Polystyrene-supported palladium(II) ethylenediamine complex: A highly active and recyclable catalyst for the synthesis of 2-benzylimidazo[2,1-b] pyridines through heteroannulation of acetylenic compounds

Article abstract of DOI:10.1002/jhet.16

The polymer-supported palladium(II) ethylenediamine [PS-en-Pd(II)] complex is a highly active catalyst for the heterocyclization that takes place during the Sonogashira reaction between an aryl iodide and 2-amino-1-(2-propynyl) pyridinium bromide. This he

Full text of DOI:10.1002/jhet.16

100
Polystyrene-Supported Palladium(II) Ethylenediamine Complex:
A Highly Active and Recyclable Catalyst for the Synthesis of
2-Benzylimidazo[2,1-b]pyridines Through Heteroannulation of
Acetylenic Compounds
Vol 46
Mohammad Bakherad,* Bahram Bahramian, Hossein Nasr-Isfahani, Ali
Keivanloo, and Nesa Doostmohammadi
Department of Chemistry, School of Sciences, Shahrood University of Technology, Shahrood, Iran
*E-mail: bakheradm@yahoo.com
Received January 11, 2008
DOI 10.1002/jhet.16
Published online 6 February 2009 in Wiley InterScience (www.interscience.wiley.com).
The polymer-supported palladium(II) ethylenediamine [PS-en-Pd(II)] complex is a highly active cata-
lyst for the heterocyclization that takes place during the Sonogashira reaction between an aryl iodide
and 2-amino-1-(2-propynyl)pyridinium bromide. This heterogeneous palladium catalyst can readily be
recovered from the reaction medium by simple filtration and reused without a significant loss in its
activity.
J. Heterocyclic Chem., 46, 100 (2009).
INTRODUCTION
edge, there has been no examples involving arylation of
imidazopyridine by [PS-en-Pd(II)] catalyzed (Sonoga-
shira coupling) reactions described to date.
Sonogashira reaction, the palladium-catalyzed cross-
coupling reaction of terminal alkynes with aryl and
vinyl halides, is one of the most important, powerful,
and versatile tools in organic synthesis, and it has been
widely applied to diverse areas such as natural product
synthesis and material science [1]. The reaction gener-
ally proceeds in the presence of a homogeneous
palladium catalyst, which makes the catalyst recovery a
tedious operation and might result in unacceptable palla-
dium contamination of the product. From the standpoint
of green chemistry, the development of more environ-
mentally benign conditions for the reaction, for example,
the use of a heterogeneous palladium catalysts’ would
be desirable [2].
In continuation of our recent studies on the synthesis
of fused heterocycles and the Pd-catalyzed reactions of
acetylenes leading to heterocyclic compounds of biolog-
ical significance [5], we became interested in developing
a novel synthesis route to 2-substituted imidazo[1,2-
a]pyridines. In this article, we wish to report the syn-
thesis of the first polystyrene-supported palladium(II)
ethylenediamine complex, abbreviated as PS-en-Pd(II),
and its catalytic properties in the Sonogashira coupling
reaction for the synthesis of imidazo[1,2-a]pyridines [6].
The supported catalyst could be reused several times
without a significant degradation in its catalytic activity.
So far, cross-linked polystyrene or silica-supported
palladium catalysts have been used for the Sonogashira
reaction [3]. Unfortunately, they often result in lower
catalytic activity compared with their soluble counter-
parts. To overcome this limitation, a novel methodology
for creating insoluble and highly active catalysts is
needed. Our approach was guided by three imperatives:
(1) the support should be easily accessible; (2) starting
with readily available and inexpensive reagents; and (3)
the ligand anchored on the support should be air stable
at room temperature, which should allow its storage in
normal bottles with unlimited shelf life. To date, a few
palladium complexes on functionalized polystyrene sup-
port have been prepared and successfully used in or-
ganic reactions [4]. However, to the best of our knowl-
RESULTS AND DISCUSSION
We used the well-known chloromethylated polysty-
rene cross-linked with 2% divinylbenzene as support,
because it is flexible enough and allows metallic atoms
to be graft on via the ligands that are attached to the
polymer beads. Reaction of the polystyrene resin with
ethylenediamine in acetonitrile under reflux and the subse-
quent reaction of the aminated polystyrene with a solution
of [PdCl2(C6H5CN)2] in ethanol gave the polymer-sup-
ported palladium(II) complex catalyst 1 (Scheme 1).
Successful functionalization of the polymer was con-
firmed by elemental analysis. The N content of the resin
was found to be 2.42% (0.82 mmol/g), which indicates
C
V
2009 HeteroCorporation

January 2009
Polystyrene-Supported Palladium(II) Ethylenediamine Complex
101
Scheme
complex 1.
1Polystyrene-supported
palladium(II)
ethylenediamine
table, reaction of the aryl iodides with compound 3 pro-
ceeded smoothly under very mild conditions, giving the
corresponding products in excellent yields.
The stability of [PS-en-Pd(II)] was studied in repeated
Sonogashira coupling reactions. The coupling reaction
of o-iodonitrobenzene with compound 3 was chosen as
a model substrate to study the catalyst reuse and stabil-
ity. The catalyst was separated from the reaction mix-
ture after each experiment by filtration, washed with
water and acetonitrile, and dried carefully before using
it in the subsequent run. The reaction promoted by the
fifth recycled catalyst gave 5a in 75% yield (Table 3,
entry 5).
The low yield could be due to the formation of by-
products. For instance, formation of a coupled interme-
diate without ring formation or ring closure without par-
ticipation of the aryl group could be responsible for the
low yield.
that only 58% of the total chlorines were substituted by
amine. The metal loading of the polymer-supported pal-
ladium complex, which was determined by neutron acti-
vation analysis (NAA), was found to be 4.35% (0.41
mmol/g). In the IR spectrum of the polymer-bound eth-
ylenediamine, the sharp CACl peak (due to the ACH2Cl
groups) at 1264 cmÀ1 in the starting polymer was prac-
tically omitted or was seen as a weak band after intro-
duction of ethylenediamine and palladium on the poly-
mer. The various IR frequencies for the catalyst were
This reusability demonstrates the stability of the het-
erogeneous catalyst. Although no significant change in
the activity of the catalyst was observed, we performed
analysis of the catalyst after the fifth run in order to
determine any change in the catalyst structure. The na-
ture of the recovered catalyst was traced by IR spectros-
copy. The results indicated that the catalyst showed no
change in its IR spectrum after reuse for several times.
To determine the absolute amount of the palladium
species leached into the solution, the crude reaction
mixtures were evaporated to dryness and analyzed by
NAA. It was shown that less than 0.5% of the total
amount of the original palladium species was lost into
the solution during the course of the reaction.
assigned as (PdAN) ꢀ 506 cmÀ1, (CAN) ꢀ 1100 cmÀ1
,
and (NAH) ꢀ 3400 cmÀ1
.
To evaluate the catalytic activity of the first polymer-
supported PS-en-Pd(II) complex, the heterocyclization
during Sonogashira coupling of 2-amino-1-(2-propynyl)-
pyridinium bromide 3 with the aryl iodides 4a–i was
studied (Scheme 2). The reactions were performed under
conditions similar to those used in the corresponding ho-
mogenous reactions. The influences of the bases, sol-
vents, amounts of copper(I) iodide, and the catalyst on
the catalytic property of the [PS-en-Pd(II)] complex
were investigated using the coupling reaction of com-
pound 3 with o-iodonitrobenzene. The results are tabu-
lated in Table 1.
In conclusion, we developed a reusable heterogeneous
catalyst [PS-en-Pd(II)] by first reacting the commercially
available cross-linked chloromethylated polystyrene with
ethylenediamine and the subsequent reaction of the
product thus formed with dibenzonitrile palladium chlo-
ride. It efficiently catalyzed the heterogeneous Sonoga-
shira coupling followed by cyclization reaction for the
syntheses of various 2-substituted imidazopyridines. The
Among the bases tested, triethylamine proved to be
the most efficient, and among the solvents used, dime-
thylformamide was the best choice. Increasing the
amount of the palladium catalyst could shorten the reac-
tion time, but does not increase the yield (entry 11).
Low palladium concentration often prolonged the reac-
tion time and decreased the yield (entries 12 and 13).
We also found that with increase in the amount of cop-
per(I) iodide, the reaction yield did not increase (entry
14). No product was obtained under copper-free condi-
tions (entry 15). Copper(I) iodide was found to be an
essential cocatalyst.
Scheme 2
The reactions had to be carried out under an argon
atmosphere, and we had to degas the mixture of DMF
and triethylamine prior to use. The experimental results
are summarized in Table 2. As it can be seen in this
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M. Bakherad, B. Bahramian, H. Nasr-Isfahani, A. Keivanloo, and N. Doostmohammadi
Vol 46
Table 1
Heterocyclization during the Sonogashira coupling of o-iodonitrobenzene with compound 3 in the presence of several bases, solvents,
and amounts of catalyst.a
Entry
Base
Solvent
[PS-en-Pd(II)] (mmol)
CuI (mmol)
Time (hours)
Yield (%)
1
Et3N
Et3N
Et3N
Et3N
DIEA
DIEA
Piperidine
Piperidine
Pyrrolidine
Pyrrolidine
Et3N
Et3N
Et3N
Et3N
Et3N
Dioxan
CH3CN
DMF
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.03
0.06
0.02
0.005
0.03
0.03
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.4
0.12
0.03
0.3
0
14
16
12
15
17
16
14
16
14
19
10
20
24
14
24
30
45
92
25
60
50
35
32
23
20
88
75
62
87
0
2
3
4
5
Et3N
DMF
6
7
DIEA
DMF
8
Piperidine
DMF
Pyrrolidine
DMF
DMF
9
10
11
12
13
14
15
DMF
DMF
DMF
a All reactions were performed using 1.5 mmol of 3, 1.0 mmol of o-iodonitrobenzene, 0.06 mmol of PPh3, 3.0 mmol of base, and 5 mL of solvent
at room temperature.
metal complex, was collected by filtration, washed thoroughly
with ethanol, and finally dried in vacuum at 70ꢁ for 24 h.
Synthesis of 2-amino-1-(2-propynyl) pyridinium bromide
(3). A mixture of 2-amino pyridine (1.9 g, 20 mmol) and pro-
pargyl bromide (2 mL, 24 mmol) in ethanol (10 mL) was
heated under reflux for 1 h. The precipitate formed was filtered
off and recrystallized from ethanol to afford the title
compound.
catalyst could be reused five times with reasonable cata-
lytic activity on the fifth cycle. The advantages of our
heterogeneous catalytic system over others are as fol-
lows: (1) the catalyst could be conveniently prepared
from commercially available reagents; and (2) excellent
performance and reusability of the catalyst.
1
80% yield; m.p. 168–169ꢁ; H NMR (DMSO-d6): d 3.85 (s,
1H, CH), 5.12 (s, 2H, CH2), 6.85–8.23 (m, 4H, PyH), 8.72(s,
2H, NH2); 13C NMR (DMSO-d6): d 43.86, 76.04, 80.46,
114.00, 115.84, 139.83, 143.57, 154.52; ir (potassium bro-
mide): 3300, 3200, 2100 cmÀ1; Anal. Calcd. for C8H9BrN2
(213.06): C, 45.09; H, 4.26; N, 13.15. Found: C, 45.50; H,
4.08; N, 13.51.
Synthesis of 2-substituted imidazo[2,1-b]pyridines (5a–i). A
mixture of the aryl iodides (1.0 mmol), [(PS-en-Pd(II)]
(60 mg, 0.03 mmol Pd), CuI (0.2 mmol), and triethylamine
(3 mmol) was stirred in DMF (5 mL) at room temperature
under an argon atmosphere. 2-Amino-1-(2-propynyl)pyridinium
bromide (3) (1.50 mmol) was then added, and the mixture was
stirred at room temperature for 12–16 h. After completion of
the reaction, the resulting solution was concentrated in vacuo,
and the crude product was subjected to column chromatogra-
phy using CHCl3:CH3OH (95:5, v/v) as eluent to afford the
pure product (Table 1).
EXPERIMENTAL
All the reagents used were of commercial reagent grade.
Chloromethylated polystyrene (4–5% Cl and 2% cross-linked
with divinylbenzene) was a Merck product. Scanning electron
micrographs of the catalyst and polymer were taken on a SEM
Philips XL 30. The IR spectra were obtained as potassium bro-
mide pellets in the range 400–4000 cmÀ1 on a Shimadzo
Model 460. The H NMR and 13C NMR spectra were recorded
on a Bruker BRX 500 AVANCE spectrometer. The elemental
analyses were obtained on a Thermo Finnigan Flash EA
microanalyzer.
Preparation of polymer-bound ethylenediamine. To func-
tionalize the polymer support with ethylenediamine, it was pre-
pared by the following procedure: to a 250-mL round bottom
flask equipped with a magnetic stir bar containing 120 mL
acetonitrile, chloromethylated polystyrene (2 g, 2.5 mmol/Cl),
and ethylenediamine (25 mmol), NaI (0.13 mmol) was added.
The reaction mixture was refluxed for 48 h at which time the
solid material and was collected by filtration and washed with
5 Â 40 mL of CH3CN, 5 Â 40 mL of CH3OH:K2CO3 (1 M)
(1:1, v/v), 5Â40 mL of CH3OH:H2O (1:1 v/v), and 3 Â 40 mL
of diethyl ether, and was subsequently dried in an oven.
Preparation of polystyrene-supported PS-en-Pd(II) com-
plex (1). The functionalized polymer was kept in contact with
100 mL of ethanol for 30 min. An ethanolic solution of 0.25 g
of [PdCl2(C6H5CN)2] was added to it and heated to 50ꢁ for
6 h. The bright yellow colored polymer, impregnated with the
1
2-(2-Nitrobenzyl)imidazo[1,2-a]pyridine (5a). This com-
1
pound was obtained as a white solid. H NMR (DMSO-d6): d
4.46(s, 2H, CH2), 6.98–8.00 (m, 8H, PyH, ArH), 8.66 (s, 1H,
imidazole proton); 13C NMR (DMSO-d6): d 34.25, 114.60,
116.24, 122.85, 123.15, 129.10, 130.22, 130.95, 132.15,
134.27, 136.23, 139.12, 146.25, 148.33; ir (potassium bro-
mide): 1510, 1340 cmÀ1
; Anal. Calcd. for C14H11N3O2
(253.25): C, 66.4; H, 4.38; N, 16.59. Found: C, 66.12; H,
4.11; N, 16.65.
2-(3-Nitrobenzyl)imidazo[1,2-a]pyridine (5b). This com-
1
pound was obtained as a white solid. H NMR (DMSO-d6): d
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Polystyrene-Supported Palladium(II) Ethylenediamine Complex
103
Table 2
Melting points and yields of 2-benzylimidazo [1,2-a]pyridines 5a–i.a
Product
Ar
Time (hours)
12
Mp (ꢁC)
Yield (%)
5a
250–251
92
71
87
72
60
83
85
77
89
5b
5c
5d
5e
5f
14
14
16
16
14
13
15
16
294–295
256–257
263–264
231–232
246–247
210–211
236–237
260–261
5g
5h
5i
a All reactions were performed using 1.5 mmol of 3, 1.0 mmol of aryliodides, 0.2 mmol of CuI, 0.03 mmol of [PS-en-Pd(II)], 0.06 mmol of PPh3,
3.0 mmol of Et3N, and 5 mL of DMF at room temperature.
4.29 (s, 2H, CH2), 6.97–8.32 (m, 8H, PyH, ArH), 8.58(s, 1H,
imidazole proton); 13C NMR (DMSO-d6): d 33.92, 114.35,
116.55, 122.30, 127.95, 128.26, 130.15, 130.90, 133.17,
133.86, 135.86, 138.60, 146.20, 147.31; ir (potassium bro-
116.76, 123.25, 128.30, 131.10, 131.87, 132.90, 135.82,
138.86, 145.27, 147.32; ir (potassium bromide): 1510, 1340
cmÀ1; Anal. Calcd. for C14H11N3O2 (253.25): C, 66.4; H,
4.38; N, 16.59. Found: C, 66.22; H, 4.26; N, 16.41.
2-(2-Methyl-4-nitrobenzyl)imidazo[1,2-a]pyridine (5d). This
compound was obtained as a white solid. 1H NMR (DMSO-
d6): d 2.35 (s, 3H, CH3), 4.28 (s, 2H, CH2), 7.00–8.02 (m, 7H,
PyH, ArH), 8.58(s, 1H, imidazole proton); 13C NMR (DMSO-
d6): d 20.03, 33.95, 114.86, 116.46, 121.65, 121.97, 125.30,
128.06, 130.83, 131.38, 133.05, 136.21, 139.13, 146.35,
147.86; ir (potassium bromide): 1520, 1340 cmÀ1; Anal.
mide): 1500, 1335 cmÀ1
;
Anal. Calcd. for C14H11N3O2
(253.25): C, 66.4; H, 4.38; N, 16.59. Found: C, 66.51; H,
4.42; N, 16.37.
2-(4-Nitrobenzyl)imidazo[1,2-a]pyridine (5c). This com-
1
pound was obtained as a white solid. H NMR (DMSO-d6): d
4.31(s, 2H, CH2), 6.96–8.31 (m, 8H, PyH, ArH), 8.65(s, 1H,
imidazole proton); 13C NMR (DMSO-d6): d 34.21, 114.60,
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M. Bakherad, B. Bahramian, H. Nasr-Isfahani, A. Keivanloo, and N. Doostmohammadi
Vol 46
Table 3
8.32(m, 8H, PyH, ArH), 8.64(s, 1H, imidazole proton); 13C
NMR (DMSO-d6): d 33.89, 51.76, 114.54, 116.28, 128.36,
129.15, 130.05, 130.68, 132.84, 136.98, 138.08, 139.31,
148.93, 167.35; ir (potassium bromide): 1710 cmÀ1; Anal.
Calcd. for C16H14N2O2 (266.29): C, 72.16; H, 5.30; N, 10.52.
Found: C, 71.74; H, 5.45; N, 10.30.
Heterocyclization during Sonogashira coupling of o-iodonitrobenzene
with compound 3 catalyzed by recycled catalyst.a
Entry
Catalyst cycle
Isolated yield (%)
1
2
3
4
5
1st
2nd
3rd
4th
5th
92
90
87
82
75
Acknowledgment. The authors thank the Research Council of
Shahrood University of Technology for the support of this work.
a All reactions were performed using 1.5 mmol of 3, 1.0 mmol of
o-iodonitrobenzene, 0.2 mmol of CuI, 0.03 mmol of [PS-en-Pd(II)],
0.06 mmol of PPh3, 3.0 mmol of Et3N, and 5 mL of DMF at room
temperature.
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2-(4-Chloro-2-nitrobenzyl)imidazo[1,2-a]pyridine (5e). This
compound was obtained as a white solid. 1H NMR (DMSO-
d6): d 4.41 (s, 2H, CH2), 6.94–8.32 (m, 7H, PyH, ArH), 8.56
(s, 1H, imidazole proton); 13C NMR (DMSO-d6): d 33.81,
114.16, 116.32, 123.30, 128.36, 130.04, 130.64, 131.24,
132.43, 134.27, 137.46, 138.87, 144.30, 148.68; ir (potassium
bromide): 1510, 1350 cmÀ1; Anal. Calcd. for C14H10ClN3O2
(287.70): C, 58.45; H, 3.50; N, 14.61. Found: C, 58.30; H,
3.41; N, 14.50.
2-(4-Chloro-3-nitrobenzyl)imidazo[1,2-a]pyridine (5f). This
compound was obtained as a white solid. 1H NMR (DMSO-
d6): d 4.25 (s, 2H, CH2), 6.95–8.03 (m, 7H, PyH, ArH), 8.59
(s, 1H, imidazole proton); 13C NMR (DMSO-d6): d 33.75,
114.37, 116.86, 123.80, 126.58, 127.72, 128.23, 130.85,
131.47, 132.36, 135.30, 137.65, 141.11, 148.15; ir (potassium
bromide): 1510, 1345 cmÀ1; Anal. Calcd. for C14H10ClN3O2
(287.70): C, 58.45; H, 3.50; N, 14.61. Found: C, 58.34; H,
3.38; N, 13.95.
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imidazole proton); 13C NMR (DMSO-d6): d 34.26, 113.15,
114.86, 116.34, 120.06, 129.10, 130.55, 131.08, 131.67,
137.35, 140.22, 141.37, 148.24; ir (potassium bromide): 2200
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N, 18.01. Found: C, 77.52; H, 4.63; N, 18.08.
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2.51(s, 3H, CH3), 4.22 (s, 2H, CH2), 6.96–7.87 (m, 8H, PyH,
ArH), 8.60(s, 1H, imidazole proton); 13C NMR (DMSO-d6): d
27.49, 34.20, 114.33, 116.12, 127.51, 129.26, 130.09, 130.77,
133.27, 135.98, 137.35, 138.49, 145.30, 198.26; ir (potassium
bromide): 1690 cmÀ1; Anal. Calcd. for C16H14N2O (250.29): C,
76.78; H, 5.64; N, 11.19. Found: C, 76.60; H, 5.46; N, 11.25.
2-[4-(Methoxycarbonyl)benzyl]imidazo[1,2-a]pyridine
1
(5i). This compound was obtained as a white solid. H NMR
(DMSO-d6): d 3.81 (s, 3H, CH3), 4.24 (s, 2H, CH2), 7.01–
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet