Synthesis of (S)-(-)-propranolol by using Cs2.5H0.5PW12O40 nanocatalyst as green, eco-friendly, reusable, and recyclable catalyst

Article abstract of DOI:10.1080/15533174.2013.832323

The Cs_2.5H_0.5PW₁₂O₄₀ nanoparticle catalyst appear to be a new and efficient solid acid catalyst for an economical, environmentally benign synthesis of (S)-(-)-propranolol. Cs_2.5H_0.5PW₁₂O₄₀ nanocatalyst are used as a new, recyclable and reusable. Synthesis of (S)-(-)-propranolol is carried out in two steps with usual reagents: heteropolyacid, (+)-tartaric acid catalyzed enantioselective synthesis of (S)-(-)-propranolol via kinetic resolution of key intermediate α-naphthyl glycidyl ether with high optical and chemical yield. With this synthesis, we have two products in the first reaction and it is not necessary to purify the crude oil. This by-product is removed in the second step by extraction and yield is satisfactory. The nanocatalyst of Cs_2.5H_0.5PW₁₂O₄₀ catalyzed the synthesis of propranolol in high yields and good selectivity.

Full text of DOI:10.1080/15533174.2013.832323

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Synthesis of (S)-(-)-Propranolol by using
Cs2.5H0.5PW12O40 Nanocatalyst as Green, Eco-Friendly,
Reusable and Recyclable Catalyst
Ali Gharibab, Manouchehr Jahangira, Mina Roshania, Nader Noroozi Pesyanc, J. (Hans) W.
Scheerend, Sara Mohadesazadehb & Shirin Lagzianb
a Department of Chemistry, Islamic Azad University, Mashhad, IRAN
b Agricultural Researches and Services Center, Mashhad, IRAN
c Department of Chemistry, Faculty of Science, Urmia University, 57159, Urmia, IRAN
d Cluster for Molecular Chemistry, Department of Organic Chemistry, Radboud University
Nijmegen, The Netherlands
Accepted author version posted online: 28 Apr 2014.
To cite this article: Ali Gharib, Manouchehr Jahangir, Mina Roshani, Nader Noroozi Pesyan, J. (Hans) W. Scheeren, Sara
Mohadesazadeh & Shirin Lagzian (2014): Synthesis of (S)-(-)-Propranolol by using Cs2.5H0.5PW12O40 Nanocatalyst as Green, Eco-
Friendly, Reusable and Recyclable Catalyst, Synthesis and Reactivity in Inorganic, Metal-Organic, and Nano-Metal Chemistry,
DOI: 10.1080/15533174.2013.832323
To link to this article: http://dx.doi.org/10.1080/15533174.2013.832323
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Synthesis of (S)-(-)-Propranolol
by using Cs2.5H0.5PW12O40 Nanocatalyst as Green, Eco-Friendly,
Reusable and Recyclable Catalyst
ALI GHARIB 1,2*, MANOUCHEHR JAHANGIR1, MINA ROSHANI1, NADER NOROOZI
PESYAN3, J. (HANS) W. SCHEEREN4, SARA MOHADESAZADEH2, SHIRIN LAGZIAN2
1Department of Chemistry, Islamic Azad University, Mashhad, IRAN
2Agricultural Researches and Services Center, Mashhad, IRAN
3Department of Chemistry, Faculty of Science, Urmia University, 57159, Urmia, IRAN
4Cluster for Molecular Chemistry, Department of Organic Chemistry, Radboud University
Nijmegen, The Netherlands
*Author to whom correspondence should be addressed: aligharib5@yahoo.com
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Abstract: Cs2.5H0.5PW12O40 nanoparticles catalyst appear to be a new and efficient solid acid
catalyst for an economical, and environmentally benign synthesis of (S)-(-)-Propranolol.
Cs2.5H0.5PW12O40 nanocatalyst are used as a new, recyclable and reusable. Synthesis of (S)-(-)-
Propranolol is carried out in two steps with usual reagents. Heteropolyacid, (+)-tartaric acid
catalyzed enantioselective synthesis of (S)-(-)-propranolol via kinetic resolution of key
intermediate α-naphthyl glycidyl ether with high optical and chemical yield. With this synthesis,
we have two products in the first reaction and it is not necessary to purify the crude oil. This by-
product is removed in the second step by extraction and yield is satisfactory. Nanocatalyst of
Cs2.5H0.5PW12O40 catalyzed the synthesis of propranolol in high yields and good selectivity.
Keywords: Cesium heteropolytungstate, nanoparticles, (S)-(-)-Propranolol, Catalyst,
Heteropolyacid, recyclable, reusable
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INTRODUCTION
Propranolol is a β-blocker and antihypertensive drug, which suffers from the first-pass
elimination resulting in decreased bioavalibility of oral doses compared to intravenous injections.
Propranolol is used in the treatment of angina and hypertension. By antagonizing the β2 -
receptor, propranolol should pose serious problems to asthmatic patients. β-Blockers of the 3-
(aryloxy)-1-(alkylamino)-2-propanol type, e.g. propranolol 4, are one such class of drugs where
the activity resides mainly in the S isomers.[1,2] Stereochemistry is one of the most important
factors in synthesis of drugs molecules. chirality is emerging as a key issue in pharmaceutical
research.[3] Prodrugs may protect a drug from first-pass effects. One of the major metabolites is
the O-glucuronide. For example, the activity of (S)-(-)-propranolol is almost 98 times higher than
that of its R enantiomer. Therefore, (R)-4 is known to act as a contraceptive drug. Methods
reported for the synthesis of (S)-propranolol involved the use of enzymes for resolution of
intermediate,[4] asymmetric epoxidation of allyl alcohol,[5] from sorbitol,[6] asymmetric
hydrogenation using chiral metal complex of the intermediate,[7] and also by employing polymer
supported reagent.[8] Heteropolyacids (HPAs) are good catalysts for both acid and
oxidationreactions. Heteropolyacids (HPAs) have been extensively studied as acid and oxidation
catalysts for many reactions and found industrial application in several processes.[9] HPAs are
promising solid acids to replace environmentally harmful liquid acid catalysts such as H2SO4.[9]
HPAs use for fine chemical industries with green processes. As stereochemistry in a drug
molecule governs its biological activity,[10] chirality is emerging as a key issue in pharmaceutical
research.[11] Heteropolyacids (HPAs), presently being used in several industrial processes, are
important for the so-called clean technologies since many of the environmental pollution and
corrosion problems of the traditional technologies are avoided. Heteropolyacids (HPAs) catalyze
a wide variety of reactions in homogeneous liquid phase offering strong options for more
efficient and cleaner processing compared to conventional mineral acids.[12] There are, however,
some specific features in the HPA catalysis. First, being stronger acids, HPAs have significantly
higher catalytic activity than mineral acids. In organic media, the molar catalytic activity of
heteropoly acid is usually 100–1000 times higher than that of H2SO4.[13] Heteropolyacids
(HPAs) have long been known as catalysts for condensation reactions, e.g., the condensation of
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acetone to mesityl oxide and alkylbenzenes.[14] It has been shown that HPA is an efficient
catalyst for condensations in the syntheses of vitamins E, K1 and C.[15] Heteropolyacids (HPAs)
are early transition metal oxygen anion clusters that exhibit a wide range of molecular sizes,
compositions, and architectures.[16] Generally, tungsten heteropoly acids are the catalysts of
choice because of their stronger acidity, higher thermal stability, and lower oxidation potential
compared to molybdenum heteropolyacids. Usually, if the reaction rate is controlled by the
catalyst acid strength, heteropolyacids shows the highest catalytic activity. The HPAs-based
catalysts, with the strong Brønsted and Lewis acid nature, have many advantages over the other
catalysts.[17]For example, Keggin-type HPAs are wellknown[18] which among them
Cs2.5H0.5PW12O40 (CsPW) with a high specific surface acidity has been applied as an effective
acid catalyst.[19]
The major goal is the development of nanocatalyst application (Cs2.5H0.5PW12O40 nanocatalyst)
in organic synthesis. We now report the application of Cs2.5H0.5PW12O40 nanocatalyst, with
exclusive properties surpassing the Keggin heteropolyacids, for highly selective in order to
synthesize (S)-(-)-Propranolol.
Results and Discussion
We use from Cs2.5H0.5PW12O40 nanocatalyst as a catalyst in synthesis of propranolol report
herein a method for efficient synthesis of (S)-isomer of propranolol via Cs2.5H0.5PW12O40
nanocatalyst /(+)-tartaric acid-catalyzed with a intermediate α-naphthyl glycidyl ether 3 (Scheme
1).
Scheme 1.
At least two products are obtained in the first step reaction, however, it is not necessary to purify
the crude oil. The by-product results from nucleophilic attack of potassium salt of naphthol to the
formed epoxide. This by-product is removed in the second step by ether extraction. The yield is
satisfactory. Spectrometric data analysis is recommended. With condensation of α-naphtol 1
together epichlorohydrin 2 in presence of KOH in methanol solvent at room temperature for 7 h
was created α-naphtyl glycidyl ether 3 with good yield 97%, ( Scheme 1). Treatment of this ether
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with excess of isopropylamine for 24 h reflux, gives (+,-)-propranolol 4 with a good yield
(93%). Using of Cs2.5H0.5PW12O40 nanocatalyst and (+)-tartaric acid allowed to stirred with α-
naphthyl-glycidyl ether for 15 min in methanol solvent, followed by addition of isopropylamine
to the same reaction gave (S)-propranolol in good optical purity and chemical yield. The
enantiomeric excess was calculated by correlation of optical rotation [α] with literature values
[α]D = -10.2.[20] Mole ratios of epoxide: epoxide, heteropolyacid (HPAs) catalyst and (+)-tartaric
acid was effected on chemical and optical yields. The best mole ratio is 1: 0.5: 1 with 77%
isolated yield of crude product which showed 90% ee of (S)-enantiomer. The best catalyst was
Cs2.5H0.5PW12O40 nanocatalyst, with high yield%. We have obtained that (S)-propranolol with
high purity (68% ee) can be provide only in two steps and without any purification or resolution
of intermediate. We suggested a preliminarily chiral complex, which kinetically favored for (S)-
enantiomer responsible for this optical purity. Finally we can concluded that enantioselective
ring opening by using Cs2.5H0.5PW12O40 nanocatalyst and (+)-tartaric acid is an efficient short
route, with simple work up and high enantiomeric excess for synthesis of (S)-(-)-Propranolol. By
using different forms of heteropolyacids catalysts, the observed selectivity. The results of the
kinetic resolution ring opening of epoxide were listed in (Table 1).
Table 1.
a) Mole ratio corresponding to epoxide 3: heteropolyacid catalyst: (+)-tartaric acid.
b) Isolated yield. c) Calculated by correlation of optical rotation [α] (C = 1.0, EtOH) with comparison of literature
values, [α]D = -10.2 (C = 1.02, EtOH).[21]
The result shows that Cs2.5H0.5PW12O40 nanocatalyst has higher activity and performance in (S)-
(-)-Propranolol reactions compared with the other heteropolyacids such as Keggin as well as
normal method using H2SO4 (Table 1). Compared with Keggin and Cs2.5H0.5PW12O40
nanocatalyst, is more active and show higher selectivity and minimizing side reactions. The
results of the synthesis of (S)-(-)-Propranolol with condensation of α-naphthol 2 with
epichlorohydrin 3 using Cs2.5H0.5PW12O40 nanocatalyst as catalysts at reflux conditions are
shown in (Table 1). The experiment was carried out for the first time by an inexpensive,
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recyclable Cs2.5H0.5PW12O40 nanocatalyst. The results show that Cs2.5H0.5PW12O40 nanocatalyst
has higher activity and performance in (S)-(-)-Propranolol reactions compared to
Cs2.5H0.5PW12O40 nanocatalyst, Keggin type under the same conditions. The best yield of (S)-(-)-
Propranolol (97%) with good selectivity was attained with Cs2.5H0.5PW12O40 nanocatalyst at
almost 24 h of reaction at reflux conditions (Table 1. entry 6). Keggin (H3[PW12O40],
H4[SiW12O40], H3[PMo12O40], H4[SiMo12O40]) heteropolyacid has also lower activity than
Cs2.5H0.5PW12O40 nanocatalyst. They lead to order 95, 93, 91, 86.5% (S)-(-)-Propranolol with
good selectivity after 24 h of reaction at reflux conditions (Table 1. entry 6).
Effect of the catalyst type:
Initially, we compared the catalytic performance of Cs2.5H0.5PW12O40 nanoparticles catalyst,
Keggin, H3[PW12O40], H4[SiW12O40], H3[PMo12O40], H4[SiMo12O40] in the synthesis of (S)-(-)-
Propranolol. The results are shown in Table 1. The yield of product decreases in the following
order:
Cs2.5H0.5PW12O40
nanoparticles catalyst> H3[PW12O40]> H4[SiW12O40]> H3[PMo12O40]>
H4[SiMo12O40]. As could be seen 12-tungstophosphoric acid, H3[PW12O40], Keggin type of
heteropolyacid, is more effective than the other heteropoly anions and in the presence of this
catalyst the highest yields of products are obtained. The interesting feature of this poly anion
compared the other heteropolyacids is its hydrolytic stability (pH 0-12), which is very important
in catalytic processes.
It is clear from these reactions that the efficiency of Cs2.5H0.5PW12O40 nanocatalyst is higher than
these of Keggin heteropolyacids. The reason is due to higher surface area available. Also, as a
matter of fact, if the particle size of nanomaterial decreases, the relative number of surface atoms
will be increased and thus the catalyst activity will be enhanced.
Synthesis and characterization of nano-catalyst CsPW :
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The catalytic properties of HPAs are modified by using of some large cations like Cs+ as
counter-cation.[22-24] This modification is done via lowering of the solubility of catalyst which
overcomes the separation problems in catalysis processes. In this work, we used ultrasound
irradiation in synthesis of CsPW to achieve a unique catalyst in nano-scale.
Study on structure and morphology of nano-catalyst CsPW:
The IR spectrum of nano-powder shows the characteristic bands of [PW12O40]3- anion at 800 cm-1
(W-Oc-W), 890 cm-1 (W-Ob-W), 985 cm-1 (W-Od) and 1080 cm-1 (P-Oa). The Oa, Ob, Oc and Od
atoms are the oxygen atoms which bonded to P and W, the corner-shared oxygen atoms of WO6
octahedra, the edge-shared oxygen atoms of WO6 octahedra and the terminal oxygen atoms,
respectively. SEM images indicate that the particles are fairly spherical. The existence of cesium,
tungsten and oxygen in CsPW was confirmed by SEM-EDX analysis (Figure. 1).
Insert Here Fig. 1.
The XRD pattern of nanoparticles CsPW was recorded in the range of 5 to 50o for 2Ɵ (Figure.
2).
Insert Here Fig. 2.
The average particles size (D) was calculated by using the Debye-Scherrer equation,[25] D =
0.89lλ (βcosƟ), where l is the wavelength of the radiation, β is the full-width at half-maximum
and Ɵ is the diffraction angle. The thermal stability of nano-catalyst CsPW was studied by its
TGA from 39 to 600 oC (Figure. 3).
Insert Here Fig. 3.
EXPERIMENTAL
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Chemicals and apparatus
All solvents were purchased from commercial sources.
Instruments
The IR spectra were recorded on a Shimadzu model impact 400D FT-IR spectrophotometer
1
using KBr pellets. H NMR were recorded on a Bruker AC-300F 400 MHz spectrometer in
1
CDCl3 using tetramethylsilane (TMS) as an internal standard with H resonant frequency of 400
MHz. Optical rotation values were considered on Bellingham Stanly polarimeter. The resultant
milky suspension was centrifuged and the solid was dried at 323 K. A multiwave ultrasonic
generator (Misonix Sonicator 4000 (S-4000), equipped with a generator, converter, converter
cable, a 1/2-inch replaceable tip horn, operating frequency at 20 kHz with a maximum power
output of 600 W) was used for the ultrasound irradiation.
Preparation of heteropolyacid catalyst
Keggin type HPAs were acquired from commercial sources. Synthesis and characterization of
nano-catalyst CsPW Acidic cesium salt of 12-tungstophosphoric acid was prepared by
stoichiometric ratio according to published method.[18] A 0.0125M aqueous solution of Cs2CO3
(20 mL) was added dropwise (rate of about l mL.min-1) to a 0.01M aqueous solution of
H3PW12O40.nH2O (20 mL) at room temperature, under ultrasound irradiation for 30 min in a
beaker. The wave amplitude in this experiment was 40 and ultrasonic energy dissipated was set
at 2.92 W, through the calorimetric method.[26] The structure and morphology of nanoparticles
Cs2.5H0.5PW12O40 have been studied by scanning electron microscope (SEM), a Leo 1450 VP
with accelerate voltage 35 kV and resolution 2.5 nm. The energy dispersive X-ray spectroscopic
(EDX) was measured with an Oxford 7353. XRD patterns were recorded on a Bruker, D8
Advance using Ni-filtered, Cu Ka radiation (l = 1.5406 A˚ ). The BET surface area was
determined via nitrogen adsorption at 77 K using Quantachrome Corporation. The sample was
outgassed at 140 8C for 10 h before the measurement. Thermo gravimetric analysis (TGA) was
performed under air with a Shimadzu TGA-50 system at a heating rate of 10 oC.min-1.
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Synthesis of epoxide (Glycidyl-α-Naphthyl Ether (3)):
Transfer 7.2 g (0.05 mol) of 1-naphthol, 5 g KOH to a round-bottom flask and add ethanol/H2O
(9:1), the mixture was stirred for 30 min at room temperature. After dissolution, add dropwise 12
mL (0.15 moles) epichlorhydrin slowly in 45 min and stirring was continued at room
temperature for 7 h. The reaction is left under magnetic stirring at room temperature for 45 min.
TLC is carried out in an eluent system (hexane/ethyl acetate 9:1) to monitor the end of the
reaction. The reaction was finished with H2O (50 mL) and extracted with chloroform (2×75 mL).
The combined organic layers were washed with water (5×100 mL) and sodium hydroxide
solution (2×30 mL), and dried over sodium sulfate. Remove ethanol by vacuum evaporator and
to give the glycidyl-α-naphthyl ether 3 in 96% yield. Extract aqueous phase with ethyl ether. The
ethyl ether extract is dried with anhydrous sodium sulfate. Filter and remove solvent to obtain the
crude brown oil.
1
bp = 201-203°C (lit[21] 203-205°C]. H-NMR (400 MHz, CDCl3, δ/ppm): 2.5-2.9 (m, 2H), 3.3
(m, 1H), 3.8-4.3 (m, 2H) 6.4-6.8 (m. 1H), 6.9-7.7 (m,5H), 7.9-8.2 (m, 1H). 13C-NMR (400 MHz,
DMSO-d6, δ/ppm): 154.2, 134.5, 134.7, 127.7, 126.5, 126.1, 125.5, 123.6, 120.4, 107.4, 69.9,
49.8, 22.4. IR (Neat, cm-1): 3050, 2980, 1580, 1540, 1500, 1460, 1390, 1340, 1310, 1270, 1240,
1180, 1100, 1080, 1020, 960, 870, 790, 770, 750, 700, 670, 640, 570. Anal. Calcd for C13H12O2:
C 77.95, H 6.06%; Found C 77.90, H 5.97%; HRMS (EI) Calcd. for C13H12O2 [M]+, 200.1001,
Found 200.1008;
Synthesis of (±)-Propranolol (4):
Transfer 0.2 g (1.0 mmol) of the solution of glycidyl-α-naphthyl ether 3 (2.0 g, 10 mmol) in
excess 20 mL isopropylamine (235 mmol; 2.78 g) and water (1 mL) and nanoparticles
Cs2.5H0.5PW12O40 catalyst was stirred and to reflux for 24 h. Removal of solvent yielded crude
(±)-propranolol (2.38 g, 92%), which could be purified by recrystalization in hexane.
mp= 95°C (lit.[28] 96°C), 1H-NMR (400 MHz, CDCl3, δ/ppm): 1.2 (d, 6H), 2.4-3.1 (m, 4H), 6.8-
8.3 (m, 7H). 13C-NMR (400 MHz, DMSO-d6, δ/ppm): 154.3, 134.6, 134.4, 127.5, 126.6,
126.2,123.6, 70.8, 69.8, 49.6, 49.1, 23.8. IR (Neat, cm-1): 3450, 3200, 3050, 2980, 1630, 1590,
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1580, 1500, 1460, 1400, 1340, 1320, 1270, 1240, 1180, 1160, 1100, 1070, 1020, 960, 870, 790,
770, 760, 640, 620, 570, 520. Anal. Calcd for C16H21NO2: C 74.11, H 8.15, N 5.41%; Found C
74.06, H 8.11, N 5.48%; HRMS (EI) Calcd. for C16H21NO2 [M]+, 259.2004, Found 259.2009;
Synthesis of (S)-(-)-Propranolol (4):
A solution of glycidyl-α-naphthyl ether 3 (8 mmol, 1.6 g), L-(+)-tartaric acid (8 mmol, 1.2 g)
and nanoparticles Cs2.5H0.5PW12O40 catalyst (0.03 g) in (20 mL) ethanol was stirred for 15 min.
The isopropylamine (16 mmol, 1.2 mL) was added and stirred and to reflux for 24 h. The
reaction mixture was cooled and filtered. The solid was washed with dichloromethane and then
treated with aqueous 10% sodium hydroxide solution (10 mL), and extracted with
dichloromethane (2×50 mL). The combined organic layer was washed with water (5×50 mL) and
dried over sodium sulfate. The solvent was removed under reduced pressure to give crude
product (1.59 g, 77% yield), that showed 90% ee for (S)-(-)-Propranolol. mp = 72°C [α] = -9.08
(C = 1.0, EtOH), [α]D = -10.2 (C = 1.02 EtOH).28
Reusability of the catalyst
The catalyst was recovered after the reaction and reused as a catalyst in the synthesis of (S)-(-)-
Propranolol. Several times recoveries had only slightly decreased the catalytic activity, pointing
to the stability and retention capability of this useful polyanion. At the end of the reaction, the
o
catalyst was filtered, washed with diethyl ether, dried at 130 C for 1 h, and reused in another
reaction. The recycled catalystwas used for three reactions without observation of appreciable
lost in its catalytic activities. In Table 2, the comparison of efficiency of nanoparticles
Cs2.5H0.5PW12O40 catalyst in the synthesis of 4 after five times is reported. As it is shown in
Table 5 the first, second, third, fourth and fifth reaction using recovered nanoparticles
Cs2.5H0.5PW12O40 catalyst afforded similar yield to those obtained in these runs. The reusability
of the catalyst was also investigated. At the end of the reaction, the catalyst was recovered by a
simple filtration. The recycled catalyst was washed with water and subjected to a second run of
the reaction process.
Table 2.
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CONCLUSIONS
In conclusion, we have reported a new catalytic method for the synthesis of propranolol using
nanoparticles Cs2.5H0.5PW12O40 catalyst as efficient, reusable and eco-friendly heterogeneous
inorganic catalysts. The advantages of this method are reusability of catalysts, easy work-up
procedure and high yields. The propranolol synthesis is carried out in two steps with usual
reagents. However, the results show that nanoparticles Cs2.5H0.5PW12O40 catalyst shows the
highest yield. Compared with mineral acids, such as H2SO4, nanoparticles Cs2.5H0.5PW12O40
catalyst is more active and shows a higher selectivity, and minimizing side reactions. Important
features of this polyanion are high thermal and hydrolytic stability throughout a wide pH range.
Eco-friendly, recyclable, and easily prepared nanoparticles Cs2.5H0.5PW12O40 catalyst is an
efficient solid acid catalyst for highly selective synthesis of (S)-(-)-Propranolol. In the
nanoparticles Cs2.5H0.5PW12O40 catalyst in both heterogeneous conditions can easily be recovered
and reused without loss of structure and activity. The CsPW catalyst was prepared ultrasonically
in the nano-scale and used as a heterogeneous catalyst for the synthesis of (S)-(-)-Propranolol.
The results of the kinetic resolution ring opening of epoxide were showed in Table1. Mole ratios
of epoxide: nanoparticles Cs2.5H0.5PW12O40 catalyst (Heteropolyacids): (+)-tartaric acid was
affected on chemical and optical yields.
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Schemes and Figures captions
Scheme 1. Synthesis of (S)-(-)-Propranolol in the presence of Cs2.5H0.5PW12O40 nanocatalyst
Fig. 1. SEM-EDX images of nanoparticles Cs2.5H0.5PW12O40.
Fig. 2. XRD pattern of nanoparticles Cs2.5H0.5PW12O40.
Fig. 3. Shows the TGA profile for nanoparticles Cs2.5H0.5PW12O40.
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O
OH
O
KOH, C2H5OH
RT, 7h
Cl
+
O
(2)
(3)
(1)
Cs2.5H0.5PW12O40
(CH3)2CH-NH2
H2O, reflux
nanocatalyst
(+)-tartaric acid
(CH3)2CH-NH2
C2H5OH, reflux
O
NH
H
HO
O
NH
OH
(S)-(-)Propranolol
(4)
(+,-)-Propranolol
(4)
Scheme 1. Synthesis of (S)-(-)-Propranolol in the presence of Cs2.5H0.5PW12O40 nanocatalyst
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Fig. 1. SEM-EDX images of nanoparticles Cs2.5H0.5PW12O40.
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Fig. 2. XRD pattern of nanoparticles Cs2.5H0.5PW12O40.
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Fig. 3. Shows the TGA profile for nanoparticles Cs2.5H0.5PW12O40.
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Table 1. Enantioselective synthesis of (S)-(-)-Propranolol via kinetic resolution of racemic
epoxide 3 catalyzed by Cs2.5H0.5PW12O40 nanocatalyst, various heteropolyacids catalysts and (+)-
Entry
Mole ratioa
b Yield %
b Yield %
b Yield %
b Yield %
b Yield %
bYield%
(H2SO4)
ee%c
Cs2.5H0.5PW12O40
nanoparticles
H3[PW12O40]
H4[SiW12O40]
H3[PMo12O40]
H4[SiMo12O40]
1
2
3
4
5
6
7
8
1: 1: 1
95
92
81
77
94
97
68
82
93
91
78
76
91
95
67
81
90
86
77
74
89
93
64
78.5
88
82.5
81
80
77
70
59
78
83
45
76
17
0
1: 0: 0
84
1: 0.5: 0.5
1: 0.5: 1
1: 0: 1
76
75.5
67
38
90
18
68
71
36
71.5
87.5
91
84.5
86.5
59
1: 0.08: 0.08
1: 0.5: 2
1: 0.5: 0.16
62.5
75
70.5
tartaric acid at reflux conditions
a) Mole ratio corresponding to epoxide 3: heteropolyacid catalyst: (+)-tartaric acid.
b) Isolated yield. c) Calculated by correlation of optical rotation [α] (C = 1.0, EtOH) with comparison of literature
values, [α]D = -10.2 (C = 1.02, EtOH).21
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Table 2. Reuse of the nanoparticles Cs2.5H0.5PW12O40 catalyst for synthesis of (S)-(-)-
Propranolol.
Entry
Run
aYield (%)
1
2
3
4
5
1
2
3
4
5
97
96
95.5
94
94
a Isolated Yields
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