Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes: Unexpected Diastereomeric-Ligand-Controlled Regiodivergence

Article abstract of DOI:10.1002/anie.202011231

A regiodivergent nickel-catalyzed hydrocyanation of a broad range of internal alkenes involving a chain-walking process is reported. When appropriate diastereomeric biaryl diphosphite ligands are applied, the same starting materials can be converted to either linear or branched nitriles with good yields and high regioselectivities. DFT calculations suggested that the catalyst architecture determines the regioselectivity by modulating electronic and steric interactions. In addition, moderate enantioselectivities were observed when branched nitriles were produced.

Full text of DOI:10.1002/anie.202011231

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes:
Unexpected Diastereomeric-Ligand-Controlled Regiodivergence
Authors: Jihui Gao, Mingdong Jiao, Jie Ni, Rongrong Yu, Gui-Juan
Cheng, and Xianjie Fang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202011231
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RESEARCH ARTICLE
Nickel-Catalyzed Migratory Hydrocyanation of Internal Alkenes:
Unexpected Diastereomeric-Ligand-Controlled Regiodivergence
Jihui Gao+,[a] Mingdong Jiao+,[a] Jie Ni+,[b] Rongrong Yu,[a] Gui-Juan Cheng,*[b] and Xianjie Fang*[a]
Abstract: We herein report
a
regiodivergent nickel-catalyzed
involving a regioselective issue would provide a novel strategy to
achieve regiodivergent synthesis (Scheme 1b).
hydrocyanation of a broad range of internal alkenes involving the
chain-walking process. When appropriate diastereomeric biaryl
diphosphite ligands are applied, the same starting materials can be
converted to either linear or branched nitriles with good yields and
high regioselectivities. DFT calculations suggested that the catalyst
architecture determines the regioselectivity via modulating electronic
and steric interactions. In addition, moderate enantioselectivities
were observed when branched nitriles were delivered.
Introduction
Over the past decades, catalytic reactions featuring
divergent regio-, chemo- or diastereoselectivities have become
an ultimate pursuit by many synthetic chemists because these
methodologies provide new access to diverse functionalized
products from the same starting materials.[1] The catalytic
conversion of one common substrate into different products
often hinges on different metal catalysts (Scheme 1a).[2] Despite
the preliminary advances in catalytic divergent reactions, this
strategy still needs to be further explored, especially in the field
of powerful remote chain-walking functionalization towards the
construction of C–C[3] and C–X (X = B,[4] O,[5] Si,[6] S,[7] N[8])
bonds. The chain-walking hydrofunctionalization of internal
alkenes, however, is still restricted to “unidirectional” events
which favors the activation of a single reaction site.[9] More
recently, a few but impressively efficient examples have been
reported regarding to the switchable and controllable site-
selectivity.[10]
Multi-chiral ligands are an important class of chiral ligands
which found wide applications in asymmetric metal catalysis.[11]
It is often necessary to study the effects of diastereomeric
ligands on the reactivity and enantioselectivity when using multi-
chiral ligands in catalytic asymmetric reactions.[12] However, the
corresponding effects on regioselectivity have received much
less attention. This is somewhat counterintuitive, as the
diastereomeric ligands have different configurations and thus
induce different regioselectivities. We therefore envision that the
use of diastereomeric ligands in metal-catalyzed reactions
Scheme 1. Background for the development of the current work.
Owing to
a
perfect atom economy, the catalytic
hydrocyanation of alkenes represents one of the most
straightforward methods for the preparation of alkyl nitriles,
which represent versatile building blocks and intermediates for
the chemical, pharmaceutical, and agrochemical industries.[13]
Although a numerous of catalytic systems have been developed
for the hydrocyanation of alkenes over the past few decades,[14]
regioselective isomerization/hydrocyanation of inactivated
aliphatic alkenes still represents a challenging topic in this field.
In 2018, Studer[15] reported a Pd-catalyzed migratory transfer
hydrocyanation of internal alkenes leading to linear nitriles. More
[a] J. Gao,+ M. Jiao,+ R. Yu, Prof. Dr. X. Fang
Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs
Frontiers Science Center for Transformative Molecules
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240, China
E-mail: fangxj@sjtu.edu.cn
[b] J. Ni,+ Prof. Dr. G.-J. Chen
Warshel Institute for Computational Biology
Shenzhen Key Laboratory of Steroid Drug Development
School of Life and Health Sciences
The Chinese University of Hong Kong (Shenzhen)
Shenzhen, 518172, China
recently, Liu[16] and Yang[17] reported
a
Ni-catalyzed
isomerization/hydrocyanation of terminal alkenes that led to
branched nitriles. It is worth mentioning that the success of
these transformations depends on the Lewis acid when applied.
Despite these elegant contributions, catalytic regiodivergent
hydrocyanation of internal olefins toward the preparation of
linear and branched nitriles, to the best of our knowledge, has
not been documented. Herein, we describe the first
diastereomeric ligand-controlled chain-walking process for
regiodivergent hydrocyanation of internal alkenes, selectively
E-mail: chengguijuan@cuhk.edu.cn
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
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10.1002/anie.202011231
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RESEARCH ARTICLE
producing benzylic and terminal nitriles with high
regioselectivities (Scheme 1b).
ligand (RA,SB,SB)-Lc afforded the linear product 3a in 68%
isolated yield with 88:12 regioselectivity (Table 1, entry 7). Either
lower (Table 1, entries 10 and 12) or higher (Table 1, entries 9
and 11) reaction temperature gave inferior results compared to
°
Results and Discussion
the reaction run at 80 C. Lowering or increasing the reaction
temperature has almost no effect on the enantioselectivity of the
reaction (Table 1, entries 9−10 vs. entry 3).
Table 1: Investigation of the reaction conditions.[a]
Phosphite ligands have proved to be effective for metal-
catalyzed hydrocyanation reactions.[14d,f,g,h,o,p,r] Hence, a series of
diastereomeric biaryl diphosphite ligands were prepared
according to the general method described in Scheme 2 (see
the SI for details). These ligands are derived from commercially
available (S)-BINOL. Of note, the cost of (S)-BINOL is similar to
rac-BINOL. Diastereomers (RA,SB,SB)-L and (SA,SB,SB)-L were
obtained through the coupling of rac-diphenol with [(S)-
BINOL]PCl. This P–O coupling was barely diastereoselective
and the two diastereomers were generated in a ca. 1:1.2~1:1.6
ratio. These two diastereomers could be separated through
column chromatography, which avoided the otherwise tedious
and sometimes difficult resolution steps.
Entry
1
Ligand
2a Yield/%b
3a Yield/%b
rrd
(SA,SB,SB)-La
(SA,SB,SB)-Lb
(SA,SB,SB)-Lc
(SA,SB,SB)-Ld
(RA,SB,SB)-La
(RA,SB,SB)-Lb
(RA,SB,SB)-Lc
(RA,SB,SB)-Ld
(SA,SB,SB)-Lc
(SA,SB,SB)-Lc
(RA,SB,SB)-Lc
(RA,SB,SB)-Lc
40(51)g
trace
91:9
2
90(60)g
3
5
90:10
90:10
90:10
78:22
87:13
88:12
86:14
89:11
88:12
83:17
88:12
3
90(88)c(64)g
4
88(57)g
4
5
6
28
40
72(68)c
50
4
6
2
7
3
8
3
90(62)g
87(63)g
5
9e
10f
11e
12f
5
Scheme 2. Preparation of the diastereomeric biaryl diphosphite ligands.
70
64
3
With these diastereomeric biaryl diphosphite ligands, we
next studied the regiodivergent migratory hydrocyanation of 1-
phenyl-3-hexene (1a). With Me2C(OH)CN as hydrogen cyanide
source under nickel catalysis and the diastereomeric biaryl
diphosphite ligands, the yield and the regioselectivity of the
corresponding nitrile products 2a and 3a were examined
respectively (Table 1). Herein, the following two characteristics
of the ligand effect were observed. 1) These diastereomeric
ligands have a dramatic effect on the regioselectivity of the
reaction. The (SA,SB,SB)-L ligands favored the formation of
branched nitrile 2a with up to 91:9 regioselectivity (Table 1,
entries 1−4). Conversely, the regioselectivity was reversed when
the (RA,SB,SB)-L ligands were employed, and the linear nitrile 3a
were obtained with up to 88:12 regioselectivity (Table 1, entries
5−8). 2) The R substituent strongly influences the yield of the
desired nitrile product without affecting the regioselectivity and
enantioselectivity of the reaction too much (Table 1, entries 1−8).
[a] Reaction conditions: 1a (0.1 mmol), Me2C(OH)CN (0.3 mmol), Ni(COD)2 (5
mol%), ligand (5 mol%), toluene (0.3 mL), 80 oC, 12 h. [b] Determined by GC
analysis using n-decane as the internal standard. [c] Isolated yield. [d] rr is the
regioisomeric ratio, which represents the ratio of the major product to the sum
of all other isomers as determined by GC analysis. [e] Reactions conducted at
100 oC. [f] Reactions conducted at 60 oC. [g] The ee values were determined
by HPLC over chiral stationary phase.
With two regioselective catalytic systems and optimized
conditions established (Table 1, entries 3 and 7), we evaluated
the substrate scope of this regiodivergent transformation
(Scheme 3). Generally, the substituents on the aryl group mainly
control the yield and regioselectivity of the branched nitrile
product 2 but slightly affect the yield and regioselectivity of the
linear nitrile product 3. Substrates containing various functional
groups such as ester (1b), nitrile (1c), phenol (1e), amine (1f),
halogen (1h), ethers (1i, 1l), boron (1j) and heterocycles such as
indole (1o) and furan (1p), were examined. All were smoothly
converted to the corresponding branched and linear nitriles in
moderate to high yields with high regioselectivities. Furthermore,
the alkene bearing an estrone skeleton (1q) was also
successfully converted into the desired products 2q and 3q in
t
Notably, the Bu-substituted (SA,SB,SB)-Lc gave the branched
product 2a in 88% isolated yield with 90:10 regioselectivity
(Table 1, entry 3). Meanwhile, the corresponding diastereomeric
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10.1002/anie.202011231
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RESEARCH ARTICLE
86% and 61% yield, respectively. Next, we studied an array of
internal alkenes with various chain lengths. Under the standard
conditions, the substrates with longer chain length afforded the
desired products in lower yields, whereas the regioselectivity of
the benzylic nitriles were uniformly ca. 90:10 (1r−1u). Evidently,
the longer chain-walking distance between the double bond and
the terminus makes the formation of linear nitriles more difficult.
Thus, the conversion, yield and regioselectivity significantly
decreased (1v−1y). It is worth mentioning that this migratory
hydrocyanation features an enantioselective potential. By
employing the Ni/(SA,SB,SB)-Lc catalyst, branched nitriles could
be obtained with moderate enantioselectivities. For example, the
ee’s of 2a, 2c and 2o were 64%, 62% and 77% ee respectively.
Remarkably, the employment of enantioselective chain-walking
strategy to construct enantiomerically enriched molecules
remains quite elusive in the previous report.
Scheme 3. Substrate scope of the regiodivergent hydrocyanation of various internal alkenes 1. [a] Reaction conditions: 1 (0.2 mmol), Me2C(OH)CN (0.6 mmol),
Ni(COD)2 (5 mol%), ligand (5 mol%), toluene (0.5 mL), 80 °C, 12 h. Yields of the isolated products after flash column chromatography (single linear or branched
product). rr, the regioisomeric ratio, represents the ratio of the major product to the sum of all other isomers as determined by GC analysis. The ee values were
determined by HPLC over chiral stationary phase.
Another consequence of our methodology is the feasibility
of the implemented regioconvergent hydrocyanation, which
would allow inexpensive chemical feedstocks such as unrefined
alkene isomers to be uniformly transformed to two different
value-added products in a single step. On one hand, treatment
of a 1:1:1:1 mixture of alkene regioisomers afforded 2a in 81%
yield with 89:11 regioselectivity on gram scale under standard
conditions (Scheme 4). On the other hand, the terminal nitrile 3a
was obtained in 70% yield with 88:12 regioselectivity.
To gain further insight into this chain-walking process, some
deuterium labeling experiments and crossover reactions were
performed (Scheme 5). Fully deuterium-labeled acetone
cyanohydrin was initially employed for the model reaction under
standard conditions (Scheme 5a). We observed deuterium
incorporation at the C1 (0.05D), C2-C5 (1.28D) and C6 (0.37D)
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positions in d-2n-1 in 83% yield with 92:8 rr, meanwhile C1
(0.40D), C2-C5 (1.64D) and C6 (0D) positions in d-3n-1 in 58%
yield with 85:15 rr. When deuterium-labeled d-1z was used as
substrate instead (Scheme 5a), the corresponding benzylic
nitrile d-2z-1 was obtained with the deuterium atom incorporated
at C1 (0.02D), C2 (0.36D), C3 (0.09D) and C4 (0.06D) in 78%
yield with 93:7 rr, and the terminal nitrile d-3z-1 was obtained
with the deuterium atom incorporated at C1 (0.05D), C2 (0.12D),
C3 (0.06D) and C4 (0.04D) in 50% yield with 79:21 rr. These two
results collectively suggested a mechanism where the Ni
catalyst walks along the carbon chain via an iterative β-H
elimination and reinsertion processes. In order to determine
whether H−Ni−CN remains ligated to the substrate throughout
the chain-walking process, a mixture of d-1z and 1aa/1n were
subjected to the reaction (Scheme 4b), the hydrocyanation
products d-2z-2, d-2aa and d-3z-2, d-3n-2 were all deuterium
labeled. If the chain-walking process would take place without
dissociation of H−Ni−CN, the product d-2aa and d-3n-2 would
be detected without any deuterium labeling. Therefore, a
mechanism in which chain-walking proceeds with the
reassociation of H−Ni−CN is proposed.
systems, the reductive elimination step (TS4) was calculated to
have the highest activation barrier and it is an irreversible step
as it leads to a very stable hydrocyanation product. Thus, the
reductive elimination step determines both the reaction rate and
regioselectivity. For Ni/(SA,SB,SB)-La system, the reductive
elimination to form 2z is more favorable than that for 3z by 2.3
kcal/mol which is consistent with experimental results that 2z is
preferred over 3z. While for Ni/(RA,SB,SB)-La system, the
formation of 3z is more favored than 2z via by 1.4 kcal/mol that
is again in agreement with experimental results.
a) deuterium-labeling studies
Ni(COD)2
(SA,SB,SB)-Lc
NC OD
CN
(0.05D)
(1.28D)
1n
1n
D3C
CD3
R
(0.37D)
d-2n-1 (83% yield, 92:8 rr)
Ni(COD)2
(RA,SB,SB)-Lc
(0.40D)
CN
NC OD
R
D3C
CD3
(0D)
(1.64D)
d-3n-1 (58% yield, 85:15 rr)
Ni(COD)2
(SA,SB,SB)-Lc (0.02D)
CN
(0.09D)
Ph
Ph
(0.06D)
D
Me2C(OH)CN
(0.36D)
d-1z
d-2z-1 (78% yield, 93:7 rr)
Ni(COD)2
(RA,SB,SB)-Lc
(0.06D)
O
O
(0.05D)
Ph
Ph
CN
R =
Me2C(OH)CN
D
(0.12D)
(0.04D)
d-1z
d-3z-1 (50% yield, 79:21 rr)
b) deuterium crossover experiment
Ph
d-1z
Ni(COD)2
(SA,SB,SB)-Lc
CN
CN
(0.02D)
Ph
D
(0.03D)
(0.01D)
Ar
(0.07D)
Ar
1aa
Ar = 4-OMePh
1:1
Me2C(OH)CN
(0.04D)
(0.06D)
(0.21D) (0.08D)
d-2z-2 (75% yield)
d-2aa (60% yield)
Ni(COD)2
(RA,SB,SB)-Lc
Ph
d-1z D
Scheme 4. Gram-scale regioconvergent experiment.
(0.03D)
R
(0.04D)(0.06D)
CN
(0D)
CN
Ph
(0.10D) (0.03D)
1n
Me2C(OH)CN
(0.14D)
d-3n-2 (55% yield)
1:1
d-3z-2 (52% yield)
To understand the divergent regioselectivities obtained with
the diastereomeric biaryl diphosphite ligands, we conducted
density functional theory (DFT) calculations.[18] The simplest
substrate 1z and ligand La were used in the calculation to
minimize the computational cost as substrate and ligand do not
reverse the regioselectivity. As shown in Figure 1a, alkene
migration of 1z via sequential alkene insertion and β-hydride
elimination will generate its isomers 1z-2 and 1z-3 which further
undergo alkene insertion and reductive elimination to generate
branched product 2z and linear product 3z, respectively.[19]
The computed free energy profiles for the reactions with
(SA,SB,SB)-La (Figure 1b and Figure S1) and (RA,SB,SB)-La
ligands (Figure S2) suggest that the alkene insertion and β-
hydride elimination (TS1, TS2, and TS3) are facile and
reversible processes with barriers lower than 13 kcal/mol. This
indicates that the isomers 1z, 1z-2 and 1z-3 are interconvertible
via chain-walking process, in line with the deuterium labeling
experiments. In both Ni/(SA,SB,SB)-La and Ni/(RA,SB,SB)-La
Scheme 5. Deuterium labeling experiments.
As shown in Figure 2, the optimized stuctures of
Ni/(SA,SB,SB)-La and Ni/(RA,SB,SB)-La catalysts show very
different features. The previous one has a more open pocket
surrounding the Ni while the latter one features with a narrow
pocket with Ni sandwiched between naphthalene rings. For
Ni/(SA,SB,SB)-La system with a large pocket, substrate could
easily accommodate the pocket without obvious steric hindrance
with ligand in the transition states of reductive elimination that
generate 2z and 3z. But the reductive elimination at benzylic
carbon is electronically more favorable due to the charge
delocalization of C1 by phenyl group which is indicated by a
shorter bond length of 1.49 Å for C1-Cphenyl in L1-TS4-1
compared with that in substrate (1.52 Å). Moreover, NBO
analysis demonstrates that the binding of phenyl group to Ni in
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L1-TS4-1 is stronger than the agostic interaction in L1-TS4-2 by
3.6 kcal/mol (Figure S3). For Ni/(RA,SB,SB)-La system, the
substrate has to squeeze into the narrow pocket. As a result, L2-
TS4-1 suffers steric repulsions between the alkyl group of
substrate and naphthalene ring and tert-butyl group of ligand
(Figure 2) and the coordination of phenyl group with Ni is
disrupted. By comparison, the substrate is relatively farther from
the naphthalene rings of ligand and no obvious steric hindrance
was detected in L2-TS4-2. In addition, a strong agostic
interaction between substrate and Ni (dNi-H = 1.73 Å vs. 2.11 Å in
L2-TS4-1) helps to stabilize L2-TS4-2. Therefore, our
computational results suggest that the coordination of
diastereomeric biaryl diphosphite ligands with Ni lead to
dramatically different catalyst architectures which generate
divergent regioselectivities by tuning the electronic and steric
interactions.
Figure 1. (a) Formation of branched product 2z and linear product 3z from Ni-catalyzed migratory hydrocyanation reaction. (b) Free energy profile of Ni-catalyzed
migratory hydrocyanation of 1z with ligand (SA,SB,SB)-La (L1). Relative free energies are in kcal/mol.
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Figure 2. Optimized geometries of Ni/La catalysts and reductive elimination transition states. H atoms of ligands are emitted for clarity and distances are shown in
Å. Distances in red and blue indicate repulsion and attractive binding interactions, respectively.
Conclusion
In summary, a generalized Ni-based catalytic platform that
promotes robust and reliable regiodivergent migratory
Acknowledgements
hydrocyanation of internal alkenes by the judicious choice of
diastereomeric biaryl diphosphite ligands was developed. This
protocol provides a wide range of linear or branched nitriles with
good yields and regioselectivities from the same starting
materials. DFT calculations suggested that the catalyst
architecture determines the regioselectivity via modulating
electronic and steric interactions. Additional work for the better
mechanistic understanding of this process and further
investigations on the development of highly enantioselective
migratory hydrocyanation of internal alkenes are in progress.
The research was supported by the Recruitment Program of
Global Experts, the startup funding from Shanghai Jiao Tong
University, and the National Natural Science Foundation of
China (21803047). The authors gratefully acknowledge Prof. Bill
Morandi (ETH, Zürich) and Prof. Wanfang Li (University of
Shanghai for Science and Technology) for inspiring discussions.
Conflict of interest
The authors declare no conflict of interest.
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Keywords: regiodivergent catalysis • remote hydrocyanation •
chain-walking • nickel catalysis • diastereomeric ligands
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10.1002/anie.202011231
Angewandte Chemie International Edition
RESEARCH ARTICLE
1012; s) R. Yu, S. Rajasekar, X. Fang, Angew. Chem. Int. Ed. 2020, 59,
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information are provided in supporting information.
[19] Other branched isomeric products could be generated via direct
reductive eliminations of int1-1 and int1-2 which are also considered in
computational study as shown in supporting information.
This article is protected by copyright. All rights reserved.

10.1002/anie.202011231
Angewandte Chemie International Edition
RESEARCH ARTICLE
RESEARCH ARTICLE
J. Gao+, M. Jiao+, J. Ni+, R. Yu, G.-J.
Cheng,* X. Fang*
Nickel-Catalyzed Migratory
Hydrocyanation of Internal Alkenes:
Unexpected Diastereomeric-Ligand-
Controlled Regiodivergence
The use of diastereomeric ligands has now allowed the regiodivergent chain-walking
hydrocyanation of internal alkenes. The reactions provided a wide range of linear or
branched nitriles with good yields and regioselectivities from the same reactants. DFT
calculations suggested that the catalyst architecture determines the regioselectivity via
the modulation of electronic and steric interactions.
This article is protected by copyright. All rights reserved.