Nickel-Catalyzed Asymmetric Addition of Aromatic Halides to Ketones: Highly Enantioselective Synthesis of Chiral 2,3-Dihydrobenzofurans Containing a Tertiary Alcohol

Article abstract of DOI:10.1021/acs.orglett.0c01612

A highly enantioselective and straightforward synthetic procedure to chiral 3-hydroxy-2,3-dihydrobenzofurans has been developed by nickel/bisoxazoline-catalyzed intramolecular asymmetric addition of aryl halides to unactivated ketones, giving 2,3-dihydrobenzofurans with a chiral tertiary alcohol at the C-3 position in good yields and excellent enantioselectivities (up to 92percent yield and 98percent ee). The gram-scale reaction also proceeded smoothly without a loss of yield and enantioselectivity.

Full text of DOI:10.1021/acs.orglett.0c01612

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Letter
Nickel-Catalyzed Asymmetric Addition of Aromatic Halides to
Ketones: Highly Enantioselective Synthesis of Chiral 2,3-
Dihydrobenzofurans Containing a Tertiary Alcohol
Ying Li,∥ Wendian Li,∥ Jiangyan Tian, Guozheng Huang,* and Hui Lv*
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ABSTRACT: A highly enantioselective and straightforward
synthetic procedure to chiral 3-hydroxy-2,3-dihydrobenzofurans
has been developed by nickel/bisoxazoline-catalyzed intramolecular
asymmetric addition of aryl halides to unactivated ketones, giving
2,3-dihydrobenzofurans with a chiral tertiary alcohol at the C-3
position in good yields and excellent enantioselectivities (up to 92%
yield and 98% ee). The gram-scale reaction also proceeded
smoothly without a loss of yield and enantioselectivity.
Scheme 1. Strategies for Asymmetric Arylation of Aldehyde
and Ketones and Related Progress
arbonyl addition is a fundamental transformation in
a
1
Corganic synthesis. As a result, the arylation of aldehydes
and ketones has been widely investigated, and many efficient
methods have been developed.2 However, most of these
approaches involved using the moisture-sensitive, low func-
tional group compatibility of organomagnesium,3 organo-
lithium,4 organozinc,5 or relatively expensive arylboron
reagents,6 which is unavoidable to generate stoichiometric
quantities of metallic byproducts or boronic acid derivatives.
Moreover, organometallic reagents and arylboron reagents are
typically prepared from the corresponding organohalides, and
extra synthetic steps are needed to produce these reagents. By
comparison, the transition-metal-catalyzed asymmetric addi-
tion of aryl halides to carbonyl compounds provides ideal
access to chiral alcohols (Scheme 1), especially for chiral
tertiary alcohols because they cannot be prepared by
asymmetric reduction of ketones. Nevertheless, only a few
reactions of this type were reported;7 almost all of the
successful examples were limited to the addition of aryl halide
to aldehydes, and the analogous addition reactions to ketones
were very difficult due to the attenuated reactivity of ketones.
Furthermore, the enantioselective addition of aryl halides to
carbonyls suffered from formidable challenges in enantiocon-
trol. Thus, transition-metal-catalyzed direct addition of aryl
halides to carbonyl compounds in an enantioselective manner
is far from established.
a
All reactions were carried out with 1 (0.2 mmol), Ni(PPh3)4 (10 mol
%), L6 (12 mol %),and Mn (2 equiv) in i-PrOH (4 mL) at 80 °C for
15 h. The yields were isolated yields. The ee values were determined
by HPLC analysis using a chiral stationary phase.
In recent years, nickel-catalyzed C−C bond-forming
reactions have become robust synthetic tools.8 In this context,
nickel-catalyzed reductive coupling of aryl halides to carbonyl
compounds to produce alcohols attracted wide attention. In
2000, Cheng reported his pioneering work on nickel-catalyzed
addition of aryl halides to aldehydes, generating secondary
alcohols with moderate to good yields.9 Unfortunately, no
enantioselectivity was observed when using chiral bisoxazoline
Received: May 12, 2020
https://dx.doi.org/10.1021/acs.orglett.0c01612
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
as ligand. Since then, Mashima,10 Voskoboynikov,11 and
Weix12 reported their excellent works on aryl halo ketone
addition and greatly expanded the scope of aryl halides and
aldehydes. Recently, Itoh and Yamaguchi achieved the first
enantioselective addition of aryl halide to aldehydes13 but only
afforded the chiral diarylmethanol in 29% yield with 46% ee.
The nickel-catalyzed intramolecular addition of aryl halides to
activated ketones was achieved by Jia and Gao,14 but the
enantioselctive variant of this reaction only gave the target
product with 36% ee. As for unactivated ketones, the nickel-
catalyzed addition of aryl halides to ketones is more
challenging, and a breakthough was made by Xu very recently
but only achieved low to moderate enantioselectivity.15 Thus,
it is still a problematic issue to achieve nickel-catalyzed highly
enantioselective arylation of unactivated ketones.15 Herein, we
report Ni-catalyzed intramolecular asymmetric addition of aryl
halides to unactivated ketones to efficiently synthesize chiral
2,3-dihydrobenzofurans bearing a tertiary alcohol at the C-3
position,16 which are the core structure of natural products
with important biological activities.17
We initiated our studies by using 2-(2-iodophenoxy)-1-
phenylethan-1-one 1a as a model substrate to explore nickel-
catalyzed asymmetric intramolecular addition of aryl iodides to
ketones. First, the reaction was conducted in i-PrOH at 80 °C
for 15 h in the presence of 10 mol % of Ni(PPh3)4 and 2 equiv
of Mn. It worked smoothly to afford the target product 2a, the
deiodinated byproduct 4a and C−O cleavage byproduct 5a at
a ratio of 48:10:42, which indicated that the chemoselectivity
of the model reaction was complicated and the background
reaction was serious (Table 1, entry 1). Then a series of
commercially available oxazoline ligands were evaluated
(Figure 1). When Pybox-type ligands, such as L1 and L2,
were employed, the reaction proceeded very well but only
afforded target product 2a in moderate yields with moderate
enantioselectivities due to the relatively high ratio of
deiodinated product 4a or the dehydrated product 6a (Table
1, entries 2 and 3). To our delight, bisoxazoline ligand L3
exhibited good catalytic performance in this reaction, furnish-
ing target product 2a in high yield with 95% enantioselectivity
(Table 1, entry 4).18 Surprisingly, increasing the steric
hindrance of the bisoxazoline ligand was detrimental to the
intramolecular addition of aryl iodide to ketone, causing the
yield and the enantioselectivity of target product to drop
greatly (Table 1, entry 5). Further ligand screening revealed
that most of the malonate-derived bisoxazolines are good
ligands for this transformation, offering chiral 2,3-dihydroben-
zofuran with good yields and excellent enantioselectivities
(Table 1, entries 6−10). Considering the yield and the
enantioselectivity, L6 was chosen as the best ligand for the
asymmetric addition of aryl iodides to ketones. When zinc was
used as the reductant, the reaction proceeded smoothly, but
the ratio of C−O cleavage product 5a was increased
dramatically (Table 1, entry 11). Subsequently, a set of nickel
precursors were examined, and the results indicated that
Ni(PPh3)4 was better than other nickel salts (Table 1, entries
12−17).
Table 1. Ligands and Nickel Salt Screening for Nickel
Catalyzed Asymmetric Addition of Aryl Iodides to Ketones
a
2a/3a/4a/5a/
b
b
c
entry
metal salt
ligand conv (%)
6a
ee (%)
1
2
3
4
5
6
7
8
9
10
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(PPh3)4
Ni(cod)2
Ni(BF4)2·6H2O
Ni(dppp)2Cl2
Ni(PPh3)2Cl2
Ni(dppf)2Cl2
Ni(OAc)2
100
48/0/10/42/0
53/0/0/0/47
71/0/19/10/0
85/0/10/5/0
6/83/0/11/0
50/50/0/0/0
88/0/12/0/0
79/17/0/0/4
66/0/27/7/0
88/8/0/4/0
63/0/0/37/0
70/0/30/0/0
0/0/0/0/100
59/0/18/14/9
82/9/9/0/0
NA
59
−31
95
−2
97
L1
L2
L3
L4
L5
L6
L7
L8
L9
L6
L6
L6
L6
L6
L6
L6
100
100
100
100
100
100
100
100
100
100
100
52
d
97
96
98
93
97
97
e
11
12
13
14
15
16
17
NA
44
100
100
66
95
72
94
49/51/0/0/0
23/61/7/9/0
100
a
Unless otherwise noted, all reactions were carried out with 1a (0.1
mmol), nickel salt (10 mol %), ligand (12 mol %), and Mn (2 equiv)
b
in i-PrOH (2 mL) at 80 °C for 15 h. The data does not represent the
yield of products. The ratio of products was determined by GC
c
analysis for qualitative ananlysis. Determined by HPLC analysis using
d
e
a chiral stationary phase. Isolated yield of 2a is 85%. Zn was used as
reductant. NA = not available.
Figure 1. Ligands screened in the Ni-catalyzed asymmetric cyclization
of 1a.
transformation, resulting in the complete inhibition of the
reaction (Table 2, entries 5−7). The temperature also has an
important impact on this reaction, no reaction occurred when
the temperature was decreased to 50 °C (Table 2, entry 8).
Under the optimized reaction conditions, the substrate
scope and the generality of the reaction were investigated, and
the results are summarized in Scheme 2. Gratifyingly, the
reaction exhibited a good compatibility to various substituted
Subsequently, the solvent effects were evaluated, and the
results revealed that solvents played an important role in this
transformation. Generally, alcohol solvents are a good choice
for this reaction, and the yields and the enantioselectivities
were increased gradually along with the decrease of acidity of
alcohol solvents (Table 2, entries 1−4). Other solvents, such as
THF, 1,4-dioxane, and toluene, were harmful to this
B
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Letter
Table 2. Solvent Screening for Nickel-Catalyzed
Asymmetric Addition of Aryl Iodides to Ketones
Scheme 2. Substrate Scope for Enantioselective Addition of
Aryl Halides to Ketones
a
b
b
c
entry
solvent
conv (%)
2a/3a/4a/5a/6a
ee (%)
1
2
3
4
5
6
7
HFIP
MeOH
EtOH
i-PrOH
THF
dioxane
toluene
i-PrOH
24
52
77
100
NR
NR
NR
NR
0/0/0/0/100
75/0/0/25/0
NA
89
94
80/0/15/5/0
d
88(85) /0/12/0/0
97
NA
NA
NA
NA
NA
NA
NA
NA
e
8
a
Unless otherwise noted, all reactions were carried out with 1a (0.1
mmol), Ni(PPh3)4 (10 mol %), L6 (12 mol %), and Mn (2 equiv) in
b
solvent (2 mL) at 80 °C for 15 h. The data does not represent the
yield of products. The ratio of the products was determined by GC
c
analysis for qualitative ananlysis. Determined by HPLC analysis using
d
a chiral stationary phase. The data in brackets is the isolated yield.
e
50 °C. NR = no reaction, NA = not available.
2-(2-iodophenoxy)-1-phenylethan-1-one, and most of them
afforded chiral 3-hydroxy-2,3-dihydrobenzofurans with good
yields and excellent enantioselectivities. When R1 is an
aromatic group (2a−2k), the electronic property and the
steric hindrance of substituents on the benzene ring have no
influence on the enantioselectivities, but the yields were
affected to some extent. It should be noted that aryl ketone
with a strong electron-withdrawing group at the para position
led to a dramatic drop in yield (2d). Fused aromatic ketone
and heteroaromatic ketone were also well tolerated in this
reaction (2l−2m). When R1 was an alkyl group, such as bulky
t-Bu or long-chain n-heptanyl (2n-2o), the reaction proceeded
very well and furnished the target product with good yields and
excellent enantioselectivities. When a substituent was installed
on the meta position of iodine, there was no impact on both
the yield and the enantioselectivity no matter the electronic
property of the substituent (2p−2q). Notably, when the linker
oxygen atom was replaced by a methylene group, the reaction
also worked very well to give chiral 1-phenyl-2,3-dihydro-1H-
inden-1-ol in 76% yield with 95% ee (2r).
Scheme 3. Gram-Scale Reaction and the Evaluation of Aryl
Bromide and Aryl Chloride
To demonstrate the synthetic utility of the current
methodology, a gram-scale reaction was conducted under the
standard conditions, affording 2a in 80% yield with 98% ee
(Scheme 3a), which indicated that the yield and the
enantioselectivity were not affected in this transformation.
Other types of aryl halides, such as aryl bromide 1s and aryl
chloride 1t, were also tested. As shown in Scheme 3, the aryl
bromide 1s was well tolerated for this transformation, giving 3-
hydroxy-2,3-dihydrobenzofuran 2a with good yield and
excellent enantioselectivity. However, the aryl chloride 1t
was not compatible for this transformation.
shown in Scheme 4. The chiral active species A was formed by
ligand exchange of Ni(PPh3)4 with chiral ligand L, followed by
oxidative addition with 1 to afford arylnickel intermediate B,
which can occur intramolecular addition to generate adduct C.
Subsequently, the protolysis of C to deliver the target product
Based on our experiment results and previously reported
reaction mechanism,9 we proposed the reaction pathway
C
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pubs.acs.org/OrgLett
Letter
Materials, Ministry of Education, Sauvage Center for Molecular
Sciences, Wuhan University, Wuhan, Hubei 430072, China;
University of Chinese Academy of Sciences, Beijing 100049,
China
Scheme 4. Proposed Reaction Mechanism
Wendian Li − Key Laboratory of Biomedical Polymers of
Ministry of Education & College of Chemistry and Molecular
Sciences, Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, Sauvage
Center for Molecular Sciences, Wuhan University, Wuhan,
Hubei 430072, China
Jiangyan Tian − Key Laboratory of Biomedical Polymers of
Ministry of Education & College of Chemistry and Molecular
Sciences, Engineering Research Center of Organosilicon
Compounds & Materials, Ministry of Education, Sauvage
Center for Molecular Sciences, Wuhan University, Wuhan,
Hubei 430072, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01612
Author Contributions
∥Y.L. and W.L. contributed equally to this work.
2 and the Ni(II) species D, which was reduced to Ni(0) in the
presence of manganese powder to complete the catalytic cycle.
In summary, we have developed a nickel-catalyzed intra-
molecular asymmetric addition of aryl halides to ketones,
offering chiral 3-hydroxy-2,3-dihydrobenzofurans with good
yields and excellent enantioselectivities. This method features a
wide substrate scope and mild conditions, which provide a
general and practical synthetic route to chiral 3-hydroxy-2,3-
dihydrobenzofurans. Moreover, the potential utility of this
method was demonstrated by a gram-scale reaction without
loss of yield and enantioselectivity. Further investigations on
nickel-catalyzed asymmetric reactions are ongoing in our lab.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21871212), the
Natural Science Foundation of Hubei Province
(2018CFB430), and the Recruitment Program of Global
Experts
REFERENCES
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01612.
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AUTHOR INFORMATION
Corresponding Authors
■
Guozheng Huang − Key Laboratory of Plant Resources and
Chemistry of Arid Zone, Xinjiang Technical Institute of Physics
& Chemistry, Chinese Academy of Sciences, Urumqi, Xinjiang
830011, China; orcid.org/0000-0002-5730-9549;
Email: g.huang@ms.xjb.ac.cn
Hui Lv − Key Laboratory of Biomedical Polymers of Ministry of
Education & College of Chemistry and Molecular Sciences,
Engineering Research Center of Organosilicon Compounds &
Materials, Ministry of Education, Sauvage Center for Molecular
Sciences, Wuhan University, Wuhan, Hubei 430072, China;
orcid.org/0000-0003-1378-1945; Email: huilv@
whu.edu.cn
̈
́
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