Enantioselective Arylcyanation of Styrenes via Copper-Catalyzed Radical Relay?

Article abstract of DOI:10.1002/cjoc.202000494

The first copper-catalyzed enantioselective arylcyanation of styrenes has been developed using readily available anilines as aryl radical precursors under mild conditions, which enables easy access to chiral 2,3-diaryl propionitriles with moderate to good

Full text of DOI:10.1002/cjoc.202000494

Chinese Journal
of Chemistry
CJC 中 国 化 学 - An International Journal
Accepted Article
Title: Enantioselective Arylcyanation of Styrenes via Copper-Catalyzed Radical Relay
Authors: Weiwen Zhuang, Pinhong Chen, and Guosheng Liu*
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This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000494.
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Chinese Journal
of Chemistry
中 国 化 学 - An International Journal
Copper catalysis, Arylcyanation, Asymmetric radical reactions, Styrene,
Meerwein arylation
Concise Report
CJC
Enantioselective Arylcyanation of Styrenes via Copper-Catalyzed Radical
†
Relay
a
a
,a,b
Weiwen Zhuang, Pinhong Chen, and Guosheng Liu*
a
State Key Laboratory of Organometallic Chemistry and Shanghai Hongkong Joint Laboratory in Chemical Synthesis, Center for Excellence in Molecular
Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032, China
b
Chang-Kung Chuang Institute, East China Normal University, Shanghai 200062, China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion The first copper-catalyzed enantioselective arylcyanation of styrenes has been developed using readily
available anilines as aryl radical precursors under mild conditions, which enables easy access to chiral 2,3-diaryl propionitriles with moderate to good
enantioselectivities. This operationally straightforward reaction exhibits broad substrate scope and functional group tolerance. Notably, this method has
been applied to the synthesis of chiral AIEgen as well as estrogen receptor-β agonist (R)-DPN.
Background and Originality Content
OH
NH
O
O
CN
O
Optically pure organonitrile compounds are featured in natural
H2
N
OH
N
H
[
1]
N
products, pharmaceuticals, and agrochemicals. Among them,
chiral 2,3-diaryl propionitriles and their derivatives have received
much attention (Figure 1). For instance, (R)-DPN is an estrogen
receptor β-selective ligand, the other diaryl propionic acids and
propionamides can be used in treatment of pulmonary embolism,
F
3
C
Cl
HO
NC
(
R)-DPN
HN
O
N
Taranabant
DX9065a
F
O
O
F
[2]
or as an antiobesity agent. In general, conventional synthesis of
chiral 2,3-diaryl propionitriles relies on the dehydration of chiral
O
O
S
N
OH
NH
N
H
H
O
N
N
[
3]
amides, asymmetric arylation of α-halonitriles. The Meerwein
O
F
arylation of alkenes represents an effective strategy for the
Glucagon receptor antagonist
γ
- Seretase inhibitor
[
4,5]
installation of an aryl group into alkenes, where the alkyl radicals
generated by aryl radical addition into alkenes would be trapped to
form various C–C and C–heteroatom bonds. However, the variants
for asymmetric Meerwein arylation of alkenes are rare, owing to
the challenging asymmetric radical control. In 2015, Zhu and
Buchwald developed an enantioselective copper-catalyzed
intramolecular radical oxyfunctionalization of alkenes, including
Figure 1 Representative bioactive molecules bearing chiral 2,3-diaryl
propanitriles and related scaffolds
reported a Cu/CPA-catalyzed asymmetric aminoarylation of alkenes
Recently, Zhang and coworkers
disclosed a copper-catalyzed enantioselective arylalkynylation of
[
7]
with aryldiazonium salts.
[
6]
[8]
oxyarylation with aryl diazonium salts. Liu and coworkers
alkenes with diaryliodonium salts.
On the basis of our developed copper-catalyzed radical relay
[
9]
process,
cyanation,
we have recently realized the enantioselective
[
10]
[11]
[12]
arylation,
and alkynylation
reactions. For
instance, the benzylic C-H cyanation has been developed, where
the key benzylic radical generated from hydrogen atom transfer
II
(
HAT) could be trapped by a chiral (Box)Cu (CN)
2
complex with
excellent enantioselectivity (Scheme 1a). For the efficient synthesis
of chiral 2,3-diaryl propanitriles, the benzylic C-H cyanation of 1,2-
Scheme 1 Enantioselective Cu-catalyzed radical cyanation
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First author et al.
(
a) Enantioselective benzylic C-H cyanation (previous study)
Table 1 Optimization of the Reaction Conditionsa,b
CN
H
Cu(CH3CN)4PF6 (5 mol%)
F
R
HAT
R
(Box)Cu (CN)
II
2
R
NH2
L (6 mol%)
CN
Ar1
Ar
1
Ar
1
+
TMSCN (4 equiv)
tBu
F
Nitrite
CH3CN (1.0 mL)
rt, 24 h
(
4.0
equiv)
tBu
Optically pure
nitriles
3a
1a
2a (3.0 equiv)
Ha
CN
R2
(Box)Cu(I)
TMSCN/NFSI
R2
O
O
N
O
O
O
O
O
N
N
N
N
N
N
N
N
R1
R1
R2
Hb
Hb
Bn
Bn
Bn
tBu
MeO
tBu
OMe
L1
L4
L2
L3
L6
Ph
O
Ph
O
site-selective HAT:
extremely challenged
R1
O
MeO
O
O
OMe
Hb
N
N
N
Bn
Bn
Bn
L5
Bn
Bn
(
b) Enantioselective arylcyanation
work
Meerwein arylation
(
this
)
NH
2
Entry
Ligand
L1
Nitrite
Yield (%)
75
Er
cat. Cu(I)/Box
TMSCN
CN
R2
R
2
R1
+
CN, 25 o
1
2
t-BuONO
BnONO
88.5:11.5
85.5:14.5
85.5:14.5
87.5:12.5
86:14
CH
3
C
R
1
tBuONO
Ar radical
generated in situ
L1
10
3
4c
L1
PhCH(CH
3
)ONO
44
diarylethanes presents an attractive method, but generally
afforded the mixture of nitriles owing to the poor site-selective HAT
in these cases. Therefore, we reasoned that if the diaryl benzylic
radicals could be selectively generated from Meerwein arylation of
styrenes, the enantioselective arylcyanation of styrenes could be
expected to synthesize chiral 2,3-diaryl propanitriles (Scheme 1b).
Herein, we communicate this study, where readily available anilines
were used as aryl radical precursors under mild conditions. This
method enables easy access to structurally diverse chiral 2,3-diaryl
L1
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
t-BuONO
20
5
L2
60
6
L3
10
52.5:47.5
8:92
7
L4
49
8
L5
37
93.5:6.5
95:5
9
10d
L6
42
L1
75
88.5:11.5
95:5
[
13]
propionitriles with good to excellent enantioselectivities, and
could be applied to synthesize estrogen receptor-β agonist (R)-DPN
1d
1
L6
40
a
Reaction Condition: Styrene 1a (0.1 mmol), aniline 2a (0.3 mmol), t-
BuONO (0.4 mmol), TMSCN (0.4 mmol), Cu(MeCN) PF (5.0 mol%), L (6.0
CN (1.0 mL) at 25 C for 24 h. H NMR yield using CH Br as an
internal standard, enantiomeric ratio (er) was determined by the HPLC on a
(
Scheme 1b).
4
6
o
b 1
mol%) in CH
3
2
2
Results and Discussion
c
o
d
chiral stationary phase. At 0 C. The reaction was conducted on a 0.2 mmol
scale, isolated yield.
Our initial studies were commenced on the reaction of 1a with
4
(
1
-fluorobenzenediazonium salt 2aa and TMSCN under chiral
L1)Cu(I) catalysis. We were delighted to find that, as shown in eq
, the reaction indeed gave the desired product 3a with good
enantioselectivity, albeit in low yield (14%; 85:15 er).
Unfortunately, further optimizing the reaction conditions did not
improve the reaction yield. The arenediazonium salt
predominately underwent the side reduction (3aa, 32% yield) and
cyanation reaction (3ab, 26% yield), which is possibly resulted from
its high concentration (eq. 1). With this speculation, we reasoned
that, gradually generating arenediazonium salt from aniline in situ
might be beneficial to lower its concentration, thereby suppressing
these side reactions.
In order to monitor the reaction by 19F NMR, 4-fluoroaniline 2a
was employed as the aryl radical source in the presence of tert-
butyl nitrite, the reaction afforded the target product 3a in 75%
yield with slightly improved enantioselectivity (Table 1, entry 1).
Cu(CH
3 6
CN)
4
PF
(5 mol%)
F
CN
N
2
BF
4
L1 (6 mol%)
+
TMSCN (2.0 equiv)
(1)
3
Other nitrite reagents (e.g., BnONO, PhCH(CH )ONO) were
tBu
CsF (1.5 equiv)
mL)
F
tBu
3a
85:15
CH
3
CN (1.0
rt, 24 h
14%
+
er)
screened for tuning the rate of the arenediazonium salt formation,
however, lower yields were observed in these reactions (entries 2
and 3). The enantioselectivity was not improved when the reaction
(
1a
2aa
-
+
Ar-H
aa 32% yield
Ar CN
3
3ab 26% yield
o
was conducted at 0 C (entry 4). Ligand screening indicated that
Box-Bn L2 gave the similar enantioselectivity (86:14 er), while Box-
t
Bu L3 gave worse result (52.5:47.5 er). Furthermore, introducing
the steric bulky benzyl group into gem-carbon of Box ligands was
essential to enhance the enantioselectivity (entries 7-9), and L6
with a larger gem-3,5-dimethoxybenzyl group performed the best
to give 3a with 95:5 er, albeit in lower yield (entry 9). When the
reactions were carried on a 0.2 mmol scale, similar results were
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Running title
Chin. J. Chem.
obtained (entries 10 and 11).
Table 2 Substrate scopesa,b
product 3h in 78% yield with 85:15 er, while the er value was
improved to 94:6 in 50% yield. Various functional groups, such as
halide, ester, nitro, cyano, ketone and sulfamide, were tolerated
under the reaction conditions. Moreover, meta-(trifluoromethyl)-
aniline also exhibited good reactivity to give the desired product 3n
NH
2
cat. Cu(CH
TMSCN / t-BuONO
CN, 25 oC, 48 h
3
CN)
4
PF
6
/ L
CN
R2
R1
+
R2
1
CH
3
R
in good yield and enantioselectivity. In addition, 2-CF
3
-pyridinyl-2-
1
2
Condition A or Condition B
3
amine were also compatible to give 3o in moderate yield with
93:7~ 94:6 er. The absolute configuration of these products was
determined by X-ray crystallography of product 3m (see SI).
Then the scope of styrenes was also surveyed, and various
substituents at para-, meta-, and ortho-positions on the benzene
rings were suitable to generate the corresponding products 3p-3w
in good yields with up to 95:5 er. Moreover, aryl bromide and aryl
borate are well tolerated, a meaningful feature with respect to
further functional group manipulation. The reaction of 2-methoxy-
Anilines:
R
X
SO
Me
2
CN
CN
CN
3
e X = Cl
A: 85% (91:9)
Ph
Ph
Ph
B: 30% (96:4)
3
c R = Me
A: 56% (88:12)
A: 72% (90:10) B: 25% (94:6)
3d X = F
3
b R = H
A: 69% (89:11)
3f X = Br
A: 70% (92:8)
3g
B: 36% (95:5)
A: 80% (93:7)
O
NO
2
CF
3
CN
CN
CN
CN
CN
Ph
Ph
Ph
Ph
3h
3i
3j
3k
A: 78% (85:15)
A: 78% (92:8)
A: 75% (93:7)
A: 84% (90.5:9.5)
B: 50% (94:6)
B: 43% (96:4)
B: 46% (95:5)
B: 52% (93:7)
5
-vinylpyridine afforded 3x in 82% yield with 85:15 er. We found
that estrone-derived styrene as well as L-menthol-tethered aniline
was amenable to this reaction and gave the corresponding
arylcyanation products 3y and 3z in moderate yields with
moderate diastereomeric excess. Notably, when the reactions of
CO
2
Et
SO
2 2
NH
CN
CN
N
CN
CN
Ph
CF
3
Ph
CF
3
Ph
Ph
3
l
3m
3n
3o
A: 82% (91.5:8.5)
A: 65% (91:9)
A: 81% (91:9)
A: 55% (93:7)
B: 41% (95:5)
B: 36% (94:6)
B: 61% (94:6)
B: 35% (94:6)
1
v and 1w were scaled up to 5 mmol and 10 mmol, respectively,
c
Styrenes:
F
F
Cl
CO2
t
Bu
the desired products 3v and 3w were obtained with the same
enantiomeric ratio (95:5 er) in similar yields.
CN
CN
CN
Br
Furthermore, diene substrate 4 bearing two terminal double
bonds also proved amenable to provide dinitrile 5 in 90% yield with
good stereoselectivity (89:11) and excellent enantioselectivity (>
99:1 er, eq. 2).
F
Br
3
p
3q
3r
7
0% (90:10)
58% (94:6)
75% (91:9)
O
SO
2
Ph
Bpin
CN
CN
CN
O
MeO
2
C
Bpin
F
mol
L1 (6 mol %)
CO Me
3
s
3t
3u
NH2
Cu(MeCN)
4
PF
6
(5
%)
2
CN
8
2% (93:7)
68% (94:6)
75% (95:5)
t-BuONO (6.0 equiv.)
TMSCN
equiv)
O
S
SO
Me
CO2nBu
+
(2)
N
CN
2
(4.0
MeCN (2.0 mL)
CN
CN
CO Me
O
2
o
CN
5
4
25
C,
48 h
MeO
2
C
>
2
q (6.0 equiv)
90% yield; 99:1 er
(2
S, 2'S)/meso = 89:11
F
3
C
MeO
N
3
v
3w
Ph
3x
2% (85:15)
6
5% (95:5)
81% (95:5)
2.74 g, 77% (95:5)
8
.41 g, 68% (95:5)d
e
1
The synthetic utility of the asymmetric arylcyanation was
examined (Scheme 2). First, tetraphenylethylene (TPE) and its
derivatives are a common class in aggregation-induced emission
luminogen (AIEgen). When the AIEgens are endowed with chirality,
the resultant chiral AIEgens can act as sensors to discriminate and
NO
2
CN
O
CN
O
H
H
H
3
y
3z
65% (72% de)
O
5
8% (70% de)
[
14]
analyze enantiomers of chiral compounds.
Cholesterol
a
Condition A: Styrene 1a (0.2 mmol), aniline 2 (0.6 mmol), t-BuONO (0.6
mmol), TMSCN (0.4 mmol), Cu(MeCN)
CN (2.0 mL) at 25 C for 48 h; Condition B: L6 was used instead of L1.
Isolated yield, enantiomeric ratio (er) was determined by the HPLC on a
possessing a high level of liquid crystal property was attached with
a tetraphenylethylene moiety through this method, providing the
chiral AIEgen 8 in 52% yield with 94:6 dr, which might be a potential
optical sensors for chiral compounds and chiral nematic liquid
4
PF
6
(5.0 mol%), L1 (6.0 mol%) in
o
b
CH
3
c
chiral stationary phase and showed in the parenthesis. Under the
[15]
crystals. The fluorescent photographs taken in tetrahydrofuran–
d
e
condition A. On a 5 mmol scale. On a 10 mmol scale.
w
water mixtures with different water fractions (f ) under 365 nm UV
irradiation indicated that product 8 indeed possessed AIE feature.
Moreover, the estrogen receptor β-selective ligand (R)-DPN was
quickly accessed by this method with (3R, 8S)-L1 after the following
oxidation reaction. Finally, product 4j could be easily converted to
amide 9 in 84% yield by hydrogenation.
To provide supporting evidences for the proposed radical
process, TEMPO and BHT were added to the standard reaction
The substrate scopes were next surveyed under the standard
conditions in entries 10 and 11 (Table 1). Aniline and p-toluidine
were suitable aryl sources to give the desired products 3b and 3c
in 72% and 56% yields with good enantiomeric ratios (Table 2). The
reactions of various electron-deficient anilines provided the
corresponding products 3d−3m in good yields (65-85%) with good
to excellent enantiomeric ratios (from 85:15 to 95:5 er). Compared
to the condition A with L1, the condition B with L6 provided higher
er values, albeit in lower yields. For example, the reaction of
styrene with 4-nitroaniline 2h in the presence of L1 afforded the
Chin. J. Chem. 2019, 37, XXX－XXX
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Report
First author et al.
Scheme 2. Synthetic applications
affording a series of chiral 2,3-diaryl propionitriles with moderate
to good enantioselectivities. Notably, this reaction has been
applied to the synthesis of chiral AIEgen as well as estrogen
receptor β agonist (R)-DPN.
AIEgen
Ph
chiral sensor
CN
O
liquid crystal
+
Ph
Ph
6
H
Ph
Ph
Standard
conditions
O
O
R
H
H
=
0
R
Experimental
General experimental procedures for the asymmetric
arylcyanation of alkenes
O
Ph
8
7
(3.0 equiv)
52% (94:6 dr)
2
H N
10
30
50
70
90 95
f
w
(vol%)
THF/H
λEX = 365 nm
O
To a 10 mL sealed tube, L1 (4.4 mg, 0.012 mmol, 6 mol%) or L6 (7.8
2
mg, 0.012 mmol, 6 mol%) and Cu(CH
3
CN)
4
PF
6
(3.7 mg, 0.010 mmol,
CN (2.0
5
mol%) were dissolved in anhydrous and oxygen-free CH
3
mL) under an atmosphere of argon. The solution was stirred at
room temperature for 30 mins, and then alkene 1 (0.2 mmol, 1.0
equiv), aniline 2 (0.6 mmol, 3.0 equiv), t-BuONO (78 μL, 0.6 mmol,
3.0 equiv) and TMSCN (52 μL, 0.4 mmol, 2.0 equiv) were
OH
Bpin
30% H
CN
CN
Standard conditions
with (3R, 8S)-L1
Bpin
1t
+
2
O
2
Bpin
MeOH/H2
rt
O,
HO
Bpin
R
(R)-DPN
92% (94:6 er)
(
)-3t
o
H
2
N
68%
(94:6
er)
sequentially added, then the mixture was stirred for 48 h at 25 C.
2
t
After the reaction was completed, solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography on silica gel with gradient of petroleum ether and
ethyl acetate to afford product 3.
SO
2
Me
BocHN
2
SO Me
CN
Raney Ni, H
2
(30 bar)
Boc
2
O (2.0 equiv)
o
1
,4-dioxane, 65
C
F
3
C
F3C
9
3
w (95:5 er)
84% (93.5:6.5
er)
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
systems, and the formation of desired product 3a was dramatically
inhibited. Benzylic radical and aryl radical were captured with
TEMPO and BHT, respectively (see SI). Radical clock experiments
were also carried out under the standard conditions (Scheme 3).
The intramolecular reaction of alkenes tethered aniline 10 afforded Acknowledgement
the cyclization cyanation product 11 in 50% yield with a 1.1:1
We are grateful for financial support from the National Nature
diastereomer ratio (88% and 98% ee, respectively). In addition, the
reaction of cyclopropane containing substrate 12 afforded the ring-
opened product 13 in 35% yield. These observations suggested
that the reaction likely involves a benzylic radical.
Science Foundation of China (NFSC, Nos. 21532009, 91956202,
1821002 and 21790330), the Science and Technology
Commission of Shanghai Municipality (Nos. 19590750400 and
7JC1401200), the strategic Priority Research Program (No.
XDB20000000), the Key Research Program of Frontier Science
QYZDJSSWSLH055), and the International Partnership Program
2
1
Scheme 3 Radical clock experiments
(
Cu(MeCN)4PF6 (5 mol%) MeO2C
L1 (6 mol%)
CN
(No. 121731KYSB20190016) of the Chinese Academy of Sciences.
MeO2C
O
TMSCN (2.0 equiv)
O
NH2
t-BuONO (1.5 equiv)
MeCN (2.0 mL)
11
50%; dr 1.1:1
8% ee/98% ee
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8
MeO2C
O
MeO2C
O
Ph
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Cu(MeCN)4
F
(6
L1 mol%)
Ph
+
TMSCN (2.0 equiv)
H2N
t-BuONO
equiv)
(
3.0
MeCN (2.0 mL)
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2a
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Conclusions
In summary, we have developed
enantioselective arylcyanation reaction of styrenes with the readily
available anilines as aryl radical precursors under mild conditions,
a copper-catalyzed
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Running title
Chin. J. Chem.
synthesis of highly potent benzodiazepine γ-secretase inhibitors:
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Luo, J.; Hu, M.; Jiang, H.; Liu, M.; Zheng, Y.-S. The Self-assembly and
Chiroptical Properties of Tetraphenylethylene Dicycle
Tetracholesterol with an AIE Effect. J. Mater. Chem. C, 2019, 7, 8236
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Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
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Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Enantioselective Arylcyanation of Styrenes via a
Copper-Catalyzed Radical Relay
NH2
CN
R2
R2
cat.
Cu(CH
TMSCN
3
CN) PF /Box
4
6
(2.0
equiv)
R1
+
R1
o
t-BuONO
CH CN, 25 C
3
2
8 examples
Ar radical
generated in situ
up to 85% yield; 95:5 er
A copper-catalyzed enantioselective arylcyanation of styrenes was developed with the readily
available anilines as aryl radical precursors under mild conditions, which allows the excess of chiral
2
,3-diaryl propionitriles with moderate to good enantioselectivities. This reaction exhibits broad
substrate scope and functional group tolerance.
a
a
Weiwen Zhuang, Pinhong Chen, and Guosheng
Liu*
,
a,b
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.