Regiocontrolled microwave assisted bifunctionalization of 7,8-dihalogenated imidazo[1,2-a]pyridines: A one pot double-coupling approach

Article abstract of DOI:10.3390/molecules170910683

The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2- a]pyridines 1a-e diversely substituted on the 2 position, towards Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig cross-coupling reactions as well as cyanation was evaluated. Various methodologies are proposed to introduce aryl, heteroaryl, alkyne, amine or cyano groups in the two positions depending on the nature of the substituent present in position 2. In both series, the substitution of the iodine atom was totally regioselective and the difficulty was to substitute the chlorine atom in a second step. Until now, only hetero(aryl) groups could be introduced though Suzuki-Miyaura cross-coupling. We overcame this problem evaluating both regioisomers in parallel. The double coupling approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/Sonogashira and cyanation/Buchwald reactions leading to polyfunctionnalized imidazo[1,2-a]pyridines.

Full text of DOI:10.3390/molecules170910683

Molecules 2012, 17, 10683-10707; doi:10.3390/molecules170910683
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Regiocontrolled Microwave Assisted Bifunctionalization of
7,8-Dihalogenated Imidazo[1,2-a]pyridines:
A One Pot Double-Coupling Approach
Emilie Marie, Sébastien Bouclé, Cécile Enguehard-Gueiffier * and Alain Gueiffier
Recherche et Innovation en Chimie Médicinale, UMR INRA 1282 Infectiologie et Santé Publique,
Université F. Rabelais, 31 avenue Monge, F-37200 Tours, France;
E-Mails: emilie.marie-2@etu.univ-tours.fr (E.M.); s.boucle@hotmail.fr (S.B.);
alain.gueiffier@univ-tours.fr (A.G.)
* Author to whom correspondence should be addressed;
E-Mail: cecile.enguehard-gueiffier@univ-tours.fr; Tel.: +33-247-367-172; Fax: +33-247-367-288.
Received: 27 July 2012; in revised form: 31 August 2012 / Accepted: 3 September 2012 /
Published: 6 September 2012
Abstract: The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2-
a]pyridines 1a–e diversely substituted on the 2 position, towards Suzuki-Miyaura,
Sonogashira, and Buchwald-Hartwig cross-coupling reactions as well as cyanation was
evaluated. Various methodologies are proposed to introduce aryl, heteroaryl, alkyne, amine
or cyano groups in the two positions depending on the nature of the substituent present in
position 2. In both series, the substitution of the iodine atom was totally regioselective and
the difficulty was to substitute the chlorine atom in a second step. Until now, only
hetero(aryl) groups could be introduced though Suzuki-Miyaura cross-coupling. We
overcame this problem evaluating both regioisomers in parallel. The double coupling
approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/Sonogashira and
cyanation/Buchwald reactions leading to polyfunctionnalized imidazo[1,2-a]pyridines.
Keywords: imidazo[1,2-a]pyridine; metallo-catalyzed cross-coupling reaction; microwave
irradiation; Suzuki-Miyaura cross-coupling; Sonogashira cross-coupling; cyanation;
Buchwald-Hartwig cross-coupling

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1. Introduction
Over the last decades, the imidazo[1,2-a]pyridine ring has been considered an important scaffold
for biomolecules in medicinal chemistry, with a broad spectrum of potential therapeutic properties
such as, for example, antibacterial [1], HIV inhibitory [2], anti-inflammatory [3] and anticancer [4]
properties. Moreover, several drug formulations containing imidazo[1,2-a]pyridine derivatives, are
marketed in the anxiolytic/hypnotic area (zolpidem, alpidem) and GDR/peptic ulcer therapy
(zolimidine). Therefore, convergent, rapid, and easy to implement functionalization routes are still
needed to introduce various modulations on this skeleton, in order to complete the putative biological
activities evaluation of these series of compounds.
In the course of our work evaluating the chemical and pharmacological properties of the
imidazo[1,2-a]pyridine series, we further pursued investigations on methods of functionalization
which would allow the rapid preparation of a number of structural variants. We thus became interested
in the regiocontrolled substitution of 7,8-dihalogenated imidazo[1,2-a]pyridine derivatives. The
introduction of various substituents such as aryl, heteroaryl, cyano and amino groups was studied and
our results in this area are the subject of this manuscript. Analogous works on double-coupling
approach in positions 3 and 6, or positions 6 and 8 of this scaffold were already presented by other
groups [5,6].
Recently in the literature, a few pharmacomodulation studies of the imidazo[1,2-a]pyridine scaffold
required this type of 7,8-disubstitution pattern for their purposes. Kettle et al. described a two-step
introduction of aryl groups in these 7 and 8 positions [7]. In our work, we propose an alternative one-step
procedure. Moreover, Trabanco et al. synthesized 7-aryl-8-cyano or 7-aryl-8-chloroimidazo[1,2-a]pyridine
derivatives starting from the convenient 7,8-dihalogenated starting material [8]. Concerning older
publications [9–11], authors usually introduced the cyano group on the pyridine ring before
cyclisation, increasing the number of synthetic steps.
2. Results and Discussion
In order to control the regioselectivity of the disubstitution pattern in positions 7 and 8 of the
imidazo[1,2-a]pyridine scaffold, we chosen as starting materials the 7-chloro-8-iodo- and 8-chloro-7-
iodoimidazo[1,2-a]pyridines 1a–e diversely substituted on the 2 position. Both series were studied
concomitantly in order to offer the largest scope of functionalization. To our knowledge, the analogous
7-bromo-8-iodo- and 8-bromo-7-iodoimidazo[1,2-a]pyridines are still not described in the literature.
Compounds 1a–e were obtained in 71–100% yields by condensation of 2-amino-3-chloro-4-
iodopyridine or 2-amino-4-chloro-3-iodopyridine, with the corresponding α-halogenoketones.
Different groups (phenyl, ethyl carboxylate, methyl) were considered in position 2 to overview the
influence of this position on the reactivity of the 7 and 8 positions of the imidazo[1,2-a]pyridine series
towards various cross-coupling reactions. Indeed, such an influence of the 2-substituent on the
reactivity of not only position 3 [12], but also of position 6 [13], was previously noticed by our group.

Molecules 2012, 17
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2.1. Regioselective Substitution of the Iodine Atom of Compounds 1a–e
Initial work focused on the regioselective substitution of iodine atom of compounds 1a–e. Three
classical cross-coupling reactions were studied: Suzuki-Miyaura, Sonogashira and Buchwald-Hartwig
reactions, as well as cyanation reactions (Schemes 1–4).
2.1.1. Suzuki Cross-Coupling on Compounds 1a–c
Suzuki cross-coupling standard conditions were first applied to 1a–c using 4-fluorophenylboronic
acid (2 equiv.), PdCl2(dppf) (0.05 equiv.), Na2CO3 (3 equiv.) in a mixture of THF-H2O at 75 °C
overnight leading to compounds 2–4 in 87%–90% yields (Scheme 1). Total conversion and
regioselectivity were observed. No influence of the 2 position was noticed.
Scheme 1. Suzuki cross-coupling reaction on position 7 of compounds 1a–c (isolated yields).
F
Cl
Cl
I
F
B(OH)2
N
N
R2
R2
N
N
1a
R2 = Phenyl
1b R2 = CO2Et
1c
2 R2 = Phenyl 90%
3
R2 = CO2Et 87%
4 R2 = CH3 89%
R2 = CH3
Reaction conditions: 4-fluorophenylboronic acid (2 equiv.), PdCl2(dppf) (0.05 equiv.), Na2CO3
(3 equiv.), THF/H2O, 75 °C, overnight, sealed tube.
2.1.2. Sonogashira Cross-Coupling on Compounds 1a–e
Optimization of Sonogashira cross-coupling conditions was conducted in position 8 of compound
1d using 4-ethynyltoluene (3 equiv.), PdCl2(dppf) (0.05 equiv.), TEA (5 equiv.) and CuI (0.1 equiv.) in
DMF at 90 °C for 1 h under microwave irradiation [14]. A partial conversion was observed (NMR
yield of 29%) and a large amount of starting material was recovered, that could not be separated from
the attempted product. A methodology developed in our laboratory using 4-ethynyltoluene (1.3 equiv.),
Pd(PPh3)4 (0.1 equiv.), PCy3HBF4 (0.3 equiv.) in the presence of t-BuONa (3 equiv.) and CuI (0.4 equiv.)
in DMF at 100 °C for 20 min under microwave irradiation was then tested. A total dehalogenation
occurred in position 8. Thus, we decided to work at lower temperature (90 °C), to change the base to
Et3N (5 equiv.) and to lower the amount of CuI (0.2 equiv.). Under these conditions, a total conversion
was observed allowing the purification of the attempted compounds 7 and 8 in moderate yields (60 and
50%, respectively) (Scheme 2). The position 7 appeared to be more reactive towards these Sonogashira
conditions than position 8, leading to compounds 5 and 6 in 71% and 77% yields respectively (Scheme 2).
The presence of N1 in close vicinity of position 8 may explain its lower reactivity. Moreover, the
2-ester function seems to lower the reactivity of the 8 position towards the Sonogashira cross-coupling.

Molecules 2012, 17
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Scheme 2. Sonogashira cross-coupling reaction on compounds 1a, 1b, 1d, 1e (isolated yields).
Cl
Cl
C CH
I
N
N
R2
N
R2
N
1a R2 = Phenyl
1b R2 = CO2Et
5 R2 = Phenyl 71%
6
R2 = CO2Et 77%
I
C CH
Cl
N
R2
N
1d
1e
R2 = Phenyl
R2 = CO2Et
Cl
N
R2
N
7
8
R2 = Phenyl 60%
R2 = CO2Et 50%
Reaction conditions: 4-ethynyltoluene (1.3 equiv.), Pd(PPh3)4 (0.1 equiv.), PCy3HBF4 (0.3 equiv.),
Et3N (5 equiv.), CuI (0.2 equiv.), DMF, 90 °C, 30 min, MW.
2.1.3. Cyanation on Compounds 1a–e
Then, we considered the cyanation of compounds 1 (Scheme 3). According to a literature
procedure, reaction of 1a with CuCN (1.6 equiv.) in acetonitrile at 160 °C for 30 min under
microwaves irradiation led to 9 in 32% yield [8]. We then changed the solvent to DMF and reaction of
1a or 1b with CuCN (1.3 equiv.) at 200 °C for 15 min under microwave irradiation, afforded 9 and 10
in respective yields of 72 and 63%. Applying the same conditions to compounds 1d–e led to formation
of dehalogenated compounds. The 8-cyano compounds 11 and 12 were obtained after reaction at
150 °C for 15 min in 69% and 46% yields, respectively. Again, the 2-ester function seems to lower the
reactivity of the 8 position towards the cyanation reaction.
Scheme 3. Cyanation on compounds 1a, 1b, 1d, 1e (isolated yields).
Cl
Cl
I
NC
N
N
CuCN
200°C
R2
R2
N
N
1a R2 = Phenyl
9
10
R2 = Phenyl 72%
R2 = CO2Et 63%
1b
R2 = CO2Et
I
CN
N
Cl
Cl
N
CuCN
150°C
R2
R2
N
N
1d R2 = Phenyl
1e R2 = CO2Et
11 R2 = Phenyl 69%
12 R2 = CO2Et 46%
Reaction conditions: CuCN (1.3 equiv.), 200 °C or 150 °C, 15 min, MW.

Molecules 2012, 17
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2.1.4. Buchwald-Hartwig Cross-Coupling on Compounds 1a–e
Finally, we carried out a short study of Buchwald-Hartwig amination to optimize the aniline
cross-coupling conditions, depending on the substituent present in position 2 of the imidazo[1,2-a]pyridine
ring (Scheme 4). A nucleophilic substitution was first attempted following the procedure described by
Tresadern et al. for the coupling of alkylpiperazine to 7-iodo-8-cyanoimidazo[1,2-a]pyridine
derivatives [9]. Treatment of 1a with N-methylpiperazine (3 equiv.), DIPEA (4 equiv.) in acetonitrile
at 180 °C for 1 h under microwave irradiation led exclusively to a mixture of starting material and
deiodinated compound. The 8-cyano group appears to greatly increase the reactivity of the adjacent
position, allowing a nucleophilic substitution.
Scheme 4. Buchwald-Hartwig cross-coupling on compounds 1a, 1b, 1d, 1e (isolated yields).
Cl
Cl
I
R7HN
N
N
R7NH2
R2
R2
N
N
a
b
1a
R2 = Phenyl
13
R2 = R7 = Phenyl 48% or 41%
14 R2 = CO2Et R7 = C6H11 40%c
1b R2 = CO2Et
I
NHR8
Cl
Cl
N
N
R8NH2
R2
R2
N
N
a
1d
1e
R2 = Phenyl
R2 = CO2Et
15
16
R2 = R8 = Phenyl 51%
R2 = CO2Et R8 = C6H11 66%c
Reaction conditions: a aniline (3 equiv.), Pd(PPh3)4 (0.1 equiv.), rac-BINAP (0.3 equiv.), t-BuONa
(3 equiv.), CuI (0.2 equiv.), DME, 85 °C, 45 min, MW; b aniline (1.1 equiv.), Pd2dba3 (0.05 equiv.),
c
rac-BINAP (0.1 equiv.), t-BuONa (3 equiv.), dioxane, 80 °C, 30 min, MW; cyclohexylamine
(13 equiv.), Pd2dba3 (0.04 equiv.), Xantphos (0.12 equiv.), K2CO3 (15 equiv.), dioxane, 150 °C,
1 h 15 min, MW.
In view to study one-pot heterogeneous double-coupling of aryl and amine groups in positions 7
and 8, Pd(PPh3)4 was preferred as catalyst in a first attempt. Thus, the reaction was achieved using
aniline (1 equiv.), Pd(PPh3)4 (0.1 equiv.), Xantphos (0.3 equiv.), K2CO3 (10 equiv.) in dioxane, but
only starting material was recovered after 90 min at 100 °C under microwave irradiation. In the same
way, only traces of the attempted compounds 13 were obtained using the following conditions: aniline
(3 equiv.), Pd(PPh3)4 (0.1 equiv.), rac-BINAP (0.3 equiv.), t-BuONa (3 equiv.) in DME at 85 °C after
2 h 30 min under microwave irradiation. Therefore, we attempted these last conditions but with a
catalytic amount of CuI (0.2 equiv.). We noticed that the reaction was completed after 45 min at 85 °C
under microwaves and we obtained 13 in 48% yield. Under the same conditions, we synthesized 15 in
51% yield (Scheme 4).
Several metallo-catalyzed procedures commonly used for aminations were also applied to
compound 1a. Only traces of the attempted compounds 13 were obtained using the following
conditions: aniline (1 equiv.), Pd(OAc)2 (0.1 equiv.), rac-BINAP (0.3 equiv.), t-BuONa (3 equiv.) in
toluene for 90 min at 90 °C under microwave irradiation. Nevertheless, compound 13 was afforded in

Molecules 2012, 17
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41% yield using aniline (1.1 equiv.), Pd2dba3 (0.05 equiv.), rac-BINAP (0.1 equiv.), t-BuONa (3 equiv.)
in dioxane at 80 °C for 30 min in a microwave apparatus. Thus, amination in positions 7 and 8 may be
achieved through different methodologies with similar yields of around 40%–50%.
The presence of the ester group in compounds 1b and 1e prevented us from using t-BuONa as base
for the amination reaction. The different approaches evaluated to introduce the aniline were
unsuccessful. We then decided to work with cyclohexylamine. The coupling reaction was first
conducted on 1b using cyclohexylamine (2 equiv.), Pd(PPh3)4 (0.1 equiv.), Xantphos (0.2 equiv.),
K2CO3 (15 equiv.) in DMF at 160 °C during 1 h under microwave irradiation. This reaction did not
afford the expected product 14. The reaction was then attempted on 1e using cyclohexylamine
(13 equiv.), Pd2dba3 (0.04 equiv.), Xantphos (0.12 equiv.), K2CO3 (15 equiv.) in dioxane for 1 h 15 min
at 150 °C under microwaves, leading to 16 in 66% yield (Table 2). These last conditions applied to 1b
led to 14 in 40% yield (Scheme 4).
2.2. Substitution of the Chlorine Atom in Position 8 of Compounds 2–6, 9–10, 14
In a second part, we focused on the substitution of the chlorine atom in position 8 of the
7-substituted imidazo[1,2-a]pyridines 2–6, 9–10, 14. The reactivity of this position was evaluated
towards the Suzuki-Miyaura cross-coupling reaction (Table 1). In a first attempt, the reaction was
performed on the ester compound 3 using 4-tolylboronic acid (1.8 equiv.), Pd(PPh3)4 (0.05 equiv.),
Na2CO3 (1.5 equiv.), in DME/H2O at 75 °C in a sealed tube, leading to the target compound 17 in 53%
yield. Nevertheless, a reaction time of 22 h was required, and addition of amounts of 4-tolylboronic
acid to the reaction mixture until 2.5 equivalents of 4-tolylboronic acid were used. A higher
temperature was incompatible with the ester group. These conditions were greatly improved using
4-tolylboronic acid (1.4 equiv.), Pd(PPh3)4 (0.1 equiv.), K2CO3 (2 equiv.) in dioxane/EtOH for 15 min
at 150 °C under microwave irradiation, leading to 17 in 95% yield. In the same conditions, 18 was
obtained in 76% yield. Starting from the 2-phenyl or 2-methyl compounds 2 or 4, compounds 19–20
and 21–22 were obtained using classical conditions (boronic acid (1.4 or 2 equiv.), Pd(PPh3)4 (0.05 equiv.),
Na2CO3 (2 equiv.), DME/H2O at 120 °C under microwave irradiation) in good yields (80 to 90%).
In these conditions, no influence of the nature of the 2-substituent was noticed on the reactivity of the
8 position.
Table 1. Functionalization in position 8 of compounds 2–4.
F
F
Cl
R8
N
N
R2
R2
N
N
2-4
17-22

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Table 1. Cont.
Isolated
Yield
Isolated
Yield
(%)
S.M.
Product
S.M.
Product
(%)
OCH3
F
F
3
95 a
3
76 a
84 b
80 b
N
N
N
CO2C2H5
CO2C2H5
N
17
18
F
F
2
2
90 b
4
4
N
N
N
N
20
19
OCH3
N
F
F
82 b
N
N
N
N
22
21
Reaction conditions: a RB(OH)2 (1.4 equiv.), K2CO3 (2 equiv.), Pd(PPh3)4 (0.1 equiv.), dioxane/EtOH,
b
150 °C, MW or RB(OH)2 (1.4 or 2 equiv.), Na2CO3 (2 equiv.), Pd(PPh3)4 (0.05 equiv.),
DME/H2O, 120 °C, MW.
The Suzuki coupling reaction was then extended to the diversely 7-substituted imidazo[1,2-
a]pyridines 5–6, 9–10, 14 (Table 2). As previously described, two synthetic routes were applied
depending on the 2-substituent. Reaction of 5 or 9 with various (hetero)arylboronic acids (1.4 or
2 equiv.) in the presence of Pd(PPh3)4 (0.05 equiv.), Na2CO3 (2 equiv.) in DME/H2O at 120 °C under
microwaves irradiation gave 23 to 25 in moderate to good yields (19%–71%). Reaction of the ester
compounds 6, 10, 14 with (hetero)arylboronic acids (1.4 or 2 equiv.) in the presence of Pd(PPh3)4
(0.1 equiv.), K2CO3 (2 equiv.) in dioxane/EtOH at 150 °C under microwave irradiation led to 27 to
35% of compounds 26–30.
Table 2. Functionalization in position 8 of compounds 5–6, 9–10, 14.
Cl
R8
R7
R7
N
N
R2
R2
N
N
5-6, 9-10, 14
23-30

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Table 2. Cont.
Isolated
Isolated
Yield
(%)
S.M.
Products
Yield
(%)
S.M.
Products
S
O
5
19 a
9
71 a
NC
N
N
N
N
23
24
N
9
42 a
14
27 b
H
N
NC
N
N
N
CO2C2H5
N
25
26
N
NH
N
NC
6
35 b
10
14
31 b
N
N
CO2C2H5
CO2C2H5
N
28
27
N
O
H
N
NC
N
10
34 b
28 b
N
N
CO2C2H5
CO2C2H5
N
29
30
a
Reaction conditions: RB(OH)2 (1.4 or 2 equiv.), Na2CO3 (2 equiv.), Pd(PPh3)4 (0.05 equiv.),
b
DME/H2O, 120 °C, MW; RB(OH)2 (1.4 or 2 equiv.), K2CO3 (2 equiv.), Pd(PPh3)4 (0.1 equiv.),
dioxane/EtOH, 150 °C, MW.
Due to the lower reactivity of the chlorine atom in position 8 of the imidazo[1,2-a]pyridines 2–6, 9–10,
14, only 8-(hetero)aryl-7-substituted compounds could be obtained through Suzuki cross-coupling
reactions. No cyanation, Sonogashira or amination reaction could be achieved at this position.
Nevertheless, the problem of chlorine reactivity could be solved starting from the regioisomers 7–8,
11, 15 iodinated in position 8.
2.3. Substitution of the Chlorine Atom in Position 7 of Compounds 7–8, 11, 15
Using the previously established experimental conditions, four examples of 7-arylimidazo[1,2-
a]pyridines 31–34 were obtained presenting an alkyne, cyano or amino group in position 8 (44 to 69%
yields) (Table 3). For compound 34, we noticed the formation of a dehalogenated compound during

Molecules 2012, 17
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the Suzuki cross-coupling reaction, and a higher amount of boronic acid was then required to complete
the reaction.
Table 3. Functionalization in position 7 of compounds 7–8, 11, 15.
R8
R8
Cl
R7
N
N
R2
R2
N
N
7-8, 11, 15
31-34
Isolated
Yield
(%)
Isolated
Yield
(%)
S.M.
Products
S.M.
Products
7
56 a
8
69 b
H3CO
H3CO
N
N
CO2C2H5
N
N
31
32
H3CO
CN
HN
N
11
61 a
15
44 a
N
N
N
33
34
Reaction conditions: a RB(OH)2 (1.4 or 2 or 5 equiv.), Na2CO3 (2 equiv.), Pd(PPh3)4 (0.05 equiv.),
b
DME/H2O, 120 °C, MW; RB(OH)2 (1.4 equiv.), K2CO3 (2 equiv.), Pd(PPh3)4 (0.1 equiv.),
dioxane/EtOH, 150 °C, MW.
2.4. Double Coupling Approach
Finally, the 7,8-diarylation of the imidazo[1,2-a]pyridine scaffold in a one-pot approach was
evaluated (Table 4). Starting from compound 1a, optimization of the Suzuki double coupling led to
the following conditions: first boronic acid (1 equiv.), Na2CO3 (3 equiv.), Pd(PPh3)4 (0.05 equiv.) in a
mixture DME/H2O for 30 min at 95 °C under microwave irradiation, then second boronic acid
(1.4 equiv.), Pd(PPh3)4 (0.05 equiv.) for 30 min at 120 °C under microwave irradiation. Compounds
18, 35 and 36 were obtained in 43 to 72% yields. Starting from the regioisomer 1d, 2 equivalents of
both boronic acids were required.
One pot cyanation/Sonogashira and cyanation/Buchwald double couplings could be performed
starting from compounds 1d–e leading to compounds 38–41 in 32 to 67% yields. After optimization,
the one pot cyanation/Sonogashira conditions required CuCN (1.2 equiv.) in DMF at 90 °C for 4 h
under microwave irradiation, then 4-ethynyltoluene (1.3 equiv.), Et3N (5 equiv.), Pd(PPh3)4 (0.1 equiv.),
PCy3HBF4 (0.3 equiv.), CuI (0.2 equiv.) at 130 °C for 1 h under microwave irradiation. The one pot

Molecules 2012, 17
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cyanation/Buchwald double coupling was performed using CuCN (1.2 equiv.) in DMF at 90 °C for 4 h
under microwave irradiation, then DIPEA (2 equiv.), 4-fluorophenylpiperidine (2 equiv.) at 130 °C for 1
h under microwave irradiation. These results encouraged us to study other heterogeneous double couplings.
Table 4. One pot double-coupling approach applied to compounds 1a, 1d and 1e.
Isolated
Yield
(%)
Isolated
Yield
(%)
S.M.
Products
S.M.
Products
OCH3
F
1a
72 a
1a
44 a
N
N
H2N
N
N
18
35
F
N
S
1a
43 a
1d
47 b
N
N
N
N
36
37
F
CN
N
CN
N
1d
1e
32 c
1d
1e
67 d
N
N
N
N
39
38
F
CN
N
CN
43 c
54 d
N
N
N
CO2C2H5
CO2C2H5
N
N
40
41
Reaction conditions: a R1B(OH)2 (1 equiv.), Na2CO3 (3 equiv.), Pd(PPh3)4 (0.05 equiv.), DME/H2O,
95 °C, 30 min, MW then R2B(OH)2 (1.4 equiv.), Pd(PPh3)4 (0.05 equiv.), 120 °C, 30 min, MW;
b
R1B(OH)2 (2 equiv.), Na2CO3 (3 equiv.), Pd(PPh3)4 (0.05 equiv.), DME/H2O, 95 °C, 1 h 30 min,
MW then R2B(OH)2 (2 equiv.), Pd(PPh3)4 (0.05 equiv.), 120 °C, 30 min, MW; c CuCN (1.2 equiv.),
DMF, 90 °C, 4 h, MW then 4-ethynyltoluene (1.3 equiv.), Et3N (5 equiv.), Pd(PPh3)4 (0.1 equiv.),
d
PCy3HBF4 (0.3 equiv.), CuI (0.2 equiv.), 130 °C, 1 h, MW; CuCN (1.2 equiv.), DMF, 90 °C, 4 h,
MW then DIPEA (2 equiv.), 4-fluorophenylpiperidine (2 equiv.), 130 °C, 1 h, MW.

Molecules 2012, 17
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3. Experimental
3.1. General
Commercial reagents were used as received without additional purification. The microwave
experiments were performed with a CEM Discover SP® equipped with an Explorer hybrid unit, only
the set point temperature was adjusted (set point pressure: 17 bar, set point power: 200 W). The
compounds were purified on a Flashsmart® flash chromatography system and columns from AIT®
1
13
and Macherey-Nagel® were used. H and C-NMR spectra were recorded on a Brüker 300 MHz
spectrometer in CDCl3 or in DMSO-d6. The possible inversion of two values in the NMR spectra is
expressed by an asterisk. The melting points were determined in a capillary apparatus Stuart® SMP3
and are uncorrected.
3.2. Synthesis
3.2.1. Obtention of the Aminochloroiodopyridines
2,3-Dichloro-4-iodopyridine [8,15]. To a solution of n-butyllithium (27.6 mL, 69 mmol, 2.5 M in
hexanes) in dry Et2O (153 mL) cooled at −78 °C, was added dropwise 2,2,6,6-tetramethylpiperidine
(11.64 mL, 69 mmol). The mixture was stirred at −78 °C for 10 min and a solution of 2,3-dichloropyridine
(10 g, 67.57 mmol) in dry THF (75 mL) was added dropwise. The resulting mixture was stirred at
−78 °C for 30 min and a solution of I2 (25.38 g, 100 mmol) in dry THF (75 mL) was added. The
reaction was cooled to room temperature overnight, quenched with a saturated aqueous solution of
Na2S2O3 and extracted with EtOAc (3 × 50 mL). The combined organic layer was washed with a
saturated aqueous solution of NaHCO3, dried with anhydrous MgSO4 and evaporated in vacuo. The
residue was purified on column chromatography [silica gel, cyclohexane/EtOAc (7:3)] to give a pale
cream solid. M.p. = 110 °C (Ref. [8] 113 °C). 67% yield. 1H-NMR (CDCl3) δ 7.89 (d, 1H, J = 5.1 Hz,
H-6), 7.73 (d, 1H, J = 5.1 Hz, H-5). 13C-NMR (CDCl3) δ 148.5, 146.6, 135.4, 134.0, 111.2.
2-Amino-3-chloro-4-iodopyridine [8]. A mixture of 2,3-dichloro-4-iodopyridine (4 g, 14.71 mmol) in
NH4OH 28% (75 mL) was heated in a Parr bomb at 129 °C for 16 h. The reaction was cooled to room
temperature and CH2Cl2 (100 mL) was added. The mixture was extracted with CH2Cl2 (3 × 100 mL), dried
with anhydrous MgSO4 and evaporated in vacuo. The residue was purified by flash chromatography
[silica gel, cyclohexane/EtOAc (7:3)] and a white solid was obtained. M.p. = 110 °C. 38% yield.
1H-NMR (CDCl3) δ 7.54 (d, 1H, J = 5.3 Hz, H-6), 7.08 (d, 1H, J = 5.3 Hz, H-5), 5.32 (s, 2H, NH2).
13C-NMR (CDCl3) δ 154.6, 145.6, 124.7, 119.4, 109.8.
t-Butyl-(4-chloropyridin-2-yl)carbamate [16,17]. To a solution of 2-amino-4-chloropyridine (3 g,
23.34 mmol) in t-BuOH (43 mL), di-t-butyl dicarbonate (5.6 g, 25.67 mmol) was added. The mixture
was stirred at 30 °C overnight. A solid appeared and was filtered off, washed with n-hexane and
1
diethyl ether to give a white solid. M.p. = 150 °C. 77% yield. H-NMR (DMSO-d6)  10.14 (bs, 1H,
NH), 8.22 (d, 1H, J = 5.4 Hz, H-6), 7.88 (d, 1H, J = 1.9 Hz, H-3), 7.14 (dd, 1H, J = 5.4–1.9 Hz, H-5),
1.47 (s, 9H, CH3). 13C-NMR (DMSO-d6)  153.69, 152.66, 149.34, 143.84, 118.29, 111.65, 80.15, 27.95.

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t-Butyl-(4-chloro-3-iodopyridin-2-yl)carbamate [17]. To a solution of t-butyl-(4-chloropyridin-2-
yl)carbamate (9 g, 39.5 mmol) in anhydrous THF (250 mL), TMEDA (14.4 mL) was added under
nitrogen atmosphere and cooled to −70 °C. To the mixture, 2.5 M in hexane n-BuLi (39.6 mL,
98 mmol) was added dropwise over a period of 30 min. The mixture was stirred at −70 °C for 1 h and
then treated dropwise with a solution of I2 (50 g, 198 mmol) in anhydrous THF (30 mL) at −70 °C.
After the addition was complete, the reaction was stirred at −70 °C for 30 min and then allowed to
warm to room temperature. The mixture was treated with an aqueous saturated solution of Na2S2O3
and stirred for 30 min. The solution was extracted with EtOAc (3 × 200 mL). The combined organic
layer was washed with brine, dried with anhydrous MgSO4 and evaporated under reduce pressure. The
product was purified by flash chromatography [silica, cyclohexane/EtOAc (7:3)] to give a white solid.
M.p. = 183 °C. 75% yield. 1H-NMR (DMSO-d6) 9.48 (s, 1H, NH), 8.30 (d, 1H, J = 5.1 Hz, H-6), 7.47
(d, 1H, J = 5.1 Hz, H-5), 1.45 (s, 9H, CH3). 13C-NMR (DMSO-d6)  154.9, 152.6, 149.0, 148.4, 122.0,
99.2, 79.4, 28.1.
2-Amino-4-chloro-3-iodopyridine [7,8,17]. A suspension of t-butyl-(4-chloro-3-iodopyridin-2-yl)carbamate
(6 g, 23.5 mmol) in 48% hydrobromic acid (12 mL) was heated at 100 °C for 10 min to give a clear
solution. The mixture was cooled, treated with ice and made basic with 10 M NaOH solution. The
precipitated product was filtered off, washed with H2O to give a cream solid. M.p. = 111 °C. 97%
1
yield. H-NMR (DMSO-d6)  7.84 (d, 1H, J = 5.2 Hz, H-6), 6.72 (d, 1H, J = 5.2 Hz, H-5), 6.44
(bs, 2H, NH2). 13C-NMR (DMSO-d6) δ 161.0, 148.4, 147.7, 113.0, 81.4.
3.2.2. General Procedure for Cyclization
8-Chloro-7-iodo-2-phenylimidazo[1,2-a]pyridine (1a). Method A. To a solution of 2-amino-3-chloro-
4-iodopyridine (1 g, 3.94 mmol) in EtOH (10 mL), was added bromoacetophenone (1.56 g,
7.87 mmol). The mixture was stirred at 65 °C overnight. The solution was then evaporated to dryness
in vacuo. The residue was dissolved in CH2Cl2 (50 mL) and the resulting solution made basic by the
addition of a saturated aqueous solution of Na2CO3. The solution was extracted with CH2Cl2 (3 × 100 mL),
the combined organic layers were dried with anhydrous MgSO4 and evaporated under reduced pressure.
The crude product was purified by flash chromatography [silica gel, cyclohexane/EtOAc (7:3)].
M.p. = 101 °C. 97% yield. 1H-NMR (CDCl3) δ 7.96 (dd, 2H, J = 8.2–1.3 Hz, Ph-2,6), 7.88 (s, 1H, H-3),
7.80 (d, 1H, J = 7.0 Hz, H-5), 7.44 (m, 2H, Ph-3,5), 7.35 (m, 1H, Ph-4), 7.12 (d, 1H, J = 7.0 Hz, H-6).
13C-NMR (CDCl3) δ 146.8, 143.0, 132.8, 128.7, 128.5, 126.4, 123.9, 121.7, 110.0, 92.1(1C not found).
Ethyl 8-chloro-7-iodoimidazo[1,2-a]pyridine-2-carboxylate (1b). Method B. To a solution of 2-amino-
3-chloro-4-iodopyridine (1 g, 3,94 mmol) in DME (18 mL), was added ethyl bromopyruvate (1.16 g,
5.91 mmol). The mixture was stirred at room temperature overnight. The solution was evaporated
in vacuo to dryness and EtOH (18 mL) was added. The mixture was stirred at 78 °C for 2 h. After
cooling to room temperature, the solution was evaporated to dryness under vacuum. The residue was
dissolved in CH2Cl2 (50 mL) and the resulting solution made basic by the addition of a saturated
solution of Na2CO3. The solution was extracted with CH2Cl2 (3 × 100 mL), the combined organic
layers were dried with anhydrous MgSO4 and evaporated under reduced pressure. The crude product
was washed with diethyl ether and n-hexane to give a pale cream solid. M.p. = 249 °C. 95% yield.

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1H-NMR (CDCl3) δ 8.66 (s, 1H, H-3), 8.33 (d, 1H, J = 6.9 Hz, H-5), 7.41 (d, 1H, J = 6.9 Hz, H-6), 4.32
13
(q, 2H, J = 7.2 Hz, CH2), 1.32 (t, 3H, J = 7.2 Hz, CH3). C-NMR (CDCl3) δ 162.6, 142.3, 136.1,
127.1, 123.0, 120.8, 97.4, 61.0, 14.7 (1C not found).
8-Chloro-7-iodo-2-methylimidazo[1,2-a]pyridine (1c). Method A. 2-Amino-3-chloro-4-iodopyridine
(1 g, 3.94 mmol) and chloroacetone (1.46 g, 15.75 mmol) were used. M.p. = 136 °C. Quantitative
1
yield. H-NMR (CDCl3) δ 7.72 (d, 1H, J = 6.9 Hz, H-5), 7.38 (s, 1H, H-3), 7.07 (d, 1H, J = 6.9 Hz,
H-6), 2.48 (s, 3H, CH3). 13C-NMR (CDCl3) δ 144.6, 131.9, 127.5, 123.6, 121.1, 111.6, 91.5, 14.4.
7-Chloro-8-iodo-2-phenylimidazo[1,2-a]pyridine (1d). Method A. 2-Amino-4-chloro-3-iodopyridine
(1 g, 3.94 mmol) and bromoacetophenone (1.56 g, 7.87 mmol) were used. M.p. = 197 °C. 72% yield.
1H-NMR (CDCl3) δ 8.03–7.94 (m, 4H, Ph-2,6, H-3, H-5), 7.44 (m, 2H, Ph-3,5), 7.36 (m, 1H, Ph-4),
6.84 (d, 1H, J = 7.0 Hz, H-6). 13C-NMR (DMSO-d6) δ 145.5, 145.2, 135.1, 133.1, 128.8, 128.1, 127.2,
125.7, 113.1, 111.5, 88.6.
Ethyl 7-chloro-8-iodoimidazo[1,2-a]pyridine-2-carboxylate (1e). Method B. 2-Amino-4-chloro-3-
1
iodopyridine (1 g, 3.94 mmol) was used as starting material. M.p. = 208 °C. 71% yield. H-NMR
(DMSO-d6) δ 8.71 (s, 1H, H-3), 8.55 (d, 1H, J = 7.3 Hz, H-5), 7.16 (d, 1H, J = 7.3 Hz, H-6), 4.33
13
(q, 2H, J = 7.0 Hz, CH2), 1.32 (t, 3H, J = 7.0 Hz, CH3). C-NMR (DMSO-d6) δ 162.2, 145.4, 137.0,
136.2, 127.9, 120.4, 114.5, 89.9, 60.5, 14.3.
3.2.3. Suzuki Cross-Coupling on Compounds 1a–c
8-Chloro-7-(4-fluorophenyl)-2-phenylimidazo[1,2-a]pyridine (2). Method C. To a solution of 1a
(500 mg, 1.41 mmol) in a mixture of THF (2.7 mL) and water (0.3 mL) in a sealed tube, were added
4-fluorophenylboronic acid (296 mg, 2.11 mmol), Na2CO3 (449 mg, 4.24 mmol) and PdCl2(dppf)
(58 mg, 0.07 mmol, 5 mol%). The mixture was stirred at 75 °C for 1 h 30 min, 4-fluorophenylboronic
acid (99 mg, 0.5 equiv.) and a few amount of PdCl2(dppf) were added. After overnight stirring at 75 °C
and cooling to room temperature, CH2Cl2 (50 mL) and water (50 mL) were added and the solution was
extracted with CH2Cl2 (3 × 50 mL). The combined organic layer was dried with anhydrous MgSO4 and
evaporated under reduced pressure. The crude residues were purified by column chromatography
(alumina, CH2Cl2). M.p. = 211 °C. 90% yield. 1H-NMR (CDCl3) δ 8.09 (d, 1H, J = 6.9 Hz, H-5), 8.02
(m, 2H, Ph-2,6), 7.92 (s, 1H, H-3), 7.52 (dd, 2H, J = 8.8–5.2 Hz, F-Ph-2,6), 7.45 (m, 2H, Ph-3,5), 7.37
(m, 1H, Ph-4), 7.18 (t, 2H, J = 8,8 Hz, F-Ph-3,5), 6.80 (d, 1H, J = 6.9 Hz, H-6). 13C-NMR (CDCl3) δ
162.6, 147.1, 134.6, 133.2, 133.1, 131.1, 128.7, 128.3, 126.4, 123.4, 115.5, 114.8, 109.4. (2C not
found) Anal. Calcd for C19H12ClFN2: C, 70.70; H, 3.75; N, 8.68. Found: C, 70.94; H, 3.67; N, 8.73.
Ethyl 8-chloro-7-(4-fluorophenyl)imidazo[1,2-a]pyridine-2-carboxylate (3). Method C: 1b (500 mg,
1.43 mmol), 4-fluorophenylboronic acid (300 mg, 2.14 mmol then 100 mg, 0.71 mmol), Na2CO3
(454 mg, 4.38 mmol) and PdCl2(dppf) (58 mg, 0.07 mmol, 5 mol%) were used. M.p. = 199 °C. 87%
yield. 1H-NMR (CDCl3) δ 8.27 (s, 1H, H-3), 8.15 (d, 1H, J = 7.2 Hz, H-5), 7.50 (dd, 2H, J = 8.7–5.4 Hz,
F-Ph-2,6), 7.17 (t, 2H, J = 8.7 Hz, F-Ph-3,5), 6.90 (d, 1H, J = 7.2 Hz, H-6), 4.46 (q, 2H, J = 7.2 Hz,
13
CH2), 1.42 (t, 3H, J = 7.2 Hz, CH3). C-NMR (CDCl3) δ 162.7, 162.7, 143.1, 137.7, 136.0, 132.6,

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131.1, 124.1, 121.5, 118.3, 116.4, 115.5, 61.3, 14.3. Anal. Calcd for C16H12ClFN2O2: C, 60.29; H,
3.79; N, 8.79. Found: C, 60.51; H, 3.57; N, 8.81.
8-Chloro-7-(4-fluorophenyl)-2-methylimidazo[1,2-a]pyridine (4). Method C. 1c (500 mg, 1.71 mmol),
4-fluorophenylboronic acid (359 mg, 2.56 mmol then 120 mg, 0.85 mmol), Na2CO3 (545 mg, 5.14 mmol)
1
and PdCl2(dppf) (70 mg, 0.09 mmol, 5 mol%) were used. M.p. = 164 °C. 89% Yield. H-NMR
(CDCl3) δ 8.06 (d, 1H, J = 6.9 Hz, H-5), 7.52 (dd, 2H, J = 8.7–5.5 Hz, F-Ph-2,6), 7.46 (s, 1H, H-3),
7.19 (t, 2H, J = 8.7 Hz, F-Ph-3,5), 6.81 (d, 1H, J = 6.9 Hz, H-6), 2.56 (s, 3H, CH3). 13C-NMR (CDCl3)
δ 162.7, 144.0, 133.0, 131.1, 123.3, 115.5, 114.7, 111.1, 14.13. (3C not found) Anal. Calcd for
C14H10ClFN2: C, 64.50; H, 3.87; N, 10.75. Found: C, 64.36; H, 3.91; N, 10.83.
3.2.4. General Procedure for Sonogashira Cross-Coupling Reaction
8-Chloro-7-(p-tolylethynyl)-2-phenylimidazo[1,2-a]pyridine (5). Method D. To a solution of 1a (500 mg,
1.41 mmol) in DMF (6 mL), were added Et3N ((1 mL, 7.06 mmol), PCy3HBF4 (156 mg, 0.42 mmol),
p-tolylacetylene (213 mg, 1.84 mmol), Pd(PPh3)4 (163 mg, 0.14 mmol) and CuI (50 mg, 0.26 mmol).
The mixture was heated at 90 °C by microwave irradiation for 30 min. After cooling to room
temperature, water (50 mL) was added and the solution was extracted with EtOAc (3 × 50 mL). The
combined organic layers were dried with anhydrous MgSO4 and evaporated under reduced pressure.
The crude residues were purified by flash chromatography (silica, cyclohexane/EtOAc (7:3)).
1
M.p. = 176 °C. 71% yield. H-NMR (CDCl3) δ 8.04–7.95 (m, 3H, Ph-2,6, H-5), 7.88 (s, 1H, H-3),
7.55–7.40 (m, 4H, Ph-3,5, CH3-Ph-2,6), 7.35 (m, 1H, Ph-4), 7.20 (d, 2H, J = 7.9 Hz, CH3-Ph-3,5), 6.90
13
(d, 1H, J = 6.8 Hz, H-6), 2.39 (s, 3H, CH3). C-NMR (CDCl3) δ 147.4, 139.4, 132.9, 131.7, 129.2,
128.7, 128.6, 128.4, 126.4, 123.2, 119.3, 118.6, 115.0, 110.2, 98.1, 84.6, 21.6 (1C not found). Anal.
Calcd for C22H15ClN2: C, 77.08; H, 4.41; N, 8.17. Found: C, 77.24; H, 4.46; N, 8.07.
Ethyl 8-chloro-7-(p-tolylethynyl)imidazo[1,2-a]pyridine-2-carboxylate (6). Method D. 1b (500 mg,
1.43 mmol), Et3N (1 mL, 7.14 mmol), PCy3HBF4 (158 mg, 0.43 mmol), p-tolylacetylene (215 mg,
1.86 mmol), Pd(PPh3)4 (165 mg, 0.14 mmol) and CuI (50 mg, 0.26 mmol) were used. M.p. = 211 °C.
77% yield. 1H-NMR (CDCl3) δ 8.21 (s, 1H, H-3), 8.04 (d, 1H, J = 7.2 Hz, H-5), 7.49 (d, 2H, J = 8.1 Hz,
CH3-Ph-2,6), 7.19 (d, 2H, J = 8.1 Hz, CH3-Ph-3,5), 6.97 (d, 2H, J = 7.2 Hz, H-6), 4.46 (q, 2H, J = 7.5 Hz,
13
CH2), 2.39 (s, 3H, CH3), 1.43 (t, 3H, J = 7.5 Hz, CH3). C-NMR (CDCl3) δ 162.5, 142.7, 139.8,
137.7, 131.8, 129.3, 126.0, 124.0, 120.6, 119.0, 116.5, 99.5, 84.0, 61.4, 21.6, 14.32 (1C not found).
Anal. Calcd for C19H15ClN2O2: C, 67.36; H, 4.46; N, 8.27. Found: C, 67.49; H, 4.41; N, 8.38.
7-Chloro-8-(p-tolylethynyl)-2-phenylimidazo[1,2-a]pyridine (7). Method D. 1d (250 mg, 0.71 mmol),
Et3N (0.5 mL, 3.53 mmol), PCy3HBF4 (78 mg, 0.21 mmol), p-tolylacetylene (107 mg, 0.92 mmol),
Pd(PPh3)4 (81 mg, 0.07 mmol) and CuI (25 mg, 0.13 mmol) were used. M.p. = 118 °C. 60% yield.
1H-NMR (CDCl3) δ 8.00 (m, 3H, H-5, Ph-2,6), 7.84 (s, 1H, H-3), 7.62 (d, 2H, J = 8.0 Hz, CH3-Ph-2,6),
7.44 (m, 2H, Ph-3,5), 7.34 (m, 1H, Ph-4), 7.20 (d, 2H, J = 8.0 Hz, CH3-Ph-3,5), 6.85 (d, 1H,
13
J = 7.4 Hz, H-6), 2.39 (s, 3H, CH3). C-NMR (CDCl3) δ 146.9, 139.3, 133.1, 132.1, 129.1, 128.9,
128.6, 128.3, 126.3, 126.2, 124.5, 119.6, 115.8, 114.2, 108.9, 81.4, 21.6 (1C not found). Anal. Calcd
for C22H15ClN2: C, 77.08; H, 4.41; N, 8.17. Found: C, 77.25; H, 4.43; N, 8.19.

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Ethyl 7-chloro-8-(p-tolylethynyl)imidazo[1,2-a]pyridine-2-carboxylate (8). Method D. 1e (250 mg,
0.71 mmol), Et3N (0.5 mL, 3.53 mmol), PCy3HBF4 (78 mg, 0.21 mmol), p-tolylacetylene (107 mg,
0.92 mmol), Pd(PPh3)4 (81 mg, 0.07 mmol) and CuI (25 mg, 0.13 mmol) were added. M.p. = 175 °C.
50% yield. 1H-NMR (CDCl3) δ 8.20 (s, 1H, H-3), 8.10 (d, 1H, J = 7.2 Hz, H-5), 7.55 (d, 2H, J = 8.0 Hz,
CH3-Ph-2,6), 7.17 (d, 2H, J = 8.0 Hz, CH3-Ph-3,5), 6.95 (d, 1H, J = 7.2 Hz, H-6), 4.44 (q, 2H, J = 7.1 Hz,
13
CH2), 2.37 (s, 3H, CH3), 1.42 (t, 3H, J = 7.1 Hz, CH3). C-NMR (CDCl3) δ 162.7, 144.8, 139.5,
137.6, 135.0, 132.0, 129.0, 125.2, 119.2, 118.0, 115.9, 113.8, 102.8, 80.9, 61.3, 21.6, 14.3. Anal. Calcd
for C19H15ClN2O2: C, 67.36; H, 4.46; N, 8.27. Found: C, 67.21; H, 4.47; N, 8.46.
3.2.5. General Procedure for Cyanation Reaction
8-Chloro-2-phenylimidazo[1,2-a]pyridine-7-carbonitrile (9). Method E. To a solution of 1a (400 mg,
1.13 mmol) in DMF (793 µL), CuCN (132 mg, 1.47 mmol) was added. The tube was evacuated and
back filled with nitrogen. Then the reaction mixture was heated at 150 °C or 200 °C by microwave
irradiation for 15 min. After cooling to room temperature, an aqueous solution of NH4OH 10%
(50 mL) and CH2Cl2 (50 mL) were added and the organic layer was washed with an aqueous solution
of NH4OH (3 × 50 mL), dried with anhydrous MgSO4 and evaporated under reduced pressure. The
crude residues were purified on column chromatography (silica gel, CH2Cl2). The reaction mixture was
heated at 200 °C by microwave irradiation. M.p. = 200 °C. 72% yield. 1H-NMR (CDCl3) δ 8.71 (s, 1H,
H-3), 8.67 (d, 1H, J = 7.0 Hz, H-5), 8.01 (m, 2H, Ph-2,6), 7.48 (m, 2H, Ph-3,5), 7.39 (m, 1H, Ph-4),
13
7.30 (d, 1H, J = 7.0 Hz, H-6). C-NMR (CDCl3) δ 147.4, 140.7, 132.4, 128.9, 128.8, 127.0, 126.7,
125.9, 115.6, 113.6, 112.6, 106.2. Anal. Calcd for C14H8ClN3: C, 66.28; H, 3.18; N, 16.56. Found: C,
65.94; H, 3.33; N, 16.72.
Ethyl 8-chloro-7-cyanoimidazo[1,2-a]pyridine-2-carboxylate (10). Method E. 1b (400 mg, 1.14 mmol)
was used as starting material. The reaction mixture was heated at 200 °C by microwave irradiation.
1
M.p. = 229 °C. 63% yield. H-NMR (CDCl3) δ 8.35 (s, 1H, H-3), 8.20 (d, 1H, J = 7.0 Hz, H-5), 7.05
13
(d, 1H, J = 7.0 Hz, H-6), 4.50 (q, 2H, J = 7.5 Hz, CH2), 1.45 (t, 3H, J = 7.5 Hz, CH3). C-NMR
(CDCl3) δ 161.9, 141.3, 139.8, 131.4, 125.3, 120.0, 114.4, 114.0, 109.3, 61.8, 14.3. Anal. Calcd for
C11H8ClN3O2: C, 52.92; H, 3.23; N, 16.83. Found: C, 53.16; H, 3.48; N, 16.97.
7-Chloro-2-phenylimidazo[1,2-a]pyridine-8-carbonitrile (11). Method E. 1d (400 mg, 1.13 mmol) was
used as starting material. The reaction mixture was heated at 150 °C by microwave irradiation.
1
M.p. = 197 °C. 69% yield. H-NMR (CDCl3) δ 8.22 (d, 1H, J = 7.2 Hz, H-5), 7.96 (m, 2H, Ph-2,6),
13
7.91 (s, 1H, H-3), 7.45 (m, 2H, Ph-3,5), 7.37 (m, 1H, Ph-4), 6.90 (d, 1H, J = 7.2 Hz, H-6). C-NMR
(CDCl3) δ 148.4, 143.3, 137.3, 132.2, 129.0, 128.8, 126.4, 113.5, 112.6, 109.3, 102.0 (1 C not found).
Anal. Calcd for C14H8ClN3: C, 66.28; H, 3.18; N, 16.56. Found: C, 66.34; H, 3.35; N, 16.51.
Ethyl 7-chloro-8-cyanoimidazo[1,2-a]pyridine-2-carboxylate (12). Method E. 1e (400 mg, 1.14 mmol)
was used as starting material. The reaction mixture was heated at 150 °C by microwave irradiation.
1
M.p. = 227 °C. 46% yield. H-NMR (CDCl3) δ 8.31 (d, 1H, J = 7.2 Hz, H-5), 8.28 (s, 1H, H-3), 7.06
13
(d, 1H, J = 7.4 Hz, H-6), 4.48 (q, 2H, J = 7.1 Hz, CH2), 1.45 (t, 3H, J = 7.1 Hz, CH3). C-NMR

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(CDCl3) δ 162.1, 139.8, 139.2, 129.6, 118.4, 115.3, 111.7, 61.8, 14.3 (2C not found). Anal. Calcd for
C11H8ClN3O2: C, 52.92; H, 3.23; N, 16.83. Found: C, 53.17; H, 3.32; N, 16.79.
3.2.6. General Procedure for Buchwald-Hartwig Cross-Coupling Reaction
N-(8-Chloro-2-phenylimidazo[1,2-a]pyridin-7-yl)aniline (13). Method F. To a solution of 1a (100 mg,
0.28 mmol) in DME (3 mL) under argon, were added successively rac-BINAP (53 mg, 0.085 mmol),
t-BuONa (81 mg, 0.85 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), CuI (10 mg, 0.053 mmol) and aniline
(77 µL, 0.85 mmol). The mixture was heated at 85 °C by microwave irradiation for 45 min. After
cooling to room temperature, water (50 mL) was added and the solution was extracted with EtOAc
(3 × 50 mL), dried with anhydrous MgSO4 and evaporated under reduced pressure. The crude residues
were purified by flash chromatography (silica, cyclohexane/EtOAc (7:3)). M.p. = 170 °C. 48% yield.
1H-NMR (CDCl3) δ 7.93 (m, 2H, Ph-2,6), 7.82 (d, 1H, J = 7.4 Hz, H-5), 7.67 (s, 1H, H-3), 7.47–7.28
(m, 5H, Ph-3,4,5, Ph-NH-3,5), 7.15 (m, 3H, Ph-NH-2,4,6), 6.75 (d, 1H, J = 7.4 Hz, H-6), 6.42 (s, 1H,
NH). 13C-NMR (CDCl3) δ 139.7, 138.2, 133.4, 129.7, 128.6, 128.1, 126.2, 124.5, 124.3, 121.9, 120.1,
108.3, 104.3 (2C not found). Anal. Calcd for C19H14ClN3: C, 71.36; H, 4.41; N, 13.14. Found: C,
71.55; H, 4.39; N, 13.26.
Ethyl 8-chloro-7-(cyclohexylamino)imidazo[1,2-a]pyridine-2-carboxylate (14). Method G. To a
solution of 1b (100 mg, 0.29 mmol) in dioxane (3 mL), were added Pd2dba3 (11 mg, 0.01 mmol),
Xantphos (20 mg, 0.03 mmol), K2CO3 (591 mg, 4.29 mmol) and cyclohexylamine (0.42 mL,
3.71 mmol). The mixture was irradiated under microwaves at 150 °C during 1 h 15 min. After cooling
to room temperature, EtOAc (50 mL) and water (50 mL) were added. The solution was extracted with
EtOAc (3 × 50 mL), dried with anhydrous MgSO4 and evaporated under reduced pressure. The crude
residues were purified by flash chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 176 °C.
40% yield. 1H-NMR (CDCl3) δ 7.98 (s, 1H, H-3), 7.90 (d, 1H, J = 7.5 Hz, H-5), 6.56 (d, 1H, J = 7.5 Hz,
H-6), 4.57 (m, 1H, NH), 4.41 (q, 2H, J = 7.0 Hz, CH2), 3.37 (m, 1H, CyHex), 2.02 (m, 2H, CyHex),
13
1.80 (m, 2H, CyHex), 1.66 (m, 1H, CyHex), 1.32 (m, 9H, CH3, CyHex). C-NMR (CDCl3) δ 163.3,
144.7, 141.3, 136.6, 124.8, 116.5, 104.2, 99.6, 60.9, 51.8, 33.6, 25.4, 24.6, 14.4. Anal. Calcd for
C16H20ClN3O2: C, 59.72; H, 6.26; N, 13.06. Found: C, 59.88; H, 6.23; N, 12.97.
N-(7-Chloro-2-phenylimidazo[1,2-a]pyridin-8-yl)aniline (15). Method F. 1d (100 mg, 0.28 mmol) was
used as starting material. M.p. = 167 °C. 51% yield. 1H-NMR (CDCl3) δ 7.92 (m, 2H, Ph-2,6), 7.82 (s,
1H, H-3), 7.76 (d, 1H, J = 7.2 Hz, H-5), 7.43 (m, 2H, Ph-3,5), 7.32 (m, 3H, Ph-4, Ph-NH-3,5), 7.00
13
(m, 4H, Ph-NH-2,6,4, NH), 6.79 (d, 1H, J = 7.2 Hz, H-6). C-NMR (CDCl3) δ 145.3, 142.2, 141.6,
133.2, 128.7, 128.6, 128.1, 127.3, 126.0, 121.9, 119.4, 119.2, 119.0, 115.7, 109.3. Anal. Calcd for
C16H20ClN3O2: C, 59.72; H, 6.26; N, 13.06. Found: C, 59.88; H, 6.23; N, 12.97.
Ethyl 7-chloro-8-(cyclohexylamino)imidazo[1,2-a]pyridine-2-carboxylate (16). Method G. 1e (100 mg,
1
0.29 mmol) was used as starting material. M.p. = 90 °C. 66% yield. H-NMR (CDCl3) δ 8.03 (s, 1H,
H-3), 7.49 (d, 1H, J = 7.2 Hz, H-5), 6.77 (d, 1H, J = 7.2 Hz, H-6), 4.43 (q, 2H, J = 7.0 Hz, CH2), 2.05
(m, 2H, CyHex), 1.77 (m, 2H, CyHex), 1.63 (m, 2H, NH, CyHex), 1.28 (m, 9H, CH3, CyHex).

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13C-NMR (CDCl3) δ 162.0, 157.0, 144.9, 133.7, 126.7, 118.5, 117.8, 114.7, 61.3, 53.2, 34.5, 25.6,
24.9, 14.3. Anal. Calcd for C16H20ClN3O2: C, 59.72; H, 6.26; N, 13.06. Found: C, 59.95; H, 6.32; N, 13.01.
3.2.7. Substitution of the Chlorine Atom in Position 8 of Compounds 2–6, 9–10, 14
Ethyl 7-(4-fluorophenyl)-8-(p-tolyl)imidazo[1,2-a]pyridine-2-carboxylate (17). Method H. To a
solution of 3 (100 mg, 0.31 mmol) in a mixture of dioxane (0.5 mL) and ethanol (0.3 mL), were added
p-tolylboronic acid (60 mg, 0.44 mmol), K2CO3 (88 mg, 0.63 mmol) and Pd(PPh3)4 (36 mg, 0.031 mmol).
The mixture was heated at 150 °C by microwave irradiation for 15 min. After cooling to room
temperature, water (50 mL) was added and the solution was extracted with CH2Cl2 (3 × 50 mL). The
organic layer was dried with anhydrous MgSO4 and evaporated under reduced pressure. The crude
residue was purified by column chromatography (silica gel, CH2Cl2). M.p. = 241 °C. 95% yield. 1H-NMR
(CDCl3) δ 8.25 (s, 1H, H-3), 8.19 (d, 1H, J = 7.2 Hz, H-5), 7.22 (d, 2H, J = 7.9 Hz, CH3-Ph-2,6), 7.12
(dd, J = 8.7–5.4 Hz, 2H, F-Ph-2,6), 7.03 (d, 2H, J = 7.9 Hz, CH3-Ph-3,5), 6.92 (m, 3H, F-Ph-3,5, H-6),
13
4.39 (q, 2H, J = 7.2 Hz, CH2), 2.30 (s, 3H, CH3), 1.38 (t, 3H, J = 7.2 Hz, CH3). C-NMR (CDCl3) δ
163.1, 161.9, 145.3, 137.6, 137.2, 135.9, 135.2, 131.3, 131.0, 129.3, 128.7, 124.5, 117.3, 117.2, 115.2,
61.0, 21.2, 14.3. (1C not found) Anal. Calcd for C23H19FN2O2: C, 73.78; H, 5.11; N, 7.48. Found: C,
74.03; H, 5.08; N, 7.56.
Ethyl 7-(4-fluorophenyl)-8-(4-methoxyphenyl)imidazo[1,2-a]pyridine-2-carboxylate (18). Method H.
4-Methoxyphenylboronic acid (96 mg, 0.63 mmol) was used. The crude residue was purified by
1
column chromatography (silica gel, CH2Cl2). M.p. = 199 °C. 76% yield. H-NMR (CDCl3) δ 8.26
(s, 1H, H-3), 8.20 (d, 1H, J = 7.2 Hz, H-5), 7.28 (d, 2H, J = 8.7 Hz, CH3O-Ph-2,6), 7.12 (dd, 2H,
J = 8.7–5.4 Hz, F-Ph-2,6), 6.96–6.91 (m, 3H, H-6, F-Ph-3,5), 6.78 (d, 2H, J = 8.7 Hz, CH3O-Ph-3,5),
4.40 (q, 2H, J = 7.2 Hz, CH2), 3.78 (s, 3H, CH3O), 1.39 (t, 3H, J = 7.2 Hz, CH3). 13C-NMR (CDCl3) δ
162.6, 161.9, 159.1, 144.9, 136.6, 136.3, 134.7, 132.3, 131.2, 128.3, 125.9, 124.9, 117.5, 117.4, 115.2,
113.3, 61.1, 55.2, 14.3. Anal. Calcd for C23H19FN2O3: C, 70.76; H, 4.91; N, 7.18. Found: C, 70.84; H,
5.11; N, 7.01.
7-(4-Fluorophenyl)-8-(p-tolyl)-2-phenylimidazo[1,2-a]pyridine (19). Method I. To a solution of 2
(100 mg, 0.31 mmol) in a mixture of DME (2 mL) and water (1 mL), were added p-tolylboronic acid
(84 mg, 0.62 mmol), Na2CO3 (66 mg, 0.62 mmol) and Pd(PPh3)4 (18 mg, 0.016 mmol, 5 mol%). The
mixture was heated at 120 °C for 30 min by microwave irradiation. After cooling to room temperature,
water (50 mL) was added and the solution was extracted with CH2Cl2 (3 × 50 mL). The organic layer
was dried with anhydrous MgSO4 and evaporated under reduced pressure. The crude residue was
purified by column chromatography (silica gel, CH2Cl2). M.p. = 222 °C. 90% yield. 1H-NMR (CDCl3)
δ 8.11 (d, 1H, J = 6.9 Hz, H-5), 7.95 (m, 2H, Ph-2,6), 7.91 (s, 1H, H-3), 7.42–7.28 (m, 5H, CH3-Ph-2,6,
Ph-3,4,5), 7.17–7.11 (m, 4H, F-Ph-2,6, CH3-Ph-3,5), 6.94 (t, 2H, J = 8.7 Hz, F-Ph-3,5), 6.85 (d, 1H,
13
J = 6,9 Hz, H-6), 2.36 (s, 3H, CH3). C-NMR (CDCl3) δ 161.8, 146.3, 145.4, 137.3, 135.9, 134.6,
133.7, 131.7, 131.4, 131.3, 128.6, 128.5, 127.8, 126.3, 123.9, 115.7, 115.1, 108.3, 21.3 (1C not found).
Anal. Calcd for C26H19FN2: C, 82.52; H, 5.06; N, 7.40. Found: C, 82.77; H, 5.39; N, 7.28.

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7-(4-Fluorophenyl)-2-methyl-8-(p-tolyl)imidazo[1,2-a]pyridine (20). Method I. 4 (100 mg, 0.38 mmol),
p-tolylboronic acid (104 mg, 0.77 mmol), Na2CO3 (82 mg, 0.77 mmol, 2 eq) and Pd(PPh3)4 (22 mg,
0.02 mmol, 5 mol%) were used. The mixture was heated for 60 min. The crude residue was purified by
1
flash chromatography (silica, CH2Cl2/MeOH (99:1)). M.p. = 195 °C. 84% yield. H-NMR (CDCl3) δ
8.11 (d, 1H, J = 7.2 Hz, H-5), 7.45 (s, 1H, H-3), 7.18 (d, 2H, J = 8.1 Hz, CH3-Ph-2,6), 7.11–7.08 (m, 4H,
F-Ph-2,6, CH3-Ph-3,5), 6.90 (t, 2H, J = 8.7 Hz, F-Ph-3,5), 6.82 (d, 1H, J = 7.2 Hz, H-6), 2.44 (s, 3H,
13
CH3), 2.29 (s, 3H, CH3). C-NMR (CDCl3) δ 161.7, 144.6, 143.7, 137.1, 135.7, 134.3, 131.8, 131.3,
130.7, 128.7, 127.3, 123.7, 114.9, 114.9, 109.9, 21.2, 14.4. Anal. Calcd for C21H17FN2: C, 79.72; H,
5.42; N, 8.85. Found: C, 79.95; H, 5.48; N, 8.75.
7-(4-Fluorophenyl)-8-(4-methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine (21). Method I. 2 (100 mg,
0.31 mmol), 4-methoxyphenylboronic acid (94 mg, 0.62 mmol) were used. The mixture was heated for
30 min. The crude residue was purified by column chromatography (silica gel, CH2Cl2). M.p. = 201 °C.
82% yield. 1H-NMR (CDCl3) δ 8.15 (d, 1H, J = 7.0 Hz, H-5), 7.99–7.89 (m, 3H, Ph-2,6, H-3), 7.43–7.27
(m, 5H, Ph-3,4,5, CH3O-Ph-2,6), 7.12 (dd, 2H, J = 9–5.4 Hz, F-Ph-2,6), 6.94 (t, 2H, J = 8.7 Hz, F-Ph-3,5),
13
6.89–6.78 (m, 3H, CH3O-Ph-3,5, H-6), 3.81 (s, 3H, CH3O). C-NMR (CDCl3) δ 161.9, 159.0, 146.0,
145.3, 135.9, 134.8, 133.5, 132.7, 131.4, 128.6, 127.9, 126.9, 126.3, 124.0, 115.8, 115.2, 113.4, 108.5,
55.2 (1 C not found). Anal. Calcd for C26H19FN2O: C, 79.17; H, 4.86; N, 7.10. Found: C, 79.35; H,
5.91; N, 7.24.
7-(4-Fluorophenyl)-2-methyl-8-(pyridin-4-yl)imidazo[1,2-a]pyridine (22). Method I. 4 (100 mg,
0.38 mmol), pyridin-4-ylboronic acid (76 mg, 0.54 mmol), Na2CO3 (82 mg, 0.77 mmol) and Pd(PPh3)4
(22 mg, 0.02 mmol, 5 mol%) were used. The mixture was heated for 60 min. The crude residue was
1
purified by flash chromatography (silica, CH2Cl2/MeOH (99:1)). M.p. = 188 °C. 80% yield. H-NMR
(CDCl3) δ 8.54 (d, 2H, J = 6.0 Hz, Pyr-2,6), 8.15 (d, 1H, J = 6.9 Hz, H-5), 7.46 (s, 1H, H-3), 7.31 (dd,
2H, J = 6.0 Hz, Pyr-3,5), 7.08 (dd, 2H, J = 8.7–5.4 Hz, F-Ph-2,6), 6.94 (t, 2H, J = 8.7 Hz, F-Ph-3,5),
13
6.87 (d, 1H, J = 6.9 Hz, H-6), 2.47 (s, 3H, CH3). C-NMR (CDCl3) δ 162.2, 148.9, 144.1, 143.2,
135.7, 134.4, 131.3, 126.2, 125.0, 124.0, 115.7, 115.5, 110.3, 14.2 (1C not found). Anal. Calcd for
C19H14FN3: C, 75.23; H, 4.65; N, 13.85. Found: C, 75.52; H, 4.56; N, 13.98.
8-(Fur-2-yl)-7-(p-tolylethynyl)-2-phenylimidazo[1,2-a]pyridine (23). Method I. 5 (100 mg, 0.29 mmol),
fur-2-ylboronic acid (65 mg, 0.58 mmol), Na2CO3 (62 mg, 0.58 mmol) and Pd(PPh3)4 (17 mg, 0.02 mmol,
5 mol%) were used. The mixture was heated for 75 min. The crude residue was purified by flash
1
chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. > 300 °C. 19% yield. H-NMR (300 MHz,
CDCl3) δ 8.08–7.96 (m, 4H, H-5, Ph-2,6, Fur-3), 7.91 (s, 1H, H-3) 7.74 (d, 1H, J = 1.7–0.9 Hz, Fur-5),
7.53–7.40 (m, 4H, Ph-3,5, CH3-Ph-2,6), 7.34 (m, 1H, Ph-4), 7.21 (d, 2H, J = 7.9 Hz, CH3-Ph-3,5), 6.98
(d, 1H, J = 6.8 Hz, H-6), 6.70 (dd, 1H, J = 3.4–1.7 Hz, Fur-4), 2.41 (s, 3H, CH3). 13C-NMR (CDCl3) δ
148.6, 145.8, 143.0, 139.0, 133.0, 131.5, 129.2, 128.7, 128.2, 126.2, 123.0, 120.5, 120.2, 117.2, 115.2,
114.5, 111.9, 109.4, 96.0, 88.5, 21.6 (1C not found). Anal. Calcd for C26H18N2O: C, 83.40; H, 4.85; N,
7.48. Found: C, 83.56; H, 4.91; N, 7.34.
2-Phenyl-8-(thien-3-yl)imidazo[1,2-a]pyridine-7-carbonitrile (24). Method I. 9 (100 mg, 0.40 mmol),
thien-3-ylboronic acid (71 mg, 0.55 mmol), Na2CO3 (84 mg, 0.79 mmol) and Pd(PPh3)4 (23 mg,

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0.02 mmol, 5 mol%) were used. The mixture was heated for 15 min. The crude residue was purified by
flash chromatography (silica, petroleum ether/EtOAc (100:0) to (20:80)). M.p. = 193 °C. 71% yield.
1H-NMR (CDCl3) δ 8.48 (dd, 1H, J = 3.0–1.3 Hz, Th-2), 8.11 (d, 1H, J = 7.0 Hz, H-5), 8.05 (dd, 1H,
J = 5.1–1.3 Hz, Th-4), 7.99 (m, 3H, H-3, Ph-2,6), 7.52 (dd, 1H, J = 5.1–3.0 Hz, Th-5), 7.45 (m, 2H,
13
Ph-3,5), 7.37 (m, 1H, Ph-4), 7.01 (d, 1H, J = 7.0 Hz, H-6). C-NMR (CDCl3) δ 148.3, 142.7, 132.7,
132.5, 130.8, 129.7, 129.0, 128.8, 128.7, 126.3, 125.3, 124.0, 118.6, 114.3, 110.6, 103.2. Anal. Calcd
for C18H11N3S: C, 71.74; H, 3.68; N, 13.94. Found: C, 71.62; H, 3.77; N, 14.05.
2-Phenyl-8-(pyridin-4-yl)imidazo[1,2-a]pyridine-7-carbonitrile (25). Method I. 9 (100 mg, 0.40 mmol),
pyridin-4-ylboronic acid (78 mg, 0.55 mmol), Na2CO3 (84 mg, 0.79 mmol), Pd(PPh3)4 (23 mg, 0.02 mmol,
5 mol%) were used. The mixture was heated for 15 min. The crude residue was purified by flash
1
chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 278 °C. 42% yield. H-NMR (CDCl3) δ
8.84 (d, 2H, J = 5.8 Hz, Pyr-2,6), 8.78 (d, 1H, J = 7.0 Hz, H-5), 8.74 (s, 1H, H-3), 7.96 (m, 2H,
13
Ph-2,6), 7.84 (m, 2H, Pyr-3,5), 7.47 (m, 2H, Ph-3,5), 7.36 (m, 2H, H-6, Ph-4). C-NMR (CDCl3) δ
149.8, 147.5, 141.8, 140.7, 132.6, 132.4, 128.9, 128.6, 127.8, 126.0, 124.7, 117.4, 113.3, 112.5, 104.9.
Anal. Calcd for C19H12N4: C, 77.01; H, 4.08; N, 18.91. Found: C, 77.12; H, 3.97; N, 18.89.
Ethyl 7-(cyclohexylamino)-8-(p-tolyl)imidazo[1,2-a]pyridine-2-carboxylate (26). Method H. 14 (100 mg,
0.31 mmol), p-tolylboronic acid (84.3 mg, 0.62 mmol) were used. The crude residue was purified by
flash chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 169 °C. 27% yield. 1H-NMR (CDCl3) δ
8.04 (d, 1H, J = 7.5 Hz, H-5), 8.00 (s, 1H, H-3), 7.35 (d, 2H, J = 8.0 Hz, CH3-Ph-2,6), 7.25 (d, 2H,
J = 8.0 Hz, CH3-Ph-3,5), 6.65 (d, 1H, J = 7.5 Hz, H-6), 4.34 (q, 2H, J = 7.0 Hz, CH2), 4.15 (s, 1H,
NH), 3.32 (m, 1H, CyHex), 2.39 (s, 3H, CH3), 1.94 (m, 2H, CyHex), 1.64 (m, 3H, CyHex), 1.20 (m,
13
8H, CH3, CyHex). C-NMR (CDCl3) δ 163.4, 146.9, 142.5, 137.7, 135.8, 130.4, 129.9, 129.6, 125.6,
115.7, 108.4, 105.3, 60.7, 52.1, 33.6, 25.5, 24.7, 21.3, 14.3. Anal. Calcd for C23H27FN3O2: C, 73.18; H,
7.21; N, 11.13. Found: C, 73.39; H, 7.18; N, 11.09.
Ethyl 8-(1H-indol-6-yl)-7-(p-tolylethynyl)imidazo[1,2-a]pyridine-2-carboxylate (27). Method H. 6
(100 mg, 0.3 mmol), indol-6-ylboronic acid (96.6 mg, 0.6 mmol), K2CO3 (83 mg, 0.59 mmol) and
Pd(PPh3)4 (34 mg, 0.03 mmol) were used. The crude residue was purified by flash chromatography
[silica, cyclohexane/EtOAc (7:3)]. M.p. = 242 °C. 35% yield. 1H-NMR (CDCl3) δ 10.17 (bs, 1H, NH),
8.17–8.09 (m, 2H, H-5, H-3), 7.78 (s, 1H, Indol-7), 7.39 (d, 1H, J = 8.1 Hz, Indol-4*), 7.24 (d, 1H,
J = 8.1 Hz, Indol-5*), 7.19–6.92 (m, 6H, H-6, CH3-Ph, Indol-2), 6.33 (s, 1H, Indol-3), 4.27 (q, 2H,
J = 7.1 Hz, CH2), 2.27 (s, 3H, CH3), 1.14 (t, 3H, J = 7.1 Hz, CH3). 13C-NMR (CDCl3) δ 161.6, 143.7,
139.2, 135.4, 134.6, 133.5, 131.6, 129.1, 128.1, 126.2, 125.6, 124.5, 121.2, 119.2, 119.0, 118.6, 118.0,
114.0, 101.1, 97.0, 87.0, 61.5, 21.5, 14.0. (1 C not found) Anal. Calcd for C27H21N3O2: C, 77.31; H,
5.05; N, 10.02. Found: C, 77.47; H, 4.98; N, 10.13.
Ethyl 7-cyano-8-(pyridin-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (28). Method H. 10 (100 mg,
0.4 mmol), pyridin-4-ylboronic acid (80 mg, 0.56 mmol), K2CO3 (112 mg, 0.8 mmol), Pd(PPh3)4
(46 mg, 0.04 mmol) were used. The crude residue was purified by flash chromatography [silica,
1
cyclohexane/EtOAc (100:0) to (10:90)]. M.p. = 185 °C. 31% yield. H-NMR (CDCl3) δ 8.86 (d, 2H,
J = 6.0 Hz, Pyr-2,6), 8.40 (s, 1H, H-3), 8.35 (d, 1H, J = 7.0 Hz, H-5), 7.91 (d, 2H, J = 6.0 Hz, Pyr-3,5),

Molecules 2012, 17
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7.19 (d, 1H, J = 7.0 Hz, H-6), 4.45 (q, 2H, J = 7.1 Hz, CH2), 1.41 (t, 3H, J = 7.1 Hz, CH3). 13C-NMR
(CDCl3) δ 162.2, 149.9, 142.2, 139.9, 126.8, 124.6, 119.3, 116.4, 115.0, 107.5, 61.7, 14.3. (2C not
found) Anal. Calcd for C16H12N4O2: C, 65.75; H, 4.14; N, 19.17. Found: C, 65.92; H, 4.28; N, 19.04.
Ethyl 7-cyano-8-(fur-2-yl)imidazo[1,2-a]pyridine-2-carboxylate (29). Method H. 10 (100 mg, 0.4 mmol),
fur-2-ylboronic acid (63 mg, 0.56 mmol), K2CO3 (112 mg, 0.8 mmol), Pd(PPh3)4 (46 mg, 0.04 mmol)
were used. The crude residue was purified by flash chromatography [silica, cyclohexane/EtOAc (7:3)].
M.p. = 185 °C. 34% yield. 1H-NMR (CDCl3) δ 8.29–8.22 (m, 2H, H-3, Fur-3), 8.07 (d, 1H, J = 7.2 Hz,
H-5), 7.78 (dd, 1H, J = 1.7–0.8 Hz, Fur-5), 7.08 (d, 1H, J = 7.2 Hz, H-6), 6.71 (dd, 1H, J = 3.6–1.7 Hz,
Fur-4), 4.48 (q, 2H, J = 7.2 Hz, CH2), 1.46 (t, 3H, J = 7.2 Hz, CH3). 13C-NMR (CDCl3) δ 162.4, 148.8,
145.3, 140.1, 138.5, 123.7, 122.2, 119.3, 118.9, 117.9, 116.2, 113.0, 61.5, 14.3. (1 C not found) Anal.
Calcd for C15H11N3O3: C, 64.05; H, 3.94; N, 14.94. Found: C, 63.92; H, 4.08; N, 15.02.
Ethyl 7-(cyclohexylamino)-8-(pyridin-4-yl)imidazo[1,2-a]pyridine-2-carboxylate (30). Method H. 14
(100 mg, 0.31 mmol), pyridin-4-ylboronic acid (76.2 mg, 0.62 mmol) were used. The crude residue
was purified by flash chromatography [silica, cyclohexane/EtOAc (6:4)]. M.p. = 182 °C. 28% yield.
1H-NMR (CDCl3) δ 8.72 (d, 2H, J = 5.1 Hz, Pyr-2,6), 7.98 (m, 2H, H-5, H-3), 7.57 (d, 2H, J = 5.1 Hz,
Pyr-3,5), 6.65 (d, 1H, J = 7.7 Hz, H-6), 4.35 (q, 2H, J = 7.0 Hz, CH2), 4.26 (m, 1H, NH), 3.35 (m, 1H,
13
CyHex), 1.91 (m, 2H, CyHex), 1.66 (m, 3H, CyHex), 1.40–1.05 (m, 8H, CH3, CyHex). C-NMR
(CDCl3) δ 163.4, 150.6, 149.9, 146.0, 142.3, 136.4, 126.6, 125.8, 121.4, 115.9, 105.0, 60.9, 52.0, 33.5,
25.4, 24.7, 14.3. Anal. Calcd for C21H24N4O2: C, 69.21; H, 6.64; N, 15.37. Found: C, 69.38; H, 6.71;
N, 15.24.
7-(4-Methoxyphenyl)-2-phenyl-8-(p-tolylethynyl)imidazo[1,2-a]pyridine (31). Method I. 7 (100 mg,
0.29 mmol), 4-methoxyphenylboronic acid (88 mg, 0.58 mmol), Na2CO3 (62 mg, 0.58 mmol),
Pd(PPh3)4 (17 mg, 0.014 mmol, 5 mol%) were used. The mixture was heated for 30 min. The crude
residue was purified by flash chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 84 °C. 56% yield.
1H-NMR (CDCl3) δ 8.12–8.01 (m, 3H, H-5, Ph-2,6), 7.87 (s, 1H, H-3), 7.75 (m, 2H, CH3O-Ph-2,6),
7.46 (m, 4H, Ph-3,5, CH3-Ph-2,6), 7.34 (m, 1H, Ph-4), 7.16 (d, 2H, J = 7.7 Hz, CH3-Ph-3,5), 7.03 (m,
13
2H, CH3O-Ph-3,5), 6.89 (d, 1H, J = 7.0 Hz, H-6), 3.89 (s, 3H, CH3O), 2.38 (s, 3H, CH3). C-NMR
(CDCl3) δ 159.7, 146.3, 145.8, 140.2, 138.7, 133.5, 131.7, 131.0, 130.5, 129.0, 128.6, 128.0, 126.3,
124.4, 120.2, 114.5, 113.6, 109.6, 108.4, 98.6, 84.3, 55.4, 21.6. Anal. Calcd for C29H22N2O: C, 84.03;
H, 5.35; N, 6.76. Found: C, 84.13; H, 5.34; N, 6.81.
Ethyl 7-(4-methoxyphenyl)-8-(p-tolylethynyl)imidazo[1,2-a]pyridine-2-carboxylate (32). Method H. 8
(100 mg, 0.30 mmol), 4-methoxyphenylboronic acid (65 mg, 0.42 mmol) were used. The crude residue
was purified by flash chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 240 °C. 69% yield.
1H-NMR (CDCl3) δ 8.22 (s, 1H, H-3), 8.13 (d, 1H, J = 7.2 Hz, H-5), 7.75 (d, 2H, J = 9 Hz, CH3O-Ph-2,6),
7.41 (d, 2H, J = 8.1 Hz, CH3-Ph-2,6), 7.12 (d, 2H, J = 8.1 Hz, CH3O-Ph-3,5), 7.08–6.98 (m, 3H, H-6,
CH3-Ph-3,5), 4.47 (q, 2H, J = 7.2 Hz, CH2), 3.89 (s, 3H, CH3O), 2.35 (s, 3H, CH3), 1.46 (t, 3H, J = 7.2 Hz,
CH3). 13C-NMR (CDCl3) δ 163.0, 160.0, 145.5, 141.8, 138.9, 137.1, 131.8, 130.6, 130.4, 129.0, 124.8,
119.9, 117.6, 116.3, 113.7, 110.9, 99.6, 83.6, 61.3, 55.4, 21.6, 14.4. Anal. Calcd for C26H22N2O3: C,
76.08; H, 5.40; N, 6.82. Found: C, 76.24; H, 5.29; N, 6.64.

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7-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a]pyridine-8-carbonitrile (33). Method I. 11 (100 mg,
0.40 mmol), 4-methoxyphenylboronic acid (84 mg, 0.55 mmol), Na2CO3 (84 mg, 0.79 mmol) and
Pd(PPh3)4 (23 mg, 0.02 mmol, 5 mol%) were used. The mixture was heated for 15 min. The crude
residue was purified by flash chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 185 °C. 61%
yield. 1H-NMR (CDCl3) δ 8.26 (d, 1H, J = 7.0 Hz, H-5), 8.00 (m, 2H, Ph-2,6), 7.88 (s, 1H, H-3), 7.62
(d, 2H, J = 9.0 Hz, CH3O-Ph-2,6), 7.44 (m, 2H, Ph-3,5), 7.35 (m, 1H, Ph-4), 7.02 (d, 2H, J = 9.0 Hz,
CH3O-Ph-3,5), 6.90 (d, 1H, J = 7.0 Hz, H-6), 3.86 (s, 3 H, CH3O). 13C-NMR (CDCl3) δ 160.8, 147.5,
144.6, 144.1, 132.7, 130.0, 128.7, 128.5, 128.4, 128.3, 126.3, 115.5, 114.4, 113.5, 108.8, 98.1, 55.4.
Anal. Calcd for C21H15N3O: C, 77.52; H, 4.65; N, 12.91. Found: C, 77.68; H, 4.53; N, 12.94.
7-(4-Methylphenyl)-N,2-diphenylimidazo[1,2-a]pyridin-8-amine (34). Method I. 15 (100 mg, 0.53 mmol),
p-tolylboronic acid (362 mg, 2.66 mmol), Na2CO3 (112.4 mg, 1.06 mmol) and Pd(PPh3)4 (30.6 mg,
0.03 mmol, 5 mol%) were used. The mixture was heated for 30 min. The crude residue was purified by
flash chromatography [silica, cyclohexane/EtOAc (70:30)] to give a white solid. M.p. = 237 °C. 44%
1
yield. H-NMR (CDCl3) 7.98 (m, 2H, Ph-3,5), 7.87 (m, 2H, H-3, H-5), 7.45 (m, 2H, Ph-2,6), 7.34
(m, 3H, Ph-4, CH3-Ph-2,6), 7.00 (m, 4H, CH3-Ph-3,5, Ph-NH-3,5), 6.88 (d, 1H, J = 7.0 Hz, H-6), 6.72
13
(m, 3H, Ph-NH-2,4,6), 2.27 (s, 3H, CH3). C-NMR (CDCl3) 141.8, 136.9, 135.4, 131.3, 130.0,
129.6, 128.9, 128.7, 128.5, 128.1, 127.9, 126.1, 120.7, 118.6, 118.2, 116.8, 108.8, 21.1 (2C not found).
Anal. Calcd for C26H21N3: C, 83.17; H, 5.64; N, 11.19. Found: C, 83.34; H, 5.77; N, 11.18.
3.2.8. General Procedures for Double-Coupling Approach
3-[8-(4-Methoxyphenyl)-2-phenylimidazo[1,2-a]pyridin-7-yl]aniline (35). Method J. To a solution of
1a (100 mg, 0.28 mmol) in DME (2 mL) and water (1 mL), were added 3-aminophenylboronic acid
(39 mg, 0.28 mmol), Na2CO3 (90 mg, 0.85 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol). After
irradiation under microwaves for 30 min at 95 °C, 4-methoxyphenylboronic acid (60 mg, 0.40 mmol)
and Pd(PPh3)4 (16 mg, 0.014 mmol) were added. The mixture was irradiated under microwaves during
30 min at 120 °C. After cooling to room temperature, CH2Cl2 (50 mL) and water (50 mL) were added
and the solution was extracted with CH2Cl2 (3 × 50 mL). The combined organic layer was dried with
anhydrous MgSO4 and evaporated under reduced pressure. The crude residue was purified by flash
1
chromatography (alumina, CH2Cl2) to give a yellow solid. M.p. = 230 °C. 44% yield. H-NMR
(CDCl3) 8.10 (d, 1H, J = 7.0 Hz, H-5), 7.94 (m, 3H, H-3, Ph-3,5), 7.42 (m, 4H, Ph-2,6, CH3O-Ph-2,6),
7.31 (m, 1H, Ph-4), 7.02 (t, 1H, J = 7.7 Hz, H2N-Ph-5), 6.86 (m, 3H, H-6, CH3O-Ph-3,5), 6.55 (m, 3H,
13
H2N-Ph-4,6,2), 3.81 (s, 3H, CH3O), 3.23 (bs, 2H, NH2). C-NMR (CDCl3) 158.8, 146.1, 146.0,
145.5, 141.0, 135.8, 133.7, 132.6, 130.6, 128.9, 128.5, 127.8, 127.3, 126.2, 123.6, 120.3, 116.4, 115.9,
113.8, 113.2, 108.2, 55.1. Anal. Calcd for C26H21N3O: C, 79.77; H, 5.41; N, 10.73. Found: C, 79.92;
H, 5.38; N, 10.63.
2-Phenyl-8-(pyridin-4-yl)-7-(thien-3-yl)imidazo[1,2-a]pyridine (36). Method J. Thien-3-ylboronic acid
(36 mg, 0.28 mmol, 1 eq) and pyridin-4-ylboronic acid (56 mg, 0.40 mmol, 1.4 eq) were used. The
crude residue was purified by flash chromatography [silica, cyclohexane/EtOAc (99:1)] to give a white
solid. M.p. = 273 °C. 43% yield. 1H-NMR (CDCl3)  8.62 (dd, 2 H, J = 4.5–1.5 Hz, Pyr-2,6), 8.16 (d,
1H, J = 7.0 Hz, H-5), 7.92 (m, 3 H, H-3, Ph-3,5), 7.49 (dd, 2 H, J = 4.5–1.5 Hz, Pyr-3,5), 7.40 (m, 2 H,

Molecules 2012, 17
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Ph-2,6), 7.32 (m, 1 H, Ph-4), 7.21 (dd, 1H, J = 5.0–2.9 Hz, Th-5), 7.09 (dd, 1H, J = 2.9–1.4 Hz, Th-2),
6.97 (d, 1H, J = 7.0 Hz, H-6), 6.76 (dd, 1H, J = 5.0–1.4 Hz, Th-4). 13C-NMR (CDCl3)  149.0, 146.9,
144.6, 144.3, 139.1, 133.5, 130.9, 128.6, 128.5, 128.1, 126.2, 125.8, 125.0, 124.6, 124.5, 115.2, 108.5
(1C not found). Anal. Calcd for C22H15N3S: C, 74.76; H, 4.28; N, 11.89. Found: C, 74.89; H, 4.21;
N, 11.78.
8-(4-Fluorophenyl)-2-phenyl-7-(p-tolyl)imidazo[1,2-a]pyridine (37). Method K. To a solution of 1d
(100 mg, 0.28 mmol) in DME (2 mL) and water (1 mL), were added 4-fluorophenylboronic acid
(79 mg, 0.56 mmol), Na2CO3 (90 mg, 0.85 mmol) and Pd(PPh3)4 (16 mg, 0.014 mmol). After
irradiation under microwaves for 1 h 30 min at 95 °C, p-tolylboronic acid (77 mg, 0.56 mmol) and
Pd(PPh3)4 (16 mg, 0.014 mmol) were added. The mixture was irradiated under microwaves for 30 min
at 120 °C. After cooling to room temperature, CH2Cl2 (50 mL) and water (50 mL) were added and the
solution was extracted with CH2Cl2 (3 × 50 mL). The organic layer was dried with anhydrous MgSO4
and evaporated under reduced pressure. The crude residue was purified by flash chromatography
[silica, cyclohexane/EtOAc (99:1)] to give a white solid. M.p. = 215 °C. 47% yield. 1H-NMR (CDCl3)
8.14 (d, 1H, J = 7.0 Hz, H-5), 7.98–7.90 (m, 3H, H-3, Ph-3,5), 7.50–7.37 (m, 4H, Ph-2,6, F-Ph-3,5),
7.32 (m, 1H, Ph-4), 7.11–6.95 (m, 6H, F-Ph-2,6, CH3-Ph-2,3,5,6), 6.92 (d, 1H, J = 7.0 Hz, H-6), 2.35
(s, 3H, CH3). 13C-NMR (CDCl3)  162.1, 146.3, 145.4, 136.9, 136.5, 133.7, 133.2, 131.0, 129.8, 129.6,
128.9, 128.5, 127.9, 126.2, 124.1, 115.9, 115.1, 114.8, 108.3, 21.1.
2-Phenyl-7-(p-tolylethynyl)imidazo[1,2-a]pyridine-8-carbonitrile (38). Method L. To a solution of 1d
(100 mg, 0.28 mmol) in DMF (3 mL), was added CuCN (31 mg, 0.34 mmol). The mixture was
irradiated under microwaves at 90 °C during 4 h. Then, 4-ethynyltoluene (47 µL, 0.37 mmol), Et3N
(198 µL, 1.41 mmol), Pd(PPh3)4 (33 mg, 0.03 mmol), PCy3HBF4 (31 mg, 0.08 mmol) and CuI (11 mg,
0.056 mmol) were added. The mixture was irradiated under microwaves at 130 °C during 1 h. After
cooling to room temperature, a solution of NH4OH 10% (50 mL) and EtOAc (50 mL) were added. The
organic layer was washed with the solution of NH4OH (3 × 50 mL), dried with anhydrous MgSO4 and
evaporated under reduced pressure. The crude residues were purified by flash chromatography [silica,
cyclohexane/EtOAc (7:3)]. M.p. = 214 °C. 32% yield. 1H-NMR (CDCl3) δ 8.22 (d, J = 7.0 Hz, 1H, H-5),
8.02 (m, 2H, Ph-2,6), 7.94 (s, 1H, H-3), 7.55 (m, 2H, CH3-Ph-2,6), 7.46 (m, 2H, Ph-3,5), 7.38 (m, 1H,
Ph-4), 7.21 (d, 2H, J = 7.9 Hz, CH3-Ph-3,5), 6.95 (d, 1H, J = 7.0 Hz, H-6), 2.41 (s, 3H, CH3).
13C-NMR (CDCl3) δ 148.5, 140.4, 132.4, 132.2, 129.3, 128.8, 128.8, 128.7, 128.0, 127.7, 126.5, 125.2,
118.3, 114.4, 114.2, 109.7, 100.5, 84.8, 21.7. Anal. Calcd for C23H15N3: C, 82.86; H, 4.54; N, 12.60.
Found: C, 82.97; H, 4.56; N, 12.68.
7-[4-(4-Fluorophenyl)piperazin-1-yl]-2-phenylimidazo[1,2-a]pyridine-8-carbonitrile (39). Method M.
To a solution of 1d (100 mg, 0.28 mmol) in DMF (3 mL), CuCN (31 mg, 0.34 mmol) was added. The
mixture was stirred at 90 °C during 4 h under microwave irradiation. Then DIPEA (0.1 mL,
0.57 mmol) and 4-fluorophenylpiperidine (98 mg, 0.57 mmol) were added. The mixture was heated at
130 °C during 1 h under microwaves irradiation. After cooling to room temperature, EtOAc (50 mL)
and a solution of NH4OH 10% (50 mL) were added. The solution was extracted with EtOAc (3 × 50 mL),
dried with anhydrous MgSO4 and evaporated under reduced pressure. The crude residue was purified

Molecules 2012, 17
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1
by flash chromatography [silica, cyclohexane/EtOAc (7:3)]. M.p. = 224 °C. 67% yield. H-NMR
(CDCl3) δ 8.06 (d, 1H, J = 7.5 Hz, H-5), 7.97 (m, 2H, Ph-2,6), 7.71 (s, 1H, H-3), 7.42 (m, 2H, Ph-3,5),
7.33 (m, 1H, Ph-4), 7.06–6.89 (m, 4H, F-Ph), 6.55 (d, 1H, J = 7.5 Hz, H-6), 3.79–3.69 (m, 4H, pip),
13
3.36–3.27 (m, 4H, pip). C-NMR (CDCl3) δ 157.7, 154.0, 147.2, 146.6, 145.4, 133.0, 129.1, 128.7,
128.2, 126.2, 118.5, 116.0, 115.8, 107.6, 105.3, 85.3, 50.5, 50.2. Anal. Calcd for C24H20FN5: C, 72.53;
H, 5.07; N, 17.62. Found: C, 72.49; H, 5.01; N, 18.73.
Ethyl 8-cyano-7-(p-tolylethynyl)imidazo[1,2-a]pyridine-2-carboxylate (40). Method L. 1e (100 mg,
0.29 mmol) was used as starting material. M.p. = 93 °C. 43% yield. 1H-NMR (CDCl3) δ 8.22 (s, 1H, H-3),
8.12 (d, 1H, J = 7.2 Hz, H-5), 7.54 (d, 2H, J = 8.0 Hz, CH3-Ph-2,6), 7.17 (d, 2H, J = 8.0 Hz, CH3-Ph-3,5),
6.96 (d, 1H, J = 7.2 Hz, H-6), 4.44 (q, 2H, J = 7.2 Hz, CH2), 2.38 (s, 3H, CH3), 1.42 (t, 3H, J = 7.2 Hz,
CH3). 13C-NMR (CDCl3) δ 162.6, 144.6, 139.6, 137.3, 135.3, 132.0, 129.0, 125.3, 119.1, 118.1, 116.0,
113.7, 102.9, 80.8, 61.4, 21.6, 14.3 (1 C not found). Anal. Calcd for C20H15N3O2: C, 72.94; H, 4.59; N,
12.76. Found: C, 73.27; H, 4.68; N, 12.81.
Ethyl 8-cyano-7-[4-(4-fluorophenyl)piperazin-1-yl]imidazo[1,2-a]pyridine-2-carboxylate (41). Method M.
1e (100 mg, 0.29 mmol) was used as starting material. M.p. = 193 °C. 54% yield. 1H-NMR (CDCl3) δ
8.20–7.91 (m, 2H, H-3, H-5), 7.07–6.88 (m, 4H, F-Ph), 6.67 (d, 1H, J = 7.0 Hz, H-6), 4.43 (q, 2H,
13
J = 7.0 Hz, CH2), 3.83 (bs, 4H, pip), 3.33 (bs, 4H, H-pip), 1.42 (t, 3H, J = 7.0 Hz, CH3). C-NMR
(CDCl3) δ 162.8, 157.9, 154.4, 145.3, 137.5, 132.5, 129.5, 123.6, 118.7, 117.2, 115.9, 107.4, 84.5,
61.3, 50.7, 49.9, 14.3. Anal. Calcd for C21H20FN5O2: C, 64.11; H, 5.12; N, 17.80. Found: C, 64.49; H,
5.08; N, 17.94.
4. Conclusions
The reactivity of the 7-chloro-8-iodo- and 8-chloro-7-iodoimidazo[1,2-a]pyridines 1a–e variously
substituted on the 2 position, towards Suzuki-Miyaura, Sonogashira, and Buchwald-Hartwig
cross-coupling reactions as well as cyanation was evaluated. Various methodologies are proposed to
introduce aryl, heteroaryl, alkyne, amine or cyano groups in the two positions depending on the nature
of the substituent present in position 2. The sensitivity of the 2-ester group obliged us to adapt the
reaction conditions, notably when a base was required. Moreover, the presence of the 2-ester seemed
to lower the reactivity of the 8 position towards the Sonogashira and the cyanation reactions.
In both series, the substitution was totally regioselective due to the differences in reactivity between
the iodine and chlorine atoms. Nevertheless, the difficulty in our cases was to substitute the chlorine
atom in the second step. Until now, only hetero(aryl) groups could be introduced though Suzuki-Miyaura
cross-coupling. We overcame this problem evaluating the both regioisomers in parallel.
The double coupling approach was also studied allowing the one pot Suzuki/Suzuki, cyanation/
Sonogashira and cyanation/Buchwald reactions leading to polyfunctionalized imidazo[1,2-a]pyridines.
New heterogeneous double coupling approaches are under investigations.
Acknowledgments
The authors thank Frédéric Montigny from the SAVIT, Tours (France) for NMR spectrometry.

Molecules 2012, 17
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References
1. Nordqvist, A.; Nilsson, M.T.; Lagerlund, O.; Muthas, D.; Gising, J.; Yahiaoui, S.; Odell, L.R.;
Srinivasa, B.R.; Larhed, M.; Mowbray, S.L.; et al. Synthesis, biological evaluation and X-ray
crystallographic studies of imidazo[1,2-a]pyridine-based Mycobacterium tuberculosis glutamine
synthetase inhibitors. Med. Chem. Commun. 2012, 3, 620–626.
2. Bode, M.L.; Gravestock, D.; Moleele, S.S.; van der Westhuyzen, C.W.; Pelly, S.C.; Steenkamp, P.A.;
Hoppe, H.C.; Khan, T.; Nkabinde, L.A. Imidazo[1,2-a]pyridin-3-amines as potential HIV-1
non-nucleoside reverse transcriptase inhibitors. Bioorg. Med. Chem. 2011, 19, 4227–4237.
3. Hieke, M.; Rödl, C.B.; Wisniewska, J.M.; la Buscato, E.; Stark, H.; Schubert-Zsilavecz, M.;
Steinhilber, D.; Hofmann, B.; Proschak, E. SAR-study on a new class of imidazo[1,2-a]pyridine-
based inhibitors of 5-lipoxygenase. Bioorg. Med. Chem. Lett. 2012, 22, 1969–1975.
4. Dahan-Farkas, N.; Langley, C.; Rousseau, A.L.; Yadav, D.B.; Davids, H.; de Koning, C.B.
6-Substituted imidazo[1,2-a]pyridines: Synthesis and biological activity against colon cancer cell
lines HT-29 and Caco-2. Eur. J. Med. Chem. 2011, 46, 4573–4583.
5. El Akkaoui, A.; Bassoude, I.; Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G.
Pd-catalyzed regiocontrolled Sonogashira and Suzuki cross-coupling reaction of
3,6-dihalogenoimidazo[1,2-a]pyridines: One-pot double-coupling approach. Tetrahedron 2011,
67, 7128–7138.
6. Szabo, R.; Crozet, M.D.; Vanelle, P. Microwave assisted double Suzuki-Miyaura cross-coupling
in the 6,8-dibromoimidazo[1,2-a]pyridine series. Synthesis 2008, 1, 127–135.
7. Kettle, J.G.; Brown, S.; Crafter, C.; Davies, B.R.; Dudley, P.; Fairley, G.; Faulder, P.; Fillery, S.;
Greenwood, H.; Hawkins, J.; et al. Diverse Heterocyclic Scaffolds as Allosteric Inhibitors of
AKT. J. Med. Chem. 2012, 55, 1261–1273.
8. Trabanco, A.A.; Tresadern, G.; Macdonald, G.J.; Vega, J.A.; de Lucas, A.I.; Matesanz, E.; Garcia, A.;
Linares, M.L.; Alonso de Diego, S.A.; Alonso, J.M.; et al. Imidazo[1,2-a]pyridines: Orally Active
Positive Allosteric Modulators of the Metabotropic Glutamate 2 Receptor. J. Med. Chem. 2012,
55, 2688–2701.
9. Tresadern, G.; Cid, J.M.; Macdonald, G.J.; Vega, J.A.; de Lucas, A.I.; Garcia, A.; Matesanz, E.;
Linares, M.L.; Oehlrich, D.; Lavreysen, H.; et al. Scaffold hopping from pyridones to
imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2
receptor. Bioorg. Med. Chem. Lett. 2010, 20, 175–179.
10. Cid-Nunez, J.M.; Trabanco-Suarez, A.A.; Macdonald, G.J. Indole and Benzoxazine Derivatives
As Modulators of Metabotropic Glutamate Receptors. PCT Int. Appl. WO 2010060589, 2010.
11. Barrio, J.R.; Petric, A.J.; Satyamurthy, N. Methods for Binding Agents to β-Amyloid Plaques.
PCT Int. Appl. WO 2005040337, 2005.
12. Enguehard, C.; Renou, J.-L.; Collot, V.; Hervet, M.; Rault, S.; Gueiffier, A. Reactivity of
3-iodoimidazo[1,2-a]pyridines using a Suzuki-Type cross-coupling reaction. J. Org. Chem. 2000,
65, 6572–6575.
13. Enguehard, C.; Hervet, M.; Théry, I.; Renou, J.-L.; Fauvelle, F.; Gueiffier, A. (Hetero)arylation of
6-helogenoimidazo[1,2-a]pyridines differently substituted at C(2): Influence of the 2-substituent
on the Suzuki cross-coupling reaction. Helv. Chim. Acta 2001, 84, 3610–3615.

Molecules 2012, 17
10707
14. Ince, S.; Haegebarth, A.; Politz, O.; Neuhaus, R.; Bömer, U.; Scott, W. Imidazopyrimidine and
Imidazopyridine Derivatives As Inhibitors of the PI3K/Akt Pathway and Their Preparation and
Use for the Treatment of Diseases. PCT Int. Appl. WO 2012007345, 2012.
15. Snégaroff, K.; Nguyen, T.T.; Marquise, N.; Halauko, Y.S.; Harford, P.J.; Roisnel, T.; Matulis, V.E.;
Ivashkevich, O.A.; Chevallier, F.; Wheatley, A.E.H.; et al. Deprotonative metalation of chloro-
and bromopyridines using amido-based bimetallic species and regioselectivity-computed CH
acidity relationships. Chem. Eur. J. 2011, 17, 13284–13297.
16. Blum, C.A.; Caldwell, T.; Zheng, X.; Bakthavatchalam, R.; Capistoti, S.; Brielmann, H.;
de Lombaert, S.; Kershaw, M.T.; Matson, D.; Krause, J.E.; et al. Discovery of novel
6,6-heterocycles as transient receptor potential vanilloid (TRPV1) antagonists. J. Med. Chem.
2010, 53, 3330–3348.
17. Schroeder, G.M.; An, Y.; Cai, Z.-W.; Chen, X.-T.; Clark, C.; Cornelius, L.A.M.; Dai, J.;
Gullo-Brown, J.; Gupta, A.; Henley, B.; et al. Discovery of N-(4-(2-amino-3-chloropyridin-4-
yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide
(BMS-777607), a selective and orally efficacious inhibitor of the Met Kinase Superfamily.
J. Med. Chem. 2009, 52, 1251–1254.
Sample Availability: Samples of all compounds are available from the authors.
© 2012 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution license
(http://creativecommons.org/licenses/by/3.0/).