Pd-catalyzed regiocontrolled Sonogashira and Suzuki cross-coupling reaction of 3,6-dihalogenoimidazo[1,2-a]pyridines: One-pot double-coupling approach

Article abstract of DOI:10.1016/j.tet.2011.06.108

New and efficient regioselective Sonogashira and Suzuki-Miyaura palladium-catalyzed coupling reactions of 3,6-dihalogenoimidazo[1,2-a]pyridines followed by another cross-coupling has been successfully developed. Various solvents, palladium species and bases were tested. Scope and limitations of this regiocontrolled palladium-catalyzed reaction were investigated. The synthesis of 3,6-disubstituted imidazo[1,2-a]pyridine derivatives using one-pot regioselective double-coupling approach was developed. This procedure affords convergent syntheses of polysubstituted compounds in high yields in a very few steps.

Full text of DOI:10.1016/j.tet.2011.06.108

Tetrahedron 67 (2011) 7128e7138
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Pd-catalyzed regiocontrolled Sonogashira and Suzuki cross-coupling reaction of
3,6-dihalogenoimidazo[1,2-a]pyridines: one-pot double-coupling approach
,
,
,
,
Ahmed El Akkaoui a b, Ibtissam Bassoude a c, Jamal Koubachi a b, Sabine Berteina-Raboin a
,
*
b
a
ꢀ
Abderrahim Mouaddib , Gerald Guillaumet
Institut de Chimie Organique et Analytique, Universite d’Orleans, UMR CNRS 6005, BP 6759, 45067 Orleans Cedex 2, France
a
ꢀ
ꢀ
b
c
ꢀ
ꢀ
ꢀ
Faculte des Sciences et Techniques, Universite Sultan Moulay Slimane, BP 523, 23000 Beni-Mellal, Morocco
ꢀ ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Organique Heterocyclique, Universite Mohammed V-Agdal, Faculte des Sciences, avenue Ibn-Batouta, Rabat, Morocco
a r t i c l e i n f o
a b s t r a c t
Article history:
New and efficient regioselective Sonogashira and SuzukieMiyaura palladium-catalyzed coupling re-
actions of 3,6-dihalogenoimidazo[1,2-a]pyridines followed by another cross-coupling has been suc-
cessfully developed. Various solvents, palladium species and bases were tested. Scope and limitations of
this regiocontrolled palladium-catalyzed reaction were investigated. The synthesis of 3,6-disubstituted
imidazo[1,2-a]pyridine derivatives using one-pot regioselective double-coupling approach was de-
veloped. This procedure affords convergent syntheses of polysubstituted compounds in high yields in
a very few steps.
Received 26 April 2011
Received in revised form 28 June 2011
Accepted 30 June 2011
Available online 6 July 2011
Keywords:
Imidazo[1,2-a]pyridines
One-pot
Ó 2011 Elsevier Ltd. All rights reserved.
Suzuki cross-coupling
Sonogashira cross coupling
1. Introduction
pyridines. We achieved selective functionalization of imidazo[1,2-
a]pyridine derivatives into dissimilarly trisubstituted aromatic
Palladium(0)-catalyzed carbonecarbon (Csp2eCsp2) bond-
forming processes are widely used in synthetic chemistry.1 Sono-
gashira2 and SuzukieMiyaura3 cross-coupling reactions have found
extensive use in natural products synthesis and for the construction
of complex molecules.4 Recently, many examples of regioselective
Sonogashira and SuzukieMiyaura5 palladium-catalyzed reactions
were described, but never in the context of imidazo[1,2-a]pyri-
dines. Conducting more than one coupling in the same reaction
vessel is quite rare.6 Within the area of heteroaromatic systems,
palladium is often used to catalyze single reactions. The use of al-
kynes as reactants in one-pot SonogashiraeSonogashira couplings
was not investigated with (hetero)aromatic systems excepted for
multiple Sonogashira reactions of hexa- and pentachlorobenzene.7
In a previous paper, we described the regioselective palladium
insertion at the position 3 of imidazo[1,2-b]pyridazines.8 Our aim
was to improve the efficiency of cross-coupling chemistry for the
preparation of polysubstituted bicyclic heterocycles with a bridge-
head nitrogen atom.9 This initial approach was further investigated
and applied to the regioselective Sonogashira and SuzukieMiyaura
palladium-catalyzed reactions of 3,6-dihalogenoimidazo[1,2-a]
compounds, which is still a significant challenge in organic syn-
thesis (Scheme 1). A synthesis of polysubstituted imidazo[1,2-a]
pyridines via microwave-assisted one-pot Suzuki coupling/
palladium-catalyzed heteroarylation and cyclization/Suzuki
coupling/palladium-catalyzed heteroarylation was already de-
veloped by our team in order to reduce the number of steps re-
quiring separation.10
Based on our recent study, the one-pot SuzukieSuzuki and one-
pot
SonogashiraeSonogashira
cross-coupling
using
3,6-
dihalogenoimidazo[1,2-a]pyridines as starting material would be
a useful method to access to desired polyfunctionalized heterocy-
clic precursors (Scheme 1).
Pd-catalyzed
Regioselective
X'
reaction
X
N
N
R
R
N
N
Pd-catalyzed
1, X= I, X'= Br
Di-coupled
One-Pot
14, X= Br, X'= I
imidazo[1,2-a]pyridines
double-coupling
* Corresponding author. Tel.: þ33 238 494 856; fax: þ33 238 417 281; e-mail
Scheme 1. Convergent approach to dissimilarly 3,6-disubstituted imidazo [1,2-a]
pyridines.
address: sabine.berteina-raboin@univ-orleans.fr (S. Berteina-Raboin).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.108

A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
7129
Table 3
2. Results and discussion
Regioselective Sonogashira and Suzuki cross-coupling on imidazo[1,2-a]pyridine 1
Br
For initial exploration, we chose 6-iodo-3-bromoimidazo[1,2-a]
Br
R
Reaction conditions
I
pyridine
1
then 6-bromo-3-iodoimidazo[1,2-a]pyridine 14 as
N
N
model system (Scheme 1).
N
N
1
6-13
2.1. Sonogashira cross-coupling on compound 1
Entry
R
Product Nꢀ
Yielda (%)
95b
Initial work focused on the optimization of the first Sonogashira
coupling reaction conditions to improve the reactionyield of desired
monosubstituted compound without generation of symmetrical
bis-alkynyl product. A model reaction was carried out with 6-iodo-
3-bromoimidazo[1,2-a]pyridine 1 and methyl propargyl ether
(1.1 equiv) under standard conditions using PdCl2(PPh3)2
(0.05 equiv) and CuI (0.2 equiv) in a mixture of DMF/Et3N at room
temperature for 24 h.9 In this case, compound 2 was obtained in only
74% yield (8% of starting material was recovered). Total conversion
was observed with 1.3 equiv of methyl propargyl ether under the
same reaction conditions and desired product 2 was generated in
92% yield (Table 3, entry 2). Influence of the Pd-catalysts on the
regioselective Sonogashira cross-coupling reaction was studied.
Replacement of PdCl2(PPh3)2 by Pd(PPh3)4 afforded compound 2
and by-product 3 in 90% and 3% yield, respectively (Table 3, entry 3).
[Pd(OAc)2 (0.05 equiv)/PPh3(0.1 equiv)] catalytic system used under
the same reaction conditions provided compound 2 and 3 in 88% and
8% yields, respectively (Table 3, entry 4).
1
6
7
OH
2
93b
OH
Ph
Ph
3
4
8
9
91b
94b
B(OH)
2
5
10
88c
OMe
B(OH)
2
6
7
11
12
13
87c
90c
85c
Table 1
Me
Optimization of regioselective Sonogashira cross-coupling on 2-phenylimidazo[1,2-
a]pyridine 1
B(OH)
2
S
B(OH)
2
8
Entry
Pd(0)/ligand
Alkyne
(equiv)
Time
(h)
Yielda
(%) 1/2/3
CHO
Yields are given as isolated products.
Alkyne (1.3 equiv), PdCl2(PPh3)2 (0.05 equiv), CuI (0.2 equiv), DMF/Et3N, rt,
2e3 h.
RB(OH)2 (1.2 equiv), K2CO3 (2 equiv), Pd(OAc)2 (0.1 equiv)/PPh3 (0.2 equiv) in
DMF at 100 ꢀC, 2 h.
a
1
2
3
4
PdCl2(PPh3)2 (0.05 equiv)
PdCl2(PPh3)2 (0.05 equiv)
Pd(PPh3)4 (0.05 equiv)
1.1
1.3
1.3
1.3
24
4
3
8/74/0
0/92/0
0/90/3
0/88/8
b
c
Pd(OAc)2(0.05 equiv)/PPh3 (0.1 equiv)
4
a
Yields are given as isolated products.
Pd(PPh3)4 (0.1 equiv) and NaOH (2 equiv) in a mixture of DME/
H2O9d at 80 ꢀC for 2 h. Desired monocoupled compound 4 and the
dicoupled 5 were isolated in 70% and 19% yield, respectively (Table
2, entry 1). Interestingly, desired compound 4 was obtained in 90%
yield when using Pd(OAc)2(0.1 equiv)/PPh3(0.2 equiv) and K2CO3
(2 equiv) in DMF at 100 ꢀC with no trace of compound 5 (Table 2,
entry 2).
2.2. Suzuki cross-coupling on compound 1 (exploration of
the potential of regioselective Suzuki reaction)
6-Iodo-3-bromo-2-phenylimidazo[1,2-a]pyridine 1 was treated
with 3-methoxyphenylboronic acid (1.2 equiv) in the presence of
Table 2
Optimization of regioselective Suzuki cross-coupling on 2-phenylimidazo[1,2-a]pyridine 1
OMe
OMe
OMe
Br
Br
3-MeOC H B(OH) (1.2 eq.)
I
6
4
2
+
N
N
N
Ph
Ph
Ph
Pd(0)/ Ligand, base
solvent
N
N
N
1
4
5
Entry
Pd(0)/ligand
Base (2 equiv)
Solvent
TꢀC/time (h)
Yielda (%) 1/4/5
1
2
Pd(PPh3)4(0.1 equiv)
Pd(OAc)2 (0.1 equiv)/PPh3(0.2 equiv)
NaOH
K2CO3
H2O/DME
DMF
Reflux/2
100/2
0/70/19
0/90/0
a
Yields are given as isolated products.

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A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
The above method was applied to the synthesis of various 3-
R
bromo-6-substituted-2-phenylimidazo[1,2-a]pyridine analogues.
Reaction of starting material 1 with various alkynes and (hetero)
arylboronic acids using our optimized conditions led to compounds
6 to 13 in excellent yields (Table 3, entries 1e7). Quantitative
conversion into the corresponding monosubstituted imidazo[1,2-a]
pyridine compounds was always observed.
Pd(0), CuI (0.2 eq.)
I
DMF/ Et N, r.t.
Br
3
Br
N
N
(1.3 eq.)
R
N
N
17: R = CH OMe, 96%
16
2
18: R = C(Me) OH, 95%
2
2.3. Sonogashira cross-coupling on compound 14 (use of 6-
bromo-3-iodo-2-phenylimidazo[1,2-a]pyridine 14 in
Sonogashira and SuzukieMiyaura reactions)
19: R = CH OH, 92%
2
20: R = Ph,
96%
Scheme 2. Regioselective Sonogashira cross-coupling on 6-bromo-3-iodoimidazo[1,2-
a]pyridine 16.
A first attempt of Sonogashira cross-coupling under optimized
reaction conditions (Table 1, entry 2) afforded desired compound 15
in 74% yield along with some starting material 14, which was re-
covered (Table 4, entry 1). When 1.5 equiv of 3-methyl propargyl
ether were used, compounds 15 and 14 were isolated in 84% and
10% yields, respectively (Table 4, entry 2). The best result was ob-
served when 2 equiv of 3-methyl propargyl ether were used (Table
4, entry 3), affording compound 15 in 90% yield. As expected ab-
sence of the phenyl group favoured coupling because of reduced
steric hindrance, compounds 17e20 were obtained in shorter re-
action times (1e1.5 h) and lesser alkyne excesses (1.3 equiv) while
preserving the yields (Scheme 2).
2.4. Suzuki cross-coupling on compound 14
Treatment of compound 14 under the optimized reaction con-
ditions afforded a separable mixture of monocoupled product 21, 3-
iododerivative 14 and dicoupled product 5, isolated in 68, 15 and 4%
yield, respectively (Table 5, entry 1). Reactivity of compound 14 was
studied with regards to reaction conditions, using various ligands
and/or palladium species. Results are summarized in Table 5. Op-
timal reaction conditions were reached by using Pd2(dba)3$CHCl3
(0.1 equiv)/AsPh3(0.2 equiv) in a mixture of dioxane/EtOH at 50 ꢀC.
Under these conditions, compound 21 was obtained in 80% yield
(Table 5, entry 6). Scope and limitations of regioselective Sonoga-
shira and Suzuki cross-coupling towards imidazo[1,2-a]pyridine 14
were evaluated with various alkynes and (hetero)arylboronic acids,
using previously optimized reaction conditions. The results show
that the compound 14 was efficiently functionalized in 3-position
and expected products were obtained in good yield (Table 6).
Table 4
Optimization of regioselective Sonogashira cross-coupling on imidazo[1,2-a]pyri-
dine 14
MeO
Pd(0), CuI (0.2 eq.)
I
2.5. Palladium-catalyzed reaction on substituted
bromocompounds
Br
DMF/ Et N, r.t.
Br
3
N
N
Ph
Ph
N
N
Monoarylations or monoalkynylations occurred first at the more
reactive CeI position, thus leaving the remaining CeBr available for
further functionalization to lead to various 3,6-disubstituted-2-
phenylimidazo[1,2-a]pyridines. Sequential cross-coupling at C-3
of 6-substituted-3-bromo-2-phenylimidazo[1,2-a]pyridine and at
C-6 of 6-bromo-3-substituted-2-phenylimidazo[1,2-a]pyridine
were achieved using the same optimized catalyst systems involved
in the first cross-coupling of compounds 1 and 14. We first focused
our efforts on the Suzuki approach. 3-Bromo-6-(p-methox-
yphenyl)-2-phenylimidazo[1,2-a]pyridine 10 was reacted with 3-
OMe
14
15
Entry
Pd(0) (0.05 equiv)
Alkyne (equiv)
Time (h)
Yielda (%) 14/15
1
2
3
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
1.3
1.5
2
4
4
3
20/74
10/84
0/90
a
Yields are given as isolated products.
Table 5
Optimization of regioselective Suzuki cross-coupling on imidazo[1,2-a]pyridine 14
MeO
OMe
OMe
I
3-MeOC H B(OH) (1.2 eq.)
6
4
2
Br
Br
N
N
N
Ph
Ph
+
Ph
Pd(0)/Ligand, base
solvent
N
N
N
14
21
5
Entry
Pd(0) (0.1 equiv)/ligand (0.2 equiv)
Base (2 equiv)
Solvent
DMF
H2O/DME
H2O/DME
DMF
EtOH/dioxane
EtOH/dioxane
EtOH/dioxane
T (ꢀC)/time (h)
Yielda (%) 14/21/5
1
2
3
4
5
6
7
Pd(OAc)2/PPh3
Pd(PPh3)4
PdCl2(PPh3)2
Pd(OAc)2/PPh3
Pd(OAc)2/PPh3
Pd(dba)2/AsPh3
Pd2(dba)3$CHCl3/AsPh3
K2CO3
NaOH
NaOH
K2CO3
K2CO3
K2CO3
K2CO3
100/24
Reflux/24
Reflux/2
50/12
50/6
50/12
15/68/4
9/66/10
10/45/36
20/60/0
0/76/8
20/64/0
0/80/0
50/6
a
Yields are given as isolated products.

A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
7131
Table 6
Table 7
Regioselective Sonogashira and Suzuki cross-coupling of imidazo[1,2-a]pyridine 14
Synthesis of dissimilarly disubstituted 2-phenylimidazo[1,2-a]pyridines
CeBr producta
Product Nꢀ
Yieldb (%)
I
Entry
R
Br
Br
N
N
Reaction conditions
OMe
Ph
Ph
MeO
63c
N
N
1
10
N
14
22-28
N
29
93d
92d
CF
Entry
1
ReM (M]H, B(OH)2)
Nꢀ
Yielda (%)
88b
3
MeO
22
2
3
4
27
15
OH
N
96b
94b
N
30
2
3
23
24
OH
Ph
OMe
MeO
86d
N
N
31
B(OH)
2
4
25
26
82c
OH
OMe
2
MeO
91e
N
N
32
33
B(OH)
2
Me
O
5
6
84c
OMe
90f
5
15
N
27
28
86c
76c
F C
3
B(OH)
2
N
a
Substituted C-bromo-2-phenylimidazo[1,2-a]pyridines.
b
c
Yields are given as isolated products.
Pd(OAc)2 (0.1 equiv)/PPh3(0.2 equiv), K2CO3 (2 equiv), boronic acid (1.2 equiv) in
B(OH)
2
DMF for 12 h, 100 ꢀC.
7
S
d
Pd(OAc)2 (0.1 equiv)/PPh3(0.2 equiv), K2CO3 (2 equiv), boronic acid (1.2 equiv)
in DMF, M.W., 20 min, 140 ꢀC.
e
PdCl2(PPh3)2 (0.05 equiv), CuI (0.2 equiv), DMF/Et3N (1/1, v/v), alkynes
a
Yield are given as isolated products.
Alkyne (2 equiv), Pd(PPh3)4 (0.05 equiv), CuI (0.2 equiv), DMF/Et3N, rt, 6 h.
RB(OH)2 (1.2 equiv) with K2CO3 (2 equiv), Pd2(dba)3$CHCl3 (0.1 equiv)/
(1.5 equiv), M.W., 20 min, 140 ꢀC.
b
c
f
PdCl2(PPh3)2 (0.05 equiv), CuI (0.2 equiv), DMF/Et3N (1/1, v/v), alkynes
(1.3 equiv), M.W., 20 min, 140 ꢀC.
AsPh3(0.2 equiv) in EtOH/dioxane (1/3, v/v), 50 ꢀC, 10-12 h.
necessary when 6-position was substituted by aromatic or alkyne
derivative.
methoxyphenylboronic acid (1.2 equiv), Pd(OAc)2 (0.1 equiv), PPh3
(0.2 equiv) and K2CO3 (2 equiv) in DMF at 100 ꢀC for 12 h. These
conditions allowed dissimilarly bis-arylated 2-phenylimidazo[1,2-
a]pyridine 29 to be obtained in 63% yield (Table 7, entry 1). Mi-
crowave irradiation was tried in order to improve the yields and to
decrease reaction times. We subjected the reaction mixtures of
compounds 10, 27 and 15 with several arylboronic acid (1.2 equiv)
to microwave heating at 140 ꢀC for 20 min using the already opti-
mized reaction conditions under conventional heating [Pd(OAc)2
(10 mol %), PPh3 (20 mol %)]. This method afforded the desired
compounds 29e31 in excellent yields (86e93%) (Table 7, entries
1e3). Then, we focused our interest on the preparation of other
derivatives by Sonogashira cross-coupling performed under mi-
crowave irradiation. Treatment of compound 2 and 15 with various
alkynes (1.5 equiv alkyne for compound 2 and 1.3 equiv alkyne for
compound 15) under the optimal Sonogashira conditions
[PdCl2(PPh3)2 (0.05 equiv), CuI (0.2 equiv) in a mixture of DMF/Et3N
(1/1, v/v), 140 ꢀC, 20 min, M.W.], led to compounds 32 and 33 in
excellent 91% and 90% isolated yields, respectively (Table 7, entries
4 and 5). Sonogashira coupling in 3-position required 2 equiv al-
kyne when 6-position was halogenated, while only 1.5 equiv were
2.6. One-pot reaction
The versatility of one-pot regioselective synthesis of 3,6-
disubstituted imidazo[1,2-a]pyridines was examined. One-pot
multistep processes are economically advantageous considering
the outlays for the catalyst, solvent, purification materials and time.
Having successfully established the protocol to produce a mono-
coupling, we shifted our focus to the one-pot bis-Sonogashira and
one-pot bis-Suzuki reactions of 3,6-dihalogenoimidazo[1,2-a]pyri-
dines with alkynes and (hetero)arylboronic acids (Scheme 1). Af-
terwards we used a single catalyst for two successive Sonogashira
reactions in which a first alkyne would react selectively at the more
reactive C-6 position of compound 1 then a second alkyne would be
added to react at the C-3 position of compound 1 (Scheme 3). Mi-
crowave irradiation in the same pot without workup was used for
that aim. The best reaction conditions were the following: 6-iodo-
3-bromo-2-phenylimidazo[1,2-a]pyridine 1 was treated succes-
sively with phenylacetylene (1.1 equiv only to limit mixture of
compounds at second step) in the presence of PdCl2(PPh3)2
(0.05 equiv), CuI (0.2 equiv) in a mixture of DMF/Et3N (1/1, v/v) and

7132
A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
3. Experimental section
3.1. General remarks and methods
All reagents were purchased from SigmaeAldrich, Acros
Organics, and Alfa Aesar and used without further purification.
Microwave-assisted reactions were carried out in a Biotage Initia-
tor microwave synthesis instrument and temperatures were
measured by an IR sensor. Melting points were determined and
uncorrected. 1H and 13C NMR were recorded on a spectrometer
(250.19 MHz 1H, 62.89 MHz 13C) and a spectrometer (400 MHz 1H,
100.6 MHz 13C) using tetramethylsilane (TMS) as the internal
standard, multiplicities were determined by the DEPT 135 se-
quence. Chemical shifts were reported in parts per million (ppm).
Coupling constants were reported in units of hertz (Hz). Splitting
patterns were designated as s, singlet, d, doublet, t, triplet, m,
multiplet. High resolution mass spectra (HRMS) were recorded
with a TOF spectrometer in the electrospray ionization (ESI) mode
or in chemical ionization (CI) mode. All commercial solvents were
used without further purification. The following solvents have
been abbreviated: ethyl acetate (EtOAc), petroleum ether (PE),
dimethylformamide (DMF), dimethoxyethane (DME), ethanol
(EtOH). Column chromatography was carried out using Silica gel
Scheme 3. One-pot two-step SonogashiraeSonogashira reaction on 6-iodo-3-bromo-
2-phenylimidazo[1,2-a]pyridine 1.
was irradiated for 10 min at 70 ꢀC (first coupling). After cooling to
room temperature, propargyl alcohol (1.5 equiv) was added and the
reaction mixture was irradiated again for 45 min at 120 ꢀC (second
coupling). These sequences afforded desired polysubstituted imi-
dazo[1,2-a]pyridine 34 in good overall yield (70%) (Scheme 2)
without side products.
One-pot two-step cross-coupling of compound 1, with 4-
methoxyphenylboronic and 4-trifluoromethylphenylboronic was
also carried out. Similarly, microwave irradiation in the same pot
without workup was used. The best reaction conditions were the
following: 6-iodo-3-bromo-2-phenylimidazo[1,2-a]pyridine 1 was
treated successively with 4-methoxyphenylboronic (1.1 equiv) in the
presence of Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), K2CO3 (2 equiv) in
DMF and was irradiated for 30 min at 120 ꢀC (first coupling, on io-
dinated position). After cooling to room temperature, 4-
trifluoromethylphenylboronic (1.3 equiv) was added and the re-
action mixturewasirradiatedagain for2 h at140ꢀC (second coupling,
on brominated position). These sequences afforded the desired pol-
ysubstituted imidazo[1,2-a]pyridine 30 in good overall yield (69%)
(Scheme 4). No byproducts were detected. This approach was applied
to the synthesis of dissimilarly 3,6-disubstituted-2-phenylimidazo
[1,2-a]pyridines in a one-pot procedure. It was found that the re-
action of 3,6-dihalogeno-2-phenylimidazo[1,2-a]pyridine 1 or 14
withvariousreagents I, followedby the additionof anotherreagentII,
after completion of the first coupling (TLC monitoring), afforded the
disubstituted products in good yield. Results summarized in Table 8
show a wide range of alkynyl reagents and arylboronic acids can be
coupled efficiently with 1 and 14 (55e75%).
60 N (spherical, neutral, 40e63 mm). Thin layer chromatography
(TLC) was carried out on silica gel 60F254254 precoated plates.
Visualization was made with UV light.
3.2. Procedure for synthesis of halogenated imidazo[1,2-a]
pyridines 1, 14 and 16
The required 6-iodo-2-phenylimidazo[1,2-a]pyridine, 6-bromo-2-
phenylimidazo[1,2-a]pyridine, and 6-bromoimidazo[1,2-a]pyridine
were prepared by condensation of the suitable 5-iodo-2-amino-
pyridine or 5-bromo-2-aminopyridine with 2-bromoacetophenone
or chloroacetaldehyde in refluxing ethanol according to a literature
procedure.11
3.2.1. 3-Bromo-6-iodo-2-phenylimidazo[1,2-a]pyridine [1]. To a so-
lution of 6-iodo-2-phenylimidazo[1,2-a]pyridine (1.0 g 3.12 mmol)
in 20 mL ACN were added 667 mg (3.74 mmol) of N-bromosucci-
nimide. The reaction was stirred at room temperature for 6 h.
Solvent was removed in vacuo then residue was diluted with
CH2Cl2 and washed successively with 10% NaOH aqueous solution,
saturated thiosulfate solution and then with water. The organic
layer was dried over magnesium sulfate and concentrated in vacuo
to afford the desired product as a white solid (1.14 g), 92% yield, mp
147e148 ꢀC; IR (ATR)
n
(cmꢁ1) 3019, 1215, 768, 696. 1H NMR
(400 MHz, CDCl3)
d 7.40e7.44 (m, 3H), 7.47e7.49 (m, 2H), 8.11 (dd,
Scheme 4. One-pot two-step SuzukieSuzuki reaction on 6-iodo-3-bromo-2-
phenylimidazo[1,2-a]pyridine 1.
J¼5.2, 3.3 Hz, 2H), 8.42 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
d 76.1,
91.6, 118.6, 128.0, 128.6, 128.7, 129.1, 133.4, 133.2, 144.1. HRMS (EI)
m/z calcd for C13H8BrIN2 [M]þ: 398.8994, found: 398.8979.
Thisstudyprovidesanewandefficientregiocontrolledpalladium-
mediated reaction at C-iodo position of imidazo[1,2-a]pyridines.
Conditions for generating selectively 6-bromo-3-aryl(alkynyl)-2-
phenylimidazo[1,2-a]pyridines and 3-bromo-6-aryl(alkynyl)-2-
phenylimidazo[1,2-a]pyridines by Pd-catalyzed regioselective Sono-
gashira and SuzukieMiyaura were defined. Access to 3,6-
disubstituted imidazo[1,2-a]pyridine with high yields using a dou-
ble Sonogashira or double SuzukieMiyaura cross-coupling reaction
startingfroma dihalogenoimidazo[1,2-a]pyridinewaspresented. The
one-pot double-coupling reaction is useful for the synthesis of a wide
range of substituted imidazo[1,2-a]pyridines. This method, which
offers several advantages including high yields and short reaction
times is currently investigated on other systems, such as imidazo[1,2-
b]pyridazines.
3.2.2. 6-Bromo-3-iodo-2-phenylimidazo[1,2-a]pyridine
[14]. To
a
solution of 6-bromo-2-phenylimidazo[1,2-a]pyridine (1.0
g
3.66 mmol) in 20 mL ACN were added 988 mg (4.39 mmol) of N-
iodosuccinimide. The reaction was stirred at room temperature for
1 h. Solvent was removed in vacuo then residue was diluted with
CH2Cl2 and washed successively with 10% NaOH aqueous solution,
saturated thiosulfate solution and then with water. The organic
layer was dried over magnesium sulfate and concentrated in vacuo
to afford the desired product as a white solid (1.40 g), 96% yield, mp
180e182 ꢀC; IR (ATR)
n
(cmꢁ1) 3019. 1467. 1215. 786. 695. 1H NMR
(400 MHz, CDCl3)
d
7.32 (dd, J¼9.4, 1.8 Hz, 1H), 7.40e7.45 (m, 1H),
7.48e7.53 (m, 3H), 8.05 (d, J¼5.2 Hz, 2H), 8.38 (s, 1H). 13C NMR
(100.6 MHz, CDCl3)
d 108.1, 118.3, 126.8, 128.5, 128.6, 128.7, 129.1,

A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
7133
Table 8
One-pot two-step SonogashiraeSonogashira and one-pot SuzukieSuzuki reactions on dihalogeno-2-phenylimidazo[1,2-a]pyridines 1 and 14
R
X'
2
1-Reagent I
R
X
1
conditions (b) or (c)
N
N
N
2-Reagent II
N
1, X= I, X' = Br
14, X= Br, X' = I
R , R = Aryles or alkynes
1 2
Entry
S.M.
Reagent I
Reagent II
Product
Nꢀ
Yielda (%)
OH
1
1
34
70b
OH
N
N
OH
2
1
35
55b
OH
N
N
OH
3
1
36
68b
HO
OH
OH
N
N
4
14
37
75b
OH
HO
N
N
Ph
5
14
38
74b
HO
OH
N
Ph
N
CF
3
B(OH)
B(OH)
2
2
MeO
6
1
30
69c
N
CF
3
OMe
N
CHO
B(OH)
B(OH)
2
2
MeO
7
1
39
71c
N
OMe
CHO
N
(continued on next page)

7134
A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
Table 8 (continued )
Entry
S.M.
Reagent I
Reagent II
Product
Nꢀ
Yielda (%)
B(OH)
2
S
MeO
B(OH)
71c
2
8
1
40
N
S
N
OMe
S.M.¼starting material.
a
Yields are given as isolated products.
b
Reaction conditions of one-pot double Sonogashira coupling: (1) Reagent I (1.1 equiv), PdCl2(PPh3)2 (0.05 equiv), CuI (0.2 equiv) DMF/Et3N (1/1, v/v), 10 min, 70 ꢀC, M.W.
(2) Reagent II (1.5 equiv) 30e45 min, 140 ꢀC, M.W.
c
Reaction conditions of one-pot double Suzuki coupling: (1) Reagent I (1.1 equiv), Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), K2CO3 (2 equiv), DMF, 30 min, 120 ꢀC, M.W. (2)
Reagent II (1.3 equiv), 2 h, 140 ꢀC, M.W.
133.2, 146.7, 148.9. HRMS (EI) m/z calcd for C13H8BrIN2 [M]þ:
398.8994, found: 398.8986.
129.2, 133.0, 144.1, 149.2. HRMS (EI) m/z calcd for C21H18N2O2
[MþH]þ: 331.1447, found: 331.1430.
3.2.3. 6-Bromo-3-iodoimidazo[1,2-a]pyridine [16]. Toasolutionof6-
bromoimidazo[1,2-a]pyridine (721 mg 3.66 mmol) in 20 mL ACN
were added 988 mg (4.39 mmol) of N-iodosuccinimide. The reaction
was stirred at room temperature for 1 h. Solvent was removed in
vacuo then residue was diluted with CH2Cl2 and washed successively
with 10% NaOH aqueous solution, saturated thiosulfate solution and
then with water. The organic layer was dried over magnesium sulfate
and concentrated in vacuo to afford the desired product as a white
3.3.3. 4-(3-Bromo-2-phenylimidazo[1,2-a]pyridin-6-yl)-2-
methylbut-3-yn-2-ol [6]. White solid, 95% yield, mp 152 ꢀC; IR (ATR)
n
(cmꢁ1) 3280, 2974, 2361, 1444, 1219, 810, 769, 689. 1H NMR
(400 MHz, CDCl3)
d 1.63 (s, 6H), 2.53e2.86 (m, 1H), 7.15e7.19 (m,
1H), 7.34e7.42 (m, 1H), 7.45e7.48 (m, 2H), 7.56 (d, J¼9.2 Hz, 1H),
8.07e8.15 (m, 2H), 8.16e8.22 (m, 1H). 13C NMR (100.6 MHz, CDCl3)
d
31.5, 65.6, 78.1, 92.1, 96.0, 117.3, 125.5, 126.8, 128.0, 128.2, 128.6,
128.7, 132.5, 143.5, 144.4. HRMS (EI) m/z calcd for C18H15BrN2O
solid (1.18 g), 96% yield, mp 209 ꢀC; IR (ATR)
n
(cmꢁ1) 3024. 1516. 711.
[M]þ: 355.0446, found: 355.0432.
698. 1H NMR (400 MHz, CDCl3)
d
7.29 (dd, J¼9.6, 1.8 Hz, 1H), 7.51 (d,
J¼9.6 Hz, 1H), 7.70 (s, 1H), 8.26e8.28 (m, 1H). 13C NMR (100.6 MHz,
3.3.4. 3-(3-Bromo-2-phenylimidazo[1,2-a]pyridin-6-yl)-prop-2-yn-
CDCl3)
d
61.4,108.4,118.6,126.4,128.6,128.6,141.1,146.5. HRMS(EI)m/
1-ol [7]. White solid, 93% yield, mp 186 ꢀC; IR (ATR) (cmꢁ1) 3244,
n
z calcd for C7H4BrIN2 [MþH]þ: 322.8675, found: 322.8678.
2984, 2360, 1440, 1032, 816, 688. 1H NMR (400 MHz, DMSO-d6)
d
4.36 (d, J¼5.8 Hz, 2H), 5.43 (t, J¼5.8 Hz, 1H), 7.33e7.33 (m, 1H),
7.42 (dd, J¼8.3, 6.3 Hz,1H), 7.49e7.52 (m, 2H), 7.67 (d, J¼9.2 Hz,1H),
3.3. Procedure for Sonogashira cross-coupling reaction of
imidazo[1,2-a]pyridine [1]
8.05e8.10 (m, 2H), 8.43e8.47 (m, 1H). 13C NMR (100.6 MHz, DMSO-
d6)
d 49.3, 79.7, 91.5, 109.0, 117.1, 126.9, 127.2, 127.9, 128.5, 128.6,
132.2, 141.9, 142.1, 143.6. HRMS (EI) m/z calcd for C16H11BrN2O [M]þ
To a solution of 3-iodo-6-bromophenylimidazo[1,2-a]pyridine 1
(100 mg 0.250 mmol) in 2 mL of a mixture of DMF/Et3N (1/1, v/v)
were added 9.5 mg (0.050 mmol) of copper iodide, alkyne
(0.325 mmol) and 8.7 mg (0.012 mmol) of bis(triphenylphosphine)
palladium dichloride. The reaction was stirred at room temperature
sealed under argon. Once TLC indicated complete consumption of
starting material (4 h), the reaction was quenched with water and
extracted with dichloromethane (2ꢂ15 mL). The combined organic
layers were dried over magnesium sulfate and concentrated in
vacuo. The resulting residue was purified by column chromatog-
raphy on silica gel (EtOAc/PE) to afford the corresponding cross-
coupling products 2, 3, 6, 7, 8 and 9.
327.0133, found: 327.0115.
3.3.5. 3-Bromo-2-phenyl-6-(phenylethynyl)imidazo[1,2-a]pyridine
[8]. White solid, 91% yield, mp 130 ꢀC; IR (ATR) (cmꢁ1) 3024, 2360,
n
1538, 1415, 1222, 824, 755, 687. 1H NMR (400 MHz, CDCl3)
d
7.30e7.42 (m, 5H), 7.47e7.51 (m, 2H), 7.55e7.50 (m, 2H), 7.59 (d,
J¼9.2 Hz, 1H), 8.09e8.16 (m, 2H), 8.27e8.41 (m, 1H). 13C NMR
(100.6 MHz, CDCl3) d 85.3, 91.4,110.2,117.4,122.5,126.7,127.6,128.0,
128.2, 128.6, 128.6, 128.7, 128.9, 131.7, 132.6, 143.6, 144.4. HRMS (EI)
m/z calcd for C21H13BrN2 [M]þ: 373.0340, found: 373.0328.
3.3.6. 3-Bromo-2-phenyl-6-(3-phenylprop-1-ynyl)imidazo[1,2-a]
pyridine [9]. White solid, 94% yield, mp 125 ꢀC; IR (ATR)
n
(cmꢁ1
3.86 (s,
)
3.3.1. 3-Bromo-6-(3-methoxyprop-1-ynyl)-2-phenylimidazo-[1,2-a]
3027, 2362, 1415, 768, 696, 686. 1H NMR (400 MHz, CDCl3)
d
pyridine [2]. Yellow solid, 92% yield, mp 92 ꢀC; IR (ATR)
n )
(cmꢁ1
2H), 7.23e7.31 (m, 2H), 7.34e7.43 (m, 5H), 7.45e7.49 (m, 2H), 7.55
3026, 2988, 2360, 1445, 1318, 1092, 820, 768, 689. 1H NMR
(400 MHz, CDCl3) 3.44 (s, 3H), 4.31 (s, 2H), 7.20e7.25 (m, 1H),
7.33e7.39 (m, 1H), 7.42e7.46 (m, 2H), 7.53 (d, J¼9.2 Hz, 1H),
8.06e8.11 (m, 2H), 8.25 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
58.0,
(dd, J¼9.2, 0.7 Hz, 1H), 8.08e8.14 (m, 2H), 8.29 (s, 1H). 13C NMR
d
(100.6 MHz, CDCl3) d 25.9, 78.6, 89.9, 110.4, 117.2, 126.7, 127.0, 127.8,
127.9,128.1,128.5,128.5,128.6,128.8,132.7,136.2,143.4,144.4. HRMS
d
(EI) m/z calcd for C22H15BrN2 [M]þ: 387.0497, found: 387.0484.
60.4, 82.4, 87.1, 109.4, 117.3, 127.2, 127.5, 127.9, 128.0, 128.6, 128.6,
132.5, 143.6, 144.4. HRMS (EI) m/z calcd for C17H13BrN2O [M]þ:
341.0289, found: 341.0278.
3.4. Procedure for Suzuki cross-coupling reaction of imidazo
[1,2-a]pyridine [1]
3.3.2. 3,6-Bis-(3-methoxyprop-1-ynyl)-2-phenylimidazo[1,2-a]pyri-
dine [3]. Brown oil; IR (ATR)
n
(cmꢁ1) 2988, 1449, 1090, 820. 1H
To a solution of 6-iodo-3-bromophenylimidazo[1,2-a]pyridine 1
(100 mg 0.250 mmol) in 2 mL of DMF were successively added the
desired (het)Ar boronic acid (0.300 mmol), potassium carbonate
(0.501 mmol), triphenylphosphine (0.050 mmol) and palladium(II)
acetate (0.025 mmol). The reaction was stirred at 100 ꢀC sealed
under argon. Once TLC indicated complete consumption of starting
NMR (400 MHz, CDCl3) 3.48 (s, 3H), 3.52 (s, 3H), 4.34 (s, 2H), 4.55
d
(s, 2H), 7.25 (dd, J¼8.7, 1.6 Hz, 1H), 7.37 (td, J¼4.7, 1.2 Hz, 1H),
7.44e7.50 (m, 2H), 7.55 (dd, J¼9.2, 0.8 Hz, 1H), 8.24e8.27 (m, 2H),
8.43 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
d 57.9, 58.0, 60.4, 60.8,
75.1, 82.4, 87.1, 98.2, 104.3, 109.3, 117.2, 127.3, 128.3, 128.6, 128.9,

A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
7135
material (2 h), the reaction was cooled to room temperature,
quenched with water and extracted with dichloromethane
(2ꢂ15 mL). The combined organic layers were dried over magne-
sium sulfate and concentrated in vacuo. The resulting residue was
purified by column chromatography on silica gel (EtOAc/PE) to af-
ford the corresponding cross-coupling products 4, 5, 10e13.
128.6, 130.7, 132.7, 135.9, 143.1, 143.8, 145.0, 191.6. HRMS (EI) m/z
calcd for C20H13BrN2O [M]þ: 377.0289, found: 377.0274.
3.5. Procedure for Sonogashira cross-coupling reaction of
imidazo[1,2-a]pyridines (14 or 16)
Toasolution of6-bromo-3-iodoimidazo[1,2-a]pyridine (14 or 16)
(14: 100 mg or 16: 81 mg, 0.250 mmol) in 2 mL of a mixture of DMF/
Et3N (1/1, v/v) were successively added the desired alkyne
(0.501 mmol), copper iodide (0.050 mmol) and 8.7 mg (0.012 mmol)
of bis(triphenylphosphine)palladium dichloride. The reaction was
stirred at room temperature sealed under argon. Once TLC indicated
complete consumption of starting material (3 h), the reaction was
quenched with water and extracted with dichloromethane
(2ꢂ15 mL). The combined organic layer were dried over magnesium
sulfate and concentratedinvacuo. Theresulting residuewas purified
by column chromatography on silica gel (EtOAc/PE) to afford the
corresponding cross-coupling products 15, 17e20, and 22e24.
3.4.1. 3-Bromo-6-(3-methoxyphenyl)-2-phenylimidazo[1,2-a]pyri-
dine [4]. White solid, 90% yield, mp 127e128 ꢀC; IR (ATR)
n
(cmꢁ1) 1586, 1487, 1465, 1286, 825, 772, 718. 1H NMR (400 MHz,
CDCl3)
d
3.88 (s, 3H), 6.95 (dd, J¼8.1, 2.2 Hz, 1H), 7.10e7.14
(m, 1H), 7.19 (d, J¼7.7 Hz, 1H), 7.38e7.41 (m, 2H), 7.45e7.54
(m, 3H), 7.69 (d, J¼9.2 Hz, 1H), 8.11e8.17 (m, 2H), 8.33 (s, 1H). 13C
NMR (100.6 MHz, CDCl3)
d 55.5, 92.2, 113.2, 113.3, 117.5, 119.6,
121.4, 126.1, 127.7, 128.0, 128.5, 128.6, 130.4, 132.9, 138.7, 143.3,
144.9, 160.3. HRMS (EI) m/z calcd for C20H15BrN2O [M]þ:
379.0434, found: 379.0446.
3.4.2. 3,6-Bis-(3-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine
[5]. White solid, 19% yield, mp 140 ꢀC; IR (ATR)
n
(cmꢁ1) 1586, 1575,
3.5.1. 6-Bromo-3-(3-methoxyprop-1-ynyl)-2-phenylimidazo-[1,2-a]
1472, 1234, 1044, 776. 1H NMR (400 MHz, CDCl3)
d
3.80 (s, 3H), 3.86
pyridine [15]. Yellow solid, 90% yield, mp 95 ꢀC; IR (ATR) (cmꢁ1
n )
(s, 3H), 6.91 (dd, J¼8.1, 2.1 Hz, 1H), 7.00e7.06 (m, 3H), 7.07e7.09 (m,
2H), 7.25e7.27 (m, 1H), 7.28e7.33 (m, 2H), 7.36 (t, J¼7.9 Hz, 1H),
7.44e7.47 (m, 1H), 7.48 (d, J¼4.2 Hz, 1H), 7.70e7.72 (m, 2H), 7.74 (d,
3057, 2923, 2360, 1516, 1492, 1492, 1088, 820, 796, 687. 1H NMR
(400 MHz, CDCl3)
d
3.52 (s, 3H), 4.54 (s, 2H), 7.31 (dd, J¼9.4, 1.8 Hz,
1H), 7.36e7.41 (m, 1H), 7.44e7.48 (m, 2H), 7.51 (d, J¼9.2 Hz, 1H),
J¼9.3 Hz, 1H), 8.12 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
d 55.5, 112.8,
8.25e8.26 (m, 2H), 8.39 (d, J¼1.1 Hz, 1H). 13C NMR (100.6 MHz,
113.3, 114.9, 116.1, 117.4, 119.5, 120.8, 121.4, 123.0, 125.5, 126.8, 127.6,
128.1, 128.4, 130.2, 130.8, 131.2, 134.2, 139.2, 143.0, 144.2, 160.2,
160.6. HRMS (EI) m/z calcd for C27H22N2O2 [MþH]þ: 407.1760,
found: 407.1751.
CDCl3) d 58.0, 60.7, 75.0, 98.3, 104.3, 107.9, 118.1, 125.2, 127.3, 128.6,
128.9, 129.8, 143.6, 143.6, 149.0. HRMS (EI) m/z calcd for
C17H13BrN2O [M]þ: 341.0289, found: 341.0270.
3.5.2. 6-Bromo-3-(3-methoxyprop-1-ynyl)imidazo[1,2-a]pyridine
3.4.3. 3-Bromo-6-(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyri-
[17]. Yellow solid, 96% yield, mp 76 ꢀC; IR (ATR) (cmꢁ1) 3063,
n
dine [10]. White solid, 88% yield, mp 198 ꢀC; IR (ATR)
n
(cmꢁ1) 2998,
2208, 1479, 1310, 1088, 902, 753. 1H NMR (400 MHz, CDCl3)
d 3.49
1605, 1512, 1439, 1245, 813, 735, 700. 1H NMR (400 MHz, CDCl3)
(s, 3H), 4.47 (s, 2H), 7.33 (dd, J¼9.6, 1.8 Hz, 1H), 7.55 (d, J¼9.6 Hz,
d
3.86 (s, 3H), 7.01 (d, J¼8.7 Hz, 2H), 7.39 (t, J¼7.3 Hz, 1H), 7.46e7.48
1H), 7.83 (s, 1H), 8.415e8.419 (m, 1H). 13C NMR (100.6 MHz, CDCl3)
(m, 3H), 7.52 (d, J¼8.7 Hz, 2H), 7.66 (d, J¼9.2 Hz, 1H), 8.14 (d,
d 57.9, 60.5, 73.2, 96.1,108.2,118.6,125.3,129.2,139.2. HRMS (EI) m/z
J¼7.7 Hz, 2H), 8.24e8.28 (m, 1H). 13C NMR (100.6 MHz, CDCl3)
calcd for C11H10BrN2O [MþH]þ: 264.9971, found: 264.9971.
d
55.5, 92.0, 114.7, 117.4, 120.6, 126.0, 127.4, 127.9, 128.2, 128.4, 128.5,
129.6, 133.0, 143.1, 144.7, 159.8. HRMS (EI) m/z calcd for
3.5.3. 4-(6-Bromoimidazo[1,2-a]pyridin-6-yl)-2-methylbut-3-yn-2-
C20H15BrN2O [M]þ: 379.0438, found: 379.0446.
ol [18]. Yellow solid, 95% yield, mp 129 ꢀC; IR (ATR) (cmꢁ1) 3206,
n
2980, 1487, 1154, 802, 690. 1H NMR (400 MHz, CDCl3)
d 1.71 (s, 6H),
3.4.4. 3-Bromo-6-(m-tolyl)-2-phenylimidazo[1,2-a]pyridine
7.32 (dd, J¼9.2, 1.6 Hz, 1H), 7.54 (d, J¼9.2 Hz, 1H), 7.79 (s, 1H), 8.32
[11]. Yellow solid, 87% yield, mp 71 ꢀC; IR (ATR)
n
(cmꢁ1) 3062,
(dd, J¼1.6, 0.8 Hz,1H). 13C NMR (100.6 MHz, CDCl3)
d 31.6, 66.1, 69.2,
2919, 1673, 1466, 1439, 1211, 826, 730, 680. 1H NMR (400 MHz,
CDCl3) 2.41 (s, 3H), 7.21e7.24 (m, 1H), 7.37e7.40 (m, 4H),
104.8, 108.2, 118.7, 125.2, 129.2, 138.7. HRMS (EI) m/z calcd for
d
C12H12BrN2O [MþH]þ: 279.0128, found: 279.0127.
7.43e7.50 (m, 3H), 7.66 (d, J¼9.2 Hz, 1H), 8.06e8.17 (m, 2H), 8.27 (d,
J¼0.7 Hz, 1H). 13C NMR (100.6 MHz, CDCl3)
d
21.6, 92.1, 117.5, 121.2,
3.5.4. 3-(6-Bromoimidazo[1,2-a]pyridin-6-yl)-prop-2-yn-1-ol
124.2, 126.1, 127.8, 127.9, 128.4, 128.5, 128.9, 129.1, 133.0, 137.1, 139.0,
143.2, 144.9. HRMS (EI) m/z calcd for C20H15BrN2 [M]þ: 363.0497,
found: 363.0498.
[19]. Yellow solid, 92% yield, mp 154 ꢀC; IR (ATR) (cmꢁ1) 3180,
n
3063, 2208,1479, 1080, 690. 1H NMR (400 MHz, DMSO-d6)
d 4.46 (d,
J¼6.0 Hz, 2H), 5.45 (t, J¼6.0 Hz, 1H), 7.51 (dd, J¼9.6, 2.0 Hz, 1H), 7.67
(d, J¼9.6 Hz, 1H), 7.91 (s, 1H), 8.68 (s, 1H). 13C NMR (100.6 MHz,
3.4.5. 3-Bromo-2-phenyl-6-(thiophen-3-yl)imidazo[1,2-a]pyridine
DMSO-d6) d 49.8, 70.6, 100.7, 107.7, 118.5, 125.3, 129.1, 138.0. HRMS
[12]. Yellow solid, 90% yield, mp 191 ꢀC; IR (ATR)
n
(cmꢁ1) 1467,1426,
(EI) m/z calcd for C10H8BrN2O [MþH]þ: 250.9815, found: 250.9812.
1145, 775, 766, 693. 1H NMR (400 MHz, CDCl3)
7.46e7.53 (m, 5H), 7.66 (dd, J¼9.2, 0.7 Hz,1H), 8.13e8.16 (m), 8.35 (s,
1H). 13C NMR (100.6 MHz, CDCl3)
92.2, 117.7, 120.6, 121.3, 122.7,
d 7.38e7.43 (m, 2H),
3.5.5. 6-Bromo-3-(phenylethynyl)imidazo[1,2-a]pyridine
d
[20]. Yellow solid, 96% yield, mp 122 ꢀC; IR (ATR) (cmꢁ1) 3059,
n
125.5, 125.9, 127.3, 127.9, 128.4, 128.6, 132.9, 138.0, 143.2, 144.8.
HRMS (EI) m/z calcd for C17H11BrN2S [M]þ: 354.9905, found:
354.9889.
2208, 1473, 1240, 684. 1H NMR (400 MHz, CDCl3)
d
7.34 (dd, J¼15.2,
2.8 Hz, 1H), 7.39e7.43 (m, 3H), 7.55 (s, 1H), 7.58e7.61 (m, 2H), 7.89
(s, 1H), 8.47 (d, J¼2.0 Hz, 1H). 13C NMR (100.6 MHz, CDCl3)
d 75.8,
99.8, 108.3, 118.8, 122.3, 125.5, 128.7, 129.1, 129.2, 131.6, 138.8. HRMS
3.4.6. 4-(3-Bromo-2-phenylimidazo[1,2-a]pyridin-6-yl)benzalde-
(EI) m/z calcd for C15H10BrN2 [MþH]þ: 297.0022, found: 297.0025.
hyde [13]. Yellow solid, 85% yield, mp 192 ꢀC; IR (ATR)
n )
(cmꢁ1
2780, 1700, 1601, 1469, 1213, 815, 771, 695. 1H NMR (400 MHz,
CDCl3)
3.5.6. 3-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-6-yl)-prop-2-yn-
d
7.41 (t, J¼7.3 Hz, 1H), 7.50 (t, J¼7.5 Hz, 2H), 7.56 (dd, J¼9.3,
1-ol [22]. White solid, 88% yield, mp 211 ꢀC; IR (ATR) (cmꢁ1) 3183,
n
1.7 Hz, 1H), 7.75 (d, J¼9.2 Hz, 1H), 7.80 (d, J¼8.1 Hz, 2H), 8.02 (d,
3082, 2972, 2360, 1491, 1088, 682. 1H NMR (400 MHz, DMSO-d6)
4.57 (d, J¼6.0 Hz, 2H), 5.55 (t, J¼6.0 Hz, 1H), 7.39e7.45 (m, 1H),
7.51 (t, J¼7.5 Hz, 2H), 7.55 (dd, J¼9.4, 1.9 Hz, 1H), 7.68 (d, J¼9.4 Hz,
J¼8.1 Hz, 2H), 8.13e8.19 (m, 2H), 8.42 (s, 1H), 10.10 (s, 1H). 13C NMR
d
(100.6 MHz, CDCl3)
d 92.6, 118.0, 122.0, 125.3, 126.4, 127.7, 128.0,

7136
A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
1H), 8.24e8.28 (m, 2H), 8.69 (d, J¼1.1 Hz, 1H). 13C NMR (100.6 MHz,
128.1, 128.5, 128.5, 129.1, 130.0, 130.3, 130.5, 133.4, 135.4, 138.6,
143.5, 143.9, 197.4. HRMS (EI) m/z calcd for C21H15BrN2O [M]þ:
391.0446, found: 391.0431.
DMSO-d6)
d 49.8, 66.2, 71.7, 103.1, 107.5, 118.2, 125.1, 126.4, 128.6,
128.7, 129.9, 132.5, 142.8, 146.4. HRMS (EI) m/z calcd for
C16H11BrN2O [M]þ: 327.0133, found: 327.0116.
ꢀ
3.6.4. 6-Bromo-2-phenyl-3-(4-trifluoromethylphenyl)imidazo-[1,2-
3.5.7. 4-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-6-yl)-2-
a]pyridine [27]. Brown solid, 86% yield, mp 192 ꢀC; IR (ATR)
n
methylbut-3-yn-2-ol [23]. White solid, 96% yield, mp 223 ꢀC; IR
(cmꢁ1) 1492, 1390, 1331, 1116, 1102, 1068, 826, 695. 1H NMR
(ATR)
n
(cmꢁ1) 3183, 2973, 2360,1491,1087, 682. 1H NMR (400 MHz,
(400 MHz, CDCl3) d 7.20e7.33 (m, 4H), 7.51e7.61 (m, 5H), 7.79 (d,
DMSO-d6)
d
1.62 (s, 6H), 5.80 (s, 1H), 7.38e7.46 (m, 1H), 7.46e7.57
J¼8.06 Hz, 2H), 8.06 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
d 107.6,
(m, 3H), 7.68 (dd, J¼9.4, 0.7 Hz, 1H), 8.27e8.28 (m, 2H), 8.60 (dd,
118.5, 119.9, 123.1, 126.7, 126.7, 126.8, 126.8, 128.2, 128.3, 128.6,
128.6, 131.0, 131.0, 133.1, 133.3, 143.7, 144.3. HRMS (EI) m/z calcd for
C20H12BrF3N2 [M]þ: 417.0214, found: 417.0203.
J¼1.8, 0.8 Hz, 1H). 13C NMR (100.6 MHz, DMSO-d6)
d 31.1, 64.1, 68.8,
103.8, 107.4, 108.7, 118.0, 124.8, 126.3, 128.5, 128.6, 129.7, 132.6,
142.7, 146.3. HRMS (EI) m/z calcd for C18H15BrN2O [M]þ: 355.0446,
found: 355.0431.
3.6.5. 6-Bromo-2-phenyl-3-(thiophen-3-yl)imidazo[1,2-a]pyridine
[28]. Brown solid, 76% yield, mp 177e178 ꢀC; IR (ATR)
n )
(cmꢁ1
3.5.8. 6-Bromo-2-phenyl-3-(phenylethynyl)imidazo[1,2-a]pyridine
1518, 1405, 1317, 1231, 777, 692, 663. 1H NMR (400 MHz, CDCl3)
7.12 (dd, J¼4.9, 1.2 Hz, 1H), 7.20e7.30 (m, 4H), 7.42e7.48 (m, 1H),
7.49e7.56 (m, 2H), 7.60e7.68 (m, 2H), 8.03 (s, 1H). 13C NMR
(100.6 MHz, CDCl3) 107.2, 116.6, 118.2, 123.7, 126.7, 127.6, 128.0,
[24]. White solid, 94% yield, mp 148 ꢀC; IR (ATR)
n
(cmꢁ1) 3021, 2360,
d
2201,1473,1319,1246, 709, 684. 1H NMR (400 MHz, CDCl3)
d 7.31 (dd,
J¼9.4, 1.8 Hz, 1H), 7.36e7.43 (m, 4H), 7.46e7.49 (m, 2H), 7.53 (d,
d
J¼9.4 Hz,1H), 7.58e7.64 (m, 2H), 8.31e8.36 (m, 2H), 8.43 (d, J¼1.0 Hz,
128.1, 128.4, 128.7, 129.0, 133.7, 143.3, 143.8. HRMS (EI) m/z calcd for
1H).13C NMR (100.6 MHz, CDCl3)
d
77.6,101.9,105.1,107.8,118.1,122.4,
C17H11BrN2S [M]þ: 354.9905, found: 354.9885.
125.3, 127.3, 128.7, 128.9, 129.1, 129.7, 131.4, 133.1, 143.6, 148.5. HRMS
(EI) m/z calcd for C21H13BrN2 [M]þ: 373.0340, found: 373.0336.
3.7. Procedure for Suzuki cross-coupling reaction of 6-
bromo-3-substituted imidazo[1,2-a]pyridines under
microwave irradiation
3.6. Procedure for Suzuki cross-coupling reaction of imidazo
[1,2-a]pyridine 14
To a solution of 6-bromo-3-substituted imidazo[1,2-a]pyridine
To a solution of 3-iodo-6-bromophenylimidazo[1,2-a]pyridine
(100 mg 0.250 mmol) in 2 mL of a mixture of 1,4-dioxane/EtOH (2/1,
v/v) were successively added the desired (het)Ar boronic acid
(0.300 mmol), potassium carbonate (0.501 mmol), triphenylarsine
(0.050 mmol) and tris(dibenzylideneacetone)dipalladium(0)-
chloroform adduct (0.025 mmol). The reaction was stirred at
50 ꢀC sealed under argon. Once TLC indicated complete consump-
tion of starting material (6 h), the reaction was cooled to room
temperature, quenched with water and extracted with dichloro-
methane (2ꢂ15 mL). The combined organic layers were dried over
magnesium sulfate and concentrated in vacuo. The resulting resi-
due was purified by column chromatography on silica gel (EtOAc/
PE) to afford the corresponding cross-coupling products 21, 25e28.
(0.26 mmol) dissolved in 2 mL of DMF in a vial microwave tube with
a
stir bar, boronic acid (0.31 mmol), potassium carbonate
(0.52 mmol), triphenylphosphine (0.052 mmol) and palladium(II)
acetate (0.026 mmol) were added under argon. The reaction vessel
was sealed with a silicon septum and subjected to microwave ir-
radiation for 20 min at 140 ꢀC. The reaction mixture was then
allowed to cool to room temperature, diluted with dichloro-
methane (15 mL) and extracted (3ꢂ). The combined organic layers
were dried over MgSO4 and concentrated under vacuum. The crude
material obtained was purified by column chromatography on silica
gel (EtOAc/PE) to give polysubstituted imidazo[1,2-a]pyridine de-
rivatives 29 to 31.
3.7.1. 6-(4-Methoxyphenyl)-3-(3-methoxyphenyl)-2-phenylimidazo
3.6.1. 6-Bromo-3-(3-methoxyphenyl)-2-phenylimidazo[1,2-a]pyri-
[1,2-a]pyridine [29]. White solid, 93% yield, mp 139 ꢀC; IR (ATR)
n
dine [21]. White solid, 80% yield, mp 144 ꢀC; IR (ATR)
n
(cmꢁ1) 1510,
(cmꢁ1) 2925, 1606, 1480, 1275, 1235, 1024, 770, 696. 1H NMR
(400 MHz, CDCl3)
1316,1250, 779, 718, 696.1HNMR(400MHz,CDCl3)
d
3.79(s, 3H), 6.95
d
3.84 (s, 3H), 3.90 (s, 3H), 6.89 (dd, J¼8.2, 1.8 Hz,
(s,1H), 7.01e7.06(m, 2H), 7.23e7.29(m, 4H), 7.46 (t, J¼7.9Hz,1H), 7.56
1H), 7.01 (s, 1H), 7.05e7.07 (m, 3H), 7.23e7.30 (m, 3H), 7.34 (d,
J¼7.9 Hz, 1H), 7.39 (d, J¼8.6 Hz, 2H), 7.45 (dd, J¼9.2, 1.5 Hz, 1H),
7.69e7.71 (m, 2H), 7.73 (d, J¼9.7 Hz, 1H), 8.05 (s, 1H). 13C NMR
(d, J¼9.4 Hz, 1H), 7.67 (d, J¼8.0 Hz, 2H), 8.04e8.09 (m, 1H). 13C NMR
(100.6 MHz, CDCl3) d 55.4, 107.1, 115.0,116.0,118.2,121.3, 122.9,123.5,
127.8,128.0,128.4,130.5,130.9,133.7,143.2,160.6. HRMS (EI) m/zcalcd
(100.6 MHz, CDCl3) d 55.4 (OCH3), 55.4 (OCH3), 112.7 (CH), 113.2
for C20H15BrN2O [M]þ: 379.0446, found: 379.0428.
(CH), 115.2, 117.3, 119.5, 120.7, 121.4, 121.7, 125.4, 126.7, 127.5, 128.0,
128.4, 130.2, 132.2, 132.2, 134.2, 139.1, 142.7, 144.0, 160.1, 160.2.
HRMS (EI) m/z calcd for C27H22N2O2 [M]þ: 407.1760, found:
407.1742.
3.6.2. 6-Bromo-3-(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyri-
dine [25]. White solid, 82% yield, mp 142 ꢀC; IR (ATR)
n
(cmꢁ1):
d 3.89 (s, 3H),
1511, 1479, 1250, 1032, 697. 1H NMR (400 MHz, CDCl3)
6.96 (dd, 1H, J¼8.1, 2.2 Hz), 7.12e7.15 (m, 1H), 7.19 (d, 1H, J¼7.6 Hz),
3.7.2. 6-(4-Methoxyphenyl)-2-phenyl-3-(4-trifluoromethylphenyl)
imidazo[1,2-a]pyridine [30]. White solid, 92% yield, mp 173 ꢀC; IR
7.39e7.43 (m, 2H), 7.46e7.54 (m, 3H), 7.70 (d, 1H, J¼9.3 Hz),
8.11e8.17 (m, 2H), 8.33 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
d
55.5,
(ATR)
(400 MHz, CDCl3)
n
(cmꢁ1) 1499, 1493, 1324, 1245, 1115, 1064, 814, 695. 1H NMR
92.2, 113.2, 113.3, 117.5, 119.6, 121.4, 126.1, 127.7, 128.0, 128.5, 128.6,
130.4, 132.9, 138.7, 143.3, 144.9, 160.3. HRMS (EI) m/z calcd for
C20H15BrN2O [M]þ: 379.0446, found: 379.0426.
d
3.81 (s, 3H), 6.94 (d, J¼8.7 Hz, 2H), 7.32e7.32
(m, 3H), 7.39 (d, J¼8.7 Hz, 2H), 7.43e7.49 (m, 1H), 7.55e7.64 (m,
4H), 7.73 (d, J¼9.3 Hz, 1H), 7.77 (d, J¼8.1 Hz, 2H), 8.05 (d, J¼0.6 Hz,
1H). 13C NMR (100.6 MHz, CDCl3)
d 55.5, 114.6, 117.6, 119.5, 119.8,
3.6.3. 1-[3-(6-Bromo-2-phenylimidazo[1,2-a]pyridin-3-yl)-phenyl]
122.7, 125.4, 126.2, 126.7 (CH), 127.2, 128.0, 128.1, 128.3, 128.5, 129.7,
130.6, 131.0, 133.7, 133.8, 143.9, 144.5, 159.7. HRMS (EI) m/z calcd for
C27H19F3N2O [MþH]þ: 445.1528, found: 445.1533.
ethanone [26]. Yellow solid, 84% yield, mp 152 ꢀC; IR (ATR) (cmꢁ1
n )
3017, 2360, 1685, 1497, 1232, 809, 695. 1H NMR (400 MHz, CDCl3)
d
2.57 (s, 3H), 7.23e7.27 (m, 4H), 7.55e7.65 (m, 5H), 7.98 (dd, J¼1.7,
0.7 Hz,1H), 8.01 (dd, J¼1.7, 0.7 Hz,1H), 8.07 (td, J¼7.1,1.8 Hz,1H). 13C
3.7.3. 6-(4-Methoxyphenyl)-3-(3-methoxyprop-1-ynyl)-2-
phenylimidazo[1,2-a]pyridine [31]. Brown oil, 86% yield; IR (ATR) n
NMR (100.6 MHz, CDCl3)
d
26.8, 107.5, 118.5, 120.3, 123.2, 128.1,

A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
7137
(cmꢁ1) 2928, 2360, 1499, 1060, 814. 1H NMR (400 MHz, CDCl3)
3.9.1. 3-[2-Phenyl-6-(phenylethynyl)imidazo[1,2-a]pyridin-3-yl]-
prop-2-yn-1-ol [34]. Yellow solid, 70% yield, mp 162 ꢀC; IR (ATR)
(cmꢁ1) 3242,1595,1494,1029, 808. 1H NMR (400 MHz, CDCl3)
3.98
d
3.53 (s, 3H), 3.87 (s, 3H), 4.57 (s, 2H), 7.03 (d, J¼8.7 Hz, 2H),
n
7.36e7.41 (m, 1H), 7.45e7.52 (m, 3H), 7.53 (d, J¼8.7 Hz, 2H), 7.69
(dd, J¼9.2, 0.8 Hz, 1H), 8.27e8.34 (m, 2H), 8.39 (dd, J¼1.7, 0.8 Hz,
d
(s, 1H), 4.65 (s, 2H), 7.28 (dd, J¼9.2, 1.6 Hz, 1H), 7.30e7.34 (m, 1H),
7.35 (d, J¼7.4 Hz,1H), 7.36e7.38 (m, 4H), 7.52e7.54 (m, 2H), 7.57 (dd,
J¼9.2, 0.7 Hz, 1H), 8.12e8.16 (m, 3H). 13C NMR (100.6 MHz, CDCl3)
1H). 13C NMR (100.6 MHz, CDCl3)
d 55.5, 57.9, 60.9, 75.8, 97.8, 104.4,
114.7, 117.3, 121.8, 127.2, 127.3, 127.4, 128.3, 128.6, 128.7, 129.6, 133.4,
144.5, 149.0, 159.8. HRMS (EI) m/z calcd for C24H20N2O2 [MþH]þ:
369.1603, found: 369.1586.
d
51.7, 73.9, 85.3, 91.5, 100.9, 104.4, 110.1, 116.7, 122.6, 127.0, 127.6,
128.6, 128.6, 128.8, 128.9, 129.5, 131.7, 132.6, 143.9, 148.4. HRMS (EI)
m/z calcd for C24H16N2O [MþH]þ: 349.1341, found: 349.1323.
3.8. Procedure for Sonogashira cross-coupling reaction under
microwave irradiation
3.9.2. 2-Methyl-4-[2-phenyl-6-(phenylethynyl)imidazo[1,2-a]pyr-
idin-3-yl]but-3-yn-2-ol [35]. Yellow solid, 55% yield, mp 141 ꢀC; IR
(ATR)
(400 MHz, CDCl3)
n
(cmꢁ1) 3257, 2980, 1498, 1391, 1314, 756, 687. 1H NMR
To a solution of imidazo[1,2-a]pyridine 2 or 15 (0.29 mmol) in
2 mL of a mixture of a mixture of DMF/Et3N (1/1, v/v) in a vial
microwave tube, alkyne (0.38 mmol), copper iodide (0.058 mmol)
and bis(triphenylphosphine)palladium dichloride (0.014 mmol)
were added under argon. The reaction vessel was sealed with
a silicon septum and subjected to microwave irradiation for 20 min
at 140 ꢀC. The reaction vessel was cooled to room temperature,
diluted with dichloromethane (15 mL) and extracted (3ꢂ). The
combined organic layers were dried over MgSO4 and concentrated
under vacuum. The crude material was purified by column chro-
matography on silica gel (EtOAc/PE) to give polysubstituted imi-
dazo[1,2-a]pyridine derivatives 32 and 33.
d
1.73 (s, 6H), 3.20e3.40 (m, 1H), 7.32 (dd, J¼9.2,
1.6 Hz,1H), 7.33e7.36 (m,1H), 7.37e7.43 (m, 5H), 7.55e7.59 (m, 2H),
7.61 (dd, J¼9.2, 0.8 Hz,1H), 8.20e8.23 (m, 3H). 13C NMR (100.6 MHz,
CDCl3)
d 31.5, 65.9, 71.0, 85.4, 91.4, 104.4, 106.8, 110.0, 117.0, 122.6,
127.2, 127.5, 128.5, 128.6, 128.8, 128.9, 129.2, 131.7, 132.9, 143.8,
148.4. HRMS (EI) m/z calcd for C20H20N2O [MþH]þ: 377.1654,
found: 377.1646.
3.9.3. 4-[3-(3-Hydroxyprop-1-ynyl)-2-phenylimidazo[1,2-a]-pyr-
idin-6-yl]-2-methylbut-3-yn-2-ol [36]. Yellow solid, 68% yield, mp
187 ꢀC; IR (ATR) (cmꢁ1) 3247, 2980, 1498, 1395, 1023, 703. 1H NMR
n
(400 MHz, DMSO-d6)
6.63e6.70 (m, 2H), 6.74e6.79 (m, 1H), 7.36e7.42 (m, 2H), 7.69 (s,
1H). 13C NMR (100.6 MHz, DMSO-d6)
31.5, 51.1, 66.4, 70.7, 81.1,
d 0.89 (s, 6H), 3.63 (s, 2H), 6.57e6.63 (m, 2H),
3.8.1. 4-[6-(3-Methoxyprop-1-ynyl)-2-phenylimidazo[1,2-a]pyridin-
d
3-yl]-2-methylbut-3-yn-2-ol [32]. Yellow solid, 91% yield, mp
91.4, 106.0, 108.7, 111.5, 117.4, 128.2, 129.1, 129.6, 130.1, 131.1, 133.8,
145.1, 148.1. HRMS (EI) m/z calcd for C21H18N2O2 [MþH]þ: 331.1447,
found: 331.1431.
106 ꢀC; IR (ATR) (cmꢁ1) 3226, 2985, 2361,1498, 1098, 808. 1H NMR
n
(400 MHz, CDCl3) d 1.72 (s, 6H), 3.47 (s,1H), 3.49 (s, 3H), 4.35 (s, 2H),
7.20 (dd, J¼9.2,1.6 Hz,1H), 7.30e7.35 (m, 3H), 7.56 (dd, J¼9.2,1.6 Hz,
1H), 8.15 (s, 1H), 8.16e8.22 (m, 2H). 13C NMR (100.6 MHz, CDCl3)
3.9.4. 3-(2-Phenyl-3-(phenylethynyl)imidazo[1,2-a]pyridin-6-yl)-
d
31.5, 58.0, 60.4, 65.9, 70.8, 82.4, 87.1, 106.9, 109.2, 117.0, 127.1,
prop-2-yn-1-ol [37]. Yellow solid, 75% yield, mp 169 ꢀC; IR (ATR)
n
128.0, 128.5, 128.8, 129.1, 132.8, 143.8, 148.4. HRMS (EI) m/z calcd for
(cmꢁ1) 3249, 2923, 2200, 1498, 1025, 748, 687. 1H NMR (400 MHz,
CDCl3)
2.60e2.87 (m, 1H), 4.50 (s, 2H), 7.22 (dd, J¼9.2, 1.5 Hz, 1H),
7.37e7.43 (m, 4H), 7.46e7.50 (m, 2H), 7.57e7.63 (m, 3H), 8.32e8.37
(m, 2H), 8.41 (s, 1H). 13C NMR (100.6 MHz, CDCl3)
51.5, 77.6, 81.7,
C22H20N2O2 [MþH]þ: 345.1603, found: 345.1584.
d
3.8.2. 3-(3-Methoxyprop-1-ynyl)-2-phenyl-6-phenylethynylimidazo
d
[1,2-a]pyridine [33]. Brown oil, 90% yield; IR (ATR)
n
(cmꢁ1) 2925,
89.6, 101.9, 105.1, 109.3, 117.2, 122.5, 127.4, 128.2, 128.7, 128.7, 128.9,
129.1, 129.2, 131.5, 133.1, 144.1, 148.6. HRMS (EI) m/z calcd for
C24H16N2O [MþH]þ: 349.1341, found: 349.1330.
2306, 1494, 1092, 888. 1H NMR (400 MHz, CDCl3)
d
3.53 (s, 3H), 4.57
(s, 2H), 7.35e7.40 (m, 5H), 7.45e7.48 (m, 2H), 7.53e7.57 (m, 2H),
7.60 (dd, J¼9.2, 0.8 Hz, 1H), 8.25e8.31 (m, 2H), 8.46e8.51 (m, 1H).
13C NMR (100.6 MHz, CDCl3)
d 58.0, 60.8, 75.2, 85.4, 91.4, 98.2,
3.9.5. 2-Methyl-4-[2-phenyl-3-(phenylethynyl)imidazo[1,2-a]pyr-
104.3,110.1,117.2,122.6, 127.3, 127.8, 128.6, 128.7,128.9, 128.9, 129.4,
131.7, 133.1, 144.1, 149.2. HRMS (EI) m/z calcd for C25H18N2O
[MþH]þ: 363.1479, found: 363.1497.
idin-6-yl]-but-3-yn-2-ol [38]. Yellow solid, 74% yield, mp 170 ꢀC; IR
(ATR)
(400 MHz, CDCl3)
7.36e7.42 (m, 5H), 7.45e7.49 (m, 2H), 7.58e7.62 (m, 3H), 8.34e8.36
(m, 2H). 13C NMR (100.6 MHz, CDCl3)
31.5, 65.6, 77.7, 78.2, 96.1,
n
(cmꢁ1) 3241, 2924, 1497, 1396, 1162, 750, 686. 1H NMR
d
1.63 (s, 6H), 7.19 (dd, J¼9.2, 1.5 Hz, 1H),
3.9. Procedure for the one-pot double dissimilarly
Sonogashira cross-coupling reaction under microwave
irradiation
d
101.8, 105.0, 109.5, 117.1, 122.5, 127.4, 127.9, 128.7, 128.9, 129.0, 129.3,
131.5, 133.1, 144.0, 148.6. HRMS (EI) m/z calcd for C26H20N2O
[MþH]þ: 377.1642, found: 377.1600.
To a argon degassed solution of 3,6-dihalogenoimidazo[1,2-a]
pyridines 1 or 14 (100 mg 0.250 mmol) in 2 mL of a mixture of DMF/
Et3N (1/1, v/v) in a vial microwave tube were subsequently added
alkyne I (0.275 mmol), copper iodide (0.050 mmol) and bis(-
triphenylphosphine)palladium dichloride (0.012 mmol). The re-
action vessel was sealed with a silicon septum and subjected to
microwave irradiation for 10 min at 70 ꢀC. Upon cooling to room
temperature alkyne II (0.375 mmol) was injected into the tube via
a syringe and the reaction mixture was subjected again to micro-
wave irradiation at 140 ꢀC for 45 min. The reaction was cooled to
room temperature, quenched with water (15 mL), and extracted
with dichloromethane (2ꢂ15 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in
vacuo. The resulting residue was purified by column chromatog-
raphy on silica gel (EtOAc/PE) to give polysubstituted imidazo[1,2-
a]pyridine derivatives 34e38.
3.10. Procedure for the one-pot double dissimilarly Suzuki
cross-coupling under microwave irradiation
To a argon degassed solution of 3-bromo-6-iodoimidazo[1,2-a]
pyridine 1 (100 mg 0.250 mmol) in DMF (2 mL) in a vial microwave
tube were subsequently added AreB(OH)2 I (0.275 mmol), potas-
sium carbonate (0.501 mmol), triphenylphosphine (0.050 mmol)
and palladium(II) acetate (0.025 mmol). The reaction vessel was
sealed with a silicon septum and subjected to microwave irradia-
tion for 30 min at 120 ꢀC with stirring. Upon cooling to room
temperature AreB(OH)2 II (0.375 mmol) was added into the tube
and the reaction mixture was subjected again to microwave irra-
diation at 140 ꢀC for 2 h. The reaction vessel was cooled to room
temperature, quenched with water (15 mL), and extracted with
dichloromethane (2ꢂ15 mL). The combined organic layers were

7138
A. El Akkaoui et al. / Tetrahedron 67 (2011) 7128e7138
Lett. 2008,10, 3203e3206; (f) Mehta, V. P.; Sharma, A.; Van der Eycken, E. Org. Lett.
2008, 10, 1147e1150; (g) Bakherad, M.; Keivanloo, A.; Bahramian, B.; Mihanpar-
ast, S. Tetrahedron Lett. 2009, 50, 6418e6420; (h) Pschierer, J.; Plenio, H. Org. Lett.
2009, 11, 2551e2554; (i) Chandra, A.; Singh, B.; Khanna, R. S.; Singh, R. M. J. Org.
Chem. 2009, 74, 5664e5666; (j) For representative papers on the Suzuki cross-
coupling reactions, see: Chandrasekhar, V.; Narayanan, R. S.; Thilagar, P. Organ-
ometallics 2009, 28, 5883e5888; (k) Arthuis, M.; Pontikis, R.; Florent, J.-C. Org.
Lett. 2009,11, 4608e4611; (l) Bhayana, B.; Fors, B. P.; Buchwald, S. L. Org. Lett. 2009,
11, 3954e3957; (m) Martin, T.; Laguerre, C.; Hoarau, C.; Marsais, F. Org. Lett. 2009,
11, 3690e3693; (n) James, C. A.; Coelho, A. L.; Gevaert, M.; Forgione, P.; Snieckus,
V. J. Org. Chem. 2009, 74, 4094e4103.
dried over magnesium sulfate, filtered, and concentrated in vacuo.
The resulting residue was purified by column chromatography on
silica gel (EtOAc/PE) to afford polysubstituted imidazo[1,2-a]pyri-
dine derivatives 30, 39 and 40.
3.10.1. 4-[6-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a]pyridi-ne-3-
yl]-benzaldehyde [39]. Yellow solid, 71% yield, mp 204 ꢀC; IR (ATR)
n
(cmꢁ1) 2720, 1697, 1602, 1498, 1388, 1244, 1176, 1020, 813, 773. 1H
NMR (400 MHz, CDCl3)
d
3.84 (s, 3H), 6.97 (d, J¼8.7 Hz, 2H),
€
5. A review: (a) Schroter, S.; Stock, C.; Bach, T. Tetrahedron 2005, 61, 2245e2267; (b)
7.27e7.34 (m, 3H), 7.42 (d, J¼8.7 Hz, 2H), 7.48 (dd, J¼9.3, 1.6 Hz, 1H),
7.58e7.62 (m, 2H), 7.68 (d, J¼8.1 Hz, 2H), 7.75 (d, J¼9.2 Hz, 1H), 8.03
(d, J¼8.1 Hz, 2H), 8.14 (s, 1H), 10.10 (s, 1H). 13C NMR (100.6 MHz,
Fairlamb, I. J. S.; O’Brien, C. T.; Lin, Z.; Lamb, K. C. Org. Biomol. Chem. 2006, 4,
1213e1216; (c) For representative papers on regioselective SuzukieMiyaura, see:
Yaziji, V.; Coelho, A.; El Maatougui, A.; Brea, J.; Loza, M. I.; Garcia-Mera, X.; Sotelo,
E. J. Comb. Chem. 2009, 11, 519e522; (d) Zhang, L.; Meng, T.; Fan, R.; Wu, J. J. Org.
Chem. 2007, 72, 7279e7286; (e) Noguchi, H.; Hojo, K.; Suginome, M. J. Am. Chem.
Soc. 2007,129, 758e759; (f) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003, 5, 4349e4352; (g) Yang,
W.; Wang, Y.; Corte, J. R. Org. Lett. 2003, 5, 3131e3134; (h) Bambuch, V.; Otmar, M.;
CDCl3)
d 55.5, 114.7, 117.7, 119.6, 120.1, 126.2, 127.2, 128.0, 128.1,
128.5, 128.5,129.7, 130.8, 131.1,133.8, 136.1,136.3, 144.3,144.7,159.7,
191.5. HRMS (EI) m/z calcd for C27H20N2O2 [MþH]þ: 405.1603,
found: 405.1586.
ꢀ
ꢀ
ꢀ
Masojıcdkova, M.; Votruba, I.; Holy, A. Tetrahedron2007, 63,1589e1601; (i) Tikad,
A.; Routier, S.; Akssira, M.; Leger, J. M.; Jarry, C.; Guillaumet, G. Org. Lett. 2007, 6,
4673e4676; (j) For representative papers on regioselective Sonogashira, see:
Reddy, E. A.; Barange, D. K.; Islam, A.; Mukkanti, K.; Pa, M. Tetrahedron 2008, 64,
7143e7150; (k) Lee, J. H.; Park, J. S.; Cho, C. G. Org. Lett. 2002, 4, 1171e1173.
3.10.2. 6-(4-Methoxyphenyl)-2-phenyl-3-thiophen-3-yl-imida-zo
[1,2-a]pyridine [40]. White solid, 71% yield, mp 135 ꢀC; IR (ATR)
n
(cmꢁ1) 2920, 1608, 1496, 1247, 1115, 1035, 773. 1H NMR (400 MHz,
CDCl3)
ꢀ
ꢀ
6. (a) Pena, M. A.; Perez, I.; Perez Sestelo, J.; Sarandeses, L. A. Chem. Commun.
2002, 2246e2247; (b) Duan, X.-F.; Li, X.-H.; Li, F.-Y.; Huang, C.-H. Synthesis
2004, 2614e2616; (c) Handy, S. T.; Sabatini, J. J. Org. Lett. 2006, 8, 1537e1539;
(d) Handy, S. T.; Mayi, D. Tetrahedron Lett. 2007, 48, 8108e8110; (e) Handy, S. T.;
Wilson, T.; Muth, A. J. Org. Chem. 2007, 72, 8496e8500; (f) Taylor, R. H.; Felpin,
F.-X. Org. Lett. 2007, 9, 2911e2914; (g) Henry, N.; Enguehard-Gueiffier, C.; Thery,
I.; Gueiffier, A. Eur. J. Org. Chem. 2008, 4824e4827; (h) Beaumard, F.; Dauban, P.;
d
3.84 (s, 3H), 6.95 (d, J¼8.7 Hz, 2H), 7.18 (dd, J¼4.9, 1.2 Hz,
1H), 7.24e7.29 (m, 1H), 7.29e7.35 (m, 2H), 7.42 (d, J¼8.7 Hz, 2H),
7.44 (s, 1H), 7.49 (dd, J¼2.9, 1.2 Hz, 1H), 7.55 (dd, J¼4.9, 2.9 Hz, 1H),
7.69e7.72 (m, 3H), 8.07e8.09 (m, 1H). 13C NMR (100.6 MHz, CDCl3)
d
55.5, 114.6, 116.5, 117.3, 120.2, 125.5, 126.3, 126.7, 127.3, 127.6,
ꢀ
ꢀ
Dodd, R. H. Org. Lett. 2008, 10, 1801e1804; (i) Mosquera, A; Riveiros, R.; Perez
Sestelo, J.; Sarandeses, L. A. Org. Lett. 2008, 10, 3745e3748; (j) Bouissane, L.;
128.0, 128.1, 128.4, 128.9, 129.7, 130.0, 134.3, 143.5, 144.2, 159.6.
HRMS (EI) m/z calcd for C24H18N2OS [MþH]þ: 383.1218, found:
383.1201.
ꢀ
Perez Sestelo, J.; Sarandeses, L. A. Org. Lett. 2009, 11, 1285e1288.
7. Ehlers, P.; Neubauer, A.; Lochbrunner, S.; Villinger, A.; Langer, P. Org. Lett. 2011,
13, 1618e1621.
8. El Akkaoui, A.; Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron Lett. 2008, 49, 2472e2475.
References and notes
9. (a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Tetrahedron
Lett. 2003, 45, 3193e3196; (b) El Kazzouli, S.; Berthaut, A.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Lett. Org. Chem. 2005, 2, 184e187; (c) Koubachi, J.;
El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Synlett 2006,
3237e3242; (d) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Synthesis 2008, 2537e2542; (e) Koubachi, J.; Berteina-Raboin, S.;
Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271e276; (f) Koubachi, J.; El
Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. J. Maroc. Chim.
Heterocycl. 2008, 7, 1e9; (g) Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron 2010, 66, 1937e1946; (h) El Akkaoui, A.; Berteina-
Raboin, S.; Mouaddib, A.; Guillaumet, G. Eur. J. Org. Chem. 2010, 862e871.
10. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. J.
Org. Chem. 2007, 72, 7650e7655.
1. For recent reviews on this topic, see: (a) Alberico, D.; Scott, M. E.; Lautens, M.
Chem. Rev. 2007, 107, 174e238; (b) Beccalli, E. M.; Broggini, G.; Martinelli, M.;
Sottocornola, S. Chem. Rev. 2007, 107, 5318e5365; (c) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442e4489.
2. For recent reviews on Sonogashira reaction, see: (a) Doucet, H.; Hierso, J.-C.
ꢀ
Angew. Chem., Int. Ed. 2007, 46, 834e871; (b) Chinchilla, R.; Najera, C. Chem. Rev.
2007, 107, 874e922.
3. For reviews on Suzuki reaction, see: (a) Martin, R.; Buchwald, S. L. Acc. Chem.
Res. 2008, 41, 1461e1473; (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95,
2457e2483; (c) Weng, Z.; Teo, S.; Hor, T. S. A. Acc. Chem. Res. 2007, 40, 676e684.
4. For representative papers on the Sonogashira cross-coupling reactions, see: (a)
Yi, C. Y.; Hua, R. M. J. Org. Chem. 2006, 71, 2535e2537; (b) Liang, Y.; Xie, Y.-X.; Li, J.-
H. J. Org. Chem. 2006, 71, 379e381; (c) Lipshutz, B. H.; Chung, D. W.; Rich, B. Org.
Lett. 2008, 10, 3793e3796; (d) Huang, H.; Liu, H.; Jiang, H.; Chen, K. J. Org. Chem.
2008, 73, 6037e6040; (e) Monnier, F.; Turtaut, F.; Duroure, L.; Taillefer, M. Org.
11. Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei, G.;
Chavignon, O.; Teulade, J.-C.; Witvrouw, M.; Balzarini, J.; De Clercq, E.; Chapat,
J.-P. J. Med. Chem. 1998, 41, 5108e5112.