Novel Schiff base ligands derived from Cinchona alkaloids for Cu(II)-catalyzed asymmetric Henry reaction

Article abstract of DOI:10.1016/j.tet.2011.08.076

A new series of Schiff bases derived from Cinchona alkaloids were developed as chiral ligands for the copper(II)-catalyzed asymmetric Henry reaction. The optimized catalyst can promote the Henry reaction of both aromatic and aliphatic aldehydes with nitro

Full text of DOI:10.1016/j.tet.2011.08.076

Tetrahedron 67 (2011) 8552e8558
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel Schiff base ligands derived from Cinchona alkaloids for Cu(II)-catalyzed
asymmetric Henry reaction
,
a
Yu Wei a, Lin Yao a, Bangle Zhang b, Wei He a , Shengyong Zhang
*
a Department of Chemistry, School of Pharmacy, Fourth Military Medical University, Shaanxi Province, Xi’an 710032, PR China
b Department of Pharmaceutics, School of Pharmacy, Fourth Military Medical University, Shaanxi Province, Xi’an 710032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 July 2011
Received in revised form 21 August 2011
Accepted 26 August 2011
Available online 31 August 2011
A new series of Schiff bases derived from Cinchona alkaloids were developed as chiral ligands for the
copper(II)-catalyzed asymmetric Henry reaction. The optimized catalyst can promote the Henry reaction
of both aromatic and aliphatic aldehydes with nitromethane or nitroethane. Those reactions can afford
the chiral
b
-nitro alcohol adducts with high enantioselectivities.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Henry reaction
Schiff base ligands
Copper complexes
Asymmetric catalysis
Cinchona alkaloids
1. Introduction
chiral catalysts for Henry reaction with a broad range of substrates
is still highly desirable.
The Henry (nitro-aldol) reaction1 is one of the most important
Chiral ligand design has played a pivotal role in the de-
velopment of efficient metal-catalyzed asymmetric reactions. A
large number chiral ligands, such as bisoxazoline,5aec bisthiazo-
line,5d bis(imidazoline),5h BINOL-oxazoline,5q salen,5g,k,7,9 N,N0-
dioxides,5j aminopyridine,5l bipiperidine,5p amino alcohol,6c Cin-
chona alkaloids,5m and nanocrystalline8 have been used in the
metal-catalyzed asymmetric Henry reaction. Recently, the eco-
nomic and environmental friendly chiral Schiff base ligands have
frequently used in asymmetric catalysis, including Henry reac-
tion.5e,k,s,9,11 In asymmetric Henry reaction, some of chiral Schiff
base-metal complexes give excellent results with aromatic alde-
hydes, but the yields and ee values are often decreased dramatically
for the aliphatic aldehydes. Cinchona alkaloids are classified as the
most ‘privileged organic chirality inducers’, owing to the advan-
tages of being inexpensive, structurally tunable and both enantio-
mers easily available according to the need.12 They and their
derivatives have been widely used in asymmetric catalysis.2b,5m In
our previous study, Cinchona alkaloids derived chiral quaternary
salts and thiourea organocatalysts have been successfully
employed in the asymmetric alkylation and Michael reaction,
respectively.11
and versatile CeC bond forming reactions in organic synthesis.
Because the resulting
into important building blocks of natural products or pharmaceu-
ticals, such as -amino alcohols, -hydroxy ketones, aldehydes,
b-nitro alcohol adducts can be transformed
b
a
carboxylic acids, azides, and sulfides,2 great efforts have been de-
voted toward the implementation of asymmetric versions of the
Henry reaction. Indeed, significant progress has been achieved in
the last few years.3e10 Since Shibasaki reported the first successful
enantioselective Henry reaction,3 various types of chiral metal
catalysts, containing chiral ligands with metal atoms (such as
copper,5 zinc,2d,6 chromium,2b,7 magnesium,8 cobalt,9 and rare
earth,3,10), and organocatalysts4 have been developed. Among
them, the Cu-catalyzed asymmetric Henry reaction has received
much attention in recent years. However, despite the significant
progress achieved, most of these methods suffer from some limi-
tations, such as the use of preformed silyl nitronates as nucleo-
philes, narrow substrate scope, relatively high catalyst loading, low
reaction temperatures, multistep synthetic procedures for ligand
preparation, or demanding the use of additives. Therefore, the de-
velopment of readily available, highly stereoselective, and practical
Herein, we report a series of novel Cinchona alkaloids derived
Schiff bases and their application in the Cu-catalyzed asymmetric
Henry reaction. To the best of our knowledge, no Cinchona alkaloids
derived Schiff base ligand has been reported. Eight new chiral Schiff
* Corresponding author. Tel./fax: þ86 29 84774470; e-mail address:
weihechem@fmmu.edu.cn (W. He).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.08.076

Y. Wei et al. / Tetrahedron 67 (2011) 8552e8558
8553
base ligands were prepared from Cinchona alkaloids with salicy-
2.2. Initial screening
laldehyde and its derivatives in high yields under mild conditions.
They were then applied in the Cu(II)-catalyzed asymmetric Henry
reaction. Under the optimized conditions, the range of substrates
was successfully expanded to both aromatic and aliphatic alde-
hydes with high enantioselectivities and good yields. Moreover,
when nitroethane instead of nitromethane was used in the Henry
reaction, products with two chiral centers were also obtained
successfully.
Initially the reactivity and enantioselectivity of various alkaloids
derived Schiff bases complexes for the Henry reaction were in-
vestigated. The reaction between benzaldehyde and nitromethane
in the presence of 10 mol % of catalyst, generated in situ from metal
source (10 mol %) and ligand (20 mol %), and Na2CO3 (100 mol %) in
THF at ꢀ20 ꢁC was chosen as a model system; the results are
summarized in Table 1. Cu(OAc)2$H2O proved to be the most suit-
able metal sources as other metal salts, such as CuCl2$2H2O, CuCl,
Cu(OTf)2, NiCl2$6H2O, AgOTf, YiOTf, Pb(OAc)2, Zn(OAc)2, and
Zn(OTf)2 gave lower reactivities and enantioselectivities. The ab-
solute configuration of the product is decided by the C8-position
and C9-position configuration of Cinchona alkaloids (entries 1e4).
Unsurprisingly, the pseudoenantiomeric derived catalyst pairs in-
duced opposite enantioselectivity in the Henry reaction. Compar-
ing entries 2 and 4 with 1 and 3, it can be seen that the additional
methoxy group at the 6-position of the Cinchona alkaloids is benefit
for the enantioselectivity. Notably, the hydroxyl group on the
phenyl of aldehyde is very important. Without the hydroxyl group
(ligand 2e), the ee value decreased from 79% to 61%, and the yield
decreased straightly from 79% to 23% (entry 5 vs entry 2). Impor-
tantly, the hydrogenated Schiff base ligand 2f gave excellent yield
but poor enantioselectivity (entry 6). It indicates the carbon-
enitrogen double bond of the Schiff base ligand is crucial for high
enantioselectivity. The C2-symmetric dimeric Schiff base ligand 2g
did not improve the performance (entry 7). The results obtained
with different Schiff bases showed that ligand 2b, derived from
quinine, was most effective. The most suitable ratio of
Cu(OAc)2$H2O to ligand 2b proved to be 1:2 (Table 1, entry 2 vs
2. Results and discussion
2.1. Synthesis of ligands
A series of new chiral Schiff base ligands derived from Cin-
chona alkaloids were prepared in high yield (Scheme 1). Thus,
four different pseudoenantiomeric of Cinchona alkaloids were
transformed into corresponding 9-amino compounds 1aed,13
followed by condensation with salicylaldehyde to give Schiff
bases 2aed in high yield (75e84%). To investigate the influence
of the different function group of the ligands on chiral induction
and catalytic activity, ligands 2e, 2f, 2g, and 2h were prepared.
Ligand 2e, without hydroxyl group, was simply synthesized by
condensation of benzaldehyde with (8S,9S)-9-amino-(9-deoxy)-
epiquinine 1b. The hydrogenated Schiff base ligand 2f was pre-
pared by reducing 2b with NaBH4. C2-Symmetric dimeric Schiff
base 2g was obtained by reaction of 1b with 1,2-
benzenedialdehyde. Finally, to decide the role of the hydroxyl
group on 2b, it was methylated with dimethyl sulfate to afford
the corresponding methyl ether 2h.
Scheme 1. Synthesis of Schiff base ligands 2aeh.

8554
Y. Wei et al. / Tetrahedron 67 (2011) 8552e8558
Table 1
hexane, and toluene, both the enantioselectivities and the chemical
yields were inferior to THF (entry1 vs entries 2e4). With the polar
protonic solvents methanol or ethanol as solvents, good yields
could be obtained, but the enantioselectivities were poor (entries 5
and 6). Strangely, when acetone or CH2Cl2 was used as solvents,
only trace product could be observed (entries 9 and 10). Using di-
oxane (entry 12) as solvent, 64% ee and 74% yield were obtained
after 12 h at 12 ꢁC (the melting point of dioxane is 11.8 ꢁC).
Screening of the Schiff base ligands and central metals in the asymmetric Henry
reactiona
Entry Metal
Ligand Ratio of
metal/ligand
Yieldb (%) eec (%) Config.d
The basic additives were believed to deprotonate the nucleo-
philes in the Henry reaction.4c Indeed, the reaction did not occur in
absence of base (Table 3, entry 1). Subsequently, the influence of
different bases on the reactivity and stereoselectivity was studied.
DABCO (entries 2 and 3), DIPEA (entry 4), Et3N (entry 7), KOH (entry
12), K2CO3 (entry 13), and Na2CO3 (entries 15e18) gave moderate to
good enantioselectivities and yields. DBU (entry 5), CsCO3 (entry
11), and NaOH (entry 14) were good bases in terms of yields, but the
enantioselectivities were disappointing. 2,20-bipyridine (entry
9e10) afforded excellent enantioselectivity (98% ee) but with
a slightly low yield. Of the bases tested, DABCO, Na2CO3, and 2,20-
bipyridine are most promising. The optimum amount of bases that
is needed to achieve good conversion and enantioselectivity was
50 mol % relative to the substrate (entries 3 and 17) for DABCO and
Na2CO3, respectively, and 300 mol % for 2,20-bipyridine.
1
2
3
4
5
6
7
8
Cu(OAc)2$H2O 2a
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1
1:2
1:1
1:1
1:2
1:1
1:1
1:2
1:1
1:3
32
79
30
56
23
95
20
23
25
10
NR
NR
11
43
79
31
58
61
8
58
64
76
68
d
d
42
4
S
S
R
R
S
S
R
S
S
S
Cu(OAc)2$H2O 2b
Cu(OAc)2$H2O 2c
Cu(OAc)2$H2O 2d
Cu(OAc)2$H2O 2e
Cu(OAc)2$H2O 2f
Cu(OAc)2$H2O 2g
CuCl2$2H2O
CuCl
2b
2b
2b
2b
2b
2b
2b
2b
2b
9
10
11
12
13
14
15
16
17
18
Cu(OTf)2
Zn(OAc)2
Zn(OTf)2
NiCl2$6H2O
AgOTf
d
d
S
7
S
YiOTf
Pb(OAc)2
Trace
Trace
48
ND
ND
74
78
d
d
S
Cu(OAc)2$H2O 2b
Cu(OAc)2$H2O 2b
76
S
a
All reactions were carried out with 0.25 mmol of benzaldehyde and 1.25 mmol
of nitromethane in 1 mL THF in the presence of 10 mol % catalyst, 100 mol % Na2CO3
at ꢀ20 ꢁC for 20 h.
Table 3
Effects of basic additives on the Cu(II)/2b complex catalyzed enantioselective Henry
reactiona
b
Isolated yield.
c
Determined by HPLC analysis (Chiralcel OD-H column).
d
By comparison with the literature data.5,10
entries 17 and 18). Based on the data summarized in Table 1,
Cu(OAc)2$H2O and ligand 2b, which gave the best results, were
chosen for subsequent studies.
Entry Base
Loading of
base (mol %)
Temperature (ꢁC) Time Yieldb eec
(h)
(%)
(%)
Solvent always plays an important role in various catalytic
processes. A series of reaction solvents, such as THF, toluene, diethyl
ether, hexane, methanol, ethanol, isopropanol, acetonitrile, ace-
tone, dichloromethane, DMF, and dioxane, were tested in the cat-
alytic enantioselective Henry reaction between benzaldehyde and
nitromethane in combination with Cu(OAc)2$H2O, ligand 2b, and
Na2CO3 (Table 2). Of the different solvents tested, THF was clearly
the best choice for this reaction in terms of yield and enantiose-
lectivity (entry 1). Using the nonpolar solvents, such as ether,
1
2
3
4
5
6
7
8
d
d
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
ꢀ20
0
24
24
24
12
12
12
12
24
24
48
12
12
12
12
24
24
24
24
24
24
24
24
NR
81
67
53
86
72
55
9
37
57
73
62
45
82
83
79
75
60
25
85
78
57
d
DABCO
DABCO
DIPEA
DBU
DMAP
Et3N
100
50
70
80
52
15
62
62
72
98
95
27
62
53
39
76
79
84
85
87
70
76
79
100
100
100
100
100
Pyridine
9
2,20-Bipyridine 100
10
11
12
13
14
15
16
17
18
19
20
21
22
2,20-Bipyridine 300
CsCO3
KOH
K2CO3
NaOH
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
100
100
100
100
200
100
50
40
30
50
50
Table 2
Screening the solvents in the asymmetric Henry reactiona
Entry
Solvent
Time (h)
Yieldb (%)
eec (%)
ꢀ10
1
2
3
4
5
6
7
8
THF
Toluene
Et2O
24
24
24
24
12
12
12
12
24
24
24
12
79
41
20
13
92
87
30
60
79
56
56
48
16
40
39
52
50
ꢀ30
a
All reactions were carried out with 0.25 mmol of benzaldehyde and 1.25 mmol
of nitromethane in 1 mL of THF in the presence of 10 mol % catalyst, at intend
temperature.
Hexane
MeOH
EtOH
i-PrOH
CH3CN
Acetone
CH2Cl2
DMF
b
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
c
9
Trace
Trace
8
NDd
NDd
22
The effects of temperature on the reaction were also tested
(Table 3, entries 17 and 20e22). As the temperature increased from
ꢀ20 ꢁC to 0 ꢁC, ee decreased significantly with an increase in the
yield. Strangely, both yield and ee decreased obviously when the
temperature decreased from ꢀ20 ꢁC to ꢀ30 ꢁC.
10
11
12e
Dioxane
74
64
a
All reactions were carried out with 0.25 mmol of benzaldehyde and 1.25 mmol
of nitromethane in the intend solvent (1 mL) at the presence of 10 mol
%
Cu(OAc)2$H2O/2b (1:2), 100 mol % of Na2CO3 at ꢀ20 ꢁC for intend time.
Overall, the optimized reaction conditions were 10 mol % of
Cu(OAc)2$H2O/2b (1:2) complex as catalyst, THF as solvent,
50 mol % Na2CO3, DABCO or 300 mol % 2,20-bipyridine as basic
additives, ꢀ20 ꢁC as reaction temperature.
b
Isolated yield.
Determined by HPLC analysis (Chiralcel OD-H column).
Not detected.
c
d
e
Reaction was carried out at 12 ꢁC.

Y. Wei et al. / Tetrahedron 67 (2011) 8552e8558
8555
2.3. Reaction with nitromethane
to form two stereocenters simultaneously still remain challenging
and less explored compare to the reaction of nitromethane.5b,14 The
promising results obtained with nitromethane above prompted us
to further evaluate the ligand 2b in the Henry reaction with
nitroethane. The preliminary results were summarized in Table 5.
Under the optimized reaction conditions, all aldehydes (both aro-
matic and aliphatic) tested gave good yields (68e91%) and high
enantioselectivities (up to 99% ee), although the diaster-
eoselectivities were rather low. The best result was obtained with
electron-rich 2-methoxybenzaldehyde (entry 6, anti/syn¼73:27,
anti: 85% ee, syn: 99% ee).
With the optimized reaction conditions in hand, the scope of
Henry reaction with nitromethane was explored (Table 4). Aromatic
aldehydes in general gave good yields (63e82%) and high enantio-
selectivities (78e98% ee). Importantly, although the highest enan-
tiomeric excesses were obtained with electron-rich 4-
methoxybenzaldehyde and 2-furaldehyde (entries 7 and 11, 98%
ee), reactions with electron-deficient aromatic 4-nitrobenzaldehyde
also gave high enantioselectivity (entry 9, 85% ee). More impor-
tantly, unlike most of other chiral copper catalysts, aliphatic cyclic,
branched or unbranched aldehydes were also excellent substrates in
our catalytic system, affording nitroaldol adducts in good yields and
high enantioselectivities (entries 12e15, 62e67% yield, 81e99% ee).
Table 5
Cu(II)/2b complex catalyzed diastereoselective Henry reactiona
In particular, 3-phenylpropanal gave almost optically pure b-nitro
alcohol adduct with 50 mol % of DABCO as basic additive (entry 12).
Table 4
Cu(II)/2b complex catalyzed enantioselective Henry reactiona
Entry Substrate
Time (h) Yieldb (%) anti/syn eec (%)
anti synd
1
3a YH
20
72
67:33
79 76
Entry
1
Substrate
Time (h)
20
Yieldb (%)
75
eec (%)
2e
3
3b Y¼4-Cl
3c Y¼2-Cl
3d Y¼4-Br
20
20
20
77
71
84
69
72
61:39
72:28
68:32
70:30
73:27
68 72
72 56
73 66
77 74
85 99
3a Y¼H
84 (S)d
4e
5
3g Y¼4-OMe 28
3h Y¼2-OMe 28
2
3b Y¼4-Cl
3c Y¼2-Cl
20
20
20
20
28
28
28
20
65
73
70
64
73
63
82
66
85 (S)
86 (S)
80 (S)
81 (S)
84 (S)
98 (S)
78 (S)
85 (S)
6
3e
4f
5e
6e
7f
8e
9f
3d Y¼4-Br
3e Y¼4-F
7
8
3k
3l
20
32
68
60
48:52
53:47
99 68
74 73
3f Y¼4-Me
3g Y¼4-OMe
3h Y¼2-OMe
3i Y¼4-NO2
10e
3g
20
81
80 (S)
9
3m
32
61
62:38
91 59
11e
12f
13f
3k
3l
20
32
32
72
62
67
98 (S)
99 (S)
81 (S)
a
All reactions were carried out with 0.25 mmol of aldehydes and 1.25 mmol of
nitroethane in 1 mL THF in the presence of 10 mol % Cu(II)/2b complex, 50 mol % of
Na2CO3 at ꢀ20 ꢁC.
b
Isolated yield.
c
Determined by chiral HPLC analysis using Chiralcel OD-H or Chiralpak AD-H
3m
column.
d
By comparison with the literature data.5b,14
DABCO (50 mol %) was used as a base.
e
14
3n
3o
32
32
66
65
86 (S)
87 (S)
These results, together with those of reactions with nitro-
methane, have shown that the new quinine derived Schiff base 2b
is a useful chiral ligand for the Cu-catalyzed asymmetric Henry
reaction of both aromatic and aliphatic aldehydes.
15f
2.5. Mechanism study
a
All reactions were carried out with 0.25 mmol of benzaldehyde and 1.25 mmol
of nitromethane in 1 mL THF in the presence of 10 mol % Cu(II)/2b complex, 50 mol %
of Na2CO3 at ꢀ20 ꢁC.
To elucidate the pathway of the Cu(II)/2b complex catalyzed
asymmetric Henry reaction, we further investigated the role of the
hydroxy group in the catalysis by using the hydroxyl protected li-
gand 2h. It was tested in the asymmetric Henry reaction of two
selected substrates under the same reaction conditions as Table 4
(Scheme 2). We can see that both yield and ee value decreased
dramatically in two occasions. By compared the infrared spectrums
of ligand 2b with the one of Cu(II)/2b complex, we also found that
the signal of hydroxyl group on 2b disappeared when it coupled
with Cu(OAc)2$H2O.15 Those help us to confirm the belief that the
hydroxyl group of the ligand takes part in the formation of the
catalyst complex.
b
Isolated yield.
c
Determined by chiral HPLC analysis using Chiralcel OD-H or Chiralpak AD-H
column.
d
By comparison with the literature data.5,10
2,20-Bipyridine (300 mol %) was used as a base.
DABCO (50 mol %) was used as basic additive.
e
f
2.4. Reaction with nitroethane
A highly enantioselective Henry reaction using nitromethane as
a nucleophile has been well documented. However, highly dia-
stereo- and enantioselective Henry reactions that use nitroethane

8556
Y. Wei et al. / Tetrahedron 67 (2011) 8552e8558
standard, and coupling constants are reported in hertz. Mass
OH
10 mol%Cu(II)/2hcomplex
O
+
NO2
CH3NO2
spectrometric analyses were done on Waters Q Tof Premier
Micromass (ESI) spectrometer. Routine monitoring of reactions was
performed by TLC, using 0.2 mm Kieselgel 60 F254 precoated alu-
minum sheets, commercially available from Merck. Visualization
was done by fluorescence quenching at 254 nm, exposure to iodine
vapor, and/or 2,4-dinitrophenylhydrazine solution. All the column
chromatographic separations were done by using silica gel (Acme,
60e120 mesh). HPLC was done on a Daicel chiral column having
0.46 cm internal diameterꢂ25 cm length. Petroleum ether used
was of boiling range 60e90 ꢁC. Reactions that needed anhydrous
conditions were run under an atmosphere of nitrogen or argon
using flame dried glassware. The organic extracts were dried over
anhydrous sodium sulfate. Evaporation of solvents was performed
at reduced pressure. THF and diethyl ether were distilled from so-
dium metal/benzophenone. CH2Cl2 and CHCl3 were distilled from
CaH2.
R
R
H
base, THF, -20 °C
3k furan-2-carbaldehyde
3l 3-phenylpropanal
4a
5k 70% ee, 30% yield;
5l 50% ee, 21% yield
Scheme 2. Asymmetric Henry reaction under Cu(II)/2h complex.
Based on the experiment results all above, two possible six co-
ordinate Cu(II) transition5d,16 states (TS A and TS B) are shown in
Fig. 1. The uncovered hydroxyl group and the carbonenitrogen
double bond of Schiff base may coordinate with the central copper.
The phenyl ring of salicylaldehyde was on a totally different di-
mensional direction with the part of Cinchona alkaloids’s backbone.
In the proposed working model for the Henry reaction of aldehyde
with nitromethane, TS A generated favoring Re-face attack of the
nitronate anion to aldehyde, which explained the Henry products
with S configurations. Si-face attack of nitromethane to aldehyde
leading to TS B is disfavored due to steric repulsion between the
substrate aldehyde and the catalyst backbone as shown in Fig. 1.
N
O
4.2. Preparation of the ligands (Scheme 1)
Re favored
H2C
N
O
H
4.2.1. (8S,9S)-9-Amino(9-deoxy)-epicinchonidine 1a, (8S,9S)-9-
OMe
R
O
amino(9-deoxy)-epiquinine
1b,
(8R,9R)-9-amino(9-deoxy)-epi-
N
N
cinchonine 1c, and (8R,9R)-9-amino(9-deoxy)-epiquinidine 1d. The
H
Ο
Ο
Cu
CCuu
N
compounds 1aed were prepared according to the literature.13
H
N
4.2.2. Synthesis of Schiff base ligand 2b. In a flask, a solution of
salicylaldehyde (0.24 mL, 2.3 mmol) and (8S,9S)-9-amino-(9-
deoxy)-epiquinine (0.513 g, 1.588 mmol) in toluene (40 mL) was
heated to reflux. After that, two scoops of Al2O3 (about 1.5 g, dried
at 110 ꢁC for 2 h before use) were added to the solution. And then
added one more scoop each hour.
MeO
A
N
R
N
O
After 4 h, the temperature was slowly cooled down to room
temperature. Then the mixture was filtrated and the residue was
washed with Et2O. The combined organic layers were removed
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (CH2Cl2/methanol/Et3N 30:1:1) to afford
H
CH2
N
Si unfavored
O
OMe
O
N
N
Ο
Ο
Cu
Cu
H
H
N
Schiff base ligand 2b (570 mg, 84% yield) as a yellow solid. ½a D25
ꢃ
N
ꢀ76.2 (c 1.0, CH2Cl2). Mp 165e166 ꢁC. IR (KBr) nmax: 3427, 2937,
2864, 1627, 1278 cmꢀ1
.
1H NMR (400 MHz, DMSO)
d
¼13.5 (s, 1H,
MeO
OH), 8.75 (t, J¼3.6, 14.0 Hz, 2H, ArH), 7.98 (d, J¼8.8 Hz, 1H, CH]N),
7.72 (t, J¼21.6, 3.6 Hz, 2H, ArH), 7.43 (dd, J¼10.0, 7.2 Hz, 2H, ArH),
7.30 (t, J¼7.2, 7.6 Hz, 1H, ArH), 6.86 (dd, J¼7.2, 8.8, 8.4 Hz, 2H, ArH),
5.89e5.80 (m, 1H, CH2]CH), 5.24 (d, J¼8 Hz, 1H, CH), 5.01e4.90 (m,
2H, CH2]CH), 3.99 (s, 3H, OCH3), 3.63e3.34 (m, 2H, CH2), 3.07 (t,
J¼12, 10.8 Hz, 1H, CH), 2.64 (d, J¼12.8 Hz, 2H, CH2), 2.21 (s, 1H, CH),
1.52 (d, J¼28.8 Hz, 3H, CH),1.30 (s,1H, CH), 0.75 (q, J¼7.2, 4.0, 7.2 Hz,
B
N
Fig. 1. Proposed working model for the Henry reaction of aldehyde with nitromethane.
3. Conclusion
1H, CH). 13C NMR (100 MHz, DMSO)
d
¼165.7, 160.2, 157.3, 147.7,
In conclusion, a novel chiral Schiff base (2b)/Cu(II) system has
been developed for the diastereo and enantioselective Henry re-
action. The reactions proceeded smoothly to provide the corre-
sponding adducts in high enantioselectivities for a wide range of
substrates. This is the first time Cinchona alkaloids derived Schiff
base ligands are used as ligands in asymmetric catalysis. A transi-
tion state model has also been proposed to account for the good
stereocontrol. Cu(II)/2b complex, being air stable, easily available,
and high enantioselectivity, is a promising catalyst for the de-
144.3, 142.2, 132.4, 131.6, 131.5, 127.5, 121.4, 121.3, 118.7, 118.6, 116.4,
114.1, 102.2, 59.7, 55.6, 39.9, 39.5, 27.5, 27.4, 25.5 ppm. HRMS (ESI,
MþH) calcd for C27H30N3O2 428.2338, found 428.2333.
4.2.3. Synthesis of Schiff base ligand 2a. Ligand 2a was prepared in
the same way as 2b from (8S,9S)-9-amino(9-deoxy)-epi-
cinchonidine with salicylaldehyde. The product was obtained as
a yellow solid, 75% yield. ½a D25
ꢃ
ꢀ88.4 (c 1.0, CH2Cl2). Mp 87e88 ꢁC. IR
(KBr) nmax: 3429, 2939, 2864, 1627, 1278 cmꢀ1. 1H NMR (400 MHz,
velopment of synthesis of chiral b-nitro alcohols.
DMSO)
d
¼13.4 (s, 1H, OH), 8.93 (s, 1H, ArH), 8.71(s, 1H, CH]N), 8.59
(d, J¼8.4 Hz, 1H, ArH), 8.06 (t, J¼8.4, 9.2 Hz, 1H, ArH), 7.75 (dd,
J¼18.8, 7.2 Hz, 2H, ArH), 7.29e7.44 (m, 3H, ArH), 6.86 (dd, J¼6.8, 7.6,
8.4 Hz, 2H, ArH), 5.92e5.83 (m, 1H, CH2]CH), 5.37 (d, J¼8.8 Hz, 1H,
CH), 4.97 (dd, J¼17.6, 13.2 Hz, 2H, CH2]CH), 3.06e3.53 (m, 3H, CH),
2.65 (d, J¼11.6 Hz, 2H, CH2), 2.24 (s, 1H, CH), 1.32 (m, 3H, CH),
1.22e1.09 (m, 1H, CH), 0.84 (m, 1H, CH). 13C NMR (100 MHz, DMSO)
4. Experimental section
4.1. General
1H and 13C NMR spectra were recorded on Mercury 400 MHz or
JEOL JNM-LA 400 MHz spectrometers. Chemical shifts are
expressed in parts per million downfield from TMS as internal
d
¼165.7, 160.2, 150.4, 148.1, 145.8, 142.2, 131.7, 130.0, 129.3, 126.9,
126.6, 123.8, 120.8, 118.7, 118.6, 102.2, 117.2, 116.3, 114.3, 59.8, 55.6,

Y. Wei et al. / Tetrahedron 67 (2011) 8552e8558
8557
39.9, 27.4, 25.6 ppm. HRMS (ESI, MþH) calcd for C26H28N3O
NMR (400 MHz, DMSO)
d
¼13.5 (s, 1H, OH), 8.78 (s, 1H, ArH), 7.97 (d,
398.2232, found 398.2227.
J¼8.4 Hz, 1H, ArH), 7.77 (s, 1H, ArH), 7.54 (s, 1H, ArH), 7.43 (t, J¼7.6,
14.8 Hz, 1H, ArH), 6.99 (d, J¼29.6 Hz, 2H, ArH), 6.60 (d, J¼38.8 Hz,
2H, ArH), 5.79e5.67 (m, 1H, CH2]CH), 5.05e4.86 (m, 2H, CH2]
CH), 4.63 (s, 1H, CH), 3.91 (s, 3H, OCH3), 3.85 (s, 2H, CH2), 3.49e3.30
(m, 3H, CH), 2.82 (s, 2H, CH2), 2.39 (s, 1H, CH), 1.61 (m, 3H, CH), 1.22
4.2.4. Synthesis of Schiff base ligand 2c. Ligand 2c was prepared in
the same way as 2b from (8R,9R)-9-amino(9-deoxy)-epicinchonine
with salicylaldehyde. The product was obtained as a yellow solid,
78% yield. ½a 2D5
ꢃ
þ65.5 (c 1.0, CH2Cl2). Mp 88e89 ꢁC. IR (KBr) nmax
:
(s, 2H, CH2), 0.76 (s, 1H, CH). 13C NMR (100 MHz, DMSO)
d
¼157.3,
3444, 2927, 2862, 1627, 1278 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
155.7, 147.8, 143.8, 131.3, 129.3, 129.2, 127.9, 125.5, 121.4, 119.7, 118.3,
114.9, 101.6, 60.6, 55.5, 45.9, 40.0, 38.1, 26.6, 24.4 ppm. HRMS (ESI,
MþH) calcd for C27H32N3O2 430.2400, found 430.2377.
d
¼9.91 (s, 1H, OH), 8.79 (d, J¼4.4 Hz, 1H, ArH), 8.46 (d, J¼9.20 Hz,
1H, CH]N), 8.08 (d, J¼11.20 Hz, 1H, ArH), 7.70e7.42 (m, 7H, ArH),
7.01 (t, J¼10.80 Hz, 1H, ArH), 5.92 (s, 1H, CH2]CH), 5.45 (s, 1H, CH),
5.13e5.07 (m, 2H, CH2]CH), 3.55 (d, J¼9.60 Hz, 1H, CH), 3.00 (m,
4H, CH), 2.31 (s, 1H, CH), 1.65 (s, 1H, CH), 1.54 (s, 1H, CH), 1.41e1.35
(m, 2H, CH), 1.00e0.87 (m, 1H, CH). 13C NMR (100 MHz, MeOD)
4.2.8. Synthesis of Schiff base ligand 2g. Ligand 2g was prepared in
the samewayas 2b from(8S,9S)-9-amino(9-deoxy)-epiquininewith
1,2-benzenedialdehyde. The product was obtained as a yellow solid,
d
¼163.4, 151.0, 148.9, 137.9, 134.0, 133.9, 133.6, 133.4, 130.8, 130.2,
54% yield. ½a 2D5
ꢃ
ꢀ65.0 (c 1.0, CH2Cl2). Mp 176e178 ꢁC. IR (KBr) nmax
:
129.9, 129.7, 129.6, 129.2, 127.9, 122.9, 120.5, 118.6, 115.4, 54.5, 49.7,
47.2, 40.5, 29.0, 27.3 ppm. HRMS (ESI, MþH) calcd for C26H28N3O
3398.2232, found 398.2227.
3413, 2972, 2860,1622,1226 cmꢀ1.1H NMR (400 MHz, CDCl3)
d
¼8.74
(d, J¼4 Hz, 2H, ArH), 8.01 (d, J¼9.2 Hz, 4H, ArH), 7.54 (d, J¼1.2 Hz, 2H,
ArH), 7.38e7.33 (m, 6H, ArH), 7.12 (s, 2H, ArH), 5.90e5.59 (m, 2H,
CH2]CH), 5.05e4.91 (m, 4H, CH2]CH), 4.67 (d, J¼20 Hz, 2H, CH),
3.85 (s, 6H, OCH3), 3.15e3.10 (dd, J¼10.4, 4, 9.6 Hz, 2H, CH),
2.85e2.60 (m, 10H, CH), 1.83e1.26 (m, 10H, CH). 13C NMR (100 MHz,
4.2.5. Synthesis of Schiff base ligand 2d. Ligand 2d was prepared in
the same way as 2b from (8R,9R)-9-amino(9-deoxy)-epiquinidine
with salicylaldehyde. The product was obtained as a yellow solid,
CDCl3)
d
¼157.7, 147.6, 142.0, 141.4, 129.3, 126.6, 120.9, 118.5, 114.7,
81% yield. ½a 2D5
ꢃ
þ70.0 (c 1.0, CH2Cl2). Mp 165e166 ꢁC. IR (KBr) nmax
:
106.3, 101.2, 71.3, 56.7, 55.8, 43.2, 42.0, 27.8, 27.3, 21.5 ppm. HRMS
3425, 2983, 2958, 1622, 1255 cmꢀ1
.
1H NMR (400 MHz, CDCl3)
(ESI, MþH) calcd for C48H53N6O2 745.4230, found 745.4225.
d¼10.00 (s, 1H, OH), 8.70 (d, J¼5.60 Hz, 1H, ArH), 8.36 (s, 1H, CH]
N), 8.01 (d, J¼12.00 Hz, 1H, ArH), 7.92 (s, 1H, ArH), 7.83 (d,
J¼10.00 Hz, 1H, ArH), 7.77 (m, 2H, ArH), 7.55 (d, J¼5.2 Hz, 1H, ArH),
7.38 (m, 2H, ArH), 5.77e5.72 (m, 1H, CH2]CH), 5.50 (s, 1H, CH),
5.01e4.88 (m, 2H, CH2]CH), 4.01 (s, 3H, OCH3), 3.66 (t, J¼11.6 Hz,
1H, CH), 3.52 (s, 1H, CH), 3.27e3.21 (m, 1H, CH), 2.76 (d, J¼15.60 Hz,
2H, CH2), 2.26 (s, 1H, CH), 1.62 (d, J¼34.8 Hz, 2H, CH2), 1.45e1.40 (m,
1H, CH), 1.26 (s, 1H, CH), 0.97e0.90 (m, 1H, CH). 13C NMR (100 MHz,
4.2.9. Ligand 2h was prepared as following step. Ligand 2b (128 mg,
0.3 mmol) and NaHCO3 were dissolved in 10 mL acetone. Dimethyl
sulfate (34 mL, 0.36 mmol) dissolved in 2 mL acetone was added into
the above solution drop by drop at 0 ꢁC. Then the mixture was
stirred at room temperature for 6 h. After that, 1 M NaOH (5 mL)
was added and stirred vigorously for 10 min to destruct the rem-
nant dimethyl sulfate. The aqueous phase was washed with ethyl
acetate (3ꢂ20 mL). The combined organic layers were removed
under reduced pressure. The residue was purified by flash chro-
matography on silica gel (CH2Cl2/methanol/Et3N 50:1:1) to afford
MeOD)
d
¼162.1, 160.0, 148.4, 146.6, 145.4, 140.5, 134.9, 133.3, 132.1,
131.9, 130.1, 129.6, 124.0, 120.0, 118.6, 117.7, 116.0, 102.8, 62.9, 60.2,
50.3, 47.6, 39.8, 28.8, 26.6, 25.4 ppm. HRMS (ESI, MþH) calcd for
C27H30N3O2 428.2338, found 428.2333.
yellow solid (2 h, 55 mg, 41% yield). ½a D25
ꢀ35.5 (c 1.0, CH2Cl2). Mp
ꢃ
183e184 ꢁC. IR (KBr) nmax: 2970, 2937, 2793, 2761, 2681, 1450 cmꢀ1
.
4.2.6. Synthesis of Schiff base ligand 2e. Ligand 2e was prepared in
the same way as 2b from (8S,9S)-9-amino(9-deoxy)-epiquinine
with benzaldehyde. The product was obtained as a light brown oil,
1H NMR (400 MHz, CHCl3)
d
¼8.77 (s, 1H, ArH), 8.39 (s, 1H, ArH),
8.05 (d, J¼9.2 Hz, 1H, ArH), 7.74 (s, 1H, ArH), 7.58 (d, J¼2.0 Hz, 1H,
ArH), 7.47 (d, J¼4.0 Hz, 2H, ArH), 7.41 (d, J¼6.8 Hz, 2H, ArH), 7.22 (d,
J¼8.0 Hz, 1H, ArH), 6.91 (d, J¼8.0 Hz, 1H, ArH), 6.84 (m, 1H, CH2]
CH), 5.82e5.74 (m, 1H, CH2]CH), 5.03e4.99 (m, 1H, CH2]CH), 4.96
(s, 1H, CH), 4.01 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.40e3.36 (m, 1H,
CH), 3.02 (s, 1H, CH), 2.94 (s, 1H, CH), 2.09 (s, 2H, CH2), 1.97 (s, 1H,
CH), 1.68 (s, 1H, CH), 1.59e1.57 (m, 1H, CH), 0.97e0.95 (m, 1H, CH).
79% yield. ½a 2D5
ꢃ
ꢀ46.4 (c 1.0, CH2Cl2). IR (KBr) nmax: 2939, 2864, 1627,
1278 cmꢀ1. 1H NMR (400 MHz, CDCl3)
d
¼8.77 (d, J¼5.2, 1H, ArH),
8.38 (s, 1H, CH]N), 8.06 (d, J¼12.4 Hz, 1H, ArH), 7.58 (s, 1H, ArH),
7.47e7.40 (m, 2H, ArH), 7.22 (d, J¼6.4 Hz, 1H, ArH), 6.92 (d,
J¼10.8 Hz, 1H, ArH), 6.84 (t, J¼10.0 Hz, 1H, ArH), 5.79 (m, 1H, CH2]
CH), 5.03e5.48 (m, 3H, CH2]CH and CH), 4.01 (s, 3H, OCH3), 3.59
(d, J¼11.6 Hz, 1H, CH), 3.27e3.16 (m, 2H, CH2), 2.82e2.78 (m, 2H,
CH2), 2.28 (s, 1H, CH), 1.68 (s, 1H, CH), 1.59 (m, 2H, CH2), 1.43 (m, 1H,
13C NMR (100 MHz, DMSO)
d¼165.7, 160.2, 159.3, 118.7, 116.3, 114.2,
102.2, 64.9, 56.1, 56.0, 55.5, 27.5, 27.4, 25.3 ppm. Anal. Calcd for
C28H31N3O2: C, 76.16; H, 7.08; N, 9.52. Found: C, 76.11; H, 7.15; N,
9.47. LC-MS (ES, MþH) calcd for C28H32N3O2 442.24, found 442.24.
CH), 0.89e0.84 (m, 1H, CH). 13C NMR (100 MHz, MeOD)
d
¼169.7,
164.1, 148.3, 145.3, 142.7, 142.6, 137.4, 132.7, 132.1, 131.5, 129.7, 129.5,
128.0, 123.8, 123.3, 115.1, 104.3, 103.3, 65.2, 61.5, 56.9, 49.3, 41.5,
40.7, 29.0, 28.7, 26.7 ppm. HRMS (ESI, MþH) calcd for C27H30N3O
412.2389, found 412.2383.
4.2.10. Preparation of Cu(II)/2b catalyst. To a solution of Schiff base
ligand 2b (201 mg, 0.5 mmol) in EtOH (10 mL), Cu(OAc)2$H2O
(50 mg, 0.25 mmol) in water (1.5 mL) was added and the mixture
was stirred for 3 h under reflux. After cooling down to 0 ꢁC, the Cu/
Schiff base 2b complex was collected and dried under reduced
pressure to afford the dark green solid (152 mg). The complex can
be stored under air at room temperature.
4.2.7. Ligand 2f was prepared as following step. A solution of 2b
(202 mg, 0.47 mmol) and NaBH4 (114 mg, 2.8 mmol) in absolute
ethanol (15 mL) was refluxed with stirring for 24 h. The solution
was cooled to room temperature and H2O (10 mL) was added to
destroy excessive NaBH4. The mixture solution was extracted with
CH2Cl2 (3ꢂ30 mL). The combined extracts were washed with
a saturated NH4Cl solution (3ꢂ10 mL), water (3ꢂ10 mL) and the
organic layer was dried over anhydrous MgSO4. After filtered and
removed the solvent under reduced pressure, white solid product
was obtained and purified by recrystallization with methanol as
4.3. General procedure for the asymmetric Henry reaction
The metal/Schiff base catalyst (0.025 mmol) was dissolved in
solvent (1 mL). Then, the corresponding aldehyde (0.25 mmol) was
added. After stirring for 1 h at room temperature, the mixture was
cool down to ꢀ20 ꢁC (or to indicated temperature). Then nitro-
alkane (1.25 mmol) and the corresponding basic additive were
added. The stirring was continued for indicated time and after that
a fawn-colored solid 2f, 92% yield. ½a D25
þ36.0 (c 1.0, CH2Cl2). Mp
ꢃ
134e135 ꢁC. IR (KBr) nmax: 3261, 2939, 2864, 1622, 1240 cmꢀ1. 1H

8558
Y. Wei et al. / Tetrahedron 67 (2011) 8552e8558
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mixture suspension was filtered through a pad of Celite to remove
the catalyst, and the filtrate solution was evaporated under reduced
pressure. The resulting residue was purified by silica gel flash col-
umn chromatography (hexane/ether¼9:1) to afford the product.
ꢀ
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Acknowledgements
The financial support of National Natural Science Foundation of
China (20702063 and 21022228) and the Young Scholar Foundation
of the Fourth Military Medical University are gratefully acknowl-
edged. And we also would like to thank Professor Weiping Chen
and Dr. Ming Li for valuable discussion.
ꢀ
J. Org. Chem. 2011, 76, 484e491; (t) Bures, F.; Szotkowski, T.; Kulhanek, J.; Py-
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Y.; Ma, Y.-D.; He, F.-Y. Tetrahedron: Asymmetry 2010, 21, 333e338; (w) Guo, Z.-L.;
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Y.; Wang, S.-J.; Wang, Z.-Y. Tetrahedron: Asymmetry 2008, 19, 1813e1819.
6. For recent examples, of the Henry reaction using Zinc complexes as catalysts,
see: (a) Trost, B. M.; Yeh, V. S. C. Angew. Chem., Int. Ed. 2002, 41, 861e863; (b)
Zhong, Y.-W.; Tian, P.; Lin, G.-Q. Tetrahedron: Asymmetry 2004, 15, 771e776; (c)
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(d) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. 2005, 117, 3949e3952; (e)
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7. For recent example, of the Henry reaction using chromium complexes as cat-
alysts see: Kowalczyk, R.; Sidorowicz, L.; Skarzewski, J. Tetrahedron: Asymmetry
2007, 18, 2581e2586.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.08.076. These data in-
clude MOL files and InChIKeys of the most important compounds
described in this article.
References and notes
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~
thesis see: (a) Kacprzak, K.; Gawronski, J. Synthesis 2001, 7, 961e998; (b) Go-
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€
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15. See Supplementary data for the infrared spectrums.
16. Lin, L.-L.; Fan, Q.; Qin, B.; Feng, X.-M. J. Org. Chem. 2006, 71, 4141e4146.