Efficient access to 2,3-diarylimidazo[1,2-a ]pyridines via a one-pot, ligand-free, palladium-catalyzed three-component reaction under microwave irradiation

Article abstract of DOI:10.1021/ol501136e

An expeditious one-pot, ligand-free, Pd(OAc)₂-catalyzed, three-component reaction for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines was developed under microwave irradiation. With the high availability of commercial reagents and great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-diarylimidazo[1,2-a]pyridines analogues.

Full text of DOI:10.1021/ol501136e

Letter
pubs.acs.org/OrgLett
Efficient Access to 2,3-Diarylimidazo[1,2‑a]pyridines via a One-Pot,
Ligand-Free, Palladium-Catalyzed Three-Component Reaction under
Microwave Irradiation
Yuanxiang Wang, Brendan Frett, and Hong-yu Li*
Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United
States
The University of Arizona Cancer Center, Tucson, Arizona 85724, United States
S
* Supporting Information
ABSTRACT: An expeditious one-pot, ligand-free, Pd(OAc)2-catalyzed, three-component reaction for the synthesis of 2,3-
diarylimidazo[1,2-a]pyridines was developed under microwave irradiation. With the high availability of commercial reagents and
great efficiency in expanding molecule diversity, this methodology is superior to the existing procedures for the synthesis of 2,3-
diarylimidazo[1,2-a]pyridines analogues.
midazo[1,2-a]pyridines are extremely popular among
Ichemists and medicinal chemists due to their remarkable
biological and pharmacological activities1 such as anticancer,2
anti-inflammatory,3 antibacterial,4 antiprotozonal,5 antiviral,6
antiulcer,7 and antifungal.8 Within the imidazo[1,2-a]pyridine
family, several products have progressed to market, including
alpidem (anxiolytic),9 necopidem (anxiolytic),10 saripidem
(anxiolytic),11 zolpidem (insomnia),12 olprinone (cardioton-
ic),13 minodronic acid (bisphosphonate),14 divalpon (anxio-
lytic),15 and zolimidine (antiulcer).16
the best of our knowledge, there has never been a report of a
one-pot, ligand-free, palladium-catalyzed, three-component
reaction to afford 2,3-diarylimidazo[1,2-a]pyridines under
microwave irradiation.
Scheme 1. Methods for the Synthesis of 2,3-
Diarylimidazo[1,2-a]pyridines
The imidazo[1,2-a]pyridine derivatives, 2,3-diarylimidazo-
[1,2-a]pyridines also exhibit a wide range of biological
activities.17 In particular, medicinal chemists have focused on
the core structure to produce inhibitors18 for PI3K, p38, and
TGF-β kinases. Owing to the attractive biological properties
of 2,3-diarylimidazo[1,2-a]pyridines, a variety of strategies to
synthesize the core structure have been developed, focusing
on (1) condensation between 2-aminopyridines and 2-bromo-
1,2-diarylethanone;19 (2) Suzuki-type cross-coupling between
3-halo-2-arylimidazo[1,2-a]pyridines and arylboronic acid,20
and (3) copper-catalyzed conversion of pyridine to 2,3-
diarylimidazo[1,2-a]pyridines.21 Very recently, Pd-, Rh-, and
Cu- catalyzed direct C−H arylations of 2-arylimidazo[1,2-
a]pyridines at C-3 have been extensively studied (Scheme
1a).22 The transformation is completed in stepwise sequences
to afford 2,3-diarylimidazo[1,2-a]pyridines. Therefore, an
efficient synthetic methodology involving commercially
available and inexpensive starting materials is required to
expeditiously synthesize diverse 2,3-diarylimidazo[1,2-a]-
pyridines. In order to develop a convenient synthetic route
in conjunction with the possibility for rapid library
diversification, we were interested in conducting the two-
step cyclization/C−H arylation in one pot (Scheme 1b). To
2-Aminopyridine (1a), 2-bromo-1-phenylethanone (2a),
and 1-bromo-4-nitrobenzene (3a) were chosen as model
substrates to optimize the reaction conditions. We initiated
our studies by examining the influence of microwave
irradiation on the conversion using KOAc as the base and
10 mol % of Pd(OAc)2 as the catalyst. First, we carried out a
reaction in DMF at 100 °C under microwave irradiation for
30 min, but only trace amounts of product 4aaa were
detected (19% yield, Table 1, entry 1). Increasing the
temperature from 100 to 120 °C improved the yield to
36% (entry 2). A high yield of 66% was obtained with a
temperature of 160 °C (entry 4). Unfortunately, yields
decreased with higher temperatures (entries 5 and 6). The
yield was optimized to 84% by increasing the reaction time to
Received: April 19, 2014
© XXXX American Chemical Society
A
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Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
Pd(OAc)2 (mol %)
base
solvent
temp (°C), time
yield (%)
1
10
10
10
10
10
10
10
2
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
CsOAc
NaOAc
K2CO3
Cs2CO3
KOAc
KOAc
KOAc
KOAc
KOAc
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMAc
NMP
xylene
dioxane
butan-1-ol
100, 30 min
120, 30 min
140, 30 min
160, 30 min
170, 30 min
180, 30 min
160, 1 h
19
36
42
66
51
49
84
45
56
68
78
67
54
35
23
77
62
35
24
11
2
3
4
5
6
7
8
160, 1 h
9
4
160, 1 h
10
11
12
13
14
15
16
17
18
19
20
6
160, 1 h
8
160, 1 h
10
10
10
10
10
10
10
10
10
160, 1 h
160, 1 h
160, 1 h
160, 1 h
160, 1 h
160, 1 h
160, 1 h
160, 1 h
160, 1 h
a
b
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3a (2 mmol), base (2 mmol), solvent (6 mL). Isolated yield.
ab
,
1 h (entry 7). Then, the reaction was performed using
different catalyst loads (entry 8−11). In the presence of 8 mol
% of Pd(OAc)2, a yield of 78% was obtained and a significant
yield was lost with lower catalytic loads.
Scheme 2. Scope of Phenyl Bromides
A variety of bases were investigated, such as KOAc, CsOAc,
NaOAc, K2CO3, and Cs2CO3. KOAc was identified as the
best base (Table 1). Finally, our study focused on testing
various solvents, such as DMF, DMAc, NMP, xylene, dioxane,
and 1-butanol, and among them, DMF was found to be
superior (Table 1).
With the optimized reaction conditions in hand, we
evaluated the scope and limitations of the transformation.
We initially assessed the reactions of various aryl bromides
with 1a and 2a (Scheme 2). First, a series of para- or meta-
substituted electron-deficient aryl bromides were examined
under the optimized conditions, and the corresponding
products (4aaa−d) were produced in good to excellent
yields. Subsequently, disubstituted aryl bromides were
subjected to the reaction and transformation occurred
smoothly. The one-pot three component reaction also worked
well with bromopyridine or bromopyrimidine, leading to the
products (4aag−i) in good yields. Bromobenzene was also
successfully employed in the reaction to produce 4aaj in 72%
yield. It should be noted that electron-rich aryl bromides gave
slightly lower yields than electron-deficient systems, affording
the corresponding 4aak−m in 56−60% yields. Biphenyl
bromide and 4-bromoisoquinoline were also found to be
suitable partners, giving 4aan and 4aao in yields of 66% and
68%, respectively.
To further examine the efficiency of this one-pot reaction
and to rapidly expand our unique compound collection, we
extended the reaction scope to other 2-aminopyridines and 2-
(bromophenyl)ethanones. As shown in Scheme 3, we were
pleased to find that methyl substituted 2-aminopyridines could
be smoothly transformed into the desired products (4baa and
4caa in 83% and 78% yield, respectively). The electron-
withdrawing (−CN) substituent was well tolerated (4daa). To
our delight, when 2-bromo-1-(4-fluorophenyl)ethanone, 4-
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (2 mmol),
Pd(OAc)2 (10 mol %), KOAc (2 mmol), DMF (6 mL), microwave,
160 °C, 1 h. Isolated yield. Reaction time is 2 h.
b
c
B
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Organic Letters
Letter
Scheme 3. Scope of Aminopyridines and 2-
a b
,
Bromophenylethanones
a
Reaction conditions: 1a (1 mmol), 2a (1 mmol), 3 (2 mmol),
Pd(OAc)2 (10 mol %), KOAc (2 mmol), DMF (6 mL), microwave,
b
160 °C, 1 h; Isolated yield.
Figure 1. Computational modeling of 4bca (A) and 4bdh (B) in the
TGFβ-R1 kinase (PDB: 3FAA24). In both cases, a pyridine moiety
hydrogen bonds to the hinge with H283. 4bca creates a contact with
the conserved lysine, L232. Both compounds access a lipophilic
pocket to the left of L232. The hinge is shown in green, the DFG
motif is shown in purple, and the C-Helix is shown in orange.
Ligand/receptor interactions are denoted with black dotted lines.
(bromoacetyl)pyridine, and 2-(bromoacetyl)pyridine were
subjected to the reaction, the corresponding products
(4bba−bda) could be isolated in good to excellent yields
(Scheme 3).
The reaction is not limited to synthesis of 2,3-
diarylimidazo[1,2-a]pyridines. Under the same reaction
conditions, 2-chloroacetaldehyde was successfully coupled
with 1a and 3a to afford 2-arylimidazo[1,2-a]pyridine 6 in
65% yield (Scheme 4).
Table 2. TGFβ-R1 Computational Affinity and Drug
Properties
a
b
c
ΔG
Kd
tPSA
MW
Scheme 4. Synthesis of 3-(4-Nitrophenyl)imidazo[1,2-
a]pyridine via the One-Pot Procedure
c
compd
(kcal/mol)
(nM)
CLogP
(Å2)
(g/mol)
4bca
4bdh
−10.4
−9.2
23.3
3.8
2.8
79.8
40.3
330
286
177.3
a
b
Calculated with Autodock Vina. Calculated from ΔG using Kd =
c
e−ΔG/RT at 298 K. Calculated with ChemDraw.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedure and characterization of all compounds
and modeling procedures of compounds 4 and 6. This
material is available free of charge via the Internet at http://
pubs.acs.org.
We also prepared compounds 4bca and 4bdh in yields of
77% and 75%, which have been found to be active on the
TGFβ-R1 kinase through a high-throughput computational
screen (Figure 1).23 Interestingly, both compounds are
predicted to bind the kinase in a similar fashion to known
TGFβ-R1 inhibitors (Figure 1)24 and have calculated
properties with druglike space (Table 2).
In summary, we have developed an expeditious one-pot
procedure to access 2,3-diarylimidazo[1,2-a]pyridines via a
ligand-free, palladium-catalyzed, microwave-assisted three-
component reaction. In addition, the availability of reagents
and ease in expanding molecule diversity make the developed
methodology operationally proficient and can facilitate rapid
library construction. Further efforts to therapeutically evaluate
the synthesized compounds are underway and will be
reported in due course.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hongyuli@pharmacy.arizona.com.
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
The authors declare no competing financial interest.
C
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Organic Letters
Letter
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ACKNOWLEDGMENTS
■
This work was supported by a training grant from The
National Institutes of Health (T32 GM008804), University of
Arizona startup funding, and The Caldwell Health Sciences
Research Fellowship.
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