Synthesis and functionalization of imidazo[1,2-a] pyridines and imidazo [1,2-a] pyrimidines on solid phase using suzuki-miyaura cross-coupling reactions

Article abstract of DOI:10.2174/157017812800221753

Microwave assisted solid phase synthesis of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines by the treatment of polymer-bound α-bromoketone with various 2-aminopyridines or 2-aminopyrimidines was achieved. Functionalizations of the 3-positions were realized by the treatment of polymer-bound 3-iodoimidazo[1,2-a]pyridine or polymer-bound 3-iodoimidazo[1,2-a] pyrimidine with various boronic acids under Suzuki-Miyaura reaction conditions. 6-Position of polymer-bound imidazo[1,2-a]pyridine was also functionalized using Suzuki-Miyaura cross-coupling reaction.

Full text of DOI:10.2174/157017812800221753

118
Letters in Organic Chemistry, 2012, 9, 118-127
Synthesis and Functionalization of Imidazo[1,2-a]Pyridines and
Imidazo[1,2-a]Pyrimidines on Solid Phase Using Suzuki-Miyaura Cross-
Coupling Reactions
Saïd El Kazzouli1,2,3, Sabine Berteina-Raboin*,1, Abderrahim Mouaddib2 and Gérald Guillaumet1
1Institut de Chimie Organique et Analytique, Université d'Orléans, UMR CNRS 6005, BP 6759, 45067 Orléans Cedex 2,
France
2Faculté des Sciences et Techniques de Beni-Mellal, Université Sultan Moulay Slimane, 23000 Beni-Mellal, Morocco
3Institute of Nanomaterials and Nanotechnology (INANOTECH), MAScIR Foundation, Avenue de l’Armée Royale,
Madinat El Irfane, 10100 Rabat, Morocco
Received July 26, 2011: Revised October 21, 2011: Accepted December 08, 2011
Abstract: Microwave assisted solid phase synthesis of imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrimidines by the
treatment of polymer-bound ꢀ-bromoketone with various 2-aminopyridines or 2-aminopyrimidines was achieved.
Functionalizations of the 3-positions were realized by the treatment of polymer-bound 3-iodoimidazo[1,2-a]pyridine or
polymer-bound 3-iodoimidazo[1,2-a]pyrimidine with various boronic acids under Suzuki-Miyaura reaction conditions. 6-
Position of polymer-bound imidazo[1,2-a]pyridine was also functionalized using Suzuki-Miyaura cross-coupling reaction.
Keywords: Imidazo[1,2-a]pyridine imidazo[1,2-a]pyrimidine, microwave irradiations, solid phase synthesis, Suzuki-Miyaura
cross-coupling.
INTRODUCTION
condensation between the resin-bound ꢀ-bromoketone and
different 2-aminopyridines or 2-aminopyrimidines under
conventional heating and microwave irradiation [28].
Dimethylformamide (DMF) was initially used as a solvent
because, on one hand, it is known to be a good solvent for
the condensation reaction and on the other hand, it provides
a good swelling property for the resin. We then used ethanol
as a solvent to overcome the solubility problems of some 2-
aminopyridine or 2-aminopyrimidine reagents and we
observed that the best results were obtained when the
reaction mixture was heated to 50°C. After the different
assays, we noticed that, under conventional heating, the
reaction times for the condensation reactions were very long
(48 to 72 h), using either ethanol or DMF as a solvent at
room temperature or at 50°C. For this reason, we used
microwave irradiation which afforded total conversions
immediately after 10 minutes of reaction time in ethanol.
Similar result was obtained using DMF as a solvent after 15
minutes. It is also important to note that total conversions
were obtained only by using an excess of 2-aminopyridine or
2-aminopyrimidine (8 equivalents were needed). Using the
optimized conditions (ethanol as solvent and 30 W as
irradiation power), all the desired products (1-6) were
obtained in total conversions and excellent yields ranging
from 72 to 86 %. These yields were calculated based on the
initial loading of the aminomethylated resin [27] (Scheme 1
and Table 1).
Imidazo[1,2-a]pyridine derivatives have been shown to
exhibit interesting bioactivity such as melatonin receptor
ligands [1-2], antiviral [3-7], antiulcer [8, 9], antibacterial
[10, 11], antifungal [12], agonist of benzodiazepine receptor
[13, 14], calcium channel blocker [15], ligand for detecting
ꢁ-amyloid [16] and constitute a novel class of orally active
nonpeptide bradykinin B2 receptor antagonists [17].
Moreover, the imidazo[1,2-a]pyridine derivatives Zolpidem
and Olprinone were commercialized as hypnotic [18] and
PDE 3 inhibitor [19] respectively.
We recently reported different studies on the synthesis
and functionalization of imidazo[1,2-a]pyridines and
imidazo[1,2-a]pyrimidines in solution [20-23] and on solid
phase [24, 25]. In continuation of our effort, herein we wish
to describe the results of the microwave synthesis of 3 and 6
functionalized imidazo[1,2-a]pyridines and imidazo[1,2-
a]pyrimidines on solid support using the Suzuki cross-
coupling reaction.
RESULTS AND DISCUSSION
We began by the synthesis of resin-bound ꢀ-
bromoketone, as we previously reported in the literature
[26]. The resin-bound ꢀ-bromoketone was obtained after
three steps starting from the commercially available
aminomethylated resin [27]. Then, we optimized the
In order to introduce various aryls or heteroaryls at the 3-
position of imidazo[1,2-a]pyridines or imidazo[1,2-
a]pyrimidines bound to solid support R2 and R3, we initially
elaborated the resin-bound 3-iodo analogs R4 and R5
(Scheme 2). It is noteworthy that the direct iodination using
iodine in pyridine was not complete because of the low
*Address correspondence to this author at the Institut de Chimie Organique
et Analytique, Université d'Orléans, UMR CNRS 6005, BP 6759, 45067
Orléans Cedex 2, France; Tel: (+33) 2 38 49 48 56;
Fax: (+33) 2 38 41 72 81; E-mail: sabine.berteina-raboin@univ-orleans.fr
1875-6255/12 $58.00+.00
© 2012 Bentham Science Publishers

Synthesis and Functionalization of Imidazo[1,2-a]Pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
119
Me
N
Me
N
=
O
N
a) cyclization
O
O
X
O
N
O
R
O
O
N
O
X
Br
O
N
O
O
R1
R
b) cleavage
N
R
N
X
OH
1-6
Scheme 1. Reagents and conditions: (a) 2-aminopyridine or 2-aminopyrimidine (8 equiv.), EtOH, 30 W (microwaves), 10 min, (b) MeONa (6
equiv.), Dioxane/MeOH (v/v 1:4), 24h.
Table 1. Imidazo[1,2-a]pyridines and Pyrimidines Synthesized Under Microwave Irradiations
Yieldsa %
Products
Entry
Conditions
Reaction times
Conversions %
N
DMF/r.t.
DMF/M.W.
EtOH/M.W.
72 h
100
100
100
80
78
82
N
15 min
10 min
1
HO
1
Br
Cl
N
EtOH/50°C
EtOH/50°C
EtOH/M.W.
48 h
72 h
98
73
75
80
N
2
3
100
100
10 min
HO
2
N
DMF/r.t.
DMF/50°C
EtOH/M.W.
72 h
72 h
97
62
71
75
N
100
100
10 min
HO
3
O
DMF/r.t.
72 h
100
100
83
86
N
4
EtOH/M.W.
10 min
N
HO
4

120 Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Kazzouli et al.
(Table 1). Contd…..
Yieldsa %
Products
Entry
Conditions
Reaction times
Conversions %
N
EtOH/50°C
EtOH/M.W.
48 h
100
100
66
72
N
N
5
10 min
HO
5
N
N
DMF/r.t.
72 h
91
54
72
N
Me
6
EtOH/M.W.
10 min
100
HO
6
a
Yields are calculated after cleavage and purification by chromatography on silica gel.
I
O
I
N
X
a) iodation
N
b) cleavage
O
N
O
N
X
N
X
N
O
OH
R2, X = CH
R3, X = N
R4, X = CH
R5, X = N
7, X = CH
8, X = N
Scheme 2. Reagents and conditions: (a) I2 (3 equiv.), CH2Cl2/pyridine (v/v 1:1); b) MeONa (6 equiv.) in Dioxane/MeOH (v/v 1:4), 24h.
Table 2. Results of Palladium Cross-Coupling Reactions on Resin-Bound 3-iodoimidazo[1,2-a]pyridines and resin-bound 3-
iodoimidazo[1,2-a]pyrimidines
I
a) Suzuki reaction
R
Conditions A, B, C, D or E
O
N
N
N
X
b) cleavage
+
N
O
N
N
X
X
OH
X = CH or N
OH
R4, X = CH
R5, X = N
9-16
Conversionsa % (Yields %)b
Boronic acids
Products
OMe
Entry
Conditions
B(OH)2
OMe
1
2
A
B
30
95 (61)b
N
N
HO
9
SMe
B(OH)2
SCH3
3
4
A
B
50
N
98 (68)
N
HO
10

Synthesis and Functionalization of Imidazo[1,2-a]Pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
121
(Table 2). Contd…..
Conversionsa % (Yields %)b
Boronic acids
Products
Entry
Conditions
S
B(OH)2
S
5
6
B
C
86
N
97 (54)
N
HO
11
S
7
8
B
C
D
E
79
94
B(OH)2
S
N
9
93
N
10
96 (43)
HO
12
B(OH)2
S
S
11
B
94 (52)
N
N
N
N
N
N
N
N
HO
HO
HO
HO
13
14
15
16
OMe
B(OH)2
OMe
12
13
B
D
90
98 (56)
N
N
N
SMe
B(OH)2
14
B
94 (50)
SMe
B(OH)2
15
16
B
E
74
91 (39)
a
b
The conversions are calculated based on 1H NMR of crude products after cleavage (compared to 1H NMR of the intermediates 7 or 8). In parentheses are mentioned the yields of
isolated products after cleavage and purification by chromatography on silica gel.
Conditions A: RB(OH)2 (4 equiv.), K2CO3 (9 equiv.), Pd(OAc)2 (0.1 equiv.) in H2O/dioxane (v/v 1:12), 80°C, 24h. Conditions B: RB(OH)2 (4 equiv.), Na2CO3 (9 equiv.), Pd(PPh3)4
(0.1 equiv.) in H2O/DME (v/v 1:2), 80°C, 24h. Conditions C: RB(OH)2 (8 equiv.), Na2CO3 (9 equiv.), Pd(PPh3)4 (0.1 equiv.) in H2O/DME (v/v 1:2), 80°C, 24h. Conditions D:
RB(OH)2 (4 equiv.), NaOH (2 equiv), Pd(PPh3)4 (0.1 equiv.) in H2O/DME (v/v 1:2), 80°C, 24h. Conditions E: RB(OH)2 (8 equiv.), NaOH (2 equiv.), Pd(PPh3)4 (0.1 equiv.) in
H2O/DME (v/v 1:2), 80°C, 24h. (b) MeONa (6 equiv.), dioxane/MeOH (v/v 1:4), 24h.

122 Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Kazzouli et al.
Table 3. Suzuki Cross-Coupling Reaction of 6-bromoimidazo[1,2-a]pyridines Bound to Solid Support
a) Suzuki reaction
Conditions D or E
R
O
N
N
b) cleavage
N
O
N
Br
OH
17-22
R6
Reagents
B(OH)2
Products
Entry
Conditions
Conversions % (Yields %)a
N
N
1
D
100 (68)
HO
17
18
MeS
B(OH)2
N
2
3
D
D
100 (65)
100 (60)
N
SCH3
HO
MeO
B(OH)2
N
N
OMe
HO
19
S
B(OH)2
S
N
4
5
D
D
98 (44)
98 (45)
N
HO
HO
20
21
B(OH)2
N
N
B(OH)2
S
S
6
7
D
E
89
N
96 (34)
N
HO
22
a
The conversions are calculated based on 1H NMR of crude products after cleavage (compared to 1H NMR of intermediate 2), in parentheses are mentioned the yields of isolated
products after purification by chromatography on silica gel.
Conditions D: (a) RB(OH)2 (4 equiv.), NaOH (2 equiv.), Pd(PPh3)4 (0.1 equiv.) in H2O/DME (v/v 1:2), 80°C, 24h. (b) MeONa (6 equiv.), dioxane/MeOH (v/v 1:4), 24h.
Conditions E: (a) RB(OH)2 (8 equiv.), NaOH (2 equiv.), Pd(PPh3)4 (0.1 equiv.) in H2O/DME (v/v 1:2), 80°C, 24h. (b) MeONa (6 equiv.), dioxane/MeOH (v/v 1:4), 24h.
swelling of the resin in pyridine: In contrast, when using a
mixture of dichloromethane and pyridine the swelling of the
aminomethylated resin was highly improved which led, with
total conversion, to the desired intermediates 7 and 8 in 80 %
and 72 % yields, respectively (Scheme 2).

Synthesis and Functionalization of Imidazo[1,2-a]Pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
123
The Suzuki cross-coupling reaction [29] was selected to
incorporate various aryl and heteroaryl groups in the 3-
position of resin-bound imidazo[1,2-a]pyridines and
imidazo[1,2-a]pyrimidines. Thus, we initially used the
reaction conditions described by De Mesmaeker et al. [27]
for Suzuki-Miyaura cross coupling on solid support using
Pd(OAc)2 as a catalyst. Unfortunately, this method gave
incomplete conversions (desired compounds were obtained
with 30 to 50% conversions, entries 1 and 2, Table 3). In
contrast, when using Pd(PPh3)4 as a catalyst [30-31] in a
mixture of DME/H2O as solvent in the presence of Na2CO3,
the desired products were obtained nearly in total
conversions. It is noteworthy that excess of boronic acids (4
to 8 equivalents) was needed to achieve total conversions. In
some cases, we found that NaOH base gave better results
than Na2CO3 (entries 9, 10, 13, 16, Table 2). Thereafter, the
cleavage from the resin was carried out using MeONa in a
mixture of 1,4-dioxane and methanol. Compounds were
obtained in good to excellent conversions in the yield range
between 39 and 68 %. It should be noted that all yields are
calculated based on the initial loading of the
aminomethylated resin (seven steps, starting from the
aminomethylated resin, Table 2). Suzuki cross-coupling
reaction gave mostly the desired products 9-16 and the
quantities of dehalogenated products did not exceed 10 %
(based on 1H NMR of crude products).
were determined by the DEPT 135 sequence. Chemical
shifts were reported in parts per million (ppm, ꢀ units).
Coupling constants were reported in units of hertz (Hz).
Splitting patterns were designated as s, singlet, d, doublet
and t, triplet. Low-resolution mass spectra (MS) were
recorded on a Perkin-Elmer SCIEX API 3000 spectrometer.
All commercial solvents were used without further
purification. The following solvents and reagents have been
abbreviated: dimethylformamide (DMF), dimethyl sulfoxide
(DMSO), ethyl acetate (EtOAc), methanol (MeOH), ethylene
glycol dimethyl ether (DME). Thin layer chromatography
(TLC) was carried out on Merck silica gel 60F254 recoated
plates. Visualization was made possible with ultraviolet
light.
Protocol of the Condensation Between Solid Support-
Bound ꢀ -Bromoketone and Various 2-Aminopyridines
or 2-Aminopyrimidines Under Microwave Irradiation
In a microwave reactor, resin R1 (300 mg, 0.18 mmol)
was swelled in 4 ml of EtOH and 2-aminopyridines or 2-
aminopyrimidines (0.72 mmol) were introduced, then the
reactor was irradiated at 30 W for 10 min. After cooling, the
resin was washed with ethanol (3 x 5 ml), ethanol/H2O (1/1,
v/v, 3 x 5 ml), H2O (3 x 5 ml), ethanol (3 x 5 ml) and CH2Cl2
(3 x 5 ml). The resin was dried under vacuum, and then 100
mg (0.06 mmol) were swelled in dioxane (3 ml). To this
resin solution, NaOMe (0.48 mmol), dissolved in MeOH (1
ml) was added. The reaction mixture was stirred for 20 hours
at room temperature, then the resin was washed three times
with 3 ml of CH2Cl2, H2O, phosphate buffer, pH=7,
H2O/EtOH, EtOH and CH2Cl2. The combined organic layer
was concentrated under vacuum and the resulting solid was
dissolved in 10 ml of CH2Cl2 and 10 ml of H2O. The mixture
was extracted three times with 10 ml of CH2Cl2. The organic
layer was filtered over celite, dried over anhydrous
magnesium sulphate and concentrated under vacuum leading
The Suzuki-Miyaura cross-coupling reaction conditions
(8 equivalents of boronic acids, NaOH as base and
Pd(PPh3)4), optimized on 3-position, were then applied for
the introduction of (hetero)aryls in the 6-position of resin-
bound 6-bromoimidazo[1,2-a]pyridine. Thus, the desired
products 17 to 22 were obtained in excellent conversions (96
to 100 %) and good yields (34 to 68 % after six steps,
starting from the initial loading of aminomethylated resin).
Results are summarized in Table 3.
CONCLUSIONS
1
to the final compounds 1-6 in good purities (based on H
In conclusion, the use of microwave irradiation has
improved the reaction times for the solid phase synthesis of
NMR).
(3-Imidazo[1,2-a]pyridin-2-yl-phenyl)-methanol 1
imidazo[1,2-a]pyridine
and
imidazo[1,2-a]pyrimidine
1
derivatives, and led to the desired products in excellent
yields. The Suzuki-Miyaura cross-coupling reaction on
mp: 73-74 °C. H NMR (DMSO-d6): ꢀ= 4.68 (s, 2H),
6.91 (dd, J = 6.6, 6.9 Hz, 1H), 7.28-7.36 (m, 2H), 7.43 (dd, J
= 7.5, 7.8 Hz, 1H), 7.56 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.5
Hz, 1H), 7.92 (s, 1H), 8.19 (s, 1H), 8.42 (d, J = 6.6 Hz, 1H).
13C NMR (DMSO-d6): ꢀ= 62.90 (CH2), 109.01 (CH), 112.23
(CH), 116.62 (CH), 123.75 (CH), 123.91 (CH), 124.98 (CH),
125.85 (CH), 126.91 (CH), 128.43 (CH), 133.72 (C), 143.05
(C), 144.51 (C), 144.87 (C). SM (IS): m/z = 225.15 [M+1].
resin-bound
3-iodoimidazo[1,2-a]pyridine
and
3-
iodoimidazo[1,2-a]pyrimidine gave the expected final
compounds in excellent conversions and yields. The
substitution of the 6-position was also very successful
leading to 6-(hetero)aryl imidazo[1,2-a]pyridine analogs.
The solid phase synthesis under microwave irradiation can
be easily used to generate the new 3 and/or 6-substituted-
imidazo[1,2-a]pyridine and pyrimidine libraries.
[3-(6-Bromo-imidazo[1,2-a]pyridin-2-yl)phenyl]-methanol
2
1
mp: 190-191 °C. H NMR (CD3OD): ꢀ= 4.67 (s, 2H),
EXPERIMENTAL SECTION
General
7.33-7.51 (m, 4H), 7.84 (d, J = 7.5 Hz, 1H), 7.90 (s, 1H),
8.18 (s, 1H), 8.68 (s, 1H). 13C NMR (CD3OD): ꢀ= 65.13
(CH2), 108.01 (C), 110.92 (CH), 118.02 (CH), 125.77 (CH),
126.18 (CH), 128.01 (CH), 128.13 (CH), 129.96 (CH),
130.22 (CH), 134.35 (C), 143.51 (C), 145.42 (C), 147.22
(C). SM (IS): m/z = 303.05 [M+1 for 79Br], 305.06 [M+1 for
81Br].
Melting points were determined with Büchi SMP-20
1
melting point apparatus and were uncorrected. H NMR and
13C NMR were recorded on a Bruker Advance DPX250
spectrometer (250.19 MHz 1H, 62.89 MHz 13C) using
tetramethylsilane as the internal standard, and multiplicities

124 Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Kazzouli et al.
[3-(6-Chloro-imidazo[1,2-a]pyridin-2-yl)phenyl]-methanol
3
organic layer was concentrated under vacuum and the
resulting residue was dissolved in 10 ml of CH2Cl2 and 10 ml
of H2O, then extracted three times with CH2Cl2. After
filtration of organic layer on celite, it was dried over
anhydrous magnesium sulphate, and concentrated under
vacuum. The residues were purified by flash
chromatography on silica gel (CH2Cl2/MeOH, 98/2, v/v),
leading to compounds 7 and 8.
1
mp: 90-92 °C. H NMR (DMSO-d6): ꢁ= 4.56 (d, J = 5.7
Hz, 2H), 5.26 (t, J = 5.7 Hz, 1H), 7.26-7.31 (m, 2H), 7.39
(dd, J = 7.5, 7.8 Hz, 1H), 7.62 (d, J = 9.7 Hz, 1H), 7.81 (d, J
= 7.8 Hz, 1H), 7.94 (s, 1H), 8.35 (s, 1H), 8.80 (d, J = 1.9 Hz,
1H). 13C NMR (DMSO-d6): ꢁ= 64.91 (CH2), 111.77 (CH),
119.49 (CH), 121.02 (C), 125.73 (CH), 126.02 (CH), 126.81
(CH), 127.73 (CH), 128.12 (CH), 130.50 (CH), 135.25 (C),
145.14 (C), 145.36 (C), 147.62 (C). SM (IS): m/z = 259.08
[M+1 for 35Cl], 261.05 [M+1 for 37Cl].
[3-(3-Iodo-imidazo[1,2-a]pyridin-2-yl)-phenyl]-methanol 7
1
mp: 97-98 °C. H NMR (DMSO-d6): ꢁ= 4.59 (s, 2H),
5.29 (s, 1H), 7.07 (dd, J = 6.6, 6.9 Hz, 1H), 7.33-7.40 (m,
2H), 7.45 (t, J = 7.5 Hz, 1H), 7.81 (d, J = 8.8 Hz, 1H), 7.94
(d, J = 7.5 Hz, 1H), 8.05 (s, 1H), 8.42 (d, J = 6.9 Hz, 1H).
13C NMR (DMSO-d6): ꢁ= 62.9 (CH2), 113.51 (CH), 116.90
(CH), 126.04 (CH), 126.12 (2ꢀCH), 126.22 (CH), 126.2 (C),
127.10 (CH), 128.01 (CH), 133.53 (C), 142.74 (C), 146.71
(C), 147.30 (C). SM (IS): m/z = 351.05 [M+1].
[3-(8-Phenoxy-imidazo[1,2-a]pyridin-2-yl)-phenyl]-
methanol 4
1H NMR (CDCl3): ꢁ= 4.72 (s, 2H), 6.43 (d, J = 7.6 Hz,
1H), 6.57 (dd, J = 7.2 Hz, 1H), 7.27-7.41 (m, 5H), 7.51 (d, J
= 7.2 Hz, 2H), 7.71 (d, J = 6.8 Hz, 1H), 7.80 (s,1H), 7.87 (d,
J = 7.8 Hz, 1H), 8.00 (s, 1H). 13C NMR (CDCl3): ꢁ= 65.31
(CH2), 103.31 (CH), 109.40 (CH), 112.32 (CH), 118.81
(CH), 124.93 (CH), 125.54 (CH), 126.55 (CH), 127.40
(2ꢀCH), 128.21 (CH), 128.83 (2ꢀCH), 128.96 (CH), 134.03
(C), 136.42 (C), 140.47 (C), 141.62 (C), 145.03 (C), 148.02
(C). SM (IS): m/z = 317.15 [M + 1].
[3-(3-Iodo-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-methanol
8
1H NMR (CD3OD): ꢁ= 4.71 (s, 2H), 7.20 (dd, J = 6.8, 7.1
Hz, 1H), 7.43-7.52 (m, 2H), 7.93 (dd, J = 1.7, 7.5 Hz, 1H),
8.02 (s, 1H), 8.58 (dd, J = 1.7, 7.5 Hz, 1H), 8.81 (dd, J = 1.9,
6.8 Hz, 1H). SM (IS): m/z = 352.00 [M+1].
(3-Imidazo[1,2-a]pyrimidin-2-yl-phenyl)-methanol 5
1H NMR (CD3OD): ꢁ= 4.68 (s, 2H, CH2), 7.05 (dd, 1H,
H6', J = 6.6, 6.9 Hz), 7.37 (dd, 1H, H6, J = 1.5, 7.5 Hz), 7.44
(t, 1H, H5, J = 7.5 Hz), 7.88 (dd, 1H, H4, J = 1.5, 7.5 Hz),
7.96 (d, 1H, H2, J = 1.5 Hz), 8.20 (s, 1H, H3'), 8.54 (dd, 1H,
H5', J = 1.9, 6.6 Hz), 8.85 (dd, 1H, H7', J = 1.9, 6.9 Hz). 13C
NMR (CD3OD): ꢁ= 65.1 (CH2), 108.8 (CH), 110.5 (CH),
125.8 (CH), 126.2 (CH), 127.3 (CH), 128.3 (CH), 130.0
(CH), 134.3 (C), 136.1 (CH), 143.6 (C), 147.5 (C), 152.1
(C). SM (IS): m/z = 226.10 [M+1].
General Procedure for Suzuki-Miyaura Cross-Coupling
To resins R4, R5 or R6 (200 mg, 0.1 mmol) swelled in
DME (3 ml), boronic acid (4 equiv. or 8 equiv.) and a
solution of sodium carbonate (9 equiv.) or a solution of
sodium hydroxide (2 equiv.) in water (1 ml) were added.
After 20 min of stirring under argon, Pd(PPh3)4 (11 mg,
0.01mmol) was added and the reaction mixture was stirred at
80°C for 24 h. After cooling, the resin was washed
successively with ethanol (3 x 5 ml), ethanol/H2O (1/1, v/v, 3
x 5 ml), H2O (3 x 5 ml), ethanol (3 x 5 ml) and CH2Cl2 (3 x 5
ml), then it was dried under vacuum. NaOMe (0.8 mmol)
dissolved in MeOH (1 ml) was added to the swelled resin in
dioxane (3 ml) and the reaction mixture was stirred for 20 h
at room temperature then the resin was washed successively
with CH2Cl2 (3x), H2O (3x), phosphate buffer, pH=7 (3x),
H2O/EtOH (3x), EtOH (3x) and CH2Cl2 (3x). The combined
organic layer was concentrated and the resulting residue was
dissolved in 10 ml of CH2Cl2 and 10 ml of H2O, then
extracted three times with CH2Cl2. The organic layer was
filtered on celite, dried over anhydrous magnesium sulphate
and concentrated under vacuum. The residues were purified
by flash chromatography on silica gel (CH2Cl2/MeOH, 98/2,
v/v), leading to compounds 9-22.
[3-(7-Methyl-imidazo[1,2-a]pyrimidin-2-yl)-phenyl]-
methanol 6
mp: 169-171 °C. 1H NMR (CDCl3): ꢁ= 2.61 (s, 3H), 4.75
(s, 2H), 6.70 (d, J = 6.9 Hz, 1H), 7.31-7.43 (m, 2H), 7.69 (s,
1H), 7.90 (d, J = 7.4 Hz, 1H), 7.99 (s, 1H), 8.24 (d, J = 6.9
Hz, 1H). 13C NMR (CDCl3): ꢁ= 25.2 (CH3), 65.51 (CH2),
105.82 (CH), 109.90 (CH), 124.81 (CH), 125.50 (CH),
127.01 (CH), 129.11 (CH), 132.42 (CH), 133.82 (C), 141.65
(C), 146.54 (C), 148.92 (C), 160.32 (C). SM (IS): m/z =
240.15 [M+1].
General Procedure for Iodination Reaction
To the resin-bound imidazo[1,2-a]pyridine R2 or resin-
bound imidazo[1,2-a]pyrimidine R3 (200 mg, 0.1 mmol)
swelled in a mixture of pyridine and dichloromethane (1:1, 4
ml), iodine (101 mg, 0.4 mmol) was added then the reaction
mixture was stirred for 16 h at room temperature. The resin
was then washed successively with different solvents:
ethanol (3 x 5 ml), ethanol/H2O (1/1, v/v, 3 x 5 ml), H2O (3 x
5 ml), ethanol (3 x 5 ml) and CH2Cl2 (3 x 5 ml). Then the
resin was dried under vacuum. NaOMe (0.8 mmol) dissolved
in MeOH (1 ml) was added to the swelled resin in dioxane (3
ml) and the reaction mixture was stirred for 20 h at room
temperature. The resin was washed successively with
CH2Cl2 (3x), H2O (3x), phosphate buffer, pH=7 (3x),
H2O/EtOH (3x), EtOH (3x) and CH2Cl2 (3x). The combined
{3-[3-(4-Methoxy-phenyl)-imidazo[1,2-a]pyridin-2-yl]-
phenyl}-methanol 9
1
mp: 177-178 °C. H NMR (DMSO-d6): ꢁ= 3.33 (s, 3H),
4.45 (s, 2H), 6.86 (dd, J = 6.6, 6.9 Hz, 1H), 7.12-7.20 (m,
3H), 7.25-7.33 (m, 2H), 7.40 (d, J = 8.8 Hz, 2H), 7.63 (d, J =
8.8 Hz, 2H), 7.78 (s, 1H), 7.96 (d, d, J = 6.9, 1H). 13C NMR
(DMSO-d6): ꢁ= 55.25 (CH3), 62.92 (CH2), 112.51 (CH),
115.10 (CH), 116.80 (CH), 120.53 (C), 121.22 (C), 123.71
(CH), 124.94 (CH), 125.42 (CH), 125.50 (CH), 125.77 (CH),
127.84 (CH), 132.11 (CH), 134.11 (C), 141.13 (C), 142,61
(C), 143.76 (C), 159.65 (C). SM (IS): m/z = 331.15 [M+1].

Synthesis and Functionalization of Imidazo[1,2-a]Pyridines
Letters in Organic Chemistry, 2012, Vol. 9, No. 2
125
{3-[3-(4-Methylsulfanyl-phenyl)-imidazo[1,2-a]pyridin-2-
yl]-phenyl}-methanol 10
[3-(3-Naphthalen-1-yl-imidazo[1,2-a]pyrimidin-2-yl)-
phenyl]-methanol 16
1
1
mp: 139-140 °C. H NMR (DMSO-d6): ꢁ= 2.55 (s, 3H),
mp: 182-183 °C. H NMR (DMSO-d6): ꢁ= 4.44 (s, 2H,
2H), 6.96 (t, J = 6.9 Hz, 1H), 7.14 (t, J = 7.5 Hz, 1H), 7.21-
7.43 (m, 5H), 7.52-7.71 (m, 4H), 8.00 (dd, J = 1.9, 6.9 Hz,
1H), 8.05 (d, J = 8.1 Hz, 1H), 8.15 (d, J = 7.5 Hz, 1H), 8.62
(m, 1H). 13C NMR (DMSO-d6): ꢁ= 65.0 (CH2), 110.75 (CH),
125.52 (CH), 126.81 (CH), 127.23 (C), 127.35 (CH), 127.62
(CH), 127.85 (CH), 127.95 (CH), 128.04 (2ꢀCH), 128.74
(CH) 129.45 (CH), 129.93 (C), 131.82 (C), 131.85 (CH),
133.51 (C), 133.73 (CH), 134.41 (C), 135.85 (C), 143.13
(C), 145.18 (C), 152.29 (CH). SM (IS): m/z = 352.15 [M+1].
4.46 (d, J= 5.6 Hz, 2H), 5.17 (t, J = 5.6, 1H), 6.88 (dd, J =
6.6, 6.9 Hz, 1H), 7.20 (d, J = 5.3 Hz, 1H), 7.27-7.33 (m, 2H),
7.39-67.46 (m, 4H), 7.64 (d, J = 9.1, 1H), 7.77 (s, 1H), 8.03
(d, J = 6.9). 13C NMR (DMSO-d6): ꢁ= 14.25 (CH3), 62.91
(CH2), 112.65 (CH), 116.87 (CH), 120.24 (C), 123.78 (CH),
125.16 (CH), 125.38 (CH), 125.54 (CH), 125.65 (CH),
125.89 (CH), 126.44 (CH), 127.89 (CH), 131.09 (CH),
133.99 (C), 139.50 (C), 141.42 (C), 142.70 (C), 143.98 (C).
SM (IS): m/z = 347.15 [M+1].
[3-(3-Thiophen-2-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-
methanol 11
[3-(6-Phenyl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-methanol
17
mp: 152-153 °C. 1H NMR (CD3OD): ꢁ= 4.68 (s,
CH2OH), 7.35-7.53 (m, 5H, HAr), 7.66-7.70 (m, 4H, HAr),
7.84 (d, 1H, HAr, J = 7.6 Hz), 7.93 (s, 1H, H2), 8.26 (s, 1H,
H3'), 8.71 (dd, 1H, H5', J = 1.2 Hz). 13C NMR (CD3OD):
ꢁ= 65.11 (CH2), 111.05 (CH), 116.78 (CH), 125.18 (CH),
125.65 (CH), 126.01 (CH), 127.23 (CH), 127.90 (CH),
128.05 (2ꢀCH), 128.81 (C), 129.09 (CH), 129.91 (CH),
130.21 (2ꢀCH), 134.42 (C), 138.20 (C), 143.50 (C), 146.01
(C), 146.42 (C). SM (IS): m/z = 301.15 [M+1].
mp: 150-151 °C. 1H NMR (CD3OD):ꢁ= 4.56 (s, 2H),
6.98 (t, J = 6.8 Hz, 1H), 7.29-7.32 (m, 4H), 7.41 (dd, J = 7.1,
8.8 Hz, 1H), 7.52 (d, J = 6.8 Hz, 1H), 7.64 (d, J = 8.8 Hz,
1H), 7.70 (s, 1H), 7.75 (dd, J = 1.9, 6.4 Hz, 1H), 7.75 (d, J =
7.1 Hz, 1H). SM (IS): m/z = 307.10 [M+1].
[3-(3-Thiophen-3-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-
methanol 12
1
mp: 155-157 °C. H NMR (CD3OD): ꢁ= 4.56 (s, 2H),
6.95 (t, J = 6.8 Hz, 1H), 7.16 (dd, J = 1.5, 6.4 Hz, 1H), 7.28-
7.48 (m, 4H), 7.60-7.71 (m, 4H), 8.15 (d, J = 6.8 Hz, 1H).
SM (IS): m/z = 307.10 [M+1].
{3-[6-(4-Methylsulfanyl-phenyl)-imidazo[1,2-a]pyridin-2-
yl]-phenyl}-methanol 18
1
mp: 159-161 °C. H NMR (CD3OD): ꢁ= 2.52 (s, 3H,
[3-(3-Benzo[b]thiophen-2-yl-imidazo[1,2-a]pyridin-2-yl)-
phenyl]-methanol 13
SCH3), 4.69 (s, 2H, CH2OH), 7.34-7.39 (m, 3H, HAr), 7.43
(dd, 1H, H5, J = 7.5, 7.8 Hz), 7.59-7.63 (m , 4H, HAr), 7.84
(d, 1H, H4, J = 7.5 Hz), 7.93 (s, 1H, H2), 8.23 (s, 1H, H3'),
8.68 (d, 1H, H5', J = 1.2 Hz). 13C NMR (CD3OD): ꢁ= 15.49
(OCH3), 65.20 (CH2), 110.81 (CH), 117.05 (CH), 124.74
(CH), 125.61 (CH), 126.02 (CH), 127.25 (CH), 127.77 (CH),
127.89 (2ꢀCH), 128.21 (2ꢀCH), 128.25 (C), 129.91 (CH),
134.74 (C), 134.80 (C), 140.44 (C), 143.52 (C), 146.80 (C),
146.85 (C). SM (IS): m/z = 347.15 [M+1].
mp: 182-183 °C. 1H NMR (250 MHz, (CD3)2SO):
ꢁ= 4.54 (s, 2H), 6.97 (dd, J= 6.6, 6.8 Hz, 1H), 7.27-7.33 (m,
2H), 7.39-7.45 (m, 3H), 7.53-7.57 (m, 2H), 7.65 (d, J= 9 Hz,
1H), 7.76 (s, 1H), 7.87-7.92 (m, 2H), 8.26 (d, J= 6.8Hz, 1H).
13C NMR (62.5 MHz, (CD3)2SO): ꢁ= 62.02 (CH2), 114.70
(CH), 117.41 (CH), 123.42 (CH), 125.36 (C), 125.64 (C),
125.89 (CH), 126.54 (CH), 127.28 (C), 127.97 (2 CH),
128.05 (CH), 128.40 (CH), 128.79 (CH), 129.45 (CH),
130.87 (C), 134.48 (C), 141.35 (C), 142.59 (C), 143.13 (C),
145.74 (C), 146.81 (C). SM (IS): m/z = 357.15 [M+1].
{3-[6-(4-Methoxyphenyl)-imidazo[1,2-a]pyridin-2-yl]-
phenyl}-methanol 19
1
mp: 174-175 °C. H NMR (CD3OD): ꢁ= 3.84 (s, 3H,
OCH3), 4.68 (s, 2H, CH2OH), 7.03 (d, 2H, H3" et H5", J = 8.8
Hz), 7.35 (d, 1H, HAr, J = 7.8 Hz), 7.42 (t, 1H, H5, J = 7.6
Hz), 7.56-7.61 (m, 4H, HAr), 7.83 (d, 1H, H4, J = 7.6 Hz),
7.89-7.92 (m, 1H, HAr), 8.20 (s, 1H, H3'), 8.61 (d, 1H, H5', J
= 1.2 Hz). 13C NMR (CD3OD): ꢁ= 30.61 (OCH3), 65.25
(CH2), 110.80 (CH), 115.66 (2ꢀCH), 116.90 (C), 124.18
(CH), 125.62 (CH), 126.01 (CH), 127.12 (CH), 127.55 (CH),
127.84 (CH), 128.30 (C), 129.03 (2ꢀCH), 129.90 (CH),
129.95 (C), 130.50 (C), 134.74 (C), 143.41 (C), 161.25 (C).
SM (IS): m/z = 331.20 [M+1].
{3-[3-(4-Methoxyphenyl)-imidazo[1,2-a]pyrimidin-2-yl]-
phenyl}-methanol 14
1
mp: 193-194 °C. H NMR (CD3OD): ꢁ= 3.88 (s, OCH3),
4.54 (s, CH2OH), 7.02 (dd, J = 6.8 Hz, 1H), 7.12 (d, J = 8.8
Hz, 2H), 7.25-7.29 (m, 2H), 7.39 (d, J = 8.8 Hz, 2H), 7.46
(dt, J =1.7, 7.1 Hz, 2H), 7.69 (s, 1H), 8.46 (dd, J = 1.9, 6.8,
1H), 8.57 (dd, J = 1.9, 1H). 13C NMR (CD3OD): ꢁ= 55.91
(CH3), 65.08 (CH2), 110.52 (CH), 116.28 (CH), 121.26 (C),
121.37 (C), 127.83 (CH), 128.03 (CH), 128.29 (CH), 129.40
(CH), 133.22 (CH), 133.35 (CH), 134.65 (C), 143.11 (C),
143.86 (C), 149.04 (C), 151.97 (CH), 162.15 (C). SM (IS):
m/z = 332.20 [M+1].
[3-(6-Thiophen-3-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-
methanol 20
1
mp: 189-190 °C. H NMR (DMSO-d6): ꢁ= 4.57 (d, 2H,
{3-[3-(4-Methylsulfanyl-phenyl)-imidazo[1,2-a]pyrimidin-
2-yl]-phenyl}-methanol 15
mp>250 °C. 1H NMR (CD3OD): ꢁ= 2.57 (s, 3H), 4 .62 (s,
2H), 7.43-7.50 (m, 7H), 7.59-7.64 (m, 2H,), 8.90 (dd, J =
1.5, 6.9 Hz, 1H), 9.07 (m, 1H). SM (IS): m/z = 348.15
[M+1].
CH2OH, J = 5.6 Hz), 5.26 (t, 1H, CH2OH, J = 5.6 Hz), 7.27
(d, 1H, H6, J = 7.5 Hz), 7.40 (t, 1H, H5, J = 7.5 Hz), 7.58-
7.72 (m, 4H, HAr), 7.84 (d, 1H, H4, J = 7.5 Hz), 7.94-7.97
(m, 2H, HAr), 8.34 (s, 1H, H3'), 8.94 (s, 1H, H5'). 13C NMR
(DMSO-d6): ꢁ= 62.91 (CH2), 109.45 (CH), 116.58 (CH),
120.68 (C), 121.21 (CH), 123.30 (CH), 123.69 (CH), 123.88
(CH), 124.71 (CH), 125.75 (CH), 125.95 (CH), 127.60 (CH),

126 Letters in Organic Chemistry, 2012, Vol. 9, No. 2
Kazzouli et al.
[7]
[8]
[9]
Gudmundsson, K. S.; Williams, J. D.; Drach, J. C.; Townsend, L.
B. Synthesis and antiviral activity of novel erythrofuranosyl
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Kaminski, J. J.; Puchalski, C.; Solomon, D. M.; Rizvi, R. K.; Conn,
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compounds. XXVIII. Imidazo[1,2-c]pyrimidines. Il Farmaco.
1991, 46, 1099-1110.
Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.;
Serra, M.; Sanna, E.; Biggio, G.; Liso, G. Novel 2-
phenylimidazo[1,2-a]pyridine derivatives as potent and selective
ligands for peripheral benzodiazepine receptors: synthesis, binding
affinity, and in vivo studies. J. Med. Chem. 1999, 42, 3934-3941.
Trapani, G.; Franco, M.; Ricciardi, L.; Latrofa, A.; Genchi, G.;
Sanna, E.; Tuveri, F.; Gagetti, E.; Biggio, G.; Liso, G. Synthesis
and binding affinity of 2-phenylimidazo[1,2-a]pyridine derivatives
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J. Med. Chem. 1997, 40, 3109-3118.
128.55 (CH), 133.64 (C), 137.69 (C), 143.00 (C), 144.05
(C), 145.06 (C). SM (IS): m/z = 307.10 [M+1].
[3-(6-Naphthalen-1-yl-imidazo[1,2-a]pyridin-2-yl)-phenyl]-
methanol 21
1H NMR (CDCl3): ꢁ= 4.78 (s, 2H, CH2OH), 7.31-7.57
(m, 7H, HAr), 7.70 (d, 1H, HAr, J = 9.1 Hz), 7.86-7.95 (m,
5H, HAr), 8.01 (s, 1H, H3'), 8.17 (s, 1H, H5'). 13C NMR
(CDCl3): ꢁ= 65.30 (CH2), 108.75 (CH), 116.75 (CH), 124.81
(CH), 125.20 (CH), 125.44 (CH), 125.52 (2ꢀCH), 126.29
(CH), 126.38 (C), 126.70 (CH), 126.83 (CH), 127.51 (CH),
128.55 (CH), 128.70 (CH), 128.86 (CH), 129.10 (CH),
131.91 (C), 133.94 (C), 134.00 (C), 135.55 (C), 141.80 (C),
145.06 (C), 146.10 (C). SM (IS): m/z = 351.15 [M+1].
[0]
[3-(6-Benzo[b]thiophen-2-yl-imidazo[1,2-a]pyridin-2-yl)-
phenyl]-methanol 22
[11]
[12]
mp: 204-205 °C. 1H NMR (CD3OD): ꢁ= 4.69 (s,
CH2OH), 7.34-7.47 (m, 4H, HAr), 7.64 (d, 1H, HAr, J = 9.3
Hz), 7.83-7.89 (m, 5H, HAr), 7.94 (s, 1H, H2), 8.26 (s, 1H,
H3'), 8.85 (s, 1H, H5'). 13C NMR (CD3OD): ꢁ= 65.01 (CH2),
114.74 (CH), 117.45 (CH), 123.46 (CH), 125.41 (CH),
125.66 (CH), 125.88 (CH), 126.52 (CH), 127.27 (C), 128.01
(2ꢀCH), 128.01 (CH), 128.40 (CH), 128.77 (CH), 129.55
(CH), 130.90 (C), 134.52 (C), 141.41 (C), 142.60 (C),
143.13 (C), 145.55 (C), 146.85 (C). SM (IS): m/z = 357.15
[M+1].
[13]
[14]
ACKNOWLEDGEMENT
[15]
[16]
[17]
Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.; Moore,
J. B., Jr. Synthesis of (aryloxy)alkylamines. 2. Novel imidazo-fused
heterocycles with calcium channel blocking and local anesthetic
activity. J. Med. Chem. 1988, 31, 2221-2227.
Declared none.
CONFLICT OF INTEREST
Zhuang, Z. P.; Kung, M. P.; Wilson, A.; Lee, C. W.; Plössl, K.;
Hou, C.; Holtzman, D. M.; Kung, H. F. Structureꢀactivity
relationship of imidazo[1,2-a]pyridines as ligands for detecting ꢁ-
amyloid plaques in the brain. J. Med. Chem. 2003, 46, 237-243.
Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Imai, K. H.
A novel class of orally active non-peptide bradykinin B2 receptor
antagonists. 1. Construction of the basic framework. J. Med. Chem.
1998, 41, 564-578.
Declared none.
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Letters in Organic Chemistry, 2012, Vol. 9, No. 2
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El Kazzouli, S.; Bouissane, L.; Khouili, M.; Guillaumet, G.
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