Copper-catalyzed decarboxylative three-component reactions for the synthesis of imidazo[1,2-a]pyridines

Article abstract of DOI:10.1002/ejoc.201200679

Imidazo[1,2-a]pyridine derivatives were synthesized through multicomponent coupling reactions of 2-aminopyridines, aldehydes, and alkynecarboxylic acids in the presence of 10 mol-% CuI/Cu(OTf)₂. Both aryl- and alkyl-substituted alkynecarboxylic acids, including propiolic acid, were good alkyne sources and afforded the desired imidazo[1,2-a]pyridines in good yields through the decarboxylative coupling reactions. Arylalkynecarboxylic acids were synthesized through palladium-catalyzed coupling reactions between aryl iodides and propiolic acid and reacted with 2-aminopyridine and aldehydes, with or without a purification step. In both cases the desired imidazo[1,2-a]pyridines were obtained in good yields. Mechanistic studies suggested that in the case of propiolic acid the decarboxylative addition predominates over terminal alkyne addition. Imidazo[1,2-a]pyridine derivatives were synthesized through three-component coupling reactions of 2-aminopyridines, aldehydes, and alkynecarboxylic acids in the presence of 10 mol-% CuI/Cu(OTf)₂ Copyright

Full text of DOI:10.1002/ejoc.201200679

Job/Unit: O20679
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FULL PAPER
DOI: 10.1002/ejoc.201200679
Copper-Catalyzed Decarboxylative Three-Component Reactions for the
Synthesis of Imidazo[1,2-a]pyridines
Thiruvengadam Palani,[a] Kyungho Park,[a] Manian Rajesh Kumar,[a] Hyun Ming Jung,[b]
and Sunwoo Lee*[a]
Keywords: Nitrogen heterocycles / Multicomponent reactions / Copper / Alkynes
Imidazo[1,2-a]pyridine derivatives were synthesized through
multicomponent coupling reactions of 2-aminopyridines, al-
dehydes, and alkynecarboxylic acids in the presence of
10 mol-% CuI/Cu(OTf)2. Both aryl- and alkyl-substituted alk-
ynecarboxylic acids, including propiolic acid, were good alk-
yne sources and afforded the desired imidazo[1,2-a]pyridines
in good yields through the decarboxylative coupling reac-
tions. Arylalkynecarboxylic acids were synthesized through
palladium-catalyzed coupling reactions between aryl iodides
and propiolic acid and reacted with 2-aminopyridine and al-
dehydes, with or without a purification step. In both cases
the desired imidazo[1,2-a]pyridines were obtained in good
yields. Mechanistic studies suggested that in the case of pro-
piolic acid the decarboxylative addition predominates over
terminal alkyne addition.
Introduction
Heteroaromatic compounds containing nitrogen atoms
are very important fragments in pharmacological and elec-
tromaterial molecules.[1] Among them, imidazopyridine de-
rivatives have been widely used as core structures in drug
discovery, their ring system being encountered in molecules
showing bioactivity such as antiviral,[2] antibacterial,[3] anti-
inflammatory,[4] and antiviral behavior.[5] In particular, im-
idazo[1,2-a]pyridine (Figure 1) is a key structure in anxi-
olytic agents (alpidem)[6] and in drugs used for the treat-
ment of insomnia (zolpidem),[7] osteoporosis (minodronic
acid),[8] and heart failure (olprinone).[9] In addition, imid-
azo[1,2-a]pyridine derivatives have received considerable at-
tention as core ligands in the field of electronic devices.[10]
The numerous synthetic methods for constructing the
core ring system include condensation of 2-aminopyridine
with carbonyl compounds and cyclization of the resulting
intermediates (Scheme 1, a and b).[11] These methods, how-
ever, have some drawbacks, such as the need to prepare the
carbonyl compounds. To address this problem, three-com-
ponent reactions of 2-aminopyridine, aldehydes, and mole-
cules containing triple bonds, such as isonitriles or alkynes,
have been developed (Scheme 1, c)[12] Although this one-
Figure 1. Imidazo[1,2-a]pyridine-based molecules.
pot approach is a straightforward way to obtain the imid-
azo[1,2-a]pyridine derivative, it has some drawbacks in
cases of low-molecular-weight alkynes and arylalkynes.
Using low-molecular-weight alkynes is very difficult in a
general organic laboratory.
Special equipment is required, for example, for the hand-
ling of acetylene gas in the synthesis of 3-methylimid-
azo[1,2-a]pyridine through a three-component reaction. Al-
ternative methods such as the condensation of carbonyl
compounds,[13] Suzuki coupling,[14] and hydroamination[15]
have been reported, but all need multi-step procedures for
the preparation of the starting materials. Even when aryl-
alkynes have been used as starting materials they have also
required multi-step reactions such as the Sonogashira reac-
[a] Department of Chemistry and Institute of Basic Science, Chon-
nam National University, Gwangju 500-757, Republic of South
Korea
Fax: +82-62-530-3389
E-mail: sunwoo@chonnam.ac.kr
Homepage: http://altair.chonnam.ac.kr/~sunwoo
[b] Department of Applied Chemistry, Kumoh National Institute
of Technology,
Gumi, 730-701, Republic of Korea
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200679.
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FULL PAPER
Table 1. Optimized conditions for the synthesis of the imidazo[1,2-
a]pyridine 4aa.[a]
Entry Catalyst
Additive[b] Base
Solvent Yield [%][d]
1
2
3
4
5
6
7
8
Pd(OAc)2
Ni(OAc)2
FeCl3
CuCl
CuBr
CuI
Cu(OAc)2
Cu(OTf)2
CuI
CuI
CuI
CuI
CuI
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
DMSO
DMSO
DMSO
DMSO 22
DMSO 23
60
–
–
–
46
58
9
Cu(OAc)2
Cu(OTf)2
TMEDA
phenanth[c]
–
DMSO 64
DMSO 85
DMSO 15
10
11
12
13
14
15
16
17
18
19
DMSO
5
Cs2CO3 DMSO 80
K3PO4
–
–
–
–
–
CuI
CuCl
CuI
CuI
CuI
–
DMSO 81
DMSO 80
DMF
NMP
toluene
diglyme trace
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
43
34
3
Scheme 1. Syntheses of imidazo[1,2-a]pyridines from 2-aminopyr-
idine.
CuI
[a] Reaction conditions:
1 (0.3 mmol), 2a (0.36 mmol), 3a
(0.36 mmol), and catalyst (0.03 mmol) were allowed to react in sol-
vent (1.0 mL) at 110 °C for 16 h. [b] 0.03 mmol of additive was
used. [c] 1,10-Phenanthroline. [d] Determined by GC with internal
standard.
tion and deprotection for their preparation. A simpler and
more general method therefore needs to be developed.
We have recently reported decarboxylative coupling reac-
tions with aryl halides and alkynecarboxylic acids for the
first time,[16] and have developed an efficient one-pot
method for synthesizing arylalkynecarboxylic acids from
aryl halides.[17]
To extend these reaction methods, we attempted to use
alkynecarboxylic acids as alkyne sources in multicompo-
nent coupling reactions. Alkynecarboxylic acids have three
advantages as alkyne sources: 1) stable storage and ease of
handling, 2) they are very good surrogates for alkynes of
lower molecular weight, such as acetylene, propyne, and bu-
tyne, which are basically gases at room temperature,[18] and
3) in the case of arylalkynecarboxylic acids they are easily
synthesized through coupling reactions of a variety of aryl
iodides and propiolic acid.[17] Here we report one-pot syn-
theses leading to imidazo[1,2-a]pyridines through multi-
component couplings of 2-aminopyridines, aldehydes, and
alkynecarboxylic acids.
Use of copper(II) complexes such as Cu(OAc)2 and
Cu(OTf)2 afforded the desired product in 46% and 58%
yields, respectively (Entries 7 and 8). When combinations of
CuI and the copper (II) complexes Cu(OAc)2 and Cu-
(OTf)2 were used, the yields were increased (Entries 9 and
10). The addition of chelating amines as ligands afforded
lower product yields (Entries 11 and 12). However, the use
of two inorganic bases – Cs2CO3 and K3PO4 – gave 80%
and 81% yields, respectively (Entries 13 and 14). When the
combination of CuCl and Cu(OTf)2, previously reported by
Gevorgyan,[12f] was used as a catalyst in this three-compo-
nent reaction with propiolic acid the yield was similar to
that obtained with CuI and Cu(OTf)2 (Entry 15). Other sol-
vents were tried instead of DMSO, but showed lower yields
(Entries 16–19). Finally, we determined the following opti-
mized conditions for the synthesis of imidazo[1,2-a]pyridine
4aa:
2-aminopyridine
(1.0 equiv.),
benzaldehyde
(1.2 equiv.), propiolic acid (1.2 equiv.), CuI (10 mol-%) and
Cu(OTf)2 (10 mol-%) in DMSO at 110 °C for 16 h.
To evaluate these optimized conditions further, we next
Results and Discussion
To address the problems inherent in previously reported used a variety of aldehydes in coupling reactions with 2-
methods, we used propiolic acid as an alkyne source and aminopyridine and propiolic acid. The results are summa-
coupled it with 2-aminopyridine and benzaldehyde. Our rized in Table 2. As expected, benzaldehyde produced an
attempts to optimize the conditions for the synthesis of the isolated yield of the desired product 4aa of 81% (Entry 1).
imidazo[1,2-a]pyridine 4aa are summarized in Table 1. As Alkyl-substituted benzaldehydes such as tolualdehydes and
catalysts, palladium, nickel, and iron did not show any ac- 4-tert-butylbenzaldehyde showed good yields (Entries 2–4).
tivity (Entries 1–3). Of the various copper(I) complexes, 2-Chlorobenzaldehyde, 4-chlorobenzaldehyde, and 3-fluo-
CuI showed the best yield (Entry 6).
robenzaldehyde afforded the corresponding imidazo[1,2-a]-
2
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Synthesis of Imidazo[1,2-a]pyridines
Table 2. Synthesis of imidazo[1,2-a]pyridines from 2-aminopyr- carboxaldehyde and furfural showed 65% and 68% yields,
idine, different aldehydes, and propiolic acid.[a]
respectively (Entries 8 and 9). Salicylaldehyde, which con-
tains a hydroxy group, also gave the desired product in 55%
yield (Entry 10). Aldehydes bearing ether and thioether
groups showed good yields (Entries 11 and 12). 6-Methoxy-
2-naphthaldehyde produced a 61% yield of the product
(Entry 13). In addition, cyclohexanecarboxaldehyde as a
representative alkanecarbaldehyde successfully afforded the
desired imidazo[1,2-a]pyridine in 70% yield (Entry 14).
We next expanded this reaction system to a variety of
alkynecarboxylic acids; the results are summarized in
Table 3. All of the alkynecarboxylic acids reacted as alkyne
sources through decarboxylation to produce the corre-
sponding imidazo[1,2-a]pyridines.
Phenylpropiolic acid produced 3-benzyl-2-phenylimid-
azo[1,2-a]pyridine (4ab) in 85% yield. 4-Substituted aryl-
alkynecarboxylic acids afforded the corresponding products
4ac, 4ad, 4ae, and 4af in 80%, 71%, 65%, and 71% yields,
respectively. 3-(Thiophen-2-yl)propiolic acid and 3-(2-naph-
thyl)propiolic acid afforded 4ag and 4ah in 61% and 63%
yields, respectively. When alkyl alkynecarboxylic acids such
as hept-2-ynoic acid and butynoic acid were used as the
alkyne sources, the desired products 4ai and 4aj were ob-
tained in 56% and 31% yields, respectively. When 4-tolu-
aldehyde was used instead of benzaldehyde, similar yields
were obtained (4cc and 4ci). In addition, substituted 2-ami-
nopyridines also produced the desired imidazo[1,2-a]pyr-
idines 4aa-1 and 4aa-2 in moderate to good yields. In no
case did we find the decarboxylative/carboxylative cyclized
products recently reported by Van der Eycken.[19]
In view of the success of the decarboxylative couplings
of alkynecarboxylic acids for the synthesis of imidazo[1,2-
a]pyridines, we attempted to use in situ preparation of aryl-
alkynecarboxylic acids through palladium-catalyzed cou-
pling of aryl iodides and propiolic acid. Coupling of aryl
iodides and propiolic acid was first conducted in the pres-
ence of DBU, [Pd(PPh)3]2Cl2, and CuI at room tempera-
ture, and provided the desired arylalkynecarboxylic ac-
ids.[20]
Next, 2-aminopyridine, benzaldehyde, and Cu(OTf)2
were added to the resulting reaction mixture without any
isolation step and the reaction was allowed to proceed at
110 °C. The results are summarized in Table 4. As expected,
all aryl iodides afforded the desired imidazo[1,2-a]pyridines
in moderate to good yields. Phenyl iodide (5a) provided 3-
benzyl-2-phenylimidazopyridine (6a = 4ab) in 85% yield,
which is almost the same as had been obtained from the
reaction of phenylpropiolic acid (Entry 1). ortho-, meta-,
and para-tolyl iodides afforded the corresponding imid-
azo[1,2-a]pyridines in 65%, 67%, and 82% yields, respec-
tively (Entries 2–4). Iodoanisoles and 4-tert-butylphenyl
iodide also produced the desired products (Entries 5–7).
Aryl iodide 5h, containing a keto group, gave the corre-
sponding imidazo[1,2-a]pyridine in 45% yield (Entry 8).
Halo-substituted, heteroaryl, and 1-naphthyl iodides
showed 64%, 59%, and 57% yields, respectively (Entries 9–
[a] Reaction conditions: 1 (3.0 mmol), 2 (3.6 mmol), 3a (3.6 mmol),
CuI (0.3 mmol), and Cu(OTf)2 (0.3 mmol) were allowed to react in
DMSO (6.0 mL) at 110 °C for 16 h. [b] Isolated yield.
pyridines in 60%, 71%, and 63% yields, respectively 11). These yields were similar to those obtained from the
(Entries 5–7). Heteroaromatic aldehydes such as pyridine-2- reactions of the corresponding arylalkynecarboxylic acids.
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T. Palani, K. Park, M. R. Kumar, H. M. Jung, S. Lee
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Table 3. Synthesis of imidazo[1,2-a]pyridines from 2-aminopyridines, aldehydes, and alkynecarboxylic acids.[a]
[a] Reaction conditions: 1 (3.0 mmol), 2 (3.6 mmol), 3a (3.6 mmol), CuI (0.3 mmol) and Cu(OTf)2 (0.3 mmol) were allowed to react in
DMSO (6.0 mL) at 110 °C for 16 h.
The two potential reaction sites in propiolic acid are the
terminal alkynyl carbon and the decarboxylative carbon.
To investigate the main reaction site, we conducted several
experiments in the presence of D2O.[21,22] As shown in
Scheme 2, when phenylacetylene was treated with 2-amino-
pyridine and C6H5CDO in the presence of D2O, the dideu-
terated product 4ab-2D was formed in 53% yield, whereas
in the absence of D2O the monodeuterated product 4ab-D
was formed in 65% yield.[22] These results suggest that one
of the benzylic protons comes from the aldehyde and the
other from water.
We next treated propiolic acid, C6H5CDO, and 2-amino-
pyridine in the presence of D2O.[21] 3-Methyl-2-phenylimid-
azo[1,2-a]pyridine and deuterated analogues were isolated
1
in 73% combined yield, as shown in Scheme 3. H NMR Scheme 2. Deuterium exchange experiments with phenylacetylene.
4
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Synthesis of Imidazo[1,2-a]pyridines
Table 4. Synthesis of imidazo[1,2-a]pyridines from 2-amino- deconvolution data analysis showed that the dideuterated
pyridines, aldehydes, aryl iodides, and propiolic acids.[a]
product 4aa-2D was formed in 55% proportion, along with
26% of the trideuterated 4aa-3D.[22]
Scheme 3. Deuterium exchange experiments with propiolic acid.
We suggest a reaction pathway based on the H/D ex-
change experimental data and the previously reported pro-
posed mechanism for the formation of imidazo[1,2-a]pyr-
idines from propiolic acid in excess D2O, as shown in
Scheme 4.
The first step is the condensation of the 2-aminopyridine
and deuterated benzaldehyde (C6H5CDO) to form the 2-
iminopyridine I. In the next step, the 2-iminopyridine reacts
with propiolic acid to form propargylamine II-1 or II-2.
Finally, the desired imidazo[1,2-a]pyridine is formed
through a copper-catalyzed 5-exo-dig cyclization.[12f,23]
With regard to the two reaction sites of propiolic acid,
we proposed two pathways to form 3-methyl-2-phenylimid-
azo[1,2-a]pyridine (4aa): path A (Scheme 4), in which the
decarboxylative coupling reaction occurs first and the inter-
mediate II-1 is produced, and path B, in which the reaction
at the terminal alkynyl carbon occurs first and the interme-
diate II-2 is produced. Intermediate II-2 could be converted
into II-1 through decarboxylation. However, in excess D2O
the yield of II-1 from the decarboxylation of II-2 is much
lower than that of II-1-D from II-2. Therefore, intermediate
III-1 with a terminal =C–H, is formed mainly through
path A and converted into 4aa-2D through rearrangement.
Path B affords the formation of 4aa-3D from intermediate
III-2, which does not have a terminal alkyne carbon proton.
The experimental results in Scheme 3 support the hypothe-
sis that the two alternative pathways, A and B, are both
involved in the reaction but that path A predominates over
path B.
Conclusions
We have developed a three-component coupling reaction
system for the synthesis of imidazo[1,2-a]pyridines from 2-
aminopyridines, aldehydes, and alkynecarboxylic acids. The
use of CuI and Cu(OTf)2 as catalysts afforded the desired
products in good yields. This reaction system demonstrated
good applicability in the use of low-molecular-weight al-
kynes such as propiolic acid. In the case of propiolic acid,
decarboxylative addition predominated over terminal al-
[a] Reaction conditions: 5 (4.5 mmol), propiolic acid (4.5 mmol),
Pd(PPh3)2Cl2, (0.225 mmol), CuI (0.45 mmol), and DBU
(9.0 mmol) were allowed to react in DMSO at 25 °C for 8 h, and
then 2-aminopyridine (3.0 mmol), benzaldehyde (3.6 mmol), CuI
(0.3 mmol), and Cu(OTf)2 (0.3 mmol) were added and allowed to
react at 110 °C for 16 h. [b] Isolated yield. [c] DBU (22.5 mmol)
was used. [d] DBU (13.5 mmol) was used.
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Scheme 4. Proposed mechanism.
142.4, 134.8, 128.5, 128.3, 127.3, 123.5, 122.8, 117.5, 115.9, 112.00,
9.64 ppm. MS (EI): m/z (%) = 208 (100) [M]+, 131 (10), 103 (20),
91 (10), 78 (35).
kyne addition. In addition, arylalkynecarboxylic acids that
had been prepared through palladium-catalyzed coupling
of aryl iodides and propiolic acid were used in situ to pro-
duce the desired imidazo[1,2-a]pyridines in moderate to
good yields by sequential reaction with 2-aminopyridine
and benzaldehyde. This multicomponent reaction system is
the first example of the use of alkynecarboxylic acids as
alkyne sources in the synthesis of imidazo[1,2-a]pyridines.
3-Methyl-2-o-tolylimidazo[1,2-a]pyridine (4ba): 2-Aminopyridine
(282 mg, 3.0 mmol), o-tolualdehyde (432 mg, 3.6 mmol), and propi-
olic acid (252 mg, 3.6 mmol) gave 4ba (470 mg, 2.11 mmol, 70%)
1
as a pale yellow solid after chromatography; m.p. 122–125 °C. H
NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 6.9, Hz, 1 H), 7.62 (dt,
J = 9.1, 1.1 Hz, 1 H), 7.37 (m, 1 H), 7.26 (m, 3 H), 7.17 (m, 1 H),
6.85 (td, J = 6.8, 1.2 Hz, 1 H), 2.40 (s, 3 H), 2.33 (s, 3 H) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 144.0, 143.2, 137.36, 134.0, 130.7,
130.2, 127.8, 125.3, 123.1, 122.8, 117.4, 116.7, 111.8, 20.1, 9.1 ppm.
HRMS (ESI): calcd. for C15H15N2 [M + H]+ 223.1235; found
223.1235.
Experimental Section
General Procedure for the Synthesis of Imidazo[1,2-a]pyridines from
Arylalkynecarboxylic Acids: 2-Aminopyridine (282 mg, 3.0 mmol),
the aldehyde (3.6 mmol, 1.2 equiv.), the alkyne carboxylic acid
(3.6 mmol, 1.2 equiv.), CuI (57.1 mg, 0.3 mmol, 10 mol-%), Cu-
(OTf)2 (108.4 mg, 0.3 mmol, 10 mol-%), and DMSO (6 mL) were
placed in a 20 mL flask. The reaction mixture was tightly sealed
and heated at 110 °C for 16 h. After cooling, the mixture was
poured into EtOAc (50.0 mL), washed with water (3ϫ25.0 mL)
and brine (3ϫ25.0 mL), and then dried with MgSO4 and passed
through a celite pad. Evaporation of the solvent under reduced
pressure provided the crude product, which was purified by column
chromatography (hexane/EtOAc 4:1) to afford the final product.
3-Methyl-2-p-tolylimidazo[1,2-a]pyridine (4ca): 2-Aminopyridine
(282 mg, 3.0 mmol), p-tolualdehyde (432 mg, 3.6 mmol), and propi-
olic acid (252 mg, 3.6 mmol) gave 4ca (485 mg, 2.18 mmol, 73%)
1
as a pale yellow solid after chromatography; m.p. 118–120 °C. H
NMR (300 MHz, CDCl3): δ = 7.89 (d, J = 6.9 Hz, 1 H), 7.77–7.66
(m, 2 H), 7.64 (d, J = 9.1 Hz, 1 H), 7.28 (dd, J = 8.5, 0.6 Hz, 2 H),
7.16 (m, 1 H), 6.84 (t, J = 6.8 Hz, 1 H), 2.63 (s, 3 H), 2.41 (s, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.3, 142.5, 137.1,
131.9, 129.2, 128.2, 123.3, 122.7, 117.3, 115.6, 111.9, 21.2, 9.6 ppm.
MS (EI): m/z (%) = 222 (100) [M]+, 221 (22), 133 (8), 91 (32).
C15H14N2 (222.29): calcd. C 81.05, H 6.35, N 12.60; found C 80.96,
H 6.37, N 12.42.
3-Methyl-2-phenylimidazo[1,2-a]pyridine (4aa):[15] 2-Aminopyridine
(282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol), and propi-
olic acid (252 mg, 3.6 mmol) gave 4aa (506 mg, 2.43 mmol, 81%)
2-(4-tert-Butylphenyl)-3-methylimidazo[1,2-a]pyridine (4da): 2-Ami-
nopyridine (282 mg, 3.0 mmol), 4-tert-butylbenzaldehyde (583 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4da
(510 mg, 1.93 mmol, 64%) as a pale yellow solid after chromatog-
raphy; m.p. 153–155 °C. 1H NMR (300 MHz, CDCl3): δ = 7.89 (d,
J = 6.9 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 2 H), 7.63 (dt, J = 9.0, 1.1 Hz,
1
as a pale yellow solid after chromatography; m.p. 156–158 °C. H
NMR (300 MHz, CDCl3): δ = 7.91 (d, J = 6.9 Hz, 1 H), 7.81 (d,
J = 7.1 Hz, 2 H), 7.65 (d, J = 9.1 Hz, 1 H), 7.47 (t, J = 7.5 Hz, 2
H), 7.35 (t, J = 7.4 Hz, 1 H), 7.23 (m, 1 H), 6.85 (t, J = 6.8 Hz, 1
H), 2.65 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.4,
6
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Synthesis of Imidazo[1,2-a]pyridines
1 H), 7.48 (m, 2 H), 7.16 (m,1 H), 6.83 (m, 1 H), 2.65 (s, 3 H), 1.37
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 150.3, 144.3, 142.5,
132.0, 128.0, 125.4, 123.25, 122.7, 117.4, 115.6, 111.9, 34.6, 31.3,
9.7 ppm. MS (EI): m/z (%) = 264 (64) [M]+, 249 (100), 234 (6), 166
(12). C18H20N2 (264.37): calcd. C 81.78, H 7.63, N 10.60; found C
81.44, H 7.41, N 11.00.
117.2, 115.9, 112.1, 111.4, 107.2, 9.1 ppm. MS (EI): m/z (%) = 198
(100) [M]+, 169 (50), 144 (10), 78 (35). C12H10N2O (198.22): calcd.
C 72.71, H 5.08, N 14.13; found C 72.54, H 5.25, N 14.26.
2-(3-Methylimidazo[1,2-a]pyridin-2-yl)phenol (4ja): 2-Aminopyr-
idine (282 mg, 3.0 mmol), 2-hydroxybenzaldehyde (439 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4ja (368 mg,
1.64 mmol, 55%) as a pale yellow solid after chromatography; m.p.
2-(2-Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (4ea): 2-Amino-
pyridine (282 mg, 3.0 mmol), o-chlorobenzaldehyde (505 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4ea
(440 mg, 1.81 mmol, 60%) as a pale yellow solid after chromatog-
raphy; m.p. 105–107 °C. 1H NMR (300 MHz, CDCl3): δ = 7.91 (d,
J = 6.9 Hz, 1 H), 7.64 (d, J = 9.1 Hz, 1 H), 7.56 (m, 1 H), 7.48 (m,
1 H), 7.35 (m, 2 H), 7.16 (m, 1 H), 6.87 (t, J = 6.8 Hz, 1 H), 2.43
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.2, 140.5, 133.8,
133.6, 132.6, 129.6, 129.2, 126.6, 123.5, 122.9, 117.8, 117.6, 112.1,
9.6 ppm. HRMS (ESI): calcd. for C14H12ClN2 [M + H]+ 243.0689;
found 243.0683.
1
98–100 °C. H NMR (300 MHz, CDCl3): δ = 7.96 (d, J = 6.9 Hz,
1 H), 7.96–7.90 (m, 2 H), 7.27–7.21 (m, 3 H), 7.07 (dd, J = 8.2,
1.2 Hz, 1 H), 6.93 (m, 2 H), 2.73 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.4, 142.3, 140.3, 129.1, 127.1, 124.2, 122.5, 118.8,
117.8, 117.5, 116.6, 115.3, 112.7, 10.3 ppm. MS (EI): m/z (%) = 224
(100) [M]+, 207 (30), 131 (20), 78 (30). C14H12N2O (224.26): calcd.
C 74.98, H 5.39, N 12.49; found C 74.84, H 5.33, N 12.65.
2-(2,3-Dihydrobenzo-1,4-dioxin-6-yl)-3-methylimidazo[1,2-a]pyridine
(4ka): 2-Aminopyridine (282 mg, 3.0 mmol), 1,4-benzodioxan-6-
carboxaldehyde (590 mg, 3.6 mmol), and propiolic acid (252 mg,
3.6 mmol) gave 4ka (510 mg, 1.92 mmol, 64%) as a pale yellow oil
after chromatography. 1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J
= 6.9 Hz, 1 H), 7.62 (d, J = 9.1 Hz, 1 H), 7.33–7.27 (m, 2 H), 7.16
(m, 1 H), 6.97 (m, 1 H), 6.84 (td, J = 6.8, 1.1 Hz, 1 H), 4.32 (d, J
= 6.8 Hz, 4 H), 2.62 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 144.2, 143.5, 143.1, 142.0, 137.8, 128.4, 123.3, 122.7, 121.6, 117.3,
117.3, 117.1, 111.9, 64.5, 64.4, 9.6 ppm. HRMS (ESI): calcd. for
C16H15N2O2 [M + H]+ 267.1134; found 267.1128.
2-(4-Chlorophenyl)-3-methylimidazo[1,2-a]pyridine (4fa): 2-Amino-
pyridine (282 mg, 3.0 mmol), p-chlorobenzaldehyde (505 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4fa
(514 mg, 2.12 mmol, 71%) as a pale yellow solid after chromatog-
raphy; m.p. 100–103 °C. 1H NMR (300 MHz, CDCl3): δ = 7.89 (d,
J = 6.9 Hz, 1 H), 7.74 (d, J = 8.7 Hz, 2 H), 7.63 (d, J = 9.1 Hz, 1
H), 7.43 (d, J = 8.7 Hz, 2 H), 7.17 (m, 1 H), 6.86 (t, J = 6.8 Hz, 1
H), 2.62 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.4,
141.3, 133.3, 133.2, 129.5, 128.7, 123.8, 122.8, 117.4, 116.0, 112.2,
9.6 ppm. MS (EI): m/z (%) = 242 (100) [M]+, 205 (30), 103 (25), 78
(40). C14H11ClN2 (242.71): calcd. C 69.28, H 4.57, N 11.54; found
C 68.92, H 4.69, N 11.14.
3-Methyl-2-[4-(methylthio)phenyl]imidazo[1,2-a]pyridine (4la): 2-
Aminopyridine (282 mg, 3.0 mmol), 4-(methylthio)benzaldehyde
(547 mg, 3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave
4la (573 mg, 2.25 mmol, 75%) as a pale yellow solid after
chromatography; m.p. 104–106 °C. 1H NMR (300 MHz, CDCl3): δ
= 7.87 (d, J = 6.9 Hz, 1 H), 7.74 (m, 2 H), 7.63 (d, J = 9.0, Hz, 1
H), 7.34 (m, 2 H), 7.16 (m, 1 H), 6.83 (m, 1 H), 2.61 (s, 3 H), 2.52
(s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.3, 141.9, 137.5,
131.7, 128.6, 126.5, 123.5, 122.7, 117.3, 115.7, 112.0, 15.8, 9.6 ppm.
MS (EI): m/z (%) = 254 (100) [M]+, 239 (20), 205 (30), 78 (20).
C15H14N2S (254.35): calcd. C 70.83, H 5.55, N 11.01; found C
70.67, H 5.33, N 11.23.
2-(3-Fluorophenyl)-3-methylimidazo[1,2-a]pyridine (4ga): 2-Amino-
pyridine (282 mg, 3.0 mmol), 3-fluorobenzaldehyde (446 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4ga
(430 mg, 1.90 mmol, 63%) as a pale yellow solid after chromatog-
raphy; m.p. 152–155 °C. 1H NMR (300 MHz, CDCl3): δ = 7.89 (dt,
J = 6.9, 1.1 Hz, 1 H), 7.58 (m, 3 H), 7.42 (m, 1 H), 7.18 (m, 1 H),
7.03 (m, 1 H), 6.85 (td, J = 6.8, 1.2 Hz, 1 H), 2.63 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 162.9 (d, J = 245.0 Hz), 144.3,
141.2, 137.1 (d, J = 8.2 Hz), 129.9 (d, J = 8.4 Hz), 123.8 (d, J =
2.9 Hz), 123.8, 122.8, 117.5, 116.2, 115.0 (d, J = 22.4 Hz), 114.1 (d,
J = 21.2 Hz), 112.2, 9.6 ppm. MS (EI): m/z (%) = 226 (91) [M]+,
225 (100), 131 (5), 109 (21). C14H11FN2 (226.25): calcd. C 74.32,
H 4.90, N 12.38; found C 74.10, H 4.94, N 12.39.
2-(6-Methoxynaphthalen-2-yl)-3-methylimidazo[1,2-a]pyridine
(4ma): 2-Aminopyridine (282 mg, 3.0 mmol), 6-methoxy-2-naph-
thaldehyde (670 mg, 3.6 mmol), and propiolic acid (252 mg,
3.6 mmol) gave 4ma (525 mg, 1.82 mmol, 61%) as a pale yellow
solid after chromatography; m.p. 157–160 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.18 (d, J = 1.2 Hz, 1 H), 7.96–7.91 (m, 2 H), 7.85–
7.80 (m, 2 H), 7.67 (d, J = 9.1 Hz, 1 H), 7.23–7.14 (m, 3 H), 6.86
(m, 1 H), 3.94 (s, 3 H), 2.71 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 157.7, 144.4, 142.5, 133.8, 130.1, 129.7, 129.0, 127.0,
126.9, 123.5, 122.8, 119.0, 117.3, 115.9, 112.0, 105.6, 55.3, 9.8 ppm.
MS (EI): m/z (%) = 288 (100) [M]+, 273 (15), 245 (20), 78 (20).
C19H16N2O (288.35): calcd. C 79.14, H 5.59, N 9.72; found C
79.18, H 5.63, N 9.37.
3-Methyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (4ha): 2-Aminopyr-
idine (282 mg, 3.0 mmol), 2-pyridinecarboxaldehyde (385 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4ha
(410 mg, 1.96 mmol, 65%) as a pale yellow solid after chromatog-
1
raphy; m.p. 92–95 °C. H NMR (300 MHz, CDCl3): δ = 8.66 (m,
1 H), 8.22 (d, J = 8.0 Hz, 1 H), 7.94 (dt, J = 6.0, 3.0 Hz, 1 H), 7.77
(m, 1 H), 7.64 (d, J = 9.1 Hz, 1 H), 7.18 (m, 2 H), 6.86 (t, J =
6.8 Hz, 1 H), 2.96 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
154.8, 148.9, 144.1, 140.2, 136.5, 124.0, 123.0, 122.1, 121.7, 119.4,
117.6, 112.3, 9.8 ppm. MS (EI): m/z (%) = 209 (100) [M]+, 131 (40),
104 (15), 78 (50). C13H11N3 (209.25): calcd. C 74.62, H 5.30, N
20.08; found C 74.65, H 5.51, N 20.94.
2-Cyclohexyl-3-methylimidazo[1,2-a]pyridine (4na): 2-Aminopyr-
idine (282 mg, 3.0 mmol), cyclohexanecarbaldehyde (403 mg,
3.6 mmol), and propiolic acid (252 mg, 3.6 mmol) gave 4na
(451 mg, 2.10 mmol, 70%) as a pale yellow oil after chromatog-
1
raphy. H NMR (300 MHz, CDCl3): δ = 7.78 (dt, J = 6.8, 1.1 Hz,
2-(Furan-2-yl)-3-methylimidazo[1,2-a]pyridine (4ia): 2-Aminopyr-
idine (282 mg, 3.0 mmol), furfural (345 mg, 3.6 mmol), and propi-
olic acid (252 mg, 3.6 mmol) gave 4ia (402 mg, 2.03 mmol, 68%) as
a pale yellow solid after chromatography; m.p. 98–101 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.87 (d, J = 6.9 Hz, 1 H), 7.59 (d,
J = 9.1 Hz, 1 H), 7.53 (dd, J = 1.8, 0.8 Hz, 1 H), 7.17 (m, 1 H),
6.87–6.81 (m, 2 H), 6.53 (m, 1 H), 2.72 (s, 3 H) ppm. 13C NMR
1 H), 7.56 (dt, J = 9.0, 1.1 Hz, 1 H), 7.07 (m, 1 H), 6.75 (m, 1 H),
2.77 (m, 1 H), 2.40 (s, 3 H), 1.84–1.77 (m, 6 H), 1.49–1.31 (m, 4
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.3, 143.8, 122.3 (2
C), 116.8, 114.0, 111.3, 36.8, 32.8, 26.7, 25.9, 8.2 ppm. HRMS
(ESI): calcd. for C14H19N2 [M + H]+ 215.1548; found 215.1543.
3-Benzyl-2-phenylimidazo[1,2-a]pyridine (4ab):[12f] 2-Aminopyridine
(75 MHz, CDCl3): δ = 150.4, 144.6, 141.9, 134.1, 123.9, 122.7, (282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol), and 3-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O20679
/KAP1
Date: 30-07-12 18:21:59
Pages: 11
T. Palani, K. Park, M. R. Kumar, H. M. Jung, S. Lee
FULL PAPER
phenylpropiolic acid (525 mg, 3.6 mmol) gave 4ab (726 mg,
128.6, 128.3, 127.8, 127.2, 125.0, 124.3, 123.4, 117.6, 117.46, 112.3,
25.0 ppm. MS (EI): m/z (%) = 290 (100) [M]+, 257 (40), 207 (20),
78 (50). C18H14N2S (290.38): calcd. C 74.45, H 4.86, N 9.65; found
C 74.33, H 4.46, N 9.81.
2.55 mmol, 85%) as a white solid after chromatography; m.p. 117–
1
119 °C. H NMR (300 MHz, CDCl3): δ = 7.80 (m, 2 H), 7.70 (m,
2 H), 7.43 (t, J = 6.5 Hz, 2 H), 7.34 (m, 3 H), 7.28 (m, 2 H), 7.18
(m, 2 H), 6.72 (m, 1 H), 4.51 (s, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 144.8, 144.0, 136.7, 134.3, 129.0 (2 C), 128.6 (2 C),
128.2 (2 C), 127.8, 127.7 (2 C), 126.9, 124.3, 123.4, 117.7, 117.5,
112.3, 29.9 ppm. MS (EI): m/z (%) = 284 (100) [M]+, 269 (10), 207
(95), 141 (10), 78 (45).
3-(Naphthalen-1-ylmethyl)-2-phenylimidazo[1,2-a]pyridine (4ah): 2-
Aminopyridine (282 mg, 3.0 mmol), benzaldehyde (382 mg,
3.6 mmol), and 3-(naphthalen-1-yl)propiolic acid (647 mg,
3.3 mmol) gave 4ah (628 mg, 1.88 mmol, 58%) as a yellow solid
after chromatography; m.p. 119–121 °C. 1H NMR (300 MHz,
CDCl3): δ = 8.18 (m, 1 H), 7.96 (m, 1 H), 7.80 (d, J = 8.3 Hz, 1
H), 7.76–7.72 (m, 3 H), 7.65–7.56 (m, 3 H), 7.40–7.27 (m, 4 H),
7.20 (m, 1 H), 6.86 (dd, J = 7.1, 1.1 Hz, 1 H), 6.68 (m, 1 H), 4.87
(s, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 145.1, 144.6, 134.4,
134.0, 131.8, 131.8, 129.0, 128.6, 128.0, 127.7, 127.8, 126.5, 126.0,
125.8, 124.3, 124.2, 123.1, 123.0, 117.6, 116.9, 112.2, 27.2 ppm. MS
(EI): m/z (%) = 334 (100) [M]+, 256 (25), 207 (65), 78 (60).
C24H18N2 (334.42): calcd. C 86.20, H 5.43, N 8.38; found C 85.90,
H 5.46, N 8.57.
3-(4-Methylbenzyl)-2-phenylimidazo[1,2-a]pyridine (4ac):[12f] 2-Ami-
nopyridine (282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol),
and 3-p-tolylpropiolic acid (528 mg, 3.3 mmol) gave 4ac (720 mg,
2.41 mmol, 80%) as a yellow solid after chromatography; m.p. 122–
1
125 °C. H NMR (300 MHz, CDCl3): δ = 7.79 (m, 2 H), 7.69 (m,
2 H), 7.44 (m, 2 H), 7.34 (m, 1 H), 7.18 (m, 1 H), 7.11 (d, J =
7.9 Hz, 2 H), 7.03 (d, J = 8.1 Hz, 2 H), 6.70 (m, 1 H), 4.46 (s, 2
H), 2.32 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.8,
144.0, 136.5, 134.5, 133.6, 129.7, 128.6, 128.2, 127.7, 127.5, 124.1,
123.4, 117.9, 117.5, 112.1, 29.5, 21.0 ppm. MS (EI): m/z (%) = 298
(100) [M]+, 283 (15), 220 (10), 207 (70), 78 (30).
3-Butyl-2-phenylimidazo[1,2-a]pyridine (4ai): 2-Aminopyridine
(282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol), and hept-
2-ynoic acid (416 mg, 3.3 mmol) gave 4ai (422 mg, 1.69 mmol,
56%) as a brown liquid after chromatography. 1H NMR (300 MHz,
CDCl3): δ = 7.95 (d, J = 6.9 Hz, 1 H), 7.79 (m, 2 H), 7.64 (m, 1
H), 7.48 (m, 2 H), 7.35 (m, 1 H), 7.16 (m, 1 H), 6.82 (m, 1 H), 3.08
(t, J = 9.0 Hz, 2 H), 1.71 (m, 2 H), 1.47 (m, 2 H), 0.97 (t, J =
7.3 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.4, 142.2,
3-(4-Ethylbenzyl)-2-phenylimidazo[1,2-a]pyridine (4ad): 2-Amino-
pyridine (282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol),
and 3-(4-ethylphenyl)propiolic acid (574 mg, 3.3 mmol) gave 4ad
(667 mg, 2.14 mmol, 71%) as a white solid after chromatography;
m.p. 154–157 °C. 1H NMR (300 MHz, CDCl3): δ = 7.80 (d, J =
6.9 Hz, 2 H), 7.69 (m, 2 H), 7.43 (m, 2 H), 7.34 (m, 1 H), 7.20–
7.11 (m, 3 H), 7.05 (d, J = 8.3 Hz, 2 H), 6.69 (t, J = 6.8 Hz, 1 H), 135.0, 128.5, 128.2, 127.4, 123.5, 122.9, 120.8, 117.7, 111.9, 29.8,
4.46 (s, 2 H), 2.62 (q, J = 7.6 Hz, 2 H), 1.22 (t, J = 7.6 Hz, 3
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.8, 144.1, 142.8,
134.6, 133.8, 128.6, 128.5, 128.2, 127.6, 127.6, 124.0, 123.4, 117.9,
117.5, 112.1, 29.47, 28.37, 15.5 ppm. HRMS (ESI): calcd. for
C22H21N2 [M + H]+ 313.1705; found 313.1705.
23.6, 22.7, 13.8 ppm. HRMS (ESI): calcd. for C17H19N2 [M + H]+
251.1548; found 251.1561.
3-Ethyl-2-phenylimidazo[1,2-a]pyridine (4aj): 2-Aminopyridine
(282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol), and but-2-
ynoic acid (504 mg, 3.3 mmol) gave 4aj (206 mg, 0.93 mmol, 31%)
as a brown oil after chromatography. 1H NMR (300 MHz, CDCl3):
δ = 7.97 (d, J = 6.9 Hz, 1 H), 7.79 (d, J = 7.0 Hz, 2 H), 7.65 (d, J
= 9.1 Hz, 1 H), 7.52–7.43 (m, 2 H), 7.37 (d, J = 7.4 Hz, 1 H), 7.17
(m, 1 H), 6.84 (m, 1 H), 3.12 (q, J = 7.5 Hz, 2 H), 1.37 (t, J =
3-(4-Methoxybenzyl)-2-phenylimidazo[1,2-a]pyridine (4ae):[12f] 2-
Aminopyridine (282 mg, 3.0 mmol), benzaldehyde (382 mg,
3.6 mmol), and 3-(4-methoxyphenyl)propiolic acid (581 mg,
3.3 mmol) gave 4ae (610 mg, 1.94 mmol, 65%) as a yellow solid
after chromatography; m.p. 128–130 °C. 1H NMR (300 MHz, 7.5 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.4, 143.7,
CDCl3): δ = 7.80 (m, 2 H), 7.68 (m, 2 H), 7.43 (m, 2 H), 7.35 (m, 141.9, 134.9, 128.5, 128.2, 127.4, 123.5, 122.8, 117.7, 112.0, 17.1,
1 H), 7.18 (m, 1 H), 7.04 (m, 2 H), 6.84 (m, 2 H), 6.71 (m, 1 H),
12.2 ppm. HRMS (ESI): calcd. for C15H15N2 [M + H]+ 223.1235;
4.44 (s, 2 H), 3.78 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = found 223.1231.
158.5, 144.8, 144.0, 134.5, 128.7, 128.6, 128.6, 128.2, 127.7, 124.1,
3-(4-Methylbenzyl)-2-p-tolylimidazo[1,2-a]pyridine (4cc): 2-Amino-
123.4, 118.0, 117.5, 114.4, 112.1, 55.3, 29.0 ppm. MS (EI): m/z (%)
pyridine (282 mg, 3.0 mmol), p-tolualdehyde (432 mg, 3.6 mmol),
and 3-p-tolylpropiolic acid (528 mg, 3.3 mmol) gave 4cc (702 mg,
= 314 (100) [M]+, 299 (40), 236 (10), 207 (60), 78 (30).
1
3-(4-Chlorobenzyl)-2-phenylimidazo[1,2-a]pyridine (4af): 2-Amino-
pyridine (282 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol),
and 3-(4-chlorophenyl)propiolic acid (595 mg, 3.3 mmol) gave 4af
(675 mg, 2.12 mmol, 71%) as a yellow oil after chromatography.
1H NMR (300 MHz, CDCl3): δ = 7.75 (m, 2 H), 7.69–7.66 (m, 2
H), 7.44 (m, 2 H), 7.38 (m, 1 H), 7.28 (m, 2 H), 7.21 (dd, J = 2.3,
1.3 Hz, 1 H), 7.07 (d, J = 8.7 Hz, 2 H), 6.74 (m, 1 H), 4.47 (s, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 145.2, 144.6, 135.5,
134.5, 133.0, 129.5, 129.3, 129.0, 128.4, 128.1, 124.6, 123.5, 117.9,
117.3, 112.7, 29.6 ppm. HRMS (ESI): calcd. for C20H16ClN2 [M +
H]+ 319.1002; found 319.1006.
2.25 mmol, 75%) as a yellow oil after chromatography. H NMR
(300 MHz, CDCl3): δ = 7.69–7.66 (m, 4 H), 7.23 (d, J = 7.8 Hz, 2
H), 7.18–7.09 (m, 3 H), 7.02 (d, J = 8.1 Hz, 2 H), 6.68 (m, 1 H),
4.43 (s, 2 H), 2.38 (s, 3 H), 2.32 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 144.7, 144.1, 137.4, 136.4, 133.7, 131.6, 129.6, 129.3,
128.0, 127.5, 123.9, 123.3, 117.6, 117.4, 112.0, 29.5, 21.2, 21.0 ppm.
HRMS (ESI): calcd. for C22H21N2 [M + H]+ 313.1705; found
313.1707.
3-Butyl-2-p-tolylimidazo[1,2-a]pyridine (4ci): 2-Aminopyridine
(282 mg, 3.0 mmol), p-tolualdehyde (432 mg, 3.6 mmol), and hept-
2-ynoic acid (416 mg, 3.3 mmol) gave 4ci (430 mg, 1.63 mmol,
39%) as a brown liquid after chromatography. 1H NMR (300 MHz,
CDCl3): δ = 7.93 (d, J = 6.9 Hz, 1 H), 7.69–7.61 (m, 3 H), 7.29 (m,
2 H), 7.14 (m, 1 H), 6.81 (m, 1 H), 3.06 (m, 2 H), 2.41 (s, 3 H),
1.68 (m, 2 H), 1.47 (m, 2 H), 0.97 (t, J = 7.3 Hz, 3 H) ppm. 13C
NMR (75 MHz, CDCl3): δ = 144.3, 142.2, 137.1, 132.0, 129.2,
128.0, 123.3, 122.9, 120.5, 117.5, 111.9, 29.8, 23.6, 22.7, 21.2,
13.8 ppm. HRMS (ESI): calcd. for C18H21N2 [M + H]+ 265.1705;
2-Phenyl-3-(thiophen-2-ylmethyl)imidazo[1,2-a]pyridine (4ag): 2-
Aminopyridine (282 mg, 3.0 mmol), benzaldehyde (382 mg,
3.6 mmol), and 3-(thiophen-2-yl)propiolic acid (502 mg, 3.3 mmol)
gave 4ag (532 mg, 1.83 mmol, 61%) as a yellow solid after
chromatography; m.p. 127–130 °C. 1H NMR (300 MHz, CDCl3): δ
= 7.84–7.79 (m, 3 H), 7.68 (m, 1 H), 7.45 (m, 2 H), 7.37 (m, 1 H),
7.19 (m, 2 H), 6.94 (m, 1 H), 6.78–6.74 (m, 2 H), 4.60 (s, 2 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 149.5, 144.9, 143.8, 140.1, 134.3, found 265.1705.
8
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20679
/KAP1
Date: 30-07-12 18:21:59
Pages: 11
Synthesis of Imidazo[1,2-a]pyridines
3,7-Dimethyl-2-phenylimidazo[1,2-a]pyridine (4aa-1): 2-Amino-4-
picoline (324 mg, 3.0 mmol), benzaldehyde (382 mg, 3.6 mmol),
and propiolic acid (252 mg, 3.3 mmol) gave 4aa-1 (463 mg,
2.08 mmol, 69%) as a yellow solid after chromatography; m.p. 155–
3-(2-Methoxybenzyl)-2-phenylimidazo[1,2-a]pyridine (6e): 2-Iodoan-
isole (1.05 g, 4.5 mmol) gave 6e (587 mg, 1.87 mmol, 62%) as a
white solid after chromatography; m.p. 141–143 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.77 (d, J = 7.1 Hz, 2 H), 7.71 (d, J =
158 °C. 1H NMR (300 MHz, CDCl3): δ = 7.83–7.72 (m, 3 H), 7.49– 6.9 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 1 H), 7.41 (t, J = 7.6 Hz, 2 H),
7.41 (m, 2 H), 7.39 (m, 1 H), 7.33 (m, 1 H), 6.67 (dd, J = 7.0,
1.6 Hz, 1 H), 2.61 (s, 3 H), 2.41 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 144.8, 141.9, 135.0, 134.3, 128.4, 128.2, 127.1, 122.1,
115.8, 115.2, 114.6, 21.3, 9.6 ppm. HRMS (ESI): calcd. for
C15H15N2 [M + H]+ 223.1235; found 223.1233.
7.33 (m, 1 H), 7.24 (m, 1 H), 7.17 (m, 1 H), 6.95 (d, J = 7.7 Hz, 1
H), 6.80–6.66 (m, 3 H), 4.43 (s, 2 H), 3.92 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 157.3, 144.8, 144.2, 134.6, 128.5, 128.1,
127.9, 127.9, 127.5, 124.8, 123.9, 123.5, 120.7, 117.6, 117.4, 112.0,
110.1, 55.3, 23.9 ppm. HRMS (ESI): calcd. for C21H18N2O [M +
H]+ 315.1497; found 315.1563.
6-Chloro-3-methyl-2-phenylimidazo[1,2-a]pyridine
(4aa-2):
2-
Amino-5-chloropyridine (385 mg, 3.0 mmol), benzaldehyde
(381 mg, 3.6 mmol), and propiolic acid (252 mg, 3.3 mmol) gave
4aa-2 (380 mg, 1.57 mmol, 45%) as a yellow oil after chromatog-
3-(4-Methoxybenzyl)-2-phenylimidazo[1,2-a]pyridine (6f = 4ae): 4-
Iodoanisole (1.05 g, 4.5 mmol) gave 6f (742 mg, 2.36 mmol, 79%)
after chromatography.
1
raphy. H NMR (300 MHz, CDCl3): δ = 7.93 (dd, J = 1.9, 0.6 Hz,
3-(4-tert-Butylbenzyl)-2-phenylimidazo[1,2-a]pyridine (6g): 4-tert-
Butyliodobenzene (1.17 g, 4.5 mol) gave 6g (764 mg, 2.24 mmol,
1 H), 7.77 (d, J = 7.0 Hz, 2 H), 7.62 (dd, J = 9.5, 0.8 Hz, 1 H),
7.50–7.43 (m, 2 H), 7.38 (m, 1 H), 7.14 (dd, J = 9.5, 2.0 Hz, 1 H),
2.62 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 143.5, 142.6,
134.2, 129.8, 128.6, 128.3, 127.7, 124.9, 120.8, 120.4, 117.7,
9.7 ppm. HRMS (ESI): calcd. for C14H12ClN2 [M + H]+ 243.0689;
found 243.0689.
1
75%) as a white solid after chromatography; m.p. 110–112 °C. H
NMR (300 MHz, CDCl3): δ = 7.80 (d, J = 7.0 Hz, 2 H), 7.72 (d,
J = 6.8 Hz, 1 H), 7.68 (d, J = 9.0 Hz, 1 H), 7.43 (m, 2 H), 7.37–
7.29 (m, 3 H), 7.17 (m, 1 H), 7.07 (d, J = 8.5 Hz, 2 H), 6.71 (m, 1
H), 4.46 (s, 2 H), 1.30 (s, 9 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 149.7, 144.8, 144.0, 134.5, 133.6, 128.6, 128.2, 127.6, 127.3,
125.9, 124.0, 123.5, 117.9, 117.5, 112.1, 34.4, 31.3, 29.4 ppm.
HRMS (ESI): calcd. for C24H24N2 [M + H]+ 341.2018; found
341.2018.
General Procedure for the Synthesis of Imidazo[1,2-a]pyridines from
Arylalkynecarboxylic Acids: The aryl iodide (4.5 mmol), propiolic
acid (918 mg, 4.5 mmol), Pd(PPh3)2Cl2 (158 mg, 0.225 mmol), CuI
(86 mg, 0.45 mmol), and DBU (1.37 g, 9.0 mmol) were allowed to
react in DMSO at 25 °C for 8 h. 2-Aminopyridine (282 mg,
3.0 mmol), benzaldehyde (382 mg, 3.6 mmol), CuI (57.1 mg,
0.3 mmol), and Cu(OTf)2 (108.4 mg, 0.3 mmol) were then added
and allowed to react at 110 °C for 16 h. After cooling, the mixture
was poured into EtOAc (50.0 mL), washed with water (3ϫ25.0
mL) and brine (3ϫ25.0 mL), and then dried with MgSO4 and
passed through a celite pad. Evaporation of the solvent under re-
duced pressure provided the crude product, which was purified by
column chromatography (hexane/EtOAc 4:1) to afford the final
product.
3-(4-Acetylbenzyl)-2-phenylimidazo[1,2-a]pyridine (6h): In the pres-
ence of DBU (3.43 g, 22.5 mmol), 4Ј-iodoacetophenone (1.11 g, 4.5
mol) gave 6h (440 mg, 1.35 mmol, 45%) as a yellow solid after
chromatography; m.p. 132–134 °C. 1H NMR (500 MHz, CDCl3): δ
= 7.91 (d, J = 8.3 Hz, 2 H), 7.77–7.73 (m, 2 H), 7.70 (d, J = 9.1 Hz,
1 H), 7.65 (t, J = 6.9 Hz, 1 H), 7.44 (t, J = 7.5 Hz, 2 H), 7.37 (d,
J = 7.4 Hz, 1 H), 7.25–7.18 (m, 3 H), 6.73 (m, 1 H), 4.55 (s, 2 H),
2.57 (s, 3 H) ppm. 13C NMR (126 MHz, CDCl3): δ = 197.5, 144.97,
144.5, 142.5, 136.0, 134.3, 129.1, 128.7, 128.1, 127.9, 127.8, 124.3,
123.1, 117.7, 116.7, 112.4, 29.9, 26.6 ppm. HRMS (ESI): calcd. for
C22H18N2O [M + H]+ 327.1497; found 327.1499.
3-Benzyl-2-phenylimidazo[1,2-a]pyridine (6a = 4ab): Phenyl iodide
(918 mg, 4.5 mmol) gave 6a (726 mg, 2.55 mmol, 85%) after
chromatography.
3-(4-Chlorobenzyl)-2-phenylimidazo[1,2-a]pyridine (6i = 4af): In the
presence of DBU (3.43 g, 22.5 mmol), 1-chloro-4-iodobenzene
(1.07 g, 4.5 mol) gave 6i (612 mg, 1.92 mmol, 64%) after
chromatography.
3-(2-Methylbenzyl)-2-phenylimidazo[1,2-a]pyridine (6b): 2-Iodotol-
uene (981 mg, 4.5 mol) gave 6b (583 mg, 1.96 mmol, 65%) as a
white solid after chromatography; m.p. 127–129 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.73–7.69 (m, 3 H), 7.62 (d, J = 6.9 Hz, 1
H), 7.45–7.37 (m, 2 H), 7.37–7.26 (m, 2 H), 7.23–7.15 (m, 2 H),
7.05 (t, J = 7.5 Hz, 1 H), 6.75–7.67 (m, 2 H), 4.36 (s, 2 H), 2.44 (s,
3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 144.9, 144.4, 136.3,
134.6, 134.5, 130.5, 128.6, 128.1, 127.6, 126.9, 126.6, 126.6, 124.1,
123.3, 117.6, 117.3, 112.2, 27.6, 19.8 ppm. HRMS (ESI): calcd. for
C21H18N2 [M + H]+ 299.1548; found 299.1548.
2-Phenyl-3-(thiophen-2-ylmethyl)imidazo[1,2-a]pyridine (6j = 4ag):
In the presence of DBU (3.43 g, 22.5 mmol), 2-iodothiophene
(945 mg, 4.5 mol) gave 6j (512 mg, 1.76 mmol, 59%) after
chromatography.
3-(Naphthalen-1-ylmethyl)-2-phenylimidazo[1,2-a]pyridine (6k
=
4ah): In the presence of DBU (2.06 g, 13.5 mmol), 1-iodonaphth-
alene (1.14 g, 4.5 mol) gave 6k (795 mg, 2.38 mmol, 79%) after
chromatography.
3-(3-Methylbenzyl)-2-phenylimidazo[1,2-a]pyridine (6c): 3-Iodotol-
uene (981 mg, 4.5 mol) gave 6c (597 mg, 2.00 mmol, 67%) as a
yellow solid after chromatography; m.p. 129–130 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.80 (d, J = 7.1 Hz, 2 H), 7.69 (t, J =
8.0 Hz, 2 H), 7.43 (t, J = 7.5 Hz, 2 H), 7.35 (t, J = 7.4 Hz, 1 H),
7.23–7.14 (m, 2 H), 7.07 (d, J = 7.6 Hz, 1 H), 7.01–6.91 (m, 2 H),
6.72 (m, 1 H), 4.46 (s, 2 H), 2.29 (s, 3 H) ppm. 13C NMR
(126 MHz, CDCl3): δ = 144.8, 144.1, 138.7, 136.7, 134.5, 128.8,
128.6, 128.3, 128.2, 127.7, 124.7, 124.1, 123.4, 117.7, 117.5, 112.1,
29.8, 21.4 ppm. HRMS (ESI): calcd. for C21H18N2 [M + H]+
299.1548; found 199.1548.
Supporting Information (see footnote on the first page of this arti-
1
cle): Mechanistic experiments and copies of the H NMR and 13C
NMR spectra.
Acknowledgments
This work was supported by the National Research Foundation,
Korean Government (grant number 2012R1A1B3000871)
3-(4-Methylbenzyl)-2-phenylimidazo[1,2-a]pyridine (6d = 4ac): 4-
Iodotoluene (981 mg, 4.5 mmol) gave 6d (732 mg, 2.45 mmol, 82%)
after chromatography.
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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Job/Unit: O20679
/KAP1
Date: 30-07-12 18:21:59
Pages: 11
T. Palani, K. Park, M. R. Kumar, H. M. Jung, S. Lee
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Received: May 20, 2012
Published Online: ᭿
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20679
/KAP1
Date: 30-07-12 18:21:59
Pages: 11
Synthesis of Imidazo[1,2-a]pyridines
Multicomponent Reactions
T. Palani, K. Park, M. R. Kumar,
H. M. Jung, S. Lee* ....................... 1–11
Copper-Catalyzed Decarboxylative Three-
Component Reactions for the Synthesis of
Imidazo[1,2-a]pyridines
Imidazo[1,2-a]pyridine derivatives were
synthesized through three-component
coupling reactions of 2-aminopyridines,
aldehydes, and alkynecarboxylic acids in
the presence of 10 mol-% CuI/Cu(OTf)2
Keywords: Nitrogen heterocycles / Multi-
component reactions / Copper / Alkynes
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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11