An imidazoline-aminophenol (IAP) nickel catalyst: Structure and catalytic activity in the enantioselective 1,4-addition of 3′-indolyl-3-oxindoles to nitroethylene

Article abstract of DOI:10.1002/chem.201304456

The structure of a nickel complex of imidazoline-aminophenol (IAP) prepared from IAP with Ni(OAc)₂ was elucidated as cis- bis(imidazolineaminophenoxide) [Ni(IAP)₂]. The [Ni(IAP)₂] complex smoothly promoted catalytic asymmetric 1,4-addition of 3′-indolyl-3-oxindole to nitroethylene to provide chiral mixed 3,3′-bisindoles with high enantioselectivities. Mechanistic studies using ESI-MS analyses suggest that one IAP ligand dissociated from [Ni(IAP) ₂] to generate the Ni-enolate of 3′-indolyl-3-oxindole. From the optically active 3,3′-mixed indole adduct, biologically important 3′-indolyl-3-pyrrolidinoindoline was successfully synthesized in a three-step reaction sequence. Copyright

Full text of DOI:10.1002/chem.201304456

DOI: 10.1002/chem.201304456
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&
Asymmetric Catalysis
An Imidazoline–Aminophenol (IAP) Nickel Catalyst: Structure
and Catalytic Activity in the Enantioselective 1,4-Addition of
3’-Indolyl-3-Oxindoles to Nitroethylene
Atsuko Awata,[a] Makiko Wasai,[a] Hyuma Masu,[b] Sayaka Kado,[b] and Takayoshi Arai*[a]
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Abstract: The structure of a nickel complex of imidazoline–
aminophenol (IAP) prepared from IAP with Ni(OAc)2 was elu-
cidated as cis-bis(imidazolineaminophenoxide) [Ni(IAP)2]. The
[Ni(IAP)2] complex smoothly promoted catalytic asymmetric
1,4-addition of 3’-indolyl-3-oxindole to nitroethylene to pro-
vide chiral mixed 3,3’-bisindoles with high enantioselectivi-
ties. Mechanistic studies using ESI-MS analyses suggest that
one IAP ligand dissociated from [Ni(IAP)2] to generate the
Ni–enolate of 3’-indolyl-3-oxindole. From the optically active
3,3’-mixed indole adduct, biologically important 3’-indolyl-3-
pyrrolidinoindoline was successfully synthesized in a three-
step reaction sequence.
Introduction
The 3,3’-bisindole skeleton is found in a large number of
natural products with bioactivity that makes it a candidate for
pharmaceutical drugs.[3] For example, gliocladin C and lepto-
sin D possess cytotoxicity against P-388 lymphocytic leukemia
cell lines (Figure 2).[4,5] Elegant synthetic methods have been
Numerous chiral ligands have been developed for conducting
highly stereoselective asymmetric reactions. Although C2 sym-
metry has been used to design privileged chiral ligands,[1] C1-
symmetric chiral ligands potentially offer a wide variety of
structural variations and properties that allow new approaches
to enantioselective reactions. New C1-symmetric imidazoline–
aminophenol (IAP; Figure 1) ligand–metal catalysts have been
Figure 1. Imidazoline-aminophenol (IAP) ligand.
developed by using solid-phase catalysis/CD-HTS (CD=circular
dichroism; HTS: high-throughput screening).
IAP was an efficient ligand for stereoselective copper-cata-
lyzed Friedel–Crafts[2a–c,e] and Henry reactions,[2a,b] and its nickel
catalyst promoted exo’-selective [3+2] cycloaddition of nitro-
alkene with iminoester.[2d] The tandem Friedel–Crafts/Henry
(FCH) reaction[2b] and exo’-selective [3+2] cycloaddition[2d] were
reactions that were made possible for the first time by using
IAP. However, the catalyst structure, which is essential for un-
derstanding the mechanism and design of new reactions, re-
mained unknown. Here, the structure of the Ni–IAP complex
was elucidated by using single-crystal X-ray diffraction analysis,
and the Ni–IAP catalyst was applied to enantioselective 1,4-ad-
dition of 3’-indolyl-3-oxindole to nitroethylene to give optically
active 3,3’-mixed indoles useful for the asymmetric synthesis of
3’-indolyl-3-pyrrolidinoindoline.
Figure 2. Examples of chiral indole-containing pyrrolidinoindolines.
examined in the total synthesis of 3,3’-bisindole alkaloids.[6,7]
For chimonanthine, the pioneering work is Overman’s enantio-
selective total synthesis that relies on two intramolecular Heck
reactions to secure the vicinal quaternary stereocenters.[7d] The
synthesis of (+)-chimonanthine by the Movassaghi group
made use of their innovative cobalt(I)-promoted reductive di-
merization for constructing the biscyclotriptamine structure.[7f]
Recently, Stephenson developed a visible-light photoredox cat-
alytic unsymmetrical coupling of pyrrolidinoindolines with in-
doles for the total synthesis of (+)-gliocladin C.[7g]
[a] A. Awata, M. Wasai, Prof. Dr. T. Arai
Department of Chemistry, Graduate School of Science
Chiba University, Inage, Chiba 263-8522 (Japan)
Fax: (+81)43-290-2889
E-mail: tarai@faculty.chiba-u.jp
[b] Prof. Dr. H. Masu, S. Kado
Center for Analytical Instrumentation, Chiba University
Inage, Chiba 263-8522 (Japan)
In addition to these syntheses, several approaches for cata-
lytic asymmetric synthesis of 3’-indolyl-3-pyrrolidinoindoline
compounds have been reported. Overman et al. reported the
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304456.
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catalytic enantioselective acylation of bisindole substrates,
which was used for the total synthesis of (+)-gliocladine C.[8]
Trost et al. described the palladium-catalyzed asymmetric reac-
tion of 3’-indolyl-3-oxindole with allenes, and converted the
3,3-disubstituted oxindole products to a pyrrolidinoindoline
core by means of a hydrocarbonation reaction.[9] Gong et al.
also reported the total synthesis of (+)-gliocladine C using
a catalytic asymmetric alkylation reaction of indole-containing
3-hydroxyoxindoles.[10,11] Taking account of the importance of
the natural-product-like mixed 3,3’-bisindoles and 3’-indolyl-3-
pyrrolidinoindolines in pharmaceutical science, the develop-
ment of divergent catalytic asymmetric approaches for these
skeletons are in demand.
Results and Discussion
In a previous study of Ni–IAP-catalyzed asymmetric reactions,
the catalyst was typically prepared in a IAP/Ni(OAc)2 ratio of
1.1:1.[2d,f] Because the catalyst prepared in this ratio showed
a reasonable high level of asymmetric induction for the exo’-
selective [3+2] cycloaddition using iminoesters in comparison
to results using the catalyst prepared in a IAP1/Ni(OAc)2 (see
Figure 1 for structure of IAP1) ratio of 2:1, we initially assumed
the catalyst would be composed in the ratio of 1:1. However,
when the catalyst solution was prepared in the ratio of 1:1,
fine crystals suitable for X-ray crystallography were difficult to
obtain due to the high solubility of the metal complex. The
ESI-MS analysis of the 1:1 catalyst solution produced a signal
at 1599.0798 corresponding to [Ni(IAP1)2 +H]+, suggesting the
existence of an IAP/Ni(OAc)2 =2:1 complex, in addition to
a peak at 1715.0192 for the 1:1 [Ni(IAP1)] complex (see the
Supporting Information).
Structure of the Ni–IAP complex
Figure 3. IAP2-nickel 2:1 complex: A) front view; B) back view; C) side view.
Compared with IAP1, IAP2 (Figure 1) has a nitro group in
phenol ring and its nickel complex is more crystalline. Based
on the ESI-MS results, fine crystals for the X-ray diffraction anal-
ysis were obtained from the mixture of IAP2/Ni(OAc)2 =2:1 in
CH2Cl2/MeOH (Figure 3). The X-ray analysis revealed that two
acetate anions of the nickel salt were exchanged with phenox-
ide anions, resulting in a IAP2/Ni ratio of 2:1. In this solvent
system, the same crystals were formed even when one equiva-
lent of IAP2 was mixed with one equivalent of Ni(OAc)2. As
shown in Figure 3, tridentate IAP ligands generate a slightly
distorted octahedral geometry around the nickel center. Inter-
estingly, the imidazoline is located cis to another imidazoline.
When four nitrogen atoms set on the horizontal coordination
plane, the two phenoxides are perpendicular. Bond length cor-
relation revealed that ionic bonding of NiÀO (2.027 ꢁ) is short-
er than the coordination bonds of NiÀN. The interaction of the
tertiary amines with nickel (2.445 ꢁ) is weaker than the coordi-
nation of the imidazolines to nickel (2.088 ꢁ). The face-to-face
packing of the two sets of phenyl rings on the imidazoline
rings enforce the unique cis-complex formation.
Catalytic asymmetric 1,4-addition of 3’-indolyl-3-oxindole
with nitroethylene
The catalytic asymmetric conjugate addition of nitroalkene
with 3-substituted oxindole is a powerful tool for enantioselec-
tive preparation of pyrrolidinoindoline.[12–16] In the seminal
work on the asymmetric 1,4-addition of 3-aryl or 3-alkyl oxin-
dole with nitroalkene, Barbas and Shibasaki independently re-
ported the enantioselective reaction using either a thiourea or
a homodinuclear MnIII Schiff base catalyst, respectively.[12a,b]
2
Maruoka et al. also reported the enantioselective base-free
phase-transfer catalyzed 1,4-addition of 3’-phenyl oxindole in
a water-rich solvent.[12c] Kanai and Matsunaga et al. reported
the total synthesis of folicanthine and calycanthine using enan-
tioselective double Michael addition of bisoxindole as the key
step.[16] Despite these advances, the conjugate addition of 3’-
indolyl-3-oxindole with nitroethylene, which would enable
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Table 1. Optimization of reaction conditions.
Table 2. Substrate scope.
Ligand
X
Y
t
[h]
Yield
[%]
ee
[%]
1
IAP2
IAP2
IAP1
IAP2
IAP1
IAP1
IAP1
21
21
21
11
11
11
11
10
10
10
10
10
5
3
3
3
3
3
89
92
85
92
86
87
95
81
82
86
80
83
85
90
2[a]
3
4
5
6
7[b]
4
20
5
[a] Reaction using pure, isolated [Ni(IAP2)2] complex (Supporting Informa-
tion). [b] Reaction was performed in o-xylene at À208C, and nitroethylene
(2) was slowly added over 5 h.
rapid access to indole-containing pyrrolidinoindoline, was not
investigated.
Initially, to achieve the catalytic asymmetric synthesis of
mixed 3,3’-bisindoles, the IAP2–nickel complex prepared from
IAP2 and Ni(OAc)2, in a ratio of 2.1:1, was used in the reaction
of Boc-protected (Boc=tert-butoxycarbonyl) 3’-indolyl-3-oxin-
dole (1a) with nitroethylene (2; Table 1). With assistance of
1,1,1,3,3,3-hexafluoro-2-propanol (HFIP), [Ni(IAP2)2] smoothly
catalyzed the desired 1,4-addition reaction in PhMe at 08C in
3 h to give chiral 3’-indolyl-3-oxindole 3a containing an all-
carbon quaternary center in 89% yield with 81% ee (entry 1).
The isolated crystalline [Ni(IAP2)2] possessed similar catalytic
activity and yielded 3a in 92% yield with 82% ee (entry 2). The
more basic [Ni(IAP1)2] catalyst improved the stereoselectivity of
3a to 86% ee (entry 3). In entries 4 and 5, catalysts prepared
from IAP2 and Ni(OAc)2 in 1.1:1 ratio were examined. Com-
pound 1a was smoothly consumed within 3 h, but yielded 3a
with slightly lower enantioselectivity. In the [Ni(IAP1)2]-cata-
lyzed reaction (entry 6), the catalyst loading was reduced to
5 mol% to obtain results similar to those of entry 3. With
5 mol% of the [Ni(IAP1)2] catalyst prepared in situ, reaction
conditions were further optimized (see details of optimization
in the Supporting Information.) Using PhMe as the solvent, re-
action at À208C gave 3a in 82% yield (6 h) with 87% ee, al-
though reaction at À408C resulted in low conversion. Solvent
screening revealed that the use of o-xylene provided 3a with
90% ee at À208C, although the yield decreased to 67% in
20 h due to the polymerization of nitroethylene (2). Slow addi-
tion of 2 was used to improve the yield of 3a to 95% with
90% ee (entry 7).
[a] Enantiomeric excess (ee) after a single recrystallization from CH2Cl2/
MeOH (48% yield).
methyl-substituted substrate afforded the desired product
with a slightly reduced enantioselectivity (3h). The N-methoxy
carbonyl and Cbz-protected substrates were also successfully
converted into 3i and 3j, respectively. Nevertheless, the non-
protected substrate (R2 =H) and N-acetyl substrates (R2 =Ac)
on the oxindole site resulted in no reaction. The highly crystal-
line nature of the chiral mixed 3,3’-bisindoles 3 enriched the
optical purity of 3m to 99% ee by a single recrystallization
from CH2Cl2/MeOH (48% yield). X-ray crystallographic analysis
of 3m revealed an (S)-configuration at the C3 position. The 7’-
methyl substrate gave 3o with excellent enantioselectivity (up
to 95% ee). In addition, enantioselective 1,4-addition proceed-
ed well for the 7’-chloro- and iodo-substrates (3p and 3q, re-
spectively). For the R4-substituent on the indole site, the non-
protected (R4 =H) and N-Boc substrate (R4 =Boc) also provided
highly optically active mixed 3,3’-bisindoles (3r, 3s). Notably,
not only the 3’-indolyl-3-oxindoles, but also the oxindole with
Under optimal conditions, the scope and limitations of enan-
tioselective 1,4-addition of 3’-indolyl-3-oxindole to nitroethyl-
ene (2) were examined in Table 2. The 3’-indolyl-3-oxindoles
containing various substituents at the 5- and 6-positions of the
oxindole ring reacted smoothly with 2 to yield products with
good-to-excellent enantioselectivies (3b–g). The 7-trifluoro-
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an ethyl pyrrole at the 3-position were effectively converted
into the corresponding 1,4-addition product with 84% ee (3t).
Since the nitro group introduced in the chiral mixed 3,3’-bis-
indoles 3 can undergo subsequent transformations, a construc-
tion of chiral indole-containing cyclotryptamine motif was ex-
amined for demonstrating the synthetic utility of reaction
product 3a (Scheme 1). After removal of the Boc-protecting
group with trifluoroacetic acid (TFA), the nitro group was re-
Scheme 1. Chemical transformation of the 1,4-adduct 3a.
duced by NiCl2·6H2O/NaBH4. Subsequent reaction with
(MeO2C)2O cleanly provided the corresponding carbamate.[16]
Finally, reductive amination of the carbamate using LiAlH4 in
THF cyclized to give pyrrolidinoindoline 4a.[12a] This three-step
transformation gave 4a in 59% yield, while maintaining enan-
tioselectivity. The short synthetic strategy described in
Scheme 1 is readily adaptable for providing biologically impor-
tant chiral 3-indolyl cyclotryptamine compounds.
Mechanistic study for the [Ni(IAP)2] catalyzed reaction
As shown in entry 2 in Table 1, the pure, isolated [Ni(IAP2)2]
complex exhibited catalytic activity in 1,4-addition reactions.
However, all the coordination sites of [Ni(IAP)2] are filled, mean-
ing the complex cannot accommodate substrate activation.
One possibility as to how the [Ni(IAP)2] acts as the catalyst is
that [Ni(IAP)2] releases one IAP ligand to allow the replacement
with substrate. The other is that [Ni(IAP)2] partially dissociates
to activate the substrate. To gain insight into the behavior of
[Ni(IAP)2] in asymmetric catalysis, a series of ESI-MS analyses
was conducted (Figure 4).[17]
In the ESI-MS spectra of [Ni(IAP1)2] in PhMe, an ion peak at
m/z 1599.0795 was observed corresponding to [(IAP1/Ni=
2:1)+H]+ (Figure 4A). Other ion peaks at m/z 828.0031 and
1715.0190 were assigned to [IAP1/Ni=1:1]+ and [2ꢂ(IAP1/Ni=
1:1)+OAc]+, respectively. Although the ion peak for [(IAP1/
Ni=2:1)+H]+ was detected in the IAP1/Ni(OAc)2 =1:1 solution
(Supporting Information), its intensity increased when the
IAP1/Ni(OAc)2 complex was prepared in a ratio of 2:1. A solu-
tion of [Ni(IAP2)2] crystals in PhMe also provided a strong ion
peak at m/z 1533.2301 assigned to [(IAP2/Ni=2:1)+H]+.[18]
When two equivalents of 3’-indolyl-3-oxindole 1a were
added to a solution of [Ni(IAP1)2] in PhMe, the [(IAP1/Ni=
2:1)+H]+ ion peak decreased, and a new ion peak m/z
1190.1687 appeared, which corresponded to [(IAP1/Ni=1:1)+
1a ]+ (Figure 4B). No ion peak over m/z 1800, which corre-
sponds to [(IAP1/Ni=2:1)+1a]+ (calcd m/z 1960.2359) was
Figure 4. ESI-MS analysis of catalytic course. A) IAP1/Ni=2:1 solution.
B) IAP1/Ni=2:1 complex+1a (2 equiv). C) Reaction mixture after comple-
tion of 1,4-addition.
found. Although we cannot discount the formation of [(IAP1/
Ni=2:1)+1a]+, the detection of [(IAP1/Ni=1:1)+1a]+ sug-
gested replacement of one IAP1 on the Ni catalyst with 1a.[19a]
In addition, formation of [(IAP1/Ni=1:1)+1a]+ indicates that
1a binds to the IAP1/Ni=1:1 complex in the enolate form,
which suggests that [Ni(IAP1)2] acts as a basic catalyst. No ion
peak corresponding to [(IAP1/Ni=1:1)+nitroalkene]+ was ob-
served, when two equivalents of nitroethylene (2a) or trans-b-
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nitrostyrene were added to the [Ni(IAP1)2] catalyst.[18] In addi-
tion, ESI-MS analysis of the reaction mixture after completion
of the 1,4-addition reaction involving 1a and 2a (Figure 4C)
resulted in a new ion peak at m/z 1263.1838, which was as-
signed to [(IAP1/Ni=1:1)+3a ]+ while the ion peak [(IAP1/
,
Ni=2:1)+H]+ decreased.
Working model of Ni–IAP-catalyzed asymmetric 1,4-addition
Based on the ESI-MS analysis and the relation between catalyst
efficiency and the IAP to Ni(OAc)2 ratio, a plausible reaction
mechanism for asymmetric 1,4-addition of 3’-indolyl-3-oxindole
with nitroethylene promoted by [Ni(IAP1)2] is summarized in
Scheme 2. The [Ni(IAP1)2] complex is formed by reaction of
Figure 5. Proposed model for enantioface selection in IAP1-Ni catalyzed 1,4-
addition of 3’-indolyl-3-oxindole. For explanations of A)–C), see text.
On the basis of these experimental results and previous re-
ports on chiral NiII complexes,[19] the plausible binding orienta-
tions are proposed in Figure 5. The metal-bound enolate of 1a
normally would have a planar structure, with the benzene
rings of both indole and oxindole in 1a facing in opposite di-
rections. The nickel-bound enolate of the oxindole 1a avoids
unfavorable steric repulsion between the indolyl group and
phenyl ring on the imidazoline of IAP1, observed in Figure 5B,
which enforces formation of the stable structure shown in Fig-
ure 5A. Thus, the nitroethylene (2) is expected to approach
from the open bottom side, because the bromine atom on the
phenoxy ring shields approach from the upper side (Fig-
ure 5C). The molecular arrangement depicted in Figure 5C re-
sults in reaction of 2 to the Re-face of 3’-indolyl-3-oxindole 1a
to provide the chiral mixed 3,3’-bisindole 3a with the appropri-
ate (S)-configuration.
Scheme 2. Plausible catalytic cycle promoted by the [Ni(IAP1)2] complex.
Ni(OAc)2 with two equivalents of IAP1. The [Ni(IAP1)2] complex
acts as a base to generate the enolate of 3’-indolyl-3-oxindole
1a. Although this type of dynamic ligand exchange seems un-
likely, this process is supported by the ESI-MS analysis shown
in Figure 4B and the following experiment. The complexes
[Ni(IAP1)2] and [Ni(IAP2)2] were independently prepared, and
mixed in one flask. After stirring for 24 h, ESI-MS analysis of the
resulting mixture contained a new ion peak at m/z=1566.1505
(C76H69Br3N7NiO8S2), corresponding to [IAP1+IAP2+Ni+H]+.
This ESI-MS study suggests the formation of [Ni(IAP1)2] com-
plex that allows a reversible process for the exchange of IAP1
and 1a. Then, 1,4-addition to nitroethylene (2) occurs in the re-
action sphere produced by the Ni–IAP1 complex to give the
zwitter ionic complex of [Ni(IAP1)(3a)]. Ligand exchange be-
tween the anion of 3a with 1a gives the chiral mixed 3,3’-bis-
indole 3a with regeneration of the enolate. The elimination of
IAP1, generated in the exchange with 1a, contributes to the
stabilization of the catalytically active Ni–IAP1 species.
Conclusion
In summary, the structure of the [Ni(IAP)2] complex was un-
equivocally determined by single-crystal X-ray crystallography,
and the [Ni(IAP)2] complex was applied to the catalytic asym-
metric 1,4-addition of 3’-indolyl-3-oxindole to nitroethylene.
The success of catalytic asymmetric formation of the chiral
mixed 3,3’-bisindole 3 provides a new method for the efficient
synthesis of distinctive indole-containing pyrrolidinoindolines.
The [Ni(IAP)2] complex acts as a Brønsted base, and catalytic
asymmetric 1,4-addition proceeded via the enolate of 3’-indol-
yl-3-oxindole 1, which was obtained by a dynamic ligand-ex-
changing process. Detailed mechanistic studies into the stereo-
selectivity and application to other asymmetric transformations
are ongoing.
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General procedure for chemical transformation of 1,4-
adduct 3a in Scheme 1
Experimental Section
General procedure for the catalytic asymmetric 1,4-addition
Deprotection of 3a: TFA (2 mL) was added to a solution of 3a
(138 mg, 0.380 mmol, 90% ee) in chloroform (2 mL). After stirring
for 1 h at 408C, the reaction mixture was concentrated under re-
duced pressure and azeotroped with PhMe (1.0 mL). Short silica
gel column chromatography (n-hexane/AcOEt=2:1) gave the
product as white solid (134 mg, obtained as mixture with small
amount of side product). Rf =0.21 (n-hexane/AcOEt=2:1).
of 3’-indolyl-3-oxindole with nitroethylene (Table 2)
IAP1 (0.0165 mmol) and Ni(OAc)2·4H2O (0.0075 mmol) were added
to a two-necked round flask containing a stir bar under Ar. MeOH
(1.5 mL) was added to the flask and the mixture was stirred for 3 h.
After removal of the solvent under reduced pressure, o-xylene
(1.5 mL) was added. To the resulting solution, 3’-indolyl-3-oxindole
(0.150 mmol) and HFIP (0.300 mmol) were added subsequently at
room temperature, then nitroethylene (0.300 mmol) was slowly
added over 5 h at À208C. After being stirred for appropriate time,
the crude mixture was directly subjected to flash silica gel column
chromatography to afford the 1,4-adduct. The enantiomeric excess-
es of the products were determined by chiral stationary phase
HPLC using a Daicel Chiralcel OD-H, Chiralpak AD-H, IA, and Chiral-
pak IC-3 column.
Reduction of nitro group and conversion to the methyl carba-
mate: The method described in reference [16] was slightly modi-
fied. NaBH4 (359 mg, 9.5 mmol) was added in one portion to
a
stirred solution of the deprotected 1,4-adduct (134 mg,
<0.380 mmol) and NiCl2·6H2O (270 mg, 1.14 mmol) in MeOH
(5 mL) and dimethyl dicarbonate (5 mL) at 08C. After being stirred
at 08C for 12 h, the reaction mixture was quenched by an addition
of saturated NH4Cl aqueous solution (10 mL). The organic layer was
extracted with AcOEt (20 ꢂ3), and the combined organic layers
were dried over anhydrous Na2SO4. After removal of Na2SO4 by a fil-
tration, the solution was concentrated under reduced pressure.
Short silica gel column chromatography (n-hexane/AcOEt=2:3)
gave the methyl carbamate as white solid (114 mg, obtained as
mixture with small amount side product). Rf =0.22 (n-hexane/
AcOEt=2:3).
General procedure for the catalytic asymmetric 1,4-addition
of 3’-indolyl-3-oxindole with nitroethylene using purely iso-
lated crystalline [Ni(IAP2)2] complex. (entry 2 in Table 1)
IAP2 (0.075 mmol) and Ni(OAc)2·4H2O (0.0375 mmol) were added
to a round flask containing a stir bar under Ar. MeOH (3.75 mL)
was added to the flask and the mixture was stirred for 3 h. The sol-
vent was removed under reduced pressure. After dissolving the
solid in CH2Cl2 (500 mL), MeOH (3 mL) was added for recrystalliza-
tion. The yellow crystals that formed at room temperature after
standing 2 days, were collected by suction, washed with MeOH
(1 mL) and dried in vacuo to yield [Ni(IAP2)2] (20.5 mg, 36%).
Reductive cyclization using LiAlH4: LiAlH4 (2.0m in THF, 783 mL,
1.57 mmol) was added to a stirred solution of the methyl carba-
mate (114 mg, <0.313 mmol) in THF (7.8 mL) at room temperature.
After being stirred at 608C for 3 h, the reaction mixture was diluted
by AcOEt (16 mL) and quenched by saturated NaHCO3 aqueous so-
lution (16 mL). The organic layer was extracted with AcOEt
(10 mLꢂ2), and the combined organic layers were dried over anhy-
drous Na2SO4. After removal of Na2SO4 by a filtration, the solution
was concentrated under reduced pressure. Neutral silica gel
column chromatography (CHCl3/MeOH=20:1) gave the product as
white solid (68.4 mg, 0.225 mmol, three steps 59% yield). Rf =0.29
(CHCl3:MeOH=15:1). 1H NMR (500 MHz, CDCl3): d=7.45 (d, J=
8.0 Hz, 1H), 7.26 (d, J=6.9 Hz, 1H), 7.18 (dd, J=8.0, 7.2 Hz, 1H),
7.09–7.06 (m, 2H), 7.00 (dd, J=8.0, 6.9 Hz, 1H), 6.84 (s, 1H), 6.72–
6.68 (m, 2H), 4.90 (s, 1H), 4.31 (br, 1H), 3.70 (s, 3H), 2.98–2.95 (m,
1H), 2.94–2.86 (m, 1H), 2.84–2.77 (m,1H), 2.49 (s, 3H), 2.31–
2.27 ppm (m, 1H); 13C NMR (125 MHz, CDCl3) d=149.9, 137.9,
135.3, 127.7, 126.4, 126.1, 124.5, 121.5, 120.3, 119.8, 118.8, 118.7,
109.3, 109.0, 89.0, 56.9, 52.3, 39.2, 36.8, 32.5 ppm; HRMS: m/z calcd
for C20H22N3 [M+H]+: 304.1808, found: 304.1807; enantiomeric
excess was determined by HPLC with a Chiralcel OD-H column
(70:30 hexane/2-propanol, 1.0 mLminÀ1, 254 nm); major enantio-
mer tr =5.3 min, minor enantiomer tr =21.1 min; [a]2D1 = +20.3 (c=
1.0 in CHCl3, 92% ee).
After dissolving the crystalline [Ni(IAP2)2] (20.5 mg) in CH2Cl2
(1.3 mL), the solvent was removed under reduced pressure to form
the amorphous solid, and the solid was dissolved in PhMe (1.3 mL).
3’-Indolyl-3-oxindole (0.134 mmol) and HFIP (0.268 mmol) were
added subsequently to this solution at room temperature. Then,
nitroethylene (0.268 mmol) was slowly added at 08C. After being
stirred for 3 h, the crude mixture was directly subjected to flash
silica gel column chromatography to afford the 1,4-adduct 3a. The
enantiomeric excess of 3a was determined by chiral stationary
phase HPLC using a Daicel Chiralpak IC-3 column.
tert-Butyl (S)-3-(1-methyl-1H-indol-3-yl)-3-(2-nitroethyl)-2-
oxoindoline-1-carboxylate (3a in Table 2)
According to the general procedure, compound 3a was obtained
by silica gel column chromatography (n-hexane/AcOEt=5:1) as
a white solid. Rf =0.21 (n-hexane/AcOEt=5:1); 1H NMR (500 MHz,
CDCl3) d=8.00 (d, J=8.3 Hz, 1H), 7.44–7.40 (m, 1H), 7.32–7.18 (m,
5H), 7.04–7.01 (m, 1H), 6.86 (s, 1H), 4.40 (ddd, J=5.4, 10.9, 13.6 Hz,
1H), 4.24 (ddd, J=5.4, 10.6, 13.6 Hz, 1H), 3.72 (s, 3H), 3.33 (ddd,
J=5.4, 10.6, 13.9 Hz, 1H), 3.02 (ddd, J=5.4, 10.9, 13.9 Hz, 1H),
1.62 ppm (s, 9H); 13C NMR (100 MHz, CDCl3) d=175.3, 149.1, 139.4,
137.6, 129.3 (2C), 127.8, 125.3, 125.0, 124.2, 122.2, 1204, 119.8,
115.6, 111.8, 109.7, 84.7, 71.3, 50.8, 33.6, 32.9, 28.0 ppm; HRMS: m/z
calcd for C24H25N3O5Na [M+Na]+: 458.1686, found: 458.1680; enan-
tiomeric excess was determined by HPLC with a Chiralpak IC-3
column (80:20 hexane: 2-propanol, 1.0 mLminÀ1, 254 nm); major
Acknowledgements
This work was supported by a Grant-in Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology (Japan), and by the Workshop on Chirality in
Chiba University (WCCU).
Keywords: asymmetric catalysis · indole 1,4-addition · nickel ·
tridentate ligands
enantiomer tr =13.9 min, minor enantiomer tr =17.2 min; [a]D21
=
À140.1 (c=1.0 in CHCl3, 90% ee); IR (neat): n˜2980, 1764, 1727,
1552, 1287, 1249, 1146, 738 cmÀ1
.
Chem. Eur. J. 2014, 20, 2470 – 2477
www.chemeurj.org
2476
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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Received: November 14, 2013
Chem. Eur. J. 2014, 20, 2470 – 2477
www.chemeurj.org
2477
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim