Chiral Cr(III)-salen complex embedded over sulfonic acid functionalized mesoporous SBA-15 material as an efficient catalyst for the asymmetric Henry reaction

Article abstract of DOI:10.1016/j.mcat.2019.110489

Designing novel catalytic system for efficient synthesis of enantiomerically pure β-hydroxy nitroalkanes is a challenging area of research. Herein, we have designed a chiral heterogeneous catalyst through the successful loading of chiral Cr(III)-salen com

Full text of DOI:10.1016/j.mcat.2019.110489

MolecularCatalysis475(2019)110489
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Molecular Catalysis
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Chiral Cr(III)-salen complex embedded over sulfonic acid functionalized
mesoporous SBA-15 material as an efficient catalyst for the asymmetric
Henry reaction
⁎
Md. Mominul Islama, Piyali Bhanjab, Mita Halderc,1, Anjan Dasa,1, Asim Bhaumikb,
,
⁎
Sk. Manirul Islama,
a Department of Chemistry, University of Kalyani, Kalyani, Nadia, 741235, WB, India
b School of Materials Sciences, Indian Association for the Cultivation of Science, Jadavpur 700 032, India
c Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700 009, India
A R T I C L E I N F O
A B S T R A C T
Keywords:
Designing novel catalytic system for efficient synthesis of enantiomerically pure β-hydroxy nitroalkanes is a
challenging area of research. Herein, we have designed a chiral heterogeneous catalyst through the successful
loading of chiral Cr(III)-salen complex over sulfonic acid functionalized SBA-15 material. The catalyst has been
thoroughly characterized by powder XRD, N2 adsorption/desorption, XPS, HR-TEM, CHN, AAS analyses and FT-
IR spectroscopy. The reactivity of the catalyst has been examined in the enantioselective Henry reaction, where
different substituted aromatic, heteroaromatic as well as aliphatic aldehydes produced corresponding β-hydroxy
nitroalkanes with excellent product yields (up to 90%) and enantioselectivities (up to 91%). Moreover, this
protocol has also been employed as the key-step to prepare enantiomerically pure drug (R)-(-)-isoproterenol
from 3,4-dimethoxybenzaldehyde.
Asymmetric synthesis
Nitroaldol reaction
Heterogeneous catalysis
Cr(III)-salen
(R)-isopoterenol
1. Introduction
have been developed and employed to achieve the goal. Amongst them
designing suitable metal-complex based catalysts of Cu [17], Zn [20],
Asymmetric nitroaldol reaction between aldehydes and nitroalkanes
(Scheme 1) is one of the most important and convenient carbon-carbon
bond formation strategy for the production of enantiomerically pure β-
hydroxy nitroalkanes [1,2]. It has drawn great attention among the
researchers due to its wide range of synthetic utilities, especially in
medicinally effectual compounds, chiral ligands, bioactive reagents,
etc. [3–6]. Moreover, chemical flexibility of the nitro group [7,8] could
make the resulting enantiopure β-hydroxy nitroalkanes highly potent,
chemically active and privileged as well as precious structural motifs
for the preparation of more useful compounds [9–11]. Hence, design
and synthesis of efficient, novel and reactive chiral catalyst for the
preparation of enantiomerically pure β-hydroxy nitroalkanes is very
challenging. Sasai et al. first reported the chiral lanthanum alkoxide
complex as an effective catalyst for this reaction [12]. Thereafter, this
area of research has been enriched over the years by successful ex-
ecution of an arsenal of chiral catalysts [13,14].
Zr [21], Co [22,23] and rare earth metals [24,25], are very important in
the field of materials chemistry. Majority of these catalytic systems
involve high catalyst loading as well as use of molecular sieves and dry
solvents to obtain high product yields. To surmount all these obstacles
together with high expenditure for the catalyst synthesis and to im-
prove the recycling efficiency of the catalyst some advanced mod-
ifications are highly desirable. Notably, the multi-faceted functions are
less developed till date. In this context, chromium-based transition
metal catalysts have witnessed considerable attention among the re-
searchers. However, reports on chiral Cr(III)-salen complex catalysed
asymmetric nitro-aldol reaction are in severe dearth in recent decades.
Although, Kowalczyk et al. [26] Zulauf et al. [27] Ouyang et al. [28]
have reported homogeneous Cr(III)-salen catalytic systems for asym-
metric Henry reaction, efficient heterogeneous chiral catalysts bearing
Cr(III) as the active metal centre for this reaction is still very demanding
specially in the context of sustainability of the processes.
In this context, a significant number of catalysts including hetero-
geneous chiral catalysts [15–17] as well as organocatalysts [18,19]
Porous nanomaterials and their functionalized analogues [29–36]
possess large specific surface area, easily tunable and consistent pores
⁎ Corresponding authors.
E-mail addresses: msab@iacs.res.in (A. Bhaumik), manir65@rediffmail.com (S.M. Islam).
1 These authors contributed equally to this manuscript.
https://doi.org/10.1016/j.mcat.2019.110489
Received 27 March 2019; Received in revised form 19 June 2019; Accepted 21 June 2019
2468-8231/©2019ElsevierB.V.Allrightsreserved.

Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
that (R)-form of this drug is around 90 times more powerful than the
(S)-form [39].
2. Experimental section
2.1. Synthesis of the chiral Cr(III) containing salen-like complex (E)
Scheme 1. Schematic presentation of asymmetric Henry reaction.
Homogeneous chiral Schiff base ligand (E) was prepared (Scheme 2)
from 3-tbutyl-2-hydroxy-benzaldehyde (A), following our previously
reported literature [37] and the steps are stated below.
of nanoscale dimensions, and good thermal stability. They are in-
tensively studied as catalyst and solid support over the years. Post
synthesis functionalization of the surfaces of mesoporous silica mate-
rials are particularly found wide scale utility in designing suitable
catalysts for the production of organic fine chemicals. Accordingly, we
have reported few key asymmetric transformations catalysed by surface
modified mesoporous SBA-15 grafted with chiral metal-salen complexes
[37,38]. To establish the strategy to construct new asymmetric CeC
bond herein, we report the synthesis of a chiral Cr(III)-salen containing
sulfonic acid functionalized SBA-15 silica material, Cr(III)@SAFSB
(Scheme 2), which catalyses efficiently for the asymmetric Henry re-
action. Furthermore, using this technique, we finally end up in syn-
thesizing medicinally persuasive drug (R)-isoproterenol as a spin off,
which is widely used for the treatment of asthma, bronchitis, heart
blockage and emphysema [39–41] etc. It is highly important to note
2.1.1. Preparation of 3-tert-butyl-5-chloromethyl-2-hydroxybenzaldehyde
(B)
In a typical synthesis 15 mmol of 3-tert-butyl-2-hydroxy benzalde-
hyde (A) and 33 mmol of paraformaldehyde were added to a pre-cooled
(5–10 ℃) medium of 11 ml concentrated HCl. Then this reaction mix-
ture was stirred at 313 K for 72 h. Thereafter, the resulting crude mix-
ture was repetitively extracted using diethyl ether, followed by washing
with saturated aqueous solution of NaHCO3 and brine. Then organic
part was dried using anhydrous Na2SO4 and evaporated to acquire B as
a yellowish crystalline solid (94% yield). The 1H NMR data of the
product was in agreement with those reported earlier.
Scheme 2. Schematic diagram for the synthesis of Cr(III)@SAFSB.
2

Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
2.1.2. Preparation of the complex C
2.4. General procedure for asymmetric nitro aldol reaction
In a typical synthesis a dry benzene solution of triethylamine
(0.5 mmol, 5 mL) was added drop wise to the stirred solution of com-
pound B (0.5 mmol, 5 mL) in dry benzene and the final mixture was
then refluxed for 36 h. After completion of the reaction the mixture was
cooled to room temperature and solvent was evaporated to furnish
quaternary aldehyde C (94% yield). The spectroscopic data of the
product was in accordance with the reported literature.
A solution of freshly prepared chiral Cr(III)@SAFSB catalyst (15 mg,
0.249 mol% of Cr) in DCM (1.0 ml) was stirred at 4 °C for 15 min fol-
lowed by the addition of aldehyde (1.0 mmol) and nitromethane
(8.0 mmol) to it. After additional stirring for 30 min at the same tem-
perature, 1.0 mmol of Et3N in DCM (1.0 ml) was added dropwise to the
former solution and the final reaction mixture was stirred at 4 °C for a
specific reaction time. The progress of reaction was monitored by thin
layer chromatography (TLC) technique. After completion of the reac-
tion solvent was evaporated by rotary evaporator and the solid sample
was purified by column chromatography over silica gel with pet ether/
ethyl acetate (85:15) as eluent. All the products were characterized
using 1H NMR. The spectroscopic data are in full agreement with those
previously reported compounds. Enantiomeric excess (ee) was de-
termined by HPLC analysis using Chiralcel OD-H column.
2.1.3. Synthetic procedure for the chiral Schiff base ligand D
Then an ethanolic (absolute) solution of (1S, 2S)-(+)-1,2-diamino-
cyclohexane (1 equivalent) was added drop wise to the ethanolic (ab-
solute) solution of complex C (2 eqvt.) and the final mixture was re-
fluxed for 9 h (monitored on TLC). Then after partial evaporation of the
solution, bright yellow crystalline product (92% yield) was precipitated
by n-hexane. The spectroscopic data of the product was in accordance
with the reported literature.
2.5. Synthesis of (R)-(-)-Isoproterenol
(R)-1-(3,4-dimethoxyphenyl)-2-nitroethanol (2 g) was prepared
using 3,4-dimethoxy benzaldehyde (1 g) and CH3NO2 by following the
optimized reaction conditions which is shown in Table 1. Thereafter,
the final drug molecule (R)-isoproterenol was prepared from (R)-1-(3,4-
dimethoxyphenyl)-2-nitroethanol (2.0 g). The step-wise conversions
were confirmed by 1H NMR, HPLC chromatograms and optical rotation
values of the products (given in electronic supporting information),
which are in full accordance with the reported values.
2.1.4. Preparation of chiral complex E
Then ethanolic solution of anhydrous CrCl2 (1.5 mmol, 15 mL) was
slowly poured into the ethanolic solution of this Schiff base ligand (D)
(1.0 mmol, 15 mL) under inert atmosphere and the solution was stirred
for 2 h, which resulted the formation of bluish brown solution. Then
the solution was exposed to air and stirring was sustained for another
15 h to obtain a dark brown solution. After completion of reaction the
resulting brown solid was extracted by dichloromethane, washed with
brine and finally dried by using anhydrous sodium sulphate. After
evaporation of the solvent, the solid mass was precipitated out from n-
hexane to get chiral Cr(III)-salen complex (E) as a dark brown solid
(88% yield). TOF-MS of C42H68Cl3CrN4O2: m/z value was found
782.4038 for (M-Cl)+; [cal. 782.4124], FTIR spectroscopic data showed
peaks of the complex at: 3385, 2959, 1651, 1592, 1532, 1437,
2.6. General procedure for recycling experiment
After completion of the reaction, the crude reaction mixture was
allowed to reach the room temperature and then extracted with ethyl
acetate. Then the catalyst was separated through centrifugation and
755 cm−1
.
Table 1
Assymetric Henry reaction catalyzed by Cr(III)@SAFSB under different con-
ditionsa.
2.2. Preparation of -SO3H functionalized SBA-15 (SAFSB)
The sulfonic acid functionalized SBA-15 support (designated as
SAFSB) was synthesized following the literature reports [42,43]. Pri-
marily, mesoporous solid support SBA-15 (F) has been synthesized
hydrothermally and then 500 mg of it was suspended in dry toluene
(15 mL). Then after addition of 5 mmol of 3-mercaptopropyl-
trimethoxysilane the ensuing mixture was refluxed for 24 h and filtered
to obtain the solid mass. Next, in order to oxidise the immobilized 3-
mercaptopropyl groups, 500 mg of the dried material was suspended in
5 g of aqueous 30 wt% H2O2 and then stirred at room temperature.
After the completion of the reaction, the resulting solid mass was fil-
tered out and washed using water and ethanol. Subsequently, the wet
mass was suspended (1 wt%) in 1 M H2SO4 solution for 4 h. Finally, the
material was washed several times with water and ethanol, and finally
dried at 60 °C under vacuum overnight before carrying out the catalytic
reactions.
Entry
Cat. (mg)
Solvent
Base
T (ºC)
t (h)
Yieldb (%)
eec
1
–
–
–
4
48
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
16
nd
74
40
66
70
87
55
79
64
75
80
69
70
89
78
10
12
39
nd
65
23
76
39
88
78
38
< 5
< 5
90
35
77
73
86
–
2
15
15
15
15
15
15
15
15
15
15
15
10
20
15
15
15
15
EtOH
Et2O
THF
Et3N
Et3N
Et3N
Et3N
Et3N
–
4
3
4
4
4
5
Toluene
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
4
6
4
7
4
8
DIPEA
Cs2CO3
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
4
9
4
10
11
12
13
14
15d
16e
17f
18g
4
−10
RT
4
4
4
2.3. Synthesis of the heterogeneous Cr(III)@SAFSB catalyst
4
4
–
4
83
Ethanolic solution of homogeneous chiral Cr(III)-salen complex (E)
(0.025 g, 5 mL) was added to the ethanolic suspension of mesoporous
solid support SAFSB (0.25 g, 15 mL). The reaction mixture was allowed
to stir at 308 K temperature for 12 h. The subsequent pale brown solid
mass was centrifuged and extracted with methanol and di-
chloromethane using soxhlet apparatus till the washing become col-
ourless. Finally, the catalyst designated as Cr(III)@SAFSB was dried
under air. The entire synthetic pathway for the designing of chiral Cr
(III)@SAFSB catalyst is presented in Scheme 2.
a
Reaction Condition: 1a (1 mmol), CH3NO2 (8 mmol), Base (1 mmol), Cr
(III)@SAFSB, Solvent (2 mL).
b
c
d
e
f
g
Isolated yield.
Determined by HPLC using Chiralcel OD-H column.
0.5 mmol Et3N is used.
SBA-15 is used as catalyst.
Organo modified SBA-15 (SAFSB) is used as catalyst.
1 mmol CH3NO2 is used.
3

Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
organic part was used to determine the product yield. Next, the sepa-
rated catalyst was repeatedly washed with ethyl acetate and distilled
water, and finally with DCM. Thereafter the catalyst was dried under
vacuum and reused for the next run.
3. Results and discussion
3.1. Characterization of Cr(III)@SAFSB catalyst
3.1.1. Powder X-ray diffraction pattern (PXRD)
The small angle PXRD pattern of SAFSB and Cr(III)@SAFSB mate-
rials are shown in Fig. 1. Fig. 1a represents the small angle XRD pattern
of SAFSB, where three characteristic diffraction peaks are observed at
2θ values of 0.88°, 1.54° and 1.76°, which could be ascribed to the three
well-defined crystalline planes 100, 110 and 200, respectively for the
two-dimensional ordered hexagonal mesophase of SBA-15 material
[29]. Further, from Fig. 1b it is seen that similar noticeable peaks ap-
pear at 2θ values of 0.90°, 1.55° and 1.79° of 2θ for Cr(III)@SAFSB
material due to the three distinctive crystal planes, suggesting the re-
tention of 2D ordered hexagonally ordered mesophase after grafting of
Cr-salen complex over the SAFSB surface.
3.1.2. UHR-TEM
To determine the nanostructure of SAFSB and Cr(III)@SAFSB ma-
terials we have carried out ultra-high resolution transmission electron
microscopy analysis. UHR-TEM images of SAFSB support are shown in
Fig. 1. Small angle powder XRD pattern of (a) SAFSB and (b) Cr(III)@SAFSB.
Fig. 2. UHR-TEM images of SAFSB (a,b) and Cr(III)@SAFSB (c,d). Respective FFT patterns are shown in the insets of Figs. 2b and 2c.
4

Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
analysis.
3.1.4. X-ray photoelectron spectroscopy (XPS)
The high resolution XPS spectra of Cr(III)@SAFSB for different
constituent elements are shown in Fig. 4. As seen from the Fig. 4a two
peaks corresponding to the spin-orbit splitting 2p1/2 (left) and 2p3/2
(right) of Cr 2p with two binding energy values of 587.4 and 576.9 eV,
respectively confirmed the existence of Cr(III) in Cr(III)@SAFSB [44].
This result suggested the penta-coordinated Cr(III) with two charge
balancing phenoxide ions and one chloride ion together with two co-
ordination bonds with two imine-N atoms in Cr(III)@SAFSB (Scheme
2). In Fig. 4b one peak appeared at the binding energy value of 168.0 eV
and this could be assigned due to the S2p component for the sulfonate
groups present in the hybrid framework. This S2p spectrum of Cr(III)@
SAFSB can be deconvoluted into two characteristic peaks at the binding
energy values of 167.4 and 168.3 eV, which could be attributed to two
components S2p1/2 and S2p3/2, respectively [45]. These characteristic
peaks further suggest that the S is present mainly in form of -SO3H
groups bonded to the carbon of the propyl group, which attached with
Si atoms at the SBA-15 surface. The peak appears at the binding energy
value of 284.8 eV for the C1 s component, shown in Fig. 4c, whereas
that at 103.2 eV could be assigned due to the Si 2p (Fig. 4d). This result
suggested the presence of silica and organic moieties in Cr(III)@SAFSB
material.
3.1.5. FT-IR spectral analysis
Figure S1 illustrates the FTIR spectra of SBA-15 (a), 3-MPTMS
functionalized SBA-15 (b), sulfonic acid functionalized SBA-15 (c),
homogeneous Cr(III) salen complex (d) and heterogeneous chiral Cr(III)
@SAFSB catalyst (e). The successful synthesis of mesoporous SBA-15
material is confirmed by the appearance of the broad and instance peak
near 3454 cm−1 (Si−OH bond) and 1079, 796 cm−1 (SieOeSi bond)
(a, Fig. S1). Next, the new peaks near about 2571 cm−1 (SeH bond) and
762 cm−1 (−CH2-S) clearly indicate the formation of 3-MPTMS func-
tionalized SBA-15 (b, Fig S1). Thereafter, the transformation of the -SH
group to -SO3H group is assigned by the complete disappearance of the
peak near 2571 cm−1 (SeH bond) and appearance of the new band at
1154 cm−1 due to the symmetric and asymmetric stretching of the SO2
moieties [46] (c, Fig S1). In the IR spectrum of homogeneous Cr(III)-
salen complex (d, Fig S1) the characteristic peaks near 1650-1400 cm−1
appear due to the presence of -C]N groups’ stretching and the CeH
deformation stretching respectively. These peaks are also present in the
heterogeneous Cr(III)@SAFSB catalyst (e, Fig S1). Hence the FTIR
spectral study undoubtedly signify the step wise modification of SBA-15
and the efficacious synthesis of chiral Cr(III)@SAFSB catalyst.
Fig. 3. (A) Nitrogen adsorption-desorption isotherm of parent SBA-15 (a) Cr
(III)@SAFSB (b) materials, where adsorption and desorption isotherms are
marked by filled and empty circles, respectively. (B) The pore size distribution
plots of pure SBA-15 (a) and Cr(III)@SAFSB (b) are shown.
Fig. 2a and b. Microscopic view perpendicular to the pore axis sug-
gested highly ordered arrangement of the mesopores. 2D ordered hex-
agonal pores with a diameter of ˜8.0 nm, are organized in a periodic
fashion throughout the whole specimen [29,30]. The periodicity of
hexagonally arranged pores are also quite clear after the loading of
chiral Cr(III) complex in Cr(III)@SAFSB material (Fig. 2c,d). The Fast
Fourier Transform (FFT) patterns of SAFSB and Cr(III)@SAFSB mate-
rials are shown in the inset of Fig. 2b and 2c respectively, suggesting the
highly ordered hexagonal array of the pore channels in both the ma-
terials.
3.1.6. Elemental analysis
The carbon, hydrogen and nitrogen content in Cr(III)@SAFSB ma-
terial are examined by CHN analysis, which suggested the elemental
contents in the material as: C = 12.52 wt%, H = 2.57 wt% and
N = 1.23 wt%. Using Varian AA240 atomic absorption spectro-
photometer (AAS), the chromium content in the supported chiral cat-
alyst was determined. The observed freshly prepared Cr(III)@SAFSB
material showed the chromium content as 0.166 mmolg−1. Further,
XPS analysis of Cr(III)@SAFSB suggested sulphur content of 14.19
atomic%. Calculated C/N, Cr/N and Cr/C ratios (based on proposed
model in Scheme 2) were 10.31, 0.928 and 0.103, whereas those ob-
served from chemical analysis of Cr(III)@SAFSB were 10.17, 0.700 and
0.069, respectively. This result agreed well considering the limit of
experimental errors in chemical analysis.
3.1.3. N2 adsorption/desorption isotherm
Fig. 3 demonstrates the nitrogen adsorption-desorption isotherms of
pure silica SBA-15 and Cr(III)@SAFSB materials. Both these isotherms
could be classified as typical type IV isotherm along with large hys-
teresis loops of type H1 [30] in high relative pressure region, which
suggested that the material contains uniform and large mesopores. The
estimated BET (Brunauer-Emmett-Teller) surface area and pore volume
of SBA-15 and Cr(III)@SAFSB materials were 765 and 407 m2 g−1, and
0.90 and 0.61 ccg−1, respectively. The pore size of the material has
been estimated from these adsorption/desorption isotherms using
NLDFT (Non-Local Density Functional Theory) method. Peak pore
width for pure silica SBA-15 was 11.1 nm, which decreased to 8.0 nm
(inset of Fig. 3) in Cr(III)@SAFSB. This result suggested that anchoring
of chiral Cr(III) complex at the pore surface of SBA-15 reduces the pore
width by 3.1 nm and this result agrees well with the UHR-TEM image
3.2. Enantioselective Henry Reaction
For establishing the optimized reaction conditions, a number of
reactions have been performed using 4-methyl-benzaldehyde (1a) and
nitro methane as the model substrates (Table 1). We are delighted to
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Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
Fig. 4. Narrow range XPS spectra of Cr 2p (a), S 2p (b), C 1s (c) and Si 2p (d) elements.
yield and 78% ee of the product yield without using any base (Entry 7,
Table 1). In contrast, both yield and ee values are increased dramati-
cally with increasing amount of base. To optimize the suitable base for
this reaction, diisopropyl ethylamine (DIPEA), Et3N, Cs2CO3, 1,8-dia-
zabicyclo-[5.4.0]-undec-7-ene (DBU) were used but 1.0 mmol of Et3N
showed the best product (Entry 8–10, Table 1). The temperature re-
quired for the reaction was also optimized. Lowering the temperature
from 4 to -10 °C, results an enhancement in reaction selectivity along
with a decreased value of product yield, while reaction at room tem-
perature severely loses both activity and selectivity (Entry 11–12,
Table 1). Next, amount of the chiral catalyst required for the reaction,
was screened and was found that only 15 mg (0.249 mol% of Cr) Cr(III)
@SAFSB catalyst shows the best results (Entry 13–14, Table 1). The
catalytic activity of SBA-15 and sulfonic acid functionalized material
SAFSB were also examined and it was found that in the both of these
cases, very low amounts of the products are formed (10 and 12%, re-
spectively) (Entry 16–17, Table 1). Moreover, reaction using equimolar
amount of nitromethane produces the corresponding product (2a), but
only with 39% yield and 83% ee (Entry 18, Table 1) Thus, our opti-
mized reaction condition provide the best result in terms of the yield
and ee of the product using Et3N as a base, 15 mg (0.249 mol% of Cr) of
Cr(III)@SAFSB catalyst at 4 °C temperature in DCM for 16 h (Entry 6,
Table 1). After achieving the optimum reaction condition, we further
extended our work for the synthesis of a bunch of β-hydroxy nitroalk-
anes using various substituted aromatic aldehydes and nitromethane
(Table 2).
Table 2
Substrate scope of Cr(III)@SAFSB catalyzed asymmetric Henry reactiona.
Entry
(R)
Product
Yieldc (%)
eed (%)
TONe
1
4-MeC6H4 (1a)
Ph (1b)
2a
2b
2c
2d
2e
2f
87
90
85
86
89
85
88
82
80
78
88
91
84
86
91
86
89
86
83
77
349
362
341
345
357
341
353
329
321
313
2
3
3-ClC6H4 (1c)
4
4-ClC6H4 (1d)
4-NO2C6H4 (1e)
4-MeOC6H4 (1f)
3,4-diMeOC6H3 (1 g)
2-thiophenyl (1 h)
2-furyl (1i)
5
6
7
2 g
2h
2i
8
9
10b
CH3(CH2)4CH2 (1 j)
2j
a
Conditions: aldehyde (1.0 mmol), CH3NO2 (8.0 mmol), Cr(III)@SAFSB
(15 mg, 2.49 × 10−6 mol or 0.249 mol% of Cr), Et3N (1.0 mmol), DCM, 4 °C
temp., 16 h.
b
c
d
e
20 h is required.
Isolated yields.
enantiomeric excesses were determined by HPLC analysis.
TON: moles of substrate converted/mole of active site.
inform that, without any catalyst, solvent and base no product was
formed (Entry 1, Table 1). Among various solvents, ethanol, diethyl
ether, tetrahydrofuran, toluene, etc. were used for this reaction, where
DCM provides the unbeatable upshots in case of yield as well as ee of
the product 2a (Entry 2–6, Table 1). The reaction provides only 55%
We are glee to report that, aromatic aldehydes, substituted with
both electron donating as well as withdrawing groups in diverse
6

Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
Scheme 3. Most plausible transition state of asymmetric Henry reaction over Cr(III)@SAFSB.
Scheme 4. Reaction pathway for the synthesis of drug R-isoproterenol.
substitution position of the phenyl ring, furnish the corresponding
products in moderate to good yields (up to 90%) and ee (up to 91%).
Parallelly, we have employed our catalyst to the asymmetric Henry
reaction using thiophene-2-carbaldehyde and furan-2-carbaldehyde
(Entry 8, 9, Table 2) as the aldehyde partner. Interestingly, the reaction
furnishes (S)-1-(thiophen-2-yl)-2-nitroethanol and (S)-1-(furan-2-yl)-2-
nitroethanol as the final product with 80–82% yield and 83–86% ee. In
addition, with these aromatic and heteroaromatic aldehydes we further
extended our endeavour for the same reaction using heptanal as an
aliphatic aldehyde partner. Here we acquired the desired product with
78% yield and 77% ee (Entry 10, Table 2).
Table 3
Comparative study for asymmetric Henry reactions over homogeneous Cr(III)-
salen complex (E) and Cr(III)@SAFSBa.
Catalyst
t (h)
Yieldb (%)
eec (%)
Homogeneous Cr(III)-salen complex (E)
14
16
82
90
92
91
Heterogeneous Cr(III)@SAFSB
a
Conditions: PhCHO (1.0 mmol), CH3NO2 (8.0 mmol), Cr(III) catalyst
(0.249 mol% of Cr), Et3N (1.0 mmol), DCM, 4 °C.
b
c
Isolated yields.
Enantiomeric excesses were determined by HPLC analysis (Figure S3-S4,
ESI).
The whole catalytic performances using Cr(III)@SAFSB chiral cat-
alyst with (S, S) configuration provide the corresponding β-hydroxy
nitroalkanes with R-configurations. Only the exceptions are thiophene-
2-carbaldehyde and furan-2-carbaldehyde due to the formal reason of
the CIP notation. Consequently, our results are in coherence with the
results obtained using chiral thiophene-salen chromium complexes by
Zulauf et al. [27] as well as podand-based dimeric Cr(III)-salen complex
by Ouyang et al. [28]. A plausible mechanism is shown in Scheme 3
based on the product’s configuration. Since the Si-face attack is hin-
dered by the steric factor, the nucleophilic attack could take place only
from Re-face giving the R enantiomer exclusively. The synthesis of the
products has been inspected by 1H-NMR spectroscopic analysis and the
corresponding ee values were estimated through HPLC analyses by the
Fig. 5. Recyclability of Cr(III)@SAFSB for the asymmetric Henry reaction.
7

Md. M. Islam, et al.
MolecularCatalysis475(2019)110489
use of Chiralcel OD-H column (ESI†). Finally, our current catalytic
system, was successfully applied for the preparation of medicinally
demanding drug (R)-isoproterenol (Section I, ESI) [47]. The total syn-
thetic path of (R)-isoproterenol drug is outlined in Scheme 4, which
revealed that chiral Cr(III)@SAFSB catalyzed asymmetric nitro aldol
reaction of 3,4-dimethoxybenzaldehyde with nitromethane has em-
ployed as the crucial step for this preparation (Section II, ESI). The
efficiency of our newly generated heterogeneous Cr(III)@SAFSB cata-
lyst was compared with the non-immobilized Cr(III)-salen complex (E)
for the representative reaction between benzaldehyde (1b) and ni-
tromethane under optimized reaction conditions and the result are
summarized in Table 3. From this result it is clear that the activity of
our heterogeneous chiral Cr(III)@SAFSB catalyst is quite similar to that
of its homogeneous non-immobilized counterpart (HPLC chromato-
grams are given in Fig S3-S4, ESI).
enantioselectivity. Diversely substituted aromatic aldehydes reacted
smoothly to furnish their corresponding products. Moreover, hetero-
cyclic as well as aliphatic aldehydes also undergo this reaction pro-
viding the respective products with good yield and ee. In addition,
using this reaction conditions as one of the key steps, chiral pure drug
(R)-isoproterenol has also been synthesized. Functionalized meso-
porous chiral catalyst reported herein offers very high surface area and
uniform distribution of active sites throughout the material, overall
time required for the reaction is comparatively low, wide variety of
substrates undergo the reaction under same reaction conditions, high
yield and enantioselectivity of the synthesized products, no need of any
additives, high turnover numbers and good recycling efficiency. Thus,
the present work may open-up enormous prospect in asymmetric cat-
alysis based on surface modified mesoporous materials in future.
Acknowledgments
3.3. Reusability of chiral Cr(III)@SAFSB catalyst
SMI thankfully acknowledges Council of Scientific and Industrial
and Research, CSIR (project reference no 02(0284)2016/EMR-II dated
06/12/2016) New Delhi, Govt. of India and Department of Science and
Technology, DST-SERB (project reference no. EMR/2016/004956),
New Delhi, Govt. of India and Board of Research in Nuclear Sciences
(BRNS), Project reference No: 37(2)/14/03/2018-BRNS/37003, Govt.
of India for providing financial support. MMI and MH acknowledge
UGC for providing UGC-MANF-SRF and UGC-SRF, respectively. PB ac-
knowledges CSIR, New Delhi for providing CSIR-SRF. We sincerely
acknowledge the DST and UGC, New Delhi, Govt. of India, for pro-
viding grant under FIST, PURSE and SAP program to the Department of
Chemistry, University of Kalyani. AB acknowledges DST-SERB, New
Delhi for an extramural project grant.
Recyclability is one of the foremost valuable characteristics of a
heterogeneous catalyst. To study the recyclability of our catalyst, we
have performed asymmetric Henry reaction using benzaldehyde and
nitromethane as the model substrate and it was found that, our newly
synthesized chiral catalyst can be recycled for 6 repeated runs without
considerable loss in its activity and selectivity (Fig. 5). This fact was
confirmed through the FTIR spectral analysis of recycled catalyst (after
sixth run). FTIR spectra of the reused catalyst (Fig. S2) contains the
necessary peaks that correspond to the functional groups present in the
material. This fact clearly represents that the functional groups in the
material remain nearly unaltered after reuse.
3.4. Leaching tests
Appendix A. Supplementary data
To examine the possibilities of metal leaching, a solution of freshly
prepared chiral Cr(III)@SAFSB catalyst (15 mg, 0.249 mol% of Cr) in
DCM (1.0 ml) was stirred at 4 °C for 15 min followed by the addition of
aldehyde (1.0 mmol) and nitromethane (8.0 mmol) to it. After addi-
tional stirring for 30 min at the same temperature, 1.0 mmol of Et3N in
DCM (1.0 ml) was added dropwise to the former solution and the final
reaction mixture was subjected for stirring at 4 °C for 8 h. Then the
catalyst was filtered out from the reaction medium at that temperature
and only 42% yield of the product was obtained by GC analysis.
Thereafter, the filtrate was further stirred for another 8 h at 4 °C.
Finally, after 16 h yield of the product was determined by GC and it was
found that no considerable conversion was taking place after separation
of the catalyst. This result clearly indicates that, the reaction did not
progress in absence of the catalyst. Further, AAS measurement was
performed using the final reaction mixture and leached metal ion (Cr
(III)) could not be detected in the filtrate or its content was below the
detection limit of the instrument (0.003 mg/L).
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.mcat.2019.110489.
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