Highly enantioselective michael addition of nitroalkanes to chalcones using chiral squaramides as hydrogen bonding organocatalysts

Article abstract of DOI:10.1021/ol102294g

A series of squaramide-based organocatalysts were facilely synthesized and applied as hydrogen bonding organocatalysts in the enantioselective Michael addition of nitroalkanes to chalcones. These organocatalysts promoted the Michael addition with low cata

Full text of DOI:10.1021/ol102294g

ORGANIC
LETTERS
2010
Vol. 12, No. 23
5450-5453
Highly Enantioselective Michael Addition
of Nitroalkanes to Chalcones Using
Chiral Squaramides as Hydrogen
Bonding Organocatalysts
Wen Yang and Da-Ming Du*
School of Chemical Engineering and EnVironment, Beijing Institute of Technology,
Beijing 100081, People’s Republic of China
dudm@bit.edu.cn
Received September 23, 2010
ABSTRACT
A series of squaramide-based organocatalysts were facilely synthesized and applied as hydrogen bonding organocatalysts in the enantioselective
Michael addition of nitroalkanes to chalcones. These organocatalysts promoted the Michael addition with low catalyst loading under high temperature
(80 °C), affording the desired R or S enantiomers of the products flexibly in high yields with excellent enantioselectivities (93-96% ee) by the
appropriate choice of organocatalysts.
The utilization of hydrogen bonding as an activation force
is widespread in asymmetric organocatalysis. In the past
decade, chiral ureas and thioureas, diols, and phosphoric acids
dominated the field of hydrogen bonding, and great advances
were achieved.1 Given the importance of hydrogen bonding
catalysts in asymmetric organocatalysis, the design and
development of new hydrogen bonding catalysts is of great
interest. In 2008, Rawal first reported novel chiral squaramide
derivatives as hydrogen bonding organocatalysts for the
conjugate addition of 1,3-dicarbonyl compounds to nitroalk-
enes, in which excellent results were achieved.2 In the past
two years, a series of squaramide-based catalysts were
developed and successfully applied in various asymmetric
reactions such as enantioselective Michael addition, Friedel-
Crafts reaction, and R-amination of 1,3-dicarbonyl com-
pounds.3 These pioneering works demonstrate that squara-
mide derivatives can serve as good hydrogen bonding
organocatalysts in asymmetric catalysis. Meanwhile, another
report about the application of squaramide-based organo-
catalysts in organic reaction has also appeared.4 Thus, the
development of new squaramides and extending their ap-
plications in various reactions are challenging tasks.
The enantioselective conjugate addition of carbanion
nucleophiles to electron-deficient R,ꢀ-unsaturated compounds
(1) For selected reviews, see: (a) Doyle, A. G.; Jacobsen, E. N. Chem.
ReV. 2007, 107, 5713. (b) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516.
(c) Akiyama, T. Chem. ReV. 2007, 107, 5744. (d) Connon, S. J. Chem.sEur.
J. 2006, 12, 5418. (e) Taylor, M. S.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2006, 45, 1520. (f) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719. (g) Schreiner, P. R. Chem. Soc. ReV. 2003, 32, 289.
(3) (a) Zhu, Y.; Malerich, J. P.; Rawal, V. H. Angew. Chem., Int. Ed.
2010, 49, 153. (b) Konishi, H.; Lam, T. Y.; Malerich, J. P.; Rawal, V. H.
Org. Lett. 2010, 12, 2028. (c) Qian, Y.; Ma, G.; Lv, A.; Zhu, H.-L.; Zhao,
J.; Rawal, V. H. Chem. Commun. 2010, 46, 3004. (d) Xu, D.-Q.; Wang,
Y.-F.; Zhang, W.; Luo, S.-P.; Zhong, A.-G.; Xia, A.-B.; Xu, Z.-Y.
Chem.sEur. J. 2010, 16, 4177. (e) Dai, L.; Wang, S.-X.; Chen, F.-E. AdV.
Synth. Catal. 2010, 352, 2137.
(2) Malerich, J. P.; Hagihara, K.; Rawal, V. H. J. Am. Chem. Soc. 2008,
130, 14416.
(4) Cheon, C. H.; Yamamoto, H. Tetrahedron 2010, 66, 4257.
10.1021/ol102294g  2010 American Chemical Society
Published on Web 11/05/2010

is one of the most important C-C bond forming reactions
in organic synthesis.5 Among various carbanion nucleophiles,
nitroalkanes have been demonstrated to be a valuable
stabilized carbanion for the conjugate addition due to the
strong electron-withdrawing nature of the nitro group and
its potent transformation to a variety of valuable functional
groups.6 In the case of nitroalkanes, the products of the
Michael addition to chalcones are useful intermediates for a
variety of further elaborated structures such as chiral ami-
nocarbonyls, pyrrolidines, γ-lactams, and γ-amino acids.7
To the best of our knowledge, after the pioneering report on
asymmetric Michael addition of nitromethane to chalcone
was reported,8a considerable efforts have been devoted to
the asymmetric Michael addition of nitroalkanes to R,ꢀ-
unsaturated ketones in the past decades;8,9 however, only a
few examples with excellent results have been reported for
the asymmetric Michael addition of nitroalkanes to chalcones.
Therefore, searching for suitable catalytic systems with high
catalytic activity and enantioselectivity is still challenging
and demanding. Herein, we would like to document the
development of a series of chiral squaramide-based organo-
catalysts for the enantioselective Michael addition of ni-
troalkanes to chalcones. The desired products were obtained
in high yields (up to 99%) with excellent enantioselectivities
(93-96% ee).
Figure 1. Structures of screened organocatalysts.
modular nature. The facile synthesis and high modular nature
facilitate the fine-tuning of their catalytic activity in organic
reactions.
Considering the bifunctional nature of the catalysts, we
expected them to promote the enantioselective Michael
addition of nitroalkanes to chalcones. Our initial screening
reaction between nitromethane and chalcone was performed
in the presence of 10 mol % catalyst I in CH2Cl2, and the
desired product was obtained in 56% yield and 88% ee at
room temperature for 72 h. For optimization of the reaction
conditions, we screened the effect of solvents and temper-
ature. The results are summarized in Table 1. Variation of
To assess the ability of chiral squaramides for the
enantioselective Michael addition of nitroalkanes to chal-
cones, a series of catalysts with various substituents I-IX
(Figure 1) were synthesized. It is noteworthy that these
quaramide-based organocatalysts can be readily prepared in
three steps from commercially available dimethyl squarate,
aromatic amines, and cinchona alkaloids, and possess high
Table 1. Screening of Reaction Conditions for the Conjugate
(5) For selected recent reviews on enantioselective conjugate additions,
see: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002,
1877. (b) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. ReV.
2007, 107, 5471. (c) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007,
3123. (d) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701.
Addition of Nitromethane to Chalconea
(6) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Luzzio, F. A. Tetrahedron 2001, 57, 915. (c) Ballini,
M.; Petrini, M. Tetrahedron 2004, 60, 1017.
t (°C) time (h) yield (%)b ee (%)c
(7) (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem.
ReV. 2005, 105, 933. (b) Corey, E. J.; Zhang, F. Y. Org. Lett. 2000, 2,
4257.
entry
solvent
CH2Cl2
MeOH
THF
ClCH2CH2Cl
CH3NO2
ClCH2CH2Cl
ClCH2CH2Cl
toluene
1
2
3
4
5
6
7
8
9
25
25
72
72
72
72
72
72
48
48
48
56
38
8
88 (S)d
18 (S)
92 (S)
90 (S)
85 (S)
92 (S)
94 (S)
93 (S)
93 (S)
(8) For selected examples of asymmetric Michael addition of nitroalkanes
to chalcones, see: (a) Colonna, S.; Hiemstra, H.; Wynberg, H. J. Chem.
Soc., Chem. Commun. 1978, 238. (b) Wang, L.; Zhang, Q.; Zhou, X.; Liu,
X.; Lin, L.; Qin, B.; Feng, X. Chem.sEur. J. 2010, 16, 7696. (c) Hua, M.;
Cui, H.; Wang, L.; Nie, J.; Ma, J. Angew. Chem., Int. Ed. 2010, 49, 2772.
(d) Vakulya, B.; Varga, S.; Soo´s, T. J. Org. Chem. 2008, 73, 3475. (e)
Suresh, P.; Pitchumani, K. Tetrahedron: Asymmetry 2008, 19, 2037. (f)
Vakulya, B.; Varga, S.; Csa´mpai, A.; Soo´s, T. Org. Lett. 2005, 7, 1967. (g)
Halland, N.; Hazell, R. G.; Jørgensen, K. A. J. Org. Chem. 2002, 67, 8331.
(h) Sundararajan, G.; Prabagaran, N. Org. Lett. 2001, 3, 389. (i) Funabashi,
K.; Saida, Y.; Kanai, M.; Arai, T.; Sasai, H.; Shibasaki, M. Tetrahedron
25
25
25
50
80
110
130
62
93
90
97
94
92
C6H5Cl
a Unless noted otherwise, reactions were carried out with 0.25 mmol of
chalcone and 2.5 mmol of nitromethane in 0.5 mL of solvent. b Isolated
yields. c Determined by HPLC. d Absolute configuration was determined
by comparison of the optical rotation with literature data.8
Lett. 1998, 39, 7557
.
(9) For selected recent examples of asymmetric Michael addition of
nitroalkanes to other unsaturated enones, see: (a) Mei, K.; Jin, M.; Zhang,
S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan, W.; Wang, W. Org. Lett.
2009, 11, 2864. (b) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun.
2008, 3302. (c) Palomo, C.; Pazos, R.; Oiarbide, M.; Garc´ıa, J. M. AdV.
Synth. Catal. 2006, 348, 1161. (d) Taylor, M. S.; Zalatan, D. N.; Lerchner,
A. M.; Jacobsen, E. N. J. Am. Chem. Soc. 2005, 127, 1313. (e) Prieto, A.;
Halland, N.; Jørgensen, K. A. Org. Lett. 2005, 7, 3897. (f) Mitchell, C. E. T.;
Brenner, S. E.; Ley, S. V. Chem. Commun. 2005, 5346. (g) Ooi, T.; Takada,
S.; Fujioka, S.; Maruoka, K. Org. Lett. 2005, 7, 5143. (h) Hanessian, S.;
the solvents had a pronounced effect on the course of the
reaction. The proton solvent MeOH gave poorer yield and
very lower enantioselectivity (entry 2), while using THF led
to an increase in the enantioselectivity (92% ee), but an
Pham, V. Org. Lett. 2000, 2, 2975
.
Org. Lett., Vol. 12, No. 23, 2010
5451

unacceptable yield (entry 3). Compared with CH2Cl2, 1,2-
dichloroethane gave better results (62% yield, 90% ee) (entry
4). When the reaction was carried out in neat nitromethane,
much higher yield and a little lower enantioselectivity (85%
ee) were achieved (entry 5). To improve the rate of the
reaction, the reaction temperature was evaluated by using
1,2-dichloroethane as the best solvent. Interestingly, the
product was obtained in high yield with a slightly increased
enantioselectivity (92% ee) at 50 °C (entry 6). When the
reaction temperature was further elevated to 80 °C, a nearly
complete conversion and higher enantoselectivity (94% ee)
were achieved within 48 h (entry 7). The reason for the
higher enantioselectivity observed at higher temperature is
not clear. We then turned our attention to higher boiling
solvents (toluene and chlorobenzene), but no better result
was obtained (entries 8 and 9).
activity. The catalysts with 3,5-(CF3)2 substitution on the
aromatic ring gave better yields than the ones with 4-CF3
and 4-F substitutions, which demonstrated that the activity
of the catalyst was improved with the increasing of the
acidity. Quinidine X and quinine XI were also tested for
comparison, but very low yields and enantioselectivities were
observed. Obviously, the best catalysts were VI and I, which
gave the R and S enantiomers in excellent yields and
enantioselectivities, respectively (>99% yield and 94% ee,
97% yield and 94% ee). With the best catalysts in hand, the
effect of catalyst loading was further investigated. When the
catalyst VI loading was reduced to 5 mol %, a comparable
result (99% yield and 95% ee) was still achieved. Catalyst
loading of 2 and 1 mol % could also maintain the enanti-
oselectivities, albeit with decreased yields. Compromising
with the yield, 2 mol % catalyst loading was chosen for
catalyst VI. Catalyst I gave lower reactivity than catalyst
VI, and 5 mol % catalyst loading was our choice.
After finding the optimized solvent and reaction temper-
ature, the screening of the squaramide-based organocatalysts
I-IX was conducted under the optimized conditions. As
summarized in Table 2, the fine-tuning of catalyst structure
Under the optimized conditions with 2 mol % catalyst VI,
a diverse array of substituted chalcones were examined. The
results are summarized in Table 3. The electronic property
Table 2. Screening of Organocatalysts and Catalyst Loading for
the Michael Addition of Nitromethane to Chalconea
Table 3. Enantioselective Michael Addition of Nitroalkanes to
Various Chalcones Using Catalyst VIa
entry
catalyst
loading (mol %)
yield (%)b
ee (%)c
entry
R1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeOC6H4 C6H5
3-MeOC6H4 C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-ClC6H4
R2
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
C6H5
product yield (%)b ee (%)c
95(R)d
95 (R)
95 (R)
95 (R)
95 (R)
96 (R)
96 (R)
96 (R)
95 (R)
96 (R)
95 (R)
96 (R)
96 (R)
95 (R)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
I
II
10
10
10
10
10
10
10
10
10
10
10
5
97
92
73
93
81
>99
84
94
80
13
12
99
89
69
89
62
94 (S)d
93 (S)
93 (S)
93 (S)
92 (S)
94 (R)d
94 (R)
94 (R)
94 (R)
33 (R)
19 (S)
95 (R)
95 (R)
95 (R)
95 (S)
95 (S)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3a
3b
3c
3d
3e
3f
94
91
81
99
96
93
91
78
66
98
98
98
86
99
III
IV
V
VI
VII
VIII
IX
X
XI
VI
VI
VI
I
3g
3h
3i
3j
3k
3l
C6H5
C6H5
C6H5
4-MeC6H4
4-ClC6H4
2
1
5
2
3m
3n
a Unless noted otherwise, reactions were carried out with 0.25 mmol of
chalcones and 2.5 mmol of nitromethane or nitroethane in 0.5 mL of
CH2ClCH2Cl at 80 °C for 60 h. b Isolated yields. c Determined by HPLC,
using a Chiralpak IA column. d Absolute configuration was determined by
comparison of the optical rotation with literature data.8
I
a Unless noted otherwise, reactions were carried out with 0.25 mmol of
chalcone and 2.5 mmol of nitromethane in 0.5 mL of CH2ClCH2Cl. b Isolated
yields. c Determined by HPLC, using a Chiralpak IA column. d Absolute
configuration was determined by comparison of the optical rotation with
literature data.8
of the substituents on the phenyl ring did not have an evident
effect on the enantioselectivity, but a little effect on the yield.
All the substrates reacted smoothly with nitromethane to give
the expected R enantiomers of the products in excellent
enantioselectivities (95-96% ee). Chalcones bearing both
electron-withdrawing and weak electron-donating substitu-
tions provided the desired products in excellent yields, while
strong electron-donating substitution MeO led to decreased
yields. The position of substituents also influenced the
enantioselectivities and yields slightly.
had a very limited effect on the enantioselectivities. Com-
parable high enantioseletivities (92-94% ee) were obtained
in all the cases. Noticeably, the quinidine- and cinchonine-
derived catalysts I-V gave the S-configured products,
whereas the quinine- and cinchonidine-derived catalysts
VI-IX provided the R-configured products with the same
efficiency. It is also noted that the acidity of the hydrogen
bond donor motifs had a certain effect on their catalytic
5452
Org. Lett., Vol. 12, No. 23, 2010

It is well-known that the R and S enantiomers commonly
show very different biological activities. The facile access
to both the R and S enantiomers of the products is of great
importance in the asymmetric catalysis. To our delight,
during the catalyst structure screening, both the R and S
enantiomers of the products can be obtained in excellent
yields and enantioselectivities respectively with catalysts IV
and I. The same substrate scope was explored in the presence
of 5 mol % catalyst I and the S enantiomers of the products
were obtained in good to high yields with excellent enan-
tioselectivities (93-96% ee). As shown in Table 4, a similar
Scheme 1. Further Investigation of Substrates Scope
Table 4. Asymmetric 1,4-Addition of Nitroalkanes to Various
Chalcones Using Catalyst Ia
On the basis of the configuration of the product (+)-3a, a
possible transition state model is hypothesized and shown
in the Supporting Information. We envisioned that the chiral
squaramide-based catalyst VI acts in a bifunctional fashion.
The chalcone is fixed and activated by the squaramide moiety
through double hydrogen bonding between the NH groups
and the carbonyl group. Meanwhile, the nitromethane is
activated by the basic quinine nitrogen atom. Then the R
product (+)-3a could be generated by the Re-face attack of
the activated chalcone.
entry
R1
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
4-MeC6H4
4-MeOC6H4 C6H5
3-MeOC6H4 C6H5
4-FC6H4
4-ClC6H4
4-BrC6H4
4-MeC6H4
4-ClC6H4
R2
C6H5
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
2-BrC6H4
C6H5
product yield (%)b ee (%)c
1
2
3
4
5
6
7
8
9
10
11
12
13
14
4a
4b
4c
4d
4e
4f
94
92
70
99
98
98
94
84
64
96
98
95
87
99
95 (S)d
94 (S)
95 (S)
94 (S)
95 (S)
93 (S)
96 (S)
95 (S)
94 (S)
96 (S)
95 (S)
95 (S)
95 (S)
94 (S)
4g
4h
4i
4j
4k
4l
C6H5
C6H5
C6H5
4-MeC6H4
In conclusion, we have developed a new series of chiral
suqaramide cinchona alkaloid-based organocatalysts which
were effective in promoting the asymmetric Michael addition
of nitroalkanes to chalcones with low catalyst loading. These
catalysts could be readily prepared and possess a high
modular nature. Remarkably, catalysts VI and I were
employed to catalyze the Michael addition of nitromethane
to chalcones at 80 °C, and both the R and S enantiomers of
the products were easily obtained in high yields with
excellent enantioselectivities (93-96% ee), respectively. This
class of chiral squaramide-based catalysts is a kind of good
hydrogen-bonding organocatalyst, and current studies are
underway to broaden their applications in asymmetric
catalysis.
4m
4n
4-ClC6H4
a Unless noted otherwise, reactions were carried out with 0.25 mmol of
chalcones and 2.5 mmol of nitromethane in 0.5 mL of CH2ClCH2Cl at 80
°C for 60 h. b Isolated yields. c Determined by HPLC, using a Chiralpak
IA column. d Absolute configuration was determined by comparison of the
optical rotation with literature data.8
tendency of the substituent effect on enantioselectivies was
observed.
In addition, the reaction of nitroethane 2b and chalcone
1a catalyzed by 2 mol % catalyst VI was also effective to
provide the corresponding products with high enantioselec-
tivities for both diastereomers (96% ee and 94% ee,
respectively), albeit with moderate yield and low diastereo-
selectivities (Scheme 1). The asymmetric Michael addition
of nitromethane 2a to (2E,4E)-1,5-diphenylpenta-2,4-dien-
1-one 5 with use of 10 mol % catalyst VI was investigated.
As shown in Scheme 1, the substrate 5 gave the desired
product 6 in moderate yield and excellent enantioselectivity
in a longer time due to its lower reactivity. The asymmetric
Michael addition of nitromethane to other linear or cyclic
enones was also investigated. No reaction occurred for
1-phenyl-2-buten-1-one, and 2-cyclohexen-1-one only gave
product 7 in 37% yield with 73% ee.
Acknowledgment. This project was partially supported
by the National Natural Science Foundation of China (Grant
nos. 20772006, 21072020), the Development Program for
Distinguished Young, and Middle-aged Teachers of Beijing
Institute of Technology.
Supporting Information Available: Experimental pro-
1
cedures and characterizations, copies of H NMR and 13C
NMR of new compounds, and HPLC profiles. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL102294G
Org. Lett., Vol. 12, No. 23, 2010
5453