Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl Halides to Afford Indolines

Article abstract of DOI:10.1002/anie.201707134

A nickel-catalyzed asymmetric reductive Heck reaction of aryl chlorides has been developed that affords substituted indolines with high enantioselectivity. Manganese powder is used as the terminal reductant with water as a proton source. Mechanistically, it is distinct from the palladium-catalyzed process in that the nickel–carbon bond is converted into a C?H bond to release the product through protonation instead of hydride donation followed by C?H reductive elimination on Pd.

Full text of DOI:10.1002/anie.201707134

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Accepted Article
Title: Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl
Halides to Access Indolines
Authors: Jianrong Steve Zhou, Xurong Qin, and Marcus Wen Yao Lee
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201707134
Angew. Chem. 10.1002/ange.201707134
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10.1002/anie.201707134
Angewandte Chemie International Edition
COMMUNICATION
Nickel-Catalyzed Asymmetric Reductive Heck Cyclization of Aryl
Halides to Access Indolines
Xurong Qin, Marcus Wen Yao Lee, and Jianrong Steve Zhou*
Abstract: A nickel-catalyzed asymmetric reductive Heck reaction of
aryl chlorides affords substituted indolines in high enantioselectivity.
Manganese powder was used as the terminal reductant and water
as proton source.
example of nickel-catalyzed asymmetric reductive Heck
cyclization of aryl chlorides that provides substituted indolines.
Many indoline derivatives have interesting bioactivities.[16]
Related to the cyclization in this study, some bioactive natural
products carry aryl rings at C2 positions of indolines, such as
mangochinine,[17] trigonoliimine C[18] and hinckdentine A[19]
(Figure 1).
Asymmetric Heck reaction of organic electrophiles has been
extensively studied since late 1980s and it has been
successfully employed in the synthesis of complex bioactive
natural products.[1-3] In comparison, the development of
asymmetric reductive Heck reaction, which produces a C-H
bond at the end in the presence of hydride donors, has only met
with limited success until recently,[4] ever since initial discovery
of the nonstereoselective process in the 1980s.[5] For examples,
Jia et al. recently reported palladium-catalyzed enantioselective
reductive cyclization of tethered aryl bromides onto indoles, in
the presence of sodium formate.[6] Zhu group[7] and our lab[8]
have also disclosed palladium-catalyzed cyclization processes
that afforded substituted oxindoles and indanones in good ee,
respectively.
Ni(OAc)2 5 mol%
Me
Me
Cl
ligand 6 mol%
N
+
Me
N
Mn (3 equiv)
N
O
H
NaOAc (3 equiv)
water (1 equiv), DMF
80 oC, 24 h
O
2a
1a
3a
Me
Me
Me
Me
N
O
O
N
O
O
O
O
O
O
N
N
N
N
N
N
Bn
Bn
Ph
Ph
t-Bu
Ph
Ph
t-Bu
L1
L3
L4
L2
5% 2a, 50% ee
56% 3a
0% 2a
44% 3a
<5% 2a, 65% ee
43% 3a
<5% 2a, 34% ee
56% 3a
CN
CN
CN
CN
O
O
O
O
O
O
O
O
Ph
Ph
N
HN
N
HN
L6
N
HN
L5
N
HN
L8
Ph
t-Bu
Ph
t-Bu
Palladium was listed as one of the strategically important
elements facing supply risk by the Committee of Science and
Technology of British House of Commons in 2011. Nickel, in
comparison, is produced in millions of tons annually and it is
over thousands-fold cheaper than palladium, rhodium and other
noble metals.[9] Compared to palladium, nickel catalysts can
easily insert into unactivated aryl chlorides and allow them to
participate in coupling reactions. Furthermore, alkylnickel
species are known to undergo much slower β-hydride
elimination than the palladium counterparts, which can be
advantageous to avoid such a step in catalytic reactions.[10]
Ph
Ph
L7
25% 2a, 92% ee
43% 3a
90% 2a, 98% ee
8% 3a
5% 2a, 88% ee
53% 3a
10% 2a, 85% ee
8% 3a
Scheme 1. The effect of chiral oxazolines in reductive Heck cyclization of
an aryl chloride.
Initially, in the model study we chose to study cyclization of
N-(o-chlorobenzoyl)-2-methylindole 1a and tested some
common ligands. Chiral diphosphines typically led to very low
yields of 2a and <20% ee (see the Supporting Information).
Initially, we found that the use of several chelating oxazolines[20]
L1-4 led to incomplete conversion of 1a and <5% yield of 2a,
along with significant amounts of byproduct 3a to our
disappointment. The formation of 3a was assisted by the nickel
catalysts based on our control experiments, rather than by the
base NaOAc alone. Fortunately, the use of Pfaltz’s semicorrin[21]
L6 gave good yield of the desired product 2a in 90% yield and
98% ee, and also significantly minimized the formation of 3a
(Scheme 1). In addition, nickel catalysts ligated with two related
semicorrins L7 and L8 have much lower catalytic activity.
Putting all the information here together, we suspect that the
active nickel catalyst is ligated with an anionic form of L6.
O
N
NH
OH
OMe
Br
H
HO
Br
N+
Me
N
N
H
N
MeO
H
X _
Br
N
NHCHO
Hinckdentine A
(unkown bioactivity)
Mangochinine
immunosuppressive
Trigonoliimine C
anti-HIV
Figure 1. Examples of bioactive fused indolines carrying 2-aryl rings.
Previously, nickel catalysts were reported to facilitate Heck-
type arylation,[11] allylation[12] and benzylation[13] of olefins. In a
recent preliminary study, a nickel-catalyzed enantioselective
Heck cyclization generated oxindoles with quaternary centers.[14]
Although Ronchi and Lebedev et al. reported the first nickel-
catalyzed reductive Heck-type reactions of aryl halides and
reactive acrylates in the 1980s,[15] an asymmetric version has
remained elusive until today. Herein, we describe the first
When Ni(COD)2 was used in a combination with L6, only
30% of 2a was generated in the almost identical ee, while more
byproduct of 3a was produced. In the absence of Mn(0), 2a was
not generated. Therefore, We suspected that (COD)Ni(0), in a
mixture with the active nickel catalyst of L6, contributed to
cleavage of the amide bond in 1a. If either Ni(PPh3)4 or
Ni(PPh3)2Cl2 was used with L6, catalytic activity was dimished
(only 10% or 19% of 2a). Probably, the phosphine binds to
nickel centers and resulted in inactive species toward insertion
of indole. The use of NiCl2(DME) in the model reaction afforded
good yield of 2a (83%). Therefore, the manganese powder is
needed to reduce Ni(OAc)2 or NiCl2(DME) to produce the active
nickel catalyst of L6 initially, but we are not sure whether
[*]
Dr. X. Qin, M. W. Y. Lee, Prof. Dr. J. Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University, Singapore 637371
E-mail: jrzhou@ntu.edu.sg
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201707134
Angewandte Chemie International Edition
COMMUNICATION
reduction of arylnickel(II) species to nickel(I) is involved in the
catalytic cycle.[22]
The nickel catalyst of L6 was successfully applied to
cyclization of other 2-alkylindole derivatives (Scheme 2),
including those carrying electron-donating OMe group (2c) and
fluorine atoms (2d and 2e). When the carbocyclic ring of indole
derivatives contained electron-withdrawing groups such as a
trifluoromethyl, nitrile or ester group, the reductive Heck process
proceeded to deliver products, but only with <20% ee values,
probably due to an earlier transition state of insertion. On the
benzamide fragment, steric factor (2f) and electron-donating
groups (2h and 2i) were also tolerated. When the benzamide
fragment had a substitution of fluorine or trifluoromethyl group
para to the C-Cl bond, the cyclization proceeded to give good
yields, but the selectivity was only <30% ee. We also
established that different alkyl groups can be present on C2
position of indoles, such as benzyl (2k), isopropyl (2l) and an
ester group (2m). A single crystal of 2h was obtained and X-ray
diffraction helped to determine its absolute configuration to be
(R).[23] When the indole ring was not substituted at C2 position,
the cyclized product was formed in <5% ee, unfortunately. A
derivative of 2,3-dimethylindole failed to cyclize.
Furthermore,
1 equiv of water was necessary in the
productive pathway. Thus, the nickel-promoted insertion process
is mechanistically distinct from the Pd(0)/(II) cycle in the
reductive Heck process reported by Jia et al.[6a] Replacement of
NaOAc by other bases led to much lower yields of 2a, for
example, with KOAc or Na2CO3 the reaction afforded <20% yield
of 2a. We also tested the cyclization of a bromo analogue of 1a,
but it only afforded 2a in 45% yield and 57% ee.
Ni(OAc)2 5 mol%
Me
Me
Cl
ligand L6 6 mol%
N
N
Mn (3 equiv)
O
NaOAc (3 equiv)
water (1 equiv), DMF
80 oC, 24 h
O
2a
1a
98% ee, 85% yield
Other examples
Me
Me
F
F
Me
N
MeO
Me
Me
N
N
N
F
2d
O
2c
2e
O
2b
O
O
97% ee, 77% yield
80% ee, 60% yield
80% ee, 73% yield
80% ee, 61% yield
The optimized nickel catalyst was also used in cyclization of
2-arylindole derivatives (Scheme 3). On the C2-aryl rings, both
electron-donating (e.g., methoxy and pyrrolidinyl in 2r-s) and
electron-withdrawing groups (e.g., CF3 and F in 2t-u) were
tolerated. To our gratification, both thiophene and pyridine (2w-x)
can also be present at C2 position, as well as a cyclopropyl ring
(2y). In examples that gave moderate yields, cleavage of the N-
indolyl amide bonds was the main side reaction.
with L8
Me
Me
Me
Me
N
Me
N
Me
OMe
OMe
N
N
OMe
2f
2g
O
O
O
O
2h
2i
95% ee, 93% yield
98% ee, 75% yield
85% ee, 91% yield
97% ee, 77% yield
O
Me
Me
Et
Ph
OEt
N
N
N
N
0%D
Ni(OAc)2 5 mol%
H
H
Me
ligand L6 6 mol%
2j
2k
2m
94% ee, 67% yield
O
O
2l
Me
Cl
O
O
(a)
N
N
Mn (3 equiv)
96% ee, 66% yield
91% ee, 58% yield
91% ee, 70% yield
NaOAc (3 equiv)
H2O (1 equiv), DMF-d7
80 oC, 20 h
O
Scheme 2. Asymmetric Heck cyclization of 2-alkylindole derivatives.
O
2a
1a
97% ee, 82% yield
NiCl2(DME) 5 mol%
Ph
Ph
Cl
ligand L6 6 mol%
N
9%D
H
N
72%D
N
D
Mn (3 equiv)
Me
Ni(OAc)2 5 mol%
O
NaOAc (3 equiv)
water (1 equiv), DMF
100 oC, 24 h
2n
O
ligand L6 6 mol%
(b)
1n
1a
+
1a
95% ee, 75% yield
Mn (3 equiv)
45% recovered
(0% D)
O
2a-d
NaOAc (3 equiv)
D2O (1 equiv), DMF
80 oC, 3 h
97% ee, 55% yield
Other examples
Me
Me
n-Bu
OMe
4%D
H
N
73%D
D
NiCl2(DME) 5 mol%
Ph
Ph
Cl
ligand L6 6 mol%
(c)
+
1n
N
N
Mn (3 equiv)
55% recovered
(0% D)
N
N
N
NaOAc (3 equiv)
D2O (1 equiv), DMF
100 oC, 3 h
O
2n-d
O
2o
O
1n
2r
2q
2p
O
O
O
95% ee, 34% yield
99% ee, 65% yield
99% ee, 72% yield
98% ee, 62% yield
96% ee, 58% yield
Scheme 4. Deuterium labeling experiments.
CF3
F
N
H
R
NiBr2(DME) 10 mol%
Me
Me
ligand L6 12 mol%
Me
Cl
N
R
R-Br
(x4)
+
N
N
Mn (3 equiv)
N
N
N
O
N
O
Na2CO3 (3 equiv)
water (0.5 equiv)
DMF, 50 oC, 48 h
O
2v
O
2t
O
2u
O
1a
2s
O
97% ee, 48% yield
92% ee, 63% yield
97% ee, 70% yield
94% ee, 65% yield
R = n-Bu 4a 99.6% ee, 35% yield
R = i-Bu 4b 99.7% ee, 31% yield
5a 45% yield
5b 52% yield
S
N
Scheme 5. Asymmetric coupling of two organic halides and a pedant
indole.
N
N
N
2y
O
2w
2x
O
O
In order to determine the source of the incoming hydrogen in
the cyclization products, we conducted labelling experiments
using either DMF-d7 or D2O (Scheme 4). When cyclization of 1a
was conducted in deuteriated DMF, no trace of deuterium was
detected in product 2a, which excluded the possibility of DMF as
96% ee, 70% yield
78% ee, 51% yield
90% ee, 51% yield
Scheme 3. Asymmetric Heck cyclization of 2-aryl- and 2-
cyclopropylindole derivatives.
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10.1002/anie.201707134
Angewandte Chemie International Edition
COMMUNICATION
the hydrogen source.[24] In comparison, in reactions of 1a and 1n
containing 1 equiv of D2O, significant amounts of deuterium was
incorporated in products 2a and 2n, while no deuterium was
detected in the recovered starting material after partial
conversions. Interestingly, careful nOe analysis of 2n revealed
that the deuterium was predominantly added syn to the inserting
aryl ring on the indoline. This indicates that after the insertion,
the resulting carbon−nickel bond was mainly protonated at the
front side of the carbon center.
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Furthermore, when cyclization of 1a was conducted together
with n-butyl bromides under slightly modified conditions, the
benzylnickel species in the catalytic cycle was trapped by C3-
alkylation to give 4a in moderate yield and 99.6% ee, along with
an uncyclized coupling product 5a (Scheme 5). In nOe analysis
of 4a, magnetization transfer was detected between the benzylic
hydrogen and methyl group on the indoline. Therefore, the butyl
group and inserting aryl ring are situated syn to each other. A
similar result was obtained in the reaction of isobutyl bromide.
These are the first examples of asymmetric coupling between
two organic halides and an unsaturated bond (indole in this case)
that give a high level of enantioselectivity.[25]
[4] Examples: a) A. Minatti, X. Zheng, S. L. Buchwald, J. Org. Chem. 2007,
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Jang, Y. J.; Larin, E. M. Angew. Chem. Int. Ed., 2017.
DOI: 10.1002/anie.201704922
The indole ring of 2a can be easily brominated by treatment
of Br2. Furthermore the amide linkage in 2a was cleaved by
NaBH4 to give alcohol 6b and deoxygenated by borane to afford
6c.[6a; 26] In all cases, no ee erosion was detected (Scheme 6).
[5] a) S. Cacchi, Pure Appl. Chem. 1990, 62, 713; b) A. L. Gottumukkala, J.
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Am. Chem. Soc. 2015, 137, 4936; b) asymmetric cyclization followed by
alkynylation: R.-R. Liu, Y.-G. Wang, Y.-L. Li, B.-B. Huang, R.-X. Liang,
Y.-X. Jia, Angew. Chem. Int. Ed. 2017, 56, 7475; Angew. Chem. 2017,
129, 7583; nonstereoselective examples: c) R.-R. Liu, Y. Xu, R.-X. Liang,
B. Xiang, H.-J. Xie, J.-R. Gao, Y.-X. Jia, Org. Biomol. Chem. 2017, 15,
2711; d) R.-R. Liu, T.-F. Xu, Y.-G. Wang, B. Xiang, J.-R. Gao, Y.-X. Jia,
Chem. Commun. 2016, 52, 13664.
Me
Me
Me
NaBH4
BH3
Me2S
N
N
H
N
THF/CH3OH
THF, reflux
2a
O
6b OH
6c
95% yield
[7] W. Kong, Q. Wang, J. Zhu, Angew. Chem. Int. Ed. 2017, 56, 3987;
96% ee
65% yield
Angew.Chem. 2017, 129, 4045.
[8] G. Yue, K. Lei, H. Hirao, J. Zhou, Angew. Chem. Int. Ed. 2015, 54, 6531;
Angew.Chem. 2015, 127, 6631.
Br2, AcOH
CH2Cl2
[9] K. S. Egorova, V. P. Ananikov, Angew. Chem. Int. Ed. 2016, 55, 12150;
Br
Me
N
Angew.Chem. 2016, 128, 12334.
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Braga, T. R. Cundari, Organometallics 2016, 35, 3170.
O
6a
90% yield
[11] a) T. M. Gøgsig, J. Kleimark, S. O. Nilsson Lill, S. Korsager, A. T.
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V. Zatolochnaya, S. Rodriguez, H. Lee, N. Grinberg, N. Haddad, N. K.
Yee, N. K. Garg, C. H. Senanayake, Angew. Chem. Int. Ed. 2016, 55,
11921; Angew. Chem. 2016, 128, 12100; an enantioselective process:
b) J.-N. Desrosiers, J. Wen, S. Tcyrulnikov, S. Biswas, B. Qu, L. Hie, D.
Kurouski, L. Wu, N. Grinberg, N. Haddad, C. A. Busacca, N. K. Yee, J. J.
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Scheme 6. Product derivatization without ee loss
In summary, we report the first example of nickel-catalyzed
asymmetric reductive Heck cyclization that provides fused
indolines in good ee values. Mechanistically, it is distinct from
the palladium-catalyzed process as reported by Jia et al. in how
the nickel-carbon bond is converted to a C-H bond to release the
product, protonation of the carbon-nickel bond versus hydride
donation followed by C-H reductive elimination on Pd.
Acknowledgements
We thank Singapore Ministry of Education Academic Research
Fund (MOE2015-T1-001-166 and MOE2014-T1-001-021) and
GSK-EDB Trust Fund (Green and Sustainable Manufacturing
Award 2013) for financial support.
Keywords: nickel catalysis • reductive Heck reaction •
[16] Stereoselective synthesis of indolines: a) R. Dalpozzo, G. Bartoli, G.
Bencivenni, Chem. Soc. Rev. 2012, 41, 7247; b) K. W. Quasdorf, L. E.
Overman, Nature 2014, 516, 181; c) C.-X. Zhuo, C. Zheng, S.-L. You,
asymmetric catalysis • indoline • cyclization
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10.1002/anie.201707134
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COMMUNICATION
Acc. Chem. Res. 2014, 47, 2558; d) S. P. Roche, J.-J. Youte Tendoung,
B. Tréguier, Tetrahedron 2015, 71, 3549.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201707134
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
H
N
D
R
R
nickel catalyst
NaOAc
Nickel-catalyzed
Xurong Qin, Marcus Wen Yao Lee, and Jianrong Steve
Zhou*
N
Cl
+ D2O + Mn
aryl insertion of
indoles is
O
97% ee
CN
O
mainly syn deuteration
O
O
Page No. – Page No.
followed by
stereospecific
protonation
N
HN
Ph
Ph
semicorrin ligand
Nickel-Catalyzed Asymmetric Reductive Heck
Cyclization of Aryl Halides to Access Indolines
This article is protected by copyright. All rights reserved.