Highly enantioselective Henry reactions of aromatic aldehydes catalyzed by an amino alcohol-copper(II) complex

Article abstract of DOI:10.1002/chem.201201565

Amino alcohol-Cu^II catalyst: Highly enantioselective Henry reactions between aromatic aldehydes and nitromethane have been developed. The reactions were catalyzed by an easily available and operationally simple amino alcohol-copper(II) catalyst

Full text of DOI:10.1002/chem.201201565

COMMUNICATION
DOI: 10.1002/chem.201201565
Highly Enantioselective Henry Reactions of Aromatic Aldehydes Catalyzed
by an Amino Alcohol–Copper(II) Complex
Dan-Dan Qin, Wen-Han Lai, Di Hu, Zheng Chen, An-An Wu, Yuan-Ping Ruan,
Zhao-Hui Zhou, and Hong-Bin Chen*[a]
The catalytic asymmetric Henry (nitroaldol) reaction is an
ideal, atom economical, and powerful method for stereose-
lective carbon–carbon bond formation. The resulting chiral
adducts, b-nitro alcohols, can be conveniently converted into
b-amino alcohols, a-hydroxy carboxylic acids, aziridines, and
other complex target molecules that are highly versatile
building blocks for the synthesis of bioactive natural prod-
ucts and pharmaceutical agents.[1,2] Since the pioneering
work initiated by Shibasaki and co-workers in 1992,[3] inter-
est in asymmetric Henry reactions has grown and various
catalysts[4] (including metal-based catalysts,[2,5] organocata-
lysts,[2c,6] and enzymes[7]) have been developed over the last
two decades. Although significant progress has been made,
many of the current catalytic systems still share a number of
disadvantages; for example, a low substrate generality, high
cost of catalysts, and harsh reaction conditions. Therefore,
the exploitation of mild, efficient, cheap, and readily avail-
able catalysts is still desirable.
Henry reaction catalyzed by a readily available amino alco-
hol–copper(II) complex.
The chiral amino alcohol ligands 1a–c and 2a–
c (Scheme 1) were easily prepared from commercially avail-
able (1S, 2R)-2-amino-1,2-diphenylethanol and (1S, 2R)-1-
amino-2-indanol, respectively.
Chiral b-amino alcohols are one of the most important li-
gands that are used extensively in catalytic asymmetric syn-
thesis; however, little attention has been focused upon their
application in Henry reactions and, hitherto, only a few ex-
amples have been reported.[8,9] In most cases, these amino
alcohol catalysts showed moderate catalytic capability and
gave only moderate to good enantioselectivities (generally
less than 90% enantiomeric excess (ee)). However, the cata-
lyst reported by Palomo and co-workers generally provided
more than 90% ee, but this catalytic system required the use
Scheme 1. Chiral amino alcohol ligands.
Our initial experiment was performed to screen the effect
of the ligand structure on the Henry reaction by using 4-
chlorobenzaldehyde as a model substrate with nitromethane
(10 equiv) in the presence of a catalyst (10 mol%) which
was generated in situ from the amino alcohol and Cu-
AHCTUNTGRENGUN(N OAc)2·H2O. The results are summarized in Table 1. It was
of N-methyl ephedrine (45%), ZnACTHNUTRGEN(UNG OTf)2 (30%), iPrNEt2
(30%) and low temperatures.[8c] Consequently, it is challeng-
ing to further explore the application of amino alcohols in
an asymmetric Henry reaction. In this communication, we
report an operationally simple and highly enantioselective
Table 1. Effect of the ligand structure on the Henry reaction.[a]
Entry
Ligand
Yield
[%][b]
ee
Config.
[a] D.-D. Qin, W.-H. Lai, D. Hu, Z. Chen, Prof. A.-A. Wu,
Prof. Y.-P. Ruan, Prof. Z.-H. Zhou, Prof. H.-B. Chen
Department of Chemistry and State Key Laboratory of
Physical Chemistry for Solid Surfaces
College of Chemistry and Chemical Engineering
Xiamen University
[%][c]
1
2
3
4
5
6
1a
1b
1c
2a
2b
2c
63
70
56
28
37
60
67
50
61
9
20
8
R
R
R
R
R
R
Xiamen, Fujian 361005 (P.R. China)
Fax : (+86)592-2185192
E-mail: hbchan@xmu.edu.cn
[a] All reactions were performed on a 1 mmol scale (Config.=configura-
tion). [b] Yield of isolated product. [c] The ee value was determined by
chiral HPLC analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201565.
Chem. Eur. J. 2012, 00, 0 – 0
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apparent that the flexibility of the C C bond associated
with the amino and hydroxyl groups in the ligand had
in terms of yield (68%) and ee value (88%) was demon-
strated (Table 3, entry 5). Catalyst loadings also had a signifi-
cant effect on the enantioselectivities; a 2.5 mol% loading
of catalyst gave the highest ee value (96%, Table 4, entry 2).
a strong influence on the coordination with CuACTHNUGTRNEUNG(OAc)2·H2O,
and consequently on the enantioselectivity of the reaction.
Ligands 1a–c were clearly superior to 2a–c in terms of ee
values, among which 1a distinguished itself as the best
ligand, although the product was obtained with only a mod-
erate ee value.
Table 4. The effect of the catalyst loading on the Henry reaction.[a]
In the subsequent studies, the reaction parameters, includ-
ing metal salts, solvents and catalyst loadings, were opti-
mized. From the data listed in Table 2, we noted that when
Entry
Cat. loading [%]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
1
2.5
5
10
15
20
24
42
57
68
64
66
95
96
94
88
90
90
Table 2. The effect of a metal salt on the Henry reaction.[a]
[a] All reactions were performed on a 1 mmol scale. [b] Yield of isolated
product. [c] The ee value was determined by chiral HPLC analysis.
Entry
Metal salt
Cu(OAc)2·H2O
CuCl2·H2O
CuSO4·5H2O
Yield
[%][b]
ee
[%][c]
1
2
3
4
5
6
7
8
9
G
63
25
25
22
20
96
77
7
67
37
15
11
0.4
4.3
1.7
2.7
–
With the optimized reaction conditions in hand, we began
to explore the generality of the method and thus examined
a variety of aromatic aldehydes (Table 5). To our delight, all
of the substrates used in this study (regardless of whether
the aromatic ring contained electron-withdrawing or elec-
tron-donating groups at the ortho, meta or para positions),
gave the corresponding R-enriched products in moderate to
good yield of isolated products (51–95%) with excellent
enantioselectivities in most cases (ꢀ90% ee). Further ex-
periments revealed that aromatic aldehydes functionalized
with electron-donating groups (Table 5, entries 28–38) fur-
nished the corresponding products with higher enantioselec-
tivities (ꢀ97% ee) than those with electron-withdrawing
groups. The only exception was 1-naphthaldehyde (91% ee,
Table 5, entry 31), probably due to its larger steric demand.
It is also worth noting that those substrates functionalized at
the 2,6-positions, for example, 2-chloro-6-fluorobenzalde-
Cu
Cu(OTf)2
Zn(OTf)2
La(OTf)3
In(OTf)3
Bi(OTf)3
(NO3)2·H2O
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
N
ND
[a] All reactions were performed on a 1 mmol scale. [b] Yield of isolated
product. [c] The ee value was determined by chiral HPLC analysis.
other copper salts were used instead of copper acetate, the
yields and ee values decreased dramatically (Table 2, en-
tries 2–5). The most likely reason for this is that the moder-
ately charged acetate anion facilitates the deprotonation of
nitromethane as a prelude to the aldol-addition process.[10]
Other metal triflates were also tested; however, the reac-
tions proceeded with very poor enantioselectivities (Table 2,
entries 6–9). Further studies showed that the reaction was
also highly sensitive to the nature of solvent employed
(Table 3); diethyl ether was found to be the superior solvent
hyde
(Table 5,
entry 15),
2,6-difluorobenzaldehyde
(entry 16), 2,4,6-trifluorobenzaldehyde (entry 17), 2,6-di-
chlorobenzaldehyde (entry 22), 2,4,6-trimethylbenzaldehyde
(entry 37), and 2,6-dimethoxybenzaldehyde (entry 38), gave
the corresponding products with enantioselectivities higher
than 97% ee.
Table 3. The effect of the solvent on the Henry reaction.[a]
Although there is a lack of structural information with re-
gards to the catalytically active species, we have proposed
a simplified distorted tetragonal-pyrimidal copper species
based on the known model.[10] Figure 1 shows the optimized
Entry
Solvent
Yield
[%][b]
ee
[%][c]
À
structures of the transition states and products for the C C
bond-forming step; A1 leads to the formation of the R-con-
figured alcohol A2, whereas B1 results in the formation of
the S-configured product B2, which have energy barriers of
20.06 and 23.02 kcalmolÀ1, respectively. This proposal is in
good agreement with the experimental observation that the
reaction could be conducted under ambient conditions, and
it also indicates that the pathway to the R-configured prod-
uct is kinetically more favorable. Detailed inspection re-
vealed that A1, in comparison with B1, was stabilized by the
1
2
3
4
5
6
7
8
MeOH
iPrOH
CH2Cl2
THF
50
54
19
44
68
48
13
40
62
81
73
88
88
77
75
82
Et2O
hexane
toulene
CH3CN
[a] All reactions were performed on a 1 mmol scale. [b] Yield of isolated
product. [c] The ee value was determined by chiral HPLC analysis.
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Amino Alcohol–Cu(II) Catalyzed Henry Reactions
COMMUNICATION
Table 5. Enantioselective Henry reactions of aromatic aldehydes.[a]
ference between R- and S-con-
figured products was 2.65 kcal
molÀ1, which is consistent with
the experimentally observed ee
value of more than 90%. These
calculations and the high enan-
tioselectivities suggest that the
R-configured product is both
kinetically and thermodynami-
cally favorable.
Entry
R
Yield
ee
Config.[d] Entry
R
Yield
ee
Config.[d]
[%][b] [%][c]
[%][b] [%][c]
1
2
3
4
5
6
7
8
2-ClC6H4
3-ClC6H4
4-ClC6H4
2-BrC6H4
3-BrC6H4
4-BrC6H4
2-FC6H4
3-FC6H4
4-FC6H4
2-NO2C6H4
3-NO2C6H4
4-NO2C6H4
4-CNC6H4
75
68
85
57
55
65
59
52
66
80
94
81
75
94
97
96
95
97
93
94
93
97
93
89
91
90
93
97
98
96
89
91
R
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
2,4-Cl2C6H3
2,5-Cl2C6H3
2,6-Cl2C6H3
3,4-Cl2C6H3
3,5-Cl2C6H3
2-CF3C6H4
3-CF3C6H4
4-CF3C6H4
C6H5
4-iPrC6H4
4-tBuC6H4
1-naphthyl
2-naphthyl
2-MeC6H4
3-MeC6H4
4-MeC6H4
3,4-Me2C6H3
2,4,6-Me3C6H2
86
83
73
78
79
68
61
72
66
63
58
64
67
72
65
66
57
51
93
84
98
96
90
92
94
95
97
97
97
91
97
97
98
97
99
98
99
R
R
R
R
R
R
R
R
R
R[e]
R[f]
R
R[f]
R
In conclusion, we have suc-
cessfully developed an amino
alcohol–copper(II) complex cat-
alyzed asymmetric Henry reac-
tion of aromatic aldehydes with
nitromethane. The mild reac-
tion conditions, tolerance of air
and moisture, lack of additives,
high efficiency and enantiose-
lectivity, and the broad sub-
strate scope makes this catalytic
system useful for the synthesis
of many valuable compounds.
The theoretical studies of the
transition states have increased
our understanding of the cata-
lytic process, and we expect
R[f]
R
9
R
10
11
12
13
14
15
16
17
18
19
R
R
R
R
R[f]
R
R
R
R
R
2-F-4-BrC6H3 91
R[e]
R[f]
R[e]
R[f]
R
2-Cl-6-FC6H3
2,6-F2C6H3
2,4,6-F3C6H2
F5C6
68
62
72
58
95
R
R[f]
R[e]
R[e]
2,3-Cl2C6H3
R
2,6-(MeO)2C6H3 86
[a] All reactions were carried out on a 1 mmol scale. [b] Yield of isolated product. [c] The ee value was deter-
mined by chiral HPLC analysis. [d] Assigned by comparing the optical rotation value with that reported in the
literature. [e] Determined by single-crystal X-ray diffraction analysis. [f] Predicted by theoretical calculations.
that this work may enable the design of new and efficient
catalysts.
Experimental Section
General procedure: A solution of 4-chlorobenzaldehyde (1.0 mmol) and
nitromethane (0.54 mL, 10.0 mmol) in ethyl ether (3.0 mL) was added to
CuACHTNUGTRNEUNG(OAc)2·H2O (5.0 mg, 0.025 mmol) and ligand 1a (6.0 mg, 0.025 mmol)
in a screw-capped vial. The mixture was stirred at ambient temperature
for 72 h and then concentrated under reduced pressure. The resulting res-
idue was purified by flash column chromatography on silica gel to give
(R)-1-(4-chlorophenyl)-2-nitroethanol as the major product (yield:
170 mg, 85%). [a]2D0 =À22.3 (c=1.0 in CH2Cl2); HPLC (Chiralpak AD-
H, 60:40 hexane/EtOH, 1.0 mLminÀ1): R major tR =5.7 min, S minor tR =
6.7 min, 96% ee.
Acknowledgements
This work was financially supported by the Fundamental Research Funds
for the Central Universities (No. 2010121014) and the National Natural
Science Foundation of China (No. 21133004).
Figure 1. Structures of the transition states and products. A1 is the R-con-
À
figured transition state for the C C bond-forming step; B1 is the S-con-
À
figured transition state for the C C bond-forming step; A2 is the R-con-
À
figured product for the C C bond-forming step; B2 is the S-configured
Keywords: amino alcohols · asymmetric catalysis · copper ·
Henry reaction · mechanistic study
À
product for the C C bond-forming step.
intramolecular hydrogen bond (1.954 ꢁ) between the hy-
droxy group and the nitronate, and the less steric interaction
of the phenyl ring. Moreover, the calculated free-energy dif-
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Received: May 4, 2012
Published online: && &&, 2012
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Amino Alcohol–Cu(II) Catalyzed Henry Reactions
COMMUNICATION
Asymmetric Catalysis
D.-D. Qin, W.-H. Lai, D. Hu, Z. Chen,
A.-A. Wu, Y.-P. Ruan, Z.-H. Zhou,
H.-B. Chen* ................... &&&& — &&&&
Highly Enantioselective Henry Reac-
tions of Aromatic Aldehydes Cata-
lyzed by an Amino Alcohol–
Copper(II) Complex
Amino alcohol–CuII catalyst: Highly
enantioselective Henry reactions
between aromatic aldehydes and nitro-
methane have been developed. The
reactions were catalyzed by an easily
available and operationally simple
amino alcohol–copper(II) catalyst (see
scheme). In total, 38 substrates were
tested and the R-configured products
were obtained in good yields with
excellent enantioselectivities.
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