Catalytic enantioselective Michael addition of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by well-defined chiral Ru amido complexes

Article abstract of DOI:10.1021/ja046296g

Well-defined chiral Ru amido complexes promoted asymmetric Michael addition of 1,3-dicarbonyl compounds including malonates, β-keto esters, and 1,3-diketones to nitroalkenes to give the corresponding adducts with excellent ees and in excellent yields. Cop

Full text of DOI:10.1021/ja046296g

Published on Web 08/20/2004
Catalytic Enantioselective Michael Addition of 1,3-Dicarbonyl Compounds to
Nitroalkenes Catalyzed by Well-Defined Chiral Ru Amido Complexes
Masahito Watanabe, Ayako Ikagawa, Hui Wang, Kunihiko Murata, and Takao Ikariya*
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology and
Frontier CollaboratiVe Research Center, O-okayama, Meguro-ku, Tokyo 152-8552, Japan
Received June 23, 2004; E-mail: tikariya@apc.titech.ac.jp
Scheme 1
The asymmetric Michael addition to nitroalkenes has been
developed as a powerful tool in organic synthesis,1-6 because
Michael adducts, optically active nitroalkanes, are versatile building
blocks for agricultural and pharmaceutical compounds.1 Although
there have been many reports of enantioselective Michael additions
with chiral catalysts, including metal-based catalysts and multi-
metallic catalysts as well as organic catalysts,7 practical Michael
additions of 1,3-dicarbonyl compounds to nitroalkenes remain
largely unexplored except for reactions with chiral Mg catalysts4
and optically active thioureas as efficient catalysts.6d We have
recently developed practical asymmetric Michael reactions of 1,3-
dicarbonyl compounds with cyclic enones catalyzed by chiral Ru
amido complexes (1)8 in which the Brønsted basic chiral Ru amido
catalyst may be responsible for high reactivity and selectivity in
the enantioselective C-C bond formation.9 We have expanded the
scope of the reaction catalyzed by chiral Ru amido complex and
found that the Michael addition of 1,3-dicarbonyl compounds to
Table 1. Asymmetric Michael Reaction of Nitroalkenes (2a-g)
with Malonates (3a-c) Catalyzed by Chiral Ru Amido Complexesa
nitroalkenes proceeds smoothly to provide the corresponding
Michael adducts in high yields and with excellent ees as shown in
Scheme 1. Fine-tuning the structures of the arene and N-sulfonyl
diamine ligands in the chiral amido complexes leads to the
achievement of the highly efficient catalytic enantioselective
reaction of nitroalkenes.
The well-defined chiral Ru catalyst, Ru[(S,S)-Msdpen](η6-hexa-
methylbenzene) ((S,S)-MsDPEN ) (1S,2S)-N-(methanesulfonyl)-
1,2-diphenylethylenediamine)9 (1c), which is an excellent catalyst
for the Michael addition of malonates to cyclic enones, effected
asymmetric Michael reaction of trans-â-nitrostyrene (2a) with
dimethyl malonate (3a) (nitroalkene/malonate/Ru ) 50:50-60:1)
at 30 °C in toluene to produce the corresponding Michael adduct
(R)-4aa with 77% ee and in a good yield (45%). Table 1 lists the
experimental results.
The outcome of the reaction with the amido complex 1 was
significantly influenced by the structures of the amido catalysts as
well as the reaction conditions. Noticeably, the reactivity and
enantioselectivity of the Ru[(S,S)-N-sulfonylated dpen](η6-hmb)
(HMB ) η6-hexamethylbenzene, (CH3)6C6) tend to increase with
the increase of the electron-donating ability of the N-substituents
of the sulfonyl groups, namely, in the order p-CH3C6H4SO2 (1b)
> 3,5-(CH3)2C6H3SO2 (1d) > 2,4,6-(CH3)3C6H2SO2 (1e) > 2,3,4,5,6-
(CH3)5C6SO2 (Ps) (1f) as a sulfonyl group in a DPEN ligand; Ru-
[(S,S)-Psdpen](η6-hmb) (1f) gave the best catalyst performance in
terms of the reactivity and selectivity, reaching up to 99% yield
and 90% ee, respectively. Even at the lower temperature, -20 °C,
the reaction of 2a and 3a with an alkene/catalyst molar ratio (S/C)
of 100 proceeded smoothly to give the Michael adduct 4aa with
95% ee and in 99% yield. The p-cymene complex (1g) gave
unsatisfactory results (34% yield, 15% ee at 30 °C). These results
indicate that the balance of the electronic and steric effect of the
arene and the sulfonyl group is crucial in determining the reactivity.
b
Ru
yield, %
c
acceptor donor catalyst
solvent
temp, °C time, h (isolated ) %eed
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2e
2f
3a
3a
3a
3a
3a
3a
3a
3b
3a
3a
3a
3a
3a
3a
3a
3a
3a
3c
1a
1b
1c
1d
1e
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
30
30
30
30
30
24
24
24
24
24
24
48
48
24
24
24
48
48
48
48
48
48
48
45
50
43
53
99
99
99 (97)
92 (90)
32
26
5
96
93
77
72
70
73
87
90
95
93
30
49
30
-20
-20
30
30
30
-20
-20
-20
-20
-20
-20
-20
CHCl3
DMF
toluene
toluene
toluene
toluene
toluene
toluene
toluene
92
93
93
95
97
98
97
98
99 (98)
99 (91)
99 (91)
99 (95)
2g
2a
a Unless otherwise noted, the reaction was carried out using 1.0 mmol
of Michael acceptors and donors (1:1-1.2) in 1.0 mL of solvent. The molar
ratio of acceptor/donor/Ru is 50:50-60:1. b Determined by 1H NMR
analysis. c Isolated yield after flash chromatography on the silica gel.
d Determined by HPLC analysis; see Supporting Information.
Similarly, the reaction of diethyl malonate (3b) with 2a in the
presence of 1f gave the Michael adduct with 93% ee in 92% yield.
Toluene is the best choice of the solvent for the present reaction,
while the conjugate addition in CHCl3, THF, DMF, or CH3CN gave
unsatisfactory results.10
The aromatic ring-substituted trans-â-nitrostyrenes (2b-e) re-
acted with 3a in toluene containing the chiral catalyst 1f at -20
°C for 48 h to give the optically active nitro compounds (4ba-ea)
with 92-95% ee in excellent yields regardless of the electronic
effect of the substituent. The reaction of p-methyl-, p-chloro-
9
11148
J. AM. CHEM. SOC. 2004, 126, 11148-11149
10.1021/ja046296g CCC: $27.50 © 2004 American Chemical Society

C O M M U N I C A T I O N S
In summary, we have successfully developed a practical enantio-
selective Michael addition of 1,3-dicarbonyl compounds with nitro-
alkenes to the optically active nitroalkanes with up to 98% ee. This
reaction is applicable to the synthesis of the intermediate of the
chiral drug, rolipram.4b,12 A large-scale reaction of 3-cyclopentyl-
oxy-4-methoxy-â-nitrostyrene4b (2.1 g) with 3a with the chiral
Ru catalyst (1f) (alkene/3a/Ru ) 100:120:1) at -20 °C gave the
optically active (R)-nitro compound4b in 94% yield (2.97 g) with
95% ee.
Figure 1. Effect of the structures of the Michael donors. The reaction
of â-keto esters gave a 1:1-1.5 mixture of diastereomers with a single
stereogenic center on benzylic carbon of the Michael adducts.
Acknowledgment. This work was financially supported by a
grant-in-aid from the Ministry of Education, Science, Sports and
Culture of Japan (No. 14078209) and partially supported by The
21st Century COE Program.
p-fluoro-, and dioxolane-substituted â-nitrostyrene gave the Michael
adducts with 92, 93, 93, and 95% ee, respectively. Similarly, the
nitroalkenes with hetero aromatic rings, thienyl (2f) and furyl (2g),
provided the Michael adducts (4fa, 4ga) in almost quantitative yield
with 97 and 98% ee, respectively, as shown in Table 1.
Supporting Information Available: Experimental procedures of
the catalytic Michael reaction and spectroscopic data for compounds
4xy (PDF). This material is available free of charge via the Internet at
http://pubs.acs.org.
The stereochemical outcome of the conjugate addition was found
to be significantly influenced by the structure of the Michael donors.
The sterically more congested methyl-substituted dimethyl malonate
3c readily reacted with trans-â-nitrostyrene 2a in toluene containing
1f to give the corresponding adduct (4ac) with 97% ee and in 99%
yield (Table 1). When â-keto esters (3d-g) (2a/keto ester/Ru )
50:60:1, -20 °C, 24 h) were used, the conjugate addition to 2a
gave the corresponding adducts in 95-97% yield as shown in
Figure 1. The enantioselectivity of the reaction was markedly
improved by increasing the bulkiness of the acyl group in the keto
esters. The reaction of acetoacetate 3d gave the product (4ad) with
58% ee, while the enantiomeric purity of the Michael adducts
increased in the order CH3 < C2H5 < C6H5 < CH(CH3)2, the ee
value reaching up to 94% with the keto ester 3f. This conjugate
addition to 2a became even more appealing when 1,3-diketones
were used as donors. The reaction of acetylacetone 3h gave the
Michael adduct in a reasonably high yield but with a poor ee, while
sterically bulkier diketone 3j provided satisfactory results in terms
of the yield and enantioselectivity, the ee value reaching to 97%
(Figure 1).
Although we have shown the possibility of the C-bound Ru
malonato complex (5a, R ) OCH3) as catalytic active intermediates
for the conjugate addition of malonates to cyclic enones, on the
basis of the X-ray crystallographic analysis and NMR investigation
of the Ru malonato complex derived from the complex 1h,9a,c the
reaction mechanism of the Michael reaction with the chiral Ru
amido complex is still controversial. A marked positive effect of
the steric hindrance in the â-keto esters and 1,3-diketones on the
stereochemical outcome of the reaction as discussed above suggests
that the reaction may proceed through C-bound or O-bound Ru
enolato intermediates (5a or 5b) depending on the structures of
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the Michael donors.11 Further investigation, including isolation
of O-bound Ru enolato complexes as the possible catalyst inter-
mediates, as well as computational analysis on the reaction
pathways, is still required.
JA046296G
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J. AM. CHEM. SOC. VOL. 126, NO. 36, 2004 11149