Regioselective synthesis of C-2 substituted imidazo[4,5-b]pyridines utilizing palladium catalysed C-N bond forming reactions with enolizable heterocycles

Article abstract of DOI:10.1016/j.tetlet.2014.01.114

In this Letter we report a rapid and facile access to C2-substituted imidazo[4,5-b]pyridine analogues utilizing palladium mediated Buchwald-Hartwig cross-coupling reactions. The use of enolizable heterocycles as cross-coupling partners resulted in a wide range of imidazo[4,5-b]pyridine analogues which are prone to have medicinal relevance. Xantphos and Pd(OAc)₂ were found to be more effective for the coupling of 2-halo imidazo[4,5-b]pyridines with pyridone nucleophiles. A regioselective approach for the synthesis of 2-substituted 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-b]pyridine is also reported.

Full text of DOI:10.1016/j.tetlet.2014.01.114

Tetrahedron Letters 55 (2014) 1778–1783
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Tetrahedron Letters
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Regioselective synthesis of C-2 substituted imidazo[4,5-b]pyridines
utilizing palladium catalysed C–N bond forming reactions with
enolizable heterocycles
a,
c
K. K. Abdul Khader a, Ayyiliath M. Sajith b,d, , M. Syed Ali Padusha , H. P. Nagaswarupa ,
⇑
⇑
A. Muralidharan b,d
a Post Graduate and Research Department of Chemistry, Jamal Mohamed College, Bharathidasan University, Tiruchirapalli, India
b Organic Chemistry Division, School of Chemical Sciences, Nehru Arts and Science College, Kannur University, Kannur, India
c Research Center, Department of Chemistry, East West Institute of Technology, Off Magadi Road, Bangalore, India
d Post Graduate and Research Department of Chemistry, Kasaragod Govt. College, Kannur University, Kasaragod, India
a r t i c l e i n f o
a b s t r a c t
Article history:
In this Letter we report a rapid and facile access to C2-substituted imidazo[4,5-b]pyridine analogues uti-
lizing palladium mediated Buchwald–Hartwig cross-coupling reactions. The use of enolizable heterocy-
cles as cross-coupling partners resulted in a wide range of imidazo[4,5-b]pyridine analogues which are
prone to have medicinal relevance. Xantphos and Pd(OAc)2 were found to be more effective for the cou-
pling of 2-halo imidazo[4,5-b]pyridines with pyridone nucleophiles. A regioselective approach for the
synthesis of 2-substituted 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-b]pyridine is also reported.
Ó 2014 Elsevier Ltd. All rights reserved.
Received 10 December 2013
Revised 24 January 2014
Accepted 25 January 2014
Available online 1 February 2014
Keywords:
Regioselective synthesis
2-Halo imidazo[4,5-b]pyridines
Enolizable heterocycles
C–N bond formation
Palladium mediated Buchwald–Hartwig
cross-coupling reaction
Imidazo[4,5-b]pyridines are an important class of heterocycles
that have been widely studied for biological activity.1 The reason
why imidazo[4,5-b]pyridines have a broad pharmacological profile
lies in their similarity and isosterism to purines.2 A combination of
biologically relevant heterocyclic systems and their further deriva-
tization is of immense interest due to the novelty and therapeutic
potential of the developed heterocycles.3 As part of our research on
imidazo[4,5-b]pyridine core4 we were interested in the C2-amina-
tion5 of this pharmaceutically relevant molecule.
The introduction of amino moiety at this position is well docu-
mented in the literature for benzimidazoles.6 In our previous work
we have successfully demonstrated the synthesis of 2-amino-1-
methyl-6-phenylimi-dazo[4,5-b]pyridine (PHIP) and 2-amino-1,6-
dimethylimidazo[4,5-b]pyridine (DMIP), which involves an
optimized palladium mediated Buchwald cross coupling reaction
of 2-halo-3-alkylimidazo[4,5-b]pyridine with benzophenone
imine.4a The C2-amination of this heterocyclic core can lead to
more diverse 2-amino deazapurine analogues7 which can be a
better substitute to the benzimidazole8 analogues leading to more
potential drug candidate. The 2-amino deazapurine analogues have
better aqueous solubility and may have a better biological profile
compared to benzimidazole ring derived analogues.
Palladium-catalysed C-N bond forming reactions of heteroaryl
halides has rapidly emerged as a valuable tool in the field of het-
erocyclic chemistry for the construction of (hetero) aryl amines.9
During the preparation of this Letter, Clark et al.7a reported the
synthesis of 2-amino-imidazo[4,5-b]pyridines via nucleophilic
substitution (SNAr) with functionalized primary and secondary
amines. As part of our research work on biologically relevant imi-
dazo[4,5-b]pyridine based structures, we were interested in intro-
ducing some pyridone analogues at C2 position of this heterocyclic
core. Unfortunately, our initial efforts to introduce pyridones via
nucleophilic substitution (SNAr) were not promising as we did
not observe any product formation (Table 1). Our subsequent ef-
forts were to employ palladium mediated C-N bond forming condi-
tions to cross-couple a wide range of enolizable heterocycles with
this heterocyclic core. The development of more efficient ligands
(Brettphos, S-phos, t-BuXphos, RuPhos etc.) by Buchwald10
prompted us to study the reactivity of 2-halo imidazopyridines
using various palladium catalyst/ligand combinations.
⇑
Corresponding authors. Tel.: +91 9865447289; fax: +91 4672331435 (M.S.A.P.).
E-mail addresses: sajithmeleveetil@gmail.com (A.M. Sajith), m.padusha@gmail.
com (M.S. Ali Padusha).
http://dx.doi.org/10.1016/j.tetlet.2014.01.114
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

K. K. Abdul Khader et al. / Tetrahedron Letters 55 (2014) 1778–1783
1779
Table 1
in both natural products and pharmacologically relevant molecules
renders them as useful synthons in the field of medicinal chemis-
try. Moreover, enolizable heterocycles11 such as 2-hydroxypyri-
dine,11c 4-hydroxypyrimidine and 3-hydroxypyridazine have
provoked great interest in biological and chemical fields as a result
of their ability to serve as models for hydrogen bonding12 tauto-
merization12 and proton shuttling12 in both chemical and biologi-
cal processes. These data directed our studies towards the
synthesis of diversely substituted pyridone analogues at the C-2
position of imidazo[4,5-b]pyridine core.
Effect of bases on cross-coupling of 3 with 2a
Entry
Base (3 equiv)
Conditions
Solvent
iYielda (%)
1
2
3
4
5
6
KOtBu
NaOtBu
K3PO4
Na2CO3
CsOAc
Cs2CO3
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0
Traces
0
0
Traces
Traces
a
Method A: Base (3 equiv), 3 (1 equiv), 2a (1.3 equiv), sealed vial, 90 °C, 15 h, 1,4-
dioxane.
Optimization of the reaction parameters was performed with 3a
to stabilize an effective catalytic system for Buchwald cross-cou-
pling of imidazo[4,5-b]pyridine core. Chloro, bromo and iodo
azoles (3a, 3b and 3c) were used as electrophiles and their synthe-
sis was performed as described in reference.4a–c Our initial at-
tempts to cross-couple 3c with pyridone (2a) using Pd(OAc)2/
BINAP, KOtBu in 1,4-dioxane were unsuccessful as we could see
major dehalogenation of 3c. The use of weaker bases like K2CO3
and Cs2CO3 also did not provide any fruitful results. Probably, iodo
analogue becomes too labile, as it is flanked between two nitrogen
atoms and hence highly reactive.13
O
N
O
HO2C
N
N
N
NH
O
Cl
S
N
NH2
Biotin Carboxylase Inhibitor Lead
An attempt was made on the use of 3a and 3b for cross-coupling
with 2a (Scheme 1). We could obtain 30% product by using 3b
along with (PdOAc)2/BINAP and Cs2CO3 in 1,4-dioxane. A base
screening was conducted and the results are shown in Table 2.
The isolated yields of the coupled products were still not promis-
ing. Failure of the aforementioned conditions prompted us to
screen various ligands for the cross-coupling of 3b with pyridone
(Table 3). To our delight, we could isolate 94% of pyridone coupled
product using (PdOAc)2/xantphos and Cs2CO3 as base. Identical re-
sult was observed when chloro intermediate (3a) was the cross
coupling partner (Scheme 1). The effect of solvents on the reaction
was studied and the results are presented in Table 4. Applying
these optimized conditions to a series of diversely substituted 2-
hydroxypyridines, allowed the rapid synthesis of N-alkylated pyr-
idines in excellent yields (Table 5). For substrates bearing electron-
withdrawing groups (Table 5, 4o) longer reaction times were
required and low yields of the coupled products were obtained.
The electron withdrawing groups on pyridone reduce the nucleo-
philicity of the nitrogen thereby making the reactions very slug-
gish. To extend the scope of this methodology, we screened a
variety of heterocycles containing more than one nitrogen atom
(Table 5, 4p, 4q and 4r). The formation of the products under these
optimized conditions was confirmed by 1H NMR and LCMS. The fi-
nal coupled products show characteristic IR absorption bands of
Pilicide (NP048),
Antibactetial
Cl
O
N
N
NH2
H2N
O
N
Cl
N
H
HN
Zar-Nestra (R115777),
Protein Inhibitor
Amrinone WIN40680,
CarditonicAgent
Figure 1. Pharmacologically relevant imidazo[4,5b]pyridines.
O
N
HO
N
N
N
N
R3
N
N
XantPhos / Pd(OAc)2
N
R1
R1
Cs2CO3/ 90 °C
1,4-Dioxane
R3= Cl (3a)
R3= Br (3b)
R3= I (3c)
pyridone at 1715 cmÀ1
.
Scheme 1. Synthesis of substituted imidazo[4,5-b]pyridin-2-yl)pyridin-2(1H)-one.
The overall efficiency of a cross-coupling process is significantly
affected by the structure of the ligand (see Fig. 2) and catalyst.
Therefore the use of ligand with appropriate steric and electronic
properties is very crucial in dealing with problematic and specific
substrates in this area. To extend the scope of this methodology
in the regioselective synthesis of 2-substituted 3H-imidazo[4,5-
The presence of substituted pyrid-2-ones in biologically rele-
vant analogues (Fig. 1) has attracted synthetic organic chemists
and hence an efficient protocol to access these compounds is of
high relevance.9a The presence of these N-alkylated heterocycles
Table 2
Effect of bases on cross-coupling of 3b with 2a
Entry
Catalytic system
Base (3 equiv)
Conditions
Solvent
iYielda (%)
1
2
3
4
5
6
Pd2(dba)3/BINAP
Pd2(dba)3/BINAP
Pd2(dba)3/BINAP
Pd2(dba)3/BINAP
Pd2(dba)3/BINAP
Pd2(dba)3/BINAP
KOtBu
KOAc
K3PO4
Na2CO3
CsOAc
Cs2CO3
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
0
0
Traces
Traces
25
30
a
i
Method A: 4 mol % Pd2(dba)3, 8 mol % BINAP, Base (3 equiv), 3b (1 equiv), 2a (1.3 equiv), sealed vial, 90 °C, 15 h, 1,4-dioxane.
Isolated yields.

1780
K. K. Abdul Khader et al. / Tetrahedron Letters 55 (2014) 1778–1783
Table 3
Effect of catalyst on cross-coupling of 3b with 2a
Entry
Catalytic system
Base (2.5 equiv)
Conditions
Solvent
iYielda (%)
1
2
3
4
5
6
7
Pd2(dba)3/BINAP
Pd2(dba)3/PPh3
(PdOAc)2/BINAP
(PdOAc)2/dppp
Pd2(dba)3/XPhos
Pd2(dba)3/Xantphos
(PdOAc)2/Xantphos
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
90 °C, 15 h
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
30
25
30
20
40
62
94
a
i
Method A: 4 mol % catalyst, 8 mol % ligand, Cs2CO3 (3 equiv), 3b (1 equiv), 2a (1.3 equiv), sealed vial, 90 °C, 15 h, 1,4-dioxane.
Isolated yields.
Table 4
b]pyridine and 1H-imidazo[4,5-b]pyridines, we treated the cou-
pled product (4c and 4c⁄) with Pd-C/H2 in Ethanol as shown in
Scheme 2. The products (5 and 5⁄) were obtained in excellent
yields.
In summary, we have developed a facile and efficient method
for the C2-amination of imidazo[4,5-b]pyridines which gave access
to diversely substituted 2-amino-imidazo[4,5-b]pyridines. Using
these protocols, various enolizable heterocycles were found to be
effective nucleophiles for the cross-coupling reactions with 2-halo
imidazo[4,5-b]pyridines. Moreover a regioselective approach for
the synthesis of 2-substituted 3H-imidazo[4,5-b]pyridine and 1H-
imidazo[4,5-b]pyridines was also performed.
Effect of solvents on cross-coupling of 3b with 2a
Entry
Solvent
% Yield of 5aa
1
2
3
4
5
6
Toluene
NMP
DMF
DMA
THF
52
NR
Traces
10–20
NR
1,4-Dioxane
94
a
Method A: 4 mol % Pd(OAc)2, 8 mol % Xantphos, Cs2CO3 (3 equiv), 3b (1 equiv),
2a (1.3 equiv), sealed vial, 90 °C, 15 h, solvents.
i
Isolated yields.
Table 5
Cross-coupling of different halo intermediates with pyridine nucleophiles
Entry
Halo intermediate
Pyridine
Product, 4
aYieldi (%)
X = Cl, a
X = Br, b
a = 94
b = 80
N
X
N
N
O
N
N
N
HO
N
N
1
2a
3a
4a
a = 90
b = 82
N
X
N
N
2
2a
N
O
N
N
N
N
3a*
4a*
N
N
X
N
N
O
N
N
3
2a
a = 96
O
O
O
O
O
O
3b
4b
O
O
4
2a
a = 91
N
N
N
O
X
N
N
3b*
N
N
4b*

K. K. Abdul Khader et al. / Tetrahedron Letters 55 (2014) 1778–1783
1781
Table 5 (continued)
Entry
Halo intermediate
Pyridine
Product, 4
aYieldi (%)
X = Cl, a
X = Br, b
N
X
N
N
O
N
N
5
6
2a
a = 90
N
N
3c
4c
N
X
N
N
N
N
O
2a
2a
a = 88
b = 86
N
N
N
3c*
4c*
N
X
N
N
O
N
N
N
7
b=90
O
O
3d
4d
O
O
N
X
N
8
2a
2a
2a
b=91
N
O
N
N
N
N
3d*
4d*
O
N
N
X
N
N
N
9
a = 95
N
N
N
3e
4e
X
X
O
N
N
N
N
N
N
N
10
a = 93
3f
4f
O
N
N
N
N
N
N
N
11
12
13
2a
2a
2a
a = 90
3g
4g
N
O
N
X
N
N
N
N
a = 92
3h
4h
N
O
N
X
N
N
N
N
N
a = 95
3i
4i
(continued on next page)

1782
K. K. Abdul Khader et al. / Tetrahedron Letters 55 (2014) 1778–1783
Table 5 (continued)
Entry
Halo intermediate
Pyridine
Product, 4
aYieldi (%)
X = Cl, a
X = Br, b
O
N
O
N
N
O
N
N
X
N
N
14
15
2a
a = 92
3j
4j
O
N
N
N
N
X
N
N
2a
a = 97
N
4k
3k
O
N
N
N
N
N
N
N
16
17
18
3a
a = 95
a = 88
a = 86
N
2b
OH
N
4l
O
N
N
O
N
N
N
O
3a
3a
N
2c
OH
4m
F
O
N
N
N
N
N
2d
OH
F
4n
HO
O
N
N
N
CF3
N
CF3
19
20
21
3a
3a
3a
3a
a = 49
a = 79
a = 80
a = 89
2e
4o
O
HO
N
N
N
N
N
N
N
N
N
2f
4p
HO
N
O
N
N
N
N
N
2g
4q
H
O
N
N
N
NH
O
N
N
H
22
2h
4r
a
Method A: 4 mol % Pd(OAc)2, 8 mol % Xantphos, Cs2CO3 (3 equiv), 3 (1 equiv), 2 (1.3 equiv), sealed vial, 90 °C, 15 h, 4-dioxane.
Isolated yields.
i

K. K. Abdul Khader et al. / Tetrahedron Letters 55 (2014) 1778–1783
1783
References and notes
PPh2
PPh2
PCy2
i-Pr
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Figure 2. Ligands used during optimization.
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N
O
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N
N
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O
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O
N
N
N
O
N
N
N
N
Pd-C/ H2
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O
Scheme 2. Synthesis of 3H and 1H-imidazo[4,5-b]pyridine analogue.
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Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
01.114.