Scope and mechanism of enantioselective michael additions of 1,3-dicarbonyl compounds to nitroalkenes catalyzed by nickel(II)-diamine complexes

Article abstract of DOI:10.1021/ja0735913

Readily prepared Ni(II)-bis[(R,R)-N,N′-dibenzylcyclohexane-1,2- diamine]Br₂ was shown to catalyze the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes at room temperature in good yields with high enantioselectivities. The two diamine ligands in this system each play a distinct role: one serves as a chiral ligand to provide stereoinduction in the addition step while the other functions as a base for substrate enolization. Ligand modification within the catalyst was also investigated to facilitate the reaction of aliphatic nitroalkenes, 1,3-diketones, and β-ketoacids. Ni(II)-bis[(R,R)-N,N′-di-p-bromo-benzylcyclohexane-1,2-diamine]Br ₂ was found to be an effective catalyst in these instances. Furthermore, monodiamine complex, Ni(II)-[(R,R)-N,N′-dibenzylcyclohexane- 1,2-diamine]Br₂, catalyzed the addition reaction in the presence of water. The proposed model for stereochemical induction is shown to be consistent with X-ray structure analysis.

Full text of DOI:10.1021/ja0735913

Published on Web 08/24/2007
Scope and Mechanism of Enantioselective Michael Additions
of 1,3-Dicarbonyl Compounds to Nitroalkenes Catalyzed by
Nickel(II)-Diamine Complexes
David A. Evans,* Shizue Mito, and Daniel Seidel
Contribution from the Department of Chemistry and Chemical Biology, HarVard UniVersity,
Cambridge, Massachusetts 02138
Received May 18, 2007; E-mail: evans@chemistry.harvard.edu
Abstract: Readily prepared Ni(II)-bis[(R,R)-N,N′-dibenzylcyclohexane-1,2-diamine]Br2 was shown to catalyze
the Michael addition of 1,3-dicarbonyl compounds to nitroalkenes at room temperature in good yields with
high enantioselectivities. The two diamine ligands in this system each play a distinct role: one serves as
a chiral ligand to provide stereoinduction in the addition step while the other functions as a base for substrate
enolization. Ligand modification within the catalyst was also investigated to facilitate the reaction of aliphatic
nitroalkenes, 1,3-diketones, and â-ketoacids. Ni(II)-bis[(R,R)-N,N′-di-p-bromo-benzylcyclohexane-1,2-
diamine]Br2 was found to be an effective catalyst in these instances. Furthermore, monodiamine complex,
Ni(II)-[(R,R)-N,N′-dibenzylcyclohexane-1,2-diamine]Br2, catalyzed the addition reaction in the presence of
water. The proposed model for stereochemical induction is shown to be consistent with X-ray structure
analysis.
Introduction
1 that facilitates this transformation at ambient temperatures (eq
1).
The Michael addition and its variants are versatile carbon-
carbon bond constructions,1 and catalytic enantioselective vari-
ants have been under development in recent years.2 Among the
array of activated olefins, nitroalkenes are attractive as the
resulting products are useful intermediates by virtue of the range
of subsequent transformations that are associated with the nitro
group such as the synthesis of chiral γ-amino acids and five-
membered nitrogen heterocycles.3-5 Metal enolates have been
employed extensively in the construction of functionalized
building blocks and thus stand as the important nucleophilic
partner in these addition reactions.2d,g,6 The purpose of this
publication is to describe the scope and mechanistic details of
the enantioselective nitroalkene Michael addition of 1,3-
dicarbonyl nucleophiles catalyzed by the chiral Ni(II) complex
Background. 1,3-Dicarbonyl compounds are promising eno-
late candidates for the development of asymmetric Lewis acid-
catalyzed reactions because of their ability to engage in two-
point binding to a chiral metal complex thus allowing for a
chelate-ordered transition state. For this reason, the Michael
(5) For some recent examples of enantioselective Michael additions to
nitroalkenes, see: (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.;
Gold J. B.; Ley, S. V. Org. Biomol. Chem. 2005, 3, 84. (b) Mitchell, C. E.
T.; Cobb, A. J. A.; Ley, S. V. Synlett 2005, 611. (c) Li, H.; Wang, Y.;
Tang, L.; Wu, F.; Liu, X.; Guo, C.; Foxman, B. M.; Deng, L. Angew. Chem.,
Int. Ed. 2005, 44, 105. (d) Wang, W.; Wang, J.; Li, H. Angew. Chem., Int.
Ed. 2005, 44, 1369. (e) Hayashi, Y.; Gotoh, H.; Shoji, M. Angew. Chem.,
Int. Ed. 2005, 44, 4212. (f) Terakado, D.; Takano, M.; Oriyama, T. Chem.
Lett. 2005, 34, 962. (g) Xu, Y.; Cordova, A. Chem. Commun. 2006, 460.
(h) Mase, N.; Watanabe, K.; Yoda, H.; Takabe, K.; Tanaka, F.; Barbas, C.
F., III. J. Am. Chem. Soc. 2006, 128, 4966. (i) Zu, L.; Wang, J.; Li, H.;
Wang, W. Org. Lett. 2006, 8, 3077. (j) Mosse, S.; Laars, M.; Kriis, K.;
Kanger, T.; Alexakis, A. Org. Lett. 2006, 8, 2559. (k) Huang, H.; Jacobsen,
E. N. J. Am. Chem. Soc. 2006, 128, 7170.
(6) For reviews on metal enolate in stereoselective Aldol reaction, see: (a)
Heathcock, C. H. Science 1981, 214, 395. (b) Evans, D. A.; Nelson, J. V.;
Taber, T. R. Top. Stereochem. 1982, 13, 1. (c) Sauamura, M.; Ito, Y.
Asymmetric Aldol Reactions. In Catalytic Asymmetric Synthesis; Ojima,
I., Ed.; VCH: New York, 1993; Chapter 7.2, pp 367-388. For some early
examples on selective enolization-addition reactions catalyzed by metals,
see: (d) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996,
61, 3520 and references therein. (e) Evans, D. A.; Nelson, S. G. J. Am.
Chem. Soc. 1997, 119, 6452. For reviews on heterobimetallic system, see:
(f) Shibasaki, M.; Sasai, H.; Arai, T.; Iida, T. Pure Appl. Chem. 1998, 70,
1027. (g) Shibasaki, M.; Yoshikawa, N. Chem. ReV. 2002, 102, 2187. (h)
Matsunaga, S.; Ohshima, T.; Shibasaki, M. AdV. Synth. Catal. 2002, 343,
1.
(1) (a) Perlmutter, P. Conjugate Addition Reactions in Organic Synthesis;
Pergamon: Oxford, 1992. (b) Lee, V. J. In ComprehensiVe Organic
Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford 1991, Vol.
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(2) For recent reviews of catalytic asymmetric Michael additions, see: (a)
Kanai, M.; Shibasaki, M. In Catalytic Asymmetric Synthesis, 2nd ed.; Ojima,
I., Ed.; Wiley: New York 2000, pp 569-592. (b) Tomioka, K.; Nagaoka,
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Lehr, F.; Weller, T. Chimia 1979, 33, 1. (b) Barrett, A. G. M.; Graboski,
G. G. Chem. ReV. 1986, 86, 751. (c) Rosini, G.; Ballini, R. Synthesis 1988,
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9
10.1021/ja0735913 CCC: $37.00 © 2007 American Chemical Society
J. AM. CHEM. SOC. 2007, 129, 11583-11592
11583

A R T I C L E S
Evans et al.
addition of 1,3-dicarbonyl compounds catalyzed by metal-
ligand complexes, based on palladium,7 scandium,8 copper,9
aluminum,10 nickel,11 magnesium,12 iridium,13 ruthenium,14
lanthanum,15 and hetero-bimetallic alminium-lithium16 com-
plexes have been investigated.
in the presence of an amine cocatalyst (N-methylmorpholine).12a
Dicarbonyl substrate coordination to the Lewis acidic metal-
ligand complex increases the acidity of the former thus
facilitating its deprotonation by a weak amine cocatalyst to
generate the required metal enolate. This technique, come to
be known as “soft enolization,” has become popular in chiral
Lewis acid-catalyzed enantioselective reactions due to the
mildness of the enolization conditions.18
The chiral catalyst complex in the present study consists of
NiBr2 coordinated to two chiral diamine ligands. It was felt that
complexation of the bidentate substrate to the metal center might
liberate one of the diamine ligands enabling it to function as a
base, thus removing the need for the addition of an ancillary
base (eq 2). Thus, the ligand would be able to fulfill a dual
role: it might function not only as a chiral scaffold, but also
one of the liberated diamine ligands might serve as the base
for substrate deprotonation.
Recent studies have led to the rapid development of catalytic
enantioselective additions of 1,3-dicarbonyl compounds to
nitroalkenes, particularly those reactions subject to organocata-
lysts.17 However, the analogous transformation using chiral
metal catalysts is still rare,11g,12,14 and the achievement of high
enantioselectivities with low catalyst loading remains an ongoing
goal. The first reported example by Barnes and co-workers
employed a Mg(II) bis(oxazoline) complex as a chiral catalyst
(7) (a) Hamashima, Y.; Hotta, D.; Sodeoka, M. J. Am. Chem. Soc. 2002, 124,
11240. (b) Hamashima, Y.; Takano, H.; Hotta, D.; Sodeoka, M. Org. Lett.
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Y.; Suzuki, T.; Sodeoka, M. AdV. Synth. Catal. 2005, 347, 1576.
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Nakajima, M.; Yamamoto, S.; Yamaguchi, Y.; Nakamura, S.; Hashimoto,
S. Tetrahedron 2003, 59, 7307. (c) Kikuchi, S.; Sato, H.; Fukuzawa, S.-i.
Synlett 2006, 1023. (d) Ogawa, C.; Kizu, K.; Shimizu, H.; Takeuchi, M.;
Kobayashi, S. Chem. Asian J. 2006, 1, 121.
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(b) Halland, N.; Velgaard, T.; Jørgensen, K. A. J. Org. Chem. 2003, 68,
5067. (c) Sibi, M. P.; Chen, J. Org. Lett. 2002, 4, 2933. For a review on
bis(oxazoline) copper(II) complexes, see: (d) Evans, D. A.; Rovis, T.;
Johnson, J. S. Pure Appl. Chem. 1999, 71, 1407. Mukaiyama-Michael
addition: (e) Evans, D. A.; Scheidt, K. A.; Johnston, J. N.; Willis, M. C.
J. Am. Chem. Soc. 2001, 123, 4480.
(10) (a) Taylor, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 2003, 125, 11204.
(b) Taylor, M. S.; Zalatan, D. N.; Lerchner, A. M.; Jacobsen, E. N. J. Am.
Chem. Soc. 2005, 127, 1313. (c) Gandelman, M.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2005, 44, 2393; Angew. Chem. 2005, 117, 2445. (d)
Vanderwal, C. D.; Jacobsen, E. N. J. Am. Chem. Soc. 2004, 126, 14724.
(11) (a) Kanemasa, S.; Oderaotoshi, Y.; Wada, E. J. Am. Chem. Soc. 1999, 121,
8675. (b) Itoh, K.; Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394. (c)
Itoh, K.; Oderaotoshi, Y.; Kanemasa, S. Tetrahedron: Asymmetry 2003,
14, 635. (d) Itoh, K.; Hasegawa, M.; Tanaka, J.; Kanemasa, S. Org. Lett.
2005, 7, 979. (e) Zhuang, W.; Hazell, R. G.; Jørgensen, K. A. Chem.
Commun. 2001, 1240. (f) Evans, D. A.; Thomson, R. J.; Franco, F. J. Am.
Chem. Soc. 2005, 127, 10816. A portion the work in this article has been
previously communicated: (g) Evans, D. A.; Seidel, D. J. Am. Chem. Soc.
2005, 127, 9958.
(12) (a) Ji, J. G.; Barnes, D. M.; Zhang, J.; King, S. A.; Wittenberger, S. J.;
Morton, H. E. J. Am. Chem. Soc. 1999, 121, 10215. (b) Barnes, D. M.; Ji,
J. G.; 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. (c) MacCulloch, A. C.; Yolka, S.; Jackson,
R. F. W. Synlett 2002, 1700. (d) Sibi, M. P.; Gorikunti, U.; Liu, M.
Tetrahedron 2002, 58, 8357. (e) Palomo, C.; Pazos, R.; Oiarbide, M.;
Garc´ıa, J. M. AdV. Synth. Catal. 2006, 348, 1161. (f) Nichols, P. J.;
DeMattei, J. A.; Barnett, B. R.; LeFur, N. A.; Chuang, T-H.; Piscopio, A.
D.; Koch. K. Org. Lett. 2006, 8, 1495.
The following discussion details the scope of the enantiose-
lective “nitroalkene-Michael” addition reaction (eq 1). The
discussion includes, kinetic studies, a probe of nonlinear effects,
the characterization of intermediate substrate-catalyst complexes
by X-ray crystallography, and the elaboration of the Michael
adducts into chiral 5-membered nitrogen heterocycles.
Results and Discussion
Catalyst Design and Activity. During our ongoing efforts
to develop new asymmetric Lewis acid-catalyzed transforma-
tions,19 the readily prepared and bench-stable nickel complexes
1 emerged as viable catalysts.11g,20,21 Table 1 shows the effect
of solvent and counterions of the nickel catalyst 1 on the reaction
time and selectivity for the Michael addition of dimethyl
malonate to nitrostyrene. Interestingly, while a number of
different counterions are tolerated (entries 5-10), the use of
(13) Tandem Nazarov Cyclization-Michael Addition Sequence: Janka, M.; He,
W.; Haedicke, I. E.; Fronczek, F. R.; Frontier, A. J.; Eisenberg, R. J. Am.
Chem. Soc. 2006, 128, 5312.
(14) Watanabe, M.; Ikagawa, A.; Wang, H.; Murata, K.; Ikariya, T. J. Am. Chem.
Soc. 2004, 125, 11148.
(15) (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2000, 122, 6506. (b) Takita, R.; Ohshima, T.;
Shibasaki, M. Tetrahedron Lett. 2002, 43, 4661. (c) Ohshima, T.; Xu, Y.;
Takita, R.; Shimizu, S.; Zhong, D.; Shibasaki, M. J. Am. Chem. Soc. 2002,
124, 14546. (d) Majima, K.; Takita, R.; Okada, A.; Ohshima, T.; Shibasaki,
M. J. Am. Chem. Soc. 2003, 125, 15837. (e) Majima, K.; Tosaki, S.-y.;
Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2005, 46, 5377.
(16) (a) Arai, T.; Sasai, H.; Aoe, K.; Okamura, K.; Date, T.; Shibasaki, M.
Angew. Chem., Int. Ed. 1996, 35, 104; Angew. Chem. 1996, 108, 103. (b)
Shimizu, S.; Ohori, K.; Arai, T.; Sasai, H.; Shibasaki, M. J. Org. Chem.
1998, 63, 7547. (c) Xu, Y.; Ohori, K.; Ohshima, T.; Shibasaki, M.
Tetrahedron 2002, 58, 2585. (d) Ohshima, T.; Xu, Y.; Takita, R.; Shibasaki,
M. Tetrahedron 2004, 60, 9569.
(17) (a) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672. (b) Hoashi, Y.; Yabuta, T.; Takemoto, Y. Tetrahedron Lett. 2004,
45, 9185. (c) Li, H.; Wang, Y.; Tang, L.; Deng, L. J. Am. Chem. Soc.
2004, 126, 9906. (d) Li, H.; Wang, Y.; Tang, L.; Wu, F.; Liu, X.; Guo, C.;
Foxman, B. M.; Deng, L. Angew. Chem., Int. Ed. 2005, 44, 105. (e) Okino,
T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am. Chem. Soc.
2005, 127, 119. (f) Wang, J.; Li, H.; Duan, W.; Zu, L.; Wang, W. Org.
Lett. 2005, 7, 4716. (g) Ye, W.; Xu, J.; Tan, C.-T.; and Tan, C.-H.
Tetrahedron Lett. 2005, 46, 6875. (h) Ye, J.; Dixon, D. J.; Hynes, P. S.
Chem. Commun. 2005, 4481. (i) McCooey, S. H.; Connon, S. J. Angew.
Chem., Int. Ed. 2005, 44, 6367. (j) Terada, M.; Ube, Hitoshi.; Yaguchi, Y.
J. Am. Chem. Soc. 2006, 128, 1454. (k) Lattanzi, A. Tetrahedron:
Asymmetry 2006, 17, 837.
(18) Early investigations performed by Lehnert using titanium: (a) Lehnert, W.
Tetrahedron Lett. 1970, 11, 4723. A variety of metal enolates accessed
transmetalation with metal salts have been examined: (b) House, H. O.;
Crumrine, D. S.; Teranishi, Y.; Olmstead, H. D. J. Am. Chem. Soc. 1973,
95, 3310. For reviews of group 3 and transition metal enolates, see: (c)
Kim, B. M.; Williams, S. F.; Masamune, S. In Comprehensive Organic
Synthesis: Additions to the C-X π-Bond Part 2; Trost, B. M., Fleming, I.,
Heathcock, C. H., Eds.; Pergamon Press: New York, 1991, Vol. 2, Chapter
1.7, pp 239. (d) Patterson, I. In Comprehensive Organic Synthesis:
Additions to the C-X π-Bond Part 2; Trost, B. M., Fleming, I., Heathcock,
C. H., Eds.; Pergamon Press: New York, 1991, Vol. 2, Chapter 1.9, pp
301.
(19) For some recent examples of soft enolization from this laboratory, see:
(a) Evans, D. A.; Tedrow, J. S.; Shaw, J. T.; Downey, C. W. J. Am. Chem.
Soc. 2002, 124, 392. (b) Evans, D. A.; Downey, C. W.; Shaw, J. T.; Tedrow,
J. S. Org. Lett. 2002, 4, 1127. (c) Evans, D. A.; Downey, C. W.; Hubbs,
J. L. J. Am. Chem. Soc. 2003, 125, 8706. (d) Evans, D. A.; Thomson, R.
J. J. Am. Chem. Soc. 2005, 127, 10506.
(20) In initial experiments, complexes derived from copper, cobalt, zinc, and
magnesium salts were found to be inferior to nickel salts in terms of the
reaction rate and selectivity.
(21) For reviews on the use of chiral diamines in asymmetric catalysis and
synthesis, see: (a) Alexakis, A.; Mangeney, P. In AdVanced Asymmetric
Synthesis; Stephenson, G. R., Ed.; Chapman & Hall: London, 1996; pp
93. (b) Bennani, Y. L.; Hanessian, S. Chem. ReV. 1997, 97, 3161. (c) Lucet,
D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580.
9
11584 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Enantioselective Michael Additions
A R T I C L E S
NiBr2, catalyst 1a, showed good solubility through a range of
solvents and afforded the best results for the reaction conducted
in toluene (entry 5). The crystal structure of catalyst 1a shown
in Figure 1 reveals that the two diamine ligands coordinate to
nickel in a trans geometry while two bromides occupy the apical
positions.
The temperature profile for the addition of diethyl malonate
to nitrostyrene catalyzed by 1a was investigated (Figure 2).
Remarkably good levels of enantioselectivity were maintained
even at elevated reaction temperatures (e.g., 85% ee at 100 °C).
For convenience, the reactions for the rest of this study were
conducted at room temperature.
Table 1. Counterion and Solvent Survey for the Michael Addition
of Dimethyl Malonate to Nitrostyrenea
Figure 2. Temperature profile for the addition of diethyl malonate to
nitrostyrene catalyzed by 1a.
Table 2. Scope of the Malonate Michael Addition with
Nitroalkenesa
time
(h)
yield
(%)
ee
(%)b
entry
R1
R2
R3
1
2
3
4
5
6
7
8
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
4-Me-Ph (2b)
4-MeO-Ph (2c)
4-Br-Ph (2d)
2-Cl-Ph (2e)
2,3-(MeO)-Ph (2f)
2,4-(MeO)-Ph (2g)
3,4-OCH2O-Ph (2h) Et
2-furyl (2i) Et
trans-PhCHdCH (2j) Et
Me
Et
H (3a)
H (3b)
4
5
99 (4a)
99 (4b)
94
95
95
95
95
95
94
95
95
95
92
93
i-Pr H (3c)
t-Bu H (3d)
10 96 (4c)
36 97 (4d)
6
48 95 (4f)
72 92 (4g)
7
7
8
6
Bn
Me
Et
Et
Et
Et
Et
Et
Et
H (3e)
Me (3f)
NHAc (3g)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
H (3b)
99 (4e)
99 (4h)
99 (4i)
99 (4j)
98 (4k)
9
10
11
12
13
14
15
16
17
a All reactions were performed at room temp on 0.25 mmol scale at 0.25
M concentration and were allowed to reach 100% conversion. b Enantio-
meric excess was determined by chiral HPLC analysis using a Chiralcel
AD column.
15 99 (4l)
72 98 (4m) 94
36 97 (4n)
14 98 (4o)
30 95 (4p)
48 94 (4q)
48 84 (4r)
120 94 (4s)
96 82 (4t)
95
95
95
89
89
88
90
Ph(CH2)2 (2k)
Et
Et
Et
Et
18c n-C5H11 (2l)
19c (Me)2CHCH2 (2m)
20c (Me)2CH (2n)
a All reactions were performed on 1 mmol scale with 2 mol % of 1a at
1 M concentration using 1.2 equiv of the 1,3-dicarbonyl compound.
b Enantiomeric excess was determined by chiral HPLC analysis using
Chiralcel OD-H, OJ-H, AD, or AD-H columns. c Conducted neat with 2
equiv of diethyl malonate.
Figure 1. Crystallographic structure of Ni(II)-bis[(R,R)-N,N′-dibenzylcy-
clohexane-1,2-diamine]Br2 (1a).
reaction time is dependent on the steric demands of the malonate
residue. When the alkyl ester group (R2) was changed from
methyl (3a) to t-butyl (3d) the required reaction time for was
increased by 9-fold. Application of substituted malonates 3f and
3g (R3 * H) had an even more significant effect upon reaction
rate. Nevertheless, uniformly excellent yields and enantiose-
lectivities were obtained for a broad range of malonate additions
with nitrostyrene 2a (R1 ) Ph, entries 1-7). Furthermore, the
reaction of diethyl malonate 3b with electron-rich and electron-
poor 2-aryl substituted nitroalkenes was equally efficient (entries
8-15). In addition, 1-nitro-4-phenyl butadiene (2j) (R1 ) HCd
Stereochemical Assignments. In the ensuing discussion, the
absolute stereochemical assignment of the 2-substituent is as
indicated in the graphics. In all instances, enantiomeric excesses
were determined after decarboxylation. Individual stereochem-
ical assignments are discussed in the Supporting Information.
Reaction Scope. The scope of the malonate addition under
optimized reaction conditions is summarized in Table 2.22 The
(22) When the amount of malonate was reduced to 1.2 equiv while increasing
the concentration to 1 M in the addition reaction, the reaction rate and
selectivity increased.
9
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A R T I C L E S
Evans et al.
Scheme 1. Synthesis of â-Phenyl-γ-aminobutanoic Acid 8a
CHPh) was also shown to be a highly efficient activated alkene
(entry 16, eq 5a). It is noteworthy that no 1,6-addition was
observed.
In contrast to the nitrostyrene derivatives, substrates possess-
ing aliphatic-2-substituents 2k-n exhibited diminished reactivity
(entries 17-20). Reasonable reaction rates were only achieved
in these cases by performing the reactions neat, and lower
enantiomeric excesses resulted (entries 18-20). This deficiency
will be addressed in subsequent temperature and ligand opti-
mization studies (vide infra).
The scope of this reaction was also extended to the use of
â-ketoesters and 1,3-diketones (Table 3). When â-ketoesters
were employed, excellent yields and good enantioselectivities
at the position â-to the nitro group were obtained, regardless
of the nature of the two substituents on the â-ketoester 5a-e
(entries 1-6). 1,3-Diketones 5f and 5g are also applicable to
the present catalytic system, although the reactions proceeded
slower, and both yields and enantioselectivities were diminished
(entries 7 and 8).
a Reaction conditions: (a) catalyst 1a (2 mol %), toluene, room temp,
36 h; (b) NiCl2‚6H2O/NaBH4, MeOH, room temp, 7 h; (c) 6 N HCl, reflux,
24 h.
could be derived from the product of Michael addition of a 1,3-
diester to nitrostyrene.
The following route was selected to be optimal in terms of
overall yield, stereoselectivity, and simplicity (Scheme 1). The
Michael additions of malonate 3h or 3i to nitrostyrene furnished
4u and 4v in 93% and 95% yield, respectively. Reduction of
the nitro moiety in 4u or 4v with NaBH4, in the presence of
nickel(II) chloride, was followed by spontaneous cyclization
with the more reactive esters to afford the thermodynamically
more stable trans-γ-lactam 7 as a single diastereomer. The
stereoselection for trans-isomer 7 indicates that epimerization
of the stereogenic center R-to the carbonyl groups is facile under
the reaction conditions. When 7 was heated at reflux in 6 N
HCl, hydrolysis of both the t-butyl ester and the lactam
functionalities and subsequent decarboxylation provided the
GABA derivative 8 in 77% overall yield.
Table 3. Scope of the â-Ketoester and 1,3-Diketone Additions to
Nitrostyrenesa
Mechanistic Investigations. Unfortunately, reactions with
catalyst 1a are not optimal under all circumstances. The
reactions of nitroalkenes possessing aliphatic-â-substituents
2k-n (Table 2, entries 17-20) or 1,3-diketones 5f and 5g as
nucleophiles (Table 3, entries 7 and 8) are accompanied by
longer reaction times, lower yields, and selectivities relative to
those obtained with nitrostyrenes or malonates. To address these
deficiencies, we sought a better understanding of the reaction
mechanism. Thus, mechanistic studies were initiated on the
Michael addition of ethyl malonate to nitrostyrene.
time
(h)
yield
(%)
ee
entry
R1
R2
R3
drb
(%)c
1d Ph (2a)
Ph (2a)
3d Ph (2a)
Me
Me
Me
OMe (5a)
OEt (5b)
OtBu (5c)
6
2
5
4
4
5
94 (6a) 1:1
96 (6b) 1:1
97 (6c) 1.5:1 93 (93)
96 (6d) 1:1 93 (93)
99 (6e) 2.5:1 90 (85)
97 (6f) 1.7:1 94 (91)
94 (94)
93 (93)
2
4
5
Ph (2a)
Ph (2a)
CHMe2 OEt (5d)
Ph
OEt (5e)
OtBu (5c)
Me (5f)
Et (5g)
6d 4-Br-Ph (2d) Me
7
8
Ph (2a)
Ph (2a)
Me
Et
110 84 (6g)
148 90 (6h)
86
87
a All reactions were performed on a 1 mmol scale with 2 mol % of 1a
The requirements of the reaction with respect to equivalents
of the diamine ligand were examined (Table 4).24 For example,
this addition reaction does not proceed in the absence of ligand
(entry 1). Although the reaction proceeds slowly when one
equivalent of diamine 9a (with respect to NiBr2) is employed a
good yield is observed (entry 2). Optimal reactivity is observed
using two equivalents of ligand 9a relative to NiBr2 (entry 3).
A slower reaction rate and a slight loss in enantioselectivity
are observed when excess diamine ligand is utilized (entries 4
and 5). The former can be ascribed to the presence of an
uncomplexed ligand that, in turn, decreases the amount of
complexed substrate available by biasing the equilibrium in
favor of the diamine complex. The slight decrease in selectivity
could be attributed to a nonselective background reaction
catalyzed solely by uncomplexed free diamine.
at 1 M concentration using 1.2 equiv of the 1,3-dicarbonyl compound.
b Determined by 1H NMR spectroscopy. c Enantioselectivity at the â-position
for major (minor) diastereomer as determined by chiral HPLC analysis using
a Chiralcel AD-H column. d Reaction was performed in THF.
Applications. We previously demonstrated that this meth-
odology is amenable to large-scale preparations with good
results being achieved even at 0.1 mol % catalyst loading.11g
The utility of this procedure was next demonstrated in the
enantioselective synthesis of â-phenyl-γ-amino butanoic acid
(8). The parent γ-amino butanoic acid (GABA) is an important
target for enantioselective synthesis because it is a principle
mammalian neurotransmitter,23 and its derivatives are commonly
found in natural products and pharmaceutical agents. The GABA
derivative 8 would be readily accessible from γ-lactam 7 which
(23) For selected reviews, see: (a) GABA in NerVous System Function; Roberts,
E., Chase, T. R., Tower, D. B., Ed.; Raven Press: New York, 1976. (b)
GABA and Benzodiazepine Receptor subtypes: Molecular Biology, Phar-
macology, and Clinical Aspects; Biggio, G., Costa, E., Ed.; Raven Press:
New York, 1990. (c) GABA in NerVous System Function the View at Fifty
Years; Martin, D. L., Olson, R. W., Ed.; Lippincott Williams & Williams
& Wilkins: Philadelphia, PA, 2000.
To demonstrate that a nonselective background diamine-
catalyzed reaction was in operation, the following experiments
(24) Nickel(II) bromide and diamine 9a were stirred in toluene for 1 h at 70 °C
before the addition of nitrostyrene 2a and diethyl malonate 3b.
9
11586 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Enantioselective Michael Additions
A R T I C L E S
Table 4. Survey of Amounts of Diamine Ligand 9aa
Table 6. Diamine Ligand Survey for the Addition of Diethyl
Malonate to 1-Nitroheptenea
9a
time
(h)
yield
(%)
ee
(%)b
entry
(equiv against Ni)
1
2
3
4
5
0
1
2
3
4
36
36
12
20
22
no reaction
92
93
91
92
94
92
90
89
a All reactions were performed on 0.5 mmol scale at 1 M concentration
using 1.2 equiv of diethylmalonate. b Enantiomeric excess was determined
by chiral HPLC analysis using a Chiralcel AD-H column.
temp
C)
time
(h)
yield
(%)
ee
(%)b
entry
X (catalyst)
(
°
1
2
3
4
5
6
7
8
H (1a)
H (1a)
room temp
50
room temp
0
48
30
40
235
9
78
46
82
16
42
12
72
76
18
106
288
84
75
84
73
93
85
80
87
76
73
76
64
80
71
73
48
89
86
87
85
88
85
87
86
88
88
88
76
85
89
27
46
were conducted (Table 5). When the reaction was performed
with diamine 9a (20 mol %), 78% yield of the adduct 4b was
obtained with 5% ee (entry 2). It is suspected that this reaction
proceeded via deprotonation of the 1,3-dicarbonyl compound
by the diamine 9a, and accordingly anticipated that the addition
of polar substituents to the N-benzyl ring would suppress this
background reaction by making the amine less basic. As
expected, when p-bromo substituted N,N′-dibenzyl diamine 9b
was used, the reaction required twice as long to reach comple-
tion, indicating that remote polar substituents have a significant
effect upon the rate of the background reaction. On the other
hand, when p-methoxy substituted N,N′-dibenzyldiamine 9c was
employed, the reaction reached completion faster than in the
case of unsubstituted diamine 9a. Reaction rates are consistent
with the basicity of the amines screened, and these results
demonstrate that diamine 9 can function as a Bronsted base.
p-Br (1g)
p-Br (1g)
p-Br (1g)
o-Br (1h)
m-Br (1i)
o-Cl (1j)
p-Cl (1k)
p-CF3 (1l)
p-NO2 (1m)
F5 (1n)
50
50
50
50
50
50
50
50
50
50
50
50
9
10
11
12
13
14
15
16
p-OMe (1o)
1p
1q
1r
a All reactions were performed on 1 mmol scale with 2 mol % of 1
using 2.0 equiv of diethylmalonate. b Enantiomeric excess was determined
by chiral HPLC analysis using a Chiralcel AD-H column.
were examined (Table 6).25 To shorten the reaction times, the
majority of experiments were conducted at 50 °C. Under these
conditions, utilizing the original catalyst 1a, the reaction time
was reduced by a third while the enantioselectivity was relatively
unaffected (entry 2). The less basic p-bromo substituted ligand
was prepared and provided an improved outcome relative to
1a at 50 °C (entry 5). Specifically, the reaction was considerably
faster and provided a higher yield of 4r while maintaining high
enantioselectivity. A reduction in temperature led to a reduction
in yield and dramatically increased reaction times (entries 3 and
4). The diminished yields have been attributed to poor catalyst
turnover. Mindful of the acceleration of the reaction rate that
resulted from incorporation of the electron-withdrawing bromide
group, we prepared other catalysts with polar substituents on
the aromatic ring and examined the reaction at 50 °C (entries
6-13). These results demonstrate complex relationship between
ligand structure and reaction rate. For example, o- and m-
bromine-substituted analogues 1h and 1i were much less
effective catalysts (entries 6 and 7), requiring longer reaction
times as well as providing lower yields of 4r relative to 1g.
These observations, also corroborated by the results obtained
with the chlorine substituted complexes 1j and 1k (entries 8
and 9), indicate a possible adverse steric effect in the transition
state of the ortho-substituted analogues. Other electron-
withdrawing ligands 1l-n required longer reaction times (entries
Table 5. The Michael Addition of Diethyl Malonate with
Nitrostyrene Catalyzed by Diamine 9a
time
(h)
yield
(%)b
ee
entry
X
(%)c
1
2
3
4
no diamine
H (9a)
Br (9b)
36
72
144
27
no reaction
78
76
83
5
0
6
OMe (9c)
a All reactions were performed on a 0.5 mmol scale at a 1 M
concentration using 1.2 equiv of diethylmalonate. b Enantiomeric excess
was determined by chiral HPLC analysis using a Chiralcel AD-H column.
Modification of Nickel Complex 1a. Analogues of catalyst
1a were investigated in an attempt to limit intrusion of the
background reaction, which was suspected to be responsible
for the decreased enantioselectivities. The basicity of the ligand
would affect not only the rate of deprotonation, of both the
complexed and uncomplexed substrate, but possibly also ligand
exchange.
Using diethyl malonate and trans-1-nitro hept-1-ene (2l) as
a representative aliphatic nitroalkene, a range of diamine ligands
(25) All catalysts were prepared and isolated before reactions were performed.
9
J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007 11587

A R T I C L E S
Evans et al.
Table 8. Scope of the Michel Addition of â-Ketoacids to
Nitroalkene Catalyzed by 1ga
10-12). This suggests that proton abstraction in these cases
may be rate limiting, as the corresponding free amine is expected
to be less basic. The p-methoxy-substituted complex 1o led to
increased reaction time relative to 1g (entry 13). 1,2-Diphenyl-
1,2-diaminoethylene derivative 1p was less effective (entry 14).
The t-butyl analogue 1q and tertiary amine complex 1r were
also examined but did not yield satisfactory results (entries 15
and 16).
Optimized catalyst 1g (Ar ) p-bromophenyl) was next
examined with substrates that proved problematic in the Michael
addition with the original catalyst 1a (Table 7). In the reactions
of â-substituted nitrostyrenes possessing unsaturated side chains,
catalyst 1g was shown to afford similar enantioselectivities and
yields to catalyst 1a (entries 1 and 2). Application of the new
catalyst 1g to alkyl-substituted nitroalkenes, which gave unsat-
isfactory results with catalyst 1a, afforded improved yields,
enantioselectivities, and dramatically improved reaction times
to reach completion (entries 3-5). Catalyst 1g was demonstrably
more successful than catalyst 1a when used with the more acidic
diketone substrates such as acetylacetone and 3,5-heptanedione
(entries 6-8). A slight improvement in enantioselectivity was
observed with substrate 5f by performing the reaction in THF
(entry 7). Variation in reaction conditions may be necessary to
achieve optimal results.
time
(h)
yield
(%)
ee
entry
R1
R2
(%)a
1
2
3
4
5
6
7
8
9
Ph (2a)
Ph (10a)
24 95 (11a) 90
38 87 (11b) 88
21 99 (11c) 94
80 77 (11d) 90
115 50 (11e) 80
160 51 (11f) 77
36 80 (11g) 90
45 89 (11h) 90
138 81 (11i) 87
4-Me-Ph (2b)
Ph (10a)
Ph (10a)
Ph (10a)
4-Br-Ph (2d)
3,4-OCH2O-Ph (2h)
trans-Ph-CHdCH (2j) Ph (10a)
n-C5H11 (2l)
Ph (2a)
Ph (10a)
4-MeO-Ph (10b)
3-MeO-Ph (10c)
4-F-Ph (10d)
Ph (2a)
Ph (2a)
a All reactions were performed on 0.25 mmol scale with 5 mol % of the
preformed catalyst 1g at 0.17 M concentration using 1.2 equiv of the
â-ketoacid. b Enantiomeric excess was determined by chiral HPLC analysis
using a Chiralcel AD-H column.
% catalyst 1g provided decarboxylative Michael adducts 11 with
the best yields and selectivities in a one-pot operation.27 In this
system, nitrostyrenes possessing an electron-deficient â-aryl
substituent 2d (R1 ) 4-Br-Ph) yielded the best results (entry
3). However, diminished yields and enantioselectivities were
observed with substrates 2j and 2l (entries 5 and 6). Electron-
donating groups on the aromatic ring 10b and 10c at the Michael
donor (entries 7and 8) are well tolerated, whereas electron-
withdrawing 10d substituents dramatically reduce the rate of
the addition reaction (entry 9).
Table 7. Scope of the Michel Addition to Nitroalkene Catalyzed by
1ga
Evidence of Proton Abstraction by the Diamine Ligand.
Having established various elements within the catalyst structure
that control reaction rates, yields, and selectivities, attention was
turned to investigation of the mechanism. NMR spectroscopic
experiments were performed upon the Ni catalyst 1g in CDCl3
(Figure 3). The 1H NMR spectrum of nickel complex 1g
contains relatively broad peaks owing to the paramagnetic
character of nickel(II) (spectrum a in Figure 3). However, when
one equivalent of acetylacetone was added to complex 1g new
signals appeared in both the 1H and 13C NMR spectra, indicating
that a ligand displacement had occurred (spectrum b in Figure
3). Spectrum b bears greater similarity to spectrum c, the HCl
salt of diamine 9b, which is the ligand within complex 1g, than
spectra d diamine 9b itself. It can be concluded that in the
presence of acetylacetone one of the diamine ligands is fully
displaced from catalyst 1g by the substrate and the liberated
diamine then deprotonates the metal-bound acetylacetone. It
should be noted that the catalyst-acetylacetone complex cannot
be observed due to the paramagnetic character of Ni(II) to which
it is complexed, thus only the noncomplexing ammonium
species is observed. This experiment confirms the hypothesis
that the diamine ligand is indeed displaced by the substrate and
thus can serve as the necessary base for the enolization event.
temp
C)
time
(h)
yield
(%)
ee
entry
R1
R2
R3
(
°
(%)b
1
2
3
Ph (2a)
OEt OEt (3b) room temp 24 99 (4b) 95
trans-PhCHdCH (2j) OEt OEt (3b) room temp 72 99 (4p) 95
Ph(CH2)2 (2k)
OEt OEt (3b) room temp 28 95 (4q) 91
4c C5H11 (2l)
OEt OEt (3b) 50
OEt OEt (3b) 50
9
93 (4r) 88
5d Me2CHCH2 (2m)
15 92 (4s) 90
6
Ph (2a)
7e Ph (2a)
Ph (2a)
Me Me (5f) room temp 18 94 (6g) 88
Me Me (5f) room temp 72 88 (6g) 90
Et Et (5g) room temp 30 91 (6h) 92
8
a All reactions were performed on 1 mmol scale with 2 mol % of 1g at
1 M concentration using 1.2 equiv of the 1,3-dicarbonyl compound.
b Enantiomeric excess was determined by chiral HPLC analysis using a
Chiralcel AD-H column. c Conducted neat with 2 equiv of diethyl malonate.
d Conducted at 2 M concentration. e Reaction was performed in THF.
â-Ketoacid Additions. While there are two reported ex-
amples of Lewis acid-catalyzed enantioselective decarboxylative
aldol reactions,26 to the best of our knowledge, there are no
examples of Lewis acid-catalyzed enantioselective decarboxyl-
ative Michael additions. As such, the utilization of â-ketoacids
in the illustrated Michael additions catalyzed by 1g was
investigated (Table 8). The intermediate adducts were anticipated
to undergo decarboxylation under the reaction conditions to
provide enantiomerically enriched products. A reaction proce-
dure using THF at room temperature in the presence of 5 mol
(27) Catalyst 1a gave both lower reactivity and selectivity (48 h, 83%, 90%
ee). All reactions proceeded with loss of yield and enantioselectivity in
other solvents: CH2Cl2 (44%, 28% ee), toluene (41%, 52% ee), ethyl acetate
(44%, 61% ee), 1,4-dioxane (90%, 88% ee), diethylether (80%, 82% ee),
acetonitrile (31%, 67% ee), and ethanol (47%, 63% ee).
(26) (a) Orlandi, S.; Benaglia, M.; Cozzi, F. Tetrahedron Lett. 2004, 45, 1747.
(b) Magdziak, D.; Lalic, G.; Lee, H. M.; Fortner, K. C.; Aloise, A. D.;
Shair, M. D. J. Am. Chem. Soc. 2005, 127, 7284.
9
11588 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Enantioselective Michael Additions
A R T I C L E S
Figure 3. 1H and 13C NMR spectra in CDCl3: (a) nickel complex 1g; (b) 1:1 mixture of nickel complex 1g and acetylacetone; (c) diamine 9b hydrochloride;
(d) diamine 9b.
Figure 5. Transition-state models for the Michael addition with nitrostyrene.
Table 9. Catalyst-Substrate Complex in the Michael Additiona
Figure 4. The ORTEP diagram of complex 12.
A Stereochemical Model. Single crystals of catalyst-
4b
6g
substrate complex 12 were isolated and subjected to X-ray
analysis in an attempt to gain direct evidence for the existence
of the proposed intermediate (eq 12). The ORTEP diagram of
complex 12 is shown in Figure 4. The nickel exhibits octahedral
geometry with the chiral diamine ligand and enolate occupying
the equatorial plane of the complex. Molecules of methanol
occupy each apical position and one bromide ion acts as a
counterion. As the conditions in which the complex was
generated mirror the reaction conditions, it seems likely that
only one diamine ligand is displaced during the reaction. It is
presumed that the apical positions are occupied either by
bromide ions or water, or one of each, under the reaction
conditions.
time
(h)
yield
(%)
ee
yield
(%)
ee
entry
catalyst
(%)b
(%)b
1
2
3
4
13 (2 mol %)
14 (2 mol %)
14 (20 mol %)
14 (100 mol %)
18
32
10
7
98
86
89
97
94
96
94
82
2
3
45
66
a All reactions were performed on 0.25 mmol scale at 0.5 M concentration
using 1.2 equiv of diethylmalonate. b Enantiomeric excess was determined
by chiral HPLC analysis using a Chiralcel AD-H column.
This crystal structure of catalyst-substrate complex 12 can
be used to rationalize the sense of stereoinduction observed in
the addition reaction (Figure 5). One can assume that in the
transition state the incipient nitronate anion is stabilized by
interaction at the open apical position on the nickel. In the
disfavored transition state (pro R addition), the nitro moiety of
the electrophile faces steric interactions with the N-benzyl group
of the ligand. On the other hand, in the favored transition state
(pro S addition), the N-benzyl group of the ligand is orientated
away from the electrophile.
The diamine-acetylacetone complexes 13 and 14 were
investigated as the catalysts in the addition reaction of diethyl
malonate 3b to nitrostyrene 2a (Table 9).28 The reaction
proceeded smoothly to deliver 4b in good yield with high
enantioselectivity in the presence of 2 mol % of complex 13.
The addition reaction with 2 mol % 14 required 32 h and
(28) Catalysts 13 and 14 were prepared from the nickel bisdiamine complexes
with 1 equiv of acetylacetone and isolated before reactions were performed.
See Supporting Information.
9
J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007 11589

A R T I C L E S
Evans et al.
presence of an excess of diethyl malonate in the reaction, the
plot of ln([nitrostyrene]/[nitorostyrene0]) versus time showed a
linear relationship (R2 ) 0.9849, Figure 7A), indicating first-
order dependence on nitrostyrene. In a similar manner, when
excess nitrostyrene was employed, the reaction was first-order
in diethyl malonate (R2 ) 0.9906, Figure 7B). In addition, within
the first 45 min, the reaction proceeded relatively slowly, but
afterward in both instances the substrate was consumed at a
constant rate. This implies that the ligand exchange step from
1 to A is slow and reversible (see Scheme 2). The complexation
of the nitrostyrene presumably represents the rate-determining
step in this catalytic cycle (A to B). After the rapid-bound
enolate addition to the bound nitrostyrene (B to C) the
subsequent deprotonation of the catalyst bound dicarbonyl
species completes this catalytic cycle (C to A).
Reaction Mechanism. On the basis of the results presented
above, we propose the mechanism shown in Scheme 2. First, a
dicarbonyl substrate displaces a diamine ligand, which in turn
deprotonates the metal-bound substrate to generate the chiral
enolate A. Complexation of the nitrostyrene on the apical
position (B) followed by nucleophilic attack of the bound enolate
to the bound nitrostyrene results in formation of the complex
C. Displacement of the product with a dicarbonyl substrate with
concurrent deprotonation regenerates enolate A in the catalytic
cycle.
Figure 6. Nonlinear effects in the Michael addition of diethyl malonate to
nitrostyrene catalyzed by 1a.
generated 4b in 86% yield with 96% ee (entry 2). Similar yields
and enantioselectivities of 4b were observed in the presence of
20 mol % 14 relative to the reaction that was performed with
2 mol % 14 (entry 3). However, acetylacetone adduct 6g was
also isolated in 2% yield (45% ee). Even the reaction with 100
mol % of 14 gave 6g in 3% yield (66% ee) with 4b in 97%
yield (82% ee). Thus, it appears that the acetylacetone ligand
in 14 can be displaced by diethyl malonate29 and the liberated
acetylacetone can then undergo a less selective reaction to
provide product 6g.
Given that this process can occur in the absence of additional
base, the substrate itself is believed to act as a proton source to
facilitate decomplexation of the Michael adduct. This is in
contrast to standard soft enolization scenarios, wherein the
conjugate acid of the ancillary base is believed to behave as a
proton donor in the final step.19
The reaction between diethyl malonate and nitrostyrene,
catalyzed by the parent NiBr2-diamine complex 1a was next
probed for nonlinear effects.30 As the data in Figure 6 indicate,
the linear relationship between enantiomeric excess and catalyst
ee reveals that the active catalyst may be a monomeric species.
This result is consistent with our kinetic studies that show that
the reaction is first order in metal complex (vide infra).
To further probe the reaction mechanism, kinetic studies of
the addition reaction of diethyl malonate to nitrostyrene with
catalyst 1a monitored by 1H NMR was performed. In the
Development of a Nickel(II) Monodiamine Catalyst. Given
that the data suggest the active catalyst contains only one
diamine ligand, monodiamine complex 15 was prepared as a
potential new catalyst. The ORTEP diagram of the tetrahedral
complex 15 is shown in Figure 8.
Nickel(II) monodiamine complex 15 was subsequently evalu-
ated as a catalyst for the Michael addition of diethyl malonate
to nitrostyrene (Table 10). Although high enantioselectivity was
achieved, the reaction was found to be sluggish when performed
with 2 mol % of 15 (75% conversion, 42 h, entry 1). However,
when the addition reaction was performed in the presence of
diamine ligand 9a, product 4b was obtained in good yield and
high enantioselectivity with a decreased reaction time (entry
2). Generation of nickel catalyst 1a in situ under these conditions
was strongly suspected. Furthermore, when racemic 9a was used
the enantioselectivity dropped significantly, an observation that
is consistent with the formation of a racemic catalyst (entry 3).
We speculate that the inefficiency of catalyst 15 may be
attributed to its tetrahedral geometry (Figure 8). An octahedral
geometry of the nickel catalyst was presumed to be required in
Figure 7. Kinetic studies on the addition of diethyl malonate to nitrostyrene: (A) excess diethyl malonate; (B) excess nitrostyrene.
9
11590 J. AM. CHEM. SOC. VOL. 129, NO. 37, 2007

Enantioselective Michael Additions
A R T I C L E S
Scheme 2. Proposed Reaction Mechanism
Table 10. Diamine-Catalyzed Michael Addition of Diethyl
assigned octahedral geometry, and two diamines and two water
molecules completed a bisaqua nickel complex. This suggests
that in the reaction the active nickel species is an bisaqua
complex and it works more efficiently to generate the enolate.31
The addition of 4 Å molecular sieves (MS 4 Å) was also found
to accelerate the addition reaction while maintaining high yields
and enantioselectivity (entry 6). On the other hand, when 2 equiv
of Et3N relative to the catalyst were used, the reaction was
sluggish and diminished yield and enantioselection were ob-
served (entry 5). This could be due to the improved donor
properties of the amine relative to the alcohol such as methanol
and ethanol (entries 8 and 9). A dramatic solvent effect was
also observed. When THF was used as the solvent, in the
presence of 5.5 equiv of water relative to the catalyst, both the
yield and enantioselectivity were reduced relative to the reaction
in toluene (entry 7). This effect was even more apparent when
methanol and ethanol were used as the solvents; yields and
enantioselectivities both suffered a diminution (entries 8 and
9). The alcoholic solvents are suspected of preferentially
occupying the apical sites on the nickel, and thus inhibit the
nitrostyrene from binding to the catalyst-substrate complex.
To further evaluate this trend, we examined the reaction with
1a in the presence of 4 Å molecular sieves or water and similar
results were observed (eq 15).
Malonate to Nitrostyrenea
time
(h)
yield
(%)
ee
entry
catalyst
additive
(%)b
1c
2
3
4
5
6
7
8
9
toluene
toluene
toluene
toluene
toluene
toluene
THF
42
9
10
10
135
24
115
50
140
70
82
93
99
52
91
90
78
72
95
95
12
94
84
94
91
61
66
9a (2 mol %)
9a (racemic, 2 mol %)
H2O (11 mol %)
Et3N (4 mol %)
MS 4A (25 mg)
H2O (11 mol %)
-
MeOH
EtOH
-
a All reactions were performed on 0.25 mmol scale at 0.5 M concentration
using 1.2 equiv of diethylmalonate. b Enantiomeric excess was determined
by chiral HPLC analysis using a Chiralcel AD-H column. c Conversion )
75%.
this reaction to facilitate catalyst turnover. If this hypothesis
were operative, introduction of two apical ligands to the square
planar complex would satiate the structural requirements of the
catalyst. As anticipated, the addition of 5.5 equiv of water with
respect to the catalyst significantly increased the reaction rate
and provided the Michael adduct 4b in quantitative yield with
high enantioselectivity (entry 4).
To gain information of the coordination state, single crystals
of 15 with water were accessed and subjected to X-ray analysis,
but it was unstable under air and the analysis failed to give
data of sufficient quality. However the structure was tentatively
These results demonstrate that water modestly retards the
reaction. We speculate that water could be coordinating to the
metal center and retarding the turnover step. Although there is
no evidence that the molecular sieves directly interact with the
(29) Ni(acac)2 was found to be an effective catalyst for Michael additions of
1,3-dicarbonyl compounds. It was confirmed that acetylacetones within Ni-
(acac)2 were replaced by â-dicarbonylates to generate Ni(â-dicarbonylate)2,
see: (a) Nelson, J. H.; Landen, G. L.; Stevens, B. N. Synth. React. Inorg.
Met.-Org. Chem. 1979, 9, 435. (b) Nelson, J. H.; Howells, P. N.; DeLullo,
G. C.; Landen, G. L.; Henry, R. A. J. Org. Chem. 1980, 45, 1246. (c) Fei,
C. P.; Chan, T. H. Synthesis 1982, 467.
(30) Girard, C.; Kagan, H. B. Angew. Chem., Int. Ed. 1997, 37, 2923.
(31) Palladium bisaqua and hydroxo complexes were found to be effective for
enolization of 1,3-dicarbonyl compounds, see ref 7a.
Figure 8. The ORTEP diagram of complex 15.
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A R T I C L E S
Evans et al.
catalyst, this additive could facilitate either product diamine
ligand exchange32 or formation of the active nickel species
relevant to the acceleration of the enolization step.33
obviated prerequisite for addition of an external base. Mecha-
nistic studies support a monomeric catalyst that undergoes ligand
exchange and subsequent activation of the dicarbonyl compound
via enolization by the liberated diamine ligand. The resulting
chiral enolate adds enantioselectively to a broad range of
nitroalkenes. Furthermore, a monodiamine catalyst analogue can
be used for this reaction in the presence of water.
Conclusions
In summary, a direct, catalytic, enantioselective Michael
addition of 1,3-dicarbonyl compounds to nitroalkenes that is
conveniently performed under ambient temperature without the
need to exclude air or moisture has been developed. The catalyst
design is centered on a Lewis acid metal complexed by two
chiral diamine ligands that are able to fulfill a dual role. Notable
features of this reaction are its operational simplicity and the
Acknowledgment. Support has been provided by the NIH
(Grant GM-33328-20), the NSF (Grant CHE-9907094), Merck,
Amgen, and Eli Lilly. Dr. R. J. Staples and Ms. Y. Aye are
gratefully acknowledged for solving X-ray crystal structures.
S.M. acknowledges financial support from the Naito Foundation.
(32) The ligand exchange from (iPrO)2TiCl2 to (BINOL)2TiCl2 is facilitated in
the presence of molecular sieves, see; (a) Mikami, K.; Motoyama, Y.;
Terada, M. J. Am. Chem, Soc. 1994, 116, 2812. (b) Mikami, K. Pure Appl.
Chem. 1996, 68, 639.
(33) Pd-hydroxo species was formed from Pd bisaqua complexes in wet acetone
in the presence of molecular sieves and the Pd-OH plays a beneficial role
as a Bronsted base in the enolization step, see ref 32 and the following:
Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999, 121, 5450.
Supporting Information Available: Experimental procedures,
spectral data for all compounds, and stereochemical proofs; CIF
files of 12 and 15. This material is available free of charge via
the Internet at http://pubs.acs.org.
JA0735913
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