Pd-Cu catalyzed heterocyclization during Sonogashira coupling: synthesis of 2-benzylimidazo[1,2-a]pyridine

Article abstract of DOI:10.1016/j.tetlet.2008.03.141

The reaction of 2-amino-1-(2-propynyl)pyridinium bromide with various iodobenzenes, catalyzed by Pd-Cu, leads to the formation of 2-benzylimidazo[1,2-a]pyridines.

Full text of DOI:10.1016/j.tetlet.2008.03.141

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 3819–3822
Pd–Cu catalyzed heterocyclization during Sonogashira
coupling: synthesis of 2-benzylimidazo[1,2-a]pyridine
Mohammad Bakherad *, Hossein Nasr-Isfahani, Ali Keivanloo, Nesa Doostmohammadi
Department of Chemistry, School of Sciences, Shahrood University of Technology, Shahrood, Iran
Received 25 September 2007; revised 28 February 2008; accepted 26 March 2008
Available online 29 March 2008
Abstract
The reaction of 2-amino-1-(2-propynyl)pyridinium bromide with various iodobenzenes, catalyzed by Pd–Cu, leads to the formation of
2-benzylimidazo[1,2-a]pyridines.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Sonogashira coupling; Aryl iodide; Imidazole; Pd-catalyzed; Imidazopyridines
Imidazopyridine derivatives are of wide interest because
of their diverse biological activities and clinical applica-
tions.1 Their core ring system is present in numerous antiv-
irial,2 antiprotozoal3 and antiherpes4 drugs.
Although several procedures have been developed for
the synthesis of imidazo[1,2-a]pyridines,5 no examples
involving arylation of imidazopyridine by Pd–Cu catal-
ayzed (Sonogashira coupling) reactions have been reported
in the literature.
on the synthesis of fused heterocycles and the Pd-catalyzed
reaction of acetylenes leading to heterocyclic compounds of
biological significance, we became interested in developing
a synthetic route to substituted imidazo[1,2-a]pyridines.
In this Letter, we report that the treatment of 2-amino-
pyridine 1 with propargyl bromide in refluxing ethanol
affords 2-amino-1-(2-propynyl)pyridinium bromide 2 in
good yield.
1
The H NMR spectrum of 2 showed a CH proton at
The Sonogashira reaction, that is, the palladium and
copper co-catalyzed coupling of terminal alkynes with aryl
and vinyl halides, is one of the most widely used C–C bond
forming reactions.6,7 It provides an efficient route to aryl
alkynes, which are interesting intermediates for the prepa-
ration of a variety of target compounds with applications
ranging from natural products8 and pharmaceuticals9 to
molecular organic materials.10 Due to the utility of the
products, the development of new catalyst systems has
received considerable attention.
3.85 ppm, CH2 protons at 5.12 ppm and a single resonance
for the NH2 group at 8.72 ppm; this signal was removed on
deuteration.
When compound 2 was treated in DMF with the aryl
halides 3a–i and triethylamine in the presence of bis(tri-
phenylphosphine)palladium chloride(II) and copper iodide
at room temperature, the 2-substituted imidazo[1,2-a]pyr-
idines 4a–i were obtained in good to high yields
(Scheme 1, Table 1).
The reactions had to be carried out under an argon
atmosphere, and the mixture of DMF and triethylamine
had to be degassed prior to use.
A possible two step mechanism for the reaction is illus-
trated in Scheme 1. First a standard Sonogashira coupling,
then a known Pd(II) catalyzed intermolecular cyclization of
a nucleophilic nitrogen moiety with the triple bond, and
finally base induced aromatization could give product 4.15
Palladium catalyzed reactions11 have been immensely
practical for both carboannulation12 and heteroannula-
tion13 processes. In continuation of our recent studies14
*
Corresponding author. Fax: +98 2733335441.
E-mail address: mbakherad@shahroodut.ac.ir (M. Bakherad).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.03.141

3820
M. Bakherad et al. / Tetrahedron Letters 49 (2008) 3819–3822
Table 1
[(PPh3)2PdCl2]
Et3N, CuI, DMF
ArI
BrH2C
C
CH
Melting points and yields of 2-benzylimidazo[1,2-a]pyridines 4a–i
3a-i
EtOH
N+
NH2
CH
Sonogashira coupling
N
NH2
Br-
Product
Ar
Mp (°C)
Yield (%)
NO
C
2
1
2
4a
250–251
78
Pd(II)
Et3N
N
NH
N
N
4b
4c
294–295
256–257
76
85
N
N
C
NO
C
2
Ar
CH2Ar
CHAr
4a-i
Scheme 1.
NO
NO
2
CH
3
However, other mechanisms for this reaction are also
plausible, for example, cyclization via initial generation of
the exocyclic olefin followed by an intermolecular Heck
reaction, which would provide a facile pathway for the
migration of the double bond into the endocyclic position,16
or alternatively a 5-exo-dig cyclization may be triggered
simply by the formation of an Ar–Pd(II) species followed
by reduction, elimination and isomerization. This type of
cyclization has been observed for acetylenic lactams.17
The presence of electron withdrawing groups such as
NO2, Cl and CN on the aryl iodide seems to be essential.
When p-iodoanisole was used as the aryl iodide, Sonogash-
ira coupling could not be achieved.
It is also noteworthy that in the case of iodobenzene as
the aryl iodide, the cyclization occurred without the
involvement of the aryl iodide. The product of this
reaction was identified as 2-methylimidazo[1,2-a]pyridine
5 (Scheme 2).
In conclusion, we have developed a successful palladium
catalyzed reaction for the synthesis of 2-arylsubstituted
imidazo[1,2-a]pyridines from the readily available starting
materials.
4d
263–264
92
2
NO
2
4e
4f
4g
4h
4i
231–232
246–247
210–211
236–237
260–261
69
66
80
75
82
Cl
NO
2
Cl
CN
COMe
1. Synthesis of 2-amino-1-(2-propynyl)pyridinium bromide 2
A mixture of 2-aminopyridine (1.9 g, 20 mmol) and
propargyl 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. Yield, 80%; mp 168–169 °C; 1H
NMR d (500 MHz, DMSO-d6): 3.85 (s, 1H, CH), 5.12 (s,
2H, CH2), 6.85–8.23 (m, 4H, PyH), 8.72 (s, 2H, NH2);
13C NMR d (125 MHz, DMSO-d6): 43.86, 76.04, 80.46,
114.00, 115.84, 139.83, 143.57, 154.52; IR, m (KBr disc):
3300, 3200, 2100 cmÀ1, MS: m/z, 212. Anal. Calcd for
C8H9BrN2: C, 45.09; H, 4.26; N, 13.15. Found: C, 45.50;
H, 4.08; N, 13.51.
COOMe
[(PPh3)2PdCl2]
Et3N, CuI, DMF
Sonogashira coupling
PhI
+
N+
NH2
Br-
N
N
C
CH
CH3
2
5
Scheme 2.
was stirred in DMF (5 mL) at room temperature under
an argon atmosphere. 2-Amino-1-(2-propynyl)pyridinium
bromide (1.27 mmol) was then added and the mixture
was stirred at room temperature for 16 h. After completion
of the reaction, the resulting solution was concentrated in
2. Syntheses of 2-substituted imidazo [2,1-a]pyridines 4a–i
A mixture of the aryl iodide (0.75 mmol), (PPh3)2PdCl2
(0.05 mmol), CuI (0.1 mmol) and triethylamine (3 mmol)

M. Bakherad et al. / Tetrahedron Letters 49 (2008) 3819–3822
3821
vacuo and the crude product was subjected to silica gel col-
umn chromatography using CHCl3–CH3OH (95:5) as elu-
ent to afford the pure product (Table 1).
disc): 2200 cmÀ1
, MS: m/z, 233. Anal. Calcd for
C15H11N3: C, 77.23; H, 4.75; N, 18.01. Found: C, 77.52;
H, 4.63; N, 18.08.
1
1
Compound 4a: H NMR d (500 MHz, DMSO-d6): 4.46
Compound 4h: H NMR d (500 MHz, DMSO-d6): 2.51
(s, 2H, CH2), 6.98–8.00 (m, 8H, PyH, ArH), 8.66 (s, 1H,
CH of imidazole); 13C NMR d (125 MHz, DMSO-d6):
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,
m (KBr disc): 1510, 1340 cmÀ1, MS: m/z, 253. Anal. Calcd
for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C,
66.12; H, 4.11; N, 16.65.
(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 d
(125 MHz, DMSO-d6): 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, m (KBr disc): 1690 cmÀ1, MS:
m/z, 250. Anal. Calcd for C16H14N2O: C, 76.78; H, 5.64;
N, 11.19. Found: C, 76.60; H, 5.46; N, 11.25.
1
1
Compound 4b: H NMR d (500 MHz, DMSO-d6): 4.29
Compound 4i: H NMR d (500 MHz, DMSO-d6): 3.81
(s, 2H, CH2), 6.97–8.32 (m, 8H, PyH, ArH), 8.58 (s, 1H,
CH of imidazole); 13C NMR d (125 MHz, DMSO-d6):
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,
m (KBr disc): 1500, 1335 cmÀ1, MS: m/z, 253. Anal. Calcd
for C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C,
66.51; H, 4.42; N, 16.37.
(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 d
(125 MHz, DMSO-d6): 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, m (KBr disc): 1710 cmÀ1, MS:
m/z, 266. Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30;
N, 10.52. Found: C, 71.74; H, 5.45; N, 10.30.
1
Compound 4c: H NMR d (500 MHz, DMSO-d6): 4.31
(s, 2H, CH2), 6.96–8.31 (m, 8H, PyH, ArH), 8.65 (s, 1H,
CH of imidazole); 13C NMR d (125 MHz, DMSO-d6):
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, m (KBr disc):
3. Synthesis of 2-methylimidazo[1,2-a]pyridine 5
A mixture of iodobenzene (0.75 mmol), (PPh3)2PdCl2
(0.05 mmol), CuI (0.1 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 (1.27 mmol) was then added and the mixture
was stirred at room temperature for 12 h. 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. Yield, 66%, mp 280–
1510, 1340 cmÀ1
, MS: m/z, 253. Anal. Calcd for
C14H11N3O2: C, 66.40; H, 4.38; N, 16.59. Found: C,
66.22; H, 4.26; N, 16.41.
1
Compound 4d: H NMR d (500 MHz, DMSO-d6): 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 d
(125 MHz, DMSO-d6): 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, m (KBr disc): 1520,
1340 cmÀ1, MS: m/z, 267. Anal. Calcd for C15H13N3O2:
C, 67.40; H, 4.90; N, 15.72. Found: C, 66.88; H, 4.74; N,
15.89.
1
281 °C; H NMR d (500 MHz, DMSO-d6): 1.21 (s, 3H,
CH3), 7.03–7.59 (m, 4H, PyH), 8.29 (s, 1H, CH of imidaz-
ole); 13C NMR d (125 MHz, DMSO-d6): 34.08, 114.54,
116.22, 130.12, 130.78, 137.06, 140.02, 147.95; IR, m (KBr
disc): 1610 cmÀ1, MS: m/z, 132. Anal. Calcd for C8H8N2:
C, 72.72; H, 6.06; N, 21.21. Found: C, 72.68; H, 6.02; N,
21.23.
1
Compound 4e: H NMR d (500 MHz, DMSO-d6): 4.41
(s, 2H, CH2), 6.94–8.32 (m, 7H, PyH, ArH), 8.56 (s, 1H,
CH of imidazole); 13C NMR d (125 MHz, DMSO-d6):
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,
m (KBr disc): 1510, 1350 cmÀ1, MS: m/z, 287. Anal. Calcd
for C14H10ClN3O2: C, 58.45; H, 3.50; N, 14.61. Found: C,
58.30; H, 3.41; N, 14.50.
Acknowledgement
The authors thank the Research Council of Shahrood
University of Technology for the support of this work.
1
Compound 4f: H NMR d (500 MHz, DMSO-d6): 4.25
(s, 2H, CH2), 6.95–8.03 (m, 7H, PyH, ArH), 8.59 (s, 1H,
CH of imidazole); 13C NMR d (125 MHz, DMSO-d6):
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,
m (KBr disc): 1510, 1345 cmÀ1, MS: m/z, 287. Anal. Calcd
for C14H10ClN3O2: C, 58.45; H, 3.50; N, 14.61. Found: C,
58.26; H, 3.41; N, 14.27.
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