An unprecedented Pd-catalyzed decarboxylative coupling reaction of aromatic carboxylic acids in aqueous medium under air: Synthesis of 3-aryl-imidazo[1,2-a]pyridines from aryl chlorides

Article abstract of DOI:10.1039/c5ob02112j

An efficient and practical protocol for palladium-catalyzed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic acids with aryl chlorides has been developed. Note that the reaction could proceed smoothly without an additive in aqueous medium under an ambient atmosphere, and the addition of H₂O could effectively promote the decarboxylative arylation. Particularly noteworthy is that these results represent the first examples of Pd-catalyzed decarboxylative coupling reactions of (hetero) aromatic carboxylic acids in aqueous medium under air, and the first successful examples of the synthesis of 3-aryl-imidazo[1,2-a]pyridines using cheap, diverse aryl chlorides and heteroaryl chlorides as the starting materials.

Full text of DOI:10.1039/c5ob02112j

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A Unprecedented Pd-catalyzed Decarboxylative Coupling Reaction
of Aromatic Carboxylic Acids in Aqueous Medium under Air:
Synthesis of 3-Aryl-imidazo[1,2-a]pyridines from Aryl Chlorides
Received 00th January 20xx,
Accepted 00th January 20xx
Bing Mu,a, b Yusheng Wu,* a, c, e Jingya Li,c, d Dapeng Zou,a Junbiao, Changa and Yangjie Wua
DOI: 10.1039/x0xx00000x
An efficient and practical protocol for palladium-catalyzed decarboxylative arylation of imidazo[1,2-a]pyridine-3-carboxylic
acids with aryl chlorides has been developed. Note that the reaction could proceed smoothly without the additive in
aqueous medium under ambient atmosphere, and the addition of H2O could effectively promote the decarboxylative
arylation. Particularly noteworthy is that these results represent the first examples of Pd-
catalyzed decarboxylative coupling reactions of (hetero) aromatic carboxylic acids in aqueous medium under air, and the
first successful examples of the synthesis of 3-aryl-imidazo[1,2-a]pyridines using cheap, diverse aryl chlorides and
heteroaryl chlorides as the starting materials.
www.rsc.org/
Introduction
preactivation of organoboron nucleophiles and aryl
iodides/aryl bromides that are often not commercially
Imidazo[1,2-a]pyridines are one of the most important
classes of organic compounds due to the abundance of the
imidazo[1,2-a]pyridine structural motif in agrochemical,1
functional materials,2 and pharmaceutical products.3 In
particular, 3-arylimidazo[1,2-a]pyridines show excellent
antiinflammatory,4 anticancer,5 antiprotozonal,6 antibacterial,7
antiulcer,8 antiviral,9 and antifungal activities.10 Owing to the
attractive biological properties of 3-arylimidazo[1,2-a]pyridine
available and severe environmental problems. Very recently, a
more streamlined and attractive strategy is established in
which the reaction can proceed via C-H arylations of
imidazo[1,2-a]pyridines at C-3,23 but these reactions were
usually performed efficiently in dry organic solvents under
nitrogen atmosphere, and the substrate scope is mainly
limited to aryl iodides/bromides or C2-substituted imidazo[1,2-
a]pyridines.24-29
derivatives,
a variety of synthetic strategies have been
developed for the construction of 3-arylimidazo[1,2-a]pyridine
scaffolds. The traditional route to 3-arylimidazo[1,2-
a]pyridines such as the condensation between 2-
aminopyridines and 2-bromo-1,2-diarylethanone,11-14 and
In the past few years, a rapidly growing number of the
decarboxylative coupling reactions as a new synthetic strategy
have been reported that give access to various valuable
product classes,30-33 since carboxylic acids have distinguishing
features of solid-state without pungent smell, non-toxicity, low
cost, ready availability, easy storage, transport and handle.34-37
However, Pd-catalyzed decarboxylative coupling reactions of
(hetero) aromatic carboxylic acids in aqueous medium under
air have not been reported, as far as we know. Therefore, Pd-
oxidative
coupling
of
2-aminopyridine
with
nitroalkenes15/alkyne16/chalcone17, usually suffers from the
prior preparation of original materials and the limited
substrate scope, thus restraining the applications of these
methodologies. Additionally Suzuki-type cross-coupling
between 3-halo-2-arylimidazo[1,2-a]pyridines and arylboronic
acid, is also important strategy for the synthesis of these
derivatives.18-22 However, the reaction usually need the
catalyzed decarboxylative coupling reactions
in
aqueous
solvent would be rich in challenges. To the best of our
knowledge, the decarboxylative coupling of imidazo[1,2-
a]pyridine-3-carboxylic acids with aryl halides was only
reported by Lee on the syntheses of 3-arylimidazo[1,2-
a]pyridine derivatives.38 The method suffers from significant
moisture and air sensitivity, and the substrate scope is mainly
limited to arylbromides.
aThe College of Chemistry and Molecular Engineering, Zhengzhou University,
Zhengzhou, PR China.
bThe College of Chemistry and Chemical Engineering, Zhengzhou Normal University,
Zhengzhou 450044, PR China.
cCollaborative Innovation Center of New Drug Research and Safety Evaluation,
Henan Province.
dTetranov Biopharm, LLC, 75 Daxue Road, Zhengzhou, PR China.
eTetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ
08901, USA.
Therefore, a catalyst system which allows the construction
of C2-unsubstituted 3-arylimidazo[1,2-a]pyridine derivatives in
aqueous medium under air, and makes the coupling partner
more economical and practical is still in demand since such
E-mail: yusheng.wu@tetranovglobal.com; Fax: +1 732 253 7327; Tel: +1 732 253
7326
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Table 1. Optimization of the reaction conditions.a
N
N
N
solvent, ligand
N
Cl
+
Pd(OAc)2, K2CO3
COOH
3a
Entry
1 d, e
2 e
3 d
4
5
6
7
8
Ligand
Solvent
DMA
DMA
DMA
DMA
Temp (oC)
160
Yield (%) b
91 c
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
PCy3
160
160
160
150
150
150
110
52
61
70
26
20
Trace
Trace
DMA
DMF
DMSO
Dioxane
DMA/H2O
(40/1)
DMA/H2O
(3/1)
Xylene/H2O
(1/1)
DMA/H2O
(40/1)
DMA/H2O
(40/1)
DMA/H2O
(40/1)
DMA/H2O
(40/1)
DMA/H2O
(40/1)
9
PCy3
PCy3
150
150
120
150
150
150
150
140
67
5
10
11
PCy3
NR
81
12
S-Phos
S-Phos
X-Phos
Ru-Phos
S-Phos
100
13f
14f
15f
16f
(96 c)
59
30
11
a
Reaction conditions: 0.3 mmol of imdazol[1,2-a]pyridine-3-carboxylic acid, 0.9
mmol of chlorobenzene, 0.9 mmol of K2CO3, 5 mol% of Pd(OAc)2, 6 mol% of ligand,
and 4 mL of solvent under air for 24 h. b GC yields. c Isolated yields.
d
0.15mmol of Cu2O. e 4 mL of dry DMA, 200 mg of 4 Å molecular sieve, under
nitrogen. f 7.5 mol% of ligand.
catalyst system has the potential to be used in industrial
process. In continuing our former works on palladium- Table 1. To make our present methodology more convenient
catalyzed decarboxylative cross-coupling reactions,39 herein, and practical, we initiated our studies by examining the
we attempt to develop a convenient and efficient protocol for influence of moisture and air on the conversion. First, we
the synthesis of 3-aryl-imidazo[1,2-a]pyridines in aqueous performed the reaction in dry DMA under nitrogen in the
medium under air via palladium-catalyzed decarboxylative presence of 0.5 equiv of Cu2O at 160 °C, and the desired
coupling of imidazo[1,2-a]pyridine-3-carboxylic acids with product was obtained in 91% isolated yield (entry 1). With the
cheap aryl/heteroaryl chlorides.
same reaction conditions above, only 52% GC yield was
obtained in the absence of Cu2O (entry 2). Then, we carried
out the reaction in DMA under air at 160 °C with Cu2O, and the
desired coupling product was obtained in 61% yields (entry 3).
However, the yields increased slightly without Cu2O in 70%
yield, indicating that the addition of Cu2O is not necessary
under air (entry 4). Lowering the reaction temperature to 150
Results and discussion
The decarboxylative cross-coupling reaction of imidazo[1,2-
a]pyridine-3-carboxylic acid with chlorobenzene was chosen as
model reaction to optimize the reaction conditions as shown in
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°C led to poor substrate conversion (entry 4 vs entry 5). Scheme 1. Decarboxylative arylation of imidazo[1,2-a]pyridine-
Subsequently, the effects of different solvents were tested at 3-carboxylic acid with aryl chlorides a, b
150 °C, and no improvement of the yield was observed (entries
6-8).To our delight, the yields significantly changed with the
addition of H2O to these catalytic systems (entry 9). However,
when the reaction was conducted in DMA/H2O (3:1), only
trace amounts of product 3a were detected (entry 10).
Obviously, DMA/H2O (40:1) as the solvent is best choice for
this reaction (entries 5-11). Then, a variety of bases were
investigated, such as K2CO3, Na2CO3, KOAc, K3PO4·7H2O, Cs2CO3
and KOtBu (see Table S1 in Supporting Information). K2CO3 was
identified as the best base. Other ligands such as S-Phos, X-
Phos, Ru-Phos were also screened (Figure 2), and obviously, S-
phos was more effective than the other ligands in this reaction
affording a 96% isolated yield (entries 12-15). Finally, the
replacement of Pd(OAc)2 with PdCl2, Pd2(dba)3, Pd(acac)2 or
Pd(CF3CO2)2 leads to a drop in yield (see Table S1 in Supporting
Information).
PCy2
iPr
P
PCy2
OMe
PCy2
OiPr
iPr
iPrO
MeO
iPr
Ru-Phos
X-Phos
PCy3
S-Phos
Figure 1. Various ligands used in Pd-catalyzed decarboxylative
arylation
With the optimized conditions in hand, the scope of the
coupling of aryl chlorides with imidazo[1,2-a]pyridine-3-
carboxylic acid is summarized in Scheme 1. The para-
substituted aryl chlorides such as 4-chlorotoluene, 4-
chloroanisole or 4-chloroacetanilide gave the corresponding
products in 94-96% yields (products 3b, 3e and 3g). Electron-
deficient aryl chlorides such as 4-chloroacetophenone or 4-
chloronitrobenzene gave the coupling product in 75 and 70%
yields, respectively (products 3m and 3n). 4-Chloroaniline and
1-chloronaphthalene was also found to be suitable coupling
partner, and gave the product in 59% and 66% yields,
respectively (products 3k, 3l). For meta or ortho-substituted
aryl chlorides such as 2-chloroanisole, 3-chloroacetanilide, 2-
chloroacetanilide or 3-chloroaniline, products 3f, 3h-j were
obtained in slightly lower yields of 53-73%. Notably, the
sterically hindered 2-chlorotoluene and 3-chlorotoluene also
proceeded smoothly, giving the desired arylation products 3d
and 3c in 88% and 99% yields, respectively. Moreover,
heteroaromatic chlorides such as 4-chloropyridine and 3-
chloropyridine were also reactive partners in this coupling to
give the product in 94 and 77% yields, respectively (products
3o and 3p). Subsequently, the scope of imidazo[1,2-a]pyridine-
3-carboxylic acids was also explored, and the results are
summarized in Scheme 1. For example, 2-methyl, 2-phenyl and
2,8-dimethyl imidazo[1,2-a]pyridine-3-carboxylic acids could
be efficiently converted into the corresponding products in
good yields (products 3r-3t). However, 6-fluoroimidazo[1,2-
a]pyridine-3-carboxylic acid had a relatively lower reactivity,
a
Reaction conditions: 0.3 mmol of imdazol[1,2-a]pyridine-3-
carboxylic acid, 0.9 mmol of aryl chlorides, 0.9 mmol of K2CO3,
5 mol% of Pd(OAc)2, 7.5 mol% of S-Phos, 4 mL of DMA, and 0.1
c
mL of H2O at 150 °C under air for 24 h. Isolated yields. 6.2
b
d
mmol (1.0 g) of imdazol[1,2-a]pyridine-3-carboxylic acid.
Without aryl chlorides.
only affording the product in moderate yield (product 3u). To
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demonstrate the scalability of the reaction, we chose the intermediate II and carboxylic acid anion which was generated
decarboxylative reaction of imidazo[1,2-a]pyridine-3- by the reaction of carboxylic acid and K2CO3 could occur to
carboxylic acid with chlorobenzene on a 1.0 g scale. The afford intermediate III. After the intermediate III underwent
desired product was isolated in 85% yield (product 3a).
the decarboxylative reaction to release one molecular CO2 to
form the intermediate IV, the reductive elimination of the
intermediate IV would afford the corresponding products (3)
and regenerate the catalytically active catalyst Pd(0)L2 to fulfill
the catalytic cycle.
Scheme 2. Comparative experiments of different reaction
conditions
Scheme 3. Proposed mechanism of palladium-catalyzed
decarboxylative arylation
N
N
N
K2CO3
COOH
Pd(OAc)2 +
N
N
N
2+ O2C
CO2 Pd
N
CO2
N
N
N
N
Pd
N
N
N
L = S-Phos
N
N
Pd(0)L2
ArCl
2
Ar
Finally, the investigation was aimed at revealing the
decarboxylative
arylation
of
imidazo[1,2-a]pyridine-3-
N
carboxylic acid as shown in Scheme 2. With the optimized
conditions, the decarboxylative arylation of imidazo[1,2-
a]pyridine-3-carboxylic acid with chlorobenzene gave the
product in 96% yield, but the direct arylation of imidazo[1,2-
a]pyridine with chlorobenzene was still very sluggish, affording
only a 34% GC yield of the arylation product. Under the same
conditions without added aryl chlorides, imidazo[1,2-
a]pyridine from hydrodecarboxylation of imidazo[1,2-
a]pyridine-3-carboxylic acid was not also detected for 2 h, and
decarboxylative homocoupling of imidazo[1,2-a]pyridine-3-
carboxylic acid was proformed in 98% yield for 24 h. On the
N
Ar
Cl
PdL2
L2Pd
Ar
N
CO2
N
COOK
K2CO3
Ar
PdL2
N
N
N
O
KCl
N
C
O
1
COOH
38
basis of the previous reports, the decarboxylative arylation
of
imidazo[1,2-a]pyridine-3-carboxylic
acid
with
bromobenzene gave the product in 73% yield for 24 h, and
without added aryl chlorides imidazo[1,2-a]pyridine from
hydrodecarboxylation of imidazo[1,2-a]pyridine-3-carboxylic
acid was afforded in high yield of 99% for 2 h. The results
indicated that the arylation products of imidazo[1,2-
a]pyridine-3-carboxylic acid were generated not by the
hydrodecarboxylation in our catalytic system.
Experimental
General Procedure for Palladium-catalyzed decarboxylative
arylation of imidazo[1,2-a]pyridine-3-carboxylic acid with aryl
chlorides
Imidazo[1,2-a]pyridine-3-carboxylic acid (0.3 mmol), aryl
chloride (0.9 mmol, 3 equiv), K2CO3 (0.9 mmol, 3 equiv),
Pd(OAc)2 (5 mol %) and S-phos (7.5 mol %) were added to a 10
mL round-bottomed flask, and then a mixed solvent of 4.0 mL
of DMA and 0.1 mL of H2O was added. The mixture was stirred
at 150 °C for 24 h under air. After the reaction was complete,
the mixture was washed with water and extracted with ethyl
acetate three times. The combined organic layer was dried
with anhydrous MgSO4 and filtered. The filtrate was
concentrated in vacuo. The crude product was purified by flash
chromatography on silica gel using ethyl acetate or
hexane/ethyl acetate as the eluent to give the pure product.
On the basis of the above-mentioned results, a possible
mechanism of palladium-catalyzed decarboxylative arylation is
outlined in Scheme 3. The first step would be the release of
Pd(0) species from Pd(OAc)2, which is possibly through ligand-
exchange of imidazo[1,2-a]pyridine-3-carboxylic acid with
acetic acid anion followed by the decarboxylative reaction and
reductive elimination to afford the homocoupling product and
the catalytically active Pd(0)L2 (I) with the assist of phosphine
ligand. Then, the oxidative addition of aryl chloride (2) to
Pd(0)L2 would take place to form the intermediate II.
Subsequently, the ligand-exchange reaction between
4 | J. Name., 2012, 00, 1-3
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The products were characterized by 1H NMR, 13C NMR, m.p.,
MS and HRMS.
12 J. G. Kettle, S. Brown, C. Crafter, B. R. Davies, P. Dudley,
G. Fairley, P. Faulder, S. Fillery, H. Greenwood, J.
Hawkins, M. James, K. Johnson, C. D. Lane, M. Pass, J.
H. Pink, H. Plant and S. C. Cosulich, J. Med. Chem.,
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Conclusions
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In conclusion, we have developed an efficient and facile
protocol for the synthesis of 3-aryl-imidazo[1,2-a]pyridines via
palladium-catalyzed decarboxylative arylation of imidazo[1,2-
a]pyridine-3-carboxylic acids with aryl chlorides. It is worth
noting that the reaction proceeded smoothly without the
additive in aqueous medium under ambient atmosphere, and
the scope of the substrate could be extended to electron-poor,
electron-neutral, electron-rich, even sterically hindered aryl
chlorides and aromatic heterocyclic chlorides. Remarkably, the
decarboxylative arylation was quite effectively promoted by
the addition of H2O. This economical and practical synthetic
protocol for 3-arylimidazo[1,2-a]pyridines may have wide
applications to the industrial process in the future.
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Acknowledgements
We are grateful to the Research Program of Fundamental
and Advanced Technology of Henan Province (122300413203),
Technology Research and Development Funds of Zhengzhou
(141PRCYY516), Postdoctoral Science Foundation of Henan
Province (2014003), and the Science and Technology
Foundation of Zhengzhou Science and Technology Bureau
(131PPTGC419-3) for financial support.
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