Enantioselective nickel-catalyzed Michael additions of azaarylacetates and acetamides to nitroalkenes

Article abstract of DOI:10.1002/chem.201202093

Put a nickel in it: Azaarylacetates and acetamides, which have been neglected as substrates in catalytic asymmetric synthesis, undergo highly enantioselective Michael additions to nitroalkenes in the presence of a chiral nickel(II)-bis(diamine) complex (see scheme; Bn=benzyl, MS=molecular sieves). This process is tolerant of a wide variety of azaarenes in the pronucleophile. Copyright

Full text of DOI:10.1002/chem.201202093

COMMUNICATION
DOI: 10.1002/chem.201202093
Enantioselective Nickel-Catalyzed Michael Additions of Azaarylacetates and
Acetamides to Nitroalkenes
Charlene Fallan and Hon Wai Lam*[a]
Azaarenes are privileged structures that appear in numer-
ous biologically active compounds such as natural products,
pharmaceuticals, and agrochemicals. Therefore, the develop-
ment of new methods for the incorporation of azaarenes
into compounds, or to functionalize preexisting azaarenes,
are of high value. Our laboratory has recently developed
two reactions that utilize alkenylazaarenes as electrophiles
for enantioselective addition reactions: copper-catalyzed
1,4-reductions,[1a] and rhodium-catalyzed 1,4-arylations.[1b]
These processes rely upon a suitably positioned C=N group
in an azaarene to activate an adjacent alkene toward a nucle-
ophilic addition (Figure 1A).[2,3] These studies led us to con-
In this context, the Trost group has reported enantioselec-
tive palladium-catalyzed allylic alkylations of alkylazaarenes
with cyclic allylic carbonates.[4] Although this protocol was
effective, stoichiometric quantities of a strong lithium amide
base, lithium hexamethyldisilazide (LiHMDS), are required
for the reactions to proceed.[4] The development of process-
es that operate under milder reaction conditions without
stoichiometric preactivation of the alkylazaarene[5] is there-
fore highly desirable, and recent reports have documented
initial progress toward this goal.[6] The research groups of
Huang,[6a–c] Rueping,[6d] and Matsunaga and Kanai[6e] have
reported non-asymmetric metal-catalyzed additions of alky-
lazaarenes to imines,[6a–d] enones,[6e] and an a,b-unsaturated
N-acylpyrrole.[6e] A catalyst-free addition of alkylazaarenes
to imines was also recently described.[7] Furthermore, there
is a body of related work on transition-metal catalyzed
À
cross-coupling reactions involving C H functionalization of
alkylazaarenes.[8] However, because of the relatively low
acidity of alkylazarenes, high temperatures and long reac-
tion times are often required to achieve acceptable yields in
these reactions, and to our knowledge, no enantioselective
variants have been reported.
One strategy for increasing the reactivity of alkylazaar-
enes is to place an additional acidifying group at the a car-
bon, which may also serve as a functional handle for further
manipulation. Although there are numerous examples of ad-
ditions of azaarylcarbonyl compounds or azaarylacetonitriles
to carbon electrophiles, enantioselective variants are virtual-
ly nonexistent. The research group of Melchiorre recently
described a secondary-amine-catalyzed asymmetric addition
of nitrobenzyl pyridines to enals,[9] a reaction that is concep-
tually related to work by Cid, Ruano, and co-workers on the
use of nitrophenylacetonitriles as pronucleophiles.[10] Given
the paucity of such processes, the development of new cata-
lytic enantioselective carbon–carbon bond-forming reactions
of alkylazaarene derivatives represents an attractive goal.[11]
Herein, we describe catalytic enantioselective Michael addi-
tions of azaarylacetates and acetamides to nitroalkenes.[12]
Azaarylacetates 1a–h were examined first (Table 1). A
brief evaluation of selected catalysts employed for the enan-
tioselective addition of 1,3-dicarbonyl compounds to nitroal-
Figure 1. Azaarenes as activating groups for enantioselective catalysis.
E=electrophile, EWG=electron-withdrawing group, Nu=nucleophile.
sider whether the C=N group of an azaarene could provide
a complementary mode of substrate activation through
acidification of the protons of an adjacent methylene
carbon. Under suitable reaction conditions, deprotonation
of this methylene carbon could occur to generate a nucleo-
phile that, under the influence of a chiral catalyst, could un-
dergo enantioselective addition to a carbon electrophile
(Figure 1B).
[a] C. Fallan, Dr. H. W. Lam
kenes[13,14] revealed that the nickel(II)-bis
ACTHNUTRGNE(NUG diamine) complex
EaStCHEM, School of Chemistry, University of Edinburgh
Joseph Black Building, The Kingꢁs Buildings
West Mains Road, Edinburgh EH9 3JJ (UK)
E-mail: h.lam@ed.ac.uk
2 developed by the research group of Evans[14d,e,15] exhibited
good activity. Stirring a 1:1 mixture of the azaarylacetate
and the nitroalkene with 5 mol% of 2 in dioxane at room
temperature in the presence of 3 ꢀ molecular sieves provid-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202093.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
1
&
ÞÞ
These are not the final page numbers!

Table 1. Addition of azaarylacetates to nitroalkenes.[a]
tures of diastereomers. Ethyl 2-pyridylacetate (1a) under-
went addition to a variety of b-(hetero)aryl-substituted ni-
troalkenes[18] with reasonable to high enantioselectivities
(80–91% ee, entries 1–3). Substrates containing other azines
are also effective partners for (E)-4-methyl-b-nitrostyrene as
demonstrated by the successful reaction of substrates bear-
ing chloropyrazine (Table 1, entry 4), dimethoxytriazine
(Table 1, entry 5), isoquinoline (Table 1, entry 6), and quina-
zoline (Table 1, entry 7) moieties, providing products in 88–
99% ee. Dimethoxytriazine 1c was poorly reactive, and
a slightly elevated temperature of 508C was required to pro-
vide 3e in 50% yield, but in 90% ee (Table 1, entry 5).
Azoles such as benzothiazole (Table 1, entries 8 and 9) and
benzisoxazole (Table 1, entry 10) are also tolerated. In con-
trast to the other examples, the diastereomers of products
3d, 3 f, 3g, and 3j were configurationally stable and separa-
ble. Furthermore, decarboxylation of 3d and 3i was readily
achieved with no loss of enantiopurity upon heating with
catalytic p-TsOH·H2O in toluene (Scheme 1).
Product
Yield d.r.[c]
ee
[%][b]
[%][d]
1
2
3
3a Ar=p-Tol
3b Ar=p-MeOC6H4 88
3c Ar=2-furyl
71
12:1
7.5:1
5:1
89
80
91
98
(45)
4
3d
66[e]
7:1[f] 94
5[g]
3e
50[h]
9:1[h] 90
6
7
3f X=CH
3g X=N
78[e]
9:1[f] 99
6:1[f] 88
60[e,i]
Scheme 1. Decarboxylation of Michael products. Ts=toluenesulfonyl.
96
(96)
94
8
9
3h R=Me
3i R=tBu
94
91
2:1
The process is not limited to azaarylacetates; azaaryl terti-
ary acetamides are also viable substrates (Table 2).[17] In
these cases, the products are configurationally stable, an ob-
servation that can be rationalized by the well-known resist-
ance of tertiary amides containing an acidic stereocenter at
the a position to undergo enolization, because of the signifi-
cant A1,3 strain that would develop.[19] Therefore, the indicat-
ed diastereomeric ratios likely reflect the inherent kinetic
diastereoselectivities of these reactions. Under reaction con-
ditions identical to those employed in Table 1, azaaryl N,N-
3.5:1
(92)
59
93
(82)
10
3ja, 3jb
1.6:1[f]
(39)[j]
[a] Reactions were conducted using 0.30 mmol of 1a-h. [b] Yields of in-
separable isolated mixtures of diastereomers. [c] Unless stated otherwise,
diastereomeric ratios of isolated product mixtures as determined by
1H NMR analysis. [d] Enantiomeric excess of the major diastereomer as
determined by HPLC analysis on a chiral stationary phase. Numbers in
parentheses refer to the ee value of the minor diastereomer. [e] Yield of
isolated pure major diastereomer. [f] Diastereomeric ratio of the unpuri-
fied reaction mixture as determined by 1H NMR analysis. [g] Reaction
conducted at 508C. [h] Product 3e slowly epimerized to a 1:1 mixture of
diastereomers upon standing. [i] A 1:1 mixture of diastereomers of 3g
was also isolated in 28% yield. [j] Yield of isolated pure major and minor
diastereomers. Bn=benzyl, MS=molecular sieves, Tol=tolyl.
dimethylACTHNUTRGENUGaN cetamides containing chloropyrazine (Table 2,
entry 1), dimethoxytriazine (Table 2, entry 2), benzothiazole
(Table 2, entries 3–10), benzisoxazole (Table 2, entries 11
and 12), or 5-phenylisoxazole (Table 2, entry 13) groups un-
derwent Michael additions to give the corresponding prod-
ucts in generally good yields and reasonable to high ee val-
ues. With substrate 5c, the b substituent of the nitroalkene
may be varied from p-tolyl (Table 2, entry 3) to p-methoxy-
phenyl (Table 2, entry 5), p-fluorophenyl (Table 2, entry 6),
p-bromophenyl (Table 2, entry 7), or 2-furyl (Table 2,
entry 8) without a major impact on diastereo- or enantiose-
lectivities. However, a sterically more demanding o-tolyl
group led to 6d in somewhat diminished selectivities
ed the Michael products with high enantioselectivities.[16,17]
Unsurprisingly, the stereocenter a to the ester carbonyl
group in many of the Michael adducts was prone to epimeri-
zation, and these products were isolated as inseparable mix-
&
2
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Nickel-Catalyzed Michael Additions
Table 2. Addition of azaarylacetamides to nitroalkenes.[a]
COMMUNICATION
Table 2. (Continued)
Product
Yield d.r.[c]
[%][b]
ee
[%][d]
49
99
(99)
13
6ma, 6mb
1:1
(49)[h]
[a] Reactions were conducted using 0.30 mmol of 5a–h. [b] Unless stated
otherwise, yields are of isolated pure major diastereomers. [c] Diastereo-
meric ratio of the unpurified reaction mixtures as determined by
1H NMR analysis. [d] Enantiomeric excess of the major diastereomer as
determined by HPLC analysis on a chiral stationary phase. Numbers in
parentheses refer to the ee value of the second diastereomer. [e] Yield of
an isolated inseparable mixture of diastereomers. [f] Reaction conducted
using 2.5 mmol each of 5c and nitroalkene. [g] Product 6k was isolated
as a 1.3:1 mixture of diastereomers. [h] Yields of isolated pure separated
diastereomers.
Product
Yield d.r.[c]
[%][b]
ee
(Table 2, entry 4). The reactions are equally effective at
larger scales; for example, reaction of 5c with a 2-furyl-sub-
stituted nitroalkene on a 2.5 mmol scale provided 6h in
95% yield, greater than 19:1 d.r., and greater than 99% ee
after a single recrystallization of the crude product (Table 2,
entry 8). Other amide groups such as Weinreb amides 5d
(Table 2, entry 9) and 5g (Table 2, entry 12), and morpholine
amide 5e (Table 2, entry 10) are tolerated. In contrast to the
majority of examples in Table 2, substrates 5 f–h underwent
reactions with low diastereoselectivities (Table 2, entries 11–
13).
Using substrate 5c for illustrative purposes, Figure 2 de-
picts plausible transition state models that lead to the four
possible stereoisomers of the products. These models are
based upon the following assumptions:[14e] 1) catalyst 2 re-
leases one diamine ligand that deprotonates the azaarene
substrate to form the reactive enolate; 2) binding of the eno-
[%][d]
1
2
6a
6b
83
>19:1
83
93
99[e]
10:1
3
4
5
6c Ar=p-Tol
6d Ar=o-Tol
6e Ar=p-
MeOC6H4
6f Ar=p-FC6H4
79
64
74
>19:1
6:1
>19:1
95
66
86
6
78
>19:1
>19:1
>19:1
95
89
7
6g Ar=p-BrC6H4 84
8[f]
6h Ar=2-furyl
95
>99
9
6i
85
>19:1
>19:1
96
95
10
6j
87
88
(66)
11
12
6k
73[g]
2:1[g]
43
81
(89)
6la, 6lb
1:1
(44)[h]
Figure 2. Model for stereochemical induction.
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
3
&
ÞÞ
These are not the final page numbers!

H. W. Lam and C. Fallan
knowledged for the award of a Leadership Fellowship to H. W. L. We
thank the EPSRC National Mass Spectrometry Service Centre at the
University of Wales, Swansea, for providing high-resolution mass spectra.
late to the nickel(II) center occurs through the amide
oxygen and azaarene nitrogen atoms, and 3) the nitroalkene
is bound to the nickel(II) center to stabilize the incipient ni-
tronate anion. The facial selectivity with respect to the nitro-
alkene may be explained by unfavorable nonbonding inter-
actions of the nitro group with a benzyl group of the ligand
that are present in TS 1 and TS 2 but are absent in TS 3 and
TS 4. In turn, the high diastereoselectivities observed with
5c (Table 2, entries 3 and 5–8) may be rationalized by an un-
favorable interaction of the nitro group with the benzene
ring of the benzothiazole present in TS 3, an interaction that
is absent in the favored transition state TS 4. Similar consid-
erations may be invoked to explain the high diastereoselec-
tivities observed with substrates 5a, 5b, 5d, and 5e (Table 2,
entries 1, 2, 9, and 10). Finally, the low to nonexistent diaste-
reoselectivities observed with substrates 5 f–h (Table 2, en-
tries 11–13) may be accounted for by the relatively open
space in the vicinity of the oxygen atom of the (benz)isoxa-
zole rings; this open space diminishes the unfavorable NO2–
azaarene interaction in TS 3 and thus reduces the energy
difference between TS 3 and TS 4.
Keywords: asymmetric catalysis
·
enantioselectivity
·
Michael addition · nickel · nitroalkenes
[1] a) L. Rupnicki, A. Saxena, H. W. Lam, J. Am. Chem. Soc. 2009, 131,
10386–10387; b) G. Pattison, G. Piraux, H. W. Lam, J. Am. Chem.
Soc. 2010, 132, 14373–14375.
[2] For related contributions, see: a) I. N. Houpis, J. Lee, I. Dorziotis, A.
Molina, B. Reamer, R. P. Volante, P. J. Reider, Tetrahedron 1998, 54,
1185–1195; b) A. Baschieri, L. Bernardi, A. Ricci, S. Suresh,
M. F. A. Adamo, Angew. Chem. 2009, 121, 9506–9509; Angew.
Chem. Int. Ed. 2009, 48, 9342–9345; c) H.-W. Sun, Y.-H. Liao, Z.-J.
Wu, H.-Y. Wang, X.-M. Zhang, W.-C. Yuan, Tetrahedron 2011, 67,
3991–3996.
[3] For enantioselective copper-catalyzed reductive couplings of alkeny-
lazaarenes with ketones, see: A. Saxena, B. Choi, H. W. Lam, J. Am.
Chem. Soc. 2012, 134, 8428–8431.
[4] a) B. M. Trost, D. A. Thaisrivongs, J. Am. Chem. Soc. 2008, 130,
14092–14093; b) B. M. Trost, D. A. Thaisrivongs, J. Am. Chem. Soc.
2009, 131, 12056–12057; c) B. M. Trost, D. A. Thaisrivongs, J. Hart-
wig, J. Am. Chem. Soc. 2011, 133, 12439–12441.
[5] For racemic additions of alkylazaarenes to aldehydes promoted by
stoichiometric quantities of dialkylboron triflates and trialkylamine
bases, see: a) H. Hamana, T. Sugasawa, Chem. Lett. 1983, 333–336;
b) H. Hamana, T. Sugasawa, Chem. Lett. 1984, 1591–1594.
[6] a) B. Qian, S. Guo, J. Shao, Q. Zhu, L. Yang, C. Xia, H. Huang, J.
Am. Chem. Soc. 2010, 132, 3650–3651; b) B. Qian, S. Guo, C. Xia,
H. Huang, Adv. Synth. Catal. 2010, 352, 3195–3200; c) B. Qian, P.
Xie, Y. Xie, H. Huang, Org. Lett. 2011, 13, 2580–2583; d) M. Ruep-
ing, N. Tolstoluzhsky, Org. Lett. 2011, 13, 1095–1097; e) H. Komai,
T. Yoshino, S. Matsunaga, M. Kanai, Org. Lett. 2011, 13, 1706–1709.
[7] Y. Yan, K. Xu, Y. Fang, Z. Wang, J. Org. Chem. 2011, 76, 6849–
6855.
[8] For representative examples, see: a) L.-C. Campeau, D. J. Schipper,
K. Fagnou, J. Am. Chem. Soc. 2008, 130, 3266–3267; b) D. J. Schip-
per, L.-C. Campeau, K. Fagnou, Tetrahedron 2009, 65, 3155–3164;
c) P. M. Burton, J. A. Morris, Org. Lett. 2010, 12, 5359–5361; d) G.
Song, Y. Su, X. Gong, K. Han, X. Li, Org. Lett. 2011, 13, 1968–
1971.
In conclusion, we have demonstrated that azaarylacetates
and acetamides, which, to our knowledge, have not been uti-
lized previously in catalytic asymmetric synthesis, undergo
highly enantioselective Michael additions to nitroalkenes in
the presence of a chiral nickel(II)-bisACTHNUTRGNEUNG(diamine) complex 2.
A wide variety of azaarenes that includes pyridines, pyra-
zines, triazines, isoquinolines, quinazolines, benzothiazoles,
and benz(isoxazoles) are compatible with this process, sug-
gesting it could be a useful method for the preparation of
enantioenriched chiral azaarene-containing building blocks.
As well as serving as a further demonstration of the versatil-
ity of nickel complex 2 in stereoselective carbon–carbon
bond construction,[20] this study suggests that the analogy be-
tween the carbonyl group and the C=N moiety in azaarenes
may serve as a rich platform for the development of addi-
tional catalytic enantioselective reactions. Studies in this
area are ongoing in our laboratories, and will be reported in
due course.
[9] S. Vera, Y. Liu, M. Marigo, E. C. Escudero-Adꢃn, P. Melchiorre,
Synlett 2011, 489–494.
[10] M. B. n. Cid, S. Duce, S. Morales, E. Rodrigo, J. L. G. a. Ruano, Org.
Lett. 2010, 12, 3586–3589.
[11] For examples of non-enantioselective Michael reactions of b-azaaryl
carbonyl compounds or azaarylacetonitriles, see: a) H. Beyer, W.
Lꢄssig, G. Schudy, Chem. Ber. 1957, 90, 592–598; b) W. M. Odijk,
G. J. Koomen, Tetrahedron 1985, 41, 1893–1904; c) M. Jeanty, F. Su-
zenet, G. Guillaumet, J. Org. Chem. 2008, 73, 7390–7393; d) S. H.
Kim, H. S. Lee, S. H. Kim, J. N. Kim, Tetrahedron Lett. 2009, 50,
3038–3041.
[12] For reviews of nitroalkenes as conjugate acceptors, see: a) A. G. M.
Barrett, G. G. Graboski, Chem. Rev. 1986, 86, 751–762; b) A. G. M.
Barrett, Chem. Soc. Rev. 1991, 20, 95–127; c) O. M. Berner, L. Tede-
schi, D. Enders, Eur. J. Org. Chem. 2002, 1877–1894.
[13] For selected examples of asymmetric organocatalytic additions of
1,3-dicarbonyl compounds to nitroalkenes, see: a) T. Okino, Y.
Hoashi, Y. Takemoto, J. Am. Chem. Soc. 2003, 125, 12672–12673;
b) H. Li, Y. Wang, L. Tang, L. Deng, J. Am. Chem. Soc. 2004, 126,
9906–9907; c) T. Okino, Y. Hoashi, T. Furukawa, X. Xu, Y. Takemo-
to, J. Am. Chem. Soc. 2005, 127, 119–125; d) H. Li, Y. Wang, L.
Tang, F. Wu, X. Liu, C. Guo, B. M. Foxman, L. Deng, Angew. Chem.
2005, 117, 107–110; Angew. Chem. Int. Ed. 2005, 44, 105–108; e) J.
Ye, D. J. Dixon, P. S. Hynes, Chem. Commun. 2005, 4481–4483;
Experimental Section
General procedure for nickel-catalyzed Michael additions: A mixture of
the azaarylacetate or azaarylacetamide (0.30 mmol), 3 ꢀ MS (60 mg),
and nickel catalyst 2 (12 mg, 0.015 mmol) in 1,4-dioxane (5 mL) was
stirred at room temperature for 5 min before addition of the nitroalkene
(0.30 mmol) in dioxane (1 mL) dropwise over 5 min. The mixture was
stirred for 18 h at room temperature, filtered through a short plug of
silica using EtOAc (30 mL) as eluent, and the solvent was removed in va-
cuo. Purification of the residue by column chromatography using silica
gel afforded the Michael adduct.
Acknowledgements
This work was supported by the Scottish Funding Council, the University
of Edinburgh, and Shasun Pharma Solutions. The EPSRC is gratefully ac-
&
4
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Enantioselective Nickel-Catalyzed Michael Additions
COMMUNICATION
f) S. H. McCooey, S. J. Connon, Angew. Chem. 2005, 117, 6525–
6528; Angew. Chem. Int. Ed. 2005, 44, 6367–6370; g) M. Terada, H.
Ube, Y. Yaguchi, J. Am. Chem. Soc. 2006, 128, 1454–1455; h) J. M.
Andrꢅs, R. Manzano, R. Pedrosa, Chem. Eur. J. 2008, 14, 5116–
5119; i) W.-M. Zhou, H. Liu, D.-M. Du, Org. Lett. 2008, 10, 2817–
2820; j) Y.-n. Xuan, S.-z. Nie, L.-t. Dong, J.-m. Zhang, M. Yan, Org.
Lett. 2009, 11, 1583–1586; k) H. Li, L. Zu, H. Xie, W. Wang, Synthe-
sis 2009, 1525–1530.
[16] The ee values were slightly lower in the absence of 3 ꢀ molecular
sieves. For a review of the effects of additives in asymmetric cataly-
sis, see: E. M. Vogl, H. Grçger, M. Shibasaki, Angew. Chem. 1999,
111, 1672–1680; Angew. Chem. Int. Ed. 1999, 38, 1570–1577.
[17] The stereochemistries of the products in this study were assigned by
analogy with those of products 3jb and 6e, which were determined
by X-ray crystallography (see the Supporting Information). The
sense of enantioselection imparted by the nickel complex 2 is consis-
tent with that reported in the literature (see Refs. [14d] and [14e]).
[18] Aliphatic nitroalkenes exhibited much lower reactivities in these re-
actions. See Refs. [14d] and [14e].
[19] a) D. A. Evans, M. D. Ennis, T. Le, N. Mandel, G. Mandel, J. Am.
Chem. Soc. 1984, 106, 1154–1156; b) D. A. Evans, H. P. Ng, J. S.
Clark, D. L. Rieger, Tetrahedron 1992, 48, 2127–2142; c) M. Ogata,
T. Yoshimura, H. Fujii, Y. Ito, T. Katsuki, Synlett 1993, 728–730;
d) J. Bartroli, E. Turmo, J. Belloc, J. Forn, J. Org. Chem. 1995, 60,
3000–3012; e) A. B. Smith, B. M. Brandt, Org. Lett. 2001, 3, 1685–
1688; f) Q. Liu, T. Rovis, Org. Lett. 2009, 11, 2856–2859.
[14] For selected examples of asymmetric metal-catalyzed additions of
1,3-dicarbonyl compounds to nitroalkenes, see: a) J. Ji, D. M.
Barnes, J. Zhang, S. A. King, S. J. Wittenberger, H. E. Morton, J.
Am. Chem. Soc. 1999, 121, 10215–10216; b) D. M. Barnes, J. Ji,
M. G. Fickes, M. A. Fitzgerald, S. A. King, H. E. Morton, F. A.
Plagge, M. Preskill, S. H. Wagaw, S. J. Wittenberger, J. Zhang, J.
Am. Chem. Soc. 2002, 124, 13097–13105; c) M. Watanabe, A. Ikaga-
wa, H. Wang, K. Murata, T. Ikariya, J. Am. Chem. Soc. 2004, 126,
11148–11149; d) D. A. Evans, D. Seidel, J. Am. Chem. Soc. 2005,
127, 9958–9959; e) D. A. Evans, S. Mito, D. Seidel, J. Am. Chem.
Soc. 2007, 129, 11583–11592; f) W.-Y. Chen, L. Ouyang, R.-Y. Chen,
X.-S. Li, Tetrahedron Lett. 2010, 51, 3972–3974.
[20] For application of 2 in complex total synthesis, see: J. Chen, J. Chen,
Y. Xie, H. Zhang, Angew. Chem. 2012, 124, 1048–1051; Angew.
Chem. Int. Ed. 2012, 51, 1024–1027.
[15] For application of a similar complex in the catalytic enantioselective
addition of a-ketoesters to nitroalkenes, see: A. Nakamura, S. Lec-
tard, D. Hashizume, Y. Hamashima, M. Sodeoka, J. Am. Chem. Soc.
2010, 132, 4036–4037.
Received: June 13, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
&
5
&
ÞÞ
These are not the final page numbers!

H. W. Lam and C. Fallan
Asymmetric Catalysis
C. Fallan, H. W. Lam* . . . . . . &&&& — &&&&
Enantioselective Nickel-Catalyzed
Michael Additions of Azaarylacetates
and Acetamides to Nitroalkenes
Put a nickel in it: Azaarylacetates and
acetamides, which have been neglected
as substrates in catalytic asymmetric
synthesis, undergo highly enantioselec-
tive Michael additions to nitroalkenes
in the presence of a chiral nickel(II)-
bisACTHNUTRGENUG(N diamine) complex (see scheme;
Bn=benzyl, MS=molecular sieves).
This process is tolerant of a wide vari-
ety of azaarenes in the pronucleophile.
&
6
&
www.chemeurj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!