One-pot sequential C-N coupling and cross dehydrogenative couplings: Synthesis of novel azole fused imidazo[1,2-a]pyridines

Article abstract of DOI:10.1039/c3cc39206f

An efficient one-pot protocol has been developed using sequential C-N coupling and intramolecular dehydrogenative cross-couplings for the synthesis of azole fused imidazo[1,2-a]pyridine derivatives in good yields (62-78%). The Royal Society of Chemistry 2

Full text of DOI:10.1039/c3cc39206f

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One-pot sequential C–N coupling and cross
dehydrogenative couplings: synthesis of novel azole
Cite this: DOI: 10.1039/c3cc39206f
fused imidazo[1,2-a]pyridines†
Received 25th December 2012,
Accepted 20th February 2013
Kasiviswanadharaju Pericherla, Poonam Khedar, Bharti Khungar and Anil Kumar*
DOI: 10.1039/c3cc39206f
www.rsc.org/chemcomm
An efficient one-pot protocol has been developed using sequential of synthetic simplicity and efficiency, atom economy, and
C–N coupling and intramolecular dehydrogenative cross-couplings environmental benefits.6–9 It avoids pre-functionalization of
for the synthesis of azole fused imidazo[1,2-a]pyridine derivatives substrates and minimizes by-product formation.
in good yields (62–78%).
A number of novel methodologies have been established to
generate diverse poly heterocycles via cross dehydrogenative
Fused heterocyclic molecular frameworks are found in a large coupling. For example, Bao and co-workers have reported
number of biologically active natural and synthetic compounds.1 intramolecular double C–H activation for imidazoles.10 Palladium
Imidazo[1,2-a]pyridine, a bicyclic N-fused imidazole, is a privileged catalyzed cross dehydrogenative coupling between structurally
structural motif present in several natural products and pharmaco- similar and different heteroarenes have been developed.4,11–16
logically relevant structures, with a wide range of activities such A convenient one-pot synthesis of benzimidazo-quinazolinones has
as anti-bacterial, anti-viral, anti-ulcer, antihelminthics, anti- been developed using Ullmann coupling and C–H amidation.17 You
inflammatory, anti-convulsant, hypnotic, gastrointestinal, and and co-workers have developed a method for coupling azoles,
immunemodulatory activities.2,3 There are several drug formula- pyridine N-oxides, and xanthines with thiophenes and furans using
tions that contain the imidazo[1,2-a]pyridine skeleton, e.g. zolpidem Pd(OAc)2 as a catalyst and Cu(OAc)2ꢀH2O as an oxidant to afford the
and alpidem (used to treat anxiety and insomnia), zolimidine (used heterodimers, in moderate to high yields.18 Zhang and co-workers
for treatment of peptic ulcers), saripidem and necopidem have reported Pd(OAc)2-catalyzed and Ag2CO3 assisted cross
(possessing sedative and anxiolytic effects), miroprofen (analgesic), dehydrogenative coupling of electron-deficient polyfluoroarenes with
and optically active GSK812397 (a candidate for treatment of HIV thiophenes, furans, and imidazoles.19 Although a variety of classical
infection) (Fig. 1). Owing to their broad biological importance, methods have been developed to synthesize imidazo[1,2-a]pyridine
considerable efforts have been directed towards the synthesis and derivatives, there is still a need for fused imidazo[1,2-a]pyridines
functionalization of imidazopyridine derivatives.4,5
because of their significance in the pharmaceutical industry.
The cross dehydrogenative coupling (CDC) has emerged as As part of our continued interest in the synthesis of novel
an efficient and straightforward method for the construction of heterocycles containing imidazo[1,2-a]pyridines,20 we report
C–C and C–N bonds in organic synthesis from the viewpoint herein an efficient protocol for the synthesis of novel azole-fused
imidazo[1,2-a]pyridines by a one-pot Ullmann-type coupling
followed by intramolecular C–C bond formation via cross
dehydrogenative coupling.
The investigation started with the Ullman coupling between
2-(2-bromophenyl)imidazo[1,2-a]pyridine (1a) and 1H-imidazole
(2a) in the presence of 5 mol% CuI in DMF at 150 1C, using
K2CO3 as base. 2-(2-(1H-Imidazol-1-yl)phenyl)imidazo[1,2-a]pyridine
Fig. 1 Structure of biologically active imidazo[1,2-a]pyridines.
(3a) was obtained in 80% yield (Scheme 1). When the catalyst
loading was increased to 10 mol%, the yield of 3a increased to 92%.
Notably the Ullmann type C–N coupling proceeded efficiently
without any external ligands. When 6-bromo-2-(2-bromophenyl)-
imidazo[1,2-a]pyridine (1b) was reacted with 2a under the opti-
mized reaction conditions, excellent regioselectivity was observed
for the C–N coupling and monosubstituted compound 2-(2-(1H-
imidazol-1-yl)phenyl)-6-bromoimidazo[1,2-a]pyridine (3b) was
Department of Chemistry, Birla Institute of Technology and Science, Pilani,
Pilani 333031, India. E-mail: anilkumar@pilani.bits-pilani.ac.in;
Fax: +91 1596 244183; Tel: +91 1596 515514
† Electronic supplementary information (ESI) available: General experimental
details, spectral data and copies of 1H and 13C NMR of 1a, 1d–f, 3a, 4a–m. See
DOI: 10.1039/c3cc39206f
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Table 1 Reaction condition optimization for one-pot synthesis of 4aa
Entry Catalyst
Oxidant
Base
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(PPh3)2Cl2 Cu(OAc)2 K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
61
41
75c
60
25
55
Pd(dppf)Cl2
Pd(OAc)2
Pd(PPh3)4
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Scheme 1 Coupling
of 2-(2-bromophenyl)imidazo[1,2-a]pyridines
with
imidazoles.
CuCl2
CuI
K2CO3
K2CO3
d
—
obtained in 85% yield. Formation of a disubstituted compound
by double C–N coupling by replacement of both bromides
was not observed, and we suspected that this was due to the
ortho-directing effect of the nitrogen atom in the imidazole
moiety of imidazo[1,2-a]pyridine. The directed ortho-cross
coupling strategy has been studied for the direct amination of
ortho-functionalized haloarenes.21,22
Cu(OAc)2 K2CO3
t-BuOOH K2CO3
Cu(OTf)2 K2CO3
Cu(OAc)2 NaOAc
Cu(OAc)2 Cs2CO3 DMF
Cu(OAc)2 Na2CO3 DMF
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
Cu(OAc)2 K2CO3
58
28
42
62
22
53
40
9
10
11
12
13
14
15
16
17
18
19
DMA
1,4-Dioxane 22
Toluene
DMSO
EDC
15
68
12
25
After optimizing the reaction conditions for the C–N
coupling, we performed a palladium-catalyzed coupling reac-
tion of 3a using 5 mol% of Pd(PPh3)2Cl2, 2 equiv. of Cu(OAc)2,
and 1.5 equiv. of K2CO3, in N,N-dimethylacetamide (DMA) at
150 1C. The reaction was completed in 1 h to give imidazo-
[1,2-a]pyrido[20,10:2,3]imidazo[4,5-c]quinoline (4a) in 55% isolated
yield. With these encouraging results in hand, we decided to
perform the C–N coupling and cross dehydrogenative coupling
reaction in a one-pot manner (Scheme 2). Thus we chose to add
the palladium catalyst to the reaction mixture containing the C–N
coupling product without isolation. When a reaction of 1a with 2a
was performed in the presence of 10 mol% of CuI, 1.5 equiv. of
K2CO3 in DMF solvent at 150 1C, followed by addition of 5 mol%
of Pd(PPh3)2Cl2, and 2 equiv. of Cu(OAc)2, 4a was obtained in 61%
isolated yield (Table 1,‡ entry 1). For optimization of reaction
conditions for the one-pot reaction a series of experiments were
conducted and the results are summarized in Table 1.
Xylene
a
Reaction conditions: 1a (1.00 mmol), 2a (1.20 mmol), CuI (0.10 mmol),
base (1.5 mmol), solvent (3.0 mL), 150 1C, 2 h, then [Pd] (0.05 mmol),
b
c
oxidant (1.2 mmol), 150 1C, 1 h. Isolated yields. Yield of 4a was 23%
when 2-(2-chlorophenyl)imidazo[1,2-a]pyridine was used instead of 1a.
d
Only 3a was formed.
By using the optimized reaction conditions as indicated in
entry 3 of Table 1, we evaluated the scope of the one-pot C–N
coupling and cross dehydrogenative coupling. Representative
products are illustrated in Scheme 3. In addition to the simple
imidazole 2a, other azoles such as 4-methylimidazole, benzimid-
azole, 1,2,4-triazoles, and 1H-imidazo[4,5-b]pyridine coupled with
1a to give the corresponding azole fused imidazo[1,2-a]pyridines
(4b–d, 4o) in good yields. Different imidazo[1,2-a]pyridine
Although the palladium catalysts Pd(dppf)Cl2, Pd(OAc)2,
Pd(PPh3)4, and Pd(dba)2 all gave the desired product, Pd(OAc)2
proved to be an ideal catalyst among these investigated (Table 1,
entry 3). It is also worth mentioning here that no designed ligand
was required for the dehydrogenative coupling with the palladium
catalyst under these conditions. Among different oxidants and
bases screened, the combination of Cu(OAc)2 and K2CO3 was
found to be the best choice for this reaction. Finally, the effect
of different solvents was also studied and it was observed that
better yields of 4a were obtained in polar aprotic solvents (e.g.
DMSO, DMA and DMF) compared to apolar solvents. DMF
proved to be the best solvent for this transformation (Table 1,
entry 1). The cross dehydrogenative coupling failed completely
when the reaction was carried out in the presence of Pd(OAc)2
but without Cu(OAc)2 (Table 1, entry 7), and only the C–N
coupled product 3a was observed. However, when reaction of 1a
and 2a was carried out using Cu(OAc)2 (1.2 equiv.) without CuI,
followed by addition of Pd(OAc)2 (5 mol%), 4a was obtained in
58% yield (Table 1, entry 8) in a reaction time of 10 h.
Scheme 2 One-pot synthesis of 4a.
Scheme 3 Synthesis of novel azole fused imidazo[1,2-a]pyridines.
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solution was purged with N2 and then stirred for 2 h at 150 1C. After 2 h,
Pd(OAc)2 (5 mol%) and Cu(OAc)2 (1.2 mmol) were added to the reaction
flask at the same temperature and the stirring was continued for an
additional 1 h. On completion of the reaction, the mixture was allowed
to cool to ambient temperature, diluted with water, and extracted with
ethyl acetate (2 ꢁ 10 mL). The organic layer was dried over anhydrous
Na2SO4 and the volatiles were evaporated. The crude compound was
purified by column chromatography on silica gel 100–200 mesh (EtOAc/
hexanes/Et3N).
derivatives such as 2-(2-bromophenyl)-6-methyl-imidazo[1,2-a]-
pyridine (1c), 2-(2-bromophenyl)-7-methyl-imidazo[1,2-a]pyridine
(1d), 2-(2-bromophenyl)-6-fluoroimidazo[1,2-a]pyridine (1e),
and 2-(2-bromophenyl)-6-chloroimidazo[1,2-a]pyridine (1f) could
also be employed to form the corresponding azole fused
imidazo[1,2-a]pyridines (4e–n, 4p) in good yields (62–78%). The
reaction with 2-(2-chlorophenyl)-imidazo[1,2-a]pyridine was
slow and only 23% of 4a was isolated when 2a was reacted with
2-(2-chlorophenyl)imidazo[1,2-a]pyridine under these reaction
conditions (Table 1, footnote c).
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initially CuI catalyzes the ortho-directed Ullman type C–N
coupling to give 3 which then undergoes double C–H activation
in the presence of the palladium(II) catalyst and Cu(OAc)2 as an
oxidant to give 4. The better catalytic activity of Pd(OAc)2 over
other palladium catalysts may be explained by the fact that the
palladium-bound acetate helps in deprotonation during the
C–H activation step. Ofial et al.23 have reported that palladium-
bound acetate plays an important role as a proton acceptor
during the second C–H bond cleavage in cross dehydrogenative
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In summary, we have successfully developed an efficient and
simple one-pot protocol for the synthesis of structurally
complex and novel azole fused imidazo[1,2-a]pyridines by
sequential Ullman-type C–N coupling and oxidative intra-
molecular C–C bond formation via double C–H activation or
CDC coupling. The scope and utility of the developed synthetic
route are general and further application of the protocol for
synthesis of novel heterocycles is in progress in our laboratory.
KP and PK are thankful to UGC, New Delhi and BITS Pilani
for research fellowship, respectively. We thank Prof. Amitabh
Jha, Department of Chemistry, Acadia University, Canada for
his kind support.
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‡ General procedure: to a solution of 1 (1 mmol) and 2 (1 mmol) in DMF
(3 mL) were added CuI (10 mol%) and K2CO3 (1.5 mmol) and the
c
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