Efficient in situ three-component formation of chiral oxazoline-Schiff base copper(ii) complexes: Towards combinatorial library of chiral catalysts for asymmetric Henry reaction

Article abstract of DOI:10.1039/b923835b

A combinatorial in situ three-component chiral oxazoline-Schiff base copper(ii) complex catalyst formation method was developed. This simple combinatorial chiral catalyst approach provided a modular library of chiral oxazoline-Schiff base copper(ii) compl

Full text of DOI:10.1039/b923835b

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Efficient in situ three-component formation of chiral oxazoline-Schiff base
copper(II) complexes: towards combinatorial library of chiral catalysts for
asymmetric Henry reaction†
Wen Yang,a Han Liub and Da-Ming Du*a
Received 13th November 2009, Accepted 14th April 2010
First published as an Advance Article on the web 10th May 2010
DOI: 10.1039/b923835b
A combinatorial in situ three-component chiral oxazoline-Schiff base copper(II) complex catalyst
formation method was developed. This simple combinatorial chiral catalyst approach provided a
modular library of chiral oxazoline-Schiff base copper(II) complex catalysts. The catalytic activity of
these in situ generated catalysts can be rapidly and conveniently evaluated in the asymmetric Henry
reaction. Moderate to good yields and enantioselectivities (up to 92% ee) were obtained under the
optimized condition. The combination of modular three-component catalyst formation and in situ
asymmetric reaction provides a new technology in asymmetric catalysis.
Schiff base metal complexes in a large variety of useful catalytic
Introduction
transformations.6 For example, as a representative type of chiral
The development of efficient methodologies for providing enan-
Schiff base, chiral Salen ligands have been successfully used in
various asymmetric reactions with excellent results.7,8
tiomerically pure products is of great value, due to the increasing
demands for chiral compounds in the development of phar-
maceuticals, agrochemicals, materials, and flavors.1 Among the
various approaches employed for obtaining chiral compounds,
asymmetric catalysis using chiral metal complexes is one of the
most efficient strategies. In order to achieve efficient and highly
enantioselective organic transformations catalytically, the design
and synthesis of chiral catalysts is very important. To the best of
our knowledge, there is no general ligand or catalyst suitable for
every reaction or every substrate. The successful development of
an efficient chiral catalyst usually depends on the combination
of rational design, experience, and a trial and error process.
In this regard, the synthesis of a large number of chiral metal
complexes for screening the highly efficient catalysts is a usual
manner. However, the synthetic procedures toward most of the
chiral ligands are always multi-step and tedious. The development
of an efficient and flexible synthetic strategy of chiral ligands or
catalysts is strongly desired. In recent years, using combinatorial
approaches,2 self-assembly,3 or modular approaches4 to generate
a library of chiral metal complexes has emerged. Such a strategy
takes advantage of its diversity and efficiency in discovering the
highly efficient and enantioselective catalysts.
Oxazoline is another type of ‘privileged ligand’ owing to its
ready accessibility, modular nature, and successful applications
in various catalytic asymmetric reactions.5 The design and appli-
cations of chiral oxazoline ligands have gained much attention
of chemists in recent years.9 Our group has also paid much
attention to the synthesis and applications of oxazoline ligands.10
We envisioned that the combination of Schiff base and oxazoline
would result in a new type of modular ligand possessing features of
both two types of privileged ligands.11 Using Schiff base formation
as a diversity-generating step at late stage in modular ligand
construction also has another significant advantage: its rapid
formation under mild condition without addition of dehydration
reagent or catalyst may provide us an opportunity to generate
active catalyst in situ without isolation and make the screening
more convenient.
Herein, we would like to document a remarkably effective
strategy for modular catalyst development based upon in situ
three-component chiral oxazoline-Schiff base copper(II) complex
catalyst formation from readily available starting materials. The
catalytic activity of these catalysts was tested in the asymmetric
Henry (nitroaldol) reaction,12,13 which can provide easy access to
chiral b-nitroalcohols.
Schiff base ligands have been recognized as ‘privileged ligands’
because they can be easily prepared through the condensation
between various aldehydes and primary amines.5 Schiff base
ligands are able to coordinate with various metals and stabilize
them in various oxidation states, which enables the applications of
Results and discussion
The oxazoline moieties 1a–d were obtained via a three-step process
encompassing coupling of 2-nitrobenzoic acid with chiral amino
alcohols, oxazoline ring formation, and reduction of the nitro
group. Compared with other approaches,14 the synthesis can be
conveniently conducted on a large scale from cheap starting mate-
rials. The details can be found in the ESI.† In our early experiment,
when the oxazoline moiety 1a was mixed with salicylaldehyde 2a
in EtOH, a clear orange solution was formed immediately at room
temperature without addition of a dehydration reagent and TsOH
aSchool of Chemical Engineering and Environment, Beijing Institute
of Technology, Beijing 100081, People’s Republic of China. E-mail:
dudm@bit.edu.cn; Tel: +86 10 68914985
bBeijing National Laboratory for Molecular Sciences (BNLMS), College of
Chemistry and Molecular Engineering, Peking University, Beijing 100871,
People’s Republic of China
† Electronic supplementary information (ESI) available: Experimental
procedures, 1H and 13C NMR spectra of new compounds, and HPLC
diagrams. See DOI: 10.1039/b923835b
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Table 1 Screening of in situ generated catalysts for the Henry reaction of
catalyst, which indicated the generation of the desired Schiff base.
However, the ligand can neither precipitate from EtOH, nor be
isolated through column chromatography (decomposed to amine
and salicylaldehyde), which made the NMR characterization of
the ligand 3aa impossible. After the addition of one equivalent of
Cu(OAc)2 to the solution, a dark green solution of the complex
catalyst 4aa was obtained and TLC showed the salicylaldehyde
2a and oxazoline 1a disappeared. After several unsuccessful
attempts to isolate the catalyst 4aa, 4-nitrobenzaldehyde 5a and
nitromethane 6 were added to the solution for asymmetric Henry
reaction. To our delight, the in situ generated inseparable complex
catalyst 4aa showed significant catalytic activity in the model
Henry reaction. Under unoptimized conditions, 91% yield and
39% ee were obtained.
Inspired by the above observation, a library of novel chiral
oxazoline-Schiff base metal complex catalysts may be easily
obtained through this in situ three-component formation way.
As a standard protocol (Scheme 1), the oxazoline moieties were
mixed with equimolar amount of salicylaldehyde derivatives in
EtOH for 30 min. After the addition of Cu(OAc)2, the mixture was
stirred for another 30 min. Thus, a 16-membered library of chiral
oxazoline-Schiff base copper(II) complex catalysts was obtained
through employing various commercially available salicylaldehyde
derivatives, the oxazoline moieties, and Cu(OAc)2. The asymmetric
Henry reaction was chosen as the model reaction for the evaluation
of the catalytic activity of the library members.
4-nitrobenzaldehyde with nitromethanea
In situ generated catalyst
(component source)
Entry
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4aa (1a + 2a + Cu(OAc)2)
4ab (1a + 2b + Cu(OAc)2)
4ac (1a + 2c + Cu(OAc)2)
4ad (1a + 2d + Cu(OAc)2)
4ba (1b + 2a + Cu(OAc)2)
4bb (1b + 2b + Cu(OAc)2)
4bc (1b + 2c + Cu(OAc)2)
4bd (1b + 2d + Cu(OAc)2)
4ca (1c + 2a + Cu(OAc)2)
4cb (1c + 2b + Cu(OAc)2)
4cc (1c + 2c + Cu(OAc)2)
4cd (1c + 2d + Cu(OAc)2)
4da (1d + 2a + Cu(OAc)2)
4db (1d + 2b + Cu(OAc)2)
4dc (1d + 2c + Cu(OAc)2)
4dd (1d + 2d + Cu(OAc)2)
91
90
94
93
95
90
95
90
91
90
96
98
93
90
98
92
39
42
25
62
44
62
33
64
47
62
27
64
49
69
27
64
9
10
11
12
13
14
15
16
a Reactions were performed with 0.5 mmol of 4-nitrobenzaldehyde and
5.0 mmol of nitromethane in 2 mL of EtOH in the presence of 10 mol %
catalyst 4 (in situ generated) at room temperature for 24 h. b Isolated
yields after column chromatography purification. c Determined by HPLC
using a Daicel Chiracel OD-H column (n-hexane–isopropanol 80 : 20 v/v,
1.0 mL min-1, 254 nm).
Scheme 1 Construction of chiral oxazoline-Schiff base copper(II) com-
Fig. 1 Screening of in situ generated catalysts.
plex catalysts library.
As indicated by the equation in Scheme 1, the in situ formation
of catalyst 4 would generate one equivalent of water and one
equivalent of acetic acid, which may affect the catalytic reaction.
To validate the reproducibility, several additives were tested in the
reaction. As shown in Table S1 (see ESI†), addition of Et3N or
NaOH to remove the acetic acid formed in the catalyst generation
step led to a significant decrease of enantioselectivity. Considering
that the acetate anion coordinated to Cu(II) works as a weak
base when it was displaced by substrate in the catalytic cycle,
the drop of enantioselectivity can be attributed to the formation
of an excess amount of acetate anion which may catalyze the
The library of chiral oxazoline-Schiff base copper(II) metal com-
plex catalysts was formed in situ and screened in an asymmetric
Henry reaction of 4-nitrobenzaldehyde 5a with nitromethane 6
at room temperature. The screening results were summarized in
Table 1. Under the catalysis of 10 mol% catalysts 4aa–dd for
8 h, up to 98% yield and 69% ee can be obtained, while the
best result was achieved when catalyst 4db composed by t-Bu
substituted oxazoline 1d and NO2 substituted salicylaldehyde 2b
was used (entry 14). For clearness, a graphic presentation of these
data was given (Fig. 1), which suggests the important role of the
aldehyde component 2 for enantioselectivity. Ligands generated
from aldehydes 2b and 2d gave high enantioselectivities similarly,
while the substituents R1 of the chiral oxazoline 1 seem to have
little effect on selectivity.
˚
background Henry reaction. Addition of 4 A molecular sieves
and anhydrous Na2SO4 to remove water also did not improve the
enantioselectivity further. When the reaction was conducted at
lower temperature, the ee values increased to some extent, while
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Table 2 Comparison of enantioselective Henry reactions using in situ
generated catalysts with pure oxazoline-Schiff base ligands and Cu(OAc)2
the time for full conversion had to be prolonged by several times.
To our surprise, the catalytic system was not very sensitive to
high temperature. The room temperature was chosen for the
compromise between reactivity and enantioselectivity.
With the optimized catalyst in hand, solvents were screened
for further improvement. As summarized in Table S2 (see ESI†),
alcohols other than EtOH gave comparable enantioselectivities
but lower yields, while 2,2,2-trifuoroethanol with high acidity in-
hibited the reaction completely. Ether-type solvents such as Et2O,
THF, and TBME improved the enantioselectivity significantly.
Dioxane retarded the reaction for its ability to coordinate with
a copper cation as a chelation ligand. The enantioselectivity can
also be improved in toluene, benzene, and dichloromethane, while
much lower yields were obtained. When the catalyst loading was
reduced to 5 mol% and 2.5 mol%, lower enantioselectivities and
yields were obtained. On the basis of the data, the optimized
condition was room temperature in Et2O using 10 mol% catalyst.
In order to prove that the above catalytic system was the
oxazoline-Schiff base copper complex catalyst, control experi-
ments were carried out. When aminophenyl oxazoline moieties
1a–d were used as ligands with Cu(OAc)2 to catalyze the model
Henry reaction of 4-nitrobenzaldehyde, moderate yields (67–72%)
and low enantioselectivities (21–46% ee) for the same (S) enan-
tiomer were achieved. The significantly inferior result indicates
that effective ligands are not the aminophenyl oxazolines 1a–d, but
the oxazoline-Schiff bases. During our screening of solvents, we
observed that the Schiff base ligands derived from NO2 substituted
salicylaldehyde and four oxazoline moieties can precipitate from
isopropanol. This discovery provided us the opportunity to
characterize the structures of the ligands 3ab–db by NMR, ESI-
MS, and IR. Other ligands can neither precipitate, nor be isolated
through column chromatography owing to the decomposition to
amine moieties and salicylaldehydes. Thus, the characterization
of other ligands is impossible. This discovery also provided us
evidence to verify that the possibility of the in situ oxazoline-Schiff
base formation. The copper(II) complex catalysts formed using
pure Schiff base ligands 3ab–3db were also tested in the Henry
reaction of 4-nitrobenzaldehyde with nitromethane in EtOH
(Table 2), similar results to in situ generated catalysts were obtained
(Table 2, entry 4 vs. Table S2, entry 1†). Meanwhile, the copper(II)
complex catalysts formed using pure Schiff base ligands 3ab–3db
were also tested in the Henry reaction of 4-nitrobenzaldehyde
with nitromethane in the optimized solvent Et2O, also similar
yields and enantioselectivities to in situ generated catalysts
4ab–4db were obtained (Table 2, entries 9–11 vs. entries 5–8), which
demonstrated that the in situ three-component generated catalysts
were equivalent to the ones generated from pure oxazoline-Schiff
base ligands and Cu(OAc)2. Further evidence is ESI mass spectra
of in situ generated catalyst 4db, where there is a peak of [M-OAc]+
at m/z 429.
Entry
Catalyst
Solvent
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
3ab + Cu(OAc)2
3bb + Cu(OAc)2
3cb + Cu(OAc)2
3db + Cu(OAc)2
4ab
EtOH
EtOH
EtOH
EtOH
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
95
94
93
95
92
93
94
97
94
95
95
96
56
62
57
70
69
72
70
80
69
72
72
82
4bb
4cb
4db
9
3ab + Cu(OAc)2
3bb + Cu(OAc)2
3cb + Cu(OAc)2
3db + Cu(OAc)2
10
11
12
a Reactions were performed with 0.5 mmol of 4-nitrobenzaldehyde and
5.0 mmol of nitromethane in 2 mL of solvent in the presence of 10 mol %
catalyst at room temperature for 24 h. b Isolated yields after column
chromatography purification. c Determined by HPLC using a Chiracel
OD-H column (n-hexane–isopropanol 80 : 20 v/v, 1.0 mL min-1, 254 nm).
Table 3 Enantioselective Henry reactions of various aldehydes with
nitromethane catalyzed by in situ three-component generated catalysta
Entry
R in product
Time/h
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
4-NO2C6H4 (7a)
3-NO2C6H4 (7b)
2-NO2C6H4 (7c)
4-ClC6H4 (7d)
4-BrC6H4 (7e)
C6H5 (7f)
24
24
24
72
72
72
96
96
72
72
72
72
48
48
48
96
97
95
86
81
85
43
71
65
56
79
71
92
82
81
82 (S)d
76 (S)
84 (S)
87 (S)
79 (S)
83 (S)
75 (S)
80 (S)
80 (S)
88 (R)
75 (S)
86 (S)
82 (S)
87 (S)
92 (S)
4-MeOC6H4 (7g)
4-MeC6H4 (7h)
1-Naphthyl (7i)
2-Furanyl (7j)
9
10
11
12
13
14
15
=
PhCH CH (7k)
PhCH2CH2 (7l)
c-C6H11 (7m)
i-C3H7(7n)
t-C4H9 (7o)
a Reactions were performed with 0.5 mmol of aldehyde and 5.0 mmol of
nitromethane in 2 mL of Et2O in the presence of 10 mol % catalyst 4db
at room temperature. b Isolated yields after the column chromatography
purification. c Determined by HPLC on Daicel Chiracel OD-H, OF, and
Chiralpak IA column. d By comparison with the literature data.13
selectivities (entries 4–8). In the cases of other aromatic aldehydes
such as 1-naphthaldehyde and 2-furanaldehyde, comparable enan-
tioselectivities and moderate yields with the case of benzaldehyde
were obtained (entries 9–10). We also tested a,b-unsaturated
cinnamaldehyde and aliphatic aldehydes, and observed similar
results to former cases (entries 11–15). The moderate catalytic
activity of our catalyst may be attributed to the anionic and
electron-rich nature of the oxazoline-Schiff base ligand. The
absolute configurations of the products were elucidated though
comparison of the optical rotation data with literature data.
The efficiency of our in situ catalytic system was evaluated
for various aldehydes under the optimized condition. In general,
moderate to good yields and enantioselectivities can be achieved in
most cases (75–92% ee). As summarized in Table 3, benzaldehydes
with strong electron-withdrawing nitro substitutions gave good
results within 24 h, which indicates their high reactivity in Henry
reaction (entries 1–3). On the contrary, substrates with weak
electron-withdrawing or even electron-donating substitutions need
prolonged reaction time to get acceptable conversion and enantio-
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CDCl3): d = 14.06 (br s, 1H), 8.65 (s, 1H), 8.38 (s, 1H), 8.25 (d,
J = 9.0 Hz, 1H), 7.94 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.5 Hz,
1H), 7.40–7.19 (m, 6H), 7.06 (d, J = 9.0 Hz, 1H), 4.66 (dd, J =
5.4 Hz, J = 6.9 Hz, 1H), 4.35 (t, J = 9.0 Hz, 1H), 4.14 (t, J =
7.8 Hz, 1H), 3.29 (dd, J = 4.5 Hz, J = 13.8 Hz, 1H), 2.77 (dd,
J = 9.0 Hz, J = 13.5 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d = 166.4, 162.4, 159.88, 159.86, 146.4, 139.7, 137.8, 132.2, 130.8,
129.2, 128.5, 127.4, 126.5, 122.4, 118.7, 118.63, 118.60, 118.1, 71.3,
68.1, 41.5; IR (KBr): n 3462, 1631, 1490, 1339, 1292, 1094, 834,
751, 700 cm-1; HR-ESIMS: m/z calcd for C23H20N3O4 (M+H):
402.14091. Found: 402.14483.
Conclusions
In summary, we reported an efficient and practical strategy for
modular catalyst construction based upon in situ three-component
chiral oxazoline-Schiff base copper complexes formation. The
simple combinatorial chiral catalyst approach provided a library
of novel modular chiral oxazoline-Schiff base copper complex
catalysts. The catalytic activity of these catalysts was tested in the
model asymmetric Henry reaction, and the chiral nitro alcohols
were obtained in moderate to good yields and enantioselectivities
(up to 92% ee). The method of in situ generation of catalysts for
rapid screening in asymmetric reactions matches the increasing
demands for environmentally benign and economic synthetic
processes. Further investigations on the applications of these
catalysts in other asymmetric reactions are underway in our
laboratory.
2-((1E)-(2-((S)-4-Isopropyl-4,5-dihydrooxazol-2-yl)phenyl-
imino)methyl)-4-nitrophenol 3cb. Orange solid, yield 82%; m.p.
123–124 ◦C. [a]D25 = +31.3 (c = 1.29, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 14.00 (br s, 1H), 8.64 (s, 1H), 8.37 (d, J = 2.1 Hz,
1H), 8.23 (dd, J = 2.1 Hz, J = 9.0 Hz, 1H), 7.95 (d, J = 7.8 Hz,
1H), 7.54 (t, J = 7.8 Hz, 1H), 7.37 (t, J = 7.5 Hz, 1H), 7.26 (d, J =
7.5 Hz, 1H), 7.06 (d, J = 9.0 Hz, 1H), 4.46–4.37 (m, 1H), 4.21–
4.11 (m, 1H), 1.94–1.87 (m, 1H), 1.01 (d, J = 6.6 Hz, 1H), 0.92 (d,
J = 6.6 Hz, 1H); 13C NMR (75 MHz, CDCl3): d = 166.5, 161.9,
160.1, 146.3, 139.6, 132.0, 130.8, 129.5, 128.5, 128.3, 127.3, 122.6,
118.5, 118.2, 73.0, 69.6, 32.6, 18.9, 17.9; IR (KBr): n 3466, 2960,
1637, 1511, 1339, 1292, 1092, 1056, 835, 751 cm-1; HR-ESIMS:
m/z calcd for C19H20N3O4 (M+H): 354.14091. Found: 354.14483.
Experimental
General methods
Melting points were measured on an XT-4 melting point apparatus
without correction. The 1H NMR spectra were recorded on
Mercury 200 and 300 MHz spectrometers, while 13C NMR spectra
were recorded at 50 and 75 MHz, respectively. Infrared spectra
were obtained on a Perkin Elmer Spectrum One spectrometer. The
ESI-MS spectra were obtained on Thermo Finnigan LCQ Deca
XP Plus mass spectrometer. Optical rotations were measured on
Perkin-Elmer 341 LC or WZZ–3 spectrometer. The enantiomeric
excesses of the products were determined by chiral HPLC using
Agilent 1200 LC instrument on Daicel Chiralcel OD-H, OF and
Chiralpak IA columns. Elemental analysis was carried out on Ele-
mentar Vario EL instrument. Commercially available compounds
were used without further purification. Column chromatography
was carried out using silica gel (200–300 mesh).
2-((1E)-(2-((S)-4-tert-Butyl-4,5-dihydrooxazol-2-yl)phenyl-
imino)methyl)-4-nitrophenol 3db. Orange solid, yield 80%; m.p.
142–143 ◦C. [a]D25 = +36.2 (c = 2.82, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 14.05 (br s, 1H), 8.62 (s, 1H), 8.36 (s, 1H), 8.23 (d,
J = 9.0 Hz, 1H), 7.95 (d, J = 7.5 Hz, 1H), 7.53 (t, J = 7.5 Hz,
1H), 7.36 (t, J = 7.5 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 7.05 (d,
J = 9.3 Hz, 1H), 4.35 (t, J = 9.0 Hz, 1H), 4.22 (t, J = 8.4 Hz, 1H),
4.09 (t, J = 9.0 Hz, 1H), 0.94 (s, 9H); 13C NMR (75 MHz, CDCl3):
d = 166.6, 161.9, 160.3, 146.3, 139.6, 131.9, 130.8, 130.4, 128.5,
128.3, 127.3, 122.7, 118.5, 118.4, 68.3, 33.8, 25.82, 25.78; IR (KBr):
n 3462, 2951, 1622, 1577, 1520, 1475, 1340, 1292, 1096, 1051,
823, 751 cm-1; HR-ESIMS: m/z calcd for C20H22N3O4 (M+H):
368.15656. Found: 368.16048.
Preparation of oxazoline-Schiff base ligands 3ab–db
A solution of 2-(2-aminophenyl)oxazoline 1a–d (0.5 mmol), 5-
nitrosalicylaldehyde 2b (84 mg, 0.5 mmol) and i-PrOH (5 mL) was
stirred for 3 h at room temperature, and lots of orange precipitate
was formed. The reaction mixture was cooled to 0 ◦C, filtered and
washed with cold i-PrOH (3 ¥ 1 mL) to afford oxazoline-Schiff
base ligands 3ab–db.
General procedure for asymmetric Henry reaction using pure
oxazoline-Schiff base ligand 3 and Cu(OAc)2
The mixture of oxazoline-Schiff base pure ligand 3 (0.05 mmol)
and anhydrous Cu(OAc)2 (9.1 mg, 0.05 mmol) were stirred for
30 min in EtOH or Et2O. 4-Nitrobenzaldehyde 5a (76 mg,
0.5 mmol) and nitromethane 6 (5.0 mmol, 0.26 mL) were added
and the mixture was stirred for 24 h at room temperature. The
reaction mixture was concentrated and purified by silica gel
column chromatography using petroleum ether–ethyl acetate 5 : 1
as eluent.
2-((1E)-(2-((S)-4-Phenyl-4,5-dihydrooxazol-2-yl)phenylimino)-
methyl)-4-nitrophenol 3ab. Orange solid, yield 93%; m.p. 153–
154 ◦C. [a]D25 = +127.4 (c = 1.38, CH2Cl2); 1H NMR (300 MHz,
CDCl3): d = 13.98 (br s, 1H), 8.60 (s, 1H), 8.31 (s, 1H), 8.16 (d,
J = 9.0 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.53 (d, J = 7.5 Hz,
1H), 7.39–7.24 (m, 6H), 6.96 (d, J = 9.0 Hz, 1H), 5.44 (t, J =
9.0 Hz, 1H), 4.79 (t, J = 9.0 Hz, 1H), 4.29 (t, J = 8.1 Hz, 1H); 13
C
General procedure for asymmetric Henry reaction catalyzed by
in situ three-component generated complex catalyst
NMR (75 MHz, CDCl3): d = 166.3, 163.3, 160.18, 160.16, 146.5,
141.9, 139.6, 132.3, 131.0, 128.6, 128.4, 128.3, 127.5, 127.4, 126.6,
118.5, 118.4, 118.3, 74.2, 70.1; IR (KBr): n 3467, 1622, 1492, 1339,
1292, 1096, 947, 835, 750, 700 cm-1; HR-ESIMS: m/z calcd for
C22H18N3O4 (M+H): 388.12526. Found: 388.12918.
A
solution of 2-(2-aminophenyl)oxazoline 1d (10.9 mg,
0.05 mmol), 5-nitrosalicylaldehyde 2b (8.4 mg, 0.05 mmol), and
diethyl ether (2 mL) was stirred for 30 min at room temperature.
Anhydrous Cu(OAc)2 (9.1 mg, 0.05 mmol) was added and stirred
for another 30 min, and the reaction mixture turned dark green.
Aldehyde 5 (0.5 mmol) and nitromethane 6 (5.0 mmol, 0.26 mL)
2-((1E)-(2-((S)-4-Benzyl-4,5-dihydrooxazol-2-yl)phenylimino)-
methyl)-4-nitrophenol 3bb. Orange solid, yield 96%; m.p. 145–
◦
146 C. [a]2D5 = +24.6 (c = 1.17, CH2Cl2); H NMR (300 MHz,
1
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were added and stirred for 24–96 h at room temperature. The
reaction mixture was concentrated and purified by silica gel
column chromatography using petroleum ether–ethyl acetate 5 : 1
as eluent.
8 For recent examples, see: (a) R. N. Loy and E. N. Jacobsen, J. Am.
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Acknowledgements
We are grateful to the National Natural Science Foundation of
China (Grant No.20772006), the Development Program for Dis-
tinguished Young and Middle-aged Teachers of Beijing Institute of
Technology and the Program for New Century Excellent Talents
in University (NCET-07-0011) for financial support.
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