Direct catalytic asymmetric vinylogous mannich-type and michael reactions of an α,β-unsaturated γ-butyrolactam under dinuclear nickel catalysis

Article abstract of DOI:10.1021/ja1002636

Chemical equation presented Direct catalytic asymmetric vinylogous reactions of an α,β-unsaturated γ-butyrolactam as a donor are described. A homodinuclear Ni2-Schiff base complex promoted a vinylogous Mannich-type reaction of N-Boc imines as well as a vinylogous Michael reaction to nitroalkenes selectively at the γ-position under simple proton-transfer conditions. Vinylogous Mannich adducts were obtained in 5:1→30:1 dr and 99% ee, and vinylogous Michael adducts were obtained in 16:1→30:1 dr and 93-99% ee.

Full text of DOI:10.1021/ja1002636

Published on Web 03/01/2010
Direct Catalytic Asymmetric Vinylogous Mannich-Type and Michael Reactions
of an r,ꢀ-Unsaturated γ-Butyrolactam under Dinuclear Nickel Catalysis
Nicholas E. Shepherd, Hirooki Tanabe, Yingjie Xu, Shigeki Matsunaga,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received January 12, 2010; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; smatsuna@mol.f.u-tokyo.ac.jp
Catalytic asymmetric vinylogous reactions of γ-butenolides and
related compounds have been intensively studied, giving versatile
functionalized chiral γ-butenolide skeletons.1-3 In contrast, the use
of their aza-analogues, R,ꢀ-unsaturated γ-butyrolactams, as donors
in catalytic asymmetric reactions is rare, despite their synthetic
utility.1a,4 For example, a vinylogous Mukaiyama Mannich-type
adduct of a siloxypyrrole was utilized as a key building block for
the synthesis of anti-influenza agent A-315675.4 Lewis acid
catalyzed asymmetric vinylogous Michael reaction of an acryloyl-
oxazolidinone5 and Lewis base catalyzed asymmetric vinylogous
aldol reaction6 using the siloxypyrrole have been recently reported.
There are, however, no reports on catalytic asymmetric Mannich-
type reactions of siloxypyrroles. Moreover, there is no example of
direct catalytic asymmetric reactions of R,ꢀ-unsaturated γ-butyro-
lactams under proton transfer conditions,7 which are more favorable
in terms of atom economy. Thus, the development of direct catalytic
asymmetric reactions of R,ꢀ-unsaturated γ-butyrolactams is highly
desirable. Herein, we describe our efforts to address these issues.
A homodinuclear Ni2-Schiff base 1 complex (Figure 1) promoted
the direct catalytic asymmetric vinylogous Mannich-type reaction
of an R,ꢀ-unsaturated γ-butyrolactam with N-Boc imines and
vinylogous Michael reaction to nitroalkenes, giving products in up
to 99% ee in both reactions.
marized in Table 1. Initial trials using dinuclear Mn2,9c Co2,9b Cu2,
and Pd2-1 complexes resulted in poor reactivity (entries 1-4). In
contrast, a dinuclear Ni2-1 complex10 smoothly promoted the
vinylogous reaction at room temperature. The R-adduct was not
detected at all, and the desired γ-adduct 5a was obtained as a single
isomer in 85% NMR conversion yield with 99% ee (entry 5). The
yield was improved by the addition of DRIERITE (CaSO4) as a
desiccant to give 5a with >95% yield and 99% ee (entry 6).
Molecular sieves also had beneficial effects to improve yield, but
there was a reproducibility problem in terms of diastereoselectivity
using molecular sieves. Thus, DRIERITE was utilized for further
studies. Catalyst loading was successfully reduced to 5 mol %
without loss of reactivity or stereoselectivity (entry 7). Control
experiments using monometallic Ni-Schiff base 2a-2c complexes
did not afford the desired Mannich adduct 5a but gave only
byproducts (entries 8-10). In entries 11-12, heterobimetallic Pd/
Ni-1 and Cu/Ni-1 complexes also did not give 5a. The results in
entries 8-12 suggested that two Ni metal centers are essential for
the chemoselective 1:1 reaction of 3 with imine 4a. We assume
that a bimetallic Lewis acid/Brønsted base bifunctional mechanism
would be operative in the present reaction, as we previously
observed in other reactions.9,10
Table 1. Optimization of Reaction Conditions
Schiff
base
time
%
%
eeb
entry
M1
M2
x
additive
(h) yielda
dra
1
2
3
4
5
6
7
8
9
Mn-OAc Mn-OAc
Co-OAc Co-OAc
1
1
1
1
1
1
1
2a
2b
2c
1
10 none
10 none
10 none
10 none
10 none
17
17 15
17 trace
17
0
-
-
-
-
-
-
-
-
Cu
Pd
Ni
Ni
Ni
Ni
Ni
Cu
Pd
Ni
Ni
3
17 85
>30:1 99
10 DRIERITE 24 >95 >30:1 99
Figure 1. Structures of dinucleating Schiff base 1-H4, bimetallic Ni2-Schiff
base 1 complex, and Schiff bases 2-H2.
Ni
5
5
5
5
5
5
DRIERITE 24 95
>30:1 99
none
none
none
Ni
DRIERITE 24
DRIERITE 24
DRIERITE 24
DRIERITE 24
DRIERITE 24
0
0
0
0
0
-
-
-
-
-
-
-
-
-
-
To realize the direct vinylogous reaction with R,ꢀ-unsaturated
γ-butyrolactam 3, the chemoselective activation of 3 as a donor
and imine 4 as an electrophile is required. However, undesirable
electrophilic activation of the R,ꢀ-unsaturated γ-butyrolactam unit
in both 3 and the vinylogous Mannich product must be avoided, as
this may lead to side reactions, such as polymerization. In addition,
the enantioselectivity, diastereoselectivity, and R/γ-selectivity of
the metal dienolate should be controlled. Among acid/base bifunc-
tional catalysts developed in our group,8 bimetallic Schiff base 1
catalysts,9-11 which were previously used for catalytic deprotona-
tion of the R-proton in carbonyl donors, showed promising results
in the present vinylogous reactions. The optimization studies using
R,ꢀ-unsaturated γ-butyrolactam 3 and N-Boc imine 4a are sum-
10 Ni
11 Pd
12 Cu
Ni
1
Determined by H NMR analysis of crude mixture. b Determined by
a
1
HPLC analysis using chiral column IA.
The substrate scope of the reaction is summarized in Table 2.12
The Ni2-1 catalyst was applicable to nonisomerizable aryl and
heteroaryl imines. High enantio- and diastereoselectivity were
achieved for aryl imines with either an electron-withdrawing or
electron-donating substituent at the ortho-, meta-, or para-position
(entries 2-7, 23:1f30:1 dr, 99% ee). With heteroaryl imines, the
reactivity somewhat decreased. Thus, the reaction was performed
9
3666 J. AM. CHEM. SOC. 2010, 132, 3666–3667
10.1021/ja1002636  2010 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Direct Catalytic Asymmetric Vinylogous Mannich-Type
Reaction of an R,ꢀ-Unsaturated γ-Butyrolactam and N-Boc Iminesa
γ-butyrolactam. Negative control experiments clearly suggested the
importance of a dinuclear Ni system. The dinuclear Ni-catalyzed
reactions proceeded selectively at the γ-position, giving vinylogous
Mannich adducts in 5:1f30:1 dr and 99% ee and vinylogous
Michael adducts in 16:1f30:1 dr and 93-99% ee. Further studies
to expand the vinylogous nucleophilicity under dinuclear Schiff
base catalysis, including trials to improve the yield with enolizable
aliphatic imines, are ongoing.
entry
R: 4
product 5
% yieldb
drc
% eed
Acknowledgment. This work was supported by the Takeda
Science Foundation (for S.M.), Grant-in-Aid for Scientific Research
(S), for Young Scientist (A), and for Scientific Research on Priority
Areas (No. 20037010, Chemistry of Concerto Catalysis). N.E.S. is
thankful for a JSPS postdoctoral fellowship. We thank Mr. Z. Chen
for fruitful discussions and Dr. M. Shiro at RIGAKU for his
assistance in X-ray crystallographic analysis of 7b.
1
2
3
4
5
6
Ph-
4a
4b
4c
4d
4e
4f
4g
4h
4i
5a
5b
5c
5d
5e
5f
5g
5h
5i
95
76
93
95
87
87
85
61
83
>30:1
30:1
26:1
>30:1
>30:1
>30:1
23:1
99
99
99
99
99
99
99
99
99
2-naphthyl
1-naphthyl
2-Cl-C6H4-
3-Me-C6H4-
4-Cl-C6H4-
4-MeO-C6H4-
2-furyl
7
8e
9e
5:1
21:1
3-thienyl
Supporting Information Available: Experimental procedures,
spectral data of new compounds, and cif files. This material is available
free of charge via the Internet at http://pubs.acs.org.
a Reaction was run using 1 equiv of 3, 1.2 equiv of 4, in THF (0.3
M) in the presence of DRIERITE unless otherwise noted. b Isolated
yield after purification by column chromatography. c Determined by 1H
NMR analysis of crude mixture. d Determined by HPLC using chiral
column IA or AD-H. e Reaction was run using 2 equiv of 3 and 1 equiv
of 4.
References
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Table 3. Direct Catalytic Asymmetric Vinylogous Michael Reaction
of an R,ꢀ-Unsaturated γ-Butyrolactam to Nitroalkenesa
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cat.
(x mol %)
time
(h)
%
yieldb
%
eed
entry
R: 6
7
drc
1
2
3
4
5
6
7
8
9
Ph-
6a
6b
6c
6d
6e
6f
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1
13 7a
12 7b
11 7c
25 7d
11 7e
15 7f
24 7g
24 7h
16 7i
36 7a
98
96
98
98
98
99
89
97
83
84
>30:1 97
29:1 99
16:1 98
>30:1 98
>30:1 98
>30:1 98
26:1 96
>30:1 99
25:1 99
29:1 93
(4) (a) DeGoey, D. A.; Chen, H.-J.; Flosi, W. J.; Grampovnik, D. J.; Yeung,
C. M.; Klein, L. L.; Kempf, D. J. J. Org. Chem. 2002, 67, 5445. (b) Barnes,
D. M.; Bhagavatula, L.; DeMattei, J.; Gupta, A.; Hill, D. R.; Manna, S.;
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Tian, Z.; Wittenberger, S. J. Tetrahedron: Asymmetry 2003, 14, 3541. For
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L.; Burreddu, P.; Rassu, G.; Pelosi, G.; Casiraghi, G.; Zanardi, F.
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G.; Burreddu, P.; Zanardi, F.; Casiraghi, G. J. Org. Chem. 2008, 73, 5446.
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5, 1466, and references therein.
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aldol process, see: (b) Yamaguchi, A.; Matsunaga, S.; Shibasaki, M. J. Am.
Chem. Soc. 2009, 131, 10842.
(9) For selected examples, see Cu-Sm catalyst: (a) Handa, S.; Gnanadesikan,
V.; Matsunaga, S.; Shibasaki, M. J. Am. Chem. Soc. 2007, 129, 4900. Co2-
1: (b) Chen, Z.; Furutachi, M.; Kato, Y.; Matsunaga, S.; Shibasaki, M.
Angew. Chem., Int. Ed. 2009, 48, 2218. Mn2-1: (c) Kato, Y.; Furutachi,
M.; Chen, Z.; Mitsunuma, H.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2009, 131, 9168.
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1255.
4-Br-C6H4-
2-Br-C6H4-
4-MeO-C6H4-
2-furyl
2-thienyl
PhCH2CH2-
i-propyl
6g
6h
(E)-Ph-CH)CH- 6i
10 Ph-
6a
a (S)-Ni2-1 catalyst was used in Table 3. Reaction was run using 2
equiv of 3 in 1,4-dioxane (0.15 M) at 50 °C. b Isolated yield after
purification by column chromatography. c Determined by 1H NMR
analysis of crude mixture. d Determined by HPLC using chiral column
IC, IB, or AD-H.
with 2 equiv of 3, and products 4h-4i were obtained in 99% ee
(entries 8-9). Unfortunately, isomerizable aliphatic imines resulted
in low yield (<20%) due to competitive isomerization to enamides
over nucleophilic activation of 3.
Trials to further expand the vinylogous nucleophilicity of 3 under
bimetallic Schiff base catalysis revealed that vinylogous Michael
reaction to nitroalkenes3b proceeded nicely in 1,4-dioxane at 50
°C using the same Ni2-1 catalyst. As summarized in Table 3, the
reaction of aryl, heteroaryl, and alkyl substituted nitroalkenes 6a-6h
proceeded smoothly with 2.5 mol % catalyst loading, and products
were obtained in 89-99% yield, 16:1f30:1 dr, and 96-99% ee
after 11-25 h (entries 1-8).12 Nitrodiene 6i was also applicable,
and the 1,4-adduct was predominantly obtained in 83% yield, 25:1
dr, and 99% ee (entry 9). Catalyst loading was successfully reduced
to 1 mol %, although enantioselectivity decreased to 93% ee (entry
10).
(11) For selected examples of related bifunctional bimetallic Schiff base
complexes in asymmetric catalysis, see: (a) Annamalai, V.; DiMauro, E. F.;
Carroll, P. J.; Kozlowski, M. C. J. Org. Chem. 2003, 68, 1973, and
references therein. (b) Yang, M.; Zhu, C.; Yuan, F.; Huang, Y.; Pan, Y.
Org. Lett. 2005, 7, 1927. (c) Hirahata, W.; Thomas, R. M.; Lobkovsky,
E. B.; Coates, G. W. J. Am. Chem. Soc. 2008, 130, 17658. (d) Mazet, C.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2008, 47, 1762. (e) Wu, B.; Gallucci,
J. C.; Parquette, J. R.; RajanBabu, T. V. Angew. Chem., Int. Ed. 2009, 48,
1126.
(12) The relative and absolute configurations of 5a and 7b were unequivocally
determined by X-ray crystallographic analysis. See Supporting Information.
In summary, we developed direct catalytic asymmetric vinylo-
gous Mannich-type and Michael reactions of R,ꢀ-unsaturated
JA1002636
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J. AM. CHEM. SOC. VOL. 132, NO. 11, 2010 3667