C O M M U N I C A T I O N S
Table 2. Scope of the Malonate Addition to Nitroalkenes (eq 2)a
time
(h)
yield
(%)b
ee
(%)c
entry
R1
R2
R3
product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
17d
18d
Ph
Ph
Ph
Ph
Ph
Me
Et
H
H
H
H
H
Me
NHAc
H
H
H
H
H
H
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
4
5
10
36
6
48
72
7
7
8
6
15
72
36
14
48
120
96
99
99
96
97
99
95
92
99
99
99
98
99
98
97
98
84
94
82
94
95
95
95
95
95
94
95
95
95
92
93
94
95
95
89
88
90
i-Pr
t-Bu
Bn
Me
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Ph
Ph
4-Me-Ph
4-MeO-Ph
4-Br-Ph
2-Cl-Ph
2,3-(MeO)-Ph
2,4-(MeO)-Ph
3,4-OCH2O-Ph
2-furyl
basic nitrogen atom, we have no evidence for this point. Further
studies will be necessary to fully elucidate the mechanism.
n-C5H11
CH2CH(Me)2
CH(Me)2
Acknowledgment. Support has been provided by the NSF and
the NIH (GM 33328-20). D.S. gratefully acknowledges a Postdoc-
toral Fellowship from the Ernst Schering Research Foundation.
Supporting Information Available: Experimental procedures,
spectral data for all compounds, and stereochemical proofs (PDF, CIF).
This material is available free of charge via the Internet at http://
pubs.acs.org.
a All reactions were performed on a 1 mmol scale with 2 mol % of the
preformed catalyst 1 at a 1 M concentration using 1.2 equiv of the 1,3-
dicarbonyl compound and toluene as the solvent. Reactions were run at
room temperature in a screw-capped vial for the indicated time. b All yields
are isolated yields after chromatographic purification. c Enantiomeric excess
was determined by HPLC using Chiracel OD-H, OJ-H, AD, or AD-H
columns. d Conducted neat with 2 equiv of diethyl malonate.
References
(1) For a recent review on catalytic enantioselective Michael reactions, see:
Krause, N.; Hoffmann-Ro¨der, A. Synthesis 2001, 171-196.
(2) For reviews, see: (a) Barrett, A. G. M.; Graboski, G. G. Chem. ReV. 1986,
86, 751-762. (b) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org.
Chem. 2002, 1877-1894.
Table 3. Scope of the â-Ketoester Addition to Nitrostyrene (eq 3)a
(3) For some recent examples of enantioselective conjugate additions to
nitroalkenes, see: (a) Luchaco-Cullis, C. A.; Hoveyda, A. M. J. Am. Chem.
Soc. 2002, 124, 8192-8193. (b) Andrey, O.; Alexakis, A.; Bernardinelli,
G. Org. Lett. 2003, 5, 2559-2561. (c) Rimkus, A.; Sewald, N. Synthesis
2004, 135-146. (d) Ishii, T.; Fujioka, S.; Sekiguchi, Y.; Kotsuki, H. J.
Am. Chem. Soc. 2004, 126, 9558-9559. (e) Andrey, O.; Alexakis, A.;
Tomassini, A.; Bernardinelli, G. AdV. Synth. Catal. 2004, 346, 1147-
1168. (f) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.; Tanaka, F.;
Barbas, C. F., III. Synthesis 2004, 1509-1521. (g) Cobb, A. J. A.;
Longbottom, D. A.; Shaw, D. M.; Ley, S. V. Chem. Commun. 2004,
1808-1809. (h) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold,
J. B.; Ley S. V. Org. Biomol. Chem. 2005, 3, 84-96.
time
(h)
yield
(%)b
ee
entry
R1
R2
R3
product
drc
(%)d
1e
2
Ph
Ph
Ph
Ph
Ph
Me
Me
Me
CH2Me2
Ph
Me
Me
Et
t-Bu
Et
Et
t-Bu
6a
6b
6c
6d
6e
6f
6
2
5
4
4
5
94
96
1:1 94 (94)
1:1 93 (93)
3e
4
97 1.5:1 93 (93)
96 1:1 93 (93)
99 2.5:1 90 (85)
97 1.7:1 94 (91)
5
(4) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
Weinheim, Germany, 2001. (b) Seebach, D.; Colvin, E. W.; Lehr, F.;
Weller, T. Chimia 1979, 33, 1.
6e
4-Br-Ph
(5) (a) Ji, J.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.; Morton,
H. E. J. Am. Chem. Soc. 1999, 121, 10215-10216. (b) Barnes, D. M.; Ji,
J.; Fickes, M. G.; Fitzgerald, M. A.; King, S. A.; Morton, H. E.; Plagge,
F. A.; Preskill, M.; Wagaw, S. H.; Wittenberger, S. J.; Zhang, J. J. Am.
Chem. Soc. 2002, 124, 13097-13105. (c) Okino, T.; Hoashi, Y.;
Takemoto, Y. J. Am. Chem. Soc. 2003, 125, 12672-12673. (d) Hoashi,
Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004, 45, 9185-9188.
(e) Watanabe, M.; Ikagawa, A.; Wang, H.; Murata, K.; Ikariya, T. J. Am.
Chem. Soc. 2004, 126, 11148-11149. (f) Li, H.; Wang, Y.; Tang, L.;
Deng, L. J. Am. Chem. Soc. 2004, 126, 9906-9907. (g) Li, H.; Wang,
Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew.
Chem., Int. Ed. 2005, 44, 105-108. (h) Okino, T.; Hoashi, Y.; Furukawa,
T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc. 2005, 127, 119-125.
(6) For the preparation and characterization (including X-ray structure) of
catalyst 1, see Supporting Information.
a,b See Table 2. c Determined by 1H NMR. d Enantioselectivity in â-posi-
tion to nitro group for major (minor) diastereomer; determined by HPLC
using a Chiracel AD-H column. e Reaction was performed in THF.
moiety. Generally, these reactions are slightly faster than their
malonate counterparts.
The utility of the process was further evaluated by performing
large-scale experiments. As highlighted in eqs 4 and 5, tert-butyl
acetoacetate and diethyl malonate, respectively, may be added to
nitrostyrene in a highly effective manner by employing only 0.1
mol % of catalyst. This probably represents the lower limit for the
catalyst:substrate ratio due to the extended reaction times. In
addition, the products derived from tert-butyl acetoacetate can
readily be transformed into γ-nitroketones (eq 6).
Transition structure B in Scheme 1 provides an attempt to
rationalize the observed sense of stereoinduction. Overall dipole
reduction and minimization of ligand-substrate interactions could
be the dominant factors accounting for the high enantioselectivities.
At the present time, we have no information as to the disposition
of the monoprotonated ligand. While our illustrations suggest that
it may still be coordinated to the Ni-center through the remaining
(7) In initial experiments, complexes derived from copper and magnesium
salts were found to be inferior to nickel salts in terms of rate and selectivity.
(8) Kanemasa et al. have used Ni(II) salts as Lewis acids in asymmetric
conjugate additions: (a) Itoh, K.; Oderaotoshi, Y.; Kanemasa, S.
Tetrahedron: Asymmetry 2003, 14, 635-639. (b) Itoh, K.; Kanemasa, S.
J. Am. Chem. Soc. 2002, 124, 13394-13395. (c) Kanemasa, S.; Oder-
aotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121, 8675-8676.
(9) For reviews on the use of chiral diamines in asymmetric catalysis and
synthesis, see: (a) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97,
3161-3195. (b) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem.,
Int. Ed. 1998, 37, 2580-2627.
(10) It is interesting to note that the free ligand catalyzes the reaction by itself
when run in EtOH, giving rise to racemic product.
JA052935R
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J. AM. CHEM. SOC. VOL. 127, NO. 28, 2005 9959