Chiral copper-salen complex grafted over functionalized mesoporous silica as an efficient catalyst for asymmetric Henry reactions and synthesis of the potent drug (R)-isoproterenol

Article abstract of DOI:10.1039/c8nj01745j

Synthesis of enantiomerically pure drug molecules using functionalized mesoporous materials bearing a chiral moiety is a longstanding goal in heterogeneous catalysis. Herein, we report an efficient and enantioselective one-pot Henry reaction over a highly

Full text of DOI:10.1039/c8nj01745j

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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
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Chiral copper-salen complex grafted over functionalized
mesoporous silica as an efficient catalyst for the asymmetric
Henry reactions and synthesis of potent drug (R)-isoproterenol
Received 00th January 20xx,
Accepted 00th January 20xx
Mita Halder,a Piyali Bhanja,b Md. Mominul Islam,c Asim Bhaumik,b,* Sk. Manirul Islam c,*
DOI: 10.1039/x0xx00000x
Synthesis of enantiomerically pure drug molecules by using functionalized mesoporous materials bearing chiral moiety is a
long standing goal in heterogeneous catalysis. Herein, we report an efficient and enantioselective one-pot Henry reaction
over highly ordered functionalized mesoporous silica supported chiral copper-salen catalyst, Cu(II)@AFS-1 in DCM at RT.
The catalyst has been characterized by UV-Vis, FT-IR spectroscopy, PXRD, N2 adsorption/desorption, HR-TEM, EPR,
thermogravimetric and elemental analyses. The diastereoselective Henry reaction of nitroethane has been carried out by
using this catalyst to obtain good yields (up to 96%) and ee (up to 95%) of β-nitroalcohols with acceptable dr (3.2:1).
Additionally, enantiomerically pure drug (R)-(-)-isoproterenol can be synthesized through asymmetric Henry reaction of
3,4-dimethoxybenzaldehyde over this chiral mesoporous Cu-catalyst as a key step.
www.rsc.org/
catalytic systems provide good to brilliant yields and
enantioselectivities but require low temperatures and high catalyst
loadings. As a fallout, further modifications are necessary in pursuit
Introduction
Asymmetric Henry (nitro aldol) reaction comprises one of the most
constructive and atom-economical methodologies to generate
enantiomerically pure β-hydroxy nitroalkanes1 through the
construction of new C-C bond. A growing interest has been paid to
the resulting β-nitro alcohols due to its multipurpose applications
for the synthesis of chiral ligands, various pharmaceutically
important structural gibbets, biologically potent compounds,2 etc.
Besides, due to the chemical versatility of the nitro group,3 the
newly formed β-nitro alcohol can easily be transformed into other
chiral building blocks by oxidation, reduction, Nef reaction,4 and
nucleophilic displacement. Further, it can also be used for the
synthesis of poly amino alcohols, natural products and poly
hydroxylated amides5 etc., which are used for the synthesis of more
complex compounds.6 Therefore, continuous and substantial efforts
have been paid to develop a simple and novel asymmetric catalytic
system for this reaction.7 In the year 1992, Sasai et. al. have
reported the pioneering work on the asymmetric version of the
to mitigate these obstacles, high expenditure of chiral catalysts and
to recycle the catalyst through immobilization of the metal-
complex on to the solid support for scaling-up. Moreover, as
compared to other metal complexes, the chiral copper(II)
complexes are found to be the most effective in catalysing the
asymmetric Henry reaction11 with good to marvellous product yield
and enantioselectivity. In this regard, a range of non-immobilized
copper containing chiral catalysts (Cu(II)-chiral C1-symmetric
dinitrogen ligand,12a (CuOTf)2.C6H5CH3-chiral tetrahydrosalen
ligand,12b Cu(II)-pyridinylmethyl diphenyl prolinolsilyl ether,12c trans-
N, N’-bis-biphenyl-4-ylmethyl-cyclohexane-1,2 diamine CuCl2
complex)12d have been reported in the literature. Besides, Kureshy
et al.13a,b Dhahagani et al.13c Khan et al.13d,e,f Jones et al.13g and
Bhosale et al.13h also reported immobilized copper salen complexes
for the asymmetric Henry reaction with moderate to good yield and
enantioselectivity. Additionally, environment friendly nature, no
need of additives and mild reaction conditions could make the
chiral metal complex bound to mesoporous support as highly
demanding heterogeneous catalyst.14 Due to high specific area,
ordered pore arrangement, high thermal and mechanical stability,
and possibility of recycling, the immobilization of a reactive metal
complexes or functional moieties over mesoporous materials could
be an ideal strategy in catalysis.15 In this context, functionalization
of the 2D-hexagonally ordered mesopore surface with organic
moieties, especially immobilization of chiral complexes is very
challenging for carrying out sustainable asymmetric catalysis over a
long period of time.16 Recently, we have reported acid
functionalized mesoporous silica bearing the chiral metal complexes
for catalytic epoxide ring opening reactions.17
nitro aldol (Henry) reaction.8 Thereafter,
a large number of
organocatalysts bearing reactive organic functionalities9 as well as
heterogeneous chiral catalysts10 have been developed for the Henry
reaction with uneven accomplishment. The majority of these
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Herein, we report the synthesis of a new chiral Cu(II)-salen
Step I:
2
)
Synthesis of homogeneous chiral Cu(II) salen complex (
complex grafted over acid functionalized periodic mesoporous
material to obtain Cu(II)@AFS-1 material (Fig. 1), which successfully
catalyses the asymmetric Henry reaction to furnish a library of β-
nitro alcohols in excellent yields along with good ee at RT in DCM
(Scheme 1). Moreover, our synthetic protocol has been efficiently
Cu(OAc)2. H2O
Ethanol,
N
N
N
O
N
Cu
2
OH HO
O
-
-
-
RT, N2 atm,
12 h, 90%
-
ClR3N
NR3Cl
ClR3N
NR3Cl
t-Bu t-Bu
t-Bu
t-Bu
1
Step II:
AFS-1
)
Synthesis of the mesoporous support (
employed for the synthesis of
a clinically potent drug (R)-
(i) CHCl3, reflux,
N2, 16 h
Isoproterenol, which is used intensively for the treatment of heart
blockage, bronchitis, asthma and emphysema.18 It is pertinent to
mention that (R)-form of this drug is around 90 times more
effectual than the (S)-form.17
O
O
O
OH
OH
OH
Si H2C
N
C
H
CO2H
+
(EtO)3Si
NH2
3
(ii) 4-Formylbenzoic Acid
MeOH, reflux, 6 h
4
AFS-1
3
Step III:
Cu(II)@AFS-1
catalyst
Synthesis of chiral
-
+
NR3Cl
OH
OH
N
O
N
N+R3
-
Cu(II)@AFS-1
CO2
Cu
R'
R'
t-Bu
O
R
CHO
+
R'
NO2
R
R
N+R3Cl-
+
EtOH
313 K, 12 h
N
O
O
DCM, RT
15 - 22 h
AFS-1
+
t-Bu
t-Bu
NO2
syn
NO2
anti
Cu
CH
N
N
R = Aryl, Heteroaryl, Aliphatic,
R' = H: 10 examples, 96% yield, up to 94% ee
t-Bu
-
CH
23
O
Cu(II)@AFS-1
R = Me: 2 examples, up to 3.2:1 sy n/anti, 96% yield, 95% ee of syn
Si
O
+
O
NR3Cl
2
SBA-15
Scheme 1 Cu(II)@AFS-1 catalysed synthesis of chiral β-nitro alcohols.
# R = Ethyl
Results and discussion
Figure 1. Outline for the synthesis of chiral Cu(II)AFS-1 catalyst (Supporting information
Section I, Fig. S1)
Synthesis of chiral Cu(II)AFS-1 catalyst:
Fig. 1 represents the stepwise synthetic pathway for the chiral
catalyst Cu(II)@AFS-1. The chiral Schiff base ligand (1) was prepared
through the stepwise functionalization of 3-tert-butyl-2-hydroxy-
benzaldehyde following our previously reported literature.16b Then
the metalation of the chiral ligand 1 furnish the homogeneous
copper(II)-salen complex 2. Besides, the surface modification of
SBA-15 produced the solid support AFS-1.16b Thereafter, the metal
salen complex 2 was grafted at the surface of AFS-1 to generate the
final chiral catalyst Cu(II)@AFS-1. The foremost possible structure of
the functionalized Schiff base ligand (1) was studied by 1H NMR
analysis (Fig S1, ESI). The spectroscopic data was in full agreement
with the literature report.
Figure 2. (a) Small angle powder XRD pattern of the Cu(II)@AFS-1 catalyst. (b)
The nitrogen adsorption-desorption isotherm of Cu(II)@AFS-1. The pore size
distribution estimated by NLDFT method is shown in inset.
HR-TEM and EPR study:
Porosity and nanostructure:
The UHR-TEM images of Cu(II)@AFS-1 material is shown in Fig 3.
From Fig 3a and 3b, it is noticed that regularly arranged ordered
hexagonal pores perpendicular to the pore axis are spread over the
whole specimen. Fig 3a, 3b and 3c represent the UHR-TEM images
of Cu(II)@AFS-1 material at three different resolutions in different
positions. The Fast Fourier Transform (FFT) pattern is shown in the
inset of Fig 3b, suggesting the presence of highly ordered hexagonal
pores in this material. Also, the channel like structural patterns are
seen parallel to the pore axis in Fig 3c. To know the definite
coordination environment changes of metal (copper) centre,
electron paramagnetic resonance (EPR) analysis has been
performed at room temperature (298 K) using freshly prepared
copper grafted acid functionalized solid catalyst Cu(II)@AFS-1. As
shown in Fig 3e, the material exhibits sharp and clear four splitting
component in low magnetic field region due to hyperfine coupling
between nuclear spin of copper and unpaired electrons, which are
−3/2, −1/2, +1/2, +3/2. From EPR spectrum other three parameters
has been obtained where g║ =2.40, average g┴ = 2.11, suggesting
the distorted tetrahedral square planar geometry of Cu(II) ions.21
The small angle powder X-ray diffraction pattern of Cu(II)@AFS-1
material is shown in Fig 2a. Three significant characteristic peaks
were observed at 2θ value of 0.92°, 1.60° and 1.84°, corresponding
to the diffraction planes of 100, 110 and 200, respectively for the
ordered 2D hexagonal mesoporous materials.19 To measure surface
area and pore size distribution, nitrogen sorption analysis has been
carried out and N2 adsorption/desorption isotherm is given in Fig
2b. The material exhibits typical type IV isotherm with a large
hysteresis loop of type H1 in the high-pressure region i.e. 0.59 to
0.87 relative pressure of nitrogen.20 As seen from Fig 2b the
appearance of large hysteresis loop in high P/P0 region suggested
the presence of uniform cylindrical mesopores in the material.18d
The BET (Brunauer-Emmett-Teller) surface area and pore volume of
this material were 174 m2 g-1 and 0.2395 cc g-1, respectively. By
employing Non-Local Density Functional Theory (NLDFT), pore size
of the material has been calculated, which suggested a peak at 7.02
nm from the pore size distribution plot (inset of Fig 2b). The De
Boer statistical thickness (t-plot) suggested that the surface area of
Cu(II)@AFS-1 was mostly obtained due to mesoporosity and there is
very low contribution of microporosity in total BET surface area.
2 | J. Name., 2012, 00, 1-3
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attributed to the evaporation of surface adsorbed moisture and
second weight loss is observed 187 to 530 °C due to the
decomposition of organic part of the material.
Figure 3. The UHR-TEM images of Cu(II)@AFS-1 material (a, b) perpendicular to the
pore axis, (c) different resolution and (d) parallel to the pore axis. The FFT pattern is
shown in the inset of figure 3b. (e) EPR spectrum of Cu(II)@AFS-1 material.
Spectroscopic studies:
In Fig.
4 the UV-Vis DRS absorption spectra of AFS-1 and
Figure 5. FT IR spectra of (a) SBA-15, (b) 3-APTES functionalized SBA-15, (c) acid
Cu(II)@AFS-1 are shown. The appearance of a new broad band near functionalized mesoporous material AFS-1 and (d) heterogeneous chiral catalyst
Cu(II)@AFS-1.
345-450 nm indicated the presence of surface bound Cu(II) sites in
the chiral catalyst. Fig. 5 represented the FT-IR spectra of SBA-15
Beyond this temperature the weight loss could be assigned due to
(a), 3-aminopropyl triethoxysilane functionalized SBA-15 (b),
the further condensation in the material. Thus, TGA analysis
carboxylic acid functionalized mesoporous material AFS-1 (c), and
revealed the good thermal stability of material, which is good
heterogeneous chiral catalyst Cu(II)@AFS-1 (d) respectively. The
enough to conduct the heterogeneous catalytic reactions.
broad peak (a, Fig. 5) near about 3000 cm-1 signifies the aliphatic C–
H stretching vibrations. The intensity of this peak raises gradually
with the surface modification of SBA-15 to Cu(II)@AFS-1. Besides
the broad peak near 1084 cm-1 (for Si-O-Si bond) and 3444 cm-1 (Si-
OH bond) undoubtedly indicate the existence of SBA-15 material. In
the spectrum ‘b’ (Fig. 5) the peak near 1556 cm-1 could be ascribed
for the deformed N-H vibrations of amido-groups of 3-APTES
functionalized SBA-15. Again, the peaks near 1350-1600 cm-1 in the
figure (c, d, Fig. 5) suggested the presence of -C=N- starching
vibrations of the surface modified catalyst. Thus, the FT-IR spectra
revealed the successful step by step modification of SBA-15 to the
chiral catalyst Cu(II)@AFS-1.
Figure 6. The TG-DTA profile diagram of Cu(II)@AFS-1.
Elemental data of the Cu(II)@AFS-1:
The CHN analysis data revealed the carbon, hydrogen and nitrogen
content in the material framework, where C = 11.22 %, H = 2.74 %
and N = 2.77 %, respectively. AAS analysis revealed the copper
content in freshly prepared Cu(II)@AFS-1 material, which was
estimated as 0.178 mmolg-1. FT-IR: 3399, 2937, 1625, 1544, 1385,
1077, 874 cm-1.
Enantioselective Henry Reaction:
Taking the aforesaid benefits of a heterogeneous catalytic system in
Figure 4. The DRS-UV-Vis absorption spectrum of AFS-1 and chiral Cu(II)@AFS-1
catalyst.
mind, our preliminary study was to evaluate the optimum reaction
conditions for the reactivity of the Cu(II)@AFS-1 catalyst. For this
Thermal stability:
purpose, 4-nitro benzaldehyde (1a) and nitromethane were chosen
To measure the thermal stability of Cu(II)@AFS-1 we have carried as the model substrates. Table 1 briefly delivers this result. The
out TGA/DTA analysis with temperature ramp of 10 °C per min. As reaction is not possible without addition of catalyst (Table 1, Entry
seen from Fig. 6 the first weight loss up to 102 °C could be 1). Even though, a range of solvents viz. ethanol, THF, benzene,
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chloroform etc. were used but DCM has furnished the best our present study, we used heterogeneous chiral mesoporous
outcomes in terms of yield and enantioselectivity of the product 2a material as an active catalyst with which an extensive study was
(Table 1, Entry 2-7). Next, we screened the amount of the catalyst done varying the temperature from 0 to 40 ºC (Table 1, Entry 7, 11-
and reaction temperature (Table 1, Entry 7-13). For 5 mg catalyst 13). We observe that at lower temperatures (Table 1, Entry 11-12)
loading the product yield value is very low (Table 1, Entry 8), while the enantioselectivities are better but the yield is very low, because
for 10 mg catalyst the reaction took place with good product yield of the lower activity of the catalyst. While at higher temperature
and ee. Next we have increased the catalyst loading from 10 to 12 (Table 1, Entry 13) the amount of yield is improved but the
º
mg. Here, product yield negligibly increases but improvement in the enantioselectivity decreases enormously. But at RT (25 C) (Table 1,
ee value was observed (Table 1, entries 7 and 9). With 15 mg Entry 7) both yield and enantioselectivity are improved. Hence an
catalyst, no further improvement of the ee value was observed, but appropriate temperature is required to gain a minimum amount of
decreases slightly. Normally, lower temperatures are beneficial in activation energy for the production of the corresponding product
asymmetric synthesis because enantioselectivity of the product is with high yield and enantioselectivity. We found that, our
enhanced.
Cu(II)@AFS-1 chiral catalyst exhibits the best catalytic activity for
carrying out the Henry reaction at RT in DCM for 15 h using just 12
mg (0.2136 mol % of Cu) of the Cu(II)@AFS-1 catalyst (Table 1, entry
7).
Table 1. Optimization table for the asymmetric Henry reaction over Cu(II)@AFS-1a
Having established the applicability of chiral Cu(II)@AFS-1
catalyst in Henry reaction as per entry 7 (Table 1), we have further
extended this optimized reaction conditions for a number of
aromatic aldehydes viz, 4-NO2 benzaldehyde, 4-Cl benzaldehyde,
benzaldehyde, 4-Me benzaldehyde, 4-MeO benzaldehyde, and 3-Cl
benzaldehyde etc., and the results are summarized in Table 2. In
terms of yield and enantioselectivity the catalyst displayed high
efficiency in most of the cases. Both electron donating or
withdrawing groups attached to the benzene ring of the
corresponding aldehydes (Table 2) have a little effect towards the
conversion (90 - 96 %) as well as enantioselectivity (85 - 94 %).
Entry
Cat.
Solvent
T [ºC]
t [h]
Yieldb
[%]
eec
(mg)
1
2
-
-
RT
RT
RT
RT
RT
RT
RT
RT
RT
RT
10
0
72
15
15
15
15
15
15
15
15
15
15
15
15
00
91
79
60
41
69
95
64
94
96
75
48
90
-
12
12
12
12
12
12
5
-
87
80
64
52
79
91
84
88
89
84
80
75
Furthermore, together
with
the
aromatic
aldehydes,
3
EtOH
THF
heteroaromatic aldehydes viz, furan-2-carbaldehyde and
thiophene-2-carbaldehyde were also the promising partners in this
work providing the desired β-nitro alcohols in 92-93% yields and 88
- 90 % ee (Table 2, Entry 8, 9). Additionally, aliphatic aldehydes,
heptanal (1j) and cyclohexanecarbaldehyde (1k) also underwent
this reaction following our optimized reaction conditions giving 84%
and 82% yields and 81% and 85% ee, respectively (Table 2, entries
10 and 11). In all these cases, Cu(II)@AFS-1 with (S, S) selectivity
afforded the (R)-nitro alcohols, except for furan-2-carbaldehyde and
thiophene-2-carbaldehyde. The latter two compounds are (S)-
configured, but just for formal reasons of the CIP notation (Table 2).
A similar observation was reported by Zulauf et al. using chiral
chromium thiophene-salen complexes.23 The selectivity and ee
values of the corresponding products have been examined by the
1H-NMR and HPLC analyses (ESI†).
4
5
PhH
CHCl3
DCM
DCM
DCM
DCM
DCM
DCM
DCM
6
7
8
9
10
15
12
12
12
10
11
12
13
40
aConditions: 1a (1.0 mmol), CH3NO2 (6.0 mmol), Cu(II)@AFS-1 (5-15 mg), solvent (2
mL), RT (25 °C). bIsolated yield. cDetermined by HPLC using Chiralcel OD-H column
Scheme 2 Synthesis of (R)-isoproterenol. Reaction conditions: (i) Cu(II)@AFS-1,
In some cases, however, better results are achieved at ambient DCM, RT, 15h, (ii) H2, 10% Pd/C, EtOH, (iii) (a) EtOH, acetone, (b) NaBH4 (iv) AlCl3,
EtSH, DCM, RT. (1H NMR and HPLC chromatograms of the products are provided
or higher temperatures since the catalyst requires activation.22 In in Figures S3-S6)
4 | J. Name., 2012, 00, 1-3
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Table 2. Variation of substrates in asymmetric nitro aldol reactiona
Entry
Aldehyde
Productb
t (h)
Yieldc (%)
eed (%)
TONe
15
95
91
445
1
16
15
15
15
94
90
96
94
90
87
94
85
440
421
449
440
2
3
4
5
15
96
93
449
6
15
16
93
93
93
88
435
435
7
8
CHO
16
22
92
84
90
81
430
393
9
S
1i
10
22
82
85
384
11
aReaction condition aldehyde (1 mmol), nitromethane (6 mmol), Cu(II)@AFS-1 (12 mg, 0.2136 mol% of Cu), DCM, RT. bAbsolute configurations were allocated through
comparing the HPLC retention time and the sign of optical rotation with the literature data. cIsolated yield. dDetermined by HPLC using Chiralcel OD-H column. eTON = moles of
substrate converted per mole of active site. (1H NMR and HPLC chromatograms of the products are given in ESI, Fig. S7-S27)
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Table 3. Substrate scope of aldehydes and nitroethane in the asymmetric henry reactiona
OH
OH
Cu(II)@AFS-1 (12 mg)
ArCHO
+
NO2
+
DCM, RT, 20 h
NO2
NO2
R
R
syn
anti
Yieldc
(%)
syn/anti
(%)d
ee(%)e
Entry
1
Aldehyde
Productb
TONf
(syn/anti)
3a
3b
96
95
3.2:1
3:1
95/84
449
2
95/66
445
aReaction conditions: aldehyde (1 mmol), nitroethane (6 mmol), Cu(II)@AFS-1 (12 mg, 0.2136 mol% of Cu), DCM, 20h, RT. bAbsolute configurations were allocated through
f
comparing the HPLC retention time. cIsolated yield. dDetermined from NMR data. eDetermined by HPLC using Chiralcel OD-H column. TON = moles of substrate converted per
mole of active site. (1H NMR and HPLC chromatograms of the products are given in ESI, Fig. S28-S31)
Recyclability and Reusability of chiral Cu(II)@AFS-1 catalyst:
Further, in order to perceive the best ability of our chiral
catalyst, diastereoselective Henry reaction24 between 4-Nitro
benzaldehyde (1a) and 4-Cl-benzaldehyde (1b) with nitroethane
has been carried out under the optimal reaction conditions. The
results are listed in Table 3. Both aldehydes provide the
corresponding products with 96% and 95% yield in addition with
good ee for syn isomers. Probably a very week intramolecular
hydrogen-bonding interaction helps to furnish the syn isomer as
major one.25 The diastereomeric ratio (dr) of the product 3a and
3b was found to be 3.2:1 and 3:1 (syn/anti).
Recyclability is the most important characteristic feature of
a heterogeneous catalyst due to their sustainable operation. 4-
nitro benzaldehyde (1a) and nitromethane were taken as model
substrates for the recycling experiments. The recycling efficiency
of Cu(II)@AFS-1 is shown in Fig. 7. From the TEM, PXRD and BET
experimental data it is quite evident that the catalyst is
uniformly porous and the active centers were homogeneously
distributed inside of the pore as well as on the outer surface of
the support. On recycling the catalyst, the little decrease in the
number of active sites could be attributed to the partial pore
blockage. But the chiral environment of the residual active
centers remains unaltered. As a result, the catalytic activity of
the catalyst gradually decreases while the enantioselectivities
basically remain unchanged upon recycling of the catalyst. Thus,
this result suggested that, chiral Cu(II)@AFS-1 catalyst can be
recycled for eight consecutive cycles in the asymmetric Henry
reaction.
The synthetic importance of our current catalytic protocol was
further scrutinized through the synthesis of medicinally and
pharmaceutically potent drug molecule (R)-isoproterenol26
(Section I, ESI). The Cu(II)@AFS-1 catalyzed asymmetric Henry
reaction
between
3,4-dimethoxybenzaldehyde
and
nitromethane was the key step for this synthesis (Section II, ESI).
Next, following the procedure established by G. Blay et al.26c and
Kureshy et al.26d (R)-isoproterenol was synthesized from 2f.
Scheme 2 illustrates the synthetic route of this drug. The overall
yield of the drug molecule is 82%. The most probable
mechanistic pathway26,13b for the asymmetric Henry reaction
catalyzed by heterogeneous chiral Cu(II)@AFS-1 catalyst is
shown in Scheme 3a and respective most plausible transition
state27,12d,13b is given in Scheme 3b.
Finally, to examine the catalytic efficiency, we have compared
the reactivity of the first cycle of our heterogeneous Cu(II)@AFS-
1 catalyst with the non-immobilized Cu(II)-salen complex for the
model reaction between benzaldehyde (1d) and nitromethane
under the optimized reaction conditions. The results are
summarized in Table 4. From this table, it is quite evident that
our heterogeneous chiral Cu(II)@AFS-1 catalyst displayed similar
catalytic activity with the homogeneous counterpart (HPLC data
is given in Fig S2, ESI).
Scheme 3. Proposed catalytic cycle (a) and transition state (b) for the asymmetric
Henry reaction over chiral Cu(II)@AFS-1 catalyst
6 | J. Name., 2012, 00, 1-3
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Moreover, the catalytic applicability of our heterogeneous chiral
Cu(II)@AFS-1 catalyst has been compared with the previously
reported homogeneous and heterogeneous catalysts (ESI†,
Table S1). This comparative study clearly indicates that our
heterogeneous Cu(II)@AFS-1 catalyst showed better catalytic
activity in terms of yield, enantioselectivity and TON.
Experimental
Synthesis of homogeneous chiral Cu(II) salen complex (2):
Notably, ethanolic solution of Cu(OAc)2.H2O (1.25 mmol, 10 mL)
was added to the ethanolic solution of the homogeneous Schiff
base ligand (1) (1 mmol, 10 mL), under N2 atmosphere. The as-
formed bluish solution was then stirred at RT for 12 h.
Thereafter, the solvent was removed and the solid mass was
extracted with DCM followed by washing with water and finally
drying over Na2SO4.Then after removal of the solvent the solid
residue was finally precipitated from n-hexane to furnish the
corresponding homogeneous chiral Cu(II) salen complex (2) as a
bluish solid (yield 90%). The obtained m/z value for the salen
complex (2) (C42H69Cl2CuN4O2) was 794.4091[(M+H)+, cal.
794.4094], which suggested efficient synthesis of the complex.
Figure 7. Reusability chart of chiral Cu(II)@AFS-1 catalyst.
Figure 8. Small angle PXRD pattern (a) and UHR-TEM (b) of the reused
Cu(II)@AFS-1.
Synthesis of heterogeneous chiral Cu(II) salen complex,
Cu(II)@AFS-1 catalyst:
To investigate the stability of the nanostructure of reused
Cu(II)@AFS-1 catalyst we have carried out some key
characterizations. The small angel PXRD pattern of the reused
Cu-catalyst (Fig. 8a, after 6th cycle) revealed the three
characteristic diffraction planes viz. 100, 110 and 200,
suggesting the nanostructure of reused catalyst has been
retained. On the other hand, UHR-TEM image (Fig. 8b) of reused
catalyst (after 6th cycle) confirms the presence of regularly
arranged ordered hexagonal pores. The FT-IR spectrum (ESI†,
Fig. S32) of the reused catalyst further clarifies the organic
functionalization at the surface of the mesoporous AFS-1
material has been retained during the course of reactions. The
possibility of leaching of the metal ion (Cu) was estimated by the
AAS analysis of the reaction mixture after the reaction. Our
chemical analysis data suggested no significant leaching of
copper metal during the course of catalytic reactions.
To the ethanolic solution of homogeneous chiral Cu(II) salen
complex (2) (0.03 g), carboxylic acid functionalized mesoporous
solid support AFS-1 (0.20 g) was added and the resulting
solution was stirred at 313 K for 12 h. Thereafter, the bluish
solid was centrifuged, cleansed thoroughly and repeatedly
extracted with MeOH and DCM on Soxhlet apparatus until the
colourless washing was appeared. Finally, the catalyst was dried
under air.
Synthesis of the drug (R)-isoproterenol:
Starting from 3,4-dimethoxy benzaldehyde and nitromethane,
clinically potent drug (R)-isoproterenol was synthesized through
stepwise modifications of the functional groups. The step by
step synthetic alterations were examined through 1H NMR,
HPLC chromatograms and optical rotation value. The detail
synthetic procedures and characterization data of the
compound 2f, 3, 4 and the final drug (R)-isoproterenol were
given in ESI (Sections I and II).
Table 4. Comparative study between the homogeneous Cu(II)-salen and
Cu(II)@AFS-1 for the asymmetric Henry reactiona
Time
(h)
Yieldb
(%)
eec
(%)
95
Catalyst
General procedure for asymmetric Henry reaction of aldehydes
with nitromethane:
Homogeneous Cu(II) salen
complex
13.5
96
A mixture of 1a (1.0 mmol), nitromethane (6.0 mmol) and
Cu(II)@AFS-1 catalyst (12 mg, 0.2136 mol % of Cu) in DCM were
Heterogeneous
chiral
15
96
94
stirred at room temperature (25 ͦC) for 15 h. The progress of the
reaction was monitored by TLC. After completion of reaction,
the catalyst was removed from the reaction mixture by simple
filtration and ethyl acetate was added. The organic phase was
washed with water and brine, and finally dried over Na2SO4.
Then the product was separated by column chromatography
Cu(II)@AFS-1 catalyst
aConditions: benzaldehyde (1 mmol), nitromethane (6 mmol), Cu(II) catalyst
(0.2136 mol % Cu), DCM, RT; b Isolated Yield, c Determined by chiral HPLC analysis
using Chiralcel OD-H column (Fig S2, ESI)
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over silica gel with pet ether/ethyl acetate (85:15) as eluent. All
the products were characterized based on their 1H NMR and
their spectroscopic data are in agreement with those previously
reported. Enantiomeric excess (ee) was determined by HPLC
analysis using Chiralcel OD-H column.
New Delhi for funding via Indo-Egypt joint project grant
(DST/INT/Egypt/P-05/2016).
Notes and references
Reusability of the catalyst:
1
(a) G. Rosini, In Comprehensive Organic Synthesis, Vol. 2
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After completion of the reaction the heterogeneous chiral
catalyst was collected through centrifugation. Thereafter the
catalyst was washed with distilled water and ethyl acetate
followed by DCM and then dried in an oven at 80
before reuse.
̊C for 2 h
2
3
Leaching test:
A mixture of 4-nitro benzaldehyde (1.0 mmol), nitromethane
(6.0 mmol) and Cu(II)@AFS-1 catalyst (12 mg, 0.2136 mol % of
4
5
Cu) in DCM were stirred at room temperature (25 ͦC) for 7 h.
Then the catalyst was separated from the reaction mixture and
the filtrate was concentrated under reduced pressure. Then
HNO3 solution [5 mL 5% (in aq)] was added to the crude material
and stirred. After that, this solution was taken in a 10 mL
volumetric flask, and the volume was made up to the mark.
Finally, this solution was studied using the AAS measurement to
calculate the amount of leached copper metal.
6
7
Conclusions
In conclusion, a new chiral Cu(II)-salen functionalized highly
ordered mesoporous material can be synthesized by using
surface functionalization route. This mesoporous chiral Cu-
catalyst displayed good catalytic activity for the asymmetric
Henry reaction to furnish chiral β-nitro alcohols. It also catalyses
the diastereoselective Henry reactions with nitroethane giving
good to excellent yields, ee and dr. Using this protocol as the
key step, enantiomerically pure drug (R)-isoproterenol has also
been prepared. In a broader context our protocol will provide a
platform for the synthesis of β-nitroalcohols using chiral Cu(II)-
salen complex grafted over the acid functionalized mesoporous
SBA-15 support. The novelty of our observation lies in (a)
comparatively good BET surface area, (b) uniform dispersion of
the active sites over the support, (c) high catalytic activity, (d)
good recyclability of the catalyst (e) room temperature reaction
(f) use of no additives, bases, (g) comparatively shorter reaction
time, (h) good enantioselectivity and (i) high TON. Thus, this
work may unlock huge opportunity for asymmetric catalysis
over functionalized mesoporous materials in future.
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Graphical Abstract
Chiral copper-salen complex grafted over functionalized mesoporous silica
as an efficient catalyst for the asymmetric Henry reactions and synthesis of
potent drug (R)-isoproterenol
Mita Halder,a Piyali Bhanja,b Md. Mominul Islam,c Asim Bhaumik*,b and Sk. Manirul
Islam,*,c
aDepartment of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700 009, India
bDepartment of Materials Science, Indian Association for the Cultivation of Science, Jadavpur 700
032, India, E-mail: msab@iacs.res.in
cDepartment of Chemistry, University of Kalyani, Kalyani, Nadia, 741235, WB, India, Tel.: +91 33
2582 8750; Fax: +91 33 2582 8282, E-mail: manir65@rediffmail.com
*Corresponding authors.
A new heterogeneous chiral catalyst Cu(II)@AFS-1 has been synthesized, which showed remarkable
catalytic activity in the asymmetric Henry reaction (ee up to 94%, yield 96%) and diastereoselective
Henry reaction (ee up to 95%, dr 3.2:1) of aromatic aldehydes with nitroalkane in DCM at RT. In
addition, enantiomerically pure drug (R)-(-)-isoproterenol has been synthesized using this protocol.
.