Enantioselective Michael reaction of 1,3-dicarbonyl compounds to 3-nitro-2H-chromenes catalyzed by chiral nickel complexes

Article abstract of DOI:10.1016/j.tetlet.2010.05.111

A chiral nickel complexes-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to 3-nitro-2H-chromenes has been developed; the products could be obtained in high yields and good enantioselectivities.

Full text of DOI:10.1016/j.tetlet.2010.05.111

Tetrahedron Letters 51 (2010) 3972–3974
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Tetrahedron Letters
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Enantioselective Michael reaction of 1,3-dicarbonyl compounds
to 3-nitro-2H-chromenes catalyzed by chiral nickel complexes
b
b
b,
Wei-Yi Chen a, , Luo Ouyang , Rui-Ye Chen , Xin-Sheng Li
*
*
a College of Chemistry, Chemical Engineering and Materials Science, Suzhou University, Suzhou 215123, China
b Zhejiang Key Laboratory for Reactive Chemistry on Solid Surfaces, Institute of Physical Chemistry, Zhejiang Normal University, Jinhua 321004, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A chiral nickel complexes-catalyzed enantioselective Michael addition of 1,3-dicarbonyl compounds to 3-
nitro-2H-chromenes has been developed; the products could be obtained in high yields and good
enantioselectivities.
Received 11 April 2010
Revised 16 May 2010
Accepted 25 May 2010
Available online 27 May 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Chiral nickel complexes
Michael reaction
3-Nitro-2H-chromene
1,3-Dicarbonyl compound
Asymmetric catalysis
The Michael addition reaction is widely recognized as one of the
most general and versatile methods for formation of C–C bonds in
organic synthesis;1 among which, the Michael reaction of nitroole-
fins represents a convenient access to nitroalkanes that are versa-
tile intermediates in organic synthesis, because the nitro
functionality can be easily transformed into amine, nitrile oxide,
ketone or carboxylic acid, hydrogen, etc., providing a wide range
of synthetically interesting compounds.2 Up to now, the develop-
ment of enantioselective catalytic protocols for this asymmetric
Michael addition to nitroalkenes has been a subject of intensive
research,3 for these optically active nitroalkanes are versatile
building blocks for agricultural and pharmaceutical compounds.
Although there have been many reports of enantioselective
Michael additions with chiral catalysts, including metal-based cat-
alysts and multimetallic catalysts as well as organic catalysts,
practical Michael additions of 1,3-dicarbonyl compounds to nitro-
alkenes remain largely unexplored except for reactions with chiral
Mg catalysts4 and optically active thioureas as efficient catalysts.
However, despite the tremendous amount of work and effort de-
voted to the development of efficient and versatile Michael reac-
tions, the structure of the electrophile has been restricted to
nitroalkenes, enones,5 and unsaturated imides,6 and the enantiose-
lective Michael reaction using cyclic nitroalkenes7 as the acceptors
has been relatively unexplored. Here, we have developed a highly
enantio- and anti-selective Michael reaction of 1,3-dicarbonyl com-
pounds and readily available cyclic nitroalkenes with chiral nickel
complexes8 as the catalysts (indicated by NMR spectroscopy). The
reactions could afford highly functionalized products with two
adjacent stereogenic carbon atoms in high levels of enantio- and
diastereoselectivities, and the Michael products are interesting cyclic
b-amino acid derivatives.
NO2
O
NO2
COOR
COOR
only anti-product
*
O
COOR
chiral Nickel complexes
+
X
*
X
COOR
R
R
NH
NH
X
Ni
X
NH
NH
R
R
R
R
R
R
Our initial studies began with the catalytic asymmetric Michael
addition of 3-nitro-2H-chromene (2a) with dimethyl malonate (3a)
in the catalytic amount of chiral nickel complexes (1a–h). The chi-
ral complexes were prepared by reacting nickel salts and chiral
diamine ligands smoothly, and it was found that the expected
Michael addition products could be obtained by aqueous workup
and column chromatography in good yields. The results are sum-
marized in Table 1.
* Corresponding authors. Tel.: +86 512 65882845; fax: +86 512 65880305
(W.-Y.C.).
First, the effects of a number of different counterions were sur-
veyed. The asymmetric Michael addition reaction carried out at
E-mail address: chenweiyi@suda.edu.cn (W.-Y. Chen).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.111

W.-Y. Chen et al. / Tetrahedron Letters 51 (2010) 3972–3974
3973
room temperature in DCM afforded the product in high yields and
good enantioselectivities (Table 1, entries 1–4). Among which, the
use of NiBr2, catalyst 1b turned out to be the best catalyst in terms
of yield and enantioselectivity.
As shown in Table 2, under the optimized reaction conditions,
all of the 3-nitro-2H-chromenes could furnish the corresponding
products in high enantioselectivities (80–95% ee) and good yields,
and only the anti-products were observed in the reactions. In con-
trast to the 3-nitro-2H-chromene derivatives, substrates bearing
an electron-donating substituent on the aromatic ring tended to
decrease their reactivity without affecting the good enantioselec-
tivity. Other 1,3-dicarbonyl compounds, such as acetylacetone
and dibenzoylmethane, were also tested under the optimized reac-
tion conditions; unfortunately, only the rac-products were ob-
tained with high yields. Meanwhile, due to the steric demands of
the malonate residue, longer reaction times were needed when
dibenzyl malonate was applied as the starting material.
Next, the effects of the solvent and temperature were also inves-
tigated (Table 1, entries 5–12). The Michael addition reaction carried
outat0 °C intolueneaffordedthedesiredproductwith92%yieldand
95% ee. Slight decrease of selectivities and yields were found when
the reactions were carried out in other solvents or at other temper-
atures. It was found that the reaction could also proceed smoothly
in polar solvent; however, the product was obtained with just 78%
ee. Meanwhile, the amount of catalyst had been optimized to
5 mol %, there was no significant increase in the yield and enantiose-
lectivity by increasing the catalyst amount to 10 mol %; the reaction
proceeded sluggishly with a slight drop in enantioselectivity when
the catalyst loading was reduced to 2 mol %. Therefore, the optimum
reaction conditions were achieved by performing the reaction of
1 equiv of 3-nitro-2H-chromene with 1.5 equiv of dimethyl malon-
ate and 5 mol % catalyst loading at 0 °C in toluene.
Prompted by these results, several other chiral diamine ligands
were synthesized, and their catalytic activities were also screened
with NiBr2 under the optimized reaction conditions (Table 1, entries
13–16). From the results, it was found that the products could be ob-
tained in comparable yields and enantioselectivities, lower catalytic
activity and stereoselectivity toward the reaction was observed.
Through this screening process, the following points could be
established: (1) The use of chiral nickel complexes, which were pre-
pared from chiral diamine ligands and nickel salts, gave the Michael
addition products in good yields with high enantioselectivities. Of
these complexes surveyed, the chiral nickel complex (1b) provided
superior levels of asymmetric induction, affording the Michael addi-
tion product in 95% ee (Table 1, entry 11). (3) In all cases tested, only
anti-selective Michael addition products were obtained (indicated
by NMR spectroscopy), no undesired side products were found un-
der these reaction conditions; and this method did not require any
other additives to promote the reaction.
The 1b-catalyzed enantioselective Michael reaction of 1,3-dicar-
bonyl compounds to 3-nitro-2H-chromene was also applicable to
chiral cyclo
mote enantioselective Michael reaction should facilitate the prepa-
ration of a wide variety of optically active cyclo -amino butylic acid.
c-amino butylic acid (Scheme 1). The ability of 1b to pro-
c
In conclusion, this Letter has described an efficient method for
the asymmetric direct Michael addition that employs 3-nitro-2H-
chromenes as the acceptors in the presence of a catalytic amount
of air- and moisture-stable chiral nickel complexes. The chiral
NO2
O
NO2
NO2
O
O
MeO
OMe
2a
2b
2c
NO2
NO2
NO2
O
O
O
NO2
O
Me
Having optimized the reaction conditions, we extended the cat-
alytic enantioselective Michael addition to a wide variety of 3-ni-
tro-2H-chromenes (Fig. 1) in the presence of the optimized chiral
nickel complex (1b). The results obtained are shown in Table 2.
Br
Me
Cl
2d
2e
2f
2g
Figure 1. Structures of 3-nitro-2H-chromenes.
Table 1
Optimization of the reaction conditionsa
NO2
NO2
O
*
O
COOMe
chiral Nickel complexes
COOMe
+
*
COOMe
COOMe
Entry
R
X
Solvent
T (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph (1a)
Ph (1b)
Ph (1c)
Ph (1d)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
Ph (1b)
4-FC6H4 (1e)
4-ClC6H4 (1f)
4-BrC6H4 (1g)
4-MeOC6H4 (1h)
Cl
DCM
DCM
DCM
DCM
THF
EA
Toluene
EtOH
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
20
20
20
20
20
20
20
20
50
10
0
ꢀ20
20
20
20
20
10
10
48
20
10
10
10
30
4
15
24
48
24
24
24
10
90
92
84
88
86
90
92
88
94
91
92
48
75
79
82
84
86
89
85
87
89
87
90
78
89
93
95
96
86
84
85
82
Br
Ac
TfO
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
Br
a
b
c
All reactions were performed on a 0.5 mmol scale with 5 mol % of catalyst at a 1 M concentration using 1.5 equiv of dimethylmalonate.
Isolated yield.
Enantiomeric excess was determined by chiral HPLC analysis using a Chiralcel AD-H column.

3974
W.-Y. Chen et al. / Tetrahedron Letters 51 (2010) 3972–3974
Table 2
6.88 (d, J = 8.0 Hz, 1H), 5.26 (q, J = 6.8 Hz, 1H), 4.77–4.73 (m, 1H),
4.49–4.47 (m, 1H), 4.41–4.37 (m, 1H), 3.94 (d, J = 7.2 Hz, 1H),
3.70 (s, 6H); 13C NMR (100 MHz, CDCl3): d 167.6, 167.5, 153.8,
129.2, 128.6, 122.1, 118.4, 117.6, 80.9, 64.5, 55.2, 53.04, 53.03,
35.9; Exact mass calcd for [C14H15NO7+H]: 310.2793, found
310.2788; The enantiomeric ratio was determined by HPLC on
Chiralpak AD-H column (10% 2-propanol/hexane, 1 mL/min),
tminor = 12.217 min, tmajor = 13.575 min.
Enantioselective Michael addition reaction of malonates to 3-nitro-2H-chromenesa
NO2
*
NO2
O
O
COOR
COOR
COOR
COOR
1b
*
+
X
Toluene, 0oC
X
only anti-product
2a-g
3a-b
4
Entry
2
R
Product
Time (h)
Yieldb (%)
eec (%)
Supplementary data
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2a
2c
2d
2f
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Me (3a)
Bn (3b)
Bn (3b)
Bn (3b)
Bn (3b)
Bn (3b)
4aa
4ba
4ca
4da
4ea
4fa
4ga
4ab
4cb
4db
4fb
4gb
24
30
30
20
20
24
24
30
36
30
30
30
92
82
81
91
96
88
91
88
80
90
88
91
95
80
88
92
92
84
86
91
91
90
92
92
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.111.
References and notes
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10
11
12
2g
a
All reactions were performed with 0.5 mmol of 2, 0.6 mmol of 3, 5 mol % of
catalyst in 0.5 mL of toluene at 0 °C.
b
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Isolated yield.
c
Enantiomeric excess was determined by chiral HPLC analysis using Chiralcel
AD-H column.
NO2
NO2
CO2Me
CO2Me
*
*
O
O
OH
b
a
96%
92% ee
Cl
CHO
Cl
Cl
*
NH2.HCl
CO2H
NH2
*
*
O
O
c
d
CO2Me
*
86%
88%
CO2Me
[α] D24 = + 47.3
(c 0.68, MeOH)
Cl
Cl
Scheme 1. Asymmetric synthesis of chiral cyclo
Supplementary data for details). Reagents and conditions: (a) n-Bu4NCl/nitroeth-
anol; (b) dimethyl malonate, 1b, toluene; (c) NaBH4, NiCl2ꢂ6H2O; (d) 6 N HCl, reflux.
c
-amino butylic acid (see
4. (a) Ji, J.; 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.; 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.
nickel complex 1b exhibited high stereoselectivity and catalytic
activity in the asymmetric Michael addition. The corresponding
Michael addition products were obtained in high yields and good
diastereo- and enantioselectivities. We believe that this method
could provide an efficient route for the preparation of chiral cyclo
5. (a) Hiemstra, H.; Wynberg, H. J. Am. Chem. Soc. 1981, 103, 417; (b) Hanessian, S.;
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c-amino butylic acid derivatives, and the availability of these com-
pounds may facilitate medicinal chemical studies in various fields.
Further work on applying this kind of chiral nickel complexes for
other organic transformations is in progress.
Typical procedure for asymmetric conjugate addition of 1,3-
dicarbonyl compounds 2 to 3-nitro-2H-chromenes 3: To a stirred
mixture of chiral nickel catalyst (5 mol %) and 3 (0.5 mmol) in tol-
uene (0.5 mL) was added 2 (0.6 mmol) at 0 °C, and the resulting
mixture was stirred for the amount of time indicated. Then, the
reaction mixture was concentrated, and the residue was purified
by column chromatography on silica gel to afford the desired prod-
7. Daniel, D.; Rene, R. Synthesis 1984, 348.
8. (a) Evans, D. A.; Mito, S.; Seidel, D. J. Am. Chem. Soc. 2007, 129, 11583; (b) Fossy, J.
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Kanemasa, S. J. Am. Chem. Soc. 2002, 124, 13394; (e) Evans, D. A.; Seidel, D. J. Am.
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Org. Lett. 2005, 7, 979.
uct 4. Compound 4aa ½a D24
ꢁ
= +50.6 (c 0.33, DCM), 95%ee; 1H NMR
(400 MHz, CDCl3): d 7.20–7.16 (m, 2H), 6.96 (t, J = 7.4 Hz, 1H),