Chiral squaramide-catalyzed highly diastereo- and enantioselective direct Michael addition of nitroalkanes to nitroalkenes

Article abstract of DOI:10.1039/c1cc15946a

An efficient highly diastereo- and enantioselective direct Michael addition of nitroalkanes to nitroalkenes catalyzed by chiral squaramide catalyst has been developed. This organocatalytic reaction with a low catalyst loading (2 mol%) proceeded well to af

Full text of DOI:10.1039/c1cc15946a

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COMMUNICATION
Chiral squaramide-catalyzed highly diastereo- and enantioselective direct
Michael addition of nitroalkanes to nitroalkeneswz
Wen Yang and Da-Ming Du*
Received 24th September 2011, Accepted 13th October 2011
DOI: 10.1039/c1cc15946a
An efficient highly diastereo- and enantioselective direct Michael
addition of nitroalkanes to nitroalkenes catalyzed by chiral squaramide
catalyst has been developed. This organocatalytic reaction with a low
catalyst loading (2 mol%) proceeded well to afford synthetically useful
1,3-dinitro compounds in high yields with high diastereoselectivities (up
to 95 : 5 dr) and excellent enantioselectivities (up to 97% ee).
with silyl nitronates.8 Despite these successes, the development of
efficient catalytic systems in pursuit of excellent enantioselectivity,
low catalyst loading, and mild reaction conditions is still challenging
and in great demand.
The utilization of hydrogen bonding as an activation force is
widespread in organocatalysis.9 Chiral squaramide is a novel type of
good hydrogen-bonding donor organocatalyst.10,11 After the
pioneering work reported by Rawal et al.,11a a series of chiral
squaramide organocatalysts have been developed and successfully
applied in various asymmetric reactions.11 Recently, our group also
reported the chiral squaramide-catalyzed asymmetric Michael addi-
tion reactions.11f,g Herein, we would like to report our new advance
on the highly diastereo- and enantioselective Michael addition of
nitroalkanes to nitroalkenes catalyzed by chiral squaramide catalysts.
Initially, a small library of squaramide catalysts I–X (Fig. 1)
was readily prepared and their catalytic performance to promote
the Michael addition of nitroalkanes to nitroalkenes was evaluated.
The addition of nitroethane to b-nitrostyrene as a model
reaction for catalyst screening was performed in CH2Cl2 in
the presence of 5 mol% catalyst loading at room temperature
for 12 h. The screening results are shown in Table 1. Both
squaramides I and II derived from chiral cyclohexane-1,2-
diamine gave good yield and diastereoselectivity, but the
former exhibited much better enantioselectivity (79% ee)
(entries 1 and 2). The substituent of the tertiary amino group
as a Lewis base has an effect on the enantioselectivity. When
squaramides III and IV bearing a piperidinyl group were
The conjugate addition of carboanion nucleophiles to electron-
deficient alkenes is widely recognized as one of the most important
carbon–carbon bond-forming reactions in organic synthesis.1,2
Owing to the strong electron-withdrawing character of the
nitro group and its facile transformations to other useful func-
tional groups, nitroalkanes are a valuable source of stabilized
carboanions as good Michael donors,3 and nitroalkenes serve
as excellent Michael acceptors.4 The Michael addition of
nitroalkanes to nitroalkenes is extremely attractive because it
can directly afford 1,3-dinitro compounds, which are useful
intermediates for a variety of further elaborated structures.5
Our group reported the first asymmetric version of this reaction
catalyzed by bis(oxazoline) or bis(thiazoline)–zinc(II) complexes,
which provided an easy access to optically active 1,3-dinitro
compounds.6 In recent years, some efforts have been also
devoted to this asymmetric Michael addition by other groups,
and a few efficient catalytic systems have been reported.7
Wang et al. revealed that a simply modified cinchona alkaloid
was a good promoter, albeit with moderate to good enantio-
selectivities.7a Feng and co-workers employed a La(OTf)3/
N,N0-dioxide complex to promote this reaction, and high
diastereoselectivities and excellent enantioselectivities were
obtained.7b Subsequently, two organocatalytic systems for this
process with excellent results were reported. Wulff and Rabalakos
developed a bifunctional DMAP-thiourea,7c while Wang et al.
reported a bifunctional amine-thiourea bearing multiple hydrogen-
bonding donors.7d Moreover, Maruoka et al. described an N-spiro
chiral ammonium bifluoride catalyzed indirect Michael addition
School of Chemical Engineering and Environment,
Beijing Institute of Technology, Beijing 100081, People’s Republic of
China. E-mail: dudm@bit.edu.cn; Fax: +86-10-68914985;
Tel: +86-10-68914985
w Electronic supplementary information (ESI) available: Experimental
procedures, characterization data, copies of NMR spectra and HPLC
chromatographs. See DOI: 10.1039/c1cc15946a
z This article is part of the joint ChemComm–Organic & Biomolecular
Chemistry ‘Organocatalysis’ web themed issue.
Fig. 1 Screened squaramide catalysts.
c
12706 Chem. Commun., 2011, 47, 12706–12708
This journal is The Royal Society of Chemistry 2011

Table 1 Screening of squaramide catalysts for the asymmetric
Michael addition of nitroethane to b-nitrostyrenea
Table 2 Optimization of reaction conditions for the asymmetric
Michael addition of nitroethane to b-nitrostyrenea
Entry
Catalyst
Yieldb (%)
drc (syn/anti)
eed (%)
drc
eed,e
Entry Solvent
Loading T/ 1C t/h Yieldb (%) (syn/anti) (%)
1
2
3
4
5
6
7
8
9
10
I
II
70
74
82
32
75
67
90
62
94
96
85 : 15
80 : 20
75 : 25
80 : 20
83 : 17
83 : 17
83 : 17
81 : 19
85 : 15
80 : 20
79
43
88
87
ꢀ82
ꢀ67
91
86
93
1
2
3
CH2Cl2
THF
PhMe
5
5
5
5
5
5
5
5
5
rt
rt
rt
rt
rt
rt
rt
rt
0
12 94
12 58
12 20
12 72
12 78
12 62
12 93
12 69
24 85
85 : 15
91 : 9
93
86
93
53
91
90
83
82
94
97
95
97
97
97
95
III
IV
V
VI
VII
VIII
IX
X
90 : 10
83 : 17
82 : 18
87 : 13
66 : 34
83 : 17
91 : 9
4
5
6
7
MeOH
CHCl3
CH2ClCH2Cl
CCl4
8
9
EtNO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
91
10
11
12
13
14f
15g
5
10
2
1
2
ꢀ20 48 92
ꢀ20 48 84
ꢀ20 48 94
ꢀ20 48 85
ꢀ20 48 79
ꢀ20 48 96
95 : 5
a
Reactions were carried out with b-nitrostyrene (0.2 mmol) and
nitroethane (1.0 mmol) in CH2Cl2 (0.5 mL). Isolated yields after
90 : 10
95 : 5
94 : 6
94 : 6
90 : 10
b
c
column chromatography purification. Determined by chiral HPLC
d
analysis. Enantiomeric excess for the major syn-diastereomer was
determined by chiral HPLC analysis.
2
a
Reactions were carried out with b-nitrostyrene (0.2 mmol) and
nitroethane (1.0 mmol) in solvent (0.5 mL). Isolated yields after
b
c
column chromatography purification. Determined by chiral HPLC
employed, an obvious increase in enantioselectivity was observed
(88% ee and 87% ee, respectively); however, squaramide III only
gave moderate diastereoselectivity and squaramide IV afforded
the product in low yield (entries 3 and 4). Squaramides V–VIII
derived from cinchona alkaloid, developed in our previous
report, were then screened (entries 5–8). Gratifyingly, quinine-
derived squaramide VII achieved a very good result (90% yield,
83 : 17 dr, 91% ee). Subsequently, C2-symmetric quinine/hydro-
quinine-derived squaramides IX and X were tested, and a better
result (94% yield, 85 : 15 dr, 93% ee) was obtained for squar-
amide IX. Therefore, squaramide IX was selected as the best
catalyst for further optimization.
d
analysis. Enantiomeric excess for the major syn-diastereomer was
e
determined by chiral HPLC analysis. The configuration of the major
syn-diastereomer was assigned to be (S,S) by comparison of the optical
rotation with literature data.6,7 f Nitroethane (0.4 mmol) was used.
g
Nitroethane (2.0 mmol) was used.
nitroethane 2a was also simply examined, but no better result
was observed (entries 14 and 15).
Having established the optimal reaction conditions, we explored
the scope of the asymmetric Michael addition of nitroalkanes to
nitroalkenes. The results are presented in Table 3. Generally, a wide
array of aromatic nitroalkenes bearing electron-neutral, electron-
withdrawing or electron-donating substitutions reacted smoothly
with nitroethane 2a to afford the corresponding adducts in good to
high yields with high diastereoselectivities and excellent enantio-
selectivities (95–97% ee) (entries 1–10). These results indicated that
the position and the electronic property of the substituent on the
aromatic ring had a limited effect on both diastereoselectivity and
enantioselectivity. Heteroaromatic nitroalkenes were also suitable
substrates, and the desired products were obtained with excellent
enantioselectivities albeit with lower yields (entries 11 and 12).
When aliphatic nitroalkene 1m served as an acceptor, very low
yield (16%) and a significant decrease in both diastereoselectivity
and enantioselectivity (67 : 33 dr, 80% ee) were observed (entry 13).
Nitropropane 2b as a donor worked well with aromatic nitroalkenes
to give good to high diastereoselectivities and excellent
enantioselectivities albeit with lower reactivity (entries 14–18).
Further substrate scope was investigated. The reaction of
branched 2-nitropropane 4 and b-nitrostyrene 1a was performed,
but no reaction occurred. Nitrodienes 5 as acceptors reacted with
nitroethane 2a to afford the 1,4-addition product 6 in moderate
yields with good diastereoselectivities and high enantioselectivities
(Scheme 1). To further evaluate the synthetic potential of this
squaramide catalytic system, the gram-scale preparation and
transformation of 3a were performed. As shown in Scheme 2, 1a
With the optimal catalyst in hand, the effect of solvents,
temperature, and catalyst loading was further investigated for
the optimal reaction conditions. The results are summarized in
Table 2. A solvent screening was first performed, and CH2Cl2
was proved to be the best reaction medium (entries 1–7).
Notably, when the model reaction was carried out in neat
nitroethane, lower yield and enantioselectivity were obtained
(entry 8). Lowering the temperature led to an increase in both
diastereoselectivity and enantioselectivity (entries 9 and 10).
When the reaction was performed at ꢀ20 1C for 48 h, the adduct
was obtained in high yield with high diastereoselectivity and
excellent enantioselectivity (95 : 5 dr, 97% ee). Subsequently,
catalyst loading was screened. Interestingly, increasing the
catalyst loading (10 mol%) resulted in a decrease in both
diastereoselectivity and enantioselectivity, while high diastereo-
selectivity and excellent enantioselectivity were maintained with a
reduced catalyst loading (2 or 1 mol%) (entries 11–13). The
phenomenon of increased enantioselectivity with decreased
catalyst loading may be ascribed to the decreased self-association
of this type of hydrogen-bonding catalyst, as it is reported that
urea and thiourea based organocatalysts can form hydrogen-
bonded aggregates.12 This phenomenon is a notable feature in
squaramide-catalyzed reactions. Considering the yield, 2 mol%
catalyst loading was chosen. Additionally, the loading of
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12706–12708 12707

Table 3 Scope of the Michael addition of nitroalkanes to nitroalkenesa
Yieldb
R2 t/h Product (%)
drc
Entry R1
(syn/anti) eed,e (%)
1
2
3
4
5
6
7
8
9
C6H5
Me 48 3a
Me 48 3b
Me 48 3c
Me 48 3d
Me 48 3e
Me 60 3f
94
98
95
83
91
91
90
88
71
95 : 5
94 : 6
92 : 8
88 : 12
94 : 6
91 : 9
94 : 6
94 : 6
88 : 12
97
96
96
95
96
96
97
97
96
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
4-MeC6H4
4-MeOC6H4 Me 60 3g
2-MeOC6H4 Me 60 3h
3,4-
(MeO)2C6H3
1-Naphthyl
2-Furanyl
2-Thienyl
i-Propyl
C6H5
4-ClC6H4
2-ClC6H4
Scheme 2 The gram-scale preparation and transformation of 3a.
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21072020), the Science
and Technology Innovation Program of Beijing Institute of
Technology (Grant Nos. 2011CX01008 and 2011CX03037) and
the Development Program for Distinguished Young and Middle-
aged Teachers of Beijing Institute of Technology.
Me 60 3i
10
11
12
13
14
15
16
17
18
Me 60 3j
Me 60 3k
Me 60 3l
Me 96 3m
Et 60 3n
Et 60 3o
Et 60 3p
79
64
63
16
79
88
72
64
58
92 : 8
95
96
95
80
92
96
96
97
96
89 : 11
79 : 21
67 : 33
88 : 12
89 : 11
81 : 19
92 : 8
Notes and references
1 (a) P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992; (b) J. L. Vicario, D. Badıa, L. Carrillo and
E. Reyes, Organocatalytic Enantioselective Conjugate Additions, RSC
Publishing, Oxford, 2010.
4-MeOC6H4 Et 72 3q
2-MeOC6H4 Et 72 3r
90 : 10
2 For selected reviews of asymmetric Michael additions, see:
(a) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701; (b) J. Christoffers,
G. Koripelly, A. Rosiak and M. Rossle, Synthesis, 2007, 1279;
(c) S. Sulzer-Mosse and A. Alexakis, Chem. Commun., 2007, 3123;
(d) J. L. Vicario, D. Badıa and L. Carrillo, Synthesis, 2007, 2065;
(e) D. Almasi, D. A. Alonso and C. Najera, Tetrahedron: Asymmetry,
2007, 18, 299.
a
Reactions were carried out with nitroalkene (0.2 mmol) and nitro-
b
alkane (1.0 mmol) in CH2Cl2 (0.5 mL). Isolated yields after column
c
chromatography purification. Determined by chiral HPLC analysis.
d
Enantiomeric excess for the major syn-diastereomer was determined
by chiral HPLC analysis. e The configuration of the major syn-diastereomer
was assigned to be (S,S) by comparison of the optical rotation with
literature data.6,7
3 R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and M. Petrini,
Chem. Rev., 2005, 105, 933.
4 O. M. Berner, L. Tedeschi and D. Enders, Eur. J. Org. Chem.,
2002, 1877.
5 R. Ballini, A. Palmieria and P. Righi, Tetrahedron, 2007, 63, 12099.
6 S.-F. Lu, D.-M. Du, J. Xu and S.-W. Zhang, J. Am. Chem. Soc.,
2006, 128, 7418.
7 (a) J. Wang, H. Li, L. S. Zu, W. Jiang and W. Wang, Adv. Synth. Catal.,
2006, 348, 2047; (b) X. Yang, X. Zhou, L. L. Lin, L. Chang, X. H. Liu
and X. M. Feng, Angew. Chem., Int. Ed., 2008, 47, 7049; (c) C. Rabalakos
and W. D. Wulff, J. Am. Chem. Soc., 2008, 130, 13524; (d) X. Q. Dong,
H. L. Teng and C. J. Wang, Org. Lett., 2009, 11, 1265.
8 T. Ooi, S. Takada, K. Doda and K. Maruoka, Angew. Chem., Int.
Ed., 2006, 45, 7606.
Scheme 1 Further investigation of substrate scope.
9 For selected reviews, see: (a) P. R. Schreiner, Chem. Soc. Rev.,
2003, 32, 289; (b) J. Seayad and B. List, Org. Biomol. Chem., 2005,
3, 719; (c) S. J. Connon, Chem.–Eur. J., 2006, 12, 5418;
(d) M. S. Taylor and E. N. Jacobsen, Angew. Chem., Int. Ed.,
2006, 45, 1520; (e) A. G. Doyle and E. N. Jacobsen, Chem. Rev.,
2007, 107, 5713; (f) T. Akiyama, Chem. Rev., 2007, 107, 5744;
(g) X. Yu and W. Wang, Chem.–Asian J., 2008, 3, 516.
10 For reviews of squaramides, see: (a) R. I. Storer, C. Aciro and
L. H. Jones, Chem. Soc. Rev., 2011, 40, 2330; (b) J. Aleman,
A. Parra, H. Jiang and K. A. Jørgensen, Chem.–Eur. J., 2011, 17, 6890.
11 For recent examples, see: (a) J. P. Malerich, K. Hagihara and
V. H. Rawal, J. Am. Chem. Soc., 2008, 130, 14416; (b) Y. Zhu,
J. P. Malerich and V. H. Rawal, Angew. Chem., Int. Ed., 2010, 49, 153;
(c) D. Q. Xu, Y.-F. Wang, W. Zhang, S.-P. Luo, A.-G. Zhong, A.-B. Xia
and Z.-Y. Xu, Chem.–Eur. J., 2010, 16, 4177; (d) L. Dai, S.-X. Wang and
F.-E. Chen, Adv. Synth. Catal., 2010, 352, 2137; (e) H. Jiang,
M. W. Paixao, D. Monge and K. A. Jørgensen, J. Am. Chem. Soc.,
2010, 132, 2775; (f) W. Yang and D.-M. Du, Org. Lett., 2010, 12, 5450;
(g) W. Yang and D.-M. Du, Adv. Synth. Catal., 2011, 353, 1241;
(h) Y. Qian, G. Ma, A. Lv, H.-L. Zhu, J. Zhao and V. H. Rawal, Chem.
Commun., 2010, 46, 3004; (i) H. Konishi, T. Y. Lam, J. P. Malerich and
V. H. Rawal, Org. Lett., 2010, 12, 2028; (j) S. V. Pansare and E. K. Paul,
Chem. Commun., 2011, 47, 1027.
(1.49 g, 10.0 mmol) reacted with nitroethane 2a with 1 mol%
catalyst IX to afford the product 3a in 82% yield with 92 : 8 dr
and 94% ee (99% ee was obtained after a simple crystallization).
The transformation of the 1,3-dinitro compound 3a (2.35 g,
10.5 mmol) to the corresponding chiral cyclic thiourea 8 was also
readily gram-scaled without change in enantioselectivity.
In summary, we have developed a squaramide-catalyzed highly
diastereo- and enantioselective direct Michael addition of nitro-
alkanes to nitroalkenes. This catalytic system with a low catalyst
loading (2 mol%) was very effective to afford the corresponding
Michael adducts in high yields with high diastereoselectivities (up
to 95 : 5 dr) and enantioselectivities (up to 97% ee). This process
provides an easy access to optically active 1,3-dinitro compounds.
Moreover, the gram-scale preparation and transformation of the
1,3-dinitro compounds to chiral cyclic thiourea can be performed
well, demonstrating the synthetic potential of this chiral squara-
mide organocatalytic system. Further studies on asymmetric reac-
tions catalyzed by squaramides are underway in our laboratory.
12 H. S. Rho, S. H. Oh, J. W. Lee, J. Y. Lee, J. Chin and C. E. Song,
Chem. Commun., 2008, 1208.
c
12708 Chem. Commun., 2011, 47, 12706–12708
This journal is The Royal Society of Chemistry 2011