Cross-linked polystyrene/titanium tetrachloride as a tightly bound complex catalyzed the modified Mannich reaction for the synthesis of piperidin-4-ones

Article abstract of DOI:10.1016/j.jorganchem.2019.04.004

Cross-linked polystyrene beads were prepared, characterized and the resulting polymer carrier was functionalized with titanium tetrachloride (TiCl₄)via complexation of polystyrene with TiCl₄ to afford the corresponding cross-linked polystyrene-TiCl₄ stable complex (PSt/TiCl₄)in an one step reaction and characterized by FT-IR, UV, TGA, DSC, XRD, SEM, BET. This tightly bound coordination complex was used as a water tolerant, heterogeneous, recoverable and reusable Lewis acid catalyst for the synthesis of substituted piperidin-4-ones via the modified Mannich multi-component condensation of ketones, aromatic aldehydes, and ammonium acetate in 1:2:1 M ratio under mild conditions. The rate of reactions was found to decrease with an increasing percentage of crosslinking and the mesh size of the copolymer beads. The catalyst is water tolerant, stable and can be easily recovered and reused at least four times without any loss of activity.

Full text of DOI:10.1016/j.jorganchem.2019.04.004

Accepted Manuscript
Cross-linked polystyrene/titanium tetrachloride as a tightly bound complex catalyzed
the modified Mannich reaction for the synthesis of piperidin-4-ones
Ali Rahmatpour, Reza Emen, Ghazal Amini
PII:
S0022-328X(19)30130-5
DOI:
https://doi.org/10.1016/j.jorganchem.2019.04.004
JOM 20754
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 7 December 2018
Revised Date: 17 February 2019
Accepted Date: 5 April 2019
Please cite this article as: A. Rahmatpour, R. Emen, G. Amini, Cross-linked polystyrene/titanium
tetrachloride as a tightly bound complex catalyzed the modified Mannich reaction for the synthesis
of piperidin-4-ones, Journal of Organometallic Chemistry (2019), doi: https://doi.org/10.1016/
j.jorganchem.2019.04.004.
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ACCEPTED MANUSCRIPT
Cross-linked polystyrene/titanium tetrachloride as a tightly bound complex
catalyzed the modified Mannich reaction for the synthesis of piperidin-4-ones
Ali Rahmatpour*, Reza Emen, Ghazal Amini
Polymer Research Laboratory, Faculty of Chemistry, Shahid Beheshti University, P. O. Box: 19839-4716, Tehran,
Iran; Fax: +98 21 22431671; Tel: +98 21 29903250
*Corresponding author E-mail: a_rahmatpour@sbu.ac.ir
Abstract
Cross-linked polystyrene beads were prepared, characterized and the resulting polymer carrier was functionalized
with titanium tetrachloride (TiCl4) via complexation of polystyrene with TiCl4 to afford the corresponding cross-
linked polystyrene-TiCl4 stable complex (PSt/TiCl4) in an one step reaction and characterized by FT-IR, UV, TGA,
DSC, XRD, SEM, BET. This tightly bound coordination complex was used as a water tolerant, heterogeneous,
recoverable and reusable Lewis acid catalyst for the synthesis of substituted piperidin-4-ones via the modified
Mannich multi-component condensation of ketones, aromatic aldehydes, and ammonium acetate in 1:2:1 molar ratio
under mild conditions. The rate of reactions was found to decrease with an increasing percentage of crosslinking and
the mesh size of the copolymer beads. The catalyst is water tolerant, stable and can be easily recovered and reused at
least four times without any loss of activity.
Keywords: Polymer/Lewis acid coordination complex, Polystyrene-supported catalyst, Substituted piperidin-4-one,
Multi-component reaction
1. Introduction
Heterogeneous catalysis is a clean and environment-friendly catalytic method. The possibility
of performing multicomponent reactions with a heterogeneous catalyst could enhance their
efficiency from an economic as well as ecological point of view [1]. Although various catalysts
have been developed to realize organic transformation under homogeneous conditions, it is still
difficult to achieve recovery and reuse of the catalysts in many cases. Preparative procedures
using polymer-supported catalysts have several advantages beacause of their nature; the most
important properties of such catalysts are as active as their homogeneous counterparts while
having the distinguishing characteristics of being easily separable from the reaction media,
reusability, higher selectivity, enhanced stability, easier handling, non-toxicity, non-
corrosiveness, and simple workup procedures [2,3].
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Over the past few years, TiCl4 has been reported as an efficient catalyst for organic synthesis and
industrially organic compounds, which exhibits, in numerous cases, a stronger activity than other
known metal chlorides, in particular those of transition elements [4–6]. Even though free TiCl4
has many advantages in a homogeneous environment, it has drawbacks such as its corrosive
nature, moisture sensitivity, less stability at room temperature, handling difficulty, a hazardous
nature, and can not be recovered. Immobilized TiCl4 catalyst is expected to solve these
problems. The heterogenisation of inorganic reagents and catalysts in an inert matrix that are
useful in organic reactions is an important goal in clean technology [7]. Polystyrene (frequently
as a cross-linked resin) is one of the most popular polymer supports, due to its availability, facile
functionalization and chemical inertness [8]. There are several different ways by which active
homogeneous catalysts have been heterogenized for use in organic synthesis. Perhaps a most
attractive method known to date is immobilization of active catalysts on an inert organic polymer
matrix [8]. One of the interesting aspects of such immobilized catalysts is that they swell under
certain solvent conditions and thus provide a near homogeneous environment for the reactants
while retaining all the advantages of a heterogeneous catalysts. The aim of this study was to
heterogenize and immobilize strong Lewis acid titanium tetrachloride directly by supporting it on
cross-linked polystyrene with specified morphology in an one step reaction without
functionalization of the polymer matrix.
We have recently reported the synthesis and use of polymer-supported Lewis acids as efficient
catalysts for a variety of organic transformations [9-14]. Cross-linked polystyrene-supported
titanium tetrachloride (PS/TiCl4), which is a tightly bound and stable complex between TiCl4 and
polystyrene-divinylbenzene copolymer. The use of the PS-TiCl4 complex catalyst has several
advantages over a conventional acid catalyst, such as its ease of handling (as a bench-top
catalyst), stability, cost efficiency, recyclability, and tunable Lewis acidity.
Nitrogen containing heterocyclic compound especially piperidin-4-ones presumably gaining
considerable importance owing to their varied biological properties such as antiviral, antifungal,
anti-tumour, analgesic activities [15-17]. Substituents (presence phenyl or para substituted
phenyl groups) at C-2 and C-6 positions of the piperidin-4-one ring moiety have a wide range of
antimicrobial activity.
Multicomponent reactions (MCRs) are chemical transformations in which three or more
reactants form a product derived from all of the inputs in a single operation without isolating the
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intermediates and therefore reducing the reaction times and energy input [18-20]. These type of
reactions introduce the most of diversity in one step, making full use of the many building blocks
available today from commercial vendors. The interest in MCRs has boosted during the past two
decades since are a very useful tool for the efficient synthesis of small molecule libraries. The
search and discovery for new as well as improvement of known MCRs is still in demand as the
best tools in combinatorial chemistry. One of these MCRs is the preparation of piperidin-4-one
d
erivatives by a three-component reaction using ketones, aromatic aldehydes, and ammonium
acetate (in 1:2:1 molar ratio) reported by Noller etal. [21]. A few number of methods are
available for the synthesis of substituted piperidin-4-ones [22-27] and a few catalysts are also
available up to now to improve the yield and reaction conditions of the modified Mannich
reaction. The main disadvantage of almost all conventional methods is that the catalysts are
destroyed in the work-up procedure and their recovery and reuse is often impossible, and most
importantly, the conventional method of synthesis of polysubstituted piperidin-4-one derivatives
necessitate a tedious work-up procedure, including the conversion of the product to its
hydrochloride salt. Thus, the development of new methods that utilize eco-friendly protocols are
highly desirable.
As part of our continuing interest in heterogeneous catalysis in organic transformations, we
report herein an efficient and eco-friendly procedure for the synthesis of substituted piperidin-4-
one derivatives from the modified Mannich condensation of ketones, aromatic aldehydes, and
ammounium acetate catalyzed by a tightly bound DVB-PS/TiCl4 complex as a reusable
heterogeneous Lewis acid catalyst in ethanol for the first time (Scheme 1). In this study, the
preparation of DVB-crosslinked PS-TiCl4 complex by directly immobilization of TiCl4 on PS
with specified crosslinking degree, mesh size, and morphology prepared by carrying out cross-
linking suspension copolymerization using xanthan gum/ or guar gum from bioresources as new
alternative synthetic suspension stabilizer is also described. A tightly bound complex PS/TiCl4
combines the advantages of being both a Lewis acid and a dehydrating agent.
<Scheme 1>
2. Experimental section
2.1. Preparation of cross-linked polystyrene copolymer beads
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Into a 250 ml three-necked round-bottomed flask equipped with a mechanical stirrer, nitrogen
gas inlet, and reflux condenser that is placed in a thermostated water bath, a mixture of distilled
water (500 parts) containing GG or XG/PVA (2 wt% in relation to the monomers) and NaCl (1%
w/v in relation to water volume) was first introduced into the flask and stirred at room
temperature for 30 min. While stirring, nitrogen was purged from the mixture, the suspending
medium was then heated to the reaction temperature. A mixture of the monomers (St and several
weight ratios of DVB cross-linker, 4, 6, 8, 10%) were first mixed well with the porogen (toluene-
heptane (3:2) mixture ) to form an organic phase in which, the initiator, AIBN, was added in the
amount of 1 mol% of monomers. The organic phase mixture was then added dropwise to the
aqueous phase, through a dropping funnel to the flask for about 30 min (The volume ratio
between the two phases (organic/aqueous) was kept constant at 1/5). The stirring rate was kept at
o
350-400 rpm and the polymerization was allowed to proceed at 80 C for 18 h. After the
polymerization, the copolymer beads were filtered out on a Buchner funnel under vacuum, and
treated in 1N HCl at boiling temperature for 15 min, washed twice with hot water, and then
vacuum filtered to remove the stabilizer. The copolymer beads were extracted thoroughly with
acetone for a few hours in a soxhlet apparatus to remove porogen and residual monomers, and
then were washed twice with acetone, two times with methanol to ensure complete removal of
impurities. Finally, the samples were dried in a vacuum oven at 50 oC for at least 8 h. The overall
conversion of the monomers to solid copolymer was determined gravimetrically. Of these beads
the 50-80 mesh size (or 170-290 µm) beads were used in the subsequent studies.
2.2. Preparation of crosslinked polystyrene-titanium tetrachloride complex (PS/TiCl4)
The carrier beads of cross-linked polystyrene (8% DVB, grain size range: (170-290 µm, 50-80
mesh size) swelled by 6 mL of dry carbon disulfide as the reaction medium were placed in a
round bottom flask (100 mL) equipped with a condenser. A solution of anhydrous TiCl4 (2 g) in
dry carbon disulfide (4 mL) was added to the dispersed polystyrene bead solution. The mixture
was kept under refluxing conditions and stirring using a magnetic stirrer for 1 h under a nitrogen
atmosphere. After cooling the reaction mixture to room temperature, cold water (50 mL) was
then cautiously added to hydrolyze the uncomplexed TiCl4. The mixture was stirred until the
bright red color disappeared, and the polymer became light yellow. The polymer beads were
collected by filtration through suction and washed thoroughly with water (100 mL) and then with
ether (10 mL) and chloroform (10 mL), respectively. The light yellow colored complex catalyst
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sample was further dried in a vacuum oven overnight at 50 C before use. The chlorine content
of PS/TiCl4 was 11.62 % analyzed by the Mohr titration method [9-11] and the loading capacity
of TiCl4 on the polymeric catalyst or the amount of TiCl4 complexed with polystyrene was
calculated to be 0.824 mmol/g complex bead [28].
2.3. Determination of the quantity of TiCl4 complexed
The PS-TiCl4 complex samples were decomposed by burning via the sodium fusion method.
The amount of TiCl4 complexed with polystyrene carrier was calculated from the chlorine
content. The chlorine content was determined volumetrically. It was also determined by the
inductively coupled plasma (ICP) spectroscopy technique from the titanium content.
2.4. Determination of acidity (pH) of the PS-TiCl4 complex
The catalyst sample was hydrolyzed in an acetone-water solution (60%, 3/2 v/v) at room
o
temperature. The pH of the resultant solution was determined at 25 C by using a standard pH
meter.
2.5. General procedure for the one-pot synthesis of 3,5-dialkyl-2,6-diarylpiperidin-4-ones 4
A mixture of benzaldehyde (2 mmol), ammonium acetate (1 mmol), ketones (1 mmol) and the
PS/TiCl4 containing certain amount of TiCl4 (0.15 gr, 0.1 mmol of TiCl4) in anhydrous ethanol
o
(8 mL) was heated at 70 C for an appropriate time as indicated by TLC (Table 2). After
completion of the reaction, the mixture was cooled to room temperature and the resulting
mixture was filtered to recover the catalyst and the filtrate was evaporated off the solvent to
afford the crude product. The recovered catalyst was washed by ethanol, ether, and dried at 60
oC for 6 h and stored in a desiccator. The crude product obtained was washed with water and
purified by recystallization from ethanol and ethanol-acetone (3:2, v/v) to afford the
corresponding pure compound. 10 mmol-scale reactions were also carried out without any
difficulties. All of the known products were characterized by comparison of their physical data,
FTIR, and 1H NMR spectra with those of authentic samples
.
3. Results and discussion
3.1. Synthesis and characterization of crosslinked poly (St-DVB) beads and their titanium
tetrachloride complex
The polymeric carrier beads as polymer support were synthesized by aqueous cross-linking
suspension radical copolymerization of styrene-divinylbenzene (with varying ratios of DVB)
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monomers using guar or xanthan gum as a biopolymer suspension stabilizer in the presence of
AIBN and non reactive diluents (Scheme 2). The present study deals with using the copolymer
beads containing (8 wt.%) of DVB as cross-linker as the polymer carrier beacause of the network
consisting of light and relatively larger number of accessible domains leading to higher
functionalization. All resins were sieved to a range of 25-80 mesh. The 50-80 mesh beads were
used as carrier in the polymer supported catalysts.
The cross-linked polystyrene analog of ethylbenzene-TiCl4 complex was synthesized by
complexation reaction of the PS with TiCl4 in an one step reaction without functionalization of
the polymer matrix. The steps involved in the preparation of DVB/PS-supported titanium
tetrachloride are given in Scheme 2. The complex formation takes place via the formation of a
coordination bond between the TiCl4 and the PS carrier. Since titanium in TiCl4 has the vacant d-
orbital (d0) so it has the ability to accept the π electron donated from the electron rich PS moiety
leading to a PS-TiCl4 complex.
<Scheme 2 >
In order to ascertain the incorporation of TiCl4 to the polymer support, FT-IR spectra were
recorded separately at different satges of synthesis (Fig. S1, see supplemenrtary data).
Comparison of the IR spectra of the PS carrier and the supported catalyst PS/TiCl4 revealed that
the peak intensity centered at 3025 cm-1 (=CH- stretching of benzene ring) significantly
decreases, indicating a reduction in the electron density on the carbon-carbon (π) double
conjugated bond. This is due to the donation of electron density from π bond to the vacant d
orbital of Ti+4 in TiCl4. The main difference between the FT-IR spectra of PS/TiCl4 complex and
crosslinked PS was at 1500-1600 cm-1 and at 500-800 cm-1. The FT-IR spectrum of PS/TiCl4
showed new peaks at 1500-1590 cm-1 due to for C-C stretching, 500-800 cm-1 for benzene ring
C-H bending, indicating the donor-acceptor interaction of carbon-carbon (π) bond on the
benzene rings with TiCl4. This interaction causes weakening carbon-carbon bond and this
characteristic absorption band (C-C stretching) negatively shifts to 1540 cm-1, indicating
coordination of the π bond with the titanium and further confirming the formation of a titanium
complex on the surface of the polymer and modification of the phenyl rings of the PS/DVB.
The FT-IR spectra of pyridine adsorbed on PS/TiCl4 Lewis acid and PS samples are shown in
Fig. S2. After adsorption of pyridine, the characteristic absorption band at 1450 cm-1 is
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originated C-C stretching vibration in pyridine molecules coordinatively chemisorbed on Lewis
sites (Ti), so it was attributed to Lewis acid sites. The other signals for pyridine molecules
coordinatively chemisorbed on Lewis sites are about 1493 and 1600 cm-1 (C-C ring vibration).
However, no band at the same wavelength was observed for the PS sample. Therefore, it was
proved that the Lewis acids were successfully immobilized on polystyrene.
The UV spectrum of the solution of PS/TiCl4 complex in CS2 showed a new absorption band at
about 262 nm, which is due to the formation of a stable Pi→P type coordination complex
between the benzene rings in the polystyrene carrier with TiCl4. This effect would also stabilize
the TiCl4 complex with polymer carrier containing phenyl groups. UV spectra of PS, PS/TiCl4
are shown in Figure S2. The probable way of complex formation is shown in Scheme S1 (see
supplementary data). As a result of the electron donation from PS moiety to TiCl4, the Lewis
acid is stabilized due to the decreased mobility of the benzene rings hindered by the long
polystyrene chain. These significant changes revealed that TiCl4 is coordinated with benzene
rings through the π bond. The white polystyrene beads becomes pale yellow after the
heterogenation with TiCl4 which gives physical evidence of complex formation taking place
between TiCl4 and polystyrene beads.
The pH of PS-TiCl4 complex catalyst dispersed in a solution of acetone-water (60%) is shown in
Fig. S4 (see supplementary data). Figure S4 shows that the acidity due to hydrolysis of this
polymeric complex in solution increases with time and reached equilibrium in 2 h. This is due to
the liberation of HCl into the acetone-water solution after reaction of TiCl4 incorporated in PS
with water. This confirms that some Lewis acid (TiCl4) is present in this polymeric complex. The
same experiment was also performed with the naked polymer which shows pH= 6.2 (Fig. S4).
Fig. S5 shows the XRD diffraction pattern of the PS carrier and the synthesized PS/TiCl4 catalyst
(see supplementary data). The virgin PS exhibited a broad diffraction peak at (2θ) ranging from
15o-30o suggesting the amorphous structure of the polymeric scaffold (see supplementary
information). But in case of PS/TiCl4 after incorporation of TiCl4 into the polymer matrix, the
intensity of characteristic reflection peak at 2θ=
15o-30o has been considerably diminished
without altering the peak position. The reason for the decrease in peak intensity is probably due
to the accommodation of TiCl4 molecules onto the PS matrix which combine the polymer chain
and it forms complexes with polystyrene. This phenomenon confirms the presence of TiCl4 in the
polystyrene matrix.
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The incorporating of TiCl4 in PS carrier was also confirmed by using TGA technique. Fig. 1
presents the thermal behavior of the PS and the as-synthesized PS-supported catalyst. The PS
bead showed single step degradation. The initial decomposition temperature of the PS was
o
occurred at about 334 C. The major degradation of the polymer chain occurs in the range of
o
o
380-440 C (midpoint 422.38 C) and the loss is related to breaking the main chain and side
o
group of PS. But in case of TiCl4 incorporated PS catalyst, the weight loss starts at about 50 C.
This weight loss could be assigned to the release of residual solvent and adsorbed water. Except
the slightly initial weight loss, the synthesized PS/TiCl4 showed one step degradation. The major
o
degradation of the polymer chain occurs in the range of 310-450 C (50 % weight loss at about
o
o
417 C and (80% weight loss at about 450 C). The degradation temperature (2nd) slightly
decreases with the incorporation of TiCl4 into the polymer matrix. The lower second degradation
temperture of catalyst relative to that of the pristine polystyrene is mainly due to loss of
crystallinity of PS by incorporation of TiCl4 and to an outlet of TiCl4 from the polystyrene
o
matrix. The TGA data reveals that PS/TiCl4 catalyst is thermally stable up to 210-270 C
(depending on percent of TiCl4 loading), and so it may be inferred that this synthesized catalyst
is sufficiently thermally stable to be applied for a variety of chemical transformations which is
carried out in that temperature range including the modified Mannich condensation.
<Figure 1>
The DSC analysis provide analogous information (Figure 2). The maximum decomposition
o
temperature (50 wt.% weight loss) for the copolymer bead prepared is about 402 C. The glass
transition temperature (Tg) of the copolymer beads (PS/DVB) with 4 and 8 wt.% DVB is about
o
108 and 119 C, respectively. No exothermic peak in the range 200-250 oC was observed. For
this peak, polymer cross-linking is responsible. Absence of such peaks in the case of copolymer
beads prepared indicates that all double bonds of monomers were consumed during
copolymerization.
<Figure 2>
SEM imaging provides more accurate information on the particle size and morphology of the
polymer support and functionalized polymer carrier. Fig. 3 shows the SEM images of the PS
carrier and the sample after immobilization. A clear change in morphology was observed after
incorporating TiCl4 onto the polymer support. It can be seen from Fig. (3a) that the PS carrier
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exhibits randomly regular shape particles and almost non uniform in their sizes with an average
diameter of 500 µm. The SEM image shown in Fig.(3b) after incorporation of TiCl4 on the
polymer matrix, randomly irregular aggreagated particles are observed. Moreover, it was
observed that the particle size becomes considerably larger than the pristine one and the surface
becomes slender smooth. The observed increase in particle diameter of the catalyst particle could
be a further evidence of an effective incorporating of TiCl4 with the polymer. The above result is
a clear indication of the chemical immobilization of the active catalyst on the support of PS.
<Figure 3>
The loading capacity of the polymeric catalyst based on its chloride content obtained by
gravimetric method and checked by atomic absorption technique was 0.824 mmol TiCl4/g of
complex catalyst beads [27]. The data obtained by these two techniques showed, within
experimental error, that the catalyzing species are in the form of TiCl4 supported on the
polymeric support.
To verify the incorporation of TiCl4 Lewis acid onto polystyrene, the corresponding structural
parameters such as surface area and total pore volumes of PS and PS/TiCl4 were caculated with
the Brunauer-Emmet-Teller (BET) method. In Table S1, porous structure parameters of the
studied PS and PS/TiCl4, and catalyst loading of PS/TiCl4 are presented. As BET surface area of
PS carrier bead is almost totally contributed by its open pore system, the catalytic functional
group prepared via this scheme should have been evenly confined in the pores. BET surface area
measurements indicated that, after immobilization, the BET surface area of PS decreased from
42 to 12.24 m2/g and pore volume decreased from 0.14 to 0.035 ml/g which was attributed to the
surface functionalization in the PS support (the loading of TiCl4 in the pores). The reduction of
both surface area and pore volume of the catalyst compared to the original PS support confirms
the presence of Lewis acid moieties within the pores of the support. The structure of the parent
material (polymer chain) was unaffected after this step; however, a decrease in the PS surface
area, as well as some blockage of pores and a slight decrease in the mean pore size are observed,
as expected (Table S1, supplementary data).
3. 2. Catalytic activity of the PS/TiCl4 complex on synthesis of polysubstituted piperidin-4-ones 4
Among a number of metal chlorides used in organic synthesis, anhydrous titanium tetrachloride
is undoubtedly one of the most effective and strong Lewis acid catalysts and shows unique
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reactivity in various organic and polymerization reactions [29]. However, it is found to be highly
toxic, corrosive, and moisture sensitive, and so its usage, storage, and separation from the
reaction mixture were invariably difficult; the strictly anhydrous conditions and stoichiometric
amounts or more are required in order to achieve good yields. Moreover, several molar
equivalents of triethylamine to titanium tetrachloride are also needed to improve the reaction
yields [30,31]. Therefore, this study aimed at developing a non-toxic, low cost, environmental-
friendly, readily available heterogeneous catalyst with high activity, simple preparation and
capable of reuse by incorporation of TiCl4 on the organic PS support. The resulting polymer
protected reagent, a stable tightly bound complex between anhydrous TiCl4 and PS-DVB
copolymer beads was used for one-pot, three-component synthesis of polyfunctionalized
piperidin-4-one compounds via a modified Mannich type reaction. The complex of the polymer
and TiCl4 provides a shelf-stable acidic, water tolerant material and it is not easily hydrolyzed by
water.
To examine the catalytic behaviour of PS/TiCl4 complex and find the optimum conditions in the
three-component modified Mannich condensation, the reaction of benzaldehyde (2 mmol),
ammonium acetate (1 mmol), and butan-2-one (1 mmol) was chosen as a model. The effects of
temperature, catalyst concentration, reaction media, and reaction time were investigated and the
results were summarized in Table 1. The initial reaction was carried out using 10 mol% of
PS/TiCl4 complex in ethanol at room temperature (Table 1, entry 10). The reaction yield was
36% after 6 h and increased with increasing temperature. The reaction temperature has a great
influence on the model reaction. The reactions were carried out in ethanol at different
temperatures ranging from 30 to 70 oC. It is clear that at lower temperatures, even if the time was
prolonged to 8 h, only low yields were obtained (Table 1, entries 10-12). The optimal
o
temperature was found to be 70 C with a 93% yield. The reason for requiring a higher
temperature was probably due to the weaker acidity of PS/TiCl4 compared to anhydrous TiCl4. In
addition, microporous pores and channels of polystyrene were unfavorable for the molecular
mass transfer process. Next, we examined the effect of the amount of catalyst on the reaction and
it was found that the catalyst dosage was also an important factor for the reaction, as 8 mol% of
PS-TiCl4 gave a yield of 82% after 4 h while 10 mol% of PS-TiCl4 was sufficient to give the
yield of 93% after 1 h. A control experiment was conducted in the absence of PS-TiCl4. This
afforded the desired product 4a in only 34 % yield after 16 h (Table 1, entry 7) and necessitate a
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tedious work-up procedure, including the conversion of the product to its hydrochloride salt,
performed according to the conventional method in literature [20], but on adding 5 and 8 mol%
catalyst to the system under similar conditions the rate of reaction was obviously accelerated, but
the yields were unsatisfactory. Increasing the amount to 10 mol% not only increased the yield
but also shortened the reaction time (Table 1, entries 8,9,11).
The choice of the solvent appeared crucial in order to maximize yield. Among the various
solvents surveyed, the highest yield was obtained in C2H5OH (Table 1, entries 1-5,12). The
highest yield obtained by using C2H5OH as the solvent can be ascribed to the fruitful swelling of
the polymer network of the catalyst and miscibility with the substrates in this media, allowing the
metal particles located inside the polymer matrix to effect the catalysis. No reaction occurred
when H2O was used as solvent, may be because of aggregation of the catalyst, caused by its
hydrophobic nature, led to inadequate access of the substrates to the active sites of the catalyst
(Table 1, entry 6). Among the various solvents tested, ethanol serve to swell the polymer and
make the titanium chloride more accessible. To confirm the activity of PS-TiCl4 complex, a
comparison experiment was carried out by using PS carrier alone under the same experimental
conditions, the desired adduct product in 34% yield was isolated (Table 1, entry 13). This
indicated that the PS itself did not promote the reaction and the catalytic activity arises from the
Lewis acid TiCl4 moiety of the polystyrene-supported catalyst. Also, PS/TiCl4 was found to be a
more effective catalyst than PS/AlCl3 for the synthesis of 4a under identical conditions (Table 1,
entry 16). In order to compare the catalytic activity of the homogeneous phase and
heterogeneous phase at the same reaction conditions and to clarify the role of the carrier PS, we
have performed the catalytic model reaction in the presence of the corresponding soluble
monomer analog, ethylbenzene-TiCl4 complex as the homogeneous phase in C2H5OH at the
same conditions (Table 1, entry 14) and the homogeneous complex afforded 4a in 82% yield.
The surface area is absent in the homogeneous catalyst of ethylbenzene-TiCl4. Thus, the yield of
the condensation product over PS/TiCl4 is much higher than the homogeneous complex catalyst.
We have also performed the model reaction in the presence of TiCl4 as the homogeneous phase
at the same experimental conditions and afforded the sticky undesired product (Table 1, entry
17). This data clearly suggests that the microporous polystyrene as support plays a crucial role in
this condensation reaction. The more efficient accessibility of the reactants to the catalyst's active
sites is probably the main reason for the improvement in the yield compared to TiCl4. On
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complexation of PS support with TiCl4, it is stabilized due to the decreased mobility of the
benzene rings hindered by the long polystyrene chain and no need the several equivalents of
organic base such as, triethylamine to stabilize TiCl4 and the improve of reaction yields [29,30].
Thus, the yield of the condensation product over our reusable and heterogeneous polystyrene-
supported TiCl4 is much higher than the homogeneous TiCl4 free form and also could be avoid
tedious extra wok-up after completion of the reaction and reduce the amount of acidic waste
water generated.
To realize whether the reaction occurred in the solid matrix of the supported catalyst or whether
TiCl4 simply released into the ethanol was responsible for the reaction, catalyst PS/TiCl4 was
stirred in ethanol for 20 min and then isolated by filtration. When the reactants were added to the
filtrate and stirred for 2.5 h, gave a low yield 35 % (Table 1, entry 15). These results indicated
the reaction takes place in the solid matrix and that release of TiCl4 is negligible. Moreover, To
rule out the presence of concurrent homogeneous catalysis, the model reaction was carried out in
the presence of the PS/TiCl4 catalyst until the conversion was about 50 % (30 min) and at that
point the catalyst was removed by filtration. Further treatment of the filtrate under similar
reaction condition did not proceed significantly (Table 1, entry 18). Additionally, the ethanol-
treated PS/TiCl4 catalyst was used for the synthesis of 4a under identical conditions. It was
observed that the yield of desired product was almost the same as its yield by using the pristine
PS/TiCl4 (Table 1, entry 19).
<Table 1>
To check the reusability of the catalyst, the model reaction to provide 4a under the conditions
described was run for four consecutive cycles, furnishing the corresponding product in 93, 92,
89, 87% isolated yields, which proved the efficiency of the catalyst for multiple usage (Table 2).
Even though after four consecutive cycles run for the reaction, the catalytic activity of PS/TiCl4
did not decrease dramatically. The gradual decrease in catalytic activity may be due to blocking
of some active sites on the catalyst surface by the residues of the reaction. Furthermore, there
were no significant differences between the IR spectra of the initial and spent catalyst, which
may indicate there was no degradation of the supported catalyst. The extent of titanium ion
leaching from the catalyst was very low (<14-16 ppm) as judged by ICP analysis.
<Table 2>
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Encouraged by the results described above, the one-pot condensation of substituted piperidin-4-
ones 4 catalyzed by PS/TiCl4 complex catalyst was extended to other aromatic aldehydes and
ketones to explore the scope of this procedure. The results are summarized in Table 3.
Accordingly, a variety of substrates were submitted to the optimum reaction conditions, and the
desired products were obtained in high yields. As can be seen from the results in Table 3,
aromatic aldehydes containing both electron-withdrawing and electron-donating groups reacted
smoothly with butan-2-one, pentan-2-one, and pentan-3-one to produce high yields of products.
The yields obtained were good to excellent without the formation of any side products. We
observed, irrespective, of groups on the aromatic ring, that the reaction time and yields are
almost close to each other.
<Table 3>
4. Conclusion
The polymer carriers, DVB-PS copolymers were synthesized by aqueous cross-linking
suspension radical copolymerization of styrene-divinylbenzene (with varying ratios of DVB)
monomers using biopolymers as a suspension stabilizer and the polymer-supported TiCl4 catalyst
was prepared by complexation of PS with TiCl4 in an one step reaction without functionalization
of the polymer matrix. PS/TiCl4 was shown to be an efficient and recyclable catalyst for the
modified Mannich condensation reaction of ketones, aromatic aldehydes, and ammonium
acetate. The advantage of this approach is to prepare catalyst displaying good activity,
selectivity, and reproducibility typical of homogeneous catalysts, combined with the
easy separability and recovery characteristics of heterogeneous catalysts.
Acknowledgements
The authors are thankful to TPC for providing the required chemicals and the Shahid Beheshti University
Research Council for partial support of this work.
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Figures/Schemes captions
Scheme 1 Synthesis of substituted piperidin-4-one derivatives catalyzed by PS/TiCl4 complex
Scheme 2 Synthesis of polymeric carrier and its titanium tetrachloride complex
Figure 1 TGA thermograph of DVB-crosslinked PS carrier (up) and PS/TiCl4 complex catalyst
(down)
Figure 2. DSC thermograph of the copolymer beads (PS/DVB) with 4 and 8 wt.% DVB (top and
bottom, respectively)
Figure 3. SEM images of PS carrier (up), PS/TiCl4 (down) samples
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Tables file
Table 1
Optimization of the PS/TiCl4 complex-catalyzed one-pot reaction of
ammonium acetate, benzaldehyde, and butan-2-one.a
Entry
Solvent
Catalyst (mol %)
Time (h)
Yieldb (%)
1
Toluene
THF
10
10
10
10
10
10
-
8
32
48
45
56
55
NRd
34
61
82
41
81
93
34
82
35
80
83
69
92
2
8
3
CHCl3
8
4
DMF
8
5
CH3CN
H2O
8
6
7c
8
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
16
8
5
8
9
8
4
10e
11f
12g
13h
14i
15j
16k
17l
18m
10
10
10
-
8
5
1
8
-
2.5
10
10
10
10
10
20 min
3
2
0.5
1
19n
a
Reaction conditions: benzaldehyde (2 mmol), ammonium acetate(1 mmol), 2-butanone (1 mmol),
b
c
solvent (6 mL), room temperature (refers here to 30 oC). Isolated yield. No catalyst.
d
h
j
e,f,g
NR: No reaction.
The reactions were conducted at r.t., 60 and 70 oC, respectively.
i
PS was used as catalyst. The ethylbenzene-TiCl4 complex was used as catalyst.
k
Catalyst was stirred in ethanol and filtered after 20 min. PS/AlCl3 (capacity: 0.47 mmol/g) was
l
m
n
used as catalyst. TiCl4 was used as catalyst. Catalyst was filtered after 30 min. Ethanol-treated
PS/TiCl4 (refluxing in ethanol for 1 h) was used as catalyst.
1

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Table 2
Recycling potential of the PS/TiCl4 for the synthesis of 4a.a
No of cycles Fresh Run 1 Run 2 Run 3 Run 4 Run 5
Yieldb(%)
Time (h)
93
1
92
1
89
1
87
87
2
85
1.4
2.5
a Reaction conditions: benzaldehyde (2 mmol), ammonium acetate (1 mmol),
butan-2-one (1 mmol), 70 oC, catalyst (10 mol%).
b Isolated yield of pure product.
Table 3
PS/TiCl4- catalyzed synthesis of 3,5-dialkyl-2,6-diarylpiperidin-4-one derivatives 4.
Entry
R
R1
R2
Product
Time (h) Yieldc(%) mp (oC) Ref.
1
2
3
4
5
6
7
8
H
CH3
CH3
CH3
CH3
C2H5
C2H5
C2H5
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
1
2
2.5
2.5
1
2
1.5
2
1.5
2
2
1.5
3
3
93
92
88
90
92
86
92
88
86
84
91
91
87
86
89
86-87[21]
4-OCH3
4-Br
4-CH3
H
4-Br
4-Cl
138-139[22]
114-116[26]
125-126 [22]
110-111[26]
98-100 [26]
111-113[26]
52-54 [26]
4-CH(CH3)2 C2H5
CH3
4-CH(CH3)2 CH3
9
H
133-134[21]
79-80 [26]
10
11
12
13
14
4-OCH3
4-CH3
3-OCH3
3-OCH3
d
CH3
CH3
CH3
C2H5
CH3
140-142[21]
148- 150[21]
95-97[22,26]
77-79[22,26]
193-194
H
H
15d
2.5
a
Reaction conditions: All reactions were conducted with aromatic aldehydes (2, 2 mmol)
(3, 1 mmol), ketone (1, 1 mmole) using PS/TiCl4 (10 mol%) in ethanol (6 mL) at 70 oC.
All of the known products were characterized by comparison of their melting points, IR, and 1H NMR spectra
,
ammonium acetate
b
c
d
with those of authentic samples. Yields refer to the isolated products. 1-naphthaldehyde was used.
2

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Schemes / Figures file
Scheme 1 Synthesis of substituted piperidin-4-one derivatives catalyzed by PS/TiCl4
complex
XG
or
XG/PVA
Cl
Ti
TiCl4
H2O, NaCl
Cl
Cl
CS2
or
CCl4
AIBN
Suspension
polymerization
Cl
Cl Ti Cl
Cl
Cl
(DVB)
(St)
PS/TiCl4
Complex
DVB-crosslinked PS
Scheme 2 Synthesis of polymeric carrier and its titanium tetrachloride complex
1

ACCEPTED MANUSCRIPT
Figure 1 TGA thermograph of DVB-crosslinked PS carrier (up) and PS/TiCl4 complex catalyst
(down)
2

ACCEPTED MANUSCRIPT
Figure 2. DSC thermograph of the copolymer beads (PS/DVB) with 4 and 8 wt.% DVB (top and
bottom, respectively)
3

ACCEPTED MANUSCRIPT
Figure 3. SEM images of PS carrier (up), PS/TiCl4 (down) samples
4

ACCEPTED MANUSCRIPT
Highlights
• Polystyrene copolymer beads were prepared by cross-linking suspension copolymerization.
•Polystyrene-TiCl4 coordination complex was prepared through finctionalization of polystyrene.
•A tightly bound complex, polystyrene-TiCl4 was efficient for the modified Mannich reaction.
•The polymeric catalyst was recovered and reused several times