Nickel(II)-Catalyzed Asymmetric Michael Addition of Oxindoles with Modified N,N,O-Tridentate Chiral Phenanthroline Ligands

Article abstract of DOI:10.1055/s-0035-1561630

Nickel(II)-catalyzed enantioselective Michael addition of N-Boc-oxindole derivatives with methyl vinyl ketone was demonstrated to give the corresponding adducts having chiral all-carbon quaternary centers with up to 87% ee in the presence of axially chira

Full text of DOI:10.1055/s-0035-1561630

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
Y. Naganawa et al.
Letter
Synlett
Nickel(II)-Catalyzed Asymmetric Michael Addition of Oxindoles
with Modified N,N,O-Tridentate Chiral Phenanthroline Ligands
Yuki Naganawa*
O
Ni(OAc)2 (10 mol%)
(S)-1c (12 mol%)
MVK (3.0 equiv)
Hiroki Abe
Ar
Me
X
N
Hisao Nishiyama*
X
N
Ar
OH
Ph
O
CH2Cl2, 25 °C, 18 h
N
Department of Applied Chemistry, Graduate School of
Engineering, Nagoya University, Chikusa, Nagoya
464-8603, Japan
O
Ph
Boc
up to 87% ee
N
Boc
e-mail_yuki.n@apchem.nagoya-u.ac.jp
hnishi@apchem.nagoya-u.ac.jp
Received: 03.03.2016
Accepted after revision: 04.04.2016
Published online: 10.05.2016
structures. Maruoka reported the pioneering study on the
enantioselective Michael addition of oxindole derivatives
under phase-transfer conditions.6 Several organocatalysts7
were designed for this kind of transformations as well as
chiral calcium catalysts.8 Therefore, the development of
new catalytic systems for enantioselective Michael addition
of oxindole derivatives is highly demanding.9
DOI: 10.1055/s-0035-1561630; Art ID: st-2016-u0151-l
Abstract Nickel(II)-catalyzed enantioselective Michael addition of N-
Boc-oxindole derivatives with methyl vinyl ketone was demonstrated to
give the corresponding adducts having chiral all-carbon quaternary
centers with up to 87% ee in the presence of axially chiral N,N,O-triden-
tate phenanthroline ligand.
Key words asymmetric synthesis, nickel, oxindole, Michael addition,
phenanthroline
N
R = Ph, R' = H (1a)
R = 3,5-xylyl, R' = H (1b)
R = Ph, R' = Ph (1c)
N
OH
R
R'
The catalytic asymmetric construction of chiral all-car-
bon quaternary centers has gained much attention in syn-
thetic organic chemistry.1 Optically active oxindole back-
bones having chiral all-carbon quaternary centers at the 3-
positions occupy ubiquitous structures seen in a broad
range of natural alkaloids2 such as horsfiline,3 coerules-
cine,3 spirotryprostatin A,4 and welwitndolinone A5 as ex-
emplified in Figure 1.
(S)-1
Previous work
Ar
Cu(OAc)2 (5 mol%)
(S)-1b (5.5 mol%)
HO
Ar
X
X
Davis' oxaziridine (1.2 equiv)
O
O
Et2O, 25 °C, 24 h
N
N
Boc
Boc
2
(R)-3
This work
H
N
Cl
O
O
Me
O
O
Ni(OAc)2 (10 mol%)
(S)-1c (12 mol%)
MVK (3.0 equiv)
N
N
Ar
Me
H
Me
NC
H
X
Ar
R
X
O
CH2Cl2, 25 °C, 18 h
O
N
O
NH
Boc
O
N
N
H
N
Boc
2
H
MeO
spirotryprostatin A
(R)-4
horsfiline (R = OMe)
coerulescine (R = H)
welwitindolinone A
Scheme 1 N,N,O-tridentate chiral phenanthroline ligand (S)-1
Figure 1 Selected examples of natural compounds having oxindole
backbones with all-carbon quaternary centers at the 3-positions
During the course of our study on the application of the
axially chiral, N,N,O-tridentate phenanthroline ligand (S)-
1,10 we demonstrated copper(II)-catalyzed enantioselective
Davis oxidation of N-Boc-3-aryloxindoles (2, Scheme 1).10d
In the presence of a copper(II) complex of (S)-1b prepared
Catalytic asymmetric Michael addition of 3-substituted
oxindole derivatives to α,β-unsaturated carbonyl com-
pounds is one of the most powerful ways to obtain these
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
Y. Naganawa et al.
Letter
Synlett
from copper(II) acetate monohydrate, asymmetric oxygen-
atom transfer of 2 using Davis’ oxaziridine occurred to give
the corresponding 3-aryl-3-hydroxy-2-oxindole derivatives
(R)-3 with high enantioselectivity. Our mechanistic study
suggests that the asymmetric induction of this hydroxyl-
ation reaction should be controlled by the effective shield-
ing of prochiral copper(II) enolate surrounding chiral ligand
(S)-1b. Based on this consideration, we envisioned that the
present catalytic system can be further extended to the use
of other electrophiles. We report the results on the devel-
opment of enantioselective Michael addition of oxindole
derivatives 2 to methyl vinyl ketone (MVK).
tioselectivity. For example, the use of Ni(acac)2, Ni(ClO4)2,
and Ni(OTf)2 did not improve the result (Table 1, entries 6–
8). In our previous researches utilizing chiral phenanthro-
line ligand (S)-1, we have found that the fine-tuning of ste-
ric effects of substituent R on the naphthyl ring improves
the enantioselectivity. Therefore, we applied (S)-1b having
bulky 3,5-xylyl groups, which was the most effective ligand
in several cases,10b–d and the reaction slightly improved the
enantioselectivity to 45% ee (Table 1, entry 9).
To further increase the enantiomeric excess, we tried to
establish an additional effective chiral environment within
(S)-1. Since 1,10-phenanthroline (phen), the core structure
of (S)-1, is highly rigid and planer, we anticipated that the
introduction of additional side chains within the phen
backbones of (S)-1 would provide greater steric factors. In
particular, the substituent R′ at the 2-position of phen
should be located in the closest position to the metal center
(Scheme 2).
Table 1 Screening of Metal Precursors and Ligands (S)-1a
O
metal (10 mol%)
(S)-1 (12 mol%)
Ph
Me
MVK (3.0 equiv)
Ph
O
CH2Cl2, 25 °C, 18 h
N
O
Boc
2a
N
Boc
(R)-4a
N
Yield (%)b
ee (%)c
N
Entry
Metal
1
OH
R
R'
1
2
Cu(OAc)2·H2O
Fe(OAc)2
1a
1a
1a
1a
25
19
52
50
91
64
9
rac.
5
additional substituent
on phenanthroline backbone
to increase steric environment
(S)-1
3
Co(OAc)2
rac.
rac.
33
23
14
5
4
Zn(OAc)2
PhLi
MnO2
(20 equiv)
(1.1 equiv)
5
Ni(OAc)2·4H2O
Ni(acac)2
1a
1a
1a
1a
1b
1c
1c
6
THF
EtOAc
N
N
N
N
–78 °C, 12 h 60 °C, 6 h
Ph
7
Ni(ClO4)2
phen
2-Ph-phen
58% yield
8
Ni(OTf)2
21
79
92
62
9
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
Ni(OAc)2·4H2O
45
87
rac.
MnO2
(20 equiv)
n-BuLi (1.1 equiv)
2-Ph-phen (1.1 equiv)
concd HCl
MeOH
10
11d
OMOM
Ph
EtOAc
60 °C, 6 h 60 °C, 12 h
THF
–78 °C, 12 h
a Reactions were performed on a 0.1 mmol scale: 2a (0.1 mmol), MVK (0.3
mmol), (S)-1 (12 mol%), metal (10 mol%). The chiral catalyst was prepared
in situ by mixing (S)-1 and metal for 2 h at 40 °C.
(S)-5
b Yield of the isolated product after column chromatography.
c The ee value was determined by HPLC using a chiral stationary phase.
d Performed with 1 equiv of i-Pr2NEt.
N
N
OH
Ph
First, we carried out the screening of metal precursors
in the reaction of N-Boc-3-phenyloxindole (2a) and MVK in
CH2Cl2 at 25 °C (Table 1). Based on the previous investiga-
tion on copper(II)-catalyzed enantioselective hydroxylation
of 2a,10d we chose copper(II) acetate monohydrate as the
initial candidate (Table 1, entry 1). However, this chiral cop-
per(II) complex generated in situ was not effective for the
Michael addition of 2a to MVK, giving the desired product
4a in 25% yield and without any enantiomeric excess. The
following screening of several metal acetates identified that
the chiral nickel(II) complex prepared in situ from nickel(II)
acetate tetrahydrate only provided 4a in good yield and
with moderate enantioselectivity (33% ee, Table 1, entries
2–5). The anionic ligand on nickel(II) had an effect on enan-
Ph
(S)-1c
40% yield
Scheme 2 The synthesis of modified ligand (S)-1c and the ORTEP dia-
gram (50% probability level). Hydrogen atoms except OH group are
omitted for clarity.
The synthesis of new ligand (S)-1c is summarized in
Scheme 2.11 The reaction of phen with 1.1 equivalents of
commercially available PhLi and oxidation of the intermedi-
ate gave 2-Ph-phen in 58% yield.12 With the similar proce-
dure to prepare (S)-1a by using 2-Ph-phen instead of
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
Y. Naganawa et al.
Letter
Synlett
phen,10a we successfully obtained the desired ligand (S)-1c
in 40% yield. We also confirmed the structure of (S)-1c by
X-ray crystallographic analysis (ORTEP diagram in Scheme
2).13 Gratifyingly, the reaction with this modified ligand (S)-
1c gave the corresponding Michael adduct 4a in 92% yield
and with 87% ee (Table 1, entry 10). The reaction with an
extra base led to the complete loss of ee (Table 1, entry 11).
The absolute configuration of 4a was determined as R by
comparison with the literature.6
With this optimized conditions in hand, we investigated
the scope of nickel(II)-catalyzed asymmetric Michael addi-
tion of oxindole derivatives 2 with MVK (Scheme 3). We
first conducted the reaction of compounds 2 having a vari-
ety of substituents at the para position of the phenyl ring of
2a. The reaction of N-Boc-3-(p-tolyl)oxindole (2b) gave the
product (S)-4b with the similar result with 2a (87% ee). In
contrast, the efficiency of this transformation seems to be
negatively affected by the electronic factors of the substitu-
ent at the position. For example, the reaction of compounds
2c–e with phenyl, methoxy, and trifluoromethyl groups led
to the decrease of enantioselectivity (65–70% ee). For alkyl
substituents, we performed the reaction of N-Boc-3-methyl-
oxindole (2f). We obtained the product 4f with 70% ee, al-
beit in low chemical yields probably due to the weaker
acidity of the α-carbon of the carbonyl moiety than 2a.
Concerning of the substituent effect of oxindole core,
compounds 2g–i having methyl, methoxy, and fluoro
groups at the 5-position were all tolerated to furnish the
Michael adducts 4g–i with good enantioselectivities (70–
80% ee). Finally, we carried out the reaction of compounds
2j and 2k with substituents at both phenyl rings and oxin-
dole cores with an enantiomeric excess of 80% ee and 81%
ee of the corresponding products 4j and 4k, respectively.
We also investigated the scope of Michael acceptors in
the reaction of 2a (Scheme 4). The reaction with acrolein
gave the product 5a in lower yield and with lower enantio-
meric excess. Also, the reaction of phenyl vinyl ketone re-
sulted in the drop of the ee value of product 5b. The reac-
tion of methyl acrylate, acrylonitrile, 3-acryloyl-2-oxazolid-
inone and 3-penten-2-one did not proceed.
O
Ni(OAc)2 (10 mol%)
(S)-1c (12 mol%)
MVK (3.0 equiv)
Ar
Me
X
X
Ar
O
N
CH2Cl2, 25 °C, 18 h
O
Boc
N
2
Boc
(R)-4
Me
Ph
MeOC
MeOC
MeOC
Ni(OAc)2 (10 mol%)
(S)-1c (12 mol%)
Michael acceptor (3.0 equiv)
Ph
R
R'
Ph
Ph
O
O
O
O
O
N
O
CH2Cl2, 25 °C, 18 h
Boc
N
N
N
N
Boc
Boc
Boc
2a
Boc
4a: 92% yield
87% ee (R)
4b: 97% yield
87% ee (R)
4c: 85% yield
70% ee (R)
(R)-4a (R = COMe, R' = H) : 92% yield, 87% ee
(R)-5a (R = CHO, R' = H) : 35% yield, 30% ee
(R)-5b (R = COPh, R' = H) : 94% yield, 43% ee
(R)-5c (R = CO2Me, R' = H) : no reaction
(R)-5d (R = CN, R' = H) : no reaction
OMe
MeOC
CF3
N
O
X =
MeOC
MeOC
Me
(R)-5e (R = COX, R' = H) : no reaction
(R)-5f (R = COMe, R' = Me) : no reaction
O
O
O
N
Scheme 4 Scope of Michael acceptor
N
NBoc
Boc
Boc
4d: 77% yield
71% ee (R)
4e: 99% yield
65% ee
4f: 25% yield
70% ee (R)
A whole of the plausible mechanism of asymmetric in-
duction in this enantioselective Michael addition is still un-
clear. However, it should be noted that the absolute stereo-
chemistry of products (R)-4 was opposite to the products in
copper(II)-catalyzed hydroxylation wherein the C–O bond
formation occurs on the re face of copper(II) enolate.10d The
similar stereoinversion of the enantioselective transforma-
tion of oxindoles between different electrophiles has been
reported in the literature. For example, Antilla reported the
α-chlorination with N-chlorosuccinimide and the Michael
addition with MVK of oxindole derivatives 2, respectively.8
In this case, the products of each transformation show the
opposite absolute configurations, even though the authors
did not give the possible explanations.
MeOC
Me
MeOC
MeO
MeOC
Ph
Ph
Ph
F
O
O
O
NBoc
N
N
Boc
Boc
4g: 89% yield
70% ee (R)
4h: 85% yield
78% ee (R)
4i: 95% yield
77% ee (R)
Me
OMe
MeOC
Me
MeOC
F
O
O
N
N
Boc
Boc
4j: 80% yield
4k: 91% yield
81% ee
80% ee
Scheme 3 Substrate scope. a Reactions were performed on a 0.1 mmol
scale: 2 (0.1 mmol), MVK (0.3 mmol), (S)-1c (12 mol%), nickel(II) ace-
tate tetrahydrate (10 mol%). The chiral catalyst was prepared in situ by
mixing (S)-1c and nickel(II) acetate for 2 h at 40 °C.
In our previous study on the copper(II)-catalyzed reac-
tion,10d we observed the significant effects of protecting
groups on nitrogen atoms of oxindole derivatives. We ratio-
nally understood the role of these substituents on the nitro-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
Y. Naganawa et al.
Letter
Synlett
gen atom not only as protecting group but also as bidentate
coordinating group with metal centers. In addition, the ste-
ric repulsion between the bulky Boc group of 2 and the 3,5-
xylyl group of (S)-1b plays also an important role to realize
good catalytic efficiency. Based on this consideration, we
examined the effect of protecting groups on nitrogen atoms
in this asymmetric Michael addition (Scheme 5).
Acknowledgment
This research was partly supported by Grants-in-Aid for Scientific Re-
search from the Japan Society for the Promotion of Science (Nos.
15H03808 and 15K21063).
Supporting Information
Supporting information for this article is available online at
MeOC
Ni(OAc)2 (10 mol%)
(S)-1c (12 mol%)
MVK (3.0 equiv)
Ph
http://dx.doi.org/10.1055/s-0035-1561630.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Ph
O
O
CH2Cl2, 25 °C, 18 h
N
N
References and Notes
PG
PG
2
(R)-4a (PG = Boc) : 92% yield, 87% ee
6a (PG = CO2Me) : 50% yield, 20% ee
6b (PG = Me) : no reaction
(1) For reviews, see: (a) Liu, Y.; Han, S.-J.; Liu, W.-B.; Stoltz, B. M.
Acc. Chem. Res. 2015, 48, 740. (b) Quasdorf, K. W.; Overman, L. E.
Nature 2014, 516, 181. (c) Das, J. P.; Marek, I. Chem. Commun.
2011, 47, 4593. (d) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 46, 7295. (e) Cozzi, P. G.; Hilgraf, R.; Zimmermann, N. Eur.
J. Org. Chem. 2007, 5969. (f) Trost, B. M.; Jiang, C. Synthesis 2006,
369. (g) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347,
1473. (h) Douglas, C. J.; Overman, L. E. Proc. Natl. Acad. Sci. U.S.A.
2004, 101, 5363. (i) Denissova, I.; Barriault, L. Tetrahedron 2003,
59, 10105. (j) Quaternary Stereocenters: Challenges and Solutions
for Organic Synthesis; Christoffers, J.; Baro, A., Eds.; Wiley-VCH:
Weinheim, 2005.
(2) (a) For reviews, see: Galliford, C. V.; Scheidt, K. A. Angew. Chem.
Int. Ed. 2007, 46, 8748. (b) Dounay, A. B.; Overman, L. E. Chem.
Rev. 2003, 103, 2945. (c) Lin, H.; Danishefsky, S. J. Angew. Chem.
Int. Ed. 2003, 42, 36.
(3) (a) Hong, S.; Jung, M.; Park, Y.; Ha, M. W.; Park, C.; Lee, M.; Park,
H. Chem. Eur. J. 2013, 19, 9599. (b) Reddy, V. J.; Douglas, C. J. Org.
Lett. 2010, 12, 952.
Scheme 5 Effect of protecting groups on nitrogen atoms of 2
The reaction of N-methyloxycarbonyl-3-phenyloxindole
led to a dramatic decrease of the enantioselectivity of prod-
uct 6a to 20% ee.14 On the other hand, the reaction of N-
methyl-3-phenyloxindole did not proceed. This result sug-
gests the importance of bulkiness and coordination ability
of the protecting groups.
Finally, we examined the relationship between the en-
antiomeric excess of ligand (S)-1c and the enantiomeric ex-
cess of the product (R)-4a and observed the positive nonlin-
ear effect (Figure 2).15 One plausible explanation is the in-
volvement of double coordination and activation by the
nickel(II) catalyst with electrophiles and nucleophiles.16
(4) Kitahara, K.; Shimokawa, J.; Fukuyama, T. Chem. Sci. 2014, 5,
904.
(5) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2005, 127, 15394.
(6) He, R.; Ding, C.; Maruoka, K. Angew. Chem. Int. Ed. 2009, 48,
4559.
(7) (a) Sun, W.; Zhu, G.; Wu, C.; Hong, L.; Wang, R. Chem. Eur. J.
2012, 18, 13959. (b) Li, X.; Xi, Z.-G.; Luo, S.; Cheng, J.-P. Org.
Biomol. Chem. 2010, 8, 77. (c) Shirakawa, S.; Kasai, A.; Tokuda,
T.; Maruoka, K. Chem. Sci. 2013, 4, 2248. (d) Wu, X.; Liu, Q.; Liu,
Y.; Wang, Q.; Zhang, Y.; Chen, J.; Cao, W.; Zhao, G. Adv. Synth.
Catal. 2013, 355, 2701. (e) Zhong, F.; Dou, X.; Han, X.; Yao, W.;
Zhu, Q.; Meng, Y.; Lu, Y. Angew. Chem. Int. Ed. 2013, 52, 943.
(f) Chen, L.; You, Y.; Zhang, M.-L.; Zhao, J.-Q.; Zuo, J.; Zhang, X.-
M.; Yuan, W.-C.; Xu, X.-Y. Org. Biomol. Chem. 2015, 13, 4413.
(g) Galzerano, P.; Bencivenni, G.; Pesciaioli, F.; Mazzanti, A.;
Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P. Chem. Eur. J.
2009, 15, 7846. (h) Bravo, N.; Mon, I.; Companyó, X.; Alba, A.-N.;
Moyano, A.; Rios, R. Tetrahedron Lett. 2009, 50, 6624.
(i) Pesciaioli, F.; Tian, X.; Bencivenni, G.; Bartoli, G.; Melchiorre,
P. Synlett 2010, 1704. (j) Freund, M. H.; Tsogoeva, S. B. Synlett
2011, 503. (k) Sun, W.; Hong, L.; Liu, C.; Wang, R. Tetrahedron:
Asymmetry 2010, 21, 2493. (l) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.;
Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Chem. Eur. J. 2012, 18, 6679.
(m) Yang, C.; Chen, W.; Yang, W.; Zhu, B.; Yan, L.; Tan, C.-H.;
Jiang, Z. Chem. Asian J. 2013, 8, 2960. (n) Wei, Y.; Wen, S.; Liu, Z.;
Wu, X.; Zeng, B.; Ye, J. Org. Lett. 2015, 17, 2732.
Figure 2 Positive nonlinear effect in the reaction with (S)-1c
In conclusion, we demonstrated the enantioselective
Michael addition of N-Boc-oxindole derivatives 2 with MVK
to give the corresponding adducts (R)-4 having chiral all-
carbon quaternary centers in the presence of a nickel(II)
complex generated in situ from a newly modified chiral
N,N,O-tridentate phenanthroline ligand (S)-1c.17 Also, we
discovered the application of chiral ligands (S)-1 in nickel
catalysis for the first time, and hence would like to further
broaden the utility of this catalytic system to other catalytic
asymmetric reactions.18,19
(8) Zheng, W.; Zhang, Z.; Kaplan, M. J.; Antilla, J. C. J. Am. Chem. Soc.
2011, 133, 3339.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
Y. Naganawa et al.
Letter
Synlett
(9) For selected recent examples on the use of other Michael
accepters, see: (a) Zhu, Q.; Lu, Y. Angew. Chem. Int. Ed. 2010, 49,
7753. (b) Wang, T.; Yao, W.; Zhong, F.; Pang, G. H.; Lu, Y. Angew.
Chem. Int. Ed. 2014, 53, 2964. (c) Zou, L.; Bao, X.; Ma, Y.; Song,
Y.; Qu, J.; Wang, B. Chem. Commun. 2014, 50, 5760. (d) Zhang, T.;
Cheng, L.; Hameed, S.; Liu, L.; Wanga, D.; Chen, Y.-J. Chem.
Commun. 2011, 47, 6644. (e) Liao, Y.-H.; Liu, X.-L.; Wu, Z.-J.;
Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Org. Lett. 2010, 12, 2896.
(f) Li, X.; Luo, S.; Cheng, J.-P. Chem. Eur. J. 2010, 16, 14290.
(g) Siau, W.-Y.; Li, W.; Xue, F.; Ren, Q.; Wu, M.; Sun, S.; Guo, H.;
Jiang, X.; Wang, J. Chem. Eur. J. 2012, 18, 9491.
(10) (a) Naganawa, Y.; Namba, T.; Aoyama, T.; Shoji, K.; Nishiyama,
H. Chem. Commun. 2014, 50, 13224. (b) Naganawa, Y.; Namba,
T.; Kawagishi, M.; Nishiyama, H. Chem. Eur. J. 2015, 21, 9319.
(c) Naganawa, Y.; Komatsu, H.; Nishiyama, H. Chem. Lett. 2015,
44, 1652. (d) Naganawa, Y.; Aoyama, T.; Nishiyama, H. Org.
Biomol. Chem. 2015, 13, 11499.
this paper. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
(14) We also tested this N-methyloxycarbonyl-3-phenyloxindole in
the enantioselective hydroxylation reaction with Davis’ oxaziri-
dine in the presence of Cu(II) complex of (S)-1b (ref. 10d). We
obtained the corresponding hydroxylated product in 89% yield
and with 86% ee. This was the slight lower ee than that of the
product in the reaction of N-Boc-3-phenyloxidole 2a (85% yield,
95% ee).
(15) (a) Girard, C.; Kagan, H. B. Angew. Chem. Int. Ed. 1998, 37, 2922.
(b) Blackmond, D. G. Acc. Chem. Res. 2000, 33, 402.
(16) We observed chiral Ni(II) complex of (S)-1c and Ni(OAc)2 in
molecular ratio of 1:1 by ESI-MS analysis. At the same time, we
did not confirm the other complex of (S)-1c and Ni(OAc)2 in
molecular ratio of 2:1. For details, see Supporting Information.
(17) General Experimental Procedures for Enantioselective
Michael Addition
(11) Procedure for the Synthesis of Ligand (S)-1c
A solution of phen (0.90 g, 5 mmol) in THF (20 mL) was cooled
to –78 °C, and PhLi (1.5 equiv, 7.5 mmol) was added dropwise.
The resulting black suspension was warmed up to room tem-
perature. After stirring overnight, the reaction mixture was
poured into water, and the aqueous phase was extracted with
EtOAc. The organic phase was dried over anhydrous MgSO4 and
concentrated under reduced pressure. To a stirred solution of
the crude product in EtOAc, MnO2 was added at room tempera-
ture. The black suspension was kept stirred at 60 °C. After stir-
ring for 6 h, the reaction mixture was filtered by Celite and con-
centrated under reduced pressure. Purification by column
chromatography on silica gel afforded 2-Ph-phen in 58% yield.
A solution of (S)-5 (780 mg, 2 mmol) in THF (10 mL) was cooled
to –78 °C, and n-BuLi (1.1 equiv, 2.2 mmol) was added drop-
wise. After stirring for 1 h, 2-Ph-phen (1.1 equiv, 2.2 mmol) was
added dropwise. After stirring overnight, the reaction mixture
was poured into water, and the aqueous phase was extracted
with EtOAc. The organic phase was dried over anhydrous MgSO4
and concentrated under reduced pressure. To a stirred solution
of the crude product in EtOAc, MnO2 was added at room tem-
perature. The black suspension was kept stirred at 60 °C. After
stirring for 6 h, the reaction mixture was filtrated by Celite and
concentrated under reduced pressure. The residue was added
MeOH and concd HCl, and heated to 60 °C. After stirring 12 h,
the reaction mixture was poured into aq NaHCO3 and the
aqueous phase was extracted with EtOAc. Purification by
column chromatography on silica gel afforded (S)-1c as a yellow
powder in 40% yield.
To a mixture of (S)-1c (7.2 mg, 12.0 μmol) and Ni(II) salts (10.0
μmol) in a Schlenk tube under Ar atmosphere, dry CH2Cl2 (0.5
mL) was added at room temperature. After stirring for 30 min at
40 °C, the reaction mixture was cooled to 25 °C, and then oxin-
dole 2 (0.1 mmol) was added at one portion to the mixture.
After stirring another 30 min, MVK (25 μL, 0.30 mmol) was sub-
jected at one portion to the mixture and stirred at the 25 °C, the
catalyst was removed by passing through short column chroma-
tography on silica gel (eluting CHCl3), and the solvent was evap-
orated. The residue was purified by column chromatography
(eluting hexane–EtOAc or toluene–EtOAc) to give the desired
products (R)-4.
Compound 4e: IR (KBr): 3414, 1982, 1764, 1732, 1619, 1480,
1465, 1412, 1395, 1371, 1325, 1253, 1148, 1072, 1017 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 7.97 (d, J = 10.2 Hz, 1 H), 7.58–7.55
(m, 2 H), 7.46–7.38 (m, 2 H), 7.28–7.15 (m, 3 H), 2.80–2.71 (m, 1
H), 2.55–2.31 (m, 2 H), 2.11–2.00 (m, 4 H), 1.64 (s, 9 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 207.0, 176.2, 149.3, 143.5, 140.1,
130.3 (q, JC–F = 32.3 Hz), 129.7, 129.4, 127.7, 125.9 (q, JC–F = 3.7
Hz), 125.3, 124.9, 123.9 (q, JC–F = 228.3 Hz), 115.8, 85.3, 56.1,
38.7, 32.0, 30.3, 28.3 ppm. HRMS–FAB: m/z calcd for
C
24H24O4NF3 [M + Na]+: 470.1550; found: 470.1534. [α]D21 +69.0
(c 0.50, CHCl3). The enantiomeric purity of the product was
determined by HPLC analysis (Daicel CHIRALPAK AD-H,
hexane–i-PrOH = 15:1, flow rate = 1.0 mL min–1): tR (minor) =
6.8 min; tR (major) = 9.8 min; ee 65%.
Compound 4j: IR (KBr): 3441, 1979, 1759, 1729, 1511, 1490,
1415, 1511, 1450, 1415, 1369, 1339, 1254, 1153, 1116, 1062,
1
Compound (S)-1c: IR (KBr): 3861, 3450, 3053, 1621, 1591, 1549,
1011 cm–1. H NMR (300 MHz, CDCl3): δ = 7.90 (d, J = 8.4 Hz, 1
1
1497, 1469, 1438, 1360, 1306, 1204, 1151, 1106 cm–1. H NMR
H), 7.29–7.18 (m, 5 H), 7.04 (d, J = 2.1 Hz, 1 H), 2.86–2.78 (m, 1
H), 2.54–2.12 (m, 9 H), 2.11 (s, 3 H), 1.72 (s, 9 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 207.2, 176.9, 149.4, 137.6, 137.5. 136.8,
134.6, 130.8, 129.6, 129.3, 127.0, 125.2, 115.3, 84.7, 56.1, 39.3,
32.0, 30.6, 28.6, 21.7, 21.5 ppm. HRMS–FAB: m/z calcd for
(300 MHz, CDCl3): δ = 8.28 (m, 3 H), 8.14 (d, J = 4.4 Hz, 1 H),
8.05–7.94 (m, 5 H), 7.82–7.79 (m, 1 H), 7.65 (d, J = 4.1 Hz, 1 H),
7.56–7.44 (m, 4 H), 7.37–7.18 (m, 9 H), 7.12–7.07 (m, 2 H),
7.03–7.00 (m, 1 H) (phenolic OH was not observed) ppm. 13C
NMR (75 MHz, CDCl3): δ = 156.8, 156.6, 156.1, 143.9, 143.4,
142.4, 140.7, 138.3, 137.4, 136.6, 136.1, 133.6, 133.3, 132.8,
129.9, 129.4, 129.1, 128.9, 128.6, 128.1, 127.9, 127.8, 127.7,
127.6, 127.4, 127.4, 126.85, 126.82, 126.5, 126.3, 126.0, 125.7,
125.2, 122.9, 121.5, 121.1, 119.6, 119.2 ppm. HRMS–FAB: m/z
C
25H29NO4 [M + Na]+: 430.1994; found: 430.1989. [α]D21 +64.2 (c
0.10, CHCl3). The enantiomeric purity of the product was deter-
mined by HPLC analysis (Daicel CHIRALPAK AD-H, hexane–i-
PrOH = 90:10, flow rate = 1.0 mL min–1): tR (minor) = 8.0 min; tR
(major) = 13.8 min; ee 80%.
21
calcd for C24H29N2O [M + H]+: 601.2280; found: 601.2284. [α]D
Compound 4k: IR (KBr): 3413, 2980, 2839, 1766, 1731, 1608,
1
–131.9 (c 0.50, CHCl3).
1580, 1513, 1483, 1394, 1347, 1254, 1146, 1033 cm–1. H NMR
(12) Jakobsen, S.; Tilset, M. Tetrahedron Lett. 2011, 52, 3072.
(13) Crystallographic data obtained for (S)-1c had been deposited
with the Cambridge Crystallographic Data Centre. CCDC
1455175 contains the supplementary crystallographic data for
(300 MHz, CDCl3): δ = 7.94 (dd, J = 8.7, 4.5 Hz, 1 H), 7.21–7.18
(m, 2 H), 7.11–7.04 (m, 1 H), 6.91–6.83 (m, 3 H), 3.78 (s, 3 H),
2.79–2.65 (m, 1 H), 2.43–2.32 (m, 2 H), 2.15–2.08 (m, 1 H), 2.05
(s, 3 H), 1.62 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 207.1,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
Y. Naganawa et al.
Letter
Synlett
176.6, 161.9, 159.4, 158.6, 149.5, 135.9 (d, JC-F = 2.3 Hz), 132.8
(d, JC–F = 7.4 Hz), 131.0, 128.2, 117.0 (d, JC–F = 7.4 Hz), 115.6 (d,
(18) For a review on Ni(II)-catalyzed enantioselective conjugate
addition, see: Pellissier, H. Adv. Synth. Catal. 2015, 357, 2745.
(19) Ni(II)-catalyzed enantioselective conjugate additions of oxin-
dole to nitroolefin have been reported, see: (a) Han, Y.-Y.; Wu,
Z.-J.; Chen, W.-B.; Du, X.-L.; Zhang, X.-M.; Yuan, W.-C. Org. Lett.
2011, 13, 5064. (b) Awata, A.; Wasai, M.; Masu, H.; Kado, S.;
Arai, T. Chem. Eur. J. 2014, 20, 2470.
JC–F = 23.0 Hz), 114.4, 112.2 (d, JC–F = 24.1 Hz), 85.1, 55.6 (d, JC–F
=
9.8 Hz), 38.8, 31.8, 30.3, 28.3 ppm. HRMS–FAB: m/z calcd for
21
C
24H26FNO5 [M + Na]+: 450.1693; found: 450.1681. [α]D +42.6
(c 0.20, CHCl3). The enantiomeric purity of the product was
determined by HPLC analysis (Daicel CHIRALPAK AD-H,
hexane–i-PrOH = 90:10, flow rate = 1.0 mL min–1): tR (minor) =
11.3 min; tR (major) = 15.9 min; ee 81%.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F