Nickel-Catalyzed Asymmetric Hydrogenation of Cyclic Alkenyl Sulfones, Benzo[ b]thiophene 1,1-Dioxides, with Mechanistic Studies

Article abstract of DOI:10.1021/acs.orglett.0c03723

A highly efficient catalytic system based on the cheap transition metal nickel for the asymmetric hydrogenation of challenging cyclic alkenyl sulfones, 3-substituted benzo[b]thiophene 1,1-dioxides, was first successfully developed. A series of hydrogenation products, chiral 2,3-dihydrobenzo[b]thiophene 1,1-dioxides, were obtained in high yields (95-99%) with excellent enantioselectivities (90-99% ee). According to the results of nonlinear effect studies, deuterium-labeling experiments, and DFT calculation investigations, a reasonable catalytic mechanism for this nickel-catalyzed asymmetric hydrogenation was provided, which displayed that the two added hydrogen atoms of the hydrogenation products could be from H2 through the insertion of Ni-H and subsequent hydrogenolysis.

Full text of DOI:10.1021/acs.orglett.0c03723

pubs.acs.org/OrgLett
Letter
Nickel-Catalyzed Asymmetric Hydrogenation of Cyclic Alkenyl
Sulfones, Benzo[b]thiophene 1,1-Dioxides, with Mechanistic Studies
Gongyi Liu, Kui Tian, Chenzong Li, Cai You, Xuefeng Tan, Heng Zhang,* Xumu Zhang,*
and Xiu-Qin Dong*
Cite This: Org. Lett. 2021, 23, 668−675
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ABSTRACT: A highly efficient catalytic system based on the
cheap transition metal nickel for the asymmetric hydrogenation of
challenging cyclic alkenyl sulfones, 3-substituted benzo[b]-
thiophene 1,1-dioxides, was first successfully developed. A series
of hydrogenation products, chiral 2,3-dihydrobenzo[b]thiophene
1,1-dioxides, were obtained in high yields (95−99%) with excellent
enantioselectivities (90−99% ee). According to the results of
nonlinear effect studies, deuterium-labeling experiments, and DFT calculation investigations, a reasonable catalytic mechanism for
this nickel-catalyzed asymmetric hydrogenation was provided, which displayed that the two added hydrogen atoms of the
hydrogenation products could be from H2 through the insertion of Ni−H and subsequent hydrogenolysis.
symmetric hydrogenation of prochiral unsaturated
compounds has been regarded as a powerful and
desired product.9k In addition, these Ni-catalyzed asymmetric
hydrogenation reactions were mainly focused on acyclic
functionalized olefins and imines as substrates, which were
always in accordance with this catalytic mechanism. In
contrast, cyclic functionalized olefin substrates have rarely
been investigated.
A
straightforward synthetic method to access chiral compounds
that has been widely applied in the fields of agrochemicals and
pharmaceuticals.1 Most well-established asymmetric hydro-
genation methods are based on heavy noble transition metal
catalytic systems, mainly focused on ruthenium,2 iridium,3
rhodium,4 and palladium.5 However, these precious metal
catalysts could suffer from the difficulties of high costs, limited
resources, strong toxicity, and negative environmental impact.
Therefore, great attention has been devoted to the develop-
ment of cheap, sustainable, earth-abundant transition metal
catalytic systems for asymmetric hydrogenation.6 In recent
years, some iron-, cobalt-, and nickel-catalyzed asymmetric
(transfer) hydrogenation reactions of prochiral unsaturated
compounds with CC, CO, or CN bonds were
reported7−9 that demonstrated the great potential advantages
of the cheap first-row transition metals in asymmetric
hydrogenation. Among these asymmetric catalytic systems,
Ni-catalyzed asymmetric hydrogenation was relatively less
investigated. Some pioneering and important research works
on Ni-catalyzed asymmetric (transfer) hydrogenation of
prochiral ketones, alkenes, ketimines, and enamides were
developed by Hamada,9a,b Chirik,9c Zhou,9d−i Zhang,9j and our
group.9k−p In 2016, Chirik and co-workers developed the Ni-
catalyzed asymmetric hydrogenation of α,β-unsaturated esters
and performed deep research on the catalytic mechanism,
proposing conjugate addition of the Ni−H species and
nonselective protonation to release the product.9c In 2017,
our group realized Ni-catalyzed asymmetric hydrogenation of
β-acylamino nitroolefins, and experimental and DFT computa-
tional investigations revealed that it also involved 1,4-hydride
addition of Ni−H and subsequent protonation to generate the
Chiral cyclic sulfone scaffolds are widely distributed in many
biologically active compounds and natural products with
important applications.10 Because of the rigidity of cyclic
functionalized olefins, the asymmetric hydrogenation of
unsaturated cyclic sulfones to access these motifs is still in
an early stage, and just a few examples involving unsaturated
cyclic sulfones have been developed.2l,3o,p,4k In 2012,
Andersson and co-workers described Ir-catalyzed enantiose-
lective hydrogenation of prochiral cyclic and acyclic unsatu-
rated sulfones with excellent results.3o In 2017, Pfaltz and co-
workers successfully developed Ir-catalyzed asymmetric hydro-
genation of cyclic alkenyl sulfones, benzo[b]thiophene 1,1-
dioxides.3p Recently, our group realized Rh/N-methylated
bisphosphine−thiourea ZhaoPhos-catalyzed asymmetric hy-
drogenation of these cyclic alkenyl sulfones with excellent
results by the assistance of the possible hydrogen-bonding
interaction between the substrate and the ligand.4k However,
cheap transition metals have never been applied to catalyze the
asymmetric hydrogenation of cyclic alkenyl sulfones. On the
Received: November 8, 2020
Published: January 20, 2021
https://dx.doi.org/10.1021/acs.orglett.0c03723
© 2021 American Chemical Society
Org. Lett. 2021, 23, 668−675
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basis of our long-standing efforts in asymmetric hydrogenation,
we are interested in the development of cheap transition metal
catalytic systems for the asymmetric hydrogenation of cyclic
alkenyl sulfones. As a continuation of our investigations, in this
work we successfully developed the first asymmetric hydro-
genation of 3-substituted benzo[b]thiophene 1,1-dioxides
catalyzed by the cheap transition metal Ni, affording a series
Scheme 1. First Asymmetric Hydrogenation of Cyclic
Alkenyl Sulfones Catalyzed by the Cheap Transition Metal
Ni
Figure 1. Structures of chiral diphosphine ligands.
Table 2. Optimization of the Reaction Conditions for Ni-
Catalyzed Asymmetric Hydrogenation of 3-
a
Phenylbenzo[b]thiophene 1,1-Dioxide (1a)
Table 1. Ligand Screening for Ni-Catalyzed Asymmetric
Hydrogenation of 3-Phenylbenzo[b]thiophene 1,1-Dioxide
a
(1a)
PH
(atm)
T
(°C)
conv.
b
ee
(%)
2
c
entry
solvent
(%)
d
1
MeOH
60
60
60
60
60
60
60
60
70
70
70
70
70
70
70
70
80
80
NR
58
NA
94
2
3
4
5
6
7
TFE:MeOH = 10:1
EtOH:MeOH = 10:1
CH2Cl2:MeOH = 10:1
THF:MeOH = 10:1
toluene:MeOH = 10:1
TFE:MeOH = 40:1
TFE:MeOH = 40:1
TFE:MeOH = 40:1
b
c
NR
NR
NR
NR
72
NA
NA
NA
NA
95
entry
ligand
conv. (%)
ee (%)
1
2
3
4
5
6
7
8
(S,S)-Me-DuPhos
(S,S)-Ph-BPE
JosiPhos
(S)-SegPhos
(Rc,Sp)-DuanPhos
(S)-BINAP
8
25
50
NR
NR
NR
83
30
95
59
NA
NA
NA
56
e
8
e
82
>99
96
96
9
a
Conditions: 0.1 mmol of 1a, 1a:Ni(OAc)2:(S,S)-Ph-BPE =
WalPhos
ZhaoPhos
1:0.01:0.011 in 1.0 mL of TFE for 50 h. The catalyst was
precomplexed in MeOH (0.1 mL for each reaction vial). THF is
tetrahydrofuran. Solvent:MeOH ratios are v/v. Determined by H
NMR analysis. The ee values were determined by HPLC on a chiral
phase. 0.1 mmol of 1a, 1a:Ni(OAc)2:(S,S)-Ph-BPE = 1:0.05:0.055 in
1.0 mL of MeOH for 50 h. 0.1 mmol of 1a, 1a:Ni(OAc)2:(S,S)-Ph-
BPE = 1:0.01:0.011 in 2.0 mL of TFE for 50 h. The catalyst was
NR
NA
a
b
1
Conditions: 0.1 mmol of 1a, 1a:Ni(OAc)2:ligand = 1:0.05:0.055 in
c
1.0 mL of CF3CH2OH (TFE) under 60 atm H2 for 40 h. The catalyst
was precomplexed in MeOH (0.5 mL for each reaction vial).
d
b
c
Determined by 1H NMR analysis. NR = no reaction. The ee values
e
were determined by HPLC on a chiral phase. NA = not available.
precomplexed in MeOH (50 μL for each reaction vial).
of enantioenriched hydrogenation products with >99%
conversion, 95−99% yield, and 90−99% ee (Scheme 1).
Importantly, a reasonable catalytic mechanism was proposed
for this hydrogenation on the basis of deuterium-labeling
experiments and DFT calculations.
Initially, a variety of readily available chiral diphosphine
ligands (Figure 1) were applied for the Ni(OAc)2-catalyzed
asymmetric hydrogenation of the model substrate 3-
phenylbenzo[b]thiophene 1,1-dioxide (1a) under 60 atm H2
at 70 °C for 40 h. The Ni(OAc)2/chiral diphosphine ligand
catalyst was generated in situ in MeOH to achieve good
solubility. (S,S)-Me-DuPhos and JosiPhos displayed poor
reactivitites and enantioselectivities (8−50% conversion and
30−59% ee; Table 1, entries 1 and 3). Although 25%
conversion was realized in the presence of (S,S)-Ph-BPE,
excellent enantioselectivity of 95% ee was obtained (Table 1,
entry 2). In addition, some other important chiral diphosphine
ligands, such as (S)-SegPhos, (Rc,Sp)-DuanPhos, (S)-BINAP,
and ZhaoPhos could not promote this Ni-catalyzed asym-
metric hydrogenation, and no desired hydrogenation product
2a was detected (Table 1, entries 4−6 and 8). WalPhos
provided good conversion (83%) with moderate enantiose-
lectivity (56% ee) (Table 1, entry 7).
In order to improve the conversion of this Ni/(S,S)-Ph-BPE-
catalyzed asymmetric hydrogenation of 1a, the reaction
conditions were further optimized in various solvents. It was
found that there was no conversion in MeOH, which was an
unfavorable solvent for this Ni-catalyzed asymmetric hydro-
genation (Table 2, entry 1). The Ni(OAc)2/(S,S)-Ph-BPE
catalytic system was dissolved well in MeOH, and it was better
to investigate other solvents in the presence of MeOH. Then
the catalyst solution was decreased to a catalyst loading of 1.0
mol % to reduce the negative effect of MeOH, and the
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a
Scheme 2. Scope Study for the Ni-Catalyzed Asymmetric Hydrogenation of 3-Substituted Benzo[b]thiophene 1,1-Dioxides
a
Conditions: 0.1 mmol of substrate, substrate 1:Ni(OAc)2:(S,S)-Ph-BPE = 1:0.01:0.011 in 2.0 mL of CF3CH2OH for 50 h. The catalyst was
b
precomplexed in MeOH (50 μL for each reaction vial). Isolated yields are shown. The ee values were determined by HPLC on a chiral phase. S:C
= 50, 60 h.
Scheme 3. Deuterium-Labeling Experiments
conversion was greatly increased to 58% (Table 2, entry 2).
Figure 2. Linear effect study of the hydrogenation of model substrate
Some other solvents were then examined, but no hydro-
1a using (S,S)-Ph-BPE with different ee values.
genation product was detected in EtOH, CH2Cl2, THF, or
toluene (Table 2, entries 3−6). The conversion was increased
to 72% with 95% ee when the ratio of TFE was increased to
TFE:MeOH = 40:1 (Table 2, entry 7). TFE may help to
accelerate the addition of the Ni−H active species to the CC
bond. Good conversion (82%) and excellent enantioselectivity
(96% ee) could be achieved at a higher reaction temperature of
80 °C (Table 2, entry 8). To our delight, >99% conversion
with 96% ee was obtained when the pressure of H2 was
increased to 70 atm (Table 2, entry 9).
Under the optimized reaction conditions, we began to
explore the substrate generality of this Ni/(S,S)-Ph-BPE-
catalyzed asymmetric hydrogenation of 3-substitued benzo[b]-
thiophene 1,1-dioxides. These results are summarized in
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Figure 3. DFT-calculated free energy profile for the proposed catalytic cycle of the Ni-catalyzed asymmetric hydrogenation.
In order to explore the possible mechanism, deuterium-
labeling experiments were carried out. The Ni-catalyzed
asymmetric hydrogenation of model substrate 1a was
conducted under 50 atm D2. Interestingly, we found that the
deuterium atoms of the product 2a-D were attached at both
the α- and β-positions (Scheme 3a). In addition, this
hydrogenation was conducted in the presence of H2 with
CF3CH2OD and CD3OD as the reaction solvents, and no
deuterium atoms were found in the hydrogenation product
(Scheme 3b). These observations are quite different from the
previous research work,9c,k indicating that this Ni-catalyzed
asymmetric hydrogenation may go through a different catalytic
pathway.
In addition, a nonlinear effect study of this Ni-catalyzed
asymmetric hydrogenation was performed. A series of
hydrogenations of model substrate 1a were carried out with
ligand (S,S)-Ph-BPE with different ee values. As shown in
Figure 2, a linear effect could be observed in this asymmetric
transformation, and it is possible that there is no catalyst self-
aggregation or ligand−substrate agglomeration in this catalytic
system.11
According to these above reaction results, DFT calculations
were performed to further reveal the possible catalytic
mechanism of this hydrogenation. Our favored computed
catalytic cycle (Figure 3) starts with the formation of Ni−H
complex B through hydrogenolysis of the coordinated Ni(II)
complex, which can be deemed as the active catalyst.
Subsequent coordination of B with substrate 1a and then
insertion of Ni−H into the double bond gives Ni−C complex
D_(S). The second hydrogenolysis delivers the desired S-
configured hydrogenated product 2a and regenerates the active
catalyst B. This catalytic process is quite different from the
previously reported 1,4-hydride addition and subsequent
Scheme 4. Gram-Scale Asymmetric Hydrogenation
Scheme 2. Substrates with electron-netural groups (1a and
1b), electron-donating groups (1c−k), and electron-with-
drawing groups (1l−p) on the phenyl ring reacted well,
affording the corresponding hydrogenation products (2a−p)
with excellent results (>99% conversion, 95−99% yields, 90−
99% ee). In addition, the position of substituents on the phenyl
ring had little influence on the reactivity and enantioselectivity.
Remarkably, the challenging substrates 1c, 1d, 1f−h, 1j, 1m,
1n, and 1p bearing steric hindrance from the ortho and meta
substituents on the phenyl ring were hydrogenated smoothly in
95−98% yield with 90−99% ee. Furthermore, the asymmetric
hydrogenation of substrate 1q with a bulky 2-naphthyl group
also proceeded smoothly to afford product 2q with full
conversion in 95% yield with 92% ee. To our delight, the alkyl
substrates with a 3-methyl group (1r), an ethyl group (1s), and
an n-propyl group (1t) also worked well to provide the
hydrogenation products 2r−t with excellent results (96−99%
yield with 90−93% ee). In addition, the 2-substitued
benzo[b]thiophene 1,1-dioxide substrates containing a phenyl
group (1u) or methyl group (1v) were then hydrogenated, but
unfortunately, there was no reaction in this Ni-catalyzed
system.
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protonation to give the desired product.9c,k In addition, the
computational details of other catalytic pathways are provided
in the Supporting Information.
To demonstrate the potential synthetic application of this
Ni-catalyzed transformation, the gram-scale asymmetric hydro-
genation on 4 mmol of model substrate 1a was conducted in
the presence of just 0.5 mol % catalyst. The desired product 2a
was obtained in full conversion and 99% yield with 97% ee,
showing the potential synthetic importance of our catalytic
system (Scheme 4).
In summary, we successfully developed the first asymmetric
hydrogenation of challenging cyclic alkenyl sulfones, 3-
substituted benzo[b]thiophene 1,1-dioxides, catalyzed by the
cheap transition metal Ni. A series of hydrogenation products,
chiral 2,3-dihydrobenzo[b]thiophene 1,1-dioxides, were ob-
tained in 95−99% yield with 90−99% ee. A reasonable
catalytic cycle was proposed for this Ni-catalyzed hydro-
genation on the basis of combined deuterium-labeling
experiments and DFT calculations. Also, we found that the
two added hydrogen atoms in the hydrogenation product
could be from H2 through insertion of Ni−H and subsequent
hydrogenolysis, which is different from the previously reported
1,4-hydride addition and subsequent protonation.
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China
Chenzong Li − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China; Pharmaceutical Research
Institute, Wuhan Institute of Technology, Wuhan, Hubei
430205, China
Cai You − Shenzhen Grubbs Institute, Southern University of
Science and Technology, Shenzhen, Guangdong 518055,
China
Xuefeng Tan − Shenzhen Grubbs Institute, Southern
University of Science and Technology, Shenzhen, Guangdong
518055, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c03723
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant 22071187), the Natural
Science Foundation of Jiangsu Province (Grant BK20190213),
and the Shenzhen Science and Technology Innovation
Committee (Grant KQTD20150717103157174). The Pro-
gram of Introducing Talents of Discipline to Universities of
China (111 Project) is also appreciated. The numerical
calculations in this paper were done on the supercomputing
system in the Supercomputing Center of Wuhan University.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c03723.
Experimental procedures and compound characteriza-
tion (PDF)
REFERENCES
■
AUTHOR INFORMATION
Corresponding Authors
■
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Xiu-Qin Dong − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China; Suzhou Institute of Wuhan
University, Suzhou, Jiangsu 215123, China; orcid.org/
0000-0002-5045-1198; Email: xiuqindong@whu.edu.cn
Xumu Zhang − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China; Shenzhen Grubbs Institute,
Southern University of Science and Technology, Shenzhen,
Guangdong 518055, China; orcid.org/0000-0001-5700-
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Heng Zhang − Engineering Research Center of Organosilicon
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Chemistry and Molecular Sciences, Wuhan University,
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Authors
Gongyi Liu − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
Chemistry and Molecular Sciences, Wuhan University,
Wuhan, Hubei 430072, China; Pharmaceutical Research
Institute, Wuhan Institute of Technology, Wuhan, Hubei
430205, China
Kui Tian − Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, College of
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