A homodinuclear Mn(III)2-Schiff base complex for catalytic asymmetric 1,4-additions of oxindoles to nitroalkenes

Article abstract of DOI:10.1021/ja903566u

(Chemical Equation Presented) Catalytic asymmetric 1,4-additions of 3-substituted oxindoles to β-aryl, β-heteroaryl, and β-alkenyl nitroalkenes are described. A new homodinuclear Mn₂(OAc) ₂-Schiff base 1 complex was required to reali

Full text of DOI:10.1021/ja903566u

Published on Web 06/12/2009
A Homodinuclear Mn(III)2-Schiff Base Complex for Catalytic Asymmetric
1,4-Additions of Oxindoles to Nitroalkenes
Yuko Kato, Makoto Furutachi, Zhihua Chen, Harunobu Mitsunuma, Shigeki Matsunaga,* and
Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received May 2, 2009; E-mail: smatsuna@mol.f.u-tokyo.ac.jp; mshibasa@mol.f.u-tokyo.ac.jp
Table 1. Screening of Bimetallic M1/M2-Schiff Base 1 Complexes
Oxindoles bearing a quaternary carbon stereocenter at the 3-position
are ubiquitous in nature and utilized as building blocks for alkaloid
for 1,4-Addition of Oxindole 3a to Nitroalkene 4aa
synthesis1a,b as well as development of potential therapeutic agents.1c
Among them, oxindoles with ꢀ-amino functionality are among the most
attractive and valuable synthetic targets. Catalytic enantioselective ap-
proaches for such a structural motif, such as the Heck reaction,2a allylic
alkylation,2b,c aldol reactions of oxindoles with ꢀ-amino moieties,2d and
cyanoamidation,2e have been reported over the past decade.2,3 Further
development to increase the structural diversity of ꢀ-aminooxindoles,
however, is highly desirable. Catalytic asymmetric 1,4-addition of
3-substituted oxindoles to nitroalkenes provides an alternative straightfor-
ward access to ꢀ-aminooxindoles with vicinal quaternary/tertiary stereo-
centers. Despite recent progress on organo- and metal-catalyzed asym-
metric 1,4-additions of various nucleophiles to nitroalkenes,4 there are no
examples using oxindoles as nucleophiles. Herein, we report a new
homodinuclear Mn2-Schiff base 1 complex (Figure 1) for catalytic
asymmetric 1,4-additions of 3-substituted oxindoles to nitroalkenes, giving
products in up to 96% ee and >30:1 dr.
entry
M1
M2
x
time (h)
drb
2:1
2:1
5:1
2:1
7:1
% yieldb
% ee
1
2
3
4
5
6
7
CoOAc
Ni
CoOAc
Ni
10
10
10
10
10
10
2.5
33
33
33
33
72
33
24
33
96
46
21
90
98
7
57
3
0
0
97
95
Cu
Pd
Zn
Cu
Pd
Zn
c
MnOAc
MnOAc
MnOAc
MnOAc
>30:1
22:1
d
e
99
a The reaction was performed in AcOEt at room temperature (20-25
°C) with 2 equiv of 3a. b Yield and dr were determined by 1H NMR
analysis of the crude mixture. c Performed in 0.2 M AcOEt. d Performed in
1.0 M AcOEt. e Isolated yield after purification by column chromatography.
aromatic ring, giving the products in high enantioselectivity
(94-96% ee; entries 2-6).9 The diastereoselectivity depended on
the substituent and decreased with an ortho substituent on the
aromatic ring (entry 6). ꢀ-Heteroaryl nitroalkenes 4g and 4h also
showed good selectivity (90-91% ee; entries 7-8). With ꢀ-alkyl
nitroalkenes, the reactivity decreased; thus, we utilized ꢀ-alkenyl-
substituted nitroalkenes 4i and 4j as the synthetic equivalent of
ꢀ-alkyl nitroalkenes in entries 9 and 10. The reactions of 4i and 4j
were run with 5 mol % Mn2-1 complex and selectively gave 1,4-
adducts in 93-87% ee. Oxindole 3b with a Bn substituent at the
3-position also gave the product 5ba in high enantioselectivity (95%
ee; entry 11). 5-Methoxyoxindole 3c and 5-fluorooxindole 3d were
applicable as well (entries 12 and 13). The catalyst loading was
further decreased to 1 mol %, giving 5aa in 99% yield and 92% ee
(entry 14). Because Mn2-1 was bench-stable, reactions using ꢀ-aryl
and ꢀ-heteroaryl nitroalkenes were successfully performed under
open-air conditions without regard to oxygen and moisture exposure
(entries 1-8, 11-14). The product 5aa was readily transformed
into ꢀ-aminooxindole 6aa, as shown in eq 1.
Figure 1. Structures of dinucleating Schiff base 1-H4, salens 2-H2, and
bimetallic Schiff base 1 complexes.
As a part of our ongoing research on bimetallic Schiff base
catalysis,5,6 we recently developed a homodinuclear Co(III)2-Schiff
base 1 complex for catalytic asymmetric 1,4-additions of ꢀ-keto
esters to nitroalkenes.5d Therefore, we began optimization studies
using Co2-1 for reactions of N-Boc oxindole 3a and nitroalkene
4a (Table 1). Initial trials with Co2-1, however, resulted in poor
enantio- and diastereoselectivity (7% ee, dr ) 2:1; entry 1).7 To
find a suitable catalyst for the reaction of oxindole 3a, we screened
other metals (entries 2-6), and a new homodinuclear Mn(III)2-
Schiff base 1 complex8 gave the best reactivity, diastereoselectivity,
and enantioselectivity (97% ee, dr > 30:1; entry 6). Furthermore,
the catalyst loading was successfully reduced to 2.5 mol % under
concentrated conditions (1.0 M), giving 5aa in 99% isolated yield,
95% ee, and 22:1 diastereoselectivity (entry 7).
To gain preliminary insight into the dinuclear Mn catalysis, we
performed several control experiments (Table 3). Use of the
monometallic Mn-salen 2a-c complexes resulted in modest
reactivity and/or selectivity (entries 1-3), suggesting the importance
of the outer Mn center for the present reaction. Heterobimetallic
Cu/Mn-1 and Pd/Mn-1 complexes showed good reactivity but
The substrate scope of the reaction is summarized in Table 2.7
The Mn2-1 complex (2.5 mol %) promoted the 1,4-additions of
oxindole 3a to various nitrostyrene derivatives 4b-f with either
an electron-donating or electron-withdrawing substituent on the
9
9168 J. AM. CHEM. SOC. 2009, 131, 9168–9169
10.1021/ja903566u CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Catalytic Asymmetric 1,4-Additions of Oxindoles 3 to
Nitroalkenes 4 Using the Mn2(OAc)2-Schiff Base 1 Complexa
configurations, and a CIF. This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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references therein. (e) Yasui, Y.; Kamisaki, H.; Takemoto, Y. Org. Lett.
2008, 10, 3303. With a chiral auxiliary: (f) Fuji, K.; Kawabata, T.; Ohmori,
T.; Shang, M.; Node, M. Heterocycles 1998, 47, 951.
(3) Other selected examples of catalytic asymmetric synthesis of oxindoles
with quaternary carbon stereocenters: (a) Lee, S.; Hartwig, J. F. J. Org.
Chem. 2001, 66, 3402. (b) Hills, I. D.; Fu, G. C. Angew. Chem., Int. Ed.
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2764. (g) Trost, B. M.; Cramer, N.; Silverman, S. M. J. Am. Chem. Soc.
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Org. Lett. 2008, 10, 3583. (i) Linton, E. C.; Kozlowski, M. C. J. Am. Chem.
Soc. 2008, 130, 16162. (j) Duffey, T. A.; Shaw, S. A.; Vedejs, E. J. Am.
Chem. Soc. 2009, 131, 14. (k) Galzerano, P.; Bencivenni, G.; Pesciaioli,
F.; Mazzanti, A.; Giannichi, B.; Sambri, L.; Bartoli, G.; Melchiorre, P.
Chem.sEur. J. [Online early access]. DOI: 10.1002/chem.200802466.
Published Online: Jan 29, 2009.
(4) Reviews of 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.
(5) (a) Handa, S.; Gnanadesikan, V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2007, 129, 4900. (b) Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga,
S.; Shibasaki, M. Angew. Chem., Int. Ed. 2008, 47, 3230. (c) Chen, Z.;
Morimoto, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130,
2170. (d) Chen, Z.; Furutachi, M.; Kato, Y.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2009, 48, 2218.
a The reaction was performed in 1.0 M AcOEt at room temperature
(20-25 °C) under an open-air atmosphere with 2 equiv of 3, unless
otherwise noted. b Determined by 1H NMR analysis. c Isolated yield
after purification by column chromatography. d Performed under Ar.
resulted in poor diastereo- and enantioselectivity (entries 4 and 5).
These results indicated that two Mn metal centers are essential for
high stereoselectivity and reactivity. Thus, we speculate that
cooperative functions of two Mn metal centers are important for
the present reaction.10 Further mechanistic studies to clarify the
precise role of two Mn metal centers are ongoing.
(6) Selected examples of related bifunctional bimetallic Schiff base catalysis
in asymmetric synthesis: (a) Annamalai, V.; DiMauro, E. F.; Carroll, P. J.;
Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973, and references therein.
(b) Hirahata, W.; Thomas, R. M.; Lobkovsky, E. B.; Coates, G. W. J. Am.
Chem. Soc. 2008, 130, 17658. (c) Wu, B.; Gallucci, J. C.; Parquette, J. R.;
RajanBabu, T. V. Angew. Chem., Int. Ed. 2009, 48, 1126.
(7) We speculate that the Co2-1 complex optimized for ꢀ-keto esters was not
suitable for N-Boc oxindole 3 because the reacting position of the enolate
derived from 3 is different from that of enolates from ꢀ-keto esters. The
Mn2-1 complex in this work is suitable for oxindole 3 but gave only modest
selectivity for ꢀ-keto esters. No reaction proceeded with N-Bn oxindole or
nonprotected oxindole. 3-Ph-N-Boc oxindole gave poor enantioselectivity.
(8) Mn(III)2(OAc)2-1 was synthesized from Mn(II)(OAc)2 and Schiff base
Table 3. Control Experiments Using Mononuclear Mn(III)(OAc)-
Salen 2a-c and Heterodinuclear Schiff Base 1 Complexes
entry
M1
M2
ligand
time (h)
dr
% yield
% ee
1
2
3
4
5
MnOAc
MnOAc
MnOAc
Cu
none
none
none
MnOAc
MnOAc
2a
2b
2c
1
33
33
33
24
24
1.5:1
4:1
4:1
2:1
2:1
69
65
18
81
95
0
44
5
6
18
1-H4inrefluxingEtOHunderair.ThestructurewasassignedasMn(III)2(OAc)2-
1 on the basis of IR and elemental analysis.
a
Pd
1
(9) The absolute and relative configurations of 5af were determined by single-
crystal X-ray analysis after removal of the Boc group.
a The major product was ent-5aa.
(10) Kinetic studies of the related Co2-1 catalyst in asymmetric 1,4-additions
of ꢀ-keto esters suggested the intramolecular cooperative mechanism (see
ref 5d). For the intermolecular bifunctional mechanism of monometallic
salen complexes, see: Jacobsen, E. N. Acc. Chem. Res. 2000, 33, 421, and
references therein.
(11) Preliminary trials with nitroethylene at room temperature gave the product
in 81% ee (not optimized), while use of ꢀ,ꢀ-disubstituted nitroalkenes
resulted in no reaction.
In summary, we have developed a homodinuclear Mn2(OAc)2-
Schiff base 1 complex as a new entry into bimetallic Schiff base
catalysis. Mn2-1 was suitable for 1,4-additions of 3-substituted
oxindoles to ꢀ-aryl, ꢀ-heteroaryl, and ꢀ-alkenyl nitroalkenes. Reactions
using 1-5 mol % of Mn2-1 proceeded at room temperature to give
products in 99-83% yield, 96-85% ee, and >30:1-5:1 dr. Further
studies to expand the electrophile scope are ongoing.11,12
Acknowledgment. This work was supported by Grants-in-Aid
for Scientific Research (S), Scientific Research on Priority Areas
(20037010, Chemistry of Concerto Catalysis, to S.M.), and Young
Scientists (A) from JSPS and MEXT.
(12) During revisions of this manuscript, Barbas and co-workers reported elegant
organocatalytic asymmetric 1,4-additions of oxindoles to nitroalkenes. See:
Bui, T.; Syed, S.; Barbas, C. F., III. J. Am. Chem. Soc. [Online early access].
DOI: 10.1021/ja903520c. Published Online: June 5, 2009.
Supporting Information Available: Experimental procedures,
spectral data for new compounds, determination of relative and absolute
JA903566U
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