Asymmetric Michael addition of nitroalkanes to nitroalkenes catalyzed by C2-symmetric tridentate bis(oxazoline) and bis(thiazoline) zinc complexes

Article abstract of DOI:10.1021/ja0604008

The first asymmetric synthesis of 1,3-dinitro compounds through Michael addition of nitroalkanes to nitroalkenes catalyzed by C₂-symmetric chiral tridentate bis(oxazoline) and bis(thiazoline) zinc complexes was achieved with high enantioselecti

Full text of DOI:10.1021/ja0604008

Published on Web 05/17/2006
Asymmetric Michael Addition of Nitroalkanes to Nitroalkenes Catalyzed by
2
C -Symmetric Tridentate Bis(oxazoline) and Bis(thiazoline) Zinc Complexes
Shao-Feng Lu, Da-Ming Du,* Jiaxi Xu, and Shi-Wei Zhang
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and
Molecular Engineering, College of Chemistry and Molecular Engineering, Peking UniVersity,
Beijing 100871, China
Received January 18, 2006; E-mail: dudm@pku.edu.cn
In carbon-carbon bond formation reactions, the use of nitro-
1
alkanes as a source of stabilized carbanions and the use of
2
nitroalkenes as Michael acceptors have attracted significant interest
in recent years. Because of the activating effect of the nitro group,
as well as its facile transformation to a legion of diverse functional-
ity, nitro compounds have been useful in the synthesis of complex
3
molecules. The conjugate addition of nitroalkanes to nitroalkenes
is particularly interesting because the reaction products (1,3-dinitro
compounds) are precursors of a variety of other 1,3-difunctionalized
Figure 1. C2-Symmetric tridentate bis(oxazoline)s and bis(thiazoline)s.
Table 1. Asymmetric Catalytic Addition of Nitroethane to
â-Nitrostyrenea
4
5
compounds, heterocycles, carbohydrate derivatives, and potentially
6
active energetic materials. However, to our best knowledge, no
studies on the catalytic asymmetric synthesis of optically active
1
,3-dinitro compounds have appeared.7
Our laboratory has demonstrated a family of chiral C
tridentate bis(oxazoline) 1 and bis(thiazoline) 2 ligands (Figure
2
-symmetric
T
conv
(%)
yieldb
(%)
drc
ee%d
(syn)
8
entry
ligand
(
°
C)
(syn:anti)
1
) for Lewis acid-catalyzed Henry reaction of nitromethane with
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
2c
2e
1c
1c
1c
rt
rt
rt
rt
rt
rt
rt
65
0
rt
52
48
96
46
26
74
11
80
50
95
43
44
82
44
21
54
nd
32
50
83
5.8:1
5.3:1
6.1:1
3.8:1
only syn
11.7:1
80
38
91
71
78
95
9
R-keto esters. In this reaction, a dinuclear zinc catalyst is proposed
to activate R-keto esters and to orient nitromethane simultaneously.
9b
g
Intrigued by the dinuclear zinc catalysts,9b,10 we investigated their
activities in the Michael addition. Herein, we report the first
asymmetric synthesis of 1,3-dinitro compounds through the catalytic
Michael addition of nitroalkanes to nitroalkenes. High enantio-
selectivities (up to 95% ee) are achieved.
g
0.7:1
6.2:1
6.5:1
83
82
85
e
9
f
10
Our initial exploratory efforts involved screening of ligands 1
and 2 for the addition of â-nitrostyrene in neat nitroethane, using
2
assigned to be syn according to the literature. However, even in
the best case (ligand 2c), results were unsatisfactory (44% yield,
1
polar solvent might help to desolvate the carbanionic intermediate
and thus alter its reactivity. Thus, we added nonpolar solvents to
the system and added Ti(O Pr)
a
Unless noted otherwise, reactions were carried out with 1 equiv of
0 mol % catalyst for 5 days. The major Michael adduct was
â-nitrostyrene (0.50 mmol), 4 equiv of nitroethane, 10 mol % ligand, 25
mol % Et2Zn, and 80 mol % Ti(O Pr)4 in a mixture of 1.2 mL of toluene
7a
i
b
and 0.8 mL of hexane for 3 days. Yield isolated after silica gel
chromatography. c Determined by H NMR. Determined by HPLC through
1
d
1.0:1 syn:anti, 69% ee). We hypothesized that addition of a less
e
the thiourea derivative; see Supporting Information. Reaction performed
by using 20 equiv of nitroethane. f Al(OiPr) was used instead of Ti(OiPr) .
3
4
g
After recrystallization from EtOH, the ee could reach >99%.
i
4
2
to activate Et Zn. Fortunately, both
when the molar ratio of nitroethane to â-nitrostyrene was increased
to 20:1. We also tried Al(O Pr) instead of Ti(O Pr) to accelerate
the catalytic circulation (entry 10), and comparable result (95%
conv, 83% yield, 6.5:1 syn:anti, 85% ee) was achieved.
the yield and enantioselectivity were improved significantly (Table
). These results indicate that bis(oxazoline) and bis(thiazoline)
i
i
3
4
1
ligands show similar enantiofacial selectivity. Ligand 1e showed
excellent diastereoselectivity with very low yield possibly due to
bulky tert-butyl groups near the reactive center (entry 5). Ligands
Results obtained in the addition of nitroalkanes to a variety of
nitroalkenes are summarized in Table 2. The temperature of the
reaction using 1c as the chiral ligand was kept at 30 °C. High
enantioselectivities were achieved with a series of substituted phenyl
nitroalkenes bearing electron-donating and electron-withdrawing
substituents (entries 1-11, 86-95% ee). These substrates afforded
acceptable syn diastereoselectivity (3.8-11.7:1 syn:anti). Naphth-
2-yl nitroethene 3i (entries 12 and 13, 3.8-7.4:1 syn:anti, 88% ee)
and fur-2-yl nitroethene 3j (entry 14, 6.7:1 syn:anti, 88% ee)
afforded good enantioselectivity and provided products with
synthetically useful levels of diastereoselectivity, too. Bis(thiazoline)
2c gave better diastereoselectivity than bis(oxazoline) 1c in our
experiments (entries 2 vs 1, 4 vs 3, 9 vs 8, and 13 vs 12,
respectively) but with slightly reduced yields. This asymmetric
1
c (entry 3) and 2c (entry 6) bearing phenyl substituents provided
significantly better enantioselectivity (up to 95% ee) than alkyl-
substituted ligands. Ligand 1c appeared to give higher performance
than ligand 2c in both substrate conversion (96% vs 74%) and
product yield (82% vs 54%).
We therefore selected ligand 1c to further optimize the reaction
conditions. Preliminary investigations suggest that the reaction is
optimally performed at or near room temperature (entries 3, 8, and
9). On one hand, high temperature might accelerate the side reaction
of â-nitrostyrene, such as dimerization and polymerization, reducing
the yield of the desired product (entry 8). On the other hand, lower
temperature decelerated the Michael addition significantly even
7418
9
J. AM. CHEM. SOC. 2006, 128, 7418-7419
10.1021/ja0604008 CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Derivation of 1,3-Dinitroalkane
Table 2. Asymmetric Catalytic Addition of Nitroalkanes to
Representative Nitroalkenes
a
conv yieldb
drc
product ee%d
entry
R1
R2
R3
(%)
(%)
(syn:anti)
(syn)
(syn)
1
2
3
4
5
6
7
8
Ph
Ph
Me
Me
Me
Me
Me
Me
H
91
74
99
91
92
96
74
94
93
89
87
92
85
93
91
95
98
87
54
83
75
83
90
67
80
79
87
83
83
66
67
68
80
88
0
5.8:1
11.7:1
6.1:1
6.9:1
6.5:1
5.8:1
9.6:1
3.9:1
9.3:1
6.2:1
3.8:1
3.8:1
7.4:1
6.7:1
5.2:1
3.4:1
4.1:1
4a
4a
4b
4b
4c
4d
4e
4f
90
95
91
89
89
91
86
91
92
90
91
88
88
88
e
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Regarding the reaction mechanism, we propose that the tridentate
4-MeC6H4
4-MeC6H4
4-MeOC6H4
2-MeOC6H4
9b
2
ligand and Et Zn form a dinuclear Zn(II) complex. One zinc atom
e
could activate the nitroalkene through the coordination of the nitro
group to the Lewis acid center. Another zinc atom coordinates to
the nitro group of nitronate. The Michael addition proceeds by the
nucleophilic attack of nitronate on the nitroalkene from the Re face
3,4-(MeO)2C6H3 Me
4-FC6H4
4-FC6H4
2-FC6H4
2-ClC6H4
naphth-2-yl
naphth-2-yl
fur-2-yl
4-ClC6H4
PhCH2CH2
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
e
9
4f
(
see Supporting Information) to afford the observed stereochemistry.
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
4g
4h
4i
4i
4j
4k
4l
4m
i
The presence of Ti(O Pr)
it may activate the Et Zn through the formation of an ate complex.
4
seems to be crucial for the reaction, and
2
e
In summary, bis(oxazoline) ligand 1c and bis(thiazoline) ligand
c were found to promote the Zn(II)-catalyzed stereoselective
2
f
nd
72
88
addition of nitroalkanes to a range of nitroalkenes. This new
procedure represents an important advance in the chemistry of the
nitro group, allowing the catalytic asymmetric synthesis of 1,3-
dinitroalkanes with high diastereoselectivity and enantioselectivity.
These 1,3-dinitroalkanes can be conveniently transformed to the
corresponding enantioenriched 1,3-diamines and cyclic thioureas.
Ph
Me Me 10
a
b
For reaction conditions, see Table 1 or Supporting Information. Yield
c
1
d
isolated after silica gel chromatography. Determined by H NMR. De-
termined by HPLC directly or through thiourea derivatives; see Supporting
Information. Ligand 2c was used instead of 1c, and the reaction was
e
f
Acknowledgment. We thank the National Natural Science
conducted at room temperature. Enantiomers of 4k and its thiourea
derivative cannot be separated by HPLC.
Foundation of China (Grant Nos. 20372001, 20572003, and
2
0521202) and Peking University for financial support.
Michael addition was successfully extended to 2-phenylethyl-
substituted nitroalkene 3l, and 72% ee was obtained (entry 16);
however, aliphatic alkyl-substituted nitroalkenes produced mixtures
of diastereoisomers that could not be analyzed by 1H NMR
spectroscopy. Other normal nitroalkanes can also be used as Michael
donors in this addition. The addition of nitromethane to â-nitro-
styrene afforded achiral product in 85% yield. The addition of
Supporting Information Available: Experimental procedures,
copies of spectra, and the crystal data of 4f and 4d (CIF file). This
material is available free of charge via the Internet at http://pubs.acs.org.
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-nitropropane to â-nitrostyrene afforded the corresponding syn
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their optical purity.
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hydrogenated to the corresponding 1,3-diamine 5b in almost
quantitative yield after evaporation of filtrates. Without further
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to afford chiral cyclic thiourea 6b in 53% yield without loss of
(
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2
(
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(
enantioselectivity (Scheme 1). Since bioactivities of 1,3-diamine
derivatives have been investigated,11 enantiopure 1,3-diamines
should be valuable synthetic intermediates. In addition, chiral
thioureas have attracted attention in recent years due to their anti-
HIV activities.12
(
JA0604008
J. AM. CHEM. SOC.
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VOL. 128, NO. 23, 2006 7419