Ni-Catalyzed Regio- A nd Enantioselective Domino Reductive Cyclization: One-Pot Synthesis of 2,3-Fused Cyclopentannulated Indolines

Article abstract of DOI:10.1021/acscatal.9b02081

Transition-metal-catalytic domino reactions represent important advances in synthetic organic chemistry. Their development benefits synthesis by providing highly efficient and step-economical methods to complex molecules with impressive selectivity. Herein, a Ni-catalyzed domino reductive cyclization of acrylamides with alkynyl bromides is reported, enabling rapid assembly of a range of substituted 2,3-fused cyclopentannulated indolines. Preliminary mechanistic studies revealed that tricyclic indolines are afforded through a highly regioselective migratory insertion of 1,3-diynes, which are formed from the homocoupling of alkynyl bromides, into the in situ generated σ-alkyl-Ni(II) species, followed by nucleophilic addition of the resulting alkenyl nickel to unactivated amides. Most importantly, a highly regio- A nd enantioselective reductive cyclization of acrylamides and internal alkynes has also been developed. This transformation takes place under mild conditions with high efficiency, providing a rapid access to structurally diverse cyclopentannulated indolines in synthetically useful yields with high regioselectivity (>20/1) and enantioselectivity (27 examples, 82-96% ee).

Full text of DOI:10.1021/acscatal.9b02081

Research Article
pubs.acs.org/acscatalysis
Cite This: ACS Catal. 2019, 9, 7335−7342
Ni-Catalyzed Regio- and Enantioselective Domino Reductive
Cyclization: One-Pot Synthesis of 2,3-Fused Cyclopentannulated
Indolines
Yuanyuan Ping,† Kuai Wang,† Qi Pan, Zhengtian Ding, Zhijun Zhou, Ya Guo, and Wangqing Kong*
The Center for Precision Synthesis (CPS), Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, People’s
Republic of China
S
* Supporting Information
ABSTRACT: Transition-metal-catalytic domino reactions rep-
resent important advances in synthetic organic chemistry. Their
development benefits synthesis by providing highly efficient and
step-economical methods to complex molecules with impressive
selectivity. Herein, a Ni-catalyzed domino reductive cyclization
of acrylamides with alkynyl bromides is reported, enabling rapid
assembly of a range of substituted 2,3-fused cyclopentannulated
indolines. Preliminary mechanistic studies revealed that tricyclic
indolines are afforded through a highly regioselective migratory
insertion of 1,3-diynes, which are formed from the homocou-
pling of alkynyl bromides, into the in situ generated σ-alkyl-Ni(II) species, followed by nucleophilic addition of the resulting
alkenyl nickel to unactivated amides. Most importantly, a highly regio- and enantioselective reductive cyclization of acrylamides
and internal alkynes has also been developed. This transformation takes place under mild conditions with high efficiency,
providing a rapid access to structurally diverse cyclopentannulated indolines in synthetically useful yields with high
regioselectivity (>20/1) and enantioselectivity (27 examples, 82−96% ee).
KEYWORDS: Ni catalysis, reductive cross-coupling, cyclization, enantioselectivity, 2,3-fused cyclopentannulated indoline,
regioselectivity
significance, many studies have been directed toward the
synthesis of these privileged structures. However, protocols for
their enantioselective preparation are still very limited;2 the
main strategy allowing access to such tricyclic skeletons has so
far relied on [3 + 2] cycloaddition reactions of functionalized
indoles with 1,3-dipoles.3 Given the wide structural diversity of
chiral cyclopentannulated indolines in target molecules, the
development of new strategies to these scaffolds from simple
and readily available starting materials continues to be highly
valuable.
he 2,3-fused cyclopentannulated indolines are widely
Tpresent as core structures in a large number of synthetic
or natural products encompassing a broad range of biological
activities such as vindolinine, kopsane, dasyrachine, spermaco-
ceine, and kopsinidine B (Figure 1).1 In view of their broad
On the other hand, catalytic cross-electrophile coupling
reactions have gained extensive attention, as they represent a
powerful tool for the construction of diverse C−C bonds and
allow reactions to proceed under very mild conditions without
any additional prefunctionalization in comparison to classical
nucleophilic/electrophilic regimes.4 Despite tremendous ad-
vances, this field of expertise remains essentially confined to
the formation of a single C−C bond,5 and highly
enantioselective catalytic variants of these processes have
rarely been explored.6,7 In connection with our interest in the
development of Ni-catalyzed enantioselective cross-electro-
Received: May 21, 2019
Revised: June 30, 2019
Figure 1. Representative natural products possessing a cyclo-
pentannulated indoline core.
© XXXX American Chemical Society
7335
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
Scheme 1. Proposed Strategy for the Synthesis of 2,3-Fused Cyclopentannulated Indolines by a Ni-Catalyzed Tandem Process
phile coupling of alkenes for the efficient construction of N-
containing heterocycles,8 we envisaged that 2,3-fused cyclo-
pentannulated indolines 3 might be assembled through the
fusion of aryl bromide tethered acrylamides 1 with alkynyl
bromides 2 in a cascade fashion (Scheme 1A).
A more complete depiction of the presumed catalytic cycle
for this tandem reaction is shown in Scheme 1B. Oxidative
addition of aryl bromide 1 to Ni(0) species followed by an
intramolecular carbonickelation produces the σ-alkyl-NiIIX
species A.9 A subsequent regioselective migratory insertion of
1,3-diyne 4, which is formed from the reductive homocoupling
of alkynyl bromide 2, into the nickel−alkyl bond of A
generates the seven-membered alkenylnickel species B. Intra-
molecular nucleophilic addition of the nickel−carbon bond of
B to the amide leads the nickel alkoxide intermediate C, which
can undergo protonolysis to release the desired product 3 and
regenerate Ni(0) catalyst upon reduction.
alkenylnickel species,11 poorly electrophilic amides have been
virtually unexplored.12 Despite the many difficulties, we were
still attracted to these challenges, as such a route would offer a
unique opportunity to rapidly assemble tricyclic indoline
skeletons from simple precursors.
Herein, we present the realization of this novel design
principle by a Ni-catalyzed tandem process, which enables the
one-pot synthesis of highly valuable 2,3-fused cyclopentannu-
lated indoline scaffolds involving multiple C−C bond
formations. In addition, to uncover the nature of the reaction
intermediates involved in this transformation, control experi-
ments and mechanistic probes were designed. Most
importantly, a highly regio- and enantioselective synthesis of
2,3-fused cyclopentannulated indolines through reductive
cyclization/coupling of alkyne-tethered aryl bromides with
asymmetric internal alkynes has been achieved, and these
results will also be presented.
At the outset of our investigations, however, it was not clear
whether such a protocol could be implemented, as a series of
challenges must be addressed. First, the Ni-catalyzed reductive
homocoupling of alkynyl bromide 2 to produce 1,3-diyne 4
must be rapid in comparison to the cyclizative coupling of aryl
bromide 1 with 2; otherwise, the formation of arylalkynylated
product 5 will be unavoidable. Second, controlling the
regioselectivity of migratory insertion across alkynes is very
difficult, since previous reports of the use of unsymmetrical
alkynes that lack electronic or steric biases typically resulted in
a mixture of regioisomers.10 Furthermore, although several
types of electrophiles have been found to be able to capture
We began our investigations by using 1a and 2a as the
model substrates to optimize the reaction conditions (Table
1). As expected, our studies revealed that the selectivity for 3aa
is challenged by a number of competitive reactions, such as the
direct coupling of Ar−Br with alkynyl bromide, the
protonation of intermediate A and the arylalkynylation
reaction to produce 5aa. After scrupulous evaluation of a
range of parameters, we were pleased to find that a
combination of NiCl2(DME), 4,4′-dimethoxycarbonyl-2,2′-
bipyridine (L1), and Mn as reducing agent in THF at 60 °C
provided 3aa in 72% isolated yield with excellent chemo- and
regioselectivity (entry 1). Using DMA as solvent led to poor
7336
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
a
Table 1. Optimization of the Reaction Conditions
b
b
entry
changes from standard conditions
yield of 5aa (%)
yield of 3aa (%)
3aa/3aa′
1
2
3
4
5
6
7
8
none
< 2
25
nr
nr
nr
nr
nr
nr
nr
<2
trace
trace
nr
nr
nr
72
51
nr
nr
nr
nr
nr
nr
nr
62
31
trace
nr
nr
nr
>20/1
nd
DMA instead of THF
L2 instead of L1
L3 instead of L1
L4 instead of L1
L5 instead of L1
L6 instead of L1
L7 instead of L1
L8 instead of L1
Ni(COD)2 instead of NiCl2(DME)
Zn0 instead of Mn0
B2Pin2 instead of Mn0
without NiCl2(DME)
without L1
9
10
11
12
13
14
15
>20/1
without Mn0
a
Reactions were carried out with 1a (0.1 mmol), 2a (0.3 mmol), Ni catalyst (10 mol %), ligand (20 mol %), Mn0 (0.4 mmol) in 2 mL of THF at
b
60 °C for 24 h, unless noted otherwise. Isolated yields.
chemoselectivity for indoline 3aa over arylalkynylated product
5aa (entry 2). As anticipated, the nature of the ligand had a
non-negligible effect on the reaction outcome. Most strikingly,
the methoxycarbonyl groups of L1 is found to be critical for
this transformation, as other bipyridine type ligands L2−L8
resulted in no reaction occurring (entries 3−9). Inferior results
were obtained with other nickel-catalyst precursor or reducing
agent combinations (entries 10−12). In line with our
expectations, formation of product 3aa was not observed in
control experiments in which Ni, ligand, or Mn were omitted
(entries 13−15).
The conditions of entry 1 in Table 1 were subsequently
employed to test the generality of this process. We were
pleasure to find that a variety of alkene-tethered aryl bromides
1 could undergo cyclizative cross coupling to furnish the target
products 3aa−pa in good yields (Scheme 2). The aryl
bromide, iodide, and triflate are competent electrophiles and
afforded indoline 3aa in good yields. Subsequently, the
substitution pattern on the aromatic ring of the aniline moiety
was studied. Substitution in a para position relative to the N
atom with both electron-donating as well as electron-
withdrawing groups was well tolerated to afford the
corresponding indolines 3ba−da in good yields. The meta-
and ortho-substituted anilides and N-(naphthalen-2-yl)amide
all posed no problems (3fa−ia, 3ja). Remarkably, a pyridine
backbone was perfectly accommodated to furnish the azaindo-
line 3ka in 60% yield, which is of particular interest due to its
prominence in natural products and drug discovery pro-
grams.13 The structure of 3ka was unequivocally established by
an X-ray crystal diffraction study.14 The cyclizative cross-
coupling reaction of N-benzyl acetanilide 1m proceeded
efficiently to provide 3ma in 69% yield. Finally, the influence
of the Cα substituents (R2) of the acrylamide double bond on
the reaction outcome was tested. Methoxymethyl, benzyl, and
phenyl substituents were well compatible (3na−pa).
The substrate scope with respect to alkynyl bromides 2 was
investigated next (Scheme 3). The alkynyl bromide and iodide
are both competent electrophiles and afforded indoline 3aa in
good yields. n-Pentyl, phenyl, trifluoromethyl, and fluoro
substituents in the para position of the aromatic ring could be
efficiently coupled producing compounds 3ab−ae in moderate
to good yields. Particularly interesting was the ability to
accommodate aryl chloride (3af) or bromide (3ag); the
alternative competing diarylated product was not observed.8
These motifs have successfully been used as counterparts in
Ni-catalyzed cross-coupling reactions, which provides an
additional handle for further derivatization. Substitution in
the meta or ortho position was also well tolerated, as
demonstrated by the efficient conversion obtained for 3ah−
ak. Importantly, heteroaromatic-substituted alkynyl bromides
such as 2-thiophene, 3-thiophene, and 3-benzothiophene
proved to be amenable substrates, producing 3am−ao in
synthetically useful yields, thus showcasing the genuine
potential of our protocol.
Control experiments were designed to unravel the reaction
mechanism (Scheme 4). When 5aa was subjected to our
optimized reaction conditions, 3aa was not observed (eq 1);
thus, the arylalkynylated product 5 as an intermediate can be
ruled out. We have also found that the 1,3-diyne 4aa can be
formed in 70% yield by homocoupling of alkynyl bromide 2a
under our standard conditions (eq 2). Interestingly, tracking
the reaction of 1a with 4aa found that the reaction went to
completion after 48 h, delivering 3aa in 71% yield (eq 3).
7337
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
Scheme 2. Substrate Scope of Aryl Bromides 1
Scheme 4. Mechanistic Study
Table 1, entry 1). Attempts to accelerate the reaction by
adding a catalytic amount of alkynyl bromide 2a found no
effect (eq 4). After careful analysis of the reaction process, we
realized that there are subtle differences in reaction conditions.
In the reactions of 1 with 2, the homocoupling of 2 produced
stoichiometric amounts of MnBr2, but at the beginning of the
reaction of 1a with 4aa, MnBr2 was not present in the reaction
system. Therefore, we set out to investigate the effect of MnBr2
on the reaction. Strikingly, by addition of 1 equiv of MnBr2 to
the catalytic reaction of 1a with 4aa, the reaction completed
much more quickly, delivering 3aa in 70% yield within 12 h
(eq 5). In addition, we found that the reaction of 1a with 2a in
the presence of MnBr2 could also be completed within 12 h
(eq 6). Taking together, these results clearly demonstrated that
MnBr2 plays a key role in significantly accelerating the reaction
by promoting the late cyclization process rather than the early
homocoupling of alkynyl bromide (compare eqs 5 and 6 with
eq 3).
Scheme 3. Substrate Scope of Alkynyl Bromides 2
To unravel the intermediates involved in this transformation,
we synthesized the σ-alkyl-NiII complex 6 following our
previous report from the oxidative addition of 1a and
subsequent migratory insertion (Scheme 4, eq 8).15 The
stoichiometric experiments with complex 6 are particularly
illustrative; we found that the target product 3aa was cleanly
produced in 74% yield in the presence of MnBr2 (compare eq
9 with eq 7). Moreover, a reaction run without nickel did not
consume starting material (Table 1, entry 13), suggesting that
direct insertion of Mn0 into aryl bromide is not likely. Taken
together, these results support the ideal of a mechanism in
These results provided direct evidence of the mechanism that
1,3-diyne 4 is the key intermediate for this transformation.
It seems to be unreasonable that the reaction time of direct
cyclization of 1a with 4aa is significantly longer than the
reaction time of 1a with 2a (compare Scheme 4, eq 3, with
7338
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
a
Table 2. Optimization of Reaction Conditions
b
c
entry
ligand
additive (equiv)
yield of 8aa (%)
ee of 8aa (%)
1
2
3
4
5
6
7
L1
65
52
47
26
24
55
60
L22
L22
L22
L22
L22
L22
Et3N (2)
DIPEA (2)
DBU (2)
K3PO4 (2)
Et3N (4)
Et3N (10)
92
93
52
72
91
90
a
Reactions were carried out with 1a (0.1 mmol), 7a (0.3 mmol), NiCl2(DME) (10 mol %), ligand (20 mol %), MnBr2 (0.1 mmol), and Mn0 (0.4
b
mmol) in 2 mL THF at 60 °C for 12 h; NaBH3CN (0.5 mmol) was added and heated at 60 °C for another 12 h, unless noted otherwise. Isolated
yields. Determined by HPLC analysis with a chiral column.
c
which an σ-alkyl-NiII species serves as the key intermediate in
the catalytic cycle. However, in the case where MnBr2 was not
added, only a trace of product 3aa was observed (eq 10), thus
confirming that MnBr2 was indispensable for the reaction to
occur.
analysis.18 Importantly, not even a trace of regioisomer 8aa′
was found in the crude reaction mixtures.
To control the absolute stereochemistry of the 2,3-fused
cyclopentannulated indolines, an enantioselective variant of the
reaction was explored (Table 2). A range of chiral ligands were
examined: BOX ligands L9−L12 and PHOX ligands L13 and
L14, which are widely used in enantioselective cross-electro-
phile reactions,7 did not give any desired product. The chiral
Pyrox ligand L22 was proved to be the most effective in terms
of enantioselectivity (94% ee), albeit with a low yield (39%
yield). To our delight, we subsequently found that base played
a key role in the reaction outcome. The addition of Et3N was
beneficial for the reactivity to give 8aa in 52% yield with 92%
ee (entry 2). A comparable result was obtained by the addition
of DIPEA (entry 3). However, the utilization of the strong
organic base DBU or inorganic base K3PO4 in place of Et3N
deteriorated the results (entries 4 and 5). The best result was
achieved when an excess of Et3N (10 equiv) was used,
providing 8aa in 60% yield with 90% ee (entry 7). The
absolute configuration (3R, 8S for 8aa) was determined
unambiguously by X-ray crystallographic analysis, and those of
all other 2,3-fused cyclopentannulated indoline products were
assigned accordingly.19
We further attempted to use operando IR to monitor the
reaction between 1a and 4aa. As shown in Figures S1 and S2 in
the Supporting Information, we were delighted to see not only
that the kinetic profiles clearly revealed the consumption of 1a
and the formation of 3aa but also that the infrared absorption
peak of the CO bond (1665 cm−1) of 1a remained almost
unchanged during the first few hours in the reaction without
adding MnBr2. However, in the case of adding MnBr2, the
absorption intensity of the CO bond began to decrease
immediately. These results indicate that MnBr2 may act as a
Lewis acid to promote the nucleophilic cyclization process. In
addition, the step of carbonyl disappearance, that is,
nucleophilic attack of the alkenylnickel species on amide,
may be the rate-determining step of this tandem process.16
On the basis of the above mechanistic study where the 1,3-
diyne is the key intermediate, we questioned whether we could
extend the scope of our protocol to simple alkynes. Therefore,
1a and asymmetric alkyne 7a were selected as benchmark
substrates to test our hypothesis. Upon modification of the
reaction protocol (entry 1, Table 1), wherein MnBr2 proved to
be crucial, the yield of indoline 8aa was boosted to 65% (entry
1, Table 2). Since some 2-hydroxyindolines are less stable for
silica gel column chromatography, a reductive step was
incorporated into the reaction sequence.17 The structure of
8aa was unequivocally established by X-ray crystallographic
With the optimized conditions in hand, we set out to explore
the scope of alkene-tethered aryl bromides 1. We were pleased
to find that a variety of alkene-tethered aryl bromides could
undergo cyclizative cross coupling to furnish the target
products 8aa−qa in good yields with excellent enantioselectiv-
ities (Scheme 5). Different substitution patterns with electron-
donating or electron-withdrawing groups on the aniline part
7339
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
a
Scheme 5. Substrate Scope of Aryl Bromides 1
Scheme 6. Substrate Scope of Internal Alkynes 7
a
3-(N-Methylmethacrylamido)naphthalen-2-yl trifluoromethanesulfo-
a
b
nate was used.
Without Et3N. Without NaBH3CN reduction.
(8ba−ha) were well-tolerated. In addition to aryl bromides,
aryl triflate was also compatible to produce the corresponding
product 8ja in 88% yield with 86% ee. Importantly, the
reaction was successfully applied to the synthesis of the
tetracyclic indoline 8la in 94% ee. The presence of a benzyl
substituent on the nitrogen atom of 8ma was compatible with
the reaction conditions. As the N-benzyl is easily removed, this
constitutes a route to N−H indolines. The acrylamide double
bond was also amenable to structural variations, so that 8oa−
qa could be also efficiently obtained with excellent
enantioselectivity.
The substrate scope with respect to internal alkynes 7 was
investigated next (Scheme 6). Notably, an exquisite
regioselectivity profile was found for a wide variety of
unsymmetrical alkynes, even without significant steric bias
(8ab−am). In all cases, a single regioisomer was obtained,
wher the alkyne carbon bearing a less electron donating group
(Ar/Het) is connected to the amide carbonyl group of 1 and
the alkyne carbon with a more electron donating substituent
(alkyl) is attached to the terminal carbon of alkene moiety.
Alkynes bearing various substituent groups on the aromatic
ring such as OMe (8ac), Me (8ad), Cl (8ae), F (8af), and CF3
(8ag) were well compatible with the current reaction
conditions. Whereas substitution meta to the triple bond was
tolerated (8ah), no product was observed when the substituent
was ortho to the triple bond. To further demonstrate the
robustness and generality of synthetic utility of our method, we
then explored the cyclization reaction with a wide range of
heterocyclic substituted alkynes, such as benzothiophene (8ai),
dibenzofuran (8aj), indole (8ak), and thiophene (8am). These
results demonstrate that the potential utility of this method-
ology for the synthesis of medicinally relevant compounds is
feasible. The cyclization reaction could also be applied to
diarylalkyne (8an) and dialkylalkyne (8ao) in high enantiose-
lectivity, albeit in slightly lower yields. Interestingly, 1,3-diyne
4aa was also accepted as a substrate, leading to the desired
product 3aa with 82% ee. There is no significant difference in
ee values in Scheme 6 when different substituted internal
alkynes 7 are used, indicating that alkynes are not involved in
the enantioselectivity-determining step, thus supporting the
assumption that the migration insertion (intramolecular
acrylamide cyclization) is the enantioselectivity-determining
step of this reaction.
In conclusion, we have reported a one-pot synthesis of 2,3-
fused cyclopentannulated indolines through the fusion of
arylbromide-tethered acrylamides with alkynyl bromides by a
nickel-catalyzed tandem process. Mechanistic studies indicated
that the tricyclic indolines are produced through a highly
regioselective migratory insertion of 1,3-diynes, which are
formed from the homocoupling of alkynyl bromides, into the
in situ generated σ-alkyl-NiII species, followed by nucleophilic
addition of the resulting alkenyl nickel to unactivated amides.
The byproduct MnBr2 can significantly accelerate the
nucleophilic cyclization process that may be the rate-
7340
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
cycloaddition of 3-nitroindoles with vinylcyclopropanes: An entry to
stereodefined 2,3-fused cyclopentannulated indoline derivatives. Org.
Lett. 2017, 19, 2266−2269. (f) Sun, M.; Zhu, Z.; Gu, L.; Wan, X.;
Mei, G.; Shi, F. Catalytic asymmetric dearomative [3 + 2]
cycloaddition of electron deficient indoles with all-carbon 1,3-dipoles.
J. Org. Chem. 2018, 83, 2341−2348. (g) Zhang, X.; Liu, W.-B.; Tu,
H.-F.; You, S.-L. Ligand-enabled Ir-catalyzed intermolecular diaster-
eoselective and enantioselective allylic alkylation of 3-substituted
indoles. Chem. Sci. 2015, 6, 4525−4529.
determining step of this transformation. Most importantly, an
enantioselective reductive cyclization of aryl bromides with
asymmetric internal alkynes has also been realized. This
transformation takes place under very mild conditions with
high efficiency, providing a rapid access to 2,3-fused cyclo-
pentannulated indoline scaffolds in a completely regioselective
and highly enantioselective manner.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.9b02081.
(4) For reviews on Ni-catalyzed reductive cross-coupling reactions,
■
S
̈
see: (a) Knappke, C. E. I.; Grupe, S.; Gartner, D.; Corpet, M.;
Gosmini, C.; Jacobi von Wangelin, A. Reductive cross-coupling
reactions between two electrophiles. Chem. - Eur. J. 2014, 20, 6828−
6842. (b) Moragas, T.; Correa, A.; Martin, R. Metal-catalyzed
reductive coupling reactions of organic halides with carbonyl-type
compounds. Chem. - Eur. J. 2014, 20, 8242−8258. (c) Everson, D. A.;
Weix, D. J. Cross-electrophile coupling: principles of reactivity and
selectivity. J. Org. Chem. 2014, 79, 4793−4798. (d) Tasker, S. Z.;
Standley, E. A.; Jamison, T. F. Recent advances in homogeneous
nickel catalysis. Nature 2014, 509, 299−309. (e) Gu, J.; Wang, X.;
Xue, W.; Gong, H. Nickel-catalyzed reductive coupling of alkyl halides
with other electrophiles: concept and mechanistic considerations. Org.
Chem. Front. 2015, 2, 1411−1421. (f) Weix, D. J. Methods and
mechanisms for cross-electrophile coupling of Csp2 halides with alkyl
electrophiles. Acc. Chem. Res. 2015, 48, 1767−1775. (g) Wang, X.;
Dai, Y.; Gong, H. Nickel-catalyzed reductive couplings. Top Curr.
Chem. (Z). 2016, 374, 43. (h) Richmond, E.; Moran, J. Recent
advances in nickel catalysis enabled by stoichiometric metallic
reducing agents. Synthesis 2018, 50, 499−513.
Experimental procedures, spectroscopic data, and NMR
spectra of all products (PDF)
Crystallographic data (CIF)
Crystallographic data (CIF)
Crystallographic data (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail for W.K.: wqkong@whu.edu.cn.
■
ORCID
Wangqing Kong: 0000-0003-3260-0097
Author Contributions
†Y.P. and K.W. contributed equally.
Notes
(5) For selected examples of Ni-catalyzed reductive cross couplings
involving multibond formation, see: (a) Durandetti, M.; Hardou, L.;
Lhermet, R.; Rouen, M.; Maddaluno, J. Synthetic applications of the
nickel-catalyzed cyclization of alkynes combined with addition
reactions in a domino process. Chem. - Eur. J. 2011, 17, 12773−
12783. (b) Yan, C.; Peng, Y.; Xu, X.; Wang, Y. Nickel-mediated inter-
and intramolecular reductive cross-coupling of unactivated alkyl
bromides and aryl iodides at room temperature. Chem. - Eur. J. 2012,
18, 6039−6048. (c) Zhao, C.; Jia, X.; Wang, X.; Gong, H. Ni-
catalyzed reductive coupling of alkyl acids with unactivated tertiary
alkyl and glycosyl halides. J. Am. Chem. Soc. 2014, 136, 17645−17651.
(d) Peng, Y.; Xu, X.; Xiao, J.; Wang, Y. Nickel-mediated stereo-
controlled synthesis of spiroketals via tandem cyclization-coupling of
β-bromo ketals and aryl iodides. Chem. Commun. 2014, 50, 472−474.
(e) Wang, X.; Liu, Y.; Martin, R. Ni-catalyzed divergent cyclization/
carboxylation of unactivated primary and secondary alkyl halides with
CO2. J. Am. Chem. Soc. 2015, 137, 6476−6479. (f) Peng, Y.; Xiao, J.;
Xu, X.; Duan, S.; Ren, L.; Shao, Y.; Wang, Y. Stereospecific synthesis
of tetrahydronaphtho[2,3-b]furans enabled by a nickel-promoted
tandem reductive cyclization. Org. Lett. 2016, 18, 5170−5173.
(g) García-Domínguez, A.; Li, Z.; Nevado, C. Nickel-catalyzed
reductive dicarbofunctionalization of alkenes. J. Am. Chem. Soc. 2017,
139, 6835−6838. (h) Shimkin, K. W.; Montgomery, J. Synthesis of
tetrasubstituted alkenes by tandem metallacycle formation/cross-
electrophile coupling. J. Am. Chem. Soc. 2018, 140, 7074−7078.
(i) Kuang, Y.; Wang, Y.; Anthony, D.; Diao, T. Ni-catalyzed two-
component reductive dicarbofunctionalization of alkenes via radical
cyclization. Chem. Commun. 2018, 54, 2558−2561. (j) Jin, Y.; Wang,
C. Ni-catalysed reductive arylalkylation of unactivated alkenes. Chem.
Sci. 2019, 10, 1780−1785.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the “1000-Youth Talents Plan”, the
National Natural Science Foundation of China (No.
21702149), and the Fundamental 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.
REFERENCES
■
(1) (a) Dewick, P. M. Medicinal Natural Products: A Biosynthetic
Approach, 2nd ed.; Wiley: New York, 2002. (b) Fattorusso, E.;
Taglialatela Scafati, O. Modern Alkaloids: Structure, Isolation, Synthesis,
and Biology; Wiley-VCH: Weinheim, Germany, 2008.
(2) For recent reviews, see: (a) Zhang, D.; Song, H.; Qin, Y. Total
synthesis of indoline alkaloids: A cyclopropanation strategy. Acc.
Chem. Res. 2011, 44, 447−457. (b) Zhuo, C.-X.; Zhang, W.; You, S.-
L. Catalytic asymmetric dearomatization reactions. Angew. Chem., Int.
Ed. 2012, 51, 12662−12686. (c) Petrovic, M.; Occhiato, E. G.
Pentannulation of heterocycles by virtue of precious metal catalysis.
Chem. - Asian J. 2016, 11, 642−659. (d) Vivekanand, T.; Satpathi, B.;
Bankar, S. K.; Ramasastry, S. S. V. Recent metal-catalysed approaches
for the synthesis of cyclopenta[b]indoles. RSC Adv. 2018, 8, 18576−
18588.
(3) For references on the enantioselective synthesis of 2,3-fused
cyclopentannulated indolines, see: (a) Xiong, H.; Xu, H.; Liao, S.; Xie,
Z.; Tang, Y. Copper-catalyzed highly enantioselective cyclopentannu-
lation of indoles with donor-acceptor cyclopropanes. J. Am. Chem. Soc.
2013, 135, 7851−7854. (b) Barluenga, J.; Tudela, E.; Ballesteros, A.;
Tomas, M. Asymmetric C2-C3 cyclopentannulation of the indole
ring. J. Am. Chem. Soc. 2009, 131, 2096−2097. (c) Lian, Y.; Davies, H.
M. L. Rhodium-catalyzed [3 + 2] annulation of indoles. J. Am. Chem.
Soc. 2010, 132, 440−441. (d) Trost, B. M.; Quancard, J. Palladium-
catalyzed enantioselective C-3 allylation of 3-substituted-1H-indoles
using trialkylboranes. J. Am. Chem. Soc. 2006, 128, 6314−6315.
(6) (a) Tollefson, E. J.; Hanna, L. E.; Jarvo, E. R. Stereospecific
nickel-catalyzed cross-coupling reactions of benzylic ethers and esters.
Acc. Chem. Res. 2015, 48, 2344−2353. (b) Cherney, A. H.; Kadunce,
N. T.; Reisman, S. E. Enantioselective and enantiospecific transition-
metal-catalyzed cross-coupling reactions of organometallic reagents to
construct C-C bonds. Chem. Rev. 2015, 115, 9587−9652. (c) Lucas,
E. L.; Jarvo, E. R. Stereospecific and stereoconvergent cross-couplings
between alkyl electrophiles. Nat. Rev. Chem. 2017, 1, 65. (d) Fu, G. C.
Transition-Metal Catalysis of Nucleophilic Substitution Reactions: A
Radical Alternative to SN1 and SN2 Processes. ACS Cent. Sci. 2017, 3,
́
(e) Laugeois, M.; Ling, J.; Ferard, C.; Michelet, V.; Ratovelomanana-
Vidal, V.; Vitale, M. R. Palladium(0)-catalyzed dearomative [3 + 2]
7341
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342

ACS Catalysis
Research Article
692−700. (e) Choi, J.; Fu, G. C. Transition metal catalyzed alkyl-alkyl
bond formation: Another dimension in cross-coupling chemistry.
Science 2017, 356, eaaf7230.
Enantioselective nickel-catalyzed anti-carbometallative cyclizations of
alkynyl electrophiles enabled by reversible alkenylnickel E/Z isomer-
ization. J. Am. Chem. Soc. 2016, 138, 8068−8071. (b) Zhang, X.; Xie,
X.; Liu, Y. Nickel-catalyzed cyclization of alkyne-nitriles with
organoboronic acids involving anti-carbometalation of alkynes.
Chem. Sci. 2016, 7, 5815−5820. (c) Yap, C.; Lenagh-Snow, G. M.
J.; Karad, S. N.; Lewis, W.; Diorazio, L. J.; Lam, H. W.
Enantioselective nickel-catalyzed intramolecular allylic alkenylations
enabled by reversible alkenylnickel E/Z isomerization. Angew. Chem.,
Int. Ed. 2017, 56, 8216−8220. (d) Karad, S. N.; Panchal, H.; Clarke,
C.; Lewis, W.; Lam, H. W. Enantioselective synthesis of chiral
cyclopent-2-enones by nickel catalyzed desymmetrization of malonate
esters. Angew. Chem., Int. Ed. 2018, 57, 9122−9125. (e) Ranjith
Kumar, G.; Kumar, R.; Rajesh, M.; Sridhar Reddy, M. A nickel-
catalyzed anti-carbometallative cyclization of alkyne-azides with
organoboronic acids: synthesis of 2,3-diarylquinolines. Chem.
Commun. 2018, 54, 759−762.
(12) There has been only one report of using highly active N-tosyl
alkynamides: Gillbard, S. M.; Chung, C.-H.; Karad, S. N.; Panchal, H.;
Lewis, W.; Lam, H. W. Synthesis of multisubstituted pyrroles by
nickel-catalyzed arylative cyclizations of N-tosyl alkynamides. Chem.
Commun. 2018, 54, 11769−11772.
(13) (a) Ping, Y.; Li, Y.; Zhu, J.; Kong, W. Construction of
quaternary stereocenters by palladium catalyzed carbopalladation-
initiated cascade reactions. Angew. Chem., Int. Ed. 2019, 58, 1562−
1573. (b) Schempp, T. T.; Daniels, B. E.; Staben, S. T.; Stivala, C. E.
A general strategy for the construction of functionalized azaindolines
via domino palladium-catalyzed Heck cyclization/Suzuki coupling.
Org. Lett. 2017, 19, 3616−3619 and references therein .
(14) CCDC 1870707 (3ka) contains supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
(7) For selected examples on stereospecific cross-electrophile
reactions, see: (a) Tollefson, E. J.; Erickson, L. W.; Jarvo, E. R.
Stereospecific intramolecular reductive cross-electrophile coupling
reactions for cyclopropane synthesis. J. Am. Chem. Soc. 2015, 137,
9760−9763. (b) Erickson, L. W.; Lucas, E. L.; Tollefson, E. J.; Jarvo,
E. R. Nickel-catalyzed cross-electrophile coupling of alkyl fluorides:
stereospecific synthesis of vinylcyclopropanes. J. Am. Chem. Soc. 2016,
138, 14006−14011. For Ni-catalyzed asymmetric reductive cross-
coupling reactions, see: (c) Cherney, A. H.; Kadunce, N. T.; Reisman,
S. E. Catalytic Asymmetric Reductive Acyl Cross-Coupling: Synthesis
of Enantioenriched Acyclic α,α-Disubstituted Ketones. J. Am. Chem.
Soc. 2013, 135, 7442−7445. (d) Cherney, A. H.; Reisman, S. E.
Nickel-Catalyzed Asymmetric Reductive Cross-Coupling Between
Vinyl and Benzyl Electrophiles. J. Am. Chem. Soc. 2014, 136, 14365−
14368. (e) Poremba, K. E.; Kadunce, N. T.; Suzuki, N.; Cherney, A.
H.; Reisman, S. E. Nickel-Catalyzed Asymmetric Reductive Cross-
Coupling To Access 1,1-Diarylalkanes. J. Am. Chem. Soc. 2017, 139,
5684−5687. (f) Kadunce, N. T.; Reisman, S. E. Nickel-Catalyzed
Asymmetric Reductive Cross-Coupling between Heteroaryl Iodides
and α-Chloronitriles. J. Am. Chem. Soc. 2015, 137, 10480−10483.
(g) Anthony, D.; Lin, Q.; Baudet, J.; Diao, T. Nickel-catalyzed
asymmetric reductive diarylation of vinylarenes. Angew. Chem., Int. Ed.
2019, 58, 3198−3202. (h) Wang, Z.; Yin, H.; Fu, G. C. Catalytic
enantioconvergent coupling of secondary and tertiary electrophiles
with olefins. Nature 2018, 563, 379−383.
(8) Wang, K.; Ding, Z.; Zhou, Z.; Kong, W. Ni-catalyzed
enantioselective reductive diarylation of activated alkenes by domino
cyclization/cross-coupling. J. Am. Chem. Soc. 2018, 140, 12364−
12368.
(15) Attempts to synthesize the corresponding Ni(II) complex using
L1 as a ligand have not been successful, probably because it is too
active and unstable.
(9) (a) Li, Y.; Wang, K.; Ping, Y.; Wang, Y.; Kong, W. Nickel-
catalyzed domino Heck cyclization/Suzuki coupling for the synthesis
of 3,3-disubstituted oxindoles. Org. Lett. 2018, 20, 921−924. (b) Yen,
A.; Lautens, M. Nickel-catalyzed intramolecular arylcyanation for the
synthesis of 3,3-disubstituted oxindoles. Org. Lett. 2018, 20, 4323−
4327. (c) Yoon, H.; Marchese, A. D.; Lautens, M. Carboiodination
catalyzed by nickel. J. Am. Chem. Soc. 2018, 140, 10950−10954.
(10) For selected reviews on Ni-catalyzed cyclization of alkynes, see:
(a) Ojima, I.; Tzamarioudaki, M.; Li, Z.; Donovan, R. J. Transition
metal-catalyzed carbocyclizations in organic synthesis. Chem. Rev.
1996, 96, 635−662. (b) Saito, S.; Yamamoto, Y. Recent advances in
the transition-metal-catalyzed regioselective approaches to polysub-
stituted benzene derivatives. Chem. Rev. 2000, 100, 2901−2916.
(c) Montgomery, J. Nickel-catalyzed cyclizations, couplings, and
cycloadditions involving three reactive components. Acc. Chem. Res.
2000, 33, 467−473. (d) Montgomery, J. Nickel-catalyzed reductive
cyclizations and couplings. Angew. Chem., Int. Ed. 2004, 43, 3890−
3908. (e) Moslin, R. M.; Miller-Moslin, K.; Jamison, T. F.
Regioselectivity and enantioselectivity in nickel-catalysed reductive
coupling reactions of alkynes. Chem. Commun. 2007, 4441−4449.
(f) Nakao, Y.; Hiyama, T. Nickel-catalyzed carbocyanation of alkynes.
Pure Appl. Chem. 2008, 80, 1097−1107. (g) Jeganmohan, M.; Cheng,
C.-H. Cobalt- and nickel-catalyzed regio- and stereoselective reductive
coupling of alkynes, allenes, and alkenes with alkenes. Chem. - Eur. J.
2008, 14, 10876−10886. (h) Malik, H. A.; Baxter, R. D.;
Montgomery, J. Nickel-Catalyzed Reductive Couplings and Cycliza-
tions. In Catalysis without Precious Metals, 1st ed.; Bullock, R. M., Ed.
Wiley-VCH: Weinheim, Germany, 2010; pp 181−210. (i) Jackson, E.
P.; Malik, H. A.; Sormunen, G. J.; Baxter, R. D.; Liu, P.; Wang, H.;
Shareef, A.-R.; Montgomery, J. Mechanistic basis for regioselection
and regio divergence in nickel-catalyzed reductive couplings. Acc.
Chem. Res. 2015, 48, 1736−1745. (j) Standley, E. A.; Tasker, S. Z.;
Jensen, K. L.; Jamison, T. F. Nickel catalysis: synergy between method
development and total synthesis. Acc. Chem. Res. 2015, 48, 1503−
1514.
(16) The σ-alkyl-NiII complex 6 could be formed at room
temperature, but no target product was detected in the catalytic
reaction at room temperature, indicating that the intramolecular
carbonickelation of alkene is not the turnover-limiting step.
(17) Martínez, A.; Webber, M. J.; Muller, S.; List, B. Versatile access
̈
to chiral indolines by catalytic asymmetric Fischer indolization.
Angew. Chem., Int. Ed. 2013, 52, 9486−9490.
(18) CCDC 1878651 (8aa) contains supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre.
(19) CCDC 1912176 ((3R,8S)-8aa) contains supplementary
crystallographic data for this paper. These data can be obtained free
of charge from The Cambridge Crystallographic Data Centre.
(11) For select examples of Ni-catalyzed cyclization of alkynyl
electrophiles, see: (a) Clarke, C.; Incerti-Pradillos, C. A.; Lam, H. W.
7342
DOI: 10.1021/acscatal.9b02081
ACS Catal. 2019, 9, 7335−7342