α-tertiary chiral
amides in 53-74% yields with 90-96% ee (3i-3m). Herterocyclic
aniline derived acrylamide was converted to chiral amide 3n in 63%
yield with 95% ee. N-Methyl-N-phenylmethacrylamide with 2b led
to the formation of corresponding chiral amide in low efficiency.
Furthermore, acrylamides with diverse substituents on alkene
moieties were examined. Different alkyl chains with varied length
Table 2. Scope for the enantioselective hydroalkylation respect to acrylamide[a]
O
O
Ph
Ar
"standard conditions"
.
Ar
R
N
H
+
N
L12
NiBr2 glyme,
R =
H
R1
3
2b
R1
I
Ph
4
and
O
Cl
CF3
O
O
O
Me
R
N
R
R
N
R
N
H
H
Me
H
Me
Me
3b, 76%, 95% ee
3c, 60%, 94% ee
3d, 50%, 93% ee
O
t-Bu
instead of 2a in the absence of TBAI.[14]
O
N
CO2Et
O
N
Ph
O
N
Table 1. Evaluation of the reaction conditions[a]
R
R
H
H
H
Me
Me
Me
NiBr2glyme (10 mol%)
3e
, 46%, 95% ee
3f
, 70%, 94% ee
3g
, 63%, 93% ee
O
L
(12 mol%)
Ph
t-Bu
Me
Me
Ph
+
OH
NHPh
TBAI (2 equiv)
O
O
O
O
(MeO)3SiH (3 equiv)
K3PO4H2O (3 equiv)
t-BuOH (4 equiv), Et2O
Br
Me
3a
PhHN
1a
R
N
2a
R
N
H
R
N
Me
H
H
Me
3h
Me
Me
3j
3i
, 60%, 94% ee
O
, 53%, 94% ee
, 63%, 94% ee
Ar
O
O
O
O
O
N
O
O
N
R
N
R
N
H
N
N
R
N
H
Me
N
H
Me
Me
3k
Me
Me
N
N
Ph
Ar = 4-fluorophenyl
Ph
Et
3l
3m
, 57%, 90% ee
, 74%, 93% ee
O
, 69%, 96% ee
L2, No product
L3, trace
Ar = 2-naphthyl
O
L1
, No product
O
O
CO2Et
Bn
Bn
R
N
H
R
NHAr
R
NHAr
O
O
O
O
O
O
Me
3n
R
R
R
n-Pr
Et
Ph
Ph
Ph
R
N
N
4a
4b
N
N
, 63%, 95% ee
O
, 73%, 88% ee
, 53%, 91% ee
N
N
Bn
Ph
L7
Ph
Bn
Ph
O
O
O
L4
L5
, R = H, 45%, 30% ee R = H ( ), 45%, 61% ee
, 65%, 87% ee
R
NHAr
Me
R
NHAr
R
NHAr
R
NHAr
OH
L6
R = Ph ( ), 36%, 70% ee
CN
Bn
N
10
Cl
, 45%, 94% ee
O
L9
R = Me, , 52%, 91% ee
O
O
O
O
R
R
4e,
4f
R
R
45%, 92% ee
, 47%, 93% ee
4c
4d
, 53%, 90% ee
R = Et, L10, 60%, 91% ee
Ph
Ph
N
L11
, 54%, 92% ee
L12
R = n-Pr,
R = n-Bu,
N
N
O
O
Me
O
, 64%, 92% ee
Ph
L8
Ph
, 47%, 77% ee
Ph
Ph
R
NHAr
[b]
R
NHAr
R
NHAr
L12
, 75%, 93% ee
R
NHAr
OMe
3
CO2Et
2
Me
4j, 35%
20:1 dr, 82% ee
Ph
[a] The reaction was run with 0.1 mmol of 1a, 0.2 mol of 2a under indicated
conditions in Et2O (3 mL) at -10 oC for 40 h. Isolated yields are shown. The
enantiomeric excess was determined by HPLC using a chiral column. [b] 4-
Phenyl-1-iodobutane (2b) was used in the absence of TBAI.
4g
4h
4i
, 54%, 89% ee
, 51%, 89% ee
, 47%, 90% ee
[a] Standard conditions: NiBr2ꞏglyme (10 mol%), (R,R)-L12 (12 mol%), 0.2 mmol
of acrylamide, 0.4 mmol of 2b, trimethoxylsilane (3 equiv), K3PO4ꞏH2O (3 equiv),
and t-butanol (4 equiv) in Et2O (3 mL) at -10 oC.
2
This article is protected by copyright. All rights reserved.

10.1002/anie.202011339
Angewandte Chemie International Edition
COMMUNICATION
Table 3. Scope for the enantioselective hydroalkylation/hydropropargylation/hydrobenzylation with respect to halides[a]
O
O
O
O
n-Bu
n-Bu
Ar
n-Bu
n-Bu
"standard conditions"
Ar
R
X
R
N
+
N
.
H
L12
NiBr2 glyme,
H
R1
N
N
2
R1
5 7
-
Ph
(R,R)-
Ph
X = Br, I
L12
Scope for R-X
Ar1 = 4-EtO2CPh, Ar2 = 2-naphthyl
O
a. Scope for alkyl halides
O
O
O
O
O
O
MeO
NHAr2
Ph
NHPh
NHAr2
NHAr1
NHAr
NHAr1
Me
PhO
2
Me
Me
Me
5c
Me
Me
Me
5g
5d
X = I
5a
5b
X = I,
X = I,
80% (94% ee)
X = I,
X = I,
X = I,
53% (94% ee)
62% (95% ee)
66% (92% ee)
73% (92% ee)
5e
Ar = Ph, , 62% (94% ee)
2
5f
Ar = Ar , , 62% (93% ee)
O
O
O
O
O
MeO
O
O
NHAr2
NHPh
O
Ph
NHAr
NHPh
3
N
OMe
Me
5h
Me
5i
5l
X-Ray for
Me
Me
X = I
X = I,
[CCDC 1993511]
X = I,
5j
X = I,
73% (89% ee)
Ar = Ph, 5k, 68% (93% ee)
67% (94% ee)
66% (94% ee)
2
5l
Ar = Ar , , 74% (93% ee)
O
N
S
O
O
O
O
N
EtO
O
NHAr1
N
O
NHPh
Me
NHAr
4
NHPh
O
Me
O
Me
Me
5m
5n
5o
5p
X = I,
53% (89% ee)
X = I,
65% (95% ee)
X = I,
72% (93% ee)
X = I,
65% (94% ee)
O
O
O
O
O
H
N
MeO2C
N
O
F3C
NHAr2
NHAr2
NHAr1
5u
NHAr2
EtO
4
N
X = I,
NHAr2
Bn
O
Me
5r
Me
Me
Me
Me
5q
5s
5t
X = Br,
X = I,
X = I,
X = Br,
74% (93% ee)
79% (97:3 dr)
78% (94% ee)
55% (89% ee)
63% (90% ee)
O
b. Scope for propargyl halides
O
NHAr2
O
Me
O
Ph
O
TMS
O
Me
NHAr2
NHAr1
NHAr1
NHAr2
NHPh
O
Me
Me
X = I, 5w
Me
X = Br, 6a
Me
Me
X = Br, 5v
X = I, 5x
X = Br, 6b
X = Br, 6c
53% (99% ee)
68% (94% ee)
32% (12% ee)
66% (94% ee)
65% (95% ee)
87% (91% ee)
c. Scope for benzyl halides
CN
CF3
MeO2C
F3C
O
O
O
O
O
NHAr1
Me
F3C
NHAr2
NHAr2
Me
NHAr2
NHAr2
Me
X = Br, 7b
86% (91% ee)
Me
Me
X = Br, 7a
97% (93% ee)
X = Br, 7c
84% (88% ee)
X = Br, 7d
84% (89% ee)
X = Br, 7e
85% (90% ee)
[a] Standard conditions, see Table 2 for detail.
were tolerated in the reaction, providing the corresponding chiral
amides with different alkyl chains in 53%-73% yields with 88%-
91% ee (4a-4c). Alkyl halide and nitrile substituted acrylamides
were compatible with the reaction conditions, furnishing the
corresponding chiral amides (4d and 4e) in 45% yield with 94%
and 92% ee, respectively. Free alcohol substituted acrylamide
could be converted to 4f in 47% yield with 93% ee. Ester and ether
were also tolerated under the reaction conditions, delivering the
desired hydroalkylation products (4g and 4h) in synthetically
useful yields with 89% ee. Benzyl substituted acrylamide could be
hydroalkylated enantioselectively to generate 4i in 47% yield with
90% ee. Trisubstituted acrylamide was converted to desired
product 4j in 35% yield with 82% ee. Unfortunately, ethyl
methacrylate gave no desired hydroalkylation product, leading to
complete reduction to give ethyl isobutyrate.
Next, we evaluated the organic halides for this reaction. As shown
in Table 3, a wide range of alkylhalides (including iodides and
bromides) were well tolerated in this reaction, forming a myriad of
enantioenriched amides in good efficiency with excellent levels of
enantioselectivity. Firstly, primary alkyl halides were tested. 2-
Phenyl-1-iodoethane was converted to chiral amide 5a in 80%
yield with 94% ee. Linear and α-branched alkyl iodides could be
transformed into corresponding amides (5b and 5c) in 66% and
73% yields with 92% ee. Ether tethered alkyl iodides reacted to
give corresponding hydroalkylation products 5d-5g in 53-62%
yields with 93-95% ee. Acyclic and cyclic acetals were well suited
for this reaction that provided corresponding chiral amides (5h
3
This article is protected by copyright. All rights reserved.

10.1002/anie.202011339
Angewandte Chemie International Edition
COMMUNICATION
and 5i) in 66% and 67% yields with 94% ee. Other functional
groups, such as esters, nitriles, amides were also compatible
under the reaction conditions, delivering the desired
hydroalkylation amides (5j-5n) in 65-74% yields with 89-95% ee.
The absolute configuration of the product was confirmed to be S
by X-ray diffraction analysis of 5l. Heterocycles, such as indoles,
thiazoles, and carbazoles worked well in the reaction, furnishing
the regio- and enantioselective hydroalkylation products (5o-5q)
in 53-74% yields with 89-94% ee. Phenylalanine derived alkyl
iodide was employed in the reaction to provide desired product 5r
in 79% yield with 97:3 dr. 1,1,1-Trifluoro-3-iodopropane was
suitable with the reaction and formed desired enantioselective
cross-coupling product 5s in 78% yield with 94% ee. α-
Bromoester and α-bromonitrile were also compatible in this
reaction, generating the corresponding chiral amides (5t and 5u)
in 55% and 63% yields with 89% and 90% ee. Cyclic and
symmetrical secondary alkyl halides were also reactive under the
reaction conditions to furnish the desired products 5v and 5w in
53% and 68% yields with 99% and 94% ee. Isopropyliodide gave
the desired product 5x in poor yield and enantioselectivity. Next,
propargyl bromides were tested. Propargyl halides are
challenging since the alkynyl moiety is reactive towards nickel
hydride. To our delight, propargyl bromides with alkyl, aryl, and
silyl substituents were all suitable substrates for the reaction that
underwent enantioselective hydropropargylation to exclusively
furnish the Csp3-Csp3 cross-coupling products (6a-6c) in good
yields (65%-87%) with excellent enantioselectivities (91-95% ee).
To the best of our knowledge, this is the first example of
enantioselective hydropropargylation of alkenes.[13] Furthermore,
various benzyl bromides could be subjected into the reaction to
deliver enantioselective hydrobenzylation of acrylamide products
(7a-7e) in 84-97% yields with 88-93% ee, representing the first
chiral amide 8b in 61% yield with 93% ee. Diacetone-D-galactose
was also compatible under the reaction conditions, provided
galactose containing chiral amide 8c in 69% yield with 97:3 dr.
Estrone could be incorporated in the reaction to deliver 8d in 67%
yield with 96:4 dr. Drug molecules oxaprozin and isoxepac were
transformed into corresponding chiral amide 8e and 8f in 51% and
56% yields with 93% and 94% ee. Vitamin E is also compatible
with the reaction and formed the desired chiral amide 8g in 63%
yield with 97:3 dr. Moreover, the other diastereomers of 8c, 8d,
and 8g could be obtained in 60%, 63% and 58% yields, with 3:97,
4:96 and 3:97 drs when (S,S)-L12 was used.
Me
O
Ph
O
Me
2b
3
Me
"standard conditions"
54%, 96% ee
+
Me
O
O
Me
O
O
(eq. 1)
N
H
N
H
10
9
Ph
3
Me
O
Me
Me
Me
O
12
>98% D
Me
(eq. 2)
"standard conditions"
57%, 94% ee
2b
+
O
N
H
O
O
N
O
11
H
NiBr2glyme (10 mol%)
(R,R)-L12 (12 mol%)
>98% D
D
O
D
Me
Ph
2b
(eq. 3)
O
+
+
Me
O
Ph2SiD2 (3 equiv)
K3PO4H2O (3 equiv)
t-BuOH (4 equiv)
NHAr
3
ArHN
Ar = 2-naphthyl
Me
ArHN
14
13, 43%, 91% ee
, 55%
>98% D
Et2O, -10 o
C
>98% D
NiBr2glyme (1.0 equiv)
(R,R)-L12 (1.2 equiv)
NiL*
O
2b
(2 equiv)
(eq. 4)
3a
1a
Me
PhHN
(MeO)3SiH (3 equiv)
K3PO4H2O (3 equiv)
t-BuOH (4 equiv)
-10 oC, 40 h
65%, 94% ee
Et2O, -10 oC, 40 h
To shed light on the mechanism of this reaction, we set up a
series of reactions to probe the reaction process. First, acrylamide
and acrylate containing substrates 9 and 11 were subjected to
standard conditions. It is interesting that 10 and 12 were obtained
in 54% and 57% yields with 96% and 94% ee, respectively (eqs.
1 and 2). Enantioselective hydroalkylation occurred at acrylamide
moiety efficiently, while 2-methylacrylate moiety was reduced to
isobutyrate without further Csp3-Csp3 bond-forming process. This
outcome suggests the Ni-catalyzed Csp3-Csp3 cross-coupling step
is facilitated by the assistance of amide group. Next, we carried
out the reaction using deuterated silane (PhSiD2)[7e] under
otherwise identical to standard conditions (eq. 3). Intriguingly,
deuterated hydroalkylation product 13 was formed in 43% yield
with 91% ee. Deuterium incorporation (>98% D) was exclusively
delivered to α-position of amide 13. No deuterium incorporation
was found on methyl group of 13. Reduction product 14 was
obtained in 55% yield. Single deuterium (>98% D) was detected
on one methyl. No deuterium was found on the other methyl group
or α-position of amide 14. These results indicate that Ni-H
insertion step into alkene to form alkyl-Ni species is irreversible
and enantio-determining. Moreover, a stepwise Ni-mediated
reaction of 1a with silane was conducted, followed by addition of
2b, the desired product 3a was obtained in 65% yield with 94%
ee (eq. 4), indicating the hydrometalation intermediate of acrylate
1a could lead to the cross-coupling product.
intermolecular enantioselective hydrobenzylation of alkenes.[12]
Table 4. Late-stage functionalization of complex molecules[a]
O
Et
N
NHAr
O
H
O
Me
O
O
Et
5
ArHN
O
Me
N
CH3
4
H
O
X = I, 8a
X = I, 8b
67%, 96:4 dr
61%, 93% ee
O
H
O
O
O
O
O
O
H
H
O
O
O
4
NHAr
4
O
O
Me
Me
8d
X = I,
67%, 96:4 dr
63%, 4: 96 dr for (S,S)-
8c
X = I, , 69%, 97:3 dr
NHAr
O
60%, 3: 97 dr for (S,S)-L12
L12
Ph
O
O
NHAr
O
Me
Ph
O
NHPh
N
O
2
2
2
Me
O
O
O
8f
X = I,
8e
X = I,
51%, 93% ee
56%, 94% ee
O
O
NHAr
4
O
Me
O
8g
Me
63%, 97:3 dr; 58%, 3: 97 dr for (S,S)-L12
[a] Standard conditions, see Table 2 for detail. Ar = 2-naphthyl.
X = I,
To demonstrate the robustness and usefulness of this protocol,
we applied this condition to late-stage functionalization of
complex molecules, including natural products and drug
molecules (Table 4). (+)-Borneol derivative could be tolerated to
give corresponding chiral amide 8a in 67% yield with 96:4 dr.
Procaine derived alkyl iodides was converted to corresponding
Based on the mechanistic results and relevant literature
reports,[9,11] a plausible mechanism is depicted in Scheme 2. First,
nickel (I) reduced from Ni (II) precursor[9,10,15] undergoes
transmetalation with silane with assistance of base to generate
nickel (I) hydride intermediate A. According to the results from
equation 3, irreversible enantioselective hydrometalation of
4
This article is protected by copyright. All rights reserved.

10.1002/anie.202011339
Angewandte Chemie International Edition
COMMUNICATION
acrylamides to give alkyl nickel intermediates B (via path a) or B’
(via path b). Intermediate B’ could give formal hydrogenation
Keywords: hydroalkylation • hydropropargylation •
hydrobenzylation • enantioselective • alkyl-alkyl cross-coupling
byproduct
via
further
protonation
or
β-hydride
elimination/reductive elimination process. Intermediate B then
undergoes an amide directed oxidative addition with alkyl halides
to give Ni(III) intermediate C, which rapidly undergoes reductive
elimination to forge the Csp3-Csp3 bond of the final product and
regenerate Ni (I) species.
[1]
[2]
a) J. A. Tobert, Nat. Rev. Drug Discov. 2003, 2, 517–526; b) C. R.
Ganellin, (Ganellin, C. R. et al. Eds.) 339–416 (Elsevier, Amsterdam,
2013).
a) C. A. G. N. Montalbetti, V. Falque, Tetrahedron 2005, 61,
10827−10852; b) V. R. Pattabiraman, J. W. Bode, Nature 2011, 480,
471−479; c) R. M. Lanigan, T. D. Sheppard, Eur. J. Org. Chem. 2013,
2013, 7453−7465; d) R. M. de Figueiredo, J.-S. Suppo, J.-M. Campagne,
Chem. Rev. 2016, 116, 12029−12122.
Ni (I)
Si-H + base
X
alkyl
H
EWG
[3]
[4]
[5]
[6]
For recent examples, see: a) D. Fiorito, Y. Liu, C. Besnard, C. Mazet, J.
Am. Chem. Soc. 2020, 142, 623−632.
Ni
H
A

M. P. Sibi, G. Petrovic, J. Zimmerman, J. Am. Chem. Soc. 2005, 127,
2390−2391.
EWG
H
H
Ni
EWG

path a
path b
EWG
a) G. C. Fu, ACS Cent. Sci. 2017, 3, 692−700; b) A. H. Cherney, N. T.
Kadunce, S. E. Reisman, Chem. Rev. 2015, 115, 9587−9652.
a) F. O. Arp, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 10482–10483; b)
C. Fischer, G. C. Fu, J. Am. Chem. Soc. 2005, 127, 4594–4595; c) S.
Son, G. C. Fu, J. Am. Chem. Soc. 2008, 130, 2756–2757; d) N. A.
Owston, G. C. Fu, J. Am. Chem. Soc. 2010, 132, 11908–11909; e) S. L.
Zultanski, G. C. Fu, J. Am. Chem. Soc. 2011, 133, 15362–15364; f) A.
Wilsily, F. Tramutola, N. A. Owston, G. C. Fu, J. Am. Chem. Soc. 2012,
134, 5794−5797; g) C. J. Cordier, R. J. Lundgren, G. C. Fu, J. Am. Chem.
Soc. 2013, 135, 10946−10949; h) X. Mu, Y. Shibata, Y. Makida, G. C.
Fu, Angew. Chem. Int. Ed. 2017, 56, 5821–5824.
alkyl
B'
Ni
X
electronically
favored
Ni
H
H
EWG
EWG
C
B
sterically
favored
EWG = CONHAr
alkyl
X
Scheme 2. Proposed mechanism for the reaction.
[7]
a) X. Lu, B. Xiao, Z. Zhang, T. Gong, W. Su, J. Yi, Y. Fu, L. Liu, Nat.
Commun. 2016, 7, 11129; b) S.-Z. Sun, M. Börjesson, R. Martin-Montero,
R. Martin, J. Am. Chem. Soc. 2018, 140, 12765−12769; c) F. Zhou, J.
Zhu, Y. Zhang, S. Zhu, Angew. Chem. Int. Ed. 2018, 57, 4058–4062; d)
S.-Z. Sun, C. Romano, R. Martin, J. Am. Chem. Soc. 2019, 141,
16197−16201; e) S. Bera, X. Hu, Angew. Chem. Int. Ed. 2019, 58,
13854–13859.
In summary,
enantioselective
a
unified protocol for the Ni-catalyzed
intermolecular diverse formal
hydrofunctionalizations of alkenes has been described for the first
time. The use of a new developed BOX ligand enables the
electronically-reversed enantioselective hydrometallation of
acrylamides followed by a Csp3-Csp3 bond-forming process to
construct a α-stereogenic center to newly-formed C-C bond in
good yields with excellent enantioselectivities, representing the
first example of catalytic asymmetric formal hydroalkylation,
hydrobenzylation, and hydropropargylation of alkenes. This
[8]
[9]
H. Sommer, F. Juliá-Hernández, R. Martin, I. Marek, ACS Cent. Sci.
2018, 4, 153−165
a) Z. Wang, H. Yin, G. C. Fu, Nature 2018, 563, 379–383; b) F. Zhou, Y.
Zhang, X. Xu, S. Zhu, Angew. Chem. Int. Ed. 2019, 58, 1754–1758.
[10] a) S.-J. He, J.-W. Wang, Y. Li, Z.-Y. Xu, X.-X. Wang, X. Lu, Y. Fu, J. Am.
Chem. Soc. 2020, 142, 214−221; b) Z.-P. Yang, G. C. Fu, J. Am. Chem.
Soc. 2020, 142, 5870−5875; c) S. Bera, R. Mao, X. Hu, ChemRxiv.
doi.org/10.26434/chemrxiv.12040398.v1.
method provides
a
general and practical access to
enantioenriched amides containing an α-tertiary stereogenic
carbon center facile to racemize. The mild conditions allow for the
synthesis of a wide range of α-branched chiral amides with broad
functional group tolerance.
[11] a) S. Zhu, S. L. Buchwald, J. Am. Chem. Soc. 2014, 136, 15913−15916;
b) S. Zhu, N. Niljianskul, S. L. Buchwald, Nat. Chem. 2016, 8, 144–150.
[12] For racemic hydrobenzylation of 1,3-diene, see: L. Lv, D. Zhu, Z. Qiu, J.
Li, C.-J. Li, ACS Catal. 2019, 9, 9199−9205.
[13] For a non-enantioselective hydropropargylation of enamide, see: S.
Watanabe, A. Ario, N. Iwasawa, J. Antibiot. 2019, 72, 490–493.
[14] For more details on the conditions optimization, see Supporting
Information.
Acknowledgements
We acknowledge NSFC (21971101 and 21801126), Guangdong
[15] Y. He, C. Liu, L. Yu, S. Zhu, Angew. Chem. Int. Ed. 2020, 59, DOI:
10.1002/anie.202010386.
Basic
and
Applied
Basic
Research
Foundation
(2019A1515011976), The Pearl River Talent Recruitment
Program (2019QN01Y261), Guangdong Provincial Key
Laboratory of Catalysis (No. 2020B121201002), Thousand
Talents Program for Young Scholars, and Shenzhen Nobel Prize
Scientists Laboratory Project (C17783101) for financial support.
We thank Prof. Jian-Fang Cui (SUSTech) for accessing a
cryogenic cooling system. We acknowledge the assistance of
SUSTech Core Research Facilities, Dr. Xiaoyong Chang
(SUSTech) for X-ray crystallographic analysis of 5l (CCDC
1993511), Dr. Yi-Zhou Zhan (SUSTech) and Peng-Fei Yang
(SUSTech) for reproducing the results of 3i, 4d, 5j, 5o, 7b, and
8e.
5
This article is protected by copyright. All rights reserved.

10.1002/anie.202011339
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Regio- & enantioselective formal hydrofunctionalizations
O
O
Si-H
+
NHR
NHR
[Ni] L*
X
X = Br, I
1o and 2o alkyl
> 60 examples
up to 99% ee
-stereogenic center
-C-C bond-forming

Alkyl-alkyl bond-forming with coinstantaneous formation of a stereogenic center is attractive yet challenging. Herein, we report the
intermolecular, regio- and enantioselective formal hydrofunctionalizations of alkenes to forge a stereogenic center α-position to the
newly formed alkyl-alkyl bond for the first time, providing a facile access to a wide range of α-branched chiral amides with broad
functional group tolerance.
6
This article is protected by copyright. All rights reserved.