Recyclable copper catalysts based on ionic-tagged C2-symmetric Indabox ligands and their application in asymmetric Henry reactions

Article abstract of DOI:10.1016/j.apcata.2012.02.044

New imidazolium/pyrrolidinium-tagged Indabox ligands were designed and prepared. Catalysts based on these ligands with Cu(OAc)₂· H₂O were applied to the asymmetric Henry reaction using various aldehydes and CH₃NO₂

Full text of DOI:10.1016/j.apcata.2012.02.044

Applied Catalysis A: General 425–426 (2012) 28–34
Contents lists available at SciVerse ScienceDirect
Applied Catalysis A: General
journal homepage: www.elsevier.com/locate/apcata
Recyclable copper catalysts based on ionic-tagged C2-symmetric Indabox ligands
and their application in asymmetric Henry reactions
Zhi-Huai Lia, Zhi-Ming Zhoua,b,∗, Xiao-Yan Haoa, Jun Zhanga, Xiao Donga, Ying-Qiang Liua,
Wen-Wen Suna, Dan Caoa
a R&D Centre for Pharmaceuticals, School of Chemical Engineering & the Environment, Beijing Institute of Technology, Beijing 100081, PR China
b State Key Laboratory of Explosion Science and Technology, Beijing Institute of Technology, Beijing 100081, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
New imidazolium/pyrrolidinium-tagged Indabox ligands were designed and prepared. Catalysts based
on these ligands with Cu(OAc)2·H2O were applied to the asymmetric Henry reaction using various
aldehydes and CH3NO2, the products were obtained in high enantioselectivity. Specifically, (R)-1-(2-
methoxylphenyl)-2-nitroethanol was obtained in 94% ee in MeOH. Furthermore, the catalyst based on 7
could be recycled at least 12 times by simple wash without an obvious loss of activity or enantioselec-
tivity. This catalytic procedure demonstrated the potential for catalyst recyclability in the asymmetric
Henry reaction. Additionally, a theoretical mechanistic study was conducted to explain the origin of the
enantioselectivity.
Received 22 December 2011
Received in revised form 22 February 2012
Accepted 24 February 2012
Available online 5 March 2012
Keywords:
Catalyst recycled
Imidazolium/pyrrolidinium-tagged
Indabox
© 2012 Elsevier B.V. All rights reserved.
Asymmetric Henry reaction
Theoretical mechanistic study
1. Introduction
handful of reports describing the immobilization and recycling of
a catalyst in asymmetric Henry reactions [3,30–37]. Lee [3] immo-
Enantioenriched 2-nitro-1-arylalkanols, which are key interme-
diates and building blocks for the synthesis of ˇ-adrenergic drugs
and natural products such as polyamino alcohols and polyhydrox-
ylated amides, are generally prepared via the Henry (nitroaldol)
reaction [1–6]. Since the first asymmetric Henry reaction was
reported by Shibasaki and co-workers, who used a series of het-
erobimetallic catalysts [7], a large number of effective asymmetric
metal-based catalytic systems have been developed [8–10], and
they [11–14] have all demonstrated their ability to promote the
asymmetric Henry reaction in high yields with high enantioselec-
tivities. Among these protocols, copper-based asymmetric catalytic
systems have been employed with various ligands [15–18]. More-
over, bis(oxazoline) complexes derived from Cu(OAc)2·H2O, like
those employed by Evans et al., were found to be promising cat-
alysts for the Henry reaction under mild reaction conditions [17].
Chiral bis(oxazoline) (box) ligands have proven to be very effec-
tive in generating high levels of activity and enantioselectivity
in many reactions [19–29]. The recyclability of box ligands has
now emerged as a priority. However, to date, there are only a
bilized a box ligand onto a magnetically separable, hierarchically
ordered mesocellular mesoporous silica (M-HMMS), and this new
catalytic system was examined in the asymmetric Henry reac-
tion between various aldehydes and CH3NO2. This catalyst was
separated magnetically and reused 5 times with little loss of reac-
tivity or enantioselectivity. Khan [31] reported catalysts derived
from C2-symmetric chiral secondary bis-amines based on the 1,2-
diaminocyclohexane structure. Partnered with copper acetate, its
application was investigated in the asymmetric Henry reaction in
the presence of different ionic liquids, with a focus on [Emim] BF4.
In this context, the catalyst could be reused 5 times with reten-
tion of the enantioselectivity. More recently, Didier [32] reported
that an anthracenyl-modified chiral bis(oxazoline) copper complex
was recovered through the formation of a charge transfer complex
between the chiral ligand and trinitrofluorenone and its subse-
quent precipitation with pentane. In recent years, the use of ionic
liquids as biphasic systems and the use of catalysts based on ionic-
tagged ligands are promising recycling methods [33]. However, to
the best of our knowledge, only a few of the ionic-tagged box com-
pounds have been used as ligands in the asymmetric Henry reaction
(Scheme 1).
Following our previous work on imidazolium-tagged box lig-
ands and their good performance and recyclability in asymmetric
reactions [37], we designed and prepared new ionic-tagged Ind-
abox ligands and investigated their performance in asymmetric
∗
Corresponding author at: R&D Centre for Pharmaceuticals, School of Chemical
Engineering & the Environment, Beijing Institute of Technology, Beijing 100081, PR
China. Tel.: +86 010 68912664; fax: +86 010 68912664.
E-mail address: zzm@bit.edu.cn (Z.-M. Zhou).
0926-860X/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.apcata.2012.02.044

Z.-H. Li et al. / Applied Catalysis A: General 425–426 (2012) 28–34
29
OTBS
TBSO
O
O
TBSO
I
N
N
TBAF
THF
2
O
O
THF, MeLi, -50°C, 2h
r.t. 3d
N
N
3
1
2OTs
OH
N
OTs
HO
N
TsO
N
CH2Cl2, Et3N, TsCl
0°C - r.t.
O
O
O
O
O
O
CH3CN, r.t.
N
N
N
N
N
N
4
5
6
toluene, 70°C
N
N
N
N
N
N
2PF6
N
2OTs
N
N
N
KPF6, H2O
O
O
O
O
N
N
N
N
7
8
HO
O
OH
O
(CH2O)n, Et3N,
O
O
CH2Cl2, THF, H2O, r.t.
O
Tf2O, DIPEA
CH2Cl2, -78°C - r.t.
N
N
N
N
O
1
9
N
N
N
N
2PF6
2OTf
TfO
O
OTf
O
N
N
N
N
N
N
H2O, KPF6
O
O
O
O
N
N
N
N
N
N
CH3CN,Reflux
12
11
10
Scheme 1. Preparation of new ionic-tagged Indabox ligand.
Henry reactions as task-specified catalysts. Because ionic liquids
can be made to have the ideal combination of cations and anions for
a given reaction, the cation moiety of the new ligands were altered
in our work. The imidazolium salt and the pyrrolidinium salt could
both be prepared, and the anion of ligands could be changed. High
enantioselectivities were obtained (up to 94% ee) in the asymmet-
ric Henry reaction between 2-methoxybenzaldehyde and CH3NO2.
Furthermore, the catalyst could be reused 12 times without any

30
Z.-H. Li et al. / Applied Catalysis A: General 425–426 (2012) 28–34
obvious loss in activity or in enantioselectivity. As the catalyst was
immobilized by ionic tag, it could be recycled in the absence of addi-
tional ionic liquids. The recycling procedure was simple and easy
to operate.
N2 atmosphere, the mixture was stirred for 8 h. The reaction
mixture was subsequently quenched by the addition of brine
(10 mL). The organic layer was washed with water (3× 10 mL)
and dried over Na2SO4, the solvent was removed under vacuum
to afford the crude product, which was purified by column chro-
matography (SiO2, EtOAc/PE 1/1 to EtOAc) to afford 5; yield:
0.430 g (55%). Mp: 42–45 ◦C. [␣]D20 = 131.8 (c = 0.28, CHCl3). 1H
NMR (500 MHz, CDCl3): ı = 7.73–7.71 (d, J = 8.0 Hz, 4H, OTs-ph-
CH), 7.50–7.48 (m, 2H, Ph-H), 7.37 (d, J = 8.0 Hz, 4H, OTs-ph-CH),
7.26–7.24 (m, 6H, Ph-H), 5.53–5.52 (d, J = 8.0 Hz, 2H, oxazoline-
CHN), 5.24–5.22 (dd, J = 7.0 Hz and 6.5 Hz, 2H, oxazoline-CHO),
3.75–3.71 (m, 4H, CH2CH2OTs), 3.32–3.24 (dd, J = 7.0 Hz and 18.0 Hz,
2H, CH(CH)CH), 2.90 (d, J = 18.0 Hz, 2H, CH(CH)CH), 2.49 (s, 6H, OTs-
CH3), 1.82–1.74 (m, 4H, CCH2CH2), 1.44–1.27 (m, 4H, CH2CH2CH2),
2. Experimental
2.1. Synthesis of new ligands
2.1.1. Synthesis of
(3aR,8aS)-2-(1,9-bis(tert-butyldimethylsilyloxy)-5-((3aR,8aS)-
8,8a-dihydro-3aH-indeno[1,2-d]
oxazol-2-yl)nonan-5-yl)-8,8a-dihydro-3aH-indeno[1,2-d]
oxazole 3
0.88 (m, 4H, CH2CH2CH2). MS (ESI): m:z = 783.2 M+1+
A solution of 1 (1.975 g, 6.00 mmol) in 90 mL of dry THF was
cooled to −50 ◦C under a N2 atmosphere. A solution of MeLi
(8.30 mL, 1.6 M in Et2O, 13.0 mmol) was added to the solution
drop wise, the resulting mixture was stirred at −50 ◦C for 1 h,
and then 2 (4.710 g, 15.0 mmol) was added slowly to the mixture.
After the addition was complete, the solution was left to warm to
room temperature and stirred for an additional 3 days. The reac-
tion mixture was quenched by the addition of water (60 mL) and
extracted with EtOAc (3× 30 mL). The organic fractions were com-
bined, washed with brine (1× 40 mL) and H2O (1× 40 mL), and dried
over Na2SO4. The solvent was removed under vacuum to afford a
thick, dark, oily residue, which was purified by column chromatog-
raphy (SiO2, PE/EtOAc, 10/1) to afford 3 as a pale yellow solid; yield:
3.360 g (80%). Mp 76–78 ◦C. [␣]D20 = 186.6 (c = 0.12, CHCl3). 1H NMR
(500 MHz, CDCl3): ı = 7.51 (m, 2H, Ph-H), 7.28–7.43 (m, 6H, Ph-H),
5.54 (d, J = 8.0 Hz, 2H, oxazoline-CHN), 5.22–5.20 (dd, J = 8.0 Hz and
7.0 Hz, 2H, oxazoline-CHO), 3.42–3.34 (m, 4H, CH2CH2O), 3.30–3.25
(dd, J = 7.0 Hz and 17.5 Hz, 2H, CH(CH)CH), 2.90–2.87 (d, J = 17.5 Hz,
2H, CH(CH)CH), 1.94–1.86 (m, 4H, CCH2CH2), 1.41–4.33 (m, 4H,
CH2CH2CH2), 1.05–0.82 (m, 4H, CH2CH2CH2), 0.90(s, 18H, tBu) 0.01
(s, 12H, OSi(CH3)2). 13C NMR (125 MHz, CDCl3): 167.8, 141.9, 139.5,
128.3, 127.3, 125.6, 124.9, 82.8, 76.3, 62.9, 45.6, 39.5, 32.9, 31.5,
26.0, 19.7, 18.2, −5.2. MS (ESI): m:z = 703.4 M+1+.
.
2.1.4. Synthesis of
1,1ꢀ-{5,5-bis((3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]
oxazol-2-yl)nonane-1,9} bis-(1-methyl-pyrrolidinium) diOTs 6
5
(0.206 g, 0.263 mmol) and 1-methylpyrrolidine (0.09 g,
1.05 mmol) were dissolved in 1 mL of CH3CN, and the solution
was stirred for 24 h under N2 atmosphere. CH3CN was removed
under high vacuum. The residue was washed with Et2O (3×
10 mL) until it changed to a white solid; yield: 0.075 g (30%). Mp:
181–184 ◦C. [␣]D20 = 111.3 (c = 0.18, CH2Cl2). 1H NMR (400 MHz,
CDCl3): ı = 7.71–7.69 (d, J = 8.0 Hz, 4H, OTs-ph-CH) 7.46 (m, 2H,
Ph-H), 7.25–7.21 (m, 6H, Ph-H), 7.12 (d, J = 8.0 Hz, 4H, OTs-ph-
CH), 5.50–5.49 (d, J = 7.5 Hz, 2H, oxazoline-CHN), 5.22–5.20 (dd,
J = 7.5 Hz and 7.0 Hz, 2H, oxazoline-CHO), 3.42 (m, 4H, CH2CH2N),
3.34–3.32 (dd, J = 7.0 Hz and 18.0 Hz, 2H, CH(CH)CH), 2.92–2.90
(br, 8H, pyrrolidine-H), 2.87–2.83 (d, J = 18.0 Hz, 2H, CH(CH)CH),
2.45 (s, 6H, OTs-CH3), 2.31 (s, 6H, pyrrolidine-CH3) 2.02 (br, 8H,
pyrrolidine-H), 1.91–1.85 (m, 4H, CCH2CH2), 1.61–1.52 (m, 4H,
CH2CH2CH2), 1.04–1.01 (m, 4H, CH2CH2CH2). 13C NMR (100 MHz,
CDCl3): 167.2, 143.9, 141.8, 139.5, 139.2, 128.6, 128.2, 127.3, 125.8,
125.0, 83.0, 75.9, 64.0, 48.1, 45.1, 39.3, 30.9, 23.7, 21.4, 20.2. HRMS
(ESI): calc. for C39H54N4O22+: 305.2117; found: 305.2111.
2.1.5. Synthesis of
2.1.2. Synthesis of
5,5-bis((3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]
1,1ꢀ-{5,5-bis((3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]
oxazol-2-yl)nonane-1,9} bis-(1,2-dimethyl-1H-imidazole) diOTs 7
5 (0.252 g, 0.32 mmol) and 1,2-dimethyl-1H-imidazole (0.193 g,
2.0 mmol) were dissolved in 2 mL of toluene, and the solution
was heated to 70 ◦C for 24 h under N2 atmosphere. Toluene
was removed under high vacuum. The residue was washed with
Et2O (3× 10 mL) until it changed to a light-yellow solid; yield:
0.156 g (51%). Mp: 77–79 ◦C. [␣]D20 = 38.5 (c = 0.26, CH2Cl2). 1H NMR
(500 MHz, CDCl3): ı = 7.67–7.65 (d, J = 8.0 Hz, 4H, OTs-ph-CH), 7.46
(m, 2H, Ph-H), 7.38 (s, 2H, imidazole-CH), 7.28 (s, 2H, imidazole-CH),
7.21 (d, J = 8.0 Hz, 4H, OTs-ph-CH), 7.09 (m, 6H, Ph-H), 5.51–5.50 (d,
J = 8.0 Hz, 2H, oxazoline-CHN), 5.24–5.21 (dd, J = 7.0 Hz and 7.0 Hz,
2H, oxazoline-CHO), 3.82–3.70 (m, 10H, CH2CH2mim + imidazole-
CH3), 3.31–3.26 (dd, J = 7.0 Hz and 18.5 Hz, 2H, CH(CH)CH), 2.92
(d, J = 18.5 Hz, 2H, CH(CH)CH), 2.59 (s, 6H, imidazole-CH3), 2.49
(s, 6H, OTs-CH3), 1.85–1.79 (m, 4H, CCH2CH2), 1.52–1.22 (m, 4H,
CH2CH2CH2), 0.90–0.75 (m, 4H, CH2CH2CH2). 13C NMR (125 MHz,
CDCl3): 167.3, 143.7, 141.9, 139.3,139.1, 128.6, 128.4, 125.4, 125.1,
122.7, 120.4, 119.0, 83.2, 76.0, 48.1, 45.1, 39.4, 35.5, 34.1, 32.1, 29.4,
21.2, 20.3, 10.7, 9.8. HRMS (ESI): calc. for C39H48N6O22+: 316.1914;
found: 316.1918.
oxazol-2-yl)nonane-1,9-diol 4
A solution of 3 (0.50 g, 0.70 mmol) in 4 mL of dry THF was
cooled to 0 ◦C under N2 atmosphere. TBAF (0.371 g) in 3 mL of THF
was added to the solution drop wise, and the resulting mixture
was warmed to room temperature and stirred for 8 h. The reac-
tion mixture was subsequently quenched by the addition of water
(10 mL), washed with EtOAc (10 mL) and then with brine (10 mL),
extracted with EtOAc (2× 5 mL). The organic fractions were dried
over Na2SO4, and the solvent was removed under vacuum to afford
the crude product, which was purified by column chromatography
(SiO2, EtOAc to EtOAc/EtOH, 1:1) to afford 4 as a yellow solid; yield:
0.236 g (71%). Mp: 120–121 ◦C. [␣]D20 = 261.9 (c = 0.40, CH2Cl2). 1
H
NMR (500 MHz, CDCl3): ı = 7.50–7.48 (m, 2H, Ph-H), 7.27 (m, 6H,
Ph-H), 5.56–5.54 (d, J = 7.5 Hz, 2H, oxazoline-CHN), 5.29–5.26 (dd,
J = 7.5 Hz and 7.0 Hz, 2H, oxazoline-CHO), 3.48 (m, 4H, CH2CH2O),
3.305–3.31 (dd, J = 7.5 Hz and 18.0 Hz, 2H, CH(CH)CH), 2.90–2.87 (d,
J = 18.0 Hz, 2H, CH(CH)CH), 1.89–1.83 (m, 4H, CCH2CH2), 1.46–1.27
(m, 4H, CH2CH2CH2), 1.15–0.95 (m, 4H, CH2CH2CH2). 13C NMR
(125 MHz, CDCl3): 168.1, 141.7, 139.4, 128.4, 127.5, 125.6, 125.0,
83.1, 75.8, 61.5, 45.7, 39.4, 31.9, 19.5. MS (ESI): m:z = 475.2 M+1+
.
2.1.6. Synthesis of
2.1.3. Synthesis of
5,5-bis((3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]
oxazol-2-yl)nonane-1,9-ditosylate 5
To a solution of 4 (0.474 g, 1.0 mmol) in 5 mL of DCM, TsCl
(0.760 g, 4.0 mmol) and Et3N (0.404 g, 4.0 mmol) were added under
1,1ꢀ-{5,5-bis((3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]
oxazol-2-yl)nonane-1,9} bis-(1,2-dimethyl-1H-imidazole) diPF6
8
7 (0.125 g, 0.13 mmol) was dissolved in 2 mL of H2O, KPF6
(0.048 g, 0.26 mmol) was added to the solution and stirred for
6 h at room temperature. The resultant white solid was filtered

Z.-H. Li et al. / Applied Catalysis A: General 425–426 (2012) 28–34
31
Table 1
and dried under vacuum to afford the product; yield: 0.100 g
(83%). Mp: 162–165 ◦C. [␣]D20 = 88.2 (c = 0.06, CHCl3). 1H NMR
(500 MHz, DMSO): ı = 7.59 (s, 2H, imidazole-CH), 7.51 (s, 2H,
imidazole-CH), 7.38 (m, 2H, Ph-H), 7.30–7.27 (m, 6H, Ph-H),
5.46–5.44 (d, J = 7.5 Hz, 2H, oxazoline-CHN), 5.23–5.20 (dd, J = 7.5 Hz
and 7.0 Hz, 2H, oxazoline-CHO), 3.87–3.85 (m, 4H, CH2CH2mim),
3.72 (s, 6H, imidazole-CH3), 3.29–3.28 (dd, J = 7.0 Hz and 18.0 Hz,
2H, CH(CH)CH), 2.78–2.75 (d, J = 18.0 Hz, 2H, CH(CH)CH), 2.51 (s,
6H, imidazole-CH3), 1.77 (m, 4H, CCH2CH2), 1.55–1.54 (m, 4H,
CH2CH2CH2), 0.95–0.94 (m, 4H, CH2CH2CH2). 13C NMR (125 MHz,
DMSO): 166.6, 144.5, 142.4, 140.2, 128.7, 127.6, 125.7, 122.7, 121.2,
82.7, 76.1, 47.6, 45.3, 39.3, 35.1, 32.0, 29.8, 29.4, 20.4, 9.5. HRMS
(ESI): calc. for C39H48N6O22+: 316.1914; found: 316.1918; calc. for
PF6−: 144.9807, found: 144.9809.
Screening of ligands for the asymmetric Henry reaction of CH3NO2 and 4-
nitrobenzaldehyde.
OH
*
CHO
ligand/Cu(OAc)2·H2O
NO2
CH3NO2
+
MeOH
O2N
O2N
.
Entrya
Ligand
Yield/%b
ee/%b
1
2
3
4
5
7
8
6
11
12
97
61
75
72
82
77
64
75
76
60
a
The ratio of aldehyde/CH3NO2/ligand/Cu(OAc)2·H2O is 1.0/50.0/0.15/0.18. The
reaction was carried out at 25 ◦C for 24 h.
b
Yields were calculated based on 4-nitrobenzaldehyde. % ee values were deter-
2.2. General procedure for the enantioselective Henry reaction
mined by HPLC analysis using a chiralcel OD-H column, hexane/i-PrOH: 85/15,
0.8 mL/min.
To an oven-dried 10 mL two-necked round-bottomed flask were
added a solution of ligand (0.05 mmol), and Cu(OAc)2·H2O (9.80 mg,
0.05 mmol) in MeOH (1 mL) and the mixture was stirred for 2 h
at 25 ◦C. Next, the aldehyde (0.34 mmol) and CH3NO2 (6.8 mmol)
were added and the resulting mixture was stirred at 0 ◦C for
the appropriate time. After completion, as monitored by TLC, the
solvent was removed, and the resulting residue was purified by
column chromatography on silica gel (Merck, 60–120 mesh, ethyl
acetate/hexane, 3:7) to afford the pure 2-nitroalcohol.
the moderate catalytic activity of our catalyst may be attributed to
the electron-rich nature of the imidazolium-tagged box ligand.
To investigate the effect of the quantity of the catalyst on the
activity and the enantioselectivity, we carried out the reaction by
varying the amount of the catalyst (Table 2). The reaction was found
to proceed with a low catalyst loading (5 mol%, Table 2, entry 1). It
seems that the catalyst loading did not cause much difference in
the activity or in the enantioselectivity (Table 2, entries 1–4), and
since Reiser had reported ligand/metal ratio affect the results of
other asymmetric reactions [39,40], the effect of the ligand/metal
ratio was tested at rt and these results are outlined in Table 2. We
observed that the activity and the enantioselectivity of the asym-
metric Henry reaction were the best when the ratio of the ligand to
the metal was 1:1 (Table 2, entry 6). Increasing or decreasing this
ratio led to lower activities or enantioselectivities (Table 2, entries
3 and 5).
The ratio of ligand to metal of 1:1 was chosen and the effi-
ciency of 7 was evaluated for various aldehydes using 15 mol% of
the catalyst (Table 3). Aiming to improve the enantioselectivity in
MeOH, the reaction temperature was decreased to 0 ◦C. The tem-
perature affects the activity and the enantioselectivity to a great
extent. Once the reaction temperature was decreased, the yield
dropped sharply and a longer reaction time was required. Ben-
zaldehydes with electron-withdrawing nitro substituents provided
better yields than substrates with weakly electron-withdrawing
or electron-donating properties (Table 3, entries 1–14). However,
benzaldehydes with electron-donating substituents gave better ee
values than substrates with electron-withdrawing substituents.
2.3. General procedure for recycling the catalyst
After the completion of the reaction, the MeOH was removed
under reduced pressure and the residue was extracted with diethyl
ether (until there was no product in diethyl ether could be deter-
mined by TLC), and transferred to another flask. Owing to the
insoluble nature of the catalyst in diethyl ether, the catalyst could
be separated through the formation of a heterogeneous system.
The residual catalyst was subjected to vacuum for 1 h, flushed with
an inert gas and charged with additional portions of MeOH (1 mL),
aldehyde (0.34 mmol) and CH3NO2 (6.8 mmol).
3. Results and discussion
3.1. Optimization of asymmetric Henry reaction
For a preliminary study, the asymmetric Henry reaction was cat-
alyzed by the catalyst based on 7, 4-nitrobenzaldehyde was used as
a representative aldehyde. As reported previously [19], the activ-
ity and the enantioselectivity of the asymmetric Henry reaction
were found to be optimal when the Lewis acid was the air-stable
Cu(OAc)2·H2O (Table 1, entry 1), providing a yield of 97% and an ee
value of 77%. Next, we screened the ligands to evaluate their cat-
alytic performance on the asymmetric Henry reaction (Table 1). The
imidazolium-tagged bis(oxazoline) 7 was found to be the optimum
ligand and yielded a higher ee than the other ligands in most cases
(Table 1, entry 1). The anions of the ligands were found to affect
the enantioselectivity and the activity. The tosyl-anion ligand 7
yielded better enantioselectivities and activities than the hexafluo-
rophosphoric salts (Table 1, entries 1–2). Meanwhile, the cation also
affected the enantioselectivity and activity. Specifically, the catalyst
derived from 6 provided the product in 75% ee. This enantioselec-
tivity was comparable to that of ligand 7; however, a lower yield
was achieved (Table 1, entry 3). Ligands with shorter alkyl-chains
on the carbon bridge yielded comparable enantioselectivities and
lower conversions than ligands with longer alkyl-chains (Table 1,
entries 4–5). Examining of solvents indicated that MeOH was the
optimized solvent in our system. Consistent with the literature [38],
Table 2
Effect of the quantity of the chiral catalyst based on ligand 7 and the ligand/metal
ratio in the preparation of 15.
OH
*
CHO
7/Cu(OAc)2·H2O
NO2
CH3NO2
+
MeOH
O2N
O2N
.
Entrya
Ligand:metal
Cat. loading
Yield/%b
ee/%b
1
2
3
4
5
6
1:1.25
1:1.25
1:1.25
1:1.25
1:0.8
5 mol%
10 mol%
15 mol%
20 mol%
15 mol%
15 mol%
87
91
97
98
83
95
71
72
77
76
78
82
1:1.0
a
The reaction was carried out at 25 ◦C for 24 h.
Yields were calculated based on 4-nitrobenzaldehyde. % ee values were deter-
b
mined by HPLC analysis using a chiralcel OD-H column, hexane/i-PrOH: 85/15,
0.8 mL/min.

32
Z.-H. Li et al. / Applied Catalysis A: General 425–426 (2012) 28–34
Table 3
Table 4
The enantioselective Henry reaction of CH3NO2 with various aldehydes catalyzed
Effects of the base on the asymmetric Henry reaction of 2-methoxybenzaldehyde
by a complex based on 7.
under the catalysis of complex based on 7.
7/Cu(OAc)2·H2O
OMe
OH
OMe OH
*
CH3NO2
CHO
RCHO
+
NO2
7/Cu(OAc)2·H2O
*
NO2
R
CH3NO2
+
MeOH, 0°C
MeOH
13
14
15
.
.
Entrya
Base/equiv
Yield/%b
ee/%b
Entrya
R
Yield/%b
ee/%b
1
2
3
4
5
6
7
Et3N/1.0
Pyridine/1.0
DMAP/1.0
1,2-dimethyl-1H-imidazole/2.0
CH3NO2/20.0
CH3NO2/10.0
79
53
67
75
49
39
33
81
90
81
87
94
94
94
1
2
3
4
5
6
7
8
9
Ph (a)
67
71
62
56
51
57
55
49
53
40
55
41
50
51
53
53
37
90
78
64
76
65
77
81
88
86
93
91
89
89
87
37
80
59
55
66
4-NO2C6H4 (b)
2-NO2C6H4 (c)
2-ClC6H4 (d)
2,4-diClC6H3 (e)
4-ClC6H4 (f)
4-BrC6H4 (g)
4-FC6H4 (h)
2-MeC6H4(i)
4-MeC6H4(j)
2-OMeC6H4 (k)
3,4-diOMeC6H3 (l)
3,5-diOMeC6H3 (m)
3,4,5-triOMeC6H2 (n)
4-pyridyl (o)
1-naphthyl (p)
3-phenylpropanal (q)
Ph (r)
CH3NO2/5.0
a
The reaction was carried out at 0 ◦C for 48 h.
Yields were calculated based on the aldehyde. % ee values were determined by
b
10c
11
12
13
14
15
16
17
18d
19d
HPLC analysis using a chiralcel OD-H column, hexane/i-PrOH: 85/15, 0.8 mL/min.
reaction was carried out in a homogeneous system, and the cata-
lyst could be separated through the formation of a heterogeneous
system. The product and the remaining material were transferred
in diethyl ether. The residual catalyst was subjected to vacuum to
remove traces of diethyl ether and was flushed with an inert gas and
charged with additional portions of MeOH, aldehyde and CH3NO2.
The activity and the enantioselectivity were maintained even after
the catalyst was reused 12 times, and as far as we known, none
of other procedures reported has achieved so many recycle times
in this reaction. The asymmetric Henry reaction using the catalyst
25 (Anti/Syn = 72:28)
29 (Anti/Syn = 99:1)
4-NO2C6H4 (s)
a
The ratio of aldehyde/CH3NO2/ligand/Cu(OAc)2·H2O is 1.0/50.0/0.15/0.15. The
reaction was carried out at 0 ◦C for 48 h.
b
Yields were calculated based on aldehyde. % ee values were determined by HPLC
analysis using chiralcel OD-H and chiralpak AD-H columns, hexane/i-PrOH.
c
The amount of CH3NO2 is 20.0 equiv.
CH3NO2 was replaced with C2H5NO2.
d
This observation is especially true for 2-methoxybenzaldehyde,
which provided ee values of 91% at 0 ◦C (Table 3, entry 11).
Moderate to good enantioselectivities could be achieved in most
cases when the reaction was carried out at 0 ◦C (Table 3, entries
1–14). In the cases of other aromatic aldehydes, such as 1-
naphthaldehyde, isonicotinaldehyde and 3-phenylpropanal, lower
or comparable enantioselectivities and yields relative to benzalde-
hyde were obtained (Table 3, entries 15–17). The optimized catalyst
system was also applied to the asymmetric Henry reaction with
nitroethane as nucleophile. The reaction of nitroethane provided
the adduct with good Anti-selectivity (Table 3, entries 18–19).
Though the enantioselectivity was moderate, the catalyst had its
potential in diasteroselective Henry reaction.
The addition of base decreased the enantioselectivity of the
reaction [8], for when 1.0 equiv. of base (Et3N, pyridine, DMAP,
1,2-dimethyl-1H-imidazole) was added, the yield of the asymmet-
ric Henry reaction increased, but the ee value decreased (Table 4,
entries 1–4), and we observed that the stronger bases more neg-
atively affected the resulting enantioselectivity provided by the
catalyst. In addition, the amount of CH3NO2 added was decreased
and the results are shown in Table 4. Decreasing the amount of
CH3NO2 to 20.0 equiv. led to an increase in the ee to 94%; however,
the yield decreased to 49% (Table 4, entry 5). Decreasing the amount
of CH3NO2 further led to even lower yields; however, the ee values
remained constant at 94% (Table 4, entries 6–7).
3.2. Recyclability of the catalyst based on ligand 7
To evaluate the recyclability of the catalysts generated from
ligand 7 (Fig. 1), the MeOH was removed under reduced pres-
sure after the completion of the reaction, and the residue was
extracted with diethyl ether until there was no product in diethyl
ether could be determined by TLC, and transferred to another flask.
Owing to the insoluble nature of the catalyst in diethyl ether, the
Fig. 1. Variations in percentage yield (1) and percentage ee (2) upon recycling of
the catalyst. (a) ligand is 7, substrate is 2-methoxybenzaldehyde and (b) ligand is 1,
substrate is 2-methoxybenzaldehyde.

Z.-H. Li et al. / Applied Catalysis A: General 425–426 (2012) 28–34
33
Fig. 2. Computational geometry of complex Cu(OAc)2-7, Cu(OAc)2-6 and Cu(OAc)2-11 (H was omitted for clarity) and possible transition structure for the asymmetric Henry
reaction.
based on 7 and 2-methoxybenzaldehyde as the substrate provided
a yield of 58% and an ee value of 90% on the 12th cycle. We assume
that the increase in yield was caused by the residual CH3NO2, which
remained with the catalyst after the diethyl ether wash. In contrast,
a conversion of 35% and an ee value of 47% were obtained using the
catalyst based on 1 with 2-methoxybenzaldehyde as the substrate.
In this experiment, the catalyst was only able to be reused 4 times,
providing a lowered yield of 35% and a poor ee value of 19% on the
4th cycle. We discerned that the ionic tag of the catalyst assured
the good recyclability.
As the catalyst was immobilized by ionic tag, it could be recycled
in the absence of additional ionic liquids. Furthermore, proce-
dure for catalyst recycling is operationally easy and simple [32].
Although the catalyst loading is not very low, our procedure pos-
sesses the potential to be used as an environmentally friendly
process in the chemical industry considering the good recyclability
of the catalyst.
environment was enhanced. One of the long alkyl chains on the
carbon bridge was more curved than the other, and with the imi-
dazolium salt tagged to it, the bulky [OTs]− anion was closely
coordinated to the Cu(II); this increased the steric bulk, making
it more difficult for the nitronate to attack from the Si face, thereby
increasing the enantioselectivity.
According to the model proposed by Evans [7,19], the most reac-
tive transition structure was in a mode such that the CH3NO2 is
perpendicular to the ligand plane and the aldehyde is in the ligand
plane. Cu(OAc)2-7 afforded adducts with an (R)-configuration, indi-
cating that the nitronate attacks the Re-face of the aldehyde.
Conversely, we found that the geometry of complex Cu(OAc)2-6
was similar to that of complex Cu(OAc)2-7, especially with respect
to the steric environment at the catalytic centre. This might be the
reason for their comparable ee values obtained when used as cata-
lysts. For complex Cu(OAc)2-11, which contains a fewer number of
alkyl-chain carbon atoms on the carbon bridge, the steric environ-
ment at the reaction site is similar, and thus, its enantioselectivity
is predicted to parallel that of complex Cu(OAc)2-7.
3.3. Mechanistic study
A theoretical mechanistic study was conducted to explain the
origin of the enantioselectivity at the molecular level. Computa-
tional calculations of the geometries of the complexes Cu(OAc)2-6,
Cu(OAc)2-7 and Cu(OAc)2-11 were performed with the B3LYP/6-
31G(d) scheme in the Gaussian03 software package. The optimal
geometries are presented in Fig. 2. For complex Cu(OAc)2-7,
because of the imidazolium salt tagged to the long alkyl chains
on the carbon bridge between the two oxazolines, the steric
4. Conclusions
In conclusion, new imidazolium/pyrrolidinium-tagged Indabox
ligands were designed and prepared conveniently from readily
available starting materials. The cation or anion moieties of these
new ligands could be readily altered. Preliminary studies revealed
that the task-specific catalysts performed well in the asymmetric
Henry reaction. The catalyst derived from 7 yielded adduct (R)-15k

34
Z.-H. Li et al. / Applied Catalysis A: General 425–426 (2012) 28–34
in 94% ee in MeOH. Furthermore, the catalyst could be recycled at
least 12 times without an obvious loss of activity or enantioselec-
tivity, which makes it a green chemical process. Additionally, the
catalyst recycling procedure is simple and easy to operate.
At the same time, the origin of the enantioselectivity was
explained by a theoretical mechanistic study. Further research on
C2-symmetric ionic-tagged box ligands and their performance in
asymmetric reactions is ongoing in our laboratory.
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Acknowledgements
The National Technological Project of the Manufacture and
Innovation of Key New Drugs (2009ZX09103-143) and the Major
Projects Cultivating Special Program in Technology Innovation
Program (Grant no. 2011CX01008) of the Beijing Institute of Tech-
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