Pd-Cu-mediated synthesis of 2-substituted imidazo[1,2-α]pyridines in water

Article abstract of DOI:10.1080/00397910802448499

The reaction of 2-amino-1-(2-propynyl)pyridinium bromide with various iodobenzenes, catalyzed by Pd-Cu, in the presence of sodium lauryl sulfate as the surfactant and cesium carbonate as the base, in water, leads to the formation of 2-substituted imidazo[

Full text of DOI:10.1080/00397910802448499

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Pd-Cu–Mediated Synthesis
of 2-Substituted
Imidazo[1,2-α]pyridines in
Water
Mohammad Bakherad a , Ali Keivanloo a & Mahdieh
Hashemi a
a Faculty of Chemistry , Shahrood University of
Technology , Shahrood, Iran
Published online: 25 Feb 2009.
To cite this article: Mohammad Bakherad , Ali Keivanloo & Mahdieh Hashemi (2009)
Pd-Cu–Mediated Synthesis of 2-Substituted Imidazo[1,2-α]pyridines in Water, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:6, 1002-1011, DOI: 10.1080/00397910802448499
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Synthetic Communications1, 39: 1002–1011, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802448499
Pd-Cu–Mediated Synthesis of 2-Substituted
Imidazo[1,2-a]pyridines in Water
Mohammad Bakherad, Ali Keivanloo, and Mahdieh Hashemi
Faculty of Chemistry, Shahrood University of Technology, Shahrood, Iran
Abstract: The reaction of 2-amino-1-(2-propynyl)pyridinium bromide with
various iodobenzenes, catalyzed by Pd-Cu, in the presence of sodium lauryl
sulfate as the surfactant and cesium carbonate as the base, in water, leads to
the formation of 2-substituted imidazo[1,2-a]pyridines.
Keywords: Aryl iodide, imidazopyridine, Pd-catalyzed, sodium lauryl sulfate,
Sonogashira coupling
INTRODUCTION
The Sonogashira reaction cocatalyzed by palladium and copper is a
powerful and straightforward method for the construction of arylated
internal alkyne compounds,[1] which have a C(sp2)–C(sp) bond and are
important intermediates in organic synthesis, including natural products,[2]
biologically active molecules,[3] molecular electronics,[4] and polymers.[5]
The original Sonogashira reaction was generally performed in the pre-
sence of large amounts of palladium and copper(I) iodide as cocatalyst
in organic solvents, which were economically and environmentally malig-
nant. This protocol has recently been improved by several modifications
such as reaction in aqueous media, in ionic liquid, or under microwave
irradiation[6] and the use of promoters (Zn, Mg, Sn) or effective ligands.[7]
However, in most of the catalytic processes, organic solvents are usually
Received July 9, 2008.
Address correspondence to Mohammad Bakherad, Faculty of Chemistry,
Shahrood University of Technology, Shahrood Post Code 3619995161, Iran.
E-mail: m.bakherad@yahoo.com
1002

2-Substituted Imidazo[1,2-a]pyridines
1003
employed as the reaction media, often creating a great deal of safety,
health, and environmental issues because of their flammability, toxicity,
and volatility. From an economic and environmental standpoint, it is
desirable to avoid any use of hazardous and expensive organic solvents.
The use of water or aqueous solution represents one of the most econo-
mically and environmentally viable alternatives to organic solvents
for metal-catalyzed reactions.[8] Several examples of Pd-catalyzed
Sonogashira reactions in aqueous media have been reported.[9]
In continuation of our recent studies[10] on the Pd-catalyzed reaction
of acetylenes leading to heterocyclic compounds of biological signifi-
cance, we became interested in developing a synthetic route to substituted
imidazo[1,2-a]pyridines[11] in water.
RESULTS AND DISCUSSION
In this communication, we report that treatment of 2-amino-1-(2-propy-
nyl) pyridinium bromide 1[11] with aryl halides 2a–i in water and in the
presence of bis(triphenylphosphine)palladium chloride(II), copper iodide,
sodium laurylsulfate, and cesium carbonate at 60 ꢀC. The 2-substituted
imidazo[1,2-a]pyridines 3a–i were obtained in moderate to high yields
(Scheme 1, Table 1). The reactions were carried out under an argon
atmosphere, and water was degassed prior to use.
For optimization of the reaction conditions, we chose the reaction of
2-amino-1-(2-propynyl) pyridinium bromide 1 with 2-iodo-5-nitrotuluene
2a as the model reaction, and the effects of the base, surfactant, and catalyst
on the reaction were examined. First, several bases were screened for the
reaction in the presence of a catalytic amount of Pd(PPh3)2Cl2. As shown
in Table 2, the reaction is significantly influenced by the base employed.
The reaction works very well when inorganic bases such as K2CO3 and
Cs2CO3 are used (entries 2 and 3 in Table 1), with the best result obtained
in the case of cesium carbonate as the base (entry 3 in Table 1).
The influences of the amounts of copper(I) iodide, surfactant, and
the catalyst were investigated using reaction of compound 1 with 2a.
The results are shown in Table 3. Increasing the amount of the palladium
Scheme 1.

1004
M. Bakherad, A. Keivanloo, and M. Hashemi
Table 1. Yields of 2-benzylimidazo[1,2-a]pyridines 3a–ia
Entry
1
Ar
Product
Yield (%)
95
3a
2
3
4
3b
3c
3d
65
70
85
5
6
3e
3f
67
70
7
3g
65
(Continued )

2-Substituted Imidazo[1,2-a]pyridines
Table 1. Continued
1005
Entry
8
Ar
Product
Yield (%)
72
3h
9
3i
83
aReaction conditions:
1 (1 mmol), 2a–h (1 mmol), Cs2CO3 (3 mmol),
Pd(PPh)3Cl2 (3 mol%), CuI (7 mol%), Sodium laurylsulfate (7 mol%), and
degassed water (5 mL) at 60 ꢀC for 10 h.
catalyst could shorten the reaction time but does not increase the yield
(entry 3). Low palladium concentration often prolonged the reaction time
and decreased the yield (entry 1).
The use of surfactant is also critical for the success of the reaction:
without a surfactant=phase-transfer reagent, the yield dropped from
95% to 10% (compare entries 2 and 8). We also found that with an
Table 2. Effect of base on the heterocyclization during Sono-
gashira coupling of compound 1 with 2-iodo-5-nitrotoluene
2a in watera
Entry
Base
Yieldb (%)
1
2
3
4
5
6
7
KOH
K2CO3
Cs2CO3
Et3N
DIEA
20
75
95
25
40
30
35
Pyrrolidine
Piperidine
aReaction conditions:
1 (1 mmol), 2a (1 mmol), base
(3 mmol), Pd(PPh)3Cl2 (3 mol%), CuI (7 mol%), sodium lauryl-
sulfate (7 mol%), and degassed water (5 mL) at 60 ꢀC for 10 h.
bIsolated yields.

1006
M. Bakherad, A. Keivanloo, and M. Hashemi
Table 3. Effects of catalyst, cocatalyst, and surfactant on the heterocyclization
during Sonogashira coupling of compound 1 with 2-iodo-5-nitritoluene 2a in
watera
Entry
Pd(PPh3)2Cl2
CuI
Sodium laurylsulfate
Yieldb (%)
1
2
3
4
5
6
7
8
2 mol%
3 mol%
5 mol%
3 mol%
—
3 mol%
3 mol%
3 mol%
5 mol%
7 mol%
10 mol%
—
7 mol%
7 mol%
7 mol%
7 mol%
7 mol%
7 mol%
7 mol%
7 mol%
7 mol%
3 mol%
12 mol%
—
75c
95
90d
nr
nr
50
60
10
aReaction conditions: 1 (1 mmol), 2a (1 mmol), Cs2CO3 (3 mmol), and degassed
water (5 mL) at 60 ꢀC for 10 h.
bIsolated yields.
cReaction time: 12 h.
dReaction time: 7 h.
increase in the amount of surfactant, the reaction yield did not increase
(entry 7). Low surfactant concentration often decreased the yield
(entry 6). No reaction was observed when either Cu(II) alone or Pd(II)
alone was used as the catalyst (entries 4 and 5).
Subsequently, the reaction of a variety of aryl iodides 2a–i and
2-amino-1-(2-propynyl) pyridinium bromide 1 were studied under the
optimal conditions. As shown in Table 1, the presence of electron-
withdrawing groups such as NO2, Cl, and CN on the aryl iodide seems
to be essential. When iodobenzene or p-iodoanisole was used as the aryl
iodide, Sonogashira coupling could not be achieved.
In conclusion, we have developed a successful palladium-catalyzed
reaction for the synthesis of 2-aryl-substituted imidazo[1,2-a]pyridines
in the presence of sodium lauryl sulfate as the surfactant and cesium
carbonate as the base in water.
EXPERIMENTAL
General Procedure for Synthesis of 2-Substituted Imidazo[2,1-a]
Pyridines 3a–i
A mixture of the aryl iodide (1 mmol), (PPh3)2PdCl2 (3 mol%), CuI
(7 mol%), sodium lauryl sulfate (7 mol%), and cesium carbonate (3 mmol)
was stirred in water (5 mL) at 60 ꢀC for 30 min under an argon

2-Substituted Imidazo[1,2-a]pyridines
1007
atmosphere. 2-Amino-1-(2-propynyl)pyridinium bromide[11] (1mmol) was
then added, and the mixture was stirred at 60ꢀC for 10h. After completion
of the reaction, the resulting solution was concentrated in vacuo, and the
crude product was subjected to silica-gel column chromatography using
CHCl3–CH3OH (95:5) as eluent to afford the pure product (Table 1).
Data
Compound 3a
Mp 262–263 ꢀC (lit.[11] 263–264 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 2.35 (s, 3H, CH3), 4.28 (s, 2H, CH2), 7.00–8.02 (m, 7H, PyH,
ArH), 8.58 (s, 1H, CH of imidazole); 13C NMR (125 MHz, DMSO-d6):
d ¼ 20.03, 33.95, 114.86, 116.46, 121.75, 121.97, 125.30, 128.06, 130.83,
131.38, 133.05, 136.21, 139.13, 146.35, 147.86; IR, n (KBr disc): 1520,
1340 cmꢁ1; MS m=z 267 (Mþ). Anal. calcd. for C15H13N3O2: C, 67.40;
H, 4.90; N, 15.72. Found: C, 66.88; H, 4.74; N, 15.89.
Compound 3b
Mp 251–252 ꢀC (lit.[11] 250–251 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 4.46 (s, 2H, CH2), 6.98–8.00 (m, 8H, PyH, ArH), 8.66 (s, 1H, CH
of imidazole); 13C NMR (125 MHz, DMSO-d6): d ¼ 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, n (KBr disc): 1510, 1340 cmꢁ1; MS m=z 253
(Mþ). Anal. calcd. for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found:
C, 66.12; H, 4.11; N, 16.65.
Compound 3c
Mp 293–294 ꢀC (lit.[11] 294–295 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 4.29 (s, 2H, CH2), 6.97–8.32 (m, 8H, PyH, ArH), 8.58 (s, 1H, CH
of imidazole); 13C NMR (125 MHz, DMSO-d6): d ¼ 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, n (KBr disc): 1500, 1335 cmꢁ1; MS m=z 253
(Mþ). Anal. calcd. for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found:
C, 66.51; H, 4.42; N, 16.37.
Compound 3d
Mp 255–257 ꢀC (lit.[11] 256–257 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 4.31 (s, 2H, CH2), 6.96–8.31 (m, 8H, PyH, ArH), 8.65 (s, 1H, CH

1008
M. Bakherad, A. Keivanloo, and M. Hashemi
of imidazole); 13C NMR (125 MHz, DMSO-d6): d ¼ 34.21, 114.60,
116.76, 123.25, 128.30, 131.10, 131.87, 132.90, 135.82, 138.86, 145.27,
147.32; IR, n (KBr disc): 1510, 1340 cmꢁ1; MS m=z 253 (Mþ). Anal.
calcd. for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C, 66.22;
H, 4.26; N, 16.41.
Compound 3e
Mp 232–233 ꢀC (lit.[11] 231–232 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 4.41 (s, 2H, CH2), 6.94–8.32 (m, 7H, PyH, ArH), 8.56 (s, 1H, CH
of imidazole); 13C NMR (125 MHz, DMSO-d6): d ¼ 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, n (KBr disc): 1510, 1350 cmꢁ1; MS m=z 287
(Mþ). Anal. calcd. for C14H10ClN3O2: C, 58.45; H, 3.50; N, 14.61.
Found: C, 58.30; H, 3.41; N, 14.50.
Compound 3f
Mp 245–246 ꢀC (lit.[11] 246–247 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 4.25 (s, 2H, CH2), 6.95–8.03 (m, 7H, PyH, ArH), 8.59 (s, 1H, CH
of imidazole); 13C NMR (125 MHz, DMSO-d6): d ¼ 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, n (KBr disc): 1510, 1345 cmꢁ1; MS m=z 287
(Mþ). Anal. calcd. for C14H10ClN3O2: C, 58.45; H, 3.50; N, 14.61.
Found: C, 58.26; H, 3.41; N, 14.27.
Compound 3g
Mp 256–257 ꢀC; 1H NMR d (500 MHz, DMSO-d6): d ¼ 4.24 (s, 2H,
CH2), 6.80–8.11 (m, 7H, ArH), 8.55 (s, 1H, CH of imidazole); 13C
NMR (125 MHz, DMSO-d6): d ¼ 33.80, 114.21, 116.67, 123.09, 125.97,
127.20, 128.32, 129.98, 131.70, 132.12, 135.15, 136.98, 140.23, 149.02,
IR, n (KBr disc): 1510, 1340 cmꢁ1; MS m=z 287 (Mþ). Anal. calcd. for
C14H10ClN3O2: C, 58.45; H, 3.50; N, 14.61. Found: C, 58.34; H, 3.44;
N, 14.47.
Compound 3h
Mp 236–237 ꢀC (lit.[11] 236–237 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 2.51 (s, 3H, CH3), 4.22 (s, 2H, CH2), 6.96–7.87 (m, 8H, PyH,
ArH), 8.60 (s, 1H, CH of imidazole); 13C NMR (125 MHz, DMSO-d6):
d ¼ 27.49, 34.20, 114.33, 116.12, 127.51, 129.26, 130.09, 130.77, 133.27,

2-Substituted Imidazo[1,2-a]pyridines
1009
135.98, 137.35, 138.49, 145.30, 198.26; IR, n (KBr disc): 1690 cmꢁ1; MS
m=z 250 (Mþ). Anal. calcd. for C16H14N2O: C, 76.78; H, 5.64; N, 11.19.
Found: C, 76.60; H, 5.46; N, 11.25.
Compound 3i
Mp 261–262 ꢀC (lit.[11] 260–261 ꢀC); 1H NMR (500 MHz, DMSO-d6):
d ¼ 3.81 (s, 3H, CH3), 4.24 (s, 2H, CH2), 7.01–8.32 (m, 8H, PyH,
ArH), 8.64 (s, 1H, CH of imidazole); 13C NMR (125 MHz, DMSO-d6):
d ¼ 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, n (KBr disc): 1710 cmꢁ1
;
MS m=z 266 (Mþ). Anal. calcd. for C16H14N2O2: C, 72.16; H, 5.30; N,
10.52. Found: C, 71.74; H, 5.45; N, 10.30.
ACKNOWLEDGMENTS
The authors thank the Research Council of Shahrood University of
Technology for the support of this work.
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