Syn -selective catalytic asymmetric 1,4-addition of α-ketoanilides to nitroalkenes under dinuclear nickel catalysis

Article abstract of DOI:10.1021/ol101185p

(Figure Presented) A syn-selective catalytic asymmetric 1,4-addition of α-ketoanilides to nitroalkenes is described. The homodinuclear Ni ₂-Schiff base 1b complex was suitable for the reaction, and products were obtained in 61-92% yield, 8.3:1 → 20:1 syn-selectivity, and 72-98% ee. Stereoselective transformation of the 1,4-adduct to a trisubstituted pyrrolidine was also performed.

Full text of DOI:10.1021/ol101185p

ORGANIC
LETTERS
2010
Vol. 12, No. 14
3246-3249
syn-Selective Catalytic Asymmetric
1,4-Addition of r-Ketoanilides to
Nitroalkenes under Dinuclear Nickel
Catalysis
Yingjie Xu,† Shigeki Matsunaga,*,† and Masakatsu Shibasaki*,†,‡
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1,
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, and Institute of Microbial Chemistry,
Tokyo, Kamiosaki 3-14-23, Shinagawa-ku, Tokyo, 141-0021, Japan
smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@mol.f.u-tokyo.ac.jp
Received May 24, 2010
ABSTRACT
A syn-selective catalytic asymmetric 1,4-addition of r-ketoanilides to nitroalkenes is described. The homodinuclear Ni2-Schiff base 1b complex
was suitable for the reaction, and products were obtained in 61-92% yield, 8.3:1 f 20:1 syn-selectivity, and 72-98% ee. Stereoselective
transformation of the 1,4-adduct to a trisubstituted pyrrolidine was also performed.
Catalytic asymmetric Michael reactions to nitroalkenes
provide versatile building blocks. Various chiral catalysts
have been developed for these reactions using aldehydes,
ketones, and 1,3-dicarbonyl compounds as nucleophiles.1 In
biosynthesis, pyruvic acid, a representative 1,2-dicarbonyl
compound, is utilized as a key C2 and C3 donor unit. The
use of related 1,2-dicarbonyl compounds such as R-ketoesters
and R-ketoanilides as nucleophiles in catalytic asymmetric
synthesis, however, is rather limited2-4 due to their high
reactivity as electrophiles. Chemoselective activation of 1,2-
dicarbonyl compounds as nucleophiles is required to avoid
undesired self-condensation reactions of 1,2-dicarbonyl
compounds. Jørgensen2 and our group3 independently re-
ported direct catalytic asymmetric Mannich-type reactions
using R-ketoesters and/or R-ketoanilides as donors, but
applications of 1,2-dicarbonyl compounds as donors in
asymmetric Michael reactions remained unsolved until a very
recent report by Sodeoka and co-workers.4 In their first
successful report, a mono-Ni chiral diamine complex pro-
moted anti-selective catalytic asymmetric 1,4-addition of
R-ketoesters to nitroalkenes, giving products in excellent anti-
selectivity and enantioselectivity. The results prompted us
† The University of Tokyo.
‡ Institute of Microbial Chemistry.
(1) Reviews on asymmetric 1,4-addition to nitroalkenes: (a) Berner,
O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877.
Organocatalysis: (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. Metal
catalysis: (c) Christoffers, J.; Koripelly, G.; Rosiak, A.; Ro¨ssle, M. Synthesis
2007, 1279.
(3) (a) Lu, G.; Morimoto, H.; Matsunaga, S.; Shibasaki, M. Angew.
Chem., Int. Ed. 2008, 47, 6847. (b) Xu, Y.; Lu, G.; Matsunaga, S.; Shibasaki,
M. Angew. Chem., Int. Ed. 2009, 48, 3353.
(4) (a) Nakamura, A.; Lectard, S.; Hashizume, D.; Hamashima, Y.;
Sodeoka, M. J. Am. Chem. Soc. 2010, 132, 4036. For non-enantioselective
1,4-addition of R-ketoesters to nitroalkenes with a stoichiometric amount
of base, see: Maeda, H.; Kraus, G. A. J. Org. Chem. 1997, 62, 2314.
(2) (a) Juhl, K.; Gathergood, N.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2001, 40, 2995. (b) Juhl, K.; Jørgensen, K. A. J. Am. Chem. Soc. 2002,
124, 2420
.
10.1021/ol101185p  2010 American Chemical Society
Published on Web 06/15/2010

to report our preliminary efforts on this issue. Under
dinuclear nickel-Schiff base 1 (Figure 1) catalysis,5-7
complementary syn-selectivity was accomplished, and prod-
ucts were obtained in up to 92% yield, >20:1 syn-selectivity,
and 98% ee.
Table 1. Optimization Studies
%
dra
additive yielda (syn/anti) eeb
%
entry
1c Ni
M
1
solvent
1a THF
none
none
none
none
none
none
none
20
4
9
6.8:1
3.0:1
14:1
8.2:1
ND
34
73
77
2c Co(OAc) 1a THF
3c Ni
1b THF
1b THF
4
5
6
7
8
9
Ni
21
76
Co(OAc) 1b THF
Mn(OAc) 1b THF
Ni
Ni
Ni
trace
trace
33
ND
ND
52
90
87
ND
1b EtOH
3.0:1
6.2:1
5.6:1
14:1
1b 1,4-dioxane none
1b 1,4-dioxane MS 5 Å
1b 1,4-dioxane MS 5
18
50
10 Ni
71e
90
Å/HFIPd
a Determined by crude 1H NMR analysis. b Determined by chiral HPLC
analysis. c Reactions were run at 0 °C in entries 1-3. d 5 equiv of HFIP
was added. e Isolated yield after purification by silica gel column
chromatography.
76% ee). With the Schiff base 1b, other metals, Co and Mn,8b
were also investigated (entries 5 and 6), but only trace, if any,
product was obtained. Among the solvents screened, 1,4-
dioxane produced the best enantioselectivity (entry 8, 90% ee).
Achiral additives to improve the reactivity were investigated, and
the addition of MS 5 Å (entry 9) and 1,1,1,3,3,3-hexafluoroiso-
propanol (HFIP, entry 10) was effective,9 giving 4aa in 71%
isolated yield, 14:1 syn-selectivity, and 90% ee (entry 10).
The substrate scope and limitations of the reaction are
summarized in Table 2. The Ni2-1b catalyst was applicable
to a broad range of nitroalkenes. Various nitrostyrene
derivatives 2b-2g with either an electron-withdrawing or
electron-donating substituent on the aromatic ring gave
products with good to excellent syn-selectivity and enanti-
Figure 1. Structures of dinucleating Schiff bases 1a-H4 and 1b-H4
and homodinculear Ni2-1a and -1b complexes.
Because dinuclear Ni2-Schiff base 1a and 1b catalysts (Figure
1) gave high selectivity in the asymmetric Mannich-type
reaction of R-ketoanilides,3b we performed optimization studies
on the reaction of nitroalkene 2a and R-ketoanilide 3a using
dinuclear Schiff base 1 complexes (Table 1).5 The Ni2-1a
complex syn-selectively promoted the reaction, and product 4aa
was obtained in 20% yield and 34% ee (entry 1). A Co2(OAc)2-
1a complex (M ) CoIIIOAc),8a which was developed for
asymmetric Michael reaction of 1,3-dicarbonyl compounds to
nitroalkenes, gave better enantioselectivity than the Ni2-1a, but
the yield was poor (entry 2, 4% yield, 73% ee). The Ni2-1b
complex derived from biphenyldiamine gave product 4aa in
good syn-selectivity (14:1) and 77% ee, but only 9% yield after
48 h at 0 °C (entry 3). Reactivity was slightly improved at rt,
while maintaining similar enantioselectivity (entry 4, 21% yield,
(7) For selected examples of related bifunctional bimetallic Schiff base
catalysis in asymmetric synthesis, see: (a) Annamalai, V.; DiMauro, E. F.;
Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973. (b) Yang,
M.; Zhu, C.; Yuan, F.; Huang, Y.; Pan, Y. Org. Lett. 2005, 7, 1927. (c)
Gao, J.; Woolley, F. R.; Zingaro, R. A. Org. Biomol. Chem. 2005, 3, 2126.
(d) Li, W.; Thakur, S. S.; Chen, S.-W.; Shin, C.-K.; Kawthekar, R. B.;
Kim, G.-J. Tetrahedron Lett. 2006, 47, 3453. (e) Mazet, C.; Jacobsen, E. N.
Angew. Chem., Int. Ed. 2008, 47, 1762. (f) Hirahata, W.; Thomas, R. M.;
Lobkovsky, E. B.; Coates, G. W. J. Am. Chem. Soc. 2008, 130, 17658. (g)
Sun, J.; Yuan, F.; Yang, M.; Pan, Y.; Zhu, C. Tetrahedron Lett. 2009, 50,
548. (h) Wu, B.; Gallucci, J. C.; Parquette, J. R.; RajanBabu, T. V. Angew.
Chem., Int. Ed. 2009, 48, 1126. See also a review: (i) Haak, R. M.;
Wezenberg, S. J.; Kleij, A. W. Chem. Commun. 2010, 46, 2713.
(8) Co2-1a: (a) Chen, Z.; Furutachi, M.; Kato, Y.; Matsunaga, S.;
Shibasaki, M. Angew. Chem., Int. Ed. 2009, 48, 2218. Mn2-1a: (b) Kato,
Y.; Furutachi, M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M.
J. Am. Chem. Soc. 2009, 131, 9168.
(5) The utility of Ni2-1 in other reactions: (a) Chen, Z.; Morimoto, H.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 2170. (b) Chen,
Z.; Yakura, K.; Matsunaga, S.; Shibasaki, M. Org. Lett. 2008, 10, 3239.
(c) Mouri, S.; Chen, Z.; Matsunaga, S.; Shibasaki, M. Chem. Commun.
2009, 5138. (d) Mouri, S.; Chen, Z.; Mitsunuma, H.; Furutachi, M.;
Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2010, 132, 1255. (e)
Shepherd, N. E.; Tanabe, H.; Xu, Y.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 3666
.
(9) We assume that HFIP had positive effects as a proton source to
accelerate product dissociation step (catalyst turnover step). For selected
examples of HFIP effects in asymmetric reactions, see: (a) Evans, D. A.;
Rovis, T.; Kozlowski, M. C.; Downey, W.; Tedrow, J. S. J. Am. Chem.
Soc. 2000, 122, 9134, and references therein. (b) Kitajima, H.; Ito, K.;
Katsuki, T. Tetrahedron 1997, 53, 17015. (c) Kawara, A.; Taguchi, T.
Tetrahedron Lett. 1994, 35, 8805. (d) Zhou, J.; Tang, Y. J. Am. Chem.
Soc. 2002, 124, 9030. (e) Takita, R.; Ohshima, T.; Shibasaki, M. Tetrahe-
dron Lett. 2002, 43, 4661.
(6) For selected other examples of bimetallic Schiff base catalysts from
our group, see the following. Cu-Sm cat.: (a) Handa, S.; Gnanadesikan,
V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900. (b)
Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2010, 132, 4925. Pd-La cat.: (c) Handa, S.; Nagawa, K.; Sohtome, Y.;
Matsunaga, S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47, 3230. Ga-
Yb cat.: (d) Mihara, H.; Xu, Y.; Shepherd, N. E.; Matsunaga, S.; Shibasaki,
M. J. Am. Chem. Soc. 2009, 131, 8384
.
Org. Lett., Vol. 12, No. 14, 2010
3247

predominantly afforded the 1,4-adduct 4ia in high syn-
selectivity and enantioselectivity (entry 11, >20:1 and 90%
ee). ꢀ-Alkyl-substituted nitroalkene 2j was also applicable,
and the product was obtained in 10:1 syn-selectivity and 92%
ee (entry 12). Ni2-1b was applicable to other R-ketoanilides
3b and 3c, giving products in >20:1 syn-selectivity and
92-83% ee (entries 13 and 14). To demonstrate the synthetic
utility of the reaction, transformation of the product to a
trisubstituted pyrrolidine was performed (Scheme 1). Reduc-
tion of 4ea with Raney-Ni in EtOH directly gave the cyclized
adduct 5ea in 71% yield.11,12
Table 2. syn-Selective Catalytic Asymmetric 1,4-Addition of
R-Ketoanilides to Nitroalkenesa
cat.
(mol
%)
%
yieldb
drc
entry
R
2
3
4
(syn/anti) % eed
1
2
3
4
5
Ph
2a 10 3a 71 4aa
2b 10 3a 87 4ba
2c 10 3a 86 4ca
2d 10 3a 77 4da
14:1 90
4-Cl-C6H4
4-Br-C6H4
3-Br-C6H4
4-MeO-C6H4
19:1 86 (96)e
8.4:1 86
Scheme 1. Transformations of Michael Adduct 4ea
8.3:1 82
2e 10 3a 92 4ea >20:1 98
2e 3a 83 4ea >20:1 97
2e 2.5 3a 68 4ea >20:1 97
6f 4-MeO-C6H4
5
7f 4-MeO-C6H4
8
9
3-MeO-C6H4
4-Me-C6H4
2f 10 3a 63 4fa
2g 10 3a 83 4ga
2h 10 3a 82 4ha
10:1 85
11:1 89
11:1 72
>20:1 90
10:1 92
10 2-thienyl
11 (E)-PhCHdCH 2i 10 3a 70 4ia
12 PhCH2CH2
13 4-MeO-C6H4
14 4-MeO-C6H4
2j 10 3a 60 4ja
2e 10 3b 74 4eb >20:1 92
2e 10 3c 61 4ec >20:1 83
In the present reaction, we assume that the two Ni centers
function cooperatively as observed in other related reactions
using Ni2-Schiff base 1a and 1b complexes.5 The postulated
reaction mechanism is summarized in Figure 3. One of the
Ni-O bonds in the outer O2O2 cavity is speculated to work
as a Brønsted base to generate Ni-enolate in situ.13 The other
Ni in the inner N2O2 cavity functions as a Lewis acid to
control the position of the nitroalkene, similar to conventional
metal-salen Lewis acid catalysis. The C-C bond formation
a Reaction was run using 1.5 equiv of 3, 5 equiv of HFIP (1,1,1,3,3,3-
hexafluoroisopropanol), and MS 5 Å (20 mg for 0.2 mmol of 2) in anhydrous
1,4-dioxane (1.0 M) at room temperature. b Isolated yield after purification
by silica gel column chromatography. c Determined by crude 1H NMR
analysis. d Determined by chiral HPLC analysis. e Number in parentheses
is the value after enantioenrichment by recrystallization from hexane/ethyl
acetate (entry 2, 81% yield). f Reaction was run for 72 h at rt.
oselectivity (entries 2-9, 8.3:1 f 20:1, 82-98% ee). Good
syn-selectivity and enantioselectivity were maintained even
with reduced catalyst loading (entry 6: 5 mol %, entry 7:
2.5 mol %), although longer reaction time was required and
yield of 4ea decreased. The absolute and relative configu-
ration of 4ea was determined by X-ray crystallographic
analysis (Figure 2).10 2-Thienyl-substituted nitroalkene 2h
Figure 2. ORTEP plot of product 4ea.
also had good syn-selectivity, but its enantioselectivity was
somewhat decreased (entry 10, 72% ee). Nitrodiene 2i
Figure 3. Postulated catalytic cycle of Ni2-1b-catalyzed asymmetric
1,4-addition.
(10) Flack parameter was -0.14. CIF file is available as Supporting
Information.
3248
Org. Lett., Vol. 12, No. 14, 2010

via the transition state (TS in Figure 3), followed by
protonation, affords the syn-adduct and regenerates the Ni2-
1b catalyst.
complex promoted the reaction at rt, and products were
obtained in 60-92% yield, 8.3:1 f 20:1 syn-selectivity, and
72-98% ee. The observed syn-selectivity was complemen-
tary to that previously reported for an anti-selective reaction
under mono-Ni-diamine catalysis by Sodeoka and co-
workers. Further studies to improve the reactivity of dinuclear
nickel catalysis are ongoing.
In summary, we succeeded in a catalytic asymmetric 1,4-
addition of R-ketoanilides to nitroalkenes under dinuclear
nickel catalysis. The homodinuclear Ni2-Schiff base 1b
(11) Minor diastereomer was not detected under the reaction condi-
tions.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research (S), Takeda Science foundation
(for S.M.), and Grant-in-Aid for Young Scientist (A). Y.X.
is thankful for a JSPS fellowship. We thank Dr. M. Shiro at
RIGAKU for his generous help and advice on X-ray
crystallographic analysis of 4ea. S.M. and Y.X. thank Prof.
M. Kanai at the University of Tokyo for his generous support
of this project.
(12) For transformations of anilide moiety into carboxylic acid, ester,
amide, and alcohol under mild reaction conditions, see: (a) Evans, D. A.;
Aye, Y.; Wu, J. Org. Lett. 2006, 8, 2071. (b) Saito, S.; Kobayashi, S. J. Am.
Chem. Soc. 2006, 128, 8704. (c) Chen, Z.; Morimoto, H.; Matsunaga, S.;
Shibasaki, M Synlett 2006, 3529, and references therein.
(13) 1H NMR analysis of the bimetallic Ni2-1a and Ni2-1b complexes
does not show any peaks, suggesting that at least one of the Ni metal centers
has non-planar coordination mode. On the basis of the molecular model,
we assume that the outer Ni center has cis-ꢀ configuration due to strain of
the bimetallic complexes. In other words, one of the Ni-O bonds of the
outer Ni center is speculated to be in apical position. Thus, the Ni-O bond
would work as a Brønsted base to deprotonate R-ketoanilide to give the
Ni-enolate intermediate. Of course, the proposed mechanism in Figure 3 is
too much speculative at the moment, and mechanistic studies, including
trials to elucidate precise coordination modes of two Ni metal centers by
X-ray single crystal analysis, are ongoing. For the utility of cis-ꢀ metal
complexes of salens in asymmetric catalysis, see a review: Katsuki, T. Chem.
Soc. ReV. 2004, 33, 437.
Supporting Information Available: Experimental pro-
cedures, spectral data of new compounds, and X-ray crystal-
lography data of 4ea in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL101185P
Org. Lett., Vol. 12, No. 14, 2010
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