Enantioselective synthesis of nitrocyclopropanes via conjugate addition of bromomalonate to nitroalkenes catalyzed by Ni(II) complexes

Article abstract of DOI:10.1016/j.tetlet.2012.04.072

A novel one-pot methodology for the catalytic enantioselective synthesis of highly functionalized nitrocyclopropanes promoted by chiral nickel complexes is developed. The treatment of bromomalonates with nitroalkenes under the mild reaction conditions aff

Full text of DOI:10.1016/j.tetlet.2012.04.072

Tetrahedron Letters 53 (2012) 3437–3439
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Enantioselective synthesis of nitrocyclopropanes via conjugate addition
of bromomalonate to nitroalkenes catalyzed by Ni(II) complexes
⇑
Hyun Joo Lee, Sun Mi Kim, Dae Young Kim
Department of Chemistry, Soonchunhyang University, Asan, Chungnam 336-745, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel one-pot methodology for the catalytic enantioselective synthesis of highly functionalized nitro-
cyclopropanes promoted by chiral nickel complexes is developed. The treatment of bromomalonates with
nitroalkenes under the mild reaction conditions afforded the corresponding Michael adducts which
cyclizes to controlled reaction conditions with excellent diasteroselectivities (>99 de) and enantioselec-
tivities (up to 99% ee).
Received 16 March 2012
Revised 13 April 2012
Accepted 18 April 2012
Available online 28 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Cyclopropanation
Asymmetric catalysis
Chiral nickel catalysts
Nitroalkenes
Conjugate addition
The cyclopropane ring is a important structural motif in a great
number of natural products and biologically active agents.1 In
addition, cyclopropyl derivatives are also valuable as synthetic
building blocks in organic synthesis.2,3 Cyclopropanes are suscepti-
ble to ring opening reaction with many nucleophilic reagents due
to high strain of the cyclopropane ring. A number of efforts have
been made to develop efficient synthetic methods of chiral cyclo-
propanes.4 Nitrocyclopropanes are a class of special cyclopropane
compounds, which are constituent of a diverse assortment of nat-
ural products.5 Furthermore, chiral nitrocyclopropanes can be con-
verted into a wide range of useful chiral compounds.6 Over the past
decade, tremendous effort has been devoted to the development of
efficient and stereoselective methodologies for cyclopropanation of
alkenes using chiral organometallic carbenoid species and yields4
achieved a highly diastero- and enantioselective synthesis of nitro-
cyclopropanes via the highly enantioselective conjugate addition
of bromomalonates to nitroalkenes using 60-demetyl quinine as
catalyst and consequent DABCO-mediated ring-closure. Nonethe-
less, the development of alternative catalysts for nitrocyclopropa-
nation via the addition of halomalonates to nitroalkenes would
be highly desirable. Recently, the efficient examples of the enantio-
selective reactions catalyzed by air- and moisture-stable nickel
complexes were reported.10 To the best of our knowledge, nitrocy-
clopropanation via the addition of bromomalonates to nitroalkenes
catalyzed by chiral nickel complexes has not been reported.
As part of research program related to the development of
synthetic methods for the enantioselective construction of stere-
ogenic carbon centers,11 we recently reported the catalytic elec-
trophilic amination, fluorination, and Michael addition reaction
of active methines promoted by chiral nickel complexes with
excellent enantioselectivities.12 In this Letter, we wish to describe
and cyclopropanation of
a,b-unsaturated aldehydes and ketones
using organocatalysts.7
On the other hand, the asymmetric synthesis of nitrocyclopro-
panes via the addition of chloromalonates to nitroalkenes and con-
sequent ring-closure of Michael adducts was reported by Connon
and co-workers.8 This reaction provided the nitrocyclopropanes
in moderate yields and enantioselectivities using cinchona alkaloid
derived thioureas as the catalysts. The similar approach has been
recently developed by Takemoto, Yan, and Lattanzi groups using
organocatalysts such as chiral bifunctional thioureas, 60-demetyl
Ar
Ar
Ar
H
N
H
N
H
N
H
N2
Br
Ni
Br
Br
Ni
Br
H
H
H
N
N
N
N
H2
Ar
Ar
Ar
quinine, or
a,a-diaryl prolinols to access highly functionalized
nitrocyclopropanes (Scheme 1).9 Among them, Yan and co-workers
4a : Ar = phenyl
4d : Ar = phenyl
4e : Ar = 1-naphthyl
4b : Ar = 4-fluorophenyl
4c : Ar = 1-naphthyl
⇑
Corresponding author. Tel.: +82 41 530 1244; fax: +82 41 530 1247.
E-mail address: dyoung@sch.ac.kr (D.Y. Kim).
Figure 1. Structures of chiral nickel catalysts.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.072

3438
H. J. Lee et al. / Tetrahedron Letters 53 (2012) 3437–3439
Table 2
NO2
X
R
RO2C
R
CO2R
NO2
Catalytic enantioselective cyclopropanation
RO2C
R
CO2R
NO2
cat.
base
+
1) cat. 4b (5 mol%)
RO2C
Ar
CO2R
NO2
RO2C
CO2R
CH2Br2, rt
RO2C
CO2R
NO2
+
Ar
2) DBU, HMPA
THF, 2 h
Br
X
2
1
3
Scheme 1. Route to nitrocyclopropanes.
Entry
1, Ar
2, R
Time (h)
Yielda (%)
3a, 87
Eeb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1a, Ph
1a, Ph
2a, Me
2b, Et
2a, Me
2b, Et
2a, Me
2b, Et
2a, Me
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
64
24
64
42
64
17
64
42
17
24
22
70
20
96
94
97
96
99
97
99
91
98
98
91
93
99
91
85
enantioselective conjugate addition of bromomalonates to nitro-
alkenes catalyzed by air- and moisture-stable chiral nickel com-
plexes (Fig. 1). The consequent intramolecular cyclopropanation
provided nitrocyclopropanes in good yields and with excellent
enantioselectivities.
3b, 99
3c, 89
3d, 96
3e, 86
3f, 97
3g, 85
3h, 92
3i, 95
3j, 93
3k, 90
3l, 89
3m, 91
3n, 70
1b, p-MeOC6H4
1b, p-MeOC6H4
1c, p-MeC6H4
1c, p-MeC6H4
1d, p-BrC6H4
1e, p-ClC6H4
1f, p-FC6H4
1g, o-NO2C6H4
1h, o-BrC6H4
1i, 2-thienyl
1j, 2-furyl
To determine suitable reaction conditions for the catalytic
enantioselective cyclopropanation reaction of nitroalkenes, we first
examined cyclopropanation reaction of nitrostyrene (1a) with
bromomalonates 2 in the presence of 5 mol % of dicationic nickel
complexes 4 in CH2Cl2 at room temperature (Table 1). We studied
the effect of the ester group of bromomalonates 2 using nickel cat-
alyst 4a in CH2Cl2 (entries 1 and 2). Diethyl bromomalonates (2b)
showed better enantioselectivity (entry 2). We surveyed the effect
of structure of nickel complexes 4. High yields with excellent
enantioselectivities (92–96% ee) were observed for structurally
variable nickel catalysts 4a–c (entries 2–4). Under the standard
reaction conditions, catalyst 4b gave better enantioselectivity
(96% ee, entry 3). However, N-monobenzyl cyclohexanediamine-
derived Ni complexes (4d–e) were not effective in this reaction
(entries 5 and 6). Next, we examined the reaction in various sol-
vents (entries 3 and 7–11). The use of CH2Cl2, toluene, dibromo-
methane and 1,2-dichloroethane gave the good results, whereas
the cyclopropanation reaction in MeOH and acetone gave lower
enantioselectivities. The absolute configuration of 3a was estab-
lished by comparison of the optical rotation and chiral HPLC anal-
ysis with previously reported values.9
1k, 1-naphthyl
a
Isolated yield: Only trans-isomer was observed by NMR analysis.
Enantiopurity was determined by HPLC analysis using chiralpak AD–H (for
b
3a–c, 3e–g, and 3m), AS (for 3d, 3h, 3i, 3k, 3l, and 3n) and chiralcel OD–H (for 3j)
columns.
H
H
O
Ni
O
N
N
O
N
O
F
F
RO
OR
Ph
Br
With optimal reaction condition in hand, we studied the gener-
ality of the enantioselective cyclopropanation reaction of aromatic
and heteroaromatic nitroalkenes 1 with bromomalonates 2.13 As it
can be seen by the results summarized in Table 2, the correspond-
ing cyclopropane derivatives 3a–n were obtained in high yields
with enantioselectivities (85–99% ee).
Although the reason for the observed enantioselectivity is still
unclear, we suppose that bromomalonates 2 are activated by the
nickel catalyst 4 in a bidentate fashion. Then, bromomalonates an-
Figure 2. Proposed transition state model for the conjugate addition.
ion attacks the si-face of double bond of nitroalkene as shown in
Figure 2.
In conclusion, we have developed an efficient catalytic cyclo-
propanation reaction of nitroalkenes with bromomalonates using
air- and moisture-stable chiral nickel complexes at room tempera-
ture. The desired cyclopropane derivatives 3 were obtained in high
yields, excellent diasteroselectivities (>99 de) and excellent enanti-
oselectivities (85–99% ee) were observed for all the substrates
examined in this work. We believe that this report provides a prac-
tical method for the preparation of chiral nitrocyclopropane deriv-
atives, and the availability of these compounds should facilitate
biochemical and medicinal studies in various fields.
Table 1
Optimization of the reaction conditions
1) cat. 4 (5 mol%)
RO2C
Ph
CO2R
NO2
RO2C
CO2R
solvent, rt
NO2
+
Ph
2) DBU, HMPA
THF, 2 h
Br
3
2
1a
Acknowledgments
Entry
2, R
Cat. 4
Solvent
Time (h)
Yielda (%)
3a, 90
3b, 92
3b, 98
3b, 89
nr
eeb (%)
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF)
funded by the Ministry of Education, Science and Technology
(2011-0002488)
1
2
3
4
5
6
7
8
9
2a, Me
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
2b, Et
4a
4a
4b
4c
4d
4e
4b
4b
4b
4b
4b
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
DBM
DCE
72
72
24
24
72
72
24
24
24
24
24
92
94
96
92
—
nr
—
References and notes
3b, 95
3b, 99
3b, 95
3b, 70
3b, 85
95
97
96
65
75
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a
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b
column.

H. J. Lee et al. / Tetrahedron Letters 53 (2012) 3437–3439
3439
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13. Typical procedure: To a stirred solution of methyl bromomalonate (2a, 47.2 mg,
0.22 mmol), Ni-catalyst 4b (8.2 mg, 0.01 mmol) in dibromethane (0.4 mL) was
added nitrostyrene (1a, 29.8 mg, 0.2 mmol) at room temperature. The reaction
mixture stirred for 64 h at room temperature. The reaction mixture was diluted
with HMPA (2 mL), and DBU (30.8 lL, 0.21 mmol) in THF (0.2 mL) was added
dropwise with vigorous stirring. The reaction mixture was stirred for 2 h, the
resulting mixture was extracted with EtOAc (20 mL), then washed with sat.
NH4Cl. The organic layer was dried over anhydrous MgSO4, filtered,
concentrated, and purified by flash column chromatography (EtOAc/hexane:
1/6)
to
afford
(2S,3R)-dimethyl
2-nitro-3-phenylcyclopropane-1,1-
dicarboxylate (3a, 87% yield, 48.5 mg). ½a D20
ꢀ
= +37.5 (c = 1.0, CHCl3); 1H NMR
(CDCl3) d 7.37–7.31 (m, 3H), 7.28–7.25 (m, 2H), 5.39 (d, J = 6.2 Hz, 1H), 4.19 (d,
J = 6.2 Hz, 1H), 3.83 (s, 3H), 3.54 (s, 3H); 13C NMR (CDCl3) d 163.8, 163.6, 130.1,
128.7, 128.6, 128.2, 66.1, 53.9, 53.3, 46.1, 37.8; MS (ESI): m/z = 280.1 [M+H]+;
HPLC (90:10, n-hexane/i-PrOH, 254 nm, 1.0 mL/min) Chiralpak AD–H column,
tR = 7.0 min (minor), 8.1 min (major), 94% ee.