Chiral enhancement in the confined space of zeolites for the asymmetric synthesis of β-hydroxy nitroalkanes

Article abstract of DOI:10.1016/j.tetasy.2010.12.016

(1S,2S)-N¹,N²-Bis(3-chlorobenzyl)cyclohexane-1,2- diamine 1a′ and (1S,2S)-N¹,N²-bis(4-chlorobenzyl) cyclohexane-1,2-diamine 1b′ were used to prepare chiral Cu(II) complexes Cu-Y-1a, Cu-Y-1b, Cu-mZSM5-1a, and Cu-

Full text of DOI:10.1016/j.tetasy.2010.12.016

Tetrahedron: Asymmetry 22 (2011) 117–123
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral enhancement in the confined space of zeolites for the asymmetric
synthesis of b-hydroxy nitroalkanes
Noor-ul Hasan Khan a,b, Mohd. Bismillah Ansari a, Eko Adi Prasetyanto a, Hailian Jin a, Sang-Eon Park a,
⇑
a Laboratory of Nano-Green Catalysis and Nano Center for Fine Chemical Fusion Technology, Department of Chemistry, Inha University, Incheon 402-751, Republic of Korea
b Discipline of Inorganic Materials and Catalysis, Central Salt and Marine Chemicals Research Institute (CSMCRI), Council of Scientific & Industrial Research (CSIR),
G. B. Marg, Bhavnagar, 364 002 Gujarat, India
a r t i c l e i n f o
a b s t r a c t
(1S,2S)-N1,N2-Bis(3-chlorobenzyl)cyclohexane-1,2-diamine 1a0 and (1S,2S)-N1,N2-bis(4-chlorobenzyl)
cyclohexane-1,2-diamine 1b0 were used to prepare chiral Cu(II) complexes Cu-Y-1a, Cu-Y-1b, Cu-
mZSM5-1a, and Cu-mZSM5-1b by a flexible ligand method using copper exchanged zeolite Y and
mesoporous ZSM-5. The characterization of zeolite supported complexes was performed by microanaly-
sis, IR-, diffuse reflectance spectroscopy (DRS), EPR spectroscopy, specific rotation and thermogravimetric
analysis (TGA). The catalytic activity of these supported complexes was explored for the asymmetric
nitroaldol reaction of various aldehydes with nitromethane at 0 °C. Excellent yields (up to 99%) of
b-hydroxy nitroalkane with an ee of up to 94% were achieved in the case of benzaldehyde as substrate.
Significantly, the performance of the supported catalyst was better in terms of enantioselectivity than the
complex under homogenous conditions. The supported catalysts were recycled four times with no obser-
vable loss in performance and no leaching of the catalytically active complex during the nitroaldol
reaction.
Article history:
Received 22 November 2010
Accepted 17 December 2010
Available online 25 January 2011
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
chiral catalysts are very expensive, their recyclability is an impor-
tant aspect from an economical and industrial point of view.
The asymmetric Henry reaction has emerged as a powerful syn-
thetic tool for preparing b-hydroxynitroalkanes1 that provides ready
access to valuable bifunctional compounds, such as b-amino alco-
Heterogenization of homogeneous catalysts, endows attributes
of homogeneous systems with attractive features of a heteroge-
nous catalyst, such as easy product separation and catalyst recov-
ery by simple filtration.51–54 This strategy has expanded rapidly for
various asymmetric organic transformations; however, there are
only few reports30,50,55,56 available on asymmetric nitroaldol
reaction. With our ongoing interest in asymmetric heterogeneous
catalysts,55–58 we herein report for the first time the use of Cu
exchanged zeolite Y and mesoporous ZSM-5 of different porosity
with chiral C2-symmetric ligands (1S,2S)-N1,N2-bis(3-chloroben-
zyl)cyclohexane-1,2-diamine 1a0 and (1S,2S)-N1,N2-bis(4-chloro-
hols,
a-hydroxy ketones, aldehydes, a-hydroxy carboxylic acids,
azides and sulphides for pharmaceutical applications.1–3 Shibasaki
reported the first asymmetric version of the nitroaldol reaction in
1992 using a BINOL-derived heterometallic complex.4–12 Since then
various chiral catalysts involving Zn,13–16 Cu,17–32,2,33–35 Co,36 Mg37
and Cr38–40 metal ions and organo-catalysts41–47 have been studied.
However, most of these methods suffer from limitations, such as
high catalyst loading, low reaction temperatures, non-recyclability
of an expensive catalyst, multistep synthetic procedures for ligand
preparation, or demanding the use of additives, such as molecular
sieves, potassium hydroxide,48,49 cetyltrimethyl ammonium
hydroxide50 sodium carbonate,1 triethylamine,1 2,6-lutidine,29 pyr-
idine29 and aromatic imines.18 Notably, the Cu-catalysed nitroaldol
reaction is the most explored one due to its low cost, non-toxic nat-
ure, and high catalytic activity under homogeneous reaction condi-
tions.17–32,2,33–35 However, the separation and recycling of the
catalyst is still a serious issue under homogeneous condition. As
benzyl)cyclohexane-1,2-diamine 1b0
for the asymmetric
nitroaldol reaction of aldehydes. The catalyst system developed
demonstrates excellent yield (>99%) of b-hydroxynitroalkanes with
high enantioselectivity (ee, 94%) as compared to a homogeneous
counterpart.
2. Results and discussion
The encapsulation of C2-symmetric chiral ligands (1S,2S)-N1,
N2-bis-(3-chlorobenzyl)-cyclohexane-1,2-diamine 1a0 and (1S,2S)-
N1,N2-bis-(4-chlorobenzyl)-cyclohexane-1,2-diamine 1b0 in Cu
exchanged zeolite Y and mesoporous ZSM-5 was carried out by
flexible ligand method59 (Scheme 1) to obtain chiral heterogeneous
⇑
Corresponding author. Tel.: +82 32 860 7675; fax: +82 32 872 8670.
E-mail address: separk@inha.ac.kr (S.-E. Park).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.12.016

118
Noor-ul Hasan Khan et al. / Tetrahedron: Asymmetry 22 (2011) 117–123
Scheme 1. Schematic representation of copper(II) complexes encapsulated in two different zeolites.
complexes Cu-Y-1a, Cu-Y-1b, Cu-mZSM5-1a and Cu-mZSM5-1b.
The basic framework of zeolite Y and mesoporous ZSM-5 remained
unchanged upon copper exchange as well as after encapsulation of
the chiral ligands 1a0 and 1b0 as evidenced by XRD measurements
that showed no significant change in the position and relative
intensity of the diffraction lines (Fig. 1). However, the surface area
and pore volume of the copper exchanged zeolite Y and mesopor-
ous ZSM-5 showed a significant decrease after encapsulation of the
complexes (Table 1) due to the presence of complexes inside the
zeolite cavity which was further confirmed by FTIR, DRS and EPR
spectroscopy.
The FTIR spectra of Cu-Y and Cu-mZSM-5 show characteristic
bands below 1200 cmꢀ1 while their encapsulated analogues Cu-
Y-1a, Cu-Y-1b, Cu-mZSM-5-1a and Cu-mZSM-5-1b show charac-
teristic peaks of the neat complexes in the 1200–1600 cmꢀ1 region
along with C–H stretching and 2900–3000 cmꢀ1 confirming the
encapsulation of 1a and 1b in Cu-Y and Cu-mZSM-5. Representa-
tive IR spectra for the neat complex 1a, supported complex Cu-
mZSM-5-1a and Cu-mZSM-5 are shown in Figure 2. Similar obser-
vations were also made by Jin et al.58 for the encapsulation of Cu-
[H4]salen/Y samples.
EPR spectra of polycrystalline neat complex Cu-1a showed
typical unresolved hyperfine features due to copper (S = 1/2 and
I = 3/2) due to nearest neighbour intermolecular spin–spin ex-
change interactions60 at 298 K (Fig. 3a). However, zeolite Y and
ZSM-5-encapsulated metal complex Cu-1a (Fig. 3b and c) showed
well-resolved metal hyperfine features similar to spectra in dilute
frozen solutions indicating the encapsulation of monomeric salen
complexes in zeolite and ZSM-5 cavities.61
The UV–vis absorption spectra of the neat complex Cu-1a, Cu-
Y-1a, and Cu-mZSM5-1a samples are shown in Figure 4. The metal
complex Cu-1a showed broad MLCT bands in the region 360, 370
and 500 nm. Upon encapsulation of Cu-1a in zeolite-Y and ZSM-5
the spectra remained largely unchanged in the region of
ꢁ370 nm indicating that the structure of the homogneous complex
is retained on encapsulation. However, the band at 500 nm in the
neat complex, was blue shifted to 480 nm, possibly due to the
interaction of Cu(II) with the zeolite framework. These results are
consistent with those reported earlier.62
For catalytic activity measurements at first we conducted the
asymmetric nitroaldol reaction of benzaldehyde as a model sub-
strate with nitromethane in the presence of catalyst 1a and 1b
(10 mol %) under homogeneous conditions (in ethanol) at 0 °C that
gave excellent product yield (83–96%) and ee (86%) in 48 h (Table 2,
entries 1 and 2). These results are in accordance with values re-
ported by Skarzewski et al.63,64 The same reactions when con-
ducted under heterogeneous conditions with catalysts supported
on zeolite-Y and mZSM-5 (100 mg containing ꢁ10 mol % of 1a/
1b) showed an increase in ee (ꢁ94%), however, the reaction took
72 h to attain the product yield that was equivalent with the
homogeneous conditions (entries 3–6). This increase in reaction
time is expected due to diffusional constraints, whereas the in-
crease in ee might be due to the confinement effect of the support
or catalytic site-isolation inside mesopores. To optimize the nitro-
aldol reaction of benzaldehyde under heterogeneous condition, we
next evaluated the effect of the solvent using Cu-Y-1a as a repre-
sentative catalyst. Among all the solvents used (entries 7–10), eth-
anol was found to be the solvent of choice which is in accordance
Figure 1. XRD patterns of: Cu-1a complex, Cu-mZSM5-1a and Cu-Y-1a.

Noor-ul Hasan Khan et al. / Tetrahedron: Asymmetry 22 (2011) 117–123
119
Table 1
Physicochemical data of the catalysts
Support
Cu contenta (mmol gꢀ1
)
N contentb (mmol gꢀ1
)
SBET(m2 gꢀ1
)
Pore Vol (cm3 gꢀ1
)
Na-Y zeolite
mZSM-5
CuY
Cu-mZSM-5
CuY-1a
CuY-1b
—
—
—
—
—
—
1.76
1.79
0.71
0.7
840
649
472
423
393
387
346
342
0.44
1.06
0.25
0.87
0.23
0.24
0.76
0.74
0.94
0.38
0.91
0.92
0.36
0.35
Cu-mZSM-5-1a
Cu-mZSM-5-1b
a
Determined by ICP-OES method.
Determined by elemental analysis method (w%).
b
Figure 4. Diffuse reflectance UV–vis absorption spectra of: Cu-1a complex, Cu-
mZSM5-1a and Cu-Y-1a.
Figure 2. FTIR spectra of Cu-1a complex, Cu-mZSM5-1a and Cu-Y-1a.
above, the absolute configuration of the b-hydroxy nitroalkane
was assigned as (R) by comparison of the specific rotation with
the literature data.18
After optimization of the solvent, temperature and amount of
the catalyst, the scope of the nitroaldol reaction with supported
catalysts Cu-Y-1a/1b and Cu-mZSM-5-1a/1b was extended to var-
ious other substituted benzaldehydes and aliphatic aldehydes un-
der the above optimized reaction condition (Table 3, entries 1 and
15). At a glance, all the chiral complexes encapsulated into zeolites
cavities and mZSM-5 used in the present study faired well as cat-
alysts in terms of product yield and ee in the nitroaldol reaction of
a wide range of substrates. The substrates with electron-withdraw-
ing groups for example, 3-nitrobenzaldehyde gave lower ee values
(ꢁ51%) when zeolite-Y was used as a support as compared to the
ee (ꢁ81%) obtained with the mZSM-5 supported catalysts. For
other substrates, both supports gave similar enhancement in the
performance of homogenous catalysts, however, mZSM-5 as a sup-
port had some edge over zeolite-Y. Possibly, a confined environ-
ment of zeolite supercage provided chiral enhancement due to
the so called confinement effect (Scheme 2). Whereas, in mZSM-
5 its channel like structure allowed the substrates to travel freely,
thereby minimizing diffusional constraints. In any case, it is re-
ported57,66,67 that by anchoring or immobilizing the catalysts onto
mesoporous materials, there is a significant increase in ee as com-
pared to its homogenous analogue. Apparently, the steric features,
aliphatic or aromatic nature of the substrates did not play a major
role in the product yield or ee.
Figure 3. EPR spectra of Cu-1a complex, Cu-mZSM5-1a and Cu-Y-1a.
with earlier reports.65 Temperature is one of the most sensitive
parameters in enantioselective reactions, therefore, we varied the
temperature of the nitroaldol reaction keeping other parameters
as per entry 3. On increasing the reaction temperature from 0 °C
to room temperature 92% product yield was obtained in 48 h but
there was a drop in ee (70%). A further increase in the reaction tem-
perature (50 °C) caused a further increase in the product yield
(99%) but the ee dropped considerably (entry 12, ee 57%). On con-
ducting this reaction with a decreased amount of catalyst 50 mg
and 25 mg at 0 °C, there was a gradual decrease in product yield
as well as ee (entries 13 and 14). In all the reactions conducted
Finally, catalyst recyclability was carried out with Cu-Y-1a and
Cu-mZSM-5-1a for the asymmetric nitroaldol of benzaldehyde as a
model substrate with nitromethane. Both the catalysts were easily
recovered by centrifugation from the reaction system and thor-
oughly washed with ethanol before use. The recovered catalysts

120
Noor-ul Hasan Khan et al. / Tetrahedron: Asymmetry 22 (2011) 117–123
Table 2
Optimization of reaction conditions for the asymmetric Henry reaction with heterogeneous catalystsa
OH
O
supported
NO2
catalyst
CH3NO2
H
+
Solvent
Entry
Catalyst
Solvent
T (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1ad
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Ethanol
Nitromethane
Toluene
CH2Cl2
0
0
0
0
0
0
0
0
0
0
rt
50
0
0
48
48
72
72
72
72
72
72
72
72
48
48
72
72
83
96
96
97
98
98
32
29
35
19
92
99
73
57
86
86
93
94
93
94
85
87
85
79
70
57
80
76
1bd
Cu-Y-1a
Cu-Y-1b
Cu-mZSM-5-1a
Cu-mZSM-5-1b
Cu-Y-1a
Cu-Y-1a
Cu-Y-1a
Cu-Y-1a
Cu-Y-1a
Cu-Y-1a
Cu-Y-1a
Cu-Y-1a
THF
Ethanol
Ethanol
Ethanole
Ethanolf
a
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of 100 mg Cu-Y-1a catalyst in 2 ml of solvent at the specified
temperature.
b
Isolated yields by column chromatography.
Determined by HPLC on a OD-H column. Reactions were conducted with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of 0.10 mmol of the
c
catalyst (10 mol %).
e
50 mg Cu-Y-1a catalyst was used.
25 mg Cu-Y-1a catalyst was used.
f
3. Conclusion
Table 3
Asymmetric Henry reaction of nitromethane with various aldehydes catalysed by
chiral Cu-Y-1a, Cu-ZSM-5-1a/Cu-Y-1b, Cu-ZSM-5-1ba
We have demonstrated the usefulness of chiral diamine com-
plexes immobilized into a zeolite cavity and mZSM-5 as truly het-
erogeneous catalysts for the asymmetric nitroaldol of various
aldehydes to give the desired b-nitroalcohols in high yield and
ees. The immobilized catalysts worked well four times with reten-
tion of their activity and enantioselectivity during the nitroaldol
reaction.
O
OH
Cu-Y-1a / 1b
(Cu-ZSM-5-1a / 1b)
NO2
CH3NO2
R
H
+
R
EtOH, 0 °C
Entry
R
Chiral supported complexes
Yieldb (%)
eec (%)
1 (15)
2 (16)
3 (17)
4 (18)
5 (19)
6 (20)
7 (21)
8 (22)
9 (23)
10 (24)
11 (25)
12 (26)
13 (27)
14 (28)
Ph
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1b (Cu-ZSM-5-1b)
Cu-Y-1b (Cu-ZSM-5-1b)
Cu-Y-1b (Cu-ZSM-5-1b)
Cu-Y-1b (Cu-ZSM-5-1b)
Cu-Y-1b (Cu-ZSM-5-1b)
Cu-Y-1b (Cu-ZSM-5-1b)
Cu-Y-1b (Cu-ZSM-5-1b)
96 (98)
96 (96)
95 (98)
94 (96)
56 (75)
80 (87)
82 (90)
97 (98)
99 (99)
96 (99)
95 (97)
88 (78)
81 (88)
81 (93)
93 (93)
51 (81)
90 (90)
93 (90)
89 (83)
74 (68)
77 (80)
94 (93)
53 (80)
90 (90)
91 (91)
65 (88)
77 (70)
79 (84)
4. Experimental
3-NO2Ph
3-ClPh
4-ClPh
4-MeOPh
PhCH2CH2
C5H11
4.1. Materials and characterization
Solvents were dried according to standard procedures and dis-
tilled prior to use. (1S,2S)-(+)-1,2-Diaminocyclohexane, nitrometh-
ane (TCI), various aldehydes, benzaldehyde, 3-NO2-, 3-Cl-, 4-Cl-,
4MeO-benzaldehyde, hydrocinnamaldehyde, heptanaldehyde,
copper acetate monohydrate (Aldrich) were used as recieved. Zeo-
lite Y was obtained from commercial source (ZEOLYST), while mes-
oporous ZSM-5 zeolites was synthesized according to our standard
procedure.68,69 All the reactions were carried out under specified
reaction conditions. 1H NMR spectra were recorded at 200 MHz
(JEOL) in CDCl3 as solvent and tetramethylsilane as an internal
standard. X-ray powder diffraction (XRD) patterns have been re-
corded on a Rigaku, D-Max III VC model, with nickel-filtered Cu
Ph
3-NO2Ph
3-ClPh
4-ClPh
4-MeOPh
PhCH2CH2
C5H11
a
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of
nitromethane in the presence of 100 mg Cu-Y-1a/1b catalyst in 2 ml of solvent at
the appointed temperature.
b
Isolated yields by the column chromatography.
Determined by HPLC on a OD-H column.
c
Ka radiation. A glass holder was used to support the catalyst sam-
ples. The samples were scanned in the 2h range of 2–60° with a
scanning rate of 4°/min. Fourier transform infrared (FTIR) spectra
were obtained from KBr pressed pellets using a Nicolet 6700 (Ther-
mo Electron Corporation) infrared spectrometer. The diffuse reflec-
tance (UV DRS) spectra of the solid samples were recorded in the
were effectively used 4 times without any noticeable loss in their
activity and enantioselectivity (Table 4). In order to detect leaching
of the complex, the reaction mixture obtained after the separation
of the catalyst was subjected to ICP, which showed no trace of Cu
metal. Also there was no trace of the chiral ligand on TLC. These
experiments clearly demonstrate that the active catalyst is well
secured inside the cavity/channel of the solid support.
region 200–800 nm using
a
spectrophotometer (Shimadzu
UV2101 model) with BaSO4 as the reference material. The electron
spin resonance (ESR) spectra were measured in a JEOL FA200

Noor-ul Hasan Khan et al. / Tetrahedron: Asymmetry 22 (2011) 117–123
121
HN
NH
O
OH
CH3NO2
CH3NO2
R
H
+
NO2
R
Solvent 0 0C
R2
R1
R1
R2
1a: R1=Cl, R2=H
1b: R1=H, R2=Cl
Scheme 2. Chiral diamine ligand employed for the asymmetric Henry reaction after encapsulation to copper zeolites.
Table 4
Recyclability data on the asymmetric Henry reaction using a supported catalysta
OH
O
NO2
Heterogeneous catalysts
EtOH, 0 °C
Catalytic runs
CH3NO2
H
+
Entry
Catalyst
Time (h)
Yieldb (%)
eec (%)
1 (5)
2 (6)
3 (7)
4 (8)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
Cu-Y-1a (Cu-ZSM-5-1a)
1
2
3
4
72
72
72
72
96 (98)
96 (98)
96 (98)
96 (97)
93 (93)
93 (93)
93 (93)
94 (93)
a
b
c
All reactions were performed with 1 mmol of benzaldehyde and 5 mmol of nitromethane in the presence of 100 mg catalyst in 2 mL of ethanol.
Isolated yields by the column chromatography.
Determined by HPLC on a OD-H column.
spectrometer at 9.06 GHz. Elemental analyses were performed
with an EA-1112 (CE Instruments). In order to determine the cop-
per content in the heterogeneous complexes, samples were ana-
lysed by the PE optima 7300 DV ICP-OES equipped with S-10
autosampler. Thermogravimetric analyses (TGAs) were performed
on Perkin-Elmer TGA-7 analyzer at a 10 °C/min scan rate in a nitro-
gen atmosphere.
4.2.2. (1S,2S)-N,N-bis(4-Chlorobenzyl)cyclohexane-1,2-diamine
1b0
Colourless oil; 1H NMR (200 MHz, CDCl3): d = 0.90–1.70 (m, 8H),
1.80 (br s, 2H), 2.15–2.25 (m, 2H), 3.57 (d, J = 13 Hz, 4H) 7.10–7.35
(m, 8H); ½a 2D5
¼ þ60 (c 1, CH2Cl2); IR (KBr): 3280, 3010, 2900, 2815,
ꢂ
1575, 1460, 1410, 1200, 1135, 810, 765, cmꢀ1
.
4.2.3. Preparation of Cu exchanged zeolites
4.2. Synthesis of chiral ligands 1a0 and 1b0
For the preparation of copper exchanged zeolite, copper acetate
monohydrate (3.5 g) was dissolved in 700 ml of warm distilled
water and 7.5 g Na-Y/mesoporous ZSM-5 zeolite were added while
stirring the solution. The resultant mass was further stirred for 8 h.
The solids were filtered and washed thoroughly with deminera-
lised water until the washing became colourless. The solid Cu-Y
obtained after the third exchange was dried at 383 K overnight in
air. The same procedure was applied for Cu-mZSM-5 sample.
The chiral ligands 1a0 and 1b0 were synthesized by the modified
reported procedure.62,63 In a 100 ml round bottom flask aldehyde/
substituted aldehydes (1 mmol) was taken in ethanol (20 ml), to
which (1S,2S)-(+)-1,2-diaminocyclohexane (0.5 mmol) was added
at 0 °C. The reaction mixture was then stirred at this temperature
for 1 h, and then refluxed for 10–12 h. After completion of the reac-
tion (checked on TLC), the reaction mixture was cooled to room
temperature and sodium borohydride (4 mmol) was added in
small fractions with stirring. The resulting solution thus obtained
was refluxed for 10 h. Subsequently, the solvent was removed on
a rotary-evaporator. The resulting mass was dissolved in dichloro-
methane (10 ml), washed with distilled water, dried over anhy-
drous sodium sulphate and evaporated to give the desired ligand
as a semi-solid. The characterization of the ligands was accom-
plished by different physicochemical techniques and the data ob-
tained were well matched with the earlier reports.63,64
4.2.4. Preparation of heterogeneous catalysts
Heterogeneous catalysts Cu-Y-1a, Cu-Y-1b, Cu-mZSM5–1a and
Cu-mZSM5-1b were prepared by encapsulating the chiral ligands
1a0 and 1b0 on to Cu-Y zeolite and Cu-mZSM-5 via flexible ligand
method.59 The chiral ligands 1a0 or 1b0 were dissolved in ethanol
and copper exchanged zeolite Cu-Y and Cu-mZSM-5 were then
added to it. The resulting solution was allowed to stir for 24 h
followed by filtration to give heterogeneous complexes Cu-Y-1a,
Cu-Y-1b, Cu-mZSM5-1a and Cu-mZSM5-1b. The unreacted chiral
ligands 1a0 and 1b0 were removed by Soxhlet extraction in methy-
lene chloride.
4.2.1. (1S,2S)-N,N-bis(3-Chlorobenzyl)cyclohexane-1,2-diamine
1a0
Pale yellow solid; mp = 60–64 °C; 1H NMR (200 MHz, CDCl3):
d = 0.89–1.76 (m, 8H), 1.88 (brs, 2H), 2.14–2.26 (m, 2H), 3.57 (d,
4.2.5. Typical procedure for the asymmetric nitroaldol reaction
Asymmetric nitroaldol reactions were carried out in magneti-
cally stirred glass reactor under dry and inert conditions. Zeolite
supported chiral copper (II) complexes, Cu-Y-1a, Cu-Y-1b, Cu-
mZSM-5-1a and Cu-mZSM-5-1b (100 mg) were taken in absolute
J = 13 Hz, 4H), 7.14–7.40 (m, 8H); ½a D25
¼ þ75 (c 1, CH2Cl2); IR
ꢂ
(KBr): 3300, 3045, 2919, 2840, 1590, 1560, 1450, 1220, 1110,
860, 770 cmꢀ1
.

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Noor-ul Hasan Khan et al. / Tetrahedron: Asymmetry 22 (2011) 117–123
ethanol (0.5 ml) and the resulting slurry was cooled to 0 °C. To the
cold slurry an appropriate aldehyde (1 mmol) was added with stir-
ring and after a lag of 15 min, nitromethane (0.6 ml) was added
through a syringe. The resulting suspension was stirred for 72 h
at 0 °C. The progress of the reaction was monitored by TLC. After
72 h, the cold reaction mixture was centrifuged and washed with
ethanol. The solid residue was dried in vacuum and kept for reuse
experiments. The solvent from the combined supernatant was re-
moved and the resultant residue was chromatographed on silica
gel column using hexane/ethyl acetate as eluent to give the desired
b-nitroalcohol. The products were analyzed by 1H NMR (CDCl3),
specific optical rotations (CH2Cl2 or CHCl3) and their enantiomeric
excess (ee) was determined by HPLC using an OD-H column with
2-PrOH/hexane (90:10) as the eluent. HPLC traces of products were
compared with the respective racemic samples.
enantiomer] and 14.88 min [minor (S)-enantiomer]. Off-white
solid with 1H NMR (200 MHz, CDCl3): d = 1.87–1.77 (m, 2H),
2.78–2.69 (m, 2H), 2.85–2.82 (m, 1H), 4.40–4.27 (m, 3H), 7.25–
7.19 (m, 3H), 7.32–7.28 (m, 2H); 13C NMR (50 MHz, CDCl3)
d = 34.51, 35.29, 67.95, 80.74, 126.52, 128.61, 128.84, 140.79 ppm.
4.3.7. (R)-(ꢀ)-1-Nitroheptan-2-ol
HPLC analysis (Chiralcel AD-H, 1.0 mL/min, n-hexane/i-PrOH,
97:3, k = 215 nm), Retention time: 20.29 min [major (R)-enantio-
mer] and 29.66 min [minor (S)-enantiomer]; Colourless oil with
1H NMR (200 MHz, CDCl3): d = 0.90 (t, J = 6.72 Hz, 3H), 1.39–1.31
(m, 5H), 1.57–1.47 (m, 3H), 2.68 (br, 1H), 4.46–4.28 (m, 3H); 13C
NMR (50 MHz, CDCl3) d = 14.01, 22.63, 25.01, 31.63, 33.86, 68.89,
80.85 ppm.
Acknowledgements
4.3. Characterization of the products
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education, Science and Technology (2009-
0083525). N.H.K. thanks to KOFST for financial support through
Brain Pool programme and also CSMCRI-CSIR India for sabbatical
leave.
4.3.1. (R)-2-Nitro-1-phenylethanol
HPLC analysis (Chiralcel OD-H column, 0.8 mL/min, hexane/i-
PrOH 90:10, k = 210 nm), Retention time: 21.03 min [major (R)-
enantiomer] and 25.99 min [minor (S)-enantiomer]; Colourless
oil with 1H NMR (200 MHz, CDCl3): d = 2.89 (br s, 1H; OH), 4.39
(dd, J = 3.2, 9.4 Hz, 1H; CH2NO2), 4.43 (dd, J = 3.2, 9.5 Hz, 1H;
CH2NO2), 5.34 (2d, J = 3.1, 3.2 Hz, 1H; CHOH), 7.13–7.33 (m, 5H;
ArH) ppm; 13C NMR (500 MHz, CDCl3): d = 69.00, 79.19, 125.10,
128.94, 129.01, 138.11 ppm.
References
1. Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2561.
2. Spangler, K. Y.; Wolf, C. Org. Lett. 2009, 11, 4724.
3. Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.
Commun. 2007, 6, 616.
4. Shibasaki, M.; Sasai, H.; Arai, T. Angew. Chem., Int. Ed. 1997, 36, 1236.
5. Handa, S.; Nagawa, K.; Sohtome, Y.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2008, 47, 3230.
6. Iseki, K.; Oishi, S.; Sasai, H.; Shibasaki, M. Tetrahedron Lett. 1996, 37, 9081.
7. Sasai, H.; Suzuki, T.; Itoh, N.; Arai, S.; Shibasaki, M. Tetrahedron Lett. 1993, 34,
2657.
8. Sasai, H.; Kim, W.; Suzuki, T.; Shibasaki, M. Tetrahedron Lett. 1994, 35, 6123.
9. Sasai, H.; Hiroi, M.; Yamada, Y. M. A.; Shibasaki, M. Tetrahedron Lett. 1997, 38,
6031.
10. Shibasaki, M.; Sasai, H. Pure Appl. Chem. 1996, 68, 523.
11. Shibasaki, M.; Sasai, H.; Arai, T.; Iida, T. Pure Appl. Chem. 1998, 70, 1027.
12. Shibasaki, M.; Yoshikawa, N. Chem. Rev. 2002, 102, 2187.
13. Trost, B. M.; Yeh, V. S. C. Angew. Chem. 2002, 114, 889; Angew. Chem., Int. Ed.
2002, 41, 861.
14. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. 2005, 117, 3949; Angew. Chem.,
Int. Ed. 2005, 44, 3881.
15. Liu, S. L.; Wolf, C. Org. Lett. 2008, 10, 1831.
16. Bulut, A.; Aslan, A.; Dogan, O. J. Org. Chem. 2008, 73, 7373.
17. Christensen, C.; Juhl, K.; Jørgensen, K. A. Chem. Commun. 2001, 2222.
18. Evans, D. A.; Seidel, D.; Rueping, M.; Lam, H. W.; Shaw, J. T.; Downey, C. W. J.
Am. Chem. Soc. 2003, 125, 12692.
19. Maheswaran, H.; Prasanth, K. L.; Krishna, G. G.; Ravikumar, K.; Sridhar, B.;
Kantam, M. L. Chem. Commun. 2006, 4066.
20. Ma, K. Y.; You, J. S. Chem. Eur. J. 2007, 13, 1863.
21. Bandini, M.; Piccinelli, F.; Tommasi, S.; Umani-Ronchi, A.; Ventrici, C. Chem.
Commun. 2007, 616.
22. Qin, B.; Xiao, X.; Liu, X. H.; Huang, J. L.; Wen, Y. H.; Feng, X. M. J. Org. Chem.
2007, 72, 9323.
23. Bandini, M.; Benaglia, M.; Sinisi, R.; Tommasi, S.; Umani-Ronchi, A. Org. Lett.
2007, 9, 2151.
24. Xiong, Y.; Wang, F.; Huang, X.; Wen, Y. H.; Feng, X. M. Chem. Eur. J. 2007, 13,
829.
25. Arai, T.; Watanabe, M.; Yanagisaka, A. Org. Lett. 2007, 9, 3595.
26. Blay, G.; Climent, E.; Fernández, I.; Hernández, V.; Pedro, J. Tetrahedron:
Asymmetry 2006, 17, 2046.
27. Blay, G.; Climent, E.; Fernández, I.; Hernández, V.; Pedro, J. Tetrahedron:
Asymmetry 2007, 18, 1603.
4.3.2. (R)-2-Nitro-1-(3-nitrophenyl)ethanol
HPLC analysis (Chiralcel OD-H column, 0.5 ml/min, hexane/i-
PrOH 85:15, k = 210 nm), Retention time: 41.97 min [major (R)-
enantiomer] and 49.10 min [minor (S)-enantiomer]; 1H NMR
(200 MHz, CDCl3) d = 2.89 (br s, 1H; OH), 8.30–7.29 (m, 4H),
5.62–5.60 (m, 1H), 4.60–4.57 (m, 2H), 3.20 (d, J = 4.2 Hz, 1H) ppm.
4.3.3. (R)-2-Nitro-1-(3-chlorophenyl)ethanol
HPLC analysis (Chiralcel OD-H column, 0.8 ml/min, hexane/i-
PrOH90:10, k = 210 nm), Retention time: 20.26 min [major(R)-enan-
tiomer]and25.91 min [minor(S)-enantiomer];Colourlessoilwith1H
NMR (200 MHz, CDCl3) d = 7.47–7.28 (m, 4H), 5.45–5.40 (m, 1H),
4.60–4.47 (m, 2H), 3.44 (d, J = 4.1 Hz, 1H) ppm; 13C NMR (50 Hz,
CDCl3) d = 69.2, 83.0, 123.0, 124.1, 126.9, 129.2, 134.8, 142.0 ppm.
4.3.4. (R)-2-Nitro-1-(4-chlorophenyl)ethanol
HPLC analysis (Chiralcel OD-H column, 0.8 mL/min, hexane/i-
PrOH 90:10, k = 210 nm), Retention time: 20.25 min [major (R)-
enantiomer] and 26.73 min [minor (S)-enantiomer]; Colourless
oil with 1H NMR (200 MHz, CDCl3): d = 2.89 (br s, 1H; OH), 4.46
(dd, J = 3.3, 9.2 Hz ,1H; CH2NO2), 4.50 (dd, J = 3.3, 9.3 Hz, 1H;
CH2NO2), 5.42 (2d, J = 3.3, 3.3 Hz, 1H; CHOH), 7.40–7.47 (m, 4H;
ArH) ppm; 13C NMR (50 MHz, CDCl3) d 69.67, 84.00, 127.30,
129.24, 134.80, 136.61 ppm.
4.3.5. (R)-2-Nitro-1-(4-methoxyphenyl)ethanol
HPLC analysis (Chiralcel OD-H column, 0.8 mL/min, hexane/i-
PrOH 90:10, k = 206 nm), Retention time: 30.63 min [major (R)-
enantiomer] and 40.28 min [minor (S)-enantiomer]; Colourless
oil with 1H NMR (200 MHz, CDCl3): d = 2.39 (br s, 1H; OH), 3.74
(s, 3H; CH3), 4.37 (dd, J = 3.2, 9.5 Hz, 1H; CH2NO2), 4.41(dd,
J = 3.2, 9.5 Hz, 1H; CH2NO2), 5.30 (2d, J = 3.2, 3.2 Hz, 1H; CHOH),
6.77–7.22 (m, 4H; ArH) ppm; 13C NMR (50 MHz, CDCl3) d 54.99,
70.37, 81.20, 114.39, 127.20, 130.21, 159.78 ppm.
28. Blay, G.; Domingo, L. R.; Hernández-Olmos, V.; Pedro, J. R. Chem. Eur. J. 2008, 14,
4725.
29. Arai, T.; Takashita, R.; Endo, Y.; Watanabe, M.; Yanagisawa, A. J. Org. Chem.
2008, 73, 4903.
30. Arai, T.; Yokoyama, N.; Yanagisawa, A. Chem. Eur. J. 2008, 14, 2052.
31. Zhang, G. Q.; Yashima, E.; Woggon, W. D. Adv. Synth. Catal. 2009, 351, 1255.
32. Selvakumar, S.; Sivasankaran, D.; Singh, V. K. Org. Biomol. Chem. 2009, 7, 3156.
33. Breuning, M.; Hein, D.; Steiner, M.; Gessner, V. H.; Strohmann, C. Chem. Eur. J.
2009, 15, 12764.
4.3.6. (R)-(+)-1-Nitro-4-phenylbutan-2-ol
HPLC analysis (Chiralcel AD-H column, 1.0 mL/min, n-hexane/
i-PrOH, 90:10, k = 215 nm), Retention time: 11.69 min [major (R)-
34. Noole, A.; Lippur, K.; Metsala, A.; Lopp, M.; Kanger, T. J. Org. Chem. 2010, 75,
1313.

Noor-ul Hasan Khan et al. / Tetrahedron: Asymmetry 22 (2011) 117–123
123
35. Constable, E. C.; Zhang, G.; Housecroft, C. E.; Neuburger, M.; Schaffner, S.;
Woggon, W. New J. Chem. 2009, 33, 1064.
36. Kogami, Y.; Nakajima, T.; Ashizawa, T.; Kezuka, S.; Ikeno, T.; Yamada, T. Chem.
Lett. 2004, 33, 614.
37. Choudary, B. M.; Ranganath, K. V. S.; Pal, U.; Kantam, M. L.; Sreedhar, B. J. Am.
Chem. Soc. 2005, 127, 13167.
52. Brunel, D.; Bellocq, N.; Sutra, P.; Cauvel, A.; Lasperas, M.; Moreau, P.; Renzo, F.
D.; Galarneau, A.; Fajula, F. Coord. Chem. Rev. 1998, 178–180, 1085.
53. Ying, J. Y.; Mchnert, C. P.; Wong, M. S. Angew. Chem., Int. Ed. 1999, 38, 56.
54. Choplin, A.; Quignard, F. Coord. Chem. Rev. 1998, 178–180, 1679.
55. Bhatt, A. P.; Pathak, K.; Jasra, R. V.; Kureshy, R. I.; Khan, N. H.; Abdi, S. H. R. J.
Mol. Catal. A: Chem. 2006, 244, 110.
38. Kowalczyk, R.; Sidorowicz, L.; Skarzewski, J. Tetrahedron: Asymmetry 2007, 18,
2581.
56. Mayani, V. J.; Abdi, S. H. R.; Kureshy, R. I.; Khan, N. H.; Das, A.; Bajaj, H. C. J. Org.
Chem. 2010, 75, 6191.
39. Kowalczyk, R.; Kwiatkowski, P.; Skarzewski, J.; Jurczak, J. J. Org. Chem. 2009, 74,
753.
57. Prasetyanto, E. A.; Lee, S.-C.; Jeong, S.-M.; Park, S.-E. Chem. Commun. 2008, 17,
1995.
40. Zulauf, A.; Mellah, M.; Schulz, E. J. Org. Chem. 2009, 74, 2242.
41. Corey, E. J.; Zhang, F. Y. Angew. Chem. 1999, 111, 2057; Angew. Chem., Int. Ed.
1999, 38, 1931.
58. Prasetyanto, E. A.; Jeong, S.-M.; Park, S.-E. Top. Catal. 2010, 53, 192.
59. Jin, C.; Fan, W.; Jia, Y.; Fan, B.; Ma, J.; Li, R. J. Mol. Catal. A: Chem. 2006, 249, 23.
60. Deshpande, S.; Srinivas, D.; Ratnasamy, P. J. Catal. 1999, 188, 261.
61. Bennur, T. H.; Srinivas, D.; Ratnasamy, P. Microporous Mesoporous Mater. 2001,
48, 111.
62. Yahiro, H.; Kimoto, K.; Yamaura, H.; Komaguchi, K.; Lund, A. Chem. Phys. Lett.
2005, 415, 126.
63. Kowalczyk, R.; Sidorowicz, L.; Skarzewski, J. Tetrahedron: Asymmetry 2008, 19,
2310.
64. Kowalczyk, R.; Skarzewski, J. Tetrahedron: Asymmetry 2009, 20, 2467.
65. Lai, G.; Wang, S.; Wang, Z. Tetrahedron: Asymmetry 2008, 19, 1813.
66. Prasetyanto, E. A.; Jeong, S.-M.; Park, S.-E. Top. Catal. 2010, 53, 192.
67. Li, C. Catal. Rev. Sci. Eng. 2004, 46, 419.
42. Ooi, T.; Doda, K.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 2054.
43. Li, H. M.; Wang, B. M.; Deng, L. J. Am. Chem. Soc. 2006, 128, 732.
44. Marcelli, T.; van der Haas, R. N. S.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem. 2006, 118, 943. Angew. Chem., Int. Ed. 2006, 45, 929.
45. Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Eur. J. Org. Chem. 2006, 2894.
46. Mandal, T.; Samanta, S.; Zhao, C. G. Org. Lett. 2007, 9, 943.
47. Uraguchi, D.; Sakaki, S.; Ooi, T. J. Am. Chem. Soc. 2007, 129, 12392.
48. Sohtome, Y.; Hashimoto, Y.; Nagasawa, K. Adv. Synth. Catal. 2005, 347, 1643.
49. Sohtome, Y.; Takemura, N.; Takada, K.; Takagi, R.; Iguchi, T.; Nagasawa, K.
Chem. Asian J. 2007, 2, 1150.
50. Ballini, R.; Fiorini, D.; Gil, M. V.; Palmieri, A. Tetrahedron 2004, 60, 2799.
51. Vankelecom, I. F. J.; Tas, D.; Parton, R. F.; de Vyver, V. V.; Jacobs, P. A. Angew.
Chem., Int. Ed. 1996, 35, 1346.
68. Park, S.-E.; Jiang, N.; Prasetyanto, E. A.; Han, D.-S.; Jin. H. Republic of Korea
Patent, 2009.
69. Jin, H.; Ok, D.-Y.; Park, S.-E. J. Mater. Chem., submitted for publication.