Highly enantioselective henry reaction catalyzed by C2-symmetric modular BINOL-oxazoline Schiff base copper(II) complexes generated in situ

Article abstract of DOI:10.1002/ejoc.201001587

A 16-member library of C₂-symmetric modular chiral BINOL-oxazoline Schiff base copper(II) complex catalysts generated in situ was easily generated in a one-pot, three-component manner. This approach avoided the need for isolation and characteri

Full text of DOI:10.1002/ejoc.201001587

FULL PAPER
DOI: 10.1002/ejoc.201001587
Highly Enantioselective Henry Reaction Catalyzed by C2-Symmetric Modular
BINOL-Oxazoline Schiff Base Copper(II) Complexes Generated in Situ
Wen Yang[a] and Da-Ming Du*[a]
Keywords: Asymmetric catalysis / Combinatorial chemistry / Ligand design / Multicomponent reactions / Schiff bases
A 16-member library of C2-symmetric modular chiral BINOL-
oxazoline Schiff base copper(II) complex catalysts generated
in situ was easily generated in a one-pot, three-component
manner. This approach avoided the need for isolation and
characterization of ligands and greatly improved the catalyst
screening efficiency. This modular catalyst library was evalu-
ated in the asymmetric Henry reaction, for which good yields
(up to 98%) and good to excellent enantioselectivities (up to
98% ee) were obtained under mild conditions.
veloped and applied in various asymmetric catalytic reac-
tions.[8]
Introduction
The Henry or nitroaldol reaction is one of the most gene-
ral and versatile methods for new carbon–carbon bond for-
mation in organic synthesis. The Henry reaction generates
β-nitro alcohol, which can further be converted into various
valuable structural motifs.[1] Since the first asymmetric ver-
sion of the Henry reaction was reported by Shibasaki in
1992,[2] catalytic asymmetric Henry reactions have gained
particular attention, and great effort has been devoted to
the development of more selective and efficient catalytic
systems for this synthetically useful transformation.[3–5] Al-
though good to excellent results have been achieved by
using these systems, the design and development of efficient
and flexible synthetic strategies involving chiral ligands or
catalysts is still needed.
In recent years, modular and combinatorial approaches
have been applied to generate a combinatorial library of
modular chiral ligands or catalysts in asymmetric cataly-
sis.[6] As efficient and flexible synthetic strategies, these ap-
proaches enable new, highly efficient and enantioselective
catalysts to be developed. Meanwhile, the modular ap-
proach also offers a powerful tool to synthesize new ligands
by combining classical ligands. Modular synthesis based on
“privileged ligand” architectures is an efficient method that
can be used to develop new prominent ligands. For exam-
ple, modular phosphite–phosphoroamidites libraries have
been used in asymmetric palladium-catalyzed allylic substi-
tution reactions and Cu-catalyzed asymmetric 1,4-addition
to enones.[7] Modular oxazoline ligands have also been de-
Due to excellent axial chirality, enantiomerically pure
1,1Ј-bi-2-naphthol (BINOL) derivatives play an important
role in ligand design for asymmetric catalysis.[9] Oxazoline
is also a type of “privileged ligand” owing to its ready ac-
cessibility, modular nature, and proven success in various
catalytic asymmetric reactions. The design and application
of chiral oxazoline ligands has gained much attention in
recent years.[10] Our group has focused on the design, syn-
thesis, and applications of the C2-symmetric oxazoline li-
gands in various asymmetric reactions in recent years.[5,11]
Schiff-base ligands have also been recognized as “privileged
ligands” because they are able to coordinate with various
metals in a large variety of useful catalytic transformations;
they can be easily prepared through condensation of vari-
ous aldehydes with primary amines.[12] In our preliminary
report,[5a] we succeeded in developing C1-symmetric modu-
lar ligands and catalysts by facile combination of salicylal-
dehyde derivatives and oxazoline through Schiff base for-
mation in situ. As a rational extension and update, we now
report on the design of new C2-symmetric modular BI-
NOL-oxazoline Schiff-base ligands, which are the combina-
torial ligands of BINOLs and the oxazoline moieties by
Schiff-base formation. We envisioned that the new C2-sym-
metric modular BINOL-oxazoline Schiff-base ligands
would possess features of the former privileged ligands.
Herein, we report on the formation of a library of new C2-
symmetric modular BINOL-oxazoline Schiff-base cop-
per(II) complex catalysts, which were easily obtained in one
pot from the combination of BINOL-dicarboxaldehydes,
oxazoline moieties, and copper(II) acetate. This modular li-
brary of complex catalysts formed in situ was screened in
the asymmetric Henry reaction of various aldehydes with
nitromethane; good yields (62–98%) and good to excellent
enantioselectivies (81–98% ee) were obtained.
[a] School of Chemical Engineering and Environment, Beijing
Institute of Technology,
Beijing 100081, P. R. of China
Fax: +86-10-68914985
E-mail: dudm@bit.edu.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001587.
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 1552–1556

Highly Enantioselective Henry Reaction
Table 1. Screening of complexes generated in situ for the Henry
reaction of 4-nitrobenzaldehyde with nitromethane.[a]
Results and Discussion
Initially, 2-aminophenyl oxazolines 1 and BINOL dicarb-
oxaldehydes 2 were synthesized for the preparation of cat-
alysts following the literature procedures.[5a,13] A small li-
brary of chiral C2-symmetric modular BINOL-oxazoline
Schiff-base copper(II) complex catalysts was then easily
built in a one-pot, three-component way (Scheme 1). The
library was screened in situ in the asymmetric Henry reac-
tion of 4-nitrobenzaldehyde with nitromethane. The screen-
ing results are presented in Table 1. During the screening
of complex catalysts 3a–p, the reaction was performed in
ethanol, in the presence of 5 mol-% complex 3, at room
temperature. Reactions reached completion within 8 hours
in almost quantitative yields and variable enantioselectivit-
ies (41–88% ee). The complex 3p, generated from 1d, (R)-
2b, and Cu(OAc)2, was clearly the best catalyst for this reac-
tion, giving good enantioselectivity (88% ee) (Table 1, entry
16). The data obtained (illustrated in Figure 1), clearly dem-
onstrates the effect of each chiral component. It can be seen
that the (R) isomer of the BINOL component is better for
asymmetric induction than the corresponding (S) isomer;
substitutes on the oxazoline ring had little effect on asym-
metric induction. Clearly, the above approach, which avoids
the need for isolation and characterization of ligands, was
effective for rapid screening of catalysts.
Entry
Complex catalyst
{source components}
Yield[b]
[%]
ee[c]
[%]
1
2
3
4
5
6
7
8
3a {1a + (S)-2a + Cu(OAc)2}
3b {1b + (S)-2a + Cu(OAc)2}
3c {1c + (S)-2a + Cu(OAc)2}
3d {1d + (S)-2a + Cu(OAc)2}
3e {1a + (S)-2b + Cu(OAc)2}
3f {1b +(S)-2b + Cu(OAc)2}
3g {1c + (S)-2b + Cu(OAc)2}
3h {1d + (S)-2b +Cu(OAc)2}
3i {1a + (R)-2a + Cu(OAc)2}
3j {1b + (R)-2a + Cu(OAc)2}
3k {1c + (R)-2a + Cu(OAc)2}
3l {1d + (R)-2a + Cu(OAc)2}
3m {1a + (R)-2b + Cu(OAc)2}
3n {1b + (R)-2b + Cu(OAc)2}
3o {1c + (R)-2b + Cu(OAc)2}
3p {1d + (R)-2b + Cu(OAc)2}
95
96
96
95
94
98
95
97
95
97
96
99
96
97
97
98
41
47
50
52
41
66
47
77
42
62
51
64
73
80
81
88
9
10
11
12
13
14
15
16
[a] Reagents and conditions: 4-nitrobenzaldehyde (0.5 mmol), ni-
tromethane (5.0 mmol), EtOH (2 mL), complex catalysts 3 (5 mol-
%), room temperature, 8 h. [b] Isolated yield after the column chro-
matographic purification. [c] Determined by HPLC analysis using
a Daicel Chiralcel OD-H column (n-hexane/2-propanol, 80:20;
1.0 mL/min; 254 nm).
Scheme 1. Preparation of complex catalysts 3.
To optimize the reaction conditions, the effect of solvent,
catalyst loading, temperature and the ratio of 1d/2b/
Cu(OAc)2 was screened. The results are shown in Table 2.
Under otherwise identical conditions, use of methanol and
2-propanol as solvent gave slightly lower enantioselectivity
(Table 2, entries 2 and 3), whereas using dichloromethane,
toluene, tetrahydrofuran (THF), or Et2O as solvent gave
only trace amounts of product (Table 2, entries 4–7). When
the complex 3p was formed in EtOH, but the Henry reac-
Figure 1. Screening of complexes generated in situ.
tion was carried out in a second solvent, modest yields and selectivity (Table 2, entry 16) was obtained. We also ad-
enantioselectivities were obtained after 24 h (Table 2, en- justed the ratio of 1d/2b/Cu(OAc)2, but no improved results
tries 8–11). The above results indicated that ethanol was were obtained. After the optimization, 5 mol-% complex
the best solvent for this Henry reaction. The product was catalyst 3p in EtOH at room temperature were established
obtained in excellent yield but with a decrease in enantio- as the standard conditions.
selectivity when Et3N or 4-Å MS was used as an additive
Under the optimal reaction conditions, a series of alde-
(79 and 80% ee, respectively). The effect of catalyst loading hydes were tested, and good to excellent yields and enantio-
was further explored and it was found that with 10 or selectivities (up to 98% ee) were achieved in most cases
2.5 mol-% catalyst loadings, lower enantioselectivities were (Table 3). Benzaldehydes with strong electron-withdrawing
obtained (83 and 71% ee, respectively). When the reaction nitro substitutions gave high yields and good enantio-
was performed at 0 °C, much lower yield and lower enantio- selectivities (Table 3, entries 1–3). Benzaldehyde and benzal-
Eur. J. Org. Chem. 2011, 1552–1556
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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W. Yang, D.-M. Du
FULL PAPER
Table 2. Optimization of the reaction conditions.[a]
Table 3. Enantioselective Henry reactions of various aldehydes with
nitromethane.[a]
Entry
R
Product Time [h] Yield [%][b] ee [%][c]
Entry
Solvent
Time [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
4-NO2Ph
3-NO2Ph
2-NO2Ph
4-ClPh
4-BrPh
Ph
4-MePh
2-MeOPh
1-naphthyl
2-furyl
PhCH=CH
PhCH2CH2
cyclohexyl
isopropyl
tBu
6a
6b
6c
6d
6e
6f
8
8
98
95
93
81
76
85
78
56
65
62
78
69
92
87
80
79
88 (S)[d]
81 (S)
87 (S)
93 (S)
81 (S)
82 (S)
85 (S)
72 (S)
81 (S)
92 (R)
87 (S)
98 (S)
98 (S)
98 (S)
98 (S)
96 (S)
1
2
3
4
5
6
7
EtOH
MeOH
iPrOH
CH2Cl2
toluene
THF
8
8
8
8
8
8
8
24
24
24
24
4
6
6
8
48
8
98
95
88
trace
trace
trace
trace
73
72
78
70
98
97
98
85
40
97
97
88
67
54
–
–
–
12
24
24
48
48
72
48
48
48
48
48
48
48
48
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
Et2O
–
8[d]
9[d]
10[d]
11[d]
12[e]
13[f]
14[g]
15[h]
16[i]
17[j]
18[k]
CH2Cl2
toluene
THF
46
49
78
50
79
80
83
71
81
69
83
9
10
11
12
13
14
15
16
Et2O
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
nonyl
[a] Reagents and conditions: aldehyde (0.5 mmol), nitromethane
(5.0 mmol), EtOH (2 mL), complex catalysts 3p (5 mol-%), room
temperature. [b] Isolated yield after column chromatography. [c]
Determined by HPLC analysis on Daicel Chiralcel OD-H, OF or
Chiralpak IA column. [d] By comparison with the literature data.[4]
8
[a] Reagents and conditions: 4-nitrobenzaldehyde (0.5 mmol), ni-
tromethane (5.0 mmol), complex 3p (5 mol-% formed in situ), sol-
vent (2 mL), room temperature. [b] Isolated yield after column
chromatography. [c] Determined by HPLC using a Chiralcel OD-
H column (n-hexane/2-propanol, 80:20; 1.0 mL/min; 254 nm). [d]
Complex 3p was formed in EtOH, whereas the Henry reaction was
carried out in the solvent shown. [e] Et3N (10 mol-%) was used as
additive. [f] Molecular sieves (4 Å, 100 mg) was used as additive.
[g] Complex 3p (10 mol-%) was employed. [h] Complex 3p (2.5 mol-
%) was employed. [i] The Henry reaction was performed at 0 °C.
[j] The ratio of 1d/2b/Cu(OAc)2 was adjusted to 6:3:5 (1d;
0.06 mmol). [k] The ratio of 1d/2b/Cu(OAc)2 was adjusted to 2:1:3
(1d; 0.05 mmol).
of 4-nitrobenzaldehyde and nitromethane with 10 mol-%
catalyst loading, the desired product was obtained with
90% yield and 80% ee (Scheme 2). Whereas, when the cor-
responding Henry reaction of 4-nitrobenzaldehyde and ni-
tromethane was conducted with 5 mol-% C2-symmetric cat-
alyst, the desired product was obtained with 98% yield and
88% ee (Table 3, entry 1) [this comparison was based on
the same amount of Cu(OAc)2]. This result demonstrated
that the three-component C2-symmetric catalysts generated
in situ were slightly better than C1-symmetric equivalents.
dehyde derivatives with weak electron-withdrawing or even
electron-donating substitutions also gave good yields and
comparable enantioselectivities, but required more pro-
longed reaction times (Table 3, entries 4–7). ortho-Methoxy-
substitution of benzaldehyde resulted a low reactivity and
slightly lower yield and enantioselectivity (Table 3, entry 8),
whereas para- or meta-methoxy-substituted benzaldehydes
gave only trace amounts of product under the same reaction
conditions. In the case of cinnamaldehyde and other aro-
matic aldehydes, such as 1-naphthaldehyde and 2-fural-
dehyde, moderate yields and good enantioselectivities were
obtained (Table 3, entries 9–11). Most remarkably, excellent
results were obtained when aliphatic aldehydes were used
as substrates. When aliphatic unbranched and even
branched or sterically hindered aldehydes were tested, good
yields and excellent enantioselectivities (96–98% ee) were
achieved (Table 3, entries 12–16).
Scheme 2. One-pot, three-component synthesis of C1-symmetric
chiral oxazoline Schiff-base copper complex and its application in
the Henry reaction of 4-nitrobenzaldehyde with nitromethane.
To verify the role of the C2-symmetric feature in the
Many attempts were made to isolate and characterize the
above complex catalytic system, control experiments were three-component complex catalysts 3p or 8 generated in
carried out. When the copper(II) complex catalyst 8, situ, however, no pure material was obtained and, thus, no
formed from BINOL monocarboxaldehyde 7[14] instead of clear structure of the catalytic complex could be deter-
dicarboxaldehyde (R)-2b, was tested in the Henry reaction mined. High-resolution mass spectra also did not give any
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Eur. J. Org. Chem. 2011, 1552–1556

Highly Enantioselective Henry Reaction
Scheme 3. Synthesis of oxazoline Schiff-base ligand 9 and its application in the Henry reaction of 4-nitrobenzaldehyde with nitromethane.
useful composition information. In our previous report, we to expand the scope of this approach to other asymmetric
demonstrated that aminophenyl oxazoline moieties 1a–d reactions.
were not effective ligands in the catalysis of the model
Henry reaction of 4-nitrobenzaldehyde.[5a] The mixture of
Experimental Section
aldehyde (S)-2b and Cu(OAc)2 did not catalyze the Henry
reaction. We further synthesized the Schiff-base ligand 9
from 1d and (S)-2b, but the product was only obtained in
24% yield. The corresponding Henry reaction of 4-ni-
trobenzaldehyde with nitromethane catalyzed by 5 mol-%
General Methods: Melting points were measured with a XT-4 melt-
ing point apparatus. 1H NMR spectra were recorded with a Varian
Mercury 200 or 300 MHz spectrometer. Infrared spectra were ob-
tained with a Perkin–Elmer Spectrum One spectrometer. The ESI-
ligand 9 and 10 mol-% Cu(OAc)2 gave the desired Henry MS spectra were obtained with a Bruker APEX IV mass spectrom-
eter. Optical rotations were measured with a Perkin–Elmer 341 LC
or WZZ-3 polarimeter. The enantiomeric excesses of the products
were determined by chiral HPLC with an Agilent 1200 LC instru-
ment and Daicel Chiralcel OD-H, OF and Chiralpak IA columns.
Commercially available compounds were used without further puri-
fication. Solvents were dried according to standard procedures.
Column chromatography was carried out using silica gel (200–
300 mesh).
product with 97% yield and 87% ee (Scheme 3). This result
is similar to that obtained by using catalyst 3p generated in
situ (Table 3, entry 1), which demonstrated that the three-
component catalysts generated in situ were equivalent to
those generated by using pure oxazoline Schiff-base ligand
and Cu(OAc)2. Although the mechanism of this catalyst
system cannot be resolved at the present time owing to the
uncertainty of the complex catalyst structure, this in situ
approach can avoid the isolation and characterization of
ligands and greatly improves the efficiency of catalyst
screening.
Compounds 1a–d were prepared according to our previous pa-
per.[5a] Compounds (R)-2a, (R)-2b, (S)-2a, (S)-2b and 7 were pre-
pared following literature procedures.[13,14]
General Procedure for Asymmetric Henry Reaction with Complex
Catalyst Generated in Situ: A solution of (S)-2-(4-tert-butyl-4,5-
dihydrooxazol-2-yl)aniline (1d; 10.9 mg, 0.05 mmol), (R)-2,2Ј-bis-
(methoxymethoxy)-1,1Ј-binaphthyl-3,3Ј-dicarboxaldehyde [(R)-2b;
10.8 mg, 0.025 mmol], and EtOH (2 mL) was stirred for 1 h at
room temperature. Anhydrous Cu(OAc)2 (9.1 mg, 0.05 mmol) was
Conclusions
We have developed a library of new C2-symmetric modu-
lar BINOL-oxazoline Schiff base copper(II) complex cata- added and the mixture was stirred for another 1 h, during which
time the reaction mixture turned brown. Aldehyde (0.5 mmol) and
nitromethane (5.0 mmol, 0.26 mL) were added and the mixture was
stirred for 8–48 h at room temperature. The reaction mixture was
concentrated and purified by silica gel column chromatography.
lysts in an efficient, one-pot, three-component method that
enables rapid evaluation of ligands and catalysts. The BI-
NOL-oxazoline Schiff base copper(II) complex 3p was
found to be an efficient catalyst that can catalyze the asym-
metric Henry reaction of various aldehydes and nitrometh-
ane under mild reaction conditions. Good yields and excel-
lent enantioselectivities (96–98% ee) were observed, espe-
cially when aliphatic aldehydes were used as substrates.
Furthermore, this new library of C2-symmetric modular BI-
NOL-oxazoline Schiff base copper(II) complex catalysts are
more efficient than the C1-symmetric modular oxazoline-
Schiff base copper(II) catalysts formed by saciylaldehyde
derivatives and corresponding oxazolines developed pre-
Synthesis of Oxazoline Schiff-Base Ligand 9: To a solution of
(R)-2,2Ј-bis(methoxymethoxy)-1,1Ј-binaphthyl-3,3Ј-dicarbaldehyde
[(R)-2b; 108 mg, 0.25 mmol] in EtOH (2 mL), was added (S)-2-(2-
aminophenyl)-4-tert-butyloxazoline (1d; 109 mg, 0.50 mmol). The
reaction mixture was stirred for 96 h at room temperature, during
which time some white precipitate was formed. The product was
obtained through filtration as a white solid (101 mg, 24%). M. p.
152–154 °C. [α]2D5 = –114.3 (c = 0.56, CH Cl ). IR: ν = 2957, 2902,
˜
2
2
2869, 1637, 1589, 1524, 1453, 1359, 1328, 1285, 1262, 1241, 1159,
1062, 969, 908, 752 cm–1. 1H and 13C NMR could not be obtained
viously.[5a] Further studies are in progress in our laboratory owing to its decomposition in solvent. HRMS (ESI): calcd.
Eur. J. Org. Chem. 2011, 1552–1556
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1555

W. Yang, D.-M. Du
FULL PAPER
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for C52H55N4O6 [M
C52H54N4O6·2C2H5OH (923.15): C 72.86, H 7.21, N 6.07; found C
73.00, H 7.18, N 6.02.
Asymmetric Henry Reaction Using Pure Oxazoline Schiff-Base Li-
gand 9 and Cu(OAc)2: A mixture of oxazoline Schiff-base pure li-
gand 9 (20.8 mg, 0.025 mmol) and anhydrous Cu(OAc)2 (9.1 mg,
0.05 mmol) were stirred for 30 min in EtOH. 4-Nitrobenzaldehyde
(4a; 75.6 mg, 0.5 mmol) and nitromethane (5.0 mmol, 0.26 mL)
were added and the mixture was stirred for 24 h at room tempera-
ture. The reaction mixture was concentrated and purified by silica
gel column chromatography (petroleum ether/ethyl acetate, 5:1) to
give 6a (101 mg, 97%) with 87% ee.
Supporting Information (see footnote on the first page of this arti-
cle): Data of well-known compounds, HPLC diagrams of Henry
products, IR and HRMS of new ligands.
Acknowledgments
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No. 21072020), the Major
Projects Cultivating Special Program in Technology Innovation
Program (Grant No. 2011CX01008) and the Development Program
for Distinguished Young and Middle-Aged Teachers of Beijing In-
stitute of Technology.
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Received: November 25, 2010
Published Online: February 2, 2011
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