Efficient and enantioselective nitroaldol reaction catalyzed by copper Schiff-base complexes

Article abstract of DOI:10.1016/j.tetasy.2006.01.032

Mild and efficient enantioselective nitroaldol reactions of nitromethane with various aldehydes were catalyzed by chiral copper Schiff-base complexes, which can be readily prepared from amino acid, yielding the corresponding adducts with high yields and g

Full text of DOI:10.1016/j.tetasy.2006.01.032

Tetrahedron: Asymmetry 17 (2006) 725–728
Efficient and enantioselective nitroaldol reaction catalyzed
by copper Schiff-base complexes
Changsheng Gan,a Guoyin Lai,a Zuhui Zhang,a Zhiyong Wanga,* and Ming-Ming Zhoub,*
aHefei National Laboratory for Physical Science at Microscale and Department of Chemistry, University of Science and
Technology of China, Hefei, Anhui 230026, PR China
bStructural Biology Program, Department of Physiology and Biophysics, Mount Sinai School of Medicine, New York University,
One Gustave L. Levy Place, New York, NY 10029-6574, USA
Received 19 December 2005; accepted 20 January 2006
Available online 15 March 2006
Abstract—Mild and efficient enantioselective nitroaldol reactions of nitromethane with various aldehydes were catalyzed by chiral
copper Schiff-base complexes, which can be readily prepared from amino acid, yielding the corresponding adducts with high yields
and good enantiometric excess (ee).
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
ration of 1a was identified by its crystal structure
(Fig. 1).
The nitroaldol reaction (or Henry reaction) is one of the
most important and atom-economical reactions1 for
carbon–carbon bond formation to generate b-nitro-
alkanols. The diversity of the transformation of adducts,
such as reduction to amines, Nef reaction to carbonyl
compounds, or dehydration to nitroalkenes, offers a
variety of applications for this reaction.2 Recent efforts
have been focused on the development of catalytic enan-
tioselective reaction variants. In these processes, differ-
ent chiral catalysts were developed, such as those
based upon BINOL by Shibasaki,3 Bis(oxazoline) by
Evans and Jørgensen,4 cinchona alkaloid by Corey,5
dinuclear zinc complexes by Trost,6 Salen–Co complexes
by Yamada,7 and amino alcohols by Palomo.8,9 Often
these reactions are required to be performed at low tem-
perature and sometimes under airproof conditions. A
chiral Schiff-base is one of the frequently used catalysts,
especially in asymmetric cyclopropanation.10,11 How-
ever, it has not yet been used in the asymmetric nitro-
aldol reaction. We herein report a novel, efficient and
mild enantioselective nitroaldol reaction catalyzed by
chiral copper Schiff-base complexes 1, which can be pre-
pared from phenylalanine.10a–d The absolute configu-
2. Results and discussion
The two enantiomers of phenylalanine (D and L) were
used, and catalysts of different configurations were pre-
pared and utilized in the reaction. It was found that
absolute configuration of the product can be controlled
by the configuration of the catalyst in a Henry reaction.
Initially, the nitroaldol reaction of nitromethane with
4-nitro-benzaldehyde was explored in order to search
for the optimal conditions, as shown in Scheme 1. Table
1 summarized the results of the initial studies. In each
instance, the reaction was carried out at ambient tem-
perature within the given reaction time. With 10 mol %
of 1a, the corresponding product was obtained in a high
yield and with a good ee (Table 1, entry 1). A decrease of
1a resulted in reduction of the reaction yield and little
variation in ee while an increase of 1a from 10 to
20 mol % led to a reduction either in yield or ee value
(Table 1, entries 1 and 2). Generally, the amount of
the catalyst could be decreased to 5% without a marked
loss in enantioselectivity (Table 1, entry 3). Increasing
the amount of nitromethane can remarkably enhance
both reaction yield and rate, but slightly reduces enantio-
selectivity (Table 1, entry 11). The reaction solvent also
has a great influence on the reaction. When the reaction
solvent was changed from toluene to methylene chloride
*
Corresponding authors. Tel.: +86 551 3603185; fax: +86 551 3631760
(M.-M.Z.); e-mail addresses: zwang3@ustc.edu.cn; Ming-Ming.zhou@
mssm.edu
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.01.032

726
C. Gan et al. / Tetrahedron: Asymmetry 17 (2006) 725–728
OH
complex 1
solvent
*
CHO
+
NO2
CH3NO2
O2N
O2N
2a
Scheme 1.
or THF, the reaction yield or ee was decreased. Espe-
cially, the ee was reduced to 7% when toluene was
replaced by methylene chloride (Table 1, entries 4 and
5). When methanol or ethanol was used as a solvent,
the corresponding reaction rate and yield were enhanced
markedly (Table 1, entries 8–11). As for ee, ethanol
favored the enantioselectivity, while methanol was dele-
terious (Table 1, entries 9 and 10). Since the catalyst is
very stable in water, we attempted to carry out this
asymmetric reaction in aqueous media. However, the
addition of water disfavored this reaction, resulting in
a decrease in yield, as well as a large decrease in ee
(Table 1, entries 14 and 15).
All the experimental data demonstrated EtOH as a
superior solvent in terms of yield and ee, consistent with
the report by Evans.4a On the other hand, the organic
base has an important influence on this reaction. The
addition of triethylamine markedly decreased enantio-
selectivities although it can improve the reaction yield
(Table 1, entries 6, 7, and 17). Additionally, reaction
temperature has a great influence on the reaction rate,
yield and the ee value. When the reaction was carried
at or below 0 ꢁC, the corresponding yield was lower
and the reaction took a longer time. The sacrifice in
Figure 1. Two opposite configurations of complex 1 and the crystal
structure of 1a.12
Table 1. Studies on the asymmetric nitroaldol reactions with chiral copper Schiff-base complexesa
Entry
Catalyst (loading)
Solvent
Reaction time (h)
Yield (%)b
ee (%)c
Configd
1
2
3
4
1a (10%)
1a (20%)
1a (5%)
1a (10%)
1a (10%)
1a (10%)
1a (10%)
1a (10%)
1a (5%)
1a (5%)
1a (5%)
1a (5%)
1a (5%)
1a (5%)
1a (5%)
1b (10%)
1b (10%)
1b (5%)
1c (5%)
PhMe
PhMe
PhMe
CH2Cl2
THF
PhMe
PhMe
EtOH
EtOH
48
48
48
48
48
48
24
24
24
24
24
6
24
24
24
48
48
24
24
65
62
45
48
56
91
95
87
85
86
91
80
52
82
78
61
80
85
83
51
45
50
7
43
17
9
80
78
28
70
56
70
23
17
34
15
64
76
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
S
R
5
6e
7f
8
9
10
11g
12h
13i
14
15
16
17f
18
19
MeOH
EtOH
EtOH
EtOH
EtOH/H2O (10:1)
EtOH/H2O (1:1)
PhMe
PhMe
EtOH
EtOH
a All reactions were performed with 0.5 mmol of 4-nitrobenzaldehyde and 2.5 mmol nitromethane in the presence of catalyst 1 at room temperature,
unless specified. The reaction procedure is described in Ref. 13.
b Isolated yield.
c Determined by chiral HPLC using a OD-H column.
d Determined by comparing the HPLC elution order of the enantiomers with an authentic sample according to the literature.4a,6
e 10 mol % triethylamine was added to the reaction system.
f 20 mol % triethylamine was added to the reaction system.
g 1 mL nitromethane was used instead of 2.5 mmol nitromethane.
h The reaction was performed at 50 ꢁC.
i The reaction was performed at 0 ꢁC.

C. Gan et al. / Tetrahedron: Asymmetry 17 (2006) 725–728
727
the yield and rate did not affect the significant enhance-
ment of the ee value (Table 1, entry 13). When the reac-
tion was carried out at 50 ꢁC, the reaction rate was
enhanced remarkably while the corresponding ee value
was reduced. Synthetically, room temperature should
be the optimized temperature for this reaction. When
we added an organic base to prompt the reaction,
however, the corresponding ee decreased dramatically.
Finally, the structure of complex 1 played a crucial role
in this enantioselective reaction. By comparison, a less
bulky complex 1a was proved to be a better ligand for
this asymmetric reaction while the complex 1b bearing
tert-butyl group disfavored the enantioselectivity (Table
1, entries 1 and 16). Catalyst 1c derived from D-phenyl-
alanine yielded the corresponding product with high
enantioselectivity, however, the absolute configuration
of the main product was R in contrary to that of the
reaction product catalyzed by 1a (entry 19).
as shown in Scheme 2. Firstly, when 1a was used to cat-
alyze this nitroaldol reaction (entries 1–11), it was found
that this catalyst worked well for various aromatic alde-
hydes, regardless of the substituents on the aromatic
rings, either electron-withdrawing or donating group
(Table 2), although the yield in entry 5 of Table 2 was
low. It seems that aromatic aldehydes with ortho-substi-
tuted groups (entries 6, 7, and 17) favor slightly the ste-
reoselectivity. Benzaldehyde, without any substituents,
however, gave the product with moderate yield and ee
(Table 2, entry 4), attributed to its lesser steric hin-
drance. Similarly, phenylethyl aldehyde, a type of ali-
phatic aldehyde, gave a moderate yield and poor ee
value (Table 2, entry 9). The other aliphatic aldehydes
tested gave moderate yields and low ee values (Table
2, entries 10 and 11). When this secondary alkyl group
was replaced by a corresponding primary alkyl group,
it was hard to observe an ee value under the experimen-
tal condition. When the catalyst 1c was employed under
the same conditions, similar results were obtained.
These phenomena indicate that steric hindrance plays
an important role in the enantioselectivity.
Under the optimized reaction conditions, different alde-
hydes were tested in order to extend the substrate scope,
OH
*
3. Conclusion
5% mol 1a (1c)
NO2
R CHO + CH3NO2
R
EtOH, rt
2
In summary, a new and facile enantioselective nitroaldol
reaction was realized at room temperature by the
employment of complex 1, yielding b-nitroalkanols with
good yield and a high ee value. Also, the product configu-
ration can be adjusted by alteration of the configuration
of 1, which can be controlled by choosing L- or D-phenyl-
alanine, as this complex was prepared from the deriva-
tives of phenylalanine and copper acetate. On the other
hand, the catalyst is very stable in air and water at room
temperature, so it does have potential in industrial
applications. Further study is currently in progress to
improve the yield and enantiomeric excess and to eluci-
date the reaction mechanism.
Scheme 2.
Table 2. Henry reaction of nitromethane with various aldehydesa
Entry
R
Product Time Yield ee
Config
(h)
(%)b
(%)c
1
2
3
4
5
6
7
8
4-NO2Ph
4-ClPh
1-Naphthyl 2c
2a
2b
24
48
48
48
72
48
60
48
60
48
48
24
48
48
48
72
48
60
48
60
48
48
85
86
73
65
43
90
71
75
61
68
72
83
81
72
67
48
88
75
69
64
64
69
78
82
81
67
75
86
77
80
45
52
61
76
81
86
51
62
85
78
81
52
54
64
S
S
S
S
S
S
S
S
Ph
2d
2e
2f
4-MeOPh
2-ClPh
2-MeOPh
4-MePh
PhCH2
i-Pr
i-Bu
4-NO2Ph
4-ClPh
2g
2h
2i
Acknowledgements
d
9
—
10
11
12
13
14
15
16
17
18
19
20
21
22
2j
S
The authors are grateful to National Nature Science
Foundation of China (Nos. 20472078 and 30572234)
and the US National Institutes of Health (to M.-M.Z.)
for their support.
2k
2a
2b
S
R
R
R
R
R
R
R
R
1-Naphthyl 2c
Ph
2d
2e
2f
4-MeOPh
2-ClPh
2-MeOPh
4-MePh
PhCH2
i-Pr
References
2g
2h
2i
1. Trost, B. M. Science 1991, 254, 1471–1477.
d
—
2. (a) Rosini, G. In Comprehensive Organic Synthesis; Trost,
B. M., Fleming, I., Heathcock, C. H., Eds.; Pergamon:
New York, 1991; Vol. 2, pp 321–340; (b) Luzio, F. A.
Tetrahedron 2001, 57, 915–945; (c) Ono, N. The Nitro
Group in Organic Synthesis; Wiley-VCH: New York, 2001.
3. (a) Sasai, H.; Suzuki, T.; Arai, S.; Arai, T.; Shibasaki, M.
J. Am. Chem. Soc. 1992, 114, 4418–4420; (b) Arai, T.;
Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki,
M. Chem. Eur. J. 1996, 2, 1368–1372.
2j
2k
R
R
i-Bu
a All reactions were performed on a 0.5 mmol scale with 5 mol % of
complex 1a or 1c in the presence of 2.5 mmol of nitromethane in
ethanol. For entries 1–11, 1a was used, while for entries 12–22, 1c
was used.
b Isolated yields after chromatographic purification.
c Enantiomeric excess was determined by HPLC using Chiracel OD-H
or OJ-H column.
d Configurations in entries 9 and 20 were not determined but they were
reversed with respect to each other.
4. (a) Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.;
Shaw, J. T.; Downey, C. W. J. Am. Chem. Soc. 2003, 125,
12692–12693; (b) Christensen, C.; Juhl, K.; Hazell, R. G.;

728
C. Gan et al. / Tetrahedron: Asymmetry 17 (2006) 725–728
Jørgensen, K. A. J. Org. Chem. 2002, 67, 4875–4881; (c)
2002, 41, 3059–3061; (c) Dossetter, A. G.; Jamison, T. F.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 1999, 38, 2398–
2400; (d) Ruck, R. T.; Jacobsen, E. N. Angew. Chem., Int.
Ed. 2003, 42, 4771–4774; (e) Ruck, R. T.; Jacobsen, E. N.
Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Com-
mun. 2001, 2222–2223; (d) Du, D. M.; Lu, S. F.; Fang, T.;
Xu, J. X. J. Org. Chem. 2005, 70, 3712–3715; (e) Lu, S. F.;
Du, D. M.; Zhang, S. W.; Xu, J. X. Tetrahedron:
Asymmetry 2004, 15, 3433–3441.
´
J. Am. Chem. Soc. 2002, 124, 2882–2883; (f) Gama, A.;
´
Flores-Lopez, L. Z.; Aguirre, G.; Parra-Hake, M.; Soma-
5. Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999,
38, 1931–1934.
nathan, R.; Cole, T. Tetrahedron: Asymmetry 2005, 16,
1167–1174.
6. (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed.
2002, 41, 861–863; (b) Trost, B. M.; Yeh, V. S. C.; Ito, H.;
Bremeyer, N. Org. Lett. 2002, 4, 2621–2623.
12. Crystal data for 1a: C56H46Cu2N2O4, fw = 938.03, grey
prism crystal, 0.7 · 0.45 · 0.2 mm, monoclinic, space
˚
˚
group P21, a = 10.705(2) A, b = 12.738(3) A, c = 34.184
3
˚
˚
7. (a) Yamada, T. Synthesis-Stuttgart 2004, 12, 1947–1950;
(b) Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.;
Ikeno, T.; Yamada, T. Chem. Lett. 2004, 33, 614–615.
8. (a) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem., Int.
Ed. 2005, 44, 3881–3884; (b) Zhong, Y.-W.; Tian, P.; Lin,
G.-Q. Tetrahedron: Asymmetry 2004, 15, 771–776.
9. (a) Palomo, C.; Oiarbide, M.; Mielgo, A. Angew. Chem.,
Int. Ed. 2004, 43, 5442–5444; (b) Klein, G.; Pandiaraju, S.;
Reiser, O. Tetrahedron Lett. 2002, 43, 7503–7506; (c)
Ko¨hn, U.; Schulz, M.; Go¨rls, H.; Anders, E. Tetrahedron:
Asymmetry 2005, 16, 2125–2131.
10. (a) Li, Z.-N.; Zheng, Z.; Chen, H. Tetrahedron: Asymme-
try 2000, 11, 1157–1163; (b) Cai, L.; Mahmoud, H.; Han,
Y. Tetrahedron: Asymmetry 1999, 10, 411–427; (c) Ara-
tani, T.; Yoneyoshi, Y.; Nagase, T. Tetrahedron Lett.
1982, 23, 685–688; (d) Aratani, T. Pure Appl. Chem. 1985,
57, 1839–1844; (e) Itagaki, M.; Hagiya, K.; Kamitamari,
M.; Masumoto, K.; Suenobu, K.; Yamamoto, Y. Tetra-
hedron 2004, 60, 7835–7843.
(7) A, b = 93.56(3)ꢁ, V = 4652.3(16) A , Z = 2, Dcalcd
=
=
1.339 g cmÀ3 l = 0.963 mmÀ1
,
,
T = 293(2) K, F000
˚
1944, MoKa radiation, k = 0.71073 A. Refinement of
1153 parameters and 1 restrains on 15,995 independent
reflections out of 27,419 measured reflections (Rint
=
0.0204) led to R1 = 0.0351 (I > 2r(I), 15,259 reflections),
wR2 = 0.0856 (all data) and S = 1.081. Bruker SMART
CCD diffractometer, structure solution by direct method,
refinement on F2. Crystallographic data for the structure
reported in this letter have been deposited with the
Cambridge Crystallographic Data Centre and allocated
the deposition numbers: CCDC 297115. Copies of the
data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EW, UK (Fax:
Int code+(1223) 336-033; E-mail: deposit@ccdc.cam.
ac.uk).
13. Typical procedure: To
a solution of complex 1a
(0.025 mmol) in ethanol was added nitromethane
(2.5 mmol) and the mixture was stirred for 2 h. Aldehyde
(0.5 mmol) was added and reacted for the indicated time.
The volatile components were removed in vacuo and the
crude product purified by column chromatography.
11. (a) Jarvo, E. R.; Lawrence, B. M.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2005, 44, 6043–6046; (b) Gademann, K.;
Chavez, D. E.; Jacobsen, E. N. Angew. Chem., Int. Ed.