Ni-Catalyzed Enantioselective Reductive Diarylation of Activated Alkenes by Domino Cyclization/Cross-Coupling

Article abstract of DOI:10.1021/jacs.8b08190

A Ni-catalyzed enantioselective reductive diarylation of activated alkenes by domino cyclizative/cross-coupling of two aryl bromides is developed. This reaction proceeds under very mild conditions and shows broad substrate scope, without requiring the use of preformed organometallic reagents. Moreover, this approach provides direct access to various bis-heterocycles bearing all-carbon quaternary centers in synthetically useful yields (up to 81%) with excellent enantioselectivity (>30 examples, 90-99% ee).

Full text of DOI:10.1021/jacs.8b08190

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Communication
Ni-Catalyzed Enantioselective Reductive Diarylation of
Activated Alkenes by Domino Cyclization/Cross-Coupling
Kuai Wang, Zhengtian Ding, Zhijun Zhou, and Wangqing Kong
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 20 Sep 2018
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Ni-Catalyzed Enantioselective Reductive Diarylation of Activated
Alkenes by Domino Cyclization/Cross-Coupling
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Kuai Wang, Zhengtian Ding, Zhijun Zhou and Wangqing Kong*
The Institute for Advanced Studies, Wuhan University, Wuhan, 430072, P. R. China
Supporting Information Placeholder
tive reductive diarylation of alkenes for providing access to a
ABSTRACT: A Niꢀcatalyzed enantioselective reductive diarylaꢀ
range of bisꢀheterocycles bearing allꢀcarbon quaternary centers,
which remains a challenging issue in synthetic chemistry (Scheme
1C).17
tion of activated alkenes by domino cyclizative/crossꢀcoupling of
two aryl bromides is developed. This reaction proceeds under
very mild conditions and shows broad substrate scope, withꢀ
out requiring the use of preformed organometallic reagents.
Moreover, this approach provides direct access to various bisꢀ
heterocycles bearing allꢀcarbon quaternary centers in synthetically
useful yields (up to 81%) with excellent enantioselectivity (>30
examples, 90ꢀ99% ee).
Scheme 1. Transition Metal Catalyzed Enantioselective Dia-
rylation of Alkenes
Transition metal catalyzed alkene diarylation reactions involvꢀ
ing simultaneous incorporation of two aryl groups across the
double bond in a single operation have received substantial attenꢀ
tion, allowing for the effective construction of complex and useful
compounds with stereocenters from easily accessible starting
materials.1 Oxidative diarylation of alkenes by installing two
identical aryl groups using a sole organometallic reagent (ArM) as
the aryl source is known.2 Alternatively, diarylation by the introꢀ
duction of an aryl nucleophile (ArM) and an aryl electrophile
(ArX) across alkenes has also been well studied.3,4,5 However,
reductive diarylation of alkenes by addition of two aryl electroꢀ
philes (ArX) without requiring the use of preꢀprepared organomeꢀ
tallic reagents remains unexploited (Scheme 1A).6,7,8
On the other hand, catalytical asymmetric alkene diarylation
reactions are rather limited. Sigman’s group demonstrated the first
Pdꢀcatalyzed asymmetric diarylation of 1,3ꢀdienes using aryldiaꢀ
zonium tetrafluoroborates and arylboronic acids in good enantiꢀ
oselectivity, albeit with moderate yield (Scheme 1B, top).9,10
Brown’s group developed a Cuꢀcatalyzed enantioselective alkene
diarylation by cyclizative coupling of alkeneꢀtethered arylꢀBPin,
derived from the corresponding aryl halides with aryl iodides
(Scheme 1B, bottom).11 Another related example was reported by
Fu et al., who demonstrated a Niꢀcatalyzed enantioselective cyꢀ
clization/coupling of arylꢀ9ꢀBBN with alkyl halides.12
Our study commenced with the reaction of Nꢀ(2ꢀbromophenyl)ꢀ
Nꢀmethylmethacrylamide 1a and phenyl bromide 2a (for a sysꢀ
tematic study of reaction conditions see Tables S1ꢀS5 in the Supꢀ
porting Information). Gratefully, the desired oxindole 3aa could
be selectively obtained in 83% yield using Ni(COD)2 (10 mol %),
L1 (20 mol %), B2Pin2 (2 equiv), Zn0 (2 equiv), K3PO4 (2 equiv)
as base and DMA as solvent (Table 1, entry 1).18 Replacing L1 by
a commercially available (S)ꢀphenylꢀPyBOX (L2), a orded 3aa
in 52% yield and 44% ee, along with the reductive Heck side
product 4aa in 20% yield (entry 3). Reducing the reaction temperꢀ
ature to 40 °C resulted in a noteworthy improvement of the enanꢀ
tioselectivity (62% ee, entry 6). Encouraged by this promising
result, a comprehensive survey of the chiral ligands L2ꢀL11 was
performed (entries 7ꢀ15), revealing that PHOXꢀtype ligand L11
was the most effective in terms of stereoselectivity (91% ee, entry
15). Remarkably, the ferrocene skeleton of L11 proved to be
critical to the selectivity of this reaction, as the formation of 4aa
was completely suppressed (compare entry 15 with entries 13ꢀ14).
Iodide sources have been shown to enhance the reactivity in
crossꢀelectrophiles couplings,19 and indeed, the addition of KI
improved the yield of 3aa to 63% without sacrificing the enantiꢀ
oselectivity (entry 16). The best result was achieved using NMP
Our efforts in transition metal catalyzed asymmetric dicarboꢀ
functionalization of alkenes,13 have recently led to the disclosure
of a Niꢀcatalyzed alkene diarylation by domino Heck cyclizaꢀ
tion/Suzuki coupling.14 However, attempts to render this domino
reaction asymmetric by us and other groups15 were not successful.
Inspired by the recent developments on Niꢀcatalyzed asymmetric
Heck cyclization,16 we decided to target an alternative enantioseꢀ
lective Heck cyclization/trapping of in situ generated σꢀalkylꢀ
Ni(II) species with aryl electrophiles by taking advantage of the
ability of Ni catalysts for facile oxidative addition and ready
access to multiple oxidation states.7,8 Herein, we present our
investigations of the first example of Niꢀcatalyzed enantioselecꢀ
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as a solvent, providing 3aa in 68% yield and 97% ee (entry 17).
reductive crossꢀcoupling reaction with a wide range of heterocyꢀ
cles. Benzodioxan (3an), pyridine (3bo), dibenzofuran (3ap),
dibenzothiophene (3bq), indole (3ar) and benzofuran (3bs) were
efficiently transformed into the corresponding products in satisꢀ
factory yields with very high enantioinduction. These results
demonstrate the potential utility of this methodology for the synꢀ
thesis of medicinally relevant compounds are feasible.22 Moreoꢀ
ver, the cross coupling of phenyl alanine derivative provided the
desired product (3bt) without epimerization of the stereocenter.
There is no significant difference in ee values when different
substituted aryl bromides 2 are used, indicating that the enantioseꢀ
lectiveꢀdetermining step of the reaction is the migratory insertion.
Finally, a series of control experiments confirmed that product
was not formed in the absence of Ni0 catalyst, Zn0 or ligand (enꢀ
tries 18ꢀ20). A reduced yield (28%) was also observed in the
absence of B2Pin2, but the enantioselectivity was preserved (comꢀ
pare entry 21 with entry 17).
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Table 1: Optimization of the Reaction Conditionsa
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Scheme 2. Substrate Scope of Aryl Bromides 2
additive
T
yield of
yield of
ee of
entry
ligand
(oC)
4aa (%)b
3aa (%)b
3aa (%)c
(equiv)
R
R
1d
2
100
25
100
80
60
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
40
L1
L1
ꢀ
< 2
50
20
13
24
38
16
36
19
28
27
18
40
26
< 2
< 2
< 2
0
83
0
ꢀ
ꢀ
Ni(COD)2 (10 mol%)/L11 (20 mol%)
O
Me
B2Pin2 (2 equiv)/Zn (2 equiv)
Me
Ar
N
+
ArBr
ꢀ
K3PO4 (2 equiv), KI (0.5 equiv)
O
Br Me
1a (R = H)
1b (R = Me)
N
Me
3
NMP, 40 o
C
3
L2
ꢀ
52
62
46
36
57
20
51
12
8
44
45
52
62
16
41
28
0
2
4
L2
ꢀ
MeO
MeO
MeO
3aa, R = H (68% y, 97% ee)
3ab, R = Me (67% y, 94% ee)
3ac, R = OMe (60% y, 90% ee)a
3ad, R = OEt (52% y, 91% ee)a
3ae, R = N(Me)2 (63% y, 95% ee)
3af, R = F (50% y, 90% ee)a
3ag, R = CN (30% y, 95% ee)a
5
L2
ꢀ
Me
Br
R
Br
6
L2
ꢀ
Br
7
L3
ꢀ
3ah (60% y, 91% ee)a
3ai (61% y, 98% ee)
8
L4
ꢀ
Me
9
L5
ꢀ
10
11
12
13
14
15
16
17e
18f
19g
20
21h
L6
ꢀ
Br
Br
Br
O
O
L7
ꢀ
6
Me
L8
ꢀ
5
n.d.
77
90
91
91
97
ꢀ
3aj (63% y, 90% ee)a 3ak (50% y, 95% ee)
3al (65% y, 97% ee)
L9
ꢀ
26
38
47
63
68
0
(R)-3al
Br
L10
L11
L11
L11
L11
L11
-
ꢀ
O
N
O
O
Br
B
Br
O
N
Br
ꢀ
O
O
KI (0.5)
KI (0.5)
KI (0.5)
KI (0.5)
KI (0.5)
KI (0.5)
3am (60% y, 90% ee)a
3an (60% y, 99% ee) 3bo (40% y, 95% ee) 3ap (61% y, 99% ee)
O
Br
Br
Br
OMe
N
0
0
ꢀ
N
Br
Me
S
Et
Me
O
0
0
ꢀ
3bq (50% y, 95% ee)
3ar (50% y, 95% ee)
3bt (44% y, > 20:1 dr)
3bs (60% y, 95% ee)
L11
< 2
28
97
aDMA/THF = 2/1
The substrate scope with respect to alkeneꢀtethered aryl broꢀ
mides 1 was investigated next (Scheme 3). First, we studied the
substitution pattern on the benzene ring of the aniline moiety. pꢀ,
mꢀ, and oꢀmethyl and pꢀfluoro anilide substrates were efficiently
transformed into the corresponding products 3ba-3ea in high
enantioselectivities. Notably, functional groups (Cl, OMe) were
found to be compatible with this transformation, thus enabling
latter availability for additional transformations (3fa-3ga). More
importantly, the reaction was successfully applied to the synthesis
of azaoxindole 3ha in 50% yield and 94% ee, which is of particuꢀ
lar interest due to their prominence in natural products and drug
discovery program.15b The influence of the Cα substituents (R3) of
the acrylamide double bond on the reaction outcome was also
examined. Benzyl, nꢀhexyl, isopropyl and methoxymethyl substitꢀ
uents are all well tolerated leading to the corresponding oxindoles
3ib-3kb and 3li in good yields with excellent enantioselectivities.
The cyclizative cross coupling reaction of Nꢀbenzyl acetanilide
1m proceeded e ciently to provide 3mi in 62% yield and 98% ee.
As the Nꢀbenzyl is easily removed, it constitutes a route to Nꢀ
unsubstituted oxindole.
aReactions were carried out with 1 (0.1 mmol), 2a (0.4 mmol), Ni(COD)2
(10 mol %), ligand (20 mol %), Zn dust (0.2 mmol), Pin2B2 (0.2 mmol),
K3PO4 (0.2 mmol) in 2 mL solvent for 96 h, unless noted otherwise.
bIsolated yields. Determined by HPLC analysis with a chiral column. dIn
c
DMA, 12 h. eIn NMP. No Ni(COD)2. gNo Zn0. No B2Pin2. B2Pin2
=
f
h
bis(pinacolato)diboron.
With optimized conditions in hand (Table 1, entry 17), we
sought to investigate the scope of aryl bromides 2. We were
pleasure to find that a variety of aryl bromides undergo cyclizaꢀ
tive cross coupling to furnish the target products in good yields
with excellent enantioselectivities (Scheme 2). Functional groups
such as alkoxyl, amino, fluoro and ketal are generally wellꢀ
tolerated (3ab-3aj). It should be noted that cyano group, which
was problematic in our previous method,14,20 was also found to be
compatible with this transformation, albeit in poor yield (3ag).
The absolute configuration of 3al was determined to be 3R by Xꢀ
ray crystallographic analysis and that of all other products were
assigned accordingly.21 Remarkably, the boronateꢀfunctionalized
aryl bromide proceeded smoothly to a ord 3am in 60% yield and
90% ee, providing an opportunity to further functionalize this
obtained product. To further demonstrate the robustness and
generality of synthetic utility of our method, we then explored the
Although the enantioenriched indoline 5aa could not be syntheꢀ
sized directly by the cyclizative cross coupling of 2ꢀbromoꢀNꢀ
methylꢀNꢀ(2ꢀmethylallyl)aniline with 2a, reduction of (R)ꢀ3aa
with LiAlH4 enabled efficient access to the enantioenriched indoꢀ
line 5aa in excellent yield and with retention of enantiopurity
(Scheme 4). Regioselective bromination of (R)ꢀ3aa provided 3na
in 94% yield and 90% ee, thus enabling further functionalization
of the oxindole ring (Scheme 4).
Scheme 3. Substrate Scope of Alkenes 1
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with 7 formed 3au in 25% (eq 8). These results indicate that the
mechanism of transmetalation can not be ruled out.
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On the basis of the above results and previous studies on the
crossꢀelectrophiles couplings,26 a proposed mechanism is outlined
in Scheme 6, in which two reaction pathways are considered.
Oxidative addition of aryl bromide 1 to Ni(0) species followed by
an intramolecular carbonickelation produces σꢀalkylꢀNi(II)X
species A, which is reduced by stoichiometric Zn/Pin2B2. A seꢀ
cond oxidative addition of the resulting σꢀalkylꢀNi(I) intermediate
B with aryl bromide 2 will form σꢀalkylꢀNi(III)ArX species C,
which undergoes subsequent reductive elimination to furnish the
desired product
3 while regenerating Ni(0) catalyst upon
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Zn/Pin2B2 reduction (Scheme 6, pathway A). Another plausible
Ni(0)/Ni(II) catalytical cycle involving transmetalation between
both Ni(II) centers A and D to form σꢀalkylꢀNi(II)ArX species E,
which generates product 3 following reductive elimination
(Scheme 6, pathway B).
Scheme 5. Mechanistic study
Scheme 4: Synthetic conversion of enantioenriched oxindoles
A series of experiments were designed to provide insight about
the reaction mechanism (Scheme 5, for details see Part 4 in the
Supporting Information). To assess the possibility of arylzinc
intermediate, PhZnBr was subjected to our optimized reaction
conditions. However, 3aa was not produced (eq 1). A reaction run
without nickel (Table 1, entry 18) did not consume starting
material, suggesting that direct insertion of zinc into aryl bromide
is not likely. The use of an organic reducing agent TDAE (tetrakis
(dimethylamino)ethylene), in place of Zn0 produced 3aa in an
appreciable yield (eq 2). By combining these results together, we
ruled out the participation of arylzinc as a key intermediate in this
transformtion.6,23 As mentioned above, in the absence of B2Pin2,
3aa was indeed observed albeit in a low yield (28%, Table 1,
entry 21). This result clearly demonstrated the catalytic pathway
could proceed in the absence of any Bꢀbased intermediates. To
futher understand the role of the possible arylboronate in the
catalytic cycle, PhBPin was added in this crossꢀcoupling reaction
(eq 3). However, 3aa was not detected. This result argues against
the intermediacy of arylboronic reagent in this transformation,
which may indicate B2Pin2 acts as a coꢀreducing agent.24
Scheme 6: Proposed Reaction Mechanism
ArNi(II)Br (D)
We serendipitously found that the σꢀalkylꢀNi(II) complex 6
could be formed at room temperature from the oxidative addition
of 1a and subsequent migratory insertion (eq 4).25 Meanwhile, the
catalytical reaction at room temperature delivered 4aa in 50%
yield with 3aa not being detected in the reaction media (Table 1,
entry 2). These results suggest that the cyclization process is not
the turnoverꢀlimiting step. When complex 6 was used in a stoichiꢀ
ometric fashion, in the absence of Ni0 catalyst, the desired product
3aa was isolated in 35% yield, along with 4aa in 34% yield (eq
5), thus supporting the ideal of a mechanism which σꢀalkylꢀNi(II)
6 serves as the key intermediate in the catalytic cycle. Since
oxidative addition of Ni(0) with aryl halide has proven to be
reversible,26 we believe that the migratory insertion process (enanꢀ
tioselectiveꢀdetermining step) should be irreversible.
ArBr
1
L
Zn(II)
Ni(0)
*
L
Zn
Ni(II)L*
O
Zn(II)
L
L
Ar
Z
Ni(I)
*
N
Zn
R1 R2
NiBr2
+
R2
N
Ni(II)L*
Ar
3
Ar
Z
O
R2
R1
E
R2
pathway
B
Ni(II)L*
Ar
Ni(III)L*
Ar
Ar
Z
Z
O
N
O
ArNi(II)Br
N
R1
A
R1
D
pathway
A
C
R2
Ni(I)L*
Finally, 2ꢀtolylꢀNi(II) complex 7 was synthesized8h,27 and subꢀ
jected to our reaction condition (without Zn0), 3au was obtained
in 20% yield (eq 7). The reaction of performed Ni(II) complex 6
Ar
Zn
ArBr
Z
O
Zn(II)
N
R1
B
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(7) For reviews on Niꢀcatalyzed reductive crossꢀcoupling reactions, see: (a)
In conclusion, we have developed a mechanistically distinct
approach to enantioselective diarylation of activated alkenes, in
which two structurally distinguishable aryl bromides react togethꢀ
er through a domino Heck cyclization/reductive crossꢀcoupling
process. The reaction occurs under mild conditions and is tolerant
Nédélec, J.ꢀY.; Périchon, J.; Troupel, M. Top Curr Chem. 1997, 185, 141. (b)
Knappke, C. E. I.; Grupe, S.; Gärtner, D.; Corpet, M.; Gosmini, C.; Jacobi von
Wangelin, A. Chem. Eur. J. 2014, 20, 6828. (c) Moragas, T.; Correa, A.;
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ney, A. H.; Kadunce, N. T.; Reisman, S. E. Chem. Rev. 2015, 115, 9587. (j)
Wang, X.; Dai, Y.; Gong, H. Top Curr Chem (Z). 2016, 374, 43. (k) Lucas, E.
L.; Jarvo, E. R. Nat. Rev. Chem. 2017, 1, 65. (l) Richmond, E.; Moran, J.
Synthesis, 2018, 50, 499 and references therein.
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7
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of
a variety of functional groups, providing various bisꢀ
heterocycles bearing allꢀcarbon quaternary centers in good yields
with excellent enantioselectivities. The further development of
enantioselective Heck cyclization and trapping the in situ generatꢀ
ed σꢀalkylꢀNi(II) species with other electrophiles, as well as
mechanistic investigations, is underway in our laboratory.
9
(8) For selected examples on Niꢀcatalyzed dicarbofunctionalization of alkenes,
see: (a) Phapale, V. B.; Buñuel, E.; GarcíaꢀIglesias, M.; Cárdenas, D. J. Angew.
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Ikawa, M.; Ogoshi, S. J. Am. Chem. Soc. 2008, 130, 12874. (d) Yan, C.ꢀS.;
Peng, Y.; Xu, X.ꢀB.; Wang, Y.ꢀW. Chem. Eur. J. 2012, 18, 6039. (e) Guisánꢀ
Ceinos, M.; SolerꢀYanes, R.; ColladoꢀSanz, D.; Phapale, V. B.; Buñuel, E.;
Cárdenas, D. J. Chem. Eur. J. 2013, 19, 8405. (f) Gu, J.; Min, Q.; Yu, L.;
Zhang, X. Angew. Chem., Int. Ed. 2016, 55, 12270. (g) Qin, T.; Cornella, J.; Li,
C.; Malins, L. R.; Edwards, J. T.; Kawamura, S.; Maxwell, B. D.; Eastgate, M.
D.; Baran, P. S. Science 2016, 352, 801. (h) GarcíaꢀDomínguez, A.; Li, Z.;
Nevado, C. J. Am. Chem. Soc. 2017, 139, 6835. (i) Walker, J. A.; Vickerman,
K. L.; Humke. J. N.; Stanley, L. M. J. Am. Chem. Soc. 2017, 139, 10228. (j)
Logan, K. M.; Sardini, S. R.; White, S. D.; Brown, M. K. J. Am. Chem.
Soc. 2018, 140, 159. (k) KC, S.; Dhungana, R.; Shrestha, B.; Thapa, S.; Khaꢀ
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Kuang, Y.; Wang, X.; Anthony, D.; Diao, T. Chem. Commun. 2018, 54, 2558.
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Sci. 2018, 9, 5278.
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ASSOCIATED CONTENT
Supporting Information
The supporting information is available free of charge on the
ACS Publication website.
AUTHOR INFORMATION
Corresponding Author
* wqkong@whu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
(9) Stokes, J. B.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. Org.
Lett. 2014, 16, 4666.
Financial support from the “1000ꢀYouth Talents Plan”, National
Natural Science Foundation of China (No. 21702149) and Funꢀ
damental Research Funds for the Central Universities
(2042018kf0012) is greatly appreciated. We are thankful to Prof.
Aiwen Lei at Wuhan University for the generous provision of
laboratory and facilities.
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