Titanium tetrachloride incorporated crosslinked polystyrene copolymer as an efficient and recyclable polymeric Lewis acid catalyst for the synthesis of Β-amino carbonyl compounds at room temperature

Article abstract of DOI:10.1080/00397911.2019.1650379

An efficient and eco-friendly procedure for one-pot synthesis of β-amino carbonyl compounds by three-component reaction of aromatic aldehydes, acetophenone, and aromatic amines via a Mannich type reaction using a stable tightly bound complex, titanium tetrachloride incorporated crosslinked polystyrene copolymer (PS/TiCl₄), as a water tolerant, recoverable, and reusable polymeric Lewis acid catalyst in ethanol at room temperature is reported. The complex of the polystyrene and TiCl₄ provides a shelf-stable acidic, water tolerant material, and it is not easily hydrolyzed by water. Our findings thus show a novel and improved modification of the Mannich type reaction in terms of mild reaction conditions, clean reaction profiles, applicability to various substrates using a simple workup procedure which makes this reaction an interesting alternative to previously applied procedures. The recyclability of the catalyst makes this protocol environmentally benign.

Full text of DOI:10.1080/00397911.2019.1650379

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Titanium tetrachloride incorporated crosslinked
polystyrene copolymer as an efficient and
recyclable polymeric Lewis acid catalyst for the
synthesis of Β-amino carbonyl compounds at
room temperature
Ali Rahmatpour, Reza Eeimen & Niloofar Goodarzi
To cite this article: Ali Rahmatpour, Reza Eeimen & Niloofar Goodarzi (2019): Titanium
tetrachloride incorporated crosslinked polystyrene copolymer as an efficient and recyclable
polymeric Lewis acid catalyst for the synthesis of Β-amino carbonyl compounds at room
temperature, Synthetic Communications, DOI: 10.1080/00397911.2019.1650379
To link to this article: https://doi.org/10.1080/00397911.2019.1650379
Published online: 27 Aug 2019.
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SYNTHETIC COMMUNICATIONSV
https://doi.org/10.1080/00397911.2019.1650379
Titanium tetrachloride incorporated crosslinked polystyrene
copolymer as an efficient and recyclable polymeric Lewis
acid catalyst for the synthesis of B-amino carbonyl
compounds at room temperature
Ali Rahmatpour , Reza Eeimen, and Niloofar Goodarzi
Polymer Research Laboratory, Faculty of Chemistry, Shahid Beheshti University, Tehran, Iran
ABSTRACT
ARTICLE HISTORY
Received 10 May 2019
An efficient and eco-friendly procedure for one-pot synthesis of
b-amino carbonyl compounds by three-component reaction of aro-
matic aldehydes, acetophenone, and aromatic amines via a Mannich
type reaction using a stable tightly bound complex, titanium tetra-
chloride incorporated crosslinked polystyrene copolymer (PS/TiCl4),
as a water tolerant, recoverable, and reusable polymeric Lewis acid
catalyst in ethanol at room temperature is reported. The complex of
the polystyrene and TiCl4 provides a shelf-stable acidic, water toler-
ant material, and it is not easily hydrolyzed by water. Our findings
thus show a novel and improved modification of the Mannich type
reaction in terms of mild reaction conditions, clean reaction profiles,
applicability to various substrates using a simple workup procedure
which makes this reaction an interesting alternative to previously
applied procedures. The recyclability of the catalyst makes this proto-
col environmentally benign.
KEYWORDS
b-Carbonyl compounds;
cross-linked polystyrene;
heterogeneous catalysis;
Lewis acid; macromolecular
support; Mannich reaction;
polystyrene-sup-
ported catalyst
GRAPHICAL ABSTRACT
Introduction
Lewis acid-catalyzed reactions are among the less environmentally friendly industrial
processes, hence there is a real and urgent necessity to develop heterogeneous solid
Lewis acid catalysts for this reaction type. One way to convert corrosive strong Lewis
acids into environmentally friendlier catalysts is to heterogenize soluble Lewis acids
CONTACT Ali Rahmatpour
a_rahmatpour@sbu.ac.ir
Polymer Research Laboratory, Faculty of Chemistry, Shahid
Beheshti University, PO Box 19839-4716, Tehran, Iran.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
A. RAHMATPOUR ET AL.
used in liquid-phase reactions by supporting them on high-surface-area solids such as
Al2O3, zeolites, clays, etc.[1,2] The type of material used as support frequently plays a
crucial role in the performance of the resulting supported catalyst. Polymer supports,
also referred to as polymeric reagents and functional polymers, are beaded or micro-
spherical polymer products with a particle size range of about 5–500 lm.[3] Basically,
the support has to be thermally and chemically stable during the reaction process and
has to provide accessibility and good dispersion of the active sites. Organic polymers as
supports provide several potential advantages over the inorganic materials. Many poly-
mers are chemically inert over a large span of pH values (acidic and basic) and resistant
to microbiological attack. Polymers allow a large variation of morphology as indicated
by the shape, form, cross-linker content, and swellability, allowing the synthesis of
highly swellable non-porous as well as highly porous non-swellable materials as films,
pellets, powders, or beads. Other great advantages of polymers are their large loading
capability of active sites and the wealth of different routes of modification and chemical
functionalization. Cross-linked polystyrenes form the basis of many commercial polymer
catalysts.[4–6] Due to its large chemical tolerance towards acids and bases, while being
widely functionalizable at the aromatic rings, it offers versatile catalyst support, espe-
cially for organic synthesis and industrial processes carried out below approxi-
mately 200 ꢀC.
TiCl4 is an acid catalyst in a homogeneous medium. A wide variety of reactions in the
homogeneous phase employing TiCl4 as an efficient catalyst is reported in the literature.[7–10]
Though there are numerous advantages in a homogeneous environment, the major draw-
backs of TiCl4 as a catalyst lie in its corrosive nature, moisture sensitivity, less stability at
room temperature, risks in handling, a hazardous nature, disposal and regeneration due to
its toxic and corrosive nature, containment, and difficulties in separation from reaction mix-
ture. Moreover, reports on the safety of titanium tetrachloride show that its toxicity is high
(LD50 ¼ 464 mg/kg).[11] Therefore, heterogenization of TiCl4 with suitable catalyst support
is an efficient way to find new environmentally friendly catalyst with high catalytic potential.
From the standpoint of environmentally benign organic synthesis, the development of
highly active and easily reusable immobilized catalysts and the use of benign solvent such as
ethanol instead of organic solvent are of great interest to chemists.
Among nitrogen-containing compounds, b-amino carbonyl scaffolds are gaining
importance in organic chemistry because of their abundance in a variety of naturally
occurring products and biologically active compounds.[12] b-Amino ketone derivatives
are generally prepared by one-pot three-component reaction of a ketone, an aldehyde,
and an amine via a Mannich type reaction using various catalysts with in situ formation
of imines from aldehydes and amines that allows for a wide range of structural varia-
tions. Because of the importance of different b-amino ketone derivatives, various cata-
lytic procedures involving aldehydes, ketones, and arylamines using Lewis acid catalysts
such as metal triflates and –chlorides,[13–22] Bronsted and heteropoly acid cata-
€
lysts,[23–25] organocatalysts,[26–31] ionic liquids,[32–36] SiO2–OSO3H, SiO2–AlCl3,[37,38]
and recently nanoparticles have been developed for the synthesis of this nitrogen-con-
taining compound.[39,40] However, some of the reported methods suffer from one or
more of the disadvantages such as the use of a large amount of catalysts, toxic reagents
and solvents, and unsatisfactory reaction times and yields. Most importantly, most

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SYNTHETIC COMMUNICATIONSV
3
catalysts suffer from the drawback of difficult separation after the reactions and there-
fore are incapable of being recycled and reused. Furthermore, some of them are corro-
sive and volatile and often cause environmental problems, which limit their use in the
synthesis of nitrogen-containing important compounds. Hence, an environmentally
benign methodology for the preparation of such compounds is of great concern in syn-
thetic organic chemistry.
Recently, we have successfully synthesized the cross-linked polystyrene copolymer
beads with the given particle size and morphology by carrying out aqueous cross-linking
suspension copolymerization and incorporated lewis acids into the framework of cross-
linked polystyrene copolymer beads, combining the properties such as catalyst selectivity
and activity with the ease of separation and catalyst reuse.[41] Immobilizing homoge-
neous Lewis acids such as TiCl4 on crosslinked PS as a support in one step without
functionalization of the copolymer bead matrix via complex formation (PS/TiCl4) is a
suitable strategy to create surface-active acidic sites on polystyrene and the resulting
polymeric lewis acid can be effective as a heterogeneous catalyst for organic transforma-
tions. It has several advantages such as mild acidity, nontoxic nature, safe, easy to han-
dle and store, stability at high temperature and provides experimental simplicity.
In the continuation of our research in using recoverable polymeric acids as catalysts
in organic transformation,[42–44] in this letter, we present the results of an extended
investigation on the activity of the titanium tetrachloride-functionalized crosslinked
polystyrene, a stable tightly bound complex PS/TiCl4, as a recyclable catalyst in
Mannich reactions leading to the formation of b-amino ketone derivatives. We have
developed a convenient synthetic method for one-pot synthesis of b-amino carbonyl
compounds 4a-r via the condensation of acetophenone 1, aromatic aldehydes 2 and
aromatic amines 3 in the presence of TiCl4-incorporated crosslinked polystyrene as a
heterogeneous polymeric Lewis acid catalyst at room temperature in high yields
(Scheme 1). The reaction takes place in ethanol as a green reaction medium at ambient
temperature. To the best of our knowledge, this is the first report for the synthesis of
b-amino carbonyl compounds over titanium tetrachloride-incorporated crosslinked
polystyrene copolymer.
Results and discussion
The polymeric carrier beads (PS/DVB) as supports were readily synthesized by an aque-
ous suspension radical copolymerization technique using styrene and divinylbenzene
CHO
NH2
R'
R
(10 mol %)
O
HN
O
PS/TiCl4
C2H5OH, r.t
Ph
Ph
CH3
R
R'
1
2
3
4
Scheme 1. Mannich reaction of acetophenone and various aromatic aldehydes and aromatic amines
catalyzed by PS/TiCl4.

4
A. RAHMATPOUR ET AL.
XG
or
XG/PVA
Cl
Ti
H2O, NaCl
TiCl4, r.t
Cl
Cl
CS2
or
CCl4
AIBN, 80oC
Suspension
Cl
Cl
Ti
Cl
polymerization
Cl
Cl
(St)
(DVB)
PS/TiCl4
Complex
DVB-crosslinked PS
Scheme 2. Schematic representation of the procedure for the synthesis of polymeric carrier and its
titanium tetrachloride complex.
monomers as we described previously.[41] The incorporation of homogeneous titanium
tetrachloride Lewis acid into the framework of cross-linked polystyrene copolymer beads
was achieved by the addition of two components in dry CCl4 or CS2 solvent under
reflux conditions in a one-step reaction leading to the polystyrene-supported TiCl4 cata-
lyst (0.824 mmol gꢁ1- TiCl4 loading). The procedure for the synthesis of (PS/TiCl4) is
depicted in Scheme 2. The complex formation takes place via the formation of a coord-
ination bond between the TiCl4 and the PS carrier. The incorporation of TiCl4 Lewis
acid onto polystyrene was verified by FT-IR, UV, pH measurement, TGA, XRD, SEM,
BET and ICP techniques (see supplemenrtary data).
To validate our hypothesis and achieve catalytic evaluation of PS/TiCl4 complex, we
took the synthesis 4a from aniline, benzaldehyde, and acetophenone as the model reac-
tion. The results are summarized in Table 1. A blank reaction was carried out using
equivalent amounts of aniline, benzaldehyde, and acetophenone. The reaction was con-
ducted at room temperature in ethanol; even after 8 h, no product was obtained. The
same reaction was performed using PS/TiCl4 as the catalyst and ethanol as a reaction
medium at room temperature. Surprisingly, 93% yield of desired product was obtained
after stirring the reaction mixture for 2.1 h (Scheme 2). Initial experiments, 10 mol% of
catalyst was tested using 1.0 mmol of each substrate in ethanol at room temperature for
2.1 h. We further investigated the optimum reaction conditions using different amounts
of PS/TiCl4 and it was found that the yields were obviously affected with different
amount of catalyst. An increase in the quantity of PS/TiCl4 from 2 to 5 mol% not only
decreased the reaction time from 8 to 5 h, but also increased the product yield slightly
from 43 to 69% (Table 1, entries 8,9). This showed that the catalyst concentration plays
a major role in the optimization of the product yield. No reaction was observed in the
absence of catalyst, while 10 mol% of PS/TiCl4 was sufficient to drive the reaction com-
pletely and an excessive amount of catalyst did not increase the yields significantly
(Table 1, entries 7,10). Subsequently, various solvents were screened in the same reac-
tion condition. Results demonstrated that the high yield of desired product 4a was
achieved with ethanol solvent. The reaction in toluene afforded very poor yields whilst
the use of THF, CHCl3, CH3CN, and DMF afforded moderate yields (Table 1, entries
1-5). Ethanol was chosen as the solvent system for this conversion, because of its swell-
ability with the catalyst and miscibility with the substrates. No reaction occurred when
H2O was used as a solvent, maybe because of the aggregation of the catalyst, caused by

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5
Table 1. Optimization of the reaction conditions of the PS/TiCl4-catalyzed one-pot reaction of aceto-
phenone, benzaldehyde, and anilinea.
Entry
Solvent
Catalyst (mol %)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7c
8
9
10
11e
12f
13g
14h
15i
16j
Toluene
THF
CHCl3
DMF
CH3CN
H2O
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
C2H5OH
10
10
10
10
10
10
–
2
5
10
10
10
–
8
8
8
8
8
8
8
8
5
2.1
1.5
1.1
6
2.5
0.5
3.5
34
48
45
56
55
NRd
NR
43
65
93
81
70
NR
46
NR
75
–
10
10
aReaction conditions: benzaldehyde (1 mmol), aniline(1 mmol), acetophenone (1 mmol), ethanol (3 mL), room tempera-
ture (refers here to 30 ꢀC).
bIsolated yield.
cNo catalyst.
dNR: No reaction.
e,fThe reactions were conducted at 60 and 80 ꢀC, respectively.
gPS was used as catalyst.
hThe ethylbenzene-TiCl4 complex was used as catalyst.
iCatalyst was filtered after 50 min.
jPS/AlCl3 (capacity: 0.47 mmol/g) was used as a catalyst.
its hydrophobic nature, led to inadequate access of the substrates to the active sites of
the catalyst (Table 1, entry 6). Finally, the data in Table 1 demonstrates the susceptibil-
ity of the reaction to the solvent in which the reactions carried out. Thus, for the model
reaction, much higher product yields are obtained with solvents capable of swelling the
polymer. Among the various solvents tested, ethanol serves to swell the polymer and
make the titanium chloride more accessible.
To optimize the reaction temperature, we carried out a study using the model
substrates in ethanol at different temperatures (Table 1, entries 11,12). Increasing the
temperature to 80 ꢀC favored side reactions and the formation of deeply colored
products. If the reaction runs at refluxing temperature, no Mannich reaction base
can be isolated. Decreasing the temperature decreases the rates of the reaction and
also the rates of the side reactions. It was found that the room temperature was an
appropriate condition in terms of reaction time and yield obtained for PS/TiCl4-cata-
lyzed one-pot three-component Mannich reaction. After several trials, the best result
with 93% yield was obtained by carrying out the reaction with 1:1:1:0.1 molar ratio
of acetophenone, benzaldehyde, aniline, and PS/TiCl4 complex at room temperature
in 3 ml of ethanol for 2.1 h.
In order to compare the catalytic activity of the homogeneous phase and heteroge-
neous phase at the same reaction conditions and to clarify the role of the cross-linked
PS, we have performed the catalytic reaction of acetophenone, benzaldehyde and aniline
in the presence of ethylbenzene-TiCl4 as the homogeneous phase at room temperature
in C2H5OH (Table 1, entry 14). The surface area is absent in the homogeneous catalyst
of ethylbenzene-TiCl4. Thus, the yield of the condensation product over PS/TiCl4 is

6
A. RAHMATPOUR ET AL.
R'
O
HN
4
NH2
CHO
O
PS/TiCl4, 10 mol%
C2H5OH, r.t
R
CH3
R'
R
3
1
2
Scheme 3. Synthesis of b-carbonyl compounds from acetophenone and various aromatic aldehydes
and aromatic amines catalyzed by PS/TiCl4.
much higher than the homogeneous complex catalyst. To confirm the catalytic activity
of PS/TiCl4, a comparison experiment was carried out by using pristine PS alone under
the same experimental conditions; no reaction occurred and the starting components
remained unreacted (Table 1, entry 13). This indicated that the PS itself did not pro-
mote the reaction. 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).
To discover whether the reaction occurred in the solid matrix of the supported cata-
lyst or whether TiCl4 simply released into the ethanol was responsible for the reaction,
catalyst PS/TiCl4 was stirred in ethanol for 50 min and then isolated by filtration. When
the reactants were added to the filtrate and stirred for 2.5 h, no reaction took place
(Table 1, entry 15). These results indicated that the reaction takes place in the solid
matrix and the release of TiCl4 is negligible.
Due to the success of the above reaction, the substrates scope of this protocol was
then investigated using the optimized conditions. As shown in Scheme 3, a variety of
both aldehydes 2 and substituted anilines 3 were reacted with acetophenone 1 in the
presence of PS/TiCl4, to afford the desired b-amino carbonyl compounds 4a-r in good
to excellent yields (82–96%). The results are summarized in Table 2. Corresponding
product yields depended on steric hindrance and electronic effect of substrates.
Reaction of aromatic aldehyde substrates with an electron-withdrawing group (–Cl,
–NO2, including –H) produced good yields (Table 2, 12–16,18,1–9). While aromatic
aldehyde substrates with an electron-donating group (–OCH3,–CH3) provided products
in very good yields (Table 2, entries 10,11,17). Aromatic amine substrates (m-and p-sub-
stituted) gave good results, while o-substituted amines (Table 2, entry 3) failed to yield
any desired product due to steric hindrance of ortho-substituents. Furthermore, amines
bearing electron-withdrawing groups gave the desired product in good yields (Table 2,
entries 4, 6–9). The use of aliphatic aldehydes (such as butyl aldehyde, propionaldehyde,
and n-octanal) and aliphatic amines (such as propylamine, ethylamine, and benzyl
amine) failed to furnish the desired products, which implies that this reaction is limited
to nonenolizable imines. In addition, the heteroaromatic aldehydes, such as 2-thiophene
carboxaldehyde, was used as a starting material in our reaction conditions and well-
tolerated with this protocol and the results are now provided in Table 2 (entry 19).
A proposed mechanism for the synthesis of b-amino carbonyl compounds 4 is pre-
sented in Scheme 4. Initially, the complex formation increases the activity of the car-
bonyl carbon atom of aromatic aldehydes by which it undergoes nucleophilic attack by
amine and generates the imine intermediate II after dehydration. Next, the imine inter-
mediate activated by Ti(IV) as Lewis acid undergoes a nucleophilic attack by enol which

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7
Table 2. PS/TiCl4 catalyzed synthesis of various b-amino carbonyl compounds 4a,b
.
R'
O
HN
NH2
CHO
O
PS/TiCl4, 10 mol%
C2H5OH, r.t
R
CH3
4
R'
R
2
3
1
Entry
R
R’
Product
Time/h
Yieldc/%
M.p(oC) Found
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
4–CH3
2–CH3
4–Cl
4–OCH3
4–Br
4–NO2
3–NO2
H
H
H
H
H
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
4o
4p
4q
4r
2.1
2.5
8
2
2.1
93
96
Trace
90
161–162
94
82
91
89
95
94
93
89
88
87
90
91
85
168–169
168–170
–
167–168
2
182–184
184–185
138–139
192–194
130–132
149–150
128–129
108–110
102–104
119–121
128–129
159–160
131–133
172–173
2.5
2.1
2.5
3.1
3.1
2.1
2.1
2.3
2.5
3.5
2.2
3
9
H 4–CO2
4–CH3
4–OCH3
4–Cl
4–NO2
F
10
11
12
13
14
15
16
17
18
19
H
4–Cl
4–Cl
4–Cl
4–Cl
3–NO2
H
4–NO2
4–OCH3
4–Cl
2–Thienyl
4s
2.5
90
aReaction conditions: All reactions were conducted with aniline (3a, 1 mmol), benzaldehyde (2a, 1 mmol), acetophenone
(1, 1 mmole) using PS/TiCl4 (10 mol%) in ethanol (3 mL) at room temperature.
bAll products were characterized by comparison of their melting points, IR, and 1H NMR spectra with those of authentic
samples.[20,21,38,39,47–50]
cYields refer to the isolated products.
in turn converts to the final product and simultaneously releases the catalyst for the
next catalytic cycle. We monitored aldehyde consumption by GC analysis and it turned
out that the Schiff base is formed (within the first 20 min of the beginning of the reac-
tion), indicating that the rate-determining step was to be the attack of in-situ generated
enolate I on the in-situ generated aldimine II as shown in Scheme 4. The proposed
mechanism is consistent with the literature.[48]
In order to verify the recyclability of the catalyst and if the catalyst could be reused, three-
component reaction under similar conditions, between benzaldehyde, aniline, and acetophe-
none, was taken as the representative case. After the reaction was over, the catalyst was sepa-
rated from the reaction mixture by filtration, washed with ethanol followed by diethyl ether.
Then, the recovered catalyst was dried at 50ꢀC under vacuum for 6 h and used for a further
five additional reaction cycles. In all cases, the PS/TiCl4 catalyst exhibited consistent catalytic
activity, establishing the recycling and reusability of the catalyst without any significant loss
in the yield of the product. Only a very small drop in the product yield in each catalytic cycle
is observed (Table 3). Along these lines, there were no significant differences between the IR
spectra of the fresh and recovered catalyst, which may indicate there was no degradation of
the supported catalyst. The extent of TiCl4 leaching from the catalyst was very low
(<10ppm) as judged by ICP analysis. From the first run to the fifth run, the titanium con-
tent of the recovered catalyst remained almost the same. All these results confirmed that our
catalyst is stable and has practical utility.

8
A. RAHMATPOUR ET AL.
TiCl4
-
O
H
2 O
Ar1
Ar1
H
N
II
Ar2
Ar2NH2
TiCl4
TiCl4
TiCl4
Ar2
O
HNAr2
Ar1
Ar1
H
N
Ph
TiCl4
O
O
Ph
CH2
CH3
Ph
I
Scheme 4. Proposed mechanism for the formation of 4.
Table 3. Recycling potential of the PS/TiCl4 for the Mannich reactiona.
No of cycles
Fresh
Run 1
Run 2
Run 3
Run 4
Run 5
Yieldb(%)
Time (h)
93
2.1
92
2.1
91
2.2
90
2.4
90
2.5
89
3
aReaction conditions: benzaldehyde (1 mmol), aniline (1 mmol), acetophenone (1 mmol), room temperature, cata-
lyst (10 mol%).
bIsolated yield of pure product.
In Table 4, the condition and efficiency of TiCl4-functionalized polystyrene copoly-
mer catalyst were compared with some other catalysts in the synthesis of 4a. The results
showed that in this work, disadvantages of some of the previous reports such as long
reaction times and low yields have been decreased. In addition, the efficiency of the pre-
sent reaction was increased.
Conclusion
In total, we presented a new catalytic protocol for the efficient synthesis of b-amino
ketone derivatives via one-pot three-component Mannich reaction of various aromatic
aldehydes, acetophenone, and aromatic amines in the presence of a tightly bound com-
plex of styrene-divinylbenzene copolymer/TiCl4 as a reusable polymeric Lewis acid

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SYNTHETIC COMMUNICATIONSV
9
Table 4. Comparison of the polymeric catalyst PS/TiCl4 with various homogeneous or heterogeneous
catalysts in Mannich reactions for the synthesis of 4a.
Entry
Catalyst
Solvent
T (oC)
Time (h)
Yield (%)
[Ref.]
1
2
3
4
5
6
BiCl3
H3Pmo12 O40
DBSA
FeCl3
NbCl5
EtOH
H2O
H2O
EtOH
EtOH
r.t.
r.t.
23
r.t.
r.t.
11
18
12
24
12
12
95
76
69
n.r.
95
98
[49]
[27]
[24]
[22]
[20]
[52]
Yb(OPf)3
PhCH3/C6F5CF3
Rare earth (III) perfluorooctane sulfonates
7
8
9
10
11
12
13
14
15
16
Pyridiniumtrifluoroacetate
[NaBArF4]
FeCl3
ZnCl2
SnCl2
SiO2/AlCl3
SiO2/SbCl3
PS-SO3H
Solvent-free
H2O
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
8
48
20
20
10
5
82
81
0
[53]
[51]
[38]
[38]
[54]
[38]
[55]
[56]
This work
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
0
93
93
93
75
75
93
4
24
3.5
2.1
PSt/AlCl3 (10 mol%)
PSt/TiCl4 (10 mol%)
EtOH
EtOH
This work
n.r.: no reaction; r.t. refers to 30 oC.
catalyst in ethanol medium. This method has the advantages of high yields, mild reac-
tion conditions, short reaction time, avoiding hazardous organic solvents, convenient
procedure, and environmental friendliness. The catalyst shows not only high catalytic
activity, but also offers many practical advantages such as thermal stability and recyc-
lability. Notably, the PS/TiCl4 catalyst could be recovered and reused several times with-
out a significant loss in its activity. The waste-free process combined with recovery and
reusability of the catalyst makes this method economic and benign for the synthesis of
b-amino carbonyl compounds.
Experimental
Materials and instrumentations
All of the information about the materials and instrumentations used in this work were
presented in the Supporting information.
Preparation of crosslinked-polystyrene carrier
The preparation of the support was designed by the sequence of reactions given in
Scheme 2. The cross-linked polystyrene copolymer beads were prepared and character-
ized as we described previously.[41]
Preparation of TiCl4-functionalized polystyrene copolymer
The as-prepared polystyrene beads (8% DVB) was dispersed in 6 mL of dry CCl4 (or
CS2) solvent and left to swell under intense stirring for 30 min at room temperature. A
solution of anhydrous TiCl4 (2 g) in dry carbon disulfide (4 mL) was added to the above
dispersion under magnetic stirring followed by refluxing in an oil bath for 1 h under a
nitrogen atmosphere. The reaction mixture was cooled to room temperature and cold

10
A. RAHMATPOUR ET AL.
water (50 mL) was then cautiously added to hydrolyze the uncomplexed TiCl4. Finally,
the solid was collected using the suction filtration followed by washing with diethyl
ether and chloroform and was dried in a vacuum oven overnight at 50 ꢀC. The loading
of TiCl4 measured by the Mohr titration method (0.824 mmol/g)
General procedure for the one-pot three-component Mannich-type reaction
A mixture of aromatic aldehydes (1 mmol), acetophenone (1 mmol), aromatic amines
(1 mmol), and PS/TiCl4 containing certain amount of TiCl4 (0.15 gr, 0.1 mmol of TiCl4)
in anhydrous ethanol (3 mL) was stirred at room temperature for a period of time listed
in Table 2 indicated by TLC or GC. After completion of the reaction, the 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 with ethanol and dried at 60 ꢀC
for 6 h and stored in a desiccator. The crude product was purified by recrystallization
from ethanol or ethanol-acetone (3:2, v/v) to afford the pure product. A 10 mmol-scale
reactions were also carried out without any difficulties. All of the products were charac-
1
terized by comparison of their physical data, FTIR, and H NMR spectra with those of
authentic samples.
The characteristic data of selected compounds
3-Anilino-1,3-diphenyl-1-propanone (Table 2, entry 1, 4a, C21H19NO)[39]
Colorless solid, mp ¼ 168–169 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3385 (NH), 2383, 1665 (CO), 1549,
1509, 1450, 1367, 1287, 1216, 1070, 992, 857, 743, 688 cmꢁ1 1H NMR (250 MHz,
.
CDCl3): d ¼ 7.90 (2H, d, J ¼ 8.50 Hz), 7.54 (2H, t, J ¼ 7.30 Hz), 7.22–7.46 (6 H, m), 7.10
(2H, t, J ¼ 7.50 Hz), 6.76 (1H, t, J ¼ 7.30 Hz), 6.69 (2H, d, J ¼ 7.8 Hz), 5.0 (1 h, t,
J ¼ 6.50 Hz), 3.59 (2H, d, J ¼ 5.80 Hz). 13C NMR (62.9 MHz, CDCl3): d ¼ 46.20, 55, 95.2,
114.0, 117.6, 118.10, 126.3, 125.1, 127.4, 128.2, 128.7, 128.8, 129.1, 129.3, 133.4, 136.6,
142.7, 146.6, 159.1, 179.2, 198.2. Anal. Calcd. for C21H19NO: C 83.69, H 6.35, N 4.65%;
Found: C 83.74, H 6.41, N 4.56%.
3-(4-chloro-phenylamino)-1,3-diphenylpropanone (Table 2, entry 4, 4d,
C21H18NO)[38,39]
Colorless solid, mp ¼ 167–168 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3369 (NH), 3010, 2320, 1661 (CO),
1594, 1490, 1448, 1405, 1280, 851, 745, 681 cmꢁ1 1H NMR (250 MHz, CDCl3):
.
d ¼ 3.41–3.50 (m, 2H), 4.65 (br, 1H), 4.92–4.94 (m,1H), 6.45–6.47 (m, 2H, ArH),
7.00–7.02 (m, 2H, ArH), 7.21–7.24 (m, 1H, ArH), 7.30–7.33 (m, 2H, ArH), 7.39–7.46
(m, 4H, ArH), 7.54–7.58 (m, 1H, ArH), 7.88–7.90 (m, 2H, ArH); 13C NMR (62.9 MHz,
CDCl3): d ¼ 46.3, 55.0, 115.0, 122.5, 126.4, 127.6, 128.3, 128.8, 129.0, 129.1, 133.6, 136.6,
142.6, 145.6, 198.3. Anal. Calcd. for C21H18NO: C 75.11, H 5.40, N 4.17%; Found: C
75.15, H 5.30, N 4.23%.

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11
3-(4-Methoxy-phenylamino)-1,3-diphenyl-propanone (Table 2, entry 5, 4e,
C21H22NO2)[21]
1
Colorless solid, mp ¼ 161–162 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3385 (NH), 1675 (CO) cmꢁ1. H
NMR (250 MHz, CDCl3): d ¼ 7.81 (d, J ¼ 7.5 Hz, 2H, Ar–H), 7.53–7.33 (m, 1H, Ar–H),
7.41–7.38 (m, 2H, Ar–H), 7.30–7.24 (m, 2H, Ar–H), 7.15 (d, J¼ 8.3 Hz, 2H, Ar–H),
6.96–7.05 (m, 1H, Ar–H), 6.71 (d, J ¼ 8.9, 2H, Ar–H), 6.51 (d, J¼ 8.6 Hz, 2H, Ar–H), 4.86
(t, 1H), 3.58 (s, 3H, –OCH3), 3.44–3.39 (m, 2H). 13C NMR (62.9 MHz, CDCl3): d ¼ 46.2,
55.3, 58.2, 115.2, 122.7, 126.2, 127.1, 128.6, 128.8, 128.9, 129.3, 132.5, 138.5, 141.7, 1510.2,
195.6. Anal. Calcd. for C21H22NO2: C 79.73, H 6.39, N 4.23%; Found: C 79.59, H 6.70,
N 4.38%.
3-(4-Bromoanilino)-1,3-diphenyl-1-propanone (Table 2, entry 6, 4f,
C21H18BrNO)[21]
Colorless solid, mp ¼ 182–184 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3380, 1676 cmꢁ1
.
1H NMR
(250 MHz, CDCl3): d ¼ 7.86 (2H, d, J ¼ 8.2 Hz), 7.51 (2H, t, J ¼ 7.3 Hz), 7.39 (2H, t,
J ¼ 7.5 Hz), 7.5 (2H, d, J ¼ 7.5 Hz), 7.20–7.28 (4H, m), 6.77 (2H, d, J ¼ 8.8 Hz), 4.99 (1H,
t, J ¼ 6.5 Hz), 3.85 (2H, d, J ¼ 6.5 Hz). 13C NMR (62.9 MHz, CDCl3): d ¼ 43.7, 59.1, 114,
114.9, 120.7, 121.2, 124.1, 127.9, 128.1, 128.6, 128.7, 128.9, 132.2, 133.6, 136.2, 137.6,
138, 139.3, 144.9, 162.9, 196.6. Anal. Calcd. for C21H18BrNO: C 66.32, H 4.77, N 3.66%;
Found: C 66.28, H 4.70, N 3.70%.
3-(4-Nitro-phenylamino)-1,3-diphenyl-propanone (Table 2, entry 7, 4 g,
C21H18N2O3)[21]
Colorless solid, mp ¼ 184–185 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3365 (NH), 1628 (CO) cmꢁ1
.
1H NMR (250 MHz, CDCl3): d ¼ 3.67 (d, J ¼ 6.80 Hz, 2H), 5.12 (t, 1H), 6.37 (brs, 2H,
Ar–H), 6.64 (d, J ¼ 6.4, 2H, Ar–H), 7.24–7.20 (m, 1H, Ar–H), 7.38–7.29 (m, 2H, Ar–H),
7.37 (d, J ¼ 7.70 Hz, 2H, Ar–H), 7.67–7.59 (m, 1H, Ar–H), 8.01 (d, J ¼ 7.2 Hz, 2H,
Ar–H). 13C NMR (62.9 MHz, CDCl3): d ¼ 45.2, 53.1, 111.7, 125.9, 126.1, 127.4, 128.9,
128.2, 128.1, 130.5, 132.8, 136.7, 138.6, 140.0, 197.8. Anal. Calcd. for C21H18N2O3: C
72.82, H 5.24, N 8.09%; Found: C 72.42, H 5.76, N 7.96%.
4-((3-oxo-1,3-diphenyl) propylamino)-benzoic acid (Table 2, entry 9, 4i,
C22H19NO3)[21]
Colorless powder, mp ¼ 192–194 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3368 (NH), 2947, 1669 (CO),
1
1608, 1273, 708 cmꢁ1. H NMR (250 MHz, CDCl3): d ¼ 11.90 (1H, s, COOH), 7.95 (2H,
d, J ¼ 7.46 Hz, ArH), 7.62 (1H, t, J ¼ 7.36 Hz, ArH), 7.58 (2H, d, J ¼ 8.79 Hz, ArH), 7.50
(2H, t, J ¼ 7.72 Hz, ArH), 7.42 (2H, d, J ¼ 7.43 Hz, ArH), 7.30 (2H, t, J ¼ 7.61 Hz, ArH),
7.19 (1H, t, J ¼ 7.33 Hz, ArH), 6.90 (1H, d, J ¼ 7.36 Hz, ArH), 6.50 (2H, t, J ¼ 8.73 Hz,
ArH), 5.55 (1H, m, NCH), 3.62 (1H, m, COCH2), 3.58 (1H, m, COCH2). Anal. Calcd.
for C22H19NO3: C 76.52, H 5.50, N 4.058%; Found: C 76.42, H 5.43, N 4.095%.

12
A. RAHMATPOUR ET AL.
3-Anilino-3-(4-methylphenyl)-1-phenyl-1-propanone (Table 2, entry 2,
4j, C22H21NO)[21]
Colorless powder, mp ¼ 130–132 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3387, 1667 cmꢁ1
.
1H NMR
(250 MHz, CDCl3): d ¼ 7.92, 2H, d, J ¼ 7.30 Hz), 7.55 (1H, t, J ¼ 8.80 Hz, 7.44 (2H, t,
J ¼ 7.80 Hz), 7.32, 2H, d, J ¼ 8.0 Hz), 7.05–7.15 (4H, m), 6.64 (1H, t, J ¼ 7.30 Hz), 6.58
(2H, d, J ¼ 8.80 Hz), 4.98 (1H, t, J ¼ 6.0 Hz), 3.50 (2H, d, J ¼ 5.50 Hz), 2.22 (3 H, s).
13C NMR (62.9 MHz, CDCl3): d ¼ 21.1, 46.2, 54.7, 114.0, 114.9, 118.0, 124.4, 126.3,
127.3, 127.9, 128.2, 128.6, 129.1, 129.4, 133.2, 136.3, 139.0, 141.7, 145.5, 147.9, 159.0,
199.10. Anal. Calcd. for C22H21NO: C 83.78, H 6.71, N 4.44%; Found: C 83.80, H 6.73,
N 4.39%.
3-Anilino-3-(4-methoxyphenyl)-1-phenyl-1-propanone(Table 2, entry 11, 4k,
C22H21NO2)[21]
1
Colorless solid, mp ¼ 149–150 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3401(NH), 1679(CO) cmꢁ1, H
NMR (250 MHz, CDCl3): d ¼ 7.92 (2H, d, J ¼ 8.3 Hz), 7.88, 1H, t, J ¼ 8.5 Hz), 7.45 (2H,
t, J ¼ 7.8 Hz), 7.34 (2H, d, J ¼ 8.8 Hz), 7.10 (2H, t, J ¼ 7.5 Hz), 6.8 (2H, d, J ¼ 8.8 Hz),
6.68 (1H, t, J ¼ 8.0 Hz), 6.60 (2H, d, J ¼ 7.5 Hz), 4.97 (1H, t, J ¼ 6.5 Hz), 3.80 (3H, s),
3.47 (2H, d, J ¼ 5.8 Hz). 13C NMR (62.9 MHz, CDCl3): d ¼ 46.2, 54.5, 55.2, 114.1, 114.2,
118.0, 123.2, 124.3, 124.9, 127.1, 127.5, 128.2, 128.7, 129.1, 133.3, 134.5, 136.1, 141.2,
145.7, 148.0, 158.8, 194.4. Anal. Calcd. for C22H21NO2: C 79.72, H 6.37, N 4.24%;
Found: C 79.69, H 6.44, N 4.19%.
[47]
3-Anilino-3-(4-chlorophenyl)-1-phenyl-1-propanone (Table 2[4l], C21H18ClNO)
Colorless solid, mp ¼128–130 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3380, 3020, 2370, 1675, 1596, 1511,
1
1404, 1289, 1089, 991, 825, 746, 687 cmꢁ1. H NMR (250 MHz, CDCl3): d ¼ 7.89 (2H, d,
J ¼ 7.0 Hz), 7.56–7.64 (2 h, m), 7.49 (2H, d, J ¼ 8.80 Hz), 7.42 (2H, d, J ¼ 9.0 Hz), 7.30
(1H, d, J ¼ 8.50 Hz), 7.11 (2 H, t, J ¼ 8.25 Hz), 6.70 (1H, t, J ¼ 8.0 Hz), 6.54 (2 H, d,
J ¼ 7.80 Hz), 4.99 (1H, t, J ¼ 6.50 Hz), 4.58 (1H, s), 3.46 (2H, d, J ¼ 5.80 Hz). 13C NMR
(62.9 MHz, CDCl3): d ¼ 46.1, 54.2, 113.8, 118.1, 122.5, 127.9, 128.2, 128.5, 128.6, 128.8,
128.9, 129.2, 129.6, 132.9, 133.4, 133.5, 136.6, 141.5, 143.2, 146.6, 197.8. Anal. Calcd. for
C21H18ClNO: C 75.11, H 5.40, N 4.17%; Found: C 75.14, H 5.33, N 4.24%.
3-Anilinio-3-(4-nitrophenyl)-1-phenyl-1-propanone (Table 2, entry 13,
4 m, C21H18N2O3)
1
White solid, mp ¼ 108–110 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3372 (NH), 1681 (CO) cmꢁ1, H
NMR (250 MHz, CDCl3): d ¼ 8.10 (2H, d, J ¼ 8.80 Hz), 7.89 (1H, d, J ¼ 8.0 Hz), 7.60
(2H, d, J ¼ 8.5 Hz), 7.57 (2H, t, J ¼ 7.3 Hz), 7.44 (2H, t, J ¼ 7.8 Hz), 7.11, 2H, t,
J ¼ 7.5 Hz), 6.70 (1H, d, J ¼ 7.30 Hz), 6.55 (2H, d, J ¼ 7.8 Hz), 5.10 (1H, t, J ¼ 6.0 Hz),
3.50 (2H, d, J ¼ 6.0 Hz). 13C NMR (62.9 MHz, CDCl3): d ¼ 45.5, 54.4, 114.1, 118.8,
123.6, 124.1, 124.2, 125.7, 127.5, 128.6, 128.8, 129.3, 129.6, 133.4, 133.8, 136.3, 141.5,
145.9, 147.2, 150.5, 197.1. Anal. Calcd. for C21H18N2O3: C 72.78, H 5.26, N 8.09%;
Found: C 72.76, H 5.28, N 8.15%.

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13
3-(4-Fluorophenyl)-1-phenyl-3-(phenylamino)propanone (Table 2, entry 14, 4n,
C21H18FNO)[38]
Colorless solid, mp ¼ 102–104 ꢀC, IR (KBr, cmꢁ1) ꢀ: 3380 (NH), 3020, 2312, 1672 (CO),
1
1600, 1548, 1507, 1425, 1167, 1102, 1062, 826, 746, 684 cmꢁ1. H NMR (250 MHz,
CDCl3): d ¼ 3.40–3.49 (m, 2H), 4.55 (br, 1H), 4.97 (t, 1H, J ¼ 7.3 Hz), 6.52–6.54 (m, 2H,
ArH), 6.67 (t, 1H, J ¼ 7.4 Hz, ArH), 6.97–7.01 (m, 2H, ArH), 7.07–7.11 (m,2H, ArH),
7.38–7.46 (m, 4H, ArH), 7.54–7.56 (m,1H, ArH), 7.88–7.90 (m, 2H, ArH). 13C NMR
(62.9 MHz, CDCl3): d ¼ 46.3, 54.2, 113.9, 115.6, 115.9, 118.1, 128.0, 128.1, 128.3, 128.8,
129.2, 133.7,146.8, 163.3, 198.2. Anal. Calcd. for C21H18FNO: C 78.999, H 5.642, N
4.388%; Found: C 78.78, H 5.65, N 4.95%.
Acknowledgments
The authors are thankful to TPC for providing the required chemicals.
Disclosure statement
There are no conflicts of interest to declare.
Funding
The authors are thankful to the Shahid Beheshti University Research Council for partial support
of this work [Grant No. 1396].
ORCID
Ali Rahmatpour
http://orcid.org/0000-0001-6524-7176
References
[1] Corma, A.; GarcıꢀA, H. Highly Efficient One-Pot Three-Component Mannich Reaction in
Water Catalyzed by Heteropoly Acids. Chem. Rev. 2003, 103, 4307–4365.
[2] Clark, J. H.; Macquarrie, D. J.; Price, P. M. Modified Silicas for Clean Technology. J.
Chem. Soc, Dalton Trans. 2000, 2, 101–110.
[3] Hodge, P. Synthesis of Organic Compounds Using Polymer-Supported Reagents,
Catalysts, and/or Scavengers in Bench Top Flow Systems. Ind. Eng. Chem. Res. 2005, 44,
8542–8553. doi:10.1021/ie040285e.
[4] Hodge, P. Organic Synthesis Using Polymer-Supported Reagents, Catalyst and Scavengers
in Simple Laboratory Flow Systems. Current Opinion in Chem. Biology 2003, 7, 362–373.
doi:10.1016/S1367-5931(03)00052-8.
[5] Barbaro, P.; Liguori, F. Heterogenized Homogeneous Catalysts for Fine Chemicals
Production: Materials and Processes; Springer: New York, 2010.
[6] Mathur, N. K.; Williams, R. E. Organic Syntheses Using Polymeric Supports, Polymeric
Reagents, and Polymeric Catalysts. J. Macromol. Sci.-Rev. Macromol. Chem. 1976, 15,
117–142. doi:10.1080/15321797608065776.
[7] Lehnert, W. Knoevenagel Kondensationen Mit TiCl4/base-IV: Umsetzungen Von
€
Aldehyden Und Ketonen Mit Phosphonoessigester Und Methylendiphosphonsaureestern.
Tetrahedron. 1974, 30, 301–305. doi:10.1002/chin.197421307.

14
A. RAHMATPOUR ET AL.
[8] Lehnert, W. Knoevenagel-Kondensationen Mit TiCl4/base-VI. 3-Alkyliden- Und 3-
Aryliden-2,4-Pentandione Aus Aldehyden Und Acetylaceton. Synthesis. 1974, 9, 667–669.
doi:10.1055/s-1974-23400.
[9] Kishikawa, K.; Furusawa, A.; Kohmoto, S.; Yamamoto, M.; Kazutoshi, Y. K.
Diastereoselective Hydrochlorination of Acrylylurea Derivatives Using Titanium
Tetrachloride and Alcohol. Chelation-Controlled Michael Addition of Chloride and
Intramolecular Proton Transfer to the.alpha.-Position. J. Org. Chem. 1993, 58, 7296–7299.
doi:10.1021/jo00077a067.
[10] Odian, G. Principles of Polymerization, Fourth Ed.; John Wiley & Sons, INC Publication:
New York, 2004.
[11] Stellman, J. M. Encyclopedia of Occupational Health and Safety. 1998.
[12] Allochio Filho, J. F.; Lemos, B. C.; de Souza, A. S.; Pinheiro, S.; Greco, S. J.
Multicomponent Mannich Reactions: General Aspects, Methodologies and Applications.
Tetrahedron. 2017, 73, 6977–7004. doi:10.1016/j.tet.2017.10.063.
[13] Wu, M.; Jing, H.; Chang, T. Synthesis of b-Amino Carbonyl Compounds via a Mannich
Reaction Catalyzed by SalenZn Complex. Catal. Commun. 2007, 8, 2217–2221. doi:10.
1016/j.catcom.2007.05.011.
[14] Zhang, C.; Dong, J.; Cheng, T.; Li, R. Y(OTf)3-Catalyzed Novel Mannich Reaction of N-
Alkoxycarbonylpyrroles, Formaldehyde and Primary Amine Hydrochlorides. Tetrahedron
Lett. 2001, 42, 461–463. doi:10.1016/S0040-4039(00)01985-7.
[15] Shou, W.-G.; Yang, Y.-Y.; Wang, Y.-G. An Efficient Synthesis of b-Amino Esters via
Zn(OTf)2-Catalyzed Mannich-Type Reaction. Tetrahedron Lett. 2006, 47, 1845–1847. doi:
10.1016/j.tetlet.2005.12.136.
[16] Kogayashi, S.; Araki, M.; Yasuda, M. One-Pot Synthesis of b-Amino Esters from
Aldehydes Using Lanthanide Triflate as a Catalyst. Tetrahedron Lett. 1995, 36, 5773–5776.
doi:10.1016/0040-4039(95)01096-Z.
[17] Pandey, G.; Singh, R. P.; Garg, A.; Singh, V. K. Synthesis of Mannich Type Products via a
Three-Component Coupling Reaction. Tetrahedron Lett. 2005, 46, 2137–2140. doi:10.
1016/j.tetlet.2005.01.118.
[18] Zhang, X.; Yin, S.; Qiu, R.; Xia, J.; Dai, W.; Yu, Z.; Au, C.-T.; Wong, W.-W. Synthesis
and Structure of an Air-Stable Hypervalent Organobismuth (III) Perfluorooctanesulfonate
and Its Use as High-Efficiency Catalyst for Mannich-Type Reactions in Water. J.
Organomet. Chem 2009, 694, 3559–3564. doi:10.1016/j.jorganchem.2009.07.018.
[19] Loh, T.-P.; Liung, S. B. K. W.; Tan, K.-L.; Wei, L.-L. Three Component Synthesis of
b-Amino Carbonyl Compounds Using Indium Trichloride-Catalyzed One-Pot Mannich-
Type Reaction in Water. Tetrahedron. 2000, 56, 3227–3237. doi:10.1016/S0040-
4020(00)00221-0.
[20] Wang, R.; Li, B.-G.; Huang, T.-K.; Shi, L.; Lu, X.-X. NbCl5-Catalyzed One-Pot Mannich-
Type Reaction: Three Component Synthesis of b-Amino Carbonyl Compounds.
Tetrahedron Lett. 2007, 48, 2071–2073. doi:10.1016/j.tetlet.2007.01.142.
[21] Wang, L.; Han, J.; Sheng, J.; Tian, H.; Fan, Z. Rare Earth Perfluorooctanoate [RE(PFO)3]
Catalyzed One-Pot Mannich Reaction: Three Component Synthesis of b-Amino Carbonyl
Compounds. Catal. Commun. 2005, 6, 201–204. doi:10.1016/j.catcom.2004.12.009.
[22] Yang, Y.-Y.; Shou, W.-G.; Wang, Y.-G. Synthesis of b-Amino Carbonyl Compounds via a
Zn(OTf)2-Catalyzed Cascade Reaction of Anilines with Aromatic Aldehydes and Carbonyl
Compounds. Tetrahedron. 2006, 62, 10079–10086. doi:10.1016/j.tet.2006.08.063.
[23] Ollevier, T.; Nadeau, E. Bismuth Triflate-Catalyzed Three-Component Mannich-Type
Reaction. J. Org. Chem. 2004, 69, 9292–9295. doi:10.1021/jo048617c.
[24] Manabe, K.; Kobayashi, S. Mannich-Type Reactions of Aldehydes, Amines, and Ketones
in a Colloidal Dispersion System Created by a Brønsted Acid-Surfactant-Combined
Catalyst in Water. Org. Lett. 1999, 1, 1965–1967. doi:10.1021/ol991113u.
[25] Manabe, K.; Mori, Y.; Kobayashi, S. Three-Component Carbon–Carbon Bond-Forming
Reactions Catalyzed by a Brønsted Acid–Surfactant-Combined Catalyst in Water.
Tetrahedron. 2001, 57, 2537–2544. doi:10.1016/S0040-4020(01)00081-3.

R
SYNTHETIC COMMUNICATIONSV
15
[26] Azizi, N.; Torkiyan, L.; Saidi, M. R. Highly Efficient One-Pot Three-Component Mannich
Reaction in Water Catalyzed by Heteropoly Acids. Org. Lett. 2006, 8, 2079–2082. doi:10.
1021/ol060498v.
[27] Goswami, P.; Das, B. Adenine as Aminocatalyst for Green Synthesis of Diastereoselective
Mannich Products in Aqueous Medium. Tetrahedron Lett. 2009, 50, 2384–2388. doi:10.
1016/j.tetlet.2009.02.218.
[28] Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas, C. F. Amine-Catalyzed Direct
Asymmetric Mannich-Type Reactions. Tetrahedron Lett. 2001, 42, 199–201. doi:10.1016/
S0040-4039(00)01908-0.
[29] Kantam, M. L.; Rajasekhar, C. V.; Gopikrishna, G.; Reddy, K. R.; Choudary, B. M. Proline
Catalyzed Two-Component, Three-Component and Self-Asymmetric Mannich Reactions
Promoted by Ultrasonic Conditions. Tetrahedron Lett. 2006, 47, 5965–5967. doi:10.1016/j.
tetlet.2006.06.042.
[30] Wu, H.; Chen, X.-M.; Wan, Y.; Ye, L.; Xin, H.-Q.; Xu, H.-H.; Yue, C.-H.; Pang, L.-L.; Ma,
€
R.; Shi, D.-Q. Stereoselective Mannich Reactions Catalyzed by Troger’s Base Derivatives in
Aqueous Media. Tetrahedron Lett. 2009, 50, 1062–1065. doi:10.1016/j.tetlet.2008.12.067.
[31] Alza, E.; RodrꢀIguez-Escrich, C.; Sayalero, S.; Bastero, A.; M. A. Chem, P. A Solid-
Supported Organocatalyst for Highly Stereoselective, Batch, and Continuous-Flow
Mannich Reactions. Chem Eur J. 2009, 15, 10167–10172.
[32] Senapak, W.; Saeeng, R.; Sirion, U.; Acid-Ionic Polymer as Recyclable Catalyst for One-
Pot Three-Component Mannich Reaction. RSC Adv. 2017, 7, 30380–30384. doi:10.1039/
C7RA04834C.
[33] Zhao, G.; Jiang, T.; Gao, H.; Han, B.; Huang, J.; Sun, D.; Mannich Reaction Using Acidic
Ionic Liquids as Catalysts and Solvents. Green Chem. 2004, 6, 75–77. doi:10.1039/
b309700p.
€
[34] Sahoo, S.; Joseph, T.; Halligudi, S. B.; Mannich Reaction in Bronsted Acidic Ionic Liquid:
A Facile Synthesis of b-Amino Carbonyl Compounds. J. Mol. Catal. A: Chem. 2006, 244,
179–182. doi:10.1016/j.molcata.2005.09.012.
[35] Dong, F.; Luo, J.; Zhou, X.-L.; Liu, Z.-L.; Mannich Reaction in Water Using Acidic Ionic
Liquid as Recoverable and Reusable Catalyst. Catal. Lett. 2007, 116, 76–80. doi:10.1007/
s10562-007-9095-8.
[36] Dong, F.; Zhenghao, F.; Zuliang, L.; Functionalized Ionic Liquid as the Recyclable Catalyst
for Mannich-Type Reaction in Aqueous Media. Catal. Commun. 2009, 10, 1267–1270.
doi:10.1016/j.catcom.2009.02.003.
[37] Wu, H.; Shen, Y.; Fan, L.-Y.; Wan, Y.; Zhang, P.; Chen, C.-F.; Wang, W.-X.;
Stereoselective Synthesis of b-Amino Ketones via Direct Mannich-Type Reaction
Catalyzed with Silica Sulfuric Acid. Tetrahedron. 2007, 63, 2404–2408. doi:10.1016/j.tet.
2007.01.015.
[38] Li, Z.; Ma, X. L.; Liu, J.; Feng, X.; Tian, G.-Q.; Zhu, A. G.; Silica-Supported Aluminum
Chloride: A Recyclable and Reusable Catalyst for One-Pot Three-Component Mannich-
Type Reactions. J. Mol. Catal. A Chem. 2007, 272, 132–135. doi:10.1016/j.molcata.2007.03.
029.
[39] Kidwai, M.; Mishra, N. K.; Bansal, V.; Kumar, A.; Mozumdar, S.; Novel One-Pot Cu-
Nanoparticles-Catalyzed Mannich Reaction. Tetrahedron Lett. 2009, 50, 1355–1358. doi:10.
1016/j.tetlet.2009.01.031.
[40] Zareyee, D.; Alizadeh, H.; One-Pot Three-Component Mannich Reaction in Water
Catalyzed by Eco-Friendly, Hydrophobic and Recyclable Sulfonic Acid Based Nanosilica
(SBA-15-Ph-PrSO3H). RSC Adv. 2014, 4, 37941–37946. doi:10.1039/C4RA05842A.
[41] Rahmatpour, A.; Goodarzi, N.; Moazzez, M.; A Novel Route for Synthesis of Cross-Linked
Polystyrene Copolymer Beads with Tunable Porosity Using Guar and Xanthan Gums
from Bioresources as Alternative Synthetic Suspension Stabilizers. Designed Monomer
Polym. 2018, 21, 116–129. doi:10.1080/15685551.2018.1489698.

16
A. RAHMATPOUR ET AL.
[42] Rahmatpour, A.; Polystyrene-Supported GaCl3: A New, Highly Efficient and Recyclable
Heterogeneous Lewis Acid Catalyst for Tetrahydropyranylation of Alcohols and Phenols.
Polyhedron. 2012, 44, 66–71. doi:10.1016/j.poly.2012.06.063.
[43] Rahmatpour, A.; Polyvinylsulfonic Acid: An Efficient, Water-Soluble and Reusable
Brønsted Acid Catalyst for the Three-Component Synthesisof 3,4-Dihydropyrimidin-
2(1H)-Ones/Thiones in Water and Ethanol. Catal. Lett. 2012, 142, 1505–1511. doi:10.
1007/s10562-012-0873-6.
[44] Rahmatpour, A.; Goodarzi, N.; Cross-Linked polystyrene-TiCl4 Complex as a Reusable
Lewis Acid Catalyst for Solvent-Free Knoevenagel Condensations of 1,3-Dicarbonyl
Compounds with Aldehydes. Catal. Commun. 2019, 124, 24–31. doi:10.1016/j.catcom.
2018.11.001.
[45] Deshmukh, P.; Padiya, K. J.; Salunkhe, M. M. Friedel–Crafts acylation reaction using poly-
mer supported aluminium chloride. J. Chem. Res (S). 1999, 9, 568–569. DOI: 10.1039/
a808986h.
[46] Eftekhari-Sis, B.; Abdollahifar, A.; Hashemi, M. M.; Zirak, M. Stereoselective synthesis of
β-Amino ketones via direct Mannich-type reactions, catalyzed with ZrOCl2·8 H2O under
solvent-free conditions. Eur. J. Org. Chem. 2006, 5152–5157. DOI: 10.1002/ejoc.200600493.
[47] Lin, Y.; Huangshu, L.; Junhua, Z.; Xiujuan, X. The Mannich reaction between aromatic
ketones, aromatic aldehydes and aromatic amines. Synthesis. 1991, 9, 717–718. DOI: 10.
1055/s-1991-26554.
[48] Li, J.; Peng, Y.; Song, G. Mannich reaction catalyzed by carboxyl-functionalized ionic
liquid in aqueous media. Catal. Lett. 2005, 102, 159–162. DOI: 10.1007/s10562-005-5849-
3.
[49] Li, H.; Zeng, H.-Y.; Shao, H.-W. Bismuth(III) chloride-catalyzed one-pot Mannich reac-
tion: three-component synthesis of β-amino carbonyl compounds. Tetrahedron Lett. 2009,
50, 6858–6860. DOI: 10.1016/j.tetlet.2009.09.131.
[50] Bigdeli, M. A.; Nemati, F.; Mahdavinia, G. H. HClO4–SiO2 catalyzed stereoselective syn-
thesis of β-amino ketones via a direct Mannich-type reaction. Tetrahedron Lett. 2007, 48,
6801–6804. DOI: 10.1016/j.tetlet.2007.07.088.
[51] Chang, C.-T.; Liao, B.-S.; Liu, S.-T. Mannich-type reactions in a colloidal solution formed
by sodium tetrakis(3,5-trifluoromethylphenyl)borate as a catalyst in water. Tetrahedron
Lett. 2006, 47, 9257–9259. DOI: 10.1016/j.tetlet.2006.10.125.
[52] Yi, W.-B.; Cai, C. Mannich-type reactions of aromatic aldehydes, anilines, and methyl
ketones in fluorous biphase systems created by rare earth (III) perfluorooctane sulfonates
catalysts in fluorous media. J. Fluorine Chem. 2006, 127, 1515–1521. DOI: 10.1016/j.jflu-
chem.2006.07.009.
[53] Yue, C.- B.; Yi, T. F.; Zhu, C. B.; Liu, G. Mannich reaction catalyzed by a novel catalyst
under solvent-free conditions. Ind. Eng. Chem. 2009, 15, 653–656. DOI: 10.1016/j.jiec.
2009.09.038.
[54] Wang, M.; Song, Z.-G.; Xin, W.; Zhao, S. SnCl2-catalyzed three-component one-pot
Mannich-type reaction: efficient synthesis of β-aminocarbonyl compounds. Monatsh
Chem. 2009, 140, 1205–1208. DOI: 10.1007/s00706-009-0163-1.
[55] Boumoud, B.; Zetchi, A.; Boumoud, T.; Debache, A. SiO2-OSbCl2 as highly effective and
reusable heterogeneous catalyst for Mannich condensation in solvent or under solvent-
Free conditions. J. Chem. Pharm. Res. 2012, 4(5), 2517–2521.
[56] Iimura, S.; Nobutou, D.; Manabe, K.; Kobayashi, S. Mannich-type reactions in water using
a hydrophobic polymer-supported sulfonic acid catalyst. Chem. Commun. 2003, 14,
1644–1645. DOI: 10.1039/b304343f.