Nickel-Catalyzed Asymmetric Reductive Arylbenzylation of Unactivated Alkenes

Article abstract of DOI:10.1021/acs.orglett.0c00688

Herein, we report a nickel-catalyzed asymmetric two-component reductive dicarbofunctionalization of aryl iodide-tethered unactivated alkenes using benzyl chlorides as the challenging coupling partner. This arylbenzylation reaction enables the efficient synthesis of diverse benzene-fused cyclic compounds bearing a quaternary stereocenter with a high tolerance of sensitive functionalities in highly enantioselective manner. The preliminary mechanistic investigations suggest a radical chain reaction mechanism.

Full text of DOI:10.1021/acs.orglett.0c00688

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Letter
Nickel-Catalyzed Asymmetric Reductive Arylbenzylation of
Unactivated Alkenes
Youxiang Jin, Haobo Yang, and Chuan Wang*
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ABSTRACT: Herein, we report a nickel-catalyzed asymmetric
two-component reductive dicarbofunctionalization of aryl iodide-
tethered unactivated alkenes using benzyl chlorides as the
challenging coupling partner. This arylbenzylation reaction enables
the efficient synthesis of diverse benzene-fused cyclic compounds
bearing a quaternary stereocenter with a high tolerance of sensitive
functionalities in highly enantioselective manner. The preliminary mechanistic investigations suggest a radical chain reaction
mechanism.
ransition-metal-catalyzed dicarbofunctionalization of un-
activated alkenes has proven to be a reliable method for
nickel-catalyzed reductive asymmetric arylalkylation of aryl
bromide appended alkenes with unactivated alkyl bromides.
11
T
concomitant formation of two C−C bonds across the olefinic
However, the use of benzyl bromide as the coupling partner in
this reaction failed because benzyl bromides outcompete aryl
bromides regarding oxidative addition to low-valent nickel and
thus have an extremely high tendency to undergo homocou-
pling. For similar reasons, the successful use of benzyl
unit, leading to a rapid increase of the molecular complex-
1
−5
ity. For instance, diverse cyclic compounds can be prepared
via dicarbofunctionalization of tethered alkenes in both redox-
4
5
neutral and reductive strategy. For the asymmetric version of
this reaction, significant progress has been achieved in recent
(
pseudo)halides in reductive cross-coupling reactions are
6
7
8
9
15,16
years, and the contributions from Fu, Brown, Kong, Shu,
rare.
To address this challenge, we envisage that the use
1
0
11
Zhang, and our group enabled the highly enantioselective
synthesis of a variety of benzene-fused carbo- or heterocycles
through diarylation, arylalkylation, arylalkenylation, and
arylalkynylation of pendant unactivated alkenes, which all
engage an enantioselective arylmetalation as the key elemen-
of more reactive aryl iodide and less reactive benzyl chlorides
could be the potential solution for a nickel-catalyzed reductive
two-component arylbenzylation of tethered unactivated
alkenes (Scheme 1B).
For optimization of the reaction conditions, the iodoben-
zene 1a containing a terminal olefinic unit and p-acetoxy
benzyl chloride (2a) were chosen as the benchmark substrates
12
13,14
tary step (Scheme 1A).
However, the incorporation of a
benzyl moiety through enantioselective dicarbofunctionaliza-
tion remains still elusive. Very recently, our group developed a
(
Table 1). Initially, a series of chiral oxazoline ligands were
surveyed (entries 1−7). In the case of PHOX (L1) and
Scheme 1. Previous Work of Asymmetric
Dicarbofunctionalization of Tethered Unactivated Alkenes
PyBOX (L2) as ligands, the formation of the desired product
3
aa was not observed (entries 1 and 2). In contrast, all of the
(
A); This work: Asymmetric Reductive Arylbenzylation of
reactions using BOX and Pyrox ligands could afford the
cyclization/cross-coupling product 3aa in moderate efficiency
Tethered Unactivated Alkenes (B)
(
entries 3−8), wherein the best outcome concerning the
enantiocontrol was achieved in the case of the Pyrox L8 (entry
8
1
). Next, various Ni precatalysts were examined (entries 9−
3), and the yield could be improved to 94% in the case of
NiBr ·diglyme (entry 13). Importantly, the level of asymmetric
2
induction remained high. Performing the reaction in other
Received: February 21, 2020
©
XXXX American Chemical Society
https://dx.doi.org/10.1021/acs.orglett.0c00688
A
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Table 1. Optimization of the Reaction Conditions for the
Ni-Catalyzed Asymmetric Reductive Arylbenzylation
and both electron-withdrawing and electron-donating groups
were well tolerated (3ga and 3ha). Moreover, the highly
enantioselective construction of the dihydrobenzofuran (3ia
and 3ja) and indoline (3ka) framework turned out to be viable
using our method. However, only poor enantiocontrol could
be achieved for the synthesis of tetrahydroisoquinoline (3la).
In this case, the use of chiral BOX L4 as ligand also led to low
enantioselectivity. Subsequently, diverse substituted benzyl and
naphtyl chlorides 2b−r were reacted with the aryl iodide
appended alkene 1a. To our delight, all of the products 3ab−
aq were afforded in excellent enantioselectivities. Of note is
that both alkyl (3ag) and aryl chloride (3an) remained intact
in this Ni-catalyzed reaction. Furthermore, the electron-
deficient benzyl chloride 2q with higher propensity to undergo
homocoupling also turned out to be a competent precursor in
the studied reaction (3aq). Unfortunately, our method could
not allow the use of secondary benzyl chlorides as the coupling
partner in this arylbenzylation reaction. In the case of benzyl
chlorides containing an aryl bromide moiety, the reactions
afforded a complex mixture. The absolute configuration of
compound 3aj (CCDC number: 1967238) was unambiguously
determined to be R through X-ray crystal structure analysis.
The stereochemistry of the other arylbenzylation products
were assigned by assuming an analogy reaction pathway.
To shed light on the mechanism of this Ni-catalyzed
asymmetric arylbenzylation, we performed a number of control
experiments. First, the tethered aryl halides were subjected to
a
b
c
entry
ligand
Ni precatalyst
solvent
yield (%)
ee (%)
1
2
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
Ni(BF ) ·6H O
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
NMP
DMF
DMA
DMA
DMA
0
0
4
2
2
Ni(BF ) ·6H O
4
2
2
Ni(BF ) ·6H O
34
52
58
65
69
66
56
88
84
91
80
93
38
52
53-
97
97
97
97
97
98
97
89
90
97
97
4
2
2
Ni(BF ) ·6H O
4
2
2
Ni(BF ) ·6H O
4
2
2
Ni(BF ) ·6H O
4
2
2
Ni(BF ) ·6H O
4
2
2
Ni(BF ) ·6H O
4
2
2
NiBr2
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
NiBr ·(dme)
2
NiCl ·(dme)
2
Ni(COD)2
the stoichiometric reaction with Ni(COD) in the presence of
2
d
NiBr ·diglyme
96 (94 )
2
the chiral ligand L8, followed by quenching with water (Table
3). In the case of the aryl iodide 1a, a high conversion was
achieved within 10 min wherein the 5-exo hydroarylation
product 4 and the dimerization product 5 were afforded in
45% and 42% yield, respectively (entry1). Notably, the
formation of 6-endo cyclization product 7 was not detected,
which is the major product in the stoichiometric reaction with
Ni(0) under the conditions of our previously reported
NiBr ·diglyme
78
33
58
45
31
2
NiBr ·diglyme
2
e
NiBr ·diglyme
2
f
NiBr ·diglyme
2
g
NiBr diglyme
2
a
Unless otherwise specified, reactions were performed on a 0.2 mmol
scale of aryl iodide 1a with 1.2 equiv of p-acetoxybenzyl chloride (2a),
1
0 mol % NiBr ·diglyme, 15 mol % ligand, and 2.0 equiv of Zn as
11
2
arylalkylation. This result suggests that this arylbenzylation
b
reductant in 0.5 mL of solvent at 40 °C for 16 h. GC yields using n-
dodecane as an internal standard. Determined by HPLC analysis on
chiral stationary phase. Yield of the isolated product. Mn was used
as the reductant instead of Zn. The bromo analogue of 1a was used
might proceed in a distinct reaction pathway. Furthermore, the
stoichiometric reaction using the corresponding aryl bromide
required a much longer reaction time to achieve a similar
conversion (entry 2). This reaction differentiating our aryl-
alkylation only in the ligand gave a different product profile
with compound 7 as a minor product (14% yield), suggesting
that the mode of the migratory insertion across the olefinic
unit is significantly influenced by the ligand. We also found
that the dimerization of benzyl chloride in the presence of
c
d
e
f
g
instead of 1a. p-Acetoxybenzyl bromide was used instead of 2a.
polar solvents such as NMP and DMF provided only inferior
results (entries 14 and 15). When Mn was used as reductant
instead of Zn, both efficiency and enantioselectivity diminished
(
entry 16). Finally, the influence of the leaving group on both
stoichiometric Ni(COD) could be complete within 10 min,
2
substrates was investigated. The use of a less reactive bromo
analogue of 1a as the coupling partner resulted in a much
lower yield (entry 17), and replacing the benzyl chloride 2a by
the corresponding more reactive benzyl bromide also
demonstrated significant detrimetal effect on the desired
reaction (entry 18). In these two cases, the homocoupling of
benzyl chloride or bromide turned out to be the major
reaction.
Under the optimal reaction conditions, we began to explore
the substrate spectrum of this Ni-catalyzed asymmetric
reductive arylbenzylation (Table 2). First, a panel of pendant
terminal alkenes 1a−f were subjected to the reaction with the
benzyl chloride 2a. Gratifying, all these reactions proceeded
smoothly, furnishing the corresponding products 3aa−fa in
high yields and enantiomeric excesses. We then studied the
electronic effect of the substitution on the tethered aryl ring,
indicating the match of the high reactivity of aryl iodide and
benzyl chloride toward Ni(0) is possibly the premise for their
efficient cross-coupling.
Next, the sequential stoichiometric reaction of 1a with
Ni(COD) and the benzyl chloride 2a was conducted in the
2
absence of the reducing agent (Scheme 2). The arylbenzylation
product 3aa was isolated in a moderate yield and slightly lower
enantioselectivity than the one of the catalytic reaction, while
the major byproduct in this sequential stoichiometric reaction
is the dimerization product 5. This result reveals that Zn could
serve as a terminal reductant in the catalytic cycle unlike our
5d,11
arylalkylation,
which require an intermediate reduction.
The difference regarding mechanism may lie in the distinct
propensity of the respective organohalides used in these
reactions to undergo reduction with low-valent Ni to generate
the corresponding radicals.
B
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−
a c
Table 2. Evaluation of the Substrate Scope the Ni-Catalyzed Asymmetric Reductive Arylbenzylation
a
Unless otherwise specified, reactions were performed on a 0.2 mmol scale of aryl iodides 1a−l with 1.2 equiv of benzyl chlorides 2a−r, 10 mol %
b
NiBr ·diglyme, 15 mol % ligand L8, and 2.0 equiv of Zn as reductant in 0.5 mL of DMA at 40 °C for 16 h. Yields of the isolated products.
2
c
d
Enantiomeric excesses were determined by HPLC analysis on chiral stationary phase. Reaction was performed on a 1 mmol scale.
Table 3. Stoichiometric Reactions of the Aryl Halides with
Ni(0) Followed by Quenching with Water
Scheme 2. Sequential Stoichiometric Reaction of the Iodide
1a with Benzyl Chloride 2a
a
Ni(0) is produced under the reductive reaction conditions and
undergoes subsequently the oxidative addition with the aryl
iodide 1, to afford the resultant Ni(II) species I, which
performs then the enantiodetermining migratory insertion to
the pendant olefinic unit. In parallel, Ni(I) reduces the benzyl
chlorides 2 to provide the benzyl radicals, which add onto the
cyclic alkyl Ni(II) intermediate II. The following facile
reductive elimination from the Ni(III) complex III furnishes
the arylbenzylation product 3 and Ni(I), which interacts with
benzyl chlorides, leading to the formation of Ni(II). Finally,
the Zn-mediated reduction of Ni(II) regenerates Ni(0), thus
closing the catalytic cycle. In addition, the homolytic Ni−C
bond cleavage of the intermediate II could provide the on-
b
b
b
b
t
yield of 4
yield of 5
yield of 6
yield of 7
entry
X
(min)
(%)
(%)
(%)
(%)
1
2
I
Br
10
60
45
59
43
15
13
12
0
14
a
Reactions were performed on a 0.2 mmol scale of aryl halides with
.0 equiv of Ni(COD) and 1.0 equiv of ligand L8 as reductant in 0.5
mL of DMA at 40 °C. GC yields using n-dodecane as an internal
1
2
b
standard.
Relying on the results of the stoichiometric reactions, we
tentatively proposed a radical chain mechanism for this Ni-
catalyzed asymmetric arylbenzylation in Scheme 3. Initially,
C
https://dx.doi.org/10.1021/acs.orglett.0c00688
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Letter
Scheme 3. Proposed Mechanism
Excellence in Molecular Synthesis, University of Science and
Technology of China, Hefei, Anhui 230026, P.R. China
Haobo Yang − School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, Shanghai 200240, P.R. China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00688
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work is supported by National Natural Science
Foundation of China (Grant No. 21772183), Fundamental
Research Funds for the Central Universities
(
WK2060190086), and “1000-Youth Talents Plan” start-up
funding as well as University of Science and Technology of
China.
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Chuan Wang − Hefei National Laboratory for Physical Science
at the Microscale, Department of Chemistry, Center for
Excellence in Molecular Synthesis, University of Science and
Technology of China, Hefei, Anhui 230026, P.R. China;
orcid.org/0000-0002-9219-1785; Email: chuanw@
ustc.edu.cn
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