Asymmetric multifunctional organocatalytic Michael addition of nitroalkanes to α,β-unsaturated ketones

Article abstract of DOI:10.1039/b804540b

Cinchona alkaloid derived primary amine thioureas organocatalyzed Michael addition of nitroalkanes to enones in good yield and up to 98% ee and offered a new way to construct quaternary stereocenters from enones and nitroalkanes. The Royal Society of Chem

Full text of DOI:10.1039/b804540b

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Asymmetric multifunctional organocatalytic Michael addition of
nitroalkanes to a,b-unsaturated ketonesw
Pengfei Li,a Yongcan Wang,a Xinmiao Liang*ab and Jinxing Ye*b
Received (in Cambridge, UK) 17th March 2008, Accepted 17th April 2008
First published as an Advance Article on the web 16th May 2008
DOI: 10.1039/b804540b
Cinchona alkaloid derived primary amine thioureas organo
catalyzed Michael addition of nitroalkanes to enones in good
yield and up to 98% ee and offered a new way to construct
quaternary stereocenters from enones and nitroalkanes.
a cinchona alkaloid derived primary amine thiourea contain-
ing a tertiary amine, which was expected to enhance the
nucleophilicity of nitromethane. As a result, the Michael
addition of nitromethane to enone was highly efficient and
enantioselectively catalysed by 2, 3, 4 and 5 (entries 2–5).
Especially with 3, up to 92% ee and 92% of conversion were
obtained without optimization. These encouraging results
indicated that cinchona alkaloid derived primary amine
thioureas might be a very efficient tool for this kind of Michael
addition.
As one of the most important chiral bond-forming processes in
organic chemistry, the field of asymmetric organocatalytic
Michael addition employing chiral organocatalysts has devel-
oped significantly and become the focus of intense research
efforts.1–4 Inspired by one of the key features of enzyme
activity, the synergistic cooperation of a number of functional
groups, chemists have successfully applied bifunctional orga-
nocatalytic strategy in organic synthesis during the past few
years.5 Such bifunctional organocatalysts will help to arrange
and activate the different reactants cooperatively, and pro-
mote the reaction with high selectivity. However, substrate
dependence still remains an important issue in many bifunc-
tional organocatalytic asymmetric reactions. Therefore, we
have a high motivation to develop a multifunctional chemical
system that can mimic the action of enzymes and effect organic
reactions with excellent efficiency and stereoselectivity.
Optimal reaction conditions were investigated and the
results are displayed in Table 1. It was found that the reaction
medium had an impact on the conversion and enantioselective
induction. The use of methanol afforded only 42% conversion
and 55% ee (entry 6), which was in accordance with the
reported results.9 The reaction in DMF also gave low conver-
sion (entry 7).10 Importantly, the reaction in THF, CH3CN,
Et2O, CH2Cl2, CHCl3 and EtOAc all proceeded with excellent
enantioselectivities and good to excellent conversions (entries
8–13) and the best results were obtained in ethyl acetate (entry
13).z It should be noted that decreasing solvent dosage
resulted in high conversion and slightly decreased enantio-
selectivies within short times (entries 14–17). Decreasing the
catalyst loading also afforded excellent conversion and enan-
tioselectivity (entries 18 and 19). When a catalyst loading of 2
mol% was employed, up to 91% conversion and 95% ee could
still be obtained (entry 19). When the catalyst was changed
from 3 to 6, the reaction rate was slowed and the configuration
of the adduct was reversed (entry 20). This indicated that
the stereochemistry was mainly controlled by the
1,2-diaminocyclohexane motif.
We here describe a new type of organocatalyst consisting of
1,2-diaminocyclohexane and 9-aminocinchona alkaloid deri-
vatives for asymmetric Michael addition of enones. The
organocatalysts provide multifunctional groups: a primary
amine, which is expected to activate and arrange the enone,6
and tertiary amine and thiourea helping to activate and
arrange the nucleophiles.7 Based on our design, cinchona
alkaloid like derived primary amine thioureas have been
synthesized (2, 3, 4, 5 and 6). For comparison, a simple
primary amine thiourea (1) was also prepared (Scheme 1).
We started our investigation using cyclohex-2-enone and
nitromethane as substrates and some representative results are
displayed in Table 1. Although the Michael addition between
aldehydes and nitroalkenes was successfully catalyzed by the
primary amine thiourea,8 the reaction catalyzed by 1 gave a
very poor result (entry 1). The main reason might be the fact
that nucleophile was not efficiently activated by 1. An essential
enhancement was achieved when the reaction was catalyzed by
Under the optimized conditions, the scope of the reaction
was explored. The results of Michael addition of nitroalkanes
to a series of cyclic enones are presented in Table 2. The results
showed that the reaction took place efficiently with good to
excellent enantioselectivities and good isolated yields. Cata-
lyzed by 3 with a loading of 5 mol%, up to 96% ee and 70%
yield were obtained after only 36 h when cyclohex-2-enone
reacted with nitromethane (entry 1). The presence of substi-
tuents at g-position on the cyclic enone did not significantly
effect the enantioselective induction and yield. The Michael
a Dalian Institute of Chemical Physics, Graduate School of the
Chinese Academy of Sciences, Chinese Academy of Science, 457
Zhongshan Road, Dalian, 116023, China.
E-mail: liangxm@dicp.ac.cn
b Engineering Research Center of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy, East China University
of Science and Technology, 130 Meilong Road, Shanghai, 200237,
China. E-mail: yejx@ecust.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization of the Michael addition products. See
DOI: 10.1039/b804540b
Scheme 1 Structures of organocatalysts.
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Table 1 Catalyst and reaction conditions screen for the reaction
between 7a and 8aa
Table 2 Asymmetric Michael addition of 8 to cyclic enones 7a
Conv.b (%)
eec (%)
Entry
n
R1
R2/R3 R4 R5 t/h Yieldb (%) eec (%)
Entry
Catalyst
Solvent
t/h
1d
2
3
4
1
1
0
2
1
1
1
1
1
1
H
H
H
H
Me
Pr
Bu
Pentyl
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
36 70
120 85
120 70
120 25 (30e)
120 82
120 70
120 72
120 79
96 80
96
87
80
92
94
94
93
93
1
2
3
4
5
6
7
8
1
2
3
4
5
3
3
3
3
3
3
3
3
3
3
3
Toluene
Toluene
Toluene
Toluene
Toluene
MeOH
DMF
THF
CH3CN
Et2O
48
48
48
48
48
48
48
48
48
48
48
48
42
24
20
24
24
30
72
96
15
65
92
86
90
42
41
89
83
77
81
84
95
97
95
92
95
95
91
76
Nd
93
92
90
90
55
83
95
96
96
96
95
97
89
95
96
87
96
95
ꢁ92
5
6f
7f
8f
9d
10g
Me Me
97
9
H
Me
Me
Me
H
H
H
48 84
98, 96
d.r. 2 : 3
95, 90
d.r. 7 : 3
91, 88
d.r. 3 : 2
10
11
12
13
14
15
16
17
18
19
20
CH2Cl2
CHCl3
EtOAc
EtOAcd
EtOAce
EtOAcf
None
11
12
1
1
Me
H
H
120 92
48 92
Me
a
Reaction conditions: a mixture of 7 (1.0 mmol), 8 (3.0 mmol) and 3
(10 mol%) in ethyl acetate (0.5 mL) was stirred at room temperature.
3
3g
3h
6g
EtOAce
EtOAce
EtOAce
b
c
Isolated yield. Detected on GC or HPLC. Catalyst (5 mol%).
d
e
f
Conversion. Catalyst (20 mol%). Catalyst (2 mol%).
g
a
Reaction conditions: a mixture of 7a (1.0 mmol), 8a (3.0 mmol), and
the catalyst (10 mol%) in the solvent (2.0 mL) was stirred at room
b
temperature for the time given. nd = not detected. Determined by
c
d
e
GC. Determined by chiral HPLC. Solvent (0.2 mL). Solvent
To further explore the scope of the reaction, the Michael
f
g
h
(0.5 mL). Solvent (1.0 mL). Catalyst (5 mol%). Catalyst
(2 mol%).
addition of nitroalkanes to acyclic enones was tested and the
results are displayed in Table 3. Most successful organocata-
lytic Michael addition reactions are limited to cyclic en-
ones.9–11,15 Jørgensen and co-workers have used imidazoline
for the addition of 2-nitropropane to acyclic enone with high
enantioselectivity and conversion.14 However, the addition of
nitromethane to acyclic enones has been reported rarely.5d
With 3, the Michael addition adducts from aromatic enones
(entries 1–7), heteroaromatic enones (entry 8) and the alkyl-
substituted enones (entries 9 and 10) were all formed in good
to excellent yields with high enantioselectivities. Different
substituents can be introduced on the aromatic ring without
compromising the yield or enantioselectivity of the reaction
(entries 3–7) except nitro group (entry 2). Excellent isolated
yield and high enantioselectivity were obtained when
nitroethane and 2-nitropropane were used as nucleophile,
respectively (entries 11 and 12). Although acyclic enones
provided low enantioselectivities compared with cyclic enones,
the cinchona alkaloid derived primary amine thioureas were
still an efficient tool for the Michael addition of nitroalkanes
to acyclic enones.
adduct was generated with 85% yield and 87% ee from 4,4-
dimethylcyclohex-2-enone (entry 2). Both enantioselectivity
and conversion of cyclopent-2-enone were lower than that of
cyclohex-2-enone.9,11 The reaction between cyclopent-2-one
and nitromethane gave 70% yield and 80% ee in the presence
of 3 (entry 3). Cyclohept-2-enone was found to react quite
slowly, however the enantioselectivity was still 92% (entry 4).
The organocatalytic enantioselective construction of
quaternary stereocenters is an important yet challenging task
in asymmetric synthesis and still receives the attention of
synthetic chemists.12 Due to steric repulsion, it is difficult to
create such centers in a C–C bond-forming event. Moreover, it
is also difficult to achieve high levels of enantiotopic face
selectivity as a result of the relatively similar steric environ-
ments presented by the non-hydrogen substituents. It should
be noted that a quaternary chiral carbon center was produced
in 90–95% ee and 70–82% isolated yield when 3-substituted
cyclohex-2-enone was reacted with nitroalkanes in the pre-
sence of 3 (entries 5–8, 11), which had rarely been reported
before. It provides a new method for construction of quatern-
ary stereocenters from cyclic enones and nitroalkanes.
In summary, we have developed a new type of multifunc-
tional catalysts exhibiting synergistic cooperation to activate
and arrange the different reactants, which is efficient tool for
the asymmetric Michael addition of nitroalkanes to enones
with high efficiency and enantioselectivity. Such cinchona
alkaloid derived primary amine thioureas offer a new way to
construct quaternary stereocenters from enones and nitroalk-
anes. Further investigations of the capacity of this methodo-
logy are currently underway and the results from these studies
will be presented in due course.
It is known that different nitroalkanes have a large effect on
the asymmetric induction of the reaction. Fortunately, the use
of different nitroalkanes all gave excellent enantioselectivities
with the cinchona derived primary amine thiourea 3 (entries
9–12). However, the diastereoselectivity is no higher than the
reported results (entries 10–12).13,14
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Table 3 Asymmetric Michael addition of 8 to cyclic enones 10a
bifunctional organocatalysts, see; (g) T. Marcelli, J. H. van Maar-
seveen and H. Hiemstra, Angew. Chem., Int. Ed., 2006, 45, 7496;
(h) T. Akiyama, J. Itoh and K. Fuchibe, Adv. Synth. Catal., 2006,
348, 999.
6. Some previous work using primary amine catalysts, see:
(a) F. Tanaka, R. Thayumanavan, N. Mase and C. F. Barbas,
III, Tetrahedron Lett., 2004, 45, 325; (b) S. Pizzarello and
A. L. Weber, Science, 2004, 303, 1151; (c) A. Cordova,
W. B. Zou, I. Ibrahem, E. Reyes, M. Engqvist and W. W. Liao,
Chem. Commun., 2005, 3586; (d) A. Cordova, I. Ibrahem, J. Casas,
H. Sunden, M. Engqvist and E. Reyes, Chem. Eur. J., 2005, 11,
4772; (e) M. Amedjkouh, Tetrahedron: Asymmetry, 2005, 16,
1411; (f) A. Bassan, W. B. Zou, E. Reyes, F. Himo and
A. Cordova, Angew. Chem., Int. Ed., 2005, 44, 7028;
(g) Y. M. Xu and A. Cordova, Chem. Commun., 2006, 460;
(h) N. J. A. Martin and B. List, J. Am. Chem. Soc., 2006, 128,
13368; (i) J. W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue,
Y. C. Chen, Y. Wu, J. Zhu and J. G. Deng, Angew. Chem., Int.
Ed., 2007, 46, 389; (j) W. Chen, W. Du, Y. Z. Duan, Y. Wu,
S. Y. Yang and Y. C. Chen, Angew. Chem., Int. Ed., 2007, 46,
7667; (k) J. W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J. G. Deng
and Y. C. Chen, Org. Lett., 2007, 9, 413; (l) S. H. McCooey and
S. J. Conon, Org. Lett., 2007, 9, 599; (m) G. Bartoli, M. Bosco,
A. Carlone, F. Pesciaioli, L. Sambri and P. Melchiorre, Org. Lett.,
2007, 9, 1403; for examples of the primary amine thiourea
catalysis, see; (n) H. B. Huang and E. N. Jacobsen, J. Am. Chem.
Soc., 2006, 128, 7170; (o) M. P. Lalonde, Y. Chen and
E. N. Jacobsen, Angew. Chem., Int. Ed., 2006, 45, 6366.
7. Some previous work using cinchona alkaloid derived thiourea
catalyst, see: refs 5d–f; (a) A. L. Tillman, J. Ye and D. J. Dixon,
Chem. Commun., 2006, 1191; (b) J. Wang, H. Li, L. S. Zu,
W. Jiang, H. X. Xie, W. H. Duan and W. Wang, J. Am. Chem.
Soc., 2006, 128, 12652; (c) A. Hamza, G. Schubert, T. Soos and
I. Papai, J. Am. Chem. Soc., 2006, 128, 13151; (d) G. Bartoli,
M. Bosco, A. Carlone, A. Cavalli, M. Locatelli, A. Mazzanti,
P. Ricci, L. Sambri and P. Melchiorre, Angew. Chem., Int. Ed.,
2006, 45, 4966; (e) for a review on thiourea catalyst, see:
S. J. Connon, Chem. Eur. J., 2006, 12, 5418.
Entry
R
R1
R2
t/h
Yieldb (%)
eec (%)
1d
2
3
4
5
6
7
8
C6H5
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
H
H
H
H
H
H
H
H
Me
H
48
72
72
72
72
96
72
96
60
60
48
48
90
60
82
91
65
70
73
68
93
84
96
98
85
73
82
84
80
85
86
78
84
84
82
84, 84
d.r. 1 : 1
4-NO2C6H4
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
2-Thienyl
Pr
9d
10d
11d
12
Bu
C6H5
C6H5
a
Reaction conditions: A mixture of 10 (1.0 mmol), 8 (3.0 mmol), and 3
(10 mol%) in the solvent (0.5 mL) was stirred at room temperature.
b
c
Isolated yield. Determined by GC or HPLC. Catalyst (20 mol%).
d
Notes and references
z General procedure for the Michael addition of nitroalkanes to a,b-
unsaturated ketones: To a solution of ethyl acetate (0.5 mL) was added
enone 7 or 10 (1.0 mmol), nitroalkane 8 (3.0 mmol) and catalyst 3 (0.10
mmol). The reaction mixture was stirred at room temperature for the
time given and then the solvent was removed under vacuum. 1 M
hydrochloric acid (5.0 mL) was added and the residue extracted with
CH2Cl2 three times. The combined organic phases were dried over
anhydrous Na2SO4, filtered and evaporated under vacuum. The
residue was purified by column chromatography on silica gel
(350–400 mesh) to yield the desired addition product.
8. E. N. Jacobsen, M. P. Lalonde and Y. G. Chen, Angew. Chem.,
Int. Ed., 2006, 45, 6366.
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(a) A. Berkessel and H. Groger, Asymmetric Organocatalysis,
Wiley-VCH, Weinheim, Germany, 2004; (b) P. I. Dalko, Enantiose-
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This journal is The Royal Society of Chemistry 2008
3304 | Chem. Commun., 2008, 3302–3304