Regioselective palladium-catalyzed arylation and heteroarylation of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1055/s-2006-951562

Palladium-catalyzed direct arylation and heteroarylation of imidazo[1,2-a]pyridines at the 3-position are described. The optimization of the reaction in conventional heating and the adaptation under microwaves irradiation is reported. The compatibility of

Full text of DOI:10.1055/s-2006-951562

LETTER
3237
Regioselective Palladium-Catalyzed Arylation and Heteroarylation of
Imidazo[1,2-a]pyridines
P
alladium
a
-Catalyze
d
m
A
rylation and
H
eter
a
oarylation
l
of
I
midazo[1,
K
2-
a
]pyridines oubachi,a,b Saïd El Kazzouli,a,b Sabine Berteina-Raboin,*a Abderrahim Mouaddib,b Gérald Guillaumeta
a
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d’Orléans, BP 6759, 45067 Orléans Cedex 2, France
E-mail: sabine.berteina@univ-orleans.fr
b
Faculté des Sciences et Techniques de Beni-Mellal, Université Caddi-Ayyad, BP 523, 23000 Beni-Mellal, Morocco
Received 26 July 2006
N
Stille or Suzuki
coupling
N
R2
Abstract: Palladium-catalyzed direct arylation and heteroarylation
of imidazo[1,2-a]pyridines at the 3-position are described. The op-
timization of the reaction in conventional heating and the adaptation
under microwaves irradiation is reported. The compatibility of the
synthesis with the presence of bromo or chloro substituents in the 6-
position was investigated.
R2
N
N
R1
R1
R3
X
III
II
arylation or
heteroarylation
iodination or
bromination
Key words: palladium-catalyzed coupling, arylation, heteroaryla-
tion, imidazo[1,2-a]pyridines, microwave irradiation
N
R2
N
R1
I
Imidazo[1,2-a]pyridine derivatives have attracted consid-
erable interest because of their therapeutic properties. For
instance, this heterocyclic system is found as antiviral,1
antiulcer,2 antibacterial,3 antifungal,4 agonist of benzodi-
azepine receptor,5 calcium channel blocker,6 b-amyloid
formation inhibitor,7 ligand for detecting b-amyloid8 and
constitute a novel class of orally active nonpeptide brady-
kinin B2 receptor antagonists.9 Indeed, the imidazo[1,2-
a]pyridine derivative zolpidem was commercialized as a
hypnotic.10
Scheme 1
oxazolo[4,5-b]pyridine.21 However, a few examples of
heteroarylation have being reported19,20 with often modest
yields. It is important to note that our work also reports the
first study of the tolerance of the (hetero)arylation reac-
tion conditions with the presence of sensitive groups.
To explore the potential of the regioselective (hetero)aryl-
ation reaction, we initially tested the conditions previous-
ly described by Li et al.19 (Table 1). Thus, the reaction of
6-chloroimidazo[1,2-a]pyridine22 (1) and 3-bromotoluene
(1.5 equiv) in the presence of palladium(II) acetate (2
mol%) and triphenylphosphine (4 mol%) in dioxane at
100 °C for 48 hours gave, after purification, only 69%
yield of 2 (Scheme 2, entry 1, Table 1). On using two
equivalents of 3-bromotoluene, under the same reaction
conditions, compound 2 was isolated in 75% yield (entry
2, Table 1). It is noteworthy that a significant amount of
the starting material was recovered. To optimize the reac-
tion conditions, we decided to investigate the reactivity of
6-chloroimidazo[1,2-a]pyridine using various ligands
and/or palladium. Thus, by the replacement of palladi-
um(II) acetate [Pd(OAc)2; 2 mol%]–triphenylphosphine
(PPh3; 4 mol%) system with Pd(OAc)2 (5 mol%)–1,1¢-
bis(diphenylphosphino)ferrocene (dppf; 10 mol%), the
yield of 2 was improved to 88% (entry 3, Table 1). The
same result was observed with tetrakis(triphenylphos-
phine)palladium(0) [Pd(PPh3)4; 10 mol%] (entry 4,
Table 1). Indeed, the catalyst system tris(dibenzylidene-
acetone)dipalladium(0) [Pd2(dba)3; 5 mol%]–triphenyl-
arsine (AsPh3; 10 mol%) afforded 2 in 83% yield (entry 5,
Table 1). Finally, we found the optimal conditions using
the Pd(OAc)2 (5 mol%)–PPh3 (10 mol%) system. Under
present conditions, compound 2 was obtained with 100%
conversion and in 92% yield (entry 6, Table 1). All the re-
actions were conducted in dioxane at 100 °C for 48 hours.
Recently, we have reported that 2,3,6-trisubstituted imi-
dazo[1,2-a]pyridine analogues exhibit a high affinity as
melatonin receptor ligands.11 In continuation of our re-
search group programme,11,12 we report herein a new, ef-
ficient and regioselective microwave directed palladium-
catalyzed arylation and heteroarylation of imidazo[1,2-
a]pyridines (Scheme 1).
As far as we know, only two approaches, including palla-
dium cross-coupling, were known to prepare intermedi-
ates such as III – the Suzuki13 and Stille14 cross-coupling
reactions (Scheme 1). All these methods, however, in-
volve two principal steps: (1) the preparation of 3-halo-
imidazo[1,2-a]pyridines from the corresponding
imidazo[1,2-a]pyridines, and (2) Suzuki13 or Stille14
cross-coupling reactions which require longer reactions
times (two steps) and expensive reagents (heteroaromatic
boronic acid for the Suzuki reaction and heteroaromatic
stannanes for the Stille reaction).
In the past few years, using palladium-catalyzed arylation,
various heterocycles have been functionalized such as
thiophene,15 furan,16 imidazole,17,18 indole,18 pyrrole,18
pyrazole,18 imidazo[1,2-a]pyrimidine,19 indolizine20 and
SYNLETT 2006, No. 19, pp 3237–3242
0
1
.1
2
.2
0
0
6
Advanced online publication: 23.11.2006
DOI: 10.1055/s-2006-951562; Art ID: G20806ST
© Georg Thieme Verlag Stuttgart · New York

3238
J. Koubachi et al.
LETTER
Table 1 Optimization of Arylation Reaction of 6-Chloroimidazo[1,2-a]pyridine with Conventional Heating
Entry
Pd (equiv)
Ligand (equiv)
PPh3 (0.04)
PPh3 (0.04)
Dppf (0.1)
–
Reactant (equiv)
Solvent
Time
48 h
48 h
48 h
48 h
48 h
48 h
36 h
Conversion
75%
Yield
69%
75%
88%
90%
83%
92%
92%
1
2
3
4
5
6
7
Pd(OAc)2 (0.02)
Pd(OAc)2 (0.02)
Pd(OAc)2 (0.05)
Pd(PPh3)4 (0.1)
Pd2(dba)3 (0.05)
Pd(OAc)2 (0.05)
Pd(OAc)2 (0.05)
1.5
2
dioxane
dioxane
84%
1.5
1.5
1.5
1.5
1.5
dioxane
96%
dioxane
98%
AsPh3 (0.1)
PPh3 (0.1)
PPh3 (0.1)
dioxane
90%
dioxane
100%
100%
dioxane–EtOH
The reaction time was slightly improved by replacement 10 in 84% and 96% yields, respectively (entries 6 and 7,
of dioxane with a mixture of dioxane–ethanol (2:1) (entry Table 2). All these reactions were clean and free from any
7, Table 1).23 In this case, the reaction was carried out at byproduct. Unfortunately, the reaction of 6-bromo-2-
reflux for 36 hours. It is important to note the tolerance of phenylimidazo[1,2-a]pyridine22 (5) and 3-bromotoluene
the arylation reaction to the presence of chloro substituent was completely ineffective and afforded a very complex
at the 6-position, which could be important for biological mixture of products (entry 8, Table 2).
activity1g,5,24, or to carry out further transformations.
We then decided to use microwave irradiation in order to
In order to study the scope and limitation of the reaction, improve the reaction times. First, we optimized the reac-
we decided to exemplify the coupling reaction of 6-chlo- tion between compound
1
and 3-bromotoluene
roimidazo[1,2-a]pyridine (1) and various aryl or hetero- (Scheme 4). Thus, we irradiated the reaction mixture at
aryl bromides using the previously optimized conditions 130 °C for 30 minutes under the already optimized condi-
(Scheme 3). The results (Table 2) showed that compound tions used under conventional heating [Pd(OAc)2 (5
1 could be efficiently functionalized in 3-position under mol%), PPh3 (10 mol%)]. In this case, compound 2 was
the palladium cross-coupling reactions. The yields were obtained with only 78% conversion (22% of starting ma-
good to excellent (79–92%, entries 1–3 and 5 in Table 2). terial was recovered). When the time of irradiation was in-
However, the coupling reaction between 1 and 5-bro- creased to one hour or one hour and 30 minutes, a
moindole gave only the starting material (entry 4, significant improvement in the yield was observed and
Table 1). This result was certainly due to the presence of compound 2 was obtained with 86% and 91% conversion,
the NH group.25 For this reason, we then decided to per- respectively. Using dioxane as solvent, complete conver-
form the reaction using alkylated indole. In this case, the sion and an excellent yield (94%) were finally obtained
desired compound 8 was isolated in 79% yield. Thereaf- after an irradiation time of two hours. Interestingly, com-
ter, the imidazo[1,2-a]pyridines 3 and 4, obtained as de- plete conversion was also achieved when the reaction was
scribed in the literature,22 were (hetero)arylated using irradiated at 130 °C in a mixture of dioxane–ethanol (2:1)
similar optimal conditions, leading to compounds 9 and for only one hour.26 Under these conditions, the desired
Pd, ligand,
K2CO3, dioxane,
100 °C, 48 h
Me
Br
N
N
N
+
N
Cl
Cl
Me
1
2
Scheme 2
N
N
R2
Pd(OAc)2 (5 mol%), Ph3P (10 mol%)
K2CO3, dioxane, 100 °C, 48 h
R2
R3Br
N
+
R1
N
R3
R1
1, R1 = Cl, R2 = H
3, R1 = H, R2 = H
4, R1 = Cl, R2 = Ph
5, R1 = Br, R2 = Ph
6–10
Scheme 3
Synlett 2006, No. 19, 3237–3242 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Arylation and Heteroarylation of Imidazo[1,2-a]pyridines
3239
Table 2 Arylation and Heteroarylation of Various Imidazo[1,2-
a]pyridines with Conventional Heating
Table 3 Optimization of the Arylation Reaction of 6-Chloroimida-
zo[1,2-a]pyridine under Microwave Irradiation
Entry R1
R2
R3
Com-
pound
Yield
92%
Entry
Reaction time Solvent
Conversion Yield
1
2
3
4
5
30 min
1 h
dioxane
78%
86%
–
1
2
Cl
Cl
H
2
dioxane
–
1 h 30 min
2 h
dioxane
91%
–
Me
H
6
80%
MeO
dioxane
100%
100%
94%
93%
1 h
dioxane–EtOH
3
4
Cl
Cl
H
H
7
8
81%
0%
N
With these results in hand, we thought that this methodol-
ogy could be extended to the synthesis of various 2,3,6-
trisubstituted imidazo[1,2-a]pyridine analogues. Thus,
starting material 1, 3, 4, 11 or 1222 (Scheme 5), reacted
with various (hetero)aryl bromides in the optimal condi-
tions (at 130 °C or 150 °C), leading to compounds 6–10
and 13–22 in excellent yields (entries 1–20, Table 4). In
contrast, to the reaction of 11 and 3-bromotoluene, using
the same reaction conditions (both at 130 °C or 150 °C),
compound 16 was obtained with moderate conversion of
60% and 65% respectively; however, the reaction was not
complete and the starting material was recovered (entries
8 and 9, Table 4). Finally, complete conversion was ob-
tained when the quantities of Pd(OAc)2 (10 mol%) and
PPh3 (20 mol%) were increased at 150 °C (entry 10,
Table 4), probably due to the presence of a phenyl group
in 2-position. Under the present conditions, compounds
10 and 18–22 were isolated in good yields from the 6-
chloroimidazo[1,2-a]pyridines derivatives 11 and 12 at
150 °C (entries 14–20, Table 4). It is worth noting that
compound 22 was obtained in complete conversion using
two equivalents of 4-bromopyridine, the excess being
needed for complete conversion to occur (entry 20,
Table 4).
N
H
5
Cl
H
8
79%
N
Pr
6
7
8
H
H
9
10
–
84%
96%
Me
Me
Me
Cl
Br
Ph
Ph
Complex
mixture
product 2 was isolated in 93% yield. Synthesis and results
are summarized in Table 3.
Pd(OAc)2 (5 mol%)
N
Ph3P (10 mol%)
K2CO3, solvent
130 °C, MW
Me
Br
N
N
+
N
Cl
Cl
Me
1
2
Scheme 4
Pd(OAc)2 (5 mol%)
Ph3P (10 mol%), K2CO3
dioxane–EtOH, MW
N
N
R2
R2
R3Br
+
N
N
R1
R1
R3
1, R1 = Cl, R2 = H
3, R1 = H, R2 = H
4, R1 = Cl, R2 = Ph
11, R1 = H, R2 = Ph
6–10 and 13–22
12, R1 = Cl, R2 = p-FC6H4
Scheme 5
Synlett 2006, No. 19, 3237–3242 © Thieme Stuttgart · New York

3240
J. Koubachi et al.
LETTER
Table 4 Arylation and Heteroarylation of Various Imidazo[1,2-a]pyridines under Microwave Irradiation
Entry
1
R1
Cl
R2
H
R3
Reaction time
1 h
T (°C)
130
Product
Conversion
100%
Yield
80%
6
MeO
2
3
Cl
Cl
H
H
1 h
2 h
130
130
7
8
100%
100%
78%
94%
N
N
Pr
4
H
H
1 h
130
9
100%
86%
Me
5
6
Cl
H
H
H
1 h
1 h
130
130
13
14
100%
100%
89%
90%
N
7
8
H
H
H
1 h
130
130
15
16
96%
60%
77%
–
MeO
Ph
1.5 h
Me
Me
Me
9
H
H
Ph
Ph
1.5 h
2 h
150
150
16
16
65%
–
10a
100%
91%
11a
12a
H
H
Ph
Ph
2 h
2 h
150
150
17
18
100%
82%
96%
66%
N
MeO
13a
14a
15a
H
Ph
Ph
Ph
3 h
150
150
150
18
18
10
94%
100%
100%
71%
76%
92%
MeO
MeO
H
3.5 h
2 h
Cl
Me
16a
17a
18a
Cl
Cl
Cl
Ph
2 h
2 h
2 h
150
150
150
19
20
21
100%
100%
100%
91%
74%
82%
N
N
Ph
p-FC6H4
N
Synlett 2006, No. 19, 3237–3242 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Arylation and Heteroarylation of Imidazo[1,2-a]pyridines
3241
Table 4 Arylation and Heteroarylation of Various Imidazo[1,2-a]pyridines under Microwave Irradiation (continued)
Entry
19a
R1
Cl
R2
R3
Reaction time
2 h
T (°C)
150
Product
Conversion
80%
Yield
64%
p-FC6H4
22
N
20b
Cl
p-FC6H4
2 h
150
22
100%
76%
N
a Reaction conditions: Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), (hetero)arylbromide (1.5 equiv).
b Reaction conditions: Pd(OAc)2 (0.1 equiv), PPh3 (0.2 equiv), 4-bromopyridine hydrochloride (2 equiv).
(9) Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.;
Imai, K. H. J. Med. Chem. 1998, 41, 564.
(10) Holm, K. J.; Goa, K. L. Drugs 2000, 59, 865.
(11) Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.;
Delagrange, P.; Caignard, D. H. PCT Int. Appl., WO
2006027474, 2006.
(12) (a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Tetrahedron Lett. 2003, 44, 6265. (b) El
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S.; Gueiffier, A. J. Org. Chem. 2000, 65, 6572.
In summary, we have described a simple, useful and effi-
cient microwave-induced palladium-mediated cross-cou-
pling reaction for direct arylation and heteroarylation of
imidazo[1,2-a]pyridines at 3-position. The method offers
several advantages including high yields, one step only
(compared to Suzuki and Stille methods) and shorter reac-
tion times. The compatibility of (hetero)arylation reaction
conditions with the presence of chloro substituent in the 6-
position may lead to the prospect of introducing various
substitutions to give highly diverse structures.
(14) (a) Kawai, Y.; Satoh, S.; Yamasaki, H.; Kayakiri, N.;
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(23) Procedure for Synthesis of 6-Chloro-3-m-tolyl-
imidazo[1,2-a]pyridine 2 under Coventional Heating:
A mixture of 3-bromotoluene (0.12 mL, 0.98 mmol), 6-
chloroimidazo[1,2-a]pyridine (0.1 g, 0.66 mmol), K2CO3
(0.18 g, 1.3 mmol), PPh3 (0.0073 g, 0.033 mmol) and
Pd(OAc)2 (0.017 g, 0.063 mmol) in 1,4-dioxane (2 mL) was
heated to 100 °C. The reaction was stirred for 48 h, and
then the mixture was cooled to r.t. and extracted with CH2Cl2
(3 ×). The combined organic layer was dried over MgSO4
and concentrated under vacuum. The residue was purified by
column chromatography on silica gel (EtOAc–PE) to give 6-
chloro-3-m-tolylimidazo[1,2-a]pyridine(2) as an oil (146
mg, 92% yield). 1H NMR (250 MHz, CDCl3): d = 2.45 (s, 3
H, CH3), 7.16 (dd, J = 1.9, 9.4 Hz, 1 H), 7.26 (d, J = 7.5 Hz,
1 H), 7.33 (m, 2 H), 7.43 (t, J = 7.5, 8.2 Hz, 1 H), 7.62 (d,
(8) Zhuang, Z. P.; Kung, M. P.; Wilson, A.; Lee, C. W.; Plössl,
K.; Hou, C.; Holtzman, D. M.; Kung, H. F. J. Med. Chem.
2003, 46, 237.
Synlett 2006, No. 19, 3237–3242 © Thieme Stuttgart · New York

3242
J. Koubachi et al.
LETTER
(26) Procedure for Synthesis of 6-Chloro-3-m-tolyl-
J = 9.4 Hz, 1 H), 7.63 (s, 1 H), 8.34 (d, J = 1.9 Hz, 1 H). 13
NMR (62.5 MHz, CDCl3): d = 22.1, 119.2, 121.6, 122.0,
125.7, 126.2, 129.2, 129.44 (2 × CH), 129.9 (2 × CH), 130.1,
133.9, 139.9.
C
imidazo[1,2-a]pyridine 2 under Microwave Irradiation:
The 6-chloroimidazo[1,2-a]pyridine (0.1 g, 0.66 mmol) was
dissolved in 1,4-dioxane–EtOH (1.5 mL; 2:1) in a
(24) Cooper, L. C.; Chicchi, G. G.; Dinnell, K.; Elliott, J. M.;
Hollingworth, G. J.; Kurtz, M. M.; Locker, K. L.; Morrison,
D.; Shaw, D. E.; Tsao, K.-L.; Watt, A. P.; Williams, A. R.;
Swain, C. J. Bioorg. Med. Chem. Lett. 2001, 11, 1233.
(25) Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S.
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microwave vial equipped with a stir bar. 3-Bromotoluene
(0.12 mL, 0.98 mmol), K2CO3 (0.18 g, 1.3 mmol), PPh3
(0.0073 g, 0.033 mmol) and Pd(OAc)2 (0.017 g, 0.063
mmol) were added under argon and subjected to microwave
irradiation for 1 h at 130 °C with stirring. The reaction vessel
was allowed to cool to r.t. and was diluted with CH2Cl2 (15
mL). The mixture was extracted with CH2Cl2 (3 ×). The
combined organic layer was dried over MgSO4 and
concentrated under vacuum. The crude material thus
obtained was purified by column chromatography on silica
gel (EtOAc–PE) to give 6-chloro-3-m-tolylimidazo[1,2-
a]pyridine(2) as an oil (148 mg, 93% yield).
Synlett 2006, No. 19, 3237–3242 © Thieme Stuttgart · New York